Palladium-catalyzed enantioselective intramolecular hydroarylation of alkynes to form axially chiral 4-aryl 2-quinolinones

Article abstract of DOI:10.1002/anie.201100152

A long-awaited asymmetric version of the intramolecular hydroarylation of alkynes to form fused ring systems has been developed. A cationic palladium(II)/(S)-xyl-H₈-binap complex was used to catalyze an enantioselective hydroarylation of alkynes at room temperature to furnish axially chiral 4-aryl 2-quinolinone derivatives in good yields with good enantioselectivity (see scheme; Bn=benzyl).

Full text of DOI:10.1002/anie.201100152

DOI: 10.1002/anie.201100152
Asymmetric Catalysis
Palladium-Catalyzed Enantioselective Intramolecular Hydroarylation
of Alkynes To Form Axially Chiral 4-Aryl 2-Quinolinones**
Tetsuro Shibuya, Yu Shibata, Keiichi Noguchi, and Ken Tanaka*
The transition-metal-catalyzed intramolecular
hydroarylation of alkynes, which was first reported
by Fujiwara and co-workers in 2000,[1] is a useful
method for the synthesis of fused aromatic com-
pounds.[2] A large number of transition-metal
catalysts have been developed to date for this
transformation.[3] Research efforts have been
focused on catalytic efficiency, substrate scope,
and regioselectivity (6-endo-dig versus 5-exo-
dig[4]), whereas no enantioselective variant of this
Scheme 1. Axially chiral 4-aryl 2-quinolinone derivatives as pharmaceutically active
compounds and chiral ligands.
transformation has been reported.[5–7] On the other
hand, recent significant advances in atroposelec-
tive biaryl synthesis[8] through transition-metal-
catalyzed enantioselective [2+2+2] cycloaddition reactions
clearly demonstrate the utility of the asymmetric cyclization
strategy for the synthesis of chiral aromatic compounds.[9–11]
As an alternative asymmetric annulation method for atropo-
selective biaryl synthesis, we recently reported an enantiose-
lective cycloisomerization of N-alkenyl aryl ethynylamides
under the catalysis of a cationic palladium(II)/xyl-segphos
complex to give axially chiral 4-aryl 2-pyridones.[12] However,
axially chiral 4-aryl 2-quinolinones rather than 4-aryl 2-
pyridones have been found as core structures of pharmaceuti-
cally active compounds[13] and chiral ligands[14] (Scheme 1).
Therefore, the development of a method for the catalytic
enantioselective synthesis of 4-aryl-2-quinolinones that would
enable facile access to new synthetic analogues of this class of
compounds in enantiomerically enriched form is an important
topic. Herein, we disclose the first catalytic enantioselective
intramolecular hydroarylation of alkynes. The reaction at
room temperature with a cationic palladium(II)/(S)-xyl-H8-
binap complex as the catalyst furnished axially chiral 4-aryl 2-
quinolinones with good ee values.
We first investigated the reaction of N-benzyl-N-phenyl-
propiolamide 1a, which contains a 2-methoxynaphthyl group
at the alkyne terminus, in the presence of a cationic
palladium(II)/(R)-binap complex (20 mol% Pd). Unfortu-
nately, no reaction was observed at room temperature in
72 hours (Scheme 2). At a higher temperature (808C), a
complex mixture was generated.
Scheme 2. Attempted enantioselective intramolecular hydroarylation of
1a with a cationic palladium(II)/(R)-binap complex. Bn=benzyl.
We anticipated that 3-aryl propiolamide 1b with an
electron-rich 2-naphthyl group on the nitrogen atom would
be more nucleophilic than 3-aryl N-phenylpropiolamide
1a.[15] Furthermore, the hydroarylation would occur at the
electron-rich 1-position of the naphthalene ring[16] to give the
axially chiral benzoquinolinone 2b with a highly configura-
tionally stable biaryl axis owing to the steric demands of the
two large ring systems. Gratifyingly, the expected regio- and
enantioselective hydroarylation proceeded to completion at
room temperature in 40 hours in the presence of a cationic
palladium(II)/(R)-binap complex[17] (10 mol% Pd) to give 2b
in high yield with moderate enantioselectivity (Table 1,
entry 1).
[*] T. Shibuya, Y. Shibata, Prof. Dr. K. Tanaka
Department of Applied Chemistry, Graduate School of Engineering
Tokyo University of Agriculture and Technology
Koganei, Tokyo 184-8588 (Japan)
Fax: (+81)42-388-7037
E-mail: tanaka-k@cc.tuat.ac.jp
Homepage: http://www.tuat.ac.jp/~tanaka-k/
Prof. Dr. K. Noguchi
Instrumentation Analysis Center
Tokyo University of Agriculture and Technology
Koganei, Tokyo 184-8588 (Japan)
[**] This research was supported partly by Grants-in-Aid for Scientific
Research (Nos. 20675002 and 21·906) from MEXT (Japan). We
thank Takasago Int. Co. for the gift of segphos, H8-binap, xyl-binap,
xyl-segphos, xyl-H8-binap, and dtbm-segphos.
