Further reactions of furans with trithiazyl trichloride; mechanistic considerations

Article abstract of DOI:10.1039/a700488e

The reaction of 2,5-diarylfurans with trithiazyl trichloride 1 to give 5-aroyl-3-arylisothiazoles in a useful one-step synthesis of isothiazoles has been extended to both weakly and strongly polarised unsymmetrical 2,5-diarylfurans. These react in an entirely analogous manner; the more electron releasing aryl group becomes incorporated into the 5-aroyl group of the isothiazole as the exclusive (strong polarisation) or the major (weak polarisation) product. However, with 3-bromo-2-(4-methoxyphenyl)-5-(4-nitrophenyl)-furan 7, where the more reactive furan β-position is now substituted, this regiospecificity is reversed (to give isothiazole 8). When one of the α-aryl groups in the furan is replaced by methyl the same regiospecific isothiazole formation is now accompanied by some ring and side chain chlorination (15 → 16 + 17 + 18). All of these results can be explained by mechanisms (Schemes 2 and 5) which involve initial electrophilic attack of the furan to give a β-thiazyl derivative. This highly reactive (nitrenoid) substituent then induces a novel opening of the furan ring 21 to give a highly delocalised intermediate 22 which recyclises to the isothiazole.

Full text of DOI:10.1039/a700488e

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Further reactions of furans with trithiazyl trichloride; mechanistic
considerations
Charles W. Rees and Tai-Yuen Yue
Department of Chemistry, Imperial College of Science, Technology and Medicine, London,
UK SW7 2AY
The reaction of 2,5-diarylfurans with trithiazyl trichloride 1 to give 5-aroyl-3-arylisothiazoles in a useful
one-step synthesis of isothiazoles has been extended to both weakly and strongly polarised unsymmetrical
2,5-diarylfurans. These react in an entirely analogous manner; the more electron releasing aryl group
becomes incorporated into the 5-aroyl group of the isothiazole as the exclusive (strong polarisation) or
the major (weak polarisation) product. H owever, with 3-bromo-2-(4-methoxyphenyl)-5-(4-nitrophenyl)-
furan 7, where the more reactive furan â-position is now substituted, this regiospecificity is reversed
(to give isothiazole 8). When one of the á-aryl groups in the furan is replaced by methyl the same
regiospecific isothiazole formation is now accompanied by some ring and side chain chlorination
(15 → 16 ϩ 17 ϩ 18). All of these results can be explained by mechanisms (Schemes 2 and 5) which
involve initial electrophilic attack of the furan to give a â-thiazyl derivative. This highly reactive (nitrenoid)
substituent then induces a novel opening of the furan ring 21 to give a highly delocalised intermediate 22
which recyclises to the isothiazole.
Introduction
N
N
S
Cl
N
S
S
We have reported the reactions of 2,5-disubstituted furans with
trithiazyl trichloride 1, which is in equilibrium with the mono-
R
R
R
R
R
R
O
O
O
N
Cl
Cl
S
S
3 N
S Cl
N
N
R
N
R
S
Cl
R
R
N
1
S
S
O
O
᎐
mer, thiazyl chloride N᎐S᎐Cl to give isothiazoles regiospecifi-
᎐
Scheme 2
cally and in good yields under mild conditions.1 We proposed
two possible mechanisms for this reaction, both initiated by the
Unsymmetrical 2,5-diarylfurans with trimer 1
monomer as the reacting species; Diels–Alder cycloaddition of
N᎐S᎐Cl across the furan 2,5-positions (Scheme 1) or electro-
2-(4-Methoxyphenyl)-5-(4-nitrophenyl)furan 2 was synthesised
from furan using the classical Gomberg reaction followed by a
palladium-catalysed coupling reaction,2 introducing the meth-
oxyphenyl group first to faciliate the aryl bromide-palladium
reaction. 4-Methoxyphenyldiazonium chloride and furan gave
2-(4-methoxyphenyl)furan in low yield (25%)3 and this was
treated with 4-bromonitrobenzene with a catalytic amount of
Pd(Ph3P)4 to give 2 in 59% yield. Treatment of 2 with one
equivalent of the trimer 1 in boiling THF cleanly gave one
product (3) in 85% yield. HRMS and microanalysis indicated
᎐
᎐
O
R
R
R
R
N
S
N
O
N
H
R
S
S
R
Cl
Cl
Cl
O
the molecular formula C17H12N2O4S. The H and 13C NMR
1
R
spectra of the product were consistent with the two possible
isomeric isothiazoles 3 and 4. The IR spectrum showed a strong
R
N
S
O
Scheme 1
NO2
philic substitution, via sulfur, at an unsubstituted β-position
(Scheme 2). We have now investigated the scope of this reaction
further, with emphasis on unsymmetrical furans, including
some with alkyl substituents, and we produce evidence favour-
ing the electrophilic substitution mechanism.
In order to distinguish between the proposed mechanisms, we
have treated unsymmetrically 2,5-disubstituted and 2,3,5-
trisubstituted furans with trithiazyl trichloride 1. It was con-
sidered that the regiochemistry of these reactions with strongly
polarised furans and those with only one free β-position would
provide useful mechanistic information. We looked first at
polarised 2,5-diarylfurans.
N
O
1
O
S
(85%)
NO2
MeO
3
2
OMe
absorption at 1643 cmϪ1, which is very similar to that of
5-(4-methoxybenzoyl)-3-(4-methoxyphenyl)isothiazole 5 (1645
cmϪ1); isothiazole 5 was prepared in an analogous reaction
between 2,5-bis(4-methoxyphenyl)furan and the trimer 1.
