Tandem conjugate additions and 3-aza-cope rearrangements of tertiary allyl amines and cyclic α-vinylamines with acetylenic sulfones. Applications to simple and iterative ring expansions leading to medium and large-ring nitrogen heterocycles

Article abstract of DOI:10.1021/jo800600a

(Chemical Equation Presented) Tertiary acyclic allyl amines and tertiary cyclic α-vinyl amines undergo conjugate additions to acetylenic sulfones to produce zwitterion intermediates, followed by 3-aza-Cope rearrangements. In the case of cyclic α-vinyl amines, the process results in ring-expansion, providing a novel route to 9- to 17-membered cyclic amines. The Hammett plot for the reaction of 8b with 2a-2f shows ρ = +1.19, which is consistent with formation of the proposed zwitterion in the rate-determining step, where electron-withdrawing substituents on the arylsulfonyl moiety stabilize the negative charge and enhance the rate of the reaction. Alternative pathways were observed in methanol in the case of 11, where a methoxy substituent promotes a dissociative mechanism of the corresponding zwitterion via a stabilized allyl cation, whereas the zwitterion derived from amine 12 undergoes ring-opening by direct attack of methanol upon the strained aziridinium moiety instead of by rearrangement. An iterative process was developed, where the product of one ring-expansion is converted into a new cyclic α-vinyl amine, followed by a repetition of the conjugate addition and [3,3] rearrangement. This protocol was illustrated by its application to the synthesis of motuporamine A and B.

Full text of DOI:10.1021/jo800600a

Tandem Conjugate Additions and 3-Aza-Cope Rearrangements of
Tertiary Allyl Amines and Cyclic r-Vinylamines with Acetylenic
Sulfones. Applications to Simple and Iterative Ring Expansions
Leading to Medium and Large-Ring Nitrogen Heterocycles
Mitchell H. Weston, Katsumasa Nakajima, and Thomas G. Back*
Department of Chemistry, UniVersity of Calgary, Calgary, Alberta, Canada T2N 1N4
tgback@ucalgary.ca
ReceiVed March 19, 2008
Tertiary acyclic allyl amines and tertiary cyclic R-vinyl amines undergo conjugate additions to acetylenic
sulfones to produce zwitterion intermediates, followed by 3-aza-Cope rearrangements. In the case of
cyclic R-vinyl amines, the process results in ring-expansion, providing a novel route to 9- to 17-membered
cyclic amines. The Hammett plot for the reaction of 8b with 2a-2f shows F ) +1.19, which is consistent
with formation of the proposed zwitterion in the rate-determining step, where electron-withdrawing
substituents on the arylsulfonyl moiety stabilize the negative charge and enhance the rate of the reaction.
Alternative pathways were observed in methanol in the case of 11, where a methoxy substituent promotes
a dissociative mechanism of the corresponding zwitterion via a stabilized allyl cation, whereas the zwitterion
derived from amine 12 undergoes ring-opening by direct attack of methanol upon the strained aziridinium
moiety instead of by rearrangement. An iterative process was developed, where the product of one ring-
expansion is converted into a new cyclic R-vinyl amine, followed by a repetition of the conjugate addition
and [3,3] rearrangement. This protocol was illustrated by its application to the synthesis of motuporamine
A and B.
Introduction
of Bronsted or Lewis acid catalysts,5 which permit the use of
milder conditions.
Medium- and large-ring nitrogen heterocycles occur wide-
spread in nature and often display interesting biological proper-
Aza variations1 of the Cope rearrangement provide the
opportunity to transpose a nitrogen functionality during the usual
allyl migration associated with this classical [3,3] sigmatropic
reaction. Thus, a variety of 2-aza-Cope rearrangements of
3-alkenylimines or, more commonly of 3-alkenyliminium spe-
cies, have been reported.2 Similarly, the 3-aza-Cope rearrange-
ments3 of allyl vinyl amines (Scheme 1) have been investigated
and are sometimes referred to as aza-Claisen or amino-Claisen
reactions.4 The 3-aza-Cope rearrangement typically requires high
temperatures that curtail its synthetic utility. This can be
mitigated by employing cationic quaternary amines as starting
materials, or through the use of tertiary amines in the presence
(2) For recent examples of 2-aza-Cope rearrangements, see: (a) Merino, P.;
Tejero, T.; Mannucci, V. Tetrahedron Lett. 2007, 48, 3385–3388. (b) Sugiura,
M.; Mori, C.; Kobayashi, S. J. Am. Chem. Soc. 2006, 128, 11038–11039. (c)
Sugiura, M.; Mori, C.; Hirano, K.; Kobayashi, S. Can. J. Chem. 2005, 83, 937–
942. (d) Earley, W. G.; Jacobsen, J. E.; Madin, A.; Meier, G. P.; O’Donnell,
C. J.; Oh, T.; Old, D. W.; Overman, L. E.; Sharp, M. J. J. Am. Chem. Soc.
2005, 127, 18046–18053. (e) Aron, Z. D.; Overman, L. E. Org. Lett. 2005, 7,
913–916. (f) Bru¨ggermann, M.; McDonald, A. I.; Overman, L. E.; Rosen, M. D.;
Schwink, L.; Scott, J. P. J. Am. Chem. Soc. 2003, 125, 15284–15285. (g)
Brummond, K. M.; Hong, S. J. Org. Chem. 2005, 70, 907–916. (h) Kvaerno,
L.; Norrby, P.-O.; Tanner, D. Org. Biomol. Chem. 2003, 1, 1041–1048. (i) Cooke,
A.; Bennett, J.; McDaid, E. Tetrahedron Lett. 2002, 43, 903–905. (j) Mu¨ller, P.;
Bernardinelli, G.; Nury, P. Tetrahedron: Asymmetry 2002, 13, 551–558. (k)
Mu¨ller, P.; Toujas, J.-L.; Bernardinelli, G. HelV. Chim. Acta 2000, 83, 1525–
1534. (l) Obrecht, D.; Zumbrunn, C.; Mu¨ller, K. J. Org. Chem. 1999, 64, 6891–
6895. (m) Rutjes, F. P. J. T.; Veerman, J. J. N.; Meester, W. J. N.; Hiemstra,
H.; Schoemaker, H. E. Eur. J. Org. Chem. 1999, 1127–1135. (n) Dorizon, P.;
Su, G.; Ludvig, G.; Nikitina, L.; Paugam, R.; Ollivier, J.; Salau¨n, J. J. Org.
Chem. 1999, 64, 4712–4724. (o) Strachan, J.-P.; Sharp, J. T.; Crawshaw, M. J.
J. Chem. Soc., Perkin Trans. 1 1999, 443–451.
* Corresponding author. Tel: (403) 220-6256. Fax: (403) 289-9488.
(1) For reviews see: (a) Nubbemeyer, U. Top. Curr. Chem. 2005, 244, 149–
213. (b) Enders, D.; Knopp, M.; Schiffers, R Tetrahedron: Asymmetry 1996, 7,
1847–1882. (c) Blechert, S. Synthesis 1989, 71–82. (d) Przheval’skii, N. M.;
Grandberg, I. I. Russ. Chem. ReV. 1987, 56, 477–491. (e) Lutz, R. P. Chem.
ReV. 1984, 84, 205–246.
4630 J. Org. Chem. 2008, 73, 4630–4637
10.1021/jo800600a CCC: $40.75 2008 American Chemical Society
Published on Web 05/23/2008

Rearrangements of Allyl Amines and Cyclic R-Vinylamines
SCHEME 1
SCHEME 3
SCHEME 2
ties. New methods for their synthesis are therefore in demand.
