Studies on the catalytic hydrogenation of Baylis-Hillman derivatives of substituted isoxazolecarbaldehydes. Unusual retention of isoxazole ring during Pd-C-promoted hydrogenation of Baylis-Hillman adducts

Article abstract of DOI:10.1016/j.tet.2004.08.068

Results of the catalytic hydrogenation of Baylis-Hillman adducts obtained from substituted 3-, 4- and 5-isoxazolecarbox-aldehydes and their corresponding acetates in the presence of Raney-Ni and Pd-C are presented. The hydrogenation of Baylis-Hillman addu

Full text of DOI:10.1016/j.tet.2004.08.068

Tetrahedron 60 (2004) 10311–10320
Studies on the catalytic hydrogenation of Baylis–Hillman
derivatives of substituted isoxazolecarbaldehydes. Unusual
retention of isoxazole ring during Pd–C-promoted hydrogenation
of Baylis–Hillman adducts*,**
*
R. Saxena, V. Singh and S. Batra
Medicinal Chemistry Division, Central Drug Research Institute, PO Box 173, Lucknow 226 001, India
Received 28 May 2004; revised 27 July 2004; accepted 19 August 2004
Abstract—Results of the catalytic hydrogenation of Baylis–Hillman adducts obtained from substituted 3-, 4- and 5-isoxazolecarbox-
aldehydes and their corresponding acetates in the presence of Raney-Ni and Pd–C are presented. The hydrogenation of Baylis–Hillman
adducts of substituted 5-isoxazolecarbaldehydes and 3-isoxazolecarbaldehydes in the presence of Raney-Ni furnishes diastereoselectively
syn enaminones over anti and in the presence of boric acid as an additive further enhancement of diastereoselectivity in favor of syn isomer is
observed. The Pd–C-promoted hydrogenation of these substrates is also diastereoselective in favor of syn isomer but occurs without the
hydrogenolysis of isoxazole-ring. The presence of boric acid as an additive in this hydrogenation exhibits no pronounced effect on
diastereoselectivity. The Raney-Ni-mediated hydrogenation of Baylis–Hillman adducts of substituted 4-isoxazolecarbaldehydes yield
pyridone derivatives and Pd–C-promoted hydrogenation of the same substrate is diastereoselective to afford the anti isomer of the resulting
products. The enaminones derived from Baylis–Hillman adducts of 3- and 5-isoxazolecarbaldehydes serve as versatile precursors for a0-
hydroxy-1,3-diketones, which undergo acid-catalyzed ring-closure reaction to afford the furanone derivatives in excellent yields.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
earlier reported.11–14 While these detailed studies address
the issue of diastereoselectivity in the reduced product under
different additives and solvent conditions, the fate of the
Baylis–Hillman adducts during hydrogenation in the
presence of Raney-Ni remains unreported. Since
the isoxazole ring is known to undergo hydrogenolysis in
the presence of Raney-Ni and Pd–C,15–18 it was desired to
evaluate the effect of these catalysts on the Baylis–Hillman
adducts of substituted isoxazolecarbaldehydes. During the
course of this study we have noted some unusual and
interesting observations, which prompt us to report our
findings.
The isoxazole heterocycle represents masked b-enaminone
and 1,3-dione systems because of the lability of the N–O
bond towards catalytic and chemical reductions under mild
conditions.1–5 This ability of the isoxazole-ring besides
making it a useful synthetic intermediate also evokes
interest to understand reasons for biological activity because
our interest in the Baylis–Hillman chemistry of isoxazole-
carbaldehydes has not only led us to generate novel
isoxazole-based synthetic intermediates but has also led to
identification of bioactive compounds.6–10
The hydrogenation studies of the Baylis–Hillman adduct
and their corresponding derivatives under heterogeneous
catalytic conditions with Pd–C and rhodium have been
2. Results and discussion
The hydrogenation of the Baylis–Hillman adducts 2a–c and
3b, originating from substituted 5-isoxazolecarbaldehydes
1a–c, in the presence of Raney-Ni in appropriate solvent led
to diastereoisomeric mixtures of the enaminones 4a–c and
5b, respectively (Scheme 1). Beside other spectroscopic
evidence, the opening of the isoxazole-ring was character-
ized by the presence of two broad singlets for NH2 protons
and an upfield shift of the isoxazole ]CH proton from d
* CDRI Communication no. 6565.
* * Presented in portion as poster at IUPAC-BNP-2004, 26th–31st,
January, 2004. PN-342.
Keywords: Baylis–Hillman; Isoxazolecarbaldehyde; Hydrogenation;
Raney-Ni; Pd–C; Enaminones; Furanone.
* Corresponding author. Tel.: C91-522-2212411-18x4368; fax: C91-522-
2223405,2223938; e-mail: batra_san@yahoo.co.uk
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.068

10312
R. Saxena et al. / Tetrahedron 60 (2004) 10311–10320
Scheme 1. Reagents and conditions (a) CH2]CHEWG, DABCO, 30 min (b) Raney-Ni, H2 (balloon at rt or Parr assembly at 30 psi), MeOH, 3 h (c) Pd–C, H2,
(balloon at rt or Parr assembly at 30 psi), MeOH or EtOAc, 2–2.5 h (6b to 4b, 10 h) (d) CH3COCl, pyridine, CH2Cl2, rt, 3–5 h (e) NaBH4, MeOH, rt, 2 h (f)
DABCO, NaBH4, THF: H2O (1:1), rt, 15 min (g) HC (HCl, H2SO4, CH3CO2H at rt, or mixture of HCO2H and CH3CO2H at 60 8C), 24 h.
6.5–5.5 of enaminone in the 1H NMR spectrum. The
hydrogenation of 3b in particular aimed to understand the
influence of the ester group on the outcome of hydrogen-
ation. The analyses of the stereochemistry of the hydrogen-
ation products were based on their 1H NMR spectra, which
revealed syn selectivity over the anti products in the range
of 2–2.5:1. Compared to these observations, the Pd–C
promoted catalytic hydrogenation of compounds 2a–c using
methanol or ethyl acetate as solvent gave diastereoisomeric
mixture of products 6a–c. The absence of the signal for the
amino group of the enamine and the unchanged chemical
result was contrary to the previous literature reports where
hydrogenolysis of the isoxazole ring under similar con-
ditions has been reported.19–21 In these cases, the reaction
was also diastereoselective in favor of syn isomer over anti
(ratio of 3:1). In our attempts to understand this unusual
behavior, the Pd–C-mediated hydrogenation was carried out
under different conditions. In the first instance in a
representative example, the Pd–C promoted hydrogenation
of compound 2b was continued for more than 24 h but no
hydrogenolysis was observed and compound 6b was
isolated exclusively. Thereafter, the reaction was carried
out with an excess of catalyst (ca. 3–5 fold) without any
success. Successively, the compound 6b was again
subjected to hydrogenation in the presence of Pd–C.
Interestingly this reaction was completed within 10 h to
1
shift of the ]CH proton of the isoxazole-ring in the H
NMR spectra coupled with mass spectra of these com-
pounds indicated that only the reduction of the methylene
group had occurred with retention of isoxazole-ring. This
Scheme 2. Reagents and conditions (a) CH2]CHCO2Me, DABCO, 30 min (b) Raney-Ni, H2 (balloon at rt or Parr assembly at 30 psi), MeOH, 3 h (c) Pd–C,
H2, (Balloon at rt or Parr assembly at 30 psi), MeOH or EtOAc, 2–2.5 h, (20b to 19b, 10 h) (d) CH3COCl, pyridine, CH2Cl2, rt, 2–3 h (e) DABCO, NaBH4,
THF: H2O (1:1), rt, 15 min (f) HC (HCl, H2SO4, CH3CO2H at rt, or mixture of HCO2H and CH3CO2H at 60 8C), 24 h.

R. Saxena et al. / Tetrahedron 60 (2004) 10311–10320
10313
Scheme 3. Reagents and conditions (a) CH2]CHCO2Me, DABCO, 2d (b) Raney-Ni, H2 (balloon at rt or Parr assembly at 30 psi), MeOH, 3 h (c) Pd–C, H2,
(balloon at rt or Parr assembly at 30 psi), MeOH or EtOAc, 2–2.5 h (d) CH3COCl, pyridine, CH2Cl2, rt, 1 h (e) PBr3, CH2Cl2, rt, 45 min.
yield the hydrogenolysis products 4b exclusively. In view of
these results, we next examined the hydrogenation of the
Baylis–Hillman adducts of 3- and 4-isoxazolecarbalde-
hydes. Similar to reactions of the Baylis–Hillman adducts of
5-isoxazolecarbaldehydes, the hydrogenation of the Baylis–
Hillman adducts (18a–b, d), derived from substituted
3-isoxazolecarbaldehydes (17a–b, d) in the presence of
Raney-Ni led to isolation of envisaged enaminones (19a–b,
d) in good yields (Scheme 2). The observed diastereo-
selectivity in favor of syn isomer over the anti isomer was
slightly better as compared to the enaminones derived from
Baylis–Hillman derivatives of 5-isoxazolecarbaldehydes
because the ratio ranged from 4 to 5:1. The hydrogenation
of adducts 18a–b, d in the presence of Pd–C afforded
diastereoisomeric mixtures (syn:anti, 2:1) of products
20a–b, d without the hydrogenolysis of the isoxazole ring.
