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Synlett 2014; 25(10): 1419-1424
DOI: 10.1055/s-0033-1339004
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© Georg Thieme Verlag Stuttgart · New York

Copper-Catalyzed Diarylation of Activated Alkenes with Diaryliodonium Salts

Yang Yang
a   Key Laboratory of Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China   Fax: +86(21)64253881   Email: wanglimin@ecust.edu.cn
,
Jianwei Han*
b   Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, The Chinese Academy of Sciences, 345 Ling Ling Road, Shanghai, 200032, P. R. of China   Fax: +86(21)54925583   Email: jianweihan@sioc.ac.cn
,
Xunshen Wu
a   Key Laboratory of Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China   Fax: +86(21)64253881   Email: wanglimin@ecust.edu.cn
,
Song Mao
a   Key Laboratory of Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China   Fax: +86(21)64253881   Email: wanglimin@ecust.edu.cn
,
Jianjun Yu
a   Key Laboratory of Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China   Fax: +86(21)64253881   Email: wanglimin@ecust.edu.cn
,
Limin Wang*
a   Key Laboratory of Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China   Fax: +86(21)64253881   Email: wanglimin@ecust.edu.cn
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Further Information

Publication History

Received: 24 February 2014

Accepted after revision: 07 April 2014

Publication Date:
19 May 2014 (online)

 
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Abstract

Cu(OTf)2-catalyzed diarylation of activated alkenes by using diaryliodonium(III) salts has been developed. With this method, arylated oxindoles can be easily accessed in good yields. Insights into the mechanism of copper-catalyzed arylations are discussed, and the findings are expected to help increase the level of understanding of catalytic arylations with diaryliodonium salts.


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Key words

alkene activation - arylation - diaryliodonium salts - oxindoles - copper triflate

Direct arylation, which allows efficient incorporation of arenes into functional molecules, has been one of the most important synthetic methodologies to have been developed in modern organic chemistry. In particular, arylation of alkenes such as the well-known Mizoroki–Heck reactions,[1] Meerwein coupling reactions,[2] and conjugate additions of activated alkenes with aryl boronic acid or organometallic reagents,[3] have been widely investigated. Among the available approaches, the use of diaryliodonium salts (Ar2I+X–) as electrophilic arylating agents has recently been developed for use in aryl-transfer reactions with olefins. In this context, several groups have made major contributions in the field of alkene arylation for Heck-type coupling reactions by using hypervalent iodine(III) reagents in a straightforward way.[4] Very recently, Gaunt et al. also developed an electrophilic carbofunctionalization of allylic amides with diaryliodonium salts for the preparation of oxazines under copper catalysis.[5]

Oxidative difunctionalization of activated alkenes for rapid access to oxindoles has also received much attention because of the potential application of the products of such reactions in pharmaceutical research.[6] A wide range of function groups including trifluoromethyl (CF3), azide (N3), halogen (Br and I), diphenylphosphine oxide [Ph2P(O)], carbonyl [RC(O)], nitro (NO2), substituted ­alkane, trifluoromethylthio (CF3S), sulfonyl (Ts) and ­oxaspirocycles have been introduced into oxindole frameworks through the application of a difunctionalization strategy[7] [8] since the elegant report of arylacetoxylation of alkenes described by Zhu and co-workers in 2010.[9] However, reports on the direct arylation of alkenes for the synthesis of arylated oxindoles are scarce.[10] As outlined in Scheme [1], the use of metal catalysts in combination with diaryliodonium salts can catalytically generate electrophilic arylating species [Scheme [1, ]Eq. (1)], and the resulting aromatic electrophiles can be used to arylate a range of nucleophiles in an efficient way; for example, in the arylation of polyfluoroarenes reported by us recently.[11] We therefore envisioned that initial arylation of alkenes with arylating species would result in an activated electrophilic intermediate that could conduct a second arylation through a C–H functionalization cascade process [Scheme [1, ]Eq. (2)].

Zoom Image
Scheme 1 Copper-catalyzed diarylation with diaryliodonium salts

Herein, we present our primary results on the copper-catalyzed diarylation of activated alkenes by using diaryliodonium(III) salts to mediate the simultaneous formation of two carbon–carbon bonds.

