Imidazole-catalyzed monoacylation of symmetrical diamines

Article abstract of DOI:10.1021/ol101604q

Figure Presented. An imidazole-catalyzed protocol for monoacylation of symmetrical diamines has been developed. The protocol gave selective monoacylation of aliphatic (cyclic and acyclic) primary and secondary diamines. In the reaction, imidazole acts as both catalyst and a leaving group. Different monoacylated piperazines and other diamines were synthesized at room temperature in an ethanol/water solvent system.

Full text of DOI:10.1021/ol101604q

ORGANIC
LETTERS
2010
Vol. 12, No. 19
4232-4235
Imidazole-Catalyzed Monoacylation of
Symmetrical Diamines
Sanjeev K. Verma, B. N. Acharya, and M. P. Kaushik*
Process Technology DeVelopment DiVision, Defence R & D Establishment,
Jhansi Road, Gwalior-474002 (MP) India
mpkaushik@rediffmail.com
Received April 17, 2010
ABSTRACT
An imidazole-catalyzed protocol for monoacylation of symmetrical diamines has been developed. The protocol gave selective monoacylation
of aliphatic (cyclic and acyclic) primary and secondary diamines. In the reaction, imidazole acts as both catalyst and a leaving group. Different
monoacylated piperazines and other diamines were synthesized at room temperature in an ethanol/water solvent system.
Monoacylated symmetrical diamines are building blocks1 or
intermediates2 of several well-established drugs such as
cardiotonic agent vesnarinone and the antihypertensive agent
prazosin.3 The synthesis of these compounds involves
chemoselective acylation on one nitrogen of symmetrical
diamines. However, the direct monoacylation of symmetrical
diamines is frequently fraught with a complication associated
with the tendency for bisacylation even with a large excess
these conditions is that the monoacylated intermediate is
more soluble in the solvent (aprotic) than the original
diamine.4 Plethoras of indirect5,6 and direct4,7 syntheses of
monoacylated symmetric diamines are reported. However,
the reported methods either use dry conditions at very low
temperature (-78 °C)7 or have used reactants not readily
available or difficult to synthesize.8 Some polymer-supported
reactions9 are also reported; however, all these methods did
(10 equiv) of diamine to acyl halides in aprotic solvent.4a
A
possible explanation of the uncontrollable diacylation under
(3) (a) Ohnishi, A.; Ishizaki, J. Clin. Pharmacol. 1988, 28, 719. (b)
Ravina, E.; Teran, C.; Santana, L.; Garcia, N.; Estevez, I. Heterocycles
1990, 31, 1967. (c) Scriabine, A.; Constantine, J. W.; Hess, H.-J.; McShane,
W. K. Experientia 1980, 24, 1150.
(1) (a) Fukushi, H.; Mabuchi, H.; Terashita, Z.-I.; Nishikawa, K.;
Sugihara, H. Chem. Pharm. Bull. 1994, 42, 551. (b) Ross, D. D.; Lednicer,
D. J. Heterocycl. Chem. 1982, 91, 975. (c) Walsh, D. A.; Green, J. B.;
Franzyshen, S. K.; Nolan, J. C.; Yanni, J. M. J. Med. Chem. 1990, 33,
2028. (d) Kurokama, M.; Sato, F.; Fujiwara, I.; Hatano, N.; Honda, Y.;
Yoshida, T.; Naruto, S.; Mastumoto, J.-I.; Uno, H. J. Med. Chem. 1991,
34, 927. Leonardi, A.; Motta, G.; Boi, C.; Testa, R.; Poggesi, E.; De
Benedetti, G.; Menziani, M. C. J. Med. Chem. 1999, 42, 427.
(2) (a) Williams, L.; Booth, S. E.; Undheim, K. Tetrahedron 1994, 50,
13697. (b) Li, R.-T.; Ding, P.-Y.; Han, M.; Cai, M.-S. Synth. Commun.
1998, 28, 295.
(4) (a) Wang, T.; Zhang, Z.; Meanwell, N. A. J. Org. Chem. 1999, 64,
7661. (b) Zhang, Z.; Yin, Z.; Meanwell, N. A.; Kadow, J. F.; Wang, T.
Org. Lett. 2003, 5, 3399. (c) Luna, A.; Alfonso, I.; Gotor, V. Org. Lett.
2002, 4, 3627. (d) Kelly, T. R.; Cavero, M. Org. Lett. 2002, 4, 2653.
(5) (a) Manoury, P. M.; Binet, J. L.; Dumas, A. P.; Lefevre-Borg, F.;
Cavero, I. J. Med. Chem. 1986, 29, 19. (b) Dhawan, B.; Southwich, P.N. L.
Org. Prep. Proced. Int. 1975, 7, 85. (c) Southwich, P. L.; Dhawan, B. Org.
Prep. Proced. Int. 1976, 8, 205. (d) Lyle, R. E.; Coppola, B. P.; Saavedra,
J. E.; Lyle, G. G. Org. Prep. Proced. Int. 1978, 10, 304.
10.1021/ol101604q  2010 American Chemical Society
Published on Web 09/02/2010

