HClO4·SiO2-mediated improved isomerization of glycidic esters to α-hydroxy-β,γ -unsaturated esters: Application in the formal synthesis of (R)-Baclofen and β-phenyl GABA analogues

Article abstract of DOI:10.1246/cl.2012.325

An efficient isomerization of glycidic esters to corresponding allylic alcohols, viz. α-hydroxy-β,γ -unsaturated esters has been brought about using HClO₄·SiO₂. Five of these allylic alcohols underwent selective S_N2' nucleophilic substitution to generate γ-azido-α,β-unsaturated esters which were readily converted to an antispastic drug Baclofen and four other β-phenyl GABA analogues.

Full text of DOI:10.1246/cl.2012.325

doi:10.1246/cl.2012.325
Published on the web February 25, 2012
325
HClO4¢SiO2-mediated Improved Isomerization of Glycidic Esters
to ¡-Hydroxy-¢,£-unsaturated Esters:
Application in the Formal Synthesis of (R)-Baclofen
and ¢-Phenyl GABA Analogues
Ranjan Basak,* Suresh Dharuman, Y. Suman Reddy, Venkata Ramana Doddi, and Yashwant D. Vankar*
Department of Chemistry, Indian Institute of Technology, Kanpur-208 016, India
(Received December 2, 2011; CL-111157; E-mail: ranjankb@rgukt.in, vankar@iitk.ac.in)
An efficient isomerization of glycidic esters to correspond-
ing allylic alcohols, viz. ¡-hydroxy-¢,£-unsaturated esters has
been brought about using HClO4¢SiO2. Five of these allylic
alcohols underwent selective SN2¤ nucleophilic substitution to
generate £-azido-¡,¢-unsaturated esters which were readily
converted to an antispastic drug Baclofen and four other ¢-
phenyl GABA analogues.
commercialized in its racemic form under the trade name
Lioresal, Baclofen, etc.12,13 In this paper we wish to report the
use of HClO4¢SiO2 as an efficient catalyst for the isomerization
of glycidic esters into ¡-hydroxy-¢,£-unsaturated esters which,
in turn, are converted into GABA derivatives, albeit in racemic
form. We envisioned the preparation of Baclofen, 3-(4-chloro-
phenyl)-4-aminobutyric acid to be derived from allylic alcohol B
(Scheme 1) via an SN2¤ azide displacement and further chemical
manipulation. The allylic alcohol in turn could be obtained from
epoxide C (a glycidic ester) through an acid-catalyzed rear-
rangement. The epoxide C could be obtained by reaction
between a ketone, especially acetophenone derivatives D and
ethyl chloroacetate.
Synthesis of chiral and achiral vinyl epoxides from ¡-
hydroxy-¢,£-unsaturated esters1 was reported a few years ago.
Conversion of ¡-hydroxy-¢,£-unsaturated esters into fluorinated
vinyl epoxides has also been demonstrated by Olah et al.2
Besides this, facile oxidation of ¡-hydroxy-¢,£-unsaturated
esters into ¡-keto-¢,£-unsaturated esters which further undergo
easily the Michael addition and the Diels-Alder reaction to form
some useful intermediates has also been reported.3 ¡-Hydroxy-
¢,£-unsaturated esters can be derived from the corresponding
glycidic esters by acid (or Lewis acid)-catalyzed regioselective
isomerizations. These acidic catalysts include LiClO4,4
Mg(ClO4)2,5 H2SO4-AcOH,6 BF3¢Et2O,3 ClSiMe3,3 Zeolite H-
ZSM 5,7 Nafion-H,2 HI,8 Ph3SiClO4,9 and Yb(OTf)3.10 However,
some of these reagents are either hygroscopic or difficult to
handle, while in some cases yields are relatively low and require
longer reaction times along with formation of some side
products. Moreover, there is no generalized reported method
for isomerization of aromatic-based glycidic esters.
R
R
X
CO2Et
NHBoc
COOEt
A
B
O
R
COOEt
O
R
C
D
Scheme 1. Retrosynthesis for the Baclofen synthesis.
