Highly enantioselective Cu-catalysed asymmetric 1,4-addition of diphenylzinc to cyclohexenone

Article abstract of DOI:10.1039/b402868f

Highly enantioselective Cu-catalysed 1,4-addition of diphenylzinc to cyclohexenone has been achieved for the first time using a monodentate phosphoramidite ligand.

Full text of DOI:10.1039/b402868f

Highly enantioselective Cu-catalysed asymmetric 1,4-addition of
diphenylzinc to cyclohexenone†
Diego Peña, Fernando López, Syuzanna R. Harutyunyan, Adriaan J. Minnaard* and Ben L. Feringa*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands. E-mail: b.l.feringa@chem.rug.nl; Fax: (+31)
50-3634296; Tel: (+31) 50-3634278
Received (in Cambridge, UK) 26th February 2004, Accepted 23rd June 2004
First published as an Advance Article on the web 23rd July 2004
Highly enantioselective Cu-catalysed 1,4-addition of diph-
enylzinc to cyclohexenone has been achieved for the first time
using a monodentate phosphoramidite ligand.
using Cu(OTf)2 (1 mol%) and ligand (S,R,R)-1 (2 mol%) at 230 °C
in toluene. Surprisingly, when the reaction was carried out under
the same experimental conditions but with ZnPh2 in the absence of
ZnMe2, a major improvement in the enantioselectivity was found,
affording 6 with a promising 76% ee (entry 1, Table 1).
The metal-catalysed enantioselective conjugate addition of organo-
metallic reagents is a widely used method for C–C bond formation
in asymmetric synthesis.1 In particular, during the last decade
considerable progress has been made in the copper-catalysed
asymmetric 1,4-addition of organozinc compounds to enones.2 This
has led to well established protocols for the highly enantioselective
addition of (functionalised) dialkylzinc reagents to a wide variety of
unsaturated systems. As a common view in the field, only
dialkylzinc reagents can be effectively used in this enantioselective
reaction. Despite the fact that diphenylzinc is known to undergo the
non-asymmetric copper-catalysed conjugate addition,3 to the best
of our knowledge no highly enantioselective version of the arylzinc
addition has been reported. This severe limitation has been
compensated by the development of the Rh-catalysed asymmetric
1,4-addition of aryl boronic acids to enones.4 This reaction allows
the enantioselective transfer of aryl and vinyl groups, but not of
alkyl groups, to the beta-position of an a,b-unsaturated carbonyl
compound.4,5 Nevertheless, the enantioselective copper-catalysed
transfer of aryl groups remains an important goal, if only because of
the difference in cost between copper and rhodium. Recently,
Reiser et al. disclosed the first example of an asymmetric phenyl
transfer to cyclohexenone using diphenylzinc as a reagent.6 With a
bisoxazoline-based copper catalyst no reaction was found using
pure diphenylzinc, whereas a 1 : 3 mixture of diphenyl- and
dimethylzinc afforded exclusively the 1,4-phenylated product with
74% ee.7
To our delight we found that by optimization of the reaction
temperature (entries 1–3), we could obtain the corresponding
1,4-addition product (S)-6 with an excellent 94% ee (entry 3) at
260 °C! As far as we know, this is the highest enantioselectivity
ever reported for an asymmetric phenyl transfer in a Cu-catalyzed
conjugate addition.
In order to study a possible matched–mismatched effect in ligand
1, we performed the reaction using ligand (R,R,R)-1, which led to
(R)-6 with 83% ee (entry 4). Therefore, in analogy with the
1,4-addition of diethylzinc to cyclohexenone,8 the matched–
mismatched effect was found to be relatively small and the absolute
configuration of the product depends on the configuration of the
BINOL moiety (compare entries 3 and 4). The use of monop-
hosphoramidites 2–4 as chiral ligands in this asymmetric conjugate
addition led to a drastic decrease in both the conversion and the
enantioselectivity (entries 5–7). Usually, biphenyl was detected as
byproduct of the reaction and/or as result of the work-up and
decomposition of the excess of ZnPh2.9 Moreover, at temperatures
below 0 °C the conjugate addition turned out to be especially
sensitive and in some cases the reaction did not run to completion.10
Using ligand (S,R,R)-1, this undesirable early termination of the
reaction was avoided by carefully performing the reaction under
rigorous water and oxygen free conditions.11
In order to explore the reaction further and since pure diarylzinc
reagents are not always easily available, we next studied the use of
in situ prepared ZnPh2 in this enantioselective conjugate addition of
phenyl groups (Table 2). Remarkably, under the previously
established experimental conditions, the use of diphenylzinc
prepared from the corresponding lithium or Grignard reagent by
Encouraged by these findings we decided to use this approach for
the phenyl transfer to enones using monodentate phosphoramidite
ligands (Fig. 1). This class of ligands affords excellent enantiose-
lection in the Cu-catalysed conjugate addition of dialkylzinc
reagents to enones.2 3-Phenylcyclohexanone (6, Scheme 1) was
selectively obtained in less than three hours with 36% ee from
cyclohexenone and a mixture of diphenyl- and dimethylzinc (1 : 1),
Scheme 1 Copper-catalysed asymmetric conjugate addition of diphenylzinc
to cyclohexenone 5.
Table 1 Ee’s obtained with monophosphoramidite ligands 1–4a
Temp.
(°C)
Conv.
Time (h) (%)b
Conf-
6c
Entry Ligand
ee (%)b
1
2
3
4
5
6
7
(S,R,R)-1
(S,R,R)-1
(S,R,R)-1
230
0
260
3
1
100
100
100
50
5
24
76
73
94
83
2
S
S
S
R
S
R
S
16
16
16
16
16
(R,R,R)-1 260
(S,R)-2
(S,R)-3
(S)-4
260
260
260
11
24
13
Fig. 1 Monodentate phosphoramidite ligands.
a See Scheme 1. Reactions were performed in toluene, using 1.5 equiv of
ZnPh2. b Determined by GC analysis with Chiraldex A-TA column.
c Determined by comparison of the optical rotation with literature values.
† Electronic supplementary information (ESI) available: experimental and
chromatographic details. See http://www.rsc.org/suppdata/cc/b4/b402868f/
1836
C h e m . C o m m u n . , 2 0 0 4 , 1 8 3 6 – 1 8 3 7
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

