Concise approach toward tetrazolo[1,5-a ][1,4]benzodiazepines via a novel multicomponent isocyanide-based condensation

Article abstract of DOI:10.1021/ol101590w

A novel and efficient method for the synthesis of heteroannulated [1,4]benzodiazepines via an isocyanide-based multicomponent reaction is reported. The tetrazolo[1,5-a][1,4]benzodiazepines were obtained by a facile azide Ugi five-center four-component reaction (U-5C-4CR) using ketones, sodium azide, ammonium chloride, and corresponding isocyanide. The aforementioned tetrazolodiazepines represent a notable class of compounds with proven platelet aggregation inhibitory and cholecystokinin agonist activities.

Full text of DOI:10.1021/ol101590w

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3894-3897
Concise Approach toward
Tetrazolo[1,5-a][1,4]benzodiazepines via
a Novel Multicomponent
Isocyanide-Based Condensation
Roman S. Borisov,† Anatoliy I. Polyakov,‡ Lidia A. Medvedeva,‡
Victor N. Khrustalev,§ Natalia I. Guranova,| and Leonid G. Voskressensky*,|
A.V. TopchieV Institute of Petrochemical Synthesis, Russian Academy of Science,
29, Leninsky AVenue, Moscow 119991, Russia, N.N. Blohin Cancer Research Center,
Russian Academy of Medical Sciences, Moscow, Russia, A.N. NesmeyanoV Institute of
Organoelement Compounds, Russian Academy of Sciences, VaViloV St 28,
B-334, Moscow 119991, Russia, and Russian People’s Friendship UniVersity,
6, Miklukho-Maklaia Street, Moscow 117198, Russia
lVoskressensky@sci.pfu.edu.ru
Received July 9, 2010
ABSTRACT
A novel and efficient method for the synthesis of heteroannulated [1,4]benzodiazepines via an isocyanide-based multicomponent reaction is
reported. The tetrazolo[1,5-a][1,4]benzodiazepines were obtained by a facile azide Ugi five-center four-component reaction (U-5C-4CR) using
ketones, sodium azide, ammonium chloride, and corresponding isocyanide. The aforementioned tetrazolodiazepines represent a notable class
of compounds with proven platelet aggregation inhibitory and cholecystokinin agonist activities.
The 1,4-benzodiazepines are a remarkable class of com-
pounds with potent tranquilizer,1 muscle relaxant,2 anti-
convulsant,3 antiseizure activity4 and sedative-hypnotic
activity, whose pharmacological and clinical eminence is
attested by the large number of reviews and books that
have been published describing their properties.5
Among the various pathways toward 1,4-benzodiazepine
derivatives, those based on the isocyanide multicomponent
reactions are especially noteworthy.
† A.V. Topchiev Institute of Petrochemical Synthesis.
‡ N.N. Blohin Cancer Research Center.
(4) Rivas, F. M.; Stables, J. P.; Murphree, L.; Edwankar, R. V.;
Edwankar, C. R.; Huang, S.; Jain, H. D.; Zhou, H.; Majumder, S.; Sankar,
S.; Roth, B. L.; Ramerstorfer, J.; Furtmu¨ller, R.; Sieghart, W.; Cook, J. M.
J. Med. Chem. 2009, 52, 1795–1798.
§ A.N. Nesmeyanov Institute of Organoelement Compounds.
| Russian People’s Friendship University.
(1) Neutel, C. I.; Hirdes, J. P.; Maxwell, C. J.; Patten, S. B. Age Ageing
1996, 25, 273–278.
(5) (a) Killam, E. K.; Suria, A. Benzodiazepines. In Antiepileptic Drugs:
Mechanisms of Action, Advances in Neurology; Glaser, G. H., Penry, J. K.,
Woodbury, D. M., Eds.; Raven Press: New York, 1980; Vol. 27, pp
597-615. (b) MacDonald, R. L. Benzodiazepines Mechanisms of Action.
In Antiepileptic Drugs, 5th ed.; Levy, R. H., Mattson, R. H., Meldrum,
B. S., Perucca, E., Eds.; Lippincott Williams and Wilkins: Philadelphia,
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10.1021/ol101590w  2010 American Chemical Society
Published on Web 08/10/2010

