Chiral amide from (1S, 2R)-(+)-norephedrine and furoic acid: An efficient catalyst for asymmetric Reformatsky reaction

Article abstract of DOI:10.1007/s12039-013-0533-4

Chiral amide derived from (1S, 2R)-(+)-norephedrine and 2-furoic acid was found to catalyse the asymmetric Reformatsky reaction between prochiral aldehydes and α-bromo ethylacetate with diethylzinc as zinc source. The corresponding chiral β-hydroxy esters were formed in 99% yield with over 80% enantiomeric excess. The presence of air was found to be essential for the effective C-C bond formation. The mechanism for the catalytic reaction was proposed. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-013-0533-4

c
J. Chem. Sci. Vol. 126, No. 1, January 2014, pp. 151–158. ꢀ Indian Academy of Sciences.
Chiral amide from (1S, 2R)-(+)-norephedrine and furoic acid: An
efficient catalyst for asymmetric Reformatsky reaction
NALLAMUTHU ANANTHI and SIVAN VELMATHI∗
Organic and Polymer Synthesis Laboratory, Department of Chemistry, National Institute of Technology,
Tiruchirappalli 620 015, India
e-mail: velmathis@nitt.edu
MS received 3 April 2013; revised 26 September 2013; accepted 29 September 2013
Abstract. Chiral amide derived from (1S, 2R)-(+)-norephedrine and 2-furoic acid was found to catalyse the
asymmetric Reformatsky reaction between prochiral aldehydes and α-bromo ethylacetate with diethylzinc as
zinc source. The corresponding chiral β-hydroxy esters were formed in 99% yield with over 80% enantiomeric
excess. The presence of air was found to be essential for the effective C-C bond formation. The mechanism for
the catalytic reaction was proposed.
Keywords. Asymmetric Reformatsky reaction; (1S, 2R)-(+)-norephedrine; 2-furoic acid; chiral amide;
diethylzinc.
1. Introduction
formations, and Reformatsky-type reactions are one
of the cornerstones.1 Classical Reformatsky reaction
involved a zinc-induced reaction between an α-halo
ester and an aldehyde or ketone. Many processes have
been developed using zinc.
Discovering remarkable stereoselectivity in the C-C
bond formation reaction has been the prime objec-
tive of organic chemists. Organometallic reactions are
among the superior processes for stereoselective bond
R'CHO
H2O
H+
R'CHCH2COOH
OZnX
R'CHCH2COOR
OZnX
XCH2COOR + Zn
XZnCH2COOR
There are more advantages in the Reformatsky reac- constitutes a method for lengthening the carbon chain.
tion over classic aldol reaction in the sense that these By proper choice of reactants, it is possible to branch
reactions can be carried out under mild neutral condi- the chain on the α-, β- carbon atoms. So far, various li-
tions. It works for a type of stearically crowded ketones. gands such as diols,6–8 carbohydrates,9 dipeptides,10 chi-
The active ester enolate can be formed in the presence ral diamines,11 amino alcohols12 and other chiral com-
of highly enolizable aldehyde or ketone functionality. plexing agents have been thoroughly investigated.13,14
Both inter and intra molecular reactions are feasible and
A general, enantioselective method affording β-
hydroxyesters in high yield and ee remains elusive and
also a variety of electrophiles can be easily used.2,3
The product, chiral β-hydroxy esters are one of the selectivities above 70% ee are rare. Skarzewski et al.
most important intermediates in organic synthesis.4,5 reported enantioselective Reformatsky reaction with
The Reformatsky reaction not only offers a conve- ethyliodoacetate and achieved enantiomeric excess up to
nient method for producing β-hydroxy esters and the 96% using manganese Salen complex.15 First enantio-
corresponding unsaturated esters and acids, but also selective one-pot, three-component imino Refromatsky
reaction was reported by Cozzi et al. in 2006, giv-
ing β-amino esters in moderate to good yields.16
Cozzi reported enantioselective Reformatsky reaction
with ketones using inexpensive and readily available
∗For correspondence
151

152
Nallamuthu Ananthi and Sivan Velmath
[ClMn(salen)] as catalyst.17 In literature, several modi-
fied Reformatsky reactions using other metals have also
been reported.18–20
2.2 Synthesis of N-((1S, 2R)-1-hydroxy-1-
phenylpropan-2-yl)furan-2-carboxamide
Chiral ligand (CL) was prepared according to the
following procedure. 2-Furoic acid (0.561 g, 5 mmol)
taken in a round-bottomed flask flushed with nitro-
gen gas was dissolved in anhydrous tetrahydrofuran
(THF). To this, triethylamine (0.1 ml, 5 mmol) was
added dropwise. Ethylchloroformate (0.7 ml, 5 mmol)
in anhydrous THF was slowly added into the flask at
0◦C and stirred for 30 min. After the formation of a
white precipitate, that is, the highly reactive anhydride,
(1S, 2R)-(+)-norephedrine (0.936 g, 5 mmol) dissolved
in anhydrous THF cooled to 0◦C was added dropwise
into the reaction mixture and the stirring was contin-
ued for 24 h. The reaction mixture was then filtered.
