Interesting results of catalytic hydrogenation of 3-(2-nitrophenyl) isoxazoles and 3- (nitrophenyl)-4,5-dihydroisoxazoles

Article abstract of DOI:10.1055/s-2006-942388

The palladium-on-carbon assisted hydrogenolysis of substituted 3-(2-nitrophenyl)isoxazoles, irrespective of substitution on the isoxazole ring, invariably leads to reduction of the nitro to the amino group with concomitant regiospecific ring closure to yi

Full text of DOI:10.1055/s-2006-942388

PAPER
1995
Interesting Results of Catalytic Hydrogenation of 3-(2-Nitrophenyl)isoxazoles
and 3-(Nitrophenyl)-4,5-dihydroisoxazoles1
Catalytic
H
ydroge
.
nation of
Nit
S
rophenyl-Subs
i
tituted
n
Isoxazoles
a
g
nd 4,5-Dihydhroisoxazoles,a S. Madapa,a G. P. Yadav,b P. R. Maulik,b S. Batra*a
a
Medicinal Chemistry Division, Central Drug Research Institute, PO Box 173, Lucknow 226001, India
Fax +91(522)2623405, 2623938; E-mail: batra_san@yahoo.co.uk
b
Molecular and Structural Biology Divisions, Central Drug Research Institute, PO Box 173, Lucknow 226001, India
Received 20 December 2005; revised 10 February 2006
observed that the reaction is fast and smooth in the pres-
ence of palladium-on-carbon. Additionally, the ring-clo-
sure reaction between the amino and the carbonyl groups
generated by cleavage of the isoxazole ring is highly re-
Abstract: The palladium-on-carbon assisted hydrogenolysis of
substituted 3-(2-nitrophenyl)isoxazoles, irrespective of substitution
on the isoxazole ring, invariably leads to reduction of the nitro to the
amino group with concomitant regiospecific ring closure to yield
substituted 4-aminoquinolines. In contrast similar hydrogenation of giospecific even in the presence of another formyl group.
3-(2-, 3-, and 4-nitrophenyl)-4,5-dihydroisoxazoles (2-isoxazo-
As an extension of this study, we also explored the hydro-
lines) results in reduction of the nitro group only with conservation
genolysis of the 3-(2-nitrophenyl)-4,5-dihydroisoxazole
of the dihydroisoxazole ring to yield the corresponding 3-(ami-
(2-isoxazoline) system. Surprisingly the 4,5-dihydroisox-
nophenyl)-4,5-dihydroisoxazoles.
azole ring, which is otherwise known to readily undergo
catalytic hydrogenolysis, is highly stable to ring cleavage
when nitrophenyl substitution is present on it. Our results
Key words: isoxazole, 4-aminoquinoline, hydrogenation, ring
transformation, regiospecific
on the catalytic hydrogenations of substituted 3-(2-nitro-
phenyl)isoxazoles and 3-(nitrophenyl)-4,5-dihydroisox-
Hydrogenation of 3-(2-nitrophenyl)-substituted isoxazole
azoles are presented in this communication.
derivatives can be utilized for the synthesis of substituted
Methyl 3-(2-Nitrophenyl)-5-methylisoxazole-4-carboxyl-
4-aminoquinoline-2- and 3-carbaldehyde2 derivatives.
ate (1a) was prepared through an earlier reported12 proce-
There are two reports3,4 wherein 3-(2-nitrophenyl)-5-phe-
dure and subjected to palladium-on-carbon mediated
nylisoxazole and 3-(2-nitrophenyl)-5-methylisoxazole-4-
catalytic hydrogenation to afford methyl 4-amino-2-meth-
carboxylate were hydrogenated in the presence of Raney
nickel in acetic acid for 20 hours or ethanol at room tem-
ylquinoline-3-carboxylate (2a) in 5–7 hours and with ex-
cellent yields (Scheme 1). To assess the general
perature to furnish 4-aminoquinoline derivatives. Howev-
applicability of the procedure, several other substituted 2-
er, in our hands the reaction in acetic acid did not work
well and the hydrogenation at room temperature took a
nitrophenyl substrates 2b–d were evaluated with similar
outcome (Table 1). Subsequently it was decided to hydro-
long time and several side products were formed. Since
genate 3-(2-nitrophenyl)isoxazole-4-carbaldehyde (1e).
the previous reports described only one example each, no
In principle, if ring opening of the isoxazole and subse-
comments were made on the scope and limitation of the
quent cyclization is highly regiospecific, it would lead to
synthetic strategy. In principle, if the regiospecificity of
4-aminoquinoline-3-carbaldehyde. On the other hand, af-
the ring-closure reaction between the amino group present
ter reduction of the nitro group to the amino group there is
on the phenyl and the carbonyl group generated by the
a possibility that it may form a Schiff base with the formyl
cleavage of the isoxazole ring is maintained, even in the
group on the isoxazole ring resulting in 3-acetyl-4-amino-
presence of different groups on the isoxazole nucleus, this
quinoline. Hence, the compound 1e was synthesized by
would become an alternate and convenient route to substi-
the literature method13 and hydrogenated. This reaction
tuted 4-aminoquinolines which is the substructural unit of
resulted in the formation of 4-aminoquinoline-3-carbalde-
several pharmacologically active compounds with anti-
hyde (2e) in excellent yield suggesting that the intramo-
malarial,5 antiulcer,6 immuno-stimulant,7 anti-HIV,8
lecular cyclization between the amino group on the phenyl
AChE inhibitory,9 and noniceptin antagonist10 activity. In
ring and the carbonyl group generated from the cleavage
addition, this procedure may serve as a method to obtain
of the isoxazole ring is regiospecific. We have been inter-
fluorinated 4-aminoquinoline derivatives which other-
ested in the transformations of Baylis–Hillman deriva-
wise require complex strategies.11 In order to evaluate the
tives afforded from substituted isoxazolecarbaldehydes to
scope of this procedure to generate substituted 4-amino-
other heterocycles.14 Consequently, two of the Baylis–
quinolines, we investigated several different substitutions
on the isoxazole nucleus employing palladium-on-carbon.
Hillman derivatives 1g and 1h (entry 7 and 8), obtained
from 3-(2-nitrophenyl)isoxazole-5-carbaldehyde, were
Compared to the Raney nickel mediated reaction, it was
also hydrogenated to afford the corresponding 4-amino-
quinoline derivatives 2g and 2h.
SYNTHESIS 2006, No. 12, pp 1995–2004
Advanced online publication: 08.05.2006
DOI: 10.1055/s-2006-942388; Art ID: P19605SS
x
x.
x
x
.
