Improved synthesis of C2-symmetrical pyridinediols and synthesis of C(s)-symmetrical pyridinediols

Article abstract of DOI:10.1002/1099-0690(200008)2000:15<2735::AID-EJOC2735>3.0.CO;2-K

Base-induced reaction of 2,6-dimethylpyridine (2,6-lutidine) (1) with two equivalents of various ketones has been reported to provide C₂-symmetrical pyridine diols 3. Closer examination reveals that competitive di-addition to a single methyl gr

Full text of DOI:10.1002/1099-0690(200008)2000:15<2735::AID-EJOC2735>3.0.CO;2-K

FULL PAPER
Improved Synthesis of C -Symmetrical Pyridinediols and Synthesis of
2
C -Symmetrical Pyridinediols
s
[
a]
[a]
[a][°]
[a]
Bartjan Koning, Jan Buter, Ron Hulst,
Roelof Stroetinga, and
Richard M. Kellogg*[
a]
Keywords: Pyridine / Alcohols / Asymmetric synthesis / Ketones / Retro reactions / Synthetic methods
Base-induced reaction of 2,6-dimethylpyridine (2,6-lutidine)
1) with two equivalents of various ketones has been re- formation of the C
ported to provide C -symmetrical pyridine diols 3. Closer ex- using potassium diisopropylamide as base; high yields of C
amination reveals that competitive di-addition to a single
methyl group can occur providing C -symmetrical pyridine
of a mechanistic proposal for the competing pathways. The
(
s
-diol 7 could be excluded completely by
2
2
-
symmetrical pyridine diols 3 are obtained. Regioselective ad-
ditions of 1 to (R)-fenchone and (−)-menthone were also
achieved.
s
diols 7. By varying the lithiation times, the formation of this
side product could be maximized or minimized on the basis
Introduction
two-step synthesis. Yields are moderate; the benzophenone-
based pyridine diol 3a is obtained in 35% yield, whereas
C -symmetrical derivatives 3b, 3c, 3d, and 3e (based on ad-
The achievements over the past few decades in develop-
2
amantanone,[ acetone, camphor, and fluorenone, re-
spectively) are obtained in yields of 51, 34, 45, and 13%,
respectively. We shall discuss some additional factors that
can have a major effect on the synthetic outcome.
14]
[9b]
[9b]
[1]
ing new chiral non-racemic reagents and asymmetric syn-
thetic methodologies[2] have been remarkable. For example,
the synthesis of many chiral non-racemic receptor molec-
ules is now a relatively simple matter. In the past, we have
developed a synthetic approach to chiral non-racemic pyr-
idine thiols and dithiols,[ and have, for example, applied
the thioethers thereof in palladium-catalyzed allylic substi-
3]
[
4]
tution.
Sterically bulky C -symmetrical pyridine diol ligands like
2
3
obtained by condensation of ketones with lutidine 1 are
of special interest as complexing agents for the development
of new homogeneous catalysts. The combination of two hy-
droxy groups and the pyridine nitrogen atom leads to li-
gands capable, for example, of stabilizing high-valent os-
mium alkoxide complexes.[ With Zr and W good poly-
merization catalysts are formed.[ Biomimetic studies of en-
5]
6]
[7]
Scheme 1. Reagents and conditions: i) nBuLi (1.1 equiv.), THF,
zymes have been conducted with some Mo complexes.
1
2
1
2
Ϫ60 °C; ii) R R CϭO; iii) nBuLi (1.1 equiv.), Ϫ80 °C; iv) R R Cϭ
O; v) 2  HCl; vi) nBuLi (2.1 equiv.), THF, room temp.
[
8]
[9]
[9]
[10]
Well-defined complexes with Ti, Zn, Co, Si,
and
[
11]
Ru have also been reported in the literature.
The synthesis of this class of compounds was first re-
ported by Tilford and Van Campen and further explored
by Berg and Holm[ in the synthesis of pyridine diol 3a.
These compounds have been of interest in our group as
[12]
Synthesis
7b]
Yields could be improved substantially by applying a
two-pot reaction in which the monoadduct 2 is first isol-
[9b]
model systems for zinc-alcohol dehydrogenase,
carboxy-
ated, and then converted into the C -symmetrical di-adduct
[
13]
[10a]
2
peptidase, and for preparation of silicon alkoxides.
Several derivatives have been prepared making use of the
described methodology for the synthesis of pyridine diols
3
by adding slightly more than two equivalents of base, fol-
lowed by the addition of the ketone (Scheme 1). Mixed
combinations can be prepared as shown by Nakayama et.
al.[ However, there is more to this than meets the eye, as
will be discussed in the following paragraphs.
[
7b,9b]
3
a (Scheme 1).
This approach consists of a one-pot,
6a]
[
a]
Department of Organic and Molecular Inorganic Chemistry,
Stratingh Institute, University of Groningen,
Nijenborgh 4, 9747 AG Groningen, The Netherlands
Fax: (internat.) ϩ 31-50/363-4296,
The monoadducts 2 formed by addition of monolithiated
lutidine to benzophenone, adamantanone, and camphor
can be isolated in 85, 88, and 89% yields, respectively. The
second reaction step, however, is less straightforward. The
time that the mixture is stirred after lithiation and before
E-mail: R.M.Kellogg@chem.rug.nl
[
°]
Biomade Institute, University of Groningen
Nijenborgh 4, 9747 AG Groningen, The Netherlands
Eur. J. Org. Chem. 2000, 2735Ϫ2743

WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
1434Ϫ193X/00/0815Ϫ2735 $ 17.50ϩ.50/0
2735

B. Koning, J. Buter, R. Hulst, R. Stroetinga, R. M. Kellogg
FULL PAPER
addition of the ketone (lithiation time) strongly influences Table 1. Effect of lithiation conditions on the yield of 3b and 7b
the yield of the desired C -symmetrical product. Using this
2
Entry
Reaction
t
1
t
2
Yield
Yield
two-pot synthetic approach, it was found that if a lithiation
time of 4 h was applied for the adamantanone derivative 2b,
after which one equivalent of adamantanone was added,
followed by work up with 2  HCl, the adamantanone-
temp. [°C]
of 7b
of 3b
1
2
3
4
5
6
7
8
9
Ϫ80
5 min
4 h
4 h
4 h
Ϫ
Ϫ
Ϫ80
34.4
18.5
19.1
20.6
61.7
61.0
60.4
58.3
66.4
63.0
54.5
28.6
4.8
35.6
20.4
23.9
34.3
16.3
29.5
38.5
41.5
14.5
37.0
45.5
71.4
95.2
Ϫ40
10 min
30 min
60 min
0.75 min
5 min
30 min
60 min
0.5 min
5 min
30 min
60 min
4 h
90 min
90 min
90 min
60 min
60 min
60 min
60 min
60 min
60 min
60 min
60 min
60 min
based C -symmetrical pyridine diol 3b could be isolated in
2
Ϫ40
7
0% yield (overall yield 62%). However, when adam-
Ϫ40
0
antanone was added after a lithiation time of only 30 min,
0
a second product, C -symmetrical pyridine diol 7b, was also
s
0
isolated. The formation of 7b must involve deprotonation
0
1
1
0
1
room temp.
room temp.
room temp.
room temp.
room temp.
of the CH group forming the dilithiated intermediate 5b
2
instead of deprotonation at the presumably sterically less 12
1
1
3
4
hindered methyl group, which gives rise to the intermediate
b (Scheme 2).
6
longer lithiation times (Entries 6Ϫ9). This trend is even
clearer at room temperature; fairly long lithiation times lead
to a striking reversal of the ratio 7b over 3b (Entries
1
0Ϫ14). From these results it seems justified to conclude
that the lithium alkoxide 4b first formed is deprotonated at
the CH group to form 5b more rapidly than at the methyl
2
group to form 6b. In other words, kLЈ Ͼ k (Scheme 2). This
L
effect is assumed to arise from coordination of the second
equivalent of n-butyllithium to the electron-rich oxygen
atom in the (presumed) chelate ring of 4b, followed by facile
intermolecular deprotonation at the CH group as shown
2
in Figure 1. A second conclusion is that 6b is thermodyn-
amically more stable than 5b. Whether the slow conversion
of 5b to 6b is due to inter- or intramolecular processes can-
not be concluded from the data of Table 1.
