Convenient synthesis of substituted aryl cyanides and 1,1-dicyanobenzyl benzoate

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Convenient Synthesis of Substituted
Aryl Cyanides and 1,1-Dicyanobenzyl
Benzoate
Pavel Pazdera a , Jan Simbera a & Milan Dlouhy b
a Centre for Syntheses at Sustainable Conditions and their
Management, Masaryk University, Faculty of Science, Department of
Chemistry , Kotlarska 2, Brno, Czech Republic
b Lucebni Zavody Draslovka Co. Kolin , Havlickova 605, Kolin, Czech
Republic
Published online: 09 Jun 2011.
To cite this article: Pavel Pazdera , Jan Simbera & Milan Dlouhy (2011) Convenient Synthesis of
Substituted Aryl Cyanides and 1,1-Dicyanobenzyl Benzoate, Organic Preparations and Procedures
International: The New Journal for Organic Synthesis, 43:3, 285-291
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Organic Preparations and Procedures International, 43:285–291, 2011
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2011.582000
Convenient Synthesis of Substituted Aryl Cyanides
and 1,1-Dicyanobenzyl Benzoate
Pavel Pazdera,1 Jan Simbera,1 and Milan Dlouhy2
1Centre for Syntheses at Sustainable Conditions and their Management, Masaryk
University, Faculty of Science, Department of Chemistry, Kotlarska 2, Brno,
Czech Republic
2Lucebni Zavody Draslovka Co. Kolin, Havlickova 605 Kolin, Czech Republic
Various substituted derivatives of benzyl cyanide such as 2,4-dichlorobenzyl cyanide 2 are
important intermediates in the pharmaceutical industry (penicillin derivatives)1 and for the
generation of a number of substances such as herbicides and pesticides.2–4 Several patents
describe methods for the preparation of benzyl cyanides5 and the most frequently used
procedure for the preparation of 2,4-dichlorobenzyl cyanide (2), involving the reaction of
2,4-dichlorobenzyl chloride (1) with NaCN or KCN (Scheme 1), is based on the general
preparation of benzyl cyanides described in Organic Syntheses.6 The reaction is usually
performed in a mixture of water and ethanol under reflux. A given method differs only in
details (molar ratio of reactants, reaction time, isolation and purifying of products).
Cl
CN-
CN-
CN
Cl
Cl
Cl
Cl
Cl
CN
Cl
Cl
Cl
3
1
2
Scheme 1
Other methods7,8 still may be problematic because of long reaction times (8–20 hours)
even under reflux with large excess of alkali cyanide. Other authors9,10 tried to modify
the reaction conditions in order to decrease the large excess of cyanide, but only managed
to increase the yield from 65% up to 78%. Some improvements in the yield were noted
when the addition was performed in the presence of alkali iodide.11,12 In all methods,
the alkali cyanide is usually dissolved in water and the benzyl halide in methanol or
ethanol. To improve the yield (80–88%), some other solvents (DMF, DMSO) have been
Received October 15, 2010; in final form January 28, 2011.
Address correspondence to Pavel Pazdera, Centre for Syntheses at Sustainable Conditions and
their Management, Masaryk University, Faculty of Science, Department of Chemistry, Kotlarska 2,
CZ-61137 Brno, Czech Republic. E-mail: pazdera@chemi.muni.cz
285

286
Pazdera et al.
used, sometimes in combination with water.13–16 Another possible improvement is the
use of phase-transfer catalysis (PTC). The preparation of benzyl cyanides using quaternary
ammonium salt as a PTC catalyst has been patented by companies such as Bayer,17 Albright
& Wilson18 etc. but yields are strongly dependent on the PTC selected varying from 35%
to 97%. High yields were obtained also in the presence tetradecyltrimethylammonium or
tetradecyldimethylbenzylammonium chloride with an optional concentration of 40% of
cyanide in solution under reflux.19–21 The possible utility of so-called three-phase catalysis
(organic phase-aqueous phase-solid phase) was studied by Regen22 but yields (88–99%)
were strongly dependent on the catalyst selected and conditions. Methods of preparation of
solid catalyst and their application are also protected by several patents.23–25 Application
of ion-exchangers as catalysts for benzyl cyanides preparation from benzyl halides was
described by Sukata.26 In the case of benzyl chloride, the product was formed in yields of
7–71% depending on ion-exchanger used. In addition at 65◦C, longer reaction times are
required (6–24 hrs).
Crown-ethers as phase-transfer catalysts have been studied as well.27,28 Crown-ethers,
containing atom of silicon adjacent to carbon and oxygen, have been patented by Arkles29
and Ando30,31 but no significant improvements in yields were achieved. Yoshimura and
Tamura applied linear PEGs32 or polyoxyalkylenediethers33 as catalysts for the replacement
of halide by the cyano group. The most recent preparation of benzyl cyanides from benzyl
halides and alkali cyanides involves the use of ionic liquids34 but no outstanding benefit of
the ionic liquids was observed (yield max. 47%, room temperature, 16 h).
Carbanion formation from benzyl cyanides is possible in presence of alkali cyanides,
especially in the cases when the phenyl rings bears an electron-withdrawing group.
In these cases, a portion of the benzyl halide reacts with this carbanion to give
2,3-diarylpropanenitrile as a side-product (Scheme 1). Typically 2,3-(dichlorophenyl)-
propanenitrile (3) is obtained in presence of strong bases such as sodium hydride,35 LDA,36
n-BuLi,37 sodium amide38 at low temperatures in aprotic solvents. We now report modified
conditions for the selective formation of 2 and 3 from the same starting material under
the conditions of Finkelstein reaction (Scheme 1). In addition methanol was used as an
alternative solvent. Low solubility of sodium cyanide in methanol (in contrast with water)
is considered to be the greatest advantage because only a small amount of sodium cyanide
is present in the solution which is a good prevention of possible side-reactions caused by
the excess of cyanide in the reaction mixture. On the other hand finely powdered sodium
cyanide should be used to be dissolved readily as soon as cyanide in solution is consumed
by the reaction.
Acyl cyanides 5 (Scheme 2) are important in organic synthesis because they can be con-
verted to α-ketoacids,39 1-amino-2-ethanol derivatives40 and a wide range of heterocyclic
CN
CN-
CN-
Ph
C
OCOPh
PhCOCN
PhCOCl
CN
6
4
5
Scheme 2

