Facile Baylis-Hillman Reaction of Substituted 3-Isoxazolecarbaldehydes: The Impact of a Proximal Heteroatom Within a Heterocycle on the Acceleration of the Reaction

Article abstract of DOI:10.1055/s-2003-41072

The fast and facile Baylis-Hillman reaction in substituted 3-isoxazolecarbaldehydes confirms the impact of the proximal heteroatom within a heterocycle towards enhanced reactivity of the formyl group for this reaction.

Full text of DOI:10.1055/s-2003-41072

PAPER
2325
Facile Baylis–Hillman Reaction of Substituted 3-Isoxazolecarbaldehydes: The
Impact of a Proximal Heteroatom Within a Heterocycle on the Acceleration of
the Reaction1
B
aylis–Hillman Re
m
action of Substitute
r
d 3-Isox
e
a
zolecarba
l
n
dehydes dra K. Roy, Sanjay Batra*
Medicinal Chemistry Division, Central Drug Research Institute, PO Box 173, Lucknow-226001, India
Fax +91(522)2223405; E-mail: batra_san@yahoo.co.uk
Received 4 July 2003
The substituted 3-isoxazolecarbaldehydes were prepared
Abstract: The fast and facile Baylis–Hillman reaction in substitut-
ed 3-isoxazolecarbaldehydes confirms the impact of the proximal
heteroatom within a heterocycle towards enhanced reactivity of the
formyl group for this reaction.
by following the synthetic strategy reported earlier.5 This
strategy involved the reaction of various substituted ace-
tophenones 1a–d with diethyl oxalate in the presence of
sodium hydride (60% in oil) (Scheme 1). The resulting
2,4-diketo esters 2a–d on treatment with hydroxylamine
hydrochloride furnished substituted 3-isoxazole esters
3a–d in excellent yields. These esters were reduced with
lithium aluminum hydride and the resulting alcohols 4a–
d were oxidized with pyridinium chlorochromate to yield
the desired substituted 3-isoxazolecarbaldehydes 5a–d.
These aldehydes 5a–d were then treated with various ac-
tivated alkenes in the presence of DABCO and in the ab-
sence of any solvent to furnish the Baylis–Hillman
adducts 6a–d, 9a–d, 10a–c and 11a–c in excellent yields
(Table 1). Contrary to the findings with their correspond-
ing 5-isomer,6 we failed to isolate ether derivatives in re-
actions of these aldehydes. The substituted 3-
isoxazolecarbaldehydes also undergo fast reaction with
acrylamide in the presence of DABCO and with cyclohex-
enone in the presence of DMAP (14a–d).
Key words: Baylis–Hillman reaction, aldehydes, heterocycles,
isoxazoles, alkenation
The Baylis–Hillman reaction has been identified as a nov-
el C–C bond forming reaction for delivering a wide array
of useful derivatives in solution and solid phase.2 The fast
reacting substrates for Baylis–Hillman reaction is of inter-
est since they help to expedite the process of exploring
and studying various synthetic and mechanistic aspects of
the reaction. We reported3 earlier that the substituted 5-
isoxazolecarbaldehydes were fast reacting electrophiles
for the Baylis–Hillman reaction and the reason ascribed
for the fast reactivity was concerned with the proximity of
the formyl group with the heteroatom (Figure 1). On the
basis of similar reasoning, it was also envisaged in our
earlier report4 that substituted 3-isoxazolecarbaldehydes
would also be fast reacting electrophiles in Baylis–Hill-
man reaction. To substantiate this hypothesis on the basis
of experimental evidence, the synthesis and Baylis–Hill-
man reaction of substituted 3-isoxazolecarbaldehydes
were undertaken. As expected, these substrates undergo
very fast and facile Baylis–Hillman reaction in solution
with a variety of alkenes under conventional conditions
and their solid phase reactions were also efficient under
ordinary conditions. The details of our results are being
presented here.
Reactions of substituted 3-isoxazolecarbaldehydes 5a–c
with the acrylate resins derived from the Wang resins led
to the assessment of their reactivity towards Baylis–Hill-
man reaction on the solid phase. Similar to the reactions
in solution phase, these aldehydes undergo fast Baylis–
Hillman reaction on solid phase to yield the desired prod-
ucts 16a–c in excellent yields and high purity (Scheme 2).
In an attempt to study the comparative reactivity of 3-, 4-
and 5-isoxazolecarbaldehydes, the profiling of the
progress of the reaction on the basis of the formation of
Baylis–Hillman adducts at different time intervals was
carried out with the help of HPLC (Table 2). However, no
significant difference was observed for the reactivities of
3- and 5–isoxazolecarbaldehydes towards Baylis–Hill-
man reaction. Compared to these situations, reaction of
substituted 4-isoxazolecarbaldehydes was sluggish and
after 45 minutes only a small fraction of the aldehyde was
converted to the adduct. These results provide experimen-
tal evidence to support the hypothesis that the presence of
a proximal heteroatom within a heterocycle does facilitate
the elimination of the base from the intermediate
(Figure 1) and accelerates the reaction. However, this
study does not provide a clue to comment on the possible
contribution of basicity of the heteroatom towards accel-
eration of the reaction.7
( )n
( )n
( )n
H
H
H
Y
Y
+
Y
O-
O-
OH
X
X
X
H
EWG
H
EWG
EWG
+
B
C
A
N
+
N
N
N
X= O, S, N
Y=N, CH
n=1, 2
Figure 1 Proton abstraction is aided by the lone pair of the hetero
atom leading to immediate release of the base (published earlier).4
SYNTHESIS 2003, No. 15, pp 2325–2330
x
x.
x
x
.
