A new approach to axially chiral bipyridine N,N′-dioxides bearing aromatic substituents and their use for catalytic asymmetric allylation of aldehydes with allyl(trichloro)silane

Article abstract of DOI:10.1002/adsc.200404054

Palladium-catalyzed cross-coupling of bipyridine N,N′-dioxide 6,6′-dichloride (R_nap,R_pyr)-1 with the aryl Grignard reagents opened a new approach to axially chiral bipyridine N,N′-dioxides (R)-2 bearing a variety of aryl groups at th

Full text of DOI:10.1002/adsc.200404054

FULL PAPERS
A New Approach to Axially Chiral Bipyridine N,N’-Dioxides
Bearing Aromatic Substituents and their Use for Catalytic
Asymmetric Allylation of Aldehydes with Allyl(trichloro)silane
Asato Kina, Toyoshi Shimada, Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Fax: (þ81)-75-753-3988, e-mail: thayashi@kuchem.kyoto-u.ac.jp
Received: February 21, 2004; Accepted: June 18, 2004
Supporting Information for this article is available on the WWW under http://asc.wiley-vch.de.
Abstract: Palladium-catalyzed cross-coupling of bi- lective for the asymmetric allylation of aldehydes
pyridine N,N’-dioxide 6,6’-dichloride (Rnap,Rpyr)-1 with allyl(trichloro)silane. The allylation took place
with the aryl Grignard reagents opened a new ap- with 0.01–0.1 mol % of (R)-2d giving homoallyl alco-
proach to axially chiral bipyridine N,N’-dioxides hols of up to 94% ee.
(R)-2 bearing a variety of aryl groups at the 6 and 6’
positions. One of the N,N’-dioxides (R)-2d which is Keywords: allylation; asymmetric catalysis; axial chir-
substituted with 3,5-dimethyl-4-methoxy groups was ality; bipyridine N,N’-dioxide; diversity-oriented strat-
found to be highly catalytically active and enantiose- egy; Lewis bases; ligand design
Introduction
Recently, Lewis base-catalyzed asymmetric allylation of
aldehydes with allyl(trichloro)silanes has been recog-
nized to beone ofthe mostefficientmethods ofobtaining
homoallyl alcohols with high enantioselectivity.[1] Some
chiral Lewis bases such as chiral phosphoramides and
chiral formamides have been first used as the enantiose-
lective catalysts for this asymmetric transformation.[1]
Since Nakajimaꢀs report in 1998[2] that axially chiral
2,2’-bipyridine N,N’-dioxides are effective as catalysts
Scheme 1. Previous synthetic route to axially chiral bipyri-
for the asymmetric allylation, this class of 2,2’-bipyridine dine N,N’-dioxides.
N,N’-dioxide derivatives has attracted considerable at-
tention[3,4] owing to their high catalytic activity and high
enantioselectivity. In our previous paper,[5] we reported Results and Discussion
a new synthetic route to axially chiral bipyridine N,N’-di-
oxides (Scheme 1), which allows us to obtain enantio- As a versatile intermediate for the preparation of bipyr-
merically pure samples without optical resolution proce- idine N,N’-dioxides bearing a variety of aryl groups at
dures. One of the bipyridine N,N’-dioxides which is sub- the 6 and 6’ positions, we designed bipyridine N,N’-diox-
stituted with phenyl groups at the 6 and 6’ positions is so ide 6,6’-dichloride (Rnap,Rpyr)-1, which is expected to be
catalytically active for the asymmetric allylation that the readily converted into 6,6’-diarylated derivatives by
amount of the catalyst can be reduced to 0.01 mol % transition metal-catalyzed cross-coupling reactions[6]
without loss of enantioselectivity. Unfortunately, howev- (Scheme 2).
er, this route has a drawback in that the 6 and 6’ substitu-
Treatment of cyclic diester N,N’-dioxides (Rnap,Rpyr)-
ents must be introduced at the first step of the prepara- 3,[5] whose preparation has been reported previously,
tion scheme, which makes it difficult to modify the bipyr- with phosphorus oxychloride and a large excess of so-
idine N,N’-dioxides at the 6 and 6’ positions. Here we re- dium chloride in dimethylformamide gave a 66% yield
port a diversity-oriented strategy for the preparation and of dichlorobipyridine (Rnap,Rpyr)-4. The high concentra-
fine-tuning of the chiral bipyridineN,N’-dioxide catalysts tion of the chloride is important for this substrate, the
for the asymmetric allylation of aldehydes.
chlorination yield being much lower (29%) in the ab-
Adv. Synth. Catal. 2004, 346, 1169–1174
DOI: 10.1002/adsc.200404054
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Asato Kina et al.
