A rhodium-catalysed Sonogashira-type coupling exploiting C-S functionalisation: Orthogonality with palladium-catalysed variants

Article abstract of DOI:10.1039/c9cc00092e

This report concerns the development of an efficient Sonogashira-type coupling of arylmethylsulfides and terminal alkynes to generate aryl alkyne motifs. Orthogonal reactivity between traditional Pd catalysts, and the Rh catalysts employed, results in the ability to selectively activate either the C-S bond or C-X bond through catalyst choice. The Rh-bisphosphine catalyst has further been shown to be able to effect a hydroacylation-Sonogashira tandem sequence, and in combination with further onward reactions has been used in the synthesis of heterocycles and polycyclic systems.

Full text of DOI:10.1039/c9cc00092e

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A rhodium-catalysed Sonogashira-type coupling
exploiting C–S functionalisation: orthogonality
with palladium-catalysed variants†
Cite this:DOI: 10.1039/c9cc00092e
Received 4th January 2019,
Accepted 25th January 2019
Milan Arambasic, Manjeet K. Majhail, Robert N. Straker,
Michael C. Willis
James D. Neuhaus and
*
DOI: 10.1039/c9cc00092e
rsc.li/chemcomm
This report concerns the development of an efficient Sonogashira- simple terminal alkynes as the coupling partner remains rare,6
type coupling of arylmethylsulfides and terminal alkynes to generate with haloalkynes,7 or hypervalent iodine reagents8 being the
aryl alkyne motifs. Orthogonal reactivity between traditional Pd reagents of choice in ‘‘inverse Sonogashira coupling reactions’’.
catalysts, and the Rh catalysts employed, results in the ability to
The activation of carbon–sulfur bonds, an area of interest in
selectively activate either the C–S bond or C–X bond through the Willis laboratory for a number of years, has seen significant
catalyst choice. The Rh–bisphosphine catalyst has further been expansion beyond the simple Kumada coupling in recent
shown to be able to effect a hydroacylation-Sonogashira tandem decades.9 Reactions such as the Liebeskind–Srogl coupling
sequence, and in combination with further onward reactions has are now regularly employed in both academic and industrial
been used in the synthesis of heterocycles and polycyclic systems.
laboratories.10 Many of these processes employ catalysts not
known for their reactivity with aryl halides, and as a result a
Since its discovery in 1975 by the laboratories of Cassar, Heck number of orthogonal processes have been developed, almost
and Sonogashira,1 the coupling of aryl halides with terminal exclusively on highly activated heteroaromatic scaffolds.11
alkynes has represented one of the most popular methods
Reports of desulfitative alkynylation are rare, and involve
of assembling aryl alkynes.2 The prototypical ‘‘Sonogashira activation of the sulfide component,12 metallated alkynes,13 or
coupling’’ revolves around the co-operative action of a Pd-catalyst are the result of the coupling of alkynyl thioethers with organo-
with a Cu-co-catalyst, used to activate the terminal alkyne. metallic reagents.14 Our laboratory has recently demonstrated
Synthetically straightforward, the reaction has been the subject that, in combination with a suitable directing group, it is possible to
of countless studies looking to expand the scope and efficiency of use Rh–bisphosphine complexes to selectively activate the C–S bond
the process. Included amongst these developments are studies of arylmethylsulfides, to effect carbothiolation reactions,15
aimed at developing Cu-free processes (in order to reduce reductive desulfurisations,16 or Suzuki-type cross coupling reactions
Cu-catalyzed Glaser-type alkyne homo-dimerization, and to reduce (Scheme 1).17 As full selectivity for C–S functionalisation over C–X
the environmental impact),3 transition metal-free processes,4 and functionalisation was in each case observed, we envisaged that
expanding the range of, and consequently selectivity between,
leaving groups.2 Whilst simple aryl/alkenyl iodides, bromides,
chlorides and triflates have provided a plethora of examples under
a number of reaction conditions, selectivity for reaction with one
halide/pseudohalide over another has not proven straightforward.
Use of a Ni-catalyst by Hu and co-workers in 2009 has shown
promising levels of selectivity by exploiting the innate reactivity of
alkyl chlorides, bromides and iodides; however, this work did not
deal with aryl substitution, and other than by redesigning the
substrate, there is no way to reverse the selectivity.5 A number of
laboratories have looked at using C–H functionalisation chemistry
to overcome this problem with some success, however, the use of
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, OX1 3TA, UK. E-mail: michael.willis@chem.ox.ac.uk
Scheme 1 Existing C–S activation methodologies and proposed chemo-
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9cc00092e
selective Sonogashira-type coupling.