J. Chem. Soc., Perkin Trans. 1, 1997
2247

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This supported structure 3 over 4 for the first reaction prod-
uct, and this was confirmed by comparison of the mass spectra
of 3 and 5, both of which showed a peak at m/z 135 (100%) for
the 4-methoxybenzoyl group. None of the isomer 4 was
the β-substitution mechanism of Scheme 2, with substitution of
the furan by SN at the only available site (C-4). The reaction is
distinctly slower because this position is deactivated by the
nitrophenyl group.†
As for the Diels–Alder cycloaddition mechanism, product 8
would indeed arise from furan 7 by way of the favoured orient-
ation shown in 6 for the unbrominated furan. However, it is
difficult to rationalise the complete reversal of this orientation
on passing from furan 2 to furan 7, as would be required in this
mechanism. Bulky substituents at the furan 2,5-positions would
also be expected to reduce the rate of cycloaddition more than
the rate of β-substitution, yet 2,5-di-tert-butylfuran reacts well
with the trimer 1 to give the corresponding isothiazole in only
slightly reduced yield.1
OMe
OMe
N
O
δ−
S
N
δ+
O
S
O
NO2
MeO
+
N
S Cl
5
4
NO2
6
OMe
Other 2,5-diarylfurans with trimer 1
observed and the reaction of trimer with furan 2 is highly
regioselective. This fits well for the electrophilic substitution
mechanism (Scheme 2) since the electron releasing methoxy-
phenyl group at C-2 and the electron withdrawing nitrophenyl
group at C-5 would both strongly direct substitution to C-3,
which then leads on to formation of the observed product 3
with the 4-methoxybenzoyl group adjacent to sulfur. The for-
mation of 3 is harder to accommodate on the Diels–Alder
mechanism (Scheme 1) since the favoured orientation 6, based
on the polarities of the two components, would lead to the
regioisomer 4, which is not observed.
If electrophilic substitution of furan 2 does occur at C-3 as
we propose, then this ring position could be ‘blocked’ by an
alternative electrophilic substitution, such as bromination, and
the consequences of this on the trimer reaction observed. We
have already shown that 3-bromo-2,5-diphenylfuran reacts with
the trimer 1 to give 5-benzoyl-4-bromo-3-phenylisothiazole
regioselectively in the standard way, without any rearrange-
ment.1 Therefore furan 2 was treated with one equivalent of N-
bromosuccinimide (NBS) to give a monobrominated product
for which all the spectroscopic data indicated the expected 3-
bromo structure 7. For example, the 1H NMR spectrum of the
We have already seen that highly polarised 2,5-disubstituted
furans react with the trimer 1 to give only one isothiazole. We
assumed that if the electronic properties of the substituents
were more evenly balanced then both isomeric isothiazoles
might be formed, and the ratio of these products could shed
further light on the reaction mechanism. Therefore 2-(4-
methylphenyl)-5-phenylfuran 9 and 2-(4-methoxyphenyl)-5-(4-
methylphenyl)furan 12 were prepared by the same method as
described above for compound 2. Methyl and methoxy sub-
stituents were chosen to facilitate the determination of the
1
product ratios by H NMR spectroscopy. The furans 9 and 12
were treated with one equivalent of the trimer in boiling THF
and the expected isothiazoles were obtained in each case
(Scheme 3), as shown by HRMS and the other spectral data.
Ph
Tol
N
1
+
N
O
O
Ph
S
Tol
S
O
Tol
Ph
11
10
9
OMe
Tol
Anis
Br
Br
1
+
O
N
O
N
N
Anis
1
S
O
Tol
O
O
S
S
Anis
(64%)
Tol
NO2
MeO
14
13
12
8
7
NO2
Tol = 4-MeC6H4
Anis = 4-MeOC6H4
brominated furan 7 showed a singlet at 6.96 ppm, whereas that
of the unbrominated compound 2 showed two doublets at 6.67
and 6.94 ppm, corresponding to the ring protons at C-3 and
C-4 respectively. 3-Bromo-2-(4-methoxyphenyl)-5-(4-nitro-
phenyl)furan 7 was then treated with trimer under the same
conditions as above (boiling THF ). Monitoring by TLC
showed the reaction to be considerably slower than that of
furan 2, but after refluxing the reaction mixture for 1 h, chrom-
atography gave a yellow product (8) in 64% yield. This had a
molecular ion at m/z 420 with a typical isotope pattern for one
bromine. HRMS and microanalysis showed the molecular for-
mula to be C17H11BrN2O4S. The 1H NMR spectrum showed the
absence of a proton on the isothiazole ring and no bromination
had occurred in the benzene rings. The mass spectrum showed
a fragment peak for 4-nitrobenzoyl and not for 4-methoxy-
benzoyl, and structure 8 was further supported by the νC᎐O
absorption at 1670 cmϪ1 compared with 1643 and 1645 cmϪ1 for
the 4-methoxybenzoyl compounds 3 and 5. Structure 8 was
finally confirmed by X-ray crystal structure determination.4
Thus, in comparison with the conversion of furan 2 into the
isothiazole 3 by trimer, furan 7 has given, more slowly, a prod-
uct 8 with the regiochemistry reversed. This result fits well for
Scheme 3
1
However, the H NMR spectra showed that each reaction had
indeed given two isomeric products, as chromatographically
inseparable mixtures. By careful spectroscopic analysis and
comparison with the isothiazoles described above and the
‘symmetrical’ 5-(4-methylbenzoyl)-3-(4-methylphenyl)isothi-
azole, the products were shown to be 10 ϩ 11 and 13 ϩ 14
respectively, in ratios of 3.3:1 (56% total yield) and 3.9:1 (65%
total yield). Thus in each case the more electron releasing aryl
group in the furan becomes part of the 5-aroyl group of the
major isothiazole product (Scheme 3). This is in agreement with
the reaction of the more highly polarised furan 2 above, where
only the ‘major’ isomer was observed. These results also fit the
electrophilic mechanism (Scheme 2) more readily than the
cycloaddition mechanism (Scheme 1). For the former, substitu-
† This result argues against another possible mechanism, considered
before,1 which involves electrophilic substitution by NSCl via nitrogen
at a furan α-position since, although C-5 is activated by the methoxy-
phenyl group, no products derived from this process were observed.
