Construction of Caryl-Calkynyl bond from copper-mediated arene-alkyne and aryl iodide-alkyne cross-coupling reactions: A common aryl-CuIII intermediate in arene C-H Activation and castro-stephens reaction

Article abstract of DOI:10.1021/ol300205r

Both copper(II)-mediated oxidative C-H bond activation and oxidative addition of copper(I) into a C-I bond produced an identical and structurally well-defined aryl-Cu(III) intermediate. The cross-coupling reaction of an aryl-Cu(III) intermediate with both terminal alkynes at an elevated temperature and alkynyllithium reagents under mild conditions led effectively to the formation of a C_aryl-C_alkynyl bond. An alternative mechanism has been proposed for the Castro-Stephens reaction.

Full text of DOI:10.1021/ol300205r

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1472–1475
Construction of CarylꢀCalkynyl Bond from
Copper-Mediated AreneꢀAlkyne and Aryl
IodideꢀAlkyne Cross-Coupling Reactions:
A Common Aryl-CuIII Intermediate in Arene
CꢀH Activation and CastroꢀStephens
Reaction
Zu-Li Wang, Liang Zhao, and Mei-Xiang Wang*
MOE Key Laboratory of Bioorganic Phosphorous Chemistry and Chemical Biology,
Department of Chemistry, Tsinghua University, Beijing 100084, China
wangmx@mail.tsinghua.edu.cn
Received January 26, 2012
ABSTRACT
Both copper(II)-mediated oxidative CꢀH bond activation and oxidative addition of copper(I) into a CꢀI bond produced an identical and structurally
well-defined aryl-Cu(III) intermediate. The cross-coupling reaction of an aryl-Cu(III) intermediate with both terminal alkynes at an elevated
temperature and alkynyllithium reagents under mild conditions led effectively to the formation of a CarylꢀCalkynyl bond. An alternative mechanism
has been proposed for the CastroꢀStephens reaction.
The CꢀH bond activation of aromatic compounds
using cost-efficient and eco-benign copper salts has
received considerable attention in recent years.1 Since
Yu’s seminal work of Cu(OAc)2-catalyzed arene CꢀH
functionalization of 2-arylpyridines in 2006,2 a number
of copper salt catalyzed and mediated intramolecular
and intermolecular aryl CꢀH bond transformations
including CꢀX (X = halogen, N, O, and S) and
CarylꢀCaryl bond formations have been reported, either
employing the directing-group strategy or starting with
activated aromatic reactants.3 Despite the burgeoning of
copper salt catalyzed and mediated aryl CꢀH bond
activations and transformations, understanding the re-
action mechanism remains largely elusive and challeng-
ing. For instance, reaction processes involving single
electron transfer2 and organocopper intermediates of
varied oxidative states3b,pꢀs have been hypothesized.
Although organocopper(III) intermediates have been
widely proposed in Cu-catalyzed reactions,4ꢀ6 well-
defined organocopper(III) compounds are scarcely re-
ported.7ꢀ9 Hedman, Hodgson, and Llobet et al.7 reported
in 2002 the aryl-Cu(III) complexes A (Scheme 1) from the
reaction of triazamacrocyclic ligands and Cu(ClO4)2 6H2O
3
under anaerobic conditions.7a The resulting aryl-Cu(III)
complexes A have been shown very recently by Stahl7b,10,11
and Ribas7b,11 to react with heteroatom nucleophiles to
form CꢀN, CꢀO, and carbonꢀhalogen bonds.
(1) Kulkarni, A.; Daugulis, O. Synthesis 2009, 4087.
(2) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 6790.
