Asymmetric induction in the arenethiolatocopper(I)-catalyzed substitution reaction of Grignard reagents with allylic substrates

Article abstract of DOI:10.1016/S0040-4020(00)00145-9

The influence of some experimental parameters on the regio- and enantioselectivity in the 'γ-selective substitution reaction of Grignard reagents RMgX with acyclic allylic acetates catalyzed by the arenethiolatocopper(I) complex (S)-1 was studied. When more bulky arenethiolatocopper(I) complexes than (S)-1 were employed in a reaction of allylic acetate 3 with n-BuMgI, the enantioselectivities observed for the γ- product were lower. With an arenethiolatocopper(I) catalyst prepared in situ, several Grignard reagents were studied in a substitution reaction with acetate 2. Compared to n-BuMgI, more bulky Grignard reagents gave no improvement of the enantioselectivity in the formation of the γ-product. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00145-9

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 2895±2903
Asymmetric Induction in the Arenethiolatocopper(I)-Catalyzed
Substitution Reaction of Grignard Reagents with
Allylic Substrates
a
Gerrit J. Meuzelaar, A. So®a E. Karlstr oÈ m, Mayra van Klaveren, Eva S. M. Persson,
a
b
a
b
Amaya del Villar, Gerard van Koten and Jan-E. B aÈ ckvall
b,
a,
*
*
a
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Debye Institute, Department of Metal-Mediated Synthesis, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
b
Received 13 December 1999; accepted 10 January 2000
AbstractÐThe in¯uence of some experimental parameters on the regio- and enantioselectivity in the g-selective substitution reaction of
Grignard reagents RMgX with acyclic allylic acetates catalyzed by the arenethiolatocopper(I) complex (S)-1 was studied. When more bulky
arenethiolatocopper(I) complexes than (S)-1 were employed in a reaction of allylic acetate 3 with n-BuMgI, the enantioselectivities observed
for the g-product were lower. With an arenethiolatocopper(I) catalyst prepared in situ, several Grignard reagents were studied in a
substitution reaction with acetate 2. Compared to n-BuMgI, more bulky Grignard reagents gave no improvement of the enantioselectivity
in the formation of the g-product. q 2000 Elsevier Science Ltd. All rights reserved.
Metal-mediated carbon±carbon bond formation has become
a versatile synthetic methodology in contemporary organic
chemistry. Copper-catalyzed reactions constitute an
Although asymmetric induction in copper-promoted
Michael additions to a,b-unsaturated systems is quite well
1
7±9
established, the corresponding enantioselective versions
important class, and well-known examples include Michael
addition reactions and cross-coupling reactions of organo2-
metallic reagents with organic halides or allylic substrates.
The allylic substitution reaction has attracted much attention
and several methods have been developed for control of the
of organocopper-based allylic substitution reactions are less
developed. Asymmetric S 2 substitution of allylic
0
substrates with a chiral leaving group by organocuprates
N
1
has been reported but catalytic procedures employing
0
1
1,12
chiral ligands on copper are scarce.
In 1995, we
3
±6
regio- and stereochemistry in this type of reactions. The
leaving group can be displaced either in an a(S 2) or g
described the ®rst example on the use of a chiral copper(I)
complex as a catalyst in the cross-coupling of Grignard
reagents with allylic substrates. E.e.'s up to 42% were
N
0
11
(
S 2 ) fashion by the organometallic reagent (Scheme 1).
N
Scheme 1. Copper-catalyzed allylic substitution reactions.
Keywords: asymmetric induction; copper catalysis; allylic substitution; cross-coupling.
*
Corresponding authors. Tel.: 146-8-6747178; fax: 146-8-154908; e-mail: jeb@organ.su.se
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00145-9

2
896
G. J. Meuzelaar et al. / Tetrahedron 56 (2000) 2895±2903
Scheme 2. An asymmetric allylic substitution reaction catalyzed by a chiral arenethiolatocopper(I) complex.
1
2
Scheme 3. Copper(I)-catalyzed asymmetric allylic substitution reactions according to D uÈ bner and Knochel.
obtained in the reaction of allylic acetates with n-BuMgI
catalyzed by chiral arenethiolatocopper(I) complex (S)-1
prepared in situ from an arenethiol and a copper salt under
various conditions.
(
Scheme 2). Recently, chiral ferrocenyl amine ligands
were employed in copper-catalyzed enantioselective substi-
tution of allyl chlorides with diorganozinc compounds
Results and Discussion
1
2
(Scheme 3). The alkylated products were obtained in up
to 87% e.e. with good S 2 selectivity but the reaction is
0
limited to sterically hindered dialkylzinc reagents.
