Regioselective synthesis of pyrazoles and isoxazoles with cyclopropanated side-chain

Article abstract of DOI:10.1002/jhet.1960

Pyrazoles and isoxazoles with cyclopropanated side-chain were prepared by cyclization of cyclopropanated 1,3,5-tricarbonyl compounds with hydrazine and hydroxylamine, respectively. The regioselectivity is influenced by the reaction conditions.

Full text of DOI:10.1002/jhet.1960

May 2014
Regioselective Synthesis of Pyrazoles and Isoxazoles with
Cyclopropanated Side-Chain
835
Franziska Bendrath,a Abiodun Falodun,b Zharylkasyn A. Abilov,c
Alexander Villinger,a and Peter Langera,d
*
aInstitut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
bDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Benin, Benin City, Nigeria
cAl-Farabi Kazakh National University, Al-Farabi ave. 71, 050040 Almaty, Kazakhstan
dLeibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
*
E-mail: peter.langer@uni-rostock.de
Received November 5, 2012
DOI 10.1002/jhet.1960
Published online 22 November 2013 in Wiley Online Library (wileyonlinelibrary.com).
Pyrazoles and isoxazoles with cyclopropanated side-chain were prepared by cyclization of cyclopropanated
1,3,5-tricarbonyl compounds with hydrazine and hydroxylamine, respectively. The regioselectivity is influenced
by the reaction conditions.
J, Heterocyclic Chem., 51, 835 (2014).
INTRODUCTION
[12]. The reaction of aliphatic 3,5-diketoester 1a with hydra-
zine hydrate (2a) afforded pyrazole 3a in good yield
(Scheme 2, Table 1). The reaction was carried out in EtOH
at 50ꢀC (method A). The reaction of 1a with phenylhydra-
zine (2b) resulted, under identical conditions, in the forma-
tion of a mixture of regioisomers. In contrast, the reaction
proceeded with excellent regioselectivity and the product
3b was isolated in 79% yield when glacial acetic acid instead
of ethanol was used (method B). Likewise, the application of
method B was also allowed for the synthesis of products
3c–e in good yields. In contrast, a regioisomeric mixture
was obtained when method A was applied. The reaction
of phenyl substituted 3,5-diketoester 1b with parent
hydrazine hydrate (2a) gave pyrazole 3f in good yield
(method A). The reaction of 1b with methyl hydrazine
afforded an unseparable 1:5 mixture of regioisomers 3g
and 4g (method B). In contrast, the reaction of 1b with
(p-nitrophenyl)hydrazine afforded a separable mixture of
3h (56%) and 4h (10%). The reaction of p-methoxyphenyl
substituted 3,5-diketoester 1c with hydrazine hydrate (2a)
gave pyrazole 3i (method A). The reaction of 1c with
methyl hydrazine gave, similar to the corresponding reac-
tion of 1b, an unseparable 1:11 mixture of regioisomers 3j
and 4j (method B). The reaction of 1c with (p-nitrophenyl)
hydrazine afforded pure 3k, albeit, in low yield. The
influence of the solvent on the regioselectivity of pyrazole
formation has been previously reported [13].
Pyrazoles are of considerable relevance in medicinal
chemistry [1]. In particular, cyclopropanated pyrazoles show
promising biological properties. For example, 1-(4-methoxy-
benzyl)-3-cyclopropyl-1H-pyrazol-5-amines exhibit antimi-
crobial activity; [2] 3-amino-5-cyclopropyl-pyrazoles have
been used for the treatment of cancer and of Alzheimer’s
disease. [3] 3-Cyclopropyl-4-(3-amino-2-methylbenzoyl)
pyrazoles, [4] N-cyclopropyl-1H-pyrazol-4-carboamides,
[5] and pyrazol-substituted O-cyclopropylcarboxy-anilides
[6] have been reported to act as herbicides and fungicides.
Zoniporide is a selective inhibitor of sodium–hydrogen
exchange in membranes and is used to reduce the risk of
perioperative heart attacks (Scheme 1) [7].
Similar to pyrazoles, isoxazoles are also of considerable
pharmacological relevance [8]. They are used as antibiotics
and antiviral agents [9], and herbicides [10]. Isoxazolyl peni-
cillins, such as dicloxacillin, are used for the fight against gram
positive bacteria that are resistant against penicillin G [11].
Herein, we report a convenient synthesis of novel
pyrazoles and isoxazoles with cyclopropanated side-chain
by regioselective cyclocondensation of readily available
cyclopropanated 3,5-diketoesters with hydrazine and
hydroxylamine, respectively.
RESULTS AND DISCUSSION
The structures of the products were confirmed by
H,1H-NOESY NMR spectroscopic studies. Relevant NOE
correlations of 3b,h,k and of 4j are shown in Schemes 3
and 4, respectively.
