Environmentally benign metal-free decarboxylative aldol and Mannich reactions

Article abstract of DOI:10.1039/b915681j

Aiming at the development of green and efficient C-C bond formations (aldol and Mannich reactions), the decarboxylative nucleophilic addition of malonic acid half ester to imines or aldehydes under mild metal-free conditions was studied. A careful control of the temperature and the appropriate choice of the organic base allowed us to obtain β-amino esters or β-hydroxy esters including α-substituted and α,α-disubstituted ones in moderate to excellent yields. ¹H NMR monitoring of the reaction unveiled two distinct mechanisms depending on the hemimalonate used. With the unsubstituted substrate, a carboxylic acid intermediate was isolated upon acid quench resulting from the nucleophilic addition of the putative enol carboxylate anion of the hemimalonate to imines/aldehydes before CO₂ loss. With substituted hemimalonates, the reaction likely involved an enolate which then added to imines/aldehydes or was competitively protonated. According to the base used, the reaction can be carried out either under solvent free-conditions or in an ionic liquid under mild conditions.

Full text of DOI:10.1039/b915681j

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PAPER
www.rsc.org/greenchem | Green Chemistry
Environmentally benign metal-free decarboxylative aldol and Mannich
reactions
Je´roˆme Baudoux, Pierre Lefebvre, Re´mi Legay, Marie-Claire Lasne and Jacques Rouden*
Received 31st July 2009, Accepted 15th October 2009
First published as an Advance Article on the web 18th November 2009
DOI: 10.1039/b915681j
Aiming at the development of green and efficient C–C bond formations (aldol and Mannich
reactions), the decarboxylative nucleophilic addition of malonic acid half ester to imines or
aldehydes under mild metal-free conditions was studied. A careful control of the temperature and
the appropriate choice of the organic base allowed us to obtain b-amino esters or b-hydroxy esters
including a-substituted and a,a-disubstituted ones in moderate to excellent yields. 1H NMR
monitoring of the reaction unveiled two distinct mechanisms depending on the hemimalonate
used. With the unsubstituted substrate, a carboxylic acid intermediate was isolated upon acid
quench resulting from the nucleophilic addition of the putative enol carboxylate anion of the
hemimalonate to imines/aldehydes before CO2 loss. With substituted hemimalonates, the reaction
likely involved an enolate which then added to imines/aldehydes or was competitively protonated.
According to the base used, the reaction can be carried out either under solvent free-conditions or
in an ionic liquid under mild conditions.
hydroxy esters and to a lesser extent to b-amino esters is rather
desirable.
Introduction
The development of organic reactions based on the twelve
principles of Green Chemistry is one of the most important
issues in today’s scientific community.1 In recent years, much
attention has been paid to the development of organocatalysis,2
an eco-friendly and cost-effective concept well-suited for in-
dustrial applications, especially when metal traces is of real
concern (pharmaceutical industry). Organocatalyzed aldol3 and
Mannich4 reactions based on enamine reactive intermediates,
two organic economical-atom transformations, have been widely
studied. With the exception of a direct aldol reaction me-
diated by silyl trifluoromethanesulfonate in the presence of
diisopropylethylamine,5 the available methods for a direct metal-
free aldol reaction of esters are nearly non existent because
of the lower enolization ability of esters compared with that
of ketones. Organocatalytic routes using ester and aldehyde
partners involved ketene (thio)acetals as ester equivalents and
chiral phosphoramides or pyridine N-oxides,6 oxazaborolidi-
none derivatives7 or triarylcarbenium ions8 as catalysts. An
aldol reaction was also observed in DMSO.9 The formation
of b-amino esters in organocatalyzed Mannich type reactions
has been studied much more.4 Usually a protected imine (or an
equivalent of imine) reacts with a dialkyl malonate,10 or a ketene
acetal. Although efficient, these approaches require more than
one step. Given their valuable roles as versatile building blocks
in the synthesis of natural products or compounds of biological
interest,11 the development of an eco-friendly synthesis of b-
Recently, we showed12 that enantioselective decarboxylative
protonation13 of a-amino substituted malonic acid half esters is
an attractive route to enantioenriched a-amino acids due to the
mild conditions and the general applicability of the reaction. As
part of an ongoing project concerning the metal-free synthesis
of functionalized carbonyl compounds14 we envisaged the use of
the organic base-catalyzed decarboxylation of malonic acid half
esters (or “hemimalonates”) as a mild and convenient procedure
to generate an enolate of ester with its subsequent reaction with
an electrophile (imines or aldehydes) (Scheme 1). The simple
malonic acid half ethyl ester 1a is a commercially available
stable b-acid ester which can be easily made quantitatively
from the very cheap diethyl malonate or the potassium salt of
ethyl hemimalonate. Recently published work15 prompted us to
describe thereafter our results focused on the following practical
issues: (i) high conversion of the reagents under stoichiometric
ratios, (ii) metal-free conditions, (iii) eco-friendly medium, (iv)
cost-effectiveness, (v) low energy demand, (vi) easy work-up.
Laboratoire de Chimie Mole´culaire et Thioorganique, UMR CNRS
6507, INC3M, FR 3038, ENSICAEN, Universite´ de Caen Basse
Normandie, 6, Bd Mare´chal Juin, 14050 Caen, France.
E-mail: jacques.rouden@ensicaen.fr; Fax: +33 23145 2877; Tel: +33
23145 2893
Scheme 1 Decarboxylative C–C bond forming reaction.
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Table 1 Influence of the cation on the outcome of the reaction of imine
2a and hemimalonates 1b-e
Results and discussion
Decarboxylative C–C bond forming reactions from malonic
acid half esters usually required the generation of a magnesium
salt16,17 or the formation of a lithium enolate.18 Under basic
conditions, N-acetyl serine esters were successfully prepared
from acetamido hemimalonate19 whereas a decarboxylative
Claisen reaction was observed20 with activated malonic acid
half esters. The related Doebner–Knoevenagel reaction was
studied both from the mechanistic21 and practical22 points of
view. Using a well-designed malonic acid half ester,23 Ohta
et al.24 demonstrated that arylmalonate decarboxylase catalyzed
an intramolecular decarboxylative aldol reaction.25
Products, ratiob
Entrya
Y
Compound 1
7a
4a
6a (E)
1
2
3
4
HNEt3
Li
Na
b
c
d
e
0
100
22
21
0
43
57
39
35
22
15
K
46
a Conditions: salt 1 (1.55 mmol, 200 mg), imine 2a (1 equiv), THF
(0.1 M), room temperature, 24 h. Conversion: 100%. b From 1H NMR
after work-up.
