Takai-Utimoto reactions of oxoalkylhalides catalytic in chromium and cobalt

Article abstract of DOI:10.1016/j.tetlet.2007.04.119

The scope of chromium(II)/cobalt(I)-catalyzed Takai-Utimoto reactions was extended to substrates with unprotected reactive functional groups. In the presence of a higher chlorosilane and manganese the first chromium(II)/cobalt(I)-catalyzed version for the

Full text of DOI:10.1016/j.tetlet.2007.04.119

Tetrahedron Letters 48 (2007) 4323–4325
Takai–Utimoto reactions of oxoalkylhalides catalytic
in chromium and cobalt
Ludger A. Wessjohanna,* and Henri S. Schrekkera,b,
*
aLeibniz Institute of Plant Biochemistry, Weinberg 3, D-06120 Halle (Saale), Germany
bLaboratory of Technological Processes and Catalysis, Institute of Chemistry, Universidade Federal do Rio Grande do Sul-UFRGS,
Bento Gonc¸alves 9500, Porto Alegre-RS, 91501-970, Brazil
Received 29 March 2007; accepted 24 April 2007
Available online 29 April 2007
Abstract—The scope of chromium(II)/cobalt(I)-catalyzed Takai–Utimoto reactions was extended to substrates with unprotected
reactive functional groups. In the presence of a higher chlorosilane and manganese the first chromium(II)/cobalt(I)-catalyzed ver-
sion for the coupling of oxoalkylhalides with aldehydes resulted.
Ó 2007 Elsevier Ltd. All rights reserved.
The application of chromium(II) reagents in organic
chemistry has resulted in a wide variety of methods for
the coupling of organic halides with aldehydes.1,2 These
reactions are characterized by mild conditions and an
excellent chemoselectivity toward aldehydes in the pres-
ence of many other electrophilic functional groups. This
has rendered them indispensible in many complex total
syntheses. Especially, the ‘simple’ generation of alkyl-
chromium(III) reagents under cobalt catalysis from
unactivated aliphatic halides, the chromium-Barbier-
type reaction known as the Takai–Utimoto reaction
(Scheme 1),3 has several advantages over other known
methods, for example, for the generation of oxo-alkyl-
organometallics, that is, ‘homoenolates’ in a more gen-
eral meaning, and their subsequent reaction with a
carbonyl electrophile (La,4 Ce,4 Nd,4 Sm,4 Zn,5 Zn–
Cu,6 Zn–Ti7). However, some unfavorable restrictions
still persist. So far a version catalytic in chromium was
not available for functionalized substrates.
Still the Takai–Utimoto reaction is one of the most effi-
cient, versatile, and mild methods to generate primary
homoenolates.1,3 The chromium(II) reagents do not
need to be activated like zinc, and allow the presence
of ketones, carboxylic esters, nitriles, and other reactive
functional groups.1 For example, ester chromium alco-
holates resulting from 3- or 4-haloalkanoates do not react
further with the lactones if worked up carefully, which is
not the case for most other methods. A severe drawback
of this reaction is its need for stoichiometric quantities
of chromium(II) chloride. For the development of dia-
stereo- and enantioselective Takai–Utimoto reactions a
version catalytic in both chromium and cobalt is highly
desirable. An approach that triggered the development
of chromium-catalyzed reactions is based on the appli-
cation of manganese in combination with scavengers
like chlorotrialkylsilanes (Scheme 2).8 The selectivity
profile of the stoichiometric reactions is preserved in this
set-up, and resulted in both racemic and enantioselective
chromium-catalyzed Nozaki–Hiyama and Nozaki–Hiy-
ama–Kishi reactions.9 This prompted us to investigate
the possibility to adapt this chromium-catalyzed strat-
egy for the synthesis of oxo-functionalized, homoeno-
late-type units.
Scheme 1. Putative mechanism for the Takai–Utimoto reaction.
Keywords: Catalysis; Alkylchromium; Cobalt; Homoaldol.
*
Corresponding authors. Tel.: +49 345 5582 1301; fax: +49 345 5582
1309 (L.A.W.); tel.: +55 51 3308 6284; fax: +55 51 3308 7304
(H.S.S.); e-mail addresses: wessjohann@ipb-halle.de; schrekker@
iq.ufrgs.br
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.119

