Synthesis of benzyloxycyanophenylboronic esters

Article abstract of DOI:10.1515/HC.2011.001

The synthesis of six new benzyloxycyanoboronic esters: 2-benzyloxy-6- cyanophenyl-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (4a), 4-benzyloxy-2- cyanophenyl-4,4,5, 5-tetramethyl-[1,3,2]dioxaborolane (4b), 4-benzyloxy-3- cyanophenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (8a), 2-benzyloxy-5- cyanophenyl-4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (8b), 3-benzyloxy-4- cyanophenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (12a), and 2-benzyloxy-5-cyanophenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (12b) is reported. Copyright by Walter de Gruyter Berlin Boston.

Full text of DOI:10.1515/HC.2011.001

Heterocycl. Commun., Vol. 17(1-2), pp. 11–16, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HC.2011.001
Synthesis of benzyloxycyanophenylboronic esters
Serry A.A. El Bialy1,2, Kamelia F. Abd El Kader2,3 and
As part of an anti-infective drug discovery research pro-
gram we needed to synthesize several different triaryl systems
David W. Boykin2,*
consisting of one or more hydroxy-substituted benzamidine
1 Department of Pharmaceutical Organic Chemistry,
groups. As these benzamidine-based triaryl systems are
Faculty of Pharmacy, Mansoura University, Mansoura
typically prepared by palladium-catalyzed Suzuki couplings
35516, Egypt
with a substituted cyanophenylboronic acid, we required
2 Department of Chemistry and Center for Biotechnology
hydroxy-protected cyanophenols as precursors (Tidwell and
and Drug Design, Georgia State University, Atlanta,
Boykin, 2003). Following construction of the triaryl frame-
GA 30303-3083, USA
work, the nitrile group can be converted to the amidine via
3 Department of Medicinal Chemistry, Faculty of
reduction of an intermediate amidoxime (Kumar et al., 1996).
Pharmacy, Mansoura University, Mansoura 35516, Egypt
Consequently, it seemed advantageous to use a hydroxy pro-
tecting group during the aryl couplings which could poten-
tially be removed simultaneously during amidine formation.
Therefore, we decided to explore the use of benzyl-protected
boronic acid esters. A survey revealed that none of the ben-
zyloxy cyanophenylboronic acid esters have been previously
reported. This report describes the synthesis and characteriza-
tion of six new isomeric benzyloxy cyanoboronic acid esters.
*Corresponding author
e-mail: dboykin@gsu.edu
Abstract
The synthesis of six new benzyloxycyanoboronic esters:
2-benzyloxy-6-cyanophenyl-4,4,5,5-tetramethyl-[1,3,2]-
dioxaborolane
(4a),
4-benzyloxy-2-cyanophenyl-4,4,5,
5-tetramethyl-[1,3,2]dioxaborolane (4b), 4-benzyloxy-3-
cyanophenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (8a),
2-benzyloxy-5-cyanophenyl-4,4,5,5-tetramethyl-[1,3,2]-
dioxaborolane (8b), 3-benzyloxy-4-cyanophenyl-4,4,5,5-
tetramethyl-[1,3,2]dioxaborolane (12a), and 2-benzyloxy-5-
cyanophenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (12b)
is reported.
Results and discussion
We initiated this study by the synthesis of 2-benzyloxy-6-
cyanophenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (4a)
and 4-benzyloxy-2-cyanophenyl-4,4,5,5-tetramethyl-[1,3,2]-
dioxaborolane (4b). As previously reported, bromination
of 3-hydroxybenzonitrile (1) yields a mixture of 2-bromo-
5-hydroxybenzonitrile (2a) and 2-bromo-3-hydroxybenzo-
nitrile (2b) which could not be readily separated (Ismail et
al., 2004). Alkylation of the mixture of phenols with benzyl
bromide yields a mixture of the benzyloxy analogs 3a and 3b,
which were more readily separated by column chromatogra-
phy (Scheme 1) (Ismail et al., 2004).
Keywords: benzyloxybenzonitriles; benzyloxycyanoboronic
esters; palladium catalyzed cross-coupling.
Introduction
Both 3a and 3b yielded NMR spectra that are similar and
require assumptions for assignment (Ismail et al., 2004). It
was deemed important to obtain unambiguous structural
information for these compounds; therefore, we obtained
an X-ray structure from crystals which were found to be
that of 3b (Figure 1) which was the structure assigned by
NMR analysis. Table 1 contains the bond lengths and
angles found for 3b. The borylation of the bromo deriva-
tives 3a and 3b using bis(pinacolato)diboran in presence
of bis(dibenzylideneacetone)palladium [Pd(dba)2] and tri-
cyclohexyl phosphine [PCy3] as a ligand, KOAc as a base
and dioxane as solvent provided 2-benzyloxy-6-cyano-
phenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (4a), and
4-benzyloxy-2-cyanophenyl-4,4,5,5-tetramethyl-[1,3,2]diox-
aborolane (4b), respectively.
