DOI: 10.1002/chem.201304759
Communication
& Heterocycles
Selective Synthesis of Functionalized Trifluoromethylated Pyrrolidines, Piperidines, and Azepanes Starting from 1-Tosyl-2(trifluoromethyl)aziridine Jeroen Dolfen,[a] Sara Kenis,[a] Kristof Van Hecke,[b] Norbert De Kimpe,*[a] and Matthias D’hooghe*[a] generation and alkylation of the 1-tosyl-2-(trifluoromethyl)aziridin-2-yl anion with electrophiles bearing an additional leaving group, followed by ring expansion as a new synthetic strategy toward functionalized 2-CF3-pyrrolidines, 2-CF3-piperidines, and 3-CF3-azepanes. The synthesis of 1-tosyl-2-(trifluoromethyl)aziridine (3), the key intermediate in this study, was based on a two-step procedure adapted from literature approaches,[2i] starting from racemic 3-amino-1,1,1-trifluoropropan-2-ol (purchased from Apollo Scientific). In a first step, aminopropanol 1 was selectively Ntosylated with TsCl in pyridine. Secondly, the ring closure of sulfonamide 2 in dry THF afforded aziridine 3 under Mitsunobu conditions in 85 % yield (Scheme 1). This adapted approach
Abstract: This paper reports on the generation and alkylation of the 1-tosyl-2-(trifluoromethyl)aziridin-2-yl anion with w,w’-dihaloalkanes, followed by a novel ring-expansion protocol toward 2-CF3-pyrrolidines, 2-CF3-piperidines, and 3-CF3-azepanes. A variety of halogen, oxygen, nitrogen, sulfur, and carbon nucleophiles was used to trigger this ring rearrangement, resulting in CF3-azaheterocycles bearing different types of functionalized side chains.
Aziridines have been widely employed in organic chemistry as versatile substrates for ring expansions toward pyrrolidines and piperidines.[1] An interesting subclass of these constrained three-membered azaheterocycles concerns the class of 2-(trifluoromethyl)aziridines.[2] Because of the unique chemical and physical properties of fluorine, such as its high electronegativity and small van der Waals radius, the presence of a trifluoromethyl group in biologically active compounds has a significant influence on their lipophilicity, metabolic stability, and pKa.[3] As a consequence, CF3-substituted azaheterocycles are increasingly used in pharmaceutical and agricultural applications.[4] In recent years, the generation and application of aziridinyl anions has emerged as a powerful tool in organic synthesis.[5] In that respect, the reactivity of 2-(trifluoromethyl)aziridin-2-yl anions has been investigated toward a selection of carbonyl compounds such as aldehydes, ketones, and acid chlorides, showing nBuLi to be a suitable base to effect deprotonation.[2i–k] Reaction of these aziridinyl anions with haloalkanes, however, has not been investigated, apart from a single example using benzyl bromide.[2j, k] In this paper, we report on the
Scheme 1. Synthesis of 1-tosyl-2-(trifluoromethyl)aziridine 3. DEAD = diethylazodicarboxylate, Ts = para-toluenesulfonyl.
toward aziridine 3 constitutes an improved method as compared to literature protocols starting from 2-(trifluoromethyl)oxirane.[2i] Subsequently, the C-alkylation of aziridine 3 with an electrophile bearing an additional leaving group was investigated as a potential entry to the synthesis of new trifluoromethylated azaheterocycles. The synthesis and reactivity study of aziridinyl anions has been the topic of several literature reports.[5] In that respect, the reactivity of the 2-(trifluoromethyl)aziridin-2-yl anion has been reported toward BnBr as a sole example of Calkylation.[2j, k] However, this reaction yielded the corresponding substitution product only in 13 % yield. Therefore, the reactivity profile of the 2-(trifluoromethyl)aziridin-2-yl anion was first explored toward MeI to assess and establish its C-alkylation aptitude. Hereby, aziridine 3 was treated with 1.1 equiv of nBuLi and 0.1 equiv of HMPA at 100 8C followed by reaction with 1.5 equiv of MeI at 40 8C, yielding 2-methyl-1-tosyl-2-(trifluoromethyl)aziridine (4) in 50 % yield (Scheme 2). The same reaction conditions were applied for the alkylation of aziridine 3 with 1-chloro-3-iodopropane and 1-chloro-4iodobutane, although unfortunately these conditions did not afford the corresponding 2-(w-chloroalkyl)-1-tosyl-2-(trifluoro-
[a] J. Dolfen, Dr. S. Kenis, Prof. Dr. N. De Kimpe, Prof. Dr. M. D’hooghe SynBioC Research Group Department of Sustainable Organic Chemistry and Technology Faculty of Bioscience Engineering Ghent University, Coupure Links 653, 9000 Ghent (Belgium) Fax: (+ 32) 9-264-62-21 E-mail: [email protected] [email protected] [b] Prof. Dr. K. Van Hecke Department of Inorganic and Physical Chemistry Ghent University, Krijgslaan 281-S3 9000 Ghent (Belgium) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201304759. Chem. Eur. J. 2014, 20, 1 – 5
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Communication Table 1. Synthesis of 2-(trifluoromethyl)pyrrolidines 6 and -piperidines 7.