We have recently reported a convenient synthesis of
cyclopropanated 3,5-diketoesters 1a–c by the reaction of
cyclopropanated dimethyl malonate with ketone enolates
© 2013 HeteroCorporation

836
F. Bendrath, A. Falodun, Z. A. Abilov, A. Villinger, and P. Langer
Vol 51
Scheme 1. Structure of Zoniporide.
NH2 group at the sterically less hindered keto group located at
carbon C-5 of 1a and subsequent cyclization to give exclu-
sively product 3c. The cyclization of arylated hydrazines 2b
and 2e with 1a, using method B, gave products 3b and 3e.
Their formation can be explained analogously. The reaction
of methyl hydrazine with aryl substituted 3,5-dioxoesters 1b
and 1c proceeded, as expected, by attack of the unprotonated
NH2 group to the more electrophilic keto group located at
carbon C-3 of 1b and 1c and afforded products 4g and 4j as
major components in the isomeric mixtures with 3g and 3j,
respectively. The employment of p-nitrophenyl hydrazine
(2d) is a special case. The application of method A in the re-
action of 2d with aliphatic 3,5-dioxoester 1a mainly afforded
3d. The product was isolated as a 5:1 mixture together with
4d in moderate yield. This can be explained by the low
nucleophilicity of the nitrogen atom attached to the electron
withdrawing p-nitrophenyl group. The reaction of 2d with
1a, carried out by application of method B, resulted in selec-
tive formation of 3d in very good yield. This can be explained
again by protonation of the nitrogen atom attached to the aryl
group. The cyclization of 2d with arylated 3,5-dioxoesters
afforded products 3h and 3k. The yields were relatively
low, and the selectivity was not complete, which might be
explained by the assumption that the nitrogen atom is not
completely protonated, because of the electron withdrawing
The structure of 3d was independently confirmed by X-ray
crystal structure analysis (Figure 1). The pyrazole and the
p-nitrophenyl moiety are nearly in plane. This can be
explained by the electronic push–pull interaction between
the two rings.
The results can be explained as follows. In case of aliphatic
3,5-dioxoester 1a, the lateral keto group is more electrophilic
than the central one, because of steric reasons. In case of aryl
substituted 3,5-dioxoesters 1b and 1c, the electrophilicity of
the lateral keto group is decreased because of the mesomeric
effect of the neighboring aryl group. The employment of
glacial acetic acid results in complete and regioselective
protonation of the more basic methyl substituted nitrogen
atom of methyl hydrazine (2c). Therefore, the reaction of 2c
with 1a, using method B, results in attack of the unprotonated
Table 1
Synthesis of pyrazoles 3 and 4.
1
2
3, 4
R1
R2
Method b
% (3)a
% (4)a
a
a
a
a
a
a
b
b
b
c
a
b
c
d
d
e
a
c
d
a
c
a
b
c
d
d
e
f
g
h
i
Me
Me
Me
Me
Me
Me
Ph
H
Ph
Me
4-NO2C6H4
4-NO2C6H4
4-MeC6H4
H
Me
4-NO2C6H4
A
B
B
A
B
B
A
B
B
A
B
B
61
79
83
0
0
0
57 (5:1)c
84
62
76
0
0
0
Ph
Ph
84 (1:5)c
56
54
10
0
4-(MeO)C6H4
4-(MeO)C6H4
4-(MeO)C6H4
H
Me
4-NO2C6H4
c
c
j
k
75 (1:11)c
d
22
0
aIsolated yields.
bMethod A: EtOH, 50ꢀC; method B: conc. AcOH, 50ꢀC.
cUnseparable mixture of regioisomers 3 and 4; in brackets: ratio (by GC analysis).
Scheme 2. Synthesis of pyrazoles 3 and 4; i: method A: EtOH, 50ꢀC, 4 h; method B: AcOH, 50ꢀC, 4 h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
Regioselective Synthesis of Pyrazoles and Isoxazoles with Cyclopropanated Side-Chain
837
Scheme 3. Relevant 1H,1H-NOESY-correlations of 3b,h,k (full line: strong; hyphenated: weak).
Scheme 4. Relevant 1H,1H-NOESY-correlations of 4j (full line: strong;
hyphenated: weak).
effect of the p-nitrophenyl group. A regiodirecting effect of
the protonation of the 3,5-diketoesters 1a-c by glacial acetic
acid may also have an effect on the selectivity.
A classic approach to isoxazoles relies on the cyclization
of hydroxylamine with 1,3-diketones [14]. The reaction of
1a,b with hydroxylamine hydrochloride (1.1 equiv.), carried
out in pyridine (20ꢀC, the 115ꢀC), afforded isoxazoles 5a,b
in good yields (Scheme 5, Table 2). The reactions proceed
with very good regioselectivity by the attack of the amino
group on the central keto group and subsequent cyclization
via the oxygen atom.
