Aryl methyl sulfides as substrates for rhodium-catalyzed alkyne carbothiolation: Arene functionalization with activating group recycling

Article abstract of DOI:10.1021/ja2108992

A Rh(I)-catalyzed method for the efficient functionalization of arenes is reported. Aryl methyl sulfides are combined with terminal alkynes to deliver products of carbothiolation. The overall process results in reincorporation of the original arene functional group, a methyl sulfide, into the products as an alkenyl sulfide. The carbothiolation process can be combined with an initial Rh(I)-catalyzed alkene or alkyne hydroacylation reaction in three-component cascade sequences. The utility of the alkenyl sulfide products is also demonstrated in simple carbo- and heterocycle-forming processes. We also provide mechanistic evidence for the course of this new process.

Full text of DOI:10.1021/ja2108992

Communication
pubs.acs.org/JACS
Aryl Methyl Sulfides as Substrates for Rhodium-Catalyzed Alkyne
Carbothiolation: Arene Functionalization with Activating Group
Recycling
Joel F. Hooper, Adrian B. Chaplin, Carlos Gonzalez-Rodríguez, Amber L. Thompson, Andrew S. Weller,*
́
and Michael C. Willis*
Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, U.K.
S
* Supporting Information
Lautens demonstrated that in specific cases it is possible to
ABSTRACT: A Rh(I)-catalyzed method for the efficient
reincorporate an iodine atom following C−C bond formation using
Pd catalysis (eq 2 in Scheme 1; AG = I).4,5 In a complementary
functionalization of arenes is reported. Aryl methyl sulfides
are combined with terminal alkynes to deliver products of
carbothiolation. The overall process results in reincorpora-
tion of the original arene functional group, a methyl sulfide,
into the products as an alkenyl sulfide. The carbothiolation
process can be combined with an initial Rh(I)-catalyzed
alkene or alkyne hydroacylation reaction in three-component
cascade sequences. The utility of the alkenyl sulfide pro-
ducts is also demonstrated in simple carbo- and heterocycle-
forming processes. We also provide mechanistic evidence for
the course of this new process.
approach, we now report chemistry based on the activation of
simple methyl aryl sulfides using Rh(I) catalysis in which an
intermolecular carbothiolation process delivers alkenyl sulfide
products. The transformation results in reincorporation of the
original methyl sulfide AG into the products in the form of an
alkenyl sulfide unit, effectively recycling the AG, which can than be
used for further transformations (eq 3 in Scheme 1). This method
achieves bond activation and formation under mild conditions, has
good functional group tolerance, and displays orthogonal reactivity
to the more usual Pd-based coupling reactions. In addition to docu-
menting the scope of this new process, we also provide evidence for
the mechanism that underpins this novel transformation.
When selecting a basic reaction framework on which to
develop an AG-recycling strategy, we chose to focus on
addition-type processes instead of cross-coupling systems
based on transmetalation, as one of our aims was to deliver a
completely atom-economic protocol. We also wanted to
employ an AG that would complement those used in traditional
arene functionalization chemistry. We therefore chose to focus
not on halide or sulfonate groups but on simple aryl methyl
sulfides (ArSMe). Although activated C−S bonds can be cleaved
by a variety of transition-metal catalysts,6 examples involving the
activation of simple aryl sulfides are significantly more limited.
