Synthesis of chiral diazine and pyridine sulfoxides. Asymmetric induction by chiral sulfoxides in an 'aromatic ortho-directed metalation- reaction with electrophiles sequence'. Diazines. 24

Full text of DOI:10.1021/jo981125d

4512
J . Org. Chem. 1999, 64, 4512-4515
Sch em e 1a
Syn th esis of Ch ir a l Dia zin e a n d P yr id in e
Su lfoxid es. Asym m etr ic In d u ction by
Ch ir a l Su lfoxid es in a n “Ar om a tic
Or th o-Dir ected Meta la tion -Rea ction w ith
Electr op h iles Sequ en ce”. Dia zin es. 24
P. Pollet, A. Turck, N. Ple´, and G. Que´guiner*
IRCOF-INSA, Laboratoire de Chimie Organique Fine et
He´te´rocyclique, UPRESA 6014, B.P. 08,
a
Reagents: (a) LTMP (2.2 equiv), 30 min, -75 °C, THF; (b)
(S)- or (R)-menthyl p-toluenesulfinate, -75 °C, 1 h 30 min.
76131 Mont St Aignan Cedex, France
Sulfoxides21,22 have not been used previously as asym-
metric directing groups for the enantioselective “ortho-
directed metalation-reaction with electrophile sequence”
in the aromatic series.
Received J une 11, 1998
Ortho-directed metalation is a useful method to func-
tionalize aromatic ring systems. We report here ortho-
directed metalations in the π-deficient heterocyclic series
(pyridazine, pyrimidine, and pyridine) using an aryl
sulfoxide as a chiral ortho-directing group. In aliphatic
series, many papers have described asymmetric induction
on sp3 carbon substituted by a chiral sulfoxide during a
metalation and reaction with electrophiles process.1-12
Very few publications have reported metalations of
aromatic rings followed by asymmetric inductions during
reaction of the lithio compound with a prochiral electro-
phile; de’s in the range 10-83% have been obtained.13-17
The only reference with sulfur derivatives is that of H.
Takahashi18 who obtained up to 82% de using chiral
sulfonamides.
The synthesis of enantiomerically pure sulfinyl pyr-
idazines was unknown. Asymmetric oxidations of 3-phen-
yl or 3-(methylthio)-6-methoxypyridazine and 2-phenyl-
or -(methylthio)pyrazine by Sharpless or Kagan’s meth-
od23-31 and using oxaziridines32-39 failed. On the other
hand, Andersen’s method40-42 using organometallics and
chiral menthyl p-toluenesulfinates, which are commer-
cially available, gave excellent enantiomeric excesses
after extensive studies (Schemes 1-3). Synthesis of
products 3a and 3b (Scheme 1) could be achieved as
follows. The preparation of 2 was carried out in the usual
conditions. The second step from 2 to 3a or 3b was
successful only if a reverse addition was used; i.e., the
reaction mixture containing the lithium derivatives was
poured into a solution of the menthyl p-toluenesulfinate
in THF. Under these conditions, 3a and 3b were obtained
Our knowledge about sulfur derivatives as directing
groups for metalations of diazines and our successful
metalations of racemic sulfoxides19,20 prompted us to
study a p-tolylsulfinyl group as a chiral directing agent.
(21) Walker, A. J . Tetrahedron Asymmetry 1992, 3, 961.
(22) Carren˜o, M. C.; Garcia Ruano, J . L.; Toledo, M. A.; Urbano, A.
Tetrahedron Asymmetry 1997, 8, 913.
(23) Arai, Y.; Suzuki, A.; Masuda, T.; Masaki, Y.; Shiro, M. J . Chem.
Soc., Perkin Trans. 1 1995, 2913.
(24) Girodier, L. G.; Rouessac, F. P. Tetrahedron Asymmetry 1994,
5, 1203.
(25) Hill, J . G.; Rossiter, B. E.; Sharpless, K. J . Org. Chem. 1983,
48, 3607.
(26) Kagan, H. B.; Dunach, E.; Nemecek, C.; Pitchen, P.; Samuel,
O.; Zhao, S. Pure Appl. Chem. 1985, 57, 1911.
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325.
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Chem. Soc. 1984, 106, 8188.
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1995, 60, 8086.
(30) Pitchen, P.; Kagan, H. B. Tetrahedron Lett. 1984, 25, 1049.
(31) Zhao, S. H.; Samuel, O.; Kagan, H. B. Tetrahedron 1987, 43,
5135.
* To whom correspondence should be addressed. Phone + 33(0) 2
35 52 29 00. Fax: + 33(0) 2 35 52 29 62. E-mail: guy.queguiner@
ircof.insa-rouen.fr.
(1) Baker, R. W.; Pocock, G. R.; Sargent, M. V.; Twiss, E. Tetrahe-
dron Asymmetry 1993, 4, 2423.
