Addition of grignard reagents to 1-(N-(Alkoxyoxalyl)-JV-methylamino)-3-methylimidazolium Salts: A general method for α-keto ester synthesis

Full text of DOI:10.1021/jo961329z

J . Org. Chem. 1996, 61, 9009-9011
9009
although it was improved (37%) when the lithium reagent
was transformed to an organocopper derivative.
Ad d ition of Gr ign a r d Rea gen ts to
1-(N-(Alk oxyoxa lyl)-N-m eth yla m in o)-3-
m eth ylim id a zoliu m Sa lts: A Gen er a l
Meth od for r-Keto Ester Syn th esis
Mar´ıa A. de las Heras, J uan J . Vaquero,
J ose´ L. Garc´ıa-Navio, and J ulio Alvarez-Builla*
Departamento de Qu´ımica Orga´nica, Universidad de Alcala´,
28871-Alcala´ de Henares, Madrid, Spain
Received J uly 12, 1996
R-Keto esters are of current interest as precursors of
R-keto acids such as pyruvic acid and analogs, oxaloacetic
acid, R-ketoglutaric acid, and R-keto acid analogs of
protein amino acids, which play essential roles in some
biosynthetic and metabolic pathways.1 In addition,
R-keto esters themselves have attracted increasing inter-
est in connection with their activity as potent inhibitors
of proteolytic enzymes,2 inhibitors of leukotriene A4
hydrolase,3 photopolymerization initiators,4 and precur-
sors in the asymmetric synthesis of R-hydroxy carboxylic
acids.5
The more important synthetic methods for these
compounds include oxidation of R-hydroxy esters,6
Friedel-Crafts acylation,7 hydrolysis and esterification
of acyl cyanides,4 oxidative cleavage of cyano keto phos-
phoranes,8 and the reaction of organometallic species
with oxalic ester derivatives.9 Most of these methods
suffer from lengthy procedures or lack of generality.
While the latter method appears to be one of the simplest
and more versatile strategies for the formation of R-keto
esters, it suffers from the serious drawbacks associated
with the addition of organometallic reagents (typically
Grignard or organolithium) to carboxylic acid derivatives,
mainly the tendency to overadd to the substrates produc-
ing undesirable side reactions.
In an attempt to improve the synthesis of 2-oxo-4-
phenyl-3-butynoic acid, claimed as a potent irreversible
inhibitor of brewers’ yeast pyruvate decarboxylase, J or-
dan and Chiu9b introduced the monoethyloxalic acid
N-methoxy-N-methylamide (2) as an alternative to sub-
strate 1. This new oxalic derivative, whose selection was
primarily based on the reactivity of N-methoxy-N-meth-
ylamides, can be formally considered as an analog of the
“Weinreb amide”,10 whose utility in organic synthesis is
well documented.11 The reaction of 2 with lithium bases
derived from phenylacetylene, 4-chlorophenylacetylene,
and 1-bromo-2-methoxyphenyl derivatives gave rise to
the desired 2-oxo esters 4 in yields between 66 and 78%.
However, when the procedure was applied to an aliphatic
nucleophile such as n-BuLi a 2-oxo amide 5 was obtained
in a 52% yield, as the major product (eq 1). With use of
2.0 equiv of base, the 1,2-diketone was isolated as the
major component.