Table 1 Optimization of Reaction Conditionsa

Entry

X

Catalyst

Solvent

Yield (%)b

 1

BF4

CuI

DCE

71

 2

BF4

CuCl

DCE

70

 3

BF4

Cu(OAc)2

DCE

48

 4

BF4

Cu(OTf)2

DCE

82

 5

BF4

CuTCc

DCE

50

 6

OTs

Cu(OTf)2

DCE

trace

 7

OTf

Cu(OTf)2

DCE

72

 8

BF4

Cu(OTf)2

MeCN

trace

 9

BF4

Cu(OTf)2

DMF

trace

10

BF4

Cu(OTf)2

EtOH

trace

11

BF4

Cu(OTf)2

toluene

52

12

BF4

Cu(OTf)2

dioxane

62

13d

PhI

Cu(OTf)2

DCE

 0

a Reaction conditions: 1a (0.5 mmol), 2 (1 mmol), cat. (0.05 mmol), solvent (2 mL), 130 °C, 16 h.

b Isolated yield.

c Copper thiopenecarboxylate.

d Iodobenzene in place of diphenyliodonium salt.

Our investigation began with an examination of the reaction of N-arylacrylamide 1a with diphenyliodonium tetrafluoroborate in the presence of various copper catalysts in dichloroethane (DCE) at 130 °C. It was found that both copper(I) and copper(II) salts could catalyze this reaction, and that the use of 10 mol% Cu(OTf)2 gave the desired product 3a in 82% yield; the use of CuCl, CuI, Cu(OAc)2 or copper thiopenecarboxylate (CuTC) resulted in decreased yields (Table [1], entries 1–5). An evaluation of the effect of counter-anions of the diphenyliodonium salts showed that [Ph2I]OTf give 3a in 72% yield, but [Ph2I]OTs gave no product. In the case of [Ph2I]OTs, a large amount of phenyl para-toluenesulfonate (PhOTs) was isolated as a byproduct, which was presumably produced from decomposition of iodonium salts. The influence of solvent on the reaction was also examined. The results showed that DCE was the best choice and that only a trace amount of the desired product was observed in polar solvents such as MeCN, DMF, or ethanol (Table [1], entries 8–10). Notably, when iodobenzene was used in place of diphenyliodonium salts, no product at all was obtained.

With the optimized reaction conditions in hand, we investigated the scope of the reaction with a range of substrates 1 with diphenyliodonium tetrafluoroborate 2a. As shown in Scheme [2], substrates with various substituents on the ortho-, meta-, and para-positions of arylacrylamides reacted well, and the desired products 3b–i were obtained in yields of 51–83%. However, no desired product was found in the case of N-free arylacrylamides. Nevertheless, substrates with N-protecting groups n-butyl, benzyl and a long chain (C12H25) afforded 3k–m in good yields of 65–74%. Substituted olefin 1n, bearing a phenyl group, was also converted into the desired product in 48% yield. Tricyclic arylated oxindole 3o was prepared in 73% yield from the corresponding acrylamide under the developed conditions. The use of meta-substituted acrylamide 1p provided a mixture of products in 66% yield with a regioselectivity of 1:1.8.

Subsequently, we examined the structural diversity of the various diaryliodonium salts 2 as arylating partners (Table [2]). Notably, regardless of the electronic nature of the substituents, a wide variety of functionalities were tolerated in the diarylation of N-arylacrylamide. Some diaryliodonium triflates were also applied in this protocol because of their availability in the laboratory and, as expected, the desired products were obtained in good yields (entries 3–5). Steric factors severely affected the reactivity, and almost no reaction took place with bis(2,4,6-trimethylphenyl)iodonium triflate (2f) as arylating reagent. Unsymmetrical aryl-mesityl iodonium reagents were also employed in the diarylation of 1a, and we were delighted to find that salts with either electron-rich or -deficient groups worked well; moreover, a broad range of ortho-, meta-, and para-substituted aryl rings could be readily transferred to give the desired products (entries 7–15). It is worth mentioning that the unsymmetrical salt [(4-MeOC6H4)(Ph)I]BF4 selectively transferred the Ar group to give the desired products 3a/4e in a yield of 75% with a ratio of 2.5:1 (entry 16). When [(2-thienyl)(Ph)I]OTf was employed under the standard conditions, 3a was formed exclusively; disappointingly, the heteroatomic ring was not transferred to give the desired product (entry 17).

Zoom Image
Scheme 2 Scope of the reaction with N-arylacrylamides. Reagents and conditions: 1 (0.5 mmol), 2a (1 mmol), Cu(OTf)2 (0.05 mmol), and DCE (2 mL), 130 °C, 16 h; Isolated yields are given.

