Crystal structure and mechanistic investigation of the reaction of 5-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile with unsaturated carbonyl compounds

Article abstract of DOI:10.1007/s11164-012-0740-5

The crystal structure of 1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-6- ethyl-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile was obtained and determined by X-ray crystallography. The reaction mechanism of 5-amino-1-(2,6-dichloro-4- (trifluoromethyl)phenyl)-1H-p

Full text of DOI:10.1007/s11164-012-0740-5

Res Chem Intermed (2013) 39:2087–2093
DOI 10.1007/s11164-012-0740-5
Crystal structure and mechanistic investigation
of the reaction of 5-amino-1-(2,6-dichloro-4-
(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile
with unsaturated carbonyl compounds
•
•
•
Chuanxiang Liu Yong Chen Yingxin Sun
Fanhong Wu
Received: 24 June 2012 / Accepted: 19 July 2012 / Published online: 4 August 2012
Ó Springer Science+Business Media B.V. 2012
Abstract The crystal structure of 1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-
6-ethyl-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile was obtained and determined by
X-ray crystallography. The reaction mechanism of 5-amino-1-(2,6-dichloro-4-
(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile with unsaturated carbonyl
compounds was further proposed.
Keywords Pyrazolopyridine Á Mechanism Á Synthesis Á Fipronil
Introduction
Pyrazole and its fused heterocyclic compounds [1, 2] such as pyrazolopyridines
are very interesting heterocyclic compounds with wide-ranging biological activities
[3, 4]. Some pyrazolo[3,4-b]pyridines have received considerable attention because
of the essential roles not only in biological activities but also in fluorescence
applications [5, 6], on the basis of their rigid molecular structure. As for 5-amino-
1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile(APPC), it is
the important intermediate in the synthesis of the famous insecticide Fipronil [7, 8],
which is a pyrazole insecticide used for insect control worldwide [9]. Meanwhile,
the intermediate APPC contains a strong electron-withdrawing group (CN) in its
three position, which might lead to its condensation and cycloaddition reactions
showing obvious differences from those conventionally reported aminopyrazole
compounds. Although our recent work has reported the reaction of intermediate
C. Liu (&) Á Y. Chen Á Y. Sun Á F. Wu (&)
School of Chemical and Environmental Engineering, Shanghai Institute of Technology,
201418 Shanghai, China
e-mail: cxliu@sit.edu.cn
F. Wu
e-mail: wfh@sit.edu.cn
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C. Liu et al.
Fig. 1 Crystal structure of (PEPC)
APPC with several a, b-unsaturated aldehydes in acid medium [10], the exact
structure characterization and substrate selectivity of a, b-unsaturated carboxyl
compounds have not been investigated extensively. In the present work, we further
describe the X-ray crystallography of 1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-6-
ethyl-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (PEPC) and discuss the possible
reaction mechanism by using several a, b-unsaturated carboxyl compounds in place
of a, b-unsaturated aldehydes.
Results and discussion
The intermediate APPC, which has three nucleophilic centers including its a-carbon
atom (pyrazole) and amino groups to react with electrophiles, is a key intermediate
not only for the synthesis of Fipronil but also for the construction of other useful
heterocyclic compounds. The synthesis of the crystal compound PEPC was shown
in our previous work [10] and its molecular structure was elucidated by X-ray
crystallography (Fig. 1; Table 1), which revealed that pyrazolo[3,4-b]pyridine was
formed.
In order to investigate the potential reaction activity of intermediate APPC, the
effect of the CN group on the product pyrazolopyridine was checked. So, firstly, the
CN group of APPC was transformed to an amide group (Compound 3, Scheme 1),
while the further condensation product between compound 3 with acrolein for
pyrazolopyridine was not obtained. This indicated that the CN group is necessary
for the construction of pyrazolopyridine, which can activate the a-carbon atom of
pyrazole. For the reaction of 1,4-benzoquinone(1) with intermediate APPC, only the
compounds 5 and 6 were obtained, and, interestingly, compound 5 can be further
transformed to 6 under a NaBH4/alcohol system. This implies that there is a
disproportionation reaction between 1,4-benzoquinone and intermediate APPC.
