Gold- or platinum-catalyzed synthesis of sulfur heterocycles: access to sulfur ylides without using sacrificial functionality

Article abstract of DOI:10.1002/anie.200904309

It's no sacrifice: Alkynes have been used as direct precursors to sulfur ylides under gold or platinum π-acid catalysis in an atom-economic manner. An intramolecular redox reaction between an alkyne group with a tethered sulfoxide unit gen-erates a sulfur ylide, which undergoes 2,3sigmatropic rearrangement. Acyclic substrates are cycloisomerized to afford functionalized dihydrothiophenones (see scheme) and dihydrothiopyranones.

Full text of DOI:10.1002/anie.200904309

Communications
DOI: 10.1002/anie.200904309
Synthetic Methods
Gold- or Platinum-Catalyzed Synthesis of Sulfur Heterocycles: Access
to Sulfur Ylides without Using Sacrificial Functionality**
Paul W. Davies* and Sꢀbastien J.-C. Albrecht
Sulfur ylides are potent reactive units which are utilized in
synthetic chemistry for a variety of powerful carbon–carbon
and carbon–heteroatom bond-forming reactions.[1] The clas-
sical preparation of ylides depend on the use of “sacrificial
functionality”: a leaving group is displaced by a sulfide with
subsequent regioselective deprotonation of the resulting
sulfonium salt [Eq. (1)];[2] or a sulfide is treated with a
metal carbene, which is formed by the decomposition of a
diazo compound with loss of molecular nitrogen [Eq. (2)].[3]
The synthetic efficiency of such processes is also adversely
affected by the manipulations required to introduce the
precursor moiety. Consequently, the appeal of ylide chemistry
is diminished by the negative implications of these strategies
on reagent usage, waste production, and functional group
tolerance.
sulfides. A gold carbenoid was generated by a rearrangement
process and led to an ylide on reaction with sulfide [Eq. (3);
R1 = allyl or propargyl, R2 = aryl or allyl].[5,6] This established
the principle of generating sulfur ylides through gold-
catalyzed rearrangement, and also represented one of the
few reactions involving low-valent sulfur in gold catalysis.[7]
However, the relative complexity of the propargylic
carboxylate precursors is limiting. Additionally, the presence
of an enol acetate adjacent to the metal carbenoid, which is
formed in situ, diverts the course of the reaction away from
that usually observed with allyl sulfonium ylides. We were
therefore keen to identify an alternative strategy using
alkynes as ylide precursors that could be used directly in
place of the usual preparation methods. Herein, we report the
successful fulfillment of this goal and its application in the
synthesis of monocyclic and fused-bicyclic, functionalized
sulfur heterocycles.
The research groups of Toste and Zhang have independ-
ently reported the gold-promoted reaction of a sulfoxide
group with a tethered alkyne to generate a-keto gold
carbenoids.[8] We considered that this approach might allow
alkynes to be used directly as precursors for the ylide site.
While the initial use of a sulfoxide group could reduce
unfavorable gold–sulfur interactions, an internal redox pro-
cess simultaneously generates the carbenoid and sulfide
components required for ylide formation [Eq. (4)].[9]
The preparation of sulfur ylides by methods which do not
depend on the use of sacrificial functionality are therefore
potentially attractive.[4] To this end, we recently established a
program to explore direct access to ylides from alkynes under
noble-metal catalysis. In our initial study we reported the
intermolecular coupling of propargylic carboxylates and
[*] Dr. P. W. Davies, Dr. S. J.-C. Albrecht
School of Chemistry, University of Birmingham
Edgbaston, B15 2TT, Birmingham (UK)
Fax: (+44)121-414-4403
E-mail: p.w.davies@bham.ac.uk
[**] Financial support from the EPSRC (EP/EO32168/1) and the
University of Birmingham is gratefully acknowledged. We thank
Johnson Matthey plc for a loan of metal salts. This research was
supported through Birmingham Science City: Innovative Uses for
Advanced Materials in the Modern World (West Midlands Centre for
Advanced Materials Project 2), with support from Advantage West
Midlands (AWM) and by the European Regional Development Fund
(ERDF).
