Synthesis of Benzyloxybromobenzonitriles

Article abstract of DOI:10.1081/SCC-120028347

The synthesis of four new benzyloxybromobenzonitriles including: 2-benzyloxy-4-bromobenzonitrile (3), 3-benzyloxy-4-bromobenzonitrile (7), 5-benzyloxy-2-bromobenzonitrile (11) and 3-benzyloxy-2-bromobenzonitrile (12) is reported.

Full text of DOI:10.1081/SCC-120028347

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 5, pp. 751–758, 2004
Synthesis of Benzyloxybromobenzonitriles
Mohamed A. Ismail, Mariappan Anbazhagan,
*
Chad E. Stephens, and David W. Boykin
Department of Chemistry, Georgia State University, Atlanta,
Georgia, USA
ABSTRACT
The synthesis of four new benzyloxybromobenzonitriles including:
2-benzyloxy-4-bromobenzonitrile (3), 3-benzyloxy-4-bromobenzonitrile
(7), 5-benzyloxy-2-bromobenzonitrile (11) and 3-benzyloxy-2-bromo-
benzonitrile (12) is reported.
Key Words: Aromatic bromination; Benzylation; Benzyloxybromo-
benzonitriles; NOE; Nucleophilic displacement.
INTRODUCTION
As part of an anti-infective drug discovery research program we needed
to synthesize several different triaryl systems consisting of one or more
*
Correspondence: David W. Boykin, Department of Chemistry, Georgia State
University, University Plaza, Atlanta, GA 30303-3083, USA; E-mail: dboykin@
gsu.edu.
751
DOI: 10.1081/SCC-120028347
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Ismail et al.
hydroxy-substituted benzamidine groups. As these benzamidine-based triaryl
systems are typically prepared by palladium-catalyzed Stille or Suzuki coup-
lings with a substituted bromobenzonitrile, we required hydroxy-protected
bromocyanophenols as precursors.[1,2] Following construction of the triaryl
framework, the nitrile group is typically converted to the amidine via reduc-
tion of the intermediate amidoxime.[3–6] Consequently, it seemed advanta-
geous to use a hydroxy protecting group during the aryl couplings which could
potentially be removed simultaneously during amidine formation. We
therefore decided to explore the use of benzyl-protected bromocyanophenols.
A survey revealed that 4-benzyloxy-3-bromobenzonitrile is the only isomer
that has been previously reported, and it appeared in the patent literature.[7]
This report describes the synthesis and characterization of four new isomeric
benzyloxybromobenzonitriles.
RESULTS
The synthesis of 2-benzyloxy-4-bromobenzonitrile is achieved in two
steps starting from 2-fluoro-4-bromobenzonitrile (1) as outlined in Sch. 1. The
key step in this approach employs displacement of flouride under mild
conditions using 2-(methylsulfonyl)ethoxide followed by elimination of
vinylmethylsulfone.[8] Conventional alkylation of the bromophenol 2 with
benzyl chloride gives the corresponding benzyloxy compound 3.
The approach used to prepare 3-benzyloxy-4-bromobenzonitrile is
presented in Sch. 2. Alkylation of the known 2-bromo-3-hydroxybenzoic
acid (4) with benzyl chloride gives the corresponding benzyloxy benzoic acid
5 in good yield. The carboxylic acid 5 is converted into the amide 6, which is
readily dehydrated to form the nitrile 7 using trifluoroacetic anhydride in the
presence of dry pyridine. In contrast, attempted dehydration of 6 by heating
neat in phosphorous oxychloride gives no extractable product.
Scheme 1. Reagents and conditions. (a) 2-(Methylsulfonyl)ethanol, NaH, DMF;
(b) benzyl chloride, K2CO3, acetone–water (1 : 1).

