A one-pot synthesis of 1,4-dithiins and 1,4-benzodithiins from ketones using the recyclable reagent 1,1′-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT)

Article abstract of DOI:10.1016/j.tetlet.2006.12.003

A novel access to 1,4-dithiins and 1,4-benzodithiins from the corresponding ketones in one-pot using the recyclable reagent, 1,1′-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT) is described. This method is mild, simple, environmentally benign and is

Full text of DOI:10.1016/j.tetlet.2006.12.003

Tetrahedron Letters 48 (2007) 1007–1011
A one-pot synthesis of 1,4-dithiins and 1,4-benzodithiins
from ketones using the recyclable reagent
1,10-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT)
Siva Murru, Veerababurao Kavala, C. B. Singh and Bhisma K. Patel*
Department of Chemistry, Indian Institute of Technology Guwahati, 781 039, Assam, India
Received 3 November 2006; revised 21 November 2006; accepted 1 December 2006
Available online 26 December 2006
Abstract—A novel access to 1,4-dithiins and 1,4-benzodithiins from the corresponding ketones in one-pot using the recyclable
reagent, 1,10-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT) is described. This method is mild, simple, environmentally
benign and is applied successfully for the ring expansion of 1,3-dithiolane to 1,4-dithiins and the ring expansion associated with
aromatisation of cyclic ketones with or without double bonds in the ring. The main feature of this method is that EDPBT acts
as a promoter in the formation of 1,3-dithiolane and as a reagent in the ring expansion step. The spent reagent can be recovered,
regenerated and reused.
ꢀ 2006 Elsevier Ltd. All rights reserved.
We have been utilising tetrabutylammonium tribromide
for bromination1 and for various other organic transfor-
mations.2 Recently we synthesised a new ditribromide
reagent, 1,10-(ethane-1,2-diyl)dipyridinium bistribromide
(EDPBT) which is superior to all known tribromides
and has several advantages over molecular bromine
and other tribromides.3 In addition to acting as an
excellent brominating agent, it has been utilised
as a catalyst for the acylation of alcohols4 and for the
synthesis of various thiazolidene-2-imine derivatives.5
In this letter we describe the utility of this reagent for
the synthesis of a variety of dihydro-1,4-dithiins and
1,4-benzodithiins from the corresponding ketones in
one-pot. The syntheses of dihydro-1,4-dithiins and 1,4-
benzodithiins have received much attention because of
their applications in synthetic organic chemistry and
medicinal chemistry. Derivatives of 1,4-dithiins show
activities as non peptide antagonists of the human Gal-
anin hGal-1 receptors.6 They have also been used for the
construction of larger rings containing sulfur atoms, for
the 1,2-transposition of carbonyl compounds,7 and as
allylic alcohol anion and acyl b-anion equivalents for
three carbon homologations.8 Further, the 1,4-benzo-
dithiin system is a useful intermediate for the synthesis
of aromatic compounds and for the preparation of
organic ferromagnets.9,10 1,4-Dithiins have also been
transformed into derivatives of 5,6-dihydro-1,4-dithiin
by reaction of butyllithium with various electro-
philes.8,11 The 5,6-dihydro-1,4-dithiin moiety has been
shown to be a useful synthetic intermediate to mimic
cis configured double bonds in the preparation of simple
alkenes and other unsaturated compounds.12 Deriva-
tives of 2,3-dihydro-1,4-dithiins are reported to be easily
oxidised affording dienophiles for use in Diels–Alder
reactions.13
Although methods have been reported for ring expan-
sion of 1,3-dithiolanes and a few for ring expansion
combined with aromatisation, no method has been
reported from ketones. Literature methods for the
preparation of dihydro-1,4-dithiins are mostly from
1,3-dithiolanes using various reagents such as N-halo-
amides,14a PhSeCl,14b molecular bromine or chlorine in
anhydrous CCl4,14c TeCl4,14d,e 2,4,6-trichloro-1,3,5-tri-
azine in DMSO,14f WCl6 in DMSO,7b SO2Cl2,14g 1,3-
dibromo-5,5-dimethylhydantoin,14h
o-iodoxybenzoic
acid (IBX)-tetraethylammonium bromide (TEAB),14i
1,3-dibromo-5,5-dimethylhydantoin (DBH)14j and tert-
butyl hypochlorite.14k Ring expanded monosubstituted
1,4-dithiins have been reported using (SiO2Cl/
DMSO)15a and N-substituted succinimides.15b
*
In spite of the several methods available in the literature,
some of the procedures suffer due to the use of expensive
Corresponding author. Tel.: +91 361 2582307; fax: +91 361
2690762; e-mail: patel@iitg.ernet.in
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.003

