WO2012054782A2 - Fluoroalkoxylation of organic compounds - Google Patents

Abstract

Methods for fluoroalkoxylating organic compounds are described herein.

Description

FLUOROALKOXYLATION OF ORGANIC COMPOUNDS

CLAIM OF PRIORITY

This application claims priority to U.S.S.N. 61/405,134, filed October 20, 2010, the contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to methods of fluoroalkoxylation of an organic compound using a silver-containing compound and a fluoroalkoxylating agent.

BACKGROUND OF INVENTION

Functionalized trifluoroalkoxylate compounds are used by a variety of industries including the pharmaceutical/biotechnology industries as well as the agriculture industry. These fluoroalkoxylated compounds often possess desirable chemical properties such as metabolic stability and increased absorption parameters (for example, through the blood brain barrier). Versatile, facile methods for producing these desirable fluoroalkoxylated compounds are described herein.

SUMMARY OF INVENTION

Described herein are novel methods for fluoroalkoxylating organic compounds.

In one aspect, the invention features a method of fluoroalkoxylating an organic compound, the method comprising providing an organic compound comprising an organostannane, a boron substituent or a silane substituent, a silver-containing compound, and a fluoroalkoxylating agent, under conditions sufficient to fluoroalkoxylate the organic compound, thereby providing a fluoroalkoxylated organic compound. In some embodiments, the organic compound is fluoroalkoxylated regiospecifically. In some embodiments, the organic compound comprises an aryl group (e.g., phenyl). In some embodiments, the aryl group may be an electron-poor aryl group, an electron-rich aryl group or an electron-neutral aryl group. In some embodiments, the aryl group is a heteroaryl group (e.g., a fused bicyclic group). In some embodiments, the heteroaryl group is an indole or quinoline. In some embodiments, the organic compound comprises a vinyl group (e.g., a substituted or unsubstituted vinyl group), wherein the organostannane, boron substituent or silane substituent is attached to the vinyl group.

1066518 1 In some embodiments, the method further comprises an oxidizing agent. In some embodiments, the oxidizing agent is Selectfluor^® (l-chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)). In some embodiments, the oxidizing agent is l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate). In some embodiments, the oxidizing agent is l-chloromethyl-4-fluoro-l,4- diazabicyclo[2.2.2]octane bis (triflate). In some embodiments, the oxidizing agent is 1- chloromethyl-4-fluoro-l,4-diazabicyclo[2.2.2]octane bis(hexafluoroantimonate).

In some embodiments, the method further comprises one or more additives (e.g., a base). In some embodiments, the method further comprises sodium hydroxide (NaOH). In some embodiments, the method further comprises sodium bicarbonate (NaHCC^). In some embodiments, the method further comprises sodium triflate (NaOTf). In some embodiments, the method further comprises sodium carbonate (NaCC>3). In some embodiments, the method further comprises sodium hydroxide and sodium bicarbonate. In some embodiments, the one or more additives to organic compound ratio is about a 1: 1 molar ratio. In some

embodiments, the one or more additives to organic compound ratio is about a 2: 1 molar ratio. In some embodiments, the one or more additives to organic compound ratio is about a 3: 1 molar ratio. In some embodiments, the one or more additives to organic compound ratio is about a 4: 1 molar ratio.In some embodiments, the organic compound comprises an organostannane. In some embodiments, the organostannane comprises a trialkyltin moiety (e.g., a tributyltin or trimethyltin moiety).

In some embodiments, the organic compound is biphenyl-4-yl-tributylstannane, tributyl(4-fluorophenyl)stannane, tributyl(4-methoxyphenyl)stannane, tributyl(2- methoxyphenyl)stannane, tributyl(3,4,5-trimethoxyphenyl)stannane, tributyl(4- bromophenyl)stannane, ethyl-4-(tributylstannyl)benzoate, methyl-6-(tributylstannyl)-2- naphthoate, i-butyl-5-(tributylstannyl)-lH-indole-l-carboxylate, methyl-2-(t- butoxycarbonylamino)-3-(4-(tributylstannyl)phenyl)propanoate, 3-deoxy-3- tributylstannylestrone, N-Boc-4-(tributylstannyl)-L-phenylalanyl-L-phenylalanine methyl ester, 6-(tributylstannyl)quinoline, or tributyl(styryl)stannane. In some embodiments, the organic compound is a stannane derivative of a vinca alkaloid (e.g., vinblastine, vincristine, vindesine or vinorelbine). In some embodiments, the organic compound is a stannane derivative of a vinca alkaloid such as the structure represented below:

In some embodiment, the organic compound is a morphine analog (e.g., codeine, oripavine, diacetylmorphine, dihydrocodeine, hydrocodone, hydromorphone, oxycodone or

oxymorphone). In some embodiments, the organic compound is a morphine derivative such as the structure represented below:

In some embodiment, the organic compound is a morphine derivative such structure represented below:

In some embodiments, the organic compound comprises one or more functional groups (e.g., an alcohol, aldehyde, ester, ketone, alkoxy group, cyano group, amine, amide, or N-oxide.) In some embodiments, the functional group is unprotected. In some embodiments, the organic compound comprises one or more chiral centers.

In some embodiments, the organic compound is a precursor to a pharmaceutically acceptable compound.

In some embodiments, the fluoroalkoxylated organic compound is fluoro-4- (trifluoromethoxy)benzene, (2-(trifluoromethoxy)vinyl)benzene, 1 -bromo-4- (trifluoromethoxy)benzene, methyl 6-(trifluoromethoxy)-2-naphthoate, 5-trifluoromethoxy- N-Boc-indole, N-Boc-4-(trifluoromethoxy)-L-phenylalanine methyl ester, 4- (trifluoromethoxy)biphenyl, N-Boc-5-trifluoromethoxyindole, 3-trifluoromethoxyestrone, 3- deoxy-3-trifluoromethoxyestrone, N-Boc-4-(trifluoromethoxy)-L-phenylalanyl-L- phenylalanine methyl ester, 6-(Trifluoromethoxy)quinoline, 4-trifluoromethoxyanisole, ethyl 4-trifluoromethoxybenzoate or 1,3,5-trifluoromethoxybenzene. In some embodiments, the fluoroalkoxylated organic compound is a fluoroalkoxylated derivative of a vinca alkaloid (e.g., vinblastine, vincristine, vindesine or vinorelbine). In some embodiments, the fluoroalkoxylated organic compound is a vinca alkaloid such as the structure represented below:

In some embodiments, the fluoroalkoxylated organic compound is a morphine analog (e.g., codeine, oripavine, diacetylmorphine, dihydrocodeine, hydrocodone, hydromorphone, oxycodone or oxymorphone). In some embodiments, the fluoroalkoxylated organic compound is methyl 3-deoxy-3-(trifluoromethoxy)normorphine-carboxylate. In some embodiments, the fluoroalkoxylated organic compound is a morphine derivative such as the structure represented below:

In some embodiments, e.g., wherein the organic compound is an organostannane, the method further comprises reacting a precursor of the organostannane with a tin-containing reagent to provide the organostannane. In some embodiments, the precursor of the organostannane comprises a halogen substituent (e.g., bromine or iodine), a Grignard substituent, a triflate substituent, a nonaflate substituent or a diazonium substituent.

In some embodiments, the organic compound comprises a boron substituent, e.g., a group of the formulae:

wherein G¹, G² and G³ are, independently, -OH, -OR, or -R;

each R is, independently, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, or optionally substituted heteroaryl,

or G¹ and G² are joined to form an optionally substituted 5- to 8-membered ring having at least one O atom directly attached to B, wherein the ring is comprised of carbon atoms and optionally one or more additional heteroatoms independently selected from the group consisting of N, S, and O; and wherein A® is a metal cation or ammonium.

In some embodiments, G¹ and G² are both -OH.

In some embodiments, G¹, G² and G³ are all -OH.

In some embodiments, the organic compound comprises a boron substituent. In some embodiments, the boron substituent is a boronic acid moiety (e.g., a -B(OH)₂ moiety).

In some embodiments, the compound comprising a boron substituent is biphenyl-4-yl- boronic acid, 4-methoxyphenylboronic acid, l-(tert-butoxycarbonyl)-lH-indol-5-ylboronic acid, naphthalene-2-ylboronic acid, 3-(methoxycarbonyl)-5-methylphenylboronic acid or 4- fluorophenylboronic acid.

In some embodiments, the organic compound comprises a silane substituent. In some embodiments, the silane substituent is a trialkoxysilane (e.g., trimethoxysilane or

triethoxy silane). In some embodiments, the silane substituent is trihydroxysilane.

In some embodiments, the silver-containing compound is a silver complex. In some embodiments, silver-containing compound is a silver salt, e.g., a silver(I) salt. In some embodiments, the silver(I) salt is silver(I) hexafluorophosphate. In some emdodiments, the silver(I) salt is silver(I) oxide. In some embodiments, the silver(I) salt is silver(I) triflate. In some embodiments, the silver(I) salt is silver(I) borofluoride. In some embodiments, the silver(I) salt is silver(I) hexafluoroantimonate.

In some embodiments, the reaction includes from about 5 to about 0.01 molar equivalents of silver-containing compound relative to the organic compound (e.g., about 3 equivalents of the silver-containing compound, about 2 equivalents of the silver-containing compound or about 1 equivalent of the silver-containing compound). In some embodiments, the reaction includes a catalytic amount silver-containing compound relative to the organic compound. In some embodiments, the reaction includes less than about 1 equivalent of the silver-containing compound, e.g., about 90%, about 80%, about 70%, about 60%, about 50 mol%, about 40 mol%, about 30 mol%, about 20 mol% or about 10 mol% of the silver- containing compound. In some embodiments, the reaction includes less than about 10 mol% of the silver-containing compound (e.g., about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, or less). In some embodiments, the fluoroalkoxylating agent is ^"OCF₃. In some embodiments, the fluoroalkoxylating reagent is represented by the following formula:

X⁺OCF₃,

wherein X is a cation.

In some embodiments, the cation is silver (Ag⁺). In some embodiments, the cation is cesium (Cs⁺). In some embodiments, the cation is ⁺NR¹ ₄ or ^""^"SR^_, wherein

each R¹ is independently Ci_6 alkyl, Ci_6 alkoxy, NR^aR^b, aryl, aralkyl, heteroaryl,

heteroaralkyl or heterocyclyl; and

each R^a and each R^b is independently hydrogen, C_1-4 alkyl, aryl or aralkyl.

In some embodiments, X is ⁺NR In some embodiments, each R¹ is independently d_₆ alkyl, aryl, aralkyl or NR^aR^b. In some embodiments, each R¹ is Ci_₆ alkyl (e.g., n-butyl).

In some embodiments, X is ⁺SR In some embodiments, each R¹ is independently d_₆ alkyl, aryl, aralkyl or NR^aR^b. In some embodiments, each R¹ is NR^aR^b. In some embodiments, each R^a and R^b is independently hydrogen or C_1-4 alkyl. In some

embodiments, each R^a and R^b is C_1-4 alkyl (e.g., methyl).

In some embodiments, the fluoroalkoxylating agent is prepared in situ.

In some embodiments, the fluoroalkoxylating agent comprises ¹⁸F or ¹⁹F.

In some embodiments, e.g., wherein the organic compound comprises a boron substituent, the method further comprises reacting a precursor of the organic compound with a boron-containing reagent to provide the organic compound comprising a boron substituent. In some embodiments, the precursor comprises a halogen substituent. In some embodiments, the precursor is borylated at an unactivated C-H bond, e.g., an aromatic, alkenyl or alkynyl C- H bond.

In some embodiments, e.g., wherein the organic compound comprises a silane substituent, the method further comprises reacting a precursor of the organic compound with a silicon-containing reagent to provide the compound comprising a silane substituent. In some embodiments, the precursor comprises a Grignard substituent (-Mg-X, wherein X is a halogen). In some embodiments, the precursor comprises a halogen substituent. In some embodiments, the precursor comprises a triflyl substituent.

In some embodiments, the method further comprises one or more additives (e.g., a base). In some embodiments, the method further comprises sodium hydroxide (NaOH). In some embodiments, the method further comprises sodium bicarbonate (NaHCC^). In some embodiments, the method further comprises sodium triflate (NaOTf). In some embodiments, the method further comprises sodium carbonate (NaCC^). In some embodiments, the method further comprises sodium hydroxide and sodium bicarbonate.

In some embodiments, the method further comprises a solvent. In some

embodiments, the solvent is a polar aprotic solvent (e.g., acetone, tetrahydrofuran (THF), acetonitrile and/or dimethylformamide (DMF)). In some embodiments, the solvent is a polar protic solvent (e.g., methanol). In some embodiments, the method comprises more than one solvent. In some embodiments, the method comprises two solvents. In some embodiments, the first solvent is present in about a 1:1 ratio (vol./vol.) with the second solvent. In some embodiments, the first solvent is present in about a 2:1 ratio (vol./vol.) with the second solvent. In some embodiments, the first solvent is present in about a 3:1 ratio (vol./vol.) with the second solvent. In some embodiments, the first solvent is present in about a 4:1 ratio (vol./vol.) with the second solvent. In some embodiments, the first solvent is acetone. In some embodiments, the second solvent is THF. In some embodiments, the first solvent is dimethylformamide (DMF). In some embodiments, the second solvent is acetonitrile.

In some embodiments, the method proceeds in one step. In some embodiments, the reaction proceeds in two steps. In some embodiments, the reaction proceeds via an intermediate. In some embodiments, the intermediate is isolated.

In some embodiments, the method further comprises an inert atmosphere. In some embodiments, the reaction is performed under anhydrous conditions. In some embodiments, the reaction is performed at ambient temperature. In some embodiments, the reaction is heated. In some embodiments, the reaction is cooled. In some embodiments, the organic compound is immobilized on a solid support. In some embodiments, the fluoroalkoxylation takes place at a late stage in the synthesis of the fluoroalkoxylated organic compound. In some embodiments, the fluoroalkoxylation is the last step in the synthesis of the

fluoroalkoxylated organic compound (e.g., wherein the organic compound is made using a multi step synthesis).

In some embodiments, the method further comprises purification (e.g., removing one or more impurities from the fluoroalkoxylated organic compound such as a tin containing product, a boron containing product or a silicon containing product) of the fluoroalkoxylated organic compound from the reaction mixture, e.g., by column chromatography on silica gel or preparative thin-layer chromatography. In some embodiments, the silver-containing compound and the fluoroalkoxylating agent are added to the organic compound comprising an organostannane, a boron substituent or a silane substituent.

In some embodiments, the silver-containing compound and an additional reagent (e.g., a base) are added to the organic compound comprising an organostannane, a boron substituent or a silane substituent, resulting in an intermediate product. In some

embodiments, the intermediate is isolated and a fluoroalkoxylating agent and a silver- containing compound are added thereto, resulting in formation of a fluoroalkoxylated organic compound.

In some embodiments, the additional reagent is a base. In some embodiments, the additional reagent is an additive. In some embodiments, the additional reagent is sodium bicarbonate (NaHCC>3). In some embodiments, the additional reagent is sodium triflate (NaOTf). In some embodiments, the additional reagent is sodium carbonate (NaCC>3). In some embodiments, the additional reagent is sodium hydroxide (NaOH).

In some embodiments, the reaction includes from about 5 to about 0.01 molar equivalents of silver-containing compound relative to the organic compound (e.g., about 3 equivalents of the silver-containing compound, about 2 equivalents of the silver-containing compound or about 1 equivalent of the silver-containing compound), from about 1 to about 3 molar equivalents of oxidizing agent relative to the organic compound (e.g., about 1.2 equivalnets of oxidizing agent).

In some embodiments, the yield of the fluoroalkoxylated organic compound from the organic compound is at least about 60% (e.g., at least about 65%, 70%, 75%, 80%, 85%, 90% or 95%). In some embodiments, the fluoroalkoxylated organic compound comprises ¹⁹F. In some embodiments, the fluoroalkoxylated organic compound comprises 18 F. In some embodiments, the fluoroalkoxylated organic compound is an imaging agent, e.g., a PET imaging agent. In some embodiments, the fluoroalkoxylated organic compound is a pharmaceutically acceptable compound. In some embodiments, the fluoroalkoxylated organic compound is 4-(trifluoromethoxy)biphenyl, l-fluoro-4-(trifluoromethoxy)benzene or (2-(trifluoromethoxy)vinyl)benzene. In some embodiments, the fluoroalkoxylated organic compound is a fluoroalkoxylated derivative of a vinca alkaloid (e.g., vinblastine, vincristine, vindesine or vinorelbine). In some embodiments, the fluoroalkoxylated organic compound features a fluoroalkoxylated vinca alkaloid as shown below:

In some embodiments, the fluoroalkoxylated organic compound is a morphine analog (e.g., codeine, oripavine, diacetylmorphine, dihydrocodeine, hydrocodone, hydromorphone, oxycodone or oxymorphone). In some embodiments, the fluoroalkoxylated organic compound features a fluoroalkoxylate wn below:

In some embodiments, the method is carried out on an sp2 hydridized carbon.

In another aspect, the invention features a method of fluoroalkoxylating an organic compound, the method comprising combining silver(I) hexafluorophosphate, an arylstannane and l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate), under conditions sufficient to fluoroalkoxylate the arylstannane, thereby providing a fluoroalkoxylated organic compound.

In another aspect, the invention features a reaction mixture comprising a silver- containing compound, an organic compound comprising an organostannane, a boron substituent or a silane substituent, and a fluoroalkoxylating agent.

In some embodiments, the reaction mixture further comprises an oxidizing agent (e.g., l-chloromethyl-4-fluoro- 1 ,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate)).

In some embodiments, the reaction mixture further comprises one or more additives (e.g., a base). In some embodiments, the reaction mixture further comprises sodium hydroxide (NaOH). In some embodiments, the reaction mixture further comprises sodium bicarbonate (NaHCC^). In some embodiments, the reaction mixture further comprises sodium triflate (NaOTf). In some embodiments, the reaction mixture further comprises sodium carbonate (NaCC^). In some embodiments, the reaction mixture further comprises sodium hydroxide and sodium bicarbonate.