The preparation of these compounds by direct ring-closure
methods such as intramolecular alkylation or acylation reactions
is often challenging because of combinations of destabilizing
Pitzer, transannular, and large-angle strain in the products, as
well as an unfavorable loss of entropy.6 Ring-closing metathesis
affords a popular and effective alternative strategy, providing
that the corresponding bis(alkene) precursor is readily available.7
A third approach is based on the expansion of an existing ring.8
In principle, a cyclic tertiary amine containing N- and R-vinyl
substituents should undergo a 3-aza-Cope rearrangement to
afford a ring-expanded product, particularly when the amine is
quaternary (Scheme 2). In related processes, [3,3] sigmatropic
rearrangements leading to ring-expanded products were observed
in the case of the addition products of a vinylazetine to a
cyclopropenone3c and in amide enolates derived from cyclic
R-vinylamines.3f,l,n
or secondary amines to acetylenic sulfones,9 followed by
intramolecular alkylations or acylations. This has provided
access to a variety of nitrogen heterocycles, such as piperidines,
pyrrolizidines, indolizidines, quinolizidines decahydroquinolines,
and quinolones.10 The products, after further transformation,
include (-)-pumiliotoxin C,10a other dendrobatid alkaloids,10b
myrtine,10c (-)-lasubine II,10c two quinolone alkaloids from the
medicinal plant Ruta chalepensis,10d and (-)-julifloridine.10e
Examples are shown in Scheme 3.
As a continuation of our studies of cyclization reactions of
acetylenic sulfones, we investigated the conjugate additions of
acyclic tertiary allyl amines and cyclic tertiary R-vinylamines
1 and 5, respectively, to acetylenic sulfones 2. The resulting
zwitterion intermediates 3 and 6 were expected to undergo
spontaneous 3-aza-Cope rearrangements to afford the corre-
sponding rearranged and ring-expanded products 4 and 7,
respectively (Scheme 4).11,12 The dipolar nature of 3 and 6 led
us to anticipate that their [3,3] sigmatropic rearrangements would
be exceptionally facile. We now report the results of this
investigation, along with mechanistic studies and a novel
iterative ring expansion based on the sequential application of
the ring-expansion protocol shown in Scheme 4.
During the past few years, we have investigated a series of
cyclization protocols based on the conjugate additions of primary
(3) For recent examples of 3-aza-Cope rearrangements, see: (a) Waetzig,
S. R.; Tunge, J. A. J. Am. Chem. Soc. 2007, 129, 4138–4139. (b) Craig, D.;
King, N. P.; Mountford, D. M. Chem. Commun. 2007, 1077–1079. (c) Hemming,
K.; O’Gorman, P. A.; Page, M. I. Tetrahedron Lett. 2006, 47, 425–428. (d)
Fiedler, D.; van Halbeek, H.; Bergman, R. G.; Raymond, K. N. J. Am. Chem.
Soc. 2006, 128, 10240–10252. (e) Fiedler, D.; Bergman, R. G.; Raymond, K. N.
Angew. Chem., Int. Ed. 2004, 43, 6748–6751. (f) Zheng, J.-F.; Jin, L-R.; Huang,
P.-Q. Org. Lett. 2004, 6, 1139–1142. (g) Davies, S. G.; Garner, A. C.; Nicholson,
R. L.; Osborne, J.; Savory, E. D.; Smith, A. D. Chem. Commun. 2003, 2134–
2135. (h) For a related example of a 1-aza-Cope rearrangement (formally the
reverse of a 3-aza-Cope process), see: Kang, J.; Kim, T. H.; Yew, K. H.; Lee,
W. K. Tetrahedron Asymmetry 2003, 14, 415–418. (i) Winter, R. F.; Rauhut, G.
Chem.sEur. J. 2002, 8, 641–649. (j) Gomes, M. J. S.; Sharma, L.; Prabhakar,
S.; Lobo, A. M.; Glo´ria, P. M. C. Chem. Commun. 2002, 746–747. (k) Cardoso,
A. S.; Lobo, A. M.; Prabhakar, S. Tetrahedron Lett. 2000, 41, 3611–3613. (l)
Lindstro¨m, U. M.; Somfai, P. Chem.sEur. J. 2001, 7, 94–98. (m) McComsey,
D. F.; Maryanoff, B. E. J. Org. Chem. 2000, 65, 4938–4943. (n) Suh, Y.-G.;
Kim, S.-A.; Jung, J.-K.; Shin, D.-Y.; Min, K.-H.; Koo, B.-A.; Kim, H.-S. Angew.
Chem., Int. Ed. 1999, 38, 3545–3547.
(9) For a review of acetylenic and allenic sulfones, see: Back, T. G.
Tetrahedron 2001, 57, 5263–5301.
(10) (a) Back, T. G.; Nakajima, K. J. Org. Chem. 1998, 63, 6566–6571. (b)
Back, T. G.; Nakajima, K. J. Org. Chem. 2000, 65, 4543–4552. (c) Back, T. G.;
Hamilton, M. D.; Lim, V. J. J.; Parvez, M. J. Org. Chem. 2005, 70, 967–972.
(d) Back, T. G.; Parvez, M.; Wulff, J. E. J. Org. Chem. 2003, 68, 2223–2233.
(e) Zhai, H.; Parvez, M.; Back, T. G. J. Org. Chem. 2007, 72, 3853–3852.
(11) Preliminary communication: Weston, M. H.; Nakajima, K.; Parvez, M.;
Back, T. G. Chem. Commun. 2006, 3903–3905.
(4) For a discussion of the use of the terms “3-aza-Cope” and “3-aza-Claisen”,
see note 1 in Walters, M. A. J. Org. Chem. 1996, 61, 978–983.
(5) For example, ab initio calculations by Walters (ref 4) revealed that the
activation energy for the [3,3] sigmatropic rearrangement of allyl vinyl amine is
34.6 kcal/mol, whereas that for its protonated counterpart is only 21.4 kcal/mol.
For early examples of the beneficial effects of quaternization or Lewis acid
catalysis, see references cited therein.
(12) For earlier studies of aza-Cope reactions that proceed via dipolar
intermediates produced from tertiary allyl amines and DMAD or propiolate esters,
see: (a) Vedejs, E.; Gingras, M. J. Am. Chem. Soc. 1994, 116, 579–588. (b)
Baxter, E. W.; Labaree, D.; Ammon, H. L.; Mariano, P. S. J. Am. Chem. Soc.
1990, 112, 7682–7692. (c) Schwan, A. L.; Warkentin, J. Can. J. Chem. 1988,
66, 1686–1694. (d) Kandeel, K. A.; Vernon, J. M. J. Chem. Soc., Perkin Trans.
1 1987, 2023–2026. (e) Hassner, A.; D’Costa, R.; McPhail, A. T.; Butler, W.
Tetrahedron Lett. 1981, 22, 3691–3694. (f) Hassner, A.; Chau, W.; D’Costa, R.
Isr. J. Chem. 1982, 22, 76–81.
(6) Smith, M. B.; March, J. March’s AdVanced Organic Chemistry sReac-
tions, Mechanisms and Structure 5th ed.; Wiley: New York, 2001; pp 184-186
and 280-281.
(7) For a review of the synthesis of nitrogen and oxygen heterocycles by
ring-closing metathesis, see: Deiters, A.; Martin, S. F. Chem. ReV. 2004, 104,
2199–2238.
(8) Hesse, M. Ring Enlargement in Organic Chemistry; VCH: Weinheim,
Germany, 1991.
J. Org. Chem. Vol. 73, No. 12, 2008 4631

Weston et al.
SCHEME 4
SCHEME 5
12 (vide infra). The polar aprotic solvent DMF delivered the
lowest yield of 7b (entry 7) because of competing polymeri-
zation. A mixture of ether and dichloromethane was used in
entry 16 because pure dichloromethane resulted in a very rapid
reaction accompanied by extensive decomposition. The products
include rings ranging from 9- to 17-membered (7a and 7d,
respectively) and can accommodate an additional heteroatom
(13), or fusion to another ring (14). Substituents on the vinyl
group were also tolerated (12a-12c). The diene moiety in 8c
resulted in the usual [3,3] instead of a possible [3,5] sigmatropic
rearrangement, although the product 12c was obtained in
relatively low yield. The use of N-methyl instead of N-
benzylamines proved unsuccessful because of rapid and exten-
sive polymerization of the starting materials. Similarly, attempts
to employ 2-substituted 1-(arylsulfonyl)acetylenes failed because
of sluggish rates attributed to increased steric hindrance and
competing side reactions.
