A facile and rapid route for the synthesis of novel 1,5-substituted tetrazole hydantoins and thiohydantoins via a TMSN3-Ugi/RNCX cyclization

Article abstract of DOI:10.1016/j.tetlet.2012.07.135

This Letter describes novel methodology for the rapid assembly of new and biologically appealing 1,5-substituted tetrazole-hydantoins and thiohydantoins. The product of a TMSN₃-Ugi multi-component reaction is treated with an excess of isocyanate or isothiocyanate to generate the final scaffold in moderate to good yields. The applicability of this solution phase methodology to the preparation of a small collection of compounds is discussed.

Full text of DOI:10.1016/j.tetlet.2012.07.135

Tetrahedron Letters 53 (2012) 5593–5596
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Tetrahedron Letters
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A facile and rapid route for the synthesis of novel 1,5-substituted tetrazole
hydantoins and thiohydantoins via a TMSN3-Ugi/RNCX cyclization
Federico Medda a, Christopher Hulme a,b,
⇑
a College of Pharmacy, BIO5 Oro Valley, 1580 E. Hanley Blvd, The University of Arizona, Tucson, AZ 85737, United States
b Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter describes novel methodology for the rapid assembly of new and biologically appealing 1,5-
substituted tetrazole-hydantoins and thiohydantoins. The product of a TMSN3-Ugi multi-component
reaction is treated with an excess of isocyanate or isothiocyanate to generate the final scaffold in mod-
erate to good yields. The applicability of this solution phase methodology to the preparation of a small
collection of compounds is discussed.
Received 26 July 2012
Accepted 30 July 2012
Available online 8 August 2012
Keywords:
Published by Elsevier Ltd.
Multi-component reaction
Trimethylsilylazide
Tetrazole
Hydantoin
In the post-genomic era, medicinal chemists have been pro-
vided with an unprecedented series of novel pharmacological tar-
gets validated with small molecules to varying degrees. Currently,
many of these targets are in dire need of small molecule partners to
elucidate their role in disease pathogenesis. As a result, there is an
increasing need to access new dimensions in chemical space in a
quest for the discovery of biologically relevant molecules in a rapid
and economic fashion. To this end, studies on the discovery and
utility of multi-component reactions offer an extremely attractive
route to deliver a multitude of new fundamental methodologies
and subsequently scaffolds for evaluation in biological systems.1
Specifically, the hydantoin (imidazoline-2,4-dione) scaffold rep-
resents a common motif in many biologically relevant compounds
with anti-convulsant, anti-muscarinic, anti-ulcer, anti-viral, and
anti-diabetic activities to name but a few.2 Interesting examples
are represented by known drugs Azimilide3 and Fosphenytoin
(Cerebyx,Ò ProdilantinÒ) and preparations of this class of molecule
still attract the interest of organic and medicinal chemists as noted
in recent work.4 In analogous fashion, 1,5-disubstituted tetrazoles
exist in a pharmacologically rich vein of chemical space,5 with their
value thought to reside in their capacity to act as effective cis-
amide bioisosteres.6 Consequently, an on-going research effort in
this laboratory has been carried out to explore the utility of the
so-called Ugi-azide MCR which delivers a scaffold in one step
containing a 1,5-disubstituted tetrazole and either a secondary or
tertiary amine, generally imparting desirable physicochemical
properties on the MCR product.7 Reported in 1961, the Ugi-azide
MCR (or TMSN3 modified Ugi reaction) differs from the classical
Ugi MCR in that an azide 4 traps out the intermediate nitrilium
ion 6 (replacing the carboxylic acid seen in the Ugi MCR) leading
to the formation of the final 1,5-disubstituted tetrazole 8 (Scheme
1).8
In a continuation of recent studies, we herein describe a strat-
egy based on a post-condensation modification of the TMSN3-Ugi
reaction product 8, which leads to the unprecedented and pharma-
cologically relevant bis-heterocyclic scaffold 9 (Scheme 2). It was
envisioned that the employment of ethyl glyoxalate 1 as the car-
bonyl component of the MCR would afford the TMSN3-Ugi product
8 where subsequent treatment of 8 with an isocyanate or isothio-
cyanate enables rapid assembly of the target scaffold 9 in two
operationally friendly synthetic operations (Scheme 2).
Thus, ethyl glyoxalate 1 and n-butylamine 2a were mixed in
dichloroethane (DCE) and subjected to microwave irradiation to
pre-form the corresponding Schiff base (Scheme 3). Addition of tri-
fluoroethanol as solvent, the aryl-isocyanide 3a, and TMSN3 with
stirring under ambient conditions afforded the condensation prod-
uct in good isolated yield.9 8a was treated with an excess of isocy-
anate 10a in ethanol at ambient temperature and 9a precipitated
as a microcrystalline powder directly from the reaction mixture,
isolated in a satisfactory 77% yield.10 The structure of 9a was
unambiguously confirmed by X-ray crystallography (Fig. 1).
With satisfactory conditions in hand, the reaction scope in
terms of substrate tolerance was explored. A small collection of
12 examples was prepared according to the same synthetic proto-
col (9a–l, Fig. 2). Seven amines (2a–g), six isonitriles (3a–f), six
⇑
Corresponding author. Address: Department of Pharmacology and Toxicology,
College of Pharmacy, BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley
Blvd., Oro Valley, AZ 85737, USA. Tel.: +1 520 626 5322.
E-mail address: hulme@pharmacy.arizona.edu (C. Hulme).
0040-4039/$ - see front matter Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2012.07.135

