Chemistry of tetrathiomolybdate: Aziridine ring opening reactions and facile synthesis of interesting sulfur heterocycles

Article abstract of DOI:10.1021/ja052969z

Benzyltriethylammonium tetrathiomolybdate, [BnEt₃N]₂MoS₄, has been used successfully to effect ring opening of aziridines in a regiospecific and stereospecific manner under mild reaction conditions without the use of Lewis

Full text of DOI:10.1021/ja052969z

Published on Web 08/26/2005
Chemistry of Tetrathiomolybdate: Aziridine Ring Opening Reactions and
Facile Synthesis of Interesting Sulfur Heterocycles
Devarajulu Sureshkumar, Srinivasa Murthy Koutha, and Srinivasan Chandrasekaran*
Department of Organic Chemistry, Indian Institute of Science, Bangalore, India
Received May 6, 2005; E-mail: scn@orgchem.iisc.ernet.in
There has been a great interest in the sulfur and nitrogen
containing compounds because of their potential biological activity
and pharmaceutical significance. Aziridines are the most widely
used chiral building blocks for the synthesis of various amino acids,
heterocycles, and alkaloids.1a Although nucleophilic ring opening
of aziridines1b has been known for over three decades, there are
only a few reports on nucleophilic ring opening of aziridines by
sulfur reagents.1 In this communication, we report our results of a
comprehensive study of regio- and stereospecific ring opening of
aziridines with benzyltriethylammonium tetrathiomolybdate,2
Figure 1. ORTEP diagram of compounds 7 and 8.
Scheme 1. Regio- and Stereospecific Aziridine Ring Opening
[BnEt3N]2MoS4 (1), an efficient sulfur transfer reagent. Use of the
reagent 1 in tandem and multistep processes in a one-pot operation
for synthesis of novel heterocyclic systems is also delineated.
To demonstrate the regio- and stereospecificity in the ring open-
ing of aziridines with 1, (()-cis-N-tosyl-1-isopropyl-2-methylaziri-
dine3 2 was treated with 1 (1 equiv; CH3CN, 28 °C, 10 h) to afford
exclusively the anti-â-aminodisulfide 3 in 80% yield. In the case
of (()-trans-N-tosyl-1-isopropyl-2-methylaziridine3 4, the syn-â-
aminodisulfide 5 was obtained in 85% yield under the given reaction
conditions. We believe that reagent 1 attacks the aziridine from
the less hindered side in a stereospecific manner followed by open-
ing of the second aziridine ring. The intermediate X undergoes
an internal redox process4 to form the â-aminodisulfide 5
(Scheme 1).
Following the successful ring opening of simple aziridines with
1, this methodology was extended to the reaction of N-tosyl
aziridinemethanol tosylate 6 with 1, which afforded trans-thiirane
Scheme 2. Thiaaza-Payne-Type Rearrangement
7 as the major product and the cyclic disulfide 8 as the minor
product (Figure 1) with excellent regio- and stereocontrol. In the
course of this thiaaza-Payne5-type rearrangement to form 7, nitrogen
migration occurs from C3, C2 to C1 position (Scheme 3).
In the case of N-tosyl homoaziridinemethanol tosylate 9, tet-
rahydrothiophene 10 was isolated as a single product in 88% yield.
Scheme 3. Tentative Mechanism for the Formation of 7 and 8
To demonstrate the utility of this methodology, the aziridine
derivative6 11 was subjected to regiospecific aziridine ring opening
and subsequent intramolecular cyclization to afford thiabicyclic
derivative 12 in 85% yield, which is a precursor for sulfur
containing unnatural amino acids.Since tetrathiomolybdate 1 con-
verts aziridine into â-aminodisulfide, it is of interest to carry out a
tandem aziridine opening-disulfide formation-reduction7a-
Michael7b reaction on an aziridino epoxide with 1. Accordingly,
treatment of trans-aziridino-epoxide8 13 with 1 in the presence of
methyl acrylate 14 led to the formation of the product 15 in 80%
yield (Scheme 5).
By incorporating a suitable Michael acceptor in the same
aziridine, intramolecular 1,4 addition can be performed as a single-
pot operation. Thus, treatment of diastereomeric mixture of carvone-
derived aziridine 16 with tetrathiomolybdate 1 (2 equiv; CH3CN,
28 °C, 3 h) yielded two diastereomers of thiabicyclononane
derivatives 17 and 18 (1:1) in 88% yield.The cis-aziridino epoxide8
19 underwent a facile ring opening of aziridine and epoxide9 rings
with tetrathiomolybdate 1 (2 equiv; CH3CN:EtOH, 1:1; 28 °C, 12
h) to afford a functionalized, bridged bicyclic disulfide10 20 in 90%
yield. This is the first report of the synthesis of a functionalized,
conformationally locked disulfide in a single-step operation.The
cis-aziridino epoxide derivative 21 was synthesized from (R)-(-
9
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J. AM. CHEM. SOC. 2005, 127, 12760-12761
10.1021/ja052969z CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 9. Reaction of Bisaziridine 23 with 1
Scheme 4. Synthesis of Tetrahydrothiophene Derivatives
Scheme 10. Reaction of Bisaziridine 26 with 1
that, in this case, cyclic monosulfide 24 and disulfide12 25 were
isolated (1:1) in 84% yield.In further expanding the scope of this
reaction, bisaziridine13 26 was treated with tetrathiomolybdate 1
(2 equiv; CH3CN, 28 °C, 1 h) to give thiepane 27 as the only
product in 90% yield. We have demonstrated here an easy and
efficient methodology for the synthesis of a thiepane14 derivative
under mild conditions, which is a potential HIV-1 protease15 and
glycosidase inhibitor.16
Scheme 5. Tandem Aziridine Opening-Disulfide
Formation-Reduction-Michael Addition in One Pot
In summary, we have reported an extensive study on nucleophilic
ring opening of various aziridines with tetrathiomolybdate 1 and
demonstrated the utility of this methodology for the synthesis of a
number of interesting sulfur heterocycles with high regio- and
stereocontrol.
Acknowledgment. D.S. thanks CSIR, New Delhi, for financial
support. We also thank DST, New Delhi for CCD X-ray facility.
Scheme 6. Synthesis of Thiabicyclononane Derivatives 17 and 18
Supporting Information Available: Experimental procedures, CIF
files, and spectral data for all new compounds (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
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and the structure was confirmed by single-crystal X-ray analysis.
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