Solvent controlled regioselective reaction of 1,2,3-benzotriazole (BtH) with pentafluorobenzene derivatives

Article abstract of DOI:10.1016/j.tet.2010.12.016

Regioselective reaction of 1,2,3-benzotriazole (BtH) with pentafluorobenzene derivatives under base conditions was investigated and its regioselectivity strongly depends on solvent, base, and electron-withdrawing group at 4-position on the perfluorophenyl

Full text of DOI:10.1016/j.tet.2010.12.016

Tetrahedron 67 (2011) 910e914
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Tetrahedron
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Solvent controlled regioselective reaction of 1,2,3-benzotriazole (BtH)
with pentafluorobenzene derivatives
,
,
a,
*
Jingwei Zhao a b, Tao Song a, Shizheng Zhu b , Liangzhong Xu
*
a College of Chemistry and Molecular Engineering, Qingdao University of Science and Technology, 53 Zhengzhou Road, Qingdao 266042, PR China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 October 2010
Received in revised form 30 November 2010
Accepted 7 December 2010
Available online 10 December 2010
Regioselective reaction of 1,2,3-benzotriazole (BtH) with pentafluorobenzene derivatives under base
conditions was investigated and its regioselectivity strongly depends on solvent, base, and electron-
withdrawing group at 4-position on the perfluorophenyl ring. Several Bt(N1)-substituted per-
fluorobenzenes were prepared by using this method.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
1,2,3-benzotriazole
Pentafluorobenzene
Substitution
1. Introduction
2. Results and discussion
Compounds with 1,2,3-benzotriazole (BtH) moiety are of great
importance with regards to pharmaceuticals, agricultural pesti-
cides, dyestuffs, photostabilizers, and dynamites.1e8 Bt-containing
compounds demonstrate excellent biological activities, such as
antiviral, antibacterial, and plant growth regulation properties. For
example, alizaprid is an antiemetic drug9 and Tinuvin P is an effi-
cient UV absorber.10 Thus, new synthetic methods for preparation
of Bt-substituted compounds are still desirable.
Fluorinated benzene derivatives have attracted considerable
interests with respect to multi facetted chemical and NMR spec-
troscopic properties and potential applications in medicinal and
material area.11,12 Particularly, introduction of fluorine atom or
fluorinated group (e.g., perfluorobenzene group) into organic
compounds usually lead to the change of the biologic and physical
properties.13 However, scientists pay less attention on investigation
of the reaction of BtH with pentafluorobenzene (PFB) halides since
1999.14 In the connection with our study on fluorinated heterocyclic
compounds, we envisioned that BtH may stereoselectively react
with electron-withdrawing group substituted pentafluorobenzene
to form a series of Bt(N1)-containing perfluorobenzenes. Herein,
we report our preliminarily results.
We began our investigation with a reaction of BtH with pen-
tafluorobenzonitrile in the presence of triethylamine (Et3N) in THF
at refluxing. In general, using BtH as a prenucleophile, the nitrogen
substitutions of BtH form a mixture of Bt (N1)-substituted product
3 and Bt(N2)-substituted product 4.2 After completion of the re-
action, as expected, a mixture of 3/4 in 46% yield with a ratio of 3/
4 in 3/1 was obtained (entries 1, Table 1). Using toluene gave the
similar results (entry 2). Interestingly, the employment of MeCN
instead of THF, 40% yields of 3 were obtained but trace amount of
4 were observed (entry 3). Unexpectedly, when ethyl alcohol was
employed as solvent under the similar reaction conditions, op-
posing results were achieved (entry 4). These results strongly
