Chiral Nonracemic Pyridine Thiols and Thioethers Applied in Palladium-Catalyzed Allylic Substitution. An Example of Near-Perfect Enantioselection

Article abstract of DOI:10.1021/jo9806299

Pyridine thiols and dithiols have been synthesized by base-induced addition of 2,6-lutidine to thiofenchone. These thiols were converted to their thioether derivatives by alkylation. Application of these compounds in palladium-catalyzed allylic substitution on 1,3-diphenylprop-2-enyl acetate gave nearly absolute enantiomeric excess (98%) and high chemical yield (96%). Isolation of a palladium allylic intermediate gave insight in the origin of chiral recognition for these systems.

Full text of DOI:10.1021/jo9806299

J . Org. Chem. 1998, 63, 5533-5540
5533
Ch ir a l Non r a cem ic P yr id in e Th iols a n d Th ioeth er s Ap p lied in
P a lla d iu m -Ca ta lyzed Allylic Su bstitu tion . An Exa m p le of
Nea r -P er fect En a n tioselection
B. Koning,† A. Meetsma,‡ and R. M. Kellogg*,†
Department of Organic and Molecular Inorganic Chemistry, and Crystal Structure Centre, University of
Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
Received April 6, 1998
Pyridine thiols and dithiols have been synthesized by base-induced addition of 2,6-lutidine to
thiofenchone. These thiols were converted to their thioether derivatives by alkylation. Application
of these compounds in palladium-catalyzed allylic substitution on 1,3-diphenylprop-2-enyl acetate
gave nearly absolute enantiomeric excess (98%) and high chemical yield (96%). Isolation of a
palladium allylic intermediate gave insight in the origin of chiral recognition for these systems.
Sch em e 1. P a lla d iu m -Ca ta lyzed Allylic
Su bstitu tion of 1,3-Dip h en ylp r op -2-en yl Aceta te
One of the more successful approaches to catalytic
asymmetric carbon-carbon bond formation is by means
of transition-metal catalysis.1 In particular, palladium-
catalyzed allylic substitution is a well-studied reaction
used to obtain chemo-, regio-, diastereo-, and enantiose-
lectivity.2 Because the reaction is well understood,
palladium-catalyzed substitution on racemic 1,3-diphe-
nylprop-2-enyl acetate 1 with malonate esters (Nu in
Scheme 1) is an excellent model for testing design
principles of asymmetric ligands.
Sch em e 2. P a lla d iu m Allyl In ter m ed ia tes
C2-Symmetrical bidentate ligands (L2) based on phos-
phines or phosphites have been used most frequently.3
In the absence of such symmetry elements, one is faced
with the additional challenge of control over two inter-
mediates, 2a and 2b, and the possible directions of
attack, a -d as illustrated in Scheme 2.
Although nonsymmetrical bidentate ligands allow more
permutations, the character of the ligands themselves
can provide the means of control. Different ligating
atoms have different effects on the reactivity of palladium
π-allyl complexes.4 For example, phosphites and phos-
phines are strongly π-accepting and therefore highly
activating, whereas nitrogen ligands activate less well.
Attack of the nucleophile is expected to take place trans
to the best π-acceptor, since the better π-acceptor is able
to withdraw electron density from the position trans to
itself and induce greater electron deficiency at this
terminus.
Design and development of ligands, both C2-symmetric
and not, has focused mainly on chiral nonracemic phos-
phorus-containing ligands and has led to, for example,
BINAPO by Trost,5 the ferrocenyl phosphites employed
by Hayashi6 and Togni,7 QUINAP by Brown,8 and more
recently, the monophosphines by Zhang.9 Well-defined
structural elements in the rigid complexes ensure high
chiral recognition.
A practical difficulty with such ligands is, in many
cases, high sensitivity to oxidation by oxygen. Less
oxidation sensitive amines and sulfides are also capable
of stabilizing the low-valent state of palladium, and
recently, some interest has shifted in the direction of non-
phosphorus-containing ligands. Some examples of non-
phosphorus-containing ligands, which are both catalyti-
cally active and give good chiral recognition, are
sparteine10 and stilbenediamine derivatives,11 semicor-
* To whom correspondence should be addressed. Tel.: 31-50-
3634232. Fax: 31-50-3634296. E-mail: R.M.Kellogg@chem.rug.nl.
† Department of Organic and Molecular Inorganic Chemistry.
‡ Crystal Structure Centre.
(1) For a review, see: (a) Kagan, H. B.; Fiaud, J . C. Top. Stereochem.
1978, 10, 175. (b) Bosnich, B.; Fryzuk, M. D. Top. Stereochem. 1981,
12, 119. (c) Frost, C. G.; Williams, J . M. J . Tetrahedron: Asymmetry
1992, 3, 1089. (d) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996,
96, 395.
(2) Ojima, I., Ed. Catalytic Asymmetric Synthesis; VCH: New York,
1993.
(3) (a) Whitesell, J . K. Chem. Rev. 1989, 89, 1581. (b) Rosini, C.;
Franzini, L.; Rafaelli, A.; Salvadori, P. Synthesis 1992, 503. (c) Andres,
J . M.; Martinez, M. A.; Pedrosa, R.; Perez-Encabo, A. Tetrahedron:
Asymmetry 1994, 5, 57.
(4) (a) Åkermark, B.; Hansson, S.; Krakenberger, B.; Vitagliano, A.;
Zetterberg, K. Organometallics 1984, 3, 679. (b) Åkermark, B.; Hans-
son, S.; Vitagliano, A. J . Am. Chem. Soc. 1990, 112, 4587. (c) Åkermark,
B.; Krakenberger, B.; Hansson, S.; Vitagliano, A. Organometallics
1987, 6, 620.
(5) Trost, B. M.; Murphy, D. J . Organometallics 1985, 4, 1143.
(6) Hayashi, T.; Yamamoto, A.; Hagihara, T.; Ito, Y. Tetrahedron
Lett. 1986, 27, 191.
(7) Togni, A.; Breutel, C.; Schnyder, A.; Spindler, F.; Landert, H.;
Tijani, A. J . Am. Chem. Soc. 1994, 116, 4062.
(8) Brown, J . M.; Hulmes, D. I.; Guiry, P. J . Tetrahedron 1994, 50,
4493.
(9) Chen, Z.; J iang, Q.; Zhu, G.; Xiao, D.; Cao, P.; Guo, C.; Zhang,
X. J . Org. Chem. 1997, 62, 4521.
(10) Togni, A. Tetrahedron: Asymmetry 1991, 2, 683.
S0022-3263(98)00629-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/17/1998

5534 J . Org. Chem., Vol. 63, No. 16, 1998
Koning et al.
rins and bisoxazolines,12 ephedra-based amino sulfides,13
sulfur-containing oxazoline ligands,14 (hydroxyalkyl)-
pyridinooxazolines,15 C2-symmetrical bis(aziridines),16
and more recently, bis(oxazolinylpyridinyl)dioxolanes.17
Sch em e 4a
Sulfides form a good perspective for development of
new ligands, since sulfur is a soft complexation site and
palladium is a soft metal ion, factors which will generally
lead to a strong complex. Furthermore, back-donation
of π-electron density from the metal to the empty
relatively low-energy d orbitals of the sulfur can contrib-
ute to the strength of the Pd(II)-S bond.18 In contrast
to trivalent phosphines and phosphites, divalent sulfide
cannot be intrinsically chiral. On complexation to a
metal, chirality can be induced at sulfur. However, the
difficulty in controlling this aspect is likely the reason
that few sulfur-containing ligands have been reported or
used. We, however, recently reported a new method for
the easy preparation of C2-symmetrical chiral and non-
chiral “pyridine dithiols” (condensation products of 2,6-
lutidine with 2 equiv of thioketone).19 “Single armed”
derivatives are intermediates in this reaction and are also
of interest. We anticipated that on use of structurally
rigid thioketones a variety of thiol- or sulfide-containing
ligands could be obtained in which the coordination
geometry is defined at the outset. The palladium-
catalyzed allylic substitution has been used to explore
the catalytic potential of these ligands.
a
Reagents and conditions: (i) BunLi (1.1 equiv), THF, -60 °C;
(ii) -60 f -40 °C; (iii) S-thiofenchone.
