NaBH4-mediated facile reduction of esters of Baylis-Hillman adducts: An efficient approach to substituted propane-1,3-diols

Article abstract of DOI:10.1055/s-2003-40992

Reduction of the ester group in the Baylis-Hillman adducts by NaBH ₄ reduction is facilitated by the secondary hydroxyl group present at their β-position. This method is efficient for the preparation of substituted propane-1,3-diols.

Full text of DOI:10.1055/s-2003-40992

LETTER
1611
NaBH -mediated Facile Reduction of Esters of Baylis-Hillman Adducts:
4
1
An Efficient Approach to Substituted Propane-1,3-Diols
E
A
fficient
A
pproac
h
r
to Subs
u
tituted Propa
n
ne-1,3-Diol sd hati Patra, Sanjay Batra,* Amiya P. Bhaduri
Medicinal Chemistry Division, Central Drug Research Institute, PO Box 173, Lucknow-226 001, India
Fax +91(522)2223405, +91(522)2223938; E-mail: batra_san@yahoo.co.uk
Received 12 May 2003
The Baylis–Hillman adducts, used as substrate for this
study, were obtained by using methods reported earlier.5
These adducts, representing the general structure 1, were
Abstract: Reduction of the ester group in the Baylis–Hillman ad-
ducts by NaBH reduction is facilitated by the secondary hydroxyl
4
group present at their b-position. This method is efficient for the
preparation of substituted propane-1,3-diols.
reduced with NaBH to furnish the diastereoisomeric mix-
4
ture of substituted propane-1,3-diols 2 along with minor6
yields (1–2% only) of the b-hydroxy esters 3 (Scheme 1).
In order to understand the driving force for the reduction
of the ester group in 1, it was necessary to investigate the
formation of the intermediate, if any, because of
transesterification7 during the NaBH4 reduction. We
found that irrespective of the nature of the alkyl group in
the ester linkage of 1 and independent of the nature of the
Key words: Baylis–Hillman reaction, NaBH , reduction, ester,
propane-1,3-diol
4
The Baylis-Hillman reaction has furnished the advantage
of obtaining products of high functional density in a single
step and these products have been utilized to access het-
2
erocycles, natural products and biodynamic agents. With
alkanol (solvent) used for NaBH reductions, the reduc-
4
an objective to develop isoxazole derivatives of biological
3
tion products always turned out to be the propane-1,3-diol
derivatives (Table 1). The next consideration for the driv-
ing force was the secondary hydroxyl group of 1 because
relevance, Baylis–Hillman adducts obtained from substi-
tuted 5-isoxazolecarbaldehydes were subjected to NaBH4
reductions. It is noteworthy that no single attempt has
8
it has been reported earlier that proximal hydroxyl group
been made earlier to understand the fate of NaBH reduc-
4
could lead to reduction of the ester group. In order to pro-
vide experimental evidence for the role of hydroxyl group
tion of Baylis–Hillman adducts. Interestingly, however,
the NaBH reductions of acetyl derivatives of Baylis–
4
4
in 1 during NaBH reduction, the need arose to synthesize
4
Hillman adducts (Figure 1) have been reported earlier.
9
compound 5. This was obtained following the methods
The present study revealed that the reductions of Baylis–
described in Scheme 2. The NaBH reduction of com-
4
Hillman adducts 1 in the presence NaBH yielded dia-
4
pound 5 yielded the product 6. It was, therefore, estab-
lished that the presence of the hydroxyl group did assist
the reduction of the ester group.
stereoisomeric mixtures of substituted propane-1,3-diols
in excellent yields. We have reasoned that the secondary
hydroxyl group, present in these adducts, facilitates the
reduction of the ester group and necessary experimental
evidence to support this reasoning has been furnished. We
also wish to report that our present observation has of-
fered a general method for the preparation of substituted
propane-1,3-diols. The details of our study are presented
herein.