To test this strategy we prepared a range of substrates A
bearing allyl units tethered to the sulfoxide group. In our
desired process, p-acid activation renders the alkyne moiety
susceptible to attack by the nucleophilic sulfoxide (Scheme 1,
A!B).[10] Evolution of the resulting intermediate C gener-
ates the a-carbonyl metal carbenoid D and concomitantly
engenders the sulfide, thus providing the two units required
for ylide formation.[11] The resulting allyl sulfonium ylide E
should undergo a 2,3-sigmatropic rearrangement to complete
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904309.
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Scheme 1. Proposed reaction mechanism.
Scheme 2. General synthesis of sulfoxide tethered enynes 4. See the
Supporting Information for experimental details. DIAD=diisopropyla-
zodicarboxylate.
the synthesis of heterocycle F.[12,13] The overall transformation
(A!F) leads to the formation of new carbon–carbon,
carbon–oxygen, and carbon–sulfur bonds.
sensitive moieties of the immediate precursors for the ylide
sites are only introduced in the final stages of the ylide
preparation [Eqs. (1) and (2)]. In contrast, the alkyne
precursor to the ylide can be introduced earlier, thus allowing
more flexible retrosynthetic analyses to be applied.
Pleasingly, the desired ylide formation and rearrangement
process proceeded smoothly when the substrates were treated
with a platinum or gold p-acidic species (Table 1). The use of
catalytic quantities of PtCl2 in ClCH2CH2Cl under mild
heating was found to be the most effective activation system
Substrates 4, which are based on motif A, bearing a range
of substituents on the sulfur center and the alkyne group were
synthesized through standard substitution strategies. Chemo-
selective oxidation of sulfide 3 was performed using hydrogen
peroxide under molybdenum catalysis (Scheme 2).[14] The
polarity of the sulfoxide unit provides practical benefit by
rendering purification at the final stage facile. Indeed, all
substrates 4 bearing terminal alkyne groups were purified
only after the final stage. By using standard strategies, the
Table 1: Platinum- or gold-catalyzed cyclizations.[a]
Entry Substrate Catalyst [M] Product
Yield [%][b] d.r.[c]
Entry Substrate Catalyst [M] Product
Yield [%][b] d.r.[c]
10
11
(E)-4h
4h
PtCl2
Au-I
53
78
1.45:1
1.45:1
1
2
(E)-4a
PtCl2
PtCl2
5a 61[d]
2.6:1
–
5h
4b
5b 51
12
(E)-4i
Au-I
5i
5j
83
55
1.06:1
3
4
5
4c
PtCl2
PtCl2
PtCl2
5c 62
–
13
14
15
4j
4k
4l
Au-I
Au-I
Au-I
–
–
–
(E)-4d
4e
5d 55–64
5e 44
4.8:1
–
5k 84
5l
60
6
7
4 f
4 f
PtCl2
Au-I
24
69
–
–
5 f
16
17
4m
4n
Au-I
Au-I
5m 83
5n 83
1.2:1
–
8
9
4g
4g
PtCl2
Au-I
60
5g
–
–
85
[a] Catalyst (5–10 mol%) was added to a solution of 4 in 1,2-dichloroethane (0.2–0.05m), the flask was sealed and heated at 708C for 18 h. [b] Yield of
isolated product after flash column chromatography. [c] Diastereomeric ratio determined from by 1H NMR spectroscopy. [d] 11% of 6 was isolated.
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for terminal alkynes (Table 1, entries 1–5).[15] Variously sub-
substitution with an ester moiety (Table 2, entry 3), the
isothiochroman-4-one product 8c was formed exclusively
under gold catalysis.
stituted allyl fragments can be tolerated in the formation of
dihydrothiophenone and dihydrothiopyranone structures.
The reactions proceed with allylic inversion (for example,
Table 1, entries 1–2).
