· (MW 221.18)
Physical Data: mp 586 ± 3 °C (in a sealed tube); sublimes at 498 °C; d 4.0 g cm-3.
Solubility: soluble in water with evolution of heat, soluble in THF, EtOAc, and ethanol.
Form Supplied in: yellowish deliquescent crystals or compact crystalline mass. Indium trichloride tetrahydrate is also commercially available.
Preparative Methods: by passing chlorine in a stream of nitrogen over indium metal heated to about 140 °C.1
Purification: by sublimation under stream of nitrogen containing chlorine.
Handling, Storage, and Precautions: extremely hygroscopic, keep tightly closed and store under nitrogen. Handle in a glove box. Toxicity MLD s.c. in rats: 10.2 mg kg-1, MLD i.v. in rabbits: 0.64 mg kg-1.
Indium trichloride has recently emerged as a useful reagent/catalyst for various organic transformations both in aqueous and organic media. Reviews on InCl3-prompted and catalyzed reactions have recently appeared.2
Indium trichloride readily undergoes transmetalation with organolithium and Grignard reagents to afford organoindium reagents, which are used for various carbon-carbon bond forming reactions.3
The allylation of aldehydes, ketones, and quinones is achieved by using a combination of metallic aluminum or zinc and a catalytic amount of InCl3.4 Only 4-6 mol % of InCl3 is sufficient for obtaining the maximum yield. When the reaction is carried out in anhydrous THF, the yields of the homoallylic alcohols are decreased owing to competing Meerwein-Ponndorf reduction. The presence of water is effective to suppress this undesired side reaction. InCl3 is considered to be reduced by aluminum or zinc to metallic indium, which forms an allylindium reagent. The allylation of aldehydes with allylic bromide in water, in the presence of stoichiometric amounts of InCl3 and tin, proceeds cleanly to give the corresponding g-adducts (1).5 The major diastereomer has the anti configuration. No allylation product is obtained when the reaction is carried out in DMF. Premixing of InCl3, tin, and substituted allylic bromides is essential for the success of this reaction to be carried out in water. The transmetalation from allylic stannane to allylic indium via an SE2´ process is postulated during the reaction, and the high anti selectivity can be explained by a six-membered ring transition state. Similarly, the reaction of unprotected carbohydrates with allyl bromide proceeds smoothly in water without heating or ultrasonication.
1,1,1-Trifluoro-4-bromobut-2-ene reacts with various aldehydes in the presence of InCl3 and tin to form trifluoromethyl-substituted allylated products in high yields and with excellent regio- and diastereoselectivity.6 Strong anti selectivity is observed in most reactions, while the syn products are formed only when 2-pyridinecarboxaldehyde and glyoxylic acid are used. This syn selectivity is due to the five-membered ring chelation of the substrates with indium. The indium trichloride-promoted, tin-mediated allylation of trifluoroacetaldehyde ethyl hemiacetal proceeds smoothly in water to afford the a-trifluoromethylated alcohol (2).7 The possible ethoxy-substituted compound is not detected.
In various donor solvents such as acetone and acetonitrile, InCl3 undergoes transmetalation with crotylstannane, and the resulting allylic indium species affords anti adducts with aldehydes (3).8 The stannane is added to a solution of aldehyde and InCl3. Premixing of the stannane and InCl3 produces an immediate precipitate, and subsequent addition of aldehyde results in slow formation of product in low yield after prolonged reaction times. Addition of the (R)-a-(methoxymethoxy) allylic stannane (>95% ee) to cyclohexanecarboxaldehyde affords predominantly the anti-adduct (anti/syn 98:2) and stereoselectively (>95% ee) (4). The transient allylic reagent is postulated via a stereospecific anti SE2´ transmetalation. This a-(methoxymethoxy) allylic stannane reacts without allylic inversion, whereas the reaction of the crotylstannane in 3 proceeds with net allylic inversion. Ethyl acetate has been found to be a superior solvent for the reactions of a-oxyallyl stannanes.9 This methodology provides efficient access to differentially protected hexose precursors. d-Oxygenated allylic stannanes also undergo transmetalation with InCl3.10 In situ addition to a-ODPS acetaldehyde leads mainly to the anti adduct, which is a potential precursor to D-(+)-altrose (5).10b Total syntheses of the annonaceous acetogenins asiminocin, asiminecin, and asimicin have been achieved on the basis of this methodology.11
Indium trichloride mediates the intramolecular cyclization of the prochiral allylstannyl diketone to afford the desymmetrized cis-cis cyclohexanol predominantly. The use of TiCl4 in place of InCl3 gives the cis-trans diastereomer (6).12
In combination with InCl3, allyltrimethylsilane allylates gem-diacetates to afford the corresponding homoallylic acetates in high yields.13 The reaction of benzylidene 1,1-diacetate with allyltrimethylsilane in the presence of 10 mol % InCl3 gives the homoallylic acetate in 90% yield (7). Similarly, several aldehyde acylals are coupled smoothly at ambient temperature, these reactions being completed within 5-10 h. Nitromethane and dichloromethane are effective solvents in terms of conversion and reaction time.
