Polyethylene Glycol (PEG-400) as an Efficient and Recyclable Reaction Medium for the One-Pot Synthesis of N-Substituted Azepines under Catalyst-Free Conditions

Abstract

Polyethylene glycol (PEG) was found to be an inexpensive nontoxic and effective medium for the one-pot synthesis of N-substituted azepines under catalyst-free conditions in excellent yields. Environmental acceptability, low cost, high yields, and recyclability of the PEG are the important features of this protocol.

anilines - dialkylacetylene dicarboxylates - 2,5-dimethoxytetrahydrofuran - N-substituted azepines - polyethylene glycol - catalyst-free conditions

References and Notes

<A NAME="RD17711ST-1">1</A> Fouche J, and Leger A. inventors; DT  2031236.  ; Chem. Abstr. 1971, 74, 76346r

<A NAME="RD17711ST-2A">2a</A> Ersmark K. Feierberg I. Bjelic S. Hamelink E. Hackett F. Blackman MJ. Hulten J. Samuelsson B. Aqvist J. Hallberg A. J. Med. Chem.  2004,  47:  110 

<A NAME="RD17711ST-2B">2b</A> Liu J. Gluzman IY. Drew ME. Goldberg DE.
J. Biol. Chem.  2005,  280:  1432 

<A NAME="RD17711ST-2C">2c</A> Kukla MJ. Breslin HJ. Diamond CJ. Grous PP. Ho CY. Miranda M. Rodgers JD. Sherill RG. De Clercq E. Pauwels R. Andries K. Moens LJ. Janssen MAC. Janssen PAJ. J. Med. Chem.  1991,  34:  3187 

<A NAME="RD17711ST-2D">2d</A> Banerjee R. Liu J. Beatty W. Pelosof L. Klemba M. Goldberg DE. Proc. Natl. Acad. Sci. U.S.A.  2002,  99:  990 

<A NAME="RD17711ST-3">3</A> Heys JR. Senderoff SG. J. Org. Chem.  1989,  54:  4702 

<A NAME="RD17711ST-4">4</A> Cross PE, and Arrowsmith JE. inventors; EP  2853231988.  ; Chem. Abstr. 1989, 110, 173115

<A NAME="RD17711ST-5A">5a</A> Kimball SD. Floyd DM. Das J. Hunt JT. Krapcho J. Rovnyak G. Duff KJ. Lee VG. Moquin RV. Turk CF. Hedberg SA. Moreland S. Brittain RJ. McMullen DM. Normandin DE. Cucinotta GG. J. Med. Chem.  1992,  35:  780 

<A NAME="RD17711ST-5B">5b</A> Das J. inventors; US  4774239.  ; Chem. Abstr. 1989, 110, 23752

<A NAME="RD17711ST-5C">5c</A> Neumeyer JL. Kula NS. Baldessarini RJ. Baindur N. J. Med. Chem.  1992,  35:  1466 

<A NAME="RD17711ST-6A">6a</A> Grunewald GL. Dahanukar VH. Criscione KR. Bioorg. Med. Chem.  2001,  9:  1957 

<A NAME="RD17711ST-6B">6b</A> Grunewald GL. Caldwell TM. Li Q. Criscione KR. J. Med. Chem.  2001,  44:  2849 

<A NAME="RD17711ST-7A">7a</A> Ramesh K. Murthy SN. Nageswar YVD. Tetrahedron Lett.  2011,  52:  2362 

<A NAME="RD17711ST-7B">7b</A> Katritzky AR. In Comprehensive Heterocyclic Chemistry   Vol. 9:  Katritzky AR. Rees CW. Scriven EFV. Pergamon Press; Oxford: 1996.  p.21 

<A NAME="RD17711ST-7C">7c</A> Tietze LF. Schimpf R. Synthesis  1993,  876 

<A NAME="RD17711ST-7D">7d</A> Shapiro ND. Toste FD. J. Am. Chem. Soc.  2008,  130:  9244 

<A NAME="RD17711ST-7E">7e</A> Wender PA. Pedersen TM. Scanio MJC. J. Am. Chem. Soc.  2002,  124:  15154 

<A NAME="RD17711ST-8A">8a</A> Dickerson TJ. Reed NN. Janda KD. Chem. Rev.  2002,  102:  3325 

<A NAME="RD17711ST-8B">8b</A> Kamal A. Reddy DR. . Tetrahedron Lett.  2005,  46:  7951 

<A NAME="RD17711ST-8C">8c</A> Suryakiran N. Srikanth Reddy T. Ashalatha K. Lakshman M. Venkateswarlu Y. Tetrahedron Lett.  2006,  47:  3853 

<A NAME="RD17711ST-9">9</A> Lingaiah N. Raghu M. Lingappa Y. Rajashaker B. Tetrahedron Lett.  2011,  52:  3401 

<A NAME="RD17711ST-10">10</A>

General Procedure for the Synthesis of N-Substituted Azapins by Using PEG as a Reaction Medium
A mixture of the requisite aniline (1.0 mmol), dialkyl-acetylene dicarboxylate (1.0 mmol), and 2,5-dimethoxy-tetrahydrofuran (1.0 mmol) was taken in PEG (5 mL) and stirred at 60 ˚C for the appropriate time. After completion of the reaction, as monitored by TLC, the reaction mixture was poured into H₂O and extracted with EtOAc. The organic layer was removed under reduced pressure, and the crude product was purified by column chromatography. The recovered PEG could be reused for a number of cycles without significant loss of activity.