1

LETTER

Synthesis of 3-sulfonyloxypyridines: Oxidative ring expansion of furylsulfonamides and NO sulfonyl transfer

Robert Hodgson,a Andrew Kennedy,b Adam Nelson*a and Alexis Perry*a
a

Department of Chemistry, University of Leeds, Leeds, LS2 9JT, UK

Synthetic Chemistry, Chemical Development, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Tel: +44 (0)113 343 6502 Fax: +44 (0)113 343 6565
E-mail: a.s.nelson@leeds.ac.uk; oldralph@hotmail.co.uk
Received: The date will be inserted once the manuscript is accepted.
b

Abstract:
N-Sulfonyl
pyridinones
derived
from
furylsulfonamides may be aromatised with concomitant NO
sulfonyl transfer to produce 3-sulfonyloxypyridines.
Key words: Furans, Pyridines, Rearrangements, Ring expansion,
Sulfonamides.

The pyridine motif is found in a wide range of biological

active compounds including pyridoxal, niacin and the
stimulant, nicotine.1 Furthermore, many substituted
pyridines have been marketed as pharmaceuticals, for
example the tuberculosis treatment isoniazid 2a and the
HIV protease inhibitor indinavir.2b
Many differentially substituted pyridines are difficult to
prepare. 2,3-Disubstituted pyridines have been
synthesised by directed metallation,3 condensation,4
nucleophilic addition to pyridinium salts 5 and [2,3]sigmatropic rearrangement.6 A p38 MAP kinase inhibitor
has been prepared by Pd-catalysed annelation of a 2chloro 3-iodo 4-bromo pyridine.7 A remarkable cascade
reaction has recently been developed for the synthesis of
pentasubstituted pyridines.8
An alternative approach involves oxidative ring
expansion of an -furyl amines (e.g. 12), and
subsequent acid-catalysed aromatisation (3) (Scheme
1).9 This approach has been applied in the synthesis of
C-nucleosides10
and
pyridine-substituted
sugar
mimetics.11

R1

oxidative
ring
expansion

NHR2
1

OH

aromatisation
N

R1

R2
2

R1

Entry

O
H

HO
SO2R2

R1

N
SO2R

OSO2R2
R1

Scheme 2

The -furylsulfonamides 9 were synthesised in two steps

from simple aromatic aldehydes (Scheme 3). Treatment
of the aldehydes 7 with p-toluenesulfonamide in the
presence of either tetraethylorthosilicate or titanium(IV)
ethoxide gave the N-sulfonyl imines 8 (Scheme 3 and
Table 1);14 addition of appropriate organometallic
reagents to these imines gave the sulfonamides 9
(Scheme 3 and Table 1).15
Ar

p-TsNH2

Ar

see Table 1,
Conditions (1)

7a; Ar=2-Fu
7b; Ar=Ph
7c; Ar=2-(5-Me)Fu

NTs
H

Ar

RM
see Table 1,
Conditions (2)

8a; Ar=2-Fu
8b; Ar=Ph
8c; Ar=2-(5-Me)Fu

NHTs
R

9a; Ar=2-Fu, R=nBu

9b; Ar=2-Fu, R=iPr
9c; Ar=Ph, R=2-Fu
9d; Ar=R=2-Fu
9e; Ar=2-(5-Me)Fu,
R=nBu

Scheme 1

Table 1

aromatisation
O and sulfonyl
transfer

oxidative
ring
R1 expansion

O
HO

In this paper we describe the development of an

oxidative cascade, in which oxidative ring expansion of
an -furyl sulfonamide (e.g. 4), acid-catalysed
aromatisation, and NO sulfonyl transfer leads to the
formation of 3-sulfonyloxypyridines such as 6. The
optimisation of this process,12 and its scope and
limitiations, are described. Aryl toluenesulfonates are
valuable precursors of highly substituted arenes.13

Scheme 3 Preparation of -furylsulfonamides

Preparation of the -furylsulfonamides 10a-e
Aldehyde

Conditions

Yield (%)

Imine

1
7a
Ti(OEt)4, CH2Cl2, 50 C
95
8a
2
8a
3
7b
Si(OEt)4, 170 C
63
8b
4
8a
5
7c
Si(OEt)4, 170 C
94
8c
a; 2-Lithiofuran was generated in situ by the reaction of nbutyllithium and furan.