a
Table 2 Ee’s obtained of (S)-6 using in situ prepared ZnPh2
Entry
in situ “ZnPh2”
Temp. (°C) Conv. (%)b ee (%)b
1
PhLi + ZnCl2
PhLi + ZnCl2
PhMgBr + ZnCl2
PhMgBr + ZnCl2
Ph3B + ZnEt2
260
260
260
260
0
44
25
18
12
100
100
< 2
42
< 2
78
71
65
2c
3
4c
5
6
PhB(OH)2 + ZnEt2
0
a See Scheme 1. Reactions were performed using 1.5 equiv of “ZnPh2”, 1
mol% of Cu(OTf)2 and 2 mol% of ligand (S,R,R)-1 in toluene for 16 h.
b Determined by GC analysis with Chiraldex A-TA column. c LiCl and
MgX2 were partially removed by filtration. See ESI for details.
Scheme 2 Cu-catalysed asymmetric conjugate addition of PhMgBr to 5.
cyclohexenone with 94% ee and full conversion, using a mono-
dentate phosphoramidite ligand. This copper-catalysed asymmetric
arylation provides the basis for an important alternative to current
rhodium-catalysed arylations. The possibility of using aryl boronic
acids as reagents followed by a boron-to-zinc exchange protocol
considerably adds to the value of this asymmetric conjugate
addition.
D. P. thanks the European Community (IHP Program) for the
award of a Marie Curie Fellowship (Contract HPMF-CT-
2002-01612). F. L. thanks the Spanish M. E. C. for a postdoctoral
fellowship.
transmetallation with ZnCl2 afforded the 1,4-addition product 6 as
a racemic mixture (entries 1 and 3). The presence of inorganic salts
(LiCl or MgX2) is presumed to be the cause of this lack of
enantioselection. In fact, moderate enantioselectivities (42–78%
ee) were obtained when the corresponding salts were partially
removed by filtration after the transmetallation process (entries 2
and 4).
In order to circumvent this problem we examined methods for
preparing salt-free diphenylzinc. Among those, boron-to-zinc
exchange procedures are promising since byproducts can fre-
quently be removed by evaporation. In particular, we prepared
diphenylzinc in situ by reaction of triphenylborane and die-
thylzinc.12 This transmetallation proceeded at room temperature in
less than 1 h, and the subsequently formed BEt3 was easily removed
from the reaction mixture under vacuum. The use of ZnPh2
generated in this way led to full conversion and 71% ee in the Cu-
catalysed 1,4-addition to cyclohexenone using (S,R,R)-1 at 0 °C
(entry 5). Remarkably, this promising enantioselectivity is similar
to the one obtained using pure diphenylzinc at that temperature
(73% ee, entry 2, Table 1). Unfortunately, it was not possible to
enhance the enantioselectivity with the boron-to-zinc exchange
methodology since reactions tested at lower temperatures led to
poor conversions.
A similar version of this transmetallation, based on the use of
readily available phenylboronic acid instead of triphenylborane has
been reported recently by Bolm and Rudolph in the asymmetric aryl
transfer reaction to aldehydes.13 Therefore, we tested this protocol
in the Cu-catalyzed enantioselective conjugate addition. Although
the transmetallation was performed under more drastic conditions
(60 °C, 12 h in toluene) we obtained full conversion and a
reasonable enantioselectivity in the subsequent asymmetric con-
jugate addition to cyclohexenone (65% ee, entry 6). Finally, the
conjugate addition of phenylmagnesium bromide was studied, as
the use of readily accessible aryl Grignard reagents provides a
highly attractive alternative to the zinc- or boron-based reagents.
Unfortunately, the phosphoramidite based copper catalyst did not