FULL PAPERS
Scheme 2. New approach to axially chiral bipyridine N,N’-di-
oxides (R)-2 bearing various aromatic substituents at the 6
and 6’ positions.
sence of sodium chloride.[7] Bipyridine dichloride 4 was
subjected to the oxidation with urea/hydrogen peroxide
adduct and trifluoroacetic anhydride.[8] Unfortunately,
the oxidation was very slow for this electron-deficient
pyridine to give only 21% of the dichlorobipyridine
N,N’-dioxide 1. The oxidation of recovered substrate 4
and its monoxide two more times gave a 47% combined
yield of the dioxide 1. The cross-coupling of dichloride
(Rnap,Rpyr)-1 with aryl Grignard reagents (3.0equivs.)
proceeded in the presence of PdCl2(dppf)[9] (5 mol %)
in tetrahydrofuran at À158C to give high yields of the
6,6’-diarylated-2,2’-bipyridine N,N’-dioxides (Rnap,Rpyr)-
5a–f, where the aryl groups are phenyl (a), 4-methoxy-
phenyl (b), 4-trifluoromethylphenyl (c), 3,5-dimethyl-
4-methoxyphenyl (d), 3,5-diphenyl-4-methoxyphenyl
(e), and 3,5-di(tert-butyl)-4-methoxyphenyl (f). It is
noteworthy that the dichloride 1 undergoes the palladi-
um-catalyzed cross-coupling under mild conditions. The
electron-withdrawing character of the pyridine N-oxide,
which accelerates the oxidative addition to a palladi-
um(0), is probably responsible for the high reactivity to-
ward the cross-coupling.[10,11] Alkaline hydrolysis of cy-
clic diester (Rnap,Rpyr)-5 gave high yields of the bipyri-
dine N,N’-dioxide diols (R)-2 which are substituted
with the aryl groups at the 6 and 6’ positions. The chiral
auxiliary, (R)-1,1’-binaphthalene-2,2’-dicarboxylic acid,
was recovered quantitatively.
Scheme 3. Preparation of axially chiral bipyridine N,N’-diox-
ides (R)-2; a) POCl3 (3 equivs.), NaCl (20equivs.), DMF,
608C, 2 h; b) H2NCONH2 ·H2O2 (3.1 equivs.), (CF3CO)2O
(3 equivs.), CH3CN/CH2Cl2, 08C to rt, 3 h, (Â3); c) ArMgBr
(3 equivs.), PdCl2(dppf) (5 mol %), THF, À158C, 1 h; d) 6 N
NaOH, MeOH.
The axially chiral bipyridine N,N’-dioxide diols (R)-2
obtained here were examined for their catalytic activity
and enantioselectivity in the asymmetric allylation of al-
dehydes 6 with allyl(trichloro)silane (Scheme 4). All of
the bipyridine N,N’-dioxides (R)-2 were highly active for
the allylation, catalyzing the reaction at À458C with
0.1 mol % loading. Table 1 summarizes the results ob-
tained for the asymmetric allylation of 4-methoxyben-
Scheme 4. Asymmetric allylation of aldehydes with allyl(tri-
chloro)silane; R¼4-MeOC6H4 (6a), 4-CF3C6H4 (6b), Ph
¼
(6c), 2-MeC6H4 (6d), 2-furyl (6e), (E)-PhCH CH (6f).
zaldehyde (6a) and 4-trifluoromethylbenzaldehyde catalysts does not strongly affect the enantioselectivity,
(6b), where the reaction was stopped after reaction peri- but it affects the catalytic activity. The electron-rich
od of 2.5 h to compare the catalytic activity. Remarkable N,N’-dioxide 2b is more catalytically active than the
points are as follows: 1) Aldehyde 6a which is substitut- electron-poor 2c. 3) Introduction of methyl or phenyl
ed with a methoxy group is always more reactive toward groups at the 3 and 5 positions on the phenyl group of
the present allylation than aldehyde 6b which is substi- N,N’-dioxides increased the enantioselectivity for the al-
tuted with a trifluoromethyl group, and the enantiose- lylation of 6b.
lectivity is always higher for 6a than for 6b irrespective
Bipyridine N,N’-dioxide 2d, which contains both 4-
of the aryl substituents on the bipyridine N,N’-dioxide methoxy group and 3,5-dimethyl groups on the phenyl
catalysts. 2) The electron-donating or -withdrawing ring, showed higher catalytic activity and higher enan-
character of the para-substituent on the N,N’-dioxide tioselectivity for the asymmetric allylation of some oth-
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Adv. Synth. Catal. 2004, 346, 1169–1174

Catalytic Asymmetric Allylation of Aldehydes with Allyl(trichloro)silane
Table 1. Asymmetric allylation of aldehydes 6a and 6b with allyl(trichloro)silane catalyzed by 0.1 mol % of (R)-2a–f.[a]
FULL PAPERS
Entry
Catalyst (Ar-)
Aldehyde
Conversion[b] [%]
Yield[c] [%]
% ee[d]
1[e]
2[e]
3
4
5
6
7
8
9
(R)-2a (Ph-)
(R)-2a (Ph-)
(R)-2b (4-MeOC6H4-)
(R)-2b (4-MeOC6H4-)
(R)-2c (4-CF3C6H4-)
6a
6b
6a
6b
6a
6b
6a
6b
6a
6b
6a
6b
100
91
100
97
93
76
100
97
94
91
100
88
96
83
96
84
78
66
98
9075
89
87
96
79
94
56
91
53
91
52
94
(R)-2c (4-CF3C6H4-)
(R)-2d (3,5-Me2-4-MeOC6H2-)
(R)-2d (3,5-Me2-4-MeOC6H2-)
(R)-2e (3,5-Ph2-4-MeOC6H2-)
R)-2e (3,5-Ph2-4-MeOC6H2-)
(R)-2f (3,5-t-Bu2-4-MeOC6H2-)
(R)-2f (3,5-t-Bu2-4-MeOC6H2-)
91
77
89
61
10(
11
12
[a]
The allylation was carried out with (R)-2a–f (0.1 mol %), allyl(trichloro)silane (1.2 equivs.), and diisopropylethylamine
(3.0equivs.) in 1.0M acetonitrile solution at À458C for 2.5 h.
