This is a repository copy of Inter- and intramolecular Diels-Alder/retro-Diels-Alder reactions of 4-silylated oxazoles . White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/925/ Article: Ducept, P.C. and Marsden, S.P. (2002) Inter- and intramolecular Diels-Alder/retro-Diels-Alder reactions of 4-silylated oxazoles. Arkivoc, 2002 (6). pp. 22-34. ISSN 1424-6376 Reuse See Attached Takedown If you consider content in White Rose Research Online to be in breach of UK law, please notify us by emailing [email protected] including the URL of the record and the reason for the withdrawal request. [email protected] https://eprints.whiterose.ac.uk/ Issue in Honor of Prof. Charles W. Rees ARKIVOC 2002 (vi) 22 -34 Inter- and intramolecular Diels-Alder/retro-Diels-Alder reactions of 4-silylated oxazoles Pascal C. Ducepta and Stephen P. Marsden*,a,b a) Department of Chemistry, Imperial College of Science, Technology and Medicine, London SW7 2AY, U. K. b) Current address: Department of Chemistry, University of Leeds, Leeds LS2 9JT, U. K. E-mail: [email protected] Dedicated to Professor Charles Rees F.R.S. on the occasion of his 75th birthday Abstract 4-Silylated oxazoles have been shown to undergo inter- and intramolecular Diels-Alder/retro- Diels-Alder reactions with electron-poor alkynes to generate polysubstituted furans. The ease of synthesis of the requisite oxazoles by the rhodium-catalysed condensation of nitriles with silylated diazoacetate greatly increases the scope of this reaction. Keywords: Silylated oxazoles, diazoacetate, furans, Diels-Alder, retro-Diels-Alder. Introduction Oxazoles are well recognised for their ability to act as azadienes in Diels-Alder cycloaddition reactions with both alkenes and alkynes.1 The adducts from the former class of reactions usually eliminate water to generate substituted pyridines, while the latter class gives substituted furans by retro-Diels-Alder elimination of nitriles. This has proven to be a powerful method for the synthesis of this important class of heterocycles and has been widely used in the context of complex natural product synthesis.2 One of the most convenient methods for the synthesis of oxazoles involves the condensation of diazocarbonyl compounds with nitriles, discovered by Huisgen in 1961.3 Although the reaction can be carried out under a range of conditions (thermal, photochemical, Lewis-acid catalysed) the use of rhodium (II) carboxylate catalysts pioneered by Helquist4 and Moody5 offers particularly mild conditions which are compatible with highly functionalised substrates. One limitation of this method is that in general these reactions work best with doubly stabilised diazocarbonyl compounds such as diazomalonates, diazoketoesters and diazoketophosphonates so as to avoid competing carbene dimerisation.6 This in turn limits the utility of this method as an approach to cycloaddition precursors, since the presence of electron- withdrawing groups on the oxazole deactivates the system toward cycloaddition and also ISSN 1424-6376 Page 22 ARKAT Issue in Honor of Prof. Charles W. Rees ARKIVOC 2002 (vi) 23 -34 oxazoles bearing carbonyl functions at the 4-position are susceptible to Cornforth rearrangement on thermolysis.7 Indeed, to our knowledge there are no known successful examples of cycloadditions of oxazoles bearing a carbonyl group at the 4-position with alkynes, and only two reports of reactions with alkenes.8 We have recently shown that 4-silylated oxazoles can be readily prepared by the condensation of silyl diazoacetates with nitriles under rhodium catalysis.9 The reluctance of silyl diazoacetates and their derived rhodium carbenoids to undergo dimerisation means that these reactions are operationally simple, requiring no precautions such as high dilution or slow addition of substrate. It therefore became apparent that were these substrates to undergo Diels- Alder reactions with alkynes, followed by subsequent retro-Diels-Alder elimination of silyl cyanide, then this would considerably broaden the scope of the overall furan synthesis. We report herein the successful Diels-Alder/retro-Diels-Alder reactions of silylated oxazoles with electron- poor alkynes in both inter- and intramolecular manifolds. Results and Discussion We elected first to study the intermolecular variant. The silylated oxazoles 1a-g were prepared from the corresponding nitrile and ethyl (triethylsilyl)diazoacetate under rhodium (II) octanoate catalysis, according to our standard procedure.9 Oxazoles 1a-f were then thermolysed in turn with dimethyl acetylenedicarboxylate 2a under the conditions shown (Scheme 1 and Table 1). Pleasingly, the desired Diels-Alder/retro-Diels-Alder sequence to yield the substituted furans 3 was observed in