pubs.acs.org/joc
direct conversion of 2-ketoacids6 into the corresponding
Formation of γ-Oxoacids and 1H-Pyrrol-2(5H)-ones
from r,β-Unsaturated Ketones and Ethyl
Nitroacetate
carboxyacids by reaction with H2O2 or N2O3/Amberlist
157 has also been described.
Within our ongoing project on chemical applications of
the nitro group,8 we considered the synthetic potential of
performing C-C bond forming reactions via nucleophilic
addition of nitronates, followed by Nef oxidations in order
to obtain R-ketoesters and their derivatives (Scheme 1).
We also envisaged the possibility of performing the Nef
oxidation9 under hydrolytic and oxidizing conditions in
order to obtain the corresponding carboxylic acid derivatives
via oxidative decarboxylation of the in situ generated
R-ketoacids.
Maialen Aginagalde,‡ Tamara Bello,‡ Carme Masdeu,†
Yosu Vara,† Ana Arrieta,‡ and Fernando P. Cossıo*,‡
´
‡Kimika Fakultatea, Kimika Organikoa I Saila, Universidad
´
del Paıs Vasco-Euskal Herriko Uniberstitatea, Manuel de
Lardizabal Etorbidea 3, 20018 San Sebastian-Donostia,
ꢀ
Spain, and †IkerChem, Ltd., Tolosa Etorbidea 72, 20018 San
ꢀ
Sebastian-Donostia, Spain
We chose R,β-unsaturated ketones 1 as suitable electro-
philes, in order to achieve an efficient addition of nitronates
and enolates to Michael acceptors10 (Scheme 2). Therefore,
this approach should constitute an alternative to the con-
jugate hydrocyanation of R,β-unsaturated ketones followed
by hydrolysis of the nitrile moiety, a methodology that can
present regiochemical issues.11
Received July 19, 2010
When R,β-unsaturated ketones 1a-i were treated with
ethyl nitroacetate and triethylamine, a ca. 1:1 mixture of the
two possible diastereomers 2-nitro-4-oxoesters was obtained
in almost quantitative yield. This mixture of diastereomers
was oxidized with H2O2/H2O in K2CO3 and methanol at
room temperature12 to yield the corresponding acids 3a-h
with medium to good yields. The yields of purified acids 3f-h
having alkyl substituents were lower. In these cases, NMR
analysis of the crude products revealed less clean reaction
mixtures. The structure of acids 3 was verified on the basis of
their spectroscopic properties and, in the case of compound
3a, by X-ray diffraction analysis.13 When the Nef oxidation
was carried out with NaOMe/MeOH under acidic condi-
tions, the expected R,δ-dioxoesters 2a-d were obtained in
acceptable yields (Scheme 2).14 Interestingly, hydrolysis
of ethyl ester 2a (NaOH 5N, rt, overnight) yielded the
Michael addition of ethyl nitroacetate on R,β-unsatu-
rated ketones followed by Nef oxidation under hydrolytic
conditions yields γ-oxoacids instead of the corresponding
R,δ-dioxoesters. A concerted decarboxylation step is
proposed on the basis of computational results. Finally,
conversion of the γ-ketoacids thus prepared into 1H-
pyrrol-2(5H)-ones by reaction with primary amines under
Paal-Knorr conditions is also reported.
(6) Hume, W. E.; Tokunaga, T.; Nagata, R. Tetrahedron 2002, 58, 3605–
3611.
(7) Marziano, N. C.; Ronchin, L.; Tortato, C.; Ronchin, S.; Vavasori, A.
