Palladium/copper bimetallic system-mediated cross-coupling of alkynes and alkenes: Two strategies to suppress β-H elimination on alkyl-palladium center

Article abstract of DOI:10.1002/adsc.201400007

This paper describes two efficient strategies to suppress β-H elimination during the palladium/copper bimetallic system-mediated cross-coupling between alkynamides and alkenes. Remote donor groups with the terminal olefins, such as toluenesulfonamide, phosphate, sulfone, etc., cooperate with the amide of alkynamides and chelate the palladium active center, to promote C(sp³)-O bond formation by suppressing the β-H elimination. Another strategy uses the rigid structure of norbornene to make an intermediate without a syn-β-hydrogen to achieve reductive elimination of the C-Cl bond.

Full text of DOI:10.1002/adsc.201400007

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DOI: 10.1002/adsc.201400007
Palladium/Copper Bimetallic System-Mediated Cross-Coupling
of Alkynes and Alkenes: Two Strategies to Suppress b-H
Elimination on Alkyl-Palladium Center
Liangbin Huang,+a Qian Wang,+a Wanqing Wu,a and Huanfeng Jianga,*
a
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, Peopleꢀs
Republic of China
Fax : (+86)-20-8711-2906; e-mail: jianghf@scut.edu.cn
+
These authors made equal contributions to this work.
Received: January 2, 2014; Revised: March 20, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400007.
À
Abstract: This paper describes two efficient strat-
egies to suppress b-H elimination during the palla-
dium/copper bimetallic system-mediated cross-cou-
pling between alkynamides and alkenes. Remote
donor groups with the terminal olefins, such as tol-
uenesulfonamide, phosphate, sulfone, etc., cooper-
ate with the amide of alkynamides and chelate the
tion, especially C heteroatom reductive elimination,
3
À
from C
N
to form Pd(IV) intermediates,[17–19] while the carbon-
carbon multiple bonds are usually sensitive to strong
oxidants. A key challenge which has attracted chem-
istsꢀ interest was how to suppress the fast b-H elimi-
nation and achieve reductive elimination to form
3
À
À
palladium active center, to promote C
N
a C heteroatom bond under mild reaction conditions
(Scheme 1, paths a and c).
formation by suppressing the b-H elimination. An-
other strategy uses the rigid structure of norbor-
nene to make an intermediate without a syn-b-hy-
drogen to achieve reductive elimination of the
Pd/Cu bimetallic catalysis has made great progress
in the Sonogashira process[20–25] and decarboxylative
cross-coupling.[26–30] And as a part of our interest in
Pd/Cu bimetallic system-mediated oxidative alkyne–
alkene cross-couplings,[31–34] we herein report the de-
velopment of two routes to suppress the b-H elimina-
tion from intermediate A (Scheme 2). Under such
a scenario, the complex A usually serves as the key in-
termediate, followed by b-H elimination to form the
C=C bond (Scheme 2, path a).[33–34] Recently, Lautens
and Tong independently reported the Pd-catalyzed in-
tramolecular carbohalogenation of a-substituted ole-
À
C Cl bond.
Keywords: bimetallic systems; cross-coupling; palla-
dium; reductive elimination; suppression of b-H
elimination
Palladium chemistry occupies a significant place in fins through CACHTNUTGRNEUNG
(sp3)-halogen bond reductive elimina-
transition metal-catalyzed C C and C X bond forma- tion.[10–16] Inspired by this seminal work and our bro-
tion reactions.[1] Traditionally, the carbon-palladium moalkynylation of norbornene,[35] we have achieved
À
À
À
species could be formed through oxidative addition or C Cl bond formation when norbornene was used as
cycloaddition of low valent Pd(0), transmetallation, the substrate in this cross-coupling, due to its rigid
C H activation, decarboxylation and nucleopallada- structure norbornene is able to prevent the corre-
tion of carbon-carbon multiple bonds with a Pd(II) sponding b-H elimination (Scheme 2, path b).
À
À
center (Scheme 1). The C Pd species captured by the
Besides, the lack of a syn-b-hydrogen could sup-
alkenes through migratory insertion could afford the press the b-H elimination from intermediate A, and
alkyl-Pd species B, which is the elementary intermedi- the coordinative saturation of the Pd center repre-
ate in Heck-type reactions.[2–3] Two strategies were sents another established strategy to suppress b-H
typically employed to quench the alkyl-Pd species B: elimination.[3] Some coordinating groups in the termi-
(i) b-H elimination to get C=C double bonds like the nal olefins, such as NHTs, vinyl, POACHTUNTRGNEUNG(OEt)2, SO2Ph,
Heck process (Scheme 1, path a);[4–9] (ii) reductive were used to cooperate with alkynamide to make the
elimination when there was no hydrogen at the b posi- Pd center coordinatively full and so promote the re-
tion (Scheme 1, path c).[10–16] The reductive elimina- ductive elimination (path c in Scheme 2). Herein, we
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Liangbin Huang et al.
