A combined experimental and natural bonding orbital charges study on the one-pot regioselective synthesis of 4-chloropyrazoles

Article abstract of DOI:10.3184/174751914X14137288281925

The mechanism of a DMF-catalysed electrophilic/nucleophilic chlorination of pyrazole is illustrated with the aid of calculations of the natural bonding orbital charges. Its high regioselectivity and good functionality tolerance of nine pyrazole substrates

Full text of DOI:10.3184/174751914X14137288281925

658 RESEARCH PAPER
VOL. 38 NOVEMBER, 658–661
JOURNAL OF CHEMICAL RESEARCH 2014
A combined experimental and natural bonding orbital charges study on the
one-pot regioselective synthesis of 4-chloropyrazoles
Yi Lia, Yuanyuan Liub*, Guanghui Xua, Kai Chenc, Guangke Hec and Bin Huangb
aCollege of Food Science and Light Industry, Nanjing Tech University, Nanjing 211816, P.R. China
bDepartment of Chemical and Pharmaceutical Engineering, Southeast University ChengXian College, Nanjing 210088, P.R. China
cCollege of Science, Nanjing Tech University, Nanjing 211816, P.R. China
The mechanism of a DMF-catalysed electrophilic/nucleophilic chlorination of pyrazole is illustrated with the aid of calculations
of the natural bonding orbital charges. Its high regioselectivity and good functionality tolerance of nine pyrazole substrates
have been experimentally demonstrated.
Keywords: chlorinated pyrazoles, small molecular catalysis, electrophilic substitution, nucleophilic substitution, natural bonding
orbital charges calculations
The discovery of the acaricide tebufenpyrad,1 insecticide
tolfenpyrad,2 and herbicide pyraflufen‑ethyl (Fig. 1),3
4‑chloropyrazoles have attracted considerable attention
due to their diverse bioactivities such as antimicrobial (A)4
and herbicidal (B) activities.5 Chen et al.6 has synthesised a
series of substituted 4‑chloropyrazoles (C) for the control of
Rhizoctonia solani.6 These 4‑chloropyrazoles (2) containing
a useful functional handle (chloro atom) at the 4‑position,
have also been employed as participants in cross‑coupling
reaction.7–9 However, existing methods for direct access to 2
are limited. Although it can be prepared by chlorination with
the use of N‑chlorinated succinimide or sulfuryl dichloride,10–12
or via condensation between hydrazines and acrylates or
1,3‑dicarbonyl precursors,13–15 these methods suffer from poor
regioselectivity, limited substrate scope, multi‑step syntheses,
or costly purification. Thus, the development of new approaches
to 2 that avoid these limitations will be of great value. Our
group has devoted considerable effort to address this issue,
and has reported a novel DMF‑catalysed 4‑chlorination of
3‑oxypyrazoles with good functionality tolerance.16
to illustrate its chlorination mechanism: (1) with a catalytic
amount of DMF, a higher yield of 2a (Scheme 1, 81%) was
obtained than without DMF; (2) the SOCl2–DMF (SD) complex
was prepared to determine whether the SD complex was the
chlorinating species (Scheme 2), and was allowed to react
with 1a in boiling CHCl3. However, only a trace of product
2a was detected by HPLC. Therefore, it seems most likely
that 1a reacts with SOCl2 first, and then the reaction with
catalyst DMF occurs; (3) the 4‑chlorination likely proceeds
via a nucleophilic attack by Cl–; because SOCl2 is normally a
source of Cl–, and the intermediacy of Cl– is feasible; (4) the
natural bonding orbital (NBO) charges of 1a indicated that the
C4 (–0.4) atom of the pyrazole ring had more negative charges
than C5 (–0.02), and the initial electrophilic attack of SOCl2
should occur at C(4) atom (Scheme 1); and (5) elemental sulfur
was isolated during the purification of 2a.
We propose a catalytic mechanism for the formation of
2a (Scheme 3). As can be seen from the NBO charges of 1a,
the initial electrophilic attack of SOCl2 occurs at the more
electron‑rich C(4) atom (–0.4) [C(5) (–0.02)], generating an
unstable intermediate I and releasing one molecule of HCl.
Subsequently, the system goes through a transition state II, in
which the complexation of I with DMF donates a delocalised
Cl– to nucleophilic substitute the SO‑DMF group, then yield
2a and regenerate DMF. The catalyst DMF acts as an electron‑
withdrawing group to accelerate the reaction rate and as a
leaving group upon protonation. Although SO has not been
detected, elemental sulfur was isolated, indicating the possible
involvement of SO in the reaction.
