WO2015168368A1 - Réactifs de fluoroalkylation et leurs utilisations - Google Patents

Réactifs de fluoroalkylation et leurs utilisations Download PDF

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WO2015168368A1
WO2015168368A1 PCT/US2015/028446 US2015028446W WO2015168368A1 WO 2015168368 A1 WO2015168368 A1 WO 2015168368A1 US 2015028446 W US2015028446 W US 2015028446W WO 2015168368 A1 WO2015168368 A1 WO 2015168368A1
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substituted
unsubstituted
compound
certain embodiments
formula
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Tobias Ritter
Filippo SADOJEVICH
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President And Fellows Of Harvard College
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
    • C07C17/263—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions
    • C07C17/266—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by condensation reactions of hydrocarbons and halogenated hydrocarbons
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/26—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton
    • C07C17/32—Preparation of halogenated hydrocarbons by reactions involving an increase in the number of carbon atoms in the skeleton by introduction of halogenated alkyl groups into ring compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/15—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/06—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/02—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to acyclic carbon atoms
    • C07C317/04—Sulfones; Sulfoxides having sulfone or sulfoxide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms

Definitions

  • Fluorinated organic compounds are used as pharmaceuticals and
  • agrochemicals in part due to their favorable pharmacological properties such as increased metabolic stability (see, for example, Miiller et al., Science 2007, 317, 1881-1886; and Jeschke, P. ChemBioChem 2004, 5, 570-589).
  • small fluoroalkyl groups such as the -CF 3 and -CF 2 CF 3 groups are widely used in materials and medicinal chemistry because of their unique chemical and electronic properties. Fluorinated organic compounds also find applications as tracers in positron emission tomography using the isotope 18 F (Lasne, et al. In Contrast Agents II, 2002; Vol. 222, pp 201-258).
  • fluorine has the highest electronegativity, the highest oxidation potential, and the smallest anionic radius of all elements, each of which complicates carbon-fluorine bond formation when compared to other carbon-heteroatom bond formations (see, for example, Chambers, R.D., Fluorine in organic chemistry. Oxford: New York, 2004; and Furuya et al. Curr. Opin. Drug Discov. Devel. 2008, 11, 803-819). Based on these challenges to the formation of carbon-fluorine bonds, numerous chemical methods have been developed to introduce fluoroalkyl groups. Examples of reagents developed for nucleophilic
  • trifluoromethylation examples include the Ruppert Prakash reagent (TMSCF 3 ) and trifluoromethylator reagents (which generate an active "CF Cu" species), while reagents developed for radical trifluoromethylation include the Langlois (NaSO 2 CF ) and the Baran reagents (Zn(SO 2 CF ) 2 ).
  • exemplary electrophilic trifluoromethylation reagents include the Umemoto and Togni reagents.
  • Fluoroalkyl iodides in particular trifluoromethyl iodide, are inexpensive sources of fluoroalkyl fragments that are useful functional groups for a variety of
  • the present invention provides compounds, reagents, systems, reaction mixtures, compositions, kits, and methods for fluoroalkylating an organic compound.
  • the present disclosure is at least partially based on the discovery that Lewis base complexes of fluoroalkyl iodides possess advantageous properties when compared to free fluoroalkyl iodides.
  • Various Lewis bases are disclosed herein for forming adducts with the fluoroalkyl iodides; these include, but are not limited to, amine bases, guanidine bases, sulfides, sulfoxides, heterocycles, and heteroarenes.
  • halogen bonded complexes of fluoroalkyl iodides possess comparable reactivity to the parent fluoroalkyl iodides, enabling them to serve as replacements for these inconvenient and difficult- to-handle reagents in a wide variety of applications.
  • R 1 is unsubstituted C 1-3 fluoroalkyl
  • each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
  • y is 1 or 2.
  • Exemplary compounds of Formula (I) include compounds of formula:
  • the present invention provides methods of fluoroalkylating an organic compound, the method comprising contacting a compound of Formula (I) with an organic compound of formula:
  • R 7', R 8°, R 9", R 10 , R 11 , R 12 , and R 1 1 3 J are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R 7 , R 11 or R 13 groups are joined to form a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring; under suitable conditions, to form a fluoroalkylated organic compound of formula:
  • the present invention further provides methods of preparing a compound of Formula (I), reaction mixtures comprising a compound of Formula (I), compositions comprising a compound D and a fluoroalkyl iodide of formula I-R 1 , and kits comprising a compound of Formula (I).
  • Figure 1 shows DFT calculation results demonstrating the orbital character of the three iodine lone pairs of trifluoromethyl iodide (CF 3 I). Shown are the two p-type and the s-type iodine lone pairs in CF 3 I.
  • Figure 2 shows DFT calculation results depicting the natural bond orbitals
  • Figure 3 shows an electrostatic potential map of trifluoromethyl iodide (CF 3 I) in Hartrees at the 0.001 electrons Bohr- isodensity surface highlighting the ⁇ -hole region.
  • Figures 4A-4E show the optimized conformation for several key compounds and their trifluoromethyl iodide (CF 3 I) adducts as determined using DFT calculations (for details of calculations, see Examples).
  • Figure 4A shows the optimized conformation of trifluoromethyl iodide (CF 3 I).
  • Figure 4B shows the optimized conformation of
  • FIG. 4C shows the optimized conformation of 1,1,3,3-tetramethylguanidine (TMG).
  • Figure 4D shows the optimized conformation of the bis-trifluoromethyl iodide (CF 3 I) adduct of tetramethylethylenediamine (TMEDA).
  • Figure 4E shows the optimized conformation of the trifluoromethyl iodide (CF 3 I) adduct of 1,1,3,3- tetramethylguanidine (TMG).
  • Figure 5 shows the X-ray structure of TMEDA » 2CF I, the experimentally measured and calculated N-I distance, and the calculated interaction energy per CF I molecule.
  • Figure 6 shows the calculated interaction energy and N-I distance for
  • Figures 7A-7B show the release of CG3I from various halogen bonded adducts.
  • Figure 7 A shows the weight loss (mol ) for CF 3 I-TMG and CF 3 I-2DMSO.
  • Figure 7B shows the weight loss (mol ) for CF 3 I-3CH 3 CN, CF 3 I-3CHC1 3 and CF 3 I-3TMG and CF 3 I-3DMSO.
  • Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Racemic refers to a compound in which the percent by weight of one enantiomer is equal to the percent by weight of the other enantiomer.
  • an enantiomerically enriched enantiomer means a compound having greater than 50% by weight of one enantiomer relative to the other enantiomer, e.g., at least 75% by weight, or at least 80% by weight.
  • the enrichment can be much greater than 80% by weight, providing a "substantially enantiomerically enriched," "substantially
  • enantiomerically pure or a "substantially non-racemic” compound, which refers to a compound with at least 85% by weight of one enantiomer relative to other enantiomer, e.g., at least 90% by weight, or at least 95% by weight.
  • Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be prepared by asymmetric syntheses. See, for example, Jacques, et ah, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S.H., et ah, Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).
  • structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19 F with 18 F, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of the disclosure.
  • Such compounds are useful, for example, as analytical tools or probes in biological assays.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C ⁇ o alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C ⁇ alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“Ci_6 alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms ("Q-5 alkyl").
  • an alkyl group has 1 to 4 carbon atoms ("C ⁇ alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“Ci_ 3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms ("C ⁇ alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“Q alkyl”). In certain embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2 -6 alkyl”).
  • Ci_6 alkyl groups include methyl (CO, ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), and n-hexyl (C 6 ).
  • alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ) and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents. In certain embodiments, the alkyl group is an unsubstituted C ⁇ o alkyl (e.g., -CH 3 ). In certain embodiments, the alkyl group is a substituted C o alkyl.
  • haloalkyl is a substituted alkyl group as described herein wherein one or more of the hydrogen atoms are independently replaced by halogen, e.g., fluoro, bromo, chloro, or iodo.
  • the haloalkyl moiety has 1 to 8 carbon atoms ("Ci- 8 haloalkyl”).
  • the haloalkyl moiety has 1 to 6 carbon atoms ("Ci-6 haloalkyl”).
  • the haloalkyl moiety has 1 to 4 carbon atoms ("Ci ⁇ haloalkyl").
  • the haloalkyl moiety has 1 to 3 carbon atoms ("Ci- 3 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("Ci- 2 haloalkyl"). Examples of haloalkyl groups include -CF 3 , -CF 2 CF 3 , -CF 2 CF 2 CF 3 , - CC1 3 , -CFCI2, -CF2CI, and the like.
  • fluoroalkyl refers to a haloalkyl group, as defined herein, wherein one or more of the hydrogen atoms are independently replaced by fluoro.