N
Reactions with preformed arenethiolatocopper(I)
complexes
1
1
In addition to our earlier work with (S)-1 as a catalyst, we
We started our investigations with arenethiolatocopper(I)
complex (S)-1 which was prepared from (2)-(S)-a-methyl-
now wish to report on a more detailed study of the
asymmetric cross-coupling reaction of Grignard reagents
R MgX with acyclic allylic substrates RCHvCHCH Y,
2
catalyzed by this type of copper complexes. We have further
investigated the experimental parameters for these
reactions. Various Grignard reagents R MgX have been
investigated in the allylic substitution reactions as well as
the in¯uence of different arenethiolato ligands in the
catalyst. We also include the results obtained with a catalyst
1
3
benzylamine according to a literature procedure. It was
previously shown that the regioselectivity of the reaction
between geranyl acetate and n-BuMgI catalyzed by an
achiral arenethiolatocopper(I) complex can be tuned to
either a or g substitution by variation of the reaction con-
0
0
1
4
ditions (Scheme 4). For the present study, using (S)-1, the
g-selective reaction conditions were chosen. Thus,
the reactions were performed in diethyl ether at 08C. The
Scheme 4. Selectivity for either the a- or g-product in an allylic substitution reaction of geranyl acetate by varying the reaction conditions: (i): Et
1
2
O, 08C,
20 min addition time of n-BuMgl, 100% g-product; (ii): THF, 2308C, 5 min addition time of n-BuMgl, 100% a-product.

G. J. Meuzelaar et al. / Tetrahedron 56 (2000) 2895±2903
Table 1. In¯uence of the addition method and the Grignard reagent (n.det.ˆnot detected)
2897
0
a
b
c
d
e
e
(8)
Entry
Substrate
R MgX
Mol% 1
AM
Yield (%)
a:g Ratio
E.e. of g (%)
[a]
D
1
2
3
4
5
6
7
8
9
2
2
2
2
2
2
3
3
3
4
n-BuMgI
n-BuMgI
15 (R)
100 (S)
15 (R)
15 (R)
14 (S)
20 (S)
13 (S)
15 (S)
13 (S)
15 (R)
A
A
A
A
C
C
A
B
C
A
100 (88)
100
(67)
0:100
0:100
0:100
0:100
0:100
0:100
0:100
0:100
0:100
0:100
41 (5)
45 (5)
50 (5)
53 (7)
42 (5)
41 (5)
34 (9)
18 (9)
30 (9)
28 (11)
24.5
14.8
24.9
n.det.
14.4
14.3
n.det.
n.det.
n.det.
210.5
f
g
n-BuMgBr
Me SiCH MgI
f
3
2
(30)
n-BuMgI
n-BuMgI
n-BuMgI
n-BuMgI
n-BuMgI
n-BuMgI
100
100
100
100
100
100
1
0
a
Amount of 1 based on monomeric copper units.
b
AMˆaddition method; Method A: The Grignard reagent (1.25 equiv.) was added to a solution of 1 and allylic substrate (1 equiv.) in diethyl ether at 08C.
Method B: The allylic acetate (1 equiv.) was added slowly to a solution of 1 and n-BuMgI (1.25 equiv.) in diethyl ether at 08C. Method C: The allylic
acetate and n-BuMgI were added separately within 120 min to a solution of 1 in diethyl ether at 08C.
c
1
Unless otherwise stated; substrate 2: yield of 5 determined by GC and H NMR. Substrate 3 or 4: yield of 9 or 11 determined by GC. Isolated yields in
parentheses.
a:g ratio determined by GC.
d
e
10a
E.e. of 5 determined by optical rotation ([a] ˆ29.4 corresponds to 88% e.e. of R-enantiomer ). E.e. of 9 determined by HPLC. E.e. of 7 and 11
D
determined by GC.
Only isolated yield was determined.
f
g
The e.e. was determined by GC. The e.e. determined by optical rotation was 46%. In all cases GC analysis gave somewhat higher e.e. values than obtained
by measuring the optical rotation.
in¯uence of some reaction parameters on the yield and
asymmetric induction of the g-product was then studied
with the use of allylic acetates 2, 3 and 4 (Table 1).
separately, at the same rate, to the reaction mixture (method
C). Methods A and C investigated with (E)-3-cyclohexyl-2-
4
d
propenylacetate (2) resulted in all cases in regioselective
formation of the g-product (Entries 1±6). Both methods
afforded g-product 5 with a signi®cant e.e., 42% e.e. with
method C and 41% e.e. with method A, respectively. The
e.e. obtained with method A could be improved to 45% by
using one equivalent of (S)-1 (Entry 2). When n-BuMgBr
was employed instead of n-BuMgI, the e.e. increased to
50% (Entry 3). The substitution reaction with the bulky
Me SiCH MgI gave g-product 7 with 53% e.e (Entry 4).
