Enantioselective carbometalation of cinnamyl derivatives: New access to chiral disubstituted cyclopropanes - Configurational stability of benzylic organozinc halides

Article abstract of DOI:10.1002/(SICI)1521-3765(19990702)5:7<2055::AID-CHEM2055>3.0.CO;2-9

A stoichiometric or catalytic amount of (-)-sparteine can serve asa promoter for the enantioselective carbolithiation of cinnamyl derivatives by primary and secondary organolithium compounds. The enantiofacial choice of the addition reaction is dependent on the stereochemistry of the initial double bond. The resulting benzylic organolithium compounds can be derivatized to a linear phenylated chain that bears two contiguous stereogenic centers with given configurations. The use of the dimethyl acetal of the (E)-cinnamyl alcohol allows the highest enantioselective carbolithiation and by simply warming the reaction mixture to room temperature, the resulting benzylic organo-lithium intermediate undergoes a 1,3-elimination to give the chiral disubstituted cyclopropane in high enantiomeric excess (90-95% ee). Another significant finding is the observation that the Li-Zn transmetalation in a benzylic species occurs with inversion of configuration, and the corresponding acyclic benzylic zinc halides have observable configurational stability at - 30°C.

Full text of DOI:10.1002/(SICI)1521-3765(19990702)5:7<2055::AID-CHEM2055>3.0.CO;2-9

FULL PAPER
Enantioselective Carbometalation of Cinnamyl Derivatives:
New Access to Chiral Disubstituted CyclopropanesÐ
Configurational Stability of Benzylic Organozinc Halides
Stephanie Norsikian,[b] Ilan Marek,*[a] Sophie Klein,[b] Jean F. Poisson,[b] and
Jean F. Normant*[b]
Abstract: A stoichiometric or catalytic
amount of ( )-sparteine can serve as a
promoter for the enantioselective car-
bolithiation of cinnamyl derivatives by
primary and secondary organolithium
compounds. The enantiofacial choice of
the addition reaction is dependent on
the stereochemistry of the initial double
bond. The resulting benzylic organo-
lithium compounds can be derivatized
to a linear phenylated chain that bears
two contiguous stereogenic centers with
given configurations. The use of the
dimethyl acetal of the (E)-cinnamyl
alcohol allows the highest enantioselec-
tive carbolithiation and by simply warm-
ing the reaction mixture to room tem-
perature, the resulting benzylic organo-
lithium intermediate undergoes a 1,3-
elimination to give the chiral disubsti-
tuted cyclopropane in high enantiomeric
excess (90 ± 95% ee). Another signifi-
cant finding is the observation that the
Li ± Zn transmetalation in a benzylic
species occurs with inversion of config-
uration, and the corresponding acyclic
benzylic zinc halides have observable
configurational stability at 308C.
Keywords: asymmetric catalysis
´
´
´
carbolithiation
organolithium
( )-sparteine
´
cyclopropane
compounds
If an efficient method was available to render such a
process asymmetric, it would acquire a tremendous utility as a
method to create asymmetric vicinal carbon atoms, partic-
ularly if acyclic substrates are employed. However, until now,
reports of such enantioselective carbometalation reactions are
scarce,[4] in spite of the increasing worldwide interest. This is
because of the difficulties associated with the enantiofacial
differentiation of an unactivated alkene. The most important
results in this field come from the asymmetric ethylmagne-
siation reactions[5] developed mainly by Hoveyda et al. and by
the asymmetric carboalumination reaction developed by
Negishi et al.[6] In both cases, the enantioselectivities arise
from chiral zirconium derivatives.[6, 7] Moreover, the enantio-
selective allylmetalation of a cyclopropene ketal with a chiral
bisoxazoline ligand was also reported by Nakamura et al.[8]
Some years ago, we were interested in the carbometalation of
unstrained and unactivated olefins by the synthesis of
geminate organobimetallic derivatives.[9] Our attention was
attracted to a report by Kuwajima et al.[10] on the diastereo-
selective carbolithiation reaction of cinnamyl alcohol. Indeed,
one very interesting result arose from this work: the
carbolithiation of these substrates proceeded in hexane only
in the presence of TMEDA to give the carbometalated product
Introduction
The formation of carbon ± carbon bonds by means of organo-
metallic reagents, which began after discoveries made by
Barbier and Grignard, has commonly been achieved by their
reactions with polar carbon electrophiles. In the search for
new types of selective formation of carbon ± carbon bonds by
the use of organometallic reagents, and following the pioneer-
ing Ziegler addition of some anionic initiators to nonpolarized
carbon ± carbon bonds,[1] the controlled carbometalation re-
action has emerged as a new tool. Carbometalation reactions
are reactions which result in the addition of the carbon ± metal
bond of an organometallic reagent across a carbon ± carbon
double bond to produce a new organometallic compound in
which the newly formed carbon ± metal bond can be used for
further synthetic transformations. An outstanding number of
ˆ
organometallic additions to C C bonds have already been
reported and reviewed.[2, 3]
[a] Dr I. Marek
Department of Chemistry, Technion-Israel Institute of Technology
Technion City, Haifa 32000 (Israel)
Fax : (‡ 972)4-823-37-35
E-mail: chilanm@tx.technion.ac.il
(Scheme 1).[11]
.
[b] Prof. J. F. Normant, S. Norsikian, S. Klein, J. F. Poisson
 Â
Â
Laboratoire de Chimie des Organoelements, associe au CNRS
This observation led us to consider the enantioselective
carbolithiation reaction of cinnamyl derivatives since it would
only be necessary to switch from an achiral diamine
(TMEDA) to a chiral one. But what kind of chiral diamine
Â
Tour 44 ± 45, Universite P. et M. Curie
4 Place Jussieu, F-75252 Paris Cedex 05 (France)
Fax : (‡ 33)1-44-27-71-50
E-mail: normant@ccr.jussieu.fr
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I. Marek, J. F. Normant et al.
FULL PAPER
Results and Discussion
Bu
Ph
Ph
nBuLi / hexane
TMEDA
then H3O+
The addition of (E)-cinnamyl alcohol (1) to a solution of
nBuLi in various solvents in the presence of ( )-sparteine
(1 equiv) led to a red solution which was then hydrolyzed to
give the corresponding alcohol (Scheme 2) in the yields and ee
values shown in Table 1.
OH
OH
Scheme 1. Carbolithiation of cinnamyl alcohol.
should be the most appropriate as a chiral ligand for
alkyllithium?. Fortunately, Hoppe et al. have shown that the
complexation of one equivalent of sBuLi with one equivalent
of ( )-sparteine leads to a chiral organometallic which
induces enantioselective deprotonation of achiral alkyl car-
bamates.[12] The lupine alkaloid ( )-sparteine is readily
available and is obtained through the extraction of
certain papilionaceous plants.[13] This diamine is also
admirably suited for the enantioselective deprotonation
of N-Boc pyrrolidines[14] and can also be utilized in
the thermodynamically controlled equilibration of configura-
tionally labile epimeric organolithium derivatives.[12, 14] There-
fore, we decided to study the effect of the complexation
of alkyllithium with ( )-sparteine in carbometalation reac-
tions, rather than in the metalation reactions previously
described.
Scheme 2. Enantioselective carbolithiation of cinnamyl alcohol.
Table 1. Effect of the solvent on the enantioselectivity.
Entry
Solvent
Yield [%][a]
ee [%][b]
1
2
3
4
THF
Et2O
hexane
cumene
61
67
81
82
0
20
78
83
[a] Based on pure isolated material. [b] Determined by 31P NMR spectro-
scopy, see ref. [16].
Abstract in Hebrew: .
As expected, ( )-sparteine has a most pronounced effect in
the absence of donor solvents, such as diethyl ether or THF
(Table 1, entries 1 and 2). Indeed, in hexane (entry 3) or even
better in cumene (entry 4),[15] higher ee values are obtained
for the carbolithiation reaction. The purity of the chiral
alcohol 12 was determined by the 31P NMR analysis of derived
diastereomeric phosphorus products.[16] The absolute config-
uration of the chiral center was determined to be S, through
comparison with data[17] reported for the corresponding acid
(Scheme 2).
Thus, this simple method (carbolithiation of cinnamyl
substrates by complexation of one equivalent of ( )-sparteine
with alkyllithium) produced the first enantioselective intro-
duction of an n-butyl group across a double bond by means of
a simple alkyllithium compound.[18]
In order to examine the scope of this reaction, we decided
to extend this carbolithiation reaction to other alkyllithium
compounds and to other cinnamyl substrates (Scheme 3,
Table 2).
Commercially available (in hydrocarbon solvent) primary
alkyllithium compounds (Table 2, entries 1 and 2) as well as a
secondary alkyllithium compound (Table 2, entry 3) led to
good ee values, whereas the addition of a tertiary alkyllithium
compound (Table 2, entry 4) gave the racemic compound in a
low yield. These results correlated well with the extent of the
complexation of the alkyllithium compounds with ( )-spar-
teine: the complexation is strongest with the sterically less
demanding organolithium derivatives and weakest with steri-
cally congested environments, such as tBuLi.[19] However,
when the same reaction was applied to nBuLi in the presence
of LiBr, and independent of the nature of the solvent (hexane,
cumene, diethyl ether, or THF), no carbolithiation reaction
Abstract in French: Une quantitØ stoechiomØtrique, ou cata-
lytique, de ( )-spartØine permet dꢀeffectuer la carbolithiation
ØnantiosØlective de dØrivØs cinnamiques par les organolithiens
primaires et secondaires. Le choix facial dØpend de la stØrØo-
chimie ((E),(Z)) de la double liaison. Les organolithiens
Ã
benzyliques ainsi formØs peuvent etre utilisØs en synth›se pour
accØder à des chaînes linØaires phØnylØes portant 2 centres
stØrØog›nes contigus, de configuration bien dØfinie. Lꢀemploi
dꢀun acØtal dØrivØ de lꢀalcool cinnamique (E) permet dꢀattein-
ndre la meilleure ØnantiosØlection, et par rØchauffement du
milieu rØactionnel à tempØrature ambiante, le lithien intermØ-
diaire provoque une Ølimination 1,3 pour engendrer un
cyclopropane disubstituØ avec un ee ØlevØ (90 ± 95%). Un
autre aspect important de ce travail concerne la transmØtalla-
tion de ces lithiens benzyliques en zinciques correspondants
avec inversion de configuration. Ces zinciques benzyliques ont
une bonne stabilitØ configurationnelle à 308C
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Configurational Stability of Benzylic Organozinc Halides
2055±2068
was observed! This result im-
plicates a mixed aggregate of
lithium halide and sparteine
which deactivates the carboli-
thiation reaction.[20] It was then
necessary to add sufficient spar-
teine to combine with all the
lithium salts present in solution.
Indeed, the carbolithiation re-
action of cinnamyl alcohol with
three equivalents of nBuLi and
then three equivalents of LiBr
occurred in the presence of four
equivalents of ( )-sparteine
(one equivalent of diamine for
each lithium bromide and one
equivalent for the alkyllithi-
um). This mixture gave the
carbometalated product with
56% ee (Table 2, entry 5). Sev-
eral other attempts were made
to try to selectively complex the
lithium salt with a nonchiral
diamine, whereby the alkyllithi-
um would be complexed by the
( )-sparteine; however, it did
not succeed.[21] Finally, in order
to minimize the amount of
chiral ligand required for the
Hex
Bu
12
Ph
OH
Et
Ph
Ph
OH
Ph
OH
Bu
14
Ph
OH
Ph
Et
15
17
33
Hept
Ph
Ph
Ph
OH
Bu
32
18
Pr
Bu
R1
Ph
OtBu
Me
R1Li
Ph
Ph
31
19
Hex
(–)-sparteine
Solvent
then H3O+
R
R
Ph
Bu
Me
Ph
NMe2
30
1 R = CH2OH
7 R = (CH2)3OH
8 R = CH2OC(Me)2OMe
9 R = Me
10 R = Bu
11 R = Ph
20
Bu
2 R = CH2OtBu
3 R = CH2NMe2
4 R = CH2NHMe
5 R = CH2NMe(Bn)
6 R = (CH2)2OH
Ph
Bu
Me
Ph
NHMe
29
21
Hept
Bu
Ph
O
O
Ph
NMe(Bn)
28
22
Bu
Ph
O
O
Ph
OH
27
23
Hex
Bu
Bu
Ph
Ph
O
O
OH
Ph
O
O
26
24
25
Scheme 3. Enantioselective carbolithiation of cinnamyl derivatives.
Table 2. Generalization of the carbolithiation reaction.
alkyllithium, which was prepared in diethyl ether from BuBr
and Li, we took advantage of the insolubility of the lithium
salt in cumene. After the formation of the alkyllithium
compound in Et2O, dry cumene was added to the reaction
mixture and Et2O was removed under vacuum. Under these
conditions, the carbometalation reaction required only one
equivalent of ( )-sparteine to give the alkylated product in a
moderate yield and with good enantioselectivity (Table 2,
entry 6). Accordingly, EtLi/LiBr (from EtBr‡ Li) as well as
heptyllithium/LiBr (from bromo-1-heptane ‡ two equivalents
of tBuLi) were added to the olefin to produce the products
with good enantioselectivity (Table 2, entries 7 and 8, respec-
tively). In contrast, whatever the experimental conditions
used, the introduction of MeLi or PhLi groups failed in this
reaction (Table 2, entries 9 and 10). Therefore, from these
results we can deduce that the enantioselective carbometala-
tion with a primary or a secondary alkyllithium compound
occurs with good enantioselectivity, whereas the introduction
of a tertiary group led to a racemic product; Me and Ph groups
failed to react.
This reaction is not restricted to the cinnamyl alcohol as the
substrate and several other cinnamyl derivatives were also
carbometalated with good enantioselectivity. The presence of
a free alcohol is not compulsory for the reaction to proceed
and similar enantioselectivity (80% ee) was obtained with the
tert-butyl ether derivative 2 (Table 2, entry 1 versus entry 11).
The absolute configuration (S) was determined after depro-
tection of the tert-butyl ether to the alcohol 12,[22] and
comparison with an authentic sample. Cinnamyldimethyl-
amine (3) also led to the carbometalated product with
Entry Sub- RLi
strate
Product Solvent Yield [%][a] ee [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
1
1
1
1
1
1
1
1
1
1
2
3
4
5
6
7
8
8
8
8
9
9
9
10
11
nBuLi
nHexLi
sBuLi
tBuLi
12
14
15
16
cumene 85
cumene 76
cumene 65
cumene 40
cumene 60
cumene 65
cumene 68
83
87
72
0
56
66
85
63
±
nBuLi/LiBr[c] 12
nBuLi/LiBr[d] 12
EtLi/LiBr[d]
HeptLi/LiBr[d] 18
MeLi
PhLi
17
cumene 50
[g]
±
±
±
±
±
±
[g]
±
nBuLi
nBuLi
nBuLi
nBuLi
nBuLi
nBuLi
nBuLi
nHexLi
sBuLi
19
20
21
22
23
24
25
26
27
hexane 82
hexane 71
80
82[f]
66
84
70
70
95
94
90
90
85
84
76
86
70
Et2O
62
hexane 64
cumene 72
cumene 75
cumene 77[e]
cumene 70[e]
cumene 80[e]
cumene 50[e]
hexane 83
hexane 86
hexane 92
hexane 73
cumene 81
HeptLi/LiBr[d] 28
nBuLi
29
30
31
32
33
nHexLi
nPrLi/LiCl[d]
EtLi/LiCl[d]
nBuLi
[a] Based on pure isolated product. [b] Determined by 31P NMR spectro-
scopy, see ref. [16]. [c] This reaction was carried out in the presence of four
equivalents of
( )-sparteine. [d] The organolithium compound was
prepared in Et2O and the addition was carried out in cumene, see text.
