Rhodium(I)-catalyzed asymmetric 1,4-addition of arylboronic acids to α,β-unsaturated amides

Article abstract of DOI:10.1021/jo010747n

The conjugate addition of arylboronic acids to α,β-unsaturated amides was carried out in the presence of a chiral rhodium catalyst and an aqueous base. The catalyst prepared in situ from Rh(acac)(CH₂=CH₂)₂ and (S)-binap provided (R)-N-benzyl-3-phenylbutanamide with 93% ee in the addition of phenylboronic acid to N-benzyl crotonamide. The reaction suffered from incomplete conversion resulting in moderate yields, but addition of an aqueous base, such as K₂CO₃ (10-50 mol%) was found to be highly effective to improve the chemical yields. The role of the base giving a RhOH species active for transmetalation with arylboronic acids was discussed.

Full text of DOI:10.1021/jo010747n

8944
J . Org. Chem. 2001, 66, 8944-8946
Rh od iu m (I)-Ca ta lyzed Asym m etr ic 1,4-Ad d ition of Ar ylbor on ic
Acid s to r,â-Un sa tu r a ted Am id es
Satoshi Sakuma and Norio Miyaura*
Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido University,
Sapporo 060-8628, J apan
miyaura@org-mc.eng.hokudai.ac.jp
Received J uly 25, 2001
The conjugate addition of arylboronic acids to R,â-unsaturated amides was carried out in the
presence of a chiral rhodium catalyst and an aqueous base. The catalyst prepared in situ from
Rh(acac)(CH2dCH2)2 and (S)-binap provided (R)-N-benzyl-3-phenylbutanamide with 93% ee in the
addition of phenylboronic acid to N-benzyl crotonamide. The reaction suffered from incomplete
conversion resulting in moderate yields, but addition of an aqueous base, such as K2CO3 (10-50
mol%) was found to be highly effective to improve the chemical yields. The role of the base giving
a RhOH species active for transmetalation with arylboronic acids was discussed.
The conjugate addition of organometallic reagents to
R,â-unsaturated carbonyl compounds is a widely used
process for carbon-carbon bond formation.1 Although
such intermolecular transfer reactions are rare for orga-
noboronic acids, various rhodium(I) complexes catalyze
the 1,4-addition of aryl- and alkenylboronic acids to R,â-
unsaturated carbonyl compounds.2-4 The additions of
arylboronic acids to unactivated alkenes such as nor-
bornene5 and vinylarenes6 were also recently found to be
catalyzed by rhodium(I) complexes. The additions to R,â-
unsaturated ketones,7 esters,8 nitroalkenes,9 and alken-
ylphosphonates10 were extended to asymmetric versions
by using a rhodium(I)-binap complex. Here, we report a
conjugate addition of arylboronic acids to R,â-unsaturated
amides (1) yielding optically active â-aryl amides (2) in
the presence of a rhodium(I)-binap catalyst (eq 1).11
Although the reaction suffered from incomplete conver-
sion resulting in moderate chemical yields, the presence
of an aqueous base was found to be very effective for
completing the reaction. Such effects of bases were
recently demonstrated in the addition of arylboronic acids
to aldehydes catalyzed by a rhodium(I)-carbene com-
plex.12
The effects of catalysts on yields and enantioselectivi-
ties in the addition of phenylboronic acid to N-benzyl
crotonamide are summarized in Table 1. All catalysts
were prepared in situ by stirring a rhodium precursor (3
mol %) and a chiral ligand (4.5 mol %). There were no
large differences in enantioselectivities (% ee) between
cationic and neutral rhodium precursors, since two
cationic rhodium(I) complexes (entries 1 and 2), Rh(acac)
(entry 3), and RhCl complex (entry 4) yielded N-benzyl-
3-phenylbutanamide with 91-93% ee. Among the ligands
employed, binap13 again exhibited the best enantioselec-
tivity (entries 5-8), as was the case in related reactions
with R,â-unsaturated ketones and esters.7-10
(1) (a) Sawamura, M.; Hamashima, H.; Ito, Y. J . Am. Chem. Soc.
1992, 114, 8295. (b) Ikeda, S.; Cui, D.-M.; Sato, Y. J . Am. Chem. Soc.
