Palladium precatalysts containing meta-terarylphosphine ligands for expedient copper-free Sonogashira cross-coupling reactions

Article abstract of DOI:10.1039/c5cy00507h

Three novel palladium complexes utilizing different variations of the evolutionary meta-terarylphosphine ligand, CyPhine, were developed. These air- and moisture-stable complexes, PdCl₂L₂ (L = CyPhine, CyPhine-CF₃ and CyPhine-nBu), demonstrated exceptional broad-based performance and operational simplicity in the copper-free Sonogashira cross-coupling of challenging (hetero-)aryl chlorides and terminal alkynes. Modifications to the periphery of the ligand scaffold showed modest improvements in the reaction rate when more electron-donating substituents were incorporated, which hints at potential design upgrades in the future.

Full text of DOI:10.1039/c5cy00507h

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Palladium precatalysts containing meta-
terarylphosphine ligands for expedient copper-
Cite this: DOI: 10.1039/c5cy00507h
free Sonogashira cross-coupling reactions†
Received 7th April 2015,
Accepted 26th May 2015
Yong Yang, Joyce Fen Yan Lim,b Xinying Chew,a Edward G. Robins,c
a
*
a
a
a
*
Charles W. Johannes, Yee Hwee Lim and Howard Jong
DOI: 10.1039/c5cy00507h
www.rsc.org/catalysis
Three novel palladium complexes utilizing different variations of
the evolutionary meta-terarylphosphine ligand, Cy*Phine, were
developed. These air- and moisture-stable complexes, PdCl2L2
(L = Cy*Phine, Cy*Phine-CF3 and Cy*Phine-nBu), demonstrated
exceptional broad-based performance and operational simplicity
in the copper-free Sonogashira cross-coupling of challenging
(hetero-)aryl chlorides and terminal alkynes. Modifications to the
periphery of the ligand scaffold showed modest improvements in
the reaction rate when more electron-donating substituents were
incorporated, which hints at potential design upgrades in the
future.
Nevertheless, advantages exist for both types. The cocktail for-
mat of catalysts prepared in situ enable self-tuning and
dynamic adjustment to accommodate different substrates.
This auto-tuning feature contrasts the single species model
for preformed catalysts that benefit from increased stability,
predictability and reproducibility. The flexibility of in situ sys-
tems also facilitates the preparation of stock solutions for
combinatorial evaluations via screening arrays; however, they
lack the robustness of precatalysts, which are typically air and
moisture stable in their solid state. Previously, our group
reported the development of an in situ Pd catalyst system,
which incorporates the evolutionary meta-terarylphosphine
ligand, Cy*Phine.3 Herein, we describe the development of Pd
The continuous development of palladium-based catalysts for
cross-coupling applications has been recognized by the scien-
tific community as one of the most valuable contributions to
synthetic chemistry.1 In line with this, there are two general
methods by which catalysts are introduced to the reaction
mixture: 1) made in situ, where the ligand and the Pd source
are added separately; and 2) via preformed Pd complexes, or
often referred to as precatalysts, which are complexes that
(should) already contain all the components required to pro-
mote catalysis. In consideration of which type of catalyst
should be employed, recent mechanistic insights offer valu-
able guidance to facilitate the decision. Well-defined
preformed catalysts tend to promote catalysis via one prevail-
ing metal species, whereas in situ generated catalysts have the
propensity to involve various metal-based species that are
4
precatalysts, PdCl2L2 (L = Cy*Phine,3 Cy*Phine-CF3 and
Cy*Phine-nBu4), that reinforce the performance benefits of
the Cy*Phine architecture, with the added advantage of prac-
ticality and operational simplicity. The activity differences
between the in situ prepared and precatalyst forms of the
Cy*Phine-based Pd systems for copper-free Sonogashira (or
Heck alkynylation5) cross-coupling reactions are also exam-
ined and discussed.
