CDI-mediated monoacylation of symmetrical diamines and selective acylation of primary amines of unsymmetrical diamines

Article abstract of DOI:10.1039/c1gc16314k

A highly efficient and green protocol for monoacylation of symmetrical diamines and chemoselective acylation of primary amines of unsymmetrical diamines has been developed.

Full text of DOI:10.1039/c1gc16314k

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
Green Chemistry
Cite this: Green Chem., 2012, 14, 326
www.rsc.org/greenchem
COMMUNICATION
CDI-mediated monoacylation of symmetrical diamines and selective
acylation of primary amines of unsymmetrical diamines†
Sanjeev K. Verma,* Ramarao Ghorpade, Ajay Pratap and M. P. Kaushik*
Received 21st October 2011, Accepted 18th November 2011
DOI: 10.1039/c1gc16314k
A highly efficient and green protocol for monoacylation
of symmetrical diamines and chemoselective acylation
of primary amines of unsymmetrical diamines has been
developed.
dry organic solvent was required. Further the synthesis of acyl
chloride for reactants with active methylene group, e.g. phenyl
acetic acid and derivatives, involves various side chain reactions
causing reduction in yield. In order to overcome these limitations
and to develop a new green protocol, CDI-mediated one-step
synthesis of acyl imidazole from carboxylic acid was attempted.
N,N-Carbonyldiimidazole (CDI) is widely used for the
synthesis of amides from carboxylic acids and amines.8 It is
synthesized by the reaction of phosgene and imidazole in highly
leak-proof systems in industry. It is easy to handle and is less
toxic compared to phosgene or thionyl chloride. The synthesis
of amides using CDI is mainly carried out in one-pot two-step
reactions of acid and amine mediated by CDI. The first step of
the reaction involves the reaction of carboxylic acid and CDI
in dry aprotic solvent (e.g. dry THF or toluene) under nitrogen
atmosphere until release of CO2 gas ceases and the intermediate
acyl imidazole is formed (step 1, Scheme 1). The reaction
mainly completed in 2–4 h depending upon the reactant and
the solvent used.4,9
In order to increase the efficiency of the process and to look for
greener alternatives, the reaction was attempted without solvent
and in different organic solvents.10 Phenyl acetic acid was chosen
as model reactant. The progress of the reaction was monitored
with 1H NMR and the disappearance of peak corresponding to
CH2 (d 3.46) was considered as reference. A very encouraging
result was observed. Reaction was fastest without any solvent.
The reaction completed in 5 min and peak corresponding to
CH2 of phenyl acetic acid disappeared and new peak (d 4.18)
corresponding to acyl imidazole appeared. The stability of acyl
imidazole formed was also checked with NMR. It was found that
the product remained stable for 20 min, after which it started
hydrolysing to give parent reactant.
Highly selective reactions capable of selecting one functionality
in the presence of others have applications in a number
of synthetic strategies.1 Such selectivity becomes more
challenging when two functionalities are the same or have
very little reactivity difference. These kinds of selectivities
mainly occur with living organisms/enzymes and have always
attracted synthetic chemists.2 Chemoselective monoacylation of
symmetrical diamines3 or chemoselective acylation of primary
amines in the presence of secondary amines4 are important
examples. Selective monoacylation of diamines is important
as the monoacylated diamines are intermediates for several
well-established drugs.5 The main challenge associated with
such selectivity is a tendency for bis-acylation even with an
excess (10 equiv.) of diamine.3 A number of attempts have
been carried out to solve the problem.3–5 However, till date
the most simple and practical method of monoacylation is
selective monoprotection of one nitrogen atom with BOC in
acidic medium,5 followed by acylation of another nitrogen and
finally deprotection to afford the desired product. However by
this method, the overall yield of the reaction is reduced.
In such a scenario, monoacylation of diamine is of great
interest. It would be a win–win situation from a green chemistry
perspective if the above reaction can be carried out in the
presence of a green solvent or with minimum use of industrially
accepted organic solvents (ethyl acetate or ethanol).6d–e Herein,
we report a highly efficient, scalable, and practical protocol for
monoacylation of symmetrical diamines in brine solution.