2
0
0
3
Advanced online publication: 23.09.2003
DOI: 10.1055/s-2003-41072; Art ID: P05803SS
© Georg Thieme Verlag Stuttgart · New York

2326
A. K. Roy, S. Batra
PAPER
O
O
O
N
O
O
N
c
b
a
CH2OH
R
CO2Et
R
R
R
CH3
1a–d
CO2Et
4a–d
3a–d
2a–d
O
N
O
N
d
e
Compd. R
no.
Compd. R'
no.
R
EWG
CHO
R
a
b
c
d
C6H5
6
CO2CH3
6–9a–d,
10–11a–c
OH
5a–d
4-Me-C6H4
4-Br-C6H4
4-F-C6H4
7
8
9
CO2CH2CH3
CO2(CH2)3CH3
CN
O
N
f
10
11
CONH2
CO2C(CH3)3
R
OH
O
14a–d
Scheme 1 Reagents and conditions: a) diethyl oxalate, NaH, toluene, reflux, 1.5 h; b) NH2OH·HCl, EtOH, reflux, 1 h; c) LiAlH4, Et2O, reflux,
30 min; d) PCC, CH2Cl2, r.t., 5 h; e) CH2=CHEWG, DABCO, 15–30 min; f) cyclohexenone, DMAP, dioxane–H2O (2:1), r.t., 1 h.
O
O
N
N
R
R
O
N
b
O
a
O
HO2C
+
R
CHO
O
O
OH
OH
16a-c
15a-c
Scheme 2 Reagents and conditions: a) DABCO, DMSO, 3 h, r.t., 600 rpm; b) CH2Cl2–TFA (1:1), 1 h, r.t.
graphy can be circumvented resulting in decrease of yields of final
products by 2–4%). To the solution of appropriate 2,4-diketo ester
2a–d (0.03 mol) in EtOH (75 mL) was added NH2OH·HCl (6.25 g,
0.09 mol) and the reaction mixture was refluxed under stirring for 1
h. The reaction mixture was cooled to 10–12 °C and the separated
solid product was filtered. The yield of esters 3a–d ranged between
72–75%. To the solution of the appropriate ester (0.019 mol) in an-
hyd Et2O was added LiAlH4 (1.13 g, 0.029 mol) and the reaction
mixture was stirred for 30 min at 40 °C. The reaction mixture was
decomposed with aq NaOH solution (10%) and the separated solid
was filtered and washed with EtOAc. The filtrate was dried and con-
centrated to obtain alcohols 4a–d (82–87%), which were used with-
out any purification. To the solution of appropriate alcohol 4a–d
(0.02 mol) in anhyd CH2Cl2 was added PCC (6.4 g, 0.03 mol) and
the reaction mixture was stirred at r.t. On completion (approx. 5 h)
the reaction mixture was passed through a small band of silica gel
(hexane–EtOAc, 85:15) to obtain the pure substituted 3-isoxazole-
carbaldehydes 5a–d as solids in 78–81% yields.
In conclusion, we have described the fast and efficient
Baylis–Hillman reaction of substituted 3-isoxazolecarbal-
dehydes with variety of alkenes. The results of the present
study support our hypothesis proposed earlier that a prox-
imal heteroatom within the heterocycle does contribute
towards acceleration of the Baylis–Hillman reaction. This
may in turn prove important for predicting the reactivity
of the formyl group for Baylis–Hillman reaction in other
heterocyclic systems.
Mps are uncorrected and were determined in capillary tubes on a hot
stage apparatus containing silicon oil. IR spectra were recorded us-
ing Perkin–Elmer’s Spectrum RX I FTIR spectrophotometer as KBr
1
disc or neat. H NMR spectra were recorded either on a Bruker
DPX-200 FT or Bruker Avance DRX-300 spectrometers, using
TMS as an internal standard (chemical shifts in values, J in Hz).
The ESMS were recorded through direct flow injections in Merck
M-8000 LCMS system and FABMS were recorded on a JEOL/ SX-
102 spectrometer. Elemental analyses were performed on Elemen-
tar’s Vario EL III microanalyzer. All HPLC were carried out on Ag-
ilent 1100 automated system having a PDA detector ( max = 220
nm, 254 nm used for this study) using a gradient run of 0–100%
MeCN in H2O containing 0.1% TFA in 25 min on a RP-18e column
(150 × 4.6 mm) having particle size of 5 m.
Baylis–Hillman Reaction; General Procedure
To a mixture of DABCO (0.15 g, 0.0013 mol) and appropriate alk-
ene (0.0053 mol) that had been stirred at r.t. for 10 min was added
the appropriate aldehyde 5a–d (0.0053 mol) under stirring and the
reaction was allowed to proceed for 10–30 min. Thereafter aq HCl
(5%; 50 mL) was added to the reaction mixture to neutralize the
base, and the mixture was extracted with EtOAc (2 × 50 mL). The
organic layers were combined, washed with brine (75 mL), dried
(Na2SO4) and evaporated under vacuum to yield an oily residue.
The residue upon trituration with hexane furnished pure products.
However analytically pure samples were obtained by passing them
through a small band of silica gel (60–120 mesh) (hexane–EtOAc,
75:25).