However when compound 20b was again subjected to
hydrogenation, the hydrogenolysis of the isoxazole-ring did
occur to afford enaminone 19b. Interestingly when the
Baylis–Hillman adducts (27a–b), derived from substituted
4-isoxazolecarbaldehydes, were subjected to hydrogenation
in the presence of Raney-Ni; the envisaged enaminones
(28a–b) could not be isolated. The two products isolated
from the reaction were identified as substituted pyridones
29a–b and enaminones 30a–b (Scheme 3). The formation of
the minor product namely the pyridone derivative (29a–b)
can be rationalized on the basis of hydrogenolysis of the
isoxazole ring followed by ring closure involving the amino
and the ester group followed by dehydration.22 The
plausible explanation for the formation of compound 30 is
shown in Figure 1. However the hydrogenation of
compounds 27a–c in the presence of Pd–C was stereo-
specific to afford the anti isomer of products 31a–c without
the cleavage of the isoxazole-ring. Since enaminones 28a–b
were not isolated during the hydrogenolysis of compounds
27a–b, no attempts were made to carry out Pd–C-promoted
hydrogenolysis of compounds 31a–c.
In the next stage of the study we directed our attention
towards evaluating the effect of hydrogenation on the
acetates derived from the Baylis–Hillman adducts of
substituted isoxazolecarbaldehydes. The Raney-Ni pro-
moted hydrogenolysis of acetates 7a–b and 8b led to
enaminones 9a–b and 10b, respectively (Scheme 1). Such
products may have resulted via hydrogenolysis of the
isoxazole-ring with simultaneous loss of acetic acid
followed by the reduction of the double bond in the
intermediate. In principle, a product similar to compound 9
could be generated from compound 12 or 13, which in turn
can be easily synthesized through reaction of sodium
borohydride with the acetate (7) under appropriate con-
ditions.9,10 In order to obtain chemical evidence for the
formation of compounds 9–10, compounds 12b and 13b
were subjected to hydrogenation in the presence of Raney-
Ni. As envisaged both reactants led to the product 9b in
good yield. To evaluate the fate of hydrogenation in the
presence of Pd–C, acetates 7a–b were subjected to
hydrogenation in the presence of this catalyst. Unlike the
corresponding Baylis–Hillman adduct (2a–b), the acetates
(7a–b) invariably furnished a separable mixture of two
products. The non-polar products were identified as 11a–b
while the polar products were 6a–b (Scheme 1). The
formation of compounds 11a–b could be rationalized based
on a similar mechanism for compounds 9–10 except for the
cleavage of the isoxazole-ring. As reported earlier13
compound 6 may have resulted from simple reduction of
Figure 1.

10314
R. Saxena et al. / Tetrahedron 60 (2004) 10311–10320
the double bond with simultaneous deacetylation. In
accordance with the literature precedence,13 we too did
not observe diastereoselectivity during the formation of
product 6. The additional chemical evidence for the
formation of product 11 was achieved by Pd–C-mediated
hydrogenation of compounds 12b and 13b, which furnished
the product 11b. Further evidence for the assigned structure
to compound 11 came from the Raney-Ni promoted
hydrogenolysis of 11b to furnish compound 9b. In addition,
when compound 11b was subjected to hydrogenation in the
presence of Pd–C the hydrogenolysis of the isoxazole-ring
does occur to yield compound 9b.
The formation of compounds 34a–c was in contrast to other
Pd–C mediated reactions carried out during this study where
the ring-cleavage did not take place. Thus the extensive
hydrogenation studies carried out herein indicate that the
behavior of the Baylis–Hillman derivatives of 5- and
3-isoxazolecarbaldehydes is very much similar during the
Raney-Ni and the Pd–C-promoted reactions whereas the
Baylis–Hillman derivatives obtained from 4-isoxazole-
carbaldehydes yields significantly different products. The
change in the ester group does not affect the outcome of the
hydrogenation reaction. At this point of time the present
investigations do not impart any explanation for the stability
of the isoxazole ring during Pd–C-promoted hydrogenation
of derivatives of Baylis–Hillman reaction of isoxazole-
carbaldehydes. Nevertheless, once the double bond present
in the side-chain is saturated the hydrogenolysis of the
isoxazole-ring does take place in the presence of Pd–C.
The Raney-Ni catalyzed hydrogenation of acetates 21a–b, d
yielded exclusively the expected enaminones 22a–b, d in
good yields (Scheme 2). However the Pd–C promoted
hydrogenation of these acetates (21a–b) gave a mixture of
two products. Based on the spectroscopic evidence these
products were identified as 23a–b and 24a–b. Contrary to
the observation with the corresponding derivatives obtained
from 5-isoxazolecarbaldehydes (7), the deacetylation does
not occur during the process and only the reduced products
23 are obtained. Further the stereochemistry of compounds
23 was in favor of the anti isomer over syn by 7:3. To
unambiguously confirm the formation of products 24a–b,
hydrogenation of compound 24b in the presence of Raney-
Ni led to isolation of product 22b. The Pd–C promoted
hydrogenation of compound 25b, that was in turn generated
from the sodium borohydride-promoted SN20 nucleophilic
substitution of hydride on the acetate 21b, yielded the
product 24b.
It has been reported earlier that the a0-hydroxy-1,3-
diketones derived from isoxazoles provide a facile synthetic
method to obtain 3(2H)-furanones derivatives.23–25 In a
similar observation Chimichi et al. recently reported the
synthesis of substituted 3(2H)-furanones through appro-
priately substituted a0-hydroxy-1,3-diketones utilizing
isoxazoles as the starting substrate. As part of our objectives
to demonstrate the synthetic utility of the enaminones
synthesized during this study, compounds 4a–b, 5b and
19a–b, d were subjected to acid-promoted cyclization-
dehydration reaction. The reaction of compounds 4a–c, 5b
and 19a–b, d with HCl or H2SO4 led to the furanones 14a–d
and 15b in moderate yields only. However excellent yields
of furanones (14a–d and15b) were achieved when the same
reaction was carried out in the presence of a mixture of
acetic acid and formic acid (Scheme 1 and 2). To provide
chemical evidence for the fact that the formation of
furanones is via the cyclodehydration of the diketo
derivatives afforded by the enaminones in the presence of
acid, compound 10b was treated with acid to yield the
diketo-derivative 16b in quantitative yields. It has been
reported26 earlier that Raney-Ni-promoted hydrogenation of
2-isoxazolines and isoxazoles, in the presence of boric acid
leads to diketo-derivatives. To assess the possibility of
generating these furanones through one pot reaction we
decided to carry out the Raney-Ni-mediated hydrogenation
of 2a–c in the presence of boric acid.27 This hydrogenation
though did not yield the desired furanones; there was a
dramatic change in the degree of diastereoselectivity
(Scheme 4). The syn isomer was preferentially obtained
over anti isomer as shown in Table 1. Encouraged by this
observation we also subjected the Baylis–Hillman
The hydrogenation of acetates (32a–c) generated from
Baylis–Hillman adducts of substituted 4-isoxazolecarb-
aldehydes was found to be significantly different. The
hydrogenolysis of compounds 32a–c in the presence of
Raney-Ni invariably led to isolation of enaminones 34a–c
(Scheme 3). Unlike the reaction of other acetates described
earlier in this text, the hydrogenolysis of the isoxazole ring
here may have proceeded with simultaneous reduction of
the methylene group and elimination of acetic acid.
However, it seems that further reduction of double bond
possibly did not occur because of the steric impedance. On
the basis of NOE studies the stereochemistry of the product
34 was assigned as Z. In our efforts to gain further insight
into the formation of product 34, the allylic bromide 33b
was generated and subjected to hydrogenolysis in the
presence of Raney-Ni. This reaction also afforded com-
pound 34b. Similarly, the Pd–C catalyzed hydrogenation of
acetates 32a–c also led to the isolation of products 34a–c.
Scheme 4. Reagents and conditions (a) Raney-Ni, H2, H3BO3, rt, 6 h.

R. Saxena et al. / Tetrahedron 60 (2004) 10311–10320
10315
Table 1. Ratio of syn and anti enaminones derivative obtained without and
with boric acid during Raney-Ni promoted hydrogenation of Baylis–
Hillman adducts of 5 and 3-isoxazolecarbaldehydes
Ni (100 mg in ethanol) in methanol (10 mL) was subjected
to hydrogenation either in the Parr assembly at 35 psi at rt or
stirred in a sealed vessel having hydrogen atmosphere
maintained by a balloon. The reaction was allowed to
continue for 2.5 h. Thereafter, the catalyst was removed by
vacuum-filtering the reaction mixture through a celite bed
with methanol. The filtrate was evaporated to obtain an oily
residue which was taken in ethyl acetate (2!20 mL) and
washed with water (20 mL). The organic layers were
collected, dried over anhydrous Na2SO4 and the solvent
was evaporated in vacuo to obtain a crude oily product.
Purification of the crude product by column chromato-
graphy over silica gel (230–400 mesh) using hexane:ethyl
acetate (3:2, v/v) as the eluent furnished compound 4a as
yellow oil.
Compound
No.
Raney-Ni only
(syn:anti)
Raney-NiCboric acid
(syn:anti)
2a
2b
2c
3b
18a
18b
18d
4a (2:1)
4b (5:2)
4c (5:2)
5b (4:1)
19a (4:1)
19b (5:1)
19d (5:1)
4a (5:1)
4b (6:1)
4c (5:1)
5b (9:1)
19a (7:1)
19b (13:2)
19d (13:2)
derivatives 2a and 18a to Pd–C-promoted hydrogenation in
the presence of boric acid. However during the process, we
did not observe any significant change in the
diastereoselectivity.
4.2.1. 6-Amino-3-hydroxy-2-methyl-4-oxo-6-phenyl-hex-
5-enoic acid methyl ester (4a). 65% (0.34 g from 0.52 g of
2a); yellow oil; [found: C, 63.83; H, 6.19; N, 5.04.
