Enantiomerically pure pyridine and 2,2'-bipyridine thioethers: New N-S chiral ligands for asymmetric catalysis. Palladium-catalyzed allylic alkylation

Article abstract of DOI:10.1016/S0957-4166(99)00352-3

Diastereomeric pure pyridine and 2,2'-bipyridine thioethers, derived from (+)-camphor, were prepared and assessed in the enantioselective palladium-catalyzed allylic substitution of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate. Enantioselectivit

Full text of DOI:10.1016/S0957-4166(99)00352-3

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3537–3546
Enantiomerically pure pyridine and 2,20-bipyridine thioethers:
new N–S chiral ligands for asymmetric catalysis. Palladium-
catalyzed allylic alkylation
Giorgio Chelucci,a,∗ Nicola Culeddu,b Antonio Saba a and Raffaela Valenti a
aDipartimento di Chimica, Università di Sassari, via Vienna 2, I-07100 Sassari, Italy
bIstituto A.T.C.A.P.A., C.N.R., via Vienna 2, I-07100 Sassari, Italy
Received 19 July 1999; accepted 11 August 1999
Abstract
Diastereomeric pure pyridine and 2,20-bipyridine thioethers, derived from (+)-camphor, were prepared and
assessed in the enantioselective palladium-catalyzed allylic substitution of 1,3-diphenylprop-2-enyl acetate with
dimethyl malonate. Enantioselectivities of up to 76% were obtained. © 1999 Elsevier Science Ltd. All rights
reserved.
1. Introduction
In contrast to the great number of chiral pyridine derivatives used as ligands for metal complexes
in asymmetric catalysis, only a few examples of sulfur-containing pyridine ligands have so far been
reported.1 Recently, we and Kellog’s group introduced the use of chiral thioalkylpyridines as ligands for
palladium-catalyzed allylic substitutions. Thus, while we prepared and assessed the diastereomerically
pure 8-phenylthio tetrahydroquinoline 11a and the 2-(1-p-tolylsulfinylalkyl)pyridines 2,1b obtaining
enantioselectivities up to 83%, Kellog achieved a higher enantiomeric excess (98%, under optimized
conditions) using the pyridine thioether 31d (Scheme 1). This interesting result prompted us to undertake
a study on the synthesis and application in asymmetric catalysis of new pyridine and 2,20-bipyridine
thioethers, derived from (+)-camphor, with the general structures 4 and 5. The palladium-catalyzed allylic
substitutions has been used to explore the catalytic potential of these ligands.2
∗
Corresponding author. E-mail: chelucci@ssmain.uniss.it
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00352-3

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G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 3537–3546
Scheme 1.
2. Results and discussion
2.1. Synthesis of the ligands
We started our investigations with the synthesis of the simpler pyridine thioether of type 4 (R=H).
Thus, the known pyridyl alcohol 8,3 prepared by addition of 2-pyridyl lithium to (+)-camphor, was dehy-
drated by treatment with sodium hydride (1 equiv.) in benzene followed by p-tolylchlorothionoformate
(Scheme 2).4 The alkene 10 was directly obtained without the detection of the expected thiocarbonate
ester intermediate 9. When the alkene was treated with thiophenol in boiling acetic acid the desired
Michael addition occurred to give a mixture of diastereomeric thioethers 11 and 12 in about a 1:4 ratio
which were then obtained in pure form through chromatography on silica gel.
Scheme 2. a: Literature; b: NaH, benzene, 50°C, 30 min then p-tolylchlorothionoformate, 12 h rt and 1 h at reflux; c: PhSH,
AcOH, reflux, 24 h
The assignment of the stereochemistry of 11 and 12 was determined on the basis of both the coupling
constants and their 1H–1H NOESY maps which, in the case of 11, correlates the proton H1 with the Me10,
suggesting that the two H1 and H2 protons have a trans orientation on the ring. The same correlation exists
in the compound 12 between the H2 proton and the Me10 (Scheme 3).
Scheme 3.

G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 3537–3546
3539
Moreover, since we and others have shown that in C1-symmetric heterobidentate ligands containing the
pyridine ring such as thioethers of type 31d and oxazolinylpyridines5 the presence of a substituent on the
6-position of the pyridine had the effect of increasing the enantioselectivity of the reaction, we devoted
our attention to the preparation of compounds of type 4 (R=Ph) in which the pyridine bears a phenyl group
on the 6 position. In this case, monolithiation of the commercially available 2,6-dibromopyridine 13 with
n-butyllithium in ether followed by trapping with (+)-camphor gave the tertiary alcohol 14 (Scheme 4).