r
10.1021/ol300205r
Published on Web 03/05/2012
2012 American Chemical Society

Heteracalixaromatics, the heteroatom-bridged calixaro-
matics, are a new generation of functional macrocyclic
host molecules in supramolecular chemistry.12 The diverse
macrocycles from the combination of heteroatoms and
(hetero)aromatic rings, combined with tunable conforma-
tions and cavities of varied electronic features owing to the
nature of the bridging heteroatoms and their ability to
form different conjugation systems with adjacent (hetero)-
aromatic components, render heteracalixaromatics highly
versatile in the recognition of various electron-neutral and
charged guest species and in the construction of supra-
molecular assemblies. We8 have reported recently that
azacalix[1]arene[3]pyridine 1a undergoes highly efficient
alcohols,13 enabling therefore the efficient functionalization
of arene CꢀH bonds. To shed light on the reactivity of
highly valent organocopper compounds and to explore
applications of aryl-Cu(III) complexes in the synthesis of
tailor-made functional heteracalixaromatics, we undertook
the current CꢀC cross-coupling reaction study. We report
herein the unprecedented CarylꢀCalkynyl bond formation
from the cross-coupling of arenes with alkynyllithium re-
agents via the structurally well-defined aryl-Cu(III) inter-
mediates. We also demonstrate for the first time that the
CastroꢀStephens reaction, the Cu(I)-mediated coupling
between aryl halides and terminal alkynes, proceeds via an
arylcopper(III) intermediate, suggesting an alternative re-
action pathway in addition to a believed copper(I)-involved
four-center transition state.
aryl CꢀH bond activation with Cu(ClO4)2 6H2O under
3
mild aerobic conditions to form a stable aryl-Cu(III) com-
pound 2a quantitatively (Scheme 1). At ambient tempera-
ture, aryl-Cu(III) 2a reacts very rapidly with diverse nucleo-
philic reagents including halides,8 various carboxylates,8
cyanide,8 thiocyanate,8 and both aliphatic and aromatic
Scheme 1. Cu(ClO4)2-Mediated Aryl CꢀH Activation
(3) (a) Uemura, T.; Imoto, S.; Chatani, N. Chem. Lett. 2006, 35, 842.
(b) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932.
(c) Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47, 6411. (d)
Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11, 5178. (e) Bernini, R.;
Fabrizi, G.; Sferrazza, A.; Cacchi, S. Angew. Chem., Int. Ed. 2009, 48,
8078. (f) Yang, L.; Lu, Z.; Stahl, S. S. Chem. Commun. 2009, 6460. (g)
Chu, L.; Yue, X.; Qing, F.-L. Org. Lett. 2010, 12, 1644. (h) Wang, W.;
Luo, F.; Zhang, S.; Cheng, J. J. Org. Chem. 2010, 75, 2415. (i) Do, H.-Q.;
Daugulis, O. Org. Lett. 2010, 11, 2517. (j) Tang, B.-X.; Song, R.-J.; Wu,
C.-Y.; Liu, Y.; Zhou, M.-B.; Wei, W.-T.; Deng, G.-B.; Yin, D.-L.; Li, J.-
H. J. Am. Chem. Soc. 2010, 132, 8900. (k) Klein, J. E. M. N.; Perry, A.;
Pugh, D. S.; Taylor, R. J. K. Org. Lett. 2010, 12, 3446. (l) Kawano, T.;
Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc. 2010, 132, 6900. (m)
John, A.; Nicholas, K. M. J. Org. Chem. 2011, 76, 4158. (o) Xu, R.; Wan,
J.-P.; Mao, H.; Pan, Y. J. Am. Chem. Soc. 2010, 132, 15531. (p) Zhang,
L.; Cheng, J.; Ohishi, T.; Hou, Z. Angew. Chem., Int. Ed. 2010, 49, 8670.
(q) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008,
130, 8172. (r) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129,
12404. (s) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1126. (t)
Do, H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130,
15185. (u) Do, H.-Q.; Daugulis, O. Chem. Commun. 2009, 6433. (v)
Kitahara, M.; Umeda, N.; Hirano, K.; Satoh, T.; Mitura, M. J. Am.
Chem. Soc. 2011, 133, 2160. (w) Yao, T.; Hirano, K.; Satoh, T.; Miura,
M. Angew. Chem., Int. Ed. 2011, 50, 2990.
We initiated our study with examination of the reaction
between pure aryl-Cu(III) species 2a and (phenylethynyl)-
lithium 3a (Table 1). At ambient temperature, the reaction
proceeded smoothly in THF to afford the desired cross-
coupling product 4a in 28% yield, along with the isolation
of azacalix[1]arene[3]pyridine 1a in 47% yield and a trace
amount of 1,4-diphenylbuta-1,3-diyne 5a, which formed
most likely from the homocoupling of alkyne (entry 1,
Table 1). The yield of 4a was then improved to 54% when
2 equiv of 3a were used (entry 2, Table 1). A further increase
of the ratio of 3a over 1a only gave rise to a marginal
increase of the chemical yield of 4a (entries 5 and 6, Table 1).
