Highly selective mono-N-benzylation and amidation of amines with alcohols or carboxylic acids using the Ph2PCl/I2/imidazole reagent system

Article abstract of DOI:10.1139/v2012-021

Chlorodiphenylphosphine, imidazole, and molecular iodine in refluxing dichloromethane are used for the efficient preparation of amides under mild reaction conditions. This reagent system also shows excellent selectivity for mono-N-alkylation of amines with alcohols. In this system, the resulting phosphorus byproduct (diphenylphosphinic acid) is easily removed by extraction using an aqueous basic solution in the workup processes, which avoids the tedious and time-consuming chromatographic methods.

Full text of DOI:10.1139/v2012-021

498
Highly selective mono-N-benzylation and
amidation of amines with alcohols or carboxylic
acids using the Ph2PCl/I2/imidazole reagent
system
Najmeh Nowrouzi and Mohammad Zareh Jonaghani
Abstract: Chlorodiphenylphosphine, imidazole, and molecular iodine in refluxing dichloromethane are used for the efficient
preparation of amides under mild reaction conditions. This reagent system also shows excellent selectivity for mono-N-
alkylation of amines with alcohols. In this system, the resulting phosphorus byproduct (diphenylphosphinic acid) is easily
removed by extraction using an aqueous basic solution in the workup processes, which avoids the tedious and
time-consuming chromatographic methods.
Key words: benzylation, amidation, imidazole, amine, alcohol, carboxylic acid, chlorodiphenylphosphine, iodine.
Résumé : On a utilisé un mélange de chlorodiphénylphosphine, d’imidazole et d’iode moléculaire dans le dichlorométhane
au reflux pour préparer des amides d’une façon efficace, dans des conditions douces. Ce système de réactifs présente aussi
une bonne sélectivité pour la mono-N-alkylation d’amines avec des alcools. Dans ce système, il est facile d’éliminer le
sous-produit phosphoré, l’acide diphénylphosphinique, par extraction du mélange réactionnel à l’aide d’une solution basique
aqueuse qui évite les méthodes chromatographiques lentes et ennuyeuses.
Mots‐clés : benzylation, amidation, imidazole, amine, alcool, acide carboxylique, chlorodiphénylphosphine, iode.
[Traduit par la Rédaction]
phenylphosphine,11
Silphos,12
tris[4-(1H,1H-perfluoro-
Introduction
octyloxyphenyl)] phosphine13 have been reported. Therefore,
development of simple, efficient, and useful methods for the
easy synthesis of organic compounds using readily available
reagents is one of the major research demands in organic
synthesis.
For many years, phosphines as reagents or catalysts have
been employed for various organic transformations. Among
these, soluble triphenylphosphine (TPP) has found significant
attention, and several applications of this reagent have been
demonstrated. This reagent has widespread use in organic
chemistry in reactions such as the Staudinger reduction,1 the
Mitsunobu reaction,2 the Wittig reaction,3 halogenation of a
hydroxyl group,4 formylation reactions,5 and nitrile and
amide formation.6 A common drawback of all these systems
is the formation of stoichiometric amounts of phosphine ox-
ides as byproducts, of which their separation from the reac-
tion mixtures is usually a difficult task, and time-consuming
chromatographic purification of the product is necessary to
obtain pure compounds. Speed and efficiency in chemical
separation are at the heart of parallel synthesis and combina-
torial chemistry and are increasingly important in traditional
synthesis as well.
We have recently reported that chlorodiphenylphosphine
(CDP), a commercially available reagent, is practically effec-
tive for the conversion of carboxylic acids, phenols, and thi-
ols to their corresponding esters in the presence of molecular
iodine.14 In this system, the resulting phosphorus byproduct
(diphenylphosphinic acid) is easily extracted with an aqueous
basic solution in the workup processes without the need of
using tedious and time-consuming chromatographic methods.
In continuation of our earlier work, we present a very easy
and efficient method for N-alkylation and amidation of
amines with alcohols or carboxylic acids.
The reaction of amines has been a topic of immense re-
search owing to their synthetic utility and biological activ-
ity.15 They are also widely used as intermediates to prepare
solvents, fine chemicals, agrochemicals, and catalysts.16
The nucleophilic attack of alkyl halides by primary amines
is useful for the preparation of secondary amines, but the re-
action is invariably slow and gives rise to a mixture of secon-
dary and tertiary amines.17 However, the toxicity of some
As a solution to this problem, in recent years many efforts
have been directed toward modifying TPP to facilitate the
isolation and purification of the desired product. In this way,
the use of expensive and not easily available reagents such as
polymer-supported TPP,7 PEG-supported (PEG = polyeth-
yleneglycol)
diphenyl(2-pyridyl)phosphine,10 (4-dimethylaminophenyl)di-
phosphine,8
polystyryldiphenylphosphine,9
Received 19 June 2011. Accepted 2 February 2012. Published at www.nrcresearchpress.com/cjc on 9 May 2012.
N. Nowrouzi and M.Z. Jonaghani. Department of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran.
Corresponding author: Najmeh Nowrouzi (email:nowrouzi@pgu.ac.ir).
Can. J. Chem. 90: 498–509 (2012)
doi:10.1139/V2012-021
Published by NRC Research Press

Nowrouzi and Jonaghani
499
Scheme 1. Formation of N-benzyl aniline using the Ph2PCl/I2/imidazole system.
