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Current Topics in Medicinal Chemistry, 2014, 14, 000-000
Trifluoromethylated Heterocycles Andrei A. Gakh1,* and Yuriy Shermolovich2 1
Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA, The University of Virginia, Charlottesville, VA 22908, USA, The Discovery Chemistry Project, Bethesda, MD 20824, USA; 2Institute of Organic Chemistry, NAS of Ukraine, Murmanskaya Str. 5, 02660, Kiev-94, Ukraine Abstract: This review is a follow-up to the previous chapter, “Monofluorinated Heterocycles” (Topics in Heterocyclic Chemistry, 2012, 33–63), and presents an overview of synthetic chemistry of heterocycles with only one trifluoromethyl group directly attached to the ring (trifluoromethylated heterocycles). Particular attention is given to the modern direct trifluoromethylation methods, including catalytic reactions, organometallic reagents, carbene and hypervalent chemistry, utilization of ionic nucleophilic and electrophilic trifluoromethylating agents, and to other pertinent trends. One of the emphases of the review is compounds with biomedical potential.
Keywords: Trifluoromethyl group, heterocycles. 1. INTRODUCTION Heterocycles containing only one trifluoromethyl group directly attached to the ring (trifluoromethylated heterocycles) constitute an extended family of organic compounds with substantial potential for application, most notably in biomedical and agricultural fields [1-3]. Minimally substituted trifluoromethylated heterocycles can also serve as attractive building blocks for fragment-based drug discovery . Examples of FDA-approved trifluoromethylated heterocyclic drugs include Trifluridine (approved in 1980), Celebrex (1988), Tipranavir (2005) and Sitagliptin (2006). FDA-approved trifluoromethylated heterocyclic drugs
N-, O- and S-trifluoromethylated heterocycles are far less common compared to their C-trifluoromethylated analogs, similar to N-fluoroheterocycles. Some of O- and Strifluoromethylated heterocyclic systems are of interest as potent electrophilic trifluoromethylating agents, and warrant additional attention from the synthetic organic chemistry perspective [7, 8]. The main subject of this review is modern synthetic chemistry of trifluoromethylated heterocycles. It is intended to be a companion for the previous chapter related to the chemistry of monofluorinated heterocycles .
In addition, trifluoromethylation chemistry provides more synthetic opportunities compared to monofluorination. As a result, reported C-trifluoromethylated heterocycles enjoy better structural diversity, with some notable exceptions outlined in the text.
O F 3C
Several critical features distinguish C-fluoro- from Ctrifluoromethyl heterocycles. C-trifluoromethylated heterocycles frequently demonstrate somewhat better chemical stability compared to their C-monofluorinated analogs. This likely derives from the “electronic stabilization” features of the trifluoromethyl group due to a strong electronwithdrawing inductive (–I) effect [5, 6]. On the other hand, the fluorine atom has a strong (–I) effect coupled with the reverse electron-donating mesomeric (+M) effect. Another distinguishing feature between –CF3 and –F involves alteration of HF -elimination pathway, which is common for some nitrogen-containing electron-rich C-fluoroheterocycles.
2. THREE-MEMBERED TRIFLUOROMETHYLATED HETEROCYCLES Trifluoromethyl derivatives are known for almost all major three-membered heterocycles. They have the highest strain compared to the sterically relaxed five- and sixmembered trifluoromethylated heterocycles, and are of substantial synthetic organic chemistry interest due to enhanced reactivity towards both electrophilic and nucleophilic agents. Some basic structures of the three-membered trifluoromethylated heterocycles are presented below.
*Address correspondence to this author at the Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA, The University of Virginia, Charlottesville, VA 22908, USA, The Discovery Chemistry Project, Bethesda, MD 20824, USA; Tel/Fax: ???????????????; E-mail: [email protected]
© 2014 Bentham Science Publishers
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N-substituted derivatives of 2-(trifluoromethyl)aziridine (1a) can be easily prepared via base-catalyzed heterocyclization of corresponding acyclic N-substituted 2-trifluormethyl2-bromoethylamines [10, 11], or 1,1,1-trifluoroacetone . These methods, however, cannot be used for the preparation of the parent 2-(trifluoromethyl)aziridine (1).
Unlike unsubstituted 2-(trifluoromethyl)aziridine (1), parent 2-(trifluoromethyl)oxirane (3) can be conveniently prepared in two steps from 3,3,3-trifluoropropene. Reaction of 3,3,3-trifluoropropene with N-bromosuccinimide in acetic acid affords 3-acetoxy-2-bromo-1,1,1-trifluoropropane. The latter compound can be converted to the desired 2(trifluoromethyl)oxirane (3) via alkali treatment . 2(Trifluoromethyl)oxirane (3) is now available in enantiomerically pure form, and can be used for the preparation of various trifluoromethylated aliphatic intermediates via ring opening pathway .