Boronic acids have been widely used in cross-coupling
reactions for carbon-carbon bond formation (Suzuki, 1999;
Littke et al., 2000). A typical preparation of arylboronic
acids involves a reaction between an organoborate and an
organometal (Li or Mg) species, usually prepared by mag-
nesium insertion or lithium-halogen exchange of the corre-
sponding aryl halides (Brown and Cole, 1983). This method
has its limitations, however; first, it is difficult to apply it
to substrates bearing functional groups not compatible with
organolithium reagents such as esters and nitriles. Second,
some aryllithium intermediates are intrinsically unstable, as
is the case for several aromatic heterocycles (Gilman and
Spatz, 1951). Alternately, arylboronic esters can be pre-
pared from aryl halides or aryl triflates via a palladium-
catalyzed cross-coupling reaction with tetraalkoxydiboron
or dialkoxyhydroborane (Ishiyama et al., 1995; Murata et
al., 2000). These methods tolerate a wide range of func-
tional groups.
Scheme 2 outlines the route used to prepare benzyloxy
m-cyanophenylboronicesters:4-benzyloxy-3-cyanophenyl-4,-
4,5,5-tetramethyl-[1,3,2]dioxaborolane (8a) and 2-benzyloxy-
5-cyanophenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane

12 S.A.A. El Bialy et al.
NC
NC
NC
HO
iii)
O
O
ii)
Br
B
Br
(78%)
(39%)
BnO
BnO
4a
i)
CN
2a
Br
3a
(84%)
HO
NC
1
NC
NC
Br
ii)
O
O
iii)
(66%)
B
OBn
(56%)
HO
BnO
2b
3b
4b
Scheme 1: Reagents and Conditions. i) Br2, HOAc
ii) benzyl bromide, K2CO3, Cs2CO3, MeCN
iii) bis(pinacolato)diboran, Pd(dba)2, PCy3, KOAc, dioxane
Scheme 1 Synthesis of benzyloxycyanophenylboronic esters 4a and 4b.
(8b) in three steps starting with the hydroxyl m-bromobenz-
aldehydes 5a,b. Conventional alkylation of the hydroxyl-5-
bromobenzaldehydes 5a,b with benzyl bromide yields the cor-
responding benzyloxy compounds 6a,b. The aldehyde group
was converted into the cyano derivatives 7a,b through the
dehydration of the corresponding oximes using acetic anhy-
dride. As before, the borylation of the bromo derivatives 7a,b
was achieved using bis(pinacolato)diboran in presence of
Pd(dba)2 and PCy3 as a ligand, KOAc as a base and dioxane as
solvent to provide phenylboronic acid esters (8a,b).
using 2-(methylsulfonyl)ethoxide followed by elimination
of vinylmethyl sulfone (Rodgers and Green, 2002; Ismail et
al., 2004). It is worthy to note that in this process the yield
obtained from the o-fluorobenzonitrile is higher than that
for the m-fluorobenzonitrile. Conventional alkylation of the
bromophenols 10a,b with benzyl bromide yields the corre-
sponding benzyloxy compounds 11a,b. The borylation of the
bromo derivative 11a,b using bis(pinacolato)diboran in pres-
ence of Pd(dba)2 and PCy3 as a ligand, KOAc as a base and
dioxane as solvent gave the target boronic acid esters 12a,b.
Finally, the synthesis of the p-cyanophenylboronic esters:
3-benzyloxy-4-cyanophenyl-4,4,5,5-tetramethyl-[1,3,2]
dioxaborolane (12a) and 2-benzyloxy-4-cyanophenyl-4,-
4,5,5-tetramethyl-[1,3,2]dioxaborolane (12b) was achieved
in three steps starting from the fluoro-4-bromobenzonitriles
9a,b as outlined in Scheme 3. The key step in this approach
employs displacement of fluoride under mild conditions
Conclusion
We have described straightforward synthetic approaches
for benzyloxy cyanoboronic acid esters: 2-benzyloxy-6-
cyanophenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (4a),
N1
C14
C4
C5
Br1
C3
C7
C6
C13
C2
C8
C12
01
C1
C9
C11
C10
Figure 1 Crystal structure for 3b.

Benzyloxycyanophenylboronic esters 13
Table 1 Bond lengths [Å] and angles [°] for 3b.