NH2
OH
Ph PCl
(1.0 equiv), I (1.0 equiv)
2
2
N
H
+
imidazole (3.0 equiv)
CH2Cl2, reflux
2.0 equiv
2.0 equiv
88 %
3.5 h
alkylating agents and also the control of monoalkylation can
be problematic. To obviate these problems, reductive amina-
tion of the carbonyl compounds,18 amide reduction,19 and the
use of catalytic systems in the presence of alcohols, such as
ruthenium, rhodium, iridium, zinc, palladium, and g-alumina,
have been reported. These conditions require strong reducing
reagents or dangerous hydrogen gas and, in many cases, are
not always selective and generate tertiary amines and (or)
quaternary ammonium salts as byproducts. In addition, most
of these catalytic systems require high reaction temperatures,
and the applicable amines and alcohols are very restricted.20
Recently, Iranpoor et al.21 reported selective methods for N-
monoalkylation of amines using the TPP system. In these
methods, careful chromatography is necessary for isolation
of the desired products from TPP oxide and the reaction mix-
ture.
Due to the wide biological, synthetic, and industrial appli-
cations of amides, the amidation reaction is considered an
important transformation in organic synthesis.22,23 Different
synthetic methodologies have been developed in the past two
decades for the formation of an amide bond, with the focus
on design and development of innovating coupling reagents.
The most popular methods for the synthesis of amides in-
volve the conversion of carboxylic acid to a more reactive
functional group, such as acyl chloride, acyl azide, acylimi-
dazoles, mixed anhydride, active esters, etc., followed by
aminolysis with amine or via an in situ activation of the car-
boxylic group by using coupling reagents.24 Although good
results have been obtained with both approaches, they often
need expensive coupling reagents, some of which are mois-
ture-sensitive and sometimes lead to the formation of byprod-
ucts requiring further separation. These drawbacks usually
limit their extensive application and give rise to the need for
development of new types of condensing reagents.
electron-withdrawing substituents at the aromatic ring pro-
ceeded to give benzyl aniline derivatives in good to excellent
yields. As the results show, the reaction works best with the
electron-rich benzyl alcohols. The electron-poor benzyl alco-
hols also provided the corresponding products, but with lon-
ger reaction times (Table 1, compare entries 5 and 9 with
entries 6 and 10). In addition to the electronic factors, steric
effects also affected the reaction in terms of time and yield.
Comparison of entries 6 and 7 in Table 1 indicate that the
existence of an ortho substituent on the phenyl ring slightly
decreases the yield and increases the time of the reaction.
Treatment of 1-phenyl ethanol with this mixed reagent sys-
tem (Table 1, entries 13–15) showed that this system is also
suitable for the conversion of the secondary benzylic alcohols
to their corresponding products. In the case of primary and
secondary aliphatic alcohols such as 1-octanol and 2-octanol
(Table 1, entries 20 and 21), no desired product was formed
even after reflux in acetonitrile for a prolonged reaction time.
These results exhibited that the reaction of non-benzylic alco-
hols with aniline in the presence of our reagent system does
not occur.
Similar to the alcohols, the nature of the substitution of the
aromatic ring in aniline was also briefly studied. Both electron-
donating and electron-withdrawing substituents react under
our reaction conditions, and the overall yields in all cases
are excellent. The reaction of benzyl alcohol with electron-
rich anilines such as p-anisidine (Table 1, entry 4) gave the
N-benzyl-4-methoxybenzenamine after 1.5 h, whereas a lon-
ger reaction time was observed for anilines bearing electron-
withdrawing groups on the phenyl moiety (Table 1, entries
2 and 3).
In addition to this, in the reaction with benzyl alcohol, the
more nucleophilic N-methylaniline produced better results as
compared with the poor nucleophilic aromatic amines such as
aniline (Table 1, compare entry 1 with entry 12).
Results and discussion
Aliphatic amines were also tested to N-alkylation, but our
attempts for alkylation of the primary aliphatic amines under
the aforementioned conditions were unsuccessful, and the
product was not obtained in this way even after refluxing in
CH3CN for 48 h. Secondary aliphatic amines (Table 1, en-
tries 18 and 19) produced their corresponding tertiary amines
in moderate yields. These reactions did not complete under
the reaction conditions after 24 h and led to the desired prod-
uct with lower yield possibly because of the steric effects.
These results are not surprising based on the nucleophilicity
of the amines. For the reaction to proceed, it is important to
have amines as the reactive nucleophile and the secondary
aliphatic amines are stronger nucleophiles than the primary
amines. In the case of the aromatic amines, the stronger acid-
ity of the amino group in aniline derivatives resulted in the
easier formation of amine anions, which are strong nucleo-
philes.
First, we investigated N-alkylation of aniline with benzyl
alcohol using the Ph2PCl/imidazole/I2 system under various
reaction conditions (Scheme 1). The optimization study re-
vealed that 1.0 equiv of both Ph2PCl and I2 and 3.0 equiv of
imidazole were sufficient to complete the reaction between
2.0 equiv of alcohol and 2.0 equiv of amine in refluxing di-
chloromethane. Similar to our previous work, it was observed
that the presence of imidazole in the reaction mixture14 not
only neutralizes the liberated halogen acids, but also enhan-
ces the reactivity of the reagent system.
With the optimized conditions in hand, we screened a rep-
resentative range of structurally different alcohols and amines
for the reaction. Representative results are summarized in Ta-
ble 1.
As shown by the data reported in Table 1, N-alkylation of
anilines with benzyl alcohols bearing electron-donating and
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Can. J. Chem. Vol. 90, 2012
Table 1. Benzylation of amines in the presence of the Ph2PCl/imidazole/I2 in CH2Cl2 at reflux conditions.