The azonine derivative 7a was formed as the pure 5Z-isomer,
presumably because of the expected constraints imposed by the
9-membered ring. This was confirmed by its olefinic coupling
constant Jcis ) 11.3 Hz. Products 7b, 7c, and 13, all containing
larger rings, were obtained solely or predominantly as the
E-isomers, as evidenced by the coupling constants Jtrans of 15.7
and 15.9 Hz for 7c and 13, respectively. An X-ray structure of
the major isomer of 7b11 confirmed its 5E geometry, as well as
its expected 2E configuration. The presence of overlapping
olefinic 1H NMR signals and the unavailability of suitable
crystals for X-ray structure determinations precluded unequivo-
cal E/Z assignments for the isolated alkene moieties of the
remaining ring-expanded compounds in Table 1, although we
assume that they are predominantly E, except in the case of 14.
Cope and similar [3,3] sigmatropic rearrangements typically
proceed in a concerted manner via the interaction of the two
respective π-systems of a 1,5-hexadiene, resulting in the
formation of a new σ-bond between the terminal positions, with
concomitant allyl migration. In the present case, three distinct
possibilities must be considered upon completion of the initial
conjugate addition of the amine to the acetylenic sulfone. First,
in anhydrous aprotic solvents such as dichloromethane or THF,
the rearrangement must proceed directly via the interaction of
the sulfone-stabilized vinyl anion with the alkene π-system in
the corresponding zwitterionic intermediate such as 3 or 6 in
Results and Discussion
We first investigated several examples of tandem conjugate
additions and 3-aza-Cope rearrangements of allyl amines 1. The
latter were prepared by N-allylation of the corresponding
secondary amines by a standard procedure.13 The results are
displayed in Scheme 5, which shows that the rearranged
products 4a-4c were obtained in moderate yield under mild
conditions from amines 1a-1c, respectively.
The results of similar reactions with cyclic R-vinyl amines
5a-5d, 8a-8c, and 9-12 with 2a are presented in Table 1.
Compounds 5a,14 5b,14 8a,15 10,16 and 1217 were obtained
by literature methods, whereas the preparation of 11 is
described in the Experimental Section. The preparation of
5c, 5d, 8b, 8c, and 9 was described in the Supporting
Information of our preliminary communication.11 Acetylenic
sulfones 2a-2f18,19 (vide infra) were obtained by known
methods.
In general, the reactions proceeded smoothly and rapidly at
temperatures ranging between -78 °C and refluxing dichlo-
romethane or THF to afford good to excellent yields of the
products. Among a variety of solvents investigated, dichlo-
romethane proved particularly effective (compare entries 1-8),
whereas methanol, a protic solvent, delivered comparable yields
of 7a and 7b (entries 2 and 8), but resulted in the formation of
anomalous products 15 and 16 (entries 17 and 18) from the
methoxyvinyl-substituted piperidine 11 and the vinylaziridine
(13) Allyldibenzylamine (1a) was prepared from allyl bromide and diben-
zylamine by the method of Alcaide, B.; Almendros, P.; Alonso, J.; Aly, M. F.
Org. Lett. 2001, 3, 3781–3784. N-Allylmorpholine (1b) and N-allylamine 1c
were prepared similarly.
(14) Compounds 5a and 5b were previously investigated in aza-Cope
rearrangements of chromium carbene complexes: Deur, C. J.; Miller, M. W.;
Hegedus, L. S J. Org. Chem. 1996, 61, 2871–2876.
(15) Nazabadioko, S.; Pe´rez, R. J.; Brieva, R.; Gotor, V. Tetrahedron:
Asymmetry 1998, 9, 1597–1604.
(16) Agami, C.; Couty, F.; Evano, G Org. Lett. 2000, 2, 2085–2088.
(17) Trost, B. M.; Fandrick, D. R. J. Am. Chem. Soc. 2003, 125, 11836–
11837.
(18) Chen, Z.; Trudell, M. L. Synth. Commun. 1994, 24, 3149–3155.
(19) Bhattacharya, S. N.; Josiah, B. M.; Walton, D. R. M. Organomet. Chem.
Synth. 1971, 1, 145–149.
4632 J. Org. Chem. Vol. 73, No. 12, 2008

Rearrangements of Allyl Amines and Cyclic R-Vinylamines
TABLE 1. Reactions of Cyclic Α-Vinyl Amines with 2a
SCHEME 6
bond cleavage20 a of the zwitterions 17 and 19 occurs in lieu
of sigmatropic rearrangement, and is either preceded or followed
(as shown in Scheme 6) by proton transfer from the solvent. In
the case of 17, C-N cleavage likely produces the methoxy-
stabilized allyl cation 18, although an SN2′ reaction with
methanol cannot be unequivocally ruled out. On the other hand,
ring-opening of 19 appears to proceed via SN2 attack by
methanol at the methylene group of the strained aziridinium
cation, either before or after proton transfer to the vinyl sulfone
moiety. This results in the formation of methyl ether 16, rather
than of products from the quenching of allyl cation 20 by
methanol (Scheme 6).20 Because the other examples that were
also performed in methanol in Table 1 (entries 2 and 8) afforded
the normal products of sigmatropic rearrangement, we attribute
the anomalous result in entry 17 to the electron-donating
methoxy substituent in amine 11, which promotes C-N
cleavage and stabilizes the resulting allyl cation 18 (Scheme
6). Similarly, in entry 18, the release of aziridine ring strain
promotes a more rapid direct ring-opening by the nucleophilic
solvent, relative to the rate of the usual [3,3] sigmatropic
rearrangement (Scheme 6). When the reactions of 11 and 12
with 2a were repeated in dichloromethane, only complex
mixtures of unidentified products were obtained.
Attempts to detect the postulated zwitterion intermediates by
NMR in several of the reactions summarized in Table 1 proved
fruitless, suggesting that the initial conjugate addition is rate-
determining, followed by the rapid sigmatropic rearrangement
of the zwitterion (or possibly of its conjugate acid in the presence
of a proton source). To confirm this assumption, as well as the
existence of the postulated zwitterion, we performed the
following experiments. The relatively slow reactions of 8b with
acetylenic sulfones 2a-2f enabled us to measure their rates
a DCM ) Dichloromethane. b RT ) Room temperature.
Scheme 4. Alternatively, in the presence of a proton source such
as methanol (e.g., entry 2 in Table 1), protonation of the vinyl
anion would produce a neutral vinyl sulfone moiety that is
tethered to an allyl group via a quaternary nitrogen atom,
resulting in a more conventional cationic 3-aza-Cope rearrange-
ment. This outcome is contingent upon protonation occurring
more rapidly than the sigmatropic rearrangement of the initial
zwitterion. The formation of products 15 and 16 in entries 17
and 18, respectively, illustrates a third possibility, wherein C-N
(20) (a) For related examples of dissociative mechanisms involving C-N
bond cleavage, see refs 12a and 12c. (b) For examples where vinylaziridines
underwent aza-Cope rearrangements upon addition to other unsaturated elec-
trophiles, in contrast to the ring-opening of 12, see refs 3l, 12e and 12f.
J. Org. Chem. Vol. 73, No. 12, 2008 4633

Weston et al.
SCHEME 7
FIGURE 1. Hammett plot for the reaction of 8b with 2a-2f.
conveniently by monitoring the formation of the corresponding
products via NMR spectroscopy, using tert-butyldimethylsilyl
phenyl ether as an internal standard. The resulting kinetic data
(see the Supporting Information) were consistent with a bimo-
lecular reaction and resulted in the Hammett plot shown in
Figure 1. The reaction constant F ) +1.19 indicates that the
transition state in the rate-determining step is significantly
stabilized by electron-withdrawing substituents on the arylsul-
fonyl moiety. These observations are consistent with a rate-
determining conjugate addition to afford the proposed zwitterion
intermediate, followed by a rapid [3,3] sigmatropic rearrangement.
