Bromoethylsulfonium salt-a more effective annulation agent for the synthesis of 6- and 7-membered 1,4-heterocyclic compounds

Article abstract of DOI:10.1021/ol8023727

(Chemical Equation Presented) Reaction of bromoethylsulfonium salt with 1,2-/1,3-aminoalcohols gave six- and seven-membered rings in good-to-excellent yields. The reactions proceed through generation of a vinyl sulfonium salt followed by annulation to give 1,4-heterocyclic compounds such as morpholines and benzoxazepines in a simple procedure. The method accommodates a range of nitrogen substituents and the amino alcohol can be substituted by amino thiols and diamines to give thiomorpholines, piperazines and benzodiazepines.

Full text of DOI:10.1021/ol8023727

ORGANIC
LETTERS
2009
Vol. 11, No. 2
257-260
Bromoethylsulfonium SaltsA More
Effective Annulation Agent for the
Synthesis of 6- and 7-Membered
1,4-Heterocyclic Compounds
Muhammad Yar, Eoghan M. McGarrigle,* and Varinder K. Aggarwal*
School of Chemistry, UniVersity of Bristol, Cantock’s Close,
Bristol, BS8 1TS, United Kingdom
V.aggarwal@bristol.ac.uk
Received October 14, 2008
ABSTRACT
Reaction of bromoethylsulfonium salt with 1,2-/1,3-aminoalcohols gave six- and seven-membered rings in good-to-excellent yields. The reactions
proceed through generation of a vinyl sulfonium salt followed by annulation to give 1,4-heterocyclic compounds such as morpholines and
benzoxazepines in a simple procedure. The method accommodates a range of nitrogen substituents and the amino alcohol can be substituted
by amino thiols and diamines to give thiomorpholines, piperazines and benzodiazepines.
Heterocyclic compounds particularly morpholines, thiomor-
pholines and piperazines are some of the most important
biologically active compounds.1 However, the synthesis of
such compounds in an efficient and straightforward manner
is not trivial. For instance when using 1,2-dihaloderivatives
to create the heterocycle low yields and side-reactions are
often reported.2
As part of our ongoing research into the chemistry of vinyl
sulfonium salts3 we recently reported an efficient method
for the synthesis of these pharmacologically important
components from ꢀ-heteroamino compounds.4 A range of
N-tosyl morpholines were synthesized in good yield from
the reaction of ꢀ-amino alcohols with diphenyl vinyl sulfo-
nium salt 1. The proposed mechanism for the reaction is
shown in Scheme 1. The cascade of events is initiated by
(1) For a review see: (a) Wijtmans, R.; Vink, M. K. S.; Schoemaker,
H. E.; van Delft, F. L.; Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis 2004,
641–662. For recent examples see: (b) Breuning, M.; Winnacker, M.;
Steiner, M. Eur. J. Org. Chem. 2007, 2100–2106. (c) D’hooghe, M.;
Vanlangendonck, T.; To¨rnroos, K. W.; De Kimpe, N. J. Org. Chem. 2006,
71, 4678–4681. (d) Pedrosa, R.; Andre´s, C.; Mendiguch´ıa, P.; Nieto, J. J.
Org. Chem. 2006, 71, 8854–8863. (e) Wilkinson, M. C. Tetrahedron Lett.
2005, 46, 4773–4775. (f) Lanman, B. A.; Myers, A. G. Org. Lett. 2004, 6,
1045–1047.
Scheme 1
.
Proposed Mechanism for Morpholine Synthesis
Using Vinyl Sulfonium Salt 1
(2) (a) Chiu, H.; Lin, Y. C.; Cheng, C. Y.; Tsai, M. C.; Yu, H. C. Bioorg.
Med. Chem. Lett. 2001, 9, 383–393. (b) Kashima, C.; Harada, K. J. Chem.
Soc., Perkin. Trans. 1 1988, 1521–1526. (c) Liang, P. H.; Hsin, L. W.;
Cheng, C. Y. Bioorg. Med. Chem. 2002, 10, 3267–3276. (d) Sakai, K.;
Yoneda, N. Chem. Pharm. Bull. 1981, 29, 1554–1560. (e) Bhatt, U.; Just,
G. HelV. Chim. Acta 2000, 83, 722–727.
10.1021/ol8023727 CCC: $40.75
Published on Web 12/12/2008
2009 American Chemical Society

