Expedient synthesis of fused azepine derivatives using a sequential rhodium(II)-catalyzed cyclopropanation/1-aza-Cope rearrangement of dienyltriazoles

Article abstract of DOI:10.1002/anie.201405356

A general method for the formation of fused dihydroazepine derivatives from 1-sulfonyl-1,2,3-triazoles bearing a tethered diene is reported. The process involves an intramolecular cyclopropanation of an α-imino rhodium(II) carbenoid, leading to a transien

Full text of DOI:10.1002/anie.201405356

Angewandte
Chemie
DOI: 10.1002/anie.201405356
Heterocycles
Expedient Synthesis of Fused Azepine Derivatives using a Sequential
Rhodium(II)-Catalyzed Cyclopropanation/1-Aza-Cope
Rearrangement of Dienyltriazoles**
Erica E. Schultz, Vincent N. G. Lindsay, and Richmond Sarpong*
Abstract: A general method for the formation of fused
dihydroazepine derivatives from 1-sulfonyl-1,2,3-triazoles
bearing a tethered diene is reported. The process involves an
intramolecular cyclopropanation of an a-imino rhodium(II)
carbenoid, leading to a transient 1-imino-2-vinylcyclopropane
intermediate which rapidly undergoes a 1-aza-Cope rearrange-
ment to generate fused dihydroazepine derivatives in moderate
to excellent yields. The reaction proceeds with similar effi-
ciency on gram scale. The use of catalyst-free conditions leads
to the formation of a novel [4.4.0] bicyclic heterocycle.
development of new stereoselective strategies to access
polycyclic, substituted azepines, and azepanes in a single
operation from readily available acyclic precursors highly
desirable. The [3,3] sigmatropic rearrangement of 1,2-divinyl-
cyclopropane derivatives is a well-established strategy to
access seven-membered ring compounds in a stereospecific
manner.[3] The analogous transformation where one of the
=
vinyl groups is replaced by a C N group is known to lead to
azepine derivatives through a similar mechanism. While 2-
aza-Cope rearrangements of this type are quite common for
2-azepinone synthesis using an isocyanate intermediate
(formed in situ),[4] examples of the corresponding 1-aza-
Cope rearrangement, which directly leads to 2,5-dihydro[1-
H]azepines, remain scarce.[5] Indeed, the preparation of the
cis-1-imino-2-vinylcyclopropanes (IVCs) required for such
a rearrangement to occur is hampered by the multiple steps
needed for their synthesis, thus discouraging the use of this
approach for the formation of azepine derivatives.[5b,6]
A
zepine and azepane derivatives are found in numerous
bioactive natural products and other compounds of pharma-
ceutical interest (Figure 1).[1,2] While a vast array of methods
have been developed through the years for their synthesis,[1]
only a few approaches exist for the preparation of their ring-
fused analogues.[1b] The ubiquity of these units in a variety of
biologically relevant compounds, such as alkaloids, makes the
In recent years, 1-sulfonyl-1,2,3-triazoles have emerged as
stable and readily available azavinylcarbene equivalents for
a variety of useful transformations.[7,8] We have recently
shown that these carbenes can be utilized in the synthesis of
3,4-fused pyrroles upon reaction with a tethered allene
functionality, through
a Rh/TMM intermediate (Sche-
me 1a).[9] To access fused azepine derivatives through an
analogous approach, we envisioned the reaction of an a-imino
metallocarbene with a tethered E,E-1,3-diene would instead
generate a cis-1-imino-2-vinylcyclopropane (IVC), which is
ideally substituted for a subsequent 1-aza-Cope rearrange-
ment (Scheme 1b). Herein, we report our studies on the
synthesis of 3,4-fused dihydroazepines, which is complemen-
tary to a recent report by Tang et al. that appeared during the
completion of this work.[10] In their report, Tang et al. achieve
an elegant divergent synthesis of nitrogen heterocycles by
Figure 1. Natural products containing fused azepine derivatives.
[*] E. E. Schultz,[+] V. N. G. Lindsay,[+] Prof. R. Sarpong
Department of Chemistry, University of California, Berkeley
Berkeley, CA 94720 (USA)
E-mail: rsarpong@berkeley.edu
[+] These authors contributed equally to this work.
[**] This work was supported by the NSF (CAREER 0643264 to R.S.) and
a Research Scholar Grant from the American Cancer Society (RSG-
09-017-01-CDD to R.S.). R.S. is a Camille Dreyfus Teacher Scholar.
We are grateful to the NSF for a graduate fellowship to E.E.S., to the
FRQNT (B3) for a postdoctoral scholarship to V.N.G.L., and to
Abbott, Eli Lilly, and Roche for financial support. We thank A.