While transition metal catalyzed decarboxylation of b-keto
acids and esters is well known, particularly in aldol and
Michael additions or in allylic substitutions,26 only a few
involve hemimalonates. Based on a biomimetic approach and
on the enhanced acidity of a thioester function relative to
simple esters, the groups of Cozzi27 and Shair28 developed the
aldol-decarboxylation reaction of aldehydes and malonic- or
methylmalonic acid half thioesters in the presence of a copper
(II) complex. Ricci et al.29 described the first organocatalytic
asymmetric decarboxylative nucleophilic addition of malonic
acid half thioesters to imines. This work led us to test the
feasibility of a decarboxylative C–C bond forming reaction using
hemimalonate 1a as a straightforward available substrate.
Based on literature precedents, the mechanism of the reaction
(Scheme 2) can involve the formation of enolate 9 (path A)29
prior to protonation (path C) or reaction with imine 2a (path
D). Direct addition of imine 2a to malonic acid half ester salt 1b
(path B)15,22,28 can also be envisaged prior to decarboxylation of
salt 7 (or 8).
Scheme 3 Reaction of hemimalonates with electrophiles.
Doebner product 6a with the inorganic salts 1c-1e, whereas the
ammonium salt 1b afforded exclusively the b-amino derivative
4a (Table 1, comparison of entry 1 with entries 2-4).
In the following experiments, NEt3 was chosen as the organic
base for the optimization of the parameters. Several solvents
were screened in the reaction carried out at 45 ◦C for 48 h.
In dichloromethane, carbon tetrachloride, toluene or dioxane,
the conversion was low (less than 50%) whereas the expected
product 4a was formed in satisfactory yields in THF, DMF or
acetonitrile (Table 2). Decreasing the amount of hemimalonate
1a had no significant influence (comparisons between entry 4).
Increasing the concentration of the imine 2a to 1.8 mol.L-1
improved the yields for the reaction carried out in DMF
(comparison of entries 4 and 5) and allowed the reaction to be
complete in 3 h in THF at 45 ◦C. The highest yield (66%) with the
lowest amounts of solvent and substrate 1a were thus obtained
Table 2 Reaction of ethyl hemimalonate 1a with imine 2a
Scheme 2 Mechanistic hypothesis for the formation of the products.
Entry 2aa conc. 1a equiv NEt3 equiv Solvent t (h) 4 yieldb%
When 1a was mixed with imine 2a in THF at 65 ◦C for 15 h but
without any base, no reaction occurred. Adding a tertiary amine
(NEt3)30 in a 1:1:2 imine/organic base/hemimalonate 1a molar
ratio, imine 2a was completely transformed at room temperature
affording b-amino ester 4a in 68% yield (Scheme 3). The same
reaction was performed with the preformed ammonium salt 1b
or with the salts 1c-1e. The results, presented in Table 1, clearly
show the benefits of using an organic ammonium countercation
in these reactions. A mixture of the expected product 4a was
formed beside the non-decarboxylated compound 7a (charac-
terized in-situ as its ammonium salt 7b) and the Knoevenagel–
1
2
3
4
5
6
7
8
0.1
0.1
0.1
1.8
0.1
1.8
0.1
1.8
1
1
THF
THF
THF
DMF
DMF
DMF
24
24
24
24
48
48
52-57
49
33
60-66
47
57
1.3
1.3
2 or 1
2
1.3
2
0.5
0.25
1
0.20
0.20
1
CH3CN 15
CH3CN 48
67
56
1
1
a Conditions: hemimalonate 1a, imine 2a (100 mg, 0.386 mmol),
molecular sieves (4 A◦) and NEt3 were stirred at 45 ◦C. b Isolated yields.
Conversion of imine 2a: 100%.
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Table 3 Reaction of hemimalonate 1a with 4-nitrobenzaldehyde 3a
in DMF (entry 4). Working under solvent-free conditions gave
only degradation products.
Entry
Basea
Solvent
Ratio 5a/6b/3a
5a Yieldb%
The reaction was attempted under catalytic conditions
(Table 2, entries 2, 3, 5, 6). In THF (0.1 M), the yield of 4a
decreased with the amine loading (entries 2 and 3). However in
DMF, under the standard conditions (1.8 M, entry 4) but with
a longer reaction time (48 h) and 0.2 equiv of base, reaction
of imine 2a with hemimalonate 1a (entry 6) afforded b-amino
ester 4a in just slightly lower yield than that obtained under
stoichiometric conditions.
1
2
3
4
5
6
7
8
9
NEt3
NEt3
DMAP
DMAP
PSe
DMFc
MeCNd
DMFc
MeCNd
DMFc
MeCNd
100/0/0
100/0/0
100/0/0
100/0/0
76/24/0
90/0/10
78
85
70
70
50
82
72g
85
72g
PS
NEt3
NEt3
NEt3
[BMIM] [PF6] 100/0/0
nof
nof
100/0/0
87/0/13
1
Next, H NMR monitoring of the reaction at room temper-
a Reagents: hemimalonate 1a (90 mg, 0.66 mmol), aldehyde 3a (100 mg,
0.66 mmol, 1.8 M in the solv◦ent), base (1 equiv). b Isolated yields with
100% conversion. c 24 h at 20 C then 15 h at 60 ◦C. d 15 h at 80 ◦C. e PS:
1,8-bis(dimethylamino)naphthalene (Proton Sponge). f 2 h at 20 ◦C then
15 h at 60 ◦C. g Reaction carried out on a gram scale.
ature of malonic acid half ester 1a with imine 2a as a function
of time clearly demonstrated the formation of carboxylic acid
intermediate 7 as a 2/1 mixture of diastereoisomers A (anti
or syn) and B (syn or anti) (Fig. 1). The experiments showed
the rapid disappearance of imine 2a concomitant with the dual
formation of A and B, then product 4a appeared after 90 min
upon the slow decarboxylation of these intermediates. Whatever
the conditions and all along the progress of the reaction, the
ratio of both diastereoisomers stayed constant. This could be
explained by the reversibility15 of the malonate nucleophilic
addition on imines, reflecting thus the relative stability of
intermediates A and B.
product 6b was a side product in the reaction carried out in
DMF (entry 5). Polar solvents being required for the reaction, we
attempted the decarboxylative aldol reaction in the hydrophobic
butyl methyl imidazolium hexafluorophosphate [BMIM][PF6],
a room temperature ionic liquid (RTIL). Indeed, due to their
properties (high polarity, no vapor pressure, high thermal
stability), RTILs are environmentally friendly substitutes for
conventional organic solvents. Under the conditions described
in entry 7, compound 5a was isolated in 72% yield.
It is worth noting that the reaction proceeded in high yield
in the absence of solvent. The isolation of the pure product
required only an acid-base work-up (entry 8). The same reaction
performed on a gram scale afforded product 5a in a slightly lower
yield due to the incomplete conversion of the starting material
(entry 9).
Attempts to carry out the reaction under catalytic conditions
of base gave no satisfactory results. A mixture of aldol 5a,
unsaturated ester 6b and unreacted aldehyde 3a was formed.