The synthesis of parent 2-(trifluoromethyl)thiiran (17) was first reported more than 25 years ago. Similar to 2(trifluoromethyl)oxirane (3), it can be prepared from 3,3,3trifluoropropene in four steps .
Three-membered trifluoromethylated heterocycles with two heteroatoms are also adequately represented. 3(Trifluoromethyl)dioxirane, which possesses an additional methyl group in 3-postion (8a), can be easily produced from 1,1,1-trifluoroacetone and potassium peroxomonosulfate . As expected, 8a is a versatile oxidizing  and epoxidizing reagent . The presence of the trifluoromethyl group might enhance the stability of 8a via the “electronic stabilization” effect mentioned earlier .
Another example of three-membered trifluoromethylated heterocycles with two heteroatoms is 2-(trifluoromethyl) oxaziridine (7), in which the trifluoromethyl group is directly connected to the nitrogen atom. It appears that the two additional fluorine atoms in the known 3,3-difluoro-2(trifluoromethyl)oxaziridine (7a) might provide additional stabilization by reducing the electron density on the nitrogen atom. Compound 7a can be prepared from perfluoro-2azapropene in one step .
Gakh and Shermolovich
Derivatives of 3-(trifluoromethyl)diaziridine (4) possessing an additional aryl group at the 3 position (4a) were prepared in two steps from corresponding aryl(trifluoromethyl) ketones . Subsequent oxidation led to the corresponding 3-aryl-3-(trifluoromethyl)diazirines (13a) – valuable photochemical precursors of aryl trifluoromethyl carbenes and isomeric diazomethanes . Reliable syntheses of the parent structures 4 and 13 have not been reported yet.
An elegant one-step synthesis of 3-chloro-3(trifluoromethyl)diazirine (13b) from easily available (trifluoromethyl)acetamidine and hypochlorite (Graham reaction) underscores the advantages of atom-efficient preparative chemistry. In this reaction hypochlorite assists heterocyclization and also acts as an oxidizing and chlorinating agent .
Photochemically labile 3-(trifluoromethyl)diazirines having additional biogenic fragments attached to the 3-postion are now widely used in biomedical applications as efficient labeling reagents . 3. FOUR-MEMBERED TRIFLUOROMETHYLATED HETEROCYCLES Four-membered trifluoromethylated heterocycles 23–36 are adequately represented in the scientific literature, but most examples include the commercially available salts of 3(trifluoromethyl)azetidine (23) and its derivatives. A substantial strain due to the unfavorable stretching of valence angles from the ideal tetrahedral arrangement to the pseudosquare geometry is a prominent feature of these heterocycles. As a result, they can be used in various applications that involve facile ring opening reactions, such as production of polymers or synthesis of functionalized acyclic intermediates. Some trifluoromethylated four-membered heterocycles are presented below.
A popular building block, 3-(trifluoromethyl)azetidine (23), is now available as a hydrochloride salt from several suppliers (CAS 1221349-18-3). A multi-step synthesis of a lesser-known 2-(trifluoromethyl)azetidine (24), in the form of N-alkyl derivatives 24a, was reported recently .
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Enantiomerically pure 4-trifluoromethylazetidine-2-one (23a), an example of trifluoromethylated biologically relevant -lactams, can be prepared in three steps using an auxiliary chiral amine .
Reliable syntheses of both parent 3- and 2(trifluoromethyl)oxetanes (26 and 27) were not found in the available synthetic organic chemistry literature. Some fluorinated derivatives of 27 were claimed to be prepared using a generic [2+2] cycloaddition reaction between trifluoroacetaldehyde and fluoroethylenes, but no preparative or spectral information was provided . The same is true for the parent 3- and 2-(trifluoromethyl)thietanes (28 and 29). Trifluoromethylated four-membered heterocycles with two heteroatoms are less frequently reported. Among the better-known compounds of this class is the perfluorinated derivative (34a) of N-trifluoromethyl-1,2-oxazetidine (34), which can be prepared by [2+2] cycloaddition reaction of trifluoronitrosomethane and tetrafluoroethylene .
The perfluorinated derivative of 35 in a form of -sultone 35a is also reported. It can be prepared in 85% yield from freshly distilled SO3 and perfluoropropene. This reaction is regioselective – only the single regioisomer of 35a is produced .
Both 2-and 3-(trifluoromethyl)pyrrolidines (37 and 38) are now commercially available. Biologically important amino acid derivatives of 37, such as chiral trifluoromethylated proline (37a), can be prepared in six steps starting from ethyl trifluoropurivate .
