Solvent-free synthesis of β-hydroxy esters and β-amino esters by indium-mediated reformatsky reaction

Article abstract of DOI:10.1055/s-2007-990799

In a convenient and efficient procedure for the solvent-free synthesis of β-hydroxy esters and β-amino esters, various aldehydes and aldimines undergo a Reformatsky reaction mediated by non-activated indium at room temperature to give the corresponding esters in good to excellent yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990799

PAPER
3233
Solvent-Free Synthesis of b-Hydroxy Esters and b-Amino Esters by
Indium-Mediated Reformatsky Reaction
S
a
olvent-Free Synth
i
esis of
’
b
-Hydro
a
xyEsters
a
n
nd
b
-
Ami no
E
st er
s
Chen,a Changfu Zhang,a,b Huayue Wu,*a Xiaochun Yu,a Weike Su,*a,c Jiang Chenga
College of Chemistry and Materials Science, Wenzhou University, Wenzhou 325027, P. R. of China
Fax +86(577)88368280; E-mail: hywu3@163.com
b
c
College of Life Science, Guizhou University, Guizhou 550025, P. R. of China
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, P. R. of China
Received 20 June 2007; revised 25 July 2007
though Adrian and co-workers reported that only the b-
amino esters formed in good yields in dry dichlo-
romethane, the reaction was unfortunately limited to aldi-
mines carrying o-methoxyphenyl as the substituent on the
nitrogen atom.21 Therefore, the development of a method
providing access to a wide variety of b-amino esters is
highly desirable. In addition, there has only been limited
progress in the development of alternative procedures in
which organic solvents are replaced.
Abstract: In a convenient and efficient procedure for the solvent-
free synthesis of b-hydroxy esters and b-amino esters, various alde-
hydes and aldimines undergo a Reformatsky reaction mediated by
non-activated indium at room temperature to give the correspond-
ing esters in good to excellent yields.
Key words: solvent-free, Reformatsky reaction, indium, b-hy-
droxy esters, b-amino esters
The Reformatsky reaction is a well-recognized C–C
bond-forming reaction of a-halo esters with aldehydes or
ketones in the presence of zinc metal to furnish b-hydroxy
esters.1 The products belong to the most important inter-
mediates in organic synthesis.2 Beside the classical zinc
method, the Reformatsky reaction can be conducted under
milder reaction conditions with activated zincs, such as
Rieke zinc,3 a zinc–copper couple,4 and zinc/silver–
graphite.5 However, these reagents usually need to be
freshly prepared because of their instability to air and
moisture. Thus, more effort has been focused on the utili-
zation of other metals, such as magnesium,6 cadmium,7
nickel,8 cerium,9 lithium,10 chromium(II),11 samarium,12
manganese13, rhodium,14 and iron15 to mediate the Refor-
matsky reaction. Having been explored widely as media-
tor of organic reactions,16 indium has emerged as an
interesting alternative with respect to the Reformatsky re-
action.17 Although the Reformatsky reaction of aldehydes
with ethyl bromo esters in the presence of indium affords
b-hydroxy esters in good to excellent yields in organic
solvents, the reactions required indium activated by potas-
sium,17a the help of ultrasonic irradiation,17c or heating un-
der reflux.17d
Aiming at the development of green and efficient organic
methodologies, we recently reported some organic reac-
tions carried out under solvent-free conditions or in ionic
liquids or aqueous media.22 To our knowledge, non-sol-
vent Reformatsky reactions have been reported rarely.23
Herein, we report on our exploration of the Reformatsky
reaction of aldehydes and aldimines in the presence of
commercially available indium under solvent-free condi-
tions.
As a first step, the Reformatsky reaction of benzaldehyde
(1a) and ethyl bromoacetate (2) in various reaction media
in the presence of indium powder was investigated
(Scheme 1; Table 1). The results clearly showed that the
Reformatsky reaction best proceeded over three hours at
room temperature under solvent-free conditions to give 3a
in 97% yield (Table 1, entry 6). Prolonging the reaction
time to six hours did not result in a further improvement
in the yield of 3a (Table 1, entry 7). The yield decreased
when organic solvent (THF) was used as the only solvent,
and this solvent also led to a longer reaction time being re-
quired for an improved yield (Table 1, entries 1 and 2).
The reaction did not proceed in solvents such as N,N-di-
methylformamide, tetrahydrofuran–water, or water alone
(Table 1, entries 3, 4, and 5).
The preparation of b-amino esters is interesting because
of their wide use as plant growth regulators and plant
growth promoters and because of their other chemical and
pharmaceutical activities.18 A straightforward and conve-
nient synthesis of b-amino esters is the addition of a Re-
formatsky reagent to an aldimine.1d,19 A complication of
this method is often the formation of the related b-lac-
tams. There have been some methods for controlling the
amounts of b-amino esters and b-lactams that form.20 Al-
Next, the solvent-free Reformatsky reaction of various al-
dehydes 1 and ethyl bromoacetate (2) was examined
(Scheme 2; Table 2). From the results shown in Table 2,
it can be seen that most of the reactions proceeded
smoothly at room temperature to give the corresponding
O
O
OH
O
In
+
Br
r.t.
