Highly substituted isoxazoles: The Baylis-Hillman reaction of substituted 4-isoxazolecarbaldehydes and attempted cyclization to isoxazole-annulated derivatives

Article abstract of DOI:10.1055/s-2003-40204

In an attempt to understand the effect of position of the formyl group on the efficiency of Baylis-Hillman reaction within isoxazolecarbaldehydes, the reactions of substituted 4-isoxazolecarbaldehydes to obtain highly substituted isoxazoles are described. Attempts to obtain isoxazole-annulated derivatives from these Baylis-Hillman adducts involving S_NR′-S_NAr substitution strategy are also described.

Full text of DOI:10.1055/s-2003-40204

PAPER
1347
Highly Substituted Isoxazoles: The Baylis–Hillman Reaction of Substituted
4-Isoxazolecarbaldehydes and Attempted Cyclization to Isoxazole-Annulated
Derivatives1
B
aylis–Hillman Re
m
action of Substitute
r
d 4-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 18 March 2003
led to molecules with potent bioresponse.10 We have ob-
served that results with this substrate, with respect to Bay-
lis–Hillman reaction, can be generalized and extended to
other aldehydes.11 During our efforts to find reasons be-
Abstract: In an attempt to understand the effect of position of the
formyl group on the efficiency of Baylis–Hillman reaction within
isoxazolecarbaldehydes, the reactions of substituted 4-isoxazole-
carbaldehydes to obtain highly substituted isoxazoles are described.
Attempts to obtain isoxazole-annulated derivatives from these Bay- hind the unusually fast reactivity of 5-isoxazolecarbalde-
lis–Hillman adducts involving SNR -SNAr substitution strategy are
also described.
hydes we have proposed that the proton abstraction in the
intermediate step is quite likely aided by the heteroatom
Key words: Baylis–Hillman reaction, 4-isoxazolecarbaldehyde,
DABCO, DMAP
present in the molecule thereby facilitating the elimina-
tion of base (Figure 1).12 This hypothesis was the outcome
of the earlier observation made by Hofmann and Rabe
where they have proposed the formation of an zwitterionic
The Baylis–Hillman reaction,2 which has witnessed an ex- intermediate that allows elimination of H and base aided
traordinary exploitation in the recent past, is now consid- by the basic heteroatom of the aldehyde.13 To provide a
ered to be a standard synthetic methodology in the arsenal chemical basis to our hypothetical assumption, we envi-
of organic and medicinal chemists. Various reasons as- sioned that substituted 4-isoxazolecarbaldehydes would
cribed to such phenomenal expansion in the scope of this be a slow reacting substrate as compared to its isomer
C–C bond forming reaction include atom-economy, easy since here there will be no heteroatom to assist the elimi-
reaction conditions (even with water as the solvent),3 mul- nation of base. To substantiate this we carried out the syn-
tifunctional products that can be diversified further for ac- thesis of substituted 4-isoxazolecarbaldehydes and
cessing heterocycles,4 intermediates that serve as subjected them to Baylis–Hillman reaction. As expected,
synthons for natural products,5 adaption for solid-phase in contrast to 5-isoxazolecarbaldehydes, substituted 4-
chemistry for combinatorial synthesis, and others.6 In ad- isoxazolecarbaldehydes are sluggish electrophiles for the
dition, this reaction gains significant importance from a Baylis–Hillman reaction. In addition it was envisaged that
medicinal point of view if it is carried out with privileged Baylis–Hillman adducts of 3-(2-chlorophenyl)-5-methyl-
scaffolds.7 The slow reaction rate that was considered to 4-isoxazolecarbaldehyde could be cyclized to obtain isox-
be one of the major drawback of this reaction, has been al- azole-annulated derivatives employing SNR -SNAr substi-
most overcome using either physical or chemical means.2 tution strategy.14 Our initial attempts toward this objective
However, not much attention has been paid towards un- along with the details of conventional Baylis–Hillman re-
derstanding a plausible mechanism behind unusually fast action with substituted 4-isoxazolecarbaldehydes are pre-
Baylis–Hillman reaction experienced by some electro- sented herein.
philes.
( )n
( )n
( )n
Isoxazole is a privileged structure that is documented to
be associated with wide range of biological activities.8 In
our objective to generate isoxazole-based chemical librar-
ies in parallel utilizing solution and solid-phase chemistry,
we initiated our studies with 5-isoxazolecarbaldehydes.
We discovered that 5-isoxazolecarbaldehyde is one of the
fastest reacting substrates for the Baylis–Hillman reac-
tion.9 This has been a synthetically and medicinally attrac-
tive proposition for us since it helps to obtain various
intermediates in an expeditious fashion. Isoxazole deriva-
tives from the Baylis–Hillman-mediated chemistry have
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 hete-
roatom leading to immediate release of the base
The substituted 4-isoxazolecarbaldehydes were prepared
as reported in the literature.15 In the first instance methyl
acetoacetate was treated with sodium methoxide to gener-
ate the intermediate that was then reacted in situ with ben-
zohydroximinoyl chloride to generate methyl 3-aryl
Synthesis 2003, No. 9, Print: 03 07 2003.
Art Id.1437-210X,E;2003,0,09,1347,1356,ftx,en;P02603SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

1348
A. K. Roy, S. Batra
PAPER
substituted 5-methyl-4-isoxazole carboxylates 1a–f. 2 equivalents of the activated alkene, the reaction was
These esters upon careful reduction with lithium alumi- more efficient and the yields were better. Of the different
num hydride furnished the methyl alcohols 2a–f quantita- activated alkenes employed, acrylonitrile gave the best re-
tively. Furthermore, these alcohols upon oxidation with sults since no starting material was recovered and yields
pyridinium chlorochromate afforded the substituted 4- of 79–89% were achieved. This was in precedence with
isoxazolecarbaldehydes 3a–f in excellent yields the earlier observation made by Basavaiah et al.17 Notably
(Scheme 1). These aldehydes were then subjected to Bay- in these aldehydes though the reactions were allowed to
lis–Hillman reaction under neat conditions. Interestingly run for more than 72 hours, in no case we observed the
even after 24 hours the reactions did not go to completion. formation of ether side-product as in the 5-isomer.18
Here it would be relevant to state that compared to alde-
hydes 3d and 3f, the reactions were fast for all other alde-
hydes. However, upon work-up and column
During this study, we also carried out base-mediated Bay-
lis–Hillman reaction with cyclohexenone and acrylamide.
The aldehydes 3a–c were treated with cyclohexenone in
chromatography we recovered 5–10% of the unreacted al-
the presence of DMAP in dioxane–water. Here too, as
dehydes along with the desired products in moderate
compared to 5-isoxazolecarbaldehydes, the reactions did
yields only. Similar to our earlier experience with Baylis–
not go to completion and products 9a–c were isolated in
Hillman reactions of substituted 5-isoxazolecarbalde-
low yields only (Scheme 1). On the other hand, the initial
hyde, we observed that in substituted 4-isoxazolecarb-
attempts of Baylis–Hillman reaction of these aldehydes
aldehydes too, as the reaction progressed the reaction
with acrylamide in the presence of DABCO were unsuc-
mixture became unusually thick thereby preventing stir-
cessful. For solid-phase Baylis–Hillman reactions using
ring using a magnetic bar. However, in contrast to the
substituted 4-isoxazolecarbaldehyde as electrophile, the
Baylis–Hillman reaction of 5-isoxazolecarbaldehyde, the
acrylic acid was immobilized onto the 2-chlorotrityl chlo-
formation of a thick slurry here was not indicative of com-
ride resin using standard technique. The acrylate resin was
then subjected to Baylis–Hillman reaction with 3b,c in
pletion of the reaction. Assuming this as the possible rea-
son for the substrate not being consumed completely, we
DMF. The reaction was continued for 48 hours followed
decided to add solvents and evaluate their effect on the
by a repeat cycle. The resin was washed, dried and finally
progress of reaction. For our studies, we also included
cleaved to obtain the Baylis–Hillman adduct 13a–c in low
some recently reported observations of fast and efficient
yields (Scheme 2). Hence, as compared to the 5-isomer,14
Baylis–Hillman reaction in homogenous medium.3a Thus,
reactions were slow and yields were also only average.
as a model we conducted the reaction of compound 3b
Thus as envisioned, the substituted 4-isoxazolecarbalde-
with methyl acrylate under various solvent conditions.
hydes are less reactive electrophiles for Baylis–Hillman
The results are shown in Table 1. In contrast to an earlier
reaction as compared to their 5-isomer. It was suggested13
that the basicity of the heteroatom affecting the migration
of protons could be the reason for fast Baylis–Hillman re-
action. However, we have observed that 5-isoxazolecar-
baldehyde reacts even faster than the 3-
pyridinecarbaldehyde (exemplified by Hoffman and Rabe
as the fastest reacting electrophile) during the Baylis–
Hillman reaction that could be possibly explained as
shown in Figure 1. The proximity of the heteroatom to the
methyl bond bearing the base is greater in 5-isoxazole
than in 4-isoxazole derivatives thus facilitating the elimi-
report,16 it was surprising that the neat conditions work
best in our hands compared to the use of any solvent. In
our earlier work9 we have observed that DMF and DMSO
too serve as good solvents for the reaction and they also
address the solvent condition to be applied for solid phase
reactions.12 But in this study we found that DMSO led to
formation of an unidentified highly polar product in major
quantity.
In an attempt to find optimal conditions to obtain maxi-
mum yield we increased the amount of the base and also
the activated alkene. With 0.5 equivalent of the base and
N O
O
O
O
O
N O
N O
a
b
c
d
R
OCH3
OCH3
R
R
R
-
Na+
CO2CH3
1a-f
CHO
3a-f
CH2OH
2a-f
e
f
Compd.