Conversion was determined by NMR analysis (7/(6þ7)).
Yield of isolated product
[b]
[c]
[d]
[e]
Determined by GLC analysis with CP-Chirasil-Dex for 7a, 7b.
Reported in Ref.[5b]
Table 2. Asymmetric allylation of aldehydes 6c–f with allyl(trichloro)silane catalyzed by 0.1 mol % of (R)-2a or (R)-2d.[a]
Entry
Aldehyde
Catalyst (Ar-)
Yield[b] [%]
% ee[c]
1
Ph (6c)
Ph (6c)
Ph (6c)
2-MeC6H4 (6d)
2-MeC6H4 (6d)
2-furyl (6e)
2-furyl (6e)
(E)-PhCH CH (6f)
(E)-PhCH CH (6f)
(R)-2d (3,5-Me2-4-MeOC6H2-)
(R)-2a (Ph-)
96
95
84
99
93
94
93
95
95
91
84
91
90
85
71
63
72
60
2[d]
3
(R)-2d (3,5-Me2-4-MeOC6H2-)[e]
(R)-2d (3,5-Me2-4-MeOC6H2-)
(R)-2a (Ph-)
4
5
6
7
(R)-2d (3,5-Me2-4-MeOC6H2-)
(R)-2a (Ph-)
(R)-2d (3,5-Me2-4-MeOC6H2-)
(R)-2a (Ph-)
¼
8
9[d]
¼
[a]
The allylation was carried out with (R)-2a or (R)-2d (0.1 mol %), allyl(trichloro)silane (1.2 equivs.), and diisopropylethy-
lamine (3.0equivs.) in 1.0M acetonitrile solution at À458C for 2.5 h.
Yield of isolated product.
[b]
[c]
Determined by HPLC analysis with Chiralcel OD-H for 7c, 7f, by HPLC analysis with Chiralpak AD for 7d, and GLC ana-
lysis with CP-Chirasil-Dex for 7e.
[d]
[e]
Reported in Ref.[5b]
0.01 mol % of (R)-2d was used, and the reaction time was 24 h.
er aldehydes. The results are summarized in Table 2, Conclusion
which also contains the data obtained with the standard
phenyl-substituted bipyridine N,N’-dioxide 2a for com- We have developed a new preparative method for axial-
parison. Although the enantioselectivity is still not satis- ly chiral bipyridine N,N’-dioxides where various aryl
factory, it was improved by about 10% by use of (R)-2d substituents can be introduced at the 6 and 6’ positions
in the reaction of benzaldehyde (6c) (entries 1 and 2), an by the palladium-catalyzed cross-coupling of the key di-
aldehyde substituted at the ortho position 6d (entries 4 chloride (Rnap,Rpyr)-1. Those containing a 4-methoxy
and 5), a heteroaryl aldehyde 6e (entries 6 and 7), and group on the phenyl groups at the 6 and 6’ positions
an alkenyl aldehyde 6f (entries 8 and 9). The high cata- were found to be more catalytically active than others
lytic activity of 2d is highlighted in entry 3 where for the asymmetric allylation of aldehydes with allyl(tri-
0.01 mol % of (R)-2d catalyzes the asymmetric allyla- chloro)silane. Highest enantioselectivity in the asym-
tion of benzaldehyde(6c) togivean 84% yield of the cor- metric allylation was observed with the bipyridine
responding homoallyl alcohol (S)-7c without loss of the N,N’-dioxide (R)-2d, which is substituted with the 4-me-
enantioselectivity (91% ee).
thoxy-3,5-dimethylphenyl group.
Adv. Synth. Catal. 2004, 346, 1169–1174
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2H), 7.47 (d, J¼8.4 Hz, 2H), 7.50(t, J¼7.6 Hz, 2H), 7.62 (d,
J¼8.6 Hz, 2H), 7.88 (d, J¼8.6 Hz, 2H), 7.90(d, J¼8.1 Hz,
2H); 13C NMR (CDCl3): d¼63.2, 125.1, 126.4, 126.7, 127.1,
127.3, 127.3, 127.9, 128.0, 132.7, 134.5, 135.3, 138.7, 142.2,
142.8, 166.2; anal. calcd. for C34H20Cl2N2O6: C 65.50, H 3.23;
found: C 65.35, H 3.38.