Recently, we have developed a protocol for monoacylation of
symmetrical diamines.7 The protocol has lot of advantages; how-
ever the overall yield decreased due to a two step synthesis of acyl
imidazole from carboxylic acid by acyl chloride intermediate and
Various acyl imidazoles 1a–10a (aliphatic, aromatic and
with active methylene group, e.g. derivatives of phenyl
acetic acids 6–10) were synthesised using hte optimized protocol
(Table 1). It is noteworthy that we were able to prepare imidazole
carboxylic esters 11a–12a by the reaction of alcohols and CDI
with 100% conversion within 10 min. The same protocol in dry
toluene required four hours under nitrogen atmosphere.9
After accomplishment of acyl imidazoles 1a–10a and imida-
zole carboxylic esters 11a–12a, the next step involves reaction of
acyl imidazoles with diamines dihydrochloride to give monoa-
cylated diamines.7
Process Technology Development Division, Defence R & D
Establishment, Jhansi Road, Gwalior, 474002, (MP), India.
E-mail: skv002002@gmail.com, mpkaushik@rediffmail.com
† Electronic supplementary information (ESI) available: Experi-
mental procedures and NMR spectra for compounds.See DOI:
10.1039/c1gc16314k
326 | Green Chem., 2012, 14, 326–329
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
Scheme 1
Table 2 Effect of NaCl and imidazole concentration on selectivity
Table 1 Synthesis of acyl imidazole and Imidazole carboxylic esters
Entry B (mol%)
NaCl (%)
C : D
E (%)
F (%)
G (%)
1
2
3
4
5
6
7
8
0.1
0.2
0.4
0.8
1
1
1
1
1
1
1
0
0
0
0
0
0
0
0
1 : 0
1 : 0
1 : 0
1 : 0
1 : 0
1 : 0.5
1 : 1
1 : 2
0 : 1
1 : 1
1 : 1
1 : 1
90
80
70
40
28
35
40
20
10
60
90
90
10
10
5
2
2
25
40
40
90
30
10
10
0
10
25
58
70
40
20
40
0
9
0
10
11
12
10
20
25
10
0
0
Acid/alcohol: CDI (1 : 1.2). 1–10 not isolated and used within 20 min.
11, 12 were isolated.
1
HPLC yield.
Piperazine dihydrochloride and benzoyl imidazole were se-
lected as model reactants and were reacted in ethanol–water
mixture (step 2, route 1 of Scheme 1), as reported earlier.7
To our disappointment, the major products were esters and
acids of the corresponding benzoyl imidazole (step 2, route 1
of Scheme 1). The result was entirely different from our earlier
report7 where N-selective monoacylation was observed. From
these results and from our earlier report7 it was clear that
imidazole/imidazole HCl concentration played an important
role in N-selective monacylation.11
In order to study the effect of imidazole on N-selective
acylation in aqueous medium, acyl imidazole was synthesized
by the reaction of acyl chloride and imidazole7 and subjected
to reaction with piperazine dihydrochloride with different mol%
of imidazole (Table 2, entries 1–5).7 It was observed that acyl
imidazole preferred hydrolysis over amide formation as the
amount of imidazole was increased in the reaction mixture.
We attempted a number of theoretically possible protocols to
reduce imidazole concentration.12 However, all the methods
failed. The reaction was further attempted by using piperazine
and piperazine dihydrochlorides in different ratios (Table 2
entries 6–8). Entry 9, Table 2, indicates N-acylation (E and F)
dominates as the concentration of free piperazine increases in
reaction mixture. The ratio of mono and diacylated product
(E : F) was maximum at 1 : 1 ratio of piperazine and piperazine
dihrochloride (entry 7, Table 2).13 No further improvement
was observed by changing ratio of piperazine and piperazine
dihrochloride (entries 5–9, Table 2).
reaction rates.14 It is expected to decrease ion exchange process
because of common ion effect. In order to achieve chemos-
electivity by decreasing proton exchange between monoacy-
lated/monoprotonated diamines and imidazole, we attempted
the reaction in different concentrations of brine solution (entries
10–12, Table 2). To our surprise, the ratio of mono to diacylated
product started increasing with the increasing concentration of
salt along with decrease in reaction rate. At 20% NaCl solu-
tion, chemoselective monoacylation of piperazine was observed
(route 2, Scheme 1). Further increase in NaCl concentration was
found to have no improvement.
