Rational design of a palladium-catalyzed Csp-Csp cross-coupling reaction inspired by kinetic studies

Article abstract of DOI:10.1002/anie.201204112

Less is More: A highly selective Pd-catalyzed C_sp-C_sp cross-coupling reaction between terminal alkynes and 1-bromoacetylenes has been developed. Catalyst loading is low (only 0.0001-0.01 mol % of Pd is required) and provides products with high selectivities and good to excellent yields under mild conditions. TBAB=tetrabutylammonium bromide, TON=turnover number. Copyright

Full text of DOI:10.1002/anie.201204112

Angewandte
Chemie
DOI: 10.1002/anie.201204112
Cross-Coupling Reactions
Rational Design of a Palladium-Catalyzed Csp–Csp Cross-Coupling
Reaction Inspired by Kinetic Studies**
Yue Weng, Ben Cheng, Chuan He, and Aiwen Lei*
Owing to the unique chemical and physical properties of
diynes, along with their wide applications in pharmaceuticals
and materials chemistry, these compounds have attracted the
attention of scientists for decades.[1] However, the synthesis of
diynes still remains a great challenge. Compared with the
intensively developed synthetic methods for biaryl and
arylalkynes (Csp2–Csp2 and Csp2–Csp couplings), the methods
for Csp–Csp coupling reactions are rare, and lack high
efficiency in most cases.[2] To date, the Glaser–Hay coupling
reaction, which was developed more than 100 years ago, still
remains the most commonly used method to prepare
conjugated diynes, mainly through the homo-coupling of
terminal alkynes.[1a,3] Cadiot-Chodkiewicz cross-coupling,
which involves alkynyl halides as electrophiles and terminal
alkynes as nucleophiles, provides a solution to access some
unsymmetrical 1,3-diynes in the presence of copper salts.[1a,4]
Although powerful for some syntheses, this protocol suffers
from poor selectivity, low efficiency, often complicated
reaction conditions, and always produces homocoupled by-
products.[1a,2j,k,5] Recently, some modified Cu-catalyzed
Csp–Csp cross-couplings have also been reported for the
construction of unsymmetrical diynes.[6]
Scheme 1. Putative pathways for Pd-catalyzed Csp–Csp cross-coupling.
OA=oxidative addition, TM=transmetalation, RE=reductive elimina-
tion.
Pd-catalysis has been extremely successful in various
types of bond formation reactions,[2a–d,i,j] which also exhibit
great potential for the synthesis of diynes. Recently, several
Pd-catalyzed Csp–Csp cross-coupling reactions have been
developed.[5,7] Improvements have been reported, although
increasing the selectivity and turnover number (TON) still
remains a challenge. A general catalytic cycle for Pd-
catalyzed Csp–Csp cross-coupling is outlined in Scheme 1.[2j]
We speculated that there is competition between reductive
elimination of and disproportionation of intermediate II. The
former leads to the cross-coupling product, whereas the latter
results in homocoupled by-products. This inherent problem
limits the general application of this synthetic method and
makes favoring the reductive elimination process critical.
Some efforts employing steric or p-acid ligands have been
developed to promote the reductive elimination.[8] On the
other hand, based on the kinetics rate law for the reductive
elimination and disproportionation (Scheme 1), simply
decreasing the loading of the Pd catalyst might be a solution
to address the challenge. As indicated in Scheme 1, the
reductive elimination rate (r1) is first order in [II], and the rate
of the disproportionation process (r2) is second order in [II].
Thus, reducing the loading of Pd-catalyst would theoretically
favor reductive elimination over disproportionation. Simply
speaking, by reducing the Pd catalyst loading to 1/100, r1 will
be decreased to 1/100, but r2 will be decreased to 1/10000. It
seems clear that the reductive elimination pathway can be
enhanced in this way.
[*] Y. Weng, B. Cheng, C. He, Prof. A. Lei
College of Chemistry and Molecular Sciences
Wuhan University, Wuhan, Hubei, 430072 (P.R. China)
E-mail: aiwenlei@whu.edu.cn
Prof. A. Lei
State Key Laboratory for Oxo Synthesis and Selective Oxidation
Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, 730000 Lanzhou (P.R. China)
[**] This work was supported by the National Natural Science
Foundation of China (21025206, 20832003, 20972118, and
20973132) and the 973 Program (2012CB725302). The authors are
also thankful for support from “the Fundamental Research Funds
for the Central Universities”, Program for New Century Excellent
Talents in University (NCET) and the Program for Changjiang
Scholars and Innovative Research Team in University (IRT1030). We
thank Prof. Lin Zhuang (Wuhan University) for providing Pd/C as
gift.