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Scheme 1. Three typical strategies to form C C or C X bonds.
Scheme 2. Nucleopalladation-initiated oxidative cross-coupling between alkynes and alkenes.
report the Pd-catalyzed Kaneda-type reaction of groups with alkynamides to construct a-methylene-g-
alkynamides with norbornene to construct C-7 func- lactones (path c in Scheme 2).
tionalized norbornylalkenes (path b in Scheme 2) and During the optimization of the reaction conditions,
ACHTUNGTRENNUNG
lactonization of the alkenes bearing coordinated we focused our attention on the cross-coupling of 3-
phenylpropiolamide 1a and norbornene 2a (Table 1).
After exploring a wide array of conditions, we deter-
mined that CH3CN was the best solvent for this trans-
formation (see the Supporting Information for de-
Table 1. Optimization of the reaction conditions.[a]
tails). When 1a and 2a were treated with 5 mol%
PdCl2 and 2 equiv. of CuCl2·2H2O in CH3CN under
air at 508C for 14 h, a satisfying isolated yield of 73%
of 3a could be obtained (Table 1, entry 1). And the
structure of 3a was confirmed by X-ray crystallo-
graphic analysis (Figure 1).[36] The screening of vari-
ous Pd catalysts led to very similar results and PdCl2
was found to be best for this reaction (Table 1, en-
tries 2–4). A higher isolated yield (83%) could be ob-
tained by increasing the amount of CuCl2·2H2O to
3 equiv. (Table 1, entries 4 and 5). Gratifyingly, a use
of a lower reaction temperature (room temperature)
gave 3a in 88% yield (Table 1, entry 6). However, the
reaction using CuBr2 instead of CuCl2 gave a trans-di-
brominated alkene product exclusively upon addition
of bromide to the alkynyl group of 1a. Therefore, the
best condition consisted of 5 mol% PdCl2, 3 equiv. of
Entry Catalyst
CuCl2·2H2O
(equiv.)
Temp.
[oC]
Yield
[%]
1
2
3
4
5
6
PdCl2
Pd(OAc)2
PdCl2A(MeCN)2
PdCl2
PdCl2
PdCl2
2
2
2
3
4
3
50
50
50
50
50
r.t.
73
63
68
83
78
88
ACHTUNGTRENNUNG
CHTUNGTRENNUNG
[a]
Reaction conditions: 1a (0.5 mmol) and 2a (0.6 mmol),
Pd catalyst (5 mol%), CuCl2·2H2O (2–4 equiv.) and
0.5 mL of acetonitrile for 12 h. Yields of isolated prod-
ucts are given.
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Palladium/Copper Bimetallic System-Mediated Cross-Coupling
ther functionalization (Scheme 3, 3g). In contrast with
the para- and meta-substituted alkynamides, the
ortho-substituted substrate failed to convert to the
product (Scheme 3, 3d). When oct-2-ynamide was
used in this transformation, the corresponding prod-
uct was obtained in good yield (Scheme 3, 3h).
Encouraged by these promising results, we further
applied these conditions to Pd-catalyzed cross-cou-
pling of N-substituted alkynamides (Scheme 4). A
series of N-benzyl-substituted alkynamides could be
transformed to the corresponding products in good
yields. For example, 3i and 3j were smoothly obtained
in 84% and 66% yields, respectively (Scheme 4). In
addition, halide functional groups, such as F, Cl, Br,
Figure 1. X-ray structure of 3a.
CuCl2·2H2O, in CH3CN at room temperature for were tolerated in this transformation and the corre-
12 h. sponding products were obtained in moderate yields
With the optimized reaction conditions in hand, we (Scheme 4, 3k–3m). N-substituted alkynamides with
next expanded the substrate scope of the Pd-catalyzed alkyl groups, such as methyl, propyl and n-butyl, also
cross-couplings between alkynamides and norbornene
(Scheme 3). Alkynamides substituted with electron-
donating groups, such as methyl and methoxy, afford-
ed the corresponding products in good yields
(Scheme 3, 3b, 3c, 3e). The 4-CN-substituted alkyn-
ACHTUNGTRENNUNGamide could be converted into the corresponding C-7
functionalized norbornylalkene in excellent yield
(Scheme 3, 3f). Bromide on the aromatic ring was
well tolerated, which provides the possibility for fur-
Scheme 4. Pd-catalyzed coupling of N-substituted alkyn-
amides with norbornene. Reaction conditions: the reactions
were carried out with norbornene (0.6 mmol), alkynamide
(0.5 mmol), PdCl2 (5 mol%), CuCl2·2H2O (3 equiv.) in
0.5 mL of acetonitrile at room temperature for 12 h. Yields
of isolated products are given.
