Synthesis of 2-(arylsulfonyl)-4-hydroxypyridines by Hetero-Diels-Alder reaction of 1,3-bis-silyl enol ethers with arylsulfonyl cyanides

Article abstract of DOI:10.1055/s-2006-942446

2-(Arylsulfonyl)-4-hydroxypyridines were prepared by Hetero-Diels-Alder reaction of 1,3-bis(trimethylsiloxy)buta-1,3-dienes (1,3-bis-silyl enol ethers) with arylsulfonyl cyanides. The products were transformed into 4-aryl-2-(arylsulfonyl)pyridines by Suzu

Full text of DOI:10.1055/s-2006-942446

PAPER
2551
Synthesis of 2-(Arylsulfonyl)-4-hydroxypyridines by Hetero-Diels–Alder
Reaction of 1,3-Bis-Silyl Enol Ethers with Arylsulfonyl Cyanides
2
-(Arylsulfonyl
h
)pyridines by
o
Hetero-Die
m
ls–Alder Reaction as Emmrich,a Helmut Reinke,b Peter Langer*b,c
a
Institut für Biochemie, Universität Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
b
c
Leibniz-Institut für Katalyse e. V., Universität Rostock , Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 2 February 2006; revised 20 March 2006
the reaction, it was shown to be important to perform the
reaction at –78 °C without the use of a solvent and to
quench the reaction by the addition of aqueous 1 M am-
monium chloride solution. No product could be isolated
Abstract: 2-(Arylsulfonyl)-4-hydroxypyridines were prepared by
Hetero-Diels–Alder reaction of 1,3-bis(trimethylsiloxy)buta-1,3-
dienes (1,3-bis-silyl enol ethers) with arylsulfonyl cyanides. The
products were transformed into 4-aryl-2-(arylsulfonyl)pyridines by
Suzuki cross-coupling reactions of the corresponding enol triflates. when the reaction was carried out at elevated temperatures
(110 °C). This can be explained by thermal O → C 1,5-si-
lyl shift of the 1,3-bis-silyl enol ether to give a 3-siloxy-4-
silylcrotonate.11 The cyclization of 1,3-bis-silyl enol
ethers 1a–f with arylsulfonyl cyanides 2a,b afforded 2-
(arylsulfonyl)-4-hydroxypyridines 3a–h. The reaction of
2a with 1,3-bis-silyl enol ethers containing a substituent
located at C4 was unsuccessful, presumably for steric rea-
sons. Likewise, the reaction of 1,3-bis-silyl enol ether 1g
(Scheme 2), containing a substituent located at C2, was
unsuccessful. This can be explained by the fact that the es-
ter derived 2-substituted 1,3-bis-silyl enol ethers undergo
a O → C 1,5-silyl shift even at ambient temperature. Em-
ployment of ethyl cyanoformate rather than 2a also
proved to be unsuccessful, due to its insufficient reactivi-
ty; decomposition was observed under forcing conditions
(neat, 120 °C).
Key words: 1,3-bis-silyl enol ethers, hetero-Diels–Alder, arylsul-
fonyl cyanide, pyridine
Hetero-Diels–Alder reactions allow the efficient synthesis
of heterocyclic frameworks. The hetero-Diels–Alder re-
action of aldehydes with Danishefsky’s diene or related
silyl enol ethers has been widely used for the synthesis of
pyran derivatives.1 In contrast, hetero-Diels–Alder reac-
tions of nitriles are relatively rare, due to the low reactiv-
ity of nitriles as hetero-dienophiles.2 Some years ago,
Breitmaier and Rüffer reported3 an efficient synthesis of
functionalized pyridines by cyclization of buta-1,3-
dienes, including 2-(siloxy)buta-1,3-dienes, with highly
reactive tosyl cyanide.4 Pyridines have also been prepared
by cyclization of pyran-2-ones with tosyl cyanide with ex-
trusion of carbon dioxide.5 The 1,3-dipolar cycloaddition
of diazomethane with tosyl cyanide has been reported to
give 1,2,3-triazines.6 Recently, the synthesis of 1-azabicy-
clo[2.2.2]oct-1-enes by cyclization of 2-(siloxy)cyclo-
hexa-1,3-dienes with tosyl cyanide has been reported.7
Herein, we report, based on the work of Breitmaier,3 the
hetero-Diels–Alder reaction of 1,3-bis(trimethylsil-
oxy)buta-1,3-dienes (1,3-bis-silyl enol ethers)8 with tosyl
cyanide. These reactions allow the convenient synthesis
of 2-(arylsulfonyl)-4-hydroxypyridines, which were
transformed into 4-aryl-2-(arylsulfonyl)pyridines by Su-
zuki reactions of the corresponding enol triflates. It should
be noted that 2-(arylsulfonyl)pyridines are of consider-
able pharmacological importance.9 The synthesis of 2-(ar-
ylsulfonyl)-4-hydroxypyridines has seldom been
reported.3,5
Me3SiO
OSiMe3
R1
OH
N
R2
1a–f
+
1. –78 °C to r.t., neat
2. aq 1 M NH4Cl
R2
S
R1
O
O
SO2CN
3a–h
2a,b
Scheme 1 Synthesis of 2-(arylsulfonyl)-4-hydroxypyridines 3a–h
The structures of 2-(arylsulfonyl)-4-hydroxypyridines
3a–h were confirmed by spectroscopic methods. The
structures of 3c and 3e were independently confirmed by
crystal structure analyses (Figures 1 and 2).12 Inspection
of the crystal lattice showed that that an intermolecular
hydrogen bond O—H···N was present. The products re-
side in the form of the hydroxypyridine rather than as the
pyridone tautomer.