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similar methodology would enable us to develop an orthogonal
Sonogashira-type process simply by switching the boronic acid
coupling partner with a terminal alkyne.
Whilst terminal alkynes had previously been used as the
coupling partner in the carbothiolation procedure, we anticipated
that the use of a thiophilic Cu-co-catalyst would favor the
alkynylation over carbothiolation, thus providing an example of
catalyst-controlled divergence of reactivity. Initial investigations
involved the combination of 2-(methylthio)acetophenone (1a)
and phenylacetylene (2a). By using the hemilabile bisphosphine
ligand DPEphos in combination with [Rh(nbd)2]BF4, copper
iodide and potassium carbonate (Table 1, entry 1), a conversion
of 25% was recorded to product 3a. By switching to the more rigid
XantPhos ligand, the conversion dropped to 13% and the product
of carbothiolation (4) was also observed (entry 2). Moving towards
small bite-angle PCP-bisphosphines, such as dppm and dcpm
(entries 3 and 4), did not show much improvement, however,
with the PCCP ligands dppe and dcpe (entries 5 and 6, respec-
tively), considerably higher conversions were achieved. Whilst the
conversion was lower with dcpe than with dppe, the improved
selectivity made it an attractive choice for further optimization. After
evaluating a number of bases, it was found that silver carbonate
could improve the conversion to 61% (entry 7). Experimenting with
various copper sources (entries 8–11) resulted in conversions of up
to 93%; however, the breakthrough came with the use of copper
bromide (entry 12). Not only was full consumption of the starting
material now observed, but only product 3a was observed in
the 1H-NMR spectrum of the crude reaction mixture. This
Scheme 2 Scope of alkyne component in Sonogashira-type coupling
reactions.
With efficient conditions for the formation of Sonogashira-
high conversion and selectivity was reflected in the excellent product 3a in hand, we moved on to investigate the range of
isolated yield of 95%. Aware that the use of stoichiometric terminal alkynes compatible with this chemistry (Scheme 2).
silver carbonate could be costly on a larger scale, alternative Aromatic alkynes proved excellent substrates, with high yields
conditions employing potassium carbonate were also developed observed for both electron-rich (3b) and electron-poor (3c and d)
(entry 13).
aryl groups, as well as heteroaromatic alkynes (3e). As anticipated,
the Rh-complex exhibited high selectivity for reaction with the
carbon–sulfur bond over that of the carbon–halide bond present
in 3c. Alkyl alkynes performed more poorly with the standard
substrate (3f–i), however we were pleased to observe that with
alternative directing groups, excellent yields were still possible
(3g). Sterically bulky groups such as tert-butyl (3h) or the
removable TIPS group (3j) were well tolerated. By using conditions
A, it was possible to perform the reaction on a 30.0 mmol scale,
using only 2.5 mol% of the active rhodium catalyst, delivering
diaryl alkyne 3a in a 96% yield.
Table 1 Optimization of Sonogashira conditions
Entry
Ligand
Cu source
Additive
Conversiona
As shown in Scheme 3, exploration of the scope of the aryl-
methylsulfide component was similarly successful, with electron-
rich (3k) and electron-poor (3l–o) examples each reacting in good
to excellent yields. The generation of halide containing products
allows for further functionalisation. It was additionally demonstrated
that more complex functionality could be tolerated elsewhere on
the scaffold (3p).
As previously mentioned, a major strength of rhodium(I)
catalysis lies in the extremely high selectivity for the activation
of one bond, in this case the C–S bond, in the presence of other
easily activated bonds, which could not be carried through
a reaction sequence if using palladium catalysis, for example.
In order to demonstrate the orthogonality of these processes,
1
2
3
4
5
6
7
8
DPEphos
Xantphos
dppm
dcpm
dppe
dcpe
dcpe
dcpe
dcpe
dcpe
dcpe
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI (2 eq.)
CuI (2 eq.)
CuTc
Cu(OAc)
CuBr (2 eq.)
CuBr (4 eq.)
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Ag2CO3
Ag2O
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
K2CO3 (2 eq.)
25%
13% (5%)
19% (5%)
30%
48% (7%)
40%
61% (12%)
84% (8%)
93% (5%)
—
9
10
11
12
13
—
dcpe
dcpe
100%, 95%b
100%
a
Conversions determined by 1H NMR spectroscopic analysis of the
crude reaction mixture, value in parentheses indicates conversion to
carbothiolation product 4. Isolated yield of 3a.
b
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Scheme 3 Scope of arylmethylsulfide component.
we first exposed compound 5, featuring both aryl bromide
and methylsulfide functional groups, to our Rh(I)-catalyzed C–S
Sonogashira conditions, followed by traditional Pd(0)-catalyzed
Sonogashira conditions for the generation of dialkyne 7
(Scheme 4). Each reaction proceeded in a very good yield, and
the same product (7), was obtained by switching the order of
the two transition metal-catalyzed processes.