Scheme 2. Deprotonation of aziridine 3 and subsequent reaction with alkylating agents.
Entry
Nucleophile (Nu or NuH)
n
Reaction conditions[a]
Product
Yield [%]
1 2 3 4 5 6 7 8 9 10 11 12 13
LiCl iPrNH2 NaCN KSCN NaOMe NaOEt LiCl iPrNH2 iBuNH2 NaCN KSCN NaOMe NaOEt
1 1 1 1 1 1 2 2 2 2 2 2 2
A B B B C C D E F G H I I
6a 6b 6c 6d 6e 6f 7a 7b 7c 7d 7e 7f 7g
74 63[b] 77[b] 98 95 58[b] 60[b] 62[b] 14[b] 70[b] 20[b] 63[b] 77[b]
[a] Reaction conditions: A) nucleophile (5 equiv), CH3CN, D, 4 h; B) nucleophile (5 equiv), CH3CN, D, 2 h; C) nucleophile (10 equiv), NuH, D, 2 h; D) nucleophile (5 equiv), NaI (5 equiv), DMF, D, 48 h; E) nucleophile (1 equiv), NaI (1 equiv), DMF, D, 5 h; F) nucleophile (5 equiv), NaI (1 equiv), CH3CN, D, 7d; G) nucleophile (1 equiv), DMF, D, 5 h; H) nucleophile (5 equiv), CH3CN, D, 18 h; I) nucleophile (10 equiv), NuH, D, 6 h. [b] After purification by preparative thin-layer chromatography (TLC).
methyl)aziridines 5. After careful monitoring of the reaction conditions, the desired aziridines 5 were eventually obtained. An equimolar amount of hexamethylphosphoramide (HMPA), as well as a low reaction temperature of 100 8C, appeared to be necessary to produce the aziridines 5 in acceptable yields (Scheme 2). On the one hand, a higher temperature resulted in an unstable 1-tosyl-2-(trifluoromethyl)aziridin-2-yl anion, which gave rise to a complex reaction mixture. On the other hand, the use of a sub-equimolar amount of HMPA could not effect efficient reaction of the aziridinyl anion with the dihalogenated electrophiles. Other possible by-products owing to initial deprotonation at the C3-position or formation of dimers were never obtained. The in situ generation of the proposed 2-(trifluoromethyl)aziridin-2-yl anion was further supported by means of a deuteration protocol using D2O in THF, affording the anticipated 2deuterioaziridine in 67 % yield. As mentioned before, aziridines 5 can be considered as eligible substrates to perform ring-expansion reactions owing to the presence of a good terminal leaving group in their side chain. Therefore, in the next part of our investigation, different nucleophiles were used to trigger ring rearrangements of aziridines 5 a and 5 b toward pyrrolidines 6 and piperidines 7, respectively. As summarized in Scheme 3 and Table 1, chloride-,
often required, whether or not in the presence of NaI (Table 1, entries 7–13). Several CF3-azaheterocycles have been incorporated in compounds with pronounced biological properties, rendering pyrrolidines 6 and piperidines 7 useful new chemical entities in medicinal-chemistry programs for further elaborations.[6] From a mechanistic point of view, the formation of pyrrolidines 6 and piperidines 7 can be rationalized considering initial ring opening of aziridines 5 by the incoming nucleophiles at the less hindered position to form the corresponding anions 8 A, followed by either direct ring closure or protonation to amines 8 B (in protic solvents) followed by ring closure, thus affording pyrrolidines 6 or piperidines 7 (Scheme 4). Further evi-
Scheme 4. Reaction mechanism for the formation of 2-(trifluoromethyl)pyrrolidines 6 and -piperidines 7. Scheme 3. Ring expansion of aziridines 5 toward pyrrolidines 6 and piperidines 7.