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753
Scheme 2. Reagents and conditions. (a) Benzyl chloride, K2CO3, acetone–water;
(b) NaOH, water; (c) SOCl2; (d) NH4OH; (e) (CF3CO)2O, pyridine.
Scheme 3 outlines the route used to prepare 5-benzyloxy-2-bromobenzo-
nitrile and 3-benzyloxy-2-bromobenzonitrile. In this approach, bromination of
3-hydroxybenzonitrile (8) yields a mixture of 2-bromo-5-hydroxybenzonitrile
(9) and 2-bromo-3-hydroxybenzonitrile (10) which could not be readily
separated. Alkylation of the mixture of phenols with benzyl chloride gives a
mixture of the benzyloxy analogs 11 and 12, which were more readily
separated by column chromatography. The structures of 11 and 12 were
assigned based upon proton NMR results and the lack of identity of either
compound with 7. The lack of identity with 7 leaves three possible structures
for the two products. Based upon reactivity considerations the least likely
structure for a product of bromination followed by alkylation is 5-benzyloxy-
3-bromobenzonitrile. In addition, the proton NMR spectrum for the benzo-
nitrile ring of the later compound should show only meta coupling with no J
value greater than approximately 2 Hz. Instead, both isolated compounds
show signals with at least one J value in the 8 Hz range thus eliminating this
structure from consideration. An NOE experiment with 11 showed enhance-
ment to each of the two protons ortho to the benzyloxy group on irradiation of
the methylene signal at 5.07 ppm, which is consistent with the structure
assigned. The assignment of the structure to 12 is made by the process of
elimination.
In conclusion, we have described straightforward synthetic approaches
for four new benzyloxybromobenzonitriles, 4-bromo-2-benzyloxybenzonitrile
(3), 4-bromo-3-benzyloxybenzonitrile (7), 2-bromo-5-benzyloxybenzonitrile
Scheme 3. Reagents and conditions. (a) Br2/AcOH; (b) benzyl chloride, K2CO3,
acetone–water.

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Ismail et al.
(11) and 2-bromo-3-benzyloxybenzonitrile (12), from readily available
starting materials. The use of these analogs in the synthesis of triaryl
hydroxybenzamidines will be reported in due course.
EXPERIMENTAL
General
Melting points were recorded using a Melt-Temp apparatus and are
uncorrected. 1H-NMR and 13C-NMR spectra were obtained on a Varian þ300
and a VXR 400 spectrometer, chemical shifts (d) are in ppm relative to TMS,
and coupling constants (J) are in hertz. Mass spectra were obtained from the
Georgia Institute of Technology, Atlanta, GA. Elemental analyses were per-
formed by Atlantic Microlab Inc., Norcross, GA. All chemicals and solvents
were purchased from Aldrich Co. or Fisher Scientific. All solvents were
reagent grade.
4-Bromo-2-hydroxybenzonitrile (2)
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 08C. Sodium hydride (720 mg,
30 mmol) was added and the reaction mixture allowed to warm to room
temperature. The mixture was quenched with a 1N HCl solution and
extracted three times with ethyl acetate. The combined EtOAc was washed
with water, brine and dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure. The crude product was purified by
column chromatography using 30% ethyl acetate in hexanes. Yield: 1.68 g
(85%). mp 162.1–162.78C (ethanol); dH (DMSO, 300 MHz) 6.91 (d, 1H, J
4.8 Hz, H), 7.09 (s, 1H,), 7.22 (d, 1H, J 4.8 Hz, H), 10.89 (s, 1H, OH); dC
(DMSO, 300 MHz) 97.8, 115.4, 118.6, 121.7, 127.1, 132.9, 159.9. Anal.
Calcd. for C7H4BrNO: C, 42.42, H, 2.02, N, 7.07. Found: C, 42.25, H,
2.17, N, 6.90.
4-Bromo-2-benzyloxybenzonitrile (3)
2-Hydroxy-4-bromobenzonitrile (990 mg, 5 mmol) was dissolved in 1 : 1
mixture of acetone and water (10 mL). To this solution potassium carbonate
(828 mg, 6 mmol) and benzyl chloride (759 mg, 6 mmol) was added and the

