Cerium(III)-catalyzed addition of diethylzinc to carbonyl compounds

Article abstract of DOI:10.1055/s-2002-34897

CeCl₃ catalyzes the addition of Et₂Zn to a variety of alipahtic and aromatic aldehydes and ketones in THF in the presence of TMSCl as a scavenger. Optimization of the applied solvent allowed to avoid the TMSCl mediated addition using CeCl₃·(THF)₂ or Ce(i-PrO)₃ as catalysts. This represents the first application of lanthanide compounds for the addition of Et₂Zn to carbonyl compounds.

Full text of DOI:10.1055/s-2002-34897

1922
LETTER
Cerium(III)-Catalyzed Addition of Diethylzinc to Carbonyl Compounds1
C
erium(III)-ca
t
talyzed
e
A
dditiono
f
f
Diethy
a
lzinc to Ca
n
rbonyl Compound
F
s
ischer,a Ulrich Groth,*a Mario Jeske,b Thorben Schütza
a
Fachbereich Chemie, Universität Konstanz, Fach M-720, Universitätsstr. 10, 78457 Konstanz, Germany
E-mail: Ulrich.Groth@uni-konstanz.de
b
Bayer AG, PH-R-EU-CR, 42096 Wuppertal
Received 1 August 2002
As a second reaction parameter the influence of the reac-
tion temperature on the yield was optimized. The results
of the cerium-catalyzed addition of diethylzinc to benzal-
dehyde are shown in Table 1. Variation of the reaction
Abstract: CeCl3 catalyzes the addition of Et2Zn to a variety of ali-
pahtic and aromatic aldehydes and ketones in THF in the presence
of TMSCl as a scavenger. Optimization of the applied solvent al-
lowed to avoid the TMSCl mediated addition using CeCl3 (THF)2
or Ce(i-PrO)3 as catalysts. This represents the first application of temperature in a range from –78 °C to –50 °C led to low
lanthanide compounds for the addition of Et2Zn to carbonyl com-
pounds.
yields of phenyl-1-propanol only (Table 1, entries 1 and
2). By increasing the reaction temperature higher yields of
Key words: lanthanides, cerium, catalysis, diethylzinc, addition to
carbonyls
the addition product were observed (Table 1, entries 3 and
4). The optimal reaction temperature was room tempera-
ture (93% yield, Table 1, entry 5). Higher reaction tem-
peratures resulted in lower yields probably caused by
Over the last decades lanthanides due to their high oxo- decomposition of diethylzinc (Table 1, entry 6).
philicity have provoked increasing interest in organic
Table 1 Influence of the Reaction Temperature of the CeCl3-
Catalyzed Addition of Diethylzinc to Benzaldehyde
chemistry. Numerous examples for their versatile utility
are known.2 Catalytic processes, however, which take ad-
vantage of the unique properties of lanthanides are still
rare. Recently, we have reported that cerium(III)-alkox-
1) 5 mol% CeCl3
1.5 eq TMSCl
2.0 eq Et2Zn, THF
OTMS
O
ides catalyze the reductive coupling of carbonyl com-
pounds to the corresponding pinacols highly
diastereoselectively and in excellent yields.3
2) sat. aq. NH4Cl
Ph
Ph
H
2
1
The addition of diethylzinc to aldehydes is currently under
investigation by a number of research groups, which have
already reached significant success regarding chemical
yields and enantiomeric purities of the addition products.
The use of catalytic amounts of enantiomerically pure
aminoalcohols as Lewis bases as well as the use of chiral
transition metal complexes as Lewis acids, e.g. titanium,
are commonly described.4–6 Herein, we wish to report the
first example of a cerium(III)-catalyzed addition of dieth-
ylzinc to carbonyl compounds. To the best of our knowl-
edge this reaction has not yet been described with other
lanthanide compounds.
Entry
Temp (°C)
Yield (%)a
1
2
3
4
5
6
–78
–50
–35
0
11
23
70
88
93
90
25
50
a Yields refer to isolated products.
We have observed that the addition proceeds in excellent
yields with the use of trimethylsilylchloride as a scaven-
ger in THF and with anhydrous cerium(III)-chloride as
catalyst. Optimization of the catalyst amounts was inves-
tigated first. Applying cerium(III)-chloride in stoichio-
metric quantities the addition product of diethylzinc to
benzaldehyde was isolated almost quantitatively. De-
creasing the amount of cerium(III)-chloride allowed the
reaction to proceed in excellent yields. Optimal reaction
conditions were determined by using 5 mol% CeCl3, 1.5
equivalents TMSCl and 2.0 equivalents diethylzinc.
Scope and limitations of the presented cerium catalyzed
addition reaction were investigated next. Different carbo-
nyl compounds were converted to their addition products
under the optimized reaction conditions described above.
The reaction of aromatic and aliphatic aldehydes led to
excellent yields and the corresponding secondary alcohols
were isolated in more than 90% yield (Table 2, entries