For example, while unstrained aryl alkyl sulfides were employed
in some early examples of Ni-catalyzed cross-coupling reactions
with Grignard reagents,7 no cases of simple aryl alkyl sulfides
taking part in addition-type processes are known.8 In ad-
dition, methyl sulfides were attractive substrates because of
their general chemical robustness, a feature not shared by a
number of S-based functional groups used in known carbo-
thiolation reactions.6
he ubiquitous nature of aromatic and heteroaromatic
Tgroups in pharmaceuticals and agrochemicals and the
requirement to manipulate these aromatic units in synthetically
useful ways have resulted in the development of an enormous
range of synthetic methods.1 Some of the most useful of these
are based on transition-metal catalysis, with those based on Pd
catalysts arguably the most widely employed.2 Despite the
utility of these methods, the majority employ an activating
group (AG), most usually a halide or sulfonate, to control both
the reactivity and regiochemistry of the reactions. Thus, all of
these transformations generate AG-derived waste byproducts
(eq 1 in Scheme 1). The recent development of methods based
on C−H functionalization (or activation) go some way toward
addressing these limitations but as yet are not general
transformations.3 In a recent elegant report, Newman and
Scheme 1
We selected the coupling of ArSMe 1a and phenylacetylene
(2a) to test our proposed methodology, and Rh(I)−DPEphos-
derived complexes proved to be efficient catalysts for the
targeted transformation. For example, under hydroacylation-
like conditions,9 the complex [Rh(DPEphos)(nbd)][BArF ]
4
[nbd = norbornadiene; ArF = 3,5-(CF3)2C6H3] promoted the
union of 1a and 2a to generate alkenyl sulfide 3a in only 5%
yield (Table 1, entry 1), but this was increased to 90% by
Received: November 29, 2011
Published: January 30, 2012
© 2012 American Chemical Society
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a
Table 1. Optimization of the Coupling of 1a and 2a
Table 2. Scope of the Rh(I)-Catalyzed ArSMe/Alkyne
Carbothiolation Process
a
b
entry
ligand
nbd
solvent
temp (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
8
acetone
DCE
55
80
30
16
4
5
70
74
90
37
98
98
95
nbd
nbd
toluene
o-xylene
acetone
o-xylene
o-xylene
o-xylene
110
130
55
nbd
1
o-xylene
o-xylene
o-xylene
o-xylene
5
130
60
0.25
4.5
30
25
a
Conditions: 1a (1.0 equiv), 2a (2.0 equiv), catalyst (5.0 mol %).
Isolated yields.
b
variation of solvent and reaction temperature (entries 2−4).
Importantly, the alkenyl sulfide products were generated as
single geometric isomers, suggesting a stereoselective addition
process.8,10,11 We postulated that substitution of the nbd li-
gand was one limiting factor in turnover. Exchange for the more
labile o-xylene gave the complex [Rh(κ2-P,P-DPEphos)(η6-o-
xylene)][BArF ] (A) (see Scheme 2 for the X-ray structure),
4
which delivered a more efficient process at a number of
different temperatures (entries 5−8). An important observation
from a practical perspective is that the complex incorporating
xylene as a ligand, A, is bench-stable and easy to handle.
The optimized conditions developed for the coupling of 1a
and 2a were then applied across a varied range of substrates
(Table 2). Both the nbd and o-xylene catalysts were evaluated
across all substrates, with reaction temperatures and times
adjusted accordingly. The process proved to be broad in scope,
tolerating a variety of steric and electronic changes to both
reaction partners. For example, products 3b and 3c
demonstrate the ability of the arylalkyne to bear either
electron-withdrawing or -donating aryl substituents. Alkyl-
substituted alkynes could also be employed (3d, 3e). To
demonstrate the ability of the process to tolerate alternative
functionality, both 2-thienyl (3f) and ferrocenyl (3g)
substituents were efficiently incorporated. Example 3g also
illustrates that phenyl sulfides can function as the AG. The final
variation of the alkyne substrate (shown in product 3h) is
significant, as it demonstrates that bromo substituents can be
tolerated on the arene ring; given the wide use of aryl bromides
in Pd-catalyzed coupling chemistry, the benign nature of this
group under the present reaction conditions holds promise for
further manipulation of the products using complementary
catalytic methods. A control experiment utilizing the para-disposed
regioisomer of 1a established that the present reaction system
requires a carbonyl group positioned ortho to the methyl sulfide
being activated (see discussion below). However, alteration of the
type of carbonyl group is possible, as is variation of the remaining
positions of the arene. For example, a methyl ester can be used in
place of the original ketone (3i), as can a longer-chain (3j) or aryl
(3g) ketone as well as an enone (3k). Electron-donating MeO
substituents (3j) or an electron-withdrawing CF3 group (3k) can
also be readily introduced onto the arene ring. Finally, an aryl
chloride-substituted product (3l) was efficiently produced, again
demonstrating the ability of the methodology to tolerate sub-
stituents useful for further product modification. The reaction can
a
Conditions: 1 (1.0 equiv), 2 (2.0 equiv), catalyst (5.0 mol %).
