Indium(I) bromide-mediated bromocyanomethylation of carbonyl compounds

Article abstract of DOI:10.1016/S0040-4039(00)00960-6

Bromocyanomethylation of a variety of carbonyl compounds to produce the corresponding 2-bromo-3-hydroxynitriles has been achieved in moderate to good yields by the action of dibromoacetonitrile and indium(I) bromide. Moderate diastereoselectivity was observed. Exclusive mono-coupling at the carbonyl group was found with 1,2-diketones and α-haloketones. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00960-6

Tetrahedron Letters 41 (2000) 5779±5782
Indium(I) bromide-mediated bromocyanomethylation of
carbonyl compounds
a
a
b,
J. A. Nobrega, Simone M. C. Gon cË alves and C. Peppe *
Â
aDepartamento de QuõÂmica Fundamental, Universidade Federal de Pernambuco, UFPE, Recife PE-50.670-901, Brazil
bDepartamento de QuõÂmica, Universidade Federal da ParaõÂba, UFPB, JoaÄo Pessoa PB-58059-900, Brazil
Received 19 May 2000; revised 9 June 2000; accepted 13 June 2000
Abstract
Bromocyanomethylation of a variety of carbonyl compounds to produce the corresponding 2-bromo-3-
hydroxynitriles has been achieved in moderate to good yields by the action of dibromoacetonitrile and
indium(I) bromide. Moderate diastereoselectivity was observed. Exclusive mono-coupling at the carbonyl
group was found with 1,2-diketones and a-haloketones. # 2000 Elsevier Science Ltd. All rights reserved.
Several organic transformations promoted by organoindium reagents have been described
1
recently. Some well-established processes include the indium-promoted reaction of allyl halides
2
and a-halo-esters with carbonyl compounds, to give homoallylic alcohols and b-hydroxy esters,
respectively. Similarly, it was demonstrated that organoindium sesquihalides, identi®ed as
3
the intermediate in these reactions, also react with enamines to a€ord homoallylamines. The
4
a-halo-organoindium reagents obtained from indium metal and Br CR (R=-CN, -CO Et),
2
2
2
form a second class of reagents which have been successfully employed in the cyclopropanation
of electron-de®cient alkenes, and in the epoxidation of carbonyl compounds (R=-CO Et).
2
Although the use of indium has been the subject of increasing interest for C±C bond-formation, the
5
use of indium(I) compounds, such as indium(I) halides, remains virtually unexplored. The
present work describes bromocyanomethylation reactions of carbonyl compounds promoted by
6
InBr (Eq. (1)), leading to the corresponding 2-bromo-3-hydroxynitriles 3. A typical procedure
ꢀ
involved the addition of CHBr CN (470 mg, 2.3 mmol) to a stirred and cooled (^5 C) suspension
2
of InBr (300 mg, 1.54 mmol) and benzaldehyde (1.54 mmol) in tetrahydrofuran (5 mL) under
nitrogen. Stirring was continued until the complete consumption of the insoluble InBr (see Table 1
for the time required). The solution obtained was then acidi®ed with HCl (0.1 M, 5 mL) and the
aqueous solution extracted twice with ethyl acetate (60 mL); the extract was sequentially washed
with a saturated solution of NaHCO and brine, dried (Na SO ), ®ltered, and evaporated to
3
2
4
*
Corresponding author. E-mail: peppe@quimica.ufpb.br
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00960-6

5
780
dryness. The reaction product 3a was separated by column chromatography on silica gel
1
13
(
hexane:ethyl acetate=5:1), analysed (C, H and N) and characterised by NMR ( H and C),
infrared spectroscopy and mass spectrometry. Yields and other reaction conditions are given in
Table 1.
ꢁ1†
Table 1
Synthesis of 2-bromo-3-hydroxynitriles promoted by InBr
The proposed mechanism leading to 3 involves the oxidative insertion of InBr into the carbon±
bromine bond of dibromoacetonitrile to give the organoindium(III) species 1. Coupling between
the bromocyanomethyl group and the carbonyl compound leads to the indium alkoxide 2, which
upon acid hydrolysis gives the ®nal product 3. The proposed intermediate 1 is analogous to the
7,8
X InCH X and X InCHX derivatives obtained from InX and CH X and CHX , respectively,
2
2
2
2
2
2
3
which have been unambiguously characterised by X-ray methods.
Table 1 shows that a variety of carbonyl compounds were successfully transformed into 3.
Aldehydes, particularly aromatic (entry 1) react faster and produce better yields than the
structurally related ketones (entry 11). Aromatic carbonyl compounds containing electron