R
Compd. EWG
a
b
c
d
e
f
C6H5
4-CH3C6H4
2-ClC6H4
4-ClC6H4
2,4-(Cl)2C6H3
4,10
5
6
7,11
8
CO2CH3
CO2C2H5
CO2(CH2)3CH3
CN
N O
N O
N O
g
R
R
AcO
HO
HO
EWG
10,11 c,e
COCH3
EWG
4-8a-f
O
9a-c
4-(OCH2C6H5)C6H4
Scheme 1 Reagents and conditions: a) NaOMe in MeOH; b) RCH(Cl)=NOH, 0 °C, MeOH, 4 h; c) LiAlH4, anhyd Et2O, 40 °C 1 h; d) PCC,
CH2Cl2, r.t., 30 min; e) DABCO, alkene, r.t., 2 d; f) DMAP, cyclohexenone, r.t., 7 d; g) AcCl, pyridine, r.t., 30 min
Synthesis 2003, No. 9, 1347–1356 ISSN 1234-567-89 © Thieme Stuttgart · New York

PAPER
Baylis–Hillman Reaction of Substituted 4-Isoxazolecarbaldehydes
1349
Table 1 Effect of Alkene, Base and Solvent on Baylis–Hillman Reaction of the Substituted 4-Isoxazolecarbaldehyde 3ba,b
Entry
1
Alkene (equiv)
Base (equiv)
Solvent
neat
Time (d)
Yield (%)c
42
CH2=CHCO2Me (1.0)
CH2=CHCO2Me (2.0)
CH2=CHCN (1.0)
DABCO (0.5)
DABCO (0.5)
DABCO (0.5)
DABCO (0.5)
DABCO (0.5)
DABCO (0.5)
aq Me3N 30% (2.5)
DABCO (0.5)
DABCO (0.5)
DABCO (0.5)
DABCO (0.5)
DABCO (0.5)
DABCO (0.5)
2
2
2
2
7
7
5
7
7
7
1
1
7
2
neat
59
3
neat
56
4
CH2=CHCN (2.0)
neat
89
5
CH2=CHCO2Me (1.0)
CH2=CHCO2Me (1.0)
CH2=CHCO2Me (1.5)
CH2=CHCO2Me (1.0)
CH2=CHCO2Me (1.0)
CH2=CHCO2Me (1.0)
CH2=CHCO2Me (1.0)
CH2=CHCO2Me (1.0)
MeOH
MeOH–H2O (1:1)
MeOH
dioxane–H2O (1:1)
CH2Cl2
THF
07
6
05
7
23
8
n.r
9
n.r
10
11
12
13
n.r.
10
DMSO
DMF
20
neat
n.r.
O
(1.0)
O
14d
DMAP (1.0)
dioxane–H2O (3:2)
7
21
(1.0)
a All reactions were carried out with 2.5 mmol of 3b.
b For comparison with substituted 5-isoxazolecarbaldehyde, see Ref.9
c n.r. = no reaction.
d Reactions of substituted 5-isoxazolecarbaldehydes with cyclohexenone in the presence of DMAP (0.2 equiv) in dioxane–H2O are completed
within 1 h to give products in 90–95% yields (unpublished).
amines were produced within an hour of reaction time and
R
R
N
O
N
O
N O
a
b
O
the product remained unchanged even after refluxing for
48 hours. TLC (hexane–ethyl acetate, 70:30) on basic alu-
mina indicated the presence of two spots very close to
O
HO2C
+
R
O
O
OH
OH
CHO
3b,c
12b,c
13b,c
Scheme 2 Reagents and Conditions: a) DABCO, DMF, r.t., 2 × 48
h; b) TFA–CH2Cl2 (5:95), 20 min
O
N
Cl
N
R
O
N
b
a
O
R
R
X
N
Cl
nation of the base. This fact was also confirmed through
the Drieding’s model of the intermediate.
EWG
AcO
NHCH2Ph
EWG
EWG
To explore the synthetic utility of the Baylis–Hillman
products described herein we decided to work upon an
earlier reported14 synthetic strategy. It was envisioned that
if acetates 10 and 11 of the Baylis–Hillman adducts of the
2-halophenyl substituted aldehyde are treated with amines
under forced conditions, the Michael adduct could under-
go cyclization in situ through SNAr substitution to yield
isoxazole annulated derivatives 16 (Scheme 3).
14,15 c,e
16 c,e
10, 11 c,e
c R= H
e R= Cl
10,14 EWG= CO2Me
11,15 EWG= CN
c
O
N
N
N
b
O
O
R
R
R
+
X
Cl
Cl
HN
CH3
CH3
Toward this objective in the first instance, compounds
4c,e and 7c,e were converted to the corresponding ace-
tates 10 and 11c,e. The acetates 10c,e were then refluxed
with benzylamine in the presence of triethylamine. How-
ever, in all cases we obtained the allyl amines 14c,e while
no cyclized derivative 16 was formed (Scheme 3). The
EWG
HO2C
MeO2C
O2N
NO2
19 c,e
18 c,e
17 c,e
Scheme 3 Reagents and Conditions: a) PhCH2NH2, Et3N, THF,
70 °C, 1 h; b) continued for 48 h; c) EtNO2, K2CO3, 60–70 °C, 30
min, 18c,e were formed only if the reaction was continued for 24 h
Synthesis 2003, No. 9, 1347–1356 ISSN 1234-567-89 © Thieme Stuttgart · New York

1350
A. K. Roy, S. Batra
PAPER
each other, which upon separation and spectroscopic anal- nulated carbocycles and heterocycles and isoxazole-based
ysis were identified as E- (less polar) and Z- (more polar) biodynamic agents. In addition it will be interesting to
isomers. The 1H NMR spectrum of the mixture indicated study the Baylis–Hillman reaction of substituted 3-isox-
these isomers to be present in almost equal quantity. The azolecarbaldehyde, which we presume will be faster as
stereochemistry of the amines was assigned on the basis compared to the 4-isomer and will also give an insight into
of NOE studies across the double bond of the polar isomer the basicity of the heteroatom affecting the rate of Baylis–
because the =CH proton could be easily irradiated in this Hillman reaction within a heterocycle. Work toward these
spectrum. Irradiation of =CH proton at = 6.50 showed perspectives is under way and will form part of our future
an increase of the allylic CH2 protons at = 3.70 by communications.
3.07% while irradiation of allylic CH2 led to an increase
for =CH proton by 5.74% indicating the Z-stereochemis-
Melting points are uncorrected and were determined in capillary
try of amines. In the E-isomer, the =CH was merged with
the aromatic proton that made it difficult to irradiate. We
also carried out a similar synthetic sequence with com-
pounds 7c and 7e to obtain the allylic amines 15c,e via the
acetates 11c,e. These amines were notably less polar com-
pared to 14 and could even be monitored on silica gel
plates using the same solvent system. These amines were
obtained with a high degree of stereoselectivity. During
NOE studies of these amines, the stereochemistry across
the double bond was assigned as Z since irradiation
of =CH proton at = 6.72 led to an enhancement of allylic
CH2 at = 3.48 (5.02%) while irradiation of CH2 proton
led to an increase in the signal of =CH proton by 6.73%.
Thus irrespective of the stereochemistry, the amines failed
to cyclize to furnish the desired products (Figure 2).
tubes on a hot stage apparatus containing silicon oil. IR spectra were
recorded using Perkin-Elmer Spectrum RX I FTIR spectrophotom-
eter while NMR spectra were recorded on Bruker DPX-200 FT
spectrometer, using TMS as an internal standard (chemical shifts in
values, J in Hz). The FABMS spectra were recorded on Jeol/SX-
102 spectrometer and ESMS were recorded through direct flow in-
jections in Merck M-8000 LCMS system. Elemental analyses were
performed either on Carlo Erba 1108 or Elementar’s Vario EL III
microanalyzer. All yields of Baylis–Hillman adducts are based on
exclusion of 5–10% aldehyde that was recovered unreacted in all re-
actions except for that with acrylonitrile.
Baylis–Hillman Reaction of Substituted 4-Isoxazolecarbalde-
hydes with Alkenes; General Procedure
To a mixture of DABCO (0.3 g, 2.67 mmol) and the appropriate al-
kene (10.6 mmol), that had been stirred at r.t. for 20 min, was added
the appropriate aldehyde 3a–f (5.3 mmol) under stirring and the re-
action was allowed to proceed for a period of 72 h. Thereafter 5%
aq HCl (50 mL) was added to the reaction mixture to neutralize the
base and the resulting mixture was extracted with EtOAc (2 × 100
mL). The organic layers were combined, washed with brine (100
mL), dried (Na2SO4) and evaporated under vacuum to yield an oily
residue. The residue was purified by column chromatography over
silica gel (60–120 mesh) using hexane–EtOAc as eluent. A mixture
of hexane–EtOAc (85:15) yielded the starting material while further
elution with hexane–EtOAc (60:40) furnished the desired products.
N
O
N
O
N
O
Cl
Cl
Cl
H
H
H
NC
CO2Me
MeO2C
NH
Ph
NH
NH
Ph
Ph
Z
E
Z
Figure 2 Stereochemistry of allyl amines
2-[Hydroxy-(5-methyl-3-phenylisoxazol-4-yl)methyl]acrylic
Acid Methyl Ester (4a)
Yield: 59%; colorless oil.
IR (neat): 1719 (ester C=O), 3407 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 2.49 (s, 3 H, CH3), 2.96, 2.97 (d,
In another strategy, the compounds 10c,e were treated
with a nitroalkane. Here too, though the SNR reaction of
the nitronate ion was successful to afford 17c,e, the in-
tramolecular SNAr and subsequent elimination of nitrous 1 H, J = 3.8 Hz, OH), 3.74 (s, 3 H, CO2CH3), 5.62 (t, 1 H, J1 = 1.4
Hz, J2 = 2.0 Hz, CH), 5.733, 5.736 (d, 1 H, J= 0.6 Hz, =CHH), 6.32
(s, 1 H, =CHH), 7.42–7.45 (m, 3 H, ArH), 7.56–7.61 (m, 2 H, ArH).