Table 1 (Continued)
Br(1)-C(3)
C(1)-C(2)
C(1)-C(6)
C(1)-H(1A)
C(2)-C(3)
C(2)-H(2A)
C(3)-C(4)
C(4)-C(5)
1.8900 (19)
1.379 (3)
1.396 (3)
0.9500
1.393 (3)
0.9500
1.388 (3)
1.397 (3)
1.442 (3)
1.392 (3)
0.9500
C(12)-C(11)-C(10)
C(12)-C(11)-H(11A)
C(10)-C(11)-H(11A)
C(11)-C(12)-C(13)
C(11)-C(12)-H(12A)
C(13)-C(12)-H(12A)
C(8)-C(13)-C(12)
C(8)-C(13)-H(13A)
C(12)-C(13)-H(13A)
N(1)-C(14)-C(4)
119.53 (19)
120.2
120.2
120.3 (2)
119.9
119.9
120.52 (19)
119.7
119.7
179.0 (2)
117.42 (15)
C(4)-C(14)
C(5)-C(6)
C(5)-H(5A)
C(6)-O(1)-C(7)
C(6)-O(1)
C(7)-O(1)
C(7)-C(8)
C(7)-H(7A)
1.360 (2)
1.441 (2)
1.500 (3)
0.9900
4-benzyloxy-2-cyanophenyl-4,4,5,5-tetramethyl-[1,3,2]-
dioxaborolane (4b), 4-benzyloxy-3-cyanophenyl-4,4,5,5-
tetramethyl-[1,3,2]dioxaborolane (8a), 2-benzyloxy-5-cy-
C(7)-H(7B)
C(8)-C(13)
C(8)-C(9)
C(9)-C(10)
C(9)-H(9A)
C(10)-C(11)
C(10)-H(10A)
C(11)-C(12)
C(11)-H(11A)
C(12)-C(13)
0.9900
1.387 (3)
1.396 (3)
1.381 (3)
0.9500
1.390 (3)
0.9500
1.383 (3)
0.9500
1.387 (3)
0.9500
anophenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane
(8b),
3-benzyloxy-4-cyanophenyl-4,4,5,5-tetramethyl-[1,3,2]diox-
aborolane (12a), and 2-benzyloxy-5-cyanophenyl-4,4,5,5-tet-
ramethyl-[1,3,2]dioxaborolane (12b) from readily available
starting materials. The use of these analogs in the synthesis of
triaryl hydroxybenzamidines will be reported in due course.
Experimental section
General
C(12)-H(12A)
C(13)-H(13A)
C(14)-N(1)
0.9500
1.145 (3)
120.75 (18)
119.6
119.6
119.80 (18)
120.1
C(2)-C(1)-C(6)
C(2)-C(1)-H(1A)
C(6)-C(1)-H(1A)
C(1)-C(2)-C(3)
C(1)-C(2)-H(2A)
C(3)-C(2)-H(2A)
C(4)-C(3)-C(2)
C(4)-C(3)-Br(1)
C(2)-C(3)-Br(1)
C(3)-C(4)-C(5)
C(3)-C(4)-C(14)
C(5)-C(4)-C(14)
C(6)-C(5)-C(4)
C(6)-C(5)-H(5A)
C(4)-C(5)-H(5A)
O(1)-C(6)-C(5)
O(1)-C(6)-C(1)
C(5)-C(6)-C(1)
O(1)-C(7)-C(8)
O(1)-C(7)-H(7A)
C(8)-C(7)-H(7A)
O(1)-C(7)-H(7B)
C(8)-C(7)-H(7B)
H(7A)-C(7)-H(7B)
C(13)-C(8)-C(9)
C(13)-C(8)-C(7)
C(9)-C(8)-C(7)
C(10)-C(9)-C(8)
C(10)-C(9)-H(9A)
C(8)-C(9)-H(9A)
C(9)-C(10)-C(11)
C(9)-C(10)-H(10A)
C(11)-C(10)-H(10A)
Melting points were recorded using a Thomas-Hoover (Uni-Melt)
capillary melting point apparatus and are uncorrected. TLC analysis
was carried out on silica gel 60 F254 precoated aluminum sheets and
1
detected under UV light. H and 13C NMR spectra were recorded
employing a Bruker Avance 400 MHz spectrometer, and chemical
shifts (δ) are in ppm relative to TMS as internal standard. Mass spec-
tra were recorded on a VG analytical 70-SE spectrometer. Elemental
analyses were obtained from Atlantic Microlab Inc. (Norcross, GA,
USA) and are within 0.4 of the theoretical values. All chemicals and
solvents were purchased from Aldrich Chemical Co. or VWR.
120.1
119.63 (18)
120.64 (15)
119.66 (15)
120.91 (18)
120.66 (18)
118.44 (18)
119.02 (18)
120.5
Synthesis of hydroxy 2-bromobenzonitrile (2a,b)
120.5
To a solution of 3-hydroxybenzonitrile (8.33 g, 70 mmol) in acetic
acid (80 ml) was dropwise added bromine (11.06 g). The reaction mix-
ture was stirred overnight and treated with aqueous sodium thiosulfate
to remove any remaining bromine. The excess solvent was removed
under reduced pressure and diluted with water to yield (11.7 g, 84%) an
inseparable white solid mixture (TLC very close Rf) of two products:
2-bromo-3-hydroxybenzonitrile (2a) and 2-bromo-5-hydroxybenzo-
nitrile (2b). The mixture is pure enough to be used in the next step.
