Reaction of furans with trithiazyl trichloride: A new synthesis of isothiazoles

Article abstract of DOI:10.1039/a700358g

Trithiazyl trichloride 1 converts 2,5-diphenylfuran into 5-benzoyl-3-phenylisothiazole 2 regiospecifically and in high yield. This is a new ring opening of furans and a new synthesis of isothiazoles. 2,5-Bis(4-methylphenyl)furan, 3-bromo-2,5-diphenylfuran, 2,3,5-triphenylfuran, 2,5-di-tert-butylfuran and its 3-chloro and 3-bromo derivatives react in an entirely analogous manner to give the corresponding isothiazoles (55-85%) in synthetically useful, one-pot, conversions. 2,5-Diphenylthiophene reacts more slowly with the trimer 1 to give the same product, 2, as the corresponding furan, probably by oxidation of the analogous thiobenzoyl compound by the reagent, which is shown to oxidise thiobenzophenone to benzophenone very rapidly. Tetraphenylcyclopentadienone 8 reacts rapidly with the trimer to give 3,4,5,6-tetraphenyl-2(1H)-pyridone 10 (56%). Possible mechanisms in which the monomer, Cl-S≡N, is the reacting species are proposed for all of these reactions.

Full text of DOI:10.1039/a700358g

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Reaction of furans with trithiazyl trichloride: a new synthesis of
isothiazoles
Xiao-Lan Duan, Ross Perrins and Charles W. Rees
Department of Chemistry, Imperial College of Science, Technology and Medicine, London,
UK SW7 2AY
Trithiazyl trichloride 1 converts 2,5-diphenylfuran into 5-benzoyl-3-phenylisothiazole 2 regiospecifically
and in high yield. This is a new ring opening of furans and a new synthesis of isothiazoles. 2,5-Bis(4-
methylphenyl)furan, 3-bromo-2,5-diphenylfuran, 2,3,5-triphenylfuran, 2,5-di-tert-butylfuran and its
3
-chloro and 3-bromo derivatives react in an entirely analogous manner to give the corresponding
isothiazoles (55–85%) in synthetically useful, one-pot, conversions. 2,5-D iphenylthiophene reacts more
slowly with the trimer 1 to give the same product, 2, as the corresponding furan, probably by oxidation of
the analogous thiobenzoyl compound by the reagent, which is shown to oxidise thiobenzophenone to
benzophenone very rapidly. Tetraphenylcyclopentadienone 8 reacts rapidly with the trimer to give 3,4,5,6-
tetraphenyl-2(1H )-pyridone 10 (56%). Possible mechanisms in which the monomer, Cl–S᎐N, is the reacting
᎐
species are proposed for all of these reactions.
Introduction
and low yielding, and their scope and mechanisms have not
been established.
In this and later papers we show that trithiazyl trichloride 1
reacts very readily with a wide range of simple organic sub-
strates and is useful for the synthesis of organic sulfur–nitrogen
compounds, particularly heterocyclic rings with N᎐S, N᎐S᎐N
and S᎐N᎐S units. Some of our earlier work has been summar-
In any given reaction the question arises as to whether the
monomer and/or the trimer is the reacting species, and we hoped
to gain some insight into this by studying possible Diels–Alder
reactions between conjugated dienes and trithiazyl trichloride.
Little is known about this, although [4 ϩ 2] cycloadditions are
1
,2
3
ised. Trithiazyl trichloride is a stable, but moisture-sensitive,
yellow crystalline solid which is prepared by heating ammo-
nium chloride with disulfur dichloride, followed by chlorination
5
possibly involved in the reactions with hexafluorobutadiene
6
and hexachlorocyclopentadiene.
ϩ
Ϫ
of the initially formed salt, S N Cl Cl (Scheme 1). Its six-
3
2
Reactions with furans
We chose 2,5-diphenylfuran as our first enophile. In boiling
tetrachloromethane for four hours the trimer reacted very
cleanly with the furan to give a stable dehydrochlorinated 1:1
adduct, C H NOS, in high yield (80%). This contained a con-
1
6
11
jugated carbonyl group (IR), probably part of a benzoyl group
MS), suggesting that the furan ring had undergone cleavage of
(
an O᎐C bond, and an S᎐N unit had become incorporated. The
product proved to be 5-benzoyl-3-phenylisothiazole 2, in
agreement with all the spectral data.
Scheme 1
membered ring has a slightly flattened chair conformation with
all three chlorines axial and on the same side of the ring, the
other side being exposed to nucleophilic attack and cycloaddi-
tions. The ring bonds are delocalised and all of equal length.
The cyclic species (the ‘trimer’) 1 is in thermal equilibrium with
The same reaction was observed with 2,3,5-triphenylfuran
which gave 5-benzoyl-3,4-diphenylisothiazole 3 in 75% yield.
No isomers of these products were detected and so incorpor-
ation of the S᎐N unit is regiospecific.
the monomer, thiazyl chloride, N᎐S᎐Cl, and on heating in inert
The yields are based on the conversion of three molecules of
the furan by one of the trimeric reagent 1. This type of ring
opening of furans is very rare; Huisgen recently reported the
(possibly related) opening of 2-methoxyfuran and 2-p-tolyl-
oxyfuran upon reaction with 2,3-bis(trifluoromethyl)fumaro-
nitrile with formation of a carboxylic ester carbonyl group from
᎐
solvents to about 60 ЊC the monomer imparts a characteristic
3
green colour to the solution. Various canonical forms (Scheme
1
) can be written for thiazyl chloride which is highly reactive.