Experimental Section
General Procedures
All moisture sensitive manipulations were carried out under a
nitrogen atmosphere. Nitrogen gas was dried by passage
through P2O5. Chemical shifts are reported in d ppm refer-
1
enced to an internal tetramethylsilane standard for H NMR
and chloroform-d (d¼77.0ppm) for 13C NMR.
General Procedure for the Palladium-Catalyzed Cross-
Coupling Reaction of (Rnap,Rpyr)-1
To a solution of (Rnap,Rpyr)-1 (100 mg, 0.160 mmol) and PdCl2
(dppf) (5.87 mg, 8.02 mmol) in tetrahydrofuran (1.6 mL) was
Materials and Reagents
Cyclic diester N,N’-dioxide (Rnap,Rpyr)-3,[5] PdCl2(dppf),[9] 4-
methoxy-3,5-di(tert-butyl)phenyl bromide,[12] and 4-methoxy-
3,5-diphenylphenyl bromide,[12] were prepared according to
the reported procedures.
added dropwise
a Grignard reagent (THF solution,
0.48 mmol) at À158C. The reaction mixture was stirred at
À158C for 1 h, before aqueous ammonium chloride was add-
ed. The mixture was extracted with chloroform three times.
The combined organic layer was washed with saturated aque-
ous sodium bicarbonate and aqueous sodium chloride, dried
over anhydrous sodium sulfate, and evaporated under reduced
pressure. The residue was chromatographed on silica gel (ace-
tone/hexane¼1/1) to give (Rnap,Rpyr)-5. The yields are listed in
Scheme 3.
Preparation of Bipyridine N,N’-Dioxide Dichloride
(Rnap,Rpyr)-1
Dichloro cyclic diester (Rnap,Rpyr)-4: A mixture of cyclic diester
N,N’-dioxide (Rnap,Rpyr)-3 (200 mg, 0.361 mmol), sodium chlor-
ide (421 mg, 7.20mmol), dimethylformamide (1.8 mL), and
phosphorus oxychloride (0.10 mL, 1.1 mmol) was stirred at
608C for 2 h. The mixture was quenched with water and ex-
tracted with chloroform three times. The combined extracts
were washed with saturated aqueous sodium bicarbonate and
aqueous sodium chloride. The organic layer was dried over an-
hydrous sodium sulfate, and evaporated under reduced pres-
sure. The residue was chromatographed on alumina (ben-
zene/ethyl acetate¼20/1) to give (Rnap,Rpyr)-4; yield: 141 mg
Cyclic diester N,N’-dioxide (Ar¼phenyl) (Rnap,Rpyr)-5a:
The analytical and spectral data for (R)-5a have been report-
ed.[5]
Cyclic diester N,N’-dioxide (Ar¼4-methoxyphenyl)
(Rnap,Rpyr)-5b: [a]2D0: þ794 (c 1.00, CHCl3); 1H NMR
(CDCl3): d¼3.85 (s, 6H), 4.94 (d, J¼12.5 Hz, 2H), 5.22 (d,
J¼12.5 Hz, 2H), 6.85 (d, J¼8.1 Hz, 2H), 6.87 (d, J¼8.6 Hz,
2H), 7.01 (d, J¼8.9 Hz, 4H), 7.17 (t, J¼7.4 Hz, 2H), 7.37 (d,
J¼8.1 Hz, 2H), 7.49 (t, J¼7.4 Hz, 2H), 7.68 (d, J¼8.7 Hz,
2H), 7.90(m, 8H); 13C NMR (CDCl3): d¼55.4, 63.9, 113.7,
124.7, 125.4, 126.3, 126.6, 127.0, 127.5, 127.7, 127.8, 127.9,
131.0, 132.8, 134.5, 134.8, 138.8, 143.0, 149.0, 160.7, 166.4.
Cyclic diester N,N’-dioxide (Ar¼4-trifluoromethylphenyl)
(Rnap,Rpyr)-5c: [a]D20: þ712 (c 1.00, CHCl3); 1H NMR (CDCl3):
d¼4.91 (d, J¼12.5 Hz, 2H), 5.30(d, J¼12.5 Hz, 2H), 6.88 (d,
J¼8.7 Hz, 2H), 6.95 (d, J¼8.1 Hz, 2H), 7.22 (t, J¼7.6 Hz, 2H),
7.44 (d, J¼8.1 Hz, 2H), 7.52 (t, J¼7.6 Hz, 2H), 7.71 (d, J¼
8.7 Hz, 2H), 7.78 (d, J¼8.3 Hz, 4H), 7.91 (d, J¼8.7 Hz, 2H),
7.92 (d, J¼8.2 Hz, 2H), 8.00 (d, J¼8.3 Hz, 4H); 13C NMR
1
(66%); [a]2D0: þ439 (c 1.00, CHCl3); H NMR (CDCl3): d¼
4.75 (d, J¼12.2 Hz, 2H), 5.60(d, J¼12.2 Hz, 2H), 6.88 (d,
J¼8.6 Hz, 2H), 7.19 (t, J¼7.6 Hz, 2H), 7.22 (d, J¼8.1 Hz,
2H), 7.33 (d, J¼8.1 Hz, 2H), 7.48 (t, J¼7.6 Hz, 2H), 7.59 (d,
J¼8.6 Hz, 2H), 7.84 (d, J¼8.6 Hz, 2H), 7.88 (d, J¼8.2 Hz,
2H); 13C NMR (CDCl3): d¼63.5, 123.6, 125.1, 127.0, 127.4,
127.6, 127.8, 127.9, 127.9, 129.6, 132.8, 134.4, 138.6, 141.6,
150.1, 155.6, 166.4; anal. calcd, for C34H20Cl2N2O4: C 69.05, H
3.41; found: C 69.15, H 3.70.