To further explore its scope, in this paper, nine pyrazole
substrates 1a–h with many functional groups have been
synthesised, and their direct chlorination is investigated. In
addition, the chlorination mechanism is illustrated with the aid
of calculations of the natural bonding orbital (NBO) charges.
Results and discussion
The reaction of 1‑phenyl‑1H‑pyrazol‑3‑ol (1a) with SOCl2 was
selected as a model, and the following results were obtained
Fig. 1 Design strategy for the target product 1.
* Correspondent. E‑mail: liuyuanyuan1985419@163.com
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JOURNAL OF CHEMICAL RESEARCH 2014 659
Scheme 1 DMF-Catalysed 4-chlorination of 1-phenyl-1H-pyrazol-3-ol (1a).
l
C
Cl-
O
S
N+
a
1
DMF
r.t.
Cl
O
H
O
S
N
l
C
l
C
CHCl3, reflux
N
Ph
O
2a
SOCl2-DMF complex
SD
(only trace)
(
)
Scheme 2 Reaction of 1a with SOCl2–DMF complex (SD).
Scheme 3 Proposed reaction pathway for the formation of 2a from 1a.
To further investigate its scope and regioselectivity,
pyrazole substrates 1b–i with alkyl or aryl groups at the 1‑ or
5‑position, with alkyl, alkoxy, hydroxyl, or O‑amide groups
at the 3‑position, were synthesised for chlorination in boiling
SOCl2 by using DMF (10 mol%) as catalyst (Table 1). The
1‑aryl‑substituted 3‑hydroxylpyrazoles 1b with an electron‑
donating group, and 1c with an electron‑withdrawing group
on the 1‑phenyl ring, giving 80% and 78% yield of 2b and 2c,
respectively, with high regioselectivity for monochlorination
at the 4‑position. The chlorination of ethoxypyrazole 1d or
methylpyrazole 1e without substitution on the N‑atom also
proceeded well, and 76% yield of 2d and 68% yield of 2e were
isolated. However, substrate 1f containing an O‑amide group,
gave a slightly lower yield (60%) of 2f, possibly due to the
partial hydrolysis of the amide moiety under acidic conditions.
In addition, 3,5‑dimethylpyrazoles 1g with phenyl group
on the N‑atom, underwent better chlorination than 1h with
methyl group (giving 75% or 70% yield of the 4‑chlorinated
products 2g and 2h, respectively). Compound 1i containing
many useful functional groups, such as alkoxy, ester, imino,
and aryl groups, with both electron‑donating and ‑withdrawing
groups, was also compatible with this direct 4‑chlorination,
and the procedure allowed the regioselective formation of 2i
in 82% yield. Significantly, this direct chlorination can avoid
tedious steps of protection and deprotection of functional
groups. Compared to the other methine C‑atom, the C(4) atom
of the pyrazole ring shows more electron‑rich to make the
electrophilic attack of SOCl2 and the nucleophilic substitution
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660 JOURNAL OF CHEMICAL RESEARCH 2014
Table 1 DMF-catalysed 4-chlorination of substrates 1a–i with SOCl2
H
Cl
R3
R3
DMF (10 mol %)
reflux, 4h
R2
SOC 2
R2
+
l
N
N
N
N
R1
R1
1a-1i
2a-2i
Substrate
R1
R2
R3
Yield/%
1a
1b
1c
1d
1e
Ph
OH
OH
OH
OEt
Me
H
H
H
Ph
Me
81 (2a)
80 (2b)
78 (2c)
76 (2d)
68 (2e)
p-CF3OC6H4
m-CF3C6H4
H
H
Fig. 2 ORTEP Plot of the molecular structure of 2f showing atom-
numbering scheme; 50% probability thermal ellipsoids.
S
S
O
H2
C
1f
Ph
p-MeC6H4
60 (2f)
N
O
(s, 2H, CH2), 4.08 (s, 3H, OCH3), 3.84 (s, 3H, OCH3); Anal. calcd for
C20H18ClN3O4: C, 60.08; H, 4.54; N, 10.51; found: C, 59.85; H, 4.59; N,
10.58%.
1g
1h
Ph
Me
Me
Me
Me
Me
75 (2g)
70 (2h)
O
Synthesis of 4‑chlorinated pyrazoles 2a–I; general procedure
SOCl2 (5 mL) was added to a round‑bottom flask, and then 1a–i
(1.0 mmol) and a catalytic amount of DMF (0.1 mmol) were added. The
mixture was heated to reflux for 4 h (reaction monitored by HPLC),
then excess SOCl2 was evaporated under reduced pressure. The residue
was dispersed in H2O (200 mL) and extracted with AcOEt. The organic
phase was separated, dried, and concentrated. It was then purified by
flash column chromatography (eluent: ethyl acetate/petroleum ether,
1:10 v/v) to afford 2a–i.
