Indium-mediated reactions

The classical aldol reaction usually employs a basic catalyst in a protic solvent. However, this process is often associated with undesirable side products. The 

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Whitesides et al. examined the effect of substituents on the allyllic moiety of the indium-mediated reactions in water and found that the use of indium at room temperature gave results comparable to those of tin-mediated reactions carried out at reflux.110 Replacement of the aqueous phase with 0.1 N HC1 further increased the rate of the reaction. The transformation can also be carried out with preformed allylindium chloride. 

Unsubstituted (3-lactams have instead been obtained, by the same authors, through indium-mediated reaction of imines with alkyl bromoacetates [52]. (3-Lactams having a wide range of substituents linked to the nitrogen atom, such as aryl, aryl alkyl, or allyl groups, could be prepared by this pathway. 

Lin, M.-J. Loh, T.-P. Indium-mediated reaction of trialkylsilyl propargyl bromide with aldehydes highly regioselective synthesis of allenic and homopropargylic alcohols. /. Am. Chem. Soc. 2003, 325,13042-13043. 

The reaction of imines with 2-pyridyl thioesters in the presence of aluminium tribromide or ethylaluminium dichloride afforded /ra r-3,4-disubstituted azetidin-2-ones < 1996T2583>. Similar stereoselective addition of silylketene thioacetals to imines is known in the presence of Lewis acids <1996T2573>. An indium-mediated reaction of ethyl bromoacetate with imines yielded 3-unsubstituted azetidin-2-ones in reasonable yields (Equation 195) <2000J(P1)2179>. 

An indium mediated reaction of o-carboxyarylpropargyl bromide 1131 with hexanal in aqueous media provides a route to the 4-allenyldihydroisocoumarin 1132 (Equation 439) <1998TL6837>. 

As shown below, a novel indium-mediated reaction of an iodoalkyne led to a 5-exo-cyclization involving radical species and as a result a 3-methylenetetrahydrofuran was obtained <02TL4585>. 

In indium-mediated reactions, a catalytic use of expensive indium is desirable from an economical standpoint, and it has been achieved in combination with more electron-positive metals. Thus, allylation of aldehydes and ketones, as well as prenylation of 2-chlorobenzoquinone, has been performed by using metallic aluminum or zinc in combination with a catalytic amount of indium(m) chloride.63 Also, allylation of aldehydes and ketones with allyl bromide is carried out with a catalytic amount of indium powder (from 0.01 to 0.1 equiv.) in THF in the presence of manganese and chlorotrimethylsilane as the reducing and oxophilic agents, respectively (Scheme 2). 64,65... 

Allylindium reagents bearing substituents at the 7-position react with carbonyl compounds in organic and aqueous media regioselectively at the 7-position, via a six-membered transition state, to afford the corresponding branched homoallylic alcohols, if no sterically bulky carbonyl or allyl substituent is involved.102 For example, the indium-mediated reaction of aldehydes with 3-bromo-l-cyano-l-propene proceeds readily in water to give cr-cyano-f3-ethylenic secondary alcohols (Scheme 4).103... 

Interestingly, the indium-mediated reactions of crotyl or cinnamyl bromide with aldehydes in the presence of 10 M water exclusively give the a-adducts regardless of the bulkiness of aldehydes (Scheme 6).105,106 NMR study has proved that the initially formed y-homoallylic alcohol is converted to the thermodynamic a-homoallylic alcohol. 

Indium-mediated reaction of a-chloropropargyl phenyl sulfide and aldehydes gives /2-hydroxysulfides regio- and stereoselectively in aqueous media (Scheme 12).1 ... 

Indium-mediated reaction of 4-bromo-l,l,l-trifluoro-2-butene with aldehydes in water proceeds stereoselectively to afford the /Ttrifluoromethylated homoallylic alcohols. Aldehydes with no chelation ability shows //////-selectivity, whereas high. //-selectivity has been attained with 2-pyridinecarboxaldehyde and glyoxylic acid (Scheme 23).134-136... 

