Potassium trifluoro(organo)borates in rhodium-catalyzed 1,4-additions to α,β-unsaturated esters

Article abstract of DOI:10.1016/j.tetlet.2005.04.038

This letter describes an efficient and enantioselective conjugate addition of highly stable potassium trifluoro(organo)borates to α,β- unsaturated esters. This reaction, catalyzed by chiral rhodium(I) complexes, affords Michael adducts with high yields an

Full text of DOI:10.1016/j.tetlet.2005.04.038

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4247–4250
Potassium trifluoro(organo)borates in rhodium-catalyzed
1,4-additions to a,b-unsaturated esters
Laure Navarre, Mathieu Pucheault, Sylvain Darses* and Jean-Pierre Genet*
` ´ ´
Laboratoire de Synthese Selective Organique et Produits Naturels, UMR 7573 (CNRS), Ecole Nationale Superieure de
Chimie de Paris, 11 rue P. et M. Curie, 75231 Paris cedex 05, France
Received 18 March 2005; revised 8 April 2005; accepted 8 April 2005
Abstract—This letter describes an efficient and enantioselective conjugate addition of highly stable potassium trifluoro(org-
ano)borates to a,b-unsaturated esters. This reaction, catalyzed by chiral rhodium(I) complexes, affords Michael adducts with high
yields and enantiomeric excesses up to 96%.
Ó 2005 Elsevier Ltd. All rights reserved.
Rhodium-catalyzed carbon–carbon bond forming reac-
tions using organometallic reagents has recently
emerged as a powerful tool in organic synthesis.1 Partic-
ularly, the asymmetric 1,4-addition of organometallics
allowed the introduction of a b-substituent to a Michael
acceptor with concomitant enantioselective control of
the newly created carbon–carbon bond.2 Among the
various organometallics, organoboronic acids have
shown to add efficiently to various activated olefins like
enones,2,3 a,b-unsaturated esters,4,5 amides,2 phospho-
nates,2 sulfones,6 or nitroalkenes2 in the so-called Miya-
ura–Hayashi reaction.
be suited for acyclic substrates, but for cyclic ones, again
a large excess of boronic acid was more adapted.4
As alternate organoboron derivatives, we have shown
that potassium trifluoro(organo)borates7 were highly
suitable either in palladium-catalyzed cross-coupling
reactions8 or in rhodium-catalyzed reactions and devel-
oped efficient protocols for asymmetric 1,4-addition to
enones9 and enamides10 where low amounts of organo-
boron derivatives had to be employed compared to
trivalent organoboron species.2,3c,11 These stable and
easily prepared tetravalent boron species allowed the
development of new reactions such as an efficient access
to chiral amino acids via 1,4-addition/enantioselective
protonation12 or a direct access to ketones from
aldehydes via a Heck-type reaction.13 Herein we want
to report for the first time the use of potassium triflu-
oro(organo)borates in rhodium-catalyzed asymmetric
1,4-addition to a,b-unsaturated esters, extending the
scope of previously described reactions (Scheme 1).9,10
Among these Michael acceptors, unsaturated ketones
have proven to be the most reactive and consequently
the most studied substrates. On the other hand, a,b-
unsaturated esters have shown to be less reactive and re-
ports of 1,4-addition of organometallic reagents to these
substrates using rhodium catalyst are very scarce.4,5
Even if organoboron derivatives have proven to be sui-
ted in this reaction, large excesses of reagents are needed
to obtain moderate yields of Michael adducts.5 Higher
yields have been achieved using in situ prepared lithium
borates ArB(OMe)3Li with careful control of the
amount of added water.4 These conditions proved to
Indeed, under standard conditions,9,10 that is, using
cationic rhodium complex as catalyst precursor in
the presence of Binap as chiral ligand, we were
[Rh(cod) ]PF 3 mol%
1
2
6
1
R
R
2
+
2
RBF K
CO R
3
CO R
2
2
(R)-Binap 3.3 mol%
Tol/H O, 110˚C
Keywords: Borates; Asymmetric catalysis; 1,4-Addition; Rhodium;
Esters.
R
2
*
Corresponding authors. Tel.: +33 144276742; fax: +33 144071062
(S.D.); tel.: +33 144276743; fax: +33 144071062 (J.-P.G.); e-mail
addresses: sylvain-darses@enscp.fr; jean-pierre-genet@enscp.fr
Scheme 1. Rh-catalyzed 1,4-additon of RBF3K to a,b-unsaturated
esters.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.038