Substituted 3-Isoxazolecarbaldehydes 5a–d; General Proce-
dure
To the solution of appropriately substituted acetophenone (0.083
mol) in anhyd toluene (200 mL) was added a suspension of NaH in
oil (60%; 6.4g, 0.16 mol) in portions and the mixture was warmed
to 45–50 °C under stirring. At this temperature a solution of diethyl
oxalate (17 mL, 0.124 mol) in anhyd toluene (50 mL) was added
dropwise under stirring. The reaction mixture was refluxed for an-
other 1.5 h. Thereafter, the reaction mixture was filtered and the fil-
trate was concentrated and column chromatographed (hexane–
EtOAc, 80:20) to remove the oil of NaH and obtain the pure 2,4-
diketo ester derivatives 2a–d in 90–95% yield (column chromato-
2-[Hydroxy-(5-phenylisoxazol-3-yl)methyl]acrylic Acid Methyl
Ester (6a)
1H NMR (CDCl3, 200 MHz): = 3.62, 3.65 (d, 1 H, J = 7.2 Hz,
OH), 3.80 (s, 3 H, CO2Me), 5.66, 5.69 (d, 1 H, J = 7.0 Hz, CH), 6.01
(s, 1 H, =CHH), 6.43 (s, 1 H, =CHH), 6.59 (s, 1 H, =CH), 7.43–7.45
(m, 3 H, ArH), 7.74–7.79 (m, 2 H, ArH).
Synthesis 2003, No. 15, 2325–2330 © Thieme Stuttgart · New York

PAPER
Baylis–Hillman Reaction of Substituted 3-Isoxazolecarbaldehydes
2327
Table 1 Characterization Data for Baylis–Hillman Adducts of Substituted 3-Isoxazolecarbaldehydes
Compd
6a
R
EWG
CO2Me
CO2Me
CO2Me
CO2Me
CO2Et
CO2Et
CO2Et
CO2Et
CO2Bu
CO2Bu
CO2Bu
CO2Bu
CN
Yield (%)a Mp (°C)
Mass (ES+) m/z
260 (M+ + 1)
IR (cm–1)
Ph
90
97–99
98–100
95–96
1721 (ester C=O), 3337 (OH)
1723 (ester C=O), 3315 (OH)
1711 (ester C=O), 3493 (OH)
1716 (ester C=O), 3473 (OH)
1715 (ester C=O), 3342 (OH)
1717 (ester C=O), 3397(OH)
1706 (ester C=O), 3485 (OH)
1712 (ester C=O), 3403 (OH)
1717 (ester C=O), 3345 (OH)
1719 (ester C=O), 3305 (OH)
1707 (ester C=O), 3496 (OH)
1712 (ester C=O), 3419 (OH)
2226 (C≡N), 3345 (OH)
6b
4-Me-C6H4
4-Br-C6H4
4-F-C6H4
Ph
93
296.40 (M+ + Na)
360.27 (M+ + Na)
300.47 (M+ + Na)
296.33 (M+ + Na)
310.33 (M+ + Na)
374.27 (M+ + Na)
6c
89
6d
85
103–104
71–72
7a
89
7b
4-Me-C6H4
4-Br-C6H4
4-F-C6H4
Ph
88
81–83
7c
83
85–86
7d
77
Oil (pale yellow) 314.40 (M+ + Na)
8a
90
67–70
77–78
81–83
324.33 (M+ + Na)
338.27 (M+ + Na)
402.20 (M+ + Na)
8b
4-Me-C6H4
4-Br-C6H4
4-F-C6H4
Ph
90
8c
89
8d
81
Oil (pale yellow) 342.40 (M+ + Na)
9a
91
135–136
133–134
139–140
105–107
139–140
163–164
154–156
227.07 (M+ + 1)
241.00 (M+ + Na)
304.67 (M+ + 1)
245.22 (M+ + 1)
267.27 (M+ + Na)
281.40 (M+ + Na)
323.33 (M+ + 1)
9b
4-Me-C6H4
4-Br-C6H4
4-F-C6H4
Ph
CN
93
2227 (C≡N), 3273 (OH)
9c
CN
90
2224 (C≡N), 3306 (OH)
9d
CN
90
2232 (C≡N), 3396 (OH)
10a
10b
10c
11a
11b
11c
14a
14b
14c
14d
16a
16b
16c
CONH2
CONH2
CONH2
CO2-t-Bu
CO2-t-Bu
CO2-t-Bu
–
79
1660 (amide C=O), 3199 (NH2), 3387 (OH)
1658 (amide C=O), 3199 (NH2), 3392 (OH)
1662 (amide C=O), 3196 (NH2), 3400 (OH)
1711 (ester C=O), 3308 (OH)
1704 (ester C=O), 3349 (OH)
1707 (ester C=O), 3371 (C=O)
1659 (C=O), 3405 (OH)
4-Me-C6H4
4-Br-C6H4
Ph
81
77
88
Oil (pale yellow) 324.23 (M+ + Na)
4-Me-C6H4
4-Br-C6H4
Me
84
85–86
82–83
338.13 (M+ + Na)
402.20 (M+ + Na)
270 (M+ + 1)b
80
90
96–98
4-Me-C6H4
4-Br-C6H4
4-F-C6H4
Ph
–
90
103–104
87–88
284 (M+ + 1)b
1650 (C=O), 3366 (OH)
–
84
370.20 (M+ + Na)
1623 (C=O), 3417 (OH)
–
79
Oil (pale yellow) 288 (M+ + 1)b
1667 (C=O), 3399 (OH)
–
89 (94)
95 (99)c
93 (99)c
191–192
179–181
139–140
268.40 (M+ + Na)
282.33 (M+ + Na)
346.33 (M+ + Na)
1690 (acid C=O), 3332 (OH)
1690 (acid C=O), 3313 (OH)
1690 (acid C=O), 3387 (OH)
4-Me-C6H4
4-Br-C6H4
–
–
a All compounds were obtained as white solids except where stated otherwise.
b FABMS.
c Analytical HPLC of the crude product show single peak.
13C NMR (CDCl3, 50.32 MHz): = 52.57 (CH3), 67.82 (CH), 98.48
(CH), 126.24 (2 CH), 127.71 (C), 127.95 (CH2), 129.34 (2 CH),
130.65 (CH), 139.67 (C), 165.87 (C), 166.85 (C), 170.72 (C).
