A gold-catalysed fully intermolecular oxidation and sulfur-ylide formation sequence on ynamides

Article abstract of DOI:10.1039/c4cc01059k

An efficient C-O, C-S and C-C bond-forming sequence leads to functionalised compounds bearing sulfur-substituted quaternary carbons. Ynamides are employed as diazo-equivalents to access the [2,3]-sigmatropic rearrangements of allyl sulfonium ylides by a t

Full text of DOI:10.1039/c4cc01059k

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A gold-catalysed fully intermolecular oxidation
and sulfur-ylide formation sequence on
ynamides†
Cite this: Chem. Commun., 2014,
50, 6001
Received 10th February 2014,
Accepted 16th April 2014
Mickael Dos Santos and Paul W. Davies*
¨
DOI: 10.1039/c4cc01059k
www.rsc.org/chemcomm
An efficient C–O, C–S and C–C bond-forming sequence leads to
functionalised compounds bearing sulfur-substituted quaternary
carbons. Ynamides are employed as diazo-equivalents to access
the [2,3]-sigmatropic rearrangements of allyl sulfonium ylides by a
three-component chemoselective oxidation and intermolecular
ylide formation.
The [2,3]-sigmatropic rearrangement of allyl sulfonium ylides is a
potent method for the formation of Csp3–Csp3 bonds.1 A signifi-
cant hydrocarbon functionalisation process is achieved when the
rearrangement is coupled with in situ ylide formation through
reaction of a sulfide with a metal carbene, formed in situ from a
sacrificial functionality such as the diazo-group (Doyle–Kirmse reac-
tion, Scheme 1).2,3 We4 and others5 have been engaged in efforts to
access the synthetic potential of these ylides using methods to
generate carbenoids that avoid the pre-installation and use of
potentially hazardous high-energy diazo groups. Our initial studies
established that sulfur ylides can be prepared from the inter-
molecular reaction of sulfides with gold-carbenes (Scheme 2).4a,d,6
However, the use of propargylic carboxylates as carbenoid precursors
impacted on the subsequent ylidic rearrangements to generally
afford products isomeric to those from [2,3]-sigmatropic pathways.
More-congested centres and synthetically valuable sulfur-substituted
quaternary carbons were inaccessible as terminal alkynes and
unsubstituted allyl groups on the sulfide7 were required.4a,d We
subsequently established that sigmatropic-rearrangements of sulfur
ylides were accessible through an intramolecular gold or platinum
catalysed cycloisomerisation of alkynyl allyl sulfoxides.4b,8 Here we
report a diazo-free oxidation-ylide formation sequence to access
sulfur-ylide rearrangements by a selective and efficient fully inter-
molecular transformation of ynamides.
Scheme 1 The Doyle–Kirmse reaction and an alternate oxidation based
route.
Scheme 2 Intermolecular trapping of gold carbenes with allyl sulfides:
ref. 4a,d
whether ynamides could be used to replace diazo compounds in
intermolecular sulfonium ylide formation to form quaternary
carbons (Schemes 1 and 3).
Significant transformations have resulted from a-oxo-gold
carbene formation by intermolecular oxidation of a C–C triple
bond.9,10,12 While these predominantly feature subsequent
intramolecular cyclisations, there are striking exceptions in the
terminal alkyne series where the mono-substituted gold carbene is
trapped with intermolecular oxygen-, nitrogen- and halide nucleo-
philes other than the oxidant.13 Similar three-component couplings
have not however been reported in the ynamide series and it is
notable that the resulting 1,1-disubstituted organogold species C/D
appears prone to oxidation even when intramolecular pathways are
available.9,10,14 A successful outcome therefore requires a high level
of reagent-compatibility and selectivity: the sulfide must not affect
In light of our,9 and others10 studies into gold-catalysed inter-
molecular atom/group-transfer onto ynamides A,11 we questioned
School of Chemistry, University of Birmingham, Edgbaston, B15 2TT, Birmingham,
UK. E-mail: p.w.davies@bham.ac.uk; Tel: +44 (0)121 4144408
† Electronic supplementary information (ESI) available: Synthetic procedures and
characterisation for all compounds. CCDC 984457. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c4cc01059k
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Ynamides bearing N-phenyl and N-methyl groups reacted
similarly (4ba vs. 4aa) while an N-benzyl equivalent was less
suited affording a lower yield of 4ca with competing over-
oxidation observed.17 The trend between N-phenyl and N-methyl
was maintained in the p-tolylsulfonamide series, albeit with
slightly higher yields (Scheme 4, 4da and 4ea). In both cases,
products from cyclisation of C/D onto the N-substituent were not
observed. An ynamide prepared from imidazole was unreactive.