2
0
0
6
Mechanistically, the initial step is the reduction of the ni-
tro group, followed by ring fission (Scheme 2) and subse-
© Georg Thieme Verlag Stuttgart · New York

1996
V. Singh et al.
PAPER
NH2
N
N
O
LiAlH4,
Et2O
10% Pd/C, H2
10% Pd/C, H2
N
O
MeOH, 40 psi, 5–7 h
R1
R2
MeOH, 40 psi, 5 h
1a
R2
R
82%
79–95%
83–89%
R1
R1
NH2
R
NO2
2a–j
3 R1 = CH2OH
4 R1 = CHO
1a–h
81%
PCC, CH2Cl2
Scheme 1
quent cyclization. The evidence for this was obtained by palladium-on-carbon or Raney nickel with few excep-
arresting the hydrogenation reaction in one hour, which tions.16 Because of this reason, the selective reduction of
gave 3-(2-aminophenyl)isoxazole (5a) along with the ex- the nitro group on the phenyl ring attached to the dihy-
pected 4-aminoquinoline derivative (Scheme 2). droisoxazole nucleus has been achieved either by tin(II)
Although during the hydrogenation of 3-(2-nitro- chloride or hydrogen sulfide in concentrated ammo-
phenyl)isoxazole-4-carbaldehyde (1e) we could isolate nia.17,18 However, none of the earlier workers have report-
only the 4-aminoquinoline-3-carbaldehyde, it was envis- ed the results with 3-(2-, 3-, and 4-nitrophenyl)-4,5-
aged that if the nitro group is reduced by circumventing dihydroisoxazoles. Thus 3-(2-nitrophenyl)-4,5-dihy-
the hydrogenolysis, the internal cyclization through the droisoxazoles 6a–g were hydrogenated in the presence of
Schiff base formation between the amino group on the palladium-on-carbon to yield the products 7a–g
phenyl ring and the formyl group on the isoxazole ring is (Scheme 3, Table 2). The structure of products 7a–g was
possible. Indeed a literature report indicated the formation proven by the X-ray crystallography of a representative
of isoxazolo[4,3-c]quinoline from the 3-(2-azidophe- product 7d.19 Further support for the presence of amino
nyl)isoxazoles by reaction with triphenylphosphine lead- group was obtained by carrying out the acetylation of a
ing to an iminophosphorane which cyclizes through an representative compound 7a to furnish the acetyl deriva-
aza-Wittig reaction.15 Hence, compound 1a was reduced tive 8a. Thus, our results indicate that the reduction of ni-
with lithium aluminum hydride to furnish the product 4. tro group in these substrates is highly chemoselective. In
However, all attempts to perform the intramolecular cy- order to evaluate whether this observation was restricted
clization with this substrate failed to yield the desired re- to palladium-on-carbon promoted reactions, hydrogena-
sult. Nevertheless, similar to 3-(2-nitrophenyl)- tions of compounds 6a–c were also carried out in the pres-
substituted isoxazoles, the catalytic hydrogenation of ence of Raney nickel. Surprisingly, here too similar
compound 4 yielded the corresponding 4-aminoquino- products 7a–c were afforded in two hours in good yields.
line-3-carbaldehyde derivative 2j in high yield. Thus, ir- The reduction of the nitro group was complete in 1–2
respective of the functional groups present on the hours and continuing the reaction even for more than 24
isoxazole ring, the palladium-on-carbon promoted cata- hours in the presence of palladium-on-carbon or Raney
lytic hydrogenation invariably leads to substituted 4-ami- nickel did not lead to any change as the isolated products
noquinolines.
were the anilines only. In our quest to further evaluate the
behavior of 3-(nitrophenyl)-derivatives of 4,5-dihy-
droisoxazoles, 3-(3-nitrophenyl)-4,5-dihydroisoxazoles,
and 3-(4-nitrophenyl)-4,5-dihydroisoxazoles were syn-
thesized and subjected to palladium-on-carbon and Raney
nickel promoted hydrogenations. Similar to 2-nitrophenyl
These results prompted us to explore similar hydrogeno-
lysis in 3-(2-nitrophenyl)-4,5-dihydroisoxazoles. It is
generally accepted that 4,5-dihydroisoxazoles undergo
ring cleavage to yield the b-diketo or b-keto hydroxy sys-
tem under hydrogenation conditions in the presence of
NH2
N
O
10% Pd/C, H2
MeOH, 40 psi, 1 h
N
O
CO2Me
+
CO2Me
N
NH2
5a
CO2Me
NO2
1a
2a
Scheme 2
AcCl, Et3N,
CH2Cl2, 3 h
N
N
O
R
O
N
R
O
10% Pd/C, H2,
MeOH, 40 psi, 1 h
R1
O2N
R1
AcHN
R1
H2N
86–89%
69–90%
6a–j
7a–j
8a,i,j
Scheme 3
Synthesis 2006, No. 12, 1995–2004 © Thieme Stuttgart · New York

PAPER
Catalytic Hydrogenation of Nitrophenyl-Substituted Isoxazoles and 4,5-Dihydroisoxazoles
1997
Table 1 Physical Parameters of Substituted 4-Aminoquinolines
Entry
Substrate
Product
Yield (%) Physical
appearance
Mp (°C)
ESI-MS or
FABMS (M+)
(m/z)
N
O
NH2
N
CO2Me
162–165
1
2
3
4
5
6
79
82
85
88
90
89
brown solid
yellow solid
217.33
251
(158–160)2
CO2Me
NO2
2a
1a
Cl
N
O
NH2
Cl
CO2Me
188–190
145–147
135–137
CO2Me
NO2
N
2b
1b
MeO
N
O
NH2
N
MeO
CO2Me
dark brown
solid
277.27
271
MeO
CO2Me
NO2
MeO
1c
2c
NH2
N
O
CO2Me
CF3
CF3
yellow solid
yellow solid
brown solid
CO2Me
NO2
N
1d
1e
1f
2d
2e
N
O
NH2
CHO
250–252
(258)2
173.16
175
CHO
O
NO2
N
NH2
N
CH2OH
152–154
100–102
NO2
N
CH2OH
2f
NH2
N
O
CO2Me
7
8
93
86
brown solid
brown solid
261
OH
N
CO2Me
NO2
OH
1g
2g
NMe
NMe
NH2
N
N
N
N
O
O
78–80
359.1
CO2Me
CO2Me
OH
NO2
OH
2h
2i
1h
3
N
NH2
CH2OH
9
83
89
off-white solid 156–158
189.13
187
CH2OH
O
NH2
N
N
NH2
CHO
227–229
yellow solid
10
(262)2
CHO
NH2
N
4
2j
Synthesis 2006, No. 12, 1995–2004 © Thieme Stuttgart · New York

1998
V. Singh et al.
PAPER
derivatives, these compounds too did not undergo ring droisoxazole-5-carboxylate (9) was hydrogenated in the
cleavage as evident from their spectroscopic and analyti- presence of palladium-on-carbon and Raney nickel sepa-
cal data. The presence of the amino group on the phenyl rately. As reported, under these conditions hydrogenoly-
ring was further established by the preparation of the cor- sis did occur to yield the corresponding 3-hydroxy-5-
responding acetates 8i and 8j. To prove that this unusual phenylpyrrolidin-2-one (10) (Scheme 4).
observation is restricted to the nitrophenyl derivatives of
4,5-dihydroisoxazoles, the methyl 3-phenyl-4,5-dihy-
Table 2 Physical Parameters of 3-(2-, 3-, and 4-Aminophenyl)-4,5-dihydroisoxazoles 7a–j via Scheme 3
Entry
Substrate
Product
Yield (%) Physical
appearance
Mp (°C)
FAB-MSa
(m/z)
N
N
N
O
O
O
O
O
O
220 (M+),
CO2Me
CO2Et
CO2Bu-t
CN
CO2Me
CO2Et
CO2Bu-t
CN
1
88
86
89
79
83
81
84
brown solid 58–60
221 (M+ + 1)
NH2
NO2
7a
7b
7c
7d
6a
6b
6c
6d
6e
N
O
O
O
O
234 (M+),
2
3
4
5
6
7
brown solid 88–90
235 (M+ + 1)
NO2
NH2
N
N
262 (M+),
brown solid 102–104
263 (M+ + 1)
NH2
NO2
N
N
off-white
82–84
solid
187 (M+),
188 (M+ + 1)
NO2
NH2
N
N
204 (M+),
brown oil
–
205 (M+ + 1)
O
O
NO2
NH2
7e
MeO
N
MeO
N
O
O
280 (M+),
CO2Me
CO2Me
yellow solid 128–130
281 (M+ + 1)
MeO
MeO
NO2
N
NH2
6f
7f
N
O
O
O
O
off-white
132–134
solid
264 (M+),
CO2Me
CO2Me
O
O
265 (M+ + 1)
NO2
NH2
6g
7g
N
N
O
O
O
220 (M+),
CO2Me
CO2Me
8
9
85
79
brown solid 78–80
221 (M+ + 1)
O2N
H2N
6h
7h
N
N
O
CO2Et
CO2Et
234 (M+),
brown solid 80–82
235 (M+ + 1)
O2N
H2N
7i
6i
Synthesis 2006, No. 12, 1995–2004 © Thieme Stuttgart · New York

PAPER
Catalytic Hydrogenation of Nitrophenyl-Substituted Isoxazoles and 4,5-Dihydroisoxazoles
1999
Table 2 Physical Parameters of 3-(2-, 3-, and 4-Aminophenyl)-4,5-dihydroisoxazoles 7a–j via Scheme 3 (continued)
Entry
10
Substrate
Product
Yield (%) Physical
appearance
Mp (°C)
110–112
FAB-MSa
(m/z)
N
N
O
O
pale yellow
220 (M+),
81
CO2Me
CO2Me
solid
221 (M+ + 1)
O2N
H2N
6j
7j
OH
N
O
146–148
(150)
11
69
white solid
178
CO2Me
O
N
H
9
10
a It was observed that all anilines show peaks for (M+) and (M+ + 1) in FAB mass spectra.