2248
J. Chem. Soc., Perkin Trans. 1, 1997

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tion of SN should predominate at the more nucleophilic β pos-
ition of the furan, adjacent to the more electron releasing
group; this group is then incorporated into the aroyl group at
the isothiazole 5-position, as shown in Scheme 2. By the same
reasoning as before, the orientation which is expected to pre-
dominate in the Diels–Alder cycloaddition process (cf. 6) leads,
in both cases, to the minor rather than the major isomer. All the
furan substituents are sufficiently similar for us to assume that
the same mechanism is operating throughout.
of 16a with excess of trimer in refluxing THF did not yield any
observable amount of either 17a or 18a. A possible mechanism
to account for their formation is proposed, tentatively, in
Scheme 5. An alternative mode of ring opening (arrows in 19) is
HN
N
a
ArCO
S
S
Cl+
S
ArCO
H
Cl+
N
H
Ar
O
b
20
19
2-Aryl-5-methylfurans with trimer 1
b
a
To test the generality of this isothiazole synthesis further we
studied the reactions of 2-(4-methoxyphenyl)-5-methylfuran
15a and 2-methyl-5-phenylfuran 15b with the trimer 1 (1 equiv.
in refluxing THF ) (Scheme 4). The furans were prepared by the
method of Girault et al.5
ArCO
S
H
Cl
ArCO
17
Cl
S
N
N
18
Me
Me
N
Cl
1
Cl
+
Scheme 5
+
N
O
N
Me
O
Ar
O
O
S
S
S
Ar
Ar
Ar
now available to the initial electrophilic substitution product.
This would give the allene 20 which could be intercepted by
chlorination (presumably by the trimer 1) at either terminus;
concomitant cyclisation via routes a and b would then give the
ring chlorinated 17 and the chloromethylisothiazole 18. In the
analogous reaction of 2,5-di-tert-butylfuran with trimer 1
under the same, and more vigorous conditions (refluxing
toluene), no ring chlorinated isothiazole product was
observed.1 This lends some support to a mechanism such as
that shown in Scheme 5 which involves the reactivity of the
furan methyl hydrogen atoms (19).
18a,b
17a,b
16a,b
15a,b
b, Ar = C6H5
a, Ar = 4-MeOC6H4
Scheme 4
The furan 15a gave three products: the expected isothiazole
16a (33%) and two of its mono-chloro derivatives 17a and 18a
in approximately equal amounts, in a chromatographically
inseparable mixture (28%). HRMS indicated the expected
molecular formula of C12H11NO2S for 16a, and a strong
carbonyl stretch at 1636 cmϪ1 suggested the presence of an
aryl ketone rather than an acetyl group. The 1H and 13C NMR
spectra were also consistent with structure 16a. In the mass
spectrum of the isomeric mixture (17a ϩ 18a) the molecular ion
had the characteristic isotope pattern for one chlorine atom,
and the molecular formula (HRMS) was C12H10ClNO2S. The
1H NMR spectrum showed the presence of two compounds,
and comparison with the spectrum of 16a revealed the presence
of the ring chlorinated product 17a; the spectra of 16a and 17a
were very similar, apart from the absence of the heterocyclic
ring proton signal in the latter. The structure of the chloro-
Conclusion
We have shown in this and an earlier paper 1 that the reaction of
di- and tri-substituted furans with the trimer 1 provides a direct
one-step, regioselective synthesis of isothiazoles. In the pres-
ence of a 2-methyl substituent, however, chlorinated by-
products are also formed. All of the (qualitative) evidence
available so far supports the reaction mechanism shown in
Scheme 2. The initially puzzling step in this mechanism is the
ready opening of the furan ring once it is substituted by the β-
thiazyl group. This is possibly more comprehensible when the
nitrenoid contribution 21 to this intermediate is considered.‡ It
is proposed that this highly reactive substituent induces a new
1
methyl compound 18a was determined from the H and 13C
NMR spectra; a singlet at 7.70 ppm was observed for the iso-
thiazole C-4 proton together with a singlet for the methylene
protons at 4.72 ppm which is in the typical range for a
chloromethyl group attached to an aromatic system. Analysis
of the 13C NMR spectrum of the mixture using the DEPT-135
technique revealed the methylene carbon at 41 ppm. Although
the formation of these chloro compounds (17a, 18a) is an
added complexity, the isothiazole forming reaction is still highly
regioselective since none of the corresponding 5-acetyl-3-
arylisothiazoles were observed.
2-Methyl-5-phenylfuran 15b and trimer 1 gave very similar
results (Scheme 4). 5-Benzoyl-3-methylisothiazole 16b was
obtained as an oil in 40% yield, together with an inseparable
mixture of the ring chlorination 17b (29%) and side chain chlor-
ination 18b (10%) products. Structures were assigned by spec-
troscopic comparison with the 4-methoxyphenyl compounds.
Thus the reactions of 2-aryl-5-methylfurans with the trimer
give isothiazoles, just like 2,5-diarylfurans, and with the same
regioselectivity. Again, for the same reasons, these results fit the
electrophilic substitution mechanism (Scheme 2) better than the
Diels–Alder mechanism (Scheme 1).
N
N
N
S
S
S
etc.
