Synthesis of 3-sulfonyloxypyridines: Oxidative ring expansion of α-furyl-sulfonamides and N→O sulfonyl transfer

Article abstract of DOI:10.1055/s-2007-973875

N-Sulfonyl pyridinones derived from α-furylsulfonamides may be aromatised with concomitant N→O sulfonyl transfer to produce 3-sulfonyloxypyridines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-973875

LETTER
1043
Synthesis of 3-Sulfonyloxypyridines: Oxidative Ring Expansion of a-Furyl-
sulfonamides and N→O Sulfonyl Transfer
S
ynthesis of 3-Su
o
lfonyloxypy
b
ridines ert Hodgson,a Andrew Kennedy,b Adam Nelson,*a Alexis Perry*a
a
Department of Chemistry, University of Leeds, Leeds, LS2 9JT, UK
Fax +44(113)3436565; E-mail: a.s.nelson@leeds.ac.uk; E-mail: oldralph@hotmail.co.uk
b
Synthetic Chemistry, Chemical Development, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Received 4 December 2006
aromatisation
and sulfonyl
transfer
oxidative
ring
expansion
O
Abstract: N-Sulfonyl pyridinones derived from a-furylsulfon-
amides may be aromatised with concomitant N→O sulfonyl trans-
fer to produce 3-sulfonyloxypyridines.
OSO2R2
R1
O
HO
N
R1
SO2R2
N
N
R1
H
SO2R2
Key words: furans, pyridines, rearrangements, ring expansion,
sulfonamides
4
5
6
Scheme 2
The pyridine motif is found in a wide range of biologically
active compounds including pyridoxal, niacin and the
stimulant, nicotine.1 Furthermore, many substituted
pyridines have been marketed as pharmaceuticals, for
example the tuberculosis treatment isoniazid2a and the
HIV protease inhibitor indinavir.2b
of this process,12 and its scope and limitiations, are de-
scribed. Aryl toluenesulfonates are valuable precursors of
highly substituted arenes.13
The a-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 re-
agents to these imines gave the sulfonamides 9 (Scheme 3
and Table 1).15
Many differentially substituted pyridines are difficult to
prepare. 2,3-Disubstituted pyridines have been synthe-
sised by directed metalation,3 condensation,4 nucleophilic
addition to pyridinium salts5 and [2,3]-sigmatropic rear-
rangement.6 A p38 MAP kinase inhibitor has been pre-
pared by Pd-catalysed annelation of a 2-chloro 3-iodo 4-
bromo pyridine.7 A remarkable cascade reaction has re-
cently been developed for the synthesis of pentasubstitut-
ed pyridines.8
Treatment of the sulfonamide 9a with MCPBA or NBS
gave the pyridinone 10a in 99% yield (Scheme 4). Previ-
ous aromatisations of pyridinones have used acid catalysis
to promote dehydration and, hence, 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 pyri-
dine 11a increased with the strength of the Lewis acid (for
example, compare entries 1, 3 and 7). Further optimisa-
tion was highly successful: exposure of the pyridinone
10a to aluminium trichloride in CH2Cl2 at –78 °C, and ad-
dition of triethylamine, gave the pyridine 11a in 92%
yield (entry 9). In contrast, treatment of the pyridinone
10a with boron trifluoride, followed by addition of meth-
anol, gave the 3-hydroxypyridine 12 in 72% yield (entry
An alternative approach involves oxidative ring expan-
sion of an a-furyl amine (e.g. 1 → 2), and subsequent
acid-catalysed aromatisation (→ 3, Scheme 1).9 This ap-
proach has been applied in the synthesis of C-
nucleosides10 and pyridine-substituted sugar mimetics.11
oxidative
ring
expansion
O
OH
R1
aromatisation
O
HO
N
R2
2
R1
N
R1
NHR2
1
3
Scheme 1
p-TsNH2
Ar
O
Ar
NTs
Ar
NHTs
RM
In this paper we describe the development of an oxidative
cascade, in which oxidative ring expansion of an a-furyl
sulfonamide (e.g. 4), acid-catalysed aromatisation and
N→O sulfonyl transfer leads to the formation of 3-sulfo-
nyloxypyridines such as 6 (Scheme 2). The optimisation
see Table 1,
conditions 2
see Table 1,
conditions 1
H
H
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
7a: Ar = 2-Fu
7b: Ar = Ph
7c: Ar = 2-(5-Me)Fu
8a: Ar = 2-Fu
8b: Ar = Ph
8c: Ar = 2-(5-Me)Fu
Fu = furyl
SYNLETT 2007, No. 7, pp 1043–1046
2
4.
