Alkynes as masked ylides: Gold-catalysed intermolecular reactions of propargylic carboxylates with sulfides

Article abstract of DOI:10.1039/b714813e

The in situ-generation of sulfur ylides by the gold-catalysed rearrangement of propargylic carboxylates in the presence of sulfides has resulted in highly efficient and novel transformations. The Royal Society of Chemistry.

Full text of DOI:10.1039/b714813e

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Alkynes as masked ylides: Gold-catalysed intermolecular reactions of
propargylic carboxylates with sulfides{
Paul W. Davies* and S e´ bastien J.-C. Albrecht
Received (in Cambridge, UK) 1st October 2007, Accepted 16th October 2007
First published as an Advance Article on the web 24th October 2007
DOI: 10.1039/b714813e
The in situ-generation of sulfur ylides by the gold-catalysed
rearrangement of propargylic carboxylates in the presence
of sulfides has resulted in highly efficient and novel
transformations.
chemistry and noble-metal-catalysed isomerisation processes
would allow a plethora of valuable new transformations to be
developed. However, several issues needed to be explored: first,
whether these p-acid catalysts retain efficacy in intermolecular
processes featuring reagents that may otherwise be considered as
8,9
The transition-metal-catalysed decomposition of diazo compounds
is a well-established and powerful strategy to access metal
carbenoids, which may then be used to generate reactive
intermediates. A powerful example is the Doyle–Kirmse reaction,
which generates new C–C and C–S bonds (Scheme 1), most
effective catalyst poisons; second, whether the reactivity profile
of the carbenoid and/or the ylide formed from it mimics that of
species derived from a-diazocarbonyl compounds.
To this end, propargylic carboxylate 6 (R = Ph, 1.00 equiv.) and
1
phenyl allyl sulfide 3 (R = Ph, 1.05 equiv.) were reacted together
1
notably under Rh(II) and Cu(I) catalysis. In this process, an allyl
in the presence of 5 mol% of a noble metal catalyst (Scheme 2,
sulfide 3 reacts with carbenoid 2 to give a sulfur ylide intermediate
2
Table 1). While cationic gold species and PtCl were ineffective, the
2
4
that is capable of undergoing a [2,3]-sigmatropic rearrangement.
simple AuCl salt afforded a new product in high yield. Analysis of
this compound using extensive NMR studies showed it to be
compound 9. No traces of isomer 8, expected from a Doyle–
This overall strategy, however, is limited: first, by safety concerns
associated with the handling and use of diazo compounds; second,
by the synthetic impact associated with the introduction of a diazo
functionality. With these factors in mind, we recently initiated a
programme to explore the utility of reactive intermediates derived
from metal carbenoids that are accessed via rearrangement
processes. By bypassing the preparation and use of diazo
compounds, this strategy should result in increased overall
synthetic efficiency, whilst also decreasing potential operating risks.
As a starting point, we studied the reaction between a
propargylic carboxylate and an allyl sulfide (Scheme 2). Within
the rapidly developing area of gold- and platinum-based homo-
1
0
Kirmse type reaction, or products resulting from cyclopropana-
tion of the allyl unit were seen, and only the (Z)-isomer of 9 was
observed (see ESI{).
Further optimisation showed the use of chlorinated solvents at
0.1 M concentration to be most effective (Table 1, entry 5).
Although good results were achieved using CH Cl at room
2
2
temperature, the reaction time was significantly reduced when
performed in ClCH CH Cl at 70 uC (Table 1, entry 10).
2
2
The same reaction conditions were applied across a number of
substrates (Table 2). Pivaloyl, acetyl and benzoyl esters may be
employed (Table 2, entries 1–3); however, the use of a para-
nitrobenzoate ester led to decomposition. Electron-rich and
electron-poor aromatic units were accommodated on the sulfide
3,4
geneous catalysis, the propargylic carboxylate moiety has invited
special interest owing to its propensity to act as an a-diazocarbonyl
5
surrogate upon rearrangement to metal carbenoid 7. This
1
1
reactivity has been successfully employed in a number of
transformations, in particular through reaction with additional
(Table 2, entries 4–8). In the latter cases, 2 equiv. of sulfide were
employed to achieve good yields (Table 2, entries 5–7), and the
enol acetates were hydrolysed to the ketones 10 before being
isolated, in order to aid purification. The propargylic acetate may
also be modified, and a high yield was observed using the ortho-
bromo substituent (Table 2, entry 9). The use of halide substituents
6,7
C–C p-systems.
