Copper and Rhodium Relay Catalysis for Selective Access to cis-2,3-Dihydroazepines

Article abstract of DOI:10.1021/acs.orglett.1c02262

A new catalytic protocol to access synthetically challenging cis-2,3-dihydroazepines is reported. The reaction starts with readily available dienals, alkynes, and sulfonyl azides as the substrates and employs copper and rhodium as relay catalysts. Key steps include a copper-catalyzed reaction between an alkyne and a sulfonyl azide to form a triazole intermediate. The subsequent activation of this triazole intermediate by a rhodium catalyst, followed by a reaction with the dienal substrate, eventually leads to the dihydroazepine product. The regio- and stereochemistries of the products are believed to be controlled through a stereospecific conrotatory 8π-electrocyclization process against a possible competing 6π-electrocyclization process.

Full text of DOI:10.1021/acs.orglett.1c02262

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Letter
Copper and Rhodium Relay Catalysis for Selective Access to cis-2,3-
Dihydroazepines
You Li,‡ Han Luo,‡ Zongyuan Tang, Yingzi Li, Luan Du, Xiaolan Xin, Shanshan Li, and Baosheng Li*
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ABSTRACT: A new catalytic protocol to access synthetically
challenging cis-2,3-dihydroazepines is reported. The reaction starts
with readily available dienals, alkynes, and sulfonyl azides as the
substrates and employs copper and rhodium as relay catalysts. Key
steps include a copper-catalyzed reaction between an alkyne and a
sulfonyl azide to form a triazole intermediate. The subsequent activation of this triazole intermediate by a rhodium catalyst, followed
by a reaction with the dienal substrate, eventually leads to the dihydroazepine product. The regio- and stereochemistries of the
products are believed to be controlled through a stereospecific conrotatory 8π-electrocyclization process against a possible
competing 6π-electrocyclization process.
itrogen-containing heterocycles are common scaffolds in
when thermodynamically unfavorable isomers are the desired
products.
N
numerous functional molecules.1 In particular, the
azepine derivatives, such as dihydroazepines, are important
core structures that are found in natural products and
pharmaceuticals (Figure 1a).2 The preparations of these
As convenient α-imino diazo precursors, N-sulfonyl-1,2,3-
triazoles4 offer great opportunities for the construction of
nitrogen-containing heterocycles.5 Recently, Fokin6a and
Murakami6b reported two compelling cycloaddition reactions
that form five-membered oxazolines and pyrroles using
triazoles as α-imino carbene precursors, respectively. We
envisioned that the three-component cascade reaction of a di-
or trienal (a), an alkyne (b), and a sulfonyl azide (c) would
provide quick access to cis-substituted 2,3-dihydroazepines in
the presence of Cu or Rh (Figure 1b). However, it has been
published that metal carbene precursors reacted with dienes to
yield azepine structural units.7 Our method can provide an
expeditious path for the divergent synthesis of cis-2,3-
dihydroazepines. One potential challenge in achieving our
proposed reaction is controlling the diastereoselectivity to
selectively obtain trans- or cis-substituted 2,3-dihydroazepine
products. Another challenge involves regioselectivity (β vs δ)
issues that lead to the formation of undesired five-membered
ring products, especially when enals devoid of substituents at
their β-carbon atoms are employed.
The design of our reaction is further elaborated in Figure 1c.
Initially, the copper-catalyzed reaction of a sulfonyl azide and
an alkyne generates the N-sulfonyl-1,2,3-triazole I.8 The
triazole then serves as an α-imino diazo precursor to provide
a metal-stabilized carbenoid under the catalysis of Rh(II).9 The
Figure 1. Representative natural products and our proposal strategy.
azepine derivatives are significantly more challenging than
those of their five- or six-membered analogs. Indeed, efficient
routes to the synthesis of nitrogen-containing heterocycles
with medium-sized rings are not particularly common.3 In
addition, the stereoselectivities of the substituents are difficult
to control due to medium-sized compounds being more
flexible than their five- or six-membered analogs, especially
Received: July 7, 2021
https://doi.org/10.1021/acs.orglett.1c02262
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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reaction of carbenoid II with an aldehyde carbonyl group then
generates the oxazoline III through a formal [3 + 2]
cycloaddition. The selective thermal cleavage of the oxazoline
C−O bond subsequently leads to the formation of the
isoelectronic intermediate IV. According to the Woodward−
Hoffmann rules,10 the intermediate IV was expected to
undergo conrotatory 8π-electrocyclizaitons to afford a new
seven-membered ring product d bearing substituents with a
specific stereochemistry. The competing chemo- and regiose-
lectivities might be fully suppressed in this cyclization process.
Herein we report our results on the stereospecific synthesis of
cis-substituted 2,3-dihydroazepines via a relay Cu- and Rh-
catalyzed cascade reaction of TsN3, alkynes, and enals.