C14H17NO4 requires C, 63.87; H, 6.51; N, 5.32]. nmax
(Neat) 1731 (CO2Me), 3406 (OH and NH2) cmK1; 1H NMR
(200 MHz, CDCl3) dZ1.07 (d, 3H, JZ7.0 Hz, –CH–
CH3anti), 1.26 (d, 3H, JZ7.2 Hz, –CH–CH3syn), 2.90–2.99
(m, 2H, 2!–CH–CH3), 3.69 (s, 3H, CO2CH3syn), 3.75 (s,
3H, CO2CH3anti), 4.34 (brs, 1H, –CH(OH)–CHanti), 4.70
(brs, 1H, –CH(OH)–CHsyn), 5.47 (s, 1H, ]CHsyn), 5.49 (s
merged with brs, 3H, ]CHanti and 2!1H of NH2), 7.44–
7.58 (m, 10H, ArH), 9.89 (brs, 2H, 2!1H of NH2); mass
(FABC) m/z 264 (MCC1).
3. Conclusions
In summary, we have described some interesting obser-
vations made during the Raney-Ni and Pd–C catalyzed
hydrogenation of the Baylis–Hillman adducts generated
from 3-, 4- and 5-isoxazolecarbaldehydes and their
corresponding acetates. For the first time we report here
the diastereoselective hydrogenation of the Baylis–Hillman
derivatives in the presence of Raney-Ni. During the course
of the present study better diastereoselectivity was achieved
by carrying out these hydrogenations in the presence of
boric acid. Presently, it is difficult to assign reason for
preservation of the isoxazole-ring in the Pd–C-promoted
hydrogenation of derivatives of Baylis–Hillman reaction
during this study. The enaminones generated from the
hydrogenation of Baylis–Hillman adducts of isoxazole-
carbaldehydes could serve as direct access to substituted a0-
hydroxy-1,3-diketones that are scarcely available.
4.2.2. 6-Amino-3-hydroxy-2-methyl-4-oxo-6-p-tolyl-hex-
5-enoic acid methyl ester (4b). 67% (1.34 g from 2.0 g of
2b); yellow oil; [found: C; 65.23, H, 6.72; N, 4.88.
C15H19NO4 requires C, 64.97; H, 6.91; N, 5.05]. nmax
(Neat) 1730 (CO2Me), 3402 (OH and NH2) cmK1; 1H NMR
(300 MHz, CDCl3) dZ1.07 (d, 3H, JZ7.2 Hz, –CH–
CH3anti), 1.26 (d, 3H, JZ7.2 Hz, –CH–CH3syn), 2.40 (s,
6H, 2!Ar–CH3), 2.87–2.97 (m, 2H, 2!–CH–CH3), 3.69
(s, 3H, CO2CH3syn), 3.74 (s, 3H, CO2CH3anti), 4.34 (t, 1H,
JZ6.0 Hz, –CH(OH)–CHanti), 4.68 (d, 1H, JZ3.0 Hz,
–CH(OH)–CHsyn), 5.45 (s, 1H, ]CHsyn), 5.48 (s, 1H,
]CHanti), 5.54 (brs, 2H, 2!1H of NH2), 7.25 (d, 4H, JZ
8.0 Hz, ArH), 7.45 (d, 4H, JZ8.0 Hz, ArH), 9.86 (brs, 2H,
2!1H of NH2); mass (ESC) m/z 300.73 (MCCNa).
4. Experimental
4.1. General
Melting points are uncorrected and were determined in
capillary tubes on a hot stage apparatus containing silicon
oil. IR spectra were recorded using a Perkin–Elmer RX I
4.2.3. 6-Amino-6-(2-chloro-phenyl)-3-hydroxy-2-methyl-
4-oxo-hex-5-enoic acid methyl ester (4c). 63% (0.72 g
from 1.14 g of 2c); yellow solid, mp 124–268C; [found: C,
56.85; H, 5.40; N, 4.44. C14H16ClNO4 requires C, 56.48; H,
5.42; N, 4.70]. nmax (KBr) 1730 (CO2Me), 3402 (OH and
1
FTIR spectrophotometer. H NMR and 13C NMR spectra
were recorded on either a 300 or a 200 MHz FT
spectrometer, using TMS as an internal standard (chemical
shifts in d values, J in Hz). The FABMS were recorded on
JEOL/ SX-102 spectrometers and ESMS were recorded
through direct flow injections in Merck M-8000 LCMS
system. Elemental analyses were performed on a Carlo Erba
1108 microanalyzer or Elementar’s Vario EL III micro-
analyzer. The spectroscopic data for all products obtained as
diastereoisomeric mixtures are presented as such and no
attempts were made to separate them. For preparation of
compounds 2, 7, 18, 21, 27 and 32 refer to Refs. 6, 8, 9.
1
NH2) cmK1; H NMR (200 MHz, CDCl3) dZ1.07 (d, 3H,
JZ7.0 Hz, –CH–CH3anti), 1.25 (d, 3H, JZ7.2 Hz, –CH–
CH3syn), 2.87–2.98 (m, 2H, 2!–CH–CH3), 3.67 (s, 3H,
CO2CH3syn), 3.72 (s, 3H, CO2CH3anti), 4.28 (brs, 1H,
–CH(OH)–CHanti), 4.67 (brs, 1H, –CH(OH)–CHsyn), 5.23
(s, 1H, ]CHsyn), 5.25 (s, 1H, ]CHanti), 6.18 (s, 2H, 2!1H
of NH2), 7.35–7.47 (m, 8H, ArH), 9.85 (brs, 2H, 2!1H of
NH2); mass (FABC) m/z 298 (MCC1).
4.2. Hydrogenation in the presence of Raney-Ni-
representative procedure
4.2.4. 6-Amino-3-hydroxy-2-methyl-4-oxo-6-p-tolyl-hex-
5-enoic acid ethyl ester (5b). 62% (0.62 g from 1.0 g from
3b); yellow solid, mp 118–120 8C; [found: C, 66.03; H,
6.98; N, 4.51. C16H21NO4 requires C, 65.96; H, 7.27; N,
A mixture of compound 2a (520 mg, 2.0 mmol) and Raney-

10316
R. Saxena et al. / Tetrahedron 60 (2004) 10311–10320
4.81]. nmax (KBr) 1726 (CO2Et), 3402 (OH and NH2) cmK1
1H NMR (200 MHz, CDCl3) dZ1.06 (d, 3H, JZ
7.2 Hz, –CH–CH3anti), 1.19–1.32 (m, 9H, –CH–CH3syn
;
]CHsyn), 5.72 (s, 1H, ]CHanti), 6.10 (brs, 2H, 2!1H of
NH2), 7.39–7.58 (m, 6H, ArH), 7.85–7.96 (m, 4H, ArH),
10.04 (brs, 2H, 2!1H of NH2), 11.40 (brs, 2H, 2!OH);
mass (FABC) m/z 264 (MCC1).
,
2!CH2CH3), 2.41 (s, 6H, 2!Ar–CH3), 2.80–2.91
(m, 2H, 2!–CH–CH3), 4.09–4.29 (m, 2q merged, 4H,
2!CO2CH2), 4.35 (d, 1H, JZ6.6 Hz, –CH(OH)–CHanti),
4.69 (d, 1H, JZ3.0 Hz, –CH(OH)–CHsyn), 5.48 (s, 1H,
]CHsyn), 5.49 (s, 1H, ]CHanti), 5.60 (s, 2H, 2!1H of
NH2), 7.25 (d, 4H, JZ8.0 Hz, ArH), 7.45 (d, 4H, JZ8.0 Hz,
ArH), 9.85 (brs, 2H, 2!1H of NH2); 13C NMR
(50.32 MHz, CDCl3) dZ9.8, 13.5, 14.5, 21.7, 44.4, 44.8,
60.9, 61.2, 75.3, 76.9, 90.0, 91.2, 126.6, 130.1, 133.9, 134.1,
141.9, 142.0, 163.4, 163.8, 174.4, 195.8, 196.0; mass (FAB)
m/z 292 (MCC1).
4.2.9. 4-Amino-3-hydroxy-2-methyl-6-oxo-6-p-tolyl-hex-
4-enoic acid methyl ester (19b). 87% (0.35 g from 0.40 g
of 18b); yellow oil; [found: C, 65.08; H, 7.02; N, 4.89.
C15H19NO4 requires C, 64.97; H, 6.91; N, 5.05]. nmax (Neat)
1652 (C]O), 1734 (CO2Me), 3402 (br OH and NH2) cmK1
;
1H NMR (200 MHz, CDCl3) dZ1.20 (d, 3H, JZ7.2 Hz,
–CH–CH3anti), 1.27 (d, 3H, JZ7.2 Hz, –CH–CH3syn), 2.38
(s, 3H, Ar–CH3syn), 2.41 (s, 3H, Ar–CH3anti), 2.78–2.89 (m,
2H, 2!–CH–CH3) 3.73 (s, 3H, CO2CH3syn), 3.76 (s, 3H,
CO2CH3anti), 4.12 (d, 1H, JZ6.4 Hz, –CH(OH)–CHanti),
4.34 (d, 1H, JZ2.6 Hz, –CH(OH)–CHsyn), 5.56 (s, 1H,
]CHsyn), 5.70 (s, 1H, ]CHanti), 6.10 (brs, 2H, 2!1H of
NH2), 7.21 (d, 2H, JZ8.0 Hz, ArHanti), 7.25 (d, 2H, JZ
8.0 Hz, ArHanti), 7.76 (d, 2H, JZ8.0 Hz, ArHsyn), 7.84 (d,
2H, JZ8.0 Hz, ArHsyn), 10.05 (brs, 2H, 2!1H of NH2),
10.72 (brs, 2H, 2!OH); mass (FABC) m/z 278 (MCC1).