The order of addition of the Grignard reagent and the allylic
acetate has an in¯uence on the outcome of the reaction
(
Table 1). Three different addition methods were studied.
The Grignard reagent was added slowly (120 min) to a solu-
tion of the catalyst and the substrate (method A), or the
substrate was added slowly to a solution of the catalyst
and the Grignard reagent (method B). In a third addition
method the substrate and the Grignard reagent were added
3
2
However, the yield of 7 in the latter case was low due to
Figure 1. Reaction time vs. conversion of 3 and e.e. of 9.

2
898
G. J. Meuzelaar et al. / Tetrahedron 56 (2000) 2895±2903
Using addition method A, we followed the progress of the
reaction of 3 with n-BuMgI catalyzed by 15 mol% of
complex (S)-1. Samples of the reaction mixture were
collected at regular time intervals and the conversion of 3
and the e.e. of g-product 9 were determined. The results are
presented in Fig.1. At the beginning the reaction is slow and
only 1% conversion of 3 is obtained after 15 min. However,
after about 20 min, the reaction becomes faster and the
conversion then increases approximately linearly with
time. The reaction reaches completion after 120 min. The
e.e. of 9 increases from 22% after 60 min addition time, to
Figure 2. Proposed intermediate in arenethiolatocopper(I)-catalyzed
substitution reactions of allylic acetates.
2
8% after 120 min addition time. The results indicate that
incomplete conversion of 2. With (E)-1-acetoxy-4-phenoxy-
catalysis does not really start until at least one equivalent (or
may be even two equivalents) of the Grignard reagent is
present relative to the amount of catalyst, i.e. the key-
intermediate will at least have one molecule of Grignard
reagent bound per copper center. The allylic acetate will
then coordinate preferably with either the re or the si-face
of the double bond to give the earlier proposed catalytic
4
b,15
2
-butene (3)
g-product 9 with complete chemo- and regioselectivity
Entries 7±9). Methods A and C proved to be superior to
as substrate, all three methods afforded
(
method B which gave the same regioselectivity, but a lower
enantioselectivity (Entry 8). Since the results obtained with
methods A and C are almost equal, the experimentally
easier addition method A was used exclusively in the further
experiments.
1
1
intermediate (Fig. 2).
In order to investigate the in¯uence of the chiral ligand in
the copper-catalyzed allylic substitution reactions, different
arenethiolatocopper(I) complexes (Fig. 3) were prepared
and tested in the reaction of acetate 3 with n-BuMgI.
Complex 13 (tetramer) was prepared starting from
(1)-(R)-a-methylbenzylamine via monomethylation of the
Both substrates 2 and 3 gave the substitution product with
complete g-selectivity and a similar enantioselectivity. In
order to study the in¯uence of the substituent R in more
detail, we employed trans-cinnamyl acetate (4) as substrate.
Compounds of this type are of special interest since it is
known that a conjugated double bond in the allylic substrate
amine moiety followed by introducing the methoxy-arm
Complex 14 was
1
6
13c
favors formation of the a-product (S 2-substitution).
N
according to a literature procedure.
However, the reaction between 4 and n-BuMgI using
addition method A with 15 mol% of (R)-1 as catalyst
resulted in complete conversion to the g-substitution
product 3-phenyl-1-heptene (11) which was formed with
prepared starting from (1)-(R)-a-ethylbenzylamine (e.e.
90%), obtained by the enantioselective addition of diethyl
zinc to benzaldehyde followed by conversion of the hydroxyl
group into an amine function by standard methods. The
synthesis of complex 15 was performed in an analogous way
1
7
28% e.e.
Figure 3. Chiral arenethiolatocopper(I) complexes applied in asymmetric substitution reactions of 3.
Table 2. Substitution reactions of 3 catalyzed by different types of chiral arenethiolatocopper(I) complexes (method A: n-BuMgI (1.25 equiv.) added within
1
20 min to a solution of 3 (1 equiv.) and 15 mol% of copper(I) complex (based on monomeric copper units) in Et
2
O at 08C)
a
a
a
b
Entry
Cu-complex
Conversion (%)
Yield of 9110 (%)
a:g (10:9) Ratio
E.e. of 9 (%)
1
2
3
4
5
(S)-1
13
14
15
16
100
100
100
100
95
100
95
0:100
5:95
0:100
0:100
2:98
34
4
12
13
0
100
86
c
95
a
1
Conversion, yield and a:g ratio determined by GC and H NMR.