A critical precatalyst design feature that was carefully
assessed was the ligand-to-metal (LTM) ratio, which has been
shown by numerous groups to have a significant impact on
the catalyst's ability to transform difficult aryl chloride
substrates.6–9 In general, the LTM effect seems to be predi-
cated on a multitude of factors including the ligand charac-
teristics, the substrate class and the reaction type. To our
knowledge, there are currently no reports of any catalyst sys-
tem that is capable of effectively performing the Sonogashira
reaction (with or without a copper co-catalyst) with aryl chlo-
ride substrates using an LTM of less than 2 : 1. The necessity
for a higher LTM ratio for Sonogashira cross-coupling is not
completely understood at this time, but it is clearly beneficial
for improved catalyst performance in copper-free Sonogashira
cross-coupling reactions. A literature survey reveals that
six precatalysts are reportedly able to perform the trans-
formation with aryl chlorides.1k,10 However, only two
dynamic in solution
– resembling that of a
cocktail.2
a Organic Chemistry, Institute of Chemical and Engineering Sciences (ICES),
Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, Helios
#03-08, Singapore 138667. E-mail: howard_jong@ices.a-star.edu.sg,
yangyo@ices.a-star.edu.sg
b School of Medical and Life Sciences, Nanyang Polytechnic, 180 Ang Mo Kio
Avenue 8, Singapore 569830
c Singapore Bioimaging Consortium (SBIC), Agency for Science, Technology and
Research (A*STAR), 11 Biopolis Way, Helios, #02-02, Singapore 138667
† Electronic supplementary information (ESI) available: Synthesis of palladium
complexes P1–P4, general information, experimental procedures and copies of
the NMR spectra of all the compounds. See DOI: 10.1039/c5cy00507h
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10e,f
examples, PdCl2IJPCy3)2
and PdIJAmphos)2Cl2 [Amphos =
IS-1 in different environments. From the evaluation, the com-
bination of K3PO4 in CH3CN was found to be most effective,
furnishing a yield ratio of 94 : 6 for 3a : 4a (Table 1, entry 6).
This result was significantly different from that of IS-1, which
afforded a substantially lower yield ratio of 47 : 2 (3a : 4a)
(Table 1, entry 2). On this basis, it is postulated that the
active catalyst for P1 and IS-1 may not be equivalent due to
the possibility of IS-1 existing as a cocktail of dynamic Pd
species in solution.2 Nonetheless, the significant response
variance in the different reaction environments was not antic-
ipated, or fully understood at this time.15 The final outcome
of the optimization experiments, however, was that the per-
formance of P1 was found to be comparable to IS-1 using a
different solvent and base combination for substrates 1a and
2a.
tBu2IJp-NMe2C6H4)P],1k,10g,h have shown the capacity to couple
challenging electron-rich substrates without the need for an
additional ligand. These state-of-the-art precatalysts both uti-
lize a di-ligated palladiumIJII) dichloride format to achieve
good catalytic performance, are tolerant of air and moisture
in their solid state, and operate without copper co-catalysts. A
catalyst design that performed in the absence of copper salts
was also an important feature as CuI was previously shown
by our group,3 and others,11 to be detrimental to Sonogashira
reactions. Furthermore, the presence of CuI salts has also
demonstrated the capacity to instigate ligand transfer from
Pd at elevated temperatures causing interference.12 Thus, we
envisaged that a PdCl2L2 setup using Cy*Phine as the ligand,
L, could make an effective precatalyst for Cu-free Sonogashira
cross-coupling.
To gauge the performance level of P1, we evaluated it
against other commercially available di-ligated palladium
precatalysts for the coupling of 1a and 2a (Chart 1).
Phosphine-based Pd systems including PdCl2IJPPh3)2,
PdCl2IJPCy3)2 and the state-of-the-art PdIJAmphos)2Cl2 were
selected. The N-heterocyclic carbene-based precatalyst,
PEPPSI-IPr was also included to offer a broader perspective
and completeness. As we were also interested in directly com-
paring the m-terarylphosphine architecture against the
biarylphosphine congener, we prepared and included a new
precatalyst, PdCl2IJXPhos)2 (P4) to the evaluation. Encourag-
ingly, precatalysts P1, P2 and P3 were all far superior to the
current commercial alternatives for copper-free Sonogashira
cross-coupling. Importantly, P1–P3 were also considerably
better than the biarylphosphine-based system P4 under stan-
dard conditions. P4 provided 75% yield of the desired prod-
uct 3a along with 19% of byproduct 4a in approximately a 4 :
1 ratio whereas P1, P2 and P3 provided 3a in greater than
94% yield with product selectivity better than 15 : 1.
