reported, using thermal or photochemical approaches,5
most notably in the pioneering work by Moore and
co-workers.5a In addition, subsequent chemical transfor-
mations such as dimerization,6 fragmentation,5k rearrange-
ment,7 and the pericyclic reaction8 have been carried
out to elucidate the interesting chemical properties of
these compounds.9 Among these conventional studies,
1,7-electrocyclization approaches for the 1,2-diazepine
nucleus using conjugated diazo-diene compounds as a
substrate seem to be a promising method to construct this
heterocyclic system. Earlier works by Sharp et al. accom-
plished syntheses of various 1,2-diazepine derivatives utiliz-
ing the 1,7-(8π)-electrocyclization,5g and then Ohno and
Eguchi et al. reported 1,2-diazepine-forming reactions
from diazo-diene compounds generated by ring cleavage
of squaric acid derivatives.5l Both of these reactions, how-
ever, required thermal activation for cyclization progress
and often suffered from side reactions with nitrogen extru-
sion and 1,5-(6π)-cyclization (pyrazole formation) to affect
the yields of 1,2-diazepines. Recently, electrocycliza-
tion reactions of zwitterionic diazo-dienolate have been
reported,5m which involve competitive 6π and 8π cycliza-
tions to produce resorcinols and 1,2-diazepines, from A and
B respectively, and the former reaction mode is a predomi-
nant pathway over the 1,2-diazepine formation. While
these findings provide potential for the 8π cyclization
strategy for 1,2-diazepine syntheses, it has been stated that
the lack of geometric fixation of the diazo-dienolate B
would be partly responsible for the limited applicability
for the efficient formation of 1,2-diazepines (Scheme 1).
Scheme 2. Strategy for 1,2-Diazepine Syntheses in This Work
We have previously developed a novel methodology for
the syntheses of 2,3-benzodiazepines, involving a tandem
4πÀ8π electrocyclization system via a highly reactive
o-quinodimethane intermediate, utilizing benzocyclobute-
nones and the diazomethylene anion as starting materials.10
Provided that the tandem system works well in the case
of monocyclic cyclobutenones, it can be a powerful strat-
egy for synthesis of unfused 1,2-diazepine derivatives
(Scheme 2). This strategy is characterized by the signifi-
cant acceleration effect of the oxy anion in the intermedi-
ate 3 and 4 toward the electrocyclization process and
exclusive outward torquoselectivity of the oxy anion sub-
stituent in the 4π-ring opening stage.11 Therefore, this
approach would be superior to prior methods in the
following ways: (1) oxy anion acceleration for both elec-
trocyclic reactions enables extremely mild reaction condi-
tions (without thermal activation), leading to suppression
of undesired nitrogen extrusion, and (2) strong outward
rotation of the oxy anion in 3 completely dictates the
orientation of the diazo group, which is crucial for the next
8π-ring closure (geometric fixation of the diazo-diene
intermediate). We report herein an efficient approach to
1,2-diazepines utilizing a formal diazomethylene insertion
reaction into the CÀC bond of cyclobutenones via a
successive 4πÀ8π electrocyclization process.
Scheme 1. Previously Reported 1,2-Diazepine Formation via 8π
Cyclization
The investigation began with the reaction between 3-
(4-methylphenyl)cyclobutenone (1a) and 2 equiv of ethyl
lithiodiazoacetate generated in situ using LDA as a base
(Table 1).12 In ethereal solvents, the tandem electrocyclic
reaction proceeded smoothly to give desired 1,2-diazepine
products as a mixture of 5a and its tautomer 6a (entries
1À3). The 1H NMR spectra of the crude reaction mixture
indicated that both 5a and 6a were produced in the same
ratio as that in Table 1 under reaction conditions,
(6) Willig, B.; Streith, J. Tetrahedron Lett. 1973, 4167.
€
(7) (a) Moore, J. A.; Puschner, H. H. J. Am. Chem. Soc. 1959, 81,
6041. (b) Moore, J. A.; Theuer, W. J. J. Org. Chem. 1965, 30, 1887.
(c) Moore, J. A.; Marascia, F. J.; Medeiros, R. W.; Wineholt, R. L. J. Org.
Chem. 1966, 31, 34. (d) Wineholt, R. L.; Wyss, E.; Moore, J. A. J. Org.
Chem. 1966, 31, 48. (e) Moore, J. A.; Medeiros, R. W.; Williams, R. L.
J. Org. Chem. 1966, 31, 52. (f) Derocque, J.-L.; Theuer, W. J.; Moore, J. A.
J. Org. Chem. 1968, 33, 4381. (g) Moore, J. A.; Freeman, W. J.; Kurita, K.;
Pleiss, M. G. J. Org. Chem. 1973, 38, 2939. (h) Anderson, C. D.; Sharp,
J. T.; Stefaniuk, E.; Strathdee, R. S. Tetrahedron Lett. 1976, 305.
(8) (a) Sasaki, T.; Kanematsu, K.; Kakehi, A.; Ichikawa, I.; Hayakawa,
K. J. Org. Chem. 1970, 35, 426. (b) Luttringer, J. P.; Streith, J. Tetrahedron
Lett. 1973, 4163. (c) Reid, A. A.; Sood, R. H.; Sharp, J. T. J. Chem. Soc.,
Perkin Trans. 1 1976, 362. (d) Kurita, J.; Kakusawa, N.; Tsuchiya, T.
J. Chem. Soc., Chem. Commun. 1987, 1880. (e) Beltrame, P.; Cadoni, E.;
Carnasciali, M. M.; Gelli, G.; Lai, A.; Mugnoli, A.; Pani, M. Heterocycles
1992, 34, 1583. (f) Beltrame, P.; Cadoni, E.; Floris, C.; Gelli, G. Tetrahedron
1993, 49, 7001.
(9) For reviews on 1,2-diazepines, see: (a) Nastasi, M. Heterocycles
1976, 4, 1509. (b) Streith, J. Heterocycles 1977, 6, 2021. (c) Snieckus, V.;
Streith, J. Acc. Chem. Res. 1981, 14, 348.
(10) (a) Matsuya, Y.; Ohsawa, N.; Nemoto, H. J. Am. Chem. Soc.
2006, 128, 13072. (b) Matsuya, Y.; Katayanagi, H.; Ohdaira, T.; Wei,
Z.-L.; Kondo, T.; Nemoto, H. Org. Lett. 2009, 11, 1361.
(11) (a) Choy, W.; Yang, H. J. Org. Chem. 1988, 53, 5796. For a
review on torquoselectivity of cyclobutenes, see: (b) Dolbier, W. R., Jr.;
Koroniak, H.; Houk, K. N.; Sheu, C. Acc. Chem. Res. 1996, 29, 471.
(12) (a) Pellicciari, R.; Natalini, B.; Cecchetti, S.; Fringuelli, R.
J. Chem. Soc., Perkin Trans. 1 1985, 493. (b) Padwa, A.; Kulkarni,
Y. S. J. Org. Chem. 1990, 55, 4144.
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