We questioned whether this mode of reactivity could therefore
be used as an alternative strategy to access reactive intermediates,
such as sulfur ylides. If successful, the combination of ylide
Scheme 1 The Doyle–Kirmse reaction.
School of Chemistry, University of Birmingham, Edgbaston,
Birmingham, UK B15 2TT. E-mail: p.w.davies@bham.ac.uk;
Fax: +44 (0)121 414 4403; Tel: +44 (0)121 414 4408
{
Electronic supplementary information (ESI) available: Experimental
Scheme 2 The
rearrangement–coupling–rearrangement
reaction
details and analytical data for new compounds. See DOI: 10.1039/
b714813e
between propargylic carboxylates and allyl sulfides.
2
38 | Chem. Commun., 2008, 238–240
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a
Table 1 Screening of reaction conditions (Scheme 2)
b
Entry Catalyst
Solvent
T/uC Time/h Yield 9 (%)
c
d
1
2
3
4
5
6
7
8
9
1
a
PPh
Me
PPh
PtCl
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
3
AuSbF
SAuCl
AuNTf
6
CH
CH
CH
2
2
2
Cl
Cl
Cl
2
2
2
23
23
23
60
23
23
23
23
40
40
40
40
40
40
40
40
18
6
—
12
—
—
85
44
24
43
50
95
2
e
3
2
d
2
PhCH
3
CH
CH
2
Cl
Cl
2
f
2
2
MeCN
PhCH
PhCH
3
3
70
Cl 70
0
ClCH CH
2
2
For the reaction of 6 (R = Ph, 1.00 equiv.) with phenyl allyl sulfide
3 (R = Ph, 1.05 equiv.) at 0.1 M concentration. Yields determined
c
by NMR against a known quantity of benzaldehyde. Formed by
mixing equimolar quantities of PPh .
reaction was observed. Degradation. At 0.5 M concentration.
1
b
d
3
AuCl and AgSbF
6
No
e
f
a
Table 2 Scope of the Au(I)-catalysed cascade reaction (Scheme 3)
1
R
2
R
b
Entry
R
Time/h Product (yield (%))
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-MeOC
p-MeC H
6 4
p-BrC
o-BrC
Me
Bu
Ph
Me
Me
Me
Me
Me
Me
6
6
4
6
5
9
9
9
5
9a (82)
9b (72)
9c (72)
9d (80)
9e (82)
10f (64)
10g (54)
10h (58)
9i (93)
Scheme 4 Potential reaction pathways.
t
An absence of chirality transfer was demonstrated in the
reaction of enantioenriched (R)-6 (Scheme 5), thus suggesting the
intermediacy of an achiral species, such as 7. Similar results were
found in intermolecular cyclopropanation processes mediated by
6
H
4
c
6
H
H
4
4
c
c
6
p-CF
3
C
6
H
4
7b
cationic gold species.
9
o-BrC
o-BrC
Ph
6
H
H
4
4
Ph
p-MeC
Allyl
d
1
1
a
0
1
6
6
H
4
Me 24
Me 42
9j (87)
10k (63)
In contrast to reactions with allyl thioethers, the use of
propargyl thioether 15 gave a mixture of isomeric products, 16
and 17, after hydrolytic work-up (Scheme 6). Although similar
e
For the reaction of carboxylates 6 (0.29 mmol) with sulfides 3
0.30 mmol) in ClCH CH Cl (0.1 M) using 5 mol% of AuCl.
Isolated yields after chromatographic purification. 2 equiv. of
(
2
2
b
c
ratios were observed with AuCl, AuCl was found to be most
3
d
sulfide and 10 mol% AuCl. On a 1.0 mmol scale using 10 mol%
AuCl. 3 equiv. of diallylsulfide.
efficacious for this process. Minor isomer 16 is analogous to the
products derived from the reaction of allyl thioethers, whereas
major isomer 17 matches that expected from direct 1,2-transfer of
the propargylic fragment from the ylide intermediate. Despite the
mixture of isomers, the reaction displays excellent chemoselectivity
with respect to the two terminal alkyne units available for reaction.
The reaction funnels cleanly through the activation of the
propargylic carboxylate rather than the reaction of the propargylic
sulfide. The reason for the shift in selectivity is, as yet, unclear.
