Regioselective synthesis of optically active (pyrazolyl)pyridines with adjacent quaternary carbon stereocenter: Chiral N,N-donating ligands

Article abstract of DOI:10.1016/j.tet.2004.10.092

Novel optically active 2-(pyrazol-1-yl)pyridines have been prepared using resolved the O-methyl ether of atrolactic acid as a source of the adjacent quaternary carbon stereocenter. Different regioisomers were formed selectively in the reaction of 2-hydraz

Full text of DOI:10.1016/j.tet.2004.10.092

Tetrahedron 61 (2005) 623–628
Regioselective synthesis of optically active (pyrazolyl)pyridines
with adjacent quaternary carbon stereocenter: chiral
N,N-donating ligands
*
Rafał Kowalczyk and Jacek Skarz˙ewski
Institute of Organic Chemistry, Biochemistry and Biotechnology, Wrocław University of Technology, Wyb. Wyspianskiego 27, PL50370
Wrocław, Poland
Received 22 July 2004; revised 8 October 2004; accepted 29 October 2004
Abstract—Novel optically active 2-(pyrazol-1-yl)pyridines have been prepared using resolved the O-methyl ether of atrolactic acid as a
source of the adjacent quaternary carbon stereocenter. Different regioisomers were formed selectively in the reaction of 2-hydrazinopyridines
with the chiral 1,3-diketone and in the nucleophilic substitution of 2-chloropyridines with the potassium salt of the chiral pyrazole. The
second route gave 2-(pyrazol-1-yl)pyridines with the stereogenic center ne0ighboring the coordinating nitrogen in the pyrazole ring. Also, new
C2-symmetric chiral ligands based on 2,6-bis(pyrazolyl)pyridine and 6,6 -bis(pirazolyl)-2,20-bipyridine structures were obtained.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
is an analogue of the O-methyl ether of mandelic acid, well
known for its high stereodiscriminating properties.7 In spite
of that fact, its synthetic use has not been explored up to
now.
Chiral chelating ligands are considered as important for
transition-metal catalyzed enantioselective reactions.1
Usually, the most successful are C2 symmetric catalysts.2
However, in some prominent cases, lack of C2 symmetry
leads to additional stereoelectronic effects that improve
enantioselectivity.2 This effect can be attained using
heterodonatig ligands, for example, N, S-3 or ligands with
donating atoms of the same element but differing in
electronic character. A plethora of chiral N,N-donating
ligands have already been described,4 but only a few of
them combine pyrazole (p-excessive, weaker basicity) and
pyridine (p-deficient, higher basicity) systems.5 The most
prepared chiral pyrazoles are those derived from the natural
monoterpenes. On the other hand, achiral ligands of this
type are well known and their complexes were studied.6 As
well as the complexing property, another feature essential
for enantioselectivity in catalysis is a stereocontrolling
element. In order to gain high chiral discrimination it is
usually located closely to the catalytically active metal
center. For all these reasons, we decided to develop the
synthesis of 2-(pyrazol-1-yl)pyridines bearing a chiral
quaternary carbon center derived from enantiomeric the
O-methyl ether of atrolactic acid. This nonracemizing acid
2. Results and discussion
A multi-gram synthesis of racemic O-methyl ether of
atrolactic acid (2) was carried out in three steps from
inexpensive rac-mandelic acid. The racemic product was
resolved by the crystallization of its brucine salt8a and
subsequently both enantiomeric acids were esterified. The
methyl ester 1 (90% e.e., 1H NMR spectroscopy with
Eu(hfc)3) and acetone underwent the Claisen condensation
using sodium hydride to give the corresponding chiral 1,3-
diketone 3 in good yield (Scheme 1).
Both enantiomeric diketones were submitted to the reaction
with hydrazine to give the respective chiral pyrazole 4.
2-Hydrazinopyridine and 2-chloro-6-hydrazinopyridine
were treated with the diketone 3 analogously and the
optically active 2-(pyrazol-1-yl)pyridines 5a and 5b
resulted in each case as a single product, respectively
(Scheme 2).
