Copper Catalysis for Selective Heterocoupling of Terminal Alkynes

Article abstract of DOI:10.1021/jacs.6b07984

A Cu-catalyzed selective aerobic heterocoupling of terminal alkynes is disclosed, which enables the synthesis of a broad range of unsymmetrical 1,3-diynes in good to excellent yields. The results disprove the long-held belief that homocouplings are exclusively favored in the Glaser-Hay reaction.

Full text of DOI:10.1021/jacs.6b07984

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Communication
Copper Catalysis for Selective Heterocoupling of Terminal Alkynes
Lebin Su, Jianyu Dong, Long Liu, Mengli Sun, Renhua Qiu, Yongbo Zhou, and Shuang-Feng Yin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07984 • Publication Date (Web): 12 Sep 2016
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Copper Catalysis for Selective Heterocoupling of Terminal Alkynes
Lebin Su,‡ Jianyu Dong,‡ Long Liu, Mengli Sun, Renhua Qiu, Yongbo Zhou,* and Shuang-Feng Yin*
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State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan
University, Changsha 410082, China
Table 1. Optimization of Conditionsa
ABSTRACT: A copper-catalyzed selective aerobic heterocou-
pling of terminal alkynes is disclosed, which enables the synthesis
of a broad range of unsymmetrical 1,3-diynes in good to excellent
yields. The results disprove the long-held belief that homocou-
plings are exclusively favored in the Glaser‒Hay reaction.
The copper-catalyzed crosscoupling of terminal alkynes (Gla-
ser‒Hay reaction) to produce 1,3-diynes is a textbook reaction1
that has wide applications2 in organic synthesis3 and material
science.4 However, compared to its extensive application to the
synthesis of symmetrical 1,3-diynes via the homocoupling of an
alkyne, the preparation of unsymmetrical 1,3-diynes, via the cou-
pling of two different alkynes, is rather limited because of the
poor selectivity.5‒8
Unsymmetrical 1,3-diynes are an important class of intermedi-
ates in organic synthesis, and they are ubiquitous structural motifs
in a large number of natural products and functional materi-
als.2a,5c,d,9 A landmark contribution to the synthesis of these com-
pounds was made based on the Cadiot–Chodkiewicz reaction,10a
and the development of its variants was also achieved.10b,c How-
ever, prefunctionalized substrates such as 1-haloalkynes are re-
quired. Direct synthetic methods that employ a vast excess of one
alkyne were recently developed, but resulting in low total heter-
oselectivity.11 A significant progress was recently made by Shi
and coworkers over the Au/phen catalytic system using
PhI(OAc)2 as an oxidant, achieving selective heterocoupling of
substituted aromatic alkynes with aliphatic alkynes.12 Nonetheless,
the copper-catalyzed selective heterocoupling of terminal alkynes
still remains a big challenge in organic synthesis.2a,5,12
Herein, we describe a copper-catalyzed selective heterocou-
pling of terminal alkynes using Glaser‒Hay-type reaction condi-
tions to produce unsymmetrical 1,3-diynes (eq 1). In addition to
the selective heterocoupling of an aromatic alkyne with an ali-
phatic alkyne, the copper-catalyzed system allows selective heter-
aReaction conditions: 2,2-dimethylpropargyl alcohol, 1a, (0.20
mmol), phenylacetylene, 2a, (0.26 mmol), [Cu] (0.01 mmol, 5.0
mol %), ligand (0.04 mmol, 20 mol %), solvent (0.4 mL), air,
ocoupling between two different aromatic alkynes and between
two different aliphatic alkynes.
50 °C, 4 h. bGC yields of 3a and 4a based on 1a, and 5a based on
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e
f
2a. 30 °C. 70 °C. CHCl3 (0.3 mL), 1,4-dioxane (0.1 mL). 5
equiv of CHCl3 (1 mmol), 1,4-dioxane (0.4 mL). g12 h. 8 h. 1a
h
i
(0.26 mmol), 2a (0.20 mmol). j1a (0.20 mmol), 2a (0.20 mmol).
