WO2007123910A2 - Copper-mediated functionalization of aryl c-h bonds, and compounds related thereto - Google Patents

Copper-mediated functionalization of aryl c-h bonds, and compounds related thereto Download PDF

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WO2007123910A2
WO2007123910A2 PCT/US2007/009382 US2007009382W WO2007123910A2 WO 2007123910 A2 WO2007123910 A2 WO 2007123910A2 US 2007009382 W US2007009382 W US 2007009382W WO 2007123910 A2 WO2007123910 A2 WO 2007123910A2
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functionality
carbonyl
oxidant
nux
air
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WO2007123910A3 (en
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Jin-Quan Yu
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Brandeis University
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/48—Aldehydo radicals
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/57—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/10—Aza-phenanthrenes

Definitions

  • One aspect of the present invention relates to methods for direct functionalization of pyi ⁇ dyl-substituted aromatic compounds.
  • a wide range of 2- arylpyridine substrates react with a diverse selection of anionic nucleophiles in the presence of copper(II) to furnish substituted arylpyridines by regioselective functionalization at the ortho position of the aryl ring.
  • the present invention allows for both mono- and di-functionalizations by manipulation of the reaction conditions.
  • the present invention provides several improvements over known methods, including functional group tolerance, e.g., toward substrates incorporating double bond and carbonyl moieties.
  • the novel transition metal-mediated carbon- heteroatom bond-forming methods provided by the present invention are applicable to a variety of synthetic transformations of aryl C-H bonds, e.g, hydroxylation, acetoxylation, halogenation, cyanation, animation, etherification, and thioetherif ⁇ cation.
  • This broad utility along with the efficacious use of O 2 as a stoichiometric oxidant in certain embodiments, marks a significant advantage over Pd-, Pt-, Rh-, and Ru-catalyzed aryl C-H functionalization reactions.
  • Figure 1 depicts the structures of arylpyridine substrates 1-13.
  • Figure 2 depicts a plot of conversion versus reaction time for two different concentrations of CuCl 2 : (A) 10 mol% CuCl 2 ; (B) 20 mol% CuCl 2 .
  • Figure 3 depicts a plot of Ln[I -c%] versus time in the presence of excess substrate
  • Figure 4 depicts a plot of Ln[I -c%] versus time in the presence of excess CuCl 2 , where c% is conversion.
  • Figure 5 depicts a plot of conversion versus time: (A) 2-(4- methoxyphenyl)pyridine; (B) 4-(pyridine-2-yl)benzaldehyde.
  • the invention utilizes a N-containing heteroaryl motif to direct transition metal-mediated regioselective functionalization of aromatic C-H bonds.
  • the present invention relates to the transformation represented by Scheme 1.
  • the reactions of the present invention can be stoichiometric or catalytic, e.g., utilizing 10-20 mol% transition metal complex.
  • the methods of the present invention work well for both mono- and di-functionalization of 2-arylpyridine substrates.
  • manipulation of reaction conditions generates the respective mono-ortho or di- ⁇ rt/z ⁇ -functionalized products:
  • the present invention relates to a method of functionalizing an aryl C-H bond as represented by Scheme A, comprising the step of combining an arylpyridine with a transition metal, a ligand, an oxidant, and NuX:
  • R represents independently for each occurrence substituted or unsubstituted alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, arylalkyl, cyano, halogen, hydroxyl, alkoxyl, aryloxy, arylalkyloxy, amino, alkylamino, arylamino, arylalkylamino, sulfhydryl, alkylthio, arylthio, arylalkylthio, nitro, azido, alkylseleno, formyl, acyl, carboxy, silyl, silyloxy, (alkyloxy)carbonyl, (aryloxy)carbonyl, (arylalkyloxy)carbonyl. (alkylamino)carbonyl, (arylamino)carbonyl, (arylalkylamino)carbonyl, alkylsulfonyl, or arylsulfonyl;
  • R' represents independently for each occurrence, substituted or unsubstituted alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, arylalkyl, cyano, halogen, hydroxyl. alkoxyl, aryloxy, arylalkyloxy, amino, alkylamino, arylamino, arylalkylamino, sulfhydryl, alkylthio, arylthio, arylalkylthio, nitro, azido, alkylseleno, formyl, acyl, carboxy, silyl, silyloxy, (alkyloxy)carbonyl, (aryloxy)carbonyl, (arylalkyloxy)carbonyl, (alkylamino)carbonyl, (arylamino)carbonyl, (arylalkylamino)carbonyl, alkylsulfonyl, or arylsulfonyl;
  • any two instances of R may be bonded together to form a ring that may be optionally substituted;
  • any two instances of R' may be bonded together to form a ring that may be optionally substituted;
  • an instance of R and an instance of R' may be bonded together to form a ring that may be optionally substituted;
  • M represents a transition metal
  • L independently for each occurrence represents a ligand
  • Nu represents an atom or molecule comprising a charged or uncharged carbon, nitrogen, oxygen, sulfur, chlorine, bromine, iodine, or phosphorus;
  • X is an electron pair or a cation
  • n represents an integer in the range 0 to 4 inclusive
  • n an integer in the range 0 to (4-q) inclusive.
  • q O or l.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said M is selected from the group consisting of Rh, Ru, Pd, Pt, and Cu.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said M is Cu.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said M is present in a stoichiometric amount relative to the arylpyridine. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said M is present in less than or equal to 20 mol% relative to the arylpyridine.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said M is present in less than or equal to 10 mol% relative to the arylpyridine.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein L is independently selected form the group consisting of OAc, Cl, F, OH, Br, (HO)PO 3 , NO 3 , Se, SO 4 , CF 3 CO 2 , ClO 4 , 2-pyrazine carboxylate, cyclohexanebutyrate, 2-ethylhexanoate, 3,5-diisopropylsalicylate, and acetylacetonate.
  • L is independently selected form the group consisting of OAc, Cl, F, OH, Br, (HO)PO 3 , NO 3 , Se, SO 4 , CF 3 CO 2 , ClO 4 , 2-pyrazine carboxylate, cyclohexanebutyrate, 2-ethylhexanoate, 3,5-diisopropylsalicylate, and acetylacetonate.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein L is independently selected from the group consisting of acetate, chlorine, and fluorine.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein L is acetate.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein L is chlorine.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein L is fluorine.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said oxidant is selected from the group consisting of peroxides, hydroperoxides, hyperperoxides, hypervalent acyloxy iodides, transition metal acyloxy complexes, dihalogens, O 2 , air, and combinations thereof.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein said oxidant is O 2 . In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said oxidant is air.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein Nu comprises an amino functionality, a hydroxyl functionality, an acetoxy functionality, a halogen functionality, a cyano functionality, a nitro functionality, a thiol functionality, an alkylthio functionality, an acyl functionality, an acyloxy functionality, or an alkoxy functionality.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein NuX is selected from the group consisting of I 2 , TMSCN, TsNH 2 , /7-CN-PhOH, PhSH, MeSSMe, H 2 O, Br 2 CHCHBr 2 , Cl 2 CHCHCl 2 , MeNO 2 , PhCH 2 NH 2 , anilines, CF 3 OH, and cyclopropyl alcohols.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is selected from the group consisting of Rh, Ru, Pd, Pt, and Cu; L is independently selected from the group consisting of OAc, Cl, F, OH, Br, (OH)PO 4 , NO 3 , Se, SO 4 , CF 3 CO 2 , ClO 4 , 2- ⁇ yrazine carboxylate, cyclohexanebutyrate, 2-ethylhexanoate, 3,5-diisopropylsalicylate, and acetylacetonate; said oxidant is selected from the group consisting of peroxides, hydroperoxides, hyperperoxides, hypervalent acyloxy iodides, transition metal acyloxy complexes, dihalogens, O 2 , air, and combinations thereof; and Nu comprises an amino functionality, a hydroxyl functionality, an acetoxy functionality, a halogen functionality, a cyano functionality
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is independently selected from the group consisting of acetate, chlorine, and fluorine; said oxidant is O 2 or air; and Nu comprises an amino functionality, a hydroxyl functionality, an acetoxy functionality, a halogen functionality, a cyano functionality, a nitro functionality, a thiol functionality, an alkylthio functionality, an acyl functionality, an acyloxy functionality, or an alkoxy functionality.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate or fluorine; said oxidant is O 2 or air; and NuX is H 2 O.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O 2 or air; and NuX is selected from the group consisting Of HOAc-Ac 2 O, Br 2 CHCHBr 2 , 1 2 , TMSCN,
  • MeNO 2 TsNH 2 , /7-CN-PhOH, PhSH, MeSSMe, PhCH 2 NH 2 , anilines, CF 3 OH, and cyclopropyl alcohols.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O 2 or air; and NuX is HOAc-Ac 2 O.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O 2 or air; and NuX is Br 2 CHCHBr 2 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O 2 or air; and NuX is I 2 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O 2 or air; and NuX is TMSCN.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O 2 or air; and NuX is MeNO 2 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O 2 or air; and NuX is TsNH 2 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O 2 or air; and NuX is ⁇ -CN-PhOH.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O 2 or air; and NuX is PhSH.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O 2 or air; and NuX is MeSSMe.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is chlorine; said oxidant is O 2 or air; and NuX is Cl 2 CHCHCl 2 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is chlorine; said oxidant is O 2 or air; and NuX is PhCH 2 NH 2 .
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is chlorine; said oxidant is O 2 or air; and NuX is CF 3 OH.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is chlorine; said oxidant is O 2 or air; and NuX is an aniline.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is chlorine; said oxidant is O 2 or air; and NuX is a cyclopropyl alcohol.
  • the present invention relates to the aforementioned method and any of the attendant definitions, wherein m is O; and n is O. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein X is H, an electron pair, or a cation; and NuX is represented by structure 27:
  • G represents, independently for each occurrence, an electron withdrawing group selected from the group consisting of formyl, acyl, -C(O)OR", -C(O)NR" 2 , nitro, nitroso, - S(O) 2 R", -SO 3 R", -S(O) 2 NR" 2 , -C(NR")-R", -C(NOR")-R", and -C(NNR" 2 )-R";
  • R" represents, independently for each occurrence, hydrogen, alkyl, aryl, heteroalkyl, heteroaryl, halogen, alkylamino, arylamino, alkylthio, arylthio, alkoxy, aryloxy, or - (CH 2 ) S -R 8 ;
  • Rg represents independently for each occurrence a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; s independently for each occurrence is an integer selected from the range 0 to 8 inclusive; z is an integer selected from the range 1 to 3 inclusive; and p is an integer equal to (3-z).
  • the present invention relates to a compound represented by formula I:
  • R represents independently for each occurrence substituted or unsubstituted alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, arylalkyl, cyano, halogen, hydroxyl, alkoxyl, aryloxy, arylalkyloxy, amino, alkylamino, arylamino, arylalkylamino, sulfhydryl, alkylthio, arylthio, arylalkylthio, nitro, azido, alkylseleno, formyl, acyl, carboxy, silyl, silyloxy, (alkyloxy)carbonyl, (aryloxy)carbonyl, (arylalkyloxy)carbonyl, (alkylarnino)carbonyl, (arylamino)carbonyl, (arylalkylamino)carbonyl, alkylsulfonyl, or arylsulfonyl;
  • R' represents independently for each occurrence, substituted or unsubstituted alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, arylalkyl, cyano, halogen, hydroxyl, alkoxyl, aryloxy, arylalkyloxy, amino, alkylamino, arylamino, arylalkylamino, sulfhydryl, alkylthio, arylthio, arylalkylthio, nitro, azido, alkylseleno, formyl, acyl, carboxy, silyl, silyloxy, (alkyloxy)carbonyl, (aryloxy)carbonyl, (arylalkyloxy)carbonyl, (alkylamino)carbonyl, (arylamino)carbonyl, (arylalkylamino)carbonyl, alkylsulfonyl, or arylsulfonyl;
  • any two instances of R may be bonded together to form a ring that may be optionally substituted;
  • any two instances of R' may be bonded together to form a ring that may be optionally substituted;
  • an instance of R and an instance of R' may be bonded together to form a ring that may be optionally substituted;
  • X represents independently for each occurrence a group comprising an atom selected from the group consisting of carbon, nitrogen, oxygen, sulfur, chlorine, bromine, iodine, and phosphorus;
  • n represents an integer in the range 0 to 4 inclusive
  • n an integer in the range 0 to (4-q) inclusive.
  • q is O or l.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X is acetoxy, hydroxyl, alkoxy, or aryloxy.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X is selected from the group consisting of Cl, Br, and I.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X is selected from the group consisting of SPh and SMe.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X is an amine.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X is cyano.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X is a radiohalide.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein n is 1; and R is /J-OMe, p-
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein m is 1; and R' is m-Me.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein rn is 0; and n is 0.
  • the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X is independently represented by structure 28:
  • G represents, independently for each occurrence, an electron withdrawing group selected from the group consisting of formyl, acyl, -C(O)OR", -C(O)NIf 2 , nitro, nitroso, - S(O) 2 R", -SO 3 R", -S(O) 2 NR" 2 , -C(NR")-R", -C(NOR")-R", and -C(NNR" 2 )-R";
  • R" represents, independently for each occurrence, hydrogen, alkyl, aryl, heteroalkyl, heteroaryl, halogen, alkylamino, arylamino, alkylthio, arylthio, alkoxy, aryloxy, or - (CH 2 ) S -R 8 ;
  • Rg represents independently for each occurrence a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; s independently for each occurrence is an integer selected from the range 0 to 8 inclusive; z is an integer selected from the range 1 to 3 inclusive; and p is an integer equal to (3-z).
  • the present invention relates to a compound selected from the group consisting of:
  • nucleophile is recognized in the art, and as used herein means a chemical moiety having a reactive pair of electrons.
  • nucleophiles include uncharged compounds such as water, amines, mercaptans and alcohols, and charged moieties such as alkoxides, thiolates, carbanions, and a variety of organic and inorganic anions.
  • Illustrative anionic nucleophiles include simple anions such as hydroxide, azide, cyanide, thiocyanate, acetate, formate or chloroformate, and bisulfite.
  • Organometallic reagents such as organocuprates, organozincs, organolithiums, Grignard reagents, enolates, acetylides, and the like may, under appropriate reaction conditions, be suitable nucleophiles. Hydride may also be a suitable nucleophile when reduction of the substrate is desired.
  • Electrophile is art-recognized and refers to chemical moieties which can accept a pair of electrons from a nucleophile as defined above. Electrophiles useful in the method of the present invention include cyclic compounds such as epoxides, aziridines, episulfides, cyclic sulfates, carbonates, lactones, lactams and the like.
  • Non-cyclic electrophiles include sulfates, sulfonates (e.g., tosylates), chlorides, bromides, iodides, and the like
  • electrophilic atom refers to the atom of the substrate which is attacked by, and forms a new bond to, the nucleophile. ' In most (but not all) cases, this will also be the atom from which the leaving group departs.
  • electron-withdrawing group is recognized in the art, and denotes the tendency of a substituent to attract valence electrons from neighboring atoms, i.e., the substituent is electronegative with respect to neighboring atoms.
  • ⁇ Hammett sigma
  • Exemplary electron-withdrawing groups include nitro, acyl, formyl, sulfonyl, trifluoromethyl, cyano, chloride, and the like.
  • Exemplary electron- donating groups include amino, methoxy, and the like.
  • Lewis base and “Lewis basic” are recognized in the art, and refer to a chemical moiety capable of donating a pair of electrons under certain reaction conditions.
  • Lewis basic moieties include uncharged compounds such as alcohols, thiols, olefins, and amines, and charged moieties such as alkoxides, thiolates, carbanions, and a variety of other organic anions.
  • Lewis acid and “Lewis acidic” are art-recognized and refer to chemical moieties which can accept a pair of electrons from a Lewis base.
  • reaction product means a compound which results from the reaction of a nucleophile and a substrate.
  • reaction product will be used herein to refer to a stable, isolable compound, and not to unstable intermediates or transition states.
  • substrate is intended to mean a chemical compound that can react with a nucleophile to yield at least one reaction product.
  • catalytic amount is recognized in the art and means a substoichiometric amount relative to a reactant. As used herein, a catalytic amount means from 0.0001 to 90 mole percent relative to a reactant, more preferably from 0.001 to 50 mole percent, still more preferably from 0.01 to 10 mole percent, and even more preferably from 0.1 to 5 mole percent relative to a reactant.
  • reactions contemplated in the present invention include reactions which are regioselective.
  • a regioselective reaction is a reaction which occurs preferentially at one reactive center rather than another non-identical reactive center.
  • a regioselective reaction of an unsymmetrically substituted epoxide substrate would involve preferential reaction at one of the two epoxide ring carbons.
  • aliphatic is an art-recognized term and includes linear, branched, and cyclic alkanes, alkenes, or alkynes.
  • aliphatic groups in the present invention are linear or branched and have from 1 to about 20 carbon atoms.
  • alkyl is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C 1 -Ca 0 for straight chain, C 3 -C 30 for branched chain), and alternatively, about 20 or fewer.
  • cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.
  • lower alkyl refers to an alkyl group, as defined above, but having from one to ten carbons, alternatively from one to about six carbon atoms in its backbone structure.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • bicyclo-ring refers to a bridged ring system, such as a quinuclidine (shown below).
  • aralkyl is art-recognized, and includes alkyl groups substituted with an aryl group ⁇ e.g., an aromatic or heteroaromatic group).