Recently, a ligand-free Pd(OAc)2 (OAc = acetate) cata-
lytic system was extensively studied in which palladium
nanoparticles (NPs) were proposed to be the active catalytic
species.[7b,9] Many of these Pd-catalyzed reactions were
reported with the use of very low catalyst loadings. This
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204112.
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encouraged us to speculate that Pd(NPs) might also be
a suitable catalyst for diynes synthesis. In fact, if Pd at the ppm
level could effectively catalyze the reaction, not only there is
economic value of the process (high TON), but it is also
beneficial for addressing Pd-contamination problems in the
work-up process. Even without a special protocol to remove
the Pd species, the Pd contamination in the products would
likely be within the limit of regulation because of the original
lower loading of the Pd precursor. Herein, we describe
a highly efficient and selective Pd-catalyzed Csp–Csp cross-
coupling reaction with low catalyst loadings (Scheme 2).
Scheme 2. Pd-catalyzed Csp–Csp cross-coupling reaction. OAc=acetate,
TBAB=tetrabutylammonium bromide.
Our initial efforts focused on the reaction of (bromo-
ethynyl)benzene (1b) and 2-methylbut-3-yn-2-ol (2t). In the
presence of 2 mol% Pd(dba)2 (dba = dibenzylideneacetone),
3bt was obtained in 78% yield and with 92:8 selectivity
(Table 1, entry 1). Interestingly, increasing the Pd catalyst
loading resulted in lower selectivity (Table 1, entries 2–4).
Figure 1. Kinetic profiles with different Pd(dba)2 loadings. a) Concen-
tration of 3bt vs. time curve for the reactions of Pd(dba)2 at 0.0067–
0.0267m monitored by in situ IR spectroscopy. Reaction conditions:
1b (1.0 mmol), 2t (1.0 mmol), CuI (2 mol%) in iPr2NH (3 mL) as
solvent at 208C; the loading of Pd(dba)2 is 2–8 mol%. b) Initial rate
vs. Pd loading curve for the reactions.
Table 1: The impact of Pd(dba)2 loading on selectivity.[a]
strates for further method development. Gratifyingly, upon
reducing the Pd catalyst loading to 0.1 mol%, 1a and 2a gave
improved results, producing the desired product in 96% yield
in the presence of additive TBAB (tetrabutylammonium
bromide) at 708C (Table 2, entry 1). Usually, tetraalkylamo-
nium halides are used as stabilizers for NPs, which would
prevent them from further aggregation and precipitation from
the reaction, as well as making the catalyst active.[10] The
effects of different Pd and TBAB loadings in this Csp–Csp
cross-coupling were also investigated (Table 2). In the
absence of Pd or Cu salts, almost no reaction occurred
(Table 2, entries 2 and 3). Without TBAB, the reaction yield
decreased dramatically (Table 2, entry 4). Moreover, the
combination of Pd(OAc)2 and TBAB afforded a better
result (Pd/TBAB = 1:30; Table 2, entry 5). However, other
ratios of Pd/TBAB led to reduced yields (Table 2, entries 6–
9).
To our delight, when 0.01 mol% Pd(OAc)2 was employed,
more than 99% of the cross-coupling product was obtained
without any 1-haloalkyne homocoupled by-product (Table 2,
entry 11). Varying the amount of CuI and iPr2NH solvent also
slightly affected the chemical yield (Table 2, entries 10–13).
The substrate scope of this transformation is shown in
Scheme 3. With 4-bromo-2-methylbut-3-yn-2-ol (1a) as a sub-
strate, the reaction was readily extended to a variety of aryl
terminal alkynes in high yields. Both electron-donating and
-withdrawing functional groups, such as Me, Ph, OMe, NMe2,
CN, acetyl (Ac), and CO2Et, were well tolerated (Scheme 3,
Entry
Pd(dba)2
[mol%]
Yield of
Selectivity[c]
3bt [%][b]
1
2
3
4
2
4
6
8
78
75
80
75
92:8
91:9
91:9
89:11
[a] Reaction conditions: 1b (1.0 mmol), 2t (1.0 mmol), CuI (2 mol%) in
iPr2NH (3 mL) as solvent at 208C; the amounts of Pd(dba)2 are given in
the table. [b] Determined by GC with biphenyl as an internal standard.