Aldehydes react with 1-substituted-3-bromo-3,3-difluoropropynes in the presence of InCl3 and tin.14 The reaction occurs exclusively at the CF2 terminus to afford the corresponding gem-difluorohomopropargyl alcohols (8). Transmetalation of allenylstannane with InCl3 and subsequent addition to a chiral aldehyde leads to the anti, syn and anti, anti adducts (9).15
Indium trichloride catalyzes the Diels-Alder reaction in water.16 The reaction of acrolein with cyclopentadiene in the presence of 20 mol % InCl3 is completed in 2 h (10). The control reaction without any catalyst goes to only 60% completion. The InCl3-catalyzed reaction shows a high endo-to-exo selectivity of 91:9, compared with 74:26 in the absence of the catalyst. In general, the InCl3-catalyzed Diels-Alder reactions are clean and the desired adducts are obtained in good to excellent yields. InCl3 can be recovered for reuse after the reaction is completed.
In the presence of 20 mol % InCl3, N-benzylideneaniline reacts with cyclopentadiene in acetonitrile at room temperature. The imine acts as a heterodiene and the reaction proceeds smoothly to give the corresponding tetrahydroquinoline derivative in 75% yield in 30 min (11).17 Similar InCl3-catalyzed Diels-Alder reactions take place with 3,4-dihydro-2H-pyrane, indene,18 and cyclic enamides,19 whereas with cyclohexen-2-one, phenanthridinone is not formed, but azabicyclo[2.2.2]octanone is isolated in 65% yield with an endo/exo ratio of 69:31 (12).20 The reaction seems to proceed through the formation of a dienolate ion by strong coordination of InCl3 with the enone. Such activation of the enone to behave as a diene by coordination with Lewis acid is unprecedented.
Indium trichloride is also an excellent catalyst for ionic Diels-Alder reactions. A variety of acyclic and cyclic olefinic acetals undergo reactions with isoprene and cyclopentadiene in the presence of 20 mol % of InCl3 to form the corresponding cyclic adducts in good yields with good selectivity (13).21 Nitromethane is the best solvent in terms of reaction time and yields. In the case of cyclopentadiene-based reactions, the endo/exo ratio is fairly good and comparable to the LiClO4- and Nafion-H-based reactions. With Yb(OTf)3 or Sc(OTf)3, no cycloadduct is formed.
Aldol and Mannich Reactions
In combination with TMSCl, InCl3 catalyzes the aldol reaction between aldehydes and trimethylsilyl enol ethers in anhydrous organic solvents.22 Recently, it has been found that the InCl3-catalyzed aldol reactions can be performed in water in good yields (14).23 Generally, the reaction proceeds cleanly under extremely mild conditions (almost neutral). The aqueous phase with InCl3 can be reused without a decrease in yields. Only a catalytic amount of InCl3 (20 mol %) is required to complete the reaction. Of special interest is the fact that water-soluble aldehydes such as glyoxylic acid and commercial formaldehyde solution can be used directly for these reactions.