suggest that the regioselectivity of above reaction is solvent-con-
trolled. Moreover, when K2CO3 was used as base other than Et3N, 3
was obtained in 65% yield and along with trace amount of 4 was
observed (entry 5). Consequently, a series of bases, such as pyri-
dine(abbreviated to Py, following is the same), KF, and NaOAc were
further examined under the similar conditions (entries 6e8,
Table 1). KF and NaOAc gave 3 as the major product in 32% and
40% yield, respectively (entries 6 and 7). Py led to extremely poor
results (entry 8). These results reveal that base also plays an
important role for this regioselective reaction. It is worthy to note
that considerable amount of the complex byproducts were
observed in the course of the above-motioned reactions because
pentafluorobenzonitrile are more active under the basic condi-
tions at high temperature.2
* Corresponding authors. E-mail address: zhusz@mail.sioc.ac.cn (S. Zhu).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.016

J. Zhao et al. / Tetrahedron 67 (2011) 910e914
911
Table 1
Optimizing reaction condition for the reaction of BtH with PFB derivatives
N
N
CN
N
F
F
F
F
F
F
F
F
N
N
N
F
Solvent, T
Base, t
N
N
CN
F
N
H
F
F
F
CN
1
2a
3a
4a
Entry
Base
Solvent
1/2
T,ꢀC
t (h)
Yield of 3, %a
Yield of 4, %a
1
2
3
4
5
6
7
8
Et3N
Et3N
Et3N
Et3N
Et3N
K2CO3
KOH
K2CO3
KF
THF
Toluene
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
1/1.2
1/2
Reflux
80
80
80
80
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
50
12
12
12
12
4
12
12
4
12
12
12
12
12
12
12
12
36
37
50
40
Trace
41
33
65
32
40
4
17
35
45
49
35
12
9
ClCH2CH2Cl
MeCN
EtOH
MeCN
MeCN
EtOH
EtOH
EtOH
EtOH
MeCN
MeCN
MeCN
MeCN
MeCN
10
Trace
70
10
8
Trace
8
10
2
Trace
10
11
12
9
9
10
11
12
13
14
15
16
NaOAc
Py
Et3N
Et3N
Et3N
Et3N
Et3N
rt
rt
rt
rt
1/3
2/1
a
Isolated yield.
With the optimal reaction conditions listed in entry 4 of Table 1,
the scope of the reaction was then probed (Table 2). After com-
pletion of the reaction (12 h), 3a was obtained in 40% yield from
2,3,4,5,6-pentafluorobenzonitrile and only trace amount of 4a
were observed (entry 1). 1,2,3,4,5-Pertafluoro-6-nitrobenze, con-
taining a strong electron-withdrawing group NO2 on the phenyl
ring, was utilized as a substrate and it gave 3b as major product in
24% yield along with 8% yield of 4b (entry 2). 2,3,4,5,6-Penta-
fluorobenzaldehyde resulted in 32% yield of 3c together with 13%
yield of 4c (entry 3). Notably, perfluorobenzene was employed as
a substrate in above reaction and no desired product was observed
by 19F NMR (entry 4). 1-Chloro-2,3,4,5,6-pentafluorobenzene led to
60% yield of 3e using K2CO3 instead of Et3N in the absence of sol-
vent (entry 5). 1-Bromo-2,3,4,5,6-pentafluorobenzene gave rise to
3f in 40% yield using toluene as solvent (entry 6). 1,2,3,4,5-Penta-
fluoro-6-iodobenzene was used as substrate leading to 3g in 35%
yield and 4g in 5% yield, respectively (entry 7).
To determine the molecular structures of 3 and 4, two repre-
sentative compounds 4a and 3e were crystallized from dichloro-
methane and n-hexane, and their X-ray diffraction analyses were
performed. Their molecular structures were shown in Fig. 1 and
Fig. 2, respectively.
Fig. 1. Molecular structure of 4a.
Table 2
Regio selective reaction of BtH with pentafluorobenzene derivatives
N
N
N
N
R
N
F
F
F
F
N
R
F
F
F
F
N
N
N
F
conditions
+
R
N
N
F
F
N
H
F
F
F
F
F
F
R
1
2a-g
4a-c, 4g
3a-c, 3e-3g
5b
Entry
R
Base
Solvent
T,ꢀC
t, h
3,%c
4, %c
5,%c
1
2
3
4
5
6
7
CN(2a)
NO2(2b)
CHO(2c)
F (2d)
Cl(2e)
Br(2f)
Et3N
Et3N
Et3N
K2CO3
K2CO3
Et3N
Et3N
CH3CN
CH3CN
CH3CN
db
Reflux
80
12
0.5
24
24
10
15
12
40
24
32
NR
60
40
35
Trace
8
13
NR
d
tracea
5
d
10
d
d
d
d
d
Reflux
Reflux
Reflux
Reflux
Reflux
db
Toluene
Toluene
I(2g)
a
Detected by 19F NMR.