shifts in d values, J in Hz). The FABMS were recorded on JEOL/
SX-102 spectrometers and ESI-MS (positive mode) were recorded
through direct flow injections in Merck M-8000 LCMS system.
Elemental analyses were performed on a Carlo Erba 1108 micro-
analyzer or Elementar’s Vario EL III microanalyzer. Compounds
1g and 1h were prepared as published earlier.20
Methyl 4-Amino-2-methylquinoline-3-carboxylate (2a);
Typical Procedure
To a soln of 1a (0.4 g, 1.85 mmol) in MeOH (10 mL), was added
10% Pd/C (100 mg) under N2. The atmosphere of the vessel was re-
placed by hydrogen gas. The reaction was carried out on the Parr as-
sembly at 40 psi at r.t. for 5–7 h. Thereafter, the catalyst was filtered
over Celite and the filtrate was evaporated to yield a residue. This
residue upon column chromatography over silica gel (CHCl3–
MeOH, 1–3%) yielded compound 2a as brown solid; yield: 0.26 g
(79%).
Figure 1 ORTEP diagram showing the crystal structure of 7d with
atomic numbering scheme for non-H atoms only at 30% probability
level.
IR (KBr): 1734 (CO2CH3), 3363 (br, NH2) cm–1.
O
N
O
HN
1H NMR (300 MHz, CDCl3): d = 2.81 (s, 3 H, CH3), 3.95 (s, 3 H,
CO2CH3), 7.01 (br s, 2 H, NH2, exchangeable with D2O), 7.42 (t,
J = 7.5 Hz, 1 H, ArH), 7.68 (t, J = 7.5 Hz, 1 H, ArH), 7.75 (d,
J = 8.1 Hz, 1 H, ArH), 7.87 (d, J = 8.1 Hz, 1 H, ArH).
10% Pd/C, H2
CO2Me
OH
9
10
13C NMR (50.32 MHz, CDCl3): d = 28.3, 51.9, 102.6, 117.4, 121.1,
125.3, 129.4, 131.6, 147.9, 154.2, 159.9, 170.3.
Scheme 4
Anal. Calcd for C12H12N2O2: C, 66.65; H, 5.59; N, 12.96. Found: C,
66.69; H, 5.52; N, 12.90.
In summary we have demonstrated the general applicabil-
ity of the palladium-on-carbon mediated hydrogenolysis
of substituted 3-(2-nitrophenyl)isoxazoles which invari-
ably results in the formation of substituted 4-aminoquino-
lines through reduction of the nitro group to amino group,
followed by isoxazole ring cleavage and concomitant re-
giospecific ring closure. This can be treated as an easy and
alternative method to achieve the synthesis of this impor-
tant class of heterocycle with desired substitutions. On the
other hand, it has been shown that the 4,5-dihydroisox-
azole ring is retained during the catalytic hydrogenation if
the 3-position is substituted with a nitrophenyl group.
Work is underway to explore the usefulness of this meth-
odology to obtain compounds of medicinal interest.
Methyl 4-Amino-6-chloro-2-methylquinoline-3-carboxylate
(2b)
IR (KBr): 1738 (CO2CH3), 3382 (br, NH2) cm–1.
1H NMR (300 MHz, CDCl3 + DMSO-d6): d = 2.85 (s, 3 H, CH3),
3.99 (s, 3 H, CO2CH3), 7.62–7.69 (m, 1 H, ArH), 7.87–7.99 (m, 1
H, ArH), 8.54–8.58 (m, 1 H, ArH).
Anal. Calcd for C12H11ClN2O2: C, 57.49; H, 4.42; N, 11.17. Found:
C, 57.38; H, 4.46; N, 11.20.
Methyl 4-Amino-6,7-dimethoxy-2-methylquinoline-3-carbox-
ylate (2c)
IR (KBr): 1733 (CO2CH3), 3385 (br, NH2) cm–1.
1H NMR (300 MHz, CDCl3 + DMSO-d6): d = 2.57 (s, 3 H, CH3),
3.88 (s, 9 H, 2 × OCH3 and CO2CH3), 7.62, 7.69 (2 × br s merged,
2 H, ArH).
Melting points are uncorrected and were determined in capillary
tubes on a hot stage apparatus containing silicon oil. IR spectra were
Anal. Calcd for C14H16N2O4: C, 60.86; H, 5.84; N, 10.14. Found: C,
60.80; H, 5.78; N, 10.30.
1
recorded using a Perkin Elmer RX I 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
Synthesis 2006, No. 12, 1995–2004 © Thieme Stuttgart · New York

2000
V. Singh et al.
PAPER
Methyl 4-Amino-2-(trifluoromethyl)quinoline-3-carboxylate
(2d)
Anal. Calcd for C11H12N2O: C, 70.19; H, 6.43; N, 14.88. Found: C,
70.04; H, 6.35; N, 14.60.
IR (KBr): 1733 (CO2CH3), 3434 (br, NH2) cm–1.
4-Amino-2-methylquinoline-3-carbaldehyde (2j)
1H NMR (200 MHz, CDCl3): d = 3.96 (s, 3 H, CO2CH3), 6.63 (br s,
2 H, NH2), 7.60–7.64 (m, 1 H, ArH), 7.75–7.85 (m, 2 H, ArH), 8.08
(d, J = 8.4 Hz, 1 H, ArH).
13C NMR (50.32 MHz, CDCl3): d = 52.8, 101.7, 118.4, 119.1,
120.9, 124.6, 127.9, 131.1, 132.2, 146.7, 153.1, 168.3.
IR (KBr): 1707 (CHO), 3312 (br, NH2) cm–1.
1H NMR (300 MHz, CDCl3 + DMSO-d6): d = 2.71 (s, 3 H, CH3),
6.04 (br s, 2 H, NH2), 7.50 (t, J = 7.5 Hz, 1 H, ArH), 7.75 (t, J = 7.5
Hz, 1 H, ArH), 7.88 (d, J = 8.1 Hz, 1 H, ArH), 7.98 (d, J = 8.1 Hz,
1 H, ArH), 9.05 (s, 1 H, CHO), 9.89 (br s, 1 H, NH2).
Anal. Calcd for C12H9F3N2O2: C, 53.34; H, 3.36; N, 10.37. Found,
C, 53.44; H, 3.22; N, 10.62.
Anal. Calcd for C11H10N2O: C, 70.95; H, 5.41; N, 15.04. Found: C,
71.04; H, 5.35; N, 15.12.