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3077.
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Chem. Soc. 1978, 100, 1558.
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(6) Cose, P. J .; Persad, A.; Simpkins, N. S. Synlett 1992, 197.
(7) Arai, Y.; Masuda, T.; Masaki, Y.; Koizumi, T. Heterocycles 1994,
38, 1751.
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1989, 30, 7091.
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1991, 32, 2943.
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Fr. 1993, 336.
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C. Tetrahedron Asymmetry 1996, 7, 3091.
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Tetrahedron 1983, 39, 1991.
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T.; Simson, M.; Seebach, D. Synthesis 1993, 1271.
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1984, 39, 1983.
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Perkin Trans. 1 1993, 701.
(18) Takahashi, H.; Tsubuki, T.; Higashiyama, K. Chem. Pharm.
Bull. 1991, 39, 260.
(19) Turck, A.; Ple´, N.; Pollet, P.; Mojovic, L.; Duflos, J .; Queguiner,
G. J . Heterocycl. Chem. 1997, 34, 621.
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Andrews, D. M. Synlett 1995, 773.
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1984, 49, 1465.
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Soc. 1992, 114, 1428.
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(36) Bullman Page, P. C.; Heer, J . P.; Bethell, D.; Collington, E. W.;
Andrews, D. M. Tetrahedron Asymmetry 1995, 6, 2911.
(37) Davies, F. A.; McCauley, J . P., J r.; Chattopadhyay, S.; Harakal,
M. E.; Towson, J . C.; Watson, W. H.; Tavanaiepour, I. J . Am. Chem.
Soc. 1987, 109, 3370.
(38) Davis, F. A.; Billmers, J . M.; Gosciniak, D. J .; Towson, J . C. J .
Org. Chem. 1986, 51, 4240.
(39) Davies, F. A.; J enkins, R., J r.; Yocklovich, S. G. Tetrahedron
Lett. 1978, 52, 5171.
(40) Andersen, K. K.; J . Am. Chem. Soc. 1964, 2, 1953.
(41) Girodier, L.; Maignan, C.; Rouessac, F. Tetrahedron Asymmetry
1992, 3, 857.
(20) Turck, A.; Ple´, N.; Pollet, P.; Queguiner, G. J . Heterocycl. Chem.,
submitted.
(42) Andersen, K. K.; Gaffield, W.; Papanikolaou, N. E.; Foley, J .
W.; Perkins, R. I. J . Am. Chem. Soc. 1964, 4, 5637.
10.1021/jo981125d CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/18/1999

Notes
J . Org. Chem., Vol. 64, No. 12, 1999 4513
Sch em e 2a
Sch em e 4a
a
Reagents: (a) BuLi (1.2 equiv), 5 min, -100 °C, THF; (b) (S)-
or (R)-menthyl p-toluenesulfinate, -75 °C, 1 h 30 min.
Sch em e 3a
a
M.A.: metalating agent.
Ta ble 1. Meta la tion a n d Rea ction w ith Ald eh yd es of
4-(p-Tolylsu lfin yl)-3,6-d im eth oxyp yr id a zin e 3a a n d 3b
R
products
metalating agent
de, %
yield, %
CH3
CH3
CH3
CH3
C2H5
C2H5
C2H5
C2H5
C6H5
C6H5
C6H5
C6H5
13a
13a
13b
13b
14a
14a
14b
14b
15a
15a
15b
15b
LDA
LTMP
LDA
LTMP
LDA
LTMP
LDA
LTMP
LDA
LTMP
LDA
96
96
98
99
96
95
97
94
93
95
93
98
53
76
63
70
40
35
30
39
50
68
30
57
a
Reagents: (a) i-PrMgCl, 1 h, rt, THF; NEt3, 5 min; (b) n-BuLi,
20 min, rt, THF; MgCl2, 30 min; (c) (S)- or (R)-menthyl p-
toluenesulfinate, -75 °C, 1 h 30 min.
LTMP
in 76% and 77% yields, respectively, with a 97% ee
(determined by HPLC). The lithiated pyrimidine 5 has
been obtained by halogen/metal exchange.43,44 The reac-
tion with menthyl p-toluenesulfinate gave products 6a ,b
in 22% and 47% yields, respectively, and in more than
99% ee (Scheme 2). Some pyridines such as 3-(p-
tolylsulfinyl)pyridines45(9a , 9b) and 2,6-dimethoxy-4-(p-
tolylsulfinyl)pyridines (12a , 12b ) were synthesized
(Scheme 3).
Sch em e 5
Starting from 3-bromopyridine derivatives (7, 10), the
Grignard compounds (8 and 11) were obtained by ex-
change with isopropylmagnesium chloride. The reaction
with menthyl p-toluenesulfinate was stereospecific. Prod-
ucts 9a ,b and 12a ,b were obtained in moderate yields
but with more than 99% ee. When 3-lithiopyridine was
used instead of the Grignard compound 8, the yields were
close but the ee decreased to 39% (9a ) and 54% (9b).
