Nitrobenzylation of α-carbonyl ester derivatives using TDAE approach

Article abstract of DOI:10.1016/j.tetlet.2004.04.166

A series of 2-hydroxy-propionic acid ethyl ester derivatives was prepared in good yields by reaction of o- and p-nitrobenzyl chlorides (1, 8) with various α-carbonyl esters in presence of tetrakis(dimethylamino)ethylene (TDAE). This reaction was generalized to α-ketolactam and α-ketomalonate.

Full text of DOI:10.1016/j.tetlet.2004.04.166

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5121–5124
Nitrobenzylation of a-carbonyl ester derivatives using
TDAE approach
a
Gamal Giuglio-Tonolo, Thierry Terme, Maurice Medebielle and Patrice Vanelle
a
b
a,
*
ꢀ
aLaboratoire de Chimie Organique Pharmaceutique LCOP, UMR CNRS 6517, Universitꢀe de la Mꢀediterranꢀee,
Facultꢀe de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France
bUniversitꢀe Claude Bernard-Lyon 1, Laboratoire SERCOF, UMR CNRS 5181, B^atiment E. Chevreul,
43, Bd du 11 novembre 1918, F-69622 Villeurbanne, France
Received 18 March 2004;revised 1 April 2004;accepted 28 April 2004
Abstract—A series of 2-hydroxy-propionic acid ethyl ester derivatives was prepared in good yields by reaction of o- and
p-nitrobenzyl chlorides (1, 8) with various a-carbonyl esters in presence of tetrakis(dimethylamino)ethylene (TDAE). This reaction
was generalized to a-ketolactam and a-ketomalonate.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Melphalan or 2-amino-3-{4-[bis-(2-chloroethyl)-amino]-
phenyl}-propionic acid was synthesized in the 1950s as
one of a series of nitrogen mustard derivatives (Scheme
1).1 Drugs of this class are clinically important anti-
pression, including leukopenia, and thrombocytopenia.
Of serious concern is the carcinogenic potential of mel-
phalan: secondary malignancies, such as acute non-
lymphocytic leukemia, myeloproliferative syndrome,
and carcinoma have been reported in patients treated
with melphalan.3 In order to minimize the side effects,
efforts were undertaken to construct new prodrugs.6
cancer agents.2 Melphalan, also known as
L-phenylala-
nine mustard is used systemically in treatment of
patients with multiple myeloma, ovarian cancer, breast
cancer, melanoma, and colorectal cancer.3 It is also
employed ‘locally’ in isolated perfusion of the limb
(melanoma of the upper or lower limb)4 or the liver
(metastases confined to the liver).5
Tetrakis(dimethylamino)ethylene (TDAE, Scheme 2) is
a reducing agent, which reacts with halogenated deriva-
tives to generate under mild conditions an anion via a
single electron transfer (SET).7 We have recently shown
that from p-nitrobenzyl chloride, TDAE could generate
a nitrobenzyl carbanion, which is able to react with
various electrophiles as aromatic aldehydes.8 More-
over, we have shown that halogenodifluoromethyl
heterocycles react with ethyl pyruvate using TDAE
methodology to form 3,3-difluoro-2-hydroxy-2-methyl-
4-oxo-butyric acid ethyl ester derivatives.9
However, melphalan, especially at high dose, shows a
diversity of toxic side effects.3 The most common side
effect occurring during therapy is bone marrow sup-
NH2
Cl
Cl
HO
O
N
CH3
N
CH3
N
Scheme 1. Structure of melphalan.
H3C
H3C
CH3
CH3
N
N
Keywords: TDAE; p-Nitrobenzyl chloride; a-Carbonyl ester; a-Hydroxy
ester.
CH3
CH3
* Corresponding author. Tel.: +33-4-9183-5580;fax: +33-4-9179-4677;
e-mail: patrice.vanelle@pharmacie.univ-mrs.fr
Scheme 2. Structure of TDAE.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.166