Time
(h)
3.5
Yield
(%)a
Entry Amine
1
Alcohol
Product
NH2
88
90
88
OH
OH
N
H
NH2
Cl
2
7
Cl
N
H
NO2
O2N
NH2
OH
OH
3
8
N
H
NH2
OCH3
4
1.5
3
93
92
90
80
H3CO
N
H
NH2
OH
OH
5
6
7
H3CO
O2N
N
H
H3CO
NH2
5.5
8
N
H
O2N
NO2
NH2
NH2
NO2
OH
N
H
OH
8
4.5
89
Cl
N
H
Cl
NH2
NH2
OCH3
OH
OH
9
15 min 94
H3CO
O2N
H3CO
N
H
H3CO
OCH3
10
5
87
H3CO
N
H
O2N
To have more insight into the applicability, selectivity, and
limitations of this new method, we performed an experiment
using binary mixtures of equimolar amounts of aniline and
different primary or secondary aliphatic amines and primary
ones with benzyl alcohol. The results of this study are pre-
sented in Table 2.
smoothly to give the benzanilide as the single product in
90% yield (Table 2, entry 1). Benzyl amine was found to be
unreacted under the reaction conditions (Table 2, entry 2).
Furthermore, the alkylation of a secondary aliphatic amine in
a dual mixture with benzyl amine as a primary aliphatic
amine also proceeded to give tribenzylamine in moderate
yield (Table 2, entry 3). The most important point regarding
this method is that aromatic and secondary aliphatic amines
As expected, reaction of a binary mixture of aniline and a
primary aliphatic amine such as butyl amine proceeded
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Nowrouzi and Jonaghani
501
Table 1. (concluded).
Time
(h)
10
Yield
Entry Amine
11
Alcohol
Product
(%)a
70
Cl
NH2
OH
O2N
N
Cl
H
O2N
H
N
OH
12
1
92
87
80
91
N
NH2
OH
OH
13
14
15
7
N
H
NH2
Cl
8.5
2
Cl
N
H
NH2
OCH3
OH
OH
OH
H3CO
N
H
NH2
16
17
48
48
nr
nr
—
—
NH2
OH
OH
18
19
N
H
24
24
50
55
N
H
N
N
O
O
NH2
OH
20
21
48
48
nr
nr
5
—
—
OH
NH2
5
Note: nr, no reaction.
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Can. J. Chem. Vol. 90, 2012
Table 2. Selective reaction of various amines with benzyl alcohol in binary mixtures usingthe
Ph2PCl/I2/imidazole reagent system.
Time
(h)
Yield
(%)a
Entry Alcohol
Binary mixture
Product
1
2
3
4
PhCH2OH
PhCH2OH
PhCH2OH
PhCH2OH
PhNH2–CH3CH2CH2NH2
PhNH2–PhCH2NH2
PhCH2NHCH2Ph–PhCH2NH2
Morpholine–PhCH2NH2
PhNHCH2Ph
PhNHCH2Ph
(PhCH2)3N
3.5
3.5
24
90
85
51
50
24
N
O
Note: The molar ratio of Ph2PCl / imidazole / I2 / PhCH2OH / binary mixture is 1.0:3.0:1.0:2.0:2.0:2.0.
aIsolated yield.
Scheme 2. Synthesis of benzanilide from the reaction of benzoic acid and aniline using the Ph2PCl/I2/imidazole system.
O
O
Ph2PCl (1.5 equiv), I (1.5 equiv)
2
NH2
OH
N
imidazole ( 4.5 equiv)
H
+
CH2Cl2, reflux
40 min
2.0 equiv
90 %
2.0 equiv
can be converted to their corresponding alkylated products in
the presence of primary aliphatic amines in binary mixtures
with excellent selectivity using the same stoichiometric
amounts of the reagents and substrates as before.
zoic acid led to a clean reaction affording the desired amide
after 30 min (Table 3, entry 4); however, the use of aniline
bearing an electron-withdrawing group such as nitro, lead to
the desired product in a relatively longer reaction time (2 h)
and lower yield (75%) because of the low nucleophilicity of
the amine (Table 3, entry 9).
As shown in Table 3, aliphatic amines (entries 10 and 11)
and also aliphatic acids (Table 3, entry 15) are suitable sub-
strates for synthesis of their corresponding amides. To show
the generality of the present method, we examined the reac-
tion of aliphatic and aromatic thiocarboxylic acids with ani-
line. In these cases, the successful transformation of
thioacids to their corresponding thioamides was observed us-
ing the same reaction conditions as for carboxylic acids (Ta-
ble 3, entries 16 and 17).
To extend the applicability of our methodology and find
out the limitations encountered in this new system, we sought
conditions for performing direct amidation of carboxylic
acids with amines, as an important transformation. In the
amidation process, we examined the reaction of benzoic acid
with aniline as a model reaction. Of the various stoichiomet-
ric amounts, the ratio of 1.5:4.5:1.5:2.0:2.0 for Ph2PCl/imidazole/
I2/PhCO2H/PhNH2 in refluxing CH2Cl2 was found to be the
best condition and resulted in benzanilide in 90% yield
(Scheme 2). This transformation occurred conveniently with
the easy removal of the produced phosphine oxide (diphen-
ylphosphinic acid) by a simple extraction.
By using this system, the amidation of carboxylic acids
with amines was also performed in a similar manner of ami-
nation and is shown in Table 3.
These results clearly demonstrate that the direct amidation
was successful for both aliphatic and aromatic amines and
acids.