For but-3-en-2-one (2), we checked its reaction activity for condensation with APPC
and found that pyrazolopyridine compound 7 was formed, which indicated that ketenes
(such as 2) may proceed via the reaction procedure differently from substituted a,
b-unsaturated aldehydes. As for 2-methylpent-2-enal (9), the minor (5 %) product 11
was isolated by careful silica gel chromatography. The proposed reaction pathway for
intermediate APPC with unsaturated carbonyl compounds is further shown in
Scheme 2. The reaction may proceed via three different reaction procedures, such as
123

Crystal structure and mechanistic investigation
2089
Table 1 The crystal data and
Compound
PEPC
structure refinements for PEPC
Empirical formula
C
16H9Cl2F3N4
Formula weight
Temperature (K)
Crystal system
Space group
385.17
293 (2)
Triclinic
P-1
˚
a (A)
7.1348 (10)
9.1199 (12)
13.2736 (18)
102.507 (2)
90.291 (2)
92.404 (2)
842.4 (2)
2
˚
b (A)
˚
c (A)
a (8)
b (8)
c (8)
3
˚
Volume (A )
Z
Absorption coefficient (mm-1
)
0.422
F (000)
Crystal size (mm3)
388
0.505 9 0.482 9 0.407
Theta range for data collection (8) 4.579–54.717
h/k/l
-8,8/-8,11/-16,16
1.044
Goodness-of-fit on F2
Final R indices [I [ 2r(I)]
R indices (all data)
R = 0.0533, wR (F2) = 0.1490
Rfactor = 0.0643,
wRfactor = 0.1573
path A, path B, and path C. Path A has been reported in our previous work [10], which
mayincludetheMichael adductanddisproportionationreaction. PathsB andCmight be
involved in C–C or C–N condensation reactions, intramolecular Diels–Alder reaction,
and aromatization [11]. In path B, the addition of a-carbon atom of pyrazole (APPC) to
a, b-unsaturated carboxyl compounds formed unstable intermediate 8, which can be
convertedintomainproductpyrazolopyridine(C–C),e.g.product7. Similarly,inpathC,
compound pyrazolopyridine(C–N) was obtained by the C–N condensation reaction of
APPC and a, b-unsaturated carboxyl compounds with the formation of a key
intermediate Schiff base, which is stable in the case of AcOH as catalyst [10], but
unstable in the case of HCl as catalyst with minor product 11 being formed. Therefore, it
is easy to obtain several kinds of pyrazolo[3,4-b]pyridine derivatives with electron-
withdrawing group (CN) through changing the different a, b-unsaturated carboxyl
compounds and the corresponding acid catalyst.
Conclusions
In summary, the crystal structure of 1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-6-
ethyl-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (PEPC) and the reaction mechanism
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C. Liu et al.
O
O
NH2
NH2
Cl
N
N
Cl
N
N
O
N
NH2
F3C
N
Cl
4
F3C
Cl
3
N
N
O
Cl
N
Cl
N
N
Cl
N
N
+
1
N
O
HN
N
NH2
F3C
Cl
F3C
Cl
F3C
Cl
APPC
5
6
OH
O
N
Cl
N
O
2
N
N
F3C
Cl
7 (75%)
N
N
Cl
N
N
Cl
N
N
O
+
9
N
N
F3C
Cl
F3C
Cl
10 (major, 70%)
11 (minor, 5%)
Scheme 1 The reaction of APPC with several a, b-unsaturated carboxyl compounds
of 5-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile with
unsaturated carbonyl compounds are further proposed. Our group is actively engaged
in developing the easily accessible pyrazolo[3,4-b]pyridine derivatives to explore
their reactivity and synthetic applications. Further development of pyrazolo[3,4-
b]pyridine-based heterocyclic compounds and the exploration of their application in
heterocyclic chemistry and intermediate research are in progress in our group.
Experimental
Commercially available reagents 1,4-benzoquinone (1), but-3-en-2-one (2), 2-meth-
ylpent-2-enal (9) and APPC were bought and used without further purification.
Solvents were treated prior to use according to the standard methods. Melting points
were taken on a micro-melting point apparatus made in Beijing and were
1
uncorrected. H NMR spectra were recorded with a Bruker WP-500SY (400 MHz)
spectrometer with CDCl3 as the solvent and TMS as the internal standard. Infrared
spectra were measured on KBr disks using a Nicolet FT-IR-20SX instrument. High
resolution mass spectra were obtained on a MicroMass GCT CA 055 spectrometer.
