Smiles rearrangement for the synthesis of 5-amino-substituted [1]benzothieno[2,3-b]pyridine

Article abstract of DOI:10.1016/S0040-4020(03)01177-3

The Smiles rearrangement was successfully applied to 4-hydroxybenzo[b]thiophene furnishing a facile entry to the 4-amino derivative. The rearrangement was extended to 5-methoxy-4-methoxycarbonyl[1]benzothieno[2,3-b]pyridine obtained via aza-Wittig/electrocyclization reaction of novel N-(4-methoxybenzothiophen-2-yl)iminomethyldiphenylphosphorane with methyl trans-4-oxo-2-pentenoate. The preparation of a novel 5-amino-4-methoxycarbonyl[1]benzothieno[2,3-b]pyridine, which is of interest as a potential secondary peptide structure mimic, was successfully achieved.

Full text of DOI:10.1016/S0040-4020(03)01177-3

Tetrahedron 59 (2003) 7515–7520
Smiles rearrangement for the synthesis of 5-amino-substituted
[1]benzothieno[2,3-b]pyridine
b
b
Carlo Bonini,a Maria Funicello,a Rosanna Scialpi and Piero Spagnolo
,
*
a
`
Dipartimento di Chimica, Universita della Basilicata, Via N. Sauro 85, 85100 Potenza, Italy
`
Dipartimento di Chimica Organica ‘A. Mangini’, Universita di Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
b
Received 11 April 2003; revised 3 July 2003; accepted 25 July 2003
Abstract—The Smiles rearrangement was successfully applied to 4-hydroxybenzo[b]thiophene furnishing a facile entry to the 4-amino
derivative. The rearrangement was extended to 5-methoxy-4-methoxycarbonyl[1]benzothieno[2,3-b]pyridine obtained via aza-Wittig/elec-
trocyclization reaction of novel N-(4-methoxybenzothiophen-2-yl)iminomethyldiphenylphosphorane with methyl trans-4-oxo-2-pentenoate.
The preparation of a novel 5-amino-4-methoxycarbonyl[1]benzothieno[2,3-b]pyridine, which is of interest as a potential secondary peptide
structure mimic, was successfully achieved.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
study we became interested in applying this new procedure
to model 4-hydroxybenzo(b)thiophene and then to a
particularly hindered 5-methoxy-substituted(1)benzo-
thieno(2,3-b)pyridine.
The direct conversion of phenols into anilines represents an
intriguing organic reaction and there are few reports in the
literature concerning this subject.1 An interesting solution
for this conversion is the Smiles rearrangement of
2-aryloxy-2-methylpropanamides, normally performed in
dioxane in the presence of a base.2
Benzothienopyridines represent a class of interesting
tricyclic compounds with reported pharmacological activity
such as antiallergic,5 antibacterial,6 or as anxioselective
agents7 without undesired side-effects typical of classical
benzodiazepines such as diazepam. We have recently
reported a new methodology8–10 to furnish [1]benzo-
thieno[2,3-b]pyridines, as well as [1]benzothieno[3,2-b]-
pyridines in acceptable yields, using the aza-Wittig/
electrocyclization reaction of N-2-(and N-3)-benzothienyl-
iminophosphoranes with a,b-unsaturated aldehydes and
ketones (Scheme 1).
This procedure is usually applicable to aromatic compounds
bearing electron-withdrawing substituents. For aromatic
substrates deactivated to nucleophilic substitution, the
alternative use of a 10:1 m0ixture of N,N-dimethylformamide
and N,N0-dimethyl-N,N -propylen-urea [DMPU; 1,3-
dimethyltetrahydropyrimidin-2-(1H)-one] has been rec-
ommended.3 To the best of our knowledge such Smiles
rearrangement has never been applied to heteroaromatic
compounds, except in the case of 4-hydroxybenzo(b)thio-
phene.2 However, in a recent study, the conversion of
phenols to ethers via aryloxy-2-methylpropanoic acids has
been replaced by a simpler procedure which has not yet
been applied to a benzothiophene substrate.3,4 In the present
Here we report our successful preparation of a novel
5-amino-4-methoxycarbonyl-substituted [1]benzothieno[2,3-
b]pyridinederivativebymeans ofthe Smilesrearrangement of
the corresponding 5-methoxy derivative which in turn became
available by the tandem aza Wittig/electrocyclization reaction
Scheme 1.
