Copper-catalyzed cycloisomerization of unactivated allene-tethered O-propargyl oximes: A domino reaction sequence toward the synthesis of hexahydropyrrolo[3,4- b]azepin-5(4 H)-ones

Article abstract of DOI:10.1021/acs.orglett.1c00837

A novel copper-catalyzed cycloisomerization of unactivated allene-tethered O-propargyl oximes has been developed for the synthesis of hexahydropyrrolo[3,4-b]azepin-5(4H)-ones. This one-pot domino reaction proceeds via a [2,3]-sigmatropic rearrangement, a

Full text of DOI:10.1021/acs.orglett.1c00837

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Letter
Copper-Catalyzed Cycloisomerization of Unactivated Allene-
Tethered O‑Propargyl Oximes: A Domino Reaction Sequence toward
the Synthesis of Hexahydropyrrolo[3,4‑b]azepin-5(4H)‑ones
Ali Nikbakht, Kamran Amiri, Hormoz Khosravi, Yirong Zhou, Saeed Balalaie,* and Bernhard Breit*
Cite This: Org. Lett. 2021, 23, 3343−3348
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ABSTRACT: A novel copper-catalyzed cycloisomerization of
unactivated allene-tethered O-propargyl oximes has been devel-
oped for the synthesis of hexahydropyrrolo[3,4-b]azepin-5(4H)-
ones. This one-pot domino reaction proceeds via a [2,3]-
sigmatropic rearrangement, a [3 + 2] cycloaddition, and another
[3,3]-sigmatropic rearrangement. The methodology offers a
practical and straightforward route for the rapid assembly of
both ring components of the fused bicyclic motifs from acyclic
precursors by simultaneously forming four new bonds (a CO, a
CN, and two C−C bonds) in a single step.
zepine and azepane derivatives are important classes of N-
carbon atoms, mainly carbocyclic compounds are obtained. On
the contrary, the cycloisomerization of various unsaturated
compounds bearing an oxime moiety can be harnessed as a
valuable synthetic building block for the synthesis of
heterocyclic frameworks.6 In this context, recently, there has
been growing interest in O-propargyl oximes as alternative
building blocks in cycloisomerization reactions, which provide
efficient protocols for the synthesis of various heterocycles due
to their ability to undergo C−O, CN, and N−O bond-
cleavage reactions.7
A
heterocycles found in a number of biologically important
molecules and numerous natural products (Figure 1).1,2
Consequently, intense interest has been directed toward the
cycloisomerization reactions of structurally different O-
propargyl oximes having different oxime groups. The nature
of these domino skeletal rearrangement reactions and the
possible reaction products depends on the nature of the
unsaturated compounds installed on the oxime moiety.
To the best of our knowledge, all previously reported
examples of the intramolecular cycloisomerization of O-
propargyl oximes lead to the formation of single-ring
heterocycles. For example, the reaction of O-propargyl oximes
(I) possessing aryl groups in the presence of catalytic amounts
of CuBr affords the corresponding azete oxides (II) through a
domino [2,3]-rearrangement and a 4π-electrocyclization path-
way.8 Employing O-propargyl oximes having alkene moieties in
the copper-catalyzed cascade reactions gives rise to the
Figure 1. Examples of biologically active azepines.
Therefore, in recent years, various synthetic approaches to
these valuable heterocyclic compounds have been introduced;3
however, there are only a few approaches toward their ring-
fused analogues, and their synthesis still remains a challenge.4
Consequently, developing new synthetic strategies that enable
the one-step assembly of their ring-fused analogues from
readily available acyclic precursors is highly desirable.
In this regard, the transition-metal-catalyzed cycloisomeriza-
tion of 1,n-enynes, 1,n-dienes and -diynes, and 1,n-allenynes
and -allenenes has emerged as a powerful synthetic approach
because it facilitates the rapid assembly of different types of
complex cyclic compounds.5 Nevertheless, because the reactive
sites of the intermediates in these transformations involve only
Received: March 10, 2021
Published: April 12, 2021
https://doi.org/10.1021/acs.orglett.1c00837
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3343−3348
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a
corresponding multisubstituted pyridines (III) via a cascade,
[2,3]-rearrangement and 6π-electrocyclization.9 The rhodium-
catalyzed cycloisomerization of O-propargyl oximes derived
from cyclopropane carbaldehyde and cyclobutyl carbaldehyde
furnishes the corresponding derivatives of azepine oxide (IV)
and azocine oxide (V), respectively.10,11 These reactions
proceed through [2,3]-rearrangement and ring expansion of
the strained cyclopropyl and cyclobutyl substituents (Scheme
1a).