The synthesis of 2-(trifluoromethyl)tetrahydrofuran (39) was accomplished by heterocyclization of the corresponding trifluoromethylated 1,4-diol .
The diastereoselective synthesis of substituted 2(trifluoromethyl)tetrahydrofuran epoxides (39b) was reported recently. The method is based on cycloaddition reactions of -(trifluoromethyl)vinylsulfonium salts .
Parent 3-(trifluoromethyl)tetrahydrofuran (40) is also known. It was prepared by heterocyclization of trifluoromethyl--chlorobutanol . 4. FIVE-MEMBERED TRIFLUOROMETHYLATED HETEROCYCLES The number of possible trifluoromethylated fivemembered heterocycles is substantially higher than threeand four-membered heterocycles combined. The same is true for available references and reported synthetic procedures. The biomedical importance of this class of fluoroorganic compounds is exemplified by Celebrex and Sitagliptin - the two FDA-approved drugs mentioned earlier.
Trifluoromethylated aromatic five-membered heterocycles are far more abundant in the literature compared to their alicyclic analogs. Parent 2- and 3-(trifluoromethyl)pyrroles (59 and 60), and corresponding N-methylated derivatives, (59a and 60a) were prepared in moderate yields (33–35%) by irradiation of the mixtures of pyrrole or N-methylpyrrole
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and trifluoromethyl iodide with a low pressure mercury lamp . Somewhat better yields were achieved by the irradiation of pyrrole or N-methylpyrrole and difluorodiiodomethane with a 450 W medium-pressure mercury lamp. A photoinduced electron-transfer mechanism was proposed for this reaction . CF3
+ N H
59, 42% (CF2I2)
CF3I (or CF2I2)
Substituted 2-(trifluoromethyl)pyrrole 59e was prepared by the reaction of -ethoxyvinyl trifluoromethyl ketone with ethyl isocyanoacetate .
Parent 3-(trifluoromethyl)pyrrole (60) can be prepared from t-butyl (E)-4,4,4-trifluorobutenoate and (tosyl)methylisocyanide via decarboxylation of intermediate 4(trifluoromethyl)pyrrole-3-carboxylic acid .
N Me hv
60, 2% (CF2I2)
Gakh and Shermolovich
+ N Me
59a, 46% (CF2I2)
N Me 60a, 3% (CF2I2)
Regioselective 2-trifluoromethylation of pyrrole and Nmethylpyrrole with CF3Br can be achieved using sodium dithionite or zinc - sulfur dioxide. These reagents induce the formation of trifluoromethyl radicals via a single electron transfer . A catalyst-free CF3SO2Na/t-BuOOH system , and a photochemically-activated CF3SO2Cl/Ru(phen)3Cl2 system  were successfully used for the synthesis of 2-(trifluoromethyl)pyrroles.
Recently discovered reactions of mesoionic 1,3oxazolium-5-olates with phosphorus  or sulfur  ylides provide a facile access to substituted 3(trifluoromethyl)pyrroles (60c). These transformations follow the classical ANRORC (Addition Nucleophilic - Ring Opening - Ring Closure) reaction pathway.
CF3Br/Zn/SO2 N R
CF3 N R R=H, 59 R=Me, 59a
Alternative direct trifluoromethylation methods entail the use of electrophilic trifluoromethylating agents, such as diaryl(trifluoromethyl)sulfonium salts , or hypervalent iodine reagents .
Microwave-induced pyrolysis of pyrrolo[1,2-c]thiazole2,2-dioxide leads to 2-styryl-3-(trifluoromethyl)pyrrole (60d) via a possible formation of (trifluoromethyl)azafulvenium methide .
The synthesis of parent 2-(trifluoromethyl)furan (61) involves a partial fluorination of furan-2,5-dicarboxylic acid with SF4 followed by catalytic high temperature decarboxylation .
Other derivatives of 59 and 60 and can be prepared by heterocyclization of appropriate trifluoromethylated synthons. For example, condensation of 1,1,1-trifluoro-2,4diones and 2-(aminomethyl)pyridine yields 2-pyridyl-3-(or 5)-(trifluoromethyl)pyrroles 59c, 59d and 60b .
Direct electrophilic trifluoromethylation of furan by reaction with the trifluoromethyl cation (generated by radiolysis of CF4) leads to the formation of a mixture of 2- and 3(trifluoromethyl)furans .
Radical trifluoromethylation of furan and its derivatives is more regioselective and gives predominantly 2(trifluoromethyl)furans 61 and 61a . This reaction likely proceeds via an addition-elimination pathway. Recent applications of this approach involve the use of boron derivatives together with modern catalytic systems .