Scheme 3. Pd-catalyzed cross-coupling of alkynamides with
norbornene. Reaction conditions: the reactions were carried
out with norbornene (0.6 mmol), alkynamide (0.5 mmol),
PdCl2 (5 mol%), CuCl2·2H2O (3 equiv.) in 0.5 mL of aceto-
nitrile at room temperature for 12 h. Yields of isolated prod-
ucts are given.
AHCTUNGTRENNUNG
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Liangbin Huang et al.
Firstly, but-3-en-1-amine was chosen for this trans-
formation. Unfortunately, a complicated result was
obtained, and no target product could be isolated
(Scheme 5). However the N-Ts-substituted but-3-en-
1-amine was a suitable coupling partner with alkyn-
AHCTUNGTREGaNNUN mide to afford the corresponding a-methylene-g-lac-
tone 5a with 65% yield. Buta-1,3-dienes also reacted
well, giving 5b and 5c in high yields. Delightfully, di-
ethyl allylphosphonate could react well with alkyn-
AHCTUNGTREGUNaNN mides to generate the corresponding products
(Scheme 5, 5d–5f). It is known that the increasing im-
portance of phosphorus compounds in organic synthe-
sis, materials science, and biology demands efficient
methods to functionalize phosphorus compounds.[37,38]
Furthermore, the chelate effect of sulfone was proven
to be feasible for these transformations (Scheme 5,
5g–5i). A structural motif bearing both a-methylene-
g-lactone and sulfone units would be a useful synthet-
ic intermediate and a privileged medicinal target.[39–44]
On the basis of the above results, a possible reac-
tion mechanism for this Pd-catalyzed cross-coupling
was proposed (Scheme 6). The righthand pathway was
initiated by trans-halopalladation of alkynamide,
which gave the vinylpalladium intermediate I. Subse-
quently, I was captured by the norbornene through
migratory insertion to produce intermediate II. The
isomer IV was generated through the “bridging” pal-
ladium intermediate III.[35,45,46] Then reductive elimi-
nation of IV afforded the product 3a. The Pd(II)
active species was regenerated via oxidation by
Scheme 5. Pd-catalyzed lactonization of electronically non-
biased olefins with alkynamides. Reaction conditions: the re-
actions were carried out with norbornene (0.6 mmol), alkyn-
ACHTUNGTRENNUNGamide (0.5 mmol), PdCl2 (5 mol%), CuCl2·2H2O (3 equiv.)
in 0.5 mL of acetonitrile at room temperature for 12 h.
Yields of isolated products are given.
afforded the respective products in satisfying isolated Cu(II). For the lefthand pathway, I was captured by
yields (Scheme 4, 3n–3p). alkene to produce intermediate V. The amide of the
On the other hand, some terminal olefins were alkynamide cooperated with group A [NHTs, vinyl,
evaluated under the optimized conditions for the Pd- PO(OEt)2, SO2Ph] in the olefin to chelate the Pd
AHCTUNGTRENNUNG
catalyzed lactonization with alkynamides (Scheme 5). center. It is known that the coordinative saturation of
Scheme 6. Proposed mechanism.
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[4] Z. He, B. Wibbeling, A. Studer, Adv. Synth. Catal.
2013, 355, 3639–3647.
[5] Z. He, S. Kirchberg, R. Frçhlich, A. Studer, Angew.
Chem. 2012, 124, 3759–3762; Angew. Chem. Int. Ed.
2012, 51, 3699–3702.
[6] E. W. Werner, M. S. Sigman, J. Am. Chem. Soc. 2011,
133, 9692–9695.
[7] L. Qin, X. Ren, Y. Lu, Y. Li, J. Zhou, Angew. Chem.
2012, 124, 6017–6021; Angew. Chem. Int. Ed. 2012, 51,
5915–5919.
[8] T.-S. Mei, E. W. Werner, A. J. Burckle, M. S. Sigman, J.
Am. Chem. Soc. 2013, 135, 6830–6833.