With the variation of substituents in both acids and
amines, it was observed that the reaction depended on the
acidity of the benzoic acid derivatives and the nucleophilicity
of the aromatic amines. As shown in Table 3, for most
cases, better results were observed for the reaction of electron-
withdrawing substituted aromatic acids (stronger aryl acids)
with the activated aromatic amines carrying electron-donating
substithents (stronger nucleophiles). For instance, reaction
of p-nitrobenzoic acid with aniline proceeded to afford the
desired product after 20 min (Table 3, entry 3), whereas
longer reaction times were required when benzoic or p-
methylbenzoic acid were employed in the reaction (Table 3,
entries 1 and 2). Treatment of p-methoxyaniline and ben-
As previously reported,14 we suggest that this reaction
might be proceeding initially by formation of 1-(diphenyl-
phosphino)imidazole (I), which in the second step reacts
with iodine. The imidazole and iodine in the produced phos-
phonium salt are then exchanged by carboxylate anion to
form the the acyloxyphosphonium ion (III). Finally the attack
of the amine at the carbonyl carbon atom of this intermediate
gives the corresponding amide along with diphenylphos-
phinic acid as a byproduct (Scheme 3).
Conclusion
In conclusion, we have developed a new, efficient, and
mild method for mono-N-benzylation of amines with alco-
hols and also for amidation of carboxylic acids with aliphatic
and aromatic amines. It should be noted that the present N-
alkylation proceeds with high selectivity for mono-N-alkylation.
In each reaction, monoalkylated aniline was formed as a
single product and no formation of dialkylated aniline was
observed. Therefore, one crucial feature embedded in this
protocol is the excellent chemoselectivity. High yields, mild
Published by NRC Research Press

Nowrouzi and Jonaghani
503
Scheme 3. Proposed mechanism for the amidation reaction.
Cl
H
N
H
N
I
Ph2P
Ph2P
I2
N
N
HN
N
N
N
Ph2PCl
+
I
(I)
(II)
I
H
N
N
H
O
Ph
P
O
RCONHR'
R'NH2
+
R
O
O
R
Ph
HN
N
Ph2P(O)OH
RCO2H
+
(III)
reaction conditions, a simple and convenient procedure,
commercially availablity of the reagents, no need for a cata-
lyst, and no prior activation in amidation are the advantages
of this system. This system also has the further advantage
that the reagent-derived byproduct (diphenylphosphinic
acid) can be removed easily by a simple aqueous workup,
which provides quick workup procedures instead of using
the tedious and time-consuming chromatographic methods.
remove the excess iodine and then washed with water, dried,
and concentrated. Flash chromatography of the organic resi-
due was performed on silica gel using n-hexane / ethyl acetate
as eluent to give the pure products.
N-Phenylbenzylamine
mp 36 °C (lit.25a 37 °C). dH (250 MHz, CDCl3): 7.22–7.43
(complex, 8H, Ph), 6.68–6.79 (complex, 2H, Ph), 4.38 (s,
2H, CH2), 4.04 (s, 1H, NH). dC (62.9 MHz, CDCl3): 148.2,
139.5, 129.3, 128.4, 127.6, 127.3, 117.6, 112.9, 48.4.
HRMS (EI+) calcd for C13H13N: 183.1048; found: 183.045
(Table 1, entry 1).
Experimental section
General methods
Solvents were dried and purified by standard procedures.
Melting points were determined in open capillary tubes in a
Buchi 530 circulating oil apparatus and are not corrected.
NMR spectra were recorded on a Bruker Avance DPX-250
(1H NMR, 250 MHz; 13C NMR, 62.9 MHz) spectrometer in
CDCl3 or DMSO-d6 using TMS as an internal standard. De-
termination of the purity of the products and the reaction
monitoring were carried out on silica gel 254 analytical
sheets or by GLC on a Shimadzu model GC-10A instrument.
Column chromatography was carried out by silica gel 60
Merck (30–270). All compounds had been reported previ-
ously, and their identities were confirmed by comparison of
their melting points and spectroscopic data with the reported
data.
N-(4-Chlorophenyl)benzylamine
mp 39 °C (lit.25b 39 °C). dH (250 MHz, CDCl3): 7.14 (d,
2H, J = 7.2 Hz, Ph), 7.02–7.05 (m, 5H, Ph), 6.44 (d, 2H,
J = 7.1 Hz, Ph), 4.37 (s, 2H, CH2), 4.08 (s, 1H, NH). dC
(62.9 MHz, CDCl3): 150.2, 141.4, 128.7, 127.3, 127.0,
125.3, 119.5, 78.2, 49.2. HRMS (EI+) calcd for C13H12ClN:
217.0658; found: 217.0649 (Table 1, entry 2).
N-(3-Nitrophenyl)benzylamine
mp 104 °C (lit.25c 107 °C). dH (250 MHz, CDCl3): 7.53–
7.55 (m, 1H, Ph), 7.42 (s, 1H, Ph), 7.21–7.37 (m, 6H, Ph),
6.86–6.89 (m, 1H, Ph), 4.42 (s, 1H, NH), 4.36 (s, 2H, CH2).
dC (62.9 MHz, CDCl3): 149.5, 148.9, 138.2, 139.8, 128.9,
127.7, 127.5, 118.8, 112.1, 106.6, 48.1. HRMS (EI+) calcd
for C13H12N2O2: 228.0899; found: 228.0894 (Table 1, entry
3).
