A cooperative copper- and palladium-catalyzed three-component coupling of benzynes, allylic epoxides, and terminal alkynes

Article abstract of DOI:10.1002/anie.200804873

(Chemical Equation Presented) A little cooperation: A cooperative copper- and palladium-catalyzed highly regio- and chemoselective three-component coupling of benzynes, allylic epoxides, and terminal alkynes provides an efficient atom-economical route to

Full text of DOI:10.1002/anie.200804873

Angewandte
Chemie
DOI: 10.1002/anie.200804873
Multicomponent Reactions
A Cooperative Copper- and Palladium-Catalyzed Three-Component
Coupling of Benzynes, Allylic Epoxides, and Terminal Alkynes**
Masilamani Jeganmohan, Sivakolundu Bhuvaneswari, and Chien-Hong Cheng*
The transition-metal-catalyzed three-component sequential
coupling of electrophiles and nucleophiles to carbon–carbon
p-components, such as alkynes, alkenes, and allenes, is an
ideal method in organic synthesis for constructing two
different consecutive carbon–carbon bonds from simple
starting materials in one pot.[1] Over the past decade, the
use of benzyne as a carbon–carbon p-component has
attracted considerable attention, owing to its capability of
À
efficiently constructing two different C C bonds ortho to
each other on a benzene ring in one pot.[2–4]
Whereas several allylic electrophiles, such as allylic
acetates, carbonates and halides, are successfully used in
three-component sequential coupling reactions, to our knowl-
edge, no such reaction using an allylic epoxide as an electro-
phile has to date been reported, most likely as a result of
complicated selectivity problems, which arise from the four
potential reactive carbon centers of allylic epoxides.[5]
In recent years, dual-metal-catalyzed reactions have
gained much attention in organic transformations, owing to
their ability in enhancing selectivity and reactivity in reac-
tions.[6] Herein, we wish to report for the first time a
cooperative palladium- and copper-catalyzed highly regio-
and chemoselective atom-economical three-component cou-
pling of benzynes with allylic epoxides and terminal alkynes.
This reaction provides an efficient strategy for the synthesis of
ortho-disubstituted arenes containing alkynyl and 4-hydroxy-
2-butenyl groups. This type of compound is useful as a
synthetic intermediate in various organic reactions.[7]
The reaction of benzyne precursor 1a with 2-vinyloxirane
(2a) and 1-hexyne (3a) in the presence of [Pd(PPh3)4]
(5.0 mol%) and CsF (3.0 equiv) in a 1:1 mixture of CH3CN
and toluene at 508C for 12 h gave two regioisomeric three-
component coupling products, 4a and 5a, in a 62:38 ratio in
79% combined yield [Eq. (1)]. No three-component coupling
reaction occurred in the absence of palladium catalyst.
To understand the nature of the present coupling reaction
and improve its regioselectivity, the activities of various
palladium phosphine complexes were examined (for detailed
studies, see the Supporting Information). A substantial
change in the regioselectivity occurred when the bidentate
phosphine complex system [Pd(dba)2]/dppp was used (dba =
dibenzylideneacetone, dppp = 1,3-bis(diphenylphosphanyl)-
propane). Products 4a and 5a were formed in an 80:20 ratio
in 69% combined yield. The addition of CuI to the reaction
mixture led to further improvement of the regioselectivity,
producing 4a exclusively in 81% isolated yield. The catalytic
reaction is also highly stereoselective, giving only the
E stereoisomer. In the absence of palladium complex, CuI,
alone with phosphine ligand, gave only the hydroalkynylation
ꢀ À
product PhC C nBu (6a). Based on these studies, we used,
as the standard catalytic conditions, [Pd(dba)2] (5 mol%),
dppp (5 mol%), and CuI (5 mol%), in a 1:1 mixture of
CH3CN and toluene.
To explore the scope of present reaction, the reactions of
substituted benzyne precursors 1b–f with 2a and 3a were
examined (Table 1). Electron-rich 3,4-dimethyl-substituted
1b provided 4b in 87% yield (Table 1, entry 1). Other
electron-rich precursors 1c and 1d afforded 4c and 4d in
84% and 77% yields, respectively (Table 1, entries 2 and 3).
Electron-deficient 3,4-diflurobenzyne precursor 1e gave 4e in
moderate 63% yield (Table 1, entry 4). As expected, an
approximately 50:50 mixture of regioisomeric products 4 f
and 4 f’ in 85% combined yield was detected for the 4-methyl-
substituted precursor 1 f (Table 1, entry 5).
