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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 is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
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The Journal of Organic Chemistry
Introduction 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. 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 2 ACS Paragon Plus Environment
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disclosed the indium-catalyzed one-pot preparation of alkyl bromides from carboxylic acids.14 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.
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
Results and Discussion 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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Table 1.
O
Reaction Conditions of Reductive Bromination of Carboxylic Acid 1aa InBr3 (5 mol%) hydrosilane (Si-H: 6 equiv) Me3SiBr (2 equiv)
H H Ph
OH solvent, 60 °C, 1 h
Ph
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1a
OH 2a + H H
Ph
Br 3a
yield (%)b entry
hydrosilane
solvent 2a
3a
1
PhSiH3
CHCl3
NDd
89
2
PhMe2SiH
CHCl3
NDd
21
3
Ph2MeSiH
CHCl3
NDd
19
4
Et3SiH
CHCl3
NDd
36
5
(EtO)3SiH
CHCl3
6
PMHS
CHCl3
NDd
94
7
TMDS
CHCl3
NDd
99 (96)
8
TMDS
toluene
NDd
99
9
TMDS
THF
No Reaction
10
TMDS
CH3CN
No Reaction
11
TMDS
MeOH
No Reaction
12
TMDS
DMF
No Reaction
13c
TMDS
CHCl3
a
No Reaction
NDd
99
The reaction was carried out with 3-phenylpropanonic acid (1a) (0.6 mmol), InBr3 (5 mol %),
hydrosilane (Si-H: 6 equiv), and Me3SiBr (2 equiv) in CHCl3 at 60 ˚C for 1 h. b NMR yield (Isolated yield is in parenthesis). c Me3SiBr (1 equiv) was used. d ND: Not detected.
Optimization of Reductive Iodination of Carboxylic Acids: To apply this procedure to a reductive iodination, several iodine sources were examined. When iodotrimethysilane (Me3SiI), which was in-situ-prepared from iodine and hexamethyldisilane,15 was used, the corresponding iodide 4a was obtained in a quantitative yield (Table 2, entry 1). However, when molecular iodine was used, the corresponding iodide 4a was obtained in an excellent yield (entry 2). This result emphatically showed that the iodosilane was in-situ-generated and that the species behaved as an 5 ACS Paragon Plus Environment
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The Journal of Organic Chemistry
iodide anion source in the iodination series.16 When a 0.5 equivalent of I2 was also used, the corresponding iodide was obtained in a good yield (entry 3). In short, these results showed that the in-situ iodide cation was efficiently reduced to an iodo anion in the reaction. Other iodine sources, such as copper(I) iodide and potassium iodide, were ineffective for this reductive iodination (entries 4 and 5). From the viewpoints of experimental handling and cost, molecular iodine was a more useful iodine source than Me3SiI, and was the best iodine source used in this reaction.
Table 2. Reaction Conditions of Reductive Iodination of Carboxylic Acid 1aa InBr3 (5 mol%) TMDS (Si-H: 6 equiv) I source
O
H H Ph
OH 2a + H H
OH CHCl3, 60 °C, 1 h
Ph 1a
Ph
I 4a
yield (%)b entry
iodide source 2a
4a
1
Me3SiI
(1 equiv)
NDc
99
2
I2
(1 equiv)
NDc
98
3
I2
(0.5 equiv)
NDc
86
4
CuI
(1 equiv)
88
8
5
KI
(1 equiv)
No Reaction
a
The reaction was carried out with 3-phenylpropanoic acid (1a) (0.6 mmol), InBr3 (5 mol %),
TMDS (Si-H: 6 equiv), and an iodide source (1 equiv) in CHCl3 at 60 ˚C for 1 h.
b
NMR yield.
c
ND: Not detected.
Substrate Scope of Reductive Iodination of Carboxylic Acids: With the optimal conditions, the scope of the direct iodination of various carboxylic acids was investigated (Table 3).17 The iodination of aliphatic carboxylic acids 1a, 1c, and 1d was transformed within one hour, and conducted the corresponding iodides 4a, 4c, and 4d in high yields (entries 1, 3 and 4). However, 6 ACS Paragon Plus Environment
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when
4-phenylbutanoic
acid
(1b)
was
used,
the
intramolecular
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cyclization
product,
1,2,3,4-tetrahydronaphthalene (4b’) was obtained as a major product rather than the desired alkyl iodide 4b. It was suggested that although the iodination of carboxylic acid 1b was rapidly completed, InBr3, which remained intact in the reaction mixture, further accelerated the annulation of the intermediate, the alkyl iodide 4b. The reducing system did not affect on functional groups, such as a methyl group, halogens, and a hydroxy group, on the benzene ring (entries 5-10). A carboxylic acid containing a nitro group 1i was transformed to the corresponding iodide 4j in a moderate yield with InBr3 (10 mol %), TMDS (Si-H: 12 equiv), and Me3SiI (1 equiv) in 1,2-dichloroethane at 80 °C. Interestingly, this result was in clear contrast with the results of the previous bromination. Use of an iodine source with a nucleophilicity that was stronger than that of bromotrimethylsilane succeeded in halogenation of the carboxylic acid. Application of the procedure to aromatic carboxylic acids was then examined. The iodination of p-methoxybenzoic acid 1k did not occur, probably due to a decrease in the electrophilicity of the carbonyl carbon (entry 11). When reactions were performed with benzoic acids 1l and 1m, which had either a chlorine or a trifluoromethyl group, the expected iodides 4l and 4m were obtained in high yields, respectively (entries 12 and 13). Carboxylic acids with terminal or internal alkenes were consumed within a short time, but did not give the corresponding iodides 4n and 4o (entries 14 and 15). Unlike the bromination of 1n and 1o, an olefin moiety was also reduced, but the desired products were not detected. The iodination of dicarboxylic acid 1p was undertaken using InBr3 (10 mol %), TMDS (Si-H: 12 equiv), and I2 (1 equiv), giving the corresponding iodide 4p in an 88% yield (entry 16). This iodination was applicable to the carboxylic acid with a thioether moiety, 1q, which produced the corresponding sulfide 4q in a 92% yield (entry 17). 7 ACS Paragon Plus Environment
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Table 3.
InBr3 (5 mol%) TMDS (Si-H: 6 equiv), I2 (1 equiv)
O R
Preparation of a Variety of Alkyl Iodidesa
OH
H H I
R
CHCl3, 60 °C
1
4
time yield entry
carboxylic acid
product (h)
1
1a
4a
2
1b
4b 0.5
0c
3
1c
4c
88
4
1d
4d