0
4.
2
0
0
7
Advanced online publication: 13.04.2007
DOI: 10.1055/s-2007-973875; Art ID: D37606ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 3 Preparation of a-furylsulfonamides

1044
R. Hodgson et al.
LETTER
Table 1 Preparation of the a-Furylsulfonamides 9a–e
Entry
Aldehyde
Conditions 1
Yield (%)
Imine
8a
Conditions 2
Product
9a
Yield (%)
1
2
3
4
5
7a
Ti(OEt)4, CH2Cl2, 50 °C 95
n-BuLi, THF, –78 °C
i-PrMgCl, THF, –78 °C
2-Lithiofuran, THF, –78 °Ca
2-Lithiofuran, THF, –78 °Ca
n-BuLi, THF, –78 °C
88
21
89
91
51
8a
9b
7b
7c
Si(OEt)4, 170 °C
Si(OEt)4, 170 °C
63
94
8b
9c
8a
9d
8c
9e
a 2-Lithiofuran was generated in situ by the reaction of n-BuLi and furan.
1. Lewis
acid
OTs
nBu
amine, the pyridines 11b and 11c 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 6 and Table 3, entry 5). Pre-
sumably, initial oxidation produced the intermediate cis-
enedione 13, which underwent cis→trans isomerisation
(Scheme 6). Similar olefin isomerisations have been re-
ported upon exposure of cis-enediones to NBS.16
MCPBA
CH2Cl2
or
O
N
N
nBu
2. Et3N
O
11a
HO
N
nBu
NBS
NaOAc
THF–H2O
NHTs
1. Lewis
acid
Ts
OH
nBu
9a
10a, 99%
2. MeOH
12
Scheme 4
Table 2 Optimisation of the Aromatisation of the Pyridinone 10a to
the Pyridine 11a
O
R
see
Table 3
OTs
R
R
O
Entry Lewis acid Solvent
Temp (°C) Quench
Yield(%),
HO
N
N
NHTs
Ts
11a
9a: R = Bu
9b: R = iPr
9c: R = Ph
9d: R = 2-Fu
10a: R = Bu
10b: R = iPr
10c: R = Ph
11a: R = Bu
1
2
Yb(OTf)3 CH2Cl2
25
–
0a
<10a
<25a
38
11b: R = iPr, 81%
11c: R = Ph, 36%
11d: R = 2-Fu, 50%
ZnCl2
BCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
25
–
10d: R = 2-Fu
3
25
–
Scheme 5
4
BF3·OEt2
BF3·OEt2
SnCl4
25
Et3N
MeOH
Et3N
Et3N
Et3N
Et3N
–
NHTs
TsHN
5
25
0b
nBu
NBS
NaOAc
O
nBu
nBu
NHTs
6
25
45
O
O
THF·H2O
7
AlCl3
25
47
O
O
8
SnCl4
–78
–78
–78
73
9e
13
14, 95%
9
AlCl3
92
Scheme 6
10
SnCl4
0a
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 N→O p-toluenesulfonyl transfer then oc-
curred 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 in-
a Determined by analysis of the crude reaction mixture by analytical
HPLC.
b The 3-hydroxypyridine 12 was isolated in 72% yield.
5). The 3-substituent of the pyridine could, therefore, be
varied simply by changing the nature of the quench used.
termediates in many acylation reactions (Scheme 7).17
A
With optimised conditions in hand, the scope and limita-
tions of the cascade were investigated. Treatment of the
sulfonamides 9b and 9c with MCPBA gave the pyridino-
nes 10b and 10c; upon exposure to Lewis acid (AlCl3,
CH2Cl2, –78 °C), followed by treatment with triethyl-
similar mechanism may account for the formation of the
pyridines 11b–d.