Initial attempts to dehydrate 14 to the corresponding alkene 15 in the usual way failed and then other
methods which can avoid the formation of ionic intermediates, because skeletal rearrangements of
fragmentations may occur,6 were evaluated. However, the formation of S-methylxanthate failed and,
unexpectedly, dehydration using the Burgess7 reagent afforded exclusively the olefin 16. In contrast,
treatment of 14 with the thionyl chloride in pyridine8 gave a 1:4 mixture of the olefins 15 and 16 which
were separated by chromatography. No appreciable change in the ratio of products was obtained when
the reaction temperature was varied from 25 to −25°C. Then, the bromopyridine 15 was cross-coupled
9
with phenylboronic acid in the presence of a catalytic amount of Pd(PPh3)4 to give the pyridine 17
in satisfactory yield (95%). Finally, the reaction of 17 with thiophenol in boiling acetic acid afforded a
mixture of thioethers 18, 19 and 20 in about a 4:2:1 ratio. It is interesting to note that in this case it has
been obtained, with the expected trans isomers 18 and 19, the cis isomer 20 which has been separated
from the others through chromatography on silica gel. The mixture of trans isomers was difficult to
purify, so we were able to obtain in the pure form only the more abundant isomer 18. The configurational
1
assignment of the stereochemistry of 18 and 19 was determined comparing their H NMR with those
1
of correletated compounds 11 and 12. That of 20 was assigned on the basis of its H–1H NOESY map
which shows a correlation of both H1 and H2 protons with the Me10, suggesting that the two protons have
a cis orientation on the ring (Scheme 3).
Scheme 4. a: n-BuLi, −78°C, 2 h then 7; b: SOCl2, pyridine, 0°C then 1 h at rt; c: PhB(OH)2, Pd(PPh3)4, Na2CO3,
toluene/MeOH, reflux; d: PhSH, AcOH, reflux, 72 h
Then, we devoted our attention to the synthesis of the dipyridine of type 5. For this purpose the
bromopyridine 15 was homocoupled in the presence of nickel(0)10 to give the bipyridine 21 (Scheme 5).
The debrominated derivative of 15 was the major by-product of the coupling reaction. Its formation
could be substantially reduced by using carefully degassed DMF solutions. Addition of thiophenol to
the double bonds of the bipyridine 21 occurred and a mixture of C2-symmetric bipyridine 22 and C1-
symmetric bipyridine 23 in about a 9:2 ratio was obtained. From this mixture only the more abundant
and useful ligand 22 was recovered in 66% yield. The stereochemistry of these bipyridines was assigned
on the basis of the comparison of their 1H NMR spectra with those of the related compounds 11 and 12.

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G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 3537–3546
Scheme 5. a: NiCl2 6H2O, Zn, PPh3, DMF; b: PhSH, AcOH, reflux, 3 h
With the compounds of type 16 in hand we evaluated the possibility to obtain a new class of pyridine
thioethers by the addition of thiophenol to the double bond of 24, obtained by cross-coupling of 16
with phenylboronic acid in the presence of Pd(0) (Scheme 6). However, several attempts to obtain the
addition of thiophenol using acetic acid and perchloric acid as an acid catalyst failed. However, a new
compound was obtained when a solution of 24 and thiophenol was heated under reflux in the presence of
50% sulfuric acid. The examination of its 1H, COSY and NOESY NMR spectra excluded the expected
structure 26 or 27 (Scheme 6) but it supports the isomeric structure 25. Its formation is strengthened
by earlier observations that 1-p-anisylcamphene, 1-p-anisylbornene and 2-p-anisyl-2-borneol undergo
rearrangement by treatment with acetic acid and sulfuric acid to produce almost exclusively 4-p-anisyl-
2-exo-bornyl acetate.11
Scheme 6. a: PhB(OH)2, Pd(PPh3)4, Na2CO3, toluene/MeOH, reflux; b: PhSH, 50% H2SO4, reflux
2.2. Palladium-catalyzed allylic alkylation
With the new ligands in hand, their ability to provide asymmetric induction in the palladium-
catalyzed alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate was examined. Allylic
substitutions were carried out at room temperature employing Trost’s procedure which used [Pd(η3-
C3H5)Cl]2 as procatalyst and a mixture of dimethyl malonate, N,O-bis(trimethylsilyl)acetamide (BSA)
and potassium acetate in a methylene chloride solution.12 The results obtained under control of the
new ligands are summarized in Table 1. All pyridine thioethers were not able to provide a reactive
palladium catalyst. The ligands 11 and 12 required about 5 days to completely convert the starting

G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 3537–3546
3541
Table 1
Allylic alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonatea
material 28 to dimethyl 1,3-diphenylprop-2-enylmalonate 29 which showed a low enantiomeric excess
(30 and 26%, respectively). It should be noted that both diastereomers 11 and 12 gave a similar level of
stereodifferentiation but opposite configuration of 29, indicating that they behave as pseudoenantiomers.
