Selective synthesis of functionalized trifluoromethylated pyrrolidines, piperidines, and azepanes starting from 1-tosyl-2-(trifluoromethyl)aziridine

Article abstract of DOI:10.1002/chem.201304759

This paper reports on the generation and alkylation of the 1-tosyl-2-(trifluoromethyl)aziridin-2-yl anion with ω,ω′- dihaloalkanes, followed by a novel ring-expansion protocol toward 2-CF ₃-pyrrolidines, 2-CF₃-piperidines, and 3-CF ₃-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. CF₃-azaheterocycles: The alkylation of the 1-tosyl-2-(trifluoromethyl)aziridin-2-yl anion with ω,ω′- dihaloalkanes, followed by a novel ring-expansion protocol leads to 2-CF ₃-pyrrolidines, 2-CF₃-piperidines, and 3-CF ₃-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).

Full text of DOI:10.1002/chem.201304759

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)aziri-
din-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.
Abstract: This paper reports on the generation and alkyla-
tion of the 1-tosyl-2-(trifluoromethyl)aziridin-2-yl anion
with w,w’-dihaloalkanes, followed by a novel ring-expan-
sion protocol toward 2-CF3-pyrrolidines, 2-CF3-piperidines,
and 3-CF3-azepanes. A variety of halogen, oxygen, nitro-
gen, sulfur, and carbon nucleophiles was used to trigger
this ring rearrangement, resulting in CF3-azaheterocycles
bearing different types of functionalized side chains.
The synthesis of 1-tosyl-2-(trifluoromethyl)aziridine (3), the
key intermediate in this study, was based on a two-step proce-
dure adapted from literature approaches,[2i] starting from race-
mic 3-amino-1,1,1-trifluoropropan-2-ol (purchased from Apollo
Scientific). In a first step, aminopropanol 1 was selectively N-
tosylated 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
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-(tri-
fluoromethyl)aziridines.[2] Because of the unique chemical and
physical properties of fluorine, such as its high electronegativi-
ty and small van der Waals radius, the presence of a trifluoro-
methyl group in biologically active compounds has a significant
influence on their lipophilicity, metabolic stability, and pKa.[3] As
a consequence, CF3-substituted azaheterocycles are increasing-
ly used in pharmaceutical and agricultural applications.[4]
Scheme 1. Synthesis of 1-tosyl-2-(trifluoromethyl)aziridine 3. DEAD=diethy-
lazodicarboxylate, Ts=para-toluenesulfonyl.
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 deprotona-
tion.[2i–k] Reaction of these aziridinyl anions with haloalkanes,
however, has not been investigated, apart from a single exam-
ple using benzyl bromide.[2j,k] In this paper, we report on the
toward aziridine 3 constitutes an improved method as com-
pared to literature protocols starting from 2-(trifluoromethyl)-
oxirane.[2i]
Subsequently, the C-alkylation of aziridine 3 with an electro-
phile 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 C-
alkylation.[2j,k] However, this reaction yielded the corresponding
substitution product only in 13% yield. Therefore, the reactivi-
ty profile of the 2-(trifluoromethyl)aziridin-2-yl anion was first
explored toward MeI to assess and establish its C-alkylation ap-
titude. Hereby, aziridine 3 was treated with 1.1 equiv of nBuLi
and 0.1 equiv of HMPA at À1008C followed by reaction with
1.5 equiv of MeI at À408C, yielding 2-methyl-1-tosyl-2-(trifluo-
romethyl)aziridine (4) in 50% yield (Scheme 2).
[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: norbert.dekimpe@UGent.be
matthias.dhooghe@UGent.be
[b] Prof. Dr. K. Van Hecke
Department of Inorganic and Physical Chemistry
Ghent University, Krijgslaan 281-S3
9000 Ghent (Belgium)
The same reaction conditions were applied for the alkylation
of aziridine 3 with 1-chloro-3-iodopropane and 1-chloro-4-
iodobutane, although unfortunately these conditions did not
afford the corresponding 2-(w-chloroalkyl)-1-tosyl-2-(trifluoro-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304759.
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Table 1. Synthesis of 2-(trifluoromethyl)pyrrolidines 6 and -piperidines 7.
