A Convenient Synthesis of 2-Acylphenylacetonitriles

Article abstract of DOI:10.1081/SCC-120027705

The reaction of 2-cyanomethylbenzoyl chloride with Grignard reagents in the presence of cuprous iodide at -5°C easily affords 2-acylphenylacetonitriles with good yield.

Full text of DOI:10.1081/SCC-120027705

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A Convenient Synthesis of 2‐Acylphenylacetonitriles
Alicia S. Cánepa a & Rodolfo D. Bravo a
a Laboratorio de Estudio de Compuestos Orgánicos, Departamento de Química, Facultad
de Ciencias Exactas , Universidad Nacional de La Plata , Calle 47 y 115, 1900, La Plata,
Argentina
Published online: 16 Aug 2006.
To cite this article: Alicia S. Cánepa & Rodolfo D. Bravo (2004) A Convenient Synthesis of 2‐Acylphenylacetonitriles,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:4,
579-588, DOI: 10.1081/SCC-120027705
To link to this article: http://dx.doi.org/10.1081/SCC-120027705
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 4, pp. 579–588, 2004
A Convenient Synthesis of
2-Acylphenylacetonitriles
*
´
Alicia S. Canepa and Rodolfo D. Bravo
´
Laboratorio de Estudio de Compuestos Organicos, Departamento de
´
Quımica, Facultad de Ciencias Exactas, Universidad Nacional de
La Plata, La Plata, Argentina
ABSTRACT
The reaction of 2-cyanomethylbenzoyl chloride with Grignard reagents in
the presence of cuprous iodide at 258C easily affords 2-acylphenyl-
acetonitriles with good yield.
Key Words: 2-Acylphenylacetonitriles; Ketones; Grignard reagents;
2-Cyanomethylbenzoyl chloride.
The 2-acylphenylacetonitriles (7) are useful compounds in the syn-
thesis of heterocyclic compounds such as 3(2H)-isoquinolinones[1–3] and
*
Correspondence: Rodolfo D. Bravo, Laboratorio de Estudio de Compuestos
´
´
Organicos, Departamento de Quımica, Facultad de Ciencias Exactas, Universidad
Nacional de La Plata, Calle 47 y 115, 1900-La Plata, Argentina; E-mail: rdb@exactas.
unlp.edu.ar.
579
DOI: 10.1081/SCC-120027705
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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Canepa and Bravo
580
Scheme 1.
3-aminoisoquinolines.[4] Only few examples for the synthesis of 2-
acylphenylacetonitriles are reported in the literature.[5–7] One of the possible
methods for their preparation is the Friedel–Crafts acylation of aromatic
compounds, but this reaction is limited by problems associated with the
control of substituent orientation. For example, the reaction of 2,4-dichloro-
benzoylchloride and 3,5-dimethoxyphenylacetonitrile afforded a mixture of 2-
and 4-(2,4-dichlorobenzoyl)-3,5-dimethoxyphenylacetonitrile.[3]
In this work we described the synthesis of 2-acylphenylacetonitriles (7),
in which the last step is the reaction between 2-cyanomethylbenzoyl chloride
(5) and Grignard reagents (6) (Sch. 1).
One of the best known methods for the preparation of ketones involves the
reaction of acid chlorides and Grignard reagents. All methods face the issue of a
second addition of the Grignard reagents to the carbonyl leading to the forma-
tion of tertiary alcohols. For example, the use of low temperature (2788C),[8,9]
addition of hexamethylphosphorotriamide (HMPT)[10] or transition metal com-
and CuI[12] have been used to avoid the undesired
[11]
pounds such as FeCl3
di-addition reaction. The order of addition of the reagents was also studied.[13]
The starting 2-cyanomethylbenzoyl chloride (5) was synthesized from
ethyl-2-methylbenzoate (1) in 4 steps (Sch. 2).
The literature method to prepare 4 involves the use of phthalide and KCN,
but this method produced a less pure compound, which can be purified by
crystallization but with a high loss of material.[14] Due to this problem we
decided to use the sequence shown in Sch. 2. Benzoate 1 was brominated with
NBS to afford bromomethylbenzoate 2.[15] The cyanation of 2 produced the
cyanomethylbenzoate 3, which, by hydrolysis in alkaline medium, afforded
the 2-cyanomethylbenzoic acid (4).
The best results in the synthesis of 2-acylphenylacetonitriles (7) were
obtained with 2-cyanomethylbenzoyl chloride (5) of high purity. Thus, the
preparation of this compound from 2-cyanomethylbenzoic acid (4) and PCl5
reported in the literature[16,17] was changed. The reaction was carried out at
08C instead of room temperature, to give 5 in better yield and purity. These
conditions avoided the formation of 3-chloro-1-isoquinolinol by intramole-
cular cyclization of 5.