Anal. Calcd for C14H13NO4: C, 64.86; H, 5.05; N, 5.40. Found: C,
64.82; H, 5.17; N, 5.13.
Synthesis 2003, No. 15, 2325–2330 © Thieme Stuttgart · New York

2328
A. K. Roy, S. Batra
PAPER
Table 2 Evaluation of the Reactivities of 3,4,5-Isoxazolecarbaldehydes (ICD)a with the Help of Analytical HPLCb
Time
(min)
Formation of BH products with methyl acrylate (%)
Time
(min)
Formation of BH products with acrylonitrile (%)
3-ICD
H
4-ICD
H
5-ICD
H
3-ICD
H
4-ICD
H
5-ICD
H
4-Me
4-Me
100:0
100:0
100:0
100:0
100:0
99:1
4-Me
4-Me
4-Me
100:0
100:0
100:0
98:2
4-Me
5
10
20
25
35
45
5:95
Cc
–
9:91
C
100:0
100:0
100:0
100:0
100:0
99:1
4:96
C
10:90
5
10
20
25
35
45
2:98
C
5:95
C
100:0
100:0
100:0
99:1
1:99
C
1:99
C
C
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
96:4
96:4
–
–
–
–
–
–
–
96:4
97:3
–
–
a All reactions were performed under neat conditions using same amount of substrates and reactants. The ratios expressed are of starting sub-
strate to product formed.
b The HPLC were performed at max of 220 and 254 nm at a gradient run of 0–100% MeCN in H2O containing 0.1% TFA in 25 min on a RP-
18e column (150 × 4.6mm) having a particle size of 5 m.
c Complete. Blank columns indicate no change in HPLC profile after completion.
2-[Hydroxy-(5-p-tolylisoxazol-3-yl)methyl]acrylic Acid Methyl
Ester (6b)
2-[Hydroxy-(5-p-tolylisoxazol-3-yl)methyl]acrylic Acid Ethyl
Ester (7b)
1H NMR (CDCl3, 200 MHz): = 2.39 (s, 3 H, CH3), 3.60, 3.64 (d,
1 H, J = 7.2 Hz, OH), 3.80 (s, 3 H, CO2Me), 5.65, 5.69 (d, 1 H,
J = 7.2 Hz, CH), 6.01 (s, 1 H, =CHH), 6.43 (s, 1 H, =CHH), 6.54 (s,
1 H, =CH), 7.23, 7.27 (d, 2 H, J = 8.0 Hz, ArH), 7.63, 7.67 (d, 2 H,
J = 8.0 Hz, ArH).
1H NMR (CDCl3, 200 MHz): = 1.20 (t, 3 H, J = 7.0 Hz, CH3),
2.33 (s, 3 H, CH3), 3.71, 3.74 (d, 1 H, J = 7.0 Hz, OH), 4.22 (q, 2 H,
J = 7.0 Hz, CO2CH2), 5.72 (s, 1 H, CH), 6.03, 6.05 (d, 1 H, J = 3.0
Hz, =CHH), 6.40, 6.41 (s, 1 H, J = 2.8 Hz, =CHH), 6.53 (s, 1
H, = CH), 7.20, 7.24 (d, 2 H, J = 8.0 Hz, ArH), 7.58–7.62 (d, 2 H,
J = 8.0 Hz, ArH).
Anal. Calcd for C15H15NO4: C, 65.92; H, 5.53; N, 5.13. Found: C,
66.10; H, 5.52; N, 5.11.
13C NMR (CDCl3, 50.32 MHz): = 14.40 (CH3), 21.78 (CH3),
61.56 (CH2), 67.17 (CH), 97.98 (CH), 125.00 (C), 126.14 (2 CH),
127.40 (CH2), 129.98 (2 CH), 140.24 (C), 140.86 (C), 165.99 (C),
166.32 (C), 170.71 (C).
2-{[5-(4-Bromophenyl)isoxazol-3-yl]hydroxymethyl}acrylic
Acid Methyl Ester (6c)
1H NMR (CDCl3, 200 MHz): = 3.79 (br s of OH merged with s of
CO2Me, 4 H, OH and CO2Me), 5.68 (s, 1 H, CH), 6.03 (s, 1 H,
CHH), 6.44 (s, 1 H, CHH), 6.60 (s, 1 H, =CH), 7.60 (s, 4 H, ArH).
Anal. Calcd for C16H17NO4: C, 66.89; H, 5.96; N, 4.88. Found: C,
67.15; H, 5.91; N, 4.86.
Anal. Calcd for C14H12BrNO4: C, 49.73; H, 3.58; N, 4.14. Found: C,
50.06; H, 3.88; N, 4.07.
2-{[5-(4-Bromophenyl)isoxazol-3-yl]hydroxymethyl}acrylic
Acid Ethyl Ester (7c)
1H NMR (CDCl3, 200 MHz): = 1.30 (t, 3 H, J = 7.2 Hz, CH3),
3.71, 3.74 (d, 1 H, J = 5.4 Hz, OH), 4.25 (q, 2 H, J = 7.2 Hz,
CO2CH2), 5.65, 5.68 (d, 1 H, J = 5.2 Hz, CH), 6.00 (s, 1 H, =CHH),
6.43 (s, 1 H, =CHH), 6.61 (s, 1 H, =CH), 7.60 (s, 4 H, ArH).
2-{[5-(4-Fluorophenyl)isoxazol-3-yl]hydroxymethyl}acrylic
Acid Methyl Ester 6d)
1H NMR (CDCl3, 200 MHz): = 3.59, 3.62 (d, 1 H, J = 7.8 Hz,
OH), 3.81 (s, 3 H, CO2Me), 5.64, 5.68 (d, 1 H, J = 7.4 Hz, CH), 6.01
(s, 1 H, =CHH), 6.43 (s, 1 H, =CHH), 6.55 (s, 1 H, =CH), 7.10–7.19
(m, 2 H, ArH), 7.72–7.79 (m, 2 H, ArH).