Isolated yields are shown. Conditions: (i) [Rh(DPEphos)(nbd)]-
[BArF ], 130 °C, o-xylene, 1 h; (ii) [Rh(DPEphos)(o-xylene)][BArF ],
4
4
b
60 °C, o-xylene, 4−24 h (see the SI for details). Reaction performed
at 25 °C. Reaction performed at 100 °C.
c
be performed on a preparatively useful scale; for example, 3a was
routinely prepared in >0.5 g (1.9 mmol) quantities. Under the
present reaction conditions, it is not possible to employ internal
alkynes or alkenes in the carbothiolation process.
With an aryl to alkenyl sulfide AG transfer in place, we next
established the key mechanistic details of this new process using A
as the precatalyst, probing the identities of the likely organo-
metallic intermediates in the catalytic cycle using a series of both
stoichiometric and catalytic experiments. The solid-state X-ray
structure of A (Scheme 2) shows η6-bound o-xylene and κ2-P,P-
DPEphos ligands, which is fully consistent with solution NMR
data. A undergoes solvent arene exchange with o-xylene-d10 (first-
order substitution, t1/2 = 20 min), showing that the o-xylene is
labile and provides access to the reactive [Rh(DPEphos)]+
fragment.
In CD2Cl2, reaction of A with 1a produces an equilibrium
mixture of the isomeric complexes [Rh( fac-κ3-P,O,P-
DPEphos)(SMe)(σ-C,κ-O-C6H4C(O)Me)][BArF ] (C) and
4
[Rh(mer-κ3-P,O,P-DPEphos)(SMe)(σ-C,κ-O-C6H4C(O)Me)]-
[BArF ] (D) alongside free o-xylene (298 K, C:D = 1.0:7.8). In
4
o-xylene-d10, a mixture of A, C, and D is established, the relative
proportions of which change with temperature (298 K, A:C:D =
0.1:0.1:1.0; 333 K, A:C:D = 0.3:0.0:1.0). Characterization of
C and D by NMR spectroscopy (CD2Cl2) and electrospray
ionization mass spectrometry (ESI-MS)12 suggested that both
C and D are Rh(III) species arising from reversible6g,13 Caryl−S
bond cleavage.6a,14 Similar NMR data were obtained for the
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occurs in the DPEphos ligand to generate an aryl thioether
and a chelating phosphine aryl oxide. As far as we are aware,
this reactivity (i.e., C−O bond cleavage) has not been pre-
viously observed for DPEphos and presents a new and interes-
ting deactivation pathway for this popular ligand. Related P−C
cleavage in phosphine ligands is well-established as a de-
activation pathway.19 Complex F sits off-cycle and is not an
active catalyst, as reacting isolated F under catalytic conditions
resulted in no turnover. We suggest that a possible mechanism
for the conversion of D to F is nucleophilic substitution by SMe
at the Caryl−O bond to afford a phenoxide and a new aryl
thioether. This bond cleavage reaction in D is considerably
slower than catalytic turnover with alkyne, and D is thus inter-
cepted by alkyne faster than P−O cleavage occurs: at 393 K,
catalysis (5 mol %) is complete in 15 min, while P−O bond
cleavage takes 6 h to go to completion at high temperature.
In view of the close structural similarities of the catalysts in
the present alkyne carbothiolation process and our earlier
hydroacylation chemistry employing S-substituted alde-
hydes,9,15 in addition to the mechanistic connections between
the two transformations, the possibility of constructing
hydroacylation/carbothiolation cascades was an attractive one.
