Ring-expansion of tertiary cyclic α-vinylamines by tandem conjugate addition to (p-toluenesulfonyl)ethyne and formal 3-aza-Cope rearrangement

Article abstract of DOI:10.1039/b607713g

A novel ring-expansion protocol is based on the conjugate additions of cyclic α-vinylamines to (p-toluenesulfonyl)ethyne, followed by aza-Cope rearrangements of the resulting zwitterions, to afford medium and large-ring cyclic amines under remarkably mild

Full text of DOI:10.1039/b607713g

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Ring-expansion of tertiary cyclic a-vinylamines by tandem conjugate
addition to (p-toluenesulfonyl)ethyne and formal 3-aza-Cope
rearrangement{
Mitchell H. Weston, Katsumasa Nakajima,{ Masood Parvez and Thomas G. Back*
Received (in Cambridge, UK) 31st May 2006, Accepted 30th June 2006
First published as an Advance Article on the web 7th August 2006
DOI: 10.1039/b607713g
substituents (e.g. 1) to the acetylenic sulfone 2, are spontaneously
followed by a formal 3-aza-Cope rearrangement of the zwitterions
3. This results in facile ring-expansions of the initial amine by four
members to afford the corresponding medium-ring or macrocyclic
amines 4 (Scheme 2). Similar ring systems are found in a number
of natural products that display interesting biological activity.5
In general, aza-Cope rearrangements6,7 and related processes8,9
proceed with difficulty and require strongly elevated temperatures
that limit their synthetic usefulness. In some instances, catalysis
with Brønsted or Lewis acids has been used to facilitate the
process. Alternatively, cationic variations of the aza-Cope
rearrangement, where a quaternary nitrogen atom is present,
proceed under milder conditions. We therefore reasoned that the
zwitterionic conjugate addition product 3 in Scheme 2 would
A novel ring-expansion protocol is based on the conjugate
additions of cyclic a-vinylamines to (p-toluenesulfonyl)ethyne,
followed by aza-Cope rearrangements of the resulting zwitter-
ions, to afford medium and large-ring cyclic amines under
remarkably mild conditions.
Compounds containing medium and large rings are often difficult
to synthesize by direct ring-closure protocols such as intramole-
cular alkylation or acylation. The formation of medium-sized rings
is impeded by unfavourable combinations of Pitzer, transannular
and large-angle strain in the products. Furthermore, closure of
large rings is accompanied by an unfavourable loss of entropy.1
The ring-expansion of a more readily available cyclic starting
material of normal ring size can provide an effective alternative to
direct ring-closures.2 We recently discovered a series of novel
cyclizations that are based upon the conjugate additions of
primary or secondary amines to acetylenic sulfones,3 followed by
intramolecular akylation or acylation (e.g., see Scheme 1). These
processes provided access to a series of piperidines, pyrrolizidines,
indolizidines, quinolizidines, decahydroquinolines and quinolones,
including (2)-pumiliotoxin C,4a various other dendrobatid alka-
loids,4b myrtine,4c (2)-lasubine II4c and two quinolone alkaloids
from the medicinal plant Ruta chalepensis.4d We now report that
the conjugate additions of cyclic, tertiary amines containing a-vinyl
rearrange under especially mild conditions and provide
a
convenient means for transforming readily available a-vinyl
N-benzylpyrrolidines, piperidines, morpholines, azepines and other
cyclic amines into sulfone-functionalized products containing
medium or large rings. In contrast to the present results with
cyclic a-vinylamines, the [3,3]sigmatropic rearrangements of acyclic
allylamines with acetylenic sulfone 2 were reported to fail, except in
the case of silylated hydroxylamine derivatives.7b Other rearrange-
ments of the conjugate addition products of allylamines with
dimethyl acetylenedicarboxylate have also been reported.10
The results of the ring-expansions of the cyclic a-vinylamines
with 2 are shown in Table 1. The required a-vinylamines 1a,11 1b11
and 7a,12 as well as acetylenic sulfone 2,13 were obtained by minor
variations of literature methods. The preparation of the remaining
starting materials 1c, 1d, 5, 7b and 9 is described in the
supplementary information.{ All of the reactions listed in Table 1
were performed in dichloromethane, with conditions ranging from
Scheme 1 Cyclizations of chloroamines with acetylenic sulfones.
Department of Chemistry, University of Calgary, Calgary, AB, Canada
T2N 1N4. E-mail: tgback@ucalgary.ca; Fax: 403-289-9488;
Tel: 403-220-6256
{ Electronic supplementary information (ESI) available: procedures,
characterization data, 1H and 13C NMR spectra for new products;
X-ray structure data for compound 4b. See DOI: 10.1039/b607713g
{ Present address: Novartis Pharmaceuticals Inc., 100 Technology Square,
Cambridge MA 02139, USA. Fax: 617-871-7043; Tel: 617-871-7459;
E-mail: katsumasa.nakajima@novartis.com
Scheme 2 Aza-Cope rearrangement of cyclic a-vinyl amines with
acetylenic sulfone 2.