Neat.
Isolated yield.
b
c

912
J. Zhao et al. / Tetrahedron 67 (2011) 910e914
which then could afford the product 4. So the ratio of 3:4 increases
along with the decrease of hyperconjugation effect in the order of
iodine, bromine, and chlorine. 3b and 5b have almost no difference
in polarity. We tried to separate them by column chromatography
and recrystallization, however, both of these two common purifi-
cation methods did not provide pure 3b or 5b.
3. Conclusion
We have developed a convenient method for synthesis of Bt
(N1)-substituted perfluorobenzene derivatives and found that
solvent and base have strong effect on the formation of Bt(N1)-
substituted product. A possible reaction mechanism was explored
as well. The further applications of Bt-containing fluorinated ben-
zene derivatives are currently under way in our group.
Fig. 2. Molecular structure of 3e.
The UV analyses of 3a and 4a indicated that lmax of Bt(N2)- and
Bt(N1)-substituted perfluorobenzonitrile occurred at 297 nm.
Comparing with lmax of BtH, both 3a and 4a led to the red shift due
to the introduction of perfluorobenzonitrile. Additionally, the ab-
sorption of 3a is much stronger than that of 4a (Fig. 3).
4. Experimental
4.1. General
0.8
1-sub
2-sub
Bt
Melting points are measured on a Temp-Melt. Apparatus are
uncorrected. 1H, 13C, and 19F NMR spectra were recorded on Bruker
AM-300 instruments with Me4Si and CFCl3 as the internal and
external standards, respectively. FT-IR spectra were obtained with
a Nicolet AV-360 spectrometer. Low resolution mass spectra
(LRMS) or high resolution mass spectra (HRMS) were obtained on
a Finnigan GCeMS 4021 or a Finnigan MAT-8430 instrument using
the electron impact ionization technique (70 eV), respectively. El-
emental analyses were performed on a VARIO EL III elemental an-
alyzer in the Analysis Department of this Institute. Single crystal
X-ray structure analysis was performed on a Bruker P4 instrument.
297
266
257
0.6
0.4
0.2
0.0
252
279
246
4.2. General procedure of the reaction of 1,2,3-benzotriazole
(BtH) and pentafluorobenzene derivatives
225
275
325
375
BtH 0.595 g (5 mmol) was dissolved in solvent 15 mL, and then
the corresponding pentafluorobenzene derivative (6 mmol) and
base (5 mmol) were added. The mixture was heated to reflux.
According to TLC analysis, when the reaction completed, the solid
was removed by filtration. Then the solvent was removed by a ro-
tary evaporator under vacuum. The mixture was isolated on silica
gel (petroleum/ethyl acetate¼10/1) to afford products 3 and 4.
wavelength (nm)
Fig. 3. UVevis absorption curve of BtH, 3a and 4a in THF.
On the basis of the results achieved, a possible mechanism is
proposed as illustrated in Scheme 1. The treatment of BtH (1) with
base readily yields the resonance hybrids including two contrib-
uting structures (I) (more stable) and (II). Consequently, I un-
dertakes the following nucleophilic substitution to produce 3. The
nucleophilic attack of II to pentafluorobenzene forms the corre-
sponding 4. When PFB halides react with BtH, the low reactivity
4.2.1. 4-(1H-benzo[d][1,2,3]triazol-1-yl)-2,3,5,6-tetra-
fluorobenzonitrile 3a. White solid, mp: 128e130 ꢀC. FT-IR (KBr)
cmꢁ1: 2243, 1652, 1609, 1500, 1209, 993, 887, 812, 770, 757, 661. 1H
NMR (CDCl3, 300 MHz):
d
8.22 (d, 1H, J¼7.8 Hz), 7.65e7.24 (m, 3H).
only leads to the formation of 3. Due to pe
3 could transform to V under heat through a concerted process,
p
hyperconjugation,15,16
19F NMR (CDCl3, 282 MHz):
d
129.1 (q, 2F, J¼8.1 Hz), ꢁ140.0 (q, 2F,
J¼8.1 Hz). LR-EI-MS m/z (%): 292(Mþ, 21), 264(79), 154(100), 124
N
N
N
N
F
N
F
F
F
F
F
F
F
N
N
N
N
N
N
base
F
F
heat
N
N
N
X
N
H
F
X
F
F
F
F
F
I
F
F
1
X
X
V
III
3
F
F
F
F
F
F
F
F
F
N
N
F
N
N
N
N
N
X
N
X
N
F
X
F
F
F
II
IV
4
Scheme 1. Possible mechanism.