R
R
+
R
R
R
R
O
O
O
22
21
N
O
O
N
23
N
N
+
O
O
24
‡ We thank a referee for the alternative suggestion that the initially
formed nitrene, before proton loss from the ring, could undergo
intramolecular cycloaddition to the carbon–carbon double bond of
the furan ring, followed by rearrangement to the isothiazole product.
For the conversion of the methylfuran 15a into 16a, 17a and
18a, it was found that the unchlorinated isothiazole 16a is not a
precursor of the chlorinated products 17a and 18a: treatment
J. Chem. Soc., Perkin Trans. 1, 1997
2249

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cleavage of the furan ring (arrows in 21) to give a highly delocal-
ised intermediate 22. This ring opening reaction is somewhat
analogous to the well known cleavage processes6 that result
from the generation of α- and β-nitrenes (and carbenes) in
furans and related five-membered heterocyclic rings, as
summarised in 23 and 24.
6.94 (1H, d, J 3.6, furan 4-H), 6.67 (1H, d, J 3.6, furan 3-H) and
3.86 (3H, s, OMe); δC(101 MHz; CDCl3) 159.75, 155.76, 150.29,
145.95, 136.40, 128.28, 125.63, 124.38, 123.40, 114.31, 111.50
(furan C-4), 106.36 (furan C-3) and 55.40 (OMe); m/z 295 (Mϩ,
82%), 265 (100, M Ϫ NO) and 250 (88).
2-(4-Methylphenyl)-5-phenylfuran 9
2-Phenylfuran 3 (346 mg, 2.4 mmol) was treated with 4-
bromotoluene (344 mg, 2 mmol) in the presence of the
palladium catalyst (116 mg, 0.1 mmol) and potassium acetate
(294 mg, 3 mmol) in DMF (5 ml). The title compound (99 mg,
21%) was obtained as a white solid, mp 98–99 ЊC (lit.,9
105.5 ЊC) (Found: Mϩ, 234.1045. Calc. for C17H14O : M,
234.1045); νmax(Nujol mull)/cmϪ1 1606s, 1499s, 1024s and 928s;
δH (400 MHz; CDCl3) 7.79–7.76 (2H, m, Ph), 7.67 (2H, d J 8.2,
p-MeC6H4), 7.45–7.41 (2H, m, Ph), 7.32–7.27 (1H, m, Ph), 7.24
(2H, d, J 8.2, p-MeC6H4), 6.75 (1H, d, J 3.5, furan-H), 6.70 (1H,
d, J 3.5, furan-H) and 2.40 (3H, s, Me); m/z 234 (Mϩ, 100%) and
220 (39, M Ϫ CH2).
Experimental
For general details see ref. 1, except that light petroleum refers
to the fraction bp 40–60 ЊC. Flash chromatography refers to the
technique described by Still et al.7 using medium pressure by a
hand bellows or small air compressor and was used throughout,
except where noted otherwise. Dry flash chromatography was
carried out with suction using a water pump according to the
technique described by Harwood.8 Merck Kieselgel 60H silica
gel was used for flash column chromatography and Merck
Kieselgel 25H silica gel was used for dry flash chromatography.
Preparative thin layer chromatography was carried out with
Whatman K4F silica gel G (40 Å) precoated plates (20 × 20 cm,
250 µm thickness). Commercial aluminium backed thin-layer
chromatography (TLC) plates (Merck Kieselgel 60F254) were
used. The TLC plates were visualised under UV light at 254 and
350 nm, or by development in iodine vapour.
2-(4-Methoxyphenyl)-5-(4-methylphenyl)furan 12
2-(4-Methoxyphenyl)furan 3 (835 mg, 4.8 mmol) was treated
with 4-bromotoluene (688 mg, 4 mmol) in the presence of the
palladium catalyst (232 mg, 0.2 mmol) and potassium acetate
(588 mg, 6 mmol) in DMF (8 ml). The title compound (315 mg,
30%) was obtained as a white solid, mp 150–152 ЊC (ethanol)
(Found: Mϩ, 264.1152. C18H16O2 requires M, 264.1150);
νmax(Nujol mull)/cmϪ1 1610m, 1502m, 1297m, 1250s, 1177m,
1115m and 1029s; δH (400MHz; CDCl3) 7.68 (2H, d, J 8.9), 7.63
(2H, d, J 8.2), 7.21 (2H, d, J 7.9), 6.95 (2H, d, J 8.9), 6.66 (1H,
d, J 3.4, furan-H), 6.59 (1H, d, J 3.4, furan-H), 3.85 (3H, s,
MeO) and 2.38 (3H, s, Me); m/z 264 (Mϩ, 100%), 249 (81,
M Ϫ Me) and 235 (21).
2-(4-Methoxyphenyl)-5-methylfuran 15a and 2-methyl-5-phenyl-
furan 15b
2-(4-Methoxyphenyl)-5-methylfuran 15a was prepared by the
method of Ayres and Smith 3 using 4-methoxyaniline (12.3 g,
0.1 mol) and 2-methylfuran (150 ml). Column chromatography
of the concentrated extract of the steam distillate on silica with
light petroleum–dichloromethane (DCM) (9:1) afforded the
title compound as a light yellow solid (2.14 g, 11%), mp 44–
45 ЊC (lit.,5 45–46 ЊC); m/z 188 (Mϩ, 95%), 173 (100, M Ϫ Me)
and 145 (30, M Ϫ MeCO).
2-Methyl-5-phenylfuran 15b was prepared by the same
method using aniline (9.3 g, 0.1 mol) and 2-methylfuran (150
ml). Column chromatography of the concentrated extract of
the steam distillate on silica with light petroleum–DCM (9:1)
afforded 2-methyl-5-phenylfuran as a light yellow solid (2.34 g,
15%), mp 38–39 ЊC (lit.,5 38–39 ЊC); m/z 158 (Mϩ, 100%), 129
(12) and 115 (44, M Ϫ MeCO).