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755
mixture was heated at 408C for 3 h (TLC indicated consumption of the
phenol). The reaction mixture was cooled and extracted with ethyl acetate,
dried over sodium sulfate and concentrated and the crude mixture was purified
by flash column chromatography (10% EtOAc-hexanes) to yield 1.29 g (90%)
of 2-benzyloxy-4-bromobenzonitrile. mp 105.38C (ether); dH (CDCl3,
300 MHz) 5.18 (s, 2H), 7.18 (m, 2H), 7.40 (m, 6H). dC (DMSO, 300 MHz)
71.0, 101.5, 115.7, 116.7, 124.5, 127.1, 128.5, 128.7, 128.8, 134.5, 134.8,
160.6. Anal. Calcd. For C14H10BrNO: C, 58.36, H, 3.50, N, 4.86. Found: C,
58.45, H, 3.37, N, 4.85.
4-Bromo-3-benzyloxybenzoic acid (5)
A mixture of 4-bromo-3-hydroxybenzoic acid[9] (3.52 g, 16.2 mmol),
benzyl chloride (4.48 g, 35.4 mmol), and potassium carbonate (4.88 g,
35.3 mmol) in acetone (60 ml) and water (20 ml) was heated at reflux for 3
days. The mixture was partially concentrated in vacuo to remove acetone,
diluted with NaOH (4N, 20 mL) and dioxane (5 mL), and heated at gentle
reflux overnight. The solution was then diluted with water and extracted with
an ether/ethyl acetate (1 : 1) mixture. The aqueous layer was acidified (con.
HCl/ice) to give a precipitate, which was filtered and rinsed with water.
Recrystallization of the product from EtOH/water gave a light tan crystalline
1
solid (3.49 g, 70%), mp 196–196.58C (lit. mp[10] 196–1988C). H NMR
(DMSO-d6): d 5.28 (s, 2H), 7.33–7.54 (m, 6H), 7.64 (d, J ¼ 1.8 Hz, 1H),
7.72–7.75 (dd, J ¼ 8.1, 1.8 Hz, 1H).
4-Bromo-3-benzyloxybenzamide (6)
A mixture of the corresponding benzoic acid (4.0 g, 13 mmol) and thionyl
chloride (ꢀ10 mL) was heated at reflux until a solution was obtained (1–2 hr).
The thionyl chloride was then removed in vacuo and the residue was dissolved
in dioxane (20 ml). With stirring, this solution was treated with NH4OH
(30 ml) to give almost immediately a thick precipitate. After 30 min, the
suspension was poured over ice water and the off-white/tan solid was col-
lected, rinsed with water, and air dried. Yield: 4.0 g, quantitative. Recrystal-
lization of a sample from EtOH/water gave a white fluffy solid, mp 182–
1838C. 1H NMR (DMSO-d6): d 5.25 (s, 2H), 7.30–7.50 (m, 6H), 7.66
(d, J ¼ 1.5 Hz, 1H), 7.68 (d, J ¼ 8.0 Hz, 1H), 8.04 (br s, NH2). IR (cm21):
3409, 3354, 3286, 3228, 3033, 2954, 2888, 1674 (w), 1655 (s), 1610, 1568,
1423, 1374, 1253, 1034, 1000, 766. MS (m/z, rel.int.); 305 (Mþ, 10), 91 (100),