[e] After deprotection of the acetal (yield of the deprotection >95%).
[f] The enantioselectivity was determined by chiral HPLC on Chirasel OD.
[g] THF, Et2O, cumene, and hexane were tested without success.
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I. Marek, J. F. Normant et al.
FULL PAPER
82% ee[23] (Table 2, entry 12), whereas the enantioselective
carbolithiation of the secondary amine 4 afforded a lower ee
(66%)[24] (Table 2, entry 13). In this case, the reaction did not
occur in the nonpolar solvent, as previously described; Et2O
was necessary to achieve this carbolithiation, and, as we have
already seen (Table 1, entry 2),
over, these three carbometalated products (Table 2, en-
tries 21 ± 23) were also derivatized into the corresponding
known acids[31] and then into the alcohols[32] (Scheme 4) in
order to corroborate their optical purities by means of NMR
spectroscopy.[16]
the carbolithiation in diethyl
ether occurred with low enan-
tioselectivity. This major draw-
back can be circumvented by
the use of benzylmethylcinna-
mylamine (5) (Table 2, entry 14),
followed by hydrogenolysis of
the benzyl moiety of the addi-
tion product. The secondary
amine was now obtained in
84% ee. The absolute configu-
ration was determined by
Ph
R
NaIO4, 2%RuCl3
HOOC
R
HO
R
BH3 :THF
20°C, 6h
CCl4, CH3CN, H2O
20°C, 2d
Me
Me
Me
29 R = Bu
30 R = Hex
31 R = Pr
37 R = Bu 85% ee
38 R = Hex 84% ee
39 R = Pr 76% ee
34 R = Bu
35 R = Hex
36 R = Pr
74%
70%
Bu
Ph
Bu
COOH
NaIO4, 2%RuCl3
HOOC
70% ee
CCl4, CH3CN, H2O
20°C,3d
Ph
33
50%
Scheme 4. Correlation of the carbometalated products.
chemical correlation with an authentic sample prepared by
tosylation of the alcohol 12 and displacement with dimethyl-
amine.
Carbolithiation of 4-phenyl-3-buten-1-ol (6, homoallylic
cinnamyl alcohol, Table 2 entry 15) and of 5-phenyl-4-penten-
1-ol (7, Table 2, entry 16) also led to the carbometalated
products with 70% ee.[25]
In the constant search to increase the enantioselectivity, we
found that the dimethyl acetal 8 of the (E)-cinnamyl alcohol
was the best substrate. Indeed, addition of nBuLi to this
substrate, in the presence of one equivalent of ( )-sparteine,
led, after hydrolysis and deprotection of the acetal moiety, to
the alkylated product in 95% ee! (Table 2, entry 17).[26] The
use of this acetal allows the reaction to be performed at
508C instead of 08C, as described for the carbolithiation of
the cinnamyl alcohol (Table 2, entry 1). The same trend was
observed for the carbolithiation with HexLi (94% ee), sBuLi
(90% ee), or an alkyllithium in the presence of lithium salts,
such as HeptLi/LiBr (90% ee) as shown in Table 2 (en-
tries 18 ± 20, respectively).
Several other substrates were also carbometalated, such as
b-butylstyrene (10) with EtLi/LiCl (entry 24) or, more
interestingly, the trans-stilbene (11) with nBuLi (entry 25)
with good enantioselectivities. In the latter example, we were
able to perform a desymmetrization of the starting material
into a chiral adduct (we were not able to prepare this product
by the carbolithiation of 10 with PhLi since the latter failed to
react (Table 2, entry 10). The corresponding optical purities as
well as the absolute configurations were deduced by chemical
correlation after oxidation[33] of the two phenyl rings into the
corresponding acids[34] (Scheme 4). An elegant intramolecular
carbometalation of cinnamyl substrates mediated by ( )-
sparteine was published recently;[12, 35] this increases the scope
of the reaction.
The stereochemistry of the olefin is crucial to the enantio-
selectivity of the carbolithiation. While the asymmetric
carbolithiation of (E)-cinnamyl alcohol gave the (S)-alkylated
product (Scheme 2), the reaction of the (Z)-1 isomer, under
the same experimental conditions, led to 12', the enantiomer
of 12 (with a (R) configuration), with 70% ee (Scheme 5).
Moreover, when the allylic alcohol is not substituted, as in the
case of 2-propen-1-ol (40), the carbolithiation reaction led to
the racemic alcohol (Scheme 5).
During this study, we realized that the presence of an allylic
ˆ
heteroatom, even in the b- or g-position from the C C
unsaturation, was not very crucial for impeding a polymer-
ization process, and we became aware of a report that styrene
undergoes efficient addition reactions with a range of organo-
lithium reagents without polymerization.[27] As we have been
able to perform such a reaction on the 5-phenyl-4-penten-1-ol
(7, Table 2, entry 16) without a trace of polymerization
(whereas a nonfavorable seven-membered metalacycle be-
tween the alcoholate and the benzylic organolithium com-
pound should be formed before hydrolysis), we investigated
the enantioselective carbolithiation of b-substituted, non-
functionalized styrenes.[28] Addition of nBuLi to b-methyl-
styrene (9) in the presence of one equivalent of sparteine, led
in 4 h at 158C, to the corresponding carbometalated product
in 85% ee (Table 2, entry 21) and without polymerization.
Additions of nHexLi (Table 2, entry 22) and nPrLi/LiCl
(Table 2, entry 23) also gave the products with good enantio-
selectivities (84 and 76% ee, respectively[29]). Optical purities
as well as the absolute configurations of 29 and 30 were
determined by comparison with authentic samples.[30] More-
Scheme 5. Enantioselective carbolithiation of the (Z)-cinnamyl alcohol.
Thus, in order to obtain an enantioselective carbometala-
tion reaction on a cinnamyl substrate, it is necessary to start
ˆ
with an ethylenic C C bond of given geometry. The stereo-
chemical selectivity is of tremendous utility since sparteine is
commercially available in only one enantiomeric form;
however, two enantiomeric carbometalated products are
available, at will, according to the stereochemistry of the
starting material.[36] Additionally, because the carbolithiation
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Configurational Stability of Benzylic Organozinc Halides
2055±2068
Table 3. Catalytic enantioselective carbolithiation reaction.
of the (Z)-b-alkylstyrenes is slower than that of their (E)
isomers,[37] we carried out a study of the kinetic resolution
during the carbolithiation of b-ethylstyrene (41). Indeed, the
addition of nBuLi to this substrate with an (E)/(Z) ratio of
90:10, gave the carbometalated derivative 42 in 87% yield and
78% ee; and the (Z)-41 was still present in the crude reaction
mixture (7%) (Scheme 6). The absolute configuration, (S), as
well as the ee of 42 were determined after derivatization into
the known alcohol 43.
Entry Substrate RLi
Product Sparteine Yield [%][a] ee [%][b]
(equiv)
1
2
3
4
5
6
7
1
3
8
8
8
8
9
nBuLi
nBuLi
nBuLi
nBuLi
nHexLi 26
sBuLi
nBuLi
12
20
25
25
0.05
0.05
0.1
0.01
0.1
55
70
84
82
92
85
92
92
70
67[c]
50[c]
65[c]
77[c]
50
27
29
0.1
0.1
[a] Based on pure isolated product. [b] Determined by 31P NMR spectro-
scopy, see ref. [16]. [c] After deprotection of the acetal (yield of the
deprotection >95%).
nBuLi / hexane
1 equiv sparteine
Ph
Ph
Bu
Ph
Ph
+
+
hexane
42
7%
(E)-41
90%
(Z)-41
10%
87%
78% ee
therefore, the reaction affords the syn product. The lithium
alkoxide functionality in 12Li, obtained after the carbolithia-
tion step, is able to fix the configuration at the benzyl
position;[40] the anti intermediate is expected to be more stable
(thermodynamic equilibration[41]) as a result of the steric
hindrance of the phenyl and alkyl groups. The reaction of the
benzylic organolithium thus formed with different electro-
philes was determined to occur with inversion of configura-
tion.[10, 42] In all cases examined, the products were obtained in
a diastereomeric ratio (dr) of >98:2 prior to purification and
with the enantioselectivity of the carbolithiation step. When
the starting material was the (Z)-1 cinnamyl alcohol (see
Scheme 5), the carbolithiation step led to the benzylic
organolithium 12'Li, the opposite enantiomer of 12Li
(Scheme 7). After reaction with diphenyl disulfide, the
enantiomeric adduct 45' was obtained with a diastereoselec-
tivity of >98/2 and an enantioselectivity of 70%. Thus, two
chiral centers were created in a one-pot operation in a
diastereospecific and enantioselective manner on an acyclic
system.
NaIO4, 2%RuCl3
HOOC
Bu
Et
HO
Bu
Et
BH3 :THF
CCl4, CH3CN, H2O
20°C, 2d
20°C, 6h
80%
43
85%
Scheme 6. Kinetic resolution in the carbometalation of b-ethylstyrene.
The enantioselective and straightforward synthesis of 42
and 43 is an interesting entry to the elaboration of the West
fragment of a potent tripeptide immunomodulator.[38]
Since these cinnamyl derivatives were shown to be un-
reactive towards the addition of alkyllithium in hydrocarbon
solvents without an external diamine, the potential for
catalysis was obvious. The results, summarized in Table 3,
show that addition of these derivatives to alkyllithium
compounds and catalytic amounts of ( )-sparteine also leads
to good enantiomeric excesses (70 ± 92% ee). Even with 1%
of chiral diamine, the chiral adduct is obtained in 85% ee
(entry 4). Moreover, the product itself is not an enantiose-
lective catalyst[39] since the hydrolysis of the reaction mixture
after only 30% conversion led to the same ee value.
In the first part of this work, we hydrolyzed the newly
formed benzylic organolithium compounds formed in these
reactions in order to study the enantioselectivity of the
carbolithiation step. However, since we had synthesized these
benzylic organolithium compounds, we decided to study the
stereochemical outcome of
We then studied the reaction of the benzylic organolithium
with an intramolecular electrophile, namely the acetal moiety
8 described in Table 2. When the chelating moiety was a
dimethyl methoxy methyl ether, the benzylic organolithium
species formed was not stabilized, and it became thermally
labile.[43] Indeed, when the reaction mixture was simply
their reactions with several
electrophiles and to create two
chiral centers in a one-pot op-
eration and in an acyclic sys-
tem. Kuwajima et al.[10] have
46
Bu
63%
Ph
OH
CH3I
Bu
d.r.> 98/2
82% ee
CH3
(E)-1
R1
Bu
Ph
Li
DCl
Ph
OH
nBuLi / hexane
recently reported the reactivity
of such benzylic organolithium
compounds, in a racemic sub-
strate, with electrophiles. When
applied to our enantioselective
approach on cinnamyl alcohol,
the reactions proceeded in a
highly diastereoselective man-
ner (Scheme 7).
All compounds had the same
1H and 13C NMR spectra as the
products prepared with TME-
DA[10] instead of ( )-sparteine;
R2
(–) sparteine
O°C, 1h /
cumene
D
44
87%
d.r. 95/5
84% ee
OH
OLi
12 Li
R1 Ph, R2 H (E)-1
R1 H, R2 Ph
(Z)-1
Bu
Ph
OH
nBuLi / hexane
(Z)-1
PhSSPh
OH
(–) sparteine
O°C, 1h /
cumene
45
61%
SPh
d.r.> 98/2
83% ee
Bu
Bu
Ph
Ph
PhSSPh
45'
60%
d.r.> 98/2
70% ee
SPh
Li
OLi
12'Li
Scheme 7. Creation of two chiral centers.
Chem. Eur. J. 1999, 5, No. 7
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I. Marek, J. F. Normant et al.
FULL PAPER
warmed to room temperature the benzylic organolithium
intermediate led to the pure chiral trans-disubstituted cyclo-
propane,[44] by means of an internal nucleophilic substitution
(Scheme 8 and Table 4).
(51),[47] and the purity of the chiral disubstituted cyclopropa-
nol (93% ee) was determined by NMR spectroscopy by the
use of chiral derivatizing agents.[16] The same sequence was
performed on the cyclopropane 47, generated in the presence
of a catalytic amount of ( )-sparteine, and the same
enantiomeric excess was obtained for 51. Then, by the use
of the same strategy as previously described on the dimethyl
cinnamyl acetal 8, several chiral purely trans-disubstituted
cyclopropanes were readily obtained in a one-pot operation
mediated by a catalytic amount of ( )-sparteine.
RLi, solvent
sparteine
-50°C
Ph
8
O
MeO
Ph
R
O
R
Ph
-50°C
Stereochemical outcome of the benzylic organolithium com-
pound formed by the carbolithiation of cinnamyl amines 3 and
52: During the course of our study on the reactivity of benzylic
organolithium compounds with electrophiles (we performed
these experiments with TMEDA instead of ( )-sparteine in
hexane, since we were only interested in the diastereoselec-
tivity of the reaction), we found that the stereochemical
outcome was unexpectedly dependent on the nature of the
heteroatom. When (E)-cinnamyl dimethylamine (3) was
treated with 1.5 equivalents of butyllithium at 08C in hexane
in the presence of 1.5 equivalent of TMEDA, we obtained the
corresponding benzylic organolithium which was then trap-
ped by several electrophiles (Scheme 10). The same stereo-
chemical outcome was obtained when the carbolithiation
reaction was performed in other solvent systems (Scheme 10).
Thus, the stereochemical outcome of the reaction of a benzylic
organolithium is totally different when the chelating group
is a lithium alcoholate (Scheme 3) or an amino group
(Scheme 10).
Li
O
OMe
to 20°C
*
*
Li
R
Ph
MeO
ee >90%
ee>90%
Scheme 8. Enantioselective cyclopropanation.
Table 4. Enantioselective cyclopropanation.
Entry[a] RLi
Cyclo-
(
)-Sparteine Solvent
propane [equiv][b]
Yield
[%][c]
ee
[%]
1
2
3
4
nBuLi
nBuLi
sBuLi[d] 48
47
47
1
cumene 60
95
93
92
92
0.1
0.1
0.1
hexane
hexane
hexane
61
66
59
HexLi
49
[a] After the carbometalation reaction, the mixture was rapidly warmed to
room temperature. [b] Based on the cinnamyl substrate. [c] Based on pure
isolated product and calculated from the cinnamyl substrate. [d] As a
mixture of two diastereomers as a result of the use of sBuLi.
The alkyl and phenyl groups in these cyclopropanes are anti
to each other and may result from a W-shaped transition
state.[45] In this transformation, the initially formed stereo-
genic center C R is invariant, when established during the
carbolithiation reaction step, whereas the benzylic carbon
atom is free to epimerize[10] and to promote the formation of
the thermodynamically more stable trans-cyclopropane. Ac-
cording to this, the optical purities of the trans-cyclopropanes
thus obtained[46] are considered to be the same as those of the
linear acetals described in Table 2.