The replacement of TMEDA with other bidentate ligands, such as
N1,N1,N2,N2-tetraethylethylenediamine (TEEDA), Phen, TMMDA,
TMTDA and bpy, resulted in no yield for the desired product
(entries 12‒15). Notably, good yield and heteroselectivity were
observed (70%, 3a/4a = 6, entry 16) by the use of N,N'-diethyl-
N,N'-dimethylethylenediamine (DEDMEDA) that has only a
slightly less steric hindrance than that of TEEDA. The reaction
was also sensitive to the reaction temperature, and a low yield of
the heterocoupling product (3a) was observed at temperatures
Initially, the reaction of 2,2-dimethylpropargyl alcohol (1a)
with phenylacetylene (2a) was tested to optimize the reaction
conditions (Table 1, see SI for details). For copper catalysts, CuCl,
CuBr, Cu2O, and CuF2 showed moderate efficiency (yield: 57-
60%, 3a/4a = 4.5~5.7, entries 1‒4) in the presence of N1,N1,N2,N2-
tetramethylethylenediamine (TMEDA). In the case of copper
powder, there was a significant improvement in both yield and
selectivity (74%, 3a/4a = 12, entry 10), whereas Cu(OH)2,
Cu(OAc)2, Cu(NO3)2, and CuO were ineffective (entries 6‒9).
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Table 2. Substrate Scopea,b
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aReaction conditions: 1 (0.20 mmol), 2 (0.26 mmol), Cu powder (0.01 mmol), TMEDA (0.04 mmol), CHCl3 (0.3 mL), 1,4-dioxane (0.1
mL), air, 50 °C, overnight. isolated yield based on 1, 3/4/5 in parentheses. 1 (0.20 mmol), 2 (0.20 mmol). compound I (0.01 mmol),
TMEDA (0.04 mmol), 1,4-dioxane (0.4 mL). e1 (1.0 mmol), 2 (1.3 mmol).
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higher or lower than 50 °C (entries 17 and 18). An investigation
of the effect of the solvent showed that a mixture of CHCl3 and
dioxane was the best for reaction performance, producing 3a in a
78% yield with excellent selectivity (3a/4a = 16, entry 22). The
reaction proceeded smoothly in the presence of only 5 equiv of
chloroform in dioxane, producing 3a in a 72% yield (entry 23),
whereas only a trace amount of 3a was observed in the absence of
chloroform (entry 24). By prolonging the reaction time to 8 h, the
yield of 3a slightly increased (83%), but the heteroselectivity
decreased due to the homocoupling of redundant 1a to 4a (3a/4a
= 12, entry 25). A comparable yield for 3a (78%) was observed
with the inversion of the 1a to 2a ratio (1.3:1, entry 26). An
equimolar mixture of two alkynes gave a satisfactory yield of 3a
(72%, 3a/4a = 10, entry 27). In contrast, a low yield of the hetero-
coupling product7,12 was observed under Glaser‒Hay reaction
conditions (47%, entry 28).
As shown in Table 2, the copper catalytic system exhibits a
wide scope of substrates and an outstanding tolerance for func-
tional groups, producing various unsymmetrical 1,3-diynes in
good to excellent isolated yields (see SI for details). Aromatic
alkynes substituted with alkyl (3b‒f), F (3g), Cl (3h), Br (3i), CF3
(3j), OMe (3k,l), aryl (3m,n), CN (3o), NH2 (3p), CH3CO (3q),
and NO2 (3r) worked well to give the corresponding conjugated
diynes in 65‒87% yields. Steric hindrance has only a slight effect
on the reaction (3b‒d), and the attachment of an electron-
withdrawing group on the phenyl ring results in higher yields for
the heterocoupling products (3g‒j). Heteroaromatic alkynes that
contain thiophene (3s) and pyridine (3t,u) also reacted efficiently.
Aliphatic alkynes are good substrates, producing the correspond-
ing conjugated diynes in good to excellent yields (63‒91%, 3v‒zi).
Functional groups, including primary alcohols (3v), secondary
alcohols (3w), tertiary alcohols (3x), benzyl alcohols (3y), esters
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(3za,zf), ethers (3zb), thioethers (3zc), acetals (3zd), amides (3ze),
characteristic Cu(II) shakeup satellites (939‒945 eV) that were
previously assigned to spinel Cu(II).13
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and silicanes (3zg), are all tolerated. In the case of ethisterone,
being a highly functionalized aliphatic alkyne, the 1,3-diyne-
derived drug-like molecule was produced in a satisfactory yield
(63%, 3zh). This clearly demonstrates the great potential of this
new methodology for accessing highly functionalized target mol-
ecules. Notably, the reaction of phenylacetylene with cyclohex-
ylacetylene, which do not include any functional substituted
groups, also proceeded selectively to afford the corresponding
product in a 63% yield (3zi).
Figure 1. Molecular structure of I. Thermal ellipsoids are drawn
at 50% probability. H atoms omitted for clarity. Selected bond
lengths (Å) and angles (deg): Cu1–Cl1 = 2.2488(8), Cu1–Cl2 =
2.2471(7), Cu1–Cl3 = 2.2559(8), Cu1–Cl4 = 2.2269(9), Cl4–
Cu1–Cl2 = 100.35(3), Cl4–Cu1–Cl1 = 101.14(3), Cl2–Cu1–Cl1 =
131.63(3), Cl4–Cu1–Cl3 = 130.36(3), Cl2–Cu1–Cl3 = 99.78(3),
Cl1–Cu1–Cl3 = 98.31(3).