E.e. determined by HPLC.
Isolated yield after puri®cation by column chromatography.
b
c

G. J. Meuzelaar et al. / Tetrahedron 56 (2000) 2895±2903
2899
Figure 4. Structure of the ligands employed in the in situ preparation of arenethiolatocopper(I) catalysts.
as described for (S)-1.13c The intermediates were
synthesized in accordance with a literature procedure.
42% e.e., respectively). The presence of one equivalent of
lithium iodide seems to have no in¯uence on the outcome of
the reaction. An increase of temperature from 0 to 208C did
not change the enantioselectivity (Entry 2). The same effect
1
7b
The structure of 15 was determined by X-ray crystal-
lography and was found to consist of trimeric units.18 The
arenethiolatocopper(I) complex 16, with a chiral isopropyl
containing oxazoline moiety, was prepared according to a
1
1
was observed with the preformed catalyst. With two
equivalents of ligand, no signi®cant change of the e.e was
found (Entry 3), indicating that one ligand molecule is
strongly bound to the copper atom in the catalytic inter-
mediate. A control experiment with CuI as catalyst, in the
absence of ligand, gave an incomplete conversion of 2
(Entry 4). The g-selectivity was still high (a:gˆ5:95), but
beside the substitution products the alcohol 3-cyclohexyl-
(2E)-propenol, formed by attack of the Grignard reagent on
the ester carbonyl group, and other unidenti®ed products
were observed. This leads to the conclusion that the
arenethiolate ligand is necessary for a fast and ef®cient
g-selective substitution reaction.
1
9
literature procedure starting from (2)-(S)-valinol.
Table 2 shows the results obtained with these catalysts.
Whereas complex (S)-1 gave the g-product with complete
selectivity in 34% e.e. (Entry 1), complex 13 gave the
substitution product in an a:g ratio of 5:95 (10:9) with
only 4% e.e. for the g-product (Entry 2). Complex 14,
with an ethyl group at the chiral carbon center, gave a
selective formation of the g-product with an e.e. of 12%
(
Entry 3). Complex 15, with a pyrrolidine ring, also gave
a completely g-selective reaction. However, the e.e. of the
g-product was low (13%). The oxazoline substituted
arenethiolatocopper(I) catalyst 16 gave 95% conversion of
the substrate and the substitution product was formed with
an a:g ratio of 2:98 (10:9). However, the g-product was
found to be racemic. The results clearly show that all
investigated complexes give the substitution product with
high g-selectivity, but complexes 13±16 all give lower
asymmetric inductions than (S)-1 for the studied reaction.
We also investigated the in¯uence of the copper source on
the outcome of the substitution reaction. With CuCl and
Cu(OTf) the conversion of 2 was complete and only the
2
g-substitution product was formed (Entries 5 and 6). The
reaction with Cu(OTf) as copper source showed a lower
2
e.e. for the g-product. From this copper salt the active
copper(I) species is formed by in situ reduction by the
Grignard reagent. The fact that CuI and CuCl both result
in formation of the g-product with the same e.e. supports the
proposal that the lithium halide present in the reaction
mixture has no in¯uence on the outcome of the reaction.
Reactions with arenethiolatocopper(I) complexes
prepared in situ
The arenthiolatocopper(I) complexes described above are
highly air-sensitive compounds and are therefore not easy
to prepare, store and handle. We therefore turned to the
possibility of performing the allylic substitution reactions
with arenethiolatocopper(I) catalysts prepared in situ from
the corresponding arenethiols and a copper(I) source. This
approach has been reported earlier by Pfaltz and
co-workers. Thus, treatment of arenethiol 17 (Fig. 4)
with n-BuLi yields the lithium arenethiolate. Subsequent
reaction with a copper(I) source gives (R)-1. Addition of
the allylic substrate and a Grignard reagent to this reaction
mixture leads to the desired reaction. One difference to the
preformed catalyst system is that the in situ prepared
catalyst will contain one equivalent of lithium salt, which
could have an effect on the reaction. We have performed
various reactions of allylic substrates 2 and 4 using catalysts
prepared in situ to study the in¯uence of different experi-
mental parameters such as the copper source and the
Grignard reagent.
