Differentiation of Diastereotopic Bromine Atoms in SN2-Reaction of gem-Dibromides:
Synthesis of a-Bromosulfones and their Use as Building Blocks
Niels Münster and Ulrich Koert*
Philipps-Universität Marburg, Fachbereich Chemie, Hans-Meerwein-Straße, 35043 Marburg
Synthetic Potential of a-Bromosulfones
Introduction
The differentiation of diastereotopic halogen atoms is an
important goal to extend the methods in the field of
stereoselective
synthesis.
So
far
gem-halogen
compounds
have
been
used
mainly
for
diastereoselective halogen-metal-exchange reactions.[1,2]
The selective substitution of one bromine-atom in a SN2reaction is a challenge faced by two problems: the
second substitution of the remaining bromine in 2 leading
to 3; second the elimination-reaction of substrate 1 to 4
or the product 2 to 5 (Scheme1).
a-Bromosulfones offer two different synthetic applications. The first one is to deprotonate in a-position
to generate a sulfonyl carbanion, which can react with a variety of electrophiles. The configurational
stability of certain a-sulfonyl carbanions has been reported.[6] The second one is the transition-metal
mediated substitution of the remaining bromine atom with nucleophiles.
Scheme 5: Possible reaction pathways for a-bromosulfones.
Reactions of Sulfonyl Carbanion
Scheme 1: Stereoselective SN2 reaction of a gem-dibromide and possible side reactions.
Treatment of bromosulfone 20 with LDA at -78 °C gave the sulfonyl carbanion which could be trapped
with a variety of electrophiles. Scheme 6 shows a selection of electrophiles and the resulting products
21, 22 and 23. The products were formed in moderate to high yields with very good
diastereoselectivities. The reaction proceeded under retention of the a-stereocenter. This could be
proved by X-ray structure of compounds 22 and 23.
Diastereoselective Synthesis of a-Bromosulfones
A clue to the puzzle was choosing a sulfinate anion as nucleophile. The SN2-reaction with aliphatic
gem-dibromides results in the formation of a-bromosulfones. In contrast to p-substituents, the sulfone
group does not accelerate SN2-reactions.[3] Therefore the reaction stops at the monosubstitution stage.
We found that gem-dibromides 6, 7 and 8 with a free hydroxyl group in g-position formed abromosulfones 10, 11 and 12 diastereoselectively by treatment of arenesulfinate 9.[4] The yield and
diastereoselectivity depends on the sterically demand of the R-group in the substrate.
Scheme 2: Diastereoselective synthesis of g-hydroxy-a-bromo-sulfones.
The hydroxyl group in the g-position is a prerequisite for good yields and diastereoselectivities. The
corresponding methyl ethers 13 and 14 gave lower yields and hardly no diastereoselectivity of the abromosulfones 15 and 16.
Scheme 6: Examples of different electrophiles they can be converted with bromosulfone 20; a) LDA,
Et2O, -78 °C.
To resolve the question of the configurational stability of a-bromosulfonyl carbanions derived from 20
we took the minor diastereomer 24 and conducted an control experiment shown in scheme 7. The
formation of compound 22 as major diastereomer indicates configurational lability.
Scheme 3: g-methoxy substituted gem-dibromides formed the a-bromosulfones with hardly no
diastereoselectivity.
Mechanistic Considerations
A possible explanation for the diastereoselectivity in the reaction of g-hydroxy aliphatic gem-dibromides
with sulfinate 9 is given in scheme 4. All gem-dibromides show a preferred conformation 17, which is
supported by the X-ray structure of compound 6 and by earlier observations.[5] The reason for this
conformational bias is the avoidance of syn-pentane interactions. The incoming nucleophile is probably
precoordinated to the hydroxyl group via hydrogen bonding (nucleophile fishing) which results in
favoured substitution of the like-bromine atom. The increasing diastereoselectivity in the series 6, 7,
and 8 can be explained by their increasing conformational bias.
Scheme 7: Experiment to investigate the configurative stabilty of a-bromosulfonyl carbanions. a) LDA,
Et2O, -78 °C.
Literature
[1] G. Köbrich, Angew. Chem. 1967, 79, 15.
[2] R. W. Hoffmann, M. Bewersdorf, K. Ditrich, M. Krüger, R. Stürmer, Angew. Chem. 1988, 100, 1232.
[3] W. M. Ziegler, R. Connor, J. Am. Chem. Soc. 1940, 62, 2596.
[4] N. Münster, K. Harms, U. Koert, Chem. Commun. 2012, 48, 1866.
[5] R. Göttlich, B. C. Kahrs, J. Krüger, R. W. Hoffmann, Chem. Commun. 1997, 247.
Scheme 4: Proposed mechanism for formation of a-bromosulfones; PMP = para-methoxy phenyl;
R2 = COC6H3-3,5-(NO2)2.
[6] H.-J. Gais, G. Hellmann, H. Günther, F. Lopez, H. J. Lindner, S. Braun, Angew. Chem. 1989, 101, 1061.
Generous support by the Deutsche Forschungsgemeinschaft and Jonas Schwaben is gratefully acknowledged.