  • alkenyl and alkynyl are art-recognized, and include unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • heteroatom is art-recognized, and includes an atom of any element other than carbon or hydrogen.
  • Illustrative heteroatom s include boron, nitrogen, oxygen, phosphorus, sulfur and selenium, and alternatively oxygen, nitrogen or sulfur.
  • aryl is art-recognized, and includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "heteroaryl” or “heteroaromatics.”
  • the aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • ortho (o-), meta (m-) and para (p ⁇ ) are art-recognized and apply to 1,2-,
  • 1,3- and 1,4-di substituted benzenes respectively.
  • the names 1,2- dimethylbenzene, ortho-dimethylbenzene and o-dimethylbenzene are synonymous.
  • heterocyclyl and “heterocyclic group” are art-recognized, and include
  • Heterocycles may also be polycycles.
  • Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine,
  • the heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluromethyl), cyano, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phos
  • polycyclyl and “polycyclic group”, are art-recognized, and include structures with two or more rings ⁇ e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms, e.g., three or more atoms are common to both rings, are termed "bridged" rings.
  • Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluromethyl), cyano, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate,
  • Carbocycle is art recognized and includes an aromatic or non-aromatic ring in which each atom of the ring is carbon.
  • the flowing art-recognized terms have the following meanings: "nitro” means -NO 2 ; the term “halogen” designates -F, -Cl, -Br or -I; the term “sulfhydryl” means -SH; the term “hydroxyl” means -OH; and the term “sulfonyl” means -SO 2 " .
  • acyl is art-recognized and refers to any group or radical of the form RCO- where R is any organic group.
  • Representative acyl group include acetyl, benzoyl, and malonyl.
  • acyloxy is art-recognized and refers to a moiety that can be represented by the general formula:
  • R' ⁇ represents a hydrogen, an alkyl, an aryl, an alkenyl, an alkynyl or -(CH2) m -R 83 where m is 1-30 and R 8 represents a group permitted by the rules of valence.
  • amine and “amino” are art-recognized and include both unsubstituted and substituted amines, e.g., a moiety that may be represented by- the general formulas:
  • R50, R51 and R52 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R61, or R50 and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure;
  • R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and
  • m is zero or an integer in the range of 1 to 8.
  • only one of R50 or R51 may be a carbonyl, e.g., R50, R51 and the nitrogen together do not form an imide.
  • R50 and R51 each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH 2 ) m -R61.
  • alkylamine includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.
  • acylamino is art-recognized and includes a moiety that may be represented by the general formula:
  • R50 is as defined above, and R54 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-R61, where m and R61 are as defined above.
  • amide is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula: wherein R50 and R51 are as defined above. Certain embodiments of the amide in the present invention will not include amides which may be unstable.
  • alkylthio is art recognized and includes an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH 2 ) m -R61, wherein m and R61 are defined above.
  • Representative alkylthio groups include methylthio, ethylthio, and the like.
  • carbonyl is art recognized and includes such moieties as may be represented by the general formulas:
  • X50 is a bond or represents an oxygen or a sulfur
  • R55 represents a hydrogen, an alkyl, an alkenyl, -(CH 2 X n -Ro lor a pharmaceutically acceptable salt
  • R56 represents a hydrogen, an alkyl, an alkenyl or -(CH 2 ) m -R61, where m and R61 are defined above.
  • X50 is an oxygen and R55 is not hydrogen
  • the formula represents an "ester”.
  • X50 is an oxygen
  • R55 is as first defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a "carboxylic acid".
  • X50 is an oxygen, and R56 is hydrogen
  • the formula represents a "formate".
  • the oxygen atom of the above formula is replaced by sulfur
  • the formula represents a "thiocarbonyl” group.
  • X50 is a sulfur and R55 or R56 is not hydrogen
  • the formula represents a "thioester.”
  • X50 is a sulfur and R55 is hydrogen
  • the formula represents a "thiocarboxylic acid.”
  • X50 is a sulfur and R56 is hydrogen
  • the formula represents a "thioformate.”
  • X50 is a bond, and R55 is not hydrogen
  • the above formula represents a "ketone” group.
  • X50 is a bond, and R55 is hydrogen
  • the above formula represents an "aldehyde” group.
  • oxime and oxime ether are art-recognized and refer to moieties that may be represented by the general formula: wherein R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH2) m -R61.
  • R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH2) m -R61.
  • R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH2) m -R61.
  • alkoxyl or "alkoxy” are art recognized and include an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An "ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(CH 2 ) m -R61, where m and R61 are described above.
  • R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.
  • sulfate is art recognized and includes a moiety that may be represented by the general formula:
  • R57 is as defined above.
  • R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
  • Q50 represents S or O
  • R59 represents hydrogen, a lower alkyl or an aryl.
  • the phosphoryl group of the phosphorylalkyl may be represented by the general formulas: wherein Q50 and R59, each independently, are defined above, and Q51 represents O, S or N.
  • Q50 is S
  • the phosphoryl moiety is a "phosphorothioate”.
  • R50 R5I R50 R51 wherein Q51, R50, R51 and R59 are as defined above, and R60 represents a lower alkyl or an aryl.
  • selenoalkyl is art-recognized and refers to an alkyl group having a substituted seleno group attached thereto.
  • exemplary "seleno ethers" which may be substituted on the alkyl are selected from one of -Se-alkyl, -Se-alkenyl, -Se-alkynyl, and - Se-(CH 2 ) m -R61, m and R61 being defined above.
  • triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, ⁇ -toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively.
  • triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, /?-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.
  • Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafiuorobutanesulfonyl, /?-toluenesulfonyl and methanesulfonyl, respectively.
  • a more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991).
  • Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • compounds of the present invention may also be optically active.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of compound of the present invention may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted , atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • the term "substituted" is also contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents may be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • Analogous substitutions may be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
  • Transition metal complexes which are useful in the present invention may be determined by the skilled artisan according to several criteria.
  • a suitable transition metal complex will have one or more of the following properties: 1) It will be capable of reaction with the substrate at the desired site; 2) It will yield a useful product upon reaction with the substrate; 3) It will not react with the substrate at functionalities other than the desired site; 4) It will not substantially undergo further undesired reaction after reacting with the substrate in the desired sense; 5) It will be able to be reoxidized by an oxidant so as to be catalytic. It will be understood that while undesirable side reactions may occur, the rates of such reactions can be rendered slow - through the selection of reactants and conditions — in comparison with the rate of the desired reaction.
  • Transition metal complexes which satisfy the above criteria can be chosen for each substrate and may vary according to the substrate structure and desired product. Routine experimentation may be necessary to determine the transition metal for a given transformation.
  • metal salts are used.
  • the metal salts are copper(II) salts.
  • transition metal acetates are used.
  • metal acetate hydrates may be used, hi certain embodiments of this invention, the metal acetate is copper(II) acetate.
  • metal halides are used.
  • copper(II) chloride is used.
  • copper(II) fluoride is used.
  • the metal species may be a copper(II) metal salt selected from the group consisting OfCu(OH) 2 , CuBr 2 , Cu 2 (OH)PO 4 , Cu(NO 3 ) 2 , CuSe, CuSO 4 , Cu(CF 3 COa) 2 , Cu(C10 4 ) 2 , copper(II) 2- pyrazine carboxylate, copper(II) cyclohexanebutyrate, copper(II) 2-ethylhexanoate, copper(II) 3,5-diisopropylsalicylate, cupric acetylacetonate, and the hydrates thereof.
  • a copper(II) metal salt selected from the group consisting OfCu(OH) 2 , CuBr 2 , Cu 2 (OH)PO 4 , Cu(NO 3 ) 2 , CuSe, CuSO 4 , Cu(CF 3 COa) 2 , Cu(C10 4 ) 2 , copper(II) 2- pyrazine
  • the copper catalyst may be provided in a lower oxidation state (e.g., Cu(I) or Cu(O)) because the stoichiometric oxidant may be used in sufficient excess to oxidize that copper to copper(II), the presumed active form.
  • the catalyst may be comprised of a metal complex as described above on solid support.
  • the catalyst may be comprised of ligands containing stereogenic centers.
  • an oxidant is required in certain embodiments of the present invention. Any oxidant capable of oxidizing a metal species can be utilized. In certain embodiments, any oxidant capable of oxidizing Cu(I) to Cu(II) is acceptable. In one embodiment, the oxidant is selected from the group consisting of peroxides, hydroperoxides, hyperperoxides, hypervalent acyloxy iodides, transition metal acyloxy complexes, dihalogens, O 2 , and air. In certain embodiments, the oxidant may be a peroxide or a hydroperoxide.
  • the oxidant is represented by R— O-O— R' or R— O— O— H, wherein R and R' are, for example, independently alkyl, aryl, or acyl.
  • R and R' are, for example, independently alkyl, aryl, or acyl.
  • the product While the selective formation of the monohydroxylated product is a synthetically useful feature, the product also inhibits the reaction and prevents catalytic turnover. This effect can be circumvented by adding Ac 2 O to the reaction mixture to acetylate Ib in the reaction mixture. As a result, the Cu loading was reduced to 10 mol% in the presence of O 2
  • Direct cyanation is a valuable transformation in heterocycle synthesis because the conversion of a nitrile moiety into a tetrazole is frequently used in drug syntheses.
  • the installation of a CN group is useful in the synthesis of drug-related tetrazole compounds, for instance FORASARTAN.
  • the use of MeNO 2 as a CN source for cyanation is practically convenient (Entry 4).
  • the reagent TsNHb was also used as a nitrogen anion source to achieve the direct animation of aryl C-H bonds (Entry 5).
  • the formation of the hydroxylated product using CuF 2 and H 2 O is also noteworthy (Entry 9).
  • the present invention also considers the use of alcohol nucleophiles such as CF 3 OH and cyclopropyl alcohols. In certain embodiments, the present invention also considers the use of other amines (e.g., anilines and PhCH 2 NH 2 ).
  • electron withdrawing groups decrease the reaction rates.
  • the substrates 2-(4-methoxyphenyl)pyridine 2 and 4-(pyridine-2-yl)benzaldehyde 5 were chlorinated following the procedure detailed herein, and the reactions were also monitored by 1 H NMR to measure conversion over time. The result described in Figure 5 shows that the rate of reaction for substrate 4-(pyridine-2-yl)benzaldehyde 5 is slower than that of 2- (4-methoxyphenyl)pyridine 2.
  • a radical-cation pathway may be invoked to explain the data obtained from these mechanistic studies (Scheme 8).
  • a single electron transfer (SET) from the coordinated Cu(II) to the aryl ring leading to the cation-radical intermediate 15 is the rate-limiting step.
  • the lack of reactivity of biphenyl suggests that the coordination of Cu(II) to the pyridine is necessary for the SET process.
  • the observed ⁇ rt ⁇ oselectivity is explained by an intramolecular anion transfer from a coordinated CuCl 2 to the cation-radicals.
  • the reactions of the present invention may be performed under a wide range of conditions, though it will be understood that the solvents and temperature ranges recited herein are not limitative and only correspond to particular modes of the processes of the invention. In general, it will be desirable that reactions are run using mild conditions which will not adversely effect the substrate, the catalyst, or the product.
  • the reaction temperature influences the speed of the reaction, as well as the stability of the reactants, products, and catalyst.
  • the manipulation of reaction temperature determines the level of functionalization observed.
  • the synthetic reactions of the present invention are carried out in a liquid reaction medium.
  • the reactions may be run without addition of solvent.
  • the reactions may be run in an inert solvent, preferably one in which the reaction ingredients, including the catalyst, are substantially soluble.
  • Suitable solvents include ethers such as diethyl ether, 1,2-dimethoxyethane, diglyme, tert-butyl methyl ether, tetrahydrofuran and the like; halogenated solvents such as chloroform, dichloromethane, dichloroethane, chlorobenzene, and the like; aliphatic or aromatic hydrocarbon solvents such as benzene, toluene, hexane, pentane and the like; esters and ketones such as ethyl acetate, acetone, and 2-butanone; polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide and the like; or combinations of two or more
  • a solvent which is not inert to the substrate under the conditions employed, e.g. , use of ethanol as a solvent when ethanol is the desired nucleophile.
  • ethanol as a solvent when ethanol is the desired nucleophile.
  • tetrabromoethane and tetrachloroethane may be used in this manner.
  • the reactions can be conducted under anhydrous conditions.
  • ethereal solvents are .
  • the reactions are run in solvent mixtures comprising an appropriate amount of water and/or hydroxide.
  • the invention also contemplates reaction in a biphasic mixture of solvents, in an emulsion or suspension, or reaction in a lipid vesicle or bilayer. In certain embodiments, it may be to perform the catalyzed reactions in the solid phase.
  • the reactions under an inert atmosphere of a gas such as nitrogen or argon.
  • a gas such as nitrogen or argon.
  • sealing of the reaction flask is critical to prevent the decomposition on the metal species.
  • the synthetic processes of the present invention can be conducted in continuous, semi-continuous or batch fashion and may involve a liquid recycle and/or gas recycle operation as desired.
  • the processes of this invention are preferably conducted in batch fashion.
  • the manner or order of addition of the reaction ingredients, catalyst and solvent are also not critical and may be accomplished in any conventional fashion.
  • the reaction can be conducted in a single reaction zone or in a plurality of reaction zones, in series or in parallel or it may be conducted batchwise or continuously in. an elongated tubular zone or series of such zones.
  • the materials of construction employed should be inert to the starting materials during the reaction and the fabrication of the equipment should be able to withstand the reaction temperatures and pressures.
  • Means to introduce and/or adjust the quantity of starting materials or ingredients introduced batchwise or continuously into the reaction zone during the course of the reaction can be conveniently utilized in the processes especially to maintain the desired molar ratio of the starting materials.
  • the reaction steps may be effected by the incremental addition of one of the starting materials to the other. Also, the reaction steps can be combined by the joint addition of the starting materials to the catalyst. When complete conversion is not desired or not obtainable, the starting materials can be separated from the product and then recycled back into the reaction zone.
  • the processes may be conducted in either glass lined, stainless steel or similar type reaction equipment.
  • the reaction zone may be fitted with one or more internal and/or external heat exchanger(s) in order to control undue temperature fluctuations, or to prevent any possible "runaway" reaction temperatures.
  • the catalyst can be immobilized or incorporated into a polymer or other insoluble matrix by, for example, covalently linking it to the polymer or solid support through one or more of its substituents. An immobilized catalyst may be easily recovered after the reaction, for instance, by filtration or centrifugation.
  • a product synthesized by a process of the present invention may be either an end- product or an intermediate in a synthesis scheme.
  • the product synthesized by a process of the present invention is an intermediate, the product may be subjected to one or more additional transformations to yield the desired end-product.
  • the set of additional transformations contemplated comprises isomerizations, hydrolyses, oxidations, reductions, additions, eliminations, olef ⁇ nations, functional group interconversions, transition metal-mediated reactions, transition metal-catalyzed reactions, bond-forming reactions, cleavage reactions, fragmentation reactions, thermal reactions, photochemical reactions, cycloadditions, sigmatropic rearrangements, electrocyclic reactions, chemoselective reactions, regioselective reactions, stereoselective reactions, diastereoselective reactions, enantio selective reactions, and kinetic resolutions.
  • the invention expressly comprises use of a process of the present invention as a step - either initial, intermediate or final - in the synthesis of known or new pharmaceuticals, e.g., antivirals, antibiotics, and analgesics, herbicides, and agrochemicals.
  • known or new pharmaceuticals e.g., antivirals, antibiotics, and analgesics, herbicides, and agrochemicals.
  • a combinatorial library for the purposes of the present invention is a mixture of chemically related compounds which may be screened together for a desired property; said libraries may be in solution or covalently linked to a solid support.
  • the preparation of many related compounds in a single reaction greatly reduces and simplifies the number of screening processes that need to be conducted. Screening for the appropriate biological, pharmaceutical, agrochemical, or physical property is done by conventional methods.
  • the substrate aryl groups used in the combinatorial reactions can be diverse in terms of the core aryl moiety, e.g., variegation in terms of the ring structure, and/or can be varied with respect to the other substituents, e.g., the functionalized products of the present invention.
  • the library is synthesized on a set of beads, each bead including a set of tags identifying the particular diversomer on that bead.
  • the beads can be dispersed on the surface of a permeable membrane, and the diversomers released from the beads by lysis of the bead linker. The diversomer from each bead will diffuse across the membrane to an assay zone, where it will interact with an enzyme assay.
  • Arylpyridines utilized as substrates in these examples were either commercially available or were readily prepared from commercially available reagents via Suzuki coupling of the corresponding boronic acid and 2-bromopyridine. Littke et al. (2000) JACS 122:4020. Transition metal species were all commercially available.
  • methyl 4-(pyridine-2-yl)benzoate 0.3 mmol, 1 equiv
  • CuCl 2 8.1 mg, 0.06 mmol, 20% equiv
  • the tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 130 0 C for 24 h.
  • the reaction mixture was diluted with 20 mL of CH 2 Cl 2 and then treated with 10 mL of saturated Na 2 S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na 2 SO 4 and concentrated under vacuum.