5122
G. Giuglio-Tonolo et al. / Tetrahedron Letters 45 (2004) 5121–5124
In continuation of our program directed toward the
study of single electron transfer (SET) reactions10 of
bioreductive alkylating agents and the development of
novel melphalan derivatives as potential antineoplastic
agents, we report herein the reaction of p-nitrobenzyl
chloride with a-carbonyl esters using TDAE leading to
2-hydroxy-3-phenyl-propionic acid ethyl ester deriva-
tives. These compounds could be suitable intermediates
of the synthesis of melphalan analogs by reduction of
nitro group followed by N-alkylation and hydrolysis of
ester function leading to a-hydroxy acid derivatives.
(Table 1). This method using TDAE presents a great
synthetic interest, as compared to benzylation reaction
using organometallic compounds;13 TDAE methodol-
ogy is a regioselective method with carbonyl esters, only
the carbonyl group reacts with nitrobenzyl anion. We
have never observed the reaction of nitrobenzyl anion
with ester moiety.
In order to generalize this reaction, we have investigated
the action of o- and p-nitrobenzyl anions with similar
carbonyl structures (a-ketolactam or ketomalonate).
The reaction of p-nitrobenzyl chloride (1) with 1-methyl
isatin (12) in presence of TDAE furnished the corre-
sponding a-hydroxy lactam (13) in 62% yield (Scheme
4). In the same conditions, the reaction of o- and p-ni-
trobenzyl chlorides (1 or 8) with diethyl ketomalonate
(14) gave the corresponding 2-hydroxy-2-nitrobenzyl
malonic acid diethyl ester (15–16) in respectively, 45%
and 81% yields (Scheme 5).
The reaction of p-nitrobenzyl chloride (1) with 3 equiv of
a-carbonyl esters (2–4) in presence of TDAE at )20 ꢁC
for 1 h followed by 2 h at room temperature led to the
corresponding a-hydroxy esters (5–7) in good yields (60–
73%) as shown in Table 1 (Scheme 3).11 The formation
of these a-hydroxy esters (5–7) may be explained by
nucleophilic addition of nitrobenzyl carbanion, formed
by action of TDAE with p-nitrobenzyl chloride (1), on
carbonyl group of a-carbonyl esters (2–4). The good
yields observed with p-nitrobenzyl chloride (1) encour-
aged us to study the reactivity of o-nitrobenzyl chloride
(8) with the same a-carbonyl esters (2–4). In the same
reaction conditions (TDAE at )20 ꢁC for 1 h followed
by 2 h at room temperature) with a-carbonyl esters (2-4),
the o-nitrobenzyl chloride (8) furnished the corre-
sponding a-hydroxy esters (9–11) in 66–80% yields
In conclusion, we have showed that o- or p-nitrobenzyl
chlorides and a-carbonyl esters react using TDAE to
prepare new a-hydroxy ester derivatives in good yields.
This method, using TDAE, is an easy, original, and mild
method to prepare p-nitrobenzyl anion in situ, com-
pared to the classical method using organometallic
compounds.13 Moreover, this method was generalized to
a-ketolactam and ketomalonate derivatives. The prepa-
Table 1. Reaction of o- or p-nitrobenzyl chloride and a-carbonyl esters using TDAEa
Nitrobenzyl chloride
a-Carbonyl ester
R1
R2
a-Hydroxy ester
Yield (%)b
1
1
1
8
8
8
2
3
4
2
3
4
H
CH2CH3
CH2CH3
CH3
5
60
73
73
71
80
66
CH3
CF3
H
612
7
CH2CH3
CH2CH3
CH3
9
CH3
CF3
10
11
a All the reactions are performed using 3 equiv of a-carbonyl ester (2–4), 1 equiv of chloride (1 or 8), and 1 equiv of TDAE in anhydrous DMF.
b % Yield relative to chloride (1 or 8).
Cl
O
O
O
TDAE
, -20°C
R1
O
R2
R
DMF
R1
R2
R
HO
O
1 R= p-NO2
8 R =o-NO2
5-7 R= p-NO2
9-11 R =o-NO2
2-4
Scheme 3. Reaction of o- or p-nitrobenzyl chloride and a-keto esters using TDAE.
Cl
O
O2N
TDAE
, -20°C
O
DMF
HO
N
N
13 62%
CH3
CH3
NO2
O
1
12
Scheme 4. Reaction of 1 and 1-methyl isatin 12 using TDAE.

