A new method for the synthesis of N-benzylamides

Article abstract of DOI:10.1081/SCC-120006004

Benzyl amides are obtained from benzyl chlorides with excellent yields in mild conditions by using hydrated ferric chloride, FeCl₃·6H₂O, as Lewis acid catalyst and common nitriles as both solvents and reagents.

Full text of DOI:10.1081/SCC-120006004

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A NEW METHOD FOR THE SYNTHESIS OF N-
BENZYLAMIDES
H. R. F. Karabulut a & M. Kacan b
a Science and Literature Faculty , Department of Chemistry , Trakya University , Edirne,
22030, Turkey
b Science and Literature Faculty , Department of Chemistry , Trakya University , Edirne,
22030, Turkey
Published online: 16 Aug 2006.
To cite this article: H. R. F. Karabulut & M. Kacan (2002) A NEW METHOD FOR THE SYNTHESIS OF N-BENZYLAMIDES, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:15, 2345-2348, DOI:
10.1081/SCC-120006004
To link to this article: http://dx.doi.org/10.1081/SCC-120006004
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 15, pp. 2345–2348, 2002
A NEW METHOD FOR THE SYNTHESIS
OF N-BENZYLAMIDES
*
H. R. F. Karabulut and M. Kacan
Trakya University, Science and Literature Faculty,
Department of Chemistry, Edirne 22030, Turkey
ABSTRACT
Benzyl amides are obtained from benzyl chlorides with
excellent yields in mild conditions by using hydrated ferric
chloride, FeCl3ꢀ6H2O, as Lewis acid catalyst and common
nitriles as both solvents and reagents.
The Ritter reaction is a well established and extensively used method
for the preparation of a wide range of amides, lactams and other hetero-
cycles.[1,2] The classical experimental procedure involves the treatment of an
alcohol or alkene with a strong protic acid, usually 85–90% sulfuric acid,
and then the trapping of carbenium ion thus formed by a nitrile, followed by
the hydrolysis of the nitrilium ion. Yields are often excellent despite the
apparent hard conditions.
A series of N-benzyl amides, ArCH2NHCOR [R¼C6H5, CH(CH3)2,
C(CH3)3], where an aryl group was electronically enriched by an electron
donating methyl group, were synthesized to examine the outcome of a new
application of the Ritter reaction.
*Corresponding author. E-mail: meschem@yahoo.com
2345
DOI: 10.1081/SCC-120006004
Copyright & 2002 by Marcel Dekker, Inc.
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2346
KARABULUT AND KACAN
In this new method, hydrated ferric chloride, FeCl3ꢀ6H2O, was used as
both the Lewis acid and the hydrating reagent instead of anhydrous Lewis
acid or sulfuric acid. Additionally, several nitriles were employed in reac-
tions as solvent and also as reagents. Finally, for amid synthesis, not only
were the benzyl alcohols used as the source of the benzyl carbenium ion,
ArCHþ2 , but also benzyl chloride and benzyl methyl ethers were used.
The yields of the reaction with benzyl chlorides was surprisingly high.
However, benzyl methyl ethers and benzyl alcohols gave slower reactions
and lower yields than the benzyl chloride reaction, because of the difficulty
in the production of the benzylic carbenium ion. Also, the use of hydrated
ferric chloride, FeCl3ꢀ6H2O gave a smooth clean reaction with respect to
anhydrous ferric chlorides, FeCl3 and sulfuric acid.
These results showed that benzyl methyl ethers, benzyl alcohols
and benzyl chlorides could be used as a precursor of the benzylic carbenium
ion, with different efficiencies, at the amid synthesis. Also, the use of nitriles
as solvent serves to obtain different amides instead of classical asetamide
product of the Ritter reaction. We then decided that, these results represent
a useful extension to the superficially investigated and little used classical
Ritter reaction of benzyl alcohol. The concept of the in situ hydrolysis of
nitrillium ion intermediates by hydrated Lewis acid catalysts may prove
beneficial in other Lewis acid mediated Ritter reactions.
EXPERIMENTAL
General procedure for the preparation of N-benzyl amides[3]: A sol-
ution of benzyl methyl ether, benzyl alcohol, benzyl chloride (10 mmol) in
nitride (25 mL) was added drowse for 15 min to a stirred solution of
ferric chloride hexahydrate (10.8 g, 40 mmol) in nitrile (25 mL) at room
temperature. When the addition was completed the mixture was stirred
and heated under reflux for the appropriate time (Tables 1, 2; reactions