nucleophilic attack of the amide on the electrophilic sulfo-
nium salt which forms an intermediate sulfur ylide 2.5 A
proton transfer unmasks a second electrophilic center and
creates a potent nucleophile, leading to the heteroatom
displacing the sulfide from 3 and forming the desired
heterocyclic product.
Although this method was highly effective for a range of
N-tosyl amino alcohols, it suffers from the need to prepare
and isolate the sensitive, oily vinyl sulfonium saltsan
especially challenging problem on a large scale. We now
report that in fact this annulation chemistry can be conducted
with the stable crystalline salt 4 which is easily prepared on
a large scale, and that the reaction is no longer limited to
tosyl sulfonamides. Furthermore, we have extended the scope
of this annulation reaction to include the pharmacologically
important 7-membered ring heterocycles (e.g., benzodiaz-
epines).
Having found suitable conditions, the scope of this new
methodology was explored (Table 2). As with the method
Table 2. Scope of the Annulation Reaction Using Bromoethyl
Sulfonium Salt 4
As noted above, the main problem associated with the
annulation reaction shown in Scheme 1 was the sensitive
nature of the oily vinyl sulfonium salt 1. Since the vinyl
sulfonium salt is generated by base from bromoethylsulfo-
nium salt 4 and base is employed in the annulation reaction
we wondered whether the sulfonium salt 4 could be used
directly in the process. This would have a major advantage
since the salt 4 is a free-flowing crystalline material, easy to
handle, facile to prepare on a large scale, and now com-
mercially available.6
Initial investigations focused on identifying a suitable base
for the proposed in situ protocol (Table 1) using the easily
Table 1. Optimization of the Base in the Annulation Protocol
Using the Bromoethyl Sulfonium Salt 4
entry
base
equiv
yield (%)
1
2
3
4
5
6
7
Et3N
DBU
NaH
DBU
NaH
DBU
NaH
6
6
6
3.5
3.5
3.1
3.1
30
74
72
86
87
77
71
accessible norephedrine-derived sulfonamide 5a as a model
substrate. The required morpholine 6a was obtained in good
yield using bases such as NaH and DBU (entries 2 and 3)
but not with Et3N (entry 1), which had been the base of
choice in our earlier studies using 1. The poor performance
is presumably due to Et3N not promoting a clean elimination
process in the conversion of bromoethyl sulfonium salt to
the vinyl sulfonium salt. The yields were further optimized
by adjusting the number of equivalents of base and it was
found that 3.5 equiv gave the best yields (entries 4 and 5).
a 2.5 equiv of 4. b 2.5 equiv of 4 and 5 equiv of NaH. c 2.5 equiv of 4
and 7.5 equiv of NaH. d 3.75 equiv 4 and 7.5 equiv of NaH.
using preformed 1, N-sulfonyl-protected amino alcohols were
converted into morpholines in good-to-excellent yields
(entries 1, 2 and 4). However the methodology is no longer
258
Org. Lett., Vol. 11, No. 2, 2009