Quaternary carbon centers could be formed using this
method, although the yield does begin to drop off as the
center that forms becomes more highly con-
In summary, we have shown that the simple and robust
alkyne functionality can be used as a direct precursor to a
sulfur ylide using gold or platinum catalysis. An internal
redox-combination strategy bypasses the need to employ
sacrificial functionality to access sulfur ylide chemistry, and
enables non-standard retrosynthetic approaches to be
employed. A range of functionalized sulfur heterocycles
have been synthesized by novel cycloisomerization reactions
of readily prepared sulfoxide tethered enynes. The study of
this reaction and wider applications of the practical principle
of using alkynes as immediate ylide precursors is under
investigation in our laboratory and will be reported in due
course.
gested (Table 1, entries 2 and 5). Small
amounts of a side product were occasionally
observed in these reactions. From the cycli-
zation of 4a, the side product was isolated
and identified as the a-chloroketone 6. A
likely pathway for the formation of 6 involves
the reaction of electrophilic platinum carbenoid D with
chlorinated solvent, in analogy to the reactions observed with
other metal carbenes.[16]
Received: August 2, 2009
Published online: September 25, 2009
Substrates incorporating an internal alkyne unit (4 f–4n)
gave the desired cyclized products in only modest yield under
platinum(II) catalysis (Table 1, entries 6, 8, and 10). However,
a significant improvement was observed upon switching to the
dichloro(pyridine-2-carboxylato)gold(III) species (Au-I;
Table 1, entries 7, 9, and 11).[17] With this method aromatic
and electron-withdrawing groups such as esters and ketones
are readily incorporated.[18] The resulting cycloisomerizations
allow highly congested and functionalized systems to be built
up rapidly in high yield from simply constructed precursors
(for example, Table 1, entries 7, 11–13, and 15). Both acyclic
and cyclic units can be incorporated into the sigmatropic
rearrangement (Table 1, entry 16). Additionally, the syntheti-
cally useful vinyl bromide functionality remains unscathed
under the reaction conditions (Table 1, entry 17).
Keywords: alkynes · gold · homogeneous catalysis ·
.
sulfur heterocycles · ylides
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alkyne and sulfoxide groups (Table 2). Under the standard
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major products respectively, through an initial 6-exo-dig
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entries 1 and 2). Only small amounts of the 1,3-dihydroben-
zo[c]thiophene products, 9a and 9b, were isolated from the
analogous process starting with 7-endo-dig cyclization. When
the electronic bias on the alkyne group was increased by
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Entry
1
7
R1
H
R2
H
[M]
Product
Yield [%][b]
´
Rudolph, J. Huck, W. Frey, J. W. Bats, M. Hamzic, Angew. Chem.
8a
9a
8b
9b
8c
55
8
2009, 121, 5962 – 5966; Angew. Chem. Int. Ed. 2009, 48, 5848 –
5852.
7a
PtCl2
53[c]
11[d]
64
[8] a) N. D. Shapiro, F. D. Toste, J. Am. Chem. Soc. 2007, 129, 4160 –
4161; b) G. Li, L. Zhang, Angew. Chem. 2007, 119, 5248 – 5251;
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2
3
7b
7c
H
Ph
H
PtCl2
CO2Et
Au-I
[a] Catalyst (10 mol%) was added to a solution of 7 in 1,2-dichloroethane
(0.2m), the flask was sealed and heated at 708C for 18 h. [b] Yield of
isolated product after flash column chromatography. [c] As a 2.8:1
mixture of diastereomers. [d] as a 1.3:1 mixture of diastereomers.
[9] Use of an internal redox process for the generation of
azomethine ylides under gold catalysis: H.-S. Yeom, J.-E. Lee,
S. Shin, Angew. Chem. 2008, 120, 7148 – 7151; Angew. Chem. Int.
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[15] A survey of catalysts and reaction conditions for the challenging
cyclization precursor 4b is provided in the Supporting Informa-
tion.
[16] For example, see: M. C. Pirrung, J. Zhang, K. Lackey, D. S.
Sternbach, F. Brown, J. Org. Chem. 1995, 60, 2112 – 2124; an
alternative would involve the reaction of the carbenoid or sulfur
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[18] No reaction was observed when substrate 4k, bearing an
activated alkyne, was treated under the usual reaction conditions
with amberlyst-15, toluene-p-sulfonic acid, or silver triflate in
place of the platinum or gold catalyst. The use of two equivalents
of BF3.OEt2 resulted in the formation of a temporary complex
which returned 4k upon treatment with silica gel.
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[11] Li and Zhang implicated a sulfur ylide in the formation of a side
product, see Ref. [8b].
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