Formation of γ-oxoacids and 1 H-pyrrol-2(5 H)-ones from α,β-unsaturated ketones and ethyl nitroacetate

Article abstract of DOI:10.1021/jo101388x

Michael addition of ethyl nitroacetate on α,β-unsaturated ketones followed by Nef oxidation under hydrolytic conditions yields γ-oxoacids instead of the corresponding α,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.

Full text of DOI:10.1021/jo101388x

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
fp.cossio@ehu.es
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,
1886–1896. (b) Fukuzumi, T.; Bode, J. W. J. J. Am. Chem. Soc. 2009, 131,
3864–3865.
(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
obtained free of charge via www.ccdc.ac.uk/data_requestcif, by emailing
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

Aginagalde et al.
JOCNote
SCHEME 1. Proposed General Synthesis of Carboxylic Acids
and R-Ketoesters from Ethyl Nitroacetate
SCHEME 2. Synthesis of γ-Ketoacids 3a-h and R,δ-Ketoesters
2a-d via Conjugate Addition-Nef Oxidation of Chalcones 1a-i
FIGURE 1. Fully optimized (B3LYP/6-311þþG** level) station-
ary points associated with the oxidative decarboxylation of
potassium pyruvate in the presence of HOO-Kþ. Carbon, oxygen,
and potassium atoms are represented in gray, red, and dark blue
colors, respectively. Bond distances are given in angstroms. Num-
bers close to the arrows are relative energies (in kcal/mol), computed
at the B3LYP(PCM,MeOH)/6-311þþG**//B3LYP/6-311þþG**
þΔZPVE level of theory (gas phase data are given in parentheses).
Figure 1. The reaction starts by a nucleophilic addition of the
hydroperoxide anion on the carbonyl group of the pyruvate.
The activation barrier associated with this process is much
lower in solution than in the gas phase.
corresponding R,δ-dioxoacid 2a0 in almost quantitative yield
(see the Supporting Information for further details). Treat-
ment of this acid with H2O2-H2O/K2CO3 at 0 °C-room
temperature led to decarboxylated acid 3a with a yield of
84%.
To gain a better understanding of the decarboxylation
step, we performed Density Functional Theory (DFT) based
calculations on the reaction between potassium pyruvate and
potassium hydroperoxide to yield the corresponding acetate
and bicarbonate salts.15,16 The main stationary points asso-
ciated with a reasonable reaction coordinate are gathered in
The intrinsic reaction coordinate17 (IRC) study of TS1 led
to intermediate INT1, which in turn evolved to the more
stable intermediate INT2, in which there is a stronger
intramolecular hydrogen bond involving 5 atoms instead
of 6. Saddle point TS2 connects INT1 with the products via a
concerted and highly synchronous cleavage of the C-C and
O-O bonds. This concerted cleavage of two σ-bonds with a
low energy barrier is remarkable. In contrast with the pre-
vious barrier, in the second step the computed activation
energy is higher in solution than in the gas phase. After IRC
analysis of TS2 and further optimization, the final products
are the acetate and bicarbonate anions. The overall reaction
is highly exothermic (ΔErxn = -101.5 kcal/mol in MeOH).
This fact and the low activation barriers associated with the
(15) The DFT calculations were carried out using the B3LYP hybrid
functional and the 6311þþG** basis set. Solvent conditions (MeOH) were
considered by means of the PCM method. See: (a) Becke, A. D. J. Chem.
Phys. 1993, 98, 5648–5652. (b) Lee, C.; Yane, W.; Parr, R. G. Phys. Rev. B
1988, 37, 785–789. (c) Raghavachari, K.; Binkley, J. S.; Seeger, R.; Pople,
J. A. J. Chem. Phys. 1980, 72, 650–654. (d) Tomasi, J.; Mennucci, B.; Cammi,
R. Chem. Rev. 2005, 105, 2999–3093.
(17) (a) Hratchian, H. P.; Schlegel, H. B. J. Chem. Phys. 2004, 120, 9918–
9924. (b) Hratchian, H. P.; Schlegel, H. B. J. Chem. Theory Comput. 2005, 1,
61–69.
(16) Frisch, M. J. Gaussian09, revision A.02; Gaussian, Inc., Wallinford,
CT, 2009. (Full reference is given in the Supporting Information.)
7436 J. Org. Chem. Vol. 75, No. 21, 2010

