International Edition:DOI:10.1002/anie.201509042German 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 C(sp2) ÀH/C(sp)ÀH 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 1:1ratio of terminal alkyne and aldehyde. Various terminal alkynes and aldehydes are suitable in this transformation.
carbons is an environmentally friendly and atom-economic strategy for C ÀC 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 received even less attention. [4]In 2012, an elegant zinc-catalyzed C(sp3) ÀH/C(sp)ÀH dehydrogenative cross-coupling 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 ÀC 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 (Scheme1).
D irect dehydrogenative cross-coupling between two hydro-
Scheme 1. Zinc-catalyzed dehydrgenative cross-coupling for C ÀC bond formation.
[*]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:[email protected]
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.
Angew. Chem. Int. Ed. 2015, 54, 1–5
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.
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 S1in the Supporting Information. In the absence of hydrogen accepter oxidants, only small amounts of the desired product 3aa (forstructure see Table 1) could be obtained (TableS1, 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 (TableS1, entries 2–5).Notably, other zinc salts were unreac-tive for achieving this transformation (TableS1, entries 6–10).Zn(OTf)2was crucial in this transformation, and was key for achieving this catalytic reaction. Efforts were also taken
to
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decrease the loading of the zinc catalyst. Use of 15mol %of Zn(OTf)2was more effective for this transformation, whereas 10mol %of Zn(OTf)2gave a decreased yield (TableS1, entries 11and 12). Furthermore, several strong Lewis acids were used as co-catalysts to enhance the reaction efficiency (TableS1, entries 13–15).Delightfully, adding an additional 5mol %of In(OTf)3led to an excellent yield (TableS1, entry 13). A control experiment showed that Zn(OTf)2was crucial for the dehydrogenative cross-coupling (TableS1, entry 16). Thus, the optimized reaction conditions include 15mol %Zn(OTf)2as the catalyst, 5mol %In(OTf)3as a co-catalyst, and 1.2equivalents 4as 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
Table 1:Substrates scope for the zinc-catalyzed dehydrogenative cross-coupling of 1a with terminal alkynes.
[a]
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]
[a]Reaction conditions:1(1.0equiv, 0.50mmol), 2a (1.0equiv, 0.50mmol), Zn(OTf)2(15mol %,0.075mmol), In(OTf)3(5mol%,0.025mmol), 4(1.2equiv, 0.60mmol), NEt 3(2.4equiv, 1.2mmol) in toluene (0.50mL) at 808C for 27h. [b]20mol %Zn(OTf)2was used.
[a]Reaction conditions:1a (1.0equiv, 0.50mmol), 2(1.0equiv, 0.50mmol), Zn(OTf)2(15mol %,0.075mmol), In(OTf)3(5mol%,0.025mmol), a , a , a -trifluoroacetophenone (4; 1.2equiv, 0.60mmol), NEt 3(2.4equiv, 1.2mmol) in toluene (0.50mL) at 808C for 27h. Tf =trifluoromethanesulfonyl, TMS =trimethylsilyl.
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)benzaldehydefurnished the desired product in 75%yield (3ka ). Other aromatic aldehydes such as 2-naphthaldehyde and thiophene-2-carb-Angew. Chem. Int. Ed. 2015, 54, 1–5
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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 10mmol scale. Coupling of 1a with 2d smoothly furnished the desired product in 68%yield (Scheme2; 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 4to 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 4to give 6b (Scheme4b). 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 (Scheme5). It
Scheme 2. Gram-scale
reactions.
To gain some insight into the reaction intermediate, some control experiments with 4were carried out. Under the standard reaction conditions, 2a could directly react with 4in the absence of aldehydes. The reaction gave the trifluoro-methyl-substituted propargylic alcohol 5in quantitative yield (Scheme3a). We then checked whether 5was an active reaction intermediate in this transformation. However, no
Scheme 5. Proposed mechanism.
Scheme 3. Study of the reaction
intermediates.
reaction between the aldehyde 1b and 5took place under the standard reaction conditions (Scheme3b). These results indicated that addition of a terminal alkyne to 4was 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
Angew. Chem. Int. Ed. 2015, 54, 1–5
is well known that C(sp)ÀH bond activation of terminal alkynes could be achieved with the combination of a certain zinc salt and an organic base. [10]This C ÀH activation would 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:
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1) C ÀH activation of the terminal alkyne; 2) activing the carbonyl group of aldehyde; 3) bridging the hydrogen transfer of the propargylic alcohol intermediate with 4. Additionally, In(OTf)3is 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)2as 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 1:1ratio 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.