It also seemed plausible that the ring-expansion reaction
that leads to medium- and large-ring nitrogen heterocycles
7 in Scheme 4 could be employed in an iterative manner if
the enamine sulfone functions of the products could in turn
be converted into new R-vinyl amines, thereby setting the
stage for a second ring expansion. We now illustrate the
iterative protocol through its application to the synthesis of
the alkaloids motuporamine A and B (21 and 22, respec-
tively). The latter products were isolated in 1998 from the
sponge Xestospongia exigua by Andersen and co-workers21
and were shown to display strong anti-invasive and antian-
giogenic activity.22 Several earlier syntheses of motupor-
amines A and B have been reported.22a,23
vinyl group into the iminium intermediates 24a and 24b was
achieved with vinylmagnesium bromide. This was accompanied
by competing ꢀ-deprotonation, thereby regenerating the starting
material, which could be easily recovered and recycled. Reduc-
tive desulfonylation24 of 25a and 25b then afforded the desired
R-vinyl amines 26a and 26b. The second ring-expansion of the
latter products proceeded more efficiently with (p-chloroben-
zenesulfonyl)ethyne (2e) than with 2a to afford the 13- and 14-
membered products 27a and 27b. Reduction of the latter, as
before, provided the parent amines 28a and 28b, which were
then converted into the bis(Cbz)-protected motuporamine A
(22) For lead references on the bioactivity of the motuporamines, see: (a)
Williams, D. E.; Craig, K. S.; Patrick, B.; McHardy, L. M.; van Soest, R.;
Roberge, M.; Andersen, R. J. J. Org. Chem. 2002, 67, 245–258. (b) Roskelley,
C. D.; Williams, D. E.; McHardy, L. M.; Leong, K. G.; Troussard, A.; Karsan,
A.; Andersen, R. J.; Dedhar, S.; Roberge, M. Cancer Res. 2001, 61, 6788–
6794. (c) McHardy, L. M.; Sinotte, R.; Troussard, A.; Sheldon, C.; Church, J.;
Williams, D. E.; Andersen, R. J.; Dedhar, S.; Roberge, M.; Roskelley, C. D.
Cancer Res. 2004, 64, 1468–1474. (d) To, K. C. W.; Loh, K. T.; Roskelley,
C. D.; Andersen, R. J.; O’Connor, T. P. Neuroscience 2006, 139, 1263–1274.
(e) Kaur, N.; Delcros, J.-G.; Martin, B.; Phanstiel, O. J. Med. Chem. 2005, 48,
3832–3839.
In the first stage of the iterative protocol, the 3-aza-Cope ring
expansions of amines 5a and 5b to 7a and 7b, respectively,
were performed as shown in entries 1 and 3 in Table 1. The
products were then transformed into the corresponding R-vinyl
amines 26a and 26b, respectively, followed by a second ring
expansion, as shown in Scheme 7. Thus, introduction of the
(23) (a) Baldwin, J. E.; Vollmer, H. R.; Lee, V. Tetrahedron Lett. 1999, 40,
5401–5404. (b) Goldring, W. P. D.; Weiler, L. Org. Lett. 1999, 1, 1471–1473.
(24) Trost, B. M.; Arndt, H. C.; Strege, P. E; Verhoeven, T. R Tetrahedron
Lett. 1976, 17, 3477–3478.
(21) Williams, D. E.; Lassota, P.; Andersen, R. J. J. Org. Chem. 1998, 63,
4838–4841.
4634 J. Org. Chem. Vol. 73, No. 12, 2008

Rearrangements of Allyl Amines and Cyclic R-Vinylamines
Hz), 116.9 (d, JCF ) 23.1 Hz), 82.5, 79.8; mass spectrum, m/z (%)
184 (M+, 75), 143 (100), 120 (50); HRMS calcd for C8H5FO2S,
183.9994; found, 183.9990.
(29a) and B (29b), respectively, by the method of Baldwin,
followed by hydrogenolysis.23a,25
The previously reported acetylenic sulfones 2a, 2b, 2c, 2e, and
Summary and Conclusions
2f were prepared similarly, by literature procedures.18,19
We have found that the reactions of tertiary acyclic allyl
amines or tertiary cyclic R-vinyl amines with acetylenic sulfones
result in initial conjugate additions, followed by 3-aza-Cope
rearrangements. In the case of cyclic R-vinyl amines, these
rearrangements result in the ring-expansion of the starting
materials by four carbon atoms, providing a novel, efficient route
to cyclic amines ranging from 9- to 17-members.
Typical Procedure for the aza-Cope Rearrangement of Acy-
clic r-Vinyl Amines: N,N-Dibenzyl-[2-(p-toluenesulfonyl)penta-
1,4-dienyl]amine (4a). A solution of acetylenic sulfone 2a (57 mg,
0.32 mmol) in dichloromethane (2 mL) was added slowly to a
solution of allyldibenzylamine (1a) (74 mg, 0.31 mmol) in
dichloromethane (1.0 mL). The mixture was stirred at room
temperature for 4 h, concentrated in vacuo, and purified via flash
chromatography (10% ethyl acetate-hexanes) to afford 76 mg
(58%) of 4a as a yellow oil: IR (film) 1622, 1294, 1135 cm-1; 1H
NMR (400 MHz) δ 7.92 (s, 1 H), 7.72 (d, J ) 8.3 Hz, 2 H),
7.42-7.21 (m, 8 H), 7.16 (d, J ) 6.8 Hz, 4 H), 5.68 (ddt, J )
17.1, 10.2, 5.1 Hz, 1 H), 4.90 (dd, J ) 10.3, 1.6 Hz, 1 H), 4.86
(dd, J ) 17.2, 1.6 Hz, 1 H), 4.39 (s, 4 H), 2.98-2.92 (m, 2 H)
2.42 (s, 3 H); 13C NMR (100 MHz) δ 147.6, 142.3, 139.9, 136.9,
136.7, 129.3, 128.9, 127.7, 127.3, 126.9, 115.5, 102.0, 55.5, 28.9,
21.4; mass spectrum, m/z (%) 417 (M+, 2), 326 (9), 262 (61), 170
(45), 91 (100); HRMS calcd for C26H27NO2S, 417.1763; found,
417.1766.
Kinetic studies were consistent with a bimolecular process,
and a Hammett plot obtained with amine 8b and a series of
acetylenic sulfones 2a-2f containing variously p-substituted
arylsulfonyl groups produced a reaction constant F ) +1.19.
Thus, the reaction is facilitated by electron-withdrawing sub-
stituents on the arylsulfonyl moiety, which stabilize a negative
charge in its proximity. These observations are consistent with
a rate-determining conjugate addition step, leading to the
formation of the zwitterion intermediate, followed by its rapid
[3,3] sigmatropic rearrangement to afford the ring-expanded
products. The anomalous formation of 15 and 16 from amines
11 and 12, respectively, in methanol demonstrates that a
dissociative mechanism leading to a stabilized allyl cation is
possible when an electron-donating methoxy group is present
at the terminus of the exocyclic vinyl group of the starting
amine, or when direct attack by methanol on a strained
aziridinium intermediate occurs more rapidly than sigmatropic
rearrangement.
Products 4b and 4c were prepared similarly.
N-[2-(p-Toluenesulfonyl)penta-1,4-dienyl]morpholine (4b). Com-
pound 4b was obtained in 46% yield as a yellow oil: IR (film)
1
1624, 1279, 1137 cm-1; H NMR (400 MHz) δ 7.70 (d, J ) 8.2
Hz, 2 H), 7.40 (s, 1 H), 7.25 (d, J ) 8.4 Hz, 2 H), 5.66 (ddt, J )
17.1, 10.1, 5.1 Hz, 1 H), 4.96 (dd, J ) 10.2, 1.7 Hz, 1 H), 4.88
(dd, J ) 17.2, 1.7 Hz, 1 H), 3.09-3.05 (m, 2 H) 2.40 (s, 3 H); 13
C
NMR (100 MHz) δ 146.0, 142.3, 139.4, 135.3, 129.2, 127.2, 115.7,
101.9, 66.5, 50.1, 29.1, 21.3; mass spectrum, m/z (%) 307 (M+, 7),
152 (100), 120 (55), 91 (25); HRMS calcd for C16H21NO3S,
307.1242; found, 307.1234.
