compounds compared with that of aldehydes can be ex-
plained by frontier molecular orbital theory.7,8
and spectroscopic data for the product were in full accord
with a novel 1,3-benzodiazepin-5-one ring system, and the
structural assignment was confirmed by single crystal X-ray
crystallographic analysis (Figure 1).13
Isatoic anhydride 1a was identified as a potential new
carbonyl dipolarophile. Isatoic anhydride derivatives are
readily available,9 versatile synthetic intermediates undergo-
ing reactions with a broad range of nucleophiles to afford
2-aminobenzoyl derivatives.10 Thus, it was thought that the
C4-carbonyl moiety within isatoic anhydride 1a may be
sufficiently activated that it would undergo cycloaddition
with an azomethine ylide 2 to afford the spiro-fused
oxazolidine 3 (Scheme 1).
Scheme 1
.
Proposed Reaction of Isatoic Anhydride with an
Azomethine Ylide
Figure 1. Single crystal X-ray structure of benzodiazepinone 5a.
The scope of this novel reaction was explored by subject-
ing N-substituted isatoic anhydride derivatives to the cy-
cloaddition reaction conditions. The derivatives 1b-f, sub-
stituted on nitrogen with alkyl, allyl, benzyl, and phenyl
groups, were readily prepared from isatoic anhydride 1a.14,15
Reaction of the isatoic anhydrides 1b-f with the azomethine
ylide 2a resulted in the corresponding N-substituted 1,3-
benzodiazepin-5-ones 5b-f respectively, which were isolated
in 71-92% yield (Table 1, entries 2-6). The higher yields
obtained for the N-substituted derivatives 5b-f, versus the
parent system 5a, was attributed to a combination of cleaner
reactions, as evidenced by NMR analyses of the crude
reaction products, and the greater stability of the N-
substituted products toward chromatographic purification.
In order to test this hypothesis, isatoic anhydride 1a was
allowed to react with azomethine ylide 2a (R ) Bn), formed
from N-(methoxymethyl)-N-(trimethylsilyl-methyl)-benzyl-
amine 411 and 0.05 mol equiv of trifluoroacetic acid (TFA)12
in the presence of 4 Å molecular sieves. To our surprise,
the benzodiazepinone 5a, rather than the anticipated spiro-
fused cycloadduct 3 (R ) Bn), was isolated as a single major
product in moderate yield (Table 1, entry 1). The analytical
Table 1. Transformation of Isatoic Anhydride and
N-Functionalized Isatoic Anhydrides into 1,3-Benzodiazepin-5-ones
(6) (a) Lown, J. W.; Smalley, R. K.; Dallas, G.; Maloney, T. W. Can.
J. Chem. 1970, 48, 89. (b) Dallas, G.; Lown, J. W.; Moser, J. P. Chem.
Commun. 1970, 278. For recent examples, see: (c) Khistiaev, K. A.;
Novikov, M. S.; Khlebnikov, A. F.; Magull, J. Tetrahedron Lett. 2008, 49,
1237. (d) Ryan, J. H.; Spiccia, N.; Wong, L. S.-M.; Holmes, A. B. Aust.
J. Chem. 2007, 60, 898.
(7) Ess, D. H.; Houk, K. N. J. Am. Chem. Soc. 2007, 129, 10646.
(8) (a) Padwa, A.; Dent, W. J. Org. Chem. 1987, 52, 235. (b) Houk,
K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am. Chem. Soc. 1973, 95,
7301. (c) Sustmann, R. Tetrahedron Lett. 1971, 12, 2717. (d) Sustmann,
R. Pure Appl. Chem. 1974, 40, 569.
entry
1
R
conda
time (h)
yield (%)b
1
2
3
4
5
6
7
8
a
b
c
d
e
f
a
b
c
d
e
f
H
Me
Et
Allyl
Bn
Ph
H
Me
Et
Allyl
Bn
Ph
A
A
A
A
A
A
B
B
B
B
B
B
24
36
16
16
40
16
3
6
2
4
3
42
92
79
71
77
80
0
88
96
76
100
90
(9) (a) Wagner, E. C.; Fegley, M. F. Org. Synth. 1947, 27, 45. (b)
Wennerberg, J.; Bjork, A.; Fristedt, T.; Granquist, B.; Jansson, K.;
Thuvesson, I. Org. Process Res. DeV. 2007, 11, 674.
(10) (a) Brouillette, Y.; Martinez, J.; Lisowski, V. Eur. J. Org. Chem.
2009, 3487. (b) Shvekhgeimer, M.-G. A. Chem. Heterocycl. Compd. 2001,
37, 385. (c) Kappe, T.; Stadlbauer, W. AdV. Heterocycl. Chem. 1981, 28,
127. (d) Coppola, G. M. Synthesis 1980, 505.
(11) Hosomi, A.; Sakata, Y.; Sakurai, H. Chem. Lett. 1984, 1117.
(12) (a) Terao, Y.; Kotaki, H.; Imai, N.; Achiwa, K. Chem. Pharm. Bull.
1985, 33, 896. (b) Terao, Y.; Kotaki, H.; Imai, N.; Achiwa, K. Chem. Pharm.
Bull. 1985, 33, 2762.
9
10
11
12
(13) Crystallographic data (CIF) for the structure reported in this
manuscript have been deposited with the Cambridge Crystallographic Data
Centre (CCDC) and allocated the deposition number CCDC-796928 for
compound 5a. A copy of the data can be obtained free of charge on
application to the CCDC, 12 Union Road, Cambridge, CB2 IEZ, UK; fax:
(44) 01223 336 033; email: deposit@ccdc.cam.ac.uk.
12
a Reaction conditions, A: 4 (1.8 equiv), 4 Å molecular sieves, TFA
(0.05 equiv), CH2Cl2, 0 °C to rt; B: 4 (1.8 equiv), 4 Å molecular sieves,
LiF (1.25 equiv), CH3CN, sonication, 35 °C. b Yield of product isolated
after chromatography and/or crystallization.
(14) Hardtmann, G. E.; Koletar, G.; Pistar, O. R. J. Heterocycl. Chem.
1975, 12, 565
.
(15) Chan, D. M. T. Tetrahedron Lett. 1996, 37, 9013
.
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