A simple, one-pot synthesis of N-Alkyl and N-aryl thieno[2,3-d] pyrimidinones from thiophene-and benzothiophene-2-yl-ureas

Article abstract of DOI:10.1080/00397911.2011.596985

We herein describe a convenient, one-pot synthesis of N-substituted thieno and benzothieno[2,3-d]pyrimidinones from the respective thiophene-2-yl ureas. This intramolecular cyclization, which presumably proceeds via a Vilsmeier-Haack dimethyliminium inter

Full text of DOI:10.1080/00397911.2011.596985

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A Simple, One-Pot Synthesis of N-Alkyl
and N-Aryl Thieno[2,3-d]pyrimidinones
from Thiophene- and Benzothiophene-2-
yl-ureas
Ian A. Yule a & Colin W. G. Fishwick a
a School of Chemistry, University of Leeds, Leeds, UK
Accepted author version posted online: 09 Feb 2012.Published
online: 02 Nov 2012.
To cite this article: Ian A. Yule & Colin W. G. Fishwick (2013): A Simple, One-Pot Synthesis of N-Alkyl
and N-Aryl Thieno[2,3-d]pyrimidinones from Thiophene- and Benzothiophene-2-yl-ureas, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
43:3, 337-344
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Synthetic Communications1, 43: 337–344, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.596985
A SIMPLE, ONE-POT SYNTHESIS OF N-ALKYL AND
N-ARYL THIENO[2,3-d]PYRIMIDINONES FROM
THIOPHENE- AND BENZOTHIOPHENE-2-YL-UREAS
Ian A. Yule and Colin W. G. Fishwick
School of Chemistry, University of Leeds, Leeds, UK
GRAPHICAL ABSTRACT
Abstract We herein describe a convenient, one-pot synthesis of N-substituted thieno and
benzothieno[2,3-d]pyrimidinones from the respective thiophene-2-yl ureas. This intramol-
ecular cyclization, which presumably proceeds via a Vilsmeier–Haack dimethyliminium inter-
mediate, has proven to be regioselective when performed in the presence of N,N0-bisarylureas
and allows for independent functionalization of the pyrimidinone N3 and C4 positions.
Keywords Regioselective; thieno[2,3-d]pyrimidinones; Vilsmeier–Haack reaction
INTRODUCTION
Thienopyrimidinones are a class of compound with wide-ranging biological
activities including melanin-concentrating hormone receptor-1 (MCH-R1) antago-
nists linked with obesity,[1] fibroblast growth factor 1 kinase (FGFR1) inhibitors as
anticancer agents,[2] and anti-varicella-zoster virus (VZV) compounds.[3] New meth-
odology for the preparation of these compounds is therefore of interest and utility.
Here, we report a convenient and mild method for the synthesis of N-alkyl or N-aryl
thieno[2,3-d]pyrimidin-2-ones from thiophene-2-yl-ureas under Vilsmeier–Haack
conditions (Fig. 1c). In an early work, Hirohashi and coworkers describe the synthesis
of the same heterocyclic core through reaction of 2-amino-3-ketothiophenes with
isocyanates, giving the corresponding thiophene-2-yl-ureas in situ prior to high-
temperature intramolecular condensation in benzene to give the thienopyrimidinone
(Fig. 1a).[4] Alternatively, Brancale and coworkers also describe a preparation of this
type of heterocycle via intramolecular cyclization of 4-methylthio-5-alkynylpyrimidi-
nones (Fig. 1b).[3] The procedure described offers improvements over these earlier
Received May 20, 2011.
Address correspondence to Colin W. G. Fishwick, School of Chemistry, University of Leeds, Leeds
LS2 9JT, UK. E-mail: C.W.G.Fishwick@leeds.ac.uk
337

338
I. A. YULE AND C. W. G. FISHWICK
Figure 1. Syntheses of thieno[2,3-d]pyrimidin-2-ones: (a) High-temperature condensation reported by
Hirohasi et al.[4] (b) Intramolecular cyclization reported by Brancale et al.[3] (c) Vilsmeier–Haack-mediated
cyclization reported herein.
approaches in that lower temperatures can be used, C4-functionalization may be
introduced during the cyclization step, and benzothieno[2,3-d]pyrimidin-2-ones can
be readily accessed.