The reaction of tosyl cyanide (2a) with 1-methoxy-1,3-
bis(trimethylsiloxy)buta-1,3-diene (1a), readily available
from methyl acetoacetate,10 afforded 4-hydroxy-2-to-
sylpyridine 3a in up to 43% yield. During optimization of
The functionalization of 2-(arylsulfonyl)-4-hydroxypy-
ridines by Suzuki cross-coupling reactions was next stud-
ied (Scheme 3, Table 2). Pyridines 3a,c were transformed
into the corresponding enol triflates 5a,b. The Suzuki re-
action of 5a with phenylboronic acid afforded 2-methoxy-
4-phenyl-6-tosylpyridine (6a). The reaction of 5b with
SYNTHESIS 2006, No. 15, pp 2551–2555
x
x.
x
x
.
2
0
0
6
Advanced online publication: 28.06.2006
DOI: 10.1055/s-2006-942446; Art ID: T01906SS
© Georg Thieme Verlag Stuttgart · New York

2552
T. Emmrich et al.
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Table 1 Synthesis of 2-(Arylsulfonyl)-4-hydroxypyridines 3a–h
Substrates
1a + 2a
1b + 2a
1c + 2a
1d + 2a
1e + 2a
1a + 2b
1b + 2b
1f + 2a
Product
3a
R1
R2
Temp (°C)
–78 to r.t.
–78 to r.t.
0 to r.t.
Timea (h)
Yieldb (%)
OMe
Me
Me
Me
Me
Me
H
24
2.5
96
48
24
24
24
28
43
30
30
33
12
10
38
31
3b
OEt
3c
CH2OMe
Me
3d
r.t.
3e
O(CH2)2OMe
OMe
–78 to r.t.
–78 to r.t.
–78 to r.t.
–78 to r.t.
3f
3g
OEt
H
3h
Oi-Pr
Me
a Reaction time after warming to r.t.
b Yield of isolated product.
Me3SiO
Me3SiO
OTf
OSiMe3
OH
Me3SiO
O
>80 °C, neat
20 °C, neat
Tf2O, py, CH2Cl2,
–78 °C to r.t.
Me3Si
OMe
OMe
4a
Tol
Tol
1a
S
N
R
S
N
R
O
O
O
O
5a,b
OSiMe3
OMe
Me3SiO
Me3Si
O
3a,c
Ar
ArB(OH)2, Pd(PPh3)4
(3 mol%), K3PO4,
dioxane, reflux
OMe
Me
Me
1g
4b
Tol
S
N
R
Scheme 2 Thermal rearrangement of 1,3-bis-silyl enol ethers
O
O
6a,b
Scheme 3
Figure 1 ORTEP plot of 3c
Synthesis 2006, No. 15, 2551–2555 © Thieme Stuttgart · New York

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2-(Arylsulfonyl)pyridines by Hetero-Diels–Alder Reaction
2553
Figure 2 ORTEP plot of 3e
HRMS (MALDI, DHBA): m/z [M + H]+ calcd for C13H14NO4S+:
280.06381; found: 280.06398.
Table 2 Synthesis of 4-Aryl-2-(arylsulfonyl)pyridines 6a,b
5,6
R
Ar
Yielda (%)
UV/Vis (MeCN): lmax (log e) = 203 (4.4), 232 (4.0), 246 nm (3.9).