70%) than the multistep synthesis that has been reported
previously.22
Using thioadamantanone, achiral pyridine thiol 5 and
dithiol 6 were synthesized.19 No products from carbanion
addition to the sulfur atom of the thioketone were
isolated. Attempts to prepare the bis-condensed product
6 in a one-step one-pot or in a two-step one-pot reaction
gave rise to lower yields.23 Chiral nonracemic pyridi-
nethiols and dithiols were prepared using optically pure
(S)-thiofenchone, prepared from (S)-(+)-fenchone (ee )
98%) or (R)-thiofenchone (from (R)-(-)-fenchone ee )
96%)).24 In this approach, the monocondensation product
7 (see further for stereochemical assignment) could be
isolated in 89% yield as either enantiomer (Scheme 4).
We were surprised to isolate a single diastereomer;
reaction of 2,6-lutidine with fenchone itself leads to
roughly equal amounts of exo and endo attack.
Attempts to synthesize the condensation product of 2,6-
lutidine 4 with optically pure thiocamphor failed due to
preferred formation of the thioenolate; this competing
reaction in the case that relatively acidic R-protons are
present appears to be a limitation of the direct approach
of Scheme 4.
Sch em e 3a
By means of HETCOR, COSY, and NOESY experi-
ments on (-)-7, addition was established to have taken
place from the exo side of thiofenchone. This is more
a
Reagents and conditions : (i) BunLi (1.1 equiv), THF, -80 °C;
(ii) -80 f -40 °C; (iii) R2CdS; (iv) BunLi (2.1 equiv), THF, -80
°C; (v) -80 f -50 °C.
Liga n d Syn th esis
The approach to the preparation of pyridine diols,
reported by Berg and Holm20 and ourselves,21 can be
extended to the preparation of certain pyridinethiols and
dithiols by using thioketones (Scheme 3). This method
is more straightforward and efficient (overall yield up to
clearly determined from spectra of the (-)-7‚HCl complex
of the monothiol adduct, prepared by passing HCl gas
through a solution of (-)-7 in dichloromethane. This
complex has a locked conformation on the NMR chemical
shift scale, and an AB system is observed for the benzylic
protons H4 and H4′ (see structure (-)-7 for the numbering
scheme, which is based on simplicity of illustration),
whereas for the free ligand a singlet was found. The
pyridine protons H1 , H2, and H3 of the HCl complex are
shifted 0.50, 0.67, and 1.74 ppm downfield, respectively.
This is consistent with protonation of the pyridine
nitrogen. Furthermore, most protons of the thiofenchone
(11) Gamez, P.; Dunjic, B.; Fache, F.; Lemaire, M. J . Chem. Soc.,
Chem. Commun. 1994, 1417.
(12) (a) Mu¨ller, D.; Umbright, G.; Weber, B.; Pfaltz, A. Helv. Chim.
Acta. 1991, 74, 232. (b) Leutenegger, U.; Umbright, G.; Fahrni, C.;
Matt, v. P.; Pfaltz, A. Tetrahedron 1992, 48, 2143. (c) Pfaltz, A. Acta
Chim. Scand. 1996, 50, 189.
(13) Koning, B.; Hulst, R.; Kellogg, R. M. Recl. Trav. Chim. Pays-
Bas 1996, 115, 49.
(14) Allen, J . V.; Coote, S. J .; Dawson, G.; Frost, C. G.; Martin, C.
J .; Williams, J . M. J . J . Chem. Soc., Chem. Commun. 1994, 2065.
(15) Nordstro¨m, K.; Macedo, E.; Moberg, C. J . Org. Chem. 1997, 62,
1604.
(16) Tanner, D.; Andersson, P. G.; Hardem, A.; Somfai, P. Tetrahe-
dron Lett. 1994, 35, 4631.
(17) Chelucci, G. Tetrahedron: Asymmetry 1997, 8, 2667.
(18) Wilkinson, G. In Comprehensive Coordination Chemistry; Per-
gamon Press: New York, 1987; Vol. 5.
(19) Koning, B.; Hulst, R.; Bouter, A.; Buter, J .; Meetsma, A.;
Kellogg, R. M. Chem. Commun. 1997, 1065.
(20) Berg, J . M.; Holm, R. H. J . Am. Chem. Soc. 1985, 107, 917.
(21) Edema, J . J . H.; Libbers, R.; Ridder, A. M.; Kellogg, R. M.; van
Bolhuis, F.; Kooijman, H.; Spek, A. L. J . Chem. Soc., Chem. Commun.
1993, 625.
(22) (a) Holm, R. H.; Berg, J . M. Acc. Chem. Res. 1986, 19, 363. (b)
Kaptein, B.; Barf, G.; Kellogg, R. M.; Van Bolhuis, F. J . Org. Chem.
1990, 55, 1890.
(23) The one-step one-pot approach involves double deprotonation
with 2.2 equiv of n-BuLi followed by 2 equiv of thioketone. In the two-
step one-pot approach, the monocondensation product is not isolated,
and a second equivalent of n-BuLi and thioketone are added after the
monoadduct has been formed.
(24) Determined on a 20% permethylated â-cyclodextrin column;
length 30 m.

Chiral Nonracemic Pyridine Thiols and Thioethers
J . Org. Chem., Vol. 63, No. 16, 1998 5535
Sch em e 5a
a
Reagents and conditions: (i) BunLi (2.1 equiv), THF, -70 °C;
(ii) -70 f -40 °C; (iii) R2CdS.
of hydrochloric acid in solid argon also consists of
polymeric strands.28 However, previous crystal struc-
tures of complexes with pyridinediols and dithiols (two
arms instead of one) show encapsulation of monomeric
hydrochloric acid into the cavity of these molecules.19,21
The monoadduct (+)-7 was further functionalized
following the general approach of Scheme 3. Addition
of n-BuLi (2.2 equiv) to a solution of the monoadduct
(+)-7 in THF, followed by the addition of 1.1 equiv of
thiofenchone, led to the dithioladduct 8 in 79% yield
(Scheme 5).
The mono- and the dithioladduct were alkylated to
afford the corresponding thioethers (+)-9 and dithioet-
hers 10. For the preparation of the methyl thioethers,
K2CO3 was used as base and methyl iodide as the
methylating reagent; the mono- and dithioether adduct
were obtained in 76% and 94% yields for (+)-9a (R )
CH3) and 10a (R ) CH3), respectively. For the prepara-
tion of the homochiral series, ethyl, isopropyl, n-propyl,
and benzyl thioethers (+)-9b-d , (-)-9e, and 10b-e
sodium hydride were used to deprotonate the thiol.
These thioethers were isolated in 50-89% yield.
F igu r e 1. X-ray structure of (-)-7‚HCl.
moiety are shifted downfield relative to the uncomplexed
ligand, and assignment of the specific protons is simpli-
fied. From HETCOR spectra, the signal at δ 1.68 could
be assigned to H5 since it clearly belongs to a CH group
(see the Supporting Information).
