Access to optically active 3-azido- and 3-aminopiperidine derivatives by enantioselective ring expansion of prolinols

Article abstract of DOI:10.1021/ol201769b

The activation of N-alkyl prolinols by XtalFluor E allowed the formation of an aziridinium intermediate that can react with tetrabutylammonium azide (nBu₄NN₃) to produce 3-azidopiperidines and/or 2-(azidomethyl)pyrrolidines, in a rat

Full text of DOI:10.1021/ol201769b

ORGANIC
LETTERS
2011
Vol. 13, No. 16
4442–4445
Access to Optically Active 3-Azido- and
3-Aminopiperidine Derivatives by
Enantioselective Ring Expansion
of Prolinols
Anne Cochi, Domingo Gomez Pardo,* and Janine Cossy*
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS (UMR 7084)
10 rue Vauquelin, 75231-Paris Cedex 05, France
domingo.gomez-pardo@espci.fr; janine.cossy@espci.fr
Received July 6, 2011
ABSTRACT
The activation of N-alkyl prolinols by XtalFluor E allowed the formation of an aziridinium intermediate that can react with tetrabutylammonium
azide (nBu4NN3) to produce 3-azidopiperidines and/or 2-(azidomethyl)pyrrolidines, in a ratio up to 100/0. These 3-azidopiperidines can be reduced
to the corresponding 3-aminopiperidines.
A great number of patents related to 3-aminopiperidine
derivatives have been taken out due to the potential bio-
logical activities of these products. For example, 3-amino-
piperidine derivatives can present antitumoral,1 anti-
bacterial,2 anti-inflammatory,3 analgesic,4 antiviral,5
antidepressive,6 and anti-ischemic7 properties. They can
also be receptor ligands of the CNS8 and can find
applications as psychotropic agents9 as well as in the
treatment of hormone deficiency10 and neurological
disorders related to β-amyloid production.11 Thus, effi-
cient and selective methods to obtain optically active
3-aminopiperidine derivatives of type A are of interest
(Figure 1).
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r
10.1021/ol201769b
Published on Web 07/27/2011
2011 American Chemical Society

activated aziridinium intermediate.17 Due to these results, we
would like to report here a direct ring expansion of N-alkyl
prolinols induced by XtalFluor E18 which allowed the
formation of an aziridinium intermediate that can react with
tetrabutylammonium azide (nBu4NN3) to produce the cor-
responding 3-azidopiperidines with good to excellent regio-,
diastereo-, and enantioselectivity (Scheme 2). We have to
point out that these two methods are complementary and
can produce 3-aminopiperidines differently substituted.
Figure 1. 3-Aminopiperidine derivatives of type A.
Contrary to the formation of 3-hydroxypiperidines
from N-alkyl prolinols via an aziridinium intermediate,12
the synthesis of 3-azido- or 3-aminopiperidines by ring
enlargement of prolinols using an azide anion or amines is
either very lengthy or problematic.13 When, after activa-
tion of N-alkyl prolinol B by SOCl2, the resulting reactive
aziridinium intermediate I was treated with an amine,
2-(methyl)aminopyrrolidine B0 was exclusively formed
and no traces of the corresponding 3-aminopiperidine
was detected.14 In the particular case of N-alkyl prolinol
C, when activated with mesyl chloride and treated with
sodium azide at 100 °C in DMF, a mixture of 3-azido-
piperidine C0 and 2-(azidomethyl)pyrrolidine C00 was
formed in a ratio of 70/30 with a global yield of 90%
(Scheme 1, eq 2).15 This is one of the few examples reported
in the literature for the transformation of an N-alkyl
prolinol to a mixture of the corresponding 3-azido-
piperidine and 2-(azidomethyl)pyrrolidine.16
Scheme 2. Ring Expansion of Prolinols Induced by XtalFluor E
At first, prolinol 1a was treated with nBu4NN3 (1.1 equiv)
in CH2Cl2 at 0 °C followed by the addition of XtalFluor E.
After 10 min, two products were formed, 3-azidopiperidine
2a and 2-(azidomethyl)pyrrolidine 3a in 70% yield, in a 1/1
ratio. As 2a and 3a were obtained with the same ratio when
the 3-hydroxypiperidine 4 was treated with XtalFluor E and
nBu4NN3, we can conclude that the aziridinium intermedi-
ate III was completely formed (Scheme 3).
Very recently, Charette et al. reported a ring expansion
of dihydropyrrole producing tetrahydropyridine via an
Scheme 1. Addition of Amines or Azide Anion on an Aziridi-
nium Intermediate
Scheme 3. Ring Expansion of Prolinol 1a and Ring Contraction
of 3-Hydroxypiperidine 4
(12) For reviews, see: (a) Cossy, J.; Gomez Pardo, D. Chemtracts
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2002, 15, 579–605. (b) Metro, T.-X.; Gomez Pardo, D.; Cossy, J.
Chem.;Eur. J. 2009, 15, 1064–1070. (c) Cossy, J.; Gomez Pardo, D.;
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Dumas, C.; Mirguet, O.; Dechamps, I.; Metro, T.-X.; Burger, B.;
Roudeau, R.; Appenzeller, J.; Cochi, A. Chirality 2009, 21, 850–856.
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(d) Metro, T.-X.; Duthion, B.; Gomez Pardo, D.; Cossy, J. Chem. Soc.
Rev. 2010, 39, 89–102.
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67, 1485–1500.
(14) (a)Reitsema,R.H. J. Am. Chem. Soc. 1949, 71, 2041–2043. (b) Biel,
J. H.; Hoya, W. K.; Leiser, H. A. J. Am. Chem. Soc. 1959, 81, 2527–2532. (c)
Hammer, C. F.; Heller, S. R.; Craig, J. H. Tetrahedron 1972, 28, 239–253.
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Org. Lett., Vol. 13, No. 16, 2011
4443