The solvent was removed by rotary evaporator, and the
residue was dissolved in ethylacetate. The organic layer
was washed with water, followed by saturated sodium
bicarbonate and finally with brine and dried over anhy-
drous sodium sulphate. The crude product was puri-
fied by column chromatography with silica gel as the
adsorbent and 90:10 hexane/ethylacetate as the eluent.
The amide was obtained as a colourless solid in 80%
yield.
Among the class of ligands screened for asymmet-
ric Reformatsky reaction, ephedrine- and norephedrine-
derived ligands are very few. A representative study
was reported by Soai et al.21 in which chiral tertiary
alcohols were obtained from aryl ketones in mode-
rate enantioselectivity using N,N-dialkylnorephedrines
as chiral ligands. Cozzi and Rivalta reported cata-
lytic asymmetric Reformatsky reaction with ketones
using ephedrine-derived ligand. They achieved enan-
tiomeric excess up to 92%.6 In 1996, Andres et al.22
reported ephedrine-derived ligands produced in the
asymmetric Reformatsky reaction between bromo-α,α-
difluoroacetate and aldehydes. The corresponding β-
hydroxy esters were formed with good enantiomeric
excess for aromatic aldehydes and moderate ee for
aliphatic aldehydes.
In 1997, Zhang and Wu reported the enantioselective
synthesis of β-hydroxy esters using chiral micelles.23
They synthesised chiral micelles from (1S, 2R)-
(+)-ephedrine and (8R, 9S)-(+)-cinchonine. These
micelles provided the asymmetric micro environments
for enantioselective β-hydroxy ester synthesis.
Melting point: 129–130◦C. [α]589 30: +70.4 (c 0.125,
CHCl3); FTIR (cm−1): 3289 (−OH), 3042 (−NH),
2872 (−CH), 1679 (C=O); 1H NMR (400 MHz,
CDCl3, 25◦C), δ (ppm): 1.1 (d, 3 J = 6.8 Hz, 3H, CH3),
3.33 (br s, 1H, OH), 4.5 (sep, 3 J = 7.9 Hz, 1H, CHNH),
4.96 (d, 3 J = 2.0, 1H, CHOH), 6.51 (t, 3 J = 1.6, 1H,
In an earlier report by our group,24 chiral amide
derived from (1S, 2R)-(+)-norephedrine and 2-furoic
acid was proven to catalyse the asymmetric diethyl-
zinc addition to prochiral aldehydes yielding the product
chiral secondary alcohols in good yield and excellent
enantioselectivity. Herein, we demonstrate for the first
time, the application of the same chiral amide ligand in
the asymmetric Reformatsky reaction with diethylzinc
as zinc source.
3
3
CH), 6.56 (d, J = 8.8 Hz, 1H, CH), 7.13 (d, J =
3.6 Hz, 1H, CH), 7.32–7.37 (m, 5H, phenyl), 7.44 (s,
1H, NH); 13C NMR, (100 MHz, CDCl3, 25◦C), δ (ppm):
14.21, 50.65, 76.2, 112.16, 114.57, 126.24, 127.53,
128.20, 140.64, 144.04, 147.67, 158.64; high resolution
mass spectroscopy (HRMS) Calculated for molecular
formula C14H15NO3: 245.1561; Found: 245.1565.
2. Materials and methods
2.1 General remarks
1H and 13C NMR spectra were recorded in CDCl3
with a Bruker AMX-400 MHz instrument using tetra-
methyl silane (TMS) as an internal standard. Commer-
cial precoated silica gel (Merck 60F-254) plates were
2.3 Typical procedure for the asymmetric
Reformatsky reaction of α-bromo ethylacetate
to benzaldehyde
used for TLC. Silica gel with 60–120 mesh was used To a solution of the CL (49 mg, 0.1 mmol) dissolved
for column chromatography. Specific rotations were in dry tetrahydrofuran (1.5 mL), Et2Zn 1M solution
recorded with a Rudolph Autopol IV polarimeter. Enan- in hexane (2 mL, 4 mmol) was added dropwise at
tiomeric excesses were determined with a Shimadzu 0◦C. To this reaction mixture, α-bromoethylacetate
2010 A HPLC instrument (Chiral column: ChiralCel (0.22 mL, 2 mmol), was added at room temperature.
OD-H, Mobile Phase: 98:2 Hexane/i-PrOH, flow rate: Then, benzaldehyde (0.1 mL, 1 mmol) and diethyl-
0.5 ml/min, UV detector λ = 254 nm). FTIR spectra zinc 1M solution in hexane (2 mL, 4 mmol) was
were recorded with a Perkin Elmer–DXB spectrometer. added simultaneously and the reaction mixture was
(Melting point was determined with a Kherea digital stirred for 1 h at room temperature. Then, the reac-
melting point apparatus and is uncorrected.)