In another aspect, the invention features a pharmaceutical composition, comprising a fluoroalkoxylated organic compound described herein (e.g., fluoro-4- (trifluoromethoxy)benzene, (2-(trifluoromethoxy)vinyl)benzene, 4- (trifluoromethoxy)biphenyl, N-Boc-5-trifluoromethoxyindole, 3-trifluoromethoxyestrone, 4- trifluoromethoxyanisole, ethyl 4-trifluoromethoxybenzoate, 1,3,5-trifluoromethoxybenzene, trifluoromethoxymorphine, a morphine fluoroalkoxy analog or a fluoroalkoxy derivative of a vinca alkaloid).

In another aspect, the invention features a kit comprising a silver-containing compound, an organic compound comprising an organostannane, a boron substituent or a silane substituent, and a fluoroalkoxylating agent.

In some embodiments, the kit further comprises an oxidizing agent (e.g., 1- chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate)).

The term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine or iodine.

The term "alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, CrC₁₂ alkyl indicates that the group may have from 1 to 12 (inclusive) carbon atoms in it. The term "haloalkyl" refers to an alkyl in which one or more hydrogen atoms are replaced by halo, and includes alkyl moieties in which all hydrogens have been replaced by halo (e.g.,

perfluoroalkyl). The terms "arylalkyl" or "aralkyl" refer to an alkyl moiety in which an alkyl hydrogen atom is replaced by an aryl group. Aralkyl includes groups in which more than one hydrogen atom has been replaced by an aryl group. Examples of "arylalkyl" or "aralkyl" include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and trityl groups.

The term "alkenyl" refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and having one or more double bonds. Examples of alkenyl groups include, but are not limited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups. One of the double bond carbons may optionally be the point of attachment of the alkenyl substituent. The term "alkynyl" refers to a straight or branched hydrocarbon chain containing 2-12 carbon atoms and characterized in having one or more triple bonds. Examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triple bond carbons may optionally be the point of attachment of the alkynyl substituent.

The terms "alkylamino" and "dialkylamino" refer to -NH(alkyl) and -NH(alkyl)₂ radicals respectively. The term "aralkylamino" refers to a -NH(aralkyl) radical. The term alkylaminoalkyl refers to a (alkyl)NH-alkyl- radical; the term dialkylaminoalkyl refers to a (alkyl)₂N-alkyl- radical The term "alkoxy" refers to an -O-alkyl radical. The term "mercapto" refers to an SH radical. The term "thioalkoxy" refers to an -S-alkyl radical. The term thioaryloxy refers to an -S-aryl radical.

The term "aryl" refers to an aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring system, wherein any ring atom capable of substitution can be substituted (e.g., by one or more substituents). Examples of aryl moieties include, but are not limited to, phenyl, naphthyl, and anthracenyl. An aryl moiety may also be a "heteroaryl" moiety. Heteroaryl refers to an aromatic monocyclic, bicyclic, or tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively). Any ring atom can be substituted (e.g., by one or more substituents).

The term "cycloalkyl" as employed herein includes saturated cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 3 to 12 carbons. Any ring atom can be substituted (e.g., by one or more substituents). The cycloalkyl groups can contain fused rings. Fused rings are rings that share a common carbon atom. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl, adamantyl, and norbornyl.

The term "fluoroalkoxylate" as employed herein refers to the replacement of a functional group (e.g., hydroxyl, trialkyltin, etc.) or hydrogen replaced with a C_1-8 alkoxy group wherein one or more of the hydrogen atoms on the C_1-8 alkoxy are replaced with a fluorine atom.

The term "heterocyclyl" refers to a nonaromatic 3-10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively). The heteroatom may optionally be the point of attachment of the heterocyclyl substituent. Any ring atom can be substituted (e.g., by one or more substituents). The heterocyclyl groups can contain fused rings. Fused rings are rings that share a common carbon atom. Examples of heterocyclyl include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino, pyrrolinyl, pyrimidinyl, quinolinyl, and pyrrolidinyl.

The term "cycloalkenyl" refers to partially unsaturated, nonaromatic, cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups having 5 to 12 carbons, preferably 5 to 8 carbons. The unsaturated carbon may optionally be the point of attachment of the cycloalkenyl substituent. Any ring atom can be substituted (e.g., by one or more substituents). The cycloalkenyl groups can contain fused rings. Fused rings are rings that share a common carbon atom. Examples of cycloalkenyl moieties include, but are not limited to,

cyclohexenyl, cyclohexadienyl, or norbornenyl.

The term "heterocycloalkenyl" refers to a partially saturated, nonaromatic 5-10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively). The unsaturated carbon or the heteroatom may optionally be the point of attachment of the heterocycloalkenyl substituent. Any ring atom can be substituted (e.g., by one or more substituents). The heterocycloalkenyl groups can contain fused rings. Fused rings are rings that share a common carbon atom. Examples of heterocycloalkenyl include but are not limited to tetrahydropyridyl and dihydropyranyl.

The term "aliphatic" or "aliphatic group", as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spiro-fused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-10 carbon atoms. In some embodiments, aliphatic groups contain 1-8 carbon atoms, 1-7 carbon atoms, 1-6 carbon atoms, 1-5 carbon atoms, 1-4 carbon atoms, 1- 3 carbon atoms, or 1-2 carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term "unsaturated", as used herein, means that a moiety has one or more double or triple bonds.

The term "substituents" refers to a group that replaces a hydrogen atom on an alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, aryl, or heteroaryl group at any atom of that group. Any atom can be substituted. Suitable substituents include, without limitation, alkyl (e.g., CI, C2, C3, C4, C5, C6, C7, C8, C9, CIO,

Cll, C12 straight or branched chain alkyl), cycloalkyl, haloalkyl (e.g., perfluoroalkyl such as

CF₃), aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy (e.g., perfluoroalkoxy such as OCF₃), halo, hydroxy, carboxy, carboxylate, cyano, nitro, amino, alkylamino, dialkylamino, SO₃H, sulfate, phosphate, methylenedioxy (-O-CH₂-O- wherein oxygens are attached to vicinal atoms), ethylenedioxy, oxo, thioxo (e.g., C=S), imino (alkyl, aryl, aralkyl), S(0)_nalkyl (where n is 0- 2), S(0)_n aryl (where n is 0-2), S(0)_n heteroaryl (where n is 0-2), S(0)_n heterocyclyl (where n is 0-2), amine (mono-, di-, alkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, and combinations thereof), ester (alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl), amide (mono-, di- , alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, and combinations thereof), sulfonamide (mono-, di-, alkyl, aralkyl, heteroaralkyl, and combinations thereof). In one aspect, the substituents on a group are independently any one single, or any subset of the aforementioned substituents. In another aspect, a substituent may itself be substituted with any one of the above substituents.

The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, internet web sites, databases, patents, patent applications and patent publications.

DETAILED DESCRIPTION

Described herein are methods of making fluoroalkoxylated organic compounds. Upon reaction of an organic compound comprising an organostannane, a boron substituent or a silane substituent, with a silver-containing compound and a fluoroalkoxylating agent, the method provides a fluoroalkoxylated organic compound in which the organostannane, boron substituent or silane substituent is replaced with a fluoroalkoxy substituent (See e.g., Schemes 1-4). In some embodiments, the organic compound is fluoroalkoxylated regiospecifically.

Scheme 1.

THF:acetone (1 :2), -30°C Scheme 2.

:ace one : , -

Scheme 3.

(R^y)₂B X⁺ OCF, F,CO.

-(R)n TT(R)n

N¾/₂ PF₆ ^{e 1 2 equiv}

^F 2.0 equiv AgPF₆

THF:acetone (1 :2), -30°C

Scheme 4.

THF:acetone (1 :2), -30°C

In the above Schemes, X⁺ is as defined above, R^x is an alkyl group, Ry is a hydroxyl or alkoxy group, R is a substituent and n may be 0, 1, 2, 3, 4 or 5. Exemplary substituents include, without limitation, alkyl (e.g., CI, C2, C3, C4, C5, C6, C7, C8, C9, CIO, Cll, C12 straight or branched chain alkyl), cycloalkyl, haloalkyl (e.g., perfluoroalkyl such as CF₃), aryl (e.g., phenyl), heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy (e.g., perfluoroalkoxy such as OCF₃), halo, hydroxy, carboxy, carboxylate, cyano, nitro, amino, alkylamino, dialkylamino, SO₃H, sulfate, phosphate, methylenedioxy (-O-CH₂-O- wherein oxygens are attached to vicinal atoms), ethylenedioxy, oxo, thioxo (e.g., C=S), imino (alkyl, aryl, aralkyl), S(0)_nalkyl (where n is 0- 2), S(0)_n aryl (where n is 0-2), S(0)_n heteroaryl (where n is 0-2), S(0)_n heterocyclyl (where n is 0-2), amine (mono-, di-, alkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, and combinations thereof), ester (alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl), amide (mono-, di- , alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, and combinations thereof), sulfonamide (mono-, di-, alkyl, aralkyl, heteroaralkyl, and combinations thereof). The substituents are independently any one single, or any subset of the aforementioned substituents. A substituent may itself be substituted with any one of the above substituents. In some embodiments, two R groups may be taken together to form a ring, e.g., an aryl, heteroaryl, cyclyl or heterocyclyl ring, which may itself be further substituted with any one of the above substituents.

Organic compounds

Methods of fluoroalkoxylating an organic compound are described herein. The organic compound may be a small organic molecule or a large organic molecule. A small organic molecule includes any molecule having a molecular weight of less than 1000 g/mol, of less than 900 g/mol, of less than 800 g/mol, of less than 700 g/mol, of less than 600 g/mol, of less than 500 g/mol, of less than 400 g/mol, of less than 300 g/mol, of less than 200 g/mol or of less than 100 g/mol. A large organic molecule include any molecule of between 1000 g/mol to 5000 g/mol, of between 1000 g/mol to 4000 g/mol, of between 1000 g/mol to 3000 g/mol, of between 1000 g/mol to 2000 g/mol, or of between 1000 g/mol to 1500 g/mol.

Organic compounds include aryl compounds, heteroaryl compounds, carbocyclic compounds, heterocyclic compounds, aliphatic compounds, heteroaliphatic compounds. In some embodiments, the organic compound is an aryl compound (e.g., a phenyl compound), or a heteroaryl compound (e.g. a quinolyl or indolyl compound). In some embodiments, the organic compound comprises a vinyl group. In some embodiments, the organic compound comprises a substituted vinyl group.

In some embodiments, the organic compound contains a chiral center. In some embodiments, 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). In some embodiments, the functional groups are unprotected. In some embodiments, the organic compound is a precursor of a pharmaceutically acceptable compound.

Organostannanes

Methods of fluoroalkoxylating an organic compound are described herein. In some embodiments, the organic compound comprises an organostannane. The organostannane may be a trialkylstannane, e.g., trimethylstannane or tributylstannane.

Exemplary organostannanes include biphenyl-4-yl-tributylstannane, tributyl(4- fluorophenyl)stannane, tributyl(4-methoxyphenyl)stannane, tributyl(2- methoxyphenyl)stannane, tributyl(3,4,5-trimethoxyphenyl)stannane, tributyl(4- bromophenyl)stannane, ethyl-4-(tributylstannyl)benzoate, methyl-6-(tributylstannyl)-2- naphthoate, i-butyl-5-(tributylstannyl)- lH-indole- 1-carboxylate, methyl-2-(t- butoxycarbonylamino)-3-(4-(tributylstannyl)phenyl)propanoate, 3-deoxy-3- tributylstannylestrone, N-Boc-4-(tributylstannyl)-L-phenylalanyl-L-phenylalanine methyl ester, 6-(tributylstannyl)quinoline, tributyl(styryl)stannane or a stannane derivative of a vinca alkaloid (e.g., vinblastine, vincristine, vindesine or vinorelbine). Exemplary organostannanes also feature a fluoroalkoxylated vinca alkaloid, such as that de icted below:

Exemplary organostannanes also include a morphine analog (e.g., codeine, oripavine, diacetylmorphine, dihydrocodeine, hydrocodone, hydromorphone, oxycodone or

oxymorphone). Exemplary organostannanes also feature a fluoroalkoxylated morphine, such as that depicted below:

Exemplary organostannanes also feature a fluoroalkoxylated morphine, such as that depicted below:

Boron substituents

Methods of fluoroalkoxylating an organic compound are described herein. In some embodiments, the organic compound comprises a boron substituent. The boron substituent may be of the formula:

wherein G¹, G² and G³ are, independently, -OH, -OR, or -R, wherein each R is, independently, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, or optionally substituted heteroaryl, or G¹ and G² are joined to form an optionally substituted 5- to 8-membered ring having at least one O atom directly attached to B, wherein the ring is comprised of carbon atoms and optionally one or more additional heteroatoms independently selected from the group consisting of N, S, and O. A⁺ may be a metal cation or ammonium.

As used herein, a boron substituent is intended to encompass free boronic acid substituents (i.e., wherein G¹ and G² are both -OH) and oligomeric anhydrides thereof (including dimers, trimers, and tetramers, and mixtures thereof), boronic ester substituents (i.e., wherein G¹ is -OH or -OR and G² is -OR), boronic acid substituents (i.e., wherein G¹ is -OH and G² is -R), borinic ester substituents (i.e., wherein G¹ is -OR and G² is -R), trihydroxoborates (i.e., wherein G¹, G² and G³ are all -OH), and trialkoxyborates (i.e., wherein G¹, G² and G³ are all -OR, e.g., -OCH₃).

In some embodiments, G¹ and G² are joined to form a 5-membered ring. Exemplary 5-membered rings include:

(H₃C)₂N(0)C C(0)N(CH₃)₂

In some embodiments, G¹ and G² are joined to form a 6-membered ring. Exemplary 6-membered rings include:

In some embodiments, G¹ and G² are joined to form an 8-membered ring. Exemplary 8-membered rings include:

wherein R^m is hydrogen, a suitable amino protecting group, or an optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, or optionally substituted heteroaryl group.

Furthermore, as used herein, a boron substituent is also intended to encompass a trifluoroborate substituent. For example, in some embodiments, a boron substituent is a group of the formula:

F

\

F wherein A® is a metal cation or ammonium.

Furthermore, as used herein, a boron substituent is also intended to encompass trihydroxy- and trialkoxy borates. For example, in some embodiments, a boron substituent is a group of the formulae:

wherein A® is a metal cation or ammonium.

Exemplary metal cations include lithium, sodium, potassium, magnesium, and calcium cations. In some embodiments, the metal cation is a potassium cation.

An organic compound comprising a boron substituent may be obtained via a variety of known methods. For example, a halogen-containing precursor may be reacted with a boron-containing compound to generate the organic compound comprising a boron substituent. An unactivated C-H bond may also be borylated, for example, using a suitable catalyst. Exemplary boron containing organic compounds include biphenyl-4-yl-boronic acid, 4-methoxyphenylboronic acid, l-(tert-butoxycarbonyl)-lH-indol-5-ylboronic acid, naphthalene-2-ylboronic acid, 3-(methoxycarbonyl)-5-methylphenylboronic acid or 4- fluorophenylboronic acid.

Silane substituents

Methods of fluoroalkoxylating an organic compound are described herein. In some embodiments, the organic compound comprises a silane substituent. The silane substituent may be a trialkoxysilane, e.g., trimethoxysilane or triethoxysilane. The silane substituent may be a trihydroxy silane.

An organic compound comprising a silane substituent may be obtained via a variety of known methods. For example, a Grignard-containing precursor may be reacted with a silicon-containing compound (e.g., a tetraalkoxysilane) to generate the organic compound comprising a silane substituent. In another example, a halogen-containing precursor or a triflyl-containing precursor may be reacted with a silicon-containing compound (e.g., a tetraalkoxysilane) in the presence of a suitable catalyst (e.g., a Pd° or Rh¹ catalyst) to generate the organic compound comprising a silane substituent.

Silver-containing compounds

The methods described herein generally include a silver-containing compound. The silver-containing compound may be a silver complex or a silver salt, e.g., a silver(I) salt. Exemplary silver salts include silver(I) salts such as silver(I) fluoride, silver(I) acetate, silver(I) tetrafluoroborate, silver(I) perchlorate, silver(I) nitrate, silver(I) carbonate, silver(I) cyanide, silver(I) benzoate, silver(I) triflate, silver(I) hexafluorophosphate, silver(I) hexafluoroantimonate, silver(I) oxide, silver(I) nitrite and silver(I) phosphate. In preferred embodiments, the silver salt is silver(I) triflate or silver(I) oxide.

Fluoroalkoxylating agents

The methods described herein generally include a fluoroalkoxylating agent and sources thereof. In some embodiments, the fluoroalkoxylating agent is commercially available. In some embodiments, the fluoroalkoxylating agent is an inorganic

fluoroakoxylating agent. Exemplary fluoroakoxylating agents include OCF₃, precursors thereof and compound of the following formula: X⁺OCF₃,

wherein X is a cation.

The fluoroalkoxylating agent may be enriched with a particular isotope of fluorine. In some embodiments, the fluoroalkoxylating agent is labeled with ¹⁹F (i.e. , transfers a ¹⁹F fluorine substituent to the organic compound). In some embodiments, reaction of the ¹⁹F- labeled fluoroalkoxylating agent with the organic compound and silver-containing compound provides a fluoroalkoxylated ¹⁹F-labeled organic compound.

18

In some embodiments, the fluoroalkoxylating agent is labeled with F (i.e. , transfers

18

an F fluorine substituent to the organic compound). In some embodiments, reaction of the

18

F-labeled fluoroalkoxylating agent with the organic compound and silver-containing compound provides a fluoroalkoxylated ¹⁸F-labeled organic compound.

However, in some embodiments, the fluoroalkoxylating agent is labeled with a mixture of ¹⁸F and ¹⁹F. In some embodiments, reaction of the mixture of ¹⁹F and ¹⁸F fluoroalkoxylating agent with the organic compound and silver-containing compound provides a mixture of fluoroalkoxylated ¹⁹F-labeled organic compound and fluoroalkoxylated ¹⁸F-labeled organic compound.

Reaction Conditions

Described herein are methods of fluoroakoxylating organic compounds using silver- containing compounds and a fluoroakoxylating agent. In some embodiments, the reaction further comprises a solvent. The solvent may be a polar aprotic solvent. Exemplary polar aprotic solvents include acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane,

dimethylformamide and dimethylsulfoxide. In some embodiments, the solvent is acetone.

