program on the discovery of multiple bond-forming reactions
for the synthesis of biologically and/or synthetically relevant
coumpounds,6 we have recently reported a very general and
eco-compatible synthesis of R-carbonylated cycloalkanones
involving a Wolff rearrangement7 of cyclic 2-diazo-1,3-
diketones followed by trapping of the transient acylketene
with nucleophiles in a domino process under microwave
irradiation.8 The synthetic applications of acylketenes are
multiple. In the past, they have been largely used for
the synthesis of heterocycles, and also for the total synthesis
of natural products.9,10 In their s-Z conformation, acylketenes
can behave as 1,3-oxadienes in inverse demand hetero
Diels-Alder reactions.9 In particular, their reactions with
preformed imines and isocyanates have led to 1,3-oxazin-
4-ones and 1,3-oxazine-2,4-diones, respectively. These two
closely related classes of compounds can occur in nature and
have proven to exhibit some potent biological activities
(Figure 1).11 In this paper, we wish to report our preliminary
would be possible by simply irradiating with microwaves a
1:1:1 mixture of a 2-diazo-1,3-diketone, an aldehyde and a
primary amine. For the reaction to proceed efficiently, the
kinetics of the imine formation should be superior to the
kinetics of the acylketene formation by Wolff rearrangement
to avoid nucleophilic addition of the amine leading to
ꢀ-ketoamide products.8 As a test reaction, we submitted an
equimolar mixture of the acylketene precursor 1a, benzal-
dehyde and n-propylamine in toluene to microwave irradia-
tion. Gratefully, after an optimization study, the expected
oxazinone 2a was isolated in 71% yield (Scheme 1).
Scheme 1. Three-Component Domino Synthesis of Oxazinones
Stimulated by this first result we examined the scope and
limits of the methodology with various acylketene precur-
sors, aldehydes and amines under the conditions optimized
for 2a (140 °C for 5 min). These results are summarized
in Table 1.
Figure 1. Representative biologically active oxazin(di)ones.
The reaction proceeded well with a variety of aromatic
(entries 1-6, 10, 11, and 13) and aliphatic (entries 7-9 and
12) aldehydes and with alkyl (entries 1 and 9), allyl (entries
3, 12 and 13), propargyl (entries 4 and 8) and benzyl (entries
2 and 5-7) amines. With enantiopure primary branched
amines a modest chiral induction was observed (entries 10
and 11), but no oxazinone products were formed when tert-
butyl amine and aniline were used, probably due to failures
in generating the imine under the reaction conditions. The
results on the domino and multicomponent microwave-
assisted eco-compatible synthesis of 1,3-oxazin-4-ones and
1,3-oxazine-2,4-diones by hetero-Diels-Alder reaction of
acylketenes generated by Wolff rearrangement with in situ
generated CdN double bonds.
Based on a literature precedent for the catalyst-free
microwave-assisted synthesis of aldimines,12 we surmised
that a three-component domino synthesis of oxazinones
(9) For reviews, see: (a) Wentrup, C.; Heilmayer, W.; Kollenz, G.
Synthesis 1994, 1219. (b) Kollenz, G.; Ebner, S. Science of Synthesis:
Houben-Weyl methods of molecular transformations; Danheiser, R., Ed.;
Georg Thieme Verlag: Stuttgart, Germany, 2006; Vol. 23, Chapter 9, pp
271-349. For recent representative examples in the heterocyclic series, see:
(c) Pemberton, N.; Jakobsson, L.; Almqvist, F. Org. Lett. 2006, 8, 935. (d)
Pemberton, N.; Pinkner, J. S.; Edvinsson, S.; Hultgren, S. J.; Almqvist, F.
Tetrahedron 2008, 64, 9368. (e) Audouard, C.; Bettaney (ne´e Middleton),
K.; Doan, C. T.; Rinaudo, G.; Jervis, P. J.; Percy, J. M. Org. Biomol. Chem.
2009, 7, 1573 For recent applications in the field of natural product total
synthesis, see: (f) Calo, F.; Richardson, J.; Barrett, A. G. M. Org. Lett.