Furthermore, HETCOR gives three sets of signals for
the three CH2 groups of the fenchone moiety (δ 1.37 and
2.28; δ 1.20 and 2.40; δ 1.43 and 1.64). On the basis of
the coupling constants of the signals at δ 1.37 and 2.28
in the 1H NMR, the fact that they exhibited COSY
interactions only with each other (see the Supporting
Information), and the NOE correlation with H5, we
assigned these signals to the bridge protons. The signal
at δ 2.28 has NOE interactions with the signal at δ 1.37,
the benzylic protons, and two of the methyl groups, and
therefore, we assigned this signal to H10. The signal at
δ 1.37 has interactions with signals at δ 2.28, 1.20, and
1.43, the latter two being from the exo-protons H9 and
H7, leaving the signals at δ 1.64 and 2.40 for the endo
protons H6 and H8. The signal at δ 1.64 has an NOE
interaction with the C16 methyl group, and therefore, it
could be assigned as H6, and subsequently, the signal at
δ 2.40 could be assigned as H8. The exo protons could
now be assigned as H7 and H9 for the signals at δ 1.43
and 1.20, respectively. From the correlation of the bridge
proton H10 with the benzylic protons, it is clear that
addition has taken place from the exo side of the
thioketone. It cannot be taken for granted that addition
of a nucleophile will occur exclusively from the exo side.
Although, for example, dissolving metal reductions of
fenchone produce almost exclusively endo alcohol (addi-
tion of hydride equivalent from the exo side),25 we26
observed that addition of 2,6-lutidine (as the monolithio
derivative) occurs roughly equally from the exo and endo
sides. On the other hand, 1,3-dipolar addition of diazo
compounds to thiofenchone gives a single adduct thought
to be exo addition product.27
P a lla d iu m -Ca ta lyzed Allylic Su bstitu tion
In initial experiments, thiols (+)-7 and 8 were used as
ligands in the palladium-catalyzed alkylation of 1,3-
diphenylprop-2-enyl acetate 1. These experiments were
carried out in dry dichloromethane at room temperature
in the presence of [(η3C3H5)PdCl]2 and the ligand. The
nucleophile was generated either from dimethyl malonate
in the presence of bis(trimethylsilyl)acetamide (BSA) and
a catalytic amount of potassium acetate or from dimethyl
malonate and sodium hydride. With sodium hydride as
base, very low conversions and low to moderate selectivi-
ties were found after 36 h (Table 1). Using BSA as base
resulted in an increase in yield for (+)-7; however, no
product was found when 8 was used. The low reactivity
with these ligands is probably due to deprotonation of
the thiol group by the bases. In order to bypass problems
arising from the reactivity of the thiol groups, the
thioethers (+)-9a -d , (-)-9e, and 10 were examined. The
first experiments were carried out with thioethers (+)-
9a and (+)-9b using NaH as base to deprotonate the
malonate. These experiments afforded the product 3 in
35 and 70% isolated yield and 46 and 81% ee for (+)-9a
By good fortune, we obtained satisfactory crystals and
were able to confirm this structural assignment of the
(-)-7‚HCl complex by crystallographic means (Figure 1).
The packing diagram (not shown) reveals a polymeric
chain with alternating HCl molecules and the ligand
moiety. The proton of hydrogen chloride is coordinated
to the pyridine nitrogen of one molecule, and the chlorine
is coordinated to the thiol hydrogen of a second molecule.
This unit is continuously repeated. The crystal structure
(25) Rautenstrauch, V. J . Chem. Soc., Chem. Commun. 1986, 1558.
(26) Koning, B.; Kellogg, R. M. To be published.
(27) Barton, D. H. R.; Guziec, F. S.; Shahak, I. J . Chem. Soc., Perkin
Trans. 1 1974, 1794.
(28) Wells, A. I. In Structural Inorganic Chemistry, 5th ed.; Clar-
endon Press: Oxford, 1990.

5536 J . Org. Chem., Vol. 63, No. 16, 1998
Koning et al.
Ta ble 1. Test Resu lts w ith Th iols (+)-7 a n d 8 a n d
Th ioeth er s (+)-9a -d , (-)-9e, a n d 10
T
(°C)
equiv of yield eea
ligand
R2
base
base/NuH (%) (%) confgna
(+)-7
8
(+)-7
8
(+)-9a Me
(+)-9b Et
(+)-9a Me
(+)-9b Et
(+)-9c i-Pr
(+)-9d n-Pr
H
H
H
H
rt NaH
rt NaH
rt BSA/KOAc
rt BSA/KOAc
rt NaH
1.5/1.5
1.5/1.5
1.2/1.5
1.2/1.5
1.5/1.5
1.5/1.5
1.2/1.5
1.2/1.5
1.2/1.5
1.2/1.5
1.2/1.5
1.2/1.5
1.2/1.5
1.2/1.5
1.2/1.5
1.2/1.5
2
4
10
80
23
81
S
R
S
35
70
80
84
93
90
96
83
80
89
80
90
46
81
53
91
82
81
92
78
84
85
85
85
R
R
R
R
R
R
R
R
R
R
R
R
rt NaH
rt BSA/KOAc
rt BSA/KOAc
rt BSA/KOAc
rt BSA/KOAc
(-)-9e benzyl rt BSA/KOAc
10a
10b
10c
10d
10e
Me
Et
n-Pr
i-Pr
rt BSA/KOAc
rt BSA/KOAc
rt BSA/KOAc
rt BSA/KOAc
benzyl rt BSA/KOAc
a
The enantiomeric excess was determined by 1H NMR using
Eu(hfc)3 as chiral shift reagent, and the absolute configurations
were established by comparing the optical rotation with literature
values for material of established absolute configuration.12,29
-
F igu r e 2. X-ray structure of 11a without the counterion PF6
.
and (+)-9b, respectively, after a reaction time of 18 h.
Using BSA as base, higher selectivities and conversions
were found for these ligands at shorter reaction times
(10 h). The next step was application of BSA as base in
combination with the other thioethers (+)-9c-d , (-)-9e,
and 10a -e. The reactions proceeded smoothly and were
complete within 10 h. The product 3 was obtained in
high yield and in moderate to high enantiomeric excess
as summarized in Table 1.
The benzyl thioethers (-)-9e and 10e were found to
perform best under these conditions, and these ligands
were selected for optimization of the allylic substitution
(Table 2). Replacement of dichloromethane by acetoni-
trile led to an increase of the enantioselectivity when (-)-
9e was used. The enantioselectivity using (-)-9e was
further optimized by using 3 equiv of base and nucleo-
phile together with lower reaction temperature. For (-)-
9e, this is theoretically the highest enantioselectivity that
could be obtained since the starting material (R)-(-)-
fenchone can only be purchased in 96% enantiomeric
purity. We therefore synthesized ligand (+)-9e under the
same conditions used for (-)-9e starting from the more
expensive (S)-(+)-fenchone, which can be purchased in
98% enantiomeric purity. Application of (+)-9e in the
allylic substitution reaction afforded the product 3 in 96%
isolated yield and 98% ee. No notable increase in the
selectivity was found when 10e was applied under the
optimized conditions.