Although significant progress was made with the
introduction of the ethyl and tert-butyl R-oxo-1H-imida-
zole-1-acetate (1), which on reaction with aryl Grignard
reagents9a produced the desired R-keto esters in yields
up to 54%, these imidazolides failed to give similar yields
when alkyl reagents were used, with the corresponding
R-keto esters being obtained in such cases in yields lower
than 26%. Moreover, it was reported9b that the substrate
1a reacted with lithium phenylacetylide to afford the
ethyl 2-oxo-4-phenyl-3-butynoate in only 10% yield,
The above considerations encouraged us to search for
an efficient new oxalic ester derivative that could selec-
tively provide both aryl and alkyl 2-oxo esters. The 1-(N-
(ethoxyoxalyl)-N-methylamino)-3-methylimidazolium io-
dide 3a was initially chosen, on the basis of our previous
reports showing the utility of 1-(N-acyl-N-methylamino)-
3-methylimidazolium salts as selective acylating reagents
toward organolithium and Grignard reagents.12
(1) (a) Cooper, A. J . L.; Ginos, J . Z.; Meister, A. Chem. Rev. 1983,
83, 321-358. (b) Kova´cs, L. Rec. Trav. Chim. Pays-Bas 1993, 112, 471-
496.
(2) (a) Patel, D. V.; Rielly-Gauvin, K.; Ryono, D. E.; Free, C. A.;
Smith, S. A.; Petrillo, E. W., J r. J . Med. Chem. 1993, 36, 2431. (b)
Ocain, T.; Rich, D. H. J . Med. Chem. 1992, 35, 451. (c) Iwanowicz, E.
J .; Lin, J .; Roberts, D. G.; Michel, I. M.; Seiler, S. M. Bioorg. Med.
Chem. Lett. 1992, 2, 1607. (d) Angelastro, M. R.; Mehdi, S.; Burkart,
J . P.; Peet, N. P.; Bey, P. J . Med. Chem. 1990, 33, 11.
(3) (a) Yuan, W.; Wong, C.-H.; Haeggstrom, J . Z.; Wetterholm, A.;
Samuelson, B. J . Am. Chem. Soc. 1992, 114, 6552. (b) Yuan, W.; Mun˜oz,
B.; Wong, C.-H.; Haeggstrom, J . Z.; Wetterholm, A.; Samuelson, B. J .
Med. Chem. 1993, 36, 211.
The salt 3a was readily accessible by reacting 1-amino-
3-methylimidazolium mesitylenesulfonate 6 with ethyl
(10) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 56, 291.
(11) (a) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25, 15. (b) O’Neill,
B. T. Comprehensive Organic Synthesis; 1991; Vol. 1, p 397. (c) Evans,
D. A.; Gauchet-Prunet, J . A. J . Org. Chem. 1993, 58, 2446. (d) Sibi, P.
M. Marvin, M.; Sharma., R. J . Org. Chem. 1995, 60, 5016. (e) Sibi, M.
P.; Christensen, J . W.; Kim, S.-G.; Eggen, M. J .; Stessman, C.; Oien,
L. Tetrahedron Lett. 1995, 36, 6209. (f) Williams, J . M.; J obson, R. B.;
Yasuda, N.; Marchesini, G.; Dolling, U.-H.; Grabowski, J . J . Tetrahe-
dron Lett. 1995, 36, 5461. (g) Sawamura, M.; Hamashima, H.; Shinoto,
H.; Ito, Y. Tetrahedron Lett. 1995, 36, 64479. (h) Davies, S. G.;
McCarthy, T. D. Synlett. 1995, 700. (i) Braslau, R.; Naik, N.; Olmstead,
M. M. J . Org. Chem. 1996, 61, 368.
(4) Photis, J . M. Tetrahedron Lett. 1980, 21, 3539.
(5) Valentine, D., J r.; Scott, J . W. Synthesis 1978, 329.
(6) (a) Peet, N. P.; Burkhart, J . P.; Angelastro, M. R.; Giroux, E. L.;
Mehdi, S.; Bey, P.; Kolb, M.; Neises, B.; Schirlin, D. J . Med. Chem.
1990, 33, 394. (b) Burkhart, J . P.; Peet, N. P.; Bey, P. Tetrahedron
Lett. 1988, 29, 3433.
(7) Micetich, R. G. Org. Prep. Proced. Int. 1970, 2, 249.
(8) Wasserman, H. H.; Ho, W.-B. J . Org. Chem. 1994, 59, 4364.
