Application of cyclic ketones in MCR: Ugi/amide coupling based synthesis of fused tetrazolo[1,5-a][1,4]benzodiazepines

Article abstract of DOI:10.1016/j.tetlet.2014.04.040

Azido-Ugi reaction involving cyclic ketone, primary amine, isonitrile, and azide afforded substituted tetrazole derivatives 5. These intermediates were hydrolyzed to corresponding acid derivatives. EDAC/HOBt mediated amide bond formation of 5 gave fused tetrazolo[1,5-a][1,4]benzodiazepine 6 in high yield and good diversity.

Full text of DOI:10.1016/j.tetlet.2014.04.040

Accepted Manuscript
Application of cyclic ketones in MCR: Ugi/amide coupling based synthesis of
fused tetrazolo[1,5-a][1,4]benzodiazepines
Swapnil G Yerande, Kiran M. Newase, Bhawani Singh, André Boltjes,
Alexander Dömling
PII:
S0040-4039(14)00639-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.040
TETL 44502
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
21 March 2014
9 April 2014
10 April 2014
Please cite this article as: Yerande, S.G., Newase, K.M., Singh, B., Boltjes, A., Dömling, A., Application of cyclic
ketones in MCR: Ugi/amide coupling based synthesis of fused tetrazolo[1,5-a][1,4]benzodiazepines, Tetrahedron
Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.040
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Tetrahedron Letters
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Application of cyclic ketones in MCR: Ugi/amide coupling based synthesis of
fused tetrazolo[1,5-a][1,4]benzodiazepines.
Swapnil G Yerande,* Kiran M. Newase,€ Bhawani Singh,† André Boltjes,‡ Alexander Dömling.‡
Acoris Research (A Division of Hikal Ltd). 3A, International Biotech Park, Hinjewadi, Pune 411 057, Maharashtra, India.
€Department of Pharmaceutical Chemistry, P.E Society’s, Modern College of Pharmacy, Sector 21, Yamunanagar, Nigdi, Pune 411044 (M.S.) India.
†Organic Research Laboratory, Department of Chemistry, Banasthali University, Banasthali-304 022, India
‡Chair of Drug Design, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherland Dept. of Pharm. Chemistry (PG),
ARTICLE INFO
ABSTRACT
Azido-Ugi reaction involving cyclic ketone, primary amine, isonitrile and azide afforded
substituted tetrazole derivatives 5. These intermediates were hydrolyzed to corresponding acid
derivatives. EDAC/HOBt mediated amide bond formation of 5 gave fused tetrazolo[1,5-
a][1,4]benzodiazepine 6 in high yield and good diversity.
Article history:
Received
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Cyclic ketone
Ugi Multi Component Reaction
Ugi /Amide coupling
Fused tetrazole-ketopiperazine
Ivar Karl Ugi, in his seminal publication in 1959
Voskressensky et.al have reported elegant synthesis of
tetrazolo[1,5-a][1,4]benzodiazepine, by reacting sodium azide,
ammonium chloride, methylisocyanobenzoate, and various
aliphatic ketones. This Azido-Ugi reaction, however, did not give
the desired tetrazolo[1,5-a][1,4]benzodiazepines when an amine
source was changed from ammonium chloride to methylamine
hydrochloride. Using methylamine hydrochloride as an amine
source, only noncyclic tetrazole derivative was isolated. All
attempts to cyclize this noncyclic tetrazole derivative to
tetrazolo[1,5-a][1,4]benzodiazepine met with failure, which
highlights the major drawback of an otherwise elegant
synthesis.6
We aspired to improve the scope of this elegant Azido-
Ugi reaction, so that larger structurally diverse tetrazolo[1,5-
a][1,4]benzodiazepine can be prepared by the use of different
amine sources. All our efforts for achieving this goal is reported
in this letter
reported the reaction of aldehyde/ketone, amine, carboxylic acid
and isonitrile for the preparation of α-aminoacyl amide
derivatives; this multicomponent reaction is now well known as
Ugi multicomponent reaction.1 Due to its ability of generating
libraries of complex molecules with high degree of diversity, Ugi
four component reaction (Ugi-4CR) is without doubt one of the
most powerful transformations that has been extensively
investigated in the recent past.2 Many research groups have
extended the potential of the U-4CR reaction by using bi-
functional starting materials.3 Hulme and co-workers combined
the U-4CR with different post-condensation reactions to produce
a large range of biologically relevant heterocycles including
indazolinones, benzazepines and benzoxazepines.4
The Azido-Ugi reaction was reported by Ugi in 1961,
where the carboxylic acid component used in the classical Ugi
reaction was replaced by hydrazoic acid (generated in situ from
NaN /TMS-N3).5 Since then Azido-Ugi reaction have been used
3
At the outset of this study, our efforts were directed to
find an appropriate reaction condition to perform the proposed
reaction using amine source other than ammonium chloride. We
commenced our study of Azido-Ugi reaction by using aniline,
methylisocyanobenzoate, TMS-N3 and cyclohexanone. The
results are summarized in Table 1. When 1 equivalent of TMS-N3
was used we could isolate 32 % of the uncyclized product 5a
(entry 1) Increasing the equivalent of the TMS-N3 to 1.3 resulted
in increased isolated yield of 5a to 43% (entry 2). When TMS-N3
in the reaction is replaced by NaN3 we could isolate only 18% of
5a (entry 3). Increasing the equivalents of TMS-N3 to 1.6
equivalents resulted in the formation of impurity 711 and only 20
% of 5a was isolated (entry 4). Under none of the above reaction
in the preparation of various classes of heterocyclic compounds:
like, benzodiazepine−tetrazoles,6 piperazinone−tetrazoles,7 and
quinoxaline−tetrazoles.8
Tetrazolo[1,5-a][1,4]benzodiazepine
have
found
application as platelet aggregation inhibitors.9 Tetrazolo fused
benzodiazepines also showed inhibitory activity at neuropeptide
cholecystokinin (CCK).10
* Corresponding author. Tel.: +91 (20) 4200 4243; fax: +91 (20)
2727 2014; e-mail address: swapnil_yerande@hikal.com (Swapnil
Yerande).