2,5-Bis(4-methoxyphenyl)furan
2-(4-Methoxyphenyl)furan (835 mg, 4.8 mmol) was treated with
4-methoxybromobenzene (748 mg, 4 mmol) in the presence of
the palladium catalyst (232 mg, 0.2 mmol) and potassium
acetate (588 mg, 6 mmol) in DMF (8 ml). The title compound
(278 mg, 25%) was obtained as a white solid, mp 197–198 ЊC
(ethanol) (lit.,10 195–196 ЊC); δH (400 MHz; CDCl3) 7.67 (4H,
dt, J 8.9, 2.5), 6.94 (4H, dt, J 8.9, 2.5), 6.58 (2H, s, furan 3-H
and 4-H) and 3.84 (6H, MeO); m/z 280 (Mϩ, 100%) and 265 (87,
M Ϫ Me).
2,5-Diarylfurans
General procedure. 2,5-Diarylfurans were synthesized by a
modification of the method described by Ohta et al. in their
synthesis of 2-arylfurans.2 The 2-arylfuran (1.2 equiv.) was
treated with an aryl bromide (1.0 equiv.) in dimethylformamide
(DMF ) in the presence of tetrakis(triphenylphosphine)-
palladium(0) catalyst (5 mol%) and potassium acetate (1.5
equiv.). The mixture was heated at 120 ЊC for 16 h. The reaction
mixture was cooled to room temperature and DMF was
removed under reduced pressure. The residue was dissolved in
DCM, and the DCM solution was filtered through Celite. The
filtrate was washed with water and the DCM solution was dried
(MgSO4), filtered and concentrated under reduced pressure.
Chromatography of the residue on silica with DCM–light
petroleum afforded the product.
3-Bromo-2-(4-methoxyphenyl)-5-(4-nitrophenyl)furan 7
2-(4-Methoxyphenyl)-5-(4-nitrophenyl)furan
2 (295 mg, 1
mmol) and N-bromosuccinimide (178 mg, 1 mmol) were dis-
solved in benzene (10 ml) and heated under reflux for 2 h. The
reaction mixture was cooled to room temperature and concen-
trated under reduced pressure. Column chromatography of the
residue on silica with DCM–light petroleum (1:1) afforded the
title compound (164 mg, 44%) as yellow needles, mp 160–162 ЊC
(ethanol) (Found: C, 54.85; H, 3.3; N, 3.7. C17H12BrNO4
requires C, 54.6; H, 3.2; N, 3.7%); νmax(Nujol mull)/cmϪ1 1603s,
1516s, 1497s, 1337s and 1259s; δH (300 MHz; CDCl3) 8.25 (2H,
dt, J 9.0, 2.2), 7.98 (2H, dt, J 9.0, 2.1), 7.77 (2H, dt, J 9.0, 2.3),
7.00 (2H, dt, J 9.0, 2.1), 6.96 (1H, s, furan 4-H) and 3.87 (3H,
s, OMe); δC(76 MHz; CDCl3) 160.00, 150.48, 149.56, 146.61,
135.26, 127.38, 124.42, 123.73, 121.82, 114.94, 114.12, 96.91
and 55.36 (OMe); m/z 375 (Mϩ, 100%), 360 (16, M Ϫ Me), 345
(32, M Ϫ NO) and 329 (29, M Ϫ NO2).
2-(4-Methoxyphenyl)-5-(4-nitrophenyl)furan 2
2-(4-Methoxyphenyl)furan (418 mg, 2.4 mmol) was treated with
4-bromonitrobenzene (404 mg, 2 mmol) in the presence of
tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmol)
and potassium acetate (294 mg, 3 mmol) in DMF (5 ml). Col-
umn chromatography on silica with DCM–light petroleum
(1:1) gave the title compound (353 mg, 59%) as yellow needles,
mp 168–170 ЊC (ethanol) (Found: C, 69.3; H, 4.45; N, 4.7; Mϩ,
295.0841. C17H13NO4 requires C, 69.15; H, 4.4; N, 4.7%; M,
295.0845); νmax(Nujol mull)/cmϪ1 1604s, 1496s, 1332s and
1257s; δH (400 MHz; CDCl3) 8.23 (2H, dt, J 9.1, 2.1), 7.80 (2H,
dt, J 9.1, 2.1), 7.69 (2H, dt, J 8.9, 2.1), 6.96 (2H, dt, J 8.9, 2.1),
5-(4-Methoxybenzoyl)-3-(4-nitrophenyl)isothiazole 3
To a refluxing solution of 2-(4-methoxyphenyl)-5-(4-nitro-
phenyl)furan 2 (295 mg, 1 mmol) in THF (10 ml), trithiazyl
trichloride 1 (245 mg, 1 mmol) in THF (10 ml) was added
dropwise. The mixture was heated under reflux for 30 min. The
reaction mixture was cooled to room temperature and concen-
trated under reduced pressure. Column chromatography of the
2250
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
residue with DCMϪlight petroleum (1:1) gave the title com-
pound (289 mg, 85%) as light yellow needles, mp 158–160 ЊC
(ethanol) (Found: C, 59.7; H, 3.5; N, 8.0; Mϩ, 340.0523.
