Synthesis of n-benzhydrylamides from nitriles by ritter reactions in formic acid

Article abstract of DOI:10.1055/s-2003-38069

Benzhydrol reacts with nitriles in refluxing formic acid to produce amides arising from the Ritter reaction. This reaction does not require a strong acid catalyst, and the products are isolated without the need for chromatography. The conditions permit the preparation of acrylamides and methacrylamides without polymerization of the nitrile.

Full text of DOI:10.1055/s-2003-38069

PAPER
681
Synthesis of N-Benzhydrylamides from Nitriles by Ritter Reactions in
Formic Acid
N
-Benzhydrylamid
l
es from
e
N
itrile
s
b
n
y
R
itter
R
eactions
in
Formic
Acid . Gullickson, David E. Lewis*
Department of Chemistry, University of Wisconsin - Eau Claire, Eau Claire WI 54702-4004, USA
Fax +1(715)8364979; E-mail: lewisd@uwec.edu
Received 27 November 2002; revised 7 January 2003
mate (9) within 20 minutes under these reaction condi-
tions. This is consistent with benzhydryl formate, which
undergoes subsequent slower solvolysis to the benzhydryl
cation (10), being the actual substrate for the reaction
Abstract: Benzhydrol reacts with nitriles in refluxing formic acid
to produce amides arising from the Ritter reaction. This reaction
does not require a strong acid catalyst, and the products are isolated
without the need for chromatography. The conditions permit the
preparation of acrylamides and methacrylamides without polymer- (Scheme 2).
ization of the nitrile.
HCO2H
Key Words: Ritter reaction, alcohols, carboxylic acids, nitriles,
amides
Ph
Ph
Ph
Ph
Ph
Ph
∆
OCHO
OH
OCHO
8
9
10
The Ritter reaction1,2 is a general method for the conver-
sion of alcohols to amines via the amides. The reaction
typically requires a strongly ionizing solvent and a strong
acid catalyst, and it is generally accepted that the reaction
proceeds by an SN1 mechanism through a nitrilium ion
(Scheme 1). Thus, the reaction is generally incompatible
with groups that are sensitive to strong acids.
Ph
Ph
H
Ph
N
R
N
C
R
C
O
Ph
11
12
Scheme 2
The relatively mild reaction conditions under which these
Ritter reactions ocurred suggested that this reaction might
be a useful general method for the formation of N-benzhy-
drylamides, potentially useful compounds as intermedi-
ates in the synthesis of pharmaceuticals. Therefore, we
explored the reaction of benzhydrol with a wide variety of
nitriles under these conditions. The results are gathered in
Table 1.
R
OH
R
OH2
R
N
C
R'
1
2
3
OH2
R'
RN
R'
RN
R'
C
OH
C
OH2
R
N C
4
5
6
In all cases, a fair to good isolated yield of the Ritter reac-
tion product was obtained after 24 hours or less under re-
flux; in no case was the strong acid catalyst typical of the
Ritter reaction9 used. It is also worth noting that the major
reaction product in each of these reactions was isolated di-
rectly from the crude reaction mixture by crystallization;
no chromatography was required. One of the most inter-
esting aspects of this reaction is the formation of the N-
benzhydrylamides from acrylonitrile and methacryloni-
trile, respectively, without competing polymerization of
the nitrile. We attribute this, in part, to the reducing nature
of the formic acid reaction medium, which may serve to
suppress such potential side reactions by preventing oxy-
gen-initiated radical polymerization.
RHN
R'
C
O
7
Scheme 1
During attempted alkylations of benzhydrol with ethyl cy-
anoacetate and malononitrile in refluxing formic acid,
conditions under which ethyl acetoacetate gives the prod-
uct of C-alkylation,3 we observed that the product was not
the expected C-alkylation product, but the N-benzhydryl-
amide of the carboxylic acid (12). This product clearly
arises from the Ritter reaction of the nitrile with the ben-
zhydryl cation, with the product initially formed from eth-
yl cyanoacetate undergoing subsequent ester hydrolysis The case of acrylonitrile is particularly interesting, since
1
and decarboxylation. TLC and H NMR monitoring re- the initial crude product is actually a mixture of N-benz-
vealed that to the extent observable at 400 MHz, all the hydrylacrylamide (18) and N-benzhydryl-3-formyloxy-
benzhydrol (8) is completely converted to benzhydryl for- propanamide (19) (Scheme 3) in varying proportions. In
general, longer reaction times appear to increase the per-
centage of 19. Recrystallization of this mixture from eth-
Synthesis 2003, No. 5, Print: 01 04 2003.