Aginagalde et al.
JOCNote
formation of the O-C bond in TS1 and with the cleavage
of the C-C and O-O bonds in TS2 are compatible with the
easy oxidative decarboxylation experimentally observed.
After preparing γ-ketoacids 3, we tested the application of
these compounds to the chemical synthesis of 1H-pyrrol-
2(5H)-ones 4.18 These latter compounds are found in many
biologically important natural and synthetic compounds.19
When a mixture of the γ-ketoacid 3 and an amine or
ammonium acetate in acetic acid was irradiated with micro-
waves at 150 W, the corresponding R,β-unsaturated-γ-lac-
tones 4 were obtained, in general with good yields (Table 1).
Under classical heating, no formation of products 4 was
observed. In the case of compound 4b its structure was
unambiguously established by X-ray diffraction analysis.12
According to our results, formation of N-aryl derivatives
(entries 5 and 6) requires longer reaction times and higher
temperatures. N-Alkyl derivatives 4b,c (entries 2 and 3) can
also be obtained in good yields. However, when the reaction
was conducted with R-amino acids or their ester derivatives
(entries 8 and 9), the corresponding decarboxylated lactones
4c,h were obtained in low yields, thus losing the stereo-
chemical information contained in the starting homochiral
amino acid moiety.
TABLE 1. Synthesis of 1H-Pyrrol-2(5H)-onesa 4a-h from γ-Ketoacids
3a,b,e
When ethyl esters 2a-d were subjected to similar Paal-
Knorr reaction conditions, the expected ethyl 3,5-diaryl-1H-
pyrrole-2-carboxylates 5a-f were obtained (Scheme 3).20
For this reaction, the reaction times and temperatures re-
quired to obtain the products with good yields under micro-
wave irradiation were similar in all cases and no significant
changes in yield were observed on going from NH to N-aryl
derivatives. In the case of pyrrole 5a, this compound was
obtained in a yield of 87% after 45 min of classical heating at
the same temperature.
In summary, Michael addition of ethyl nitroacetate on
R,β-unsaturated carbonyl compounds followed by Nef oxi-
dation can yield either γ-ketoacids or R,δ-diketoesters
depending on the hydrolytic or nonhydrolytic oxidizing
reaction conditions. The computational study on a model
system supports a reasonable stepwise mechanism for the
oxidative decarboxylation of the intermediate R,δ-diketoa-
cids. This proposal is compatible with the reaction condi-
tions of the hydrolytic Nef reaction. Cyclization reaction of
these γ-ketoacids in the presence of ammonium salts yields
1H-pyrrol-2(5H)-ones in good yields, thus providing a novel
and convergent entry to these biologically interesting com-
pounds.
(18) For pioneering, although conceptually different methodologies for
the preparation of these compounds see: (a) Moon, M. W. J. Org. Chem.
1977, 42, 2219–2223. (b) Shin, C.; Yonezawa, Y.; Watanabe, E. Tetrahedron
Lett. 1985, 26, 85–88. See also ref 17.
(19) See for example: (a) Snider, B. B.; Neubert, B. J. J. Org. Chem. 2004,
ꢀ
69, 8952–8955. (b) Gouault, N.; Le Roch, M.; Cornee, C.; David, M.; Uriac,
P. J. Org. Chem. 2009, 74, 5614–5617. (c) Rosas, N.; Sharma, P.; Arellano, I.;
ꢀ ꢀ
Ramırez, M.; Perez, M.; Hernandez, S.; Cabrera, A. Organometallics 2005,
´
24, 4893–4895. (d) Shiraki, R.; Sumino, A.; Tadano, K.; Ogawa, S. Tetra-
aConditions: 3 (0.4 mmol), amine (2 mmol), AcOH (0.1 mL), micro-
wave irradiation. bPMP: p-methoxyphenyl group. cIsolated yields of
pure products.
ꢁ
hedron Lett. 1995, 36, 5551–5554. (e) Grison, C.; Geneve, S.; Coutrot, P.
Experimental Section
Tetrahedron Lett. 2001, 42, 3831–3834. (f) Green, M. P.; Prodger, J. C.;
Hayes, C. J. Tetrahedron Lett. 2002, 43, 6609–6611. (g) Murai, M.; Miki, K.;
Ohe, K. J. Org. Chem. 2008, 73, 9174–9176. (h) Shiraki, R.; Sumino, A.;
Tadano, K.; Ogawa, S. J. Org. Chem. 1996, 61, 2845–2852. (i) Dittami, J. P.;
Xu, F.; Qi, H.; Martin, N. W.; Bordner, J.; Decosta, D. L.; Kiplinger, J.;
Reiche, J.; Ware, R. Tetrahedron Lett. 1995, 36, 4201–4204. (j) Green, M. P.;
Prodger, J. C.; Hayes, C. J. Tetrahedron Lett. 2002, 43, 2649–2652.
(20) For a related reaction leading to ethyl 2,5-disubstituted-1H-pyrrole-
3-carboxylates see: Minetto, G.; Raveglia, L. F.; Sega, A.; Taddei, M. Eur. J.
Org. Chem. 2005, 5277–5288.
Typical Experimental Procedure for the Preparation of
γ-Ketoacids 3a-h. A solution of chalcone 1 (6 mmol) and ethyl
nitroacetate (6 mmol) in triethylamine (2.5 mL, 18 mmol) was
stirred at 75 °C overnight. Ethyl acetate (100 mL) was added and
the solution obtained was washed with 1 N HCl (4 ꢀ 50 mL),
dried over Na2SO4, and evaporated under reduced pressure to
yield an oil that was dissolved in MeOH (18 mL). A solution of
J. Org. Chem. Vol. 75, No. 21, 2010 7437