tion mixture was quenched with 2M HCl, the

Norephedrine-based catalyst for asymmetric Reformatsky reaction
153
solvent was removed by rotary evaporation. The aque- 98:2 Hexane/i-PrOH, flow rate: 0.5 ml/min, UV detec-
1
3
ous layer was extracted with ethylacetate. The opti- tor λ = 254 nm. H NMR: 1.29 (t, 3H, J = 6.6 Hz,
3
cally active (R)-ethyl-3-hydroxy-3-phenyl propanoate CH3), 2.60 (m, 2H, J = 6.2 Hz, CH2), 4.12 (q, 2H,
3
was obtained in 60% yield after purification by col- 3 J = 3.6 Hz, CH2), 5.10 (t, 1H, J = 4.5 Hz, CH),
3
umn chromatography with silica gel as an adsorbent 5.18 (s, 1H, OH), 7.40–8.05 (m, 4H, J = 7.3 Hz,
589
using 98:2 hexane : ethyl acetate as an eluent. α]
=
Ar-H). 13C NMR: 14.21, 42.14, 61.30, 66.55, 124.34,
21
+30.1◦ (c 1.1, CHCl3); Lit25 ee 98% [α] = +44.0◦ 128.23, 128.43, 135.42, 147.24, 173.26. HRMS Cal-
589
21
(c 1.013, CHCl3) HPLC conditions: Chiralcel OD-H, culated for molecular formula C11H13NO5: 239.2257
11.96 (major), 13.20 (minor), 98:2 Hexane/i-PrOH, found: 239.2260.
1
flow rate: 0.5 ml/min, UV detector λ = 254 nm H
NMR (400 MHz, CDCl3, 25◦C), δ (ppm): 1.31 (t, 3 J =
3
6.6 Hz, 3H, CH3), 2.80 (oct, J = 9 Hz, 2H, CH2),
2.7 (R)-ethyl-3-hydroxy-3-(3-nitrophenyl)propanoate
3
3
3.57 (t, J = 3.5 Hz, 1H, CHOH), 4.14 (q, 2H, J =
4.6 Hz, CH2), 5.56 (s, 1H, OH), 7.22 (m, 3 J = 7.2 Hz,
5H, phenyl). 13C NMR (100 MHz, CDCl3, 25◦C),
δ (ppm): 14.11, 43.15, 61.20, 71.12, 127.24, 127.83,
128.70, 140.64, 144.04, 173.14; HRMS Calculated
for molecular formula C11H14O3: 194.2314; Found:
194.2317.
589
[α] −32.8◦ (c = 2, CH2Cl2), 90% ee. HPLC condi-
21
tions: Chiralcel OD-H, 14.32 (Major), 16.05 (Minor),
98:2 Hexane/i-PrOH, flow rate: 0.5 ml/min, UV detec-
tor λ = 254 nm. 1H NMR: 1.29 (t, 3H, 3 J
=
6.6 Hz, CH3), 2.60 (m, 2H, 3 J = 6.2 Hz, CH2),
4.12 (q, 2H, 3 J
=
3.6 Hz, CH2), 5.10 (t, 1H,
3 J = 4.5 Hz, CH), 5.18 (s, 1H, OH), 7.55–8.29 (m,
3
4H, J = 7.3 Hz, Ar-H). 13C NMR: 14.11, 43.12,
2.4 (R)-ethyl-3-hydroxy-3-p-tolylpropanoate
61.33, 70.15, 122.44, 123.27, 129.43, 133.22, 141.14,
148.21, 173.24. HRMS: Calculated for molecular for-
mula C11H13NO5 239.2257 Found: 239.2261.