The indium-mediated reaction of 2-(bromomethyl)acrylic acid with carbonyl compounds gives the corresponding 7-hydroxy-a-methylene carboxylic acids, and a-methylene-7-lactones are obtained after acidic workup (Scheme 28).80,144-146 The indium-mediated addition of 4-bromocrotonic acid to a variety of aldehydes and ketones proceeds exclusively at the ct-carbon of the carboxylic acid. The effect of solvent, including an ionic liquid, is minimal allowing a wide choice of conditions (Scheme 29).61... 

Allylindium, generated by transmetallation of 5-benzyloxy-4-methyl-2-pentenyl(tributyl)stannane, reacts with benzaldehyde leading to the l,5-< /z//-CE)-stereoisomer with a useful level of 1,5-stereoinduction (Equation (13)).151 2-C-branched sugars and C-disaccharides are prepared diastereoselectively by the indium-mediated reaction of 4-bromo-2-enpyranoside (Equation (14)).152... 

The indium-mediated reaction of cinnamyl bromide with 5-formyluracil derivatives gives the corresponding homoallylic alcohols (Equation (21)). The presence of G4 carbonyl is essential for high diasteroselection owing to the complexation with indium.182... 

The indium-promoted intramolecular cyclization of -substituted (Z)- 52 and ( )-7-bromo-5-heptenophenones 53 in aqueous THF gives yjw-2-vinylcyclopentanol 54 irrespective of the double-bond geometry in the starting material. These results suggest that the indium-mediated reactions involve intramolecularly coordinated transition states, where the development of a as 5/6-bicyclic framework is most energetically feasible (Scheme 53).210... 

Indium-mediated Barbier-type reaction of glyoxal monoacetal with bromomethyl acrylonitrile or bromomethyl-acrylate gives a masked a-hydroxy aldehyde (Equation (48)).91 The reaction of 3-bromo-2-chloro-l-propene, an aldehyde, and indium in water gives the corresponding homoallyl alcohol, which upon ozonolysis in methanol furnishes a / -hydroxy ester. The overall reaction is equivalent to the Reformatsky reaction, which cannot be realized by a direct indium-mediated reaction of an ct-halo ester with an aldehyde in water (Scheme 59).235... 

The allene aryl (5-lactones have conveniently been synthesized via the indium-mediated reaction of aldehydes with (<9-methoxycarbonylaryl)propargyl bromide in aqueous ethanol (Equation (55)).246 Indium-mediated ultrasonication reaction between aldehydes and l-bromo-2-butyne gives 1-substituted ( )-2,5-dimethyl-2,5,6-heptatrien-l-ols in moderate to good yields (Scheme 62).247... 

The allylation of imines with allylindium reagents in organic solvents gives the corresponding homoallylic amines.251-253 Under solvent-free conditions, the indium-mediated reaction of iV-benzylideneaniline furnishes a mixture of mono-allylated 79 and bis-allylated products 80 (Equation (56)). The bis-allylated product 80 presumably arises via a formation of an iminium salt, which is subsequently attacked by the allylindium nucleophiles. Formation of 80 is entirely suppressed by addition of allyl bromide to indium metal prior to any addition of the imine (Grignard-type reaction).254... 

Trifluoromethylaldimine reacts with various allylic bromides, under Barbier conditions in the presence of indium in DMF, to provide the corresponding homoallylamines (Equation (57)).255 a-Methylene-y-butyro-lactams are prepared by the indium-mediated reaction of 2-(bromomethyl)acrylic acid with aldimines (Equation (58)).256... 

Indium-mediated reaction of enamines with allyl bromides gives homoallylamines. The addition of one equivalent of acetic acid accelerates the reaction. An analogous reaction of methyl bromoacetate in place of allylic bromides is also possible. The iminium salts formed by protonation of the enamines are considered to be the intermediates (Scheme 70).271 272... 