Ph
H
OEt
Ph
OEt
1a
2
3a
SYNTHESIS 2007, No. 20, pp 3233–3239
x
x.
x
x
.
2
0
0
7
Advanced online publication: 21.09.2007
DOI: 10.1055/s-2007-990799; Art ID: F11707SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Reagents and conditions: PhCHO (1a; 1 equiv),
BrCH2CO2Et (2; 1.8 equiv), In powder (1 equiv).

3234
X. Chen et al.
PAPER
Table 1 Reformatsky Reaction of Benzaldehyde and Ethyl Bromo-
acetate Catalyzed by Indium Powder in Various Reaction Media
Table 2 Reformatsky-Type Reaction of Various Aldehydes with
Ethyl Bromoacetate Mediated by Indium Powder under Solvent-Free
Conditionsa
Entry
Solvent
THF
Time (h)
Yielda (%)
Entry
1
R1
Product
3a
Time (h) Yieldb (%)
1
3
10
10
10
10
3
55
78
0
Ph
3
97
90
94
92
98
94
98
65
96
91
85
86
2
THF
2
4-FC6H4
4-BrC6H4
4-ClC6H4
3-BrC6H4
PMP
3b
3
3
THF–H2O
H2O
3
3c
3
4
0
4
3d
3.5
3
5
DMF
0
5
3e
6
solvent-free
solvent-free
97
97
6
3f
3
7
6
7
Tol
3g
3.5
4
a Isolated yield.
8
2-HOC6H4
3h
O
OH
O
O
In
solvent-free, r.t.
9
1,3-benzodioxol-5-yl 3i
3
+
Br
R1
H
R1
OEt
OEt
10
11
12
2-furyl
3j
3k
3l
3.5
3.5
3.5
1
2
3
CH=CHPh
(CH2)2Ph
Scheme
2
Reagents and conditions: aldehyde 1 (1 equiv),
BrCH2CO2Et (2; 1.8 equiv), In powder (1 equiv).
a Reagents and conditions: aldehyde 1 (1.0 mmol), BrCH2CO2Et (2;
b-hydroxy esters 3 in excellent yields, and that side reac- 1.8 mmol), In powder (1.0 mmol).
b Isolated yield.
tions such as unselective dehydration were not observed.
The reaction proceeded well with both aromatic and ali-
ly selectively depending on the reagent ratios. When two
phatic aldehydes. Electron-withdrawing and -donating
groups on the aromatic ring and the site of substitution of
such groups did not seem to affect the reaction significant-
ly, neither in product yield nor in reaction rate (Table 2,
entries 1–8). It is worth mentioning that 2-hydroxybenzal-
dehyde, containing an acidic hydrogen, reacted with ethyl
bromoacetate (2) to provide the desired product in moder-
ate yield (Table 2, entry 8). Interestingly, a heteroaromat-
ic aldehyde provided the corresponding product in
excellent yield (Table 2, entry 10). Treatment of piperonal
with ethyl bromoacetate (2) gave the desired product 3i in
96% yield (Table 2, entry 9). With cinnamaldehyde, the
reaction occurred regiospecifically, and the 1,2-addition
product was obtained solely, without double-bond
isomerization occurring concomitantly (Table 2, entry
11). The corresponding b-hydroxy esters 3 were not ob-
tained, even after the reaction time was prolonged to five
hours, when the substrate was extended to acetophenone;
this demonstrated the chemoselectivity of this reaction.
equivalents ethyl bromoacetate (2) and one equivalent in-
dium powder were used, mono- and bis-b-hydroxy esters
3m and 4m were obtained in a ratio of 83:5. When the rel-
ative amounts of indium power and ethyl bromoacetate
(2) were increased, 3m and 4m were obtained in the re-
versed ratio of 3:86 (Scheme 3).
When ethyl 2-bromopropanoate was used as the a-halo
ester (Scheme 4), the diastereoselectivity could be detect-
1
ed by H NMR spectroscopy. Benzaldehyde, 4-methyl-
benzaldehyde, and 4-chlorobenzaldehyde reacted with
ethyl 2-bromopropanoate to give the corresponding b-hy-
droxy esters 5a, 5b, and 5c in 90–97% yield, and in syn/
anti ratios between 39:61 and 42:58 (Scheme 4). The ex-
O
O
OH
O
In
+
Br
solvent-free, r.t.
R1
H
R1
OEt
OEt
1
5
We then investigated the solvent-free Reformatsky reac-
tion of terephthalaldehyde (1m) with ethyl bromoacetate
(2) (Scheme 3). It is interesting that the corresponding
mono- and bis-b-hydroxy esters 3m and 4m formed high-
Scheme 4 Reformatsky reaction of ethyl 2-bromopropanoate and
various benzaldehydes under solvent-free conditions (5a, R1 = Ph,
97% yield, syn/anti = 39:61; 5b, R1 = Tol, 95% yield, syn/anti =
42:58; 5c, R1 = 4-ClC6H4, 90% yield, syn/anti = 40:60)
OEt
O
OEt
O
O
HO
In
solvent-free, r.t.