These results provide clear evidence that the meta-teraryl-
based precatalysts (P1–P3) offer a significant performance
advantage compared to the biaryl-based system. Furthermore,
the excellent capability demonstrated by the Cy*Phine-based
systems circumvented drawbacks associated with other
precatalysts, such as the requirement of copper co-catalysts
(e.g. PdCl2IJPPh3)2 and PEPPSI-IPr), the need for slow addition
strategies (e.g. PdIJAmphos)2Cl2), and a general substrate
scope limitation (e.g. PdCl2IJPCy3)2).
PdCl2IJCy*Phine)2 (P1) was prepared in a facile manner by
reacting 2 equivalents of Cy*Phine with PdCl2IJCH3CN)2 in
CH3CN at 80 °C for 30 minutes under an argon atmosphere.
A yellow precipitate was formed, which was collected via vac-
uum filtration to obtain the PdCl2IJCy*Phine)2 precatalyst in
high yield (85%). Optionally, PdCl2IJCOD) can be combined
with 2 equivalents of Cy*Phine in THF at room temperature
to produce the equivalent precatalyst after overnight agita-
tion.13 The synthetic procedure was found to be highly robust
and enabled the synthesis of related precatalysts P2 and P3
to evaluate the performance impact of modifications to the
ligand periphery (Scheme 1). Notably, all of the precatalysts,
P1–P3, were isolated as air- and moisture-stable solids.14
The catalytic performance of precatalyst P1 was first evalu-
ated against our recently reported Pd-Cy*Phine in situ system
(IS-1) by performing the identical benchmark reaction stud-
ied previously (Table 1).3 Under these conditions, complete
conversions were achieved for both P1 and IS-1, affording the
desired product, 1-IJtert-butyl)-4-IJphenylethynyl)benzene (3a)
and the concomitant byproduct IJE)-but-1-en-3-yne-1,4-
diyldibenzene (4a) in 87 and 13% yield, respectively for P1
(Table 1, entry 3). The results showed marginally lower yields
and selectivity than those obtained for IS-1, which achieved
91 and 9% for 3a and 4a, respectively (Table 1, entry 1).
While the outcome from the head-to-head comparison was
satisfactory, a solvent and base screen was conducted to
determine if the performance of P1 responded similarly to
To establish the effect of modifications to the periphery of
Cy*Phine, an electron-withdrawing group (P2) and an
electron-donating group (P3) were selected and indepen-
dently incorporated into the third ring of the meta-teraryl
scaffold. From the results of our benchmark reaction using
substrates 1a and 2a, it was found that the ligand substitu-
tions did not evoke a significant performance impact relative
to P1 as all three precatalysts (P1–P3) afforded excellent
results (94–95% yields) with negligible selectivity differences
(Table 1, entries 6, 16–17).
However, to gain further insight, a more in-depth compar-
ison was conducted by which the test reactions were moni-
tored over time. The empirical rate comparison between
Scheme 1 Synthesis of preformed palladium complexes PdCl2L2 (L =
Cy*Phine, Cy*Phine-CF3, Cy*Phine-nBu).
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Table 1 Optimization of reaction conditionsa
Entry
Precatalyst
Solvent
Base
Yieldb (%)
1
2
3
4
5
6
7
8
IS-1c
IS-1c
P1
P1
P1
P1
P1
P1
P1
P1
P1
P1
P1
P1
P1
P2
P3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Toluene
DMSO
Cs2CO3
K3PO4
Cs2CO3
K2CO3
Na2CO3
K3PO4
CsF
91 : 9
47 : 2
87 : 13
85 : 10
56 : 6
94 : 6
78 : 12
24 : 19
24 : 22
86 : 12
15 : 8
48 : 15
54 : 7
32 : 13
30 : 11
94 : 6
Piperidine
Et3N
9
10
11
12
13
14
15
16
17
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
DMF
1,4-dioxane
1,2-DCE
NMP
CH3CN
CH3CN
95 : 5
a
Reaction conditions: 1 mol% Pd precatalyst, 0.5 mmol of 1-tert-butyl-4-chlorobenzene (1a), 0.6 mmol of phenylacetylene (2a), 1 mL of solvent,
b
1 mmol of base, 90 °C, 6 h. GC-FID yield of 3a and 4a as a ratio of 3a : 4a based on 0.5 mmol of 1a using dodecane as an internal standard.
c
IS-1 = PdCl2IJCH3CN)2 and 2 equiv. of Cy*Phine were added separately to the reaction mixture to form the catalyst in situ.