The solvent may be a polar protic solvent. Exemplary polar protic solvents include methanol, ethanol, isopropanol and n-butanol. In some embodiments, the solvent is methanol.

In some embodiments, the reaction is performed under ambient temperature, pressure and atmosphere. In some embodiments, the reaction is performed in an inert atmosphere (e.g., an atmosphere that is substantially free of dioxygen). In some embodiments, the reaction is performed under anhydrous conditions (e.g., in a solvent that is substantially free of water). In some embodiments, the reaction is heated. In some embodiments, the reaction is cooled.

In some embodiments, the reaction is performed at room temperature (e.g., about 20-25 °C).

In some embodiments, the reaction is catalytic. For example, in some embodiments, the reaction includes less than about 1 equivalent of the silver-containing compound, e.g., about 90%, about 80%, about 70%, about 60%, about 50 mol%, about 40 mol%, about 30 mol%, about 20 mol% or about 10 mol% of the silver-containing compound. In some embodiments, the reaction includes less than about 10 mol% of the silver-containing compound (e.g., about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, or less).

In some embodiments, the fluoroalkoxylating reaction is performed on an organic compound that is immobilized on a solid support. The term "solid support" refers a material to which a compound is attached to facilitate identification, isolation, purification, or chemical reaction selectivity of the compound. Such materials are known in the art and include, for example, beads, pellets, disks, fibers, gels, or particles such as cellulose beads, pore-glass beads, silica gels, polystyrene beads optionally cross-linked with divinylbenzene and optionally grafted with polyethylene glycol, poly-acrylamide beads, latex beads, dimethylacrylamide beads optionally cross-linked with Ν,Ν'-bis-acryloyl ethylene diamine, glass particles coated with hydrophobic polymer, and material having a rigid or semi-rigid surface. The solid supports optionally have functional groups such as amino, hydroxy, carboxy, or halo groups, (see, Obrecht, D. and Villalgrodo, J.M., Solid-Supported

Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries, Pergamon-Elsevier Science Limited (1998)), and include those useful in techniques such as the "split and pool" or "parallel" synthesis techniques, solid-phase and solution-phase techniques, and encoding techniques (see, for example, Czarnik, A.W., Curr. Opin. Chem. 5 o. , (1997) 1, 60).

In some embodiments, the fluoroalkoxylating of the compound comprising an organostannane, a boron substituent or a silane substituent takes place at a late stage in the synthesis of the fluoroalkoxylated organic compound. In some embodiments, the fluoroalkoxylation is the last step in the synthesis of the fluoroalkoxylated organic compound.

In some embodiments, subsequent to the reaction, one or more components of the reaction mixture (e.g., a fluoroalkoxylated organic compound) are purified from the reaction mixture. In some embodiments, the fluoroalkoxylated organic compound is purified by column chromatography on silica gel. In some embodiments, the fluoroalkoxylated organic compound is purified by preparative thin-layer chromatography.

Reaction products Described herein are methods of making fluoroalkoxylated organic compounds. In some embodiments, the fluoroalkoxylated organic compounds are generated from their corresponding precursors in yields of at least about 60% (e.g., at least about 65%, 70%, 75%, 80%, 85%, 90% or 95%).

The reaction conditions described herein are tolerant of many functional groups as well as chiral centers. In some embodiments, the fluoroalkoxylated organic compound is further substituted by one or more functional groups, such as alcohols, aldehydes, ketones, esters, alkenes, alkoxy groups, cyano groups, amines, amides and N-oxides. In some embodiments, the fluoroalkoxylated 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 of the chiral center occurs during the reaction).

In some embodiments, the fluoroalkoxylated organic compound comprises ¹⁹F. In some embodiments, the ¹⁹F-containing fluoroalkoxylated organic compound is an imaging agent, such as an MRI imaging agents. In some embodiments, the ¹⁹F-containing

fluoroalkoxylated organic compound may be used as a probe, such as a biological NMR probes for use in in vivo NMR spectroscopy.

In some embodiments, the fluoroalkoxylated organic compound comprises ¹⁸F. In

18

some embodiments, the F-containing fluoroalkoxylated organic compound is an imaging agent, such as a PET imaging agent.

In some embodiments, the fluoroalkoxylated organic compound is a pharmaceutically acceptable compound. In some embodiments, the fluoroalkoxylated organic compound is a pharmaceutical agent approved by the United States Food and Drug Administration (FDA) for administration to a human (see, for example,

www.accessdata.fda.gov/scripts/cder/drugsatfda/).

In some embodiments, the fluoroalkoxylated organic compound is a compound having pharmaceutical activity.

Methods of treatment

The compounds and compositions described herein can be administered to cells in culture, e.g. in vitro or ex vivo, or to a subject, e.g., in vivo, to treat, prevent, and/or diagnose a variety of disorders, including those described herein below.

As used herein, the term "treat" or "treatment" is defined as the application or administration of a compound, alone or in combination with, a second compound to a subject, e.g., a patient, or application or administration of the compound to an isolated tissue or cell, e.g., cell line, from a subject, e.g., a patient, who has a disorder (e.g., a disorder as described herein), a symptom of a disorder, or a predisposition toward a disorder, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve or affect the disorder, one or more symptoms of the disorder or the predisposition toward the disorder (e.g., to prevent at least one symptom of the disorder or to delay onset of at least one symptom of the disorder).

As used herein, an amount of a compound effective to treat a disorder, or a

"therapeutically effective amount" refers to an amount of the compound which is effective, upon single or multiple dose administration to a subject, in treating a cell, or in curing, alleviating, relieving or improving a subject with a disorder beyond that expected in the absence of such treatment.

As used herein, an amount of a compound effective to prevent a disorder, or "a prophylactically effective amount" of the compound refers to an amount effective, upon single- or multiple-dose administration to the subject, in preventing or delaying the occurrence of the onset or recurrence of a disorder or a symptom of the disorder.

As used herein, the term "subject" is intended to include human and non-human animals. Exemplary human subjects include a human patient having a disorder, e.g., a disorder described herein or a normal subject. The term "non-human animals" of the invention includes all vertebrates, e.g., non-mammals (such as chickens, amphibians, reptiles) and mammals, such as non-human primates, domesticated and/or agriculturally useful animals, e.g., sheep, dog, cat, cow, pig, etc.

Described herein are compounds and compositions useful in the treatment of a disorder. In general, the compounds described herein are fluoroalkoxylated derivatives of a pharmaceutical agent. Also envisioned herein are other compounds, wherein one or more fluorine moieties have been added to the pharmaceutical agent, e.g., replacing a hydrogen or functional group such as an -OH with a fluorine.

Compositions and routes of administration

The compositions delineated herein include the compounds delineated herein (e.g., a compound described herein), as well as additional therapeutic agents if present, in amounts effective for achieving a modulation of disease or disease symptoms, including those described herein. The term "pharmaceutically acceptable carrier or adjuvant" refers to a carrier or adjuvant that may be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d- a- tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium

carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hy droxy alky Icy clodextrins, including 2- and 3- hydroxypropyl- -cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of the formulae described herein.

The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer' s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions. Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.

The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

Topical administration of the pharmaceutical compositions of this invention is useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol,

polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents.

Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches are also included in this invention.

The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance

bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

When the compositions of this invention comprise a combination of a compound of the formulae described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention.

Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.

The compounds described herein can, for example, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or

subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Alternatively, such preparations contain from about 20% to about 80% active compound.

Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the treating physician.

Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.

Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

Kits

The compounds used in the methods described herein (e.g., an organic compound comprising an organostannane, a boron substituent or a silane substituent, a silver-containing compound and a fluoroalkoxylating agent) may be provided in a kit. The kit includes (a) a compound used in a method described herein, and, optionally (b) informational material. The informational material can be descriptive, instructional, marketing or other material that relates to the methods described herein and/or the use of the compounds for the methods described herein.

The informational material of the kits is not limited in its form. In one embodiment, the informational material can include information about production of the compound, molecular weight of the compound, concentration, date of expiration, batch or production site information, and so forth. In one embodiment, the informational material relates to methods for administering the compound. In one embodiment, the informational material can include instructions to administer a compound described herein in a suitable manner to perform the methods described herein, e.g., in a suitable dose, dosage form, or mode of administration (e.g., a dose, dosage form, or mode of administration described herein). In another embodiment, the informational material can include instructions to administer a compound described herein to a suitable subject, e.g., a human, e.g., a human having or at risk for a disorder described herein.

The informational material of the kits is not limited in its form. In many cases, the informational material, e.g., instructions, is provided in printed matter, e.g., a printed text, drawing, and/or photograph, e.g., a label or printed sheet. However, the informational material can also be provided in other formats, such as Braille, computer readable material, video recording, or audio recording. In another embodiment, the informational material of the kit is contact information, e.g., a physical address, email address, website, or telephone number, where a user of the kit can obtain substantive information about a compound described herein and/or its use in the methods described herein. Of course, the informational material can also be provided in any combination of formats.

In addition to a compound described herein, the composition of the kit can include other ingredients, such as a solvent or buffer, a stabilizer, a preservative, a flavoring agent (e.g., a bitter antagonist or a sweetener), a fragrance, a dye or coloring agent, for example, to tint or color one or more components in the kit, or other cosmetic ingredient, and/or a second agent for treating a condition or disorder described herein. Alternatively, the other ingredients can be included in the kit, but in different compositions or containers than a compound described herein. In such embodiments, the kit can include instructions for admixing a compound described herein and the other ingredients, or for using a compound described herein together with the other ingredients.

In some embodiments, the components of the kit are stored under inert conditions

(e.g., under Nitrogen or another inert gas such as Argon). In some embodiments, the components of the kit are stored under anhydrous conditions (e.g., with a desiccant). In some embodiments, the components are stored in a light blocking container such as an amber vial.

A compound described herein can be provided in any form, e.g., liquid, dried or lyophilized form. It is preferred that a compound described herein be substantially pure and/or sterile. When a compound described herein is provided in a liquid solution, the liquid solution preferably is an aqueous solution, with a sterile aqueous solution being preferred.

When a compound described herein is provided as a dried form, reconstitution generally is by the addition of a suitable solvent. The solvent, e.g., sterile water or buffer, can optionally be provided in the kit.

The kit can include one or more containers for the composition containing a compound described herein. In some embodiments, the kit contains separate containers, dividers or compartments for the composition and informational material. For example, the composition can be contained in a bottle, vial, or syringe, and the informational material can be contained in a plastic sleeve or packet. In other embodiments, the separate elements of the kit are contained within a single, undivided container. For example, the composition is contained in a bottle, vial or syringe that has attached thereto the informational material in the form of a label. In some embodiments, the kit includes a plurality (e.g., a pack) of individual containers, each containing one or more unit dosage forms (e.g., a dosage form described herein) of a compound described herein. For example, the kit includes a plurality of syringes, ampules, foil packets, or blister packs, each containing a single unit dose of a compound described herein. The containers of the kits can be air tight, waterproof (e.g., impermeable to changes in moisture or evaporation), and/or light-tight.

The kit optionally includes a device suitable for administration of the composition, e.g., a syringe, inhalant, pipette, forceps, measured spoon, dropper (e.g., eye dropper), swab (e.g., a cotton swab or wooden swab), or any such delivery device. In a preferred

embodiment, the device is a medical implant device, e.g., packaged for surgical insertion.

EXAMPLES

All reactions were carried out under an inert nitrogen atmosphere unless otherwise indicated. Dichloromethane was dried by passage through alumina. Except as indicated otherwise, reactions were magnetically stirred and monitored by thin layer chromatography (TLC) using EMD TLC plates pre-coated with 250 μιη thickness silica gel 60 F254 plates and visualized by fluorescence quenching under UV light. In addition, TLC plates were stained using eerie ammonium molybdate or potassium permanganate stain. Flash chromatography was performed on Dynamic Adsorbents Silica Gel 40-63 μιη particle size using a forced flow of eluent at 0.3-0.5 bar pressure. Concentration under reduced pressure was performed by rotary evaporation at 25-30 °C (and at 5 °C when specified) at appropriate pressure. Purified compounds were further dried under vacuum (0.01-0.2 Torr depending on volatility of compound). NMR spectra were recorded on a Varian Mercury 400 (400 MHz for ^]H, 100 MHz for ¹³C, and 375 MHz for ¹⁹F acquisitions) or Unity/Inova 500 (500 MHz for ^]H, 125 MHz for ¹³C, and 470 MHz for ¹⁹F acquisitions). ¹³C NMR spectra are recorded ^]H decoupled. ¹⁹F NMR spectra are recorded ^]H coupled. Chemical shifts are reported in ppm with the solvent resonance as the internal standard (CDC1₃, 23 °C, ^]H NMR: 7.26 ppm, ¹³C NMR: 77.16 ppm). Data is reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad; coupling constants in Hz; integration. High-resolution mass spectra were obtained on Jeol AX-505 or SX-102 spectrometers at the Harvard University Mass Spectrometry Facilities. Anhydrous THF was obtained by distillation over sodium/benzophenone. Dry acetone was was obtained by distillation over B2O₃.

Triethylamine and N,N-diisopropylethylamine were distilled over calcium hydride, n- Butyllithium, tris(dimethylamino)sulfonium difluorotrimethylsilicate, silver

hexafluorophosphate, tetrakis(triphenylphosphine)palladium, lithium chloride,

hexabutylditin, 1,4-dioxane (anhydrous, 99.8% in Sure/Seal™), 4-(dimethylamino)pyridine, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1- hydroxybenzotriazole (HOBt), N-phenyltriflimide, and methyl chloroformate were purchased from Aldrich and used as received. Sodium bicarbonate and sand were purchased from Mallinckrodt Chemicals and used as received. l-Chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), ammonium hexafluorophosphate, and tributyltin chloride were purchased from Alfa Aesar and used as received.

Trifluoromethanesulfonic acid was purchased from Oakwood Products, Inc. and used as received. Phosphorus pentoxide was purchased from Acros Organics and used as received. NMR spectroscopic data of known compounds correspond to the data given in the appropriate references. NMR spectra of new compounds are attached. Arylstannanes were prepared and used within 1 week and l-chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) was prepared and used with one month for the trifluoromethoxylation reactions.

Compounds

Example 1. General procedure for the trifluoromethoxylation of aryl stannanes

To a 25 mL oven-dried two-neck round-bottom flask charged with a magnetic bar, tris(dimethylamino)sulfonium difluorotrimethylsilicate (222 mg, 1.00 mmol, 2.00 equiv) in an one dram vial, which was prepared in a glove box, sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv), and aryl stannane (0.500 mmol, 1.00 equiv) were added under a low nitrogen flow. To the flask, anhydrous THF (2.00 mL) was added at -30 °C under a nitrogen flow using a 3 mL syringe. Trifluoromethyl trifluoromethanesulfonate (SI) (0.450 g, 0.300 mL, 2.10 mmol, 4.10 equiv) in a Schlenk flask subsequently was added at -30 °C under a nitrogen flow using a 1 mL syringe, which was cooled by crushed dry ice wrapped in aluminum foil, while the suspension was stirred vigorously at -30 °C. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of 1 -chloromethyl-4- fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv) and silver hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) in dry acetone (6.0 mL), which was prepared in a glovebox in a 25 mL round-bottom flask was added by cannula. The reaction mixture was stirred for 2 to 4 hours in the dark, then warmed to 23 °C. The reaction mixture was filtered through a pad of celite eluting with CH₂CI₂ and the filtrate concentrated in vacuo. The residue was purified via column chromatography on silica gel to afford the desired trifluoromethoxylated compound. Example 2. General procedure for the trifluoromethoxylation of arylboronic acids

To an anhydrous methanol solution of sodium hydroxide (1.00 N, 0.500 mL, 1.00 equiv) in an oven-dried 4 dram vial with a resealable PTFE/silicone disc under a nitrogen flow, which was charged with a magnetic bar, was added arylboronic acid (0.500 mmol, 1.00 equiv) at 23 °C and stirred for 15 minutes. The reaction mixture was then cooled to 0 °C and silver hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv), which was prepared in an oven- dried 0.5 dram vial in a glove box was added quickly and the suspension was stirred for 30 minutes at 0 °C. The solvent was removed under reduced pressure at 0 °C, and the residual methanol was removed under reduced pressure by co-evaporation with anhydrous THF (2 x 0.500 mL). To the residue was added tris(dimethylamino)sulfonium difluorotrimethylsilicate (276 mg, 1.00 mmol, 2.00 equiv) and sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv), which was prepared in a one dram vial in a glove box, and then anhydrous THF (2.0 mL) was added to the mixture at -30 °C. Trifluoromethyl trifluoromethanesulfonate (SI) (0.600 g, 0.400 mL, 2.80 mmol, 5.50 equiv) in a Schlenk flask subsequently was added to the reaction mixture at -30 °C under a nitrogen flow using a 1 mL syringe, which was cooled by crushed dry ice wrapped in aluminum foil, while the suspension was stirred vigorously at -30 °C, and the suspension was stirred further at -30 °C for 30 minutes. A solution of l-chloromethyl-4- fluoro-l,4-diazoniabicyclo[2.2.2]octane bis (hexafluorophosphate) (la) (282 mg, 0.600 mmol,

1.20 equiv) in dry acetone (6.0 mL), which was cooled to -30 °C was added. The suspension was stirred for 1 hour and then filtered through a pad of celite eluting with CH₂CI₂ and the filtrate concentrated in vacuo. The residue was purified via column chromatography to afford the desired trifluoromethoxylated compound.

Most reagents were stored in a glovebox for optimal results. The reaction could also be performed without the use of a glovebox when fresh reagents were used.

Example 3. Trifluoromethyl trifluoromethanesulfonate (SI)

0* , O 0.31 equiv P₂O_s , O

F₃C OH 110 °C OCF₃

56% _S1

Trifluoromethyl trifluoromethanesulfonate (SI) is commercially available from Oakwood Products, Inc. It can be prepared in 80% yield by a procedure published by Taylor and Martin from triflic anhydride and SbFs as catalyst in one step.