OHC
CHO
O
+
Br
OHC
+
OEt
OH
OH
4m
1m
EtO
2
3m
Scheme 3 Reformatsky reaction of terephthalaldehyde (1m) and ethyl bromoacetate (2) under two different sets of conditions. Reagents and
conditions: (a) 1m (1 equiv), BrCH2CO2Et (2; 1.8 equiv), In powder (1 equiv), 3.5 h; yields: 83% (3m) and 5% (4m); (b) 1m (1 equiv),
BrCH2CO2Et (2; 4.0 equiv), In powder (2 equiv), 6 h; yields: 3% (3m), 86% (4m).
Synthesis 2007, No. 20, 3233–3239 © Thieme Stuttgart · New York

PAPER
Solvent-Free Synthesis of b-Hydroxy Esters and b-Amino Esters
3235
cellent yields make the method superior to others previ- are mild; the procedure is equally compatible with alde-
ously reported.13,15,24
hydes and aldimines; the selectivity for forming b-amino
esters is complete; and the reaction is broadly applicable
to various aldimines.
We next investigated the Reformatsky reaction of various
aldimines 6 under similar conditions (Scheme 5; Table 3).
b-Amino esters 7 were prepared in good yields under sol-
vent-free conditions, but they needed longer reaction
times and were obtained in slightly lower yields than the
b-hydroxy esters. It should be noted that no b-lactams
were observed (by TLC) to form from various aldimines
6, even for R2 substituents other than o-methoxyphenyl
(Table 3, entries 1–6). The complete selectivity of this
procedure compares favorably to that of other reported
Chemicals and solvents were either purchased or purified by stan-
dard techniques. Metallic indium (99.999% purity) was purchased
from Sinopharm Chemical Reagent Co., Ltd. IR spectra were re-
corded on a Bruker-EQUINOX55 spectrometer. Mass spectra were
determined on a Thermo Finnigan LCQ-Advantage spectrometer.
1H and 13C NMR spectra were recorded on a Bruker AC 300 instru-
ment at r.t.; CDCl3 was used as solvent and TMS as internal stan-
dard; chemical shifts (d) are reported relative to TMS. Silica gel 60
methods.21,22 The reactions of aldimines 6 (Scheme 5), GF254 was used for analytical and preparative TLC.
unlike the comparable reactions of aldehydes 1 with ethyl
2-bromopropanoate (Scheme 4), led to essentially no dia-
stereoselectivity in products 7 under the same conditions
(see Table 3, entry 9).
b-Hydroxy- and b-Amino Esters 3a–m, 4m, 5a–c, and 7a–i;
General Procedure
A commercially available In bar was crushed into a powder with a
file, and the In powder (20–40 mesh; 0.12 g, 1 mmol) was placed in
a Schlenk tube fitted with a magnetic stir bar. Then the aldehyde 1
(1 mmol) or aldimine 6 (1 mmol) and the a-halo ester (1.8 mmol)
R2
R2
O
HN
R1
O
N
In
were added via the injector. The resulting mixture was vigorously
stirred under N2 at r.t. After the reaction was completed, a sat.
NH4Cl soln (5 mL) was poured into the mixture, which was then
stirred for several minutes. EtOAc (2 × 10 mL) was added and the
organic layer was separated and dried (Na2SO4). The residue was
purified by flash chromatography (silica gel, PE–EtOAc, 10:1).
This afforded the corresponding b-hydroxy- or b-amino ester.
+
Br
solvent-free, r.t.
R1
H
OEt
OEt
R3
R3
7
6
Scheme 5 Reagents and conditions: aldimine 6 (1 equiv), ethyl a-
bromo ester (1.8 equiv), In powder (1 equiv).
Ethyl 3-Hydroxy-3-phenylpropanoate (3a)
Table 3 Synthesis of b-Amino Esters by a Reformatsky Reaction
Yellow oil.17c
Mediated by Indium Powder under Solvent-Free Conditionsa
IR (film): 3470, 2982, 1728, 1266, 1193, 701 cm–1.
Entry R1
R2
R3
Product Yieldb
(%)
1H NMR (300 MHz, CDCl3): d = 1.25 (t, J = 7.14 Hz, 3 H), 2.72 (m,
2 H), 3.38 (d, J = 3.45 Hz, 1 H, OH), 4.17 (q, J = 7.14 Hz, 2 H), 5.12
(m, 1 H), 7.25–7.38 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 14.14, 43.42, 60.86, 70.34, 125.70,
127.78, 128.54, 142.63, 172.36.
MS (EI, 70 eV): m/z = 194 [M+], 177, 147, 120, 107, 105, 91, 88,
79, 77, 61, 60.