DISCUSSION
The thiophene-2-yl-ureas used as substrates in the present work could be pre-
pared conveniently from the corresponding thiophene-2-carboxylic acids via Curtius
rearrangement, under conditions described by Bloxham et al.[5] Carboxylic acids 1,
4a, and 4b were refluxed respectively in a mixture of dichloromethane (DCM) and
thionyl chloride to give the corresponding acid chlorides prior to reaction with
sodium azide. Curtius rearrangement in refluxing toluene led to the corresponding
thiophene-2-yl-isocyanates, which were quenched in situ with ethylamine or aniline
to give thiophene-2-yl-ureas 2a, 2b, and 5a–d (Scheme 1). Addition of the ureas to
a cooled, premixed solution of dimethylformamide and phosphorus oxychloride in
chloroform followed by a short period of heating led to the desired thieno[2,3-d]
pyrimidin-2-ones in moderate yield (22–79%). Of particular interest was the obser-
vation that in the case of N,N0-bisarylureas (2b, 5b, and 5d), cyclization occured regio-
selectively to give the thiophenyl-fused heterocycles (6b, 6c, and 6e), substantially

THIENO[2,3-d]PYRIMIDIN-2-ONES
339
Scheme 1. Reagents and conditions: (a) SOCl2, DCM, DMF (cat.), 65 ꢀC, 16h; then NaN3, THF, 0 ꢀC–rt,
0.5 h; then PhMe, 115 ꢀC, 2 h; then RNH2, rt, 16h, 45–78%; (b) DMF or DMA, POCl3, CHCl3 or 1,4-diox-
ane, 0–75 ꢀC or 0–110 ꢀC, 0.5ꢁ 4 h, 22–79%.
Figure 2. Heterocycles potentially available through application of this methodology.
increasing the utility of this reaction. Additionally, it was found that dimethylforma-
mide could be replaced with dimethylacetamide, thus delivering a methyl substituent
to the C4 position (6c).
In summary, we have described a simple, efficient, one-pot, regioselective
synthesis of thieno[2,3-d]pyrimidin-2-ones from thiophene-2-yl-ureas. Through
choice of reactant, the functionality can be independently varied at positions N3
and C4. Though not explored herein, we anticipate that this methodology would
be applicable to the synthesis of similarly substituted pyrolo[2,3-d]pyrimidin-2-ones
and furo[2,3-d]pyrimidin-2-ones (Fig. 2).
EXPERIMENTAL
Flash column chromatography was carried out using geduran silica gel 60
(40–63 mm) supplied by Merck Chemicals. Thin-layer chromatography (TLC) was
conducted using aluminium precoated silica-gel plates (Macherey-Nagek 818133,
0.20 mm thick) supplied by Merck chemicals. All reagents were obtained from
commercial sources and were used without further purification. EtOAc refers to ethyl
acetate, MeOH to methanol, THF to tetrahydrofuran, petrol to petroleum ether (bp
40–60 ꢀC), ether to diethylether, and DCM to dichloromethane. Microanalysis was
performed using a Carlo Erba 1108 elemental analyzer, and high-resolution mass

340
I. A. YULE AND C. W. G. FISHWICK
spectrometry (HRMS) was carried out using a VG Autospec mass spectrometer
operating at 70 eV, using electron spray ionization (ES), correct to four decimal
places. Infrared (IR) spectra were recorded on a Perkin-Elmer Spectrum One Fourier
transform (FT)–IR spectrometer. Vibrational frequencies are reported in wavenum-
bers (cmꢁ1). Melting points were recorded on a Reichert hotstage apparatus and are
reported uncorrected.