The diastereoselective production of homoallylic indium alkoxides can be accomplished by a kinetic resolution process [194]. The indium-mediated reaction of benzaldehyde with 2-butenyl bromide has always been observed to be unselec-tive. The use of alkoxide or halide modifiers in the reactions of allylindium reagents has previously been shown to provide synthetically useful reagents [195], Upon addition of 2-butenylindium sesquibromide to benzaldehyde it was determined that newly formed syn and anti homoallylic alcohols undergo decomposition at a similar rate, but as the concentration of the anti homoallylic alcohol reaches zero, the rate of decomposition of the syn alcohol slows dramatically. Thus, the syn homoallylic alcohol can be obtained in high diastereoselectivity, albeit low yield. 

Furthermore, the isopropylated product has been converted into a-amino acid (Scheme 7.19) through cleavage of the N-N bond of the diaster-eochemically pure product by hydrogenolysis in the presence of Pearlman s catalyst. In earlier work on triethylborane-induced radical reactions in organic solvents, oxime ether showed excellent reactivity. Thus we expect that the direct comparison of indium-mediated reactions with triethylborane-induced reactions would lead to informative and instructive suggestions regarding the reactivity and stereochemical course of the transformation in question. 

Indium enolates, prepared conveniently by transmetalation of hfhium enolates with IriCl j, react wifh aldehydes to give fhe corresponding -hydroxy esters [80]. Ultrasound irradiation promotes fhe Reformatsky reaction of aldehydes and ethyl bromoacetate wifh indium [81]. Indium-mediated Reformatsky reaction of phenyl a-bromoalkanoates wifh ketones or aldehydes gives di-, tri-, and tetrasubstituted -lactones (Scheme 8.57) [82]. Indium-mediated reaction of imines with ethyl bromoacetate gives 3-unsubstituted -lactams (Scheme 8.58) [83]. An indium-Refor-matsky reagent prepared from 2-(chlorodifluoroacetyl)furan couples with aldehydes (Scheme 8.59) [84]. 

Carbonyl compounds are efficiently transformed into 2,2-dichloro-3-hydroxyni-triles by the action of trichloroacetonitrile and indium(I) bromide (Scheme 8.60) [85 a]. Bromocyanomethylation of carbonyl compounds is also achieved by reaction of dibromoacetonitrile and indium(I) bromide [85 b]. Indium-mediated reaction of a-chloropropargyl phenyl sulfide and aldehydes gives /i-hydroxysulfides regio- and stereoselectively in aqueous media (Scheme 8.61) [86]. 

More unexpected was the formation of cyclopropane during the indium-mediated reaction of dibenzylidene acetone with allyl bromide which gave l,l-distyryl-2-(but-3-enyl)cyclopropane as a mixture of four isotopomers (Scheme 31) [158]. In a related reaction, a simple and efficient one-pot method was developed to give chiral homoallylic amines and amino acids from the respective aldehydes with high stereoselectivity [159]. 

Though some of these reactions use enolisable aldehydes, none uses enolisable Michael acceptors so the question of competition of this a reaction with extended enolisation proper has not arisen. One alternative approach uses an indium-mediated reaction of the y-brominated ester 163 with aldehydes to give either non-conjugated 165 or conjugated 166 a -products.43... 

Substitution. Indium-mediated reaction of iodoalkynes with glycals or glycosyl... 

Propargylation. An approach to epoxyalkynes involves indium-mediated reaction of a-chloropropargyl sulfides with carbonyl compounds. Interestingly, opposite stereoselectivity is shown by a reaction using In and InCl,. 

Very recently, 3-deoxy-3,3-difluoro-D-ribohexose 32 was also conveniently prepared starting from the gew-difluoromethylenated synthon 15 in the Qing group. 1 As the first step, indium-mediated reaction of 15 with 1 -(R)-glyceraldehyde acetonide 25 gave the versatile intermediate 26 with anti isomer as major product (anti/syn = 7.7 1)... 

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