OH
O
OH OH
OH O
NaBH
4
+
R
OAlk
3 (minor)
R
OAlk
R
solvent
1
2 (major)
For key to R and Alk refer to Table 1
Scheme 1
OAc O
O
NaBH4
R
R
OAlk
OAlk
R
R
OAlk
In order to ascertain the general applicability of the
present method for obtaining substituted propane-1,3-
diols, it was considered desirable to evaluate the nature of
Prototype I
O
OAc O
DABCO,
NaBH4
NaBH reduced products, obtained from substrates that do
4
OAlk
Prototype II
not possess a,b-unsaturation. This prompted to study the
reaction of compound 7 with NaBH . The nitro derivative
4
7
was obtained by following the strategy described in
10
Scheme 3. The NaBH reduction of compound 7 gave
Figure 1 Reported synthetic applications of NaBH in Baylis–
Hillman chemistry
4
4
the propane-1,3-diol derivative 8 in good yields.
In summary we have described a facile and efficient
NaBH -mediated conversion of esters of the Baylis–
4
Synlett 2003, No. 11, Print: 02 09 2003. Web: 05 08 2003.
Art Id.1437-2096,E;2003,0,11,1611,1614,ftx,en;D10803ST.pdf.
DOI: 10.1055/s-2003-40992
Hillman adducts to the corresponding substituted 1,3-diol
systems. The methodology will add to the expanding
synthetic utility of the Baylis–Hillman adducts.
©
Georg Thieme Verlag Stuttgart · New York

1
612
A. Patra et al.
LETTER
OAc O
DABCO,
NaBH4
O
O
NaBH4
R
OAlk
R
OAlk
R
OAlk
THF: H
5 min
2
O,
MeOH
1
4a,b
5a,b
6a,b
a R= 3-Nitrophenyl, Alk= Et (4a, 5a), Me (6a)
b R=3-(2-Chlorophenyl)-5-methyl-isoxazol-4-yl), Alk= Me
Scheme 2
Table 1 Reduction of Various Baylis–Hillman adducts with NaBH4
Entry
R
Alkyl
Solvent
Time
h)
Yield
(%)
Diastereo- Physical State
meric ratio
(
1
2
3
4
5
6
7
8
9
3-Nitrophenyl
Me
Et
MeOH
MeOH
EtOH
2.5
3.0
5.5
6.0
6.0
3.0
3.0
3.0
6.0
3.0
3.0
2.5
91
88
90
87
88
79
81
93
89
80
91
90
3:1
3:1
3:1
3:1
3:1
3:1
1:1
1:1
1:1
1:1
1:1
1:1
Pale yellow oil
Pale yellow oil
Pale yellow oil
Pale yellow oil
Pale yellow oil
Colorless oil
3-Nitrophenyl
3-Nitrophenyl
Et
3-Nitrophenyl
n-Bu
n-Bu
n-Bu
Me
Me
Et
EtOH
3-Nitrophenyl
n-BuOH
MeOH
MeOH
MeOH
EtOH
4-Trifluromethyl
3-(Phenyl)-isoxazol-5-yl
3-(4-Methyl-phenyl)-isoxazol-5yl
3-(4-Methyl-phenyl)-isoxazol-5yl
3-(2-Chlorophenyl)-isoxazol-5-yl
3-(2, 4-Dichloro-phenyl)-isoxazol-5-yl
3-(4-Benzyloxy-phenyl)-isoxazol-5yl
Colorless oil
Colorless oil
Colorless oil
1
1
1
0
1
2
Et
MeOH
MeOH
MeOH
Colorless oil
Me
Me
Colorless oil
Pale-yellow solid
(
108–110 °C)
1
1
1
3
4
5
3-(4-Methyl-phenyl)-5-methyl-isoxazol-4-yl
3-(2-Chlorophenyl)-5-methyl-isoxazol-4-yl
3-(2,4-Dichlorophenyl)-5-methyl-isoxazol-4-yl
Me
Me
Me
MeOH
MeOH
MeOH
3.0
3.0
3.0
91
91
83
5:2
3:2
1:1
Colorless oil
Colorless oil
Colorless oil
OH
OH
OH OH
1
-Methyl
CO Et
CO Et
2
2
NaBH4
MeOH
piperazine
MeOH
N
N
NO
2
NO
2
N
NO
2
N
Me
Me
1
7
8
Scheme 3
Acknowledgment
References
One of the author (AP) gratefully acknowledges the financial sup-
port from CSIR, India in the form of senior research fellowship.
(1) CDRI Communication No. 6400.