9
In addition to aromatic and aliphatic alkynes, this copper-
catalyzed reaction is applicable to the heterocoupling between two
different aromatic alkynes, and unsymmetrical aryl-aryl 1,3-
diynes were selectively produced in 71‒87% yields (3zj‒zp).
Remarkably, despite slight differences in reactivity for the C(sp)‒
H bonds, p-tolyacetylene and o-tolyacetylene were well “discrim-
inated” in the catalytic reaction, giving the desired product in a 71%
yield (3zo), which may be resulted from their different steric hin-
drance, too. The reaction of two different aliphatic alkynes also
resulted in selective formation of heterocoupling products, and a
variety of unsymmetrical alkyl-alkyl 1,3-diynes were generated in
70‒77% yields (3zq‒zt). Even in the cases of two alkynes in an
exact 1:1 molar ratio, satisfactory yields (58‒80%) and total het-
eroselectivity (3/(3+4+5), 64‒86%) were obtained (3a, 3p, 3s, 3zc,
3zi, 3zl, 3zm, 3zn, 3zp, 3zq, and 3zt).
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In the ESI-MS spectra of I in methanol, the peak at m/z 367.0
was assigned to [I+CH3OH]+ (calcd m/z 367.6), indicating that
the structure of I was maintained in solution. Indeed, using I as
the catalyst in dioxane, the heterocoupling of 1a and 2a produced
3a in a 70% yield in air (eq 3), and comparable results were also
observed in the reaction of other substrates, including that of two
aromatic alkynes or two aliphatic alkynes (Table 2, 3g, 3n, 3zh,
3zk, and 3zr). The stoichiometric reaction of 1a with 2a over
copper compound I under N2 produced the heterocoupling prod-
uct 3a in a 61% yield. These results suggest that I served as the
active catalytic species.
The method can be applied to the synthesis of unsymmetrical-
polyynes, such as conjugated triyne and tetrayne. For example,
triyne 8 is selectively produced in a 72% yield from buta-1,3-
diyn-1-ylbenzene 6 and 1a (Scheme 1, A). Treatment of 3a with
3p under one-pot deprotection/oxidation conditions produced
tetrayne 9 in a 69% yield (Scheme 1, B). The gram-scale synthesis
of 3a was successfully achieved (79%, see SI for details). There-
fore, we envision important applications for this method, especial-
ly for the synthesis of electronic, optical, and natural materials.
By combining an electron-rich aromatic alkyne (2p, with a rela-
tively stronger π-electron donating ability) with two electron-
deficient aromatic alkynes (2j and 2q, of relatively higher acidity),
good heteroselectivity (3zm, 72% and 3zl, 65%) was observed
between the electron-rich alkyne and electron-deficient alkynes
(eq 4). The selective heterocoupling reaction between 2j and 2q
also occurred, giving the heterocoupling product (3zp) in a 18%
yield. With the dominance of the heterocoupling reactions, the
homocoupling reactions of both 2j and 2q became minor and
produced the homocoupling products in extremely low yields (4%
and 7%, respectively, see SI for details). Thus, we deduce that a
bigger difference between the reactivity of the alkynes leads to
higher heteroselectivity for the desired product.
Scheme 1. Synthesis of Unsymmetrical Polyynes
To gain insights into the mechanism, several control experi-
ments were conducted. The reaction was accomplished in the
presence of a catalytic amount of copper powder under N2, but a
longer time was required (eq 2), giving a slightly lower yield and
selectivity (3a: 64%, 3a/4a = 9:1) than the reaction conducted
under air. The results indicate that despite its inferiority to air,
chloroform can serve as an oxidant.
Regarding the Glaser‒Hay coupling mechanism,1c,14 both the
deprotonation and π-complexation of the alkyne with copper are
mandatory, and the dimeric copper acetylides are the intermedi-
ates that are most currently accepted (Figure 2, left). Obviously, it
is difficult to control the chemoselectivity similar to that of the
Cadiot–Chodkiewicz reaction (Figure 2, right).9a,b
After treatment of the copper powder with TMEDA in chloro-
form under dry N2 at 50 °C for 24 h, a pale yellow solid, I, was
isolated in a 86% yield. The structure of I was unambiguously
confirmed using single-crystal X-ray crystallography (Figure 1).
The X-ray analysis showed that the copper center was coordina-
tively saturated inside a tetrahedron structure with similar Cu–Cl
distances of 2.2269(9), 2.2471(7), 2.2488(8), and 2.2559(8) Å.