Oxazolidinone-derived ynamide 1f could be used to form 4fa but
greater conversion and selectivity for ylide formation was achieved
using a bulky phosphine-derived catalyst Au-II in place of the
phosphite–gold complex, identifying potentially significant influ-
encing factors between different types of ynamides (see ESI†).
The sulfonamide-derived ynamides were used throughout the
remainder of this study into structural effects on the relative
efficacy of the standard conditions. The reaction remained effec-
tive in the presence of S-aryl, S-benzyl- and S-alkyl allyl sulfides
2b–e as well as bisallylsulfide 2f (Scheme 5). Unsurprisingly, a
more electron-deficient aryl bromide substituent renders the ylide
pathway less competitive against oxidation with B30% yield of
the over-oxidation product determined from the crude reaction
mixture.
The role of the ynamide C-substituent was next tested under
the standard conditions (Scheme 6). None of the desired product
from ylide formation was observed when anisole-derived ynamide
1g was reacted with sulfides 2a or 2b with the over-oxidation
product 5 instead predominating. A preference for over-oxidation
against an intramolecular reaction has recently been reported
when using p-anisole derived ynamide.10f In contrast, both induc-
tively and mesomerically electron-withdrawing groups were well
tolerated (4hb and 4ib). Alkyl-substituted gold carbenoids are
prone to 1,2-insertion9a and this intramolecular pathway was
indeed preferred, affording 6 with low conversion of the hexyne-
derived ynamide 1j. A conjugated ene-ynamide 1k did not follow a
recently reported 4-p-electrocyclisation pathway10c instead reacting
productively to afford functionalised tertiary allylic thioether 4ka.
By analogy to the effects encountered in diazo-derived metal
carbene chemistry, changing the ynamide C-substituent was
expected to influence the reactivity of the resulting carbenoid.2
However, the impact of the electronic influence on the chemo-
selectivity of these ynamide-based reactions is informative:
the formation of the desired compound 4 requires the active
organogold species to react preferentially with the polarisable sulfur
nucleophile 2 in preference to the dipolar oxygen-nucleophile 3.
Scheme 3 A gold-catalysed intermolecular oxidation – intermolecular
trapping manifold for ynamides.
activation or oxidation of the ynamide (A - B - C).15 Ylide
formation must then compete successfully with cyclopropanation
(G) and oxidation (H) of organogold species C and/or D.
After exploring a variety of parameters including catalyst, solvent
and oxidant with various ynamides (see ESI†), reaction conditions
were found to effect the complexity-increasing cascade from
ynamides 1 into the functionalised tertiary thioethers 4 (Scheme 4).
Competing double-oxidation to form imido-ketones (H) was observed
throughout this study alongside incomplete consumption of 1, and
this pathway was exclusively observed using Au(III) or NHC–Au(I)
catalysts. However, good conversion and selectivity for the formation
of 4 was achieved using a combination of cationic gold phosphite
complex Au-I alongside methylpicolinate N-oxide 3. The reactions
were run in dichloromethane at room temperature and reagents
1:2:3 were added at the start of the reaction in a near-stoichiometric
1 : 1.2 : 1.3 ratio respectively (Scheme 4). Recourse to continual
or portion-wise slow-addition strategies that maintain a low
concentration of oxidant to favour reaction with the desired
nucleophile was avoided. This preference was maintained
throughout the study in order to explore the extent and influences
on the observed chemoselective preference for sulfide attack at
the organogold intermediate.13,16
Scheme 4 The ynamide-based Doyle–Kirmse type reaction.