Treatment of the sulfonamide 9a with mCPBA or NBS

gave the pyridinone 10a in 99% yield (Scheme 4).
Template for SYNLETT and SYNTHESIS Thieme Stuttgart New York

Conditions
n

BuLi, THF, 78 C
PrMgCl, THF, 78 C
2-Lithiofuran, THF, 78 Ca
2-Lithiofuran, THF, 78 Ca
n
BuLi, THF, 78 C
i

Product

Yield (%)

9a
9b
9c
9d
9e

88
21
89
91
51

Previous aromatisations of pyridinones have used acid

catalysis to promote dehydration and, hence,
2015-05-05

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LETTER

aromatisation.9,10 We investigated the aromatisation of

the pyridinone 10a in the presence of a range of Lewis
acids (Scheme 4); selected examples are described in
Table 2. The yield of the pyridine 11a increased with the
strength of the Lewis acid (for example, compare entries
1, 3 and 7). Further optimisation was highly successful:
exposure of the pyridinone 10a to aluminium trichloride
in CH2Cl2 at 78 C, and addition of triethylamine, gave
the pyridine 11a in 92% yield (entry 9). In contrast,
treatment of the pyridinone 10a with boron trifluoride,
followed addition of methanol, gave the 3hydroxypyridine 12 in 72% yield (entry 5). The 3substituent of the pyridine could, therefore, be varied
simply by changing the nature of the quench used.
Table 2

Bu

NBS
NaOAc
THFH2O

NHTs
9a

O
HO

2. NEt3

Bu

11a

Bu

Ts

1. Lewis
acid

10a, 99%

2. MeOH

OH
n

Bu

12

Scheme 4

Optimisation of the aromatisation of the pyridinone 10a to the pyridine 11a

Entry
Lewis acid
Solvent
Temperature
1
Yb(OTf)3
CH2Cl2
25 C
2
ZnCl2
CH2Cl2
25 C
3
BCl3
CH2Cl2
25 C
4
BF3.OEt2
CH2Cl2
25 C
5
BF3.OEt2
CH2Cl2
25 C
6
SnCl4
CH2Cl2
25 C
7
AlCl3
CH2Cl2
25 C
8
SnCl4
CH2Cl2
78 C
9
AlCl3
CH2Cl2
78 C
10
SnCl4
THF
78 C
a; Determined by analysis of the crude reaction mixture by analytical HPLC.
b; The 3-hydroxy pyridine 12 was isolated in 72% yield.

With optimised conditions in hand, the scope and

limitations of the cascade were investigated. Treatment
of the sulfonamides 9b and 9c with mCPBA gave the
pyridinones 10b and 10c; upon exposure to Lewis acid
(AlCl3, CH2Cl2, 78 C), followed by treatment with
triethylamine, the pyridines 11a and 11b were obtained
(Scheme 5 and Table 3, entries 2 and 3). Oxidation of
the difurylsulfonamide 9d with NBS gave the pyridine
11d directly; in this case, Lewis acid-mediated
aromatisation was not required (entry 4).12 In contrast,
treatment of the sulfonamide 9e with either NBS or
mCPBA gave the trans-enedione 14 (Scheme 4.7 and
Table 3, entry 5). Presumably, initial oxidation produced
the intermediate cis-enedione 13, which underwent cis
trans isomerisation (Scheme 6). Similar olefin
isomerisations have been reported upon exposure of cisenediones to NBS.16
Table 3

OTs

1. Lewis
acid

mCPBA
CH2Cl2
or

Quench
NEt3
MeOH
NEt3
NEt3
NEt3
NEt3
-

Yield, 11a
0%a
<10%a
<25%a
38%
0%b
45%
47%
73%
92%
0%a

O
O

OTs

See

Table 3

NHTs

HO

N
Ts

R
i

9b; R = Pr
9c; R = Ph
9d; R = 2-Fu

10b; R = Pr
10c; R = Ph
10d; R = 2-Fu

R
i

11b; R = Pr, 81%

11c; R = Ph, 36%
11d; R = 2-Fu, 50%

Scheme 5
NHTs

TsHN
n

Bu

NHTs

NBS
NaOAc

Bu

Bu

THFH2O
O

9e

O
13

14, 95%

Scheme 6

Oxidation and aromatisation of the -furylsulfonamides 10a-e

Entry
1

Substrate
9a

9b

9c

4
5

9d
9e

Conditions
(1) NBS, NaOAc, THFH2O, 0 C
(2) AlCl3, CH2Cl2, 78 C
(3) Et3N
(1) mCPBA
(2) AlCl3, CH2Cl2, 78 C
(3) Et3N
(1) mCPBA
(2) AlCl3, CH2Cl2, 78 C
(3) Et3N
NBS, NaOAc, THFH2O, 0 C
NBS, NaOAc, THFH2O, 0 C