Scheme 2. Reagents and conditions: i) nBuLi (1.1 equiv.), THF; ii)
ketone; iii) 2  HCl
Figure 1. Six-membered intermediate
Using the data of Table 1 as guide, the reaction condi-
Experiments at different temperatures and with different tions were optimized for formation of the C -diol 7b. This
s
lithiation times were conducted in order to obtain further entailed lithiation and quenching at room temperature after
mechanistic insight. In these experiments, monosubstitution a lithiation time of 30 s.
product 2b was treated with two equivalents of n-butylli-
When similar temperature- and time-dependent lithiation
thium under the given conditions. The ratios of the C -sym- experiments were carried out with the diphenylcarbinol 2a,
s
metrical adduct 7b to C -symmetrical adduct 3b were deter- only C -symmetrical diol 3a and some starting materials in
2
2
mined, after quenching the reaction with adamantanone the reaction mixture were detected. However, when longer
1
and workup with 2  HCl, by means of H-NMR spectro- lithiation times were used at room temperature, starting
scopy. The results are given in Table 1; t is the time be- material was still recovered, despite the fact that lithiation
1
tween the addition of n-butyllithium and the addition of at this temperature and with these reaction times should
the adamantanone, and t is the time the mixture is stirred be complete. It was also observed that the yield of the C2-
2
after the addition of the ketone and before it is quenched symmetrical diol 3a increased with prolonged lithiation
with HCl.
times. These observations can be explained by the forma-
At Ϫ80 °C lithiation is slow (Entries 1, 2) and even at tion of intermediate 5a, although no trace of the C -adduct
s
Ϫ40 °C complete lithiation requires several hours (Entries 7a was detected. Only on modification of the workup pro-
3
Ϫ5). Lithiation is far more rapid at 0 °C, and there is a cedure was the C -symmetrical diol 7a obtained. When 2 
s
clear tendency with short lithiation times for 7b to predom- NH Cl was used in the workup, C -symmetrical diol 7a
4
s
inate over 3b, although the ratio tends towards the latter at could be isolated in moderate to low yield (5Ϫ35%) de-
2736
Eur. J. Org. Chem. 2000, 2735Ϫ2743

2 s
Improved Synthesis of C -Symmetrical Pyridinediols and Synthesis of C -Symmetrical Pyridinediols
FULL PAPER
pending on the reaction conditions applied (Ϫ80 °C to aldol reaction takes place providing either the starting mat-
room temp.). The usual workup with 2  HCl is, apparently, erial 10d or the benzophenone adduct 10a (Scheme 4).
too acidic to keep the diol 7a intact. Experiments with vari-
ous lithiation times and at different temperatures followed
by workup with 2  NH Cl showed the same phenomenon
4
as observed for the adamantanone adduct. Initially,
lithiation of the alkoxide 4a is preferred at the CH group
2
forming dilithio species 5a, which is converted into 6a at
prolonged lithiation times. When the C -diol 7a was stirred
s
with 2  HCl it indeed reverted to the benzophenone mono-
adduct 2a and benzophenone (Scheme 3).
Scheme 4. Reagents and conditions: i) BuLi (2.1 equiv.), THF, Ϫ60
°
4
C; ii) benzophenone; iii) 2  NH Cl
In previous investigations of addition of the CH group
2
of this type of compounds to a carbonyl functionality the
[7a][9b][10a,16]
C -diols were never reported.
s
The observation
that in most of these cases only low to moderate yields of
the C -diol 3 are obtained, and the observation that starting
2
materials are recovered, are consistent with lithiation and
Scheme 3. Retro aldol reaction
addition having occurred at the CH group. We conclude
2
that addition reaction at this position can and does take
place, and that in some cases the C -symmetrical diols 7
can be isolated, provided that they are sufficiently stable to
survive retro aldol reaction.
This retro aldol reaction is probably initiated by pro-
tonation of the pyridine nitrogen atom of 8, after which the
benzophenone is expelled, affording intermediate 9, which
tautomerizes to the pyridine. The retro aldol reaction can
and also occurs
upon purification of the product by means of column chro-
matography on silica. This reaction is also observed for the
s
The almost exclusive synthesis of the C -diols 3 as single
2
also be induced by sonication or heat,[
15]
product is possible, although long lithiation times (lithiation
time of at least 4 h) are required to ensure that all the kin-
etic product is converted into the thermodynamic product.
Another possibility is to make use of the understanding
that was gained in conducting the time-dependent
lithiations, of the intermediates. If a base is used that less
readily leads to the six-membered intermediate chelate (Fig-
C -diol 7b under acidic conditions at higher temperatures.
s
The best conditions for the formation of the C -diol 7a
s
(35% yield) were found to be 0 °C with a lithiation time of
1
min. The optimal conditions for the formation of the C2-
ure 1), the deprotonation at the CH group should not be
2
diol 3a involve a lithiation time of 4 h at room temp. to
afford 3a in 67% yield.
kinetically favored, and deprotonation should only take
place at the less hindered methyl group. When the adam-
When the time- and temperature-dependent lithiation antanone-based alcohol 2b was deprotonated with 2.1
was carried out for the camphor adduct 2d, again an in- equivalents of potassium diisopropylamide (KDA) and
crease in the formation of the camphor-based C -diol 3d quenched with adamantanone after only 15 min of stirring,
2
upon longer lithiation times was observed. Recovery of the C -diol 3b was obtained as sole product in 95% yield
2
starting material at room temperature was substantial. The (Scheme 5). KDA is a very strong base, and the potassium
C -diol 7d, however, could not be detected, even when a does not strongly coordinate with the nitrogen and oxygen
s
mild workup procedure was applied. The best preparative atoms. After deprotonation of the hydroxy group, the se-
results for the C -diol 3d were at Ϫ40 °C; at higher temper- cond attack apparently occurs at the sterically less hindered
2
atures more side products are obtained. This diol adduct methyl group, and no reaction at the CH group is ob-
2
probably is too unstable to be isolated. The fact that double served. This approach is very selective and provides the C2-
addition can take place at one methyl group is established diols exclusively after stirring for a short time. Sterically
in an experiment where the 2-picoline-based camphor alco- more hindered lithium bases such as sBuLi and tBuLi were
hol 10d is dilithiated to afford 11, which is quenched with not investigated to see whether they would lead to in-
benzophenone leading to the mixed diol 12. This product, creased selectivity.
however, is also very unstable and upon workup the starting
When this new approach was applied in the synthesis of
camphor-based alcohol 10d was isolated together with a the benzophenone- and camphor-based C -diols 3a and 3d,
2
reasonable quantity of benzophenone-based alcohol 10a. the products were isolated in high yields (Table 2).
Addition at the CH group does take place, but the mixed
The C -diols also have interesting features, as they are
2
s
adduct formed is too unstable to be isolated and a retro known to coordinate several metals.[ It would thus be de-
17]
Eur. J. Org. Chem. 2000, 2735Ϫ2743
2737

B. Koning, J. Buter, R. Hulst, R. Stroetinga, R. M. Kellogg
FULL PAPER
chone and (Ϫ)-menthone were less successful. Addition to
(
R)-fenchone afforded inseparable exo and endo adducts in
equal amounts. Addition of the lithio species 15 to (Ϫ)-
menthone gave the cis and trans isomers 2g in a ratio of
1
6:5 in favor of the cis adduct (Scheme 7). These isomers
Scheme 5. Reagents and conditions: i) KDA (2.1 equiv.), THF, Ϫ50
could be separated by means of column chromatography.
The configurations of the isomers were deduced from the
HETCOR, COSY, and NOESY NMR spectral data (not
1
2
°
4
C; ii) R R CϭO (2.1 equiv.); iii) 2  NH Cl
2
Table 2. Summary of optimized yields for the synthesis of C -diols 3
Used ketone
Mono-adduct 2
yield using nBuLi)
Di-adduct 3
(yield using KDA)
Overall yield of 3
(
Benzophenone
Adamantanone
2a (85%)
2b (88%)
2d (90%)
3a (90%)
3b (95%)
3d (95%)
77%
84%
86%
(
R)-(ϩ)-Camphor
sirable to have a synthetic approach that would selectively
afford these materials. In our hands it was not possible to
synthesize the lutidine-based C -diols as single products,
s
free of the formation of the thermodynamically more stable
C -diols. Since lithiation at the methyl group is thermodyn-
2
amically favored over lithiation at the CH position, and
2
since the conversion of the kinetic product to the thermo-
dynamically product occurs, it will be very difficult to syn-
thesize the C -diols selectively using this approach. This
s
problem is readily circumvented by use of 2-picoline (13),
which when deprotonated with n-butyllithium and
quenched with benzophenone, adamantanone, acetone, or
camphor provides pyridine alcohols 10 in good yields. The
isolated pyridine alcohols 10 were subsequently lithiated
with two equivalents of n-butyllithium and allowed to react
Scheme 7. Reagents and conditions: i) nBuLi (1.1 equiv.), THF,
Ϫ60 °C; ii) (Ϫ)-menthone; iii) 2  NH
THF, 0 °C
4
Cl; iv) nBuLi (2.1 equiv.),
with a second ketone in order to give the desired C -diol
s
1
4. For the benzophenone, adamantanone, and acetone ad-
ducts, the C -diols 14a, 14b, and 14c were found in 33, 26,
s
and 30% isolated yields, respectively (Scheme 6). The diols
1
4a and 14b undergo retro aldol reaction to the pyridine
alcohol 10 and the ketones under acidic conditions and el-
evated temperatures, therefore making purification of the
compounds very difficult. The diol 14c is more stable, and
retro aldol reaction occurs only above 100 °C or under
Figure 2. a) (left): cis adduct; b) (right): trans adduct
shown). An NOE interaction of the equatorial benzylic
CH protons (Figure 2a) with proton H and the axial pro-
acidic conditions. When camphor was used no C -diol
2
f
s
ton H for the cis isomer was observed, whereas for the
could be isolated and only starting materials were reco-
vered.
Efforts to add, facially selective if possible, the mono-
lithiated lutidine 15 to other chiral ketones like (R)-fen-
a
trans isomer interaction of the axial benzylic proton (Fig-
ure 2b) with either one of these protons is absent.
When the cis-2g isomer was lithiated with two equivalents
of n-butyllithium and allowed to react with (Ϫ)-menthone,
the bis-product was formed as a mixture of the isomers cis-
cis-3g and cis-trans-3g in a ratio of 6:1. The cis-cis-3g iso-
mer could be selectively crystallized from a mixture of
water/ethanol.