Anal. Calcd for C15H14BrNO4: C, 51.16; H, 4.01; N, 3.98. Found: C,
50.94; H, 4.05; N, 3.91.
Anal. Calcd for C14H12FNO4: C, 60.65; H, 4.36; N, 5.05. C, 60.36;
H, 4.36; N, 4.80.
2-{[5-(4-Fluorophenyl)isoxazol-3-yl]hydroxymethyl}acrylic
Acid Ethyl Ester (7d)
1H NMR (CDCl3, 200 MHz): = 1.30 (t, 3 H, J = 7.2 Hz, CH3),
3.77 (br s, 1 H, OH), 4.25 (q, 2 H, J = 7.2 Hz, CO2CH2), 5.66 (s, 1
H, CH), 5.99 (s, 1 H, =CHH), 6.43 (s, 1 H, =CHH), 6.55 (s, 1
H, =CH), 7.10–7.19 (m, 2 H, ArH), 7.72–7.79 (m, 2 H, ArH).
2-[Hydroxy-(5-phenylisoxazol-3-yl)methyl]acrylic Acid Ethyl
Ester (7a)
1H NMR (CDCl3, 200 MHz): = 1.31 (t, 3 H, J = 7.0 Hz, CH3),
3.71, 3.74 (d, 1 H, J = 7.0 Hz, OH), 4.25 (q, 2 H, J = 7.0 Hz,
CO2CH2), 5.66, 5.69 (d, 1 H, J = 6.0 Hz, CH), 5.99 (s, 1 H, =CHH),
6.43 (s, 1 H, =CHH), 6.60 (s, 1 H, =CH), 7.43–7.48 (m, 3 H, ArH),
7.74–7.79 (m, 2 H, ArH).
Anal. Calcd for C15H14FNO4: C, 61.85; H, 4.84; N, 4.81. C, 61.55;
H, 5.06; N, 4.73.
2-[Hydroxy-(5-phenylisoxazol-3-yl)methyl]acrylic Acid Butyl
Ester (8a)
Anal. Calcd for C15H15NO4: C, 65.92; H, 5.53; N, 5.13. Found: C,
66.04; H, 5.61; N, 4.86.
1H NMR (CDCl3, 200 MHz): = 0.92 (t, 3 H, J = 7.2 Hz, CH3),
1.32–1.43 (m, 2 H, CH2), 1.58–1.68 (m, 2 H, CH2), 3.73, 3.76 (d, 1
Synthesis 2003, No. 15, 2325–2330 © Thieme Stuttgart · New York

PAPER
Baylis–Hillman Reaction of Substituted 3-Isoxazolecarbaldehydes
2329
H, J = 7.4 Hz, OH), 4.20 (t, 2 H, J = 6.6 Hz, CO2CH2), 5.66, 5.69
(d, 1 H, J = 7.0 Hz, CH), 5.99 (s, 1 H, = CHH), 6.43 (s, 1 H, =CHH),
6.60 (s, 1 H, =CH), 7.43–7.48 (m, 3 H, ArH), 7.74–7.79 (m, 2 H,
ArH).
Anal. Calcd for C13H9BrN2O2: C, 51.17; H, 2.97; N, 9.18. Found: C,
51.52; H, 2.95; N, 8.78.
2-{[5-(4-Fluorophenyl)isoxazol-3-yl]hydroxymethyl}acryloni-
trile (9d)
Anal. Calcd for C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C,
67.90; H, 6.26; N, 4.39.
1H NMR (CDCl3, 200 MHz): = 3.47 (s, 1 H, OH), 5.56 (s, 1 H,
CH), 6.17 (s, 1 H, =CHH), 6.26 (s, 1 H, =CHH), 6.61 (s, 1 H, =CH),
7.11–7.20 (m, 2 H, ArH), 7.73–7.80 (m, 2 H, ArH).
2-[Hydroxy-(5-p-tolylisoxazol-3-yl)methyl]acrylic Acid Butyl
Ester (8b)
Anal. Calcd for C13H9FN2O2: C, 63.93; H, 3.71; N, 11.47. Found:
C, 63.85; H, 4.01; N, 11.13.
1H NMR (CDCl3, 200 MHz): = 0.92 (t, 3 H, J = 7.2 Hz, CH3),
1.35–1.47 (m, 2 H, CH2), 1.57–1.68 (m, 2 H, CH2), 2.39 (s, 3 H,
CH3), 3.63, 3.66 (d, 1 H, J = 7.4 Hz, OH), 4.20 (t, 2 H, J = 6.6 Hz,
CO2CH2), 5.64, 5.68 (d, 1 H, J = 7.0 Hz, CH), 5.98 (s, 1 H, =CHH),
6.42 (s, 1 H, =CHH), 6.54 (s, 1 H, =CH), 7.23, 7.27 (d, 2 H, J = 8.0
Hz, ArH), 7.63–7.67 (d, 2 H, J = 8.0 Hz, ArH).
2-[Hydroxy-(5-phenylisoxazol-3-yl)methyl]acrylamide (10a)
1H NMR (CDCl3, 200 MHz): = 5.66, 5.69 (d, 1 H, J = 5.8 Hz,
OH), 5.75 (s, 1 H, =CHH), 5.94, 5.97 (d, 1 H, J = 6.0 Hz, CH), 6.12
(s, 1 H, =CHH), 6.65 (s, 1 H, =CH), 7.40–7.49 (m, 4 H, ArH and
NH2), 7.73–7.78 (m, 2 H, ArH).
