Efficient synthesis of thiopyrans using a sulfur-enabled anionic cascade

Article abstract of DOI:10.1002/anie.201108261

The fifth element: An efficient new synthetic method for accessing 3,6-dihydro-2H-thiopyrans 1 in one pot has been developed. This method employs an anionic cascade, which is triggered by the addition of a vinyl nucleophile to a carbonyl group followed by S to O thiophosphate migration and an intramolecular thiolate displacement. The scope is demonstrated for a range of ketone and ester substrates.

Full text of DOI:10.1002/anie.201108261

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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
under http://dx.doi.org/10.1002/anie.201108261.
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Table 1: Optimization studies for one-pot anionic cascade.
Entry
Alkoxide[a]
t
3/4[b]
Yield [%][c]
1
none
1 h
–
0[d]
2
3
4
5
6
7
8
9
10
11
12
13
KOtBu
KOiPr
KOEt
5 min
5 min
12 h
20 h
20 h
24 h
48 h
72 h
72 h
7.5:1
8:1
7:1
6.5:1
7:1
7:1
6:1
6:1
–
70
58
48
51
55
41
47
42
KOMe
NaOtBu
NaOiPr
NaOEt
NaOMe
LiOtBu
LiOiPr
LiOEt
trace[d]
trace[d]
0[d]
72 h
1 week
1 week
–
–
–
LiOMe
0[d]
Scheme 2. One-pot synthesis of thiopyrans. Given yield is that of the
[a] 3 equivalents. [b] Thiopyran/thietane product ratio after HCl workup.
[c] Yield of isolated product. [d] Protonated form of 2 (alcohol) isolated in
75% yield.
isolated product and the thiopyran/thietane product ratio is given
within parentheses. [a] 1.5:1 trans/cis-2,6-thiopyran ratio; [b] 1.2:1
trans/cis-2,6-thiopyran ratio.
(entry 2) to the crude mixture resulted in the cascade
proceeding rapidly to completion. The smaller the alcohol,
and the tighter the binding to the counterion the slower the
counterion exchange.
Table 2: Synthesis of 4-vinyl thiopyrans.
This new one-pot cascade reaction could indeed be
generalized. Twelve successful examples are presented in
Scheme 2. These products (7a–k) were accessed in high yields
and in one pot by first subjecting the keto thiophosphates 5a–
5d to four different vinyl Grignard reagents (6a–d) and then
adding 1.1 equivalents of potassium tert-butoxide to the
intermediate magnesium alkoxide. In all cases the intermedi-
ate thiolate cyclized to form the desired product. The
thiopyran products 7g and 7h were obtained as mixtures of
isomers, which modestly favored the 2,6-trans diastereomer. It
is worth noting that, although THF was a well suited solvent
to ensure both a high yielding Grignard addition and efficient
in situ cyclization, it was not always the best solvent for
achieving the highest 6-endo/4-exo cyclization ratios. For
example, when the protonated form of 2 was independently
treated with a base in different solvents, acetonitrile and
dimethylsulfoxide emerged as being superior to tetrahydro-
furan with respect to cyclization ratios (overall yields are
equivalent for the substrates shown). Thus, depending on the
thiopyran substrate being pursued, treating the crude vinyl
carbinol with a base in acetonitrile might on occasion provide
better results than when employing the one-pot approach.
This success prompted us to evaluate the potential of the
esters 8 (Table 2) as suitable cascade substrates.[10] The
resulting 1,3-diene products would be of greater synthetic
interest. Conversion of the esters into the desired divinyl
alkoxides failed with Grignard and lithium reagents, but was
accomplished using the less basic vinyl cerium counter-
Entry
1
Substrate
Product
Yield [%][a]
70 (85)
2
3
71 (79)
69 (81)
4
5
73 (78)
71 (83)
6
68 (85)
[a] Yield of the isolated thiopyran. Yield within parentheses is that of the
crude divinyl carbinol.
parts.[11] The resulting cerium alkoxides where more challeng-
ing to exchange in situ than the magnesium alkoxides. The
thiopyran products (9a–f) were obtained in high yields by
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treating the crude divinyl carbinol intermediates with potas-
sium tert-butoxide.
As a demonstration of the usefulness of these products, we
reacted diene 9e with N-phenylmaleimide (10, Scheme 3) and
were delighted to find that a single diasteromer (11) was
Alder reaction between 18 and the enone 19, thus affording
the thiosteroid scaffold 20.[16] When the sulfur atom was
reductively removed, a complex indene product (21) resulted.
This new method for synthesizing 3,6-dihydro-2H-thio-
pyran scaffolds is broader in scope and more versatile than
currently existing methods, which rely on unstable thiocar-
bonyl groups,[17] vinylphosphonium precursors,[18] expensive
catalysts,[19] or complex starting materials.[20] Most commonly,
3,6-dihydro-2H-thiopyran products are accessed from inter-
mediates like 4-oxothianes by addition and subsequent
dehydration or enolatization and cross couplings. These
approaches not only use additional steps but commonly
suffer from the lack of control in forming the thiopyran
double bond, the same limitation that the thiocarbonyl
cycloaddition strategy is plagued by when unsymmetrical
dienes are used.
In summary, we report a new method for synthesizing
thiopyran products from readily available building blocks.
This programmed anionic cascade is dependent upon sub-
strate structure, sulfur substituents, and reaction conditions to
proceed in a single pot. The method works for b-substituted
ketones and esters using either alkyl or aryl thiolate partners.
Furthermore, we have demonstrated that the concept can be
extended to thiophenols. The nineteen examples presented
herein serve as a testament to the usefulness and versatility of
this new method. The 1,3-diene containing thiopyran products
provide access to highly complex scaffolds when coupled with
a Diels–Alder reaction and sulfur specific transformations. By
coupling this new strategy to asymmetric conjugate addition
of thionucleophiles to enones and enoates, access could be
provided to chiral building blocks. Future efforts are focused
on utilizing this one-pot anionic cascade blueprint to access
alternate useful heterocyclic frameworks.
Scheme 3. Expedient synthesis of steroidal scaffolds. mCPBA=meta-
chloroperbenzoic acid.
produced. Furthermore, upon treatment with styrene 12,[12]
the thiosteroidal construct 13[13] was obtained in high yield
using only a two-pot reaction sequence. To further demon-
strate the power and versatility of sulfur in synthesis, 13 was
separately reduced[14] (14) and ring contracted[15] (15) to
afford complex products that do not contain sulfur but owe
their efficient assembly to sulfur.
We wondered if this new anionic cascade could be
extended to include phosphate-capped thiophenol substrates.
Towards that end, the thioester 16 (Scheme 4) was obtained in
one step from commercially available methyl 2-mercapto-
Received: November 23, 2011
Published online: January 10, 2012
Keywords: carbocycles · cyclizations · steroids ·
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sulfur heterocycles · synthetic methods
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