Keywords: Smiles rearrangement; heterocyclic rings; aza Wittig reaction; aminobenzothienopyridine.
*
Corresponding author. Tel.: þ39-971-202252; fax: þ39-971-202223; e-mail: funicello@unibas.it
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01177-3

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C. Bonini et al. / Tetrahedron 59 (2003) 7515–7520
Scheme 2.
of N-(4-methoxybenzothiophen-2-yl)iminomethyldiphenyl-
phosphorane with methyl trans-4-oxo-2-pentenoate. This
kind of aminobenzothienopyridine appears of particular
interest since, in principle, it might behave like a turn of a
secondary peptide structure due to the presence of both
methoxycarbonyl and amino substituents in the appropriate 4-
and 5-positions.11 Furthermore, [1]benzothieno[2,3-b]pyri-
dines bearing a substituent in the benzene moiety have only
been prepared in low yields or in a multistep sequence.6,12
compound 1, but the reported protocol has presently been
changed in the light of a subsequent work.3 We could in fact
obtain directly 2-(benzo(b)thiophen-4-yloxy)-2-methyl-
propanamide in 53% yield upon refluxing the sodium salt
of the compound 1 and 2-bromo-2-methylpropanamide in
dry 1,4-dioxane for 4 h (Scheme 2). The derived propana-
mide 2 was subsequently submitted to the Smiles rearrange-
ment by treatment with sodium hydride in a refluxing 10:1
mixture of DMF/DMPU for 2 h. The resultant N-(benzo-
(b)thiophen-4-yl)-2-hydroxy-2-methylpropanamide 3 was
eventually converted into 4-aminobenzothiophene 4 in 91%
yield upon treatment with 6 M HCl for 2 h at 1008C. The
facile conversion of the compound 1 into 4-amino-
benzo[b]thiophene 4 in 40% overall yield led us to extend
the above procedure to an interesting tricyclic compound
such as the 5-hydroxy[1]benzothieno[2,3-b]pyridine 9,
R¼H (Scheme 3), which might have been transformed
eventually into the target 5-amino-4-methoxycarbonyl-2-
methyl[1]benzothieno[2,3-b]pyridine 12 (Scheme 4).
2. Results and discussion
Available 4-hydroxybenzo[b]thiophene 113 can be con-
sidered a suitable heteroaromatic substrate for the use of the
‘Smiles rearrangement’ methodology, recently reported for
non-activated aromatic rings. In the Smiles rearrangement
the preliminary conversion of phenol into 2-aryloxy-2-
methylpropanamide is of primary importance: such a
conversion can be efficiently achieved by treatment with
sodium hydride in hexamethylphosphoric triamide for 1 h.2
A similar conversion has originally been applied also to the
According to our previous protocol, we initially planned to
convert the phenol 1 into the iminophosphorane 7, R¼H and
Scheme 3.

C. Bonini et al. / Tetrahedron 59 (2003) 7515–7520
7517
Scheme 4.
thence to prepare the 5-hydroxybenzothienopyridine 9,
R¼H by subsequent aza-Wittig/electrocyclization reaction
with methyl trans-4-oxo-2-pentenoate.10 However, our
initial efforts to directly prepare azide 6, R¼H via azidation
of 1 with tosyl azide10,14 only resulted in fragmentation of
the resultant triazene salt to intractable material. This
result led us to examine the alternative use of the O-silyl
protected azide 6a, which could be obtained in good yield
(80%) by azidation of the silyloxybenzothiophene 5a.
