The chromium(II)-mediated coupling of secondary alkylhalides with aromatic aldehydes

Article abstract of DOI:10.1055/s-2007-984887

The scope of chromium(II)-mediated Takai-Utimoto reactions was extended to previously unconvertable secondary alkylhalides. Optimization allowed yields of up to over 95%. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984887

LETTER
2139
The Chromium(II)-Mediated Coupling of Secondary Alkylhalides with
Aromatic Aldehydes
T
akai–Utimoto
u
Reactions of
d
Secondary A
g
lkylhalides er A. Wessjohann,*a Gisela Schmidt,a Henri S. Schrekker*a,b
a
Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120 Halle (Saale), Germany
Fax +49(345)55821309; E-mail: wessjohann@ipb-halle.de
b
Laboratory of Technological Processes and Catalysis, Institute of Chemistry, UFRGS, Bento Gonçalves 9500, Porto Alegre-RS,
CEP 91501-970, P.O. Box 15003, Brazil
Fax +55(51)33087304; E-mail: schrekker@iq.ufrgs.br
Received 31 May 2007
Dedicated in memoriam Dr. Martin W. G. de Bolster
resulting from the reaction of 3- or 4-haloalkanoates with
aldehydes usually do not react further to the five- or six-
membered lactones if worked up carefully, which is not
the case for most other methods.1a,2i,k Unfortunately, some
unfavorable restrictions persist. So far, the reaction could
not be extended beyond primary alkylhalides. Although
the chemoselective production of at least a-methyl-
branched alcohols is highly desirable to access
polyketide-type structural motifs with complex sub-
strates, which is required for many natural product total
syntheses, an extension to secondary halides has not yet
been realized. In principle, secondary and even tertiary
chromium(III) alkyls have been reported from metal–
chromium(III) exchange reactions.8 The reason why
unactivated secondary aliphatic halides could not yet be
coupled in the Takai–Utimoto reaction might be seen in
the higher stability of the corresponding radicals, but also
b-hydride elimination has been discussed.1a,3,9 However,
according to a literature report, the one-electron reduction
of primary, secondary, and tertiary alkyl radicals with
chromium(II) should be fast,10 whereas others report no
reactivity of allylhalides with chromium(II) if the oxo
compound as reaction partner is omitted.9 In any case,
only primary alkylchromium(III) was considered suffi-
ciently stable as organometallic species to give useful re-
actions other than Wurtz homocouplings, whereas
benzylic, secondary and tertiary alkylchromium(III) inter-
mediates are considered to be in equilibrium with their
homolytic cleavage products (Scheme 2). For allyl-
chromium, both preferences are discussed, and their
application in Hiyama–Nozaki reactions is widely docu-
mented.1,9 Also, Co(I) reactions to secondary and tertiary
alkyl Co(III) complexes are well documented.11 This sup-
ported us to study the behavior of unactivated secondary
aliphatic halides in the Takai–Utimoto reaction in more
detail with the aim to extent the scope of this reaction to
secondary alkyls.
Abstract: The scope of chromium(II)-mediated Takai–Utimoto
reactions was extended to previously unconvertable secondary
alkylhalides. Optimization allowed yields of up to over 95%.
Key words: chromium, cobalt, alkylchromium, secondary, cataly-
sis
Chromium(II) reagents are valuable as highly selective
reductive coupling agents of organic halides with alde-
hydes.1,2 These reactions are characterized by mild condi-
tions and an excellent chemoselectivity toward aldehydes
in the presence of many other electrophilic functional
groups. 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 This has rendered them indispensible in many
complex total syntheses.1 Especially, the ‘simple’ genera-
tion of alkylchromium(III) reagents from unactivated
aliphatic halides under cobalt catalysis, the chromium
Barbier-type reaction known as the Takai–Utimoto
reaction (Scheme 1),3 has several advantages over other
known methods.
R1X
CrX2
R1
R1Co(III)X
R1CrX2
Co(I)
Co(II)X
OCrX2
CrX3
CrX2
R1 R2
R2CHO
Scheme 1 Generally accepted mechanism for the Takai–Utimoto
reaction
It is one of the most efficient, versatile, and mild methods
to generate oxo-alkylorganometallics, i.e. primary
‘homoenolates’ in a more general meaning,1,3 and their
subsequent reaction with a carbonyl electrophile (other
metals less conveniently used are La,4 Ce,4 Nd,4 Sm,4 Zn,5
Zn–Cu,6 Zn–Ti7). For example, chromium alcoholates
equilibrium
Cr(II)X2
R
Cr(III)X2
R
+
R = benzyl, sec. alkyl,
tert. alkyl
R = allyl = ?