(2) Basavaiah, D.; Jaganmohan Rao, A.; Satyanarayana, T.
Chem. Rev. 2003, 103, 811.
(
3) (a) Batra, S.; Srinivasan, T.; Rastogi, S. K.; Kundu, B.; Patra,
A.; Bhaduri, A. P.; Dikshit, M. Bioorg. Med. Chem. Lett.
2002, 12, 1905. (b) Patra, A.; Batra, S.; Bhaduri, A. P.;
Khanna, A. K.; Chander, R.; Dikshit, M. Bioorg. Med.
Chem. 2003, 11, 2269.
Synlett 2003, No. 11, 1611–1614 © Thieme Stuttgart · New York

LETTER
Efficient Approach to Substituted Propane-1,3-Diols
1613
(
4) (a) Basavaiah, D.; Kumaragurubaran, N. Tetrahedron Lett.
001, 42, 477. (b) Im, Y. J.; Kim, J. M.; Mun, J. H.; Kim, J.
2-Methyl-1-(3-p-tolyl-isoxazol-5-yl)-propane-1,3-diol
–
1
2
(entries 8 and 9): HPLC (t = 14.68 min); IR (Neat, cm )
R
1
N. Bull. Korean Chem. Soc. 2001, 22, 349.
3401 (OH); H NMR (CDCl , 200 MHz) d 0.88, 0.92 (d, 3
H, J = 7.0 Hz, CH ), 0.93, 0.97 (d, 3 H, J = 7.0 Hz, CH ),
3
(
5) (a) Patra, A.; Batra, S.; Kundu, B.; Joshi, B. S.; Roy, R.;
Bhaduri, A. P. Synthesis 2001, 276. (b) Roy, A. K.; Batra, S.
Synthesis 2003, 1347. (c) Ciganek, E. Org. React. 1997, 51,
3
3
2.21–2.29 (m, 2 H, 2 × CH), 2.37 (s, 6 H, 2 × CH ), 3.05 (br
3
s, 2 H, 2 × OH, exchangeable with D O), 3.69–3.80 (m, 4 H,
2
201.
2 × CH ), 4.37 (br s, 2 H, 2 × OH, exchangeable with D O),
2
2
(
6) General Procedure for Reaction of NaBH with Baylis–
4.81, 4.84 (d, 2 H, J = 7.0 Hz, 2 × CH), 5.12, 5.13 (d, 2 H,
J = 2.6 Hz, 2 × CH), 6.53 (s, 2 H, 2 × =CH), 7.21, 7.25 (d, 4
H, J = 8.0 Hz, 2 × 2Ar-H), 7.63, 7.67 (d, 4 H, J = 8.0 Hz, 2
4
Hillman adducts. To the solution of appropriate Baylis–
Hillman adduct (2 mmol) in solvent (5 mL) was added
+
NaBH (Aldrich, pellet 7/16¢¢, 98%) (0.12 g, 3 mmol) with
× 2 Ar-H); Mass (FAB+) m/z 248 (M + 1). Anal. calcd for
4
stirring at 0–5 °C. After addition of NaBH , the reaction was
C H NO : C, 68.00; H, 6.93; N, 5.66. Found C, 67.96; H,
4
14 17
3
allowed to continue for appropriate time (Table 1) at r.t.
Thereafter, the reaction mixture was quenched with water
and extracted with ethyl acetate (2 × 25 mL). The organic
layers were pooled, washed with brine (30 mL), dried
6.84; N, 6.00%.
1-[3-(2-Chloro-phenyl)-isoxazol-5-yl]-2-methyl-
propane-1,3-diol (entry 10): IR (Neat, cm ) 3373 (OH); H
–
1
1
NMR (CDCl , 200 MHz) d 0.95, 0.99 (d, 3 H, J = 7.0 Hz,
3
(
Na SO ) and concentrated in vacuum to obtain an oily
CH ), 1.00, 1.04 (d, 3 H, J = 7.0 Hz, CH ), 2.11 (br s, 1 H,
2
4
3
3
residue. This residue was passed through a small band of
silica gel using hexane:ethyl acetate (3:2, v/v) to furnish
diasteroisomeric mixture of 1,3-diols. The HPLC profile of
representative diols show only single peak in a gradient
system of 0% acetonitrile in water to 100% acetonitrile in
water containing 0.1% of TFA over a period of 25 min on
RP-18e column (150 × 4.6 mm) at l = 220 nm and 254 nm.