Entry
Nucleophile
(Nu or NuH)
n
Reaction
conditions[a]
Product
Yield
[%]
1
2
3
4
5
6
7
8
LiCl
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
6a
6b
6c
6d
6e
6 f
7a
7b
7c
7d
7e
7 f
74
iPrNH2
NaCN
KSCN
NaOMe
NaOEt
LiCl
iPrNH2
iBuNH2
NaCN
KSCN
NaOMe
NaOEt
63[b]
77[b]
98
95
58[b]
60[b]
62[b]
14[b]
70[b]
20[b]
63[b]
77[b]
9
10
11
12
13
Scheme 2. Deprotonation of aziridine 3 and subsequent reaction with alkyla-
ting agents.
I
7g
[a] Reaction conditions: A) nucleophile (5 equiv), CH3CN, D, 4 h; B) nucleo-
phile (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) nucleo-
phile (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 À1008C, 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 de-
protonation at the C3-position or formation of dimers were
never obtained.
often required, whether or not in the presence of NaI (Table 1,
entries 7–13). Several CF3-azaheterocycles have been incorpo-
rated in compounds with pronounced biological properties,
rendering pyrrolidines 6 and piperidines 7 useful new chemical
entities in medicinal-chemistry programs for further elabora-
tions.[6]
The in situ generation of the proposed 2-(trifluoromethyl)-
aziridin-2-yl anion was further supported by means of a deuter-
ation protocol using D2O in THF, affording the anticipated 2-
deuterioaziridine in 67% yield.
From a mechanistic point of view, the formation of pyrroli-
dines 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
8A, followed by either direct ring closure or protonation to
amines 8B (in protic solvents) followed by ring closure, thus af-
fording pyrrolidines 6 or piperidines 7 (Scheme 4). Further evi-
As mentioned before, aziridines 5 can be considered as eligi-
ble 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 aziri-
dines 5a and 5b toward pyrrolidines 6 and piperidines 7, re-
spectively. As summarized in Scheme 3 and Table 1, chloride-,
Scheme 4. Reaction mechanism for the formation of 2-(trifluoromethyl)pyr-
rolidines 6 and -piperidines 7.
Scheme 3. Ring expansion of aziridines 5 toward pyrrolidines 6 and piperi-
dines 7.
dence for this mechanism was provided by the detection of
amines 8B in the crude NMR spectra (10–20%, CDCl3). In addi-
tion to full characterization by means of NMR analysis, the
structure of pyrrolidine 6e and piperidine 7 f was also con-
firmed by means of X-ray analysis (see the Supporting Informa-
tion).
amine-, cyanide-, thiocyanate-, methoxide-, and ethoxide-in-
duced ring rearrangements were effectively realized to provide
an efficient entry into a variety of functionalized 2-CF3-pyrroli-
dines and -piperidines. The ring rearrangements toward piperi-
dines 7 were found to be harder to perform. In that respect,
a higher boiling solvent (N,N-dimethylformamide, DMF) was
Further evidence to support this aziridine-ring-opening hy-
pothesis was provided by treatment of 2-methyl-2-CF3-aziridine
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Communication
(4) with NaCN in DMF, furnishing the corresponding 3-amino-
4,4,4-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 5b with 5 equiv of iPrNH2 or iBuNH2
and 1 equiv of NaI in CH3CN did not exclusively afford the an-
ticipated 2-isoalkylaminomethyl-1-tosyl-2-(trifluoromethyl)pi-
peridines 7b and 7c. Surprisingly, the major isomers (60–
75:25–40, major/minor) were identified as 1-isoalkyl-3-tosylami-
Figure 1. Molecular structure of 1-isopropyl-3-tosylamino-3-(trifluoromethyl)-
azepane 9a, showing thermal displacement ellipsoids at the 50% probability
level.
no-3-(trifluoromethyl)azepanes 9. Addition of an equimolar ing in mind the fact that azepanes have been incorporated in
amount of NaI appeared to be necessary to induce ring closure for example the anticonvulsant drugs carbamazepine and oxa-
in these cases. Application of the same reaction conditions for carbazepine, and the antiparkinsonian drug Talipexole, these
the ring expansion of aziridine 5a toward the corresponding trifluoromethylated azepanes 9 can be considered as useful
pyrrolidine 6b (entry 2, Table 1), however, did not afford any new entities.[9]
trace of 1-isopropyl-3-tosylamino-3-(trifluoromethyl)piperidine.