dence for this mechanism was provided by the detection of amines 8 B in the crude NMR spectra (10–20 %, CDCl3). In addition to full characterization by means of NMR analysis, the structure of pyrrolidine 6 e and piperidine 7 f was also confirmed by means of X-ray analysis (see the Supporting Information). Further evidence to support this aziridine-ring-opening hypothesis was provided by treatment of 2-methyl-2-CF3-aziridine
amine-, cyanide-, thiocyanate-, methoxide-, and ethoxide-induced ring rearrangements were effectively realized to provide an efficient entry into a variety of functionalized 2-CF3-pyrrolidines and -piperidines. The ring rearrangements toward piperidines 7 were found to be harder to perform. In that respect, a higher boiling solvent (N,N-dimethylformamide, DMF) was &
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Communication (4) with NaCN in DMF, furnishing the corresponding 3-amino4,4,4-trifluoro-3-methylbutanenitrile through selective ring opening at C3. It should be noted that this strategy for ring rearrangements of 2-(w-chloroalkyl)aziridines complements previously reported methods relying on initial halide displacement by the aziridine nitrogen toward strained bicyclic intermediates followed by ring opening.[7] Treatment of aziridine 5 b with 5 equiv of iPrNH2 or iBuNH2 and 1 equiv of NaI in CH3CN did not exclusively afford the anticipated 2-isoalkylaminomethyl-1-tosyl-2-(trifluoromethyl)piperidines 7 b and 7 c. Surprisingly, the major isomers (60– 75:25–40, major/minor) were identified as 1-isoalkyl-3-tosylamino-3-(trifluoromethyl)azepanes 9. Addition of an equimolar amount of NaI appeared to be necessary to induce ring closure in these cases. Application of the same reaction conditions for the ring expansion of aziridine 5 a toward the corresponding pyrrolidine 6 b (entry 2, Table 1), however, did not afford any trace of 1-isopropyl-3-tosylamino-3-(trifluoromethyl)piperidine. From a mechanistic point of view, initial regiospecific ring opening of aziridine 5 b at the C3 position by the alkylamine and additional substitution of chloride by iodide results in intermediates 10. Finally, prototropy and subsequent ring closure induced by the isoalkylamino moiety of intermediates 11 affords 1-isoalkyl-3-tosylamino-3-(trifluoromethyl)azepanes 9 (route a, Scheme 5). Another possible mechanism for the trans-
Figure 1. Molecular structure of 1-isopropyl-3-tosylamino-3-(trifluoromethyl)azepane 9 a, showing thermal displacement ellipsoids at the 50 % probability level.
ing in mind the fact that azepanes have been incorporated in for example the anticonvulsant drugs carbamazepine and oxacarbazepine, and the antiparkinsonian drug Talipexole, these trifluoromethylated azepanes 9 can be considered as useful new entities.[9] The incorporation of the obtained trifluoromethylated azaheterocycles 6, 7, and 9 in larger biological systems requires the removal of the N-protecting group. Therefore, in a final stage of this research, deprotection of a representative example was carried out as a proof of concept. In that respect, detosylation of pyrrolidine 6 e was attained by reaction with concentrated sulfuric acid, resulting in pyrrolidine oxalic acid complex 13 after 6 h at 50 8C in a pressure vial (Scheme 6). The
Scheme 6. Detosylation of pyrrolidine 6 e.
structure of complex 13 was confirmed by single-crystal X-ray diffraction analysis (see the Supporting Information). In summary, deprotonation of 1-tosyl-2-(trifluoromethyl)aziridine and subsequent reaction of the obtained aziridinyl anion with w,w’-dihalogenated alkanes resulted in 2-(w-chloroalkyl)1-tosyl-2-(trifluoromethyl)aziridines. Owing to the presence of a good terminal leaving group, ring expansion of these alkylated aziridines toward a variety of novel functionalized pyrrolidines, piperidines, and azepanes could be realized as a new synthetic strategy in the field of heterocyclic synthesis. Finally, detosylation of one of the obtained ring systems resulted in a CF3-substituted azaheterocycle suitable for further elaboration by the free NH moiety.
Scheme 5. Ring expansion of aziridine 5 b toward azepanes 9.
formation of aziridine 5 b into azepanes 9 comprises initial halide substitution by the alkylamine toward the corresponding 2-(4-aminobutyl)aziridines 12, followed by intramolecular ring opening induced by the amino moiety toward azepanes 9 (route b, Scheme 5). The molecular identity of azepanes 9 was unequivocally established by means of a single-crystal X-ray structure analysis of compound 9 a (Figure 1). The ring expansion of aziridine 5 b toward seven-membered heterocycles is surprising. Moreover, only a few reports on aziridine-to-azepane ring expansions are known in the literature,[8] making this ring transformation a rare and peculiar one. BearChem. Eur. J. 2014, 20, 1 – 5
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Acknowledgements The authors are indebted to Ghent cial support. K. Van Hecke thanks (project AUGE/11/029 "3D-SPACE: Aiming for Chemical Excellence") for 3
University (BOF) for finanthe Hercules Foundation 3D Structural Platform funding.