In order to get more insight in the reaction mechanism
and the mechanism of introduction of chirality into the
product, the allylic intermediate 11 was synthesized. This
complex was prepared from (+)-9c and [(η3C3H5)PdCl]2
using AgPF6 to replace the chloride. The 1H NMR
spectrum showed a mixture of the two diastereomeric
complexes 11a and 11b in which the allylic moiety is
coordinated either exo or endo to the palladium relative
to the thioether. The ratio between the two diastereo-
meric complexes was determined to be 3:4 at 20.0 °C (see
the Supporting Information). Temperature-dependent
studies of this complex showed an increase in the
preference for 11b as the temperature decreased. Elu-
1
cidation of the H NMR spectrum was accomplished by
COSY and NOESY experiments. From the integrals of
the specific signals and from the COSY experiments, we
could assign the signals at δ 2.94, 3.58, 4.33, 4.88, and
5.88 as belonging to the minor diastereomer and the
signals at δ 3.39, 3.65, 4.33, 4.68, and 5.70 to the major
1
diastereomer. The signals in the H NMR spectrum at
δ 5.70 and 5.88 correspond to the protons H2 of the
diastereomeric complexes as was deduced from their
integrals, couplings, and chemical shifts. Assuming that
the coupling constant between H2 protons and the protons
cis to H2 is smaller than the coupling between the trans
protons, we assigned the signals at δ 4.33, 4.68, and 4.88
to the protons cis relative to H2. The signals at δ 2.94,
3.39, 3.58, and 3.65 were assigned as the protons trans
to the H2 protons. Remarkable in the spectrum is that
there is no geminal coupling between the protons of the
terminal CH2 group of the allylic moiety, as is also found
for the geminal protons in the [(η3C3H5)PdCl]2 complex.30
Since the protons H3 of the allylic moiety trans to the
sulfur atom are slightly less electron rich due to the
electron-withdrawing character of the sulfur, they will
adsorb at lower field than the H1 protons trans to
nitrogen, and therefore, they could be assigned as the
signals at δ 4.68 and 4.88. Therefore, the signal at 4.33
corresponds to the H1 protons of both diastereomers.
Likewise, the signals at δ 3.58 and 3.65 correspond to
the protons H3′ trans to the sulfur atom and the signals
at δ 2.94 and 3.49 correspond to the protons H1′.
More information about the complex was obtained from
the X-ray diffraction (Figure 2). Only the minor isomer
corresponding to structure 11a crystallized from the
mixture. At first it was assumed that the structure of
the major diastereomer had been determined. NOESY
experiments, however, gave convincing data to suppose
(30) Elschenbroick, Ch.; Salzer, A. In Organometallics, 2nd ed.;
VCH: Weinheim, 1992; p 285.
(31) Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre. Deposition numbers are
101825, 101829, and 101830. Copies of the data can be obtained free
of charge on application to the Director, CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (Fax: int code +(1223)336-033, E-mail:
teched@chemcrys.cam.ac.uk).
(29) von Matt, P.; Pfaltz, A. Angew. Chem., Int. Ed. Engl. 1993, 32,
566.

Chiral Nonracemic Pyridine Thiols and Thioethers
J . Org. Chem., Vol. 63, No. 16, 1998 5537
Ta ble 2. Op tim iza tion w ith Th ioeth er s (-)-9e, (+)-9e, a n d 10e
ligand
R2
T (°C)
solvent
base
equiv of base/NuH
yield %)
eea
confgna
(-)-9e
(-)-9e
(-)-9e
(+)-9e
10e
benzyl
benzyl
benzyl
benzyl
benzyl
rt
0
0
0
0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
BSA/KOAc
1.2/1.5
1.2/1.5
3/3
3/3
3/3
94
96
95
96
75
93
95
96
98
86
R
R
R
S
R
a
The enantiomeric excess was determined by 1H NMR using Eu(hfc)3 as chiral shift reagent, and the absolute configurations were
established by comparing the optical rotation with literature values for material of established absolute configuration.12,29
otherwise. In the NOESY spectrum, we observed an
interaction between H3 of the allyl group (δ 4.88) and the
6-methyl group of the pyridine ring (δ 2.64) and an
interaction between H1′ (δ 2.94) and one of the methyl
groups from the fenchone moiety (δ 1.41). From these
interactions, we concluded that this is the structure that
is found in the X-ray diffraction since herein the H3
proton is adjacent to the methyl group and the H1′
positioned closely to the fenchone methyl group. The
minor diastereomer thus corresponds to structure 11a .
For the major diastereomer, we find an NOE interaction
for H3′ (δ 3.65) with the pyridine methyl group (δ 2.80)
and an NOE interaction between H1 (δ 4.33) and one of
the methyl groups from the fenchone moiety (δ 1.30),
indicating that this corresponds to structure 11b.
In the crystal structure, the palladium is coordinated
to the sulfur, the nitrogen atom, and C1, C2, and C3 of
the allylic moiety embedded in a square-planar coordina-
tion for palladium. The bond length of Pd-C3 (trans to
sulfur) is somewhat longer than the Pd-C1 bond length,
giving C3 some more π character. Therefore, C1 and C3
are expected to exhibit distinctly different reactivities
toward nucleophiles.
Compound 14 lacking the 6-methyl group was prepared.
Allylic substitution proceeded readily, and 3 was obtained
in good yield but only in 47% ee and as the S enantiomer.
Clearly, control over the manner of complexation has
been lost by elimination of this small but essential methyl
group.
When the C2-symmetrical dithioethers 10 are applied,
the chemical yields and the enantioselectivities are still
high. The substituents R on the sulfur do not have a
great impact on the stereoselectivity of the reaction,
whereas for the ligands (+)-9a -d and (-)-9e there is a
reasonable correlation between the size of the substituent
R and the ee of 3 (Table 1).
Ca u ses of In d u ction a n d Com p a r ison w ith C2
Liga n d s
The yields of the allylic substitution are good, the
reaction times are acceptable, and the ee’s of the opti-
mized reactions are virtually absolute. The thioethers
(+)-9a -d and (-)-9e constantly provide substitution
product 3 of R absolute configuration. The bulk of the
substituent on sulfur has a moderate correlation with
improved enantiomeric excesses. The structure of the
complex 11a (Figure 2) confirms our expectation that
sulfide is rigidly coordinated in a six-membered ring and
that the fenchyl methyl groups force a single absolute
configuration, in this case S, on the coordinated sulfur.
The isolated methyl group at the 6-position of the
pyridine ring plays a key role in determining the orienta-
tion of the π-allyl complex; one end of the allyl group is
forced against the steric bulk of the fenchyl methyls,
whereas the 6-methyl group exerts controlling influence
on the other end of the allyl group. We believe that for
the 1,3-diphenylallyl group used here these interactions
enforce structure 12b rather than 12a in which the
phenyl groups are oriented toward the steric bulk on both
sides. Attack of the malonate nucleophile should logically
occur away from the greatest steric bulk, in other words
on the side of the pyridine ring bearing only the 6-methyl
group. This is electronically also expected as the soft
nucleophile attacks trans to the softer sulfide, which is
the better π acceptor. This leads to the observed R
configuration of 3.
To obtain more insight into this allylic substitution,
we attempted to isolate the Pd-allylic intermediate of 10e
and [(η3C3H5)PdCl]2. However, a structure was isolated
1
that was characterized by COSY and H NMR as being
fully symmetrical (see the Supporting Information) but
devoid of allyl group. The ligand is unambiguously
coordinated as can be seen in the downfield shift of the
pyridine protons and the increase in coupling between
the two diastereotopic benzylic protons of the thioether.
The observation that the system still exhibits a C2
symmetry is proof for the complexation of the palladium
to both sulfur atoms; otherwise, an asymmetrical system
would have been obtained. Recrystallization of this
complex from dichloromethane by isothermal distillation
of hexane into the solution afforded the Pd-Cl complex
-
15 as BF4 salt as was established by X-ray diffraction
(Figure 3). The palladium-allyl complex involved in
reaction seems to be too labile and degrades to 15. This
instability has thwarted all subsequent attempts to
obtain the desired palladium-allyl complex. The pal-
ladium chloride complex 15 exhibits square-planar co-
ordination of the palladium to the sulfur and nitrogen
atoms.