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Table 1 Ring expansion of a-vinyl cyclic amines with 2
Conditionsa,b
Starting amine
Product (yield)
(temp., time)
1a (n = 1)
1b (n = 2)
1c (n = 3)
1d (n = 9)
4a (87%)
4b (91%)
4c (89%)
4d (63%)
0 uC, 0.5 h
0 uC, 0.5 h
0 uC, 0.5 h
RT, 30 h
5
6 (87%)
RT, 12 h
Fig. 1 ORTEP diagram of 4b with displacement ellipsoids plotted at
50% probability level; 3 disordered H-atoms at 0.5 occupancy each around
C16 have been ignored.
7a R = H; R9 = Me
7b R = Me; R9 = H
8a (89%)
8b (86%)
RT, 12 h
Reflux, 8 h
Normal 3-aza-Cope reactions are [3,3]sigmatropic rearrange-
ments that proceed in a concerted manner and involve the
interaction of p-orbitals at the respective terminal positions of the
vinyl and allyl moieties of the precursor amine. The present
reaction is somewhat different because it presumably requires the
interaction of a sulfone-stabilized vinyl anion with an alkene
p-orbital in intermediate 3. There is no direct evidence that the
present reaction is concerted and other mechanisms, such as a
dissociative process proposed earlier for related aza-Cope
reactions,10a,b followed by recombination, cannot be ruled out.
However, attempts to trap the corresponding dissociated inter-
mediate 11b with nucleophilic solvents such as methanol failed and
neither 12b nor its v-methoxy isomer were formed (Scheme 3).
Similarly, attempts to detect 3b or other intermediates by
9
a
10 (58%)
RT, 12 h
b
All reactions were performed in dichloromethane. RT = room
temperature.
0.5 h at 0 uC for 4a–4c to 8 h at reflux for 8a. A typical procedure
is available in the supplementary information.{ The reactions of
1a–1d indicate that simple cyclic a-vinylamines can be converted
into either medium-ring (4a–4c) or macrocyclic (4d) products in
excellent to good yields, respectively. The method can be used to
incorporate other heteroatoms, as shown by the formation of 6
from the morpholine derivative 5. Additional substituents are
tolerated at either the a- or b-position of the vinyl moiety, as
exemplified by the preparation of the methyl-substituted products
8a and 8b, formed with only a modest reduction in reaction rate
compared to the rate of the corresponding unsubstituted amine 1b.
The dienylamine 9 also underwent a [3,3] rearrangement instead of
the analogous [3,5] process, although in somewhat diminished
yield.
1
monitoring the reaction of 1b with 2 by H NMR spectroscopy
in CDCl3 were unsuccessful, probably because the formation of
intermediate 3b is rate-limiting and the subsequent step or steps are
too fast to allow observable accumulation of 3b or other
intermediates.
A selection of further transformations that are possible for the
products is illustrated with 4c in Scheme 4. Thus, the enamine and
Based on the olefinic coupling constant Jcis = 11.3 Hz, we
conclude that the 9-membered product 4a has the 5Z configura-
tion. On the other hand, the 10-membered homologue 4b was
obtained as a 95 : 5 mixture of 5E and 5Z isomers, based on
integration of the NMR signals from H-2 at d 7.62 and 7.53,
respectively. The 5E-configuration of the major isomer was
indicated by X-ray crystallography (Fig. 1),§ which also confirmed
the expected 2E configuration. The 10-membered oxazecine 6 was
similarly obtained as a mixture of E : Z isomers in the ratio of 9 : 1
(integration of H-2 signals at d 7.67 and 7.59, respectively), with
the major isomer identified by its H-5/H-6 coupling constant
Jtrans = 15.9 Hz. The 11-membered homologue 4c was obtained as
the pure E isomer (Jtrans = 15.7 Hz). Overlapping olefinic NMR
signals and the unavailability of suitable crystals for X-ray
structures precluded the unambiguous determination of 5E/Z
geometry for 4d, 8a, 8b and 10, although we assume that the
E-configuration was favoured in these examples.
Scheme 3 Dissociative mechanism for the formation of 4b.
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1 M. B. Smith and J. March, March’s Advanced Organic Chemistry—
Reactions, Mechanisms and Structure, Wiley, New York, 5th edn., 2001,
pp. 184–186 and 280–281.
2 M. Hesse, Ring Enlargement in Organic Chemistry, VCH, Weinheim,
1991.
3 For a review of acetylenic and allenic sulfones, see: T. G. Back,
Tetrahedron, 2001, 57, 5263.
4 (a) T. G. Back and K. Nakajima, J. Org. Chem., 1998, 63, 6566; (b)
T. G. Back and K. Nakajima, J. Org. Chem., 2000, 65, 4543; (c)
T. G. Back, M. D. Hamilton and V. J. J. Lim, J. Org. Chem., 2005, 70,
967; (d) T. G. Back, M. Parvez and J. E. Wulff, J. Org. Chem., 2003, 68,
2223.