We next examined the effect on the reaction of various
substituted allylic epoxides 2b–e with 1a and 2a (Table 1). All
of these reactions were completely regioselective, although
stereoselectivity varied with the epoxides used. For 2-methyl-
2-vinyloxirane 2b, the reaction gave 4g in 57% yield in
ꢀ
addition to hydroalkynylation product PhC C-nBu3 (6a,
[*] Dr. M. Jeganmohan, S. Bhuvaneswari, Prof. Dr. C.-H. Cheng
Department of Chemistry, National Tsing Hua University
Hsinchu 30013 (Taiwan)
35% yield). In order to suppress hydroalkynylation, the
reaction was carried out in the absence of CuI. In this case no
hydroalkynylation product was detected and the yield of the
three-component coupling product 4g was increased to 79%
with an 85:15 E/Z stereoisomeric ratio (Table 1, entry 6).
Similarly, 2-phenyl-2-vinyloxirane (2c) provided 4h in 75%
yield with an 80:20 E/Z stereoisomeric ratio (Table 1,
entry 7). Under the optimized reaction conditions, isoprene
Fax: (+886)3572-4698
E-mail: chcheng@mx.nthu.edu.tw
[**] We thank the National Science Council of the Republic of China
(NSC 96-2113M-007-020-MY3) for support of this research.
Supporting Information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200804873.
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Table 1: Results of the three component coupling of benzynes with allylic
epoxides and 1-hexyne (3a).[a]
Table 2: Results of the three component coupling of benzyne 1a, 2-
vinyloxirane 2a, and terminal alkynes 3b–k.[a]
Entry
1
2
4
Yield
[%][b]
Entry
3
4
Yield [%][b]
1
2
87
92
1
2
3
4
5
87
84
77
63
85
2a
2a
2a
2a
3
72
4
5
83
79[c]
6
77
6
7
1a
1a
79[c,d]
7
8
76
59[c]
75[c,d]
9
82
80
8
9
1a
1b
69[d]
74
10
[a] Unless otherwise stated, all reactions were carried out using benzyne
1 (1.1 mmol), allylic epoxide 2 (1.2 mmol), 1-hexyne 3 (1.0 mmol),
[Pd(dba)2] (5 mol%), dppp (5 mol%), CuI (5 mol%), CsF (3.0 mmol) in
CH3CN/toluene (8.0 mL, 1:1 mixture) at 508C for 12 h. [b] Yields of
isolated product. [c] The reaction was carried out at 708C.
[a] Unless otherwise stated, all reactions were carried out using benzyne
1 (1.1 mmol), allylic epoxide 2 (1.2 mmol), 1-hexyne 3 (1.0 mmol),
[Pd(dba)2] (5 mol%), dppp (5 mol%), CuI (5 mol%), CsF (3.0 mmol) in
CH3CN/toluene (8.0 mL, 1:1 mixture) at 508C for 12 h. dba=dibenzyl-
ideneacetone; dppp=1,3-bis(diphenylphosphanyl)propane. [b] Yields of
isolated product. [c] The catalytic reaction was carried out with a catalytic
system of [Pd(dba)2] (5 mol%) and tri-2-furylphosphine (20 mol%) in
CH3CN (6 mL). [d] E/Z stereoisomeric ratio: 4g 85:15, 4h 80:20,
4i 82:18.
thiophene (3d) afforded 4m in 72% yield (Table 2, entry 3).
Other terminal acetylenes, including tert-butyl acetylene (3e),
methyl propargyl ether (3 f), propargyl acrylate (3g), methyl
hex-5-ynoate (3h), and pent-4-yn-1-ol (3i), afforded 4n–r in
83, 79, 77, 76, and 59% yields, respectively (Table 2, entries 4–
8). The catalytic reaction conditions are tolerant to the
presence of functional groups OMe, CO2Me, S, and OH on
the terminal alkynes 3. In addition, 1,3-enynes, 3j and 3k, also
efficiently participated in the reaction, giving products 4s and
4t in 82 and 80% yields, respectively (Table 2, entries 9 and
10).
epoxide (2d) afforded a three-component coupling product 4i
in 69% yield with an 82:18 E/Z stereoisomeric ratio (Table 1,
entry 8). In the reaction, the hydroalkynylation product
ꢀ
PhC C-nBu (6a) was detected in 22% yield. Interestingly,
the reaction of a cis/trans mixture (45:55) of 2-phenyl-3-
vinyloxirane 2e[8] with 1b and 3a gave only the E isomer 4j in
74% yield (Table 1, entry 9).