Dichloro cyclic diester N,N’-dioxide (Rnap,Rpyr)-1: A sus-
pension of dichloro cyclic diester (Rnap,Rpyr)-4 (3.02 g,
5.11 mmol) and urea-hydrogen peroxide adduct (1.49 g,
15.8 mmol) in dichloromethane (5.1 mL) and acetonitrile
(5.1 mL) was cooled to 08C. Trifluoroacetic anhydride
(2.2 mL, 15 mmol) was slowly added and the reaction mixture
was stirred at 08C for 1 h and at room temperature for addi-
tional 2 h. The reaction was quenched by the addition of an
aqueous solution of sodium sulfite and stirred for 15 minutes,
followed by dilution with chloroform. The organic layer was
separated and washed with saturated aqueous sodium bicar-
bonate, and aqueous sodium chloride. It was dried over anhy-
drous sodium sulfate, and evaporated under reduced pressure.
The residue was chromatographed on silica gel (acetone/
hexane¼1/1) to give (Rnap,Rpyr)-1; yield: 665 mg (21%). The re-
covered substrate and the monoxide were subjected to the ox-
idation two more times to give (Rnap,Rpyr)-1; combined yield:
1.48 g (47%); [a]2D0: þ797 (c 1.00, CHCl3); 1H NMR (CDCl3):
d¼4.95 (d, J¼12.7 Hz, 2H), 5.07 (d, J¼12.7 Hz, 2H), 6.78
(d, J¼8.4 Hz, 2H), 6.87 (d, J¼8.5 Hz, 2H), 7.20(t, J¼7.6 Hz,
(CDCl3): d¼63.5, 123.8 (q, JC-F ¼272.5 Hz), 125.2 (q, JC-F ¼
3.6 Hz), 125.3, 127.0(q, JC-F ¼18.6 Hz), 127.4, 127.9, 127.9,
128.0, 129.8, 131.2, 131.4, 131.7, 132.8, 134.6, 135.8, 136.4,
139.1, 142.8, 148.0, 166.2.
Cyclic diester N,N’-dioxide (Ar¼3,5-dimethyl-4-methoxy-
phenyl) (Rnap,Rpyr)-5d: [a]2D0: þ756 (c 1.00, CHCl3); 1H NMR
(CDCl3): d¼2.37 (s, 12H), 3.78 (s, 6H), 4.95 (d, J¼12.5 Hz,
2H), 5.20(d, J¼12.5 Hz, 2H), 6.86 (d, J¼8.1 Hz, 2H), 6.88
(d, J¼8.6 Hz, 2H), 7.21 (t, J¼7.6 Hz, 2H), 7.38 (d, J¼8.1 Hz,
2H), 7.51 (t, J¼7.6 Hz, 2H), 7.58 (s, 4H), 7.71 (d, J¼8.7 Hz,
2H), 7.91 (d, J¼8.7 Hz, 2H), 7.92 (d, J¼8.1 Hz, 2H); 13C
NMR (CDCl3): d¼16.2, 59.6, 63.8, 125.4, 126.5, 126.6, 127.0,
127.4, 127.7, 127.7, 127.8, 127.8, 127.9, 130.0, 130.9, 132.8,
134.5, 135.0, 138.8, 143.0, 149.2, 158.2, 166.4.
Cyclic diester N,N’-dioxide (Ar¼3,5-diphenyl-4-methoxy-
phenyl) (Rnap,Rpyr)-5e: [a]2D0: þ554 (c 0.502, CHCl3);
1H NMR (CDCl3): d¼3.22 (s, 6H), 4.95 (d, J¼12.5 Hz, 2H),
5.24 (d, J¼12.5 Hz, 2H), 6.87 (d, 8.7 Hz, 2H), 6.90(d, J¼
8.0Hz, 2H), 7.19 (t, J¼7.7 Hz, 2H), 7.37 (t, J¼7.4 Hz, 4H),
7.45 (t, J¼7.4 Hz, 8H), 7.48 (d, J¼8.0Hz, 2H), 7.49 (t, J¼
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Catalytic Asymmetric Allylation of Aldehydes with Allyl(trichloro)silane
FULL PAPERS
7.7 Hz, 2H), 7.66 (d, J¼8.4 Hz, 8H), 7.69 (d, J¼8.6 Hz, 2H),
7.88 (d, J¼8.6 Hz, 2H), 7.89 (d, J¼8.0Hz, 2H), 7.92 (s, 4H);
13C NMR (CDCl3): d¼60.5, 63.6, 125.3, 126.7, 126.9, 127.0,
127.3, 127.4, 127.6, 127.8, 127.9, 128.0, 128.2, 129.3, 131.6,
132.8, 134.5, 135.1, 135.6, 138.0, 138.7, 143.0, 148.8, 156.1, 166.3.