Better facial selectivity for the (R)-fenchone derivative
was obtained when the lithium in the monolithio species 15
was replaced by CeCl , followed by the addition of (R)-
3
fenchone. Alkylcerium reagents are known to give clean
,2-addition to ‘‘difficult’’ ketones.[ This is presumed to
18]
1
be due to the reduced basicity and the oxaphilicity of the
alkylcerium reagent.[ Furthermore, complexation of the
19]
Scheme 6. Reagents and conditions: i) nBuLi (1.1 equiv.), THF,
1
2
Ϫ60 °C; ii) R R CϭO; iii) 2  NH
4
Cl; iv) nBuLi (2.1 equiv.), THF cerium to the carbonyl functionality, and subsequent attack
2738
Eur. J. Org. Chem. 2000, 2735Ϫ2743

2 s
Improved Synthesis of C -Symmetrical Pyridinediols and Synthesis of C -Symmetrical Pyridinediols
FULL PAPER
of the alkyl group to the carbon atom enhances selectivity. to Ϫ60 °C. n-Butyllithium (1.6  in hexane, 59.4 mL, 95.0 mmol)
was added under stirring. The mixture was warmed to Ϫ50 °C
and stirring was continued for 1 h before benzophenone (17.3 g,
We thought that complexation of the alkyl reagent to the
carbonyl group could improve the regioselectivity of the ad-
9
5.0 mmol) in 25 mL of THF was added by means of a canula.
dition reaction to (R)-fenchone and (Ϫ)-menthone. Indeed,
some improvement was found when the cerium species 16
was synthesized from the lithio species 15 and allowed to
react with (R)-fenchone. However, although the endo/exo
isomer ratio for this reaction improved to 1:2 at Ϫ50 °C in
The mixture was allowed to reach ambient temperature overnight,
and was acidified to pH ϭ 1 with 2  HCl. After stirring for 1 h,
the mixture was neutralized with 2  NaOH. The aqueous layer
was extracted with ethyl acetate twice and the organic layers were
dried with MgSO . After concentration in vacuo, the product was
4
THF, a mixture of the two isomers was obtained. When recrystallized from methanol yielding a colorless solid (23.0 g,
the reaction temperature was lowered to Ϫ80 °C, a small 79.5 mmol, 85%) with m.p. 124Ϫ125 °C. Ϫ IR (KBr): ν˜ ϭ 3250,
improvement of the ratio to 1:4 was found. Addition of the 2900, 1610, 1600, 1450, 1100, 800, 700, 550 cm . Ϫ 1H NMR
Ϫ1
(
7
300 MHz, CDCl
3
): δ ϭ 2.47 (s, 3 H), 3.67 (s, 2 H), 6.90 (m, 2 H),
cerium species 16 to (Ϫ)-menthone, however, led to far
better results. When (Ϫ)-menthone was allowed to react
with 16 at Ϫ80 °C only the cis isomer 2g was formed
.15 (m, 2 H), 7.23 (m, 4 H), 7.40 (m, 1 H), 7.49 (m, 4 H), 8.17
1
3
(
7
(
2
br, OH), Ϫ C NMR (300 MHz, CDCl
8.2 (s), 120.9 (d), 121.4 (d), 126.1 (d), 126.2 (d), 127.7 (d), 137.0
d), 147.3 (s), 156.7 (s), 158.4 (s). Ϫ HRMS: calcd. 289.147; found
89.147. Ϫ C20 19NO (289.4): calcd. C 83.03, H 6.62, N 4.84;
found C 83.13, H 6.47, N 4.87.
3
): δ ϭ 24.1 (q), 46.7 (t),
(Scheme 8).
H
2
(
-[(6-Methyl-2-pyridinyl)methyl]-2-adamantanol (2b): 2,6-Lutidine
1) (3.84 g, 35.8 mmol) was dissolved in 100 mL of THF and cooled
to Ϫ50 °C. Subsequently, n-butyllithium (1.6  in hexane, 22.6 mL,
6.2 mmol) was added and stirring was continued for 30 min. A
3
Scheme 8. Reagents and conditions: i) nBuLi (1.1 equiv.), THF,
solution of adamantanone (5.4 g, 36 mmol) in 10 mL of THF was
added slowly and stirring was continued overnight allowing the
mixture to reach room temp. slowly. The solution was quenched
with 2  HCl and stirred for 15 min before it was neutralized with
3 4
Ϫ70 °C; ii) CeCl THF; iii) (Ϫ)-menthone; iv) 2  NH Cl
Conclusions
2
 NaOH. The solution was extracted twice with ethyl acetate.
Aided by the understanding of the lithiation process, an The combined organic layers were washed with brine and dried
with Na
2 4
SO . After being taken to dryness, the product was recrys-
approach has been developed that allows the preparation
tallized from hexane yielding a colorless solid (8.1 g, 31.5 mmol,
of chiral as well as achiral C -symmetrical pyridine diols
2
8
1
1
8%) with m.p. 131Ϫ132 °C. Ϫ IR (KBr): ν˜ ϭ 3250, 2900, 1610,
600, 1450, 1000, 700 cm . Ϫ H NMR (200 MHz, CDCl
.4Ϫ2.0 (m, 12 H), 2.28 (m, 2 H), 2.50 (s, 3 H), 3.08 (s, 2 H), 6.48
in high yields. The synthetic approach to C -symmetrical
s
Ϫ1
1
3
): δ ϭ
pyridine diols opens up a route to interesting new ligands
the complexation behavior of which is currently under in-
(
s, OH), 6.94 (d, J ϭ 11.7 Hz, 1 H), 6.98 (d, J ϭ 11.7 Hz, 1 H),
vestigation. The use of CeCl in the addition reaction of
13
3
7.49 (dd, J ϭ 11.7 Hz, J ϭ 11.7 Hz, 1 H). Ϫ C NMR (200 MHz,
CDCl ): δ ϭ 24.1 (q), 27.2 (d), 32.6 (t), 34.4 (t), 37.1 (d), 38.3 (t),
to the cis-pyridine diol. The application of CeCl in the ad- 43.2 (t), 75.2 (s), 120.8 (d), 121.2 (d), 136.8 (d), 157.2 (s), 158.8 (s).
2
,6-lutidine to (Ϫ)-menthone gave a regiospecific addition
3
3
dition reactions opens up a new perspective for regioselec- Ϫ HRMS: calcd. 257.178; found 257.179. Ϫ C17
H23NO (257.4):
tive addition to chiral ketones, as shown for (Ϫ)-menthone. calcd. C 79.33, H 9.01, N 5.44. found C 78.96, H 9.05, N 5.45.
(
[
5
(
1R,2S)-1,7,7-Trimethyl-2-[(6-methyl-2-pyridinyl)methyl]bicyclo-
2.2.1]heptan-2-ol (2d): To a solution of 2,6-lutidine (1) (6.0 g,
6 mmol) in 250 mL of THF at Ϫ60 °C was added n-butyllithium
1.6  in hexane, 38.5 mL, 61.6 mmol). The mixture was stirred at
Experimental Section
General Remarks: All reactions were carried out under Ar. The
following solvents were distilled prior to use: THF was distilled
from Na wire, acetonitrile and dichloromethane were distilled from
Ϫ60 °C for 30 min and (R)-(ϩ)-camphor (8.5 g, 56 mmol) in 20 mL
of THF was added. Stirring was continued for 1 h at Ϫ60 °C. The
mixture was quenched with 1  HCl, stirred for 30 min and neutral-
ized with 2  NaOH. The solution was extracted with ethyl acetate
twice and the combined organic layers were washed with brine and
CaH
2
, and diethyl ether, ethyl acetate, and hexane were distilled
. Ϫ Column chromatography was performed on alumina
Merck 90, II/III, 0.063Ϫ0.200 mm) or silica gel (Aldrich 60,
from P
(
2
O
5
4
dried with MgSO . After removal of the solvents in vacuo, the
2
30Ϫ400 mesh). Ϫ Elemental microanalyses were carried out in
1
13
product was purified by means of kugelrohr distillation (75 °C,
the analytical department of this laboratory. Ϫ H- and C-NMR
0
.4 Torr) yielding 2d as a colorless solid (13.0 g, 50.1 mmol, 90%)
spectra were recorded using a Varian Unity Plus 500, a Varian
VXR 300 instrument or a Genuine 200 instrument. The chemical
2
3
with m.p. 38Ϫ39 °C. Ϫ [α]
D
ϭ Ϫ28.7 (c ϭ 1.5, acetone). Ϫ IR
Ϫ1
1
(KBr): ν˜ ϭ 3300, 3000, 1610, 1600, 1450, 1100, 830, 800 cm . Ϫ
shifts are expressed relative to CDCl
3
for H-NMR (at δ ϭ 7.26)
1
and 1 C-NMR (at δ ϭ 76.91). NOESY,
were performed using standard Varian pulse programs. Ϫ Deuter-
ated solvents were dried with an Al (activity 1) column just
3
[20]
[21]
H NMR (300 MHz, CDCl
m, 1 H), 1.07 (s, 3 H), 1.30 (m, 1 H), 1.41 (m, 2 H), 1.63 (m, 2
H), 1.98 (m, 1 H), 2.44 (s, 3 H), 2.88 (s, 2 H), 6.65 (br, OH), 6.91
3
): δ ϭ 0.45 (s, 3 H), 0.76 (s, 3 H), 1.05
and COSY
spectra
(
2
O
3
(
7
d, J ϭ 7.7 Hz, 1 H), 6.94 (d, J ϭ 7.7 Hz, 1 H), 7.45 (dd, J ϭ
prior to use. All other reagents were obtained from Aldrich or
Acros Chimica and used as received, unless otherwise noted.