The inorganic chemistry of trithiazyl trichloride has been
extensively developed but its applications in organic synthesis
4
7
are rare, partly because its known reactions are often complex
the ring oxygen atom.
J. Chem. Soc., Perkin Trans. 1, 1997
1617

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The furan–trithiazyl trichloride reaction also provided a new
and attractive (one-step) route to the isothiazoles 2 and 3. Since
there are still only a relatively limited number of good syntheses
of this important ring system, we decided to explore the scope
of this reaction. The only reported formation of isothiazoles by
incorporation of the S᎐N unit are with allylic compounds:
cholesteryl acetate and the trimer 1 gave a low yield (11%) of a
isolated in 85% yield as the sole organic product after the
standard chromatographic work-up. The trimer is possibly act-
ing as a chlorinating agent to give an intermediate which is
hydrolysed on silica gel [eqn. (1)]. It was shown in a similar
4
fused isothiazole and methacrylonitrile and the trimer in the
presence of excess of sulfuryl chloride, which behaves as an
8
equivalent of ‘NSCl ’, gave 5-cyanoisothiazole (78%).
3
series of experiments that the trimer did not oxidise the more
stable thioamide function in thiobenzamide, 1,1Ј-thiocarbonyl-
diimide, 2-mercaptobenzoxazole and 2-mercaptobenzothiazole.
Since thiophene 1,1-dioxides normally undergo Diels–Alder
reactions, with loss of sulfur dioxide, much more readily than
the parent thiophenes, 2,5-diphenylthiophene 1,1-dioxide, benzo-
thiophene 1,1-dioxide, and 2,3-dibromobenzothiophene 1,1-
dioxide were treated with the trimer in boiling tetrachlorometh-
ane, but no reaction was observed with any of these com-
pounds. This suggests that they are too electron-deficient to
undergo cycloaddition to the monomer or trimer or, alternat-
ively, that the monomer/trimer reactions are not cycloadditions
at all (see below). Finally a compound that is known to be a
highly reactive Diels–Alder diene, tetraphenylcyclopentadi-
enone (tetracyclone) 8, was treated with the reagent 1 in boiling
tetrachloromethane. It reacted very rapidly to give 3,4,5,6-
tetraphenyl-2(1H)-pyridone 10 (56%) after crystallisation from
ethanol; the same product was obtained in slightly lower yield
Treating 2,5-bis(4-methylphenyl)furan with trimer 1 in boil-
ing tetrachloromethane for four hours gave the analogous 5-(4-
methylbenzoyl)-3-(4-methylphenyl)isothiazole in 53%. An α-
unsubstituted furan was chlorinated in this position by the tri-
mer: 2,4-diphenylfuran gave 2-chloro-3,5-diphenylfuran (46%)
as the major product, and 5-benzoyl-4-phenylisothiazole was
not observed. Fully substituted furans such as 3,4-dibromo-2,5-
diphenylfuran and 3-bromo-2,4,5-triphenylfuran did not react
with 1; clearly a ring hydrogen, for subsequent loss as hydrogen
chloride, is a requirement for the reaction. 3-Bromo-2,5-
diphenylfuran 4, however, gave 5-benzoyl-4-bromo-3-phenyl-
isothiazole 5 in excellent yield (85%).
(45%) when the reaction was run at room temperature. This
reaction is reminiscent of that between tetracyclone 8 and
9
hydrazoic acid to give the same pyridone 10. A possible mech-
anism, with the monomer adding as a nitrene, is shown in
The reactions of furan and 2,5-dimethylfuran with 1 were
complex, even under milder conditions. With furan, various
solvents (CCl , THF, PhMe and Et O) and neat furan were used
4
2
at a number of temperatures from reflux down to Ϫ20 ЊC, but
each led to a complex mixture. With 2,5-dimethylfuran it was
suspected that the active hydrogens on the methyl groups were
responsible for the complications and hence we turned to 2,5-
di-tert-butylfuran. This reacted with trimer in boiling tetrachloro-
methane to give 3-tert-butyl-5-pivaloylisothiazole 7 (X = H) as
the only isothiazole observed, and again the reaction was
regiospecific. However the yield (40%) was disappointing; this
may have resulted from the steric requirement of the tert-butyl
groups and more forcing conditions were employed. The yield
improved to 50% in boiling dioxane and 55% in boiling toluene.
The 3-halogeno derivatives 6 (X = Br and Cl) gave the 3-tert-
butyl-4-halogeno-5-pivaloylisothiazoles 7 (X = Br and Cl) in
boiling toluene (50–55%), and again the 3,4-dibromo derivative
gave no reaction with the trimer.
Scheme 2
Scheme 2; the rearrangement of the aziridine 9 so formed, and
the N᎐S cleavage on work-up, could be catalysed by traces
of hydrogen chloride generated from the moisture-sensitive
reagent 1. It is also possible that the monomer (or trimer) could
undergo conjugate addition as a nitrogen nucleophile to the
reactive Michael acceptor 8, followed by collapse to aziridine 9
(or a related species).
