Z -Selective dimerization of aromatic terminal alkynes catalyzed by an iridium(I)-N-heterocyclic carbene-phosphine system

Article abstract of DOI:10.1055/s-0032-1318271

The development of an iridium-catalyzed regio- and stereoselective dimerization process has enabled the formation of (Z)-enyne products. More specifically, low catalyst loadings of an iridium(I) complex, featuring a bulky N-heterocyclic carbene-phosphine

Full text of DOI:10.1055/s-0032-1318271

LETTER
▌587
lZett-eSr elective Dimerization of Aromatic Terminal Alkynes Catalyzed by an
Iridium(I)–N-Heterocyclic Carbene–Phosphine System
Z-Selective Dimerization of Aromatic Terminal Alkynes
Calum D. Forsyth, William J. Kerr,* Laura C. Paterson
Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, Scotland, UK
Fax +44(141)5484246; E-mail: w.kerr@strath.ac.uk
Received: 10.01.2013; Accepted after revision: 30.01.2013
In contrast, the Z-selective head-to-head homodimeriza-
Abstract: The development of an iridium-catalyzed regio- and ste-
tion of terminal alkynes C is much less common. Whilst
reoselective dimerization process has enabled the formation of (Z)-
synthetic methods have emerged towards a Z-selective
enyne products. More specifically, low catalyst loadings of an irid-
ium(I) complex, featuring a bulky N-heterocyclic carbene–phos- pathway,8
a,c,d,9,12b,13
this arena is still relatively underde-
phine ligand combination, has been successfully employed in this veloped. Indeed, there remains a requirement for a robust
selective head-to-head dimerization of terminal alkynes via C–H
activation.
and reliable reaction protocol for the dimerization of al-
kynes over a wide range of substrates to form products
Key words: alkynes, enynes, dimerization, C–H activation, iridium such as C. Herein we now report a catalytic process for the
delivery of head-to-head dimerized alkyne products with
Z-selectivity using low loadings of transition-metal cata-
The dimerization of terminal alkynes is one of the most lyst.
expedient and atom-economical routes towards conjugat-
Recent research within our laboratory has led to the prep-
aration and application of a series of novel iridium(I)
complexes featuring both a sterically demanding N-het-
erocyclic carbene (NHC) along with an appreciably en-
1
ed enyne compounds. Indeed, such products are versatile
2
building blocks in organic synthesis, as well as in mate-
3
rials science. As such, a number of transition metals have
emerged within catalyst systems for this transformation,
14
cumbered phosphine ligand (Figure 1). Such complexes
4
5
6
7
8
including gold, palladium, iron, nickel, iridium, and,
are readily handled, and we have previously showcased
the ability of these complexes to facilitate hydrogen iso-
9
very recently, zirconium. However, the establishment of
methods that deliver desirable levels of regio- and stereo-
control provides a continuing challenge within this area.
Scheme 1 displays the potential enyne isomers obtainable
via this dimerization process. In addition to these prod-
14
tope exchange by arene C–H activation, with activity far
in excess of the current industry standard, Crabtree’s cat-
15
alyst. More recently, work within our laboratories has
highlighted the extremely efficient performance of these
ucts, competing cyclotrimerization10 or butatriene
16
novel complexes in selective hydrogenation reactions.
formation8
c,d,11
are also observed reaction outcomes. Nev-
ertheless, the formation of branched enynes, that is, head-
to-tail coupled products A, has been readily achieved via
Au and Pd catalysis.4 Additionally, the head-to-head
coupled (E)-enynes B have been prepared without inci-
dent, employing a range of metal catalysts.6,7,8b–d,12
Mes
N
PF6
,5
1a: PR3 = PBn3
1b: PR3 = PPh3
1c: PR3 = PMe2Ph
N
Ir
Mes
PR3
Figure 1 Iridium(I) complexes bearing a bulky NHC–phosphine li-
R
gand combination
R
R
As part of our ongoing endeavors to extend the applicabil-
ity of our emerging catalyst series, we wished to investi-
gate their ability to promote a selective alkyne
dimerization process through activation of a terminal al-
kyne C–H bond (Scheme 2). Indeed, we anticipated that
the specific electronic and steric properties imparted by
the mixed NHC–phosphine ligand system would lead to
efficient alkyne coupling.
[
M]
2
R
this work
R
R
R
A
B
C
head-to-tail
coupled
enyne
head-to-head
coupled
(E)-enyne
head-to-head
coupled
(Z)-enyne
Scheme 1 Homodimerization of terminal alkynes
1
a, 1b or 1c
solvent
SYNLETT 2013, 24, 0587–0590
Advanced online publication: 18.02.2013
2
(Z)-3
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1318271; Art ID: ST-2013-D0035-L
Georg Thieme Verlag Stuttgart · New York
Scheme 2 Head-to-head homodimerization of terminal alkynes
©