With CuBr´Me S the conversion and the e.e. of the
2
g-product were much lower (Entry 7). This is probably
caused by the coordinated dimethyl sul®de which hampers
formation of the catalytic intermediate (Fig. 2). Replace-
ment of the iodide in the Grignard reagent by bromide had
a negative in¯uence on the outcome of the substitution
reaction. With n-BuMgBr the reaction was not completely
g-selective and the e.e. of the g-product was lower (Entry
8). This is in contrast to the reaction with n-BuMgBr in the
presence of the preformed copper complex which gave the
g-product with 50% e.e. (Table 1). Replacement of CuI by
CuBr as copper source gave the g-product with a slightly
improved e.e. of 36% (Entry 9). We also investigated ligand
1
9
13b
1
7b
18
(Fig. 4) in the allylic substitution reaction of 2.
Preparation of a preformed copper(I) arenethiolate with
this ligand proved to be cumbersome. The catalyst prepared
from 18 and CuI gave complete conversion of 2 and the
reaction was g-selective. However, the e.e. observed for
the g-product was only 10% (Entry 10).
The reaction of 2 with n-BuMgI, using the catalyst
generated from 17 and CuI, resulted in selective formation
of the g-product (Table 3, Entry 1). The e.e. was almost the
same as that observed with the preformed catalyst (40 and
Ligand 19 (Fig. 4) was prepared from commercially avail-
able (1)-(R)-1-(1-naphthyl)ethylamine. The arenethiolato-
copper catalyst prepared from 19 gave complete conversion
of 2 in a reaction with n-BuMgI (Entry 11). The a:g ratio

2
900
G. J. Meuzelaar et al. / Tetrahedron 56 (2000) 2895±2903
Table 3. Substitution reactions of 2 and 4 catalyzed by arenethiolatocopper(I) complexes prepared in situ (unless otherwise stated the reactions were carried out
with a copper(I) complex prepared from arenethiol 17. The Grignard reagent (1.25 equiv.) was added within 120 min to a solution of the allylic acetate
(
2
1 equiv.) and 15 mol% of the copper(I) complex (prepared in situ) in Et O at 08C)
0
a
a
b
Entry
Substrate
R MgX
Copper salt
T (8C)
Conversion (%)
a:g Ratio
E.e. of g (%)
1
2
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
4
4
4
n-BuMgI
CuI
CuI
CuI
CuI
CuCl
Cu(OTf)
CuBr´Me
CuI
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
0
20
0
0
0
0
0
0
0
0
0
0
230
0
100
100
100
65
100
100
60
100
100
100
100
100
100
100
100
80
0:100
0:100
0:100
5:95
0:100
0:100
0:100
8:92
8:92
0:100
3:97
0:100
0:100
0:100
0:100
30:70
±
40
40
39
±
40
35
7
n-BuMgI
n-BuMgI
n-BuMgI
n-BuMgI
n-BuMgI
n-BuMgI
n-BuMgBr
n-BuMgBr
n-BuMgI
n-BuMgI
i-PrMgI
i-PrMgI
i-PrMgBr
Me SiCH
3
i-BuMgBr
PhMgI
n-BuMgI
i-PrMgI
i-PrMgBr
c
d
4
5
6
7
8
2
2
S
30
36
10
9
e
10
11
12
13
14
15
16
17
18
19
20
f
g
35
34
29
14
37
40
±
30
18
25
2
MgI
20
0
h
0
±
0
0
0
100
100
100
0:100
0:100
0:100
a
b
c
d
e
f
Conversion and a:g ratio determined by GC. Isolated yields at 100% conversion: 50±95%.
E.e. determined by GC.
Ligand to copper ratio 2:1.
No ligand added.
Ligand 18 was employed.
Ligand 19 was employed.
The (S)-enantiomer was formed in excess (see text).
No allylic substitution observed. A reaction performed at 208C gave no improvement.
g
h
was 3:97 and the e.e. of the g-product was 35%. Complex
R)-1 and the complexes prepared from (R)-17 or (R)-18
08C there was almost no conversion of 2. The reaction of
2 with PhMgI resulted in recovery of 2 and formation of
3-cyclohexyl-(2E)-propenol (Entry 17). This shows that a
copper(I) arenethiolato complex is not a suitable catalyst for
reactions with aryl Grignard reagents.
(
always gave (R)-5 in excess. However, the catalyst prepared
from (R)-19 gave (S)-5 in excess. The reason for this change
in enantioselectivity is at the moment not clear but further
investigations are underway. In this case a seven-membered
chelate would be formed instead of the six-membered
chelate formed from (R)-1 (cf. Fig. 2).
