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Synlett 2019; 30(08): 932-938
DOI: 10.1055/s-0037-1611780
letter
© Georg Thieme Verlag Stuttgart · New York

Acetic Acid-Promoted Rhodium(III)-Catalyzed Hydroarylation of Terminal Alkynes

Chang-Lin Duan
a   Department of Chemistry, Shanghai Normal University, 100 Guilin Road, Shanghai 200234, P. R. of China   Email: shipingy@shnu.edu.cn
b   CAS Key Laboratory of Synthetic Chemistry of Natural Substances,Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China   Email: tianping@sioc.ac.cn   Email: lingq@sioc.ac.cn
,
Xing-Yu Liu
b   CAS Key Laboratory of Synthetic Chemistry of Natural Substances,Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China   Email: tianping@sioc.ac.cn   Email: lingq@sioc.ac.cn
d   School of Physical Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, P. R. of China
,
Yun-Xuan Tan
b   CAS Key Laboratory of Synthetic Chemistry of Natural Substances,Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China   Email: tianping@sioc.ac.cn   Email: lingq@sioc.ac.cn
,
Rui Ding
c   Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, P. R. of China   Email: tianping@shutcm.edu.cn
,
Shiping Yang*
a   Department of Chemistry, Shanghai Normal University, 100 Guilin Road, Shanghai 200234, P. R. of China   Email: shipingy@shnu.edu.cn
,
Ping Tian  *
b   CAS Key Laboratory of Synthetic Chemistry of Natural Substances,Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China   Email: tianping@sioc.ac.cn   Email: lingq@sioc.ac.cn
c   Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, P. R. of China   Email: tianping@shutcm.edu.cn
,
Guo-Qiang Lin*
b   CAS Key Laboratory of Synthetic Chemistry of Natural Substances,Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China   Email: tianping@sioc.ac.cn   Email: lingq@sioc.ac.cn
c   Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, P. R. of China   Email: tianping@shutcm.edu.cn
› Author Affiliations

Financial support was generously provided by the NSFC (Nos. 21572251, 21572253, and 21871184), the SMEC (No. 2019-01-07-00-10-E00072), the STCSM (No. 18401933500), the 973 Program (No. 2015CB856600), and the CAS (Nos. XDB 20020100 and QYZDY-SSW-SLH026).
Further Information

Publication History

Received: 18 February 2019

Accepted after revision: 13 March 2019

Publication Date:
26 March 2019 (online)

 
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◊Both authors contributed equally to this work

Abstract

Rhodium(III)-catalyzed hydroarylation of terminal alkynes has not previously been achieved because of the inevitable oligomerization and other side reactions. Here, we report a novel Cp*Rh(III)-catalyzed hydroarylation of terminal alkynes in acetic acid as solvent to facilitate the C–H bond activation and subsequent transformations. This reaction proceeds under mild conditions, providing an effective approach to the synthesis of alkenylated heterocycles in high to excellent yields (31–99%) with a broad substrate scope (37 examples) and good functional-group compatibility. In this transformation, the loading of the alkyne can be reduced to 1.2 equivalents, which indicates the significant role of HOAc in lowering the reaction temperature and suppressing the oligomerization of the terminal alkyne. Preliminary mechanistic studies are also presented.


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Key words

acetic acid - rhodium catalysis - hydroarylation - alkynes

◊These authors contributed equally to this work.

Transition-metal-catalyzed C–H bond activation has received considerable attention because it avoids the need for prior functionalization of substrates and provides an atom-economical method for organic synthesis.[1] Among transition-metal catalysts, the Cp*Rh(III) complex (Cp* = pentamethylcyclopentadienyl) has proven to be one of the most powerful catalysts because of its high reactivity, tolerance to robust reaction conditions, and broad substrate compatibility.[2] Because of the wide utility of alkynes as coupling partners,[3] the Cp*Rh(III)-catalyzed hydroarylation of alkynes through C–H bond activation has made significant progress in the past decade.

In 2010, Fagnou and co-workers reported the first example of a Cp*Rh(III)-catalyzed intermolecular hydroarylation of alkynes with indole by using an acetanilide directing group (Scheme [1]).[4a] In 2014, the Miura group realized a C–H alkenylation of a benzene ring by using sulfoxide[4b] and phenylphosphine sulfide[4c] as directing groups. The same C–H functionalization was then extended to chromones,[4d] tetrazole,[4f] and 1-(2H)-phthalazinone[4e] by other groups (Scheme [1]); these reactions might have considerable potential for use in organic synthesis and pharmaceutical chemistry.[5] Also, similar ortho-alkenylations of benzene with internal alkynes have been reported by the groups of Wang,[4g] Loh,[4h] and Nicholls.[4i] Moreover, the Shi group demonstrated that pyridines with strong coordination of nitrogen atom were well tolerated in this reaction.[4j] More recently, Miura and co-workers reported the C–H alkenylation of benzothiophenes without the aid of any directing group.[4k]

Zoom Image
Scheme 1 Cp*Rh(III)-catalyzed hydroarylations of alkynes. DG = directing group; Cp* = pentamethylcyclopentadienyl.