1999, 121, 4712. (c) Murahashi, S.-I.; Naota, T.; Taki, H.; Mizuno, M.;
Takaya, H.; Komiya, S.; Mizuho, Y.; Oyasato, N.; Hiraoka, M.; Hirano,
M.; Fukuoka, A. J . Am. Chem. Soc. 1995, 117, 12436. (d) Trost, B. M.
Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281. For reviews: (e)
Tomioka, K.; Nagaoka, Y.; Yamaguchi, M. In Comprehensive Asym-
metric Catalysis; J acobsen, E. N., Pfaltz, A., Yamamoto H., Eds.;
Springer: Berlin, 1999; Vol. 3, pp 1105-1139. (f) Alexakis, A. Transi-
tion Metals for Organic Synthesis; Beller, M., Bolm, C., Eds.; Wiley-
VCH: Weinheim, 1998; Vol. 1, Chapter 3.10. (g) B. H. Lipshutz,
Organometallics in Synthesis; Schlosser, M., Ed.; Wiley: New York,
1994; p 283.
The absolute configuration of the product was estab-
lished by using the reaction of phenylboronic acid with
crotonamide (1, R1 ) Me, R2 ) H) since the N-benzyl
derivative strongly resisted the acid-catalyzed hydrolysis.
The reaction catalyzed by the (S)-binap complex provided
3-phenylbutanamide ([R]D -30.9 (c 1.01, CDCl3)), which
was then converted into (R)-3-phenylbutanoic acid ([R]D
-44.8 (c 0.76, benzene))14 via the acid-catalyzed hydroly-
sis. Thus, the stereochemical pathway in the insertion
of an unsaturated amide into the Rh-C bond can be
rationalized by the same mechanism as that of R,â-
unsaturated ketones7 or other Michael acceptors.8-10
(2) Sakai, M.; Hayashi, H.; Miyaura, N. Organometallics 1997, 16,
4229.
(3) Itooka, R.; Iguchi, Y.; Miyaura, N. Chem. Lett. 2001, 722.
(4) Batey, R. A.; Thadani, A. N.; Smil, D. V. Org. Lett. 1999, 1, 1683-
1686.
(5) Oguma, K.; Miura, M.; Satoh, T.; Nomura, M. J . Am. Chem. Soc.
2000, 122, 10464.
(6) Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou, K.; Matin-Matute,
B. J . Am. Chem. Soc. 2001, 123, 5358.
(7) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura,
N. J . Am. Chem. Soc., 1998, 120, 5579.
(8) Sakuma, S.; Sakai, M.; Itooka, R.; Miyaura, N. J . Org. Chem.
2000, 65, 5951.
(9) Hayashi, T.; Senda, T.; Ogasawara, M. J . Am. Chem. Soc. 2000,
122, 10716.
(10) Hayashi, T.; Senda, T.; Takaya, Y.; Ogasawara, M. J . Am.
Chem. Soc. 1999, 121, 11591.
(11) Preliminary results were discussed in: Organoboranes for
Synthses; Ramachandran, P. V., Brown, H. C., Eds.; ACS Symposium
Series 783; American Chemical Society: Washington, DC, 2000;
Chapter 7.
(12) Fu¨rstner, A.; Krause, H. Adv. Synth. Catal. 2001, 343.
(13) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345.
(14) Suzuki, I.; Kin, H.; Yamamoto, Y. J . Am. Chem. Soc. 1993, 115,
10139.
10.1021/jo010747n CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/27/2001

Asymmetric 1,4-Addition of Arylboronic Acids
J . Org. Chem., Vol. 66, No. 26, 2001 8945
Ta ble 1. Effect of Ca ta lyst in th e Asym m etr ic Ad d ition
of P h en ylbor on ic Acid to N-Ben zyl Cr oton a m id ea
yieldb
entry
Rh(I) precursor
ligand
(%)
% ee
c
1
2
3
4
5
6
7
[Rh(cod)(MeCN)2]BF4 (S)-binapd
53
60
67
64
82
36
10
91
93
93
93
48
43
7
c
[Rh(cod)2]BF4
(S)-binapd
Rh(acac)(C2H4)2
(S)-binapd
c
[RhCl(cod)]2
(S)-binapd
Rh(acac)(C2H4)2
Rh(acac)(C2H4)2
Rh(acac)(C2H4)2
(R,R)-chiraphose
(S,S)-Me-duphosf
(R,R)-diopg
a
A mixture of N-benzyl crotonamide (1 mmol) and phenylbo-
ronic acid (2 mmol) in aqueous dioxane was stirred at 100 °C for
16 h in the presence of a rhodium(I) precursor (3 mol %) and a
b
phosphine ligand (4.5 mol %). Isolated yields. c cod ) 1,5-cyclo-
d
octadiene. (S)-(-)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl.