OH), 2.27–2.36 (m, 2 H, 2 × CH), 3.51, 3.54 (d, 1 H, OH),
3.74–3.88 (m, 4 H, 2 × CH ), 4.87–4.93 (m, 1 H, CH), 5.19
2
(br s, 1 H, CH), 6.73, 6.74 (2 s almost merged, 2 H, 2 ×
=CH), 7.34–7.52 (m, 6 H, 2 × 3Ar-H), 7.52–7.75 (m, 2 H, 2
+
× Ar-H); Mass (FAB+) m/z 268 (M + 1). Anal. calcd for
C H ClNO : C, 58.32; H, 5.27; N, 5.23. Found: C, 58.09;
1
3
14
3
H, 4.99; N, 5.00%.
2
-Methyl-1-(3-nitro-phenyl)-propane-1,3-diol (entries 1–
1-[3-(2,4-Dichloro-phenyl)-isoxazol-5-yl]-2-methyl-
propane-1,3-diol (entry 11): IR (Neat, cm ) 3374 (OH); H
–
1
1
–1
1
5
): IR (Neat, cm ) 3379 (OH); H NMR (CDCl , 300 MHz)
3
d 0.75, 0.77 (d, 3 H, J = 7.0 Hz, CH ), 0.81, 0.83 (d, 3H, J =
NMR (CDCl , 200 MHz) d 0.94, 0.98 (d, 3 H, J = 7.0 Hz,
3
3
7
.0 Hz, CH ), 1.98–2.09 (m, 2 H, 2 × CH), 2.69 (s, 2 H, 2 ×
CH ), 0.99, 1.03 (d, 3 H, J = 7.0 Hz, CH ), 1.98 (br s, 2 H, 2
3
3
3
OH, exchangeable with D O), 3.68–3.91 (m, 4 H, 2 × CH ),
× OH), 2.23–2.38 (m, 2 H, 2 × CH), 3.69–3.91 (br s merged
2
2
3
1
2
2
.96 (s, 2 H, 2 × OH, exchangeable with D O), 4.69, 4.71 (d,
with m, 6 H, 2 × CH and OH), 4.87, 4.91 (d, 1 H, J = 7.0
2
2
H, J = 7.5 Hz, CH), 5.24 (s, 1 H, CH), 7.52 (dt, 2 H, J =
Hz, CH), 5.18, 5.19 (d, 1 H, J = 2.4 Hz, CH), 6.72, 6.73 (2 s
almost merged, 2 H, 2 × =CH), 7.31–7.36 (m, 2 H, 2 × Ar-
H), 7.51,7.52 (2 s almost merged, 2 H, 2 × Ar-H), 7.66, 7.70
1
.4 Hz, J = 7.8 Hz, 2 × Ar-H), 7.68, 7.71 (d, 2 H, J = 7.7 Hz,
2
× Ar-H), 8.13 (dt almost merged, 2 H, J = 2.0 Hz, J = 7.8
1
3
2
1
+
Hz, 2 × Ar-H), 8.23 (s, 2 H, 2 × Ar-H); C NMR (CDCl ,
(2 s, 2 H, 2 × Ar-H); Mass (FAB+) m/z 302 (M + 1). Anal.
3
7
6
1
5.46 Hz) d 9.8 (CH ), 13.6 (CH ), 41.0 (CH), 41.4 (CH),
calcd for C H Cl NO : C, 51.68; H, 4.34; N, 4.64. Found:
3
3
13 13
2
3
6.3 (CH ), 67.4 (CH ), 75.0 (CH), 79.4 (CH), 120.09 (CH),
C, 51.89; H, 4.51; N, 4.40%.
