Enantioselective rhodium-catalysed 1,4-additions of 2-heteroarylzinc donors using Me-DUPHOS

Article abstract of DOI:10.1039/b806098c

The enantioselective 1,4-addition of 2-(substituted)thienylzinc and 2-furanylzinc reagents has been achieved (up to 99: 1 er) using a complex derived from [Rh(C₂H₄)₂Cl]₂ and Me-DUPHOS. The Royal Society of Chemistry.

Full text of DOI:10.1039/b806098c

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Enantioselective rhodium-catalysed 1,4-additions of 2-heteroarylzinc
donors using Me-DUPHOSw
ˆ
Jerome Le Notre, Joseph C. Allen and Christopher G. Frost*
ˆ
´
Received (in Cambridge, UK) 10th April 2008, Accepted 7th May 2008
First published as an Advance Article on the web 23rd June 2008
DOI: 10.1039/b806098c
The enantioselective 1,4-addition of 2-(substituted)thienylzinc
and 2-furanylzinc reagents has been achieved (up to 99 : 1 er)
therefore decided to examine 2-heteroarylzinc donors (avail-
able as commercially available solutions or prepared by
using
a complex derived from [Rh(C2H4)2Cl]2 and Me-
directed metallation–zincation).w
DUPHOS.
At the outset we examined the addition of the thienylzinc
reagent 2a to cyclohexenone 1, as shown in Scheme 1. In the
absence of any additives, the reaction resulted in a complex
mixture including oligomeric products from subsequent con-
jugate additions of the intermediate zinc enolate. The intro-
duction of chlorotrimethylsilane (1.5 equivalents) in the
reaction mixture suppressed the tandem conjugate addition
reactions by forming a more stable enolate and side reactions
are avoided.8 The product 3a was obtained in high isolated
yield. Interestingly, Woodward et al. have reported a detailed
study of a related cascade process that occurs in the copper-
catalysed addition of alkylzinc reagents to cyclohexenone.9
With the conjugate addition of 2a demonstrated in good
yield, we immediately initiated work on developing an enan-
tioselective reaction (selected results shown in Table 1). A
number of enantiopure ligands were identified that afforded
product 3b with good enantioselectivity, including (R)-BINAP
(93 : 7 er) and (S)-SYNPHOS (17 : 83 er). The optimal ligands
turned out to be Carreira’s (R,R,R)-DOLEFIN ligands (up to
98 : 2 er) and (R,R)-Me-DUPHOS (up to 98 : 2 er) with (R,R)-
Me-DUPHOS providing higher isolated yields of products
(Table 1, entry 11). Remarkably, the addition of 2-thienylzinc
bromide afforded product with excellent enantioselectivity
(98 : 2 er) in the presence of [Rh(C2H4)2Cl]2 and (R,R)-Me-
DUPHOS despite there being a significant conversion to
product (41%, Table 1, entry 1) in the absence of the rhodium
catalyst.10 Preliminary kinetic studies have revealed that the
catalytic reaction stalls after one hour suggesting some catalyst
decomposition to inactive species over longer reaction times
(Table 1, entries 12–16). The addition of extra [Rh(C2H4)2Cl]2
(2 mol%) and (R,R)-Me-DUPHOS (2.2 mol%) after one hour
led to an increased conversion to product of 86% after three
hours. The observed enantioselectivity remained constant over
time with (R,R)-Me-DUPHOS affording predominantly the
The transition-metal catalysed conjugate addition of organo-
metallics to activated alkenes is an important tool for organic
synthesis.1 For the addition of aryl and alkenyl groups, the
elegant rhodium-catalysed addition of organoboron reagents
to a,b-unsaturated carbonyl acceptors, pioneered by Hayashi
and Miyaura, offers high enantioselectivities in a predictable
fashion.2 In each case, the sense of asymmetric induction can
be reliably predicted by means of simple stereochemical mod-
els when using enantiopure BINAP (or related ligands).3 The
process hinges on an efficient transmetallation to rhodium
followed by carbometallation to afford an Z3-oxa-p-allylrho-
dium complex that is protonated to afford the product. A
significant side-reaction is the protodeboronation pathway
that necessitates the use of two to five equivalents of the
organoboron donor to achieve satisfactory yields of product.4
Other organometallics are known to participate in the key
transmetallation to rhodium and are becoming more widely-
used in enantioselective synthesis (notably arylzinc reagents
and arylsiloxanes).5 More recently, the palladium-catalysed
addition of arylboronic acids and arylsiloxanes has emerged as
a practical alternative.6
Despite the advances in catalyst design and substrate
(acceptor) diversity, the structure of the donor remains sur-
prisingly limited to aryl and a small number of alkenyl
derivatives (alkyl organometallics are not currently viable
donors as the rhodium alkyl complexes are kinetically unstable
and rapidly undergo b-hydride elimination). A conspicuous
limitation is the general application of heteroaromatic donors
and particularly 2-heteroaryl donors in the rhodium-catalysed
addition reaction. Our initial experiments with 2-heteroaryl-
boronic acids under the standard aqueous conditions returned
the protonated heteroarene as the major product.7 It appeared
the rate of protodeboronation is significantly faster than the
rate of carbometallation and this undesirable pathway pre-
dominates. As organozinc reagents do not require water for
catalyst turnover and transmetallate at room temperature, we
Department of Chemistry, University of Bath, Claverton Down, Bath,
UK BA2 7AY. E-mail: c.g.frost@bath.ac.uk; Fax: 44 01225 386231;
Tel: 44 01225 386142
w Electronic supplementary information (ESI) available: Experimental
details and compound characterisations. See DOI: 10.1039/b806098c
Scheme 1
ꢀc
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Chem. Commun., 2008, 3795–3797 | 3795