  • a “substituted fluoroalkyl group” refers to an alkyl group as defined herein comprising fluoro substituent(s) and one or more additional different substituent(s).
  • An “unsubstituted fluoroalkyl group” refers to an alkyl group as defined herein comprising only fluoro substituent(s).
  • Perhaloalkyl is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by halogen, e.g., fluoro, bromo, chloro, or iodo. In certain embodiments, all of the haloalkyl hydrogen atoms are replaced with fluoro to provide a perfluoroalkyl group. In certain embodiments, all of the haloalkyl hydrogen atoms are replaced with chloro to provide a "perchloro alkyl" group.
  • halogen e.g., fluoro, bromo, chloro, or iodo.
  • all of the haloalkyl hydrogen atoms are replaced with fluoro to provide a perfluoroalkyl group.
  • all of the haloalkyl hydrogen atoms are replaced with chloro to provide a "perchloro alkyl" group.
  • heteroalkyl refers to an alkyl group as described herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms within the parent chain ("heteroCi-io alkyl").
  • a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4
  • heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4
  • heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4
  • heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms within the parent chain ("heteroCi-6 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroCi-s alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms within the parent chain (“heteroCi ⁇ alkyl").
  • a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain ("heteroCi-s alkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain ("heteroC ⁇ alkyl"). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 2 -6 alkyl"). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted
  • heteroalkyl or substituted (a "substituted heteroalkyl") with one or more substituents.
  • the heteroalkyl group is an unsubstituted heteroCi-io alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-io alkyl.
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more double bonds (e.g., 1, 2, 3, or 4 double bonds).
  • an alkenyl group has 2 to 9 carbon atoms ("C2-9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms ("C 2 -8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms (“C 2 _ 7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C 2 -6 alkenyl”).
  • an alkenyl group has 2 to 5 carbon atoms ("C 2 _5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2 _4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2 _3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms ("C 2 alkenyl”).
  • the one or more carbon- carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl).
  • C 2 - alkenyl groups examples include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1- butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C 2 _6 alkenyl groups include the aforementioned C 2 ⁇ alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (Cg), octatrienyl (Cg), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a
  • substituted alkenyl with one or more substituents.
  • the alkenyl group is an unsubstituted C 2 _io alkenyl.
  • the alkenyl group is a substituted C 2 _io alkenyl.
  • heteroalkenyl refers to an alkenyl group as described herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms within the parent chain (“heteroC ⁇ io alkenyl").
  • a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms within the parent chain ("heteroC 2 _9 alkenyl"). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms within the parent chain (“heteroC 2 _g alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms within the parent chain (“heteroC 2 _7 alkenyl").
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms within the parent chain ("heteroC 2 _6 alkenyl"). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2
  • heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and lor 2 heteroatoms within the parent chain ("heteroC 2 ⁇ alkenyl”).
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain ("heteroC 2 -3 alkenyl”).
  • a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2 _6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is
  • the heteroalkenyl group is an unsubstituted heteroC ⁇ io alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC ⁇ io alkenyl.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more triple bonds (e.g., 1, 2, 3, or 4 triple bonds) and optionally one or more double bonds (e.g., 1, 2, 3, or 4 double bonds) ("C ⁇ io alkynyl").
  • an alkynyl group has 2 to 9 carbon atoms (“C 2 _9 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C 2 _g alkynyl”).
  • an alkynyl group has 2 to 7 carbon atoms ("C 2 _ 7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2 _6 alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2 _5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2 ⁇ alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2 _ 3 alkynyl”). In certain embodiments, an alkynyl group has 2 carbon atoms ("C 2 alkynyl”).
  • the one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).
  • Examples of C 2 _ alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like.
  • C 2 _6 alkenyl groups include the aforementioned C 2 ⁇ alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (Cg), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C 2 _ 10 alkynyl. In certain embodiments, the alkynyl group is a substituted C 2 _ 10 alkynyl.
  • heteroalkynyl refers to an alkynyl group as described herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain.
  • a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms within the parent chain (“heteroC 2 -io alkynyl").
  • a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms within the parent chain ("heteroC 2 -9 alkynyl"). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms within the parent chain ("heteroC 2 -8 alkynyl"). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms within the parent chain (“heteroC 2 - 7 alkynyl").
  • a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms within the parent chain ("heteroC 2 -6 alkynyl"). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC 2 -5 alkynyl"). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain (“heteroC 2 ⁇ alkynyl").
  • a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain ("heteroC 2 -3 alkynyl"). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroC 2 -6 alkynyl"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents.
  • the heteroalkynyl group is an unsubstituted heteroC 2 -io alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC 2 -io alkynyl.
  • carbocyclyl refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C3_ 14 carbocyclyl") and zero heteroatoms in the non-aromatic ring system.
  • a carbocyclyl group has 3 to 10 ring carbon atoms ('3 ⁇ 4_ 10 carbocyclyl”).
  • a carbocyclyl group has 3 to 9 ring carbon atoms (“C3_9 carbocyclyl”).
  • a carbocyclyl group has 3 to 8 ring carbon atoms (“C3_8 carbocyclyl”).
  • a carbocyclyl group has 3 to 7 ring carbon atoms ('3 ⁇ 4_ 7 carbocyclyl"). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ('3 ⁇ 4_ 6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("Cs-io carbocyclyl").
  • Exemplary C 3 _ 6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C 3 _g carbocyclyl groups include, without limitation, the aforementioned C 3 _ 6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (Cg), cyclooctenyl (Cg), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (Cg), and the like.
  • Exemplary C 3 _ 10 carbocyclyl groups include, without limitation, the
  • C 3 _g carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-lH-indenyl (C 9 ), decahydronaphthalenyl (Cio), spiro[4.5]decanyl (C 10 ), and the like.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro-fused ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon- carbon double or triple bonds.
  • exemplary fused bicyclic systems include, but are not limited to, decalin (cis or trans decalin).
  • Exemplary fused tricyclic systems include, but are not limited to, fluorenyl.
  • Exemplary spiro-fused bicyclic systems include, but are not limited to, spiropentane.
  • Exemplary bridged bicyclic systems include, but are not limited to, norbornane, norbornene, bicyclo[2.2.2]octane, bicyclo[2.2.2]oct-2-ene, bicyclo[3.2.1]octane, and bicyclo[2.2.1]heptan-2-one.
  • Exemplary bridged tricyclic systems include, but are not limited to adamantane.
  • Carbocyclyl includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted
  • carbocyclyl or substituted (a "substituted carbocyclyl") with one or more substituents.
  • the carbocyclyl group is an unsubstituted C 3 _ 14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C 3 _ 14 carbocyclyl.
  • heterocyclyl refers to a radical of a 3- to 14- membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon- carbon double or triple bonds.
  • Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • the heterocyclyl group is either monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro-fused ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)) and can be saturated or can contain one or more carbon- carbon double or triple bonds.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents.
  • the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl").
  • a heterocyclyl group is a 5-8 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl").
  • a heterocyclyl group is a 5-6 membered non- aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl").
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl.
  • Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl,
  • Exemplary 5- membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl, and dithiolanyl.
  • Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C -u aryl").
  • an aryl group has 6 ring carbon atoms ("C 6 aryl”; e.g., phenyl).
  • an aryl group has 10 ring carbon atoms ("C 10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl).
  • an aryl group has 14 ring carbon atoms ("C 14 aryl”; e.g., anthracenyl).
  • Aryl also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.
  • each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents.
  • the aryl group is an unsubstituted Ce- 14 aryl.
  • the aryl group is a substituted Ce_ 14 aryl.
  • alkyl or "arylalkyl” is a subset of “alkyl” and refers to an alkyl group, as described herein, substituted by one or more aryl groups, as described herein, wherein the point of attachment is on the alkyl moiety.
  • heteroaryl refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-14 membered heteroaryl").
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system.
  • Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
  • a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl").
  • a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl").
  • a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl").
  • the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently
  • the heteroaryl group is an unsubstituted 5- 14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
  • Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl.
  • Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • 5- membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
  • Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • 6- membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,
  • Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
  • Heteroaralkyl or “heteroarylalkyl” is a subset of “alkyl” and refers to an alkyl group, as described herein, substituted by one or more heteroaryl groups, as described herein, wherein the point of attachment is on the alkyl moiety.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • partially unsaturated is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl moieties) as herein defined.
  • saturated refers to a ring moiety that does not contain a double or triple bond, i.e. , the ring contains all single bonds.