4248
L. Navarre et al. / Tetrahedron Letters 46 (2005) 4247–4250
Table 2. Asymmetric 1,4-addition of RBF3K to a,b-unsaturated
pleased to find that the 1,4-addition of potassium
trifluoro(phenyl)-borate (2a) to ethyl hex-2-enoate (1a)
occurred smoothly affording the expected adduct 3a in
95% yield and 90% ee (Table 1, entry 1). In order to fur-
ther improve the enantioselectivity of the reaction, other
bidentate chiral ligands were evaluated in this reaction
model under standard conditions. However, despite sev-
eral attempts (see Table 1 for some selected examples),
the enantioselectivity could not be improved and the
highest enantiomeric excesses were obtained using
Binap. MeOBiphep chiral ligand derivatives14 show lower
level of enantioselectivity (entry 2) and in many cases no
chiral induction was observed (entries 3–5). It is unclear
at present if formation of racemic products results from
unfavorable steric interactions of the substrate with the
chiral rhodium complex or from a 1,4-addition cata-
lyzed by achiral rhodium complex because of incomplete
complexation of the chiral ligand. Using ferrocenyl chi-
ral Josiphos derivatives,15 slower reactions and modest
chiral induction were observed. Further optimizations
of the reaction parameters such as the solvent or temper-
ature did not result in any improved reactivity nor
enantioselectivity. Thus, it appeared, at present, that
reaction conditions optimized for the 1,4-addition of
potassium trifluoro(organo)borates to enones9 or a,b-
unsaturated amides10 also proved to be optimal for
a,b-unsaturated esters.
estersa
Entry
1
Product
Yieldb
96
eec
Ph
84 (R)d
CO Me
3b
2
Ph
2
98
86 (R)d
3c
CO Et
2
Ph
Ph
3
4
91
93
85 (S)
93 (S)
3d
3e
CO Bn
2
CO iPr
2
Ph
5
6
96
88
86 (S)
87 (S)
3f
CO Et
2
O
3g
CO Et
2
Ph
7
8
95
50
86 (S)
91 (S)
CO Et 3h
2
Br
CO iPr 3i
2
Indeed, in the presence of cationic [Rh(cod)2]PF6 in
combination with (R) or (S)-Binap, 1,4-addition of
potassium aryltrifluoroborates to a,b-unsaturated esters
9
75
90 (S)
CO iPr 3j
2
Table 1. Influence of the chiral bidentate ligand on the enantioselec-
tivity of the 1,4-additiona
Ph
10
11
87
66
96 (S)
90 (S)
[Rh(cod) ]PF 3 mol%
CO iPr 3k
2
6
2
Pr
Pr
+
PhBF K
3
CO Et
CO Et
2
2
*
L* 3.3 mol%
Ph
1a
Entry
2a
3a
Tol/H O, 110˚C
2
Cl
Ligand (L*)
Yieldb
eec (%)
1
2
3
4
5
6
7
8
(S)-Binap
95
100
100
91
90 (S)
72 (S)
0
CO iPr 3l
2
(S)-MeOBiphep
(S)-pDMA-MeOBiphepd
(R)-2-Furyl-MeOBiphepe
(R)-3,5-tBu-MeOBiphepf
(R,S)-Josiphos
CF3
0
23
30
0
12
13
54
89 (S)
93 (R)
31 (R)
21 (R)
52 (R)
g
(S,R)-Cy2PF-PPh2
(R,S)-Cy2PF-PCy2
33
<5
h
CO iPr
3m
2
a Reactions conducted using 0.5 mmol of 1a, 2 equiv of 2a with
3 mol % of [Rh(cod)2][PF6] and 3.3 mol % L* at 110 °C in 2 ml
toluene/water 20:1.
O
55e
O
3n
b Isolated yield of 1,4-addition adduct 3a.
c Determined by HPLC using Daicel Chiralcel OD-H column (hexane/
iPrOH 99:1, 0.5 ml/min).
Ph
a Reactions conducted using 0.5 mmol of 1, 2 equiv of 2 with 3 mol %
of [Rh(cod)2][PF6] and 3.3 mol % (R)-Binap at 110 °C in 2 ml tolu-
ene/water 20:1.
d pDMA-MeObiphep: 6,60-dimethoxy-2,20-bis[di(4-dimethylaminophen-
yl)-phosphanyl)-1,10-biphenyl.
e 2-furylMeObiphep: 6,60-dimethoxy-2,20-bis[di(2-furyl)phosphanyl)-1,10-
biphenyl.
b Isolated yields of 1,4-addition adducts 3.
c Determined by HPLC using Daicel Chiralcel OD-H column excepted
3j (Chiralcel OJ) and 3n (Chiralpak AS-H). Absolute configuration
of the adducts was established by comparison of the sign of optical
rotation or chiral HPLC retention time with that of configurationally
assigned compounds.
f 3,5-tBu-MeOBiphep: 6,60-dimethoxy-2,20-bis[di(3,5-di-tert-butylphen-
yl)-phosphanyl)-1,10-biphenyl.
g Cy2PF-PPh2: 1-[2-(dicyclohexylphosphanyl)ferrocenyl]-ethyldiphenyl-
phosphane.
h Cy2PF-PCy2: 1-[2-(dicyclohexylphosphanyl)ferrocenyl]-ethyldicyclo-
hexylphosphane.
d Using (S)-Binap as chiral ligand.
e Reaction conducted with 4 equiv of aryltrifluoroborate.