  • Method 1 In a 20 mL tube, 2-phenylpyridine (46.5 mg, 0.3 mmol, 1 equiv), Cu(O Ac) 2 (54.6 mg, 0.3 mmol, 1 equiv) and TMS-CN (59.5 mg, 0.6 mmol, 2 equiv) were dissolved in 1 mL of MeCN under atmospheric air. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 130 0 C for 24 h. The reaction mixture was diluted with 20 mL of CH 2 Cb and then treated with 10 mL of saturated Na 2 S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine.
  • substrate 14 (31.2 mg, 0.2 mmol, 1 equiv) and Cu(OAc) 2 (36.4 mg, 0.2 mmol, 1 equiv) were dissolved in 1 mL of Br 2 CHCHBr 2 under atmospheric air.
  • the tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 130 0 C for 5 h.
  • the reaction mixture was diluted with 20 mL of CH 2 Cl 2 and then treated with 10 mL of saturated Na 2 S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na 2 SO 4 and concentrated under vacuum.

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Abstract

One aspect of the present invention relates to methods for direct functionalization of pyridyl-substituted aromatic compounds. In certain embodiments, 2-arylpyridine substrates react with anionic nucleophiies in the presence of copper(II) to furnish substituted arylpyridines. In other embodiments, the present invention allows for both mono- and di- functionalizations from manipulation of the reaction conditions. The transition metal- mediated carbon-heteroatom bond-forming methods are applicable to a variety of synthetic transformations of aryl C-H bonds.

Description

Copper-Mediated Functionalization ofΛryl C-H Bonds, and Compounds Related Thereto
RELATED APPLICATIONS
This application claims the benefit of priority to the filing date of United States
Provisional Patent Application serial number 60/792,901, filed April 18, 2006; the entirety of which is hereby incorporated by reference.
BACKGROUND OF THE INVENTION
The controlled functionalization of C-H bonds is one of the most challenging and difficult reactions in organic chemistry. Generally, it requires either stoichiometric amounts of toxic heavy-metal salts or expensive catalysts containing transition metals (such as Pd, Pt, Rh, and Ru). New catalytic synthetic methods in chemistry that satisfy increasingly strict environmental constraints are in great demand by the pharmaceutical and chemical industries. In addition, novel catalytic procedures are necessary to produce the new classes of compounds that are becoming the targets of molecular and biomolecular research. Among heterocyclic compounds, functionalized arylpyridines are used extensively as intermediates in the synthesis of drugs, pharmaceuticals, herbicides, and agrochemicals. Shimizu et al. Jap. Pat. No. JP 01261367A.
The development of transition-metal-mediated C-H activation reactions directed by functional groups has witnessed substantial progress in the past three decades. A wide range of metal catalysts, including Ru, Rh, Pt, and Pd, have been exploited with varying degrees of success. See Dyker (1999) Angew. Chem. Int. Ed. Engl. 38:1698; Pfeffer (2002) Chem. Rev. 102:1731; Murai et al. (1999) Nature 366:529; Jun et al. (1997) JOC 62:1200; Lenges et al. (1999) JACS 121:6616; Ellman et al. (2001) JACS 123:9692. However, the ever-increasing cost of these metals detracts from the allure of their use. Consequently, a need exists for a general and efficient method for functionalizing aryl C-H bonds based on a strategy that does not comprise a rare, costly transition metal, such as Pd, Pt, Au, Rh, Ru. Likewise, a need also exists for a general and efficient oxidation method wherein the oxidant is safe and cost-effective. Attention was turned to Cu-catalyzed C-H functionalization reactions in light of the remarkable progress made in the development of Cu-catalyzed carbon-heteroatom bond forming reactions that were previously catalyzed predominantly by Pd(II) catalysts. See Buchwald et al. (1997) JACS 119:10539; Buchwald et al. (2003) JACS 125:2890; Jerphagnon et al. (2005) Org. Lett. 7:5241. Within the last decade, bulk palladium has sold on the international metal market for roughly five-thousand times the cost of bulk copper. Therefore, based on catalyst cost, the aforementioned transformations would be orders of magnitude more appealing if they could be achieved with catalysts comprising copper in place of more rare transition metals, such as palladium. Abstraction of hydrogen from allylic C-H bonds using Cu(I)/tert~butyl hydroperoxide has been successfully exploited in peroxidation (see Eames et al. Angew. Chem. Int. Ed. Engl. (2001) 40:3567) and alkylation reactions (Li et al. JACS (2006) 128:56). Since the pyridyl group has been used to direct C-H activation reactions catalyzed by Ru(II), Rh(I) and Pd(II) catalysts (see Sanford et al. (2004) JACS 126:2300), efforts were launched to develop C-H functionalization reactions directed by a pyridyl group using Cu(II) catalysts.
SUMMARY OF THE INVENTION
One aspect of the present invention relates to methods for direct functionalization of pyiϊdyl-substituted aromatic compounds. In certain embodiments, a wide range of 2- arylpyridine substrates react with a diverse selection of anionic nucleophiles in the presence of copper(II) to furnish substituted arylpyridines by regioselective functionalization at the ortho position of the aryl ring. In other embodiments, the present invention allows for both mono- and di-functionalizations by manipulation of the reaction conditions.
The present invention provides several improvements over known methods, including functional group tolerance, e.g., toward substrates incorporating double bond and carbonyl moieties. In certain embodiments, the novel transition metal-mediated carbon- heteroatom bond-forming methods provided by the present invention are applicable to a variety of synthetic transformations of aryl C-H bonds, e.g, hydroxylation, acetoxylation, halogenation, cyanation, animation, etherification, and thioetherifϊcation. This broad utility, along with the efficacious use of O2 as a stoichiometric oxidant in certain embodiments, marks a significant advantage over Pd-, Pt-, Rh-, and Ru-catalyzed aryl C-H functionalization reactions. BRIEF DESCRIPTION OF THE FIGURES
Figure 1 depicts the structures of arylpyridine substrates 1-13.
Figure 2 depicts a plot of conversion versus reaction time for two different concentrations of CuCl2: (A) 10 mol% CuCl2; (B) 20 mol% CuCl2.
Figure 3 depicts a plot of Ln[I -c%] versus time in the presence of excess substrate
2-phenylpyridine, where c% is conversion.
Figure 4 depicts a plot of Ln[I -c%] versus time in the presence of excess CuCl2, where c% is conversion.
Figure 5 depicts a plot of conversion versus time: (A) 2-(4- methoxyphenyl)pyridine; (B) 4-(pyridine-2-yl)benzaldehyde.
DETAILED DESCRIPTION OF THE INVENTION
Overview
In certain embodiments, the invention utilizes a N-containing heteroaryl motif to direct transition metal-mediated regioselective functionalization of aromatic C-H bonds. In certain embodiments, the present invention relates to the transformation represented by Scheme 1.
Scheme 1
Figure imgf000004_0001
wherein Py is an optionally substituted pyridine. In further embodiments, the subject reaction is functionalization with a nucleophilic anion, as shown in Scheme 2:
Scheme 2
Figure imgf000004_0002
The reactions of the present invention can be stoichiometric or catalytic, e.g., utilizing 10-20 mol% transition metal complex. For example, the methods of the present invention work well for both mono- and di-functionalization of 2-arylpyridine substrates. As represented in Scheme 3, manipulation of reaction conditions generates the respective mono-ortho or di-ørt/zø-functionalized products:
Scheme 3
Figure imgf000005_0001
130-C 100°C
92% yield 63% yield
Methods of the Invention
In certain embodiments, the present invention relates to a method of functionalizing an aryl C-H bond as represented by Scheme A, comprising the step of combining an arylpyridine with a transition metal, a ligand, an oxidant, and NuX:
Scheme A
Figure imgf000005_0002
wherein
R represents independently for each occurrence substituted or unsubstituted alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, arylalkyl, cyano, halogen, hydroxyl, alkoxyl, aryloxy, arylalkyloxy, amino, alkylamino, arylamino, arylalkylamino, sulfhydryl, alkylthio, arylthio, arylalkylthio, nitro, azido, alkylseleno, formyl, acyl, carboxy, silyl, silyloxy, (alkyloxy)carbonyl, (aryloxy)carbonyl, (arylalkyloxy)carbonyl. (alkylamino)carbonyl, (arylamino)carbonyl, (arylalkylamino)carbonyl, alkylsulfonyl, or arylsulfonyl;
R' represents independently for each occurrence, substituted or unsubstituted alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, arylalkyl, cyano, halogen, hydroxyl. alkoxyl, aryloxy, arylalkyloxy, amino, alkylamino, arylamino, arylalkylamino, sulfhydryl, alkylthio, arylthio, arylalkylthio, nitro, azido, alkylseleno, formyl, acyl, carboxy, silyl, silyloxy, (alkyloxy)carbonyl, (aryloxy)carbonyl, (arylalkyloxy)carbonyl, (alkylamino)carbonyl, (arylamino)carbonyl, (arylalkylamino)carbonyl, alkylsulfonyl, or arylsulfonyl;
any two instances of R may be bonded together to form a ring that may be optionally substituted;
any two instances of R' may be bonded together to form a ring that may be optionally substituted;
an instance of R and an instance of R' may be bonded together to form a ring that may be optionally substituted;
M represents a transition metal;
L independently for each occurrence represents a ligand;
Nu represents an atom or molecule comprising a charged or uncharged carbon, nitrogen, oxygen, sulfur, chlorine, bromine, iodine, or phosphorus;
X is an electron pair or a cation;
m represents an integer in the range 0 to 4 inclusive;
n represents an integer in the range 0 to (4-q) inclusive; and
q is O or l.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said M is selected from the group consisting of Rh, Ru, Pd, Pt, and Cu.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said M is Cu.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said M is present in a stoichiometric amount relative to the arylpyridine. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said M is present in less than or equal to 20 mol% relative to the arylpyridine.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said M is present in less than or equal to 10 mol% relative to the arylpyridine.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein L is independently selected form the group consisting of OAc, Cl, F, OH, Br, (HO)PO3, NO3, Se, SO4, CF3CO2, ClO4, 2-pyrazine carboxylate, cyclohexanebutyrate, 2-ethylhexanoate, 3,5-diisopropylsalicylate, and acetylacetonate.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein L is independently selected from the group consisting of acetate, chlorine, and fluorine.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein L is acetate.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein L is chlorine.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein L is fluorine.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said oxidant is selected from the group consisting of peroxides, hydroperoxides, hyperperoxides, hypervalent acyloxy iodides, transition metal acyloxy complexes, dihalogens, O2, air, and combinations thereof.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said oxidant is O2. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein said oxidant is air.
Tn certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein Nu comprises an amino functionality, a hydroxyl functionality, an acetoxy functionality, a halogen functionality, a cyano functionality, a nitro functionality, a thiol functionality, an alkylthio functionality, an acyl functionality, an acyloxy functionality, or an alkoxy functionality.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein NuX is selected from the group consisting of I2, TMSCN, TsNH2, /7-CN-PhOH, PhSH, MeSSMe, H2O, Br2CHCHBr2, Cl2CHCHCl2, MeNO2, PhCH2NH2, anilines, CF3OH, and cyclopropyl alcohols.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is selected from the group consisting of Rh, Ru, Pd, Pt, and Cu; L is independently selected from the group consisting of OAc, Cl, F, OH, Br, (OH)PO4, NO3, Se, SO4, CF3CO2, ClO4, 2-ρyrazine carboxylate, cyclohexanebutyrate, 2-ethylhexanoate, 3,5-diisopropylsalicylate, and acetylacetonate; said oxidant is selected from the group consisting of peroxides, hydroperoxides, hyperperoxides, hypervalent acyloxy iodides, transition metal acyloxy complexes, dihalogens, O2, air, and combinations thereof; and Nu comprises an amino functionality, a hydroxyl functionality, an acetoxy functionality, a halogen functionality, a cyano functionality, a nitro functionality, a thiol functionality, an alkylthio functionality, an acyl functionality, an acyloxy functionality, or an alkoxy functionality.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is independently selected from the group consisting of acetate, chlorine, and fluorine; said oxidant is O2 or air; and Nu comprises an amino functionality, a hydroxyl functionality, an acetoxy functionality, a halogen functionality, a cyano functionality, a nitro functionality, a thiol functionality, an alkylthio functionality, an acyl functionality, an acyloxy functionality, or an alkoxy functionality. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate or fluorine; said oxidant is O2 or air; and NuX is H2O.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is selected from the group consisting Of HOAc-Ac2O, Br2CHCHBr2, 12, TMSCN,
MeNO2, TsNH2, /7-CN-PhOH, PhSH, MeSSMe, PhCH2NH2, anilines, CF3OH, and cyclopropyl alcohols.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is HOAc-Ac2O.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is Br2CHCHBr2.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is I2.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is TMSCN.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is MeNO2.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is TsNH2. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is ^-CN-PhOH.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is PhSH.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is MeSSMe.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is chlorine; said oxidant is O2 or air; and NuX is Cl2CHCHCl2.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is chlorine; said oxidant is O2 or air; and NuX is PhCH2NH2.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is chlorine; said oxidant is O2 or air; and NuX is CF3OH.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is chlorine; said oxidant is O2 or air; and NuX is an aniline.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein M is Cu; L is chlorine; said oxidant is O2 or air; and NuX is a cyclopropyl alcohol.
In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein m is O; and n is O. In certain embodiments, the present invention relates to the aforementioned method and any of the attendant definitions, wherein X is H, an electron pair, or a cation; and NuX is represented by structure 27:
Figure imgf000011_0001
27 wherein
G represents, independently for each occurrence, an electron withdrawing group selected from the group consisting of formyl, acyl, -C(O)OR", -C(O)NR"2, nitro, nitroso, - S(O)2R", -SO3R", -S(O)2NR"2, -C(NR")-R", -C(NOR")-R", and -C(NNR"2)-R";
R" represents, independently for each occurrence, hydrogen, alkyl, aryl, heteroalkyl, heteroaryl, halogen, alkylamino, arylamino, alkylthio, arylthio, alkoxy, aryloxy, or - (CH2)S-R8;
Rg represents independently for each occurrence a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; s independently for each occurrence is an integer selected from the range 0 to 8 inclusive; z is an integer selected from the range 1 to 3 inclusive; and p is an integer equal to (3-z). Compounds of the Invention
In certain embodiments, the present invention relates to a compound represented by formula I:
Figure imgf000011_0002
wherein
R represents independently for each occurrence substituted or unsubstituted alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, arylalkyl, cyano, halogen, hydroxyl, alkoxyl, aryloxy, arylalkyloxy, amino, alkylamino, arylamino, arylalkylamino, sulfhydryl, alkylthio, arylthio, arylalkylthio, nitro, azido, alkylseleno, formyl, acyl, carboxy, silyl, silyloxy, (alkyloxy)carbonyl, (aryloxy)carbonyl, (arylalkyloxy)carbonyl, (alkylarnino)carbonyl, (arylamino)carbonyl, (arylalkylamino)carbonyl, alkylsulfonyl, or arylsulfonyl;
R' represents independently for each occurrence, substituted or unsubstituted alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, arylalkyl, cyano, halogen, hydroxyl, alkoxyl, aryloxy, arylalkyloxy, amino, alkylamino, arylamino, arylalkylamino, sulfhydryl, alkylthio, arylthio, arylalkylthio, nitro, azido, alkylseleno, formyl, acyl, carboxy, silyl, silyloxy, (alkyloxy)carbonyl, (aryloxy)carbonyl, (arylalkyloxy)carbonyl, (alkylamino)carbonyl, (arylamino)carbonyl, (arylalkylamino)carbonyl, alkylsulfonyl, or arylsulfonyl;
any two instances of R may be bonded together to form a ring that may be optionally substituted;
any two instances of R' may be bonded together to form a ring that may be optionally substituted;
an instance of R and an instance of R' may be bonded together to form a ring that may be optionally substituted;
X represents independently for each occurrence a group comprising an atom selected from the group consisting of carbon, nitrogen, oxygen, sulfur, chlorine, bromine, iodine, and phosphorus;
m represents an integer in the range 0 to 4 inclusive;
n represents an integer in the range 0 to (4-q) inclusive; and
q is O or l. In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X is acetoxy, hydroxyl, alkoxy, or aryloxy.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X is selected from the group consisting of Cl, Br, and I.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X is selected from the group consisting of SPh and SMe.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X is an amine.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X is cyano.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein X is a radiohalide.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein n is 1; and R is /J-OMe, p-
Figure imgf000013_0001
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein m is 1; and R' is m-Me.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions, wherein rn is 0; and n is 0.
In certain embodiments, the present invention relates to the aforementioned compound and any of the attendant definitions,, wherein X is independently represented by structure 28:
Figure imgf000014_0001
28 wherein
G represents, independently for each occurrence, an electron withdrawing group selected from the group consisting of formyl, acyl, -C(O)OR", -C(O)NIf2, nitro, nitroso, - S(O)2R", -SO3R", -S(O)2NR"2, -C(NR")-R", -C(NOR")-R", and -C(NNR"2)-R";
R" represents, independently for each occurrence, hydrogen, alkyl, aryl, heteroalkyl, heteroaryl, halogen, alkylamino, arylamino, alkylthio, arylthio, alkoxy, aryloxy, or - (CH2)S-R8;
Rg represents independently for each occurrence a substituted or unsubstituted aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; s independently for each occurrence is an integer selected from the range 0 to 8 inclusive; z is an integer selected from the range 1 to 3 inclusive; and p is an integer equal to (3-z).