Two large Cl–Cu–Cl angles of 131.63(3)º and 130.36(3)º allows
attack by alkynes. In the Cu 2p3/2 XPS spectra of I (see SI Fig. 1),
a peak at a binding energy of ~933.9 eV was accompanied by
Figure 2. Reaction intermediates in the Glaser coupling reaction
(left) and Cadiot–Chodkiewicz coupling reaction (right).
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(4) (a) Wang, J.; Shen, Y.; Kessel, S.; Fernandes, P.; Yoshida, K.; Ya-
Although the details of the reaction mechanism remain to be
clarified, we consider that the good heteroselectivity is perhaps
due to the unique structure of copper complex I. It is assumed that
the electropositive bis-cation, i.e., the quaternary ammonium of
TMEDA, may trap and activate the stronger π-electron donating
alkyne (of lower acidity) via a cation-π interaction.15 The copper
center bonds to four highly electronegative atoms (Cl), and its
coordinatively saturated nature resists the π-coordination of the
C≡C triple bond to Cu, but it may favor selective ligand exchange
with an alkyne of higher acidity. Thus, the two different alkynes
could be “discriminated” by the copper center and bis-cation,
respectively.16 Compared to I, Li2CuCl4 or (Et4N)2CuCl4 provides
poor yield and selectivity, which further confirms the above sug-
gestion. In addition, the steric hindrance of both the ligand and
alkynes can affect this heteroselectivity, suggesting that it may be
another factor for the “discrimination” of two different alkynes.
gai, S.; Kurth, D. C.; Moehwald, H.; Nakanishi, T. Angew. Chem. Int. Ed.
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In summary, we present a new copper catalysis that leads to se-
lective oxidative cross-coupling of terminal alkynes under mild
conditions, enabling the synthesis of a broad range of unsymmet-
rical aryl-aryl, aryl-alkyl and alkyl-alkyl 1,3-diynes in good to
excellent yields. Both chloroform and TMEDA are essential in-
gredients for the formation of the copper(II) catalyst I. Catalyst I
can “distinguish” two different alkynes on the basis of their dif-
ferences in intrinsic reactivity and steric hindrance, resulting in
selective heterocoupling. The present findings not only provide a
general, efficient and simple method for the preparation of un-
symmetrical 1,3-diynes and polyynes but also open a new dimen-
sion of copper catalysis.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: zhouyb@hnu.edu.cn.
*E-mail: sf_yin@hnu.edu.cn.
(12) Peng, H. H.; Xi, Y. M.; Ronaghi, N.; Dong, B. L.; Akhmedov, N.
G.; Shi, X. D. J. Am. Chem. Soc. 2014, 136, 13174.
(13) Liu, P.; Hensen, E. J. M. J. Am. Chem. Soc. 2013, 135, 14032.
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T.; Kropf, A. J.; Bunel, E. E.; Lan, Y.; Lei, A. J. Am. Chem. Soc. 2014,
136, 16760. (b) Zhang, G.; Yi, H.; Zhang, G.; Deng, Y.; Bai, R.; Zhang,
H.; Miller, J. T.; Kropf, A. J.; Bunel, E. E.; Lei, A. J. Am. Chem. Soc.
2014, 136, 924. (c) Fomina, L.; Vazquez, B.; Tkatchouk, E.; Fomine, S.
Tetrahedron 2002, 58, 6741. (d) Vilhelmsen, M. H.; Jensen, J.; Tortzen, C.
G.; Nielsen, M. B. Eur. J. Org. Chem. 2013, 701. (e) Bohlmann, F.;
Schönowsky, H.; Inhoffen, E.; Grau, G. Chem. Ber. 1964, 97, 794.
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E. J. M. J. Am. Chem. Soc. 2013, 135, 14032. (b) Nagy, E.; Germain, E. S.;
Cosme, P.; Maity, P.; Terentis, A. C.; Lepore, S. D. Chem. Commun. 2016,
52, 2311.
Author Contributions
‡ L.S. and J.D. contributed equally to this work.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Financial support by the National NSF of China (nos. 21172062,
21273066, 21273067, and 21573065) and the NSF of Hunan
Province (2016JJ1017) is appreciated. We also thank Prof. Wan-
zhi Chen (Zhejiang University) and Prof. C.T Au (HNU adjunct
professor) for their kind help.
(16) See SI for further comments on the mechanism.
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Journal of the American Chemical Society
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Copper Catalysis for Selective Heterocoupling of Terminal Alkynes
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Lebin Su, Jianyu Dong, Long Liu, Mengli Sun, Renhua Qiu, Yongbo Zhou, and Shuang-Feng Yin
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