P1–P3 revealed kinetic differences between the precatalyst
series (Chart 2) with a general trend that correlated an
improved reaction rate with more electron-donating substitu-
ents on the third phenyl ring of Cy*Phine. After 2 h, the
product yields showed a rate trend of P3 > P1 > P2 in
approximately 5% increments, which corresponded to the
electron-donating properties of the R-substituent of the third
ring (R = −nBu > −H > −CF3). Similarly, a performance
enhancement effect was also reported by Buchwald's group
with the incorporation of an electron-donating group (−nBu)
to the peripheral ring of their Pd-terarylphosphine system for
nucleophilic aryl fluorination reactions.16
A substrate scope overview for P1 is provided in Table 2
with a more comprehensive list found in the ESI.† Overall,
highly electron-rich, or unprotected, aryl chloride substrates
such as pyrimidines, pyrazines, aldehydes, phenols and ani-
lines
– which are typically problematic for copper-free
Sonogashira reactions – were all efficiently coupled with P1
using Method I without complications (Table 2, entries 1–7).
Potential catalyst poisons, such as 2-ethynylpyridine and
electron-rich alkynes such ethynyl-3,5-dimethoxybenzene
could also be cross-coupled smoothly (Table 2, entries 8–9,
respectively).
More
sensitive
substrates,
like
Chart
1 A performance comparison of P1–P4 with commercially
available precatalysts in the benchmark reaction using 1a and 2a
reaction conditions: 1 mol% Pd precatalyst, 0.5 mmol of 1-tert-butyl-
4-chlorobenzene (1a), 0.6 mmol of phenylacetylene (2a), 1 mL of
CH3CN, 1 mmol of K3PO4, 90 °C, 6 h. GC-FID yield of 3a and 4a based
on 0.5 mmol of 1a using dodecane as an internal standard.
Chart 2 Kinetic profiles of precatalysts P1–P3 for the benchmark
reaction using 1a and 2a. Yields determined by GC-FID using dodecane
as an internal standard.
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Table 2 Selected substrate scopea
Yieldc (%)
method
Yieldc (%)
method
Yieldc (%)
method
Entry
1
Entry
7
Entry
13
P1
IS-1d
95, I
99, I
90, I
91, A
3m
3n
3g
3a
3b
3c
2
3
82, I
91, I
8
9
80, I
14
15
97, I
85, I
89, A
90, A
3h
3i
92, Ib
3o
4
5
82, I
75, I
10
11
84, II
60, II
16
17
97, I
93, I
95, B
99, C
3d
3p
3q
3j
3k
3e
6
87, I
12
90, II
18
52, Ib 95, D
83, Ie
3r
3l
3f
a
Reaction conditions: Method I: 1 mol% P1 IJPdCl2IJCy*Phine)2), 0.5 mmol of aryl chloride 1, 0.6 mmol of alkyne 2, 1 mmol of K3PO4, 1.0 mL
b
of CH3CN, 90 °C, 6 h. 12 h reaction time was used instead. Method II: as per method I, except 1 mmol of NEt3, 1.0 mL of THF, 60 °C, and 12
h were used instead. Method A: 1 mol% IS-1 (0.005 mmol of PdCl2IJCH3CN)2, 0.010 mmol of Cy*Phine), 1 mmol of Cs2CO3, 1.0 mL of CH3CN.
