The facile synthesis of α-aryl-α-hydroxy esters via one-pot vicarious nucleophilic substitution and oxidation

Article abstract of DOI:10.1039/a900986h

The anion produced by the vicarious nucleophilic substitution reaction of nitroarenes and α-chloro esters is hydroxylated by the action of air and benzaldehyde, thereby producing α-hydroxy esters.

Full text of DOI:10.1039/a900986h

The facile synthesis of a-aryl-a-hydroxy esters via one-pot vicarious
nucleophilic substitution and oxidation
Nicholas J. Lawrence,* Olivier Lamarche† and Nabil Thurrab‡
Department of Chemistry, UMIST, PO Box 88, Manchester, UK M60 1QD. E-mail: n.lawrence@umist.ac.uk
Received (in Liverpool, UK) 4th February 1999, Accepted 1st March 1999
The anion produced by the vicarious nucleophilic substitu-
tion reaction of nitroarenes and a-chloro esters is hydroxy-
lated by the action of air and benzaldehyde, thereby
producing a-hydroxy esters.
of the post-VNS anion 3a with air in the absence of
benzaldehyde gave a mixture of a-hydroxy ester 5a and ketone
p-nitroacetophenone in near equal proportions. We then applied
this intriguing one-pot VNS–hydroxylation process to the
reaction of ethyl 2-chlorobutanoate 1b with nitrobenzene and
obtained the ester 5b. This ester was also obtained in 40% yield
when the post-VNS anion was prepared via direct deprotonation
(NaH, DMF) of ethyl 2-(p-nitrophenyl)butanoate followed by
oxidation with air and benzaldehyde. In this case the ester was
accompanied by 2-(p-nitrophenyl)propiophenone (8%) and the
diester 6b (10% as 1:1 mixture of racemic:meso stereo-
isomers). As confirmation of its structure, the diester 6b was
obtained in 89% yield (racemic:meso 1:1) by treatment of the
post-VNS anion 3b with iodine (Scheme 2).6 Since such an
oxidative coupling is thought to occur via a mechanism
involving single electron transfer,5 this reaction also sheds light
on the mechanism of the hydroxylation reaction (vide supra).
Reaction of ethyl a-chlorophenylacetate with nitrobenzene
gave ethyl benzoylformate in 35% yield when the VNS reaction
was performed at 0 °C for 1 h and 25 °C for 1.5 h; the product
presumably arising from direct oxidation of the anion of 1c. The
hydroxy ester 5c was obtained, albeit in low yield, when
nitrobenzene was used in excess (1.5 equiv.) and a longer period
of time was used for the VNS reaction (0 °C for 1 h and 25 °C
for 3 h). It seems that the enolate derived from 1c is
insufficiently nucleophilic to react efficiently with nitro-
benzene. We then applied the hydroxylation reaction to other
nitroarenes (Table 1).
The recently developed process of vicarious nucleophilic
substitution (VNS), pioneered by Makosza and co-workers,1,2
offers a selective mild method for the controlled substitution of
hydrogen atoms of aromatic systems. As part of our contribu-
tion to the study of the VNS reaction we have developed3 a one-
pot coupling reaction of three components (a nitroarene, a
stabilised carbanion derived from 1 and an electrophilic species
E+) for the construction of nitroarenes 4 bearing an adjacent
quaternary chiral centre, as illustrated in Scheme 1.4,5 This
process first involves a VNS reaction between the nitroarene
and the carbanion to give the intermediate anion 3 via loss of
HX from the s-adduct 2. This post-VNS anion is sufficiently
nucleophilic to be quenched in situ with a variety of electro-
philes E+ to give the para-functionalised nitroarene 4.
During the study of the reaction of the post-VNS anion 3 with
aldehydes, we serendipitously discovered a process for the
synthesis of a-aryl-a-hydroxy esters. When the anion 3a (R =
Me), derived from ethyl 2-chloropropionate 1a, was reacted
with benzaldehyde we did not observe the formation of an aldol
product. However on one occasion, when air was inadvertently
introduced into the reaction flask, we obtained the hydroxy ester
5a in approximately 50% yield. A careful study of the reaction
revealed that the yield could be increased to 66% when 3 equiv.
of the ester is used with respect to nitrobenzene (Scheme 2).§ In
most of these reactions a small amount (5–10%) of p-
nitroacetophenone was also produced. It was clear that both
benzaldehyde and air were required in the reaction. In the
absence of air, the only product obtained upon work up (4, R =
Me, E = H) arose from protonation of the anion 3. The reaction
Reaction of ethyl 2-chlorobutanoate 1b with o- and m-
chloronitrobenzenes (entries 1 and 2) and two nitro-substituted
pyridines (entries 3 and 4) gave the hydroxy ester products in
which the VNS nucleophile has added para to the nitro group,
1
as determined from their H NMR spectra.¶ The product from
2-nitrothiophene with ethyl 2-chloropropionate 1a (entry 5) is
1
the 5-substituted hydroxy ester 5e, as determined from its H
nmr spectrum.¶ A pair of doublets were observed at d 7.05 and
7.80 with a coupling constant of 4.3 Hz corresponding to signals
from H-3 and H-4 (expected coupling constants:7 J3,4 3.45–4.35
Hz and J4,5 4.90–5.80 Hz). At low temperature (233 °C, NH3,
KOH), 2-nitrothiophene is attacked by a variety VNS nucleo-
philes predominantly at the 3-position.8 However, as the
nucleophile 1a provides a tertiary anion, it is not surprising that
at room temperature the 5-substituted isomer is the exclusive
product. It should be noted that oxidation of nitrobenzylic
carbanions (made by deprotonation of products of VNS
reaction) to aldehydes and ketones has been reported.9
O–
O–
N+
NO2
O–
O–
N+
NO2
R
CO2Et
3
CO2Et
R
E+
H
– HX
X
NaH, DMF
H
H
X
R
O–
CO2Et
1a–c
CO2Et
O
The oxidation of enolates by oxygen is, of course, not without
precedent. For example, Wasserman and Lipshutz have shown
R
E
N+
a
b
c
R = Me
R = Et
R = Ph
2
4
Cl
NO2
NO2
O2N
NO2
OEt
O
(1) NaH,
R
R
O
1
and
OEt
3'
HO
R
(2) PhCHO/air
OEt
Scheme 1
EtO2C
CO2Et
Et Et
H
O
a
b
c
R = Me
R = Et
R = Ph
6b (10% from 1b)
5a 66%
5b 44%
5c 31%
† Undergraduate research assistant from the Ecole Nationale Supérieure de
Synthèses, de Procédés, et d’Ingénierie Chimiques d’Aix-Marseille.
‡ MSc candidate from the University of Al Azhar, Gaza, Palastine.
Scheme 2
Chem. Commun., 1999, 689–690
689