Having established the optimal reaction conditions, the
substrate scope of the transformation was next examined using
a range of dienals, alkynes, and sulfonyl azides (Table 2).
a b
,
Table 2. Substrate Scope
To test the feasibility of our proposed strategy, we used
CuTC and Rh2(Oct)4 as the relay catalysts for the cascade
reaction of dienal 1a, phenylacetylene 1b, and TsN3 1c (Table
1). More specifically, after 1b was fully transformed into the
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
solvents
yields (%)
1
2
3
4
5
6
7
8
9
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(Oct)4
Rh2(OAc)4
Rh2(TFA)4
Rh2(esp)2
chloroform
1,2-DCE
DCM
benzotrifluoride
chlorobenzene
toluene
toluene
toluene
toluene
toluene
72
49
66
47
62
c
81 (75)81 (75)
51
46
51
0
10
11
d
Rh2(Oct)4
toluene
0
a
Reactions were performed according to a one-pot protocol using the
a
b
All reactions of 1a (0.1 mmol), 1b (0.15 mmol), and 1c (0.2 mmol)
standard conditions unless otherwise noted. Isolated yield.
were performed in the presence of CuTC (10 mol %) and Rh(II) (1
mol %) in 1.0 mL of solvent at room temperature for 6.0 h, after
which the reaction mixture was heated at 80 °C in an oil bath for 8.0
Initially, a series of terminal alkynes b were examined to react
with δ-phenyl dienal 1a and TsN3 1c. Aryl alkynes provided
the products 2d−4d in high yields. Replacing the aromatic unit
with alkenyl groups also gave the desired products 5d and 6d
in good yields. The alkyl-substituted alkynes, such as
cyclohexylacetylene and t-butyclethyne, were investigated,
and the same reaction conditions resulted in a 1,2-alkyl
migration reaction to afford α,β-unsaturated imines.12
b
c
h. Isolated yield. The mixture was directly reacted at 80 °C for 8.0
d
h. Without CuTC. CuTC, copper(I) thiophene-2-carboxylate
hydrate; Rh2(Oct)4, rhodium(II) octanoate dimer; Rh2(OAc)4,r
hodium(II) acetate dimer; Rh2(TFA)4,r hodium(II) trifluoroacetate
dimer; Rh2(esp)2, bis[rhodium(α,α,α′,α′-tetramethyl-1,3-benzenedi-
propionic acid)].
To expand the scope of this reaction, we explored the
reactivities of the substituted dienals under the optimal
reaction conditions. Gratifyingly, a broad range of β-
monosubstituted, δ-monosubstituted, and β,δ-disubstituted
dienals worked well, furnishing the desired products in good
yields (7d−32d). The dienals with δ-p-Me-phenyl, δ-p-Cl-
phenyl, and δ-alkyl were investigated, affording the products
7d−9d in high yields. In addition, the introduction of an ester
moiety at the δ-position of the dienal substrate did not affect
the reaction outcome (10d). Moreover, the δ-substituted
dienal also gave the target product 11d in a 63% yield.
Subsequently, the β,δ-disubstituted dienals were investigated
under our standard conditions (12d−32d). Among these
substrates, the presence of the β-tBu and β-cyclohexyl
substituents had a detrimental effect on the yields, decreasing
those of the corresponding products to 66% and 56% (31d and
32d), respectively. The dienal with γ,δ-disubstitutions was
triazole at room temperature (r.t.), the resulting mixture was
reacted at 80 °C for 8.0 h. As anticipated, the reaction afforded
the desired cis-substituted 2,3-dihydroazepine 1d in a range of
solvents (Table 1, entries 1−6). Various Rh(II) catalysts
(Table 1, entries 7−9) were subsequently investigated, and
Rh2(Oct)4 was found to be the best choice in terms of
reactivity (81% yield; Table 1, entry 6). When the mixture was
directly reacted at 80 °C, the reaction also successfully afforded
the desired product, albeit in a lower yield (Table 1, entry 6).
Further control experiments indicate that the both Cu(I) and
Rh(II) as cocatalysts are essential for the transformation
(Table 1, entries 10 and 11). Additionally, we treated enal 1a
and N1-tosyl-1,2,3-triazole with the Rh catalyst at 80 °C in
toluene, to obtain 1d in an 87% yield.11 This result further
demonstrated the Rh is the catalyst for the formation of
intermediate III rather than copper.
B
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found to be amenable to the optimized reaction conditions,
affording the product 33d in a high yield, while the substrates
bearing fused-rings at the α,β-positions of their dienal
components afforded multicyclic products 34d and 35d in
high yields. Switching the tosyl-azide to a mesyl-azide also led
to the expected products (i.e., 36d and 37d) in good yields.