In conclusion, we have reported a convenient and
straightforward synthesis of novel pyrazoles and isoxazoles
with cyclopropanated side-chain.
EXPERIMENTAL
General procedure for the synthesis of 3 and 4. To a solution
of 1 (1.0 equiv.) in ethanol (2.5 mL per mmol of 1) (method A) or
in glacial acetic acid (2.5 mL per mmol of 1) (method B) was
added at 20ꢀC the hydrazine derivative 2 (1.1 equiv.), and the
mixture was stirred for 4 h at 50ꢀC. The precipitate was filtered
off and the filtrate was concentrated in vacuo. The residue was
purified by chromatography (silica gel, heptane/EtOAc = 30/1).
Methyl
1-(5-methyl-1H-pyrazol-3-yl)cyclopropane-carboxylate
(3a). Starting with 1a (1.0 mmol, 184 mg), hydrazine hydrate (2a)
(80% aq. solution, 1.1 mmol, 0.07mL) in 2.5 mL of ethanol, 3a
was isolated by chromatography (heptane/EtOAc= 15/1! 1/1) as
a yellow oil (109 mg, 61%). 1H NMR (300 MHz, CDCl3)
d = 1.30–1.33 (m, 2H, JH,H = 3.40Hz, CH2), 1.65–1.69 (m, 2H,
JH,H =3.40Hz, CH2), 2.27 (s, 3H, CH3), 3.71 (s, 3H, OCH3),
5.89 (1H, CH), 6.18 (br, 1H, NH). 13C NMR (75MHz, CDCl3)
d = 11.7 (CH3), 18.0 (CH2), 21.6 (Cq), 52.2 (OCH2), 104.0
(CH), 143.0, 147.4 (CN), 173.8 (COOCH3). IR (ATR, cmꢁ1):
ev = 3195 (m), 3138 (m), 3107 (m), 2952 (m), 2871 (w), 1720
(s), 1578 (m). MS (EI, 70 eV): m/z = 180 (M+, 100), 148 (52),
120 (98), 91 (25), 79 (26). HRMS (EI, 70 eV) calcd for
C9H12N2O2: 180.08933 (M+); found: 180.08933.
Figure 1. ORTEP plot of 3d (50% probability level). [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
Scheme 5. Synthesis of isoxazoles 5a,b; i: (1) pyridine, 20ꢀC, 20 min; (2)
115ꢀC, 1 h; (3) Et2O, 10% HCl.
Methyl
1-(5-methyl-2-phenyl-2H-pyrazol-3-yl)cyclopropane-
carboxylate (3b). Starting with 1a (1.0 mmol, 184mg),
phenylhydrazine (2b) (1.1mmol, 120mg) in 2.5 mL of ethanol,
3b was isolated by chromatography (heptane/EtOAc = 30/1! 10/
1) as a red oil (202 mg, 79%). 1H NMR (300 MHz, CDCl3)
d = 1.18–1.22 (m, 2H, CH2), 1.59–1.62 (m, 2H, CH2), 2.32
(s, 3H, CH3), 3.47 (s, 3H, OCH3), 6.08 (s, 1H, CH), 7.29–7.34
(m, 1H, Ph), 7.38–7.45 (m, 4H, Ph). 13C NMR (75 MHz, CDCl3)
d = 13.5 (CH3), 18.9 (CH2), 20.8 (Cq), 52.2 (OCH3), 107.8 (CH),
124.3, 127.2, 128.8 (CHPh), 140.4, 142.0 (CN), 146.7 (Cq,Ph),
173.0 (COOCH3). IR (ATR, cmꢁ1): ev = 3063 (w), 3015 (w),
Table 2
Synthesis of isoxazoles 5a,b.
1
5
R
% (5)a
a
b
a
b
Me
Ph
63
62
aIsolated yields.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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F. Bendrath, A. Falodun, Z. A. Abilov, A. Villinger, and P. Langer
Vol 51
2950 (w), 2926 (w), 2871 (w), 2844 (w), 1720 (s), 1578 (m).