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CF3I. An ipso-substitution reaction pathway via a carbene intermediate is a likely mechanism of formation of the minor 2-(perfluroalkyl)thiophenes . Traditional heterocyclization and cycloaddition reactions are the most common venues for the synthesis of polysubstituted (trifluoromethyl)furans. For example, rhodiumcatalyzed formal [3+2] cycloaddition reactions of ethyl 2diazo-4,4,4-trifluoroacetoacetate with arylacetylenes leads to the formation of di-substituted 2-(trifluoromethyl)furans 61b, among other products .
The same approach was used for the preparation of disubstitued 3-(trifluoromethyl)furan 62a by employing a different diazo compound .
Similar to 2-(trifluoromethyl)furan (61), unsubstituted 2(trifluoromethyl)thiophene (63) can be prepared by a partial fluorination of thiophene-2,5-dicarboxylic acid followed by high temperature Cu-catalyzed decarboxylation .
Modern synthetic approaches towards 2-(trifluoromethyl) thiophene (63) utilize trifluoromethylation reactions with “CuCF3“ species. These reagents can be generated in situ from (trifluoromethyl)trimetoxyborates in the presence of Cu(I)/1,10-phenanthroline complex . An alternative scheme employs (trifluoromethyl)cuprates prepared from CF3H and alkoxycuprates .
Direct trifluoromethylation of thiophene can be achieved via a combination of AgOTf, KF and Me3SiCF3. The major disadvantage of this method is moderate regioselectivity which results in the formation of difficult-to-separate mixtures of 2- and 3-(trifluoromethyl)thiophenes 63 and 64 . A better regioselectivity could be expected with the CF3SO2Cl/Ru(phen)3Cl2 photocatalytic trifluoromethylation system .
Poly-aryl substituted 3-(trifluoromethyl)thiophenes (64a and 64b) can be prepared via the 1,3-dipolar cycloaddition reaction of 1,3-dithiolium-4-olanes with (trifluoromethyl)alkynes. This reaction is not regioselective in respect to aryl groups attached to the 1,3-dithiolium-4-olane ring, and gives a mixture of two regioisomers 64a and 64b .
The 1,3-dipolar cycloaddition reaction of (trifluorometyl)diazomethane and acetylene leads to 3-(trifluoromethyl) pyrazole (65) in almost quantitative yield . An alternative approach involves the use of a sulfoxide derivative of 3,3,3-trifluoropropene and diazomethane .
Another preparative method for the synthesis of 3(trifluoromethyl)pyrazole (65) is based on the reaction of 4ethoxy-1,1,1-trifluoro-3-buten-2-one with hydrazine .
The heterocyclization reaction of -trifluoromethylated vinamidinium salts with hydrazine leads to 4(trifluoromethyl)pyrazole (66) .
A similar heterocyclization approach was used for the industrial scale production of the FDA-approved drug Celebrex which has 3-(trifluoromethyl)pyrazole moiety. Regioselectivity of this synthesis was improved by careful optimization of the reaction conditions .
A practical method for the synthesis of N(trifluoromethyl)pyrazole (67) was developed only recently. This compound was prepared in two steps from pyrazole and dibromodifluoromethane . It is interesting to note that perfluoroalkylation of 3halothiophenes with perfluoroalkyl iodides and Cu at elevated temperatures typically produces a mixture of major 3(perfluoroalkyl)thiophenes and minor 2-(perfluoroalkyl) thiophenes. However, only 3-(trifluoromethyl)thiophene (64) was detected in the similar reaction of 3-iodothiophene with
The synthesis of 2-(trifluoromethyl)imidazole (68) was reported for the first time only in 1978. It was prepared in
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low yield from imidazole through a rare AdditionElectrophilic-Ring-Opening-Ring-Closure (AERORC) reaction pathway  employing the classical Bamberger cleavage reaction . A more efficient alternative synthesis of 2(trifluoromethyl)imidazole (68) is based on the reaction of imidazole-2-carboxylic acid with SF4 .
N-substituted 2-(trifluoromethyl)imidazoles (68a) can be prepared using Cu-mediated regioselective trifluoromethylation of corresponding 1-arylimidazoles .
Radical trifluoromethylation of imidazoles with CF3I under or UV irradiation conditions yields a mixture of 2- and 4(5)-(trifluoromethyl)imidazoles (68 and 69) . Electrochemically generated CF3 radicals give similar results. The radical attack preferentially occurs at the C-4 position .
The original preparative synthesis of 4(5)(trifluoromethyl)imidazole (69) was based on the heterocyclization of 3,3-dibromo-1,1,1-trifluoroacetone .
Similar to N-(trifluoromethyl)pyrazole (67), N(trifluoromethyl)imidazole (70) can be prepared in two steps from imidazole and CF2Br2 .