Analytical thin-layer chromatography (TLC) was carried out on precoated plated
(silica gel 60F254), and spots were visualized with ultraviolet light. Crystals were
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Crystal structure and mechanistic investigation
2091
N
N
N
Cl
N
N
R1
R2
Cl
N
N
OH
R1
R2
Cl
N
N
R1
R2
-H2O
HN
F3C
Cl
R3
HN
N
HN
Hydropyrazolopyridine
F3C
Cl
F3C
Cl
R3
R3
Disproportionation
Path A
N
N
R1
R3
Cl
N
Cl
N
N
Cl
N
N
D-A
R1
R2
R2
-H2O
N
[O]
O
R3
R2
+
Path B
NH
N
NH2
R1
F3C
Cl
F3C
Cl
F3C
Cl
APPC
R3
8
Pyrazolopyridine(C-C)
Path C
N
N
Cl
N
N
R3
R2
Cl
N
N
D-A
[O]
R2
R3
N
N
F3C
Cl
F3C
R1
R1
Schiff base
Pyrazolopyridine(C-N)
Scheme 2 Proposed reaction pathways
obtained by slow evaporation from ethanol solutions of the pure compound PEPC.
A colorless single crystal of suitable size was selected for X-ray diffraction analysis.
Data were collected on a Bruker Smart and the unit cell dimensions were obtained
by least-squares refinement.
General synthesis of intermediates and the target compounds
5-Amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carboxamide
(3)
A solution of 5-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-
carbonitrile (3.20 g, 0.01 mol), hydrogen peroxide solution (27.5 %, 2 ml) and
ammonia (2 ml) in acetonitrile (20 ml) was stirred for 5 h at room temperature.
Then, the solution was added 30 ml water, and extracted with chloroform
(30 ml 9 3). The organic layer was dried over Na2SO4. The solvent was
concentrated to afford the crude product 3, which was directly used in the next
step. GC–MS: 338 [M]?, 320, 213, 143.
(E)-5-(Allylideneamino)-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-
carboxamide (4)
A solution of 5-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-
carboxamide (3, 3.38 g, 0.01 mol), acrolein (1.12 g, 0.02 mol) and 3 drops HCl in
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C. Liu et al.
acetonitrile (20 ml) was refluxed for the required reaction time, according to TLC
(PE:EA = 8:1). The mixture was cooled to room temperature and the solution was
added to 30 ml water, and extracted with chloroform (30 ml 9 3). The organic
layer was dried over Na2SO4. The solvent was concentrated and the residue was
purified by silica gel chromatography to afford the white solid 4, yield 70 %; mp
157.3–164.2 °C; IR (KBr); v 3,435, 3,358, 3,148, 1,707, 1,664, 1,305, 1,128,
1
813 cm–1; H NMR (400 MHz, CDCl3): d 6.03 (d, 2H, J = 12 Hz, CH2), 6.52 (m,
1H, CH), 6.79 (s, 2H, NH2), 6.88 (s, 1H, pyrazole), 7.74 (s, 2H, ArH), 8.32 (d,
J = 9.1 Hz, 1H, CH). EIMS, m/z (%): 376 [M]? (15.77), 361 (29.18), 358 (100.00),
334 (22.27), 298 (35.38), 296 (66.47), 280 (6.30), 271 (26.97), 213 (29.51), 178
(10.79), 143 (8.63), 66 (8.33), 39 (13.42). HRMS Calcd for C14H9N4OF3Cl2:
376.0106. Found: 376.0114.
Synthesis of target compounds 5 and 6
A solution of 5-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-
carbonitrile (3.20 g, 0.01 mol), 1,4-benzoquinone (1.08 g, 0.01 mol) and 3 drops
HCl in acetonitrile (20 ml) was refluxed for the required reaction time, according to
TLC (PE:EA = 8:1). The mixture was cooled to room temperature and the solution
was added to 30 ml water, and extracted with chloroform (30 ml 9 3). The organic
layer was dried over Na2SO4. The solvent was concentrated and the residue was
purified by silica gel chromatography to afford the white solids 5 and 6.
