Synthesis of a novel pyrrolo-benzoxaborole scaffold and its derivatization via Friedel-Crafts reaction catalyzed by anhydrous stannic chloride

Article abstract of DOI:10.1016/j.cclet.2011.06.005

A novel pyrrolo-benzoxaborole, 6-(pyrrol-1-yl)-1,3-dihydro-1-hydroxy-2,1- benzoxaborole, was synthesized with 27% overall yield over six steps from 2-bromo-1-methyl-4-nitrobenzene as starting material. Its derivatization was achieved via Friedel-Crafts re

Full text of DOI:10.1016/j.cclet.2011.06.005

Available online at www.sciencedirect.com
Chinese Chemical Letters 22 (2011) 1411–1414
www.elsevier.com/locate/cclet
Synthesis of a novel pyrrolo-benzoxaborole scaffold and its
derivatization via Friedel–Crafts reaction catalyzed by anhydrous
stannic chloride
*
Pu Hua Wu, Qing Qing Meng, Hu Chen Zhou
School of Pharmacy, Shanghai Jiaotong University, Shanghai 200240, China
Received 28 April 2011
Available online 29 July 2011
Abstract
A novel pyrrolo-benzoxaborole, 6-(pyrrol-1-yl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, was synthesized with 27% overall
yield over six steps from 2-bromo-1-methyl-4-nitrobenzene as starting material. Its derivatization was achieved via Friedel–Crafts
reaction catalyzed by anhydrous stannic chloride with various acyl chlorides giving 3-acyl-1-phenylpyrroles as the main products.
# 2011 Hu Chen Zhou. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Benzoxaborole; Friedel–Crafts reaction; Stannic chloride; 3-Acyl-1-arylpyrrole
Benzoxaboroles have recently been drawing attention due to their newly discovered application as clinically useful
agents [1]. For example, 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690, Fig. 1) exhibited excellent
antifungal activity by inhibiting leucyl-tRNA synthetase (LeuRS). The boron atom of AN2690 is critical for the
activity by forming a tetrahedral covalent adduct with the terminal cis-diol on tRNA [2]. Recently, 5-
aryloxybenzoxaboroles 1 (Fig. 1) are reported to show good potency against phosphodiesterase 4 which is a
therapeutic target for the treatment of inflammation such as asthma and chronic obstructive pulmonary disease [3].
Although benzoxaboroles have attracted great attention in medicinal chemistry, the reports about their synthetic
methodologies are limited [4,5]. Considering the excellent biological profile of substituted benzoxaboroles and their
increasing importance in pharmaceutical and biological research [4,6], we are urged to develop a convenient and
versatile synthesis of novel benzoxaborole scaffolds.
We report here the design and synthesis of 6-(pyrrol-1-yl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole 8, a
medicinally useful scaffold, for the first time with 27% overall yield over six steps from the commercially available 2-
bromo-1-methyl-4-nitrobenzene 2. Subsequent acylation of compound 8 catalyzed by Lewis acids was investigated. It
was demonstrated that the benzoxaborole functionality well tolerated the reaction condition, and SnCl4 was proved to
be a more effective catalyst than AlCl3 to give both 20- and 30-regioisomers in sufficient yields.
The retrosynthetic analysis of compound 8 showed that 2-bromo-1-methyl-4-nitrobenzene 2 can be utilized as
starting material which was easily converted to methyl 4-amino-2-bromobenzoate 5, the precursor of cyclization.
* Corresponding author.
E-mail address: hczhou@sjtu.edu.cn (H.C. Zhou).
1001-8417/$ – see front matter # 2011 Hu Chen Zhou. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2011.06.005