Template for SYNLETT and SYNTHESIS Thieme Stuttgart New York

Product
11a

Yield
92%

11b

81%

11c

36%

11d
14

50%
95%

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LETTER

We propose that aromatisation of the pyridinone 10a

occurred via acid-catalysed dehydration and enolisation
to give the pyridinium salt 15 (Scheme 7). Presumably,
intermolecular NO p-toluenesulfonyl transfer then
occurred to give the pyridine 11a. With a methanol
quench, we suggest that the intermediate 15 is
intercepted to yield the 3-hydroxypyridine 12. The
pyridinium derivative 15 is analogous to the acylated
DMAP complexes which are intermediates in many
acylation reactions (Scheme 7).17 A similar mechanism
may account for the formation of the pyridines 11b-d.
O
HO

N
Ts
10a

Bu

OH

Lewis
acid

Bu

Ts
15

OTs
N

Bu

11a

Scheme 7

In summary, an oxidative cascade has been developed

and exploited in the synthesis of a range of 2-substituted3-sulfonyloxypyridines
from
simple
-furyl
sulfonamides. The method allowed the synthesis of
pyridines with aryl-, heteroaryl- or alkyl 2-substituents.
The reaction proceeded with NO sulfonyl transfer, a
process which could be prevented by quenching with
methanol. However, it was not possible to prepare a 6substituted pyridine because cis trans isomerisation
of the intermediate enedione competed with
aromatisation. The method may find application in the
synthesis of other 2,3-disubstituted pyridines.

Aromatisation of N-sulfonyl pyridinones

11a: Aluminium trichloride (427 l of a 1 M solution in
nitrobenzene, 0.427 mmol) was added to a stirred
solution of the pyridinone 10a (115 mg, 0.356 mmol) in
dichloromethane (8 mL) at 78 C. After 0.5 h, the
reaction was quenched with triethylamine (0.5 mL) and
was poured onto water. The layers were separated and
the aqueous layer was extracted with dichloromethane (3
10 mL). The combined organic extracts were dried
(MgSO4) and concentrated under reduced pressure to
give a crude product. Purification by flash
chromatography, eluting with 2:8 ethyl acetatepetrol,
gave the pyridine 11a (100 mg, 92%) as a colourless oil,
RF 0.7 (4:6 ethyl acetatepetrol); max/cm-1 (film) 1598,
1440, 1314, 1162 and 1112; H (300 MHz; CDCl3) 8.43
(1 H, dd, J 4.7 and 1.1, 6-H), 7.72 (2 H, d, J 8.1, tosyl 3and 5-H), 7.51 (1 H, dd, J 8.3 and 1.1, 4-H), 7.34 (2 H,
d, J 8.1, tosyl 2- and 6-H), 7.13 (1 H, dd, J 8.3 and 4.7,
5-H), 2.46 (3H, s, tosyl Me), 1.48 (2 H, m, 1-H), 1.26 (4
H, m, 2- and 3-H) and 0.86 (3 H, m, 4-H); C (75
MHz; CDCl3) 156.5, 147.9, 146.3, 145.1, 133.0, 130.4,
129.8, 128.8, 122.2, 32.2, 30.8, 23.0, 22.2 and 14.2; m/z
(ES+) 306 (100%, MH+); (Found: MH+, 306.1163.
C16H19NO3S requires MH, 306.1164).
Template for SYNLETT and SYNTHESIS Thieme Stuttgart New York

11b: RF 0.6 (4:6 ethyl acetatepetrol); max/cm-1 (film)