2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communication Keywords: azepanes · aziridines · aziridinyl piperidines · pyrrolidines · trifluoromethyl
anions
[4] a) F. M. D. Ismail, J. Fluorine Chem. 2002, 118, 27 – 33; b) J.-P. Bgu, D. Bonnet-Delpon, Bioorganic and Medicinal Chemisry of Fluorine, John Wiley & Sons, Hoboken, 2008; c) K. Mller, C. Faeh, F. Diederich, Science 2007, 317, 1881 – 1886; d) H.-J. Bçhm, D. Banner, S. Bendels, M. Kansy, B. Kuhn, K. Mller, U. Obst-Sander, M. Stahl, ChemBioChem 2004, 5, 637 – 643; e) K. L. Kirk, J. Fluorine Chem. 2006, 127, 1013 – 1026; f) V. De Matteis, D. F. L. Van, H. Jakobi, S. Lindell, J. Tiebes, F. P. J. T. Rutjes, J. Org. Chem. 2006, 71, 7527 – 7532; g) Fluorine and the Environment: Agrochemicals, Archaeology, Green Chemistry & Water (Ed.: A. Tressaud), Elsevier, Amsterdam, 2006; h) P. Kirsch, Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim, 2004; i) M. Quirmbach, H. Steiner, Chim. Oggi 2009, 27, 23 – 26. [5] S. Florio, R. Luisi, Chem. Rev. 2010, 110, 5128 – 5157. [6] a) I. Jlalia, N. Lensen, G. Chaume, E. Dzhambazova, L. Astasidi, R. Hadjiolova, A. Bocheva, T. Brigaud, Eur. J. Med. Chem. 2013, 62, 122 – 129; b) H. Fukui, T. Shibata, T. Naito, J. Nakano, T. Maejima, H. Senda, W. Iwatani, Y. Tatsumi, M. Suda, T. Arika, Bioorg. Med. Chem. Lett. 1998, 8, 2833 – 2838; c) Z. Xin, H. Peng, A. Zhang, T. Talreja, G. Kumaravel, L. Xu, E. Rohde, M.-Y. Jung, M. N. Shackett, D. Kocisko, S. Chollate, A. W. Dunah, P. A. Snodgrass-Belt, H. Moore Arnold, A. G. Taveras, K. J. Rhodes, R. H. Scannevin, Bioorg. Med. Chem. Lett. 2011, 21, 7277 – 7280. [7] a) W. Van Brabandt, R. Van Landeghem, N. De Kimpe, Org. Lett. 2006, 8, 1105 – 1108; b) M. D’hooghe, W. Aelterman, N. De Kimpe, Org. Biomol. Chem. 2009, 7, 135 – 141. [8] a) K. Vervisch, M. D’hooghe, K. W. Tçrnroos, N. De Kimpe, J. Org. Chem. 2010, 75, 7734 – 7740; b) S. Kim, J.-Y. Yoon, Synthesis 2000, 1622 – 1630; c) B. M. Trost, D. R. Fandrick, T. Brodmann, D. T. Stiles, Angew. Chem. 2007, 119, 6235 – 6237; Angew. Chem. Int. Ed. 2007, 46, 6123 – 6125. [9] a) W. Schindler, US 2,948,718, CAN55:8246, 1960; b) W. Schindler, DE 2,011,087, CAN73:109711, 1970.