A 250-mL round-bottomed flask charged with a magnetic stir bar, 30-cm Vigreux column, and 100-mL round-bottomed receiving flask were dried in an oven for 12 hours at 135 °C. The system was assembled while the glass was hot and cooled under vacuum to 25 °C and then backfilled with N₂ and kept under a N₂ atmosphere. To the dry 250-mL round- bottomed flask charged with a magnetic stir bar was added sequentially sand (10.0 g), phosphorous pentoxide (25.0 g, 180 mmol, 0.310 eq), and trifluoromethanesulfonic acid (50.0 mL, 84.8 g, 565 mmol, 1.00 eq). The receiving flask was cooled to -78 °C. The reaction mixture was stirred at room temperature for 3 hours, then heated until reaching 110 °C (30 °C every 15 minutes) for a total of 8 hours. The distillate collected in the 100-mL round-bottomed Schlenk flask was then sealed and attached to a N₂ line. To the 100-mL round-bottomed flask at 0 °C was added a precooled solution of 3 M KOH (50 mL) at 0 °C. To the 100-mL round-bottomed flask at 0 °C was attached a short-path distillation apparatus with a 100-mL round-bottomed Schlenk flask as the collection flask was cooled to -78 °C. The 100-mL round-bottomed flask was warmed with a water bath to 25 °C and the distillate collected via short-path distillation in the 100-mL round-bottomed Schlenk flask cooled to -78 °C. The 100-mL round-bottomed Schlenk flask was then sealed after all the distillate was collected, allowed to warm to 25 °C, and attached to a vacuum transfer apparatus with a 50-mL longbodied Schlenk flask. The vacuum transfer apparatus was flamed dried under vacuum and allowed to cool to 25 °C. The distillate was then transferred via vacuum transfer at 0 °C (frozen solid with liquid nitrogen first, then during vacuum transfer allowed to warm to 0 °C) over 15 minutes and the liquid collected in the 50-mL longbodied Schlenk flask, cooled with liquid nitrogen, to give 34.5 g of the target compound as a colorless liquid (56%). The compound was stored in the 50-mL longbodied Schlenk flask at -20 °C.

NMR Spectroscopy: ¹³C NMR (100 MHz, CDC1₃, 23 °C, δ): 118.8 (q, / = 273 Hz), 118.4 (q, / = 320 Hz). ¹⁹F NMR (375 MHz, CDC1₃, 23 °C, δ): -73.5 (q, / = 4.5 Hz), -52.9 (q, J = 3.0 Hz). The previously reported spectroscopic data are ¹⁹F NMR (CFCI₃, 23 °C, δ): - 74.0 (q, / = 3.5 Hz), -53.3 (q, / = 3.5 Hz).

Example 4. Tris(dimethylamino)sulfonium trifluoromethoxide (TAS · OCF₃) (1)

Typically, 1 was prepared in situ outside of a glovebox. For characterization purposes, we also synthesized it as a purified material as follows:

All manipulations were carried out in a dry box under a N₂ atmosphere. To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (330 mg, 1.20 mmol, 1.00 equiv) in anhydrous THF (12 mL) in a 20 mL vial with a resealable PTFE/silicone disc at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (0.392 g, 0.261 mL, 1.80 mmol, 1.5 equiv) using a syringe (both SI and the syringe were cooled to -30 °C). The suspension was stirred vigorously at -30 °C and at 23 °C for 15 min and 30 min,

respectively. The suspension was filtered off and washed with THF (3 x 3 mL) to afford 243 mg of the title compound as a colorless solid (82% yield).

NMR Spectroscopy: ^]H NMR (500 MHz, CD₂C1₂, 23 °C, δ): 2.93 (s, 18H). ¹³C NMR

(125 MHz, CD₂C1₂, 23 °C, δ): 38.7. ¹⁹F NMR (470 MHz, CD₂C1₂, 23 °C, δ): -20.5 (s, br).

Example 5. Synthesis of l-Chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la)

1a

To 1 -chloromethyl-4-fluoro- 1 ,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.06 g, 3.00 mmol, 1.00 equiv) in H₂0 (9.0 mL) at 23 °C was added ammonium

hexafluorophosphate (2.93 g, 18.0 mmol, 6.00 equiv). After stirring for 1 h, the suspension was filtered off and washed with H₂0 (5 x 5 rriL) and Et₂0 (10 mL) to afford 1.43 g of the title compound (la) as a colorless solid (quantitative yield).

NMR Spectroscopy: ^]H NMR (400 MHz, acetonitrile-J3, 23 °C, δ): 5.27 (s, 2H), 4.70 (dt, Jup = 7.6 Hz, 7.2 Hz, 6H), 4.24 (t, J = 7.2, 6H). ¹³C NMR (125 MHz, acetonitrile-J6, 23 °C, δ): 70.08, 58.18 (d, /_CF = 15.3 Hz), 54.67. ¹⁹F NMR (375 MHz, acetonitrile-J3, 23 °C, δ): 47.61 (s, IF), -72.89 (d, 7_FP = 710 Hz, 6F). ³¹P NMR (162 MHz, acetonitrile-J3, 23 °C, δ): - 143.5 (h, JFP = 710 Hz). Mass Spectrometry: HRMS-FIA (m/z): Calcd for [M - PF₆]⁺, 325.04659. Found 325.04664.

Example 6. Tributyl(4-biphenyl)stannane

88% 2

To 4-bromobiphenyl (3.00 g, 12.9 mmol, 1.00 equiv) in anhydrous THF (30 mL) at - 78 °C was added nBuLi (2.5 M in hexanes, 5.1 mL, 13 mmol, 1.0 equiv). The reaction mixture was stirred at -78 °C for 30 min before the addition of Bu₃SnCl (4.20 g, 3.50 mL, 12.9 mmol, 1.00 equiv). After stirring for 1.0 hr at -78 °C, the reaction mixture was warmed to 23 °C and the solvent was removed in vacuo. The residue was dissolved in 20 mL of Et₂0 and filtered through a plug of neutral alumina. The filtrate was concentrated in vacuo and the residue purified via column chromatography on silica gel eluting with hexanes to afford 3.76 g of the title compound as a colorless oil (88% yield).

R/ = 0.58 (hexanes). NMR Spectroscopy: Ή NMR (400 MHz, CDC1₃, 23 °C, δ):

7.69-7.57 (m, 6H), 7.58-7.51 (m, 2H), 7.44-7.38 (m, 1H), 1.75-1.59 (m, 6H), 1.52-1.40 (: 6H), 1.27-1.09 (m, 6H), 0.99 (t, J = 7.3 Hz, 9H). ¹³C NMR (100 MHz, CDC1₃, 23 °C, δ): 141.5, 140.0, 137.0, 128.9, 127.3, 127.2, 127.1 , 126.8, 29.3, 27.6, 13.9, 9.8.

Example 7. 4-(Trifluoromethoxy)biphenyl (3)

2.0 equiv TAS · OCF₃

1.2 e uiv F-TEDA-PF

2.0 equiv NaHC0₃

THF:acetone (1 :3)

2 -30 °C 3

88% To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (222 mg,

1.00 mmol, 2.00 equiv), sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv), and tributyl(4-biphenyl)stannane (2) (253 mg, 0.500 mmol, 1.00 equiv) in anhydrous THF (2.00 mL) at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (0.45 g, 0.30 mL,

2.1 mmol, 4.1 equiv)(0.45 g, 0.30 mL, 2.1 mmol, 4.1 equiv), and the suspension was stirred vigorously. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane

bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv) and silver

hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) in dry acetone (6.0 mL) was added by cannula. The reaction mixture was stirred for 2.5 hours in the dark, then warmed to 23 °C. The reaction mixture was filtered through a pad of celite eluting with CH₂CI₂ and the filtrate concentrated in vacuo. The residue was purified via column chromatography on silica gel eluting with hexanes/CH₂Cl₂ 19:1 (v/v) to afford 104 mg of the title compound as a white solid (88% yield).

R_f = 0.53 (hexanes/CH₂Cl₂ 19:1 (v/v)). NMR Spectroscopy: ^]H NMR (500 MHz, CDC1₃, 23 °C, δ): 7.64-7.59 (m, 4H), 7.51-7.48 (m, 2 H), 7.41 (t, 7 = 7.3 Hz, 1H), 7.34 (d, / = 8.2 Hz, 2H). ¹³C NMR (100 MHz, CDC1₃, 23 °C, δ): 148.8 (q, / = 2 Hz), 140.1, 140.0, 129.0, 128.6, 127.8, 127.3, 121.4, 120.7 (q, / = 256 Hz). ¹⁹F NMR (375 MHz, CDC1₃, 23 °C, δ): -58.2.

Example 8. l-Methoxy-4-(trifluoromethoxy)benzene (6)

.0 equiv TAS · OCF3

.2 equiv F-TEDA-PFg

2.0 equiv AgPF₆ ^^-^0CF

M O"^^ 2.0 equiv NaHC0₃ MeO'

THF:acetone (1 :3)

5 -30 °C

87%

To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (275 mg, 1.00 mmol, 2.00 equiv), sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv), and tributyl(4-methoxyphenyl)stannane¹ (5) (199 mg, 0.500 mmol, 1.00 equiv) in anhydrous THF (2.00 mL) at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (0.45 g, 0.30 mL, 2.1 mmol, 4.1equiv), and the suspension was stirred vigorously. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of l-chloromethyl-4- fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv) and silver hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) in dry acetone (6.0 mL) was added by cannula. The reaction mixture was stirred for 2 hours in the dark, then warmed to 23 °C. The reaction mixture was filtered through a pad of celite eluting with CH₂CI₂ and the filtrate concentrated in vacuo at 5 °C. The residue was purified via column chromatography on silica gel eluting with pentane/CH₂Cl₂ 9:1 (v/v) to afford 84 mg of the title compound as a clear liquid (87% yield).

R_f = 0.48 (pentane/CH₂Cl₂ 9: 1 (v/v)). NMR Spectroscopy: ^]H NMR (500 MHz,

CDC1_3, 23 °C, δ): 7.15 (d, 7 = 9.2 Hz, 2H), 6.89 (dd, 7 = 9.2 Hz, 3.7 Hz, 2H), 3.81 (s, 3H). ¹³C NMR (125 MHz, CDC1₃, 23 °C, δ): 158.3, 142.9 (q, 7 = 2 Hz), 122.6, 120.8 (q, 7 = 256 Hz), 114.8, 55.7. ¹⁹F NMR (470 MHz, CDC1₃, 23 °C, δ): -58.9. Example 9. (4-Bromophenyl)tributylstannane (7) nBuLi,

THF, -78 °C _^SnBih

Br'^^ then Bu₃SnCI g_r

95% 7

To 1 ,4-dibromobenzene (1.2 g, 5.0 mmol, 1.0 equiv) in THF (13 mL) at -78 °C was added nBuLi (1.6 M in hexane, 3.1 mL, 5.0 mmol, 1.0 equiv). The reaction mixture was stirred at -78 °C for 30 min before the addition of Bu₃SnCl (1.6 g, 1.4 mL, 5.0 mmol, 1.0 equiv). After stirring for 1 hr at -78 °C, the reaction mixture was warmed to 23 °C and the solvent was removed in vacuo. The residue was dissolved in 20 mL of Et₂0 and filtered through a plug of neutral alumina. The filtrate was concentrated in vacuo and the residue purified via column chromatography on silica gel eluting with hexanes to afford 2.1 g of the title compound as a colorless oil (95% yield).

R/= 0.50 (hexanes). NMR Spectroscopy: ^]H NMR (500 MHz, CDC1₃, 23 °C, δ): 7.48

(d, 7 = 7.8 Hz, 2H), 7.35 (d, 7 = 7.8 Hz, 2H), 1.59-1.53 (m, 6H), 1.40-1.32 (m, 6H), 1.10- 1.07 (m, 6H), 0.92 (t, 7 = 7.3 Hz, 9H). ¹³C NMR (125 MHz, CDC1₃, 23 °C, δ): 140.7, 138.0, 131.1, 122.9, 29.2, 27.5, 13.8, 9.8. Example 10. l-Bromo-4-(trifluoromethoxy)benzene (8)

2.0 equi TAS · OCF₃

1.2 e uiv F-TEDA-PF

2.0 equiv NaHC0₃

THF:acetone (1 :3)

7 -30 °C 8

84%

To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (275 mg, 1.00 mmol, 2.00 equiv), sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv), and (4- bromopheny^tributylstannane¹ (7) (223 mg, 0.500 mmol, 1.00 equiv) in anhydrous THF (2.00 mL) at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (0.45 g, 0.30 mL, 2.1 mmol, 4.1 equiv), and the suspension was stirred vigorously. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of l-chloromethyl-4- fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv) and silver hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) in dry acetone (6.0 mL) was added by cannula. The reaction mixture was stirred for 2.5 hours in the dark, then warmed to 23 °C. The reaction mixture was filtered through a pad of celite eluting with CH2CI2 and the filtrate concentrated in vacuo at 5 °C. The residue was purified via column chromatography on silica gel eluting with pentane/CH₂Cl₂ 1:1 (v/v) to afford 101 mg of the title compound as a clear liquid (84% yield).

R_f = 0.86 (pentane/CH₂Cl₂ 1: 1 (v/v)). NMR Spectroscopy: ^]H NMR (400 MHz, CDCI_3, 23 °C, δ): 7.52 (dd, J = 8.8 Hz, 1.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H). ¹³C NMR (100 MHz, CDC1₃, 23 °C, δ): 148.4 (q, / = 2 Hz), 133.1, 122.9, 120.3, 120.5 (q, / = 258 Hz). ¹⁹F NMR (375 MHz, CDC1₃, 23 °C, δ): -58.5.

Example 11. Ethyl 4-(trifluoromethoxy)benzoate (10)

2.0 equiv TAS · OCF₃

1.2 e uiv F-TEDA-PF

THF:acetone (1 :3)

9 -30 °C 10

79% To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (275 mg, 1.00 mmol, 2.00 equiv), sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv), and ethyl 4- (tributylstannyl)benzoate (9) (220 mg, 0.500 mmol, 1.00 equiv) in anhydrous THF (2.00 mL) at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (0.45 g, 0.30 mL, 2.1 mmol, 4.1 equiv), and the suspension was stirred vigorously. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of l-chloromethyl-4- fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv) and silver hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) in dry acetone (6.0 mL) was added by cannula. The reaction mixture was stirred for 2 hours in the dark, then warmed to 23 °C. The reaction mixture was filtered through a pad of celite eluting with CH2CI2 and the filtrate concentrated in vacuo at 5 °C. The residue was purified via column chromatography on silica gel eluting with pentane/CH₂Cl2 1 : 1 (v/v) to afford 92 mg of the title compound as a light yellow oil (79% yield).

R_f = 0.89 (pentane/CH₂Cl₂ 1: 1 (v/v)). NMR Spectroscopy: ^]H NMR (400 MHz, CDCI_3, 23 °C, δ): 8.09 (d, J = 9.2 Hz, 2H), 7.26 (d, J = 9.2 Hz, 2H), 4.39 (q, J = 7.2 Hz, 2H), 1.40 (t, / = 6.8 Hz, 2H). ¹³C NMR (100 MHz, CDC1₃, 23 °C, δ): 165.6, 152.7 (q, / = 2 Hz), 131.6, 129.1, 120.5, 120.4 (q, / = 257 Hz), 61.4, 14.4. ¹⁹F NMR (375 MHz, CDC1₃, 23 °C, δ): -58.1. Example 12. Synthesis of ethyl 4-(trifluoromethoxy)benzoate (10) on gram scale

80%

To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (1.65 g, 6.00 mmol, 2.00 equiv), sodium bicarbonate (594 mg, 6.00 mmol, 2.00 equiv), and ethyl 4- (tributylstannyl)benzoate (9) (1.32 g, 3.00 mmol, 1.00 equiv) in anhydrous THF (12.0 mL) at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (2.6 g, 1.8 mL, 12 mmol, 4.0 equiv), and the suspension was stirred vigorously. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of l-chloromethyl-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (1.69 g, 3.60 mmol, 1.20 equiv) and silver hexafluorophosphate (1.52 mg, 6.00 mmol, 2.00 equiv) in dry acetone (36.0 mL) was added by cannula. The reaction mixture was stirred for 2 hours in the dark, then warmed to 23 °C. The reaction mixture was filtered through a pad of celite eluting with CH2CI2 and the filtrate concentrated in vacuo at 5 °C. The residue was purified via column

chromatography on silica gel eluting with pentane/CH₂Cl₂ 1:1 (v/v) to afford 563 mg of the title compound as a light yellow oil (80% yield).

R_f = 0.89 (pentane/CH₂Cl₂ 1: 1 (v/v)). NMR Spectroscopy: ^]H NMR (400 MHz, CDCI_3, 23 °C, δ): 8.09 (d, J = 9.2 Hz, 2H), 7.26 (d, J = 9.2 Hz, 2H), 4.39 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 6.8 Hz, 2H). ¹³C NMR (100 MHz, CDC1₃, 23 °C, δ): 165.6, 152.7 (q, J = 2 Hz), 131.6, 129.1, 120.5, 120.4 (q, / = 257 Hz), 61.4, 14.4. ¹⁹F NMR (375 MHz, CDC1₃, 23 °C, δ): -58.1.

Example 13. l-Methoxy-2-(trifluoromethoxy)benzene (12)

77% To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (275 mg,

1.00 mmol, 2.00 equiv), sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv), and tributyl(2-methoxyphenyl)stannane (11) (199 mg, 0.500 mmol, 1.00 equiv) in anhydrous THF (2.00 mL) at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (0.45 g, 0.30 mL, 2.1 mmol, 4.1 equiv), and the suspension was stirred vigorously. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of 1- chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv) and silver hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) in dry acetone (6.0 mL) was added by cannula. The reaction mixture was stirred for 2.5 hours in the dark, then warmed to 23 °C. The reaction mixture was filtered through a pad of celite eluting with CH₂C1₂ and the filtrate concentrated in vacuo at 5 °C. The residue was purified via column chromatography on silica gel eluting with pentane/CH₂Cl₂ 9:1 (v/v) to afford 74 mg of the title compound as a clear oil (77% yield). R_f = 0.57 (pentane/CH₂Cl₂ 9: 1 (v/v)). NMR Spectroscopy: ^]H NMR (500 MHz, CDC1₃, 23 °C, δ): 7.24-7.23 (m, 2H), 6.99 (d, / = 7.8 Hz, 1H), 6.93 (t, / = 7.8 Hz, 1H), 3.87 (s, 3H). ¹³C NMR (125 MHz, CDC1₃, 23 °C, δ): 152.2, 138.3 (q, / = 2 Hz), 128.0, 123.0, 120.8 (q, / = 257 Hz), 120.7, 113.1, 56.1. ¹⁹F NMR (470 MHz, CDC1₃, 23 °C, δ): -58.6.