Art Id.1437-210X,E;2003,0,05,0681,0684,ftx,en;M05102SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
anol–water resulted in selective crystallization of 18; two
recrystallizations gave material that was approximately
90% pure. While this side reaction does reduce the poten-

682
G. C. Gullickson, D. E. Lewis
PAPER
Table 1 Ritter Reactions of Benzhydrol with Nitriles and Formic Acid
Ph2CHOH + RCN → Ph2CHNHCOR
Nitrile
Product
Yield (%)
Mp (°C) (lit.)
144–146 (147–148)
234–235 (234–235)
170–173 (170–171)
176–177
Ref.
3,4
EtO2CCH2CN
CH2(CN)2
MeCONHCHPh2 (13)
CH2(CONHCHPh2)2 (14)
PhCONHCHPh2 (15)
MeC6H4CONHCHPh2 (16)
EtCONHCHPh2 (17)
H2C=CHCONHCHPh2 (18)a
H2C=C(Me)CONHCHPh2 (20)
–
80
3,5
6
60
PhCN
75
4-MeC6H4CN
EtCN
76
–
7
76
138–139 (144.5)
(178–179)
8
H2C=CHCN
H2C=C(Me)CN
Anthracene-9-CN
69a
69
160–162
–
–
low
–
a Obtained as a mixture with HCO2CH2CH2CONHCHPh2 (19) in varying proportions.
tial usefulness of this method for the formation of acryla-
mides, it is worth reiterating that there is no evidence for
polymerization of the nitrile under these reaction condi-
tions.
Table 2 Reactions of Alcohols with Benzonitrile and Formic Acid
Alcohol
Product
Yield (%)
cyclohexanol
2-methylcyclohexanol
l-menthol
–
–
–
0
0
0
PhCH2OH
PhCH2NHCOPh (21) 50a
PhCH=CHCH2OH
Ph3COH
complex mixture
Ph3CH
–
76
a Based on 1H NMR spectrum of mixture with PhCH2OCHO (22)
Scheme 3
hand, gave a complex mixture from which no product
could be isolated cleanly. When compared to the 80%
yield of the N-benzhydryl amide and the lack of formation
of the N-menthyl amide under the same conditions, one
may conclude that there is a threshold cation stability that
is important for the key solvolysis step to proceed at a rea-
sonable rate. More importantly, the reactions of benzhy-
drol were remarkably free of side products, especially
products of the Koch–Haaf carboxylation.10,11
In order to explore the scope and limitations of this reac-
tion, we have explored the reaction of benzonitrile and
formic acid with a series of alcohols capable of giving rise
to a relatively stable carbocation. The results of these Rit-
ter reactions are summarized in Table 2. The results reveal
that only unsaturated alcohols capable of giving a strongly
resonance-stabilized carbocation give any Ritter reaction
product under these conditions. Neither cyclohexanol, nor
2-methylcyclohexanol, nor menthol gave a Ritter reaction
product with benzonitrile in formic acid under these same
reaction conditions; GC–MS analysis of the menthol reac-
tion mixture revealed it to be almost exclusively menthyl
formate. These observations are consistent with there be-
ing a threshold carbocation stability for the Ritter reaction
product to be formed at a reasonable rate under these re-
action conditions, adding a degree of chemoselectivity to
the overall reaction.
The data in Tables 1 and 2 reveal that there is a second
factor operating in this reaction. It appears that steric hin-
drance about the carbocation center or about the cyano
group plays an important role in preventing the reaction
under these reaction conditions. Thus, anthracene-9-car-
bonitrile, a fairly hindered nitrile, gave only a low yield of
a badly contaminated amide. Triphenylmethanol, the al-
cohol capable of giving the most stabilized carbocation,
gave triphenylmethane as the sole product of the reaction;
in this reaction, the carbocation is more hindered and less
reactive than in the benzhydryl case, and this may account
for the lack of formation of the amide product in favor of
the long-known reduction by formic acid.12,13
Two obvious alcohols to test under these reaction condi-
tions were benzyl alcohol and cinnamyl alcohol. After 24
hours under reflux, benzyl alcohol had been converted to
an approximately 50:50 mixture of benzyl formate and N-
benzylbenzamide (21); cinnamyl alcohol, on the other
Synthesis 2003, No. 5, 681–684 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
N-Benzhydrylamides from Nitriles by Ritter Reactions in Formic Acid
683
Yield: 11.48 g (76%); recrystallization from aq EtOH gave white
crystals; mp 176–177 °C.
