Direct synthesis of N-acylalkylenediamines from carboxylic acids under mild conditions

Article abstract of DOI:10.1081/SCC-200026630

Monoacylated piperazine derivatives were prepared directly from carboxylic acids and piperazine using triphenylphosphine (TPP) and N-bromosuccinimide (NBS) in dichloromethane. Inexpensive and readily available reagents, excellent yields, short reaction times and mild reaction conditions are important features of this method.

Full text of DOI:10.1081/SCC-200026630

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Direct Synthesis of
N‐Acylalkylenediamines from
Carboxylic Acids Under Mild
Conditions
a
a
B. P. Bandgar & S. V. Bettigeri
a
Organic Chemistry Research Laboratory, School
of Chemical Sciences, Swami Ramanand Teerth
Marathwada University, Vishnupuri, Nanded,
431606, India
Version of record first published: 06 Jan 2011.
To cite this article: B. P. Bandgar & S. V. Bettigeri (2004): Direct Synthesis of
N‐Acylalkylenediamines from Carboxylic Acids Under Mild Conditions, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 34:16, 2917-2924
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w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 16, pp. 2917–2924, 2004
Direct Synthesis of N-Acylalkylenediamines
from Carboxylic Acids Under Mild
Conditions
*
B. P. Bandgar and S. V. Bettigeri
Organic Chemistry Research Laboratory, School of Chemical Sciences,
Swami Ramanand Teerth Marathwada University, Vishnupuri,
Nanded, India
ABSTRACT
Monoacylated piperazine derivatives were prepared directly from
carboxylic acids and piperazine using triphenylphosphine (TPP) and
N-bromosuccinimide (NBS) in dichloromethane. Inexpensive and
readily available reagents, excellent yields, short reaction times
and mild reaction conditions are important features of this method.
Key Words: Monoacylated derivatives of diamines; Triphenyl-
phosphine; N-bromosuccinimide; Carboxylic acids.
*
Correspondence: B. P. Bandgar, Organic Chemistry Research Laboratory, School of
Chemical Sciences, Swami Ramanand Teerth Marathwada University, Vishnupuri,
Nanded 431606, India; Fax: 0091-2462-229245; E-mail: bandgar_bp@yahoo.com.
2
917
DOI: 10.1081/SCC-200026630
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2
918
Bandgar and Bettigeri
INTRODUCTION
The importance of monoacylated piperazine derivatives in materials and
medicinal chemistry has developed various methods for their preparation. The
method involving the conversion of esters to amides is somewhat limited
[
1]
[2–8]
because it requires either drastic conditions or special reagents
may interfere with other functional groups in the molecule. Milder catalysts
that
[
9]
[10]
such as 2-pyridone
however, the generality of these reactions has not been examined. Another
and boron tribromide
have also been used;
[
11]
[12]
[13]
method using activated amines such as tin,
titanium,
and aluminium
amides has been addressed; however, no practical technique is available for
the synthesis of tertiary amides. Direct monoacylation of symmetrical
[14]
diamines becomes frequently problematic due to competitive bis-acylation.
For instance, under normal basic conditions, the bis-adduct is isolated as the
major product. A possible explanation for the uncontrollable bis-acylation
of the symmetrical secondary diamines under these conditions is that
the monobenzoylated intermediate is more soluble in the solvent than pipera-
zine and it reacts preferentially with the aryl carboxyl derivative to provide the
observed bis-acylated product. Therefore, a number of indirect multistep
[
15a–d]
processes have been developed,
which involve protecting one of the
nitrogen atoms, acylating the other and deprotecting to give the desired
products. The same objective was also achieved by a rather laborious
procedure involving the addition of starting materials in several batches
[15e]
with very cautious control of the pH value of the reaction system.
problem of bis-acylation can be somewhat circumvented using recently
The
[16–18]
reported methods.
However, these methods suffer from drawbacks,
such as the use of a strongly basic lithium reagent, drastic reaction conditions,
long reaction times, the use of aggressive and expensive reagents, application
to limited substrates, and difficulties in separation/purification of the products.
Therefore, it is of interest to develop an alternative process for efficient, rapid
and selective preparation of monoacylated piperazine derivatives under mild
conditions.
In this communication, we report the use of triphenylphosphine (TPP)
with N-bromosuccinimide (NBS) for the selective monoacylation of pipera-
zine under mild reaction conditions (Sch. 1).
EXPERIMENTAL
The carboxylic acid was first activated with TPP and NBS to furnish inter-
mediate, (5) which was further treated with piperazine to afford monoacylated
piperazine under mild reaction conditions. This method converts carboxylic