Anal. Calcd for C18H21NO4: C, 68.55; H, 6.71; N, 4.44. Found: C,
68.71; H, 6.74; N, 4.44.
Anal. Calcd for C13H12N2O3: C, 63.93; H, 4.95; N, 11.47. Found: C,
63.86; H, 5.08; N, 11.64.
2-{[5-(4-Bromophenyl)isoxazol-3-yl]hydroxymethyl}acrylic
Acid Butyl Ester (8c)
2-[Hydroxy-(5-p-tolylisoxazol-3-yl)methyl]acrylamide (10b)
1H NMR (CDCl3, 200 MHz): = 2.50 (s, 3 H, CH3), 5.66 (s, 1 H,
OH),), 5.74 (s, 2 H, CH, =CHH), 6.12 (s, 1 H, =CHH), 6.58 (s, 1
H, =CH), 7.24, 7.27 (d, 2 H, J = 8.0 Hz, ArH), 7.34 (s, 1 H, NH2),
7.62, 7.66 (d, 2 H, J = 8.0 Hz, ArH).
1H NMR (CDCl3, 200 MHz): = 0.91 (t, 3 H, J = 7.2 Hz, CH3),
1.32–1.38 (m, 2 H, CH2), 1.61–1.68 (m, 2 H, CH2), 3.79, 3.82 (d, 1
H, J = 7.4 Hz, OH), 4.18 (t, 2 H, J = 6.2 Hz, CO2CH2), 5.65, 5.68
(d, 1 H, J = 7.4 Hz, CH), 5.98, 6.00 (d, 1 H, =CHH), 6.42 (s, 1 H,
=CHH), 6.60 (s, 1 H, =CH), 7.59 (s, 4 H, ArH).
Anal. Calcd for C14H14N2O3: C, 65.11; H, 5.46; N, 10.85. Found: C,
65.22; H, 5.56; N, 11.01.
13C NMR (CDCl3, 50.32 MHz): = 14.03 (CH3), 19.50 (CH2),
30.91 (CH3), 65.57 (CH2), 67.79 (CH), 98.95 (CH), 125.03 (C),
126.60 (C), 127.66 (CH2), 127.77 (2 CH), 132.64 (2 CH), 139.82
(C), 166.14 (C), 166.45 (C), 169.54 (C).
2-{[5-(4-Bromophenyl)isoxazol-3-yl]hydroxymethyl}acryla-
mide (10c)
1H NMR (CDCl3, 200 MHz): = 5.66, 5.69 (d, 1 H, J = 5.8 Hz,
OH), 5.75 (s, 1 H, =CHH), 5.92, 5.94 (d, 1 H, J = 5.2 Hz, CH), 6.12
(s, 1 H, =CHH), 6.66 (s, 1 H, =CH), 7.39 (s, 1 H, NH2), 7.61, 7.62
(d, J = 2.6 Hz, 3 H, ArH).
Anal. Calcd for C17H18BrNO4: C, 53.70; H, 4.77; N, 3.68. Found: C,
53.83; H, 4.72; N, 4.07.
2-{[5-(4-Fluorophenyl)isoxazol-3-yl]hydroxymethyl}acrylic
Acid Butyl Ester (8d)
Anal. Calcd for C13H11BrN2O3: C, 48.32; H, 3.43; N, 8.67. Found:
C, 48.25; H, 3.59; N, 8.88.
1H NMR (CDCl3, 300 MHz): = 0.92 (t, 3 H, J = 6.0 Hz, CH3),
1.26–1.44 (m, 2 H, CH2), 1.60–1.70 (m, 2 H, CH2), 3.74 (br s, 1 H,
OH), 4.20 (t, 2 H, J = 6.6 Hz, CO2CH2), 5.67 (s, 1 H, CH), 6.00 (s,
1 H, =CHH), 6.43 (s, 1 H, =CHH), 6.55 (s, 1 H, =CH), 7.157 (t, 2
H, J = 6.0 Hz, ArH), 7.73–7.77 (m, 2 H, ArH).
2-[Hydroxy-(5-phenylisoxazol-3-yl)methyl]acrylic Acid tert-
Butyl Ester (11a)
1H NMR (CDCl3, 200 MHz): = 1.47 [s, 9 H, C(CH3)3], 3.90 (br s,
1 H, OH), 5.65 (s, 1 H, CH), 5.92 (s, 1 H, =CHH), 6.34 (s, 1
H, =CHH), 6.59 (s, 1 H, =CH), 7.42–7.45 (m, 3 H, ArH), 7.73–7.78
(m, 2 H, ArH).
Anal. Calcd for C17H18FNO4: C, 63.94; H, 5.68; N, 4.39. Found: C,
63.88; H, 5.68; N, 4.38.
2-[Hydroxy-(5-phenylisoxazol-3-yl)methyl]acrylonitrile (9a)
1H NMR (CDCl3, 200 MHz): = 3.13 (s, 1 H, OH), 5.55, 5.57 (d, 1
H, J = 4.0 Hz, CH), 6.169, 6.175 (d, 1 H, J = 1.4 Hz, =CHH), 6.255,
6.262 (d, 1 H, J = 1.4 Hz, =CHH), 6.65 (s, 1 H, =CH), 7.45–7.50
(m, 3 H, ArH), 7.76–7.81 (m, 2 H, ArH).
Anal. Calcd for C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C,
67.71; H, 6.35; N, 4.55
2-[Hydroxy-(5-p-tolylisoxazol-3-yl)methyl]acrylic Acid tert-Bu-
tyl Ester (11b)
1H NMR (CDCl3, 300 MHz): = 1.48 [s, 9 H, C(CH3)3], 2.39 (s, 3
H, CH3), 3.79, 3.81 (d, 1 H, J = 7.2 Hz, OH), 5.61, 5.63 (d, 1 H,
J = 6.6 Hz, CH), 5.90 (s, 1 H, =CHH), 6.32 (s, 1 H, =CHH), 6.53 (s,
1 H, =CH), 7.24, 7.26 (d, 2 H, J = 7.8 Hz, ArH), 7.64–7.66 (d, 2 H,
J = 7.8 Hz, ArH).
