388
O. Lohse et al. / Tetrahedron Letters 42 (2001) 385–389
Scheme 5.
chlorosulfonyl isocyanate3 and delivered oxcarbazepine
2 in 80% yield (Scheme 4).
rington, C. In The Chemistry of Heterocyclic Systems,
Azepines, Part 1, Rosowsky, A., Ed.; John Wiley & Sons:
New York, 1984, pp. 384.
An alternative strategy was to first protect the carbonyl
function in 13 as its methyl enol ether4c and then to
remove the allyl group using t-BuOK in DMSO. Ad-
vantageously, in the case of the thus obtained enol
ether 15, carbamoylation could be cleanly effected with
in-situ generated isocyanic acid (Scheme 5).3
6. (a) Fouche, J.; Leger, A., German Patent 2,202,486, 1972;
Chem. Abstr. 1972, 77, 152012. (b) Fouche, J.; Leger, A.,
German Patent 2,039,396, 1972; Chem. Abstr. 1972, 77,
5379.
7. The remote metalation and cyclization of diethyl N-
methyl-o-tolylanthranilamide
to
N-methyl
diben-
zazepinone was first reported by the Snieckus group . See:
MacNeil, S. L.; Gray, M.; Briggs, L. E.; Li, J. J.;
Snieckus, V. Synlett 1998, 419.
Thus we have demonstrated that the remote metalation
of N-protected N-o-tolyl-anthranilamides is an efficient
strategy for the large-scale synthesis of Trileptal® in
only five steps from readily available starting material.19
Scale-up development and application of this strategy
to various analogs are on-going and will be reported in
due course.
8. Conventional reagents such as activated chloroformates
cannot cleave n-alkyl groups on the dibenzazepinone
system. Martin, P., personnal communication.
9. Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L.
Acc. Chem. Res. 1998, 31, 805.
10. We prepared different amides (R=Me, Et, iPr, morpho-
line) in order to test their reactivity and to find crystalline
intermediates.
11. P(o-Tol)3 gave only 10% conversion, DPEPhos proved
less efficient than BINAP and P(t-Bu)3 gave no reaction.
12. The reactions were run very concentrated (1.5 M). Yields
of pure compound after silica gel filtration and recrystal-
lization: 5a=91%, mp 73–74°C (120 g scale); 5b=88%,
oil; 5c=74%, mp 95–97°C; 5d=76%, mp 141–143°C.
13. We attempted to introduce silyl-protecting groups how-
ever they turned out to be too labile and desilylation was
always observed during work-up. Carbamates were not
considered as they have been shown to give five-mem-
bered ring closure (oxindole).7
Acknowledgements
We are greatly indebted to S. MacNeil and V. Snieckus
for useful discussion and for sharing with us unpub-
lished
information
(Regioselective
Diben-
zo[b,f ]azepinone Formation by Directed Remote
Lateral Metalation, personal communication and work
in progress). We also thank K. Killius and M. Weibel
for their technical assistance.
14. Less satisfactory results were obtained with the method
of Vitale and Chiocconi: Vitale, A. A.; Chiocconi, A. A.
J. Chem. Res. (S) 1996, 336.
References
15. (a) For a review on Lateral Directed Ortho Metalation,
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York, 1995, p. 1. (b) For a general review on DoM, see:
Green, L.; Chauder, B.; Snieckus, V. J. Heterocyclic
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18. ROESY experiment measured in DMSO at 600 MHz.
19. Typical ring-closure experiment: A solution of diiso-
propylamine (19.0 g, 0.188 mol) and TMEDA (21.82 g,
review on dibenz[b,f ]azepinones, see: Renfroe, B.; Har-
.
.