Contrary to these reports, it has been claimed that hydrolysis of silyl enol ethers is superior to the desired aldol reactions with aldehydes in water. The reactions have been found to proceed, to a certain degree, in the presence of InCl3 under neat (solvent-free) conditions, while substrate limitations have been observed. With the surfactant sodium dodecylsulfate (SDS, 35 mM, 0.2 equiv), benzaldehyde and 3-phenylpropionaldehyde react with 1-phenyl-1-trimethylsilyloxypropene in water at room temperature in the presence of 0.2 equiv of InCl3 to give the corresponding aldol adducts in 75% and 54% yields, respectively.24 An aldol reaction between the silyl enol ether derived from D-glucose and commercial formaldehyde in water is efficiently catalyzed by InCl3 to give the corresponding adduct diastereoselectively (R/S 96:4).25 One-pot Mannich-type reactions between aldehydes, amines, and silyl enol ethers are also catalyzed by InCl3 in water to give b-amino ketones and esters in moderate-to-good yields. With glyoxylic acid monohydrate as the aldehyde component, a-amino acids can be obtained (15).26 The aldimine-selectivity of InCl3 over aldehyde has been demonstrated in the addition with the silyl enol ether of propiophenone.27
Indium trichloride promotes the conjugate addition of primary and secondary amines to a, b-ethylenic compounds, such as acrylate, crotonate, and acrylonitrile, in water under mild conditions.28 When the reaction of acrylonitrile with diisopropylamine is performed in the presence of InCl3 (20 mol %), the monosubstituted product is obtained as the sole product in high yield. The catalyst can be reused without a decrease in yield. Under neat conditions, InCl3 is also an effective catalyst for Michael addition of silyl enol ethers and ketene silyl enol ethers to a, b-unsaturated ketones and esters, affording the corresponding Michael adducts in moderate to good yields (16).29
The reductive Friedel-Crafts alkylation of aromatics with aldehydes or ketones, using chlorodimethylsilane as a hydride source, is effectively promoted by a catalytic amount of InCl3 (17), whereas the more popular type of Friedel-Crafts catalyst, such as AlCl3, ZnCl2, and CF3SO3H, show less effect.30 Both aromatic and aliphatic ketones can be utilized to give the corresponding alkylated aromatics in moderate-to-good yields, while aliphatic aldehydes like hexanal result in the quantitative formation of dialkyl ether. Functional groups such as halogens, esters, and ethers on the ketones are tolerable under the reductive conditions.
The combination of InCl3 with silver perchlorate affords a system for catalytic acylation of electron-rich aromatics (18).31 The use of silver perchlorate as an additive provides the most active system. As well as acetic anhydride, acetyl chloride and isopropenyl acetate perform as satisfactory acyl donors.
Lithium indium hydride (LiInH4), prepared by mixing LiH and InCl3 in diethyl ether, readily reduces aldehydes (19).32 Reductions of ketones are less effective, giving a lower yield of alcohol. Acid chlorides are converted to esters with this reagent; esters, in turn, are little affected. The reducing ability of LiInH4 is increased by the introduction of phenyl group(s); LiPhInH3 and LiPh2InH2 readily reduce aldehydes, ketones, acid chlorides, and even esters to the corresponding alcohols.
Dichloroindium hydride (Cl2InH), generated by the reaction of InCl3 and tributyltin hydride, is successfully used for the reduction of carbonyl compounds and for the debromination of alkyl bromides.33 This reductant has features such as the chemoselective reduction of functionalized benzaldehydes, chelation-controlled reduction of benzoin methyl ether, and 1,4-reduction of chalcone. Dichloroindium hydride itself is inert to the reduction of acid chlorides. However, by the addition of 20 mol % of triphenylphosphine, high-yield reduction to aldehydes can be realized (20).34 The over-reduction to alcohols is negligible. This reduction works even with a catalytic amount of InCl3 (10 mol %). Neither electron-withdrawing nor -releasing substituents on aromatic acid chlorides disturb the facile formation of aldehydes, and cyano and nitro substituents tolerate the reduction conditions. Primary aliphatic acid chlorides also give good yields, even when terminal olefin and chlorine substituents are present. Bulky aliphatic acid chlorides give low yields accompanied with over-reduction to alcohols.
The combination of chlorodimethylsilane and a catalytic amount (5 mol %) of InCl3 is effective for deoxygenation of aryl ketones and sec-benzylic alcohols to the corresponding hydrocarbons (21).35 This system is selective for a carbonyl group and the functionalities such as halogens, esters, ethers, and nitro groups tolerate the reduction conditions.
