A new mechanistic pathway under Sonogashira reaction protocol involving multiple acetylene insertions

Article abstract of DOI:10.1039/c001109f

An unreported product outcome from an intended Sonogashira coupling is presented. The generality of this finding has been demonstrated by screening of a range of pre-catalysts. Mechanistic studies are consistent with the tetra-aryl benzene product forming

Full text of DOI:10.1039/c001109f

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A new mechanistic pathway under Sonogashira reaction protocol involving
multiple acetylene insertions†
Roderick C. Jones,*a Allan J. Canty,*a Tom Caradoc-Davies,b Noel W. Davies,c Michael G. Gardiner,a
Philip J. Marriott,d Christian P. G. Ru¨hled and Vicki-Anne Tolhursta
Received 19th January 2010, Accepted 19th February 2010
First published as an Advance Article on the web 4th March 2010
DOI: 10.1039/c001109f
An unreported product outcome from an intended Sono-
gashira coupling is presented. The generality of this finding
has been demonstrated by screening of a range of pre-
catalysts. Mechanistic studies are consistent with the tetra-
aryl benzene product forming by interception of the aryl
halide oxidative addition intermediate by repeated acetylene
insertion.
Formation of carbon-carbon bonds using protocols discovered
by Sonogashira,1a Cassar,1b and Heck1c has developed into widely
utilised processes for the coupling of C(sp2) halides (R1X) with
2
1
2
≡
≡
alkynes (R C CH) to form R C CR , mediated predominantly
by palladium pre-catalysts.1,2 Except for Glaser coupling to form
2
2
2b,d,h,i
≡
≡
R C CC CR , byproducts
have been rarely reported for
Sonogashira coupling.1c,2c,d,l3 Herein we report the unexpected
formation of C6H2R1(R2)3 (5) that was discovered during catalytic
activity screening of a class of N~S chelated Pd(II) complexes
under Sonogashira reaction protocol, Scheme 1. Reaction con-
ditions could be optimised to selectively give either the antic-
1
2
≡
ipated product, R C CR (4), or 5 in high yield using a 2-
organothiomethylpyridine ligand (pyCH2SMe). The formation of
5 was subsequently also identified in reactions mediated by var-
ious common pre-catalyst systems. Catalytic and stoichiometric
reaction studies are consistent with the synthesis of 5 occurring
via the insertion of three phenylacetylene molecules following the
oxidative addition of the aryl halide.
Scheme 1 Optimised synthesis of Sonogashira coupling product (4) and
tetra-aryl species (5), and molecular structure of 5. Reaction conditions:
n
2 (1.5 mmol), 3 (2.25 mmol), 1 (1 mol%), Na2CO3 (3.0 mmol), Bu4NCl
(2.25 mmol), DMA (5 mL), 24 h under Ar.‡
fragments was obtained (41%) without any Sonogashira product
4, rising to 63% yield at 140 C. The use of additional alkyne in
the reaction (1 : 3 ratio of 2:3) gave only minor yield improvement.
Product 5 was characterised by 1H NMR spectroscopy and
X-ray crystallography, and also synthesised independently for
comparison of spectroscopic, HPLC and GC-MS data.7
Complex 14 was initially examined as a precatalyst under
conditions typical for Sonogashira catalysis, with Na2CO3 as
a base,2a,j,5a nBu4NCl as a salt additive,2a,5b 1 mol% Pd,5c,d in
N,N-dimethylacetamide (DMA)2i,j over a temperature range 25–
140 ◦C for 24 h under argon. 4-Iodonitrobenzene (2) reacts with
phenylacetylene (3) at 25 ◦C to give the anticipated product 4
in 95% yield, together with 5% of the known compound6 1-(4-
nitrophenyl)-2,4,6-triphenylbenzene (5). Reactions conducted at
higher temperatures gave the Sonogashira product 4 in lower
yield and, at 120 ◦C, 5 involving incorporation of three alkyne
◦
We explored other pre-catalysts and protocols searching for
related findings to better understand the occurrence of byproducts
in Sonogashira catalysis. Reaction of 2 with 3 using the widely
employed pre-catalyst1a,b,2,5e PdCl2(PPh3)2 (6) under similar con-
ditions to those reported initially by Sonogashira (0.5 mol% 6,
1 mol% CuI, room temperature, in Et2NH)1a gave 4 only (95%
yield) and, under these conditions, catalyst 1 gave a lower yield
of 4 (32%), 5 was not observed, and a minor amount of Glaser
product (16%). Reaction of 2 and 3 under the conditions of
Scheme 1 at 120 ◦C using 6 gave 4 (76%) and a product of
molecular weight 427, indistinguishable from 5 by GC-MS (18%).