Short reaction times led to a decrease in the formation of 4a
(entry 3, Table 1), while a longer reaction period did not
affect the yield (entry 4, Table 1). The reaction was not very
sensitive to low temperatures (entries 7 and 8, Table 1),
whereas an elevated temperature had a detrimental effect on
the reaction (entry 9, Table 1). It is interesting to note that
oxygen did not interfere with the cross-coupling as the
reaction exposed to oxygen (1 atm) proceeded equally well
to produce 4a in a comparable yield, albeit the oxidative
atmosphere facilitated the formation of homocoupling
product 5a from 3a (entry 10, Table 1). The use of other
solvents such as 1,4-dioxane, diethyl ether, 1,2-dimetho-
xyethane, and toluene resulted in lower yields (see Support-
ing Information (SI)).
(4) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593.
(5) Chen, B.; Hou, X.-L.; Li, Y.-X.; Wu, Y.-D. J. Am. Chem. Soc.
2011, 133, 7668.
(6) (a) Modern Organocopper Chemistry; Krause, N., Ed.; Wiley-VCH,
GmbH: Weinheim, 2002. (b) Monnier, F.; Taillefer, M. Angew. Chem., Int.
Ed. 2009, 48, 6954. (c) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S.
Angew. Chem., Int. Ed. 2011, 50, 11062.
(7) (a) Ribas, X.; Jackson, D. A.; Donnadieu, B.; Mahıa, J.; Parella,
´
T.; Xifra, R.; Hedman, B.; Hodgson, K. O.; Llobet, A.; Stack, T. D. P.
Angew. Chem., Int. Ed. 2002, 41, 2991. Preparation of A under aerobic
conditions was reported in 2010. (b) King, A. E.; Huffman, L. M.;
Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am. Chem. Soc. 2010,
ꢀ
132, 12068. (c) Ribas, X.; Calle, C.; Poater, A.; Casitas, A.; Gomez, L.;
Xifra, R.; Perella, T.; Benet-Buchholz, J.; Schweiger, A.; Mitrikas, G.;
ꢁ
Sola, M.; Llobet, A.; Stack, T. D. J. Am. Chem. Soc. 2010, 132, 12299.
(8) Yao, B.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. Chem. Com-
mun 2009, 2899.
(9) (a) Kinoshita, I.; Wright, L. J.; Kubo, S.; Kimura, K.; Sakata, A.;
Yano, T.; Miyamoto, R.; Nishioka, T.; Isobe, K. Dalton Trans. 2003,
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1993. (b) Pawlicki, M.; Kanska, I.; Latos-Grazynski, L. Inorg. Chem.
_ ꢀ
2007, 46, 6575.
(10) Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 9196.
(11) (a) Casitas, A.; King, A. E.; Parella, T.; Costas, M.; Stahl, S. S.;
Under the optimized conditions, the generality of the
cross-coupling reaction of the aryl-Cu(III) species with
alkynyllithiums was investigated. We were pleased to find
that all alkynyllithiums 3bꢀi tested underwent reaction
with aryl-Cu(III) compounds 2aꢀc to give products 4bꢀm
in 34ꢀ87% yields (Table 2). As assembled in Table 2, for
ꢁ
Ribas, X. Chem. Sic. 2010, 1, 326. (b) Casitas, A.; Poater, A.; Sola, M.;
Stahl, S. S.; Costas, M.; Ribas, X. Dalton Trans. 2010, 39, 10458.
(12) For recent reviews: (a) Wang, M.-X. Acc. Chem. Res. 2012, 45, 182.
(b) Wang, M.-X. Chem. Commun. 2008, 4541. (c) Maes, W.; Dehaen, W.
Chem. Soc. Rev. 2008, 37, 2393. (d) Tuse, H.; Ishibashi, K.; Tamura, R. Top.
Heterocycl. Chem. 2008, 17, 73.
(13) Wang, Z.-L.; Zhao, L.; Wang, M.-X. Org. Lett. 2011, 13, 6560.