MS (FAB+): m/z = 274 (M+ + 1).
acid to furnish the desired compound 19 did not take place
(Scheme 3). The stereochemistry of these products was
assigned as E, based on the literature.19 However, heating
the reaction mixture for a prolonged period decreased the
yield of the products as there was appreciable formation
of polar impurities that were not isolated. But a mass spec-
trum of the mixture did indicate the presence of molecular
ion peaks corresponding to acrylic acid derivatives 18c,e
that may have obviously resulted due to hydrolysis of the
ester in the presence of base.
Anal. Calcd for C15H15NO4: C, 65.92; H, 5.53; N, 5.13. Found: C,
65.89; H, 5.50; N, 5.22.
2-{Hydroxy-[5-methyl-3-(4-methylphenyl)isoxazol-4-yl]meth-
yl}acrylic Acid Methyl Ester (4b)
Yield: 59%; pale yellow oil.
IR (neat): 1710 (ester C=O), 3397 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 2.39 (s, 3 H, CH3), 2.47 (s, 3 H,
CH3), 2.98, 2.99 (d, 1 H, J = 3.6 Hz, OH), 3.74 (s, 3 H, CO2CH3),
5.61 (br s, 1 H, CH), 5.73 (s, 1 H, =CHH), 6.32 (s, 1 H, =CHH),
7.21, 7.25 (d, 2 H, J = 8.0 Hz, ArH), 7.45, 7.49 (d, 2 H, J = 8.0 Hz,
ArH).
In conclusion, we have described the Baylis–Hillman re-
actions of substituted 4-isoxazolecarbaldehyde in solu-
tion- and solid-phase and have shown the influence of
position of the formyl group within a heterocycle on the
rate of reaction. We speculate that Baylis–Hillman ad-
ducts of 4-isoxazolecarbaldehyde described herein will be
of high synthetic importance for obtaining isoxazole-an-
MS (FAB+): m/z = 288 (M+ + 1).
Anal. Calcd for C16H17NO4: C, 66.89; H, 5.96; N, 4.88. Found: C,
66.66; H, 5.98; N, 4.70.
Synthesis 2003, No. 9, 1347–1356 ISSN 1234-567-89 © Thieme Stuttgart · New York

PAPER
Baylis–Hillman Reaction of Substituted 4-Isoxazolecarbaldehydes
1351
2-{[3-(2-Chlorophenyl)-5-methylisoxazol-4-yl]hydroxymeth-
yl}acrylic Acid Methyl Ester (4c)
2-{Hydroxy-[5-methyl-3-(4-methylphenyl)isoxazol-4-yl]meth-
yl}acrylic Acid Ethyl Ester (5b)
Yield: 59%; colorless oil.
Yield: 55%; colorless oil.
IR (neat): 1718 (ester C=O), 3402 cm–1 (OH).
IR (neat): 1710 (ester C=O), 3397 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 2.52 (s, 3 H, CH3), 2.82 (br s, 1 H,
OH), 3.66 (s, 3 H, CO2CH3), 5.37 (s, 1 H, CH), 5.69 (s, 1 H, =CHH),
6.20 (s, 1 H, =CHH), 7.35–7.48 (m, 4 H, ArH).
1H NMR (CDCl3, 200 MHz): = 1.25 (t, 3 H, J = 7.2 Hz, CH3),
2.39 (s, 3 H, CH3), 2.47 (s, 3 H, CH3), 2.98, 2.99 (d, 1 H, J = 3.6 Hz,
OH), 4.20 (q, 2 H, J = 7.0 Hz, CO2CH2), 5.61 (br s, 1 H, CH), 5.72
(s, 1 H, =CHH), 6.32 (s, 1 H, =CHH), 7.21, 7.25 (d, 2 H, J = 8.0 Hz,
ArH), 7.45, 7.49 (d, 2 H, J = 8.0 Hz, ArH).
MS (FAB+): m/z = 308 (M+ + 1).
Anal. Calcd for C15H14ClNO4: C, 58.55; H, 4.59; N, 4.55. Found: C,
58.60; H, 4.69; N, 4.50.
MS (FAB+): m/z = 302 (M+ + 1).
Anal. Calcd for C17H19NO4: C, 67.76; H, 6.36; N, 4.65. Found: C,
67.81; H, 6.66; N, 4.70.
2-{[3-(4-Chlorophenyl)-5-methylisoxazol-4-yl]hydroxymeth-
yl}acrylic Acid Methyl Ester (4d)
Yield: 54%; colorless oil.
IR (neat): 1718 (ester C=O), 3402 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 2.48 (s, 3 H, CH3), 2.97, 2.99 (d,
1 H, J = 3.6 Hz, OH), 3.74 (s, 3 H, CO2CH3), 5.60 (br s, 1 H, CH),
5.73 (s, 1 H, =CHH), 6.31 (s, 1 H, =CHH), 7.44, 7.48 (d, 2 H, J = 8.0
Hz, ArH), 7.56, 7.60 (d, 2 H, J = 8.0 Hz, ArH).
2-{[3-(2-Chlorophenyl)-5-methylisoxazol-4-yl]hydroxymeth-
yl}acrylic Acid Ethyl Ester (5c)
Yield: 50%; colorless oil.
IR (neat): 1711 (ester C=O), 3401 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 1.23 (t, 3 H, J = 7.2 Hz, CH3),
2.52 (s, 3 H, CH3), 2.77 (br s, 1 H, OH), 4.14 (q, 2 H, J = 7.0 Hz,
CO2CH2), 5.37 (s, 1 H, CH), 5.64 (s, 1 H, =CHH), 6.17 (s, 1 H,
=CHH), 7.35–7.44 (m, 4 H, ArH).
MS (FAB+): m/z = 308 (M+ + 1).
Anal. Calcd for C15H14ClNO4: C, 58.55; H, 4.59; N, 4.55. Found: C,
58.36; H, 4.28; N, 4.89.
MS (FAB+): m/z = 322 (M+ + 1).
Anal. Calcd for C16H16ClNO4: C, 59.73; H, 5.01; N, 4.35. Found: C,
60.04; H, 5.02; N, 4.57.
2-{[3-(2,4-Dichlorophenyl)-5-methylisoxazol-4-yl]hydroxyme-
thyl}acrylic Acid Methyl Ester (4e)
Yield: 51%; colorless oil.
IR (neat): 1718 (ester C=O), 3402 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 2.51 (s, 3 H, CH3), 2.76, 2.78 (d,
1 H, J = 4.0 Hz, OH), 3.68 (s, 3 H, CO2CH3), 5.35, 5.37 (d, 1 H,
J = 4.0 Hz, CH), 5.71 (s, 1 H, =CHH), 6.22 (s, 1 H, =CHH), 7.31 (s,
2 H, ArH), 7.49 (s, 1 H, ArH).
2-{[3-(4-Chlorophenyl)-5-methylisoxazol-4-yl]hydroxymeth-
yl}acrylic Acid Ethyl Ester (5d)
Yield: 50%; colorless oil.
IR (neat): 1711 (ester C=O), 3402 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 1.26 (t, 3 H, J = 7.2 Hz, CH3),
2.50 (s, 3 H, CH3), 3.04, 3.06 (d, 1 H, J = 3.6 Hz, OH), 4.20 (q, 2 H,
J = 7.2 Hz, CO2CH2), 5.59 (br s, 1 H, CH), 5.70 (s, 1 H, =CHH),
6.26 (s, 1 H, =CHH), 7.42, 7.44 (d, 2 H, J = 8.0 Hz, ArH), 7.52, 7.56
(d, 2 H, J = 8.0 Hz, ArH).
MS (FAB+): m/z = 342 (M+ + 1).
Anal. Calcd for C15H13Cl2NO4: C, 52.65; H, 3.83; N, 4.09. Found:
C, 52.67; H, 3.95; N, 3.90.
MS (FAB+): m/z = 322 (M+ + 1).
2-{[3-(4-Benzyloxyphenyl)-5-methylisoxazol-4-yl]hydroxyme-
thyl}acrylic Acid Methyl Ester (4f)
Anal. Calcd for C16H16ClNO4: C, 59.73; H, 5.01; N, 4.35. Found: C,
59.36; H, 4.92; N, 4.42.
Yield: 47%; colorless oil.
2-{[3-(2,4-Dichlorophenyl)-5-methylisoxazol-4-yl]hydroxyme-
thyl}acrylic Acid Ethyl Ester (5e)
Yield: 52%; colorless oil.
IR (neat): 1709 (ester C=O), 3402 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): 1.24 (t, 3 H, J = 7.2 Hz, CH3), 2.52
(s, 3 H, CH3), 2.87, 2.89 (d, 1 H, J = 4.0 Hz, OH), 4.14 (q, 2 H,
J = 7.0 Hz, CO2CH2), 5.35, 5.37 (s, 1 H, J = 4.0 Hz, CH), 5.65 (s, 1
H, =CHH), 6.19 (s, 1 H, =CHH), 7.31 (s, 2 H, ArH), 7.48 (s, 1 H,
ArH).
IR (neat): 1718 (ester C=O), 3399 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 2.46 (s, 3 H, CH3), 2.98 (br s, 1 H,
OH), 3.74 (s, 3 H, CO2CH3), 5.10 (s, 2 H, OCH2), 5.62 (s, 1 H, CH),
5.73 (s, 1 H, =CHH), 6.32 (s, 1 H, =CHH), 7.00, 7.04 (d, 2 H, J = 8.0
Hz, ArH), 7.28–7.35 (m, 5 H, ArH), 7.52, 7.56 (d, 2 H, J = 8.0 Hz,
ArH).
MS (FAB+): m/z = 380 (M+ + 1).