Reactions with thiophenes and tetraphenylcyclopentadienone
2
,5-Diphenylthiophene was treated with the trimer 1 exactly as
for the corresponding furan, in the expectation that the analo-
gous thiobenzoylisothiazole 2 (S for O) would be formed; how-
ever the product proved to be the benzoylisothiazole 2 identical
with that from 2,5-diphenylfuran. The thiophene was less
reactive towards the trimer than the furan, in keeping with its
greater aromaticity, and the best yield of 2 from the thiophene
was only 25%, compared with 85% from the furan. We propose
that the thiobenzoyl derivative 2 (S for O) is the initial product
but under the reaction and work-up conditions this is converted
into the ketone 2. To test this, thiobenzophenone was prepared
from benzophenone and phosphorus pentasulfide in refluxing
carbon disulfide. On addition of the trimer to a solution of
thiobenzophenone, the intense blue colour of the thioketone
was immediately discharged to yield benzophenone which was
Mechanism of the furan–trimer reactions
At the temperatures of these reactions the trimer 1 is substan-
tially dissociated into the monomer and we assume that this
highly reactive species is primarily responsible for the sub-
sequent S᎐N transferring process, which is in keeping with the
observed stoichiometry. Our original hypothesis was that thi-
azyl chloride would undergo cycloaddition to give the adduct
11 which would rearrange to 12 as shown (Scheme 3) and
aromatise with loss of hydrogen chloride to give the isothiazole
2 isolated. The regiochemistry is controlled by which bridging
C᎐O bond migrates and this is expected to be driven in the
direction shown (arrows in 11) by the strong polarisation
ϩ
Ϫ
(S ᎐N ) of the sulfur᎐nitrogen double bond. In the extreme,
this polarisation could induce the cycloadduct 11 to open as
1
618
J. Chem. Soc., Perkin Trans. 1, 1997

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formation could be achieved by electrophilic attack on the
ϩ
Ϫ
furan by monomer (᎐ NS Cl ), through sulfur at the β-position
᎐
1
6 or through nitrogen at the α-position 17 (Scheme 4). The
opposite modes of cycloaddition or of substitution would yield
regioisomers which we have not observed with any of the furans
studied. It is notable that the four 2,3,5-trisubstituted furans
investigated (2,3,5-triphenyl, 3-bromo-2,5-diphenyl, 3-bromo-
2
,5-di-tert-butyl and 2,5-di-tert-butyl-3-chloro) each gave only
one isothiazole product, cleanly and in good to very good yield.
This would appear to argue against a mechanism initiated by
attack at the (different) α-positions, and thus the Diels–Alder or
β-substitution mechanisms are considered more likely and we
are now trying to distinguish between them.
Experimental
General details
Light petroleum refers to the fraction boiling between 60 and
8
0 ЊC which was distilled before use. Benzene, toluene, xylene
and diethyl ether were dried over sodium wire for several
days. Tetrahydrofuran was purified by distillation from potas-
sium metal under nitrogen. Dichloromethane (DCM) and
tetrachloromethane were dried by distillation from phosphorus
pentaoxide and stored over 4 Å molecular sieves. Chloroform
was washed with water, dried over sodium sulfate, distilled
from phosphorus pentaoxide and stored over 4 Å molecular
sieves. Pyridine was dried and distilled over potassium
hydroxide.
Infra-red spectra were recorded on a Perkin-Elmer 1710FT
1
spectrometer with internal calibration. H HMR spectra were
recorded on a JEOL GSX270 spectrometer at 270 MHz, a
Bruker WM250 at 250 MHz, a Bruker AMX-400 at 400 MHz
1
3
or a Bruker AM-500 at 500 MHz and C spectra on the same
machines at 69, 62.9, 100 and 125 MHz respectively. Chemical
shifts are given in ppm, and are referenced to the residual peak
of the solvent or to tetramethylsilane. Low resolution mass
spectra and accurate mass measurements were recorded on a
VG Micromass 7070B or VG Autospec instrument using elec-
tron impact ionisation unless stated otherwise.
Column chromatography was performed on either Merck
Kieselgel 60H (70–230 mesh) or Crossfield 60H (60–230 mesh)
silica. Samples were applied as a saturated solution in a suitable
solvent or pre-adsorbed onto silica. TLC analysis was carried
out on Merck Kieselgel GF254 aluminium-backed plates.
Scheme 3
shown in 13 to give the acyclic intermediate 14, which could
collapse to 12 or cyclise directly to the isothiazole.
Conversion of the furan into the isothiazole can also be rep-
resented formally as the cycloaddition of thiazyl chloride across
the 2- and 4-positions of the furan ring 15, with accompanying
rearrangement, as shown in Scheme 4. The same overall trans-
1
0
Trithiazyl trichloride 1
A mixture of disulfur dichloride (200 ml), ammonium chloride
200 g) and sulfur (50 g) was refluxed gently overnight. The air
condenser bearing the dark brown crystals of S N Cl which
(
3
2
2
sublimed out of the reaction mixture was transferred to a pre-
dried flask and chlorine gas passed through the system. The
S Cl formed was removed under reduced pressure to leave
2
2
trithiazyl trichloride as a bright yellow solid. The chlorination
and removal of S Cl was repeated until no more discolouration
2
2
occurred on chlorination. The bright yellow trithiazyl tri-
chloride was used without further purification. The residue
from the formation of S N Cl was destroyed by mixing thor-
3
2
2
oughly with solid sodium hydrogen carbonate.
