Copper-catalyzed three-component coupling of arynes, terminal alkynes and activated alkenes

Article abstract of DOI:10.1039/b809409h

The three-component coupling of benzynes with terminal alkynes and activated alkenes in the presence of CuI, PCy₃ and CsF in a 1: 1 mixture of CH₃CN and THF at 50°C for 5 h gave 1-alkyl-2-alkynylbenzenes in good to moderate yields. The Royal Society of Chemistry.

Full text of DOI:10.1039/b809409h

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Copper-catalyzed three-component coupling of arynes, terminal alkynes
and activated alkenesw
Sivakolundu Bhuvaneswari, Masilamani Jeganmohan and Chien-Hong Cheng*
Received (in Cambridge, UK) 3rd June 2008, Accepted 10th July 2008
First published as an Advance Article on the web 1st September 2008
DOI: 10.1039/b809409h
The three-component coupling of benzynes with terminal alkynes
and activated alkenes in the presence of CuI, PCy3 and CsF in a
1 : 1 mixture of CH3CN and THF at 50 1C for 5 h gave 1-alkyl-
2-alkynylbenzenes in good to moderate yields.
the three-component coupling of benzynes with terminal
alkynes and alkenes. Herein, we wish to report this new
copper-catalyzed reaction.
The reaction of (2-(trimethylsilyl)-3,4-dimethylphenyl tri-
flate) 1a with 1-hexyne (2a) and ethyl vinyl ketone (3a) in
the presence of CuI (10 mol%), PCy3 (2 mol%) and CsF
(3.0 equiv.) in a 1 : 1 (v/v) ratio of THF and CH3CN at 50 1C
for 5 h gave three-component coupling product 4a in 82%
isolated yield (Table 1, entry 1). No three-component coupling
reaction occurs in the absence of either CuI or ligand. The
product formation of 4a can be explained by alkynylcupration
of benzyne with cuprous acetylide to give 2-alkynylphenyl-
cuprous reagent followed by 1,4-addition to activated alkenes
(vide infra).
Transition metal-catalyzed aryne-involving three-component
coupling reaction to form two different carbon–carbon bonds
at the two adjacent aryne carbons has drawn substantial
attention recently in organic synthesis.1–9 In 2000, Yamamoto’s
group reported a palladium-catalyzed carbocyclization of
arynes with alkynes and allylic halides and also a bisallylation
of arynes with allyl chloride and allyl stannane.1 Chatani et al.
reported a palladium-catalyzed carbocyclization of arynes with
allylic halides and CO.2 We reported a palladium-catalyzed
three-component coupling of benzynes with allylic
halides or acetates and organometallic reagents3 and also a
carbocyclization of arynes with aromatic iodides and bicyclic
alkenes.4 Larock’s group described a palladium catalyzed
carbocyclization of arynes with aromatic iodides and alkynes.5
Greaney and co-workers showed three-component Heck type
coupling of arynes with organic halides and alkenes.6 Very
recently, Zhang and co-workers observed a copper-catalyzed
three-component coupling of benzynes with terminal alkynes
and allylic halides.7
The phosphine ligand used is crucial for the success of the
present reaction. Various phosphine ligands (10 mol%) such
as PPh3, PCy3, P(n-Bu3), P(o-tolyl)3, P(o-anisyl)3, P(p-anisyl)3,
P(2-furyl)3, dppe and dppb were examined for the reaction of
1a with 2a and 3a in the presence of CuI (5 mol%) in a 1 : 1
ratio of THF and CH3CN at 50 1C for 5 h. Among them,
highly electron-rich and sterically hindered PCy3 gave 4a in
75% yield. Other phosphine ligands were less effective for the
reaction providing 4a in only 10–35% yields. In all these
reactions, a side product 4-(hex-1-ynyl)-1,2-dimethylbenzene
(5a) from addition of 1-hexyne to 3,4-dimethylbenzyne was
observed in various amounts. In order to suppress the forma-
tion of this side product, different ratios of PCy3 and CuI, 2 : 1,
3 : 1, 2 : 5 and 1 : 5 were tested. No side product was observed
when the ratio is 1 : 5 (PCy3, 2 mol%; CuI, 10 mol%) and the
expected product 4a was formed in 89% yield.