588
C. D. Forsyth et al.
LETTER
In order to evaluate this hypothesis, alkyne homodimer- butylphosphine) was employed within this study. Howev-
ization, promoted by complexes 1a–c, was investigated er, this failed to induce prominent Z-selectivity; as noted
using phenylacetylene as our starting substrate (Table 1). in Table 2, entry 5, a reversal of stereoselectivity in favor
Pleasingly, on our initial application, complex 1a promot- of the (E)-enyne was displayed. Furthermore, alternative
ed the desired transformation at a catalyst loading of only additives either delivered the product(s) in diminished
2.4 mol%, with 87:13 selectivity towards the Z-isomer, al- yields or failed to promote the reaction at all (Table 2, en-
beit in a modest 29% yield. Notably, none of the head-to- tries 6–8).
tail homodimerized product was observed. Complexes 1b
Table 2 Additive Study
and 1c were also screened; whilst, again, none of the head-
to-tail isomer was identified, lower Z/E ratios and chemi-
cal yields were exhibited. In all of these initial processes,
appreciable byproduct formation was also noted. From
our previous studies,1 complex 1a has, to date, proved
to be the most versatile of this new group of catalysts. Ac-
cordingly, we were encouraged by the initial result in this
Ph
Ph
1a (2.4 mol%)
+
Ph
4,16
additive, toluene
reflux, 16 h
Ph
Ph
2
(Z)-3
(E)-3
Yield of 3 (%)a
Z/Eb
study with 1a to further probe the synthetic utility of this Entry
Additive (mol%)
–
novel species.
1
29
82
73
71
38
–
87:13
90:10
72:28
79:21
34:66
–
Table 1 Homodimerization Studies with Complexes 1a–c
2
Bn P (30)
3
Ph
3c
Bn P (30)
3
1
(
a, 1b or 1c
2.4 mol%)
Ph
+
4d
5
Bn P (30)
Ph
3
toluene
reflux, 16 h
Ph
Ph
Bu P (30)
3
(
Z)-3
(E)-3
6
dppb (30)
COD (30)
Entry
Complex
Yield of 3 (%)a
Z/Eb
7
–
–
1
2
3
1a
1b
1c
29
22
26
87:13
72:48
67:33
8
Et N (30)
28
82:18
3
a
Isolated yield.
b
c
d
1
Determined by H NMR spectroscopy.
Reaction performed in a sealed tube.
Reaction performed in a microwave reactor at 120 °C for 1 h.
a
Isolated yield.
b
1
Determined by H NMR spectroscopy.
Following the establishment of this procedure with iridi-
um complex 1a at relatively low catalyst loading, coupled
With the promising initial result in hand, we were keen to
enhance the performance of our emerging iridium catalyst
system as applied to this alkyne dimerization. Our goal
was to increase the yield of the regioselective head-to-
head coupling process whilst simultaneously improving
the observed stereoselection. In this regard, through the
stabilization of key reaction intermediates and the promo-
tion of a certain reaction pathway, it is known that the ad-
dition of specific ligands within such transition-metal-
mediated processes can enhance alkyne coupling efficien-
with Bn P additive, a number of alternative terminal al-
3
kyne substrates were examined (Table 3). Pleasingly, in
every case, the head-to-head (Z)-enyne product was pre-
pared in excess. Initially, we probed the applicability of
our optimal conditions using 4-tolylacetylene (Table 3,
entry 2) with an isolated yield of 72% and a Z/E ratio of
81:19 being obtained. Our attention then turned to further
substituted aryl alkynes, specifically containing para-sub-
stituted halogens. More specifically, many transition-met-
al catalysts promote protodehalogenation, and we were
eager to test the ability of our catalyst to facilitate the de-
sired transformation in a completely chemoselective man-
ner. The homodimerization of 4-fluorophenylacetylene
proceeded in an excellent yield with good stereocontrol
(Table 3, entry 3). Especially pleasing was the ability of
complex 1a to facilitate the homodimerization of 4-chlo-
rophenylacetylene (Table 3, entry 4) and 4-bromophenyl-
acetylene (Table 3, entry 5) in good yield with appreciable
levels of stereoselectivity. The electronic nature of the
substrates was investigated further with the electron-do-
nating 4-methoxyphenylacetylene (Table 3, entry 6) being
reacted under the optimized conditions. Disappointingly,
the desired products were formed in poor yield with only
6
,7,8c,d
cy and selectivity.
As such, we probed the use of var-
ious additives within our developing system, with a range
of representative results displayed in Table 2. As shown
by entry 2 (Table 2), the dimerization of phenylacetylene
proceeded very effectively in the presence of triben-
zylphosphine (Bn P; 30 mol%), with a much improved
3
yield of 82% being obtained, coupled with enhanced lev-
els of Z selectivity. Performing similar processes with
Bn P under more forcing reaction conditions (sealed tube
3
or microwave) did not offer any improvement in terms of
yield or selectivity. It has previously been reported that al-
tering the nature of phosphine additives has a pronounced
8
c
effect on the dimerization stereoselectivity observed.
Accordingly, an alternative electron-rich phosphine (tri-
Synlett 2013, 24, 587–590
© Georg Thieme Verlag Stuttgart · New York