589
21
[α]
−6.18◦ (c = 1, CH2Cl2), HPLC conditions:
Chiralcel OD-H, 10.96 (major), 14.20 (minor), 98:2
Hexane/i-PrOH, flow rate: 0.5 ml/min, UV detector
1
3
λ = 254 nm. H NMR: 1.30 (t, 3H, J = 6.6 Hz,
3
CH3), 2.19 (s, 3H, CH3), 2.61 (m, 2H, J = 8.9 Hz,
2.8 (R)-ethyl-3-hydroxy-3-(4-nitrophenyl)propanoate
3
CH2), 4.12 (q, 2H, J = 3.6 Hz, CH2), 4.64 (t, 1H,
589
[α] −20.3◦ (c = 1, CH2Cl2), 76% ee. HPLC condi-
3 J = 4.6 Hz, CH), 5.17 (s, 1H, OH), 6.79–7.07 (m,
4H, 3 J = 7.3 Hz, Ar-H) 13C NMR: 14.13, 24.36, 43.31,
61.53, 71.26, 127.12, 129.20, 137.66, 173.33. HRMS
Calculated for molecular formula C12H16O3: 208.2554;
Found: 208.2558.
21
tions: Chiralcel OD-H, 15.03 (Major), 17.08 (Minor),
98:2 Hexane/i-PrOH, flow rate: 0.5 ml/min, UV detec-
1
3
tor λ = 254 nm. H NMR: 1.29 (t, 3H, J = 6.6 Hz,
3
CH3), 2.60 (m, 2H, J = 6.3 Hz, CH2), 4.12 (q, 2H,
3 J = 3.6 Hz, CH2), 5.10 (t, 1H, J = 4.6 Hz, CH),
3
3
5.18 (s, 1H, OH), 7.60–8.20 (m, 4H, J = 7.3 Hz,
2.5 (R)-ethyl-3-hydroxy-3-(4-ethoxyphenyl)propanoate
Ar-H). 13C NMR: 14.21, 43.14, 61.30, 71.30, 124.24,
128.13, 146.34, 172.96. HRMS: Calculated for molec-
ular formula C11H13NO5 239.2257, Found: 239.2259.
589
[α]
−4.3◦ (c = 1, CH2Cl2), HPLC conditions:
21
Chiralcel OD-H, 12.07 (major), 15.89 (minor), 98:2
Hexane/i-PrOH, flow rate: 0.5 ml/min, UV detector
λ = 254 nm. 1H NMR: 1.30 (t, 3H, 3 J = 6.6 Hz, CH3),
3
3
1.35(t, 3H, J = 6.3 Hz, CH3), 2.60 (m, 2H, J =
3.7 Hz, CH2), 4.01 (q, 2H, 3 J = 3.6 Hz, CH2), 4.12 (q,
2H, 3 J = 3.7 Hz, CH2), 5.14 (t, 1H, 3 J = 4.5 Hz, CH),
2.9 (R)-ethyl-3-hydroxy-3-(2-hydroxyphenyl)propanoate
589
[α] −17.2◦ (c = 1.1, CH2Cl2), 64% ee. HPLC con-
21
3
5.23 (s, 1H, OH), 6.71–7.11 (m, 4H, J = 7.3 Hz,
ditions: Chiralcel OD-H, 14.85 (Major), 17.52 (Minor),
Ar-H). 13C NMR: 14.10, 14.81, 43.18, 61.30, 64.60,
71.26, 114.62, 127.70, 132.28, 156.90, 173.24. HRMS
Calculated for molecular formula C13H18O4: 238.2812
found: 238.2814.
98:2 Hexane/i-PrOH, flow rate: 0.5 ml/min, UV detec-
1
3
tor λ = 254 nm. H NMR: 1.29 (t, 3H, J = 6.6 Hz,
3
CH3), 2.60 (m, 2H, J = 6.2 Hz, CH2), 4.12 (q, 2H,
3 J = 3.6 Hz, CH2), 5.10 (t, 1H, J = 4.6 Hz, CH),
3
5.18 (s, 1H, OH), 6.66–7.20 (m, 4H, 3 J = 7.2 Hz, Ar-
H), 9.83 (s, 1H, OH). 13C NMR: 14.21, 43.44, 61.34,
65.40, 116.23, 121.64, 129.13, 154.34, 173.16. HRMS:
Calculated for molecular formula C11H14O4: 142.1026,
Found: 142.1030.
2.6 (R)-ethyl-3-hydroxy-3-(2-nitrophenyl)propanoate
589
[α] 25.2◦ (c = 1, CH2Cl2), 87% ee. HPLC con-
21
ditions: Chiralcel OD-H, 8.77 (major), 13.00 (minor),

154
Nallamuthu Ananthi and Sivan Velmath
2.10 (R)-ethyl-3-hydroxy-3-(1H-pyrrol-2-yl)propanoate 98:2 Hexane/i-PrOH, flow rate: 0.5 ml/min, UV detec-
1
3
tor λ = 254 nm. H NMR: 0.96 (t, 3H, J = 6.6 Hz,
589
[α] −8.6◦ (c = 1, CH2Cl2), 48% ee. HPLC condi-
3
CH3), 1.28 (t, 3H, J = 6.2 Hz, CH3), 1.33 (m, 2H,
21
3 J = 6.2 z, CH2), 1.42 (m, 2H, J = 6.2 Hz, CH2),
3
tions: Chiralcel OD-H, 13.97 (Major), 17.97 (Minor),
3
3
98:2 Hexane/i-PrOH, flow rate: 0.5 ml/min, UV detec-
2.53 (m, 2H, J = 6.2 Hz, CH2), 3.88 (m, 1H, J =
4.6 Hz, CH), 3.99 (q, 2H, 3 J = 6.2 Hz, CH2), 4.84 (s,
1H, OH). 13C NMR: 14.11, 14.44, 16.24, 39.62, 41.84,
61.37, 67.56, 173.36. HRMS: Calculated for molecular
formula C8H16O3: 160.2114 found 160.2118.