5
6
Anal. Calcd for C13H13NO4S: C, 55.90; H, 4.69; N, 5.01. Found: C,
56.21; H, 5.08; N, 4.98.
a
OMe
Ph
87
92
87
94
4-Hydroxy-2-ethoxy-6-tosylpyridine (3b)
b
CH2OMe
3,4-(MeO)2C6H3
Compound 1b (756 mg, 2.76 mmol) was added to 2a (200 mg, 1.10
mmol) at –78 °C. The mixture was allowed to warm to r.t. over 1 h
and then stirred at this temperature for 2.5 h. Product 3b was isolat-
ed by chromatography (silica gel, n-hexane–EtOAc, 3:1) as a color-
less solid; yield: 95 mg (30%); mp 123 °C.
a Yield of isolated product.
3,4-dimethoxyphenylboronic acid gave 4-(3,4-dimeth-
oxyphenyl)-2-(methoxymethyl)-6-tosylpyridine (6b).
IR (KBr): 3610 (w), 3544 (w), 3394 (w), 3090 (m), 3049 (m), 2986
(m), 2930 (m), 2897 (m), 2795 (w), 2736 (w), 2671 (w), 2606 (w),
2552 (w), 2508 (w), 1606 (s), 1554 (s), 1490 cm–1 (m).
2-(Arylsulfonyl)-4-hydroxypyridines 3a–h; General Procedure
To the arylsulfonyl cyanide 2a,b (1.0 equiv) was added dropwise
the 1,3-bis-silyl enol ether 1a–f (2.0–2.5 equiv) at the temperature
given. The mixture was allowed to warm to r.t. and was stirred until
the arylsulfonyl cyanide was no longer detected by TLC. To the
mixture was added aq 1 M NH4Cl (30 mL) and CH2Cl2 (30 mL).
The organic and aqueous layers were separated and the aqueous lay-
er was extracted with CH2Cl2 (30 mL). The combined organic lay-
ers were dried (Na2SO4) and filtered and the solvent was
concentrated under reduced pressure. The residue was purified by
column chromatography (silica gel, hexanes–EtOAc).
3
1H NMR (300 MHz, acetone-d6): d = 1.23 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 2.42 (s, 3 H, Ar-CH3), 4.23 (q, 3J = 7.0 Hz, 2 H,
OCH2CH3), 6.26 (d, 4J = 1.9 Hz, 1 H, Py), 7.28 (d, 4J = 1.9 Hz, 1 H,
Py), 7.44 (d, J = 8.4 Hz, 2 H, Ar), 7.92 (d, J = 8.4 Hz, 2 H, Ar),
3
3
10.26 (s, 1 H, OH).
13C NMR (75 MHz, acetone-d6): d = 15.3 (OCH2CH3), 22.2 (Ar-
CH3), 63.7 (OCH2CH3), 100.4, 106.6 (CH, Py), 130.4, 131.1 (CH,
Ar), 138.1, 146.2 (C, Ar), 159.1, 167.1, 168.6 (C, Pyr).
MS (CI, isobutane): m/z (%) = 294 (100) [M + 1]+.
HRMS (MALDI, DHBA): m/z [M + H]+ calcd for C14H16NO4S+:
294.07946; found: 294.07968.
4-Hydroxy-2-methoxy-6-tosylpyridine (3a)
Compound 1a (574 mg, 2.21 mmol) was added to 2a (200 mg, 1.10
mmol) at –78 °C. The mixture was allowed to warm r.t. over 30 min
and then stirred at this temperature for 24 h. Product 3a was isolated
by chromatography (silica gel, n-hexane–EtOAc, 3:1) as a colorless
solid; yield: 132 mg (43%); mp 126 °C.
UV/Vis (MeCN): lmax (log e) = 267 (3.6), 248 (3.8), 232 (3.9), 202
nm (4.3).
4-Hydroxy-2-(methoxymethyl)-6-tosylpyridine (3c)
Compound 1c (945 mg, 3.45 mmol) was added to 2a (250 mg, 1.38
mmol) at 0 °C. The mixture was warmed to r.t. and then stirred at
this temperature for 4 d. Product 3c was isolated by chromatography
(silica gel, n-hexane–EtOAc, 4:1) as a colorless solid; yield: 120 mg
(30%); mp 137 °C.
IR (KBr): 3357 (w), 3090 (w), 3066 (w), 3024 (w), 2959 (w), 2919
(w), 2856 (w), 2794 (w), 2715 (w), 2685 (w), 2626 (w), 2581 (w),
2521 (w), 1611 (s), 1562 (s), 1475 (s), 1436 cm–1 (s).
1H NMR (300 MHz, acetone-d6): d = 2.41 (s, 3 H, Ar-CH3), 3.79 (s,
3 H, OCH3), 6.29 (d, 4J = 1.9 Hz, 1 H, Py), 7.31 (d, 4J = 1.9 Hz, 1
H, Py), 7.43 (d, 3J = 8.4 Hz, 2 H, Ar), 7.94 (d, 3J = 8.4 Hz, 2 H, Ar),
10.28 (s, 1 H, OH).