4-Aminoquinoline-3-carbaldehyde (2e)
[3-(2-Aminophenyl)-5-methylisoxazol-4-yl]methanol (3)
To a stirred soln of 1a (1.5 g, 5.72 mmol) in anhyd Et2O (40 mL)
was added LiAlH4 (0.33 g, 8.6 mmol) in portions at 0 °C. The ice
bath was removed and the reaction was allowed to proceed at r.t. for
1 h. Upon completion the mixture was carefully decomposed with
ice-cold 10% NaOH soln. The precipitate was filtered and the fil-
trate was washed thoroughly with H2O. The organic layer was dried
and evaporated to yield a residue. This residue upon column chro-
matography over silica gel (60–120) (hexane–EtOAc, 40:60) to
gave pure 3 as a brown oil; yield: 0.95 g (82%).
IR (KBr): 1710 (CHO), 3428 (br, NH2) cm–1.
1H NMR (200 MHz, CDCl3 + DMSO-d6): d = 7.45–7.52 (m, 1 H,
ArH), 7.70–7.78 (m, 1 H, ArH), 7.90 (d, J = 8.6 Hz, 1 H, ArH), 8.27
(d, J = 8.4 Hz, 1 H, ArH), 8.67 (s, 1 H, ArH), 9.97 (s, 1 H, CHO).
13C NMR (50.32 MHz, DMSO-d6): d = 109.3, 118.2, 124.1, 125.6,
129.5, 132.6, 149.1, 153.9, 155.9, 193.4.
Anal. Calcd for C10H8N2O: C, 69.76; H, 4.68; N, 16.27. Found: C,
69.68; H, 4.62; N, 16.30.
IR (neat): 3443 (br, NH2 and OH) cm–1.
1H NMR (200 MHz, CDCl3): d = 2.52 (s, 3 H, CH3), 3.58 (s, 2 H,
CH2OH), 7.54–7.60 (m, 3 H, ArH), 8.12–8.17 (m, 1 H, ArH).
(4-Aminoquinolin-2-yl)methanol (2f)
IR (KBr): 3331 (br, NH2) cm–1.
1H NMR (300 MHz, CDCl3 + DMSO-d6): d = 4.51 (s, 2 H, CH2),
6.74, 6.79 (2 × s merged, 3 H, ArH and NH2), 7.33–7.35 (m, 1 H,
ArH), 7.56–7.58 (m, 1 H, ArH), 7.68 (d, 1 H, J = 7.8 Hz, ArH), 8.10
(d, 1 H, J = 7.8 Hz, ArH).
13C NMR (50.32 MHz, DMSO-d6): d = 64.9, 99.5, 118.1, 122.7,
123.4, 128.3, 129.4, 147.9, 152.6, 162.4.
ESI-MS: m/z = 205.40 (M+ + 1).
Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C,
64.58; H, 6.05; N, 13.60.
3-(2-Aminophenyl)-5-methylisoxazole-4-carbaldehyde (4)
To the stirred soln of 3 (0.5 g, 2.45 mmol) in anhyd CH2Cl2 (20 mL)
was added PCC (1.05 g, 4.9 mmol) and the reaction was allowed to
proceed at r.t. for 16 h. Thereafter the mixture was filtered through
a silica gel column (hexane–EtOAc, 50:50) to afford compound 4
as an orange solid; yield: 0.4 g (81%); mp 134–136 °C.
Anal. Calcd for C10H10N2O: C, 68.95; H, 5.79; N, 16.08. Found: C,
68.84; H, 5.72; N, 16.20.
Methyl 3-(4-Aminoquinolin-2-yl)-3-hydroxy-2-methyl-
propionate (2g)
IR (KBr): 1724 (CO2CH3), 3366 (br, NH2) cm–1.
IR (KBr): 1684 (CHO), 3432 (br, NH2) cm–1.
1H NMR (300 MHz, CDCl3): d = 1.15 (d, J = 7.2 Hz, 3 H, CH3),
2.78–2.88 (m, 1 H, CH), 3.67 (s, 3 H, CO2CH3), 4.90 (d, J = 5.4 Hz,
1 H), 6.58 (s, 1 H, ArH), 7.41–7.46 (m, 1 H, ArH), 7.62–7.67 (m, 1
H, ArH), 7.75 (d, J = 8.1 Hz, 1 H, ArH), 7.93 (d, J = 8.1 Hz, 1 H,
ArH).
1H NMR (200 MHz, CDCl3): d = 2.80 (s, 3 H, CH3), 7.54–7.58 (m,
1 H, ArH), 7.70–7.76 (m, 2 H, ArH), 8.25–8.29 (m, 1 H, ArH), 9.79
(s, 1 H, CHO).
13C NMR (50.32 MHz, CDCl3): d = 12.4, 116.5, 123.8, 125.4,
131.7, 132.7, 134.0, 148.8, 159.9, 177.0, 183.1.
Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found: C,
64.56; H, 6.12; N, 10.60.
FAB-MS: m/z = 203 (M+ + 1).
Anal. Calcd for C11H10N2O2: C, 65.34; H, 4.98; N, 13.85. Found: C,
65.04; H, 5.15; N, 14.06.
Methyl 3-(4-Aminoquinolin-2-yl)-3-hydroxy-2-(4-methyl-
piperazin-1-ylmethyl)propionate (2h)
IR (KBr): 1731 (CO2CH3), 3396 (br, NH2) cm–1.
Methyl 3-(2-Aminophenyl)-5-methylisoxazole-4-carboxylate
(5a)
1H NMR (300 MHz, DMSO-d6): d = 2.26 (s, 3 H, NCH3), 2.30–2.45
(m, 8 H, 4 × CH2N), 2.60–2.70 (m, 2 H, NCH2), 3.05–3.15 (m, 1 H,
CHCH2), 3.63 (s, 3 H, CO2CH3), 4.96 (d, J = 1.8 Hz, 1 H, CHOH),
6.75 (s, 2 H, NH2), 7.47–7.51 (m, 1 H, ArH), 7.68–7.75 (m, 2 H,
ArH), 7.83–7.89 (m, 1 H, ArH), 8.22–8.26 (m, 1 H, ArH).
Yellow solid; mp 192–194 °C.
IR (KBr): 1733 (CO2CH3), 3391 (br, NH2) cm–1.
1H NMR (300 MHz, CDCl3): d = 2.91 (s, 3 H, CH3), 3.98 (s, 3 H,
CO2CH3), 7.00 (br s, 2 H, NH2), 7.59 (t, J = 7.5 Hz, 1 H, ArH), 7.83
(t, J = 7.5 Hz, 1 H, ArH), 7.99 (d, J = 8.1 Hz, 1 H, ArH), 8.82 (d,
J = 8.4 Hz, 1 H, ArH).
Anal. Calcd for C19H26N4O3: C, 63.67; H, 7.31; N, 15.63. Found: C,
63.56; H, 7.12; N, 150.60.
ESI-MS: m/z = 233.4 (M+ + 1), 255.0 (M+ + Na).
(4-Amino-2-methylquinolin-3-yl)methanol (2i)
IR (KBr): 3433 (br, NH2) cm–1.
Anal. Calcd for C12H12N2O3: C, 62.06; H, 5.21; N, 12.06. Found: C,
62.20; H, 5.34, N, 12.15.
1H NMR (300 MHz, CDCl3 + DMSO-d6): d = 2.55 (s, 3 H, CH3),
4.63 (s, 2 H, CH2), 6.59 (br s, 2 H, NH2), 7.33 (t, J = 7.8 Hz, 1 H,
ArH), 7.55 (t, J = 7.8 Hz, 1 H, ArH), 7.66 (d, J = 8.1 Hz, 1 H, ArH),
8.16 (d, J = 8.1 Hz, 1 H, ArH).