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Table 1 Developing an enantioselective processa
Entry
Ligandb
Temp./1C
Time/h
Conversion (yield%)c
Er 3bd (R : S)
1e
2
3
4
5
6
7
8
—
(R)-DIOP
(R)-BINAP
RT
50
50
50
50
50
35
RT
RT
RT
RT
RT
RT
RT
RT
16
4
4
4
4
41
1 : 1
33 (26)
89 (70)
30 (22)
499 (80)
44 (36)
50 (41)
78 (71)
33 (33)
35 (32)
76 (71)
38
55 : 45
93 : 7
17 : 83
93 : 7
97 : 3
91 : 9
98 : 2
98 : 2
3 : 97
98 : 2
95.5 : 4.5
96 : 4
97 : 3
96.5 : 3.5
(S)-SYNPHOS
(R,R,R)-DOLEFINf
(R,R)-Me-DUPHOS
(R,R)-iPr-DUPHOS
(R,R)-Me-DUPHOS
(R,R,R)-DOLEFIN
(S,S,S)-DOLEFIN
(R,R)-Me-DUPHOS
(R,R)-Me-DUPHOS
(R,R)-Me-DUPHOS
(R,R)-Me-DUPHOS
(R,R)-Me-DUPHOS
4
16
16
16
16
4
0.5
1
4
9
10
11g
12h
13h
15h
16h
a
61
65
67
8
Reaction conditions: 1 (1.0 equiv.), 2b (0.5 M in THF, 1.5 equiv.), chlorotrimethylsilane (1.5 equiv.), [Rh(C2H4)2Cl]2 (3 mol%), ligand
b
(3.6 mol%) in THF (1 ml). Ligand structures shown in ESI. Isolated yields after column chromatography. Determined by HPLC analysis
c
d
using Chiralcel OJ column, hexane : iPrOH = 98 : 2, flow rate 1.0 ml minꢁ1
.
e
f
No catalyst or ligand added. (1R,4R,8R)-5-Benzyl-8-methoxy-1,8-
g
h
dimethyl-2-(20-methylpropyl)bicyclo[2.2.2]octa-2,5-diene. [Rh(C2H4)2Cl]2 (5 mol%), ligand (6 mol%). Kinetic study.
(R)-enantiomer of product 3b. The sense of asymmetric
induction is the same as with (R)-BINAP and implies steric
blocking of the upper left and bottom right quadrants by the
methyl substituents leading to a-Re-face coordination of
cyclohexenone to rhodium as shown in Scheme 2.
selectivity compared to 2-thienylzinc bromide, particularly in
the case of 5d. This may indicate that secondary interactions
between the sulfur donor and either zinc or another rhodium
complex is important in dictating the transition state leading
to high enantioselectivity.12
Following the success of the initial experiments, the scope of
the 2-thienylzinc donor and the acceptor was investigated to
establish the versatility of the reaction (Scheme 3). In the
addition to cyclohexenone, a selection of donors were found to
provide products with good enantioselectivities (3a–3d). In the
addition to cyclopentenone, the addition of 2b afforded pro-
duct 4b with low enantioselectivity (63 : 37 er).11 However, in
the absence of catalyst, a quantitative conversion to product
was noted with this substrate. Clearly, the rate of the enantio-
selective carbometallation, the rate of the background addi-
tion reaction and the rate of catalyst decomposition are
intimately linked to the overall enantioselectivity obtained.
An attractive solution was to switch to a less reactive substrate
that did not undergo the addition reaction in the absence of a
catalyst. A suitable acceptor was the cyclic lactone 5,6-