Subsequent Staudinger reaction of 6a with methyl-
diphenylphosphine10 readily furnished the corresponding
phosphorane 7a.
3. Conclusions
In this paper, we have reported the first preparation of
4-aminobenzo(b)thiophene in only three steps by using a
modified procedure of the Smiles rearrangement. Further-
more, we have shown that such Smiles rearrangement,
coupled with the aza Wittig/electrocyclization reaction, can
provide a useful entry to novel 5-amino-substituted
[1]benzothieno[2,3-b]pyridines such as the amino-
benzothienopyridine 12. This tricyclic compound 12 is of
special interest due to the concomitant presence of
carbomethoxy and amino group in the 4 and 5 positions,
respectively.
Reaction of phosphorane 7a with methyl trans-4-oxo-2-
pentenoate gave only a poor yield (14%) of the desired
benzothienopyridine 9a (Scheme 3). Presumably, in this
case, the electrocyclization process of the aza-Wittig imine
8a was strongly limited by the presence of the bulky
silyloxy substituent in the peri position. However, the
analogous methoxy-substituted phosphorane 7b, which was
easily available from methoxybenzothiophene 5b, follow-
ing the same procedure, was found to react smoothly with
methyl trans-4-oxo-2-pentenoate, in chloroform at 508C, to
give directly the fused pyridine 9b in 91% yield via
electrocyclization of the imine 8b (Scheme 3).
4. Experimental
4.1. General
Column chromatography was carried out on Merck silica
gel (0.063–0.200 mm particle size) by progressive elution
with petroleum ether/ethyl acetate mixtures. H and 13C
NMR spectra were normally carried out in CDCl3 solutions
on a Bruker AM 300 MHz. IR spectra were carried out on a
Perkin–Elmer 883. Mass spectra were obtained with a
Hewlett–Packard 5971 mass-selective detector on a
Hewlett–Packard 5890 gas chromatograph (OV-1 capillary
column between 70–2508C (208C min21).
1
This readily prepared 5-methoxy-substituted benzothieno-
pyridine 9b was then demethylated with lithium bromide
(Scheme 4) and directly treated with 2-bromo-2-methyl-
propanamide following the same procedure as employed
for 4-hydroxybenzothiophene 1, to obtain the propanamide
10 in 70% yield. Compound 10 was then subjected to
the Smiles rearrangement by treatment with sodium
hydride in a 10:1 mixture of DMF/DMPU at 1008C for
2 h. The rearranged amide 11, obtained in 70% yield, was
finally converted to the target 5-amino-4-methoxycarbonyl-
benzothienopyridine 12 in acceptable yield (50%) upon
hydrolysis in 6 M HCl at 1008C for 2 h (Scheme 4).
Dichloromethane, chloroform and carbon tetrachloride were
dried with anhydrous CaCl2; diethyl ether and 1,4-dioxane
were dried using sodium/benzophenone. Dry dimethyl-
formamide was commercially available. 4-Hydroxy-
benzothiophene 1 was prepared according to the
literature.13 2-Bromo-2-methylpropanamide was syn-
thesised as recently reported3 and used in Smiles rearrange-
ment as reported in the same paper to obtain the suitable
2-aryloxy-2-methylpropanamide.
Unfortunately, probably due to competing hydrolysis of the
carbomethoxy group, the resultant yield of the target
compound 12 could not exceed 50% even when other
hydrolytic conditions were attempted.