5
-Benzoyl-3-phenylisothiazole 2
Method (1). To a stirred solution of 2,5-diphenylfuran (550
mg, 2.5 mmol) in tetrachloromethane (10 ml), trithiazyl tri-
chloride 1 (122 mg, 0.5 mmol) in tetrachloromethane (5 ml)
was added dropwise. No significant temperature change was
observed, but the solution turned green. The mixture was
stirred at ambient temperature for 0.5 h and then heated at
reflux for 2.5 h. The solvent was evaporated and the residue was
separated by flash chromatography on silica gel. Elution with
dichloromethane (40%) in light petroleum gave a minor product
which was tentatively assigned as 5-benzoyl-4-chloro-3-
Scheme 4
J. Chem. Soc., Perkin Trans. 1, 1997
1619

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ϩ
ϩ
phenylisothiazole, m/z 301 (M , isotope, 7%), 299 (M , 19) in
agreement with isotope cluster abundance calculations for
C H ClNOS. Elution with dichloromethane (60%) in light
silica gel. Elution with dichloromethane (40%) in light petrol-
eum gave a minor product which was tentatively assigned the
structure 5-(4-methylbenzoyl)-4-chloro-3-(4-methylphenyl)iso-
1
6
10
ϩ
ϩ
petroleum gave 5-benzoyl-3-phenylisothiazole 2 as a clear oil
283 mg, 71% based on 1) (Found: M , 265.0561. C H NOS
requires M, 265.0561); νmax(neat)/cm 3280 (Ar–H), 3062 (Ar–
H), 2925, 2854, 1651 (C᎐O), 1598 (C᎐C), 1579, 1521, 1498,
448, 1387, 1305, 1273, 1214, 1180, 1117, 1078, 1028, 975, 936,
thiazole (18 mg, 5%), m/z 327 (M , 18%), 293 (M Ϫ Cl ϩ H,
ϩ
ϩ
(
15), 119 (CH C H CO , 100). Elution with dichloromethane
1
6
11
3
6
4
Ϫ1
(50%) in light petroleum gave the title compound (163 mg, 53%),
mp 100–101.5 ЊC (Found: C, 73.7; H, 5.1; N, 4.7. C H NOS
᎐
᎐
18 15
Ϫ1
1
9
requires C, 73.7; H, 5.15; N, 4.8%); νmax(Nujol)/cm 1648
10, 844, 793, 769; δ (270 MHz, CDCl ) 7.42–7.60 (5H, m,
(C᎐O), 1603, 1501, 1418, 1405, 1311, 1283, 1263, 1211, 1203,
H
3
ArH), 7.65–7.72 (1H, m, ArH), 7.96–8.02 (4H, m, ArH), 8.04
1179, 1111, 1069, 1042, 1016, 968, 953, 934; δ (270 MHz,
H
(
1H, s, 4-H); δ (69 MHz, CDCl ) 124.85 (CH), 126.95 (CH),
CDCl ) 2.35 (3H, s, CH ), 2.45 (3H, s, CH ), 7.27–7.36 (4H, m,
C
3
3
3
3
ϩ
1
1
1
28.90 (CH), 128.98 (CH), 129.33 (CH), 139.72 (CH), 133.67,
ArH), 7.83–7.92 (4H, m, ArH), 7.95 (1H, s, 4-H); m/z 293 (M ,
ϩ
ϩ
ϩ
34.11 (CH), 137.17, 164.94, 167.99, 186.34; m/z 266 (M ϩ 1,
79%), 202 (Mϩ Ϫ C H , 6), 174 (M Ϫ CH C H CO, 4) 119
7
7
3
6
4
ϩ
ϩ
ϩ
ϩ
7%), 265 (M , 91), 188 (M Ϫ Ph, 25), 105 (PhCO , 100), 77
(CH C H CO , 100), 91 (C H , 39).
3 6 4 7 7
ϩ
(Ph , 60).
Method (2). To a stirred solution of 2,5-diphenylfuran (190
2-Chloro-3,5-diphenylfuran
1
3
mg, 0.84 mmol) in tetrachloromethane (10 ml) was added a
solution of trithiazyl trichloride (68 mg, 0.28 mmol) in tetra-
chloromethane (5 ml). The reaction mixture was heated at
reflux for 2.5 h, cooled and evaporated. The residue was
separated on silica gel by chromatography. Elution with
dichloromethane (40%) in light petroleum gave 5-benzoyl-3-
phenylisothiazole, identical with the above product, as a clear
oil (179 mg, 81%).