dihydro-2H-pyran-2-one; pleasingly this was found to under-
go highly enantioselective additions of 2-heteroarylzinc donors
(5a, 5b, 5c and 5e up to 99 : 1 er). The use of 3-thienylzinc
bromide as the donor resulted in appreciably lower enantio-
To extend the utility of this method, we have explored the
use of 2-furanylzinc reagents in the addition reaction. Using
Scheme 2
Scheme 3
ꢀc
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Scheme 4
the established conditions, the products 3f and 5f were
obtained in reasonable yields and good enantioselectivities
(Scheme 4). To our knowledge, these are the first examples
of enantioselective rhodium-catalysed conjugate additions in-
volving furan as a donor.
In summary, we have successfully demonstrated that 2-
heteroarylzinc donors can be utilised in the enantioselective
rhodium-catalysed conjugate addition reaction. Furthermore,
we have revealed that a complex derived from [Rh(C2H4)2Cl]2
and Me-DUPHOS is superior to established catalyst systems
for this challenging transformation. We are continuing to
explore the scope of this process with a broader range of
heteroaromatic donors.
The authors would like to thank the EPSRC and the
University of Bath for funding (to JCA and JLN). Dr Anneke
Lubben (Mass Spectrometry Service at the University of Bath)
is also thanked for valuable assistance.
Notes and references
1 M. P. Sibi and S. Manyem, Tetrahedron, 2000, 56, 8033; N. C. O.
Tomkinson, Rodd’s Chemistry of Carbon Compounds, Volume V,
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Amsterdam, 2001, ch. 6N. Krause and A. Hoffmann-Roder,
Synthesis, 2001, 171.
2 For reviews see: T. Hayashi, Synlett, 2001, 879; T. Hayashi and K.
Yamasaki, Chem. Rev., 2003, 103, 2829; K. Fagnou and M.
Lautens, Chem. Rev., 2003, 103, 169; S. Darses and J.-P. Genet,
Eur. J. Org. Chem., 2003, 4313; T. Hayashi, Bull. Chem. Soc. Jpn.,
2004, 77, 13.
10 Although rarely observed, 2-heteroaryl groups have been reported
to add to cyclohexenone using mixed alkyl(trimethylsilylmethyl)-
zinc reagents without the need for transition metal catalysis, see: P.
Jones, C. K. Reddy and P. Knochel, Tetrahedron, 1998, 54, 1471.
11 Performing the reactions at lower temperatures did not improve
the enantioselectivity.
3 T. Hayashi, M. Takahashi, Y. Takaya and M. Ogasawara, J. Am.
Chem. Soc., 2002, 124, 5052.
4 For representative examples see: T. Hayashi, K. Ueyama, N.
Tokunaga and K. Yoshida, J. Am. Chem. Soc., 2003, 125, 11508;
R. Itooka, Y. Iguchi and N. Miyaura, J. Org. Chem., 2003, 68, 6;
12 For an elegant illustration of this concept, see: J. Shannon, D.
Bernier, D. Rawson and S. Woodward, Chem. Commun., 2007,
3945.
ꢀc
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Chem. Commun., 2008, 3795–3797 | 3797