124.37 (18)
115.73 (17)
119.89 (18)
107.04 (15)
110.3
110.3
110.3
110.3
108.6
119.00 (18)
120.53 (18)
120.47 (18)
120.40 (19)
119.8
119.8
120.29 (19)
119.9
General procedures for synthesis of the benzyloxy
bromobenzonitriles
Bromo hydroxybenzonitrile (3.96 g, 0.02 mol) was dissolved in
(60 ml) MeCN. To this solution K2CO3 (8.28 g, 0.06 mol), Cs2CO3
(3.25 g, 0.01 mol) were added and the reaction mixture was heated at
40°C for 15 min. Benzyl bromide (3.40 g, 0.02 mol) was added and
the reaction was heated at reflux for 3 h. Water (100 ml) was added
and the reaction mixture was extracted with ethyl acetate, dried over
sodium sulfate and concentrated. The crude mixture was purified by
119.9

14 S.A.A. El Bialy et al.
CHO
CHO
R2
CN
CN
iii)
ii)
R1
R1
R1
i)
R1
R2
R1
No
(90-93%)
(91-96%)
Br
(69-71%)
5a
5b
6-8a
6-8b
OH
H
OBn
H
H
O
Br
Br
B
O
OH
H
OBn
R2
R2
R2
5a,b
6a,b
7a,b
8a,b
Scheme 2: Reagents and Conditions. i) benzyl bromide, K2CO3, Cs2CO3, MeCN
ii) NH2OH HCl, pyridine, acetic anhydride
iii) bis(pinacolato)diboran, Pd(dba)2, PCy3, KOAc, dioxane
Scheme 2 Synthesis of benzyloxycyanophenylboronic esters 8a and 8b.
flash column chromatography (20% EtOAc-hexanes). The synthe-
sis, by various methods, and physical data of all the benzyloxy bro-
mobenzonitriles, except 7b, has been previously reported. Limited
data for 7b appears in a patent (Cooper et al., 2010).
0.02 mol) gave (5.42 g, 93%), mp 70–71°C, lit mp 67.5–69.5°C
(Fresneda et al., 2001). 1H NMR (DMSO-d6, 400 MHz) δ: 10.31 (s,
1H, CHO), 7.77 (dd, J=2.4, 8.8 Hz, 1H, H-4), 7.74 (d, J=2.4 Hz, 1H,
H-6), 7.49 (d, J=7.6 Hz, 2H, Ar-H), 7.40 (t, J=7.6 Hz, 2H, Ar-H), 7.34
(d, J=7.2 Hz, 1H, Ar-H), 7.28 (d, J=8.8 Hz, 1H, H-3), 5.27 (s, 2H,
CH2). 13C NMR (DMSO-d6, 100 MHz) δ: 188.0 (CHO), 159.6 (C-2),
138.3 (C-4), 136.0 (C-1'), 129.2 (C-3'), 128.5 (C-4'), 128.1 (C-2'),
126.0 (C-1), 116.8 (C-3), 112.7 (C-5), 70.3 (CH2).
3-Benzyloxy-2-bromobenzonitrile (3a)
The mixture of 2a and 2b was benzylated using the general procedure;
afterwards, 3a and 3b were obtained pure by column chromatogra-
phy. For compound 3a, yield (6.56 g, 39%), mp 86–88°C (hexanes/
ether), lit mp 93.5–94°C (Ismail et al., 2004). 1H NMR (CDCl3,
400 MHz) δ: 7.54–7.46 (m, 5H, Ar-H), 7.49 (d, 1H, J=6.8 Hz, H-4),
7.41 (d, 1H, J=7.2 Hz, H-6), 7.15 (t, 1H, J=6.4, H-5), 5.17 (s, 2H,
CH2); (CDCl3, 100 MHz) δ: 155.4 (C-3), 136.0 (C-1'), 129. 9 (C-5),
128.6 (C-3'), 128.2 (C-4'), 127.6 (C-2'), 126.5 (C-6), 117.3 (C-4),
115.8 (C-1), 115. 7 (CN), 114.4 (C-2), 70.7 (CH2).
4-Benzyloxy-3-bromobenzaldehyde (6b)
Using the general procedures for synthesis of the benzyloxy bro-
mobenzonitrile; 3-bromo-4-hydroxybenzaldehyde (5b) (4.02 g,
0.02 mol) gave (5.24 g, 90%), mp 101–102°C, lit mp 97–98°C
1
(Qin et al., 2008). H NMR (DMSO-d6, 400 MHz); δ 9.87 (s, 1H,
CHO), 8.13 (d, J=2.4 Hz, 1H, H-2), 7.93 (dd, J=8.4, 2.4 Hz, 1H,
H-6), 7.39 (d, J=7.6 Hz, 2H, Ar-H), 7.29 (t, J=7.6 Hz, 2H, Ar-H),
7.18 (d, J=7.2 Hz, 1H, Ar-H), 7.10 (d, J=8.4 Hz, 1H, H-5), 5.25 (s,
2H, CH2). 13C NMR (DMSO-d6, 100 MHz); δ: 188.3 (CHO), 159.6
(C-2), 138.3 (C-4), 136.0 (C-1'), 129.2 (C-3'), 128.5 (C-4'), 128.1
(C-2'), 126.0 (C-1), 116.8 (C-3), 112.7 (C-5), 70.2 (CH2).