When the potassium salt of chiral pyrazole 4 was used in a
nucleophilic substitution with 2,6-dichloropyridine,
depending upon the ratio of reagents, the other (pyrazo-
lyl)pyridine 6 or 7 was formed (Scheme 3).
Keywords: Cyclization; Pirazolylpyridines; Quaternary carbon stereocen-
ter; Nitrogen chiral ligands.
* Corresponding author. Tel.: C48 71 3203224; fax: C48 71 3284064;
e-mail: jacek.skarzewski@pwr.wroc.pl
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.092

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Scheme 1.
bulky group.10 Here, both reactions were regioselective and
the structures of the products were unambiguously estab-
lished by 1H NMR spectroscopy. Thus, the cyclization
products 5 showed the presence of a 30-methyl group dZ
2.2–2.3 ppm, while the substitution products 6 and 9
showed the 50-methyl deshielded by the pyridine moiety
to dZ2.5–2.7 ppm. This interpretation has already been
proposed for similar compounds.11 Moreover, 2,6-bis(pyr-
azol-1-yl)pyridine derivative 7 formed in the substitution of
2,6-dichloropyridine with four equivalents of the potassium
salt of chiral pyrazole was a regio- and diastereomerically
pure product of C2-symmetry with both pyrazole 50-methyl
groups appearing as a single resonance at dZ2.55 ppm.
Additionally, inspection of a molecular model for the
prevailing trans,trans-conformation of 50-methyl derivative
7 suggests that the O-methyl group should be deshielded by
the pyrazole nitrogen lone pair (observed dZ3.26 ppm). A
similar chemical shift was found for 9 (dZ3.27 ppm). This
effect is not expected for 5a (observed dZ3.06 ppm). This
explanation is in accord with nuclear Overhauser effects that
Scheme 2.
The products 5b and 6 are regioisomers and both types of
compounds have already been reported. Generally, the
reaction of arylhydrazines with unsymmetrical 1,3-dike-
tones leads to mixtures of both regioisomers.9 On the other
hand, the pyrazoles bearing bulky substituents give main
products of N-arylation at the nitrogen furthest from the
Scheme 3.

R. Kowalczyk, J. Skarz˙ewski / Tetrahedron 61 (2005) 623–628
625
we observed in the respective NOESY spectra, namely for
5a: OMe gave a strong cross-peak with 3-H and for 7: no
such NOE enhancement was detected between OMe and
3-H.
mixture was heated at 90 8C for 12 h. After cooling the
mixture was treated slowly with water until the layers were
separated. The aqueous phase was saturated with NaCl and
extracted with toluene (100 mL). The combined organic
phase was washed with brine (50 mL), dried (Na2SO4).
Concentration by distilling off toluene afforded 73 g of the
crude product (71.5% by GC/MS, 79% yield), that was
directly submitted to the next reaction.
An attempted direct nucleophilic substitution with 2-
chloropyridine failed, so we activated this derivative by its
oxidation to the respective N-oxide. In this case we obtained
the corresponding 2-(pyrazol-1-yl)pyridine-1-oxide 8 as a
single product. Finally, the deoxygenation of 8 with
phosphorus trichloride in the presence of excess pyridine
gave the required N,N-complexing ligand 9 (Scheme 3).
3.2.1. 2-Methoxy-2-phenylpropionic acid (2). To a
solution of LDA in THF (4.55 M, 75 mL, 0.34 mol) stirred
under argon atmosphere at K60 8C was added for 1 h, by a
syringe, a solution of crude a-methoxy-a-phenylacetic acid
methyl ester (52.2 g, 0.29 mol) in dry THF (100 mL). The
mixture was allowed to warm to 0 8C and it was further
stirred for 60 min. After cooling again to K60 8C, a solution
of methyl iodide (23 mL, 0.37 mol) in THF (25 mL) was
added for 45 min, the mixture was left for 30 min at this
temperature and allowed to warm to 20 8C. After 18 h, the
reaction mixture was quenched by the addition of HCl
(100 mL, 10% aq) and ether (100 mL). The separated
organic layer was washed with HCl (100 mL, 1 M, aq),
water (100 mL), NaHCO3 (50 mL, sat. aq), brine (50 mL)
and dried (Na2SO4). Concentration in vacuo gave brown oil
(45.5 g), which was treated with solution of NaOH pallets
(12.06 g, 0.30 mol) in the mixture of C2H5OH–H2O
(150 mL, 11:4, v/v) and allowed to crystallize for 2 days
at rt. The filtered crystals were washed with cold C2H5OH,
recrystallized from C2H5OH–H2O (11:2, v/v) giving pure
sodium salt of O-methyl atrolactic acid (45.6 g, 96%) as a
white solid.