13C NMR (75 MHz, acetone-d6): d = 22.2 (Ar-CH3), 54.8 (OCH3),
100.2, 106.9 (CH, Py), 130.4, 131.1 (CH, Ar), 138.0, 146.2 (C, Ar),
158.9, 167.5, 168.7 (C, Py).
IR (KBr): 3427 (s), 3097 (w), 3071 (w), 3067 (w), 2991 (w), 2931
(w), 2830 (w), 1602 (s), 1442 cm–1 (m).
1H NMR (300 MHz, acetone-d6): d = 2.41 (s, 3 H, Ar-CH3), 3.37 (s,
3 H, OCH3), 4.39 (s, 2 H, PyCH2OCH3), 7.06 (d, 4J = 2.3 Hz, 1 H,
3
Py), 7.42 (d, J = 8.5 Hz, 2 H, Ar), 7.54 (d, 4J = 2.3 Hz, 1 H, Py),
7.89 (d, 3J = 8.5 Hz, 2 H, Ar), 10.32 (s, 1 H, OH).
13C NMR (75 MHz, acetone-d6): d = 21.5 (Ar-CH3), 58.8 (OCH3),
75.0 (PyrCH2OCH3), 109.3, 111.7 (CH, Py), 129.7, 130.5 (CH, Ar),
137.6, 145.6 (C, Ar), 160.8, 163.0, 167.0 (C, Py).
MS (CI, isobutane): m/z (%) = 280 (100) [M + 1]+.
Synthesis 2006, No. 15, 2551–2555 © Thieme Stuttgart · New York

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T. Emmrich et al.
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MS (CI, isobutane): m/z (%) = 294 (100) [M + 1]+.
13C NMR (75 MHz, acetone-d6): d = 54.2 (OCH3), 99.7, 106.4 (CH,
Py), 129.8, 129.9 (CH, Ar), 134.6 (CH, Ar), 140.3 (C, Ar), 158.1,
166.9, 168.0 (C, Py).
UV/Vis (MeCN): lmax (log e) = 245 (4.0), 228 (4.1), 203 nm (4.5).
Anal. Calcd for C14H15NO4S: C, 57.32; H, 5.15; N, 4.77. Found: C,
57.42; H, 5.17; N, 5.01.
MS (CI, isobutane): m/z (%) = 266 (100) [M + 1]+.
UV/Vis (MeCN): lmax (log e) = 273 (3.6), 267 (3.6), 243 nm (3.7).
4-Hydroxy-2-methyl-6-tosylpyridine (3d)
Anal. Calcd for C12H11NO4S: C, 54.33; H, 4.18; N, 5.28. Found: C,
54.59; H, 4.03; N, 5.10.
Compound 1d (671 mg, 2.75 mmol) was added to 2a (265 mg, 1.46
mmol) at r.t. The mixture was stirred for 48 h at this temperature.
Product 3d was isolated by chromatography (silica gel, n-hexane–
EtOAc, 3:1) as a colorless solid; yield: 127 mg (33%); mp 140 °C
(dec).
2-Ethoxy-4-hydroxy-6-(phenylsulfonyl)pyridine (3g)
The compound 1b (327 mg, 1.20 mmol) in the presence of hydro-
quinone (0.5 mol%) was added to 2b (100 mg, 0.6 mmol) at –78 °C.
The mixture was allowed to warm to r.t. over 1 h and then stirred at
this temperature for 24 h. Product 3g was isolated by chromatogra-
phy (silica gel, n-hexane–EtOAc, 2:1) as a yellow-tinged solid;
yield: 64 mg (38%); mp 114 °C; the product was contaminated with
hydroquinone which could not be completely removed.
IR (KBr): 3098 (w), 3065 (w), 3027 (w), 2959 (w), 2928 (w), 2872
(w), 1609 (s), 1550 (s), 1458 cm–1 (s).
1H NMR (300 MHz, acetone-d6): d = 2.37, 2.41 (s, 2 × 3 H, Ar-CH3,
4
Py-CH3), 6.85 (d, J = 2.1 Hz, 1 H, Py), 7.42 (d, 3J = 8.1 Hz, 2 H,
4
3
Ar), 7.47 (d, J = 2.1 Hz, 1 H, Py), 7.89 (d, J = 8.1 Hz, 2 H, Ar),
10.15 (s, 1 H, OH).
IR (KBr): 3327 (w), 3238 (w), 3090 (w), 3064 (w), 3043 (w), 3034
(w), 2987 (w), 2926 (m), 2863 (w), 2689 (w), 2615 (w), 1608 (s),
1560 (m), 1510 (w), 1460 cm–1 (s).