DiPasquale for solving the crystal structures of 2a and 4 (displayed
with CYLView), supported by NIH Shared Instrumentation Grant
(S10-RR027172).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201405356.
Scheme 1. Synthesis of fused heterocycles using azavinylcarbene equiv-
alents. TMM=trimethylenemethane, Ts=4-toluenesulfonyl.
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intermolecular reaction of triazoles with 1,3-dienes to provide
access to azepine or pyrroline derivatives, with the pyrroline
products being favored over extended reaction times.
Herein, we report a general method for the expedient
synthesis of fused azepine derivatives as the sole products
from dienyltriazoles. Our mechanistic studies strongly suggest
that the reaction proceeds by a sequential intramolecular
rhodium(II)-catalyzed cyclopropanation/1-aza-Cope rear-
rangement. The stereospecific nature of each step in this
transformation is critical and allows a highly diastereoselec-
tive process, leading to fused 2,5-dihydro[1H]azepines in good
to excellent yields.
substituted substrates, including phenyl, electron-rich and
electron-poor dienyls are tolerated (entries 2–4). In addition,
internal substitution of the diene portion is compatible with
the transformation, albeit proceeding in slightly lower yield to
the dihydroazepine (entry 2 versus 5). Furthermore, dienyl-
triazole substrates bearing N-tosylamine or diester groups
Table 2: Substrate scope of the intramolecular [Rh2(Adc)4]-catalyzed
dihydroazepine formation.[a]
Applying the reaction conditions we previously developed
for the formation of 3,4-fused pyrroles from allenyltriazoles to
the dienyltriazole 1a (Table 1),[9a] we were delighted to
observe the formation of the dihydroazepine 2a in 54%
yield (entry 1). A major byproduct observed in the reaction
was the a,b-unsaturated N-tosylimine 3, resulting from
a competing 1,2-hydride shift from the rhodium(II) carbenoid
intermediate.[11] To combat this challenge, we investigated
a variety of more sterically encumbered rhodium(II) com-
plexes (entries 3–6).[12] Gratifyingly, we found that [Rh2-
(Adc)4] affords the desired dihydroazepine in increased yield
(entry 6). Varying the nature of the solvent and the concen-
tration of the reactants did not significantly improve the
yield.[13] Decreasing the temperature to 608C and increasing
the reaction time to 16 hours afforded 2a in 74% isolated
yield (entry 7), along with a minimal amount of 3.
Entry
1
Substrate
Product
t [h]
Yield [%][b]
16
74
2
3
4
5
6
7
0.5
0.5
16
92
61
69
63
72
72
By using the optimized reaction conditions, a range of
dienyltriazole substrates is transformed into the correspond-
ing 3,4-fused dihydroazepines (Table 2). A variety of aryl-
Table 1: Catalyst optimization for the intramolecular rhodium(II)-cata-
lyzed dihydroazepine formation.[a]
16
0.5
0.5
Entry
[Rh2L4]
T [8C]
t
2a
Yield [%][b,c]
140[d]
140[d]
140[d]
140[d]
140[d]
140[d]
60
0.25 h
0.25 h
0.25 h
0.25 h
0.25 h
0.25 h
16 h
54 (34)
47 (48)
18 (70)
58 (18)
66 (33)
68 (17)
74 (14)
8
9
0.5
0.5
45 (60)[c]
1
2
3
4
5
6
7
[Rh2(Ooct)4]
[Rh2(OAc)4]
[Rh2(tpa)4]
[Rh2(OPiv)4]
[Rh2(esp)2]
[Rh2(Adc)4]
[Rh2(Adc)4]
92
[a] Only one diastereomer of the dihydroazepine product 2a was
observed by 1H NMR spectroscopy in all cases. [b] Yield of the isolated
product. [c] Yield of imine 3, as determined by NMR spectroscopy, is
given within parentheses. [d] Reaction was performed in a microwave
apparatus. Adc=1-adamantanecarboxylate, esp=a,a,a’,a’-tetramethyl-
1,3-benzenedipropionic acid, Ooct=octanoate, Piv=pivaloyl.
[a] Only one diastereomer of the dihydroazepine product was observed
by 1H NMR spectroscopy in all cases. [b] Yield of isolated product.
[c] Yield within parentheses is that obtained when [Rh2(Ooct)4] was used
at 1408C in the microwave for 0.25 h. PMP=4-MeOC6H4, PNP=
4-O2NC6H4, E=CO2Me.