L. Navarre et al. / Tetrahedron Letters 46 (2005) 4247–4250
4249
occurred smoothly in a biphasic solvent (toluene/water)
P
at 110 °C (Table 2).16 The influence of the ester moiety
on either reactivity or enantioselectivity was evaluated
using several crotonic esters derivatives (entries 1–4).
From these results, it appeared that increasing steric
hindrance at the ester moiety resulted in an increase
of the enantiomeric excesses without affecting the yields.
Among these esters, isopropyl derivatives seemed to be
the most adapted affording the 1,4-addition adduct 3e
in 93% yields and 93% ee.17
Rh X
P
*
1
R
2
ArBF K
3
CO R
2
ArH
Ar
1
H O
2
R
XBF K
3
2
CO R
2
P
Rh Ar
P
*
Scheme 2. Proposed simplified mechanism.
Other potassium aryltrifluoroborates also added effi-
ciently to different unsaturated esters (Table 2). Once
again, from these results it appeared that the levels of
enantioselectivity using ethyl esters (entries 5–7,
ee = 86–87%) were always slightly lower than those ob-
served with isopropyl esters (entries 8–12, ee >89%).
Concerning the potassium aryltrifluoroborate partner,
it seems that the electronic nature of the substituents
does not greatly influence their reactivity: either elec-
tron-withdrawing (entry 12) or releasing groups (entry
6) were tolerated on the aromatic ring. a,b-unsaturated
lactones showed lower reactivity under these conditions,
as observed in the addition of boronic acids,4 but a 55%
yield was obtained in the 1,4-addition of potassium
trifluoro(phenyl)trifluoroborate to 2(5H)-furanone (3n)
with 93% enantiomeric excess.
very proned to hydrolysis, a competitive process with
the insertion of the carbon–carbon double bond2
(Scheme 2).
These results may explain that larger amounts of organo-
boronic acids are needed in such carbometallation
processes compared to potassium trifluoro(organo)-
borates, because the importance of hydrolysis may be
correlated with their fast transmetallation rate. Indeed,
using two equivalents of organoboron derivatives, lower
yields of 1,4-addition adduct were observed using boro-
nic acids (Fig. 1). On the other hand, with potassium tri-
fluoro(organo)borates, transmetallation seems to be rate
determining, preventing accumulation of aryl-rhodium
species and their hydrolysis. Further studies are under-
way to elucidate this difference of reactivity.
In order to get further insight on the reaction pathway,
the reactivity of trifluoroborates and boronic acids was
evaluated under our conditions (see Fig. 1). The 1,4-
addition of phenylboronic acid and potassium tri-
fluoro(phenyl)borate (2a) to ethyl oct-2-enoate (1h), in
the presence of 3 mol % [Rh(cod)2]PF6 and 3.3 mol %
(R)-Binap in toluene/water at 110 °C was analyzed by
GC/MS. The main feature of these kinetics revealed a
great difference of reactivity between these organoboron
derivatives: reaction with phenylboronic acid takes place
instantaneously whereas an induction period is observed
with potassium trifluoro(phenyl) borate.10 These results
indicate that transmetallation of boronic acids is fast to
the Rhodium/Binap precursor whereas it did not happen
or to a lesser extend with trifluoroborate derivatives.
This fast transmetallation of boronic acids resulted in
an accumulation of phenyl-rhodium species which are
From these preliminary results, potassium trifluoro-
(organo)borates appear to be very efficient partners
in rhodium-catalyzed enantioselective 1,4-additions to
a,b-unsaturated esters. These highly stable and easily
prepared boron derivatives seem to be more suited than
the boronic acid analogues in such reaction. It is also
noteworthy that the reaction proceeds with high yields
and good to excellent enantiomeric excesses whatever
the electronic properties of the aryltrifluoroborates, pro-
viding a useful tool in organic synthesis. Indeed, the use
of potassium trifluoro(organo)borates in such carbomet-
allation processes proved to be superior to boronic
acids.
Acknowledgements
We are grateful to Dr. R. Schmidt and Dr. M. Scalone
(Hoffmann La Roche) for the generous gift of MeO-Bip-
hep chiral ligand and derivatives. L.N. and M.P. thank
100
50
0
`
the Ministere de la Recherche for a grant.
References and notes
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Appl. Chem. 2004, 76, 465.
0
20
40
60
80
100
time (min)
Figure 1. Compared reactivity of PhBF K 2a ( ) and PhB(OH) ( ) in
2
3. For recent work see: (a) Amengual, R.; Michelet, V.;
Genet, J.-P. Synlett 2002, 1791; (b) Itooka, R.; Iguchi, Y.;
r
rhodium-catalyzed 1,4-addition to ethyl oct-2-enoate (1h).
3