R = prim. alkyl
SYNLETT 2007, No. 13, pp 2139–2141
Advanced online publication: 12.07.2007
DOI: 10.1055/s-2007-984887; Art ID: S02807ST
© Georg Thieme Verlag Stuttgart · New York
1
3
.0
8
.2
0
0
7
Scheme 2 Formation/homolytic cleavage equilibrium of
chromium(III) organyls

2140
L. A. Wessjohann et al.
LETTER
The only reactivity study for a secondary halide is found
in the original work of Takai et al. where cyclododecyl
iodide was reacted with benzaldehyde.3 Cyclododecane
and cyclododecene were the only products reported, while
the aldehyde remained unchanged. This is an indication,
that the Cr(II)-mediated reduction of a secondary aliphatic
halide is working in principle, but fails in the carbon–car-
bon coupling. Based on our experience,2 we decided to
test the reaction under improved conditions, starting with
isopropyl iodide as sterically least strained secondary
halide. All reactions were performed under similar condi-
tions (DMF, 55 °C, 16 h), using 2.5 equivalents of chro-
mium(II) chloride, 10 mol% lithium iodide, and
benzaldehyde as electrophile. The reaction temperature,
cobalt catalyst, lithium iodide amount, and solvent were
varied. The results are summarized in Table 1. The reac-
tivity of chromium(II) chloride is not sufficient to directly
reduce primary aliphatic halides, and a substitution reac-
tion with its chloride counterion takes place instead, there-
by producing unreactive alkyl chloride. Hence the need
for cobalt catalysis. In contrast to this, secondary and
tertiary aliphatic halides are readily reduced to form the
intermediate radical, which is rapidly reduced in a second
step by chromium(II) chloride to reversibly form the
alkylchromium(III) species (Scheme 2).12 Performing the
reaction in the absence of a cobalt catalyst and lithium
iodide resulted in a moderate yield of alcohol 3a (entry 1).
Table 1 Reactivity of Secondary Aliphatic Iodides with
Chromium(II) Chloridea,b
OH
CrCl2, Lil
[cobalt cat.]
O
R1
R1
Ph
OH
R3
+
R3
I
H
+
DMF, 55 °C,
16 h
R2
R2
Ph
OH
1
2
3
4
3a: R1 = R2 = Me, R3 = Ph
1a: R1 = R2 = Me
2a: R3 = Ph
3b: R1,R2 = –(CH2)5–, R3 = Ph
3c: R1 = Me, R2 = Et, R3 = Ph
3d: R1 = R2 = Me, R3 = 4-MeC6H4m
3e: R1 = R2 = Me, R3 = furan-2-yl
1b: R1,R2 = –(CH2)5– 2b: R3 = 4-MeC6H4
1c: R1 = Me, R2 = Et
O
2c: R3
=
Entry
1
2
Cobalt catalyst Remark
Yield
(%)c
1
2
a
a
a
a
a
a
a
a
b
c
a
a
a
a
a
a
a
a
a
a
b
c
None
No LiI
52 (3a)
72 (3a)
70 (3a)
0 (3a)
None
LiI (10 mol%)
LiI (250 mol%)
THF as solvent
55 °C
3
None
4
None
d
5
Vitamin B12
70 (3a)
>95 (3a)
>95 (3a)
52 (3a)
58 (3b)f
44 (3c)
55 (3d)f
39 (3e)f
6
Co(porphin)e
55 °C
d
7
Vitamin B12
20 °C
8
Co(porphin)e
20 °C
d
9
Vitamin B12
20 °C
The presence of catalytic or stoichiometric amounts of
lithium iodide improved the yield, independent of the
amount (entries 2 and 3). In the presence of lithium iodide
an increased reactivity for chromium(II)-mediated reac-
tions is often observed, especially in THF. This effect has
been explained by the putative formation of better soluble,
anionic chromate(II) species, e.g. Li2[CrX4].1a,2b In DMF,
CrCl2 is quite well soluble, and a simple Lewis acid and/
or iodide-exchange catalysis of the lithium iodide additive
might prevail.