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P.H. Wu et al. / Chinese Chemical Letters 22 (2011) 1411–1414
OH OH
Y
B
B
O
O
F
X
O
1
AN2690
X = N or CH
Y = Variable functional groups
Fig. 1. Structures of AN2690 and 5-aryloxybenzoxaboroles 1.
After the pyrrol-1-yl benzene 6 was formed by means of the Paal–Knorr reaction, the boron atom was introduced
utilizing n-BuLi/B(i-PrO)3. Subsequent intramolecular esterification of ortho-(hydroxymethyl)phenylboronic acid
completed the construction of benzoxaborole skeleton 8 [4,6,7–12].
The synthetic route is outlined in Scheme 1. First, the oxidation of 2-bromo-1-methyl-4-nitrobenzene 2 with
KMnO4 in a mixture of pyridine and water gave acid 3 in 68% yield. Acid 3 was refluxed in thionyl chloride to give
corresponding acyl chloride, which was then converted to methyl ester 4 in situ in dry methanol in the presence of
triethylamine with 95% yield over two steps. Reduction of methyl 2-bromo-4-nitrobenzoate 4 by tin dichloride
dihydrate gave amine 5 in 94% yield. Subsequent condensation of amine 5 with 2,5-dimethoxytetrahydrofuran formed
pyrrol-1-ylbenzene derivative 6 with 84% yield. Reduction of ester 6 provided the benzyl alcohol 7. To avoid involving
expensive palladium catalyst, boronylation was carried out using n-Butyl lithium/B(i-PrO)3 method. Subsequent
hydrolysis and spontaneous cyclization in the presence of 2 mol/L HCl gave the desired scaffold 6-(pyrrol-1-yl)-
benzoxaborole 8.
Next, derivatization of compound 8 was established by the Lewis acid-catalyzed acylation of pyrrole ring. It was
reported that reaction of 1-phenylpyrroles with an excess of acid anhydride catalyzed by orthophosphoric acid can give
3-acyl-1-arylpyrroles [13]. AlC13-catalyzed acylation reactions of 1-substituted pyrrole were also reported to give 3-
acyl derivatives regioselectively [14]. To avoid the opening of the oxaborole ring in the presence of orthophosphoric
acid, the former methodology was not employed in this case. Thus, we tried to complete the acylation of compound 8
using two Lewis acids with strong to weak Friedel–Crafts activity, i.e. AlCl3 and SnCl4, as catalysts [15]. Although
both Lewis acids gave 3-acylpyrroles as main products, the reactions catalyzed by AlCl3 are more complex than those
catalyzed by SnCl4. TLC observation of the reactions showed complex products in the case of AlC13-catalyzed
CH3
COOCH3
Br
COOH
COOCH3
Br
Br
Br
N
Br
b, c
d
a
e
COOCH3
NO2
NO2
NO2
NH2
5
6
3
4
2
R
R
O
O
OH
B
O
OH
1
OH
1'
N
N
N
Br
N
6
B
B
g, h
f
i
O
O
OH
8
7
9a: R = Phenyl
9b: R = Phenyl
10a: R = 4-Fluorophenyl
11a: R = 2-Chlorophenyl
12: R = Methyl
10b: R = 4-Fluorophenyl
11b: R = 2-Chlorophenyl
13: R = Propyl
Scheme 1. Reagents and conditions: (a) KMnO4, pyridine, H2O, reflux, 12 h (68%); (b) SOCl2, reflux, 6 h; (c) CH3OH, triethylamine, 1 h (95% for
two steps); (d) SnCl2ꢀ2H2O, ethyl acetate, reflux, 1 h (94%); (e) 2, 5-dimethoxytetrahydrofuran, AcOH, reflux, 30 min (84%); (f) LiBH4, THF,
CH3OH, 0 8C, 12 h (93%); (g) n-BuLi, (i-PrO)3B, THF, ꢁ80 8C, 12 h; (h) 2 mol/L HCl (57% for two steps); (i) acyl chloride, SnCl4, CH2Cl2, 12 h,
(9a: 23%; 9b: 12%; 10a: 22%; 10b: 5%; 11a: 18%; 11b: 7%; 12: 28%; 13: 38%).

