Zinc-Catalyzed Dehydrogenative Cross-Coupling of Terminal Alkynes with Aldehydes: Access to Ynones

Article abstract of DOI:10.1002/anie.201509042

Because of the lack of redox ability, zinc has seldom been used as a catalyst in dehydrogenative cross-coupling reactions. Herein, a novel zinc-catalyzed dehydrogenative C(sp²)-H/C(sp)-H cross-coupling of terminal alkynes with aldehydes was dev

Full text of DOI:10.1002/anie.201509042

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International Edition: DOI: 10.1002/anie.201509042
German Edition: DOI: 10.1002/ange.201509042
Homogeneous Catalysis
Zinc-Catalyzed Dehydrogenative Cross-Coupling of Terminal Alkynes
with Aldehydes: Access to Ynones
Shan Tang, Li Zeng, Yichang Liu, and Aiwen Lei*
Abstract: Because of the lack of redox ability, zinc has seldom
been used as a catalyst in dehydrogenative cross-coupling
reactions. Herein, a novel zinc-catalyzed dehydrogenative
2
À
À
C(sp ) H/C(sp) H cross-coupling of terminal alkynes with
aldehydes was developed, and provides a simple way to access
ynones from readily available materials under mild reaction
conditions. Good reaction selectivity can be achieved with a 1:1
ratio of terminal alkyne and aldehyde. Various terminal
alkynes and aldehydes are suitable in this transformation.
D
irect dehydrogenative cross-coupling between two hydro-
carbons is an environmentally friendly and atom-economic
À
Scheme 1. Zinc-catalyzed dehydrgenative cross-coupling for C C bond
formation.
À
strategy for C C bond formation since it does not require
prefunctionalization of the substrate.[1] However, most of
these reactions rely on the use of redox transition metals.
Transition metals with poor redox ability have seldom been
applied in these transformations. Zinc salts are abundant,
cheap, nontoxic, and exhibit environmentally benign proper-
ties. These features have attracted organic chemists to use
zinc salts as catalysts in many organic transformations.[2]
However, the interest in zinc as a catalyst core in cross-
coupling is underdeveloped when compared with other
transition metals.[3] Because of the lack of redox ability,
dehydrogenative cross-coupling through zinc catalysis has
Ynones are important structural motifs in organic chemis-
try because of their biomedical and material significance, and
their widespread use in the synthesis of bioactive products.[6]
Over the past decade, numerous efforts have been devoted to
this reaction and impressive progress has been achieved.[7]
However, most reactions require the use of functionalized
materials such as alkynyl metal reagents, alkynyl halides, acyl
halides, and a-keto acids. Direct utilization of readily
available materials, aldehydes and terminal alkynes, to
access ynones would be a much more appealing approach.
Actually, zinc salts have been reported to act as catalysts for
promoting the coupling of terminal alkynes with aldehydes.[8]
However, these reactions are only able to access propargylic
alcohols. An extra oxidation step is required for accessing
ynones. Recently, our group found that excess amounts of zinc
iodide could mediate the dehydrogenation reaction of the
in situ generated propargylic alcohols with an additional
amount of aldehyde.[9] However, the use of a large excess of
zinc salts and aldehydes hindered this protocol from general
application. Herein, utilizing a zinc salt as the catalyst in the
selective dehydrogenative cross-coupling between terminal
alkynes and aldehydes has great significance in terms of both
concept innovation and practical application.
received even less attention.[4] In 2012, an elegant zinc-
catalyzed C(sp ) H/C(sp) H dehydrogenative cross-coupling
3
À
À
of propargylic amines and terminal alkynes was demonstrated
by Nakamura and Sugiishi.[5] The C C bond of the prop-
ꢀ
argylic amine acted as an internal oxidant, and was reduced to
=
C C after a zinc-promoted hydrogen-transfer process. This
report proved that zinc salts were able to act as catalysts in
dehydrogenative cross-coupling reactions. Admittedly, the
application of zinc catalysis in dehydrogenative C C bond
formation reactions remains challenging. Herein, we report
our progress on a zinc-catalyzed dehydrogenative cross-
coupling of terminal alkynes with aldehydes to access
ynones (Scheme 1).