1
3
.7 Hz, J ϭ 7.7 Hz, 1 H). Ϫ C NMR (300 MHz, CDCl
3
): δ ϭ
1
1.1 (q), 20.9 (q), 21.3 (q), 24.2 (q), 27.1 (t), 30.7 (t), 44.9 (t), 47.4
2-(6-Methyl-2-pyridinyl)-1,1-diphenyl-1-ethanol (2a): 2,6-Lutidine (d), 49.5 (s), 52.2 (s), 81.1 (s), 120.8 (d), 121.1 (d), 136.9 (d), 156.8
(1) (10.0 g, 93.3 mmol) was dissolved in 200 mL of THF and cooled
(s), 159.7 (s). Ϫ HRMS: calcd. 259.194; found 259.194 Ϫ
Eur. J. Org. Chem. 2000, 2735Ϫ2743
2739

B. Koning, J. Buter, R. Hulst, R. Stroetinga, R. M. Kellogg
FULL PAPER
C
17
H25NO (259.4): calcd. C 78.72, H 9.71, N 5.40; found C 78.75,
4 h and quenched by the addition of benzophenone (0.6 g,
H 9.78, N 5.54.
3.5 mmol). After stirring for 1 h, 2  NH
mixture was extracted twice with dichloromethane. The combined
organic layers were washed with brine and dried with Mg SO
After removal of the solvent, the C -diol was recrystallized from
water/ethanol affording 3a as colorless crystals (1.1 g, 2.3 mmol,
4
Cl was added and the
2
-({6-[(2-Hydroxy-2-adamantyl)methyl]-2-pyridinyl}methyl)-2-ada-
mantanol (3b) with n-Butyllithium: The mono-adduct 2b (1.1 g,
.3 mmol) was dissolved in 50 mL of THF and n-butyllithium (1.6
in hexane, 5.6 mL, 9.0 mmol) was added to deprotonate the start-
ing material. The mixture was stirred for 4 h before adamantanone
0.7 g, 4.3 mmol) in 5 mL of THF was added. After stirring for 1 h
 HCl was added and after stirring for 30 min it was neutralized
2
4
.
2
4

1
6
7%). Ϫ H NMR (300 MHz, CDCl
OH), 6.61 (d, J ϭ 8.1 Hz, 2 H), 7.2 (m, 21 H). Ϫ C NMR
): δ ϭ 48.0 (t), 78.0 (s), 122.8 (d), 126.0 (d), 126.5
d), 127.9 (d), 136.8 (s), 146.5 (d), 157.3 (s).
3
): δ ϭ 3.61 (s, 4 H), 5.17 (br,
13
2
(
1
(
(
300 MHz, CDCl
3
with 2  NaOH. The solution was extracted with dichloromethane
twice and the combined organic layers were washed with brine and
2-(6-Methyl-2-pyridinyl)-1,1,3,3-tetraphenyl-1,3-propanediol (7a):
The mono-adduct 2a (0.95 g, 3.29 mmol) was dissolved in 75 mL
of dry THF and cooled to 0 °C. Subsequently, n-butyllithium (1.6
4
dried with MgSO . After removal of the solvent, the product was
recrystallized from ethanol yielding 3b as colorless needles (1.2 g,
3
2
.0 mmol, 70%) with m.p. 199Ϫ200 °C. Ϫ IR (KBr): ν˜ ϭ 3500,  in hexane, 4.5 mL, 7.2 mmol) was added. The red mixture was
Ϫ1
1
850, 1610, 1600, 1450, 700 cm . Ϫ H NMR (300 MHz, CDCl
3
): stirred for 1 min and a solution of benzophenone (0.60 g,
3.31 mmol) in 5 mL of THF was added. Stirring was continued for
δ ϭ 1.4Ϫ1.9 (m, 20 H), 2.00 (m, 4 H), 2.24 (m, 4 H), 3.13 (s, 4 H),
4
.21 (s, 2 OH), 7.07 (d, J ϭ 7.7 Hz, 2 H), 7.55 (t, J ϭ 7.7 Hz, 1 H). another hour and the mixture was quenched with 2  NH
4
Cl and
): δ ϭ 27.3 (d), 32.7 (t), 34.6 (t), extracted twice with dichloromethane. The organic layers were
SO . After removal of the solvents
by means of rotary evaporation, the solid mixture of C and C
product was washed with hot diethyl ether to leave the C product
after filtration. The ether was removed affording the C product,
which was recrystallized from ethyl acetate/hexane (1:4) yielding a
13
Ϫ
C NMR (300 MHz, CDCl
3
3
7.2 (d), 38.3 (t), 44.6 (t), 75.4 (s), 122.5 (d), 136.8 (d), 158.3 (s). Ϫ combined and dried with Na
2
4
HRMS: calcd. 407.282; found 407.282. Ϫ C27 (407.6):
H
37NO
2
2
s
calcd. C 79.56, H 9.15, N 3.44; found C 79.44, H 9.10, N 3.48.
2
s
Time-Dependent Lithiations for 2b: The mono-adduct 2b
(
2.5 mmol) was dissolved in 50 mL of THF and cooled to the tem-
perature given in Table 1, n-butyllithium (1.6  in hexane,
.5 mmol) was added and the mixture was stirred for the given time
1
colorless solid (0.30 g, 0.64 mmol, 35%), m.p.146Ϫ147 °C. Ϫ
NMR (300 MHz, CDCl ): δ ϭ 2.31 (s, 3 H), 4.90 (s, 1 H), 6.23 (d,
J ϭ 6.7 Hz,1 H), 6.56 (d, J ϭ 6.7 Hz, 1 H), 6.7Ϫ6.8 (m, 9 H),
H
3
5
t
13
1
(see Table 1). Subsequently, adamantanone (2.5 mmol) in 5 mL
6
(
(
.9Ϫ7.0 (m, 4 H), 7.2Ϫ7.3 (m, 8 H), 8.48 (br, 2 OH). Ϫ C NMR
300 MHz, CDCl ): δ ϭ 23.9 (q), 56.8 (d), 82.4 (s), 120.1 (d), 125.6
d), 125.9 (d), 126.1 (d), 126.6 (d),127.1 (d), 127.3 (d), 127.8 (d),
2
of THF was added. Stirring was continued for the given time t at
the given temperature. The mixture was quenched with 2  HCl,
stirred for 30 min and neutralized with 2  NaOH. The solution
3
1
4
35.2 (d), 144.5 (s), 148.1 (d), 155.0 (s),159.9 (s). Ϫ HRMS: calcd.
71.220; no proper HRMS could be obtained CI (NH ) gave a
(471.6): calcd. C 84.05, H
.20, N 2.97; found C 83.36, H 6.21, N 2.98.
4
was extracted twice with dichloromethane and dried with MgSO .
3
The product distribution given in Table 1 was determined by means
molecular ion at m/z 472. Ϫ C33H29NO
2
6
1
of H NMR.
2
-[(2-Hydroxy-2-adamantyl)(6-methyl-2-pyridinyl)methyl]-2-ada-
(1R,2S)-2-[(6-{[(1R,2S)-2-Hydroxy-1,7,7-trimethylbicyclo[2.2.1]-
hept-2-yl]methyl}-2-pyridinyl)methyl]-1,7,7-trimethylbicyclo-
[2.2.1]heptan-2-ol (3d) with n-Butyllithium: The mono-adduct 2d
(1.0 g, 3.9 mmol) was dissolved in 50 mL of THF and cooled to
Ϫ40 °C. n-Butyllithium (1.6  in hexane, 2.6 mL, 4.2 mmol) was
added and the mixture was stirred for 3 h at Ϫ40 °C. After cooling
mantanol (7b): The mono-adduct 2b (0.5 g, 2.0 mmol) was dis-
solved in 50 mL of THF and cooled to 0 °C. n-Butyllithium (1.6 
in hexane, 2.6 mL, 4.2 mmol ) was added by syringe and the mix-
ture was stirred for 45 s. A solution of adamantanone (0.3 g,
2
.1 mmol) in 2 mL of THF was added at once. Stirring was con-
tinued for 1 h at 0 °C and the mixture was quenched with 2  HCl, to Ϫ60 °C, (R)-(ϩ)-camphor (0.6 g, 3.9 mmol) in 5 mL of THF
stirred for 30 min at room temp. and neutralized with 2  NaOH.