(9) (a) Nimitz, J . S.; Mosher, H. S. J . Org. Chem. 1981, 46, 211. (b)
Chiu, C. C.; J ordan, F. J . Org. Chem. 1994, 59, 5763.
(12) Heras, M. A.; Molina, A.; Vaquero, J . J .; Garc´ıa-Navio, J . L.;
Alvarez-Builla, J . J . Org. Chem. 1993, 58, 5862.
S0022-3263(96)01329-1 CCC: $12.00 © 1996 American Chemical Society

9010 J . Org. Chem., Vol. 61, No. 25, 1996
Notes
Sch em e 1
Ta ble 1. r-Keto Ester s 4 P r ep a r ed by Rea ction of
oxalyl chloride to yield the aminide 7a (63%), which was
easily converted into 3a (97%) by N-methylation with
methyl iodide in dry acetonitrile (Scheme 1). After
elimination of the solvent the salt was isolated as a
slightly hygroscopic yellow oil, stable to storage and able
to be used without further purification.
Gr ign a r d Rea gen ts w ith 3
Although both aryl and alkyl R-keto esters can be
prepared easily and in high yields (Table 1) by using salt
3a , several points are noteworthy. The formation of a
metalated intermediate 8 plays an essential role in the
success of the reaction, since the direct addition of 1.1
equiv of the organometallic reagent gave low conversion,
with 3a being extensively recovered. Alternatively, when
8 was preformed (LDA/THF), the addition of 1.0 equiv
of alkyl- or arylorganolithium produced mixtures of the
R-keto esters, R-diketones, and R-hydroxy ketones. Only
with the addition of 1.0 equiv of aryl Grignard reagents
to 8 were the corresponding R-keto esters obtained as the
sole reaction products. The procedure was then extended
to acetylenic derivatives. Addition of (phenylethynyl)-
and propynylmagnesium bromide (Table 1, entries 4 and
5) resulted in the formation of the corresponding R-keto
esters in yields up to 70%.13 Finally, the procedure was
tested with alkylmagnesium halides, and it was found
to be highly chemoselective, leading to alkyl R-keto esters
(Table 1, entries 7 and 9-12) with no signs of 2-oxo amide
formation.
To further establish the versatility of the method it was
also applied to the salt 3b with the corresponding tert-
butyl esters also obtained in good yields (Table 1, entries
2, 6, and 8).
In conclusion, the use of the new oxalic ester deriva-
tives 3, following the strategy outlined here, provides an
easy an efficient method for the preparation of a variety
of R-keto esters. Furthermore, the activation of the
carbonyl group of the amide moiety via a metalated
intermediate and the behavior of the 1-methyl-3-(methyl-
amino)imidazolium moiety as a leaving group suggests
considerable generality for the procedure.
Exp er im en ta l Section
General experimental techniques and analytical measure-
ments were applied as previously described.14 Chromatography
was performed on silica gel 60 (230-400 mesh). All reagents
were obtained from commercial sources. THF was distilled from
sodium-benzophenone. CH3CN was dried from calcium hy-
dride. All solutions of organometallic reagents were titrated
before use. Reactions involving organometallics were carried
out under an argon atmosphere in glassware that had been dried
at 100 °C for at least 3 h. LDA was used as a commercial 2 M
solution in THF, and Grignard reagents were used as com-
mercial solutions in THF (Table 1, entries 1, 2, 4-8, and 12),
Et2O (Table 1, entry 10) or prepared according to standard
(13) The ethyl 2-oxo-4-phenyl-3-butynoate has recently been pre-
pared by benzotriazole methodology in good yield. Katritzky, A. R.;
Lang, H. J . Org. Chem. 1995, 60, 7612.
(14) Santiesteban, I.; Siro, J .; Vaquero, J . J .; Garc´ıa-Navio, J . L.;
Alvarez-Builla, J .; Castan˜o, O.; Andre´s, J . L. J . Org. Chem. 1995, 60,
5667.