MS (EI, 70eV): m/z = 256 (M+, 100), 241 (24), 197 (78), 182
(21), 154 (18), 77 (27). HRMS (EI, 70eV) calcd for C15H16N2O2:
256.12063 (M+); found: 256.12066.
d = 19.1 (CH2), 21.2 (Cq), 52.4 (OCH3), 100.9 (CH), 125.5,
127.8, 128.6 (CHPh), 132.0 (Cq,Ph), 146.3, 128.9 (CN), 173.4
(COOCH3). IR (ATR, cmꢁ1): ev = 3322 (s), 3088 (w), 3066 (w),
3041 (w), 3006 (w), 2955 (w), 2918 (w), 2848 (w), 1713 (s),
1605 (w), 1586 (w), 1560 (s), 1515 (m). HRMS (EI, 70 eV)
calcd for C14H14N2O2 (242.10498, M+): 242.10487. Anal.
calcd for C14H14N2O2 (242.273): C, 69.41; H, 5.82; N, 11.56.
Found: C, 69.01; H, 6.09; N, 11.42.
Methyl
1-(2,5-dimethyl-2H-pyrazol-3-yl)cyclopropane-carboxylate
(3c). Starting with 1a (1.0 mmol, 184 mg), methylhydrazine (2c)
(1.1mmol, 51 mg) in 2.5 mL of ethanol, 3c was isolated by
chromatography (heptane/EtOAc = 25/1! 3/1) as a colorless oil
(160mg, 83%). 1H NMR (300 MHz, CDCl3) d = 1.18–1.22
(m, 2H, CH2), 1.65–1.69 (m, 2H, CH2), 2.21 (s, 3H, CH3), 3.68
(s, 3H, OCH3), 3.74 (s, 3H, NCH3), 5.86 (s, 1H, CH). 13C NMR
(75 MHz, CDCl3) d = 13.4 (CH3), 17.2 (CH2), 19.8 (Cq), 36.3
(NCH3), 52.6 (OCH3), 105.9 (CH), 141.4, 146.9 (CN), 173.0
(COOCH3). IR (ATR, cmꢁ1): ev = 3097 (w), 3014 (w), 2951 (m),
2847 (w), 1722 (s), 1558 (m). MS (EI, 70 eV): m/z = 194 (M+,
100), 179 (23), 162 (22), 135 (42), 133 (41), 94 (23). HRMS (EI,
70eV) calcd for C10H14N2O2: 194.10498 (M+); found: 194.10473.
Methyl
carboxylate (3g) and methyl 1-(2-methyl-5-phenyl-2H-pyrazol-3-yl)
cyclopropane-carboxylate (4g). Starting with 1b (0.50 mmol,
1-(1-methyl-5-phenyl-1H-pyrazol-3-yl)cyclopropane-
124 mg), methylhydrazine (2c) (0.55 mmol, 26 mg) in 1.0 mL of
glacial acetic acid, 3g was isolated by chromatography
(heptane/EtOAc = 15/1 ! 5/1) as a colorless oil (107 mg) as an
unseparable 1:5 mixture of 3g and 4g (ratio by GC). 3g: 1H
NMR (300 MHz, CDCl3) d = 1.39–1.43 (m, 2H, CH2CH2),
1.60–1.63 (m, 2H, CH2CH2), 3.70 (s, 3H, OCH3), 3.83 (s, 3H,
NCH3), 6.39 (s, 1H, CH), 7.27–7.48 (m, 5H, Ph). 13C NMR
(75 MHz, CDCl3) d = 17.6 (CH2), 22.5 (Cq), 37.3 (NCH3), 52.2
(OCH3), 106.7 (CH), 128.3, 128.6, 128.7 (CHPh), 130.6, 144.1,
149.4 (Cq), 174.2 (COOCH3). IR (ATR, cmꢁ1): ev = 3060 (w),
3017 (w), 2950 (m), 2847 (w), 1721 (s), 1642 (w), 1605 (w),
1549 (m), 1500 (m). MS (EI, 70 eV): m/z = 256 (M+, 100), 255
(48), 197 (46), 196 (70), 195 (58), 181 (14). HRMS (EI, 70 eV)
calcd for C15H16N2O2: 256.12063 (M+); found: 256.12087. 4g:
1H NMR (300 MHz, CDCl3) d = 1.27–1.31 (m, 2H, CH2CH2),
1.72–1.75 (m, 2H, CH2CH2), 3.70 (s, 3H, OCH3), 3.87 (s, 3H,
NCH3), 6.39 (s, 1H, CH), 7.27–7.48 (m, 3H, Ph), 7.74–7.77
(m, 2H, Ph). 13C NMR (75 MHz, CDCl3) d = 17.3 (CH2), 19.9
(Cq), 36.7 (NCH3), 52.7 (OCH3), 103.7 (CH), 125.3, 127.5,
128.5 (CHPh), 133.2, 142.3, 149.4 (Cq), 172.8 (COOCH3). IR
(ATR, cmꢁ1): ev = 3060 (w), 3017 (w), 2950 (m), 2847 (w),
1721 (s), 1642 (w), 1605 (w), 1549 (m), 1500 (m). MS (EI,
70 eV): m/z = 256 (M+, 100), 255 (48), 197 (46), 196 (70), 195
(58), 181 (14). HRMS (EI, 70 eV) calcd for C15H16N2O2:
256.12063 (M+); found: 256.12087.