Aryl Cyanides and 1,1-Dicyanobenzyl Benzoate
287
compounds.41 Aroyl cyanides are also important intermediates for the production of
herbicides.42 Furthermore substituted benzoyl cyanides are very often used as selective
benzoylating agents in peptide synthesis43 and are also used as excellent cyanobenzoylat-
ing reagents for aldehydes.44 The most commonly described method for the preparation
of benzoyl cyanides is the reaction of aroyl chlorides with sodium or potassium cyanide
in the presence of cuprous cyanide. There are also preparations of benzoyl cyanides by
reaction of stoichiometric amount of cuprous cyanide and benzoyl chloride in acetonitrile
or phenylacetonitrile at about 80◦C45 or without solvent at the temperatures about 220◦C.46
In addition, the synthesis of 5 by the reaction of equimolar amount of benzoyl chloride and
anhydrous hydrogen cyanide in pyridine47 gave yields of about 78%. With the use of PTC
(organic solvent–water), benzoyl chloride and alkali cyanide48 gave yields of only 60%.
Some other preparations of benzoyl cyanide have been described in several patents.49–53 In
the literature, there are also described many reactions for the preparation of 5 in different
solvents and with the application of ultrasound.54–59 The most used solvents are acetonitrile,
benzene, benzonitrile and salts such as LiCN and CuCN are used as a cyanide source. The
reactions proceed rather rapidly (2–3 h) and in reasonable yields (65–90%) but higher tem-
peratures are necessary (90–130◦C). Further are also described solid-liquid PTC systems
(S-L PTC) using copolymers (propylene-ethyleneglycol)60 and 18-crown-6-ethers.61,62 By
using three-phase transfer catalysis in the presence of Amberlite XAD-2 in benzene, very
low yields of 6 were obtained.63,64 Formation of 6 (Scheme 1) occurs mostly in aprotic
solvents (acetonitrile,58 benzene,63 etc.) in low yields. The formation of 6 may be viewed
as arising from attack of cyanide ion on benzoyl cyanide followed by benzoylation of the
resulting intermediate. Some derivatives of 6 are used for the preparation of malonic acid
derivatives.65,66 Very often these methods give mixtures of both products 5 and 6. By the
carefully selected conditions, we were able to devise procedures for the selective prepara-
tion of 5 and 6 (Scheme 2). The choice of the solvent is considered to be the most crucial
factor.
In conclusion, the methods reviewed in the introductory section of the present paper
reveal several disadvantages that led us to devise cleaner and simpler procedures for the
selective preparation of 2 and 3 in good yields. Similarly, simple and improved routes to
compounds 5 and 6 are also described.
Experimental Section
1H-NMR spectra were acquired on a Bruker Avance 500 MHz spectrometer. Chemical shifts
(δ) are reported in ppm. Melting points were determined on Boetius microscope with digital
thermometer and are not corrected. Gas chromatography was acquired at Shimadzu GC-
17A. Mass spectra were measured on GC-MS Trio 1000 (Fison Instruments) apparatus.
Comparison of all data with standard data from literature confirmed the identity of all
synthesized products. Starting materials were obtained from Fluka (2,4-dichlorobenzyl
chloride), Acros Organics (benzoyl chloride) and Lucebni zavody Draslovka a. s. Kolin
(sodium cyanide). The yields and mp. of the products are summarized in Table 1.
2,4-Dichlorobenzyl Cyanide (2)
To a solution of 13.76 g (0.071 mol) of 2,4-dichlorobenzyl chloride in 60 ml of methanol
was added 3.46 g (0.071 mol) of finely powdered sodium cyanide and 0.35 g (0.002 mol)