4‑Chloro‑1‑phenyl‑1H‑pyrazol‑3‑ol (2a): White crystals; m.p.
180–181 °C (lit.12 179–181 °C); yield 0.16 g (81%); 1H NMR (400 MHz,
DMSO‑d6) δ 11.00 (s, 1H, OH), 8.54 (s, 1H, CH), 7.69–7.21 (m, 5H,
ArH); Anal. calcd for C9H7ClN2O: C, 55.54; H, 3.63; N, 14.39; found:
C, 55.75; H, 3.58; N, 14.32%. The spectral data match those previously
reported.12
N
H3CO
OCH3
O
1i
p-ClC6H4
H
82 (2i)
of Cl– only take place at. With the help of the NBO charges
calculations, the probability and position of this chlorination on
the pyrazole ring can be speculated. The regioselectivity of this
chlorination and structural elucidation of the products were
unequivocally determined by H NMR spectra and single‑
crystal X‑ray diffraction analysis of 2f (Fig. 2).
1
Experimental
All reagents were of analytical grades. High‑performance liquid
chromatography was recorded on a P680 chromatograph (column:
Kromasil 100‑5C18; mobile phase: methanol/ultra‑pure water,
3:1; flow: 0.6 mL min–1). Column chromatography was carried on
flash silica gel (300–400 mesh) by using mixtures of ethyl acetate
and petroleum ether as eluent. Melting points were measured on an
X‑4 microscope electrothermal apparatus (Taike, China) and were
uncorrected. 1H NMR spectra were recorded in [D6]DMSO or CDCl3
with Bruker AV‑300 (300 MHz), AV‑400 (400 MHz), or AV‑500
(500 MHz) spectrometers, with tetramethylsilane as an internal
standard. Elemental analyses were performed on a Flash EA‑1112
elemental analyser.
4‑Chloro‑1‑[4‑(trifluoromethoxy)phenyl]‑1H‑pyrazol‑3‑ol (2b):
White crystals; m.p. 137–138 °C; yield 0.22 g (80%); 1H NMR
(400 MHz, CDCl3) δ 7.62 (s, 1H, CH), 7.40 (d, J=8.8 Hz, 2H, ArH), 7.25
(d, J=8.8 Hz, 2H, ArH); Anal. calcd for C10H6ClF3N2O2: C, 43.11; H,
2.17; N, 10.05; found: C, 43.31; H, 2.14; N, 10.13%.
4‑Chloro‑1‑[3‑(trifluoromethyl)phenyl]‑1H‑pyrazol‑3‑ol (2c):
White crystals; m.p. 112–113 °C; yield 0.21 g (78%); 1H NMR
(400 MHz, CDCl3) δ 7.74 (s, 1H, CH), 7.64 (t, J=7.6 Hz, 2H, ArH), 7.55
(t, J=7.6 Hz, 1H, ArH), 7.47 (d, J=7.6 Hz, 1H, ArH); Anal. calcd for
C10H6ClF3N2O: C, 45.73; H, 2.30; N, 10.67; found: C, 45.55; H, 2.34; N,
10.75%.
4‑Chloro‑3‑ethoxy‑5‑phenyl‑1H‑pyrazole (2d): Yellow oil; yield
1
0.17 g (76%); H NMR (DMSO‑d6, 500 MHz) δ 12.66 (s, 1H, NH),
Synthesis of pyrazole substrates 1a–h; general procedure
Compounds 1a–c were prepared from ethyl acrylate via two steps
including addition–cyclisation and oxidation.16,17 Compounds 1d and
1f were prepared according to the literature.16 Compounds 1e, 1g and
1h were synthesised by the reaction of acetyl acetone and hydrazine
derivatives under alkaline conditions.18 Spectral data of 1a–h match
those previously reported.16–18
7.70–7.43 (m, 5H, PhH), 4.24 (q, J=7.0 Hz, 2H, CH2), 1.34 (t, J=7.0 Hz,
3H, CH3); Anal. calcd for C11H11ClN2O: C, 59.33; H, 4.98; N, 12.58;
found: C, 59.55; H, 4.93; N, 12.67%. The spectral data match those
previously reported.16
4‑Chloro‑3,5‑dimethyl‑1H‑pyrazole (2e): White crystals; m.p.