Proton (1H) and carbon (13C) NMR spectra were recorded on a 300=75-MHz
Bruker DPX300 or a 500=125-MHz Bruker Advance 500 FT spectrometer as indi-
cated, using an internal deuterium lock. Chemical shifts are reported in parts per mil-
lion (ppm) and are reported with reference to tetramethylsilane (TMS) as an internal
standard. Samples were prepared in either deuterated chloroform (CDCl3) or deut-
erated dimethylsulfoxide (d6-DMSO), as indicated. Solvents for this purpose were
obtained from Sigma-Aldrich chemical company Ltd. Liquid chromatographic–
mass spectrometric (LC-MS) analysis was carried out using an Agilent Technologies
1200 series HPLC coupled to a Bruker HCT Ultra mass spectrometer (column 50 ꢂ
20 mm C18 reverse phase, solvent mix water=acetonitrile=0.1% formic acid, UV
detection 190–750 nm, gradient 95:5 H2O–MeCN to 10:90 H2O–MeCN, flow rate
1.5 cm3 minꢁ1).
Preparation of Thiophene-2-yl Ureas (2a, 2b, and 5a–5d)
Dimethylformamide (50 mL) was added to a stirred suspension of the appropri-
ate carboxylic acid (1.00 g, 5.61 mmol) in DCM (20 mL) and thionyl chloride (20 mL).
The mixture was heated to 65 ꢀC for 16 h, cooled to room temperature, and evaporated
in vacuo. The crude acid chloride was dissolved in THF (30 mL), cooled to 0 ꢀC, and
treated dropwise with a solution of sodium azide (0.40 g, 6.17 mmol) in water (10 mL).
The mixture was warmed to room temperature, stirred for 0.5 h, and extracted with
DCM (2 ꢂ 40 mL) followed by ethyl acetate (2 ꢂ 20 mL). The combined organic
extracts were dried (MgSO4), the solvents removed in vacuo and the resulting residue
dissolved in toluene (40 mL). This solution was then heated under reflux for 2 h, cooled
to room temperature, treated with the appropriate amine (8.40 mmol), and stirred at
room temperature overnight. Phenyl ureas 2b, 5b, and 5d were collected by filtration,
washed with ether and air dried. Ethyl ureas 2a, 5a, and 5c did not precipitate. The
reaction mixtures were evaporated in vacuo, and the products obtained following col-
umn chromatography (SiO2) were eluted with the indicated solvent mixture.
Selected Data
1-(Benzo[b]thiophen-2-yl)-3-ethylurea (2a, C11H12N2OS). Eluting with 2:1
petrol–EtOAc to 1:1 petrol–EtOAc gave the title compound (0.272 g, 1.53 mmol,
45%) as a light yellow solid, mp 178–180 ꢀC (from EtOH); Rf 0.20 (2:1 petrol–
EtOAc); dH (500 MHz, DMSO-d6); 9.70 (1H, br), 7.73 (1H, d, J 7.7), 7.54 (1H,
d, J 8.1), 7.24 (1H, t, J 7.3), 7.11 (1H, t, J 7.7), 6.67 (1H, s), 6.34 (1H, br), 3.16
(2H, dq, J 5.6 and 7.2), 1.08 (3H, t, J 7.2); dC (125 MHz, DMSO-d6); 154.1,
142.7, 137.9, 134.1, 124.1, 121.5, 121.4, 120.8, 102.2, 34.1, 15.3; nmax=cmꢁ1 (solid):
3379, 1655, 1573 and 1456; m=z (ES) 221.1 (10%, MHþ), 243.1 (90% MNaþ),
Found MNaþ, 243.056; C11H12N2OS requires MNa 243.057.