The optimized conditions were attempted for a variety of dif-
ferent reactants (1a to 12a of Table 1) and diamines 13–23 of Fig.
1 for monoacylation and monocarbamate formation (Table 3).
Entries 1–11, 15 and 19–21 of Table 3 indicate good conversion
with secondary cyclic and acyclic diamines, while entries 12, 14
and 16–18 of Table 3 indicate good conversion with primary
diamines. Entries 6–10 of Table 3 indicate good result with
reactants having active methylene group. The protocol was also
attempted for carbamate formation, it was observed from entry
21 and 22 that the protocol gave chemospecific monocarbamate
formation. All the results indicate that the protocol is effective
for cyclic, acyclic, primary as well as secondary diamines for
chemoselective benzoylation and carbamate formation.
The scope of the reaction was further explored for the
highly selective acylation of primary amines in the presence
of secondary amines (Table 4). It is clear from Table 4 that
selectivity is maintained for small alkyl chains as well as for
Recently, brine solution has been reported to influence
various organic transformations by increasing or decreasing the
This journal is
The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 326–329 | 327
©

View Article Online
Table 3 Chemoselective monoacylation and carbamate formation
Table 4 Acylation of primary amines in the presence of secondary
amines
Yielda
C (%)
Yielda
D (%)
Total
yielda
Entry
A
B
C* %
c¢(c¢¢)
D* %
d¢(d¢¢)
E* %
e¢(e¢¢)
Total yield
g¢(g¢¢)
1
2
3
4
5
6
7
8
1a
2a
3a
4a
5a
6a
7a
8a
9a
10a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
11a
12a
13
13
13
13
13
13
13
13
13
13
14
15
16
17
18
19
20
21
22
23
1a
1a
83
90
88
80
70
88
84
80
87
68
80
92
0
68
90
88
80
72
90
88
95
96
5
0
4
8
23
4
5
5
5
20
12
0
0
25
0
88
90
92
88
94
92
89
84
92
88
92
92
0
93
90
92
90
92
92
92
95
96
Entry
R
1
2
3
4
5
methyl
ethyl
propyl
isopropyl
0(0)
0(0)
0(0)
0(0)
88(90)
90(92)
92(90)
96(94)
94(92)
6(3)
5(2)
2(0)
0(0)
0(0)
94(93)
95(94)
94(90)
96(94)
94(92)
4-amino piperidine 0(0)
9
c¢, d¢, e¢,g¢: isolated yield by method 1: acyl imidazole was synthesized
by the reaction of benzoic acid and CDI and was reacted with diamine
monohydrochloride in 20% brine solution. c¢¢, d¢¢, e¢¢,g¢¢: isolated yield
by method 2: acyl imidazole was synthesized by the reaction of acyl
halide and imidazole and was reacted with piperazine dihydrochloride
in ethanol–water mixture.
10
11
12
13
14
15
16
17
18
19
20
21
22
4
10
20
2
4
0
0
a isolated yield.
Scheme 2 Monoacylation of primary amines in the presence of
secondary amines.
amount of imidazole7 or because of equilibrium reaction with
diamine.13 Deprotonation always occurs at primary amines
because they are less basic than secondary amines. The mono-
protonated diamines have only primary free nitrogen, Hence,
chemoselectivity is observed. The diacylation is also controlled
because of slow proton exchange between monoprotonated
diamine or monoacyl diamine with imidazole in brine solution.
In conclusion, we have developed a simple protocol for
monoacylation of symmetrical and unsymmetrical diamines. It
is particularly noteworthy that this protocol is the first example
of monoacylation of symmetrical diamines in brine solution and
selective acylation of primary amines. The protocol is applicable
for monoacylation of a wide variety of substrates. The protocol
is green in nature as it uses only industrially preferred organic
solvents (ethyl acetate and ethanol),6d,6e and further no dry
organic solvent at any stage of reaction is used.