Finally, we studied some reactions of 4 with Grignard
reagents in the presence of the catalyst prepared in situ
from ligand 17 and CuI (Table 3, Entries 18±20). In all
cases the substitution reaction was completely g-selective.
Again the reaction with n-BuMgI gave the g-product with a
moderate e.e. (30%, Entry 18).
Since the substitution reactions with n-butylmagnesium
halides gave the g-product with only moderate enantioselec-
tivities we have investigated other, more bulky Grignard
reagents. Some results are included in Table 3. It is note-
worthy that the secondary Grignard reagents i-PrMgI and
1
8,19
i-PrMgBr can also be employed (Entries 12±14).
With
Conclusions
all Grignard reagents the g-selectivity was complete except
for the reaction with i-BuMgBr (Entry 16). However, the
enantioselectivities were always lower than found with the
n-butyl Grignard reagents. The bulky Me SiCH MgI gave
the g-product with an e.e. not higher than 37% (Entry 15)
which is substantially lower than the enantioselectivity
obtained with the preformed catalyst. The reaction with
this Grignard reagent had to be carried out at 208C. At
We have shown that the outcome of the asymmetric substi-
tution reaction of allylic acetates with Grignard reagents
catalyzed by a chiral arenethiolatocopper(I) catalyst
depends on the addition procedure of the reactants. Using
the most convenient addition method we followed the
progress of an allylic substitution reaction in time. At
least one equivalent of Grignard reagent relative to the
3
2

G. J. Meuzelaar et al. / Tetrahedron 56 (2000) 2895±2903
2901
1
amount of copper species is necessary to start the catalytic
reaction, which provides further support for our earlier
proposed structure of the catalytic intermediate. Varying
the chiral ligand in the catalysts showed that any group
larger than a methyl group on the amino function lowers
the chiral induction in the formation of the g-product.
Performing the reactions with an arenethiolatocopper(I)
catalyst prepared in situ was also possible. Different
Grignard reagents were investigated and it was shown that
reagents more bulky than n-BuMgI gave the g-products
with the same or with lower enantioselectivity. We are
currently investigating various other chiral nitrogen- and
sulfur-containing ligands in the copper-catalyzed
asymmetric substitution reaction of allylic acetates.
H NMR spectrum (CD OD) should be shifted 1.45 ppm
3
down®eld.
8-(1-Dimethylaminoethyl)-1-naphthalenethiol (19). (1)-
(R)-1-(1-Naphthyl)ethylamine (2 g, 11.7 mmol) was mixed
with formic acid (5 ml) at 08C. Formaldehyde (37% aq.,
5 ml) was added dropwise to the stirred reaction mixture.
The resulting solution was re¯uxed overnight (or until CO2-
evolution had ceased). The reaction mixture was acidi®ed
with conc. HCl (aq.) and washed with Et O (2£20 ml). The
2
aqueous phase was made alkaline with sat. NaOH (aq).
Extraction with Et O (3£50 ml) followed by drying over
2
Na SO and evaporation of the solvent in vacuo gave the
4
2
crude (R)-1-(1-naphthyl)ethyl-N-dimethylamine which was
puri®ed by bulb-to-bulb distillation (1508C, 1.5 mm Hg) to
1
9
yield 1.70 g (73%) of the pure product. [a] ˆ167.38
D
Experimental
(cˆ1.1 in CHCl ). Spectral data were in accordance with
3
2
those reported earlier. This amine (250 mg, 1.25 mmol)
1
General: Mass spectra were determined using a Thermo-
quest 2000A GC±MS with a Varian DB-5 column
was dissolved in dry Et O (5 ml) and t-BuLi (1.7 M in pen-
2
tane, 0.8 ml) was added dropwise at room temperature. The
clear red solution was stirred for 1 h and then added via
canula to a suspension of sublimed S (40 mg) in Et O
1
13
(
15 m£0.32 mm). H (300 MHz) and C (75 MHz) NMR
spectra were recorded using a Varian Mercury 300 spectro-
meter with CDCl as solvent using residual CHCl (7.26 and
8
2
3
3
(2 ml). The reaction mixture was stirred overnight. Conc.
HCl (aq., 105 ml) was added. After 10 min all volatiles were
removed in vacuo. The residue was dissolved in CH Cl and
77.0 ppm, respectively) as internal standard. The infrared
spectrum of 19 was recorded using a Perkin±Elmer Spec-
trum One spectrophotometer. The e.e. was determined
either with analytical HPLC using a Chiralcel OD-H column
2
2
®ltered through a short silica column. Crystallization from
CH Cl and Et O yielded 97 mg (33%) of 19 as pale yellow
2
2
2
(
9
eluent: 99±99.5% hexane, 0.5±1% 2-propanol, compound
) or GC using a CP-Chirasil-Dex CB column (708C
needle-shaped crystals which were washed with Et O and
2
1
8
dried in vacuo. [a] ˆ265.28 (cˆ0.99 in CHCl ).