Anal. Calcd for C13H10N2O2: C, 69.02; H, 4.46; N, 12.38. Found: C,
68.76; H, 4.52; N, 12.18.
2-[Hydroxy-(5-p-tolylisoxazol-3-yl)methyl]acrylonitrile (9b)
1H NMR (CDCl3, 200 MHz): = 2.41 (s, 3 H, CH3), 3.18 (s, 1 H,
OH), 5.55 (s, 1 H, CH), 6.17 (s, 1 H, =CHH), 6.248, 6.252 (d, 1 H,
J = 0.8 Hz, =CHH), 6.59 (s, 1 H, =CH), 7.25, 7.29 (d, 2 H, J = 8.0
Hz, ArH), 7.64, 7.68 (d, 2 H, J = 8.0 Hz, ArH).
Anal. Calcd for C18H21NO4: C, 68.55; H, 6.71; N, 4.44. Found:
68.40; H, 6.79; N, 4.07.
2-{[5-(4-Bromophenyl)isoxazol-3-yl]hydroxymethyl}acrylic
Acid tert-Butyl Ester (11c)
Anal. Calcd for C14H12N2O2: C, 69.99; H, 5.03; N, 11.66. Found: C,
69.84; H, 5.06; N, 11.57.
1H NMR (CDCl3, 300 MHz): = 1.48 [s, 9 H, C(CH3)3], 3.89 (br s,
1 H, OH), 5.62 (s, 1 H, CH), 5.90 (s, 1 H, =CHH), 6.33 (s, 1
H, =CHH), 6.60 (s, 1 H, =CH), 7.58–7.65 (m, 4 H, ArH).
2-{[5-(4-Bromophenyl)isoxazol-3-yl]hydroxymethyl}acryloni-
trile (9c)
1H NMR (CDCl3, 200 MHz): = 3.19 (br s, 1 H, OH), 5.56 (s, 1 H,
CH), 6.18 (s, 1 H, =CHH), 6.26, 6.265 (d, 1 H, J = 1.0 Hz, =CHH),
6.66 (s, 1 H, =CH), 7.62 (s, 4 H, ArH).
Anal. Calcd for C17H18BrNO4: C, 53.70; H, 4.77; N, 3.68. Found: C,
53.92; H, 4.89; N, 3.40.
Synthesis 2003, No. 15, 2325–2330 © Thieme Stuttgart · New York

2330
A. K. Roy, S. Batra
PAPER
Baylis–Hillman Reaction of Cyclohexenone; General Proce-
dure
TFA (50%) in CH2Cl2 for 1 h. The filtrate was evaporated and lyo-
philized using t-BuOH–H2O (4:1).
A mixture of appropriate compound 5a–d (0.0035 mol), DMAP
(0.084g, 0.0006 mol) and cyclohexenone (0.34 mL, 0.0035 mol) in
dioxane–H2O (3:2; 5 mL) mixture was stirred at r.t. for 1 h. There-
after the reaction mixture was extracted with EtOAc (2 × 30 mL).
The usual work up of the organic layer furnished a residue that upon
trituration with hexane furnished pure solid products. For com-
pound 14d, column chromatography (silica gel; hexane–EtOAc, 85:
15) yielded the pure derivative.
2-[Hydroxy-(5-phenylisoxazol-3-yl)methyl]acrylic Acid (16a)
95% purity; Rt 13.12 min.
1H NMR (CDCl3–DMSO-d6, 200 MHz): = 5.71 (s, 1 H, CH), 6.06
(s, 1 H, =CHH), 6.44 (s, 1 H, =CHH), 6.60 (s, 1 H, =CH), 7.41–7.46
(m, 3 H, ArH), 7.74–7.77 (m, 2 H, ArH).
13C NMR [CDCl3 + DMSO-d6 (a drop), 50.32 MHz]: = 65.71
(CH), 98.08 (CH), 125.31 (2 CH), 126.10 (CH2), 127.15 (C), 128.65
(2 CH), 129.72 (CH), 140.32 (C), 165.73 (C), 167.45 (C), 169.32
(C).
2-[Hydroxy-(5-phenylisoxazol-3-yl)methyl]cyclohex -2-enone
(14a)
1H NMR (CDCl3, 300 MHz): = 1.99–2.07 (m, 2 H, CH2), 2.42–
2.52 (m, 4 H, 2 CH2), 4.10 (br s, 1 H, OH), 5.60 (s, 1 H, CH), 6.63
(s, 1 H, =CH), 7.05 (t, 1 H, J = 3.0 Hz, =CH), 7.39–7.44 (m, 3 H,
ArH), 7.74–7.77 (m, 2 H, ArH).
Anal. Calcd for C13H11NO4: C, 63.67; H, 4.52; N, 5.71. Found: C,
63.70; H, 4.59; N, 5.51.
Anal. Calcd for C13H11NO4·H2O: C, 59.31; H, 4.97; N, 5.32. Found:
C, 59.59; H, 4.87; N, 5.18.
Anal. Calcd for C16H15NO3 C, 71.36; H, 5.61; N, 5.20. Found: C,
71.23; H, 5.68; N, 5.30.
2-[Hydroxy-(5-p-tolylisoxazol-3-yl)methyl]acrylic Acid (16b)
99% purity; Rt 14.59 min.