With the chiral sulfoxides prepared, we could now use
them as chiral ortho-directing groups. A preliminary
study was necessary to optimize this metalation reaction.
The best metalation reaction conditions were found to
be 3.2 equiv of lithium 2,2,6,6-tetramethylpiperidide
(LTMP) or lithium diisopropylamide (LDA) as metalating
agents for 1 h at -75 °C, followed by reaction with
various aldehydes at -75 °C (Scheme 4, Table 1).
These results indicated that the diastereoselectivity in
these reactions was almost complete. The X-ray data
allowed us to assign the absolute configuration of com-
pounds 13 and 14. It was found that the stereogenic
carbon of the secondary alcohol of 13a and 14b had an
opposite configuration to that of the sulfoxides, a (R)
sulfoxide leading to the (RS) diastereoisomer. It was not
possible to crystallize correctly the other products in order
to perform X-ray analysis; however, it can be supposed
that they have the same configuration (Schemes 4, 5).
The remarkable diastereoselectivity observed could be
favored by the high steric hindrance in the molecule
(3a ,b). To test a less-hindered substrate, the same
reaction was performed with pyrimidine (6a ,b) and
pyridine (9a ,b). Numerous attempts to metalate 5-(p-
tolylsulfinyl)pyrimidine (6a ,b) have failed but the reac-
tion worked with 3-(p-tolylsulfinyl)pyridine (9a ,b). The
best experimental conditions for the metalation of this
pyridine substrate required the use of 3.2 equiv of LDA
as metalating agent for 90 min at -75 °C (Scheme 5).
The reaction with various electrophiles at -75 °C gave
the results summarized in Table 2. All attempts to
metalate these compounds with LTMP as metalating
agent failed.
For pyridines 9a ,b (Table 2), diastereoselectivity was
complete with benzaldehyde and 2,2-dimethylpropanal
as electrophiles. Products 18a ,b and 19a ,b were obtained
in low yields (25, 37, 13, and 18%, respectively) but with
total diastereoselectivity (>99%). Unhindered aliphatic
aldehydes such as acetaldehyde and propionaldehyde
gave products 16a ,b and 17a ,b in low yields and low de’s.
In all cases, the yields were low, making the results with
3-(p-tolylsulfinyl)pyridine (9a ,b) unsatisfactory. So we
planned to use another substrate in the pyridine series
which would give a more stable lithium derivative than
(43) Gronowitz, S.; Roe, J . Acta Chem. Scand. 1965, 19, 1741.
(44) Boehner, B.; Forey, W.; Shurter, R.; Pissiotas, G. (Ciba-Geigy
A.-G.) Eur. Pat. Appl. EP96, 004, 1983; Chem. Abstr. 1980, 100,
139152c.
(45) Imanishi, T.; Obika, S.; Nishiyama, T.; Nishimoto, M.; Hamano,
Y.; Miyashita, K.; Iwata, C. Chem. Pharm. Bull. 1996, 44, 267.

4514 J . Org. Chem., Vol. 64, No. 12, 1999
Notes
) 97%. IR (KBr) 2953, 1013 cm-1; HRMS m/z 278 (M+), 229,
139; 1H NMR (200 MHz, CDCl3) δ 2.37 (s, 3H), 4.00 (s, 3H), 4.07
(s, 3H), 7.26 (d, 2H, J ) 8.0 Hz), 7.59 (m, 3H). Anal. Calcd for
Ta ble 2. Meta la tion a n d Rea ction w ith Ald eh yd es of
3-(p-Tolylsu lfin yl)p yr id in e 9a ,b a n d
3-(p-tolylsu lfin yl)-2,6-d im eth oxyp yr id in e 12a ,b
C
13H14N2O3S: C, 56.17; H, 5.07; N, 10.08. Found: C, 56.20; H,
starting
5.10; N, 10.11.
material
R
products
de, %
14, 0a
yield, %
(S)-5-(p-Tolylsu lfin yl)p yr im id in e (6a ). Into a 100 mL
round-bottomed two-necked flask provided with a thermometer
and magnetic stirring bar and under an atmosphere of dry argon
was placed dry THF (10 mL). After cooling to -100 °C,
n-butyllithium (1.6 M, 2.40 mL, 3.8 mmol) and then 5-bromo-
pyrimidine 4 (0.50 g, 3.2 mmol) dissolved in dry THF (5 mL)
were introduced. The reaction mixture was stirred for 10 min
at -100 °C. (R)-Menthyl p-toluenesulfinate (2.40 g, 8.3 mmol)
in dry THF (10 mL) was added, and stirring was continued for
4 h at -75 °C. The mixture was hydrolyzed with a saturated
NH4Cl solution (5 mL) and extracted with CH2Cl2 (3 × 20 mL).