À
We started our research by using benzaldehyde (1a) and
p-tolylacetylene (2a) in a model reaction to test the reaction
conditions. Optimization of the reaction is shown in Table S1
in the Supporting Information. In the absence of hydrogen
accepter oxidants, only small amounts of the desired product
3aa (for structure see Table 1) could be obtained (Table S1,
entry 1). Different ketones were then added into the reaction
system and a,a,a-trifluoroacetophenone (4) gave a satisfac-
tory yield for this dehydrogenative cross-coupling reaction
(Table S1, entries 2–5). Notably, other zinc salts were unreac-
tive for achieving this transformation (Table S1, entries 6–10).
Zn(OTf)2 was crucial in this transformation, and was key for
achieving this catalytic reaction. Efforts were also taken to
[*] S. Tang, L. Zeng, Y. Liu, Prof. A. Lei
College of Chemistry and Molecular Sciences, the Institute for
Advanced Studies (IAS), Wuhan University
Wuhan 430072, Hubei (P.R. China)
E-mail: aiwenlei@whu.edu.cn
Homepage: http://aiwenlei.whu.edu.cn/Main_Website/
Prof. A. Lei
National Research Center for Carbohydrate Synthesis, Jiangxi Normal
University, Nanchang 330022 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201509042.
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decrease the loading of the zinc catalyst. Use of 15 mol% of
Zn(OTf)2 was more effective for this transformation, whereas
10 mol% of Zn(OTf)2 gave a decreased yield (Table S1,
entries 11 and 12). Furthermore, several strong Lewis acids
were used as co-catalysts to enhance the reaction efficiency
(Table S1, entries 13–15). Delightfully, adding an additional
5 mol% of In(OTf)3 led to an excellent yield (Table S1,
entry 13). A control experiment showed that Zn(OTf)2 was
crucial for the dehydrogenative cross-coupling (Table S1,
entry 16). Thus, the optimized reaction conditions include
15 mol% Zn(OTf)2 as the catalyst, 5 mol% In(OTf)3 as a co-
catalyst, and 1.2 equivalents 4 as the oxidant.
With the optimized reaction conditions established, we
turned to explore the functional-group tolerance of this zinc-
catalyzed dehydrogenative cross-coupling. Firstly, different
terminal alkynes were applied as substrates to react with 1a.
The reaction of para-, meta-, and ortho-methyl-substituted
phenylacetylene all proceeded well and afforded the corre-
sponding ynones in good yields (3aa–ac; Table 1). Simple
phenylacetylene showed similar reactivity in this reaction
(3ad). Notably, halide substituents such as F, Cl, and Br were
all tolerated in this transformation, thus providing a possibility
for further functionalization (3ae–ai). A slightly decreased
reactivity was observed for the reaction with electron-
deficient phenylacetylenes (3aj and 3ak). The desired
product was obtained in 81% yield when electron-rich p-
methoxylphenylacetylene was used (3al). Other aromatic
alkynes were also applied as substrates. 1-Ethynylnaphtha-
lene was efficient for the construction of ynones (3am), and 2-
ethynylthiophene was also applied in this transformation but
only a 46% yield could be obtained (3an). Aliphatic alkynes
were also tried in this dehydrogenative cross-coupling reac-
tion and moderate to good yields were observed under the
standard reaction conditions (3ao and 3ap). It is worthy of
noting that trimethyl silyl acetylene did generate the desired
product with a satisfactory yield under the standard reaction
conditions (3aq).
The reactions of p-tolylacetylene with various aldehydes
were also conducted. The para-, meta-, and ortho-methyl-
substituted benzaldehydes were all suitable in this trans-
formation and furnished the desired product in good yields
(3ba–da; Table 2). Benzaldehydes bearing halide substituents
Table 2: Substrates scope for the zinc-catalyzed dehydrogenative cross-
coupling of aldehydes with 2a.[a]
Table 1: Substrates scope for the zinc-catalyzed dehydrogenative cross-
coupling of 1a with terminal alkynes.[a]
[a] Reaction conditions: 1 (1.0 equiv, 0.50 mmol), 2a (1.0 equiv,
0.50 mmol), Zn(OTf)2 (15 mol%, 0.075 mmol), In(OTf)3 (5 mol%,
0.025 mmol), 4 (1.2 equiv, 0.60 mmol), NEt3 (2.4 equiv, 1.2 mmol) in
toluene (0.50 mL) at 808C for 27 h. [b] 20 mol% Zn(OTf)2 was used.