5-Benzyloxy-2-bromobenzonitrile (3b)
The mixture of 2a and 2b was benzylated using the general proce-
dure; afterwards, 3a and 3b were obtained pure by column chroma-
tography. For compound 3b, yield (9.43 g, 56%), mp 103–102°C
(hexanes/ether), lit mp 101.0–101.5°C (Ismail et al., 2004). 1H NMR
(CDCl3, 400 MHz); δ: 7.53 (d, J=8.4 Hz, 1H, H-3), 7.63 (s, 1H,
H-6), 7.45–7.33 (m, 5H), 7.38 (d, J=8.8 Hz, 1H, H-5), 5.15 (s, 2H);
(CDCl3, 100 MHz) δ: 157.7 (C-5), 137.0 (C-3), 134.2 (C-1'), 128.6
(C-3'), 128.2 (C-4'), 128.0 (C-2'), 126.5 (C-6), 122.5 (C-4), 120.5
(C-6), 117.1 (C-2), 115.0 (CN), 115.0 (C-1), 70.11 (CH2).
General method for synthesis of nitriles from
aldehydes
A 5-ml pyridine solution of 0.7 g NH2OH·HCl (6.95 g, 0.1 mol)
was added to a stirred solution of 6a,b (3.5 g, 0.012 mol) in (5 ml)
pyridine and (5.5 ml) acetic anhydride and heated at reflux for 4 h.
The reaction mixture was neutralized with aqueous NaHCO3 and ex-
tracted by ethyl acetate. The organic layer was dried (Na2SO4) and
then concentrated to dryness under reduced pressure. The product
was purified by column chromatography on silica gel using 10%
EtOAc-hexanes.
2-Benzyloxy-5-bromobenzaldehyde (6a)
Using the general procedures for synthesis of the benzyloxy bro-
mobenzonitrile; 5-bromo-2-hydroxybenzaldehyde (5a) (4.02 g,
CN
R1
CN
CN
CN
No
R1
R2
R1
R1
R2
R1
R2
i)
(85-55%)
ii)
iii)
9a
9b
10a
10b
11,12a
11,12b
F
H
OH
H
OBn
H
H
F
H
OH
H
R2
(93-96%)
(64-72%)
R2
B
O
Br
Br
Br
O
9a,b
10a,b
11a,b
12a,b
OBn
Scheme 3: Reagents and Conditions. i) 2-(methylsulfonyl)ethanol, NaH, DMF
ii) benzyl bromide, K2CO3, Cs2CO3, MeCN
iii) bis(pinacolato)diboran, Pd(dba)2, PCy3, KOAc, dioxane
Scheme 3 Synthesis of benzyloxycyanophenylboronic esters 12a and 12b.

Benzyloxycyanophenylboronic esters 15
2-Benzyloxy-5-bromobenzonitrile (7a)
3-Benzyloxy-4-bromobenzonitrile (11b)
Yield (3.33 g, 96%), mp 79–80°C, lit mp 74–76°C (Zhang et al.,
2010). H NMR (DMSO-d6, 400 MHz); δ: 7.98 (d, J=2.4 Hz, 1H,
Using the general procedures for synthesis of the benzyloxy bro-
mobenzonitrile; 3-bromo-4-hydroxybenzonitrile (10b) (3.96 g,
0.02 mol) gave (5.53 g, 96%), mp 87–90°C, lit mp 113.5–114°C
1
H-6), 7.82 (dd, J=2.4, 8.8 Hz, 1H, H-4), 7.48 (d, J=7.4 Hz, 2H,
Ar-H), 7.42 (t, J=7.6 Hz, 2H, Ar-H), 7.33 (d, J=7.2 Hz, 1H, Ar-H),
7.30 (d, J=8.8 Hz, 1H, H-3), 5.30 (s, 2H, CH2). 13C NMR (DMSO-
d6, 100 MHz); δ: 159.2 (C-2), 137.4 (C-4), 135.5 (C-1'), 135.4 (C-6),
128.4 (2×C-3'), 128.0 (C-4'), 127.3 (C-2'), 115.7 (C-3), 114.7 (CN),
111.8 (C-5), 102.9 (C-1), 70.4 (CH2).