2009, 11, 4910, and references 7b-f therein. (g) Crimmins, M. T.; Smith,
A. C. Org. Lett. 2006, 8, 1003. (h) Marshall, J. A.; Eidam, P. M. Org. Lett.
2008, 10, 93. (i) Hoye, T. R.; Danielson, M. E.; May, A. E.; Zhao, H.
Angew. Chem., Int. Ed. 2008, 47, 9743. For a recent review, see: (j) Reber,
K. P.; Tilley, S. D.; Sorensen, E. J. Chem. Soc. ReV. 2009, 38, 3022.
(10) (a) Tidwell, T. T. Ketenes II; John Wiley & Sons: Hoboken, NJ,
2006. (b) Tidwell, T. T. Eur. J. Org. Chem. 2006, 563.
(4) For recent monographs or edited volumes on MAOS, see: (a) Kappe,
C. O.; Dallinger, D.; Murphree, S. S. Practical MicrowaVe Synthesis for
Organic Chemists: Strategies, Instruments, and Protocols; Wiley-VCH:
Weinheim, Germany, 2009. (b) Topics in Current Chemistry Vol. 266:
MicrowaVe Methods in Organic Synthesis, Larhed, M.; Olafsson, K., Eds.;
Springer, Berlin/Heidelberg, Germany, 2006. (c) MicrowaVe in Organic
Synthesis, 2nd Edition LoupyA., Ed.; Wiley-VCH, Weinheim, Germany,
2006. For recent representative reviews on MAOS and its applications, see
(d) Kappe, C. O. Chem. Soc. ReV. 2008, 37, 1127. (e) Coquerel, Y.;
Rodriguez, J. Eur. J. Org. Chem. 2008, 1125. (f) Dallinger, D.; Kappe,
C. O. Chem. ReV. 2007, 107, 2563.
(5) We define eco-compatibility as both economical and ecological
compatibility.
(6) For selected most recent examples, see: (a) Coquerel, Y.; Filippini,
M.-H.; Bensa, D.; Rodriguez, J. Chem.sEur. J. 2008, 14, 3078. (b) Reboul,
I.; Boddaert, T.; Coquerel, Y.; Rodriguez, J. Eur. J. Org. Chem. 2008, 5379.
(c) Boddaert, T.; Coquerel, Y.; Rodriguez, J. AdV. Synth. Catal. 2009, 351,
1744. (d) Virolleaud, M.-A.; Sridharan, V.; Mailhol, D.; Bonne, D.; Bressy,
C.; Chouraqui, G.; Commeiras, L.; Coquerel, Y.; Rodriguez, J. Tetrahedron
2009, 65, 9756.
(11) (a) Moya, P.; Castillo, M.; Primo-Yu´fera, E.; Couillaud, F.;
Martinez-Manez, R.; Garcera, M.-D.; Miranda, M. A.; Primo, J.; Martinez-
´
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M.-A.; Primo, J.; Miranda, M. A.; Primo-Yu´fera, E. Eur. J. Org. Chem.
1999, 221. (c) Nicoletti, R.; Buommino, E.; De Filippis, A.; Lopez-Gresa,
M. P.; Manzo, E.; Carella, A.; Petrazzuolo, M.; Tufano, M. A. World J.
Microbiol. Biotechnol. 2008, 24, 189. (d) Doms, P.; Santel, H. J.; Dollinger,
M. Eur. Pat. Appl. EP0638563, 1995.
(7) For a review, see: (a) Kirmse, W. Eur. J. Org. Chem. 2002, 2193.
For a recent illustrative example, see: (b) Karpov, G.; Kuzmin, A.; Popik,
V. V. J. Am. Chem. Soc. 2008, 130, 11771.
(8) Presset, M.; Coquerel, Y.; Rodriguez, J. J. Org. Chem. 2009, 74,
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(12) Paquin, L.; Hamelin, J.; Texier-Boullet, F. Synthesis 2006, 1652.
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