P.H. Wu et al. / Chinese Chemical Letters 22 (2011) 1411–1414
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reaction whereas only two main components were observed in the case of SnC14-catalyzed reactions. We reasoned that
AlCl3, a strong Lewis acid in terms of Friedel–Crafts activity, may have led to low substrate selectivity and side
reactions such as the acylation of the benzene ring [15]. Eventually, SnCl4 was employed as the catalyst for the
acylation. The acetylation and butyrylation of compound 8 provided 30-acyl product 12, 13 and trace amount of 20-acyl
product, while various benzoylations provided 20-acyl products 9b–11b as well as 30-acyl products 9a–11a with
separable yields. In the case of benzoyl chloride and 2-chlorobenzoyl chloride, the ratio of 30- to 20-acyl selectivity was
approximately 2:1 (9a:9b, 11a:11b). However, 4-fluorobenzoyl chloride gave an increased ratio of 5:1 (10a:10b). The
30-substitution pattern of 9a–11a, 12 and 13 are consistent with the presence of 40-H NMR signals at 6.6–6.9 ppm (dd,
J = 1–2, 2–3.2 Hz) resulting from the coupling with 20-H and 50-H. On the other hand, the structures of 2-acylpyrroles
9b–11b corroborate with the 40-H signals at 6.3–6.4 ppm (dd, J = 2.8, 3.6–4.0 Hz) arising from the coupling with two
neighboring protons, 30-H and 50-H.
In summary, we successfully synthesized 6-(pyrrol-1-yl)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole 8 with a 27%
overall yield from commercially available 2-bromo-1-methyl-4-nitrobenzene 2 over 6 steps. To demonstrate the
versatile application of 6-(pyrrol-1-yl)-benzoxaborole 8, we investigated the acylation reactions on the pyrrole ring
using different Lewis acids, and obtained derivatives 9a–13 [16] with various acyl substituents at 20- or 30-position. In
light of the medicinal significance of benzoxaboroles, we believe the efficient synthesis of this new scaffold will
facilitate its further application in new drug discovery.
Acknowledgments
We thank National Science Foundation of China (No. 20702031), Ministry of Science and Technology of China
(No. 2009CB918404), E-Institutes of Shanghai Universities (EISU) Chemical Biology Division, and National
Comprehensive Technology Platforms for Innovative Drug R&D (No. 2009ZX09301-007) for financial support of this
work. We also thank Instrumental Analysis Center of SJTU for providing the NMR service.
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[16] Analytic data for compound 8–13. Compound 8: 1H NMR (400 MHz, DMSO-d6): d 9.27 (s, 1H), 7.79 (d, 1H, J = 2.4 Hz), 7.65 (dd, 1H, J = 8
and 2.4 Hz), 7.47 (d, 1H, J = 8 Hz), 7.29 (dd, 2H, J = 2.4 and 2 Hz), 6.25 (dd, 2H, J = 2.4 and 2 Hz) and 5.03 (s, 2H); 13C NMR (100 MHz,
DMSO-d6): d 140.4, 124.4, 124.1, 122.2, 120.4, 111.9, 70.9; mp: 120–122 8C. Compound 9a: 1H NMR (400 MHz, CDCl3): d 7.89 (s, 1H), 7.87
(s, 1H), 7.80 (d, 1H, J = 1.6 Hz), 7.62 (m, 1H), 7.50 (m, 5H), 7.11 (dd, 1H, J = 2.8 and 2.4 Hz), 6.88 (dd, 1H, J = 2.8 and 1.6 Hz), 5.53 (s, 1H)
and 5.15 (s, 2H); 13C NMR (100 MHz, CDCl3): d 191.1, 152.7, 139.8, 139.3, 131.8, 129.1, 128.5, 126.6, 126.4, 124.4, 123.2, 122.6, 121.6,
112.7, 71.1; HRMS (ESI): [M+H]+ calcd. for C18H15BNO3 304.1145, found 304.1143; mp: 148–151 8C. Compound 9b: 1H NMR (400 MHz,
CDCl3): d 7.80 (s, 1H), 7.62 (s, 1H), 7.56 (m, 2H), 7.41 (m, 4H), 7.08 (m, 1H), 6.90 (m, 1H), 6.38 (dd, 1H, J = 3.6 and 2.8 Hz) and 5.03 (s, 2H);
13C NMR (100 MHz, CDCl3): d 185.1, 153.1, 140.0, 139.1, 132.2, 131.6, 131.3, 129.7, 128.8, 128.3, 127.4, 123.8, 121.8, 109.7, 71.2; HRMS
(ESI): [M+H]+ calcd. for C18H15BNO3 304.1145, found 304.1152; mp: 120–124 8C. Compound 10a: 1H NMR (400 MHz, CDCl3): d 7.94 (d,
1H, J = 8.4 Hz), 7.92 (d, 1H, J = 8.4 Hz), 7.82 (d, 1H, J = 1.6 Hz), 7.63 (t, 1H, J = 2.0 Hz), 7.55 (dd, 1H, J = 8.4 and 2 Hz), 7.46 (d, 1H,
J = 8 Hz), 7.18 (d, 1H, J = 8.4 Hz), 7.15 (d, 1H, J = 8.4 Hz), 7.12 (dd, 1H, J = 3.2 and 2.0 Hz), 6.86 (dd, 1H, J = 3.2 and 1.6 Hz) and 5.16 (s,
2H); 13C NMR (100 MHz, DMSO-d6): d 187.6, 164.0 (d, J = 250 Hz), 152.3, 138.1, 135.7 (d, J = 3 Hz), 131.3 (d, J = 9 Hz), 126.1, 125.0,