  • alkylene is the divalent moiety of alkyl
  • alkenylene is the divalent moiety of alkenyl
  • alkynylene is the divalent moiety of alkynyl
  • heteroalkylene is the divalent moiety of heteroalkyl
  • heteroalkenylene is the divalent moiety of heteroalkenyl
  • heteroalkynylene is the divalent moiety of heteroalkynyl
  • carbocyclylene is the divalent moiety of carbocyclyl
  • heterocyclylene is the divalent moiety of heterocyclyl
  • arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as described herein, are, in certain embodiments, optionally substituted.
  • Optionally substituted refers to a group which may be substituted or unsubstituted (e.g., "substituted" or
  • substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a "substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position.
  • substituted is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound.
  • the present invention contemplates any and all such combinations in order to arrive at a stable compound.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
  • Exemplary carbon atom substituents include, but are not limited to, halogen, -
  • each instance of R cc is, independently, selected from hydrogen, C ⁇ o alkyl, Cno perhaloalkyl, C 2 _io alkenyl, C 2 _io alkynyl, C ⁇ o heteroalkyl, C 2 _io heteroalkenyl, C 2
  • each instance of R ee is, independently, selected from d_ 6 alkyl, d_ 6 perhaloalkyl, C 2 6 alkenyl, C 2 _ 6 alkynyl, d_ 6 heteroalkyl, C 2 _ 6 heteroalkenyl, C 2 _ 6 heteroalkynyl, C 3 _io carbocyclyl, C 6 -io aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;
  • each instance of R ff is, independently, selected from hydrogen, d_ 6 alkyl, d_ 6 perhaloalkyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, d_ 6 heteroalkyl, C 2 _ 6 heteroalkenyl, C 2
  • heteroalkynyl C 3 _ 14 carbocyclyl, 3-14 membered heterocyclyl, C 6 -i 4 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups.
  • halo or halogen refers to fluorine (fluoro, -F), chlorine (chloro,
  • Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms.
  • the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an "amino protecting group").
  • nitrogen protecting groups such as amide groups (e.g., -
  • picolinamide 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p- phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, ( ⁇ '- dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o- nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o- phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o- nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o- (benzoyloxymethyl)benzamide.
  • Nitrogen protecting groups such as carbamate groups include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-i-butyl-[9-( 10,10-dioxo-l 0, 10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1- (l-adamantyl)-l-methylethyl
  • Nitrogen protecting groups such as sulfonamide groups include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,- trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5, 6-tetramethyl-4- methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6- trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7, 8-pentamethylchroman-6-sulfonamide (Pmc), methanes
  • Ts p-toluenesulfonamide
  • Mtr 2,
  • nitrogen protecting groups include, but are not limited to,
  • phenothiazinyl-(10)-acyl derivative N'-p-toluenesulfonylaminoacyl derivative, N'- phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N- 2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-l, 1,4,4- tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted l,3-dimethyl-l,3,5- triazacyclohexan-2-one, 5-substituted l,3-dibenzyl-l,3,5-triazacyclohexan-2-one, 1- substituted 3,5-dinitro-4-pyridone,
  • the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an "hydroxyl protecting group").
  • oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,
  • DPMS diphenylmethylsilyl
  • TMPS i-butylmethoxyphenylsilyl
  • dimethylphosphinothioyl dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).
  • the substituent present on an sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group").
  • Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
  • Lewis acid refers to a species as defined by IUPAC, that is "a molecular entity (and the corresponding chemical species) that is an electron-pair acceptor and therefore able to react with a Lewis base to form a Lewis adduct, by sharing the electron pair furnished by the Lewis base.”
  • exemplary Lewis acids include, without limitation, boron trifluoride, aluminum trichloride, tin tetrachloride, titanium tetrachloride, and iron tribromide.
  • Lewis base refers to a species as defined by IUPAC, that is "a molecular entity (and the corresponding chemical species) that is able to provide a pair of electrons and thus capable of coordination to a Lewis acid, thereby producing a Lewis adduct"
  • exemplary Lewis bases include, without limitation, anions, amines, imines, ethers, thioethers, alkenes, alkynes, or carbonyl groups.
  • halogen bond refers to a bond occurring when "there is evidence of a net attractive interaction between an electrophilic region associated with a halogen atom in a molecular entity and a nucleophilic region in another, or the same, molecular entity.”
  • a dashed line drawn between a Lewis base or electron donor group (D) and a halogen X (e.g., fluorine, chlorine, bromine, or iodine) which is attached to an organic compound R represents a halogen bond, for example:
  • a typical halogen-bonded complex may have one or more of the following non-limiting features:
  • the interatomic distance between X and the appropriate nucleophilic atom of D tends to be less than the sum of the van der Waals radii.
  • the length of the R-X covalent bond usually increases relative to the unbonded R-X.
  • the angle D— X-R tends to be close to 180°, i.e. , the halogen bond acceptor D approaches X along the extension of the X-R bond.
  • the halogen bond strength decreases as the electronegativity of X increases, and the electron withdrawing ability of R decreases.
  • the forces involved in the formation of the halogen bond are primarily electrostatic, but polarization, charge transfer, and dispersion contributions all play a role. The relative roles of the different forces may vary from one case to the other.
  • the D— X halogen bond usually affects the nuclear magnetic resonance (NMR) observables (e.g., chemical shift values) of nuclei in both X-R and D, both in solution and in the solid state.
  • NMR nuclear magnetic resonance
  • the binding energies of the peaks associated with X with the X-ray photoelectron spectrum (XPS) of the complex shift to lower energies relative to unbonded X.
  • Halogen bonding has only recently been defined by IUPAC, but the phenomenon has long been appreciated and taken advantage of in several applications such as molecular recognition. Halogen bonding has received relatively little attention from synthetic organic chemists when compared to other non-covalent interactions such as hydrogen bonding.
  • Lewis base complexes of fluoroalkyl iodides are complexes that possess advantageous properties when compared to free fluoroalkyl iodides.
  • trifluoromethyl iodide and 1, 1,3,3-tetramethylguanidine (TMG) form a 1 : 1 adduct that is liquid at 23 °C, and can be dispensed accurately with a syringe.
  • TMG*CF I adduct stored in a glass vial with a Teflon sure seal at 0 °C in a refrigerator showed no signs of decomposition, loss in content of CF 3 I, or pressure build-up over two months.
  • the TMG*CF 3 CF 2 I reagent can be readily prepared and is a liquid.
  • sulfoxide complexes such as the dimethyl sulfoxide adducts of CF I and CF CF 2 I can be prepared and used in a fashion analogous to the TMG adducts.
  • the present application also discloses amine, heterocycle, and heteroarene complexes of fluoroalkyl iodides. In certain instances, these complexes are amorphous or crystalline solids (e.g. , tetramethylethylenediamine » (CF 3 I) 2 ), which offers additional handling benefits.
  • halogen bonded complexes of fluoroalkyl iodides possess comparable reactivity to parent fluoroalkyl iodides, enabling them to serve as replacements for these inconvenient and difficult-to-handle reagents in a wide variety of applications.
  • the present invention provides compounds, reagents, systems, reaction mixtures, compositions, kits, and methods for fluoroalkylating an organic compound. [0068] In one aspect, the present invention is directed to a compound of the Formula
  • R 1 is unsubstituted C 1-3 fluoroalkyl
  • each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
  • y is 1 or 2.
  • R 1 is unsubstituted C 1-3 fluoroalkyl.
  • R 1 is -CF 3 .
  • R 1 is -CHF 2 .
  • R 1 is -CH 2 F.
  • R 1 is -CF 2 CF 3 .
  • R 1 is -CF 2 CHF 2 .
  • R 1 is -CF 2 CH 2 F.
  • R 1 is - CHFCF 3 .
  • R 1 is -CHFCHF 2 .
  • R 1 is - CHFCH 2 F.
  • R 1 is -CF(CF 3 ) 2 .
  • R 1 is - CH(CF 3 ) 2 .
  • R 1 is -CF 2 CF 2 CF 3 .
  • y is 1 or 2. In certain embodiments, y is 1. In certain embodiments, y is 2.
  • each instance of R 2 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R groups are joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring.
  • D is N(R 2 ) 3 ; and one instance of R 2 is hydrogen.
  • D is N(R ) 3 ; and two instances of R are hydrogen.
  • D is N(R 2 ) 3 ; and at least one instance of R 2 is substituted or unsubstituted alkyl. In certain embodiments, D is N(R ) 3 ; and at least one
  • R is substituted or unsubstituted C 1-6 alkyl.
  • D is N(R ) 3 ; and at least one instance of R is unsubstituted Ci_6 alkyl (e.g. , methyl, ethyl, or propyl).
  • Ci_6 alkyl e.g. , methyl, ethyl, or propyl.