From the products observed in those reactions, Path B
of the mechanism was mainly operating with unsubstituted
hemimalonate at room temperature. The unstable carboxylic
acid 8a, as a mixture of two diastereoisomers, was isolated
and characterized. Such an intermediate was postulated in the
condensation of b-ketoacid salts with aldehydes.31
The scope of the reaction was then examined changing the
electrophilic partner of hemimalonate 1a. The reactions of 1a
with various aldehydes and imines were carried out in DMF
or acetonitrile in the presence of NEt3. The results are shown
in Table 4. Due to the instability of the imines used, average
yields were obtained for the corresponding Mannich products
(entries 1-4). Aldehydes bearing an electron-withdrawing group
led to the aldol products with good yields (entries 6-9). Yields
from halogenated aldehydes were slightly lower (entries 8-13).
Benzaldehyde, pyridine carboxaldehyde, diphenylethanal gave
moderate results, due to an incomplete conversion (entries 5,
14, 15). No reaction was observed with 4-methoxybenzaldehyde
and n-hexanal (data not shown).
Fig. 1 Monitoring of the reaction mixture 1a, imine 2a, NEt3 in DMF-
d7 as a function of time at room temperature.
Having demonstrated the feasibility of forming a C–C bond
from decarboxylative Mannich type reaction of malonic acid
half ester 1a, we attempted a decarboxylative aldol reaction
using 4-nitrobenzaldehyde 3a and hemimalonate 1a (Table 3).
In the presence of NEt3 or DMAP (1 equiv) in DMF or
acetonitrile (entries 1-4), the reaction of aldehyde 3a with
hemimalonate 1a led exclusively to the expected aldol product
5a in satisfactory yields. Similar results were obtained when
1,8-bis(dimethylamino)naphthalene (proton sponge “PS”) was
used in acetonitrile (entry 6) whereas the Knoevenagel–Doebner
Finally, the reaction was examined with a-substituted malonic
acid half esters 11a-c, disubstituted a-methyl-a-phenyl hemi-
malonate 11d and a-acetamido-a-benzyl hemimalonate 11e.
The first attempts to carry out the reaction of a-phenylmalonate
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Table 4 Reaction of hemimalonate 1a with imines and aldehydes
11a with 4-nitrobenzaldehyde in the presence of NEt3 in ace-
tonitrile were unsuccessful. The sole product of the reaction was
ethyl phenylacetate, resulting from the competitive protonation
of the intermediate enolate (path A then C of the mechanistic
hypothesis, Scheme 2).
Entry Electrophile
1
Product
Yields Aa (%) Bb
4a 77
84
Such an enhanced reactivity of ethyl a-phenylmalonic acid
half ester towards the decarboxylation was observed in the
sulfenylation of the hemiester 1a.32 In order to avoid the fast
protonation of the enolate, NEt3 was substituted by proton
sponge [1,8-bis(dimethylamino)naphthalene] as a better proton
scavenger. Gratifyingly, this base allowed the decarboxylative
aldolisation reaction at 0 ◦C in acetonitrile and 12a was isolated
in 76% yield (Table 5, entry 1). In DMF, the reaction was less
efficient (entry 2). The reaction attempted in [BMIM][PF6] did
not improve the yield of 12a, and 10% of the side-product ethyl
phenylacetate was formed (entry 3).
The reaction involving the less reactive substituted deriva-
tives 11b and 11c required heating in DMF to achieve the
decarboxylation and afforded the hydroxy esters 12b and 12c in
68% and 77% yields respectively (entries 4, 5). Hemimalonates
11d and 11e bearing a quaternary carbon were subjected to
the decarboxylative aldol reaction under different conditions of
bases and solvents. Whereas the reaction of hemimalonate 11d
and 4-nitrobenzaldehyde 3a in the presence of NEt3 led only to
the protonated side product (ethyl 2-phenylpropanoate, data not
shown), the proton sponge mediated reaction of 3a with 11d or
11e in DMF, afforded compound 12d or 12e in 39% or 78% yields
respectively (entries 6, 9). Working in [BMIM][PF6] at room
temperature improved significantly the yield of 12d (entry 7)
whereas 12e was formed in 51% yield in this solvent. Although
these yields seem moderate, the reaction allowed the formation
of a quaternary carbon and of two consecutive stereogenic
centers under very mild conditions. Due to the disubstituted
nature of the starting material, only the mechanistic hypothesis
described by Path A then C on Scheme 2 is operating, i.e. the
decarboxylation occurred first generating the enolate which was
then trapped by the aldehyde before the protonation took place.
2
3
4
4b 47
4c 55
4d 51
52
59
49
5
6
5a nr
5b 78
26
85
7
8
5c 81
5e 81
86
81
9
5f 79
5g 70
73
67
10
11
12
5h 72
66
68
5i
5j
57
80
Conclusion
We have demonstrated that, using a metal-free procedure, the
simple commercially available malonic acid half ethyl ester 1a
was an efficient reagent for the formation of b-hydroxy esters
and b-amino esters from aryl aldehydes and arylimines via
decarboxylative aldol and Mannich type reactions respectively.
This one-step organic base-mediated procedure, possible under
catalytic conditions in some cases, can replace favourably
the well-known two-reaction sequence involving nucleophilic
addition of malonate diester followed by a subsequent decar-
boxylation reaction. The simplicity of this synthetic approach
which can be carried out in an open flask, even under solvent-
free conditions or in ionic liquids, may render it applicable
on a large scale. Depending on the malonyl starting material
used (substituted or not), two different mechanisms can be
involved which may dictate the choice of the organic base
used. With a-substituted and a,a-disubstituted hemimalonates,
two consecutive stereogenic centers are created, including a
quaternary carbon with the later substrates.
13
14
15
75
52
5k 39
5l
38
48
63
16
EtO2C-CHO
5n 62
a Reaction carried out in DMF (imine or aldehyde: 1.8 M), NEt3
(1 equiv), room temperature for 24 h then 60 ◦C for 15 h. b Reaction
carried out in acetonitrile (imine or aldehyde: 1.8 M), NEt3 (1 equiv),
80 ◦C, 15 h.