G. Giuglio-Tonolo et al. / Tetrahedron Letters 45 (2004) 5121–5124
Cl
5123
O
O
O
TDAE
, -20°C
OCH2CH3
OCH2CH3
OCH2CH3
R
DMF
O
OCH2CH3
HO
R
O
1 R= p-NO2
8 R =o-NO2
15 R= p-NO2 45%
16 R =o-NO2 81%
14
Scheme 5. Reaction of 1 or 8 with diethyl ketomalonate 14 using TDAE.
P., Ed.;Research Signpost: Trivandum, 2002;pp 1–43;(b)
ꢀ
ration of a-hydroxy acid analogs of melphalan (reduc-
tion of nitro, alkylation, and hydrolysis) and the phar-
macological evaluation of all intermediates are under
active investigation.
Medebielle, M.;Dolbier, W. R., Jr.;Burkholder, C.;Ait-
Mohand, S.;Langlois, B.;Billard, T.;Keyrouz, R.;
Okada, E.;Ashida, T. In Electron Transfer Reactions in
Organic Synthesis;Vanelle, P., Ed.;Research Signpost:
Trivandum, 2002;pp 89–97;(c) Vanelle, P.;Terme, T.;
Crozet, M. P. Rec. Res. Dev. Org. Chem. 2001, 5, 129–150;
ꢀ
(d) Dolbier, W. R., Jr.;Ait-Mohand, S.;M edebielle, M.
Acknowledgements
Tetrahedron Lett. 2001, 42, 3459–3462;(e) Vanelle, P.;
Terme, T.;Gellis, A.;Crozet, M. P. Res. Adv. Org. Chem.
2000, 1, 27–41;(f) Burkholder, C.;Dolbier, W. R., Jr.;
This work was supported by the Centre National de la
Recherche Scientifique. We express our thanks to
M. Noailly for H and 13C NMR spectra recording.
ꢀ
Medebielle, M. J. Fluorine Chem. 2000, 102, 369–376;(g)
ꢀ
Medebielle, M.;Fujii, S.;Kato, K. Tetrahedron 2000, 56,
2655–2664.
1
11. General procedure for the reaction of p-nitrobenzyl
chloride (1 or 8) and carbonyl esters (2–4), ketolactam
(12) and ketomalonate (14) using TDAE. Into a two-
necked flask equipped with a silica gel drying tube and a
nitrogen inlet was added, under nitrogen at )20 ꢁC, 7 mL
of anhydrous DMF solution of 1 (0.52 g, 3 mmol) and
corresponding carbonyl derivatives 2–6 (9 mmol, 3 equiv).
The solution was stirred and maintained at this temper-
ature for 30 min and then was added dropwise (via a
syringe) the TDAE (0.60 g, 3.3 mmol). A red color
immediately developed with the formation of a white fine
precipitate. The solution was vigorously stirred at )20 ꢁC
for 1 h and then warmed up to room temperature for 2 h.
After this time TLC analysis (dichloromethane) clearly
showed that 1 or 8 was totally consumed. The orange-red
turbid solution was filtered (to remove the octamethyl-
oxamidinium dichloride) and hydrolyzed with 80 mL of
H2O. The aqueous solution was extracted with toluene
(3 · 40 mL), the combined organic layers washed with H2O
(3 · 40 mL), and dried over MgSO4. Evaporation of the
solvent left an orange viscous liquid as crude product.
Purification by silica gel chromatography (dichloro-
methane) and recrystallization from hexane/ethanol (9/1)
gave the corresponding a-hydroxy derivatives. New prod-
ucts: 5;orange solid;mp 36 ꢁC, 1H NMR (CDCl3): d
1.30 (t, J ¼ 7:2 Hz, 3H);2.93 (d, J ¼ 5:1 Hz, 1H);3.05
(dd, JAB ¼ 14:0 Hz and J ¼ 6:9 Hz, 1H);3.24 (dd,
JAB ¼ 14:0 Hz and J ¼ 4:3 Hz, 1H);4.24 (q, J ¼ 7:2 Hz,
References and notes
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ꢀ
Mohand, S.;Takechi, N.;M edebielle, M.;Dolbier, W. R.,
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Keirouz, R.;Okada, E.;Ashida, T. Synlett 2001, 821–823;
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ꢀ
Dolbier, W. R., Jr.;M edebielle, M. J. Org. Chem. 1998,
2H);4.46 (m, 1H);7.41 (d,
J ¼ 8:6 Hz, 2H);8.15 (d,
J ¼ 8:6 Hz, 2H). 13C NMR (CDCl3) 14.0;37.2;62.1;70.3;
124.8;127.9;131.7;132.7;133.2;149.9;174.0. Anal. Calcd
for C11H13NO5 (239.22): C, 55.23;H, 5.48;N, 5.86.
ꢀ
Found: C, 55.19;H, 5.51;N, 5.55.
7;white solid;mp
1
121 ꢁC, H NMR (CDCl3): d 3.28 (d, JAB ¼ 13:8 Hz, 1H);
3.39 (d, JAB ¼ 13:8 Hz, 1H);3.82 (bs, 1H);3.85 (s, 3H);
7.42 (d, J ¼ 8:9 Hz, 2H);8.16 (d, J ¼ 8:9 Hz, 2H). 13C
NMR (CDCl3) 37.2;54.3;78.2;123.1;123.4;131.3;140.5;
147.6;168.9. Anal. Calcd for C 11H10F3NO5 (293.20): C,
45.06;H, 3.44;N, 4.78. Found: C, 45.01;H, 3.18;N, 4.81.
9;colorless oil, 1H NMR (CDCl3): d 1.28 (t, J ¼ 7:2 Hz,
3H);2.93 (d, J ¼ 5:6 Hz, 1H);3.20 (dd, JAB ¼ 13:8 Hz and
63, 5385–5394.
8. Giuglio-Tonolo, G.;Terme, T.;M edebielle, M.;Vanelle,
ꢀ
P. Tetrahedron Lett. 2003, 44, 6433–6435.
ꢀ
9. Medebielle, M.;Kato, K.;Dolbier, W. R., Jr.
2002, 9, 1541–1543.
10. (a) Terme, T.;Crozet, C. P.;Maldonado, J.;Vanelle, P. In
Electron Transfer Reactions in Organic Synthesis;Vanelle,
Synlett