  • D is N(R ) 3 ; and at least one instance of R is branched C 1-6 alkyl (e.g. ,
  • D is N(R ) 3 ; and two instances of R are independently substituted or unsubstituted alkyl. In certain embodiments, D is N(R ) 3 ; and two instances of R are independently substituted or unsubstituted C 1-6 alkyl. In certain
  • D is N(R ) 3 ; and two instances of R are independently unsubstituted Ci_6 alkyl
  • D is N(R ) 3 ; and two instances of R are independently branched Ci_6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).
  • Ci_6 alkyl e.g. , isopropyl, isobutyl, or i-butyl.
  • D is N(R ) 3 ; and all three instances of R are independently substituted or
  • D is N(R ) 3 ; and all three instances of R are independently substituted or unsubstituted Ci_6 alkyl. In certain embodiments, D is N(R ) 3 ; and all three instances of R are independently unsubstituted Ci_6 alkyl (e.g. , methyl, ethyl, or
  • D is N(R ) 3 ; and all three instances of R are independently branched Ci_6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).
  • D is N(R 2 ) 3 ; and at least one instance of R 2 is substituted or unsubstituted carbocyclyl. In certain embodiments, D is N(R ) 3 ; and at least one instance of R is substituted or unsubstituted 3-6 membered carbocyclyl. In certain
  • D is N(R ) 3 ; and at least one instance of R is unsubstituted 3-6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).
  • R unsubstituted 3-6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).
  • D is N(R ) 3 ; and at least one instance of R is monosubstituted 3-6 membered carbocyclyl.
  • D is N(R 2 ) 3 ; and at least one instance of R 2 is substituted or unsubstituted heterocyclyl. In certain embodiments, D is N(R ) 3 ; and at least one instance of R is substituted or unsubstituted 3-6 membered heterocyclyl. In certain 2 2
  • D is N(R ) 3 ; and at least one instance of R is unsubstituted 3-6 membered heterocyclyl (e.g. , aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl).
  • R unsubstituted 3-6 membered heterocyclyl (e.g. , aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl).
  • D is N(R ) 3 ; and at least one instance of R is monosubstituted 3-6 membered heterocyclyl.
  • D is N(R 2 ) 3 ; and at least one instance of R 2 is substituted or unsubstituted aryl. In certain embodiments, D is N(R ) 3 ; and at least one
  • R is substituted or unsubstituted phenyl.
  • D is N(R ) 3 ;
  • R is unsubstituted phenyl.
  • D is N(R ) 3 ; and at least one instance of R is monosubstituted phenyl.
  • D is N(R 2 ) 3 ; and at least one instance of R 2 is substituted or unsubstituted heteroaryl. In certain embodiments, D is N(R ) 3 ; and at least one instance of R is substituted or unsubstituted 5-6 membered heteroaryl. In certain
  • D is N(R ) 3 ; and at least one instance of R is unsubstituted 5-6 membered heteroaryl (e.g., imidazolyl, oxazolyl, pyridyl, or pyrimidyl). In certain embodiments, D is
  • N(R ) 3 ; and at least one instance of R is monosubstituted 5-6 membered heteroaryl.
  • D is N(R 2 ) 3 ; and two R 2 groups are joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring.
  • D is a compound of Formula (II):
  • each instance of R 4 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R 4 groups are joined to form a substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic ring;
  • z is 1-5, inclusive.
  • all instances of R 4 are hydrogen.
  • D is a compound of Formula (II); and one instance of
  • R is hydrogen.
  • D is a compound of Formula (II); and two instances of R are hydrogen.
  • D is a compound of Formula (II); and three instances of R are hydrogen.
  • D is a compound of Formula (II); and all four instances of R are hydrogen.
  • D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted alkyl.
  • D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted C 1-6 alkyl.
  • D is a compound of Formula (II); and at least one instance of R is unsubstituted Ci_6 alkyl (e.g. , methyl, ethyl, or propyl). In certain embodiments, D is a compound of Formula (II); and at least one instance of R is methyl. In certain embodiments,
  • D is a compound of Formula (II); and at least one instance of R is branched C 1-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).
  • R is branched C 1-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).
  • D is a compound of Formula (II); and two instances of R are independently substituted or unsubstituted alkyl.
  • D is a compound of Formula (II); and two instances of R are independently substituted or unsubstituted C 1-6 alkyl.
  • D is a compound of Formula (II); and two instances of R are independently unsubstituted C 1-6 alkyl (e.g. , methyl, ethyl, or propyl).
  • D is a compound of Formula (II); and two instances of R are methyl.
  • D is a compound of Formula (II); and two instances of R are independently branched C 1-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).
  • D is a compound of Formula (II); and three instances of R are independently substituted or unsubstituted alkyl.
  • D is a compound of Formula (II); and three instances of R are independently substituted or unsubstituted Ci_6 alkyl.
  • D is a compound of Formula (II); and three instances of R are independently unsubstituted C 1-6 alkyl (e.g. , methyl, ethyl, or propyl).
  • D is a compound of Formula (II); and three instances of R are methyl.
  • D is a compound of Formula (II); and three instances of R are independently branched Ci_6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).
  • D is a compound of Formula (II); and all four instances of R are independently substituted or unsubstituted alkyl.
  • R is independently substituted or unsubstituted alkyl.
  • D is a compound of Formula (II); and all four instances of R are independently substituted or unsubstituted Ci_6 alkyl.
  • D is a compound of Formula (II); and all four instances of R are independently unsubstituted Ci_6 alkyl (e.g. , methyl, ethyl, or propyl).
  • D is a compound of Formula (II); and all four instances of R are methyl. In certain embodiments, D is a compound of Formula (II); and all four instances of
  • R are independently branched Ci_6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).
  • D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted carbocyclyl.
  • D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted 3-6 membered carbocyclyl.
  • D is a compound of Formula (II); and at least one instance of R is unsubstituted 3-6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).
  • D is a compound of
  • Formula (II); and at least one instance of R is mono substituted 3-6 membered carbocyclyl.
  • D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted heterocyclyl.
  • D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted 3-6 membered heterocyclyl.
  • D is a compound of Formula (II); and at least one instance of R is unsubstituted 3-6 membered heterocyclyl (e.g. , aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl).
  • D is a compound of Formula (II); and at least one instance of R is substituted 3-6 membered heterocyclyl (e.g. , aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl).
  • D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted heterocyclyl.
  • D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted aryl. In certain embodiments, D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted phenyl. In certain embodiments, D is a compound of Formula (II); and at least one instance of R is unsubstituted phenyl. In certain embodiments, D is a compound of Formula (II); and at least one instance of R is mono substituted phenyl.
  • D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted heteroaryl.
  • D is a compound of Formula (II); and at least one instance of R is substituted or unsubstituted 5-6 membered heteroaryl.
  • D is a compound of Formula (II); and at least one instance of R is unsubstituted 5-6 membered heteroaryl (e.g. , imidazolyl, oxazolyl, pyridyl, or pyrimidyl).
  • D is a compound of Formula (II); and at least one instance of R is mono substituted 5-6 membered heteroaryl.
  • D is a compound of Formula (II); and two R 2 groups are joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring.
  • D is a compound of Formula (II); and four R groups are joined to
  • z is 1-5, inclusive. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3. In certain embodiments, z is 4. In certain embodiments, z is 5.
  • Ci_6 alkyl e.g. , methyl
  • R is methyl.
  • Ci_6 alkyl e.g. , methyl, ethyl, or propyl.
  • C 1-6 alkyl e.g. , methyl, ethyl, or propyl.
  • Ci_6 alkyl e.g. , methyl, ethyl, or propyl.
  • R is unsubstituted 3- 6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).
  • R unsubstituted 3- 6 membered heterocyclyl (e.g. , aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl).
  • D is substituted or unsubstituted aryl.
  • R unsubstituted 5-6 membered heteroaryl (e.g. , imidazolyl, oxazolyl, pyridyl, or pyrimidyl).
  • R S(R ) 2 ; and at least one instance of R is unsubstituted C 1-6 alkyl (e.g. , methyl, ethyl, or
  • R S(R ) 2 ; and both instances of R are independently branched C 1-6 alkyl (e.g. , isopropyl,
  • R unsubstituted 3-6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).
  • R unsubstituted 3-6 membered heterocyclyl (e.g. , aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl).
  • R is substituted or unsubstituted phenyl.
  • 0 S(R ) 2 ; and at least one instance of R is monosubstituted phenyl.
  • 0 S(R ) 2 ; and at least one instance of R is monosubstituted 5-6 membered heteroaryl.
  • D is substituted or unsubstituted heterocyclyl. In certain embodiments, D is substituted or unsubstituted 3-6 membered heterocyclyl. In certain embodiments, D is unsubstituted 3-6 membered heterocyclyl. In certain embodiments, D is monosubstituted 3-6 membered heterocyclyl. In certain embodiments, D is substituted or unsubstituted azetidine. In certain embodiments, D is substituted or unsubstituted pyrrolidine. In certain embodiments, D is substituted or unsubstituted piperidine. In certain embodiments, D is substituted or unsubstituted piperazine. In certain embodiments, D is substituted or unsubstituted morpholine.