4.2.5. 6-Amino-2-methyl-4-oxo-6-phenyl-hex-5-enoic
acid methyl ester (9a). 65% (0.37 g from 0.57 g of 7a);
yellow oil; [found: C, 67.71; H, 7.01; N, 5.67. C14H17NO3
requires C, 68.00; H, 6.93; N, 5.66]. nmax (Neat) 1728
(CO2Me), 3406 (br, NH2) cmK1 1H NMR (200 MHz,
;
CDCl3) dZ1.22 (d, 3H, JZ6.8 Hz, –CH–CH3), 2.32–2.55
(m, 1H, –CH–CH3), 2.83–3.06 (m, 2H, –CH–CH2), 3.69 (s,
3H, CO2CH3), 5.38 (brs, 1H, NH2), 5.42 (s, 1H, ]CH),
7.42–7.56 (m, 5H, ArH), 9.89 (brs, 1H, NH2); mass (ESC)
m/z 270.80 (MCCNa).
4.2.10. -Amino-6-(4-chloro-phenyl)-3-hydroxy-2-methyl-
6-oxo-hex-4-enoic acid methyl ester (19d). 73% (0.42 g
from 0.48 g of 18d); sticky solid; [found: C, 56.24; H, 5.51;
N, 5.01. C14H16ClNO4 requires C, 56.48; H, 5.42; N, 4.70].
4.2.6. 6-Amino-2-methyl-4-oxo-6-p-tolyl-hex-5-enoic
acid methyl ester (9b). 67% (0.27 g from 0.40 g of 7b);
white solid; mp 80–828C; [found: C, 68.54; H, 7.11; N, 5.23.
C15H19NO3 requires C, 68.94; H, 7.33; N, 5.36]. nmax (KBr)
1720 (CO2Me), 3394 (br, NH2) cmK1; 1H NMR (200 MHz,
CDCl3) dZ1.22 (d, 3H, JZ6.8 Hz, –CH–CH3), 2.39 (s, 3H,
Ar–CH3), 2.44–2.55 (m, 1H, –CH–CH3), 2.82–3.03 (m, 2H,
–CH–CH2), 3.69 (s, 3H, CO2CH3), 5.21 (brs, 1H, NH2),
5.41 (s, 1H, ]CH), 7.23 (d, 2H, JZ8.2 Hz, ArH), 7.46 (d,
2H, JZ8.2 Hz, ArH), 9.90 (brs, 1H, NH2); 13C NMR
(CDCl3, 50.32 MHz) dZ17.6, 21.7, 36.2, 46.0, 52.1, 94.64,
126.5, 130.0, 134.6, 141.4, 161.5, 177.4, 197.3; mass
(ESC) m/z 284.80 (MCCNa).
nmax (Neat) 1730 (CO2Me), 3406 (br OH and NH2) cmK1
;
1H NMR (200 MHz, CDCl3) dZ1.20 (d, 3H, JZ7.2 Hz,
–CH–CH3anti), 1.29 (d, 3H, JZ7.2 Hz, –CH–CH3syn), 2.82–
2.89 (m, 2H, 2!–CH–CH3), 3.73 (s, 3H, CO2CH3syn), 3.76
(s, 3H, CO2CH3anti), 4.36 (d, 1H, JZ7.4 Hz, –CH(OH)–
CHanti), 4.81 (d, 1H, JZ4.6 Hz, –CH(OH)–CHsyn), 5.58 (d,
1H, ]CHsyn), 5.65 (s, 1H, ]CHanti), 6.11 (brs, 1H, 1H of
NH2), 6.52 (brs, 1H, 1H of NH2), 7.37 (d, 4H, JZ8.6 Hz,
ArH), 7.78 (d, 4H, JZ8.6 Hz, ArH), 10.05 (brs, 1H, 1H of
NH2), 10.32 (brs, 1H, 1H of NH2); mass (FABC) m/z 298
(MCC1).
4.2.11. 4-Amino-2-methyl-6-oxo-6-phenyl-hex-4-enoic
acid methyl ester (22a). 83% (0.66 g from 0.80 g of
21a); yellow oil; [found: C, 68.20; H, 6.79; N, 5.97.
C14H17NO3 requires C, 68.00; H, 6.93; N, 5.66]. nmax (Neat)
1734 (CO2Me), 3396 (br, NH2) cmK1; 1H NMR (200 MHz,
CDCl3) dZ1.27 (d, 3H, JZ7.0 Hz, –CH–CH3), 2.59–2.82
(m, 3H, –CH–CH2 and –CH–CH2), 3.71 (s, 3H, CO2CH3),
5.50 (brs, 1H, 1H of NH2), 5.69 (s, 1H, ]CH), 7.39–7.58
(m, 3H, ArH), 7.85–7.96 (m, 2H, ArH), 10.08 (brs, 1H, 1H
of NH2); mass (FABC) m/z 248 (MCC1).
4.2.7. 6-Amino-2-methyl-4-oxo-6-p-tolyl-hex-5-enoic
acid ethyl ester (10b). 65% (0.33 g from 0.5 g of 8b);
yellow oil; [found: C, 69.94; H, 7.33; N, 5.32. C16H21NO3
requires C, 69.79; H, 7.69; N, 5.09]. nmax (Neat) 1727
(CO2Et), 3409 (br, NH2) cmK1 1H NMR (200 MHz,
;
CDCl3) dZ1.21 (d, 3H, JZ7.2 Hz, –CH–CH3), 1.25, (t,
3H, JZ7.0 Hz, CH2CH3), 2.39 (s, 3H, Ar–CH3), 2.43–2.53
(m, 1H, –CH–CH3), 2.81–3.01 (m, 2H, –CH–CH2), 4.15 (q,
2H, JZ7.0 Hz, CO2CH2), 5.20 (brs, 1H, NH2), 5.42 (s, 1H,
]CH), 7.23 (d, 2H, JZ8.0 Hz, ArH), 7.44 (d, 2H, JZ
8.0 Hz, ArH), 9.89 (brs, 1H, NH2); mass (ESC) m/z 298.53
(MCCNa).
4.2.12. 4-Amino-2-methyl-6-oxo-6-p-tolyl-hex-4-enoic
acid methyl ester (22b). 85% (0.33 g from 0.35 g of
21a); yellow oil; [found: C, 69.03; H, 7.17; N, 5.50.
C15H19NO3 requires C, 68.94; H, 7.33; N, 5.36]. nmax (Neat)
1734 (CO2Me), 3497 (br, NH2) cmK1; 1H NMR (200 MHz,
CDCl3) dZ1.27 (d, 3H, JZ7.0 Hz, –CH–CH3), 2.38 (s, 3H,
Ar–CH3), 2.59–2.82 (m, 3H, –CH–CH2 and –CH–CH2),
3.71 (s, 3H, CO2CH3), 5.50 (brs, 1H, 1H of NH2), 5.69 (s,
1H, ]CH), 7.21 (d, 2H, JZ8.0 Hz, ArH), 7.77 (d, 2H,
JZ8.0 Hz, ArH), 10.10 (brs, 1H, 1H of NH2); mass
(FABC) m/z 262 (MCC1).
4.2.8. 4-Amino-3-hydroxy-2-methyl-6-oxo-6-phenyl-hex-
4-enoic acid methyl ester (19a). 70% (0.84 g from 1.20 g
of 18a); white solid, mp 88–908C; [found: C, 63.57; H, 6.67;
N, 4.99. C14H17NO4 requires C, 63.87; H, 6.51; N, 5.36].
nmax (KBr) 1653 (C]O), 1733 (CO2Me), 3410 (br, OH and
1
NH2) cmK1; H NMR (300 MHz, CDCl3) dZ1.22 (d, 3H,
JZ7.2 Hz, –CH–CH3anti), 1.30 (d, 3H, JZ7.2 Hz, –CH–
CH3syn), 2.85–2.90 (m, 2H, 2!–CH–CH3), 3.75 (s, 6H, 2!
CO2CH3), 4.18 (d, 1H, JZ6.6 Hz, –CH(OH)–CHanti), 4.36
(d, 1H, JZ4.6 Hz, –CH(OH)–CHsyn), 5.70 (s, 1H,
4.2.13. 4-Amino-6-(4-chloro-phenyl)-2-methyl-6-oxo-
hex-4-enoic acid methyl ester (22d). 85% (0.21 g from

R. Saxena et al. / Tetrahedron 60 (2004) 10311–10320
10317
0.25 g of 21d); yellow oil; [found: C, 59.77; H, 5.99; N,
5.21. C14H16ClNO3 requires C, 59.68; H, 5.72; N, 4.97].
nmax (Neat) 1729 (CO2Me); 3478 (br, NH2) cmK1; 1H NMR
(200 MHz, CDCl3) dZ1.27 (d, 3H, JZ7.0 Hz, –CH–CH3),
2.23–2.48 (m, 1H, –CH–CH3), 2.57–2.86 (m, 2H, –CH–
CH2), 3.71 (s, 3H, CO2CH3), 5.65 (s, 1H, ]CH), 5.70 (brs,
1H, 1H of NH2), 7.37 (d, 2H, JZ8.0 Hz, ArH), 7.80 (d, 2H,
JZ8.0 Hz, ArH), 10.10 (brs, 1H, 1H of NH2); mass (ESC)
m/z 282.47 (MCC1).
0.53 g of 32b); yellow solid, mp 76–788C; [found: C, 70.33;
H, 6.76; N, 4.99. C16H19NO3 requires C, 70.31; H, 7.01; N,
5.12]. nmax (KBr) 1705 (COMe and CO2Me), 3377 (br,
1
NH2) cmK1; H NMR(200 MHz, CDCl3) dZ1.36 (s, 3H,
]C–CH3), 2.17 (s, 3H, COCH3), 2.35 (s, 3H, Ar–CH3),
3.68 (s, 3H, CO2CH3), 5.31 (brs, 1H, NH2), 7.14 (d, 1H, JZ
8.0 Hz, ArH), 7.22 (m, 2H, JZ8.0 Hz, ArH), 7.46 (d, 1H,
JZ1.2 Hz, C–CH]C); mass (FABC) m/z 274 (MCC1).
