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Synlett 2010(9): 1341-1344  
DOI: 10.1055/s-0029-1219921
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Indium(I)-Mediated Radical Carbon-Carbon Bond-Forming Reaction in Aqueous Media

Masafumi Uedaa, Hideto Miyabeb, Masafumi Toriia, Takahiro Kimuraa, Okiko Miyata*a, Takeaki Naito*a
a Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
Fax: +81(78)4417554; Fax: +81(78)4417642; e-Mail: miyata@kobepharma-u.ac.jp; e-Mail: taknaito@kobepharma-u.ac.jp;
b School of Pharmacy, Hyogo University of Health Sciences, Minatojima, Chuo-ku, Kobe 650-8530, Japan

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Publication History

Received 12 March 2010
Publication Date:
06 May 2010 (online)

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Abstract

The carbon-carbon bond-forming radical reactions using indium(I) chloride and copper(I) chloride proceeded effectively through a single-electron transfer process in aqueous media.

Key words

indium(I) chloride - copper(I) chloride - radical addition - oxime ether - domino reaction - aqueous media

The indium-mediated carbon-carbon bond-forming reactions in aqueous media have been of great importance in organic synthesis. [¹-³] Particularly, a low first ionization potential of 5.79 eV makes indium(0) metal attractive for electron-transfer reactions. [²] However, indium-mediated radical reaction has received much less attention, [³-7] although the use of indium has continued to increase in synthetic organic chemistry. Recently, we started to investigate the utility of indium(0) in radical reactions and found that indium(0) has the potential to induce radical reactions as a radical initiator via single electron-transfer process. [4] As a novel related method, indium(0) and iodine mediated reductive radical cyclization of iodoalkenes and iodoalkynes has also been reported by Yanada and Takemoto. [5] Very recently, Loh’s group reported an efficient method for the alkylation of imines and nitrones promoted by indium-copper in aqueous media. [8] On the other hand, the utility of indium(I) salts as promoters of radical reactions was much less explored, probably because the second ionization potential for indium is much higher (18.86 eV). [9] [¹0] Therefore, indium(I) halides are only employed for the reactions of a limited number of substrates and the latent reactivities are not disclosed completely so far. [9] Additionally, indium-mediated reactions show considerable potential but current vagaries limit their acceptance. [¹a] From synthetic point of view, it is necessary to broaden the scope of indium chemistry by introducing structural diversity on the starting radical acceptors which should open routes to the efficient synthesis of a large amount of compounds.

In this communication, we present an efficient method for promoting the aqueous-medium radical addition to a variety of substrates involving carbon-nitrogen or carbon-carbon double bonds and the α,β-unsaturated analogue by using the suitable combination of indium(I) chloride and copper(I) chloride. [¹¹] [¹²]

Table 1 Isopropyl Radical Addition to Oxime Ether 1

Entry InXn Solvent Additive Yield (%)a
 1b InCl H2O-MeOH none 63
 2b InCl CH2Cl2 none no reaction
 3b InBr H2O-MeOH none trace
 4b InI H2O-MeOH none no reaction
 5c InCl H2O-MeOH CuCl 97
 6c InCl CH2Cl2 CuCl no reaction
 7c InCl H2O-MeOH CuBr 74
 8c InCl H2O-MeOH CuI 65
 9c InCl H2O-MeOH CuCl2 50
10d InBr H2O-MeOH CuCl 84
11d InI H2O-MeOH CuCl 18 (74)
12e none H2O-MeOH CuCl no reaction
13b InCl2 H2O-MeOH none 24 (50)
14c InCl2 H2O-MeOH CuCl 45 (22)
15c InCl3 H2O-MeOH CuCl no reaction
a Isolated yield; yields in parentheses are for the recovered starting material 1.
b Reactions were carried out with i-PrI (5 equiv X 2) and InXn (10 equiv).
c Reactions were carried out with i-PrI (5 equiv X 2), InXn (10 equiv), and CuXn (1 equiv).
d Reactions were carried out with i-PrI (5 equiv X 2), InX (10 equiv), and CuCl (4 equiv).
e Reaction was carried out with i-PrI (5 equiv X 2) and CuCl (4 equiv).