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Table 5 Decarboxylative aldolisation of a-substituted and disubstituted malonic acid hemi esters
Entry
Acida
Base
Conditions: Solvent, Temp Time
Product 12 yieldb %
syn/antic ratio%
1
2
3
4
5
6
7
8
9
11a
11a
11a
11b
11c
11d
11d
11e
11e
PS
PS
PS
NEt3
NEt3
PS
PS
PS
MeCN, 0 ◦C 18 h
12a, 76
12a, 43
12a, 65
12b, 68
12c, 77
12d, 39
12d, 56
12e, 51
12e, 78
44/56
45/55
50/50
50/50
34/66
50/50
50/50
50/50
50/50
DMF, 0 ◦C 60 h
[BMIM][PF6], 20 ◦C 48 h
DMF, 0 ◦C 60 h, then 60 ◦C 5 h
DMF, 0 ◦C 60 h, then 60 ◦C 5 h
DMF, 20 ◦C 48 h
[BMIM][PF6] 20 ◦C 48 h
[BMIM][PF6] 20 ◦C 48 h
DMF, 20 ◦C 48 h
PS
a Acid 11 (1.1 equiv), base (1 equiv), aldehyde 3a (1 equiv). b Isolated yield. c Ratio in the crude product, from 1H NMR spectra.
1
diastereomer: H NMR (500 MHz, DMF-d7) d 1.18 [t, 3 H,
Experimental
3JHH = 7.5 Hz, CH3(Et)], 1.19 (t, 9 H, JHH = 7.5 Hz, CH3),
3
2.30 [s, 3 H, CH3(Ar)], 3.01 (q, 6 H, 3JHH = 7.5 Hz, CH2), 3.62
General
3
3
(d, 1 H, JHH = 10.0 Hz, CH), 4.04 [q, 2 H, JHH = 7.5 Hz,
CH2(Et)], 5.06 (t, 1 H, 3JHH = 9.5 Hz, CH), 7.06 (m, 3 H, HAr),
7.12 (d, 2 H, 3JHH = 8.0 Hz, HAr), 7.28 (m, 2 H, HAr), 7.43 (d, 2
Acetonitrile (MeCN), tetrahydrofuran (THF), toluene and
dichloromethane were dried with a Pure-SolvTM 400 Solvent
Purification System. Dimethylformamide (DMF) and triethy-
lamine (Et3N) were distilled from CaH2 under a stream of
nitrogen prior to use. Commercially available compounds
(aldehydes, tosylamine, p-methoxybenzylamine, benzyl chlo-
ride, methyl iodide, 1,8-bis(dimethylamino)naphthalene, di-
ethyl malonate, diethyl a-phenylmalonate, and diethyl a-
acetamidomalonate) were used as received. N-Tosylimines
and N-4-methoxybenzylimine precursor of compound 4b were
prepared according Kim et al.33 Diethyl phenacylmalonate,34
diethyl 2-methyl, 2-phenylmalonate,35 and diethyl 2-(N-
acetamido)-2-benzylmalonate36 were prepared by alkylation
of diethyl malonate, diethyl a-phenylmalonate, and diethyl
a-acetamidomalonate respectively. Ethyl hemimalonates were
obtained by selective hydrolysis37 of the corresponding dialkyl-
malonates and their spectroscopic properties were in good
agreement with those reported for 1a,37 11a,37 11b,38 11c,39
11d.40,41 The spectral data of the known products 4a,42 5a,43 5b,44
5c,44 5e,45 5f-5i,44 5l,46 5n,47 were in agreement with literature
data.
H, 3JHH = 8.0 Hz, HAr), 8.10 (d, 1 H, 3JHH = 9.5 Hz, NH). 13
C
NMR (125 MHz, DMF-d7) d 8.5 (CH3), 13.9 [CH3(Et)], 20.6
(CH3), 45.0 (CH2), 58.5 (CH), 60.0 (CH2), 62.5 (CH), 126.6,
127.4, 128.2, 128.9, 139.5, 140.6, 142.0 (CAr), 169.1 (C O), 169.5
=
1
=
(C O). Second diastereomer: H NMR (500 MHz, DMF-d7) d
3
3
0.95 [t, 3 H, JHH = 7.0 Hz, CH3(Et)], 1.19 (t, 9 H, JHH
=
7.5 Hz, CH3), 2.39 [s, 3 H, CH3(Ar)], 3.01 (q, 6 H, 3JHH = 7.5 Hz,
CH2), 3.45 (d, 1 H, 3JHH = 9.5 Hz, CH), 3.81 [ABX3 syst., 2 H,
CH2(Et)], 4.62 (s, 1 H, 3JHH = 9.5 Hz, CH), 7.19 (m, 3 H, HAr),
3
7.29 (m, 2 H, HAr), 7.31 (d, 2 H, JHH = 8.0 Hz, HAr), 7.57 (d,
2 H, 3JHH = 8.0 Hz, HAr). 13C NMR (125 MHz, DMF-d7) d 8.5
(CH3), 13.5 [CH3(Et)], 20.6 (CH3), 45.0 (CH2), 58.0 (CH), 59.8
(CH), 59.9 (CH2), 127.1, 127.2, 127.8, 128.1, 129.4, 138.1, 140.6,
142.7 (CAr), 168.9 (C=O), 171.0 (C=O).
Reaction between malonate 1a and aldehyde 3a. Freshly
distilled triethylamine (1.06 mL, 7.6 mmol) was added to a
solution of malonic acid half ethylester 1a (1 g, 7.6 mmol) in
CH2Cl2 (11 mL). Para-nitrobenzaldehyde 3a (1.37 g, 9.1 mmol)
was added to the solution and the reaction was stirred at room
temperature for 20 h. The mixture was quenched with HCl (1
N) and extracted with CH2Cl2 to afford 0.95 g of the unstable
carboxylic acid intermediate 8a (49% yield) which was rapidly
characterized by 1H and 13C NMR shortly after as a mixture of
two diastereomers.