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[1] a) X. E. Hu, Tetrahedron 2004, 60, 2701 – 2743; b) A. L. Cardoso, T. M. V. D. Pinho e Melo, Eur. J. Org. Chem. 2012, 6479 – 6501; c) G. S. Singh, M. D’hooghe, N. De Kimpe, Chem. Rev. 2007, 107, 2080 – 2135; d) L. I. Kas’yan, V. A. Pal’chikov, Y. S. Bondarenko, Russ. J. Org. Chem. 2011, 47, 1609 – 1652; e) S. Stankovic´, M. D’hooghe, S. Catak, H. Eum, M. Waroquier, V. Van Speybroeck, N. De Kimpe, H.-J. Ha, Chem. Soc. Rev. 2012, 41, 643 – 665; f) P. Lu, Tetrahedron 2010, 66, 2549 – 2560. [2] a) S. Kenis, M. D’hooghe, G. Verniest, V. D. Nguyen, T. A. Dang Thi, T. Van Nguyen, N. De Kimpe, Org. Biomol. Chem. 2011, 9, 7217 – 7223; b) R. Maeda, K. Ooyama, R. Anno, M. Shiosaki, T. Azema, T. Hanamoto, Org. Lett. 2010, 12, 2548 – 2550; c) R. Maeda, R. Ishibashi, R. Kamaishi, K. Hirotaki, H. Furuno, T. Hanamoto, Org. Lett. 2011, 13, 6240 – 6243; d) S. Kenis, M. D’hooghe, G. Verniest, M. Reybroeck, T. A. Dang Thi, C. Pham The, T. Thi Pham, K. W. Tçrnroos, N. Van Tuyen, N. De Kimpe, Chem. Eur. J. 2013, 19, 5966 – 5971; e) T. Katagiri, M. Takahashi, Y. Fujiwara, H. Ihara, K. Uneyama, J. Org. Chem. 1999, 64, 7323 – 7329; f) F. Grellepois, J. Nonnenmacher, F. Lachaud, C. Portella, Org. Biomol. Chem. 2011, 9, 1160 – 1168; g) G. Rinaudo, S. Narizuka, N. Askari, B. Crousse, D. Bonnet-Delpon, Tetrahedron Lett. 2006, 47, 2065 – 2068; h) N. M. Karimova, Y. L. Teplenicheva, A. F. Kolomiets, A. V. Fokin, Russ. Chem. Bull. 1997, 46, 1136 – 1139; i) T. Katagiri, Y. Katayama, M. Taeda, T. Ohshima, N. Iguchi, K. Uneyama, J. Org. Chem. 2011, 76, 9305 – 9311; j) Y. Yamauchi, T. Kawate, T. Katagiri, K. Uneyama, Tetrahedron 2003, 59, 9839 – 9847; k) Y. Yamauchi, T. Kawate, H. Itahashi, T. Katagiri, K. Uneyama, Tetrahedron Lett. 2003, 44, 6319 – 6322. [3] a) W. R. Dolbier, J. Fluorine Chem. 2005, 126, 157 – 163; b) A. V. Bezdudny, A. N. Alekseenko, P. K. Mykhailiuk, O. V. Manoilenko, O. V. Shishkin, Y. M. Pustovit, Eur. J. Org. Chem. 2011, 1782 – 1785; c) R. Filler, R. Saha, Future Med. Chem. 2009, 1, 777 – 791; d) B. E. Smart, J. Fluorine Chem. 2001, 109, 3 – 11; e) A. Bariau, W. Bux Jatoi, P. Calinaud, Y. Troin, J.-L. Canet, Eur. J. Org. Chem. 2006, 3421 – 3433; f) Q.-H. Li, Z.-Y. Xue, H.-Y. Tao, C.-J. Wang, Tetrahedron Lett. 2012, 53, 3650 – 3653.
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Communication
COMMUNICATION & Heterocycles
CF3-azaheterocycles: The alkylation of the 1-tosyl-2-(trifluoromethyl)aziridin-2yl anion with w,w’-dihaloalkanes, followed by a novel ring-expansion protocol leads to 2-CF3-pyrrolidines, 2-CF3-piperidines, and 3-CF3-azepanes. A variety of halogen, oxygen, nitrogen, sulfur, and carbon nucleophiles was used to trigger this ring rearrangement, resulting in CF3-azaheterocycles bearing different types of functionalized side chains (see scheme; HMPA = hexamethylphosphoramide, Ts = para-toluenesulfonyl).
Chem. Eur. J. 2014, 20, 1 – 5
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J. Dolfen, S. Kenis, K. Van Hecke, N. De Kimpe,* M. D’hooghe* && – && Selective Synthesis of Functionalized Trifluoromethylated Pyrrolidines, Piperidines, and Azepanes Starting from 1-Tosyl-2(trifluoromethyl)aziridine
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2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communication
& Heterocycles
Selective Synthesis of Functionalized Trifluoromethylated Pyrrolidines, Piperidines, and Azepanes Starting from 1-Tosyl-2(trifluoromethyl)aziridine Jeroen Dolfen,[a] Sara Kenis,[a] Kristof Van Hecke,[b] Norbert De Kimpe,*[a] and Matthias D’hooghe*[a] generation and alkylation of the 1-tosyl-2-(trifluoromethyl)aziridin-2-yl anion with electrophiles bearing an additional leaving group, followed by ring expansion as a new synthetic strategy toward functionalized 2-CF3-pyrrolidines, 2-CF3-piperidines, and 3-CF3-azepanes. The synthesis of 1-tosyl-2-(trifluoromethyl)aziridine (3), the key intermediate in this study, was based on a two-step procedure adapted from literature approaches,[2i] starting from racemic 3-amino-1,1,1-trifluoropropan-2-ol (purchased from Apollo Scientific). In a first step, aminopropanol 1 was selectively Ntosylated with TsCl in pyridine. Secondly, the ring closure of sulfonamide 2 in dry THF afforded aziridine 3 under Mitsunobu conditions in 85 % yield (Scheme 1). This adapted approach
Abstract: This paper reports on the generation and alkylation of the 1-tosyl-2-(trifluoromethyl)aziridin-2-yl anion with w,w’-dihaloalkanes, followed by a novel ring-expansion protocol toward 2-CF3-pyrrolidines, 2-CF3-piperidines, and 3-CF3-azepanes. A variety of halogen, oxygen, nitrogen, sulfur, and carbon nucleophiles was used to trigger this ring rearrangement, resulting in CF3-azaheterocycles bearing different types of functionalized side chains.