Cyclic diester N,N’-dioxide [Ar¼3,5-di(tert-butyl)-4-me-
thoxyphenyl] (Rnap,Rpyr)-5f: [a]2D0: þ632 (c 1.00, CHCl3);
1H NMR (CDCl3): d¼1.50(s, 36H), 3.77 (s, 6H), 4.94 (d, J¼
12.4 Hz, 2H), 5.24 (d, J¼12.4 Hz, 2H), 6.86 (d, J¼8.2 Hz,
2H), 6.88 (d, J¼8.7 Hz, 2H), 7.21 (t, J¼7.6 Hz, 2H), 7.36 (d,
J¼8.2 Hz, 2H), 7.51 (t, J¼7.6 Hz, 2H), 7.70(d, J¼8.6 Hz,
2H), 7.78 (s, 4H), 7.91 (d, J¼8.6 Hz, 2H), 7.92 (d, J¼8.2 Hz,
2H); 13C NMR (CDCl3): d¼32.1, 36.0, 64.0, 64.4, 125.4, 126.8,
126.8, 126.9, 127.1, 127.5, 127.8, 127.9, 128.0, 128.1, 132.9,
134.5, 134.6, 138.7, 143.2, 143.6, 150.1, 160.8, 166.5.
(R)-3,3’-Bis(hydroxymethyl)-6,6’-bis(3,5-dimethyl-4-me-
thoxyphenyl)-2,2’-bipyridine N,N’-dioxide [(R)-2d]: [a]2D0:
1
þ157 (c 0.25, CHCl3); H NMR (CDCl3): d¼2.31 (s, 12H),
3.76 (s, 6H), 4.27 (d, J¼12.2 Hz, 2H), 4.33 (br, 2H), 4.87 (br,
2H), 7.48 (s, 4H), 7.57 (d, J¼8.3 Hz, 2H), 7.59 (d, J¼8.3 Hz,
2H); 13C NMR (CDCl3): d¼16.2, 59.7, 62.4, 127.3, 127.9,
128.4, 130.1, 130.9, 138.8, 142.2, 149.4, 158.3; HRMS (FAB):
calcd. for C30H33N2O6 [Mþ þH]: 517.2339; found: 517.2344.
(R)-3,3’-Bis(hydroxymethyl)-6,6’-bis(3,5-diphenyl-4-me-
thoxyphenyl)-2,2’-bipyridine N,N’-dioxide [(R)-2e]: [a]2D0: þ
1
33.4 (c 0.25, CHCl3); H NMR (CDCl3): d¼3.21 (s, 6H), 4.32
(d, J¼12.2 Hz, 2H), 4.39 (br, 2H), 4,74 (br, 2H), 7.35 (t, J¼
7.4 Hz, 4H), 7.42 (t, J¼7.6 Hz, 8H), 7.61 (d, J¼7.1 Hz, 8H),
7.63 (d, J¼8.2 Hz, 2H), 7.69 (d, J¼8.2 Hz, 2H), 7.82 (s, 4H);
13C NMR (CDCl3): d¼60.5, 62.3, 127.4, 127.5, 127.9, 128.2,
128.3, 129.2, 131.6, 135.6, 137.9, 139.1, 142.1, 148.9, 156.2;
HRMS (FAB): calcd. for C50H41N2O6 [Mþ þH]: 765.2965;
found: 765.2961.
General Procedure for the Hydrolysis of (Rnap,Rpyr)-
5a–c
(R)-3,3’-Bis(hydroxymethyl)-6,6’-bis(3,5-di(tert-butyl)-4-
methoxyphenyl)-2,2’-bipyridine N,N’-dioxide [(R)-2f]: [a]2D0:
1
þ112 (c 0.27, CHCl3); H NMR (CDCl3): d¼1.44 (s, 36H),
To a suspension of (Rnap,Spyr)-5a–c (0.11 mmol) in methanol
(6 mL) was added 6 N aqueous sodium hydroxide (1 mL). Af-
ter stirring at room temperature for 34 h, methanol was re-
moved from the reaction mixture to give a white precipitate.
It was filtered, and the filter cake was washed with 15% aque-
ous sodium hydroxide to give (R)-3,3’-bis(hydroxymethyl)-
6,6’-disubstituted-2,2’-bipyridine N,N’-dioxides [(R)-2a–c].
The yields are listed in Scheme 3.