  • D is a compound of Formula (III):
  • each instance of R 5 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R 5 groups are joined to form a substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic ring;
  • n 0- 12, inclusive
  • all instances of R 5 are hydrogen.
  • D is a compound of Formula (III); and at least one instance of R 5 is substituted or unsubstituted alkyl.
  • D is a compound of Formula (III); and at least one instance of R 5 is substituted or unsubstituted Ci_6 alkyl.
  • D is a compound of Formula (III); and at least one instance of R 5 is unsubstituted C 1-6 alkyl (e.g. , methyl, ethyl, or propyl).
  • D is a compound of Formula (III); and at least one instance of R 5 is branched C 1-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).
  • D is a compound of Formula (III); and at least one instance of R 5 is substituted or unsubstituted carbocyclyl.
  • D is a compound of Formula (III); and at least one instance of R 5 is substituted or unsubstituted 3-6 membered carbocyclyl.
  • D is a compound of Formula (III); and at least one instance of R 5 is unsubstituted 3-6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).
  • D is a compound of Formula (III); and at least one instance of R 5 is monosubstituted 3-6 membered carbocyclyl.
  • D is a compound of Formula (III); and at least one instance of R 5 is substituted or unsubstituted heterocyclyl.
  • D is a compound of Formula (III); and at least one instance of R 5 is substituted or unsubstituted 3-6 membered heterocyclyl.
  • D is a compound of Formula (III); and at least one instance of R 5 is unsubstituted 3-6 membered heterocyclyl (e.g. , aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl).
  • D is a compound of Formula (III); and at least one instance of R 5 is monosubstituted 3-6 membered heterocyclyl.
  • D is a compound of Formula (III); and at least one instance of R 5 is substituted or unsubstituted aryl. In certain embodiments, D is a compound of Formula (III); and at least one instance of R 5 is substituted or unsubstituted phenyl. In certain embodiments, D is a compound of Formula (III); and at least one instance of R 5 is unsubstituted phenyl. In certain embodiments, D is a compound of Formula (III); and at least one instance of R 5 is monosubstituted phenyl.
  • D is a compound of Formula (III); and at least one instance of R 5 is substituted or unsubstituted heteroaryl.
  • D is a compound of Formula (III); and at least one instance of R 5 is substituted or unsubstituted 5-6 membered heteroaryl.
  • D is a compound of Formula (III); and at least one instance of R 5 is unsubstituted 5-6 membered heteroaryl (e.g. , imidazolyl, oxazolyl, pyridyl, or pyrimidyl).
  • D is a compound of Formula (III); and at least one instance of R 5 is monosubstituted 5-6 membered heteroaryl.
  • m is 0- 12, inclusive. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain
  • m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain embodiments, m is 7. In certain embodiments, m is 8. In certain embodiments, m is 9. In certain embodiments, m is 10. In certain embodiments, m is 11. In certain embodiments, m is 12.
  • D is substituted or unsubstituted heteroaryl. In certain embodiments, D is substituted or unsubstituted 5-6 membered heteroaryl. In certain embodiments, D is unsubstituted 5-6 membered heteroaryl. In certain embodiments, D is monosubstituted 5-6 membered heteroaryl. In certain embodiments, D is substituted or unsubstituted imidazole. In certain embodiments, D is substituted or unsubstituted thiazole. In certain embodiments, D is substituted or unsubstituted oxazole. In certain embodiments, D is substituted or unsubstituted triazole.
  • D is substituted or unsubstituted oxadiazole. In certain embodiments, D is substituted or unsubstituted thiadiazole. In certain embodiments, D is substituted or unsubstituted piperidine. In certain embodiments, D is substituted or unsubstituted pyrimidine. [00121] In certain embodiments, D is a com ound of Formula (IV):
  • each instance of R 6 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR 6a , -SR 6a , or -N(R 6a ) 2 , wherein each instance of R 6a is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R 6a groups are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and
  • p 1-5, inclusive.
  • D is a compound of Formula (IV); and at least one instance of R 6 is substituted or unsubstituted alkyl.
  • D is a compound of Formula (IV); and at least one instance of R 6 is substituted or unsubstituted Ci_6 alkyl.
  • D is a compound of Formula (IV); and at least one instance of R 6 is unsubstituted C 1-6 alkyl (e.g. , methyl, ethyl, or propyl).
  • D is a compound of Formula (IV); and at least one instance of R 6 is branched C 1-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).
  • D is a compound of Formula (IV); and at least one instance of R 6 is substituted or unsubstituted carbocyclyl.
  • D is a compound of Formula (IV); and at least one instance of R 6 is substituted or unsubstituted 3-6 membered carbocyclyl.
  • D is a compound of Formula (IV); and at least one instance of R 6 is unsubstituted 3-6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).
  • D is a compound of Formula (IV); and at least one instance of R 6 is monosubstituted 3-6 membered carbocyclyl.
  • D is a compound of Formula (IV); and at least one instance of R 6 is substituted or unsubstituted heterocyclyl.
  • D is a compound of Formula (IV); and at least one instance of R 6 is substituted or unsubstituted 3-6 membered heterocyclyl.
  • D is a compound of Formula (IV); and at least one instance of R 6 is unsubstituted 3-6 membered heterocyclyl (e.g. , aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl).
  • D is a compound of Formula (IV); and at least one instance of R 6 is monosubstituted 3-6 membered heterocyclyl.
  • D is a compound of Formula (IV); and at least one instance of R 6 is substituted or unsubstituted aryl. In certain embodiments, D is a compound of Formula (IV); and at least one instance of R 6 is substituted or unsubstituted phenyl. In certain embodiments, D is a compound of Formula (IV); and at least one instance of R 6 is unsubstituted phenyl. In certain embodiments, D is a compound of Formula (IV); and at least one instance of R 6 is monosubstituted phenyl.
  • D is a compound of Formula (IV); and at least one instance of R 6 is substituted or unsubstituted heteroaryl.
  • D is a compound of Formula (IV); and at least one instance of R 6 is substituted or unsubstituted 5-6 membered heteroaryl.
  • D is a compound of Formula (IV); and at least one instance of R 6 is unsubstituted 5-6 membered heteroaryl (e.g. , imidazolyl, oxazolyl, pyridyl, or pyrimidyl).
  • D is a compound of Formula (IV); and at least one instance of R 6 is monosubstituted 5-6 membered heteroaryl.
  • D is a compound of Formula (IV); and at least one instance of R 6 is -OR 6a .
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6a is hydrogen.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6a is substituted or unsubstituted alkyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6a is substituted or unsubstituted C 1-6 alkyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6a is unsubstituted C 1-6 alkyl (e.g. , methyl, ethyl, or propyl).
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6a is methyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6a is branched C 1-6 alkyl (e.g. , isopropyl, isobutyl, or t-butyl).
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6a is substituted or unsubstituted carbocyclyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6a is substituted or unsubstituted 3-6 membered carbocyclyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6a is unsubstituted 3-6 membered carbocyclyl (e.g.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6: is monosubstituted 3-6 membered carbocyclyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6a is substituted or unsubstituted heterocyclyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6: is substituted or unsubstituted 3-6 membered heterocyclyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6a is unsubstituted 3-6 membered heterocyclyl (e.g.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6: is monosubstituted 3-6 membered heterocyclyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6a is substituted or unsubstituted aryl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6a is substituted or unsubstituted phenyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6a is unsubstituted phenyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6a is monosubstituted phenyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6a is substituted or unsubstituted heteroaryl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6: is substituted or unsubstituted 5-6 membered heteroaryl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6a is unsubstituted 5-6 membered heteroaryl (e.g., imidazolyl, oxazolyl, pyridyl, or pyrimidyl).
  • D is a compound of Formula (IV); at least one instance of R 6 is -OR 6a ; and R 6: is monosubstituted 5-6 membered heteroaryl.
  • D is a compound of Formula (IV); and at least one instance of R 6 is -SR 6a .
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6a is hydrogen.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6a is substituted or unsubstituted alkyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6a is substituted or unsubstituted Ci_6 alkyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6a is unsubstituted C 1-6 alkyl (e.g. , methyl, ethyl, or propyl).