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SYNTHESIS OF N-BENZYLAMIDES
2347
Table 1. Preparation of N-Benzyl Amides. ArCH2NHCOR by Reaction of
ArCH2X with Nitriles (NCR) and FeCl3Á6H2Oa
Entry
ArCH2X (Ar)
Nitrile
X
Yield, %b
1
C6H5
C6H5
NC–C6H5
NC–C6H5
OCH3
OH
22
12
20
6
2
3
C6H5
C6H5
NC–CH(CH3)2
NC–CH(CH3)2
NC–C(CH3)3
NC–C(CH3)3
NC–C6H5
OCH3
OH
4
5
C6H5
C6H5
OCH3
OH
18
6
6
7
3-CH3C6H4
3-CH3C6H4
3-CH3C6H4
3-CH3C6H4
3-CH3C6H4
3-CH3C6H4
OCH3
OH
20
8
8
NC–C6H5
9
10
NC–CH(CH3)2
NC–CH(CH3)2
NC–C(CH3)3
NC–C(CH3)3
NC–C6H5
OCH3
OH
18
7
11
12
OCH3
OH
18
5
132,4,6-(CH
3)3C6H2
OCH3
OH
85
27
76
25
75
23
14
15
16
17
18
2,4,6-(CH3)3C6H2
2,4,6-(CH3)3C6H2
2,4,6-(CH3)3C6H2
2,4,6-(CH3)3C6H2
2,4,6-(CH3)3C6H2
NC–C6H5
NC–CH(CH3)2
NC–CH(CH3)2
NC–C(CH3)3
NC–C(CH3)3
OCH3
OH
OCH3
OH
b
aAll reactions were conducted for 12 h at reflux temperature; Isolated yield.
Table 2. Preparation of N-Benzyl Amides. ArCH2NHCOR by the Reaction of
ArCH2Cl with Nitriles and FeCl3Á6H2Oa
Time
(h)b
Yield
(%)c
Entry
ArCH2Cl (Ar)
Nitrile
1
2
C6H5
C6H5
C6H5
NC–C6H5
12
12
12
10
10
10
10
10
10
8
92
88
88
87
72
86
88
82
94
94
86
88
NC–CH(CH3)2
NC–C(CH3)3
NC–C6H5
3
4
3-CH3C6H4
3-CH3C6H4
3-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
2,4,6-(CH3)3C6H2
2,4,6-(CH3)3C6H2
2,4,6-(CH3)3C6H2
5
NC–CH(CH3)2
NC–C(CH3)3
NC–C6H5
6
7
8
NC–CH(CH3)2
NC–C(CH3)3
NC–C6H5
9
10
11
12
NC–CH(CH3)2
NC–C(CH3)3
8
8
aThe reaction was conducted in the presence of 10 mmol ArCH2Cl, 40 mmol
FeCl3Á6H2O; bReflux temperature; cIsolated yield. For details, see Experimental step.

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2348
KARABULUT AND KACAN
were monitored by TLC). The cooled reaction mixture was then poured on
to crushed ice (15 g) and 2N HCl (15 mL) and ether (15 mL) were added. The
organic phase was separated, washed with 2N HCl (15 mL), water (15 mL)
and saturated NaCl solution (15 mL). It was then dried (MgSO4), filtered,
and the filtrate evaporated under reduced pressure to give the crude product.
All of the amides thus prepared are known compounds and the crude, prod-
ucts were purified by crystallization. The pure products were compared
(m.p., IR, H NMR) with genuine samples prepared independently.
ACKNOWLEDGMENT
M. Kacan is grateful to TUBITAK and Trakya University
Edirne/Turkey for financial support.
REFERENCES
1. Krimen, L.I.; Cota, D.J. Org. Reactions 1969, 17, 213.
2. Bishop, R. In Comprehensive Organic Synthesis; Pergamon Press; 1991;
Vol. 6, pp. 261.
3. Kacan, M.; Killop, A.Mc. Synth. Commun. 1993, 23(15), 2185–2199.
Received in the UK May 7, 2001