Our laboratory has previously demonstrated that in situ
generated Rh–dcpe complexes are effective catalysts for alkene
and alkyne hydroacylation reactions,18 and we were therefore
intrigued by the possibility of conducting a tandem hydroacylation-
Sonogashira sequence, resulting in the three-component coupling
of an aldehyde with two distinct alkynes, forming two new C–C
bonds, using a single rhodium catalyst (Scheme 5). Such a process
would be a powerful method to rapidly build up molecular
Scheme 5 Tandem hydroacylation-Sonogashira sequence.
complexity from simple, commercially available building blocks.
We began by reducing potential complications by using the same
alkyne for both steps of the reaction, with fluoro-substituted
phenylacetylene affording the product (9a) in good yield over two
Scheme 4 Reversible selectivity between Rh- and Pd-catalyzed Sonogashira
Scheme 6 Tandem reactions for the synthesis of heterocycles and
reactions.
extended ring systems.
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10, 3793; (c) L. Dong-Hwan, H. Qiu, M.-h. Cho, I.-M. Lee and
M.-J. Jin, Synlett, 2008, 1657; (d) Y. Liang, Y.-X. Xie and J.-H. Li,
J. Org. Chem., 2006, 71, 379; (e) V. K. Kanuru, S. M. Humphrey,
J. M. W. Kyffin, D. A. Jefferson, J. W. Burton, M. Armbru¨ster and
R. M. Lambert, Dalton Trans., 2009, 7602.
4 (a) P. Appukkuttan, W. Dehaen and E. Van der Eycken, Eur. J. Org. Chem.,
2003, 4713; (b) N. E. Leadbeater, M. Marco and B. J. Tominack, Org. Lett.,
2003, 5, 3919; (c) M. S. Maji, S. Murarka and A. Studer, Org. Lett., 2010,
12, 3878.
5 O. Vechorkin, D. Barmaz, V. Proust and X. Hu, J. Am. Chem. Soc.,
2009, 131, 12078.
6 M. Shang, H.-L. Wang, S.-Z. Sun, H.-X. Dai and J.-Q. Yu, J. Am. Chem.
Soc., 2014, 136, 11590.
7 (a) I. V. Seregin, V. Ryabova and V. Gevorgyan, J. Am. Chem. Soc.,
2007, 129, 7742; (b) A. S. Dudnik and V. Gevorgyan, Angew. Chem.,
Int. Ed., 2010, 49, 2096; (c) M. Tobisu, Y. Ano and N. Chatani, Org.
Lett., 2009, 11, 3250.
8 (a) C. Feng and T.-P. Loh, Angew. Chem., Int. Ed., 2014, 53, 2722;
(b) F. Xie, Z. Qi, S. Yu and X. Li, J. Am. Chem. Soc., 2014, 136, 4780.
9 (a) L. Wang, W. He and Z. Yu, Chem. Soc. Rev., 2013, 42, 599;
(b) S. Otsuka, K. Nogi and H. Yorimitsu, Top. Curr. Chem., 2018, 376.
10 (a) L. S. Liebeskind and J. Srogl, J. Am. Chem. Soc., 2000, 122, 11260;
steps. We were pleased to discover that the use of differing alkynes
for each step was also easily achieved. A range of alkynes was
employed, generating hydroacylation-Sonogashira products 9b–g.
Compound 9g, in particular, contains synthetic handles for further
functionalisation on each of the constituent components, which
would be extremely difficult to prepare using Pd- or Ni-catalyzed
methods.
Further reaction sequences, generating increasingly complex
products were subsequently attempted, as depicted in Scheme 6.
By employing suitably protected propargyl amines as substrates
for the first step in the hydroacylation-Sonogashira sequence,19
a
three-step, two-pot synthesis of highly functionalised pyrrole 11
was achieved in a good yield, requiring only a single chromato-
graphic purification to obtain the pure heterocycle. An alternative
sequence resulted in the combination of the hydroacylation-
Sonagashira steps with a p-acid-catalysed [4+2]-cycloaddition
reaction between an isochromenylium ion and a styrene derivate,
ultimately yielding 1,2-dihydronaphthylene 13 after subsequent
´
(b) H. Prokopcova and C. O. Kappe, Angew. Chem., Int. Ed., 2009,
48, 2276.