1
116–117 °C (lit.10 117–118 °C); yield 0.09 g (68%); H NMR (CDCl3,
300 MHz) δ 11.83 (s, 1H, NH), 2.26 (s, 6H, CH3); Anal. calcd for
C5H7ClN2: C, 45.99; H, 5.40; N, 21.45; found: C, 45.78; H, 5.45; N,
21.53%. The spectral data match those previously reported.10
Synthesis of pyrazole substrate 1i; general procedure
K2CO3 (0.35 g, 2.5 mmol) was added to
1‑(4‑chlorophenyl)‑1H‑pyrazol‑3‑ol (0.19 g, 1.0 mmol) in acetone
(30 mL). Then methyl (E)‑2‑[2‑(bromomethyl)phenyl]‑2‑
a
solution of
2‑{[4‑Chloro‑1‑phenyl‑5‑(p‑tolyl)‑1H‑pyrazol‑3‑yl]oxy}‑1‑(2‑
thioxothiazolidin‑3‑yl)ethanone (2f): Yellow crystals; m.p. 195–196 °C;
1
(methoxyimino)acetate (0.3 g, 1.05 mmol) was added slowly. The
mixture was refluxed for 4 h, filtered, and solvent was evaporated
under reduced pressure. The residue was purified by flash column
chromatography (eluent: AcOEt/petroleum ether, 1:12 v/v) to afford
pyrazole substrate 1i.
yield 0.27 g (60%); H NMR (CDCl3, 500 MHz) δ 7.27–7.14 (m, 9H,
ArH), 5.78 (s, 2H, CH2), 4.61 (t, J=7.6 Hz, 2H, CH2), 3.38 (t, J=7.6 Hz,
2H, CH2), 2.36 (s, 3H, CH3); Anal. calcd for C21H18ClN3O2S2: C, 56.81;
H, 4.09; N, 9.46; found: C, 56.58; H, 4.03; N, 9.52%.
4‑Chloro‑3,5‑dimethyl‑1‑phenyl‑1H‑pyrazole (2g): Yellow oil;
1
Methyl (E)‑2‑[2‑({[1‑(4‑chlorophenyl)‑1H‑pyrazol‑3‑yl]oxy}methyl)
phenyl]‑2‑(methoxyimino)acetate (1i): White solid; m.p. 131–132 °C;
yield 0.16 g (75%); H NMR (CDCl3, 300 MHz) δ 7.48–7.32 (m, 5H,
PhH), 2.35 (s, 3H, CH3), 2.26 (s, 3H, CH3); Anal. calcd for C11H11ClN2:
C, 63.93; H, 5.36; N, 13.55; found: C, 63.72; H, 5.31; N, 13.63%. The
spectral data match those previously reported.10
1
yield 0.33 g (82%); H NMR (400 MHz, CDCl3) δ 7.66 (d, J=2.4 Hz,
1H, CH), 7.62–7.19 (m, 8H, ArH), 5.85 (d, J=2.4 Hz, 1H, CH), 5.18
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JOURNAL OF CHEMICAL RESEARCH 2014 661
4‑Chloro‑1,3,5‑trimethyl‑1H‑pyrazole (2h): Yellow oil; yield 0.1 g
(70%); H NMR (CDCl3, 500 MHz) δ 3.67 (s, 3H, CH3), 2.20 (s, 3H,
CH3), 2.19 (s, 3H, CH3); Anal. calcd for C6H9ClN2: C, 49.84; H, 6.27;
N, 19.37; found: C, 49.65; H, 6.21; N, 19.46%. The spectral data match
those previously reported.10
Received 30 July 2014; accepted 29 September 2014
Paper 1402794 doi: 10.3184/174751914X14137288281925
Published online: 13 November 2014
1
Methyl (E)‑2‑[2‑({[4‑chloro‑1‑(4‑chlorophenyl)‑1H‑pyrazol‑3‑yl]
oxy}methyl)phenyl]‑2‑(methoxyimino)acetate (2i): White solid; m.p.
147–148 °C (lit.19 147–148 °C); yield 0.36 g (82%); 1H NMR (400 MHz,
CDCl3) δ 7.68 (s, 1H, CH), 7.61–7.20 (m, 8H, ArH), 5.23 (s, 2H, CH2),
4.03 (s, 3H, MeO), 3.84 (s, 3H, MeO); Anal. calcd for C20H17Cl2N3O4: C,
55.31; H, 3.95; N, 9.68; found: C, 55.52; H, 3.91; N, 9.62%. The spectral
data match those previously reported.19
References
1
2
G.J. Devine, M. Barber and I. Denholm, Pest Manag. Sci., 2001, 57, 443.