We first report the results of an experiment to probe the utility of InCl as a radical initiator. In views of our previous success in promoting radical reaction by indium(0) metal [4a] and of recently reported Loh’s work, [8] we began to investigate the reaction of glyoxylic oxime ether 1 with isopropyl iodide under several reaction conditions using indium(I) salts. [¹³] On our initial attempt, the reaction using InCl in H2O-MeOH gave the desired adduct 2 in 63% yield (Table  [¹] , entry 1). Aqueous solvent was essential to achieve good conversions; when the reaction was carried out in organic solvent such as CH2Cl2, no desired product was observed (entry 2). In contrast to InCl, InBr and InI were less effective under the similar reaction conditions (entries 3 and 4). It is important to emphasize that InCl worked well in aqueous media, in spite of a high second ionization potential of indium. Therefore, as one possible reaction pathway, we propose that the first step of the present reaction would be the disproportionation of InCl giving indium(0) metal (Scheme  [¹] ). [¹4] Another role of InCl would be the activation of oxime ether group as Lewis acid. [¹0] Further experiments showed that the addition of CuCl led to an enhancement in chemical yield (entry 5). The monophasic reaction of 1 in H2O-MeOH gave the isopropylated product 2 in 97% yield without formation of significant byproducts such as a reduced product. At this stage, the role of CuCl in our reactions was questioned. We assume that one role would involve the activation of InCl or the promotion of disproportionation by redox reaction between indium(I) and copper(I). [¹5] Other copper(I) salts were also investigated but provided poor results relative to CuCl (entries 7 and 8). The addition of CuCl2 did not affect the chemical efficiency (entry 9). The combination of InBr and CuCl accelerated the reaction with good activity (entry 10), in contrast, the reaction using InBr in the absence of CuCl gave only a trace amount of product (entry 3). It was reported that copper(I) salts promoted radical reactions; [¹6] thus, we tried the reaction with CuCl in the absence of indium(I) salts, however, no reaction took place (entry 12). More interestingly, InCl2 promoted the reaction to form the product 2 in moderate yields (entries 13 and 14). However, InCl3 did not work (entries 15). [7] On the basis of these results, we concluded that the best conditions are shown in entry 5. As an alkyl radical precursor, primary iodide such as methyl iodide did not work and tert-butyl iodide gave a complex mixture. It is important to note that the reaction using InCl and CuCl was suppressed by the addition of a galvinoxyl free radical as radical scavenger. Thus, the present indium(I)-induced reaction proceeded through a radical mechanism based on a single-electron transfer process (Scheme  [¹] ), which was analogously proposed by Loh’s group under different reaction conditions but with no systematic investigation and discussion involving scavenger experiment. [8]

Scheme 1 Proposed reaction pathway from 1 to 2

To survey the scope and limitations of the present method, we next investigated the reaction of hydrazones 3 and 5 (Scheme  [²] ). [¹7] Under analogous reaction conditions using InCl-CuCl system, the reaction of 3 with isopropyl radical was facile to give product 4a in 93% yield. The sec-butyl and cyclopentyl iodides worked well. Good diastereoselectivity was observed in the reaction of hydrazone 5, although its reaction was slightly less effective, which was attributed to the greater steric bulk. In general all reactions found here took place effectively as in the case of In(0)-mediated reaction. [4]

Scheme 2 Alkyl radical addition to hydrazones 3 and 5

Further application of InCl-CuCl system into the α,β-­unsaturated imines 7a and 7b led us very interesting result as follows. Treatment of conjugated oxime ether 7a with isopropyl iodide in the presence of InCl and CuCl in H2O-EtOH gave regioselectively β-addition product 9a in 58% yield (Table  [²] , entry 1). Interestingly, lacking of CuCl gave a mixture of two products 8a and 9a in 18% and 22% yields, respectively, with 4% yield recovery of 7a (entry 2). The former product 8a is β-isopropyl and α-hydroxy adduct. [¹7c] When H2O-Et2O was employed as a solvent, two products 8a and 9a were produced more efficiently in 40% and 38% yields, respectively (entry 3). In order to explain the origin of hydroxy group on adduct 8a, oxygen saturated ether was employed as H2O-Et2O system, but both alkyl adduct 9a and hydroxylated alkyl adduct 8a were formed in less yields indicating that too much amount of oxygen retards the reaction (entries 4 and 5). As an alternative solvent system, H2O-CH2Cl2 combination in the absence of CuCl gave both products 8a and 9a in better yields (entry 6). The corresponding conjugated hydrazone 7b worked well to afford isopropyl adduct 9b in moderate yield with a trace amount of hydroxylated alkyl adduct 8b under InCl-CuCl conditions in H2O-Et2O or H2O-EtOH (entries 7 and 8).