Table 1 Reaction of nitroarenes to give hydroxy esters
benzylic anions to peroxides. In summary, we have developed
an intriguing one-pot VNS–hydroxylation reaction using inex-
pensive reagents that lead to novel a-aryl-a-hydroxy esters.
We thank the University of Al Azhar, Palastine and
ENSSPICAM (Marseille) for financial support to N. T. and
O. L. respectively and the EPSRC for Research Grants (GR/
L52246: NMR spectrometer; GR/L84391: chromatographic
equipment).
Entry Nitroarene
Ester Product
Yield (%)
NO2
NO2
1
1b
53
5d
Cl
Cl
Cl
OEt
Et
HO
O
NO2
Notes and references
NO2
Cl
§ To a stirred slurry of NaH (0.74 g of a 60% dispersion in oil, 18.5 mmol)
in dry DMF (10 cm3) at 0 °C was added dropwise solution of ethyl
2-chloropropionate 1a (1.68 g, 12.33 mmol) and nitrobenzene (0.76 g, 6.16
mmol) in dry DMF (10 cm3). The deep blue–purple reaction mixture was
stirred at 0 °C for 60 min and room temperature for 2 h. Benzaldehyde (0.98
g, 9.25 mmol) was added and the reaction mixture stirred at room
temperature under an atmosphere of dry air for 24 h. The resulting brown
mixture was poured onto a slurry of ice and hydrochloric acid (1 m, 20 cm3)
and extracted with CHCl3 (3 3 20 cm3). The solvent (DMF and CHCl3) was
removed from the combined extracts in vacuo. CHCl3 (75 cm3) was added
to the residue. This solution was washed with water (5 3 75 cm3) and aq.
NaHCO3 (5 3 75 cm3), dried (MgSO4) and evaporated in vacuo. The
residue was purified by chromatography to give the hydroxy ester 5a.
¶ Selected data for 5d: dH(300 MHz, CDCl3) dH 1.25 (3H, t, J 7.15,
OCH2CH3), 1.85 (3H, s, CH3), 3.75 (1H, s, OH), 4.25 (2H, q, J 7.15,
OCH2CH3), 7.84 (1H, d, J 8.7, H-6A), 8.15, (1H, dd, J 8.7 and 2.3, H-5A) and
8.23 (1H, d, J 2.3, H-3A). For 5e: dH 0.90 (3H, t, J 7.4, CH2CH3), 1.30 (3H,
t, J 7.2, OCH2CH3), 1.98 (1H, dq, J 14.7 and 7.4, CHaHbCH3), 2.20 (1H, dq,
J 14.7 and 7.4, CHaHbCH3), 3.95 (1H, s, OH), 4.19–4.38 (2H, m,
OCH2CH3), 7.67 (1H, d, J 8.6 and 1.9, H-6A), 7.85 (1H, d, J 8.6, H-5A) and
7.87 (1H, d, J 1.9, H-2A). For 5f: dH 0.92 (3H, t, J 7.4, CH2CH3), 1.32 (3H,
t, J 7.2, CO2CH2CH3), 1.45 (3H, J 6.9, OCH2CH3), 2.01 (1H, dq, J 14.7 and
7.4, CHaHbCH3), 2.23 (1H, dq, J 14.7 and 7.4, CHaHbCH3), 3.97 (1H, s,
OH), 4.18–4.40 (4H, m, 2 3 OCH2CH3), 7.85 (1H, d, J 1.8, H-4A) and 8.30
(1H, d, J 1.8, H-6A). For 5g: dH 0.95 (3H, t, J 7.4 Hz, CH2CH3), 1.28 (3H,
t, J 7.2, OCH2CH3), 2.02 (1 H, dq, J 14.7 and 7.4, CHaHbCH3), 2.37 (1H,
dq, J 14.7 and 7.4, CHaHbCH3), 4.20–4.32 (2H, m, OCH2CH3), 4.35 (1H,
s, OH), 7.78 (1H, d, J 8.3, H-5A) and 8.25 (1H, d, J 8.3, H-4A). For 5h: dH 1.35
(3H, t, J 7.15, OCH2CH3), 1.80 (3H, s, CH3), 4.24 (1H, s, OH), 4.26–4.40
(2H, m, CH2CH3), 7.05 (1H, d, J 4.3, 3A-H) and 7.80 (1H, J 4.3, 4A-H).
2
1b
62
5e
OEt
Et
HO
O
NO2
NO2
OEt
OEt
N
N
3
1b
52
5f
OEt
Et
HO
O
NO2
NO2
Cl
Cl
4
1b
50
5g
N
N
OEt
Et
HO
O
S
NO2
5
1a
44
5h
NO2
S
OEt
Me
HO
O