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F. Medda, C. Hulme / Tetrahedron Letters 53 (2012) 5593–5596
Scheme 1. Four-component TMSN3-UGI reaction mechanism.
Scheme 2. Retrosynthetic analysis (X = O or S).
Scheme 3. Synthesis of 9a via post-condensation modification of the TMSN3-Ugi product 8a.
Table 1
Optimization of the final cyclization reaction
Compound
R3NCX (n equiv)
T (°C)
Time (h)
Methoda
9a
9b
9c
9d
9e
9f
9g
9h
9i
4-Br-PhNCO (10a, 3)
4-F-PhNCO (10b, 6)
4-EtO-PhNCO (10c, 6)
PhNCO (10d, 2)
4-EtO-PhNCO (10c, 3)
4-EtO-PhNCO (10c, 3)
4-EtO-PhNCO (10c, 3)
3-Me-PhNCO (10e, 6)
EtNCO (10f, 3)
rt
rt
rt
rt
rt
rt
120
120
140
130
180
180
12
36
36
24
6
2
1.5
2
2
2
2
2
A
A
A
A
A
A
B
B
B
B
B
B
9j
9k
9l
PhNCO (10d, 6)
TMSNCS (10g, neat)
TMSNCS (10g, neat)
a
Method A: EtOH, room temperature; Method B: EtOH, microwave irradiation.
optimal for different examples (Table 1). Target compounds 9a–f
formed smoothly at room temperature (49–77%), and further
improvement was gained in the formation of bis-heterocyclics
9g–j through the use of microwave irradiation at higher tempera-
tures, affording 9g–j in good yields (59–99%). Remarkably, most of
the final products 9a–j were formed as microcrystalline solids and
easily isolated by suction filtration, thus greatly facilitating the
production process.
Intrigued by the possibility to replace one of the carbonyl func-
tional groups of the hydantoin core with a thio-carbonyl moiety,
we employed neat TMSNCS for the production of 9k and 9l. Ele-
vated temperatures generated by microwave irradiation enabled
Figure 1. Crystal structure of 9a.
isocyanates (10a–f), and one isothiocyanate (10g) were employed
to impart significant diversity in the final collection of analogues.
The TMSN3-Ugi condensations afforded the desired condensation
products in modest to high yields (8a–i, 21–60%) and generally,
treatment of these products with an excess of isocyanate afforded
the expected products 9a–j in good to excellent yields (49–99%).
Stoichiometry and conditions employed (room temperature vs.
microwave irradiation, method A vs. method B, respectively) were

