A reactivity switch in the gold-catalysed coupling of allyl sulfides with propargylic carboxylates

Article abstract of DOI:10.1055/s-0031-1289866

The gold-catalysed coupling of allyl sulfides with propargylic carboxylates follows different pathways depending upon the choice of nonmigrating group on the sulfur and the aromatic group at the propargylic position of the alkyne substrate. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1289866

70
CLUSTER
A Reactivity Switch in the Gold-Catalysed Coupling of Allyl Sulfides with
Propargylic Carboxylates
R
eactivity Sw
a
itch in the
G
u
old-Catalys
l
ed Coupling o
W
f
A
llyl Sulfides . Davies,* Sebastien J.-C. Albrecht
School of Chemistry, University of Birmingham, Edgbaston, B15 2TT, Birmingham, UK
Fax +44(121)4144403; E-mail: p.w.davies@bham.ac.uk
Received 7 September 2011
to react normally and undergo [2,3]-sigmatropic rear-
Abstract: The gold-catalysed coupling of allyl sulfides with prop-
argylic carboxylates follows different pathways depending upon the
choice of nonmigrating group on the sulfur and the aromatic group
at the propargylic position of the alkyne substrate.
rangement,3 the absence of isomer 6 suggests either a fast
subsequent evolution of 6 by [3,3]-sigmatropic rearrange-
ment or that direct S–C allyl transfer from 5 to afford 3 is
preferred.
Key words: gold, sulfur ylides, alkynes, propargylic carboxylates,
coupling
OAc
OAc
2a
[M]
Ph
Ph
[M]
1a
The rearrangement of propargylic carboxylates by activa-
tion of the alkyne with a p-acid has proven to be a privi-
leged process in the development of novel and diverse
efficient synthetic methodologies.1 As part of a pro-
gramme to access sulfur ylides from alkynes, to bypass
prior installation of sacrificial functionality such as a di-
azo unit, we demonstrated an intramolecular coupling of
propargylic carboxylates such as 1a with allyl sulfides 2a
to afford 3aa (Scheme 1).2–5
[M]
S
[M] = AuCl
Ph
4
5
direct S-C allyl
transfer
[2,3]-
sigmatropic
[M]
OAc
OAc
Ph
S
Ph
S
Ph
Ph
not
observed
3aa
6aa
O
O
Scheme 2 Proposed mechanism in the gold-catalysed coupling
reaction
O
AuCl (5 mol%)
ClCH2CH2Cl
O
Ph
SPh
SPh
Ph
This reaction provides efficient access to a structural mo-
tif populated with functional groups suited for subsequent
orthogonal activation. In order to pursue the synthetic op-
portunities that this motif offered, we were interested in
exploring whether the phenyl unit in the propargylic car-
boxylate could be replaced with a heteroaromatic group
that would have greater use in subsequent synthetic appli-
cation.12 Propargylic carboxylates incorporating a furan
or thiophene, 1b and 1c, were therefore prepared and test-
ed in the catalysis reaction with allyl phenyl sulfide. How-
ever, only trace conversion was observed (Table 1, entries
1 and 2). p-Methoxybenzene-derived substrate 1d was
then employed to assess whether the unproductive reac-
tion system stemmed from the electron-rich character of
the heteroaromatic units. This was borne out when 1d
proved similarly unreactive (Table 1, entry 3). In contrast,
the para-carboxylate 1e reacted smoothly with allyl sul-
fide to afford the desired product 3ea in high yield
(Table 1, entry 4).