all but two cases. Where successful, the yields of the adducts were moderate to good except in the case of the simple methyl-substituted oxazole 1b, which gave a very messy reaction from which only 18% of the clean furan could be isolated. Attempted reaction of the corresponding ethyl homologue also gave a messy reaction from which it was not possible to obtain completely pure furan, and it therefore appears that 2-alkyloxazoles are poor substrates for this reaction. As expected, the aryl- and heteroaryl-substituted oxazoles 1a,c required higher temperatures to drive the reactions as a consequence of the loss of stabilising conjugation through the cycloaddition step. 1 O 1 O R OEt PhH or PhMe, ∆ R OEt MeO2C CO2Me N + MeO C CO Me SiEt3 2 2 1a-f 2a 3a-f Scheme 1. ISSN 1424-6376 Page 23 ARKAT Issue in Honor of Prof. Charles W. Rees ARKIVOC 2002 (vi) 24 -34 Table 1: Cycloaddition of oxazoles 1a-f with dimethyl acetylenedicarboxylate 2a Entry R1 Temp. Solvent Yield a Ph 100 PhMe 65 b Me 60 PhH 18 c 2-thiophenyl 120 PhMe 52 d CO2Me 120 PhMe 62 e 2-furanyl 110 PhMe 0a f NMe2 60 PhH 0 a - 43% yield of 4 isolated (see Scheme 2) The reaction of 2-furanyl oxazole 1e with 2a gave an unoptimised 43% yield of a 1:1 cycloadduct 4 from addition across the more electron-rich furan ring rather than the oxazole (Scheme 2). The highly electron-rich dimethylamino-substituted oxazole 1f underwent a rapid reaction to produce a new, more polar product as judged by TLC analysis, but despite significant effort this material could not be isolated following column chromatography. MeO2C CO2Me O OEt PhMe, ∆ O OEt O MeO2C CO2Me O N + 43% N SiEt3 SiEt3 1e 2a 4 Scheme 2. We next investigated the intermolecular reactions of oxazoles 1a/g with less activated dienophiles. Both oxazoles reacted in a completely regioselective manner with methyl propiolate 2b to generate the furans 5a/g in moderate yield (Scheme 3 and Table 2). The regioselectivity mirrors that previously observed8a,10 and as expected from the alignment of the electron-rich 2- position of the oxazole with the electron-deficient terminus of the alkyne. Notably, the presence of only a single activating group meant that higher temperatures were required than for the corresponding reactions with 2a. In the light of this, it was felt that less-active dienophiles would be less likely still to undergo cycloaddition and indeed the oxazoles were recovered unchanged from attempted reaction with methyl 3-phenylpropiolate 2c, diphenylacetylene 2d and trimethylsilylacetylene 2e. 1 O R1 O OEt R OEt 2 3 PhMe, PhEt or DCB ∆ + R R N 2 R3 SiEt3 R 1a,g 2b-e 5a,b Scheme 3. ISSN 1424-6376 Page 24 ARKAT Issue in Honor of Prof. Charles W. Rees ARKIVOC 2002 (vi) 25 -34 Table 2: Attempted cycloaddition of oxazoles 1a,g with dienophiles 2b-e Entry R1 R2 R3 Temp. Solvent Yield a Ph H CO2Me 160 PhEt 43 b Et H CO2Me 110 PhMe 40 c Ph Ph CO2Me 160 PhEt 0 d Et Ph CO2Me 160 PhEt 0 e Et Ph Ph 180 DCB 0 f Et H SiMe3 180 DCB 0 Finally, we turned our attention to intramolecular variants of the reaction. Three potential substrates were prepared, with varying degrees of activation in the dienophile part of the molecule. The diactivated and monoactivated oxazoles 6a/b were prepared by the route shown in Scheme 4. Thus, condensation of 4-(tert-butyldimethylsilyloxy)pentanenitrile11 with ethyl (triethylsilyl)diazoacetate under rhodium catalysis gave a 79% yield of the oxazole 7. Deprotection with TBAF yielded alcohol 8 which was oxidised under Swern conditions to yield aldehyde 9. Addition of lithiated methyl propiolate12 or trimethylsilylacetylene to 9 gave the alcohols 10a/b, which were oxidised with Dess-Martin periodinane to give 6a/b in good yield. OR Et Si CO Et CN 3 2 i 7 R = TBS TBSO + O N2 OEt ii 8 R = OH N SiEt3 iii R X O Y 10 X = H, Y = OH iv or v vi O O 6 X,Y = O OEt OEt N N SiEt3 9 SiEt3 10/6a R = CO2Me 10/6b R = SiMe 3 Scheme 4. (i). 1% Rh2(oct)4, benzene, 79%; (ii). TBAF, THF, r.t., 91%; (iii). (COCl)2, DMSO, o o n CH2Cl2, -78 C, then Et3N, -78 C to r.t., 73%; (iv). methyl propiolate, BuLi, THF/Et2O/pentane, -120oC, then add 9, -120oC to -78 oC, 78%; (v). trimethylsilylacetylene, nBuLi, THF, -78oC, then add 9, 90%; (vi). Dess-Martin periodinane, CH2Cl2, 77% (6a) and 80% (6b). ISSN 1424-6376 Page 25 ARKAT Issue in Honor of Prof. Charles W. Rees ARKIVOC 2002 (vi) 26 -34 The non-activated alkyne 6c was simply prepared by condensation of 7-phenylhept-6-ynylnitrile 11 with ethyl (triethylsilyl)diazoacetate to give 6c in 62% yield (Scheme 5). Ph 1% Rh (oct) CN Et3Si CO2Et 2 4 + PhH, reflux Ph N2 O OEt 11 62% N 6c SiEt3 Scheme 5. The Diels-Alder/retro-Diels-Alder reactions of 6a/b proceeded smoothly to give the desired dihydrobenzofuranones 12a/b in good yield (Scheme 6).