Method B: as per method A, except 1 mmol of Et3N, 1 mL of THF, 60 °C, and 6 h were used instead. Method C: 1 mol% IS-2 (0.005 mmol of
PdIJOAc)2, 0.015 mmol of Cy*Phine), 1 mmol of Cs2CO3, 1 mL of CH3CN, 90 °C, 3–16 h. Method D: as per method C, except K3PO4 was used as
c
d
e
the base. Average isolated yields of two runs. Isolated yield values and the conditions for methods A–D were obtained from ref. 3. 1 mol%
P1 and 1 mol% additional Cy*Phine were used (LTM = 3 : 1).
chloropyridazines, required a lower reaction temperature (60
°C) and a different solvent and base combination (THF/NEt3,
Method II) to efficiently promote the alkynylation reaction
(Table 2, entries 10–12).
to 83% from 52%. Therefore, in cases where LTM ratios
greater than 2 : 1 are required, the use of IS-1 should be
considered.
Nonetheless, most substrates can be transformed by P1
using only two methods, as opposed to four methods when
IS-1 was employed. This simplified protocol for P1 adds yet
another level of convenience, in addition to its ease of han-
dling, being an air- and moisture-stable solid. Importantly,
the added practicality of P1 does not hinder its high perfor-
mance and its substrate scope is inclusive of examples that
contain heteroaromatic groups on both coupling partners
(Table 2, entries 8, 11–12, 15–16). These examples are of par-
ticular interest as they are representative of substrates used
to prepare industrially valuable molecules.17
Initially, it was determined that the performance of P1
and IS-1 were similar; however, a closer examination across
several different substrates revealed subtle differences
(Table 2, entries 13–18). Using only Method I, P1 was able to
achieve results that were comparable with, or greater than,
IS-1 which utilized three different methods for five different
substrate pairs (Table 2, entries 13–17). Despite being able to
streamline the protocol for P1, a significant difference in per-
formance was observed when propargyl alcohol was coupled
with 4-chlorobenzonitrile (Table 2, entry 18). The employ-
ment of IS-1 with Method D achieved nearly double the yield
of P1 using Method I. The major difference was the LTM
ratio of 3 : 1 utilized by IS-1 as opposed to P1 that had a
preformed LTM of 2 : 1. This increased LTM ratio was found
to be generally effective to improve the performance of IS-1
in the presence of very challenging substrates, such as
propargyl alcohols and propargyl amines.3 This augmenta-
tion effect was further verified when the experiment was
repeated with 1 mol% P1 and an extra 1 mol% Cy*Phine was
added to the reaction mixture (to bring the LTM ratio up to
3 : 1). The outcome was an isolated yield improvement of 3f
Conclusions
In conclusion, we have added two meta-terarylphosphine
ligands (Cy*Phine-CF3 (L2) and Cy*Phine-nBu (L3)) to the
Cy*Phine series and prepared several novel air- and
moisture-stable precatalysts P1–P3, including P4 as
a
biarylphosphine-based precatalyst derived from XPhos. In a
comparison, P1–P3 all outperformed P4, but relative to one
another P1, P2 and P3 were equally productive in our bench-
mark reaction. However, the presence of an electron-
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donating substituent on the peripheral phenyl ring of the
ligand structure resulted in an incremental reaction rate
enhancement. A systematic evaluation of P1 in copper-free
Sonogashira cross-coupling reactions revealed a competitive
level of performance relative to IS-1, in general. However, dif-
ferences emerged in the instances where an LTM ratio of 3 : 1
is necessary to furnish high yields. The employment of P1
was found to be very convenient with its streamlined protocol
compared to IS-1, which added practicality and increased its
attractiveness as a high performance precatalyst. Further-
more, P1 was found to be substantially more efficient than
other state-of-the-art precatalyst alternatives for challenging,
industrially valuable substrates. Further developments related
to ligand design improvements are under way, as well as the
extension of their applications to other Pd-catalyzed cross-
coupling reactions.
5 Alkynylation reactions in the absence of copper co-catalysts
were first reported by Heck and associates. However, Heck
alkynylation reactions are more commonly referred to as
copper-free Sonogashira reactions. H. A. Dieck and F. R.
Heck, J. Organomet. Chem., 1975, 93, 259–263.
6 For arylation of primary amides and aliphatic alcohols, an
LTM ratio of 1 : 1 is effective as recently been shown by
Buchwald and co-workers using their 3rd generation Pd
precatalysts. For details, see: N. C. Bruno and S. L.
Buchwald, Org. Lett., 2013, 15, 2876–2879.