1-[3-(4-Benzyloxy-phenyl)-isoxazol-5-yl]-2-methyl-
2
2
21.6 (CH), 122.0 (CH), 122.6 (CH), 129.0 (CH), 129.3
(
×
CH), 132.4 (CH), 132.9 (CH), 145.2 (C), 145.5 (C), 148 (2
C); Mass (FAB+) m/z 212 (M + 1). Anal. calcd for
propane-1,3-diol (entry 12): HPLC (t = 17.68 min); IR
R
+
–1
1
(KBr, cm ) 3382 (OH); H NMR (CDCl , 200 MHz) d 0.91,
3
C H NO : C, 56.86; H, 6.20; N, 6.63. Found: C, 57.01; H,
0.94 (d, 3 H, J = 7.0 Hz, CH ), 0.96, 1.00 (d, 3 H, J = 7.0 Hz,
10
13
4
3
6
.30; N, 6.55%.
CH ), 2.04 (br s, 2 H, 2 × OH), 2.29–2.30 (m, 2 H, 2 × CH),
3
2-Methyl-1-(4-trifluoromethyl-phenyl)-propane-1,3-diol
3.66–3.87 (m, 4 H, 2 × CH ), 4.15 (s, 2 H, 2 × OH), 2.95 (s,
2
–
1
1
(entry 6): IR (Neat, cm ) 3396 (OH); H NMR (CDCl , 200
1 H, OH), 4.82, 4.85 (d, 1 H, J = 7.0 Hz, CH), 5.09, 5.11 (m,
3
MHz) d 0.73, 0.76 (d, 3 H, J = 7.0 Hz, CH ), 0.81, 0.84 (d, 3
5 H, s of 2 × OCH merged with m of CH), 6.51 (s, 2 H, 2 ×
3
2
H, J = 7.0 Hz, CH ), 1.97–2.10 (m, 2 H, 2 × CH), 2.58, 2.60
=CH), 7.01, 7.05 (d, 4 H, J = 8.8 Hz, 2 × 2Ar-H), 7.29–7.41
(m, 10 H, 2 × 5Ar-H), 7.70, 7.74 (d, 4 H, J = 8.8 Hz, 2 × 2
3
(
d, 2 H, J = 4.4 Hz, OH), 3.42 (br s, 2 H, OH), 3.71–3.84 (m,
+
4
1
7
H, 2 × CH ), 4.62, 4.66 (d, 1 H, J = 6.9 Hz, CH), 5.06 (brs,
Ar-H); Mass (FAB+) m/z 339 (M + 1). Anal. calcd for
2
H, CH), 7.44, 7.88 (d, 4 H, J = 8.0 Hz, 2 × 2Ar-H), 7.59,
C H NO : C, 70.78; H, 6.24; N, 4.13. Found: C, 70.58; H,
2
0
21
4
.63 (d, 4 H, J = 8.0 Hz, 2 × 2 Ar-H); Mass (FAB+) m/z 235
5.99; N, 4.14%.
+
(
M + 1). Anal. calcd for C H F O : C, 56.41; H, 5.59.
2-Methyl-1-(5-methyl-3-p-tolyl-isoxazol-4-yl)-propane-
1
5
13
3
2
–
1
1
Found: C, 56.60; H, 5.77%.
-Methyl-1-(3-phenyl-isoxazol-5-yl)-propane-1,3-diol
1,3-diol (entry 13): IR (Neat, cm ) 3403 (OH); H NMR
(CDCl , 200 MHz) d 0.49, 0.53 (d, 3 H, J = 7.0 Hz, CH ),
2
3
3
–
1
(
(
entry 7): HPLC (t = 13.01 min); IR (Neat, cm ) 3369
OH); H NMR (CDCl , 200 MHz) d 0.93, 0.97 (d, 3 H, J =
0.90, 0.94 (d, 3 H, J = 7.0 Hz, CH ), 1.77–1.86 (m, 2 H, 2 ×
R
3
1
CH), 2.04 (s, 2 H, 2 × OH), 2.38 (s, 6 H, 2 × CH ), 2.49 (s, 3
3
3
7.0 Hz, CH ), 0.99, 1.02 (d, 3 H, J = 7.0 Hz, CH ), 2.22–2.38
H, CH ), 2.55 (s, 3 H, CH ), 2.98 (br s, 2 H, 2 × OH), 3.50–
3
3
3
3
(
4
m, 2 H, 2 × CH), 3.68–3.90 (m, 6 H, 2 × CH and 2 × OH),
3.62 (m, 4 H, 2 × CH ), 4.55, 4.60 (d, 1 H, J = 9.4 Hz, CH),
2
2
.86, 4.89 (d, 1 H, J = 6.8 Hz, CH), 5.16 (d, 1 H, J = 2.8 Hz,
4.95, 4.98 (d, 1 H, J = 5.0 Hz, CH), 7.20–7.23 (m, 4 H, 2 ×
2Ar-H), 7.43, 7.47 (d, 2 H, J = 8.0 Hz, 2 Ar-H), 7.54, 7.58
CH), 6.59 (s, 2 H, 2 × =CH), 7.43–7.46 (m, 6 H, 2 × 3Ar-H),
1
3
+
7
.79–7.82 (m, 4 H, 2 × 2 Ar-H); C NMR (CDCl , 50.32
(d, 2 H, J = 8.0 Hz, 2 Ar-H); Mass (FAB+) m/z 262 (M + 1).