The solution was extracted twice with dichloromethane and dried
was added and stirring was continued for ca. 12 h, allowing the
mixture to reach ambient temperature. The mixture was quenched
with MgSO
4
.The product was purified by means of column chro-
with 2  NH Cl and extracted twice with dichloromethane. The
4
matography [silica, hexane/diethyl ether (9:1)] affording a colorless
combined organic layers were washed with brine and dried with
solid (0.4 g, 1.0 mmol, 52%) with m.p. 194Ϫ195 °C. Ϫ IR (KBr):
MgSO . The product was purified by means of column chromato-
4
Ϫ1
1
ν˜ ϭ 3372, 2931, 2898, 1594, 1572, 1456, 1057, 978 cm . Ϫ
NMR (300 MHz, CDCl
H), 1.39 (d, J ϭ 12.2 Hz, 2 H) 1.48 (d, J ϭ 9.3 Hz, 2 H), 1.60
m, 2 H), 1.67 (m, 4 H), 1.77Ϫ1.84 (m, 6 H), 2.04 (d, J ϭ 12.7 Hz,
H
graphy [SiO , hexane/diethyl ether (9:1)] yielding 3d as a colorless
2
3
): δ ϭ 0.86 (s, 2 H), 1.21 (d, J ϭ 12.2 Hz, solid, which was recrystallized from ethanol/water (2:1) (1.0 g,
2
3
2
2.3 mmol, 60%), m.p. 124Ϫ125 °C. Ϫ [α]D ϭ Ϫ98.8 (c ϭ 2.5, acet-
one). Ϫ IR (KBr): ν˜ ϭ 3450, 3000, 1630, 1620, 1500, 1060, 850
(
Ϫ1
1
2
H), 2.23 (d, J ϭ 12.7 Hz, 2 H), 2.40 (m, 4 H), 2.55 (s, 3 H), 3.93 cm . Ϫ H NMR (300 MHz, CDCl ): δ ϭ 0.51 (s, 6 H), 0.77 (s,
3
(
(
(
(
s, 1 H), 7.02 (d, J ϭ 7.8 Hz, 1 H), 7.07 (d, J ϭ 7.8 Hz, 1 H), 7.10 6 H), 1.04 (s, 6 H), 1.10 (m, 2 H), 1.44 (m, 6 H), 1.68 (m, 4 H),
s, 2 OH), 7.48 (dd, J ϭ 7.8 Hz, J ϭ 7.8 Hz, 1 H). Ϫ 1 C NMR
300 MHz, CDCl ): δ ϭ 26.5 (q), 27.0 (d), 32.9 (t), 33.0 (t), 34.2
t), 35.1 (t), 36.8 (d), 37.6 (d), 38.0 (t), 47.9 (q), 80.2 (s), 121.0 (d),
3
1.94 (m, 2 H), 2.91 (s, 4 H), 4.44 (br, 2 OH), 7.04 (d, J ϭ 7.7 Hz,
1
3
3
2 H), 7.49 (t, J ϭ 7.7 Hz, 1 H). Ϫ C NMR (300 MHz, CDCl3):
δ ϭ 10.8 (q), 20.9 (q), 21.4 (q), 27.1 (t), 30.6 (t), 44.9 (t), 45.8 (t),
123.6 (d), 136.0 (d), 157.3 (s), 160.8 (s). Ϫ HRMS: calcd. 407.282; 46.8 (d), 49.4 (s), 52.5 (s), 80.8 (s), 122.5 (d), 137.2 (d), 159.1 (s).
found 256 (Ϫ C10
molecular ion at m/z 408. Ϫ C27
9
H
15O), 238 (Ϫ C10
H
17
O
2
). Ϫ CI (NH
(407.6): calcd. C 79.37, H
.37, N 3.43; found C 79.46, H 9.28, N 3.43.
3
) gave a Ϫ HRMS: calcd. 411.314; found 411.314. Ϫ C H NO (411.6):
27 41 2
H
37NO
2
calcd. C 78.78, H 10.04, N 3.40; found C 78.64, H 9.82, N 3.42.
1R,2S)-1,7,7-Trimethyl-2-(2-pyridinylmethyl)bicyclo[2.2.1]heptan-
(
2
-[6-(2-Hydroxy-2,2-diphenylethyl)-2-pyridinyl]-1,1-diphenyl-1-
2-ol (10d): n-Butyllithium (1.6  in hexane, 21.8 mL, 34.9 mmol)
was added to a stirred solution of 2-methylpyridine (3.2 g,
34.8 mmol) in 75 mL of THF at Ϫ60 °C. After stirring for 30 min,
a solution of (R)-(ϩ)-camphor (5.4 g, 35 mmol) in 5 mL of THF
[22]
ethanol (3a) with n-Butyllithium: A solution of mono-adduct 2a
1.0 g, 3.5 mmol) was stirred at 0 °C and n-butyllithium (1.6  in
hexane, 4.6 mL, 7.4 mmol) was added. The mixture was stirred for
(
2740
Eur. J. Org. Chem. 2000, 2735Ϫ2743

2 s
Improved Synthesis of C -Symmetrical Pyridinediols and Synthesis of C -Symmetrical Pyridinediols
FULL PAPER
was added by syringe. Stirring was continued for 3 h allowing the
mixture to reach room temp. The mixture was quenched with 2  isolated by two-fold extraction with dichloromethane. The organic
NH Cl and extracted twice with ethyl acetate, after which the com- layers were washed with brine and dried with Na SO . After re-
bined organic layers were washed with brine and dried with
MgSO . After removal of the solvent, the product was purified by
°C, and subsequently quenched with 2  NH
4
Cl. The product was
4
2
4
moval of the solvents, the product was recrystallized from water/
ethanol affording 3a as colorless crystals (0.76 g, 1.62 mmol, 90%).
4
kugelrohr distillation (120 °C, 0.1 Torr) yielding 10d as a colorless Experimental data were in full accordance with those described in
oil (6.2 g, 25 mmol, 72%): [α]2
3
ϭ Ϫ15.9 (c ϭ 0.6, acetone). Ϫ IR
previous paragraphs.
D
(
KBr): ν˜ ϭ 3300, 2950, 1650, 1630, 1450, 1050, 800, 500 cmϪ1. Ϫ
1
(1R,2S)-2-[(6-{[(1R,2S)-2-Hydroxy-1,7,7-trimethylbicyclo[2.2.1]-
hept-2-yl]methyl}-2-pyridinyl)methyl]-1,7,7-trimethylbicyclo-
H NMR (300 MHz, CDCl
d, J ϭ 13.2 Hz, 1 H), 1.09 (m, 1 H), 1.11 (s, 3 H), 1.41 (m, 3 H),
.70 (m, 2 H), 2.06 (d, J ϭ 13.2 Hz, 1 H), 2.91 (s, 2 H), 6.31 (br,
OH), 7.17 (m, 2 H), 7.61 (t, J ϭ 7.7 Hz, 1 H), 8.45 (d, J ϭ 4.0 Hz,
3
): δ ϭ 0.48 (s, 3 H), 0.81 (s, 3 H), 0.98
(
1
[
1
2.2.1]heptan-2-ol (3d) with KDA: Mono-adduct 2d (0.5 g,
.9 mmol) was dissolved in 50 mL of THF and a solution of KDA
(0.16  in THF, 25 mL, 4.0 mmol) was added at Ϫ50 °C. After
stirring for 15 min, solution of (R)-(ϩ)-camphor (0.3 g,
.0 mmol) in 5 mL of THF was added. Stirring was continued for
h while the solution was allowed to reach ambient temperature.
Cl and extracted twice
with dichloromethane. The combined organic layers were washed
with brine and dried with MgSO . The product was recrystallized
H). Ϫ 1 C NMR (300 MHz, CDCl
q), 27.1 (t), 30.6 (t), 44.9 (d), 45.1 (t), 47.3 (t), 49.4 (s), 52.8 (s),
1.1 (s), 121.3 (d), 124.2 (d), 136.7 (d), 147.8 (d), 160.4 (s). Ϫ
HRMS: calcd. 245.178; found 245.178 Ϫ C16 23NO (245.4): calcd.
3
1
3
): δ ϭ 11.0 (q), 20.9 (q), 21.3
a
(
8
2
2
H
The mixture was quenched with 2  NH
4
C 78.32, H 9.45, N 5.71; found C 78.33, H 9.54, N 5.44.
Reaction of (10d) with n-Butyllithium and Benzophenone to Obtain
4
10a: To a stirred solution of 10d (0.7 g, 2.7 mmol) in 50 mL of from ethanol/water (2:1) (0.8 g, 1.8 mmol, 95%). All experimental
THF at Ϫ60 °C was added n-butyllithium (1.6  in hexane, 3.5 mL,
data are in full accordance with those described in previous para-
graphs.
5
(
.6 mmol) followed after 5 min by the addition of benzophenone
0.5 g, 2.7 mmol). The mixture was stirred for 1 h, allowing it to
reach ambient temperature, and was quenched with 2  NH Cl.
The solution was extracted with dichloromethane twice and the
4
organic layers were washed with brine and dried with Na SO .
1
,1-Diphenyl-2-(2-pyridinyl)-1-ethanol (10a): To a solution of 2-
4
picoline (13) (3.9 g, 42 mmol) in 100 mL of THF at Ϫ60 °C was
added n-butyllithium (1.6  in hexane, 26.3 mL, 42.1 mmol) and
the mixture was stirred for 30 min. A solution of benzophenone
2
After removal of the solvent, the product 10a and the starting mat-
erial 10d were separated by means of crystallization from hexane,
from which the benzophenone adduct 10a crystallized as colorless
needles (0.3 g, 1.1 mmol, 40%) with m.p. 155Ϫ156 °C. Ϫ IR (KBr):
(
7.6 g, 42 mmol) in 10 mL of THF was added. Stirring was con-
tinued for 1 h allowing the mixture to reach ambient temperature.
The mixture was quenched with 2  NH Cl, extracted twice with
ethyl acetate and the combined organic layers were dried with
MgSO . The product was recrystallized from ethanol yielding a
4
Ϫ1
1
ν˜ ϭ 3200, 3000, 1600, 1580, 1450, 1100, 850, 800, 700 cm . Ϫ H
NMR (300 MHz, CDCl ): δ ϭ 3.70 (s, 2 H), 7.05 (m, 2 H), 7.14
m, 2 H), 7.24 (t, J ϭ 8.1 Hz, 4 H), 7.47 (m, 5 H), 7.74 (br, OH),
4
3
colorless solid (10.8 g, 39.4 mmol, 94%). All spectroscopic data are
in accordance with those described in previous paragraphs.