Aziridines have been widely employed in organic chemistry as versatile substrates for ring expansions toward pyrrolidines and piperidines.[1] An interesting subclass of these constrained three-membered azaheterocycles concerns the class of 2-(trifluoromethyl)aziridines.[2] Because of the unique chemical and physical properties of fluorine, such as its high electronegativity and small van der Waals radius, the presence of a trifluoromethyl group in biologically active compounds has a significant influence on their lipophilicity, metabolic stability, and pKa.[3] As a consequence, CF3-substituted azaheterocycles are increasingly used in pharmaceutical and agricultural applications.[4] In recent years, the generation and application of aziridinyl anions has emerged as a powerful tool in organic synthesis.[5] In that respect, the reactivity of 2-(trifluoromethyl)aziridin-2-yl anions has been investigated toward a selection of carbonyl compounds such as aldehydes, ketones, and acid chlorides, showing nBuLi to be a suitable base to effect deprotonation.[2i–k] Reaction of these aziridinyl anions with haloalkanes, however, has not been investigated, apart from a single example using benzyl bromide.[2j, k] In this paper, we report on the
Scheme 1. Synthesis of 1-tosyl-2-(trifluoromethyl)aziridine 3. DEAD = diethylazodicarboxylate, Ts = para-toluenesulfonyl.
toward aziridine 3 constitutes an improved method as compared to literature protocols starting from 2-(trifluoromethyl)oxirane.[2i] Subsequently, the C-alkylation of aziridine 3 with an electrophile bearing an additional leaving group was investigated as a potential entry to the synthesis of new trifluoromethylated azaheterocycles. The synthesis and reactivity study of aziridinyl anions has been the topic of several literature reports.[5] In that respect, the reactivity of the 2-(trifluoromethyl)aziridin-2-yl anion has been reported toward BnBr as a sole example of Calkylation.[2j, k] However, this reaction yielded the corresponding substitution product only in 13 % yield. Therefore, the reactivity profile of the 2-(trifluoromethyl)aziridin-2-yl anion was first explored toward MeI to assess and establish its C-alkylation aptitude. Hereby, aziridine 3 was treated with 1.1 equiv of nBuLi and 0.1 equiv of HMPA at 100 8C followed by reaction with 1.5 equiv of MeI at 40 8C, yielding 2-methyl-1-tosyl-2-(trifluoromethyl)aziridine (4) in 50 % yield (Scheme 2). The same reaction conditions were applied for the alkylation of aziridine 3 with 1-chloro-3-iodopropane and 1-chloro-4iodobutane, although unfortunately these conditions did not afford the corresponding 2-(w-chloroalkyl)-1-tosyl-2-(trifluoro-
[a] J. Dolfen, Dr. S. Kenis, Prof. Dr. N. De Kimpe, Prof. Dr. M. D’hooghe SynBioC Research Group Department of Sustainable Organic Chemistry and Technology Faculty of Bioscience Engineering Ghent University, Coupure Links 653, 9000 Ghent (Belgium) Fax: (+ 32) 9-264-62-21 E-mail: [email protected] [email protected] [b] Prof. Dr. K. Van Hecke Department of Inorganic and Physical Chemistry Ghent University, Krijgslaan 281-S3 9000 Ghent (Belgium) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201304759. Chem. Eur. J. 2014, 20, 1 – 5
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Communication Table 1. Synthesis of 2-(trifluoromethyl)pyrrolidines 6 and -piperidines 7.
Scheme 2. Deprotonation of aziridine 3 and subsequent reaction with alkylating agents.