We then investigated the effects of a variety of axially
chiral biaryl bisphosphine ligands (Scheme 3) on the yield and
enantioselectivity of the reaction. Among the three bis(di-
phenylphosphine) ligands examined (Table 1, entries 1–3),
(R)-H8-binap furnished 2b with the highest enantioselectivity
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100152.
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Table 1: Screening of chiral ligands for the palladium-catalyzed enantio-
selective intramolecular hydroarylation of 1b.
observed with the (S)-xyl-H8-binap ligand. Finally, a pro-
longed reaction time (72 h) enabled the amount of palladium
required to be decreased to 5 mol%.
We explored the scope of the enantioselective intra-
molecular hydroarylation of alkynes in the presence of the
cationic palladium(II)/(S)-xyl-H8-binap complex for the syn-
thesis of axially chiral 4-aryl 2-quinolinone derivatives
(Table 2). With respect to the substituent at the alkyne
Entry
Ligand
t
[h]
Conv.
[%][a]
Yield
[%][b]
ee
[%]
terminus,
2-methoxynaphthalene
(Table 2,
entry 1),
2-methoxy-6-methylbenzene (entry 2), and 2-methoxymeth-
oxynaphthalene (entry 3) derivatives 1b–d all furnished the
desired benzoquinolinones 2b–d in good yields and with good
ee values. Not only naphthalene derivatives, but also the
carbazole derivative 1e, could be used. The corresponding
fused quinolinone 2e was obtained in good yield with perfect
regioselectivity, although the ee value was moderate (Table 2,
entry 4). 3-Aryl propiolamides bearing various electron-rich
aryl groups on the nitrogen atom could also be employed. The
reactions of tri- and dimethoxyphenyl derivatives 1 f–h
proceeded to give the corresponding axially chiral quinoli-
nones 2 f–h in good yields with good ee values (Table 2,
entries 5–7). Interestingly, the reactions of 3,4-disubstituted
substrates 1i (Table 2, entry 8) and 1j (entry 9) proceeded to
give the sterically less demanding regioisomers 2i and 2j,
respectively, with perfect regioselectivity, although the prod-
uct yields were lower, and the ee value of 2j was moderate. In
contrast, the reaction of 3-methoxyphenyl derivative 1k
proceeded to give the sterically more encumbered regioiso-
mer 2k as the major product, along with the sterically less
encumbered minor regioisomer 2k’ (Scheme 4).
1
2
3
4
5
6
7
8
9
10
11
12
13[c]
(R)-binap
(R)-segphos
40
40
40
40
40
40
40
40
40
40
40
40
72
94
99
100
81
79
100
54
43
55
39
77
93
64
76
73
76
99
12
25
40
33
70
>99
94
69 (+)
69 (+)
75 (+)
75 (+)
72 (+)
90 (À)
(R)-H8-binap
(R)-xyl-binap
(R)-xyl-segphos
(S)-xyl-H8-binap
(R)-dtbm-segphos
(R,R)-Me-duphos
(R,R)-quinoxP*
(S,S)-chiraphos
(S,S)-bdpp
<2
<2
17 (+)
46 (À)
50 (À)
60 (+)
92 (À)
(S,S)-diop
(S)-xyl-H8-binap
100
100
[a] Conversion was determined by 1H NMR spectroscopy. [b] Yield of the
isolated product. [c] The reaction was carried out with 5 mol% of
[Pd(CH3CN)4](BF4)2 and 6 mol% of (S)-xyl-H8-binap.
Scheme 4. Palladium-catalyzed enantioselective intramolecular hydro-
arylation of 1k.
Scheme 3. Structures of chiral bisphosphine ligands.
The presence of the 2-alkoxy-substituted aryl group at the
alkyne terminus is important for both reactivity and enantio-
selectivity. Although the 2-methylnaphthalene derivative 1l
did participate in this reaction, the reaction was sluggish, and
the ee values observed for the product were moderate
(Scheme 5). The effect of the substituents on the nitrogen
atom was also examined. Interestingly, the enantioselectivity
of the reaction decreased dramatically when the nonmasked
NH propiolamide 1m was used (Scheme 6).