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instead of the ether tether furnish the corresponding 3,4-fused
dihydroazepines in moderate to good yields (entries 6–8). In
the case of 1h, the observed yield of the corresponding
product (2h) was significantly lower as a result of side-
reactions, presumably arising from intramolecular attack of
the proximal ester groups on the rhodium carbene inter-
mediate. Importantly, the all-carbon tethered dihydroazepine
2i, corresponding to a portion of tetrapetalone A (Figure 1),
could be accessed in excellent yield using the optimized
reaction conditions (entry 9). In all cases, only one diastereo-
mer of the dihydroazepine product is observed. Notably,
dienyltriazole substrates which would yield a 6-7-fused
dihydroazepine product afford only the corresponding 1,2-
hydride-shift product. It is noteworthy that the 1-aza-Cope
rearrangement was found to proceed significantly more
slowly for substrates 1d and 1e, where the IVC intermediates
were observed by NMR spectroscopy after 0.5 hours, and
complete conversion was only achieved after 16 hours.
Scheme 3. Different possible mechanistic pathways for the dihydroaze-
pine formation.
Finally, the reaction is amenable to a gram-scale synthesis
of dihydroazepines, as exemplified with 2a (Scheme 2a).
Interestingly, we also found that in the absence of a rho-
either Path B or C could give rise to a mixture of both isomers.
Notably, the single diastereomer 2a obtained from the
reaction, as determined by X-ray analysis, is consistent with
the [2+1]/[3,3] sequence depicted in Path A (Scheme 2a).
To obtain further insight, several other triazoles were
synthesized and evaluated (Scheme 4). To gain support for
the intermediacy of iminocyclopropanes, the alkenyltriazole
1j (Scheme 4a), which lacks the distal alkenyl group required
for the subsequent 1-aza-Cope to occur, was submitted to the
standard reaction conditions. The iminocyclopropane 5a was
obtained as a single diastereomer in 66% yield (determined
by NMR spectroscopy). Although 1-sulfonyl-1,2,3-triazoles
are known to lead to iminocyclopropanes by intermolecular
cyclopropanation with alkenes,[7,8a,b] to our knowledge, the
analogous intramolecular cyclopropanation has never been
reported. Thus the viability and stereoselectivity of such
Scheme 2. Gram-scale synthesis of the dihydroazepine 2a and metal-
free access to [4.4.0] bicycle 4.
dium(II) catalyst under more forcing conditions, a distinct
heterocyclic product (4) was formed in 50% yield, presum-
ably arising from a ketenimine intermediate (Scheme 2b).[14]
For both types of products (that is, 2a and 4), the structure
and relative configuration was confirmed by X-ray analysis.[15]
The rhodium(II)-catalyzed dihydroazepine formation
can, in principle, occur through three distinct mechanistic
pathways (Scheme 3). First, the azavinyl-substituted rhodium
carbenoid species formed by reaction of the dienyltriazole
with the rhodium catalyst could undergo a [2+1] cyclo-
addition with the proximal alkenyl group to generate a cis-
IVC, which could undergo a [3,3] sigmatropic rearrangement
to directly afford the dihydroazepine product (Path A).
Alternatively, the IVC intermediate could undergo ring-
opening to a zwitterionic intermediate, thus generating an
allyl cation capable of ring-closure by an intramolecular
N attack of the azanide thus formed on the distal alkenyl
moiety (Path B). Similarly, the rhodium carbenoid which is
formed initially could be attacked by the dienyl moiety to
generate a rhodium-bound zwitterion, which is able to cyclize
by an analogous mechanism (Path C). While the stereospe-
cificity of Path A should lead to a single diastereomer of the
product bearing the predicted stereochemistry as shown,
Scheme 4. Experimental mechanistic insights: [3,3] sigmatropic rear-
rangement versus zwitterionic pathways.
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a mechanistic step is confirmed by this observation. The
sterically encumbered dienyltriazoles 1k and 1l (Scheme 4b)
led to the formation of IVC intermediates (5b and 5c,
respectively), which do not undergo the subsequent 1-aza-
Cope rearrangement. This lack of reactivity is likely due to an
unfavorable interaction with the cis-R group in the transition
state of the [3,3] rearrangement, significantly slowing the rate
of this pathway.[16,17] The fact that none of the dihydroazepine
was observed in this particular case strongly suggests that
a concerted mechanism is operative for the rearrangement, as
the increased flexibility of a ring-opened zwitterionic inter-
mediate (as shown in Path B or C) should still allow the
cyclization to occur. Notably, the formation of such zwitter-
ionic intermediates should not be hampered by the steric
hinderance of the distal alkenyl moiety in either 1k or 1l.
