Ugi/Robinson-Gabriel reactions directed toward the synthesis of 2,4,5-trisubstituted oxazoles

Article abstract of DOI:10.1016/j.tetlet.2012.02.030

This Letter discloses a novel concise synthesis of a series of 2,4,5-trisubstituted oxazoles via a tandem Ugi/Robinson-Gabriel sequence. Herein, 2,4-dimethoxybenzylamine 1 was used as an ammonia equivalent in combination with arylglyoxal 3 and supporting Ugi reagents, an isonitrile and carboxylic acid. As such the product of the acid treated Ugi intermediate is ideally configured to undergo a Robinson-Gabriel cyclodehydration reaction to yield the desired oxazole scaffold 5.

Full text of DOI:10.1016/j.tetlet.2012.02.030

Tetrahedron Letters 53 (2012) 1998–2000
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ugi/Robinson–Gabriel reactions directed toward the synthesis
of 2,4,5-trisubstituted oxazoles
Arthur Y. Shaw a, Zhigang Xu a, Christopher Hulme a,b,
⇑
a Department of Pharmacology and Toxicology, College of Pharmacy, BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd., Oro Valley, AZ 85737, USA
b Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
This Letter discloses a novel concise synthesis of a series of 2,4,5-trisubstituted oxazoles via a tandem
Ugi/Robinson–Gabriel sequence. Herein, 2,4-dimethoxybenzylamine 1 was used as an ammonia equiva-
lent in combination with arylglyoxal 3 and supporting Ugi reagents, an isonitrile and carboxylic acid. As
such the product of the acid treated Ugi intermediate is ideally configured to undergo a Robinson–Gabriel
cyclodehydration reaction to yield the desired oxazole scaffold 5.
Received 28 January 2012
Revised 2 February 2012
Accepted 6 February 2012
Available online 13 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reactions
Ugi reaction
Robinson–Gabriel reaction
2,4,5-Trisubstituted oxazoles
Vilsmeier–Haack reaction
Multicomponent reactions (MCRs) are powerful transformations
in which three or more starting materials are incorporated in a
one-pot manner to produce highly decorated products. Isocyanide-
based multicomponent reactions (IMCRs) are of particular interest
owing to the large number of starting materials available and a wide
range of readily accessible pharmacologically relevant scaffolds.1
The most well-known IMCR, the Ugi reaction, is carried out through
the reaction of an amine, carbonyl compound, carboxylic acid, and
isocyanide, which undergoes a condensation step to afford the cor-
known Robinson–Gabriel oxazole synthesis which involves intra-
molecular cyclization of an amide carbonyl onto a ketone group
embedded in an N-acyl
a-aminoketone 6 with ensuing the elimi-
nation of water.10,11 To continue our research theme of developing
robust methodologies with high user uptake in the pharmaceutical
sector, it was envisioned that the application of 2,4-dimethoxyben-
zylamine 1 in the Ugi reaction, previously exploited by Sheehan
et al,12 in combination with arylglyoxal 3 and supporting reagents
would enable oxazole synthesis in one single second step through
acid mediated deprotection of the 2,4-dimethoxybenzyl protecting
group followed by concomitant cyclodehydration (i.e., the Robinson–
Gabriel reaction), Scheme 1.
responding functionalized
a
-acylamino amide.2 The usefulness of
this process as a powerful diversity generating step is demonstrated
by tremendous applications in the synthesis of potential drug-like
libraries of small molecules.1c,3 Indeed, an increasing number of
elaborate, operationally friendly post-condensation modifications
have been developed that employ the Ugi MCR to install structural
diversity with strategically positioned internal amine nucleophiles
promoting a series of ring-closing events.4 This methodology has
been utilized for the design of pharmacologically relevant molecular
scaffolds, some of which have ultimately led to clinical evaluation.5
Oxazoles are a class of five-membered heterocycles with plenti-
ful applications in the pharmaceutical industry and natural prod-
ucts chemistry.6 Thanks to the merits of their useful properties
and widespread distribution in nature, methodologies to develop
the oxazole core structure have attracted a great deal of attention
over the years.7–9 Among the developed methodologies is the well-
Herein, we report the successful optimization of this methodol-
ogy and production of a series of congeners submitted to the
MeO
OMe
NH2
R1
OH
R2
O
+
HN
Ar
O
2
1
1. Ugi Reaction
N
R1
O
+
2. Robinson-Gabriel
Reaction
O
O
5
+
CN R2
Ar
4
3
⇑
Corresponding author. Tel.: +1 520 626 5322.
E-mail address: hulme@pharmacy.arizona.edu (C. Hulme).
Scheme 1. Concise synthesis of 2,4,5-trisubstituted oxazole 5 via a tandem Ugi/
Robinson–Gabriel sequence.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.030