[9] M. Chen, J. Wang, Z. Chai, C. You, A. Lei, Adv. Synth.
Catal. 2012, 354, 341–346.
[10] Y. Lan, P. Liu, S. G. Newman, M. Lautens, K. N. Houk,
Chem. Sci. 2012, 3, 1987–1995.
[11] S. G. Newman, M. Lautens, J. Am. Chem. Soc. 2011,
133, 1778–1780.
[12] S. G. Newman, J. K. Howell, N. Nicolaus, M. Lautens, J.
Am. Chem. Soc. 2011, 133, 14916–14919.
[13] D. A. Petrone, M. Lischka, M. Lautens, Angew. Chem.
Int. Ed. 2013, 52, 10635–10638.
[14] X. Jia, D. A. Petrone, M. Lautens, Angew. Chem. 2012,
124, 10008–10010; Angew. Chem. Int. Ed. 2012, 51,
9870–9872.
the metal center represents one established strategy
to suppress b-H elimination. The five- or six-mem-
bered palladacycle intermediate V was transformed
to the intermediate VI by isomerization, which was
3
À
followed by C
N
to give the five-membered lactones. Finally, the Pd(II)
active species was regenerated via oxidation by
Cu(II).
In conclusion, we have developed two efficient
methods to suppress the b-H elimination during con-
struction of C-7 functionalized norbornylalkenes and
a-methylene-g-lactone via Pd-catalyzed cross-cou-
pling reactions between alkynamides and alkenes.
This transformation features high reactivity under
mild conditions from easily available materials. Fur-
thermore, the highly functionalized a-methylene-g-
lactone is an important moiety existing in numerous
natural products with biological activities, which also
illustrates that the remote group-assisted strategy is
highly interesting and useful. Therefore, the search
for methods to suppress b-H elimination is still attrac-
tive and further study is underway in our laboratory.
[15] H. Liu, C. Chen, L. Wang, X. Tong, Org. Lett. 2011, 13,
5072–5075.
[16] H. Liu, C. Li, D. Qiu, X. Tong, J. Am. Chem. Soc. 2011,
133, 6187–6193.
[17] K. MuÇiz, Angew. Chem. 2009, 121, 9576–9588; Angew.
Chem. Int. Ed. 2009, 48, 9412–9423.
Experimental Section
Typical Experimental Procedure for the Pd/Cu-
Catalyzed Cross-Coupling of Alkynes and Alkenes
The mixture of alkynamide (0.5 mmol), PdCl2 (5 mol%) or
[18] P. Sehnal, R. J. K. Taylor, I. J. S. Fairlamb, Chem. Rev.
PdACHTUNGTRENNUNG(OAc)2 (5 mol%), olefin (0.6 mmol), CuCl2·2H2O
2010, 110, 824–889.
(3 equiv.) and acetonitrile (0.5 mL) was stirred at room tem-
perature for 12 h. After completion, the reaction was
quenched by the addition of water (10 mL), and the mixture
was extracted with ethyl acetate (3ꢂ10 mL), the combined
extract was dried with MgSO4 and the solvent was evaporat-
ed under vacuum. The residue was separated by chromatog-
raphy on silica gel to give the pure product.
[19] E. M. Beccalli, G. Broggini, M. Martinelli, S. Sottocor-
nola, Chem. Rev. 2007, 107, 5318–5365.
[20] K. Osakada, T. Yamamoto, Coord. Chem. Rev. 2000,
198, 379–399.
[21] K. Sonogashira, Y. Fujikura, T. Yatake, N. Toyoshima,
S. Takahashi, N. Hagihara, J. Organomet. Chem. 1978,
145, 101–108.
[22] C. He, J. Ke, H. Xu, A. Lei, Angew. Chem. 2013, 125,
1567–1570; Angew. Chem. Int. Ed. 2013, 52, 1527–1530.
[23] K. Sonogashira, J. Organomet. Chem. 2002, 653, 46–49.
[24] M. H. Pꢃrez-Temprano, J. A. Casares, P. Espinet, Chem.
Eur. J. 2012, 18, 1864–1884.
Acknowledgements
The authors thank the National Natural Science Foundation
of China (21172076 and 21202046), the National Basic Re-
search Program of China (973 Program; 2011CB808600),
[25] K. Osakada, T. Takizawa, T. Yamamoto, Organometal-
lics 1995, 14, 3531–3538.
[26] L. J. Goossen, G. Deng, L. M. Levy, Science 2006, 313,
662–664.
[27] B. Song, T. Knauber, L. J. Goossen, Angew. Chem.