e (2R,3R)-(+)-2,3-Bis(diphenylphosphino)butane. f (+)-1,2-Bis[(2S,-
g
5S)-2,5-dimethylphospholano]benzene. (2S,3S)-(+)-4,5-Bis(di-
phenylphosphinomethyl)-1,2-dimethyl-2,3-dioxolane.
Ta ble 2. Effects of Acid s a n d Ba ses in th e Ad d ition of
P h en ylbor on ic Acid to N-Ben zyl Cr oton a m id ea
entry
additive
equiv
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
none
AcOH
MeSO3H
TsOH
HCl
CF3SO3H
B(OH)3
Eu(OTf)3
Yb(OTf)3
Et3N
67
15
0
0
0
0
75
tr
F igu r e 1. Effect of base in the addition of phenylboronic acid
to N-benzyl crotonamide.
0.05
0.05
0.05
0.05
0.05
1.00
0.05
0.05
2.00
2.00
2.00
0.05
0.05
0.05
0.05
the reaction was significantly accelerated by the addition
of 10 mol % of aqueous K2CO3, resulting in 89% yield
after 6 h (dotted line and 2). The reaction, which was
inhibited by the addition of HCl (5 mol %) to Rh(acac)-
(C2H4)2/(S)-binap (3 mol %), restarted spontaneously
when the mixture was treated with aqueous K2CO3 (15
mol %) (dotted line and O). All of these results are
consistent with the view that bases act for the conversion
of the RhCl or Rh(acac) complex 3 to the corresponding
RhOH complex 4,15 which has been proposed to be an
active intermediate for transmetalation with organobo-
ronic acids (eq 2).2,3,8,11,16 Although the addition of (S)-
tr
59
71
tr
85
82
88
85
KF
NaOAc
KHCO3
K2CO3
K3PO4
KOH
a
A mixture of N-benzyl crotonamide (1 mmol) and phenylbo-
ronic acid (2 mmol) in aqueous dioxane (6/1, 6 mL) was stirred at
100 °C for 16 h in the presence of an acid or a base (0.05-1.0
b
equiv), Rh(acac)(C2H4)2 (3 mol %), and (S)-binap (4.5 mol %). GC
yields based on the amide. The enantioselectivities were in a range
of 93-94% ee.
Although the rhodium-binap complex achieved high
enantioselectivities, the addition to the unsaturated
amides suffered from incomplete conversion resulting in
moderate chemical yields (<70%). It was found that
various acids strongly retard the reaction and, reversely,
that the addition of a base accelerates the reaction (Table
2). The inhibitory effect of acids can be in the order of
acid strength since it was smaller for acetic acid (entry
2) and very large for MeSO3H, TsOH, HCl, and CF3SO3H
(entries 3-6). Water-stable Lewis acids such as Eu(OTf)3
and Yb(OTf)3 were also found to be strong inhibitors
(entries 8 and 9). On the other hand, the addition of an
inorganic base exerts a remarkable accelerating effect
(entries 13-16). The effect was independent of the basic
strengths of NaHCO3, K2CO3, K3PO4, and KOH or the
stoichiometry in a range of 5 to 200 mol %, except that
NaOAc exceptionally resulted in no reaction (entry 12).
The presence of a base did not influence the high
enantioselectivity of the rhodium/binap complex.
binap to [RhOH(cod)]2 is a convenient alternative for the
preparation of RhOH/binap complex (solid line and 0),
the slow ligand exchange resulting in incomplete com-
plexation decreased the enantioselectivities.