Recently, the utility of HClO4¢SiO2 as a stable and solid
acidic reagent for a variety of useful transformations has been
reported.11 It therefore occurred to us that such a catalyst could
also be utilized for the conversion of glycidic esters into the
corresponding ¡-hydroxy-¢,£-unsaturated esters. Further, we
also realized that ¡-hydroxy-¢,£-unsaturated esters could serve
as useful precursors for procuring £-aminobutyric acid (GABA)
derivatives, such as Baclofen 1 and Phenibut 2 (Figure 1), which
are important inhibitory neurotransmitters involved in dispens-
ing of several psychological and physiological responses in
the biological systems.12 Although the therapeutic effect of
Baclofen is associated with the (¹)-R-isomer, still it has been
Isomerization of the glycidic ester 3 (Table 1) was per-
formed using 10% weight equivalent of HClO4¢SiO2 in
refluxing benzene which led to the isolation of the required
allylic alcohol 4 in 93% yield. Reduction in the amount of the
reagent led to longer reaction time and unreacted starting
material was recovered, hence, we used minimum of 10% weight
equivalent of the catalyst. The reaction was found to work with
several glycidic esters which were derived from variously
substituted aromatic ketones (Table 1) and nonaromatic ketones
(Table 2). As we are interested in conversion to allylic alcohols,
we prepared glycidic esters following the reported procedure1f,1g
and are reporting the results of glycidic esters in Tables 1 and 2.
The diastereomeric ratios are based on comparison of proton
intensities of the corresponding protons. In this regard glycidic
ester 17 was isolated as a single diastereomer and has been
assigned trans configuration based on NOE experiments.
Irradiation of H-2 and H-4 (methyl protons) showed negligible
enhancement in the signals of one another, while showed 0.4%
enhancement for phenyl protons. Thus the H-2 proton and
methyl group are trans oriented with respect to one another.
When the reactions were performed with glycidic esters having
Cl
COOH
NH2
COOH
NH2
2
1
Phenibut
Baclofen
Figure 1. Structures of Baclofen and Phenibut.
Chem. Lett. 2012, 41, 325-327
© 2012 The Chemical Society of Japan
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326
Table 1. Isomerization of glycidic esters derived from acetophenonesa
Table 2. Isomerization of glycidic esters derived from cyclic ketonesa
OH
Ethyl
HClO4·SiO2
(Cat.)
Benzene,
CO2Et reflux
4
HClO4·SiO2
Benzene,
reflux
Me
Ethyl chloroacetate
Sodium sand,
xylene, 0 °C, 2 h
Me
R
allylic alcohol
chloroacetate
O
ketone
Glycidic ester
R
R
O
3
CO2Et
NaH, MeCN
60 °C-reflux,
6 h
2
Allylic alcohol
Ketone
Glycidic ester
Glycidic
ester
Time
Sr. No.
Ketone
Yield/%
Allylic alcohol
Yield/%
(mins)
30
Glycidic
Allylic
Ketone
R =
Cat. Time
/mg /min
Sr. No.
ester/Yield alcohol/
CO2Et
HO
HO
CO2Et
O
O
O
(dr)
Yield
32/64%
1
71
82
1
2
3
4
5
6
Phenyl
42/93%
5
5
5
5
5
5
30
30
30
30
10
30
(3:1)
2810
2710
CO2Et
5/83%
(1:1)
710/55%
(6.7:1)
9/74%
(6:1)
11/48%
(2:1)
13/90%
(5:1)
o-Tolyl
6/80%
810/94%
10/90%
12/62%
14/66%
CO2tE
O
p-Tolyl
2
3
4
5
57
44
32
41
30
30
30
15
79
72
83
91
m-Methoxyphenyl
p-Methoxyphenyl
o-Chlorophenyl
307
297 dr = 1:2.5
dr = 1:1
CO2tE
CO2Et
O
HO
O
15/90%
(13:1)
17b/87%
19/76%
(6:1)
Ph
Ph
Ph
O
7
8
9
m-Chlorophenyl
p-Chlorophenyl
o-Fluorophenyl
16/76%
18/85%
20/74%
5
5
5
30
30
30
3110
3210 dr = 2:3
dr = 4:1
CO2Et
O
CO2Et
HO
21/86%
(13:1)
23/88%
(1.7:1)
25/89%
(2:1)
10
11
12
p-Fluorophenyl
m-Nitrophenyl
p-Nitrophenyl
22/78%
24/86%
26/88%
5
15
35
30
150
210
3310
3410
HO
CO2Et
CO2Et
O
O
3510
3610
aReactions were carried out at 50 mg scale in 1.5 mL of dry
benzene. The compound solutions were preheated to reflux and
catalyst was added at this temperature under N2 atmosphere.16
bOnly single isomer isolated.
