organic chemists intend tofind simple and mild conditions,
using naturally occurring molecules. In connection with
these objectives, we report thereafter the decarboxylative
aldol reaction of functionalized R-amino-Malonic Acid
Half Oxyesters (MAHOs) as cheap glycine equivalents
with aldehydes under very mild metal-free conditions for
the direct synthesis of polyfunctional esters.
Table 1. Decarboxylative Aldol Reaction of 1aa
Malonic acid and its derivatives have been used in various
reactions as acetic acid equivalents due to the ease of func-
tionalizing the central methylene and then to decarboxylate.
MAHOs and MAHTs (Malonic Acid Half Thioesters), hav-
ing a free carboxylic acid group, add directly under mild con-
ditions onto various electrophiles with concomitant loss of
CO2. Of particular interest are the decarboxylative Claisen,9
Aldol or Mannich,10 Michael,11 and the Knoevenagelꢀ
Doebner12 reactions with those substrates. In most reports,
the starting hemimalonates are unsubstituted on the central
methylene because of the lower reactivity of similar substrates
bearing an alkyl group.10b,dꢀf The amido-MAHOs, easily
obtained from the cheap amidomalonate diesters, have been
rarely used in those reactions,13 although they afford poten-
tially highly functionalized products.
We became interested in those amido-MAHO derivatives
while studying their asymmetric decarboxylative protonation
for a direct access to enantioenriched R-amino acids.14 Fol-
lowing our initial work on the decarboxylative Aldol (and
Mannich) reaction with unsubstituted MAHOs,10f we envi-
saged this reaction sequence with amido-MAHOs where two
consecutive stereogenic centers are established in a single
operation. We focused on developing mild metal-free condi-
tions and on the control of the syn/anti diastereoselectivity.
drb
yield
(%)
entry
solvent
base
Et3N
(anti/syn)
1
DMF
DMF
DMF
THF
EtOH
DCM
CCl4
THF
THF
THF
THF
THF
EtOH
THF
93/7
71%
63%c
79%
92%
83%
70%
93%
92%
92%d
74%e
99%
99%
80%
70%f
2
Et3N
DIPEA
DIPEA
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DMAP
DABCO
KOH
ꢀ
100/0
77/23
88/12
94/6
3
4
5
6
100/0
96/4
7
8
100/0
100/0
100/0
100/0
100/0
1/1
9
10
11
12
13
14
1/1
a Conditions: 1a (0.4 mmol) with 4-nitrobenzaldehyde (0.48 mmol,
1.2 equiv) and the base (0.4 mmol, 1 equiv) in 0.7 mL of solvent, 15 h at rt.
b Diasteromeric ratios were determined by 1H NMR analysis of the
crude. c At 10 °C. d Using 7 mol % of Et3N. e Carried out on 1 g of 1a
(4 mmol) using 5 mol % of Et3N. f 48 h at rt.
The reaction of benzamido-MAHO 1a with 4-nitrobenzal-
dehyde was first studied in various solvents at rt (Table 1).
To optimize the decarboxylative aldol reaction, selected
bases were screened in various solvents at rt. In a first
attempt in DMF, triethylamine showed a promising result
affording the aldol products in 71% yield and a 97/3 dia-
stereomeric ratio in favor of the anti-adduct 2a (entry 1).
Decreasing the temperature slightly to 10 °C enabled 2a to
be obtained with complete anti selectivity (entry 2). With
the bulkier base DIPEA, the diastereomeric ratio dropped
to 77/23 in DMF (entry 3) and 88/12 in THF (entry 4).
Several solvents were tested with Et3N (entries 5ꢀ8). In
THF and DCM the reaction gave only the anti-diastereomer
2a in 92% and 70% yield, respectively. The reaction
performed using a substoichiometric amount of Et3N
(7 mol %) led to the same result, high yield and selectivity
(entry 9). Ona gramscale of 1a, with only5 mol % ofEt3N,
the reaction yielded 2a as the sole diastereomer in good
yield (entry10). Other bases such as DMAP and DABCO
led to the same high levels of selectivity and yield in THF
(entries 11ꢀ12). Potassium hydroxide afforded the aldol
products in good yields but without selectivity (entry 13).