However, all these cases required high reaction temperatures and were limited to internal alkyne substrates. To our surprise, the Cp*Rh(III)-catalyzed hydroarylation of terminal alkynes had not been realized, due to their incidental oligomerization and other side reactions.[6] [7] [8] It was therefore necessary to develop a more general method for this reaction under mild conditions that could be applied to terminal alkynes. Here, we report the results of our researches on Cp*Rh(III)-catalyzed hydroarylations of terminal alkynes promoted by acetic acid as the solvent.

Inspired by Huang’s elegant work on Brønsted acid-enhanced Cp*Rh(III)-catalyzed conjugate addition of aryl C–H bonds to α,β-unsaturated ketones,[9] we surmised that the use of HOAc as a solvent might promote aryl C–H bond activation and suppress oligomerization of terminal alkynes. Thus, in an initial experiment, we treated 2-phenylpyridine (1a) with ethynylbenzene (2a) in the presence of [Cp*RhCl2]2 (5 mol %) in HOAc at 100 °C. We were pleased to find that the desired hydroarylation product 3aa was obtained in 67% yield (Table [1], entry 1). The addition of Cu(OAc)2 was detrimental to the reaction (entry 2) due to the oxidative character of Cu(II). On lowering the reaction temperature to 60 or 40 °C, quantitative yields were obtained (entries 3 and 4). To our delight, the reaction proceeded smoothly even at the room temperature, albeit with a slight decrease in yield to 88% (entry 5).

Table 1 Selected optimization studiesa

Entry

1a/2a

Solvent

Temp (°C)

Yieldb (%)

1

2:1

HOAc

100

67

2c

2:1

HOAc

100

47

3

2:1

HOAc

60

99

4

2:1

HOAc

40

99

5

2:1

HOAc

rt

88

6

1:2

HOAc

rt

92

7

1:1.2

HOAc

rt

99

8

1:1.2

MeOH

rt

0

9

1:1.2

F3CCH2OH

rt

0

10

1:1.2

(F3C)2CHOH

rt

0

11

1:1.2

H2O

rt

0

12d

1:1.2

HOAc

rt

33

13e

1:1.2

HOAc

rt

99 (94)f

a Reaction conditions: 1a (0.2 mmol), 2a, [Cp*RhCl2]2 (5 mol%), AgSbF6 (30 mol%), solvent (1 mL), under argon.

b Determined by 1H NMR analysis with CH2Br2 as an internal standard.

c In the presence of Cu(OAc)2 (40 mol%) as additive.

d Without AgSbF6.

e [Cp*RhCl2]2 (2.5 mol%) and AgSbF6 (15 mol%) were used.

f Isolated yield.

On adjusting the ratio of 1a to 2a (Table [1], entries 6–7), the yield increased to 99% and 1.2 equivalents of the alkyne were found to be sufficient for this reaction, confirming that HOAc is effective in suppressing undesired oligomerization. Other protic solvents [MeOH, F3CCH2OH, (F3C)2CHOH, or H2O] failed to give the desired product (entries 8–11). A control experiment showed that a poor yield (33%) was obtained in the absence of AgSbF6 (entry 12). Finally, reducing the catalyst loading to 2.5 mol% did not influence the catalytic efficiency (entry 13).

With the optimized conditions in hand, we first explored the scope for the alkyne (Scheme [2]). Neither electron-donating nor electron-withdrawing groups had any obvious effect on the formation of the hydroarylation products 3aa–ae. It was noteworthy that halogen atoms F, Cl, and Br remained intact after the reaction (3af–ah). Alkynes with ortho- or meta-substituents on the benzene also gave the corresponding products smoothly (3ai–aj).

Zoom Image
Scheme 2 Substrate scope of alkynes. Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2 (0.24 mmol, 1.2 equiv), [Cp*RhCl2]2 (2.5 mol %), AgSbF6 (15 mol %), HOAc (1.0 mL), rt, under argon, 12 h. Yields of the isolated products are reported. a 1a (0.4 mmol, 2 equiv) and 2 (0.2 mmol, 1 equiv) were used. b The ratio of the regioisomers was determined by 1H NMR analysis. c At 80 °C. d 2a (0.48 mmol, 2.4 equiv) was used.

Next, other aromatic rings were tested under our conditions. 2-Ethynylthiophene (2k), containing a hetaromatic ring, and 2-ethynylnaphthalene (2l) or 1-ethynylpyrene (2m), bearing larger extended conjugate systems, were also converted into the desired products (Scheme [2]; 3ak–am). Most importantly, various other aliphatic alkynes were equally suitable for this protocol, which showed excellent regioselectivity (Scheme [2]; 3an–ap). As for ethynyl(triisopropyl)silane (2q), the hydroarylation reaction also proceeded well to give product 3aq, albeit with a slightly lower yield and regioselectivity. Furthermore, a dialkenylated product 3aa′ was obtained by increasing both the loading of 2a and the reaction temperature. However, an ester-substituted alkyne [ethyl propiolate (2r)] and an internal alkyne [diphenylacetylene (2s)], failed to give the corresponding hydroarylation products 3ar and 3as.