1
2
3
4
5
6
7
8
9
Ph
Ph
H
H
H
H
H
H
H
H
Me
7a
7b
7c
7d
7e
7f
85
82
81
77
80
81
80
78
82
4-ClC6H4
Tol
Tol
Ph
Ph
Ph
Tol
Ethyl 3-(4-Fluorophenyl)-3-hydroxypropanoate (3b)
4-ClC6H4
4-ClC6H4
2-MeOC6H4
2-MeOC6H4
Ph
Yellow oil.25
Tol
Ph
IR (film): 3464, 2984, 1728, 1510, 1223, 838 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.20 (t, J = 7.11 Hz, 3 H), 2.57–
2.72 (m, 2 H), 3.71 (br s, 1 H, OH), 4.10 (q, J = 7.11 Hz, 2 H), 5.04
(m, 1 H), 6.94–7.00 (m, 2 H), 7.26–7.31 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 13.98, 43.44, 60.80, 69.60, 115.05,
115.34, 127.31, 127.42, 138.50, 138.54, 160.54, 163.80, 172.06.
MS (EI, 70 eV): m/z = 212 [M+], 196, 195, 153, 125, 125, 97, 95,
88, 61, 60.
7g
7h
7ic
Tol
Ph
a Reagents and conditions: aldimine 6 (1.0 mmol), a-halo ester (1.8
mmol), In powder (1.0 mmol), 5 h.
b Isolated yield.
c The syn/anti ratio is 1:1 (by 1H NMR spectroscopy).
Ethyl 3-(4-Bromophenyl)-3-hydroxypropanoate (3c)
Yellow oil.17c
IR (film): 3446, 2925, 1725, 1189, 826 cm–1.
In conclusion, this solvent-free reaction provides a simple
and efficient process for the synthesis of b-hydroxy esters
and b-amino esters by a coupling reaction between alde-
hydes or aldimines and a-halo esters in the presence of in-
dium powder. The present method has some significant
advantages: the selectivity for obtaining either mono-b-
hydroxy esters or bis-b-hydroxy esters is excellent; it is an
environmentally benign process, in which the use of sol-
vents is avoided; yields are excellent; reaction conditions
1H NMR (300 MHz, CDCl3): d = 1.25 (t, J = 7.14 Hz, 3 H), 2.68 (m,
2 H), 3.47 (br s, 1 H, OH), 4.16 (q, J = 7.14 Hz, 2 H), 5.07 (m, 1 H),
7.22–7.25 (m, 2 H), 7.44–7.47 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.13, 43.17, 61.02, 69.67, 121.58,
127.44, 131.63, 141.56, 172.22.
MS (EI, 70 eV): m/z = 274 [M+ + 2], 272 [M+], 257, 255, 187, 185,
183, 159, 157, 155, 91, 88, 78, 77, 61, 60.
Synthesis 2007, No. 20, 3233–3239 © Thieme Stuttgart · New York

3236
X. Chen et al.
PAPER
Ethyl 3-(4-Chlorophenyl)-3-hydroxypropanoate (3d)
1H NMR (300 MHz, CDCl3): d = 1.26 (t, J = 7.14 Hz, 3 H), 2.66–
2.71 (m, 2 H), 3.20 (d, J = 3.45 Hz, 1 H), 4.17 (q, J = 7.14 Hz, 2 H),
5.04 (m, 1 H), 5.94 (s, 2 H), 6.75–6.88 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 14.16, 43.39, 60.89, 70.18, 101.05,
106.34, 108.18, 119.09, 136.59, 147.12, 147.83, 172.37.
Yellow oil.17c
IR (film): 3444, 2925, 1725, 1191, 830 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.25 (t, J = 7.14 Hz, 3 H), 2.68 (m,
2 H), 3.47 (br s, 1 H, OH), 4.17 (q, J = 7.14 Hz, 2 H), 5.08 (m, 1 H),
7.26–7.31 (m, 4 H).
MS (EI, 70 eV): m/z = 238 [M+], 221, 193, 151, 149, 123, 121, 93,
65, 60.
13C NMR (75 MHz, CDCl3): d = 14.08, 43.17, 60.96, 69.59, 127.05,
128.63, 133.42, 141.00, 172.20.
Ethyl 3-(2-Furyl)-3-hydroxypropanoate (3j)
MS (EI, 70 eV): m/z = 230 [M+ + 2], 228 [M+], 213, 211, 171, 169,
141, 139, 113, 111, 91, 88, 77, 61, 60.
Yellow oil.17c
IR (film): 3456, 2983, 2930, 1730, 1288, 1158, 739 cm–1.
Ethyl 3-(3-Bromophenyl)-3-hydroxypropanoate (3e)
1H NMR (300 MHz, CDCl3): d = 1.22 (t, J = 7.11 Hz, 3 H), 2.80–
2.84 (m, 2 H), 3.48 (br s, 1 H, OH), 4.14 (q, J = 7.11 Hz, 2 H), 5.09
(m, 1 H), 6.22–6.29 (m, 2 H), 7.32–7.33 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.08, 39.97, 60.91, 64.12, 106.22,
110.22, 142.15, 154.91, 171.81.
Yellow oil.17c
IR (film): 3449, 2926, 1725, 1190, 889 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.26 (t, J = 7.14 Hz, 3 H), 2.70 (m,
2 H), 3.46 (br s, 1 H, OH), 4.18 (q, J = 7.14 Hz, 2 H), 5.08 (m, 1 H),
7.19–7.25 (m, 4 H).
MS (EI, 70 eV): m/z = 184 [M+], 167, 139, 137, 110, 97, 95, 94, 69,
68, 65, 60.
