Table 2 Evolution of iododerivatives 2 on alumina
achieved since a ‘‘slow motion’’ reaction was possible in
deuterated benzene, allowing a direct observation of kinetic
and thermodynamic products by NMR in the NIS-promoted
cyclization. Thus, the formation of the thermodynamically
favoured piperidine 2 via the kinetically favoured pyrrolidine 3
by a 5-exo-trig route was confirmed. The new data on the
influence of the bulkiness of the substituent at the nitrogen on
the regioselectivity of the kinetic aziridinium ring-opening are
also noteworthy.12
R
Ratio 4/ 5
Yieldb (%)
Me
Et
Pr
Allyl
Bn
iPr
cHex
tBu
4a/ 5a: 66/34
4b/ 5b: 62/38
4c/ 5c: 60/40
4d/ 5d: 60/40
4e/ 5e: 57/43
4f/ 5f: 0/100
4g/ 5g: 0/100
4h/ 5h: 100/0a
88
70
77
89
86
86
95
60
This research was supported by the Ministry of Education
and Science (Spain)-FEDER through project CTQ2007-61338/
BQU.
Notes and references
1 For recent examples in natural product synthesis, see:
(a) M. A. Arnold, K. A. Day, S. G. Duron and D. Y. Gin,
´
a
b
Starting from 3h. After column chromatography.
J. Am. Chem. Soc., 2006, 128, 13255; (b) D. C. Beshore and
A. B. Smith, J. Am. Chem. Soc., 2008, 130, 13778;
(c) C. S. Schindler, C. R. J. Stephenson and E. M. Carreira, Angew.
Chem., Int. Ed., 2008, 47, 8852; (d) H. Zhang, Z. Lin, H. Huang,
H. Huo, Y. Huang, J. Ye and P. Huang, Chin. J. Chem., 2010, 28,
1717.
2 Inter alia: (a) M. Amjad and D. W. Knight, Tetrahedron Lett.,
2006, 47, 2825; (b) F. A. Davies, M. Song and A. Augustine,
J. Org. Chem., 2006, 71, 2779; (c) M. C. Marcotullio,
V. Campagna, S. Sternativo, F. Constantino and M. Curini,
Synthesis, 2006, 2760; (d) M. C. Elliott, N. N. E. El Sayed and
J. S. Paine, Org. Biomol. Chem., 2008, 6, 2611.
3 (a) F. Diaba, E. Ricou and J. Bonjoch, Org. Lett., 2007, 9, 2633;
(b) R. Surmont, G. Verniest, J. W. Thuring, P. ten Holte,
F. Derooe and N. De Kimpe, Org. Biomol. Chem., 2010, 8, 4514.
4 H. M. Lovick and F. E. Michael, J. Am. Chem. Soc., 2010, 132,
1249, see ref. 15 of this paper.
5 (a) B. E. Blough, S. W. Mascarella, R. B. Rothman and
F. I. Carroll, J. Chem. Soc., Chem. Commun., 1993, 758; (b)
S. H. L. Verhelst, B. P. Martinez, M. S. M. Timmer, G. Lodder,
G. A. Van der Marel, H. S. Overkleeft and J. H. Van Boom,
J. Org. Chem., 2003, 68, 9598; (c) H. Faltz, C. Bender and
J. Liebscher, Synthesis, 2006, 2907.
Scheme 3 Mechanism of formation of 2, 3, 4 and 5.
6 Sometimes, the 5-exo product was trapped in situ avoiding its ring-
enlargement: E. M. Dangerfield, M. S. M. Timmer and
B. L. Stocker, Org. Lett., 2009, 11, 535. Moreover, specific
structural trends of the formed products make that the 5-exo
compound was the isolated product: (a) K. C. Majumdar,
U. K. Kundu, U. Das, N. K. Jana and B. Roy, Can. J. Chem.,
2005, 83, 63; (b) S. G. Davies, R. L. Nicholson, P. D. Rice,
P. M. Roberts, A. J. Russell, E. D. Savory, A. D. Smith and
J. E. Thompson, Tetrahedron: Asymmetry, 2009, 20, 758.
7 Only 1a has been previously reported: M. Tokuda, Y. Yamada,
T. Tagaki and H. Suginome, Tetrahedron, 1987, 43, 281.
8 D. V. Gribkov, K. C. Hultzsch and F. Hampel, J. Am. Chem. Soc.,
2006, 128, 3748.
9 For a key ring-enlargement in vindoline synthesis through an
iodide attack upon an aziridinium intermediate to form the
embedded piperidine ring, see: Y. Sasaki, D. Kato and
D. L. Boger, J. Am. Chem. Soc., 2010, 132, 13533.
10 (a) T. J. Greshock and R. L. Funk, Org. Lett., 2001, 3, 3511;
(b) M. A. Graham, A. H. Wadsworth, M. Thornton-Pett and
C. M. Rayner, Chem. Commun., 2001, 966; (c) S. Y. Yun, S. Catak,
W. K. Lee, M. D’hooghe, N. De Kimpe, V. Van Speybroeck,
M. Waroquier, Y. Kim and H.-J. Ha, Chem. Commun., 2009, 2508
and references therein.
nature of the N-substituent as well as the nucleophile. The
mechanism involved in the formation of compounds 2–5 is
depicted in Scheme 3. The more stable piperidines 2 generated
from the initial pyrrolidine 3 can be explained by assuming a
late transition state for the ring-opening of aziridinium compounds
6, in which the attack of the iodide, a soft nucleophile,
occurred at the methine carbon.9 In contrast, in the irrevers-
ible Al2O3-promoted ring opening of 6 there is a mismatched
structural trend, since the less substituted aziridinium carbon
has an opposite counterpart effect on the substituent bulkiness
at the nitrogen atom, generating steric crowding. Thus, in an
early transition state the hard nucleophile did not exclusively
give alcohols 4 (pathway b) by a regioselective attack at the
methylene carbon,10 which was hindered in the aziridinium
intermediate 6, and an increase of the attack ratio at the
methine carbon giving piperidinol compounds 5 (pathway a)
was observed, correlated with the steric demand of the
N-substituent. The latter process is exclusive to the sterically
11 For an example in which the substrate-control induces a kinetic
ring opening by hydroxide at the methine carbon of an aziridinium
intermediate, see: M. E. Kuehne, F. J. Okuniewicz, C. L. Kirkemo
and J. C. Bohnert, J. Org. Chem., 1982, 47, 1335.
encumbered aziridinium intermediates
6 generated from
2f and 2g, which embodies branched N-alkyl groups, leading
to piperidines 5f and 5g, respectively.11
12 For a recent study about the ring-opening reaction mechanisms of
non-fused 2-substituted aziridinium salts, see: M. D’hooghe,
S. Catak, S. Stankovic, M. Waroquier, Y. Kim, H.-J. Ha,
V. Van Speybroeck and N. De Kimpe, Eur. J. Org. Chem., 2010,
4920.
In conclusion, we have developed a straightforward method
for the preparation of 5-iodo-2-phenylpiperidines by reaction
of NIS with 1-phenylpent-4-en-1-amines. A better understanding
of the iodoaminocyclization of d-alkenyl amines has been
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3251–3253 3253