Application of rhodium complexes of chiral diphenylphosphino-functionalized N-heterocyclic carbenes as catalysts in enantioselective conjugate additions of arylboronic acids

Article abstract of DOI:10.1002/adsc.200404327

The Rh complex 1a of (S,S)-1-(2-diphenylphosphanylnaphthalen-1-yl)-3-(2- isopropylphenyl)-4,5-diphenylimidazolidin-2-ylidene was found to promote enantioselective conjugate additions of arylboronic acids to enones and α,β-unsaturated esters with up to 98%

Full text of DOI:10.1002/adsc.200404327

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DOI: 10.1002/adsc.200404327
Application of Rhodium Complexes of Chiral Diphenyl-
phosphino-Functionalized N-Heterocyclic Carbenes as Catalysts
in Enantioselective Conjugate Additions of Arylboronic Acids
Jean-Michel Becht, Erhard Bappert, Günter Helmchen*
Organisch-Chemisches Institut der Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
Fax: (þ49)-6221-544-205, e-mail: g.helmchen@urz.uni-heidelberg.de
Received: October 10, 2004; Revised: April 24, 2005; Accepted: May 6, 2005
Abstract: The Rh complex 1a of (S,S)-1-(2-diphenyl-
phosphanylnaphthalen-1-yl)-3-(2-isopropylphenyl)-
4,5-diphenylimidazolidin-2-ylidene was found to pro-
mote enantioselective conjugate additions of aryl-
boronic acids to enones and a,b-unsaturated esters
with up to 98% yield and>99% ee. Products of
the latter reaction can be transformed into GABA
antagonists.
Figure 1. Chiral rhodium(I) carbene complexes 1a and 1b.
Keywords: asymmetric catalysis; boronic acids; chiral
N-heterocyclic carbenes; conjugate addition; rhodium
In our previous synthesis of GABA analogues accord-
ing to Scheme 1 we used a catalyst prepared from (R)- or
(S)-BINAP and [Rh(acac)(C2H4)2] (3 mol %); the addi-
tion reaction required a reaction time of 24–48 h at
N-Heterocyclic carbenes (NHCs) have found useful ap- 1008C.[5] Among a series of arylboronic acids the parent
plications as ligands of late transition metal catalysts or compound phenylboronic acid gave the lowest enantio-
as organocatalysts over the last few years.[1] An emerg- meric excess of only 86% in the addition to ester 2. In
ing area of application of NHCs is asymmetric catalysis view of the importance of 4-amino-3-aryl-butyric
using chiral NHCs.[2] In a previous report, we have de- acids,[6] improvement was desirable. Naturally, we eval-
scribed a short and efficient route to the rhodium com- uated complex 1a as catalyst, when it became available.
plex 1a (Figure 1).[3] This complex is stable against air For this purpose, the a,b-unsaturated ester 2 was reacted
and moisture. It efficiently catalyzed asymmetric hydro- with phenylboronic acid (2.0 equivs.) using 3 mol % of
genations of substituted acrylic acid derivatives.[2] Here- 1a as catalyst. Remarkably, the addition product (R)-3
in, we report the application of 1a as a new catalyst for was obtained with>99% ee[7] within 2 h at a reaction
asymmetric conjugate additions of arylboronic acids to temperature of 658C. This is an enormous improvement
electron-deficient alkenes.[4] This reaction was previous- in comparison to our previous results. Even considered
ly employed by us for the synthesis of GABA analogues
using BINAP as a chiral ligand.[5]
Complex 1a was obtained as a 2:1 mixture of iso-
mers.[3] We had assumed that these isomers are atrop-
À
isomers with respect to the i-PrC6H4 N bond. In order
to corroborate this hypothesis, we decided to synthesize
the rhodium complex 1b (Figure 1), which cannot give
À
rise to atropisomers with respect to the C6H5 N bond.
Complex 1b was prepared via a route analogous to
that reported for 1a. As anticipated, 31P NMR (CDCl3)
indicated for 1b the presence of only one compound,
characterized by a doublet at d¼21.7 ppm (d, JRh,P
¼
163.9 Hz).
Scheme 1. Use of complex 1a as catalyst in the conjugate ad-
dition of phenylboronic acid to a,b-unsaturated ester 3.
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Jean-Michel Becht et al.
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no reaction occurred in the absence of a base. Decreas-
ing the amount of the arylboronic acid to 1.5 equivs. af-
forded the addition product in a lower yield (53%), yet
high ee of 93% (entry 3). Other bases, for example, dii-
sopropylethylamine or diethylmethylamine, gave no
further improvement with respect to yield and enantio-
meric excess (entries 4 and 5); no product was observed
in the presence of DBU, DABCO, piperidine or 3-meth-
ylpyrrolidine. Only traces (<10%) of product were
formed under the optimal reaction conditions with a de-
creased catalyst loading of 1 mol %.
Scheme 2. Conjugate addition of arylboronic acids to cyclic
enones.
The procedure was then applied successfully to a
in the more general context of additions of boronic acids variety of arylboronic acids, containing both electron-
to a,b-unsaturated esters it is remarkable; the best ee withdrawing or electron-donating substituents. Very
values so far obtained are in the range 90–96%, to the high yields and>90% ee were generally obtained
best of our knowledge,[4] with the exception of an addi- (entries 6–10). While the sterically hindered 2-tolylbor-
tion to an unsaturated lactone wherein 98% ee was ach- onic acid also gave the expected addition product
ieved.[4j]
with 87% yield and 84% ee (entry 11), the conjugate ad-
The excellent result described above prompted us to dition of 2-naphthylboronic acid afforded only naphtha-
study the catalytic activity of 1a in reactions of cyclic lene, resultingfromthehydrolysis ofthearylboronicacid.
enones with various arylboronic acids (Scheme 2). The
The reaction of 2-cyclopentenone with phenylboronic
reaction conditions were optimized by using 2-cyclohex- acid gave the expected product in 73% yield and 88% ee
enone and phenylboronic acid as benchmark substrates (entry 12); the reaction rate was lower than that with 2-
(Table 1).
cyclohexenone, and a large excess of phenylboronic acid
2-Cyclohexenone was initially reacted at room tem- (5.0 equivs.) has to be used in order to obtain full conver-
perature with an excess of phenylboronic acid sion of the enone. 2-Cycloheptenone afforded the ex-
(2.0 equivs.) in dioxane/H2O (10:1) in the presence of pected product in 50% yield and 78% ee under standard
Cs2CO3 (2.0 equivs.) as base. No reaction took place conditions (entry 13). Increasing the amount of phenyl-
and the substrates were recovered. Better results were boronic acid to 5.0 equivs. did not improve the yield but
obtained by heating the reaction mixture at 658C for gave rise to a lower ee of 49%. A decrease of enantiose-
2 h: 74% yield, 67% ee (entry 1). Improved yield and lectivity with>2.0 equivs. of arylboronic acid was gener-
ee resulted upon using a homogeneous mixture with ally observed. Much lower yield and ee was obtained
Et3N asa base: 91% yield, 94% ee (entry 2). Noteworthy, with 1b as catalyst, presumably due to rapid degradation
Table 1. Enantioselective conjugate additions of arylboronic acids to cyclic enones according to Scheme 2 (reaction tempera-
ture: 658C, solvent: dioxane/H2O, 10: 1, reaction time: 2 h).
Entry
n
R
Base
Conditions[a]
Product
Yield [%][b, c]
ee [%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
2
2
2
2
2
2
2
2
2
2
2
1
3
H
H
H
H
Cs2CO3
Et3N
Et3N
i-Pr2EtN
Et2NMe
Et3N
Et3N
Et3N
Et3N
Et3N
A
A
B
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
74
91
53
91
91
79
98
93
73
96
87
73
50
67
94
93
93
94
94
94
94
95
95
84
88
78
A
A
A
A
A
A
A
A
C
H
3-Cl
4-Cl
4-F
4-CF3
4-OMe
2-Me
H
Et3N
Et3N
Et3N
4g
4h
4i
H
A
[a]
Conditions A: 1.0 equiv. of enone, 2.0 equivs. of boronic acid, 2.0 equivs. of base. Conditions B: 1.0 equiv. of enone,
1.5 equivs. of boronic acid, 2.0 equivs. of base. Conditions C: 1.0 equiv. of enone, 5.0 equivs. of boronic acid, 2.0 equivs.
of base.
[b]
Isolated yield after flash chromatography on silica gel.
[c] 1H and 13C NMR spectra are in accordance with literature reports.[4i]
[d]
Determined by chiral HPLC using separation conditions described in the literature.[4i]
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Adv. Synth. Catal. 2005, 347, 1495 – 1498

