Letter
Direct Conversion of Alcohols to α‑Chloro Aldehydes and α‑Chloro
Ketones
Yuanyuan Jing, Constantin G. Daniliuc, and Armido Studer*
̈
̈
Institute of Organic Chemistry, Westfalische Wilhems-University, Corrensstraße 40, 48149 Munster, Germany
*
S Supporting Information
ABSTRACT: Direct conversion of primary and secondary
alcohols into the corresponding α-chloro aldehydes and α-
chloro ketones using trichloroisocyanuric acid, serving both as
stoichiometric oxidant and α-halogenating reagent, is reported.
For primary alcohols, TEMPO has to be added as an oxidation
catalyst, and for the transformation of secondary alcohols
(
TEMPO-free protocol), MeOH as an additive is essential to
promote chlorination of the intermediary ketones.
α-Halo carbonyl compounds such as α-chloro aldehydes are
versatile building blocks for natural product synthesis. In
Scheme 1. Direct Conversion of Alcohols to the
Corresponding α-Halo Carbonyl Derivatives
1
general, these compounds are prepared via halogenation of the
2
corresponding aldehydes or ketones. Starting with alcohols,
the targeted α-halo carbonyl derivatives are available by
oxidation and subsequent α-halogenation in a two-step
sequence, in which the intermediate aldehydes and ketones
are generally isolated. In terms of process economy, one-pot
oxidation with subsequent α-halogenation would be more
appropriate. Along these lines, Christmann recently disclosed
an elegant method for direct transformation of primary alcohols
to the corresponding α-chloro aldehydes by TEMPO-catalyzed
alcohol oxidation followed by chlorination using enamine
acetophenone (3a) was directly formed in the presence of
alcohol additives. Initial experiments were conducted in
dichloromethane at room temperature for 2 h. If the reaction
was conducted in the absence of any additive, ketone 2a was
quantitatively obtained (Table 1, entry 1). However, upon
addition of MeOH (1 equiv), the chlorinated ketone 3a was
formed as the major product (80%) along with 20% of
acetophenone (entry 2). A good result was also achieved with
2,2,2-trifluoroethanol as additive (70%, entry 6), and EtOH
supported ketone chlorination, albeit in a lower yield (49%,
entry 3). With other alcohols such as i-PrOH, t-BuOH, and
hexafluoro-2-propanol, the reaction stopped after a clean
alcohol oxidation (entries 4, 5, and 7), and the same result
was also obtained using DMF as an additive. Solvent screening
revealed that the reaction did not work in THF or DMSO, and
in acetone only a low-yielding oxidation to the ketone 2a was
achieved (entries 9, 10, and 12). EtOAc worked less efficiently
than DCM (entry 11) and the best result was obtained in the
presence of 2 equiv of MeOH (entry 13).
3
catalysis as a one pot sequence. An even more experimentally
simple process would use the same reagent for both oxidation
and α-halogenation.
In the literature, we found only a few reports where the
oxidant currently acts as the halogenation reagent. Benzylic
secondary alcohols are transformed to α-chloro acetophenones
4
with m-chloroperbenzoic acid/HCl. An example on the use of
N-chlorosuccinimide for oxidation and chlorination of a
5
secondary benzylic alcohol was disclosed, and the same
substrate class was oxidatively chlorinated to the corresponding
6
α-chloro acetophenones with p-TosNCl . In the t-BuOCl-
2
mediated oxidation of 2-propanol, α-chloro acetone was
7
observed in low yield. We also found few reports on the
analogous transformation comprising oxidation and α-bromi-
8
nation of alcohols.
Herein we disclose highly practical direct conversion of
various primary and secondary benzylic and aliphatic alcohols
to the corresponding α-chloro carbonyl derivatives using
commercially available and very cheap trichloroisocyanuric
As a control experiment, we ran the reaction in the absence
of TEMPO catalyst and noted slow transformation of 1a to
acetophenone (22%, entry 14). This experiment revealed that
under the applied conditions (DCM, 1 equiv MeOH) TEMPO
is not necessary for alcohol oxidation. However, oxidation in
9
acid (TCCA) as an oxidant and α-halogenating reagent
(
Scheme 1). For alcohols that are not oxidized by TCCA,
10
TEMPO is added as a catalyst.
During studies on the TEMPO-catalyzed oxidation of 1-
phenylethanol (1a) to acetophenone (2a) with TCCA as
Received: August 19, 2014
Published: September 8, 2014
11
stoichiometric oxidant (1 equiv) we noted that α-chloro
©
2014 American Chemical Society
4932
dx.doi.org/10.1021/ol5024568 | Org. Lett. 2014, 16, 4932−4935