6002 | Chem. Commun., 2014, 50, 6001--6004
Scheme 5 Effect of the non-migrating group on the allyl sulfide.
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reaction of substituted allyl sulfides 2h with metal carbenes
derived from donor–acceptor diazocompounds.6,19 The relative
stereochemistry of the major diastereoisomer was confirmed by
X-ray analysis (Scheme 7) and is consistent with a preference for
the cinnamyl phenyl group to be positioned anti to the amide
group across an envelope transition state. Rapid access to these
N,N-disubstituted amide derivatives by the ynamide strategy may
therefore provide additional synthetic advantages.
In conclusion, a gold-catalysed cascade reaction is reported for
the practical complexity-increasing synthesis of functionalised
tertiary thioethers directly from ynamides. Selectivity for sulfur
ylide formation over competing processes is rationalised and can
be achieved when all reagents are added at the start of the process
with a near-stoichiometric reagent loading. The products are
consistent with those expected from [2,3]-sigmatropic rearrange-
ment of allyl sulfonium ylides. This report demonstrates that
ynamides can be used as synthetically attractive replacements to
1,1-disubstituted diazocompounds in intermolecular processes.
The authors thank the European Union FP7 Marie-Curie IEF for
funding (Fellowship to MDS: ESAMY). We thank the EPSRC UK
National Crystallography Service at the University of Southampton
for the collection of the crystallographic data20 and Dr Louise Male
(University of Birmingham) for its analysis. The facilities used in
this research were part supported through Birmingham Science
City AM2 by Advantage West Midlands and the European Regional
Development Fund.
Scheme 6 Effect of the ynamide C-substituent on the reaction outcome.
Nucleophilic attack can occur either alongside- or after elimination
of methylpicolinate (Scheme 3, C - E vs. C - D - E).8–10,12,13
Considering the contrasting natures of the nucleophiles, a favour-
able attack of the sulfide on the vinyl gold carbenoid C, bearing a
relatively-uncharged carbon centre, appears more likely than on
the cationic carbon of gold carbene D. The strongly p-acidic
phosphite ligand affords significant cationic character to D by
decreasing the ability of gold to donate electron density.18
However, these same electronic characteristics should aid the
desired chemoselectivity by disfavouring the elimination of
methylpicolinate required to form D. On this basis, the reactivity
of electron-rich ynamide 1g (R1 = p-MeOC6H4) can be explained by
the mesomeric contribution from the anisole MeO-group aiding
elimination of the nucleofuge to form D and disfavouring ylide
formation.
Sulfides with substituted allyl units were then explored to
ascertain if a [2,3]-sigmatropic rearrangement was operative.
Pleasingly, and in contrast with other systems,7 both 2-vinyl-
tetrahydrothiophene 2g and cinnamyl derivative 2h underwent
clean reactions. The functionalised 8-membered sulfur hetero-
cycle 4eg and the tertiary thioether bearing a vicinal tertiary
stereogenic centre 4eh are the products expected from sulfur-ylide
formation and [2,3]-sigmatropic rearrangement with allylic inver-
sion (Scheme 7).‡2,6,19 Interestingly, formation of 4eh proceeded
with higher diastereoselectivity than is normally observed from the
Notes and references
‡ Crystal data for 4eh: C36H31NO3S2, M = 589.74, monoclinic, a =
16.0175(3) Å, b = 9.6290(2) Å, c = 19.5279(5) Å, b = 98.570(1)1, U =
2978.2(1) Å3, T = 120(2) K, space group P21/c, Z = 4, 34 108 reflections
measured, 6813 unique (Rint = 0.0607) which were used in all calcula-
tions. The final R1 was 0.0458 (I 4 2s(I)) and wR(F2) was 0.1150 (all data).
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Scheme 7 Reactions of ynamide-derived sulfur ylides displaying allylic
inversion. Crystal structure of 4eh with ellipsoids drawn at the 50%
probability level.
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