A dramatic effect on both stereoselectivity and catalytic activity was observed by the presence in the
6-position of the pyridine ring of a phenyl group. Thus, the ligand 18 gave a 77% enantiomeric excess
but it provided a less effective palladium catalyst with respect to the related ligand 12; in fact the reaction
required 7 days to achieve a 39% conversion. The trans isomer 20 was very ineffective regarding both
catalytic activity and stereoselectivity.
Finally, the bipyridine 22, showing a comparable reactivity with respect to the related ligand 18,
afforded poorer enantioselectivity (48%). It should be noted that for ligand 22 it is possible to single out,
on the basis of a molecular modelling study, two limit conformations, both maintaining a C2-symmetry:
in the former case it could behave as bis-bidentate ligands (A, Scheme 7), whereas in the latter it could
coordinate to a metal atom in a tetradentate fashion (B, Scheme 7).
Scheme 7.
In conclusion we have developed new diastereomerically pure pyridine and 2,20-bipyridine thioethers,
and demonstrated their catalytic activity and stereodifferentianting ability in the palladium-catalyzed
enantioselective alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate. A deeper investi-

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G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 3537–3546
gation aimed at the determination of the catalytic species involved in the examined catalytic process and
to the application of this kind of ligand in other enantioselective reactions is now in progress.
3. Experimental
3.1. General methods
1
Melting points were determined on a Buchi 510 capillary apparatus and are uncorrected. The H
NMR (300 MHz) spectra were obtained with a Varian VXR-300 spectrometer. Optical rotations were
measured with a Perkin–Elmer 241 polarimeter in a 1 dm tube. Elemental analyses were performed on a
Perkin–Elmer 240 B analyzer.
3.2. Starting material
(1R,2R,4R)-2-exo-Hydroxy-2-endo-(pyridin-2-yl)-1,7,7-trimethylbicyclo[2.2.1]heptane 8 was prep-
ared according to a reported procedure.3 2-Bromopyridine, 2,6-dibromopyridine, (+)-camphor (98%
pure, [α]25D +44.1 (c 10, C2H5OH) and p-tolylchlorothionoformate were purchased from Aldrich A.G.
3.3. (1R,4R)-2-(Pyridin-2-yl)-1,7,7-trimethylbicyclo[2.2.1]-2-heptene 10
A solution of 8 (2.17 g, 9.4 mmol) in benzene (10 ml) was added dropwise to a mixture of NaH (0.23
g, 9.6 mmol) in benzene (30 ml). After 2 h at room temperature the mixture was heated at 50°C for 0.5
h. After cooling to room temperature, p-tolylchlorothionoformate (1.93 g, 10.3 mmol) was added. The
mixture was stirred for 12 h at room temperature and was then heated under reflux for 1 h. The reaction
mixture was taken up in 10% NaOH and the separated organic phase was dried over anhydrous Na2SO4
and the solvent evaporated off. The residue was purified by flash chromatography on a silica gel column
(eluent: petroleum ether:methylene chloride=2:8) to give unreacted 8 (1.2 g) and 10: 0.51 g (58%, based
1
on the converted starting material); oil; [α]25 −131.2 (c 1.4, CHCl3); H NMR (CDCl3) δ: 8.57 (m,
D
1H), 7.57 (dt, 1H, J=7.5, 1.8 Hz), 7.29 (dt, 1H, J=7.5, 1.2 Hz), 7.07 (ddd, 1H, J=7.5, 4.8, 1.2 Hz), 6.35 (d,
1H, J=3.3 Hz), 2.44 (t, 1H, J=3.6 Hz), 2.01–1.91 (m, 1H), 1.75–1.67 (m, 1H), 1.46–1.37 (m, 1H), 1.26
(s, 3H), 1.14–1.06 (m, 1H), 0.90 (s, 3H), 0.84 (s, 3H). Anal. calcd for C15H19N: C, 84.46; H, 8.98; N,