LETTER
Z-Selective Dimerization of Aromatic Terminal Alkynes
589
18
a slight bias towards the (Z)-enyne product; the majority of increasing attention in recent years. Following this, in
1
1a,19
of the mass balance in this instance was made up of unre- a well-precedented process,
complex b can isomerize
acted starting alkyne. In contrast, the electron-withdraw- to the vinylidene complex c by intraligand hydrogen
ing 4-trifluoromethylphenylacetylene underwent dimer- transfer. Intramolecular migration of the alkyne unit onto
ization in good yield with the (Z)-enyne, again, being the α-carbon of the vinylidene moiety results in formation
formed preferentially.
of the cis-enyne iridium species d. As supported by the
detailed observations of Wakatsuki when employing Ru
complexes within related processes, the cis form of the
Table 3 Substrate Scope
11a
R
enyne unit within d is believed to be favored to avoid any
repulsive interactions between the (alkenyl) R group and
the specific bulky ligand sphere around Ir, which would
occur in the trans form. The cycle is completed by proto-
demetalation to provide the desired product II and return-
ing intermediate a. Mechanistic studies relating to the use
of our emerging iridium catalysts within a series of syn-
thetic transformations are presently ongoing within our
laboratories.
R
1
a (2.4 mol%)
R
+
Bn3P (30 mol%)
toluene, reflux
16 h
R
R
4
(Z)-5
(E)-5
Entry
Alkyne 4 (R)
Yield of 5 (%)a Z/Eb
1
2
3
4
5
6
Ph
82
72
82
74
79
16
75
90:10
81:19
85:15
77:23
85:15
55:45
77:23
4-MeC H
In summary, as part of a program of work within our lab-
oratory to expand the applicability of novel iridium com-
plexes 1, we have now developed a catalytic system for
effective alkyne dimerization. As promoted by the elec-
tron-rich nature and combined steric bulk of the ligand set
within the catalyst system, the established method deliv-
ers specifically the head-to-head coupled products in a Z-
selective process. Under the optimized reaction condi-
tions, complex 1a facilitates the homodimerization of a
range of aryl alkynes with excellent levels of regiochemi-
cal control.
6
4
4-FC H
6
4
4-ClC H
6
4
4-BrC H
6
4
4-MeOC H
6
4
7
4-F CC H
4
3
6
a
Isolated yield.
b
1
Determined by H NMR spectroscopy.
Based on our observed reaction products, as well as appre-
Representative Experimental Procedure (Table 3, Entry 1)
