V. V. Potapov et al. / Tetrahedron Letters 50 (2009) 2790–2792
2791
Br
O
O
N
N
K2CO3, 18-Crown-6
CH3CN, r.t., 8-10 h
KOH
O
+
H
H
O
EtOH/H2O
N
H
2
H
O
O
OMe
1
3 (70%)
4 (90%)
OMe
OH
R1 NH2
N
N
R2 NC
a: R1=iso-pentyl, R2=4-OMe-Ph
b: R1=4-Me-benzyl, R2=4-OMe-phenyl
c: R1=iso-pentyl, R2=3,5-di-OMe-phenyl
4
O
MeOH, 50 ºC
5-10 h
d: R1=4-Me-benzyl, R2=3,5-di-OMe-phenyl
R1
HN
R2
O
5a-d
(20-30%)
Scheme 1. Synthesis of N-substituted 6-oxo-4,5,6,11-tetrahydropyrrolo[1,2-b][2,5]benzodiazocine-4-carboxamides 5a–d.
In somecases, purecrystallinesubstancescouldbe obtained, thus
allowing analysis of the individual compounds through X-ray
crystallography. For instance, the structure of 5b was
unambiguously established as 5-(4-methoxyphenyl)-N-(4-methyl-
benzyl)-6-oxo-4,5,6,11-tetrahydropyrrolo[1,2-b][2,5]benzodiazo-
cine-4-carboxamide (Fig. 1), by single-crystal X-ray analysis. Single
crystals of compounds suitable for X-ray analysis were grown by
slow evaporation from diethyl ether. The corresponding valence
angles and bond lengths of these molecules in the asymmetric unit
are the same within three standard deviations. As shown in Figure
1, the space orientation of two bulky substituents derived from
amine and isonitrile components is completely different. The inner
1,4-diazocine space turn can also be clearly recognized. Presumably,
the observed conformation corresponds to the global minima of the
free kinetic energy.
offers a large number of potential input reactants and resulting
products. Therefore, the synthetic scope of the method described
will be broadened in further paper. It is quite obvious that the
obtained compounds represent valuable starting points for the
development of compounds of biological interest. The use of com-
pounds from series V in the search for novel bioactive agents is
under investigation in ChemDiv. Inc company and will be reported
in due course.
Acknowledgment
We thank Dr. Yan A. Ivanenkov (ChemDiv. Inc) for discussion
and invaluable help in preparation of the manuscript.
Supplementary data
In summary, we have shown that unique heterocyclic
compounds can be efficiently prepared by a novel modification of
Ugi MCR reaction of heterocyclic aldehyde-acid, amines, and isoni-
triles. Considering the ease of the preparation of initial reactants,
convenient synthesis, and isolation of products, this synthetic
route provides a new valuable entry to novel eight-membered
heterocyclic systems which can be reasonably regarded as unique
bioisosteric analogs of related biologically active six- and seven-
membered heterocyclic compounds. As a synthetic tool for creat-
ing diverse compound libraries, the MCR developed in this work
Supplementary data (including synthetic procedures for
compounds obtained in this work, corresponding NMR spectra and
HRMS protocols as well as detailed X-ray data, is available online
with the paper in ScienceDirect) associated with this article can be
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Figure 1. ORTEP plots (50% probability thermal ellipsoids) of compound 5b.
Hydrogen atoms are omitted.