The combined organic extracts were dried over MgSO4 and
evaporated. Column chromatography on silica gel with ethyl
acetate as an eluent afforded 6a as a white solid (47%, 0.65 g);
9a ,b
9a ,b
9a ,b
9a ,b
12a ,b
12a ,b
12a ,b
12a ,b
CH3
16a ,b
17a ,b
18a ,b
19a ,b
20a ,b
21a ,b
22a ,b
23a ,b
27, 18
27, 18
25, 37
13, 18
75, 89
53, 73
60, 63
60, 77
C2H5
t-C4H9
C6H5
CH3
C2H5
t-C4H9
C6H5
26, 20
>99, >99
>99, >99
38, 36
28, 20
>99, >99
>99, >99
a
Diastereoisomers could not be separated on the chiracel OD
column.
1
mp 136 °C; ee > 99%; IR (KBr) 3026, 1053 cm-1; H NMR (200
MHz, CDCl3) δ_2.43 (s, 3H), 7.36 (d, 2H, J ) 8.0 Hz), 7.60 (d,
2H, J ) 8.0 Hz), 8.90 (s, 2H), 9.27 (s, 1H). Anal. Calcd for
C11H10N2OS: C, 60.60; H, 4.62; N, 12.85. Found: C, 60.82; H,
4.57; N, 12.67.
(S)-3-(p-Tolylsu lfin yl)p yr id in e (9a ). Metalating agent: i-
PrMgBr; T1 ) rt. Yield: 34%; mp 56 °C; ee > 99%. IR (KBr)
-1
3048, 2922, 1050 cm
;
1H NMR (200 MHz, CDCl3) δ 2.39 (s,
3H), 7.31 (d, 2H, J ) 8.1 Hz), 7.38-7.45 (dd, 1H, J ) 8.1 Hz, J
) 4.8 Hz), 7.56 (d, 2H, J ) 8.1 Hz), 7.96-8.02 (dt, 1H, J ) 8.1
Hz, J ) 1.8 Hz), 8.67 (dd, 1H, J ) 4.8 Hz, J ) 1.8 Hz), 8.77 (d,
1H, J ) 1.8 Hz). Anal. Calcd for C12H11NOS: C, 66.33; H, 4.98;
N, 6.37. Found: C, 66.39; H, 5.25; N, 6.22.
F igu r e 1.
9a ,b and less steric hindrance at the C-4 position than
pyridazines 3a ,b . So, 2,6-dimethoxy-3-(p-tolylsulfinyl)-
pyridine (12a ,b) was chosen (Scheme 5). A good de was
obtained with hindered aldehydes as previously with
compounds 9a ,b, and it can be noticed that yields were
better (Table 2).
In summary, excellent diastereoselectivity was ob-
tained with 3,6-dimethoxy-4-(p-tolylsulfinyl)pyridazine
3a ,b independently of the steric hindrance of the alde-
hyde. With pyridine sulfoxides 9a ,b and 12a ,b, the de’s
were high with hindered aldehydes and low with the less
bulky aldehydes. These results can be explained by the
geometry of the heterocyclic substrate which presents a
convex and a concave face (Figure 1). The concave face
being more crowded, the approach of the aldehyde took
place on the less-hindered convex face leading to the
SC,RS diastereoisomer. In the case of pyridinic substrate,
the steric hindrance was lower and the unhindered
aldehydes could approach by both faces leading to the
two diastereoisomers.
(S)-2,6-Dim eth oxy-4-(p-tolylsu lfin yl)p yr id in e (12a ). Met-
alating agent: n-BuLi (1.6 M)/MgCl2; T1 ) rt. Yield: 26%; mp
-1
106-108 °C; ee > 99%. IR (KBr) 3025, 2950, 1041 cm
;
1H
NMR (200 MHz, CDCl3) δ 2.38 (s, 3H), 3.92 (s, 3H), 3.96 (s, 3H),
6.45 (d, 1H, J ) 8.2 Hz), 7.25 (d, 2H, J ) 8.2 Hz), 7.58 (d, 2H,
J ) 8.2 Hz), 7.97 (d, 1H, J ) 8.2 Hz). Anal. Calcd for C14H15
-
NO3S: C, 60.70; H, 5.46; N, 5.06; S, 11.58. Found: C, 61.07; H,
5.48; N,4.89; S, 11.42.