6.56. Found: C, 84.25; H, 8.77; N, 6.38.
3.4. (1R,2S,3R,4S)-3-exo-Phenylthio-2-endo-(2-pyridinyl)-1,7,7-trimethylbicyclo[2.2.1]heptane
and (1R,2R,3S,4S)-3-endo-phenylthio-2-exo-(2-pyridinyl)-1,7,7-trimethylbicyclo[2.2.1]heptane 12
11
Acetic acid (10 drops) was added to a solution of 10 (0.5 g, 2.4 mmol) and thiophenol (5 ml), and
the resulting mixture was heated under reflux for 24 h. The reaction mixture was taken up in ethyl ether
and the resulting solution was washed with 10% NaOH. The separated organic phase was dried over
anhydrous Na2SO4, the solvent was evaporated off and the residue was purified by flash chromatography
on silica gel (eluent: petroleum ether:methylene chloride=2:8) to give 11 and 12.
Compound 11: 0.078 g (10%); Rf 0.66; oil; [α]25 −46.33 (c 1.2, CHCl3); 1H NMR (CDCl3) δ: 8.52
D
(d, 1H, J=3.9 Hz), 7.54 (dt, 1H, J=7.8, 1.5 Hz), 7.39 (dd, 2H, J=7.2, 1.5 Hz), 7.22–7.05 (m, 5H), 4.96 (d,
1H, J=6.6 Hz), 2.73 (d, 1H, J=7.8 Hz), 2.21 (t, 1H, J=9.6 Hz), 2.01 (t, 1H, J=3.6 Hz), 1.75–1.66 (m, 2H),

G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 3537–3546
3543
1.44 (m, 1H), 1.10 (s, 3H), 0.89 (s, 3H), 0.67 (s, 3H). Anal. calcd for C21H25NS: C, 77.97; H, 7.79; N,
4.33. Found: C, 77.85; H, 7.66; N, 4.45.
Compound 12: 0.289 g (38%); Rf 0.57; oil; [α]25 +61.46 (c 1.2, CHCl3); 1H NMR (CDCl3) δ: 8.57
D
(dd, 1H, J=5.1, 0.9 Hz), 7.54 (dt, 1H, J=7.5, 1.8 Hz), 7.23–7.04 (m, 7H), 4.21 (d, 1H, J=6.8 Hz), 3.35
(dd, 1H, J=6.8, 2.1 Hz), 2.03 (d, 1H, J=4.2 Hz), 1.90 (m, 1H), 1.58 (m, 2H), 1.30 (s, 3H), 1.10 (m, 1H),
0.93 (s, 3H), 0.82 (s, 3H). Anal. calcd for C21H25NS: C, 77.97; H, 7.79; N, 4.33. Found: C, 77.87; H,
7.76; N, 4.22.
3.5. (1R,2R,4R)-2-exo-Hydroxy-2-endo-(6-bromopyridin-2-yl)-1,7,7-trimethylbicyclo[2.2.1]heptane 14
A solution of 2,6-dibromopyridine (4.74 g, 20 mmol) in anhydrous diethyl ether was cooled at −78°C
and the resulting suspension was treated with a 1.6 M solution of n-butyllithium in n-hexane (13.7 ml, 22
mmol) over a period of 10 min. The precipitate dissolved and a clear yellow solution resulted. After
stirring at this temperature for 2 h a solution of (+)-camphor (3.0 g, 20 mmol) in diethyl ether (10
ml) was added dropwise. The solution was stirred for 30 min at −78°C and was then allowed to warm
slowly to room temperature. Water was added, the organic phase was separated and the aqueous phase
extracted with ethyl ether. The combined organic phase was dried over anhydrous Na2SO4, the solvent
was evaporated off and the residue was purified by flash chromatography on silica gel (eluent: petroleum
ether:ethyl acetate=7:3) to give pure 14: 2.05 g (33%); mp 113°C; [α]25D −65.3 (c 1.5, CHCl3); 1H NMR
(CDCl3) δ: 7.52 (t, 1H, J=7.6 Hz), 7.40 (d, 1H, J=7.6 Hz), 7.36 (d, 1H, J=7.6 Hz), 4.35 (s, 1H), 2.27 (m,
1H), 2.14 (d, 1H, J=13.9 Hz), 1.90 (t, 1H, J=4.4 Hz), 1.79 (m, 1H), 1.30 (m, 2H), 1.24 (s, 3H), 0.90 (s,
3H), 0.85 (s, 3H), 0.75 (m, 1H). Anal. calcd for C15H20BrNO: C, 56.77; H, 6.13; N, 4.73. Found: C,
56.87; H, 6.26; N, 4.52.