that lithium enolates of esters react with molecular oxygen to
give a-hydroxy esters (after reduction of the first formed
peroxide with sodium sulfite).10 A similar procedure lacking the
reductive work-up gives the a-hydroperoxy acids from car-
boxylic acids.11 The post-VNS hydroxylation we observe is
possibly occurring via initial oxidation of the anion 3, via single
electron transfer, to a radical which combines with an oxygen
radical anion to give peroxide 7 which is trapped by benzalde-
hyde to give species 8 (Scheme 3). Finally a 1,3-hydride shift
gives the alkoxide 8.12 Clearly the formation of products such as
6 indicate a mechanism involving radicals. We found that the
enolate of 1c, generated by reaction of sodium hydride, in the
absence of nitrobenzene, does not react with oxygen. This
suggests that the nitro group also plays a role in the oxidation
process, in addition to activating the arene to attack by the VNS
nucleophile and stabilising the anion 3. This is in agreement
with the finding of Russel and Bemis13 that nitrobenzene acts as
a single eletron transfer catalyst in the oxidation of stabilised
1 O. N. Chupakhin, V. N. Charushin and H. C. van der Plas, Nucleophilic
Aromatic Substitution of Hydrogen, Academic Press Inc., London,
1994. For reviews of aromatic vicarious nucleophilic substitution, see
M. Makosza, Chimia, 1994, 48, 499; M. Makosza and J. Winiarski, Acc.
Chem. Res., 1987, 20, 282; M. Makosza, Synthesis, 1991, 103; M.
Makosza and A. Kwast, J. Phys. Org. Chem., 1998, 11, 341; and ref.
2.
2 M. Makosza and K. Wojciechowski, Liebigs Ann./Recl., 1997, 1805.
3 N. J. Lawrence, J. Liddle and D. A. Jackson, Tetrahedron Lett., 1995,
36, 8477.
4 N. J. Lawrence, J. Liddle and D. A. Jackson, Synlett, 1996, 55; S. M.
Bushell, J. P. Crump, N. J. Lawrence and G. Pineau, Tetrahedron, 1998,
54, 2269.
5 M. D. Drew, N. J. Lawrence, D. A. Jackson, J. Liddle and R. G.
Pritchard, Chem. Commun., 1997, 189.
6 T. Langer, M. Illich and G. Helmchen, Tetrahedron Lett., 1995, 36,
4409.
7 S. Gronwitz, Adv. Heterocycl. Chem., 1963, 1, 1.
8 M. Makosza and E. Kwast, Tetrahedron, 1995, 51, 8339.
9 K. Wojciechowski, Synth. Commun., 1997, 27, 135; J.-P. Wulf, K. K.
Sienkiewicz, M. Makosza and E. Schmitz, Leibigs Ann. Chem., 1991,
537. Also see ref. 2.
O–
O
O–
O
O–
O
O–
O
N+
N+
N+
N+
10 H. H. Wasserman and B. H. Lipshutz, Tetrahedron Lett., 1975, 1731.
11 D. A. Konen, L. S. Silbert and P. E. Pfeffer, J. Org. Chem., 1975, 40,
3253.
PhCHO
O2
via SET
12 We did not try to isolate the benzoic acid which would be produced by
the proposed mechanism. We intentionally performed a base wash as
part of the work2up to remove any acidic by-products. We will report
further on the mechanism in due course.
OEt
OEt
OEt
OEt
R
R
R
R
O
O
O
O
O
O
O
O
O
3
8
7
H
Ph
13 G. A. Russell and A. G. Bemis, J. Am. Chem. Soc., 1966, 88, 5491.
O
Scheme 3
Communication 9/00986H
690
Chem. Commun., 1999, 689–690