1
3
tor λ = 254 nm. H NMR: 1.29 (t, 3H, J = 6.6 Hz,
3
CH3), 2.60 (m, 2H, J = 6.2 Hz, CH2), 4.12 (q, 2H,
3 J = 3.6 Hz, CH2), 4.99 (s, 1H, NH), 5.10 (t, 1H,
3 J = 4.6 Hz, CH), 5.18 (s, 1H, OH), 6.06–6.40 (m,
3H, J = 7.3 Hz, Ar-H). 13C NMR: 14.11, 43.84,
3
61.30, 70.46, 106.03, 108.33, 117.86, 133.20, 173.26.
HRMS: Calculated for molecular formula C9H13NO3:
183.200, Found: 183.203.
3. Results and discussion
The chiral amide was synthesised from (1S, 2R)-
(+)-norephedrine and 2-furoic acid (scheme 1) as per
the reported procedure with ethylchloroformate as the
activating reagent.24 Treatment of 2-furoic acid with
ethyl chloroformate in the presence of triethylamine in
THF gave a mixed anhydride, which was subsequently
reacted with (1S, 2R)-(+)-norephedrine to give the CL
in 80% yield.
The Reformatsky reaction involves formation of an
organozinc halide as an intermediate which then adds
to the carbonyl compound to form an addition com-
plex analogous to those involving in the Grignard
reaction between Grignard reagent and carbonyl com-
pounds. The intermediate complex is then decomposed
in the presence of dilute acid to yield the final pro-
duct. Activation of zinc by treatment with iodine or
dibromomethane, or washing with dilute hydrochloric
acid prior to use, are only moderately successful in the
most known procedures. There are numerous reports on
asymmetric Reformatsky reaction using dialkylzinc as
zinc source.8,17,26,27
2.11 (R)-ethyl-3-hydroxy-3-(thiophen-2-yl)propanoate
589
[α] −20.3◦ (c = 1, CH2Cl2), 53% ee. HPLC condi-
21
tions: Chiralcel OD-H, 15.03 (Major), 17.08 (Minor),
98:2 Hexane/i-PrOH, flow rate: 0.5 ml/min, UV detec-
1
3
tor λ = 254 nm. H NMR: 1.29 (t, 3H, J = 6.6 Hz,
3
CH3), 2.60 (m, 2H, J = 6.2 Hz, CH2), 4.12 (q, 2H,
3 J = 3.6 Hz, CH2), 5.10 (t, 1H, J = 4.6 Hz, CH),
3
3
5.18 (s, 1H, OH), 6.62–6.96 (m, 3H, J = 7.2 Hz,
Ar-H). 13C NMR: 14.11, 43.84, 61.30, 70.46, 125.53,
126.33, 126.86, 143.60, 173.06. HRMS: Calculated
for molecular formula C9H12O3S: 200.2568 found
200.2571.
2.12 (R)-ethyl-3-(furan-2-yl)-3-hydroxypropanoate
589
[α] −17.2◦ (c = 1.1, CH2Cl2), 45% ee. HPLC condi-
21
tions: Chiralcel OD-H, 14.85 (Major), 17.528 (Minor),
98:2 Hexane/i-PrOH, flow rate: 0.5 ml/min, UV detec-
1
3
tor λ = 254 nm. H NMR: 1.29 (t, 3H, J = 6.6 Hz,
3
CH3), 2.60 (m, 2H, J = 6.2 Hz, CH2), 4.12 (q, 2H,
Cozzi and Revalta found that the complexating abi-
lity of the ligand in the transition state and the amount of
the ligand are important factors for the enantioselecti-
vity.6 According to Fernandez-Ibanez et al., the pres-
ence of oxygen in the form of air is found to be essential
to achieve an effective C-C bond formation.8 It is
known that dialkylzinc in the presence of oxygen forms
the more reactive alkyl peroxides (RZnOOR),29–31 which
are able to initiate radical reactions.31–35 The reaction
3 J = 3.6 Hz, CH2), 5.10 (t, 1H, J = 4.6 Hz, CH),
3
3
5.18 (s, 1H, OH), 6.18–7.40(m, 3H, J = 7.3 Hz,
Ar-H). 13C NMR: 14.11, 41.34, 61.30, 65.06, 105.83,
110.33, 141.60, 153.56, 173.46. HRMS: Calculated for
molecular formula C9H12O4: 184.1898 found 184.1901.