Eur. J. 2012, 18, 9500–9504; c) T. Tsuchimoto, H. Utsugi, T. Sugiura, S. Horio, Adv. Synth. Catal. 2015, 357, 77–82.
T. Sugiishi, H. Nakamura, J. Am. Chem. Soc. 2012, 134, 2504–2507.
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. D Souza,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.
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. 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.
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.
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.
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.
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.
[5][6]
[7]
Acknowledgments
This work was supported by the 973Program (2012CB725302),the National Natural Science Foundation of China (21390400,[1**********], 21272180, 21302148), the Hubei Province Natural Science Foundation of China (2013CFA081),the Research Fund for the Doctoral Program of Higher Education of China ([1**********]002),and the Ministry of Science and Technology of China (2012YQ120060).The support from theProgram of Introduc-ing Talents of Discipline to Universities of China (111Program) is also appreciated.
Keywords:C ÀH activation ·cross-coupling ·dehydrogenation ·homogeneous catalysis ·zinc
[8]
[9]
[10]
[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.
[11]
[12]
Received:September 26, 2015
Published online:&&&&, &&&&
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2015Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2015, 54, 1–5
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Communications
Homogeneous Catalysis S. Tang, L. Zeng, Y . Liu, A. Lei*
&&&&—&&&&
Zinc-Catalyzed Dehydrogenative Cross-Coupling of Terminal Alkynes with Aldehydes:Access to
Ynones
Angew. Chem. Int. Ed. 2015, 54, 1–5Cross paths :The title reaction for C(sp2) Àmild reaction conditions. Notably, a good H/C(sp)ÀH cross-coupling of terminal reaction selectivity and efficiency could be alkynes with aldehydes was developed. It achieved with a 1:1ratio of terminal provides a simple way to access ynones alkyne and aldehyde.
from readily available materials under
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International Edition:DOI:10.1002/anie.201509042German 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 C(sp2) ÀH/C(sp)ÀH 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 1:1ratio of terminal alkyne and aldehyde. Various terminal alkynes and aldehydes are suitable in this transformation.
carbons is an environmentally friendly and atom-economic strategy for C ÀC 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 received even less attention. [4]In 2012, an elegant zinc-catalyzed C(sp3) ÀH/C(sp)ÀH dehydrogenative cross-coupling 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 ÀC 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 (Scheme1).
D irect dehydrogenative cross-coupling between two hydro-
Scheme 1. Zinc-catalyzed dehydrgenative cross-coupling for C ÀC bond formation.
[*]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:[email protected]
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.
Angew. Chem. Int. Ed. 2015, 54, 1–5
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.
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 S1in the Supporting Information. In the absence of hydrogen accepter oxidants, only small amounts of the desired product 3aa (forstructure see Table 1) could be obtained (TableS1, 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 (TableS1, entries 2–5).Notably, other zinc salts were unreac-tive for achieving this transformation (TableS1, entries 6–10).Zn(OTf)2was crucial in this transformation, and was key for achieving this catalytic reaction. Efforts were also taken
to
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decrease the loading of the zinc catalyst. Use of 15mol %of Zn(OTf)2was more effective for this transformation, whereas 10mol %of Zn(OTf)2gave a decreased yield (TableS1, entries 11and 12). Furthermore, several strong Lewis acids were used as co-catalysts to enhance the reaction efficiency (TableS1, entries 13–15).Delightfully, adding an additional 5mol %of In(OTf)3led to an excellent yield (TableS1, entry 13). A control experiment showed that Zn(OTf)2was crucial for the dehydrogenative cross-coupling (TableS1, entry 16). Thus, the optimized reaction conditions include 15mol %Zn(OTf)2as the catalyst, 5mol %In(OTf)3as a co-catalyst, and 1.2equivalents 4as 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
Table 1:Substrates scope for the zinc-catalyzed dehydrogenative cross-coupling of 1a with terminal alkynes.