3
MHz) 11.05 (CH ), 13.68 (CH ), 39.76 (CH), 39.95 (CH),
Anal. calcd for C H NO : C, 68.94; H, 7.33; N, 5.36.
3
3
15 19
4
6
6.21 (CH ), 66.78 (CH ), 70.55 (CH), 72.43 (CH), 100.22
Found: C, 69.18; H, 7.22; N, 5.14%.
2
2
(
(
1
CH), 100.35 (CH), 127.22 (4 × CH), 129.21 (C), 129.25
1-[3-(2-Chloro-phenyl)-5-methyl-isoxazol-4-yl]-
propane-1,3-diol (entry 14): IR (Neat, cm ) 3377 (OH); H
–
1
1
C), 129.3 (4 × CH), 130.4 (2 × CH), 162.6 (C), 162.7 (C),
+
74.8 (C), 174.9 (C); Mass (FAB+) m/z 234 (M + 1). Anal.
NMR (CDCl , 200 MHz) d 0.55, 0.58 (d, 3 H, J = 7.0 Hz,
3
calcd for C H NO : C, 67.45; H, 7.68; N, 5.62. Found C,
CH ), 0.88, 0.91 (d, 3 H, J = 7.0 Hz, CH ), 1.67–1.72 (m, 1
14
12
2
3
3
67.36; H, 7.64; N, 6.00%.
H, CH), 1.93–1.97 (m, 1 H, CH), 2.57 (s, 3 H, CH ), 2.59 (s,
3
Synlett 2003, No. 11, 1611–1614 © Thieme Stuttgart · New York

1
614
A. Patra et al.
LETTER
IR (Neat, cm ) 1722 (CO Me); H NMR (CDCl , 200 MHz)
–
1
1
3
H, CH ), 3.07 (s, 2 H, 2 × OH), 3.51–3.65 (m, 4 H, 2 ×
3
2
3
CH ), 4.33, 4.38 (d, 1 H, J = 9.6 Hz, CH), 4.73, 4.75 (d, 1 H,
d 2.42 (s, 3 H, CH ), 3.33 (s, 2 H, CH ), 3.67 (s, 3 H,
2
3
2
J = 4.4 Hz, CH), 7.35–7.52 (m, 8 H, 2 × 4Ar-H); Mass
FAB+) m/z 282 (M + 1). Anal. calcd for C H ClNO : C,
CO Me), 5.14 (s, 1 H, =CH ), 6.02 (s, 1 H, =CH ), 7.29–7.49
2 2 2
+
+
(
(m, 4 H, Ar-H); Mass (FAB+) m/z 292 (M + 1). Anal. calcd
1
3
14
3
58.32; H, 5.27; N, 5.23. Found C, 58.31; H, 5.22; N, 5.44%.
for C H ClNO : C, 61.76; H, 4.84; N, 4.80. Found: C,
1
5
14
3
1
-[3-(2,4-Dichloro-phenyl)-5-methyl-isoxazol-4-yl]-
61.56; H, 4.99; N, 5.04%.