4.2.20. (Z) 4-Acetyl-5-amino-5-(2-chloro-phenyl)-2-
methyl-penta-2,4-dienoic acid methyl ester (34c). 80%
(0.24 g from 0.30 g of 32c); yellow solid, mp 118–1208C;
[found: C, 61.08; H, 5.82; N, 4.97. C15H16ClNO3 requires C,
61.33; H, 5.49; N, 4.77]. nmax (KBr) 1707 (COMe and
4.2.14. 5-Acetyl-3-methyl-6-phenyl-1H-pyridin-2-one
(29a). 15% (0.045 g from 0.30 g of 27a); yellow solid, mp
163–165 8C; [found: C, 73.24; H, 6.62; N, 5.44 C14H13NO2
requires C, 73.99; H, 6.16; N, 5.77]. nmax (KBr) 1697
(COMe), 1667 (CONH) cmK1; 1H NMR (300 MHz, CDCl3)
dZ1.82 (s, 3H, ]C–CH3), 2.02 (s, 3H, COCH3), 7.33–7.51
(m, 5H, ArH), 7.70 (s, 1H, CH]C–CH3), 10.72 (brs, 1H,
NH); mass (FABC) m/z 228 (MCC1).
CO2Me), 3369 (br, NH2) cmK1 1H NMR (200 MHz,
;
CDCl3) dZ1.58 (s, 3H, ]C–CH3), 2.14 (s, 3H, COCH3),
3.64 (s, 3H, CO2CH3), 7.17–7.38 (m, 4H, ArH), 7.49 (d, 1H,
JZ1.2 Hz, C–CH]C); mass (FABC) m/z 294 (MCC1).
4.2.15. 5-Acetyl-3-methyl-6-p-tolyl-1H-pyridin-2-one
(29b). 16% (0.080 g from 0.50 g of 27b); yellow solid,
mp 164–166 8C; [found: C, 74.93; H, 6.45; N, 5.98.
C15H15NO2 requires C, 74.67; H, 6.27; N, 5.81]. nmax
4.3. Hydrogenation in the presence of Pd–C.
Representative procedure
To the methanolic solution of compound 2a (520 mg,
2.0 mmol), 75 mg of 10% Pd–C was added under nitrogen
atmosphere. The atmosphere of the vessel was replaced by
hydrogen gas. The reaction was carried out either on the
Parr assembly at 30 psi at rt or through stirring in a sealed
vessel having hydrogen atmosphere maintained by a
balloon. After completion, the reaction mixture was filtered
over a pad of celite and the solvent was concentrated under
reduced pressure to obtain an oily residue. This residue was
purified over silica gel (230–400 mesh) column using
hexane: ethyl acetate (80:20, v/v) as eluent to yield 6a as
yellow oil.
(KBr) 1699 (COMe), 1668 (CONH) cmK1 1H NMR
;
(200 MHz, CDCl3) dZ1.81 (s, 3H, ]C–CH3), 2.04 (s,
3H, COCH3), 2.41 (s, 3H, Ar–CH3), 7.15 (s, 4H, ArH), 7.72
(s, 1H, CH]C–CH3), 10.72 (brs, 1H, NH); mass (FABC)
m/z 242 (MCC1).
4.2.16. 4-Amino-4-phenyl-but-3-en-2-one (30a). 58%
(0.17 g from 0.30 g of 27a); yellow solid, mp 93–95 8C;
[found: C, 66.93; H, 7.51; N, 7.58. C10H11NO$H2O requires
C, 67.02; H, 7.31; N, 7.82]. nmax (KBr) 1697 (COMe), 3395
1
(NH2) cmK1; H NMR (200 MHz, CDCl3) dZ2.15 (s, 3H,
COCH3), 5.31 (brs, 1H, NH2), 5.45 (s, 1H, ]CH), 7.42–
7.45 (m, 3H, ArH), 7.52–7.57 (m, 2H, ArH), 9.98 (brs, 1H,
NH2), 13C NMR (50.32 MHz, CDCl3) dZ30.2, 95.6,
126.6, 129.3, 137.7, 161.3, 197.9; mass (FABC) m/z 162
(MCC1).
4.3.1. 3-Hydroxy-2-methyl-3-(3-phenyl-isoxazol-5-yl)-
propionic acid methyl ester (6a). 78% (0.41 g from
0.52 g of 2a); yellow oil; [found: C, 64.72; H, 5.98; N,
5.25. C14H15NO4 requires C, 64.36; H, 5.79; N, 5.36]. nmax
(Neat) 1732 (CO2Me), 3429 (br, OH) cmK1 1H NMR
;
4.2.17. 4-Amino-4-p-tolyl-but-3-en-2-one (30b). 58%
(0.29 g from 0.50 g of 27b); yellow solid, mp 58–60 8C;
[found: C, 71.33; H, 6.79; N, 7.45. C11H13NO.1/2H2O
requires C, 71.71; H, 7.11; N, 7.60]. nmax (KBr) 1694
(200 MHz, CDCl3) dZ1.22 (d, 3H, JZ7.2 Hz, –CH–
CH3anti), 1.31 (d, 3H, JZ7.2 Hz, –CH–CH3syn), 3.07–3.14
(m, 2H, 2!–CH–CH3), 3.67 (s, 3H, CO2CH3syn), 3.72 (s,
3H, CO2CH3anti), 4.96 (t, 1H, JZ6.0 Hz, –CH(OH)–
CHanti), 5.34 (d, 1H, JZ5.6 Hz, –CH(OH)–CHsyn), 6.59
(s, 1H, ]CHsyn), 6.62 (s, 1H, ]CHanti), 7.43–7.46 (m, 6H,
ArH), 7.77–7.82 (m, 4H, ArH); mass (FABC) m/z 262
(MCC1).
1
(COMe), 3402 (NH2) cmK1; H NMR (200 MHz, CDCl3)
dZ2.15 (s, 3H, COCH3), 2.39 (s, 3H, Ar–CH3), 5.34 (brs,
1H, NH2), 5.44 (s, 1H, ]CH), 7.23 (d, 2H, JZ8.0 Hz,
ArH), 7.44 (d, 2H, JZ8.0 Hz, ArH), 10.01 (brs, 1H, NH2);
mass (FABC) m/z 176 (MCC1).
4.2.18. (Z) 4-Acetyl-5-amino-2-methyl-5-phenyl-penta-
2,4-dienoic acid methyl ester (34a). 65% (0.45 g from
0.53 g of 32a); Brown solid, mp 96–988C; [found: C, 69.77;
H, 6.63; N, 5.55. C15H17NO3 requires C, 69.48; H, 6.61; N,
5.40]. nmax (KBr) 1699 (COMe and CO2Me), 3441 (br,
4.3.2. 3-Hydroxy-2-methyl-3-(3-p-tolyl-isoxazol-5-yl)-
propionic acid methyl ester (6b). 80% (0.54 g from
0.67 g of 2b); white solid; mp 68–70 8C; [found: C, 65.68;
H, 6.32; N, 4.70. C15H17NO4 requires C, 65.44; H, 6.22, N,
5.09]. nmax (KBr) 1738 (CO2Me), 3417 (br, OH) cmK1; 1H
NMR (200 MHz, CDCl3) dZ1.21 (d, 3H, JZ7.2 Hz, –CH–
CH3anti), 1.31 (d, 3H, JZ7.2 Hz, –CH–CH3syn), 2.39 (s, 6H,
2!Ar–CH3), 3.07–3.14 (m, 2H, 2!–CH–CH3), 3.67 (s,
3H, CO2CH3syn), 3.72 (s, 3H, CO2CH3anti), 4.94 (t, 1H, JZ
6.8 Hz, –CH(OH)–CHanti), 5.27 (t, 1H, JZ1.5 Hz,
–CH(OH)–CHsyn), 6.56 (s, 1H, ]CHanti), 6.59 (s, 1H,
CHsyn), 7.24 (d, 4H, JZ8.0 Hz, ArH), 7.68 (d, 4H, JZ
8.0 Hz, ArH); mass (FABC) m/z 276 (MCC1).
1
NH2) cmK1; H NMR(200 MHz, CDCl3) dZ1.36 (s, 3H,
]C–CH3), 2.18 (s, 3H, COCH3), 3.67 (s, 3H, CO2CH3),
5.31 (brs, 1H, NH2), 7.38 (s, 5H, ArH), 7.44 (d, 1H, JZ
1.2 Hz, C–CH]C), 10.67 (brs, 1H, NH2); mass (ESC) m/z
260.60 (MCC1).
4.2.19. (Z) 4-Acetyl-5-amino-2-methyl-5-p-tolyl-penta-
2,4-dienoic acid methyl ester (34b). 85% (0.45 g from

10318
R. Saxena et al. / Tetrahedron 60 (2004) 10311–10320
4.3.3. 3-[3-(2-Chloro-phenyl)-isoxazol-5-yl]-3-hydroxy-
2-methyl-propionic acid methyl ester (6c). 81% (0.20 g
from 0.25 g of 3c); pale yellow oil; [found: C, 56.66; H,
5.77; N, 5.74. C14H14ClNO4 requires C, 56.36; H, 5.79; N,
5.36]. nmax (Neat) 1734 (CO2Me), 3401 (br, OH) cmK1; 1H
NMR (200 MHz, CDCl3) dZ1.22 (d, 3H, JZ7.2 Hz, –CH–
CH3anti), 1.31 (d, 3H, JZ7.2 Hz, –CH–CH3syn), 3.07–3.14
(m, 2H, 2!–CH–CH3), 3.73 (s, 3H, CO2CH3syn), 3.76 (s,
3H, CO2CH3anti), 4.97 (t, 1H, JZ6.0 Hz, –CH(OH)–
CHanti), 5.31 (t, 1H, JZ1.5 Hz, –CH(OH)–CHsyn), 6.59 (s,
1H, ]CHanti), 6.73 (s, 1H, ]CHsyn), 7.33–7.50 (m, 6H,
ArH), 7.69–7.82 (m, 2H, ArH); mass (ESC) m/z 296.23
(MCC1).