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Tetrahedron Letters
conditions tested we could see the formation of desired
tetrazolo[1,5-a][1,4]benzodiazepine 6a.
With optimized reaction condition (as per entry 2), in
hand for the preparation of 5 we decided to check the reaction
scope in terms of substrate tolerance. A small collection of
fourteen derivatives were prepared using the optimized synthetic
protocol. As seen from the Scheme 1 variety of cyclic ketones
reacted in the Azido-Ugi reaction to give moderate yield of
compound 5. To our delight suitably N protected strained cyclic
ketone azetidine-3-one also participated in the Azido-Ugi
reaction forming previously unknown compounds 5b and 5g in
moderate yield. With a diverse library of tetrazole 5 in hand we
now turned our attention to the formation of target compound 6
from 5.
Table 1. Optimization of Azido-Ugi reaction
Reactant Mole Conditions
Entry Ratio (1:2:3:4)
Yield % of 5
1
2
3
4
1:1:1.3:1
MeOH, RT, 48 h
MeOH, RT, 48 h
Aq. MeOH, RT, 48 h
MeOH, RT, 48 h
32
43
18
20
1:1:1.3:1.3
1:1:1.3:1.3a
1:1:1.3:1.6
a Used NaN3 instead of TMSN3 and aniline hydrochloride salt.
Scheme 1. Preparation of Ugi products