(
.37 (d, J ϭ 4.4 Hz, 1 H). Ϫ 1 C NMR (300 MHz, CDCl
6.9 (t), 78.3 (s), 121.4 (d), 124.5 (d), 126.1 (d), 126.3 (d), 127.8 (d),
36.8 (d), 147.1 (s), 147.8 (d), 159.2 (s). Ϫ HRMS: calcd. 275.131;
3
8
4
1
3
): δ 0
2
-(2-Pyridinylmethyl)-2-adamantanol (10b): 2-Picoline (13) (0.9 g,
9
.7 mmol) was dissolved in 75 mL of THF and cooled to Ϫ60 °C.
found 275.132 Ϫ C19
H17NO (275.4): calcd. C 82.88, H 6.22, N
Subsequently, n-butyllithium (1.6  in hexane, 6.9 mL, 11 mmol )
was added and stirring was continued for 30 min. Adamantanone
(1.65 g, 10.9 mmol) in 5 mL of THF was slowly added and the
reaction mixture was stirred for 1 h. After the reaction was
5.09; found C 82.37, H 6.23, N 5.05.
Preparation of KDA:[23] To a stirred solution of potassium tert-bu-
toxide (0.9 g, 8.0 mmol) in 50 mL of THF was added diisopropyla-
mine (0.8 g, 8.0 mmol), and the mixture was cooled to Ϫ100 °C. n-
Butyllithium (1.6  in hexane, 5.0 mL, 8.0 mmol) was added over a
period of 10 min and the solution was stirred for 30 min before use.
quenched with 2  NH
ethyl acetate and the combined organic layers were dried with
MgSO . The product was purified by means of column chromato-
graphy [silica, hexane/diethyl ether (3:1)] yielding 10b as a colorless
4
Cl, the solution was extracted twice with
4
2
-({6-[(2-Hydroxy-2-adamantyl)methyl]-2-pyridinyl}methyl)-2-ada- solid (1.8 g, 7.4 mmol, 74%) with m.p. 87Ϫ88 °C. Ϫ IR (KBr): ν˜ ϭ
Ϫ1
1
mantanol (3b) with KDA: The mono-adduct 2b (0.5 g, 1.9 mmol)
was dissolved in 25 mL of THF and cooled to Ϫ50 °C. A freshly
prepared potassium diisopropylamide solution (0.16  in THF,
3300, 2900, 1600, 1590, 1400, 950, 800 cm . Ϫ H NMR
(300 MHz, CDCl ): δ ϭ 1.4Ϫ2.0 (m, 12 H), 2.33 (d, J ϭ11.0 Hz,
2 H), 3.14 (s, 2 H), 6.05 (br, OH), 7.15 (m, 2 H), 7.61 (t, J ϭ 7.7 Hz,
3
1
3
4
1
3
.0 mmol, 25 mL) was added by canula. Stirring was continued for 1 H), 8.50 (d, J ϭ 5.5 Hz, 1 H). Ϫ C NMR (300 MHz, CDCl ):
5 min before adamantanone (0.3 g, 2.0 mmol) in 5 mL of THF
Cl,
extracted twice with dichloromethane, and dried with MgSO
δ ϭ 27.3 (d), 27.4 (d), 32.7 (t), 34.6 (t), 37.2 (d), 38.4 (t), 43.6 (t),
75.4 (s), 121.3 (d), 124.4 (d), 136.6 (d), 148.3 (d), 159.6 (s). Ϫ
was added. After 1 h, the mixture was quenched with 2  NH
4
4
.
HRMS: calcd. 243.162; found 243.163. Ϫ C16H21NO (243.4): calcd.
After filtration, the solvents were removed under reduced pressure
to obtain 3b as a solid that was recrystallized from ethanol yielding
colorless needles (0.8 g, 1.8 mmol, 95%). Experimental data were
in full accordance with those described in previous paragraphs.
C 78.97, H 8.70, N 5.76. found C 78.95, H 8.79, N 5.81.
2
-Methyl-1-(2-pyridinyl)-2-propanol (10c):[24] To a stirred solution
of 2-picoline (13) (0.7 g, 7.4 mmol) in 50 mL of THF at Ϫ50 °C
was added n-butyllithium (1.6  in hexane, 5.0 mL, 8.1 mmol) fol-
lowed by the addition of acetone (0.6 g, 10 mmol) after stirring for
15 min. Stirring was continued for another 15 min, and the solution
2
-[6-(2-Hydroxy-2,2-diphenylethyl)-2-pyridinyl]-1,1-diphenyl-1-
ethanol (3a) with KDA: To a stirred solution of the mono-adduct
2
a (0.52 g, 1.80 mmol) in 50 mL of THF at Ϫ70 °C was added a was quenched with NH
freshly prepared solution of KDA (0.25  in THF, 14.8 mL, The combined organic layers were washed with brine and dried
.7 mmol). The red solution was stirred for 15 min and benzo- with MgSO . The product was obtained after distillation by means
of kugelrohr (60 °C, 0.05 Torr) affording 10c (0.6 g, 3.8 mmol,
4
Cl and extracted twice with ethyl acetate.
3
4
phenone (1.81 g, 0.33 mmol) in 5 mL of THF was added. Stirring
was continued for 1 h, allowing the reaction mixture to reach Ϫ10
1
51%). Ϫ H NMR (300 MHz, CDCl
3
): δ ϭ 1.14 (s, 6 H), 2.84 (s,
Eur. J. Org. Chem. 2000, 2735Ϫ2743
2741

B. Koning, J. Buter, R. Hulst, R. Stroetinga, R. M. Kellogg
FULL PAPER
2
H), 5.6 (br, OH), 7.05 (d, J ϭ 8.1 Hz, 1 H), 7.10 (m, 1 H), 7.55 lecular ion at m/z 152. Ϫ C12
t, J ϭ 8.1 Hz, 1 H), 8.42 (d, J ϭ 4.4 Hz, 1 H). Ϫ 13C NMR
9.16, N 6.70; found C 68.63, H 9.00, N 6.47.
300 MHz, CDCl ): δ ϭ 29.3 (q), 48.5 (t), 70.6 (s), 121.3 (d), 124.2
2
H19NO (209.3): calcd. C 68.85, H
(
(
(
3
(
1R,2RS)-1,3,3-Trimethyl-2-[(6-methyl-2-pyridinyl)methyl]-
d), 136.6 (d), 148.2 (d), 159.8 (s).
bicyclo[2.2.1]heptan-2-ol (2f): 2,6-Lutidine (1) (1.0 g, 0.9 mmol) in
50 mL of THF was lithiated with n-butyllithium (1.6  in hexane,
6.2 mL, 9.9 mmol) at Ϫ60 °C. After stirring for 10 min (R)-(Ϫ)-
fenchone (1.4 g, 9.2 mmol) in 5 mL of THF was added and stirring
1,1,3,3-Tetraphenyl-2-(2-pyridinyl)-1,3-propanediol (14a): To a solu-
tion of the mono-adduct 10a (1.0 g, 3.6 mmol) in 50 mL of THF
at room temp. was added n-butyllithium (1.6  in hexane, 4.8 mL,
7
4
.7 mmol). The mixture was stirred for 15 min and benzophenone was continued for 1 h. NH Cl was added and the mixture was ex-
(
0.7 g, 3.6 mmol) in 5 mL of THF was added. The mixture was
stirred overnight. The mixture was quenched with 2  NH Cl and
extracted with dichloromethane, and the organic layer dried with
MgSO . The mixture was concentrated and the solid was washed
tracted with ethyl acetate yielding 2f as a mixture of the exo and
endo isomers (1.9 g, 7.3 mmol, 79%). Ϫ H NMR (300 MHz,
CDCl ): δ ϭ 0.67 (s, 3 H), 0.76 (s, 3 H), 0.86 (s, 3 H), 0.90(s, 3 H),
3
0.99 (s, 3 H), 1.05 (s, 3 H), 1.1Ϫ1.8 (m, 12 H), 2.1Ϫ2.3 (m, 2 H),
2.47 (s, 6 H), 2.85 (d, J ϭ 15.6, 2 H), 2.95 (s, 2 H), 3.03 (d, J ϭ
15.6, 2 H), 6.95 (m, 4 H), 7.5 (m, 4 H).
1
4
4
with hot methanol and recrystallized from ethyl acetate/hexane
yielding a colorless solid (0.6 g, 1.2 mmol, 33%) with m.p. 143Ϫ144
°
7
1
1
C. Ϫ H NMR (300 MHz, CDCl
3
): δ ϭ 5.02 (s, 1 H), 6.53 (d, J ϭ
(
1RS,2S,5R)-2-Isopropyl-5-methyl-1-[(6-methyl-2-pyridinyl)-
methyl]cyclohexanol (2g): To a solution of 2,6-lutidine (1) (0.7 g,
.5 mmol) in 50 mL of THF at Ϫ60 °C was added n-butyllithium
1.6  in hexane, 4.1 mL, 6.5 mmol). After stirring for 10 min, (Ϫ)-
.7 Hz,1 H), 6.8Ϫ7.1 (m, 14 H), 7.3 (m, 8 H), 8.21 (d, J ϭ 4.8 Hz,
H), 8.27 (br, 2 OH). Ϫ 13C NMR (300 MHz, CDCl
3
): δ ϭ 57.0
6
(
(
d), 82.4 (s), 120.7 (d), 125.7 (d), 125.8 (d), 126.0 (d), 126.6 (d),
27.1 (d), 127.3 (d), 127.9 (d), 134.9 (d), 144.5 (s), 146.3 (d), 148.1
s),160.9 (s). Ϫ HRMS: calcd. 457.204; no proper HRMS could be
obtained. CI (NH ) gave molecular ions at m/z 183 and 276. Ϫ
(457.6): calcd. C 84.00, H 5.95, N 3.06; found C 83.87,
H 5.99, N 3.11.