Similarly, the bidentate ligand complexes PdCl2(L2) (L2 = 1,2-
bis(diphenylphosphino)ethane2i,5e and 1,10-phenanthroline) gave
aSchool of Chemistry, University of Tasmania, Hobart, Tasmania, Australia.
E-mail: Allan.Canty@utas.edu.au; Fax: +61 3 62262858; Tel: +61 3 6226
2162
bAustralian Synchrotron, Clayton, Victoria, Australia
cCentral Science Laboratory, University of Tasmania, Hobart, Tasmania,
Australia
dAustralian Centre for Research on Separation Science (ACROSS), School
of Applied Sciences, RMIT University, Melbourne, Victoria, Australia
† Electronic Supplementary Information (ESI) available: Experimental
procedures, synthesis and characterisation of 5 and 7, X-ray crystallo-
graphic data (CIF) for 5 and 7 (CCDC Numbers: 755775 and 755776),
and results for catalysis. See DOI:10.1039/c001109f/
◦
both 4 (84, 87%) and 5 (11, 10%) at 120 C, but 2,2¢-bipyridine
led to GC-MS data showing the absence of 4 and at least two
species of molecular weight 427, the major component being
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indistinguishable from 5 (overall yield 66%: the isolation of
isomeric products with 1 is discussed later in regard to certain
aryl halide substrates).
During catalysis (of 2 with 3) using 1, Scheme 1 conditions,
≡
added PhC CPh is not incorporated (1,2,4,6-Ph4C6H2 or more
highly Ph substituted benzenes are not formed) and added 4-
≡
The incorporation of two alkyne units into a fulvene product
NO2C6H4C CPh (4) does not increase yields of 5. These observa-
1,3-(Me3Si)2C5H2CHPh in palladium mediated reactions of the
tions suggest that 4, if liberated from palladium as the Sonogashira
product in Scheme 1, is not incorporated into catalysis to form 5
via a mixed acetylene cyclotrimerisation pathway.
3
=
≡
vinyl halide PhCH CHI with Me3SiC CH has been reported. A
mechanistic proposal for this outcome entailed repeated insertion
of two acetylenes with the alkenyl species formed from oxidative
These results are consistent with the view that 5 is formed via a
=
≡
addition of PhCH CHI, followed by cyclisation via intramolec-
partial Sonogashira process involving insertion of three PhC CH
ular migration of the alkenyl group onto the terminal alkene
functionality of the C6 fragment and finally product release by b-
H elimination. Preliminary mechanistic findings in our study are
consistent with a similar mechanism for the formation of the six-
membered cyclised product 5 based on three acetylene insertions.
Our evidence is not consistent with alternative well established
mechanisms for cyclo-oligomerisation of acetylenes known for a
wide range of metal complexes,2g,8,9 including palladium reagents
(see below).8a,b,d-k9a,d-f
molecules into a PdIIC6H4-4-NO2 intermediate. The participating
ligands involved in the competing reaction pathways are shown in
≡
Scheme 2. The insertion of PhC CH (A) averts the release of the
Sonogashira product 4 via involvement of PhC C (B), leading to
-
≡
the tetra-aryl benz◦ene product 5. It is noteworthy that added CuI
(10 mol%) at 120 C does not affect the reaction specificity (0%
4, 42% 5, no Glaser coupling, Scheme 1 conditions), despite the
increased acetylide availability that would promote the formation
of the Sonogashira product 4.