4.1.1. 2-(1-Benzothiophen-4-yloxy)-2-methylpropana-
mide 2. 4-Hydroxybenzothiophene 1 (100 mg, 0.67 mmol)
was stirred in dry 1,4-dioxane (6 ml) with sodium hydride
(40 mg, 1.33 mmol) for 3 h at 308C in a nitrogen

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C. Bonini et al. / Tetrahedron 59 (2003) 7515–7520
atmosphere. Then, 2-bromo-2-methylpropanamide was
added and the reaction mixture was kept at 1008C and
stirred for 4 h.
crude product was chromatographed on silica gel, using
petroleum ether/ethyl acetate 95:5 as eluant, to give 5a as a
thick oil (604 mg, 75%). (Found: C, 63.59; H, 7.59; S,
12.15%. C14H20OSSi requires: C, 63.58; H, 7.62; S,
12.12%), dH (300 MHz, CDCl3): 7.72–7.67 (m, 2H),
7.53–7.37 (m, 2H), 6.99–6.93 (m, 1H), 1.35 (s, 9H), 0.50
(s, 6H); dC (75 MHz): 150.7, 141.5, 133.5, 125.3, 124.3,
121.0, 115.7, 113.1, 25.7, 18.5, 20.4. m/z: 264 (Mþ), 207
(100).
After cooling, the sodium bromide was filtered and the
organic solution was diluted with ethyl acetate and washed
first with 2 M NaOH and then with water and brine. After
solvent removal the crude product was chromatographed on
silica gel, using petroleum ether/ethyl acetate 1:1 as eluant,
to give the title compound as a white solid (83 mg, 53%).
Elemental analysis and melting point was in accordance to
reported data,2 while spectroscopic data were as follows. dH
(300 MHz, CDCl3): 7.57–7.53 (m, 1H); 7.47–7.43 (m, 1H),
7.37–7.33 (m, 1H); 7.25–7.20 (m, 1H); 6.87–6.83 (m, 1H);
6.77 (bs, 1H); 5.57 (bs, 1H); 1.65 (s, 6H); dC (75 MHz):
178.5, 148.4, 139.4, 139.3, 128.0, 122.2, 114.6, 111.8, 67.3,
23.0. nmax/cm21 3520, 3420 (NH2); 1690 (CO)
4.1.5. 4-Methoxybenzo(b)thiophene 5b. A solution of
4-hydroxybenzothiophene 1 (131 mg, 0.87 mmol) in 10 ml
of anhydrous 1,4-dioxane was treated with sodium hydride
(2.5 mmol) at 308C for ca. 2 h. After this time methyl iodide
(1.04 mmol) was added to the resultant mixture and then
stirred at 508C in inert atmosphere for 25 h: filtration and
solvent removal gave an oily residue.
4.1.2. N-(1-Benzothiophen-4-yl)-2-hydroxy-2-methyl-
propanamide 3. To a solution of the compound 2
(141 mg, 0.60 mmol) in a mixture of N,N-dimethylforma-
mide (DMF)/1,3-dimethyltetrahydropyrimidin-2-(1H)-one
(DMPU) 10:1 was added sodium hydride (44 mg, 2 mmol)
and the reaction mixture was kept at 1008C for 2 h. After
this time, the temperature was cooled to 258C and the
solution was poured into 50 ml of water and extracted with
an equal amount of ethyl acetate. Then the organic layer was
washed with 50 ml of water for four times, dried over
sodium sulphate and after removal of solvent the crude
product was purified on silica gel using petroleum ether/
ethyl acetate 1:1 as eluant furnishing N-(1-benzothiophen-4-
yl)-2-hydroxy-2-methylpropanamide 3 (116 mg) in 82%
yield. Elemental analysis and melting point was in accord
with reported data,2 while spectroscopic data was as
follows. dH (300 MHz, CDCl3): 9.17 (bs, 1H); 8.03–7.99
(m, 1H); 7.64–7.60 (m, 1H); 7.32–7.28 (m, 1H); 7.24–7.20
(m, 2H) 3.18 (bs, 1H); 1.58 (s, 6H); dC (75 MHz): 174.2,
140.7, 132.0, 131.7, 126.3, 125.0, 119.0, 116.3, 74.5, 28.1.