First diastereomer: 1H NMR (500 MHz, CDCl3) d 1.08 [t, 3 H,
J = 7.2 Hz, CH3(Et)], 3.74 (d, 1 H, J = 7.6 Hz, CH), 3.99-4.07
[m, 2 H, CH2(Et)], 5.35 (d, 1 H, J = 7.6 Hz, CH), 7.55 (d, 2
H, J = 8.5 Hz, HAr), 8.14 (d, 2 H, J = 8.5 Hz, HAr). 13C NMR
(125 MHz, CDCl3) d 13.7 [CH3(Et)], 59.3 (CH), 62.0 [CH2(Et)],
Characterization of the intermediates, ammonium salt 7b and
carboxylic acid 8a
Reaction between malonate 1a and imine 2a. Freshly distilled
triethylamine (28 mL, 0.2 mmol) was added to a solution of
malonic acid half ethyl ester 1a (32 mg, 0.2 mmol) in dried
DMF-d7 (1 mL). In a NMR tube, imine 2a (31 mg, 0.12 mmol)
was weighed then 0.6 mL of the previous solution was added
to start the reaction. The ammonium salt 7b of carboxylic acid
intermediate was characterized in-situ by H NMR (-20 ◦C)
after a few minutes in the form of two diastereomers. First
256 | Green Chem., 2010, 12, 252–259
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=
71.9 (CH), 123.5, 127.6, 147.5, 147.8 (CAr), 167.3 (C O), 170.8
[dA(ABX), 1 H, JAB = 15.2, JBX = 6.4 Hz, Hb(CH2)], 3.75 [s, 3 H,
CH3(OMe)], 4.01 [m, 2 H, CH2(Et)], 4.85 (m, 1 H, CH), 5.83
(dd, 1 H, J = 10.0 Hz, NH), 6.63 (dd, 1 H, J = 8.4, 0.8 Hz,
HAr), 6.70 (dt, 1 H, J = 8.4 Hz, 0.8 Hz, HAr), 6.95 (dd, 1 H,
J = 8.4 Hz, 0.8 Hz, HAr), 7.03 (d, 2 H, J = 8.3 Hz, HTs ),
7.10 (dt, 1 H, J = 8.4 Hz, 0.8 Hz, HAr), 7.49 (d, 2 H, J =
8.3 Hz, HTs ). 13C NMR (100 MHz, CDCl3) d 14.1 [CH3(Et)],
31.4 [CH3(Ts)], 40.4 (CH2), 53.3 (CH), 55.2 [CH3(OMe)], 60.7
[CH2(Et)], 110.5, 120.5, 126.9, 128.9, 129.9, 129.3, 142.8, 156.3
1
=
(C O). Second diastereomer: H NMR (500 MHz, CDCl3) d
1.12 [t, 3 H, J = 7.2 Hz, CH3(Et)], 3.79 (d, 1 H, J = 5.8 Hz,
CH), 4.07-4.14 [m, 2 H, CH2(Et)], 5.41 (d, 1 H, J = 5.8 Hz,
CH), 7.55 (d, 2 H, J = 8.5 Hz, HAr), 8.14 (d, 2 H, J = 8.5 Hz,
HAr). 13C NMR (125 MHz, CDCl3) d 13.8 [CH3(Et)], 58.7 (CH),
62.2 [CH2(Et)], 71.7 (CH), 123.5, 127.3, 147.5, 147.9 (CAr), 168.3
=
=
(C O), 169.9 (C O).
=
=
Typical procedures
(CAr), 170.5 (C O). IR (neat) 3265 (N-H), 1733 (C O), 1325,
1248, 1160 cm-1. HRMS (ESI) Calcd for C19H24NO5S (MH+):
378.1375, Found: 378.1367; MS (ESI) m/z 378 (M + H)+, 207.
The organic base (1 equiv) was added to a stirred mixture of
the aldehyde or imine (1 equiv), the malonic acid half ethylester
(1.1 equiv) and the solvent. This mixture was stirred for a given
time at a chosen temperature. In procedures A-D, the volatile
compounds were removed under vacuum. The residue was
diluted in ether/dichloromethane (1:1), washed with aqueous
saturated NaHCO3, then with HCl (1 N) and dried over MgSO4.
The solvents were removed under vacuum, and the residue
was purified by silica-gel column chromatography to give the
expected product.
Ethyl 3-(4-methylphenylsulfonamido)-3-(4-cyanophenyl)pro-
panoate 4d (Procedure A). Under nitrogen and in the presence
of molecular sieves (4A). [70 mg, 51% yield from imine
˚
(110 mg)]. Rf 0.11 (Cyclohexane/AcOEt = 70:30). Yellow oil.
1H NMR (400 MHz, (CDCl3) d 1.12 [t, 3 H, J = 7.2 Hz,
CH3(Et)], 2.38 [s, 3 H, CH3(Ts)], 2.70 [dA(ABX), 1 H, JAB = 16.0,
JAX = 5.6 Hz, Ha(CH2)], 2.76 [dA(ABX), 1 H, JAB = 16.0, JBX
=
6.4 Hz, Hb(CH2)], 4.00 [q, 2 H, J = 7.2 Hz, CH2(Et)], 4.77 (m, 1
H, CH), 6.16 (d, 1 H, J = 8.0 Hz, NH), 7.17 (d, 2 H, J = 8.0 Hz,
HAr), 7.26 (d, 2 H, J = 8.0 Hz, HAr), 7.47 (d, 2 H, J = 8.4 Hz,
HAr), 7.57 (d, 2 H, J = 8.4 Hz, HAr). 13C NMR (100 MHz,
CDCl3) d 14.0 [CH3(Et)], 21.5 [CH3(Ts)], 40.6 (CH2), 53.8 (CH),
61.3 [CH2(Et)], 111.6 (CAr), 118.4 (CN), 127.1, 127.4, 129.6,
Procedure Base Solvent
Temperature and time
A
B
C
NEt3 DMF
NEt3 MeCN
cf. Table 4 and Table 5 (entries 4-5).
80 ◦C, 15 h
PS
DMF MeCN cf. Table 3 entries 5, 6 and Table 5,
entries 1-3, 6-9.
=
132.3, 137.2, 143.8, 144.8 (CAr), 170.3 (C O). IR (neat) 3164
D
E
NEt3 no
PS
20 ◦C, 2 h then 60 ◦C, 15 h
-1
=
(N-H), 2227 (CN), 1712 (C O), 1270, 1160 cm . HRMS (ESI)
[BMIM][PF6] 20 ◦C, 48 h
Calcd for C19H21N2O4S (MH+): 373.1222, Found: 373.1231 MS
(ESI) m/z 373 (M + H)+, 202, 172.
In Procedure E, The reaction mixture was extracted with
Et2O. The organic layer was washed with H2O, dried over
MgSO4, filtered and concentrated under reduced pressure. The
residue was purified by silica-gel column chromatography.
Ethyl 3-hydroxy 3-(2-trifluoromethylphenyl)propanoate 5j
(Procedure A). [190 mg, 80% yield from aldehyde (157 mg)].
Rf 0.31 (Cyclohexane/AcOEt = 90:10). Colorless oil. 1H NMR
(400 MHz, CDCl3) d 1.27 [t, 3 H, J = 7.2 Hz, CH3(Et)], 2.56-
2.71 (m, 2 H, CH2), 3.64 (d, 1 H, J = 2.9 Hz, OH), 4.19 [q, 2 H,
J = 7.2 Hz, CH2(Et)], 5.52-5.55 (m, 1 H, CH), 7.38 (t, 1 H, J =
7.5 Hz, HAr), 7.55-7.63 (M, 2 H, HAr), 7.82 (d, 1 H, J = 7.5 Hz,
HAr). 13C NMR (100 MHz, CDCl3) d 14.1 [CH3(Et)], 43.4 (CH2),
61.0 [CH2(Et)], 65.9 (CH), 122.1, 125.4 (q, J = 5.8 Hz, CF3),
126.6 (q, J = 22.9 Hz, CF3) 127.6, 127.7, 132.4, 141.4 (CAr),
Ethyl 3-N-[(4-methoxyphenyl)methyl]-3-(4-nitrophenyl)pro-
panoate 4b (Procedure B). Under nitrogen and in the presence
˚
of molecular sieves (4A). [69 mg, 52% yield from imine (99 mg)].