Recently, we demonstrated
a nickel-catalyzed three-
component coupling of arynes with activated alkenes and
organoboronic acids.8 In the reaction, alkenyl and aromatic
boronic acids worked very well, but alkynylmetal reagents
such as alkynyltin was not active as an organometallic regent
for the nickel-catalyzed three-component coupling reaction. In
the effort to develop an efficient method for three-component
coupling of arynes with activated alkenes and alkynylation
reagents, we tested the reaction with various alkynylmetal
reagents. In the presence of catalytic amounts of CuI,
Ni(COD)2 and PCy3 (tricyclohexylphosphine), 3,4-dimethyl-
benzyne precursor 1a, CsF, terminal alkyne 2a and ethyl vinyl
ketone (3a) underwent a three-component coupling reaction to
give 4a in good yield. However, during optimization studies we
were surprised that in the absence of nickel catalyst, copper(I)
in the presence of a phosphine ligand can serve as a catalyst in
The use of binary solvent system improved the product yield
of the present reaction. If the catalytic reaction was carried out
in CH3CN alone, product 4a was produced in 55% yield along
with side product 5a in 45% yield. In the 1 : 1 binary solvent
systems of CH3CN with THF, CH2Cl2, toluene or DME, the
CH3CN–THF and CH3CN–CH2Cl2 mixtures gave 4a in 89
and 87% yields, respectively. The other binary systems
afforded 4a in 35 and 20% yields, respectively. The catalytic
activity of various cuprous halides, CuI, CuBr, CuCl and
CuCN were examined. CuI appears to have the highest
activity giving 4a in 89% yield. The others afforded 4a in 75,
69 and 55% yields, respectively. Based on these optimization
studies, we chose CuI (10 mol%), PCy3 (2 mol%) in a mixture
of CH3CN and THF (1 : 1) as the standard catalytic condi-
tions for the studies shown in Table 1.
Department of Chemistry, National Tsing Hua University, Hsinchu,
30013, Taiwan. E-mail: chcheng@mx.nthu.edu.tw;
Fax: 886-3-5724698; Tel: 886-3-5721454
w Electronic supplementary information (ESI) available: General
experimental procedure, spectral data (1H, 13C NMR and HRMS)
and copies of 1H and 13C NMR spectra of all compounds. See DOI:
10.1039/b809409h
Under the standard reaction conditions, other benzyne
precursors 1b–e also reacted smoothly with 2a and 3a
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Table 1 Results of the three-component coupling of arynes 1a–e,
1-hexyne 2a and ethyl vinyl ketone 3aa
CuI 5 mol%), PCy3 (10 mol%) and various inorganic bases
such as Li2CO3, Na2CO3, K2CO3 and Cs2CO3 in a 1 : 1 ratio
of CH2Cl2 and CH3CN at 50 1C for 5 h. Among them, K2CO3
Table 2 Results of the three-component coupling of arynes 1a–b with
various terminal alkynes 2 and activated alkenes 3a
Entry 1
2
3
Product 4
Yield (%)b
1
2
3
4
1b 2b 3a
1b 2c 3a
1b 2d 3a
1b 2e 3a
4f: R3 = n-octyl 77 (85)
75 (83)
4g: R3 = t-Bu
4h: R3 = Ph
59c
4i: R3 = 3-thienyl 56c
5
1b 2f 3a
4j
79 (85)
6
1a 2g 3a
4k: R3 = CO2Me 76d
a
Unless otherwise mentioned, all reactions were carried out using
7
8
1a 2h 3a
1b 2a 3b
4l
72
79
benzyne precursor 1 (1.0 mmol), 1-hexyne 2 (1.0 mmol), ethyl vinyl
ketone 3 (2.0 mmol), CuI (10 mol%), PCy3 (2 mol%), CsF (3.0 mmol)
and CH3CN–THF (1 : 1) at 50 1C for 5 h. bIsolated yields; yield in the
parenthesis was determined by 1H NMR using mesitylene as an
internal standard. cReaction was carried out using CuI (5 mol%),
PCy3 (10 mol%) and K2CO3 (1.5 mmol). dThe regioisomeric ratio
4e : 4e0 is 1 : 1.