70 °C
82%
1a
2a
3aa
Scheme 1 Gold-catalysed intermolecular coupling of allyl sulfides
with propargylic carboxylates
The coupling proceeded through the widely encountered
1,2-rearrangement pathway to generate the vinyl car-
benoid 4 (Scheme 2). Though such systems had been very
successfully employed as one-centre reactive intermedi-
ates in intermolecular reactions such as cyclopropana-
tion,6,7 this reactivity should afford product 6aa from a
[2,3]-sigmatropic rearrangement.8 Instead, overall two-
centre 1,3-C,C-dipole reactivity of 4 was observed in this
process: On formation of ylide 5 the newly installed adja-
cent enol acetate was involved in the subsequent reaction
evolution to give 3 as a single isomer. Such incorporation
of the three-carbon unit of propargylic carboxylates has
been observed in other reactions, for instance in the inter-
molecular sense with a,b-unsaturated imines9 or alkenes10
or intramolecularly with allyl ethers.11 As allyl sulfur
ylides generated from gold carbenoids have been shown
Following this trend, the use of a deactivated heteroaryl
unit seemed appropriate, and the conjugated furan deriva-
tive 1f was prepared from known aldehyde 713 to continue
the study (Scheme 3). The enolizable carbonyl unit in 1f
has two functions: to render the heteroaromatic ring elec-
tron-deficient, and to test the functional-group compati-
SYNLETT 2012, 23, 70–73
Advanced online publication: 11.11.2011
DOI: 10.1055/s-0031-1289866; Art ID: Y04311ST
x
x
.x
x
.2
0
1
1
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Reactivity Switch in the Gold-Catalysed Coupling of Allyl Sulfides
71
tion and gave isomer 6fc as the major product, again with
3fc identified in low yield (Table 2, entry 5). The use of
methyl allyl sulfide 2d gave 6fd in excellent yield as a ca.
2:1 mix of geometric isomers (Table 2, entry 6) with none
of isomer 3fd observed. A complete switch in reaction
outcome is therefore observed relative to the use of phenyl
allyl sulfide.
Table 1 Effect of the Aromatic Substituent on the Gold-Catalysed
Coupling
O
O
O
AuCl (5 mol%)
O
R
SPh
PhS
ClCH2CH2Cl
70 °C
R
1b–e
2a
Table 2 The Impact of the Nonmigrating Sulfur Substituent in the
Coupling Reaction
3(b–e)a
O
R =
MeO
AcO
O
S
1b
1c
1d
Time (h)
20
1e
O
OPiv
OPiv
SR1
SR1
O
Entrya
1
Product, yield (%)b
traces
O
catalyst (5 mol%)
ClCH2CH2Cl
1
2
3
4
1b
1c
1d
1e
1f
3f
(a–
d)
O
20
traces
14 h, 70 °C
2a–d
72
traces
O
OPiv
SR1
16
3ea 80
a AuCl (5%) was added to a solution of 1 and 2a (1.1 equiv) in DCE
(0.1 M), the flask was sealed and heated at 70 °C.
(E/Z)-6f(a–d)
b Yield of isolated product after flash column chromatography.
Entrya
R1
Ph
Ph
Bn
Catalyst
AuCl
Product, yield (%)b
3fa 81
1
2
3
1. –78 °C, THF
O
O
O
O
Li
TMS
O
O
OPiv
O
AuCl3
AuCl
3fa 74
2. Piv2O
3. K2CO3, MeOH
H
(E)-6fb 63
3fb/(Z)-6fb (1:0.6) 19c
(E)-6fb 67d
7
8
60%
2.4 M
aq HCl, MeOH
0 °C
4
5
Bn
AuBr3
AuCl
O
Allyl
(E)-6fc 57
3fc/(Z)-6fc/1f (1:0.6:0.3) 25c
O
SPh
O
OPiv
OPiv
O
2a
6
Me
AuCl
(E)-6fd 66
(Z)-6fd 30
SPh
AuCl (5 mol%)
ClCH2CH2Cl
14 h, 70 °C
a Catalyst (5%) was added to a solution of 1f and 2a–d (1.1 equiv) in
DCE (0.1 M), the flask was sealed and heated at 70 °C for 14 h.
b Yield of isolated product after flash column chromatography.
c Ratio determined from 1H NMR spectroscopy.
3fa
81%
1f
94%
Scheme 3 Preparation of 1f and its use in the gold-catalysed cou-
pling with 2a
d A mixture of other product isomers alongside unreacted starting ma-
terial was also observed.
bility of this sulfur ylide preparation. Pleasingly, under the
standard conditions, the coupling of 1f with 2a proceeded
smoothly to afford the coupling product 3fa in high yield
as a single isomer.