D
3
1
isotherm). Optical rotations were measured using a
Perkin±Elmer 241 polarimeter at the sodium D line
(
was used for ¯ash column chromatography. TLC was
performed on deactivated silica (0.25 mm, Merck F254).
All reactions were run under a dry argon or nitrogen
atmosphere. Diethyl ether was dried over Na-benzophenone
prior to use. Grignard reagents were made according to
mpˆ1258C. H NMR: d 7.72 (dd, Jˆ8.0 Hz, 1.6 Hz, 1H),
7.62 (d, Jˆ8.6 Hz, 2H), 7.46 (d, Jˆ8.6 Hz, 1H), 7.40 (ddd,
Jˆ8.4, 6.8, 1.6 Hz, 1H), 7.26 (ddd, Jˆ7.9, 6.9, 1.0 Hz, 1H),
4.77 (q, Jˆ6.9 Hz, 1H), 2.76 (s, 6H), 1.91 (d, 6.9 Hz, 3 H9).
lˆ589 nm). Merck silica gel (Silica 60, 230±400 mesh)
1
3
C NMR: d 136.8, 131.4, 130.3, 129.0, 128.7, 126.8, 126.3,
125.1, 122.7, 118.4, 65.0, 40.5, 14.8. IR (CHCl ): 3018,
3
2
2952, 1614, 1589, 1476, 1220, 1210, 1080, 780 cm .
1
2
0
standard procedures and titrated before use. trans-
Cinnamyl acetate (4) was purchased from Lancaster and
used without further puri®cation. (1)-(R)-a-Methylbenzyl-
amine (e.e. 99%) was purchased from Acros. (1)-(R)-
Naphthylethylamine was purchased from Lancaster. (E)-3-
General procedure for the arenethiolatocopper(I)
catalyzed cross-coupling reactions with preformed
copper catalysts
Slow additions were carried out using a dropping funnel or a
syringe pump under an atmosphere of dry, oxygen-free
nitrogen.
4
d
Cyclohexyl-2-propenylacetate (2) and (E)-1-acetoxy-4-
were prepared according to
4
b,15
phenoxy-2-butene (3)
literature procedures. The spectral data were consistent
with those previously reported. The copper complexes
Addition method A. The required amount of (R)- or (S)-1
was dissolved in toluene (15 ml). The allylic substrate
(1 mmol), dissolved in Et O (15 ml), was added and the
2
1
3c
13c
17
13, 14, 15,
13c,17
19
and 16 and the arenethiols 17
13b
1
,
1
7b
and 18 were prepared according to literature procedures.
The NMR data of 1, 13, 16, 17 and 18 were consistent with
those reported in the references.
reaction mixture cooled to 08C. The Grignard reagent
(1.25 mmol) in Et O (100 ml) was added dropwise over
2
2 h. After complete addition, the reaction mixture was
stirred for another 30 min. The reaction mixture was
Synthesis of the arenethiol ligands
quenched with NH Cl and the internal standard n-dodecane
4
(
1
R)-(2-Piperidino)-2-ethyl-1-benzenethiol (18). Compound
8 was prepared according to Ref.17b, but a modi®ed work-
was added. A GC-sample was taken and the reaction
mixture was then extracted with Et O (6£25 ml) and the
2
up procedure was used. After addition of conc. HCl (aq.), all
volatiles were evaporated. The residue was dissolved in
CH Cl and ®ltrated through a short column of silica. The
solvent was evaporated in vacuo and the crude product was
crystallized from CH Cl by addition of Et O. The resulting
white needle-shaped crystals were washed with Et O and
combined organic layers were dried (MgSO ). The solvent
4
was evaporated in vacuo and the crude product was
puri®ed by ¯ash column chromatography with pentane as
eluent.
2
2
2
2
2
Addition method B. The required amount of (R)- or (S)-1
was dissolved in toluene (15 ml). The Grignard reagent
(1.25 mmol) was added to the catalyst and the reaction
2
dried in vacuo to yield 31% of 18. The NMR data were in
accordance with those reported except that all signals in the

2
902
G. J. Meuzelaar et al. / Tetrahedron 56 (2000) 2895±2903
rt
D
mixture was cooled to 08C. The allylic substrate (1 mmol),
dissolved in Et O (100 ml), was added dropwise over 2 h.
