SF5-Enolates in Ti(IV)-Mediated Aldol Reactions

Article abstract of DOI:10.1021/acs.joc.6b00946

The F···Ti bonding in the transition structures determines high trans- and syn-diastereoselectivities for aldol reactions of SF₅-acetates with aldehydes in the presence of TiCl₄ in the non-nucleophilic solvent CH₂Cl_2<

Full text of DOI:10.1021/acs.joc.6b00946

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SF5-Enolates in Ti(IV)-Mediated Aldol Reactions
Maksym V. Ponomarenko, Simon Grabowsky, Rumpa Pal, Gerd-Volker Röschenthaler, and Andrey A Fokin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00946 • Publication Date (Web): 06 Jul 2016
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The Journal of Organic Chemistry
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SF5ꢀEnolates in Ti(IV)ꢀMediated Aldol Reactions
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Maksym V. Ponomarenko,*† Simon Grabowsky,‡ Rumpa Pal,‡ GerdꢀVolker Röschenthaler,† Andrey
A. Fokin§
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†Department of Life Sciences and Chemistry, Jacobs University Bremen gGmbH, Campus Ring 1,
28759 Bremen, Germany
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‡Universität Bremen, Institut für Anorganische Chemie und Kristallographie, Leobener Str. NW2,
28359 Bremen, Germany
§Department of Organic Chemistry, Kiev Polytechnic Institute, pr. Pobedy 37, 03056 Kiev, Ukraine
*Corresponding author Eꢀmail: m.ponomarenko@jacobsꢀuniversity.de
ABSTRACT: The F…Tiꢀbonding in the transition structures determines high transꢀ and synꢀ
diastereoselectivities for aldol reactions of SF5ꢀacetates with aldehydes in the presence of TiCl4 in the
nonꢀnucleophilic solvent CH2Cl2. Such bonding is canceled in nucleophilic solvents where opposite
cisꢀstereochemistry is observed. The potential of thus obtained stereoisomeric SF5ꢀarylacrylates as
dipolarophiles in the preparation of SF5ꢀcontaining heterocycles is demonstrated.
Pentafluoroꢀλ6ꢀsulfanylꢀcontaining organic compounds attract substantial interest with respect
to their potential in organic electronics, pharmaceuticals, and agrochemicals,1 as well as due to
constantly growing impact of organofluorides in upꢀtoꢀdate materials.2 The most recent development is
associated with the availability of the SF5ꢀbuilding blocks that were previously difficult to access.
However, the number of SF5ꢀcontaining aliphatic compounds is still limited.1c,1e
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Enolizationꢀaldolization reactions are one of the most versatile, centuryꢀold, carbonꢀcarbon
bond forming tool for natural product synthesis and drug discovery.3 The studies of stereoselective
aldol reactions are particularly important area examining enolate geometries, the influence of
mediators, and reaction conditions. The lack of methods for αꢀfunctionalization of the αꢀSF5 carbonyl
compounds may be attributed to instability of the starting material when reactions can be accompanied
by the elimination of the SF5ꢀgroup under basic or nucleophilic conditions.4 Despite the progress in
aldol addition reactions of fluorinated5 and trifluomethylated enolates,6 the number of reports on
reactions through SF5ꢀenolates is limited. The first approach towards αꢀfunctionalized αꢀSF5 carboxyl
compounds is based on IrelandꢀClaisen rearrangement.7 Recently, the first examples of antiꢀ
diastereoselective boronꢀmediated aldol additions of αꢀSF5ꢀesters were reported,8 where the observed
antiꢀdiastereoselectivities were explained8b through the ZimmermanꢀTraxler model.9 However, as the
configuration of the resulting aldol not necessary is associated with the structure of the intermediate
enolate,3 the mechanistic interpretations of the stereochemical outcome still require rigorous scrutiny.
Herein we found experimental and computational evidence that the stereochemistry of the aldol
reactions of model SF5ꢀacetate promoted by TiCl4 is determined by the coordination of titanium with
the SF5ꢀmoiety of the enol in Zꢀconfiguration.
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The stability of SF5ꢀintermediates plays a key role4a,4b,7ꢀ8 in the reactivity of the enols generated
from αꢀSF5ꢀacetates. The reaction of methyl SF5ꢀacetate (1)10 with salicylaldehyde (2a) leads to
complete elimination of the SF5ꢀgroup, and only product 3 together with starting 2a were isolated from
the reaction mixture (Scheme 1). No reaction was observed in presence of various soft mediators3
where 1 and 2a almost fully recovered (Scheme 1).
TiCl4 in the presence of tertiary amines has been shown to be an effective system for
enolization–aldolization reactions,3c especially of αꢀfluorinated, and αꢀtrifluoromethylated acetates11
where Ti…F interactions in the transition structures not only result in high diastereoselectivities but
also prevent the fluorine group loss.11c,11d
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The Journal of Organic Chemistry
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SCHEME 1. Reactivity of methyl SF5ꢀacetate
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a) neat, Al2O3, 12h, rt; b) Ph3P, toluene, 80 °C, 6h;
c) Et3N (2 equiv), CH2Cl2, 2 weeks, rt;
d) TiCl4 (2 equiv), 6h, rt; e) BF3ꢀEt2O (2 equiv), 24 h, rt.
We assumed that involvement of the SF5ꢀgroup into the Ti…F interaction may enhance stability
of the intermediates in the aldol reactions of the SF5ꢀenol generated from 1. We found that when an
excess of Et3N was slowly added to a suspension of 1, 2b and TiCl4 (1M in CH2Cl2) in THF at –30 °C
the SF5ꢀcontaining products were observed only as admixtures. The aldehyde 2b was almost fully
recovered after workup and the starting SF5ꢀester 1 was not detected by NMR (Table 1, entry 1). In
contrast, the reaction with neat TiCl4 occurs with the formation of two isomeric SF5ꢀolefins Eꢀ4b and
Zꢀ5b isolated in low yields together with acetylene derivative 6b as a main product (entry 2). The fact
that olefins Eꢀ4b and Zꢀ5b were not changed while exposed in a mixture of TiCl4/Et3N, as well as with
excess of Et3N in THF shows that acetylene 6b forms independently.
The yields of the SF5ꢀcontaining products increase if an excess of Et3N is added in one portion
into the vigorously stirred mixture of the starting materials in THF at 0 °C (entry 3). The use of neat
TiCl4 in THF12 slightly increases the formation of the Zꢀ5b isomer (entry 4). Similar results were
obtained in reactions of aromatic aldehydes 2c–e carried out under the same conditions (entries 5–7).
In all cases Zꢀ5b–e isomers were formed as the main products.
However, the reactions of aldehydes 2c,f, which contain electron withdrawing groups (Cl, NO2)
in the aromatic ring, proceed nonꢀselectively giving complex mixtures of products (entry 5, 8). Along
with the formation of Eꢀ4, Zꢀ5, and 6, aldol adducts of the SF5ꢀester 1 (syn/antiꢀArCH(OH)ꢀ
CH(SF5)CO2CH3) were observed in up to 10% yield by NMR. In both reactions about half of the
starting aldehydes were recovered in spite of full consumption of the ester 1.
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