Fig. 1 Amines selected for monoacylation/monocarbamate formation.
sterically hindered isopropyl groups. No acylation of secondary
amine was observed. In line with our anticipation, selectivity of
the present protocol (method 1) was compared with our earlier
report (method 2).7 It was observed that both the methods were
highly efficient for selective acylation of primary amines.
On the basis of these results and literature precedents,
a plausible mechanism for the observed mono-selectivity is
proposed. The acyl imidazole preferred hydrolysis over amide
formation with the reaction of diamine dihydrochloride in
aqueous medium. This may be due to higher reactivity of acyl
imidazole in excess of imidazole, where acyl imidazole hydrolyses
before in situ generation of piperazine monohydrochloride. It has
been verified with NMR that acyl imidazole hydrolyses within
2 min with piperazine dihydrochloride and water. The maxi-
mum conversion was observed with piperazine and piperazine
dihydrochloride (1 : 1 ratio) as it has one free nitrogen available
for acylation.13 Increase in selectivity with brine solution may
be attributed to a decrease in reaction rate or decrease in rate
of proton exchange between diamine monohydrochloride or
monoacylated piperazine with excess of imidazole.
Experimental section
General procedure 1: Synthesis of phenyl-
piperazin-1-yl-methanone
The chemoselective acylation of primary amines is explained
in Scheme 2. The dihydrochloride salt of unsymmetrical di-
amines give monohydrochloride diamines either because of pKa-
controlled selective deprotonation in the presence of a catalytic
In a round bottom flask add 0.01 mole (1.36 g) phenyl acetic
acid and 0.012 moles (1.94 g) of CDI. Mix the reaction mixture
with spatula to start the reaction. CO2 gas starts releasing
with exothermic reaction. Leave the reaction mixture at room
328 | Green Chem., 2012, 14, 326–329
This journal is
The Royal Society of Chemistry 2012
©

View Article Online
temperature for 5 min till solid reaction mixture turned to pale
yellow liquid. In a separate round bottom flask add 0.05 moles
(0.43 g) of piperazine and 0.05 moles (0.80 g) of piperazine
dihydrochloride in 20 ml of water. Stir the reaction mixture
for 5 min and add 4 g of NaCl. Add this brine solution to
the round bottom flask containing acyl imidazole. Stir the
reaction mixture for half hour. The aqueous layer was washed
with 4 ¥ 5 ml of ethyl acetate to remove diacylated product.
10 ml of saturated solution of NaOH was added to the aqueous
layer and washed with ethyl acetate (4 ¥ 10 ml). The aqueous
layer was discarded. The organic layer was washed with water
(4 ¥ 10 ml), dried over anhydrous Na2SO4 and concentrated to
give pale yellow coloured liquid. The pure product 2-phenyl-1-
(piperazin-1-yl)ethanone was purified by flash chromatography
as a colourless liquid.
General procedure 3: Monoacylation of unsymmetrical diamines
Monoacylation of unsymmetrical diamines has been achieved
following general procedure 1 and general procedure of our
earlier report.7
Notes and references
1 For a review, see: N. O. V. Sonntag, Chem. Rev., 1953, 52, 237.
2 (a) J. A. DeMoss, S. M. Genuth and G. D. Novelli, Proc. Natl. Acad.
Sci. U. S. A., 1956, 42, 325–332; (b) L. Gardossi, D. Bianchi and A.
M. Klibanov, J. Am. Chem. Soc., 1991, 113, 6328.
3 T. Wang, Z. Zhang and N. A. Meanwell, J. Org. Chem., 1999, 64,
7661.
4 S. P. Rannard and N. J. Davis, Org. Lett., 2010, 14, 2117.
5 (a) D. A. Walsh, J. B. Green, S. K. Franzyshen, J. C. Nolan and
J. M. Yanni, J. Med. Chem., 1990, 33, 2028; (b) M. Kurokama, F.
Sato, I. Fujiwara, N. Hatano, Y. Honda, T. Yoshida, S. Naruto, J.-I.