2.13 (R)-ethyl-3-hydroxyhexanoate
[α] −4.6◦ (c = 1, CH2Cl2), 30% ee. HPLC condi- temperature of most of the reported Reformatsky reac-
589
21
tions: Chiralcel OD-H, 12.97 (Major), 16.67 (Minor), tions with various ligands was room temperature.25,36–38
OH
OH
O
H
EtCOOCl, Et3N, THF
rt, 24 h
NH2
N
+
COOH
O
CH3
CH3
O
CL
Scheme 1. Synthesis of chiral ligand (CL) from (1S, 2R)-(+)-norephedrine and 2-furoic acid.

Norephedrine-based catalyst for asymmetric Reformatsky reaction
HO
155
O
O
O
20 mol% CL
H
H
+
Br
OC2H5
OC2H5
Et2Zn, Air
R
R
THF, rt, 1 h
Scheme 2. Asymmetric Reformatsky reaction catalysed by chiral ligand.
Considering the above mentioned facts, initially β-hydroxy ester, the amount of diethylzinc and the
asymmetric Reformatsky reaction (scheme 2) was car- amount of the catalyst were further increased. With 4
ried out using 5 mol% of CL as catalyst for the reac- equivalents of diethylzinc, the asymmetric Reformatsky
tion between α-bromo ethylacetate and benzaldehyde reaction was carried out with 20 mol% of the catalyst at
in tetrahydrofuran as solvent at room temperature with room temperature. Under these conditions, we obtained
2 equivalents of diethylzinc as zinc source in the pres- almost the same enantioselectivity (46% ee) and simi-
ence of air. There was no product formation. The opti- lar conversion (50%) (table 1, entry 7). Then, the reac-
misation of reaction conditions is given in table 1. tion was carried out with 20 mol% of the catalyst with
Even under reflux condition, no progress in the reac- 8 equivalents of diethylzinc at room temperature which
tion was observed. As mentioned above, the amount resulted in the product chiral β-hydroxy ester in 60%
of ligand plays an important role on yield and enan- yield with 67% ee (table 1, entry 8). Further increase
tiomeric excess of the product. Hence, amount of cata- in the amount of the catalyst also resulted in the same
lyst was increased to 10 mol%. The reaction was carried enantiomeric excess and yield.
out at room temperature and at the refluxing tempera-
ture of THF. With 10 mol% of the catalyst at different the presence of air, diethylzinc was added in two por-
temperatures also, there was no product conversion. tions. Four equivalents of diethylzinc was added at the
In order to avoid the total oxidation of diethylzinc in
With 10 mol% of chiral ligand, the amount of beginning with chiral ligand. Another 4 equivalents of
diethylzinc was increased from 2 to 3 equivalents and diethylzinc and aldehyde were added simultaneously. In
the reaction was carried out at room temperature. The order to determine the effect of air on the reaction, the
product chiral β-hydroxy ester was formed in 50% reaction was carried in the absence of air under inert gas
yield with 45% ee at room temperature (table 1, entry atmosphere. In the absence of air, the product was not
5). However, raising the reaction temperature to reflux formed (table 1, entry 9).
condition did not improve the enantiomeric excess.
Based on the coordination mode of the catalyst CL
Hence, room temperature was finalized as the opti- with diethylzinc24 and also on the radical pathway pro-
mised reaction temperature for the reaction. In order posed by Fernandez-Ibanez et al.7,8 for asymmetric
to increase the enantiomeric excess of the product Reformatsky reaction of ketones in the presence of air,
Table 1. Optimization of reaction conditions for asymmetric Reformatsky reaction between benzaldehyde and α-
bromoethylacetate using CL.