were also tolerated in this transformation and good reactivity
was observed (3ea–ha). Both strongly electron-deficient and
strongly electron-rich benzaldehydes were suitable in this
transformation. The para- and ortho-methoxy-substituted
benzaldehydes gave the corresponding ynones in high yields
(3ia and 3ja), and 4-(trifluoromethyl)benzaldehyde furnished
the desired product in 75% yield (3ka). Other aromatic
aldehydes such as 2-naphthaldehyde and thiophene-2-carb-
[a] Reaction conditions: 1a (1.0 equiv, 0.50 mmol), 2 (1.0 equiv,
0.50 mmol), Zn(OTf)2 (15 mol%, 0.075 mmol), In(OTf)3 (5 mol%,
0.025 mmol), a,a,a-trifluoroacetophenone (4; 1.2 equiv, 0.60 mmol),
NEt3 (2.4 equiv, 1.2 mmol) in toluene (0.50 mL) at 808C for 27 h.
Tf =trifluoromethanesulfonyl, TMS=trimethylsilyl.
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=
aldehyde showed good reactivity in this transformation (3la
and 3ma). Aliphatic aldehydes, such as pivalaldehyde, bear-
ing no a-hydrogen atom, showed a good reactivity in this
transformation (3na). However, aliphatic aldehydes bearing
a-hydrogen atoms were not suitable in this transformation
because they are susceptible to forming aldol byproducts.
The scalability of this novel ynone synthesis was evaluated
by performing the zinc-catalyzed dehydrogenative cross-
coupling in a 10 mmol scale. Coupling of 1a with 2d smoothly
furnished the desired product in 68% yield (Scheme 2; 3ad).
Similarly, the gram-scale reaction between 1a and 2q
afforded the desired product in 44% yield (3aq). These
results highlight the potential of this dehydrogenative cross-
coupling in practical applications.
the C O group of 4 to give [D1]2,2,2-trifluoro-1-phenylethan-
1-ol (6a; Scheme 4a). At the same time, the deuterium of
[D1]-2a added to oxygen atom of the C O group of 4 to give
6b (Scheme 4b). These two reactions provided a clear view of
the hydrogen-transfer pathway during the dehydrogenative
cross-coupling reaction.
=
Scheme 4. Isotope-labeling experiments.
Based on the experimental results and previous mecha-
nistic studies,[9,10] a tentative reaction mechanism is proposed
for the dehydrogenative cross-coupling process (Scheme 5). It
Scheme 2. Gram-scale reactions.
To gain some insight into the reaction intermediate, some
control experiments with 4 were carried out. Under the
standard reaction conditions, 2a could directly react with 4 in
the absence of aldehydes. The reaction gave the trifluoro-
methyl-substituted propargylic alcohol 5 in quantitative yield
(Scheme 3a). We then checked whether 5 was an active
reaction intermediate in this transformation. However, no
Scheme 5. Proposed mechanism.
À
is well known that C(sp) H bond activation of terminal
alkynes could be achieved with the combination of a certain
zinc salt and an organic base.[10] This C H activation would
À
lead to the formation of an alkynyl zinc species (B).
Nucleophilic addition of the alkynyl zinc to the zinc coordi-
nated aldehyde A would lead to the formation of the
propargylic alcohol complex C. The hydrogen-acceptor
oxidant 4,[11] could then coordinate to C, and a hydrogen-
transfer process would take place, through a then six-
membered transition-state E, to furnish the final product
and a zinc alcohol (F). Finally, the catalytic cycle is completed
with the protonation of F to give 2,2,2-trifluoro-1-phenyl-
ethan-1-ol. There are three roles for zinc in this reaction:
Scheme 3. Study of the reaction intermediates.
reaction between the aldehyde 1b and 5 took place under the
standard reaction conditions (Scheme 3b). These results
indicated that addition of a terminal alkyne to 4 was not
involved in the dehydrogenation process.
For understanding the mechanism of the dehydrogenation
process, reactions with deuterated substrates were carried
out. The deuterium of [D1]-1a added to the carbon atom of
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À
Eur. J. 2012, 18, 9500 – 9504; c) T. Tsuchimoto, H. Utsugi, T.