C17H12N2O4S requires C, 60.0; H, 3.55; N, 8.2%; M, 340.0518);
Ph), 7.29 (2H, d, J 7.9, Tol) and 2.42 (3H, s, Me); δC(101 MHz;
CDCl ) 186.22 (C᎐O), 185.84 (C᎐O) 167.88, 167.76, 165.06,
᎐
᎐
3
164.84, 144.73, 139.77, 134.41, 134.06, 133.61, 133.56, 129.63,
129.58, 129.50, 129.46, 129.24, 128.88, 128.81, 126.85, 126.76,
124.75, 124.64, 124.56, 21.70 (Me) and 21.34 (Me); m/z 279
(Mϩ, 49%), 265 (38, M Ϫ CH2), 202 (3, M Ϫ Ph), 188 (18,
M Ϫ MeC6H4), 176 (2, M Ϫ PhCN), 160 (4, M Ϫ MeC6H4CO),
119 (82, MeC6H4CO), 105 (100, PhCO), 91 (40, MeC6H4) and
77 (90, Ph).
νmax(Nujol mull)/cmϪ1 1643vs (C᎐O), 1598vs, 1519vs and
᎐
1386vs; δH (300 MHz; CDCl3) 8.32 (2H, dt, J 8.9, 2.0), 8.16 (2H,
dt, J 8.9, 2.0), 8.07 (1H, s, isothiazole 4-H), 8.00 (2H, dt, J 8.9,
2.0), 7.04 (2H, dt, J 8.9, 2.0) and 3.92 (3H, s, OMe); δC(76 MHz;
CDCl ) 184.21 (C᎐O), 166.47, 165.02, 164.43, 148.27, 139.53,
᎐
3
131.90, 129.41, 127.70, 124.47, 124.26, 114.29 and 55.61 (OMe);
m/z 340 (Mϩ, 15%), 310 (30, M Ϫ NO) and 135 (100,
MeOC6H4CO).
Reaction of 2-(4-methoxyphenyl)-5-(4-methylphenyl)furan 12
with trithiazyl trichloride 1
To a refluxing solution of the 2-(4-methoxyphenyl)-5-(4-
methylphenyl)furan 12 (135 mg, 0.5 mmol) in THF (5 ml),
trithiazyl trichloride 1 (122 mg, 0.5 mmol) in THF (5 ml) was
added dropwise. The mixture was heated under reflux for 30
min. The mixture was cooled to room temperature and concen-
trated under reduced pressure. Column chromatography of the
residue on silica with DCM–light petroleum (1:1) gave a 3.9:1
mixture of two inseparable isomers 13 and 14 as a white solid
(102 mg, 65%) (Found: Mϩ, 309.0822. C18H15NO2S requires M,
4-Bromo-3-(4-methoxyphenyl)-5-(4-nitrobenzoyl)isothiazole 8
To a refluxing solution of 3-bromo-2-(4-methoxyphenyl)-5-(4-
nitrophenyl)furan 7 (188 mg, 0.5 mmol) in THF (10 ml), trithi-
azyl trichloride 1 (122 mg, 0.5 mmol) in THF (5 ml) was added
dropwise. The mixture was heated under reflux for 1 h. The
reaction mixture was cooled to room temperature and concen-
trated under reduced pressure. Column chromatography of
the residue with DCM–light petroleum (1:1) gave the title
compound (134 mg, 64%) as yellow needles, mp 134–135 ЊC
(ethanol) (Found: C, 48.6; H, 2.65; N, 6.7; Mϩ, 419.9620.
C17H11BrN2O4S requires C, 48.7, H, 2.6; N, 6.7%; M, 419.9602);
309.0824); νmax(Nujol mull)/cmϪ1 1645vs (C᎐O), 1597s and
᎐
1385s; δH (500 MHz; CDCl3), the major isomer, 5-(4-
methoxybenzoyl)-3-(4-methylphenyl)isothiazole 13, 8.00 (2H, dt,
J 8.9, 2.0), 7.96 (1H, s, isothiazole 4-H), 7.86 (2H, d, J 8.2), 7.27
(2H, d, J 8.2), 7.02 (2H, dt, J 8.9, 2.0), 3.91 (3H, s, OMe) and
2.40 (3H, s, Me); the minor isomer, 5-(4-methylbenzoyl)-3-(4-
methoxyphenyl)isothiazole 14, 8.00 (2H, m), 7.93 (1H, s, iso-
thiazole 4-H), 7.90 (2H, dt, J 8.9, 2.1), 7.34 (2H, d, J 8.0), 6.98
(2H, dt, J 8.5, 2.0), 3.86 (3H, s, OMe) and 2.47 (3H, s, Me);
νmax(Nujol mull)/cmϪ1 1670vs (C᎐O), 1526vs and 1393vs;
᎐
δH (400 MHz; CDCl3) 8.38 (2H, dt, J 8.9, 2.2), 8.09 (2H, dt, J
8.9, 2.2), 7.82 (2H, dt, J 8.9, 2.2), 7.01 (2H, dt, J 8.9, 2.2) and
3.88 (3H, s, OMe); δ (101 MHz; CDCl ) 185.60 (C᎐O), 166.85,
᎐
C
3
160.92, 158.14, 150.85, 140.70, 130.88, 130.51, 125.74, 124.06,
113.81, 109.56 and 55.38 (OMe); m/z 420 (Mϩ, 23%), 390 (11,
M Ϫ NO), 150 (9, O2NC6H4CO), 133 (9, MeOC6H4CN) and
120 (100).
δ (126 MHz; CDCl ) 185.95 (C᎐O), 184.78 (C᎐O), 167.77,
᎐
᎐
C
3
167.52, 165.27, 165.04, 164.13, 160.74, 144.67, 139.71, 131.84,
131.53, 129.71, 129.58, 129.49, 129.47, 128.90, 128.31, 126.90,
126.79, 124.27, 124.17, 114.23, 114.10, 55.57 (OMe), 55.31
(OMe), 21.70 (Me) and 21.31 (Me); m/z 309 (Mϩ, 37%), 295 (9,
M Ϫ CH2), 202 (2, M Ϫ MeOC6H4), 192 (3, M Ϫ MeC6H4CN),
174 (1, M Ϫ MeOC6H4CO), 135 (100, MeOC6H4CO), 119 (16,
MeC6H4CN), 107 (7, MeOC6H4) and 91 (12, MeC6H4).