Scheme 3 shows two successful cascade processes. In the first
Scheme 2
Scheme 3
product of oxidative addition of the structurally similar
aldehyde 2-(methylthio)benzaldehdye to [Rh(DPEphos)]+,9e
and related precursors,15 to give acyl hydride complexes with
chelated ArSMe ligands that are closely related to the structures
suggested for C and D. We also showed that in these com-
plexes the DPEphos ligand can act in a hemiliable manner,16
suggesting that interconversion between C and D could occur
via O-decoordination to access a conformationally flexible
five-coordinate intermediate. The reaction between A and
4-(methylthio)acetophenone (the para isomer of 1a) in o-xylene-
d10 (298−333 K) resulted in no reaction, demonstrating the
requirement that the carbonyl group be positioned ortho to the
methyl sulfide in this system. Heating a mixture of A, C, and D
with just the alkyne 1-bromo-4-ethynylbenzene (40 equiv, 333 K,
6 h) resulted in the formation of the expected product 3h. A and
D were also observed at the end of the reaction.17
example, o-MeS-aldehyde 4a was combined with an excess of
alkyne 2b under the action of the complex [Rh(DPEphos)-
On the basis of these observations, we suggest the catalytic
cycle shown in Scheme 2. Addition of 1a to A generates an
equilibrium mixture of A and products resulting from Ar−S bond
cleavage. Addition of alkyne then results in productive turnover by
insertion and then reductive elimination, giving an overall
carbothiolation of the alkyne.8,18 We suggest that migration of
SMe to the alkyne occurs first11 (to form E), followed by reductive
elimination of the vinyl and aryl groups; a similar sequence of
events was delineated for the hydroacylation reaction of alkenes
and o-SMe-substituted aromatic aldehydes.9d This sequence
returns the reactive [Rh(DPEphos)]+ fragment. During catalysis
(5 mol % A, 333 K), sampling the reaction showed that D was the
only significant organometallic species at all intermediate times, as
observed by 31P{1H} NMR spectroscopy (xylene, 298 K),
indicating that either alkyne insertion or reductive elimination of
the product is the likely turnover-limiting step.
(o-xylene)][BArF ]; initial alkyne hydroacylation generated
4
enone 1b in situ, which then underwent C−S activation/
alkyne insertion to deliver alkenyl sulfide 3m in 66% overall
yield. Alternatively, initial alkene hydroacylation could be
employed: reaction of 4a with methyl acrylate and the same
Rh−DPEphos catalyst led initially to ketone 1c, after which
addition of alkyne 2b afforded 3n in 72% yield for the two-step,
one-pot cascade process.
To demonstrate the utility of the developed AG-recycling
strategy, we briefly explored the chemistry of the alkenyl sulfide
products. For example, treatment of 3a with aqueous Lewis acid
conditions transformed it into the corresponding ketone 5.
Direct treatment of 5 with base resulted in intramolecular aldol
condensation to form phenol 6 (Scheme 4). Alternatively,
reaction of 3n with ammonium acetate solution resulted in the
direct formation of isoquinoline 7. Since 3n was prepared by an
initial Rh(I)-catalyzed hydroacylation reaction, the ArSMe
group was integral to three consecutive transformations: Rh(I)-
catalyzed alkene hydroacylation (4a → 1c), Rh(I)-catalyzed
alkyne carbothiolation (1c → 3n), and isoquinoline formation
In the absence of alkyne,12 extended heating of A with 1a
(1.5 equiv, 393 K) cleanly formed a new complex F (first-order
conditions, t1/2 = 60 min). NMR, ESI-MS, and single-crystal
X-ray diffraction (XRD) analysis of F (Scheme 2) showed that
C−O bond cleavage accompanied by C−S bond formation
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(4) Newman, S. G.; Lautens, M. J. Am. Chem. Soc. 2011, 133, 1778.
(5) For a relayed Pd-catalyzed intramolecular cyclization of an
iododiene, see: Liu, H.; Li, C.; Qiu, D.; Tong, X. J. Am. Chem. Soc.
2011, 133, 6187.
Scheme 4
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Tanaka, M. Org. Lett. 2007, 9, 263. Thiocyanates: (b) Kamiya, I.;
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Igarashi, Y.; Tagami, Y.; Yamaguchi, M.; Kabuto, C. Tetrahedron Lett.
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SR bond in their recent report on alkenylative cross-coupling.
However, the resultant Ph−Ni species expels PhH as a byproduct.
See: Ishizuka, K.; Seike, H.; Hatakeyama, T.; Nakamura, M. J. Am.
Chem. Soc. 2010, 132, 13117−13119.
(3n → 7). Finally, conversion of 3a to the corresponding
sulfonium salt 8 and then reaction with Et2Zn under Ni
catalysis resulted in cross-coupling, leading to trisubstituted
alkene 9.20,21
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In conclusion, we have developed a novel Rh(I)-catalyzed
carbothiolation of alkynes using simple aryl methyl sulfides.