An interesting C2-symmetric tetradentate ligand 10 was
obtained by the reductive homocoupling of the 2-chloro-6-
(pyrazol-1-yl)pyridine 6 with Ni(Ph3P)2Cl2/Zn/Ph3P.12
Even though the starting material was of 90% e.e., both
C2-symetric derivatives, 7 and 10 were obtained as
enantiopure products and no meso-diastereomers could be
detected.
It is noteworthy that0 the nucleophilic substitution products
7, 9 and 10 with 5 -methyl groups contain a potentially
highly stereodiscriminating center at 30-positions, in close
proximity to the complexed metal. This makes them very
promising chiral ligands. However, preliminarily examin-
ation of their catalytic use in the Pd-catalyzed allylic
alkylation of dimethyl malonate with rac-1,3-diphenyl-2-
propenyl acetate3b gave ca 30% e.e. as the best result. Further
work on the catalytic use of the new ligands with other
transition metals is currently underway in our laboratory.
To the solution of sodium salt of 2 (40.2 g, 225 mmol) in
water (100 mL) was added in 5 portions HCl (23 mL, 12 M,
aq). The resulted emulsion was extracted successively with
toluene (10!20 mL). The combined organic extract was
washed with water (60 mL) and filtered through a paper
filter to give a clear and colorless liquid which was
evaporated leaving of title compound rac-2 (28.7 g, 87%
yield) as a light yellow oil.
3. Experimental
3.1. General
Melting points were determined using a Boetius hot-stage
apparatus and are uncorrected. IR spectra were recorded on
a Perkin Elmer 1600 FTIR spectrophotometer. 1H NMR and
13C NMR spectra were measured on a Bruker CPX (1H,
300 MHz) or a Bruker Avance (1H, 500 MHz) spectrometer
using TMS as an internal standard. Observed rotations at
589 nm were measured using an Optical Activity Ltd.
Model AA-5 automatic polarimeter. GC/MS analyses were
determined on a Hewlett-Packard 5890 II gas chromato-
graph (25 m capillary column) with a Hewlett Packard mass
spectrometer 5971 A operating on the electron impact mode
(70 eV). High resolution mass spectra were recorded on a
Finnigan MAT 95 spectrometer operating on the same mode
(EI, 70 eV). Separations of products by chromatography
were performed on silica gel 60 (230–400 mesh) purchased
from Merck. Thin layer chromatography analyses were
performed using silica gel 60 precoated plates (Merck).
Resolution of the diastereomeric salts of rac-2 (24.7 g) with
brucine was carried out according to the literature
procedure8a and gave 11.37 g (46%) of R-(K)-2-methoxy-
2-phenyl-propionic acid, R-(K)-2: [a]DZK25.5 (c 1,
MeOH), lit8a: K26 (c 1, MeOH) and free S-(C)-2: 7.22 g
(29%), [a]DZC24 (c 1.2, MeOH), lit8a: C25 (c 1, MeOH),
lit8b: C37.6 (c 8.8, MeOH) for 97% e.e.; m/z (EI, 70 eV)
180 (0.02, MC), 135 (100), 105 (11), 77 (17), 43 (38%). IR
and 1H NMR spectroscopic data identical to that reported in
the literature.13
3.2.2. R-(K)-2-Methoxy-2-phenylpropionic acid methyl
ester (R-(K)-1). A solution of R-(K)-2 (9.70 g, 53.8 mmol)
in methanol (100 mL) with DOWEX 50Wx4 resin, HC-
form (2.7 g) was left for 4 days. Then, after the addition of
methyl orthoformate (6 mL), the mixture was refluxed for
10 h. After evaporation the crude product was dissolved in
CH2Cl2 (100 mL) and left overnight over anhd. K2CO3.