To a stirred solution of 2,4-diphenylfuran (210 mg, 0.95
mmol) in tetrachloromethane (10 ml) was added trithiazyl tri-
chloride (72 mg, 0.3 mmol) in tetrachloromethane (5 ml). The
reaction mixture was heated at reflux for 2.5 h. The solvent was
evaporated and the residue was separated on silica gel by chro-
matography. Elution with dichloromethane (50%) in light pet-
roleum gave 2-chloro-3,5-diphenylfuran as a pale green solid
Ϫ1
(110 mg, 46%), mp 253–254 ЊC; νmax(Nujol)/cn 3056, 1592,
1
492, 1449, 1360, 1124, 1100, 1055, 1027, 966, 932, 908, 808,
5
-Benzoyl-3,4-diphenylisothiazole 3
755, 709, 689, 669; δ (270 MHz, CDCl ) 6.88 (1H, s, 4-H),
H
3
To a mixture of benzil (15.8 g) and acetophenone (10.5 g), a
solution of potassium hydroxide (3 g) in ethanol (54 ml) and
water (4.5 ml) was added dropwise. The mixture was warmed
and when the benzil was dissolved, the flask was allowed to
stand for 2 days in the cold room (4 ЊC). The crystalline precipi-
tate was collected and washed with a small amount of ethanol
to give 1,2,4-triphenylbut-2-ene-1,4-dione (26 g). The crude
product was heated at reflux with triethyl phosphite (17 ml) in
triethylene glycol dimethyl ether (210 ml) for 3 h. The solvent
was distilled at normal pressure and the residue was extracted
with hexane; after cooling the crystals were collected and
recrystallised from hexane to give 2,3,5-triphenylfuran as col-
7.26–7.46 (6H, m, ArH), 7.65 (2H, dd, ArH), 7.76 (2H, dd,
ϩ ϩ
ArH); m/z 256 (M , isotope, 12%), 254 (M , 38), 220
ϩ
ϩ
(M Ϫ Cl ϩ H, 87), 191 (M Ϫ COCl, 100), 165 (13), 149 (12).
3,4-Dibromo-2,5-diphenylfuran
To a solution of 2,5-diphenylfuran (2.2 g, 10 mmol) in tetra-
chloromethane (25 ml) at room temperature was added N-
bromosuccinimide (NBS) (2.2 equiv.). The mixture was stirred
at room temperature until no starting material remained (TLC).
The mixture was filtered through a pad of silica and the solvent
removed under reduced pressure. The title compound was
obtained as white needles, mp 89–91 ЊC; δ (270 MHz, CDCl )
H
3
1
1
ourless crystals (15 g, 61%), mp 98–100 ЊC (lit., 93–94 ЊC);
8.18 (4H, m), 7.54 (6H, m); δ (69 MHz, CDCl ) 147.9 (quat. C),
C
3
Ϫ1
νmax(Nujol)/cm 1594, 1488, 1145, 1073, 1055, 1027, 953, 934,
128.9 (C3 ϩ C4 of furan ring), 128.4 (p- ϩ o-C of Ph), 125.4
ϩ
9
04, 806, 756, 693, 662; δ (270 MHz, CDCl ) 7.25–7.50 (12H,
(m-C of Ph), 102.4 (quat. C) (Found: M 377.9090. C H Br O
H
3
16 10
2
ϩ
ϩ
m, ArH), 7.60–7.67 (2H, m, ArH), 7.75–7.82 (2H, m, ArH).
To a solution of 2,3,5-triphenylfuran (592 mg, 2 mmol) in
tetrachloromethane (1 ml) was added a solution of trithiazyl
trichloride 1 (122 mg, 0.5 mmol) in tetrachloromethane (4 ml)
with stirring at room temperature under nitrogen. During the
addition no significant temperature change was observed, but
the mixture turned green. The mixture was heated at reflux for
requires M 377.9078); m/z 380 [(M ϩ 2) , 36%], 378 (M , 70),
ϩ ϩ ϩ
376 [(M Ϫ 2) , 37], 105 (PhCO , 99), 77 (Ph , 100).
3-Bromo-2,4,5-triphenylfuran
To a mixture of 3,4-dibromo-2,5-diphenylfuran (440 mg, 1.17
mmol), phenylboronic acid (314 mg, 2.2 equiv.), benzene (2.5
ml), ethanol (0.8 ml, 20 equiv.) and 2  aqueous sodium car-
bonate (2.6 ml, 4.4 equiv.) was added tetrakis(triphenyl-
phosphine)palladium(0) (68 mg, 5 mol%). The mixture was
heated at reflux until no starting material could be detected by
TLC (24 h). The reaction mixture was poured into water,
2
0 h. The resulting red solution was evaporated and the residue
was separated by chromatography on silica gel. Elution with
dichloromethane (60%) in light petroleum gave 5-benzoyl-3,4-
diphenylisothiazole 3 as colourless needles (385 mg, 75%), mp
1
03.5–104.5 ЊC (Found: C, 77.7; H, 4.15; N, 4.2. C H NOS
extracted with DCM and dried (MgSO ). The solvent was
2
2
15
4
Ϫ1
requires C, 77.4; H, 4.4; N, 4.1%); νmax(Nujol)/cm 1675 (CO),
removed under pressure and the product purified by column
chromatography (eluent DCM–light petroleum). The title com-
pound was isolated as a white solid (374 mg, 85%), mp 128–
1
1
633, 1598, 1580, 1515, 1392, 1349, 1310, 1269, 1224, 1182,
097, 1075, 1029, 956, 935, 855, 781, 757, 729, 707; δ (270
H
1
4
ϩ
ϩ
MHz, CDCl ) 7.04–7.17 (5H, m), 7.26–7.34 (5H, m), 7.38–7.50
129 ЊC (lit., 129 ЊC); m/z 376 [(M ϩ 2) , 75%], 374 (M , 77),
3
ϩ ϩ
(3H, m), 7.70–7.75 (2H, m); δ (69 MHz, CDCl ) 128.04, 128.17,
189 (46), 105 (PhCO , 98), 77 (Ph , 100).