Speculations for the explanation of the stereochemical
outcome for the dithioethers at this stage, without
knowing the active catalytic species, are inappropriate.
The role of the methyl group at the 6-position of the
pyridine ring is readily demonstrated to be profound.

5538 J . Org. Chem., Vol. 63, No. 16, 1998
Koning et al.
was prepared using the same procedure as for (-)-7 starting
from 2,6-lutidine and (S)-thiofenchone, affording (+)-7 in
comparable yields: mp 114-115 °C; [R]23 ) +85.8 (c 3.6,
D
methanol).
2-Meth yl-6-[[(1S,2S)-1,3,3-tr im eth yl-2-su lfa n ylbicyclo-
[2.2.1]h ep t-2-yl]m eth yl]p yr id in e. HCl ((-)-7‚HCl). A so-
lution of the monoadduct (-)-7 (0.25 g, 0.91 mmol) in dichlo-
romethane (10 mL) was passed through a stream of HCl for 2
min. The mixture was stirred for 2 h, and the solvent was
carefully evaporated at reduced pressure to yield the crude
HCl complex, which was recrystallized from hexane/dichlo-
romethane (0.27 g, 0.87 mmol, 95%): mp 181-182 °C; [R]23
D
) -62.1 (c 2.9, chloroform); H NMR δ 0.89 (s, 3H), 1.08 (s,
3H), 1.16 (s, 3H), 1.20 (m, 1H), 1.37 (d, J ) 10.99 Hz, 1H),
1.43 (m, 1H), 1.52 (s, SH), 1.64 (m, 1H), 1.69 (m, 1H), 2.28 (d,
J ) 10.99 Hz, 1H), 2.40 (m, 1H), 2.98 (s, 3H), 3.26 (d, J ) 17.2
Hz, 1H), 4.43 (d, J ) 17.2 Hz, 1H), 7.42 (d, J ) 7.69 Hz, 1H),
8.09 (dd, J ) 8.05, 7.69 Hz, 1H), 8.80 (d, J ) 8.05 Hz, 1H);
C-NMR δ 17.65 (q), 24.44 (t), 26.07 (q), 29.39 (q), 33.68 (t),
40.20 (t), 44.44 (t), 45.31 (s), 50.68 (d), 56.15 (s), 63.29 (s),
124.39 (d), 124.83 (d), 143.09 (d), 153.48 (s), 157.91 (s); HRMS
-
F igu r e 3. X-ray structure of 15 without the counterion BF4
.
Con clu sion s
In these easily accessible systems, we have found a new
class of ligands for the palladium-catalyzed allylic sub-
stitution reaction. The optimized results with the mono-
thioethers can scarcely be improved in terms of yield and
ee. The possibility of introducing other groups at the 6
position of the pyridine ring (as tert-butyl) give these
systems high potential for other catalytic applications.
Such possibilities are currently being explored.
calcd 311.147, found 275.171 (- HCl). Anal. Calcd for C17H26
-
NSCl: C, 65.46; H, 8.40; N, 4.49; Cl, 11.37. Found: C, 65.16;
H, 8.22; N, 4.42; Cl, 11.38.
2,6-Bis[[(1R ,2R )-1,3,3-t r im e t h yl-2-su lfa n ylb icyclo-
[2.2.1]h ep t-2-yl]m eth yl]p yr id in e (8). To a solution of (+)-7
(0.29 g, 1.05 mmol) in 50 mL of THF at -70 °C was added
n-butyllithium (1.6 M in hexane, 1.4 mL, 2.2 mmol). The
mixture was stirred for 90 min at -40 °C and cooled to -70
°C again. A solution of (R)-thiofenchone (0.20 g, 1.19 mmol)
in 5 mL of THF was added, and the mixture was stirred at
-70 °C for 1 h. The cooling bath was removed, and the
mixture was allowed to stir at ambient temperature overnight.
The mixture was poured into 15 mL of 5 N HCl solution and
stirred for 1 h before it was neutralized with a 2 N NaOH
solution. The mixture was extracted three times with dichlo-
romethane. The combined organic layers were washed with
brine and dried over MgSO4. The product was purified by
means of column chromatography (silica gel, hexane/dichlo-
romethane (2:1)) yielding 8 as a colorless solid (0.37 g, 0.83
Exp er im en ta l Section
Gen er a l Rem a r k s. All reactions were carried out under
an argon atmosphere. The following solvents were distilled
prior to use: THF was distilled from Na wire, acetonitrile and
dichloromethane were distilled over CaH2, and diethyl ether,
ethyl acetate, and hexane were distilled over P2O5. Column
chromatography was performed on alumina (Merck 90, II/III,
0.063-0.200 mm) or silica gel (Aldrich 60, 230-400 mesh).
Elemental microanalyses were carried out in the analytical
department of this laboratory. (R)- and (S)-thiofenchone were
prepared following literature procedures starting from (R)-(-
)-fenchone and (S)-(+)-fenchone, respectively.32 All other
starting materials were purchased from Aldrich, Acros, or
Fluka.
2-Meth yl-6-[[(1S,2S)-1,3,3-tr im eth yl-2-su lfa n ylbicyclo-
[2.2.1]h ep t-2-yl]m eth yl]p yr id in e ((-)-7). To a solution of
2,6-lutidine (4) (0.35 g, 3.3 mmol) in 50 mL of THF at -60 °C
was added n-butyllithium (1.6 M in hexane, 2.1 mL, 3.4 mmol).
The mixture was stirred for 1 h at -40 °C and cooled to -60
°C again. A solution of (S)-thiofenchone (0.56 g, 3.3 mmol) in
5 mL of THF was added, and the mixture was stirred at -60
°C for 1 h. The cooling bath was removed, and the mixture
was allowed to stir at ambient temperature overnight. The
mixture was poured into 15 mL of 5 N HCl and stirred for 1
h before being neutralized with 2 N NaOH. The mixture was
extracted three times with dichloromethane. The combined
organic layers were washed with brine and dried over MgSO4.
The product was purified by means of Kugelrohr distillation
(135 °C, 2.0 mmHg), yielding a colorless solid (0.81 g, 2.9 mmol,
89%): mp 113-114 °C; [R]23D -87.5 (c 3.6, methanol); 1H NMR
δ 0.79 (s, 3H), 1.15 (m, 2H), 1.19 (s, 3H), 1.26 (s, 3H), 1.40 (m,
1H), 1.64 (m, 1H), 1.76 (m, 1H), 1.93 (m, 1H), 2.19 (m, 1H),
2.52 (s, 3H), 3.30 (s, 2H), 4.67 (br, SH), 6.92 (d, J ) 7.63 Hz,
1H), 7.06 (d, J ) 7.93 Hz, 1H), 7.42 (dd, J ) 7.63, 7.93 Hz,
1H); 13C NMR δ 18.19 (q), 24.38 (t), 27.31 (q), 28.79 (q), 33.62
(t), 40.27 (t), 45.54 (s), 47.89 (t), 50.85 (d), 54.37 (s), 62.34 (s),
119.80 (d), 121.47 (d), 136.03 (d), 156.20 (s), 161.15 (s); HRMS
calcd 275.171, found 275.171. Anal. Calcd for C17H25NS: C,
74.13; H, 9.15; N, 5.08. Found: C, 74.10; H, 9.11; N, 5.10.
