FULL PAPER DOI: 10.1002/ejoc.201300030
A Convenient Route to 1-Alkyl-5-trifluoromethyl-1,2,3-triazole-4-carboxylic Acids Employing a Diazo Transfer Reaction Rustam T. Iminov,[a] Alexander V. Mashkov,[a] Bohdan A. Chalyk,[b] Pavel K. Mykhailiuk,[a,b] Anton V. Tverdokhlebov,*[a,b] Andrey A. Tolmachev,[a,b] Yulian M. Volovenko,[a] Oleg V. Shishkin,[c] and Svetlana V. Shishkina[c] Keywords: Synthetic methods / Medicinal chemistry / Nitrogen heterocycles / Amines / Azides / Fluorine The reaction of ethyl 3-(alkylamino)-4,4,4-trifluoro-but-2enoates with mesyl azide in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) gave ethyl 1-alkyl-5-trifluoro-
methyl-1,2,3-triazole-4-carboxylates in good yields. Further hydrolysis of the ester group afforded the title compounds on a multigram scale.
Introduction Hitherto derivatives of 1,2,3-triazole have not been isolated from natural sources. Nevertheless this heterocyclic core has found numerous applications in medicine[1] and especially in peptidomimetic chemistry.[1a,1b] In particular, the 1-alkyl-1,2,3-triazole-4-carboxylic acid scaffold appears to be very promising, as exemplified by the discovery of at least two medications based on this structure (see Figure 1). The first one, named Rufinamide, is already marketed as an anticonvulsant drug for the treatment of Lennox-Gastaut syndrome, a severe form of epilepsy. It was developed[2] by Novartis AG and approved by the FDA in 2008. Recently, an improved synthesis of Rufinamide, as well as a comprehensive overview of its medicinal usage, have been published.[3,4] The second compound, known under the names CAI, L651582, and NSC609974, is an anticancer drug currently being developed. Namely, its phase II clinical trials have been completed,[5] and the phase III studies began[6] in 2008 and are continuing presently. Fluorine-containing heterocycles are widely recognized for their biological activities as prospective molecules for use in the medicinal and agricultural fields.[7] The unique nature of fluorine substituents[7g] has a profound impact on the physicochemical properties of substances, and, therefore, on their biochemical behavior. In regard to 1,2,3-triazoles, certain 1-alkyl-5-trifluoromethyl derivatives have been claimed as tachykinin receptor antagonists by Eli [a] Kiev National Taras Shevchenko University, 62 Volodimirska St., 01033 Kiev, Ukraine E-mail:
[email protected] Homepage: www.enamine.net [b] Enamine Ltd., 23 Alexandra Matrosova St., 01103 Kiev, Ukraine [c] STC, Institute for Single Crystals, NAS of Ukraine, 60 Lenina Ave., 61001 Kharkiv, Ukraine Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201300030. Eur. J. Org. Chem. 2013, 2891–2897
Figure 1. Drugs with 1-alkyl-1,2,3-triazole-4-carboxylic acid scaffold.
Lilly,[8] as herbicides by Syngenta,[9] and as pesticides by Bayer Cropscience.[10] Notably, all of these patents[8–10] have been issued during the last decade and are believed to represent preliminary results in the field. The growing interest in fluorine-substituted 1,2,3-triazoles is confronted with a lack of available building blocks and methods for their preparation. Hence, the elaboration of new, scalable approaches to fluorinated 1,2,3-triazoles has become an urgent task. Among them, the 1-alkyl-5-trifluoromethyl-1,2,3-triazole-4carboxylic acid scaffold, which combines a motif of known drugs with the benefits of fluorine substituents, seems to be the most promising. Two approaches to the above-mentioned core have been previously described, and both have utilized azide chemistry (see Scheme 1). The first one involved a [3+2] cycloaddition reaction between an azide and 4,4,4-trifluoro-2-butynoic acid esters 3.[8,11] This approach suffered from insufficient regioselectivity producing mixtures of isomeric triazoles 4 and 5 with ratios ranging from 1:1 to 3:1 depending on the nature of substituent R1. The factors affecting the selectivity were studied both empirically[11a,11b] and by employing quantum chemical calculations,[11c] but no practical methods for the preparation of compounds 4 or 5 without the
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2891
A. V. Tverdokhlebov et al.
FULL PAPER
Scheme 1. Known approaches to 5-trifluoromethyl-1,2,3-triazole-4-carboxylates.