Anal. Calcd for C22H21NO5: C, 69.64; H, 5.58; N, 3.69. Found: C,
69.64; H, 5.75; N, 3.79.
MS (FAB+): m/z = 356 (M+ + 1).
2-[Hydroxy-(5-methyl-3-phenylisoxazol-4-yl)methyl]acrylic
Acid Ethyl Ester (5a)
Anal. Calcd for C16H15Cl2NO4: C, 53.95; H, 4.24; N, 3.93. Found:
C, 54.19; H, 4.37; N, 4.01.
Yield: 57%; colorless oil.
2-{[3-(4-Benzyloxyphenyl)-5-methylisoxazol-4-yl]hydroxyme-
thyl}acrylic Acid Ethyl Ester (5f)
Yield: 45%; colorless oil.
IR (neat): 1718 (ester C=O), 3399 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 1.26 (t, 3 H, J = 7.2 Hz, CH3),
2.50 (s, 3 H, CH3), 3.04, 3.06 (d, 1 H, J = 3.6 Hz, OH), 4.20 (q, 2 H,
J = 7.2 Hz, CO2CH2), 5.59 (br s, 1 H, CH), 5.70 (s, 1 H, =CHH),
6.26 (s, 1 H, =CHH), 7.42, 7.44 (d, 2 H, J = 8.0 Hz, ArH), 7.52, 7.56
(d, 2 H, J = 8.0 Hz, ArH).
IR (neat): 1707 (ester C=O), 3431 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 1.25 (t, 3 H, J = 7.2 Hz, CH3),
2.49 (s, 3 H, CH3), 3.02, 3.04 (d, 1 H, J = 3.6 Hz, OH), 4.20 (q, 2 H,
J = 7.0 Hz, CO2CH2), 5.62 (t, 1 H, J1 = 1.4 Hz, J2 = 1.8 Hz, CH),
5.71 (s, 1 H, =CHH), 6.32 (s, 1 H, =CHH), 7.41–7.45 (m, 3 H, ArH),
7.56–7.61 (m, 2 H, ArH).
MS (FAB+): m/z = 288 (M+ + 1).
Anal. Calcd for C16H17NO4: C, 66.89; H, 5.96; N, 4.88. Found: C,
67.11; H, 6.01; N 4.77.
Synthesis 2003, No. 9, 1347–1356 ISSN 1234-567-89 © Thieme Stuttgart · New York

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A. K. Roy, S. Batra
PAPER
MS (FAB+): m/z = 394 (M+ + 1).
Anal. Calcd for C18H20ClNO4.H2O: C, 58.78; H, 6.03; N, 3.81.
Found: C, 58.81; H, 6.29; N, 4.12.
Anal. Calcd for C23H23NO5: C, 70.21; H, 5.89; N, 3.56. Found: C,
70.28; H, 6.19; N, 3.84.
2-{[3-(2,4-Dichlorophenyl)-5-methylisoxazol-4-yl]hydroxyme-
thyl}acrylic Acid Butyl Ester (6e)
Yield: 56%; colorless oil.
IR (neat): 1711 (ester C=O), 3401 cm–1 (OH).
2-[Hydroxy-(5-methyl-3-phenylisoxazol-4-yl)methyl]acrylic
Acid Butyl Ester (6a)
Yield: 56%; colorless oil.
IR (neat): 1709 (ester C=O), 3430 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 0.92 (t, 3 H, J = 7.2 Hz, CH3),
1.28–1.39 (m, 2 H, CH2), 1.52–1.63 (m, 2 H, CH2), 2.51 (s, 3 H,
CH3), 2.85, 2.87 (d, 1 H, J = 4.4 Hz, OH), 4.08 (q, 2 H, J = 7.0 Hz,
CO2CH2), 5.55, 5.37 (d, 1 H, J = 4.0 Hz, CH), 5.65 (s, 1 H, =CHH),
6.18 (s, 1 H, =CHH), 7.31 (s, 2 H, ArH), 7.48 (s, 1 H, ArH).
1H NMR (CDCl3, 200 MHz): = 0.91 (t, 3 H, J = 7.2 Hz, CH3),
1.25–1.38 (m, 2 H, CH2), 1.53–1.63 (m, 2 H, CH2), 2.48 (s, 3 H,
CH3), 3.02, 3.04 (d, 1 H, J = 3.8 Hz, OH), 4.14 (t, 2 H, J = 6.6 Hz,
CO2CH2), 5.61 (t, 1 H, J1 = 1.4 Hz, J2 = 2.2 Hz, CH), 5.71 (s, 1 H,
=CHH), 6.31 (s, 1 H, =CHH), 7.41–7.44 (m, 3 H, ArH), 7.57–7.62
(m, 2 H, ArH).
13C NMR (CDCl3, 50.32 MHz): = 12.60 (CH3), 14.04 (CH3),
19.44 (CH2), 30.87 (CH2), 64.30 (CH), 65.38 (CH2), 109.97 (CH),
113.51 (CH), 126.16 (CH2), 128.96 (2 × CH), 129.11 (2 × CH),
129.39 (CH), 129.93 (CH), 140.78 (C), 162.93 (C), 166.59 (C),
168.90 (C).
MS (FAB+): m/z = 384 (M+ + 1).
Anal. Calcd for C18H19Cl2NO4: C, 56.26; H, 4.98; N, 3.65. Found:
C, 55.95; H, 4.73; N, 3.30.
2-{[3-(4-Benzyloxyphenyl)-5-methylisoxazol-4-yl]hydroxyme-
thyl}acrylic Acid Butyl Ester (6f)
Yield: 46%; colorless oil.
MS (FAB+): m/z = 316 (M+ + 1).
IR (neat): 1718 (ester C=O), 3399 cm–1 (OH).
Anal. Calcd for C18H21NO4: C, 68.55; H, 6.71; N, 4.44. Found: C,
68.58; H, 7.04; N, 4.51.
1H NMR (CDCl3, 200 MHz): = 0.91 (t, 3 H, J = 7.2 Hz, CH3),
1.27–1.42 (m, 2 H, CH2), 1.51–1.65 (m, 2 H, CH2), 2.54 (s, 3 H,
CH3), 2.91 (br s, 1 H, OH), 4.08 (q, 2 H, J = 7.0 Hz, CO2CH2), 5.37
(s, 1 H, CH), 5.63 (s, 1 H, =CHH), 6.16 (s, 1 H, =CHH), 7.31–7.48
(m, 4 H, ArH).
2-[Hydroxy-[5-methyl-3-(4-methylphenyl)isoxazol-4-yl)meth-
yl]acrylic Acid Butyl Ester (6b)
Yield: 56%; colorless oil.
IR (neat): 1711 (ester C=O), 3409 cm–1 (OH).
MS (FAB+): m/z = 422 (M+ + 1).
Anal. Calcd for C25H27NO5: C, 71.24; H, 6.46; N, 3.32. Found: C,
71.21; H, 6.83; N, 3.56.
1H NMR (CDCl3, 200 MHz): = 0.92 (t, 3 H, J = 7.2 Hz, CH3),
1.28–1.39 (m, 2 H, CH2), 1.53–1.64 (m, 2 H, CH2), 2.39 (s, 3 H,
CH3), 2.47 (s, 3 H, CH3), 3.01, 3.03 (d, 1 H, J = 3.6 Hz, OH), 4.14
(t, 2 H, J = 6.6 Hz, CO2CH2), 5.61 (br s, 1 H, CH), 5.72 (s, 1 H,
=CHH), 6.32 (s, 1 H, =CHH), 7.21, 7.25 (d, 2 H, J = 8.0 Hz, ArH),
7.49, 7.53 (d, 2 H, J = 8.0 Hz, ArH).
2-[Hydroxy-(5-methyl-3-phenylisoxazol-4-yl)methyl]acryloni-
trile (7a)
Yield: 90%; white solid; mp 86–88 °C.
IR (KBr): 2234 (C N), 3402 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 2.53 (m, 4 H, s of CH3 merged
with d of OH), 5.33 (t, 1 H, J1 = 2.0 Hz, J2 = 2.4 Hz, CH), 6.02, 6.03
(2 s almost merged, 2 H, =CH2), 7.44–7.49 (m, 3 H, ArH), 7.54–
7.59 (m, 2 H, ArH).
MS (FAB+): m/z = 330 (M+ + 1).
Anal. Calcd for C19H23NO4: C, 69.28; H, 7.04; N, 4.25. Found: C,
69.66; H, 7.39; N, 4.26.
2-{[3-(2-Chlorophenyl)-5-methylisoxazol-4-yl]hydroxymeth-
yl}acrylic Acid Butyl Ester (6c)
Yield: 55%; colorless oil.
IR (neat): 1710 (ester C=O), 3403 cm–1 (OH).
MS (FAB+): m/z = 241 (M+ + 1).
Anal. Calcd for C14H12N2O2: C, 69.99; H, 5.03; N, 11.66. Found: C,
70.14; H, 5.22; N, 11.59.
1H NMR (CDCl3, 200 MHz): = 0.91 (t, 3 H, J = 7.2 Hz, CH3),
1.27–1.42 (m, 2 H, CH2), 1.51–1.65 (m, 2 H, CH2), 2.54 (s, 3 H,
CH3), 2.91 (br s, 1 H, OH), 4.08 (q, 2 H, J = 7.0 Hz, CO2CH2), 5.37
(s, 1 H, CH), 5.63 (s, 1 H, =CHH), 6.16 (s, 1 H, =CHH), 7.31–7.48
(m, 4 H, ArH).
2-{Hydroxy-[5-methyl-3-(4-methylphenyl)isoxazol-4-yl]meth-
yl}acrylonitrile (7b)
Yield: 89%; white solid; mp 116–118 °C.