2-Meth yl-6-[[(1R,2R)-1,3,3-tr im eth yl-2-su lfa n ylbicyclo-
[2.2.1]h ep t-2-yl]m eth yl]p yr id in e ((+)-7). This compound
mmol, 79%): mp 139-140 °C; [R]23 -80 (c 4.0, CHCl3); 1H
D
NMR δ 0.83 (s, 6H), 1.15 (m, 2H), 1.16 (s, 6H) 1.20 (s, 6H),
1.23 (d, J ) 10.5 Hz, 2H), 1.41 (m, 2H), 1.65 (d, J ) 4.4 Hz,
2H), 1.73 (m, 2H), 1.97 (d, J ) 10.5 Hz, 2H), 2.26 (d, J ) 16.6
Hz, 2H), 2.28 (m, 2H), 3.35 (d, J ) 16.6 Hz, 2H), 3.36 (s, 2SH),
7.46 (m, 3H); 13C NMR δ 18.15 (q), 24.65 (t), 27.39 (q), 29.34
(q), 33.79 (t), 40.30 (t), 45.44 (s), 49.18 (t), 51.02 (d), 55.08 (s),
62.74 (s), 121.57 (d), 135.54 (d), 169.24 (s); HRMS calcd
443.268, found 443.268. Anal. Calcd for C27H41NS2: C, 73.08;
H, 9.31; N, 3.16. Found: C, 73.08; H, 9.31; N, 3.15.
Gen er a l P r oced u r e A for th e Syn th esis of Th ioeth er s
(+)-9a a n d 10a . To 1.0 mmol of thiol or dithiol adduct,
dissolved in 50 mL of acetone, were added K2CO3 (1.5 equiv)
and iodomethane (2.0 equiv). The mixture was stirred at
reflux conditions overnight. After being cooled to rt, the
mixture was filtered and the solvent evaporated. The product
was purified by means of column chromatography (silica gel,
hexane/diethyl ether 6:1).
Gen er a l P r oced u r e B for th e Syn th esis of Th ioeth er s
9 a n d 10. To 1.0 mmol of thiol or dithiol adduct, dissolved in
50 mL of THF, was added sodium hydride (1.5 equiv) and
stirring continued for 10 min. To this solution was added the
alkyl halide (1.5 equiv) and stirring continued overnight at
rt. Water (10 mL) was added, and the mixture was extracted
twice with dichloromethane. The combined organic layers
were washed with brine and dried over MgSO4. The product
was purified by means of column chromatography (silica gel,
hexane/diethyl ether 6:1).
2-Meth yl-6-[[(1R,2R)-1,3,3-tr im eth yl-2-(m eth ylsu lfan yl)-
bicyclo[2.2.1]h ept-2-yl]m eth yl]pyr idin e ((+)-9a). This com-
pound was prepared according to general procedure A starting
from (+)-7 (0.50 g, 1.82 mmol), K2CO3 (0.37 g, 2.7 mmol), and
iodomethane (0.51 g, 3.6 mmol) to yield a colorless solid that
was recrystallized from hexane (0.40 g, 1.38 mmol, 76%): mp
(32) Scheeren, J . W.; Ooms, P. H. J .; Nivard, R. J . F. Synthesis 1973,
149.
1
65-67 °C; [R]23 +21 (c 1.2, CHCl3); H NMR δ 0.87 (s, 3H),
D

Chiral Nonracemic Pyridine Thiols and Thioethers
J . Org. Chem., Vol. 63, No. 16, 1998 5539
1.15 (s, 3H), 1.18 (s, 3H), 1.2 (m, 2H), 1.37-1.55 (m, 2H), 1.7
(m, 1H), 1.98 (s, 3H), 2.04 (m, 1H), 2.53 (s, 3H), 2.6 (m, 1H),
3.34 (dd, J ) 17.57, 22.96 Hz, 2H), 6.94 (d, J ) 7.57 Hz, 1H),
°C (0.45 g, 0.91 mmol, 89%): mp 38-39 °C; [R]23 +15 (c 4.0,
CHCl3); HRMS calcd 499.333, found 499.333. Anal. Calcd for
C31H49NS2: C, 74.49; H, 9.88; N, 2.80. Found: C, 72.96; H,
10.05; N, 2.73.
D
7.48 (dd, J ) 7.57, 8.05 Hz, 1H), 8.20 (d, J ) 8.05 Hz, 1H); 13
C
NMR δ 13.58 (q), 20.07 (q), 24.23 (q), 24.49 (q), 24.68 (t), 29.44
(q), 34.61 (t), 41.39 (t), 41.99 (t), 46.78 (s), 51.11 (d), 56.15 (s),
60.78 (s), 120.20 (d), 120.52 (d), 135.99 (d), 156.73 (s), 160.82
(s); HRMS calcd 289.185, found 289.186. Anal. Calcd for
2,6-Bis[[(1R,2R)-1,3,3-tr im eth yl-2-(isop r op ylsu lfa n yl)-
bicyclo[2.2.1]h ep t-2-yl]m eth yl]p yr id in e (10c). This com-
pound was prepared according to the general procedure B
starting from 8 (1.00 g, 2.26 mmol), sodium hydride (0.14 g,
5.83 mmol), and isopropyl bromide (0.69 g, 5.61 mmol). The
dithioether was recrystallized from ethanol at -20 °C to yield
10c as a colorless solid (0.60 g, 1.14 mmol, 50%): mp 82-84
C
18H27NS: C, 74.69; H, 9.40; S, 11.08. Found: C, 74.93; H,
9.44; S, 11.05.
2-Meth yl-6-[[(1R,2R)-1,3,3-tr im eth yl-2-(eth ylsu lfa n yl)-
bicyclo[2.2.1]h ep t-2-yl]m eth yl]p yr id in e ((+)-9b). For this
compound, general procedure B was used, starting from (+)-7
(0.50 g, 1.82 mmol), sodium hydride (0.09 g, 3.6 mmol) and
ethyl bromide (0.29 g, 2.7 mmol). (+)-9b was obtained as a
colorless solid after Kugelrohr distillation (0.5 mmHg, 150 °C)
°C; [R]23 +41 (c 2.0, CHCl3); HRMS calcd 527.362, found
D
527.364. Anal. Calcd for C33H53NS2: C, 75.08; H, 10.12; N,
2.65. Found: C, 74.97; H, 10.22; N, 2.69.
2,6-Bis[[(1R,2R)-1,3,3-t r im et h yl-2-(n -p r op ylsu lfa n yl)-
bicyclo[2.2.1]h ep t-2-yl]m eth yl]p yr id in e (10d ). From 8
(0.48 g, 1.08 mmol), sodium hydride (0.07 g, 2.92 mmol), and
n-propyl iodide (0.46 g, 2.71 mmol), 10d was obtained as a
solid that was recrystallized from ethanol at -20 °C (0.36 g,
(0.43 g, 1.42 mmol, 78%): mp 65-66 °C; [R]23 +10 (c 7.8,
D
CHCl3); HRMS calcd 303.203, found 303.202. Anal. Calcd for
C
19H29NS: C, 75.19; H, 9.63; N, 4.61. Found: C, 75.12; H,
9.64; N, 4.57.
0.68 mmol, 63%): mp 90-91 °C; [R]23 +24.1 (c 4.1, CHCl3);
D
2-Met h yl-6-[[(1R,2R)-1,3,3-t r im et h yl-2-(isop r op ylsu l-
fan yl)bicyclo[2.2.1]h ept-2-yl]m eth yl]pyr idin e ((+)-9c). This
material was synthesized according to the general procedure
B starting from (+)-7 (0.50 g, 1.82 mmol), sodium hydride (0.09
g, 3.6 mmol), and isopropyl bromide (0.33 g, 2.7 mmol). The
product was obtained after Kugelrohr distillation (0.5 mmHg,
160 °C) as a colorless solid (0.50 g, 1.58 mmol, 87%): mp 47-
HRMS calcd 527.362, found 527.361. Anal. Calcd for C33H53-
NS2: C, 75.08; H, 10.12; N, 2.65. Found: C, 75.02; H, 10.16;
N, 2.70.