1008
S. Murru et al. / Tetrahedron Letters 48 (2007) 1007–1011
and toxic reagents, difficulty in handling and longer
reaction times. Moreover, all the reported procedures
involve two steps and the synthesis usually starts from
the 1,3-dithiolane. Earlier we reported the thioacetalisa-
tion of various carbonyl compounds using a cata-
lytic quantity of tetrabutylammonium tribromide
(TBATB).2f We have utilised the acidic properties of
EDPBT for the thioacetalisation of carbonyl com-
pounds followed by ring expansion of the in situ gener-
ated thioacetal to give 1,4-dithiins in one-pot.16
A plausible mechanism for the ring expansion is pro-
posed in Scheme 1. The first step of the reaction consists
of 1,3-dithiolane formation.2e Consumption of a further
equivalent of bromine forms bromosulfonium ion (X).
The bromosulfonium ion (X) loses a molecule of HBr
forming sulfanyl vinylbenzene intermediate (Y). Finally
intramolecular nucleophilic attack leads to the desired
product. This method was successfully applied to p-nitro-
acetophenone 2 and m-nitroacetophenone 3 both of
which gave the corresponding ring expanded 1,4-dithiins
2a and 3a, respectively, in good yields (Table 1). 4-Iso-
butylacetophenone 4 gave 1,4-dithiin 4a under identical
In an initial reaction acetophenone 1 (5 mmol) was trea-
ted with 1,2-ethanedithiol (5.5 mmol), and a catalytic
quantity of EDPBT (0.5 mmol) in acetonitrile (10 mL)
and stirred for 0.5 h. During this time acetophenone
was converted to the corresponding 1,3-dithiolane.
Although the rate of 1,3-dithiolane formation for differ-
ent ketones is different,2e we maintained a uniform time
of 0.5 h for all the substrates. To the reaction mixture, a
further quantity of EDPBT (2.5 mmol) was added and
stirring was continued for 15 min. The desired ring ex-
panded product, 1,4-dithiin 1a was isolated in good
yield. The structure of 1a was unambiguously confirmed
by single crystal X-ray diffraction analysis as shown in
Figure 1. It should be mentioned here that when a
similar reaction was performed with the 1,3-dithiane of
ketones using methyltriphenylphosphonium tribromide,
deprotection of the ketone without ring expansion was
reported.17f
Table 1. Formation of 1,4-dithiins from ketonesa
Substrate
Productb
Timec
(min)
Yieldd
(%)
S
O
S
15
25
85
72
1a
1
O
S
S
2
2a
O2N
O2N
O
S
S
3
3a
25
30
68
75
NO2
NO2
O
S
S
4
4a
O
S
S
20
30
73
78
5
5a
O
S
S
6
6a
Cl
Cl
O
S
S
25
25
30
50e
55e
70
S
S
7
+
+
7
Figure 1. ORTEP diagram with atom numbering of 1a.
HO
O
S
S
S
S
8
8
O
S
S
H2N
SH
HS
S
EDPBT (0.1 eq)
S
9
9a
O
EDPBT (0.5 eq)
+
a Reactions were monitored by TLC.
S
b Products were characterised by IR, 1H and 13C NMR.
c An additional 0.5 h for 1,3-dithiolane formation in the first step was
S
S
Br
S
S
Br
S
required.
d Yield of isolated product.
Br
H
(X)
(Y)
e Yield refers to [1,2,5,6]-tetrathiocane, starting ketone was isolated in
<90% yield.
Scheme 1. Proposed mechanism of formation of 1,4-dithiins.