Chromatography on silica gel, using petroleum ether/ethyl
acetate 9:1 as eluant, furnished the title compound 5b as a
thick red oil (130 mg, 91%). (Found: C, 65.85; H, 4.88; S,
19.56%. C9H8OS requires C, 65.83; H, 4.91; S, 19.52%); dH
(300 MHz, CDCl3): 7.65–7.5 (m, 2H); 7.45–7.38 (m, 2H);
6.84–6.80 (m, 1H); 3.99 (s, 3H); dC (75 MHz): 155.0,
141.2, 130.5, 125.3, 124.6, 120.5, 115.0, 104.1, 55.9. m/z:
164 (Mþ), 149 (100).
4.1.6. [(2-Azido-1-benzothiophen4-yl)oxy]-(tert-butyl)di-
methylsilane 6a. Compound 5a (300 mg, 1.14 mmol) in
6 ml of dry diethyl ether was treated, in inert atmosphere,
with n-butyllithium 1.6 M in hexane (1.25 mmol) and
refluxed for 1 h. Then the reaction mixture was cooled to
2708C and, slowly, tosyl azide (476 mg, 1.3 mmol) in 3 ml
of dry diethyl ether was added. After 5 h at this temperature
the obtained triazene salt was filtered on buckner, washed
with dry diethyl ether and then treated at 08C with an
aqueous solution of sodium pyrophosphate decahydrate
(556 mg, 1.25 mmol, in 5 ml of water). After 15 min of
stirring at this temperature the suspension was filtered on
buckner and extracted twice with diethyl ether and then with
ethyl acetate until the organic phase appeared colourless.
n
max/cm21: 3450 (NH), 3250 (OH), 1670 (CO).
4.1.3. 4-Aminobenzo[b]thiophene 4. 70 mg (0.3 mmol) of
N-aryloxy compound 3 was refluxed in 6 M HCl for two
hours, then the reaction mixture was cooled to 258C and
treated with NaOH solution until neutrality. The aqueous
solution was extracted with diethyl ether, dried over sodium
sulphate and after solvent removal the crude was purified on
silica gel using petroleum ether/ethyl acetate 9:1 as eluant to
give the title compound (41 mg, 91%) as a white solid. Mp
508C (lit.15 50–518C). Spectroscopic data was as follows.
dH (300 MHz, CDCl3): 7.46–7.42 (m, 1H), 7.40–7.36 (m,
1H), 7.18–7.13 (m, 2H), 6.66–6.62 (m, 1H), 4.08 (bs, 2H);
dC (75 MHz):141.3, 129.1, 128.5, 125.3, 124.0, 119.5,
113.2, 109.1. nmax/cm21: 3440, 3340 (NH2), m/z: 149 (Mþ).
Then, after solvent removal, the crude product was purified
by chromatography on florisil (eluant petroleum ether/ethyl
acetate 8:2) giving the title compound (279 mg, 80%) as a
thick yellow oil (Found: C, 55.07; H, 6.21; N, 13.78; S,
10.44%. C14H19N3OSSi requires C, 55.05; H, 6.27; N,
13.76; S, 10.50%); nmax/cm21 2110 (N3); dH (300 MHz,
CDCl3): 7.50–7.40 (m, 1H), 7.19–7.11 (m, 1H), 6.89 (s,
1H), 6.72–6.68 (m, 1H), 1.07 (s, 9H), 0.27 (s, 6H); dC
(75 MHz): 142.7, 125.3, 124.5, 121.0, 115.6, 115.0, 113.6,
108.3, 25.8, 15.9, 20.53.
4.1.7. 2-Azido-4-methoxy-1-benzothiophene 6b. Com-
pound 5b (130 mg, 0.8 mmol) in 4 ml of dry diethyl ether
was treated, in inert atmosphere, with n-butyllithium 1.6 M
in hexane (0.9 mmol) and refluxed for 1 h. Then the reaction
mixture was cooled to 2708C and tosyl azide (170 mg,
0.9 mmol) in 4 ml of dry diethyl ether was added dropwise.