1
(Ismail et al., 2004). H NMR (DMSO-d6, 400 MHz); δ: 7.51 (d,
1H, J=8.8 Hz, C-5), 7.34 (m, 5H, Ar-H), 7.19 (d, 1H, J=2.4 Hz,
H-2), 7.05 (dd, 1H, J=8.8 Hz, H-6) 5.18 (s, 2H, CH2). 13C NMR
(DMSO-d6, 100 MHz); δ: 157.9 (C-3), 135.6 (C-1'), 134.2 (C-5),
129.0 (C-3'), 128.7 (C-4'), 127.6 (C-2'), 121.8 (C-2), 120.1 (C-6),
117.2 (C-4), 116.4 (C-1), 116.1 (CN), 70.8 (CH2).
4-Benzyloxy-3-bromobenzonitrile (7b)
General procedure for the synthesis of
benzyloxycyanoboronic acid esters
Yield (3.14 g, 91%), mp 98–100°C. 1H NMR (DMSO-d6, 400 MHz);
δ: 8.10 (s, 1H, H-2), 7.82 (d, J=8.4 Hz, 1H, H-6), 7.48 (d, J=6.8 Hz,
2H, H-2'), 7.41 (t, J=6.8 Hz, 2H, H-3'), 7.35 (d, J=6.8 Hz, 1H, H-5),
7.34 (d, J=6.8 Hz, 1H, H-4'), 5.32 (s, 2H, CH2). 13C NMR (DMSO-
d6, 100 MHz); δ: 158.0 (C-4), 136.2 (C-2), 135.5 (C-1'), 133.4 (C-6),
128.3 (C-3'), 127.9 (C-2'), 117.4 (C-5), 114.3 (CN), 111.6 (C-3),
104.4 (C-1), 70.3 (CH2). Anal. calcd. for C14H10BrNO: C, 58.36; H,
3.50; N, 4.86. Found: C, 58.46; H, 3.49; N, 4.80.
To a degassed dioxane (30 ml) was added bis(dibenzylideneacetone)
palladium (0.143 g, 0.25 mmol), and tricyclohexyl phosphine
(0.168 g, 0.6 mmol) and the solution was allowed to stir for 30 min
at 25°C. Aryl bromide (1.44 g, 5 mmol), KOAc (0.736 g, 7.5 mmol)
and bis(pinacolato) diboran were added sequentially and the reac-
tion mixture was vigorously stirred. The mixture was warmed to
90–100°C for 24 h under a nitrogen atmosphere. The solvent was
removed under reduced pressure and the residue was dissolved in
EtOAc (150 ml), then washed with water and passed through celite,
dried (Na2SO4) and evaporated. The product was purified by column
chromatography on silica gel using 30% EtOAc-hexanes as eluent.
Synthesis of hydroxy-4-bromobenzonitriles (10a,b)
To a stirred solution of 2-fluoro-4-bromobenzonitrile (2.0 g, 10 mmol)
in 15 ml of anhydrous DMF was added 2-(methylsulfonyl) ethanol
(1.86 g, 15 mmol) and the solution was cooled to 0°C. Sodium hy-
dride (60% oil dispersion) (720 mg, 30 mmol) was added and the
reaction mixture was allowed to warm to room temperature. The mix-
ture was quenched with a 1-N HCl solution and extracted three times
with ethyl acetate. The combined EtOAc was washed with water,
brine and dried over anhydrous Na2SO4. The solvent was removed
under reduced pressure. The crude product was purified by column
chromatography using 30% ethyl acetate in hexanes as the eluent.
2-Benzyloxy-6-cyanophenyl-4,4,5,5-tetramethyl-
[1,3,2]dioxaborolane (4a)
1
Yield (1.3 g, 78%), mp 85–86°C. H NMR [(CD3)2CO, 400 MHz];
δ: 7.56 (m, 3H, H-3,4,5), 7.40 (d, J=7.2, 2H, H-2'), 7.38 (t, J=7.2 Hz,
2H, H-3'), 7.33 (d, J=7.6 Hz, 1H, H-4'), 5.17 (s, 2H, CH2), 1.33 (s,
12H, 4 CH3). 13C NMR [(CD3)2CO, 100 MHz]; δ: 162.9 (C-2), 137.7
(C-1'), 132.8 (C-4), 129.2 (C-3'), 128.8 (C-4'), 128.5 (C-2'), 125.2
(C-1), 125.6 (C-5), 119.3 (C-3), 117.3 (CN), 117.0 (C-6), 85.4 [2C-
(CH3)2], 71.1 (CH2), 25.1 (4 CH3). Anal. calcd. for C20H22BNO3:
C, 71.66; H, 6.62; N, 4.18. Found: C, 71.39; H, 6.67; N, 4.17.
