Microwave-mediated synthesis and manipulation of a 2-substituted-5- aminooxazole-4-carbonitrile library

Article abstract of DOI:10.1016/j.tetlet.2012.01.081

A 2-substituted-5-aminooxazole-4-carbonitrile library has been synthesised and modified via microwave-mediated and flow chemistries. One synthesised compound, 5-(1H-pyrrol-1-yl)-4-(1H-tetrazol-5-yl)-2-(thien-2-yl)oxazole, contains three distinct heterocyc

Full text of DOI:10.1016/j.tetlet.2012.01.081

Tetrahedron Letters 53 (2012) 1656–1659
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-mediated synthesis and manipulation of a
2-substituted-5-aminooxazole-4-carbonitrile library
John Spencer a, , Hiren Patel a, Jahangir Amin a, Samantha K. Callear b, Simon J. Coles b, John J. Deadman c,
,
⇑
Christophe Furman d, Roxane Mansouri d, Philippe Chavatte d, Régis Millet d
a School of Science, University of Greenwich at Medway, Chatham Maritime, Kent ME4 4TB, UK
b UK National Crystallography Service, School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UK
c Avexa Ltd, 576 Swan Street, Richmond, Victoria 3121, Australia
d Université Lille Nord de France, ICPAL, EA 4481, IFR114, 3 rue du Professeur Laguesse, BP-83, F-59006 Lille, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A 2-substituted-5-aminooxazole-4-carbonitrile library has been synthesised and modified via micro-
wave-mediated and flow chemistries. One synthesised compound, 5-(1H-pyrrol-1-yl)-4-(1H-tetrazol-5-
yl)-2-(thien-2-yl)oxazole, contains three distinct heterocycles attached to the central oxazole core, high-
lighting the structural diversity of this approach. Three oxazoles had micromolar ki values against can-
nabinoid (CB1/CB2) receptors.
Received 6 December 2011
Revised 9 January 2012
Accepted 20 January 2012
Available online 28 January 2012
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Keywords:
Microwave-assisted synthesis
Oxazoles
Parallel synthesis
Flow chemistry
The oxazole scaffold has found widespread utility in medicinal
chemistry and is present in a number of natural products.1 Several
synthetic routes to these heterocycles have been described with
many recent examples displaying high levels of atom economy,
amenable to parallel synthesis.2
Functionalise, e.g.cyclise, amide
/ sulfonamide, diazotisation
NH2
O
R1
The 2-substituted-5-aminooxazole-4-carbonitrile skeleton
(Fig. 1) provides a drug-like template for diversity orientated syn-
thesis3 of a low molecular weight fragment library by functionalisa-
tion at the 2-, 4- and 5-positions. For example, variation of R1 would
enable the introduction of alkyl, aryl and heterocyclic units of var-
ied size and electronic properties. Next, the primary amine group
was identified as a useful synthon towards heterocycles or amides,
and the nitrile function is amenable to cycloaddition and reduction
chemistry. The ultimate aim was to carry out each step in a micro-
wave reactor or via flow chemistry to speed up the reaction and
achieve high yields.
N
N
Various functionalities enabling
H bonding, steric, electronic
manipulations.
Modify,
e.g. cycloaddition, reduction
Figure 1. Schematic aim to diversify an oxazole fragment scaffold.
reactions worked generally very well for heterocyclic, aromatic
and cyclic compounds although they were less successful for al-
kyl-containing oxazoles such as the example whose preparation
We synthesised the oxazoles 44 using microwave conditions5
and the reactions were usually high yielding (Table 1). The mecha-
nism is likely to involve the formation of an amide intermediate fol-
lowed by an intramolecular nucleophilic attack by the carbonyl
function on one of the nitrile groups as a key step. The microwave
was attempted using acetyl chloride (variable yields obtained).6
A
number of derivatives were characterised in the solid state, includ-
ing 4c (CCDC 850249) and 4f (CCDC 850250).