Methyl
1-(5-methyl-2-(p-nitrophenyl)-2H-pyrazol-3-yl)
Starting with 1a (1.0 mmol,
cyclopropane-carboxylate (3d).
184 mg), p-nitrophenylhydrazine (2d) (1.1 mmol, 168 mg) in
2.5 mL of ethanol, 3d was isolated by chromatography (heptane/
EtOAc = 50/1 ! 7/1) as a colorless solid (254 mg, 84%), mp 139–
1
141ꢀC. H NMR (300 MHz, CDCl3) d =1.24–1.28 (m, 2H, CH2),
1.69–1.73 (m, 2H, CH2), 2.28 (s, 3H, CH3), 3.45 (s, 3H, OCH3),
3
4
6.13 (s, 1H, CH), 7.71–7.74 (dd, 2H, JH,H =9.25Hz, JH,
3
4
H =2.08Hz), 8.24–8.27 (dd, 2H, JH,H =9.25Hz, JH,H =2.08Hz).
13C NMR (75 MHz, CDCl3) d =13.4 (CH3), 19.3 (CH2), 21.1 (Cq),
52.4 (OCH3), 110.1 (CH), 122.9, 124.4 (CHPh), 142.5 (CN), 145.4
(Cq,Ph), 145.4 (CN), 150.3 (Cq,Ph), 172.3 (COOCH3). IR (ATR,
cmꢁ1): ev = 3141 (w), 3111 (w), 2997 (w), 2949 (w), 2926 (m),
2853 (w), 1721 (s), 1681 (w), 1595 (s), 1568 (m), 1502 (m). MS
(EI, 70 eV): m/z = 301 (M+, 100), 242 (25), 196 (50), 195 (34), 154
(16). Anal. calcd for C15H15N3O4 (301.297): C, 59.79; H, 5.02; N,
13.95. Found: C, 59.74; H, 5.18; N, 13.85. For details of the X-ray
crystal structure analysis, see ref. 15 [15].
Methyl 1-(5-methyl-2-(p-tolyl)-2H-pyrazol-3-yl)cyclopropane-
carboxylate (3e).
Starting with 1a (1.0 mmol, 184 mg), p-
Methyl 1-(2-(p-nitrophenyl)-5-phenyl-2H-pyrazol-3-yl)
cyclopropane-carboxylate (3h) and methyl 1-(1-(p-nitrophenyl)-5-
phenyl-1H-pyrazol-3-yl)cyclopropane-carboxylate (4h).
Starting with 1b (0.50 mmol, 124 mg), p-nitrophenylhydrazine
(2d) (0.55 mmol, 84 mg) in 1 mL of glacial acetic acid, 3h was
isolated by chromatography (heptane/EtOAc = 30/1 ! 5/1) as a
yellow solid (100 mg, 56%). In addition, 4h was isolated as a
yellow solid (17 mg, 10%). 3h: mp = 125–127ꢀC. 1H NMR
(300 MHz, CDCl3) d = 1.36–1.40 (m, 2H, CH2CH2), 1.79–1.82
(m, 2H, CH2CH2), 3.52 (s, 3H, OCH3), 6.69 (s, 1H, CH),
7.36–7.46 (m, 3H, Ar), 7.84–7.89 (m, 4H, Ar), 8.33–8.36 (m,
2H, Ar). 13C NMR (75 MHz, CDCl3) d = 19.6 (CH2), 21.4
(Cq), 52.7 (OCH3), 107.6 (CH), 123.5, 124.7, 125.8, 128.6,
128.7 (CHPh), 132.2, 143.4, 145.6, 145.9, 152.7 (Cq), 172.4
(COOCH3). IR (ATR, cmꢁ1): ev = 3142 (w), 3088 (w), 2951
(w), 2920 (w), 2849 (w), 1725 (s), 1606 (w), 1592 (s), 1564
(m), 1505 (w), 1496 (s). MS (EI, 70 eV): m/z = 363 (M+, 100),
304 (18), 258 (31), 257 (20), 154 (11). HRMS (ESI, 70 eV)
calcd for C20H18N3O4 (364.12918, [M + H]+): 364.12948.