We then analyzed in more detail the impurities formed in this reaction and found that, in several cases, trace amounts of the undesired diarylated product were observed by LC–MS spectrometry experiments. During the synthesis of 3j, although none of the desired product was formed, arylated and diarylated products were obtained in 21 and 39% yield, respectively [Scheme [3, ]Eq. (1)]. The by-products were finally identified as 5 and a double arylated product 6, which is consistent with the meta-selectivity observed in the copper-catalyzed C–H bond arylation by Gaunt et al.[12a] Moreover, when olefin 7 was subjected to the reaction conditions [Scheme [3, ]Eq. (2)], para-arylation of the aromatic ring of 7 was found, but no cyclized product was observed.[12b] It was clear that the reaction site on the aromatic ring or on the olefin (Scheme [3, ] A, B, or C) was determined by the directing groups (amide or ester) on the substrates; as a result, the product outcomes differ significantly using this procedure.

Table 2 Scope of Reaction with Diaryliodonium Saltsa

Entry

2

X

Ar1

Ar2

Product

Yield (%)b

1

2a′

BF4

2-MeC6H4

2-MeC6H4

4a

56

2

2b

BF4

4-ClC6H4

4-ClC6H4

4b

70

3

2c

OTf

4-FC6H4

4-FC6H4

4c

55

4

2d

OTf

4-tBuC6H4

4-tBuC6H4

4d

57

5

2e

OTf

4-MeOC6H4

4-MeOC6H4

4e

60

6

2f

OTf

mesityl

mesityl

4f

–

7

2a′′

BF4

mesityl

Ph

3a

75

8

2p

BF4

mesityl

2-MeC6H4

4a

49

 9

2g

BF4

mesityl

4-MeC6H4

4g

59

10

2h

BF4

mesityl

4-EtO2C-C6H4

4h

67

11

2i

OTf

mesityl

3-MeC6H4

4i

61

12

2j

OTf

mesityl

2-BrC6H4

4j

40

13

2k

OTf

mesityl

4-BrC6H4

4k

58

14

2l

OTf

mesityl

3-FC6H4

4l

56

15

2m

OTf

mesityl

2-ClC6H4

4m

48

16

2n

BF4

4-MeOC6H4

Ph

3a/4e

54/21

17

2o

OTf

2-Thienyl

Ph

3a

53

a Reaction conditions: 1a (0.5 mmol), 2 (1 mmol), Cu(OTf)2 (0.05 mmol), DCE (2 mL), 130 °C, 16 h.

b Isolated yield.

We next sought to investigate the mechanism of this reaction. On the basis of previous reports,[7] the possible presence of radical intermediates[4d] in the oxidative difunctionalization of N-arylacrylamides was examined. A control experiment to establish the involvement of radical species in the reaction was carried out with the inclusion of the radical inhibitor 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO; 3 equiv) in the reaction of 1a and 2a under the same reaction conditions; in this case only 7% yield of the desired product 3a was obtained [Scheme [4, ]Eq. (1)].

Zoom Image
Scheme 3 The site reactivity of the copper-catalyzed arylation

Gaunt and Macmillan have pioneered the development of enantioselective arylations by employing Cu-PhBox catalyst 9.[13] Thus, an asymmetric version of the diarylation of 1a was also attempted by using the same chiral catalyst 9; however, only 3% ee of 3a was obtained in 50% yield at a temperature of 60 °C [Scheme [4, ]Eq. (2)]. Although it is premature to draw precise conclusions on the existence of radicals or carbocations in the reaction at this stage, the above results together with control experiments imply a possible radical mechanism in the diarylation of activated alkenes 1.

Zoom Image
Scheme 4 Control experiment and an asymmetric version of the diarylation of 1a

In summary, the copper-catalyzed diarylation of activated alkenes by using diaryliodonium(III) salts has been developed.[14] Arylated oxindoles were synthesized in yields of 40–83%. A broad applicability of this method for the construction of relevant chemical entities is anticipated, and further studies on the reaction mechanism and asymmetric catalysis in this reaction are ongoing in our laboratory.


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Acknowledgment

This work was supported by the National Nature Science Foundation of China (NSFC, 21272069, 21202186) and the Fundamental Research Funds for the Central Universities, Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/products/ejournals/journal/ 10.1055/s-00000083.
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Zoom Image
Scheme 1 Copper-catalyzed diarylation with diaryliodonium salts
Zoom Image
Scheme 2 Scope of the reaction with N-arylacrylamides. Reagents and conditions: 1 (0.5 mmol), 2a (1 mmol), Cu(OTf)2 (0.05 mmol), and DCE (2 mL), 130 °C, 16 h; Isolated yields are given.
Zoom Image
Scheme 3 The site reactivity of the copper-catalyzed arylation
Zoom Image
Scheme 4 Control experiment and an asymmetric version of the diarylation of 1a