However, the formation of 17 contrasts with the Cu(I)-catalysed
e
further exemplifies the chemoselectivity of gold catalysts toward
alkynes and allows synthetic handles to be introduced for future
manipulation (Table 2, entries 6, 7, 9, 10). Bis-allyl sulfide also
undergoes the reaction cleanly, and the product was isolated as a
ketone (Table 2, entry 11).
A proposed mechanistic scenario for the formation of 9 is
shown in Scheme 4. Nucleophilic attack of the carbonyl unit onto
gold-activated alkyne 11 is followed by back-donation from the
3
,5
metal to generate gold carbenoid 7. Subsequent reaction with a
thioether generates ylide 13, which may or may not be associated
with AuCl. The subsequent evolution of 13 may then proceed
through one of two pathways: a 1,2-shift or a [2,3]-sigmatropic
rearrangement of the allyl fragment affording 8, as per the Doyle–
Kirmse process, followed by Cope rearrangement to 9; or an
overall oxygen-assisted 1,4-shift affording betaine 14, and
Scheme 5 Use of an enantioenriched substrate.
12
subsequent elimination of AuCl.
Scheme 3 Gold-catalysed rearrangement–addition reactions.
This journal is ß The Royal Society of Chemistry 2008
Scheme 6 Use of propargylic sulfide.
Chem. Commun., 2008, 238–240 | 239

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Notes and references
1
Reviews: (a) M. P. Doyle, M. A. McKervey and T. Ye, Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds, Wiley-
Interscience, New York, 1998; (b) A.-H. Li, L.-X. Dai and
V. K. Aggarwal, Chem. Rev., 1997, 97, 2341.
2
For recent discussions over whether the sulfur ylide is metal-bound to
some extent, see: (a) M. Ma, L. Peng, C. Li, X. Zhang and J. Wang,
J. Am. Chem. Soc., 2005, 127, 15016; (b) M. Reggelin, Top. Curr. Chem.,
2
007, 275, 1 and references therein.
II
I
3
4
For a review on the use of Pt , Au and other late transition-metal
templates as p-acidic catalysts, see: A. F u¨ rstner and P. W. Davies,
Angew. Chem., Int. Ed., 2007, 46, 3410.
Selected reviews: (a) D. J. Gorin and F. D. Toste, Nature, 2007, 446,
395; (b) C. Nieto-Oberhuber, S. L o´ pez, E. Jim e´ nez-N u´ n˜ ez and
A. M. Echavarren, Chem.–Eur. J., 2006, 12, 5916; (c) A. S. K.
Hashmi, Chem. Rev., 2007, 107, 3180; (d) A. S. K. Hashmi and
G. J. Hutchings, Angew. Chem., Int. Ed., 2006, 45, 7896; (e) G. C. Lloyd-
Jones, Org. Biomol. Chem., 2003, 1, 215.
Scheme 7
A cascade rearrangement–coupling–rearrangement–cycloi-
somerisation reaction.
Doyle–Kirmse reactions of propargylic sulfides, which afford
5 For recent reviews, see: (a) N. Marion and S. P. Nolan, Angew. Chem.,
Int. Ed., 2007, 46, 2750; (b) J. Marco-Contelles and E. Soriano, Chem.–
Eur. J., 2007, 13, 1350.
2a
allene products via a [2,3]-sigmatropic rearrangement.
In order to explore the relative proclivities of allyl and propargyl
fragments to undergo the shift process, 6 was reacted with allyl
propargyl sulfide 18 (Scheme 7). The major product of the reaction
was dihydrothiophene 19 (with ,10% by mass of a complex
mixture of other products). A likely reaction pathway involves the
preferential formation of 20 through a shift of the propargylic
fragment. Subsequent gold-catalysed carbothiolation sees the
formation of a dihydrothiophene core with a S A C shift of the
allyl unit. While endocyclic carboheteroatom additions have
previously been used to prepare benzothiophenes and other fused
aromatic systems, to the best of our knowledge, this is the first
report of an endo-mode 1,2-carbothiolation of an alkyne to afford
6
For representative intramolecular examples using gold catalysts, see: (a)
V. Mamane, T. Gress, H. Krause and A. F u¨ rstner, J. Am. Chem. Soc.,
2004, 126, 8654; (b) N. Marion, P. De Fr e´ mont, G. Lemi e` re,
E. D. Stevens, L. Fensterbank, M. Malacria and S. P. Nolan, Chem.
Commun., 2006, 2048; (c) X. Shi, D. J. Gorin and F. D. Toste, J. Am.
