Communication
doi.org/10.1002/chem.202005400
Chemistry—A European Journal
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Synthetic Methods |Hot Paper|
A Titanium-Catalyzed Reductive a-Desulfonylation
Abstract: A titanium(III)-catalyzed desulfonylation gives
access to functionalized alkyl nitrile building blocks from
a-sulfonyl nitriles, circumventing traditional base-mediat-
ed a-alkylation conditions and strong single electron
donors. The reaction tolerates numerous functional
groups including free alcohols, esters, amides, and it can
be applied also to the a-desulfonylation of ketones. In ad-
dition, a one-pot desulfonylative alkylation is demonstrat-
ed. Preliminary mechanistic studies indicate a catalyst-de-
pendent mechanism involving a homolytic CÀS cleavage.
Scheme 1. Desulfonylations and desulfonylative couplings.
Sulfonyl groups provide a versatile platform for organic
chemistry.[1] In combination with a subsequent desulfonylation,
they are often used as traceless linchpins for the construction
of molecular frameworks.[2] Here, several transition-metal-cata-
lyzed and free-radical-based desulfonylative cross-couplings
have been developed.[3,4] The reductive removal of sulfonyl
groups at aliphatic carbon centers, however, requires strong
single-electron-donating reagents such as Na(Hg), Al(Hg), Mg-
MeOH, SmI2, TiCl4-Zn, but it becomes facilitated at benzylic and
allylic centers, and at a-positions of electron-withdrawing
groups.[2] The reductive a-desulfonylation of carbonyls and ni-
triles can be achieved with SmI2, under free radical conditions
using tin hydrides, or with magnesium in small alcoholic sol-
vents, for example.[2,5] Photochemical protocols have been re-
ported as well and for particularly activated substrates even
zinc in acidic media can be sufficient to achieve the CÀS clea-
vage.[2e,6,7] A transition metal catalyzed reductive desulfonyla-
tion that complements these reactions, on the other hand, has
remained desirable.
sponding desulfonylation by titanium(III) single electron trans-
fer catalysis that is based on a non-optimized example from
this earlier work. Moreover, a first application towards a desul-
fonylative alkylation reaction is explored.
The investigations started with the desulfonylation of 3-
phenyl-2-(phenylsulfonyl)propionitrile (1a) using the previous
conditions:[11] in presence of Cp2TiCl2 as catalyst, zinc, and the
additives ZnCl2, Coll·HCl, and TMSCl, a clean desulfonylation to
3-phenylprionitrile (2a) occurred in 56% yield (Coll=2,4,6-colli-
dine). Since thiophenol was produced as byproduct, three
equivalents of zinc were added to account for the sulfonyl re-
duction and the turnover-enabling catalyst reduction. In the
following optimization studies, it was possible to further im-
prove the conditions in order to achieve the desired CÀS cleav-
age in a clean fashion and with maximized yield (Table 1).[13]
A
concentration of c=0.25m proved to be ideal and an interest-
ing dependence of the yield on the catalyst properties, the sol-
vent, and the reaction temperature was observed. In THF at
608C the highest yield was achieved with (EtCp)2TiCl2 and cata-
lysts with a significantly stronger reduction potential and in-
Titanium(III) catalysis is a modern tool for organic synthe-
sis.[8–10] As part of our interest in catalytic reductive functional
group cleavage reactions, we have recently developed a mild
titanium(III)-catalyzed decyanation of geminal dinitriles
(Scheme 1).[11,12] Herein, we report the realization of a corre-
*
creased steric bulk such as rac-(ebthi)TiCl2 and Cp2 TiCl2 gave
inferior results. Changing the solvent to toluene and raising
*
the temperature to 110 8C inverted this trend and Cp2 TiCl2
gave the highest yield (96%). It is noteworthy that all additives
were required to achieve this high yield. No reaction was ob-
served in absence of the titanium catalyst (THF, 608C and tolu-
ene, 110 8C).[13] This is important, because 1) Zn-TMSCl mixtures
have been reported to promote radical reactions by single
electron transfer at elevated temperature,[14] and 2) Zn-mediat-
ed desulfonylations at activated positions have literature prec-
edence.[7] Lowering the catalyst amount to 5 mol% reduced
the yield to 43%.[13]
[a] C. Kern, J. Selau, Dr. J. Streuff
Institut für Organische Chemie
Albert-Ludwigs-Universität Freiburg
Albertstr. 21, 79104 Freiburg im Breisgau (Germany)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
ꢀ 2021 The Authors. Published by Wiley-VCH GmbH. This is an open access
article under the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided the
original work is properly cited.
The effectiveness of the catalytic desulfonylation was dem-
onstrated on a range of substrates bearing common functional
Chem. Eur. J. 2021, 27, 6178 –6182
6178
ꢀ 2021 The Authors. Published by Wiley-VCH GmbH