need of tedious chromatographic separations have been developed. The second approach was based on the reaction of azides with trifluoromethyl-substituted 1,3-dicarbonyls 6 or the enaminones 7 derived from them.[12,13] Initially, the method was developed for enaminones 7.[13a,13b] The reaction was assumed to proceed through a cycloaddition of the azide with the alkene moiety of 7, followed by an elimination of the secondary amine. Later, it was shown that enaminones 7 could be obtained in situ from the appropriate dicarbonyls 6 and a secondary amine.[13c] And finally, azides were found to undergo a straightforward reaction with compounds 6 in the presence of bases such as triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). This probably occurred through a cycloaddition with the corresponding enols or enolates.[12] In contrast to the approach with alkyne 3, an excellent selectivity was observed, and triazoles 8 were the only isolated products regardless of whether starting materials 6 or 7 were used.[12,13] However, the reaction required compounds 6 or 7 and the azide to be heated at 70–90 °C at least for several hours[12b] and often for 1–2 days,[13] albeit the yields were good. Furthermore, in some cases, satisfactory results were only obtained by carrying out the reaction under solvent-free conditions, since dilution with any solvent decreased the rate and yields dramatically.[12b,13a,13b] Therefore, the range of suitable azides was limited to aryl- and benzyl-type derivatives and hence this method was inapplicable for the synthesis of triazoles 8 with small R1 alkyl substituents because of the volatile nature of the corresponding alkyl azides. However, in light of the modern trend of lowering the molecular weight of drug candidates, these types of building blocks are in the most demand from a medicinal chemistry perspective, and simultaneously, they remain the least available. Moreover, the prolonged heating of bulk amounts of concentrated azides can be an explosion hazard, even in the case of relatively stable aryl and benzyl azides. Therefore, the scalability of the method is also in question. Furthermore, the alkylation of ethyl 5-trifluoromethyl1H-1,2,3-triazole-4-carboxylate (9)[14] with methyl iodide was examined[9] as a possible route to the corresponding Nmethyl triazoles. This reaction gave a mixture of three isomeric triazoles, of which the major component was N-22892
www.eurjoc.org
substituted methyl derivative 10 (64 %), the minor product 11 (30 %) was a result of alkylation at N-3, and a trace amount (6 %) of ethyl 1-methyl-5-trifluoromethyl-1,2,3-triazole-4-carboxylate (12) was detected.[9] Thereby, alkylation of 1H-1,2,3-triazoles was unsuitable for the synthesis of the target core. Instead, the reaction occurred predominantly at the N-2 atom, obviously because of the strong electronwithdrawing character of both the CF3 and ester groups, which decreased the nucleophilicity at the 1- and 3-positions.
Results and Discussion The aforementioned methods for the preparation of fluorinated 1,2,3-triazoles utilized azides in such a manner that all three nitrogen atoms became a part of the triazole ring. There have been instances, however, in the syntheses of nonfluorinated 1,2,3-triazoles when only two of the nitrogen atoms of the azide reagent became a part of heterocyclic core (see Scheme 2). Thus, treatment of enaminones 13 (see Scheme 3) with sulfonyl azides or related azides with strong electron-withdrawing groups reportedly gave triazoles 18.[15–18] In early works, the reaction was assumed to proceed through an initial [3+2] cycloaddition to give triazoline 14, followed by a Dimroth rearrangement to give intermediate 15 that underwent a final aromatization at the expense of the elimination of sulfonamide (see Scheme 3, path A).[15] Nevertheless, further investigations[16] revealed that the reaction depended strongly on the electrophilicity of the azide, the nucleophilicity of substrate 13, and the bulkiness of the R1 substituent. As a result, the more reliable path B,[16] which included formation of the triazene intermediate 16 followed by an intramolecular addition of the secondary amine moiety to the N=N double bond and the elimination of sulfonamide, was suggested and supported by calculations.[16a] The latter pathway had received common recognition, and the method was successfully employed in the syn-
Scheme 2. Retrosynthetic approaches to 1,2,3-triazole core.