J. Zhao et al. / Tetrahedron 67 (2011) 910e914
913
(45). Anal. Calcd for C13H4F4N4 (%): C, 53.44; H,1.38; N,19.17. Found:
C, 53.38; H, 1.66; N, 18.79.
(CDCl3, 282 MHz):
J¼9.0 Hz). LR-EI-MS m/z (%): 301(13), 238(100), 63(41).
d
ꢁ134.8 (d, 2F, J¼9.0 Hz), ꢁ139.9 (d, 2F,
4.2.7.1. X-ray data of compound 3e. Empirical formula
C12H4ClF4N3:FW¼301.63; temperature 293 (K); Triclinic P-1;
4.2.2. 4-(2H-benzo[d][1,2,3]triazol-2-yl)-2,3,5,6-tetra-
fluorobenzonitrile 4a. White solid, mp: 137e140 ꢀC. FT-IR (KBr)
cmꢁ1: 2246, 1647, 1545, 1500, 1435, 1349, 1248, 1002, 865, 760. 1H
ꢀ
ꢀ
ꢀ
ꢀ
wavelength 0.71 A; a¼6.5911(8) A, b¼7.5241(9) A, c¼12.2772(15) A,
3
ꢀ
ꢀ
a
¼76.975(2)ꢀ,
b
¼86.409(2)ꢀ,
¼79.681(2) . V¼584.14(12) A ; Z¼2,
g
NMR (CDCl3, 300 MHz):
d
8.91 (dd, 2H, J¼3.3, 6.9 Hz), 8.46 (dd, 2H,
Dc¼1.715 mg/m3; absorption coefficient 0.371 mmꢁ1; F (000)¼300;
J¼3.3, 6.9 Hz). 19F NMR (CDCl3, 282 MHz):
d
ꢁ129.5 (q, 2F,
size 0.427ꢂ0.369ꢂ0.311 mm; 2.82<
q<27.00; reflections collected
J¼13.2 Hz), ꢁ141.3 (q, 2F, J¼13.2 Hz). LR-EI-MS m/z (%): 292(100),
188(41), 90(28). Anal. Calcd for C13H4F4N4 (%): C, 53.44; H, 1.38; N,
19.17. Found: C, 53.66; H, 1.28; N, 19.30.
3460; Absorption correction Empirical; transmission 1.00max-
0.758min; goodness of fit on F2 1.054; final R indices R1¼0.0474,
wR2¼0.1360. CCDC number is 705403.
4.2.2.1. X-ray data of compound 4a. Empirical formula
C13H4F4N4:FW¼292.20; temperature 293 (K); monoclinic P2(1)/c;
4.2.8. 1-(4-Bromo-2,3,5,6-tetrafluorophenyl)-1H-benzo[d][1,2,3]tri-
azole 3f. White solid, mp: 138e139 ꢀC. FT-IR (KBr) cmꢁ1: 1518,
1500, 1432, 1289, 1054, 974, 887, 796, 744, 632. 1H NMR (CDCl3,
ꢀ
ꢀ
ꢀ
wavelength 0.71 A; a¼7.9074(8) A, b¼11.7360(12) A, c¼12.9927
3
ꢀ
ꢀ
(13) A,
a
¼90ꢀ,
b
¼96.154(2)ꢀ,
g
¼90ꢀ. V¼1198.8(2) A ; Z¼4,
300 MHz):
d
8.21 (d, 1H, J¼7.5 Hz), 7.65 (t, 1H, J¼7.5 Hz), 7.53 (t, 1H,
Dc¼1.619 mg/m3; absorption coefficient 0.146 mmꢁ1; F(000)¼584;
J¼7.5 Hz), 7.42 (d, 1H, J¼7.5 Hz). 19F NMR (CDCl3, 282 MHz):
size 0.480ꢂ0.423ꢂ0.396 mm; 2.34<
q<27.00; reflections collected
d
ꢁ130.2 (q, 2F, J¼9.0 Hz), ꢁ143.2 (q, 2F, J¼9.0 Hz). 13C NMR (CDCl3,
6932; Absorption correction Empirical; transmission 1.00max-
0.763min; goodness of fit on F2 0.966; final R indices R1¼0.0436,
wR2¼0.1110. CCDC number is 705402.