Scheme 2. Preparation of tetrazolo[1,5-a][1,4]benzodiazepine derivatives
Our efforts to cyclize 5 into desired 6 have been
predominantly used in the amide bond (peptide bond) formation
and is now well established reagent.14 Since DCC generates urea
derivatives as byproducts which often have similar solubility as
the desired product, water-soluble carbodiimides have been
developed whose corresponding urea by products are readily
separated by extraction with water. The most popular
carbodiimide of this kind is EDAC (N-(3-dimethylaminopropyl)-
N’-ethylcarbodiimide), It also allows amide bond formation in
alcohol or aqueous solutions.15 In 1970, Ko¨nig and Geiger first
reported the use of HOBt as a racemization suppressant in
peptide coupling reactions with carbodiimide coupling reagents.
summarized in Table 2. When this work was under progress
Voskressensky et.al12 have reported the cyclization of the Azido-
Ugi- tetrazole derivative derived from benzylamine,
methylisocyanobenzoate, cyclohexanone, and sodium azide by
treating it with NaH in DMF at room temperature. When this
condition was used for the cyclization of 5d derived from 4-
methoxy aniline we did not observe formation of 6d (entry 1).
o
Raising the reaction mass temperature to 100 C did not result in
the formation of 6d. (entry 2). Similarly attempted cyclization
failed in the acidic condition (entry 3). Only starting material was
recovered when the reaction was carried out in the refluxing
toluene (entry 4). Addition of PTSA to refluxing toluene instead
of giving cyclized product 6d gave the acid hydrolyzed product
8d (entry 5).13 Heating 5d with methanol in a sealed tube did not
give the desired product (entry 6). The observed failure of
formation of 6d via cyclization of 5d can be attributed to the
lower nucleophilicity of the aromatic amine functionality (4-
methoxy aniline).
16
HOBt have a role in not only suppressing racemization, but
also enhancing the reactivity.
We envisioned that the desired cyclized derivatives 6d
can be obtained by hydrolysis of the ester moiety present in 5d,17
the acid 8d thus formed is well poised to undergo cyclization
mediated by amide bond formation. Such protocol if developed
will serve as a generic method for the preparation of 6 from 5,
and will be independent of the nucleophilicity of the amine
source used in the Azido-Ugi reaction.
Carbodiimide-mediated amide bond formation remains
a most frequently used technique in organic synthesis. As a major
advantage, carbodiimides do not require prior activation of the
carboxylic acid. Dicyclohexylcarbodiimide (DCC) has been