Example 14. Tributyl(3,4,5-trimethoxyphenyl)stannane (13)

73%

13

To 5-bromo-l,2,3-trimethoxybenzene (1.2 g, 4.9 mmol, 1.0 equiv), in anhydrous THF (12 mL) at -78 °C was added nBuLi (2.5 M in hexanes, 2.1 mL, 5.3 mmol, 1.1 equiv). The reaction mixture was stirred at -78 °C for 30 min before the addition of Bu₃SnCl (1.6 g, 1.3 mL, 4.9 mmol, 1.0 equiv). After stirring for 1.0 hr at -78 °C, the reaction mixture was warmed to 23 °C and the solvent was removed in vacuo. The residue was dissolved in 20 mL of Et₂0 and filtered through a plug of neutral alumina. The filtrate was concentrated in vacuo and was purified by chromatography on silica gel eluting with hexanes/EtOAc 5:1 (v/v) to afford 1.6 g of the title compound as a colorless oil (73% yield).

R_f = 0.47 (hexanes/EtOAc 5:1 (v/v)). NMR Spectroscopy: ^]H NMR (400 MHz, CDC1₃, 23 °C, δ): 6.66 (s, 2H), 3.88(s, 6H), 3.86 (s, 3H), 1.59-1.55 (m, 6H), 1.38-1.33 (m, 6H), 1.09-1.05 (m, 6H), 0.91 (t, / = 7.2 Hz, 9H). ¹³C NMR (100 MHz, CDC1₃, 23 °C, δ): 153.0, 138.4, 136.7, 113.0, 60.8, 56.2, 29.2, 27.4, 13.7, 9.9.

Example 15. l,2,3-Trimethoxy-5-(trifluoromethoxy)benzene (14)

2.0 equiv TAS · 0CF₃

1.2 equiv F-TEDA-PFg

2.0 equiv AgPF₆

2.0 equiv NaHC0₃

THF:acetone (1 :3)

-30 °C

13 14

75%

To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (275 mg, 1.00 mmol, 2.00 equiv), sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv), and tributyl(3,4,5-trimethoxyphenyl)stannane (13) (229 mg, 0.500 mmol, 1.00 equiv) in anhydrous THF (2.00 mL) at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (0.45 g, 0.30 mL, 2.1 mmol, 4.1 equiv), and the suspension was stirred vigorously. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of 1- chloromethyl-4-fluoro-l ,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv) and silver hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) in dry acetone (6.0 mL) was added by cannula. The reaction mixture was stirred for 4 hours in the dark, then warmed to 23 °C. The reaction mixture was filtered through a pad of celite eluting with CH₂CI₂ and the filtrate concentrated in vacuo. The residue was purified via column chromatography on silica gel eluting with hexanes/CH₂Cl₂ 1 :2 (v/v) to afford 94 mg of the title compound as a clear oil (75% yield).

R_f = 0.28 (hexanes/CH₂Cl₂ 1 :2 (v/v)). NMR Spectroscopy: ^]H NMR (500 MHz, CDC1_3, 23 °C, δ): 6.45 (s, 2H), 3.84 (s, 6H), 3.82 (s, 3H). ¹³C NMR (100 MHz, CDC1₃, 23 °C, δ): 153.7, 145.3 (q, J = 2 Hz), 136.8, 120.6 (q, J = 257 Hz), 99.0, 61.0, 56.3. ¹⁹F NMR (470 MHz, CDCI₃, 23 °C, δ): -58.4. Mass Spectrometry: HRMS-FIA (m/z): Calcd for CioH₁₂F₃0₄ [M + H]⁺, 253.0682. Found, 253.0685.

Example 16. Methyl 6-(tributylstannyl)-2-naphthoate (15)

15

52%

To a suspension of lithium chloride (635 mg, 15.0 mmol, 5.00 equiv), hexabutylditin

(3.44 g, 3.00 mL, 6.00 mmol, 2.50 equiv), and methyl 6-bromo-2-naphthoate (795 mg, 3.00 mmol, 1.00 equiv) in anhydrous dioxane (30.0 mL) at 25 °C was added palladium tetrakis triphenylphosphine (173 mg, 0.150 mmol, 0.0500 equiv). The reaction mixture was heated to 100 °C and stirred for 12 hours, then cooled to room temperature. The reaction mixture was filtered through a pad of celite eluting with CH₂C1₂, and the filtrate concentrated in vacuo.

The residue was purified via column chromatography on silica gel eluting with

hexanes/EtOAc 3: 1 (v/v) to afford 741 mg of the title compound as a clear oil (52% yield).

R_f = 0.75 (hexanes/EtOAc 3: 1 (v/v)). NMR Spectroscopy: ^]H NMR (400 MHz,

CDC1_3, 23 °C, δ): 8.61 (s, 1H), 8.08 (dd, / = 8.8 Hz, 1.6 Hz, 1H), 8.01 (s, 1H), 7.96-7.86 (m, 2H), 7.66 (d, / = 8.1 Hz, 1H), 3.99 (s, 3H), 1.70-1.53 (m, 6H), 1.43-1.30 (m, 6H), 1.29-1.09 (m, 6H), 0.93 (t, 7 = 7.3 Hz, 9H). ¹³C NMR (125 MHz, CDC1₃, 23 °C, δ): 167.4, 143.7, 136.4, 135.1, 134.0, 132.4, 131.2, 128.1, 127.9, 127.3, 125.2, 52.2, 29.2, 27.5, 13.8, 9.8. Mass Spectrometry: HRMS-FIA (m/z) Calcd for C24H₃70₂Sn [M + H]⁺, 477.1810. Found, 477.1795.

Example 17. Methyl 6-(trifluoromethoxy)-2-naphthoate (16)

76%

To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (275 mg, 1.00 mmol, 2.00 equiv), sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv), and methyl 6- (tributylstannyl)-2-naphthoate (15) (238 mg, 0.500 mmol, 1.00 equiv) in anhydrous THF (2.00 mL) at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (0.45 g, 0.30 mL, 2.1 mmol, 4.1 equiv), and the suspension was stirred vigorously. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of l-chloromethyl-4- fluoro- l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv) and silver hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) in dry acetone (6.0 mL) was added by cannula. The reaction mixture was stirred for 2.5 hours in the dark, then warmed to 23 °C. The reaction mixture was filtered through a pad of celite eluting with CH₂C1₂ and the filtrate concentrated in vacuo. The residue was purified via column chromatography on silica gel eluting with hexanes/CH₂Cl₂ 1 :2 (v/v) to afford 102 mg of the title compound as a clear oil (76% yield).

R_f = 0.52 (hexanes/CH₂Cl₂ 1 :2 (v/v)). NMR Spectroscopy: ^]H NMR (400 MHz, CDC1₃, 23 °C, δ): 8.61 (s, 1H), 8.11 (dd, / = 8.7 Hz, 1.8 Hz, 1H), 7.98 (d, / = 9.2 Hz, 1H), 7.86 (d, / = 8.7 Hz, 1H), 7.68 (s, 1H), 7.39 (dd, / = 9.2 Hz, 1.8 Hz, 1H), 3.99 (s, 3H). ¹³C NMR (100 MHz, CDC1₃, 23 °C, δ): 167.0, 148.7 (q, / = 2 Hz), 135.9, 131.7, 130.9, 130.8, 128.2, 128.1, 126.6, 120.9, 120.7 (q, / = 257 Hz), 117.8, 52.5. ¹⁹F NMR (375 MHz, CDC1₃, 23 °C, δ): -58.0. Mass Spectrometry: HRMS-FIA (m/z): Calcd for Ci₃H₁₀F₃O3 [M + H]⁺, 271.0577. Found, 271.0573. Example 18. 5-Tributylstannyl-/V-Boc-indole (17)

To a suspension of lithium chloride (297 mg, 7.00 mmol, 2.00 equiv), hexabutylditin (3.05 g, 2.65 mL, 5.25 mmol, 1.50 equiv), and 5 -bromo-N-Boc -indole (1.04 g, 3.50 mmol, 1.00 equiv) in anhydrous dioxane (17.5 mL) at 25 °C was added palladium tetrakis triphenylphosphine (75.0 mg, 0.175 mmol, 0.0500 equiv). The reaction mixture was heated at 100 °C and stirred for 2.5 hours at this temperature, then cooled to room temperature. The reaction mixture was filtered through a pad of celite eluting with CH₂C1₂, and the filtrate concentrated in vacuo. The residue was purified via column chromatography on silica gel eluting with hexanes/EtOAc 9:1 (v/v) and further purified by evaporation of impurities via kugelrohr at 150 °C at 200 millitorr to afford 1.50 g of the title compound as a clear oil (85% yield).

R_f = 0.50 (hexanes/EtOAc 9:1 (v/v)). NMR Spectroscopy: Ή NMR (500 MHz, CDC1_3, 23 °C, δ): 8.15 (d, / = 6.0 Hz, 1H), 7.70 (s, 1H), 7.60 (d, / = 3.2 Hz, 1H), 7.44 (d, J = 6.0 Hz, 1H), 6.59 (d, / = 3.2 Hz, 1H), 1.70 (s, 9H), 1.67-1.55 (m, 6H), 1.43-1.35 (m, 6H), 1.20-1.06 (m, 6H), 0.96 (t, J = 6.0 Hz, 9H). ¹³C NMR (100 MHz, CDC1₃, 23 °C, δ): 150.0, 135.4, 132.0, 134.7, 130.8, 129.2, 125.5, 114.9, 107.2, 83.6, 29.3, 28.3, 27.5, 13.8, 9.8. Example 19. 5-Trifluoromethoxy-/V-Boc-indole (18)

72%

To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (275 mg, 1.00 mmol, 2.00 equiv), sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv), and 5- tributylstannyl-N-Boc-indole (17) (253 mg, 0.500 mmol, 1.00 equiv) in anhydrous THF (2.00 mL) at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (0.45 g, 0.30 mL, 2.1 mmol, 4.1 equiv), and the suspension was stirred vigorously. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of l-chloromethyl-4- fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv) and silver hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) in dry acetone (6.0 mL) was added by cannula. The reaction mixture was stirred for 2.5 hours in the dark, then warmed to 23 °C. The reaction mixture was filtered through a pad of celite eluting with CH2CI2 and the filtrate concentrated in vacuo. The residue was purified via column chromatography on silica gel eluting with hexanes/CH₂Cl₂ 1: 1 (v/v) to afford 108 mg of the title compound as a clear oil (72% yield).

R_f = 0.70 (hexanes/CH₂Cl₂ 1 : 1 (v/v)). NMR Spectroscopy: ^]H NMR (500 MHz,

CDCI_3, 23 °C, δ): 8.17 (d, 7 = 7.8 Hz, 1H), 7.66 (d, / = 3.4 Hz, 1H), 7.42 (s, 1H), 7.18 (d, / = 7.3 Hz, 1H), 6.57 (d, / = 3.4 Hz, 1H), 1.68 (s, 9H). ¹³C NMR (125 MHz, CDC1₃, 23 °C, δ): 149.4, 145.0 (q, J = 2 Hz), 133.6, 131.3, 127.8, 123.9 (q, 7 = 256 Hz), 117.8, 116.1, 113.4, 107.2, 84.3, 28.3. ¹⁹F NMR (375 MHz, CDC1₃, 23 °C, δ): -58.5. Mass Spectrometry:

HRMS-FIA (m/z): Calcd for C9H7F₃NO [M - C₅H₉0₂ (Boc) + H]⁺, 202.0480. Found, 202.0485.

Example 20. /V-Boc-4-(trifluoromethoxy)-L-phenylalanine methyl ester (20)

2.0 equiv TAS · OCF₃

1.22 eeqquuiivv FF--TTEEDDAA--PPFI g

C0₇Me 2. n0 _a e„quiv AgPF₆ J30,Me

NHBoc . . . NHBoc

2.0 equiv NaHC0₃ F₃CO

THF:acetone (1 :3)

-30 °C 20

75% To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (275 mg,

1.00 mmol, 2.00 equiv), sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv), and N-Boc-4- (tributylstannyl)-L-phenylalanine methyl ester (19) (284 mg, 0.500 mmol, 1.00 equiv) in anhydrous THF (2.00 mL) at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (0.45 g, 0.30 mL, 2.1 mmol, 4.1 equiv), and the suspension was stirred vigorously. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of 1- chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv) and silver hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) in dry acetone (6.0 mL) was added by cannula. The reaction mixture was stirred for 2.5 hours in the dark, then warmed to 23 °C. The reaction mixture was filtered through a pad of celite eluting with CH2CI2 and the filtrate concentrated in vacuo. The residue was purified via column chromatography on silica gel eluting with CH2CI2 to afford 136 mg of the title compound as a white solid (75% yield).

R_f = 0.29 (CH₂C1₂). NMR Spectroscopy: ^]H NMR (500 MHz, CDC1_3, 23 °C, δ):

7.17-7.12 (m, 4H), 4.99 (d, / = 7.7 Hz, 1H), 4.60-4.58 (m, 1H), 3.71 (s, 3H), 3.17-3.00 (m, 1H), 1.41 (s, 9H). ¹³C NMR (125 MHz, CDC1₃, 23 °C, δ): 172.2, 155.1, 148.5, 135.0, 130.8, 121.1 , 120.6 (q, J = 255 Hz), 80.2, 54.4, 52.5, 38.0, 28.4. ¹⁹F NMR (470 MHz, CDC1₃, 23 °C, δ): -58.3. Mass Spectrometry: HRMS-FIA (m/z): Calcd for CieHzc^NOsNa [M + Na]⁺, 386.1186. Found, 386.1190.

Example 21. 3-Deoxy-3-trifluoromethoxyestrone (22)

21 22

72%

To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (275 mg, 1.00 mmol, 2.00 equiv), sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv), and 3-deoxy- 3-(tributylstannyl)estrone (21) (272 mg, 0.500 mmol, 1.00 equiv) in anhydrous THF (2.00 rriL) at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (0.45 g, 0.30 rriL, 2.1 mmol, 4.1 equiv), and the suspension was stirred vigorously. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of l-chloromethyl-4- fluoro- l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv) and silver hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) in dry acetone (6.0 rriL) was added by cannula. The reaction mixture was stirred for 4 hours in the dark, then warmed to 23 °C. The reaction mixture was filtered through a pad of celite eluting with CH2CI2 and the filtrate concentrated in vacuo. The residue was purified via column chromatography on silica gel eluting with CH2CI2 to afford 122 mg of the title compound as a white solid (72% yield).

R_f = 0.42 (CH2CI2). NMR Spectroscopy: ^]H NMR (500 MHz, CDC1_3, 23 °C, δ): 7.29 (d, / = 8.7 Hz , 1H), 6.99 (d, / = 8.7 Hz, 1H), 6.94 (s, 1H), 2.92 (dd, / = 8.5 Hz, 3.5 Hz, 2 H), 2.51 (dd, / = 18.5 Hz, 8.5 Hz, 1H), 2.42-2.39 (m, 1H), 2.30-2.26 (m, 1H), 2.19-2.11 (m, 1H), 2.09-2.02 (m, 2H), 1.99-1.96 (m, 1H), 1.66-1.44 (m, 6H), 0.92 (s, 3H). ¹³C NMR (125 MHz, CDC1₃, 23 °C, δ): 220.7, 147.4 (q, J = 2 Hz), 138.6, 138.5, 126.8, 121.1 , 120.5 (q, J = 255 Hz), 118.3, 50.5, 48.0, 44.2, 38.1, 35.9, 31.7, 29.5, 26.4, 25.9, 21.7, 13.9. ¹⁹F NMR (375 MHz, CDCI₃, 23 °C, δ): -58.2. Mass Spectrometry: HRMS-FIA (m/z): Calcd for C2₀H22F₃O2 [M + H]⁺, 339.1566. Found, 339.1565.

Example 22. V-Boc-4-(tributylstannyl)-L-phenylalanyl-L-phenylalanine methyl ester (23)

To N-Boc-4-(tributylstannyl)-L-phenylalanine (422 mg, 0.742 mmol, 1.00 equiv) and L-phenylalanine methyl ester hydrochloride (160 mg, 0.742 mmol, 1.00 equiv) in CH2CI2 (30 mL) at 0 °C was added l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (427 mg, 2.23 mmol, 3.00 equiv), 1-hydroxybenzotriazole (HOBt) ( 201 mg, 1.49 mmol, 2.00 equiv), N,N-diisopropylethylamine (288 mg, 388 μL·, 2.23 mmol, 3.00 equiv) and 4-(dimethylamino)pyridine (9.1 mg, 0.074 mmol, 0.10 equiv). After stirring for 1 hr at 0 °C, the reaction mixture was warmed to 23 °C and further stirred for 12 hr. The reaction mixture was quenched with water (10 mL), and CH2CI2 (5 mL) was added. The phases were separated and the aqueous phase was extracted with CH2CI2 (2 x 5 mL). The combined organic phases were washed with brine (5 mL) and dried (Na2S0₄). The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel, eluting with hexanes/EtOAc 3 : 1 (v/v), to afford 389 mg of the title compound as a colorless foam (73% yield).

R/ = 0.30 (hexanes/EtOAc 3: 1 (v/v)). NMR Spectroscopy: ^]H NMR (500 MHz, CDCI₃, 23 °C, δ): 7.39 (d, / = 7.3 Hz, 2H), 7.23-7.21 (m, 3H), 7.15 (d, / = 6.9 Hz, 2H), 6.97 (dd, J = 7.3 Hz, 1.8 Hz, 2H), 6.38 (d, J = 6.9 Hz, 1H), 4.90 (br s, 1H), 4.80 (br s, 1H), 4.35 (br s, 1H), 3.68 (s, 3H), 3.09-2.99 (m, 4H), 1.55-1.50 (m, 6H), 1.38 (s, 9H), 1.36-1.29 (m, 6H), 1.05-1.01 (m, 6H), 0.87 (t, 7 = 7.3 Hz, 9H). ¹³C NMR (125 MHz, CDC1₃, 23 °C, δ): 171.5, 171.0, 155.4, 140.4, 136.9, 136.2, 135.8, 129.3, 129.1 , 129.0, 128.6, 127.2, 80.3, 55.6, 53.4, 52.4, 38.1, 29.1, 28.3, 27.5, 13.8, 9.7.