Finally, the ring-expansion protocol can be employed itera-
tively by conversion of the enamine sulfone moiety of the initial
ring-expanded product to a new R-vinyl substituent, followed
by a second 3-aza-Cope rearrangement and ring-expansion in
the usual manner. The iterative protocol was demonstrated in
the synthesis of the marine natural products motuporamine A
and B.
N,N,N′-Tribenzyl-N′-[(1E)-2-(p-toluenesulfonyl)penta-1,4-die-
nyl]ethane-1,2-diamine (4c). Compound 4c was obtained in 74%
1
yield as a yellow oil: IR (film) 1616, 1273, 1127 cm-1; H NMR
(300 MHz) δ 7.68 (d, J ) 8.2 Hz, 2 H), 7.66 (s, 1 H), 7.35-7.25
(m, 15 H), 7.01 (d, J ) 6.7 Hz, 2 H), 5.75-5.55 (m, 1 H),
4.91-4.79 (m, 2 H), 4.26 (s, 2 H), 3.57 (s, 4 H), 3.23 (t, J ) 6.6
Hz, 2 H), 2.87-2.79 (m, 2 H), 2.59 (t, J ) 6.6 Hz, 2 H), 2.41 (s,
3 H); 13C NMR (50 MHz) δ 147.4, 142.1, 140.1, 138.9, 137.3,
136.7, 129.2, 128.8, 128.7, 128.3, 127.5, 127.3, 127.1, 126.6, 115.4,
101.0, 59.1, 55.2, 51.8, 50.9, 28.8, 21.4; mass spectrum (CI), m/z
(%) 551 (M+1, 100), 224 (30), 210 (20); HRMS calcd for
C35H38N2O2S, 550.2654; found, 550.2628.
Typical Ring-Exapansion Procedure: (2E,5Z)-N-Benzyl-3-(p-
toluenesulfonyl)azacyclonona-2,5-diene (7a, Table 1, entry 1). A
solution of acetylenic sulfone 2a (84 mg, 0.47 mmol) in dichlo-
romethane (3 mL) was added to a solution of N-benzyl-2-
vinylpyrrolidine (5a)14 (87 mg, 0.47 mmol) in dichloromethane (15
mL) over 10 min at 0 °C. After 30 min at 0 °C, the mixture was
concentrated and purified by flash chromatography (10% ethyl
acetate-hexanes) to afford 149 mg (87%) of 7a as a yellow oil:
IR (film) 1616, 1283, 1135 cm-1; 1H NMR (300 MHz) δ 7.95 (d,
J ) 8.2 Hz, 2 H), 7.84 (s, 1 H), 7.26-7.05 (m, 3 H), 7.02-6.88
(m, 2 H), 6.91 (d, J ) 8.2 Hz, 2 H), 5.43 (dt, J ) 11.3, 8.2 Hz, 1
H), 5.13 (dt, J ) 11.3, 6.7, Hz, 1 H), 3.72 (s, 2 H), 3.26 (d, J )
6.7 Hz, 2 H), 2.81 (t, J ) 4.9 Hz, 2 H), 1.97 (s, 3 H), 1. 92-1.80
(m, 2 H), 1.15-1.02 (m, 2 H); 13C NMR (75 MHz) δ 149.4, 142.5,
139.9, 137.6, 130.0, 129.5, 128.9, 128.0, 127.6, 127.4, 124.6, 103.2,
60.5, 48.9, 29.4, 25.4, 24.2, 21.6; mass spectrum, m/z (%) 367 (M+,
2), 212 (27), 91 (100); HRMS calcd for C22H25NO2S, 367.1606;
found, 367.1590.
Experimental Section
NMR spectra were taken in CDCl3 unless otherwise noted. Flash
chromatography was performed on silica gel (230-400 mesh).
(p-Fluorobenzenesulfonyl)ethyne (2d). p-Flourobenzenesulfonyl
chloride (2.00 g, 10.3 mmol) was dissolved in dichloromethane
(15 mL) and AlCl3 (1.37 g, 10.3 mmol) was added. This mixture
was stirred for 30 min, cooled to 0 °C, and a solution of
bis(trimethylsilyl)acetylene (1.75 g, 10.3 mmol) in dichloromethane
(15 mL) was added. This was warmed to room temperature over
30 min and stirred for a further 24 h. The reaction was quenched
with 10% HCl solution, extracted with dichloromethane, dried, and
concentrated. The crude product was dissolved in THF (10 mL)
and a K2CO3/KHCO3 (7.0 × 10-3 M, 20 mL) buffer solution was
added. The mixture was stirred for 30 min, extracted with ethyl
acetate, dried, concentrated, and purified by flash chromatography
(10% ethyl acetate-hexanes) to afford 1.27 g (67%) of 2d as a
pale yellow solid: mp 57-58 °C (from ether); IR (film) 2070, 1591,
1
1335, 1170 cm-1; H NMR (200 MHz) δ 8.03-7.96 (m, 2 H),
7.29-7.21 (m, 2 H), 3.65 (s, 1 H); 13C NMR (50 MHz) δ 166.2
(d, JCF ) 258.1 Hz), 136.6 (d, JCF ) 1.5 Hz), 130.6 (d, JCF ) 10.3
(25) The removal of the Cbz groups from 29a and 29b was effected by
hydrogenolysis, as reported by Baldwin et al.,23a to afford the crude motupor-
amines A and B (21 and 22, respectively). Attempts to purify the triamines 21
and 22 as the free bases was ineffective, and the products were more easily
isolated as the protected derivatives 29a and 29b. Alternatively, isolation and
purification of 21 and 22 as the corresponding bis-N-acetyl derivatives has also
been reported.21,23
The other products in Table 1 were produced in a similar manner
under the conditions given in the Table and their characterization,
except for 14-16 (see below), was described in the Supporting
Information of our preliminary communication.11
J. Org. Chem. Vol. 73, No. 12, 2008 4635

Weston et al.
(2E,5Z)-1-Aza-3-(p-toluenesulfonyl)-[7.4.0]bicyclotrideca-2,5-di-
ene (14). Acetylenic sulfone 2a (69 mg, 0.38 mmol) in dichlo-
romethane (3 mL) was added slowly to a solution of vinyl
indolizidine 1017 (58 mg, 0.38 mmol) in ether (5 mL) at -78 °C.
The solution was allowed to warm to room temperature after 3 h
and was concentrated and purified via chromatography (25% ethyl
acetate-hexanes) to give 77 mg (61%) of 14 as a yellow oil. The
product decomposed rapidly when concentrated and so spectra are
(E)-N-Benzyl-3-(p-toluenesulfonyl)azacyclonon-2-ene (23a). Pal-
ladium on charcoal (10%, 106 mg) was added to a solution of
azonine 7a (2.04 g, 5.55 mmol) in methanol (40 mL). The
suspension was stirred under hydrogen (1 atm) overnight, filtered
through Celite, concentrated and purified by flash chromatography
(10% ethyl acetate-hexanes) to afford 2.04 g (100%) of 23a as a
clear oil: IR (film) 1617, 1278, 1126 cm-1; 1H NMR (200 MHz) δ
7.70 (d, J ) 8.0 Hz, 2 H), 7.68 (s, 1 H), 7.42-7.20 (m, 7 H), 4.37
(s, 2 H), 3.35 (m, 2 H), 2.46 (m, 2 H), 2.41 (s, 3 H), 1.67-1.33
(m, 8 H); 13C NMR (50 MHz) δ 147.4, 142.1, 140.3, 137.1, 129.2,
128.8, 127.9, 127.4, 127.2, 103.2, 60.4, 45.5, 30.3, 29.0, 26.9, 24.0,
23.9, 21.4; mass spectrum, m/z (%) 369 (M+, 35), 214 (55) 172
(100). HRMS calcd for C22H27NO2S, 369.1763; found, 369.1771.