J. Mol. Catal. A.: Chem. 2005, 235, 26–34.
(8) (a) Zubia, A.; Ropero, S.; Otaegui, D.; Ballestar, E.; Fraga, M. F.;
Oxidative decarboxylation of R-oxoacids is an important
biochemical process that requires the participation of en-
zymes such as the pyruvate dehydrogenase complex that in
turn involves acetyl-CoA and NADH as cofactors.1 This
reaction also plays an important role in nonheme iron
enzymes such as JMJ2DA histone demethylases.2 Nonenzy-
matic related oxidative decarboxylations involving iodine,2,3
hydroxyamino acids,4 and Cu(I)/Pd(0) pairs5 to yield amides
and lactones, respectively, have been reported. Similarly,
Boix-Chornet, M.; Berdasco, M.; Martinez, A.; Coll-Mulet, L.; Cossı
Esteller, M. Oncogene 2009, 28, 1477–1484. (b) Arrieta, A.; Otaegui, D.;
Zubia, A.; Cossıo, F. P.; Dıaz-Ortiz, A.; de la Hoz, A.; Herrero, M. A.;
´
o, F. P.;
´
´
Prieto, P.; Foces-Foces, C.; Pizarro, J. L.; Arriortua, M. I. J. Org. Chem.
2007, 72, 4313–4322. (c) Zubia, A.; Mendoza, L.; Vivanco, S.; Aldaba, E.;
Carrascal, T.; Lecea, B.; Arrieta, A.; Zimmerman, T.; Vidal-Vanaclocha, F.;
Cossıo, F. P. Angew. Chem., Int. Ed. 2005, 44, 2903–2907.
´
(9) (a) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017–1047. (b)
Ballini, R.; Marcantoni, E.; Petrini, E.; Rosini, G. Synthesis 1988, 915–917.
(10) Ballini, R.; Bosica, G.; Fiorni, D.; Palmieri, A.; Petrini, M. Chem.
Rev. 2005, 105, 933–971.
(11) Iida, H.; Morozimato, T.; Hamana, H.; Matsumoto, K. Tetrahedron
Lett. 2007, 48, 2037.
(1) Mooney, B. P.; Miernyk, J. A.; Randall, D. D. Annu. Rev. Plant Biol.
2002, 53, 357–375.
(2) (a) Cole, P. A. Nat. Chem. Biol. 2008, 4, 590–597. (b) Ng, S. S.;
Kavanagh, K. L.; McNough, M. A.; Butler, D.; Pilka, E. S.; Llenara,
B. M. R.; Bray, J. E.; Savitsky, P.; Gileadi, O.; van Delft, F.; Rose, N. R.;
Offer, J.; Scheinost, J. C.; Oppermann, V. Nature 2007, 448, 87–91.
(3) Cho, C.-C.; Liu, J.-N.; Chien, C.-H.; Shie, J.-J.; Chen, Y.-C.; Fang,
J.-M. J. Org. Chem. 2009, 74, 1549–1556.
(4) (a) Sanki, A. K.; Talan, R. S.; Sucheck, S. J. J. Org. Chem. 2009, 74,
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(12) Olah, G. A.; Arvanagui, M.; Vankar, Y. D.; Surya Prakash, G. K.
Synthesis-Stuttgart 1980, 662.
(13) CCDC 770165 and CCDC 770164 contain the supplementary crys-
tallographic data for compounds 3a and 4b, respectively. These data can be
data_request@ccdc.com.ac.uk or by contacting The Cambridge Cristallo-
graphy Data Centre, 12 Union Rd, Cambridge CB2 1EZ, UK; fax þ44 1223
336033.
(5) Gooβen, L. S.; Rudolphi, F.; Oppel, C.; Rodrı
´
guez, N. Angew. Chem.,
(14) For a related example see: Milne, C.; Powell, A.; Jim, J.; Al Nakeed,
M.; Smith, C. P.; Micklefield, J. J. Am. Chem. Soc. 2006, 128, 11250–11259.
Int. Ed. 2008, 47, 3043–3045.
DOI: 10.1021/jo101388x
r
Published on Web 10/01/2010
J. Org. Chem. 2010, 75, 7435–7438 7435
2010 American Chemical Society