yield significant ee’s in the conjugate addition of PhMgBr to 5
(Scheme 1). On the contrary, satisfactory results were found
employing the recently introduced ferrocenyldiphosphine-copper
catalyst.14 Using JosiPhos 7 as the ligand in Et2O a regioselectivity
of 77 : 23 and ee of 44% could be reached (Scheme 2). Changing
the solvent to tBuOMe an excellent regioselectivity 90 : 10 and high
ee of 70% were found. Although ee’s have to be optimized further,
this promising methodology opens the possibility of replacing
precious Rh catalysts with cheap Cu complexes in the asymmetric
aryl transfer to enones.4
Notes and references
1 (a) K. Tomioka and Y. Nagaoka, in Comprehensive Asymmetric
Catalysis, eds. E. N. Jacobsen, A. Pfaltz and H. Yamamoto, Springer-
Verlag, Berlin/Heidelberg, 1999, vol. 3, chapter 31.1; (b) N. Krause and
A. Hoffmann-Röder, Synthesis, 2001, 171.
2 (a) B. L. Feringa, Acc. Chem. Res., 2000, 33, 346; (b) B. L. Feringa, R.
Naasz, R. Imbos and L. A. Arnold, in Modern Organocopper
Chemistry, eds. N. Krause, Wiley-VCH, Weinheim, 2002, chapter 7; (c)
A. Alexakis and C. Benhaim, Eur. J. Org. Chem., 2002, 3221.
3 M. Kitamura, T. Miki, K. Nakano and R. Noyori, Tetrahedron Lett.,
1996, 37, 5141.
4 (a) T. Hayashi and K. Yamasaki, Chem. Rev., 2003, 103, 2829; (b) R.
Itooka, Y. Iguchi and N. Miyaura, J. Org. Chem., 2003, 68, 6000; (c) J.-
G. Boiteau, A. J. Minnaard and B. L. Feringa, J. Org. Chem., 2003, 68,
9481.
5 (a) For a recent review on catalysed asymmetric arylation reactions, see:
C. Bolm, J. P. Hildebrand, K. Muñiz and N. Hermanns, Angew. Chem.,
Int. Ed., 2001, 40, 3284; (b) M. Pucheault, S. Darses and J. P. Genet,
Eur. J. Org. Chem., 2002, 21, 3552.
6 M. Schinnerl, M. Seitz, A. Kaiser and O. Reiser, Org. Lett., 2001, 3,
4259; M. Schinnerl, M. Seitz, A. Kaiser and O. Reiser, Org. Lett., 2002,
3, 471.
7 It is presumed that methylphenylzinc is formed in equilibrium with
diphenylzinc and dimethylzinc. Apparently, the phenyl group is
selectively transferred from that mixed zinc species. For the previous
use of this concept in the asymmetric addition of diphenylzinc to
aldehydes, see: (a) C. Bolm, N. Hermanns, J. P. Hildebrand and K.
Muñiz, Angew. Chem., Int. Ed., 2001, 40, 3284; (b) J. Rudolph, T.
Rasmussen, C. Bolm and P.-O. Norrby, Angew. Chem., Int. Ed., 2003,
42, 3002.
8 B. L. Feringa, M. Pineschi, L. A. Arnold, R. Imbos and A. H. M. de
Vries, Angew. Chem., Int. Ed., 1997, 36, 2620.
9 It is known that biphenyl can be easily obtained from diphenylzinc. See
for example: S. Hilpert and G. Grüttner, Chem. Ber., 1913, 46, 1675.
10 For instance, this occurs if samples were taken during the course of the
reaction or if the solvent (toluene) was not freshly distilled from sodium
under nitrogen and subsequently deoxygenated.
11 See Electronic Supplementary Information for details.
12 M. Rottländer, N. Palmer and P. Knochel, Synlett, 1996, 573.
13 C. Bolm and J. Rudolph, J. Am. Chem. Soc., 2002, 124, 14850.
14 B. L. Feringa, R. Badorrey, D. Peña, S. R. Harutyunyan and A. J.
Minnaard, Proc. Natl. Acad. Sci. USA, 2004, 101, 5834.
In conclusion, highly enantioselective copper-catalysed con-
jugate addition to enones is no longer limited to the use of
dialkylzinc reagents, since a phenyl group can also be transferred to
C h e m . C o m m u n . , 2 0 0 4 , 1 8 3 6 – 1 8 3 7
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