In conclusion, we have identified a selective method for
preparing N-benzhydrylamides, especially, by the Ritter
reaction without the need for the strong acid catalysts nor- IR (KBr): 3318 (m), 1636 (s), 1525 (m), 1503 (m, sh), 1496 (m),
752 (m), 737 (m), 702 (m) cm–1.
mally required by this reaction. In addition, these reac-
1H NMR: δ = 7.71 (2 H, m, COArHortho), 7.37–7.22 (12 H, m, ArH),
6.64 (1H, br d, NH), 6.44 (1 H, d, J = 7.7 Hz, Ph2CH), 2.40 (3 H, s,
ArCH3).
tions illustrate the potential utility of the formate ester as
a leaving group in SN1 reactions that is highly selective for
the most stable carbocation.
13C NMR: δ = 166.5 (s), 142.2 (s), 141.6 (s), 131.4 (d),129.4 (d),
128.8 (d), 127.62 (d), 127.59 (d), 127.1 (d), 57.5 (d), 21.6 (q).
Mps were measured on a Fisher–Johns hotstage mp apparatus and
are uncorrected. 1H NMR spectra were recorded as CDCl3 solutions
using a JEOL Eclipse NMR spectrometer operating at 400 MHz;
peak positions are reported as δ (ppm) downfield from internal
Me4Si. 13C NMR spectra were recorded as CDCl3 solutions at 100
MHz; peak positions are reported in ppm relative to the center peak
of CDCl3 (δ = 77.1) and peak multiplicities as singlet (s), doublet (d)
triplet (t) or quartet (q). IR spectra were recorded as KBR pellets us-
ing a Nicolet Avatar 360 FTIR spectrophotometer; peak intensities
are reported as weak (w), medium (m) or strong (s). TLC was car-
ried out on Merck Kieselgel 60F254. GC–MS was carried out using
a Hewlett-Packard 5890 Series II Gas instrument. Microanalyses
were carried out by Galbraith Laboratories, Knoxville, TN. Formic
acid (98%) was used as obtained from EM Science; benzhydrol was
used as obtained from ACROS Chemicals; all other compounds
were used as obtained from Aldrich Chemical Company.
Anal. Calcd for C21H19NO: C, 83.69; H, 6.35; N, 4.65. Found: C,
83.61; H, 6.55; N, 4.65.
N-(Diphenylmethyl)propanamide (17)
From a solution of benzhydrol (9.21 g, 50.0 mmol) and propionitrile
(2.75 g, 50.0 mmol) in formic acid (40 mL), this procedure gave N-
(diphenylmethyl)propanamide (17).
Yield: 9.03 g (76%); white crystals; mp 138–139 °C (lit.7 144.5 °C).
IR (KBr): 3321 (w m), 3253 (m),1643 (s), 1536 (m), 1493 (w m),
739 (m), 696 (m) cm–1.
1H NMR: δ = 7.35–7.21 (10 H, m, ArH), 6.26 (1 H, d, J = 8.1 Hz,
Ph2CH), 6.03 (1 H, br d, NH), 2.29 (2 H, q, J = 7.7 Hz,
COCH2CH3), 1.19 (3 H, t, J = 7.7 Hz, CH2CH3).
13C NMR: δ = 172.7 (s), 141.6 (s), 128.7 (d), 127.43 (d), 127.39 (d),
56.8 (d), 29.8 (t), 9.8 (q).
Ritter Reactions of Benzhydrol; Standard Procedure
A solution of benzhydrol (1.00 equiv) and the nitrile (1.00 equiv) in
formic acid (ca. 1 mL/mmol) was stirred 5–6 h under reflux until
TLC analysis showed that neither benzhydrol nor benzhydryl for-
mate remained. The resulting solution was poured into an equal vol-
ume of deionized H2O, and the mixture was allowed to stir for 30
min. When the result was a waxy solid, the H2O was decanted from
the solid, and the crude solid was dried by azeotropic distillation
with toluene (ca. 0.6 mL/mmol benzhydrol used) under a Dean–
Stark H2O separator. When the resultant material was an oil, the
precipitate was extracted into CH2Cl2 (1 mL/mmol benzhydrol
used), dried (Na2SO4), evaporated under reduced pressure, and dis-
solved in hot toluene (ca. 0.6 mL/mmol benzhydrol used). The hot
toluene solution was diluted with hexane until saturation. Cooling
of the solution gave crystals which were recovered by vacuum fil-
tration. Where specified, this product was recrystallized from aque-
ous EtOH. The reactions between benzhydrol and ethyl
cyanoacetate or malononitrile were carried out as reported else-
where.3
N-(Diphenylmethyl)propenamide (18) and N-(Diphenylmeth-
yl)-3-formyloxypropanamide (19)
From a solution of benzhydrol (9.21 g, 50.0 mmol) and acrylonitrile
(2.65 g, 50.0 mmol) in formic acid (40 mL), this procedure gave a
white powder (8.19 g, 69%), shown by 1H NMR spectroscopy to be
a 1:1 mixture of N-(diphenylmethyl)propenamide (18) and N-
(diphenylmethyl)-3-formyloxypropanamide (19).