Solvent evaporation gave pure (GC) title product R-(C)-1
(8.8 g, 84%) as a yellowish oil; [a]DZK12.9 (c 0.92,
MeOH); Lit.8a [a]DZK12, (c 1, MeOH). The enantiomeric
3.2. a-Methoxy-a-phenylacetic acid methyl ester
To the mechanically stirred mixture of methyl mandelate
(61 g, 0.37 mol), K2CO3 (300 g, 2.2 mol) and Adogenw
(6.9 g) in toluene (230 mL), at room temperature was added
dropwise for 2 h (CH3O)2SO2 (52 mL, 0.55 mol). The
mixture was left for 2 days and after this time another
portion of (CH3O)2SO2 (7 mL) was added and the stirred
1
excess of 90% was determined by H NMR in CCl4 in the

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R. Kowalczyk, J. Skarz˙ewski / Tetrahedron 61 (2005) 623–628
presence of 10 mol% of Eu(hfc)3; DdZ0.055 ppm for the
ester methyl singlet was observed with the signal for the
major levoratory enantiomer shifted downfield. S-(C)-1,
(90% yield); [a]DZC11.9 (c 0.9, MeOH); lit.8c for 44%
e.e. [a]DZC6.4 (MeOH); m/z (EI, 70 eV) 194 (0.2, MC),
135 (100), 105 (12), 77 (17), 43 (23%). IR and H NMR
spectroscopic data identical to that reported in the
literature.13
S-(K)-4; [a]DZK35.7 (c 0.98, MeOH).
3.2.5. R-2-[5-(1-Methoxy-1-phenylethyl)-3-methylpyra-
zol-1-yl]pyridine (R-5a). A solution of R-(C)-3 (100 mg,
0.46 mmol), 2-hydrazinopyridine (50 mg, 0.46 mmol) and
TsOH (catalytic amount) in ethanol (1.5 mL) was refluxed
for 5 h and then left at room temperature for 2 days. Solvent
was removed in vacuo and the residue was treated with
water (10 mL) and extracted with CH2Cl2 (5!10 mL). The
combined organic layers were washed with brine (10 mL),
dried (Na2SO4) and evaporated in vacuo. Purification of the
crude product by column chromatography on silica gel
(CHCl3/ethyl acetate/EtOH 2:1:0.025, v/v/v) gave the title
compound (58 mg, 43% yield) as a brown oil; Rf 0.34
(CHCl3/ethyl acetate/EtOH 2:1:0.025); [a]DZC28 (c 0.84,
MeOH); nmax (liquid film) 3086, 3058, 3025, 2983, 2935,
2827, 1590, 1575, 1477, 1446, 1364, 1103, 1066 cmK1; dH
(300 MHz, CDCl3) 8.24 (1H, dd, JZ4.8, 1.5 Hz), 7.33 (1H,
dt, JZ7.9, 1.5 Hz), 6.97–7.11 (6H, m), 6.72 (1H, d, JZ
7.9 Hz), 6.29 (1H, s), 3.06 (3H, s), 2.30 (3H, s), 1.76 (3H, s);
dC (75 MHz, CDCl3) 152.8, 148.8, 148.1, 147.2, 145.2,
136.9, 127.7, 126.9, 125.8, 122.7, 121.0, 108.9, 77.5, 51.0,
26.8, 13.7; m/z (EI, 70 eV) 293 (6.7, MC), 278 (100), 78
(21), 77 (12%); HRMS (EI): MC found 293.1533.
C18H19ON3 requires 293.1528.