aReactions were carried out at 50 mg scale in 1.5 mL of dry
benzene with 5 mg HClO4¢SiO2. The compound solutions were
preheated to reflux and catalyst was added at this temperature
under N2 atmosphere.16
electron-donating substituents on the phenyl ring, the yields of
the allylic alcohols were found to be higher in general (Table 1,
Entries 2-4). Strangely, when the electron-donating group was
m-methoxy, the yield of allylic alcohol 10 was found to be 90%
(Table 1, Entry 4), while p-methoxy-substituted phenyl glycidic
ester 11 generated the corresponding allylic alcohol 12 in only
62% yield (Table 1, Entry 5) along with some polar intractable
mixture of compounds. However, electron-withdrawing sub-
stituents yielded slightly lower yields of allylic alcohols in
general (Table 1, Entries 6-10) as compared to electron-
donating substituents. When the electron-withdrawing-group
nitro functionality was used as a substituent, the yields of the
corresponding allylic alcohols 24 and 26 were found to be at par
(Table 1, Entries 11 and 12) with the yields obtained from
electron-donating substituents. But, it required higher amount of
the catalyst and longer time interval for the reaction to complete.
Also it was found that the yields obtained for the isomerization
of glycidic esters derived from nonaromatic ketones were a little
lower in general as compared to isomerization yields of the
aromatic ketone-based glycidic esters (Table 2).
O
elimination
of Ha
δ+
COOEt
Hb
δ+
·
H SiO2
R
O
H
HClO4·SiO2
O
COOEt
II
COOEt
Ha
R
elimination
of Hb
R
COOEt
OH
I
R
III
Scheme 2. Mechanism of the isomerization of glycidic esters.
alcohol III, respectively. The ease of elimination of a particular
proton i.e., Ha or Hb depends upon their respective acidities
and antiperiplanarity with respect to the cleaving C-O bond.
Although the acidity of Ha proton is much higher than that of Hb
proton, but its fixed conformation at the tertiary carbon center
makes its elimination difficult due to which the formation of
¡-keto esters is known to occur only under drastic conditions
and with poor yields. However, the acidity of the Hb proton is
very low, but as it can achieve antiperiplanarity, the elimination
does not require drastic conditions like Ha proton.
A tentative mechanism for such an isomerization is shown
in Scheme 2. It is expected that when glycidic ester reacts
with the acidic catalyst, partial positive charge develops at the
benzylic carbon leading to structure I. The elimination of the
proton Ha or Hb would lead to either ¡-keto ester II or an allyl
Based upon the mechanism (Scheme 2), the low yield of
allylic alcohol 12 (Table 1, Entry 5) can be rationalized. The
partial positive charge developed at the benzylic carbon in the
Chem. Lett. 2012, 41, 325-327
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

327
R
the primary amine led to the protected ¢-phenyl-£-aminobutyric
acids (GABA) 47 (protected racemic phenibut), 48, 49, 50
(protected Baclofen), and 51.14
R
OMs
COOEt
NaN3,
acetone/H2O,
OH
MsCl, Et3N
COOEt
4:1, 70 °C,
3 h
CH2Cl2, 0 °C
15 min.
Of the azido esters 42-46, compound 45 has been converted
into (R)-Baclofen upon sequential reductions with Ru(II)-(S)-
BINAP, H2 (200 psi),15 and NaBH4-CoCl2, followed by hydrol-
ysis, thus completing its formal synthesis.
