Asymmetric conjugate addition of arylboronic acids to enones catalyzed by rhodium-monodentate phosphoramidite complexes in the presence of bases

Article abstract of DOI:10.1055/s-2003-39315

Rhodium(I)-catalyzed 1,4-addition of arylboronic acids to α,β-unsaturated carbonyl compounds was carried out in the presence of a chiral phosphoramidite ligand based on (R)-binol and dialkylamines. The reaction was significantly accelerated in the presence of a base such as KOH and Et₃N, allowing the reaction to be completed within 6 hours at 50°C. The addition to 2-cyclohexenone achieved enantioselectivities up to 99%, though they were less effective for 2-cyclopentenone (79% ee), 2-cycloheptenone (77% ee) and acyclic enones (31-43% ee).

Full text of DOI:10.1055/s-2003-39315

1
040
LETTER
Asymmetric Conjugate Addition of Arylboronic Acids to Enones Catalyzed by
Rhodium-Monodentate Phosphoramidite Complexes in the Presence of Bases
A
Y
symmetric Conju
u
gate
A
dditio
k
n
of
A
rylbor
i
onic Acids to
IE nonesguchi, Ryoh Itooka, Norio Miyaura*
Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Fax +81(11)7066561; E-mail: miyaura@org-mc.eng.hokudai.ac.jp
Received 5 March 2003
for cyclic enones. Since the enantioselectivity was re-
duced, by raising the reaction temperature the presence of
a base was critical to carry out the reaction under mild
Abstract: Rhodium(I)-catalyzed 1,4-addition of arylboronic acids
to a,b-unsaturated carbonyl compounds was carried out in the pres-
ence of a chiral phosphoramidite ligand based on (R)-binol and di-
alkylamines. The reaction was significantly accelerated in the conditions and to achieve high enantioselective. The reac-
presence of a base such as KOH and Et N, allowing the reaction to tion was completed within 6 hours at 50 °C in the pres-
3
be completed within 6 hours at 50 °C. The addition to 2-cyclohex-
enone achieved enantioselectivities up to 99%, though they were
less effective for 2-cyclopentenone (79% ee), 2-cycloheptenone
ence of 1 equivalent of KOH or Et N in striking contrast
to the reaction occurring at 90 °C in the absence of a base.
3
(
77% ee) and acyclic enones (31–43% ee).
ArB(OH)2 (2)
R3
R1
R3
Ar
R1
Key words: arylboronic acids, rhodium catalyst, phosphoramidite,
asymmetric, conjugate addition
Rh(I)/4 catalyst
KOH (1 equiv)
R2
O
R2
O
dioxane-H2O (6/1)
1
3
50 °C
The conjugate addition of nucleophiles to activated alk-
enes such as Michael reaction of enolates or organocopper
reagents to enones is a widely used process in organic
chemistry. It was recently demonstrated that rhodium(I)
complexes are excellent catalysts for such conjugate addi-
B(OH)2
O
O
1
P
NR2
Z
2a: Z=H
b: Z=3-Cl
2c: Z=3-MeO
2
tions of aryl- and alkenylboronic acids to a,b-unsaturated
2
carbonyl compounds or other Michael acceptors. Since
4
4
4
a: NR2=NEt2
4d: NR2= -N
various chiral phosphines are available for rhodium cata-
lysts, the protocol was recently extended to asymmetric
i
b: NR2=N( Pr)2
c: NR2=NBn2
3
4e: NR2= -N
O
versions using chiral P-P ligands such as BINAP and
4
diphosphonites and P-N ligands such as amidomono-
5
Scheme 1 Asymmetric 1,4-addition of arylboronic acids to enones
phosphines. Although BINAP achieved high enantiose-
lectivities practical for the addition to both cyclic and
acyclic enones, the reactions often used large excesses of The effects of representative phosphoramidite ligands 4
organoboronic acid because of a competitive hydrolytic and enones are summarized in Table 1. The catalyst was
B-C bond cleavage of organoboronic acids due to a low prepared in situ by mixing Rh(acac)(C H ) (3 mol%) and
2
4 2
catalyst efficiency requiring a temperature of over 100 °C two equivalents of 4 at room temperature for 1 hour. The
in an aqueous solvent. This problem has recently been rhodium complexes Rh(acac)(coe) , [RhCl(C H ) ] and
2
2
4 2 2
solved by the use of RhOH-binap catalyst that completes [Rh(OH)(cod)] also gave analogous yields and enanti-
2
6
the reaction at 35 °C. However, the substrates that can be oselectivities to those of Rh(acac)(C H ) . The addition of
2
4 2
used have been limited to relatively simple substrates be- phenylboronic acid to 2-cyclohexenone at 50 °C for 6