Synlett 2007, No. 7, 1043–1046 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Sulfonyloxypyridines
1045
Table 3 Oxidation and Aromatisation of the a-Furylsulfonamides 10a–e
Entry
1
Substrate
Conditions
Product
Yield (%)
9a
(1) NBS, NaOAc, THF–H2O, 0 °C
(2) AlCl3, CH2Cl2, -78 °C
(3) Et3N
11a
92
81
36
2
3
9b
9c
(1) MCPBA
(2) AlCl3, CH2Cl2, –78 °C
(3) Et3N
11b
11c
(1) MCPBA
(2) AlCl3, CH2Cl2, –78 °C
(3) Et3N
4
5
9d
9e
NBS, NaOAc, THF–H2O, 0 °C
NBS, NaOAc, THF–H2O, 0 °C
11d
14
50
95
Compound 11b
O
OH
Lewis
acid
OTs
Rf = 0.6 (4:6 EtOAc–PE). IR (film): nmax = 2091, 1643, 1377, 1192,
1084 cm–1. 1H NMR (300 MHz, CDCl3): d = 8.49 (1 H, dd, J = 4.6,
1.4 Hz, 6-H), 7.73 (2 H, d, J = 8.3 Hz, tosyl 3- and 5-H), 7.49 (1 H,
dd, J = 8.2, 1.4 Hz, 4-H), 7.34 (2 H, d, J = 8.3 Hz, tosyl 2- and 6-H),
7.12 (1 H, dd, J = 8.2, 4.6 Hz, 5-H), 3.13 (1 H, sept, J = 6.8 Hz, 1¢-
H), 2.46 (3 H, s, tosyl-Me), 1.03 (6 H, d, J = 6.8 Hz, 2¢-H). 13C NMR
(75 MHz, CDCl3): d = 160.8, 148.1, 146.3, 130.4, 128.9, 122.1,
29.1, 22.1, 21.8. MS (ES+): m/z (%) = 292 (95) [MH+]. HRMS: m/z
calcd for C15H17NO3S [MH]: 292.1007. Found [MH+]: 292.1000.
HO
N
Ts
nBu
N
nBu
N
nBu
Ts
15
10a
11a
Scheme 7
In summary, an oxidative cascade has been developed and
exploited in the synthesis of a range of 2-substituted-3-
sulfonyloxypyridines from simple a-furyl sulfonamides.
The method allowed the synthesis of pyridines with aryl,
heteroaryl or alkyl 2-substituents. The reaction proceeded
with N→O sulfonyl transfer, a process which could be
prevented by quenching with methanol. However, it was
not possible to prepare a 6-substituted pyridine because
cis→trans isomerisation of the intermediate enedione
competed with aromatisation. The method may find ap-
plication in the synthesis of other 2,3-disubstituted
pyridines.
Compound 11c
Rf = 0.7 (4:6 EtOAc–PE). IR (film): nmax = 1597, 1429, 1377, 1168,
1091 cm–1. 1H NMR (300 MHz, CDCl3): d = 8.47 (1 H, dd, J = 3.9,
1.5 Hz, pyr 6-H), 7.74 (1 H, dd, J = 8.2, 1.5 Hz, pyr 4-H), 7.31 (2 H,
d, J = 8.2 Hz, tosyl 3- and 5-H), 7.17 (4 H, m, 3¢-, 4¢- and 5¢-H and
pyr 5-H), 7.04 (2 H, dd, J = 8.2, 1.4 Hz, 2¢- and 6¢-H), 6.79 (2 H, d,
J = 8.2 Hz, tosyl 2- and 6-H), 2.20 (3 H, s, Me). 13C NMR (75 MHz,
CDCl3): d = 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, 22.0. MS (ES+): m/z (%) = 326
(100) [MH+]. HRMS: m/z calcd for C18H15NO3S [MH]: 326.0851.
Found [MH+]: 326.0857.