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2891–2897
Route to 1-Alkyl-5-trifluoromethyl-1,2,3-triazole-4-carboxylic Acids
Scheme 3. Synthesis of 1,2,3-triazoles through diazo transfer reaction.
thesis of various 1,2,3-triazoles and their fused derivatives.[17] Due to a resemblance of the initial steps of the process to diazo transfer reactions, this approach to the 1,2,3-triazole core is usually referred to by the same name,[16,17] although some authors have continued to support the unusual and unproven claims of path A, even in recent publications.[18] The main advantage of this diazo transfer approach to 1,2,3-triazoles is the unequivocal substitution of the products, which is entirely predefined by the structure of the starting enaminone. This feature prompted us to employ the method for the preparation of 1-alkyl-5-trifluoromethyl-1,2,3-triazoles (see Scheme 4). Thus, the enamino esters 20 were obtained by condensation of appropriate primary amines with ethyl 4,4,4-trifluoroacetoacetate (19) according to previously described procedures.[19] Typically, diazo transfer reactions with sulfonyl azides were carried out in anhydrous acetonitrile in the presence of sodium hydride.[16c,17a,17c,17d] The application of these conditions to the reaction of compounds 20 with mesyl azide afforded simultaneously inspiring and discouraging results. Namely, the desired products 21 were observed and even isolated from the reaction mixture, but the reaction was very slow, and conversion was poor. Perhaps, the strong electron-withdrawing properties of the CF3 group decreased the nucleo-
Scheme 4. Reagents and conditions: (i) RNH2, CHCl3, AcOH, reflux; (ii) DBU (3 equiv.), MeSO2–N3 (3 equiv.), –20 °C 씮 room temp.; (iii) LiOH, THF/water, room temp., and then aqueous HCl. For R group assignment, see Table 1. Eur. J. Org. Chem. 2013, 2891–2897
philicity of the enamine carbon atom and, thus, hampered the reaction. This reasoning is in agreement with the general trends of the diazo transfer reaction.[16,17] DBU facilitated the reaction of 3-oxo esters with aryl azides,[12a] and it was suggested to do the same in the present case. However, DBU appeared to invoke vigorous decomposition of the mesyl azide at temperatures over 0 °C, which was accompanied by a huge amount of gas evolution. After several experiments, –20 °C was determined as the optimal temperature for the reaction, since at this point formation of the triazoles 21 did occur, but decomposition of the mesyl azide was negligible, albeit visible. Therefore, a series of ethyl 1-alkyl-5-trifluoromethyl-1,2,3-triazole-4-carboxylates 21 was obtained in 75–85 % yield (see Table 1). Usual hydrolysis of the ester group with LiOH·H2O furnished acids
Table 1. Preparation of compounds 21 and 22.
[a] Starting material. [b] No reaction observed. [c] Obtained from compound 21i.
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2893
A. V. Tverdokhlebov et al.
FULL PAPER 22. Moreover, the procedures were readily scalable, which allowed for the preparation of up to 20 g of compounds 22 in one run. Certain important aspects should be emphasized. First, this method provided the most desired triazoles 22a–22e, which contained small alkyl substituents at the 1-position, in good yields. These compounds were basically unavailable through other known approaches,[8,9,11–13] and, indeed, their present synthesis has no alternative to date. However, a tertiary alkyl group could not be introduced in this way because we were unable to obtain the appropriate triazole starting from the tert-butyl derivative 20h. This was an expected limitation of the method because in the course of previous studies, N-tert-butyl enaminones 13 were found to be inert towards sulfonyl azides.[17b,17c] Enamino ester 20i, with additional functionality, was also employed in the reaction to afford triazole 21i. The latter was converted into acid 22i and amine 21j, thus offering different opportunities for further modification. Since primary amines containing additional functionalities, and therefore the enamino esters of type 20 produced from them, are generally more accessible than the corresponding azides, the present method opens greater possibilities for further derivatization of triazoles 21 and 22. Furthermore, the diazo transfer reaction was applied to the synthesis of benzyl- and phenyl-substituted triazoles 21f and 21g. These derivatives have already been prepared through previously known approaches,[11–13] and, therefore in this case, scalability was the only advantage of the present method. However, the synthesis of benzyl derivative 21f required a modification of the typical procedure. Upon treatment with organic bases, enamino ester 20f was reported to undergo isomerization to imine 23 (see Figure 2).[20] As the standard procedure required the slow addition of mesyl azide to a mixture of compound 20 and DBU, it induced the isomerization of derivative 20f prior to the diazo transfer reaction. To overcome the issue, the reagents were introduced in the reverse order, that is, the DBU was added dropwise to a mixture of enamino ester 20f and mesyl azide, which resulted in the smooth formation of the target triazole 21f.