IR (KBr): 2223 (C N), 3404 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 2.39 (s, 3 H, CH3), 2.45 (s, 2 H,
CH3), 3.39, 3.41 (d, 1 H, J = 4.0 Hz, OH), 5.27, 5.28 (d, 1 H, J = 3.6
Hz, CH), 6.00 (s, 2 H, =CH2), 7.20, 7.24 (d, 2 H, J = 8.0 Hz, ArH),
7.39, 7.43 (d, 2 H, J = 8.0 Hz, ArH).
MS (FAB+): m/z = 350 (M+ + 1).
Anal. Calcd for C18H20ClNO4: C, 61.80; H, 5.76; N, 4.00. Found: C,
62.02; H, 5.89; N, 4.01.
MS (FAB+): m/z = 255 (M+ + 1).
2-{[3-(4-Chlorophenyl)-5-methylisoxazol-4-yl]hydroxymeth-
yl}acrylic Acid Butyl Ester (6d)
Yield: 49%; colorless oil.
Anal. Calcd for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found: C,
71.05; H, 5.68; N, 11.18.
IR (neat): 1711 (ester C=O), 3401 cm–1 (OH).
2-{[3-(2-Chlorophenyl)-5-methylisoxazol-4-yl]hydroxymeth-
yl}acrylonitrile (7c)
Yield: 79%; pale yellow oil.
IR (neat): 2231 (C N), 3397 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 2.55 (s, 3 H, CH3), 2.72 (br s, 1 H,
OH), 5.11 (s, 1 H, CH), 5.88 (s, 1 H, =CHH), 5.89 (s, 1 H, =CHH),
7.36–7.47 (m, 4 H, ArH).
1H NMR (CDCl3, 200 MHz): = 0.91 (t, 3 H, J = 7.2 Hz, CH3),
1.27–1.42 (m, 2 H, CH2), 1.51–1.65 (m, 2 H, CH2), 2.54 (s, 3 H,
CH3), 2.91 (br s, 1 H, OH), 4.08 (q, 2 H, J = 7.0 Hz, CO2CH2), 5.37
(s, 1 H, CH), 5.63 (s, 1 H, =CHH), 6.16 (s, 1 H, =CHH), 7.31–7.48
(m, 4 H, ArH).
MS (FAB+): m/z = 350 (M+ + 1).
Synthesis 2003, No. 9, 1347–1356 ISSN 1234-567-89 © Thieme Stuttgart · New York

PAPER
Baylis–Hillman Reaction of Substituted 4-Isoxazolecarbaldehydes
1353
MS (FAB+): m/z = 275 (M+ + 1).
3-[Hydroxy-{5-methyl-3-[(4-methxlphenyl)isoxazol-4-yl]meth-
yl}but-3-en-2-one (8b)
Yield: 48%; pale yellow oil.
IR (neat): 1674 (C=O), 3421 cm–1 (OH).
Anal. Calcd for C15H14ClN2O2: C, 62.18; H, 4.87; N, 9.67. Found:
C, 62.34; H, 5.10; N, 10.05.
2-{[3-(4-Chlorophenyl)-5-methylisoxazol-4-yl]hydroxymeth-
yl}acrylonitrile (7d)
Yield: 79%; pale yellow solid; mp 75–77 °C.
IR (KBr): 2230 (C N), 3425 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): 2.53 (s, 3 H, CH3), 2.59, 2.61 (d, 1
H, J = 3.6 Hz, OH), 5.32 (s, 1 H, CH), 6.05 (2 s almost merged, 2
H, =CH2), 7.41, 7.45 (d, 2 H, J = 8.0 Hz, ArH), 7.54, 7.58 (d, 2 H,
J = 8.0 Hz, ArH).
1H NMR (CDCl3, 200 MHz): = 2.34 (s, 3 H, CH3), 2.38 (s, 3 H,
CH3), 2.48 (s, 3 H, CH3), 3.11, 3.33 (d, 1 H, J = 3.2 Hz, OH), 5.66
(s, 1 H, CH), 5.86 (s, 1 H, =CHH), 6.15 (s, 1 H, =CHH), 6.03 (s, 2
H, =CH2), 7.19, 7.23 (d, 2 H, J = 8.0 Hz, ArH), 7.43, 7.47 (d, 2 H,
J = 8.0 Hz, ArH).
MS (FAB+): m/z = 272 (M+ + 1).
Anal. Calcd for C16H17NO3·0.5H2O: C, 68.32; H, 6.40; N, 4.98.
Found: C, 68.78; H, 6.60; N, 5.00.
MS (FAB+): m/z = 275 (M+ + 1).
3-{[3-(2-Chlorophenyl)-5-methylisoxazol-4-yl]hydroxymeth-
yl}but-3-en-2-one (8c)
Yield: 56%; pale yellow oil.
Anal. Calcd for C14H11ClN2O2: C, 61.21; H, 4.03; N, 10.19. Found:
C, 60.89; H, 4.29; N, 9.85.
2-{[3-(2,4-Dichlorophenyl)-5-methylisoxazol-4-yl]hydroxyme-
thyl}acrylonitrile (7e)
Yield: 79%; white solid; mp 127–129 °C.
IR (KBr): 2230 (C N), 3397 cm–1 (OH).
IR (neat): 1680 (C=O), 3434 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 2.22 (s, 3 H, CH3), 2.53 (s, 3 H,
CH3), 2.56, 2.57 (d, 1 H, J = 3.2 Hz, OH), 5.41 (s, 1 H, CH), 5.84
(s, 1 H, =CHH), 6.02 (s, 1 H, =CHH), 7.33–7.46 (m, 4 H, ArH).
1H NMR (CDCl3, 200 MHz): = 2.44, 2.46 (d, 1 H, J = 4.0 Hz,
OH), 2.56 (s, 3 H, CH3), 5.11 (t, 1 H, J1 = J2 = 2.0 Hz, CH), 5.94 (t,
2 H, J1 = 1.8 Hz, J2 = 2.2 Hz, =CH2), 7.36 (s, 2 H, ArH), 7.51 (s, 1
H, ArH).
MS (FAB+): m/z = 292 (M+ + 1).
Anal. Calcd for C15H14ClNO3: C, 61.76; H, 4.84; N, 4.80. Found: C,
61.80; H, 5.01; N, 4.97%.
13C NMR (CDCl3, 50.32 Hz): = 12.52 (CH3), 65.56 (CH), 113.75
(C), 116.87 (C), 124.24 (C), 126.66 (C), 127.91 (CH), 130.06
(CH2), 130.23 (CH), 133.29 (CH), 134.69 (C), 137.27 (C), 159.89
(C), 169.58 (C).
3-{[3-(4-Chlorophenyl)-5-methylisoxazol-4-yl]hydroxymeth-
yl}but-3-en-2-one (8d)
Yield: 46%; pale yellow oil.
IR (neat): 1676 (C=O), 3424 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 2.31 (s, 3 H, CH3), 2.49 (s, 3 H,
CH3), 2.54, 2.55 (d, 1 H, J = 3.2 Hz, OH), 5.41 (s, 1 H, CH), 5.83
(s, 1 H, =CHH), 6.03 (s, 1 H, =CHH), 7.36–7.63 (m, 4 H, ArH).
MS (FAB+): m/z=309 (M+ + 1).
Anal. Calcd for C14H10Cl2N2O2: C, 54.39; H, 3.26; N, 9.06. Found:
C, 54.77; H, 3.26; N, 8.84.
MS (FAB+): m/z = 292 (M+ + 1).
2-{[3-(4-Benzyloxyphenyl)-5-methylisoxazol-4-yl]hydroxyme-
thyl}acrylonitrile (7f)
Yield: 79%; white solid; mp 66–68 °C.
Anal. Calcd for C15H14ClNO3: C, 61.76; H, 4.84; N, 4.80. Found: C,
61.91; H, 5.15; N, 4.69.
IR (KBr): 2231 (C N), 3396 cm–1 (OH).
3-{[3-(2,4-Dichlorophenyl)-5-methylisoxazol-4-yl]hydroxyme-
thyl}but-3-en-2-one (8e)
Yield: 48%; pale yellow oil.
IR (neat): 1629 (C=O), 3434 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 2.25 (s, 3 H, CH3), 2.52 (s, 3 H,
CH3), 2.74, 2.76 (d, 1 H, J = 4.0 Hz, OH), 5.39, 5.41 (d, 1 H, J = 3.6
Hz, CH), 5.88 (s, 1 H, =CHH), 6.06 (s, 1 H, =CHH), 7.33 (s, 2 H,
ArH), 7.47 (s, 1 H, ArH).
1H NMR (CDCl3, 200 MHz): = 2.46 (s, 3 H, CH3), 3.02, 3.04 (d,
1 H, J = 3.6 Hz, OH), 5.09 (s, 2 H, OCH2), 5.28 (s, 1 H, CH), 6.02
(s, 2 H, =CH2), 6.99–7.04 (d, 2 H, J = 8.6 Hz, ArH), 7.33–7.52 (m,
7 H, ArH).
MS (FAB+): m/z = 346 (M+ + 1).
Anal. Calcd for C21H18N2O3: C, 72.82; H, 5.24; N, 8.09. Found: C,
72.66; H, 5.42; N, 8.21.
MS (FAB+): m/z = 326 (M+ + 1).
3-[Hydroxy-(5-methyl-3-phenylisoxazol-4-yl)methyl]but-3-en-
2-one (8a)
Yield: 48%; pale yellow oil.
Anal. Calcd for C15H13Cl2NO3: C, 55.23; H, 4.02; N, 4.29. Found:
C, 54.88; H, 4.37; N, 4.18.
IR (neat): 1685 (C=O), 3433 cm–1 (OH).
3-{[3-(4-Benzyloxyphenyl)-5-methylisoxazol-4-yl]hydroxyme-
thyl}but-3-en-2-one (8f)
Yield: 42%; pale yellow oil.