13C NMR (75 MHz, acetone-d6): d = 22.1 (Ar-CH3), 24.8 (Py-CH3),
108.8, 114.7 (CH, Py), 130.4, 131.1 (CH, Ar), 138.4, 146.1 (C, Ar),
161.5, 163.0, 167.1 (C, Py).
MS (CI, isobutane): m/z (%) = 264 (100) [M + 1]+.
HRMS (MALDI, DHBA): m/z [M + H]+ calcd for C13H14NO3S+:
3
1H NMR (300 MHz, acetone-d6): d = 1.21 (t, J = 7.0 Hz, 3 H,
OCH2CH3), 4.22 (q, 3J = 7.0 Hz, 2 H, OCH2CH3), 6.27 (d, 4J = 1.9
Hz, 1 H, Py), 7.30 (d, 4J = 1.9 Hz, 1 H, Py), 7.61–7.73 (m, 3 H, Ar),
8.03–8.07 (m, 2 H, Ar), 10.19 (s, 1 H, OH).
264.06889; found: 264.06897.
13C NMR (75 MHz, acetone-d6): d = 15.2 (OCH2CH3), 63.7
(OCH2CH3), 100.5, 106.6 (CH, Py), 130.4, 130.6 (CH, Ar), 135.2
(CH, Ar), 141.0 (C, Ar), 158.8, 167.2, 168.5 (C, Py).
UV/Vis (MeCN): lmax (log e) = 238 (4.0), 228 (4.1), 203 nm (4.5).
Anal. Calcd for C13H13NO3S: C, 59.30; H, 4.98; N, 5.32. Found: C,
59.92; H, 5.68; N, 5.47.
MS (EI, 70 eV): m/z (%) = 279 (5) [M+], 264 (100) [M – CH3]+, 251
(38) [M – C2H4]+, 235 (30) [M – C2H5O]+.
4-Hydroxy-2-(2-methoxyethoxy)-6-tosylpyridine (3e)
HRMS (MALDI, DHBA): m/z [M + H]+ calcd for C13H14NO4S+:
280.06381; found: 280.06396.
Compound 1e (1.25 g, 4.13 mmol) was added to 2a (300 mg, 1.65
mmol) at –78 °C. The mixture was allowed to warm up to r.t. over
1.5 h and then stirred at this temperature for 24 h. Product 3e was
isolated by chromatography (silica gel, n-hexane–EtOAc, 3:1) as a
colorless solid; yield: 63 mg (12%); mp 105 °C.
UV/Vis (MeCN): lmax (log e) = 274.04 (3.5), 267.68 (3.5), 223.43
nm (3.9).
4-Hydroxy-2-isopropoxy-6-tosylpyridine (3h)
IR (KBr): 3512 (w), 3333 (m), 3178 (w), 3146 (w), 3098 (w), 2975
(m), 2930 (m), 1605 (s), 1567 (m), 1441 cm–1 (s).
Compound 1f (795 mg, 2.76 mmol) was added to 2a (200 mg, 1.10
mmol) at –78 °C. The mixture was allowed to warm up to r.t. over
1 h and then stirred at this temperature for 28 h. Product 3h was iso-
lated by column chromatography (n-hexane–EtOAc, 3:1) as a yel-
low highly viscous oil; yield: 106 mg (31%); the product was
contaminated with isopropyl acetoacetate which could not be com-
pletely removed.
1H NMR (300 MHz, acetone-d6): d = 2.41 (s, 3 H, Ar-CH3), 3.27 (s,
3
3 H, OCH3), 3.57 (t, J = 4.6 Hz, 2 H, OCH2CH2OCH3), 4.32 (t,
3J = 4.6 Hz, 2 H, OCH2CH2OCH3), 6.31 (d, 4J = 2.0 Hz, 1 H, Py),
7.31 (d, 4J = 2.0 Hz, 1 H, Py), 7.44 (d, 3J = 8.2 Hz, 2 H, Ar), 7.50 (d,
3J = 8.2 Hz, 2 H, Ar), 10.33 (s, 1 H, OH).
13C NMR (75 MHz, acetone-d6): d = 22.1 (Ar-CH3), 59.3 (OCH3),
67.1, 71.7 (OCH2CH2OCH3, OCH2CH2OCH3), 100.4, 106.8 (CH,
Py), 130.4, 131.1 (CH, Ar), 137.9, 146.2 (C, Ar), 158.9, 167.0,
168.7 (C, Py).