The scope of this method was further examined with
various terminal alkynes (Table 2). Phenyl acetylene (3b) and
4-methoxy phenyl acetylene (3c) reacted with 1a and 2a
providing 4k and 4l in 87 and 92% yields, respectively
(Table 2, entries 1 and 2). The heterocyclic alkyne, 3-ethynyl
For further understanding of regioselectivity in the
present catalytic reaction, the reaction of substituted 2,3-
divinyloxiranes 2 f and g with 1b and 3a was investigated in
the presence of [Pd(dba)2]/dppp (see below). In this case, a
29:71 cis/trans mixture of 2 f (R3 = Ph)[8] afforded only the
392
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E isomer 4u in 75% yield, in a highly regio-, stereo- and
chemoselective manner. Similarly, a 25:75 cis/trans mixture of
2-(but-1-enyl)-3-vinyloxirane (2g)[8] provided the E isomer
4v in 73% yield. In this reaction, there were four possible
reaction sites, but reaction only occurred at the less-hindered
unsubstituted alkene carbon of 2 f and g.
addition of copper reagents or organometallic reagents to
palladium p-allyl complexes.[5,11]
For the three-component coupling reaction catalyzed by
palladium complex alone, the mechanism is likely similar to
that proposed for the reaction of benzynes, allyl chlorides and
alkynylstannanes.[2d]
In the presence of [AuCl(PPh3)] (2 mol%) and AgSbF6
(6 mol%), in CH2Cl2 at room temperature for 6 h, product
4m underwent cyclization to give substituted 1,4-dioxane
derivative 10a in 79% yield in a highly regioselective manner
(Scheme 2). The reaction occurs by the intramolecular 6-
endo-dig cyclization of the enyne group in 4m, to provide
A proposed mechanism for the cooperatively palladium-
and copper-catalyzed three-component coupling (Scheme 1)
incorporates two catalytic cycles, operating in tandem. In the
Scheme 2. Gold-catalyzed cyclization of 4.
intermediate 11, followed by dimerization of 11.[7a,12] The
structure of 10a was confirmed by X-ray crystallographic
studies. Under similar reaction conditions, 4l and 4o also
underwent cyclization in a highly regioselective manner to
give products 10b and c in 83 and 75% yields, respectively. To
our knowledge this cyclization is to date unprecedented in
literature.[7a,12]
Scheme 1. Proposed mechanism of palladium- and copper-catalyzed
three-component coupling reaction.
In summary, we have demonstrated a cooperative palla-
dium- and copper-catalyzed atom-economical three-compo-
nent coupling of benzynes with allylic epoxides and terminal
alkynes. Although, the three-component reaction also pro-
ceeds in the presence of the palladium complex alone without
CuI, the dual-metal catalyst system greatly enhances the
regioselectivity of the reaction. Extension of this three-
component reaction to other carbon–carbon p-components
and detailed mechanistic studies of the catalytic reaction are
in progress.
copper catalytic cycle, the reaction is initiated by the
formation of cuprous acetylide 6 from terminal alkyne 3
and CuI in the presence of CsF. Alkynylcupration of
benzyne[9] with cuprous acetylide 6 affords arylcuprous
intermediate 7.[10] Attack of 7 at the less hindered unsub-
stituted carbon of the p-allyl group or at the palladium center
of p-allylpalladium intermediate 8 affords the Pd0 intermedi-
ate 9 and regenerates the CuI species. Dissociation of product
4 from 9 regenerates the Pd0 active catalyst, which then
undergoes oxidative addition with allylic epoxide 2 to form
intermediate 8 for further reaction with 7.
Received: October 6, 2008
Published online: December 3, 2008
The proposed alkynylcupration of benzyne with cuprous
acetylide 6 in the present dual-metal-catalyzed reaction is
supported by: a) the formation of hydroalkynylation products
as side products in the catalytic reactions; b) the facile
hydroalkynylation of benzynes by terminal alkynes, catalyzed
by the CuI/dppp or dppe system; c) the recently reported CuI-
catalyzed three-component coupling reaction involving
arynes and terminal alkynes;[10] d) the known nucleophilic
Keywords: arynes · copper · cross-coupling · cyclization ·
palladium
.
[1] a) M. Jeganmohan, C.-H. Cheng, Chem. Commun. 2008, 3101;
b) H. Kuniyasu, H. Kurosawa, Chem. Eur. J. 2002, 8, 2660; c) S.