Notes
J . Org. Chem., Vol. 61, No. 25, 1996 9011
procedures (Table 1, entries 3, 9 and 11). 1-Amino-3-methylimi-
dazolium mesitylenesulfonate (6) was prepared as previously
described.12
2.13 (s, 3H), 1.36 (t, J ) 7.3 Hz, 3H) ppm. Anal. Calcd for
C7H8O3: C, 60.00; H, 5.75. Found: C, 59.86; H, 5.56.
ter t-Bu t yl 2-oxo-3-p en t yn oa t e (Ta b le 1, en t r y 6): pale
yellow oil; IR (neat) 3074, 2931, 2221, 1732, 1684, 1454, 1372,
1151, 1032 cm-1; 1H NMR (CDCl3, 300 MHz) δ 2.13 (s, 3H), 1.55
(s, 9H) ppm. Anal. Calcd for C9H12O3: C, 64.27; H, 7.19.
Found: C, 64.13; H, 7.18.
1-((Alk oxyoxa lyl)a m in o)-3-m eth ylim id a zoliu m Hyd r ox-
id e In n er Sa lts 7. Gen er a l P r oced u r e. To a mixture of
1-amino-3-methylimidazolium mesitylenesulfonate (3.36 mmol,
1 g) and K2CO3 (13.44 mmol, 1.85 g) in methylene chloride (30
mL) was slowly added a solution of the corresponding alkoxy-
oxalyl chloride (4 mmol) in methylene chloride (15 mL), and the
mixture was stirred at room temperature for 18 h. The reaction
mixture was then filtered through Celite, and the solid was
washed with methylene chloride (50 mL). The filtrate and the
washes were combined and concentrated under reduced pres-
sure. The residue was triturated with ethyl acetate. The title
compounds were isolated by filtration and recrystallized from
ethyl acetate.
The structure of the following compounds was confirmed by
comparison of their spectral and/or analytical data with those
of authentic samples or previously reported data.
Eth yl 2-oxo-2-p h en yla ceta te (Ta ble 1, en tr y 1):16 IR (neat)
1
2926, 1730, 1695, 1451, 1247, 1200, 1158, 1023 cm-1; H NMR
(CDCl3, 300 MHz) δ 8.03-8.00 (m, 2H), 7.67-7.63 (m, 1H), 7.54-
7.49 (m, 1H), 4.46 (q, J ) 6.9 Hz, 2H), 1.43 (t, J ) 6.9 Hz, 3H)
ppm.
ter t-Bu t yl 2-(4-m et h ylp h en yl)-2-oxoa cet a t e (Ta ble 1,
en tr y 2):17 IR (neat) 3075, 2929, 1734, 1701, 1439, 1375, 1113,
7a : white powder, 63%; mp 129-130 °C; IR (KBr) 3158, 3093,
1032 cm-1 1H NMR (CDCl3, 300 MHz) δ 7.87 (d, J ) 8.0 Hz,
;
3056, 1719, 1622, 1557, 1505, 1454, 1320, 1216, 1109, 1095 cm-1
;
1H NMR (300 MHz, DMSO-d6) δ 9.51 (s, 1H), 7.63 (s, 1H), 7.50
(s, 1H), 4.09 (q, J ) 7.3 Hz, 2H), 3.79 (s, 1H), 1.20 (t, J ) 7.3
Hz, 1H) ppm; MS (EI, 70 eV) m/ z (rel int) 197 (M+, 3), 124 (100),
82 (33), 56 (14). Anal. Calcd for C8H11N3O3: C, 48.73; H, 5.62;
N, 21.31. Found: C, 48.37; H, 5.40; N 21.00.
2H), 7.30 (d, J ) 8.0 Hz, 2H), 2.44 (s, 3H), 1.54 (s, 9H) ppm.
