Communications
DOI: 10.1002/anie.200800373
Nitrogen Heterocycles
An Annulation Reaction for the Synthesis of Morpholines,
Thiomorpholines, and Piperazines from b-Heteroatom Amino
Compounds and Vinyl Sulfonium Salts**
Muhammad Yar, Eoghan M. McGarrigle, and Varinder K. Aggarwal*
The nitrogen-containing heterocycles comprising morpho-
lines, thiomorpholines, and piperazines are some of the most
important pharmacophores in medicinal chemistry.[1] How-
ever, the direct synthesis of such compounds by alkylation of
b-amino alcohols/thiols/amines with 1,2-dihalo derivatives is
often fraught with low yields and side reactions.[2] 1,2-
Dihalogen derivatives are generally poor electrophiles and
reactions are often accompanied by competing elimination
processes. A solution to this problem is to carry out a three-
step sequence employing an a-halogen acid halide as the
electrophile.[3] Following amide formation and intramolecular
alkylation, reduction finally furnishes the required hetero-
cycles. Herein, we describe the application of a novel concept
to prepare these pharmacologically important heterocycles
from b-amino alcohols/thiols/amines in one step and high
yield.
produce the required heterocycle. Although vinyl onium salts
have been employed in three-component coupling reactions
with nucleophiles and electrophiles,[4] their potential to react
according to the pathway shown in Scheme 1 has not
previously been recognized.[5]
Of the readily available vinyl onium salts, it was thought
that sulfonium and phosphonium would be better at promot-
ing the conjugate addition step than ammonium since the
ylide intermediate is better stabilized.[6] However, to promote
cyclization leaving group ability of the onium is critical and
this falls in the order S > N @ P. [7] These considerations led us
to examine vinyl sulfonium salts, and in particular diphenyl
vinyl sulfonium salt 1.[4c,8] This salt was easily prepared
through a modified procedure as shown in Scheme 2.[9] In this
We reasoned that soft electrophiles operating under less
basic conditions would minimize competing elimination
pathways and therefore considered the possibility of employ-
ing Michael acceptors. This led us to vinyl onium salts (e.g., 1).
We expected that, following conjugate addition of one of the
heteroatoms, an ylide 4 would be generated that could
undergo proton transfer with the other heteroatom
(Scheme 1). The heteroatom anion generated, 5, would then
attack the onium ion electrophile to effect ring-closure and
Scheme 2. Synthesis of diphenyl vinyl sulfonium salt 1.
modification, the conventional 5 day reflux has been replaced
by a 5 h reflux using toluene in place of CH2Cl2 and the Ag2O
base has been replaced with inexpensive KHCO3 in a THF/
H2O mixture. After a short reaction time clean elimination
occurred with this base although after a few hours the product
of water addition began to be observed.[10]
A range of amino alcohols 2a–f bearing sulfonamide
residues[11] with different degrees of substitution and stereo-
chemistry were tested (Table 1, entries 1–6). In all cases
morpholines 3a–f were obtained in very high yield. This novel
process is especially noteworthy for its simplicity of reaction
conditions (Et3N, CH2Cl2, RT) and workup. Evaporation of
the reaction mixture and simple chromatography allowed
easy separation of the nonpolar by-product (Ph2S) from the
polar morpholine. Although limited to sulfonamides, the use
of the more easily cleaved nosylamide is noteworthy (Table 1,
entry 6).
Scheme 1. Proposed annulation reaction for heterocycle synthesis
mediated by vinyl sulfonium salt 1.
[*] M. Yar, Dr. E. M. McGarrigle, Prof. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS81TS (UK)
Fax: (+44)117-929-8611
E-mail: v.aggarwal@bristol.ac.uk
No such limitations applied to the reactions of b-amino-
thiols. A range of b-aminothiols 2g–i bearing different levels
of functionality and substitution were smoothly converted
into the corresponding thiomorpholines in near quantitative
yield (Table 1, entries 7–9). The products were easily isolated
in this case by an acid/base wash to give essentially pure
material.
[**] M.Y. thanks the Higher Education Commission of Pakistan for
support of a studentship. V.K.A. thanks the Royal Society for a
Wolfson Research Merit Award and the EPSRC for a Senior Research
Fellowship.
Supporting information for this article is available on the WWW
3784
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 3784 –3786