13C NMR (50.32 MHz, DMSO-d6): d = 22.9, 56.4, 111.7, 117.9,
122.3, 123.3, 127.5, 128.9, 146.4, 149.8, 157.2.
3-(2-, 3-, and 4-Nitrophenyl)-4,5-dihydroisoxazoles (6)
These 4,5-dihydroisoxazoles were prepared as described in the lit-
erature.21
Synthesis 2006, No. 12, 1995–2004 © Thieme Stuttgart · New York

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Catalytic Hydrogenation of Nitrophenyl-Substituted Isoxazoles and 4,5-Dihydroisoxazoles
2001
Methyl 3-(2-Nitrophenyl)-4,5-dihydroisoxazole-5-carboxylate
(6a)
Yellow oil; yield: 87%.
1H NMR (200 MHz, CDCl3): d = 3.50–3.61 (m, 2 H, CH2CH), 3.82
(s, 3 H, CO2CH3), 3.99 (s, 6 H, 2 × OCH3), 5.24–5.29 (m, 1 H,
CHCH2), 6.96 (s, 1 H, ArH), 7.72 (s, 1 H, ArH).
IR (neat): 1743 (CO2CH3) cm–1.
FAB-MS: m/z = 311 (M+ + 1).
1H NMR (200 MHz, CDCl3): d = 3.54–3.62 (m, 2 H, CH2), 3.87 (s,
3 H, CO2CH3), 5.23–5.32 (m, 1 H, CH), 7.58–7.72 (m, 3 H, ArH),
8.10–8.14 (m, 1 H, ArH).
Anal. Calcd for C13H14N2O7: C, 50.33; H, 4.55; N, 9.03. Found: C,
50.18; H, 4.76; N, 9.33.
Methyl 3-(6-Nitro-1,3-benzodioxol-5-yl)-4,5-dihydroisoxazole-
5-carboxylate (6g)
Pale yellow solid; yield: 76%; mp 121–123 °C.
IR (KBr): 1754 (CO2CH3) cm–1.
FAB-MS: m/z = 251 (M+ + 1).
Anal. Calcd for C11H10N2O5: C, 52.80; H, 4.03; N, 11.20. Found: C,
52.87; H, 4.08; N, 11.25.
Ethyl 3-(2-Nitrophenyl)-4,5-dihydroisoxazole-5-carboxylate
(6b)
Brown oil; yield: 83%.
1H NMR (200 MHz, CDCl3): d = 3.47–3.57 (m, 2 H, CH2CH), 3.86
(s, 3 H, CO2CH3), 5.22–5.30 (m, 1 H, CHCH2), 6.19 (s, 2 H, CH2),
6.93 (s, 1 H, ArH), 7.63 (s, 1 H, ArH).
IR (neat): 1743 (CO2Et) cm–1.
FAB-MS: m/z = 295 (M+ + 1).
1H NMR (200 MHz, CDCl3): d = 1.36 (t, J = 7.1 Hz, 3 H, CH3CH2),
3.45–3.70 (m, 2 H, CH2CH), 4.31 (q, J = 7.1 Hz, 2 H, CH2CH3),
5.21–5.30 (m, 1 H, CHCH2), 7.27–7.76 (m, 3 H, ArH), 8.10–8.13
(m, 1 H, ArH).
Anal. Calcd for C12H10N2O7: C, 48.99; H, 3.43; N, 9.52. Found: C,
48.92; H, 3.35; 9.46.
Methyl 3-(3-Nitrophenyl)-4,5-dihydroisoxazole-5-carboxylate
(6h)
FAB-MS: m/z = 265 (M+ + 1).
White solid; yield: 81%; mp 92–94 °C.
IR (KBr): 1755 (CO2CH3) cm–1.
Anal. Calcd for C12H12N2O5: C, 54.55; H, 4.58; N, 10.60. Found: C,
54.61; H, 4.50; N, 10.65.
1H NMR (200 MHz, CDCl3): d = 3.68–3.76 (m, 2 H, CH2CH), 3.85
(s, 3 H, CO2CH3), 5.24–5.33 (m, 1 H, CHCH2), 7.62 (t, J = 8.0 Hz,
1 H, ArH), 8.10 (d, J = 7.8 Hz, 1 H, ArH), 8.27–8.32 (m, 1 H, ArH),
8.45 (s, 1 H, ArH).
tert-Butyl 3-(2-Nitrophenyl)-4,5-dihydroisoxazole-5-carbox-
ylate (6c)
Yellow solid; yield: 80%; mp 76–78 °C.
IR (KBr): 1738 (CO2-t-Bu) cm–1.
FAB-MS: m/z = 251 (M+ + 1).
1H NMR (200 MHz, CDCl3): d = 1.54 (s, 9 H, 3 × CH3), 3.47–3.58
(m, 2 H, CH2CH), 5.09–5.18 (m, 1 H, CHCH2), 7.58–7.74 (m, 3 H,
ArH), 8.08–8.12 (m, 1 H, ArH).
Anal. Calcd for C11H10N2O5: C, 52.80; H, 4.03; N, 11.20. Found: C,
52.92; H, 4.13; N, 11.27.
Ethyl 3-(3-Nitrophenyl)-4,5-dihydroisoxazole-5-carboxylate
(6i)
White solid; yield: 83%; mp 65–67 °C.
IR (KBr): 1748 (CO2Et) cm–1.
FAB-MS: m/z = 293 (M+ + 1).
Anal. Calcd for C14H16N2O5: C, 57.53; H, 5.52; N, 9.58. Found: C,
57.62; H, 5.58; N, 9.62.
3-(2-Nitrophenyl)-4,5-dihydroisoxazole-5-carbonitrile (6d)
Off-white solid; yield: 77%; mp 122–124 °C.
IR (KBr): 2248 (CN) cm–1.
1H NMR (200 MHz, CDCl3): d = 3.52–3.88 (m, 2 H, CH2CH),
5.43–5.51 (m, 1 H, CHCH2), 7.60–7.78 (m, 3 H, ArH), 8.17–8.22
(m, 1 H, ArH).
1H NMR (200 MHz, CDCl3): d = 1.34 (t, J = 7.2 Hz, 3 H, CH3CH2),
3.66–3.72 (m, 2 H, CH2CH), 4.30 (q, J = 7.2 Hz, 2 H, CH2CH3),
5.20–5.30 (m, 1 H, CHCH2), 7.58–7.66 (m, 1 H, ArH), 8.08–8.13
(m, 1 H, ArH), 8.26–8.32 (m, 1 H, ArH), 8.44–8.46 (m, 1 H, ArH).
FAB-MS: m/z = 265 (M+ + 1).
Anal. Calcd for C12H12N2O5: C, 54.55; H, 4.58; N, 10.60. Found: C,
54.64; H, 4.63; N, 10.66.
FAB-MS: m/z = 218 (M+ + 1).
Anal. Calcd for C10H7N3O3: C, 55.30; H, 3.25; N, 19.35. Found: C,
55.43; H, 3.21; N, 19.38.
Methyl 3-(4-Nitrophenyl)-4,5-dihydroisoxazole-5-carboxylate
(6j)
Off-white solid; yield: 86%; mp 159–161 °C.
IR (KBr): 1755 (CO2CH3) cm–1.
1H NMR (200 MHz, CDCl3): d = 3.66–3.72 (m, 2 H, CH2CH), 3.84
(s, 3 H, CO2CH3), 5.24–5.33 (m, 1 H, CHCH2), 7.86 (d, J = 8.5 Hz,
2 H, ArH), 8.28 (d, J = 8.5 Hz, 2 H, ArH).
1-[3-(2-Nitrophenyl)-4,5-dihydroisoxazol-5-yl]ethanone (6e)
Brown oil; yield: 79%.
