Indium(III)-catalyzed reductive bromination and iodination of carboxylic acids to alkyl bromides and iodides: Scope, mechanism, and one-pot transformation to alkyl halides and amine derivatives

Article abstract of DOI:10.1021/jo401529j

Highly effective indium(III)-catalyzed reductive bromination or iodination of a variety of carboxylic acids with 1,1,3,3-tetramethyldisiloxane (TMDS) and a source of bromine or iodine is described. This functional group interconversion has high tolerance for several functional groups, such as halogens, a hydroxy group, a nitro group, an olefin part, and a sulfide moiety. This indium catalytic system is also applicable to the reductive iodination of aldehyded, acyl chlorides, and esters. Furthermore, this reducing system can be applied to the one-pot synthesis of alkyl halides and amine derivatives via the addition of nucleophiles. Insight into the reaction mechanism was gained via the time course of ¹H and ¹³C NMR monitoring experiments and the corresponding stepwise reactions.

Full text of DOI:10.1021/jo401529j

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Article
Indium(III)-Catalyzed Reductive Bromination and Iodination of
Carboxylic Acids to Alkyl Bromides and Iodides: Scope, Mechanism,
and One-Pot Transformation to Alkyl halides and Amine Derivatives
Toshimitsu Moriya, Shinichiro Yoneda, Keita Kawana, Reiko Ikeda, Takeo Konakahara, and Norio Sakai
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 02 Oct 2013
Downloaded from http://pubs.acs.org on October 2, 2013
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The Journal of Organic Chemistry
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Introduction
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A functional group interconversion (FGI) with the carbonyl compounds, such as aldehydes,
ketones, esters, and carboxylic acids, has been occupied the central and important position of
synthetic organic chemistry.1 Among them, a reductive FGI from the carboxylic acids to alkyl
halides has been attracted considerable attention in our field,2 because the producing alkyl halides
can be easily converted to organic chemicals, such as Grignard reagents and organic lithium
compounds, or highly valuable organic compounds, such as amines, ethers, and nitriles.3 Also,
because carboxylic acids generally show tolerance to the common reducing reagents, achievement
of the FGI with this reducible reagent is of interest from the viewpoint of molecular conversion. A
conventional method for the preparation of alkyl halides from carboxylic acids generally requires
the following troublesome two steps: firstly, a carbonyl moiety was reduced to a primary alcohol
with a strong reducing agent, such as lithium aluminum hydride (LAH); secondly, the primary
alcohol obtained was treated with a hydrogen halide or a phosphorus halide.4 However, the
transformation with LAH declines chemoselectivity toward other functional groups, due to its high
reducing ability and moisture sensitivity.
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Thus far, the indium(III)-catalyzed reductive FGI of alcohols,5 ketones,6 aldehydes,6 and acyl
halides,7 the radical reduction of organic halides8 and the 1,4-reduction of enones,9 has been
developed by several groups. We have developed the reducing system with indium tribromide
(InBr3) and triethylsilane (Et3SiH) undertook the deoxygenation of carboxylic acids and amides,
which lead to the preparation of primary alcohols and secondary amines.10,11 With this reducing
reagent, the reductive FGI of several reducing reagents, such as a ketone and an acetal, and
esterification of a carboxylic acid, have also been achieved.12,13 Moreover, we have recently
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The Journal of Organic Chemistry
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disclosed the indium-catalyzed one-pot preparation of alkyl bromides from carboxylic acids.14
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In this paper, firstly, as an extension of our previous letter, we examined the direct preparation of
alkyl iodides via the indium-catalyzed reduction of carboxylic acids and derivatives, such as
aldehydes, acyl halides and esters, with a siloxane and an iodine source (path A-D in Scheme 1).
Secondly, to show the utility of alkyl iodides prepared by this method, we performed the
consecutive transformation of in-situ-prepared alkyl iodides to alkyl chlorides, fluorides and amine
derivatives using a one-pot method (path E-G in Scheme 2). Finally, we elucidated the reaction
mechanism of a reductive transformation series from a carboxylic acid to an alkyl halide by
NMR-monitoring of the reaction system. Herein, we report the full details.
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Scheme 1. InBr3-Catalyzed Reductive Iodination of Carboxylic Acids and Its Derivatives
Scheme 2. Consecutive Transformation of the In-Situ Prepared Alkyl Iodides
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The Journal of Organic Chemistry
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Results and Discussion
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Opitimization of Reductive Bromination of Carboxylic Acids: Table 1 shows the details of
re-examination of the optimal conditions for hydrosilanes and solvents in the direct bromination of
carboxylic acids. Firstly, when 3-phenylpropanoic acid (1a) was treated with 5 mol% of InBr3 and 6
equiv (Si-H) of PhSiH3, and 2 equiv of Me3SiBr in CHCl3 at 60 ˚C, the corresponding alkyl bromide
3a was obtained in a 89% yield (entry 1, in Table 1). The reaction with dimethylphenylsilane
(PhMe2SiH), methyldiphenylsilane (Ph2MeSiH) or Et3SiH resulted in a significant decrease in the
yield of 2a (entries 2-4). When the reaction was conducted with triethoxysilane ((EtO)3SiH), the
corresponding bromide 2a was not obtained at all (entry 5). In contrast, ethereal hydrosilanes, such
as polymethylhydrosilane (PMHS) and TMDS, were very effective, and the corresponding bromide
2a was obtained in an excellent yield (entries 6 and 7). The screening of hydrosilanes for the
bromination of 1a identified TMDS as the optimal hydrosilane source. The solvent effect was
remarkable for this reaction. The use of chloroform and toluene resulted in a satisfactory
bromination of carboxylic acid (entries 7 and 8). However, the reaction in tetrahydrofuran (THF),
acetonitrile (CH3CN), methanol (MeOH) and dimethylformamide (DMF) did not proceed at all
(entries 9-12). The bromination proceeded in a quantitative yield, even when one equivalent of
Me3SiBr was used (entry 13). Consequently, the results of our examinations showed that the
optimal conditions for the bromination of carboxylic acid 1a were InBr3 (5 mol %), TMDS (Si-H: 6
equiv), and Me3SiBr (1 equiv) in CHCl3 at 60 °C. The detailed scope of the direct bromination of a
variety of carboxylic acids with the conditions is described in the previous work.14
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