1
3.2.3. R-5-Methoxy-5-phenyl-hexane-2,4-dione (R-(C)-
3). To a sodium hydride (1.56 g, 32.5 mmol, 50% dispersion
in oil) at 25 8C were added a solutions of R-(C)-1 (2.99 g,
15.4 mmol) in dry ether (8 mL) and, under inert atmosphere
by a syringe for 1.5 h, acetone (1.82 g, 31.4 mmol) in dry
ether (8 mL). After 45 min the reaction flask was placed on
a sonic bath and the addition was continued for the next
40 min. Then the mixture was poured into ether (20 mL),
quenched by the addition of water and acidified to pHZ2.5
with HCl (1 M). The layers were separated and the aqueous
layer was extracted with ether (6!8 mL). The combined
extracts were washed with brine (10 mL), dried (Na2SO4)
and the solvent evaporated in vacuo giving 3.40 g of oiled
mixture containing 78% (GC/MS) of the title compound
(2.65 g, 78% yield). This crude product was submitted to the
following step without purification. An analytical sample of
R-(C)-3 was isolated using column chromatography on
silica gel (10% ethyl acetate/n-hexane) as a yellow oil; Rf
0.45 (10% ethyl acetate/n-hexane); [a]DZC91 (c 0.4,
MeOH); nmax (liquid film) 3089, 3060, 3026, 2987, 2937,
2831, 1729, 1712, 1599, 1447, 1246, 1173, 1134, 1072,
1047 cmK1; dH (300 MHz, CDCl3), for the main (81%)
tautomer 15.05 (1H, bs, –OH), 7.28–7.46 (5H, m, Ph), 5.96
(1H, s, –CHZ), 3.25 (3H, s, O–Me), 2.07 (3H, s, Me), 1.70
(3H, s, Me); dC (75 MHz, CDCl3) 202.1, 187.5, 141.5, 128.2,
127.7, 126.2, 96.3, 86.2, 51.8, 23.8, 20.3; m/z (EI, 70 eV) 220
(0.14, MC), 135 (100), 105 (7.5), 77 (10), 43 (22%); HRMS
(EI): MC found 220.1104. C13H16O3 requires 220.1099.
3.2.6. R-2-Chloro-6-[5-(1-methoxy-1-phenylethyl)-3-
methylpyrazol-1-yl] pyridine (R-5b). A solution of R-(C)-
3 (129 mg, 0.58 mmol) and 2-chloro-6-hydrazinopyridine
(84 mg, 0.58 mmol) in ethanol (6 mL) was refluxed for 3 h,
then stirred at room temperature for 17 h and finally
concentrated in vacuo. Purification of the residue by column
chromatography (silica gel, 10% ethyl acetate/n-hexane) gave
the title compound (84 mg, 44%) as a red oil; Rf 0.33 (10%
ethyl acetate/n-hexane); [a]DZC32 (c 0.74, MeOH); nmax
(liquid film) 3087, 3060, 3027, 2983, 2935, 2826, 1581, 1550,
1455, 1411, 1364, 1133, 1100, 1068 cmK1; dH (300 MHz,
CDCl3) 7.35 (1H, t, JZ7.8 Hz), 7.13–7.04 (5H, m), 7.01 (1H,
dd, JZ7.8, 0.7 Hz), 6.80 (1H, dd, JZ7.8, 0.7 Hz), 6.31 (1H,
s), 3.06(3H, s), 2.28(3H, s), 1.86(3H, s); dC (75 MHz, CDCl3)
152.3, 149.3, 148.9, 148.3, 139.4, 127.7, 127.5, 127.0, 126.1,
122.9, 118.7, 109.3, 76.7, 50.6, 26.1, 13.7; m/z (EI, 70 eV) 329
(2, MC C2), 327 (7, MC), 312 (100), 297 (32), 210 (14), 105
(13), 77 (13%); HRMS (EI): MC found 327.1145. C18H18O
35ClN3 requires 327.1138.
S-(K)-3 [a]DZK96 (c 0.45, MeOH), 79% of the main
tautomer by NMR.