13C NMR (75 MHz, CDCl3): d = 14.08, 43.18, 60.96, 69.56, 122.61,
124.24, 128.84, 130.05, 130.77, 144.85, 172.08.
(E)-Ethyl 3-Hydroxy-5-phenylpent-4-enoate (3k)
MS (EI, 70 eV): m/z = 274 [M+ + 2], 272 [M+], 227, 225, 200, 198,
187, 185, 183, 159, 157, 155, 105, 91, 88, 77, 61, 60.
Yellow oil.17c
IR (film): 3455, 3027, 2982, 1730, 1599, 1165, 1029, 969, 912, 743
cm–1.
1H NMR (300 MHz, CDCl3): d = 1.27 (t, J = 7.14 Hz, 3 H), 2.62–
2.65 (m, 2 H), 3.20 (br s, 1 H, OH), 4.19 (q, J = 7.14 Hz, 2 H), 4.72
(m, 1 H), 6.20–6.26 (dd, J = 6.1, 15.9 Hz, 1 H), 6.66 (d, J = 15.9 Hz,
1 H), 7.24–7.40 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 14.20, 41.60, 60.85, 68.90, 126.56,
127.80, 128.59, 130.05, 130.76, 136.50, 172.19.
MS (EI, 70 eV): m/z = 220 [M+], 203, 202, 174, 146, 133, 131, 128,
115, 104, 103, 91, 77, 60, 55.
Ethyl 3-hydroxy-3-(4-methoxyphenyl)propanoate (3f)
Yellow oil.17c
IR (film): 3482, 2982, 1729, 1247, 1174, 834 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.24 (t, J = 7.11 Hz, 3 H), 2.69 (m,
2 H), 3.30 (br s, 1 H, OH), 3.77 (s, 3 H), 4.14 (q, J = 7.11 Hz, 2 H),
5.08 (m, 1 H), 6.84–6.87 (m, 2 H), 7.26–7.28 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.10, 43.38, 55.21, 60.75, 69.91,
113.83, 126.94, 134.82, 159.12, 172.30.
MS (EI, 70 eV): m/z = 224 [M+], 207, 179, 137, 135, 109, 94, 97,
77, 65, 60.
Ethyl 3-Hydroxy-5-phenylpentanoate (3l)
Yellow oil.17c
Ethyl 3-Hydroxy-3-p-tolylpropanoate (3g)
IR (film): 3462, 2930, 1727, 1252, 1184, 1031, 746, 700 cm–1.
Yellow oil.17c
1H NMR (300 MHz, CDCl3): d = 1.28 (t, J = 7.14 Hz, 3 H), 1.74–
1.88 (m, 2 H), 2.46–2.51 (m, 2 H), 2.71–2.84 (m, 2 H), 3.13 (d,
J = 4.01 Hz, 1 H, OH), 4.03 (m, 1 H), 4.18 (q, J = 7.14 Hz, 2 H),
7.17–7.32 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 14.18, 31.79, 38.18, 41.14, 60.72,
67.28, 125.91, 128.43, 128.48, 141.79, 172.96.
IR (film): 3457, 2982, 2921, 1729, 1181, 1161, 1035, 817 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.26 (t, J = 7.11 Hz, 3 H), 2.34 (s,
3 H), 2.72 (m, 2 H), 3.26 (br s, 1 H, OH), 4.18 (q, J = 7.11 Hz, 2 H),
5.08 (m, 1 H), 7.15–7.17 (m, 2 H), 7.25–7.28 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.12, 21.07, 43.33, 60.79, 70.16,
125.60, 129.16, 137.43, 139.60, 172.38.
MS (EI, 70 eV): m/z = 208 [M+], 193, 134, 121, 119. 93, 91, 77, 65,
60.
MS (EI, 70 eV): m/z = 223 [M+ + 1], 205, 204, 159, 131, 130, 129,
117, 115, 91, 77, 65, 60.
Ethyl 3-(4-Formylphenyl)-3-hydroxypropanoate (3m)
Yellow oil.
IR (film): 3449, 2983, 1725, 1703, 1378, 1207, 1034, 836, 729 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.17 (t, J = 7.14 Hz, 3 H), 2.65–
2.67 (m, 2 H), 4.18 (q, J = 7.14 Hz, 2 H), 4.16 (br s, 1 H, OH), 5.14
(m, 1 H), 7.48 (d, J = 8.19 Hz, 2 H), 7.77 (d, J = 8.19 Hz, 2 H), 9.89
(s, 1 H).
13C NMR (75 MHz, CDCl3): d = 14.03, 43.18, 61.01, 69.76, 126.25,
129.96, 135.63, 149.59, 171.91, 192.13.
Ethyl 3-Hydroxy-3-(2-hydroxyphenyl)propanoate (3h)
Yellow oil.17c
IR (film): 3356, 3347, 2983, 1712, 1239, 1101, 885 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.27 (t, J = 7.14 Hz, 3 H), 2.69–
2.98 (m, 2 H), 4.19 (q, J = 7.14 Hz, 2 H), 4.48 (br s, 1 H, OH), 5.29
(m, 1 H), 6.81–7.19 (m, 4 H), 8.16 (s, 1 H, ArOH).