The incorporation of the obtained trifluoromethylated aza-
From a mechanistic point of view, initial regiospecific ring heterocycles 6, 7, and 9 in larger biological systems requires
opening of aziridine 5b at the C3 position by the alkylamine the removal of the N-protecting group. Therefore, in a final
and additional substitution of chloride by iodide results in in- stage of this research, deprotection of a representative exam-
termediates 10. Finally, prototropy and subsequent ring clo- ple was carried out as a proof of concept. In that respect, de-
sure induced by the isoalkylamino moiety of intermediates 11 tosylation of pyrrolidine 6e was attained by reaction with con-
affords 1-isoalkyl-3-tosylamino-3-(trifluoromethyl)azepanes
9
centrated sulfuric acid, resulting in pyrrolidine oxalic acid com-
(route a, Scheme 5). Another possible mechanism for the trans- plex 13 after 6 h at 508C in a pressure vial (Scheme 6). The
Scheme 6. Detosylation of pyrrolidine 6e.
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)aziri-
dine 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 alkylat-
Scheme 5. Ring expansion of aziridine 5b toward azepanes 9.
ed aziridines toward a variety of novel functionalized pyrroli-
dines, piperidines, and azepanes could be realized as a new
formation of aziridine 5b into azepanes 9 comprises initial synthetic strategy in the field of heterocyclic synthesis. Finally,
halide substitution by the alkylamine toward the correspond- detosylation of one of the obtained ring systems resulted in
ing 2-(4-aminobutyl)aziridines 12, followed by intramolecular a CF3-substituted azaheterocycle suitable for further elabora-
ring opening induced by the amino moiety toward azepanes 9 tion by the free NH moiety.
(route b, Scheme 5).
The molecular identity of azepanes 9 was unequivocally es-
Acknowledgements
tablished by means of a single-crystal X-ray structure analysis
of compound 9a (Figure 1).
The authors are indebted to Ghent University (BOF) for finan-
The ring expansion of aziridine 5b toward seven-membered
cial support. K. Van Hecke thanks the Hercules Foundation
heterocycles is surprising. Moreover, only a few reports on azir-
(project AUGE/11/029 "3D-SPACE: 3D Structural Platform
idine-to-azepane ring expansions are known in the literature,[8]
Aiming for Chemical Excellence") for funding.
making this ring transformation a rare and peculiar one. Bear-
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Communication
[4] a) F. M. D. Ismail, J. Fluorine Chem. 2002, 118, 27–33; b) J.-P. Bꢁguꢁ, D.
Bonnet-Delpon, Bioorganic and Medicinal Chemisry of Fluorine, John
Wiley & Sons, Hoboken, 2008; c) K. Mꢂller, C. Faeh, F. Diederich, Science
2007, 317, 1881–1886; d) H.-J. Bçhm, D. Banner, S. Bendels, M. Kansy, B.
Kuhn, K. Mꢂller, 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, Ar-
chaeology, Green Chemistry & Water (Ed.: A. Tressaud), Elsevier, Amster-
dam, 2006; h) P. Kirsch, Modern Fluoroorganic Chemistry, Wiley-VCH,
Weinheim, 2004; i) M. Quirmbach, H. Steiner, Chim. Oggi 2009, 27, 23–
26.
Keywords: azepanes
piperidines · pyrrolidines · trifluoromethyl
·
aziridines
·
aziridinyl anions
·
[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. Hiro-
taki, 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. Uneya-
ma, 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. Ri-
naudo, S. Narizuka, N. Askari, B. Crousse, D. Bonnet-Delpon, Tetrahedron
Lett. 2006, 47, 2065–2068; h) N. M. Karimova, Y. L. Teplenicheva, A. F. Ko-
lomiets, 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.
[5] S. Florio, R. Luisi, Chem. Rev. 2010, 110, 5128–5157.
[6] a) I. Jlalia, N. Lensen, G. Chaume, E. Dzhambazova, L. Astasidi, R. Hadjiolo-
va, 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. Snod-
grass-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.
Received: December 4, 2013
Published online on && &&, 0000
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Communication
COMMUNICATION
CF3-azaheterocycles: The alkylation of
the 1-tosyl-2-(trifluoromethyl)aziridin-2-
yl anion with w,w’-dihaloalkanes, fol-
lowed by a novel ring-expansion proto-
col leads to 2-CF3-pyrrolidines, 2-CF3-pi-
peridines, and 3-CF3-azepanes. A variety
of halogen, oxygen, nitrogen, sulfur,
and carbon nucleophiles was used to
trigger this ring rearrangement, result-
ing in CF3-azaheterocycles bearing dif-
ferent types of functionalized side
chains (see scheme; HMPA=hexameth-
ylphosphoramide, Ts=para-toluenesul-
fonyl).
&
Heterocycles
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
Chem. Eur. J. 2014, 20, 1 – 5
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These are not the final page numbers! ÞÞ