A. Y. Shaw et al. / Tetrahedron Letters 53 (2012) 1998–2000
1999
O
MeO
N
OMe
NH2
HN
OH
+
F3C
F3C
MeO
OMe
N
F3C
O
O
MeOH
rt, 36 hr
1
2a
O
N
H
O
O
+
O
7, 72%
NC
+
5a
, 57%
H+
O
4a
-H2O
Cyclization
F3C
O
3a
H
N
Debenzylation
N
H
O
O
6
Scheme 2. Synthesis of oxazole 7.
Molecular Libraries Small Molecule Repository (MLSMR). Thus, the
Ugi product 5a was prepared via an Ugi reaction (MeOH, rt, 36 h,
57%) that utilized 2,4-dimethoxybenzylamine 1, 4-trifluorobenzoic
acid 2a, phenylglyoxal 3a, and n-butylisonitrile 4a, Scheme 2.
The 2,4-dimethoxybenzyl moiety in the Ugi product 5a can be
easily removed upon acid treatment to generate the N-acyl
HN
N
F3C
O
O
a-aminoketone 6, Scheme 2. Cyclodehydration conditions for the
conversion of the N-acyl -aminoketone 6 to the oxazole 7 were
a
CHO
subsequently examined. Interestingly, exposure of 5a to 1.2 equiv
of phosphorus oxychloride (POCl3) (DMF, 80 °C, 2 h) resulted in
debenzylation and desired cyclodehydration. However, significant
formylation of the aryl ring derived from phenylglyoxal was also
8
, 51%
Figure 1. Formylated oxazole
8
derived from sequential Robinson–Gabriel/
Vilsmeier–Haack reactions.
F
HN
F
HN
F
HN
HN
O
N
HN
N
N
O
O
N
N
N
O
O
O
O
O
O
N
F
F
O
O
F
Cl
9
10
11
12
13
(63%, 68%)
(47%, 53%)
(51%, 62%)
(48%, 60%)
(42%, 62%)
F3C
HN
HN
HN
HN
HN
N
N
S
N
N
N
N
O
O
O
O
O
N
O
O
O
O
O
OMe
Cl
OCF3
OCF3
OCF3
Cl
14 (65%, 73%)
15 (61%, 66%)
16 (57%, 71%)
17 (46%, 62%)
18 (63%, 72%)
O
O
HN
N
N
N
H
N
O
H
N
N
O
CbzN
O
HN
O
CHO
O3CF
19 (50%, 67%)
20 (63%, 71%)
21 (63%, 59%)
Figure 2. Synthesis of 2,4,5-trisubstituted oxazoles 9–21 (Ugi % isolated yield, deprotection/cyclodehydration % isolated yield).