2,6-Bis[[(1R ,2R )-1,3,3-t r im e t h yl-2-(b e n zylsu lfa n yl)-
bicyclo[2.2.1]h ep t-2-yl]m eth yl]p yr id in e (10e). From 8
(0.50 g, 1.13 mmol), sodium hydride (0.11 g, 4.58 mmol), and
benzyl bromide (0.58 g, 3.39 mmol), 10e was obtained as a
colorless solid that was recrystallized from dichloromethane/
ethanol (0.56 g, 0.90 mmol, 80%): mp 135-136 °C; [R]23D -100
(c 2.6, CHCl3); HRMS calcd 623.362, no proper HRMS could
be obtained; CI(NH3) gave a molecular ion at m/ e 624. Anal.
Calcd for C41H53NS2: C, 78.92; H, 8.56; S, 10.28. Found: C,
78.75; H, 8.63; S, 10.25.
48 °C; [R]23 +40 (c 3.7, CHCl3); HRMS calcd 317.218, found
D
317.218. Anal. Calcd for C20H31NS: C, 75.65; H, 9.84; N, 4.41.
Found: C, 75.60; H, 9.85; N, 4.35.
2-Met h yl-6-[[(1R,2R)-1,3,3-t r im et h yl-2-(n -p r op ylsu l-
fa n yl)b icyclo[2.2.1]h ep t -2-yl]m et h yl]p yr id in e ((+)-9d ).
Preparation of this compound was accomplished according to
general procedure B starting from (+)-7 (1.00 g, 3.63 mmol),
sodium hydride (0.17 g, 7.08 mmol), and n-propyl iodide (0.92
g, 5.41 mmol) to afford (+)-9d after Kugelrohr distillation (0.5
mmHg, 170 °C) as a colorless solid (0.78 g, 2.46 mmol, 68%):
mp 42-43 °C; [R]23D +13.8 (c 4.0, CHCl3); HRMS calcd 317.218,
found 317.220. Anal. Calcd for C20H31NS: C, 75.65; H, 9.84;
S, 10.10. Found: C, 76.02; H, 9.84; S, 10.06.
P a lla d iu m -Allyl Com p lex of (+)-9c (11). A solution of
[Pd(η3-C3H5)Cl]2 (0.10 g, 0.27 mmol) and (+)-9c (0.20 g, 0.63
mmol) in dichloromethane (10 mL) was stirred for 1 h and
treated with AgPF6 (0.16 g, 0.63 mmol) in 10 mL of THF.
Stirring continued for 10 min, and the mixture was filtered
over Celite. The solution was washed with brine and dried
over MgSO4. After evaporation of the solvent, the solid was
recrystallized from hexane/dichloromethane by slow evapora-
tion of the solvent, yielding 11 as colorless crystals (0.24 g,
0.52 mmol, 94%); 11 isomerized upon dissolution: 1H NMR of
11a δ 0.83 (t, J ) 7.32 Hz, 3H), 1.17 (s, 3H), 1.26 (m, 1H),
1.27 (s, 3H), 1.38 (m, 2H), 1.46 (m, 1H), 1.57 (s, 3H), 1.64 (m,
2H), 1.81 (m, 1H), 1.92 (m, 1H), 2.08 (m, 1H), 2.17 (m, 1H),
2.35 (m, 1H), 2.64 (s, 3H), 2.94 (d, J ) 12.21 Hz, 1H), 3.58 (d,
J ) 13.67 Hz, 1H), 3.64 (d, J ) 12.20 Hz, 1H), 3.76 (d, J )
12.20 Hz, 1H), 4.33 (d, J ) 6.35 Hz, 1H), 4.88 (d, J ) 5.38 Hz,
1H), 5.89 (m, 1H), 7.38 (d, J ) 7.81 Hz, 1H), 7.65 (d, J ) 7.81
Hz, 1H), 7.84 (dd, J ) 7.81, 7.81 Hz, 1H). 1H NMR of 11b: δ
0.90 (t, J ) 7.32 Hz, 3H), 1.18 (s, 3H), 1.26 (m, 1H), 1.30 (s,
3H), 1.38 (m, 2H), 1.41 (s, 3H), 1.46 (m, 1H), 1.62 (m, 2H),
1.64 (m, 2H), 1.75 (m, 1H), 1.92 (m, 1H), 2.08 (m, 2H), 2.17
(m, 1H), 2.80 (s, 3H), 3.39 (d, J ) 13.18 Hz, 1H), 3.40 (d, J )
14.16 Hz, 1H), 3.47 (d, J ) 14.16 Hz, 1H), 4.33 (d, J ) 6.35
Hz, 1H), 4.67 (d, J ) 6.84 Hz, 1H), 5.70 (m, 1H), 7.41 (d, J )
7.32 Hz, 1H), 7.59 (d, J ) 7.82 Hz, 1H), 7.84 (dd, J ) 7.32,
7.82 Hz, 1H).
2-Meth yl-6-[[(1R,2R)-1,3,3-tr im eth yl-2-(ben zylsu lfan yl)-
bicyclo[2.2.1]h ept-2-yl]m eth yl]pyr idin e ((-)-9e). This com-
pound was prepared according to procedure B starting from
(+)-7 (0.39 g, 1.42 mmol), sodium hydride (0.05 g, 2.1 mmol),
and benzyl bromide (0.29, 1.7 mmol) to yield a colorless solid
(0.42 g, 1.25 mmol, 81%): mp 57-58 °C; [R]23 -28 (c 2.2,
D
CHCl3); HRMS calcd 365.217, found 365.218. Anal. Calcd for
C
24H31NS: C, 78.85; H, 8.55; N, 3.83. Found: C, 78.83; H,
8.73; N, 3.71.
2-Meth yl-6-[[(1S,2S)-1,3,3-tr im eth yl-2-(ben zylsu lfa n yl)-
bicyclo[2.2.1]h ept-2-yl]m eth yl]pyr idin e ((+)-9e). This com-
pound was prepared as described above but starting from (-)-
7: mp 57-58 °C; [R]23 +30 (c 2.0, CHCl3).
D
2,6-Bis[[(1R ,2R )-1,3,3-t r im e t h yl-2-(m e t h ylsu lfa n yl)-
bicyclo[2.2.1]h ep t-2-yl]m eth yl]p yr id in e (10a ). This mate-
rial was prepared according to general procedure A starting
from 8 (1.0 g, 2.26 mmol), K2CO3 (0.48 g, 3.4 mmol), and
methyl iodide (0.62 g, 4.5 mmol) to yield 10a as a colorless
solid that was recrystallized from hexane (1.0 g, 2.12 mmol,
1
94%): mp 164-165 °C; [R]23 +33 (c 1.2, CHCl3); H NMR δ
2-[[(1R,2R)-1,3,3-Tr im eth yl-2-su lfan ylbicyclo[2.2.1]h ept-
2-yl]m eth yl]p yr id in e (13). To a solution of 2-methylpyridine
(3.20 g, 34.4 mmol) in 150 mL of THF at -70 °C was added
n-butyllithium (1.6 M in hexane, 21 mL, 33.6 mmol). The
mixture was stirred for 30 min at -40 °C and cooled to -70
°C again. A solution of (R)-thiofenchone (4.70 g, 27.9 mmol)
in 15 mL of THF was added and the mixture allowed to reach
ambient temperature in 3 h. To the mixture was added 15
mL of 5 N HCl. Stirring was continued for 15 min and the
solution subsequently neutralized with 2 N NaOH. The
mixture was extracted three times with dichloromethane, and
the combined organic layers were washed with brine and dried
over MgSO4. The product was purified by means of column
chromatography (silica gel, hexane/diethyl ether 9:1) and
recrystallization from hexane to yield 13 as colorless needles
D
0.87 (s, 6H), 1.14 (s, 6H), 1.18 (s, 6H), 1.20 (m, 4H), 1.42 (m,
2H), 1.53 (d, J ) 4.39 Hz, 2H), 1.72 (m, 2H), 1.96 (s, 6H), 1.98
(m, 2H), 2.61 (m, 2H), 3.21 (d, J ) 17.58 Hz, 2H), 3.43 (d, J )
17.58 Hz, 2H), 7.50 (t, J ) 7.86, 1H), 8.13 (d, J ) 7.86 Hz,
2H); 13C NMR δ 13.57 (q), 20.16 (q), 24.20 (q), 24.75 (t), 29.43
(q), 34.66 (t), 41.34 (t), 41.99 (t), 46.71 (s), 51.10 (d), 56.05 (s),
60.91 (s), 120.77 (d), 135.38 (d), 159.87 (s); HRMS calcd
471.298, found 471.299. Anal. Calcd for C29H45NS2: C, 73.83;
H, 9.61; N, 2.97. Found: C, 73.67; H, 9.61; N, 2.95.