General procedure for the conversion of amines to N-
benzyl amines
Benzyl alcohol (2.0 mmol) was added to a mixture of
chlorodiphenylphosphine (1.0 mmol), imidazole (3.0 mmol),
and iodine (1.0 mmol) in refluxing dichloromethane. Amine
(2.0 mmol) was then added to the reaction mixture. After
completion of the reaction, the residue was washed with satu-
rated aqueous sodium carbonate (3 × 5 mL) until all diphen-
ylphosphinic acid was removed from the organic phase. The
aqueous phase was separated, and the organic phase was
washed with aqueous sodium thiosulfate (2 × 5 mL) to
N-(4-Methoxyphenyl)benzylamine
mp 50 °C (lit.25b 51 °C). dH (250 MHz, CDCl3): 7.17 (d,
2H, J = 7.3 Hz, Ph), 7.06–7.08 (m, 3H, Ph), 6.48 (d, 2H,
J = 8.0 Hz, Ph), 6.34 (d, 2H, J = 7.9 Hz, Ph), 4.39 (s, 2H,
CH2), 4.11 (s, 1H, NH), 3.76 (s, 3H, OMe). dC (62.9 MHz,
CDCl3): 153.5, 141.2, 140.7, 127.8, 127.6, 127.0, 117.1,
115.3, 55.2, 50.1. HRMS (EI+) calcd for C14H15NO:
213.1154; found: 213.1147 (Table 1, entry 4).
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Can. J. Chem. Vol. 90, 2012
Table 3. Synthesis of amides by the Ph2PCl/imidazole/I2 system in CH2Cl2 under reflux.
Time
Yield
Entry Amine
1
Acid
Product
(min) (%)a
NH2
NH2
CO2H
40
50
20
30
90
93
90
89
H
N
O
CH3
NO2
CO2H
CO2H
2
3
H
N
H3C
O
O
NH2
H
N
O2N
NH2
CO2H
H
N
4
H3CO
O
H3CO
NO2
NH2
CO2H
H
N
5
10
40
94
91
H3CO
O2N
O
O
H3CO
H3CO
CH3
NH2
CO2H
6
H
N
H3CO
H3C
NH2
CO2H
CO2H
H
7
55
80
87
77
N
Cl
O
Cl
NH2
H
8
O2N
N
O2N
O
4-Methoxy-N-phenylbenzylamine
6.68–6.84 (m, 3H, Ph), 4.38 (s, 2H, CH2), 4.11 (s, 1H, NH).
dC (62.9 MHz, CDCl3): 146.4, 144.9, 143.7, 130.5, 128.4,
124.5, 117.7, 113.5, 48.9. HRMS (EI+) calcd for
C13H12N2O2: 228.0899; found: 228.0885 (Table 1, entry 6).
mp 61 °C (lit.25b 63 °C). dH (250 MHz, CDCl3): 7.31 (d,
2H, J = 7.5 Hz), 6.51–7.13 (m, 9H, Ph), 4.39 (s, 2H, CH2),
3.91 (s, 1H, NH), 3.74 (s, 3H, OMe). dC (62.9 MHz, CDCl3):
157.8, 149.1, 131.8, 129.9, 129.6, 128.3, 118.6, 115.5, 56.1,
49.7. HRMS (EI+) calcd for C14H15NO: 213.1154; found:
213.1150 (Table 1, entry 5).
2-Nitro-N-phenylbenzylamine
mp 45 °C (lit.25e 44 °C). dH (250 MHz, CDCl3): 8.10 (d,
1H, J = 8.0 Hz, Ph), 7.74 (d, 1H, J = 8.0 Hz, Ph), 7.59 (t,
1H, J = 7.6 Hz, Ph), 7.44 (t, 1H, J = 7.8 Hz, Ph), 7.23 (t,
2H J = 8.0 Hz, Ph), 6.80 (t, 1H, J = 7.3 Hz, Ph), 6.63 (d,
2H, J = 8.4 Hz, Ph), 4.75 (s, 2H, CH2), 4.42 (s, 1H, NH).
4-Nitro-N-phenylbenzylamine
mp 67 °C (lit.25d 67 °C). dH (250 MHz, CDCl3): 8.13–8.18
(m, 2H, Ph), 7.56–7.71 (m, 2H, Ph), 7.23–7.37 (m, 2H, Ph),
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Nowrouzi and Jonaghani
505
Table 3. (concluded).
Time
Yield
Entry Amine
Acid
Product
(min) (%)a
NH2
CO2H
9
2 h
75
H
N
O2N
O
O 2N
CO2H
NH2
O
10
11
30
40
92
92
N
H
O
CO2 H
NH2
N
H
H3C
CH3
H
N
CO2H
12
13
2.5 h
2 h
89
91
N
O
H
N
NO2
CO2H
N
N
O2N
O
H
N
CH3
CO2 H
14
15
3 h
45
91
88
H3C
O
NH2
NH2
NH2
O H
H
N
O
O
COSH
H
N
16
17
1 h
45
90
85
S
SH
H
N
O
S
dC (62.9 MHz, CDCl3): 148.25, 147.53, 135.78, 133.77,
129.81, 129.42, 128.03, 125.22, 118.03, 112.95, 45.76.
HRMS (EI+) calcd for C13H12N2O2: 228.0899; found:
228.0891 (Table 1, entry 7).
N-(4-Methoxybenzyl)-4-anisidine
mp 90 °C (lit.25g 92 °C). dH (250 MHz, CDCl3): 6.96 (d,
2H, J = 8.6 Hz, Ph), 6.65 (d, 2H, J = 8.8 Hz, Ph), 6.56 (d,
2H, J = 8.8 Hz, Ph), 6.35 (d, 2H, J = 8.7 Hz, Ph), 4.33 (s,
2H, CH2), 3.71 (s, 6H, OMe). dC (62.9 MHz, CDCl3): 158.8,
152.2, 142.5, 131.6, 128.8, 114.9, 114.1, 114.0, 55.8, 55.3,
48.7. HRMS (EI+) calcd for C15H17NO2: 243.1259; found:
243.1248 (Table 1, entry 9).
