Organic Letters
Letter
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
Org. Lett. XXXX, XXX, XXX−XXX