The relative configurations of the products could be assigned
unambiguously by the NMR spectra and X-ray diffraction
patterns (28d and 33d). Generally, the reaction displayed a
good functional group tolerance with single regio- and
diastereoselectivities. In all cases, the competitive side products
Scheme 2. Gram-Scale Synthesis and Divergent Synthesis of
Azepines in a One-Pot Operation
1
were not observed on the crude H NMR spectra.
To test a possible 10π-electrocyclization process with the
currently developed method in the formation of the nine-
membered heterocycles, two trienals were subjected to the
standard reaction conditions (Scheme 1a). However, all
Scheme 1. Investigating the Reactivity and Selectivity of
Trienals and Indole Aldehyde
afforded the substituted 3H-azepine product 1f rather than the
1H-azepine product 1f′. We consider that the 1H-azepine 1f′
might be a thermodynamically unstable structure due to the
spatial repulsion between the coplanar methyl group and the
phenyl group. Finally, after the β,δ-diphenyl-substituted dienal
was fully converted to the corresponding product 12d,
increasing the temperature to 140 °C led to the isomerization
of the diene structural unit via 1,5-hydrogen migration to give
the more thermodynamically stable conjugated structure 2,7-
dihydroazepine 1g. In general, our transformations are
practical and convenient for the construction of structurally
diverse azepines with potential applications in the preparation
of molecular libraries.
In summary, we have developed a three-component cascade
reaction for accessing cis-substituted 2,3-dihydroazepines. This
reaction proceeds through a stereospecific conrotatory 8π-
electrocyclization process that controls the diastereo- and
regioselectivities of the reaction. The possible competing 6π-
electrocyclization reactions are fully suppressed in all cases.
Attractively, the cis-substituted 2,3-dihydroazepines could serve
as platform building blocks for the divergent synthesis of
various azepines via tunable one-pot routes. In particular,
complex polycyclic products can also be selectively obtained
using our cascade reaction as the key step.
spectroscopic and analytical evidence suggested that the
formation of a nine-membered product from a trienal through
a 10π-electrocyclization reaction is not possible. The
corresponding cis-substituted 2,3-dihydroazepine products
(38d and 39d) were afforded with exquisite site selectivities.
Furthermore, to expand the reaction mode to an aromatic
system, the indole aldehyde 34a bearing a multiple-conjugated
enal structure was reacted under standard reaction conditions
(Scheme 1b). To our delight, the reaction was amenable to the
optimized reaction conditions, resulting in the formation of
2,7-dihydroazepine 40d in a high yield. A sequential
dearomatization and aromatization process might be involved
in this transformation. As an overview of the results, the
reactions of various enals, alkynes and azides worked well in a
stereospecific manner. Although some mechanistic details of
this reaction remain unclear and are the topic of further
investigation, these stereospecific reaction results support an
8π-electrocyclizaiton mechanism.
To demonstrate the practical utility of the developed
method, the gram-scale reactions of 1a and 7a were also
carried out, deliveirng the corresponding products 1d and 12d
in 74% and 78% yields, respectively (Scheme 2a). Next, the
practical utility of this strategy was further demonstrated by the
divergent synthesis of structurally significant nitrogen-contain-
ing seven-membered ring products (Scheme 2b). We deduced
that the 1H-azepine 1e might be formed from cis-substituted
2,3-dihydroazepines 1d through the elimination of Ts in the
presence of a base. As we expected, after converting the
substrate 1a into 1d, the addition of DBU led to the 1H-
azepine product 1e at room temperature in a 65% yield.
Interestingly, the X-ray structure suggested that the reaction of
the γ,δ-disubstituted dienal substrate under the same condition
ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02262.
General procedures, characterization and X-ray data, and
NMR spectra (PDF)
Accession Codes
CCDC 1583678, 1866403, and 1951627 contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
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AUTHOR INFORMATION
Corresponding Author
■
Baosheng Li − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing 400044, China;
orcid.org/0000-0002-6953-687X; Email: libs@
cqu.edu.cn
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Authors
You Li − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing 400044, China
Han Luo − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing 400044, China
Zongyuan Tang − School of Chemistry and Chemical
Engineering, Chongqing University, Chongqing 400044,
China
Yingzi Li − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing 400044, China
Luan Du − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing 400044, China
Xiaolan Xin − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing 400044, China
Shanshan Li − School of Chemistry and Chemical Engineering,
Chongqing University, Chongqing 400044, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02262
Author Contributions
‡Y.L. and H.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NSFC (Grant 21772019) and the
Venture & Innovation Support Program for Chongqing
Overseas Returnees (cx2019007 and cx2020047). The authors
wish to acknowledge Mr. Xiangnan Gong of the Analytical and
Testing Center of Chongqing University for the single-crystal
X-ray diffraction analysis of products 28d, 33d, and 1f.
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