Bu
Ph
D
54 anti
d.r. 95/5
70%
For R = Me
MeOD
BuLi / hexane
TMEDA
NR2
OR
BuLi / THF
TMEDA
Ph
Bu
Bu
Ph
Li
Ph
MeSSMe
R = Me, Et
OR
BuLi / THF
NR2
MeS
NR2
NR2
(E)-3 R = Me
(E)-52 R = Et
R = Me 53a anti
R = Et 53b anti
In order to prove this enantioselection and the absolute
configuration, the cyclopropane 47 was derivatized into a
known alcohol (Scheme 9).
d.r. 95/ 5
70%
BuLi / hexane
TMEDA
NEt2
Ph
1°) MeOH,
cat. H2SO4
2°) DIBAL-H
HO
(Z)-52
Ph
HOOC
Bu
NaIO4, 2%RuCl3
Scheme 10. Stereochemical outcome of the benzylic organolithium com-
pound in the cinnamyl dialkylamine series.
CCl4, CH3CN, H2O
20°C, 3 d
Bu
Bu
50
81%
51
47
65%
Evidence for the stereochemical assignments of the prod-
ucts 53 and 54 was obtained by comparison with authentic
samples, prepared independently.[48] In the case of 54, the two
93% ee
R,R
Scheme 9. Correlation of the disubstituted cyclopropane.
1
benzylic protons are well distinguished by H NMR spectro-
scopy (ABX system) so that the diastereoselectivity can be
easily determined. The high diastereoselectivity observed in
this reaction may again be accounted for by a thermodynamic
control of the organolithium intermediate, as shown by the
formation of the same product starting from the (Z)-cinnamyl
The (1R)-phenyl-(2R)-butyl cyclopropane (47) was first
oxidized[33] into the corresponding acid 50 in 81% yield. The
esterification followed by the reduction of the resulting ester
led to the known (2R)-butyl-(1R)-cyclopropyl methanol
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Configurational Stability of Benzylic Organozinc Halides
2055±2068
amine (Z)-52. Thus, a tertiary amino group (NEt2 or NMe2) at
the appropriate position blocks the configuration of the
benzyllithium, after thermodynamic equilibration,[41] through
coordination which allows a diastereoselective introduction of
electrophiles with retention of configuration. The same trend
was recently reported on a secondary amine, and PM3
semiempirical calculations as well as 1H NMR measurements
explained the different stereoselectivities between the lithium
reagents derived from the cinnamyl alcohol and cinnamyl
amines in their reactions with electrophiles.[42]
R
Ph
R
DCl
Ph
XR
INVERSION
RETENTION
D
BrZn
XR
syn
path A
Contrathermodynamic
product
Ph
R
ZnBr2
syn adduct
Li
XR
path B
Ph
R
R
DCl
Ph
XR
RETENTION
INVERSION
BrZn
D
XR
syn
Configurational stability of benzylic organozinc halides:
We have previously seen that the reaction of several
electrophiles with the benzylic organolithium 12Li (which
contains an alcoholate moiety, see Scheme 7) gave the
alkylated product with an inversion of the configuration and
with very good diastereoselectivity (98:2). Taking this obser-
vation into account, we were interested to study a new
electrophile in this reaction which would provide the means to
investigate the configurational stability of benzylic organo-
metallic compounds. Indeed, if we consider that a zinc salt can
be an electrophile in this reaction, the thermodynamic
benzylic organolithium ALi (Scheme 11) should also react
thermodynamic
product
anti adduct
Scheme 12. Configurational stability of the benzylic organic halide.
The first hypothesis is that the transmetalation occurred
with inversion of the configuration so that quenching with
DCl with retention would lead to the syn product (Scheme 12,
path A). The second hypothesis is the opposite process:
transmetalation with retention of configuration and reaction
with DCl with inversion which would lead to the same syn
product (Scheme 12, path B). In order to discriminate be-
tween these two hypotheses, we investigated the configura-
tional stability of the intermediate benzylic organozinc halide
at various time intervals: according to path A, the syn adduct
should be sensitive to the experimental conditions (such as
solvents, temperature, nature of the Zn X derivatives),
whereas the anti adduct from path B is the thermodynamic
product, and should be insensitive to these experimental
parameters. The results are summarized in Table 5, and in
Schemes 13 and 14.
Starting from the tertiary amine 3,the transmetalation from
Li to ZnX occurred with inversion of configuration to lead to
the less stable syn isomer 20ZnX (compare entry 1 with
entries 2 and 3 in Table 5) and the configurational stability of
this organozinc bromide derivative was dependent on the
temperature (compare entries 2 and 3 with entries 4 and 5).
Therefore, the benzylic organozinc bromide slowly epimer-
Bu
Ph
Bu
Ph
DCl
Ph
XR
BuLi / TMEDA
hexane
INVERSION
D
Li
A Li
XR
XR
syn
XR = OH 1
XR = NMe2
XR = OLi, 12Li
XR = NMe2 20Li
XR = OH 44
Idem Scheme 7
3
1 chemical step;
one inversion
ZnBr2
Ph
Bu
Bu
DCl
Ph
XR
BrZn
D
XR
syn
XR = OH 44
XR = NMe2 54
A ZnBr ?
2 chemical steps; one inversion
Scheme 11. Stereochemical outcome of the transmetalation of a benzylic
organolithium to the corresponding organozinc halide.
Table 5. Configurational stability of the benzylic organozinc halide after various
time intervals.
with ZnX2 with inversion of the configuration to give a new
benzylic organozinc halide AZnBr; however, this entity
would be a contrathermodynamic moiety (phenyl syn to
alkyl, see Scheme 11). Knowing the high covalent character of
organozinc halides,[49] and their configurational stability,[50] we
thus had an opportunity to study such configurational stability
in the benzylic series.[53]
The transmetalation of the benzylic organolithium inter-
mediate ALi (12Li or 20Li, Scheme 11) with a solution of
zinc bromide in Et2O at 608C, followed by slow warming to
308C, and quenching the resulting benzylic organozinc
bromide with DCl or MeOD led to the syn adducts. In both
cases the overall process occurred with an overall complete
inversion of the stereochemistry[51] for the two chemical steps
(transmetalation and reaction with the electrophile). How can
we explained these results? There are two possible hypoth-
eses (Scheme 12).
Entry Substrate Zinc
additive[a]
T [8C]
Time before Product syn:anti[c]
quenching
with DCl[b]
1
2
3
4
5
6
7
8
9
3
3
3
3
3
3
3
3
3
3
1
1
none
20
30
30
30 min
30 min
4 h
54
54
54
54
54
54
54
54
54
54
44
44
8:92
98:2
98:2
ZnBr2
ZnBr2
ZnBr2
ZnBr2
ZnBr2
ZnCl2
BuZnBr
Et2Zn
Et2Zn
ZnBr2
ZnBr2
30 to 0 15 min
0
50
30 to 0 15 min
30 to 0 30 min
0
50
30
50
70:30
50:50
2:98
70:30
30:70
20:80
20:80
98:2
1 h
2 h
1 h
30 min
4 h
10
11
12
1 h
2:98
[a] The zinc derivative was slowly introduced at 608C in Et2O. [b] DCl was
added at 608C. [c] A value of 98/2 indicates that only one stereoisomer was
1
detected by H NMR spectroscopy (400 MHz) with ꢀ80 ± 95% deuteration.
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I. Marek, J. F. Normant et al.
FULL PAPER
replaced by an alkylzinc moiety (entry 8) or a zincate
(entries 9 and 10), the diastereomeric ratio was in favor of
the thermodynamic product. This points to the great differ-
ence between an organozinc halide and a bisorganozinc[50b] or
zincate reagent as regards their configurational stability.
When the chelating group was an alcoholate moiety
(alcoholate 12Li), the same stereochemical outcome was
observed: the transmetalation into the benzylic organozinc
halide occurred with inversion of the configuration to lead to
the contrathermodynamic product (syn adduct) at low
temperatures and the electrophile reacts with retention of
configuration to give 44 with d.r. > 98/2 (entry 11). However,
if this benzylic organozinc bromide intermediate is heated at
508C for 2 h, a complete epimerization occurred to give the
trans organometallic derivative, and, after reaction with the
same electrophile, the opposite diastereomer was obtained
(entry 12).[53]
Bu
Ph
D
NMe2
DCl
Retention
Bu
Ph
Ph
Bu
Ph
Li
ZnBr2
nBuLi / hexane
Inversion
TMEDA
BrZn
hexane
NMe2
NMe2
NMe2
20ZnBr
3
20 Li
+ 50°C / 2h
Bu
Bu
Ph
D
Ph
DCl
Retention
BrZn
NMe2
NMe2
In the latter case (see Scheme 14), the reaction was
performed in the presence of ( )-sparteine, instead of
TMEDA (as in Scheme 13) and both diastereomers of 44
were obtained by means of this strategy; however, both with
84% ee.
Scheme 13. Synthesis of both diasteroisomers starting from a common
substrate.
Bu
Ph
Bu
Ph
Li
DCl
Ph
OH
nBuLi / hexane
Inversion
(–) sparteine
O°C, 1h /
cumene
D
44 syn
87%
d.r. 95/5
84% ee
OH
OLi
Conclusions
12 Li
1
ZnBr2
- 30°C / 4h
Inversion
The carbolithiation reaction of styryl derivatives by various
primary and secondary alkyllithium compounds with a
stoichiometric or catalytic amount of ( )-sparteine led to
the alkylated product with very good enantioselectivities
(ꢁ95% ee). The addition is dependent on the stereochemistry
of the initial double bond, and the resulting benzylic organo-
lithium compounds can be derivatized to the linear pheny-
lated chain which bears two contiguous stereogenic centers
with given configurations (d.r. ꢂ 98:2). When the starting
material is the dimethyl acetal, a new access to several
disubstituted pure trans-cyclopropanes is available with very
good enantioselectivities (ꢂ95% ee) in the presence of a
catalytic amount of ( )-sparteine. Finally, the observation
that the Li ± Zn transmetalation in a benzylic species occurs
with inversion of configuration led us to study the configura-
tional stability of benzylic organozinc halides; we were able to
demonstrate that they have a remarkable configurational
stability up to 308C.
Bu
Bu
Ph
Ph
OH
DCl
Retention
D 44 syn
78%
d.r. 95/5
84% ee
BrZn
OZnBr
12 ZnBr syn
+ 50°C / 2h
Epimerization
Bu
Bu
Ph
Ph
OH
DCl
Retention
44 Anti
73%
d.r. 95/5
84% ee
D
BrZn
OZnBr
12 ZnBr anti
Scheme 14. Enantioselective carbometalation of cinnamyl alcohol and
reactivity of the corresponding zinc derivatives.
ized to produce the more stable anti diastereoisomer. This
epimerization is remarkably slow so that the varying ratios of
products can be observed as a function of time. When the
reaction mixture was heated at 508C for 2 h (entry 6), the
thermodynamic product was obtained quantitatively. There-
fore, because both diastereoisomers are available on warming
the reaction mixture, path A of Scheme 12 is operative; the
transmetalation occurred with inversion of configuration to
give a benzylic organozinc halide configurationally stable up
to a temperature of 308C,[52] and the latter reacts with DCl
with retention of configuration (Scheme 13).
Experimental Section
General: Experiments involving organometallic compounds were carried
out under a positive pressure of dry nitrogen. All glassware was oven-dried
at 1508C overnight and assembled quickly while still hot under a stream of
nitrogen. Liquid nitrogen was used as a cryogenic fluid at all given
temperatures, unless otherwise stated, referred to internal ones. Diethyl
ether and THF were distilled from sodium benzophenone ketyl. ZnBr2 was
melted under a stream of nitrogen and handled as a 1m solution in diethyl
ether. ( )-Sparteine was purchased from Aldrich and used as received.
Organolithium reagents were titrated with 2-butanol (1m in toluene) with
1,10-phenantroline as the indicator. NMR spectra were recorded on either
a Brucker AC400 or a AC200 spectrometer in CDCl3. Chemical shifts are
reported in part per million (ppm) relative to tetramethylsilane (TMS) as
the internal standard (0.1%) in the 1H NMR spectra. If a trimethylsilyl
Although the electronegativity of the chlorine atom in
ZnCl2 should allow a more tight cyclic transition state in favor
of the syn isomer, the diastereomeric ratio was unchanged
(entry 4 versus entry 7). Meanwhile, if the lithium atom is
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Configurational Stability of Benzylic Organozinc Halides
2055±2068
moiety was present within the molecule, then CHCl3 was used as the
reference. In 13C NMR spectra, CDCl3 (d ˆ 77.2) was used as the reference.
dropwise over a period of 0.5 h at 08C. The remainder of the procedure is
analogous to that of procedure A.
Procedure for the derivatization of alcohols for the determination of the
enantiomeric excesses:[16] Into a dried NMR tube were introduced the
chiral diamine ((1R,2R)-(‡)-N,N'-dimethyl-1,2-diphenyl-1,2-ethanedi-
amine (0.15 mmol, 38.4 mg) or (1S,2S)-( )-N,N'-dimethyl-1,2-bis[3-(tri-
fluoromethyl)phenyl]-1,2-ethanediamine (0.15 mmol, 59.6 mg) or (1R,2R)-
Carbolithiation of cinnamyl acetal 8: General procedure: RLi (6 mmol)
was prepared in Et2O, then Et2O was removed under vacuum and dry
cumene (5 mL) was added. ( )-Sparteine (0.46 mL, 2 mmol) was added at
788C and the mixture was allowed to warm to 08C for a few minutes. The
solution was then cooled to 508C and a solution of 8 (2 mmol, 0.41 g) in
dry cumene (3 mL) was added dropwise over a period of 0.5 h. The
remainder of the procedure is analogous to that of procedure B.
(
)-N,N'-dimethylcyclohexane diamine (0.15 mmol, 22.7 mg)) and CDCl3
(1 mL). The tube was shaken until completed dissolution. N,N-Diethylani-
line (0.75 mmol, 130 mL) was added with a microsyringe, followed by slow
addition of PCl3 (0.15 mmol, 12.8 mL) also with a microsyringe. The NMR
tube was shaken and an exothermic reaction took place. The alcohol to be
analyzed (0.15 mmol) was then added into the NMR tube. For the special
cases of (S)-2-benzyl-hexyl-methylamine (21) and (S)-3-benzyl-1-heptanol
(23) and 4-benzyloctan-1-ol (24), selenium or sulfur were added, respec-
tively. The NMR tube was shaken and the 31P spectrum was recorded.
Carbolithiation of b-alkylated styrene: General procedure: RLi (6.6 mmol)
was prepared in Et2O, then Et2O was removed under vacuum and dry
hexane (5 mL) was added. ( )-Sparteine (0.46 mL, 2 mmol) was added at
508C and the mixture was allowed to warm to 08C for a few minutes. The
solution was then cooled to 208C and a solution of b-alkylated styrene
(2 mmol) in dry hexane (3 mL) was added dropwise over a period of 0.5 h.
The remainder of the procedure is analogous to that of procedure C.
General procedure for the carbolithiation with RLi in hexane and in the
presence of a stoichiometric amount of ( )-sparteine:
Carbolithiation reaction with a catalytic amount of ( )-sparteine: General
procedure:
Carbolithiation of cinnamyl alcohol, homologues, and cinnamyl amines:
General procedure A: A solution of the cinnamyl derivative (x mmol) in
dry solvent (see Table 2) (x ‡ 1 mL) was added dropwise over a period of
0.5 h at 108C to a solution of RLi (3x mmol) in hexane in the presence
of ( )-sparteine (x mmol) in dry solvent (see Table 2) (x ‡ 2 mL). The
red reaction mixture was stirred at 08C for 1 h. After cooling to 08, the
reaction mixture was poured into 1n HCl (for the alcohols) or NH3/NH4Cl
(for the amines). The aqueous layer was extracted with diethyl ether (2 Â
10 mL) and the combined organic phases were dried over MgSO4. The
solvent was evaporated and the residue was then chromatographed on
silica gel.