(E)-N-Benzyl-3-(p-toluenesulfonyl)azacyclodec-2-ene (23b). The
same procedure as for the preparation of 23a was followed, using
1
reported on a crude sample. IR (film) 1730, 1604, 1278 cm-1; H
NMR (200 MHz) δ 7.69 (d, J ) 8.4 Hz, 2 H), 7.47 (s, 1 H), 7.23
(d, J ) 8.4 Hz, 2 H), 5.66-5.47 (m, 1 H), 5.24-5.10 (m, 1 H),
4.32-4.15 (m, 1 H), 3.55-2.90 (m, 3 H), 2.50-2.30 (m, 2 H),
2.39 (s, 3 H), 2.00-1.07 (m, 9 H); 13C NMR (50 MHz) δ 148.9,
142.0, 139.9, 129.2, 128.8, 127.0, 126.0, 98.7, 52.5, 50.1, 31.9,
30.7, 26.6, 26.3, 22.3, 21.4, 18.9; mass spectrum, m/z (%) 331 (M+,
15), 176 (100), 91 (20); HRMS calcd for C19H25NO2S, 331.1606;
found, 331.1598.
N-Benzyl-2-(2-methoxyvinyl)piperidine (11) and (E)-1-[N-Ben-
zyl-N-(5E-7,7-dimethoxyhept-5-enyl)amino]-2-(p-toluenesulfo-
nyl)ethene (15). To a solution of (methoxymethyl)triphenylphos-
phonium chloride (2.21 g, 6.46 mmol) in THF (15 mL) was added
nBuLi (2.27 mL, 5.68 mmol) at -78 °C. The solution was warmed
to 0 °C and stirred for 1 h at 0 °C. The red mixture was cooled to
–78 °C and N-benzylpiperdine-2-carbaldehyde15 (1.05 g, 5.17
mmol) in THF (15 mL) was added. The mixture was allowed to
warm to room temperature over 3 h and was furthered stirred for
6 h. The reaction was quenched with saturated NaHCO3 solution,
extracted with ether, dried, and concentrated under a vacuum.
Because the triphenyphosphine oxide could not be separated from
11, the crude product was used without purification in the
subsequent step: 1H NMR (200 MHz) δ 7.48-7.07 (m, 5 H), 5.99
(d, J ) 6.5 Hz, 1 H), 4.55 (dd, J ) 6.5, 6.3 Hz, 1 H), 4.11 (d, J )
13.5 Hz, 1 H), 3.62 (s, 3 H), 3.20 (m, 1 H) 3.16 (d, J ) 13.5 Hz,
1 H), 2.81 (m, 2 H), 1.9-1.3 (m, 6 H); mass spectrum, m/z (%)
231 (M+, 68), 200 (100), 91 (76); HRMS calcd for C15H21NO,
231.1623; found, 231.1622.
1
7b and affording 100% of 23b: IR (film) 1626, 1126 cm-1; H
NMR (200 MHz) δ 7.70 (d, J ) 8.0 Hz, 2 H), 7.55 (s, 1 H),
7.45-7.20 (m, 7 H), 4.37 (s, 2 H), 3.33 (t, J ) 6.9 Hz, 2 H),
2.46-2.38 (m, 2 H), 2.41 (s, 3 H), 1.75-1.38 (m, 10 H); 13C NMR
(50 MHz) δ 146.3, 142.1, 140.3, 137.2, 129.2, 128.7, 127.8, 127.6,
127.1, 105.9, 60.5, 44.4, 28.0, 26.3, 25.3, 23.2, 22.1, 21.5 21.4;
mass spectrum, m/z (%) 383 (M+, 76), 186 (55), 91 (100); HRMS
calcd for C23H29NO2S, 383.1919; found, 383.1897.
N-Benzyl-3-(p-toluenesulfonyl)-2-vinylazacyclononane (25a). Tri-
flic acid (0.56 mL, 6.3 mmol) was added slowly to a solution of
azonine 23a (1.15 g, 3.11 mmol) in dichloromethane (25 mL) at
-10 °C. The solution was stirred for 30 min at -10 °C, followed
by the slow addition of vinylmagnesium bromide in ether solution
(12.8 mL, 12.8 mmol). The mixture was warmed to room
temperature over 2 h, quenched with saturated NaHCO3 solution,
filtered, extracted with dichloromethane, dried, concentrated, and
purified via flash chromatography (10% ethyl acetate-hexanes) to
give 503 mg (44%) of recovered 23a and 558 mg (45%; 80% based
on recovered starting material) of 25a (single diastereomer) as a
yellow oil: IR (film) 1287, 1130 cm-1; 1H NMR (200 MHz) δ 7.63
(d, J ) 8.0 Hz, 2 H), 7.35-7.14 (m, 7 H), 5.63 (dt, J ) 16.9, 7.9
Hz, 1 H), 5.32 (dd, J ) 10.3, 1.8 Hz, 1 H), 5.03 (dd, J ) 16.9, 1.9
Hz, 1 H), 3.61 (d, J ) 13.0 Hz, 1 H), 3.40 (d, J ) 13.0 Hz, 1 H),
3.24-3.12 (m, 1 H), 3.00-2.73 (m, 2 H) 2.42 (s, 3 H), 2.36-2.18
(m, 1 H), 2.10-0.97 (m, 10 H); 13C NMR (50 MHz) δ 144.0, 138.8,
135.9, 132.5, 129.5, 129.2, 128.9, 128.2, 126.9, 118.8, 65.5, 61.8,
56.1, 44.5, 26.9, 26.3, 22.1, 21.5, 19.8, 19.7; mass spectrum, m/z
(%) 397 (M+, 3), 242 (100), 91 (55); HRMS calcd for C24H31NO2S,
397.2076; found, 397.2092.
Amine 11 (0.35 mmol) was dissolved in methanol (5 mL) and
cooled to -78 °C. After addition of acetylenic sulfone 2a (63 mg,
0.35 mmol), the solution was kept at -78 °C for 3 h and was then
stirred at room temperature for an additional 3 h. The solution was
concentrated and purified via flash chromatography (25% ethyl
acetate-hexanes) to afford 100 mg (64%) of 15 as a yellow oil:
1
IR (film) 1608, 1134 cm-1; H NMR (200 MHz) δ 7.71 (d, J )
6.8 Hz, 2 H), 7.48 (d, J ) 12.8 Hz, 1 H), 7.38- 7.10 (m, 7 H), 5.71
(dt, J ) 15.9, 6.8 Hz, 1 H), 5.42 (dd, J ) 15.9, 5.2 Hz, 1 H), 4.98
(d, J ) 12.8 Hz, 1 H), 4.72 (d, J ) 5.1 Hz, 1 H), 4.30 (s, 2 H),
3.30 (s, 6 H), 3.25-2.85 (m, 2 H), 2.40 (s, 3 H), 2.10-1.98 (m, 2
H), 1.68-1.15 (m, 4 H); 13C NMR (50 MHz) δ 149.9, 142.1, 134.3,
129.3, 128.8, 128.7, 127.9, 127.2, 127.1, 126.1, 103.0, 93.5, 59.3,
52.7, 48.7, 31.5, 28.0, 25.9, 21.4; mass spectrum, m/z (%) 411 (M+
- MeOH, <1), 256 (100), 91 (90); HRMS calcd for C24H29NO3S
(M+ - MeOH), 411.1868; found, 411.1886.
