Asymmetric Negishi reaction for sterically hindered couplings: synthesis of chiral binaphthalenes

Article abstract of DOI:10.1016/j.tetasy.2006.10.008

A new synthetic approach affording, for the first time chiral binaphthalene derivatives via an asymmetric Negishi reaction, in good yields (55-95%) and good enantioselectivities (49-85% ee), is reported.

Full text of DOI:10.1016/j.tetasy.2006.10.008

Tetrahedron: Asymmetry 17 (2006) 2593–2595
Asymmetric Negishi reaction for sterically hindered
couplings: synthesis of chiral binaphthalenes
*
Miroslav Genov, Beatriz Fuentes, Pablo Espinet and Beatriz Pelaz
Qu ı´ mica Inorg a´ nica, Facultad de Ciencias, Universidad de Valladolid, 47071 Valladolid, Spain
Received 8 August 2006; accepted 5 October 2006
Abstract—A new synthetic approach affording, for the first time chiral binaphthalene derivatives via an asymmetric Negishi reaction, in
good yields (55–95%) and good enantioselectivities (49–85% ee), is reported.
ꢀ
2006 Elsevier Ltd. All rights reserved.
1
. Introduction
Pd(4-6)/L*(7)
R
+
R
R'
Chiral binaphthalenes are amongst the most useful chiral
ligands and auxiliaries employed in asymmetric synthe-
2
R'
Br
Zn
1
–3
sis.
Although the Stille and Suzuki–Miyaura reactions
are very efficient for aryl–aryl carbon bond formation,
sterically congested coupling partners (such as naphthyls)
have the problems of poor yields and extensive deborona-
tion in the Suzuki couplings. The naphthyl–naphthyl
coupling using organozinc compounds as nucleophiles
1a: R = Me
2a: R' = Me
3a: R = R' = Me
1
1
1
b: R = OBn
2b: R' = OBn
2c: R' = OMe
3b: R = R' = OBn
3c: R = R' = OMe
3d: R = H; R' = Me
c: R = OMe
d: R = H
(
Negishi reaction) is a possible alternative to overcome
4
3e: R = OBn; R' = OMe
this problem, but has not yet been explored. However,
there are interesting precedents. For non-enantioselective
couplings, Dai and Fu have developed a general method-
ology for the coupling of sterically hindered unactivated
Pd source:
5
Fe
NMe2
PPh2
aryl chlorides with Pd catalysts, and Milne and Buch-
4: Pd dba ·CHCl
3
L* =
2
3
wald have reported a very efficient new catalytic system
5: [(MeCN) Pd](BF )
4
4 2
6
for the preparation of hindered biaryls. Very recently,
6
: Pd(OAc)2
7, (R,Sp)-(-)-PFNMe
asymmetric Negishi couplings involving secondary a-
bromo amides and secondary benzylic halides have been
reported by Fu et al. using chiral (i-Pr)-Pybox/Ni
Scheme 1.
7
,8
catalyst.
The results are shown in Table 1. The reaction conditions
chosen were those giving the best results in our previous
studies with Suzuki–Miyaura reactions. After some preli-
minary experiments, we discovered that a fairly simple
and easily accessible chiral ligand, the ferrocenyl mono-
Herein we report our studies on the first Pd catalyzed syn-
thesis of chiral binaphthalenes by an asymmetric Negishi
reaction (Scheme 1), as an example of an enantioselective
coupling of extended, sterically demanding aromatic sys-
tems (such as substituted 1-halonaphthalenes and substi-
tuted naphthylzinc compounds) under Negishi conditions.
9
phosphine ligand (R,S )-(2-diphenylphosphino-ferrocen-
P
yl)-ethyldimethylamine ((R,S )-(ꢀ)-PFNMe) 7, which is
P
easily available from commercial (R)-(+)-N,N-dimethyl-1-
1
0
*
Corresponding author. Tel.: +34 983423231; fax: +34 983423013;
e-mail: espinet@qi.uva.es
ferrocenylethylamine, performed better than other more
sophisticated and expensive phosphine ligands.
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.10.008