Carbolithiation of cinnamyl alcohol: A solution of cinnamyl alcohol
(2 mmol) in dry cumene (3 mL) was added dropwise over a period of 0.5 h
at 108C to a solution of RLi/hexane (6 mmol) in the presence of ( )-
sparteine (0.046 mL) in dry cumene (5 mL). The red reaction mixture was
stirred at 08C for 1 h. The remainder of the procedure is analogous to that
of procedure A.
Carbolithiation of cinnamyl acetal 8: To a solution of RLi/hexane (3 equiv)
in dry hexane (10 mL) was added ( )-sparteine (0.1 mL when the reaction
was performed with 10% mol and 10 mL when the reaction was performed
with 1% mol) at 788C. The mixture was allowed to warm to 08C for a few
minutes and then cooled to 508C. A solution of 8 (0.93 g, 4.5 mmol) in dry
hexane (5 mL) was added dropwise over a period of 1 h. The orange
Carbolithiation of cinnamyl acetal: General procedure B: To a solution of
RLi/hexane (2.2 equiv) in dry solvent (5 mL) was added ( )-sparteine
(0.46 mL, 2 mmol) at 788C. The mixture was allowed to warm to 08C for
a few minutes. The solution was then cooled to 508C and a solution of 8
(0.41 g, 2 mmol) in dry solvent (3 mL) was added dropwise over a period of
0.5 h. The orange reaction mixture was stirred at 508C for 5 ± 6 h,
quenched with MeOH (1 mL) at 808C, and then with HCl (1n, 5 mL) at
08C. The aqueous layer was extracted with diethyl ether (3 Â 15 mL), the
combined organic phases were washed with saturated solution of NaHCO3,
and then dried over K2CO3. The solvents were removed under reduced
pressure and the product was purified by column chromatography (silica
gel, cyclohexane/ethyl acetate: 95/5) to afford the carbometalated product.
reaction mixture was stirred at
508C for 7 ± 8 h. The mixture was
quenched with MeOH (1 mL) at 808C and then with HCl (1n, 10 mL) at
08C. The aqueous layer was extracted with diethyl ether (3 Â 20 mL), the
combined organic phases were washed with a saturated solution of
NaHCO3, and then dried over K2CO3. The solvents were removed under
reduced pressure and the product was purified by column chromatography
(silica gel, cyclohexane/AcOEt 95:5) to afford the carbometalated product.
Carbolithiation of b-methylstyrene (9): ( )-Sparteine (0.46 mL, 2 mmol)
was added to a solution of nBuLi (2.8 mL, 1.6n/hexane, 2.2 equiv) in dry
hexane (5 mL) at 508C. The mixture was allowed to warm to 08C for a
few minutes and then cooled to 208C. A solution of b-methylstyrene
(2 mmol) in dry hexane (3 mL) was added dropwise over a period of 0.5 h.
The orange reaction mixture was stirred at 08C for 8 h then for 12 h at room
temperature. The mixture was quenched with HCl (1n, 5 mL) at 208C.
The aqueous layer was extracted with diethyl ether (3 Â 15 mL), the
combined organic phases were washed with brine, and then dried over
MgSO4. The solvents were removed under reduced pressure and the
product was purified by column chromatography (silica gel, pentane) to
afford the carbometalated product.
Carbolithiation of b-alkylated styrenes: General procedure C: To
a
solution of RLi/hexane (2.2 equiv) in dry hexane (5 mL) was added ( )-
sparteine (0.46 mL, 2 mmol) at 508C. The mixture was allowed to warm
to 08C for a few minutes and then cooled to 208C. A solution of b-
alkylated styrene (2 mmol) in dry hexane (3 mL) was added dropwise over
a period of 0.5 h. The orange reaction mixture was stirred at 208C for 4 h.
The mixture was quenched with HCl (1n, 5 mL) at 208C. The aqueous
layer was extracted with diethyl ether (3 Â 15 mL), the combined organic
phases were washed with brine, and then dried over MgSO4. The solvents
were removed under reduced pressure and the product was purified by
column chromatography (silica gel, pentane) to afford the carbometalated
product.
(2S)- and (2R)-2-Benzyl-1-hexanol (12): The reaction was performed on 1
(0.523 g, 4 mmol) according to Procedure A (eluent: cyclohexane/ethyl-
acetate: 80/20).
(S)-12: Yield: 85% (0.632 g); [a]D25
(90 MHz, CDCl3): d ˆ 136.83 (s, 91.5%), 137.50 (s, 8.5%), 83% ee.
ˆ
4.1 (c ˆ 0.02, CH2Cl2); 31P NMR
Carbolithiation of trans-stilbene (11): General procedure D: A solution of
nBuLi (1.6m/hexane, 2.2 equiv) was added at 108C to a solution of trans-
stilbene (11, 0.45 g, 2.5 mmol) and ( )-sparteine (0.57 mL, 2.5 mmol) in dry
cumene. The orange reaction mixture was then stirred at 08C for 8 h. The
mixture was quenched with HCl (1n, 5 mL) at 208C. The aqueous layer
was extracted with diethyl ether (3 Â 15 mL), the combined organic phases
were washed with brine, and then dried over MgSO4. The solvents were
removed under reduced pressure and the product was purified by column
chromatography (silica gel, cyclohexane) to afford the carbometalated
product in 81% yield.
(R)-12: Yield: 63% (0.484 g); [a]2D0 ˆ 3.5 (c ˆ 0.01, CH2Cl2); 31P NMR
(36.22 MHz, CDCl3): d ˆ 139.25 (s, 85%), 139.86 (s, 15%), ee ˆ 70%;
1H NMR (200 MHz, CDCl3): d ˆ 0.90 (t, J ˆ 7.1 Hz), 1.15 ± 1.40 (m, 6H),
1.70 (m, 1H), 2.65 (d, J ˆ 7.1 Hz, 2H), 3.50 (d, J ˆ 5.1 Hz, 2H), 7.10 ± 7.35
(m, 5H); 13C NMR (100 MHz, CDCl3): d ˆ 13.92, 22.83, 28.98, 30.15, 37.35,
41.33, 64.34, 125.57, 128.02, 129.03, 140.73.
(2S)-2-Benzyl-1-octanol (14): The reaction was performed on 1 (0.201 g,
1.5 mmol) according to Procedure A (eluent: cyclohexane/ethyl acetate:
Carbolithiation with RLi in Et2O and in the presence of a stoichiometric
amount of ( )-sparteine: General Procedure E:
80/20). Yield: 76% (0.25 g); [a]D25
ˆ
5.29 (c ˆ 0.02, CHCl3); 1H NMR
(400 MHz, CDCl3): d ˆ 0.87 (t, J ˆ 6.7 Hz, 3H), 1.2 ± 1.4 (m, 8H), 1.8 (m,
1H), 2.63 (d, J ˆ 7.1 Hz, 2H), 3.52 (d, J ˆ 4.7 Hz, 2H), 7.1 ± 7.35 (m, 5H);
13C NMR (50 MHz, CDCl3): d ˆ 14.09, 15.28, 22.66, 29.60, 30.84, 31.84,
37.71, 41.61, 65.87, 125.86, 128.3, 129.18; 31P NMR (162 MHz, (1R,2R)-(‡)-
N,N'-dimethyl-1,2-diphenyl-1,2-ethanediamine, CDCl3): d ˆ 137.81 (s,
Carbolithiation of cinnamyl alcohol: General procedure: RLi (9 mmol)
was prepared in Et2O, then Et2O was removed under vacuum and dry
cumene was added. After the addition of ( )-sparteine (3 mmol), a
solution of cinnamyl derivatives (3 mmol) in dry cumene (5 mL) was added
Chem. Eur. J. 1999, 5, No. 7
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0507-2063 $ 17.50+.50/0
2063

I. Marek, J. F. Normant et al.
FULL PAPER
93.5%), 138.58 (s, 6.5%); 87% ee; anal. calcd for C15H24O: C 81.76, H
10.98; found C 81.70, H 10.99.
64% (0.62 g); [a]D25
ˆ
6.2 (c ˆ 0.01, CH2Cl2); 1H NMR (400 MHz, CDCl3):
d ˆ 0.87 (m, 3H), 1.2 ± 1.27 (m, 6H) 1.9 (m, 1H), 2.16 (s, 3H), 2.24 (m, 2H),
2.5 (dd, J ˆ 7.2, 13.5 Hz,1H), 2.78 (dd, J ˆ 5.6, 13.6 Hz, 1H), 3.46 (m, 2H),
7.16 ± 7.34 (m, 10H); 13C NMR (50 MHz, CDCl3): d ˆ 14.08, 23.02, 28.72,
31.36, 37.86, 38.53, 42.59, 61.63, 62.66, 125.45, 126.69, 127.96, 128.04, 128.84,
129.27, 139.63, 141.29; anal. calcd for C21H29N: C 85.36, H 9.9; N,4.74;
found: C 85.72, H 10.15, N 5.03
(2S,3RS)-2-Benzyl-3-methyl-1-pentanol (15): The reaction was performed
on 1 (0.523 g, 4 mmol) according to Procedure A (eluent: cyclohexane/
ethyl acetate 80:20). Yield: 65% (0.5 g); 1H NMR ( 400 MHz, CDCl3): d ˆ
0.98 (m, 6H), 1.25 (s, 1H), 1.28 (m, 2H), 1.55 (m, 2H), 1.8 (m, 1H), 2.42 (dd,
J ˆ 9.7, 13.7 Hz, 1H), 2.66 (d, J ˆ 8 Hz, 2H), 2.7 (dd, J ˆ 13.7 Hz, 1H), 3.5
(m, 2H), 7.2 ± 7.3 (m, 5H); 13C NMR (100 MHz, CDCl3): d ˆ 12.18, 12.32,
15.80, 15.39, 26.98, 26.81, 33.70, 34.64, 34.97, 35.38, 47.40, 63.01, 63.58,
125.92, 128.47, 129.13, 139; 31P NMR (160 MHz, CDCl3): d ˆ diaster-
eoisomer 1: 138.97 (s, 14%), 137.55 (s, 86%); 72% ee; diastereoisomer 2:
138.47 (s, 14%), 136.98 (s, 86%); 70% ee.
3-Butyl-4-phenyl-1-butanol (23): The reaction was performed on 4-phenyl-
3-butene-1-ol (6, 0.592 g 4 mmol) according to Procedure A (eluent:
cyclohexane/ethylacetate 80:20). Yield: 72% (0.6 g); H NMR (200 MHz,
1
CDCl3): d ˆ 0.89 (m, 3H), 1.3 (m, 6H), 1.5 (q, J ˆ 6.8 Hz, 2H), 1.6 (m, 1H),
1.75 (m, 1H),.2.48 (dd, J ˆ 7.2, 13.5 Hz, 1H) 2.58 (dd, J ˆ 6.8, 13.5 Hz, 1H),
3.6 (m, 2H), 7.1 ± 7.3 (m, 5H); 13C NMR (100 MHz, CDCl3): d ˆ 14.11,
(2S)-2-Benzyl-3,3-dimethyl-1-butanol (16): The reaction was performed on
1 (0.523 g, 4 mmol) according to Procedure A (eluent: cyclohexane/ethyl
acetate 80:20). Yield: 40% (0.3 g); 1H NMR (200 MHz, CDCl3): d ˆ 1.05 (s,
9H), 1.55 (m, 1H), 2.5 (dd, J ˆ 10.7, 13.7 Hz, 1H), 2.9 (dd, J ˆ 3.4, 13.7 Hz),
3.64 (m, 2H), 7.10 ± 7.45 (m, 5H); 13C NMR (50 MHz, CDCl3): d ˆ 28.42, 38,
34, 53, 62.60, 125.47, 127, 128.42, 129, 142.28. 31P NMR (160 MHz, CDCl3):
d ˆ 136.76 (s, 50%), 135.48 (s, 50%); 0% ee.
(2S)-2-Benzyl-1-butanol (17): The reaction was performed on 1 (0.4 g,
3 mmol) according to procedure E (eluent: cyclohexane/ethyl acetate
70:30). Yield: 68% (0.335 g); [a]2D5 ˆ 4 (c ˆ 0.08, CH2Cl2); 1H NMR
(400 MHz, CDCl3): d ˆ 0.93 (t, J ˆ 7.5 Hz, 3H), 1,37 (m, 2H), 1.7 (m,
1H), 1.85 (m, 1H), 2.62 (m, 2H), 3.50 (d, J ˆ 5.4 Hz, 2H), 7.2 ± 7.3 (m, 5H);
13C NMR (100 MHz, CDCl3): d ˆ 11.73, 23.69, 37.68, 44.53, 64.79, 126.25,
128.70, 129.61, 141.32; 31P NMR (36.22 MHz, CDCl3): d ˆ 136.96 (s, 92%),
137.84 (s, 7%); 85% ee; anal. calcd for C11H16O: C 80.43, H 9.83; found C
80.57, H 9.67.
22.98, 26.91, 28.7, 33.13, 36.42, 40.65, 60.95, 125.72, 128.17, 129.17, 141.25; 31
P
NMR (36.22 MHz, CDCl3, (1R,2R)-( )-N,N'-dimethylcyclohexane di-
amine, S8): d ˆ 88.33 (s, 15%), 83.35 (s, 85%); 70% ee.
4-Butyl-5-phenyl-1-pentanol (24): The reaction was performed on 5-phe-
nyl-4-en-1-pentanol (7, 0.65 g 4 mmol) according to Procedure A (eluent:
cyclohexane/ethyl acetate 80:20). Yield: 75% (0.6 g); [a]2D5 ˆ 2.5 (c ˆ 0.01,
CHCl3); 1H NMR (400 MHz, CDCl3): d ˆ 0.91 (t, J ˆ 6.7, 3H), 1.25 ± 1.45
(m, 6H), 1.5 ± 1.7 (m, 4H), 2.55 (dd, J ˆ 7.2, 13.5 Hz, 1H), 2.61 (dd, J ˆ 6.9,
13.5, 1H), 3.6 (t, J ˆ 6.6 Hz, 2H), 7.15 ± 7.35 (m, 5H); 13C NMR (100 MHz,
CDCl3): d ˆ 14.25, 23.14, 28.87, 29.13, 29.90, 32.94, 39.58, 40.61, 63.42,
125.75, 128.25, 129.28, 141.64; 31P NMR (162 MHz, CDCl3, (1R,2R)-(‡)-
N,N'-dimethyl-1,2-diphenyl-1,2-ethanediamine, Se): d ˆ 83.38 (s, 15%),
83.40 (s, 85%); 70% ee.
(2S)-[2-Benzyl-1-(1-methoxy-1-methylethoxy)]hexane (25): The reaction
was performed on 8 (0.41 g 2 mmol) according to Procedure B. Yield: 77%
(0.4 g); 1H NMR (400 MHz, CDCl3): d ˆ 0.89 (t, J ˆ 7.3 Hz, 3H), 1.4 ± 1.2
(m, 12H), 1.86 (m, 1H), 2.56 (dd, J ˆ 7.1, 13.5 Hz, 1H), 2.74 (dd, J ˆ 7.1,
13.6 Hz, 1H), 3.2 (s, 3H), 7.3 ± 7.5 (m, 5H); 13C NMR (50 MHz, CDCl3):
d ˆ 14.08, 22.97, 24.46, 29.17, 30.81, 38.01, 40.44, 48.42, 62.60, 99.25, 125.61,
128.06, 129.23, 141.19; anal. calcd for C17H28O2: C 77.22, H 10.67; found C
77.15, H 10.78.