Next, we examined the scope of the arylpyridine under our optimized conditions. Phenylpyridines with various functional groups at the para-position of the benzene ring, including an aldehyde group, gave the corresponding hydroarylation products in high yields (Scheme [3]; 3ba–ha). Next, the effects of substituents on the directing pyridine ring were investigated. 3-Methyl-2-phenylpyridine needed a higher temperature (80 °C) to complete this transformation due to the increased steric effect during C–H bond activation (Scheme [3]; 3ia).

Zoom Image
Scheme 3 Substrate scope of arylpyridines. Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2a (0.24 mmol, 1.2 equiv), [Cp*RhCl2]2 (2.5 mol %), AgSbF6 (15 mol %), HOAc (1.0 mL), rt, under argon, 12 h. Yields of isolated products are reported. a At 80 °C. b 2a (0.48 mmol, 2.4 equiv) was used.

Substitutions at other positions of the pyridine ring had no influences on the formation of the product under the standard conditions (Scheme [3], 3ja–la). Moreover, replacement of the phenyl ring with a thiophene or indole moiety was also tolerated, and the corresponding alkenylation products 3ma–oa were obtained in high yields. Next, other directing groups were tested. The more-hindered isoquinoline remained reactive at 80 °C (Scheme [3]; 3pa). Pyrazole also served as a directing group to afford the desired product (Scheme [3], 3qa). By controlling the amount of 2a, we were able to prepare the mono- or dialkenylated 2-phenylpyrimidines 3ra and 3ra′ selectively. Finally, to highlight the utility of this method, various 6-arylpurines were tested under our conditions.[10] We were pleased to find that various N-9 substituents, including isopropyl, cyclopropyl, and allyl groups, did not affect the high efficiency of this reaction (Scheme [3]; 3sa–ua).

Several experiments were conducted to gain further insight into this hydroarylation reaction. First, the rhodacyclic complex 4 was used in the reaction, and the product 3aa was obtained in high yield [Scheme [4](a)], indicating that 4 is probably the catalytically active species. Then, the pentadeuterated 2-phenylpyridine (1a-d 5) was treated under standard conditions in the absence of an alkyne, and 2-phenylpyridine was recovered with only 2% of D remaining [Scheme [4](b)], showing that a reversible C–H activation process had occurred. Two deuterium-labeling experiments were carried out in the presence of CH3COOD, and significant deuteration was observed at the olefinic C–H position [Scheme [4](c)], confirming that the solvent participates in the protonolysis and that the C–H bond cleavage in the terminal alkyne is reversible. Also, the low deuterium incorporation on the ortho C–H bond demonstrated inhibition of a second C–H bond activation. In addition, when the deuterated 2p-d 1 (95%) was treated with 1a in HOAc, obvious H–D exchange occurred on the terminal hydrogen of the alkyne, further confirming the reversibility of C–H bond cleavage in the terminal alkyne [Scheme [4](c)]. Next, a kinetic isotope effect (KIE) study was performed through an intermolecular competition reaction [Scheme [4](d)]. The result of this experiment (kH/kD = 2.0) showed that C–H bond activation might be involved in the turnover-limiting step.

Zoom Image
Scheme 4 Mechanistic studies

In conclusion, we have developed a novel Cp*Rh(III)-catalyzed alkenylation of arenes with terminal alkynes under mild conditions.[11] This reaction offers a convenient method for the construction of alkenylated heterocycles with excellent regioselectivity, broad substrate scope, and good functional-group compatibility. Furthermore, the low alkyne loading (1.2 equivalents) indicated that incidental oligomerization was effectively suppressed by the use of HOAc as solvent. AcOH as solvent also suppressed the inherent substrate-inhibition effect in this type of reaction. Studies on other Cp*Rh(III)-catalyzed C–H bond-activation reactions are in progress in our laboratory.


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Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0037-1611780.
  • Supporting Information


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Zoom Image
Scheme 1 Cp*Rh(III)-catalyzed hydroarylations of alkynes. DG = directing group; Cp* = pentamethylcyclopentadienyl.
Zoom Image
Scheme 2 Substrate scope of alkynes. Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2 (0.24 mmol, 1.2 equiv), [Cp*RhCl2]2 (2.5 mol %), AgSbF6 (15 mol %), HOAc (1.0 mL), rt, under argon, 12 h. Yields of the isolated products are reported. a 1a (0.4 mmol, 2 equiv) and 2 (0.2 mmol, 1 equiv) were used. b The ratio of the regioisomers was determined by 1H NMR analysis. c At 80 °C. d 2a (0.48 mmol, 2.4 equiv) was used.
Zoom Image
Scheme 3 Substrate scope of arylpyridines. Reaction conditions: 1 (0.2 mmol, 1.0 equiv), 2a (0.24 mmol, 1.2 equiv), [Cp*RhCl2]2 (2.5 mol %), AgSbF6 (15 mol %), HOAc (1.0 mL), rt, under argon, 12 h. Yields of isolated products are reported. a At 80 °C. b 2a (0.48 mmol, 2.4 equiv) was used.
Zoom Image
Scheme 4 Mechanistic studies