ring opening of the bicyclic intermediate. Such processes have 11 (a) A. Aguilar-Aguilar and E. Pen˜a-Cabrera, Org. Lett., 2007, 9, 4163;
(b) C. Kusturin, L. S. Liebeskind, H. Rahman, K. Sample, B. Schweitzer,
J. Srogl and W. L. Neumann, Org. Lett., 2003, 5, 4349; (c) A. Tikad,
S. Routier, M. Akssira, J.-M. Leger, C. Jarry and G. Guillaumet, Org. Lett.,
been effected by a number of p-acids, and the conditions used
herein were first reported by Yamamoto et al. in 2003.20
In conclusion, we have developed a novel Sonogashira-type
coupling between arylmethylsulfides and terminal alkynes. Utilizing
an electrophilic Rh–bisphosphine catalyst system, the reaction
has been shown to exhibit tolerance to a broad range of
functional groups, many of which would not be tolerated under
alternative TM-catalysis. This selectivity has been demonstrated
in the orthogonal activation of either a C–S bond or C–X bond by
either Rh or Pd respectively. In addition, the reactions reported here
show how divergent reactivity for the same reaction components
can be achieved by catalyst and reagent selection, with Sonogashira
and not carbothiolation products being obtained.
2007, 9, 4673; (d) V. P. Mehta, A. Sharma, K. Van Hecke, L. Van Meervelt
and E. Van der Eycken, J. Org. Chem., 2008, 73, 2382; (e) N. Kaval,
B. K. Singh, D. S. Ermolat’ev, S. Claerhout, V. S. Parmar, J. Van der Eycken
and E. Van der Eycken, J. Comb. Chem., 2007, 9, 446.
12 (a) V. P. Mehta, A. Sharma and E. Van der Eycken, Org. Lett., 2008,
10, 1147; (b) Z.-Y. Tian, S.-M. Wang, S.-J. Jia, H.-X. Song and
C.-P. Zhang, Org. Lett., 2017, 19, 5454.
13 A. Baralle, H. Yorimitsu and A. Osuka, Chem. – Eur. J., 2016, 22, 10768.
14 (a) L. Melzig, J. Stemper and P. Knochel, Synthesis, 2010, 2085;
(b) C. Savarin, J. Srogl and L. S. Liebeskind, Org. Lett., 2001, 3, 91.
´
´
15 (a) J. F. Hooper, A. B. Chaplin, C. Gonzalez-Rodrıguez, A. L. Thompson,
A. S. Weller and M. C. Willis, J. Am. Chem. Soc., 2012, 134, 2906;
(b) M. Arambasic, J. F. Hooper and M. C. Willis, Org. Lett., 2013, 15, 5162.
16 J. F. Hooper, R. D. Young, A. S. Weller and M. C. Willis, Chem. – Eur. J.,
2013, 19, 3125.
17 J. F. Hooper, R. D. Young, I. Pernik, A. S. Weller and M. C. Willis,
Chem. Sci., 2013, 4, 1568.
18 (a) A. B. Chaplin, J. F. Hooper, A. S. Weller and M. C. Willis, J. Am.
Conflicts of interest
´
Chem. Soc., 2012, 134, 4885; (b) T. J. Coxon, M. Fernandez, J. Barwick-
There are no conflicts to declare.
Silk, A. I. McKay, L. E. Britton, A. S. Weller and M. C. Willis, J. Am.
Chem. Soc., 2017, 139, 10142; (c) R. N. Straker, M. K. Majhail and
M. C. Willis, Chem. Sci., 2017, 8, 7963; (d) R. N. Straker, M. Formica,
J. D. Lupton, J. Niu and M. C. Willis, Tetrahedron, 2018, 74, 5408;
(e) M. Castaing, S. L. Wason, B. Estepa, J. F. Hooper and M. C. Willis,
Angew. Chem., Int. Ed., 2013, 52, 13280.
Notes and references
1 (a) K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett.,
1975, 16, 4467; (b) L. Cassar, J. Organomet. Chem., 1975, 93, 253;
(c) H. A. Dieck and F. R. Heck, J. Organomet. Chem., 1975, 93, 259.
19 M. K. Majhail, P. M. Ylioja and M. C. Willis, Chem. – Eur. J., 2016,
22, 7879.
´
2 R. Chinchilla and C. Najera, Chem. Rev., 2007, 107, 874.
¨
3 (a) V. P. W. Bohm and W. A. Hermmann, Eur. J. Org. Chem., 2000, 20 N. Asao, T. Kasahara and Y. Yamamoto, Angew. Chem., Int. Ed., 2003,
3679; (b) B. H. Lipshutz, D. W. Chung and B. Rich, Org. Lett., 2008,
42, 3504.
Chem. Commun.
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