2091, 1643, 1377, 1192 and 1084; H (300 MHz; CDCl3)
8.49 (1 H, dd, J 4.6 and 1.4, 6-H), 7.73 (2 H, d, J 8.3,
tosyl 3- and 5-H), 7.49 (1 H, dd, J 8.2 and 1.4, 4-H), 7.34
(2 H, d, J 8.3, tosyl 2- and 6-H), 7.12 (1 H, dd, J 8.2 and
4.6, 5-H), 3.13 (1 H, septet, J 6.8, 1-H), 2.46 (3 H, s,
tosyl-Me) and 1.03 (6 H, d, J 6.8, 2-H); C (75 MHz;
CDCl3) 160.8, 148.1, 146.3, 130.4, 128.9, 122.1, 29.1,
22.1 and 21.8; m/z (ES+) 292 (95%, MH+); (Found MH+,
292.1000. C15H17NO3S requires MH, 292.1007).
11c: RF 0.7 (4:6 ethyl acetatepetrol); max/cm-1 (film)
1597, 1429, 1377, 1168 and 1091; H (300 MHz; CDCl3)
8.47 (1 H, dd, J 3.9 and 1.5, pyr 6-H), 7.74 (1 H, dd, J
8.2 and 1.5, pyr 4-H), 7.31 (2 H, d, J 8.2, tosyl 3- and 5H), 7.17 (4 H, m, 3-, 4- and 5-H and pyr 5-H), 7.04 (2
H, dd, J 8.2 and 1.4, 2- and 6-H), 6.79 (2 H, d, J 8.2,
tosyl 2- and 6-H) and 2.20 (3 H, s, Me); C (75 MHz;
CDCl3) 152.7, 148.5, 145.7, 136.3, 132.9, 131.5, 129.8,
129.5, 129.1, 128.4, 128.2, 123.6, 115.0 and 22.0; m/z
(ES+) 326 (100%, MH+); (Found: MH+, 326.0857.
C18H15NO3S requires MH, 326.0851).
11d:12 RF 0.3 (3:7 ethyl acetatepetrol); max/cm-1 (film)
1435, 1377, 1195, 1174 and 1093; H (500 MHz; CDCl3)
8.52 (1 H, dd, J 4.6 and 1.4, pyr 6-H), 7.71 (1 H, dd, J
8.3 and 1.4, pyr 4-H), 7.59 (2 H, d, J 8.4, tosyl 3- and 5H), 7.47 (1 H, dd, J 1.7 and 0.6, furyl 5-H), 7.19 (1 H,
dd, J 8.3 and 4.6, pyr 5-H), 6.79 (2 H, d, J 8.4, tosyl 2and 6-H), 7.04 (1 H, dd, J 3.4 and 0.6, furyl 3-H), 6.45 (1
H, dd, J 3.4 and 1.7, furyl 4-H) and 2.37 (3 H, s, Me); C
(125 MHz; CDCl3)148.6, 147.7, 145.9, 143.8, 131.9,
130.7, 129.5, 128.5, 127.9, 126.4, 122.3, 111.8, 113.8
and 21.6; m/z (EI) 315 (28%, M+), 160 (61), 132 (100),
and 39 (62); (Found: MH+, 316.0642. C16H13NO4S
requires MH, 316.0643).
12: Boron trifluoride diethyl etherate (21 l, 0.163
mmol) was added to a stirred solution of the pyridinone
10a (50 mg, 0.148 mmol) in dichloromethane (7 mL).
After 0.1 h, methanol (25 l, 0.178 mmol) was added,
the resulting solution was stirred for 0.1 h and
concentrated under reduced pressure to give a crude
product. Purification by flash chromatography, eluting
with 40 : 60 ethyl acetatepetrol, gave the pyridinol 12
(16 mg, 71%) as a colourless oil, RF 0.3 (40 : 60 ethyl
acetatepetrol); max/cm-1 (film) 2958, 2930, 1577, 1457
and 1288; H (500 MHz; CDCl3) 7.99 (1 H, dd, J 4.8 and
2.2, 6-H), 7.18 (1 H, dd, J 8.1 and 2.2, 4-H), 7.04 (1 H,
dd, J 8.1 and 4.8, 5-H), 2.90 (2 H, t, J 7.7, 1-H), 1.70 (2
H, p, J 7.7, 2-H), 1.38 (2 H, m, 3-H) and 0.90 (3 H, t, J
7.5, 4-H); C (75 MHz; CDCl3) 151.8, 150.1, 138.4,
123.5, 122.5, 31.5, 30.6, 22.7 and 13.9; m/z (ES+) 152
(100%, MH+).
Acknowledgment
We thank EPSRC and GlaxoSmithKline for funding.

2015-05-05

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LETTER

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Template for SYNLETT and SYNTHESIS Thieme Stuttgart New York

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R
NHTs

NBS
or
mCPBA

OTs

AlCl3
HO

Ts

R = Alkyl, Aryl or Heteroaryl

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