Ikeda, Acc. Chem. Res. 2001, 34, 511; d) E.-I. Negishi, C. Copret,
Angew. Chem. Int. Ed. 2009, 48, 391 –394
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
393

Communications
S. Ma, S.-Y. Liou, F. Liu, Chem. Rev. 1996, 96, 365; e) I.
Nakamura, Y. Yamamoto, Chem. Rev. 2004, 104, 2127; f) S. Ma,
Chem. Rev. 2005, 105, 2829.
[5] C. Courillon, S. Thorimbert, M. Malacria in Handbook of
Organopalladium Chemistry for Organic Synthesis (Ed.: E.-I.
Negishi), Wiley, New York, 2002, chap. V.2.1.5, pp. 1795.
[6] S. Kamijo, Y. Yamamoto in Multimetallic Catalysis in Organic
Synthesis (Eds.: M. Shibasaki, Y. Yamamoto), Wiley-VCH,
Weinheim, 2004, chap. 1.
[7] Selected references: a) A. Fꢀrstner, P. W. Davies, Angew. Chem.
2007, 119, 3478; Angew. Chem. Int. Ed. 2007, 46, 3410; b) I. J. S.
Fairlamb, Angew. Chem. 2004, 116, 1066; Angew. Chem. Int. Ed.
2004, 43, 1048.
[8] D. W. Lupton, D. K. Taylor, Tetrahedron 2002, 58, 4517.
[9] Benzyne generation: Y. Himeshima, T. Sonoda, H. Kobayashi,
Chem. Lett. 1983, 1211.
[10] a) C. Xie, L. Liu, Y. Zhang, P. Xu, Org. Lett. 2008, 10, 2393; b) S.
Bhuvaneswari, M. Jeganmohan, C.-H. Cheng, Chem. Commun.
2008, 5013.
[11] a) H. Matsuhashi, S. Asai, K. Hirabayashi, Y. Hatanaka, A.
Mori, T. Hiyama, Bull. Chem. Soc. Jpn. 1997, 70, 1493; b) A. M.
Echavarren, D. R. Tueting, J. K. Stille, J. Am. Chem. Soc. 1988,
110, 4039; c) J. A. Marshall, Chem. Rev. 1989, 89, 1503.
[12] a) C. Bruneau, Angew. Chem. 2005, 117, 2380; Angew. Chem.
Int. Ed. 2005, 44, 2328; b) Coinage Metals in Organic Synthesis
(Eds.: B. H. Lipshutz, Y. Yamamoto), Chem. Rev. 2008, 108,
3239 – 3442.
[2] a) E. Yoshikawa, K. V. Radhakrishnan, Y. Yamamoto, J. Am.
Chem. Soc. 2000, 122, 7280; b) E. Yoshikawa, K. V. Radhak-
rishnan, Y. Yamamoto, Tetrahedron Lett. 2000, 41, 729; c) N.
Chatani, A. Kamitani, M. Oshita, Y. Fukumoto, S. Murai, J. Am.
Chem. Soc. 2001, 123, 12686; d) M. Jeganmohan, C.-H. Cheng,
Org. Lett. 2004, 6, 2821; e) M. Jeganmohan, C.-H. Cheng,
Synthesis 2005, 1693; f) T. T. Jayanth, M. Jeganmohan, C.-H.
Cheng, Org. Lett. 2005, 7, 2921; g) J. L. Henderson, A. S.
Edwards, M. F. Greaney, J. Am. Chem. Soc. 2006, 128, 7426.
[3] a) J. L. Henderson, A. S. Edwards, M. F. Greaney, Org. Lett.
2007, 9, 5589; b) S. Bhuvaneswari, M. Jeganmohan, C.-H. Cheng,
Org. Lett. 2006, 8, 5581; c) Z. Liu, R. C. Larock, Angew. Chem.
2007, 119, 2587; Angew. Chem. Int. Ed. 2007, 46, 2535; d) T. T.
Jayanth, C.-H. Cheng, Angew. Chem. 2007, 119, 6025 – 6028;
Angew. Chem. Int. Ed. 2007, 46, 5921 – 5924; e) S. Bhuvaneswari,
M. Jeganmohan, C.-H. Cheng, Chem. Commun. 2008, 2158.
[4] Other aryne reactions: Cycloaddition: a) E. Guitian, D. Perez,
D. Pena, Top. Organomet. Chem. 2005, 14, 109; Bimetallation of
arynes: b) H. Yoshida, K. Tanino, J. Ohshita A. Kunai, Angew.
Chem. 2004, 116, 5162; Angew. Chem. Int. Ed. 2004, 43, 5052;
Carbocyclization: c) T. T. Jayanth, T. C.-H. Cheng, Chem.
Commun. 2006, 894.
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