The reaction without a base gave the product yet in a
longer reaction time and with a 1/1 diastereomeric ratio
(entry 14). This illustrates the catalytic effect of amine
bases and their beneficial effect on the selectivity. To
confirm that no epimerization of the product occurred
once it is formed, treatment of 2a as an anti/syn diaster-
eomeric mixture (2/1 ratio) with Et3N in THF afforded the
same ratio after 4 days at rt. As the cheapest of the most
(9) For selected decarboxylative Claisen reactions of MAHOs or
MAHTs, see: (a) Ireland, R. E.; Marshall, J. A. J. Am. Chem. Soc. 1959,
81, 2907. (b) Kobuke, Y.; Yoshida, J.-I. Tetrahedron Lett. 1978, 4, 367. (c)
Brooks, D. W.; Lu, L. D.-L.; Masamune, S. Angew. Chem., Int. Ed. 1979,
18, 72. (d) Clay, R. J.; Collom, T. A.; Karrick, G. L.; Wemple, J. Synthesis
1993, 290. (e) Ryu, Y.; Scott, A. I. Tetrahedron Lett. 2003, 44, 7499.
(10) For selected decarboxylative aldol and Mannich reactions of
MAHOs or MAHTs, see: (a) Orlandi, S.; Benaglia, M.; Cozzi, F. Tetra-
hedron Lett. 2004, 45, 1747. (b) Fortner, K. C.; Shair, M. D. J. Am. Chem.
Soc. 2007, 129, 1032 and references therein. (c) Ricci, A.; Petterson, D.;
Bernardi, L.; Fini, F.; Fochi, M.; Perez Herrera, R.; Sgarzani, V. Adv.
Synth. Catal. 2007, 349, 1037. (d) Blaquiere, N.; Shore, D. G.; Rousseaux,
S.; Fagnou, K. J. Org. Chem. 2009, 74, 6190. (e) Pan, Y.; Kee, C. W.; Jiang,
Z.; Ma, T.; Zhao, Y.; Yang, Y.; Xue, H.; Tan, C.-H. Chem.;Eur. J. 2011,
8363. (f) Baudoux, J.; Lefevre, P.; Lasne, M.-C.; Rouden, J. Green Chem.
2010, 12, 252. (g) Hara, N.; Nakamura, S.; Funahashi, Y.; Shibata, N. Adv.
Synth. Catal. 2011, 353, 2976. (h) Yin, L.; Kanai, M.; Shibasaki, M.
Tetrahedron 2012, 68, 3497. (i) Li, X.-J.; Xiong, H.-Y.; Hua, M.-Q.; Nie,
J.; Zheng, Y.; Ma, J.-A. Tetrahedron Lett. 2012, 53, 2117.
(11) For selected decarboxylative Michael reactions of MAHOs or
MAHTs, see: (a) Lubkoll, J.; Wennemers, H. Angew. Chem., Int. Ed.
2007, 46, 6841. (b) Furutachi, M.; Mouri, S.; Matsunaga, S.; Shibasaki,
M. Chem.;Asian J. 2010, 5, 2351. (c) Bae, H. Y.; Some, S.; Lee, J. H.;
Kim, J.-Y.; Song, M. J.; Lee, S.; Zhang, Y. J.; Song, C. E. Adv. Synth.
Catal. 2011, 353, 3196.
(12) For selected KnoevenagelꢀDoebner reactions of MAHOs or
MAHTs, see: (a) Rodriguez, J.; Waegell, B. Synthesis 1988, 534. (b) List,
B.; Doehring, A.; Hechaverria Fonseca, M. T.; Job, A.; Rios Torres, R.
Tetrahedron 2006, 62, 476.
(13) Xu, F.; Zacuto, M.; Yoshikawa, N.; Desmond, R.; Hoerrner, S.;
Itoh, T.; Journet, M.; Humphrey, G. R.; Cowden, C.; Strotman, N.;
Devine, P. J. Org. Chem. 2010, 75, 7829.
(14) (a) Amere, M.; Lasne, M.-C.; Rouden, J. Org. Lett. 2007, 9, 2621.
(b) Seitz, J.; Baudoux, J.; Bekolo, H.; Cahard, D.; Plaquevent, J.-C.; Lasne,
M.-C.; Rouden, J. Tetrahedron 2006, 62, 6155. (c) For a review on
enantioselective decarboxylative protonations, see: Blanchet, J.; Baudoux,
J.; Amere, M.; Lasne, M.-C.; Rouden, J. Eur. J. Org. Chem. 2008, 5493.
Org. Lett., Vol. 15, No. 22, 2013
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