3.74 (s, 6H), 4.30(d, J¼11.9 Hz, 2H), 4.41 (d, J¼11.9 Hz,
2H), 7.61 (d, J¼8.3 Hz, 2H), 7.64 (d, J¼8.3 Hz, 2H), 7.69 (s,
4H); 13C NMR (CDCl3): d¼32.0, 35.9, 62.8, 64.3, 126.1, 128.1,
128.1, 128.8, 138.4, 142.6, 143.5, 150.4, 161.0; HRMS(FAB):
calcd. for C42H57N2O6 [Mþ þH]: 685.4217; found: 685.4221.
(R)-3,3’-Bis(hydroxymethyl)-6,6’-diphenyl-2,2’-bipyridine
N,N’-dioxide[(R)-2a]: The analytical and spectral data for(R)-
2a have been reported.[5]
General Procedure for the Asymmetric Allylation
Catalyzed by (R)-2:
(R)-3,3’-Bis(hydroxymethyl)-6,6’-bis(4-methoxyphenyl)-
2,2’-bipyridine N,N’-dioxide [(R)-2b]: [a]2D0: À151 (c 0.25,
CHCl3/MeOH¼1/1); 1H NMR (CDCl3): d¼3.86 (s, 6H), 4.29
(d, J¼11.9 Hz, 2H), 4.39 (t, J¼11.0Hz, 2H), 4.96 (d, J¼
9.7 Hz, 2H), 6.98 (d, J¼8.7 Hz, 4H), 7.62 (s, 4H), 7.81 (d, J¼
8.7 Hz, 4H); 13C NMR (CDCl3): d¼55.4, 63.1, 113.7, 124.1,
127.8, 129.1, 131.2, 138.5, 142.7, 149.6, 160.9; HRMS(FAB):
calcd. for C26H25N2O6 [Mþ þH]: 461.1713; found: 461.1712.
(R)-3,3’-Bis(hydroxymethyl)-6,6’-bis(4-trifluoromethyl-
phenyl)-2,2’-bipyridine N,N’-dioxide [(R)-2c]: [a]2D0: À21.7 (c
0.25, CHCl3/MeOH¼1/1); 1H NMR (CDCl3): d¼4.33 (d, J¼
11.5 Hz, 2H), 4.44 (m, 4H), 7.65 (d, J¼8.1 Hz, 2H), 7.69 (d,
J¼8.1 Hz, 2H), 7.74 (d, J¼8.1 Hz, 4H), 7.93 (d, J¼8.1 Hz,
4H); 13C NMR (CDCl3): d¼60.9, 123.8 (q, JC-F ¼274 Hz),
To a solution of a given catalyst (R)-2 (0.001 mmol, 0.1 mol %),
aldehyde 6 (1.00 mmol) and diisopropylethylamine (0.52 mL,
3.0mmol) in acetonitrile (1 mL) was added dropwise allyl(tri-
chloro)silane (0.17 mL, 1.2 mmol) at À458C. The reaction
mixture was stirred at À458C for 2.5 h, before 1 mL of 3 N so-
dium hydroxide was added. The mixture was stirred at room
temperature for additional 10min, and then extracted with di-
ethyl ether three times. The combined organic layer was wash-
ed with aqueous sodium chloride, dried over anhydrous so-
dium sulfate, and evaporated under reduced pressure. The res-
idue was purified by flash column chromatography (ethyl ace-
tate/hexane¼1/5) to give the corresponding homoallyl alcohol
[(S)-7]. The yields and ees are listed in Tables 1 and 2.
(S)-1-(2-Methylphenyl)-3-buten-1-ol [(S)-7d]:[13] [a]D20:
À46.8 (c 1.26, EtOH); 90% ee by HPLC analysis: tR (R)-(þ),
15.8 min; (S)-(À), 18.1 min (Daicel Chiralpak AD, hexane/2-
propanol¼19/1, 0.50 mL/min); ref.[13] for (R)-7d of 65% ee:
125.3 (q, JC-F ¼4.1 Hz), 127.8, 128.1, 130.1, 131.8 (q, JC-F
¼
32.1 Hz), 135.4, 141.0, 141.1, 147.6; HRMS(FAB): calcd. for
C26H19F6N2O4 [Mþ þH]: 537.1249; found: 537.1254.
1
[a]D: þ30.4 (EtOH); H NMR (CDCl3): d¼1.95 (br, 1H),
2.36 (s, 3H), 2.46 (m, 2H), 4.98 (m, 1H), 5.15 (ddt, J¼10.2,
1.9, 1.1 Hz, 1H), 5.18 (ddt, J¼17.3, 1.9, 1.6 Hz, 1H), 5.85
(dddd, J¼17.3, 10.2, 7.7, 6.5 Hz, 1H), 7.12 (d, J¼7.4 Hz, 1H),
7.17 (t, J¼7.4 Hz, 1H), 7.23 (t, J¼7.7 Hz, 1H), 7.48 (d, J¼
7.7 Hz, 1H); 13C NMR (CDCl3): d¼19.0, 42.6, 69.6, 118.2,
125.1, 126.2, 127.2, 130.3, 134.3, 134.7, 141.9.