1–3). Acetophenone was converted in 87% yield to 1-
methyl-1-phenyl-propion-1-ol (Table 2, entry 4).
To discuss the regioselectivity of the reaction, the cerium-
catalyzed addition of diethylzinc to benzylidenacetone
was investigated. It proceeded in a highly 1,2-selective
manner with a yield of 73% (Table 2, entry 5). The 1,4-
product was not isolated. The lower reactivity of ketones
in comparison to aldehydes resulted in decreasing yields
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1922,1924,ftx,en;G21402ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
Cerium(III)-catalyzed Addition of Diethylzinc to Carbonyl Compounds
1923
Cerium(III)-isopropoxide8 is readily soluble in toluene
and therefore it is possible to avoid complex solvent mix-
tures. Optimized reaction conditions require the use of
only 5 mol% Ce(i-PrO)3 and 2 equivalents of diethylzinc
(Table 3, entry 6). An extended reaction time increased
the yield significantly (Table 3, entry 7), whereas pro-
longed reaction times of more than 34 hours led to side
reactions such as the Meerwein–Ponndorf–Verley reduc-
tion, but no pinacol coupling was observed. Even after
these long reaction times starting material was still re-
maining in all cases.
Table 4 shows a few examples of the Ce(O-i-Pr)3 system.9
They illustrate that electron withdrawing nitrile substitu-
ents in para- and meta- position led to improved yields of
addition product. ortho-Substitution causes a decrease in
yield presumably due to steric effects.
Table 2 CeCl3-Catalyzed Addition of Diethylzinc to Different Car-
bonyl Compounds
1) 5 mol% CeCl3
1.5 eq TMSCl
O
R2
R1
OTMS
2.0 eq Et2Zn, THF, rt
2) sat. aq. NH4Cl
R1
R2
3
4
Entry R1
R2
H
Time [h]
Yield [%]a
1
2
3
4
5
Ph
15
15
15
48
72
93
95
90
87
73
p-MeOPh
c-C6H11
Ph
H
H
Me
Me
Ph(CH=CH)
a Yields refer to isolated products.
Table 4 Ce(i-PrO)3-Catalyzed Addition of Dietylzinc to Various
Substituted Benzaldehydes
(Table 2, entries 4 and 5 vs 1–3). Even when the reaction
time was prolonged, starting material was still present.
1) 5 mol% Ce(O-i-Pr)3
2.0 eq Et2Zn, toluene, rt, 34h
O
OH
A disadvantage of TMSCl as a scavenger is its ability to
mediate the addition of diethylzinc to aldehydes, even
without a catalyst, up to 20% at room temperature.7 The
fact that the reactivity of diethylzinc increases as the po-
larity of the solvent decreases enabled us to show that,
presumably due to enhanced transmetalation, the
CeCl3 (THF)2 complex alone is sufficient to catalyze the
addition reaction when toluene is used as solvent (Table 3,
entries 1 and 2). Due to side reactions longer reaction
times do not improve yields significantly. Low solubility
of CeCl3 (THF)2 in toluene causes lower concentration of
active catalyst which prohibits higher yields. To improve
solubility, mixtures of toluene and THF were investigated
and optimal yields were obtained using a 5:1 ratio
(Table 3, entry 3).
R
H
R
2) 2N HCl
7
6
Entry
R
Yield [%]a
1
2
3
4
p-NC-Ph
m-NC-Ph
o-NC-Ph
p-MeO-Ph
67
59
22
10b
a Yields refer to isolated products.
b 50 °C.
The electron donating methoxy substituent prevented any
addition reaction at room temperature and required harsh-
er reaction conditions (Table 4, entry 4).
Table 3 Ce(III)-Catalyzed Addition of Diethylzinc to Benzalde-
hyde
In summary, we developed a novel cerium-catalyzed ad-
dition of zincorganyls to carbonyl compounds. We were
able to reach high yields using TMSCl as a scavenger
and cerium(III)-chloride as catalyst in THF. Using
CeCl3 (THF)2 and Ce(i-PrO)3 in toluene, respectively, it is
possible to avoid the TMSCl mediated addition. Future
efforts will be directed towards variation of ligands for
the applied cerium catalyst in order to improve the chem-
ical yields as well as to run this process in an asymmetric
fashion.
1) 5 mol% catalyst
2.0 eq Et2Zn, rt
O
OH
2) 2N HCl
Ph
H
Ph
5
1
Entry Solvent
Catalyst
Time (h)
18
Yield (%)a
1
2
3
4
5
6
7
Toluene
Toluene
5:1b
–
<5
35
52
25
7
CeCl3 (THF)2
CeCl3 (THF)2
CeCl3 (THF)2
CeCl3 (THF)2
Ce(i-PrO)3
Ce(i-PrO)3
18
18
Acknowledgement
3:1b
18
The authors are grateful to the Fonds der Chemischen Industrie and
the EU-Commission, Directorate XII, for financial support. M. J.
thanks the Stiftung Stipendienfonds des Verbandes der Chemischen
Industrie, S. F. the Cusanuswerk – Bischöfliche Hochbegabtenför-
derung and T. S. the Konrad-Adenauer-Stiftung for a Ph.D. fel-
lowship. We also thank Witco for the generous donation of
diethylzinc.
1:1b
18
Toluene
Toluene
18
48
58
34
a Yields refer to isolated products.
b Toluene:THF ratio.
Synlett 2002, No. 11, 1922–1924 ISSN 0936-5214 © Thieme Stuttgart · New York