Derivatives of 2 - and 4-(trifluoromethyl)imidazoles are frequently reported as biologically active compounds, such as a hepatoselective glucokinase activator , and orally active 5-lipoxygenase inhibitors . Both 3- and 5-(trifluoromethyl)isoxazoles (72, CAS 32990-29-7 and 73, CAS 116584-43-1) are now commercially available. 3-(Trifluoromethyl)isoxazole (72) was initially prepared in the course of unrelated study of the 1,3dipolar cycloaddition reactions of trifluoroacetonitrile Noxide with alkyl vinyl ethers. The intermediate 3trifluoromethyl-5-ethoxy-2-isoxazoline was converted to 3(trifluoromethyl)isoxazole by treatment with concentrated H2SO4 .
A halogen exchange reaction of 5-(trichloromethyl) isoxazole with SbF3 /SbCl5 leads to 5-(trifluoromethyl) isoxazole (73) .
Gakh and Shermolovich
An alternative synthesis of 5-(trifluoromethyl)isoxazole (73) is based on heterocyclization of 4-ethoxy-1,1,1trifluoro-3-buten-2-one with hydroxylamine followed by dehydration with large excess of P2O5 . Regioselective syntheses of substituted (trifluoromethyl)isoxazoles 72 and 73 are also known .
It appears that a practical synthesis of the parent 4(trifluoromethyl)isoxazole (71) has not been reported in the available chemical literature, but derivatives of 71 are known. For example, ethyl 3-phenyl-4-(trifluoromethyl) isoxazole-5-carboxylate (71a) can be prepared using a regioselective 1,3-dipolar cycloaddition pathway .
A similar situation was observed for the parent trifluoromethylated oxazoles (74–76). None of them have been reported in the available scientific literature, but their derivatives are known. One example includes the unexpected formation of substituted 5-(trifluoromethyl)oxazoles (75a) in the Dakin-West reaction of N-acylprolines with trifluoroacetic anhydride .
The synthesis of three possible unsubstituted (trifluoromethyl)isothiazoles (77–79) has not been found in the available scientific sources. Their derivatives are known. Chlorinated and brominated (trifluoromethyl)isothiazoles were prepared by fluorination of corresponding carboxylic acids with SF4 .
Among three regioisomeric (trifluoromethyl)thiazoles (80–82), the synthesis of only one, 2(trifluoromethyl)thiazole (81), was reported recently .
Trifluoromethylation of 4-methylthiazole using CF3SO2Cl in photoredox catalytic conditions yields predominantly 4-methyl-5-(trifluoromethyl)thiazole (80a) .
Unsubstituted 4-trifluoromethyl-1,2,3-triazole (83) was initially prepared by the 1,3-dipolar cycloaddition reaction of trifluoroacetonitrile with (trimethylsilyl)diazomethane. This slow reaction requires 12 weeks for completion at room temperature . A more convenient preparative synthesis of 83 from trifluoromethylated fluorovinyl sulfones and (trimethylsilyl)azide was also reported .
The synthesis of 3(5)-trifluoromethyl-1,2,4-triazole (86) can be found only in the patent literature. According to these records, 86 was prepared by hydrolysis-decarboxylation of 3(5)-trifluoromethyl-5(3)-trichloromethyl-1,2-4-triazole at elevated temperatures , or from ethyl trifluoroacetate .
Treatment of substituted 5-(trifluoromethyl)-1,2,4oxadiazoles (see below) with hydrazine leads to corresponding 3(5)-trifluoromethyl-1,2,4-triazoles (86a) via ANRORC reaction sequence .
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verse approach starting from trifluoroacetyl hydrazide is also feasible .
Substituted 2-amino-5-trifluoromethyl-1,3,4-thiadiazoles (93a) are perhaps the most explored among other derivatives of trifluoromethylated thiadiazoles (93–96). They can be easily prepared in one step from thiosemicarbazides and trifluoroacetic anhydride or trifluoroacetic acid/PPA [85, 86].
Direct radical trifluoromethylation of 2-amino-1,3,4thiadiazole using CF3SO2Na/t-BuOOH leads to 2-amino-5trifluoromethyl-1,3,4-thiadiazole (93b) in moderate yield .
A convenient synthesis of 5-(trifluoromethyl)tetrazole (97) is based on a formal “[3+2] cycloaddition” reaction of sodium azide with trifluoroacetonitrile. The actual mechanism of this reaction likely involves nucleophilic addition of azide anion to the activated triple bond followed by spontaneous heterocyclization . Similar to other tetrazole derivatives with electron-withdrawing groups, 97 is a strong acid and easily produces stable salts .