Anal. calcd for C20H17N3O4 (363.367): C, 66.11; H, 4.72; N,
11.56. Found: C, 66.12; H, 4.96; N, 11.50. 4h: mp = 122–
124ꢀC. 1H NMR (300 MHz, CDCl3) d = 1.54–1.58 (m, 2H,
CH2CH2), 1.68–1.71 (m, 2H, CH2CH2), 3.74 (s, 3H, OCH3),
6.72 (s, 1H, CH), 7.24–7.28 (m, 2H, Ar), 7.34–7.46 (m, 5H,
Ar), 8.13–8.16 (m, 2H, Ph). 13C NMR (75 MHz, CDCl3)
d = 18.2 (CH2), 22.7 (Cq), 52.3 (OCH3), 110.9 (CH), 124.3,
tolylhydrazine (2e) (1.1 mmol, 135 mL) in 2.0 mL glacial acetic
acid, 3e was isolated by chromatography (heptane/EtOAc = 16/
1 ! 3/1) as a brownish solid (165 , 62%), mp 89–90ꢀC. 1H
NMR (300 MHz, CDCl3) d = 1.15–1.19 (m, 2H, CH2CH2),
1.55–1.59 (m, 2H, CH2CH2), 2.30 (s, 3H, CH3), 2.26 (s, 3H,
3
CH3), 3.49 (s, 3H, OCH3), 6.06 (s, 1H, CH), 7.19 (d, 2H, JH,
H = 8.12 Hz, Ph), 7.31 (d, 2H, JH,H = 8.12 Hz, Ph). 13C NMR
3
(75 MHz, CDCl3) d = 13.6 (CH3), 18.9 (CH2), 20.8
(Cq[CH2]2), 21.0 (CH3), 52.3 (OCH3), 107.6 (CH), 124.3,
129.4 (CHPh), 137.2, 138.0, 142.0, 148.5 (Cq), 173.2
(COOCH3). IR (ATR, cmꢁ1): ev = 3092 (w), 3045 (w), 2992
(w), 2951 (w), 2922 (m), 2851 (w), 1716 (s), 1612 (w),
1586 (w), 1556 (m), 1517 (s). MS (EI, 70 eV): m/z = 270
(M+, 100), 255 (21), 211 (79), 195 (25), 154 (12), 91 (14).
HRMS (ESI, 70 eV) calcd for C16H19 N2NaO2: 293.0126
([M + Na]+); found: 293.1259.
Methyl
1-(5-phenyl-1H-pyrazol-3-yl)cyclopropane-carboxylate
(3f). Starting with 1b (1.0 mmol, 246 mg), hydrazine hydrate (2a)
(80% aq. solution, 1.1 mmol, 0.07 mL) in 2.5 mL of ethanol, 3f
was isolated by chromatography (heptane/EtOAc = 15/1 ! 1/1)
as a slightly yellow solid (182 mg, 70%), mp 86–88ꢀC. 1H
NMR (300 MHz, CDCl3) d = 1.28–1.31 (m, 2H, JH,H = 3.40 Hz,
CH2), 1.61–1.65 (m, 2H, JH,H = 3.40 Hz, CH2), 3.61 (s, 3H,
OCH3), 6.28 (s, 1H, CH), 7.17–7.31 (m, 3H, Ph), 7.61–7.64
(m, 2H, Ph), 9.61 (s, 1H, NH). 13C NMR (75 MHz, CDCl3)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Regioselective Synthesis of Pyrazoles and Isoxazoles with Cyclopropanated Side-Chain
839
124.3, 128.5, 128.8, 128.9 (CHAr), 130.1, 144.8, 145.7, 145.9,
152.9 (Cq), 173.6 (COOCH3). IR (ATR, cmꢁ1): ev = 3142
(w), 3116 (w), 3087 (w), 2952 (w), 2922 (w), 2849 (w),
1725 (s), 1607 (w), 1592 (s), 1565 (m), 1552 (w), 1497
(s). MS (EI, 70 eV): m/z = 363 (M+, 100), 304 (15), 258
(28), 257 (20), 154 (10). HRMS (ESI, 70 eV) calcd for
C20H18N3O4 (364.12918, [M + H]+): 364.12914. Anal. calcd
for C20H17N3O4 (363.367): C, 66.11; H, 4.72; N, 11.56.
Found: C, 66.24; H, 5.18; N, 11.07.
mp = 136–138ꢀC. 1H NMR (300 MHz, CDCl3) d = 1.35–1.39 (m,
2H, CH2CH2), 1.77–1.82 (m, 2H, CH2CH2), 3.50 (s, 3H, OCH3),
3.84 (s, 3H, OCH3), 6.61 (s, 1H, CH), 6.92–6.98 (m, 2H, Ar),
7.76–7.88 (m, 4H, Ar), 8.29–8.35 (m, 2H, Ar). 13C NMR
(75 MHz, CDCl3) d = 19.6 (CH2), 21.4 (Cq), 52.7, 55.3 (OCH3),
107.3 (CH), 114.1, 123.3, 124.7 (CHAr), 124.9 (Cq), 127.1
(CHAr), 143.3, 145.7, 145.7, 152.5, 160.0 (Cq), 172.5
(COOCH3). IR (ATR, cmꢁ1): ev = 3115 (w), 3090 (w), 3020 (w),
2996 (w), 2947 (w), 2918 (m), 2848 (m), 1725 (s), 1683 (w),
1611 (w), 1594 (s), 1564 (w), 1511 (s). MS (EI, 70 eV):
m/z = 394 (M+, 15N, 24), 393 (M+, 14N, 100), 378 (5), 334 (6),
332 (5), 288 (10). HRMS (EI, 70eV) calcd for C21H19N3O5:
393.13192 (M+): found: 393.13246.