IR (neat): 1722 (COCH3) cm–1.
1H NMR (200 MHz, CDCl3): d = 2.42 (s, 3 H, CH3), 3.48–3.53 (m,
2 H, CH2CH), 5.06–5.15 (m, 1 H, CHCH2), 7.52–7.72 (m, 3 H,
ArH), 8.08–8.13 (m, 1 H, ArH).
FAB-MS: m/z = 251 (M+ + 1).
Anal. Calcd for C11H10N2O5: C, 52.80; H, 4.03; N, 11.20. Found: C,
52.96; H, 4.12; N, 11.26.
FAB-MS: m/z = 235 (M+ + 1).
Anal. Calcd for C11H10N2O4: C, 56.41; H, 4.30; N, 11.96. Found: C,
56.49; H, 4.33; N, 11.92.
Methyl 3-(2-Aminophenyl)-4,5-dihydroisoxazole-5-carbox-
ylate (7a); Typical Procedure Using Palladium-on-Carbon
To a soln of 6a (0.75 g, 3.0 mmol) in MeOH (20 mL) was added
10% Pd/C (125 mg) under N2. The atmosphere of the vessel was re-
placed by hydrogen gas. The reaction was carried out on the Parr as-
sembly at 40 psi at r.t. for 1 h. Thereafter, the catalyst was filtered
over Celite and the filtrate was evaporated to yield a residue. This
Methyl 3-(4,5-Dimethoxy-2-nitrophenyl)-4,5-dihydroisoxazole-
5-carboxylate (6f)
Pale yellow solid; yield: 75%; mp 130–132 °C.
IR (KBr): 1732 (CO2CH3) cm–1.
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2002
V. Singh et al.
PAPER
residue upon column chromatography over silica gel (hexane–
EtOAc, 90:10) yielded a brown solid; yield: 0.58 g (88%).
Anal. Calcd for C11H12N2O2: C, 64.69; H, 5.92; N, 13.72. Found: C,
64.76; H, 6.12; N, 13.86.
Methyl 3-(2-Aminophenyl)-4,5-dihydroisoxazole-5-carbox-
ylate (7a); Typical Procedure Using Raney Nickel
Methyl 3-(2-Amino-4,5-dimethoxyphenyl)-4,5-dihydro-
isoxazole-5-carboxylate (7f)
A mixture of 6a (0.67 g, 2.68 mmol) and Raney Ni (0.1 g wet) in
MeOH (10 mL) was subjected to hydrogenation at 40 psi in the Parr
assembly for 3 h. The catalyst was removed by filtration over Celite
and the filtrate was concentrated. The residue thus obtained was
subjected to column chromatography over silica gel (hexane–
EtOAc, 90:10) to afford pure 7a as a brown solid; yield: 0.50 g
(85%).
IR (KBr): 1744 (CO2CH3), 3457 (br, NH2) cm–1.
1H NMR (200 MHz, CDCl3): d = 3.70–3.74 (m, 2 H, CH2CH), 3.81
(s, 6 H, 2 × OCH3), 3.87 (s, 3 H, CO2CH3), 5.09 (t, J = 9.2 Hz, 1 H,
CHCH2), 6.26 (s, 1 H, ArH), 6.61 (s, 1 H, ArH).
13C NMR (50.32 MHz, CDCl3): d = 41.2, 53.2, 56.1, 57.5, 76.4,
99.9, 102.5, 113.6, 141.1, 143.4, 152.7, 157.3, 171.5.
IR (KBr): 1741 (CO2CH3), 3467 (br, NH2) cm–1.
Anal. Calcd for C13H16N2O5: C, 55.71; H, 5.75; N, 9.91. Found: C,
55.97; H, 5.62; N, 10.19.
1H NMR (200 MHz, CDCl3): d = 3.72–3.83 (m, 5 H, CH2CH and
CO2CH3), 5.06–5.15 (m, 1 H, CHCH2), 6.71–6.75 (m, 2 H, ArH),
7.14–7.27 (m, 2 H, ArH).
13C NMR (50.32 MHz, CDCl3): d = 40.8, 53.2, 76.6, 110.9, 116.3,
116.8, 130.0, 131.5, 147.3, 157.8, 171.3.
Methyl 3-(6-Amino-1,3-benzodioxol-5-yl)-4,5-dihydro-
isoxazole-5-carboxylate (7g)
IR (KBr): 1740 (CO2CH3), 3450 (br, NH2) cm–1.
1H NMR (200 MHz, CDCl3): d = 3.67 (d, J = 8.8 Hz, 2 H, CH2CH),
3.82 (s, 3 H, CO2CH3), 5.07 (t, J = 8.8 Hz, 1 H, CHCH2), 5.89 (s, 2
H, OCH2O), 6.27 (s, 1 H, ArH), 6.58 (s, 1 H, ArH).
HRMS: m/z calcd for C11H12N2O3: 220.0848; found: 220.0837.
Ethyl 3-(2-Aminophenyl)-4,5-dihydroisoxazole-5-carboxylate
13C NMR (50.32 MHz, CDCl3): d = 41.3, 53.2, 76.4, 97.3, 101.6,
(7b)
102.8, 108.0, 139.7, 144.6, 150.6, 157.4, 171.4.
IR (KBr): 1738 (CO2Et), 3447 (br, NH2) cm–1.
Anal. Calcd for C12H12N2O5: C, 54.55; H, 4.58; N, 10.60. Found: C,
54.89; H, 4.66; N, 10.66.
1H NMR (200 MHz, CDCl3): d = 1.33 (t, J = 7.2 Hz, 3 H, CH3CH2),
3.71–3.76 (m, 2 H, CH2CH), 4.27 (q, J = 7.2 Hz, 2 H, CH2CH3,),
5.05, 5.10 (dd, J1 = 8.4 Hz, J2 = 1.0 Hz, 1 H, CHCH2), 5.63 (br s, 2
H, NH2), 6.66–6.75 (m, 2 H, ArH), 7.14–7.23 (m, 2 H, ArH).
13C NMR (50.32 MHz, CDCl3): d = 14.5, 40.8, 62.4, 76.8, 111.0,
116.3, 116.8, 130.0, 131.5, 147.3, 157.7, 170.8.
Methyl 3-(3-Aminophenyl)-4,5-dihydroisoxazole-5-carbox-
ylate (7h)
IR (KBr): 1742 (CO2CH3), 3449 (br, NH2) cm–1.
1H NMR (200 MHz, CDCl3): d = 3.58–3.72 (m, 2 H, CH2CH), 3.82
(s, 3 H, CO2CH3), 5.13, 5.18 (dd, J1 = 8.2 Hz, J2 = 1.6 Hz, 1 H,
CHCH2), 6.72–6.77 (m, 1 H, ArH), 6.96–7.23 (m, 3 H, ArH).
Anal. Calcd for C12H14N2O3: C, 61.53; H, 6.02; N, 11.96. Found: C,
61.65; H, 6.16; N, 12.03.
13C NMR (50.32 MHz, CDCl3): d = 39.5, 53.2, 78.2, 113.2, 117.6,
tert-Butyl 3-(2-Aminophenyl)-4,5-dihydroisoxazole-5-carbox-
ylate (7c)
117.7, 129.7, 130.1, 147.3, 156.8, 171.2.
IR (KBr): 1732 (CO2-t-Bu), 3449 (br, NH2) cm–1.
Anal. Calcd for C11H12N2O3: C, 59.99; H, 5.49; N, 12.72. Found: C,
59.80; H, 5.46; N, 12.85.