THIENO[2,3-d]PYRIMIDIN-2-ONES
341
1-(Benzo[b]thiophen-2-yl)-3-phenylurea (2b, C15H12N2OS). Filtering,
washing with ether, and air drying gave the title compound (0.385 g, 1.44 mmol,
51%) as a light beige powder, mp 209–211 ꢀC (from EtOH); Rf 0.37 (2:1 petrol–
EtOAc); dH (500 MHz, DMSO-d6; 9.96 (1H, br), 8.89 (1H, br), 7.79 (1H, d, J 8.1),
7.61 (1H, d, J 8.1), 7.49 (2H, d, J 8.1), 7.32 (2H, t, J 8.1), 7.28 (1H, t, J 7.3), 7.17
(1H, t, J 7.3), 7.03 (1H, t, J 7.7), 6.84 (1H, s); dC (125 MHz, DMSO-d6; 151.7,
141.4, 139.1, 137.7, 134.2, 128.8, 124.2, 122.3, 121.9, 121.6, 121.2, 118.6, 103.8;
n
max=cmꢁ1 (solid); 3319, 1642, 1557, 1435 and 1237; m=z (ES) 269.1 (30%, MHþ),
291.1 (70% MNaþ), Found MHþ, 269.0739; C15H12N2OS requires MH 269.0749.
1-(4,5-Dimethylthiophen-2-yl)-3-ethylurea (5a, C9H14N2OS). Eluting with
2:1 petrol–EtOAc gave the title compound (0.499 g, 2.50 mmol, 78%) as a light yellow
solid, mp 92–94; Rf 0.18 (2:1 petrol–EtOAc); dH (300 MHz, CHCl3): 6.47 (1H, s), 5.97
(1H, br s), 4.84 (1H, br), 3.27 (2H, dq, J 5.2 and 7.2), 2.28 (3H, s), 2.07 (3H, s), 1.12
(3H, t, J 7.2); m=z (ES) 199.1 (30%, MHþ), 221.1 (70% MNaþ), Found MHþ,
199.0898; C9H14N2OS requires MH 199.0900.
1-(4,5-Dimethylthiophen-2-yl)-3-phenylurea (5b, C13H14N2OS). Filtering,
washing with ether, and air drying gave the title compound (0.470 g, 1.91 mmol,
55%) as a light yellow powder, mp 184–186 ꢀC (from EtOH): Rf 0.49 (2:1 petrol–
EtOAc); dH (300 MHz, DMSO-d6); 9.36 (1H, br s), 8.71 (1H, br s), 7.44 (2H, d, J
7.2), 7.28 (2H, t, J 7.7), 6.97 (1H, t, J 7.2), 6.25 (1H, s), 2.20 (3H, s), 2.01 (3H, s);
dC (75 MHz, DMSO-d6); 151.6, 139.5, 136.1, 129.6, 129.0, 121.9, 121.6, 118.1,
112.3, 13.3, 12.1; nmax=cmꢁ1 (solid); 3210, 1643 and 1590; m=z (ES) 247.1 (20%,
MHþ), 269.1 (80% MNaþ). Found MHþ, 247.0897, C13H14N2OS requires MH
247.0900, LC-MS: rT ¼ 1.96 min; m=z (ESþ) found MHþ, 247.1.
1-Ethyl-3-(thiophen-2-yl)urea (5c, C7H10N2OS). Eluting with 2:1 petrol–
EtOAc gave the title compound (0.383 g, 2.33 mmol, 58%) as a beige solid, mp
117–119 ꢀC (from EtOAc–petrol); Rf 0.19 (2:1 petrol–EtOAc); dH (300 MHz,
DMSO-d6): 9.40 (1H, s), 6.74 (2H, app. d, J 2.9), 6.39 (1H, t, J 2.4), 6.17 (1H, br t,
J 5.2), 3.10 (2H, dq, J 5.7 and 7.2), 1.04 (3H, t, J 7.2); dC (75 MHz, DMSO-d6);
154.2, 142.1, 123.9, 114.8, 107.8, 34.2, 15.4; nmax=cmꢁ1 (solid): 3327, 2983, 1640,
1580 and 1274; m=z (ES) 171.1 (30%, MHþ), 193.0 (70% MNaþ). Found MNaþ,
193.0414; C7H10N2OS requires MNa 193.0406.