13C NMR (75 MHz, CDCl3): d = 14.05, 41.15, 61.19, 71.15, 117.30,
119.97, 125.68, 126.65, 129.20, 155.42, 172.91.
MS (EI, 70 eV): m/z = 210 [M+], 193, 192, 147, 146, 123, 121, 118,
95, 91, 77, 65, 60.
MS (EI, 70 eV): m/z = 222 [M+], 193, 135, 133, 119, 105, 91, 86,
84, 79, 77, 65, 60.
Anal. Calcd for C12H14O4: C, 64.85; H, 6.35. Found: C, 64.62; H,
6.15.
Ethyl 3-(1,3-Benzodioxol-5-yl)-3-hydroxypropanoate (3i)
Yellow oil.23a
IR (film): 3452, 2982, 2905, 1726, 1243, 1036, 813 cm–1.
Diethyl 3,3¢-(1,4-Phenylene)bis(3-hydroxypropanoate) (4m)
Yellow solid; mp 43–45 °C.
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IR (KBr): 3496, 2984, 1726, 1379, 1274, 1161, 1037, 842 cm–1.
MS (EI, 70 eV): m/z = 244 [M+ + 2], 242 [M+], 227, 225, 171, 169,
143, 141, 139, 102, 91, 77, 74, 73, 56.
1H NMR (300 MHz, CDCl3): d = 1.25 (t, J = 7.14 Hz, 6 H), 2.65–
2.74 (m, 4 H), 3.42 (d, 2 H, OH), 4.17 (q, J = 7.14 Hz, 4 H), 5.14
(m, 2 H), 7.27–7.38 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 14.11, 43.34, 60.87, 70.27, 125.65,
127.76, 128.51, 142.51, 172.41.
anti-5c
1H NMR (300 MHz, CDCl3): d = 1.09 (d, J = 7.14 Hz, 3 H), 1.23 (t,
J = 7.23 Hz, 3 H), 2.67–2.77 (m, 1 H), 3.15 (d, J = 3.03 Hz, 1 H),
4.12 (q, J = 7.23 Hz, 2 H), 5.06 (t, J = 3.42 Hz, 1 H), 7.25–7.33 (m,
4 H).
MS (EI, 70 eV): m/z = 310 [M+], 293, 292, 223, 221, 219, 205, 204,
13C NMR (75 MHz, CDCl3): d = 10.61, 14.03, 46.15, 60.82, 72.87,
193, 163, 135, 133, 131, 105, 91, 79, 77, 65, 60.
127.36, 128.32, 133.09, 139.83, 175.71.
Anal. Calcd for C16H22O6: C, 61.92; H, 7.15. Found: C, 61.78; H,
7.00.
syn-5c
1H NMR (300 MHz, CDCl3): d = 1.00 (d, J = 7.23 Hz, 3 H), 1.23 (t,
J = 7.23 Hz, 3 H), 2.67–2.77 (m, 1 H), 3.21 (d, J = 4.62 Hz, 1 H),
4.15 (q, J = 7.23 Hz, 2 H), 4.71 (dd, J = 8.10, 4.59 1 H), 7.25–7.33
(m, 4 H).
Ethyl 3-Hydroxy-2-methyl-3-phenylpropanoate (5a)
Yellow oil.14
Mixture of syn- and anti-5a
IR (film): 3449, 2925, 1726, 1161, 1033, 701 cm–1.
13C NMR (75 MHz, CDCl3): d = 14.07, 14.38, 46.95, 60.82, 75.54,
127.95, 128.55, 133.63, 140.09, 175.62.
MS (EI, 70 eV): m/z = 208 [M+], 191, 135, 107, 102, 91, 79, 77, 73,
65, 56.
Ethyl 3-Anilino-3-phenylpropanoate (7a)
Yellow solid;19 mp 69–70 °C.
anti-5a
1H NMR (300 MHz, CDCl3): d = 1.13 (d, J = 7.14 Hz, 3 H), 1.21 (t,
J = 7.14 Hz, 3 H), 2.75–2.81 (m, 1 H), 3.00 (m, 1 H, OH), 4.12 (q,
J = 7.14 Hz, 2 H), 5.08 (t, J = 3.72 Hz, 1 H), 7.24–7.35 (m, 5 H).
IR (KBr): 3382, 2975, 1714, 1601, 1288, 751, 695 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.19 (t, J = 7.14 Hz, 3 H), 2.72–
2.82 (m, 2 H), 4.11 (q, J = 7.14 Hz, 2 H), 4.57 (s, 1 H, NH), 4.81–
4.86 (m, 1 H), 6.55–6.70 (m, 3 H), 7.08–7.40 (m, 7 H).
13C NMR (75 MHz, CDCl3): d = 14.10, 42.89, 54.98, 60.76, 113.63,
117.73, 126.23, 127.40, 128.72, 129.11, 142.17, 146.79, 171.10.
MS (EI, 70 eV): m/z = 269 [M+], 183, 182, 180, 135, 105, 104, 93,
91, 77, 65.