F. Medda, C. Hulme / Tetrahedron Letters 53 (2012) 5593–5596
5595
Figure 2. Example analogues (x% = TMSN3-Ugi yield; y% = final cyclization yield; Z = method employed).
Res. 1998, 20, 178; (c) Matzukura, M.; Daiku, Y.; Ueda, K.; Tanaka, S.; Igarashi, T.;
Minami, N. Chem. Pharm. Bull. 1992, 40, 1823; (d) Knabe, J.; Baldauf, J.; Ahlhelm,
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the formation of 9k (75% yield), and 9l (25% yield) respectively. The
difference in the yields between 9k and 9l can be rationalized by
the weaker nucleophilic character of the aniline-like TMSN3-Ugi
product 8l.
In summary, a series of novel and biologically appealing 1,5-
substituted tetrazole-hydantoins and thiohydantoins were pre-
pared in two steps via rigidification of the TMSN3-Ugi condensa-
tion product through treatment with an excess of isocyanates or
isothiocyanate. Being characterized by four points of diversity,
the novel chemotypes are rapidly assembled in two operationally
friendly steps and the methodology proved to be general and toler-
ated a wide range of functional groups. Due to the potential biolog-
ical activity of the novel scaffolds and the applicability of this
methodology to high-throughput synthesis, we expect this article
to be embraced by the lead generation community.
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Acknowledgements
This research was supported by the NIH (RC2MH090878 and
P41GM086190). We acknowledge Dr. Sue A. Roberts and Mr. Gab-
riel H. Hall for small molecule X-ray crystal structure determina-
tion, and are grateful to Dr. David Bishop for proofreading and
editing the final version of the text and graphics.
6. Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379.
7. For recent examples of post-condensation modifications of Ugi and Passerini
products see: (a) Shaw, A. Y.; McLaren, J. A.; Nichol, G. S.; Hulme, C. Tetrahedron
Lett. 2012, 53, 2592; (b) Xu, Z.; Shaw, A. Y.; Dietrich, J.; Cappelli, A. P.; Nichol,
G.; Hulme, C. Mol. Divers. 2012, 16, 73; (c) Shaw, A. Y.; Xu, Z.; Hulme, C.
Tetrahedron Lett. 2012, 53, 1998; (d) Gunawan, S.; Petit, J.; Hulme, C. ACS Comb.
Sci. 2012, 14, 160; (e) Gunawan, S.; Nichol, G.; Hulme, C. Tetrahedron Lett. 2012,
53, 1664; (f) Shaw, A. Y.; Medda, F.; Hulme, C. Tetrahedron Lett. 2012, 53, 1313;
(g) Xu, Z.; Shaw, A. Y.; Dietrich, J.; Cappelli, A. P.; Nichol, G.; Hulme, C. Mol.
Diversity 2012, 16, 73; (h) Shaw, A. Y.; McLaren, J. A.; Nichol, G. S.; Hulme, C.
Tetrahedron Lett. 2012, 53, 2592; (i) Shaw, A. Y.; Xu, Z.; Hulme, C. Tetrahedron
Lett. 2012, 53, 1998; (j) De Moliner, F.; Hulme, C. Org. Lett. 2012, 14, 1354.
8. (a) Ugi, I.; Steinbruckner, C. Chem. Ber. 1961, 94, 734; (b) Ugi, I.; Steinbruckner,
C. Angew. Chem. 1960, 72, 267.
References and notes
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10. General procedure for the preparation of 9a: Ethyl glyoxalate (1, 50% solution
in toluene, 1.1 g, 5.28 mmol, 1 equiv) and 1-butylamine (2a, 385 mg,
was added, and the reaction was stirred at room temperature for 12 h. The final
product 9a precipitated from the reaction mixture and was isolated by suction
filtration as a white microcrystalline solid (220 mg, 0.43 mmol, 77%). Crystals
suitable for X-ray crystal structure determination were obtained by means of
slow evaporation from EtOAc–hexane. Mp 185–188 °C; 1H NMR (400 MHz,
CDCl3) d: 7.58–7.39 (m, 5H), 7.28–7.24 (m, 2H), 5.24 (s, 1H), 3.92–3.85 (m, 1H),
3.24–3.16 (m, 1H), 2.22 (s, 3H), 1.58–1.54 (m, 2H), 1.35–1.33 (m, 2H), 0.92 (t,
3H, J = 7.4 Hz); 13C NMR (100 MHz, CDCl3) d: 165.3 (C), 154.4 (C), 150.7 (C),
141.3 (C), 133.0 (CH), 132.6 (CH), 131.0 (CH), 130.9 (C), 130.4 (C), 129.7 (C),
128.1 (CH), 127.6 (CH), 122.7 (C), 54.7 (CH), 53.6 (CH3), 42.5 (CH2), 42.5 (CH2),
29.9 (CH2), 13.9 (CH3); LC MS [M+1]+ m/z 503.00.
5.28 mmol, 1 equiv) were dissolved in DCE (10 mL) in
a 35-mL vial and
subjected to microwave irradiation at 120 °C for 1 h using a CEM initiator.
CF3CH2OH (5 mL) was added, followed by azidotrimethylsilane (4, 610 mg,
5.28 mmol, 1 equiv) and 2-chloro-6-methyl-phenylisocianide (3a, 797 mg,
5.28 mmol, 1 equiv), and the resulting mixture was stirred at room
temperature for 12 h. After removal of the solvent under reduced pressure,
8a was purified by silica gel column chromatography (EtOAc–hexane, 0–30%)
and isolated as a pale yellow oil (500 mg, 1.42 mmol, 54%). 8a (250 mg,
0.80 mmol, 1 equiv) was dissolved in dry ethanol (2 mL) under a nitrogen
atmosphere, 4-bromo-phenylisocyanate (10a, 474 mg, 2.40 mmol, 3 equiv)