In certain embodiments, the present invention relates to a compound selected from the group consisting of:
Figure imgf000014_0002
Figure imgf000015_0001
Definitions
For convenience, certain terms employed in the specification, examples, and appended claims are collected here.
The term "nucleophile" is recognized in the art, and as used herein means a chemical moiety having a reactive pair of electrons. Examples of nucleophiles include uncharged compounds such as water, amines, mercaptans and alcohols, and charged moieties such as alkoxides, thiolates, carbanions, and a variety of organic and inorganic anions. Illustrative anionic nucleophiles include simple anions such as hydroxide, azide, cyanide, thiocyanate, acetate, formate or chloroformate, and bisulfite. Organometallic reagents such as organocuprates, organozincs, organolithiums, Grignard reagents, enolates, acetylides, and the like may, under appropriate reaction conditions, be suitable nucleophiles. Hydride may also be a suitable nucleophile when reduction of the substrate is desired.
The term "electrophile" is art-recognized and refers to chemical moieties which can accept a pair of electrons from a nucleophile as defined above. Electrophiles useful in the method of the present invention include cyclic compounds such as epoxides, aziridines, episulfides, cyclic sulfates, carbonates, lactones, lactams and the like. Non-cyclic electrophiles include sulfates, sulfonates (e.g., tosylates), chlorides, bromides, iodides, and the like The terms "electrophilic atom", "electrophilic center" and "reactive center" as used herein refer to the atom of the substrate which is attacked by, and forms a new bond to, the nucleophile.' In most (but not all) cases, this will also be the atom from which the leaving group departs.
The term "electron-withdrawing group" is recognized in the art, and denotes the tendency of a substituent to attract valence electrons from neighboring atoms, i.e., the substituent is electronegative with respect to neighboring atoms. A quantification of the level of electron-withdrawing capability is given by the Hammett sigma (σ) constant. This well known constant is described in many references, for instance, J. March, Advanced Organic Chemistry, McGraw Hill Book Company, New York, (1977 edition) pp. 251-259. The Hammett constant values are generally negative for electron donating groups (σ [P] = - 0.66 for NH2) and positive for electron withdrawing groups (σ [P] = 0.78 for a nitro group), σ [P] indicating para substitution. Exemplary electron-withdrawing groups include nitro, acyl, formyl, sulfonyl, trifluoromethyl, cyano, chloride, and the like. Exemplary electron- donating groups include amino, methoxy, and the like.
The terms "Lewis base" and "Lewis basic" are recognized in the art, and refer to a chemical moiety capable of donating a pair of electrons under certain reaction conditions. Examples of Lewis basic moieties include uncharged compounds such as alcohols, thiols, olefins, and amines, and charged moieties such as alkoxides, thiolates, carbanions, and a variety of other organic anions.
The terms "Lewis acid" and "Lewis acidic" are art-recognized and refer to chemical moieties which can accept a pair of electrons from a Lewis base.
The term "regioisomers" refers to compounds which have the same molecular formula but differ in the connectivity of the atoms. Accordingly, a "regioselective process" is one which favors the production of a particular regioisomer over others, e.g., the reaction produces a statistically significant preponderance of a certain regioisomer. The term "reaction product" means a compound which results from the reaction of a nucleophile and a substrate. In general, the term "reaction product" will be used herein to refer to a stable, isolable compound, and not to unstable intermediates or transition states.
The term "substrate" is intended to mean a chemical compound that can react with a nucleophile to yield at least one reaction product.
The term "catalytic amount" is recognized in the art and means a substoichiometric amount relative to a reactant. As used herein, a catalytic amount means from 0.0001 to 90 mole percent relative to a reactant, more preferably from 0.001 to 50 mole percent, still more preferably from 0.01 to 10 mole percent, and even more preferably from 0.1 to 5 mole percent relative to a reactant.
As discussed more fully below, the reactions contemplated in the present invention include reactions which are regioselective. A regioselective reaction is a reaction which occurs preferentially at one reactive center rather than another non-identical reactive center.
For example, a regioselective reaction of an unsymmetrically substituted epoxide substrate would involve preferential reaction at one of the two epoxide ring carbons.
The term "aliphatic" is an art-recognized term and includes linear, branched, and cyclic alkanes, alkenes, or alkynes. In certain embodiments, aliphatic groups in the present invention are linear or branched and have from 1 to about 20 carbon atoms.
The term "alkyl" is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-Ca0 for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer. Likewise, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.
Unless the number of carbons is otherwise specified, "lower alkyl" refers to an alkyl group, as defined above, but having from one to ten carbons, alternatively from one to about six carbon atoms in its backbone structure. Likewise, "lower alkenyl" and "lower alkynyl" have similar chain lengths.
The term "bicyclo-ring" as used herein refers to a bridged ring system, such as a quinuclidine (shown below).
Figure imgf000018_0001
The term "aralkyl" is art-recognized, and includes alkyl groups substituted with an aryl group {e.g., an aromatic or heteroaromatic group).
The terms "alkenyl" and "alkynyl" are art-recognized, and include unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
The term "heteroatom" is art-recognized, and includes an atom of any element other than carbon or hydrogen. Illustrative heteroatom s include boron, nitrogen, oxygen, phosphorus, sulfur and selenium, and alternatively oxygen, nitrogen or sulfur. The term "aryl" is art-recognized, and includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "heteroaryl" or "heteroaromatics." The aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, fluoroalkyl (such as trifluromethyl), cyano, or the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls. The terms ortho (o-), meta (m-) and para (p~) are art-recognized and apply to 1,2-,
1,3- and 1,4-di substituted benzenes, respectively. For example, the names 1,2- dimethylbenzene, ortho-dimethylbenzene and o-dimethylbenzene are synonymous.
The terms "heterocyclyl" and "heterocyclic group" are art-recognized, and include
3- to about 10-membered ring structures, such as 3- to about 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles may also be polycycles. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluromethyl), cyano, or the like.
The terms "polycyclyl" and "polycyclic group", are art-recognized, and include structures with two or more rings {e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms, e.g., three or more atoms are common to both rings, are termed "bridged" rings. Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, fluoroalkyl (such as trifluromethyl), cyano, or the like.
The term "carbocycle" is art recognized and includes an aromatic or non-aromatic ring in which each atom of the ring is carbon. The flowing art-recognized terms have the following meanings: "nitro" means -NO2; the term "halogen" designates -F, -Cl, -Br or -I; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" means -SO2 ".
The term "acyl" is art-recognized and refers to any group or radical of the form RCO- where R is any organic group. Representative acyl group include acetyl, benzoyl, and malonyl.
- IS - The term "acyloxy" is art-recognized and refers to a moiety that can be represented by the general formula:
Figure imgf000020_0001
wherein R'π represents a hydrogen, an alkyl, an aryl, an alkenyl, an alkynyl or -(CH2)m-R83 where m is 1-30 and R8 represents a group permitted by the rules of valence.
The terms "amine" and "amino" are art-recognized and include both unsubstituted and substituted amines, e.g., a moiety that may be represented by- the general formulas:
Figure imgf000020_0002
wherein R50, R51 and R52 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH2)m-R61, or R50 and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. hi certain embodiments, only one of R50 or R51 may be a carbonyl, e.g., R50, R51 and the nitrogen together do not form an imide. In other embodiments, R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH2)m-R61. Thus, the term "alkylamine" includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.
The term "acylamino" is art-recognized and includes a moiety that may be represented by the general formula:
Figure imgf000020_0003
wherein R50 is as defined above, and R54 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-R61, where m and R61 are as defined above.
The term "amido" is art recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula:
Figure imgf000021_0001
wherein R50 and R51 are as defined above. Certain embodiments of the amide in the present invention will not include amides which may be unstable.
The term "alkylthio" is art recognized and includes an alkyl group, as defined above, having a sulfur radical attached thereto. In certain embodiments, the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2)m-R61, wherein m and R61 are defined above. Representative alkylthio groups include methylthio, ethylthio, and the like.
The term "carbonyl" is art recognized and includes such moieties as may be represented by the general formulas:
Figure imgf000021_0002
wherein X50 is a bond or represents an oxygen or a sulfur, and R55 represents a hydrogen, an alkyl, an alkenyl, -(CH2Xn-Ro lor a pharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl, an alkenyl or -(CH2)m-R61, where m and R61 are defined above. Where X50 is an oxygen and R55 is not hydrogen, the formula represents an "ester". Where X50 is an oxygen, and R55 is as first defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a "carboxylic acid". Where X50 is an oxygen, and R56 is hydrogen, the formula represents a "formate". In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a "thiocarbonyl" group. Where X50 is a sulfur and R55 or R56 is not hydrogen, the formula represents a "thioester." Where X50 is a sulfur and R55 is hydrogen, the formula represents a "thiocarboxylic acid." Where X50 is a sulfur and R56 is hydrogen, the formula represents a "thioformate." On the other hand, where X50 is a bond, and R55 is not hydrogen, the above formula represents a "ketone" group. Where X50 is a bond, and R55 is hydrogen, the above formula represents an "aldehyde" group.
The terms "oxime" and "oxime ether" are art-recognized and refer to moieties that may be represented by the general formula:
Figure imgf000022_0001
wherein R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH2)m-R61. The moiety is an "oxime" when R is H; and it is an "oxime ether" when R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, or -(CH2)m-R61. The terms "alkoxyl" or "alkoxy" are art recognized and include an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An "ether" is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -O-(CH2)m-R61, where m and R61 are described above.
The term "sulfonate" is art recognized and includes a moiety that may be represented by the general formula:
Figure imgf000022_0002
in which R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl. The term "sulfate" is art recognized and includes a moiety that may be represented by the general formula:
Figure imgf000022_0003
in which R57 is as defined above.
The term "sulfonamido" is art recognized and includes a moiety that may be represented by the general formula:
Figure imgf000022_0004
in which R50 and R56 are as defined above.
The term "sulfamoyl" is art-recognized and includes a moiety that may be represented by the general formula:
Figure imgf000023_0001
in which R50 and R51 are as defined above.
The term "sulfonyl" is art recognized and includes a moiety that may be represented by the general formula:
O S R58
O in which R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
The term "sulfoxido" is art recognized and includes a moiety that may be represented by the general formula:
Figure imgf000023_0002
in which R58 is defined above. The term "phosphoryl" is art-recognized and may in general be represented by the formula:
Figure imgf000023_0003
wherein Q50 represents S or O, and R59 represents hydrogen, a lower alkyl or an aryl. When used to substitute, e.g., an alkyl, the phosphoryl group of the phosphorylalkyl may be represented by the general formulas:
Figure imgf000024_0001
wherein Q50 and R59, each independently, are defined above, and Q51 represents O, S or N. When Q50 is S, the phosphoryl moiety is a "phosphorothioate".
The term "phosphoramidite" is art recognized and includes moieties represented by the general formulas:
Figure imgf000024_0002
wherein Q51, R50, R51 and R59 are as defined above.
The term "phosphonamidite" is art recognized and includes moieties represented by the general formulas:
R60 R60 Q51 P O Q51 P— OR59
N N
\ / \
R50 R5I R50 R51 wherein Q51, R50, R51 and R59 are as defined above, and R60 represents a lower alkyl or an aryl.
The term "selenoalkyl" is art-recognized and refers to an alkyl group having a substituted seleno group attached thereto. Exemplary "seleno ethers" which may be substituted on the alkyl are selected from one of -Se-alkyl, -Se-alkenyl, -Se-alkynyl, and - Se-(CH2)m-R61, m and R61 being defined above.
The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, ^-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, /?-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively. The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms, represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafiuorobutanesulfonyl, /?-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations. The abbreviations contained in said list, and all abbreviations utilized by organic chemists of ordinary skill in the art are hereby incorporated by reference.
The phrase "protecting group" as used herein means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, compounds of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)- isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. V It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted , atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
The term "substituted" is also contemplated to include all permissible substituents of organic compounds. Tn a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
Analogous substitutions may be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
The definition of each expression, e.g. alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure unless otherwise indicated expressly or by the context.
For purposes of the invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. .
Catalysts of the Invention
Transition metal complexes which are useful in the present invention may be determined by the skilled artisan according to several criteria. In general, a suitable transition metal complex will have one or more of the following properties: 1) It will be capable of reaction with the substrate at the desired site; 2) It will yield a useful product upon reaction with the substrate; 3) It will not react with the substrate at functionalities other than the desired site; 4) It will not substantially undergo further undesired reaction after reacting with the substrate in the desired sense; 5) It will be able to be reoxidized by an oxidant so as to be catalytic. It will be understood that while undesirable side reactions may occur, the rates of such reactions can be rendered slow - through the selection of reactants and conditions — in comparison with the rate of the desired reaction. Transition metal complexes which satisfy the above criteria can be chosen for each substrate and may vary according to the substrate structure and desired product. Routine experimentation may be necessary to determine the transition metal for a given transformation. In certain embodiments of the present invention, metal salts are used. In certain embodiments of this invention, the metal salts are copper(II) salts. In certain embodiments of the present invention, transition metal acetates are used. In other embodiments, metal acetate hydrates may be used, hi certain embodiments of this invention, the metal acetate is copper(II) acetate. In other embodiments, metal halides are used. In certain embodiments of this invention, copper(II) chloride is used. In other embodiments of this invention, copper(II) fluoride is used. In further embodiments, the metal species may be a copper(II) metal salt selected from the group consisting OfCu(OH)2, CuBr2, Cu2(OH)PO4, Cu(NO3)2, CuSe, CuSO4, Cu(CF3COa)2, Cu(C104)2, copper(II) 2- pyrazine carboxylate, copper(II) cyclohexanebutyrate, copper(II) 2-ethylhexanoate, copper(II) 3,5-diisopropylsalicylate, cupric acetylacetonate, and the hydrates thereof. One of ordinary skill in the art will appreciate that the copper catalyst may be provided in a lower oxidation state (e.g., Cu(I) or Cu(O)) because the stoichiometric oxidant may be used in sufficient excess to oxidize that copper to copper(II), the presumed active form. In certain embodiments, the catalyst may be comprised of a metal complex as described above on solid support. In certain embodiments, the catalyst may be comprised of ligands containing stereogenic centers.
Oxidants of the Invention
An oxidant is required in certain embodiments of the present invention. Any oxidant capable of oxidizing a metal species can be utilized. In certain embodiments, any oxidant capable of oxidizing Cu(I) to Cu(II) is acceptable. In one embodiment, the oxidant is selected from the group consisting of peroxides, hydroperoxides, hyperperoxides, hypervalent acyloxy iodides, transition metal acyloxy complexes, dihalogens, O2, and air. In certain embodiments, the oxidant may be a peroxide or a hydroperoxide. In certain embodiments, the oxidant is represented by R— O-O— R' or R— O— O— H, wherein R and R' are, for example, independently alkyl, aryl, or acyl. Examples of such peroxides and hydroperoxides are MeC(=0)00*Bu, PhC(=O)OOtBu, [PhC(=O)]2O2, [CH3(CH2)πC(=O)]2θ2 (wherein n is an integer >1 (e.g., n = 10)), tBuOOiBu, and JBuOOH.
Hydroxylation Reactions
Remarkably, initial investigations examining the efficacy of a pyridyl motif to direct Cu-catalyzed ør//zo-selective C-H functionalizations revealed that the reaction of 2- phenylpyridine 1 with 1 equiv Of Cu(OAc)2 and 1 equiv Of H2O in acetonitrile under O2 (1 atm) at 1300C for 36 h gave hydroxylated product Ib in 67% yield (Scheme 4). Labeling experiments using H2 18O, and the formation of Ib in 30% yield in the absence of O2, showed that the oxygen atom from Cu(OAc)2 was incorporated into product Ib. These results indicate that, under these reaction conditions, the first step involves formation of the acetoxylated product, which subsequently undergoes rapid hydrolysis catalyzed by the intramolecular pyridyl group.
,Py
Figure imgf000028_0001
Reactions of 2-arylpyridine substrate derivatives 2-5 gave only the mono-hydroxylated products 2a-5a and unreacted starting materials under the same conditions (Scheme 5).
Scheme 5
Figure imgf000028_0002
Entry Substrate R Yield (%)
1 2 OMe 77 2 3 Me 56 3 4 CH=CH2 61 4 5 CHO 43 The high mono-selectivity is likely due to the binding of the hydroxyl group and the nitrogen in the product to Cu(II), which prevents further reaction. The tolerance of the double bond functionality (Entry 3) is a significant advantage over Pd-catalyzed C-H functionalization reactions.
Catalytic Acetoxylation
While the selective formation of the monohydroxylated product is a synthetically useful feature, the product also inhibits the reaction and prevents catalytic turnover. This effect can be circumvented by adding Ac2O to the reaction mixture to acetylate Ib in the reaction mixture. As a result, the Cu loading was reduced to 10 mol% in the presence of O2
(Scheme 6).
Scheme 6
Figure imgf000029_0001
Catalytic Chlorination
Remarkably, it was discovered that the reaction of 2-phenylpyridine 1 with 20 mol% Cu(OAc)2 in Cl2CHCHCl2 gave dichlorinated product Id in 92% isolated yield. Analysis of the reaction mixture by 1H NMR and pH measurements indicated that Cl2CHCHCl2 was partially converted to Cl2C=CHCl and HCl5 which provided the Cl anion source. The presence of a small amount of HCl was shown to promote the reoxidation of Cu(O) and Cu(I) to Cu(II) by O2. The reaction of a wide range of 2-arylpyridines 1-13 (Figure 1) with 20 mol% CuCl2 in Cl2CHCHCl2 afforded chlorinated products in excellent yields (Table 1). Table L Cu(II) -Catalyzed Chlorination of Aryl C-H Bonds3
Figure imgf000030_0001
"20 mol% CuCl2, Cl2CHCHCl2, O2(I atm), 13O0C, 24 h. b100 0C.