1H NMR (200 MHz, CDCl3): d = 1.51 (s, 9 H, 3 × CH3), 3.67 (d,
J = 9.2 Hz, 2 H, CH2CH), 4.96 (t, J = 9.2 Hz, 1 H, CHCH2), 5.62 (br
s, 2 H, NH2), 6.66–6.75 (m, 2 H, ArH), 7.14–7.23 (m, 2 H, ArH).
13C NMR (50.32 MHz, CDCl3): d = 28.4, 40.7, 77.4, 111.2, 116.3,
116.8, 130.0, 131.4, 147.3, 157.6, 169.7.
Ethyl 3-(3-Aminophenyl)-4,5-dihydroisoxazole-5-carboxylate
(7i)
IR (KBr): 1716 (CO2Et), 3451 (br, NH2) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.33 (t, J = 7.2 Hz, 3 H, CH3),
3.57–3.62 (m, 2 H, CH2CH), 4.27 (q, J = 7.1 Hz, 2 H, CH2CH3),
5.11, 5.16 (dd, J1 = 8.6 Hz, J2 = 1.4 Hz, 1 H, CHCH2), 6.72–6.77
(m, 1 H, ArH), 6.96–7.23 (m, 3 H, ArH).
Anal. Calcd for C14H18N2O3: C, 64.10; H, 6.92; N, 10.68. Found: C,
63.89; H, 6.73; N, 10.60.
3-(2-Aminophenyl)-4,5-dihydroisoxazole-5-carbonitrile (7d)
Anal. Calcd for C12H14N2O3: C, 61.53; H, 6.02; N, 11.96. Found: C,
61.42; H, 5.88; N, 12.06.
IR (KBr): 2249, 2213 (CN), 3466 (br, NH2) cm–1.
1H NMR (200 MHz, CDCl3): d = 3.81–3.86 (m, 2 H, CH2CH), 5.28
(t, J = 8.6 Hz, 1 H, CHCH2), 5.60 (br s, 2 H, NH2), 6.69–6.78 (m, 2
H, ArH), 7.09–7.24 (m, 2 H, ArH).
13C NMR (50.32 MHz, CDCl3): d = 42.9, 65.5, 109.8, 116.6, 117.2,
117.7, 129.5, 130.1, 132.3, 147.5, 160.0.
Methyl 3-(4-Aminophenyl)-4,5-dihydroisoxazole-5-carbox-
ylate (7j)
IR (KBr): 1742 (CO2CH3), 3458 (br, NH2) cm–1.
1H NMR (200 MHz, CDCl3): d = 3.55–3.59 (m, 2 H, CH2CH), 3.78
(s, 3 H, CO2CH3), 5.10 (t, J = 9.2 Hz, 1 H, CHCH2), 6.63 (d, J = 8.6
Hz, 2 H, ArH), 7.43 (d, J = 8.6 Hz, 2 H, ArH).
13C NMR (50.32 MHz, CDCl3): d = 39.7, 53.1, 77.9, 115.0, 118.5,
128.9, 149.3, 156.4, 171.5.
Anal. Calcd for C10H9N3O: C, 64.16; H, 4.85; N, 22.45. Found: C,
64.26; H, 4.89; N, 22.49.
1-[3-(2-Aminophenyl)-4,5-dihydroisoxazol-5-yl]ethanone (7e)
IR (neat): 1721 (COCH3), 3470 (br, NH2) cm–1.
Anal. Calcd for C11H12N2O3: C, 59.99; H, 5.49; N, 12.72. Found: C,
60.12; H, 5.72; N, 12.58.
1H NMR (200 MHz, CDCl3): d = 2.36 (s, 3 H, COCH3), 3.58–3.70
(m, 2 H, CH2CH), 4.90, 4.95 (dd, J1 = 6.6 Hz, J2 = 4.80 Hz, 1 H,
CHCH2), 6.68–6.75 (m, 2 H, ArH), 7.15–7.24 (m, 2 H, ArH).
13C NMR (50.32 MHz, CDCl3): d = 26.7, 39.3, 83.1, 111.1, 116.3,
117.0, 130.2, 131.6, 147.2, 158.4, 208.2.
Methyl 3-[2-(Acetylamino)phenyl]-4,5-dihydroisoxazole-5-car-
boxylate (8a); Typical Procedure
To a stirred soln of 7a (0.30 g, 1.36 mmol) in dry CH2Cl2 (3 mL)
was added Et3N (0.28 mL, 2.04 mmol) followed by dropwise addi-
tion of a soln of AcCl (0.19 mL, 2.72 mmol) in dry CH2Cl2 (3 mL)
Synthesis 2006, No. 12, 1995–2004 © Thieme Stuttgart · New York

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Catalytic Hydrogenation of Nitrophenyl-Substituted Isoxazoles and 4,5-Dihydroisoxazoles
2003
at 0 °C. When the addition was complete, the reaction was contin-
ued at r.t. for 2 h. The mixture was extracted with CH2Cl2 (2 × 15
mL) and H2O (20 mL). The combined organic layer was washed
with brine, dried (anhyd Na2SO4), and evaporated to obtain an oily
residue. The residue was purified through column chromatography
over silica gel (hexane–EtOAc, 80:20) to give 8a as a pale yellow
solid; yield: 0.3 g (86%); mp 150–152 °C.
(5) (a) Reuben, B. G.; Wittcoff, H. A. Pharmaceutical
Chemicals in Perspective; Wiley: New York, 1989.
(b) McIntosh, H. M.; Greenwood, B. M. Ann. Trop. Med.
Parasitol. 1998, 92, 265. (c) Deshpande, S. S.; Sheridan, R.
E.; Adler, M. Toxicon 1997, 35, 433. (d) Slater, A. F.
Pharmacol. Ther. 1993, 57, 203. (e) O’Neill, P. M.;
Willock, D. J.; Hawley, S. R.; Bray, P. G.; Storr, R. C.;
Ward, S. A.; Park, B. K. J. Med. Chem. 1997, 40, 437; and
references therein. (f) Madrid, P. B.; Sherrill, J.; Liou, A. P.;
Weisman, J. L.; DeRisi, J. L.; Guy, R. K. Bioorg. Med.
Chem. Lett. 2005, 15, 1015.
IR (KBr): 1755 (CO2CH3), 3458 (NH) cm–1.
1H NMR (200 MHz, CDCl3): d = 2.23 (s, 3 H, COCH3), 3.75–3.81
(m, 2 H, CH2CH), 3.85 (s, 3 H, CO2CH3), 5.14, 5.19 (dd, J1 = 7.8
Hz, J2 = 2.4 Hz, 1 H, CHCH2), 7.08–7.16 (m, 1 H, ArH), 7.28–7.32
(m, 1 H, ArH), 7.41–7.49 (m, 1 H, ArH), 8.69–8.73 (m, 1 H, ArH),
10.49 (br s, 1 H, NH).
13C NMR (50.32 MHz, CDCl3): d = 25.9, 40.6, 53.4, 77.0, 115.3,
120.9, 123.3, 129.7, 132.0, 138.7, 157.8, 169.7, 170.6.
(6) (a) Andrews, I. P.; Bannister, R.; Etridge, S. K.; Lewis, N. J.;
Mullane, M. V.; Wells, A. S. Tetrahedron Lett. 1995, 36,
7743. (b) Ife, R. F.; Brown, T. H.; Keeling, D. J.; Leach, C.
A.; Meeson, M. L.; Persons, M. E.; Reavill, D. R.; Theobald,
C. J.; Wiggall, K. J. J. Med. Chem. 1992, 35, 3413.
(7) Moyer, M. P.; Weber, F. H.; Gross, J. L.; Isaac, J. W.; Saint
Fort, R. Bioorg. Med. Chem. Lett. 1992, 2, 1589.
FAB-MS: m/z = 263 (M+ + 1).