not have synthetic applicability. Due to these limitations, a
simple and direct monoacylation of symmetrical diamines
was required to be developed. To date, the most simple and
practical method of monoacylation is selective monoprotec-
tion of one nitrogen atom with BOC in acidic medium,
followed by acylation of another nitrogen and finally
deprotection to afford the desired product.5 However, by this
method, the overall yield of the reaction is reduced.
imidazole and piperazine and piperazine dihydrochloride (1:
1) in different solvent systems (DCM, acetonitrile, ethanol,
water, and ethanol-water mixture) (entries 1-5, Table 1).
Table 1. Standardization of Reaction Conditions
In continution of our work on the synthesis of bioactive
compounds, we required the quantitative scale syntheses of
a library of monoacylated diamines as reaction intermediates.
Since no method was available in the literature, a new
method was required. Herein, we report the monoacylation
of symmetrical diamines by the use of imidazole as a leaving
group as well as a catalyst in the water/ethanol system.
Tosyl imidazole is a well-known reagent used for esteri-
fication reactions.10 Because of the lesser reactivity of the
reagent, it is also used for selective esterification between
two diols.11 The same method was attempted for selective
amide formation by the reaction of benzoic acid and
piperazine in the presence of tosyl imidazole (Scheme 1).
diamine
ratio (2:3)
entry
solvent
DCM
acetonitrile
ethanol
ratioa (4:5) yieldb (4) %
1
2
3
4
1:1
1:1
1:1
1:1
1:1
2:3
3:2
3:1
10
10
30
40
water
ethanol +
water (1:1)
ethanol +
water (1:1)
ethanol +
water (1:1)
ethanol +
water (1:1)
ethanol +
water (1:1)
ethanol +
water (1:1)
ethanol +
water (1:1)
ethanol +
water (1:1)
ethanol +
water (1:1)
ethanol +
water (1:1)
5
1:1
1:2
1:4
1:6
1:8
0:1
2:1
4:1
8:1
1:0
4:1
4:1
5:1
5:1
7:1
9:1
4:1
3:1
1:2
1:4
50
57
65
71
74
80
40
38
25
10
6
Scheme 1
7
8
9
10
11
12
13
14
Interestingly, instead of attaining the amide of acid, a
selective tosyl group transfer on one NH bond of the
piperazine was observed. When the same reaction was
repeated without the use of an acid source, predominately
ditosylated product was obtained. This observation gave us
an idea that selective monoacylation can be carried out by
the reaction of acyl imidazole and diamines in the presence
of an acid source.
a Determined by LC-MS. b LC-MS yield of monoacylated product.
The reaction of benzoyl imidazole and piperazine in the
presence of benzoic acid was attempted for a selective
N-acylation reaction.12 To our disappointment, the reaction
gave only 30% monoacylated product, and no improvement
in the result was observed with the change of reaction
conditions. The reaction was then attempted between benzoyl
An improvement in results with 50% monoacylation was
observed with the ethanol-water (1:1) mixture as a solvent
system. A mixture of piperazine and piperazine dihydro-
chloride was used to synthesize the monohydrochloride salt
of piperazine by an equilibrium reaction.13 The ethanol-water
system (1:1) was found to be the best solvent, essentially
because all the components of the reaction, e.g., piperazine,
piperazine dihydrochloride, and acyl imidazole, are soluble.
After optimizing the solvent system, the reaction parameters
were standardized by changing the ratio of piperazine to
piperazine dihydrochloride (entries 6-14, Table 1). It was
observed that a direct correlation exists between yield and
molar ratio of piperazine dihydrochloride. Surprisingly, 80%
monoacylation was observed with 100% piperazine dihy-
drochloride (entry 10, Table 1).
(6) Dorokhova, M. I.; Alekseeva, E. N.; Kuznetsova, I. A.; Portnov,
M. A.; Rozanova, Y. M.; Tikhnova, O. Y.; Mikhalev, V. A. Pharm. Chem.
J. 1974, 737, and references therein.
(7) (a) Jacobi, K. Ber. Chem. 1933, 66, 113. (b) Cymerman-Craig, J.;
Rogers, W. P.; Tate, M. E. Aust. J. Chem. 1956, 9, 397. (c) Desai, M.;
Watthey, J. W. H.; Zuckerman, M. Org. Prep. Proced. Int. 1976, 8, 85.
Masaguer, C. F.; Ravina, E. Tetrahedron Lett. 1996, 37, 5171.
(8) Picard, C.; Arnaud, N.; Tisnes, P. Synthesis 2001, 10, 1471.
(9) Wang, Y.; Jin, J.; Moore, M. L.; Graybill, T. L.; Wang, F.; Wang,
M. A.; Wang, B.; Jin, Q.; Rivero, R. A. Tetrahedron Lett. 2004, 45, 6645.
(10) Soltani, M. N. R.; Behrouz, S.; Faghihi, M. A.; Khalafi-Nezhad,
A. Tetrahedron Lett. 2008, 49, 1115.
(11) Wang, Z.; He, G.; Lu, R. Monatsh. Chem. 2008, 139, 1109.
(12) The benzoyl imidazole for the reaction was synthesized by the
reaction of benzoyl chloride and imidazole in 1:2 ratios in DCM. The
imidazole hydrochloride formed in the reaction was filtered off, and the
organic layer was concentrated under vacuum and used as such.
(13) Craig, J. C.; Young, R. J. Org. Synth., Coll. 1973, 5, 88.
Org. Lett., Vol. 12, No. 19, 2010
4233