limited to tosyl sulfonamides.7 For instance, the more easily
cleaved SES group8 was also found to be suitable, giving
access to N-SES-substituted morpholines (entries 3 and 5).
The SES-protected morpholine 6f (from entry 5, Table 2)
was easily converted to the Fmoc-protected morpholine 7,
an important building block for a range of biologically active
compounds (Scheme 2).9 In a broad ranging study of the
This simple method was also effective for the synthesis
of thiomorpholines11 and piperazines from ꢀ-amino thiol and
bis-tosylamides, respectively, in excellent yields (entries 9
and 10). Moreover, no chromatography was required for the
purification of thiomorpholine, which was isolated as its HCl
salt after the work up. It is noteworthy that no racemization
of potentially labile chiral centers bearing acidic protons was
detected under these mild conditions (entries 4, 5 and 9).
Although one can draw a plausible mechanism involving
successive SN2 displacements of diphenylsulfide and bromide
from 4, we believe that the reactions proceed through
formation of vinyl sulfonium salt 1 followed by conjugate
addition to 1 as in Scheme 1. Indeed, by monitoring the
Scheme 2
.
Application of Methodology to the Synthesis of
Fmoc-Morpholine (3S) Carboxylate 7
12
1
reaction using H NMR, 1 was clearly identified.
Finally, after the successful application of this methodol-
ogy to the synthesis of 6-membered 1,4-heterocyclic com-
pounds, its extension to the synthesis of more challenging
7-membered heterocycles13 9 was explored. Such com-
pounds, especially when fused to an aromatic group,
represent a “privileged motif” in medicinal chemistry.14-18
For example, the 1,4-benzodiazepine family show a broad
spectrum of therapeutic activity19 including dampening of
the central nervous system (e.g., valium), muscle relaxant,
antibiotic, antiulcer, anti-HIV agent, and Ras farnesyltrans-
ferase inhibitors. We therefore targeted tetrahydro 1,4-
benzodiazepines and 1,4-benzoxazepines in our study. Grati-
fyingly, employing N-tosyl 1,3-amino alcohols and 1,3-
diamines in this simple protocol yielded 1,4-oxazepines and
1,4-diazepines in moderate-to-excellent yields (Table 3). The
range of N-substituents10 that were compatible with the
annulation process it was discovered that N-aryl groups could
successfully be employed. Thus treatment of N-aromatic and
N-heteroaromatic ꢀ-amino alcohols with bromoethyl sulfo-
nium salt and NaH in CH2Cl2 yielded the required morpho-
lines in good-to-excellent yields (entries 6, 7 and 8).
Morpholines with N-aromatic and N-heteroaromatic groups
are common motifs in molecules of pharmaceutical interest,1
and this new methodology provides a facile route for their
preparation.
Table 3. Synthesis of 1,4-Benzoxazepines and
1,4-Benzodiazepines
(3) For vinyl sulfonium salts see: (a) Kokotos, C. G.; McGarrigle, E. M.;
Aggarwal, V. K. Synlett 2008, 2191–2195. (b) Unthank, M. G.; Tavassoli,
B.; Aggarwal, V. K. Org. Lett. 2008, 10, 1501–1504. (c) Unthank, M. G.;
Hussain, N.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2006, 45, 7066–
7069; Angew. Chem. 2006, 118, 7224-7227. (d) Kim, K.; Jimenez, L. S.
Tetrahedron: Asymmetry 2001, 12, 999–1005, and references therein. (e)
Wang, Y.; Zhang, W.; Colandrea, V. J.; Jimenez, L. S. Tetrahedron 1999,
55, 10659–10672. For epoxidation reactions of butadienylsulfonium salts,
see: (f) Rowbottom, M. W.; Mathews, N.; Gallagher, T. J. Chem. Soc.,
Perkin Trans. 1 1998, 3927–3929. For recent examples of the application
of vinyl phosphonium salts see: (g) Kumarn, S.; Shaw, D. M.; Ley, S. V.
Chem. Commun. 2006, 3211–3213.
(4) (a) Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Angew. Chem.,
Int. Ed. 2008, 47, 3784–3786. Angew. Chem. 2008, 120, 3844-3846; For
an application see: (b) Hansch, M.; Illa, O.; McGarrigle, E. M.; Aggarwal,
V. K. Chem. Asian J. 2008, 3, 1657–1663.
(5) For a recent review on the use of ylides in reactions that form rings
other than 3-membered rings see: Sun, X.-L.; Tang, Y. Acc. Chem. Res.
2008, 41, 937–948.
(6) This salt is now commercially available from Aldrich.
(7) Nucleophiles with two acidic protons on the same atom have been
shown to react with vinyl sulfonium salts to give 3-membered rings (e.g.,
primary amines give aziridines): see ref 4a and (a) Gosselck, J.; Be´ress, L.;
Schenk, H. Angew. Chem., Int. Ed. Engl. 1966, 5, 596–597; Angew. Chem.
1966, 78, 606. (b) Johnson, C. R.; Lockard, J. P. Tetrahedron Lett. 1971,
12, 4589–4592. (c) Takaki, K.; Agawa, T. J. Org. Chem. 1977, 42, 3303–
3304. (d) Matsuo, J.; Yamanaka, H.; Kawana, A.; Mukaiyama, T. Chem.
Lett. 2003, 32, 392–393. Where the nucleophile can be resonance-stabilized
forming an enolate, 5-membered rings have also been obtained: (e) Braun,
H.; Huber, G. Tetrahedron Lett. 1976, 17, 2121–2124. (f) Batty, J. W.;
Howes, P. D.; Stirling, C. J. M. J. Chem. Soc., Perkin 1 1973, 65–68;
ref 7b.
a 2.2 equiv of bromoethyl sulfonium salt and 5.5 equiv of NaH are
used.
(8) Weinreb, S. M.; Demko, D. M.; Lessen, T. A. Tetrahedron Lett.
1986, 27, 2099–2102.
Org. Lett., Vol. 11, No. 2, 2009
259

mixed N-tosyl/N-SES 1,3-diamine 8d was also employed and
again the 1,4-diazepine 9d was formed in excellent yield.
This heterocycle bears orthogonally protected amines which
can be deprotected and derivatized as required.
Acknowledgment. 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, the EPSRC for a Senior Research Fellowship, and
Merck for research support. We thank Dr. Matt Unthank
(GSK, Tonbridge, UK) for helpful discussions.
In summary, a new protocol for the efficient synthesis of
6- and 7-membered heterocyclic compounds from readily
available amino alcohols/thiols and diamines has been
described. This methodology shows considerable scope as a
wide range of amino substituents can be used in the reaction.
Bromoethyl sulfonium salt 4 was employed as an effective
reagent to generate vinyl sulfonium salt 1 in situ for this
simple annulation reaction. Pharmacologically important
morpholines, thiomorpholines, piperazines, benzoxazepines
and benzodiazepines were obtained in good-to-excellent
yields using this practical, mild procedure.
Supporting Information Available: Experimental pro-
cedures and characterization data including NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL8023727
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