288
Pazdera et al.
Table 1
Prepared Cyano Compounds 2, 3, 5, 6
mp. (◦C)
Yield
(%)
Time
(hrs)
Product
Found
lit.
2
3
5
6
87
88
92
82
6
12
3
61–62
107–108
28–29
62–62.58
108–108.535
28–3171
1
96–98
98–9968
of sodium iodide. The reaction mixture was stirred at 50–52◦C for 6 h. The progress of the
reaction was monitored by GC (methanol). After this time, the separated sodium chloride
(4.07 g, 0.069 mol, 98%), was filtered off and rinsed with hot methanol (10 ml). The filtrate
was evaporated in vacuo and the residue was purified by vacuum distillation to afford 11.35 g
(87%) of pure 2,4-dichlorobenzyl cyanide, bp.140–142◦C/10 mm Hg. Upon cooling white
crystals, mp. 61–62◦C, lit.8 mp. 62–62.5◦C, were obtained. 1H-NMR (300 MHz, CDCl3):
δ 3.80 (s, 2H, -CH2-CN), 7.32–7.44 (m, 3H, ArH).
2,3-bis(2,4-Dichlorophenyl)propanenitrile (3)
A mixture of 1.95 g (0.01 mol) of 2,4-dichlorobenzyl chloride, 0.735 g (0.015 mol) of finely
powdered sodium cyanide, 75 mg (0.005 mol) sodium iodide and 100 mg (0,0005 mol)
of benzyltrimethylammonium chloride in 20 ml of acetone was stirred for 12 h at 25◦C.
After the reaction was completed (GC, acetone) the solvent was evaporated in vacuo and
the 1.80 g (96%) of yellowish crude product which was purified by crystallization from
2-propanol to give 3 (1.58 g, 88%) as a pale yellow solid, mp. 107–108◦C, lit.35 mp.
108–108.5◦C. 1H-NMR (300 MHz, CDCl3): δ 3.65–3.83 (m, 2H, -CH2-), 4.35–4.39 (m,
1H, -CH-CN), 7.11–7.71 (m, 6H, ArH).
Benzoyl Cyanide (5)
To a 250 ml flask equipped with reflux condenser and calcium chloride tube, 28.0 g (0.2 mol)
of pure benzoyl chloride, 80 ml of pure ethyl acetate were added followed by 10.78 g
(0.22 mol) of finely powdered sodium cyanide; the reaction mixture was refluxed for 3 h
under vigorous stirring. After this time, GC (no solvent) analysis showed about 6% of
unreacted benzoyl chloride. Therefore 0.8 g of sodium cyanide was added and the mixture
was refluxed another hour to complete the reaction. This is important because it is difficult to
separate unreacted benzoyl chloride from the benzoyl cyanide by distillation. After cooling,
the separated sodium chloride was removed by vacuum filtration and washed with 10 ml
of hot ethyl acetate. The solvent was then removed in vacuo and the residue was distilled
to afford 24.2 g (92%) of pure benzoyl cyanide, bp. 68–72◦C/4–5 mm Hg, mp. 28–29◦C,
lit.71 bp. 88◦C/13 mm Hg, mp. 28–31◦C. 1H-NMR72 (300 MHz, CDCl3): δ 7.24–7.84 (m,
3H, ArH), 8.00–8.67 (m, 2H, ArH).

Aryl Cyanides and 1,1-Dicyanobenzyl Benzoate
1,1-Dicyanobenzyl Benzoate (6)
289
A mixture of 18.5 g (0.13 mol) benzoyl chloride and 0.43 g Aliquat 336 in 100 ml of
toluene was added to a stirred and cooled (7–8◦C) aqueous solution of 4.9 g (0.1 mol) of
sodium cyanide and 1.35 g (0.03 mol) of sodium hydroxide in 500 ml of water (the purpose
of adding sodium hydroxide is to prevent acidification of the system as a result of benzoyl
chloride hydrolysis). The reaction mixture was stirred for 1 h at room temperature. Then
an aliquot part of the organic phase was analyzed by GC (toluene) and the presence of
benzoyl chloride was not detected. The organic phase was then separated and concentrated
HCl was added into aqueous residue until neutral pH. A pale yellow precipitate of 6
(16.6 g, 97%) containing 3.5% of benzoic acid was collected. Crystallization of the crude
product from ethyl acetate yielded the pure product (14.5 g, 82%) as white crystals, mp.
96–98◦C, lit.68 mp. 98–99◦C. MS [M/Z+, (Ir/%)]: 262 (5, M+), 141 (20, Ph-C+(CN)2), 105
1
(100, Ph-CO+), 77 (50, Ph+). H-NMR (300 MHz, CDCl3): δ 7.38–7.42 (m, 1H, ArH),
7.66–7.69 (m, 2H, ArH), 7.88–7.90 (m, 2H, ArH), 7.56–7.62 (m, 2H, ArH), 8.17–8.21
(m, 3H, ArH).
Acknowledgement
This workt was supported by the grant of Ministry of Education of the Czech Republic
(Grant No.CEZ: J07/98: 143100011) and Ministry of Industry and Trade of the Czech
Republic (Grant No.2A-1TP/ 09).
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