2594
M. Genov et al. / Tetrahedron: Asymmetry 17 (2006) 2593–2595
a
Table 1. Results from the asymmetric Negishi couplings
b
c
Entry
Bromide 1
Reagent 2
Product 3
Pd source
Temperature (ꢁC)
Time (h)
Yield (%)
ee (%) (conf.)
1
2
3
4
5
6
7
8
1a
1a
1b
1b
1c
1c
1d
1b
2a
2a
2b
2b
2c
2c
2a
2c
3a
3a
3b
3b
3c
3c
3d
3e
4
5
6
4
6
4
4
4
60
60
50
50
50
50
60
60
24
24
96
96
48
24
72
72
95
95
60
65
70
70
95
55
85 (S)
85 (S)
53 (S)
66 (S)
49 (S)
54 (S)
62 (S)
60 (n/a)
a
All reactions were carried out in THF (12.5 ml per 1 mmol of 1); ratio bromide (1)/zinc compound (2) = 1/1.5; 5 mol % Pd and 20 mol % ligand were
applied.
b
c
Isolated yield after column chromatography.
Determined by specific rotation
13–15
9
and HPLC measurements.
2
. Results and discussion
pling partners which, in our examples, is determined by
the substituent at the a-position of the Br or B atom respec-
tively of 1 and 2. Compound 3d (Table 1, entry 7) has been
synthesized with equal enantioselectivity but much better
Naphthyl bromides used were obtained commercially 1a or
were synthesized according to literature procedures 1b and
c. The bis(naphthalen-1-yl)zinc compounds 2a–c were
1
1
13
1
yield than with the corresponding Suzuki reaction.
obtained from the corresponding lithium compounds by
1
2
a modified literature procedure, treating the correspond-
ing lithium organometallic derivative with ZnCl solution
2
3
. Conclusion
in THF followed by filtration. The zinc compounds
obtained were used as THF solutions in the coupling
reactions.
In conclusion we have reported the first synthesis of chiral
binaphthalene derivatives using an enantioselective Negishi
cross-coupling reaction. This method is superior to the
Suzuki equivalent. The protocol is extremely efficient
affording up to 85% enantioselectivity and 95% yield
The reactions proceeded smoothly in THF under anhy-
drous conditions at moderate temperatures (50 and
60 ꢁC). As palladium sources Pd(0) (4) and Pd(II) (5 and
6) species were used. Applying the Pd catalysts 4–6 in
5 mol % and ligand 7 in 20 mol % we hoped to achieve a
0
in the synthesis of 2,2-dimethyl-1,1 -binaphthalene 3a.
Moreover, preliminary results show that these reaction
conditions can be applied to the efficient enantioselective
synthesis of a wider range of other naphthalene derivatives,
either with 7 or chiral ferrocenyl monophosphine ligands
with a similar structure. Looking at the trend of the yields
and enantioselectivities observed in Table 1, these results
may be even better for binaphthyl derivatives with some-
what bulkier substituents. These studies are currently in
progress in our laboratory.
high enantiomeric excess. Very good results were obtained,
especially for the couplings of 1a with 2a. (Table 1, entries
1
and 2). Compared to the results of the corresponding Su-
9
zuki reaction, the couplings reported herein proceeded
with better yields (almost quantitative), equal enantioselec-
tivities, and in remarkably shorter reaction times (24 h).
The same results were obtained with Pd
2
dba
3
ꢁ CHCl
3
4
or with [Pd(NCMe) ](BF ) 5. The coupling of 1b with 2b
4
4 2
proceeded with lower yields and enantioselectivities, but
using 4 instead of Pd(OAc) 6 increased the enantioselectiv-
ity (Table 1, entry 3 vs 4). Similar results were found for the
2
Acknowledgements
coupling of 1c with 2c, however, for shorter reaction times
This work was supported by the Direcci o´ n General de
Investigaci o´ n (MEC, Grant no. CTQ2004–07667), the pro-
gram Consolider Ingenio 2010 (Grant CSD2006-0003) and
the Junta de Castilla y Le o´ n (Project VA060/03). A Marie
Curie fellowship to M.G. (HPMD-CT-2000-00058) is also
gratefully acknowledged.
(
Table 1, entry 5 vs 6). The enantioselectivity observed in
the reactions decreased in the order Me > OBn > OMe
and appears to depend on the steric demand of the cou-
Typical procedure for the Negishi coupling reactions (see Table 1 and
Scheme 1): In a flame dried 50 ml Schlenk flask with a Young’s tap and
Teflon stirring bar were introduced 0.16 mmol of the desired bromide
1a–c, the palladium source 4–6 (0.008 mmol Pd), and the chiral ligand 7
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