Entry
Nucleophile (Nu or NuH)
n
Reaction conditions[a]
Product
Yield [%]
1 2 3 4 5 6 7 8 9 10 11 12 13
LiCl iPrNH2 NaCN KSCN NaOMe NaOEt LiCl iPrNH2 iBuNH2 NaCN KSCN NaOMe NaOEt
1 1 1 1 1 1 2 2 2 2 2 2 2
A B B B C C D E F G H I I
6a 6b 6c 6d 6e 6f 7a 7b 7c 7d 7e 7f 7g
74 63[b] 77[b] 98 95 58[b] 60[b] 62[b] 14[b] 70[b] 20[b] 63[b] 77[b]
[a] Reaction conditions: A) nucleophile (5 equiv), CH3CN, D, 4 h; B) nucleophile (5 equiv), CH3CN, D, 2 h; C) nucleophile (10 equiv), NuH, D, 2 h; D) nucleophile (5 equiv), NaI (5 equiv), DMF, D, 48 h; E) nucleophile (1 equiv), NaI (1 equiv), DMF, D, 5 h; F) nucleophile (5 equiv), NaI (1 equiv), CH3CN, D, 7d; G) nucleophile (1 equiv), DMF, D, 5 h; H) nucleophile (5 equiv), CH3CN, D, 18 h; I) nucleophile (10 equiv), NuH, D, 6 h. [b] After purification by preparative thin-layer chromatography (TLC).
methyl)aziridines 5. After careful monitoring of the reaction conditions, the desired aziridines 5 were eventually obtained. An equimolar amount of hexamethylphosphoramide (HMPA), as well as a low reaction temperature of 100 8C, appeared to be necessary to produce the aziridines 5 in acceptable yields (Scheme 2). On the one hand, a higher temperature resulted in an unstable 1-tosyl-2-(trifluoromethyl)aziridin-2-yl anion, which gave rise to a complex reaction mixture. On the other hand, the use of a sub-equimolar amount of HMPA could not effect efficient reaction of the aziridinyl anion with the dihalogenated electrophiles. Other possible by-products owing to initial deprotonation at the C3-position or formation of dimers were never obtained. The in situ generation of the proposed 2-(trifluoromethyl)aziridin-2-yl anion was further supported by means of a deuteration protocol using D2O in THF, affording the anticipated 2deuterioaziridine in 67 % yield. As mentioned before, aziridines 5 can be considered as eligible substrates to perform ring-expansion reactions owing to the presence of a good terminal leaving group in their side chain. Therefore, in the next part of our investigation, different nucleophiles were used to trigger ring rearrangements of aziridines 5 a and 5 b toward pyrrolidines 6 and piperidines 7, respectively. As summarized in Scheme 3 and Table 1, chloride-,
often required, whether or not in the presence of NaI (Table 1, entries 7–13). Several CF3-azaheterocycles have been incorporated in compounds with pronounced biological properties, rendering pyrrolidines 6 and piperidines 7 useful new chemical entities in medicinal-chemistry programs for further elaborations.[6] From a mechanistic point of view, the formation of pyrrolidines 6 and piperidines 7 can be rationalized considering initial ring opening of aziridines 5 by the incoming nucleophiles at the less hindered position to form the corresponding anions 8 A, followed by either direct ring closure or protonation to amines 8 B (in protic solvents) followed by ring closure, thus affording pyrrolidines 6 or piperidines 7 (Scheme 4). Further evi-
Scheme 4. Reaction mechanism for the formation of 2-(trifluoromethyl)pyrrolidines 6 and -piperidines 7. Scheme 3. Ring expansion of aziridines 5 toward pyrrolidines 6 and piperidines 7.
dence for this mechanism was provided by the detection of amines 8 B in the crude NMR spectra (10–20 %, CDCl3). In addition to full characterization by means of NMR analysis, the structure of pyrrolidine 6 e and piperidine 7 f was also confirmed by means of X-ray analysis (see the Supporting Information). Further evidence to support this aziridine-ring-opening hypothesis was provided by treatment of 2-methyl-2-CF3-aziridine
amine-, cyanide-, thiocyanate-, methoxide-, and ethoxide-induced ring rearrangements were effectively realized to provide an efficient entry into a variety of functionalized 2-CF3-pyrrolidines and -piperidines. The ring rearrangements toward piperidines 7 were found to be harder to perform. In that respect, a higher boiling solvent (N,N-dimethylformamide, DMF) was &
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Communication (4) with NaCN in DMF, furnishing the corresponding 3-amino4,4,4-trifluoro-3-methylbutanenitrile through selective ring opening at C3. It should be noted that this strategy for ring rearrangements of 2-(w-chloroalkyl)aziridines complements previously reported methods relying on initial halide displacement by the aziridine nitrogen toward strained bicyclic intermediates followed by ring opening.[7] Treatment of aziridine 5 b with 5 equiv of iPrNH2 or iBuNH2 and 1 equiv of NaI in CH3CN did not exclusively afford the anticipated 2-isoalkylaminomethyl-1-tosyl-2-(trifluoromethyl)piperidines 7 b and 7 c. Surprisingly, the major isomers (60– 75:25–40, major/minor) were identified as 1-isoalkyl-3-tosylamino-3-(trifluoromethyl)azepanes 9. Addition of an equimolar amount of NaI appeared to be necessary to induce ring closure in these cases. Application of the same reaction conditions for the ring expansion of aziridine 5 a toward the corresponding pyrrolidine 6 b (entry 2, Table 1), however, did not afford any trace of 1-isopropyl-3-tosylamino-3-(trifluoromethyl)piperidine. From a mechanistic point of view, initial regiospecific ring opening of aziridine 5 b at the C3 position by the alkylamine and additional substitution of chloride by iodide results in intermediates 10. Finally, prototropy and subsequent ring closure induced by the isoalkylamino moiety of intermediates 11 affords 1-isoalkyl-3-tosylamino-3-(trifluoromethyl)azepanes 9 (route a, Scheme 5). Another possible mechanism for the trans-
Figure 1. Molecular structure of 1-isopropyl-3-tosylamino-3-(trifluoromethyl)azepane 9 a, showing thermal displacement ellipsoids at the 50 % probability level.