Rf 0.29 (Cyclohexane/AcOEt = 85:15). White solid (mp
105 ◦C). 1H NMR (400 MHz, CDCl3) d 1.21 [t, 3 H, J = 7.2 Hz,
CH3(Et)], 2.77 [dA(ABX), 1 H, JAB = 15.2, JAX = 7.6 Hz, CH2(Ha)],
2.82 [dA(ABX), 1 H, JAB = 15.2, JBX = 7.6 Hz, CH2(Hb)], 3.70 (s,
3 H, OMe), 4.12 [q, 2 H, J = 7.2 Hz, CH2(Et)], 4.83 (dd, 1 H,
J = 5.6, 7.6 Hz, CH), 6.46 (d, 2 H, J = 9.2 Hz, HAr), 6.69 (d,
2 H, J = 9.2 Hz, HAr), 7.56 (d, 2 H, J = 8.8 Hz, HAr), 8.18
(d, 2 H, J = 8.8 Hz, HAr).13C NMR (100 MHz, CDCl3) d 14.1
[CH3(Et)], 26.9 (CH2), 43.3 (MeO), 55.5 (CH), 61.1 [CH2(Et)],
114.8, 115.2, 124.0, 127.4, 140.1, 147.3, 150.2, 153.7 (CAr), 170.6
172.2 (C O). 19F NMR (376 MHz, CDCl3) d -58.47. IR (neat)
=
-1
=
3473 (O-H), 1717 (C O), 1310, 1157, 1109 cm . HRMS (ESI)
Calcd for C12H14O3F3 (MH+): 263.0895, Found: 263.0901. MS
(ESI) m/z 263 (M + H)+, 245, 203; Anal Calcd: C 54.96, H 5.00;
Found: C 54.76; H 5.13.
Ethyl 3-hydroxy 3-(2-pyridinyl)propanoate 5k (Procedure B).
=
(CO). IR (neat) 3385 (N-H), 1726 (C O), 1605, 1509, 1342,
[90 mg, 52% yield from aldehyde (96 mg)]. Rf 0.25 (Cyclohex-
1234, 1177, 1031 cm-1. HRMS (ESI) Calcd for C18H21N2O5
(MH+): 345.1450, Found: 345.1445; MS (ESI) m/z 345 (M +
H)+, 299, 257, 124, 123.
1
ane/AcOEt = 70:30). Light brown oil. H NMR (400 MHz,
CDCl3) d 1.25 [t, 3 H, J = 7.2 Hz, CH3(Et)], 2.79 [dA(ABX), 1 H,
JAB = 16.0, JAX = 8.0 Hz, CH2(Ha)], 2.94 [dB(ABX), 1 H, JAB
=
Ethyl 3-(4-methylphenylsulfonamido)-3-(2-methoxyphenyl)-
16.0, JBX = 4.4 Hz, CH2(Hb)], 4.17 [q, 2 H, J = 7.2 Hz, CH2(Et)],
5.21 [dX(ABX), 1 H, JAX = 8.0, JBX = 4.4 Hz, CH), 7.26-7.29 (m, 1
H, HAr), 7.48 (d, 1 H, J = 8.0 Hz, HAr), 7.77 (dt, 1 H, J = 8.0 Hz,
2.0 Hz, HAr), 8.56 (d, 1 H, J = 4.0 Hz, HAr). 13C NMR (100 MHz,
CDCl3) d 14.1 [CH3(Et)], 42.5 (CH2), 60.7 [CH2(Et)], 70.1 (CH),
propanoate 4c (Procedure B). Under nitrogen and in the
˚
presence of molecular sieves (4A). [200 mg, 59% yield
from imine (112 mg)]. White solid (mp 148 ◦C). Rf 0.28
1
(Cyclohexane/AcOEt = 80:20). H NMR (400 MHz, CDCl3)
=
d 1.13 [t, 3 H, J = 7.2 Hz, CH3(Et)], 2.30 [s, 3 H, CH3(Ts)],
2.76 [dA(ABX), 1 H, JAB = 15.2, JAX = 7.2 Hz, Ha(CH2)], 2.88
120.3, 122.6, 136.9, 148.5, 160.8 (CAr), 171.9 (C O). IR (neat)
-1
=
3365 (O-H), 1718 (C O), 1596, 1163, 1024 cm . HRMS (ESI)
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Calcd for C11H14NO3 (MH+): 196.0974, Found: 196.0975. MS
CH3), 2.97 [dA(ABX), 1 H, JAB = 20.8, JAX = 7.2 Hz, CH2(Ha)],
(ESI) m/z 196 (M + H)+, 178, 150, 132.
3.17-3.43 (m, 3 H), 4.06-4.15 [m, 2 H, CH2(Et)], 5.31 [br.s, 1
3
H, CH(OH)], 7.25-7.56 (m, 5 H, HAr), 7.79 (d, 2 H, JHH
=
Ethyl 2-phenyl-3-hydroxy-3-(4-nitrophenyl)propanoate 12a
(Procedure C). [50 mg, 77% yield from aldehyde (32 mg)].
Rf 0.29 (Cyclohexane/AcOEt = 80:20). Light brown oil. First
diastereomer: 1H NMR (400 MHz, CDCl3) d 1.11 (t, 3 H, J =
7.2 Hz, CH3), 3.20 (bs, 1 H, OH), 3.81 (d, H, J = 6.0 Hz,
CHPh), 4.02-4.13 (m, 2 H, CH2), 5.42 (d, 1 H, J = 6.0 Hz,
CHOH), 7.19-7.22 (m, 2 H, HAr), 7.28-7.41 (m, 3 H, HAr), 7.41
(d, 2 H, J = 8.8 Hz, HAr), 8.12 (d, 2 H, J = 8.8 Hz, HAr). 13C
NMR (100 MHz, CDCl3) d 13.9 (CH3), 58.8 (CPh), 61.4 (CH2),
8.4 Hz, HAr), 8.12 (d, 2 H, JHH = 8.4 Hz, HAr),. 13C NMR
(100 MHz, CDCl3) d 14.0 (CH3), 34.7 (CH2), 47.8 (CH), 61.4
[CH2(Et)], 72.6 (CH), 123.7, 126.9, 128.0, 128.6, 133.5, 136.3,
3
=
=
147.4, 148.6, 173.2 (C O), 198.1 (C O). IR (neat) 3475 (O-H),
-1
=
=
1725 (C O), 1683 (C O), 1517, 1343 cm . HRMS (ESI):
Calcd. for C19H19NO6 (MH+): 358.1291. Found: 358.1293.
Ethyl 2-phenyl-2-methyl-3-hydroxy-3-(4-nitrophenyl) propa-
noate 12d (Procedure E or Procedure C). Purification on
silica-gel column chromatography (cyclohexane/Et2O = 90:10).