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
CuCl
AgOTf
PPh3AuCl
AuCl3
In(OTf)3
CuBr
[Cu(COD)Cl]2
Cu(CH3CN)4BF4
CuBr
CuBr
CuBr
solvent
temp (°C) yield (%)
Z/E
1
2
3
4
5
6
7
8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
MeCN
THF
100
100
100
100
100
100
100
100
80
120
100
100
100
100
44
78:22
Scheme 1. (a) Domino Skeletal Rearrangement Reactions of
O-Propargylic Oximes and (b) Cycloisomerization of
Unactivated Allene-Tethered O-Propargyl Oximes
12
69
64
55
40
66
22
35
40
n.r.
79:21
79:21
78:22
79:21
81:19
86:14
80:20
80:20
9
10
11
12
13
14
CuBr
CuBr
DMF
toluene
a
Reaction conditions: 1a (0.2 mmol), solvent [0.1 M], catalyst (5 mol
b
%). Isolated yields.
Moreover, the effect of the temperature was also investigated.
By lowering the temperature from 100 to 80 °C, the yield was
decreased to 40% (Table 1, entry 9). When the reaction
temperature was increased from 100 to 120 °C, no
improvement in yield was observed (Table 1, entry 10).
The starting material remained untouched in the absence of
the catalyst (Table 1, entry 14). Interestingly, using the Z
isomer of the starting material instead of the E isomer under
the optimized reaction conditions (5 mol % CuBr in toluene at
100 °C) lead to the desired product in an almost similar yield
with similar E/Z ratios (66% yield, 78:22 E/Z). Hence,
subjecting a mixture of Z/E isomers of the starting material to
the reaction conditions yielded the same result (66% yield,
79:21 Z/E).
With optimal reaction conditions in hand, we proceeded to
investigate the substrate scope of this domino cycloisomeriza-
tion process using various O-propargyl allenyloximes. As
illustrated in Scheme 2, O-propargyl allenyloximes with either
electron-poor or electron-rich aryl substituents at the
propargylic position lead to the desired product in good to
high yields (Scheme 2, 2a−2i), and both aromatic and
aliphatic substituents at the alkyne terminus were tolerated
(Scheme 2, 2k and 2l). Aliphatic substituents at the
propargylic position afforded the corresponding product, albeit
in lower yields (Scheme 2, 2m).
On the basis of our recent work on the rhodium-catalyzed
cycloisomerization of 1,6-allenenes,12 we envisioned that O-
propargyl oximes having an allene moiety would be interesting
substrates in cycloisomerization reactions to construct
interesting structurally complex heterocycles. Herein we report
the copper-catalyzed cycloisomerization of new, well-designed
O-propargylic oximes 1 having an allene moiety, which
provides easy access to fused, bicyclic hexahydropyrrolo[3,4-
b]azepin-5(4H)-one scaffolds (Scheme 1b).
We commenced our studies with (E)-O-propargyl allenylox-
ime E-1a as the model substrate. Subjecting the substrate E-1a
to 5 mol % of CuCl in toluene at 100 °C for 12 h furnished the
hexahydropyrrolo[3,4-b]azepin-5(4H)-one product 2a as a
mixture of Z and E configurations of the exocyclic double bond
of the product 2a in a 78:22 (Z/E) ratio in 44% yield (entry
1). The structure of the bicyclic compound was unambiguously
determined by NMR measurements and X-ray crystallographic
analysis.
Optimization of the reaction conditions for the formation of
2a was achieved by examining the effects of different catalysts
and solvents (Table 1). Control experiments mediated by
AgOTf, Ph3PAuCl, AuCl3, and In(OTf)3 as catalysts were
found to lead to a mixture of unknown decomposition
products along with 2a in 12% yield in the case of the latter
(Table 1, entries 2−5). Using other Cu-based catalysts such as
CuBr, [Cu(COD)Cl]2, and Cu(CH3CN)4BF4 revealed that
CuBr is the best catalyst for the domino process, which gave
access to the desired product in 69% yield with a E/Z ratio of
79:21 (Table 1, entries 6−8). Further screening of various
solvents revealed that the reaction proceeds best in toluene.
On the basis of the previously described results, our
mechanistic hypothesis is described as shown in Figure 2b.
First, the π-activation of the alkyne moiety of the O-propargylic
oximes 1 by CuBr leads to the formation of N-allenyl nitrones
E-3 and Z-3 via a well-known [2,3]-sigmatropic rearrangement.
These two isomers are in equilibrium with each other under
the reaction conditions. Next, the [3 + 2] dipolar cycloaddition
(1,3-DC) of the generated Z,E-nitrone 3 with the allenyl
moiety leads to methylene-N-allenylisoxazolidine Int.A. To
gain further mechanism insight into this 1,3-DC reaction as the
key step that has a main role in the diastereoselectivity of the
reaction, density functional theory (DFT) calculations were
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Scheme 2. Exploration of Substrate Scope
a
Ellipsoid probability level of the ORTEP diagram is 50%.
carried out at the B3LYP/6-311++G(d,p)-PCM(toluene)//
B3LYP/6-31G(d,p) level of theory using the Gaussian 09
package.13,14
A mesyl group was used as a model for the tosyl group in
intermediate 3 (Figure 2). The relative Gibbs free energy of
eight possible transition states (TSs) of the DC reaction
showed that the Z-3 isomer is more reactive than the E-3
isomer, and this intramolecular DC primarily proceeds in an
exo manner (Figure 2a). The Gibbs free-energy difference
between TS-Cis-ZA and TS-Cis-ZB (0.54 kcal·mol−1) well
illustrates the ratio of stereoisomers obtained from the
reaction. (The calculated Z/E based on Boltzmann popula-
tions is 71:29.)