[c] Molar ratio of 3bt/1,4-diphenylbutadiyne. dba=dibenzylidene-
acetone.
Further kinetic investigation of this reaction was con-
ducted (Figure 1). The kinetic profiles of [3bt] vs. time
(Figure 1a) almost overlapped, regardless of the initial
concentration of Pd(dba)2. As shown in Figure 1b, plotting
the reaction initial rate vs. Pd loading showed a zero-order
kinetic dependence on the mol% of Pd used. This observation
is abnormal, and clearly indicated that the roles of Pd
catalysts in this reaction are complicated.
The selectivity of the Pd catalyzed Csp–Csp cross-coupling
shown in Table 1 encouraged us to further examine the
effectiveness of unsymmetrical 1,3-diynes synthesis. After
some attempts, 4-bromo-2-methylbut-3-yn-2-ol (1a) and
phenylacetylene (2a) were found to be better model sub-
2
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Table 2: Conditions optimization for the Csp–Csp cross-coupling of
4-bromo-2-methylbut-3-yn-2-ol 1a and phenylacetylene 2a.[a]
Entry
[Pd] (mol%)
TBAB
CuI
iPr2NH Yield [%][b]
[mol%]
[mol%]
[mL]
1
2
3
4
5
6
7
8
Pd(dba)2 (0.1)
none
3.0
none
3.0
none
3.0
1.0
0.5
0.1
10.0
2
2
5
5
5
5
5
5
5
5
5
5
5
3
10
96
trace
trace
58
97
77
87
73
80
94
Pd(dba)2 (0.1)
Pd(dba)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.01) 0.3
Pd(OAc)2 (0.01) 0.3
Pd(OAc)2 (0.01) 0.3
Pd(OAc)2 (0.01) 0.3
none
2
2
2
2
2
2
2
9
10
11
12
13
0.2
0.2
0.2
>99
97
97
[a] Reactions were carried out on 1a (1.0 mmol) in the presence of [Pd]/
TBAB and CuI in iPr2NH solvent at 708C. [b] Yield determined by GC
analysis with biphenyl as an internal standard. dba=dibenzylidene-
acetone, TBAB=tetrabutylammonium bromide.
3ab–3ae and 3ai–3ak). Aryl alkynes bearing fluoro, chloro,
or bromo groups could also be introduced to give the desired
cross-coupling products, demonstrating the exceptional che-
moselectivity of this method (Scheme 3, 3af–3ah). Further-
more, terminal alkynes containing benzodioxole, methylsul-
fonylbenzene, methoxynaphthalene, or aminopyridine moi-
eties could be converted into the corresponding unsymmet-
rical 1,3-diyne scaffold in good to excellent yields (Scheme 3,
3al–3ao). Alkyl terminal alkynes such as prop-2-ynyl acetate
(2p), 4-methyl-N-(prop-2-ynyl)benzenesulfonamide (2q),
2-(prop-2-ynyloxy)tetrahydro-2H-pyran (2r), and 2-(prop-2-
ynyl)isoindoline-1,3-dione (2s) also reacted well under the
standard conditions (Scheme 3, 3ap–3as). Moreover, (bro-
moethynyl)benzene (1b) reacted smoothly with both aryl and
alkyl terminal alkynes to afford the corresponding diyne
products in good yields (Scheme 3, 3bt, 3bd, and 3bi).
This transformation could be readily scaled up. In fact,
when 100 mmol (16.3 g) of 1a was employed with Pd(OAc)2
(0.0001 mol%) as the catalyst precursor, a TON of up to
350000 was achieved, along with a turnover frequency (TOF)
of up to 43750 hÀ1 (Scheme 4). No homocoupled by-product
was observed in this reaction, indicating that the selectivity
was still high. To the best of our knowledge, this is the highest
TON for the Pd-catalyzed Csp–Csp cross-coupling reaction
reported to date.
