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. 2012 Jul 8;68(27-28):5606-5611.
doi: 10.1016/j.tet.2012.04.068. Epub 2012 Apr 26.

Synthesis of Tetrazolo-Fused Benzodiazepines and Benzodiazepinones by a Two-Step Protocol Using an Ugi-Azide Reaction for Initial Diversity Generation

Steven Gunawan  1 , Muhammad Ayaz, Fabio De Moliner, Brendan Frett, Christine Kaiser, Nina Patrick, Zhigang Xu, Christopher Hulme
Affiliations

Synthesis of Tetrazolo-Fused Benzodiazepines and Benzodiazepinones by a Two-Step Protocol Using an Ugi-Azide Reaction for Initial Diversity Generation

Steven Gunawan et al. Tetrahedron. .

Abstract

A two-step strategy for the synthesis of arrays of tricyclic tetrazolo-fused benzodiazepines and benzodiazepinones has been investigated. The protocol uses ortho-N-Boc phenylisocyanides and phenylglyoxaldehydes or ethyl glyoxylate in the 4-component Ugi-Azide reaction to afford MCR (Multi Component Reactions) derived adducts equipped with the desired diversity inputs. A subsequent acidic treatment (TFA/DCE) allows a simultaneous deprotection-cyclization leading to the final products.

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Figures

Figure 1
Figure 1
Structurally close benzodiazepine-based drugs showing different activities.
Figure 2
Figure 2
The pivotal collection of benzodiazepinones 8. Yields represent the combined two overall steps.
Figure 3
Figure 3
Solved crystal structure of 8a showing two unique molecules in the asymmetric unit.
Figure 4
Figure 4
Synthesized benzodiazepines 10 and 11. Yields represent the combined two overall steps.
Scheme 1
Scheme 1
Mechanism of the 4-component Ugi-Azide reaction (compatible with 1ry or 2ry amines).
Scheme 2
Scheme 2
Synthetic route toward tetrazolo-fused benzodiazepinones 8.
Scheme 3
Scheme 3
Synthetic route toward tetrazolo-fused benzodiazepines 10 and 11.
See this image and copyright information in PMC

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