A novel method for the efficient synthesis of 2-arylamino-2-imidazolines

Article abstract of DOI:10.1016/S0040-4039(00)01102-3

A novel method for the efficient synthesis of 2-arylamino-2-imidazolines is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01102-3

Tetrahedron Letters 41 (2000) 6563±6566
A novel method for the ecient synthesis of
2-arylamino-2-imidazolines
Sreenivasa R. Mundla,a,* Larry J. Wilson,b Sean R. Klopfenstein,b William L. Seibelb
and Nick N. Nikolaidesb
aProcter & Gamble Pharmaceuticals, Chemical Development, Woods Corners, PO Box 191,
Norwich, NY 13815, USA
bProcter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Road,
Mason, OH 45040, USA
Received 12 May 2000; revised 23 June 2000; accepted 26 June 2000
Abstract
A novel method for the ecient synthesis of 2-arylamino-2-imidazolines is described. # 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: aminoimidazoline; 2-methythio-2-imidazoline; arylamine; benzimidazole.
Aminoimidazoline derivatives 1 have been used broadly in medicine, as cardiovascular
antihypertension agents, as sedatives and analgesics, as agents for the treatment of drug and
alcohol withdrawal symptoms, as diuretic agents, as antidiarreheal agents, and as agents which
lower intraocular pressure.1 For example, clonidine is one of the most widely known alpha-2-
adrenoreceptor agonists and antihypertensive agents.2a Indanazoline is a useful vasoconstrictive
agent.2b,c Over the past four decades, a number of methods to produce these aminoimidazoline
derivatives 1 from the corresponding arylamines 2 have been reported in the literature. For
example, Chapleo et al.3 have reported the synthesis of clonidine analogs by reacting an aromatic
amine with 2-methylthio-2-imidazoline in the presence of pyridine. One of the most commonly
used approaches entails a three-step protocol involving the conversion of an amine to the
isothiocyanate, treatment of the isothiocyanate with ethylenediamine, followed by a cyclization
step using mercuric oxide or acetate to form the 2-amino-2-imidazoline.4 Recently, Munk et al.5
have reported that yields in the formation of 2-amino-2-imidazolines can be moderately improved
over Chapleo's procedure by coupling an aromatic primary amine with an imidazoline sulfonic
acid. There had also been reports in which a 2-chloro-2-imidazoline is coupled with an amine.6
From our experience, many of the known methods have one or more limitations. For example,
* Corresponding author. Present address: P&G Pharmaceuticals, Health Care Research Center, 8700 Mason-
Montgomery Rd, Mason, OH 45040, USA. Tel: 001-513-622-2327; fax: 001-513-622-2675; e-mail: mundlasr@pg.com
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01102-3

6564
using toxic reagents like mercuric acetate, low yields, aqueous work-up procedures during
isolation and harsh reaction conditions. Thus, we decided to develop a more economical and
high yielding method suitable for producing a wide variety of aminoimidazoline derivatives.
In this communication, we wish to disclose a highly ecient, convergent method for the
synthesis of 2-arylamino-2-imidazolines 1 from the corresponding arylamines 2. As shown in
Scheme 1, this method involves the preparation of an N-acylated-2-methylthio-2-imidazoline
derivative 4 and its coupling with an arylamine 2 in a protic solvent followed by removal of the
protecting group in the same pot under relatively mild conditions.
Scheme 1. Reagents and conditions: (a) acylating agent, (CH2Cl)2 or DMAC, TEA, 0ꢀC to rt, 2±6 h; (b) 2a, 10%
AcOH/EtOH, rt to 65ꢀC, 16 h; (c) re¯ux, 14 h
As shown in Scheme 1 and Table 1, we conveniently synthesized a variety of N-acylated-2-
methylthio-2-imidazoline derivatives 4a±g from the commercially available 2-methylthio-2-imid-
azoline hydroiodide 3, which can also be prepared by reaction of ethylenethiourea with
iodomethane.7a Thus, exposure of 3 to an acylating agent (see Table 1) in the presence of
triethylamine furnished 4 in excellent yields.7b,10 This method of preparation of 4b and 4e is more
convenient and is higher yielding than the method reported by Kohn et al.8a,b They have reported
the preparation of 4b from ethylenethiourea, ®rst by converting into an N-carbo-
methoxyimidazolidinethione in 32% yield, followed by alkylation with iodomethane and
chromatographic puri®cation in 61% yield. Similarly, they have prepared 4e by alkylating the
N-acetylimidazolinethione9 with iodomethane in 38% yield.
Table 1

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As summarized in Table 1, individual reaction of the 4-ethyl-5-aminobenzimidazole 2a with
various imidazoline precursors 4a±g in 10% acetic acid±ethanol (15 ml/g) at 60±75ꢀC for 10±16 h,
followed by heating to re¯ux for 14 h, furnished the 2-arylamino-2-imidazoline derivative 1a in
good yield.10 The product 1a was isolated as a di-acetate salt. The isolation process involves
concentration of the reaction mixture to an oily residue followed by crystallization. This method
of isolation avoided the laborious aqueous work-up.
When we applied this convergent method to produce a variety of substituted 2-arylamino-2-
imidazolines, we found that the reaction conditions described above worked well with electron-rich
arylamines. Arylamines in which the amino group is either sterically hindered (2,6-dichloroaniline)
or which bear an electron withdrawing group (4-nitroaniline) did not perform as well. As shown
in Table 2, by using modi®ed reaction conditions, we have successfully applied this method to the
synthesis of a representative set of 2-arylamino-2-imidazolines 1 and isolated them as the acetate
salts.10
Table 2
In summary, we have developed an ecient method for the convergent synthesis of a variety of
2-arylamino-2-imidazoline derivatives 1 from the corresponding aryl amines 2. This method was
found to be highly advantageous over the other known methods and suitable for large scale
preparations, as it is high yielding, and avoids the use of toxic reagents and harsh reaction
conditions. In addition, the procedure for the synthesis of N-protected 2-thiomethyl-2-imidazolines
is very simple and also high yielding.
Acknowledgements
We would like to thank P&GP management for their support and encouragement and Drs.
David E. Portlock, Patricia A. Matson and Thomas L. Cupps for their comments during the
preparation of this manuscript.

6566
References
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2-methylthio-2-imidazoline hydroiodide (3; 4.5 g, 18.4 mmol) in dichloroethane (15 ml) was added triethylamine
(1.4 ml). The resulting homogeneous solution was cooled in an ice bath at 0±5ꢀC and methyl chloroformate (2.36
g, 25 mmol) was added in a dropwise manner. After completion of addition, the reaction mixture was allowed to
warm up to room temperature and stirred for 6 h. The reaction mixture was concentrated under reduced pressure.
Ethyl acetate (150 ml) was added to the residue and the mixture was ®ltered to remove the insoluble salts. The salts
were rinsed with ethyl acetate (25 ml) and the combined ®ltrates were concentrated under reduced pressure to
furnish 4b (3.07 g, 96%).
8. (a) Kohn, H.; Kohn, B. A.; Steenberg, M. L.; Buckley, J. P. J. Med. Chem. 1977, 20, 158. (b) Kohn, H.; Cravey,
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10. All products were identi®ed by proton NMR and MS spectral data.