4m
(Table 1). Thus, benzyne precursor 1b gave 4b in 65% isolated
yield (entry 2). In addition, a side product hex-1-ynylbenzene
(5b) from addition of 1-hexyne to benzyne was observed in
25% isolated yield. Electron-rich benzyne precursors 1c and 1d
afforded the corresponding products 4c and 4d in 81 and 75%
yields, respectively (entries 3 and 4). As expected, the reaction
of 4-methylbenzyne precursor 1e gave a mixture of regio-
isomeric products 4e and 4e0 in ca. a 1 : 1 ratio in 79%
combined yields (entry 5). It should be noted that no direct
addition of alkyne with benzyne was observed in the reactions
of electron-rich benzyne precursors (entries 1, 3–5) with 2a and
3a and the product yields are higher than that using unsub-
stituted benzyne as the substrate (entry 2). In order to suppress
the side reaction of unsubstituted benzyne with 1-hexyne, the
reaction of 1b with 2a and 3a was examined in the presence of
9
1b 2a 3c
1b 2a 2d
1b 2a 3e
1b 2a 3f
4n: R4 = CO2Et 65c
4o: R4 = CO2Me 67c
10
11
12
4p: R4 = CN
39c
4q: R4 = SO2Ph 32c
a
Unless otherwise mentioned, all reactions were carried out using
benzyne precursor 1 (1.0 mmol), terminal alkyne 2 (1.0 mmol),
activated alkene 3 (2.0 mmol), CuI (5 mol%), PCy3 (10 mol%), CsF
(2.5 mmol), K2CO3 (1.5 mmol) and CH3CN–CH2Cl2 (1 : 1) at 50 1C
b
1
for 5 h. Isolated yields; yields in parenthesis were determined by H
c
NMR using mesitylene as an internal standard. The direct addition
of terminal alkyne to benzyne was observed. In these reactions,
3.0 mmol of activated alkene and 2.5 mmol of K2CO3 were used.
For entries 11 and 12, the catalytic reaction was carried out at 70 1C
d
for 5 h. The catalytic reaction was carried out at 50 1C for 12 h.
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gave 4b in 87% yield without the formation of side product
hex-1-ynylbenzene (5b).7 Others afforded 4b in 75, 60 and 55%
yields, respectively, along with a side product 5b in various
amounts. K2CO3 is probably used as a base to neutralize the
proton released during the alkynylcupration of benzyne.10
The reaction conditions were also effective for electron-rich
benzyne precursors 1a and 1c–e. In the reaction, the corre-
sponding three-component coupling products 4a, 4c–e were
observed in 82, 79, 77 and 80% yields, respectively. The
reaction conditions were employed also for the studies shown
in Table 2.
The present three-component coupling reaction was success-
fully extended to various terminal alkynes (Table 2). Thus,
1-decayne (2b) and tert-butylacetylene (2c) reacted with 1b and
3a providing 4f and 4g in 77 and 75% yields, respectively
(entries 1 and 2). Phenyl acetylene (2d) and 3-ethynylthiophene
(2e) furnished 4h and 4i in 59 and 56% yields, respectively
(entries 3 and 4). In addition to 4h and 4i, side products
diphenyl acetylene (5c) and 3-(phenylethynyl)thiophene (5d)
were observed in 31 and 34% isolated yields, respectively.
1-Ethynylcyclohex-1-ene (2f) afforded 4j in 79% yield (entry
5). Under similar reaction conditions, methyl hex-5-ynoate
(2g) and prop-2-ynylcyclopentane (2h) also reacted efficiently
with 1a and 3a to afford three-component coupling products
4k and 4l in 76 and 72% yields, respectively (entries 6 and 7).
In addition to ethyl vinyl ketone (3a), n-propyl vinyl ketone
(3b) also underwent coupling reaction effectively with 1b and
2a to give 4m in 79% yield (entry 8). Other activated alkenes
such as ethyl acrylate (3c), methyl acrylate (3d), acrylonitrile
(3e) and vinylsulfonylbenzene (3f) also efficiently participated
in the coupling reaction with 1b and 2a to give coupling
products 4n–q in 65, 67, 39 and 32% yields, respectively
(entries 9–12). In these reactions, a side product hex-1-ynyl-
benzene (5b) was observed in 24, 21, 49 and 52% isolated
yields, respectively.
Scheme 1
with other p-components and organometallic reagents and
detailed mechanistic investigation are in progress.
We thank the National Science Council of Republic of
China (NSC-96-2113-M-007-020-MY3) for support of this
research.