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P.H. Wu et al. / Chinese Chemical Letters 22 (2011) 1411–1414
123.6, 122.7, 122.1, 121.8, 115.3 (d, J = 22 Hz), 111.6, 69.7; HRMS (ESI): [M+H]+ calcd. for C18H14BFNO3 322.1051, found 322.1059; mp:
160–162 8C. Compound 10b: 1H NMR (400 MHz, CDCl3): d 7.90 (d, 1H, J = 8.4 Hz), 7.88 (d, 1H, J = 8.4 Hz), 7.62 (s, 1H), 7.42 (dd, 1H, J = 8
and 1.6 Hz), 7.39 (d, 1H, J = 8 Hz), 7.12 (m, 3H), 6.87 (dd, 1H, J = 4.0 and 1.2 Hz), 6.35 (dd, 1H, J = 3.6 and 2.8 Hz) and 5.16 (s, 2H); 13
C
NMR (100 MHz, CDCl3): d 183.6, 165.3 (d, J = 250 Hz), 153.2, 140.0, 135.3 (d, J = 3 Hz), 132.1 (d, J = 9 Hz), 131.6, 131.1, 128.8, 127.3,
123.5, 121.9, 115.4 (d, J = 22 Hz), 109.7, 71.2; HRMS (ESI): [M+H]+ calcd. for C18H14BFNO3 322.1051, found 322.1051; mp: 114–117 8C.
Compound 11a: 1H NMR (400 MHz, CDCl3): d 7.75 (d, 1H, J = 1.6 Hz), 7.50 (dd, 1H, J = 8.4 and 2.4 Hz), 7.45 (m, 6H), 7.09 (m, 1H), 6.81
(dd, 1H, J = 2.8 and 1.6 Hz) 5.42 (s, 1H) and 5.13 (s, 2H); 13C NMR (100 MHz, DMSO-d6): d 188.1, 152.5, 139.5, 137.9, 131.0, 129.9, 129.6,
128.7, 127.1, 126.9, 126.2, 123.7, 122.8, 122.6, 122.2, 110.8, 69.8; HRMS (ESI): [M+H]+ calcd. for C18H14BClNO3 338.0755, found
338.0757; mp: 165–168 8C. Compound 11b: 1H NMR (400 MHz, CDCl3): d 7.69 (d, 1H, J = 1.2 Hz), 7.50, (dd, 1H, J = 8 and 2.0 Hz), 7.39 (m,
5H), 7.09 (dd, 1H, J = 2 and 2.8 Hz), 6.66 (dd, 1H, J = 4.0 and 1.6 Hz), 6.35 (dd, 1H, J = 4.0 and 2.8 Hz), 5.45 (s, 1H) and 5.14 (s, 2H); 13
C
NMR (100 MHz, DMSO-d6): d 182.1, 153.0, 138.9, 138.8, 133.3, 131.1, 130.6, 130.0, 129.6, 129.0, 128.4, 127.2, 126.8, 124.1, 121.7, 110.1,
69.8; HRMS (ESI): [M+H]+ C18H14BClNO3 calcd. 338.0755, found 338.0757; mp: 131–135 8C. Compound 12: 1H NMR (400 MHz, CD3OD):
d 8.00 (t, 1H, J = 2 Hz), 7.79 (d, 1H, J = 1.6 Hz), 7.67 (dd, 1H, J = 8.4 and 1.6 Hz), 7.53 (d, 1H, J = 8.4 Hz), 7.26 (dd, 1H, J = 3.2 and 2 Hz),
6.75 (dd, 1H, J = 3.2 and 1.6 Hz), 5.14 (s, 2H) and 2.47 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d 192.3, 152.1, 138.2, 127.2, 125.1, 123.3,
122.7, 121.9, 121.5, 109.8, 69.7, 27.0; HRMS (ESI): [M+H]+ calcd. for C13H13BNO3 242.0988, found 242.0990; mp: 189–191 8C. Compound
1
13: H NMR (300 MHz, DMSO-d6): d 9.30 (s, 1H), 8.16 (m, 1H), 7.91 (d, 1H, J = 2.1 Hz), 7.78 (dd, 1H, J = 8.4 and 2.1 Hz), 7.53 (d, 1H,
J = 8.4 Hz), 7.40 (m, 1H), 6.66 (dd, 1H, J = 3 and 1.5 Hz), 5.05 (s, 2H), 2.78 (t, 2H, J = 7.2 Hz), 1.61 (m, 2H) and 0.93 (t, 3H, J = 7.5 Hz); 13
C
NMR (100 MHz, DMSO-d6): d 195.4, 152.6, 138.8, 127.5, 125.1, 123.8, 123.2, 122.4, 122.0, 110.4, 70.3, 41.1, 18.4, 14.3; HRMS (ESI):
[M+H]+ calcd. for C15H17BNO3 270.1301, found 270.1303; mp: 122–124 8C.