General procedure for the synthesis of isoxazoles 5a,b. To a
solution of pyridine (2 mL per mmol of 1) was added hydroxylamine
hydrochloride (1.1 equiv.) and 1 (1.0 equiv.). After stirring for 20 min
at 20ꢀC, the mixture was heated under reflux for 1 h. The solvent was
removed in vacuo and to the residue were added diethyl ether and
hydrochloric acid (10%). The layers were separated, and the
aqueous layer was extracted three times with diethyl ether. The
combined organic layers were dried (Na2SO4), filtered and the
filtrate was concentrated in vacuo. The residue was purified by
chromatography (silica gel).
Methyl 1-(5-(p-methoxyphenyl)-1H-pyrazol-3-yl)cyclopropane-
carboxylate (3i). Starting with 1c (1.0 mmol, 276 mg), hydrazine
hydrate (2a) (80% aq. solution, 1.1 mmol, 0.07 mL) in 2.5 mL
of ethanol, 3i was isolated by chromatography (heptane/
1
EtOAc = 15/1 ! 1/1) as a colorless oil (147 mg, 54%). H NMR
(300 MHz, CDCl3) d = 1.35–1.39 (m, 2H, CH2), 1.69–1.72
(m, 2H, CH2), 3.70, 3.81 (OCH3), 6.29 (s, 1H, CH), 6.87–6.92
3
4
(dd, 2H, JH,H = 8.88 Hz, JH,H = 3.02 Hz, Ph), 7.59–7.64
3
4
(dd, 2H, JH,H = 8.88Hz, JH,H = 3.02Hz, Ph), 10.05 (br s, 1H,
NH). 13C NMR (75 MHz, CDCl3) d = 19.0 (CH2), 21.3 (Cq), 52.4,
55.2 (OCH3), 100.4 (CH), 114.0 (CHPh), 124.7 (Cq), 126.8
(CHPh), 146.4, 148.5 (CN), 159.4 (Cq), 173.4 (COOCH3). IR
(ATR, cmꢁ1): ev = 3312 (s), 3106 (w), 3092 (w), 3017 (w), 2957
(w), 2938 (w), 2916 (w), 2832 (w), 1721 (s), 1615 (m), 1562 (m),
1527 (s). MS (EI, 70eV): m/z = 272 (M+, 100), 213 (20),
212 (30), 211 (27), 184 (17), 169 (17). HRMS (EI, 70eV) calcd
for C15H16N2O3 (272.11554, M+): 272.11544.
1-(5-Methylisoxazol-3-yl)cyclopropane-carboxylate
(5a).
Starting with 1a (1.0 mmol, 184 mg), hydroxylamine
hydrochloride (1.1 mmol, 77 mg) in 2.0 mL of pyridine, 5a was
isolated by chromatography (heptane/EtOAc = 15/1) as a
colorless oil (113 mg, 63%). 1H NMR (300 MHz, CDCl3)
d = 1.49–1.53 (m, 2H, CH2CH2), 1.69–1.73 (m, 2H,
CH2CH2), 2.26 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 6.25 (s, 1H,
CH). 13C NMR (75 MHz, CDCl3) d = 11.2 (CH3), 18.3 (CH2),
21.5 (Cq), 52.4 (OCH3), 103.9 (CH), 159.8 (CN), 169.0, 171.2
(CO). IR (ATR, cmꢁ1): ev = 3129 (w), 3003 (w), 2956 (w), 2849
(w), 1728 (s), 1604 (s), 1500 (w). MS (EI, 70eV): m/z = 181 (M+,
100), 149 (17), 82 (44), 59 (30), 53 (42), 39 (21). Anal. calcd for
C9H11NO3 (181.189): C, 59.66; H, 6.12; N, 7.73. Found: C,
59.57; H, 6.38; N, 7.52.
Methyl 1-(1-methyl-5-(p-methoxyphenyl)-1H-pyrazol-3-yl)
cyclopropane-carboxylate (4j) and methyl 1-(2-methyl-5-(p-
methoxyphenyl)-2H-pyrazol-3-yl)cyclopropane-carboxylate
(3j).