In the presence of an ortΛø-substituent on the pyridine (Entry 11) the mono- chlorinated product was obtained as a major product, which indicates that the steric hindrance around the N atom of the pyridyl group prevents further chlorination. It is also observed that electron-withdrawing groups attached to the aryl ring result in lower conversion (Entry 7). Remarkably, mono-selectivity was also achieved by carrying out the reaction at a lower temperature (1000C, Entry 2).
Aryl C-H Functionalization
Remarkably, this reactivity was extended to cyanation, animation, etherifϊcation and thioetherification reactions by using a combination of Cu(OAc)2 and various nucleophilic anions (Table 2). The mono-fiinctionalized products are obtained as major products.
Direct cyanation is a valuable transformation in heterocycle synthesis because the conversion of a nitrile moiety into a tetrazole is frequently used in drug syntheses. Amantini et al. (2004) JOC 69:2896. Specifically, the installation of a CN group is useful in the synthesis of drug-related tetrazole compounds, for instance FORASARTAN. The use of MeNO2 as a CN source for cyanation is practically convenient (Entry 4). The reagent TsNHb was also used as a nitrogen anion source to achieve the direct animation of aryl C-H bonds (Entry 5). The formation of the hydroxylated product using CuF2 and H2O is also noteworthy (Entry 9). In certain embodiments, the present invention also considers the use of alcohol nucleophiles such as CF3OH and cyclopropyl alcohols. In certain embodiments, the present invention also considers the use of other amines (e.g., anilines and PhCH2NH2).
Table 2. Cu(II)-Mediated Diverse C-H Functionalizationsa
Figure imgf000031_0001
entry anion source solvent product (X) yield
1 Br2CHCHBr2 Br, 1f 65% 2 I2 CICH2CH2CI I, 19 61 %b 3 TMSCN MeCN CN, 1h 42% 4 MeNO2 CN, 1h 67% 5 TsNH2 MeCN TsNH1 Ii 74%
6 P-CN-PhOH MeCN P-CN-PhO, 1j 35% 7 PhSH DMSO PhS, 1k 40% 8 MeSSMe DMSO MeS, 11 51% 9 H2O DMSO OH, 1b 22%c al equiv Cu(OAc)2, air, solvent, 1300C, 24 h; b100°C, 8 h. c 1 equiv CuF2. Note: In entry 1, 10-20% di-functionalized products were also obtained.
Interestingly, by running the iodination reaction (entry 2) at 130 0C using PhI as a solvent, the dimerized product, Im, was obtained in 67% yield. Presumably, the initially formed iodinated product, Ig, underwent Ullmann coupling to give Im.
Dimerization
Figure imgf000031_0002
Mechanistic Investigations Isotope effect
No isotope effect was observed in an intramolecular competition experiment using deuterium-labeled substrate 14 (Scheme 7). This result suggests that the reaction mechanism is different from Pd-catalyzed functionalization reactions, in which substantial isotope effects are usually observed. Yu et al. (2005) Angew. Chem. Int. Ed. 44:2112.
Scheme 7
*n" +
Figure imgf000032_0001
Determination of Rate Order
Second, the chlorination reaction was found to be first order in both 2-phenylpyridine and CuCl2. 2-Phenylpyridine was chlorinated following the procedure detailed herein. The reaction was monitored by 1H NMR to measure the conversion over time. The data obtained using 10 mol% and 20 mol% CuCl2 are described in Figure 2. The slope of plot A is 0.78 and the slope of plot B is 0.44. Taken together, these data are consistent with the reaction being first order in CuCl2.
According to the equation of first order reaction (below), the plot of In[I -c%] versus time gives a straight line (where c% is the percentage conversion). As depicted in Figure 3, the plot obtained using 20 mol% CuCl2 was in agreement with equation 1, which further indicates that the reaction is first order in CuCl2.
The equation of first order
In[A] = In[A]0 -kt [A]: concentration
[A]0 : initial concentration ln[A]/[A]0 =-kt [A] = [A]0(I -c%) c%: conversion ln[1-c%] = -kt (equation 1)
In the presence of excess CuCl2 (5 equiv), the substrate 2-phenylpyridine was chlorinated following the procedure detailed herein. As depicted in Figure 4, the plot of In[I -c%] versus time also gives a straight line, which suggests that the reaction is first order in substrate. Electronic Effect
In certain embodiments, electron withdrawing groups decrease the reaction rates. The substrates 2-(4-methoxyphenyl)pyridine 2 and 4-(pyridine-2-yl)benzaldehyde 5 were chlorinated following the procedure detailed herein, and the reactions were also monitored by 1H NMR to measure conversion over time. The result described in Figure 5 shows that the rate of reaction for substrate 4-(pyridine-2-yl)benzaldehyde 5 is slower than that of 2- (4-methoxyphenyl)pyridine 2.
Possible Mechanism A radical-cation pathway may be invoked to explain the data obtained from these mechanistic studies (Scheme 8). A single electron transfer (SET) from the coordinated Cu(II) to the aryl ring leading to the cation-radical intermediate 15 is the rate-limiting step. The lack of reactivity of biphenyl suggests that the coordination of Cu(II) to the pyridine is necessary for the SET process. The observed σrtΛoselectivity is explained by an intramolecular anion transfer from a coordinated CuCl2 to the cation-radicals. Alternatively, an electrophilic attack of the pyridyl coordinated Cu(II) on the aryl ring could take place in a similar manner to that of the Pb(TFA)4 mediated oxidation of aryl C-H bonds. See Kochi et al. (1973) JACS 95:7114; and Sheldon, R.A.; Kochi. J.K. Metal-Catalyzed Oxidations of Organic Compounds; Academic Press: New York, 1981. The subsequent loss of a proton would give an unusual cyclometalated aryl Cu(II) complex that could undergo reductive elimination to give the functionalized products and Cu(O).
Scheme 8
Figure imgf000033_0001
Reaction Conditions
The reactions of the present invention may be performed under a wide range of conditions, though it will be understood that the solvents and temperature ranges recited herein are not limitative and only correspond to particular modes of the processes of the invention. In general, it will be desirable that reactions are run using mild conditions which will not adversely effect the substrate, the catalyst, or the product. For example, the reaction temperature influences the speed of the reaction, as well as the stability of the reactants, products, and catalyst. In certain embodiments of the present invention, the manipulation of reaction temperature determines the level of functionalization observed.
In general, the synthetic reactions of the present invention are carried out in a liquid reaction medium. The reactions may be run without addition of solvent. Alternatively, the reactions may be run in an inert solvent, preferably one in which the reaction ingredients, including the catalyst, are substantially soluble. Suitable solvents include ethers such as diethyl ether, 1,2-dimethoxyethane, diglyme, tert-butyl methyl ether, tetrahydrofuran and the like; halogenated solvents such as chloroform, dichloromethane, dichloroethane, chlorobenzene, and the like; aliphatic or aromatic hydrocarbon solvents such as benzene, toluene, hexane, pentane and the like; esters and ketones such as ethyl acetate, acetone, and 2-butanone; polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide and the like; or combinations of two or more solvents. Furthermore, in certain embodiments, it may be advantageous to employ a solvent which is not inert to the substrate under the conditions employed, e.g. , use of ethanol as a solvent when ethanol is the desired nucleophile. In certain embodiments of the present invention, tetrabromoethane and tetrachloroethane may be used in this manner. In embodiments where water or hydroxide are not nucleophiles, the reactions can be conducted under anhydrous conditions. In certain embodiments, ethereal solvents are . In embodiments where water or hydroxide are nucleophiles, the reactions are run in solvent mixtures comprising an appropriate amount of water and/or hydroxide.
The invention also contemplates reaction in a biphasic mixture of solvents, in an emulsion or suspension, or reaction in a lipid vesicle or bilayer. In certain embodiments, it may be to perform the catalyzed reactions in the solid phase.
In certain embodiments it is preferable to perform the reactions under an inert atmosphere of a gas such as nitrogen or argon. In many embodiments sealing of the reaction flask is critical to prevent the decomposition on the metal species. The synthetic processes of the present invention can be conducted in continuous, semi-continuous or batch fashion and may involve a liquid recycle and/or gas recycle operation as desired. The processes of this invention are preferably conducted in batch fashion. Likewise, the manner or order of addition of the reaction ingredients, catalyst and solvent are also not critical and may be accomplished in any conventional fashion.
The reaction can be conducted in a single reaction zone or in a plurality of reaction zones, in series or in parallel or it may be conducted batchwise or continuously in. an elongated tubular zone or series of such zones. The materials of construction employed should be inert to the starting materials during the reaction and the fabrication of the equipment should be able to withstand the reaction temperatures and pressures. Means to introduce and/or adjust the quantity of starting materials or ingredients introduced batchwise or continuously into the reaction zone during the course of the reaction can be conveniently utilized in the processes especially to maintain the desired molar ratio of the starting materials. The reaction steps may be effected by the incremental addition of one of the starting materials to the other. Also, the reaction steps can be combined by the joint addition of the starting materials to the catalyst. When complete conversion is not desired or not obtainable, the starting materials can be separated from the product and then recycled back into the reaction zone.
The processes may be conducted in either glass lined, stainless steel or similar type reaction equipment. The reaction zone may be fitted with one or more internal and/or external heat exchanger(s) in order to control undue temperature fluctuations, or to prevent any possible "runaway" reaction temperatures. Furthermore, the catalyst can be immobilized or incorporated into a polymer or other insoluble matrix by, for example, covalently linking it to the polymer or solid support through one or more of its substituents. An immobilized catalyst may be easily recovered after the reaction, for instance, by filtration or centrifugation.
Subsequent Transformations
A product synthesized by a process of the present invention may be either an end- product or an intermediate in a synthesis scheme. In cases where the product synthesized by a process of the present invention is an intermediate, the product may be subjected to one or more additional transformations to yield the desired end-product. The set of additional transformations contemplated comprises isomerizations, hydrolyses, oxidations, reductions, additions, eliminations, olefϊnations, functional group interconversions, transition metal-mediated reactions, transition metal-catalyzed reactions, bond-forming reactions, cleavage reactions, fragmentation reactions, thermal reactions, photochemical reactions, cycloadditions, sigmatropic rearrangements, electrocyclic reactions, chemoselective reactions, regioselective reactions, stereoselective reactions, diastereoselective reactions, enantio selective reactions, and kinetic resolutions. The invention expressly comprises use of a process of the present invention as a step - either initial, intermediate or final - in the synthesis of known or new pharmaceuticals, e.g., antivirals, antibiotics, and analgesics, herbicides, and agrochemicals.
Combinatorial Libraries The subject C-H functionalization reaction readily lends itself to the creation of combinatorial libraries of arylpyridines for the screening of pharmaceutical, agrochemical, or other biological or medically-related activity or material related qualities. A combinatorial library for the purposes of the present invention is a mixture of chemically related compounds which may be screened together for a desired property; said libraries may be in solution or covalently linked to a solid support. The preparation of many related compounds in a single reaction greatly reduces and simplifies the number of screening processes that need to be conducted. Screening for the appropriate biological, pharmaceutical, agrochemical, or physical property is done by conventional methods.
Diversity in the library can be created at a variety of different levels. For instance, the substrate aryl groups used in the combinatorial reactions can be diverse in terms of the core aryl moiety, e.g., variegation in terms of the ring structure, and/or can be varied with respect to the other substituents, e.g., the functionalized products of the present invention.
A variety of techniques are available in the art for generating combinatorial libraries of small organic molecules such as the subject arylpyridines. See, for example, Blondelle et a. (1995) Trends Anal. Chem. 14:83; the Affymax U.S. Pat. Nos. 5,359,115 and 5,362,899; the Ellman U.S. Pat. No 5,288,514; the Still et al. PCT publication WO 94/08051 ; Chen et al. (1994) JACS 116:2661; Kerr et al. (1993) JACS 115:252; PCT publications WO 92/100092, WO 93/09668, and WO 91/07087; and the Lemer et al. PCT publication WO 93/20242. Accordingly, a variety of libraries on the order of about 16 to 1,000,000 or more diversomers of the subject arylpyridines can be synthesized and screened for particular activity or property. In an exemplary embodiment, a library of substituted diversomers can be synthesized using the subject functionalization reaction adapted to the techniques described in the Still et al. PCT publication WO 94/08051, e.g., being linked to a polymer bead by a hydrolyable or photolyzable group e.g., located at one of the positions of the aryl group or a substituent of the pyridyl or the like. According to the Still et al. technique, the library is synthesized on a set of beads, each bead including a set of tags identifying the particular diversomer on that bead. In one embodiment, which is particularly suitable for discovering enzyme inhibitors, the beads can be dispersed on the surface of a permeable membrane, and the diversomers released from the beads by lysis of the bead linker. The diversomer from each bead will diffuse across the membrane to an assay zone, where it will interact with an enzyme assay.
EXEMPLIFICATION
The invention may be understood with reference to the following examples, which are presented for illustrative purposes only and which are non-limiting. Arylpyridines utilized as substrates in these examples were either commercially available or were readily prepared from commercially available reagents via Suzuki coupling of the corresponding boronic acid and 2-bromopyridine. Littke et al. (2000) JACS 122:4020. Transition metal species were all commercially available.
General Information
Organic solutions were concentrated by rotary evaporation (house vacuum, ~25 Torr) at 23-300C. Flash column chromatography was performed by employing silica gel (60-A pore size, 230-400 mesh, standard grade). Analytical thin layer chromatography (TLC) was performed using aluminum plates pre-coated with silica gel (0.25 mm, 60-A pore size, 230-400 mesh, Merck KGA) impregnated with a fluorescent indicator (254 mm). TLC plates were visualized by exposure to ultraviolet light (UV) and/or exposure to phosphmolybdic acid (PMA) followed by brief heating on a hot plate. Proton nuclear magnetic resonance (1H NMR) spectra and carbon nuclear magnetic resonance (13C NMR) were recorded with Varian Mercury 400 (400 MHz / 100 MHz) NMR spectrometers. Chemical shifts for protons are reported in parts per million scale (δ scale) and internally referenced to tetramethylsilane signal. Chemical shifts for carbon are reported in parts per million (δ scale) and referenced to the carbon resonances of the solvent (CDCI3: δ 77.36, the middle peak). Data are represented as follows: chemical shift (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet, dt = double triplet, td = triple doublet), coupling constant in Hz, and integration. Infrared (IR) spectra were recorded on a Perkin Elmer FT-IR Spectrometer with a thin film on the KBr plate. High resolution mass spectra (HRMS) were obtained at the Mass Spectrometry Facilities of University of Illinois at Urbana-Champaign.
EXAMPLE 1 Synthesis of 2-(pyridine-2-yl)phenol (Ib)
Figure imgf000038_0001
In a 20 mL tube, 2-phenylpyridine (0.3 mmol, 1 equiv), Cu(OAc)2 (54.6 mg, 0.3 mmol, 1 equiv) and H2O (5.4 μL, 0.3 mmol, 1 equiv) were dissolved in 1 mL of dry MeCN under * oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 36 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rf = 0.35 in 2:1 hexane: ether), the title product was obtained as a colorless oil (34.4 mg, 67%). 1H NMR (400 MHz, CDCl3) δ 14.39 (s, IH), 8.52 (d, J== 4.8 Hz, IH), 7.93 (d, J= 8.4 Hz, IH), 7.87-7.84 (m, IH), 7.81 (d, J= 8.0 Hz, IH), 7.31 (td, J= 7.6, 1.2 Hz, IH), 7.27-7.24 (m, IH), 7.03 (d, J= 8.0 Hz, IH), 6.92 (td, J = 7.6, 1.2 Hz, IH); 13C NMR (100 MHz5 CDCl3) δ 160.29, 158.10, 146.08, 138.05, 131.77, 126.39, 121.79, 119.31, 119.05, 118.89; IR (thin film) v 2923, 1594, 1477, 1270 cm"1; HRMS (TOF) Calcd for CnH10NO (M+ H) 172.0762, found 172.0768.
Hydroxylation by CuF 2
In a 20 mL tube, substrate (0.3 mmol, 1 equiv), CuF2 (30.5 mg, 0.3 mmol, 1 equiv) and
H2O (27 μL, 1.5 mmol, 5 equiv) were dissolved in 1 mL of dry DMSO under atmospheric air. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at
1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Rf = 0.35 in 2:1 hexane: ether), Ib was obtained as a colorless oil (11.2 mg, 22%).