5124
G. Giuglio-Tonolo et al. / Tetrahedron Letters 45 (2004) 5121–5124
J ¼ 8:3 Hz, 1H);3.54 (dd, JAB ¼ 13:8 Hz and J ¼ 4:3 Hz,
3H);7.13 (d, J ¼ 8:7 Hz, 2H);7.98 (d, J ¼ 8:7 Hz, 2H). 13
NMR (CDCl3) 26.1;44.4;77.1;108.6;122.9;123.2;124.3;
128,6;130.1;131.0;131.1;141.9;142.9;147.0;177.5. Anal.
C
1H);4.24 (q, J ¼ 7:2 Hz, 2H);4.49 (m, 1H);7.36–7.59 (m,
3H);7.90–7.94 (m, 1H). 13C NMR (CDCl3) 14.0;37.2;
62.1;70.3;124.8;127.9;131.7;132.7;133.2;149.9;174.0.
Anal. Calcd for C11H13NO5 (239.22): C, 55.23;H, 5.48;N,
5.86. Found: C, 54.93;H, 5.41;N, 5.91. 10;white solid;mp
Calcd for C16H14N2O4 (298.29): C, 64.42;H, 4.73;N, 9.39.
Found: C, 64.38;H, 4.80;N, 9.26. 15;white solid;mp
1
57 ꢁC, H NMR (CDCl3): d 1.28 (t, J ¼ 7:2 Hz, 6H);3.44
1
43 ꢁC, H NMR (CDCl3): d 1.27 (t, J ¼ 7:2 Hz, 3H);1.44
(s, 2H);3.82 (bs, 1H);4.25 (q, J ¼ 7:2 Hz, 4H);7.44 (d,
J ¼ 8:8 Hz, 2H);8.13 (d, J ¼ 8:8 Hz, 2H). 13C NMR
(CDCl3) 14.0;39.9;62.9;78.7;123.1;131.3;142.5;147.2;
169.4. Anal. Calcd for C14H17NO7 (311.29): C, 54.02;H,
(s, 3H);3.21 (bs, 1H);3.46 (s, 2H);4.17 (q,
2H);7.33–7.53 (m, 3H);7.78–7.82 (m, 1H).
(CDCl3) 14.0;26.2;40.6;62.3;74.8;124.5;127.9;130.4;
J ¼ 7:2 Hz,
13C NMR
132.0;133.2;151.1;175.9. Anal. Calcd for C
(253.25): C, 56.91;H, 5.97;N, 5.53. Found: C, 56.61;H,
6.00;N, 5.54. 11;white solid;mp 89
(CDCl3): d 3.75 (s, 2H);3.83 (s, 3H);3.93 (bs, 1H);
7.38–7.57 (m, 3H);7.80–7.85 (m, 1H). 13C NMR (CDCl3)
32.8;54.4;77.2;123.1;124.8;127.2;128.8;132.3;133.2;
12H15NO5
5.50;N, 4.50. Found: C, 54.16;H, 5.50;N;4.54.
16;pale
yellow solid;mp 47 ꢁC, 1H NMR (CDCl3): d 1.25 (t,
J ¼ 7:1 Hz, 6H);3.79 (bs, 1H);3.80 (s, 2H);4.21 (q,
J ¼ 7:1 Hz, 4H);7.33–7.49 (m, 3H);7.77–7.81 (m, 1H). 13C
NMR (CDCl3) 13.8;35.2;62.8;78.7;124.5;128.1;129.0;
ꢁC, 1H NMR
132.0;133.1;151.2;169.4. Anal. Calcd for C
14H17NO7
151.1;169.1. Anal. Calcd for C 11H10F3NO5 (293.20): C,
45.06;H, 3.44;N, 4.78. Found: C, 45.01;H, 3.18;N, 4.81.
(311.29): C, 54.02;H, 5.50;N, 4.50. Found: C, 53.53;H,
5.44;N;4.14.
12. Crawford, M.;Little, W. T. J. Chem. Soc. 1959, 729–732.
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1
13;yellow solid;mp 193 ꢁC, H NMR (CDCl3): d 3.03 (s,
3H);3.26 (d, JAB ¼ 12:8 Hz, 1H);3.37 (d, JAB ¼ 12:8 Hz,
1H);3.78 (b s, 1H);6.68 (d, J ¼ 7:8 Hz, 1H);7.04–7.33 (m,