C
3
1
1
1
28.29, 128.34, 128.87, 128.99, 129.77, 130.07, 132.87, 133.69,
ϩ
34.77, 136.47, 138.60, 160.98, 166.92, 188.87; m/z 341 (M ,
5-Benzoyl-4-bromo-3-phenylisothiazole 5
ϩ
ϩ
00%), 264 (M ϪϩPh, 12), 236 (M Ϫ PhCO, 22), 105
To a solution of 2,5-diphenylfuran (2.2 g, 10 mmol) in tetra-
chloromethane (25 ml) at room temperature was added NBS (1
equiv.). The mixture was stirred at room temperature until no
starting material remained (TLC). The mixture was filtered
through a pad of silica and the solvent removed under reduced
pressure to give 3-bromo-2,5-diphenylfuran 4 as an off-white
ϩ
(PhCO , 76), 77 (Ph , 74).
5
-(4-Methylbenzoyl)-3-(4-methylphenyl)isothiazole
1
2
To a stirred solution of 2,5-bis(4-methylphenyl)furan (266
mg, 1.06 mmol) in tetrachloromethane (2 ml), trithiazyl tri-
chloride (84 mg, 0.34 mmol) in tetrachloromethane (5 ml) was
added dropwise. The solution turned green. The mixture was
heated at reflux for 4 h under nitrogen. The solvent was evapor-
ated and the residue was separated by flash chromatography on
1
5
solid, mp 65–66 ЊC (lit., 65–66 ЊC).
3-Bromo-2,5-diphenylfuran 4 (344 mg, 1 mmol) was dis-
solved in toluene (10 ml) and the mixture heated to reflux. The
solution was allowed to cool slightly, the trimer 1 (80 mg,
1
620
J. Chem. Soc., Perkin Trans. 1, 1997

View Article Online
0
.33 equiv.) was added and the mixture was refluxed overnight.
yellow oil (130 mg, 50%), identical with a sample prepared by
The solvent was removed under reduced pressure and the resi-
due purified by column chromatography on silica gel (eluent
DCM–light petroleum). The title compound 5 was isolated as a
yellow oil (167 mg, 55%), identical with a sample prepared by
bromination of 5-benzoyl-3-phenylisothiazole 2 with NBS as
chlorination of 3-tert-butyl-5-pivaloylisothiazole with NCS as
described for 2,5-diphenylfuran above; δ (270 MHz, CDCl )
H
3
t
t
1.36 (9H, s, Bu ), 1.33 (9H, s, Bu ); δ (69 MHz, CDCl ) 202
C
3
(carbonyl C), 173 (C5 of het. ring), 156 (C3 of het. ring), 107
(C4 of het. ring), 46 (quat. C of pivaloyl), 39 (quat. C of tert-
butyl), 29 (Me of pivaloyl), 26 (Me of tert-butyl); m/z 261
ϩ
described for 2,5-diphenylfuran; m/z 346 [(M ϩ 2) , 1.5%], 344
ϩ
ϩ
ϩ
ϩ
ϩ
ϩ
t
ϩ
tϩ
(
M , 1.5), 264 [(M Ϫ Br) , 15], 105 (PhCO , 100), 77 (Ph , 59).
[(M ϩ 2) , 0.3%], 259 (M , 0.8) [(M Ϫ Bu ) , 3.5], 57 (Bu ,
00).
1
3
2
-tert-Butyl-5-pivaloylisothiazole 7 (X ؍ H)
16
,5-Di-tert-butylfuran (180 mg, 1 mmol) was dissolved in
3,4-Dibromo-2,5-di-tert-butylfuran
tetrachloromethane and the mixture heated to reflux. The solu-
tion was allowed to cool slightly, the trimer 1 (80 mg, 0.33
equiv.) was added and the mixture was refluxed overnight. The
solvent was removed under reduced pressure and the residue
purified by column chromatography on silica gel (eluent DCM–
light petroleum). The title compound 7 (X = H) was isolated as a
colourless oil, which crystallised on standing (40%), mp 29–
To a solution of 2,5-di-tert-butylfuran (1.8 g, 10 mmol) in tetra-
chloromethane (20 ml) was added NBS (2.2 equiv.). The mix-
ture was stirred at room temperature for 1 week and the mixture
filtered through a pad of silica. The title compound was isolated
as a yellow oil (2.81 g, 83%); δ (270 MHz, CDCl ) 1.36 (s,
H
3
t
ϩ
ϩ
2 × Bu ); m/z 388 (M , 16%), 323 [(M Ϫ Me) , 91], 199
t
ϩ
tϩ
[(M Ϫ Br Ϫ Bu ) , 29], 57 (Bu , 100).