Aginagalde et al.
JOCNote
SCHEME 3. Synthesis of Ethyl 3,5-Diaryl-1H-pyrrole-2-
carboxylates 5a-f from R,δ-Ketoesters 2a-d under Microwave
Irradiation
solution), dried over Na2SO4, and evaporated under reduced
pressure to obtain the corresponding ethyl esters 2.
Ethyl 2-(4-methoxyphenyl)-4-oxo-4-phenylbutanoate (2a):
yield 70%, yellow oil; νmax/cm-1 (KBr) 2979, 2915, 1726,
1
1679, 1254, 1182, 1035; H NMR (500 MHz, CDCl3) δ 7.94
(d, J = 7.3 Hz, 2H), 7.61-7.52 (m, 1H), 7.44 (t, J = 7.7 Hz, 2H),
7.29-7.21 (m, 2H), 6.87 (d, J = 8.7 Hz, 2H), 5.09 (dd, J = 10.3,
4.0 Hz, 1H), 4.27 (m, J = 13.1, 8.4, 4.8 Hz, 2H), 3.98 (dd, J =
18.1, 10.4 Hz, 1H), 3.78 (s, 3H), 3.38 (dd, J = 18.1, 4.0 Hz, 1H),
1.30 (t, J = 7.1 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 197.7,
192.4, 160.8, 159.6, 136.3, 133.6, 130.3, 128.8, 128.4, 127.3,
114.8, 62.6, 55.5, 47.9, 43.1, 14.1. Anal. Calcd for C20H20O5:
C, 70.6; H, 5.9. Found: C, 70.5 ; H, 5.8.
General Procedure for the Preparation of 1H-Pyrrol-2(5H)-
ones 4a-h. A mixture of the γ-ketoacid 3 (0.4 mmol), the
corresponding amine or ammonium acetate (2 mmol), and
acetic acid (0.1 mL) in a closed vessel was irradiated in a
monomode microwave oven at 150 W for the time and at the
temperature reported in Table 1. After finishing the irradiation,
the mixture was allowed to reach room temperature and the
vessel was opened. Ethyl acetate (20 mL) was added and the
resulting solution was washed with NaHCO3 (3 ꢀ 20 mL, satu-
rated aqueous solution), dried over Na2SO4, and evaporated
under reduced pressure to obtain the corresponding product 4.
3-(4-Methoxyphenyl)-5-phenyl-1,5-dihydro-2H-pyrrol-2-one (4a):
yield 72%, white solid, mp 188-190 °C; νmax/cm-1 (KBr) 3193,
3054, 2932, 1678, 1261, 1035; 1H NMR (500 MHz, MeOD) δ 7.84
(d, J = 8.4 Hz, 2H), 7.44-7.22 (m, 6H), 6.94 (d, J = 8.4 Hz, 2H),
5.32 (s, 1H), 3.82 (s, 3H); 13C NMR (126 MHz, MeOD) δ 179.3,
169.1, 149.9, 147.0, 145.0, 142.2, 138.6, 138.1, 138.0, 137.8, 137.2,
137.0, 136.8, 133.5, 123.4, 64.7, 53.0. Anal. Calcd for C17H15NO2:C,
77.0; H, 5.7; N, 5.3 . Found: C, 76.8; H, 5.4; N,5.6.
H2O2 (12 mL, 33% in H2O) and K2CO3 (4.0 g) were added at
0 °C and the mixture was stirred at room temperature overnight.
The reaction mixture was acidified with 6 N HCl and then was
extracted with CH2Cl2 (3 ꢀ 25 mL), dried over Na2SO4, and