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Synthesis of 2-Acylphenylacetonitriles
581
Scheme 2.
Four procedures for the reaction of 5 with Grignard reagents were tested:
at low temperature (2788C) (procedure A), with addition of HMPT at room
temperature (procedure B) and at 258C (procedure C), or addition of CuI at
258C (procedure D). The yields of 7a–7f are summarized in Table 1. In all
cases inverse addition was used. In the procedures A–C, excess of acid
chloride 5 was employed.
The best results were obtained using one equivalent of CuI at 258C
(procedure D). After the addition was completed, this temperature was
maintained for one hour and then the mixture was allowed to warm to room
temperature. Hydrolysis followed by extraction with ethyl ether afforded
Table 1. Comparative yields of the synthesis of 2-acylphenylacetonitriles 7.
Yield (%)
Compound (7)
RX (6)
Method A Method B Method C Method D
7a
7b
7c
7d
7e
7f
C2H5I
9
11
32
31
6
7
6
11
9
69
61
65
66
63
59
(CH3)2CHBr
C6H5CH2Cl
C6H5Br
27
29
9
30
31
11
11
4-ClC6H4Br
4-CH3C6H4Br
8
8
Notes: Method A: 2788C to room temperature. Method B: HMPT, room temperature.
Method C: HMPT, 258C to room temperature. Method D: CuI, 258C to room
temperature.

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Table 2. Melting points and elemental analysis of 2-acylphenylacetonitriles 7.
Elemental analysis
Found
H
Calculated
H N
Product
(7)
Mp
(8C)
Formula
(MW)
C
N
C
7a
7b
7c
7d
7e
7f
61–2
(EtOH)
—
C11H11ON
(173.21)
76.15 6.40 7.95 76.15 6.35 8.08
76.97 7.06 7.49 77.02 6.94 7.48
81.52 5.66 5.91 81.72 5.53 5.95
81.61 5.06 6.34 81.61 5.01 6.33
C12H13NO
(187.23)
81–81.5
(EtOH)
—
C16H13NO
(235.27)
C15H11NO
(221.24)
82.5–83
(EtOH)
79–80
C15H10NOCl 70.46 4.02 5.30 70.48 3.91 5.48
(255.69)
C16N13NO
(235.28)
81.47 5.62 5.89 81.68 5.57 5.95
(EtOH)
crude product, which was purified by column chromatography. The yields did
not improve by using higher quantities of CuI or acid chloride. The addition of
Grignard reagents (6) to the 2-cyanomethylbenzoyl chloride (5) in the absence
of CuI, even at low temperature (2788C), or with the addition of HMPT
afforded high quantities (70–80%) of the tertiary alcohols.
1
The products were identified using IR, H NMR, 13C NMR, MS and
elemental analysis. The data are collected in Tables 2 and 3.
In summary, the use of CuI in the synthesis of ketones by reaction of
benzoyl chloride 5 and Grignard reagents 6 provides a convenient method to
obtain 2-acylphenylacetonitriles (7).
We can conclude that the described method is suitable for the preparation
of the ketones in the presence of a relatively acidic methylene group adjacent
to both a nitrile and aryl group.
EXPERIMENTAL
All reactions sensitive to moisture and air were performed under an inert
atmosphere of Ar. Thin layer chromatography was performed on Merck pre-
coated silica gel 60 F254 plates and column chromatography was carried out
using silica gel (Merck 60, 230–400 mesh). All reagents were of commercial

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Synthesis of 2-Acylphenylacetonitriles
583
d
d