[a]
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]
[a]Reaction conditions:1(1.0equiv, 0.50mmol), 2a (1.0equiv, 0.50mmol), Zn(OTf)2(15mol %,0.075mmol), In(OTf)3(5mol%,0.025mmol), 4(1.2equiv, 0.60mmol), NEt 3(2.4equiv, 1.2mmol) in toluene (0.50mL) at 808C for 27h. [b]20mol %Zn(OTf)2was used.
[a]Reaction conditions:1a (1.0equiv, 0.50mmol), 2(1.0equiv, 0.50mmol), Zn(OTf)2(15mol %,0.075mmol), In(OTf)3(5mol%,0.025mmol), a , a , a -trifluoroacetophenone (4; 1.2equiv, 0.60mmol), NEt 3(2.4equiv, 1.2mmol) in toluene (0.50mL) at 808C for 27h. Tf =trifluoromethanesulfonyl, TMS =trimethylsilyl.
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)benzaldehydefurnished the desired product in 75%yield (3ka ). Other aromatic aldehydes such as 2-naphthaldehyde and thiophene-2-carb-Angew. Chem. Int. Ed. 2015, 54, 1–5
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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 10mmol scale. Coupling of 1a with 2d smoothly furnished the desired product in 68%yield (Scheme2; 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 4to 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 4to give 6b (Scheme4b). 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 (Scheme5). It
Scheme 2. Gram-scale
reactions.
To gain some insight into the reaction intermediate, some control experiments with 4were carried out. Under the standard reaction conditions, 2a could directly react with 4in the absence of aldehydes. The reaction gave the trifluoro-methyl-substituted propargylic alcohol 5in quantitative yield (Scheme3a). We then checked whether 5was an active reaction intermediate in this transformation. However, no
Scheme 5. Proposed mechanism.
Scheme 3. Study of the reaction
intermediates.
reaction between the aldehyde 1b and 5took place under the standard reaction conditions (Scheme3b). These results indicated that addition of a terminal alkyne to 4was 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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is well known that C(sp)ÀH bond activation of terminal alkynes could be achieved with the combination of a certain zinc salt and an organic base. [10]This C ÀH activation would 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:
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1) C ÀH activation of the terminal alkyne; 2) activing the carbonyl group of aldehyde; 3) bridging the hydrogen transfer of the propargylic alcohol intermediate with 4. Additionally, In(OTf)3is 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)2as 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 1:1ratio 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.
Eur. J. 2012, 18, 9500–9504; c) T. Tsuchimoto, H. Utsugi, T. Sugiura, S. Horio, Adv. Synth. Catal. 2015, 357, 77–82.
T. Sugiishi, H. Nakamura, J. Am. Chem. Soc. 2012, 134, 2504–2507.
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. D Souza,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.
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. 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.
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.
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.
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.
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.
[5][6]
[7]
Acknowledgments
This work was supported by the 973Program (2012CB725302),the National Natural Science Foundation of China (21390400,[1**********], 21272180, 21302148), the Hubei Province Natural Science Foundation of China (2013CFA081),the Research Fund for the Doctoral Program of Higher Education of China ([1**********]002),and the Ministry of Science and Technology of China (2012YQ120060).The support from theProgram of Introduc-ing Talents of Discipline to Universities of China (111Program) is also appreciated.
Keywords:C ÀH activation ·cross-coupling ·dehydrogenation ·homogeneous catalysis ·zinc
[8]
[9]
[10]
[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.
[11]
[12]
Received:September 26, 2015
Published online:&&&&, &&&&
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Communications
Homogeneous Catalysis S. Tang, L. Zeng, Y . Liu, A. Lei*
&&&&—&&&&
Zinc-Catalyzed Dehydrogenative Cross-Coupling of Terminal Alkynes with Aldehydes:Access to
Ynones
Angew. Chem. Int. Ed. 2015, 54, 1–5Cross paths :The title reaction for C(sp2) Àmild reaction conditions. Notably, a good H/C(sp)ÀH cross-coupling of terminal reaction selectivity and efficiency could be alkynes with aldehydes was developed. It achieved with a 1:1ratio of terminal provides a simple way to access ynones alkyne and aldehyde.
from readily available materials under
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