3.2.4. R-3(5)-(1-Methoxy-1-phenyl-ethyl)-5(3)-methyl-
1H-pyrazole (R-(C)-4). A solution of the crude diketone
R-(C)-3 (2.99 g, 12 mmol) and hydrazine monohydrate
(2 mL, 41.2 mmol) in absolute ethanol (5 mL) was refluxed
for 0.5 h and left overnight at room temperature. Ethanol
was evaporated and the residue was partitioned between
water (10 mL) and Et2O (10 mL). The organic layer was
washed with water (10 mL), brine (10 mL), dried (Na2SO4),
and the solvent evaporated in vacuo. Purification of the
crude product by column chromatography (silica gel,
CHCl3/ethyl acetate/EtOH 2:1:0.05, v/v/v) gave the title
compound R-(C)-4 (1.55 g, 60% yield) as a yellow oil; Rf
0.34 (CHCl3/ethyl acetate/EtOH 2:1:0.05); [a]DZC36
(c 0.86, MeOH); nmax (liquid film) 3396, 3190, 3104,
2936, 2871, 1582, 1493, 1464, 1367, 1185, 1104 cmK1; dH
(300 MHz, CDCl3) 7.24–7.41 (5H, m, Ph), 5.99–6.12 (1H,
bs, NH), 5.86 (1H, s, H-4, pyrazole), 3.19 (3H, s, OMe), 2.27
(3H, s, Me), 1.85 (3H, s, Me); dC (75 MHz, CDCl3) 151.9,
145.3, 144.5, 128.1, 126.1, 112.6, 103.9, 77.7, 51.0, 25.2,
12.4; m/z (EI, 70 eV) 216 (16, MC), 201 (100), 185 (51),
139 (16), 105 (30), 77 (27%); HRMS (EI): MC found
216.1261. C13H16ON2 requires 216.1263.
3.2.7. R-2-Chloro-6-[3-(1-methoxy-1-phenyl-ethyl)-5-
methylpyrazol-1-yl]pyridine (R-6). To a solution of R-
(C)-4 (380 mg, 1.76 mmol) in toluene (15 mL) pieces of
potassium (70 mg, 1.79 mmol) were added followed by the
addition of two drops of abs. EtOH. The mixture was stirred
at 90 8C until the metal was dissolved. Most of toluene was
removed under the reduced pressure and the remaining
suspension was treated with a solution of 2,6-dichloropyr-
idine (260 mg, 1.76 mmol) in DMF (5 mL) and kept for 5
days at 67 8C. The mixture was concentrated in vacuo,
treated with water (10 mL) and extracted with CH2Cl2 (5!
10 mL). The combined organic layers were dried (Na2SO4)
and evaporated in vacuo. Purification of the crude product
by column chromatography on silica gel (10% ethyl acetate/
n-hexane) gave the title compound (352 mg, 62%) as a
colourless oil; Rf 0.50 (10% ethyl acetate/n-hexane);
[a]DZC76 (c 0.5, MeOH); nmax (liquid film) 3088, 3059,

R. Kowalczyk, J. Skarz˙ewski / Tetrahedron 61 (2005) 623–628
627
3026, 2985, 2934, 2826, 1577, 1557, 1472, 1434, 1375,
1131, 1120 cmK1; dH (300 MHz, CDCl3) 7.84 (1H, d, JZ
8.0 Hz), 7.65 (1H, dd, JZ8.0, 7.8 Hz), 7.41 (2H, d, JZ
7.9 Hz), 7.25 (2H, dd, JZ7.9, 7.0 Hz), 7.17 (1H, t,
JZ7.0 Hz), 7.09 (1H, d, JZ7.8 Hz), 5.97 (1H, s), 3.20
(3H, s), 2.57 (3H, s), 1.86 (3H, s); dC (75 MHz, CDCl3)
157.5, 153.3, 148.7, 145.9, 142.3, 140.5, 128.0, 126.9,
126.0, 120.6, 113.8, 108.5, 78.5, 51.2, 24.6, 14.9; m/z (EI,
70 eV) 329 (0.2, MC C2), 327 (0.8, MC), 312 (81), 297
(100), 112 (50), 103 (30), 77 (56), 51 (20%); HRMS (EI):
MC found 327.1139. C18H18O35ClN3 requires 327.1138.
