Indium Reformatsky reactions

The zinc-mediated Reformatsky reaction is one of the classical methods for carbon-carbon bond formation. To date, various main group metals and transition metals have been used for this reaction. Rieke s activated indium powder mediates readily the coupling of ethyl a-bromoacetate and a variety of carbonyl compounds yielding /3-hydroxy esters in good yields (Scheme 87).3 Later, commercially available indium powder has been found to be equally effective for the indium-based Reformatsky reaction in THF.28 This indium Reformatsky reaction is accelerated by ultrasound irradiation (Scheme 88).322,323 Indium(i) iodide also mediates the Reformatsky reaction of aldehydes and ketones to give /3-hydroxy esters, presumably via organoindium(m) diiodide (Scheme 89).27... 

Bieber reported that the reaction of bromoacetates is greatly enhanced by catalytic amounts of benzoyl peroxide or peracids and gives satisfactory yields with aromatic aldehydes. A radical chain mechanism, initiated by electron abstraction from the organometallic Reformatsky reagent, is proposed (Scheme 8.27).233 However, an alternative process of reacting aldehydes with 2,3-dichloro-l-propene and indium in water followed by ozonolysis provided the Reformatsky product in practical yields.234 An electrochemical Reformatsky reaction in an aqueous medium and in the absence of metal mediator has also been reported.235... 

The indium-mediated aqueous Reformatsky reaction was used in the synthesis of a,a-difluoro- 3-hydroxy ketones (Eq. 8.93).236... 

The use of Fe, indium, and zinc as sacrificial anodes in the electrochemically assisted Reformatsky reaction of ethyl 2-bromoalkanoates with succinic anhydride is found to be effective, giving l-ethyl-3-oxohexanedioates in 49 80%... 

Hydroxycyclopropanation, /fvmr-/3-deutero-styrene, 4, 275 Hydroxy-diyne ligand, with trinuclear Os clusters, 6, 742 /3-Hydroxy esters, via indium-mediated Reformatsky reactions, 9, 706... 

Hydroxy nitriles, via indium-mediated Reformatsky reactions, 9, 708... 

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 indium-induced Reformatsky reaction with stoichiometric amounts of chiral amino alcohols such as cinnco-nine and cinchonidine gives optically active /3-hydroxy esters with 40%-70% ee (Table 19). In contrast to the smooth reaction with uncomplexed indium-based Reformatsky reagents, ketones do not react with the complexed indium Reformatsky reagents. Other chiral ligands, including (—)-spartein, (—)-norephedrine, (+)-(l-methylpyrrolidin-2-yl)diphenylmethanol, (+)-Dibutyl tartrate and (+)-l,l -bi-2-naphthol, are not effective for this reaction.324... 

Table 19 Indium-mediated enantioselective Reformatsky reaction. Reproduced with permission from the Royal Society of Chemistry...

Indium mediates the Reformatsky reaction of y>-quinones to give good yields of />-quinols under mild conditions. Naturally occurring quinol esters such as jacaranone are conveniently prepared in a one-pot synthesis (Scheme 90).326... 

The indium-mediated Reformatsky reaction of phenyl a-bromoalkanoates with ketones or aldehydes gives di-, tri-, and tetrasubstituted /3-lactones (Table 21).327-329 A similar reaction of imines with ethyl bromoacetate gives 3-unsubstituted /3-lactams (Equation (83)).330 331... 

An indium Reformatsky reagent has been prepared from 2-(chlorodifluoroacetyl)furan, which couples with aldehydes (Equation (84)).334 A similar Reformatsky-type reaction between some /3-aminovinyl chlorodifluoromethyl... 

Application of zinc as a sacrificial anode often overcomes the difficulties with activation of zinc in the Reformatsky reaction and the problems with uncontrolled exothermic reactions. When zinc or indium is employed for the reaction, the amount of electricity used is less than the theoretical, and this suggests that the anode acts as activated metal and reacts with the bromo compound [175]. 

Araki, S., Ito, H., Butsugan, Y. Synthesis of P-hydroxyesters by Reformatsky reaction using indium metal. Synth. Commun. 1988,18, 453-458. 

Table 9. Summary of reformatsky reaction of carbonyl compounds with activated indium and ethyl bromoacetate1)...

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]. 

The Henry reaction is an aldol-type reaction between a nitroalkane and an aldehyde in the presence of a base. Since basic reagents are also catalysts for the aldol condensation, the nitroaldol reactions must be strictly controlled. An interesting alternative lies in the use of surfactants to perform the reaction in an aqueous medium [63], The Reformatsky reaction, which involves a-haloketones and aldehydes, can be mediated by zinc, tin or indium in water in the latter case the proportion of undesirable reduction products could be strongly reduced [64]. 

In an electrochemical version of the modified Reformatsky reaction a sacrificial indium anode is used. Using this method, fully substituted /3-lactones are obtained directly from the proper substrates. 

Reformatsky reaction. An active form of indium can be prepared by reduction of InCla (Alfa) with potassium metal in refluxing xylene (compare activation of zinc, 5, 753). 

The activated indium can be used to effect the Reformatsky reaction of carbonyl compounds with ethyl bromoacetate. High yields can be realized when an excess of the carbonyl compound is used. ... 

A one-pot preparation of 4-iodomethyloxetan-2-one is reported (93SL899). Electrochemically generated organometallic compounds react with ketones in a Reformatsky reaction to give esters or lactones (93AG1218) and the formation of P-lactones is favoured when a sacrificial indium anode is used (94JOC3161). 

The highly reactive indium powder reported in Sections 6.1 and 6.2 reacts readily with a-haloesters to give an indium Reformatsky-type reagent which will add to ketones and aldehydes to give p-hydroxy esters. The Reformatsky reaction using zinc metal has been used in the preparation of p-hydroxy esters for many years. Recent improvements have made this reaction a very reliable reaction (see Section 3.10). 

The more than 125-year-old Reformatsky reaction of aldehydes or ketones with a-haloesters is a valuable alternative to the aldol reaction leading also to P-hydroxycarboxylic esters [158]. In its classic version, the reaction occurs through zinc enolates, but not only zinc can serve as a mediator but also various other metals in low oxidation stage like titanium, indium, and samarium. In... 

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