The key step of these methods is the Ugi four-component
condensation6 performed with anthranilic7 or N-protected
anthranilic acids,8 o-nitrobenzoic acids,9 and convertible
isocyanides. Alternative approaches are based on the use of
bifunctional reagents such as ethyl glyoxylate,10 amino acid
esters,11 N-Boc-aminoaldehydes,12 or N-Boc-1,2-diamino-
ethanes.13 However, to the best of our knowledge, no
information on the synthesis of heteroannulated [1,4]benzo-
diazepines using isocyanide-based multicomponent reactions
has yet been published. We have recently embarked on a
research program to evolve new methodologies that employ
multicomponent reactions for the construction of hetero-
cycles14,15 in view of their distinct advantages of conver-
gence, economy, efficiency, and eco-friendliness.
However, the protocol was not effective for achieving
tetrazole-fused diazepinone. Later, modifying the synthetic
pathway, these workers obtained tetrazole-fused azepinone
by using bifunctional N-Boc-aminoaldehyde as the aldehyde
component.20 The most recent paper by Nayak and Batra21
reports on MCR-based synthesis of tetrazolodiazepines
starting from Baylis-Hillman adducts of acrylates (Scheme
2). These last three papers disclose the only examples of
Scheme 2. Reported Synthesis of Tetrazole-Fused Diazepinones
Originally reported in 1961, the azide Ugi reaction
involves Schiff base formation from the appropriately
substituted aldehyde or ketone and primary amine, followed
by its reaction with an isocyanide. The resulting intermediate
nitrilium ion 1 then reacts with azide, affording substituted
tetrazoles 2 in good yields16 (Scheme 1). The literature search
Scheme 1. Mechanism of the Tetrazole-U-4-CR
Ugi reaction-based synthesis of tetrazolodiazepines; however,
none of them is a true MCR, that is, the reaction in which
all components are mixed together to yield the product.19-21
This paper reports a novel, facile azide Ugi five-center
four-component reaction (U-5C-4CR) which yields substi-
tuted tetrazolo[1,5-a][1,4]benzodiazepinessa family of com-
pounds with proven platelet aggregation inhibitory22 and
cholecystokinin (CCK) agonist23 activities (Scheme 3).
revealed that, in the subsequent years, this reaction has been
exploited to synthesize some tetrazolo-fused heterocycles.
Kalinski et al. reported the synthesis of 4,5-dihydrotetra-
zolo[1,5-a]quinoxalines through the combination of Ugi and
SNAr reactions.17 Umkehrer et al. disclosed efficient synthesis
of tetrazolopiperazine framework through U-5C-4CR.18
Hulme and co-workers reported the synthesis of tetrazole-
fused ketopiperazine through Ugi reaction followed by
intramolecular cyclization.19
Scheme 3. Syntheses of Compounds 1-19 via U-5C-4CR
(6) Reviews: (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39,
3168–3210. (b) Ugi, I.; Werner, B.; Do¨mling, A. Molecules 2003, 8, 53–
66. (c) Uchida, H.; Suzuki, T.; Mamo, D. C.; Mulsant, B. H.; Kikuchi, T.;
Takeuchi, H.; Tomita, M.; Watanabe, K.; Yagi, G.; Kashima, H. J. Anxiety
Disorders 2009, 23, 477–481.
(7) (a) Kennedy, A. L.; Fryer, A. M.; Josey, J. A. Org. Lett. 2002, 4,
1167–1170. (b) Keating, T. A.; Armstrong, R. W. J. Org. Chem. 1996, 61,
8935–8939. (c) Keating, T. A.; Armstrong, R. W. J. Am. Chem. Soc. 1996,
118, 2475–2583. (d) Lindhorst, T.; Bock, H.; Ugi, I. Tetrahedron 1999,
55, 7411–7420.
(8) Hulme, C.; Peng, J.; Tang, S.-Y.; Burns, C. J.; Morize, I.;
Labaudiniere, R. J. Org. Chem. 1998, 63, 8021–8023.
In our approach, the desired tetrazolodiazepines were
synthesized by simply mixing 1 mmol of a ketone with 1.2
mmol of sodium azide, 1.2 mmol of ammonium chloride,
(9) Marcaccini, S.; Miliciani, M.; Pepino, R. Tetrahedron Lett. 2005,
46, 711–713.
(10) Hulme, C.; Cherrier, M.-P. Tetrahedron Lett. 1999, 40, 5295–5299.
Org. Lett., Vol. 12, No. 17, 2010
3895