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6a is methyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6a is branched C 1-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6a is substituted or unsubstituted carbocyclyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6 is substituted or unsubstituted 3-6 membered carbocyclyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6a is unsubstituted 3-6 membered carbocyclyl (e.g.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6 is monosubstituted 3-6 membered carbocyclyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6a is substituted or unsubstituted heterocyclyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6 is substituted or unsubstituted 3-6 membered heterocyclyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6a is unsubstituted 3-6 membered heterocyclyl (e.g.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6 is monosubstituted 3-6 membered heterocyclyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6a is substituted or unsubstituted aryl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6a is substituted or unsubstituted phenyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6a is unsubstituted phenyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6a is monosubstituted phenyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6a is substituted or unsubstituted heteroaryl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6 is substituted or unsubstituted 5-6 membered heteroaryl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6a is unsubstituted 5-6 membered heteroaryl (e.g., imidazolyl, oxazolyl, pyridyl, or pyrimidyl).
  • D is a compound of Formula (IV); at least one instance of R 6 is -SR 6a ; and R 6a is monosubstituted 5-6 membered heteroaryl.
  • D is a compound of Formula (IV); and at least one instance of R 6 is -N(R 6a ) 2 .
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is hydrogen.
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is substituted or unsubstituted alkyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is substituted or unsubstituted C 1-6 alkyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is unsubstituted C 1-6 alkyl (e.g. , methyl, ethyl, or propyl).
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is methyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is branched C 1-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and each instance of R 6a is hydrogen. In certain embodiments, D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and each instance of R 6a is independently substituted or unsubstituted alkyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and each instance of R 6a is independently substituted or unsubstituted C 1-6 alkyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and each instance of R 6a is independently unsubstituted C 1-6 alkyl (e.g. , methyl, ethyl, or propyl).
  • R 6 is -N(R 6a ) 2 ; and each instance of R 6a is independently unsubstituted C 1-6 alkyl (e.g. , methyl, ethyl, or propyl).
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and each instance of R 6a is methyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and each instance of R 6a is independently branched C 1-6 alkyl (e.g. , isopropyl, isobutyl, or i-butyl).
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is substituted or unsubstituted carbocyclyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is substituted or unsubstituted 3-6 membered carbocyclyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is unsubstituted 3-6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).
  • R 6 is -N(R 6a ) 2
  • R 6a is unsubstituted 3-6 membered carbocyclyl (e.g. , cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is mono substituted 3-6 membered carbocyclyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is substituted or unsubstituted heterocyclyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is substituted or unsubstituted 3-6 membered heterocyclyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is unsubstituted 3-6 membered heterocyclyl (e.g.
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is mono substituted 3-6 membered heterocyclyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is substituted or unsubstituted aryl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R 6 is - N(R 6a ) 2 ; and at least one instance of R 6a is substituted or unsubstituted phenyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is unsubstituted phenyl. In certain embodiments, D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is monosubstituted phenyl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is substituted or unsubstituted heteroaryl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is substituted or unsubstituted 5-6 membered heteroaryl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is unsubstituted 5-6 membered heteroaryl (e.g.
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and at least one instance of R 6a is monosubstituted 5-6 membered heteroaryl.
  • D is a compound of Formula (IV); at least one instance of R 6 is -N(R 6a ) 2 ; and both R 6a groups are joined to form a substituted or unsubstituted heterocyclic or heteroaryl ring.
  • p is 1-5, inclusive. In certain, embodiments, p is 1. In certain, embodiments, p is 2. In certain, embodiments, p is 3. In certain, embodiments, p is 4. In certain, embodiments, p is 5.
  • D is tetramethylguanidine (TMG)
  • TEDA tetramethylethylenediamine
  • DABCO l,4-diazabicyclo[2.2.2]octane
  • DMAP 4- dimethylaminopyridine
  • DMSO dimethyl sulfoxide
  • D is not ammonia, trimethylamine, triethylamine, N- methyl piperidine, quinuclidine, pyridine, collidine, tetrahydrothiophene, or dimethyl sulfoxide.
  • a compound described herein is a compound of
  • a compound described herein is a compound of
  • a compound described herein is a compound of
  • a compound described herein is a compound of
  • R 1 , R 2 , R 4 , and z are as described herein.
  • R 1 is -CF 3 .
  • R 1 is -CF 2 CF 3 .
  • z is 2.
  • each instance of R 4 is hydrogen.
  • each instance of R 2 is substituted or unsubstituted Ci_6 alkyl.
  • each instance of R is methyl.
  • R 1 is -CF 3 or -CF 2 CF 3 ; z is 2; and each instance of R 2 is methyl.
  • a compound described herein is a compound of
  • R 1 , R 5 , and m are as described herein.
  • R 1 is -CF 3 .
  • R 1 is -CF 2 CF .
  • m is 0.
  • each instance of R 5 is hydrogen.
  • R 1 is -CF or -CF 2 CF ; and m is 0.
  • a compound described herein is a compound of
  • R is -CF .
  • R 1 is -CF 2 CF .
  • p is 1.
  • a compound of Formula (IV-a) is /?ara-substituted.
  • R 6 is -N(R 6a ) 2 .
  • each instance of R 6a is methyl.
  • R 1 is -CF 3 or -
  • a compound described herein is a compound of
  • R 1 and R2 are as described herein.
  • R 1 is -CF 3 .
  • R 1 is -CF 2 CF 3 .
  • four instances of R 2 are independently substituted or unsubstituted Ci_6 alkyl; and one instance of R is hydrogen.
  • four instances of R 2 are methyl; and one instance of R 2 is hydrogen.
  • four instances of R 2 are methyl; one instance of R 2 is hydrogen; and R 1 is -CF or -CF 2 CF 3 .
  • a compound described herein is a compound of
  • R 1 and R2 are as described herein.
  • R 1 is -CF 3 .
  • R 1 is -CF 2 CF 3 .
  • all four instances of R 2 are methyl.
  • all four instances of R 2 are methyl; and R 1 is -CF or -CF 2 CF .
  • a compound described herein is a compound of
  • R 1 and R 2 are as described herein.
  • the halogen bond is between the O atom of the sulfoxide and the iodine atom of the fluoroalkyl iodide.
  • R 1 is -CF 3 .
  • R 1 is -CF 2 CF 3 .
  • each instance of R is independently substituted or unsubstituted Ci_6 alkyl.
  • both instances of R 2 are methyl.
  • both instances of R 2 are methyl; and R 1 is -CF or -CF 2 CF .
  • a compound of Formula (I) is of formula:
  • An organic compound useful as a starting material in the methods provided herein is an organic molecule of any molecular weight.
  • the molecule is a small organic molecule.
  • the small organic molecule includes any molecule having a molecular weight of less than 1000 g/mol.
  • the organic compound contains a chiral center.
  • the organic compound is further substituted with one or more functional groups (e.g., alcohols, aldehydes, ketones, esters, alkenes, alkoxy groups, cyano groups, amines, amides, and N-oxides).
  • the functional groups are unprotected.
  • the organic compound is a precursor of a pharmaceutical agent.
  • the organic compound comprises an acidic group.
  • the organic compound is substituted with one or more nucleophilic groups.
  • the organic compound is an anion.
  • the organic compound is substituted with one or more electrophilic groups.
  • compounds of Formula (I) are useful in fluoroalkylation reactions, wherein the compounds of Formula (I) serve as a source of an electrophilic fluoroalkyl group.
  • a compound of Formula (I) is contacted with an alkyne of Formula (a-2) in the presence of a base to afford a compound of Formula (b-2):
  • R 1 is as defined herein, and R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • a compound of Formula (I) is contacted with an hydroxy organic compound of Formula (a-3) in the presence of a base to afford a compound of Formula (b-3):
  • R 1 is as defined herein, and R 9 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • a compound of Formula (I) is contacted with a thiol of Formula (a-4) in the presence of a base to afford a compound of Formula (b-4):
  • R 1 is as defined herein, and R 10 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • a compound of Formula (I) is contacted with an amine of Formula (a-7) in the presence of a base to afford a compound of Formula (b-7):
  • R 1 is as defined herein
  • R 13 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R 13 groups are joined to form a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring.
  • a compound of Formula (I) is contacted with an alkene of Formula (a-1) to afford a compound of Formula (b-1):
  • R 1 is as defined herein, and each R 7 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R groups are joined to form a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl ring.
  • a compound of Formula (I) is contacted with a carbonyl containing compound of Formula (a-5) in the presence of a reducing agent or under metal halogen exchange conditions to afford a compound of Formula (b-5):
  • R 1 is as defined herein, and R 11 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R 11 groups are joined to substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl ring.
  • a compound of Formula (I) is contacted with an aldehyde compound of Formula (a-6) in the presence of a reducing agent or under metal halogen exchange conditions to afford a compound of Formula (b-6):
  • R is as defined herein, and R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • fluoroalkylation of alkenes of Formula (a-1) can generally be accomplished under radical or non-radical conditions, e.g., in the case of nonradical conditions, via addition of R 1 -! across the double bond, followed by HI elimination,
  • fluoroalkylation of carbonyls of Formula (b-5) or (b-6) can generally be accomplished under reaction conditions wherein an anion is generated.