Figure 3. X-ray crystal structure of compound 22b·H2O with the atom numbering used in the crystallographic analysis. The trifluoromethyl group is disordered over the two A and B positions with a population 25:75 %, respectively, as a result of the rotation around the C-2–C-3 bond.
(24)[22] and ethyl 4,4,4-trifluoroacetoacetate. Further treatment with mesyl azide afforded triazole 26. Again, the reverse addition procedure was employed because of the benzylic nature of the N-substituent in compound 25. Hydrolysis of ester 26 furnished the corresponding acid 27, which was smoothly converted into the target derivative 28 by means of a 1,1⬘-carbonyldiimidazole-mediated amide formation. The 73 % overall yield of compound 28 through the four-step sequence was achieved. The screening of derivative 28 and its comparison with Rufinamide are believed to be of interest.
Figure 2. The product of base-induced isomerization of compound 20f.
The structure of the prepared compounds 21 and 22 was initially confirmed by the comparison of derivatives 21f and 21g with the authentic samples obtained through known methods.[21] Then, to exclude any doubt, an X-ray crystallographic study was carried out for derivative 22b (see Figure 3) to prove the structure unambiguously. To display an advantage of the diazo transfer approach, it was applied to the synthesis of trifluoromethyl-substituted Rufinamide analogue 28 (see Scheme 5). Thus, enamino ester 25 was obtained from 2,6-difluorobenzylamine 2894
www.eurjoc.org
Scheme 5. Reagents and conditions: (i) ethyl 4,4,4-trifluoroacetoacetate, AcOH, CHCl3; (ii) MeSO2–N3, DBU; (iii) LiOH·H2O, THF, room temp., and then aqueous HCl; (iv) 1,1⬘-carbonyldiimidazole (CDI), acetonitrile, and then NH4OH.
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2891–2897
Route to 1-Alkyl-5-trifluoromethyl-1,2,3-triazole-4-carboxylic Acids
Conclusions The present research has resulted in a new approach to 1alkyl-5-trifluoromethyl-1,2,3-triazole-4-carboxylic acids 22, which are essential building blocks for medicinal and agricultural chemistry that were hitherto unavailable. The diazo transfer reaction has been implemented for the preparation of fluorine-containing 1,2,3-triazoles and was shown to be simple, easy to handle, safe, and scalable, thus providing substantial benefits over previously known methods.[8,9,11–13] The unequivocal substitution pattern of the products 21 is the main reaction feature determined a common successful outcome.
Experimental Section General Methods: Enamino esters 20a,[19c] 20c,[19e] 20f,[19a,19b] and 20g,[19d] as well as difluorobenzylamine 24[22] and mesyl azide[23] were prepared according to the described procedures. Other reagents were commercially available. All melting points were measured in open capillary tubes with a Thiele apparatus. The 1H, 13C, and 19F NMR spectroscopic data were recorded using [D6]DMSO and CDCl3 solutions with a Bruker Avance 500 (500 MHz for 1H NMR, 125 MHz for 13C NMR, and 470 MHz for 19F NMR) spectrometer. Chemical shifts (δ) are given in ppm downfield from an internal standard of Me4Si (for 1H and 13C NMR) and CFCl3 (for 19 F NMR). Coupling contants (J) are reported in Hz. Elemental analyses were performed at the Microanalytical Department of the Institute of Organic Chemistry, NAS, Kiev, Ukraine. The purity of all prepared compounds was determined by LC–MS with an Agilent 1100 instrument. General Procedure for Preparation of Ethyl 3-Amino-4,4,4-trifluoro2-butenoates 20b, 20d, 20e, 20h, and 20i: The appropriate primary amine (0.18 mol) was added dropwise to a stirred solution of ethyl 4,4,4-trifluoroacetoacetate (33.1 g, 0.18 mol) and acetic acid (10.8 g, 0.18 mol) in CHCl3 (400 mL), while the temperature was kept below 10 °C by external cooling. After the addition was complete, the mixture was heated at reflux