4-Bromo-2-hydroxybenzonitrile (10a)
Yield (1.68 g, 85%), mp 165–166°C, lit mp 162.1–162.7°C (Ismail
et al., 2004). 1H NMR (DMSO-d6, 400 MHz); δ: 10.89 (s, 1H, OH);
7.57 (d, 1H, J=8.0 Hz, H-6), 7.18 (s, 1H, H-3), 7.13 (d, 1H, J=8.0 Hz,
H). 13C NMR (DMSO-d6, 100 MHz); δ: 161.3 (C-2), 135.1 (C-6),
128.2 (C-4), 123.2 (C-5), 119.5 (C-3), 116.9 (CN), 98.9 (C-1).
4-Benzyloxy-2-cyanophenyl-4,4,5,5-tetramethyl-
[1,3,2]dioxaborolane (4b)
Yield (1.1 g, 66%), mp 105–106°C. 1H NMR [(CD3)2CO, 400 MHz];
δ: 7.82 (d, J=8.4 Hz, 1H, H-6), 7.50 (d, J=7.6, 2H, H-2'), 7.41 (d,
J=8.0 Hz, 2H, H-3'), 7.40 (s, 1H, H-3), 7.36 (d, 1H, J=7.6 Hz, H-4'),
7.32 (dd, J=8.4, 2.4 Hz, H-5), 5.26 (s, 2H, CH2), 1.35 (s, 12H, 4
CH3). 13C NMR [(CD3)2CO, 100 MHz]; δ: 161.9 (C-4), 138.8 (C-1'),
137.4 (C-6), 129.5 (C-3'), 129.0 (C-4'), 128.7 (C-2'), 120.5 (C-3),
119.7 (C-5), 119.7 (C-2), 119.1 (CN), 85.2 [2C-(CH3)2], 71.0 (CH2),
25.2 (4 CH3). Anal. calcd. for C20H22BNO3: C, 71.66; H, 6.62;
N, 4.18. Found: C, 71.58; H, 6.63; N, 4.24.
4-Bromo-3-hydroxybenzonitrile (10b)
Yield (1.1 g, 55%), mp 158–160°C. 1H NMR (DMSO-d6, 400 MHz);
δ: 10.53 (s, 1H, OH), 7.6.1 (d, 1H, J=7.2 Hz, H-5), 7.23 (s, 1H, H-2),
7.04 (dd, 1H, J=1.6, 7.2 Hz, H-6). 13C NMR (DMSO-d6, 100 MHz);
δ: 157.1 (C-3), 134.2 (C-5), 122.7 (C-6), 121.0 (C-2), 117.2 (CN),
114.8 (C-4), 112.6 (C-1).
2-Benzyloxy-4-bromobenzonitrile (11a)
4-Benzyloxy-3-cyanophenyl-4,4,5,5-tetramethyl-
[1,3,2]dioxaborolane (8a)
Using the general procedures for synthesis of the benzyloxy bro-
mobenzonitrile; 5-bromo-2-hydroxybenzonitrile (10a) (3.96 g,
0.02 mol) gave (5.35 g, 93%). mp 101–103°C, lit mp 105.3°C
(Ismail et al., 2004). 1H NMR (DMSO-d6, 400 MHz); δ: 7.43–7.37
(m, 5H, Ar-H), 7.33 (d, 1H, J=2.8 Hz, H-6), 7.18 (d, 1H, J=1.8 Hz,
H-3), 7.15 (dd, 1H, J=8.0, 1.8 Hz, H-5), 5.17 (s, 2H, CH2). 13C NMR
(DMSO-d6, 100 MHz); δ: 160.7 (C-2), 135.0 (C-1'), 134.7 (C-6),
129.0 (C-3'), 128.9 (C-4), 128.6 (C-4'), 127.2 (C-2'), 124.7 (C-5),
116.8 (C-3), 101.6 (C-1), 115.8 (CN), 71.6 (CH2).
Yield (1.18 g, 71%), mp 156–157°C. 1H NMR [(CD3)2CO, 400 MHz];
δ: 8.04 (d, J=1.6 Hz, 1H, H-2), 7.92 (dd, J=8.8, 1.6 Hz, 1H, C-6),
7.46 (dd, J=7.6 Hz, 2H, H-2'), 7.38 (dt, J=7.6, 1.6 Hz, 2H, H-3'),
7.33 (dd, J=7.6, 1.6 Hz, 1H, H-4'), 7.00 (dd, J=8.4, 1.6 Hz, 1H, H-5),
5.25 (s, 2H, CH2), 1.38 (s, 12H, 4 CH3). 13C NMR [(CD3)2CO, 100
MHz]; δ: 162.3 (C-4), 140.9 (C-2), 140.8 (C-6), 135.56 (C-1'), 128.8
(C-3'), 128.3 (C-4'), 127.1 (C-2'), 123.3 (C-1), 116.4 (CN), 112.2
(C-5), 102.3 (C-3), 84.3 [2C-(CH3)2], 70.6 (CH2), 24.9 (4 CH3).

