1,5-Benzodiazepine-2-ones Containing Peptoid Backbone
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 501
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NMR spectra of 15b-k compounds are similar to those
of 15a, except for the group bonded to NC)O which
exhibits characteristic signals with appropriate chemical
shifts.
It is noteworthy that, in the single crystal state, the product
is a dimer due to intermolecular hydrogen bonding of
NHC)O in the benzodiazepine rings (Figure 4).
The 1H and 13C NMR of entries 6-8 (Table 1) confirmed
the presence of four compounds: two regioisomers, each with
a conformational isomerism. For more details of spectro-
scopic data of entries 1-8 (Table 1), see Supporting
Information. The structures of all products are shown in
Figure 5.
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Regarding the well-documented general mechanism of the
Ugi reaction,18,19 we proposed a five key step plausible
mechanism for the mentioned reaction (Scheme 4). Since
diketene is a strained ꢀ-lacton ring, it is reasonable to propose
that the first step begins through a nucleophilic addition of
NH2 to diketene followed by ring-opening and proton transfer
to produce N-(2-aminophenyl)-3-oxobutanamide 16.20g Then,
the other NH2 condenses with a ketone moiety via an
intramolecular process to form 4-methyl-1,3-dihydro-2H-1,5-
benzodiazepin-2-one 12 that could be converted to iminium
salt 17 in the presence of carboxylic acid 13, a Brønsted
acid in the third step. Cyclohexyl isocyanide is subsequently
added to the iminium salt 17 to produce the reactive nitrilium
intermediate 18. The reactive O-acyl iminolate 19 is formed
via the R-addition of carboxylate anion to the nitrilium ion
18. The final step involves O- to N-acyl transfer (Mumm
rearrangement) to afford the corresponding substituted 1,5-
benzodiazepine-2-one 15.
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Conclusion
(10) Zhu, J., Bienayme, H., Eds. Multicomponent Reactions; Wiley-
VCH: Weinheim, 2005.
A concise and efficient one-pot synthesis of substituted
1,5-benzodiazepine-2-ones with a peptoid backbone has
been developed based on Ugi-4CR, using o-phenylendi-
amine and diketene instead of amine and aldehyde in a
reaction with carboxylic acid and cyclohexyl isocyanide.
The product is of potential synthetic and pharmacological
interest. This study brings forward a new concept of
conformational isomerism in solution phase. In addition,
the dimeric structure of the product in the single crystal
state may be of theoretical and experimental interest. Easy
reaction performance in neutral conditions with no bases
or catalysts, high yield, and simple purification of products
are the advantages of our work. The simplicity of the
present procedure makes it an interesting alternative to
the complex multistep approaches.
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Supporting Information Available. Experimental pro-
1
cedures, IR, mass, H and 13C NMR for all compounds,
crystallographic data, and ORTEP/X-ray structure for 15a.
This material is available free of charge via the Internet at
References and Notes
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