3
6
1 ЊC (Found: C, 64.0; H, 8.4; N, 6.1. C H NOS requires C,
12 19
Ϫ1
4.0; H, 8.5; N, 6.2%); νmax(neat)/cm 1682 (C᎐O); δ (270
Reaction of 2,5-diphenylthiophene with trithiazyl trichloride
H
t
17
17
MHz, CDCl ) 7.61 (1H, s, ring H), 1.37 (9H, s, Bu ), 1.35 (9H, s,
Bu ); δ (125 MHz, CDCl ) 198 (carbonyl C), 180 (C5 of het.
2,5-Diphenylthiophene
had mp 151–152 ЊC (lit., 149–
3
t
150 ЊC); δ (60 MHz, CDCl ) 6.7 (2H, s, thiophene ring pro-
C
3
H
3
ring), 162 (C3 of het. ring), 124 (C4 of het. ring), 44.2 (quat. C
tons), 7.2–7.5 (6H, m, PhH), 7.6–8.0 (4H, m, PhH). To a stirred
solution of 2,5-diphenylthiophene (210 mg, 0.88 mmol) in tetra-
chloromethane (10 ml) under nitrogen, trithiazyl trichloride
(72 mg, 0.3 mmol) in tetrachloromethane (4 ml) was added
dropwise. The reaction mixture was heated at reflux for 2.5 h.
The solvent was evaporated to give a brown oil which was puri-
fied by chromatography on silica gel. Elution with dichlo-
romethane (60%) in light petroleum gave an orange oil (90 mg)
which slowly became darker. It was rechromatographed to give
5-benzoyl-3-phenylisothiazole 2 (40 mg, 17%), identical with
that described earlier. Yields of up to 25% were obtained in
repeat experiments.
of pivaloyl), 36.5 (quat. C of tert-butyl), 30.0 (Me of pivaloyl),
ϩ
2
[
7.2 (Me of tert-butyl); m/z 225 (M , 21%), 210 (16), 168
t
ϩ
t
ϩ
tϩ
(M Ϫ Bu ) , 62], 141 [(M Ϫ Bu CN) , 34], 57 (Bu , 100).
3
-Bromo-2,5-di-tert-butylfuran 6 (X ؍ Br)
2
,5-Di-tert-butylfuran (1.8 g, 10 mmol) was dissolved in tetra-
chloromethane (20 ml) and NBS (1 equiv.) added. The mixture
was stirred at room temperature for 2 days, filtered through a
pad of silica and the title compound was isolated as a yellow
t
oil; δ (270 MHz, CDCl ) 5.95 (1H, s, ring H), 1.45 (9H, s, Bu ),
1
H
3
t
ϩ
ϩ
.30 (9H, s, Bu ); m/z 260 [(M ϩ 2) , 12%], 258 (M , 13), 243
ϩ t ϩ tϩ
[
(M Ϫ Me) , 95], 121 [(M Ϫ Bu Ϫ HBr) , 45], 57 (Bu , 28).
Thiobenzophenone
4
3
-Bromo-3-tert-butyl-5-pivaloylisothiazole 7 (X ؍ Br)
-Bromo-2,5-di-tert-butylfuran 6 (X = Br) (258 mg, 1 mmol)
A suspension of benzophenone (18.2 g), phosphorus penta-
sulfide (6.7 g) and triethylamine (10 ml) in carbon disulfide
(45 ml) was refluxed gently for 1 h under nitrogen. The mixture
was dissolved in toluene (10 ml) and the mixture heated to
reflux. The solution was allowed to cool slightly, the trimer
was filtered, and the CS removed under reduced pressure. The
2
1
(80 mg, 0.33 equiv.) was added and the mixture was refluxed
thiobenzophene was sublimed from the deep blue residue at
reduced pressure (0.5 mmHg) to give bright blue crystals mp
46–47 ЊC (lit., 50–51 ЊC).
overnight. The solvent was removed under reduced pressure
and the residue purified by column chromatography on silica
gel (eluent DCM–light petroleum). The title compound was isol-
ated as a yellow oil (167 mg, 55%), identical with a sample
prepared by bromination of 3-tert-butyl-5-pivaloylisothiazole
with NBS as described for 2,5-diphenylfuran above; δ (270
MHz, CDCl ) 1.36 (9H, s, Bu ), 1.35 (9H, s, Bu ); δ (69 MHz,
CDCl ) 203 (carbonyl C), 174 (C5 of het. ring), 159 (C3 of het.
ring), 107 (C4 of het. ring), 46 (quat. C of pivaloyl), 39 (quat.
1
8
Reaction of thiobenzophenone with the trimer
Thiobenzophenone (396 mg, 2 mmol) was dissolved in tetra-
chloromethane (15 ml) and the mixture heated to reflux. The
solution was allowed to cool slightly and the trimer 1 (500 mg,
1 equiv.) added; the bright blue colour of the solution disap-
peared immediately. The mixture was refluxed for a further 1 h,
the solvent removed under reduced pressure and the residue
purified by column chromatography. Benzophenone (310 mg,
H
t
t
3
C
3
C of tert-butyl), 29 (Me of pivaloyl), 26 (Me of tert-butyl); m/z
ϩ
t
ϩ
tϩ
3
05 [(M ϩ 2) , 0.4%], 246 [(M Ϫ Bu ) , 13.6], 57 (Bu , 100).