7 N-heterocyclic carbene (NHC)-based Pd systems frequently
employ a 1 : 1 LTM strategy. The PEPPSI precatalysts have
been effective in Negishi, Kumada–Tamao–Corriu and
Suzuki–Miyaura reactions. For examples, see: E. A. Kantchev,
B. C. J. O'Brien and M. G. Organ, Angew. Chem., Int. Ed.,
2007, 46, 2768–2813.
8 The importance of a higher LTM ratio (1.5 : 1, or more) to
furnish good results and to prevent catalyst deactivation for
reactions such as the Suzuki–Miyaura reaction and
Buchwald–Hartwig amination has been shown by numerous
research groups. For examples, see: (a) A. F. Littke, C. Dai
and G. C. Fu, J. Am. Chem. Soc., 2000, 122, 4020–4028; (b)
A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed., 2002, 41,
4176–4211; (c) A. Zapf, A. Ehrentraut and M. Beller, Angew.
Chem., Int. Ed., 2000, 39, 4153–4155; (d) J. P. Wolfe, R. A.
Singer, B. H. Yang and S. L. Buchwald, J. Am. Chem. Soc.,
1999, 121, 9550–9561; (e) E. R. Strieter, D. G. Blackmond and
S. L. Buchwald, J. Am. Chem. Soc., 2003, 125, 13978–13980.
9 Buchwald's group previously reported the need to add an
additional ligand to their monophosphine-ligated, 2nd
generation Pd XPhos precatalyst in order to achieve good
results in their alkynylation reactions, see: W. Shu and S. L.
Buchwald, Chem. Sci., 2011, 2, 2321–2325.
10 (a) D.-H. Lee, H. Qiu, M.-H. Cho, I.-M. Lee and M.-J. Jin,
Synlett, 2008, 11, 1657–1660; (b) D.-H. Lee, Y.-J. Kwon and
M.-J. Jin, Adv. Synth. Catal., 2011, 353, 3090–3094; (c) J. Ruiz,
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Li, J. Zhang, G. Ren and Y. Wu, Tetrahedron, 2007, 63,
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Acknowledgements
We thank Ms. Doris Tan (ICES) for the HRMS and EA analy-
ses. Financial support for this work was provided by the
A*STAR Joint Council Office (JCO), the Singapore 1st JCO
Developmental Programme (DP) (grant JCO 1230400020), the
A*STAR Institute of Chemical and Engineering Sciences
(ICES) and the A*STAR Singapore Bioimaging Consortium
(SBIC).
Notes and references
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4 See the ESI† for details regarding the preparation of
Cy*Phine-CF3 and Cy*Phine-nBu. Buchwald and co-workers
have also recently reported the synthesis and use of a similar
nBu-substituted terarylphosphine ligand used in nucleo-
philic fluorination; see ref. 16a.
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13 Details for an alternative method to prepare P1: to an oven-
dried round bottom flask, PdCl2IJCOD) (28.6 mg, 0.1 mmol,
1.0 equiv.) and anhydrous THF (5 mL) were added. With
rapid stirring, Cy*Phine (110.8 mg, 0.2 mmol, 2.0 equiv.)
was added. The vial was capped under argon and stirred vig-
orously at room temperature overnight. The solvent was con-
centrated in vacuo and pentane (10 mL) was added. The
resulting yellow precipitate was filtered through a sintered
glass frit, washed with pentane (3 × 5 mL), and dried under
reduced pressure to afford a yellow solid (111 mg, 85%).
14 Precatalysts P1–P3 have been stored on the benchtop for at
least 30 days without any observable loss of catalytic activity.
15 More detailed studies need to be conducted to elucidate the
complex phenomenon. We postulate that the differences in
solubility of the catalysts and bases, as well as the number
of catalyst species in solution, could all potentially impact
the performance.
16 (a) H. G. Lee, P. J. Milner and S. L. Buchwald, J. Am. Chem.
Soc., 2014, 136, 3792–3795; (b) T. J. Maimone, P. J. Milner, T.
Kinzel, Y. Zhang, M. K. Takase and S. L. Buchwald, J. Am.
Chem. Soc., 2011, 133, 18106–18109.
17 Efficient transformations of these types of substrates is
often beyond the capabilities of other catalyst systems, see:
ref. 1k and 10.
Catal. Sci. Technol.
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