The reaction is stereospecific, delivering single isomers of
alkenyl sulfide products. Importantly, we have demonstrated
that this new transformation is an example of AG recycling, in
that the initial methyl sulfide AG is embedded in the alkenyl
sulfide product, providing a versatile group for further synthetic
transformations. Given the robust nature of the process
(tolerance to temperature variation, scale, and incorporation
into cascade processes), the broad substrate scope, and the
ability to generate the bench-stable catalyst from simple and
readily available components, we believe that this new reaction
has the potential to find wide application in synthesis.
(9) (a) Willis, M. C. Chem. Rev. 2010, 110, 725. (b) Willis, M. C.;
McNally, S. J.; Beswick, P. J. Angew. Chem., Int. Ed. 2004, 42, 340.
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Currie, G. S. J. Org. Chem. 2006, 71, 5291. (d) Moxham, G. L.;
Randell-Sly, H.; Brayshaw, S. K.; Weller, A. S.; Willis, M. C. Chem.
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(10) The geometry of the alkenyl sulfide was confirmed by single-
crystal XRD of the tosylhydrazone derivative of 3b [see the Supporting
Information (SI) for details].
(11) Kuniyasu, H.; Takekawa, K.; Yamashita, F.; Miyafuji, K.; Asano,
S.; Takai, Y.; Ohtaka, A.; Tanaka, A.; Sugoh, K.; Kurosawa, H.; Kambe,
N. Organometallics 2008, 27, 4788.
(12) See the SI for a discussion of the characterization data and
additional reactions to probe the mechanism.
(13) (a) Jones, W. D. Inorg. Chem. 2005, 44, 4475. (b) Vicic, D. A.;
Jones, W. D. J. Am. Chem. Soc. 1999, 121, 7606. (c) Garcia, J.; Mann,
B.; Adams, H.; Bailey, N.; Maitlis, P. J. Am. Chem. Soc. 1995, 117,
2179.
ASSOCIATED CONTENT
* Supporting Information
Experimental details, characterization data, and reactions of A
with excess alkyne. This material is available free of charge via
the Internet at http://pubs.acs.org.
■
S
(14) (a) Curtis, M.; Druker, S. J. Am. Chem. Soc. 1997, 119, 1027.
(b) Hossain, M. M.; Lin, H.-M.; Shyu, S.-G. Organometallics 2003, 22,
3262. (c) Goh, L.; Tay, M.; Mak, T.; Wang, R. Organometallics 1992,
11, 1711.
(15) Pawley, R. J.; Moxham, G. L.; Dallanegra, R.; Chaplin, A. B.;
Brayshaw, S. K.; Weller, A. S.; Willis, M. C. Organometallics 2010, 29,
1717.
(16) Braunstein, P.; Naud, F. Angew. Chem., Int. Ed. 2001, 40, 680.
(17) Trimerization of the alkyne was also observed. For a review, see:
Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100, 2901. Separate experi-
ments under the same conditions of temperature and concentration showed
AUTHOR INFORMATION
Corresponding Author
andrew.weller@chem.ox.ac.uk; michael.willis@chem.ox.ac.uk
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the EPSRC and the Xunta de Galicia (Angeles
■
́
Alvarino contract and an Estadias: 2009/188 and 2010/163 to
̃
that alkyne trimerization is catalyzed by A (333 K, 2.5 mol % A, t1/2
=
C.G.-R.) for support of this work, the Diamond Light Source
for an award of beamtime on I19, and Drs. Kirsten Christensen
and David R. Allan for support.
16 min). However, as minimal trimerization was observed under catalytic
conditions, it is not competitive with C−S bond cleavage of the ketone.
(18) Bichler, P.; Love, J. A. Top. Organomet. Chem. 2010, 31, 39.
(19) van Leeuwen, P. W. N. M.; Chadwick, J. C. Homogeneous
Catalysts: Activity−Stability−Deactivation; Wiley-VCH: Weinheim,
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(21) The alkene geometry in compound 9, resulting from an
inversion, was unexpected. The geometries of the alkenes in both 3a
and 9 were established using NOE experiments. The geometry of the
intermediate 8 was established using XRD (see the SI for details).
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