Pyrrole-substituted oxazoles 5 were synthesised in virtually
quantitative yields via reaction of oxazoles 4 with 2,5-dimethoxy-
tetrahydrofuran in acetic acid in a microwave reactor (Table 2).7
Tetrazoles are often deployed as carboxylic acid bioisosteres in
medicinal chemistry.8 We initially attempted unsuccessfully to
⇑
Corresponding author. Tel.: +44 (0) 208 331 8215; fax: 44 (0) 208 331 9805.
E-mail addresses: j.spencer@gre.ac.uk, j.spencer@greenwich.ac.uk (J. Spencer).
Present address: JDJ Bioservices, 576 Swan Street, Richmond, Victoria 3121,
Australia.
0040-4039/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.081

J. Spencer et al. / Tetrahedron Letters 53 (2012) 1656–1659
1657
Table 1
Microwave-mediated synthesis of an oxazole library
R1
NMP
SOCl2
CN
O
N
R1CO2H
R1COCl
+
O
MW
120 °C
H2N
CN
S
O
NH2
NC
2
1
4
HO
3
4c
4f
Entry
1
Product
R1
Yielda (%)
93
Entry
7
Product
R1
Yielda (%)
94
S
O
4a
4b
4c
4d
4g
4h
4i
O
O
2
3
4
77
71
81
8
75
95
71
NC
Br
9
10
4j
N
N
F
5
6
4e
4f
96
95
11
4k
84
N
a
Isolated yield.
Table 2
Cyclisation reactions on oxazoles
R1
R1
R1
O
N
µW, AcOH,
115 °C, 15 min
Bu2SnO
Me3SiN3
O
N
O
N
N
HN
N
µW, 1,4-dioxane,
140 °C, 4 h.
MeO
O
N
NC
N
NH2
NC
N
6
OMe
4
5
Entry
1
Product
R1
Yield (%)
97
Entry
5
Product
R1
Yield (%)
S
S
5a
6a
52
65
2
5f
97
6
6f
(continued on next page)

1658
J. Spencer et al. / Tetrahedron Letters 53 (2012) 1656–1659
Table 2 (continued)
Entry
Product
R1
Yield (%)
98
Entry
7
Product
R1
Yield (%)
98
O
O
3
4
5g
6g
NC
5h
97
—
—
—
—
form tetrazole analogues using a published general microwave-
mediated synthesis from nitriles, with sodium azide and zinc bro-
mide in DMF and water.9 This lack of reactivity may be due to ste-
ric hindrance. Sterically hindered nitriles have been shown to be
converted into tetrazoles using trimethylsilyl azide and diabutyl-
tin-oxide in 1,4-dioxane in a microwave oven.10 Using these condi-
tions the desired compounds 6 were obtained in reasonable yields
(Table 2). Their structures were confirmed by 1H NMR spectros-
copy (DMSO-d6) by the appearance of a very low-field NH signal
at ca. 17 ppm.11 Analogue 6a is quite remarkable in that it contains
an oxazole scaffold substituted with three different heterocycles,
underlining the broad synthetic scope of this approach. We did
not attempt the cyclisation reaction of 5h due to the presence of
two nitrile functionalities. Analogues 5g (CCDC 850252) and 6g
(CCDC 850255) were characterised in the solid state.
Further diversification of the oxazole scaffold is summarised in
Scheme 1. Hence, the nitrile functionality in 5 was reduced, in an
H-Cube,12 to form the primary amines 7 (the purity of 7 was lim-
ited to ca. 80%). The next step investigated was the Sandmeyer
reaction on 4c.13 The yield of 8c was moderate (52%) and a mixture
of two compounds was observed from the crude 1H NMR spectrum.
The other compound was presumed to be a deaminated 2-H com-
pound, which was not isolated. Bromide 8c was deemed to be a
suitable precursor for Buchwald–Hartwig aminations.14 An
R1
N
O
H-Cube, RaneyNi
CatCart
(Table 2)
R2
N
2
O
N
5
-1
°
1 ml min , 70 C,
50 bar.