1H NMR (300 MHz, acetone-d6): d = 1.19 and 1.24 [d, 3J = 6.3 Hz,
6 H, OCH(CH3)2], 2.42 (s, 3 H, Ar-CH3), 5.00–5.12 [m, 1 H,
OCH(CH3)2], 6.21 (d, 4J = 2.0 Hz, 1 H, Py), 7.25 (d, 4J = 2.0 Hz, 1
H, Py), 7.44 (d, 3J = 8.1 Hz, 2 H, Ar), 7.91 (d, 3J = 8.1 Hz, 2 H, Ar),
10.30 (s, 1 H, OH).
MS (CI, isobutane): m/z (%) = 324 (100) [M + 1]+.
13C NMR (75 MHz, acetone-d6): d = 21.8, 21.9 (3 × CH3), 70.7
[OCH(CH3)2], 100.1, 105.5 (CH, Py), 129.8, 130.4 (CH, Ar), 137.4,
145.5 (C, Ar), 158.4, 166.0, 168.0 (C, Py).
UV/Vis (MeCN): lmax (log e) = 246 (3.9), 231 (4.0), 204 nm (4.4).
Anal. Calcd for C15H17NO5S (323.08): C, 55.71; H, 5.30; N, 4.33.
Found: C, 55.99; H, 5.31; N, 4.67.
2-Methoxy-6-tosyl-4-[(trifluoromethylsulfonyl)oxy]pyridine
(5a); Typical Procedure
4-Hydroxy-2-methoxy-6-(phenylsulfonyl)pyridine (3f)
Compound 1a (466 mg, 1.80 mmol) was added to 2b (150 mg, 0.90
mmol) at –78 °C. The mixture was allowed to warm to r.t. over 30
min and then stirred at this temperature for 24 h. Product 3f was iso-
lated by chromatography (silica gel, n-hexane–EtOAc, 5:1) as a col-
orless solid; yield: 24 mg (10%); mp 140 °C.
To a soln of 3a (123 mg, 0.44 mmol) and pyridine (70 mg, 0.88
mmol) in CH2Cl2 (10 mL) was added Tf2O (0.11 mL, 0.66 mmol) at
–78 °C. The mixture was allowed to warm up to r.t. over 4 h and
then stirred at this temperature for 1 h. The mixture was directly pu-
rified by chromatography (CH2Cl2) to give 5a as a colorless oil that
crystallized upon standing overnight at –20 °C; yield: 156 mg
(87%).
1H NMR (300 MHz, CDCl3): d = 2.45 (s, 3 H, Ar-CH3), 3.92 (s, 3
H, OCH3), 6.77 (d, 4J = 1.9 Hz, 1 H, Py), 7.36 (d, 3J = 8.5 Hz, 2 H,
Ar), 7.68 (d, 4J = 1.9 Hz, 1 H, Py), 7.96 (d, 3J = 8.5 Hz, 2 H, Ar).
IR (KBr): 3441 (w), 3271 (w), 3267 (w), 3259 (w), 3252 (w), 3092
(w), 3065 (m), 3015 (w), 2956 (m), 2924 (m), 2853 (m), 2797 (w),
2682 (m), 2628 (m), 2582 (w), 2522 (w), 2479 (w), 1613 (s), 1556
(s), 1472 (s), 1435 cm–1 (s).
1H NMR (300 MHz, acetone-d6): d = 3.78 (s, 3 H, OCH3), 6.29 (d,
J = 1.9 Hz, 1 H, Py), 7.32 (d, J = 1.9 Hz, 1 H, Py), 7.62–7.73 (m, 3
H, Ar), 8.05–8.08 (m, 2 H, Ar), 10.33 (s, 1 H, OH).
Synthesis 2006, No. 15, 2551–2555 © Thieme Stuttgart · New York

PAPER
2-(Arylsulfonyl)pyridines by Hetero-Diels–Alder Reaction
2555
13C NMR (75 MHz, CDCl3): d = 21.7 (CH3-Ar), 55.0 (OCH3),
117.9, 120.2, 120.9 (CH, Ar, Py), 128.9 (CH, Ar), 129.3 (C, Ar),
129.6 (CH, Ar), 136.1, 144.6, 149.6 150.8, 151.0, 158.6, 160.7 (C,
Py, Ar).
MS (EI, 70 eV): m/z (%) = 413 (20) [M+], 383 (100), 334 (35).
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107.1, 108.4 (CH, Py), 118.5 (q, JC–F = 319.1 Hz, OSO2CF3),
129.3, 129.8 (CH, Ar), 134.7, 145.5 (C, Ar), 157.9, 158.7, 165.8 (C,
Py).
HRMS (EI): m/z [M]+ calcd for C22H23NO5S: 413.1291; found:
413.1298.