The standardized reaction condition was attempted with
a wide variety of the reactant and is presented in Table 2. It
is observed from Table 2 that the protocol gave a good result
for a wide range of substrates. Entries 1-7 and 9 indicate
good yield for the monoacylation of cyclic secondary
diamines with substituated benzoyl chlorides and ethanoyl
chloride. Entry 8 shows that no reaction was observed when
an alkyl group is present adjacent to a secondary amine. This
might be attributed to steric hindrance around the amine.
This phenomenon was expoited to examine acylation of
unsymmetrical 2,6-dimethylpiperazine, for which only monoa-
cylated product was formed (entry 9, Table 2). Similar to
this, when tosylation was carried out on symmetrical diamine,
chemospecific tosylation on one nitrogen was obsereved with
no sign of ditosylated product.
Table 2. Acylation of Symmetrical Diamines and Amino
Alcohols
Selectivity for monoacylation was found to decrease for
both primary and secondary diamines with an increase in
carbon chain length (entries 10-12 and 13-16, Table 2).
This led to the decrease in yield for monoacylated products.
Probably, the amino groups of diamine behave more as
amino groups of monoamine with an increase in chain length.
The protocol for monoacylation was also attempted for
chemoselective acylation and tosylation of the NH group in
aminoalcohols. In this case, chemospecific acylation and
tosylation were observed only at nitrogen. However, when
the same reaction was attempted with a conventional method,
the reaction gave a mixture of O-acylated, N-acylated, and
diacylated product.14 All the results indicate that the protocol
is effective for cyclic and acyclic aliphatic diamines and
aminoalcohals for acylation, benzoylation, and tosylation,
respectively.
After standardization of the reaction conditions, the
upscaling of the reaction with benzoyl imidazole and
piperazine dihydrochloride as model reactant was carried out.
It was observed that the reaction gave good results with 0.1
mol of benzoyl imidazole with 74% (14 g) of isolated
monacylated product.
On the basis of the above observations and literature
reports, a plausible mechanism for the observed selectivity
for the monoacylation of symmetrical diamines (considering
piperazine as the model substrate) is proposed in Scheme 2.
Selective formation of piperazine monohydrochloride and
the lower pKa of imidazole (pKa ) 6.95)15 than monoben-
zoylated piperazine hydrochloride (pKa )7.78)16 are the key
factors for monobenzoylation. To validate our hypothesis,
pure benzoyl imidazole was reacted with piperazine dihy-
drochloride under the same reaction conditions. Surprisingly,
no benzoylation was observed. This is because in piperazine
dihydrochloride both the nitrogens are protected and hence
not available for reaction. However, when a catalytic amount
of imidazole was added, good yield was observed. Imidazole
(pKa ) 6.95)15 can abstract the proton from piperazine
dihydrochloride (pKa ) 9.82)15 to give piperazine monohy-
(14) Reaction of benzoyl chloride with aminoalcohols in DCM at
0 °C.
(15) Albert, A.; Serjeant, E. P. The Determination of Ionization
Constants, 2nd ed.; Chapman and Hall Ltd.: London; 1971; Chapter 8, pp
94-95.
a 4:5 LC-MS ratio. b Isolated yield of monoacylated product. c LC-MS
yield. R is RCO for tosyl group.
(16) Hall, H. K., Jr. J. A.m. Chem. Soc. 1957, 79, 5441.
4234
Org. Lett., Vol. 12, No. 19, 2010