Axially chiral 4-aryl 3-bromo-2-quinolinones have been
employed as key intermediates in the synthesis of pharma-
ceutically important compounds[13c] and chiral ligands[14]
(Scheme 1). Therefore, we examined the bromination of the
(Table 1, entry 3). When the steric bulk of the aryl substitu-
ents on the phosphorus atoms of the biaryl bisphosphine
ligands was increased, the enantioselectivity improved
(Table 1, entries 4–6), whereby (S)-xyl-H8-binap furnished
2b in the highest yield with the highest ee value (Table 1,
entry 6). However, the use of sterically more demanding
(R)-dtbm-segphos as a ligand furnished racemic 2b in poor
yield (Table 1, entry 7). Chiral non-biaryl bisphosphine
ligands (Scheme 3) were also examined (Table 1, entries 8–
12); however, the observed ee values did not exceed that
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Table 2: Palladium-catalyzed enantioselective intramolecular hydroarylation of 1b–j to give axially chiral
4-aryl 2-quinolinones 2b–j.[a]
new axially chiral benzoquinoli-
none (À)-2b. The desired reaction
proceeded smoothly with NBS as
the brominating agent in DMF at
room temperature to give the cor-
responding bromide (À)-3 in high
yield (Scheme 7). The absolute
configuration of bromide (À)-3
was determined unambiguously to
be S by the anomalous-dispersion
method.[18]
Entry
1
2
Yield [%][c]
(ee [%])
(t [h], conversion [%][b])
(R)-(À)-2b
1
1b
1c
1d
94 (92)
90 (98)
65 (84)
(72, 100)
(À)-2c
2
A possible mechanism for the
(48, 90)
enantioselective
formation
of
axially chiral benzoquinolinone
(R)-2b through the enantioselec-
tive hydroarylation of 1b under the
(À)-2d
catalysis of
a cationic palladi-
3[d]
(72, 74)
um(II)/(S)-xyl-H8-binap complex
is shown in Scheme 8. The forma-
tion of intermediate A through
bidentate chelation of the alkyne
moiety and the alkoxy group of 1b
by the cationic palladium center
would induce high reactivity and
the rigid chiral environment. The
avoidance of steric interaction
between the benzyl group of 1b
and the equatorial aryl group on
the phosphorus atom of (S)-xyl-H8-
binap in the chelation of intermedi-
ate A would control the axial chir-
ality to give (R)-2b. Indeed, the
reaction rate and enantioselectivity
of the reaction of 2-methylnaph-
thalene derivative 1l were lower
than for the 2-methoxynaphthalene
derivative 1b (Table 2, entry 1
versus Scheme 5). Furthermore,
the reaction of the sterically less
demanding NH propiolamide 1m
proceeded with significantly lower
(À)-2e
4[d]
1e
75 (54)
(72, 84)
(À)-2 f
5
6
7
1 f
1g
1h
97 (71)
90 (87)
75 (70)
(24, 100)
(À)-2g
(24, 100)
(À)-2h
(24, 85)
enantioselectivity
observed for the sterically demand-
ing N-benzylpropiolamide 1b
than
that
(Table 2, entry 1 versus Scheme 6).
In conclusion, the first enantio-
selective intramolecular hydroary-
lation of alkynes to form axially
chiral 4-aryl 2-quinolinones was
developed by using a cationic pal-
ladium(II)/(S)-xyl-H8-binap com-
plex as a catalyst at room temper-
ature. Future studies will focus on
the application of this asymmetric
annulation strategy to the enantio-
selective synthesis of various chiral
aromatic compounds.
(À)-2i
8
1i
1j
50 (80)
44 (55)
(72, 91)
(+)-2j
(72, 54)
9[e]
[a] Reactions were conducted with [Pd(CH3CN)4](BF4)2 (5 mol%), (S)-xyl-H8-binap (6 mol%), and 1b–j
in (CH2Cl)2 at room temperature. [b] Conversion was determined by 1H NMR spectroscopy. [c] Yield of
the isolated product. [d] The reaction was carried out with 10 mol% of [Pd(CH3CN)4](BF4)2 and
12 mol% of (S)-xyl-H8-binap. [e] (R)-binap was used as the ligand.
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Communications
the residue by preparative TLC (hexane/EtOAc 1:1) furnished (R)-
(À)-2b (61.9 mg, 0.140 mmol, 94% yield, 92% ee).
Received: January 8, 2011
Published online: March 31, 2011
Keywords: alkynes · asymmetric catalysis · axial chirality ·
.
hydroarylation · quinolinones
Scheme 5. Palladium-catalyzed enantioselective intramolecular hydro-
arylation of 1l.
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Scheme 6. Palladium-catalyzed enantioselective intramolecular hydro-
arylation of 1m.
Scheme 7. Bromination of 4-aryl 2-quinolinone (R)-(À)-2b to give
bromide (S)-(À)-3. DMF=N,N-dimethylformamide, NBS=N-bromo-
succinimide.
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Scheme 8. Possible mechanism for the enantioselective formation of
(R)-2b with a cationic palladium(II)/(S)-xyl-H8-binap catalyst.
Experimental Section
Representative procedure: Under an argon atmosphere, [Pd-
(CH3CN)4](BF4)2 (3.3 mg, 0.0075 mmol) and (S)-xyl-H8-binap
(6.7 mg, 0.0090 mmol) were dissolved in (CH2Cl)2 (0.4 mL), and the
mixture was stirred at room temperature for 5 min. This mixture was
then added to a solution of 1b (66.2 mg, 0.150 mmol) in (CH2Cl)2
(1.1 mL) at room temperature, and the resulting mixture was stirred
at room temperature for 72 h and then concentrated. Purification of
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