for 1 d. Upon cooling, the reaction mixture was cautiously added to a saturated aqueous NaHCO3 solution (600 mL). The organic layer was separated, washed sequentially with 5 % aqueous NaHCO3 (2 ⫻ 200 mL) and water (2 ⫻ 200 mL), and then dried with Na2SO4. The solvent was evaporated, and the residue was distilled under reduced pressure to give compounds 20b, 20d, 20e, 20h, and 20i as yellow liquids. General Procedure for Preparation of 1-Substituted Ethyl 5-Trifluoromethyl-1,2,3-triazole-4-carboxylates 21a–21e, 21g, and 21i: DBU (73 mL, 0.486 mol) was added in one portion to a solution of compound 20 (0.168 mol) in acetonitrile (500 mL) that was stirring and cooled to –20 °C. Mesyl azide (58.9 g, 0.486 mol) was then added dropwise to the mixture at the same temperature. After the addition was complete, the mixture was warmed slowly (over 1– 2 h) to room temperature, and the stirring was continued for 1 d. The solvent was removed in vacuo, and the residue was dissolved in EtOAc (400 mL). The resulting solution was washed sequentially with a saturated aqueous NaHSO4 solution (5 ⫻ 300 mL) and water (2 ⫻ 300 mL) and then dried with Na2SO4. The organic extract was evaporated, and the residue was purified by column chromatography (silica gel, hexane/tBuOMe, 9:1) to yield 21a–21e, 21g, and 21i as colorless liquids. Ethyl 1-Benzyl-5-trifluoromethyl-1,2,3-triazole-4-carboxylate (21f): Mesyl azide (58.9 g, 0.486 mol) was added in one portion to a soluEur. J. Org. Chem. 2013, 2891–2897
tion of compound 20f (45.9 g, 0.168 mol) in acetonitrile (500 mL) that was stirring and cooled to –20 °C. DBU (73 mL, 0.486 mol) was then added dropwise to the mixture at the same temperature. The remaining steps were carried out as in the previous procedure to afford compound 21f as a colorless liquid. General Procedure for the Preparation of 1-Substituted 5-Trifluoromethyl-1,2,3-triazole-4-carboxylic Acids 22a–22g and 22i: LiOH·H2O (7.7 g, 0.183 mol) was added in one portion to a solution of the ester 21 (0.122 mol) in THF/water (1:1, 200 mL). The reaction mixture was stirred until the solid had dissolved and was then left overnight at room temperature. The solvents were removed in vacuo, and the residue was dissolved in water (150 mL). The resulting solution was washed with diethyl ether (1 ⫻ 100 mL). The aqueous layer was concentrated to half of its volume and then acidified with 30 % hydrochloric acid (25 mL). A precipitate formed and was filtered and dried to give 22a–22g and 22i as white powders. Ethyl 1-(Piperidin-4-yl)-5-trifluoromethyl-1,2,3-triazole-4-carboxylate Hydrochloride (21j·HCl): Trifluoroacetic acid (TFA, 35 mL, 0.46 mol) was added in one portion to a solution of compound 21i (18.0 g, 0.046 mol) in CH2Cl2 (350 mL), and the mixture was stirred at room temperature until the evolution of gas had ceased (12 h). The solvent was removed in vacuo. The residue was dissolved in diethyl ether (150 mL), and to this solution was added anhydrous dioxane (25 mL) saturated with gaseous HCl. The resulting solid precipitate was filtered and dried to yield the hydrochloride salt of compound 21j (12.8 g, 85 %) as a white powder. Ethyl 3-[(2,6-Difluorobenzyl)amino]-4,4,4-trifluorobut-2-enoate (25): 2,6-Difluorobenzylamine (3.0 g, 20.9 mmol) was added dropwise to a stirred solution of ethyl 4,4,4-trifluoroacetoacetate (2.8 mL, 19.1 mmol) and acetic acid (1.2 mL, 20.9 mmol) in CHCl3 (15 mL), while the temperature was kept below 10 °C by external cooling. After the addition was complete, the mixture was heated at reflux for 1 d. Upon cooling, the reaction mixture was cautiously added to a saturated aqueous NaHCO3 solution (20 mL). The organic layer was separated, washed sequentially with a 5 % aqueous NaHCO3 solution (20 mL) and brine (20 mL), and dried with Na2SO4. The solvent was evaporated, and the residue was