Organic Letters
Letter
a
hindrance at the nucleophilic site of a cycloaddition partner
would promote a faster cyclization step at the C5 carbon.
Herein, we report a kinetically controlled Pd-catalyzed (5 + 4)
cycloaddition of activated vinylcyclopropanes with 1-azadiene-
s8a,b,9a for the synthesis of azonane heterocycles (Scheme 1d).
To conduct this study, we initially involved VCP 1a bearing
two methyl ester groups and benzofuran-derived 1-azadiene 2a
as test substrates. Under the usual conditions (Pd2dba3, dppe,
CH2Cl2, rt), we observed the formation of spiro compound 3a
originating from a (3 + 2) cycloaddition involving the VCP as
a nucleophilic 1,3-dipole and the CC bond of the azadiene
as an electrophilic 1,2-dipole.17 A remarkably different
outcome was observed with VCP 1b bearing two cyano
electron-withdrawing groups. Under the same conditions, a fast
transformation (<1 min) was observed and furnished the
expected 9-membered ring 4a18 as a major product along with
a mixture of diastereomers of the cyclopentane spiro
compound 5a (4a/5a = 75:25). Interestingly, 5a was the
only cycloadduct observed after 4 h (rt), and a careful
monitoring of the 4a/5a ratio by 1H NMR spectroscopy
revealed that (5 + 4) cycloadduct 4a was gradually converted
to (3 + 2) cycloadduct 5a under these reaction conditions
(Scheme 2).
Table 1. Optimization of the Reaction Conditions
entry
ligand
solvent
4a/5a
yield (%)
b
1
2
3
4
5
6
dppe
dppe
dppe
dppe
dppe
CH2Cl2
toluene
methanol
Et2O
acetone
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
75:25
72:28
65:35
65:35
63:37
>96:4
>96:4
>96:4
>96:4
58
b
42
b
41
b
62
b
56
c
bipyridine
64
d
c
7
phenanthroline
phenanthroline
phenanthroline
74
e
c
8
71
f
c
9
73
a
Reaction conditions: 1b (0.075 mmol), 2a (0.05 mmol), Pd2dba3
(0.0025 mmol), ligand (0.005 mmol) in solvent (0.5 mL) at room
temperature. NMR yields Isolated yields. Reaction time: 5 min.
b
c
d
e
f
Reaction time: 16 h. 2a (3.00 mmol), reaction time: 5 min.
respectively, were readily converted to the corresponding nine-
membered heterocycles. We continued to question the
importance of the electronic properties of this aromatic moiety
and demonstrated that electron-withdrawing substituents such
as a fluorine (4h) or a trifluoromethyl (4i) group at the para
position could be installed. Substitutions at the meta position
(3-F for 2j and 3-CN for 2k) were also tolerated as the
expected azonanes 4j (90%) and 4k (98%) were generated in
high yields. Halogen atoms are susceptible to alteration of the
course of this reaction as an oxidative insertion of the Pd0
catalyst can occur. We were pleased to observe the efficient
formation of azonanes 4l (2-Cl, 66%) and 4m (5-Br-2-OMe,
76%). Under the same reaction conditions, azadiene 2n (50%)
bearing an electron-rich 2-thiophenyl group was converted to
the expected nine-membered ring.
Scheme 2. Preliminary Studies
Finally, the reactivity of benzofuran-derived azadienes with
different sulfonamide groups was examined, and 2-nitro-
sulfonamide 4o (80%) as well as benzenesulfonamide 4p
(64%) were isolated (Scheme 3).
We then focused our attention toward linear 1-azadienes
6a−f derived from various chalcones. These substrates present
an ambitious challenge as the (5 + 4) cycloaddition does not
come with an aromatization step driving the azadiene to act as
a 4-atom synthon rather than a 2-atom synthon. We first
investigated the behavior of N-Ts-azadiene 6a derived from
benzylideneacetophenone and were pleased to observe that the
nine-membered heterocycle remained the major product under
the previously optimized reaction conditions as a 85:15
mixture of the expected (5 + 4) cycloadduct 7a along with
cyclopentane 8a was obtained (74%). The presence of an
electron-rich aryl Ar1, substituted with a methoxy group at the
para position, did not influence the 7b/8b (84:16) isomeric
ratio, but the mixture was isolated in a moderate yield of 47%.
Electron-withdrawing groups on Ar1 restored the reactivity:
azonanes 7c and 7d were isolated as the major products with a
better selectivity of 90:10 and 87:13, respectively. The ease of
preparation of acyclic 1-azadienes bearing different Ar2 aryl
groups allowed us to further review the scope of this
monocyclic azonane synthesis. In this case, electrophilic
partners with electron-deficient p-nitrophenyl and p-trifluor-
omethylphenyl substituents also reacted promptly to generate
7e (7e/8e = 88:12) and 7f (7f/8f = 91:9) with similar
selectivities, showing that electronic properties of these 1-
After this encouraging preliminary result, an array of solvents
was tested but did not allow for a more selective formation of
9-membered azonane 4a (Table 1, entries 1−5). Gratifyingly, a
Pd2dba3/N,N-bidentate ligand catalytic system led to the
exclusive formation of the (5 + 4) cycloadduct 4a (4a/5a >
96:4) which was isolated in good yield (74%) using
phenanthroline as ligand (Table 1, entry 7), and in this case,
no conversion of 4a to 5a was observed after 16 h (Table 1,
entry 8). These conditions proved to be suitable for the gram-
scale synthesis (1.10 g, 73%) of 4a (Table 1, entry 9). It is
worth pointing out that VCP 1a bearing two methyl esters was
exclusively converted to the corresponding spiro compound
under these conditions, highlighting the importance of the two
cyano groups.19
Having these optimized conditions in hand, we then
examined the scope of this (5 + 4) cycloaddition by involving
benzofuran-derived azadienes bearing an array of aromatic
substituents at position C4. Electron-rich phenyl groups were
well tolerated, and azonane with p-anisyl (4b), p-tolyl (4c),
3,4-dimethoxyphenyl (4d), and m-methoxyphenyl (4e) groups
were smoothly generated. Steric hindrance on this aromatic
group had little influence on this cycloaddition as azadienes 2f
(82%) and 2g (76%) with an o-tolyl and a 1-naphthyl group,
2333
Org. Lett. 2021, 23, 2332−2336