2-Methyl-3-(3-nitro-phenyl)-propionic acid methyl
–
1
1
propane-1,3-diol (entry 15): IR (Neat, cm ) 3402 (OH); H
–
1
NMR (CDCl , 200 MHz) d 0.54, 0.58 (d, 3 H, J = 7.0 Hz,
ester(6a) Yield: 77% as pale yellow oil; IR (Neat, cm )
3
1
CH ), 0.87, 0.91 (d, 3 H, J = 7.0 Hz, CH ), 1.83–2.10 (m, 2
1717 (CO Me); H NMR (CDCl , 200 MHz) d 1.91, 1.22 (d,
3 H, J = 6.6 Hz, CH ), 2.77–2.86 (m, 2 H, CH ), 3.06–3.14
(m, 1 H, CH), 3.65 (s, 3 H, CO Me), 7.45–7.88 (m, 2 H, Ar-
H), 8.05–8.10 (d merged into s, 2 H, Ar-H); Mass (FAB+) m/
3
3
2
3
H, 2 × CH), 2.55 (s, 3 H, CH ), 2.58 (s, 3 H, CH ), 2.73 (br
3
3
3
2
s, 2 H, 2 × OH), 3.34 (br s, 2 H, 2 × OH), 3.46–3.72 (m, 4 H,
2
2
1
7
3
4
× CH ), 4.33, 4.38 (d, 1 H, J = 9.6 Hz, CH), 4.72, 4.74 (d,
2
+
H, J = 4.4 Hz, CH), 7.31–7.35 (m, 4 H, 2 × 2Ar-H), 7.51,
.52 (2 s almost merged, 2 H, 2 × Ar-H); Mass (FAB+) m/z
z 224 (M + 1). Anal. calcd for C H NO : C, 61.27; H,
1
2
13
4
5.57; N, 5.95. Found: C, 60.99; H, 5.61; N, 6.04%.
3-[3-(2-Chloro-phenyl)-5-methyl-isoxazol-4-yl]-2-
methyl-propionic acid methyl ester(6b) Yield: 88% as
+
16 (M + 1). Anal. calcd for C H Cl NO : C, 51.68; H,
1
3
13
2
3
.34; N, 4.64. Found: C, 51.51; H, 4.39; N, 4.50%.
–
1
1
(
(
7) Padhi, S. K.; Chadha, A. Synlett 2003, 639.
pale yellow oil; IR (Neat, cm ) 1722 (CO Me); H NMR
2
8) (a) Periasamy, M.; Thirumalaikumar, M. J. Organomet.
Chem. 2000, 609, 137. (b) Khanapure, S. P.; Saha, G.;
Sivendran, S.; Powell, W. S.; Rokacha, J. Tetrahedron Lett.
(CDCl , 200 MHz) d 0.88, 0.91 (d, 3 H, J = 6.6 Hz, CH ),
3
3
1.15–1.19 (m, 1 H, CH), 2.18–2.39 (m, 4 H, s of CH merged
3
with m of 1 H of CH ), 2.55–2.70 (m, 1 H of CH ), 3.57 (s,
2
2
2
000, 41, 5653. (c) Barnett, J. E. G.; Kent, P. W. J. Chem.
3 H, CO Me), 7.20–7.39 (m, 4 H, Ar-H); Mass (FAB+) m/z
2
+
Soc. 1963, 2743. (d) Tsuboi, S.; Furutani, H.; Utaka, M.;
Takeda, A. Tetrahedron Lett. 1987, 28, 2709.
294 (M + 1). Anal. calcd for C H ClNO : C, 61.33; H,
1
5
16
3
5.49; N, 4.77. Found: C, 61.21; H, 5.38; N, 4.87%.