The impact of the nonmigrating group on the reaction
pathway was subsequently examined in the reactions of
phenyl-substituted propargylic carboxylates (Scheme 4).
Only isomer 3ab was observed from the reaction of 1a
with benzyl allyl sulfide. Similarly, 3gd was formed from
the pivalate 1g. However, when using allyl methyl sulfide
2d, the product from [2,3]-sigmatropic rearrangement of
the sulfur ylide 6gd was observed as the major product
alongside 3gd.
With a heteroaryl unit now accommodated in this cou-
pling, attention turned to exploring the nature of the non-
migrating group on the sulfur (Table 2). Surprisingly, the
switch from S-phenyl- to S-benzyl allyl sulfide resulted in
the formation of the expected coupling product 3fb in
small quantities only. The major product was instead iso-
mer 6fb, isolated predominantly as the E isomer, which is
expected from a [2,3]-sigmatropic rearrangement of the
sulfur ylide intermediate. The use of Au(I) or Au(III) pre-
catalysts gave consistent results for either benzyl allyl sul-
fide or allyl phenyl sulfide (Table 2, entries 1 vs. 2 and 3
vs. 4). Diallyl sulfide 2c was then employed in the reac-
To study whether isomer 3 results from a fast rearrange-
ment of 6, or vice versa, the structural isomers 3gd and
6gd were separated by HPLC and heated independently in
1,2-dichloroethane at 70 °C with: (i) no catalyst; (ii) AuCl
(10 mol%); (iii) AuCl3 (10 mol%). No interconversion be-
tween isomers or other reaction was observed under any
© Thieme Stuttgart · New York
Synlett 2012, 23, 70–73

72
P. W. Davies, S. J.-C. Albrecht
CLUSTER
lylic to methyl, presumably allowing greater rotational
freedom around the ylidic S–C bond.
O
O
R1
SBn
O
O
R1
The difference in reactivity between 1a and 1f, with the
latter more likely to afford the product of [2,3]-sigmatro-
pic rearrangement, may result from the smaller furan unit
aiding the sigmatropic pathway on steric grounds. How-
ever, the effect of the conjugated carbonyl unit on reduc-
ing the localised anionic character at C-3 could well
decrease the relative rate of the allyl cation migration onto
this position.
2b
Ph
SBn
Ph
AuCl (5 mol%)
ClCH2CH2Cl
70 °C
1a (R1 = Me)
1g (R1 = t-Bu)
3ab 85%
3gb 66% (+16% 1g)
SMe
2d
AuCl (5 mol%)
ClCH2CH2Cl
70 °C
In summary, a heteroaromatic unit can be incorporated
into the gold-catalysed intermolecular coupling reaction
between a propargylic carboxylate and an allyl sulfide.
Sulfur ylides can even be installed by this method in the
presence of an enolizable carbonyl group. The [2,3] rear-
rangement of sulfur ylides prepared directly from propar-
gylic carboxylates is observed for the first time, and the
outcome of this reaction is highly dependent upon the
choice of the nonmigrating sulfur substituent. The struc-
turally isomeric products are formed by divergent path-
ways from the sulfur ylide and a complete switch in
reaction outcome was observed when using S-phenyl and
S-methyl allyl sulfide.
O
O
O
t-Bu
O
t-Bu
Ph
SMe
Ph
SMe
3gd
:
6gd
1
1.9
74%
Scheme 4 Coupling of methyl and benzyl allyl sulfides
of these conditions. To rule out an active catalyst for the
Cope rearrangement only being formed during a coupling
reaction, (E/Z)-6gd was also added to a reaction between
1a and 2e and was recovered unaffected alongside the ex-
pected product 3ae (Scheme 5).14
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
O
Acknowledgment
O
O
Financial support from the EPSRC (EP/EO32168/1) and the Uni-
versity of Birmingham is gratefully acknowledged. We thank John-
son Matthey plc for a generous loan of metal salts. Instrumentation
used for this research was part supported by Birmingham Science
City AM2 with support from AWM and ERDF.