Org. Lett., Vol. 14, No. 6, 2012
1473

example, alkynyllithium reagents bearing a benzene ring
thatissubstitutedbyanelectron-donatingor -withdrawing
group (entries 1ꢀ3, Table 2), a 2-thienyl moiety (entry 4,
Table 2), or an aliphatic substituent such as a (cyclohexyl)-
methyl (entry 5, Table 2) and tert-butyl group (entry 6,
Table 2) reacted effectively with 2a to afford the correspond-
ing products 4bꢀg. The reaction of [(trimethylsilyl)-
ethynyl]lithium 3h with 2a proceeded equally efficiently to
yield 4h in 59% yield (entry 7, Table 2). Aryl-Cu(III) com-
plexes containing a para-methyl (2b) or chloro group (2c)
were also good substrates in the cross-coupling reaction
with 3b and 3h, with moderate to good yields of the pro-
ducts 4iꢀl being obtained (entries 8ꢀ11). The reaction of
[(40-ethynylbiphenyl-4-yl)ethynyl]lithium 3i with aryl-
Cu(III) complex 2a was also effective, resulting in the
formation of functionalized macrocycle 4m, albeit in a
slightly lower yield (entry 12, Table 2).
Table 2. Cross-Coupling Reaction between 2 and 3
entry
reactant 2
reactant 3
4 (%)a
1
2a (R1 = H)
2a (R1 = H)
2a (R1 = H)
2a (R1 = H)
2a (R1 = H)
2a (R1 = H)
2a (R1 = H)
2b (R1 = Me)
2b (R1 = Me)
2c (R1 = Cl)
2c (R1 = Cl)
2a (R1 = H)
3b (R2 = 4-t-Bu-C6H4)
3c (R2 = 4-MeO-C6H4)
3d (R2 = 4-F-C6H4)
3e (R2 = 2-thienyl)
3f (R2 = c-C6H11CH2)
3g (R2 = t-Bu)
4b (71)
4c (43)
4d (50)
4e (56)
4f (41)
4g (66)
4h (59)
4i (75)
4j (58)
4k (87)
4l (51)
4m (34)
2
3
4
5
6
7
3h (R2 = Me3Si)
Table 1. Optimization of Reaction between 2a and 3aa
8
3b (R2 = 4-t-Bu-C6H4)
3h (R2 = Me3Si)
9
10
11
12
3b (R2 = 4-t-Bu-C6H4)
3h (R2 = Me3Si)
3i (R2 = EBPb)
a Isolated yield. b EBP = 40-ethynylbiphenyl-4-yl.
Scheme 2. One-Pot Synthesis of 4a
entry
2a:3a
temp
4a (%)
5a (%)
1a (%)
1
1:1
1:2
1:2
1:2
1:3
1:4
1:2
1:2
1:2
1:2
0 °C f rt
0 °C f rt
0 °C f rt
0 °C f rt
0 °C f rt
0 °C f rt
ꢀ40 °C
28
54
49
53
58
56
48
50
24
53
3
19
17
18
11
13
11
12
15
27
47
26
29
27
21
30
32
32
42
28
2
3b
4c
5
6
7
8
0 °C
9
10d
0 °C f 60 °C
0 °C f rt
a To a solution of 2a (0.5 mmol) in THF at 0 °C was added a solution
of 3ain THF. After10min, thereactionmixture was keptstirringatroom
temperature for 45 min. All yields are isolated yields. b Reaction time was
30 min. c Reaction time was 23 h. d Under O2 (1 atm) atmosphere.
It is worth mentioning that, to the best of our knowledge,
the above results represent the first example of CꢀC bond
formation mediated by an isolable Cu(III) species.14 This
novel and unique CarylꢀCalkynyl bond formation reaction is
also reminiscent of the seemingly relevant CastroꢀStephens
reaction between aryl halides and terminal alkynes,15 which
is mediated by Cu(I) salts. The mechanism of this desig-
nated name reaction has long been believed to proceed
through a vague four-centered transition state.16 Discovery
of the high reactivity of arylcopper(III) complexes toward
alkynyllithiums led us to investigate the alternative pathway
of the CastroꢀStephens reaction. As depicted in Scheme 3,
To demonstrate the simplicity and practicality of copper
salt mediated aryl CꢀH bond activation and functionali-
zation, tandem aryl CꢀH activation and CarylꢀCalkynyl
bond formation reactions were conducted. Without isola-
tion and purification of aryl-Cu(III) complex 2a, direct
aryl CꢀH activation of azacalix[1]arene[3]pyridine 1a with
Cu(ClO4) 6H2O in an open vial followed by, after removal
3
of solvent, treatment with (phenylethynyl)lithium 3a in
THF furnished 4a in 51% yield (Scheme 2).