(10) 3-Hydroxy-2-(4-methyl-piperazin-1-ylmethyl)-3-(3-
nitro-phenyl)-propionic acid ethyl ester(7) Yield: 97% as
(
9) General Procedure for DABCO-mediated Reaction of
NaBH with Acetate of Baylis–Hillman Adducts. To the
4
–
1
1
solution of appropriate acetate (2 mmol) obtained from the
Baylis–Hillman adducts in THF:water (3 mL, 1:1, v/v) was
added DABCO (0.22 g, 2 mmol) and the reaction was
allowed to proceed at r.t. As soon as the solution becomes
pale yellow oil; IR (Neat, cm ) 1727 (CO Et); H NMR
2
(CDCl , 200 MHz) d 0.95 (2t merged, 6 H, J = 7.0 Hz, 2 ×
3
CH ), 2.31 (s, 6 H, 2 × NCH ), 2.52–3.13 (m, 20 H, 2 ×
3
3
5CH ), 3.89 (q, 4 H, J = 7.0 Hz, CO CH ), 5.08, 5.13 (d, 1
2
2
2
clear (ca 15 min), NaBH (0.08 g, 2 mmol) was added with
H, J = 8.8 Hz, CH), 5.44, 5.46 (d, 1 H, J = 4.4 Hz, CH), 7.44–
7.70 (m, 4 H,2 × 2Ar-H), 8.12, 8.16 (d 2 H, J = 8.0 Hz, 2 ×
4
stirring. The reaction was complete in 15 min., after which
the reaction mixture was extracted with ethyl acetate and
usual work up of the organic layer furnished a residue. This
residue upon filtration through a small band of silica gel
afforded the desired compounds as oils. These compounds
+
Ar-H), 8.28 (s, 2 H, 2 × Ar-H); Mass (FAB+) m/z 224 (M +
1). Anal. calcd for C H N O : C, 58.11; H, 7.17; N, 11.96.
1
7
25
3
5
Found: C, 57.91; H, 7.57; N, 12.08%.
2-(4-Methyl-piperazin-1-ylmethyl)-1-(3-nitro-phenyl)-
propane-1,3-diol(8) Yield: 82% as pale red yellow oil; IR
were subjected to reduction with NaBH as described earlier.
4
–
1
1
2
-(3-Nitro-benzyl)-acrylic acid ethyl ester(5a) Yield: 94%
(Neat, cm ) 3345 (OH); H NMR (CDCl , 200 MHz) d
3
–
1
1
as pale yellow oil; IR (Neat, cm ) 1718 (CO Et); H NMR
1.99–2.06 (m, 1 H, CH), 2.27 (s, 3 H, CH ), 2.32–2.91 (m,
2
3
(
2
=
CDCl , 200 MHz) d 1.26 (t, 3 H, J = 7.0 Hz, CH ), 3.73 (s,
10 H, 5 × N-CH ), 3.36–3.48 (m, 2 H, CH ), 4.86, 4.90 (d, 1
3
3
2
2
H, CH ), 4.18 (q, 2 H, J = 7.0 Hz, CO CH ), 5.59 (s, 1 H,
H, J = 8.0 Hz, CH), 7.50 (t, 1 H, J = 8.0 Hz, Ar-H), 7.69, 7.73
2
2
2
CH ), 6.31 (s, 1 H, =CH ), 7.42–7.58 (m, 2 H, Ar-H), 8.09
(d, 1 H, J = 8.0 Hz, Ar-H), 8.10, 8.14 (dt, 1 H, J = 2.0 Hz,
2
2
1
1
3
13
(
s, 2 H, Ar-H); C NMR (CDCl , 50.32 Hz) d 14.45 (CH),
8.29 (CH ), 61.34 (CH ), 121.88 (CH), 124.12 (CH),
J2 = 8.0 Hz, Ar-H), 8.25 (s, 1 H, Ar-H); C NMR (CDCl3,
3
3
1
1
50.32 Hz) d 43.60 (CH), 46.23 (CH ), 53.83 (CH ), 55.37 (2
2
2
3
2
27.46 (CH ), 129.64 (CH), 135.58 (CH), 139.43 (C),
× CH ), 61.13 (2 × CH ), 63.29 (CH ), 76.47 (CH), 122.13
2
2
2
2
41.50 (C), 148.73 (C), 166.60 (C); Mass (FAB+) m/z 236
(CH), 122.94 (CH), 129.57 (CH), 133.34 (CH), 145.94 (C),
+
+
(
M +1). Anal. calcd for C H NO : C, 61.27; H, 5.57; N,
148.74 (C); Mass (FAB+) m/z 310 (M + 1). Anal. calcd for
1
2
13
4
5.95. Found: C, 60.99; H, 5.61; N, 6.04%.
C H N O : C, 58.24; H, 7.49; N, 13.58. Found: C, 57.99;
1
5
23
3
4
2-[3-(2-Chloro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-
H, 7.38; N, 13.76%.
acrylic acid methyl ester(5b) Yield: 92% as pale yellow oil;
Synlett 2003, No. 11, 1611–1614 © Thieme Stuttgart · New York