Catalytic
amount (mol%)
Et2Zn
(equivalents)
Absolute
S. No.
Solvent
Temperature (◦C)
Yield (%)a
ee (%)b
configurationc
1
2
3
4
5
6
7
8
9d
5
5
THF
THF
THF
THF
THF
THF
THF
THF
THF
rt
65
rt
65
rt
65
rt
rt
2
2
2
2
3
3
4
8
8
0
0
0
0
0
0
0
45
0
46
67
0
–
–
–
–
(R)
–
(R)
(R)
–
10
10
10
10
20
30
30
0
50
50
50
60
0
rt
aIsolated yield after column chromatography
bDetermined by HPLC analysis using chiralcel OD-H column
cAbsolute configuration was assigned by comparison with the sign of specific rotation in literature data25
dReaction carried out in the absence of air

156
Nallamuthu Ananthi and Sivan Velmath
CH2COOEt
BrCH2COOEt
Et2Zn
O
CH3
N
O
H
OH CL
O
CH3
O
H
BrZnO
O
H
HO
N
Zn
H+
O
OEt
CH3
O
OEt
A
Br
D
O
E
H
O
N
Zn
O
O
Br
H
O
Zn
Br
O
OEt
O
CH3
N
Zn
C
O
O
Br
O
BrZnCH2COOEt
B
H
Figure 1. Proposed catalytic cycle for the asymmetric Reformatsky reaction
catalysed by CL with diethylzinc in the presence of air.
we suggest a possible mechanism for the catalytic reac- the carbonyl group of benzaldehyde resulting in com-
tion (figure 1). The presence of air was found to be pound D which on acid work-up gave the product chiral
crucial for effective C-C bond formation.
β-hydroxy ester. The chiral ligand provides the neces-
Initially, the chiral ligand CL reacts with diethylzinc sary asymmetric environment for the substrates which
and α-bromo ethyl acetate to form complex A. Addi- results in the enantiopure β-hydroxy ester. Formation
tion of benzaldehyde to complex A results in complex of complex A is evident from IR spectroscopy. In the IR
B. Addition of another molecule of BrZnCH2COOEt spectrum of complex A, the stretching frequency of NH
to complex B, results in complex C. In complex C, and OH group is shifted to higher frequency than that
the double bond of the α-bromo ethyl acetate attacks of pure chiral ligand CL. Frequency of carbonyl group
Table 2. Asymmetric Reformatsky reaction between various substituted benzaldehydes with α-bromo ethylacetate cata-
lysed by 20 mol% of CL.
Absolute
S. No
Aldehyde
Yield (%)a
ee (%)b
configurationc
1
2
3
4
5
6
7
8
Benzaldehyde
p-Methyl benzaldehyde
p-Methoxy benzaldehyde
o-Nitro benzaldehyde
m-Nitro benzaldehyde
p-Nitro benzaldehyde
Salicylaldehyde
Pyrrole-2-carboxaldehyde
Thiophene-2-carboxaldehyde
Furan-2-carboxaldehyde
Butyraldehyde
60
90
95
95
95
80
95
57
60
50
35
67
77
47
87
90
76
64
48
53
45
30
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(S)
9
10
11
aIsolated yield after column chromatography
bDetermined by HPLC analysis using chiralcel OD-H column
cAbsolute configuration was assigned by comparison with the sign of the specific rotation in literature data25

Norephedrine-based catalyst for asymmetric Reformatsky reaction
is same as that of chiral ligand CL. Hence, it is evident References
157
that chiral ligand CL coordinates to zinc metal through
OH and NH groups.
1. Reformatsky S 1887 Chem. Ber. 20 1210
2. Becker D, Brodsky N and Kalo I 1978 J. Org. Chem. 43
2557
3. Barco A, Benett S and Pollini G P 1980 J. Org. Chem.
45 4776
4. Henecka H 1952 In Methoden der organischen chemie
(Stuttgart: T V Georg)
5. Rathke M W 1970 J. Org. Chem. 35 3966
6. Cozzi P G and Rivalta E 2005 Angew. Chem. Int. Ed. 44
3600
7. Fernandez-Ibanez M A, Macia B, Minnaard A J and
Feringa B L 2008 Chem. Commun. 22 2571
8. Fernandez-Ibanez M A, Macia B, Minnaard A J and
Feringa B L 2008 Org. Lett. 10 4041
9. Emmerson P G D, Hems W P and Davis B G 2005
Tetrahedron: Asymmetry 16 213
10. Wang Z Y, Shen J, Jiang C S and You T P 2000 Chin.
Chem. Lett. 11 659
11. Mukaiyama T and Asami M 1985 Top. Curr. Chem. 127
133
In order to explore the synthetic utility of the catalyst
CL in the asymmetric Reformatsky reaction, various
substituted aldehydes with both electron donating and
withdrawing groups, aliphatic aldehyde and heteroyclic
aldehydes were reacted with α-brmoethylacetate. The
results are presented in table 2.