ing in mind the fact that azepanes have been incorporated in for example the anticonvulsant drugs carbamazepine and oxacarbazepine, and the antiparkinsonian drug Talipexole, these trifluoromethylated azepanes 9 can be considered as useful new entities.[9] The incorporation of the obtained trifluoromethylated azaheterocycles 6, 7, and 9 in larger biological systems requires the removal of the N-protecting group. Therefore, in a final stage of this research, deprotection of a representative example was carried out as a proof of concept. In that respect, detosylation of pyrrolidine 6 e was attained by reaction with concentrated sulfuric acid, resulting in pyrrolidine oxalic acid complex 13 after 6 h at 50 8C in a pressure vial (Scheme 6). The
Scheme 6. Detosylation of pyrrolidine 6 e.
structure of complex 13 was confirmed by single-crystal X-ray diffraction analysis (see the Supporting Information). In summary, deprotonation of 1-tosyl-2-(trifluoromethyl)aziridine and subsequent reaction of the obtained aziridinyl anion with w,w’-dihalogenated alkanes resulted in 2-(w-chloroalkyl)1-tosyl-2-(trifluoromethyl)aziridines. Owing to the presence of a good terminal leaving group, ring expansion of these alkylated aziridines toward a variety of novel functionalized pyrrolidines, piperidines, and azepanes could be realized as a new synthetic strategy in the field of heterocyclic synthesis. Finally, detosylation of one of the obtained ring systems resulted in a CF3-substituted azaheterocycle suitable for further elaboration by the free NH moiety.
Scheme 5. Ring expansion of aziridine 5 b toward azepanes 9.
formation of aziridine 5 b into azepanes 9 comprises initial halide substitution by the alkylamine toward the corresponding 2-(4-aminobutyl)aziridines 12, followed by intramolecular ring opening induced by the amino moiety toward azepanes 9 (route b, Scheme 5). The molecular identity of azepanes 9 was unequivocally established by means of a single-crystal X-ray structure analysis of compound 9 a (Figure 1). The ring expansion of aziridine 5 b toward seven-membered heterocycles is surprising. Moreover, only a few reports on aziridine-to-azepane ring expansions are known in the literature,[8] making this ring transformation a rare and peculiar one. BearChem. Eur. J. 2014, 20, 1 – 5
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Acknowledgements The authors are indebted to Ghent cial support. K. Van Hecke thanks (project AUGE/11/029 "3D-SPACE: Aiming for Chemical Excellence") for 3
University (BOF) for finanthe Hercules Foundation 3D Structural Platform funding.
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Communication Keywords: azepanes · aziridines · aziridinyl piperidines · pyrrolidines · trifluoromethyl
anions
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Communication
COMMUNICATION & Heterocycles
CF3-azaheterocycles: The alkylation of the 1-tosyl-2-(trifluoromethyl)aziridin-2yl anion with w,w’-dihaloalkanes, followed by a novel ring-expansion protocol leads to 2-CF3-pyrrolidines, 2-CF3-piperidines, and 3-CF3-azepanes. A variety of halogen, oxygen, nitrogen, sulfur, and carbon nucleophiles was used to trigger this ring rearrangement, resulting in CF3-azaheterocycles bearing different types of functionalized side chains (see scheme; HMPA = hexamethylphosphoramide, Ts = para-toluenesulfonyl).
Chem. Eur. J. 2014, 20, 1 – 5
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J. Dolfen, S. Kenis, K. Van Hecke, N. De Kimpe,* M. D’hooghe* && – && Selective Synthesis of Functionalized Trifluoromethylated Pyrrolidines, Piperidines, and Azepanes Starting from 1-Tosyl-2(trifluoromethyl)aziridine
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