Possibly as a result of a similar steric effect, it is noteworthy
that 1,1-disubstituted dienes, which would generate a quater-
nary center in the product, only reacted sluggishly. Finally, the
Z,E-dienyltriazole 1m (Scheme 4c), which leads to a trans-
IVC (5d), was also found to be unreactive toward dihydro-
azepine formation. This observation can be attributed to the
inability of such an intermediate to engage in a concerted 1-
aza-Cope rearrangement. The corresponding zwitterionic
intermediate formed from 1m should be identical to the
case of the E,E-dienyltriazole 1b, which in contrast to 1m,
leads to dihydroazepine formation in excellent yield in only
0.5 hours (Table 2, entry 2). These results strongly support
a sequential intramolecular rhodium(II)-catalyzed cyclopro-
panation/1-aza-Cope rearrangement as the operative path-
way for dihydroazepine formation (Scheme 3, Path A).
Moreover, if a zwitterionic intermediate is involved in the
process, the formation of the corresponding five-membered
heterocycle (pyrroline) would be expected to be competitive,
as the generation of five-membered ring compounds from this
type of zwitterionic intermediate is typically a fast proc-
ess.[3f,8g,10] Notably, this type of product was not observed in
any case throughout this study, again lending support to
Path A.
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In summary, a general approach for the synthesis of fused
dihydroazepines from dienyltriazoles is reported. A range of
substrates have been found to participate in the transforma-
tion, and several mechanistic investigations strongly support
a sequential intramolecular rhodium(II)-catalyzed cyclopro-
panation/1-aza-Cope rearrangement as the operative mech-
anistic pathway. The reaction can be scaled with similar
efficiency, and the use of catalyst-free conditions provides
access to a novel [4.4.0] bicyclic heterocycle. Given the
ubiquity of these scaffolds in biologically relevant com-
pounds, this work should prove valuable for the synthesis of
new and useful fused azepine-based building blocks.
Received: May 16, 2014
Published online: && &&, &&&&
Keywords: azavinylcarbene · dihydroazepine · heterocycles ·
[9] a) E. E. Schultz, R. Sarpong, J. Am. Chem. Soc. 2013, 135, 4696 –
4699; b) For a similar methodology using alkynes instead of
.
rearrangements · rhodium
4
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Chemie
allenes, see: Y. Shi, V. Gevorgyan, Org. Lett. 2013, 15, 5394 –
5396; c) For an intermolecular version of this reaction, see: B.
Chattopadhyay, V. Gevorgyan, Org. Lett. 2011, 13, 3746 – 3749;
d) T. Miura, K. Hiraga, T. Biyajima, T. Nakamuro, M. Mur-
akami, Org. Lett. 2013, 15, 3298 – 3301.
22 – 23; b) P. Panne, A. DeAngelis, J. M. Fox, Org. Lett. 2008, 10,
2987 – 2989.
[13] See the Supporting Information for details.
[14] E. J. Yoo, S. Chang, Curr. Org. Chem. 2009, 13, 1766 – 1776.
[15] CCDC 998199 (2a) and CCDC 998200 (4) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[16] Similar substitution effects have recently been demonstrated to
significantly slow down the divinylcyclopropane rearrangement
with various derivatives, by impeding the adoption of the
requisite boat conformation needed for the [3,3] sigmatropic
rearrangement to take place. J. D. Osler, W. P. Unsworth, R. J. K.
Taylor, Org. Biomol. Chem. 2013, 11, 7587.
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5666.
[11] Such a 1,2-hydride shift has been shown to be a significant side-
reaction for other a-alkyl azavinyl-substituted rhodium carbe-
noids. For example, see Refs. [8c and 8e].
[12] Steric interactions between the ligands on RhII and the metal
carbenoid substituents have been hypothesized to favor cyclo-
propanation over 1,2-hydride migration for intermolecular
reactions: a) P. Panne, J. M. Fox, J. Am. Chem. Soc. 2007, 129,
[17] For a related study, see: J. T. Su, R. Sarpong, B. M. Stoltz, W. A.
Goddard, J. Am. Chem. Soc. 2003, 125, 24 – 25.
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Communications
Heterocycles
E. E. Schultz, V. N. G. Lindsay,
R. Sarpong*
&&&& — &&&&
Expedient Synthesis of Fused Azepine
Derivatives using a Sequential
Rhodium(II)-Catalyzed
Cyclopropanation/1-Aza-Cope
Rearrangement of Dienyltriazoles
A general method for the formation of
fused dihydroazepines from 1-sulfonyl-
1,2,3-triazoles bearing a tethered diene is
reported. The process involves an intra-
molecular cyclopropanation of an a-
imino rhodium(II) carbenoid, leading to
a transient 1-imino-2-vinylcyclopropane
intermediate which rapidly undergoes a 1-
aza-Cope rearrangement to generate the
products in moderate to excellent yields.
Ts =4-toluenesulfonyl.
6
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