(2S)-2-Benzyl-1-nonanol (18): The reaction was performed on 1 (0.4 g,
3 mmol) according to procedure E (eluent: cyclohexane/ethyl acetate
70:30). Yield: 50% (0.351 g); [a]D25
ˆ
3.2 (c ˆ 0.01, CH2Cl2).1H NMR
(200 MHz, CDCl3): d ˆ 0.83 (t, J ˆ 6.1 Hz, 3H), 1.1 ± 1.35 (m, 12H), 1.75 (m,
1H), 2.6 (d, J ˆ 7.1 Hz, 2H) 3.5 (d, J ˆ 5.1 Hz, 2H), 7.1 ± 7.35 (m, 5H);
13C NMR (50 MHz, CDCl3): d ˆ 14.11, 22.67, 26.95, 29.28, 29.88, 30.73,
31.86, 37.64, 42.55, 64.83, 125.82, 129.16, 129.55, 140.83; 31P NMR
(2S)-[2-Benzyl-1-(1-methoxy-1-methylethoxy)]octane (26): The reaction
was performed on 8 (0.41 g, 2 mmol) according to Procedure B. Yield: 70%
(0.41 g); 1H NMR (400 MHz, CDCl3): d ˆ 0.89 (t, J ˆ 7.3 Hz, 3H), 1.4 ± 1.2
(m, 12H), 1.86 (m, 1H), 2.56 (dd, J ˆ 7.1, 13.5 Hz, 1H), 2.74 (dd, J ˆ 7.1,
13.6 Hz, 1H), 3.2 (s, 3H), 7.3 ± 7.5 (m, 5H); 13C NMR (50 MHz, CDCl3):
d ˆ 14.08, 22.97, 24.46, 29.17, 30.81, 38.01, 40.44, 48.42, 62.60, 99.25, 125.61,
128.06, 129.23, 141.19; anal. calcd for C17H28O2: C 77.22, H 10.67; found C
77.15, H 10.78.
(162 MHz,
(1R,2R)-(‡)-N,N'-dimethyl-1,2-diphenyl-1,2-ethanediamine,
CDCl3): d ˆ 137.52 (s, 81.5%), 138.32 (s, 18.5%); 63% ee.
(2S)-2-Benzyl-1-tert-butoxyhexane (19): The reaction was performed on 2
(0.125 g, 1.1 mmol) according to Procedure A (eluent: cyclohexane/ethyl
acetate 98:2). Yield: 82% (0.185 g); [a]D25
ˆ
0.4 (c ˆ 0.01, CH2Cl2);
1H NMR (400 MHz, CDCl3): d ˆ 0.7% (t, J ˆ 6.9 Hz, 3H), 1.07 (s, 9H),
1.18 ± 1.24 (m, 6H), 1.70 (m, 1H), 2.44 (dd, J ˆ 6.8, 13.5 Hz, 1H), 2.63 (dd,
J ˆ 6.8, 13.5 Hz, 2H), 3.09 (m, 2H), 7.07 ± 7.18 (m, 5H); 13C NMR
(100 MHz, CDCl3), 14,53, 23.44, 28.01, 29.62, 31.17, 38.33, 41.19, 63.71,
125.94, 128.42, 129.75, 141,85; anal. calcd for C17H28O: C 82.19H, 11.37;
found C 82.68H, 11.65.
(2S)-[2-Benzyl-1-(1-methoxy-1-methylethoxy)-3-methyl]pentane (27): The
reaction was performed on 8 (0.41 g, 2 mmol) according to Procedure B.
Yield: 80% (0.422 g); 1H NMR (200 MHz, CDCl3): d ˆ 0.8 ± 0.95 (m, 6H),
1.0 ± 1.6 (m, 9H), 1.85 (m, 1H), 2.4 ± 2.8 (m, 2H), 3.1 (s, 3H), 3.14 (s, 3H),
3.2 ± 3.5 (m, 2H), 7.1 ± 7.35 (m, 10H); 13C NMR (50 MHz, CDCl3): d ˆ
13.09, 13.23, 16.34, 25.37, 27.59, 27.72, 34.82, 35.53, 36.44, 45.67, 46.08, 61.35,
61.76, 100.75, 126.49, 129.06, 130.03; anal. calcd for C17H28O2: C 77.22, H
10.67; found C 77.09, H 10.76.
N,N-Dimethyl-(2S)-2-benzyl-1-hexanamine (20): The reaction was per-
formed on 3 (0.322 g, 2 mmol) according to Procedure A (eluent: cyclo-
hexane/diethyl ether 1:1 containing a few drops of 32% aqueous NH3).
Yield: 71% (0.306 g); [a]D25
ˆ
11.96 (c ˆ 0.02, CH2Cl2).1H NMR
(400 MHz, CDCl3): d ˆ 0.88 (m, 3H), 1.28 (m, 6H), 1.81 (m,1H), 2.10
(dd, J ˆ 7.6, 12.9 Hz, 2H), 2.20 (s, 6H), 2.50 (dd, J ˆ 7.5, 13.6 Hz, 1H), 2.70
(dd, J ˆ 5.9, 13.6 Hz, 1H), 7.20 ± 7.30 (m, 5H); 13C NMR (50 MHz, CDCl3):
d ˆ 14.38, 23.30, 29.16, 31.73, 38.13, 38.79, 46.15, 64.28, 125.80, 128.26,
129.60, 141.41; anal. calcd for C15H25N: C 82.13, H 11.49; N, 6.38; found C
81.93, H 11.36; N, 6.25; HPLC analysis (UV monitoring (n ˆ 254 nm),
Chiracel OD column; flow rate: 0.1 mLmin 1; eluent: hexane; 82% ee.
(2S)-[2-Benzyl-1-(1-methoxy-1-methylethoxy)]nonane (28): The reaction
was performed on 8 (0.41 g, 2 mmol) according to procedure E (eluent:
cyclohexane/ethyl acetate 95:5). Yield: 50% (0.306 g); 1H NMR (400 MHz,
CDCl3): d ˆ 0.9 (t, J ˆ 6.9 Hz, 3H), 1.2 ± 1.4 (m, 18H), 1.86 (m, 1H), 2.56
(dd, J ˆ 7, 13.4 Hz, 1H), 2.74 (dd, J ˆ 7.0, 13.5 Hz, 1H), 3.2 (s, 3H), 3.29 (m,
2H), 7.15 ± 7.4 (m, 5H); 13C NMR (100 MHz, CDCl3): d ˆ 14.24, 22.79,
24.59, 29.41, 29.83, 30.01, 31.25, 31.98, 38.16, 40.58, 48.54, 62.71, 99.84,
125.74, 128.16, 139.36, 141.31; anal. calcd for C20H34O2: C 78.38, H 11.18;
found C 78.21, H 11.26.
(2S)-N-Methyl-2-benzyl-hexanamine (21): The reaction was performed on
4 (0.294 g, 2 mmol) according to Procedure A (eluent: CH2Cl2/methanol
90:10 containing a few drops of 32% aqueous NH3). Yield: 66% (0.258 g);
(2S)-2-Benzylhexane (29): The reaction was performed on 9 (0.26 mL,
[a]2D5
ˆ
4.38 (c ˆ 0.01, CH2Cl2).1H NMR (200 MHz, CDCl3): d ˆ 0.87 (m,
2 mmol) according to Procedure C. Yield: 83% (0.292 g); [a]D25
ˆ
7.72
3H), 1.30 (m, 6H), 1.50 (m,1H), 1.8 (m, 1H), 2.39 (s, 3H), 2.47 (d, J ˆ
6.0 Hz, 2H), 2.60 (d, J ˆ 6.0 Hz, 2H), 7.10 ± 7.30 (m, 5H); 13C NMR
(50 MHz, CDCl3): d ˆ 13.99, 22.89, 26.87, 31.57, 36.48, 38.90, 39.88, 55.17,
125.64, 128.43, 129.05, 1409.8; 31P NMR (36.22 MHz, CDCl3): d ˆ 83.32 (s,
83%), 83.53 (s, 17%); 66% ee; anal. calcd for C14H23N: C 81.88, H 11.30; N,
6.82; found C 81.24, H 11.65; N, 6.78.
(c ˆ 0.05, Et2O); 1H NMR (400 MHz, CDCl3): d ˆ 0.91 (d, J ˆ 6.6 Hz, 3H),
0.96 (t, J ˆ 6.64 Hz, 3H), 1.2 ± 1.5 (m, 6H), 1.78 (m, 1H), 2.42 (dd, J ˆ 8.24,
13.32 Hz, 1H), 2.71 (dd, J ˆ 6, 13.32 Hz, 1H), 7.2 ± 7.4 (m, 5H); 13C NMR
(100 MHz, CDCl3): d ˆ 12.67, 17.92, 21.48, 27.89, 33.53, 34.98, 42.25, 124.06,
126.56, 127.69, 140.18.
(2S)-2-Benzyloctane (30): The reaction was performed on 9 (0.26 mL,
N-Benzyl-N-methyl-(2S)-2-benzyl-1-hexanamine (22): The reaction was
performed on 5 (0.5 g, 2.1 mmol) according to Procedure A (eluent:
cyclohexane/diethyl ether 1:1 containing a few drops of 32% NH3). Yield:
2 mmol) according to Procedure C. Yield: 86% (0.351 g); [a]D25
ˆ
10.08
(c ˆ 0.05, Et2O); 1H NMR (400 MHz, CDCl3): d ˆ 0.75 (d, J ˆ 6.6 Hz, 3H),
0.8 (t, J ˆ 6.6 Hz, 3H), 1.05 ± 1.35 (m, 10H), 1.65 (m, 1H), 2.26 (dd, J ˆ 8.2,
2064
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0507-2064 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 7

Configurational Stability of Benzylic Organozinc Halides
2055±2068
13.3 Hz, 1H), 2.52 (dd, J ˆ 6,0, 13.3 Hz, 1H), 7.05 ± 7.25 (m, 5H); 13C NMR
(100 MHz, CDCl3): d ˆ 14.57, 19.84, 23.14, 27.54, 30.03, 32.38, 35.47, 37.21,
44.17, 125.98, 128.47, 129.62, 142.12.
precipitate was filtered through a hyflo plug and washed with CH2Cl2.
The aqueous phase was then extracted with CH2Cl2 (2 Â 10 mL) and the
combined organic phases were washed with a saturated solution of
NaHCO3 (3 Â 10 mL).The aqueous extracts were combined, and a solution
of HCl (35%) was added until the pH reached 1. The mixture was extracted
with CH2Cl2 (3 Â 20 mL). The organic layers were dried over MgSO4,
filtered, and concentrated under reduced pressure to provide the crude acid
which was filtered over SiO2 with Et2O as the eluent.
(2S)-2-Benzylpentane (31): The reaction was performed on 9 (0.26 mL,
2 mmol) according to procedure E. Yield: 92% (0.298 g); [a]D25
ˆ
4.96
(0.05, Et2O); 1H NMR (200 MHz, CDCl3): d ˆ 0.9 (m, 6H), 1.1 ± 1.4 (m,
4H), 1.75 (m, 1H), 2.35 (dd, J ˆ 8.1, 13.3 Hz, 1H), 2.65 (dd, J ˆ 6.0, 13.3 Hz,
1H), 7.1 ± 7.4 (m, 5H); 13C NMR (50 MHz, CDCl3): d ˆ 14.45, 19.51, 20.37,
34.93, 39.22, 43.91, 125.71, 128.19, 129.31, 141.77.
(3S)-3-Methylheptanoic acid (34): The reaction was performed on 29
(0.27 g, 1.5 mmol). Yield: 71% (0.154 g); [a]D25
ˆ
2.34 (c ˆ 0.10, CHCl3);
(3R)-3-Benzylheptane (32): The reaction was performed on 10 (0.32 g,
2 mmol) according to procedure E. Yield:73% (0.277 g); [a]2D5 ˆ ‡ 7.09
(c ˆ 0.05, Et2O).
(2S)-2-Benzyl-1-nonanol (18): The reaction was performed on 1 (0.4 g,
3 mmol) according to procedure E (eluent: cyclohexane/ethyl acetate
1H NMR (200 MHz, CDCl3): d ˆ 0.87 (t, J ˆ 6.3 Hz, 3H), 0.94 (d, J ˆ
6.5 Hz, 3H), 1.1 ± 1.4 (m, 6H), 1.9 (m, 1H), 2.1 (dd, J ˆ 8.03, 14.82 Hz,
1H), 2.33 (dd, J ˆ 5.9, 14.81 Hz, 1H); 13C NMR (50 MHz, CDCl3): d ˆ
13.99, 19.63, 22.72, 29.05, 30.07, 36.30, 41.63, 180.17.
70:30). Yield: 50% (0.351 g); [a]D25
ˆ
3.2 (c ˆ 0.01, CH2Cl2); 1H NMR
(3S)-3-Methylnonanoic acid (35): The reaction was performed on 30
(0.39 g, 1.9 mmol). Yield: 60% (0.196 g); [a]D25
ˆ
2.83 (c ˆ 0.5, CHCl3);
(200 MHz, CDCl3): d ˆ 0.83 (t, J ˆ 6.1 Hz, 3H), 1.1 ± 1.35 (m, 12H), 1.75 (m,
1H), 2.6 (d, J ˆ 7.1 Hz, 2H), 3.5 (d, J ˆ 5.1 Hz, 2H), 7.1 ± 7.35 (m, 5H);
13C NMR (50 MHz, CDCl3): d ˆ 14.11, 22.67, 26.95, 29.28, 29.88, 30.73,
31.86, 37.64, 42.55, 64.83, 125.82, 129.16, 129.55, 140.83; 31P NMR
1H NMR (200 MHz, CDCl3): d ˆ 0.88 (t, J ˆ 6.6 Hz, 3H), 0.96 (d, J ˆ
6.6 Hz, 3H), 1.1 ± 1.4 (m, 10H), 1.95 (m, 1H), 2.16 (dd, J ˆ 8, 14.74 Hz,
1H), 2.33 (dd, J ˆ 5.84, 14.7 Hz, 1H); 13C NMR (50 MHz, CDCl3): d ˆ
13.99, 19.60, 22.56, 26.77, 29.30, 30.07, 31.76, 36.59, 41.58, 180.00.
(162 MHz,
(1R,2R)-(‡)-N,N'-dimethyl-1,2-diphenyl-1,2-ethanediamine,
CDCl3): d ˆ 137.52 (s, 81.5%), 138.32 (s, 18.5%); 63% ee.