1-Phenyl-(thiophen-2-yl)urea (5d, C11H10N2OS). Filtering, washing with
ether, and air-drying gave the title compound (0.509 g, 2.33 mmol, 60%) as an
off-white powder, mp 217–219 ꢀC (from EtOH); Rf 0.40 (2:1 petrol–EtOAc); dH
(500 MHz, DMSO-d6); 9.72 (1H, br s), 8.71 (1H, br s), 7.45 (2H, d, J 8.0), 7.29
(2H, t, J 8.0), 6.99 (1H, t, J 7.7), 6.88 (1H, d, J 5.5), 6.82 (1H, d, J 4.0), 6.56 (1H,
br); dC (125 MHz, DMSO-d6); 151.7, 141.0, 139.4, 128.8, 124.1, 122.0, 118.4, 115.9,
109.5; nmax=cmꢁ1 (solid); 3083, 1646, 1566, 1441 and 1243; m=z (ES) 219.1 (70%,
MHþ), 241.0 (30% MNaþ). Found MHþ, 219.0588; C11H10N2OS requires MH
219.0587, LC-MS; rT ¼ 1.75 min; m=z (ESþ) found MNaþ, 241.0.
Preparation of Thieno[2,3-d]pyrimidin-2-ones (3a, 3b, 6a, 6b, 6d, 6e)
The appropriate thiophene-2-yl-urea (0.490 g, 2.46 mmol) was added to a
stirred solution of dimethylformamide (0.38 mL, 4.92 mmol) and phosphorus(V)

342
I. A. YULE AND C. W. G. FISHWICK
oxychloride (0.34 mL, 3.69 mmol) in chloroform (25 mL) at 0 ꢀC. The mixture was
stirred for 10 min, warmed to 75 ꢀC for 45 min (3a, 6a, and 6d) or 4 h (3b, 6b, and
6e), cooled to room temperature, and reduced in vacuo. The resulting residue was
partitioned between saturated aqueous sodium bicarbonate solution (10 mL) and
ethyl acetate (30 mL). The layers were separated, and the aqueous layer was further
extracted with ethyl acetate (2 ꢂ 30 mL). The combined organic fraction was dried
(MgSO4) and reduced in vacuo and the product was purified using column chroma-
tography (SiO2) eluting with the specified solvents.
Selected Data
3-Ethylbenzothieno[2,3-d]pyrimidin-2(3H)-one (3a, C12H10N2OS). Eluting
with neat EtOAc gave the title compound (0.210 g, 0.91 mmol, 79%) as off-white
microcrystals, mp > 250 ꢀC (from EtOH); Rf 0.20 (EtOAc), Found: C, 62.4; H,
4.35; N, 12.2; C12H10N2OS requires C, 62.6; H, 4.40; N, 12.2%, dH (500 MHz,
DMSO-d6); 9.25 (1H, s, 4-H), 7.98 (1H, d, J 7.5, 5-H), 7.88 (1H, d, J 8.0, 8-H),
7.50–7.27 (2H, m), 4.04 (2H, q, J 7.2, 3-CH2CH3), 1.37 (3H, t, J 7.2, 3-CH2CH3);
dC (125 MHz, DMSO-d6); 178.0, 152.9, 143.6, 134.1, 131.2, 127.0, 126.0, 123.3,
120.6, 113.6, 46.2, 14.1; nmax=cmꢁ1 (solid); 2983, 1643, 1510, 1455 and 1372; m=z
(ES) 231.1 (100%, MHþ), Found MHþ, 231.0588; C12H10N2OS requires MH
231.0587, LC-MS; rT ¼ 1.52 min; m=z (ESþ) found MHþ, 231.0.