AuCl (5 mol%)
ClCH2CH2Cl
O
Ph
Ph
S
1a
2e
S
70 °C
O
OMe
3ae
80%
OMe
Ph
O
t-Bu
SMe
References and Notes
(1) Reviews: (a) Fürstner, A.; Davies, P. W. Angew. Chem. Int.
Ed. 2007, 46, 3410. (b) Hashmi, A. S. K.; Hutchings, G. J.
Angew. Chem. Int. Ed. 2006, 45, 7896. (c) Gorin, D. J.;
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(e) Marco-Contelles, J.; Soriano, E. Chem. Eur. J. 2007, 13,
1350.
(2) Davies, P. W.; Albrecht, S. J.-C. Chem. Commun. 2008, 238.
(3) For our further studies into the formation of sulfur ylides
from alkynes, see: (a) Davies, P. W.; Albrecht, S. J. C.
Angew. Chem. Int. Ed. 2009, 48, 8372. (b) Davies, P. W.
Pure Appl. Chem. 2010, 82, 1537.
(4) For a diazo-free transition-metal-catalysed cyclisation–
aromatisation approach to generate sulfur ylides, see: Kato,
Y.; Miki, K.; Nishino, K. F.; Ohe, K.; Uemura, S. Org. Lett.
2003, 5, 2619.
(5) For examples of low-valent sulfur employed alongside
effective gold-catalysed organic synthesis, see:
(E/Z)-6gd
added and recovered
unchanged
Scheme 5 Control reaction to assess interconversion of isomers
This lack of interconversion between isomers is consistent
with the formation of 3 directly from 5 by transfer of the
allyl cation from sulfur to the nucleophilic C-3 carbon.
Though generally a facile process in sulfur ylide chemis-
try, the [2,3]-sigmatropic rearrangement of ylide 5 ap-
pears to be disfavored in this specific process in the
presence of a competing S–C allyl migration pathway.
Steric congestion between the nonmigrating S-substituent
and the enol acetate unit may affect the ability of 5 to
adopt the conformation about the S–C bond that is re-
quired for sigmatropic rearrangement. It is notable that in-
creasing quantities of [2,3]-sigmatropic rearrangement
product 6 are observed as the steric environment directly
at sulfur decreases, going from Caromatic, benzylic, and al-
(a) Nakamura, I.; Sato, T.; Yamamoto, Y. Angew. Chem. Int.
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Synlett 2012, 23, 70–73
© Thieme Stuttgart · New York

CLUSTER
Reactivity Switch in the Gold-Catalysed Coupling of Allyl Sulfides
73
Int. Ed. 2006, 45, 1897. (e) Arcadi, A.; Bianchi, G.; Di
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(12) Only very limited success has been observed with aliphatic
substituents at the propargylic position. Aldehyde-derived
systems are observed to give only trace amounts of con-
version or undergo degradation. Ketone derivative A-1
proceeds sluggishly to give the desired coupling product
A-3a in low yield (Scheme 6).
(6) Johansson, M. J.; Gorin, D. J.; Staben, S. T.; Toste, F. D.
J. Am. Chem. Soc. 2005, 127, 18002.
(7) We observed cyclopropanation as the major pathway when
allyl sulfides bearing greater substitution at the alkene were
employed.
O
O
(8) (a) Kirmse, W.; Kapps, M. Chem. Ber. 1968, 101, 994.
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O
AuCl (5 mol%)
ClCH2CH2Cl
SPh
O
SPh
70 °C, 72 h
26%
2a
A-3a
A-1
Scheme 6
(13) Hashmi, A. S. K.; Kurpejović, E.; Wölfle, M.; Frey, W.;
Bats, J. W. Adv. Synth. Catal. 2007, 349, 1743.
(14) Similarly, neither (E)- or (Z)-6gd were observed when 3gd
was added to an ongoing reaction.
© Thieme Stuttgart · New York
Synlett 2012, 23, 70–73

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