3.6. (1R,4R)-2-(6-Bromopyridin-2-yl)-1,7,7-trimethylbicyclo[2.2.1]-2-heptene 15 and (1R,4R)-2-
methylidene-1-(6-bromopyridin-2-yl)-3,3-dimethylbicyclo[2.2.1]heptane 16
Thionyl chloride (0.48 ml, 6.6 mmol) was added dropwise to a cooled (0°C) solution of 14 (2.0 g, 6.45
mmol) in pyridine (10 ml). The mixture was kept at 0°C for 30 min and then stirred at room temperature
for 1 h. A 10% solution of sodium carbonate was added and the resulting mixture was extracted with
ethyl ether. The separated organic phase was dried over anhydrous Na2SO4, the solvent was evaporated
off and the residue was purified by chromatography on silica gel (eluent: petroleum ether:methylene
chloride=8:2) to give pure 15 and 16.
1
Compound 15: 0.34 g (19%); oil; [α]25 −146.3 (c 2.0, CHCl3); H NMR (CDCl3) δ: 7.40 (t, 1H,
D
J=7.8 Hz), 7.25 (d, 1H, J=7.8 Hz), 7.22 (d, 1H, J=7.8 Hz), 6.44 (d, 1H, J=3.3 Hz), 2.43 (t, 1H, J=3.3 Hz),
1.95 (m, 1H), 1.67 (m, 1H), 1.35 (m, 1H), 1.27 (s, 3H), 1.06 (m, 1H), 0.85 (s, 3H), 0.83 (s, 3H). Anal.
calcd for C15H18BrN: C, 61.50; H, 6.21; N, 4.79. Found: C, 61.65; H, 6.26; N, 4.62.
Compound 16: 1.33 g (75%); oil; [α]25D +73.7 (c 1.9, CHCl3); 1H NMR (CDCl3) δ: 7.47 (t, 1H, J=7.6
Hz), 7.30 (d, 1H, J=7.6 Hz), 7.19 (d, 1H, J=7.6 Hz), 4.60 (s, 1H), 4.24 (s, 1H), 2.29 (dd, 1H, J=9.8, 2.0
Hz), 2.08–1.99 (m, 2H), 1.84 (m, 2H), 1.68–1.58 (m, 2H), 1.14 (s, 3H), 1.13 (s, 3H). Anal. calcd for
C15H18BrN: C, 61.50; H, 6.21; N, 4.79. Found: C, 61.55; H, 6.36; N, 4.82.
3.7. (1R,4R)-2-(6-Phenylpyridin-2-yl)-1,7,7-trimethylbicyclo[2.2.1]-2-heptene 17
A solution of 15 (1.4 g, 4.8 mmol) and tetrakis(triphenylphosphane)palladium(0) (0.16 g, 0.14 mmol)
in toluene (9.6 ml) was treated with a solution of Na2CO3 (1.01 g, 9.5 mmol) in H2O (4.8 ml) followed

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G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 3537–3546
by a solution of phenylboronic acid (0.7 g, 5.7 mmol) in methanol (2.4 ml). The mixture was stirred at
80–85°C for 14 h. After cooling at room temperature, a solution of concentrated aqueous NH3 (2.4 ml)
in saturated aqueous Na2CO3 (24 ml) was added, and the mixture was extracted with CH2Cl2 (3×40
ml). The combined organic layers were washed with brine (50 ml) and dried over anhydrous Na2SO4.