1-{N-Benzyl-N-[2-(1-methoxybut-3-enyl)]amino}-2-(p-toluene-
sulfonyl)ethene (16). Acetylenic sulfone 2a (48 mg, 0.26 mmol)
was added to a solution of vinylaziridine 1217 (42 mg, 0.26 mmol)
in methanol (5 mL) at 0 °C, the solution was warmed to room
temperature and stirring was continued for 12 h. The mixture was
concentrated and purified via flash chromatography (25% ethyl
acetate-hexanes), affording 85 mg (89%) of 16 as a light yellow
oil: IR (film) 1609, 1274, 1135 cm-1; 1H NMR (200 MHz) δ 7.71
(d, J ) 7.8 Hz, 2 H), 7.51 (d, J ) 12.8 Hz, 1 H), 7.38-7.12 (m,
7 H), 5.73-5.47 (m, 1 H), 5.33-5.20 (m, 2 H), 5.00 (d, J ) 12.8
Hz, 1 H), 4.40 (m, 2 H), 3.85-3.60 (m, 1 H), 3.35-2.95 (m, 2 H),
3.22 (s, 3 H), 2.41 (s, 3 H); 13C NMR (50 MHz) δ 150.7, 142.2,
142.0, 135.1, 129.3, 128.7, 127.7, 127.2, 126.1, 119.4, 94.0, 80.4,
60.3, 56.4, 21.4; mass spectrum, m/z (%) 371 (M+, 5), 300 (20),
216 (30), 91 (100); HRMS calcd for C21H25NO3S, 371.1555; found,
371.1531.
N-Benzyl-3-(p-toluenesulfonyl)-2-vinylazacyclodecane (25b). The
same procedure as for the preparation of 25a was followed, using
23b and affording 30% of recovered 23b and 64% (92% based on
recovered starting material) of 25b (3:1 mixture of two diastere-
omers) as a yellow oil: IR (film) 1282, 1139 cm-1; 1H NMR (200
MHz) major diastereomer δ 7.60 (d, J ) 8.2 Hz, 2 H), 7.37-7.16
(m, 7 H), 5.52 (dt, J ) 16.9, 9.5 Hz, 1 H), 5.31 (dd, J ) 10.3, 2.0
Hz, 1 H), 4.98 (dd, J ) 17.1, 1.9 Hz, 1 H), 3.72 (d, J ) 13.3 Hz,
1 H), 3.23 (d, J ) 13.3 Hz, 1 H); minor diastereomer δ 7.76 (d, J
) 8.0 Hz), 5.11 (dd, J ) 17.0, 2.1 Hz); 13C NMR (50 MHz) major
diastereomer δ 144.0, 138.7, 132.8, 129.4, 129.3, 129.2, 129.0,
128.2, 126.8, 119.2, 66.9, 60.3, 54.3, 47.8, 27.1, 27.0, 24.9, 24.1,
22.6, 21.5, 21.5; mass spectrum, m/z (%) 411 (M+, 3), 256 (90),
91 (100); HRMS calcd for C25H33NO2S, 411.2232; found, 411.2244.
N-Benzyl-2-vinylazacyclononane (26a). To a solution of sulfo-
nylazonane 25a (202 mg, 0.508 mmol) in saturated K2HPO4 in
methanol (15 mL) was added 10% Na/Hg (1.50 g). The mixture
was stirred at room temperature for 4 h, filtered through Celite,
concentrated, and purified via flash chromatography (hexanes to
5% ethyl acetate-hexanes) to afford 73 mg (59%) of 25a as a
1
yellow oil: IR (film) 1143, 1070, 983, 904 cm-1; H NMR (200
MHz) δ 7.44-7.15 (m, 5 H), 5.74 (m, 1 H), 5.15 (dd, J ) 10.4,
2.1 Hz, 1 H), 4.95 (dd, J ) 17.2, 2.1 Hz, 1 H), 3.70 (d, J ) 13.2
Hz, 1 H), 3.52 (d, J ) 13.2, 1 H), 3.10-2.78 (m, 2 H), 2.30-2.15
(m, 1 H), 1.90-1.10 (m, 12 H); 13C NMR (50 MHz) δ 140.7, 137.2,
4636 J. Org. Chem. Vol. 73, No. 12, 2008

Rearrangements of Allyl Amines and Cyclic R-Vinylamines
129.3, 128.0, 126.5, 115.8, 61.8, 57.6, 44.3, 28.6, 27.5, 27.2, 21.0,
20.3, 19.5; mass spectrum, m/z (%) 243 (M+, 15), 186 (64), 152
(65), 91 (100); HRMS calcd for C17H25N, 243.1987; found,
243.1983.
acetate-hexanes), affording 30 mg (85%) of 28a as a clear oil: 1H
NMR (200 MHz) δ 2.65 (t, J ) 5.2 Hz, 4 H), 1.7-1.2 (m, 20 H);
13C NMR (50 MHz) δ 47.9, 27.9, 26.5, 26.0, 25.4, 24.6; lit.22a1H
NMR (400 MHz, MeOH-d4) δ 2.64 (t, J ) 5.9 Hz, 4 H), 1.55 (m,
4 H), 1.39 (m, 16 H); 13C NMR (100 MHz, MeOH-d4) δ 48.0,
28.1, 27.3, 27.0, 26.5, 25.4.
N-Benzyl-2-vinylazacyclodecane (26b). The same procedure as
for the preparation of 26a was followed, using 25b and affording
56% of 26b as a yellow oil: IR (film) 1139, 1113, 1076, 1027,
Azacyclotetradecane (28b). Compound 27b was hydrogenated
as in the preparation of 28a, affording 100% of (E)-N-benzyl-3-
(p-chlorobenzenesulfonyl)-azacyclotetradec-2-ene as a clear oil: IR
1
996, 914 cm-1; H NMR (200 MHz) δ 7.44-7.15 (m, 5 H), 5.72
(ddd, J ) 17.1, 9.5, 7.7 Hz, 1 H), 5.15 (dd, J ) 10.4, 2.2 Hz, 1 H),
4.95 (dd, J ) 17.1, 2.2 Hz, 1 H), 3.81 (d, J ) 13.3 Hz, 1 H), 3.22
(d, J ) 13.3 Hz, 1 H), 2.90 (td, J ) 12.8, 4.1 Hz, 1 H), 2.37-2.26
(m, 2 H), 2.00-1.15 (m, 14 H); 13C NMR (50 MHz) δ 140.5, 137.0,
129.2, 128.0, 126.4, 116.0, 60.5, 54.9, 47.0, 30.1, 26.6, 26.5, 26.0,
24.9, 23.7, 22.8; mass spectrum, m/z (%) 257 (M+, 3), 166 (100),
91 (83); HRMS calcd for C18H27N, 257.2144; found, 257.2139.
N-Benzyl-3-(p-chlorobenzenesulfonyl)azacyclotrideca-2,5-di-
ene (27a). Acetylenic sulfone 2e (100 mg, 0.50 mmol) was added
to a solution of azacyclononane 26a (80 mg, 0.33 mmol) in
dichloromethane (5 mL) and stirred at room temperature for 24 h.
The mixture was concentrated and purified via flash chromatography
(10% ethyl acetate-hexanes), affording 105 mg (72%) of 27a (ca.
2.5:1 mixture of geometric isomers) as a yellow oil, which was
used directly in the next step.
1
(film) 1626, 1130 cm-1; H NMR (200 MHz) δ 7.67 (d, J ) 8.7
Hz, 2 H), 7.52 (s, 1 H), 7.39 (d, J ) 8.7 Hz, 2 H), 7.40-7.13 (m,
5 H), 4.42 (s, 2 H), 3.23 (t, J ) 6.4 Hz, 2 H), 2.21 (t, J ) 6.7 Hz,
2 H), 1.80-1.15 (m, 18 H); 13C NMR (50 MHz) δ 147.3, 142.0,
137.8, 137.1, 128.8, 128.7, 128.4, 127.8, 127.0, 104.1, 55.4, 53.4,
27.8, 27.2, 25.8, 25.7, 25.4, 25.1, 25.0, 24.3, 24.0, 23.5; mass
spectrum, m/z (%) 459 (M+, 5), 284 (98), 186 (40), 91 (100); HRMS
calcd for C26H34ClNO2S, 459.1999; found, 459.2019.