Representative results of asymmetric additions of
arylboronic acids to R,â-unsaturated amides in the pres-
ence of K2CO3 (50 mol %), as well as RhCl/(S)-binap
catalyst (3 mol %), are summarized in Table 3. Phenyl-
boronic acid was added to a series of crotonamides to
evaluate the effect of N-substituents on yields or enan-
tioselectivity (entries 1-4). Under basic conditions using
K2CO3 (50 mol %), crotonamide and its N-phenyl, N-
cyclohexyl, and N-benzyl derivatives provided the addi-
tion products with 89% ee, 90% ee, 93% ee, and 93% ee,
respectively (entries 1-4), though no reaction was ob-
served for N,N-dialkyl derivatives such as the piperidine
amide. A series of reactions of para-substituted arylbo-
ronic acids showed the superiority of electron-deficient
arylboronic acids. Phenylboronic acid and its 4-trifluo-
romethyl derivative reacted much faster, and much better
yields and enantioselectivities were obtained (entries 4
The effect of added bases on the reaction rate is shown
in Figure 1. The addition of phenylboronic acid to
N-benzyl crotonamide at 100 °C in the presence of Rh-
(acac)/(S)-binap (3 mol %) resulted in 76% yield after 4
h. Further prolongation to 16 h was no longer effective
to complete the reaction (solid line and 9). In contrast,
(15) Uson, R.; Oro, L. A.; Cabeza, J . A. Inorg. Synth. 1985, 23, 126.
(16) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.

8946 J . Org. Chem., Vol. 66, No. 26, 2001
Sakuma and Miyaura
Ta ble 3. Asym m etr ic Ad d ition of P h en ylbor on ic Acid to r,â-Un sa tu r a ted Am id esa
entry
amides
ArB(OR)2
PhB(OH)2
PhB(OH)2
PhB(OH)2
yieldb (%)
% ee
[R]20 (CDCl3)
D
1
2
3
4
5
6
7
8
9
(E)-CH3CHdCHCONH2
(E)-CH3CHdCHCONHPh
62
88
80
85
82
74
50
tr
89
19
90
88
89
90
93
93
92
87
77
-30.9 (1.01)
-51.8 (1.01)
-30.1 (1.01)
-12.1 (1.00)
-5.3 (1.03)
-11.6 (1.00)
-11.6 (1.00)
(E)-CH3CHdCHCONHc-C6H11
(E)-CH3CHdCHCONHCH2Ph
(E)-CH3CHdCHCONHCH2Ph
(E)-CH3CHdCHCONHCH2Ph
(E)-CH3CHdCHCONHCH2Ph
(E)-PhCHdCHCONHCH2Ph
(E)-C5H11CHdCHCONHCH2Ph
(E)-(CH3)2CHCHdCHCONHCH2Ph
(E)-CH3CHdCHCONHCH2Ph
(E)-CH3CHdCHCONHCH2Ph
PhB(OH)2
4-CF3C6H4B(OH)2
4-MeC6H4B(OH)2
4-MeOC6H4B(OH)2
PhB(OH)2
PhB(OH)2
91
95
91
91
-4.6 (1.00)
-8.0 (1.00)
10
11
12
PhB(OH)2
PhB(O2C2H4)c
PhB(O2C2 Me4)d
a
A mixture of an amide (1 mmol), ArB(OR)2 (2 mmol), and K2CO3 (0.5 mmol) in aqueous dioxane (6/1. 3.5 mL) was stirred at 100 °C
for 16 h in the presence Rh(acac)(C2H4)2 (3 mol %), and (S)-binap (4.5 mol %). Isolated yields. c 2-Phenyl-1,3-2-benzodioxaborole. 2-
Phenyl-4,4,5,5-tetramethyl-1,3,2-benzodioxaborole.
b
d
solution were sampled with a syringe (ca. 0.1 mL) and poured
into a stirred mixture of ethyl acetate and water. The yields
of N-benzyl-3-phenylbutanamide determined by GC analysis
are shown in the figure by the solid line and 9.
A mixture of Rh(acac)(C2H4)2 (0.06 mmol), (S)-binap (0.09
mmol), phenylboronic acid (4 mmol), N-benzyl crotonamide (2
mmol), and K2CO3 (0.2 mmol, 10 mol %) in 1,4-dioxane (12
mL) and water (2 mL) was stirred at 100 °C. The yields at
specific intervals are shown by the dotted line and 2. An
analogous reaction using K2CO3 (1 mmol, 50 mol %) resulted
in yields identical to that when using 10 mol % K2CO3.