(3S)-3-Methylhexanoic acid (36): The reaction was performed on 31
(0.284 g, 1.75 mmol). Yield: 80% (0.182 g); [a]D25
ˆ
1.73 (c ˆ 0.02,
(2S)-1,2-Biphenylhexane (33): The reaction was performed on 11 (0.45 g,
2.5 mmol) according to procedure D. Yield: 81% (0.482 g); [a]2D5 ˆ ‡35.7
(c ˆ 0.03, Et2O); 1H NMR (400 MHz, CDCl3): d ˆ 0.8 (t, J ˆ 7.4 Hz, 3H),
1.05 ± 1.5 (m, 4H), 1.65 (m, 2H), 2.8 (m, 1H), 2.85 (dd, J ˆ 2.8, 8.1 Hz, 2H),
7.0 ± 7.3 (m, 10H); 13C NMR (50 MHz, CDCl3): d ˆ 14.42, 23.14, 30.17,
35.68, 44.30, 48.45, 126.10, 128.17, 128.41, 128.57, 129.56, 141.27, 145.74; anal.
calcd for C12H22: C 90.70, H 9.30; found C 90.70, H 9.33.
CHCl3); 1H NMR (200 MHz, CDCl3): d ˆ 0.85 (t, J ˆ 6.7 Hz, 3H), 0.92
(d, J ˆ 6.6 Hz, 3H), 1.1 ± 1.4 (m, 4H), 1.9 (m, 1H), 2.05 (dd, J ˆ 8.1, 14.7 Hz,
1H), 2.3 (dd, J ˆ 5.8, 14.7 Hz, 1H); 13C NMR (50 MHz, CDCl3): d ˆ 14.08,
19.61, 19.97, 29.87, 38.89, 41.64, 179.99.
(3S)-3-Ethylheptanoic acid: The reaction was performed on 42 (0.264 g,
1.4 mmol). Yield: 90% (0.277 g); [a]D25
(400 MHz, CDCl3): d ˆ 0.89 (m, 6H), 1.2 ± 1.45 (m, 8H), 1.8 (m, 1H), 2.29
(dd, J ˆ 1.4, 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d ˆ 10.81, 14.14,
22.97, 26.29, 28.82, 33.05, 36.30, 38.73, 180.51.
ˆ
1.15 (c ˆ 0.02, CHCl3).1H NMR
(2S)-3-Benzylheptane (42): The reaction was performed on 41 (0.264 mg,
2 mmol) ((E)/(Z) 90/10) according to procedure C. Yield: 87% (0.33 g);
[a]2D5
ˆ
6.39 (c ˆ 0.05, Et2O); 1H NMR (200 MHz, CDCl3): d ˆ 0.9 (m,
6H), 1.15 ± 1.3 (m, 8H), 1.59 (m, 1H), 2.55 (d, J ˆ 7 Hz, 1H), 7.1 ± 7.4 (m,
5H); 13C NMR (100 MHz, CDCl3): d ˆ 10.97, 14.34, 23.27, 25.61, 29.07,
32.55, 40.35, 41.31, 125.70, 128.25, 129.38, 142.03.
Butylsuccinic acid: To a solution of (S)-1,2-diphenylhexane (33, 0.35 g,
1.47 mmol) in CCl4 (12 mL), CH3CN (12 mL), and H2O (25 mL) was added
sodium metaperiodate (9.12 g, 29 equiv). To this biphasic solution was
added ruthenium trichloride hydrate (15 mg, 4.5%) and the mixture was
stirred vigorously for three days at room temperature. The resulting
mixture was then diluted with CH2Cl2 (20 mL). The precipitate was filtered
through a hyflo plug and washed with CH2Cl2. The aqueous phase was then
extracted with CH2Cl2 (2 Â 10 mL) and the combined organic phases were
washed with a saturated solution of NaHCO3 (3 Â 10 mL). The aqueous
extracts were combined, a HCl (35%) solution was added until the pH
reached 1, and the mixture was extracted with CH2Cl2 (3 Â 20 mL). The
organic layers were dried over MgSO4, filtered, and concentrated under
reduced pressure to provide the crude acid which was recrystallized in
2-Methyl-1-hexanol: A solution of 2-propen-1-ol (40, 0.230 g, 4 mmol) in
dry cumene (3 mL) was added dropwise over a period of 0.5 h at 108C to
a solution of nBuLi/hexane (7.5 mL, 12 mmol) in the presence of ( )-
sparteine (0.92 mL, 4 mmol) in dry cumene (5 mL). The reaction mixture
was stirred at 08C for 1 h. After cooling, the reaction mixture was poured
into a solution of HCl (1n). The aqueous layer was extracted with diethyl
ether (2 Â 10 mL) and the combined organic phases were dried over
MgSO4. After evaporation of the solvent the residue was chromatographed
(silica gel, pentane/ethyl acetate 80:20). Yield: 64% (0.300 g); 0% ee;
1H NMR (200 MHz, CDCl3): d ˆ 0.88 (m,6H); 1.38 (m, 7H); 3.33 (m, 2H);
5.14 (s, 1H).
water. Yield: 50% (0.128 g); [a]D25
ˆ
17.22 (c ˆ 0.01, EtOH); 1H NMR
(400 MHz, CDCl3): d ˆ 0.73 (t, J ˆ 6.8 Hz, 3H), 1.17 (m, 4H), 1.46 (m, 2H),
2.5 (m, 2H), 2.7 (m 1H); 13C NMR (100 MHz, CDCl3): d ˆ 13.39, 22.11,
28.60, 31.26, 35.97, 41.56, 176.92, 180.47; 31P NMR (162 MHz, (1S,2S)-(‡)-
N,N'-dimethyl-1,2-diphenyl-1,2-ethanediamine, CDCl3): d ˆ 136.54 (s,
85%), 137.09 (s, 85%), 137.25 (s, 15%), 137.51 (s, 15%); 70% ee.
Deprotection of dimethylacetal: General procedure F: Dimethylacetal
(25 ± 28) was dissolved in MeOH (5 mL) and aqueous HCl solution (4n,
0.5 mL) was added. The resulting mixture was refluxed for 1 h, cooled to
room temperature, and then quenched by the addition of a saturated
NaHCO3 solution. The aqueous layer was extracted with diethyl ether. The
combined organic phases were dried over K2CO3 and evaporated under
reduced pressure. Purification by flash chromatography (SiO2, cyclohex-
ane/AcOEt 75/25) afforded the alcohol as a colorless oil (>95% yield).
General procedure for the reduction of the acid with BH3 ´ THF: To a
solution of acid (x mmol) in THF (5x mL) was added a solution of BH3 ´
THF (1m, THF, 1 equiv) at 08C and the mixture was allowed to warm to
room temperature and stirred for 6 h. The mixture was then quenched with
an aqueous solution of HCl (1n) at 08C. The aqueous layer was extracted
with diethyl ether (3 Â 10 mL), the organic extracts were washed with a
saturated solution of NaHCO3 (5 mL), dried over K2CO3, filtered, and
concentrated under reduced pressure. The resulting residue was purified by
column chromatography (SiO2, pentane/diethyl ether 80:20) to afford the
expected alcohol as a colorless oil.
(2S)-2-Benzylhexanoic acid ((S)-13): Chromium(vi) oxide (1.11 g,
11.1 mmol) in sulfuric acid (6.75 mL, 4m) was added to a solution of (S)-
2 (0.576 g, 3 mmol) in acetone (5 mL) in an ice cooled bath. After 1 h of
stirring, sodium sulfite was added, and the product was extracted with
diethyl ether. The extract was dried over anhydrous sodium sulfate. After
evaporation of the solvent, the residue was purified on silica gel (eluent:
cyclohexane/ethyl acetate 60:40). Yield: 64% (0.433 g); [a]2D5 ˆ 18.2 (c ˆ
1
(3S)-3-Methylheptan-1-ol (37): The reaction was performed on 34 (0.15 g,
0.07, benzene); H NMR (400 MHz, CDCl3): d ˆ 0.80 (m, 3H), 1.20 ± 1.70
1.04 mmol). Yield: 70% (0.095 g); [a]D25
ˆ
1.82 (c ˆ 0.06, CHCl3);
(m, 6H), 2.60 (m, 1H), 2.75 (dd, J ˆ 9.50, 14 Hz,1H), 2.95 (dd, J ˆ 9.5,
14 Hz, 1H), 7.10 ± 7.25 (m, 5H), 9.5 (s, 1H); 13C (50 MHz, CDCl3): d ˆ
13.02, 22.69, 22.50, 31.61, 38.25, 47.55, 126.57, 128.56, 129.03, 139.32, 181.94.
1H NMR (400 MHz, CDCl3): d ˆ 0.9 (m, 6H), 1.1 ± 1.65 (m, 9H), 3.7 (m,
2H); 13C NMR (50 MHz, CDCl3): d ˆ 14.05, 19.61, 22.93, 29.16, 29.49,
36.79, 39.38, 61.15; 31P NMR (162 MHz, (1S,2S)-(‡)-N,N'-dimethyl-1,2-
diphenyl-1,2-ethanediamine, CDCl3): d ˆ 139.29 (s, 7.5%), 139.51 (s,
92.5%); 85% ee.
Derivatization of n-benzylalkanes into acids: General procedure: To a
solution of n-benzylalkane (x mmol) in CCl4 (4x mL), CH3CN (4x mL),
and H2O (8.2x mL) was added sodium metaperiodate (14.5x equiv). To
this biphasic solution was added ruthenium trichloride hydrate (2.2% mol)
and the mixture was stirred vigorously for three days at room temperature.
The resulting mixture was then diluted with CH2Cl2 (20 mL). The
(3S)-3-Methylnonan-1-ol (38): The reaction was performed on 35 (0.166 g,
0.96 mmol). Yield: 74% (0.113 g); [a]D25
ˆ
3.02 (c ˆ 0.05, CHCl3);
1H NMR (400 MHz, CDCl3): d ˆ 0.9 (m, 6H), 1.1 ± 1.65 (m, 13H), 3.7 (m,
Chem. Eur. J. 1999, 5, No. 7
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2065

I. Marek, J. F. Normant et al.
FULL PAPER
2H); 13C NMR (50 MHz, CDCl3): d ˆ 14.29, 19.81, 22.87, 27.11, 29.67, 29.80,
32.11, 37.34, 40.13, 61.34; 31P NMR (162 MHz, (1S,2S)-(‡)-N,N'-dimethyl-
1,2-diphenyl-1,2-ethanediamine, CDCl3): d ˆ 139.11 (s, 8%), 139.32 (s,
92%); 84% ee.
Methyl (1R,2R)-2-butylcyclopropanecarboxylate: To a solution of cyclo-
propane 50 (1.1 mmol) in methanol (10 mL) was added a few drops of a
H2SO4 (95%) solution. The mixture was stirred for two days at room
temperature. A saturated solution of NaHCO3 was then added and the
aqueous layer was extracted with diethyl ether (2 Â 10 mL). The organic
extracts were dried over K2CO3, filtered, and concentrated under reduced
pressure. The resulting residue was purified by column chromatography
(3S)-3-Methylhexan-1-ol (39): The reaction was performed on 36 (0.15 g,
1.2 mmol). Yield: 70% (0.098 g); [a]D25
ˆ
1.1 (c ˆ 0.04, CHCl3); 1H NMR
(200 MHz, CDCl3): d ˆ 0.80 (m, 6H), 1.05 ± 1.6 (m, 7H), 2.0 (m, 1H), 3.58
(m, 2H); 13C NMR (100 MHz, CDCl3): d ˆ 14.68, 19.93, 20.39, 29.59, 39.80,
40.27, 61.44; 31P NMR (162 MHz, (1S,2S)-(‡)-N,N'-dimethyl-1,2-diphenyl-
1,2-ethanediamine, CDCl3): d ˆ 139.07 (s, 12%), 139.32 (s, 88%); 76% ee.
(SiO2, pentane/diethyl ether 95:5). Yield: 73% (0.134 g); [a]D25
ˆ
70 (c ˆ
0.08, CHCl3); 1H NMR (400 MHz, CDCl3): d ˆ 0.71 (m, 1H), 0.9 (m, 4H),
0.9 (t, J ˆ 7 Hz, 3H), 1.15 (m, 1H), 1.25 ± 1.5 (m, 8H), 3.67 (s, 3H); 13C NMR
(100 MHz, CDCl3): d ˆ 14.05, 15.61, 20.02, 22.41, 23.05, 31.33, 32.80, 51.60,
175.07; 93% ee; anal. calcd for C9H16O2: C 69.19, H 10.32; found C 69.05, H
10.36.
(3S)-3-Ethylheptan-1-ol (43): The reaction was performed on (S)-3-ethyl-
heptanoic acid (0.19 g, 1.2 mmol). Yield: 70% (0.122 g); [a]D25
ˆ
0.32 (c ˆ
1
0.05, CHCl3); H NMR (400 MHz, CDCl3): d ˆ 0.89 (m, 6H), 1.2 ± 1.6 (m,
11H), 2.25 (m, 1H), 3.64 (t, J ˆ 14 Hz, 2H); 13C NMR (50 MHz, CDCl3):
d ˆ 10.89, 14.32, 23.30, 26.17, 29.03, 33.09, 35.81, 36.64, 61.31.
(1R,2R)-2-butylcyclopropanemethanol (51): To
a solution of methyl
[(1R,2R)-1-(2-butylcyclopropyl)]methanoate (0.85 mmol) in dry diethyl
ether (10 mL) was added at 08C a solution of DiBAlH (1m in hexane,
2.2 equiv) and the mixture was allowed to warm to room temperature and
stirred for 1 h. The mixture was then quenched with MeOH (1 mL) at 08C
and an aqueous HCl (1n) solution. The aqueous layer was extracted with
diethyl ether (2 Â 10 mL). The organic extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure. The resulting residue
was purified by column chromatography (SiO2, pentane/diethyl ether
Enantioselective cyclopropanation: General procedure: To a solution of
RLi/hexane (3.3 equiv) in dry solvent (10 mL) was added ( )-sparteine
(0.7 mL when the reaction was performed with one equivalent and 70 mL
when the reaction was performed with 10% mol) at 788C and the
mixture was allowed to warm to 08C for a few minutes. The solution was
then cooled to 508C and a solution of 8 (0.62 g, 3 mmol) in dry solvent
(5 mL) was added dropwise over a period of 0.5 h. After 7 h at 508C, the
orange reaction mixture was rapidly warmed to room temperature and
stirred for 12 h. The mixture was then poured into an aqueous HCl (2n)
solution and the aqueous layer was extracted with diethyl ether (3 Â
10 mL). The combined organic phases were washed with brine and dried
over MgSO4. The solvents were removed under reduce pressure and the
product was purified by column chromatography (silica gel, cyclohexane)
to afford the expected cyclopropane as a colorless oil.
70:30). Yield: 89% (0.097 g); [a]D25
ˆ
26.1 (c ˆ 0.02, CHCl3); 1H NMR
(400 MHz, CDCl3): d ˆ 0.5 ± 0.3 (m, 2H), 0.6 (m, 1H), 0.8 ± 1.0 (m, 4H),
1.2 ± 1.5 (m, 6H), 2.8 (m, 1H), 3.43 (s, 2H); 13C NMR (100 MHz, CDCl3):
d ˆ 9.82, 14.02, 17.07, 21.07, 22.38, 31.73, 33.18, 67.13; 31P NMR (162 MHz,
(1R,2R)-(‡)-N,N'-dimethyl-1,2-diphenyl-1,2-ethanediamine, CDCl3): d ˆ
139.98 (s, 96.5%), 140.41 (s, 3.5%); 93% ee; anal. calcd for C8H16O: C
74.94, H 12.58; found C 74.88, H 12.65.