13C NMR (75 MHz, CDCl3): d = 10.79, 14.06, 46.38, 60.71, 73.64,
125.99, 127.45, 128.21, 141.38, 175.84.
syn-5a
1H NMR (300 MHz, CDCl3): d = 1.00 (d, J = 7.14 Hz, 3 H), 1.25 (t,
J = 7.14 Hz, 3 H), 2.72–2.81 (m, 1 H), 3.15 (m, 1 H, OH), 4.17 (q,
J = 7.14 Hz, 2 H), 4.73 (dd, J = 8.43, 4.47 Hz, 1 H), 7.24–7.36 (m,
5 H).
Ethyl 3-Anilino-3-(4-chlorophenyl)propanoate (7b)
Yellow solid;18c mp 76–78 °C.
13C NMR (75 MHz, CDCl3): d = 14.08, 14.43, 47.12, 60.72, 76.29,
126.62, 127.94, 128.40, 141.58, 175.84.
IR (KBr): 3351, 2926, 1714, 1600, 1381, 1305, 829, 748 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.20 (t, J = 7.11 Hz, 3 H), 2.76–
2.79 (m, 2 H), 4.11 (q, J = 7.11 Hz, 2 H), 4.61 (br s, 1 H, NH), 4.80
(t, J = 6.72 Hz, 1 H), 6.51–6.68 (m, 3 H), 7.07–7.27 (m, 6 H).
Ethyl 3-Hydroxy-2-methyl-3-p-tolylpropanoate (5b)
Yellow oil.26
13C NMR (75 MHz, CDCl3): d = 14.09, 42.70, 54.41, 60.88, 113.67,
Mixture of syn- and anti-5b
IR (film): 3459, 2929, 1724, 1250, 1180, 1033, 814 cm–1.
118.02, 127.67, 128.89, 129.16, 133.07, 140.71, 146.45, 170.84.
MS (EI, 70 eV): m/z = 305 [M+ + 2], 303 [M+], 218, 216, 214, 211,
69, 139, 104, 93, 77, 65.
MS (EI, 70 eV): m/z = 222 [M+], 205, 177, 149, 121, 119, 102, 93,
91, 77, 74, 73, 65, 56.
Ethyl 3-Anilino-3-p-tolylpropanoate (7c)
Yellow solid; mp 74–76 °C.
IR (KBr): 3363, 1719, 1382, 1280, 814 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.20 (t, J = 7.14 Hz, 3 H), 2.31 (s,
3 H), 2.78 (d, J = 6.72 Hz, 2 H), 4.10 (q, J = 7.14 Hz, 2 H), 4.52 (br
s, 1 H, NH), 4.80 (t, J = 6.72 Hz, 1 H), 6.51–6.68 (m, 3 H), 7.07–
7.27 (m, 6 H).
anti-5b
1H NMR (300 MHz, CDCl3): d = 1.01 (d, J = 7.14 Hz, 3 H), 1.20 (t,
J = 7.11 Hz, 3 H), 2.33 (s, 3 H), 2.72–2.80 (m, 1 H), 3.15 (t, J = 3.30
Hz, 1 H, OH), 4.12 (q, J = 7.11 Hz, 2 H), 5.03 (t, J = 3.66 Hz, 1 H),
7.13–7.26 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 10.91, 14.03, 21.04, 46.44, 60.62,
73.58, 125.88, 128.84, 137.02, 138.44, 175.77.
13C NMR (75 MHz, CDCl3): d = 14.10, 21.03, 42.91, 54.70, 60.71,
113.62, 117.65, 126.11, 129.08, 129.39, 136.99, 139.15, 146.85,
171.16.
MS (EI, 70 eV): m/z = 283 [M+], 197, 196, 194, 191, 149, 119, 117,
104, 93, 91, 77, 65.
syn-5b
1H NMR (300 MHz, CDCl3): d = 1.00 (d, J = 7.14 Hz, 3 H), 1.26 (t,
J = 7.11 Hz, 3 H), 2.34 (s, 3 H), 2.72–2.80 (m, 1 H), 3.15 (t, J = 3.30
Hz, 1 H), 4.18 (q, J = 7.11 Hz, 2 H), 4.71 (dd, J = 8.58, 4.35 Hz, 1
H), 7.13–7.26 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 14.10, 14.46, 21.07, 47.11, 60.68,
76.18, 126.55, 129.09, 137.66, 138.58, 175.88.
Anal. Calcd for C18H21NO2: C, 76.29; H, 7.47. Found: C, 76.18; H,
7.34.
Ethyl 3-(p-Toluidino)-3-p-tolylpropanoate (7d)
Yellow solid; mp 29–31 °C.
Ethyl 3-(4-Chlorophenyl)-3-hydroxy-2-methylpropanoate (5c)
Yellow oil.27
IR (KBr): 3398, 2982, 2923, 1729, 1517, 1371, 1293, 1167, 810
cm–1.
Mixture of syn- and anti-5c
IR (film): 3455, 2931, 1722, 1184, 1091, 826 cm–1.
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X. Chen et al.