4-Chloro-N-phenylbenzylamine
mp 47 °C (lit.25f 50 °C). dH (250 MHz, CDCl3): 6.61–7.12
(m, 9H, Ph), 4.29 (s, 2H, CH2), 3.92 (s, 1H, NH). dC
(62.9 MHz, CDCl3): 148.6, 139.1, 133.4, 129.8, 128.3,
128.0, 119.2, 114.5, 48.3. HRMS (EI+) calcd for
C13H12ClN: 217.0658; found: 217.0641 (Table 1, entry 8).
N-(4-Nitrobenzyl)-4-anisidine
mp 97 °C (lit.25h 97 °C). dH (250 MHz, CDCl3): 8.14 (dt,
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506
Can. J. Chem. Vol. 90, 2012
2H, J = 8.8, 2.0 Hz, Ph), 7.52 (d, 2H, J = 8.8 Hz, Ph), 6.75
(dt, 2H, J = 9.0, 2.3 Hz, Ph), 6.53 (dt, 2H, J = 9.0, 2.3 Hz,
Ph), 4.40 (s, 2H, CH2), 3.71 (s, 3H, OMe). dC (62.9 MHz,
CDCl3): 152.2, 147.4, 146.8, 140.9, 127.6, 123.6, 114.5,
114.0, 55.9, 46.2. HRMS (EI+) calcd for C14H14N2O3:
258.1004; found: 258.1001 (Table 1, entry 10).
(EI+) calcd for C11H15NO: 177.1154; found: 177.1148 (Ta-
ble 1, entry 19).
General procedure for the conversion of acids to amides
To a stirred solution of Ph2PCl (1.5 mmol) and imidazole
(4.5 mmol) in 5 mL dichloromethane at reflux were added
iodine (1.5 mmol) and acids (2.0 mmol), successively.
Amines (2.0 mmol) were then added to the reaction mixture.
After completion of the reaction, the organic layer was
washed with saturated aqueous sodium carbonate (3 ×
5 mL) and then aqueous sodium thiosulfate (2 × 5 mL), and
then dried. The residue was subjected to flash chromatogra-
phy over silica gel by using n-hexane / ethyl acetate as eluent
to give the pure amides.
N-(4-Nitrobenzyl)-4-chloroaniline
mp 95 °C (lit.25i 97 °C). dH (250 MHz, CDCl3): 8.07 (d,
2H, J = 8.5 Hz, Ph), 7.32 (d, 2H, J = 8.5 Hz, Ph), 7.05 (d,
2H, J = 8.8 Hz, Ph), 6.37 (d, 2H, J = 8.8 Hz, Ph), 4.32 (s,
2H, CH2), 4.00 (s, 1H, NH). dC (62.9 MHz, CDCl3): 147.8,
146.4, 145.7, 129.7, 127.9, 122.7, 120.9, 114.9, 46.2.
HRMS (EI+) calcd for C13H11ClN2O2: 262.0509; found:
262.0493 (Table 1, entry 11).
Benzanilide
mp 161 °C (lit.25a 163 °C). dH (250 MHz, CDCl3): 7.15–
8.08 (complex, 11H, Ph). dC (62.9 MHz, CDCl3): 165.8,
137.9, 133.6, 131.8, 128.8, 128.4, 127.0, 124.6, 120.3.
HRMS (EI+) calcd for C13H11NO: 197.0841; found:
197.0835 (Table 3, entry 1).
N-Methyl-N-phenylbenzylamine
mp 37 °C (lit.25j 38 °C). dH (250 MHz, CDCl3): 7.02–7.27
(m, 7H, Ph), 6.71–6.86 (m, 3H, Ph), 4.33(s, 2H, CH2), 3.11
(s, 3H, Me). dC (62.9 MHz, CDCl3): 149.4, 135.9, 129.7,
128.7, 126.0, 125.2, 117.4, 112.6, 59.3, 38.1. HRMS (EI+)
calcd for C14H15N: 197.1204; found: 197.1193 (Table 1, en-
try 12).
4-Methyl-N-phenylbenzamide
mp 147 °C (lit.26a 145 °C). dH (250 MHz, CDCl3): 7.90 (s,
1H, NH), 7.68 (d, 2H, J = 8.0 Hz, Ph), 7.59 (d, 2H, J =
7.6 Hz, Ph), 7.42 (t, 2H, J = 7.8 Hz, Ph), 7.25 (d, 2H, J =
8.2 Hz, Ph), 7.23 (t, 1H, J = 7.4 Hz, Ph), 2.38 (s, 3H, Me).
dC (62.9 MHz, CDCl3): 167.2, 142.5, 137.8, 131.6, 129.5,
129.1, 128.4, 124.6, 119.8, 21.3. HRMS (EI+) calcd for
C14H13NO: 211.0997; found: 211.0988 (Table 3, entry 2).
N-(1-Phenylethyl)aniline
mp 52 °C (lit.25k 50 °C). dH (250 MHz, CDCl3): 6.63–6.64
(m, 2H, Ph), 6.74–6.80 (m, 1H, Ph), 7.18–7.22 (m, 2H, Ph),
7.31–7.33 (m, 1H, Ph), 7.40–7.49 (m, 4H, Ph), 4.53 (q, 1H,
J = 6.4 Hz, CH), 4.04 (s, 1H, NH), 1.50 (d, 3H, J = 6.4 Hz,
Me). dC (62.9 MHz, CDCl3): 147.2, 145.2, 129.1, 128.6,
126.8, 125.8, 117.2, 113.3, 53.2, 24.9. HRMS (EI+) calcd
for C14H15N: 197.1204; found: 197.1196 (Table 1, entry 13).