The preparative two-step synthesis of 1-trifluoromethyl1,2,4-triazole (88) is known. The final displacement of bromine can be achieved only at elevated temperatures in low yield . 5. SIX-MEMBERED HETEROCYCLES Synthetic procedures for the preparation of the parent (trifluoromethyl)oxadiazoles (89–92) have not been reported yet, but many substituted derivatives of 89–92 are now commercially available. Some of these derivatives are of interest as building blocks for the synthesis of biologically relevant molecules, and precursors to other trifluoromethylated heterocyclic compounds [80, 81]. For example, 3substituted-5-(trifluoromethyl)-1,2,4-oxadiazoles (91a) were prepared in one step from the corresponding aryl amidoximes and trifluoroacetic anhydride [81, 82].
A similar reaction of aryl hydrazides with trifluoroacetic anhydride, followed by heterocyclization with PCl5, gives 2aryl-5-trifluoromethyl-1,3,4-oxadiazoles (92a) . A re-
The family of six-membered trifluoromethylated heterocycles includes several biomedically important compounds, such as 5-(trifluoromethyl)uracil (127a), a dioxo-derivative of 5-(trifluoromethyl)pyrimidine (127).
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Gakh and Shermolovich
All three regioisomers of (trifluoromethyl)piperidine (100, CAS 154727-51-2-102; 101, CAS 768-31-0; 102, CAS 155849-49-3) are currently commercially available as stable hydrochlorides, and even in enantiomerically pure form (100). They were initially prepared by the reactions of corresponding amino acids with SF4 . Modern methods of synthesis include reactions of cyclic imines (or their trimers) with Me3 SiCF3 in acidic conditions . Chemically reactive N-(trifluoromethyl)piperidine (103) is also known .
The most popular derivatives of three regioisomeric (trifluoromethyl)tetrahydropyrans (104–106) are trifluoromethylated -lactones. Photoredox radical trifluoromethylation of cyclic enolsilane leads to -trifluoromethyl--lactone 105a under mild conditions .
N-(trifluoromethyl)morpholine (113) is a rare example of an alicyclic heterocycle with trifluoromethyl group directly attached to the nitrogen atom. Perhaps the most convenient preparative synthesis of 113 is based on fluorination of N(formyl)morpholine with SF4 . Similar to N-(trifluoromethyl)piperidine (103), N-(trifluoromethyl)morpholine (113) reacts vigorously with water.
The electrochemical cross-Kolbe reaction of 3-hydroxy2-(trifluoromethyl)propionic acid with ethyl succinate followed by treatment with HCl gives -trifluoromethyl-lactone 105b .
Electrophilic trifluoromethylation of a cyclic enamine was successfully used for the synthesis of 3(trifluoromethyl)tetrahydro-4H-pyran-4-one 105c .
Contrary to trifluoromethylated piperidines and morpholines (110–113), (trifluoromethyl)dioxanes and (trifluoromethyl)thioxanes (114–119) are largely unexplored. Some trivial members of this group include commercially available 2-(trifluoromethyl)-1,3-dioxane (115, CAS 112252-95-6), and 2-(trifluoromethyl)-1,4-dioxane (117), which only recently appeared in the patent literature, but without synthetic procedures .
Unsubstituted tetrahydro-4H-pyran-4-one can also serve as an intermediate for the synthesis of functionalized (trifluoromethyl)tetrahydropyrans. This strategy is illustrated in the synthesis of 4-trifluoromethyl-4-aminotetrahydropyran via nucleophilic trifluoromethylation of tetrahydro-4H-pyran-4-one imine with CF3SiMe3 .
Aromatic trifluoromethylated six-membered heterocycles enjoyed better literature coverage compared to their alicyclic analogs, although not as good as the corresponding monofluorinated heterocycles. For example, 2-fluoropyridine was discovered back in 1915 . In comparison, its trifluoromethylated analog, 2-(trifluoromethyl)pyridine (120), was prepared for the first time only in 1956 by [4+2] cycloaddition reaction of trifluoroacetonitrile and butadiene in the gas phase at 475 °C in 88% yield . The compound was subsequently prepared by fluorination of picolinic acid with SF4 in HF . A similar reaction of nicotinic acid with SF4 yields the expected 3-(trifluoromethyl)pyridine (121) .
Several alicyclic trifluoromethylated heterocycles with two heteroatoms, including (2-trifluoromethyl)piperazine (110, CAS 131922-05-9), and (3-trifluoromethyl)morpholine (112 MDL MFCD18250297) are currently commercially available. Preparative multi-step synthesis of the two regioisomeric C-trifluoromethylated morpholines (111 and 112) starting from 2-(trifluoromethyl)oxirane (3) was reported recently .