Subsequently, the calculations suggest a unique concerted
[3,3]-sigmatropic rearrangement that leads to the selective
formation of cis-Z-2 and cis-E-2 (kinetic products)15 from
Int.A1 and Int.A2, respectively (Figure 3, Figure S1, and
Scheme 3.) The energy barrier of this [3,3]-sigmatropic
Figure 2. (a) Proposed reaction mechanism. (b) Optimized
transition-state structures of the DC reaction. The relative Gibbs
free energies at the B3LYP/6-311++G(d,p)-PCM(toluene)//B3LYP/
6-31G(d,p) level of theory are given in parentheses (in kcal/mol).
rearrangement (12.7 kcal/mol) is lower than that of the prior
1,3-DC reaction (22.2 kcal/mol). Finally, the cis-fused kinetic
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Letter
AUTHOR INFORMATION
Corresponding Authors
■
Saeed Balalaie − Peptide Chemistry Research Center, K. N.
Toosi University of Technology, Tehran 15875-4416, Iran;
Medical Biology Research Center, Kermanshah University of
Medical Sciences, Kermanshah 6714415185, Iran;
orcid.org/0000-0002-5764-0442; Email: Balalaie@
kntu.ac.ir
Bernhard Breit − Institut fur Organische Chemie, Albert-
Ludwigs-Universitat Freiburg, 79104 Freiburg im Breisgau,
Germany; orcid.org/0000-0002-2514-3898;
Email: bernhard.breit@Chemie.uni-freiburg.de
Figure 3. Potential energy surface (PES) for the formation of trans-Z-
2 as the major isomer. All energies are in kcal/mol
Authors
Ali Nikbakht − Institut fur Organische Chemie, Albert-
Ludwigs-Universitat Freiburg, 79104 Freiburg im Breisgau,
Germany; Peptide Chemistry Research Center, K. N. Toosi
University of Technology, Tehran 15875-4416, Iran
Kamran Amiri − Institut fur Organische Chemie, Albert-
Ludwigs-Universitat Freiburg, 79104 Freiburg im Breisgau,
Germany; Peptide Chemistry Research Center, K. N. Toosi
University of Technology, Tehran 15875-4416, Iran;
orcid.org/0000-0001-5455-4832
Scheme 3. Cycloisomerization of 1n under the Optimized
Reaction Condition
Hormoz Khosravi − Institut fur Organische Chemie, Albert-
Ludwigs-Universitat Freiburg, 79104 Freiburg im Breisgau,
Germany; Peptide Chemistry Research Center, K. N. Toosi
University of Technology, Tehran 15875-4416, Iran;
orcid.org/0000-0002-6588-448X
Yirong Zhou − Institut fur Organische Chemie, Albert-
Ludwigs-Universitat Freiburg, 79104 Freiburg im Breisgau,
Germany
products tautomerize to the thermodynamically more stable
trans-E-2 and trans-Z-2.
In summary, we have developed a novel method for the
synthesis of a broad range of hexahydropyrrolo[3,4-b]azepin-
5(4H)-ones via copper-catalyzed intermolecular cycloisomeri-
zation. Remarkably, this reaction allows the construction of
one CO, one CN, and two C−C bonds by the cleavage of
one C−O, one N−O, and one CN bond in a single
synthetic operation via a [2,3]-sigmatropic rearrangement/[3 +
2] cycloaddition/[3,3]-sigmatropic rearrangement sequence of
unactivated allene-tethered O-propargyl oximes. This method-
ology is distinguished by a broad scope, a high yield, low
catalyst loadings, and a mild, operationally simple strategy.
Reaction selectivity is supported by DFT calculations involving
the sequence of a 1,3-dipolar cycloaddition, a novel Claisen-
type rearrangement, and a keto−enol tautomerization. Hence,
this new intramolecular cyclization has the potential to be used
in pharmaceutical exploitation and the total synthesis of
natural products containing azepin motifs.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00837
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for a fellowship from the Alexander von
Humboldt Foundation for the Research Group Linkage
Program financial support. We thank Dr. Daniel Kratzert for
the X-ray crystal structure analysis (Institut fur anorganische
̈
Chemie, Albert-Ludwigs-Universitat Freiburg).
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General experimental procedures, computational details,
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and H NMR, 13C NMR, and HR-MS spectra of all
compounds (PDF)
Accession Codes
CCDC 1810670 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
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data_request@ccdc.cam.ac.uk, or by contacting The Cam-
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