Reaction of 12Li and 12'Li with electrophiles:
(1R,2R)-1-Butyl-2-phenylcyclopropane (47): Yield: 60% (0.313 g) when
the reaction was performed with a stoichiometric amount of ( )-sparteine
in cumene and 61% (0.32 g) when the reaction was performed with a
Synthesis of (2R,3S)-2-butyl-3-phenyl-3-phenylthio-1-propanol (45) and
(2S,3R)-2-butyl-3-phenyl-3-phenylthio-1-propanol (45'): A solution of (E)-
1 or (Z)-1 (0.523 g, 4 mmol) in dry cumene (3 mL) was added dropwise
over a period of 0.5 h at 08C to a solution of nBuLi/hexane (7.5 mL,
12 mmol) in the presence of ( )-sparteine (0.92 mL, 4 mmol) in dry
cumene (5 mL). The red reaction mixture was stirred at 08C for another
0.5 h, allowed to warm to room temperature, and then stirred for 1 h. After
cooling to 608C, dry tetrahydrofuran (15 mL) was added, followed by
diphenyl disulfide (5.23 g, 24 mmol). The reaction was completed by
stirring for 1 h at room temperature. The reaction mixture was poured into
a saturated solution of NaHCO3. The aqueous layer was extracted with
diethyl ether (2 Â 10 mL) and the combined organic phases were washed
with HCl (1n) and dried over MgSO4. After evaporation of the solvent, the
residue was chromatographed (silica gel, CH2Cl2).
catalytic amount of
(
)-sparteine in hexane; [a]D25
ˆ
85.5 (c ˆ 0.03,
1
CHCl3) with ee ˆ 93%; H NMR (400 MHz, CDCl3): d ˆ 0.8 (m, 1H), 0.9
(m, 4H), 1.1 (m, 1H), 1.4 (m, 6H), 1.6 (m, 1H), 7.0 ± 7.3 (m, 5H); 13C NMR
(100 MHz, CDCl3): d ˆ 14.2, 16.3, 22.6, 23.3, 24.0, 31.7, 34.1, 125.2, 125.7,
128.3, 144.3; anal. calcd for C13H18: C 89.59, H 10.41; found C 89.12, H
10.58.
(1R,2R)-1-(1-Methylpropyl)-2-phenylcyclopropane (48): Yield: 66%
(0.345 g); 1H NMR (400 MHz, CDCl3): d ˆ 0.8 (m, 1H), 0.85 ± 0.95 (m,
7H), 0.97 ± 1.0 (m, 6H), 1.05 (m, 6H), 1.43 (m, 2H), 1.58 (m, 2H), 1.68 (m,
1H), 1.72 (m, 1H), 7.05 ± 7.3 (m, 10H); 13C NMR (100 MHz, CDCl3): d ˆ
11.71, 11.97, 19.28, 19.37, 21.77, 23.26, 29.65, 30.04, 30.44, 40.23, 40.37, 125.08,
125.56, 125.72, 128.19, 144.08, 144.23; anal. calcd for C13H18: C 89.59, H
10.41; found C 89.42, H 10.48.
45 (2R,3S): Yield: 61% (0.732 g); [a]D25
NMR (36.22 MHz, CDCl3): d ˆ 136.36 (s, 88%), 136.83 (s, 12%); 76% ee,
(the enantiomeric purity of the chiral diamine was 92%, thus eecorr ˆ 83%).
ˆ
156.4 (c ˆ 0.100, CH2Cl2); 31P
(1R,2R)-1-Hexyl-2-phenylcyclopropane (49): Yield: 59% (0.34 g); [a]D25
ˆ
71.1 (c ˆ 0.03, CHCl3); 1H NMR (400 MHz, CDCl3): d ˆ 0.77 (m, 1H),
0.93 (m, 4H), 1.05 (m, 1H), 1.2 ± 1.5 (m, 10H), 1.6 (m, 1H), 7.05 ± 7.3 (m,
5H); 13C NMR (100 MHz, CDCl3): d ˆ 14.12, 16.20, 22.67, 23.24, 23.92,
29.16, 29.89, 31.89, 34.46, 125.08, 125.55, 128.19, 144.15; anal. calcd for
C15H22: C 89.04, H 10.96; found C 88.88, H 11.01.
45' (2S,3R): Yield: 60% (0.720 g); [a]2D5 ˆ 131 (c ˆ 0.11), CH2Cl2); 31P NMR
(90 MHz, CDCl3): d ˆ 136.49 (s, 17.5%), 136.96 (s, 82.5%); 65% ee (the
enantiomeric purity of the chiral diamine was 92%, thus eecorr ˆ 70%);
1H NMR (200 MHz CDCl3) 0.87 (t, J ˆ 6.6 Hz, 3H), 1.10 ± 1.55 (m, 6H),
1.70 (m, 1H), 2.03 (m, 1H), 3.53 (dd, J ˆ 4.2, 11.1 Hz, 1H), 3.73 (dd, J ˆ 6.0,
10.9 Hz, 1H), 4.40 (d, J ˆ 6.7 Hz, 1H), 7.12 ± 7.37 (m, 10H); 13C NMR
(50 MHz, CDCl3): d ˆ 13.98, 22.81, 27.71, 29.45, 46.64, 55.83,62.90, 126.51,
126.92, 128.24, 128.36, 128.62, 131.21, 135.61, 141.25; anal. calcd for
C18H24OS: C 75.95, H 8.05; found C 75.20, H 7.89.
[(1R,2R)-1-(2-Butylcyclopropyl)]methanoic acid (50): To a solution of the
cyclopropane 47 (1.8 mmol, 0.225 g) in CCl4 (7 mL), CH3CN (7 mL), and
H2O (14.5 mL) was added sodium metaperiodate (5.6 g, 14.5 equiv). To this
biphasic solution was added ruthenium trichloride hydrate (8 mg,
2.2% mol). The mixture was stirred vigorously for three days at room
temperature and then diluted with CH2Cl2 (20 mL). The precipitate was
filtered through a hyflo plug and washed with CH2Cl2. The aqueous phase
was then extracted with CH2Cl2 (2 Â 10 mL) and the combined organic
phases were washed with a saturated solution of NaHCO3 (3 Â 10 mL). The
aqueous extracts were combined and a HCl (35%) solution was added until
the pH reached 1. The mixture was extracted with CH2Cl2 (3 Â 20 mL) and
the organic layers were dried over MgSO4, filtered, and concentrated under
reduced pressure to provide the crude acid which was filtered over SiO2
(2R,3S)-2-Butyl-3-phenyl-1-butanol (46): A solution of (E)-1 (0.523 g,
4 mmol) in dry cumene (3 mL) was added dropwise over a period of 0.5 h at
08C to a solution of nBuLi/hexane (7.5 mL, 12 mmol) in the presence of
(
)-sparteine (0.92 mL, 4 mmol) in dry cumene (5 mL). The red reaction
mixture was stirred at 08C for another 0.5 h, was allowed to warm to room
temperature, and then stirred for 1 h. After cooling to 608C, dry
tetrahydrofuran (15 mL) was added, followed by methyl iodide (1.5 mL,
24 mmol). The reaction was completed by stirring for 1 h at room
temperature. The reaction mixture was poured into HCl (1n). The aqueous
layer was extracted with diethyl ether (2 Â 10 mL) and the combined
organic phases were dried over MgSO4. After evaporation of the solvent,
the residue was chromatographed (silica gel, CH2Cl2). Yield: 63%
(0.520 g); [a]2D5 ˆ 8.7 (c ˆ 0.01, CH2Cl2); 31P NMR (36.22 MHz, CDCl3):
d ˆ 137.73 (s, 91%), 136.79 (s, 9%); 82% ee; 1H NMR (400 MHz, CDCl3):
with Et2O as the eluent. Yield: 81% (0.168 g); [a]D25
ˆ
76.7 (c ˆ 0.04,
CHCl3); 1H NMR (400 MHz, CDCl3): d ˆ 0.8 (m, 1H), 0.9 (m, 4H), 1.1 ± 1.5
(m, 8H); 13C NMR (50 MHz, CDCl3): d ˆ 14.2, 16.43, 20.16, 22.38, 24.1,
31.27, 32.76, 161.36; 93% ee; anal. calcd for C8H14O2: C 67.57, H 9.92; found
C 67.65, H 10.01.
2066
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0507-2066 $ 17.50+.50/0
Chem. Eur. J. 1999, 5, No. 7

Configurational Stability of Benzylic Organozinc Halides
2055±2068
d ˆ 0.91 (t, J ˆ 6.9 Hz, 3H), 1.22 ± 1.67 (m, 6H), 1.30 (d, J ˆ 7.1 Hz, 3H),
1.67 (m, 1H), 2.85 (q, J ˆ 7.3 Hz, 1H), 3.41 (dd, J ˆ 4.9, 11.0 Hz, 1H), 3.52
(dd, J ˆ 5.2, 11.0, 1H), 7.20 ± 7.35 (m, 5H); 13C NMR (50 MHz, CDCl3): d ˆ
14.05, 18.52, 23.10, 27.65, 29.30, 40.35, 47.03, 63.45, 126.04, 127.54, 128.37,
146.38.
10 mmol) and acetyl chloride (0.7 mL, 10 mmol) in dry diethyl ether
(10 mL)] was added dropwise at 608C and the reaction completed by
stirring overnight at room temperature. After cooling, the reaction mixture
was poured into NH3 (20%) in water (3 mL).The aqueous layer was
extracted with diethyl ether (2 Â 10 mL).The organic layer was treated
overnight with an aqueous solution of Na2S, washed with Na2CO3 (10 mL),
and dried over K2CO3. After evaporation of the solvent the residue was
chromatographed (silica gel, cyclohexane/diethyl ether 1:1 which contained
a few drops of 32% NH3). Yield: 69% (0.305 g); 1H NMR (400 MHz,
CDCl3 major isomer): d ˆ 0.88 (m, 3H), 1.28 (m, 6H), 1.81 (m,1H), 2.10
(dd, J ˆ 7.6, 12.9 Hz, 2H), 2.20 (s, 6H), 2.66 (d, J ˆ 5.7 Hz, 1H), 7.20 ± 7.30
(m, 5H).
(2R)-2-[(S)-phenyl(deuterio)methyl]-1-hexanol (44): A solution of (E)-1
(0.523 g, 4 mmol) in dry cumene (3 mL) was added dropwise over a period
of 0.5 h at 08C to a solution of nBuLi/hexane (7.5 mL, 12 mmol) in the
presence of ( )-sparteine (0.92 mL, 4 mmol) in dry cumene (5 mL). The
red reaction mixture was stirred at 08C for another 0.5 h, was warmed to
room temperature, and then stirred for 1 h. After cooling to 608C, DCl
(prepared from D2O (0.48 mL, 24 mmol) and acetyl chloride (1.7 mL,
24 mmol) in dry diethyl ether (20 mL)) was added dropwise at 608C, the
mixture was allowed to warm to room temperature. The reaction was
completed by stirring for 1 h at room temperature. After cooling, the
reaction mixture was poured into HCl (1n). The aqueous layer was
extracted with diethyl ether (2 Â 10 mL) and the combined organic phases
were dried over MgSO4. After evaporation of the solvents, the residue was
chromatographed (silica gel, cyclohexane/ethyl acetate 80:20). Yield: 87%
[1] K. Ziegler, K. Bähr, Chem. Ber. 1928, 61, 253.
[2] P. Knochel, Comprehensive Organic Synthesis (Eds.: B Trost, I.
Fleming), Pergamon, New York, 1991, 4, 865.
[3] I. Marek, J. F. Normant, Carbometalation Reactions in Cross Cou-
pling Reactions (Eds.: P. J. Stang, F. Diederich,), Wiley-VCH 1998,
271.
[4] The authors wish to point out the large difference between the
enantioselective carbometalation with a chiral ligand on the organo-
metallic derivative (chiral complexation) with the diastereoselective
carbometalation generated by a chiral substrate (even if the chiral
moiety can be cleaved in a second step). In this bibliographic section,
only the former case is described. For the references concerning the
second alternative, see ref. [3].
[5] a) A. H. Hoveyda, J. P. Morken, J. Org. Chem. 1993, 58, 4237; b) J. P.
Morken, M. T. Didiuk, A. H. Hoveyda, J. Am. Chem. Soc. 1993, 115,
6997; c) M. S. Visser, N. M. Heron, M. T. Didiuk, J. F. Sagal, A. H.
Hoveyda, J. Am. Chem. Soc. 1996, 118, 4291; d) A. H. Hoveyda, J. P.
Morken, Angew. Chem. 1996, 108, 1378; Angew. Chem. Int. Ed. Engl.
1996, 35, 1262; e) A. F. Houri, Z. Xu, D. A. Cogan, A. H. Hoveyda, J.
Am. Chem. Soc. 1995, 117, 2943; f) Z. Xu, C. W. Johannes, A. F. Houri,
D. S. La, D. A. Cogan, G. E. Hofinela, A. H. Hoveyda, J. Am. Chem.
Soc. 1997, 119, 10302; g) J. P. Morken, M. T. Didiuk, M. S. Visser,
A. H. Hoveyda, J. Am. Chem. Soc. 1994, 116, 3123; h) M. S. Visser,
A. H. Hoveyda, Tetrahedron 1995, 51, 4383; i) S. M. Visser, J. P. A.
Harrity, A. H. Hoveyda, J. Am. Chem. Soc. 1996, 118, 3779; j) L. Bell,
R. J. Whitby, R. J. Jones, M. C. H. Standen, Tetrahedron Lett. 1996, 37,
7139.
[6] a) D. Y. Kondakov, E. I. Negishi, J. Am. Chem. Soc. 1995, 117, 10771;
b) D. Y. Kondakov, E. I. Negishi, J. Am. Chem. Soc. 1996, 118, 1577;
c) G. Dawson, C. A. Durrant, G. G. Kirk, R. J. Whitby, R. V. H. Jones,
M. C. H. Standen, Tetrahedron Lett. 1997, 38, 2335.
[7] a) F. R. W. P. Wild, H. Wasiucionek, G. Huttner, H. Brintzinger, J.
Organomet. Chem. 1985, 288, 63; b) B. Chin, S. L. Buckwald, J. Org.
Chem. 1997, 62, 2267.
[8] a) M. Nakamura, M. Arai, E. Nakamura, J. Am. Chem. Soc. 1995, 117,
1179; b) E Nakamura, Pure Appl. Chem. 1996, 68, 123.
[9] I. Marek, J. F. Normant, Chem. Rev. 1996, 96, 3241.
(0.675 g); [a]2D5
ˆ
4.13 (c ˆ 0.12 CH2Cl2); d.r. ˆ 95:5; 31P NMR
(36.22 MHz, CDCl3, (1R,2R)-(‡)-N,N'-dimethyl-1,2-diphenyl-1,2-ethane-
diamine): d ˆ 136.81 (s, 92%), 137.48 (s, 8%); 84% ee; 1H NMR (200 MHz,
CDCl3): d ˆ 0.90 (t, J ˆ 7.1 Hz), 1.15 ± 1.40 (m, 6H), 1.70 (m, 1H), 2.65 (m,
1H), 3.50 (d, J ˆ 5.1 Hz, 2H), 7.10 ± 7.35 (m, 5H).
N,N'-Dimethyl-(2S*)-[(S*)-(methylthio)benzyl]-1-hexanamine
(53a);
N,N'-diethyl-(2S*)-[(S*)-(methylthio)benzyl]-1-hexanamine (53b): To a
solution of (E)-3 or (E)-52 (0.378 g, 2 mmol, R ˆ Et) or (0.322 g, 2 mmol,
R ˆ Me) in dry hexane (20 mL) was added nBuLi (1.82 mL, 1.65m in
hexane, 3 mmol) followed by dry TMEDA (0.45 mL, 3 mmol) at 708C.