Modern trifluoromethylation methods employ halopyridines as starting materials. The reaction of 2-bromopyridine with sodium trifluoroacetate and copper(I) iodide proceeds smoothly in NMP giving 2-(trifluoromethyl)pyridine in 41% yield . Methyl 3-oxo--(fluorosulfonyl)perfluoropentanoate can also be used as a potent trifluoromethylating agent. In the pres-
ence of copper(I) iodide, this compound reacts not only with 2-bromopyridine, but also with 2-chloropyridine . (Trifluoromethyl)copper, generated in situ from CF3SiMe3 and copper(I) iodide in the presence of potassium fluoride, reacts with 2-, 3- and 4-iodopyridines to give the corresponding trifluoromethylated products in good-to-moderate yields . The reaction of AgF and CF3Si(Me)3 followed by a redox transmetallation with elemental copper generates the reactive “CuCF3” species, which demonstrates good reactivity towards some iodopyridines . Fluoroform can be used for the preparation of “ligand-less” CuCF3. This active reagent is capable of trifluoromethylating of 2chloronicotinic acid . An inexpensive system based on methyl chlorodifluoroacetate/KF/CuI was successfully applied for the kilogram-scale synthesis of methyl 6-chloro-5(trifluoromethyl)nicotinate . Besides halopyridines, boron derivatives of pyridine can also be used . In another example, copper-mediated trifluoromethylation of 2chloropyridyl-5-boronic acid was achieved using CF3SO2Na and t-butyl hydroperoxide . The same CF3SO2Na/tBuOOH system was successfully used for direct trifluoromethylation of pyridines under catalyst-free conditions .
N-Heterocyclic carbene , triphenyl phosphine , and 1,10-phenanthroline  complexes of CuCF3 with well-defined structures are excellent, easy-to-handle trifluoromethylating reagents. These complexes can be prepared by ligand exchange using CF3SiMe3 as a source of trifluoromethyl moiety. The complexes react with all three isomers of iodopyridine to provide a valuable synthetic route to the corresponding 2-, 3- and 4-trifluoromethyl pyridines [105-107].
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Trifluoromethylated pyridines can be prepared from acyclic components, but this strategy is less common. The syntheses of 4-(trifluoromethyl)pyridine (122) and its derivative (122a) starting from ethyl trifluoroacetate are examples of this rare approach .
N-(trifluoromethyl)pyridinium salts (123) were prepared by electrophilic trifluoromethylation of pyridine with O(trifluoromethyl)oxonium salts. Substituted pyridines with one electron-withdrawing group were also successfully trifluoromethylated with these reagents. So far, this is the only practical method for the preparation of these interesting compounds .
Trifluoromethylated pyridazines (124–125) are poorly represented in the literature relative to their (trifluoromethyl)pyridine counterparts (120–123). Regioisomeric 2and 3-(trifluoromethyl)pyridazines (124 and 125) were isolated in small yields from the gas-phase reaction of (trifluoromethyl)benzene with hydrazine and ozone .
The 1,10-phenanthroline complex of CuCF3 was successfully used for the preparation of novel anti-HIV protease inhibitor, Tipranavir (121a), which was approved by FDA in 2005 . Unlike pyridazines, preparative synthetic methods for trifluoromethylated pyrimidines are quite common in the literature. Sodium trifluoroacetate in the presence of copper(I) iodide was successfully used for the synthesis of 2(trifluoromethyl)pyrimidine (126) from 2-bromopyrimidine in 34% yield . Conversion of 2-chloropyrimidine to 2(trifluoromethyl)pyrimidine (126) can also be achieved with Cu-CF2 Br2-DMA system in 46% yield .
Another approach to the synthesis of (trifluoromethyl)pyridines is based on the ring expansion with trifluoromethylated carbenes. The reaction of chloro (trifluoromethyl)carbene, generated from chloro(trifluoromethyl)diazirine (13b), with pyrrole yields 3-(trifluoromethyl)pyridine (121) .
The previously described “CuCF3” reagent (prepared by the reaction of AgF with CF3SiMe3 followed by the redox transmetallation with elemental copper) reacts with 5bromopyrimidine to give 5-(trifluoromethyl)pyrimidine (127), among other perfluoroalkylated products .
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A preparative synthesis of 5-(trifluoromethyl)pyrimidine (127) is based on the reaction of a -trifluoromethylated vinamidinium salt with formamidine hydrochloride .
Gakh and Shermolovich
Trifluoromethylated tetrazines 137–139 remain an obscure class of compounds. Among the better known examples are red-colored derivatives of 3-trifluoromethyl-1,2,4,5tetrazine (139), which can be prepared via heterocyclization of the properly functionalized trifluoromethylated hydrazides in several steps .
A biomedically important dioxo derivative of 127, 5(trifluoromethyl) pyrimidine-2,4-dione (127a), more commonly known as 5-(trifluoromethyl)uracil, can be produced using several different synthetic approaches [114-116]. One of the less known methods entails electrolysis of a solution of uracil in TFA . The compound 127a was successfully used for the preparation of FDA-approved antiviral drug Trifluridine . Trifluridine can also be prepared by direct radical trifluoromethylation of uridine .