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Ismail et al.
65 (25). High resolution mass calcd. for C14H12BrNO2: 305.00514. Observed
305.00505.
4-Bromo-3-benzyloxybenzonitrile (7)
To a chilled suspension of the corresponding benzamide (12.0 g,
39.2 mmol) and dry pyridine (6.21 g, 78.5 mmol) in dioxane (150 mL) was
added trifluoroacetic anhydride (10 g, 47.6 mmol) portionwise over 10 min
and the mixture was stirred at room-temperature for 3 hr. The resulting
solution was diluted with excess water and ice to give a white/pink solid,
which was collected, rinsed with water, and air dried. Purification by
chromatography (silica gel) eluting with a gradient of 0–20% ether in hexanes
gave the title benzonitrile as a colorless crystalline solid, mp 113.5–1148C. 1H
NMR (CDCl3): d 5.19 (s, 2H), 7.12–7.15 (m, 2H), 7.35–7.48 (m, 5H), 7.67
(d, J ¼ 8.4 Hz, 1H). Irradiation of the methylene singlet at 5.19 ppm resulted
in a strong NOE enhancement of one half of the multiplet at 7.12–7.15 (H at
2-position), thus confirming the position of the bromine as assigned. 13C NMR
(DMSO-d6): d 70.6, 111.5, 117.0, 117.6, 118.2, 125.9, 127.5, 128.1, 128.6,
134.2, 135.9, 154.9. IR (cm21): 3093, 3066, 3033, 2230, 1587, 1481, 1408,
1291, 1006, 723, 693. Anal. calcd. for C14H10BrNO: C, 58.36; H, 3.50. Found.
C, 58.45; H, 3.44.
2-Bromo-5-benzyloxybenzonitrile (9) and
2-Bromo-3-benzyloxybenzonitrile (10)
To a solution of 3-hydroxy-benzonitrile (8.33 g, 70 mmol) in acetic acid
(80 mL) was dropwise added bromine (11.06 g). The reaction mixture was
stirred overnight and treated with sodium thiosulfate (aq.) to remove any
remaining bromine. The excess solvent was removed under reduced pressure
and dilute with water to afford 9 g of a white solid (a mixture of two products 9
and 10, TLC very close Rf). A mixture of 9 and 10 (1.96 g, 10 mmol), benzyl
chloride (1.4 g, 11 mmol), and potassium carbonate (1.52 g, 11 mmol) in
acetone (50 ml) and water (2 ml) was heated at reflux for 24 hr. The reaction
mixture was filtered, the filterate was evaporated and the residue was extracted
from aqueous solution by using EtOAc (150 mL Â 3 times). The solvent was
evaporated and the residue (a mixture of 11 and 12) was chromatographed on
silica gel by using a gradient of 0–30% ether in hexanes to give 5-benzyloxy-
2-bromo-benzonitrile (11) followed by 3-benzyloxy-2-bromo-benzonitrile
(12).

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2-Bromo-5-benzyloxybenzonitrile (11)
757
Yield 42%, mp 101–101.58C (hexanes/ether). 1H NMR (CDCl3): d 5.07
(s, 2H), 7.06 (dd, J ¼ 8.7, 2.7 Hz, 1H), 7.22 (d, J ¼ 2.7 Hz, 1H), 7.36–7.43
(m, 5H), 7.53 (d, J ¼ 8.7 Hz, 1H). Irradiation of the methylene singlet at
5.07 ppm resulted in a strong NOE enhancement of the doublet of doublets at
7.06 (H at 4-position) and doublet at 7.22 (H at 6-position), thus confirming
the position of the bromine as assigned. 13C NMR (CDCl3): d 70.7, 115.9,
116.3, 117.0, 119.9, 121.6, 127.4, 128.5, 128.8, 134.0, 135.4, 157.7. IR
(cm21): 3092, 3069, 3033, 2233, 1591, 1474, 1460, 1396, 1320, 1244, 1004,
756, 696. Calcd. for C14H10BrNO: C, 58.36; H, 3.50. Found. C, 58.70; H, 3.51.
2-Bromo-3-benzyloxybenzonitrile (12)
1
Yield 27%, mp 93.5–948C (hexanes/ether). H NMR (CDCl3): d 5.20
(s, 2H), 7.13 (d, J ¼ 8.1 Hz, 1H), 7.25–7.46 (m, 7H). 13C NMR (CDCl3): d
71.1, 115.8, 117.1, 117.2, 117.4, 126.1, 126.9, 128.3, 128.7, 135.4, 155.8. IR
(cm21): 3066, 3030, 2233, 1585, 1565, 1464, 1389, 1283, 1081, 1061, 783,
692. MS (m/z, rel.int.); 287 (Mþ, 10), 168 (5), 91 (100), 65 (20). High
resolution mass calcd. for C14H10BrNO: 286.994. Observed 286.992. Anal.
calcd. for C14H10BrNO: C, 58.36; H, 3.50. Found. C, 58.00; H, 3.48.
ACKNOWLEDGMENT
This work was supported by NIH Grants GM-61587 and NIAID
AI-46365 and an award from the Bill and Melinda Gates Foundation.
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Received in the USA August 7, 2003

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