Gen er a l P r oced u r e for Met a la t ion w it h E lect r op h ile
Sequ en ce. A solution of n-butyllithium (1.6 M or 2.5 M in
hexane) was added to cold (-40 °C), stirred anhydrous THF (10
mL) under an atmosphere of dry argon. Diisopropylamine or
2,2,6,6-tetramethylpiperidine was introduced. The solution was
warmed to 0 °C and kept for 20 min at this temperature. It was
then cooled to -75 °C. A solution of the substrate to metalate
dissolved in THF (5 mL) was added, and the mixture was stirred
for t1 at -75 °C, followed by reaction with the corresponding
electrophile for
a further t2 (the volatility of acetaldehyde
required a large excess). Hydrolysis was then carried out at -75
°C using a mixture of 35% aqueous HCl (1 mL), ethanol (4 mL),
and THF (5 mL). The reaction solution was warmed to 0 °C,
made slightly basic with a saturated NaHCO3 solution, and was
evaporated nearly to dryness. The residue was extracted with
CH2Cl2 (3 × 20 mL). The combined organic extracts were dried
over MgSO4 and evaporated. The crude product was purified by
column chromatography on silica gel.
Exp er im en ta l Section
Gen er a l P r oced u r e for Syn t h esis of Su lfin a t e (3a ,b ;
9a ,b; 12a ,b). Into a 100 mL round-bottomed two-necked flask
provided with thermometer and magnetic stirring bar and under
an atmosphere of dry argon was placed dry THF (10 mL). After
cooling to T1 °C, metalating agent (2.2 mmol) was introduced.
A solution of the substrate (1.0 mmol) dissolved in THF (5 mL)
was added, and the reaction mixture was stirred for 1 h at T1
°C. It was poured by double-needle over a solution of (R or S)-
menthyl p-toluenesulfinate (2.2 mmol) in dry THF and under
atmosphere of dry argon. The reaction mixture was stirred for
2 h at -75 °C. A saturated NH4Cl solution (5 mL) was added.
Neutralization was then carried out with a saturated NaHCO3
solution (1 mL). The resulting mixture was concentrated and
was extracted with CH2Cl2 (3 × 20 mL). The combined organic
extracts were dried over MgSO4 and evaporated. Column chro-
matography on silica gel with ethyl acetate/light petroleum ether
(3/7) as an eluent afforded pure product.
(S)-3,6-Dim eth oxy-5-(1-h yd r oxyeth yl)-4-(p-tolylsu lfin yl)-
p yr id a zin e (13a ). Metalation of (S)-3,6-dimethoxy-4-(p-tolyl-
sulfinyl)pyridazine 3a (0.10 g, 0.4 mmol) according to the general
procedure with n-butyllithium 1.6 M (0.72 mL, 1.2 mmol) and
2,2,6,6-tetramethylpiperidine (0.19 mL, 1.2 mmol), t1 ) 60 min,
followed by reaction with acetaldehyde (1.00 mL, 18.0 mmol), t2
) 30 min, was carried out. Purification by column chromatog-
raphy eluting with ethyl acetate/light petroleum ether (1/1)
afforded 13a as a pale yellow solid (76%, 88.2 mg); mp 146 °C;
de ) 96%. IR (KBr) 3300, 2979, 2948, 1028 cm-1; 1H NMR (200
MHz, CDCl3) δ 1.66 (d, 3H, J ) 6.7 Hz), 2.38 (s, 3H), 4.00 (s,
3H), 4.12 (s, 3H), 4.00-4.12 (m, 1H), 5.88 (q, 1H, J ) 6.7 Hz),
7.29 (d, 2H, J ) 8.2 Hz), 7.62 (d, 2H, J ) 8.2 Hz). Anal. Calcd
for C15H18N2O4S: C, 55.95; H, 5.63; N, 8.70. Found: C, 55.63;
H, 5.83; N, 8.62.
(S)-3,6-Dim eth oxy-5-(1-h ydr oxypr opyl)-4-(p-tolylsu lfin yl)-
p yr id a zin e (14a ). Metalation of (S)-3,6-dimethoxy-4-(p-tolyl-
sulfinyl)pyridazine 3a (0.10 g, 0.4 mmol) according to the general
procedure with n-butyllithium 1.6 M (0.72 mL, 1.2 mmol) and
(S)-3,6-Dim eth oxy-4-(p-tolylsu lfin yl)pyr idazin e (3a). Met-
alating agent: LTMP; T1 ) -75 °C. Yield: 76%; mp 110 °C; ee

Notes
J . Org. Chem., Vol. 64, No. 12, 1999 4515
2,2,6,6-tetramethylpiperidine (0.19 mL, 1.2 mmol), t1 ) 60 min,
followed by reaction with propionaldehyde (0.06 mL, 0.7 mmol),
t2 ) 60 min, was carried out. Purification by column chroma-
tography eluting with ethyl acetate/light petroleum ether (1/1)
afforded 14a as a white solid (40%, 46.8 mg); mp 134 °C; de )
96%. IR (KBr) 3319, 2940, 2870, 1029 cm-1; 1H NMR (200 MHz,
CDCl3) δ 1.08 (t, 3H, J ) 7.4 Hz), 1.85-2.07 (m, 2H), 2.38 (s,
3H), 3.98 (s, 3H), 4.10 (s, 3H), 3.90-4.12 (m, 1H), 5.56-5.63 (m,
1H), 7.28 (d, 2H, J ) 8.6 Hz), 7.61 (d, 2H, J ) 8.6 Hz). Anal.