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L. A. Wessjohann, H. S. Schrekker / Tetrahedron Letters 48 (2007) 4323–4325
(2-bromoethyl)benzene was not fully consumed. Possi-
ble explanations might be a thwarted formation of the
alkylchromium species or hindered regeneration of
chromium(II). The moderate yield is obviously also
the consequence of another side reaction, of the
aliphatic halide, which was further confirmed when
propanal was added slowly (entry 3). In this case bro-
mide 2a was fully converted, which indicates that
TBDMSCl promotes a side reaction. Addition of
TBDMSCl over a period of 15 h improved the catalytic
reaction significantly and resulted in a complete con-
sumption of (2-bromoethyl)benzene (entry 4).
Scheme 2. Putative mechanism for the chromium-catalyzed Takai–
Utimoto reaction (the additional cobalt-catalytic cycle—cf. Scheme
1—which takes place in the dotted box is omitted for clarity).
A Takai–Utimoto reaction of oxo-functionalized alkyl
halides, that is, a homoaldol type reaction catalytic in
chromium was the ultimate goal believed to be amenable
if the chemoselectivity of chromium(III) reactions was
also preserved in the catalyzed version. Indeed, carbox-
ylic ester 2b can be coupled with benzaldehyde to afford
alcohol 4b in a good yield (entry 6). Even an alcohol like
in 2c that normally needs to be protected, can be con-
verted to the desired alcohol 4c without protection. In
the stoichiometric Takai–Utimoto reaction this is quite
efficient (entry 7).2i However, under the slower catalytic
conditions (entry 8) a much lower yield is obtained,
probably because 1 equiv of the silylchloride is used up
by reaction with the alcohol thereby producing detri-
mental HCl. Additionally, the high concentration of
the alcohol versus chromium(II) chloride might cause
problems. During our studies, Kishi reported a similar
chromium-catalyzed coupling of aliphatic halides with
aldehydes.9b,g,h High yields were obtained with a chro-
mium-catalyst loading of 1.0 mol %, however, sensitive
functional groups like intramolecular carbonyls were
not included in his study.
Crucial was the choice of the chlorotrialkylsilane, as the
course of the reaction was dramatically influenced by
this. TMSCl directed the reaction mainly toward pinac-
olization10 instead of the desired product. In contrast,
the sterically more demanding TBDMSCl resulted in
good yields of the desired product, and largely sup-
pressed pinacolization. The development of the chro-
mium(II)-catalyzed Takai–Utimoto reaction was
performed with TBDMSCl, and an aliphatic aldehyde
as this combination is less sensitive toward pinacoliza-
tion.10 The results are summarized in Table 1. The reac-
tion with an excess of alkyl bromide 2a afforded alcohol
4a in 28% yield (entry 1). In spite of the low yield, this
result proved that the reaction can be performed cata-
lytic in chromium because the theoretical maximum of
7.5% yield for a stoichiometric process was clearly sur-
passed. Responsible for the reduced yield compared to
the use of stoichiometric amounts of Cr(II) is the forma-
tion of TBDMS–ether 5 as a result of a reduction of
propanal.2j,10,11 The application of propanal in a two-
fold excess versus (2-bromoethyl)benzene resulted only
in a small increase in yield (entry 2). To our surprise,
In conclusion, a Takai–Utimoto reaction catalytic in
both chromium and cobalt has been developed, using
manganese as bulk reductant, and the chlorotrialkyl-
Table 1. The chromium-catalyzed Takai–Utimoto reaction for the synthesis of homoaldol unitsa
Entry
1
2
1:2:3
Remark
Yieldb (%)
1
2
3
4
1a
1a
1a
1a
2a
2a
2a
2a
1.0:1.8:2.4
2.0:1.0:2.0
2.0:1.0:2.0
2.0:1.0:2.0
None
None
Slow addition of 1a
Slow addition of 3
28 (4a)
37 (4a)
18 (4a)
56 (4a)
5
6
1b
1b
2b
2b
Stoichiometric in Cr(II)
2.0:1.0:2.0
>90 (4b)
59 (4b)
None
7
8
1b
1b
2c
2c
Stoichiometric in Cr(II)
2.0:1.0:2.0
60 (4c)
24 (4c)
None
a 15.0 mol % Cr(II); see experimental part for detailed reaction conditions, CN–B12 = cyanocobalamine (vitamin B12).
b Isolated yield based on minor component.

L. A. Wessjohann, H. S. Schrekker / Tetrahedron Letters 48 (2007) 4323–4325
4325
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