After 5 h at this temperature, the obtained triazene salt was
filtered on buckner, washed with dry diethyl ether and then
treated at 08C with an aqueous solution of sodium
pyrophosphate decahydrate (413 mg, 0.9 mmol, in 4 ml of
4.1.4. 4-(tert-Butyldimethylsilyloxy)benzo[b]thiophene
5a. 4-Hydroxybenzothiophene 1 (512 mg, 3.05 mmol) was
dissolved in 10 ml of dry dichloromethane and to this
solution were added tert-butyldimethylsilylchloride
(4.58 mmol), imidazole (9.15 mmol) and a catalytic amount
of 4-dimethylaminopyridine. The resulting mixture was
stirred in inert atmosphere for 3 h at room temperature, then
was filtered and washed with saturated ammonium chloride
solution and twice with water. After solvent removal the

C. Bonini et al. / Tetrahedron 59 (2003) 7515–7520
7519
water). After 15 min of stirring at this temperature the
suspension was filtered on buckner and extracted twice with
diethyl ether and then with ethyl acetate until the organic
phase appeared colourless.
9H), 0.15 (s, 6H); dC (75 MHz): 169.5, 154.2, 151.9, 150.5,
149.5, 141.5, 131.7, 128.4, 117.7, 117.0, 116.2, 53.9, 29.8,
26.2, 25.7, 19.8, 18.5, 20.4. m/z: 287 (Mþ).
Methyl 5-methoxy-2-methyl(1)benzothieno[2,3-b]pyridine-
4-carboxylate 9b. This was obtained as a thick oil (31 mg,
91%). (Found: C, 62.72; H, 4.58; N, 4.85; S, 11.13%.
C15H13NO3S requires C, 62.70; H, 4.56; N, 4.87; S,
11.16%); dH (300 MHz, CDCl3): 7.75–7.70 (m, 1H),
7.57–7.50 (m, 1H), 7.47–7.40 (m, 1H), 6.95–6.90 (m,
1H), 3.98 (s, 6H), 2.72 (s, 3H); dC (75 MHz): 169.4, 167.8,
156.8, 139.4, 138.2, 132.5, 131.2, 129.1, 128.8, 118.2,
115.6, 106.6, 55.9, 30.3. m/z: 287 (Mþ).
Then, after solvent removal, the crude product was purified
by chromatography on florisil (eluant petroleum ether/ethyl
acetate 8:2) giving the title compound (126 mg, 77%) as a
thick yellow oil. Found: C, 52.65; H, 3.47; N, 20.45; S,
15.63%. C9H7N3OS requires: C, 52.67; H, 3.44; N, 20.47; S,
15.62%; nmax/cm21 2113 (N3); dH (300 MHz, CDCl3):
7.35–7.20 (m, 2H); 7.05 (s, 1H); 6.80–6.75 (m, 1H); 3.95
(s, 3H); dC (75 MHz): 152.7, 139.5, 138.2, 125.3, 124.6,
117.1, 115.7, 110.3, 50.5.
4.1.11. Methyl 5-(2-amino-1,1-dimethyl-2-oxoethoxy)-2-
methyl(1)benzothieno[2,3-b]pyridine-4-carboxylate 10.