4250
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69, 8045.
12. For a racemic version: (a) Navarre, L.; Darses, S.; Genet,
J.-P. Eur. J. Org. Chem. 2004, 69; For tandem 1,4-
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719.
13. Pucheault, M.; Darses, S.; Genet, J.-P. J. Am. Chem. Soc.
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16. General procedure for the 1,4-addition of potassium
trifluoro(organo)borates on a,b-unsaturated esters: A
septum-capped vial equipped with a magnetic stirring
bar was charged with potassium (naphth-2-yl)trifluoro-
borate (2 equiv, 1 mmol, 234.1 mg), [Rh(cod)2][PF6]
(3 mol %, 6.9 mg), (R)-Binap (3.3 mol %, 10.3 mg). The
vial was closed and evacuated under vacuum and placed
under an argon atmosphere. Degassed toluene (2 ml) and
water (100 ll) followed by isopropyl hex-2-enoate
(0.5 mmol, 72 ll) were added and the mixture was stirred
in a preheated oil bath at 110 until completion of the
reaction (GC). After cooling the vessel at room temper-
ature, the reaction mixture was purified by silica gel
chromatography (ethyl acetate/cyclohexane 20:1) to afford
4. Takaya, Y.; Senda, T.; Kurushima, H.; Ogasawara, M.;
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Chem. 2000, 65, 5951.
´
6. Mauleon, P.; Carretero, J. C. Org. Lett. 2004, 6, 3195.
7. For review on potassium organotrifluoroborates chemis-
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8. Darses, S.; Michaud, G.; Genet, J.-P. Eur. J. Org. Chem.
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11. For other rhodium-catalyzed 1,4-additions using RBF3K
see: (a) Moss, R. J.; Wadsworth, K. J.; Chapman, C. J.;
Frost, C. G. Chem. Commun. 2004, 1984; (b) Duursma,
A.; Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de
Vries, J. G.; Minnard, A. J.; Feringa, B. L. Org. Biomol.
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Lefort, L.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries,
25
3j as a colorless oil (106.8 mg, 75% yield). ½aꢀD +14.5
25
(c 0.94, CHCl3), lit.4 ½aꢀD ꢁ16 (c 0.94, CHCl3). HPLC
(Daicel Chiralcel OJ, hexane/propan-2-ol 99:1, 1 ml/min,
215 nm) tR = 10.0 (S) and 12.1 min (R).
17. tert-Butylester derivatives which are not easily available
were not tested.