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Canepa and Bravo
584
d
d

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Synthesis of 2-Acylphenylacetonitriles
585
quality or were purified before use; the solvents were dried by means of
standard methods. Cuprous iodide was dried at 608C under reduced pressure
(1 mbar) for 4 h. Grignard reagents 6 were prepared in THF by means of
standard methods. Melting points were determined with a Bu¨chi apparatus.
FT-IR spectra were recorded on a Perkin Elmer 1600 infrared spectrometer,
NMR spectra were recorded on a Brucker AC 250 spectrometer and were
reported in ppm downfield from TMS employed as an internal standard (d).
The mass spectra were recorded in a Finnigan Model 4500 Mass spectrometer.
Elemental analysis was carried out at the Institut fu¨r Organische Chemie of the
Stuttgart University.
Ethyl 2-Methylbenzoate (1)
Compound 1 was prepared from 2-methylbenzoic acid, absolute EtOH
and concentrated H2SO4 according to the literature method.[15] The product
was purified by distillation at 578C (0.3 mbar); yield: 74.6 g (89%), (lit.[15] bp
568C, 0.3 mbar).
Ethyl 2-(Bromomethyl)benzoate (2)
Compound 2 was prepared from ethyl 2-methylbenzoate 1 for benzylic
bromination with NBS according to the literature method in 84% yield after
distillation at 91–958C (0.2 mbar), (lit.[15] bp 90–958C, 0.2 mbar).
2-(Cyanomethyl)ethylbenzoate (3)
To a stirred solution of 2 (121.45 g, 0.50 mol) in EtOH (625 mL) was
added a solution of KCN (32.5.3 g, 0.50 mol) in H2O (70 mL). The reaction
mixture was refluxed for 4 h, cooled to r.t. and the solid was removed by
filtration. The resulting solution was evaporated and the residue was poured
onto H2O (230 mL). The organic layer was separated, the aqueous layer was
extracted with CHCl3 (2 ꢀ 80 mL), and the combined organic layers were
washed with H2O (4 ꢀ 80 mL), 5% HNaCO3 (80 mL) and H2O (80 mL). The
extracts were dried (Na2SO4), concentrated and purified by distillation; yield:
74.65 g (79%); bp 119–1208C (1 mbar) (lit.[18] bp 1188C, 1 mbar).

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Canepa and Bravo
586
2-(Cyanomethyl)benzoic acid (4)
To an aqueous solution of 1 N NaOH (400 mL, 0.40 eq) 2-(cyano-
methyl)ethylbenzoate 3 (73.71 gr, 0.39 mol) was added. The mixture was
stirred vigorously for 5 h at 408C. The solution obtained was cooled at 58C and
acidified with 37% HCl (72 mL). The white solid precipitate was filtered,
washed with cold water and dried in vacuo at 408C; yield: 59.02 g (94%); mp
117–1188C (lit.[14] mp 113–1148C). Spectral data (1H-NMR, IR, MS) were
identical with a sample obtained with a reported method.[14]
2-(Cyanomethyl)benzoyl chloride (5)
To a stirred solution of 4 (8.05 g, 50.0 g) in dry Et2O (350 mL), PCl5
(10.91 g, 52.5 mmol) was added at 0–28C. The reaction was stirred at this
temperature for 7 h. The solvent and POCl3 were removed in vacuo and the
crude product (mp: 48–508C) was purified by flash chromatography (CH2Cl2)
to give a white solid, yield: 8.1 g (90%); mp 55–55.58C.
1H-RMN (CDCl3) d ¼ 4.12 (s, 2 H, CH2–CN), 7.37–7.64 (m, 3 H, H-4,
H-5, H-6), 8.38 (d, 1 H, J ¼ 7.5, H-3).
2-Acylphenylacetonitriles (7); General Procedure A
To a stirred solution of 2-(cyanomethyl)benzoylchloride 5 (718 mg,
4.0 mmol) in THF (4 mL) was added dropwise over about 0.5 h a THF solution
of Grignard reagent (1 M, 2 mL, 2.0 mmol) at 2788C. The mixture was
allowed to warm to r.t. followed by hydrolysis with 5% HCl (5 mL). The
aqueous layer was extracted with Et2O (2 ꢀ 2 mL), the combined organic
extracts were washed with H2O (2 mL), 5% HNaCO3 (2 mL) and H2O (2 mL).
The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue
was purified by column chromatography (toluene/chloroform 80 : 20) to give
7a–7f (Table 1).
General Procedure B
To a stirred solution of 2-(cyanomethyl)benzoylchloride 5 (718 mg,
4.0 mmol) in THF (4 mL) was added dropwise over about 0.5 h a mixture of
solution of Grignard reagent in THF (1 M, 2 mL, 2.0 mmol) and HMPT (1.08 mL,
6.0 mmol) at room temperature. The mixture was stirred for 1 h followed by
hydrolysis. Work up as described above gave the products 7a–7f (Table 1).