Mastumoto and H. Uno, J. Med. Chem., 1991, 34, 927; (c) Z. Zhang,
Z. Yin, N. A. Meanwell, J. F. Kadow and T. Wang, Org. Lett., 2003,
5, 3399; (d) P. M. Manoury, J. L. Binet, A. P. Dumas, F. Lefevre-Borg
and I. Cavero, J. Med. Chem., 1986, 29, 19.
General procedure 2: Synthesis of N-BOC piperazine
(monocarbamate of diamines)
6 (a) A. S. Matlack, Introduction to Green Chemistry, Marcel Dekker,
New York, 2001; (b) A. Bruckmann, A. Krebs and C. Bolm, Green
Chem., 2008, 10, 1131–1141; (c) Y. Hayashi, Angew. Chem., Int. Ed.,
2006, 45, 8103; (d) R. K. Henderson, C. Jimenez-Gonzalez, D. J. C.
Constable, S. R. Alston, G. G. A. Inglis, G. Fisher, J. Sherwood, S.
P. Binks and A. D. Curzons, Green Chem., 2011, 13, 854–862; (e) K.
Alfonsi, J. Colberg, P. J. Dunn, T. Fevig, S. Jennings, T. A. Johnson,
H. P. Kleine, C. Knight, M. A. Nagy, D. A. Perry and M. Stefaniak,
Green Chem., 2008, 10, 31–36.
The synthesis is mainly carried out in two steps. First step,
synthesis of tert-butyl 1H-imidazole-1-carboxylate: In a round
bottom flask add 0.01 mol (0.75 g) of t-butanol and 0.012
mole (1.94 g) of CDI. Stir the reaction mixture for 10 min
at 40 ◦C. Add 10 ml of ethyl acetate in it. Wash the organic
layer with 2 ¥ 5 ml of 0.1 N HCl and 2 ¥ 10 ml of water. Dry
organic layer over anhydrous Na2SO4 and concentrated to give
coloured liquid. The product formed is enough pure to be used
for next step. Second step, synthesis of N-BOC piperazine: In a
separate round bottom flask add 0.05 mol (0.43 g) of piperazine
and 0.005 mol (0.80 g) of piperazine dihydrochloride in 20 ml
of water. Stir the reaction mixture for 5 min and add 4 g of
NaCl. Add tert-butyl 1H-imidazole-1-carboxylate from first step
to the brine solution. Stir the reaction mixture for half hour.
10 ml of saturated solution of NaOH was added to the aqueous
layer and washed with ethyl acetate (4 ¥ 15 ml). The aqueous
layer was discarded. The organic layer was washed with water
(4 ¥ 5 ml), dried over anhydrous Na2SO4 and concentrated
to give pale yellow coloured liquid. The pure product N-BOC
piperazine was purified by flash chromatography as a colourless
liquid.
7 S. K. Verma, B. N. Acharya and M. P. Kaushik, Org. Lett., 2010, 12,
4232.
8 H. A. Staab, Angew. Chem., Int. Ed. Engl., 1962, 1, 351.
9 S. P. Rannard and N. J. Davis, Org. Lett., 2010, 12, 4232.
10 CDCl3, DMSO, C6D6 and neat. In neat conditions, the reaction was
performed without solvent and NMR was recorded in CDCl3.
11 Route 1 of Scheme 1 gave one mole of imidazole for every mole
of acyl imidazole formed, while in an earlier report7 imidazole HCl
formed was filtered off and catalytic amount of imidazole HCl left in
reaction mixture.
12 For example, use of acid, solid supports and imidazole complexing
agents.
13 Piperazine monohydrochloride was formed by equilibrium reaction
of piperazine and piperazine dihydrochloride (1 : 1) as reported in: J.
C. Craig and R. J. Young, Org. Synth., Coll., 1973, 5, 88.
14 (a) Brine solution: V. Maya, M. Raj and V. K. Singh, Org. Lett., 2007,
9, 13; (b) Benjamin List, Chem. Rev., 2007, 107, 5413; (c) Y. Hayashi,
Angew. Chem., Int. Ed., 2006, 45, 8103.
This journal is
The Royal Society of Chemistry 2012
Green Chem., 2012, 14, 326–329 | 329
©