(15) (a) Castro, C. E.; Stephens, R. D. J. Org. Chem. 1963, 28, 2163.
(b) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 13. (c) Okuro,
K.; Furuune, M.; Enna, M.; Miura, M.; Nomura, M. J. Org. Chem.
1993, 58, 4716. (d) Rossi, R.; Carpita, A.; Bellina, F. Org. Prep. Proced.
Int. 1995, 27, 127.
(14) CuI-catalyzed benzylation of pentafluorobenzene with benzyl
bromide was reported in ref 3s, and Cu(acac)2-catalyzed allylation
of electron-deficient arenes with ally phosphates was reported in
ref 3w.
(16) Posner, G. H. Org. React. 1975, 22, 253.
1474
Org. Lett., Vol. 14, No. 6, 2012

in the presence of a substoichiometric amount of CuO-
SO2CF3 under typical CastroꢀStephens reaction condi-
tions, reaction of iodobenzene compound 68 with ethynyl-
benzene 7 afforded cross-coupling product 4a in 76% yield.
Significantly, interaction of iodo-substituted azacalix-
[1]arene[3]pyridine 68 with a Cu(I) salt produced a highly
valent organocopper product aryl-CuIII[OSO2CF3]2 8 in
67% yield. The same aryl-CuIII[CF3SO3ꢀ]2 compound 8
was also obtained readily from straightforward arene CꢀH
bond activation of 1a with Cu(OSO2CF3)2. The aryl-CuIII
[CF3SO3ꢀ]2 complex 8 exhibited identical reactivity as the
aryl-CuIII[ClO4ꢀ]2 complex 2a toward alkynyllithium 3a,
yielding 4a in 58% yield (see SI). Very pleasingly, treatment
of aryl-CuIII[OSO2CF3]2 intermediate 8 with ethynyl-
benzene 7 under CastroꢀStephens reaction conditions led
to the formation of the CarylꢀCsp bond in 62% yield
(Scheme 3). On the basis of aforementioned evidence, it
seems that the CastroꢀStephens reaction proceeds most
probably through an oxidative addition of Cu(I) into
the CꢀI bond to form an arylcopper(III) intermediate.
It allowed us to propose an alternative reaction mechanism
involving Cu(I)/Cu(III) in addition to a long believed Cu(I)-
involved four-center transition state.16
All products including aryl-Cu(III) complex 8 were fully
characterized by means of spectrocopic data. X-ray struc-
tures of 4e and 4h show a 1,3-alternate conformation of the
azacalixarene ring (see SI).
Inconclusion, wehave demonstratedthatcopper(II) salt
mediated aryl CꢀH bond activation of azacalix[1]arene-
[3]pyridines under mild aerobic conditions produced aryl-
Cu(III) complexes, which underwent effective cross-cou-
pling reactions with alkynyllithium reagents to form the
CarylꢀCalkynyl bond. The method provides a general and
unique synthetic route to regiospecifically alkynylated
azacalixaromatics, which can serve as a springboard to
various tailor-made functional macrocyclic host mole-
cules, very useful in the study of supramolecular chemistry
(results will be reported elsewhere). We have also shown
for the first time experimental evidence that the Castroꢀ
Stephens reaction of aryl iodide embedded in azacalix-
[1]arene[3]pyridine proceeds through oxidative addition of
Cu(I) into the CꢀI bond to form the same structurally
well-defined arylcopper(III) intermediate, which sub-
sequently undergoes a cross-coupling reaction with terminal
alkynes to produce a CarylꢀCalkynyl bond forming product.
Though in-depth studies are badly needed, the outcomes
may also imply that aryl-Cu(III) species are genuine inter-
mediates in Cu-catalyzed or -mediated carbonꢀcarbon and
carbonꢀheteroatom bond formation reactions. Studies on
the copper salt catalyzed aryl CꢀH bond activation and
diverse chemical bond forming reactions with a broad
substrate scope are being actively pursued in this laboratory.
Scheme 3. CastroꢀStephens Reaction via an ArylꢀCu(III)
Intermediate 8
Acknowledgment. We thank NNSFC (21132005,
21121004, 20972161), MOS (2011CB932501), and Tsinghua
University for financial support.
Supporting Information Available. Experimental de-
tails and characterization data, X-ray structures of 4e and
4h (CIFs). This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
1475