Eth yl 2-oxo-4-p h en yl-3-bu tyn oa te (Ta ble 1, en tr y 4):9b,13
IR (neat) 2963, 2930, 2174, 1739, 1677, 1446, 1260, 1187, 1153,
1078, 1017 cm-1 1H NMR (CDCl3, 300 MHz) δ 7.74-7.71 (m,
;
2H), 7.54-7.51 (m, 1H), 7.36-7.29 (m, 2H), 4.37 (q, J ) 6.9 Hz,
2H), 1.37 (t, J ) 6.9 Hz, 3H) ppm.
7b: white powder, 60%; mp 160-161 °C; IR (KBr) 3150, 2980,
Eth yl 2-oxoh exa n oa te (Ta ble 1, en tr y 7):16 IR (neat) 2962,
2873, 1728, 1462, 1259, 1053 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 4.31 (q, J ) 7.3 Hz, 2H), 2.83 (t, J ) 7.3 Hz, 2H), 1.67-1.54
(m, 4H), 1.37 (t, J ) 7.3 Hz, 3H), 0.92 (t, J ) 7.3 Hz, 3H) ppm.
ter t-Bu tyl 2-oxoh exa n oa te (Ta ble 1, en tr y 8):18 IR (neat)
1
1719, 1606, 1564, 1512, 1366, 1327, 1243, 1157, 1120 cm-1; H
NMR (300 MHz, CDCl3 ) δ 9.888(s, 1H), 7.51 (s, 1H), 6.92 (s,
1H), 3.84 (s, 1H), 1.57 (s, 9H) ppm. Anal. Calcd for C10H15
-
N3O3: C, 53.32; H, 6.71; N, 18.66. Found: C, 53.08; H, 6.69; N
18.42.
2959, 2930, 2861, 1723, 1459, 1359, 1258, 1136, 1086, 1031 cm-1
;
1-(N-(Alk oxyoxa lyl)-N-m eth yla m in o)-3-m eth ylim id a zo-
liu m Iod id es 3. Gen er a l P r oced u r e. To a suspension of the
corresponding aminide 7 (1 mmol) in dry CH3CN (5 mL) was
added methyl iodide (4 mmol, 0.44 mL), and the mixture was
stirred at reflux for 6 h. The reaction mixture was concentrated
under reduced pressure to give the salts as yellow oils.
3a : 97%; IR (neat) 3141, 3085, 1744, 1704, 1585, 1468, 1377,
1253, 1211, 1091 cm-1; 1H NMR (300 MHz, CD3OD) δ 7.75 (d, J
) 2.2 Hz, 1H), 7.54 (d, J ) 2.2 Hz, 1H), 3.91 (s, 3H), 3.62 (q, J
) 6.9 Hz, 2H), 2.94 (s, 3H), 1.17 (t, J ) 6.9 Hz, 3H) ppm; Anal.
Calcd for C9H14N3O3 212.1031, found 212.1035.
1H NMR (CDCl3, 300 MHz) δ 2.76 (t, J ) 7.3 Hz, 2H), 1.46-
1.66 (m, 4H), 1.48 (s, 9H), 0.91 (t, J ) 7.3 Hz, 3H) ppm.
Eth yl 2-oxo-5-h exen oa te (Ta ble 1, en tr y 9):19 IR (neat)
2964, 1725, 1445, 1259, 1092, 1020 cm-1; 1H NMR (CDCl3, 300
MHz) δ 5.75-5.86 (m, 1H), 4.94-5.10 (m, 2H), 4.33 (q, J ) 7.2
Hz, 2H), 2.95 (t, J ) 6.9 Hz, 2H), 2.36-2.43 (m, 2H), 1.37 (t, J
) 7.2 Hz, 3H) ppm.
Eth yl 2-cyclop en tyl-2-oxoa ceta te (Ta ble 1, en tr y 10):20
IR (neat) 2959, 2871, 1727, 1450, 1261, 1093, 1023 cm-1 1H
;
NMR (CDCl3, 300 MHz) δ 4.33 (q, J ) 7.3 Hz, 2H), 3.49 (m,
1H), 1.87-1.95 (m, 2H), 1.78-1.85 (m, 2H), 1.58-1.67 (m, 4H),
1.37 (t, J ) 7.3 Hz, 3H) ppm.