75 MHz):
d 109.5, 120.7, 125.0, 129.4, 133.4, 140.1e140.0(m), 143.3
(d, J¼19.2 Hz), 146.1e145.5(m), 149.4e149.2(m). HR-ESI-MS m/z:
346, 348. Calcd mass for C12H4N3BrF4: 344.9525. Found: 344.9529.
4.2.3. Mixture of 1-(2,3,5,6-tetrafluoro-4-nitrophenyl)-1H-benzo[d]
[1,2,3]triazole 3b and 1-(2,3,4,5-tetrafluoro-6-nitrophenyl)-1H-benzo
[d][1,2,3]triazole 5b. White solid. FT-IR (KBr) cmꢁ1: 1645, 1561,
1501, 1350, 1163, 1051, 992, 779, 749. 1H NMR (CDCl3, 300 MHz):
4.2.9. 1-(2,3,5,6-Tetrafluoro-4-iodophenyl)-1H-benzo[d][1,2,3]tri-
azole 3g. White solid, mp: 168e170 ꢀC. FT-IR (KBr) cmꢁ1: 1514,
1480,1288,1054, 967, 787, 745. 1H NMR (CDCl3, 300 MHz):
d 8.20 (d,
1H, J¼7.5 Hz), 7.63 (t, 1H, J¼7.5 Hz), 7.51 (t, 1H, J¼7.5 Hz), 7.43e7.40
d
8.23(m, 1H), d
7.73e7.45(m, 3H). 19F NMR (CDCl3, 282 MHz):
(d, 1H, J¼7.5 Hz). 19F NMR (CDCl3, 282 MHz):
d
ꢁ117.3 (q, 2F,
d
ꢁ139.4(m, 0.36F), ꢁ140.1(m, 2F), ꢁ142.8(m, 0.36F), ꢁ143.8(m, 2F),
J¼12.4 Hz), ꢁ142.9 (q, 2F, J¼12.4 Hz). LR-EI-MS m/z (%): 393(Mþ,
22), 365(15), 238(100), 148(25). Anal. Calcd for C12H4IF4N3 (%): C,
36.67; H, 1.03; N, 10.69. Found: C, 36.65; H, 1.09; N, 10.70.
ꢁ145.6(m, 0.36F), ꢁ146.9(m, 0.36F). LR-EI-MS m/z (%): 312(Mþ, 43),
238(100), 218(19), 188(12), 148(21). Anal. Calcd for C12H4F4N4O2
(%): C, 46.17; H, 1.29; N, 17.95. Found: C, 46.23; H, 1.13; N, 17.79.