Example 23. V-Boc-4-(trifluoromethoxy)-L-phenylalanyl-L-phenylalanine methyl ester (24)

67%

To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (273 mg, 0.992 mmol, 2.00 equiv), sodium bicarbonate (83.0 mg, 0.992 mmol, 2.00 equiv), and N- Boc-4-(tributylstannyl)-L-phenylalanyl-L-phenylalanine methyl ester (23) (355 mg, 0.496 mmol, 1.00 equiv) in anhydrous THF (2.00 mL) at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (0.45 g, 0.30 mL, 2.1 mmol, 4.1 equiv) , and the suspension was stirred vigorously. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of l-chloromethyl-4-fluoro-l ,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv) and silver

hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) in dry acetone (6.0 mL) was added by cannula. The reaction mixture was stirred for 2 hours in the dark, then warmed to 23 °C. The reaction mixture was filtered through a pad of celite eluting with CH2CI2 and the filtrate concentrated in vacuo. The residue was purified via column chromatography on silica gel eluting with hexanes/acetone 3 : 1 (v/v) to afford 170 mg of the title compound as a white solid (67% yield).

R_f = 0.45 (hexanes/acetone 3 : 1 (v/v)). NMR Spectroscopy: ^]H NMR (500 MHz, CDC1_3, 23 °C, δ): 7.25-7.23 (m, 3H), 7.20 (d, / = 8.3 Hz , 1H), 7.12 (d, / = 7.8 Hz , 1H), 7.01 (dd, / = 7.8 Hz, 2.0 Hz, 1 H), 6.26-6.24 (m, 1H), 4.93-4.91 (m, 1H), 4.78-4.77 (m, 1H), 4.32-4.31 (m, 1H), 3.69 (s, 3H), 3.12-2.99 (m, 5H), 1.40 (s, 9H). ¹³C NMR (125 MHz, CDC1₃, 23 °C, δ): 171.5, 170.6, 155.4, 148.4, 135.6, 130.9, 129.3, 128.7, 127.3, 120.6 (q, / = 255 Hz), 121.2, 115.6, 80.5, 55.7, 53.3, 52.5, 38.0, 37.8, 28.3. ¹⁹F NMR (375 MHz, CDC1₃, 23 °C, δ): -58.3. Mass Spectrometry: HRMS-FIA (m/z): Calcd for C25H30F3N2O6 [M + H]⁺, 511.2051. Found, 511.2040. Example 24. 3-(Trifluoromethanesulfonyl)morphine (S2)

S2

To morphine (23.7 g, 83.1 mmol, 1.00 equiv) in CH₂CI₂ (500 mL) was added N- phenyltriflimide (30.0 g, 84.0 mmol, 1.01 equiv) and triethylamine (24.8 g, 34.0 mL, 0.245 mol, 2.95 equiv). The reaction mixture was stirred at reflux for 10 hours. The reaction was cooled to 23 °C and diluted with CH₂CI₂ (250 mL). The organic phase was washed with NaHCC>3 (30 mL) and the aqueous layer was extracted with CH₂CI₂ (3 x 150 mL). The combined organic phases were washed with brine (500 mL) and dried with Na₂S0₄. The filtrate was concentrated in vacuo and the resulting residue the residue was purified by chromatography on silica gel eluting with CH₂Cl₂/MeOH 9: 1 (v/v) to afford 30.5 g of the title compound as a light beige solid (88% yield).

R_f = 0.53 (CH₂Cl₂/MeOH 9: 1 (v/v)). NMR Spectroscopy: ^]H NMR (500 MHz, CDC1_3, 23 °C, δ): 6.89 (d, / = 8.4 Hz, 1H), 6.64 (d, / = 8.4 Hz, 1H), 5.72-5.69 (m, 1H), 5.30- 5.26 (m, 1H), 5.02 (d, / = 6.4 Hz, 1H), 4.24-4.16 (m, 1H), 3.38 (dd, / = 5.9 Hz, 3.3 Hz , 1H), 3.08 (d, / = 18.8 Hz, 1H), 2.92-2.90 (m, 1H), 2.70 (t, / = 2.6 Hz, 1H), 2.61 (dd, / = 13.2, Hz, 4.6 Hz, 1H), 2.44 (s, 3H), 2.42-2.28 (m, 2H), 2.10 (dt, / = 12.4 Hz, 5.1 Hz, 1H), 1.90 (d, / = 7.3 Hz, 1H). ¹³C NMR (100 MHz, CDC1₃, 23 °C, δ): 149.7, 135.8, 133.9, 130.8, 129.7, 128.3, 121.3, 120.4, 118.8 (q, / = 323 Hz), 93.7, 66.6, 58.7, 46.2, 43.5, 43.2, 40.6, 35.3, 21.1. ¹⁹F NMR (375 MHz, CDC1₃, 23 °C, δ): -73.4.

Example 25. Methyl 3-(trifluoromethanesulfonyl)normorphine-carboxylate (S3)

S2 S3

To 3-trifluoromethanesulfonyl morphine (S2) (4.50 g, 10.8 mmol, 1.00 equiv) in

CHCI₃ (110 mL) was added NaHC0₃ (13.6 g, 0.162 mol, 15.0 equiv) and methyl chloroformate (17.4 g, 14.2 mL, 0.183 mol, 17.0 equiv). The reaction mixture was stirred at reflux for 18 h. The reaction was cooled to 23 °C and quenched with H₂0 (100 mL). The aqueous layer was extracted with CH₂C1₂ (3 x 100 mL). The combined organic phases were washed with brine (100 mL) and dried with Na₂S0₄. The filtrate was concentrated in vacuo and the resulting residue the residue was purified by chromatography on silica gel eluting with hexanes/EtOAc 2:3 (v/v) to afford 4.67 g of the title compound as a pale yellow solid (94% yield).

R_f = 0.29 (hexanes/EtOAc 2:3 (v/v)). NMR Spectroscopy: ^]H NMR (500 MHz, CDC1_3, 23 °C, δ): 6.93 (d, / = 8.3 Hz, 1H), 6.65 (d, / = 8.3 Hz, 1H), 5.76 (d, / = 9.2 Hz, 1H), 5.31-5.28 (m, 1H), 5.02 (d, / = 6.5 Hz, 1H), 4.85-4.84 (m, 1H), 4.20-4.03 (m, 2H), 3.75 (s, 3H)*, 3.00-2.87 (m, 3H), 2.79 (d, / = 19.0 Hz, 1H), 2.57 (s, 1H), 2.00-1.91 (m, 2H). ¹³C NMR (125 MHz, CDC1₃, 23 °C, δ): 149.8, 135.0, 134.7, 132.8, 131.0, 127.1, 126.9, 121.8, 120.4, 118.8 (q, / = 320 Hz), 93.5, 66.3, 53.0. 50.0, 43.9, 39.6*, 37.3, 35.1 , 30.1 *. ¹⁹F NMR (470 MHz, CDCI₃, 23 °C, δ): -73.4. Mass Spectrometry: HRMS-FIA (m/z): Calcd for Ci₉H₁₈F₃N07SNa [M + Na]⁺, 484.0648. Found, 484.0664. *Two signals attributed to a mixture of rotamers

Example 26. Methyl 3-deoxy-3-(tributylstannyl)normorphine-carboxylate (25)

To a suspension of lithium chloride (551 mg, 13.0 mmol, 3.00 equiv), hexabutylditin (5.03 g, 4.38 mL, 8.67 mmol, 2.00 equiv), and methyl 3-

(trifluoromethanesulfonyl)normorphine-carboxylate (S3) (2.00 g, 4.33 mmol, 1.00 equiv) in anhydrous dioxane (40.0 mL) at 25 °C was added palladium tetrakis triphenylphosphine (250 mg, 0.217 mmol, 0.0500 equiv). The reaction mixture was heated and stirred at 105 °C for 24 hours, then cooled to room temperature. The reaction mixture was filtered through a pad of celite eluting with CH₂C1₂, and the filtrate concentrated in vacuo. The residue was purified via column chromatography on silica gel eluting with hexanes/EtOAc 1 : 1 (v/v) to afford 1.51 g of the title compound as a light yellow oil (58% yield). R_f = 0.85 (hexanes/EtOAc 2:3 (v/v)). NMR Spectroscopy: ^]H NMR (500 MHz, CDC1_3, 23 °C, δ): 7.08 (d, J = 7.3 Hz, 1H), 6.62 (d, J = 7.3 Hz, 1H), 5.72 (d, J = 9.2 Hz, 1H), 5.32-5.26 (m, 1H), 4.96 (s (rotamers), 1H), 4.76 (dd, / = 6.6 Hz, 1.1 Hz, 1H), 4.18-4.11 (m, 1H), 4.00 (dd, / = 13.5 Hz, 4.0 Hz, 1H), 3.73 (s, 3H)*, 3.06-2.69 (m, 4H), 2.53 (s, 1H), 1.96- 1.85 (m, 2H), 1.61-1.42 (m, 6H), 1.37-1.24 (m, 6H), 1.15-0.98 (m, 6H), 0.88 (t, / = 5.3 Hz, 9H). ¹³C NMR (100 MHz, CDC1₃, 23 °C, δ): 165.3, 155.9, 136.2, 134.6, 134.4, 127.3, 126.3, 119.6, 116.4, 89.3, 66.6, 52.9, 50.3, 42.8, 40.1*, 37.6, 35.7, 30.2*, 29.3, 27.4, 13.8, 9.8. Mass Spectrometry: HRMS-FIA (m/z): Calcd for C₃oH45N0₄SnNa [M + Na]⁺, 626.2262. Found, 626.2251. *Two signals attributed to a mixture of rotamers.

Example 27. Methyl 3-deoxy-3-(trifluoromethoxy)normorphine-carboxylate (26)

To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (497 mg, 1.80 mmol, 2.00 equiv), and sodium bicarbonate (151 mg, 1.80 mmol, 2.00 equiv) in anhydrous THF (3.60 mL) at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (786 mg, 524 μL·, 3.6 mmol, 4.0 equiv), and the suspension was stirred vigorously. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of 1- chloromethyl-4-fluoro-l ,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (509 mg, 1.08 mmol, 1.20 equiv) and silver hexafluorophosphate (456 mg, 1.80 mmol, 2.00 equiv) in dry acetone (8.0 mL) was added by cannula. Immediately afterwards, a solution of methyl 3-deoxy-3-tributylstannyl-normorphine-carboxylate (25) (543 mg, 0.901 mmol, 1.00 equiv) in dry acetone (2.8 mL) is added dropwise. The reaction mixture was stirred for 4 hours in the dark, then warmed to 23 °C. The reaction mixture was filtered through a pad of celite eluting with CH2CI2 and the filtrate concentrated in vacuo. The residue was purified via column chromatography on silica gel eluting with hexanes/acetone 3 : 1 (v/v) to afford 212 mg of the title compound as a white foam (59% yield).

R_f = 0.24 (hexanes/acetone 3 : 1 (v/v)). NMR Spectroscopy: ^]H NMR (500 MHz, CDC1_3, 23 °C, δ): 6.94 (d, / = 8.3 Hz, 1H), 6.62 (d, / = 8.3 Hz, 1H), 5.75 (d, / = 8.8 Hz, 1H), 5.31-3.26 (m, 1H), 4.98-4.82 (m, 2H), 4.19^1.02 (m, 2H), 3.73 (s, 3H), 3.02-2.76 (m, 3H), 2.55 (s, 1H), 2.00-1.90 (m, 2H). ¹³C NMR (100 MHz, CDC1₃, 23 °C, δ): 155.9, 150.2, 134.4, 133.2, 131.8, 130.5, 127.2, 123.1 , 120.8 (q, / = 257 Hz), 120.5, 92.4, 66.2, 53.0, 50.0, 43.6, 39.5*, 37.4, 35.3, 29.9*. ¹⁹F NMR (375 MHz, CDC1₃, 23 °C, δ): -59.2. Mass Spectrometry: HRMS-FIA (m/z): Calcd for C19H19F₃NO5 [M + H]⁺, 398.1210. Found, 398.1212. *Two signals attributed to a mixture of rotamers.

Example 28. Synthesis of Trifluoromethoxy morphine (36).

A dry 5 gram vial was charged with tris(dimethylamino)sulfonium

trifluoromethylsilicate (38.0 mg, 0.14 mmol, 2.0 equiv), sodium bicarbonate (11.7 mg, 0.14 mmol, 2.0 equiv), and dry THF (0.3 ml). The solution was cooled to -30 °C and

trifluoromethyl trifluormethanesulfonate was added (100 μΐ). The solution was stirred at -30 °C for 30 min and then a solution of silver hexafluorophosphate (35.0 mg, 0.14 mmol, 2.0 equiv) and l-chloromethyl-4-fluoro-l ,4-diazoniabicyclo[2.2.2]octane

bis(hexafluorophosphate) (39.0 mg, 0.08 mmol, 1.2 equiv) in dry acetone (0.5 ml) was added. A solution of tert-butyldimethyl silyl carbamate protected morphine stannane (48.6 mg, 0.07 mmol, 1.0 equiv) in dry acetone was added to the previous solution drop-wise. The solution was stirred at -30 °C in the dark for 2 hours and then warmed up to 25 °C. The reaction mixture was filtered through celite with dichloromethane, concentrated in vacuo, and the residue purified on silica gel eluting with hexanes/EtOAc 2: 1 (v/v) to afford 20 mg.

Example 29. 6-(Trifluoromethoxy)quinoline (S5)

4.0 equiv TAS · OCF₃

2.0 equiv F-TEDA-PF₆

2.0 equiv AgPF₆

2.0 equiv NaHC0₃

THF:acetone (3:10)

S4 -50 °C S5

16% To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (511 mg, 2.00 mmol, 4.00 equiv), and sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv) in anhydrous THF (2.00 mL) at -50 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (600 mg, 400 μL·, 2.8 mmol, 5.5 equiv) , and the suspension was stirred vigorously. The reaction mixture was stirred at -50 °C for 30 minutes, then a solution of silver

hexafluorophosphate (253 mg, 1.00 mmol, 2.00 equiv) in dry acetone (1.25 mL) was added dropwise concurrently as a separate solution of 6-(tributylstannyl)quinoline (S4) (209 mg, 0.500 mmol, 1.00 equiv) in dry acetone (1.75 mL) was added dropwise at -50 °C. A solution of l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (471 mg, 1.00 mmol, 2.00 equiv) in dry acetone (3 mL) was then slowly added dropwise over 5 minutes at -50 °C. The reaction mixture was stirred for 3 hours in the dark, then warmed to 23 °C. The reaction mixture was filtered through a pad of celite eluting with CH2CI2 and the filtrate concentrated in vacuo. The residue was purified via column chromatography on silica gel eluting with hexanes/acetone 3: 1 (v/v) to afford 15.0 mg of the title compound as a clear oil (14% yield). The experiment was repeated to give 17% yield.

R_f = 0.40 (hexanes/acetone 3: 1 (v/v)). NMR Spectroscopy: ^]H NMR (400 MHz, CDC1_3, 23 °C, δ): 8.96 (d, / = 2.7 Hz, 1H), 8.19-8.16 (m, 2H), 7.66 (s, 1H), 7.59 (d, / = 9.2 Hz, 1H), 7.48 (dd, / = 8.2 Hz, 4.1 Hz, 1H). ¹³C NMR (125 MHz, CDC1₃, 23 °C, δ): 150.8, 147.2, 146.4, 136.3, 131.8, 128.6, 123.9, 122.2, 117.9. The OCF₃ carbon was not observed in the ¹³C NMR due to insufficient quantity of the product. ¹⁹F NMR (375 MHz, CDC1₃, 23 °C, δ): -58.2. Mass Spectrometry: HRMS-FIA (m/z): Calcd for C1₀H7F₃NO [M + H]⁺, 214.0481. Found, 214.0480.

Example 30. Synthesis of tributyl(4-fluorophenyl)stannane (S6)

'BuLi

98% S6

To l-bromo-4-fluorobenzene (1.75 g, 10.0 mmol, 1.00 equiv) in Et₂0 (25 mL) at -78 °C was added TiuLi (1.7 M in pentane, 11.8 mL, 20 mmol, 2.0 equiv). The reaction mixture was stirred at -78 °C for 30 min before the addition of "Bu₃SnCl (3.26 g, 10.0 mmol, 1.00 equiv). The reaction mixture was warmed to 23 °C and stirred for 1.0 hr before being filtered through a plug of neutral alumina. The filtrate was concentrated in vacuo to afford 3.76 g of the title compound as a colorless oil (98% yield).

R/ = 0.63 (hexanes). NMR Spectroscopy: ^]H NMR (600 MHz, CDC1₃, 23 °C, δ): 7.41 (dd, 7 = 8.4 Hz, 6.6 Hz, 2H), 7.04 (dd, 7 = 9.6 Hz, 8.4 Hz, 2H), 1.59-1.46 (m, 6H), 1.36-1.30 (m, 6H), 1.11-1.09 (m, 6H), 0.89 (t, 7 = 6.0 Hz, 9H). ¹³C NMR (100 MHz, CDC1₃, 23 °C, δ): 163.24 (d, 7 = 245 Hz), 137.83 (d, 7 = 6.9 Hz), 136.65 (d, 7 = 4.6 Hz), 115.11 (d, 7 = 19.0 Hz), 29.07, 27.38, 13.66, 9.65. ¹⁹F NMR (375 MHz, CDC1₃, 23 °C, δ): -114.1.