1) C H activation of the terminal alkyne; 2) activing the
Sugiura, S. Horio, Adv. Synth. Catal. 2015, 357, 77 – 82.
[5] T. Sugiishi, H. Nakamura, J. Am. Chem. Soc. 2012, 134, 2504 –
2507.
[6] a) L. F. Tietze, R. R. Singidi, K. M. Gericke, H. Bçckemeier, H.
Laatsch, Eur. J. Org. Chem. 2007, 5875 – 5878; b) M. C. Bagley,
C. Glover, E. A. Merritt, Synlett 2007, 2459 – 2482; c) D. M.
DꢀSouza, T. J. J. Muller, Nat. Protoc. 2008, 3, 1660 – 1665; d) A.
Fraile, A. Parra, M. Tortosa, J. Alemµn, Tetrahedron 2014, 70,
9145 – 9173; e) G. Abbiati, A. Arcadi, F. Marinelli, E. Rossi,
Synthesis 2014, 687 – 721.
carbonyl group of aldehyde; 3) bridging the hydrogen transfer
of the propargylic alcohol intermediate with 4. Additionally,
In(OTf)3 is also likely to play a role in the activation of the
terminal alkyne and aldehyde,[12] and is thus beneficial for
achieving good reaction efficiency.
In conclusion, we have disclosed a novel zinc-catalyzed
reaction system for the dehydrogenative cross-coupling
between aldehydes and terminal alkynes. This reaction
protocol provides an atom economic way for the synthesis
of ynones. The use of Zn(OTf)2 as catalyst and a,a,a-
trifluoroacetophenone as oxidant was key for achieving this
catalytic transformation. Notably, neither terminal alkyne nor
aldehyde needed to be used in an excess amount. A good
reaction selectivity was achieved, even with 1:1 ratio of
terminal alkyne and aldehyde. The study of the substrate
scope showed that various terminal alkynes and aldehydes
were selectively converted into the corresponding ynones in
high selectivity and good yields. Delightfully, this reaction
could also be conducted on gram scale, which is important for
future application.
[7] a) M. S. Mohamed Ahmed, A. Mori, Org. Lett. 2003, 5, 3057 –
3060; b) R. J. Cox, D. J. Ritson, T. A. Dane, J. Berge, J. P. H.
Charmant, A. Kantacha, Chem. Commun. 2005, 1037 – 1039;
c) B. Liang, M. Huang, Z. You, Z. Xiong, K. Lu, R. Fathi, J.
Chen, Z. Yang, J. Org. Chem. 2005, 70, 6097 – 6100; d) J. Liu, X.
Peng, W. Sun, Y. Zhao, C. Xia, Org. Lett. 2008, 10, 3933 – 3936;
e) X.-F. Wu, H. Neumann, M. Beller, Chem. Eur. J. 2010, 16,
12104 – 12107; f) X.-F. Wu, B. Sundararaju, H. Neumann, P. H.
Dixneuf, M. Beller, Chem. Eur. J. 2011, 17, 106 – 110; g) X.-F.
Wu, H. Neumann, M. Beller, Angew. Chem. Int. Ed. 2011, 50,
11142 – 11146; Angew. Chem. 2011, 123, 11338 – 11342; h) Y. Yu,
W. Yang, D. Pflästerer, A. S. K. Hashmi, Angew. Chem. Int. Ed.
2014, 53, 1144 – 1147; Angew. Chem. 2014, 126, 1162 – 1165; i) Z.
Wang, L. Li, Y. Huang, J. Am. Chem. Soc. 2014, 136, 12233 –
12236; j) H. Huang, G. Zhang, Y. Chen, Angew. Chem. Int. Ed.
2015, 54, 7872 – 7876; Angew. Chem. 2015, 127, 7983 – 7987; k) H.
Tan, H. Li, W. Ji, L. Wang, Angew. Chem. Int. Ed. 2015, 54, 8374 –
8377; Angew. Chem. 2015, 127, 8494 – 8497; l) H. Wang, L. N.
Guo, S. Wang, X.-H. Duan, Org. Lett. 2015, 17, 3054 – 3057;
m) X. Liu, L. Yu, M. Luo, J. Zhu, W. Wei, Chem. Eur. J. 2015, 21,
8745 – 8749; n) H. Wang, F. Xie, Z. Qi, X. Li, Org. Lett. 2015, 17,
920 – 923; o) B. Yu, H. Sun, Z. Xie, G. Zhang, L.-W. Xu, W.