1
(
menthone (1.0 g, 6.5 mmol) in 5 mL of THF was added. Stirring
was continued for 1 h at Ϫ60 °C before the mixture was quenched
3
with NH
4
Cl and extracted with ethyl acetate. The organic layer was
. The cis and trans prod-
32 2
C H27NO
washed with brine and dried with MgSO
4
ucts in the mixture with a ratio of 2:1 were separated by means of
column chromatography (silica, hexane/diethyl ether 10:1) yielding
the pure isomers.
2
(
1
(
-[(2-Hydroxy-2-adamantyl)(2-pyridinyl)methyl]-2-adamantanol
14b): A solution of n-butyllithium (1.6  in hexane, 6.3 mL,
0 mmol) was added to a stirred solution of mono-adduct 10b
1.2 g, 5.0 mmol) in 75 mL of THF at 0 °C. Stirring was continued
trans-2g: (0.5 g, 2.0 mmol, 30%), m.p. 60Ϫ62 °C. Ϫ [α]2
3
ϭ ϩ67
D
1
(
c ϭ 0.8, acetone). Ϫ H NMR (500 MHz, CDCl
3
): δ ϭ 0.72 (d,
for 30 min and adamantanone (0.8 g, 5.1 mmol) in 5 mL of THF
was added. The mixture was stirred for another hour and quenched
with 2  NH
thane, the combined organic layers were dried with MgSO
concentration of the solution, the solid was washed with hot hex-
ane leaving 14b as a white solid (0.5 g, 1.3 mmol, 26%) with m.p.
1
7
(
2
(
8
2
J ϭ 6.5 Hz, 3 H), 0.87 (d, J ϭ 7.0 Hz, 1 H), 0.91 (m, 2 H), 1.03
d, J ϭ 7.0 Hz, 3 H), 1.33 (m, 2 H), 1.37 (m, 2 H), 1.67 (m, 1 H),
.73 (m, 1 H), 2.44 (dq, J ϭ 7.0 Hz, J ϭ 7.0 Hz, 1 H), 2.52 (s, 3
H), 2.94 (dd, J ϭ 14.0 Hz, J ϭ 14.0 Hz, 2 H), 6.91 (d, J ϭ 7.5 Hz,
(
1
4
Cl. The solution was extracted twice with dichlorome-
. After
4
1
1
H), 7.01 (d, J ϭ 7.8 Hz, 1 H), 7.51 (dd, J ϭ 7.0 Hz, J ϭ 7.8 Hz,
H). Ϫ C NMR (300 MHz, CDCl ): δ ϭ 19.2 (q), 22.3 (q), 23.4
3
1
3
83Ϫ184 °C. Ϫ IR (KBr): ν˜ ϭ 3400, 2950, 1650, 1630, 1450, 1100,
(
7
t), 24.86 (q), 24.78 (q), 30.3 (d), 35.0 (t), 38.9 (t), 47.8 (t), 51.9 (d),
5.6 (s), 120.8 (d), 121.2 (d), 136.9 (d), 157.3 (s), 159.4 (s). Ϫ
HRMS: calcd. 261.209; found 261.209. Ϫ C17 27NO (261.4): calcd.
Ϫ1
1
3
50 cm . Ϫ H NMR (300 MHz, CDCl ): δ ϭ 0.82 (s, 2 H), 1.21
m, 3 H), 1.46 (m, 4 H) 1.6Ϫ1.9 (m, 13 H), 2.05 (d, J ϭ 12.1 Hz,
H), 2.23 (d, J ϭ 12.1 Hz, 2 H), 2.44 (m, 4 H), 3.98 (s, 1 H), 6.82
s, 2 OH), 7.19 (m, 1 H), 7.28 (d, J ϭ 8.1 Hz, 1 H), 7.59 (m, 1 H),
H
C 78.11 H 10.41, N 5.36; found C 78.12, H 10.57, N 5.12.
.59 (d., J ϭ 5.1 Hz, 1 H). Ϫ 13C NMR (300 MHz, CDCl
6.6 (d), 27.0 (d), 32.9 (t), 33.0 (t), 34.3 (t), 35.2 (t), 36.9 (d), 37.7
): δ ϭ
23
3
cis-2g: (1.0 g, 3.8 mmol, 59%), m.p. 64Ϫ66 °C. Ϫ [α]D ϭ Ϫ121 (c ϭ
1
0.6, acetone). Ϫ H NMR (300 MHz, CDCl ): δ ϭ 0.67 (d, J ϭ
3
(
(
d), 38.1 (t), 48.0 (d), 80.3 (s), 121.5 (d), 126.5 (d), 136.1 (d), 148.7
d), 161.9 (s). Ϫ HRMS: calcd. 393.267; no proper HRMS could be 6.9 Hz, 3 H), 1.05 (m, 1 H), 1.15 (m, 1 H), 1.52 (m, 2 H), 1.67 (m,
6.2 Hz, 3 H), 0.75 (m, 2 H), 0.88 (d, J ϭ 6.9 Hz, 3 H), 0.94 (d, J ϭ
obtained. CI (NH
393.6): calcd. C 79.35, H 8.96, N 3.56; found C 78.60, H 9.09,
N 3.64.
3
) gave a molecular ion at m/z 394. Ϫ C26
H
35NO
2
2 H), 2.19 (dq, J ϭ 6.9 Hz, J ϭ 6.9 Hz, 1 H), 2.44 (d, J ϭ 3.9, 1
H), 2.45 (s, 3 H), 3.31 (d, J ϭ 13.9 Hz, 1 H), 6.84 (d, J ϭ 7.3 Hz,
1 H), 6.93 (d, J ϭ 7.7 Hz, 1 H), 7.44 (dd, J ϭ 6.9 Hz, J ϭ 7.7 Hz,
(
1
3
1
(
5
H). Ϫ C NMR (300 MHz, CDCl
q), 23.8 (q), 24.2 (q), 26.2 (d), 27.7 (d), 35.4 (t), 46.1 (t), 47.4 (t),
1.1 (d), 74.7 (s), 120.6 (d), 121.5 (d), 136.8 (d), 157.1 (s), 159.9 (s).
Ϫ HRMS: calcd. 261.209; found 261.209. Ϫ C17 27NO (261.4):
3
): δ ϭ 18.0 (q), 20.8 (t), 22.4
2,4-Dimethyl-3-(2-pyridinyl)-2,4-pentanediol (14c): To a stirred solu-
tion of 10c (0.4 g, 2.4 mmol) in 50 mL of THF at Ϫ30 °C was
added n-butyllithium (1.6  in hexane, 3.0 mL, 4.9 mmol). The so-
lution was stirred for 30 min and acetone (0.2 g, 3.0 mmol) was
added. After stirring for 1 h, the mixture was quenched with 2 
H
calcd. C 78.11 H 10.41, N 5.36; found C 78.04, H 10.39, N 5.49.
NH
the combined organic layers were dried with MgSO
material was removed by means of kugelrohr distillation (80 °C,
.05 Torr) and the residue was purified by means of column chro-
4
Cl. The solution was extracted twice with ethyl acetate and
(1R,2S,5R)-1-[(6-{[(1R,2S,5R)-1-Hydroxy-2-isopropyl-5-methyl-
cyclohexyl]methyl}-2-pyridinyl)methyl]-2-isopropyl-5-methylcyclo-
hexanol (cis-cis-3g): The mono-adduct cis-2g (0.7 g, 2.5 mmol) was
dissolved in 50 mL of THF and cooled to 0 °C, n-butyllithium (1.6
 in hexane, 3.4 mL, 5.4 mmol) was added and the mixture was
stirred for 5 min. (Ϫ)-Menthone (0.4 g, 2.5 mmol) in 3 mL of THF
4
. The starting
0
matography [silica, hexane/ethyl acetate (1:1)] affording 14c as a
colorless oil (0.2 g, 0.7 mmol, 30%). Ϫ 1H NMR (300 MHz,
CDCl
3
): δ ϭ 1.00 (s, 6 H), 1.37 (s, 6 H), 2.74 (s, 1 H) 5.11 (br, was added and the mixture was stirred overnight. The mixture was
OH), 7.05 (d, J ϭ 7.7 Hz, 1 H), 7.13 (m, 1 H), 7.58 (dd, J ϭ quenched with NH Cl and extracted twice with dichloromethane.
The combined organic layers were dried with Na SO . After con-
centration in vacuo, the solid was crystallized from water/ethanol
2
7
4
.7 Hz, J ϭ 7.7 Hz, 1 H), 8.45 (d., J ϭ 4.0 Hz, 1 H). Ϫ 1 C NMR
3
2
4
(300 MHz, CDCl
3
): δ ϭ 31.4 (q), 31.6 (q), 62.2 (d), 74.2 (s), 121.6
(
2
d), 126.3 (d), 136.5 (d), 147.9 (d), 162.7 (s). Ϫ HRMS: calcd. affording cis-cis-3g as a colorless solid (0.4 g, 1.0 mmol, 40%), m.p.