Removal of the solvent under reduced pressure gave a residue with was purified by flash chromatography
(eluent: petroleum ether:methylene chloride=8:2) to give pure 17: 1.30 g (95%); oil; [α]25 −153.2 (c
D
1.1, CHCl3); 1H NMR (CDCl3) δ: 8.06 (d, 2H, J=7.8 Hz), 7.61 (t, 1H, J=7.8 Hz), 7.52 (d, 1H, J=7.8 Hz),
7.50–7.34 (m, 3H), 7.27 (d, 1H, J=7.6 Hz), 6.38 (d, 1H, J=3.7 Hz), 2.44 (t, 1H, J=3.4 Hz), 2.01–1.91 (m,
1H,), 1.76–1.68 (m, 1H), 1.55–1.47 (m, 1H), 1.39 (s, 3H), 1.17–1.06 (m, 1H), 0.91 (s, 3H), 0.85 (s, 3H).
Anal. calcd for C21H23N: C, 87.50; H, 8.01; N, 4.84. Found: C, 87.55; H, 8.16; N, 4.89.
3.8. (1R,2S,3R,4S)-3-exo-Phenylthio-2-endo-(6-phenylpyridin-2-yl)-1,7,7-trimethylbicyclo[2.2.1]hept-
ane 18, (1R,2R,3S,4S)-3-endo-phenylthio-2-exo-(6-phenylpyridin-2-yl)-1,7,7-trimethylbicyclo[2.2.1]-
heptane 19 and (1R,2R,3R,4S)-3-exo-phenylthio-2-exo-(6-phenylpyridin-2-yl)-1,7,7-trimethylbicyclo-
[2.2.1]heptane 20
Acetic acid (20 drops) was added to a solution of 17 (1.25 g, 4.3 mmol) and thiophenol (12.5 ml),
and the resulting mixture was heated under reflux for 72 h. The reaction mixture was taken up in ethyl
ether and the resulting solution was washed with 10% NaOH. The separated organic phase was dried
over anhydrous Na2SO4, the solvent was evaporated off and the residue was purified by chromatography
on silica gel (eluent: petroleum ether:ethyl acetate=20:1) to give 18, 19 and 20.
Compound 18: 0.67 g (39%); mp 84–85°C; [α]25 −108.4 (c 0.8, CHCl3); 1H NMR (CDCl3) δ: 8.07
D
(dd, 2H, J=8.7, 1.8 Hz), 7.62–7.49 (m, 2H), 7.49–7.39 (m, 3H), 7.19 (m, 2H), 7.07 (m, 2H), 6.99 (m,
2H), 4.49 (d, 1H, J=6.3 Hz), 3.41 (dd, 1H, J=6.6, 2.1 Hz), 2.07 (d, 1H, J=4.5 Hz), 1.91 (m, 1H), 1.66 (m,
2H), 1.31 (s, 3H), 1.12 (m, 1H), 0.96 (s, 3H), 0.87 (s, 3H). Anal. calcd for C27H29NS: C, 81.16; H, 7.32;
N, 3.51. Found: C, 81.31; H, 7.26; N, 3.57.
1
1
Compound 19: 0.38 g (90% pure by H NMR); H NMR (CDCl3) (selected data) δ: 8.00 (dd 1H,
J=8.1, 1.8 Hz), 5.17 (m, 1H), 2.80 (d, 1H, J=8.0 Hz), 1.16 (s, 3H), 0.90 (s, 3H), 0.74 (s, 3H).
Compound 20: 0.19 g (11%); oil; [α]25 −141.3 (c 1.6, CHCl3); 1H NMR (CDCl3) δ: 8.25 (dd, 2H,
D
J=3.3, 1.5 Hz), 7.61 (d, 1H, J=3.9 Hz), 7.49 (m, 3H), 7.39 (m, 3H), 7.26–7.23 (m, 2H), 7.18–7.13 (m,
1H), 7.10–7.04 (m, 1H), 4.18 (dt, 1H, J=11.4, 3.3 Hz), 3.63 (dd, 1H, J=11.4, 1.8 Hz), 2.52 (m, 1H),
2.03–1.92 (m, 2H), 1.74–1.67 (m, 1H), 1.18 (m, 1H), 1.15 (s, 3H), 1.03 (s, 3H), 0.77 (s, 3H). Anal. calcd
for C27H29NS: C, 81.16; H, 7.32; N, 3.51. Found: C, 81.21; H, 7.46; N, 3.67.