Starting with 1c (0.50 mmol, 138 mg), methylhydrazine
(2c) (0.55 mmol, 26 mg) in 1.0 mL of glacial acetic acid, an
unseparable 1:11 mixture of 3j and 4j (ratio by GC) was
isolated by chromatography (heptane/EtOAc = 20/1 ! 5/1) as a
slightly yellow oil (107 mg, 75%). 4j: 1H NMR (300 MHz,
CDCl3) d = 1.38–1.42 (m, 2H, CH2CH2), 1.59–1.62 (m, 2H,
CH2CH2), 3.69 (s, 3H, OCH3), 3.80 (s, 3H, NCH3), 3.85
(s, 3H, OCH3), 6.33 (s, 1H, CH), 6.95–6.99 (m, 2H, Ph),
7.32–7.37 (m, 2H, Ph). 13C NMR (75 MHz, CDCl3) d = 17.6
(CH2), 22.5 (Cq), 37.2 (NCH3), 52.3, 55.3 (OCH3), 106.5
(CH), 114.0 (CHPh), 126.7 (Cq,Ph), 130.0 (CHPh), 143.3,
149.3, 159.7 (Cq), 174.3 (COOCH3). IR (ATR, cmꢁ1):
ev = 3002 (w), 2950 (m), 2840 (w), 1720 (s), 1612 (m), 1576
(w), 1508 (s). MS (EI, 70 eV): m/z = 286 (M+, 100), 285
(50), 227 (38), 226 (55), 225 (46), 211 (13). HRMS (EI,
70 eV) calcd for C16H18N2O3 (286.13119, M+): 286.13129.
3j: 1H NMR (300 MHz, CDCl3) d = 1.27–1.30 (m, 2H,
CH2CH2), 1.70–1.74 (m, 2H, CH2CH2) 3.70 (s, 3H, OCH3),
3.80 (s, 3H, NCH3), 3.85 (s, 3H, OCH3), 6.32 (s, 1H, CH),
6.90–6.91 (m, 2H, Ar), 7.66–7.69 (m, 2H, Ar). 13C NMR
(75 MHz, CDCl3) d = 17.3 (CH2), 19.9 (Cq), 36.6 (NCH3),
52.7, 55.2 (OCH3), 103.3 (CH), 114.0 (CHPh), 122.9 (Cq,Ph),
126.7 (CHPh), 142.3, 149.5, 159.3 (Cq), 172.8 (COOCH3).
IR (ATR, cmꢁ1): ev = 3002 (w), 2950 (m), 2840 (w), 1720
(s), 1612 (m), 1576 (w), 1508 (s). MS (EI, 70eV): m/z = 286
(M+, 100), 285 (50), 227 (38), 226 (55), 225 (46), 211 (13).
HRMS (EI, 70eV) calcd for C16H18N2O3 (286.13119, M+):
286.13129.
Methyl 1-(5-phenylisoxazol-3-yl)cyclopropane-carboxylate
(5b).
Starting with 1b (0.50mmol, 123 mg), hydroxylamine
hydrochloride (0.55 mmol, 39 mg) in 2.0mL of pyridine, 5b was
isolated by chromatography (heptane/EtOAc = 30/1! 15/1) as a
colorless oil (74 mg, 62%). 1H NMR (300MHz, CDCl3) d = 1.61–
1.65 (m, 2H, CH2CH2), 1.77–1.81 (m, 2H, CH2CH2), 3.77 (s, 3H,
OCH3), 6.77 (s, 1H,. CH), 7.44–7.46 (m, 3H, Ph), 7.79–7.82 (m,
2H, Ph). 13C NMR (75MHz, CDCl3) d = 18.8 (CH2), 21.9 (Cq),
52.6 (OCH3), 101.5 (CH), 126.7, 128.8 (CHPh), 129.1 (Cq,Ph),
129.9 (CHPh), 162.6 (CN), 169.9, 171.3 (CO). IR (ATR,
cmꢁ1): ev = 3125 (s), 3053 (w), 3022 (w), 2953 (m), 2916
(m), 2847 (m), 1724 (s), 1611 (s), 1581 (m), 1504 (w). MS
(EI, 70 eV): m/z = 244 (M+, 15N, 16), 243 (M+, 14N, 100),
144 (57), 127 (12), 117 (36), 77 (35). HRMS (EI, 70 eV)
calcd for C14H13NO3: 243.08899 (M+); found: 243.08968.
Acknowledgments. Financial support by the EU (EFRE program)
and by the State of Mecklenburg–Vorpommern is gratefully
acknowledged.
REFERENCES AND NOTES
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Starting with 1c (0.50 mmol,
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