4-Nitro-N-phenylbenzamide
mp 211–213 °C (lit.26b 211–212 °C). dH (250 MHz, d6-
DMSO): 10.54 (s, 1H, NH), 8.36 (d, 2H, J = 8.8 Hz, Ph),
8.16 (d, 2H, J = 8.8 Hz, Ph), 7.76 (d, 2H, J = 8.3 Hz, Ph),
7.36 (m, 2H, Ph), 7.10–7.15 (m, 1H, Ph). dC (62.9 MHz,
CDCl3): 164.2, 157.5, 134.1, 133.8, 129.2, 128.7, 124.1,
123.5, 120.4. HRMS (EI+) calcd for C13H10N2O3: 242.0691;
found: 242.0680 (Table 3, entry 3).
4-Chloro-N-(1-phenylethyl)aniline
mp 59 °C (lit.25k 62 °C). dH (250 MHz, CDCl3): 7.29–7.33
(m, 4H, Ph), 7.21–7.25 (m, 1H, Ph), 7.00–7.02 (m, 2H, Ph),
6.40–6.43 (m, 2H, Ph), 4.41 (q, 1H, J = 6.6 Hz, CH), 4.03
(s, 1H, NH), 1.53 (d, 3H, J = 6.6 Hz, Me). dC (62.9 MHz,
CDCl3): 145.7, 144.6, 128.9, 128.7, 127.0, 125.7, 121.8,
114.3, 53.5, 24.9. HRMS (EI+) calcd for C14H14ClN:
231.0815; found: 231.0809 (Table 1, entry 14).
N-(4-Methoxyphenyl)benzamide
mp 154 °C (lit.26c 156–157 °C). dH (250 MHz, CDCl3):
7.77 (d, 2H, J = 8.1 Hz, Ph), 7.64 (s, 1H, NH), 7.39–7.61
(m, 5H, Ph), 6.78 (d, 2H, J = 8.5 Hz, Ph), 3.85 (s, 3H,
OMe). dC (62.9 MHz, CDCl3): 165.7, 155.9, 137.1, 132.3,
131.2, 128.9, 127.5, 122.0, 114.9, 55.4. HRMS (EI+) calcd
for C14H13NO2: 227.0946; found: 227.0940 (Table 3, entry
4).
4-Methoxy-N-(1-phenylethyl)aniline25k
dH (250 MHz, CDCl3): 7.20–7.38 (m, 5H, Ph), 6.66–6.69
(d, 2H, J = 8.4 Hz, Ph), 6.44–6.47 (d, 2H, J = 8.4 Hz, Ph),
4.42 (q, 1H, J = 6.6 Hz, CH), 3.60 (S, 3H, OMe), 1.47 (d,
3H, J = 6.6 Hz, Me). dC (62.9 MHz, CDCl3): 151.9, 144.4,
141.5, 128.6, 126.8, 125.9, 114.7, 114.5, 55.7, 54.2, 25.0.
HRMS (EI+) calcd for C15H17NO: 227.131; found: 227.130
(Table 1, entry 15).
N-(4-Methoxyphenyl)-4-nitrobenzamide
mp 198–200 °C (lit.26d 199–201 °C). dH (250 MHz, d6-
DMSO): 10.45 (s, 1H, NH), 8.33 (d, 2H, J = 8.7 Hz, Ph),
8.16 (d, 2H, J = 8.7 Hz, Ph), 7.70 (d, 2H, J = 8.9 Hz, Ph),
6.93 (d, 2H, J = 8.9 Hz, Ph), 3.74 (s, 3H, OMe). dC
(62.9 MHz, d6-DMSO): 163.3, 155.8, 149.0, 140.6, 131.7,
129.0, 123.4, 122.0, 113.7, 55.1. HRMS (EI+) calcd for
C14H12N2O4: 272.0797; found: 272.0785 (Table 3, entry 5).
Tribenzylamine
mp 91 °C (lit.25l 91 °C). dH (250 MHz, CDCl3): 7.44–7.21
(m, 15H, Ph), 3.56 (s, 6H, CH2). dC (62.9 MHz, CDCl3):
140.1, 129.2, 128.6, 127.3, 58.3. HRMS (EI+) calcd for
C21H21N: 287.1674; found: 287.1670 (Table 1, entry 18).
N-Benzylmorpholine
mp 168 °C (lit.25l 170 °C). dH (250 MHz, CDCl3): 7.20–
7.29 (m, 5H, Ph), 3.68 (t, 4H, J = 4.8 Hz, CH2), 2.41 (t,
4H, J = 4.6 Hz, CH2), 3.45 (s, 2H, PhCH2). dC (62.9 MHz,
CDCl3): 137.7, 129.2, 128.2, 127.1, 67.0, 63.5, 53.6. HRMS
N-(4-Methoxyphenyl)-4-methylbenzamide
mp 166 °C (lit.26e 166 °C). dH (250 MHz, CDCl3): 9.35 (s,
1H, NH), 7.88 (d, 2H, J = 8.4 Hz, Ph), 7.73 (d, 2H, J =
9.3 Hz, Ph), 7.28 (d, 2H, J = 8.4 Hz, Ph), 6.90 (d, 2H, J =
Published by NRC Research Press

Nowrouzi and Jonaghani
507
9.3 Hz, Ph), 3.77 (s, 3H, OMe), 2.38 (s, 3H, Me). dC
(62.9 MHz, CDCl3): 164.8, 156.3, 141.8, 131.2, 129.2,
128.2, 127.4, 114.5, 55.9, 24.3. HRMS (EI+) calcd for
C15H15NO2: 241.1103; found: 241.1100 (Table 3, entry 6).