Example 31. Effect of fluoride source on the yield of Ag-mediated

trifluoromethoxylation reaction

2.0 equiv fluoride source

1.2 equiv F-TEDA-PF₆

2.0 equiv AgPF₆

2.0 equiv NaHC0₃

THF:acetone (1 :3)

S6 -30 °C 35

To a suspension of fluoride source (0.400 mmol, 2.00 equiv), sodium bicarbonate (33.6 mg, 0.400 mmol, 2.00 equiv), and (4-fluorophenyl)tributylstannane (S6) (77.0 mg, 0.200 mmol, 1.00 equiv) in anhydrous THF (0.800 mL) at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (0.18 g, 0.12 mL, 0.83 mmol, 4.1 equiv), and the suspension was stirred vigorously. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (113 mg, 0.240 mmol, 1.20 equiv) and silver

hexafluorophosphate (101 mg, 0.400 mmol, 2.00 equiv) in dry acetone (2.4 mL) was added. The reaction mixture was stirred for 2 hours in the dark, then warmed to 23 °C. To the reaction mixture was added 3-nitrofluorobenzene (20.0 \lL, 0.188 mmol, 0.939 equiv). The yield was determined by comparing the integration of the ¹⁹F NMR (375 MHz, acetone-^, 23 °C) resonance of l-fluoro-4-(trifluoromethoxy)benzene (-117.0 ppm, -59.9 ppm), 1,4- difluorobenzene (-121.7 ppm), 4,4'-difluorobiphenyl (-118.0 ppm), 4-fluorophenol (-128.4 ppm), and fluorobenzene (-115.4 ppm) with that of 3-nitrofluorobenzene (-112.0 ppm). Yields are reported as percentages (by ¹⁹F NMR) in Table SI.

Table SI: Effect of fluoride source on the yield of trifluoromethoxylation

-117.0 -121.7 -118.0 -128.4 -115.4 ppm ppm ppm ppm ppm

Example 32. Effect of Ag salt on the yield of Ag-mediated trifluoromethoxylation reaction

To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (110 mg,

0.400 mmol, 2.00 equiv), sodium bicarbonate (33.6 mg, 0.400 mmol, 2.00 equiv), and (4- fluorophenyl)tributylstannane (S6) (77.0 mg, 0.200 mmol, 1.00 equiv) in anhydrous THF (0.800 mL) at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (0.18 g, 0.12 mL, 0.83 mmol, 4.1 equiv), and the suspension was stirred vigorously. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of l-chloromethyl-4- fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (113 mg, 0.240 mmol, 1.20 equiv) and silver salt (0.400 mmol, 2.00 equiv) in dry acetone (2.4 mL) was added. The reaction mixture was stirred for 2 hours in the dark, then warmed to 23 °C. To the reaction mixture was added 3-nitrofluorobenzene (20.0 \lL, 0.188 mmol, 0.939 equiv). The yield was determined by comparing the integration of the ¹⁹F NMR (375 MHz, acetone-^, 23 °C) resonance of l-fluoro-4-(trifluoromethoxy)benzene (-117.0 ppm, -59.9 ppm), 1,4- difluorobenzene (-121.7 ppm), 4,4'-difluorobiphenyl (-118.0 ppm), 4-fluorophenol (-128.4 ppm), and fluorobenzene (-115.4 ppm) with that of 3-nitrofluorobenzene (-112.0 ppm). Yields are reported as percentages (by ¹⁹F NMR) in Table S2.

Table S2: Effect of Ag salt source on the yield of trifluoromethoxylation

Example 33. Effect of solvent on the yield of Ag-mediated trifluoromethoxylation reaction

To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (110 mg,

0.400 mmol, 2.00 equiv), sodium bicarbonate (33.6 mg, 0.400 mmol, 2.00 equiv), and (4- fluorophenyl)tributylstannane (S6) (77.0 mg, 0.200 mmol, 1.00 equiv) in anhydrous solvent (0.800 mL) at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (0.18 g, 0.12 mL, 0.83 mmol, 4.1 equiv), and the suspension was stirred vigorously. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of l-chloromethyl-4- fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (113 mg, 0.240 mmol, 1.20 equiv) and silver hexafluorophosphate (101 mg, 0.400 mmol, 2.00 equiv) in anhydrous solvent (2.4 mL) was added. The reaction mixture was stirred for 2 hours in the dark, then warmed to 23 °C. To the reaction mixture was added 3-nitrofluorobenzene (20.0 \lL, 0.188 mmol, 0.939 equiv). The yield was determined by comparing the integration of the ¹⁹F NMR (375 MHz, acetone-^, 23 °C) resonance of l-fluoro-4-(trifluoromethoxy)benzene (-117.0 ppm, -59.9 ppm), 1,4-difluorobenzene (-121.7 ppm), 4,4'-difluorobiphenyl (-118.0 ppm), 4- fluorophenol (-128.4 ppm), and fluorobenzene (-115.4 ppm) with that of 3- nitrofluorobenzene (-112.0 ppm). Yields are reported as percentages (by ¹⁹F NMR) in Table S3.

Table S3: Effect of solvent on the yield of trifluoromethoxylation

117.0 ppm 121.7 ppm 118.0 ppm 128.4 ppm 115.4 ppm

MeCN 6 19 2 <1 3

DMF <1 <1 <1 <1 <1 acetone <1 23 2 1 <1

THF <1 <1 <1 <1 <1

1 :3

41 2 1 <1 <1

THF/acetone Example 34. Effect of temperature on the yield of Ag-mediated trifluoromethoxylation reaction

To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (110 mg,

0.400 mmol, 2.00 equiv), sodium bicarbonate (33.6 mg, 0.400 mmol, 2.00 equiv), and (4- fluorophenyl)tributylstannane (S6) (77.0 mg, 0.200 mmol, 1.00 equiv) in anhydrous THF (0.800 mL) at the corresponding temperature was added trifluoromethyl

trifluoromethanesulfonate (SI) (0.18 g, 0.12 mL, 0.83 mmol, 4.1 equiv), and the suspension was stirred vigorously. The reaction mixture was stirred at the corresponding temperature for 30 minutes, then a solution cooled to the corresponding temperature of l-chloromethyl-4- fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (113 mg, 0.240 mmol, 1.20 equiv) and silver hexafluorophosphate (101 mg, 0.400 mmol, 2.00 equiv) in dry acetone (2.4 mL) was added. The reaction mixture was stirred for 2 hours in the dark, then warmed to 23 °C. To the reaction mixture was added 3-nitrofluorobenzene (20.0 \lL, 0.188 mmol, 0.939 equiv). The yield was determined by comparing the integration of the ¹⁹F NMR (375 MHz, acetone-^, 23 °C) resonance of l-fluoro-4-(trifluoromethoxy)benzene (-117.0 ppm, -59.9 ppm), 1,4-difluorobenzene (-121.7 ppm), 4,4'-difluorobiphenyl (-118.0 ppm), 4-fluorophenol (-128.4 ppm), and fluorobenzene (-115.4 ppm) with that of 3-nitrofluorobenzene (-112.0 ppm). Yields are reported as percentages (by ¹⁹F NMR) in Table S4.

Table S4: Effect of temperature on the yield of trifluoromethoxylation

Example 35. Effect of additives on the yield of Ag-mediated trifluoromethoxylation reaction

2.0 equiv TAS · OCR

1.2 equiv F-TEDA-PF(

2.0 equiv AgPFg

2.0 equiv additive

THF:acetone (1 :3)

S6 -30 °C 35

To a suspension of tris(dimethylamino)sulfonium difluorotrimethylsilicate (110 mg, 0.400 mmol, 2.00 equiv), additive (0.400 mmol, 2.00 equiv), and (4- fluorophenyl)tributylstannane (S6) (77.0 mg, 0.200 mmol, 1.00 equiv) in anhydrous THF (0.800 mL) at -30 °C was added trifluoromethyl trifluoromethanesulfonate (SI) (0.18 g, 0.12 mL, 0.83 mmol, 4.1 equiv), and the suspension was stirred vigorously. The reaction mixture was stirred at -30 °C for 30 minutes, then a solution cooled to -30 °C of l-chloromethyl-4- fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (113 mg, 0.240 mmol, 1.20 equiv) and silver hexafluorophosphate (101 mg, 0.400 mmol, 2.00 equiv) in dry acetone (2.4 mL) was added. The reaction mixture was stirred for 2 hours in the dark, then warmed to 23 °C. To the reaction mixture was added 3-nitrofluorobenzene (20.0 \lL, 0.188 mmol, 0.939 equiv). The yield was determined by comparing the integration of the ¹⁹F NMR (375 MHz, acetone-^, 23 °C) resonance of l-fluoro-4-(trifluoromethoxy)benzene (-117.0 ppm, -59.9 ppm), 1,4-difluorobenzene (-121.7 ppm), 4,4'-difluorobiphenyl (-118.0 ppm), 4-fluorophenol (-128.4 ppm), and fluorobenzene (-115.4 ppm) with that of 3-nitrofluorobenzene (-112.0 ppm). Yields are reported as percentages (¹⁹F NMR) in Table S5.

Table S5: Effect of additives on the yield of trifluoromethoxylation

Example 36. Synthesis of 16-desmethoxyvinorelbine-16-trimethylstannane (37)

To 16-desmethoxyvinorelbine 16-triflate (60.0 mg, 66 μmol, 1.00 equiv) in dioxane (16 rriL) was added hexamethylditin (41 μΐ, 1.98 mmol, 3.00 equiv) and lithium chloride (20.6 mg, 2.96 mmol, 45 equiv). The reaction was degassed with argon and palladium tetrakistriphenylphosphine was added (15 mg, 13 μιηοΐ, 0.2 equiv). The reaction mixture was heated to 70 °C and stirred for 7 h. The reaction was allowed to cool to 23 °C and concentrated in vacuo. The resulting residue was purified by prepTLC with CH₂Cl₂/MeOH 9:1 (v/v) to afford 28.8 mg of the title compound (37) as a white solid (47% yield).

NMR Spectroscopy: ^]H NMR (500 MHz, CDC1₃, 23 °C, δ): 8.27 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.24-7.21 (m, 3H), 6.42 (bs, 1H), 6.12 (s, 1H), 5.87 (dd, / = 2.9 Hz, 4.9 Hz, 1H), 5.57 (bm, 1H), 5.37 (s, 2H), 5.30 (s, 1H), 4.45-4.42 (m, 1H), 4.07-4.04 (bm, 1H), 3.95-3.92 (m, 2H), 3.86 (s, 3H), 3.84-3.74 (m, 3H), 3.73 (s, 1 H), 3.66 (s, 3H), 3.70-3.62 (m, 3H), 3.48 (s, 1H), 3.39-3.29 (m, 4H), 3.19-2.88 (m, 2H), 2.85 (s, 3H), 2.80-2.64 (m, 3H), 2.17 (s, 3H), 2.10-2.01 (m, 4H) 1.69-1.67 (m, 2H), 1.25-1.23 (m, 2H), 1.07-1.04 (t, 7.5 Hz, 3H), 0.96-0.93 (t, 6.5 Hz, 3H), 0.66 (s, 3H).

Example 37. Synthesis of 16-desmethoxy-16-trifluoromethoxyvinorelbine (38)

A dry 5 gram vial will be charged with tris(dimethylamino)sulfonium

trifluoromethylsilicate (38.0 mg, 0.14 mmol, 2.0 equiv), sodium bicarbonate (11.7 mg, 0.14 mmol, 2.0 equiv), and dry THF (0.3 ml). The solution will then be cooled to -30 °C and trifluoromethyl trifluormethanesulfonate added (100 μΐ). The solution will then be stirred at -30 °C for 30 min and then a solution of silver hexafluorophosphate (35.0 mg, 0.14 mmol, 2.0 equiv) and l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (39.0 mg, 0.08 mmol, 1.2 equiv) in dry acetone (0.5 ml) added. A solution of 16-desmethoxyvinorelbine-16-trimethylstannane (64.8 mg, 0.07 mmol, 1.0 equiv) (37) in dry acetone would be added to the previous solution drop-wise. The solution will be stirred at -30 °C in the dark for 2 hours and then warmed to 25 °C. The reaction mixture will be filtered through celite with CH2CI2, concentrated in vacuo, and the residue purified on silica gel eluting with CILC MeOH 2:1 (v/v) to afford 16-desmethoxy-16- trifluoromethoxyvinorelbine (38).

Example 38. 4-(Trifluoromethoxy)biphenyl (3)

NaOH, MeOH;

2.0 equiv AgPFg, 0 °C;

72%

To a solution of sodium hydroxide in anhydrous methanol (1.00 N, 0.500 mL, 1.00 equiv) at 23 °C was added biphenyl boronic acid (99.0 mg, 0.500 mmol, 1.00 equiv) and stirred for 15 minutes. The reaction mixture was then cooled to 0 °C and silver

hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) was added and the suspension was stirred for 30 minutes at 0 °C. The solvent was removed under reduced pressure at 0 °C, and the residual methanol was removed under reduced pressure by co-evaporation with anhydrous THF (2 x 0.500 mL). To the residue was added anhydrous THF (2.0 mL) and then tris(dimethylamino)sulfonium difluorotrimethylsilicate (276 mg, 1.00 mmol, 2.00 equiv) and sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv) successively. The reaction was cooled to -30 °C and to the suspension was added trifluoromethyl trifluoromethanesulfonate (SI) (0.60 g, 0.40 mL, 2.8 mmol, 5.5 equiv) and the suspension was then stirred at -30 °C for 30 minutes. A solution of l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv.) in dry acetone (6.0 mL) was added. The suspension was stirred for 1 hour and then filtered through a pad of celite eluting with CH2CI2 and the filtrate concentrated in vacuo. The residue was purified via column chromatography on silica gel eluting with pentane/CTLC^ 20:1 (v/v) to afford 86.2 mg of the title compound as a white solid (72% yield). R_f = 0.53 (hexanes/CH₂Cl₂ 19:1 (v/v)). NMR Spectroscopy: ^]H NMR (500 MHz, CDC1₃, 23 °C, δ): 7.64-7.59 (m, 4H), 7.51-7.48 (m, 2 H), 7.41 (t, 7 = 7.3 Hz, 1H), 7.34 (d, / = 8.2 Hz, 2H). ¹³C NMR (100 MHz, CDC1₃, 23 °C, δ): 148.8 (q, / = 2 Hz), 140.1, 140.0, 129.0, 128.6, 127.8, 127.3, 121.4, 120.7 (q, / = 256 Hz). ¹⁹F NMR (375 MHz, CDC1₃, 23 °C, δ): -58.2.

Example 39. l-Methoxy-4-(trifluoromethoxy)benzene (6)

NaOH, MeOH;

2.0 equiv AgPF₆, 0 °C;

63%

To a solution of sodium hydroxide in anhydrous methanol (1.00 N, 0.500 iriL, 1.00 equiv) at 23 °C was added 4-methoxyphenylboronic acid (76.0 mg, 0.500 mmol, 1.00 equiv) and stirred for 15 minutes. The reaction mixture was then cooled to 0 °C and silver hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) was added and the suspension was stirred for 30 minutes at 0 °C. The solvent was removed under reduced pressure at 0 °C, and the residual methanol was removed under reduced pressure by co-evaporation with anhydrous THF (2 x 0.500 iriL). To the residue was added anhydrous THF (2.0 iriL) and then tris(dimethylamino)sulfonium difluorotrimethylsilicate (276 mg, 1.00 mmol, 2.00 equiv) and sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv) successively. The reaction was cooled to -30 °C and to the suspension was added trifluoromethyl trifluoromethanesulfonate (SI) (0.60 g, 0.40 iriL, 2.8 mmol, 5.5 equiv) and the suspension was then stirred at -30 °C for 30 minutes. A solution of l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv.) in dry acetone (6.0 iriL) was added. The suspension was stirred for 1 hour and then filtered through a pad of celite eluting with CH₂C1₂ and the filtrate concentrated in vacuo. The residue was purified via column chromatography on silica gel eluting with pentane/Et₂0 5: 1 (v/v) to afford 60.5 mg of the title compound as a pale yellow oil (63% yield).

R_f = 0.48 (pentane/CH₂Cl₂ 9: 1 (v/v)). NMR Spectroscopy: ^]H NMR (500 MHz, CDC1₃, 23 °C, δ): 7.15 (d, / = 8.5 Hz, 2H), 6.89 (d, / = 9.0 Hz, 2H), 3.81 (s, 3H). ¹³C NMR (125 MHz, CDCI₃, 23 °C, δ): 158.3, 142.9 (q, J = 2 Hz), 122.6, 120.8 (q, J = 254 Hz), 114.8, 55.7. ¹⁹F NMR (470 MHz, CDC1₃, 23 °C, δ): -58.9.

Example 40. 5-Trifluoromethoxy-jV-Boc-indole (18)

NaOH, MeOH;

2.0 equiv AgPF₆, 0 °C;

7^6%

To a solution of sodium hydroxide in anhydrous methanol (1.00 N, 0.500 mL, 1.00 equiv) at 23 °C was added N-Boc-indol-5-ylboronic acid (130.5 mg, 0.500 mmol, 1.00 equiv) and stirred for 15 minutes. The reaction mixture was then cooled to 0 °C and silver hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) was added and the suspension was stirred for 30 minutes at 0 °C. The solvent was removed under reduced pressure at 0 °C, and the residual methanol was removed under reduced pressure by co-evaporation with anhydrous THF (2 x 0.500 mL). To the residue was added anhydrous THF (2.0 mL) and then tris(dimethylamino)sulfonium difluorotrimethylsilicate (276 mg, 1.00 mmol, 2.00 equiv) and sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv) successively. The reaction was cooled to -30 °C and to the suspension was added trifluoromethyl trifluoromethanesulfonate (SI) (0.60 g, 0.40 mL, 2.8 mmol, 5.5 equiv) and the suspension was then stirred at -30 °C for 30 minutes. A solution of l-chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv.) in dry acetone (6.0 mL) was added. The suspension was stirred for 1 hour and then filtered through a pad of celite eluting with CH2CI2 and the filtrate concentrated in vacuo. The residue was purified via column chromatography on silica gel eluting with pentane/CH₂Cl₂ 10: 1 (v/v) to afford 114 mg of the title compound as a pale yellow oil (76% yield).

R_f = 0.70 (hexanes/CH₂Cl₂ 1 : 1 (v/v)). NMR Spectroscopy: ^]H NMR (500 MHz, CDC1_3, 23 °C, δ): 8.17 (d, / = 7.8 Hz, 1H), 7.66 (d, / = 3.4 Hz, 1H), 7.42 (s, 1H), 7.18 (d, J 7.3 Hz, 1H), 6.57 (d, / = 3.4 Hz, 1H), 1.68 (s, 9H). ¹³C NMR (125 MHz, CDC1₃, 23 °C, δ) 149.4, 145.0 (q, J = 2 Hz), 133.6, 131.3, 127.8, 123.9 (q, 7 = 256 Hz), 117.8, 116.1, 113.4, 107.2, 84.3, 28.3. ¹⁹F NMR (375 MHz, CDC1₃, 23 °C, δ): -58.5. Mass Spectrometry: HRMS-FIA (m/z): Calcd for C9H7F₃NO [M - C5H9O2 (Boc) + H]⁺, 202.0480. Found,

202.0485.