IR (KBr): 3277, 3061, 3029, 1715, 1667, 1652, 1619, 1539, 1189,
757, 741, 698 cm–1.
1H NMR (mixture): δ = 8.02 (1 H, s, HCO2), 7.4–7.1 (20 H, m,
PhH), 6.5-6.0 (m, 5 H, HC=CH2, NH), 5.69 (2 H, br d, Ph2CH), 4.49
(2 H, t, J = 6.2 Hz, OCH2), 2.63 (2 H, t, J = 6.2 Hz, CH2CONH).
N-(Diphenylmethyl)-2-methylpropenamide (20)
From a solution of benzhydrol (9.21 g, 50.0 mmol) and methacry-
lonitrile (3.35 g, 50.0 mmol) in formic acid (40 mL), this procedure
gave N-(diphenylmethyl)-2-methylpropenamide (20).
Yield: 8.72 g (69%); white crystals; mp 160–162 °C.
N-(Diphenylmethyl)benzamide (15)
From a solution of benzhydrol (9.31 g, 50.5 mmol) and benzonitrile
(9.55 g, 93 mmol) in formic acid (50 mL), this procedure gave N-
(diphenylmethyl)benzamide (15).
IR (KBr): 3324 (m), 1652 (s), 1609 (s), 1525 (s), 1209 (m), 758 (m),
738 (m), 698 (s) cm–1.
1H NMR: δ = 7.4–7.2 (10 H, m, PhH), 6.34 (1 H, br d, NH), 6.29 (1
H, d, J = 7.7 Hz, Ph2CH), 5.75 (1 H, s, C=CH), 5.38 (1 H, s, C=CH),
2.00 (3 H, s, C=CCH3).
Yield: 10.90 g (75%); recrystallization from aq EtOH gave white
crystals; mp 170–173 °C (lit.6 170–171 °C).
IR (KBr): 3311 (m), 1638 (s), 1520 (s), 1495 (m), 1486 (m), 706
(m), 692 (m) cm–1.
13C NMR: δ = 167.5 (s), 141.5 (s, 2 C), 140.1 (s), 128.8 (d, 4 C),
127.6 (d, 4 C), 127.5 (d, 2 C), 119,9 (t), 57.1 (d), 18.7 (q).
1H NMR: δ = 7.81 (3 H, m, ArH), 7.55–7.25 (12 H, m, ArH), 6.74
(1 H, br d, NH), 6.45 (1 H, d, J = 7.7 Hz, Ph2CH).
Anal. Calcd for C17H17NO: C, 81.24; H, 6.82; N, 5.57. Found: C,
81.33; H, 7.00; N, 5.59.
13C NMR: δ = 166.6 (s), 141.5 (s, 2 C), 134.3 (s), 131.8 (d), 128.8
(d, 4 C), 128.7 (d, 2 C), 128.66 (d, 4 C), 127.63 (d, 2 C), 127.2 (d, 2
C), 57.6 (d).
Benzyl Formate (22) and N-Benzylbenzamide (21)
A solution of benzyl alcohol (6.13 g, 56.7 mmol) and benzonitrile
(5.27 g, 51.1 mmol) in formic acid (40 mL) was heated for 24 h un-
der reflux. Analysis of the reaction mixture after this time showed
it to be a 1:1 mixture of benzyl formate (22) and N-benzylbenza-
mide (21). Separation of the mixture was not attempted.
N-(Diphenylmethyl)-4-methylbenzamide (16)
From a solution of benzhydrol (9.21 g, 50.0 mmol) and p-toluoni-
trile (5.86 g, 50.1 mmol) in formic acid (40 mL), this procedure
gave N-(diphenylmethyl)-4-methylbenzamide (16).
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684
G. C. Gullickson, D. E. Lewis
PAPER
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Acknowledgments
Financial support of this research by grants from Research Corpo-
ration (Cottrell College Science Award No. CC4677), the National
Institutes of Health (Grant # 1 R15 DA013578-01), and the Univer-
sity of Wisconsin - Eau Claire Office of Research and Sponsored
Programs is gratefully acknowledged.
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Synthesis 2003, No. 5, 681–684 ISSN 0039-7881 © Thieme Stuttgart · New York