5-(4-Methoxybenzoyl)-3-(4-methoxyphenyl)isothiazole 5
To a refluxing solution of 2,5-bis(4-methoxyphenyl)furan (280
mg, 1 mmol) in refluxing THF (10 ml), trithiazyl trichloride 1
(245 mg, 1 mmol) in THF (10 ml) was added dropwise. The
mixture was heated under reflux for 30 min. The reaction mix-
ture was cooled to room temperature and concentrated under
reduced pressure. Column chromatography of the residue with
DCM–light petroleum (1:1) gave the title compound (189 mg,
58%) as a light yellow oil (Found: Mϩ, 325.0764. C18H15NO3S
Reaction of 2-(4-methoxyphenyl)-5-methylfuran 15a with
trithiazyl trichloride 1
To a refluxing solution of 2-(4-methoxyphenyl)-5-methylfuran
15a (376 mg, 2 mmol) in THF (15 ml), trithiazyl trichloride 1
(489 mg, 2 mmol) in THF (15 ml) was added dropwise. The
mixture was heated under reflux; after 15 min no starting
material 15a was observed (TLC). The mixture was cooled to
room temperature and concentrated under reduced pressure.
Column chromatography of the residue on silica with DCM–
light petroleum (3:1) gave a 1:1 mixture of 4-chloro-5-(4-
methoxybenzoyl)-3-methylisothiazole 17a and 3-chloromethyl-5-
(4-methoxybenzoyl)isothiazole 18a as a brown oil (145 mg, 27%)
(Found: Mϩ, 267.0100. C12H10ClNO2S requires M, 267.0121);
requires M, 325.0773); νmax(neat)/cmϪ1 1645vs (C᎐O), 1600s
᎐
and 1507s; δH (400 MHz; CDCl3) 8.00 (2H, dt, J 8.9, 2.9), 7.93
(1H, s, isothiazole 4-H), 7.92 (2H, dt, J 8.9, 2.9), 7.02 (2H, dt, J
8.9, 2.9), 6.98 (2H, dt, J 8.9, 2.9), 3.91 (3H, s, OMe) and 3.86
(3H, s, OMe); δ (101 MHz; CDCl ) 184.91 (C᎐O), 167.47,
᎐
C
3
164.97, 164.18, 160.76, 131.91, 129.84, 128.38, 127.19, 123.98,
114.28, 114.15, 55.64 (OMe) and 55.39 (OMe); m/z 325 (Mϩ,
36%) and 135 (100, MeOC6H4CO).
Reaction of 2-(4-methylphenyl)-5-phenylfuran 9 with trithiazyl
trichloride 1
νmax(neat)/cmϪ1 1651vs (C᎐O), 1599s, 1573s, 1510s, 1422, 1314s,
᎐
To a refluxing solution of 2-(4-methylphenyl)-5-phenylfuran 9
(100 mg, 0.43 mmol) in THF (5 ml), trithiazyl trichloride 1 (105
mg, 0.43 mmol) in THF (5 ml) was added dropwise. The mix-
ture was heated under reflux for 30 min. The mixture was then
cooled to room temperature and concentrated under reduced
pressure. Column chromatography of the residue on silica with
DCM–light petroleum (1:1) gave a 3.3:1 mixture of two
inseparable isomers 10 and 11 (65 mg, 56%) as a colourless oil
(Found: Mϩ, 279.0722. C17H13NOS requires M, 279.0719);
νmax(neat)/cmϪ1 1651vs (C᎐O), 1605s, 1274s and 1182; δ (400
MHz; CDCl3), the major isomer, 5-(4-methylbenzoyl)-3-
phenylisothiazole 10, 8.025 (1H, s, isothiazole 4-H), 8.01–7.98
(2H, m, Ph), 7.92 (2H, d, J 8.2, Tol), 7.59–7.56 (1H, m Ph),
7.51–7.44 (2H, m, Ph), 7.37 (2H, d, J 7.9, Tol) and 2.49 (3H, s,
Me); the minor isomer, 5-benzoyl-3-(4-methylphenyl)isothiazole
11, 8.03 (1H, s, isothiazole 4-H), 8.01–7.98 (2H, m, Ph), 7.88
(2H, d, J 8.2, Tol), 7.70–7.68 (1H, m, Ph), 7.51–7.44 (2H, m,
1261s and 1171s; δH (400 MHz; CDCl3) 7.94 (2H, dt, J 9.0, 2.5,
2Ј-H), 7.88 (2H, dt, J 9.0, 2.5, 2Ј-H), 7.70 (1H, s, isothiazole 4-
H, 18a), 7.00 (2H, dt, J 9.0, 2.1, 3Ј-H), 6.97 (2H, dt, J 9.0, 2.1,
3Ј-H), 4.72 (2H, s, CH2Cl, 18a), 3.90 (3H, s, OMe), 3.89 (3H, s,
OMe) and 2.52 (3H, s, Me, 17a); δC(126 MHz; CDCl3) 184.69
(C᎐O), 184.28 (C᎐O), 166.00, 165.84, 164.77, 164.63, 164.26,
᎐
᎐
155.86, 132.42, 131.86, 129.28, 129.14, 126.18, 123.55, 114.16,
114.08, 55.59 (OMe), 41.04 (CH2Cl, 18a) and 17.53 (Me, 17a);
m/z 267 (Mϩ, 18%), 135 (100, MeOC6H4CO) and 77 (20, Ph).