  • reagents useful for generation of an anionic intermediate include alkali or alkaline earth metals (e.g. , lithium or magnesium metal), an organometal species (e.g. , an organolithium reagent), or an organic reducing agent (e.g., tetrakis(dimethylamino)ethylene (TDAE)), e.g. :
  • the reactions described herein further include the use of a solvent.
  • exemplary solvents include non-polar solvents (e.g. , toluene, dioxane, or benzene) or polar solvents (DMF, THF, MeCN).
  • the reaction is performed under ambient temperature, pressure, and atmosphere. In certain embodiments, the reaction is performed under an inert atmosphere (e.g., an atmosphere that is substantially free of dioxygen or water). In certain embodiments, the reaction is performed under anhydrous conditions (e.g., in a solvent that is substantially free of water). In certain embodiments, the reaction is heated. In certain embodiments, the reaction is cooled (e.g., -30 °C). In certain embodiments, the reaction is performed at room temperature (e.g. , about 20-25 °C).
  • the reaction conditions comprise an additional reagent such as a base (e.g. , an alkyl amine base such as triethylamine or an inorganic base such as K2CO3).
  • the reaction conditions comprise a radical initiator (e.g. , AIBN) or a photoredox catalyst (e.g. , a ruthenium bipyridine catalyst).
  • a base e.g. , an alkyl amine base such as triethylamine or an inorganic base such as K2CO3
  • the reaction conditions comprise a radical initiator (e.g. , AIBN) or a photoredox catalyst (e.g. , a ruthenium bipyridine catalyst).
  • the reaction conditions comprise irradiation with visible light.
  • the reaction conditions comprise an organic reducing agent (e.g. , TDAE).
  • TDAE organic reducing agent
  • a compound of Formula D serves as a base, and no additional base is added.
  • a compound of the present invention or a compound useful in the methods described herein is immobilized on a solid support.
  • a compound of Formula (I), (I-a), (I-b), (I-c), (II), (Il-a), (III), (Hl-a), (IV), (IV-a), (V), (V-a), (V-b), (VI), (Vl-a), (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a-7), (b-1), (b- 2), (b-3), (b-4), (b-5), (b-6), or (b-7) is immobilized on a solid support.
  • the fluoroalkylated organic compounds are generated from their corresponding precursors (e.g., compounds of Formulae (a-l)-(a-7)) in yields of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100%.
  • the reaction conditions described herein are tolerant of many functional groups as well as chiral centers.
  • the fluoroalkylated organic compound is further substituted by one or more functional groups, such as aldehydes, ketones, esters, alkenes, alkoxy groups, cyano groups, amines, amides, and N-oxides.
  • the fluoroalkylated organic compound contains a chiral center that is derived from the starting material. The stereochemistry at the chiral center may remain substantially unchanged (e.g., little to no racemization or epimerization of the chiral center occurs during the reaction).
  • the fluoroalkylated organic compound is 19 F labeled.
  • the labeled organic compound is an imaging agent, such as an MRI imaging agents.
  • the labeled organic compound may be used as a probe, such as a biological NMR probes for use in in vivo NMR spectroscopy.
  • the fluoroalkylated organic compound is 18 F labeled.
  • the 18 F-labeled organic compound is an imaging agent, such as a PET imaging agent.
  • the fluoroalkylated organic compound is a compound having biological activity.
  • the fluoroalkylated organic compound is a compound with pharamacologic activity (i.e., binds to a receptor or enzyme).
  • Fluoroalkylation reagents as described herein e.g., compounds of Formula
  • (I)) are generally prepared by contacting a compound of Formula D (e.g.,
  • a fluoroalkyl iodide of Formula I-R 1 e.g., I-CF 3 or I-CF 2 CF 3
  • the gaseous fluoroalkyl iodide is condensed at low temperatures (e.g., to -78 °C) using a suitable apparatus (e.g., a Schlenk flask).
  • a compound of Formula D is then added to the liquid fluoroalkyl iodide.
  • the molar ratio of fluoroalkyl iodide to D is approximately 1: 1.
  • the molar ratio of fluoroalkyl iodide to D is approximately 1:2. In certain embodiments, the molar ratio of fluoroalkyl iodide to D is approximately 2: 1. In certain embodiments, the molar ratio of fluoroalkyl iodide to D is approximately 1:5. In certain embodiments, the molar ratio of fluoroalkyl iodide to D is approximately 5: 1. In certain embodiments, the fluoroalkyl iodide is in significant molar excess of D (10-fold or greater). In certain embodiments, D is in significant molar excess of the fluoroalkyl iodide (10-fold or greater). In certain embodiments, the reaction mixture is cooled (e.g., to -78 °C). In certain
  • the reaction mixture includes an additional solvent. In certain embodiments, the reaction mixture does not include additional reagents. The reaction mixture is then warmed to ambient temperature. In certain embodiments, residual fluoroalkyl iodide is removed from the reaction mixture by evaporation. In certain embodiments, the resulting compound of Formula (I) is a solid. In certain embodiments, the resulting compound of Formula (I) is a liquid. In certain embodiments, the resulting compound of Formula (I) is a solution in excess compound of Formula D. In certain embodiments, the compound of Formula (I) is stored at low temperatures (e.g., 0 °C). In certain embodiments, the compound of Formula (I) is stored in a light proof container.
  • reaction mixtures comprising any of the aforementioned reagents and compounds of Formula (I), (I-a), (I-b), (I-c), (II), (Il-a), (III), (Ill-a), (IV), (IV-a), (V), (V-a), (V-b), (VI), (Vl-a), (a-1), (a-2), (a-3), (a-4), (a-5), (a-6), (a- 7), (b-1), (b-2), (b-3), (b-4), (b-5), (b-6), or (b-7).
  • reaction mixtures include, but are not limited to those used for the preparation of compounds of Formula (I) or wherein a compound of Formula (I) is utilized as a fluoroalkylation reagent.
  • compositions comprising compounds of
  • the composition further comprises a solvent (e.g. , a non-polar or polar organic solvent).
  • a solvent e.g. , a non-polar or polar organic solvent.
  • the molar ratio of fluoroalkyl iodide to D is approximately 1 : 1. In certain embodiments, the molar ratio of fluoroalkyl iodide to D is approximately 1 :2. In certain embodiments, the molar ratio of fluoroalkyl iodide to D is approximately 2: 1. In certain embodiments, the molar ratio of fluoroalkyl iodide to D is approximately 1 :5. In certain embodiments, the molar ratio of fluoroalkyl iodide to D is approximately 5: 1.
  • the fluoroalkyl iodide is in significant molar excess of D (10-fold or greater). In certain embodiments, D is in significant molar excess of the fluoroalkyl iodide (10-fold or greater). In certain
  • the composition further comprises a fluoroalkylation substrate of formula (a- 1), (a-2), (a-3), (a-4), (a-5), (a-6), or (a-7).
  • the fluoroalkylation reagents described herein may be provided in a kit.
  • the kit typically includes (a) the fluoroalkylation reagent (e.g., a compound of Formula (I)), and, optionally (b) informational material.
  • the informational material can be descriptive, instructional, or promotional or other material that relates to the methods described herein and/or the use of the compounds for the methods described herein.
  • the kit may include additional reagents.
  • the kit may include a base (e.g., an alkyl amine base such as triethylamine or an inorganic base such as K 2 CO 3 ).
  • the kit may include a solvent (e.g.
  • the kit may include a radical initiator reagent (e.g. , AIBN).
  • the kit may include a photoredox catalyst (e.g., a ruthenium bipyridine catalyst).
  • the kit may include an organic reducing agent (e.g. , TDAE)
  • the informational material of the kits is not limited in its form.
  • the informational material can include information about production of the fluoroalkylation reagent, molecular weight of the fluoroalkylation reagent, concentration, date of expiration, batch or production site information, and so forth.
  • the informational material relates to methods for using the fluoroalkylation reagent.
  • the informational material e.g. , instructions
  • the informational material is provided in printed matter, e.g. , a printed text, drawing, and/or photograph, e.g. , a label or printed sheet.
  • the informational material can also be provided in other formats, such as computer readable material, video recording, or audio recording.
  • the informational material of the kit is contact information, e.g. , a physical address, e-mail address, website, or telephone number, where a user of the kit can obtain substantive information about a fluorination reagent described herein and/or its use in the methods described herein.
  • the informational material can also be provided in any combination of formats.
  • the components of the kit are stored under inert conditions (e.g., under nitrogen or another inert gas such as argon). In certain embodiments, the components of the kit are stored under anhydrous conditions (e.g. , with a desiccant). In certain embodiments, the components are stored in a light blocking container such as an amber vial.