A combination of chlorodimethylsilane and allyltrimethylsilane effectively promotes the deoxygenative allylation of aromatic ketones in the presence of a catalytic amount of InCl3 to give the terminal alkenes (22). The choice of solvent is definitely significant in this deoxygenative allylation; the reaction of acetophenone proceeds only in dichloromethane or 1,2-dichloroethane. Aldehydes and aliphatic ketones give complicated mixtures.36
The reaction of aldehydes with homoallyl alcohols mediated by InCl3 generates 4-chlorotetrahydropyrans with high stereoselectivity.37 Benzaldehyde and 1-phenylbut-3-en-1-ol are stirred with InCl3 in dichloromethane at room temperature, giving 4-chloro-2,6-diphenyltetrahydropyran in 81% yield (23). The two phenyl groups and the chlorine are equatorial. Other aromatic and aliphatic aldehydes are similarly converted into 4-chlorotetrahydropyran derivatives with both high yields and high stereoselectivity. The cross-cyclization of aldehydes with trans-homoallylic alcohols generates (up-down-up) 2,3,4-trisubstituted tetrahydropyrans, whereas with cis-homoallylic alcohols give (up-up-up) 2,3,4-trisubstituted products (24). By contrast, the reaction of both cis- and trans-homoallyl mercaptans with aldehydes provides the same major diastereomers (up-down-up).38 A similar stereochemical correlation is observed for the InCl3-catalyzed cross-cyclization between epoxides and homoallyl alcohols.39 The reaction of 3-trimethylsilylallyltributylstannane with aliphatic aldehydes leads to the formation of 2,6-dialkyl-3,4-dihydropyrans with a cis diastereoselectivity.40 With aromatic aldehydes, no distinctive product is obtained.
InCl3 is used for the cyclization of a-diazoketones with nitriles to produce 2,5-disubstituted oxazoles (25). However, 2-3 equiv of InCl3 are necessary for complete consumption of the a-diazoketone and to suppress a-chloroketone formation.41
When one equiv of D-glucal is treated with 10 mol % of InCl3·3H2O in acetonitrile for 2.5 h at ambient temperature, the chiral furan diol is obtained in 82% yield. As expected, D-galactal also undergoes transformation to afford the same product (26).42
InCl3-catalyzed reactions of ethyl diazoacetate with aldimines give aziridine carboxylates under mild conditions. N-Benzylidene aniline reacts with ethyl diazoacetate in the presence of 2 mol % InCl3 at room temperature for 1-3 h to afford the corresponding aziridine together with the corresponding enamine by-products. The latter can be easily removed by silica gel chromatography to give the pure cis-aziridine in 50% yield (27).43
A microwave-assisted one-pot procedure for the synthesis of quinolines has been achieved by use of InCl3. Amines and alkyl vinyl ketones react on the surface of InCl3-impregnated silica gel without any solvent, affording 4-alkylquinolines in high yields (28).44
A b-dicarbonyl compound, an aldehyde, and urea are coupled together in refluxing THF in the presence of InCl3 (10 mol %) to give the corresponding dihydropyrimidinones (29).45 A variety of substituted aromatic, aliphatic, and heterocyclic aldehydes have been subjected to this condensation. b-Keto aldehydes do not produce the corresponding dihydropyrimidinones.
1-Aryl-, 1,1-diaryl-, and 1-alkyl-1-aryl-substituted epoxides undergo rearrangement via an exclusive hydride shift to give the respective aryl-substituted acetaldehydes. As phenyl group migration occurs more readily than hydride migration, stilbene oxide is changed to diphenylacetaldehyde (30).46 InCl3 can be used as an efficient reagent for the conversion of aldoximes to nitriles and ketoximes to amides. Benzaldoxime is treated with InCl3 in MeCN to afford benzonitrile in 98% yield. When benzophenone oxime is reacted with InCl3 under the same conditions, the Beckmann rearrangement occurs within 15 min to give benzanilide in 95% yield (31).47 Sonication of a mixture of a carbonyl compound, an amine, and diethyl phosphite in THF in the presence of a catalytic amount of InCl3 produces a-aminophosphonate in a one-pot operation (32).48
Indium iodide (InI).
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Shuki Araki & Tsunehisa Hirashita
Nagoya Institute of Technology, Nagoya, Japan
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