4
Tetrahedron
Table 2. Optimization of cyclization step.
1883-1887 (c) Tempest, P.; Ma, V.; Thomas, S.; Hua, Z.;
Kelly, M. G. and Hulme, C., Tetrahedron Lett., 2001, 42,
4959-4962 (d) Tempest, P.; Ma, V.; Kelly, M. G.; Jones, W.
and Hulme, C. , Tetrahedron Lett., 2001, 42, 4963-4968 (e)
Nixey, T.; Kelly, M.; Semin, D. and Hulme, C., Tetrahedron
Lett., 2002, 43, 3681-3684 (f) Tempest, P.; Pettus, L.; Gore,
V. and Hulme, C., Tetrahedron Lett., 2003, 44, 1947-1950.
5 Ugi, I.; Steinbruckner, C. Chem. Ber. 1961, 94, 734..
6 R. S. Borisov, A. I. Polyakov, L. A. Medvedeva, V. N.
Khrustalev, N. I.
Entry
Conditions
NaH DMF, RT
NaH DMF, 100 °C
DMF, AcOH 100 °C
Toluene, Reflux
Yield (%)
NR
1
2
3
4
5
6
7
Decompose
NR
NR
PTSA, Toluene, Reflux
MeOH , sealed tube, 80 °C
i. LiOH, aq. MeOH
ii. EDAC.HCl, HOBt
80a
NR
63b
Guranova and L. G. Voskressensky, Org. Lett., 2010, 12,
3894.
a isolated yield of 8d, b isolated yield of 6d over two steps.
To our delight using this approach involving ester
hydrolysis/amide formation, gave us the target compound 6d in
moderate yield (entry 7). Scheme 2 represents the scope of this
generic cyclization protocol of tetrazole derivatives 5 obtained by
the Azido-Ugi reaction. As can be seen various primary aromatic
amines (entries 6a, 6c, 6d, 6e, 6j and 6i), primary cyclic amines
(entries 6b and 6g) were well tolerated and gave the target
product in moderate yield. Suitably protected azetidine-3-one
also gave the desired product (entries 6b, 6g and 6i) in
acceptable yield.
7 T. Nixey, M. Kelly and C. Hulme, Tetrahedron Lett., 2000,
41, 8729.
8 C. Kalinski, M. Umkehrer, S. Gonnard, N. Jager, G. Ross
and W. Hiller,
Tetrahedron Lett., 2006, 47, 2041
9 Blackburn, B. K.; Robarge, K.; Somers, T. C. U.S. Patent
5705890,1998.
In conclusion, Azido-Ugi five-centered four-component
reaction (U-5C-4CR) protocol was developed for the preparation
of tetrazole 5. The scope of this Ugi azide reaction was expanded
to include various primary amines and cyclic ketones. The
tetrazole 5 formed was readily converted into the substituted
tetrazolo[1,5-a][1,4]benzodiazepine 6 via ester hydrolysis/amide
bond formation protocol. Future efforts in our laboratories are
aiming to find a solid supported protocol to close the ring to
rapidly access large libraries of tricyclic tetrazole derivatives 6
and will be reported in due course.
10 Freidinger, R. M.; Evans, B. E.; Bock, M. G. European
Patent EP 0523846, 1993.
11 Spectral data for side product. Methyl 2-(1H-tetrazol-1-yl)
1
benzoate (7): White solid, H NMR (400 MHz, DMSO-d6) δ
3.53 (S, 3H), 7.7 – 7.9 (m, 3H), 8.1(m, 1H), 9.8 (s, 1H)
LCMS-Purity 99.30%, Observed Mass: M+1-205.05,
Expected Mass. 204.18.
Acknowledgements Authors would like to thank Mrs Nilam
Amit Bhor for preparing graphical abstract.
12 R. S. Borisov,, A. I. Polyakov, L. A. Medvedeva, N. I.
Guranova,, L. G. Voskressensky, Russ.Chem.Bull., Int.Ed.,
2012, 61, 1609 – 1615.
Reference and notes
1Ugi, I; Meyr, R.; Fetzer, U.; Steinbrückner, C. Angew.
Chem. 1959, 71, 386.
13 Spectra data of acid intermediate 2-(5-(1-(4-
methoxyphenylamino)
2 Marcaccini, S.; Torroba, T. Nat. Protoc. 2007, 2, 632–639.
3 (a) Wright, D. L.; Robotham, C. V.; Aboud, K.,
Tetrahedron Lett., 2002, 43, 943-946 (b) Xiang, Z.; Luo, T.;
Lu, K.; Cui, J.; Shi, X.; Fathi, R.; Chen, J. and Yang, Z., Org.
Lett., 2004, 6, 3155-3158 (c) Pirrung, M. C.; Sarma, K. D., J.
Am. Chem. Soc., 2004, 126, 444-445. (d) Gedey, S.; Van der
Eycken, J. and Fulop, F., Org. Lett., 2002, 4, 1967-1969.
4 (a) Hulme, C.; Ma, L.; Romano, J. and Morrissette, M.,
Tetrahedron Lett., 1999, 40, 7925-7928 (b) Hulme, C.; Ma,
L.; Cherrier, M-P.; Romano, J.; Morton, G.; Duquenne, C.;
Salvino, J. and Labaudiniere, R., Tetrahedron Lett., 2000, 41,
cyclohexyl)-1H-tetrazol-1-yl)benzoic acid (8d) : White solid,
1H NMR (300 MHz, CDCl3) 1.2o-1.60 (m, 6H), 1.70-2.10 (m,
4H), 3.61 (s, 3H), 5.19 (s, 1H), 6.20 (d, 2H), 6.62 (d, 2H),
6.90 (d, 1H), 7.58 (t, 1H), 7.70 (t, 1H), 8.10 (d, 1H), 13.20
(bs, 1H).
14: Sheehan, J. C.; Hess, G. P. J. Am. Chem. Soc. 1955, 77,
1067–1068.
15 Nozaki, S. J. Peptide Res. 1999, 54, 162.
16: Ko¨nig, W.; Geiger, R. Chem. Ber. 1970, 103, 788–798..

17 Methyl 2-(5-(1-(4-methoxyphenylamino)cyclohexyl)-1H-
1
tetrazol-1-yl)benzoate (5d): White solid, H NMR (300 MHz,
CDCl3) 1.20 - 1.65 (m, 6 H), 1.80- 2.40 (m, 4H), 3.55 (s, 3H),
3.72 (s, 3H), 6.26 (d, 1H, J=7.8 Hz), 6.90 (d, 2H, J=7.5),
7.02 (d, 1H), 7.43 (t, 1H), 7.57 (t, 1H), 8.11 (d, 1H)

6
Tetrahedron
Graphical abstract