16 S.A.A. El Bialy et al.
Anal. calcd. for C20H22BNO3: C, 71.66; H, 6.62; N, 4.18. Found:
C, 71.60; H, 6.64; N, 4.23.
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2-Benzyloxy-5-cyanophenyl-4,4,5,5-tetramethyl-
[1,3,2]dioxaborolane (8b)
Yield (1.15 g, 69%), mp 109–110°C. 1H NMR [(CD3)2CO, 400 MHz];
δ: 7.93 (dd, J=8.8, 2.0 Hz, 1H, H-4), 7.85 (d, J=2.0 Hz, 1H, H-6),
7.59 (d, J=7.2 Hz, 2H, H-2'), 7.40 (t, J=7.6 Hz, 2H, H-3'), 7.33 (d,
J=7.2 Hz, 1H, H-4'), 7.25 (d, J=8.8 Hz, 1H, H-3), 5.24 (s, 2H, CH2),
1.30 (s, 12H, 4 CH3). 13C NMR [(CD3)2CO, 100 MHz]; δ: 165.6
(C-2), 139.8 (C-6), 137.0 (C-4), 136.6 (C-1'), 128.2 (C-3'), 127.5
(C-4'), 126.6 (C-2'), 118.9 (CN), 113.1 (C-3), 102.9 (C-5), 83.7 [2C-
(CH3)2], 69.2 (CH2), 24.5 (4 CH3). Anal. calcd. for C20H22BNO3:
C, 71.66; H, 6.62; N, 4.18. Found: C, 71.66; H, 6.67; N, 4.08.
3-Benzyloxy-4-cyanophenyl-4,4,5,5-tetramethyl-
[1,3,2]dioxaborolane (12a)
Yield (1.0 g, 64%), mp 65–66°C. 1H NMR [(CD3)2CO, 400 MHz]; δ:
7.69 (d, J=8.0 Hz, 1H, H-5), 7.56 (d, 2H, J=8.0 Hz, C-6), 7.55 (s, 1H,
H-2), 7.46 (dd, J=8.0, 3.6, 2H, H-2'), 7.42 (t, J=7.6 Hz, 2H, H-3'),
7.37 (d, J=7.2 Hz, 1H, H-4'), 5.32 (s, 2H, CH2), 1.35 (s, 12H, 4 CH3).
13C NMR [(CD3)2CO, 100 MHz]; δ: 160.6 (C-2), 137.3 (C-1), 134.0
(C-5), 129.5 (C-3'), 129.0 (C-4'), 128.4 (C-2'), 128.0 (C-6), 119.0
(C-2), 116.8 (CN), 105.4 (C-4), 85.4 [2C-(CH3)2], 71.3 (CH2), 25.2
(4 CH3). Anal. calcd. for C20H22BNO3: C, 71.66; H, 6.62; N, 4.18.
Found: C, 71.87; H, 6.64; N, 4.20.
2-Benzyloxy-4-cyanophenyl-4,4,5,5-tetramethyl-
[1,3,2]dioxaborolane (12b)
Yield (1.2 g, 72%), mp 102–103°C. 1H NMR [(CD3)2CO, 400 MHz];
δ: 7.90 (d, J=8.4 Hz, 1H, C-6), 7.57 (d, J=7.2, 2H, H-2'), 7.50 (d,
J=7.2 Hz, 2H, H-3'), 7.48 (d, J=2.4 Hz, 1H, H-3), 7.41 (d, J=8.4 Hz,
1H, H-5), 7.37 (d, J=7.2 Hz, 1H, H-4'), 5.34 (s, 2H, CH2), 1.45 (s,
12H, 4 CH3). 13C NMR [(CD3)2CO, 100 MHz]; δ: 162.1 (C-2),
138.8 (C-1), 137.6 (C-5), 129.6 (C-3'), 129.1 (C-4'), 128.7 (C-2'),
120.7 (C-6), 119.9 (C-2), 119.8 (CN), 118.3 (C-4), 85.4 [2C-(CH3)2],
71.2 (CH2), 25.3 (4 CH3). Anal. calcd. for C20H22BNO3: C, 71.66;
H, 6.62; N, 4.18. Found: C, 71.93; H, 6.69; N, 4.26.
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Acknowledgements
This work was supported by an award from the Bill and Melinda
Gates Foundation. Serry A.A. El Bialy was supported by a Fulbright
Fellowship awarded by the Binational Fulbright Commission of
Egypt. We thank Dr. Kenneth Hardcastle, Emory University, X-ray
Crystallography Center, for obtaining the crystal structure.
Zhang, P.; Zou, M. -F.; Rodriguez, A. L.; Conn, P. J.; Newman, A.
H. Structure-activity relationships in a novel series of 7-substi-
tuted-arylquinolines and 5-substituted-aryl benzothiazoles at the
metabotropic glutamate receptor subtype 5. Bioorg. Med. Chem.
2010, 18, 3026–3035.

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