14.6, 21.9, 44.8, 44.9, 52.5, 68.3, 69.5, 97.5, 98.1, 125.0,
126.2, 130.1, 140.9, 165.6, 165.9, 170.9, 175.9, 176.3; mass
(FABC) m/z 276 (MCC1).
4.3.8. 3-[5-(4-Chloro-phenyl)-isoxazol-3-yl]-3-hydroxy-
2-methyl-propionic acid methyl ester (20d). syn:anti 2:1
87% (0.58 g from 0.67 g of 18d); white solid; mp 134–368C;
[found: C, 57.04; H, 4.89; N, 4.77. C14H14ClNO4 requires C,
56.86; H, 4.77, N, 4.74]. nmax (KBr) 1733 (CO2Me), 3427
1
(br, OH) cmK1; H NMR (200 MHz, CDCl3) dZ1.26 (d,
3H, JZ7.0 Hz, –CH–CH3anti), 1.28 (d, 3H, JZ7.0 Hz,
–CH–CH3syn), 3.03–3.10 (m, 1H, –CH–CH3syn), 3.42–3.48
(m, 1H, –CH–CH3anti), 3.74 (s, 6H, 2!CO2CH3), 4.93 (t,
1H, JZ3.0 Hz, –CH(OH)–CHanti), 5.27 (brs, 1H,
–CH(OH)–CHsyn), 6.61 (s, 1H, 2!]CH), 7.43 (d, 4H,
JZ8.6 Hz, ArH), 7.70 (d, 4H, JZ8.6 Hz, ArH); mass
(FABC) m/z 296 (MCC1).
4.3.4. 2-Methyl-3-(3-phenyl-isoxazol-5-yl)-propionic
acid methyl ester (11a). 38% (0.21 g from 0.55 g of 7a);
white solid; mp 94–96 8C; [found: C, 68.76; H, 5.89; N,
5.36. C14H15NO3 requires C, 68.56; H, 6.16; N, 5.71]. nmax
1
(KBr) 1733 (CO2Me) cmK1; H NMR (300 MHz, CDCl3)
4.3.9. 3-Acetoxy-2-methyl-3-(5-phenyl-isoxazol-3-yl)-
propionic acid methyl ester (23a). syn:anti 3:7 17%
(0.097 g from 0.58 g of 21a); yellow oil; [found: C, 63.55;
H, 5.76; N, 4.66. C16H17NO5 requires C, 63.36; H, 5.65; N,
dZ1.26 (d, 3H, JZ7.2 Hz, –CH–CH3), 2.89–2.97 (m, 2H,
–CH–CH2), 3.19–3.24 (m, 1H, –CH–CH3), 3.76 (s, 3H,
CO2CH3), 6.35 (s, 1H, ]CH), 7.46–7.53 (m, 3H, ArH),
7.81–7.86 (m, 2H, ArH); mass (ESC) m/z 246.47 (MCC1).
1
4.62] nmax (Neat) 1745 (COMe and CO2Me) cmK1; H
NMR (200 MHz, CDCl3) dZ1.20 (d, 3H, JZ7.2 Hz, –CH–
CH3anti), 1.32 (d, 3H, JZ7.2 Hz, –CH–CH3syn), 2.09 (s, 3H,
COCH3anti), 2.16 (s, 3H, COCH3syn), 3.17–3.25 (m, 2H,
2!–CH–CH3), 3.70 (s, 3H, CO2CH3syn), 3.75 (s, 3H,
CO2CH3anti), 6.16 (d, 1H, JZ9.0 Hz, –CH(OAc)–CHanti),
6.31 (d, 1H, JZ6.0 Hz, CH(OAc)–CHsyn), 6.49 (s, 1H,
]CHsyn), 6.52 (s, 1H, ]CHanti), 7.44–7.49 (m, 6H, ArH),
7.75–7.79 (m, 4H, ArH); mass (FABC) m/z 304 (MCC1).
4.3.5. 2-Methyl-3-(3-p-tolyl-isoxazol-5-yl)-propionic acid
methyl ester (11b). 25% (0.16 g from 0.65 g of 7b); white
solid; mp 78–80 8C; [found: C, 69.48; H, 6.61; N, 5.40.
C15H17NO3 requires C, 69.64; H, 6.41, N, 5.33]. nmax (KBr)
1726 (CO2Me) cmK1; 1H NMR (300 MHz, CDCl3) dZ1.27
(d, 3H, JZ7.2 Hz, –CH–CH3), 2.39 (s, 3H, Ar–CH3), 2.89–
2.96 (m, 2H, –CH–CH2), 3.18–3.21 (m, 1H, –CH–CH2),
3.70 (s, 3H, CO2CH3), 6.31 (s, 1H, ]CH), 7.24 (d, 2H, JZ
8.0 Hz, ArH), 7.67 (d, 2H, JZ8.0 Hz, ArH); 13C NMR
(CDCl3, 50.32 MHz) dZ17.4, 21.8, 30.8, 38.6, 52.3, 100.4,
109.94, 126.7, 127.0, 129.9, 140.4, 162.8, 171.4, 175.7;
mass (FABC) m/z 260 (MCC1).
4.3.10. 3-Acetoxy-2-methyl-3-(5-p-tolyl-isoxazol-3-yl)-
propionic acid methyl ester (23b). syn:anti 2:3 15%
(0.038 g from 0.25 g of 21b); white solid, mp 60–628C;
[found: C, 63.96; H, 5.85; N, 4.49. C17H19NO5 requires C,
64.34; H, 6.03; N, 4.41]. nmax (KBr) 1745 (COMe, CO2Me),
1
cmK1; H NMR (200 MHz, CDCl3) dZ1.20 (d, 3H, JZ
4.3.6. 3-Hydroxy-2-methyl-3-(5-phenyl-isoxazol-3-yl)-
propionic acid methyl ester (20a). syn:anti 2:1 85%
(0.13 g from 0.15 g of 18a); white solid, mp 74–76 8C;
[found: C, 64.11; H, 5.99; N, 4.98. C14H15NO4 requires C,
64.36; H, 5.79, N, 5.36]. nmax (Neat) 1731 (CO2Me), 3403
(br, OH) cmK1; 1H NMR (200 MHz, CDCl3) dZ1.24–1.31
(m, 6H, 2!–CH–CH3), 3.04–3.11 (m, 1H, –CH–CH3syn),
3.33–3.36 (m, 1H, –CH–CH3anti), 3.78 (s, 6H, 2!CO2CH3),
4.91, 4.98 (t, 1H, JZ6.53 Hz, –CH(OH)–CHanti), 5.28 (t,
1H, JZ1.5 Hz, –CH(OH) –CHsyn), 6.60 (s, 2H, 2!]CH),
7.44–7.49 (m, 6H, ArH), 7.76–7.80 (m, 2H, ArH); mass
(FABC) m/z 262 (MCC1).
7.2 Hz, –CH–CH3anti), 1.31 (d, 3H, JZ7.2 Hz, –CH–
CH3syn), 2.09 (s, 3H, COCH3anti), 2.15 (s, 3H, CH3syn),
2.39 (s, 6H, 2!CH3), 3.15–3.23 (m, 2H, 2!–CH–CH3),
3.70 (s, 3H, CO2CH3syn), 3.74 (s, 3H, CO2CH3anti), 6.13 (d,
1H, JZ8.8 Hz, –CH(OAc)–CHanti), 6.30 (d, 1H, JZ6.0 Hz,
–CH(OAc)–CHsyn), 6.43 (s, 1H, ]CHsyn), 6.45 (s, 1H,
]CHanti), 7.27 (d, 4H, JZ8.0 Hz, ArH), 7.66 (d, 4H,
JZ8.0 Hz, ArH); mass (ESC) m/z 340.47 (MCCNa).
4.3.11. 2-Methyl-3-(5-phenyl-isoxazol-3-yl)-propionic
acid methyl ester (24a). 52% (0.30 g from 0.58 g of
21a); yellow oil; [found: C, 68.55; H, 5.91; N, 5.83.
C14H15NO3 requires C, 68.56; H, 6.16, N, 5.71]. nmax (Neat)
1735 (CO2Me), 3456 (br, OH) cmK1; 1H NMR (200 MHz,
CDCl3) dZ1.28 (d, 3H, JZ7.0 Hz, –CH–CH3), 2.82–3.12
(m, 3H, –CH–CH3 and –CH2–CH), 3.71 (s, 3H, CO2CH3),
6.37 (s, 1H, ]CH), 7.42–7.48 (m, 3H, ArH), 7.73–7.77 (m,
2H, ArH); 13C NMR (50.32 MHz, CDCl3) dZ8.8, 30.2,
39.1, 52.9, 99.87, 126.2, 127.9, 129.3, 130.5, 162.6, 170.2,
176.2; mass (FABC) m/z 246 (MCC1).