Further elution with DCM afforded 5-(4-methoxybenzoyl)-3-
methylisothiazole 16a as a light brown solid (154 mg, 33%), mp
81–83 ЊC (DCM–light petroleum) (Found: Mϩ, 233.0509.
C12H11NO2S requires M, 233.0511); νmax(Nujol mull)/cmϪ1
᎐
H
1636vs (C᎐O), 1597vs, 1509vs and 1261vs; δ (400 MHz;
᎐
H
CDCl3) 7.96 (2H, dt, J 8.9, 2.5, 2Ј-H), 7.43 (1H, s, isothiazole
4-H), 7.00 (2H, dt, J 8.9, 2.5, 3Ј-H), 3.90 (3H, s, OMe) and 2.57
(3H, s, Me); δ (126 MHz; CDCl ) 184.90 (C᎐O), 167.21, 164.48,
᎐
C
3
J. Chem. Soc., Perkin Trans. 1, 1997
2251

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164.07, 131.85, 129.78, 127.17, 114.03, 55.59 (OMe) and 19.05
(Me); m/z 233 (Mϩ, 35%), 192 (3, M – MeCN) and 135 (100,
MeOC6H4CO).
167.32, 163.98, 136.95, 133.40, 129.11, 128.62, 127.59 and 18.93
(Me); m/z 203 (Mϩ, 38%), 162 (5, M Ϫ MeCN), 126 (32,
M Ϫ Ph), 105 (100, PhCO) and 77 (69, Ph).
Reaction of 2-methyl-5-phenylfuran 15b with trithiazyl
trichloride 1
Acknowledgements
To a refluxing solution of the furan 15b (316 mg, 2 mmol) in
THF (15 ml), trithiazyl trichloride 1 (489 mg, 2 mmol) in THF
(15 ml) was added dropwise. The mixture was heated under
reflux; after 15 min, no starting material 15b was observed
(TLC). The mixture was cooled to room temperature and con-
centrated under reduced pressure. Column chromatography of
the residue on silica with DCM–light petroleum (75:25) gave a
3:1 mixture of 5-benzoyl-4-chloro-3-methylisothiazole 17b and
5-benzoyl-3-chloromethylisothiazole 18b as a brown oil (187 mg,
39%) (Found: Mϩ, 237.0016. C11H8ClNOS requires M,
We thank the Commonwealth Scholarship Commission and
the British Council for a scholarship to T.-Y. Y., MDL Inform-
ation Systems (UK) Ltd for financial support, the Wolfson
Foundation for establishing the Wolfson Centre for Organic
Chemistry in Medical Science at Imperial College, and Profes-
sor D. J. Williams for the X-ray crystal structure determination.
References
1 X.-L. Duan, R. Perrins and C. W. Rees, J. Chem. Soc., Perkin
Trans. 1, 1997, 1617.
2 A. Ohta, Y. Akita, T. Ohkuwa, M. Chiba, R. Fukunaga,
A. Miyafuyi, T. Nakata, N. Tani and Y. Aoyagi, Heterocycles, 1990,
31, 1951.
3 D. C. Ayres and J. R. Smith, J. Chem. Soc. (C), 1968, 2737.
4 D. J. Williams, Imperial College, personal communication.
5 J. P. Girault, P. Scribe and G. Dana, Bull. Soc. Chim. Fr., 1973, 1760.
6 For an excellent review, see T. L. Gilchrist, Adv. Heterocycl. Chem.,
1987, 41, 41.
7 W. C. Still, M. Kahn and A. Mitra, J. Org. Chem., 1978, 43, 2923.
8 L. M. Harwood, Aldrichimica Acta, 1985, 18, 25.
9 A. E. Siegrist and H. R. Meyer, Helv. Chim. Acta, 1969, 52, 1282.
10 P. S. Bailey, H. M. White and H. O. Colomb, J. Org. Chem., 1965,
30, 487.
237.0015); νmax(neat)/cmϪ1 1661vs (C᎐O), 1635vs, 1607vs and
᎐
1283vs; δH (400 MHz; CDCl3) 7.91–7.85 (2H, m, 17b and 18b),
7.71 (1H, s, isothiazole 4-H, 18b), 7.65–7.61 (1H, m, 17b and
18b), 7.53–7.47 (2H, m, 17b and 18b), 4.70 (2H, s, CH2Cl, 18b)
and 2.51 (3H, s, Me, 17b); δ (126 MHz; CDCl ) 186.06 (C᎐O),
᎐
C
3
185.74 (C᎐O), 166.01, 165.48, 165.01, 155.14, 136.55, 136.32,
᎐
134.15, 134.09, 133.69, 129.64, 129.17, 128.78, 128.69, 126.69,
40.94 (CH2Cl, 18b) and 17.48 (Me, 17b); m/z 237 (Mϩ, 18%),
160 (7, M Ϫ Ph), 105 (100, PhCO) and 77 (46, Ph).
Further elution with DCM gave 5-benzoyl-3-methyliso-
thiazole 16b as a light brown solid (163 mg, 40%), mp 28–30 ЊC
(DCM–light petroleum) (Found: Mϩ, 203.0411. C11H9NOS
requires M, 203.0405); νmax(Nujol mull)/cmϪ1 1657vs (C᎐O),
᎐
1598vs and 1402vs; δH (400 MHz; CDCl3) 7.91–7.87 (2H, m),
7.63–7.59 (1H, m), 7.50–7.46 (2H, m), 7.41 (1H, s, isothiazole
Paper 7/00488E
Received 21st January 1997
Accepted 7th February 1997
4-H) and 2.53 (3H, s, Me); δ (126 MHz; CDCl ) 186.22 (C᎐O),
᎐
C
3
2252
J. Chem. Soc., Perkin Trans. 1, 1997