Zhang, Z. Gao, Org. Lett. 2015, 17, 3298 – 3301; p) W. Ai, Y. Wu,
H. Tang, X. Yang, Y. Yang, Y. Li, B. Zhou, Chem. Commun.
2015, 51, 7871 – 7874; q) X.-H. Ouyang, R.-J. Song, C.-Y. Wang,
Y. Yang, J.-H. Li, Chem. Commun. 2015, 51, 14497 – 14500.
[8] a) D. E. Frantz, R. Fässler, E. M. Carreira, J. Am. Chem. Soc.
2000, 122, 1806 – 1807; b) N. K. Anand, E. M. Carreira, J. Am.
Chem. Soc. 2001, 123, 9687 – 9688; c) M. Hosseini-Sarvari, Z.
Mardaneh, Bull. Korean Chem. Soc. 2011, 32, 4297 – 4303.
[9] a) J. Yuan, J. Wang, G. Zhang, C. Liu, X. Qi, Y. Lan, J. T. Miller,
A. J. Kropf, E. E. Bunel, A. Lei, Chem. Commun. 2015, 51, 576 –
579; b) X. Qi, L. Yingzi, G. Zhang, Y. Li, A. Lei, C. Liu, Y. Lan,
Dalton Trans. 2015, 44, 11165 – 11171.
Acknowledgments
This work was supported by the 973 Program
(2012CB725302), the National Natural Science Foundation
of China (21390400, 21520102003, 21272180, 21302148), the
Hubei Province Natural Science Foundation of China
(2013CFA081), the Research Fund for the Doctoral Program
of Higher Education of China (20120141130002), and the
Ministry of Science and Technology of China
(2012YQ120060). The support from theProgram of Introduc-
ing Talents of Discipline to Universities of China (111
Program) is also appreciated.
À
Keywords: C H activation · cross-coupling · dehydrogenation ·
homogeneous catalysis · zinc
How to cite: Angew. Chem. Int. Ed. 2015, 54, 15850–15853
Angew. Chem. 2015, 127, 16076–16079
[10] a) D. E. Frantz, R. Fässler, C. S. Tomooka, E. M. Carreira, Acc.
Chem. Res. 2000, 33, 373 – 381; b) R. Fässler, C. S. Tomooka,
D. E. Frantz, E. M. Carreira, Proc. Natl. Acad. Sci. USA 2004,
101, 5843 – 5845.
[11] a) A. M. Whittaker, V. M. Dong, Angew. Chem. Int. Ed. 2015, 54,
1312 – 1315; Angew. Chem. 2015, 127, 1328 – 1331; b) L.-J. Gu, C.
Jin, H.-T. Zhang, Chem. Eur. J. 2015, 21, 8741 – 8744.
[12] a) R. Takita, Y. Fukuta, R. Tsuji, T. Ohshima, M. Shibasaki, Org.
Lett. 2005, 7, 1363 – 1366; b) R. Takita, K. Yakura, T. Ohshima,
M. Shibasaki, J. Am. Chem. Soc. 2005, 127, 13760 – 13761.
[1] a) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215 – 1292;
b) J. Le Bras, J. Muzart, Chem. Rev. 2011, 111, 1170 – 1214;
c) S. A. Girard, T. Knauber, C.-J. Li, Angew. Chem. Int. Ed. 2014,
53, 74 – 100; Angew. Chem. 2014, 126, 76 – 103; d) C.-J. Li, Acc.
Chem. Res. 2009, 42, 335 – 344.
[2] S. Enthaler, X.-F. Wu, Zinc Catalysis: Applications in Organic
Synthesis, Wiley-VCH, Weinheim, 2015.
[3] a) X.-F. Wu, H. Neumann, Adv. Synth. Catal. 2012, 354, 3141 –
3160; b) S. Enthaler, ACS Catal. 2013, 3, 150 – 158.
[4] a) L.-Q. Lu, X.-F. Wu, Zinc Catalysis, Wiley-VCH, Weinheim,
2015, pp. 33 – 56; b) T. Tsuchimoto, Y. Iketani, M. Sekine, Chem.
Received: September 26, 2015
Published online: November 13, 2015
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