3.9. 6,60-Bis{(1R,4R)-1,7,7-trimethylbicyclo[2.2.1]-2-hepten-2-yl}-2,20 -bipyridine 21
Zinc powder (0.44 g, 7 mmol) was added at 60°C to a stirred mixture of nickel(II) chloride hexahydrate
(1.59 g, 7.0 mmol) and triphenylphosphine (6.4 g, 24 mmol) in DMF (50 ml). After 1 h, a solution of
15 (1.78 g, 6.0 mmol) in DMF (30 ml) was added. The mixture was stirred at 80°C for 21 h, and then
taken up with ether and washed with dilute ammonia solution (120 ml), H2O (100 ml), and finally with
5% HCl (100 ml). The organic phase was dried over anhydrous Na2SO4, the solvent was evaporated off
and the residue chromatographed on silica gel (eluent: petroleum ether:methylene chloride=8:2) to give
1
pure 21: 1.06 g (82%); mp 126–128°C; [α]25 −185.7 (c 1.2, CHCl3); H NMR (CDCl3) δ: 8.26 (dd,
D
1H, J=7.6, 0.7 Hz), 7.68 (t, 1H, J=7.7 Hz), 7.34 (dd, 1H, J=7.7, 0.9 Hz), 6.37 (d, 1H, J=3.3 Hz), 2.45 (t,
1H, J=3.5 Hz), 1.98 (m, 1H), 1.74 (m, 1H), 1.52 (m, 1H), 1.39 (s, 3H), 1.13 (m, 1H), 0.91 (s, 3H), 0.86
(s, 3H). Anal. calcd for C30H36N2: C, 84.86; H, 8.55; N, 6.60. Found: C, 84.65; H, 8.57; N, 6.73.

G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 3537–3546
3545
3.10. 6,60-Bis{(1R,2S,3R,4S)-3-exo-phenylthio-1,7,7-trimethylbicyclo[2.2.1]heptan-2-endo-yl}-2,20 -
bipyridine 22 and 6-{(1R,2S,3R,4S)-3-exo-phenylthio-1,7,7-trimethylbicyclo[2.2.1]heptan-2-endo-yl}-
60-{(1R,2R,3S,4S)-3-endo-phenylthio-1,7,7-trimethylbicyclo[2.2.1]heptan-2-exo-yl}-2,20 -bipyridine 23
Acetic acid (20 drops) was added to a solution of 21 (1.06 g, 2.5 mmol) and thiophenol (10 ml), and
the resulting mixture was heated under reflux for 3 h. The reaction mixture was taken up in ethyl ether
and the resulting solution was washed with 10% NaOH. The separated organic phase was dried over
anhydrous Na2SO4, the solvent was evaporated off and the residue was purified by flash chromatography
(eluent: petroleum ether:methylene chloride=2:8) to give 22 and 23.
1
Compound 22: 1.06 g (66%); mp 157–158°C; [α]25 −124.4 (c 1.2, CHCl3); H NMR (CDCl3) δ:
D
8.31 (d, 1H, J=7.8 Hz), 7.66 (t, 1H, J=7.8 Hz), 7.21 (d, 2H, J=7.2 Hz), 7.01–6.96 (m, 4H), 4.48 (d, 1H,
J=6.4 Hz), 3.43 (dd, 1H, J=6.4, 1.7 Hz), 2.1 (d, 1H, J=4.4 Hz), 1.94 (m, 1H), 1.67 (m, 2H), 1.33 (s, 3H),
1.13 (m, 1H), 0.96 (s, 3H), 0.87 (s, 3H). Anal. calcd for C42H48N2S2: C, 78.21; H, 7.50; N, 4.34. Found:
C, 78.35; H, 7.66; N, 4.41.
1
Compound 23: H NMR (CDCl3) (selected data) δ: 8.24 (d, 1H, J=7.8 Hz), 8.17 (d, 1H, J=7.8 Hz),
5.15 (d, 1H, J=7.8 Hz), 4.47 (d, 1H, J=6.9 Hz), 3.43 (dd, 1H, J=6.9, 2.1 Hz), 2.80 (d, 1H, J=7.8 Hz).
