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 article info Article history: Received 6 December 2011 Revised 9 January 2012 Accepted 20 January 2012 Available online 28 January 2012 Keywords: Microwave-assisted synthesis Oxazoles Parallel synthesis Flow chemistry abstract 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 k i values against can- nabinoid (CB1/CB2) receptors. Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved. 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 The 2-substituted-5-aminooxazole-4-carbonitrile skeleton (Fig. 1) provides a drug-like template for diversity orientated syn- thesis 3 of a low molecular weight fragment library by functionalisa- tion at the 2-, 4- and 5-positions. For example, variation of R 1 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. We synthesised the oxazoles 4 4 using microwave conditions 5 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 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 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 0040-4039/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2012.01.081 ⇑ Corresponding author. Tel.: +44 (0) 208 331 8215; fax: 44 (0) 208 331 9805. E-mail addresses: [email protected], [email protected](J. Spencer). Present address: JDJ Bioservices, 576 Swan Street, Richmond, Victoria 3121, Australia. N O R 1 NH 2 Various functionalities enabling H bonding, steric, electronic manipulations. Functionalise, e.g.cyclise, amide / sulfonamide, diazotisation Modify, e.g. cycloaddition, reduction N Figure 1. Schematic aim to diversify an oxazole fragment scaffold. Tetrahedron Letters 53 (2012) 1656–1659 Contents lists available at SciVerse ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Transcript
Tetrahedron Letters 53 (2012) 1656–1659
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier .com/ locate / tet let
Microwave-mediated synthesis and manipulation of a2-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, UKb UK National Crystallography Service, School of Chemistry, University of Southampton, Highfield, Southampton SO17 1BJ, UKc Avexa Ltd, 576 Swan Street, Richmond, Victoria 3121, Australiad 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:Received 6 December 2011Revised 9 January 2012Accepted 20 January 2012Available online 28 January 2012
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.
Crown Copyright � 2012 Published by Elsevier Ltd. All rights reserved.
N
O
R1
NH2
Various functionalities enablingH bonding, steric, electronic
Figure 1. Schematic aim to diversify an oxazole fragment scaffold.
The oxazole scaffold has found widespread utility in medicinalchemistry and is present in a number of natural products.1 Severalsynthetic routes to these heterocycles have been described withmany recent examples displaying high levels of atom economy,amenable to parallel synthesis.2
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 wouldenable the introduction of alkyl, aryl and heterocyclic units of var-ied size and electronic properties. Next, the primary amine groupwas identified as a useful synthon towards heterocycles or amides,and the nitrile function is amenable to cycloaddition and reductionchemistry. The ultimate aim was to carry out each step in a micro-wave reactor or via flow chemistry to speed up the reaction andachieve high yields.
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 carbonylfunction on one of the nitrile groups as a key step. The microwave
reactions worked generally very well for heterocyclic, aromaticand cyclic compounds although they were less successful for al-kyl-containing oxazoles such as the example whose preparationwas attempted using acetyl chloride (variable yields obtained).6 Anumber of derivatives were characterised in the solid state, includ-ing 4c (CCDC 850249) and 4f (CCDC 850250).
Pyrrole-substituted oxazoles 5 were synthesised in virtuallyquantitative 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 inmedicinal chemistry.8 We initially attempted unsuccessfully to
1658 J. Spencer et al. / Tetrahedron Letters 53 (2012) 1656–1659
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 beconverted 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 signalat ca. 17 ppm.11 Analogue 6a is quite remarkable in that it containsan oxazole scaffold substituted with three different heterocycles,underlining the broad synthetic scope of this approach. We did
N O
R1
NC NH2
H-Cube, RaneyNiCatCart
NC
t-butyl nitrite, CuBr2
4
N
NC
1-Boc-piperazine, DBU,Pd catalyst, t-Bu3P. HBF4,Mo(CO)6, µW, 170 °C, 6 m
N O
R1
NC NH R3
O
11
Product R1 R3 Yield (%)
11a
11d
11f
S
COCH2CO2Me 77
PS-NMM, R3COCl.
Ph
COMe
COCH2CO2Me
51
66
1 ml min-1, 70 °C,
50 bar.
5
(Table 2)
(for 4c)
Scheme 1. Reactio
not attempt the cyclisation reaction of 5h due to the presence oftwo nitrile functionalities. Analogues 5g (CCDC 850252) and 6g(CCDC 850255) were characterised in the solid state.
Further diversification of the oxazole scaffold is summarised inScheme 1. Hence, the nitrile functionality in 5 was reduced, in anH-Cube,12 to form the primary amines 7 (the purity of 7 was lim-ited to ca. 80%). The next step investigated was the Sandmeyerreaction on 4c.13 The yield of 8c was moderate (52%) and a mixtureof 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 asuitable precursor for Buchwald–Hartwig aminations.14 An
N
ON
NH2
N O
Br
N O
NC NR4R5
O
N
O
NBoc
Amine (NHR4R5), Pd(OAc)2,BINAP, KO-t-Bu,
in, THF
7f (R2=H)7g (R2=OMe)
Product NR4R5 Yield (%)9c1
9c2
9c3
O N 52
N30
NNO
O63
8c 9
10c
µW, 170 °C, 15 min,1,4-dioxane.
R2
ns of oxazoles.
Table 3Displacement of hCB1 and hCB2 at 10�5 M concentration
J. Spencer et al. / Tetrahedron Letters 53 (2012) 1656–1659 1659
attempt was made to synthesise 9c via an SNAr reaction withoutany 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 withmolybdenum 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 aBuchwald–Hartwig amination side product 9c3 (as observed by1H NMR and by TLC). The 1H NMR spectrum of compound 10cwas very distinct to that of 9c3, for example in amide 10c thepiperazine group displays 4H at d = 3.70 and 4H at d = 3.55 dueto 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 NMRspectrum. Finally, we decided to acylate a selected number ofamine derivatives in our oxazole library to evaluate the effect ofconverting a basic amine into a neutral amide. The addition of1.2 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 wescreened the oxazole library against (human) hCB1 and hCB2receptors at a 10 lM concentration against the reference com-pound ([3H]-CP-55,940). Three compounds, 5f, 7f and 7g displayedmoderate affinity towards these receptors and were re-evaluatedaffording high micromolar affinities (Table 3).
In summary, a diverse oxazole library has been synthesisedusing mainly microwave mediated chemistry.18 Modificationaround the oxazole motif can occur at positions-2, -4 and -5 afford-ing a number of ‘rule of three’ fragments, which will be furtherelaborated in due course to establish structure–activity relation-ships (SAR).19 Many of the oxazoles described herein have beenstructurally characterised in the solid state.
Acknowledgements
The EPSRC Mass Spectrometry Unit (Swansea University) isacknowledged for HRMS measurements. The EPSRC is thankedfor 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 GreenwichUniversity, GRE, and the School of Science are thanked for the pur-chase of CHN instrumentation.
Supplementary data
Supplementary data (experimental and analytical data (1H, 13Cspectra, MS, elemental analysis) for compounds are provided, aswell as X-ray crystallography) associated with this article can befound, in the online version, at doi:10.1016/j.tetlet.2012.01.081.
References and notes
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