The above compound was reduced with sodium cyanoborohy-
dride and TFA by the same procedure as in the preparation of 28a,
affording 74% of N-benzyl-3-(p-chloro-benzenesulfonyl)azacy-
clotetradecane, isolated as clear oil: IR (film) 1583, 1304, 1148
1
cm-1; H NMR (200 MHz) δ 7.72 (d, J ) 8.7 Hz, 2 H), 7.51 (d,
J ) 8.9 Hz, 2 H), 7.30-7.05 (m, 5 H), 3.58 (d, J ) 13.3 Hz, 1 H),
3.24 (d, J ) 13.7 Hz, 1 H), 3.04 (m, 1 H), 2.80-2.40 (m, 3 H),
2.35-2.15 (m, 1 H), 2.05-1.10 (m, 20 H); 13C NMR (50 MHz) δ
140.1, 130.0, 129.3, 129.0, 128.1, 127.0, 62.7, 58.2, 54.1, 53.0,
26.6, 26.2, 26.0, 25.8, 25.5, 25.2, 24.7, 24.6, 24.1, 23.7; mass
spectrum, m/z (%) 461 (M+, 2), 370 (25) 286 (50), 91 (100). HRMS
calcd for C26H36ClNO2S, 461.2155; found 461.2134.
N-Benzyl-3-(4-chlorobenzenesulfonyl)azacyclotetradeca-2,5-di-
ene (27b). The same procedure as for the preparation of 27a was
followed, using 26b and affording 89% of 27b (ca. 1.5:1 mixture
of geometric isomers) as a yellow oil, which was used directly in
the next step.
Azacyclotridecane (28a). Palladium on charcoal (10%, 18 mg)
was added to a solution of azacyclotridecadiene 27a (105 mg, 0.236
mmol) in methanol (10 mL). The suspension was stirred under
hydrogen (1 atm.) overnight, filtered through Celite, concentrated,
and purified by flash chromatography (10% ethyl acetate-hexanes)
to afford 105 mg (100%) of (E)-N-benzyl-3-(p-chlorobenzenesulfo-
nyl)azacyclotridec-2-ene as a clear oil: IR (film) 1617, 1283, 1139,
1087 cm-1; 1H NMR (200 MHz) δ 7.67 (d, J ) 8.7 Hz, 2 H), 7.51
(s, 1 H), 7.39 (d, J ) 8.9 Hz, 2 H), 7.36-7.12 (m, 5 H), 4.44 (s,
2 H), 3.24 (t, J ) 6.9 Hz, 2 H), 2.28 (t, J ) 7.2 Hz, 2 H), 1.70-1.00
(m, 16 H); 13C NMR (50 MHz) δ 147.3, 141.9, 138.1, 137.4, 129.1,
129.0, 128.7, 128.0, 127.3, 105.5, 57.4, 52.1, 28.0, 27.4, 26.2, 26.1,
25.5, 25.3, 25.2, 24.4; mass spectrum, m/z (%) 445 (M+, 15), 270
(100) 172 (25), 91 (43); HRMS calcd for C25H32ClNO2S, 445.1842;
found, 445.1857.
The reduction of the above compound with sodium and liquid
ammonia was carried out by the same procedure as in the
1
preparation of 28a, affording 28b in 65% yield: H NMR (200
MHz) δ 2.68 (t, J ) 5.7 Hz, 4 H), 1.70-1.15 (m, 22 H); 13C NMR
(50 MHz) δ 45.9, 26.9, 25.9, 25.1, 24.3, 23.8, 23.2.
Motuporamine A (21). Azacyclotridecane (28a) was converted
into 29a by the procedure of Baldwin et al.23a in 83% yield; H
1
NMR (200 MHz) δ 7.35 (m, 10 H), 5.12 (s, 2 H), 5.09 (s, 2 H),
3.35-3.16 (m, 6 H), 2.88-2.45 (m, 6 H), 2.12-1.99 (m, 2 H),
1.77-1.26 (m, 22 H); 13C NMR (50 MHz) δ 156.3, 136.3, 128.5,
128.4, 128.1, 128.0, 67.3, 66.5, 59.0, 57.3, 44.8, 44.0, 37.8, 26.6,
25.6, 25.4, 25.1, 22.8, 19.9. Hydrogenolysis of bis(carbobenzyl-
oxy)motuporamine A (29a) afforded crude 21.25
Motuporamine B (22). Azacyclotetradecane (28b) was con-
verted into 29b by the procedure of Baldwin et al.23a in 77% yield;
1H NMR (200 MHz) δ 7.33 (m, 10 H), 5.12 (s, 2 H), 5.08 (s, 2 H),
3.34-3.16 (m, 6 H), 2.91-2.41 (m, 6 H), 2.14-1.96 (m, 2 H),
1.80-1.14 (m, 24 H); 13C NMR (50 MHz) δ 156.4, 136.4, 128.5,
128.4, 128.1, 128.0, 67.3, 66.5, 59.3, 57.0, 44.9, 43.9, 38.0, 29.6,
26.3, 26.1, 25.7, 23.6, 23.4, 19.2. Hydrogenolysis of bis(carboben-
zyloxy)motuporamine B (29b) afforded crude 22.25
Kinetic Determinations. NMR tubes were charged with 8b (20
mg, 0.093 mmol) and the respective acetylenic sulfones 2a-2f
(0.093 mmol) in a solution of tert-butyldimethylsilyl phenyl ether
(0.050 M, internal standard) in CDCl3 (1.00 mL). The reactions
were maintained at 21 °C and monitored by measuring the
disappearance of the diastereotopic benzylic methylene signal in
8b and the appearance of the methylene singlets in the correspond-
ing aza-Cope products. For plots of the results, see the Supporting
Information.
Trifluoroacetic acid (0.38 mL, 5.1 mmol) was added to a
suspension of the above product (220 mg, 0.493 mmol) and
NaCNBH3 (308 mg, 4.90 mmol) in dichloromethane (15 mL). The
mixture was stirred for 30 min at room temperature, refluxed for
30 min, cooled to room temperature, quenched with 10% KOH
solution, extracted with dichloromethane, dried, and concentrated
in vacuo. The crude amine was purified via flash chromatography
(10% ethyl acetate-hexanes) to afford 165 mg (75%) of N-benzyl-
3-(p-chlorobenzenesulfonyl)azacyclotridecane as a clear oil: IR
1
(film) 1317, 1139 cm-1; H NMR (200 MHz) δ 7.71 (d, J ) 8.5
Hz, 2 H), 7.53 (d, J ) 8.7 Hz, 2 H), 7.28-7.03 (m, 5 H), 3.55 (d,
J ) 13.0 Hz, 1 H), 3.26 (d, J ) 13.3 Hz, 1 H) 2.76 (dd, J ) 13.1,
2.3 Hz, 1 H), 2.60-2.22 (m, 4 H), 1.80-1.00 (m, 18 H); 13C NMR
(50 MHz) δ 140.1, 138.4, 136.8, 130.0, 129.3, 129.2, 128.1, 127.1,
63.0, 58.6, 55.4, 54.7, 27.0, 26.2, 26.1, 25.5, 25.4, 24.8, 24.1, 23.7,
23.2; mass spectrum, m/z (%) 447 (M+, 5), 356 (55) 272 (95), 91
(100); HRMS calcd for C25H34ClNO2S, 447.1999; found, 447.1979.
To a solution of the above product (87 mg, 0.19 mmol) in dry
THF (5 mL) at -78 °C was added liquid ammonia (5 mL), followed
by the addition of sodium (275 mg, 11.9 mmol). This mixture was
stirred for 30 min at -78 °C, ethanol was added (0.05 mL), and
the solution was stirred at -78 °C for a further 2 h. It was allowed
to warm to -30 °C and NH4Cl was added carefully. A saturated
NaHCO3 solution was added, the mixture was warmed to room
temperature, extracted with ethyl acetate, dried, concentrated, and
purified using flash chromatography (hexanes to 5% ethyl
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada for financial support.
Supporting Information Available: 1H and 13C NMR
spectra of new compounds, and kinetic plots for the reactions
of 8b with 2a-2f (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JO800600A
J. Org. Chem. Vol. 73, No. 12, 2008 4637