S. Suzuki and K. Yoshitani, Japanese patent 09194305, 1997; Chem. Abstr.,
1997, 127, 157969.
3
4
5
Y. Miura, M. Ohnishi, T. Mabuchi and I. Yanai, Brighton Crop Prot. Conf.
Weeds, 1993, 1, 35.
D. Stierli, A. Daina, H. Walter, H. Tobler and R. Rajan, WO patent
2009012998, 2009; Chem. Abstr., 2009, 150, 214379.
K. Moedritzer and M.D. Rogers, European patent 371947, 1990; Chem.
Abstr., 1990, 113, 211973.
X‑ray crystallography
Crystal data were collected on a Nonius CAD‑4 diffractometer by
using MoKα (0.71073 Å) radiation. The structures were solved by direct
methods using SHELXS‑97 and refined by full‑matrix least‑squares
on F2 for all data using SHELXL‑97.20 All non‑H‑atoms were refined
anisotropically, and the H‑atoms were added at calculated positions.
The isotropic temperature factors were fixed at 1.2 times (1.5 times
for Me group) the equivalent isotropic displacement parameters of the
C‑atom to which the H‑atom is attached.
CCDC‑955904 contains the supplementary crystallographic data
for 2f. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_
request/cif (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: +44 1223 3360‑33; e‑mail: deposit@ccdc.cam.ac.uk).
6
7
H. Chen, Z. Li and Y. Han, J. Agric. Food Chem., 2000, 48, 5312.
T. Kinzel, Y. Zhang and S.L. Buchwald, J. Am. Chem. Soc., 2010, 132,
14073.
8
9
J. Baffoe, M.Y. Hoe and B.B. Toure, Org. Lett., 2010, 12, 1532.
A.S. Guram, A.O. King, J.G. Allen, X. Wang, L.B. Schenkel, J. Chan, E.E.
Bunel, M.M. Faul, R.D. Larsen, M.J. Martinelli and P.J. Reider, Org. Lett.,
2006, 8, 1787.
10 Z. Zhao and Z. Wang, Synth. Commun., 2007, 37, 137.
11 F. Varano, D. Catarzi, V. Colotta, F.R. Calabri, O. Lenzi, G. Filacchioni,
A. Galli, C. Costagli, F. Deflorian and S. Moro, Bioorg. Med. Chem., 2005,
13, 5536.
12 D.F. O’Brien and J.W. Gates Jr., J. Org. Chem., 1966, 31, 1538.
13 G. Lutze, K. Kirschke and N. Krauss, J. Prakt. Chem./Chem.‑Ztg., 1993,
335, 616.
14 X. Zhang, H. Zhu, H. Tan, J. Ni, H. He, X. Zeng, L. Liu, Y. Zhang, Y.
Zhou, H. Feng, J. Shi and N. Wang, Chinese patent 101735199, 2010; Chem.
Abstr., 2010, 153, 174961.
NBO charges calculations
The NBO charges calculations were carried out in the ground state (in
vacuo) with Gaussian 09 software using the B3LYP/6‑31G** method.21,22
15 S.M. Batterjee, Tinctoria, 2002, 99, 26.
16 Y. Liu, G. He, K. Chen, Y. Jin, Y. Li and H. Zhu, Eur. J. Org. Chem., 2011,
5323.
17 Y. Li, R. Liu, Z. Yan, X. Zhang and H. Zhu, Bull. Korean Chem. Soc., 2010,
31, 3341.
18 K. Anandarajagopal, J. Anbu Jeba Sunilson, A. Illavarasu, N.
Thangavelpandian and R. Kalirajan, Int. J. Chem. Tech. Res., 2010, 2, 45.
19 Y. Li, Y. Liu, N. Chen, K. Lv, X. Xiong and J. Li, HeIv. Chim. Acta, 2014,
97, 1269.
20 G.M. Sheldrick, Acta Crystallogr., Sect. A, 2008, 64, 112.
21 P.C. Hariharan and J.A. Pople, Theor. Chim. Acta, 1973, 28, 213.
22 Y. Li, Y. Liu, H. Wang, X. Xiong, P. Wei and F. Li, Molecules, 2013, 18,
877.
Electronic Supplementary Information
The X‑ray crystallographic analysis of 2f and the NBO
charges calculations of 1a–I are available through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp‑data
The authors gratefully acknowledge the financial support
from the Science Foundation for Youth Scholars of Jiangsu
Province (BK20130749) and the Youth Foundation of Southeast
University ChengXian College (7303600001) of China.
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