1924
S. Fischer et al.
LETTER
(6) Lewis acids: (a) Yoshioka, M.; Kawakita, T.; Ohno, M.
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(9) General Experimental Procedure: The reactions were
carried out under argon atmosphere using Schlenk
techniques. Substances, which are sensitive against moisture
and oxidation were stored in a glove box. Reactions were
typically performed on a 1.5 mmol scale. In a Schlenk tube
5 mL of solvent were added to the catalyst (usually
0.075 mmol, 0.05 equiv). Then, 3 mL of an 1 M solution of
diethylzinc (3 mmol, 2 equiv) in the applied solvent were
transferred to the reaction via canulla. To the reaction
mixture 1.5 mL of a 1 M solution of aldehyde (1.5 mmol,
1 equiv) in the used solvent were then added slowly by using
a syringe pump. When TMSCl was used as a scavenger
1.5 mL of a 1.5 M solution (2.25 mmol, 1.5 equiv) in the
chosen solvent were added simultaneously using the same
syringe pump. After careful addition of 25 mL of sat. aq
NH4Cl or 2 N HCl, respectively, the aqueous phase was
extracted with ethylether (3 30 mL). The combined and
dried (MgSO4) organic layers were then liberated from the
solvent and purified by flash chromatography eluting with
EtOAc/petroleum ether.
Synlett 2002, No. 11, 1922–1924 ISSN 0936-5214 © Thieme Stuttgart · New York