Chem. Soc., 2005, 127, 5802.
7 Selected intermolecular examples: (a) Ru(II): K. Miki, K. Ohe and
S. Uemura, J. Org. Chem., 2003, 68, 8505; (b) Cationic Au(I) complexes:
M. J. Johansson, D. J. Gorin, S. T. Staben and F. D. Toste, J. Am.
Chem. Soc., 2005, 127, 18002; (c) Using Pt catalysis: K. Miki, M. Fujita,
S. Uemura and K. Ohe, Org. Lett., 2006, 8, 1741.
8 For gold-catalysed intramolecular processes involving sulfur nucleo-
philes, see: (a) I. Nakamura, T. Sato and Y. Yamamoto, Angew. Chem.,
Int. Ed., 2006, 45, 4473; (b) I. Nakamura, G. B. Bajracharya, H. Wu,
K. Oishi, Y. Mizushima, I. D. Gridnev and Y. Yamamoto, J. Am.
Chem. Soc., 2004, 126, 15423; (c) L. Peng, X. Zhang, S. Zhang and
J. Wang, J. Org. Chem., 2007, 72, 1192.
8a,13
semi-saturated heterocycles.
Overall, this process involves three
key stages: gold-catalysed rearrangement, ylide formation and
rearrangement, and gold-catalysed cycloisomerisation. Although
the overall yield of 19 is modest, the large number of bond forming
processes and the very significant increase in molecular complexity
from the simple starting materials renders this cascade process
attractive, especially when considering the numerous selectivity
issues at play.
9
L. L. Hegedus and R. W. McCabe, Catalyst Poisoning, Marcel Dekker,
New York, 1984.
0 A cyclisation–aromatisation approach has been used to generate
1
rhodium carbenoids for subsequent use in a Doyle–Kirmse process,
when run in the presence of a 10-fold excess of allyl sulfide: Y. Kato,
K. Miki, F. Nishino, K. Ohe and S. Uemura, Org. Lett., 2003, 5, 2619.
11 A competition reaction shows that the product of the more electron-rich
allyl sulfur ylide is formed predominantly:.
In summary, the use of gold-catalysed isomerisations to access
reactive sulfur ylide intermediates has been shown to be a viable
intermolecular strategy.
A highly efficient rearrangement–
coupling–rearrangement process has been developed that utilises
simple, readily constructed precursors to access highly functiona-
lised materials under mild conditions. This study demonstrates that
the gold carbenoids derived from propargylic carboxylates can
show a complementary mode of reactivity to carbenoids
derived from a-diazo carbonyl compounds, with the propargylic
carboxylate reacting as an overall 1,3-dipolar synthon rather
than a 1,1-dipolar species. Further exploration of the reactivity of
ylides derived from gold carbenoids and a study into the
mechanism of this process is under way, and will be reported in
due course.
1
2 For an example using Rh(II), where the b-carbon of vinyl carbenoids is
involved in the transformation, see: M. Hamaguchi, T. Misumi and
T. Oshima, Tetrahedron Lett., 1998, 39, 7113 and references therein.
1
3 For examples of heteroatom A carbon shifts in noble metal-catalysed
cyclisations, see: endo-mode: (a) A. F u¨ rstner, E. K. Heilmann and
P. W. Davies, Angew. Chem., Int. Ed., 2007, 46, 4760; (b) A. F u¨ rstner
and P. W. Davies, J. Am. Chem. Soc., 2005, 127, 15024; (c) I. Nakamura,
Y. Mizushima and Y. Yamamoto, J. Am. Chem. Soc., 2005, 127, 15022.
For exo-mode, see: (d) A. F u¨ rstner, F. Stelzer and H. Szillat, J. Am.
Chem. Soc., 2001, 123, 11863; (e) A. F u¨ rstner, F. Stelzer and H. Szillat,
J. Am. Chem. Soc., 2000, 122, 6785; (f) F. M. Istrate and F. Gagosz,
Org. Lett., 2007, 9, 3181.
We thank the EPSRC (EP/E032168/1) and the University of
Birmingham for their financial support of this programme.
2
40 | Chem. Commun., 2008, 238–240
This journal is ß The Royal Society of Chemistry 2008