Synthesis of N-Acylalkylenediamines
2919
Scheme 1.
acid group into the amide moiety in a one-pot synthesis at room temperature.
The desired monoacylated product, (6) could easily be purified by simple
recrystallization or using silica gel chromatography. The byproducts such as
TPP oxide and pyridinium hydrobromide were easily removed by filtration
1
followed by aqueous work-up. The H NMR revealed that the formation of
monoacylated piperazine derivative. The methodology was found to be
general, a variety of carboxylic acids, such as aliphatic, unsaturated, aromatic,
and heterocyclic acids were smoothly converted into the corresponding mono-
acylated piperazine derivatives. We prepared N-acylalkylenediamine (entry
k), an useful precursor of the popular antihypertensive drug Doxazosin, in
[1]
9
6% yield at room temperature in 30 min. The recently reported method
for this compound required 3 hr and at 1108C with 61% yield. Various
diamines (entries p–u) were examined for this transformation and it was
found to work satisfactory. In conclusion, a convenient and straightforward
protocol has been developed to convert piperazine into monosubstituted
piperazine derivatives (Table 1).
Typical Procedure
A mixture of 2,3-dihydrobenzo[1,4]dioxin-carboxylic acid (180 mg,
1
mmol) and triphenylphosphine (527 mg, 2 mmol) in dichloromethane
10 mL) was cooled to 0–58C. The NBS (410 mg, 2.5 mmol) was added and
the reaction mixture was stirred for 15 min. A mixture of piperazine (86 mg,
mmol) and pyridine (197 mg, 2.5 mmol) was added to the above reaction
mixture at room temperature and stirring was continued for 30 min. After
(
1

2
920
Bandgar and Bettigeri

Synthesis of N-Acylalkylenediamines
2921

2
922
Bandgar and Bettigeri

Synthesis of N-Acylalkylenediamines
2923
the completion of reaction (TLC), the solvent was removed, the residue was
extracted with n-hexane (3 ꢀ 5 mL) and washed with water (10 mL) and aq.
sodium bicarbonate (10%, 10 mL).The crude product was further purified
by column chromatography (pet.ether : ethyl acetate ¼ 8 : 2).
N-(2,3-Dihydrobenzo[1,4]dioxin-2-carbonyl)piperazine (6k). M.p. ¼ 84–
2
1 1
8
58C; IR (KBr): 1640, 3450 cm ; H NMR (300 MHz, CDCl ): d 2.15 (s, 1H,
3
NH), 2.80–2.90 (m, 2H), 2.95–3.00 (m, 2H), 3.50–3.65 (m, 2H), 3.70–3.80
(
m, 2H), 4.40 (dd, J ¼ 12.0, 8.5 Hz, 1H), 4.50 (dd, J ¼ 12.0, 2.5 Hz, 1H), 4.90
13
(
dd, J ¼ 8.5, 2.5 Hz, 1H), 6.90–7.10 (m, 4H); C NMR (75 MHz, CDCl ):
3
d ¼ 40.2 (2C), 45.7, 50.3, 65.1, 70.5, 115.1, 120.2, 122.4, 123.9, 144.2, 145.6,
þ
1
70.2; EIMS : m/z (%) ¼ 248 (M , 25), 111 (100); Anal. calcd. for
C H ,N O : C, 62.89; H, 6.50; N, 11.28. Found: C, 63.02; H, 6.41; N, 11.35.
2 3
13
16
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Received in India April 22, 2004