4-Methyl-N-methyl-N-phenylbenzamide
mp 66 °C (lit.26l 68 °C). dH (250 MHz, CDCl3): 7.21 (m,
4H, Ph), 7.13 (tt, 1H, J = 1.2, 6.6 Hz, Ph), 7.00 (d, 2H, J =
7.2 Hz, Ph), 6.94 (d, 2H, J = 7.8 Hz, Me), 3.46 (s, 3H), 2.24
(s, 3H, Me). dC (62.9 MHz, CDCl3): 170.7, 145.2, 139.8,
132.9, 129.1, 128.9, 128.3, 126.8, 126.3, 38.5, 21.3. HRMS
(EI+) calcd for C15H15NO: 225.1154; found: 225.1141 (Ta-
ble 3, entry 14).
N-(4-Chlorophenyl)benzamide
mp 187 °C (lit.26f 188–190 °C). dH (250 MHz, CDCl3):
7.75 (d, 2H, J = 7.0 Hz, Ph), 7.71 (s, 1H, NH), 7.64–7.52
(m, 5H, Ph), 7.43 (d, 2H, J = 8.7 Hz, Ph). dC (62.9 MHz,
CDCl3): 163.9, 137.3, 132.2, 128.9, 127.6, 126.7, 126.1,
121.6, 120.8. HRMS (EI+) calcd for C13H10ClNO:231.0451;
found: 231.0442 (Table 3, entry 7).
N-Phenylpropionamide
mp 97–99 °C (lit.26m 98–100 °C). dH (250 MHz, CDCl3):
7.15 (s, 1H, NH), 7.07–7.52 (m, 5H, Ph), 2.39 (2H, q, J =
7.5 Hz, COCH2), 1.25 (3H, t, J = 7.5 Hz, COCH2CH3). dC
(62.9 MHz, CDCl3): 172.0, 137.9, 128.9, 124.1, 119.7, 30.7,
9.6. HRMS (EI+) calcd for C9H11NO: 149.0841; found:
149.0834 (Table 3, entry 15).
N-(3-Nitrophenyl)benzamide
mp 155 °C (lit.26g 157 °C); dH (250 MHz, d6-DMSO): 9.80
(s, 1H, NH), 7.52–7.55 (m, 1H, Ph), 7.42 (s, 1H, Ph), 7.23–
7.37 (m, 6H, Ph), 6.86–6.89 (m, 1H, Ph). dC (62.9 MHz,
CDCl3): 164.8, 148.6, 136.8, 134.2, 132.2, 129.9, 128.9,
127.7, 127.5, 116.7, 115.5. HRMS (EI+) calcd for
C13H10N2O3: 242.0691; found: 242.0684 (Table 3, entry 8).
N-Phenylbenzothioamide
mp 102–103 °C (lit.26n 100–101 °C). dH (250 MHz,
CDCl3): 9.00 (s, 1H, NH), 7.27–7.87 (m, 10H, Ph). dC
(62.9 MHz, CDCl3): 198.4, 142.8, 139.1, 131.3, 129.0,
128.5, 127.2, 127.0, 124.0. HRMS (EI+) calcd for
C13H11NS: 213.0612; found: 213.0601 (Table 3, entry 16).
N-(4-Nitrophenyl)benzamide
mp 197 °C (lit.26h 198–199 °C). dH (250 MHz, d6-DMSO):
9.95 (s, 1H, NH),7.83–8.18 (d, 2H, J = 7.2 Hz, Ph), 7.69–
7.76 (m, 3H, Ph), 7.39–7.55 (m, 4H, Ph). dC (62.9 MHz, d6-
DMSO): 164.0, 143.1, 141.4, 131.6, 129.2, 128.6, 128.1,
123.3, 120.0. HRMS (EI+) calcd for C13H10N2O3: 242.0691;
found: 242.0681 (Table 3, entry 9).
N-Phenylethanethioamide
mp 74–76 °C (lit.26n 75–76 °C). dH (250 MHz, CDCl3):
9.51 (s, 1H, NH), 7.33–7.48 (m, 5H, Ph), 2.75 (s, 3H, Me).
dC (62.9 MHz, CDCl3): 200.7, 137.8, 128.8, 127.1, 124.4,
30.1. HRMS (EI+) calcd for C8H9NS: 151.0456; found:
151.0441 (Table 3, entry 17).
N-Benzylbenzamide
mp 104–106 °C (lit.26i 103–104 °C). dH (250 MHz,
CDCl3): 7.70 (d, 2H, J = 8.4 Hz, Ph), 7.21–740 (m, 8H,
Ph), 6.53 (s, 1H, NH), 4.54 (d, 2H, J = 5.7 Hz, CH2). dC
(62.9 MHz, CDCl3): 167.4, 138.2, 134.4, 131.5, 128.8,
128.6, 127.9, 127.6, 127.0, 44.1. HRMS (EI+) calcd for
C14H13NO: 211.0997; found: 211.0990 (Table 3, entry 10).
Acknowledgements
We thank the Persian Gulf University Research Council for
generous partial financial support of this study.
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mp 104–106 °C (lit.26k 103–104 °C). dH (250 MHz,
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Ph), 6.71–6.93 (m, 5H, Ph), 3.52 (s, 3H, Me). dC
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C14H13NO: 211.0997; found: 211.0987 (Table 3, entry 12).
N-Methyl-4-nitro-N-phenylbenzamide
mp 109–111 °C (lit.26a 106–107 °C). dH (250 MHz,
CDCl3): 8.01–8.33 (m, 4H, Ph), 6.63–6.82 (m, 5H, Ph), 3.46
(s, 3H, Me). dC (62.9 MHz, CDCl3): 165.7, 150.6, 144.3,
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