2-(Methoxymethyl)-6-tosyl-4-[(trifluoromethylsulfonyl)oxy]py-
ridine (5b)
The reaction was carried out following the procedure as given for
the synthesis of 5a. Starting with 3c (70 mg, 0.24 mmol), Tf2O (0.06
mL, 0.36 mmol), and pyridine (38 mg, 0.48 mmol) in CH2Cl2 (7
mL), 5b was isolated as a colorless oil that crystallized upon stand-
ing overnight at –20 °C; yield: 93 mg (92%).
UV/Vis (MeCN): lmax (log e) = 314 (3.9), 283 (3.8), 237 nm (4.2).
Fluorescence (MeCN): Flmax (lEx): 442 nm (318).
Anal. Calcd for C22H23NO5S: C, 63.90; H, 5.61. Found: C, 64.08; H,
6.31.
1H NMR (300 MHz, CDCl3): d = 2.44 (s, 3 H Ar-CH3), 3.47 (s, 3 H,
OCH3), 4.59 (s, 2 H, Py-CH2OCH3), 7.35 (d, 3J = 8.7 Hz, 2 H, Ar),
7.54 (d, 4J = 2.3 Hz, 1 H, Py), 7.94 (d, 3J = 8.7 Hz, 2 H, Ar), 7.97 (d,
4J = 2.3 Hz, 1 H, Py).
13C NMR (75 MHz, CDCl3): d = 21.7 (CH3-Ar), 59.0 (OCH3), 73.8
(Py-CH2OCH3), 113.3, 116.2 (CH, Py), 118.5 (q, 1JC–F = 318.8 Hz,
OSO2CF3), 129.2, 129.9 (CH, Ar), 134.8, 145.5 (C, Ar), 157.7,
161.1, 164.7 (C, Py).
Acknowledgement
Financial support from the state of Mecklenburg-Vorpommern
(Landesforschungsschwerpunkt ‘Neue Wirkstoffe und Screening-
verfahren’) is gratefully acknowledged.
References
2-Methoxy-4-phenyl-6-tosylpyridine (6a); Typical Procedure
To a soln of 5a (60 mg, 0.145 mmol), K3PO4 (60 mg, 0.28 mmol),
and Pd(PPh3)4 (5 mg, 4.4 mmol) in dioxane (1 mL) under an inert at-
mosphere was added a soln of phenylboronic acid (24 mg, 0.20
mmol) in dioxane (5 mL). The mixture was heated under reflux for
5 h. The mixture was allowed to cool and CH2Cl2 (100 mL) and sat.
aq NH4Cl (100 mL) were added. The organic and the aqueous layer
were separated and the aqueous layer was extracted with CH2Cl2.
The combined organic layers were dried (Na2SO4) and filtered and
the filtrate was concentrated in vacuo. The residue was purified by
chromatography (n-hexane–EtOAc, 3:1 to 0:1) to give 6a as a slight
brownish, highly viscous oil; yield: 43 mg (87%).
(1) (a) Boger, D. L.; Weinreb, S. M. Hetero-Diels–Alder
Methodology in Organic Synthesis; Academic Press: San
Diego CA, 1987. (b) Tietze, L. F.; Schneider, C. J. Org.
Chem. 1991, 56, 2476.
(2) For cycloaddition reactions of nitriles, see: Collier, S.;
Langer, P. In Science of Synthesis; Shinkai, I.; Murahashi,
S., Eds.; Thieme: Stuttgart, 2004, Chap. 19.5.15.
(3) Breitmaier, E.; Rüffer, U. Synthesis 1989, 623.
(4) Sulfonyl cyanides have been used as electrophilic cyanation
reagents, see: (a) Christophersen, C.; Begrup, M.; Ebdrup,
S.; Petersen, H.; Vedsoe, P. J. Org. Chem. 2003, 68, 9513.
(b) Boymond, L.; Rottlaender, M.; Cahiez, G.; Knochel, P.
Angew. Chem. Int. Ed. 1998, 37, 1701. (c) Jensen, T.;
Teiler, J.; Waernmark, K. J. Org. Chem. 2002, 67, 6008.
(5) Wang, T.; Hendrickson, J. Org. Prep. Proced. Int. 2003, 35,
623.
IR (KBr): 3419 (w), 2977 (w), 2933 (w), 1653 (w), 1604 (s), 1540
(m), 1462 cm–1 (s).
1H NMR (300 MHz, CDCl3): d = 2.43 (s, 3 H, Ar-CH3), 3.91 (s, 3
H, OCH3), 7.04 (d, 4J = 1.3 Hz, 1 H, Py), 7.34 (d, 3J = 8.1 Hz, 2 H,
Ar), 7.42–7.54 (m, 3 H, Ar, Py), 7.58–7.68 (m, 2 H, Ar), 7.98–8.02
(m, 3 H, Ar).