3b: 96%; IR (neat) 3140, 3070, 3070,1739, 1704, 1585, 1468,
1377, 1253, 1211, 1091 cm-1; 1H NMR (300 MHz, CD3OD) δ 9.43
(s, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 4.01 (s, 3H), 3.54 (s, 3H), 1.53
(s, 9H) ppm; MS (70 eV, CI) m/ z (rel int) 240 (100, M+), 165
(30), 112 (16), 83 (3). Anal. Calcd for C11H18IN3O3: C, 35.92;
H, 4.94; N, 11.44. Found: C, 36.18; H, 5.02; N, 11.34.
Gen er a l Meth od for th e Syn th esis of r-Keto Ester s 4.
LDA (0.55 mmol, 0.27 mL, 2 M solution in THF) was added
dropwise to a solution of 3 (0.5 mmol, 0.17 g) in 5 mL of dry
THF at room temperature, and the mixture was ultrasonically
irradiated for 30 min. The corresponding Grignard reagent (0.55
mmol) was then added dropwise to at -78 °C. The reaction
mixture was allowed to warm to room temperature and then
quenched with hydrochloric acid (5%, 5 mL) and extracted with
ethyl ether (3 × 5 mL). The combined organic extracts were
dried over Na2SO4 and concentrated under reduced pressure.
The residue was purified by column chromatography on silica
gel. Elution with hexane/EtOAc (9:1) gave pure R-keto esters.
Eth yl 2-oxo-2-(2-th ien yl)a ceta te (Ta ble 1, en tr y 3):15 pale
yellow oil; IR (neat) 2930, 2858, 1764, 1740, 1452, 1309, 1187,
Eth yl 2-oxo-3-p h en ylp r op a n oa te (Ta ble 1, en tr y 11):21
IR (neat) 2985, 2937, 1742, 1451, 1315, 1191, 1012 cm-1 1H
;
NMR (CDCl3, 300 MHz) δ 7.36-7.41 (m, 5H), 5.31 (s, 2H), 4.35
(q, J ) 6.9 Hz, 2H), 1.37 (t, J ) 6.9 Hz, 3H) ppm.
Eth yl 3,3-d im eth yl-2-oxobu ta n oa te (Ta ble 1, en tr y 12):
22 IR (neat) 2961, 2928, 1709, 1400, 1256, 1197, 1087, 1019 cm-1
;
1H NMR (CDCl3, 300 MHz) δ 4.34 (q, J ) 7.3 Hz, 2H), 1.35 (t,
J ) 7.3 Hz, 3H), 1.11 (s, 9H) ppm.
Ack n ow led gm en t. The authors acknowledge sup-
port of this work from the the Comisio´ Interdeparta-
mental de Recerc¸a i Innovacio´ Te´cnologica (CIRIT,
project QFN94-4619) for financial support and the
Ministerio de Educacio´n y Ciencia for a studentship
(M.A.H.). We also thank to Professor A. R. Katritzky
for helpful suggestions.
J O961329Z
1099, 1020 cm-1 1H NMR (CDCl3, 300 MHz) δ 7.23-7.28 (m,
;
2H), 7.02 (dd, J ) 1.2, 4.9 Hz, 1H), 4.36 (q, J ) 7.3 Hz, 2H),
1.38 (t, J ) 7.3 Hz, 3H) ppm. Anal. Calcd for C8H8O3S: C,
52.16; H, 4.38; S, 17.40. Found: C, 51.80; H, 4.15; S, 17.56.
Eth yl 2-oxo-3-p en tyn oa te (Ta ble 1, en tr y 5): pale yellow
oil; IR (neat) 2927, 2856, 2221, 1740, 1683, 1451, 1174, 1019
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;
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