1-(2,6-Dichloro-4-(trifluoromethyl)phenyl)-5-(4-oxocyclohexa-2,
5-dienylideneamino)-1H-pyrazole-3-carbonitrile (5)
mp 157.2–158.6 °C; 1H NMR (400 MHz, CDCl3): d 6.61 (s, 1H, CH), 6.65–6.74 (m, 2H,
p-benzoquinone), 7.07–7.11 (dd, J1 = 2.8 Hz, J2 = 10.4 Hz, 1H, p-benzoquinone),
7.52–7.55 (dd, J1 = 2.8 Hz, J2 = 10.4 Hz, 1H, p-benzoquinone), 7.76 (s, 2H, ArH).
1-(2,6-Dichloro-4-(trifluoromethyl)phenyl)-5-(4-hydroxyphenylamino)-1H-
pyrazole-3-carbonitrile (6)
mp 190.1–190.9 °C; 1H NMR (400 MHz, CDCl3): d 4.76 (s, 1H, OH), 5.08 (s, 1H,
NH), 6.78 (d, J = 8.9 Hz, 2H, ArH), 6.94 (d, J = 8.9 Hz, 2H, ArH), 7.79 (s, 2H,
ArH); EIMS, m/z (%): 412 [M]? (100), 377 (5.23), 342 (11.81), 212 (3.89), 178
(3.81), 119 (10.95). HRMS Calcd for C17H9N4OF3Cl2: 412.0106. Found: 412.0106.
1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-4-methyl-1H-pyrazolo[3,4-b]pyridine-
3-carbonitrile (7)
A solution of 5-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-
carbonitrile (3.20 g, 0.01 mol), but-3-en-2-one (1.68 g, 0.02 mol) and 3 drops HCl
in acetonitrile (20 ml) was refluxed for the required reaction time, according to TLC
(PE:EA = 8:1). The mixture was cooled to room temperature and the solution was
added to 30 ml water, and extracted with chloroform (30 ml 9 3). The organic
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Crystal structure and mechanistic investigation
2093
layer was dried over Na2SO4. The solvent was concentrated and the residue was
purified by silica gel chromatography to afford the white solid 7: yield 75 %; mp
153.2–153.9 °C; IR (KBr): v 2,239, 1,583, 1,310, 1,171, 1,128, 831, 785, 565 cm-1
;
1H NMR (400 MHz, CDCl3): d 2.91 (s, 3H, CH3), 7.22 (d, J = 4.5 Hz, 1H,
pyridine), 7.82 (s, 2H, ArH), 8.52 (d, J = 4.6 Hz, 1H, pyridine); EIMS, m/z (%):
370 [M]? (6.45), 337 (17.33), 335 (100.00), 300 (5.22), 283 (7.02), 248 (3.11), 213
(3.24), 178 (3.17), 143 (3.32), 78 (2.88), 51 (3.57). HRMS Calcd for C15H7N4F3Cl2:
370.0000. Found: 370.0005.
1-(2,6-Dichloro-4-(trifluoromethyl)phenyl)-6-ethyl-5-methyl-1H-pyrazolo
[3,4-b]pyridine-3-carbonitrile (11)
The procedure and the target compound 10 were reported in [10]. The target
compound 11 was isolated by silica gel chromatography to afford the white solid,
yield 5 %; mp 158.5–159.0 °C; IR (KBr): v 3,043, 2,239, 1,592, 1,579, 1,310,
1,124, 870 cm-1; 1H NMR (400 MHz, CDCl3): d 1.43 (t, J = 7.6 Hz, 3H), 2.49 (s,
3H), 3.23 (m, 2H), 7.82 (s, 2H), 8.42 (s, 1H); 13C NMR (100 MHz, CDCl3) d: 153.8,
150.2, 146.2, 136.5, 136.0, 134.4, 134.1, 127.9, 126.1, 126.0, 123.5, 120.8, 120.0,
115.9, 113.3, 22.3, 15.3, 14.2; EIMS, m/z (%): 398 [M]? (24.34), 363 (100), 348
(13.13), 336 (8.23); HRMS Calcd for C17H11N4F3Cl2: 398.0313; Found: 398.0313.
Acknowledgments We are grateful for financial support from the Science Foundation of Shanghai
Institute of Technology (YJ2010-49), the Opening Fund of Shanghai Key Laboratory of Chemical
Biology (No. SKLCB-2011-08), and the National Natural Science Foundation of China (Grant No.
20972050, No. 21172148 and No. 21005049).
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