Compound 11d12
Rf = 0.3 (3:7 EtOAc–PE). IR (film): nmax = 1435, 1377, 1195, 1174,
1093 cm–1. 1H NMR (300 MHz, CDCl3): d = 8.52 (1 H, dd, J = 4.6,
1.4 Hz, pyr 6-H), 7.71 (1 H, dd, J = 8.3, 1.4 Hz, pyr 4-H), 7.59 (2 H,
d, J = 8.4 Hz, tosyl 3- and 5-H), 7.47 (1 H, dd, J = 1.7, 0.6 Hz, furyl
5-H), 7.19 (1 H, dd, J = 8.3, 4.6 Hz, pyr 5-H), 6.79 (2 H, d, J = 8.4
Hz, tosyl 2- and 6-H), 7.04 (1 H, dd, J = 3.4, 0.6 Hz, furyl 3-H), 6.45
(1 H, dd, J = 3.4, 1.7 Hz, furyl 4-H), 2.37 (3 H, s, Me). 13C NMR (75
MHz, CDCl3): d = 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, 21.6. MS (EI): m/z (%) =
315 (28 [M+], 160 (61), 132 (100), 39 (62). HRMS: m/z calcd for
C16H13NO4S [MH]: 316.0643. Found [MH+]: 316.0642.
Aromatisation of N-Sulfonyl Pyridinones
Compound 11a
To a stirred solution of the pyridinone 10a (115 mg, 0.356 mmol) in
CH2Cl2 (8 mL) was added AlCl3 (427 mL of a 1 M solution in ni-
trobenzene, 0.427 mmol) at –78 °C. After 0.5 h, the reaction was
quenched with Et3N (0.5 mL) and was poured onto H2O. The layers
were separated and the aqueous layer was extracted with CH2Cl2 (3
× 10 mL). The combined organic extracts were dried (MgSO4) and
concentrated under reduced pressure to give a crude product. Puri-
fication by flash chromatography, eluting with 2:8 EtOAc–PE, gave
the pyridine 11a (100 mg, 92%) as a colourless oil, Rf 0.7 (4:6
EtOAc-PE). IR (film): nmax = 1598, 1440, 1314, 1162, 1112 cm–1.
1H NMR (300 MHz, CDCl3): d = 8.43 (1 H, dd, J = 4.7, 1.1 Hz, 6-
H), 7.72 (2 H, d, J = 8.1 Hz, tosyl 3- and 5-H), 7.51 (1 H, dd, J =
8.3, 1.1 Hz, 4-H), 7.34 (2 H, d, J = 8.1 Hz, tosyl 2- and 6-H), 7.13
(1 H, dd, J = 8.3, 4.7 Hz, 5-H), 2.46 (3 H, s, tosyl Me), 1.48 (2 H,
m, 1¢-H), 1.26 (4 H, m, 2¢- and 3¢-H), 0.86 (3 H, m, 4¢-H). 13C NMR
(75 MHz, CDCl3): d = 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., 14.2. MS (ES+): m/z
(%) = 306 (100) [MH+]. HRMS: m/z calcd for C16H19NO3S: [MH]:
306.1164. Found [MH+]: 306.1163.
Compound 12
To a stirred solution of the pyridinone 10a (50 mg, 0.148 mmol) in
CH2Cl2 (7 mL) was added BF3·OEt2 (21 mL, 0.163 mmol). After
0.1 h, MeOH (25 mL, 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 EtOAc–PE, gave the pyridinol 12 (16 mg, 71%) as a co-
lourless oil, Rf = 0.3 (40: 60 EtOAc–PE). IR (film): nmax = 2958,
2930, 1577, 1457, 1288 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.99
(1 H, dd, J = 4.8, 2.2 Hz, 6-H), 7.18 (1 H, dd, J = 8.1, 2.2 Hz, 4-H),
Synlett 2007, No. 7, 1043–1046 © Thieme Stuttgart · New York

1046
R. Hodgson et al.
LETTER
7.04 (1 H, dd, J = 8.1, 4.8 Hz, 5-H), 2.90 (2 H, t, J = 7.7 Hz, 1¢-H),
1.70 (2 H, p, J = 7.7 Hz, 2¢-H), 1.38 (2 H, m, 3¢-H), 0.90 (3 H, t, J =
7.5 Hz, 4¢-H). 13C NMR (75 MHz, CDCl3): d = 151.8, 150.1, 138.4,
123.5, 122.5, 31.5, 30.6, 22.7, 13.9. MS (ES+): m/z (%) = 152 (100)
[MH+].
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