After complete addition, the reaction mixture was stirred for
another 30 min. The work-up procedure was the same as
described for method A.
An e.e. of 30% corresponds to [a] ˆ211.28 (cˆ1.25 in
CHCl ). The spectral data were in accordance with the
3
2
6
e
literature.
1
3-Cyclohexyl-4-methyl-1-pentene (20). H NMR: d 5.51
(
ddd, Jˆ17.0, 10.2, 7.1 Hz, 1H), 5.02 (dd, Jˆ10.3, 2.6 Hz,
Addition method C. The required amount of (R)- or (S)-1
was dissolved in toluene (15 ml) and the reaction mixture
was cooled to 08C. The Grignard reagent (1.25 mmol),
1H), 4.87 (m, Jˆ17.0, 2.5 Hz, 1H), 1.68 (m, 6H), 1.46 (m,
1H), 1.15 (m, 6H), 0.85 (d, 3H, Jˆ6.9 Hz), 0.78 (d, 3H,
1
3
Jˆ6.6 Hz). C NMR: d 139.25, 116.26, 57.18, 38.54,
dissolved in Et O (50 ml), and the allylic substrate
2
32.09, 30.19, 27.52, 27.14, 27.09, 27.02, 21.87, 21.40.
MS: 166 (M , 0.3), 138 (21), 123 (12), 95 (14), 81 (100),
67 (90), 55 (64).
1
(
1 mmol), dissolved in Et O (50 ml), were added separately
2
at the same time to the catalyst solution in 2 h. After
complete addition, the reaction mixture was stirred for
another 30 min. The work-up procedure was the same as
described for method A.
1
3-Cyclohexyl-5-methyl-1-hexene (22). H NMR: d 5.53
(ddd, Jˆ17.0, 10.0, 6.8 Hz, 1H), 4.96 (dd, Jˆ10.2, 2.2 Hz,
1
H), 4.90 (ddd, Jˆ17.0, 2.5, 0.8 Hz, 1H), 1.86 (m, 1H), 1.60
1
3
General procedures for the arenethiolatocopper(I) cat-
alyzed cross-coupling reactions with catalysts prepared
in situ
(m, 6H), 1.10 (m, 8H), 0.87 (d, Jˆ6.6 Hz, 6H). C NMR: d
141.65, 114.45, 47.76, 42.16, 41.17, 39.01, 33.36, 31.26,
29.68, 26.82, 26.35, 22.63, 21.55. MS: 180 (M , 0.1), 152
1
(
14), 124 (16), 96 (40), 81 (85), 67 (84), 55 (100).
Addition of the Grignard reagent was carried out using a
syringe pump under an atmosphere of dry, oxygen-free
argon.
3-Phenyl-4-methyl-1-pentene (24). The spectral data were
1
0d
in accordance with the literature. The e.e.'s obtained by
GC were in agreement with the e.e.'s obtained after com-
parison of the optical rotation with the literature value
The chiral arenethiol ligand (0.085 mmol) was dissolved in
Et O (45 ml) and the solution was cooled to 2788C. A
2
D
5
([a]
for (R)-24).
ˆ295.58 (cˆ1.5 in CHCl
) corresponds to 78% e.e.
3
2
1
0d
solution of n-BuLi in hexanes (1.6 M, 75 ml) was added
and the mixture was stirred for 10 min. The solution was
warmed to 08C and copper(I) iodide (0.085 mmol) was
added. (In an alternative procedure, which gave equal
results, the solution of the lithium arenethiolate was added
Acknowledgements
to a suspension of CuI in Et O.) The solution was stirred at
2
Financial support from the Netherlands Organization for
Scienti®c Research (NWO), the Royal Swedish Academy
of Sciences, The Swedish Foundation for Strategic Research
and the Swedish Natural Science Research Council is
gratefully acknowledged.
0
8C for another 30 min and then the allylic substrate
0.549 mmol), dissolved in Et O (5 ml), was added by
(
syringe. The Grignard reagent (1.25 equiv. of a solution in
2
Et O) was added dropwise over 2 h. After complete
2
addition, the reaction mixture was stirred for 1 h. The
reaction was quenched by adding a 2 M solution of HCl
(
10 ml). The organic layer was separated and the aqueous
layer was extracted three times with a 1:1 mixture of
pentane and ether. The combined organic layers were
washed with a saturated solution of NaCl and dried
(MgSO ). The substitution products were puri®ed by ¯ash
4
column chromatography with pentane as eluent.
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d
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3
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1
4b
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1
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9
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1
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1
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