3-Phenylbenzothieno[2,3-d]pyrimidin-2(3H)-one (3b, C16H10N2OS). Elut-
ing with 1:1 petrol–EtOAc gave the title compound (0.205 g, 0.74 mmol, 66%) as
light yellow microcrystals, mp 235–238 ꢀC (from EtOH); Rf 0.55 (EtOAc); dH
(300 MHz, DMSO-d6); 9.31 (1H, s, 4-H), 8.14–8.01 (1H, m), 7.94–7.89 (1H, m),
7.63–5.59 (4H, m), 7.57–7.51 (1H, m), 7.47–7.43 (2H, m); dC (75 MHz, DMSO-d6);
179.5, 152.6, 143.9, 140.8, 134.2, 131.2, 129.1, 128.8, 127.3, 127.0, 126.1, 123.3,
121.3, 114.0; nmax=cmꢁ1 (solid); 2987, 1664, 1502 and 1451; m=z (ES) 279.1 (20%,
MHþ), 301.0 (80% MNaþ), Found MNaþ, 301.0402; C16H10N2OS requires MNa
301.0406, LC-MS: rT ¼ 1.68 min; m=z (ESþ) found MHþ, 279.0.
3-Ethyl-5,6-dimethylthieno[2,3-d]pyrimidin-2(3H)-one (6a, C10H12N2
OS). Eluting with 2.5% MeOH in DCM gave the title compound (0.320 g,
1.52 mmol, 62%) as an off-white solid, mp 218–220 ꢀC (from EtOH); Rf 0.10
(EtOAc), Found: C, 57.9; H, 5.85; N, 13.5; C10H12N2OS requires C, 57.7; H, 5.80;
N, 13.5%, dH (300 MHz, DMSO-d6); 8.61 (1H, s), 4.00 (2H, q, J 7.2), 2.29 (3H, s),
2.09 (3H, s), 1.28 (3H, t, J 7.2); nmax=cmꢁ1 (solid): 3051, 2978, 1679, 1643 and
1505; m=z (ES) 209.1 (50%, MHþ), 231.1 (80% MNaþ), Found MNaþ, 231.0570.
C10H12N2OS requires MNa 231.0563.
5,6-Dimethyl-3-phenylthieno[2,3-d]pyrimidin-2(3H)-one (6b, C14H12N2
OS). Eluting with 2.5% MeOH in DCM gave the title compound (0.220 g, 0.86 mmol,
69%) as a beige crystalline solid, mp 182–185 ꢀC (from EtOH); Rf 0.16 (2.5% MeOH=
DCM), Found: C, 65.3; H, 4.70; N, 10.9; C14H12N2OS requires C, 65.6; H, 4.70; N,
10.9%; dH (500 MHz, DMSO-d6); 8.57 (1H, s), 7.59–7.49 (5H, m), 2.33 (3H, s), 2.12
(3H, s); dC (125 MHz, DMSO-d6); 178.5, 152.3, 142.4, 142.3, 141.0, 129.0, 128.7,
126.9, 123.5, 119.9, 13.2, 10.4; nmax=cmꢁ1 (solid); 3047, 1652, 1621 and 1496; m=z

THIENO[2,3-d]PYRIMIDIN-2-ONES
343
(ES) 257.1 (60%, MHþ), 279.1 (40% MNaþ); Found MHþ, 257.0741, C14H12N2OS
requires MH 257.0743, LC-MS; rT ¼ 1.56 min, m=z (ESþ) found MHþ, 257.0.