NH2
NC
7f
(R =H)
7g (R2=OMe)
NH2
4
t-butyl nitrite, CuBr2
PS-NMM, R3COCl.
Amine (NHR4R5), Pd(OAc)2,
(for 4c)
BINAP, KO-t-Bu,
R1
°
µW, 170 C, 15 min,
1,4-dioxane.
O
N
O
N
O
N
NR4R5
O
NC
Br
NC
8c
9
N
NC
H
R3
1-Boc-piperazine, DBU,
11
Pd catalyst, t-Bu3P. HBF4,
Product NR4R5 Yield (%)
°
Mo(CO)6, µW, 170 C, 6 min, THF
9c1
Product
R1
R3
Yield (%)
77
O
52
N
S
11a
COCH2CO2Me
30
N
9c2
9c3
COMe
51
66
11d
11f
O
N
N
Ph
COCH2CO2Me
63
O
O
N
NBoc
N
NC
O
10c
Scheme 1. Reactions of oxazoles.

J. Spencer et al. / Tetrahedron Letters 53 (2012) 1656–1659
1659
Table 3
Supplementary data
Displacement of hCB1 and hCB2 at 10À5 M concentration
Supplementary data (experimental and analytical data (1H, 13C
spectra, MS, elemental analysis) for compounds are provided, as
well as X-ray crystallography) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2012.01.081.
HO
HO
OH
References and notes
CP 55,940
1. See, for example: (a) Wang, B.; Hansen, T. M.; Weyer, L.; Wu, D.; Wang, T.;
Christmann, M.; Lu, Y.; Ying, L.; Engler, M. M.; Cink, R. D.; Lee, C. S.; Ahmed, F.;
Forsyth, C. J. J. Am. Chem. Soc. 2011, 133, 1506–1516; (b) Bagley, M. C.; Dale, J.
W.; Meritt, E. A.; Xiong, X. Chem. Rev. 2005, 105, 685–714; (c) Jin, Z. Nat. Prod.
Rep. 2011, 28, 1143–1191.
Entry
Oxazole
Ki (Â10À5 M)
hCB2
hCB1
1
2
3
5f
7f
7g
1.42 1.07
1.87 1.01
10.18 2.51
—
2. (a) Thompson, M. J.; Adams, H.; Chen, B. J. Org. Chem. 2009, 74, 3856–3865; (b)
Verrier, C.; Martin, T.; Hoarau, C.; Marsais, F. J. Org. Chem. 2008, 73, 7383–7386;
(c) Ohnmacht, S. A.; Mamone, P.; Culshaw, A. J.; Greaney, M. F. Chem. Commun.
2008, 1241–1243; (d) Zhang, J.; Coqueron, P. Y.; Vors, J. P.; Ciufolini, M. A. Org.
Lett. 2010, 12, 3942–3945; (e) Strotman, N. A.; Chobanian, H. R.; Guo, Y.; He, J.;
Wilson, J. E. Org. Lett. 2010, 12, 3578–3581; (f) Shi, B.; Blake, A. J.; Lewis, W.;
Campbell, I. B.; Judkins, B. D.; Moody, C. J. J. Org. Chem. 2010, 75, 152–161; (g)
Shibahara, F.; Yamaguchi, E.; Murai, T. J. Org. Chem. 2011, 76, 2680–2693; (h)
Boogaerts, I. I. F.; Nolan, S. P. J. Am. Chem. Soc. 2010, 132, 8858–8859; (i) Wu, B.;
Wen, J.; Zhang, J.; Li, J.; Xiang, Y.-Z.; Yu, X.-Q. Synlett 2009, 500–504.