4.3.7. 3-Hydroxy-2-methyl-3-(5-p-tolyl-isoxazol-3-yl)-
propionic acid methyl ester (20b). syn:anti 2:1 89%
(0.18 g from 0.20 g of 18b); white solid; mp 90–928C;
[found: C, 64.75; H, 6.48; N, 5.24. C15H17NO4 requires C,
64.44; H, 6.22, N, 5.09]. nmax (KBr) 1738 (CO2Me), 3458
1
(br, OH) cmK1; H NMR (200 MHz, CDCl3) dZ1.26 (d,
3H, JZ7.2 Hz, –CH–CH3anti), 1.28 (d, 3H, JZ7.2 Hz,
–CH–CH3syn), 2.40 (s, 6H, 2!Ar–CH3), 3.02–3.09 (m, 1H,
–CH–CH3syn), 3.48–3.74 (m, 1H, –CH–CH3anti), 3.74 (s,
6H, 2!CO2CH3), 4.93 (t, 1H, JZ6.2 Hz, –CH(OH)–
CHanti), 5.26 (t, 1H, JZ1.5 Hz, –CH(OH)–CHsyn), 6.54 (s,
2H, 2!]CH), 7.26 (d, 4H, JZ8.0 Hz, ArH), 7.66 (d, 4H,
JZ8.0 Hz, ArH); 13C NMR (50.32 MHz, CDCl3) dZ11.5,
4.3.12. 2-Methyl-3-(5-p-tolyl-isoxazol-3-yl)-propionic
acid methyl ester (24b). 49% (0.12 g from 0.25 g of
21b); white solid, mp 83–848C; [found: C, 69.52; H, 6.60;
N, 5.12. C15H17NO3 requires C, 69.48; H, 6.61; N, 5.40].

R. Saxena et al. / Tetrahedron 60 (2004) 10311–10320
10319
nmax (KBr) 1730 (CO2Me), 3446 (br, OH) cmK1; 1H NMR
(200 MHz, CDCl3) dZ1.27 (d, 3H, JZ6.6 Hz, –CH–CH3),
2.39 (s, 3H, Ar–CH3), 2.81–3.11 (m, 3H, –CH–CH3 and
–CH2–CH), 3.71 (s, 3H, CO2CH3), 6.31 (s, 1H, ]CH), 7.24
(d, 2H, JZ8.0 Hz, ArH), 7.64 (d, 2H, JZ8.0 Hz, ArH);
mass (ESC) m/z 260.36 (MCC1).
4.5. Reaction of enamine ketones with acetic acid–formic
acid mixture. Representative procedure
The compound 4a (525 mg, 2.0 mmol) was stirred in 4 mL
of acetic acid–formic acid (80%) mixture (50:50, v/v) at
60 8C for 24 h. After cooling to room temperature, the
mixture was partitioned between ethyl acetate (30 mL) and
water (25 mL). The organic layer was separated and
successively washed with 10% NaHCO3 aq. solution
(until the washing was neutral). The organic layer was
finally washed with brine, dried over Na2SO4 and
evaporated to obtain a residue. This residue upon column
chromatography over silica gel using hexane: ethyl acetate
(85:15, v/v) furnished the product.
4.3.13. 3-Hydroxy-2-methyl-3-(5-methyl-3-phenyl-isoxa-
zol-4-yl)-propionic acid methyl ester (31a). anti 60%
(0.25 g from 0.42 g of 27a); white solid, mp 84–858C;
[found: C, 65.55; H, 5.91; N, 4.83. C15H17NO4 requires C,
65.44; H, 6.22; N, 5.09]. nmax (KBr) 1733 (CO2Me), 3411
(br, OH) cmK1; 1H NMR (200 MHz, DMSOd6) dZ0.69 (d,
3H, JZ7.0 Hz, –CH–CH3), 2.52 (s, 3H, ]C–CH3), 2.67–
2.85 (m, 1H, –CH–CH3), 3.56 (s, 3H, CO2CH3), 4.66–4.71
(m, 1H, –CH(OH)–CH), 7.53–7.55 (m, 3H, ArH), 7.73–7.76
(m, 2H, ArH); mass (FABC) m/z 276 (MCC1).
4.5.1. 2-(3-Oxo-5-phenyl-2, 3-dihydro-furan-2-yl)-pro-
pionic acid methyl ester (14a). syn:anti 1:1 88% (0.46
from 0.52 g of 4a); pale yellow oil; [found: C, 63.23; H,
5.88. C14H14O4$H2O requires C, 63.63; H, 6.10] nmax (Neat)
4.3.14. 3-Hydroxy-2-methyl-3-(5-methyl-3-p-tolyl-isoxa-
zol-4-yl)-propionic acid methyl ester (31b). anti 63%
(0.26 g from 0.41 g of 27b); pale yellow solid, mp 100–
1028C; [found: C, 66.36; H, 6.88; N, 4.72. C16H19NO4
requires C, 66.42; H, 6.62; N, 4.84]. nmax (KBr) 1714
1
1697 (C]O), 1740 (CO2Me) cmK1; H NMR (200 MHz,
CDCl3) dZ1.13 (d, 3H, JZ7.2 Hz, –CH–CH3anti), 1.41,
1.44 (d, 3H, JZ7.2 Hz, –CH–CH3syn), 3.12–3.21 (m, 2H,
2!CH), 3.69 (s, 3H, CO2CH3syn), 3.81 (s, 3H, CO2CH3anti),
4.80 (d, 1H, JZ5.6 Hz, –CO–CH–O–anti), 5.13, 5.14 (s, 1H,
JZ3.1 Hz, –CO–CH–O–syn), 6.07 (s, 1H, ]CHanti), 6.08 (s,
1H, CHsyn), 7.44–7.58 (m, 6H, ArH), 7.78–7.85 (m, 4H,
ArH); 13C NMR (50.3 MHz, CDCl3) dZ12.72, 13.94,
41.35, 43.66, 44.16, 46.10, 47.1, 52.8, 53.0, 86.2, 94.5, 99.7,
102.1, 127.7, 127.9, 128.2, 128.7, 128.8, 129.3, 130.5,
133.5, 134.1, 134.9, 171.2, 174.6, 175.5, 189.4, 195.4; mass
(ESC) m/z 269.60 (MCCNa).
(CO2Me), 3411 (br, OH) cmK1 1H NMR (200 MHz,
;
CDCl3) dZ0.84 (d, 3H, JZ7.2 Hz, –CH–CH3), 2.40 (s, 3H,
Ar–CH3), 2.55 (s, 3H, ]C–CH3), 2.74–2.83 (m, 1H, –CH–
CH3), 3.71 (s, 3H, CO2CH3), 4.84, 4.89 (d, 1H, JZ9.8 Hz,
–CH(OH)–CH), 7.25 (d, 2H, JZ8.0 Hz, ArH), 7.60 (d, 2H,
JZ8.0 Hz, ArH); mass (FABC) m/z 290 (MCC1).
4.3.15. 3-[3-(2-Chloro-phenyl)-5-methyl-isoxazol-4-yl]-
3-hydroxy-2-methyl-propionic acid methyl ester (31c).
anti 63% (0.32 g from 0.50 g of 18a); white solid, mp 108–
1108C; [found: C, 57.89; H, 5.14; N, 4.27. C15H16ClNO4
requires C, 58.16; H, 5.21; N, 4.52]. nmax (KBr) 1730
4.5.2. 2-(3-Oxo-5-p-tolyl-2, 3-dihydro-furan-2-yl)-pro-
pionic acid methyl ester (14b). 88% (0.40 from 0.45 g of
4b); pale yellow solid, mp 108–110 8C; [found: C, 68.91; H,
5.90. C15H16O4 requires C, 69.22; H, 6.20]. nmax (KBr) 1694
(C]O), 1740 (CO2Me) cmK1; 1H NMR (200 MHz, CDCl3)
dZ1.12 (d, 3H, JZ7.2 Hz, –CH–CH3anti), 1.41 (d, 3H, JZ
7.2 Hz, –CH–CH3syn), 2.43 (s, 6H, 2!Ar–CH3), 3.11–3.20
(m, 2H, 2!CH), 3.69 (s, 3H, CO2CH3syn), 3.80 (s, 3H,
CO2CH3anti), 4.79 (d, 1H, JZ5.6 Hz, –CO–CH–O–anti),
5.12, (d, 1H, JZ3.0 Hz, –CO–CH–O–syn), 6.03 (s, 1H,
]CHanti), 6.04 (s, 1H, ]CHsyn), 7.29 (d, 4H, JZ8.0 Hz,
ArH), 7.69 (d, 4H, JZ8.0 Hz, ArH), 7.73 (d, 4H, JZ8.0 Hz,
ArH); 13C NMR (50.32 MHz, CDCl3) dZ12.8, 14.0, 22.2,
31.3, 43.6, 44.6, 46.1, 47.2, 52.9, 53.1, 94.4, 98.9, 104.7,
125.8, 127.9, 128.3, 130.6, 132.4, 145.3, 170.9, 171.4,
174.6, 189.8, 195.5; mass (FABC) m/z 261 (MCC1).
(CO2Me), 3425 (br, OH) cmK1 1H NMR (200 MHz,
;
CDCl3) dZ0.90 (d, 3H, JZ7.2 Hz, –CH–CH3), 2.56 (s, 3H,
]C–CH3), 2.65–2.79 (m, 1H, –CH–CH3), 3.67 (s, 3H,
CO2CH3), 4.63 (d, 2H, JZ9.8 Hz, –CH(OH)–CH), 7.35–
7.52 (m, 4H, ArH); mass (ESC) m/z 310.53 (MCC1).
4.4. Preparation of allylic bromide-typical procedure
To the stirred solution of compound 27b (500 mg,
1.74 mmol) in dry dichloromethane (5 mL) was added a
solution of PBr3 (0.17 mL, 1.74 mmol) dropwise at 0 8C.
The reaction was allowed to proceed for 30 min at same
temperature. Thereafter the reaction mixture was decom-
posed with ice-cold water and extracted with dichloro-
methane (2!20 mL). The organic layers were combined,
dried (Na2SO4) and evaporated to furnish a residue that
crystallizes on triturating with hexane to yield 0.48 g of
bromide.