2-(Trifluoromethyl)pyrazine (129) was prepared by the fluorination of the corresponding carboxylic acid with SF4. It was subsequently used for the synthesis of compounds with central serotoninmimetic activity .
Innate C–H trifluoromethylation of some substituted pyrazines with the CF3SO2Na/t-BuOOH system leads to the corresponding (trifluoromethyl)pyrazines (129a) . Similar results were observed using the CF3SO2Cl/Ru(phen)3Cl2 photocatalytic system .
6-(Trifluoromethyl)pentazine (140) remains unknown as of today, along with all other “classic” derivatives of this intriguing heterocycle . It is expected that the trifluoromethyl group might stabilize the pentazine ring via the “electronic stabilization” effect [5, 6]. Possible methods for the synthesis of 140 include heterocyclization of transient trifluoromethylated diazomethyl azide in low-temperature matrix isolation conditions and other approaches.
Contrary to extensively studied (trifluoromethyl)pyridines (120–122), unsubstituted (trifluoromethyl) pyrylium salts (141–143) have not been reported in available synthetic organic chemistry literature, but their derivatives are known. The most popular derivatives of 141–143 are trifluoromethylated 4H-pyran-4-ones and 2H-pyran-2-ones. Readily available 1-aryl-4,4,4-trifluorobutane-1,3-diones were successfully used for the synthesis of 4-aryl-6trifluoromethyl-2H-pyran-2-ones (143a) .
Derivatives of 2-(trifluoromethyl)-1,3,5-triazine (135) containing additional amino groups in the 4- and 6-positions are popular among other trifluoromethylated triazines (130– 136) due to their potential as biologically active compounds [119, 120]. These derivatives (135a) can be prepared by heterocyclization of ethyl trifluoroacetate with appropriately substituted biguanides .
Similar reactions of different carbonyl components with ethyl trifluoroacetate in the presence of a strong base leads to substituted 2-trifluoromethyl-4H-pyran-4-ones (143b) .
Ethyl 2-diazo-4,4,4-trifluoroacetoacetate is a new and versatile intermediate for the synthesis of 5-trifluoromethyl1,2,4-triazines (133a), which in turn can be used for the preparation of substituted 2-(trifluoromethyl)pyridines (120a) .
Unlike (trifluoromethyl)pyrylium salts (141–143), trifluoromethylated thiopyrylium salts (146) are known. As expected, these thiopyrylium salts (146) easily react with a variety of nucleophiles to give the corresponding covalent addition products 146a and 146b .
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Some trifluoromethylated pyrans can be converted to corresponding thiopyrans via an oxygen-sulfur exchange. For example, 4-oxo-6-trifluoromethyl-4H-thiopyran-2-carboxylic acid (146c) can be prepared from 4-oxo-6-trifluoromethyl4H-pyran-2-carboxylic acid (143c). The thiopyran acid 146c gives the expected decarboxylation product, 4-oxo-6trifluoromethyl-4H-thiopyran (146d), at elevated temperatures .
6. CONCLUSIONS – THE “WISH LIST” Although the available pool of trifluoromethylated heterocycles is more structurally diverse than the corresponding pool of monofluorinated heterocycles , some “white spots” remains on the map of the parent (unsubstituted) trifluoromethylated heterocycles. Particular attention could be given to the poorly developed synthetic chemistry of Ntrifluoromethylated heterocycles. Some trifluoromethylated heterocycles from the current “wish list” are presented below.
m-Chloro-peroxybenzoic acid, m-ClC6H4 CO3H
Methanesulfonyl chloride, MeSO2Cl
Trifluoroacetic acid, CF3 COOH
Tetrahydrofuran, (CH2)5O Triethylamine trihydrofluoride, Et3N•3HF
p-Toluenesulfonic acid, p-MeC6H4SO2OH
REFERENCES    
CONFLICT OF INTEREST  
ACKNOWLEDGEMENTS This paper is a contribution from the Discovery Chemistry Project funded in part by the U.S. Department of Energy in collaboration with the National Institutes of Health. Oak Ridge National Laboratory is managed and operated by UTBattelle, LLC, under contract DE-AC05-00OR22725 for the U.S. Department of Energy. The content of this publication does not necessarily reflect the views or policies of the U.S. Department of Health and Human Services and the U.S. Department of Energy, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
The author(s) confirm that this article content has no conflicts of interest.
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Received: October 15, 2013
Revised: January 27, 2014
Accepted: January 27, 2014
Gakh and Shermolovich 
  
  
  
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