In summary, a new reagent system has been introduced for
the isomerization of various aromatic-based glycidic esters to the
corresponding ¡-hydroxy-¢,£-unsaturated esters (allylic alco-
hols). The reagent works equally well with cyclic ketone derived
glycidic esters. Five of these ¢-phenyl-derived allylic alcohols
were readily converted to £-aminobutyric acid ester analogues
including Baclofen.
4
R = H ,
37 R = H ,
91%
76%
14
38
R = o-Cl,
R = o-Cl,
16 R = m-Cl,
18 R = p-Cl,
22
39 R = m-Cl, 72%
40 R = p-Cl,
41
75%
72%
R = p-F,
R = p-F,
R
R
H2, 10% Pd/C
2
3
MeOH, rt, 2 h,
COOEt
COOEt
then Boc2O, 1 h
4
NHBoc
N3
42 R = H ,
43
70%
75%
47 R = H ,
48
70%
60%
69%
59%
66%
R = o-Cl,
R = o-Cl,
44 R = m-Cl, 74%
49 R = m-Cl,
50 R = p-Cl,
45 R = p-Cl,
46
75%
72%
R = p-F,
51
R = p-F,
Cl
Cl
Ref 15
YDV thanks Council of Scientific and Industrial Reasearch,
New Delhi for financial support [Grant No. 01(2298)/09/EMR-
II] and Department of Science and Technology, New Delhi for
J. C. Bose Fellowship. RB, SD, YSR, and VRD acknowledge
Council of Scientific and Industrial Research, New Delhi for
Senior Research Fellowships.
COOEt
COOH
HCl
N3
45
NH2
R-(-) Baclofen
Scheme 3. Conversion of isomerized allylic alcohols into Baclofen
derivatives.16
glycidic ester 11 upon treatment with HClO4¢SiO2 catalyst is
resonance stabilized. This reactive center may undergo other
low-energy reactions even before isomerization could take place.
This resulted in the formation of a polar intractable mixture of
compounds along with low yield of the allylic alcohol 12. The
high reactivity of this center is reflected in the reduced time
required for completion of the reaction. Similarly, when
reactions were performed on glycidic esters 23 and 25 (Table 1,
Entries 11 and 12) at reflux temperature, the partial positive
charge developed at the benzylic positions of the corresponding
glycidic esters becomes difficult because of the deactivation due
to the nitro functionality. Due to this, the C-O bond cleavage
occurs at elevated temperatures. However, at reflux temperature,
cleavage of C-O bond took place with facile elimination of
proton to yield the allylic alcohol in very good yields. The
reluctance of the C-O bond cleavage is reflected in the increased
requirement of the amount of catalyst along with the extended
time required for the completion of the reaction. The greater
reactivity of the glycidic ester 35 to form allylic alcohol 36
amongst nonaromatic ketone-derived glycidic esters (Table 2,
Entry 5) appears to be due to opening of the more strained
epoxide on the cyclopentane ring compared to epoxide on a
cyclohexane ring or cycloheptane ring.
The allylic alcohols 4, 14, 16, 18, and 22 were subjected
to mesylation (Scheme 3) to yield the corresponding allylic
mesylates 37-41 in moderate to good yields. These mesylates
underwent selective SN2¤ nucleophilic displacement with azide
ion to yield allylic azides 42-46 in moderate yields. The
geometry of the allylic azides has been determined through NOE
experiments for two representative compounds 42 and 45.
Irradiation of the H-2 and H-4 protons led only to negligible
enhancements in the signals of one another while for the phenyl
protons showed enhancement of nearly 1.5%. Thus, the allylic
and alkene protons are trans oriented with respect to each other.
Under these reaction conditions, no trace of the product via an
SN2 displacement could be isolated. Further one-pot hydro-
genation of the double bond and azide reduction with 10%
Pd/C-catalyzed conditions followed by in situ Boc protection of
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Chem. Lett. 2012, 41, 325-327
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/