13C NMR (75 MHz, CDCl3): d = 21.6 (Ar-CH3), 54.1 (OCH3),
112.2, 113.5 (CH, Py), 127.0, 129.1, 129.2, 129.5, 129.8 (C, Ar),
135.9, 136.7, 144.6 (C, Ar), 152.7, 156.4, 164.8 (C, Py).
(6) van Leusen, A. M.; Jagt, J. C. .
(7) McClure, C. K.; Link, J. S. J. Org. Chem. 2003, 68, 8256.
(8) For a review of 1,3-bis-silyl enol ethers, see: Langer, P.
Synthesis 2002, 441.
(9) (a) Hirokawa, Y.; Horikawa, T.; Kato, S. Chem. Pharm.
Bull. 2000, 48, 1847. (b) Cutshall, N. S.; Ursino, R.; Kucera,
K. A.; Latham, J.; Ihle, N. C. Bioorg. Med. Chem. Lett. 2001,
14, 1951. (c) Bonnet, V.; Mongin, F.; Trecourt, F.;
Queguiner, G.; Knochel, P. Tetrahedron 2002, 58, 4429.
(d) Ohnmacht, C. J.; Russell, K.; Empfield, J. R.; Frank, C.
A.; Gibson, K. H. J. Med. Chem. 1996, 39, 4592. (e) Yogi,
S.; Hokama, K.; Tsuge, O. Bull. Chem. Soc. Jpn. 1987, 60,
335. (f) Reiffenrath, V.; Bremer, M. Angew. Chem., Int. Ed.
Engl. 1994, 33, 1386; Angew. Chem. 1994, 106, 1435.
(g) Furukawa, N.; Tsuruoka, M.; Fujihara, H. Heterocycles
1986, 24, 3337.
UV/Vis (MeCN): lmax (log e) = 242 nm (4.4).
MS (EI, 70 eV): m/z (%) = 339 (3) [M+], 338 (5), 275 (100).
Anal. Calcd for C19H17NO3S: C, 67.24; H, 5.05. Found: C, 67.38; H,
5.35.
4-(3,4-Dimethoxyphenyl)-2-(methoxymethyl)-6-tosylpyridine
(6b)
The reaction was carried out following the procedure as given for
the synthesis of 6a. Starting with 5b (41 mg, 0.096 mmol), 2,3-
dimethoxyphenylboronic acid (23 mg, 0.13 mmol), K3PO4 (33 mg,
0.15 mmol), and Pd(PPh3)4 (3 mg, 2.9 mmol) in dioxane (5 mL), 6a
was isolated as a colorless oil; yield: 37 mg (94%).
(10) Molander, G. A.; Cameron, K. O. J. Am. Chem. Soc. 1993,
115, 830.
(11) Anderson, G.; Cameron, D. W.; Feutrill, G. I.; Read, R. W.
Tetrahedron Lett. 1981, 22, 4347.
IR (KBr): 3422 (m), 3075 (w), 2974 (m), 2928 (s), 2859 (m), 1735
(m), 1647 (w), 1596 (s), 1521 (s), 1452 cm–1 (s).
(12) Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC-295095(3c) and CCDC-297417(3e).
Copies of this data can be obtained, free of charge, on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: +44(1223)336033 or e-mail:
1H NMR (300 MHz, CDCl3): d = 2.42 (s, 3 H, Ar-CH3), 3.47 (s, 3
H, Py-CH2OCH3), 3.95 (s, 3 H, ArOCH3), 3.99 (s, 3 H, ArOCH3),
4.61 (s, 2 H, Py-CH2OCH3), 6.98 (d, 3J = 8.4 Hz, 1 H, Ar), 7.18 (d,
4J = 2.1 Hz, 1 H, Ar), 7.28–7.38 (m, 1 H, Ar), 7.32 (d, 3J = 8.3 Hz,
3
2 H, Ar), 7.76 (d, 4J = 1.5 Hz, 1 H, Py), 7.97 (d, J = 8.3 Hz, 2 H,
Ar), 8.26 (d, 4J = 1.5 Hz, 1 H, Py).
deposit@ccdc.cam.ac.uk) or via www.ccdc.cam.ac.uk/
conts/retrieving.html.
13C NMR (75 MHz, CDCl3): d = 21.6 (Ar-CH3), 56.0, 56.2 (Ar-
OCH3), 58.9 (Py-CH2OCH3), 74.7 (Py-CH2OCH3), 109.8, 111.5,
Synthesis 2006, No. 15, 2551–2555 © Thieme Stuttgart · New York