EXAMPLE 2 Synthesis of 5-methoxy-2-(pyridine-2-yl)phenol (2a)
Figure imgf000039_0001
In a 20 mL tube, 2-(4-methoxyphenyl)pyridine (0.3 mmol, 1 equiv), Cu(OAc)2 (54.6 mg, 0.3 mmol, 1 equiv) and H2O (5.4 μL, 0.3 mmol, 1 equiv) were dissolved in 1 mL of dry MeCN under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 130°C for 36 h. The reaction mixture was diluted with 20 mL Of CH2CI2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice, with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rf = 0.30 in 2:1 hexane: ether), the title product was obtained as a pale yellow solid (33.8 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 14.73 (s, IH), 8.45 (d, J= 4.8 Hz, IH), 7.79-7.78 (m, 2H), 7.79 (d, J= 8.8 Hz, IH), 7.18-7.15 (m, IH), 6.54 (s, IH), 6.50 (d, J= 8.8 Hz, IH), 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 162.31, 161.88, 157.84, 145.53, 137.59, 127.09, 120.50, 118.21, 112.00, 106.59, 102.07, 55.30; IR (thin film) v 1594, 1473, 1245, 1159 cm"1; HRMS (TOF) Calcd for Ci2Hi2NO2 (M + H) 202.0868, found 202.0862.
EXAMPLE 3
Synthesis of 5-methyl-2-(pyridine-2-yl)phenol (3a)
Figure imgf000039_0002
In a 20 mL tube, 2-(4-methylphenyl)pyridine (0.3 mraol, 1 equiv), Cu(OAc)2 (54.6 mg, 0.3 mmol, 1 equiv) and H2O (5.4 μL, 0.3 mmol, 1 equiv) were dissolved in 1 mL of dry MeCN under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 36 h. The reaction mixture was diluted with 20 mL Of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rf = 0.41 in 2:1 hexane: ether), the title product was obtained as a pale yellow oil (31.1 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 14.35 (s, IH), 8.48 (d, J = 4.8 Hz, IH), 7.88 (d, J = 8.0 Hz, IH), 7.81(td, J= 7.2, 1.6 Hz, IH), 7.68 (d, J = 8.0 Hz, IH), 7.21 (t, J= 8.0 Hz, IH), 6.85 (s, IH), 6.73 (d, J= 8.0 Hz, IH); 13C NMR (100 MHz3 CDCl3) δ 159.82, 157.81, 145.61, 141.95, 137.53, 125.83, 120.96, 119.82, 118.75, 118.57, 116.10, 21.33; IR (thin film) v 3054, 1265 cm"1; HRMS (TOF) Calcd for Ci2H]2NO2 (M + H) 186.0919, found 186.0915.
EXAMPLE 4 Synthesis of 2-(pyridine-2-yl)-5-vinylphenol (4a)
Figure imgf000040_0001
In a 20 mL tube, 2-(4-vinylphenyl)pyridine (0.3 mmol, 1 equiv), Cu(OAc)2 (54.6 mg, 0.3 mmol, 1 equiv) and H2O (5.4 μL, 0.3 mmol, 1 equiv) were dissolved in 1 mL of dry MeCN under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 36 h. The reaction mixture was diluted with 20 mL Of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rf = 0.35 in 2:1 hexane: ether), the title product was obtained as a pale yellow oil (36.1 mg, 61%). 1H NMR
(400 MHz, CDCl3) δ 14.40 (s, IH), 8.51 (d, J= 4.0 Hz, IH), 7.91 (d, J= 8.4 Hz, IH), 7.86
(t, J= 7.6 Hz, IH), 7.76 (d, J= 8.0 Hz, IH), 7.25 (m, IH), 7.08 (s, IH), 6.98 (d, J= 8.0 Hz, IH), 6.70 (dd, J= 18.0, 10.8 Hz, IH), 5.83 (d, J= 17.6 Hz, IH), 5.32 (d, J= 10.8, IH); 13C NMR (100 MHz, CDCl3) δ 160.10, 157.57, 145.85, 140.68, 137.72, 136.27, 126.20, 121.39, 118.96, 116.90, 115.98, 115.16; IR (thin film) v 3054, 1596, 1266 cm"1; HRMS (TOF) Calcd for Ci3Hi2NO (M + H) 198.0919, found 198.0923.
EXAMPLE 5 Synthesis of 3-hydroxy-4-(pyridine-2-yl)benzaldehyde (5a)
Figure imgf000041_0001
In a 20 mL tube, 4-(pyridine-2-yl)benzaldehyde (0.3 mmol, 1 equiv), Cu(OAc)2 (54.6 mg, 0.3 mmol, 1 equiv) and H2O (5.4 μL, 0.3 mmol, 1 equiv) were dissolved in 1 mL of dry MeCN under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 36 h. The reaction mixture was diluted with 20 mL Of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rf = 0.29 in 2:1 hexane: ether), the title product was obtained as a pale yellow solid (25.7 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 14.59 (s, IH), 10.00 (s, IH), 8.58 (d, J = 4.8 Hz, IH), 8.02-7.92 (m, 3H), 7.50 (s, IH), 7.44 (d, J= 8.4 Hz, IH), 7.36 (t, J= 7.2 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 191.93, 160.41, 156.55, 146.09, 138.34, 138.15, 126.74, 123.73, 122.75, 120.49, 120.01, 118.71; IR (thin film) v 3055, 1698, 1594, 1419, 1265 cm"1; HRMS (TOF) Calcd for C12Hi0NO2 (M + H) 200.0712, found 200.0708.
EXAMPLE 6 Labeling Experiment
Figure imgf000041_0002
In a 20 mL tube, substrate (0.3 mmol, 1 equiv), Cu(OAc)2 (54.6 mg, 0.3 mmol, 1 equiv) and H2 18O (5.4 μL, 0.3 mmol, 1 equiv) were dissolved in 1 mL of dry MeCN under N2. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 130°C for 24 h. The reaction mixture was diluted with 20 mL of CH2CI2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Rf = 0.35, in 2:1 hexane and ether) to give the product in 30% yield. By the analysis of GC-MS, no I8O-labeled hydroxylated product was detected and only hydroxylated product Ib was obtained.
EXAMPLE 7
Synthesis of 2-(pyridine-2-yl)phenyl acetate (Ia) and 2-(ρyridin-2-yl)-l,3-phenylene diacetate (Ic)
Figure imgf000042_0001
In a 40 mL tube, 2-phenylpyridine (46.5 mg, 0.3 mmol, 1 equiv), and Cu(OAc)2 (5.5.mg, 0.03 mmol, 10% equiv) were dissolved in 1 mL Of HOAc-Ac2O (1:1) under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 48 h. After the reaction solvent was removed under vacuum, the residue was neutralized with 5 mL of saturated NaHCO3 aqueous solution and then treated with 5 mL of saturated Na2S aqueous solution. The mixture was diluted with 20 mL Of CH2Cl2 and filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel. Title product Ia (Rf = 0.17, in 1:2 hexane and ether) was obtained as a colorless oil (23.7 mg, 37%) and title product Ic (Rf = 0.14 in 1:3 hexane and ether) was obtained as a white solid (45.6 mg, 56%). Ia: 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J = 4.8 Hz, IH), .7.73 (td, J= 8.0, 1.6 Hz, IH), 7.70 (dd, J= 7.2, 2.0 Hz, IH), 7.53 (d, J= 8.0 Hz, IH), 7.43 (td, J= 8.0, 2.0 Hz, IH), 7.35 (td, J= 7.2, 1.2 Hz, IH), 7.24 (ddd, J= 8.0, 4.8, 1.2 Hz, IH), 7.16 (dd, J= 8.0, 1.6 Hz, IH), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.74, 156.08, 149.86, 148.34, 136.56, 133.42, 131.08, 129.99, 126.67, 123.87, 123.50, 122.47, 21.25; IR (thin film) v 3063, 1762, 1188 cm'1; HRMS (TOF) Calcd for C3H12NO2 (M + H) 214.0868, found 214.0871 . Ic: 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J= 4.8 Hz, IH), 7.30 (td, J= 7.6, 1.6 Hz, IH), 7.45 (t, J= 7.6 Hz, IH), 7.32 (dd, J= 8.0, 1.2 Hz, IH), 7.29-7.25 (m, IH), 7.10 (d, J= 8.0 Hz, 2H), 2.03 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 169.30, 152.62, 149.81, 149.40, 136.27, 129.70, 127.86, 125.41, 122.83, 121.01, 20.94; IR (thin film) v 2933, 1771, 1456, 1369, 1192 cm"1; HRMS (TOF) Calcd for Ci5H]4NO4 (M + H) 272.0923, found 272.0919.
EXAMPLE 8
Synthesis of 2-(2,6-dichlorophenyl)pyridine (Id)
Figure imgf000043_0001
In a 40 mL tube, 2-phenylpyridine (0.3 mmol, 1 equiv) and CuCl2 (8.1 mg, 0.06 mmol,
20% equiv) were dissolved in 1 mL of Cl2CHCHCl2 under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL Of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rf = 0.21 in 2:1 hexane: ether), the title compound was obtained as a colorless oil (61.8 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J= 4.8 Hz, IH), 7.82 (td, J= 7.6, 1.6 Hz, IH), 7.41 (d, J= 8.0 Hz, 2H), 7.35 (dd, J= 8.4, 4.4 Hz, 2H), 7.28 (t, J = 7.6 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 155.73, 149.86, 138.64, 136.61, 134.85, 130.06, 128.36, 125.24, 123.19; IR (thin film) v 2924, 1699, 1558 cπf1; HRMS (TOF) Calcd for C11H8Cl2N (M + H) 224.0034, found 224.0025.
EXAMPLE 9 Synthesis of 2-(2-chlorophenyl)pyridine (Ie)
Figure imgf000043_0002
In a 40 mL tube, 2-phenylpyridine (0.3 mmol, 1 equiv) and CuCl2 (8.1 mg, 0.06 mmol, 20% equiv) were dissolved in 1 mL of Cl2CHCHCl2 under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1000C for 24 h. The reaction mixture was diluted with 20 mL of CH2CI2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SC^ and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rr = 0.19 in 2:1 hexane: ether), the title product was obtained as a colorless oil (35.8 mg, 63%). A substantial amount of di-chlorinated product Id was also obtained as a colorless oil (15.5 mg, 23%).
Ie: 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J= 4.8 Hz, IH), 7.76 (td, J= 7.6, 2.0 Hz, IH), 7.65 (d, J= 8.0 Hz, IH), 7.60 (dd, J= 7.2, 2.4 Hz, IH), 7.48 (dd, J= 7.2, 1.6 Hz, IH), 7.39- 7.31 (m, 2H), 7.29 (ddd, J= 7.6, 4.8, 1.2 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 157.20, 149.88, 139.51, 136.16, 132.45, 131.86, 130.42, 129.91, 127.33, 125.19, 122.72; IR (thin film) v 2924, 1585, 1458, 751 cm'1; HRMS (TOF) Calcd for CnH9ClN (M + H) 190.0424, found 190.0428.
EXAMPLE lO
Synthesis of 2-(2,6-dichloro-4-methoxyphenyl)pyridine (2b)
Figure imgf000044_0001
In a 40 mL tube, 2-(4-methoxyphenyl)pyridine (0.3 mmol, 1 equiv) and CuCl2 (8.1 mg, 0.06 mmol, 20% equiv) were dissolved in 1 mL of Cl2CHCHCl2 under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rr = 0.17 in 2:1 hexane: ether), the title product was obtained (70.9 mg, 93%). 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J= 4.8 Hz, IH), 7.79 (td, J = 8.0, 1.6 Hz. IH), 7.32 (dd, J= 8.0, 3.6 Hz, 2H), 6.97 (s, 2H); 3.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.05, 155.79, 149.88, 136.60, 135.33, 131.39, 125.92, 123.10, 114.42, 56.16; IR (thin film) v 2937, 1602, 1424, 1303, 1051 cm"1; HRMS (TOF) Calcd for Ci2HioCl2NO (M + H) 254.0139, found 254.0142. EXAMPLE I l Synthesis of 2-(2,6-dichloro-4-methylρhenyl)pyridine (3b)
Figure imgf000045_0001
In a 40 mL tube, 2-(4-methylphenyl)pyridine (0.3 mmol, 1 equiv) and CuCl2 (8.1 mg, 0.06 mmol, 20% equiv) were dissolved in 1 mL of Cl2CHCHCl2 under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rf = 0.30 in 2:1 hexane: ether), the title product was obtained (61.4 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 4.8 Hz, IH)5 7.79 (td, J= 7.6, 1.2 Hz, IH), 7.32 (dd, J= 8.0, 4.0 Hz, 2H), 7.22 (s, 2H), 2.36 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.91, 149.90, 140.75, 136.60, 135.83, 134.40, 129.01, 125.56, 123.14, 21.17; IR (thin film) v 2923, 1601, 1426 cm"1; HRMS (TOF) Calcd for CI2HI 0CI2N (M + H) 238.0190, found 238.0196.
EXAMPLE 12 Synthesis of 2-(2-chloro-4-vinylphenyl)pyridine (4b)
Figure imgf000045_0002
In a 40 mL tube, 2-(4-vinylphenyl)pyridine (0.3 mmol, 1 equiv) and CuCl2 (8.1 mg, 0.06 mmol, 20% equiv) were dissolved in 1 mL of Cl2CHCHCl2 under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rf = 0.21 in 2:1 hexane: ether), the title product was obtained as a colorless oil (33.0 mg, 51%). 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 4.0 Hz, IH)5 7.76 (td, J = 1.6, 1.6 Hz, IH), 7.67 (d, J= 8.0 Hz, IH), 7.58 (d, J = 8.0 Hz, IH), 7.52 (s, IH), 7,40 (dd, J= 8.0, 2.0 Hz, IH), 7.28 (dd, J= 6.4, 4.8 Hz, IH), 6.70 (dd, J = 17.6, 10.8 Hz, IH), 5.83 (d, J= 17.6 Hz, IH), 5.36 (d, J = 10.8 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 156.87, 149.92, 139.49, 138.53, 136.15, 135.53, 132.65, 132.02, 128.08, 125.21, 125.13, 122.72, 116.19; IR (thin film) v 1463 cm"1; HRMS (TOF) Calcd for Ci3HIiClN (M+) 216.0580, found 216.0579.
EXAMPLE 13 Synthesis of 3,5-dichloro-4-(pyridine-2-yl)benzaldehyde (5b)
Figure imgf000046_0001
In a 40 mL tube, 4-(pyridine-2-yl)benzaldehyde (0.3 mmol, 1 equiv) and CuCl2 (8.1 mg, 0.06 mmol, 20% equiv) were dissolved in 1 mL of CI2CHCHCI2 under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2CI2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rf = 0.12 in 2:1 hexane: ether), the title product was obtained as a white solid (62.0 mg, 82%).1H NMR (400 MHz, CDCl3) δ 9.99 (s, IH), 8.78 (d, J= 4.8 Hz, IH), 7.92 (s, 2H), 7.86 (td, J= 8.0, 1.2 Hz, IH), 7.41-7.39 (m, H), 7.35 (d, J= 8.0 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 189.60, 154.86, 150.23, 143.90, 137.66, 136.98, 136.34, 129.27, 124.98, 123.82; IR (thin film) v 3067, 1706, 1549, 1364, 1200 cm" '; HRMS (TOF) Calcd for Ci2H8Cl2NO (M + H) 258.0452, found 258.0456. EXAMPLE 14
Synthesis of 2-(2-chloro-4-(trifluoromethyl)phenyl)pyridine (6a) and 2-(2,6-dichloro-4-(trifluoromethyl)phenyl)pyridine (6b)
Figure imgf000047_0001
In a 40 mL tube, 2-(4-trifluoromethylphenyl)pydrine (0.3 mmol, 1 equiv) and CuCl2 (8.1 mg, 0.06 mmol, 20% equiv) were dissolved in 1 mL of Cl2CHCHCb under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum to furnish two products. After purification by column chromatography, 6a (Rf = 0.24 in 2:1 hexane: ether) was obtained as a colorless oil (32.5 mg, 42%), and 6b (Rf = 0.34 in 2:1 hexane: ether) was obtained as a colorless oil (17.5 mg, 20 %). 6a: 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 4.8 Hz, IH), 7.81 (td, J = 7.6, 1.6 Hz, IH), 7.74 (d, J= 10.2 Hz, 2H), 7.68 (d, J= 8.0 Hz, IH), 7.62 (d, J= 8.0 Hz, IH)5 7.35 (td, J = 7.6, 1.6 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 155.85, 150.13, 142.83, 136.42, 133.13, 132.47, 128.49, 127.55 (d, J = 3.8 Hz), 125.16, 124.15 (d, J = 3.8 Hz), 123.42; IR (thin film) v 1325, 1130 cm"1; HRMS (TOF) Calcd for C12H8ClF3N (M + H) 258.0297, found 258.0284.
6b: 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J= 4.8 Hz, IH), 7.86 (td, J= 7.6, 1.6 Hz, IH), 7.69 (s, 2H), 7.41-7.38 (m, IH), 7.34 (d, J = 6.8 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 154.70, 150.28, 142.11, 136.99, 135.95, 132.68 (q, J= 33.4 Hz), 127.53, 125.54 (q, J= 3.7 Hz), 125.05, .124.23, 123.81; IR (thin film) v 2924, 1385, 1317 cnT1; HRMS (TOF) Calcd for Ci2H7Cl2F3N (M + H) 291.9908, found 291.9896. EXAMPLE 15
Synthesis of Methyl 3,5-dichloro-4-(pyridine-2-yl)benzoate (7a)
Figure imgf000048_0001
In a 40 mL tube, methyl 4-(pyridine-2-yl)benzoate (0.3 mmol, 1 equiv) and CuCl2 (8.1 mg, 0.06 mmol, 20% equiv) were dissolved in 1 mL of Cl2CHCHCl2 under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rf = 0.24 in 2:1 hexane: ether), the title product was obtained as a yellow solid (68.5 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J = 4.8 Hz, IH), 8.07 (s, 2H), 7.84 (td, J = 8.0, 1.6 Hz, IH), 7.40-7.33 (m, 2H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.98, 155.09, 150.14, 142.62, 136.88, 135.34, 132.17, 129.48, 125.09, 123.64, 53.10; IR (thin film) v 2953, 1729, 1377, 1293, 1263 cm'1; HRMS (TOF) Calcd for Ci3HioCl2N02 (M + H) 282.0089, found 282.0081.