[54 mg, 39% yield from 3a (100 mg). Two diastereoisomers.
73.8 (COH), 123.3, 127.5, 128.2, 128.7, 129.2, 133.4, 147.5, 148.0
1
=
(CAr), 172.6 (C O). Second diastereomer: H NMR (400 MHz,
1
CDCl3) d 1.22 (t, 3 H, J = 6.8 Hz, CH3), 3.49 (d, 1 H, J =
4.0 Hz, OH), 3.78 (d, 1 H, J = 9.2 Hz, CHPh), 4.14-4.27 (m,
2 H, CH2), 5.27 (dd, 1 H, J = 9.2 Hz, J = 4.0 Hz, CHOH),
7.02-7.05 (m, 2 H, HAr), 7.20-7.23 (m, 5 H, HAr), 8.03 (d, 2 H,
J = 8.4 Hz, HAr). 13C NMR (100 MHz, CDCl3) d 14.0 (CH3),
59.9 (CPh), 61.6 (CH2), 75.7 (COH), 123.2, 127.5, 128.0, 128.4,
Colorless oil. First diastereomer: H NMR (400 MHz, CDCl3)
d 1.13 (t, 3 H, 3JHH = 7.2 Hz, CH3), 1.44 (s, 3 H, CH3), 3.70 (d,
3
1 H, JHH = 2.6 Hz, OH), 4.14 (ABX3, 2 H, CH2O), 5.30 [d, 1
3
H, JHH = 2.6 Hz, CH(OH)], 6.80-7.23 (m, 7 H, HAr), 7.97 (d,
2 H, 3JHH = 8.8 Hz, HAr). 13C NMR (400 MHz, CDCl3) d 13.9
(CH3), 19.2 (CH3), 55.5 (CH), 61.7 (ArCH), 77.9, 122.4, 127.8,
=
=
128.8, 134.5, 147.4, 148.0 (CAr), 173.1 (C O). IR (neat) 3526 (O-
128.0, 129.2, 137.0, 146.2, 147.4 (CAr), 176.5 (C O). Second
-1
H), 2984, 1705 (C O), 1517, 1345 cm . HRMS (ESI): Calcd.
diastereomer: 1H NMR (400 MHz, CDCl3) d 1.13 (t, 3 H, 3JHH
=
=
for C18H20NO5 (MH+): 330.1341. Found: 330.1330.
7.2 Hz, CH3), 1.42 (s, 3 H, CH3), 3.91 (d, 1 H, JHH = 3.0 Hz,
3
3
OH), 4.14 (ABX3, 2 H, CH2O), 5.43 [d, 1 H, JHH = 3.0 Hz,
Ethyl
2-(phenylmethyl)-3-hydroxy-3-(4-nitrophenyl)pro-
CH(OH)], 6.78-7.23 (m, 7 H, HAr), 7.83 (d, 2 H, 3JHH = 8.8 Hz,
HAr). 13C NMR (400 MHz, CDCl3) d 14.1 (CH3), 19.2 (CH3),
56.3 (CH), 61.8 (ArCH), 77.9, 122.1, 126.6, 127.9 (CHar), 128.4,
panoate 12b (Procedure A). [147 mg, 68% yield from 3a
(100 mg)]. Rf 0.28 (Cyclohexane/AcOEt = 80:20). Colorless
oil. First diastereomer: 1H NMR (400 MHz, CDCl3)·d 0.94 (t, 3
=
128.7, 139.0, 145.9, 147.1 (CAr), 177.1 (C O). HRMS (ESI)
Calcd for C18H20NO5 (MH+): 330.1341, Found: 313.1330.
3
H, JHH = 6.8 Hz, CH3), 2.81-2.86 (m, 1 H, CHBn), 2.97-3.02
(m, 2 H, CH2Ph), 3.44 (br.s, 1 H, OH), 3.89-3.96 [m, 2 H,
3
CH2(Et)], 5.16 [d, 1 H, JHH = 3.8 Hz, CH(OH)], 7.04 (d, 2
2-(N-acetylamino)-2-carboethoxy-3-(phenylmethyl)propionic
acid 11e48. [1.7 g, 89% yield from malonate (2 g)]. White solid
3
H, JHH = 8.7 Hz, HAr), 7.13-7.25 (m, 3 H, HAr), 7.58 (d, 2 H,
◦
3JHH = 8.7 Hz, HAr), 8.20 (d, 2 H, 3JHH = 8.7 Hz, HAr). 13C NMR
(100 MHz, CDCl3) d 13.8 (CH3), 32.8 (CH2Ph), 54.4 (CHBn),
60.9 [CH2(Et)], 72.9 (CHOH), 123.6, 126.5, 127.1, 128.4, 128.8,
(mp 135 C). H NMR (CDCl3) d 1.24 [t, 3 H, J = 7.2 Hz,
CH3(Et)], 1.92 [s, 3 H, CH3], 3.39 [dA(AB), 1 H, JAB = 13.6 Hz,
CH2], 3.45 [dB(AB), 1 H, JAB = 13.6 Hz, CH2], 4.12 [q, 2 H,
J = 7.2 Hz, CH2(Et)], 6.99-7.29 (m, 5 H, HAr), 13.74 (bs, 1
H, CO2H). 13C NMR (CDCl3) d 13.8, 22.2, 37.3, 61.3, 66.8,
126.7, 128.1, 129.8, 135.6, 167.5, 168.3, 169.2. IR (neat) 3324
(O-H), 1721 (C O), 1598, 1525, 1201 cm . HRMS (ESI) Calcd
for C14H17NO5 (MH+): 280.1172, Found: 280.1185.