3.11. (1R)-2-Methylidene-1-(6-phenylpyridin-2-yl)-3,3-dimethylbicyclo[2.2.1]heptane 24
A solution of 16 (0.75 g, 2.56 mmol) and tetrakis(triphenylphosphine)palladium (0.09 g, 0.075 mmol)
in toluene (5.2 ml) was treated with a solution of Na2CO3 (0.54 g, 5.1 mmol) in H2O (2.6 ml) followed
by a solution of phenylboronic acid (0.38 g, 3.1 mmol) in methanol (1.3 ml). The mixture was stirred
at 80–85°C for 14 h. After cooling at room temperature, a solution of concentrated aqueous NH3 (1.3
ml) in saturated aqueous Na2CO3 (12.7 ml) was added, and the mixture was extracted with CH2Cl2
(3×20 ml). The combined organic layers were washed with brine (25 ml) and dried over anhydrous
Na2SO4. Removal of the solvent under reduced pressure gave a residue which was purified by flash
chromatography (eluent: petroleum ether:methylene chloride=2:8) to give pure 24: 0.66 g (89%); oil;
[α]25D +60.3 (c 1.7, CHCl3); 1H NMR (CDCl3) δ: 8.07 (d, 2H, J=7.8 Hz), 7.61–7.50 (m, 2H), 7.43–7.32
(m, 3H), 7.12 (d, 1H, J=7.5 Hz), 4.60 (s, 1H), 4.31 (s, 1H), 2.40 (dd, 1H, J=9.8, 1.7 Hz), 2.21–2.14 (m,
1H), 2.01 (d, 1H, J=3.4 Hz), 1.88 (m, 2H), 1.65 (m, 2H), 1.16 (s, 6H). Anal. calcd for C21H23N: C, 87.15;
H, 8.01; N, 4.84. Found: C, 87.35; H, 8.06; N, 4.71.
3.12. (1S,3S,4S)-3-exo-Phenylthio-1-(6-phenylpyridin-2-yl)-4,7,7-trimethylbicyclo[2.2.1]heptane 25
A mixture of 24 (0.56 g, 1.9 mmol), thiophenol (4 ml) and 50% sulfuric acid (0.5 ml) was heated under
reflux for 96 h. The mixture was taken up in ethyl ether and washed with 10% NaOH. The separated
organic phase was dried over anhydrous Na2SO4, the solvent was evaporated off and the residue was
purified by chromatography on neutral aluminium oxide (eluent: petroleum ether:ethyl ether=95:5) to
1
give pure 25: 0.26 g (34%); oil; [α]25 +1.87 (c 1.2, CHCl3); H NMR (CDCl3) δ: 8.07 (d, 2H, J=7.3
D
Hz), 7.60–7.51 (m, 2H), 7.44–7.31 (m, 5H), 7.24 (t, 2H, J=8.1 Hz), 7.15 (t, 2H, J=8.8 Hz), 3.41 (dd,
1H, J=5.9, 3.2 Hz), 2.93–2.85 (m, 1H), 2.62 (m, 1H), 2.37 (dd, 1H, J=9.3, 4.2 Hz), 1.87 (dt, 1H, J=12.2,
4.6 Hz), 1.63–1.52 (m, 1H), 1.48–1.36 (m, 1H), 1.20 (s, 3H), 1.0 (s, 3H), 0.84 (s, 3H). Anal. calcd for
C27H29NS: C, 81.16; H, 7.32; N, 3.51. Found: C, 81.25; H, 7.46; N, 3.61.

3546
G. Chelucci et al. / Tetrahedron: Asymmetry 10 (1999) 3537–3546
3.13. Allylic alkylation of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate: general procedure
A solution of ligand (0.04 mmol, 10 mol%) and [{Pd(η3-C3H5)Cl}2] (4 mg, 2.5 mol%) in dry CH2Cl2
(2 ml) was stirred at room temperature for 15 min. This solution was treated successively with a solution
of rac-(E)-1,3-diphenyl-2-propenyl acetate (0.4 mmol) in CH2Cl2 (1 ml), dimethyl malonate (1.2 mmol),
N,O-bis(trimethylsilyl)acetamide (1.2 mmol) and anhydrous potassium acetate (3.5 mol%). The reaction
mixture was stirred for the appropriate time (see Table 1) until conversion was complete as shown by TLC
analysis (light petroleum:ether=3:1). The reaction mixture was diluted with ether (25 ml), washed with
ice-cold saturated aqueous ammonium chloride. The organic phase was dried (Na2SO4) and concentrated
under reduced pressure. The residue was purified by flash chromatography (light petroleum:ether=3:1) to
afford dimethyl 1,3-diphenylprop-2-enylmalonate. The enantiomeric excess was determined from the 1H
NMR spectrum in the presence of enantiomerically pure shift reagent Eu(hfc)3; splitting of the signals
for one of the two methoxy groups was observed.
Acknowledgements
Thanks are due to Mr. Mauro Mucedda for experimental assistance. Financial support by M.U.R.S.T.
is gratefully acknowledged.
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