4.2.10. 2-(2,3,5,6-Tetrafluoro-4-iodophenyl)-2H-benzo[d][1,2,3]tri-
azole 4g. White solid, mp: 173e174 ꢀC. FT-IR (KBr) cmꢁ1: 1563,
1489,1270,1208, 975, 914, 805, 743, 621. 1H NMR (CDCl3, 300 MHz):
4.2.4. 2-(2,3,5,6-Tetrafluoro-4-nitrophenyl)-2H-benzo[d][1,2,3]tri-
azole 4b. White solid, mp: 100e103 ꢀC. FT-IR (KBr) cmꢁ1: 1632,
1554, 1493, 1345, 1232, 1014, 950, 876, 781, 754. 1H NMR (CDCl3,
d
7.98 (dd, 2H, J¼3.0, 3.9 Hz), 7.52 (dd, 2H, J¼3.0, 3.9 Hz). 19F NMR
300 MHz):
1H, J¼2.7 Hz),
ꢁ141.5(m, 2F),
d
7.99(d, 1H, J¼3.0 Hz),
d
7.96(d, 1H, J¼3.0 Hz),
d 7.54(d,
(CDCl3, 282 MHz):
d
ꢁ117.5 (q, 2F, J¼8.2 Hz), ꢁ144.5 (q, 2F,
d
7.52(d, 1H, J¼3.0 Hz). 19F NMR (CDCl3, 282 MHz):
J¼8.2 Hz). 13C NMR (CDCl3, 75 MHz):
d
89.0, 118.6, 128.3, 141.3,
d
d
ꢁ144.2(m.2F). LR-EI-MS m/z (%): 312(Mþ, 100),
145.5, 146.0, 153.6. LR-EI-MS m/z (%): 393(Mþ, 100), 238(20), 162
(83), 148(13). HR-EI-MS: Calcd mass for C12H4N3IF4: 392.9386.
Found: 392.9388.
266(22), 162(23), 117(7.26). Anal. Calcd for C12H4F4N4O2 (%): C,
46.17; H, 1.29; N, 17.95. Found: C, 45.95; H, 1.09; N, 17.77.
4.2.5. 4-(1H-benzo[d][1,2,3]triazol-1-yl)-2,3,5,6-tetra-
fluorobenzaldehyde 3c. White solid, mp: 107e109 ꢀC. FT-IR (KBr)
cmꢁ1:1710, 1648, 1521, 1497, 1370, 1274, 1052, 977, 961, 753, 622. 1H
Acknowledgements
This work is financially supported by the National Natural Sci-
ence Foundation of China (NNSFC) (Nos 20972178 and 21032006)
and National Basic Research Program (No. 2007CB80800).
NMR (CDCl3, 300 MHz):
d
d
10.43(s, 1H),
d
8.24e8.21(m, 1H),
ꢁ142.72 to
7.69e7.44(m, 3H). 19F NMR (CDCl3, 282 MHz):
d
ꢁ172.86(m, 2F), ꢁ142.98 to ꢁ143.13(m. 2F). LR-EI-MS m/z (%): 295
d
(Mþ, 37), 267(32), 238(100), 220(46), 189(21). Anal. Calcd for
C13H5F4N3O (%): C, 52.89; H, 1.71; N, 14.23. Found: C, 52.89; H, 1.43;
N, 14.18.
Supplementary data
Supplementary data related to this article can be found online
version, at doi:10.1016/j.tet.2010.12.016. These data include MOL
files and InChIKeys of the most important compounds described in
this article.
4.2.6. 4-(2H-benzo[d][1,2,3]triazol-2-yl)-2,3,5,6-tetra-
fluorobenzaldehyde 4d. White solid, mp: 160e162 ꢀC. FT-IR (KBr)
cmꢁ1: 1706, 1648, 1498, 1242,1153, 1045, 996, 953, 755, 633, 621. 1H
NMR (CDCl3, 300 MHz):
d 10.41(s, 1H), d 8.01e7.96(m, 2H),
d
7.56e7.26(m, 2H). 19F NMR (CDCl3, 282 MHz):
d
ꢁ143.57 to
References and notes
ꢁ143.73(m, 2F),
d
ꢁ145.06 to ꢁ145.20(m.2F). 13C NMR (CDCl3,
75 MHz): d 181.5, 148.3 (m), 145.7, 143.6 (m), 141.0 (m), 128.7, 118.7,
1. Katritzky, A. R.; Strah, S.; Belyakov, S. A. Tetrahedron 1998, 54, 7167e7178.
2. Mokrosz, J. L.; Paluchowska, M. H.; Chojnacka-Wojcik, E.; Filip, M.; Char-
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115.7 (m). LR-EI-MS m/z (%): 295(Mþ, 100), 191(12), 162(42), 118
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295.0369. Found: 295.0373.
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azole 3e [3]. White solid, mp: 119e121 ꢀC. 1H NMR (CDCl3,
300 MHz):
d
8.16 (d, 1H, J¼8.4 Hz), 7.58e7.32 (m, 3H). 19F NMR

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