distilled under reduced pressure to give compound 25 (4.5 g, 69 %) as yellow liquid. Ethyl 1-(2,6-Difluorobenzyl)-5-trifluoromethyl-1,2,3-triazole-4-carboxylate (26): Mesyl azide (4.8 g, 0.040 mol) was added in one portion to a solution of enamino ester 25 (4.1 g, 0.013 mol) in acetonitrile (150 mL) that was stirring and cooled to –20 °C. DBU (6.0 mL, 0.040 mol) was then added dropwise to the mixture at the same temperature. After the addition was complete, the mixture was warmed slowly (over 1–2 h) to room temperature, and the stirring was continued for 1 d. The solvent was removed in vacuo, and the residue was dissolved in EtOAc (50 mL). The resulting solution was washed sequentially with a saturated aqueous NaHSO4 solution (3 ⫻ 15 mL) and water (2 ⫻ 15 mL), and then dried with Na2SO4. The organic extract was evaporated, and the residue was purified by column chromatography (silica gel, hexane/tBuOMe, 9:1) to yield 26 (3.8 g, 86 %) as a colorless liquid. 1-(2,6-Difluorobenzyl)-5-trifluoromethyl-1,2,3-triazole-4-carboxylic Acid (27): LiOH·H2O (0.28 g, 6.7 mmol) was added in one portion to a solution of ester 26 (1.51 g, 4.5 mmol) in THF/water (1:1, 20 mL). The reaction mixture was stirred until the solid had dissolved and was then left overnight at room temperature. The solvents were removed in vacuo, and the residue was dissolved in water (15 mL). The resulting solution was washed with diethyl ether (7 mL). The aqueous layer was concentrated to half of its
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2895
A. V. Tverdokhlebov et al.
FULL PAPER volume and then acidified with 30 % hydrochloric acid (15 mL). The resulting precipitate was filtered and dried to give compound 27 (1.30 g, 94 %) as a white powder. 1-(2,6-Difluorobenzyl)-5-trifluoromethyl-1,2,3-triazole-4-carboxamide (F3C-Rufinamide, 28): CDI (0.58 g, 3.6 mmol) was added to a solution of acid 27 (1.01 g, 3.3 mmol) in acetonitrile (10 mL) that was stirring and cooled to 0 °C. The reaction mixture was stirred until the evolution of gas had ceased (≈1 h). A 25 % aqueous ammonia solution (0.61 g, 36.0 mmol) was then added at once, and the mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the residue was triturated with water. The solid was filtered and recrystallized from ethanol to yield 28 (0.95 g, 95 %) as a white powder. X-ray Crystal Structure Analysis of Compound 22b: Intensities of 11055 reflections (2843 independent, Rint = 0.023) were measured with an Xcalibur-3 diffractometer operated in the ω-2θ scan mode, 2θmax = 60°, and using graphite-monochromated Mo-Kα radiation (λ = 0.71073 Å). Crystal data: C6H6O2N3F3·H2O, Mr = 227.15, monoclinic, a = 9.808(1) Å, b = 6.3413(6) Å, c = 15.924(2) Å, β = 99.56(1)°, V = 976.6(2) Å3, T = 293 K, space group P21/c, Z = 4, μ (Mo-Kα) = 0.158 mm–1. The structure was solved by direct method with the SHELXTL program package.[24] The positions of the hydrogen atoms were located from electron difference density maps and refined by the riding model with Uiso = nUeq of the carrier atom (n = 1.5 for the methyl group and n = 1.2 for the remainder of the hydrogens). Hydrogen atoms participating in hydrogen bonds (COOH and H2O) were refined isotropically. During the refinement, the restraints were placed on the C–F and Csp3–Csp3 bonds lengths (1.34 and 1.54 Å, respectively). Full-matrix leastsquares refinement against F2 with anisotropic approximation for the non-hydrogen atoms using 2686 reflections was converged to wR2 = 0.174, R1 = 0.055 [for 1812 reflections with F ⬎ 4σ(F)], S = 1.025. CCDC-913681 (for 22b) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Supporting Information (see footnote on the first page of this article): Characterizations of all new compounds prepared, including m.p. or b.p. values, elemental analyses data, and copies of 1H, 13C, and 19F NMR spectra.