Scheme 3. Substrate scope for the reactions of bromoalkynes 1 and
terminal alkynes 2. Isolated yields. [a] Reaction conditions:
1 (1.0 mmol) and 2 (1.5 mmol) in the presence of Pd(OAc)2
(0.01 mol%), TBAB (0.3 mol%) and CuI (0.2 mol%) in iPr2NH (5 mL)
at 708C. [b] Reaction conditions: 1 (0.5 mmol) and 2 (0.75 mmol) in
the presence of Pd(OAc)2 (0.01 mol%), TBAB (0.3 mol%) and CuI
(2 mol%) in iPr2NH (3 mL) at 708C. [c] Reaction conditions:
1 (1.0 mmol) and 2 (1.5 mmol) in the presence of Pd(OAc)2
(0.01 mol%), TBAB (0.3 mol%) and CuI (2 mol%) in iPr2NH (5 mL)
at 708C.
To verify whether Pd(NPs) were involved in this cross-
coupling reaction, a ligand poisoning experiment was carried
out with in situ IR spectroscopy.[11] As shown in Figure 2,
under the standard conditions this transformation proceeded
smoothly, providing 96% yield of product (TON = 9600,
TOF = 9600 hÀ1) and the kinetic profile of [3aa] vs. time fit
a nearly straight line. As a comparison, when the ligand PPh3
was added into the reaction at 30 min, an obvious inflection
point was observed and the reaction was suppressed.
Scheme 4. Gram scale experiment. Reaction conditions: 1a
(100 mmol) and 2a (150 mmol) in the presence of Pd(OAc)2
(0.0001 mol%), TBAB (0.3 mol%) and CuI (2 mol%) in iPr2NH
(150 mL) at 708C. Yield of isolated product shown.
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(0.2 mol%) in iPr2NH (5 mL) was stirred under N2 at 708C for
5 min. Then Pd(OAc)2 (0.01 mol%) was added in one portion. After
reaction completion, as indicated by TLC and GC, the mixture was
quenched with dilute hydrochloric acid (4 mL, 2m), and the solution
was extracted with ethyl acetate (3 ꢀ 15 mL). The organic layers were
combined and dried over sodium sulfate. The pure product was
obtained by flash column chromatography on silica gel (petroleum
ether/ethyl acetate, 20:1) to afford 3aa in 99% yield. 1H NMR
(300 MHz, CDCl3): d = 7.42–7.40 (m, 2H), 7.26–7.24 (m, 3H), 2.34
(br, 1H), 1.52 ppm (s, 6H); 13C NMR (75 MHz, CDCl3): d = 132.7,
129.4, 128.6, 121.7, 86.9, 79.0, 73.4, 67.3, 65.9, 31.3 ppm.
Figure 2. Concentration of 3aa vs. time curve for the reaction of 1a
(0.33m) with 2a (0.5m) and Pd(OAc)2 (0.01 mol%) as the catalyst
precursor in the presence of TBAB (0.3 mol%) monitored by in situ IR
Received: May 27, 2012
Revised: July 10, 2012
Published online: && &&, &&&&
&
*
spectroscopy at 708C ( ); : the same conditions, but with PPh3
(0.05 mol%) added at 30 min.
Keywords: alkynes · cross-coupling · kinetics · nanoparticles ·
.
palladium
Kinetic studies on the effect of the Pd catalyst loading
were also performed by in situ IR spectroscopy (Pd loading of
0.008–0.5 mol%). As shown in Figure 3, the reaction rate was
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cross-coupling reaction between terminal alkynes and
1-bromoacetylenes. High selectivity and good to excellent
yields could be attained with low catalyst loadings (only
0.0001–0.01 mol% of Pd is required). Preliminary kinetic
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Cross-Coupling Reactions
Y. Weng, B. Cheng, C. He,
A. Lei*
&&&& — &&&&
Rational Design of a Palladium-Catalyzed
Csp–Csp Cross-Coupling Reaction Inspired
by Kinetic Studies
Less is More: A highly selective Pd-
Pd is required) and provides products
with high selectivities and good to excel-
lent yields under mild conditions. TBAB=
tetrabutylammonium bromide, TON=
turnover number.
catalyzed Csp–Csp cross-coupling reaction
between terminal alkynes and 1-bromoa-
cetylenes has been developed. Catalyst
loading is low (only 0.0001–0.01 mol% of
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!