2
3
1
09.141; no proper HRMS could be obtained. CI(NH
3
) gave a mo-
125Ϫ126 °C. Ϫ [α]
D
ϭ Ϫ109 (c ϭ 1.3, acetone). Ϫ H NMR
2742
Eur. J. Org. Chem. 2000, 2735Ϫ2743

2 s
Improved Synthesis of C -Symmetrical Pyridinediols and Synthesis of C -Symmetrical Pyridinediols
FULL PAPER
Synthesis, Wiley, Chichester, 1995. Ϫ [ R. A. Aitken, S. N.
Kil e´ ny, Asymmetric Synthesis, Blackie Academic & Profes-
sional, London, 1992.
[3]
2c]
(
(
1
(
7
1
(
300 MHz, CDCl
d, J ϭ 6.9 Hz, 6 H), 0.94 (d, J ϭ 6.6 Hz, 6 H), 1.05 (m, 2 H),
.4Ϫ1.8 (m, 10 H), 2.20 (m, 2 H), 2.49 (d, J ϭ 13.2 Hz, 2 H), 3.32
d, J ϭ 13.2 Hz, 2 H), 3.75 (br, 2 OH), 6.99 (d, J ϭ 7.7 Hz, 2 H),
3
): δ 0.67 (d, J ϭ 6.4 Hz, 6 H), 0.8 (m, 4 H), 0.89
B. Koning, R. Hulst, A. Bouter, J. Buter, A. Meetsma, R. M.
Kellogg, Chem. Commun. 1997, 1065Ϫ1066.
[4]
.50 (t, J ϭ 7.7 Hz, 1 H). Ϫ 13C NMR (300 MHz, CDCl
8.1 (q), 20.8 (t), 22.3 (q), 23.7 (q), 26.1 (d), 27.6 (d), 35.1 (t), 47.1
): δ ϭ
B. Koning, A. Meetsma, R. M. Kellogg, J. Org. Chem. 1998,
3
6
3, 5533Ϫ5540.
[
5]
Z.-Y. Li, W.-Y. Yu, C.-M. Che, C.-K. Poon, R.-J. Wang,
t), 47.4 (t), 51.0 (d), 74.7 (s), 122.3 (d), 136.8 (d), 159.2 (s). Ϫ
T. C. W. Mak, J. Chem. Soc., Dalton Trans. 1992, 1657Ϫ1661.
HRMS: calcd. 415.345; found 415.345. Ϫ C27 (395.5):
calcd. C 78.02, H 10.91, N 3.37; found C 77.91, H 10.99, N 3.37.
H45NO
2
[6] [6a]
S. Igai, I. Imaoka, N. Mitani, Ube Industries, Japan, Patent
[6b]
JP 09012582 A2, 1989 (Chem. Abstr. 1997, 126, 225669). Ϫ
Y. Nakayama, N. Ikushima, A. Nakamura, Chem. Lett. 1997,
Dichloro[(6-methyl-2-pyridinyl)methyl]cerium (16): To a stirred solu-
tion of 2,6-lutidine (1) (0.1  solution in THF, 10 mL, 1.0 mmol)
at Ϫ70 °C was added n-butyllithium (0.6 mL, 1.0 mmol). After stir-
8
61Ϫ862.
[
7] [7a]
V. C. Gibson, E. L. Marshall, C. Redshaw, W. Clegg,
M. R. J. Elsegood, J. Chem. Soc., Dalton Trans. 1996,
[
7b]
·THF[25]
4197Ϫ4199. Ϫ
984, 106, 3035Ϫ3036.
H. Mack, M. S. Eisen, J. Chem. Soc., Dalton Trans. 1998,
17Ϫ921.
J. M. Berg, R. H. Holm, J. Am. Chem. Soc.
ring for 15 min, this solution was added to CeCl
3
(0.1
1
solution in THF, 10 mL, 1.0 mmol) at Ϫ70 °C. The solution was
stirred for 1 h at Ϫ50 °C and used as such for the addition reactions
to ketones.
[8]
9
[
9] [9a]
R. M. Kellogg, B. Kaptein, J. Buter, J. Bull. Soc. Chim. Belg.
[9b]
1
990, 99, 703Ϫ705. Ϫ
F. van Bolhuis, J. Org. Chem. 1990, 55, 1890Ϫ1901.
10] [10a]
B. Kaptein, G. Barf, R. M. Kellogg,
General Procedure for the Addition of 16 to Ketones: To a stirred
solution of 16 (0.05  solution in THF, 20 mL, 1.0 mmol) at Ϫ70
[
J. J. H. Edema, R. Libbers, A. Ridder, R. M. Kellogg, J.
[10b]
Organomet. Chem. 1994, 464, 127Ϫ132. Ϫ
A. Chandrasekaran, R. O. Day, R. R. Holmes, Inorg. Chem.
996, 35, 4342Ϫ4346.
T. K. Prakasha,
°
C was added a solution of the ketone (1.0 mmol) in 2 mL of THF.
Stirring was continued for 3 h after which the solution was
quenched with NH Cl and extracted with ethyl acetate twice. The
combined organic layers were washed with brine and dried with
MgSO
1
4
[11]
P.-M. Chan, W.-Y. Yu, C.-M. Che, K.-K. Cheung, J. Chem.
Soc., Dalton Trans. 1998, 3183Ϫ3190.
[
[
[
12]
13]
14]
4
.
C. H. Tilford, M. G. van Camphen, J. Am. Chem. Soc. 1954,
7
6, 2431Ϫ2441.
(
[
1R,2RS)-1,3,3-Trimethyl-2-[(6-methyl-2-pyridinyl)methyl]bicyclo-
2.2.1]heptan-2-ol (2f) with CeCl : According to the above general
procedure starting from 16 (0.05  solution in THF, 22 mL,
.1 mmol) and (R)-(Ϫ)-fenchone (0.2 g, 1.1 mmol), a mixture of
endo and exo isomers 2f was obtained in a ratio of 4:1 (0.2 g,
.6 mmol, 54%). The spectra for these isomers are in accordance
with those described in previous paragraphs.
A. M. Ridder, R. Libbers, J. J. H. Edema, R. M. Kellogg, un-
published results.
3
J. J. M. Edema, R. Libbers, A. M. Ridder, R. M. Kellogg, F.
van Bolhuis, H. Kooijman, A. L. Spek,. J. Chem. Soc., Chem.
Commun. 1993, 625Ϫ627.
R. Taylor, J. Chem. Soc., Perkin Trans. 2 1983, 809Ϫ811.
J. Quick, C. Mondello, M. Humora, T. Brennan, J. Org. Chem.
1978, 43, 2705Ϫ2708.
1
[15]
[16]
0
[
17] [17a]
K. Nonoyama, M. Nonoyama, Transition Met. Chem.
[17b]
(
1R,2S,5R)-2-Isopropyl-5-methyl-1-[(6-methyl-2-pyridinyl)methyl]-
cyclohexanol (cis-2g) with CeCl : According to the above general
procedure starting from 16 (0.05  solution in THF, 36 mL,
.8 mmol) and (Ϫ)-menthone (0.3 g, 1.8 mmol) cis-2g was obtained
1987, 12, 497Ϫ500. Ϫ
S. Schmidt, L. Omnes, F. W. Heine-
mann, J. Kuhnigk, C. Krueger, A. Grohmann, Z. Naturforsch.,
B: Chem. Sci. 1998, 53, 946Ϫ954.
3
[
18] [18a]
T. Iamamoto, N. Takiyama, K. Nakamura, T. Hatajima,
1
[18b]
Y. Kamiya, J. Am. Chem. Soc. 1989, 111, 4392Ϫ4398. Ϫ
H.-J. Liu, N. H. Al-said, Tetrahedron Lett. 1991, 32,
5473Ϫ5476.
as a colorless solid after column chromatography (silica, hexane/
diethyl ether 9:1) (0.2 g, 0.8 mmol, 45%). Spectra were in full ac-
cordance with those described in previous paragraphs.
[
[
19]
T. Imamoto, Y. Sugiura, N. Takiyama, Tetrahedron Lett. 1984,
2
5, 4233Ϫ4236.
20] [20a]
J. Jeener, B. H. Meier, P. Bachmann, R. R. Ernst, J. Chem.
[20b]
Phys. 1979, 71, 4546Ϫ4553. Ϫ
D. Neuhaus, M. William-
Acknowledgments
B. K. has been partially supported by a grant from the Dutch Na-
tional Science Foundation (NWO) administered through the Office
for Chemical Research (CW).
son, The Nuclear Overhauser Effect in Structural and Con-
formational Analysis, VCH Publishers, Cambridge, 1989.
A. Bax, R. Freeman, J. Magn. Reson. 1981, 44, 542Ϫ561.
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[
[
21]
22]
9
17Ϫ925.
[
23]
E. Pasquinet, P. Rocca, F. Marsais, A. Godard, G. Queguiner,
Tetrahedron 1998, 54, 8771Ϫ8782.
J. Büchi, W. Broger, G. Schmidt. Helv. Chim. Acta 1965, 48,
275Ϫ279.
[
1] [1a]
J. D. Morrison, Asymmetric Synthesis, vol. 5; Academic
[1b]
[24]
25]
Press, New York, 1985. Ϫ
ies and Ligands in Asymmetric Synthesis; Wiley, New York,
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J. Seyden-Penne, Chiral Auxiliar-
[
1
S. F. Martin, Org. Synth. 1998, 76, 228.
[
2] [2a]
G. Proctor, Asymmetric Synthesis, Oxford University Press,
Received December 10, 1999
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2b]
[O99668]
Eur. J. Org. Chem. 2000, 2735Ϫ2743
2743