cause of the highly rigid coordination space of a BINAP hours in aqueous dioxane (6/1) resulted in 19% yield in
ligand.
the absence of a base (entry 1). In contrast, the yields were
almost quantitative in the presence of 1 equivalent of Et N
In connection with our interest in rhodium-catalyzed reac-
tions of organoboronic acids, we report here the results of
a preliminary study on the effects of monodentate phos-
phoramidite ligands 4 and bases in the 1,4-addition of
3
or KOH (entries 2 and 3). Phosphoramidites are sensitive
to hydrolysis with water, but their rhodium complexes
were sufficiently stable to be used in alkaline solution,
whereas the yields decreased when a catalyst of less than
1 mol% was used. The enantioselectivities dramatically
changed in a series of N,N-dialkylamino derivatives (en-
tries 3–7). Among the ligands studied, N,N-diethyl deriv-
ative 4a exhibited the best enantioselectivity (98–99% ee,
entries 2 and 3). The selectivities were reduced by increas-
ing the bulkiness of amino groups (entries 4–6) except for
the morpholine derivative 4e, which exceptionally
arylboronic acids to a,b-unsaturated carbonyl compounds
7
(
Scheme 1). Among the various phosphoramidite ligands
8
extensively studied by Feringa and co-workers, diethyl-
amino derivative 4a was found to be an excellent catalyst
Synlett 2003, No. 7, Print: 02 06 2003.
Art Id.1437-2096,E;2003,0,07,1040,1042,ftx,en;U04403ST.pdf.
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Conjugate Addition of Arylboronic Acids to Enones
1041
showed a high selectivity comparable to that of the N,N- ee and 11% ee, respectively. Although reoptimisation of
diethylamino derivative (entry 7). The phosphoramidites the ligands for acyclic enones showed that the N,N-diiso-
derived from (R)-(+)-binol generally afforded (R)-3-phe- propyl derivative 4b increases the selectivity to 31–43%
nylcyclohexanone.
ee (entries 12 and 13), all attempts at an enantioselective
reaction practical for acyclic enones failed. An extension
of the protocol to a,b-unsaturated lactones suffered from
a slow addition and a high sensitivity to saponification. Fi-
nally, an 84% ee was achieved by heating the mixture at
9
Table 1 Asymmetric 1,4-Addition of Arylboronic Acids to Enones
a
(
Scheme 1)
Entry Enone
ArB(OH)2 Ligand
Yield
(%)
Ee (%)
–
9
0 °C in the absence of bases (entry 14).
2
3
1b
In conclusion, Feringa’s phosphoramidites were found to
be excellent ligands for the rhodium-catalyzed conjugate
addition of arylboronic acids to cyclic enones. High reac-
tion rates and enantioselectivities up to 99% were ob-
tained for 2-cyclohexenone when the reactions were
carried out at 50 °C in the presence of a base. Because of
the availability of various derivatives by a simple synthet-
ic route, phosphoramidites are practical chiral ligand that
are easily variable depending upon the substrates.
2a
4a
19
O
2c
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2b
2c
2b
4a
4a
4b
4c
4d
4e
4a
4a
4a
90
95
38
5
99 (R)
98 (R)
22 (R)
24 (R)
51 (R)
89 (R)
99
67
68
75
84
97
Representative Procedure (Entry 3 in Table 1):
A flask charged with Rh(acac)(C H ) (0.03 mmol), 4a (0.06 mmol)
2
4 2
and PhB(OH) (1.5 mmol) was flushed with argon. 1,4-Dioxane–
2
98
H O (6/1, 3 mL) and KOH (10 M in H O, 0.1 mL, 1 mmol) were
2
2
successively added. After being stirred for 1 h, 2-cyclohexenone (1
mmol) was added. The resulting mixture was then stirred for 6 h at
1
1
0
79
O
5
0 °C. Chromatography over silica gel gave (R)-3-phenylcyclohex-
2
0
anone: 95% yield, 98% ee, [a]D +21.4 (c 0.95, CHCl ). The enan-
3
1
2a
4a
67
77
tiomeric excess was determined by HPLC analysis using a chiral
stationary phase column (Daicel Chiralpak AD) with hexane/2-
propanol = 98/2.
O
1
1
2
3
O
2a
2a
4b
4b
50
39
43
31
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9
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(
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7
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Synlett 2003, No. 7, 1040–1042 ISSN 1234-567-89 © Thieme Stuttgart · New York

1
042
Y. Iguchi et al.
LETTER
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Synlett 2003, No. 7, 1040–1042 ISSN 1234-567-89 © Thieme Stuttgart · New York