.
Angewandte
Communications
DOI: 10.1002/anie.201108261
Synthetic Methods
Efficient Synthesis of Thiopyrans Using a Sulfur-Enabled Anionic
Cascade**
Fang Li, David Calabrese, Matthew Brichacek, Ivy Lin, and Jon T. Njardarson*
Sulfur is the fifth most important element, following carbon,
hydrogen, oxygen, and nitrogen, in the context of biological
significance and representation in important natural and
nonnatural constructs. Its unique properties also make it one
of the most chemically versatile of the early elements. For
example, sulfur compounds are: 1) great nucleophiles; 2)
readily reduced and oxidized; 3) good at stabilizing carban-
ions and carbocations; 4) a source of useful ylide and
umpolung chemistry; 5) of great utility in radical chemistry;
6) able to be chiral at sulfur; 7) found in the cores of
important chiral auxiliaries, and 8) the key enabling element
for more than twenty name reactions in organic chemistry.[1]
In terms of pharmaceuticals, sulfur is solidly the most
significant and successful element following the four key
elements of life (C, H, N, and O), with seven of the ten best-
selling pharmaceuticals worldwide containing sulfur.[2]
As a part of our program focused on the development of
new useful synthetic transformations involving sulfur as the
central element,[3] we report a new anionic cascade[4] that
provides convergent access to thiopyran products[5] in a single
pot from simple starting materials (Scheme 1). The inspira-
tion for the design of this new reaction originated from a
desire to extend our ring expansion investigations to include
vinyl thietanes, which we envisioned could be converted into a
thiopyran upon treatment with a metal catalyst. Intrigued by
the simple and convergent thiirane synthetic approach we had
utilized for our formal synthesis of biotin, we postulated that
the thiopyran constructs could possibly be accessed in a single
step from an appropriately functionalized carbonyl construct
containing a thiol group at the b position instead of a ring
expansion path. This new one-pot anionic cascade would be
initiated upon addition of a vinyl nucleophile to the carbonyl
group, at which point the substitutent on sulfur migrates to
the newly formed alkoxide, thus forming a new leaving group
and a thiolate nucleophile. Ketones and esters were expected
to be the most suitable substrates for this new anionic cascade.
Tertiary substitution of the alkoxide, formed by coupling the
two carbon fragments together, was expected to ensure
preference for the desired 6-endo cyclization pathway over
the competing 4-exo pathway.
The most critical part of the reaction design was the
nature of the thiol substitutent (XYZ; Scheme 1). A suitable
substitutent would be required to 1) survive the addition of
the carbon nucleophile, 2) readily transfer from sulfur to the
alkoxide, and 3) transform the alkoxide into a good leaving
group. Literature precedents suggested three structural
frameworks that might fit our criteria: 1) thiocarbonate- or
xanthate-type acyl groups,[6] 2) thio-substituted heterocy-
cles,[7] or 3) phosphates.[8] Phosphates were chosen as the
group to study the feasibility of the anionic cascade because of
their ease of substrate synthesis, stability toward carbon
nucleophiles, and leaving group ability (Z = P, Y = OR and
X = O or S; Scheme 1).
To test our hypothesis, we chose to explore the addition of
vinyl nucleophiles to the aryl ketone thiophosphate 1
(Table 1). The addition product would afford a tertiary
alkoxide, which would then undergo a migration of the
thiophosphate to form a thiolate nucleophile, which we
expected would favor the 6-endo cyclization pathway. Vinyl
Grignard addition to the aryl ketone 1 proceeded well to form
2 without interference from the thiophosphate group. Inter-
estingly, in tetrahydrofuran with magnesium as the alkoxide
counterion, the expected in situ anionic cascade to form 3 or 4
did not take place. Instead, the corresponding alcohol was
isolated (entry 1).
Scheme 1. One-pot anionic cascade route to thiopyrans.
Presumably the magnesium counterion impedes thiophos-
phate transfer to the alkoxide. However, treatment of the
corresponding alcohol with an alkoxide base or sodium
hydride resulted in a facile cyclization, which afforded the
thiopyran 3 as the major product following an acidic
workup.[9] We postulated that an alkali metal alkoxide
additive might exchange out the magnesium in situ and
allow the proposed anionic cascade to proceed in one pot
(Table 1, entries 2–13). After screening lithium, sodium, and
potassium alkoxides in methanol, ethanol, 2-propanol, or tert-
butanol, it became clear that adding potassium tert-butoxide
[*] F. Li, I. Lin, Prof. J. T. Njardarson
Department of Chemistry and Biochemistry, University of Arizona
1306 E. University Blvd., Tucson, AZ 85721 (USA)
E-mail: njardars@email.arizona.edu
D. Calabrese, M. Brichacek
Department of Chemistry and Chemical Biology, Cornell University
Baker Laboratory, Ithaca, NY 14853-1301 (USA)
[**] We thank the NSF (CHE-0848324) and the University of Arizona for
financial support.
Supporting information for this article is available on the WWW
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Angew. Chem. Int. Ed. 2012, 51, 1938 –1941