The benzothienopyridine 9b (31 mg, 0.11 mmol) was
treated with lithium bromide (31 mg, 0.36 mmol) in 5 ml
of dioxane at room temperature for 19 h. The resulting
mixture was then directly treated with 2-bromo-2-methyl-
propanamide (18 mg, 0.11 mmol) according to a known
procedure.3 Chromatography gave the title compound as a
thick oil (28 mg, 70%). (Found: C, 60.30; H, 5.03; N, 7.85;
S, 8.97%. C18H18N2O4S requires: C, 60.32; H, 5.06; N,
7.82; S, 8.95%). dH (300 MHz, CDCl3): 7.48 (s, 1H), 7.46–
7.42 (m, 1H), 7.24–7.22 (m, 1H), 6.92–6.90 (m, 1H), 6.58
(bs, 1H), 5.72 (bs, 1H), 3.98 (s, 3H), 2.72 (s, 3H), 1.55 (s,
6H); dC (75 MHz): 175.2, 169.2, 165.4, 156.4, 149.6, 139.8,
139.0, 138.1, 131.3, 128.0, 124.5, 118.0, 114.3, 106.2, 66.0,
55.5, 24.2, 22.4. m/z: 358 (Mþ).
4.1.8. [(4-[tert-Butyl(dimethyl)silyl]oxy-1-benzothio-
phen-2-yl) imino](methyl)diphenylphosphorane 7a.
This was prepared from the azide 6a (140 mg, 0.46 mmol)
and methyldiphenylphosphine (92 mg, 0.46 mmol) follow-
ing a procedure recently reported10 for unsubstituted
benzothiophene. Chromatography with petroleum ether/
ethyl acetate 70:30 as eluant gave the title compound
(88 mg, 40%) as a brown powder, mp 90–928C (diethyl
ether). (Found: C, 67.66; H, 6.79; N, 2.99; S, 6.73%.
C27H32NOPSSi requires C, 67.89; H, 6.75; N, 2.93; S,
6.71%); dH (300 MHz, CDCl3): 7.83–7.77 (m, 5H), 7.58–
7.37 (m, 5H), 7.11–7.06 (m, 1H), 6.87–6.77 (m, 1H), 6.52–
6.49 (m, 1H), 6.02 (s, 1H), 2.25–2.20 (d, 3H, JPH¼12.8 Hz);
0.95 (s, 9H), 0.1 (s, 6H); dC (75 MHz): 168.3, 151.7, 147.5,
135.8, 134.7, 134.0, 132.2, 131.2, 130.8, 129.5, 129.0, 128.8,
120.9, 116.1, 113.2, 101.9, 25.7, 18.3, 14.5, 13.8, 20.42.
4.1.12. Methyl 5-[(2-hydroxy-2-methylpropanoyl)-
amino]-2-methyl(1)benzothieno[2,3-b]pyridine-4-car-
boxylate 11. This was obtained as a thick oil (19 mg, 70%)
from the above compound 10 (27.6 mg, 0.078 mmol)
according to a known procedure.3 (Found: C, 60.34; H,
5.05; N, 7.84; S, 8.97%. C18H18N2O4S requires: C, 60.32;
H, 5.06; N, 7.82; S, 8.95%); dH (300 MHz, CDCl3): 7.48 (s,
1H), 7.45 (s, 1H) 7.30–7.25 (m, 2H), 6.98–6.92 (m, 1H),
3.97 (s, 3H), 2.73 (s, 3H), 1.8 (s, 1H), 1.30 (s, 6H); dC
(75 MHz): 175.2, 169.2, 162.21, 156.7, 149.6, 139.8, 139.0,
138.1, 131.0, 128.7, 118.2, 115.6, 105.7, 68.3, 55.8, 29.9,
24.4. m/z: 358 (Mþ).