2-[Hydroxy-(5-p-tolylisoxazol-3-yl)methyl]cyclohex-2-enone
(14b)
1H NMR (CDCl3–DMSO-d6, 300 MHz): = 2.39 (s, 3 H, CH3),
5.69 (s, 1 H, CH), 6.02 (s, 1 H, =CHH), 6.43 (s, 1 H, =CHH), 6.55
(s, 1 H, =CH), 7.24, 7.26 (d, 2 H, J = 8.0 Hz, ArH), 7.63–7.65 (d, 2
H, J = 8.0 Hz, ArH).
1H NMR (CDCl3, 300 MHz): = 1.99–2.08 (m, 2 H, CH2), 2.39 (s,
3 H, CH3), 2,42–2.53 (m, 4 H, 2 CH2), 3.97 (br s, 1 H, OH), 5.58 (s,
1 H, CH), 6.57 (s, 1 H, =CH), 7.05 (t, 1 H, J = 3.9 Hz, =CH), 7.235–
7.26 (d, 2 H, J = 8.0 Hz, ArH), 7.64–7.66 (d, 2 H, J = 8.0 Hz, ArH).
Anal. Calcd for C14H13NO4: C, 64.86; H, 5.05; N, 5.40. Found; C,
64.61; H, 5.03; N, 5.20.
13C NMR (CDCl3, 50.32 MHz): = 21.83 (CH3), 22.74 (CH2),
26.14 (CH2), 38.78 (CH2), 67.70 (CH), 98.20 (CH), 125.10 (C),
126.15 (2 CH), 130.00 (2 CH), 138.68 (C), 140.84 (C), 149.00
(CH), 166.41 (C), 170.67 (C), 200.71 (C).
2-{[5-(4-Bromophenyl)isoxazol-3-yl]hydroxymethyl}acrylic
Acid (16c)
99% purity; Rt 15.45 min.
1H NMR (CDCl3–DMSO-d6, 300 MHz): = 5.70 (s, 1 H, CH), 6.07
(s, 1 H, =CHH), 6.43 (s, 1 H, =CHH), 6.62 (s, 1 H, =CH), 7.61 (s, 4
H, ArH).
Anal. Calcd for C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C,
71.83; H, 5.95; N, 5.04.
2-{[5-(4-Bromophenyl)isoxazol-3-yl]hydroxymethyl}cyclohex-
2-enone (14c)
Anal. Calcd for C13H10BrNO4 C, 48.17; H, 3.11; N, 4.32. Found: C,
48.44; H, 3.51; N, 3.99.
1H NMR (CDCl3, 200 MHz): = 2.01–2.09 (m, 2 H, CH2), 2.43–
2.54 (m, 4 H, 2 CH2), 4.10, 4.14 (d, 1 H, J = 7.2 Hz, OH), 5.56 (s, 1
H, CH), 6.64 (s, 1 H, =CH), 7.04 (t, 1 H, J = 4.0 Hz, =CH), 7.60–
7.62 (d, 4 H, J = 2.2 Hz, ArH).
Acknowledgment
Anal. Calcd for C16H14BrNO3·H2O: C, 52.48; H, 4.40; N, 3.82.
Found: C, 52.72; H, 4.49; N, 3.42.
One of the authors (AKR) gratefully acknowledges the financial
support in the form of fellowship from ICMR, India. Authors also
acknowledge the inputs by Dr. A. P. Bhaduri towards accomplish-
ment of this work.
2-{[5-(4-Fluorophenyl)isoxazol-3-yl]hydroxymethyl}cyclohex-
2-enone (14d)
1H NMR (CDCl3, 300 MHz): = 1.93–2.08 (m, 2 H, CH2), 2.44–
2.63 (m, 4 H, 2 CH2), 4.08 (br s, 1 H, OH), 5.57 (s, 1 H, CH), 6.54
(s, 1 H, =CH), 7.03–7.17 (m, 3 H, ArH, =CH), 7.73–7.77 (m, 4 H,
ArH).
References
(1) CDRI Communication No. 6430.
(2) Basavaiah, D.; Jaganmohan, R. A.; Satyanarayana, T. Chem.
Rev. 2003, 103, 811.
(3) Patra, A.; Batra, S.; Kundu, B.; Joshi, B. S.; Roy, R.;
Bhaduri, A. P. Synthesis 2001, 276.
Anal. Calcd for C16H14FNO3·1/2 H2O: C, 64.85; H, 5.10; N, 4.72.
Found: C, 64.69; H, 5.07; N, 4.73.
Baylis–Hillman Reaction on Solid Support; General Procedure
To Wang acrylate resin (100 mg each in 3 PP syringes) prepared8
from Wang resin (1.13 mmol/g, Novabiochem) in DMSO (800 L)
was added DABCO (2 equiv). After 15 min of shaking, the solution
of substituted 3-isoxazolecarboxaldehydes 5a–c (4.0 equiv) in
DMSO (300 L) was added to the respective reaction vessel. The
resulting mixture was shaken at 600 rpm for 3 h. Subsequently, the
resin was washed with DMF (6 × 4 mL), MeOH (6 × 4 mL), CH2Cl2
(3 × 4 mL) and Et2O (2 × 4mL). Finally the resins were cleaved with
(4) Roy, A. K.; Batra, S. Synthesis 2003, 1347.
(5) Pei, Y.; Wickham, B. O. S. Tetrahedron Lett. 1993, 34,
7509.
(6) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl.
1983, 22, 795.
(7) Patra, A.; Roy, A. K.; Joshi, B. S.; Roy, R.; Batra, S.;
Bhaduri, A. P. Tetrahedron 2003, 59, 663.
(8) Hamper, B. C.; Kolodziej, S. A.; Scates, A. M.; Smith, R. G.;
Cortez, E. J. Org. Chem. 1998, 63, 708.
Synthesis 2003, No. 15, 2325–2330 © Thieme Stuttgart · New York