and 1 mmol of the corresponding isocyanide in aqueous
methanol (Scheme 3).
After 24-48 h of vigorous stirring at room temperature,
the target products precipitated from the reaction mixture
(see Supporting Information for more detailed information
and Figure 1 for the list of compounds synthesized).
mation for details). Heterocyclic isonitrile, methyl 3-isocy-
anothiophene-2-carboxylate, in this reaction gave the desired
tetrazolothienodiazepine 20 in 46% yield (Scheme 4).
Scheme 4
.
Syntheses of Tetrazolothienodiazepine 20 and
Methylaminotetrazole 21
Our attempts to use aliphatic aldehydes in this MCR all
failed, with no isolable products being formed. In this regard,
significant tarring was observed, caused most likely by self-
condensation of the aldehydes under the reaction conditions.
The use of methylamine hydrochloride instead of ammonia
salt led to the sole formation of noncyclic amino tetrazole
derivative 21 (Scheme 4). Attempts to cyclize it were
unsuccessful: compound 21 was unchanged when heated at
reflux in methanol, whereas it deteriorated under more
forcing conditions, such as in boiling glacial acetic acid.
In conclusion, we have developed an effective proce-
dure for novel syntheses of substituted tetrazolo[1,5-
a][1,4]benzodiazepines via tetrazole U-5C-4CR of o-
aminobenzoate-derived isonitriles, aliphatic ketones, am-
(11) Faggi, C.; Marcaccini, S.; Pepino, R.; Pozo, M. C. Synthesis 2002,
2756–2760.
(12) Tempest, P.; Pettus, L.; Gore, V.; Hulme, C. Tetrahedron Lett. 2003,
44, 1947–1950.
(13) Tempest, P.; Ma, V.; Kelly, M. G.; Jones, W.; Hulme, C.
Tetrahedron Lett. 2001, 42, 4963–4968.
(14) Voskressensky, L. G.; Kulikova, L. N.; Listratova, A. V.; Borisov,
R. S.; Kukaniev, M. A.; Varlamov, A. V. Tetrahedron Lett. 2010, 51, 2269–
2270.
(15) Polyakov, A. I.; Eryomina, V. A.; Medvedeva, L. A.; Tihonova,
N. I.; Listratova, A. V.; Voskressensky, L. G. Tetrahedron Lett. 2009, 50,
4389–4393.
(16) (a) Ugi, I.; Steinbruckner, C. Chem. Ber. 1961, 94, 734–739. (b)
Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8.
(17) Kalinski, C.; Umkehrer, M.; Gonnard, S.; Jager, N.; Ross, G.; Hiller,
W. Tetrahedron Lett. 2006, 47, 2041–2044.
(18) Umkehrer, M.; Kolb, J.; Burdack, C.; Ross, G.; Hiller, W.
Tetrahedron Lett. 2004, 45, 6421–6424.
(19) Nixey, T.; Kelly, M.; Hulme, C. Tetrahedron Lett. 2000, 41, 8729–
8733.
(20) Nixey, T.; Kelly, M.; Semin, D.; Hulme, C. Tetrahedron Lett. 2002,
43, 3681–3684.
Figure 1. Tetrazolodiazepines synthesized by U-5C-4CR.
(21) Nayak, M.; Batra, S. Tetrahedron Lett. 2010, 51, 510–516.
(22) Blackburn, B. K.; Robarge, K.; Somers, T. C. U.S. Patent 5705890,
1998.
The structure of tetrazolodiazepine 16 was unambiguously
elucidated by X-ray crystallography (see Supporting Infor-
(23) Freidinger, R. M.; Evans, B. E.; Bock, M. G. European Patent EP
0523846, 1993.
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Org. Lett., Vol. 12, No. 17, 2010

monia chloride, and sodium azide. Work aimed at
expanding the scope of this reaction to use primary amines
and aldehydes is currently underway and will be reported
in due course.
Supporting Information Available: General experimen-
tal procedures, compound characterization data, X-ray and
NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the
Russian foundation for basic research (Grant No. 10-03-
00243-a).
OL101590W
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3897