Rh Complexes of Chiral Diphenylphosphino-Functionalized NHCs
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of this compound under the reaction conditions. Similar Acknowledgements
À
results were obtained upon replacing the BF4 counter
anion by PF6 in 1b.
À
This work was supported by the EC (RTN HPRN-CT-2001-
00172) and the Fonds der Chemischen Industrie. We thank Mar-
ta Zajaczkowski for her competent synthesis of catalyst 1b.
Considering that our catalyst is a fairly new one and
that this type of C,P-catalysts has been relatively little
explored, ee values of up to 95% are respectable. How-
ever, it must be pointed out that for the addition of aryl-
boronic acids to cyclic enones better results (>99% ee)
have been already reported.[2i,4a–d]
References and Notes
Recently, Hayashi et al. described the use of organo-
zinc reagents in the rhodium-catalyzed conjugate addi-
tion to enones.[8] However, when phenylzinc chloride
was reacted with 2-cyclohexenone, using 1a as a catalyst,
the addition product was generated in <30% yield and
<80% ee.
In summary, we have shown that the NHC complex 1a
induces high yields and enantioselectivities in rhodium-
catalyzed enantioselective conjugate additions of aryl-
boronic acids to enones and a,b-unsaturated esters.
Combined with our previous results for hydrogenation
reactions, this demonstrates considerable potential of
this new class of catalysts. The synthesis of other chiral
NHCs and their application in asymmetric catalysis
are currently in progress.
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General
Catalysts 1a and 1b were prepared according to the procedure
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General Procedure for the Enantioselective Conjugate
Addition of Arylboronic Acids to Enones and a,b-
Unsaturated Esters
Enones: Under an atmosphere of argon, a Schlenk tube was
charged with a solution of freshly prepared 1a (4.00 mg,
3.87 mmol, 0.03 equivs.) in dioxane (1 mL). Et3N (50.0 mL,
258 mmol, 2.0 equivs.), arylboronic acid (258 mmol,
2.0 equivs.), enone (129 mmol, 1.0 equiv.) and water (0.1 mL)
were successively added at room temperature. The mixture
was heated at 658C for 2 h. Then, ethyl acetate (10–15 mL)
was added and the mixture was extracted with water (10–
15 mL). The organic layer was dried over Na2SO4 and concen-
trated under vacuum. The residue was subjected to flash chro-
matography on silica gel (column: 15ꢀ0.5 cm, eluent: petrole-
um ether/ethyl acetate, 9:1). The eluent was analyzed by TLC,
the fractions containing the product were concentrated under
vacuum and the residue kept under high vacuum until constant
weight was reached.
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product are described in full detail in ref.[5a]
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