8
5%) was isolated as the sole organic product, identical with an
2
,5-Di-tert-butyl-3-chlorofuran 6 (X ؍ Cl)
authentic sample.
2
,5-Di-tert-butylfuran (1.8 g, 10 mmol) was dissolved in tetra-
chloromethane (20 ml) and N-chlorosuccinimide (NCS) (1
3,4,5,6-Tetraphenylpyridin-2(1H)-one 10
equiv.) added. The mixture was stirred at room temperature for
Method (1). Tetraphenylcyclopentadienone 8 (384 mg, 1
mmol) was dissolved in tetrachloromethane (15 ml) and the
mixture heated to reflux. The solution was allowed to cool
slightly and the trimer 1 (245 mg, 1 equiv.) added. The deep
purple colour of the solution disappeared immediately on add-
ition of the trimer. The mixture was then refluxed overnight.
The precipitate was filtered off and recrystallised from ethanol.
The title compound was isolated as white needles (224 mg,
2
days and then separated by filtration through a pad of silica.
The title compound was isolated as a yellow oil (1.68 g, 65%);
δ (270 MHz, CDCl ) 7.51 (1H, s, het. ring H), 1.26 (18H, s,
H
3
t
ϩ
tϩ
2
× Bu ); m/z 258 (M , 13%), 243 (95), 121 (45), 57 (Bu , 28).
3
-tert-Butyl-4-chloro-5-pivaloylisothiazole 7 (X ؍ Cl)
2
,5-Di-tert-butyl-3-chlorofuran (260 mg, 1 mmol) was dissolved
9
in toluene (10 ml) and the mixture heated to reflux. The solu-
tion was allowed to cool slightly and the trimer 1 (80 mg, 0.33
equiv.) was added and the mixture was then refluxed overnight.
The solvent was removed under reduced pressure and the resi-
due purified by column chromatography on silica gel (eluent
DCM–light petroleum). The title compound was isolated as a
56%), identical with an authentic sample, mp 271–273 ЊC (lit.,
ϩ
ϩ
272–273 ЊC); m/z 399 (M , 75%), 388 [(M Ϫ 1) , 100].
Method (2). Tetraphenylcyclopentadienone (384 mg, 1 mmol)
was dissolved in tetrachloromethane (15 ml) and the trimer (245
mg, 1 equiv.) added at room temperature. The deep purple col-
our of the solution disappeared rapidly. The mixture was then
J. Chem. Soc., Perkin Trans. 1, 1997
1621

View Article Online
stirred at room temperature overnight. The precipitate was fil-
tered off and recrystallised from ethanol. The title compound
5 J. Passmore and M. J. Schriver, Inorg. Chem., 1988, 27, 2749.
6
7
A. Haas and T. Mischo, Can. J. Chem., 1989, 67, 1902.
G. Urrutia-Desmaison, G. Mloston and R. Huisgen, Tetrahedron
Lett., 1994, 35, 4977, 4981.
(180 mg, 45%), was identical with that described above.
8
9
A. Apblett and T. Chivers, J. Chem. Soc., Chem. Commun., 1987, 24,
1
889.
Acknowledgements
R. L. Eagan, M. A. Ogliaruso and J. P. Springer, J. Org. Chem.,
1986, 51, 1544.
We thank Zeneca Specialties, the Thorpe Bequest (Imperial
College) and MDL Information Systems (UK) Ltd for financial
support, the Wolfson Foundation for establishing the Wolfson
Centre for Organic Chemistry in Medical Science at Imperial
College, and Dr Paul Worthington, Zeneca Agrochemicals,
for a generous gift of 2,5-di-tert-butylfuran.
1
1
0 W. L. Jolly and K. D. Maguire, Inorg. Synth., 1967, 9, 107.
1 M. J. Haddadin, B. J. Agha and R. F. Tabri, J. Org. Chem., 1979, 44,
4
94.
1
1
2 G. Nowlin, J. Am. Chem. Soc., 1950, 72, 5754.
3 F. Barba, M. D. Velasco and A. Guirado, Synthesis, 1981, 625.
14 C. F. H. Allen and H. B. Rosener, J. Am. Chem. Soc., 1927, 49, 2110.
1
1
5 P. M. G. Bavin, J. Pharm. Pharmacol., 1965, 17, 236.
6 H. Wynberg and U. E. Wiersum, J. Org. Chem., 1965, 30, 1058.
References
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1
8 E. Schaumann, U. Wriede and G. Rühter, Angew. Chem., Int. Ed.
Engl., 1983, 22, 55.
1
2
C. W. Rees, J. Heterocycl. Chem., 1992, 29, 639.
X.-G. Duan, X.-L. Duan, C. W. Rees and T.-Y. Yue, J. Heterocycl.
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3
4
Gmelin Handbook of Inorganic Chemistry, Sulfur-Nitrogen
Compounds, Part 2, Springer-Verlag, Berlin, 8th edn., 1985, p. 92.
D. H. R. Barton and W. A. Bubb, J. Chem. Soc., Perkin Trans. 1,
Paper 7/00358G
Received 14th January 1997
Accepted 6th February 1997
1
977, 916.
1
622
J. Chem. Soc., Perkin Trans. 1, 1997