Acknowledgments The authors are grateful to Vladimir A. Lipetskiy for the chromatographic purifications and Ivan I. Vyzir for the preparation of 2,6difluorobenzylamine. [1] For the most recent reviews about 1,2,3-triazole chemistry and applications, see: a) D. S. Pedersen, A. Abell, Eur. J. Org. Chem. 2011, 2399–2411; b) Y. L. Angell, K. Burgess, Chem. Soc. Rev. 2007, 36, 1674–1689; c) V. P. Krivopalov, O. P. Shkurko, Russ. Chem. Rev. (Engl. Transl.) 2005, 74, 339–379. [2] R. Portmann, US Patent 6,156,907, 2000. [3] W. H. Mudd, E. P. Stevens, Tetrahedron Lett. 2010, 51, 3229– 3231. [4] H. A. Wier, A. Cerna, T.-Y. So, Pediatric Drugs 2011, 13, 97– 106. [5] a) W. M. Stadler, G. Rosner, E. Small, D. Hollis, B. Rini, S. D. Zaentz, J. Mahoney, M. J. Ratain, J. Clin. Oncol. 2005, 23, 3726–3732; b) J. P. Dutcher, L. Leon, J. Manola, D. M. Friedland, B. Roth, G. Wilding, Cancer 2005, 104, 2392–2399. 2896
www.eurjoc.org
[6] E. A. Johnson, R. S. Marks, S. J. Mandrekar, S. L. Hillman, M. D. Hauge, M. D. Bauman, E. J. Wos, D. F. Moore, J. W. Kugler, H. E. Windschitl, D. L. Graham, A. M. Bernath, T. R. Fitch, G. S. Soori, J. R. Jett, A. A. Adjei, E. A. Perez, Lung Cancer 2008, 60, 200–207. [7] a) D. O’Hagan, J. Fluorine Chem. 2010, 131, 1071–1081; b) K. Müller, C. Faeh, F. Diederich, Science 2007, 317, 1881–1886; c) S. Purser, P. R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 2008, 37, 320–330; d) W. K. Hagmann, J. Med. Chem. 2008, 51, 4359–4369; e) R. Filler, Y. Kobayashi, L. M. Yagupolskii, in: Organofluorine Compounds in Medicinal Chemistry and Biochemical Applications, Elsevier, Amsterdam, 1993; f) T. Hiyama, in: Organofluorine Compounds, Springer-Verlag, Berlin, 2000; g) B. E. Smart, J. Fluorine Chem. 2001, 109, 3–11. [8] A. K. Amegadzie, K. M. Gardinier, E. J. Hembre, P. A. Hipskind, L. N. Jungheim, B. S. Muehl, K. A. Savin, K. J. Trasher, WO 2005/000821, 2005. [9] a) J. Black, J. A. Boehmer, E. J. T. Chrystal, A. M. Kozakiewicz, A. Plant, WO 2007/071900, 2007; b) J. E. Boehmer, M. M. W. McLachlan, WO 2007/096576, 2007. [10] R. Fischer, C. Grondal, E. R. Gesing, H.-J. Wroblowsky, A. Hense, E.-M. Franken, A. Voerste, U. Goergens, US Patent 275676, 2011. [11] a) S. J. Coats, J. S. Link, D. Gauthier, D. J. Hlasta, Org. Lett. 2005, 7, 1469–1472; b) J. Wei, J. Chen, J. Xu, L. Cao, H. Deng, W. Sheng, H. Zhang, W. Cao, J. Fluorine Chem. 2012, 133, 146–154; c) B. Gold, N. E. Shevchenko, N. Bonus, G. B. Dudley, I. V. Alabugin, J. Org. Chem. 2012, 77, 75–89; d) Z. Shan, M. Peng, H. Fan, Q. Lu, C. Zhao, Y. Chen, Bioorg. Med. Chem. Lett. 2011, 21, 1731–1735. [12] a) F. Stazi, D. Cancogni, L. Turco, P. Westerduin, S. Bacchi, Tetrahedron Lett. 2010, 51, 5385–5387; b) Yu. A. Rozin, J. Leban, W. Dehaen, V. G. Nenajdenko, V. M. Muzalevskiy, O. S. Eltsov, V. A. Bakulev, Tetrahedron 2012, 68, 614–618. [13] a) W. Peng, S. Zhu, Synlett 2003, 187–190; b) W. Peng, S. Zhu, Tetrahedron 2003, 59, 4395–4404; c) L. J. T. Danence, Y. Gao, M. Li, Y. Huang, J. Wang, Eur. J. Org. Chem. 2011, 17, 3584– 3587. [14] This compound was prepared by means of a cycloaddition between p-methoxybenzyl azide and ethyl 4,4,4-trifluoro-2-butynoate followed by cleavage of the p-methoxybenzyl (PMB) group from the resulting triazoles.