EXAMPLE 16
Synthesis of 2-(2,6-dichloro-3-fluorophenyl)pyridine (8a)
Figure imgf000048_0002
In a 40 mL tube, 2-(3-fluorophenyl)pyridine (0.3 mmol, 1 equiv) and CuCl2 (8.1 mg, 0.06 mmol, 20% equiv) were dissolved in 1 mL of Cl2CHCHCl2 under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rf = 0.30 in 2:1 hexane: ether), the title product was obtained as a colorless oil (66.1 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 4.8 Hz, IH), 7.83 (tt, J= 7.6, 1.8 Hz, IH), 7.40-7.32 (m, 3H),.7.17 (td, J= 8.4, 1.6 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 158.74, 156.26, 154.89, 150.13, 140.34, 136.88, 129.61, 129.57, 129.03, 128.95, 125.28, 123.59, 117.29, 117.06; IR (thin film) v 3065, 1584, 1450, 1239 cm"1 ; HRMS (TOF) Calcd for CnH7Cl2FN (M + H) 240.9940, found 241.9935.
EXAMPLE 17 Synthesis of 2-(2-chloro-6-methylphenyl)pyridine (9a)
Figure imgf000049_0001
In a 40 mL tube, 2-(6-methylphenyl)pyridine (0.3 mmol, 1 equiv) and CuCl2 (8.1 mg, 0.06 mmol, 20% equiv) were dissolved in 1 mL of CI2CHCHCI2 under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rf = 0.23 in 2:1 hexane: ether), the title product was obtained as a colorless oil (56.2 mg, 92%). 1H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 4.8 Hz, IH), 7.69 (td, J= 7.6, 1.6 Hz, IH), 7.32-7.29 (m, 2H), 1.26-1 Al (m, 2H), 2.09 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.86, 149.97, 139.53, 138.87, 136.63, 133.34, 129.32, 128.89, 127.22, 125.22, 122.64, 20.74; IR (thin film) v 1559, 1456 cm"1; HRMS (TOF) Calcd for Ci2Hi1ClN (M + H) 204.0580, found 204.0579.
EXAMPLE 18 Synthesis of 2-(2-chlorophenyl)-3-methylpyridine (10a)
Figure imgf000049_0002
In a 40 mL tube, 2-phenyl-3-methylpyridine (0.3 mmol, 1 equiv) and CuCl2 (8.1 mg, 0.06 mmol, 20% equiv) were dissolved in 1 mL of Cl2CHCHCl2 under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 130°C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rf = 0.19 in 2:1 hexane: ether), the title product was obtained as a colorless oil (55.6 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J= 4.8 Hz5 IH), 7.59 (d, J= 6.4 Hz, IH), 7.48-7.46 (m, IH), 7.36-7.31 (m, 3H), 7.24 (dd, J = 7.6, 4.8 Hz, IH), 2.17 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.49, 147.08, 139.87, 138.05, 133.08, 132.47, 130.71, 129.80, 129.67, 127.24, 123.20, 19.12; IR (thin film) v 2925, 1570, 1431 cm'1; HRMS (TOF) Calcd for Ci2Hi ,ClN (M + H) 204.0580, found 204.0571.
EXAMPLE 19 Synthesis of 2-(2,6-dichlorophenyl)quinoline (11 a)
Figure imgf000050_0001
In a 40 mL tube, 2-phenylquinoline (0.3 mmol, 1 equiv) and CuCl2 (8.1 mg, 0.06 mmol, 20% equiv) were dissolved in 1 mL of Cl2CHCHCl2 under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL Of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rf = 0.36 in 2:1 hexane: ether), the title product was obtained as a pale yellow oil (45.2 mg, 55%). 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J= 8.4 Hz, IH), 8.19 (d, J= 8.8 Hz, IH), 7.91 (d, J= 8.0 Hz, IH), 7.78 (td, J= 6.4, 1.2 Hz, IH), 7.62 (t, J= 8.0 Hz, IH), 7.45 (d, J= 8.0 Hz, 2H), 7.43 (s, IH), 7.34 (dd, J= 7.2, 2.0 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 157.76, 148.40, 139.98, 136.01, 132.03, 130.42, 130.22, 130.02, 130.01, 127.90, 127.52, 127.11, 123.1 1 ; IR (thin film) v 3059, 1598, 1504, 1436 cm"1; HRMS (TOF) Calcd for Ci5H10Cl2N (M + H) 274.0190, found 274.0180. EXAMPLE 20 Synthesis of 10-chlorobenzo[h]quinoline (12a)
Figure imgf000051_0001
In a 40 mL tube, benzo[h]quinoline (0.3 mmol, 1 equiv) and CuCl2 (8.1 mg, 0.06 mmol, 20% equiv) were dissolved in 1 mL of CbCHCHCl2 under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL Of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether (Rf = 0.39 in 2:1 hexane: ether), the title product was obtained as a yellow solid (57.7 mg, 90 %). 1H NMR (400 MHz3 CDCl3) δ 9.11 (dd, J = 4.0, 1.6 Hz, IH)3 8.17 (dd, J= 8.0, 1.2 Hz, IH), 7.83 (dd, J= 8.0, 1.2 Hz, 2H), 7.78 (d, J= 8.8 Hz5 IH), 7.69 (d, J = 8.8 Hz, IH), 7.54 (td, J = 7.2, 1.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 147.97, 146.82, 136.66, 136.00, 132.67, 131.87, 128.49, 128.02, 127.95, 127.90, 126.97, 122.06; IR (thin film) v 2926, 1557, 1418 cm"1; HRMS (TOF) Calcd for Ci3H9ClN (M + H) 214.0424, found 214.0432.
EXAMPLE 21 . Synthesis of 2-(3-chloronaphthalen-2-yl)pyridine (13a) and
2-(l,3-dichloronaphthalen-2-yl)pyridine (13b)
Figure imgf000051_0002
In a 40 mL tube, 2-(naphtalen-2-yl)pyridine (0.3 mmol, 1 equiv) and CuCl2 (8.1 mg, 0.06 mmol, 20% equiv) were dissolved in 1 mL of CI2CHCHCI2 under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2Sθ4 and concentrated under vacuum to furnish two products. After purification by column chromatography on silica gel with a gradient eluent of hexane and ether, 13a (Rf = 0.15 in 2: 1 hexane: ether) was obtained as a yellow solid (21.6 mg, 30%), and 13b (Rf = 0.20 in 2:1 hexane: ether) was obtained as a yellow solid (53.5 mg, 65%). 13a: 1H NMR (400 MHz, CDCl3) δ 8.77 (d, J= 4.8 Hz, IH), 8.08 (s, IH), 7.99 (s, IH), 7.87 (d, J = 8.0 Hz, IH), 7.82-7.78 (m, 2H), 7.71 (d, J = 8.0 Hz, IH), 7.55-7.48 (m, 2H), 7.33 (dd, J = 7.2, 4.8 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 157.26, 149.86, 137.38, 136.18, 133.95, 132.20, 131.40, 130.06, 128.69, 128.55, 127.66, 127.03, 126.88, 125.42, 122.77; IR (thin film) v 3055, 1592, 1475 cm'1; HRMS (TOF) Calcd for Ci5HnClN (M + H) 240.0580, found 240.0571.
13b: 1H NMR (400 MHz, CDCl3) δ 8.80 (d, J= 4.8 Hz, IH), 8.31 (d, J= 8.0 Hz, IH), 7.92 (s, IH), 7.85-7.79 (m, 2H), 7.63-7.56 (m, 2H), 7.39-7.35 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 156.63, 149.97, 136.72, 136.43, 134.23, 132.68, 131.28, 130.03, 128.32, 127.96, 127.64, 127.20, 125.60, 125.48, 123.28; IR (thin film) v 2923, 1590, 1489, cm"1; HRMS (TOF) Calcd for Ci5H10Cl2N (M + H) 274.0190, found 274.0188.
EXAMPLE 22
Synthesis of 2-(2~bromophenyl)pyridine (If) and 2-(2,6-dibromophenyl)pyridine (IF)
Figure imgf000052_0001
In a 20 mL tube, 2-phenylpyridine (46.5 mg, 0.3 mmol, 1 equiv) and Cu(OAc)2 (54.6 mg, 0.3 mmol, 1 equiv) were dissolved in 1 mL of Br2CHCHBr2 under atmospheric air. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Rf = 0.18 in 2:1 hexane: ether), If was obtained as a colorless oil (45.6 mg, 65%). A certain amount of di-brominated IP (Rf = 0.29 in 2:1 hexane: ether) was also obtained as a pale yellow oil (18.8 mg, 20%). If: 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 4.8 Hz, IH), 7.76 (td, J= 8.0, 2.0 Hz, IH), 7.67 (d, J= 7.6 Hz, IH), 7.59 (dd, J= 8.0, 1.2 Hz, IH), 7.53 (dd, J= 7.2, 1.2 Hz, IH), 7.39 (td, J= 7.2, 1.2 Hz, IH), 7.31-7.23 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 158.64, 149.73, 141.54, 136.14, 133.58, 131.72, 130.03, 127.85, 125.05, 122.73, 122.07; IR (thin film) v 1457 cm"1; HRMS (TOF) Calcd for CnH9BrN (M + H) 233.9918, found 233.9921.
IF: 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J= 4.8 Hz, IH), 7.82 (td, J= 8.0, 1.6 Hz, IH), 7.63 (d, J= 8.0 Hz, 2H), 7.37-7.30 (m, 2H), 7.13 (t, J= 8.0 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 158.80, 149.61, 141.88, 136.56, 131.95, 130.73, 124.68, 123.85, 123.15; IR (thin film) v 1419 cm'1; HRMS (TOF) Calcd for Ci ,H8Br2N (M + H) 311.9023, found 311.9023.
EXAMPLE 23
Synthesis of 2-(2-iodophenyl)pyridine (Ig) and 2-(2,6-diiodophenyl)pyridine (Ig')
Figure imgf000053_0001
In a 20 mL tube, 2-phenylpyridine (46.5 mg, 0.3 mmol, 1 equiv), Cu(OAc)2 (54.6 mg, 0.3 mmol, 1 equiv) and I2 (76.2 mg, 0.3 mmol, 1 equiv) were dissolved in 1 mL of C1CH2CH2C1 under atmospheric air. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1000C for 8 h. The reaction mixture was diluted with 20 mL of CH2CI2 and then treated with 5 mL of saturated Na2S2O3 aqueous solution and 20 mL of saturated Na2S aqueous solution sequentially. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Rf = 0.18 in 2:1 hexane: ether), Ig was obtained as a colorless oil (51.4 mg, 61%). A certain amount of di-iodinated Ig' (Rf = 0.27 in 2:1 hexane: ether)) was also obtained as a pale yellow oil (12.2 mg, 10%). Ig: 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J= 4.8 Hz, IH), 7.96 (d, J = 8.0 Hz, IH), 7.77 (td, J= 7.6, 1.6 Hz, IH), 7.50 (d, J= 7.2 Hz, IH), 7.47-7.41 (m, 2H), 7.30 (dd, J= 6.4, 4.8 Hz, IH), 7.08 (td, J = 6.4, 2.4 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 161.11, 149.57, 145.37, 140.07, 136.31, 130.59, 130.03, 128.58, 124.72, 122.83, 97.01; IR (thin film) v 3050, 1588, 1456 cm"1; HRMS (TOF) Calcd for C1H9IN (M + H) 281.9780, found 281.9792. Ig': 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 4.8 Hz, IH), 7.82 (t, J = 7.6 Hz, IH), 7.41 (d, J = 8.0 Hz, 2H), 7.36-7.33 (m, 2H)5 7.28 (t, J = 8.0 Hz, IH); 13C NMR (100 MHz, CDCl3) 5 155.85, 149.99, 138.76, 136.72, 134.95, 130.17, 128.46, 125.34, 123.29; IR (thin film) v 1594, 1559, 1428, 1192 cm'1; HRMS (TOF) Calcd for CnH9I2N (M + H) 407.8746, found 407.8741.
EXAMPLE 24 Synthesis of 2-(pyridine-2-yl)benzonitrile (Ih)
Figure imgf000054_0001
Method 1: In a 20 mL tube, 2-phenylpyridine (46.5 mg, 0.3 mmol, 1 equiv), Cu(O Ac)2 (54.6 mg, 0.3 mmol, 1 equiv) and TMS-CN (59.5 mg, 0.6 mmol, 2 equiv) were dissolved in 1 mL of MeCN under atmospheric air. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cb and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2Sθ4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Rf = 0.23 in 1:2 hexane: ether) to give the title product as a colorless oil (22.7 mg, 42%). 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 4.8 Hz, IH), 7.87-7.83 (m, 2H), 7.80 (td, J= 8.4, 1.2 Hz, 2H), 7.70 (td, J= 8.0, 1.2 Hz, IH), 7.51 (td, J = 8.0, 1.2 Hz, IH), 7.36 (ddd, J = 7.6, 4.8, 1.2 Hz, IH); 13CNMR (100 MHz, CDCl3) δ 155.56, 150.30, 143.81, 137.19, 134.47, 133.19, 130.31, 129.10, 123.69, 123.59, 119.05, 111.37; IR (thin film) v 2225, 1586 cm0; HRMS (TOF) Calcd for C12H9N2 (M + H) 181.0766, found 181.0762. Method 2: In a 20 mL tube, 2-phenylpyridine (46.5 mg, 0.3 mmol, 1 equiv), and Cu(OAc)2 (54.6 mg, 0.3 mmol, 1 equiv) were dissolved in 1 mL Of MeNO2 under oxygen. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 130°C for 24 h. The reaction mixture was diluted with 20 mL Of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice .with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Rf = 0.23 in 1:2 hexane: ether) to give the title product as a colorless oil (36.2 mg, 67%).
EXAMPLE 25 Synthesis of N-(2-(pyridine-2-yl)phenyl)p-toluenesulfonamide (Ii)
Figure imgf000055_0001
In a 20 rnL tube, 2-phenylpyridine (46.5 mg, 0.3 mmol, 1 equiv), Cu(OAc)2 (54.6 mg, 0.3 mmol, 1 equiv) and/>-toluenesulfonamide (103.0 mg, 0.6 mmol, 2 equiv) were dissolved in 1 mL of MeCN under atmospheric air. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Rf = 0.34 in 1:2 hexane: ether) to give the title product as a white solid (71.9 mg, 74 %). 1H-NMR (400 MHz, CDCl3) δ 8.61 (d, J = 4.4 Hz, IH), 7.73-7.69 (m, 2H), 7.53 (d, J= 8.0 Hz, IH), 7.41-7.33 (m, 4H), 7.26-7.24 (m, 2H), 7.16 (t, J= 7.6 Hz, IH), 6.97 (d, J= 8.4 Hz, 2H)5 2.28 (ss 3H); 13C NMR (100 MHz. CDCl3) δ 157.45, 147.74, 143.25, 137.76, 137.16, 136.74, 130.50, 129.46, 128.82, 127.77, 127.09, 124.98, 123.74, 122.58, 122.39, 21.76; IR (thin film) v 1338, 1162 cm"1; HRMS (TOF) Calcd for Ci8HnN2O2S (M + H) 325.1011, found 325.1019.
EXAMPLE 26 Synthesis of 4-(2-(pyridine-2-yl)phenoxy)benzonitrile (Ij)
Figure imgf000055_0002
In a 20 mL tube, 2-phenylpyridine (46.5 mg, 0.3 mmol, 1 equiv), Cu(OAc)2 (54.6 mg, 0.3 mmol, 1 equiv) and 4-cyanophenol (71.5, mg, 1.2 mmol, 2 equiv) were dissolved in 1 mL of MeCN under atmospheric air. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Rf = 0.18 in 1:1 hexane: ether) to give the title product as a white solid (28.6 mg, 35 %). 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 4.8 Hz, IH)5 7.91 (d, J= 7.6 Hz, IH), 7.67-7.60 (m, 2H), 7.49 (d, J= 8.0 Hz, 2H), 7.45 (d, J = 7.6 Hz, IH), 7.39 (t, J= 7.6 Hz, IH), 7.19-7.16 (m, IH)5 7.11 (d, J= 8.0 Hz, IH)5 6.91 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz5 CDCl3) δ 161.76, 154.87, 151.91, 150.08, 136.43, 134.37, 133.54, 132.20, 130.83, 126.46, 124.69, 122.65, 122.07, 119.14, 117.60, 105.85; IR (thin film) v 2225, 1489, 1236 cm"1; HRMS (TOF) Calcd for Ci8Hi2N2O (M + H) 272.0950, found 272.0954.