5 Examples include (a) the motuporamines: D. E. Williams, P. Lassota
and R. J. Andersen, J. Org. Chem., 1998, 63, 4838; (b) halitulin and
related compounds: Y. Kashman, G. Koren-Goldshlager, M. D. G.
Gravalos and M. Schleyer, Tetrahedron Lett., 1999, 40, 997; (c)
palustrine and other spermidine alkaloids: B. B. Toure´ and D. G. Hall,
J. Org. Chem., 2004, 69, 8429 and references cited therein.
6 For reviews see: (a) D. Enders, M. Knopp and R. Schiffers, Tetrahedron
Asymmetry, 1996, 7, 1847; (b) S. Blechert, Synthesis, 1989, 71; (c)
N. M. Przheval’skii and I. I. Grandberg, Russian Chem. Rev., 1987, 56,
477; (d) R. P. Lutz, Chem. Rev., 1984, 84, 205.
Scheme 4 Further transformations of 4c.
7 For recent examples of 3-aza-Cope rearrangements of acyclic allyl vinyl
amines, see: (a) D. Fiedler, R. G. Bergman and K. N. Raymond,
Angew. Chem. Int. Ed., 2004, 43, 6748; (b) M. J. S. Gomes, L. Sharma,
S. Prabhakar, A. M. Lobo and P. M. C. Glo´ria, Chem. Commun., 2002,
746; (c) D. F. McComsey and B. E. Maryanoff, J. Org. Chem., 2000, 65,
4938; (d) A. S. Cardoso, A. M. Lobo and S. Prabhakar, Tetrahedron
Lett., 2000, 41, 3611; (e) M. A. Walters, J. Org. Chem., 1996, 61,
978.
8 For recent examples of 2-aza-Cope rearrangements of 3-alkenyliminium
species, see: (a) Z. D. Aron and L. E. Overman, Org. Lett., 2005, 7, 913;
(b) K. M. Brummond and J. Lu, Org. Lett., 2001, 3, 1347.
9 For recent examples of aza-Claisen rearrangements, see: (a) J.-F. Zheng,
L.-R. Jin and P.-Q. Huang, Org. Lett., 2004, 6, 1139; (b) S. G. Davies,
A. C. Garner, R. L. Nicholson, J. Osborne, E. D. Savory and
A. D. Smith, Chem. Commun., 2003, 2134; (c) J. Kang, T. H. Kim,
K. H. Yew and W. K. Lee, Tetrahedron Asymmetry, 2003, 14, 415; (d)
U. M. Lindstro¨m and P. Somfai, Chem. Eur. J., 2001, 7, 94; (e)
Y.-G. Suh, S.-A. Kim, J.-K. Jung, D.-Y. Shin, K.-H. Min, B.-A. Koo
and H.-S. Kim, Angew. Chem., Int. Ed., 1999, 38, 3545.
isolated alkene moieties can each be reduced selectively with
sodium cyanoborohydride or by catalytic hydrogenation to afford
13 and 14, respectively, while the sulfone moiety of 13 can be
employed to introduce an additional substituent via alkylation of
the corresponding a-carbanion, as in the case of 15.
In summary, these preliminary experiments indicate that the
ring-expansions of cyclic a-vinylamines with acetylenic sulfone 2
proceed under remarkably mild conditions without the need for
catalysts. They provide efficient and convenient access to cyclic
amines with medium or large rings, tolerate the presence of other
heteroatoms and substituents, and permit further useful transfor-
mations of the products.
We thank the Natural Sciences and Engineering Research
Council of Canada for financial support.
10 (a) E. Vedejs and M. Gingras, J. Am. Chem. Soc., 1994, 116, 579; (b)
A. L. Schwan and J. Warkentin, Can. J. Chem., 1988, 66, 1686; (c)
K. A. Kandeel and J. M. Vernon, J. Chem. Soc., Perkin Trans. 1, 1987,
2023.
11 Compounds 1a and 1b were previously investigated in aza-Cope
rearrangements with chromium carbene complexes: C. J. Deur,
M. W. Miller and L. S. Hegedus, J. Org. Chem., 1996, 61, 2871.
12 S. Nazabadioko, R. J. Pe´rez, R. Brieva and V. Gotor, Tetrahedron:
Asymmetry, 1998, 9, 1597.
Notes and references
§ Crystal data: C23H27NO2S, M = 381.52, crystal system = orthorhombic,
space group = Pbca. Unit cell dimensions: a = 17.003(4), b = 11.331(4), c =
3
˚
˚
˚
21.365(7) A, V = 4116(2) A , Z = 8, MoKa radiation (l = 0.71073 A), T =
173(2) K, m = 0.175 mm21, number of reflections measured = 8795, unique
reflections = 4661, observed reflections (I . 2.0 s I) = 3640, Rint = 0.022,
R = 0.0430 and wR = 0.1052 for observed data. CCDC 609578. For
crystallographic data in CIF or other electronic format see DOI: 10.1039/
b607713g
13 Z. Chen and M. L. Trudell, Synth. Commun., 1994, 24, 3149.
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Chem. Commun., 2006, 3903–3905 | 3905