Full text of DOI:10.1016/S0040-4039(00)01671-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9233–9237
Highly enantioselective copper-catalyzed substitution of
allylic chlorides with diorganozincs
Frank D u¨ bner and Paul Knochel*
Ludwig-Maximilians-Universit a¨ t M u¨ nchen, Department Chemie, Butenandtstraße 5-13, Haus F,
81377 Munich, Germany
Received 14 September 2000; accepted 22 September 2000
Abstract
The new ferrocenyl ligand 1i allows the performance of a highly enantioselective copper catalyzed
SN2%-allylic substitution of allylic chlorides with diorganozincs, providing substituted products with
enantiomeric excesses of up to 98%. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: copper; enantioselective allylation; zinc; asymmetric synthesis; ferrocene.
The allylic substitution reaction of allylic electrophiles with organometallic reagents is an
1–3
excellent method for forming new carbonꢀcarbon bonds. Palladium(0)-catalyzed allylic substi-
tutions have proven to be excellent methods for the enantioselective substitution with stabilized
organometallic reagents such as malonate anions or related species; however, enantioselective
4–9
substitution with alkyl groups is more limited.
Alternatively, copper-catalyzed allylic substitutions with alkyl organometallics show more
10–12
promise. Unfortunately, only moderate enantioselectivities have been obtained up to now.
Recently, we have reported that ferrocenyl amines such as 1c are excellent ligands for the
enantioselective substitution of allylic chlorides with diorganozincs. The enantiomeric excess
with dineopentylzinc reaches 87%, but the reaction requires a temperature of −90°C and is
1
2
limited to very hindered diorganozincs. Thus, under these conditions, the substitution of
cinnamyl chloride with the less hindered dipentylzinc provides an enantiomeric excess of only
2
6%.
Herein, we wish to report the use of an improved ligand, which allows the reaction to be
performed at −30°C and leads to products with enantioselectivities of up to 98%. Thus, we have
prepared a range of ferrocenyl amines of type 1, starting from the readily prepared ferrocenyl
13
ketones 2a–i, followed by an enantioselective CBS reduction, providing the corresponding
*
Corresponding author. Fax: 089/2180-7680; e-mail: paul.knochel@cup.uni-muenchen.de
0
040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01671-3

9234
alcohols 3a–i in good yields (60–88%) and excellent enantioselectivities (>99% ee). The acylation
of the alcohols 3a–i with acetic anhydride in pyridine furnishes the corresponding acetates,
which by treatment with aqueous ammonia in CH CN provide the ferrocenyl amines 1a–i in
3
4
0–60% yield (Scheme 1). These ligands were tested in the substitution of cinnamyl chloride with
dineopentylzinc [THF, −50°C, CuBr·Me S (1 mol%), ligand 1 (10 mol%)] leading to product 6a
2
(
Table 2).
Scheme 1.
We observed that steric hindrance in the ligand is a key parameter for obtaining a high
enantioselectivity. Thus, both the naphthyl (entry 3 of Table 1) and the 9-phenanthrenyl
substituted ligands (entry 5) gave better results than the phenyl substituted system (Ar=Ph).
However, best results were obtained by introducing sterically hindered substituents on the
phenyl ring (entries 4, 6, 7, 8 and 9), leading finally to the ferrocenyl amine 1i as the best ligand
(
92% ee).
Table 1
Optimization of the ferrocenyl amine ligand 1 for the copper catalyzed allylic substitution of cinnamyl chloride
with dineopentylzinc
Entry
Ar
Catalyst
S 2%/S 2
ee (%)
N
N
1
2
3
4
5
6
7
8
9
Phenyl
1-Naphthyl
2-Naphthyl
p-Biphenyl
9-Phenanthrenyl
o-Bromophenyl
p-tert-Butylphenyl
3,5-Dimethylphenyl
3,5-Di-tert-Butylphenyl
1a
1b
1c
1d
1e
1f
1g
1h
1i
95:5
93:7
95:5
97:3
98:2
96:4
96:4
97:3
98:2
32
33
42
38
61
38
56
66
a
92
a
20
[
h] =+62 (c 1.5, CHCl ).
D 3
A further improvement in the reaction conditions, by the simultaneous addition of the
diorganozinc 4 and the allylic chloride 5 in 3 h using a syringe pump, increased the enantioselec-
tivity of product 6 and avoided the using of very low reaction temperatures (−30°C instead of
14
−
50°C or −90°C). The results are summarized in Table 2 and Scheme 2.
Dineopentylzinc still gives the best results, with over 98% ee in the case of p-trifluoromethyl-
cinnamyl chloride (entry 2 of Table 2). Remarkably, now n-dialkylzincs such as dipentylzinc
entry 7) and diethylzinc (entry 8) also give satisfactory results (44–65% ee).
(

9235
Table 2
Enantioselective addition of diorganozincs to allylic chlorides catalyzed by CuBr·DMS (1 mol%) in the presence
of the chiral ligand 1i at −30°C (simultaneous addition of the reagents)

9236
Scheme 2.
1
5
By using mixed diorganozinc reagents, specifically n-alkyl-neo-pentylzincs, it was further
possible to increase the enantioselectivity of the reaction. In the case of ethyl as the n-alkyl
group, compound 6h is formed with 52% ee compared to 44% ee using diethylzinc (Table 2,
entry 8). Interestingly, the formation of product 6a was not observed; only the ethyl group is
transferred, leading to 6h.
2
–9
As well as simple alkyl groups, functionalized diorganozincs, such as di(4-acetoxybutyl)zinc
and di(4-carboethoxybutyl)zinc
6
,16
7
8 also add to cinnamyl chloride with 50% ee, providing the
functionalized products 9 and 10 in 63–75% yield and with complete S 2%-regiocontrol (Scheme 3).
N
Scheme 3.
In summary, we have found that the new ferrocenylamine 1i allows enantioselective allylic
substitution reactions to be performed for the first time with primary and secondary dialkylzincs
as well as with functionalized diorganozincs with a good level of enantioselectivity. Further
improvement of the reaction conditions and the investigation of intramolecular substitutions are
1
7
currently underway in our laboratories.
Acknowledgements
We thank Zeneca Ltd for a fellowship to F.D. and the Fonds der Chemischen Industrie for
generous support. We thank the BASF AG, Degussa AG and Chemetall GmbH for the
generous gift of chemicals.

9237
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6
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8
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1
3. Schwink, L.; Knochel, P. Chem. Eur. J. 1998, 4, 950–968; for recent applications of related chiral ferrocenyl
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14. The absolute configuration of products 6 were determined as cited in Ref. 12.
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17. Typical procedure. Preparation of ethyl 5-phenyl-6-heptenoate (10). To a cooled (−30°C) solution of CuBr·SMe2
(4.11 mg, 0.02 mmol) and ligand 1i (68.2 mg, 0.20 mmol) in THF (5 mL) is added the diorganozinc 8 (2.40 mmol)
in THF and cinnamyl chloride (0.31 g, 2.00 mmol) simultaneously over a period of 3 h. After usual work up, the
crude residue is purified by chromatography (silica gel, pentane). Evaporation of the solvents furnishes product
1
0 (232 mg, 1.00 mmol, 50% yield, 50% ee) as a colorless oil.
.