IR (neat): 1679 (C=O), 3434 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 2.31 (s, 3 H, CH3), 2.45 (s, 3 H,
CH3), 2.50 (s, 1 H, OH), 5.08 (s, 1 H, OCH2), 5.65 (s, 1 H, CH), 5.87
(s, 1 H, =CHH), 6.13 (s, 1 H, =CHH), 6.97, 7.01 (d, 2 H, J = 8.0 Hz,
ArH), 7.29–7.61 (m, 7 H, ArH).
1H NMR (CDCl3, 200 MHz): = 2.49 (s, 3 H, CH3), 2.57 (s, 3 H,
CH3), 3.10 (br s, 1 H, OH), 5.67 (s, 1 H, CH), 5.87 (s, 1 H, =CHH),
6.15 (s, 1 H, =CHH), 7.40–7.49 (m, 3 H, ArH), 7.54–7.64 (m, 2 H,
ArH).
13C NMR (CDCl3, 50.32 MHz): = 12.58 (CH3), 26.77 (CH3),
64.15 (CH), 127.22 (CH2), 128.91 (2 CH), 129.21 (2 CH),
129.51(CH), 129.92 (CH), 148.16 (C), 162.66 (C), 168.90 (C),
200.53 (C).
MS (FAB+): m/z = 363 (M+ + 1).
MS (FAB+): m/z = 258 (M+ + 1).
Anal. Calcd for C22H21NO4·H2O: C, 69.27; H, 6.07; N, 3.67. Found:
C, 69.38; H, 5.68; N, 3.72.
Anal. Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44. Found: C,
70.36; H, 5.47; N, 5.28.
Synthesis 2003, No. 9, 1347–1356 ISSN 1234-567-89 © Thieme Stuttgart · New York

1354
A. K. Roy, S. Batra
PAPER
Baylis–Hillman Reaction of Substituted 4-Isoxazolecarbalde-
hydes with Cyclohexenone; General Procedure
(2 ×), and Et2O (2 ×). Finally, the resins were cleaved with 5% TFA
in CH2Cl2 for 20 min. The filtrate was evaporated and lyophilized
using t-BuOH–H2O (4:1).
A mixture of the appropriate aldehyde 1a–d (4 mmol), DMAP (50
mol%) and cyclohexenone (4 mmol) in dioxane–H2O (5 mL, 3:2)
mixture was stirred at r.t. for 7 d. Thereafter, the reaction mixture
was extracted with EtOAc (2 × 30 mL). The usual work-up of the
organic layer furnished a residue that was column chromatographed
over silica gel. Elution with a mixture of hexane–EtOAc (85:15) as
eluent yielded the starting aldehyde, while further elution with the
same eluent mixture with a ratio of 40:60 furnished the desired
products.
2-{Hydroxy-[5-methyl-3-(4-methylphenyl)isoxazol-4-yl]meth-
yl}acrylic Acid (13b)
Purity: 34% based on analytical HPLC of crude product (Rt 13.78
min at
= 220 nm in a gradient run of 0–100% MeCN in H2O
max
(containing 0.1% TFA) in 20 min on a RP-18e column (150 × 5
mm) having particle size of 5 m); yield: 21%; white solid; mp 165–
166 °C.
IR (KBr): 1697 (C=O), 3446 cm–1 (OH).
2-[Hydroxy-(5-methyl-3-phenylisoxazol-4-yl)methyl]cyclohex-
2-enone (9a)
Yield: 23%; yellow solid; mp 79–81 °C.
IR (KBr): 1668 (C=O), 3330 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 1.87–1.92 (m, 2 H, CH2), 2.24–
2.26 (m, 2 H, CH2), 2.37–2.42 (m, 2 H, CH2), 2.51 (s, 3 H, CH3),
3.38, 3.39 (d, 1 H, J = 3.4 Hz, OH), 5.30 (s, 1 H, CH), 6.64 (t, 1 H,
J = 4.0 Hz, =CH), 7.41–7.46 (m, 3 H, ArH), 7.52–7.55 (m, 2 H,
ArH).
1H NMR (CDCl3 + a drop of DMSO-d6, 200 MHz): = 2.38 (s, 3
H, CH3), 2.43 (s, 3 H, CH3), 2.76 (s, 1 H, OH), 5.54 (s, 1 H, CH),
5.88 (s, 1 H, =CHH), 6.28 (s, 1 H, =CHH), 7.20, 7.24 (d, 2 H, J = 8.0
Hz, ArH), 7.58, 7.62 (d, 2 H, J = 8.0 Hz, ArH).
MS (FAB+): m/z = 274 (M+ + 1).
Anal. Calcd for C15H15NO4: C, 65.92; H, 5.53; N, 5.13. Found: C,
66.18; H, 5.59; N, 4.81.
2-{[3-(2-Chlorophenyl)-5-methylisoxazol-4-yl]hydroxymeth-
yl}acrylic Acid (13c)
MS (FAB+): m/z = 284 (M+ + 1).
Anal. Calcd for C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C,
72.29; H, 5.85; N, 4.77.
Purity: 29% based on analytical HPLC of crude product (Rt 12.93
min at
= 220 nm in a gradient run of 0–100% MeCN in H2O
max
(containing 0.1% TFA) in 20 min on a RP-18e column (150 ×
5mm) having particle size of 5 m); yield: 19%; pale yellow solid;
mp 148–149 °C.
2-{Hydroxy-[5-methyl-3-(4-methylphenyl)isoxazol-4-yl]meth-
yl}cyclohex-2-enone (9b)
Yield: 25%; light brown solid; mp 79–81 °C.
IR (KBr): 1670 (C=O), 3336 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 1.91–1.98 (m, 2 H, CH2), 2.26–
2.28 (m, 2 H, CH2), 2.38–2.46 (m, 5 H, s of CH3 merged with m of
CH2), 2.49 (s, 3 H, CH3), 3.46 (br s, 1 H, OH), 5.64 (s, 1 H, CH),
6.66 (t, 1 H, J = 4.0 Hz, =CH), 7.18, 7.22 (d, 2 H, J = 8.0 Hz, ArH),
7.40, 7.44 (d, 2 H, J = 8.0 Hz, ArH).
IR (KBr): 1702 (acid C=O), 3395 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 2.50 (s, 3 H, CH3), 3.73 (s, 1 H,
OH), 5.35 (s, 1 H, CH), 5.82 (s, 1 H, =CHH), 6.32 (s, 1 H, =CHH),
7.31–7.48 (m, 4 H, ArH).
MS (FAB+): m/z = 293 (M+ + 1).
Anal. Calcd for C16H14ClNO5: C, 57.25; H, 4.12; N, 4.77. Found:
57.11; H, 4.39; N, 4.51.
MS (FAB+): m/z = 298 (M+ + 1).
Anal. Calcd for C18H19NO3: C, 72.71; H, 6.44; N, 4.71. Found: C,
72.98; H, 6.08; N, 5.00.
Acetylation of Alcohols 4, 7c,e; General Procedure
To a stirred solution of the appropriate alcohol 4, 7c,e (3.25 mmol)
in anhyd CH2Cl2 (5 mL) was added pyridine (0.48 mL, 6.0 mmol)
followed by dropwise addition of a solution of acetyl chloride (0.46
mL, 6.5 mmol) in anhyd CH2Cl2 (3 mL) at 0 °C. After the addition
was complete, the stirring was continued at r.t. for 1 h. The reaction
mixture was extracted with CH2Cl2 (2 × 30 mL) and H2O (50 mL).
The organic layers were combined, washed with brine, dried
(Na2SO4) and evaporated to give an oily residue. The residue was
purified on a small band of silica gel (60–120 mesh) using hexane–
EtOAc (85:15) as eluent to obtain pure acetates.
2-{[3-(2-Chlorophenyl)-5-methylisoxazol-4-yl]hydroxymeth-
yl}cyclohex-2-enone (9c)
Yield: 17%; pale yellow oil.
IR (neat): 1664 (C=O), 3398 cm–1 (OH).
1H NMR (CDCl3, 200 MHz): = 1.79–1.88 (m, 2 H, CH2), 2.15–
2.21 (m, 2 H, CH2), 2.23–2.30 (m, 2 H, CH2), 2.56 (s, 3 H, CH3),
3.08, 3.10 (d, 1 H, J = 3.8 Hz, OH), 5.36, 5.38 (d, 1 H, J = 3.8 Hz,
CH), 6.58 (t, 1 H, J = 4.0 Hz, =CH), 7.32–7.46 (m, 4 H, ArH).
MS (FAB+): m/z = 317 (M+ + 1).
2-{Acetoxy-[3-(2-chlorophenyl)-5-methylisoxazol-4-yl]meth-
yl}acrylic Acid Methyl Ester (10c)
Yield: 85%; white solid; mp 93–95 °C.
IR (KBr): 1708 (ester C=O), 1745 cm–1 (acetyl C=O).
Anal. Calcd for C17H16ClNO3: C, 64.26; H, 5.08; N, 4.41. Found: C,
64.45; H, 5.08; N, 4.56.
1H NMR (CDCl3, 200 MHz): = 2.06 (s, 3 H, CH3), 2.56 (s, 3 H,
CH3), 5.36 (s, 1 H, =CHH), 6.12 (s, 1 H, =CHH), 6.45 (s, 1 H, CH),
7.22–7.47 (m, 4 H, ArH).