General Procedure for the Hydrolysis of (Rnap,Rpyr)-
5d–f
To a solution of (Rnap,Rpyr)-5d–f (0.100 mmol) in methanol
(20mL) and tetrahydrofuran (5 mL) was added 6 N aqueous
sodium hydroxide (5 mL), and the mixture was stirred at
408C for 79 h. After removal of methanol, the aqueous layer
was extracted with chloroform three times. The combined or-
ganic layer was washed with aqueous sodium chloride, dried
over anhydrous sodium sulfate, and evaporated to give (R)-
3,3’-bis(hydroxymethyl)-6,6’-disubstituted-2,2’-bipyridine N,N’-
dioxides [(R)-2d–f]. The yields are listed in Scheme 3.
(S)-1-(2-Furyl)-3-buten-1-ol [(S)-7e]:[14] [a]D20: À28.7 (c 1.60,
CHCl3); 71% ee by GLC analysis: tR (S)-(À) 12.3 min; (R)-(þ),
13.1 min (CP-Chirasil-Dex CB, column temperature 958C);
Ref.[14] for (R)-7e of 83% ee: [a]D29: þ24.9 (c 1.0, CHCl3);
1H NMR (CDCl3): d¼2.08 (br, 1H), 2.63 (m, 2H), 4.75 (br,
1H), 5.12 (ddt, J¼10.2, 1.8, 1.1 Hz, 1H), 5.14 (ddt, J¼17.1,
1.8, 1.5 Hz, 1H), 5.81 (ddt, J¼17.1, 10.2, 7.1 Hz, 1H), 6.25 (m,
Adv. Synth. Catal. 2004, 346, 1169–1174
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1173

Asato Kina et al.
FULL PAPERS
1H), 6.33 (dd, J¼3.3, 1.8 Hz, 1H), 7.37 (dd, J¼1.8, 0.9 Hz, 1H);
13C NMR (CDCl3): d¼40.0, 66.9, 106.0, 110.1, 118.3, 133.7,
141.9, 156.0.
(S)-1-(4-Methoxyphenyl)-3-buten-1-ol [(S)-7a], (S)-1-(4-
Trifluoromethylphenyl)-3-buten-1-ol [(S)-7b], (S)-1-Phenyl-
3-buten-1-ol [(S)-7c], (S)-1-Phenyl-1,5-hexadien-3-ol [(S)-
7f]: The analytical and spectral data for alcohols, (S)-7a, 7b,
7c, and 7f have been reported.[5]
[4] S. E. Denmark, Y. Fan, J. Am. Chem. Soc. 2002, 124,
4233.
[5] a) T. Shimada, A. Kina, S. Ikeda, T. Hayashi, Org. Lett.
2002, 4, 2799; b) T. Shimada, A. Kina, T. Hayashi, J.
Org. Chem. 2003, 68, 6329.
[6] a) Metal-Catalyzed Cross-Coupling Reactions, (Eds.: F.
Diederich, P. J. Stang), Wiley-VCH, New York, 1998;
b) J. Tsuji, Palladium Reagents and Catalysts, Innovations
in Organic Synthesis, Wiley, New York, 1995.
[7] These references gave us good suggestions to find new
reaction conditions, although the procedures shown are
not effective for our substrate (Rnap,Rpyr)-3; a) M. Hama-
na, I. Kumadaki, Yakugaku Zasshi 1966, 86, 1090; b) J.-C.
Jung, Y.-J. Jung, O.-S. Park, Synth. Commun. 2001, 31,
2507.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Re-
search, the Ministry of Education, Japan. Asato Kina thanks
the Japan Society for the Promotion of Science for the award
of a fellowship for graduate students.
[8] S. Caron, N. M. Do, J. E. Sieser, Tetrahedron Lett. 2000,
41, 2299.
[9] T. Hayashi, M. Konishi, Y. Kobori, M. Kumada, T. Higu-
chi, K. Hirotsu, J. Am. Chem. Soc. 1984, 106, 158.
[10] Palladium-catalyzed cross-coupling of chloropyridine N-
oxides has been reported: O. Lohse, P. Thevenin, E.
Waldvogel, Synlett 1999, 45.
[11] For a recent review on the palladium-catalyzed cross-
coupling of aryl chlorides, see: A. F. Littke, G. C. Fu, An-
gew. Chem. Int. Ed. 2002, 41, 4176.
[12] H. Yang, A. S. Hay, Synthesis 1992, 467.
[13] S. E. Denmark, D. M. Coe, N. E. Pratt, B. D. Griedel, J.
Org. Chem. 1994, 59, 6161.
[14] A. Yanagisawa, H. Kageyama, Y. Nakatsuka, K. Asaka-
wa, Y. Matsumoto, H. Yamamoto, Angew. Chem. Int. Ed.
1999, 38, 3701.
References and Notes
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asc.wiley-vch.de
Adv. Synth. Catal. 2004, 346, 1169–1174