Example 41. 2-(Trifluoromethoxy)naphthalene (31)

NaOH, MeOH;

2.0 e uiv A PF 0

2.0 equiv TAS · OCF3, THF

2.0 equiv NaHC0₃, -30 °C then

30 1.2 equiv F-TEDA-PF₆, acetone 31

64%

To a solution of sodium hydroxide in anhydrous methanol (1.00 N, 0.500 mL, 1.00 equiv) at 23 °C was added 2-naphthylboronic acid (30) (86.0 mg, 0.500 mmol, 1.00 equiv) and stirred for 15 minutes. The reaction mixture was then cooled to 0 °C and silver hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) was added and the suspension was stirred for 30 minutes at 0 °C. The solvent was removed under reduced pressure at 0 °C, and the residual methanol was removed under reduced pressure by co-evaporation with anhydrous THF (2 x 0.500 mL). To the residue was added anhydrous THF (2.0 mL) and then tris(dimethylamino)sulfonium difluorotrimethylsilicate (276 mg, 1.00 mmol, 2.00 equiv) and sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv) successively. The reaction was cooled to -30 °C and to the suspension was added trifluoromethyl trifluoromethanesulfonate (SI) (0.60 g, 0.40 mL, 2.8 mmol, 5.5 equiv) and the suspension was then stirred at -30 °C for 30 minutes. A solution of l-chloromethyl-4-fluoro- l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv.) in dry acetone (6.0 mL) was added. The suspension was stirred for 1 hour and then filtered through a pad of celite eluting with CH₂CI₂ and the filtrate concentrated in vacuo. The residue was purified via column chromatography on silica gel eluting with pentane/CH₂Cl₂ 9: 1 (v/v) to afford 68.2 mg of the title compound as a pale yellow oil (64% yield).

R_f = 0.75 (pentane/CH₂Cl₂ 9: 1 (v/v)). NMR Spectroscopy: ^]H NMR (500 MHz, CDC1_3, 23 °C, δ): 7.89-7.83 (m, 3H), 7.68 (s, 1H), 7.56-7.52 (m, 2H), 7.35 (d, / = 7.3 Hz, 1H). ¹³C NMR (100 MHz, CDC1₃, 23 °C, δ): 147.0 (q, / = 2 Hz), 133.7, 131.9, 130.2, 127.9, 127.2, 126.5, 120.8 (q, J = 258 Hz), 120.3, 118.3.* ¹⁹F NMR (375 MHz, CDC1₃, 23 °C, δ): -

59.2. *Only 9 aromatic carbon signals observed due to overlap of two carbon signals. Example 42. Methyl 3-methyl-5-(trifluoromethoxy)benzoate (33)

NaOH, MeOH;

2.0 e uiv A PF 0 °C

1.2 equiv F-TEDA-PF₆, acetone

32 33

65%

To a solution of sodium hydroxide in anhydrous methanol (1.00 N, 0.500 mL, 1.00 equiv) at 23 °C was added 3-methoxycarbonyl-5-methylphenylboronic acid (32) (97.0 mg, 0.500 mmol, 1.00 equiv) and stirred for 15 minutes. The reaction mixture was then cooled to 0 °C and silver hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) was added and the suspension was stirred for 30 minutes at 0 °C. The solvent was removed under reduced pressure at 0 °C, and the residual methanol was removed under reduced pressure by co- evaporation with anhydrous THF (2 x 0.500 mL). To the residue was added anhydrous THF (2.0 mL) and then tris(dimethylamino)sulfonium difluorotrimethylsilicate (276 mg, 1.00 mmol, 2.00 equiv) and sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv) successively. The reaction was cooled to -30 °C and to the suspension was added trifluoromethyl trifluoromethanesulfonate (SI) (0.60 g, 0.40 mL, 2.8 mmol, 5.5 equiv) and the suspension was then stirred at -30 °C for 30 minutes. A solution of l-chloromethyl-4-fluoro- l ,4- diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv.) in dry acetone (6.0 mL) was added. The suspension was stirred for 1 hour and then filtered through a pad of celite eluting with CH2CI2 and the filtrate concentrated in vacuo. The residue was purified via column chromatography on silica gel eluting with

pentane/CH₂Cl₂ 4: 1 (v/v) to afford 75.6 mg of the title compound as a colorless oil (65% yield).

R_f = 0.57 (pentane/CH₂Cl₂ 3: 1 (v/v)). NMR Spectroscopy: ^]H NMR (500 MHz, CDC1_3, 23 °C, δ): 7.80 (s, 1H), 7.69 (s, 1H), 7.22 (s, 1H), 3.93 (s, 3H), 2.43 (s, 3H). ¹³C NMR (125 MHz, CDC1₃, 23 °C, δ): 166.1, 149.3 (q, / = 2 Hz), 140.6, 131.9, 128.8, 126.2, 120.6 (q, 7 = 258 Hz), 119.3, 52.6, 21.4. ¹⁹F NMR (470 MHz, CDC1₃, 23 °C, δ): -59.4. Mass Spectrometry: HRMS-FIA (m/z) Calcd for C1₀H9F₃O₃ [M + H]⁺, 235.0577. Found, 235.0590. Example 43. l-Fluoro-4-(trifluoromethoxy)benzene (35)

NaOH, MeOH;

2.0 e uiv A PF 0 °C

2.0 equiv TAS · OCF₃, THF

2.0 equiv NaHC0₃, -30 °C then

34 1.2 equiv F-TEDA-PF₆, acetone 35

67%

To a solution of sodium hydroxide in anhydrous methanol (1.00 N, 0.500 mL, 1.00 equiv) at 23 °C was added 4-fluorophenylboronic acid (34) (86.0 mg, 0.500 mmol, 1.00 equiv) and stirred for 15 minutes. The reaction mixture was then cooled to 0 °C and silver hexafluorophosphate (252 mg, 1.00 mmol, 2.00 equiv) was added and the suspension was stirred for 30 minutes at 0 °C. The solvent was removed under reduced pressure at 0 °C, and the residual methanol was removed under reduced pressure by co-evaporation with anhydrous THF (2 x 0.500 mL). To the residue was added anhydrous THF (2.0 mL) and then tris(dimethylamino)sulfonium difluorotrimethylsilicate (276 mg, 1.00 mmol, 2.00 equiv) and sodium bicarbonate (84.0 mg, 1.00 mmol, 2.00 equiv) successively. The reaction was cooled to -30 °C and to the suspension was added trifluoromethyl trifluoromethanesulfonate (SI) (0.60 g, 0.40 mL, 2.8 mmol, 5.5 equiv) and the suspension was then stirred at -30 °C for 30 minutes. A solution of l-chloromethyl-4-fluoro- l,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (la) (282 mg, 0.600 mmol, 1.20 equiv.) in dry acetone (6.0 mL) was added. The suspension was stirred for 1 hour and 3-nitrofluorobenzene (20.0 \lL, 0.188mmol) was added to the reaction mixture. The yield (67 ) was determined by comparing integration of the peak of l-fluoro-4-(trifluoromethoxy)benzene (-117.0 ppm) with that of 3-nitrofluorobenzene (-112.0 ppm).

Claims

WHAT IS CLAIMED IS:

1. A method of fluoroalkoxylating an organic compound, the method comprising providing an organic compound comprising an organostannane, a silver-containing compound, and a fluoroalkoxylating agent, under conditions sufficient to fluoroalkoxylate the organic compound, thereby providing a fluoroalkoxylated organic compound.

2. The method of claim 1 , wherein the organic compound is fluoroalkoxylated

regiospecifically.

3. The method of claim 1, wherein the organic compound comprises an aryl group (e.g., a phenyl group).

4. The method of claim 3, wherein the aryl group may be an electron-poor aryl group, an electron-rich aryl group, an electron-neutral aryl group or an ortho,ortho-disubstituted aryl group.

5. The method of claim 3, wherein the aryl group is a heteroaryl group (e.g., a fused bicyclic group).

6. The method of claim 5, wherein the heteroaryl group is an indole or quinoline.

7. The method of claim 1, wherein the organic compound comprises a vinyl group (e.g., a substituted or unsubstituted vinyl group), wherein the organostannane is attached to the vinyl group (e.g., a styrene).

8. The method of claim 1, wherein the organic compound comprises an organostannane.

9. The method of claim 8, wherein the organostannane comprises a trialkyltin moiety (e.g., a tributyltin or trimethyltin moiety).

10. The method of claim 1, wherein organic compound comprises one or more functional groups (e.g., an alcohol, aldehyde, ester, ketone, alkoxy group, cyano group, amine, amide, or N-oxide).

11. The method of claim 10, wherein the functional group is unprotected.

12. The method of claim 1, wherein the organic compound comprises one or more chiral centers.

13. The method of claim 1, wherein the organic compound is biphenyl-4-yltributylstannane, tributyl(4-fluorophenyl)stannane, tributyl(styryl)stannane or a stannane derivative of a vinca alkaloid (e.g., vincristine, vinblastine, vindesine or vinorelbine).

14. The method of claim 1, wherein the organic compound is represented by the following formula:

15. The method of claim 1 wherein, the fluoroalkoxylated organic compound is fluoro-4- (trifluoromethoxy)benzene, (2-(trifluoromethoxy)vinyl)benzene, 4- (trifluoromethoxy)biphenyl, N-Boc-5-trifluoromethoxyindole, 3-trifluoromethoxyestrone, 4- trifluoromethoxyanisole, ethyl 4-trifluoromethoxybenzoate, 1,3,5-trifluoromethoxybenzene or a fluoroalkoxy derivative of a vinca alkaloid (e.g., vinblastine, vincristine, vindesine or vinorelbine).

16. The method of claim 1 wherein, the fluoroalkoxylated organic compound is represented by the following formula:

17. The method of claim 8, wherein the method further comprises reacting a precursor of the organostannane with a tin-containing reagent to provide the organostannane.

18. The method of claim 21, wherein the precursor of the organostannane comprises a halogen substituent (e.g., bromine or iodine), a Grignard substituent, a triflate substituent, a nonaflate substituent or a diazonium substituent.

19. The method of claim 1, wherein the organic compound is a precursor to a

pharmaceutically acceptable compound.

20. The method of claim 1 , wherein the silver-containing compound is a silver complex.

21. The method of claim 1, wherein silver-containing compound is a silver salt, e.g., a silver(I) salt.

22. The method of claim 32, wherein the silver(I) salt is silver(I) hexafluorophosphate.

23. The method of claim 1, wherein the reaction includes from about 5 to about 0.01 molar equivalents of silver-containing compound relative to the organic compound (e.g., about 3 equivalents of the silver-containing compound, about 2 equivalents of the silver-containing compound or about 1 equivalent of the silver-containing compound).

24. The method of claim 1 , wherein the reaction includes a catalytic amount silver-containing compound relative to the organic compound.

25. The method of claim 1, wherein the reaction includes less than about 1 equivalent of the silver-containing compound, e.g., about 90%, about 80%, about 70%, about 60%, about 50 mol%, about 40 mol%, about 30 mol%, about 20 mol% or about 10 mol% of the silver- containing compound.

26. The method of claim 1, wherein the reaction includes less than about 10 mol of the silver-containing compound (e.g., about 9%, about 8%, about 7%, about 6%, about 5%, about 4%, about 3%, about 2%, about 1%, or less).

27. The method of claim 1, wherein the fluoroalkoxylating agent comprises ¹⁸F or ¹⁹F.

28. The method of claim 1, wherein the fluoroalkoxylating agent is OCF₃ or a precursor thereof.

29. The method of claim 1, wherein the reaction further comprises a solvent.

30. The method of claim 29, wherein the solvent is a polar aprotic solvent.

31. The method of claim 30, wherein the solvent is acetone.

32. The method of claim 30, wherein the solvent is THF.

33. The method of claim 29, wherein the solvent is a polar protic solvent.

34. The method of claim 33, wherein the solvent is methanol.

35. The method of claim 1, wherein the reaction further comprises a reagent.

36. The method of claim 35, wherein the reagent is an acid.

37. The method of claim 1, wherein the reaction includes a second reagent.

38. The method of claim 37, wherein the second reagent is a salt.

39. The method of claim 38, wherein the salt is sodium triflate.

40. The method of claim 39, wherein the second reagent is present in an amount from about a 1 : 1 molar ratio with the silver- Ar compound.

41. The method of claim 39, wherein the second reagent is present in an amount from about a 1:2 molar ratio with the silver- Ar compound.

42. The method of claim 1, wherein the reaction proceeds in one step.

43. The method of claim 1, wherein the reaction proceeds in two steps.

44. The method of claim 1, wherein the reaction proceeds via an intermediate.

45. The method of claim 44, wherein the intermediate is isolated.

46. The method of claim 1 , wherein the reaction further comprises an inert atmosphere.

47. The method of claim 1, wherein the reaction is performed under anhydrous conditions.

48. The method of claim 1, wherein the reaction is performed at ambient temperature.

49. The method of claim 1, wherein the reaction is heated.

50. The method of claim 1 , wherein the reaction is cooled.

51. The method of claim 1, wherein the organic compound is immobilized on a solid support.

52. The method of claim 1 , wherein the fluoroalkoxylation takes place at a late stage in the synthesis of the fluoroalkoxylated organic compound.

53. The method of claim 1, wherein the fluoroalkoxylation is the last step in the synthesis of the fluoroalkoxylated organic compound.

54. The method of claim 53, wherein the organic compound is made using a multi step synthesis.

55. The method of claim 1, wherein the method further comprises purification of the fluoroalkoxylated organic compound from the reaction mixture.

56. The method of claim 55, wherein the purification is by column chromatography on silica gel or preparative thin-layer chromatography.

57. The method of claim 1, wherein the silver-containing compound and the

fluoroalkoxylating agent are added to the organic compound comprising an organostannane, a boron substituent or a silane substituent.

58. The method of claim 1, wherein the silver-containing compound and an additional reagent (e.g., a base) are added to the organic compound comprising an organostannane, resulting in an intermediate product.

59. The method of claim 58, wherein the intermediate is isolated and a fluoroalkoxylating agent and a silver-containing compound are added thereto, resulting in formation of a fluoroalkoxylated organic compound.

60. The method of claim 1, wherein the reaction is catalytic (e.g., the reaction includes a catalytic amount silver-containing compound relative to the organic compound).

61. The method of claim 1, wherein the yield of the fluoroalkoxylated organic compound from the organic compound is at least about 60% (e.g., at least about 65%, 70%, 75%, 80%, 85%, 90% or 95%).

62. The method of claim 1 , wherein the fluoroalkoxylated organic compound comprises ¹⁹F.

63. The method of claim 1, wherein the fluoroalkoxylated organic compound comprises 18 F.

64. The method of claim 1 , wherein the fluoroalkoxylated organic compound is an imaging agent.

65. The method of claim 64, wherein the fluoroalkoxylated organic compound is PET imaging agent.

66. The method of claim 1 , wherein the fluoroalkoxylated organic compound is a pharmaceutically acceptable compound.

67. The method of claim 1, wherein the fluoroalkoxylating agent is OCF₃.

68. The method of claim 1, wherein fluoroalkoxylating reagent is represented by the following formula:

X⁺OCF₃,

wherein X is a cation.

69. The method of claim 68, wherein the cation is silver (Ag⁺).

70. The method of claim 68, wherein the cation is cesium (Cs⁺).

71. The method of claim 68, wherein the cation is ⁺NR^!4 or ^""^"SR^_, wherein

each R¹ is independently Ci_6 alkyl, Ci_6 alkoxy, NR^AR^B, aryl, aralkyl, heteroaryl, heteroaralkyl or heterocyclyl; and

each R^A and each R^B is independently hydrogen, C₁-4 alkyl, aryl or aralkyl.

72. The method of claim 71 , wherein ⁺X is ⁺NR

73. The method of claim 72, wherein each R¹ is independently Ci_6 alkyl, aryl, aralkyl or NR^AR^B.

74. The method of claim 73, wherein each R¹ is Ci_6 alkyl (e.g., n-butyl).

75. The method of claim 71, wherein X is ⁺SR

76. The method of claim 75, wherein each R¹ is independently Ci_6 alkyl, aryl, aralkyl or NR^AR^B.

77. The method of claim 76, wherein each R¹ is NR^aR^b.

78. The method of claim 77, wherein each R^a and R^b is independently hydrogen or C_1-4 alkyl.

79. The method of claim 78, wherein each R^a and R^b is C_1-4 alkyl (e.g., methyl).

80. The method of claim 1 , further comprising an oxidizing agent.

81. The method of claim 80, wherein the oxidizing agent is Selectfluor^® (N-chloromethyl-N'- fluorotriethylenediammonium bis(tetrafluoroborate)) .

82. The method of claim 80, wherein the oxidizing agent is Selectfluor^® (N-chloromethyl-N'- fluorotriethylenediammonium bis(hexafluorophosphate)).

83. The method of claim 80, wherein the oxidizing agent is Selectfluor^® (N-chloromethyl-N'- fluorotriethylenediammonium bis(triflate)) .

84. The method of claim 80, wherein the oxidizing agent is Selectfluor^® (N-chloromethyl-N'- fluorotriethylenediammonium bis(hexafluoroantimonate) .

85. A method of fluoroalkoxylating an organic compound, the method comprising combining silver(I) triflate, an arylstannane, a base, an additional reagent and N-chloromethyl-N'- fluorotriethylenediammonium bis(hexafluorophosphate), under conditions sufficient to fluoroalkoxylate the arylstannane, thereby providing a fluoroalkoxylated organic compound.

86. A reaction mixture comprising a silver-containing compound, an organic compound comprising an organostannane, and a fluoroalkoxylating agent.

87. A pharmaceutical composition, comprising a fluoroalkoxylated compound described herein.

88. A kit comprising a silver-containing compound, an organic compound comprising an organostannane, and a fluoroalkoxylating agent.