As the ring expansion of N-alkyl prolinols, via an
aziridinium intermediate, is favored under kinetic control
when steric hindered substituents are present at N1 and
C4,19 compounds 1bꢀ1h were prepared20 and treated
with XtalFluor E in the presence of nBu4NN3. The results
are reported in Table 1.
superior to 92/8 (Table 1, entries 1ꢀ3). The steric hin-
drance of the N-alkyl group, such as a trityl group, could
also increase the proportion of 3-azidopiperidine but was
not as effective as the substituent at C4, as the ratio 2e/3e
was 88/12 (Table 1, entry 4). However, by combining the
steric hindrance of N1 and C4 in prolinol 1f, 2f was
exclusively formed in 65% yield (Table 1, entry 5). It is
worth mentioning that even if 3-azidopiperidines 2g
and 2h were the major compounds, the piperidine/pyrro-
lidine ratio was not as good as that for the trans-2,4-di-
substituted prolinols 1bꢀd and 1f.
Table 1. Ring Expansion of 4-Hydroxyprolinol Derivatives
We have to point out that for piperidines 2bꢀd and 2f,
the diastereoselectivity was greater than 95/5, and for
compound 2e, the enantioselectivity exceeded 95/5.
Amines and carbamates were tolerated under the
conditions developed for the ring expansion of N-alkyl
prolinols to the corresponding 3-azidopiperidines (nBu4NN3,
XtalFluor E). The results are reported in Table 2.
Table 2. Ring Expansion of 4-Aminoprolinol Derivatives
a Separable by chromatography on silica gel. b Inseparable. c The
reaction was carried out at ꢀ78 °C for 4.5 h. d The reaction was carried
out at ꢀ78 °C for 20 min. e The reaction was carried out at 0 °C for
30 min. f The reaction was carried out at 0 °C for 2.5 h.
By increasing the steric hindrance at C4 in N-benzyl-
prolinols 1bꢀd, the ratio of 3-azidopiperidine 2/2-(azido-
methyl)pyrrolidine 3 was increased and the ratio 2/3 was
(15) Kim, D.-K.; Kim, G.; Kim, Y.-W. J. Chem. Soc., Perkin Trans. 1
1996, 803–808.
a Separable by chromatography on silica gel. b Inseparable. c The
reaction was carried out for 4.5 h. d The reaction was carried out for
2.5 h. e The reaction was carried out for 15 min.
(16) For related reactions, see: (a) Setoi, H.; Takeno, H.; Hashimoto,
M. Heterocycles 1986, 24, 1261–1264. (b) Furneaux, R. H.; Gainsford,
G. J.; Mason, J. M.; Tyler, P. C. Tetrahedron 1995, 51, 12611–12630. (c)
Lonkar, P. S.; Kumar, V. A. Bioorg. Med. Chem. Lett. 2004, 14, 2147–
2149. (d) Fukuhara, M.; Nishi, T.; Fujii, Y. WO 2007/108209; Chem.
Abstr. 2007, 147, 412648. (e) Pluvinage, B.; Ghinet, M. G.; Brzezinski,
R.; Boraston, A. B.; Stubbs, K. A. Org. Biomol. Chem. 2009, 7, 4169–
4172.
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LaFlamme, F.; Mirmehrabi, M.; Tadayon, S.; Tovell, D.; Couturier, M.
J. Org. Chem. 2010, 75, 3401–3411.
Contrary to the C4-hydroxylated prolinols, the cis-amino
substituted prolinols were transformed exclusively to the
corresponding 3-azidopiperidines (Table 2, entries 5ꢀ6)
and the trans-amino substituted prolinols led to a mixture
of piperidines/pyrrolidines in a ratio which was increased
in favor of the piperidine when the steric hindrance was
increased at N1 (Table 2, entries 1ꢀ3).
As fluorine atoms can have a big impact on the
biological activity of compounds, the ring expansion of
4-fluoropyrrolidines has been considered. The results are
reported in Table 3.
ꢀ
(19) (a) Dechamps, I.; Gomez Pardo, D.; Cossy, J. Synlett 2007, 263–
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267. (b) Dechamps, I.; Gomez Pardo, D.; Cossy, J. Eur. J. Org. Chem.
2007, 4224–4234.
(20) The requisite substrates 1aꢀh, 4, 5aꢀf, and 8aꢀc were prepared
from the corresponding proline; see the Supporting Information.
4444
Org. Lett., Vol. 13, No. 16, 2011