5
781
withdrawing groups (entries 2 and 3) or electron donating groups (entries 4 and 12) were trans-
formed to the corresponding derivatives 3. a,b-Unsaturated carbonyl substrates, such as cinna-
maldehyde (entry 5) and 2-cyclohexen-1-one (entry 10) gave 1,2-addition products exclusively.
Carbonyl compounds containing an hydroxyl group, such as ethylacetoacetate and salicylalde-
hyde, did not react and were completely recovered at the end of the reaction, suggesting that
acidic substituents on the carbonyl compound inhibit reaction.
Product formation proceeded with poor diastereoselectivity for aromatic (entries 1±4) and
a,b-unsaturated (entry 5) aldehydes, but anti-addition was found to be preferred when aliphatic
aldehydes were used. The anti:syn diastereomeric ratio decreases in the following order: pival-
aldehyde>isobutyraldehyde>propionaldehyde (entries 6±8), suggesting a mechanism governed
by steric hindrance e€ects (Scheme 1), in which the two heteroatoms (Br and O) will align anti to
9
each other to eliminate electron±electron repulsion. The spatial orientation of the R group of the
aldehyde and the cyano group of the organometallic reagent on the transition state will determine
diastereoselection; gauche orientation (left-hand pathway) imposes maximum steric hindrance
raising the energy of the transition state; consequently, the right-hand pathway leading to the anti
product will be favoured.
Scheme 1.
The organoindium species 1 reacts with a-halo ketones (entries 13±15) chemospeci®cally to give
the corresponding derivatives 3, with no signs of dehalogenation and/or substitution. With
1
,2-diketones, only mono addition products were isolated (entries 16 and 17). The present reac-
tion is directly related to the Darzens condensation between a-halo-nitriles and carbonyl
compounds, giving rise to the formation of glycidic nitriles. An obvious synthetic application of
10
3 is the preparation of glycidic nitriles, via epoxidation (Eq. (2)), and indeed this can be achieved
ꢀ
by addition of an equimolar amount of triethylamine to a cold (5 C) solution of 3 in methanol.
After 3 hours, all the volatiles were removed and the residue was partioned in H O/CH Cl ; the
2
2
2
organic solvent was dried (Na SO ), ®ltered, and evaporated to dryness to give the corresponding
2
4
1
glycidic nitriles; H NMR spectroscopy showed quantitative conversion to the oxiranes,
integration revealed a 1:9 ratio for oxiranes 4a:5a and a 1:1 ratio for 4b:5b. These results clearly
con®rm the syn:anti ratio reported in Table 1 (entries 6 and 2, respectively).

5
782
ꢁ2†
1
The H NMR of the mixtures of glycidic nitriles 4c, 5c and 4d, 5d were assigned on the basis on
NOE di€erence spectroscopy. The molar ratio 4c:5c of 3:1 again con®rms the data in Table 1
entry 11). Finally, epoxidation of the alcohol derived from a,a-dichloroacetophenone (entry 15)
(
occurred chemoselectively to give the epi-a,a-diclorohydrin derivatives 4d and 5d in a molar ratio
of 1:5.
The reaction between carbonyl compounds and dibromoacetonitrile mediated by InBr is an
attractive method for the preparation of 2-bromo-3-hydroxy nitriles. Good stereocontrol, leading
to the anti-diastereomer, was observed from bulky aliphatic aldehydes. These compounds allow
easy entry into the formation of glycidic nitriles, including their epi-a-chloro and epi-a,a-dichloro
derivatives, which are synthetically useful building blocks in organic synthesis.
Acknowledgements
C.P. thanks CAPES/FAPESQ-PB for ®nancial support. J.A.N. thanks CNPq for the award of
a scholarship and Dr. L. Bieber for helpful discussions.
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ꢀ
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