1
=
138.3, 147.5, 148.6 (CAr), 174.2 (C O). IR (neat) 3481 (O-H);
-1
1
=
1722 (C O); 1603; 1519; 1344 cm . Second diastereomer: H
NMR (400 MHz, CDCl3) d 0.90 (t, 3 H, 3JHH = 7.2 Hz, CH3),
3
-1
=
2.84-3.00 (m, 3 H, CHBn), 3.68 (d, 1 H, JHH = 8.0 Hz, OH),
3
3.82-3.95 [m, 2 H, CH2(Et)], 4.79 [dd, 1 H, JHH = 8.0 Hz,
3JHH = 4.3 Hz, CH(OH)], 7.11-7.24 (m, 5 H, HAr), 7.41 (d, 2
Ethyl 2-(N-acetylamino) -2-(phenylmethyl) -3-hydroxy-3-(4-
nitrophenyl) propanoate 12e (Procedure C). [144 mg, 77% yield
from 11e (134 mg)]. First diastereomer: Light brown solid (mp
125 ◦C). Rf 0.25 (Cyclohexane/AcOEt = 70:30). 1H NMR
(400 MHz, CDCl3) d 1.21 [t, 3 H, J = 7.2 Hz, CH3(Et)], 1.98
(s, 3 H, COCH3), 3.05-3.10 (m, 2 H, CH2Ph), 4.05-4.21 [m, 2
H, CH2(Et)], 5.60 (s, 1 H, CHOH), 5.85 (bs, 1 H, OH), 5.99
(s, 1 H, NH), 7.02 (m, 2 H, HAr), 7.26 (m, 2 H, HAr), 7.48
(d, 2 H, J = 6.8 Hz, HAr), 8.19 (d, 2 H, J = 6.8 Hz, HAr),
8.26-8.33 (m, 1 H, HAr). 13C NMR (100 MHz, CDCl3) d 13.9
[CH3(Et)], 24.1 (COCH3), 37.6 (CH2Ph), 62.8 [CH2(Et)], 70.7,
77.0 (COH), 123.3, 127.6, 128.1, 128.8, 129.7, 131.3, 134.7,
H, JHH = 8.5 Hz, HAr), 8.11 (d, 2 H, JHH = 8.5 Hz, HAr). 13C
NMR (100 MHz, CDCl3) d 13.9 (CH3), 35.8 (CH2Ph), 53.9
(CHBn), 61.0 [CH2(Et)], 72.9 (CHOH), 123.6, 126.8, 126.9,
3
3
=
128.6, 129.0, 137.7, 147.4, 149.7 (CAr), 174.2 (C O). IR (neat)
3531 (O-H), 1732 (C O), 1604, 1516, 1351 cm . HRMS (ESI):
Calcd. for C18H20NO5 (MH+): 330.1341. Found: 330.1330.
-1
=
Ethyl
2-[hydroxy(4-nitrophenyl)methyl]-4-oxo-4-phenyl-
butanoate 12c (Procedure A). [55 mg, 77% yield from 3b
(50 mg)]. Rf 0.2 (Cyclohexane/AcOEt = 70:30). Colorless oil.
1
Major diastereomer: H NMR (400 MHz, CDCl3) d 1.06 (t, 3
H, 3JHH = 7.2 Hz, CH3), 3.20-3.43 (m, 3 H), 3.77 (d, 1 H, 3JHH
=
=
=
6.2 Hz, OH), 3.98-4.06 [m, 2 H, CH2(Et)], 5.09 [t, 1 H, 3JHH
147.4, 170.4, 172.3 (C O). IR (neat) 3260 (OH), 1728, 1645
(C O), 1510, 1345 cm . HRMS (ESI) Calcd for C20H23N2O6
=
6.2 Hz, CH(OH)], 7.25-7.56 (m, 5 H, HAr), 7.84 (d, 2 H, 3JHH
-1
=
8.4 Hz, HAr), 8.12 (d, 2 H, JHH = 8.4 Hz, HAr),. 13C NMR
(100 MHz, CDCl3) d 14.0 (CH3), 37.4 (CH2), 47.3 (CH), 61.4
[CH2(Et)], 73.0 (CH), 123.6, 127.0, 128.1, 128.7, 133.7, 136.2,
(MH+): 387.1556, found: 378.1567. Second diastereomer: Light
brown solid (mp 123 ◦C). Rf 0.1 (Cyclohexane/AcOEt = 70:30).
1H NMR (400 MHz, CDCl3) d 1.43 [t, 3 H, J = 7.2 Hz,
CH3(Et)], 1.98 (s, 3 H, COCH3), 3.46 [d, 1 H, J = 14.0 Hz,
CH2Ph (Ha)], 4.07 [d, 1 H, J = 14.0 Hz, CH2Ph (Hb)], 4.23-4.32
3
=
=
147.5, 149.0, 173.6 (C O), 197.4 (C O). Minor diastereomer:
1H NMR (400 MHz, CDCl3) d 1.12 (t, 3 H, JHH = 7.2 Hz,
3
258 | Green Chem., 2010, 12, 252–259
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[m, 2 H, CH2(Et)], 5.47 [d, 1 H, J = 10.4 Hz, CHOH], 6.36
(s, 1 H, NH), 7.02 (m, 2 H, HAr), 7.25-7.33 (m, 5 H, HAr), 8.14
[d, 2 H, J = 6.8 Hz, HAr]. 13C NMR (100 MHz, CDCl3) d
14.1 [CH3(Et)], 23.6 (COCH3), 38.0 (CH2Ph), 63.3 [CH2(Et)],
72.2, 77.9 (COH), 123.4, 126.9, 127.5, 128.6, 129.6, 135.2, 147.5,
J. Am. Chem. Soc., 1975, 97, 6277; (c) Y. Kobuke and J.-I. Yoshida,
Tetrahedron Lett., 1978, 4, 367; (d) D. W. Brooks, L. D.-L. Lu and
S. Masamune, Angew. Chem. Int. Ed. Engl., 1979, 18, 72; (e) D. J.
Krysan, Tetrahedron Lett, 1996, 37, 3303.
17 (a) M. Banwell, D. Hockless, B. Jarrott, B. Kelly, A. Knill, R.
Longmore and G. Simpson, J. Chem. Soc., Perkin 1, 2000, 3555;
(b) J. E. McMurry, W. A. Andrus and J. H. Musser, Synth. Commun.,
1978, 8, 53.
18 M. Ihara, M. Takahashi, H. Niitsuma, N. Taniguchi, K. Yasui and
K. Fukumoto, J. Org. Chem., 1989, 54, 5413.
=
148.2, 170.6, 172.9 (C O). IR (neat) 3286 (OH), 1713, 1641
-1
=
(C O), 1519, 1347 cm . HRMS (ESI) Calcd for C20H23N2O6
(MH+): 387.1556, found: 378.1563.
19 H. Hellmann and H. Piechota, Liebigs Ann. Chem., 1960, 631, 175.
20 Y. Ryu and A. I. Scott, Tetrahedron Lett., 2003, 44, 7499.
21 (a) B. List, A. Doehring, M. T. Hechavarria Fonseca, K. Wobser, H.
van Thienen, R. Rios Torres and P. L. Galilea, Adv. Synth. & Cat.,
2005, 347, 1558; (b) B. List, A. Doehring, M. T. Hechavarria Fonseca,
A. Job and R. Rios Torres, Tetrahedron, 2006, 62, 476.
22 M. Tanaka, O. Oota, H. Hiramatsu and K. Fujiwara, Bull. Chem.
Soc. Jpn, 1988, 61, 2473.
Acknowledgements
We gratefully acknowledge Ministe`re de l’Enseignement
Supe´rieur et de la Recherche for
ANR “Mesorcat”, CNRS and its program “Chimie pour le
De´velopement Durable”, Re´gion Basse-Normandie, and the
European Union (FEDER funding) for financial supports.
a fellowship to PL,
23 [2-(3-oxopropyl)phenyl]malonic acid.
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