Table 1. Rhodium-Catalyzed Asymmetric 1,4-Addition of
Phenylmetal Species to 4-Quinolone 1a
Table 2. Rhodium-Catalyzed Asymmetric 1,4-Addition of
Arylzinc Reagents to 4-Quinolonesa
entry
Ph-M
conditionsa
yield (%)
eeb (%)
1
2
3
PhB(OH)2
PhZnCl
PhZnCl
A
B
C
10
35
88
99 (R)
99 (R)
98 (R)
a Conditions A: KOH (30 mol %), 1,4-dioxane/H2O (10/1), 50 °C, 20
h. Conditions B: THF, 20 °C, 20 h; then H2O quench. Conditions C:
Me3SiCl (3.0 equiv), THF, 20 °C, 20 h; then 10% HCl(aq) quench. b ee
was determined by chiral HPLC on a Chiralcel OD-H column with hexane/
2-propanol ) 90/10.
amount of 1,4-adduct 2a was obtained (10% yield) with a
recovery of unreacted 1a (72%), although the enantioselec-
tivity of 2a was very high (99% ee).
In an attempt to improve the reactivity, we then explored
the possibility of catalytic asymmetric 1,4-addition of phen-
ylzinc chloride (entry2), which is known to be an effective
nucleophile to structurally similar 2,3-dihydro-4-pyridone
substrates under rhodium catalysis, achieving high yield and
ee.6 Although substrate 1a was completely comsumed by
the use of phenylzinc chloride, 1,4-adduct 2a was obtained
only in 35% yield (with 99% ee), and the rest of the starting
material was converted to unidentified products.
In the hope that the addition of chlorotrimethylsilane might
facilitate the activation of substrate toward 1,4-addition (as
a Lewis acid) and/or the stabilization of the product (by
forming a silyl enol ether),7 we then conducted a reaction in
the presence of chlorotrimethylsilane under otherwise identi-
cal conditions as in entry 2. To our delight, 1,4-adduct 2a
was obtained in 88% yield after hydrolytic workup, and the
ee of this product stayed as high (98% ee; entry 3).8
As shown in Table 2, several other 4-quinolones bearing
substituents on the fused benzene ring can also undergo the
1,4-addition reaction under these conditions, not only with
phenylzinc chloride but also with various other arylzinc
chlorides, to afford a variety of 2-aryl-2,3-dihydro-4-quino-
lones in high yield with excellent enantioselectivity (72-
100% yield, 86-99% ee). It is worth noting that the reactions
are best conducted when a THF solution of arylzinc chloride
and a THF solution of chlorotrimethylsilane are simulta-
neously added to a mixture of 4-quinolones and Rh/(R)-binap
catalyst in THF.9
a Conditions: [RhCl(C2H4)2]2 (7.5 mol % Rh), (R)-binap (8.2 mol %),
Me3SiCl (3.0 equiv), THF, 20 °C, 20 h; then 10% HCl(aq) quench. b ee
was determined by chiral HPLC on a Chiralcel OD-H column with hexane/
2-propanol unless otherwise noted. c ee was determined by chiral HPLC
on a Chiralpak AD-H column with hexane/2-propanol.
1, entry 3) was removed under basic aqueous conditions,
obtaining known compound 3 in 82% yield with no erosion
of ee (98% ee; eq 2). By comparison of the optical rotation
(9) General Procedure. Compound 1 (0.20 mmol) was added to a
solution of [RhCl(C2H4)2]2 (2.9 mg, 15 µmol of Rh) and (R)-binap (10.3
mg, 16.5 µmol) in THF (0.46-0.66 mL) at room temperature. ArZnCl
(0.77-0.66 mL, 0.60 mmol; 0.78-0.91 M solution in THF) and chloro-
trimethylsilane (0.77-0.66 mL, 0.60 mmol; 0.78-0.91 M solution in THF)
were simultaneously added dropwise to it over 10 min, and the resulting
mixture was stirred for 20 h at 20 °C. The reaction was quenched with
HCl (10% aqueous), and the mixture was stirred for 1 h at room temperature.
This was extracted with Et2O, and the organic layer was dried over MgSO4,
filtered, and concentrated under vacuum. The residue was purified by silica
gel preparative TLC with EtOAc/hexane to afford the desired 1,4-adduct
2.
To determine the absolute configuration of these 1,4-
adducts, the benzyloxycarbonyl group of 2a (98% ee; Table
(5) (a) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N.
J. Am. Chem. Soc. 1998, 120, 5579-5580. (b) Hayashi, T.; Takahashi, M.;
Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 2002, 124, 5052-5058.
(6) Shintani, R.; Tokunaga, N.; Doi, H.; Hayashi, T. J. Am. Chem. Soc.
2004, 126, 6240-6241.
(7) Hayashi, T.; Yamamoto, S.; Tokunaga, N. Angew. Chem., Int. Ed.
2005, 44, 4224-4227.
(8) The use of other chlorotrialkylsilanes (e.g., Et3SiCl and t-BuMe2-
SiCl) is not effective for promoting this 1,4-addition reaction.
(10) (a) Antus, S.; Baitz-Ga´cs, E.; Kajta´r, J.; Snatzke, G.; To¨ke´s, A. L.
Liebigs Ann. Chem. 1994, 497-502. (b) To¨ke´s, A. L.; Szila´gyi, L. Synth.
Commun. 1987, 17, 1235-1245.
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Org. Lett., Vol. 7, No. 23, 2005