4.1.9. [(4-methoxy-1-benzothiophen-2-yl)imino]-
(methyl)diphenylphosphorane 7b. This was prepared
from the azide 6b (126 mg, 0.62 mmol) and methyl-
diphenylphosphine (124 mg, 0.62 mmol) following
a
procedure recently reported10 for unsubstituted benzo-
thiophene. Chromatography with petroleum ether/ethyl
acetate 70:30 as eluant gave the title compound (196 mg,
84%) as a red oil (Found: C, 70.04; H, 5.36; N, 3.69; S,
8.50%. C22H20NOPS requires C, 70.01; H, 5.34; N, 3.71; S,
8.49%); dH (300 MHz, CDCl3): 7.62–7.50 (m, 5H), 7.43–
7.32 (m, 5H), 6.98–6.90 (m, 1H), 6.87–6.80 (m, 1H), 6.53–
6.48 (m, 1H), 6.08 (s, 1H), 3.70 (s, 3H), 2.25–2.20 (d, 3H,
JPH¼12.8 Hz); dC (75 MHz): 157.0, 152.3, 140.2, 135.3,
133.0, 132.5, 132.0, 131.7, 131.4, 130.0 129.5, 128.2, 125.8,
121.0, 114.3, 101.5, 55.5, 15.5.
4.1.13. Methyl 5-amino-2-methyl(1)benzothieno[2,3-
b]pyridine-4-carboxylate 12. Compound 11 (19 mg,
0.054 mmol) was dissolved in 6 M HCl (3 ml) and the
resulting mixture was stirred at 1008C for 2 h. After cooling
to 258C the mixture was slowly treated with a solution of
20% NaOH until neutrality, then extracted twice with ethyl
acetate and dried over sodium sulphate. Removal of the
solvent gave the compound 12 as a thick oil (7 mg, 50%).
(Found: C, 61.78; H, 4.42; N, 10.32; S, 11.79%.
C14H12N2O2S requires: C, 61.75; H, 4.44; N, 10.29; S,
11.77%. dH(300 MHz, CDCl3): 7.77 (m, 1H), 7.52 (m, 1H),
7.46 (s, 1H), 7.0 (m, 1H), 6.64 (s, 2H), 3.97 (s, 3H), 2.72 (s,
3H); dC (75 MHz): 170.2, 161.1, 152.0, 144.0, 139.3, 137.7,
127.1, 126.1, 123.2, 119.7, 121.3, 113.8, 52, 24.3.
4.1.10. Synthesis of the (1)benzothieno[2,3-b]pyridines
9a,b. A solution of the appropriate iminophosphorane 7a,b
(0.12 mmol) in 3 ml of dry chloroform was treated with
15 mg (0.12 mmol) of methyl trans 4-oxo-2-pentenoate and
then stirred in inert atmosphere for 34 h at 458C. After
removal of the solvent, the crude product was chromato-
graphed on silica gel, using petroleum ether/ethyl acetate
70:30 as eluant.
Methyl 5-[tert-butyl(dimethyl)silyl]oxy-2-methyl(1)benzo-
thieno[2,3-b]pyridine-4-carboxylate 9a. This was obtained
as a thick oil (7 mg, 14%). (Found: C, 62.00; H, 6.53; N,
3.58; S, 8.24%. C20H25NO3SSi requires: C, 61.98; H, 6.50;
N, 3.61; S, 8.27%); dH (300 MHz, CDCl3): 7.50–7.25 (m,
3H), 7.00–6.95 (m, 1H), 3.90 (s, 3H), 2.72 (s, 3H), 0.81 (s,
Acknowledgements
`
The authors gratefully acknowledge Universita di Bologna

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C. Bonini et al. / Tetrahedron 59 (2003) 7515–7520
7. Benham, C. D.; Blackburn, T. P.; Johns, A.; Kotecha, N. R.;
Martin, R. T.; Thomas, D. R.; Thompson, M.; Ward, R. W.
Bioorg. Med. Chem. Lett. 1995, 5, 2455.
and MIUR (Ministry of Instruction, University and
Research—Rome) for financial support (Project FIRB
RBNE017F8N).
8. Funicello, M.; Degl’Innocenti, A.; Scafato, P.; Spagnolo, P.;
Zanirato, P. J. Chem. Soc., Perkin Trans. 1 1996, 214.
9. Bonini, C.; Funicello, M.; Chiummiento, L.; Spagnolo, P.
Tetrahedron 2000, 56, 1517.
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