2,6-Bis[[(1R,2R)-1,3,3-tr im eth yl-2-(eth ylsu lfan yl)bicyclo-
[2.2.1]h ep t-2-yl]m eth yl]p yr id in e (10b). For this compound,
general procedure B was used, starting from 8 (0.45 g, 1.02
mmol), sodium hydride (0.06 g, 2.50 mmol), and ethyl bromide
(0.27 g, 2.48 mmol). Compound 10b was obtained as a
colorless solid that was recrystallized from methanol at -20
(7.11 g, 27.2 mmol, 81%): mp 96-97 °C; [R]23 +109 (c 2.8,
D

5540 J . Org. Chem., Vol. 63, No. 16, 1998
Koning et al.
CH2Cl2); 1H NMR δ 0.80 (s, 3H), 1.15 (m, 2H), 1.19 (s, 3H),
1.24 (s, 3H), 1.4 (m, 1H), 1.65 (m, 1H), 1.76 (m, 1H), 1.95 (d,
J ) 10.25 Hz, 1H), 2.20 (m, 1H), 3.34 (s, 2H), 4.30 (s, SH),
7.08 (dd, J ) 5.12, 6.95 Hz, 1H), 7.31 (d, J ) 8.06 Hz, 1H),
in dichloromethane (10 mL) was stirred for 1 h and treated
with AgBF4 (39 mg, 0.20 mmol) in 10 mL of THF. Stirring
continued for 30 min, and the mixture was filtered over Celite.
The solution was washed with brine and dried over MgSO4.
After evaporation of the solvent, the complex was obtained as
a yellow solid that was recrystallized from dichloromethane
by isothermal distillation of hexane into the solution. Com-
pound 15 was obtained as yellow crystals suitable for X-ray
crystallization (0.12 g, 0.14 mmol, 88%): 1H NMR δ 0.68 (s,
6H), 1.28 (s, 6H), 1.38 (d, J ) 10.42 Hz, 2H), 1.44 (s, 6H), 1.46
(m, 2H), 1.62 (m, 2H), 1.74 (d, J ) 3.74 Hz, 2H), 1.95 (m, 4H),
2.19 (d, J ) 11.2 Hz, 2H), 2.46 (d, J ) 13.2 Hz, 2H), 3.32 (d,
J ) 14.6 Hz, 2H), 3.71 (d, J ) 13.2 Hz, 2H), 3.74 (d, J ) 14.6
Hz, 2H), 7.16 (d, J ) 7.47 Hz, 4H), 7.33 (t, J ) 7.62 Hz, 2H),
7.42 (dd, J ) 7.62, 7.47 Hz, 4H), 8.12 (d, J ) 7.77 Hz, 2H),
8.34 (t, J ) 7.77 Hz, 1H).
7.54 (dd, J ) 8.06, 6.95 Hz, 1H), 8.49 (d, J ) 5.12 Hz, 1H); 13
C
NMR 18.31 (q), 24.56 (t), 27.28 (q), 28.97 (q), 33.77 (t), 40.42
(t), 45.63 (s), 48.23 (t), 50.95 (d), 54.58 (s), 120.62 (d), 124.73
(d), 135.74 (d), 147.57 (d), 161.92 (s); HRMS calcd 261.156,
found 261.155. Anal. Calcd for C16H23NS: C, 73.51; H, 8.87;
N, 5.36. Found: C, 73.73; H, 8.88; N, 5.41.
2-[[(1R,2R)-1,3,3-Tr im eth yl-2-(ben zylsu lfa n yl)bicyclo-
[2.2.1]h ep t-2-yl]m eth yl]p yr id in e (14). This compound was
prepared from 13 (0.75g, 2.87 mmol), sodium hydride (0.10g,
4.3 mmol), and benzyl bromide (0.51, 2.98 mmol) according to
general procedure B. The product was recrystallized from
hexane at -20 °C to afford 14 as a colorless solid (0.60g, 1.72
mmol, 60%): mp 104-105 °C; [R]23 -43 (c 3.5, CHCl3); 1H
D
NMR δ 0.91 (s, 3H), 1.16 (s, 3H), 1.23 (m, 2H), 1.28 (s, 3H),
1.48 (m, 1H), 1.58 (d, J ) 4.39 Hz, 1H), 1.77 (m, 1H), 2.02 (d,
J ) 9.52 Hz, 1H), 2.75 (m, 1H), 3.42 (d, J ) 17.57 Hz, 1H),
3.53 (d, J ) 10.25 Hz, 1H), 3.6 (d, J ) 17.57 Hz, 1H), 3.82 (d,
J ) 10.25 Hz, 1H), 7.2 (m, 5H), 7.64 (dd, J ) 7.69, 8.06 Hz,
1H), 8.47 (d, J ) 8.06 Hz, 1H), 8.53 (d, J ) 4.03 Hz); 13C NMR
δ 20.24 (q), 24.07 (q), 24.80 (t), 29.36 (q), 34.75 (t), 34.88 (t),
42.07 (s), 42.39 (t), 47.18 (s), 51.02 (d), 56.09 (s), 120.86 (d),
123.95 (d), 126.85 (d), 128.34 (d), 128.94 (d), 135.72 (d), 137.58
(s), 148.47 (d), 161.39 (s); HRMS calcd 351.202, no proper
HRMS could be obtained; CI(NH3) gave a molecular ion at m/e
352. Anal. Calcd for C23H29NS: C, 78.58; H, 8.31; N, 3.98.
Found: C, 78.29; H, 8.33; N, 3.98.
Ack n ow led gm en t. B.K. is partially supported by
the Netherlands Scientific Organization (N.W.O.) ad-
ministered by the Office for Chemical Research (S.O.N.).
Su p p or tin g In for m a tion Ava ila ble: Crystal data collec-
tion, data reduction, and structure solution and refinement
for (-)-7‚HCl, 11b, and 15,31 product characterization of (+)-
9b-d , (-)-9e, and 10b-e, COSY and HETCOR spectra of (-)-
7‚HCl, and 1H NMR spectra of 11 and 15 (12 pages). This
material is contained in libraries on microfiche, immediately
follows this article in the microfilm version of the journal, and
can be ordered from the ACS; see any current masthead page
for ordering information.
P a lla d iu m Ch lor id e Com p lex of 10e. A solution of [Pd-
(η3-C3H5)Cl]2 (37 mg, 0.10 mmol) and 10e (0.10 g, 0.16 mmol)
J O9806299