d
10
11
12
Vitamin B12
20 °C
d
a
a
Vitamin B12
20 °C
d
Vitamin B12
20 °C
a CrCl2 (2.50 equiv), cobalt catalyst (5 mol%), LiI (10 mol%), alde-
hyde 2 (1.00 equiv), and iodide 1 (1.10 equiv).
b Reaction without aliphatic halide 1 resulted in 68% pinacol coupling
product 4.
c Isolated yield based on aldehyde.
d Cyanocobalamine.
e Cobalt tetramethoxyphenylporphyrin.
Substitution of DMF by THF as solvent had a dramatic
effect: No product was obtained under these conditions
(entry 4). A possible reason may be the decreased reduc-
tion potential of chromium(II) chloride in THF.13 Per-
forming the reaction in DMF in the presence of a cobalt
catalyst afforded distinct results. Although no additional
positive effect was observed with cyanocobalamine (vita-
min B12) added, alcohol 3a was obtained in an excellent
yield in the presence of a new cobalt catalyst for the
Takai–Utimoto reaction: cobalt tetramethoxyphenylpor-
phyrin (entries 5 and 6). Surprisingly, a lower temperature
had an opposite effect on both reactions (entries 7 and 8).
Now, the reaction with cyanocobalamine resulted in an
excellent yield, and a strong decrease was observed for
cobalt tetramethoxyphenylporphyrin. Obviously, the co-
balt catalyst is also involved in the reaction of secondary
aliphatic halides, and the cobalt-dependent transforma-
tions (Scheme 1) of cyanocobalamine and cobalt tetra-
methoxyphenylporphyrin are differently influenced by a
temperature change. The origin may lie in differences in
the reduction potentials of the various cobalt oxidation
f Reactions of other substrates were not optimized for yield.
states – a factor of known importance,2i,3 different kinetic
temperature profiles, nucleophilicity, and solubility dif-
ferences. The coupling reaction of cyclohexyl iodide and
sec-butyl iodide with benzaldehyde ocurred in moderate
to good yields, which demonstrates that the scope of this
reaction is not limited to isopropyl iodide (entry 9). How-
ever, the aldehyde partner needs to have the proper redox
or radical-stabilizing potential in order to allow good
yields, for example through conjugation to an aromatic
system.
In conclusion, secondary a-branched aliphatic halides can
be efficiently coupled with aromatic aldehydes in a mod-
ified chromium(II)-mediated Takai–Utimoto reaction
with and even without cobalt catalysis. Excellent yields
are easily achieved by variation of catalyst and conditions.
The procedure possesses all characteristics required for an
application in the synthesis of complex molecules, due to
the mild reaction conditions.
Synlett 2007, No. 13, 2139–2141 © Thieme Stuttgart · New York

LETTER
Takai–Utimoto Reactions of Secondary Alkylhalides
2141
General Methods
Wessjohann, L. A. J. Org. Chem. 2002, 67, 1975.
All reactions were carried out under an argon atmosphere in flame-
dried glassware using standard syringe and septa techniques. The
commercial reagents 1a,b, 2, cyanocobalamine (vitamin B12),
cobalt tetramethoxyphenylporphyrin, lithium iodide, and chromi-
um(II) chloride (99.9% from Strem Chemicals) were used as pur-
chased. The THF was distilled from potassium/benzophenone.
Absolute DMF was purchased from Fluka. Benzaldehyde was
distilled from potassium hydride. Spectral data of the known
compounds 3a,14 3b,15 3c,16, 3d,17, 3e,18 and 419 were in accordance
with the literature data. Thin-layer chromatography was carried out
on Merck silica 60/F-254 aluminium-backed plates. Flash chroma-
tography was performed using Merck silica gel 60 (40-60 mm).
NMR spectra were recorded in CDCl3. Chemical shifts d are quoted
in parts per million (ppm), and coupling constants J are given in
Hertz (Hz).
(g) Schrekker, H. S.; Micskei, K.; Hajdu, C.; Patonay, T.; de
Bolster, M. W. G.; Wessjohann, L. A. Adv. Synth. Catal.