Baylis–Hillman Reaction of Substituted 4-Isoxazolecarbalde-
hydes 3b,c with Acrylic Acid on Solid Support; General Proce-
dure
The 2-chlorotrityl chloride resin (200 mg, 1.4 mmol/g, Novabio-
chem) after swelling in anhyd CH2Cl2 was treated with acrylic acid
(4 equiv) and Et3N (6 equiv) in CH2Cl2 as reported earlier.6d Two PP
syringes fitted with frits were charged with the resins. To each of
this reaction vessel, DABCO (3 equiv) in DMF (200 L) was added
and left aside for 15 min. Thereafter, a solution of different alde-
hydes 3b,c (5 equiv) in DMF (300 L) was added to the respective
reaction vessel and the reaction mixture was shaken at 600 rpm. Af-
ter 48 h, the reaction sequence was repeated for another 48 h. There-
after, the resins were washed with DMF (3 ×), MeOH (3 ×), CH2Cl2
13C NMR (CDCl3, 50.32 MHz): = 12.08 (CH3), 21.11 (CH3),
52.43 (CH3), 64.89 (CH), 111.89 (C), 125.98 (CH2), 126.63 (CH),
128.87 (CH), 129.89 (CH), 131.21 (CH), 132.17 (CH), 134.56 (C),
136.69 (C), 160.88 (C), 165.27 (C), 169.46 (C).
MS (FAB+): m/z = 350 (M+ + 1).
Anal. Calcd for C17H16ClNO5: C, 58.38; H, 4.61; N, 4.00. Found: C,
58.49; H, 4.43; N, 4.05.
Synthesis 2003, No. 9, 1347–1356 ISSN 1234-567-89 © Thieme Stuttgart · New York

PAPER
Baylis–Hillman Reaction of Substituted 4-Isoxazolecarbaldehydes
1355
2-{Acetoxy-[3-(2,4-dichlorophenyl)-5-methylisoxazol-4-yl]me-
thyl}acrylic Acid Methyl Ester (10e)
(CH), 131.48 (CH), 131.90 (CH), 132.21 (CH), 133.73 (2 C),
135.52 (2 C), 140.09 (2 C), 161.07 (2 C), 167.11 (2 C), 167.68 (2 C).
Yield: 82%; white solid; mp 76–78 °C.
IR (KBr): 1704 (ester C=O), 1738 cm–1 (acetyl C=O).
1H NMR (CDCl3, 200 MHz): = 2.06 (s, 3 H, CH3), 2.56 (s, 3 H,
CH3), 5.44 (s, 1 H, =CHH), 6.16 (s, 1 H, =CHH), 6.43 (s, 1 H, CH),
7.24–7.35 (m, 2 H, ArH), 7.48–7.49 (m, 1 H, ArH).
MS (FAB+): m/z = 397 (M+ + 1).
Anal. Calcd for C22H21ClN2O3: C, 66.58; H, 5.33; N, 7.06. Found:
C, 66.77; H, 5.39; N, 6.95.
(E/Z)-2-(Benzylaminomethyl)-3-[3-(2,4-dichlorophenyl) -5-me-
thylisoxazol-4-yl]acrylic Acid Methyl Ester (14e)
Yield: 75%; mixture of E- and Z-isomers (colorless oil).
IR (neat): 1714 (ester C=O), 3350 cm–1 (NH).
MS (FAB+): m/z = 384 (M+ + 1).
Anal. Calcd for C17H15Cl2NO5: C, 53.14; H, 3.94; N, 3.65. Found:
C, 52.88; H, 3.91; N, 3.70.
1H NMR (CDCl3, 200 MHz): (E-isomer) = 2.45 (s, 3 H, CH3), 3.16
(s, 2 H, CH2), 3.45 (s, 3 H, CO2CH3), 3.77 (s, 2 H, CH2), 7.15–7.39
(m, 8 H, 7 × ArH and =CH2), 7.48 (s, 1 H, ArH); (Z-isomer) =
2.37 (s, 3 H, CH3), 3.49 (s, 2 H, CH2), 3.56 (s, 3 H, CO2CH3), 3.71
(s, 2 H, CH2), 6.48 (s, 1 H, =CH2), 7.15–7.39 (m, 7 H, 7 × ArH),
7.48 (s, 1 H, ArH).
Acetic Acid 1-[3-(2-Chlorophenyl)-5-methylisoxazol-4-yl]-2-cy-
anoallyl Ester (11c)
Yield: 88%; white solid; mp 49–51 °C.
IR (neat): 1750 (acetyl C=O), 2231 cm–1 (C≡N).
1H NMR (CDCl3, 200 MHz): = 2.09 (s, 3 H, CH3), 2.61 (s, 3 H,
CH3), 5.68, 5.69 (d, 1 H, J = 1.4 Hz, =CHH), 5.91, 5.92 (d, 1 H,
J = 1.4 Hz, =CHH), 6.13 (s, 1 H, CH), 7.35–7.47 (m, 4 H, ArH).
Mass (FAB+): m/z = 430 (M+ + 1).
Anal. Calcd for C22H20Cl2N2O3: C, 61.26; H, 4.67; N, 6.49. Found:
C, 61.22; H, 4.51; N, 6.60.
MS (FAB+): m/z = 317 (M+ + 1).
Anal. Calcd for C16H13ClN2O3: C, 60.67; H, 4.14; N, 8.84. Found:
C, 60.93; H, 4.14; N, 8.92.
(Z)-2-(Benzylaminomethyl)-3-[3-(2-chlorophenyl)-5-methyl-
isoxazol-4-yl]acrylonitrile (15c)
Yield: 69%; colorless oil.
IR (neat): 2218 (C N), 3399 cm–1 (NH).
Acetic Acid 2-Cyano-1-[3-(2,4-dichlorophenyl)-5-methylisox-
azol-4-yl]allyl Ester (11e)
Yield: 86%; white solid; mp 80–82 °C.
IR (neat): 1744 (acetyl C=O), 2232 cm–1 (C≡N).
1H NMR (CDCl3, 200 MHz): = 2.11 (s, 3 H, CH3), 2.61 (s, 3 H,
CH3), 5.76 (s, 1 H, =CHH), 5.97 (s, 1 H, =CHH), 6.12 (s, 1 H, CH),
7.31–7.39 (s, 2 H, ArH), 7.50–7.53 (m, 7 H, ArH).
1H NMR (CDCl3, 200 MHz): = 2.60 (s, 3 H, CH3), 3.47 (s, 2 H,
CH2), 3.74 (s, 2 H, CH2), 6.72 (s, 1 H, =CH), 7.19–7.52 (m, 5 H,
ArH and NH).
13C NMR (CDCl3, 50.32 MHz): = 14.11 (CH3), 51.65 (CH2),
52.23 (CH2), 112.08 (C), 117.18 (C), 117.61 (C), 127.60 (CH),
127.80 (CH), 128.23 (C), 128.63 (2 CH), 128.98 (2 CH), 130.44
(CH), 131.84 (CH), 132.25 (CH), 133.81 (CH), 139.18 (2 C),
161.01 (C), 168.54 (C).
MS (FAB+): m/z = 351 (M+ + 1).
Anal. Calcd for C16H12Cl2N2O3: C, 54.72; H, 3.44; N, 7.98. Found:
C, 54.54; H, 3.38; N, 7.60.
MS (FAB+): m/z = 364 (M+ + 1).
Anal. Calcd for C21H18ClN3O: C, 69.32; H, 4.99; N, 11.55. Found:
C, 69.52; H, 5.12; N, 11.66%.
Attempted Conversion of Baylis–Hillman Products to Annulat-
ed Isoxazoles
1. Reaction with Benzylamine; General Procedure
To the appropriate acetate 10, 11c,e (0.7 mmol) in THF was added
Et3N (0.2 mL, 1.4 mmol) followed by benzylamine (0.234 mL, 2.1
mmol) and the mixture was refluxed under stirring in an oil bath.
After completion of the reaction, the mixture was extracted with
EtOAc (2 × 30 mL) and H2O (40 mL). The combined organic layers
were dried (Na2SO4) and evaporated to obtain an oily residue. The
amines 14c,e were purified by chromatography on basic alumina
using hexane–EtOAc (75:25) as eluent. Amines 15c,e were purified
on silica gel (230-400 mesh) using hexane–EtOAc (70:30) as elu-
ent.
(Z)-2-(Benzylaminomethyl)-3-[3-(2,4-dichlorophenyl) -5-meth-
ylisoxazol-4-yl]acrylonitrile (15e)
Yield: 79%; off white solid; mp 85–86 °C.
IR (neat): 2218 (C≡N), 3399 cm–1 (NH).
1H NMR (CDCl3, 200 MHz): = 2.59 (s, 3 H, CH3), 3.48 (s, 2 H,
CH2), 3.75 (s, 2 H, CH2), 6.72 (s, 1 H, =CH), 7.20–7.31 (m, 5 H,
ArH), 7.38 (s, 2 H, ArH), 7.50 (s, 1 H, NH).
13C NMR (CDCl3, 50.32 MHz): = 14.05 (CH3), 51.89 (CH2),
52.56 (CH2), 112.03 (C), 117.60 (C), 117.98 (C), 126.89 (C),
127.78 (CH), 128.06 (CH), 128.48 (2 CH), 128.97 (2 CH), 130.40
(CH), 132.91 (CH), 133.05 (CH), 134.57 (C), 137.39 (C), 139.52
(C), 160.19 (C), 168.77 (C).
2-(Benzylaminomethyl)-3-[3-(2-chlorophenyl)-5-methylisox-
azol-4-yl]acrylic Acid Methyl Ester (14c)
Yield: 81%; mixture of E- and Z-isomers (colorless oil).
MS (FAB+): m/z = 398 (M+ + 1).
IR (neat): 1718 (ester C=O), 3350 cm–1 (NH).
Anal. Calcd for C21H17Cl2N3O: C, 63.33; H, 4.30; N, 10.55. Found:
C, 62.93; H, 4.65; N, 10.25.
1H NMR (CDCl3, 200 MHz): (E-isomer) = 2.45 (s, 3 H, CH3), 3.18
(s, 1 H, NH), 3.56 (s, 5 H, CH2 merged with CO2CH3), 3.76 (s, 2 H,
CH2), 7.15–7.48 (s, 10 H, =CH merged with ArH); (Z-isomer) =
2.38 (s, 3 H, CH3), 3.18 (s, 1 H, NH), 3.43 (s, 2 H, CH2), 3.56 (s, 3
H, CO2CH3), 3.70 (s, 2 H, CH2), 6.49 (s, 1 H, =CH), 7.15–7.48 (s, 9
H, ArH).