Calcd for C16H20N2O4S: C, 57.19; H, 6.00; N, 8.34. Found: C,
56.93; H, 6.28; N, 8.36.
(S)-3,6-Dim eth oxy-5-(r-h ydr oxyben zyl)-4-(p-tolylsu lfin yl)-
p yr id a zin e (15a ). Metalation of (S)-3,6-dimethoxy-4-(p-tolyl-
sulfinyl)pyridazine 3a (0.10 g, 0.4 mmol) according to the general
procedure with n-butyllithium 1.6 M (0.72 mL, 1.2 mmol) and
diisopropylamine (0.16 mL, 1.2 mmol), t1 ) 60 min, followed by
reaction with benzaldehyde (0.08 mL, 0.7 mmol), t2 ) 60 min,
was carried out. Purification by column chromatography eluting
with ethyl acetate/light petroleum ether/cyclohexane (1/1/1)
afforded 15a as a white solid (50%, 68.7 mg); mp 180 °C; de )
93%. IR (KBr) 3258, 3014, 2948, 1026 cm-1; 1H NMR (200 MHz,
CDCl3) δ 2.34 (s, 3H), 2.40 (s, 3H), 4.02-4.07 (m, 6H), 5.31 (m,
1H), 6.25 (m, 1H), 6.49 (s, 1H), 6.92 (s,1H), 7.08-7.33 (m, 8H),
7.75 (d, 1H). Anal. Calcd for C20H20N2O4S: C, 62.56; H, 5.25; N,
7.29. Found: C, 62.93; H, 5.12; N, 7.09.
(S)-4-(1-Hyd r oxyeth yl)-3-(p-tolylsu lfin yl)p yr id in e (16a ).
Metalation of (S)-3-(p-tolylsulfinyl)pyridine 9a (0.10 g, 0.5 mmol)
according to the general procedure with n-butyllithium 2.5 M
(0.59 mL, 1.5 mmol) and diisopropylamine (0.21 mL, 1.5 mmol),
t1 ) 60 min, followed by reaction with acetaldehyde (1.00 mL,
18.0 mmol), t2 ) 60 min, was carried out. Purification by column
chromatography eluting with ethyl acetate afforded 16a as an
orange oil (27%, 32.2 mg); de ) 14%. IR (KBr) 3344, 3052, 2974,
1045, 1013 cm-1; 1H NMR (200 MHz, CDCl3) δ 1.21 (d, 3H, J )
6.4 Hz), 1.35 (d, 3H, J ) 6.4 Hz), 2.38 (s, 3H), 4.10 (m, 1H), 5.19
(m, 1H), 7.27 (m, 2H), 7.40-7.52 (m, 3H), 8.58 (d, 1H), 8.64 (d,
1H), 8.81 (s, 1H), 8.90 (s, 1H). Anal. Calcd for C14H15NO2S: C,
64.43; H, 5.79; N, 5.37. Found: C, 64.58; H, 5.56, N, 5.21.
(S)-4-(1-Hydr oxypr opyl)-3-(p-tolylsu lfin yl)pyr idin e (17a).
Metalation of (S)-3-(p-tolylsulfinyl)pyridine 9a (0.10 g, 0.5 mmol)
according to the general procedure with n-butyllithium 2.5 M
(0.74 mL, 1.5 mmol) and diisopropylamine (0.26 mL, 1.5 mmol),
t1 ) 60 min, followed by reaction with propionaldehyde (0.07
mL, 0.6 mmol), t2 ) 60 min, was carried out. Purification by
column chromatography eluting with ethyl acetate afforded 17a
as an orange oil (27%, 33.7 mg); de ) 26%. IR (KBr) 3347, 2964,
2922, 1047 cm-1; 1H NMR (200 MHz, CDCl3) δ 0.89 (t, 3H, J )
7.1 Hz), 1.60 (m, 2H), 2.37 (s, 3H), 3.90 (m, 1H), 4.15 (m, 1H),
4.93 (m, 1H), 7.27 (m, 2H), 7.39-7.47 (m, 3H), 8.55 (d, 1H, J )
4.7 Hz), 8.57 (d, 1H, J ) 4.7 Hz), 8.81 (s, 1H), 8.81 (s, 1H). Anal.
Calcd for C15H17NO2S: C, 65.51; H, 6.23; N, 5.09. Found: C,
65.31; H, 6.45; N, 5.07.