When treated with nBu4NN3 and XtalFluor E, the
trans-4-fluoroprolinol 8a was transformed to piperidine
9a and pyrrolidine 10a in a ratio of 93/7 in favor of 9a
with a global yield of 66% (Table 3, entry 1). For the
cis-4-fluoroprolinol 8b, the ratio of piperidine/pyrrolidine
was 1 to 1 (Table 3, entry 2), and this ratio was excellent
when two fluorine atoms were present at C4 (9c/10c = 91/9,
Table 3, entry 3).
piperidines can be achieved easily as each nitrogen is
orthogonally protected (Scheme 4).
Scheme 4. Staudinger Reduction of the Azido Group
Table 3. Ring Expansion of 4-Fluoroprolinol Derivatives
In conclusion, we have shown that N-alkyl prolinols
can be transformed to an aziridinium intermediate by
using XtalFluor E and that this intermediate was able to
react with nBu4NN3 to produce 3-azidopiperidines in
good yield and excellent diastereo- and enantioselectivity.
The ratio of the 3-azidopiperidines and 2-(azidomethyl)-
pyrrolidines depends on the steric hindrance at N1 and C4
as well as on the nature and relative stereochemistry of the
substituents present in the N-alkylprolinols at C2 and C4.
In order to understand the influence of the substituents at
C4, theoretical calculations are under investigation and
will be reported in due course.
a Inseparable.
Substituted 3-aminopiperidines of type A can be
synthesized easily in good yield from the 3-azido-
piperidine products via Staudinger reduction21 of the azido
group (Scheme 4). Further selective functionalization
of the different nitrogen atom present in the obtained
Supporting Information Available. Experimental pro-
cedure and characterization data of compounds 1gꢀh,
2aꢀh, 3aꢀh, 5aꢀf, 6aꢀf, 7aꢀf, 8aꢀc, 9aꢀc, 10aꢀc, and
11ꢀ14. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635–646.
Org. Lett., Vol. 13, No. 16, 2011
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