13C NMR (CDCl3, 50.32 MHz): (E/Z-isomeric mixture) = 12.38
(CH3), 12.49 (CH3), 46.32 (CH2), 52.22 (2 CH2), 52.47 (2 CH3),
53.74 (CH2), 112.14 (C), 112.87 (C), 125.99 (CH), 127.21 (2 CH),
127.47 (2 CH), 128.45 (2 CH), 128.54 (2 CH), 128.76 (2 CH),
128.99 (CH), 129.30 (CH), 130.41 (CH), 130.56, (CH), 131.27
2. Reaction with Nitroethane; General Procedure
To a prestirred mixture of K2CO3 (414 mg, 3.0 mmol) and nitroet-
hane (0.14 mL, 2.0 mmol) in DMF (3 mL) was added a solution of
the appropriate 10c,e (1.0 mmol) in DMF and the reaction mixture
was stirred at 60 °C for 1 h. Thereafter the mixture was neutralized
with aq HCl (20%). Usual work-up of the mixture led to an oily res-
idue that was purified through column chromatography using hex-
ane–EtOAc (85:15) as eluent.
Synthesis 2003, No. 9, 1347–1356 ISSN 1234-567-89 © Thieme Stuttgart · New York

1356
A. K. Roy, S. Batra
PAPER
(5) (a) Franck, X.; Figadère, B. Tetrahedron Lett. 2002, 43,
(E)-3-[3-(2-Chlorophenyl)-5-methylisoxazol-4-yl]-2-(2-nitro-
propyl)acrylic Acid Methyl Ester (17c)
Yield: 79%; pale yellow oil.
IR (neat): 1718 (ester C=O), 1656, 1550 cm–1 (NO2).
1H NMR (CDCl3, 200 MHz): = 1.31, 1.34 (d, 3 H, J = 6.6 Hz,
CH3), 2.24–2.35 (m, 1 H,CHH), 2.43 (s, 3 H, CH3), 2.60–2.71 (m, 1
H,CHH), 3.78 (s, 3 H, CO2CH3), 4.65–4.78 (m, 1 H, CH), 7.35–7.50
(m, 5 H, 4 × ArH merged with =CH).
1449. (b) Detterbeck, R.; Hesse, M. Tetrahedron Lett. 2002,
43, 6887. (c) Anand, R. V.; Bakhtram, S.; Singh, V. K.
Tetrahedron Lett. 2002, 43, 5393. (d) Iwabuchi, Y.;
Sugihara, T.; Esumi, T.; Hatakeyama, S. Tetrahedron Lett.
2001, 42, 7867.
(6) (a) Patra, A.; Roy, A. K.; Batra, S.; Bhaduri, A. P. Synlett
2002, 8319. (b) Batra, S.; Rastogi, S. K.; Kundu, B.; Patra,
A.; Bhaduri, A. P. Tetrahedron Lett. 2000, 41, 5971.
(c) Rastogi, S. K.; Gupta, P.; Srinivasan, T.; Kundu, B. Mol.
Div. 2000, 5, 91. (d) Richter, H.; Walk, T.; Holtzel, A.;
Jung, G. J. Org. Chem. 1999, 64, 1364.
(7) (a) Sajiki, H.; Yamada, A.; Yasunaga, K.; Tsunada, T.;
Amer, M. F. A.; Hirota, K. Tetrahedron Lett. 2003, 44,
2179. (b) Zhu, S.; Hudson, T. H.; Kyle, D. E.; Lin, A. J. J.
Med. Chem. 2002, 45, 3491. (c) Pathak, R.; Pant, C. S.;
Shaw, A. K.; Bhaduri, A. P.; Gaikwad, A. N.; Sinha, S.;
Srivastava, A.; Srivastava, K. K.; Chaturvedi, V.;
Srivastava, R.; Srivastava, B. S. Bioorg. Med. Chem. 2002,
10, 3187.
(8) (a) MDDR in MDL database. (b) Nantermet, P. G.; Barow,
J. C.; Lundell, G. F.; Pellicore, J. M.; Rittle, K. E.; Young,
M. B.; Friedanger, R. M.; Connoly, T. M.; Condra, C.;
Karczewski, J.; Bednar, R. M.; Gaul, S. L.; Gould, R. J.;
Prendergast, K.; Selnick, H. G. Bioorg. Med. Chem. Lett.
2002, 12, 319. (c) Zamponi, G. W.; Stotz, S. C.; Staples, R.
J.; Andro, T. M.; Nelson, J. K.; Hulubei, V.; Blumenfeld, A.;
Natale, N. R. J. Med. Chem 2003, 46, 87.
Mass (ES+): m/z = 365.60 (M+ + 1), 387.27 (M+ + Na).
Anal. Calcd for C17H17ClN2O5: C, 55.97; H, 4.70; N, 7.68. Found:
C, 56.08; H, 4.99; N, 7.63.
(E)-3-[3-(2,4-Dichlorophenyl)-5-methylisoxazol-4-yl]-2-(2-ni-
tropropyl)acrylic Acid Methyl Ester (17e)
Yield: 77%; white solid; mp 115–116 °C.
IR (KBr): 1713 (ester C=O), 1643, 1546 cm–1 (NO2).
1H NMR (CDCl3, 200 MHz): = 1.35, 1.38 (d, 3 H, J = 6.6 Hz,
CH3), 2.31–2.40 (m, 1 H, CHH), 2.43 (s, 3 H, CH3), 2.60–2.70 (m,
1 H, CHH), 3.79 (s, 3 H, CO2CH3), 4.76–4.80 (m, 1 H, CH), 7.32–
7.42 (m, 3 H, 2 × ArH merged with =CH), 7.49 (s, 1 H, ArH).
13C NMR (CDCl3, 50.32 MHz): = 12.54 (CH3), 19.52 (CH3),
34.16 (CH2), 52.82 (CH3), 81.91 (CH), 111.47 (C), 127.24 (C),
128.00 (CH), 130.50 (CH), 131.35 (C), 131.45 (CH), 132.78 (CH),
130.44 (CH), 134.41 (C), 137.11 (C), 159.80 (C), 166.64 (C),
168.02 (C).
Mass (FAB+): m/z = 399 (M+ + 1).
(9) Patra, A.; Batra, S.; Kundu, B.; Joshi, B. S.; Roy, R.;
Bhaduri, A. P. Synthesis 2001, 276.
(10) Patra, A.; Batra, S.; Bhaduri, A. P.; Khanna, A. K.; Chander,
R.; Dikshit, M. Bioorg. Med. Chem. 2003, 11, 2269; and
references cited therein.
Anal. Calcd for C17H16Cl2N2O5: C, 51.14; H, 4.04; N, 7.02. Found:
C, 50.83; H, 4.10; N, 6.83.
(11) Patra, A.; Batra, S.; Joshi, B. S.; Roy, R.; Kundu, B.;
Bhaduri, A. P. J. Org. Chem. 2002, 67, 5783.
(12) Batra, S.; Srinivasan, T.; Rastogi, S. K.; Kundu, B.; Patra,
A.; Bhaduri, A. P.; Dikshit, M. Bioorg. Med. Chem. Lett.
2002, 12, 1905.
Acknowledgments
One of the authors (AKR) gratefully acknowledges the financial
support in the form of a fellowship from ICMR, India. The authors
also acknowledge the help extended by Mr. Rajesh K. Grover SRF
(CSIR) towards carrying out the NOE studies.
(13) Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed. Engl.
1983, 22, 795.
(14) (a) Kim, J. N.; Kim, H. S.; Gong, J. H.; Chung, Y. M.
Tetrahedron Lett. 2001, 42, 8341. (b) Kim, J. N.; Yang, J. I.;
Gong, J. H.; Lee, K. Y. Tetrahedron Lett. 2001, 42, 4195.
(15) Doyle, F. P.; Hanson, J. C.; Long, A. A. W.; Nayler, J. H. C.;
Stove, E. R. J. Chem Soc. 1963, 5838.
(16) Masunari, A.; Ishida, E.; Trazzi, G.; Almeida, W. P.; Coelho,
F. Synth. Commun. 2001, 31, 2127.
(17) Basavaiah, D.; Rao, A. J.; Krishnamacharyulu, M. Arkivoc
2002, VII, 136; www.arkat-usa.org.
(18) Patra, A.; Roy, A. K.; Joshi, B. S.; Roy, R.; Batra, S.;
Bhaduri, A. P. Tetrahedron 2003, 59, 633.
(19) Chamakh, A.; M’hirsi, M.; Villieras, J.; Lebreton, J.; Amri,
H. Synthesis 2000, 295.
References
(1) CDRI Communication No. 6389.
(2) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811.
(3) (a) Cai, J.; Zhou, Z.; Zhao, G.; Tang, C. Org. Lett. 2002, 4,
4723. (b) Lee, K. Y.; Gong, J. H.; Kim, J. N. Bull. Korean
Chem. Soc. 2002, 23, 659. (c) Yu, C.; Liu, B.; Hu, L. J. Org.
Chem. 2001, 66, 5413. (d) Auge, J.; Lubin, N.; Lubineau, A.
Tetrahedron Lett. 1994, 35, 7947.
(4) (a) Kim, J. N.; Lee, K. Y. Curr. Org. Chem. 2002, 6, 627.
(b) Kaye, P. T.; Musa, M. A. Synthesis 2002, 2701. (c) Lee,
K. Y.; Kim, J. M.; Kim, J. N. Tetrahedron 2003, 59, 385.
(d) Lee, K. Y.; Kim, J. M.; Kim, J. N. Synlett 2003, 357.
Synthesis 2003, No. 9, 1347–1356 ISSN 1234-567-89 © Thieme Stuttgart · New York