evaporated under reduced pressure to yield the corresponding
γ-ketoacid 3, which was triturated with Et2O.
2-(4-Methoxyphenyl)-4-oxo-4-phenylbutanoic acid (3a): yield
82%, white solid, mp 155-156 °C; νmax/cm-1 (KBr) 3038-
2839, 2960, 1699, 1673, 1244, 1040; 1H NMR (500 MHz, CDCl3)
δ 7.95 (d, J = 7.2 Hz, 2H), 7.55 (d, J = 6.9 Hz, 1H), 7.45 (d, J =
7.3 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.1 Hz, 2H),
4.27 (d, J = 5.7 Hz, 1H), 3.87 (dd, J = 17.9, 9.9 Hz, 1H), 3.79 (s,
3H), 3.27 (d, J = 15.2 Hz, 1H); 13C NMR (126 MHz, CDCl3)
δ 197.7, 178.1, 159.4, 136.6, 133.5, 130.0, 129.3, 128.8, 128.3,
114.6, 55.5, 45.5, 42.6. Anal. Calcd for C17H16O4: C, 71.8; H, 5.7.
Found: C, 71.7 ; H, 5.7.
General Procedure for the Preparation of rδ-Dioxoesters
2a-d. A solution of chalcone 1 (6 mmol) and ethyl nitroacetate
(6 mmol) in triethylamine (2.5 mL, 17.94 mmol) was stirred at
75 °C overnight. Ethyl acetate (100 mL) was added and the
solution obtained was washed with 1 N HCl (4 ꢀ 50 mL), dried
over Na2SO4, and evaporated under reduced pressure, to yield a
residue that was treated with a 0.5 M solution of sodium
methoxide in methanol (16 mL, 8 mmol). The resulting mixture
was stirred for 4 h. Then, it was poured over a mixture of H2SO4
(3 mL) and MeOH (16 mL) at -20 °C. The resulting mixture was
stirred at 20 °C for 5 min, and then allowed to reach room
temperature. H2O (15 mL) was added, methanol was removed
under reduced pressure, and the resulting aqueous solution was
extracted with CH2Cl2 (2 ꢀ 150 mL). The combined organic
layers were washed with NaCl (2 ꢀ 50 mL, saturated aqueous
Acknowledgment. Financial support from the UPV/
EHU-GV/EJ (Grant IT-324-07) and the Spanish MICINN
(Grant CTQ2007-67528) and Ingenio-Consolider (CSD2007-
00006) is gratefully acknowledged. T.B. and M.A. thank their
respective MICINN and GV/EJ fellowships. SGIKer techni-
cal support (MICINN, GV/EJ, and European Social Fund) is
gratefully acknowledged.
Supporting Information Available: Full characterization of
all novel compounds, crystallographic data of compounds 3a
and 4b, complete ref 16, and full computational characterization
of stationary points reported in Figure 1. This material is
available free of charge via the Internet at http://pubs.acs.org.
7438 J. Org. Chem. Vol. 75, No. 21, 2010