[9] [15] a) R. T. Chakrasali, H. Ila, H. Junjappa, Synthesis 1988, 851– 854; b) M. F. Gordeev, A. V. Komkov, V. S. Bogdanov, A. V. Dorokhov, Izv. Akad. Nauk SSSR, Ser. Khim. 1990, 1392–1397; c) Z. T. Huang, M.-X. Wang, J. Org. Chem. 1992, 57, 184–90. [16] a) R. Augusti, C. Kascheres, J. Org. Chem. 1993, 58, 7079– 7083; b) R. Augusti, C. Kascheres, Tetrahedron 1994, 50, 6723– 6726; c) G. A. Romeiro, L. O. R. Pereira, M. C. B. V. de Souza, V. F. Ferreira, A. C. Cunha, Tetrahedron Lett. 1997, 38, 5103– 5106. [17] a) A. C. Cunha, L. O. R. Pereira, R. O. P. de Souza, M. C. B. V. de Souza, V. F. Ferreira, Nucleosides Nucleotides 2001, 20, 1555–1569; b) J. O. F. Melo, C. L. Donnici, R. Augusti, M. T. P. Lopes, A. G. Mikhailovskii, Heterocycl. Commun. 2003, 9, 235–238; c) J. O. F. Melo, P. M. Ratton, R. Augusti, C. L. Donnici, Synth. Commun. 2004, 34, 369–376; d) F. C. da Silva, M. C. B. V. de Souza, I. I. P. Frugulhetti, H. C. Castro, S. L. O. Souza, T. M. L. de Souza, D. Q. Rodrigues, A. M. T. Souza, P. A. Abreu, F. Passamani, C. R. Rodrigues, V. F. Ferreira, Eur. J. Med. Chem. 2009, 44, 373–383; e) S.-J. Yan, Y.-J. Liu, L. Liu, J. Lin, Bioorg. Med. Chem. Lett. 2010, 20, 5225–5228. [18] a) J. Gu, W. Xiong, Z. Zhang, S. Zhu, Synthesis 2011, 1717– 1722; b) A. V. Dorokhov, A. V. Komkov, Russ. Chem. Bull. 2004, 53, 676–680. [19] a) V. Michaut, F. Metz, J.-M. Paris, J.-C. Plaquevent, J. Fluorine Chem. 2007, 128, 889–895; b) H. Ohkura, D. O. Berbasov, V. A. Soloshonok, Tetrahedron 2003, 59, 1647–1656; c) R. G. Hanreich, H.-T. Wu, M. A. Oliver, D. K. Hoglen, US Patent 2003/216594, 2003; d) W. Wan, J. Hou, H. Jiang, Z. Yuan, A.
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 2891–2897
Route to 1-Alkyl-5-trifluoromethyl-1,2,3-triazole-4-carboxylic Acids Goubin, J. Hao, G. Zhao, Eur. J. Org. Chem. 2010, 1778–1786; e) A. W. Lutz, S. H. Trotto, J. Heterocycl. Chem. 1972, 9, 513– 522. [20] a) V. A. Soloshonok, A. G. Kirilenko, S. V. Galushko, V. P. Kukhar, Tetrahedron Lett. 1994, 35, 5063–5064; b) V. Michaut, F. Metz, J.-M. Paris, J.-C. Plaquevent, J. Fluorine Chem. 2007, 128, 500–506; c) V. A. Soloshonok, V. P. Kukhar, Tetrahedron 1996, 52, 6953–6964; d) V. A. Soloshonok, A. G. Kirilenko, V. P. Kukhar, G. Resnati, Tetrahedron Lett. 1993, 34, 3621– 3624.
Eur. J. Org. Chem. 2013, 2891–2897
[21] The comparison of 1H, 13C, and 19F NMR spectroscopic data of compounds 21f and 21g with the reported data[13] revealed their sameness. [22] A. M. Roe, R. A. Burton, G. L. Willey, M. W. Baines, A. C. Rasmussen, J. Med. Chem. 1968, 11, 814–819. [23] J. H. Boyer, C. H. Mack, N. Goebel, L. R. Morgan, J. Org. Chem. 1958, 23, 1051–1053. [24] G. M. Sheldrick, Acta Crystallogr., Sect. A 2008, 64, 112–122. Received: January 9, 2013 Published Online: April 3, 2013
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2897