The cooling bath was removed and the resultant red reaction mixture was
stirred at 08C for 3 h. MeSSMe (0.54 mL, 6 mmol) in hexane (10 mL) was
added dropwise at 608C and the reaction completed by stirring for 1 h at
room temperature. After cooling, the reaction mixture was poured into
aqueous NH3 (3 mL, 20%). The aqueous layer was extracted with diethyl
ether (2 Â 10 mL) and the combined organic phases were dried over
K2CO3. After evaporation of the solvent, the residue was chromatographed
(silica gel, cyclohexane/diethyl ether 1:1 containing a few drops of 32%
NH3). Yield: 73% (0.427 g, R ˆ Et); 1H NMR (200 MHz, CDCl3): d ˆ 0.85
(t, J ˆ 6.0 Hz, 3H), 0.9 (t, J ˆ 7 Hz, 6H), 1.25 (m, 6H), 1.85 (s 3H), 2 (m,
1H), 2.25 (m, 2H), 2.47 (q, J ˆ 7 Hz, 4H) 4.09 (d, J ˆ 5.1 Hz, 1H), 7.15 ± 7.40
(m, 5H); 13C NMR (50 MHz, CDCl3): d ˆ 11.27, 13.84, 14.76, 22.78, 28.95,
29.30, 41.88, 46.70, 53.69, 54.92, 126.44, 127.60, 129.15, 140.25. Yield: 68%
(0.360 g, R ˆ Me); 1H NMR (200 MHz, CDCl3 major isomer) 0.85 (m, 3H),
1.25 (m, 6H), 1.65 (m, 1H), 1.90 (s, 3H), 2.10 (m, 2H), 2.25 (s, 6H), 4.13 (d,
J ˆ 4.4 Hz, 1H), 7.20 ± 7.40 (m, 5H); 13C NMR (50 MHz, CDCl3): d ˆ 13.96,
14.91, 22.80, 26.60, 29.41, 41.62, 45.66, 53.50, 61.26, 126.60, 128.01, 129.26,
139.86; anal. calcd for C16H27NS: C 72.39, H 10.25; found C 72.98, H 10.78.
N,N'-Dimethyl-(2R*)-[(S*)-deuterobenzyl]-1-hexanamine: To a solution
of (E)-3 (0.322 g, 2 mmol) in dry hexane (20 mL) was added nBuLi
(1.82 mL, 1.65m in hexane, 3 mmol) followed by dry TMEDA (0.45 mL,
3 mmol) at 708C. The cooling bath was removed and the resultant red
reaction mixture was stirred at 08C for 3 h. MeOD (0.3 mL, 6 mmol) in
hexane (3 mL) was added dropwise at 608C and the reaction completed
by stirring for 1 h at room temperature. After cooling, the reaction mixture
was poured into NH3 (20%) in water (3 mL). The aqueous layer was
extracted with diethyl ether (2 Â 10 mL) and the combined organic phases
were dried over K2CO3. After evaporation of the solvent the residue was
chromatographed (silica gel, cyclohexane/diethyl ether 1:1 containing a few
drops of 32% NH3). Yield: 70% (0.308 g); 1H NMR (400 MHz, CDCl3
major isomer): d ˆ 0.88 (m, 3H), 1.28 (m, 6H), 1.81 (m,1H), 2.10 (dd, J ˆ
7.6, 12.9 Hz, 2H), 2.20 (s, 6H), 2.51 (d, J ˆ 7.7 Hz, 1H), 7.20 ± 7.30 (m, 5H);
13C NMR (50 MHz, CDCl3): d ˆ 14.09, 23.05, 26.98, 31.56, 37.69, 38.27,
38.65, 45.91, 64.09, 125.72, 126.03, 129.37, 141.20; anal. calcd for C15H24DN:
C 81.75, H 11.89; found C 82.10, H 11.50.
[10] a) T. Kato, S. Marumoto, I. Sato, I. Kuwajima, Synlett 1991, 671; b) S.
Marumoto, I. Kuwajima, Chem. Lett. 1992, 1421.
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A Tambute. Tetrahedron Lett.
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[12] D. Hoppe, T. Hense, Angew. Chem. 1997, 109, 2376; Angew. Chem. Int.
Ed. Engl. 1997, 36, 2282, and references therein.
[13] D. Hoppe, Encyclopedia of reagents for the Organic Synthesis, Vol 7
(Ed.: L. A. Paquette), 1st ed., Wiley, Chichester 1995, 4662.
[14] P. Beak, A. Basu, D. J. Gallagher, Y. S. Park, S. Thayumanavan, Acc.
Chem. Res. 1996, 29, 552, and references therein.
[15] As a result of the low solubility of the starting material in hexane,
cumene was preferred for the carbolithiation of cinnamyl alcohol.
[16] a) A. Alexakis, J. C. Frutos, S. Mutti, P. Mangeney, J. Org. Chem. 1994,
59, 3326; b) A. Alexakis, S. Mutti, P. Mangeney, J. Org. Chem. 1992, 57,
1224.
N,N'-Dimethyl-(2R*)-[(R*)-deuterobenzyl]-1-hexanamine: To a solution
of (E)-3 (0.322 g, 2 mmol) in dry hexane (20 mL) was added nBuLi
(1.82 mL, 1.65m in hexane, 3 mmol) followed by dry TMEDA (0.45 mL,
3 mmol) at 708C. The cooling bath was removed and the resultant red
reaction mixture was stirred at 08C for 3 h. ZnBr2 (4 mL, 1n in diethyl
ether, 4 mmol) was added dropwise and the reaction mixture was stirred at
the required temperature (see Table 1). DCl [prepared from D2O (0.4 mL,
[17] K. Soai, H. Hayashi, A. Shinozaki, H. Umebayashi, Y. Yamada, Bull.
Chem. Soc. Jpn. 1987, 60, 3450.
[18] S. Klein, I. Marek, J. F. Poisson, J. F. Normant, J. Am. Chem. Soc. 1995,
117, 8853.
Chem. Eur. J. 1999, 5, No. 7
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0947-6539/99/0507-2067 $ 17.50+.50/0
2067

I. Marek, J. F. Normant et al.
FULL PAPER
[19] D. J. Gallagher, H. Du, S. A. Long, P. Beak, J. Am. Chem. Soc. 1996,
118, 11391.
[20] This puzzling outcome is still unexplained; however it has been
already been reported: see, ref. [11a].
[21] M. Imai, A. Hagihara, H. Kawasaki, K. Manabe, K. Koga J. Am.
Chem. Soc. 1994, 116, 8829.
[22] The ee value was determined after deprotection of the tert-butyl
diethyl ether into the corresponding alcohol; see, A. Alexakis, M.
Gardette, S. Colin Tetrahedron Lett. 1988, 29, 2954.
Williams, J. G. Philipps, J. C. Huffman, J. Org. Chem. 1981, 46, 4101;
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[23] The enantioselection of the carbolithiation of the N,N'-dimethyl-(2S)-
benzyl-1-hexanamine was determined by chiral HPLC on Chirace-
l OD.
[24] The ee value was also determined by 31P NMR spectroscopic analysis
of the diastereomeric phosphorus product. See ref. [16].
[25] The absolute configurations were not determined; however, by
analogy with all the other examples, we consider them to be (S).
[26] S. Norsikian, I. Marek, J. F. Poisson, J. F. Normant J. Org. Chem. 1997,
62, 4898.
[27] a) X. Wei, R. J. K. Taylor, Tetrahedron Assymetry 1997, 8, 665; b) X.
Wei, R. J. K. Taylor, Tetrahedron Lett. 1996, 37, 4209; c) X. Wei,
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Richey, Jr., A. S. Heyn, W. F. Erickson, J. Org. Chem. 1983, 48, 3821.
[28] S. Norsikian, I. Marek, J. F. Normant, Tetrahedron Lett. 1997, 38, 7523.
[29] In the case of the addition of nPrLi, the ee value is lower (76% instead
of 85%) since the preparation of this reagent required Et2O as the
solvent. See discussion in the text.
[42] For a more complete discussion, see: C. Mück-Lichtenfeld, H.
Ahlbrecht, Tetrahedron 1996, 52, 10025.
[43] The formation of cyclopropane by 1,3-elimination between an
organogembismetallic and a methoxymethyl ether has already been
described: a) I. Marek, D. Beruben, J. F. Normant, Tetrahedron Lett.
1995, 36, 3695; b) D. Beruben, I. Marek, J. F. Normant, N. Platzer, J.
Org. Chem. 1995, 60, 2488; c) D. Beruben, I. Marek, J. F. Normant, N.
Platzer, Tetrahedron Lett. 1993, 34, 7575.
[44] For some representative formations of chiral cyclopropanes, see:
a) A. B. Charette, J.F Marcoux, Synlett 1995, 1197, and references
therein; b) J. Salaün, Chem. Rev. 1989, 89, 1247; c) D. Romo, A. I.
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W. R. Cantrell, Jr., J. L. Olive, J. Am. Chem. Soc. 1993, 115, 9468;
e) M. P. Doyle in Catalytic Asymmetric Synthesis (Ed.: I. Ojima),
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26, 339; g) D. A. Evans, K. A. Woerpel, M. J. Scott, Angew. Chem.
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[46] For a previous report on the synthesis of chiral cyclopropane mediated
by a stoichiometric amount of ( )-sparteine, see: M. Paetow, M.
Kotthaus, M. Grehl, R. Fröhlich, D. Hoppe, Synlett 1994, 1034.
[47] T. Imai, H. Mineta, S. Nishida, J. Org. Chem. 1991, 55, 4986.
[48] The correlation was made from the alcohols 30 and 31 by tosylation
and displacement with dimethylamine.
[32] a) M. Bergdahl, M. Nilsson, T. Olsson, K. Stern, Tetrahedron 1991, 47,
9691; b) T. Tsunoda, M. Nagaku, C. Nagino, Y. Kawamura, F. Ozaki,
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Masset, M. Maltz, C. W. Murtiashaw, S. L. Pezzullo, T. Staigers,
Tetrahedron Asymmetry, 1996, 7, 435.
[49] P. Knochel, R. D. Singer Chem. Rev. 1993, 93, 2117.
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1995, 723; b) C. Darcel, F. Flachsmann, P. Knochel, Chem. Commun.
1998, 205; c) R. Duddu, M. Eckhardt, M. Furlong, P. Knoess, S.
Berger, P. Knochel, Tetrahedron 1994, 50, 2415; d) F. Lhermitte, P.
Knochel, Angew. Chem. 1998, 110, 2598; Angew. Chem. Int. Ed. 1998,
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109, 274; Angew. Chem. Int. Ed. Engl. 1997, 36, 245; f) Sakami, T.
Houkawa, M. Asaoka, H. Takei, J. Chem. Soc. Perkin Trans. 1, 1995,
285; g) T. Houkawa, T. Ueda, S. Sakami, M. Asaoka, H. Takei,
Tetrahedron Lett. 1996, 37, 1045.
[51] Cases where some organometallic compounds react with inversion of
configuration are: the [2,3] Wittig rearrangement: a) K. Tomooka, T.
Igarashi, M. Watanabe, T. Nakai, Tetrahedron Lett. 1992, 33, 5795;
b) R. Hoffmann, R. Brückner, Angew. Chem. 1992, 104, 646; Angew.
Chem. Int. Ed. Engl. 1992, 31, 647; c) K. Brickmann, R. Brückner,
Chem. Ber. 1993, 126, 1227; d) E. J. Verneer, T. Cohen, J. Am. Chem.
Soc. 1992, 114, 375. For the [1,2] Wittig rearrangement, see: e) R.
Hoffmann, T. Bückert, R. Brückner, Tetrahedron Lett. 1993, 34, 297;
f) E. J. Verneer, T. Cohen, J. Org. Chem. 1992, 57, 1072. For the
transmetalation of metalated allyl carbamates with [Ti(OiPr)4], see:
g) D. Hoppe, O. Zschage, Angew. Chem. 1989, 101, 67; Angew. Chem.
Int. Ed. Engl. 1989, 28, 69; h) D. Hoppe, T. Krämer, Tetrahedron Lett.
1987, 28, 5149; i) B. Peschke, J. Lüûmann, M. Dyrbusch, D. Hoppe,
Chem. Ber. 1992, 125, 1421. For lithiated benzylic carbamates, see: j) D.
Hoppe, A. Carstens, T. Kramer, Angew. Chem. 1990, 102, 1455;
Angew. Chem. Int. Ed. Engl. 1990, 29, 1424. For the benzylic lithium
derivatives, see: ref. [10].
[33] H. J. Carlsen, T. Katsuki, V. S. Martin, K. B. Sharpless J. Org. Chem.
1981, 46, 3936.
[34] [a]D ˆ 26.5 (c ˆ 0.1; EtOH) according to K.Petterson, Arkiv för Kemi
1953,7, 39.
[35] a) M. J. Woltering, R. Fröhlich, D. Hoppe, Angew. Chem. 1997, 109,
1804; Angew. Chem. Int. Ed. Engl. 1997, 36, 1764; b) M. Oestreich, R.
Fröhlich, D. Hoppe, Tetrahedron Lett. 1998, 39, 1745; c) M. J.
Woltering, R. Fröhlich, B. Wibbeling, D. Hoppe, Synlett 1998, 797.
For some references on the carbocyclization of chiral organolithium,
see: I. Coldham, R. Hufton, D. J. Snowden J. Am. Chem. Soc. 1996,
118, 5322; K. Tomooka, N. Komone, T. Nakai, Tetrahedron Lett. 1997,
38, 8939.
[36] However, when the same reaction was applied to the dimethyl acetal
(or the cinnamyl diethylamine) of (Z) sterochemistry, (Z)-8, the
opposite enantiomer is effectively obtained; however, the enantiose-
lectivity dropped to only 30%.
[37] The carbolithiation of (Z)-9 occurred in 8 h at 08C to yield only 50%
of carbometalated product with 28% ee.
[38] a) C.K-F. Chiu, Tetrahedron Asymmetry 1995, 6, 881; b) J. P. Rizzi, US
Patent, 4, 767,743, 1988.
[39] For a highlight, see: C. Bolm, F. Bienewald, A. Seger, Angew. Chem.
1996, 108, 1767; Angew. Chem. Int. Ed. Engl. 1996, 35, 1657, and
references therein.
[40] When an electrophile (such as MeOD) is added to the benzylic
organolithium compound, generated by carbolithiation on b-methyl-
styrene (no intramolecular chelation), the diastereoselectivity is poor
(d.r. ˆ 60:40).
[52] The benzylic organolithium compound epimerizes very rapidly, even
at 788C, see: ref. [10].
[53] S. Klein, I. Marek, J. F. Normant, J. Org. Chem. 1994, 59, 2925.
[41] For epimerization of carbanionic centers into the thermodynamic
product, see: a) P. G. Mc Dougal, B. D. Condon, M. D. Lafosse, Jr.,
A. M. Lauro, D. Vanderveer, Tetrahedron Lett. 1988, 29, 2547; b) R.
Hoffmann, M. Bewersdorf, Tetrahedron Lett. 1990, 31, 67; c) D. R.
Received: December 2, 1998 [F 1473]
2068
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Chem. Eur. J. 1999, 5, No. 7