EXAMPLE 27 Synthesis of 2-(2-(phenylthio)phenyl)pyridine (Ik)
Figure imgf000056_0001
In a 20 mL tube, 2-phenylpyridine (46.5 mg, 0.3 mmol, 1 equiv), Cu(OAc)2 (54.6 mg, 0.3 mmol, 1 equiv) and benzenethiol (66.1 mg, 0.6 mmol, 2 equiv) were dissolved in 1 mL of DMSO under atmospheric air. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Rf = 0.18 in 2:1 hexane: ether) give the title product as a yellow solid (31.6 mg, 40%). 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J= 4.8 Hz, IH), 7.73 (td, J= 7.6, 1.2 Hz, IH), 7.58 (d, J= 8.0 Hz, IH)5 7.53 (dd, J= 7.6, 1.2 Hz, IH), 7.33- 7.22 (m, 9 H); 13C NMR (100 MHz, CDCl3) δ 158.57, 149.38, 141.50, 136.28, 135.86, 135.77, 132.49, 131.64, 130.67, 129.51, 129.28, 127.63, 127.03, 124.56, 122.47; IR (thin film) v 3055, 1582 cm"1; HRMS (TOF) Calcd for Ci7Hi4NS (M + H) 264.0847, found 264.0839. EXAMPLE 28
Synthesis of 2-(2-(methylthio)phenyl)pyridine (11) and 2-(2,6-bis(methylthio)phenyl)pyridine (H')
Figure imgf000057_0001
In a 20 mL tube, 2-phenylpyridine (46.5 mg, 0.3 mmol, 1 equiv), Cu(OAc)2 (54.6 mg, 0.3 mmol, 1 equiv) and CH3SSCH3 (56.5 mg, 0.6 mmol, 2 equiv) were dissolved in 1 mL of DMSO under atmospheric air. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 24 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Rf = 0.13 in 2:1 hexane: ether) to give the product 11 as a pale yellow oil (30.8 mg, 51%). A certain amount of di-substitued product 11' (Rf = 0.20 in 1:1 hexane: ether) was also obtained as yellow oil (14.8 mg, 20%). 11: 1H NMR (400 MHz, CDCl3) δ 8.72 (d, J= 4.8 Hz, IH), 7.76 (t, J= 7.6 Hz, IH), 7.56 (d, J = 8.0 Hz, IH), 7.43 (d, J = 7.6 Hz, IH), 7.40-7.33 (m, 2H), 7.29-7.22 (m, 2H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.74, 149.47, 139.89, 137.66, 136.44, 130.24, 129.19, 126.24, 125.19, 124.48, 122.48, 16.72; IR (thin film) v 2919, 1583, 1457 cm"1; HRMS (TOF) Calcd for C12Hi2NS (M+ H) 202.0690,' found 202.0696. 11': 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J= 4.8 Hz, IH), 7.80 (td, J= 7.6, 1.6 Hz, IH), 7.39-7.31 (m, 3H), 7.10 (d, J = 8.0, 2H), 2.35 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 157.32, 150.32, 138.82, 137.94, 136.75, 129.35, 125.92, 123.13, 122.14, 16.42; IR (thin film) v 1558 cm"1; HRMS (TOF) Calcd for Ci3Hi4NS2 (M+ H) 248.0568, found 248.0563. EXAMPLE 29 Preparation of Substrate 14
Figure imgf000058_0001
To the solution of 2-(2-bromophenyl)ρyridine (70.0 mg, 0.3 mmol, lequiv) in 5 mL of dry ether, n-Butyl lithium (0.37 mL of 1.6M in hexane, 0.6 mmol, 2 equiv) was added dropwise at -400C under nitrogen atmosphere. After stirring for 30 min, the reaction mixture was quenched with 0.5 mL of D2O at the same temperature and continued stirring for half an hour. The reaction mixture was diluted with 20 mL of ethyl acetate and washed with 20 mL of brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel (Rf = 0.30 in 2:1 hexane: ether) to give the ortho-duetero compound 14 as a clear liquid (42.0 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 8.70 (d, J= 4.8 Hz, IH), 7.99 (d, J= 8.0 Hz, IH), 7.78-7.72 (m, 2H), 7.50-7.47 (m, 2H), 7.42 (t, J = 7.6 Hz, IH), 7.22-7.19 (m, IH); 13C NMR (100 MHz, CDCl3) δ 157.79, 150.02, 139.66, 137.08, 129.29, 129.09, 128.97, 127.22, 122.43, 120.91; IR (thin film) v 3057, 1586, 1458 cm'1; HRMS (TOF) Calcd for CnH9DN (M + H) 157.0876, found 157.0882.
EXAMPLE 30 Bromination of Substrate 14
Figure imgf000058_0002
1 : 1
In a 20 mL tube, substrate 14 (31.2 mg, 0.2 mmol, 1 equiv) and Cu(OAc)2 (36.4 mg, 0.2 mmol, 1 equiv) were dissolved in 1 mL of Br2CHCHBr2 under atmospheric air. The tube was sealed with a Teflon lined cap, and the reaction mixture was stirred at 1300C for 5 h. The reaction mixture was diluted with 20 mL of CH2Cl2 and then treated with 10 mL of saturated Na2S aqueous solution. The mixture was filtered through a pad of Celite, and the filtrate was washed twice with brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the brominated product. The 1H NMR analysis showed that the conversion was 30% and the ratio of ortho-proton product to ort/zo-deuterium product is 1:1 (compared with the standard 1H NMR spectrum of unlahelled 2-(2-bromophenyl)pyridine, the integration of the peak at 7.53 ppm was 0.5 instead of 1).
INCORPORATION BY REFERENCE
All of the U.S. patents and U.S. patent application publications cited herein are hereby incorporated by reference.
EQUIVALENTS
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intented to be encompassed by the following claims.

Claims

We claim:
1. A method of functionalizing an aryl C-H bond as represented by Scheme A, comprising the step of combining an arylpyridine with a transition metal, a ligand, an oxidant, and NuX:
Scheme A
Figure imgf000060_0001
wherein
R represents independently for each occurrence substituted or unsubstituted alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, arylalkyl, cyano, halogen, hydroxyl, alkoxyl, aryloxy, arylalkyloxy, amino, alkylamino, arylamino, arylalkylamino, sulfhydryl, alkylthio, arylthio, arylalkylthio, nitro, azido, alkylseleno, formyl, acyl, carboxy, silyl, silyloxy, (alkyloxy)carbonyl, (aryloxy)carbonyl, (arylalkyloxy)carbonyl, (alkylamino)carbonyl, (arylamino)carbonyl, (arylalkylamino)carbonyl, alkylsulfonyl, or arylsulfonyl;
R' represents independently for each occurrence, substituted or unsubstituted alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, arylalkyl, cyano, halogen, hydroxyl, alkoxyl, aryloxy, arylalkyloxy, amino, alkylamino, arylamino, arylalkylamino, sulfhydryl, alkylthio, arylthio, arylalkylthio, nitro, azido, alkylseleno, formyl, acyl, carboxy, silyl, silyloxy, (alkyloxy)carbonyl, (aryloxy)carbonyl, (arylalkyloxy)carbonyl, (alkylamino)carbonyl, (arylamino)carbonyl, (arylalkylamino)carbonyl, alkylsulfonyl. or arylsulfonyl;
any two instances of R may be bonded together to form a ring that may be optionally substituted;
any two instances of R' may be bonded together to form a ring that may be optionally substituted;
an instance of R and an instance of R' may be bonded together to form a ring that may be optionally substituted;
M represents a transition metal; L independently for each occurrence represents a ligand;
Nu represents an atom or molecule comprising a charged or uncharged carbon, nitrogen, oxygen, sulfur, chlorine, bromine, iodine, or phosphorus;
X is an electron pair or a cation;
m represents an integer in the range 0 to 4 inclusive;
n represents an integer in the range 0 to (4-q) inclusive; and
q is 0 or 1.
2. The method of claim 1, wherein said M is selected from the group consisting of Rh, Ru, Pd, Pt, and Cu.
3. The method of claim 1, wherein said M is Cu.
4. The method of claim 1, wherein said M is present in a stoichiometric amount relative to the arylpyridine.
5. The method of claim 1, wherein said M is present in less than or equal to 20 mol% relative to the arylpyridine.
6. The method of claim 1, wherein said M is present in less than or equal to 10 mol% relative to the arylpyridine.
7. The method of claim 1, wherein L is independently selected form the group consisting of OAc, Cl, F, OH, Br, (HO)PO3, NO3, Se, SO4, CF3CO2, ClO4, 2-pyrazine carboxylate, cyclohexanebutyrate, 2-ethylhexanoate, 3,5-diisopropylsalicylate, and acetylacetonate.
8. The method of claim 1, wherein L is independently selected from the group consisting of acetate, chlorine, and fluorine.
9. The method of claim 1, wherein L is acetate.
10. The method of claim 1, wherein L is chlorine.
11. The method of claim 1, wherein L is fluorine.
12. The method of claim 1, wherein said oxidant is selected from the group consisting of peroxides, hydroperoxides, hyperperoxides, hypervalent acyloxy iodides, transition metal acyloxy complexes, dihalogens, O2, air, and combinations thereof.
13. The method of claim 1, wherein said oxidant is O2.
14. The method of claim 1, wherein said oxidant is air.
15. The method of claim 1, wherein Nu comprises an amino functionality, a hydroxyl functionality, an acetoxy functionality, a halogen functionality, a cyano functionality, a nitro functionality, a thiol functionality, an alkylthio functionality, an acyl functionality, an acyloxy functionality, or an alkoxy functionality.
16. The method of claim 1, wherein NuX is selected from, the group consisting of I2, TMSCN, TsNH2, /J-CN-PhOH, PhSH, MeSSMe, H2O, Br2CHCHBr2, Cl2CHCHCl2, MeNO2, PhCH2NH2, anilines, CF3OH, and cyclopropyl alcohols.
17. The method of claim 1, wherein M is selected from the group consisting of Rh, Ru, Pd, Pt, and Cu; L is independently selected from the group consisting of OAc, Cl, F, OH,
Br, (OH)PO4, NO3, Se, SO4, CF3CO2, ClO4, 2-pyrazine carboxylate, cyclohexanebutyrate, 2-ethylhexanoate. 3,5-diisopropylsalicylate, and acetylacetonate; said oxidant is selected from the group consisting of peroxides, hydroperoxides, hyperperoxides, hypervalent acyloxy iodides, transition metal acyloxy complexes, dihalogens, O2, air, and combinations thereof; and Nu comprises an amino functionality, a hydroxyl functionality, an acetoxy functionality, a halogen functionality, a cyano functionality, a nitro functionality, a thiol functionality, an alkylthio functionality, an acyl functionality, an acyloxy functionality, or an alkoxy functionality.
18. The method of claim 1, wherein M is Cu; L is independently selected from the group consisting of acetate, chlorine, and fluorine; said oxidant is O2 or air; and Nu comprises an amino functionality, a hydroxyl functionality, an acetoxy functionality, a halogen functionality, a cyano functionality, a nitro functionality, a thiol functionality, an alkylthio functionality, an acyl functionality, an acyloxy functionality, or an alkoxy functionality.
19. The method of claim 1, wherein M is Cu; L is acetate or fluorine; said oxidant is O2 or air; and NuX is H2O.
20. The method of claim 1., wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is selected from the group consisting of HOAc-Ac2O, Br2CHCHBr2, I2, TMSCN, MeNO2, TsNH2, /7-CN-PhOH, PhSH, MeSSMe, PhCH2NH2, anilines, CF3OH, and cyclopropyl alcohols.
21. The method of claim 1, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is HOAc-Ac2O.
22. The method of claim 1, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is Br2CHCHBr2.
23. The method of claim 1, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is I2.
24. The method of claim 1, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is TMSCN.
25. The method of claim 1, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is MeNO2.
26. The method of claim 1, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is TsNH2.
27. The method of claim 1, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is p-CN-PhOH.
28. The method of claim 1, wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is PhSH.
29. The method of claim I5 wherein M is Cu; L is acetate; said oxidant is O2 or air; and NuX is MeSSMe.
30. The method of claim 1, wherein M is Cu; L is chlorine; said oxidant is O2 or air; and NuX is Cl2CHCHCl2.
31. The method of claim 1, wherein M is Cu; L is chlorine; said oxidant is O2 or air; and NuX is PhCH2NH2.
32. The method of claim 1, wherein M is Cu; L is chlorine; said oxidant is O2 or air; and NuX is an aniline.
33. The method of claim 1, wherein M is Cu; L is chlorine; said oxidant is O2 or air; and NuX is CF3OH.
34. The method of claim 1, wherein M is Cu; L is chlorine; said oxidant is O2 or air; and NuX is a cyclopropyl alcohol.
35. The method of any one of claims 1-34, wherein m is 0; and n is 0.
36. A compound represented by formula I:
Figure imgf000064_0001
I wherein
R represents independently for each occurrence substituted or unsubstituted alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, arylalkyl, cyano, halogen, hydroxyl, alkoxyl, aryloxy, arylalkyloxy, amino, alkylamino, arylamino, arylalkylamino, sulihydryl, alkylthio, arylthio, arylalkylthio, nitro, azido, alkylseleno, formyl, acyl, carboxy, silyl, silyloxy, (alkyloxy)carbonyl, (aryloxy)carbonyl, (arylalkyloxy)carbonyi, (alkylamino)carbonyl, (arylamino)carbonyl, (arylalkylamino)carbonyl, alkylsulfonyl, or arylsulfonyl;
R' represents independently for each occurrence, substituted or unsubstituted alkyl, cycloalkyl, alkenyl, aryl, heteroaryl, arylalkyl, cyano, halogen, hydroxyl, alkoxyl, aryloxy, arylalkyloxy, amino, alkylamino, arylamino, arylalkylamino, sulfhydryl, alkylthio, arylthio, arylalkylthio, nitro, azido, alkylseleno, formyl, acyl, carboxy, silyl, silyloxy, (alkyloxy)carbonyl, (aryloxy)carbonyl, (arylalkyloxy)carbonyl, (alkylamino)carbonyl, (arylamino)carbonyl, (arylalkylamino)carbonyl, alkylsulfonyl, or arylsulfonyl; any two instances of R may be bonded together to form a ring that may be optionally substituted;
any two instances of R' may be bonded together to form a ring that may be optionally substituted;
an instance of R and an instance of R' may be bonded together to form a ring that may be optionally substituted;
X represents independently for each occurrence a group comprising an atom selected from the group consisting of carbon, nitrogen, oxygen, sulfur, chlorine, bromine, iodine, and phosphorus;
m represents an integer in the range 0 to 4 inclusive;
n represents an integer in the range 0 to (4-q) inclusive; and
q is 0 or 1.
37. The compound of claim 36, wherein X is acetoxy, hydroxyl, alkoxy, or aryloxy.
38. The compound of claim 36, wherein X is selected from the group consisting of Cl, Br, and I.
39. The compound of claim 36, wherein X is selected from the group consisting of SPh and SMe.
40. The compound of claim 36, wherein X is an amine.
41. The compound of claim 36, wherein X is cyano.
42. The compound of claim 36, wherein X is a radiohalide.
43. The compound of claim 36, wherein n is 1; and R is /?-OMe, p-CH=CH2, p-Me, p-
Figure imgf000065_0001
44. The compound of claim 36, wherein m is 1; and R' is rø-Me.
45. The compound of any one of claims 36-44, wherein m is 0; and n is 0.
6. A compound selected from the group consisting of:
Figure imgf000066_0001
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CN101812022A (en) * 2010-04-20 2010-08-25 上海大学 Ortho-monovinylphenyl substituted compound of aryl pyrimidine and synthesizing method thereof
JP2012126718A (en) * 2010-11-25 2012-07-05 Tosoh Corp 2,2'-substituted biphenyl derivative, method for producing the same, and organic electroluminescent device comprising the same as constituent
CN103288711A (en) * 2013-05-30 2013-09-11 天津大学 Preparation method of 3-hydroxy-2-alkoxy-3-phenyl-isoindol-1(2H)-ketone derivatives
WO2013188771A2 (en) * 2012-06-15 2013-12-19 Georgetown University Catalytic c-h bond activation for the synthesis of ethers and thioethers

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Title
DATABASE HCAPLUS [Online] 05 December 2002 Database accession no. (138:17951) *
DATABASE HCAPLUS [Online] 1980 Database accession no. (94:16846h) *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101812022A (en) * 2010-04-20 2010-08-25 上海大学 Ortho-monovinylphenyl substituted compound of aryl pyrimidine and synthesizing method thereof
JP2012126718A (en) * 2010-11-25 2012-07-05 Tosoh Corp 2,2'-substituted biphenyl derivative, method for producing the same, and organic electroluminescent device comprising the same as constituent
WO2013188771A2 (en) * 2012-06-15 2013-12-19 Georgetown University Catalytic c-h bond activation for the synthesis of ethers and thioethers
WO2013188771A3 (en) * 2012-06-15 2014-02-20 Georgetown University Catalytic c-h bond activation
US9416080B2 (en) 2012-06-15 2016-08-16 Georgetown University Catalytic C—H bond activation
CN103288711A (en) * 2013-05-30 2013-09-11 天津大学 Preparation method of 3-hydroxy-2-alkoxy-3-phenyl-isoindol-1(2H)-ketone derivatives
CN103288711B (en) * 2013-05-30 2015-07-29 天津大学 The preparation method of 3-hydroxyl-2-alkoxyl group-3-phenyl isoindole-1 (2H)-one analog derivative

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