  • the fluoroalkylation reagent described herein can be provided in any form, e.g. , liquid, dried, or lyophilized form. Typically the fluoroalkylation reagent described herein is substantially pure and/or sterile. When the fluoroalkylation reagent described herein is provided as a dried form, reconstitution generally is by the addition of a suitable solvent.
  • the kit can include one or more containers for the composition containing the fluoroalkylation reagent described herein.
  • the kit contains separate containers, dividers or compartments for the composition and informational material.
  • the composition can be contained in a bottle, vial, or ampule, and the informational material can be contained in a plastic sleeve or packet.
  • the separate elements of the kit are contained within a single, undivided container.
  • the composition is contained in a bottle, vial, or ampule that has attached thereto the
  • kits can be air tight, waterproof (e.g. , impermeable to changes in moisture or evaporation), and/or light-tight.
  • TLC Thin layer chromatography
  • EMD TLC plates pre-coated with 250 ⁇ thickness silica gel 60 F 254 plates and visualized by fluorescence quenching under UV light and KMn0 4 stain.
  • Flash chromatography was performed using silica gel (230-400 mesh) purchased from Silicycle Inc.
  • NMR spectra were recorded on either a Varian Unity/Inova 600 spectrometer operating at 600 MHz for 1H acquisitions, a Varian Unity/Inova 500 spectrometer operating at 500 MHz and 125 MHz for 1 H and 13 C acquisitions, respectively, or a Varian Mercury 400
  • Lewis bases were evaluated for their ability to create stable halogen bonded adducts with CF 3 I. The following procedure was followed. A known amount of Lewis base (250 mg in each case) was weighed in a three necked flask that was cooled to -20 °C. An excess amount of CF 3 I (approximately 5-10 mL) was condensed in with the aid of a cold finger that was cooled to -78 °C. The reaction mixture was then stirred at the refluxing temperature of CF 3 I (-22 °C) for 20 minutes and then excess CF 3 I was evaporated off and the reaction mixture was warmed until +23 °C. As soon as the reaction mixture reached room temperature, a known amount was weighed and analyzed via 19 F-NMR in the presence of 1- fluoro-3-nitrobenzene. Tested Lewis bases and the results obtained are reported in the table below (Table 1).
  • Enolether 5 (100 mg, 0.36 mmol, 1.00 eq) was dissolved in THF (1.8 mL).
  • TDAE tetrakis(dimet ylamino)ethylene
  • TMG*CF 3 I can be used in Stephenson's photoredox-catalyzed oxidative olefin trifluoromethylation (see (E)- 1,1,1 - trifluorotridec-2-ene (2)). Likewise, thiol trifluoromethylation can be accomplished with TMG*CF 3 I (see 4-chlorophenyl trifluoromethyl sulphide (4)). In both cases, TMG acts as a base in addition to providing a liquid source of CF 3 I. In other cases, we found the presence of TMG to be detrimental.
  • TMG*CF I was not a suitable CF I surrogate for the MacMillan trifluoromethylation of enol ethers under photoredox catalysis.
  • 2 DMSOCF 3 I proved effective both in the MacMillan trifluoromethylation, as well as in the TDAE-mediated trifluoromethyl addition to aldehydes (see 3,3,3-trifluoro-l-phenylpropan-l- one (6) and 2,2,2-trifluoro-l-(naphthalen-l-yl)ethanol (8), respectively).
  • TMG « CF 3 CF 2 I is effective for pentafluoroethylation (see (E)- l,l ,l,2,2-pentafluorotetradec-3-ene (9) and 4- chlorophenyl pentafluoroethyl sulfide (10)).
  • Basis set I includes Stuttgart/Dresden (SDD) quasirelativistic pseudopotentials multielectron-fit wood-boring (MWB) on I (MWB46) with the basis set (4s5p)/[2s3p extended by d-polarization functions (0.289), 9 6-31G(d,p) 10 on H and 6-311G(d) 8 on C, N, F.
  • Geometry optimizations were performed using the B3LYP, 11 ' 12 ' 13 M06-2X, 14 and &>B97X-D 15 functionals with the BS I basis set.
  • Natural bond orbitals were generated using an isosurface value of 0.01 with B3LYP/BS I.
  • the electrostatic potential of trifluoromethyl iodide is mapped onto the electron density using an isovalue of 0.001 electrons ⁇ (a.u.) " with GaussView5 for the optimized structure using B3LYP/BS I .
  • BSSE Basis set superposition error
  • C-I bond distances of molecular CF 3 I are given in parentheses.
  • energies are calculated using equations (1), (2) and (3).
  • the total energies of all fragments n of a particular complex (TMEDA-2 CF 3 I or TMG-CF 3 I) are calculated in the monomer geometry (MG) and in the complex (CG) within both the monomer basis (MB) and the complex basis (CB).
  • the Oxygen-bound structure was found to be more stable than the S-bound structure with both (0B97X-D and M06-2X functionals.
  • BSSE-corrected differences in energy between the oxygen-and sulfur-bound structures are as following: -5.22 kcal-mol 1 (M06-2X) and -4.03 kcal-mol 1 (coB97X-D).
  • C-I bond distances of molecular CF 3 I are given in parentheses.
  • energies are calculated using equations (1), (2) and (3).
  • the total energies of all fragments n of a particular complex are calculated in the monomer geometry (MG) and in the complex (CG) within both the monomer basis (MB) and the complex basis (CB).
  • N-(4-ethoxyphenyl)acetamide (45.0 mg, 0.250 mmol, 1.00 eq), TBHP (70% aqueous, 0.140 mL, 1.00 mmol, 4.00 eq) and FeSC mO (14.0 mg, 0.0500 mmol, 0.200 eq) were dissolved in glacial acetic acid (2.00 mL).
  • TMG'CFsI (0.100 mL, 0.500 mmol, 2.00 eq) was added, the reaction vessel was sealed and heated at 120 °C for 24 hours. The reaction mixture was diluted with saturated aqueous sodium carbonate (50 mL) and the resulting mixture extracted with ethyl acetate (3 x 25 mL).
  • reaction mixture was diluted with saturated aqueous sodium carbonate (50 mL) and the resulting mixture extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate extracts were dried (MgS0 4 ) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with CH 2 Cl 2 /hexanes (1:2 to 1: 1) to afford 32.4 mg (0.123 mmol, 49%) of a mixture of 10a and 10b in a 3.0: 1 ratio. Further purification by preparative TLC
  • the reaction mixture was diluted with saturated aqueous sodium carbonate (50 mL) and the resulting mixture extracted with ethyl acetate (3 x 25 mL). The combined ethyl acetate extracts were dried (MgSC ⁇ ) and concentrated in vacuo. The residue was purified by preparative TLC eluting with acetone/hexanes (1: 1) to afford 45.1 mg (0.130 mmol, 52%) of a mixture of 11a and lib in a 1.7: 1 ratio as a white solid. We were unable to separate the isomers by chromatography and so the compounds were characterized as a mixture.
  • Enolether 20 (100 mg, 0.360 mmol, 1.00 eq) was dissolved in THF (1.8 mL).
  • reaction mixture was then diluted with 0.5M HCl (4 mL) and the resulting mixture extracted with pentane/Et 2 0 1: 1 v/v (3 x 4 mL).
  • the combined organic extracts were dried (Na 2 S0 4 ) and concentrated under reduced pressure.
  • the residue was purified by flash chromatography on silica gel eluting with a solvent mixture of pentane/CH 2 Cl 2 (4: 1 v/v) to yield 21 as a white solid (54 mg, 79%). [the product was found to sublime when dried on high vacuum] .
  • the reagent TMG*CF 3 CF 2 l can be substituted for TMG*CF 3 I to afford pentafluoroethylated products.
  • Positional selectivities are generally modest; generation of mixtures of positional isomers is common for direct arene trifluoromethylations.
  • Direct arene trifluoromethylation using TMG*CF I is an effective and operationally simple method made possible by the condensed-phase nature of the reagent.
  • the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim.
  • any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim.
  • elements are presented as lists, e.g. , in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features.

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Abstract

Cette invention concerne des complexes liés par un halogène de Formule (I), dans laquelle est une liaison halogène ; R1 est un fluoroalkyle C1-3 non substitué ; D est N(R2)3, ((R2)2N)2C=NR2, 0=S(R2)2, un hétérocyclyle substitué ou non, ou un hétéroaryle substitué ou non, et dans laquelle R2 et y sont tels que définis dans la description. D----(I−−R1)y (I) Des procédés de préparation de composés de Formule (I), des compositions, des réactifs et des kits comprenant un composé de Formule (I), et des procédés de fluoroalkylation d'un composé organique à l'aide d'un composé de Formule (I) sont en outre décrits.
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