ciation of previously elucidated pathways of similar trans-
To a flame-dried, N -purged, three-necked round-bottom flask, fit-
formations,8
c,11a,17
2
we propose that the reaction proceeds
ted with a condenser, was added phenylacetylene (100 mg, 0.98
mmol), complex 1a (25 mg, 0.0237 mmol, 2.4 mol%), triben-
by the pathway described below (Scheme 3). The iridium
complex undergoes an initial oxidative addition, with ter- zylphosphine (97 mg, 0.32 mmol), and dry toluene (3.0 mL). The
minal alkyne I, to form complex a. It is believed that the reaction mixture was heated to reflux and allowed to stir for 16 h.
After this time, the reaction mixture was concentrated in vacuo, and
the crude product was purified by silica column chromatography
electron-rich ligand environment then facilitates a subse-
quent oxidative addition of a second alkyne unit to deliver
intermediate b; such Ir(V) species have been the subject
(
eluent: Et O–hexane, 5:95) to yield the dimerized product (82 mg,
2
8
2% yield). The product distribution was confirmed by analysis of
1
the H NMR spectrum to be 90:10 Z/E. More specifically, the ratio
of products was established by integration of the specific olefinic
proton signals and comparison with literature data.
6
,13,20,21
H
H
(Ln)Ir
R
R
Z)-1,4-Diphenylbut-1-ene-3-yne6
,13,20,21
(
–1
1
IR (CH Cl ): 3053, 3031, 1487 cm . H NMR (400 MHz, CDCl ):
2
2
3
δ = 7.95 (d, 2 H, J = 7.6 Hz, ArH), 7.51–7.32 (m, 8 H, ArH), 6.73
(d, 1 H, J = 11.8 Hz, olefinic CH), 5.92 (d, 1 H, J = 11.8 Hz, olefin-
ic CH) ppm. C NMR (100 MHz): δ = 138.6, 136.4, 131.5, 128.7,
b
H
R
13
I
1a
128.6, 128.5, 128.3, 126.3, 123.3, 107.4, 97.4, 88.7 ppm.
H
1
LnIr
H
R
Olefinic H NMR signals used to determine product ratio:
Ir
R
(Z)-Enyne:6,13,20,21 6.73 (d, J = 11.8 Hz) and 5.92 (d, J = 11.8 Hz)
ppm.
a
R
c
Ln
R
E)-Enyne:6,21 7.06 (d, J = 16.2 Hz) and 6.40 (d, J = 16.2 Hz) ppm.
(
H
II
LnIr
R
R
Acknowledgment
R
d
The authors are grateful to the EPSRC for funding (CDF) and the
EPSRC Mass Spectrometry Service, University of Wales, Swansea,
for analyses. We also thank Mr. Alvaro Mallagaray, Universidad
San Pablo CEU, Spain, for input to the initial stages of this program.
H
R
I
Scheme 3 Potential mechanistic pathway
©
Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 587–590

5
90
C. D. Forsyth et al.
LETTER
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