3. (a) Delvare, C.; Harris, C. S.; Hennequin, L.; Koza, P.; Lambert-van der Brempt,
C.; Pelleter, J.; Willerval, O. ACS Comb. Sci. 2011, 13, 449–452; (b) Thomas, G. L.;
Wyatt, E. E.; Spring, D. R. Curr. Opin. Drug Discovery Dev. 2006, 9, 700–712; (c)
Dandapani, S.; Marcaurelle, L. A. Curr. Opin. Chem. Biol. 2010, 14, 362–370.
4. (a) Freeman, F.; Kim, D. Tetrahedron Lett. 1989, 30, 2631–2632; For related
systems, see: (b) Nolt, M. B.; Smiley, M. A.; Varga, S. L.; McClain, R. T.;
Wolkenberg, S. E.; Lindsley, C. W. Tetrahedron 2006, 62, 4698–4704.
5. (a) Spencer, J. Fut. Med. Chem. 2010, 2, 161–168. and references therein; (b)
Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284. and references therein.
6. This reaction may depend on the volatility of the acid chloride used: acetyl
chloride (bp = 52 °C) generally gave variable yields (which were usually better
when using rubber sealed septa for the microwave vessel) whereas
cyclpropane carbonyl chloride (bp = 119 °C) and cyclohexyl carbonyl chloride
(bp = 180 °C) gave better yields. We thank the reviewer for raising this and
other important points.
7.46 1.99
attempt was made to synthesise 9c via an SNAr reaction without
any Pd catalyst source, but the yield of the reaction was very poor
(20%, neat amine). However, using a Pd(OAc)2 precatalyst, com-
pounds 9c1–c3 were obtained in moderate yields as white solids.
A related aminocarbonylation reaction was performed with
molybdenum hexacarbonyl as a solid source of carbon monoxide,
Herrmann–Beller’s catalyst as a source of Pd(0) and DBU as base,
to convert 8c into 10c.15,16 This reaction was found to also give a
Buchwald–Hartwig amination side product 9c3 (as observed by
1H NMR and by TLC). The 1H NMR spectrum of compound 10c
was very distinct to that of 9c3, for example in amide 10c the
piperazine group displays 4H at d = 3.70 and 4H at d = 3.55 due
to the presence of a carbonyl group. In contrast, in 9c3 the pipera-
zine signals integrate as a multiplet for 8H at d = 3.47 in its 1H NMR
spectrum. Finally, we decided to acylate a selected number of
amine derivatives in our oxazole library to evaluate the effect of
converting a basic amine into a neutral amide. The addition of
1.2 equiv of an acid chloride to 4 using PS-NMM (polymer sup-
ported base) led to the amide derivatives 11 in good yields.
Given our interest in cannabinoid receptor ligands,17 we
screened the oxazole library against (human) hCB1 and hCB2
7. Miles, K. C.; Mays, S. M.; Southerland, B. K.; Auvil, T. J.; Ketcha, D. M. Arkivoc
2009, xiv, 181–190.
8. (a) Alexiou, P.; Demopoulos, V. J. J. Med. Chem. 2010, 53, 7756–7766; (b)
Hadden, M.; Goodman, A.; Guo, C.; Guzzo, P. R.; Henderson, A. J.; Pattamana, K.;
Ruenz, M.; Sargent, B. J.; Swenson, B.; Yet, L.; Liu, J.; He, S.; Sebhat, I. K.; Lin, L.
S.; Tamvakopoulos, C.; Peng, Q.; Kan, Y.; Palyha, O.; Kelly, T. M.; Guan, X. M.;
Metzger, J. M.; Reitman, M. L.; Nargund, R. P. Bioorg. Med. Chem. Lett. 2010, 20,
2912–2915; (c) Biot, C.; Bauer, H.; Schirmer, R. H.; Davioud-Charvet, E. J. Med.
Chem. 2004, 47, 5972–5983.