3.2.10. R-2-[3-(1-Methoxy-1-phenylethyl)-5-methyl-pyr-
azol-1-yl]pyridine (R-9). To a vigorously stirred suspen-
sion of R-8 (87 mg, 0.3 mmol) in toluene (1.2 mL) and
pyridine (0.8 mL) at 0 8C was added dropwise, by a syringe,
phosphorus trichloride (0.1 mL, 1.2 mmol). The mixture
was warmed to room temperature for 25 min and sonicated
for further 30 min. Then, it was quenched with ice in
NaHCO3 (sat. aq), made alkaline (pHy9), and extracted
with ether (5!5 mL). The combined organic layers were
washed with brine (5 mL), dried (K2CO3), evaporated in
vacuo and dried overnight in a vacuum desiccator over
H2SO4 giving the title compound R-9 (50 mg, 59%, O97%
pure, GC/MS) as a colourless oil; Rf 0.59 (3.5% EtOH/
CHCl3); [a]DZC90 (c 0.96, MeOH); nmax (liquid film)
3086, 3060, 2984, 2934, 2826, 1591, 1579, 1557, 1475,
1429, 1370, 1144, 1089 cmK1; dH (300 MHz, CDCl3) 8.41–
8.42 (1H, m), 7.93 (1H, d, JZ8.1 Hz), 7.78 (1H, dt, JZ8.1,
1.5 Hz), 7.49 (2H, d, JZ7.4 Hz), 7.21–7.34 (3H, m), 7.15
(1H, dd, JZ6.8, 1.5 Hz), 6.02 (1H, s), 3.27 (3H, s), 2.63
(3H, s), 1.93 (3H, s); dC (75 MHz, CDCl3) 156.8, 153.9,
147.4, 146.2, 141.6, 138.2, 128.1, 126.8, 126.1, 120.9,
116.3, 107.9, 78.5, 51.2, 25.0, 14.6; m/z (EI, 70 ev) 293 (1.5,
MC), 278 (69), 263 (100), 216 (10), 105 (17), 78 (38), 77
(21), 51 (13%); HRMS (EI): MC found 293.1527.
C18H19ON3 requires 293.1528.
3.2.8.
R,R-2,6-Bis[3-(1-methoxy-1-phenylethyl)-5-
methylpyrazol-1-yl]pyridine (R,R-7). To a solution of
R-(C)-4 (746 mg, 3.45 mmol) in toluene (15 mL) was
added potassium (144 mg, 3.68 mmol) and the reaction
mixture was heated to 90 8C under neutral atmosphere until
whole metal was dissolved. The mixture was concentrated in
vacuo, treated with DMF (6 mL) and 2,6-dichloropyridine
(127 mg, 0.86 mmol) and heated for 5 days in 110 8C.
Cooled mixture was concentrated, poured into water
(10 mL) and extracted with ether (5!8 mL). The combined
organic layers were washed with brine (5 mL), dried
(Na2SO4) and evaporated in vacuo. Purification of the
crude product by column chromatography on silica gel
(n-hexane/CHCl3/ethyl acetate, 6:1:1, v/v/v) gave the title
compound (R,R)-7 (186 mg, 43%) as a colourless oil; Rf
0.42 (n-hexane/CHCl3/ethyl acetate, 6:1:1); [a]2D0C88 (c
2.48, MeOH); nmax (liquid film) 3088, 3058, 3026, 2984,
2935, 2826, 1598, 1584, 1471, 1435, 1359, 1145, 1123,
1075 cmK1; dH (500 MHz, CDCl3) 7.87 (1H, t, JZ8.1 Hz),
7.76 (2H, d, JZ8.1 Hz), 7.66 (4H, d, JZ7.9 Hz), 7.27–7.32
(4H, m), 7.20–7.23 (2H, m), 5.98 (2H, s), 3.26 (6H, s), 2.55
(6H, s), 1.92 (6H, s); dC (125 MHz, CDCl3) 157.7, 152.0,
146.3, 141.6, 140.8, 128.4, 127.3, 126.5, 114.7, 108.2, 78.9,
51.6, 24.9, 14.8; m/z (EI, 70 eV) 507 (1.2, MC), 445 (13), 43
(100), 39 (13%); HRMS (EI): MC found 507.2632.
C31H33O2N5 requires 507.2634.