3-Ethylthieno[2,3-d]pyrimidin-2(3H)-one (6d, C8H8N2OS). Eluting with
5% MeOH in DCM, followed by refluxing in MeOH with activated charcoal owing
to strong color, and triturating with EtOAc gave the title compound (0.086 g,
0.48 mmol, 22%) as a beige powder, mp > 250 ꢀC (from EtOH); Rf 0.31 (5% MeOH=
DCM); dH (300 MHz, DMSO-d6); 8.88 (1H, s, 4-H), 7.29 (1H, d, J 6.7, 6-H), 7.08 (1H,
s, J 6.7, 5-H), 3.99 (2H, q, J 7.2, 3-CH2CH3), 1.29 (3H, t, J 7.2, 3-CH2CH3); nmax=cmꢁ1
(solid); 3328, 1631 and 1380; m=z (ES) 229.0 (70%, MHþ), 251.0 (30% MNaþ); Found
MHþ, 229.0420. C12H8N2OS requires MH 229.0430, LC-MS; rT ¼ 0.16 min, m=z
(ESþ) found MHþ, 181.0.
3-Phenylthieno[2,3-d]pyrimidin-2(3H)-one (6e, C12H8N2OS). Eluting with
2:1 EtOAc–petrol followed by trituration with EtOAc gave the title compound
(0.084 g, 0.368 mmol, 27%) as an orange powder, mp 225–227 ꢀC (from EtOH); Rf
0.19 (EtOAc); dH (300 MHz, DMSO-d6); 8.84 (1H, s), 7.57–7.51 (5H, m), 7.34
(1H, d, J 5.7), 7.08 (1H, d, J 5.7); dC (75 MHz, DMSO-d6); 179.6, 152.1, 145.6,
140.9, 129.1, 128.7, 126.8, 123.7, 120.5, 117.6; nmax=cmꢁ1 (solid); 3068, 1649, 1485
and 1452; m=z (ES) 203.0 (100%, MNaþ), Found MNaþ, 203.0254, C8H8N2OS
requires MNa 203.0250, LC-MS: rT ¼ 1.35 min, m=z (ESþ) found MHþ, 229.0.
Preparation of 4,5,6-Trimethyl-3-phenylthieno[2,3-d]pyrimidin-
2(3H)-one 6c
Phosphorus(V) oxychloride (0.085 mL, 0.91 mmol) was added to a solution of
dimethylacetamide (0.11 mL, 1.22 mmol) in chloroform (10 mL) at 0 ꢀC. The mixture
was stirred for 10 min and treated with 5b (0.150 g, 0.61 mmol). The mixture was
warmed to 75 ꢀC for 2 h, cooled to room temperature, and reduced in vacuo. The
resulting residue was redissolved in 1,4-dioxane (10 mL) and warmed to 110 ꢀC for
10 min, upon which a heavy green precipitate was observed. The mixture was cooled
to room temperature and partitioned between saturated aqueous sodium bicarbonate
(20 mL) and ethyl acetate (30 mL). The layers were separated, and the aqueous phase
was further extracte with ethyl acetate (2 ꢂ 30 mL). The combined organic fraction
was dried (MgSO4) and reduced in vacuo. The resulting orange solid was purified
by column chromatography, eluting with 2.5% methanol in DCM, to give the title
compound (0.119 g, 0.44 mmol, 72%) as a light yellow crystalline solid, mp 204–
207 ꢀC (from EtOH): Rf 0.33 (2.5% MeOH=DCM); dH (500 MHz, DMSO-d6); 7.58
(2H, t, J 7.7), 7.51 (1H, t, J 7.7), 7.34 (2H, d, J 7.7), 2.33 (6H, s), 2.28 (3H, s); dC
(125 MHz, DMSO-d6); 177.1, 154.3, 152.9, 138.6, 129.6, 128.7, 127.9, 127.1, 117.9,
18.7, 14.6, 13.3; nmax=cmꢁ1 (solid): 2919, 1657, 1581 and 1495; m=z (ES) 271.1
(60%, MHþ), 293.1 (40% MNaþ); (Found MHþ, 271.0902. C15H14N2OS requires
MH 271.0900); LC-MS; RT ¼ 1.60 min, m=z (ESþ) found MHþ, 271.0.
ACKNOWLEDGMENTS
The authors would like to thank Craig Avery for useful discussion, and Biota
Europe Ltd (UK) for support during the course of this research.

344
I. A. YULE AND C. W. G. FISHWICK
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