9. Demko, Z. P.; Sharpless, K. B. Org. Lett. 2001, 3, 4091–4094.
10. Lukyanov, S. M.; Bliznets, I. V.; Shorshnev, S. V.; Aleksandrov, G. G.; Stepanov,
A. E.; Vasil’ev, A. A. Tetrahedron 2006, 62, 1849–1863.
11. Bauer, M.; Harris, R. K.; Rao, R. C.; Apperley, D. C.; Rodger, C. A. J. Chem. Soc.,
Perkin Trans. 2 1998, 475–481.
12. Jones, R. V.; Godorhazy, L.; Varga, N.; Szalay, D.; Urge, L.; Darvas, F. J. Comb.
Chem. 2006, 8, 110–116.
13. Ito, K.; Suzuki, T.; Sakamoto, Y.; Kubota, D.; Inoue, Y.; Sato, F.; Tokito, S. Angew.
Chem., Int. Ed. 2003, 42, 1159–1162.
14. See for example: (a) Heo, J. N.; Song, Y. S.; Kim, B. T. Tetrahedron Lett. 2005, 46,
4621–4625; (b) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144–1157;
(c) Sheng, Q.; Hartwig, J. F. Org. Lett. 2008, 10, 4109–4112.
receptors at a 10 lM concentration against the reference com-
pound ([3H]-CP-55,940). Three compounds, 5f, 7f and 7g displayed
moderate affinity towards these receptors and were re-evaluated
affording high micromolar affinities (Table 3).
In summary, a diverse oxazole library has been synthesised
using mainly microwave mediated chemistry.18 Modification
around the oxazole motif can occur at positions-2, -4 and -5 afford-
ing a number of ‘rule of three’ fragments, which will be further
elaborated in due course to establish structure–activity relation-
ships (SAR).19 Many of the oxazoles described herein have been
structurally characterised in the solid state.
15. For recent examples, see: (a) Begouin, A.; Queiroz, M. Eur. J. Org. Chem. 2009,
2820–2827; (b) Cardullo, F.; Donati, D.; Merlo, G.; Paio, A.; Petricci, V.; Taddei,
M. Synlett 2009, 47–50; (c) Letavic, M. A.; Ly, K. S. Tetrahedron Lett. 2007, 48,
2339–2343.
16. Recently reported aminocarbonylation processes are Pd-free, see for example:
(a) Ren, W.; Yamane, M. J. Org. Chem. 2010, 75, 8410–8415; (b) Roberts, B.;
Liptrot, D.; Alcaraz, L.; Luker, L. T.; Stocks, M. J. Org. Lett. 2010, 12, 4280–4283.
17. El Bakali, J.; Muccioli, G. G.; Renault, N.; Pradal, D.; Body-Malapel, M.; Djouina,
M.; Hamtiaux, L.; Andrzejak, V.; Chavatte, P.; Desreumeaux, P.; Lambert, D. M.;
Millet, R. J. Med. Chem. 2010, 53, 7918–7931.
18. For some of our earlier microwave chemistry, see: (a) Spencer, J.; Patel, H.;
Rathnam, R. P.; Nazira, A. Tetrahedron 2008, 64, 10195–10200; (b) Spencer, J.;
Nazira, A.; Patel, H.; Rathnam, R. P.; Verma, J. Synlett 2007, 2557–2558.
19. For recent reviews, see: (a) Congreve, M.; Chessari, G.; Tisi, D.; Woodhead, A. J.
J. Med. Chem. 2008, 51, 3661–3680; (b) de Kloe, G. E.; Bailey, D.; Leurs, R.; de
Esch, I. J. P. Drug Discovery Today 2009, 14, 630–646.
Acknowledgements
The EPSRC Mass Spectrometry Unit (Swansea University) is
acknowledged for HRMS measurements. The EPSRC is thanked
for funding the X-ray crystallography unit. We are grateful to John-
son Matthey for a loan of precious metal salts (Pd), Avexa for finan-
cial assistance for a Ph.D. studentship (H.P.) and Greenwich
University, GRE, and the School of Science are thanked for the pur-
chase of CHN instrumentation.