A mixture of Rh(acac)(C2H4)2 (0.06 mmol), (S)-binap (0.09
mmol), phenylboronic acid (4 mmol), and N-benzyl crotonamide
(2 mmol) in dioxane (12 mL) and H2O (2 mL) was treated with
1 N HCl (0.1 mL, 0.1 mmol) at room temperature. No reaction
was observed during 3 h at 100 °C. Aqueous K2CO3 (2 M, 0.15
mL, 0.3 mmol) was then added to the mixture. The yields at
specific intervals are plotted in the figure by the dotted line
and O.
A mixture of [RhOH(cod)]2 (0.03 mmol) and (S)-binap (0.09
mmol) in dioxane (2 mL) was stirred for 2 h at room temper-
ature. Phenylboronic acid (4 mmol), N-benzyl crotonamide
(2 mmol), dioxane (10 mL), and H2O (2 mL) were then added,
and the mixture was stirred at 100 °C. The yields determined
by GC analysis are shown in the figure by the solid line
and 0.
and 5) than those of 4-methyl- and 4-methoxyphenylbo-
ronic acid (entries 6 and 7). Such an effect of substituents
was also observed in the addition to R,â-unsaturated
ketones or esters, though it was not as significant as
those of the amides. As seen in many of our previous
reactions with enones and R,â-unsaturated esters,8 the
bulkiness of â-substituents significantly affected chemical
yields (entries 8-10). The rhodium-binap catalyst can be
limitedly used for â-methyl and â-primary alkyl unsatur-
ated amides (entries 4 and 9) because analogous reactions
were very slow for phenyl and isopropyl derivatives
(entries 8 and 10). Under similar reaction conditions
using a base, both ethylenegycol and pinacol ester of
phenylboronic acid smoothly added to the amides with
enantioselectivities comparable to that of phenylboronic
acid (entries 11 and 12). The reaction can be applied to
the synthesis of more functionalized derivatives, since
various pinacol arylboronic esters are now accessible by
the palladium-catalyzed cross-coupling reaction of halo-
arenes or triflates with bis(pinacolato)diboron17-19 or by
the analogous coupling reaction of haloarenes with pi-
nacolborane,20,21 and both reactions tolerate various
functional groups.
Gen er a l P r oced u r e for 1,4-Ad d ition to R,â-Un sa tu r -
a ted Am id es (Ta ble 3). Rh(acac)(C2H4)2 (0.03 mmol), (S)-
binap (0.045 mmol), arylboronic acid (2 mmol), K2CO3 (0.5
mmol), and R,â-unsaturated amide (1 mmol) were added to
the flask containing a magnetic stirring bar, a septum inlet,
and a reflux condenser. The flask was flashed with argon and
then charged with 1,4-dioxane (3 mL) and water (0.5 mL). The
mixture was stirred for 16 h at 100 °C. The product was
extracted with ethyl acetate, washed with brine, and dried over
anhydrous magnesium sulfate. Chromatography over silica gel
gave the desired product. HPLC analysis was directly per-
formed with chiral stationary phase column, Chiralcel OD-H,
OB-H and AD, purchased from Dicel.
Exp er im en ta l Section
Effect of Ba ses (F igu r e 1). Rh(acac)(C2H4)2 (0.06 mmol),
(S)-binap (0.09 mmol), phenylboronic acid (4 mmol), and
Ν-benzyl crotonamide (2 mmol) were added to a flask contain-
ing a magnetic stirring bar, a septum inlet, and a reflux
condenser. Τhe flask was flashed with argon and charged with
1,4-dioxane (12 mL), water (2 mL), and pentadecane (0.72
mmol) as an internal standard. The mixture was then stirred
for 16 h at 100 °C. At suitable time intervals, portions of
(17) Ishiyama, T.; Murata, M.; Miyaura, N. J . Org. Chem. 1995, 60,
7508.
(18) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett.
1997, 38, 3447.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and spectral and/or analytical data of the products This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) For a review: Ishiyama, T.; Miyaura, N. J . Organomet. Chem.
2000, 611, 392.
(20) Murata, M.; Watanabe, S.; Masuda, Y. J . Org. Chem., 1999,
62, 6458.
(21) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J . Org. Chem.
2000, 65, 164.
J O010747N