We prepared and characterised PdI(C6H4-4-NO2)(pyCH2SMe)
(7)10 (Fig. 1) as an anticipated intermediate in Sonogashira
catalysis following oxidative addition of the aryl iodide to a Pd(0)
≡
complex. In stoichiometric reactions, 7 reacted with PhC CH
(3.5 equiv, Scheme 1 conditions) giving 4 (18% yield) and 5 (22%
yield) at 25 and 120 ◦C, respectively, with complete selectivity
in accord with the outcomes discussed above for the catalytic
reactions of complex 1 at these temperatures. The relatively
≡
low yields of 4 and 5 result from competing PhC CH cyclo-
oligomerisation by Pd(0) following product release. Indeed, in
Scheme 2 Graphical depiction of the key product discriminating stages
of the competing acetylene insertion (tetra-aryl benzene product pathway:
A) and acetylide involvement (Sonogashira product pathway: B).
the absence of aryl halide 2, complex 1 under the conditions of
◦
Scheme 1 at both 25 and 120 C supports cyclo-oligomerisation
≡
of PhC CH, giving C4H2Ph2, C6H3Ph3 (main product) and
C8H4Ph4. Low yields of C6H3Ph3 in catalysis (of 2 and 3) with
1 importantly highlights the relatively rapid oxidative addition of
2 to in situ formed Pd(0) relative to cyclotrimerisation of 3 in both
temperature regimes.
We have demonstrated that there are ligand effects on the
selectivity of these reaction outcomes. The acetylene insertion
pathway is favoured at higher temperature and, in particular, by
bidentate ligands. It is feasible that this requires hemilability9b,c,11
that would be facilitated at higher temperature. In this regard,
the contrasting behaviour of 1,10-phenanthroline and the more
flexible 2,2¢-bipyridine ligated pre-catalysts is noted (mainly 4 for
the former, exclusively acetylene insertion chemistry for the latter).
The rate of reductive elimination from PdII-aryl complexes
featuring electron withdrawing para-substituents is known to
be reduced in related Pd mediated C–C coupling reactions.12 It
was thus of interest to investigate variously activated aryl halide
substrates to establish any effects on the product distribution.
The expectation was to steer the outcome towards conventional
Sonogashira products in the case of less activated aryls if species
B, Scheme 2, undergoes faster reductive elimination giving 4.
In the case of phenyl iodide, for example, we still observed
complete selecti◦vity for insertion chemistry over the Sonogashira
product at 120 C, although a range of products corresponding
to incorporation of three phenyl acetylenes have been identified
that we have been unable to structurally assign as yet. We hope to
report on these products at a later stage along with a mechanistic
understanding of this intriguing selectivity which is likely to have
its basis in either the insertion or cyclisation processes.
We have reported a new reaction pathway leading to a previously
unreported product outcome arising from Sonogashira reaction
condition protocols. Initially identified during catalytic activity
screening of a class of N~S chelated Pd(II) complexes, but later
Fig. 1 Molecular structure of PdI(C6H4-4-NO2)(pyCH2SMe) (7).
3800 | Dalton Trans., 2010, 39, 3799–3801
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confirmed as occurring using a range of previously reported pre-
catalysts, this structural assignment is clearly of importance in
the broader context of byproduct identification for this widely
used catalytic C–C coupling reaction. Mechanistic studies are
consistent with the tetra-aryl benzene product forming by inter-
ception of the aryl halide oxidative addition product by insertion
of three molecules of phenylacetylene and, for PdCl2(pyCH2SMe)
(1) as pre-catalyst, the reaction can be tuned to give either
the Sonogashira product or tetra-aryl benzene in high yield.
The extensive studies of the general applicability of this new
finding and a more detailed exploration of mechanistic issues have
commenced.
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7 Product 5 was obtained in a similar manner to the GC standard 1-(4-
methyl-3-nitrophenyl)-2,4,6-triphenylbenzene‡.
We thank the Australian Research Council for financial support.
Data for the structure solutions of 5 and 7 were obtained on
the PX2 and PX1 beamlines, respectively, at the Australian
Synchrotron, Victoria, Australia.
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Notes and references
‡ 5 was isolated by HPLC with yields calculated by GC-MS with 1-(4-
methyl-3-nitrophenyl)-2,4,6-triphenylbenzene as standard. The standard
was obtained by Suzuki coupling of 2,4,6-(triphenyl)phenylboronic acid
with 4-methyl-3-nitro-iodobenzene, using a modification of the proto-
col reported using 2-dicyclohexylphosphino-2¢,6¢-dimethoxybiphenyl [S-
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This journal is
The Royal Society of Chemistry 2010
Dalton Trans., 2010, 39, 3799–3801 | 3801
©