Aromatic aldehydes produce the corresponding chi-
ral β-hydroxy esters in good yield and enantioselecti-
vity compared to aliphatic aldehyde. Heterocyclic alde-
hydes gave the corresponding products in less enantio-
selectivity (table 2, entries 8, 9 and 10). This may be
due to the extra coordination of hetero atoms present
in the aldehydes with diethylzinc. Benzaldehydes with
electron withdrawing groups gave the corresponding β-
hydroxy esters with good yield and enantioselectivity
(table 2, entries 4, 5 and 6). Reformatsky reaction of m-
nitro benzaldehyde gave the corresponding β-hydroxy
ester in 95% yield with 90% ee (entry 5). Aromatic
aldehydes substituted with electron donating groups
gave the corresponding chiral product in less ee (entries
2 and 3) and good yield compared to electron withdraw-
ing groups substituted benzaldehydes. Aliphatic alde-
hyde butyraldehyde gave the chiral ester in 35% yield
with 30% ee. All the β-hydroxy esters formed are in R-
configuration except the β-hydroxy ester formed from
butyraldehyde.
12. Soai K and Kawase Y 1991 Tetrahedron: Asymmetry 2
781
13. Seebach D and Langer W 1979 Helv. Chim. Acta. 62
1701
14. Andres J M, Pedrosa R and Perez-Encabo A 2000
Tetrahedron 56 1217
15. Skarzewski J, Gupta A and Vogt A 1995 J. Mol. Catal.
A103 63
16. Cozzi P G and Rivalta E 2006 Pure Appl. Chem.
78 287
17. Cozzi
2951
P G 2006 Angew. Chem. Int. Ed. 45
18. Marioka K, Hashimoto S, Kitagawa Y, Yamamaoto H
and Nozaki H 1977 J. Am. Chem. Soc. 99 7705
19. Harada T and Mukaiyama T 1982 Chem. Lett. 161
20. Imamoto T, Kusumoto T, Tawarayama Y, Sugiura Y and
Yokoyama M 1984 J. Org. Chem. 49 3904
21. Soai K, Oshio A and Saito T 1993 J. Chem. Soc. Chem.
Commun. 811
22. Andres J M, Maria M A, Rafael P and Alfonso P E 1996
Synthesis 9 1070
23. Zhang Y and Wu W 1997 Tetrahedron: Asymmetry 8
4. Conclusion
To conclude, the (1S, 2R)-(+)-norephedrine and 2-
furoic acid derived amide was found to catalyse the
asymmetric Reformatsky reaction of aldehydes with
α-bromo ethylacetate. The product chiral β-hydroxy
esters were formed in good yield and enantiomeric
excess. All the hydroxy esters were formed in R-
configuration. The presence of air was found to be
essential leading to the chiral products through a radical
mechanism. Hence, the reaction can be carried out with-
out the need for air exclusion which makes the catalyst
more attractive. Finally, this catalyst is advantageous in
such a way that the synthesis is very easy.
3575
24. Ananthi N, Balakrishnan U, Vinu A, Ariga K and
Velmathi S 2009 Tetrahedron: Asymmetry 20 1731
25. Boaz N W 1992 J. Org. Chem. 57 4289
26. Fernandez-Ibanaz M A, Macia B, Minnard A J and
Feringa B L 2008 Angew. Chem. Int. Ed. 47 1317
27. Yang T K 2007 Tetrahedron: Asymmetry 18 949
28. Lewinski J, Ochal Z, Bojarski E, Tratkiewicz E,
Justyniak I and Lipkowski J 2003 Angew. Chem. Int. Ed.
42 4643
29. Lewinski J, Sliwinski W S, Dranka M, Justyniak I and
Lipkowski J 2006 Angew. Chem. Int. Ed. 45 4826
30. Bertrand M, Feray L and Gastaldi S 2002 Compt. Rend.
Chim. 5 623
31. Yamada K I, Yamamoto Y and Tomioka K 2003 Org.
Lett. 5 1797
Acknowledgements
The authors thank the Department of Science and Tech-
nology (DST) (SR/S1/OC-06/2011), New Delhi and
Council of Scientific and Industrial Research (CSIR)
(01(2282)/08/EMR-II), New Delhi for financial sup-
port in the form of sponsored projects.
32. Yamada K I, Yamamoto Y, Maekawa M and Tomioka K
2004 J. Org. Chem. 69 1531

158
Nallamuthu Ananthi and Sivan Velmath
33. Yamada K I, Yamamoto Y, Maekawa M, Akindele T, 36. Ocampo R, Dolbier Jr W R, Abboud K A and Zuluaga F
Umeki H and Tomioka K 2006 Org. Lett. 8 87 2002 J. Org. Chem. 67 72
34. Yamamoto Y, Yamada K I and Tomioka K 2004 Tetra- 37. Katritzky A R, Hong Q and Yang Z 1995 J. Org. Chem.
hedron Lett. 45 795 60 3405
35. Yamamoto Y, Maekawa M, Akindele T, Yamada K I and 38. Adrian J C and Snapper M L 2003 J. Org. Chem. 68
Tomioka K 2005 Tetrahedron 61 379 2143