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Synthesis of 2-Acylphenylacetonitriles
587
General Procedure C
The solution of 5 in THF at 258C, was treated in the same manner as
described in General Procedure B.
General Procedure D
To a stirred suspension of CuI (950 mg, 5.0 mmol) in dry THF (15 mL)
was added a solution of 2-(cyanomethyl)benzoylchloride 5 (898 mg,
5.0 mmol) in THF (15 mL). The reaction mixture was cooled at 258C and a
solution of Grignard Reagent 6 (1 M, 5 mL, 5.0 mmol) was added during 1 h.
After being stirred for 1 h, the mixture was allowed to warm to r.t. followed by
hydrolysis with 5% HCl (10 mL). The aqueous layer was extracted with Et2O
(3 ꢀ 3 mL). The combined organic extracts were washed with H2O, dried
(Na2SO4) and concentrated in vacuo. The residue was purified in the same
manner as described above to give 7a–7f (Table 1).
ACKNOWLEDGMENT
The authors wish to thank CICBA for financial support and Dr. P. Colinas
for valuable discussions.
REFERENCES
1. Lu, Q.; Bovonsombat, P.; Agosta, W. Novel photochemical hydrolysis
of o-acetylphenylacetonitriles to amides. J. Org. Chem. 1996, 61,
3729–3732.
2. Lu, Q.; Bovonsombat, P.; Agosta, W. Photochemical hydrolysis of
o-acetylphenylacetonitriles. Tetrahedron Lett. 1995, 36, 8941–8944.
3. Broadhurst, M.; Hassall, C.; Thomas, G. Tetracycline studies. Part 5. New
syntheses of anthracenes and anthraquinones through benzophenone
carbanions. J. Chem. Soc. Perkin 1977, 1, 2502–2512.
4. Zdrojewski, T.; Jonczyk, A. A general approach to 3-aminoisoquinoline,
its N-mono- and N, N-disubstituted derivates. Tetrahedron 1995, 51 (45),
12439–12444.
5. Watt, D.S. A reiterative functionalization of unactivated carbon–hydro-
gen bonds. Photolysis of a-peracetoxynitriles. J. Am. Chem. Soc. 1976,
98, 271–273.

ORDER
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´
Canepa and Bravo
588
6. Freerksen, R.; Pabst, W.E.; Raggio, M.L.; Sherman, S.A.; Wroble, R.R.;
Watt, D.S. Photolysis of a-peracetoxynitriles. 2. A comparison of two
synthetic approaches to 18-cyano-20-ketosteroids. J. Am. Chem. Soc.
1977, 99, 1536–1541.
7. Jonczyk, A.; Lipiak, D.; Sienkiewicz, K. New [1,4] sigmatropic re-
arrangement of ammonium benzylides: synthesis of ortho-cyanomethyl-
substitutedaromaticaldehydes. Synlett 1991, 7, 493–496.
8. Sato, F.; Inoue, M.; Oguro, K.; Sato, M. Preparation of ketones by direct
reaction of Grignard reagents with acid chlorides in tetrahydrofuran.
Tetrahedron Lett. 1979, 44, 4303–4306.
9. Forbes, C.P.; Wenteler, G.L.; Wiechers, A. An improved method for the
use of acetal-substituted Grignard reagents in organic synthesis. J. Chem.
Soc. Perkin 1977, 1, 2353–2355.
´ ´ ´
10. Fauvarque, J.; Ducom, J.; Fauvarque, J.F. Proprietes des organomagne-
´
siens dans l’hexamethylphosphorotriamide (HMPT). Action sur quelques
´
composes trivalents. Comptes Rendus 1972, Serie C, 511–514.
11. Cason, J.; Kraus, K. Mechanism of the reactions of Grignard reagents and
organocadmiun reagents with acid chlorides in presence of ferric chloride.
J. Org. Chem. 1961, 26, 1772–1779.
´
12. Dubois, J.; Boussu, M. Condensation chlorure d’acide–organomagnesien
´
´ ´
en presence d’halogenure cuivreux: competition des reations hetero-
´
´ ´ ´
lytique et homolytique. Synthese de cetones aliphatiques ramifiees.
Tetrahedron 1973, 29, 3943–3557.
13. Dubois, J.E.; Boussu, M.; Lion, C. Investigation of optimal conditions for
the synthesis of hindered aliphatic ketones. Catalytic orientation of the
condensation of Rli or RMgX-R’COCl by cuprous halides. Tetrahedron
Lett. 1971, 12, 829–832.
14. Price, C.C.; Rogers, R.G. o-Carboxiphenylacetonitrile. Organic Synthesis
Collective 1960, 3, 174–175.
15. Anzalone, L.; Hirsch, J. Substituent effects on hydrogenation of aromatic
rings: hydrogenation vs. hydrogenolysis in cyclic analogues of benzyl
ethers. J. Org. Chem. 1985, 50, 2128–2132.
16. Gompper, R.; Kutter, E.; Kast, H. Stable of o-quinodimethanes. Angew.
Chem. Int. Ed. 1967, 6, 171–172.
17. Yanagida, S.; Komori, S. The reaction of nitriles with acyl chlorides in the
presence of hydrogen chloride. Synthesis 1973, 4, 189–202.
18. Price, C.C.; Lewis, F.M.; Meister, M. Grignard reagent—homophthalic
anhydride reaction. J. Am. Chem. Soc. 1939, 61, 2760–2762.
Received in the USA August 14, 2003

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