(s, 1H). Anal. Calcd for C19H17NO2S: C, 70.65; H, 5.30; N, 4.34.
Found: C, 70.92; H, 5.51; N, 4.03.
(S)-4-(1-Hyd r oxyeth yl)-2,6-d im eth oxy-3-(p-tolylsu lfin yl)-
p yr id in e (20a ). Metalation of (S)-2,6-dimethoxy-3-(p-tolylsulfin-
yl)pyridine 12a (0.10 g, 0.4 mmol) according to the general
procedure with n-butyllithium 2.5 M (0.72 mL, 1.1 mmol) and
diisopropylamine (0.15 mL, 1.1 mmol), t1 ) 90 min, followed by
reaction with acetaldehyde (1.00 mL, 18.0 mmol), t2 ) 30 min,
was carried out. Purification by column chromatography eluting
with ethyl acetate/light petroleum ether (1/1) afforded 20a as a
yellow oil (75%, 87.3 mg); de ) 38%. IR (KBr) 3360, 2925, 1060,
1012 cm-1 1H NMR (200 MHz, CDCl3) δ 1.30 (d, 3H, J ) 6.1
;
Hz), 1.50 (d, 3H, J ) 6.4 Hz), 2.38 (s, 6H), 3.80 (s, 3H), 3.91 (s,
3H), 3.95.(s, 3H), 3.99 (s, 3H), 4.00 (m, 1H), 5.08 (m, 2H), 5.48
(q, 1H, J ) 6.4 Hz), 6.48 (s, 1H), 6.58 (s, 1H), 7.23 (d, 2H, J )
8.1 Hz), 7.25 (d, 2H, J ) 8.1 Hz), 7.25 (d, 2H, J ) 8.2 Hz), 7.47
(d, 2H, J ) 8.2 Hz). Anal. Calcd for C16H19NO4S: C, 59.87; H,
5.97; N, 4.36; S, 9.99. Found: C, 60.02; H, 6.11; N,4.27; S, 10.20.
(S)-4-(1-Hydr oxypr opyl)-2,6-dim eth oxy-3-(p-tolylsu lfin yl)-
p yr id in e (21a ). Metalation of (S)-2,6-dimethoxy-3-(p-tolylsulfin-
yl)pyridine 12a (0.10 g, 0.4 mmol) according to the general
procedure with n-butyllithium 2.5 M (0.72 mL, 1.1 mmol) and
diisopropylamine (0.15 mL, 1.1 mmol), t1 ) 90 min, followed by
reaction with propionaldehyde (0.04 mL, 0.6 mmol), t2 ) 60 min,
was carried out. Purification by column chromatography eluting
with ethyl acetate/light petroleum ether (1/1) afforded 21a as a
yellow oil (53%, 63.7 mg); de ) 28%. IR (KBr) 3362, 2925, 1060
cm-1 1H NMR (200 MHz, CDCl3) δ 0.78 (t, 3H, J ) 4.9 Hz),
;
1.00 (t, 3H, J ) 4.9 Hz), 1.53-1.73 (m, 2H), 1.71-1.78 (m, 2H),
2.37 (s, 3H), 2.38 (s, 3H), 3.78 (s, 3H), 3.90 (s, 3H), 3.93 (s, 3H),
3.95 (s, 3H), 4.00 (m, 1H), 4.67 (m, 1H), 4.87 (m, 1H), 5.21 (m,
1H), 6.45 (s, 1H), 6.54 (s, 1H), 7.23 (d, 2H, J ) 8.1 Hz, Htol),
7.24 (d, 2H, J ) 8.2 Hz), 7.41 (d, 2H, J ) 8.2 Hz), 7.47 (d, 2H,
J ) 8.2 Hz). Anal. Calcd for C17H21NO4S: C, 60.95; H, 6.32; N,
4.18. Found: C, 61.34; H, 6.54; N, 4.14.
(S)-4-(1-H yd r oxy-2-m et h ylp r op yl)-2,6-d im et h oxy-3-(p -
tolylsu lfin yl)p yr id in e (22a ). Metalation of (S)-2,6-dimethoxy-
3-(p-tolylsulfinyl)pyridine 12a (0.10 g, 0.4 mmol) according to
the general procedure with n-butyllithium 2.5 M (0.72 mL, 1.1
mmol) and diisopropylamine (0.15 mL, 1.1 mmol), t1 ) 90 min,
followed by reaction with 2,2-dimethylpropanal (0.06 mL, 0.6
mmol), t2 ) 60 min, was carried out. Purification by column
chromatography eluting with ethyl acetate/light petroleum ether
(1/1) afforded 22a as a pale yellow solid (58%, 75.4 mg); mp 110
°C dec; de > 99%. IR (KBr) 3250, 2935, 1064, 1015 cm-1 1H
;
NMR (200 MHz, CDCl3) δ 0.97 (s, 9H), 2.33 (s, 3H), 3.70-3.80
(m, 1H), 3.71 (s, 3H), 3.86 (s, 3H), 5.27 (m, 1H), 6.54 (s, 1H),
7.14 (d, 2H), 7.39 (d, 2H). Anal. Calcd for C19H25NO4S: C, 62.87;
H, 6.94; N, 3.86; S, 8.83. Found: C, 63.01; H, 6.97; N, 3.74; S,
9.10.