3.2.11. R,R-6,60-Bis[3-(1-methoxy-1-phenylethyl)-5-
methylpyrazol-1-yl]-[2,20]bipyridine (R,R-10). A suspen-
sion of [NiCl2(PPh3)2] (441 mg, 0.67 mmol), PPh3 (353 mg,
1.34 mmol), and zinc dust (48 mg, 0.73 mmol), in DMF
(3 mL) was vigorously stirred in argon atmosphere at 50 8C
changing color from dark blue to brown-deep red. Then, a
solution of R-6 (221 mg, 0.67 mmol) and slight amount of
NaI in DMF (2 mL) was added, by a syringe, and the whole
mixture was stirred at 50 8C for 24 h. Cooled mixture was
quenched by addition of NH3 (10 mL, 25% aq) and brine
(5 mL) and extracted with CH2Cl2 (5!8 mL). The
combined organic layers were washed with water (5 mL),
brine (5 mL), dried (Na2SO4) and evaporated in vacuo. The
crude product, dried from DMF in a desiccator over sulfuric
acid, was purified by column chromatography (silica gel,
2.5% EtOH/CHCl3) and gave the title compound (R,R)-10
(95 mg, 48%) as a white solid, mp 116–118 8C;
[a]DZC137, (c 0.7, CH2Cl2); nmax (KBr) 3109, 3085,
3058, 2985, 2931, 2824, 1589, 1569, 1466, 1430, 1370,
1090 cmK1; dH (300 MHz, CDCl3) 8.15 (2H, d, JZ7.7 Hz),
7.97 (2H, d, JZ8.0 Hz), 7.85 (2H, dd, JZ8.0, 7.7 Hz), 7.44
(4H, d, JZ7.1 Hz), 7.26 (4H, dd, JZ7.7, 7.1 Hz), 7.15–7.19
(2H, m), 6.01 (2H, s), 3.27 (6H, s), 2.75 (6H, s), 1.88 (6H, s);
dC (75 MHz, CDCl3) 157.0, 153.7, 153.3, 146.1, 141.4,
139.3, 128.0, 126.8, 126.1, 117.9, 116.2, 108.2, 78.6, 51.2,
24.7, 15.5; m/z (EI, 70 eV) 584 (12, MC), 569 (37), 552
(79), 522 (100), 277 (14), 269 (13), 105 (11%); HRMS (EI):
MC found 584,2922. C36H36O2N6 requires 584.2900.
3.2.9. R-2-[3-(1-Methoxy-1-phenylethyl)-5-methyl-pyra-
zol-1-yl]pyridine-1-oxide (R-8). To the stirred solution of
R-(C)-4 (220 mg, 1.0 mmol) in toluene (3 mL) pieces of
potassium were added (46 mg, 1.1 mmol) and the resulted
suspension was heated in 80 8C under argon until whole
metal was dissolved. After cooling, a solution of 2-chloro-
pyridine N-oxide (200 mg, 1.5 mmol) in DMF (3 mL) was
added dropwise from syringe for 35 min, stirred at this
temperature for the next 30 min, and then at 60 8C for 22 h.
Most of the solvents were evaporated and remaining DMF
was removed in a desiccator. Purification of the crude
product by column chromatography (gradient chloroform/
chloroform–ethanol 2:0.07, v/v) gave 70 mg of recovered 4
(32%) and the title compound R-8 (149 mg, 47%) as a
colourless solid, mp 203–205 8C (EtOH); [a]DZC80
(c 0.22, MeOH); nmax (KBr) 3128, 3100, 3046, 2980,
1557, 1511, 1431, 1370, 1257, 1118, 1030 cmK1; dH
(300 MHz, CDCl3) 8.30–8.32 (1H, m), 7.53–7.57 (1H, m),
7.48 (2H, d, JZ7.3 Hz), 7.20–7.34 (5H, m), 6.05 (1H, s),
3.27 (3H, s), 2.26 (3H, s), 1.88 (3H, s); dC (75 MHz, CDCl3)
159.2, 145.8, 145.5, 144.1, 140.3, 128.0, 126.9, 126.4,
126.1, 125.45, 125.40, 106.1, 78.4, 51.2, 24.7, 11.6; m/z (EI,
70 eV) 277 (12), 260 (100), 249 (18), 78 (54), 51 (22%).
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