PAPER
1H NMR (300 MHz, CDCl3): d = 1.22 (t, J = 7.14 Hz, 3 H), 2.21 (s,
3 H), 2.33 (s, 3 H), 2.79 (d, J = 6.72 Hz, 2 H), 4.12 (q, J = 7.14 Hz,
2 H), 4.40 (br s, 1 H, NH), 4.80 (t, J = 6.72 Hz, 1 H), 6.51 (d,
J = 8.34 Hz, 2 H), 6.91 (d, J = 8.34 Hz, 2 H), 7.14 (d, J = 7.98 Hz,
2 H), 7.20 (d, J = 7.98 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.10, 20.02, 21.03, 42.93, 54.90,
60.66, 113.79, 126.12, 126.81, 129.35, 129.58, 136.88, 139.33,
144.56, 171.22.
13C NMR (75 MHz, CDCl3): d = 14.07, 21.02, 43.25, 54.51, 55.42,
60.65, 109.35, 111.10, 116.68, 121.08, 126.12, 129.34, 136.72,
136.88, 139.32, 146.82, 171.06.
MS (EI, 70 eV): m/z = 313 [M+], 227, 226, 214, 210, 209, 149, 136,
129, 121, 120, 119, 91, 89, 77, 65.
Anal. Calcd for C19H23NO3: C, 72.82; H, 7.40. Found: C, 72.53; H,
7.23.
MS (EI, 70 eV): m/z = 297 [M+], 211, 210, 208, 191, 180, 149, 119,
118, 117, 107, 91, 77, 65.
Ethyl 3-Anilino-2-methyl-3-phenylpropanoate (7i)
Yellow oil;29 mixture of syn- and anti-isomers.
Anal. Calcd for C19H23NO2: C, 76.73; H, 7.80. Found: C, 76.48; H,
7.61.
IR (film): 3382, 2981, 1718, 1718, 1381, 1275, 1200, 725, 696 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.18–1.37 (m, 12 H), 2.91–2.99
(m, 1 H), 3.01–3.08 (m, 1 H), 4.10–4.20 (m, 4 H), 4.63 (m, 2 H,
NH), 4.82 (m, 1 H), 4.93 (m, 1 H), 6.63–6.75 (m, 6 H), 7.13–7.18
(m, 4 H), 7.25–7.42 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 11.87, 13.92, 13.97, 15.17, 46.04,
46.62, 59.53, 60.44, 60.48, 60.57, 113.25, 113.46, 117.20, 117.40,
126.69, 126.79, 127.15, 127.23, 128.29, 128.38, 128.92, 129.01,
140.58, 141.12, 146.82, 146.94, 173.98, 174.82.
Ethyl 3-(4-Chloroanilino)-3-phenylpropanoate (7e)
Yellow solid;20b mp 57–59 °C.
IR (KBr): 3386, 1718, 1385, 1292, 807 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.19 (t, J = 7.14 Hz, 3 H), 2.72–
2.85 (m, 2 H), 4.11 (q, J = 7.14 Hz, 2 H), 4.64 (br s, 1 H, NH), 4.76–
4.80 (m, 1 H), 6.45–6.49 (m, 2 H), 7.01–7.06 (m, 2 H), 7.22–7.37
(m, 5 H).
13C NMR (75 MHz, CDCl3): d = 14.09, 42.76, 55.08, 60.83, 114.75,
122.36, 126.15, 127.56, 128.80, 128.94, 141.66, 145.35, 171.03.
MS (EI, 70 eV): m/z = 283 [M+], 181, 182, 180, 117, 104, 91, 77,
65, 51.
MS (EI, 70 eV): m/z = 305 [M+ + 2], 303 [M+], 218, 216, 214, 108,
137, 135, 127, 111, 105, 91, 77, 65.
Acknowledgment
We are grateful to the National Natural Science Foundation of
China (No. 20504023) and Natural Science Foundation of Zhejiang
Province (No. Y405015 and Y404039) for financial support.
Ethyl 3-(4-Chloroanilino)-3-p-tolylpropanoate (7f)
Yellow solid; mp 46–47 °C.
IR (KBr): 3374, 1714, 1382, 1293, 810 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.17 (t, J = 7.14 Hz, 3 H), 2.29 (s,
3 H), 2.73–2.76 (m, 2 H), 4.08 (q, J = 7.14 Hz, 2 H), 4.65 (br s, 1 H,
NH), 4.72 (m, 1 H), 6.45 (d, J = 8.70 Hz, 2 H), 7.01 (d, J = 8.70 Hz,
2 H), 7.10 (d, J = 4.90 Hz, 2 H), 7.20 (d, J = 4.90 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 14.09, 21.01, 42.78, 54.79, 60.77,
114.72, 122.25, 126.03, 128.90, 129.45, 137.16, 138.62, 145.40,
171.06.
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Ethyl 3-(2-Methoxyanilino)-3-phenylpropanoate (7g)
Yellow oil.28
IR (film): 3416, 2934, 1734, 1515, 1251, 740 cm–1.
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1H NMR (300 MHz, CDCl3): d = 1.22 (t, J = 7.01 Hz, 3 H), 2.32 (s,
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Synthesis 2007, No. 20, 3233–3239 © Thieme Stuttgart · New York

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Solvent-Free Synthesis of b-Hydroxy Esters and b-Amino Esters
3239
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