Table 2 Isopropyl Radical Reaction to α,β-Unsaturated Imines 7a and 7b a

Entry Substrate Solvent Additive (1 equiv) Time (h) Yield of 8a,b b (%)c Yield of 9a,b (%)c
1 7a H2O-EtOH CuCl  3 - 58
2 7a H2O-EtOH none  5 18 22d
3 7a H2O-Et2O CuCl  7 40 38
4 7a H2O-Et2Oe none  5 28 22d
5f 7a H2O-Et2Oe none  6 19 10d
6 7a H2O-CH2Cl2 none 24 30 47
7 7b H2O-Et2O CuCl  5 trace 50d
8 7b H2O-EtOH CuCl  5 trace 61
a Reactions were carried out with i-PrI (5 equiv X 2) and InCl (10 equiv) under air atmosphere.
b Obtained as 3.7-2.3:1 ratio of anti/syn isomers.
c Isolated yields.
d A small amount of substrate was recovered. e Pretreatment of Et2O with O2 gas.
f Reaction was carried out under O2 gas.

Reaction pathway from conjugated oxime ether 7a to isopropyl adduct 9a is reasonably explained through two step process of SET via a carbanion intermediate D, while the pathway from 7a to β-isopropyl and α-hydroxy adduct 8a is not clear but proposed as shown in Scheme  [³] .

Scheme 3 Proposed reaction pathway from 7a to 8a and 9a

To gain further insight into the utility of InCl-CuCl system, we next examined the reaction of several radical acceptors which were employed in our previous studies (Scheme  [4] ). [4] [¹8] [¹9] Reaction of N-Ts imine 10 proceeded smoothly to give the desired product 11 in good yield. [¹8] Next, radical addition to electron-deficient C=C bond was investigated. Radical 1,4-addition to 12 proceeded effectively to provide a new carbon-carbon bond-forming method in aqueous media. Phenyl vinyl sulfone 14 also worked well without significant polymerization. The InCl-CuCl system was successfully applied to the domino radical addition-cyclization-trapping reaction of 16. [¹9]

Scheme 4 Radical addition to various substrates 10, 12, 14, and 16

In conclusion, we have disclosed an efficient InCl-CuCl system promoting the radical reactions in aqueous media which are amenable to green chemistry. In conjunction with Loh’s group works, [8] our found InCl-CuCl-mediated reaction is proved to be quite general and applicable to a substrate of wide scope, because it does not require the use of moisture-sensitive irritant tin hydride and any special precautions such as drying, degassing, and purification of solvents.

Acknowledgment

This work was supported in part by Grant-in-Aid for Young Scientists (B) (M.U.), for Scientific Research (C) (H.M.), for Scientific Research (B) (T.N.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Our thanks are also directed to the Science Research Promotion Fund of the Japan Private School Promotion Foundation for a research grant.

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General Procedure for the Reaction of Oxime Ether 1
To a microtube containing oxime ether 1 (50 mg, 0.26 mmol), i-PrI (1.3 mL, 1.3 mmol), indium salt (2.6 mmol), copper salt (0.26 mmol), and MeOH (0.2 mL) H2O was added dropwise (0.4 mL) at r.t. After the reaction mixture was vigorously stirred at the same temperature for 1 h, i-PrI (1.3 mL, 1.3 mmol) was added to the reaction mixture. After being vigorously stirred at the same temperature for 1 h, the reaction mixture was diluted with aq 36% potassium sodium (+)-tartrate and then extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated under reduced pressure. Purification of the residue by preparative TLC (hexane-EtOAc, 4:1) afforded the adduct 2 4b in the yields shown in Table  [¹] .

13

General Procedure for the Reaction of Oxime Ether 1
To a microtube containing oxime ether 1 (50 mg, 0.26 mmol), i-PrI (1.3 mL, 1.3 mmol), indium salt (2.6 mmol), copper salt (0.26 mmol), and MeOH (0.2 mL) H2O was added dropwise (0.4 mL) at r.t. After the reaction mixture was vigorously stirred at the same temperature for 1 h, i-PrI (1.3 mL, 1.3 mmol) was added to the reaction mixture. After being vigorously stirred at the same temperature for 1 h, the reaction mixture was diluted with aq 36% potassium sodium (+)-tartrate and then extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated under reduced pressure. Purification of the residue by preparative TLC (hexane-EtOAc, 4:1) afforded the adduct 2 4b in the yields shown in Table  [¹] .

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Scheme 1 Proposed reaction pathway from 1 to 2

Scheme 2 Alkyl radical addition to hydrazones 3 and 5

Scheme 3 Proposed reaction pathway from 7a to 8a and 9a

Scheme 4 Radical addition to various substrates 10, 12, 14, and 16