2013, 125, 3026–3030; Angew. Chem. Int. Ed. 2013, 52,
2954–2958.
Guangdong
Natural
Science
Foundation
(10351064101000000 and S2012040007088) and the Funda-
mental Research Funds for the Central Universities
(2014ZP0004 and 2014ZZ0046) for financial support.
[28] L. J. Goossen, N. Rodrꢄguez, P. P. Lange, C. Linder,
Angew. Chem. 2010, 122, 1129–1132; Angew. Chem.
Int. Ed. 2010, 49, 1111–1114.
References
[29] L. J. Goossen, N. Rodrꢄguez, C. Linder, J. Am. Chem.
Soc. 2008, 130, 15248–15249.
[1] C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Cola-
cot, V. Snieckus, Angew. Chem. 2012, 124, 5150–5174;
Angew. Chem. Int. Ed. 2012, 51, 5062–5085.
[2] J. Le Bras, J. Muzart, Chem. Rev. 2011, 111, 1170–1214.
[3] I. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 2000,
100, 3009–3066.
[30] L. J. Goossen, N. Rodrꢄguez, B. Melzer, C. Linder, G.
Deng, L. M. Levy, J. Am. Chem. Soc. 2007, 129, 4824–
4833.
[31] Y. Wen, L. Huang, H. Jiang, H. Chen, J. Org. Chem.
2012, 77, 2029–2034.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
Liangbin Huang et al.
[32] L. Huang, Q. Wang, X. Liu, H. Jiang, Angew. Chem.
2012, 124, 5794–5798; Angew. Chem. Int. Ed. 2012, 51,
5696–5700.
[33] P. Zhou, L. Huang, H. Jiang, A. Wang, X. Li, J. Org.
Chem. 2010, 75, 8279–8282.
[39] M. G. Edwards, M. N. Kenworthy, R. R. A. Kitson,
M. S. Scott, R. J. K. Taylor, Angew. Chem. 2008, 120,
1961–1963; Angew. Chem. Int. Ed. 2008, 47, 1935–1937.
[40] H. M. R. Hoffmann, J. Rabe, Angew. Chem. 1985, 97,
96–112; Angew. Chem. Int. Ed. Engl. 1985, 24, 94–110.
[41] R. R. A. Kitson, A. Millemaggi, R. J. K. Taylor, Angew.
Chem. 2009, 121, 9590–9615; Angew. Chem. Int. Ed.
2009, 48, 9426–9451.
[34] P. Zhou, H. Jiang, L. Huang, X. Li, Chem. Commun.
2011, 47, 1003–1005.
[35] Y. Li, X. Liu, H. Jiang, B. Liu, Z. Chen, P. Zhou,
Angew. Chem. 2011, 123, 6465–6469; Angew. Chem.
Int. Ed. 2011, 50, 6341–6345.
[42] A. Albrecht, Ł. Albrecht, T. Janecki, Eur. J. Org.
Chem. 2011, 2747–2766.
[36] CCDC 978952 contains the supplementary crystallo-
graphic data for compound 3a. These data can be ob-
tained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
[43] M. G. Edwards, M. N. Kenworthy, R. R. A. Kitson, A.
Perry, M. S. Scott, A. C. Whitwood, R. J. K. Taylor,
Eur. J. Org. Chem. 2008, 4769–4783.
[44] T. P. Montgomery, A. Hassan, B. Y. Park, M. J. Krische,
J. Am. Chem. Soc. 2012, 134, 11100–11103.
[37] Y.-C. Kim, S. G. Brown, T. K. Harden, J. L. Boyer, G.
Dubyak, B. F. King, G. Burnstock, K. A. Jacobson, J.
Med. Chem. 2001, 44, 340–349.
[38] T. Baumgartner, R. Rꢃau, Chem. Rev. 2006, 106, 4681–
4727.
[45] F. Chauvet, A. Heumann, B. Waegell, J. Org. Chem.
1987, 52, 1916–1922.
[46] L. F. Lourie, Y. A. Serguchev, G. V. Shevchenko, M. V.
Ponomarenko, A. N. Chernega, E. B. Rusanov, J. A. K.
Howard, J. Fluorine Chem. 2006, 127, 377–385.
6
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Palladium/Copper Bimetallic System-Mediated Cross-
Coupling of Alkynes and Alkenes: Two Strategies to
Suppress b-H Elimination on Alkyl-Palladium Center
7
Adv. Synth. Catal. 2014, 356, 1 – 7
Liangbin Huang, Qian Wang, Wanqing Wu,
Huanfeng Jiang*
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