2004, 346, 731. (h) Wessjohann, L. A.; Wild, H.; Schrekker,
H. S. Tetrahedron Lett. 2004, 45, 9073. (i) Wessjohann, L.
A.; Gabriel, T.; Schrekker, H. S. unpublished results.
(j) Micskei, K.; Hajdu, C.; Wessjohann, L. A.; Mercs, L.;
Kiss-Szikszai, A.; Patonay, T. Tetrahedron: Asymmetry
2004, 15, 1735. (k) Wessjohann, L. A.; Schrekker, H. S.
Tetrahedron Lett. 2007, 48, 4323.
(3) Takai, K.; Nitta, K.; Fujimura, O.; Utimoto, K. J. Org.
Chem. 1989, 54, 4732.
(4) Fukuzawa, S.-I.; Sumimoto, N.; Fujinamo, T.; Sakai, S.
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(5) (a) Tamaru, Y.; Nakamura, T.; Sakaguchi, M.; Ochiai, H.;
Yoshida, Z. J. Chem. Soc., Chem. Commun. 1988, 610.
(b) Houkawa, T.; Ueda, T.; Sakami, S.; Asaoka, M.; Takei,
H. Tetrahedron Lett. 1996, 37, 1045.
(6) Yeh, M. C. P.; Knochel, P.; Santa, L. E. Tetrahedron Lett.
1988, 29, 3887.
Typical Procedure for the Modified Takai–Utimoto Reaction of
a-Branched Secondary Aliphatic Iodides (Table 1, entry 7)
To CrCl2 (200 mg, 1.63 mmol, 2.50 equiv), cyanocobalamine (vita-
min B12, 44 mg, 33 mmol, 0.05 equiv), and LiI (8.7 mg, 65 mmol,
0.10 equiv) was added DMF (2.5 mL) under vigorous stirring. After
a few minutes, benzaldehyde (0.65 mmol, 1.00 equiv) and iodide 1a
(0.72 mmol, 1.10 equiv) were added in this order. The resulting
mixture was stirred for 16 h at 20 °C, and the reaction was quenched
with H2O (2.5 mL). The water layer was extracted with Et2O, and
the combined organic fractions were washed with H2O and aq NaCl
solution. The organic layer was dried over MgSO4 and concentrated
in vacuo. The crude product was purified by flash chromatography,
usually with a hexane–Et2O mixture as eluent.
(7) (a) Rozema, M. J.; Sidduri, A.; Knochel, P. J. Org. Chem.
1992, 57, 1956. (b) Ochiai, H.; Nishihara, T.; Tamaru, Y.;
Ysohida, Z.-I. J. Org. Chem. 1988, 53, 1343.
(c) Armstrong, J. D. III; Hartner, F. W. Jr.; DeCamp, A. E.;
Volante, R. P.; Shinkai, I. Tetrahedron Lett. 1992, 33, 6599.
(d) DeCamp, A. E.; Kawaguchi, A. T.; Volante, R. P.;
Shinkai, I. Tetrahedron Lett. 1991, 32, 1867.
(8) (a) Sneeden, R. P. A.; Zeiss, H. H. J. Organomet. Chem.
1971, 26, 101. (b) Nishimura, K.; Kuribayashi, H.;
Yamamoto, A.; Sakuji, I. J. Organomet. Chem. 1972, 37,
317.
(9) Mulzer, J.; Strecker, A. R.; Kattner, L. Tetrahedron Lett.
2004, 45, 8867.
Acknowledgment
(10) Kochi, J. K.; Powers, J. W. J. Am. Chem. Soc. 1970, 92, 137.
(11) Brown, K. L. Chem. Rev. 2005, 105, 2075.
(12) Takai, K.; Matsukawa, N.; Takahashi, A.; Fujii, T. Angew.
Chem. Int. Ed. 1998, 37, 152; Angew. Chem. 1998, 110, 150.
(13) Kochi, J. K.; Mocadlo, P. E. J. Am. Chem. Soc. 1966, 4094.
(14) Palmer, M. J.; Kenny, J. A.; Walsgrove, T.; Kawamoto, A.;
Wills, M. J. Chem. Soc., Perkin Trans. 1 2002, 1, 416.
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(16) Nichols, M. A.; McPhail, A. T.; Arnett, E. M. J. Am. Chem.
Soc. 1991, 113, 6222.
H.S.S. thanks the state of Saxony-Anhalt (HWP) for support.
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