(S)-4-(1-Hyd r oxy-2-m eth ylp r op yl)-3-(p-tolylsu lfin yl)p yr -
id in e (18a ). Metalation of (S)-3-(p-tolylsulfinyl)pyridine 9a (0.06
g, 0.3 mmol) according to the general procedure with n-
butyllithium 1.6 M (0.58 mL, 0.9 mmol) and diisopropylamine
(0.12 mL, 0.9 mmol), t1 ) 60 min, followed by reaction with 2,2-
dimethympropanal (0.05 mL, 0.4 mmol), t2 ) 60 min, was carried
out. Purification by column chromatography eluting with ethyl
acetate afforded 18a as a pale yellow solid (25%, 24.8 mg); mp:
(S)-4-(r-Hydr oxyben zyl)-2,6-dim eth oxy-3-(p-tolylsu lfin yl)-
p yr id in e (23a ). Metalation of (S)-2,6-dimethoxy-3-(p-tolylsulfin-
yl)pyridine 12a (0.10 g, 0.4 mmol) according to the general
procedure with n-butyllithium 2.5 M (0.72 mL, 1.1 mmol) and
diisopropylamine (0.15 mL, 1.1 mmol), t1 ) 90 min, followed by
reaction with benzaldehyde (0.04 mL, 0.6 mmol), t2 ) 60 min,
was carried out. Purification by column chromatography eluting
with ethyl acetate/light petroleum ether (1/1) afforded 23a as a
pale yellow solid (60%, 81.6 mg); mp 134 °C; de > 99%. IR (KBr)
3250, 2935, 1064, 1015 cm-1; 1H NMR (200 MHz, CDCl3) δ 2.41
(s, 3H), 3.88 (s, 3H), 4.02 (s, 3H), 5.42 (m, 1H), 5.90 (s, 1H), 6.11
(s, 1H), 7.03-7.08 (m, 2H), 7.23-7.30 (m, 5H), 7.51 (d, 2H, J )
8.2 Hz). Anal. Calcd for C21H21NO4S: C, 65.80; H, 5.53; N, 3.66.
Found: C, 65.74; H, 5.66; N, 3.65.
158 °C; de > 99%. IR (KBr) 3171, 2919, 1046 cm-1 1H NMR
;
(200 MHz, CDCl3) δ 0.89 (t, 3H, J ) 7.1 Hz), 1.60 (m, 2H), 2.37
(s, 3H), 3.90 (m, 1H), 4.15 (m, 1H), 4.93 (m, 1H), 7.27 (m, 2H),
7.39-7.47 (m, 3H), 8.55 (d, 1H, J ) 4.7 Hz), 8.57 (d, 1H, J ) 4.7
Hz), 8.81 (s, 1H), 8.81 (s, 1H). Anal. Calcd for C17H21NO2S: C,
67.39; H, 6.98; N, 4.62. Found: C, 67.12; H, 7.10; N, 4.47.
(S)-4-(r-Hydr oxyben zyl)-3-(p-tolylsu lfin yl)pyr idin e (19a).
Metalation of (S)-3-(p-tolylsulfinyl)pyridine 9a (0.10 g, 0.5 mmol)
according to the general procedure with n-butyllithium 2.5 M
(0.74 mL, 1.5 mmol) and diisopropylamine (0.26 mL, 1.5 mmol),
t1 ) 60 min, followed by reaction with benzaldehyde (0.10 mL,
0.7 mmol), t2 ) 60 min, was carried out. Purification by column
chromatography eluting with ethyl acetate afforded 19a as a
beige solid (13%,18.1 mg); mp 158 °C; de > 99%. IR (KBr) 3171,
2919, 1046 cm-1; 1H NMR (200 MHz, CDCl3) δ 2.41 (s, 3H), 4.20
(m, 1H), 6.11 (s, 1H), 7.10 (d, 2H, J ) 8.0 Hz),7.20 (m, 2H), 7.32
(m, 3H), 7.50 (d, 2H, J ) 8.0 Hz), 8.60 (d, 1H, J ) 4.6 Hz), 8.96
Su p p or tin g In for m a tion Ava ila ble: Purification of ma-
terials and data for 3b, 6b, 9b, 12b, 13b, 14b, 15b, 16b, 17b,
18b, 19b, 20b, 21b, 22b, 23b. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O981125D