4.5.3. 2-[5-(4-Chloro-phenyl)-3-oxo-2,3-dihydro-furan-
2-yl]-propionic acid methyl ester (14d). 85% (0.34 from
0.40 g of 4d); pale yellow sticky solid; [found: C, 60.00; H,
4.91. C14H13ClO4 requires C, 59.90; H, 4.67]. nmax (Neat)
1
1694 (C]O), 1738 (CO2Me) cmK1; H NMR (200 MHz,
CDCl3) dZ1.13 (d, 3H, JZ7.2 Hz, –CH–CH3anti), 1.42 (d,
3H, JZ7.2 Hz, –CH–CH3syn), 3.16–3.21 (m, 2H, 2!CH),
3.69 (s, 3H, –CO2CH3syn), 3.81 (s, 3H, CO2CH3anti), 4.79 (d,
1H, JZ5.6 Hz, –CO–CH–O–anti), 5.14 (d, 1H, JZ3.0 Hz,
–CO–CH–O–syn), 6.03 (s, 1H, ]CHanti), 6.08 (s, 1H,
]CHsyn), 7.47 (d, 4H, JZ8.6 Hz, ArH), 7.74 (d, 4H, JZ
8.0 Hz, ArH), mass (FABC) m/z 281 (MCC1).
4.4.1. (E) 2-Bromomethyl-3-(5-methyl-3-p-tolyl-isoxazol-
4-yl)-acrylic acid methyl ester (33b). 95%; yellow solid,
mp 128–130 8C; [found: C, 54.52; H, 4.60; N, 4.12.
C15H17NO3 requires C, 54.87; H, 4.61; N, 4.00;]. nmax
1
(KBr) 1723 (CO2Me) cmK1; H NMR (300 MHz, CDCl3)
dZ2.37 (s, 3H, Ar–CH3), 2.39 (s, 3H, ]CH–CH3), 3.88 (s,
3H, CO2CH3), 4.09 (s, 2H, ]C–CH2–Br), 7.25 (d, 2H, JZ
8.0 Hz, ArH), 7.42 (s, 1H, ]CH–C–), 7.50 (d, 2H, JZ
8.0 Hz, ArH); mass (ESC) m/z 350.80 (MCC1).
4.5.4. 2-(3-Oxo-5-p-tolyl-2,3-dihydro-furan-2-yl)-propio-
nic acid ethyl ester (15b). 89% (0.89 g from 1.0 g of 5b);

10320
R. Saxena et al. / Tetrahedron 60 (2004) 10311–10320
S. Synthesis 2003, 1347–1356. (c) Roy, A. K.; Batra, S.
Synthesis 2003, 2325–2330.
pale yellow oil; [found: C, 69.87; H, 6.65. C16H18O4
requires C, 70.06; H, 6.61]. nmax (Neat) 1699 (C]O), 1734
(CO2Me) cmK1; 1H NMR (200 MHz, CDCl3) dZ1.10–1.46
(m, 12H, 4!CH2CH3), 2.43 (s, 6H, 2!Ar–CH3), 3.00–3.20
(m, 2H, 2!–CH–CH3), 4.13–4.29 (m, 4H, 2!CO2CH2–),
4.76, (d, 1H, JZ5.4 Hz, –CO–CH–O–anti), 5.13 (d, 1H, JZ
3.0 Hz, –CO–CH–O–syn), 6.02 (s, 1H, ]CHanti), 6.04
(s, 1H, ]CHsyn), 7.29 (d, 4H, JZ8.0 Hz, ArH), 7.69
(d, 2H, JZ8.0 Hz, ArH), 7.73 (d, 2H, JZ8.0 Hz, ArH);
mass (FABC) m/z 275 (MCC1).
7. Roy, A. K.; Rajaraman, B.; Batra, S. Tetrahedron 2004, 60,
2301–2310.
8. (a) Patra, A.; Batra, S.; Bhaduri, A. P. Synlett 2003,
1611–1614. (b) Saxena, R. A.; Patra, A.; Batra, S. Synlett
2003, 1439–1442. (c) Patra, A.; Roy, A. K.; Batra, S.; Bhaduri,
A. P. Synlett 2002, 1819–1822.
9. Batra, S.; Roy, A. K.; Patra, A.; Bhaduri, A. P.; Surin,
W. S.; Raghvan, S. A. V.; Sharma, P.; Kapoor, K.; Dikshit, M.
Bioorg. Med. Chem. 2004, 12, 2059–2077.
4.5.5. 6-Hydroxy-2-methyl-4-oxo-6-p-tolyl-hex-5-enoic
acid methyl ester (16b). 89% (0.089 g from 0.1 g of 9b);
yellow oil; [found: C, 68.76; H, 6.77. C15H18O4 requires C,
68.68; H, 6.92]. nmax (Neat) 1690 (C]O), 1736 (CO2Me),
10. Patra, A.; Batra, S.; Bhaduri, A. P.; Khanna, A.; Chander, R.;
Dikshit, M. Bioorg. Med. Chem. 2003, 11, 2269–2276.
11. Bouzide, A. Org. Lett. 2002, 4, 1347–1350.
12. Mateus, C. R.; Feltrin, M. P.; Costa, A. M.; Coelho, F.;
Almeida, W. P. Tetrahedron 2001, 57, 6901–6908.
13. Mateus, C. R.; Almeida, W. P.; Coelho, F. Tetrahedron Lett.
2000, 41, 2533–2536.
1
3455 (OH) cmK1; H NMR (200 MHz, CDCl3) dZ1.25
(d, 3H, JZ7.0 Hz, –CH–CH3), 2.40 (s, 3H, Ar–CH3), 2.41–
2.48 (m, 1H, –CH–CH3), 2.84–3.04 (m, 2H, –CH–CH2),
3.70 (s, 3H, CO2CH3), 6.14 (s, 1H, ]CH–CO–), 7.24
(d, 2H, JZ8.0 Hz, ArH), 7.77 (d, 2H, JZ8.0 Hz, ArH);
mass (FABC) m/z 263 (MCC1).
14. (a) Brown, J. M.; Cutting, I.; James, A. P. Bull. Soc. Chim. Fr.
1988, 211–217. (b) Brown, J. M.; Cutting, I. J. Chem. Soc.,
Chem. Commun. 1985, 578–579.
15. Sainsbury, M. Trost, B. M., Ed.; Comprehensive Organic
Synthesis; Pergamon: New York, 1991; Vol. 8, pp 644–646.
16. Bianchi, G.; DeAmici, M. J. Chem. Soc., Chem. Commun.
1978, 962–963.
Acknowledgements
The authors acknowledge Mrs. A. Patra for initiating this
work in the lab and Dr. A. P. Bhaduri for helpful
discussions. Two of the authors (R. S. and V. S.) acknowl-
edge the financial support from CSIR and DST, respectively
in the form of fellowship. This work was supported by the
financial grant under DST Project no. SR/SI/OC-04/2003.
17. Amicchio, S.; Morrocchi, S.; Ricca, A. Tetrahedron Lett.
1974, 2793–2796.
18. Stork, G.; Ohashi, M.; Kamachi, H.; Kakisawa, H. J. Org.
Chem. 1971, 36, 2784–2786.
19. Chimichi, S.; Boccalini, M.; Cosimelli, B.; Viola, G.; Vedaldi,
D.; Dall’ Acqua, F. Tetrahedron Lett. 2002, 43, 7473–7476.
20. Chimichi, S.; Boccalini, M.; Cosimelli, B.; Dall’ Acqua, F.;
Viola, G. Tetrahedron 2003, 43, 5215–5223.
21. Pei, Y.; Wickham, B. O. S. Tetrahedron Lett. 1993, 34,
7509–7512.
References and notes
22. Stuyter, M. A. T.; Pandit, U. K.; Speckaamp, W. N.; Huismon,
H. O. Tetrahedron Lett. 1966, 87–90.
1. Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Simoni, D.
Synthesis 1987, 857–869.
23. Casnati, G.; Quilico, A.; Vita-Finzi, P. Gazz. Chim. Ital. 1966,
96, 1073–1083.
2. Li, C. S.; Lacasse, E. Tetrahedron Lett. 2002, 43, 3565–3568.
3. Jones, R. C. F.; Dunn, S. H.; Duller, K. A. M. J. Chem. Soc.,
Perkin Trans. 1 1996, 1319–1321.
24. Casnati, G.; Ricca, A. Tetrahedron Lett. 1967, 327–330.
25. Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Simoni, D.
Tetrahedron Lett. 1984, 25, 4313–4316.
4. Kenar, J. A. J. Am. Oils Chem. Soc. 2003, 80, 1027–1032.
5. (a) Jones, R. C. F.; Bhalay, G.; Carter, P. A.; Duller,
K. A. M.; Dunn, S. H. J. Chem. Soc., Perkins Trans. 1 1994,
2513–2515. (b) Jones, R. C. F.; Bhalay, G.; Carter, P. A.;
Duller, K. A. M.; Vulto, S. I. E. J. Chem. Soc., Perkins Trans. 1
1999, 765–776. (c) Jones, R. C. F.; Dawson, C. E.; O’Mahony,
M. J. Synlett 1999, 873–876.
26. (a) Kozikowski, A. P.; Goldstein, S. J. Org. Chem. 1983, 48,
1139–1141. (b) Jensen, S.; Torssell, K. B. G. Acta Chem.
Scand. 1995, 49, 53–56.
27. (a) Thomsen, I.; Torssell, K. B. G. Acta Chem. Scand. 1988,
B42(5), 309–313. (b) Ueno, T.; Oikawa, M.; Oikawa, H.;
Ichihara, A. Biosci. Biotechnol. Biochem. 1995, 59,
2104–2110.
6. (a) Patra, A.; Batra, S.; Kundu, B.; Joshi, B. S.; Roy, R.;
Bhaduri, A. P. Synthesis 2001, 276–281. (b) Roy, A. K.; Batra,