an impurity when we used the benzoyl imidazole produced
by the reaction of benzoyl chloride and imidazole as such
without purification.
Scheme 2. Mechanism of Monoacylation
When a mixture of piperazine and piperazine dihydro-
chloride was used, a significant amount of diacylated
products were obtained with an increase in the molar ratio
of piperazine (Table 1, entries 11-14). This might be
attributed to the reaction of acyl imidazole with free
piperazine present in an equilibrium mixture of piperazine,
piperazine monohydrochloride, and piperazine dihydrochlo-
ride.
Acyl imidazole is highly essential in the reaction system
for two reasons. First, it is the source of imidazole, a weak
base which primarily converts piperazine dihydrochloride to
monohydrochloride. Second, imidazole is a better leaving
group and weaker nucleophile than piperazine monohydro-
chloride which facilitates the formation of acyl piperazine
from acyl imidazole.
In conclusion, a novel, simple, and scalable method for
monoacylation of symmetrical diamines was developed. The
protocol has a wide range of applicability and is also useful
for chemoselective tosylation of symmetrical amines and
aminoethanols.
drochloride (pKa ) 5.68)15 in situ (step 1, Scheme 2). The
free nitrogen atom reacts with benzoyl imidazole to generate
the N-benzoyl piperazine monohydrochloride and an imida-
zole molecule (step 2, Scheme 2). The free imidazole again
follows step 1. In this way, the process undergoes a cyclic
pathway of in situ generation of imidazole and piperazine
monohydrochloride. Furthermore, due to lower pKa value,
imidazole could not abstract the proton from N-benzoyl
piperazine hydrochloride (pKa ) 7.78). In the reported
process, this catalytic amount of imidazole was present as
Supporting Information Available: General experimental
1
procedures for monoacylation and H and 13C spectra for
the representative compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL101604Q
Org. Lett., Vol. 12, No. 19, 2010
4235