2000
A. Y. Shaw et al. / Tetrahedron Letters 53 (2012) 1998–2000
Tetrahedron Lett. 1939, 2009, 50; (d) Xu, Z; Shaw, A. Y.; Dietrich, J; Cappelli, A.
P.; Nichol, G.; Hulme, C. Mol. Div. 2012, in press.
observed as the result of an additional Vilsmeier–Haack reaction
exemplified in oxazole 8, Figure 1.13
5. (a) Hulme, C.; Peng, J.; Tang, S. Y.; Burns, C. J.; Morize, I.; Labaudiniere, R. J. Org.
Chem. 1998, 63, 8021; (b) Nixey, T.; Hulme, C. Tetrahedron Lett. 2002, 43, 6833;
(c) Habashita, H.; Kokubo, M.; Hamano, S. I.; Hamanaka, N.; Toda, M.;
Shibayama, S.; Tada, H.; Sagawa, K.; Fukushima, D.; Maeda, K.; Mitsuya, H. J.
Med. Chem. 2006, 49, 4140; (d) Nishizawa, R.; Nishiyama, T.; Hisaichi, K.;
Matsunaga, N.; Minamoto, C.; Habashita, H.; Takaoka, Y.; Toda, M.; Shibayama,
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Chem. Lett. 2007, 17, 727; (e) Huang, Y.; Dömling, A. Chem. Biol. Drug Des. 2010,
76, 130.
In further studies, upon treatment of 5 in 10% TFA (trifluoroace-
tic acid)/DCE at reflux for 20 h, only N-acyl
a-aminoketone 6 was
observed. Moreover, use of 10% TFAA (trifluoroacetic anhydride)
in DCM (rt, 16 h) as the possible dehydrating reagent afforded only
trace amounts of the desired product. Consequently, Robinson–
Gabriel reaction conditions were employed in which 5 was treated
with concentrated sulfuric acid (H2SO4) at 60 °C for 2 h to success-
fully afford oxazole 7 in a highly acceptable 72% isolated yield,
Scheme 2.14 Encouraged by the robustness of this protocol, a series
of the oxazole products were thus synthesized in good isolated
yields, Figure 2. Several isocyanides such as cyclopentyl-9, cyclo-
hexyl-10, n-pentyl-11, benzyl-12, and n-butyl-13 were utilized
and all performed well in both steps of the methodology. Little ef-
fect on the yield of the two-step reaction sequence was observed
when either 4-chlorophenylglyoxal (13–15) or 4-trifluorometh-
oxyphenylglyoxal (16–19) was employed.
As noted earlier, an additional Vilsmeier–Haack reaction was
observed when utilizing POCl3 in DMF at 80 °C for 2 h. As shown
in Figure 2, the Ugi product with a N-Cbz protecting group was sub-
jected to the Robinson–Gabriel/Vilsmeier–Haack conditions to gen-
erate the oxazole 20 which bears a formyl group at the 4-position of
the aryl ring derived from the phenylglyoxal, leaving the Cbz pro-
tecting group intact. Conversely, the Ugi product treated with con-
centrated H2SO4 at 60 °C for 4 h resulted in the Robinson–Gabriel
cyclodehydration reaction and also removed the Cbz protecting
group in the same pot to yield the corresponding oxazole 21 with
a free 2° amine. As a result, both oxazole analogs 20 and 21 can
be utilized for further diversification of the oxazole scaffold.
In summary, we have successfully employed an Ugi/Robinson–
Gabriel sequence in which an ammonia equivalent and an arylgly-
oxal were incorporated into the initial Ugi reaction and subsequent
acid treatment with H2SO4 enabled amidic deprotection and
Robinson–Gabriel cyclization to afford the corresponding tri-
substituted oxazole-carboxamide analogs 5.
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Acknowledgments
13. Vilsmeier, A.; Haack, A. Ber. 1927, 60, 119.
14. For the preparation of Ugi product 5 and general library protocol: To a solution of
2,4-dimethoxybenzenylamine 1 (334.2 mg, 2.0 mmol), 4-trifluorobenzoic acid
2a (380 mg, 2.0 mmol), phenylglyoxal monohydrate 3a (304 mg, 2.0 mmol),
and n-butylisonitrile 4a (166 mg, 2.0 mmol) in methanol (3 mL), the resulting
mixture was stirred at room temperature for 36 h. The reaction solution was
concentrated in vacuo and the residue was purified by column
chromatography (hexane/ethyl acetate, 1/9 to 1/3) to obtain the Ugi product
5 (633 mg, 57%). For the preparation of oxazole product 7 and general library
protocol: To a solution of Ugi product 5 (600 mg, 1.07 mmol) in concentrated
sulfuric acid (10 mL), the reaction mixture was stirred at 60 °C for 2 h and
cooled in an ice bath. Ethyl acetate (30 mL) was added to the solution, followed
by the addition of 1 N NaOH (30 mL) to neutralize. The organic layer was
washed with brine, dried over MgSO4, evaporated in vacuo to give the crude
product 7. The crude product was further purified by silica gel column
We would like to thank the Office of the Director, NIH, and the
National Institute of Mental Health for funding (1RC2MH090878-
01). Particular thanks to N. Schechter (PSM) for copy editing.
References and notes
1. (a)For relevant reviews see: Multicomponent Reactions; Zhu, J., Bienayme, H.,
Eds.; Wiley-VCH: Weinheim, 2005; (b) Hulme, C.; Gore, V. Curr. Med. Chem.
2003, 10, 51; (c) Dömling, A. Chem. Rev. 2006, 106, 17; (d) Hulme, C.; Lee, Y.-S.
Mol. Div. 2008, 12, 1; (e) Bienayme´, H.; Hulme, C.; Oddon, G.; Schmitt, P. Eur. J.
Chem. 2000, 6, 3321; (f) Hulme, C.; Nixey, T. Curr. Opin. Drug Discovery Dev.
2003, 6, 921; (g) Akritopoulou-Zanze, I.; Djuric, S. W. Heterocycles 2007, 73, 125.
2. (a) Ugi, I. Angew. Chem. 1962, 74, 9; (b) Ugi, I.; Steinbrucker, C. Chem. Ber. 1961,
94, 734; (c) Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8; (d) Ugi, I.; Domling, A.;
Horl, W. Endeavor 1994, 18, 115.
chromatography (hexanes/ethyl acetate, 1/9 to 1/4) to afford oxazole
7
(299 mg, 72%) as 8.40 (ddd,
a
white solid. 1H NMR (400 MHz, CDCl3)
d
J = 16.9, 14.1, 8.9 Hz, 3H), 8.27 (d, J = 7.7 Hz, 1H), 7.74 (t, J = 7.7 Hz, 1H), 7.64 (t,
J = 7.8 Hz, 1H), 7.59–7.35 (m, 4H), 3.69–3.39 (m, 2H), 1.73–1.61 (m, 2H), 1.55–
1.40 (m, 2H), 1.06–0.95 (m, 3H) ppm. 13C NMR (100 MHz, CDCl3) d 161.02,
156.89, 152.72, 130.78, 130.09, 129.56, 128.44, 128.37, 127.34, 127.30, 127.04,
123.42, 123.38, 39.18, 31.84, 20.29, 13.83 ppm. ESI 389 [MH]+.
3. Akritopoulou-Zanze, I. Curr. Opin. Chem. Biol. 2008, 12, 324.
4. (a) Nixey, T.; Tempest, P.; Hulme, C. Tetrahedron Lett. 2002, 43, 1637; (b) Hulme,
C.; Ma, L.; Romano, J.; Cherrier, M. P.; Salvino, J.; Labaudiniere, R. Tetrahedron
Lett. 1889, 2000, 41; (c) Hulme, C.; Chappeta, S.; Griffith, C.; Lee, Y. S.; Dietrich, J.