Notes and references
1 (a) E. Yoshikawa, K. V. Radhakrishnan and Y. Yamamoto,
J. Am. Chem. Soc., 2000, 122, 7280; (b) E. Yoshikawa, K. V.
Radhakrishnan and Y. Yamamoto, Tetrahedron Lett., 2000, 41,
729.
2 N. Chatani, A. Kamitani, M. Oshita, Y. Fukumoto and S. Murai,
J. Am. Chem. Soc., 2001, 123, 12686.
3 (a) M. Jeganmohan and C.-H. Cheng, Org. Lett., 2004, 6, 2821; (b)
M. Jeganmohan and C.-H. Cheng, Synthesis, 2005, 5, 1693; (c) T.
T. Jayanth, M. Jeganmohan and C.-H. Cheng, Org. Lett., 2005, 7,
2921; (d) S. Bhuvaneswari, M. Jeganmohan and C.-H. Cheng,
Chem. Commun., 2008, 2158.
4 S. Bhuvaneswari, M. Jeganmohan and C.-H. Cheng, Org. Lett.,
2006, 8, 5581.
5 Z. Liu and R. C. Larock, Angew. Chem., Int. Ed., 2007, 46, 2535.
6 (a) J. L. Henderson, A. S. Edwards and M. F. Greaney, J. Am.
Chem. Soc., 2006, 128, 7426; (b) J. L. Henderson, A. S. Edwards
and M. F. Greaney, Org. Lett., 2007, 9, 5589.
7 While preparing the manuscript, a report of copper-catalyzed
three-component coupling of benzynes with terminal alkynes and
allylic halides was appeared in the literature. In the reaction,
K2CO3 was used to suppress the direct addition of terminal alkyne
to benzyne. See: C. Xie, L. Liu, Y. Zhang and P. Xu, Org. Lett.,
2008, 10, 2393.
A possible reaction mechanism for the present three-com-
ponent coupling reaction is shown in Scheme 1. Reaction of
terminal alkyne with Cu(I) species in the presence of CsF
(or K2CO3) gives copper acetylide 6. Alkynylcupration of
benzyne11 with cuprous acetylide 6 affords arylcuprous inter-
mediate 7. Conjugate addition of 7 to activated alkene 3 gives
intermediate 8. Protonation of intermediate 8 gives product 4
with regeneration of the catalyst. The observation of a side
8 T. T. Jayanth and C.-H. Cheng, Angew. Chem., Int. Ed., 2007, 46,
5927.
9 Selected literature references for transition metal-catalyzed
aryne-involving reactions: [2+2+2] Co-cylotrimerization reac-
tions: (a) E. Guitian, D. Perez and D. Pena, Top. Organomet.
Chem., 2005, 14, 109; (b) T. T. Jayanth, M. Jeganmohan and C.-H.
Cheng, J. Org. Chem., 2004, 69, 8445; (c) J.-C. Hsieh, D. K.
Rayabarapu and C.-H. Cheng, Chem. Commun., 2004, 532; (d)
J.-C. Hsieh and C.-H. Cheng, Chem. Commun., 2005, 2459.
Bismetallation of arynes: (e) H. Yoshida, J. Ikadai, M. Shudo,
J. Ohshita and A. Kunai, J. Am. Chem. Soc., 2003, 125, 6638; (f) H.
Yoshida, K. Tanino, J. Ohshita and A. Kunai, Angew. Chem., Int.
Ed., 2004, 43, 5052. Carbocyclization reaction: (g) T. T. Jayanth
and C.-H. Cheng, Chem. Commun., 2006, 894.
product 1-aryl-1-alkyne can be explained by the protonation
ꢁ
of intermediate 7 in the presence of HF or HCO3
.
In conclusion, we have developed a copper(I)-catalyzed three-
component coupling of arynes with terminal alkynes and
activated alkenes providing 1-alkyl-2-alkynylbenzenes. In most
of the three-component coupling reactions, only palladium and
nickel complexes were generally employed. This new copper-
catalyzed reaction highlights the potential of using copper as an
inexpensive and efficient catalyst for the three-component
coupling reactions. Further extension of this coupling reaction
10 A. B. Dounay and L. E. Overman, Chem. Rev., 2003, 103, 2945.
11 Benzyne generation: Y. Himeshima, T. Sonoda and H. Kobayashi,
Chem. Lett., 1983, 1211.
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