Anal. Calcd for C13H14N2O4: C, 59.54; H, 5.38; N, 10.68. Found: C,
59.29; H, 5.41; N, 10.72.
(8) Kireev, D. B.; Chretien, J. R.; Raevsky, D. A. Eur. J. Med.
Chem. 1995, 30, 395.
(9) (a) Marco, J. L.; Carreiras, M. C. Mini Rev. Med. Chem.
2003, 3, 518. (b) Doucet-Personeni, C.; Bentley, P. D.;
Fletcher, R. J.; Kinkaid, A.; Kryger, G.; Pirard, B.; Taylor,
A.; Taylor, R.; Taylor, J.; Viner, R.; Silman, I.; Sussman, J.
L.; Greenblatt, H. M.; Lewis, T. J. Med. Chem. 2001, 44,
3203. (c) Han, Y. F.; Li, C. P.; Chow, E.; Wang, H.; Pang,
Y. P.; Carlier, P. R. Bioorg. Med. Chem. 1999, 7, 2569.
(10) Shinkai, H.; Ito, T.; Iida, T.; Kitao, Y.; Yamada, H.; Uchida,
I. J. Med. Chem. 2000, 43, 4667.
Ethyl 3-[3-(Acetylamino)phenyl]-4,5-dihydroisoxazole-5-car-
boxylate (8i)
Colorless oil; yield: 86%.
IR (neat): 1740 (CO2Et), 3306 (NH) cm–1.
1H NMR (200 MHz, CDCl3): d = 1.33 (t, J = 7.1 Hz, 3 H, CH3CH2),
2.19 (s, 3 H, COCH3), 3.59–3.66 (m, 2 H, CH2CH), 4.25 (q, J = 7.1
Hz, 2 H, CH2CH3), 5.16 (t, J = 9.2 Hz, 1 H, CHCH2), 7.31–7.44 (m,
2 H, ArH), 7.64–7.68 (m, 1 H, ArH), 7.79 (s, 1 H, ArH).
(11) Medebielle, M.; Hohn, S.; Okada, E.; Myoken, H.; Shibata,
D. Tetrahedron Lett. 2005, 46, 7817.
(12) Roy, A. K.; Batra, S. Synthesis 2003, 1347.
FAB-MS: m/z = 277 (M+ + 1).
Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found: C,
64.55; H, 6.58; N, 10.68.
(13) Balsamo, A.; Coletta, I.; Guglielmotti, A.; Landolfi, C.;
Mancini, F.; Martinelli, A.; Milanese, C.; Minutolo, F.;
Nencetti, S.; Orlandini, E.; Pinza, M.; Rapposelli, S.;
Rosello, A. Eur. J. Med. Chem. 2003, 38, 157.
(14) (a) Saxena, R.; Singh, V.; Batra, S. Tetrahedron 2004, 60,
10311. (b) Singh, V.; Saxena, R.; Batra, S. J. Org. Chem.
2005, 70, 353. (c) Roy, A. K.; Pathak, R.; Yadav, G. P.;
Maulik, P. R.; Batra, S. Synthesis 2006, in press.
(15) Purwono, B.; Smalley, R. K.; Porter, T. C. Synlett 1992, 231.
(16) (a) Kozikowski, A. P.; Stein, P. D. J. Am. Chem. Soc. 1982,
104, 4023. (b) Curran, D. P. J. Am. Chem. Soc. 1982, 104,
4024. (c) Curran, D. P. J. Am. Chem. Soc. 1983, 105, 4024.
(d) Auricchio, S.; Ricca, A. Tetrahedron 1987, 43, 3983.
(17) Quan, M. L.; Ellis, C. D.; He, M. Y.; Liauw, A. Y.; Lam, P.
Y. S.; Rossi, K. A.; Knabb, R. M.; Luettgen, J. M.; Wright,
M. R.; Wong, P. C.; Wexler, R. R. Bioorg. Med. Chem. Lett.
2003, 13, 1023.
Methyl 3-[4-(Acetylamino)phenyl]-4,5-dihydroisoxazole-5-car-
boxylate (8j)
White solid; yield: 89%; mp 127–129 °C.
IR (KBr): 1759 (CO2CH3), 3528 (NH) cm–1.
1H NMR (200 MHz, CDCl3): d = 2.20 (s, 3 H, COCH3), 3.63 (d,
J = 9.0 Hz, 2 H, CH2CH), 3.82 (s, 3 H, CO2CH3), 5.18 (t, J = 9.1 Hz,
1 H, CHCH2), 7.54–7.59 (m, 4 H, ArH).
FAB-MS: m/z = 263 (M+ + 1).
Anal. Calcd for C13H14N2O4: C, 59.54; H, 5.38; N, 10.68. Found: C,
59.23; H, 5.25; N, 10.44.
Acknowledgment
(18) Vittorio, F.; Ronsisvalle, G.; Pappalardo, M. S.; Blandino,
G. Farmaco 1985, 40, 359.
The financial assistance to three of the authors (VS, SM and GPY)
from DST and CSIR New Delhi in the form of fellowship is grate-
fully acknowledged. This work was partially supported through a fi-
nancial grant under DST Project no. SR/SI/OC-04/2003.
(19) Crystal data of compound 7d: C10H9N3O, M = 187.2;
orthorhombic, P212121, a = 5.710 (1), b = 9.925 (1),
c = 16.153 (3) Å, V = 915.4 (3) Å3, Z = 4, Dc = 1.358g cm–
3, m (Mo–Ka) = 0.09 mm–1, F(000) = 392.0, colorless block,
crystal dimensions 0.225 × 0.175 × 0.150 mm, 1370
reflections measured (Rint = 0.019), 1230 unique, R = 0.0456
[(D/s)max = 000)], wR2 = 0.1087 for 1270 on F2 values of
reflections with I>2s(I), S = 1.028 for all data and 128
parameters. Unit cell determination and intensity data
collection (2q = 50°) were performed on a Bruker P4
diffractometer at 293 (2) K. Structure solutions was
performed by direct methods and refinements by full-matrix
least-squares methods on F2. Programs: XSCANS [Siemens
Analytical X-ray Instrument Inc.: Madison, WI, USA, 1996)
was used for data collection and data processing],
References
(1) CDRI Communication no 8402. A part of this work was
presented as a poster at the CSIR-ACS conference OCCB-
2006 at NCL Pune from 7–9th January, 2006.
(2) (a) Godard, A.; Queguiner, G. J. Heterocycl. Chem. 1980,
17, 465. (b) Veronese, A. C.; Callegari, S. A.; Salah, S. A. A.
Tetrahedron Lett. 1990, 31, 3485.
(3) Thomsen, I.; Torssel, K. B. G. Acta Chem. Scand. B 1988,
42, 309.
(4) Jensen, S.; Torssel, K. B. G. Acta Chem. Scand. B 1995, 19,
53.
SHELXTL-NT [(Bruker Axs Inc.: Madison, Wisconsin,
Synthesis 2006, No. 12, 1995–2004 © Thieme Stuttgart · New York

2004
V. Singh et al.
PAPER
(20) (a) Patra, A.; Batra, S.; Kundu, B.; Joshi, B. S.; Roy, R.;
USA 1997) was used for structure determination,
refinements and molecular graphics]. Further details of the
crystal structure investigation can be obtained from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EZ, UK (CCDC deposition no. of
compound 7d: 297540.
Bhaduri, A. P. Synthesis 2001, 276. (b) 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.
(21) Srivastava, S.; Bajpai, L. K.; Batra, S.; Bhaduri, A. P.;
Maikuri, J. P.; Gupta, G.; Dhar, J. D. Bioorg. Med. Chem.
1999, 7, 2607.
Synthesis 2006, No. 12, 1995–2004 © Thieme Stuttgart · New York