S. Murru et al. / Tetrahedron Letters 48 (2007) 1007–1011
1009
Table 2. Formation of 1,4-dithiins and 1,4-benzodithiins from
conditions. Propiophenone
5 and p-chloropropio-
ketonesa
phenone 6 yielded the ring expanded products 5a and
6a, respectively. However, when the reaction was
performed with p-hydroxy acetophenone 7 and p-
aminoacetophenone 8, the ring expanded products were
not obtained, instead the starting materials along with
[1,2,5,6]-tetrathiocane were obtained. The formation
of [1,2,5,6]-tetrathiocane is not due to oxidation of
1,2-ethanedithiol.
Substrate
Productb
Timec
(min)
Yieldd
(%)
S
O
S
10
30
69
10a
Ph
Ph
S
S
O
In the first step of the reaction of p-hydroxy and p-
amino acetophenones with 1,2-ethanedithiol both were
consumed forming the corresponding 1,3-dithiolanes.
We have theoretically,2a as well as experimentally,2f
proven that the presence of an electron donating
substituent (OH, NH2) on the aromatic ring favours
thioacetalisation. Thus, recovery of the starting ketones
7 and 8 along with the formation of [1,2,5,6]-tetrathio-
cane can be explained by the following mechanism
(Scheme 2). Due to the presence of OH and NH2
substituents in the para position of the aromatic ring
the quinone formation pathway is more favoured over
proton abstraction returning the carbonyl compound
along with [1,2,5,6]-tetrathiocane.
40
40
60
60
60
63
11
11a
S
O
62
12
S
12a
S
O
70e
70e
75f
12
S
S
12b
12b
O
13
S
O
S
For ketones 1–6 the formation of the intermediate Y
(Scheme 1) occurs via elimination of a methyl proton
associated with C–S bond cleavage. In the case of phenyl-
acetone 9 where the carbonyl group is flanked by a
methyl and a methylene group, proton abstraction occurs
from the methylene carbon because of its higher acidity,
ultimately leading to the product 9a regioselectively.
S
14
14a
S
O
67f
72f
S
60
60
15
14a
Symmetrical ketones such as dibenzyl ketone 10, cyclo-
octanone 11 and cyclohexanone 12 were smoothly con-
verted to 1,4-dithiins 10a, 11a and 12a, respectively, with
0.6 equiv of EDPBT (Table 2). When cyclohexanone 12
was reacted with 1.6 equiv of EDPBT, it was converted
into the 1,4-dithiin derivative with concomitant aromat-
isation of the cyclohexane ring, thus affording the valu-
able 1,4-benzodithiin heterocyclic ring system 12b. In
this transformation, a total of three bromine equivalents
is needed, 1 equiv for the 1,4-dithiin ring formation and
2 equiv for aromatisation of the cyclohexane ring system
as shown in Scheme 3. Literature revealed a few such
ring expansions associated with aromatisation all start-
ing from the corresponding 1,3-dithiolanes only.9,17
O
S
S
16a
16
MeO
MeO
a Reactions were monitored by TLC.
b Products were characterised by IR, 1H and 13C NMR.
c An additional 0.5 h for 1,3-dithiolane formation in the first step was
required.
d Yield of isolated product.
e 1.6 equiv of EDPBT was used.
f 1.1 equiv of EDPBT was used.
Br
S
S
S
+
+
S
S
S
S
S
The first step of the 1,4-benzodithiin synthesis consists
of the formation of dihydro-1,4-dithiin 12a with the con-
EDPBT
0.5 eq.
EDPBT
0.5 eq.
H
S
(12a)
S
S
H
S
+
S
S
S
Br
OH2
Br
EDPBT (0.5 eq)
Br
+
S
S
X
S
+
+
X
X
S
S
S
S
H
X = OH, NH2
EDPBT
0.5 eq.
S
O
H
S
Br
(12b)
H
S
S
S
+
O
S
S
Scheme 3. A plausible mechanism for formation of 1,4-benzodithiins.
Br
X
X
S
S
S
H
Br
H
sumption of 1 equiv of bromine, that is, 0.5 equiv of
EDPBT followed by two subsequent electrophilic
attacks by bromine at one of the sulfur atoms with
Scheme 2. Proposed mechanism for the formation of [1,2,5,6]-tetra-
thiocane and regeneration of the starting ketone.

1010
S. Murru et al. / Tetrahedron Letters 48 (2007) 1007–1011
M.; Patel, B. K. Org. Biomol. Chem. 2004, 1670; (f)
Gopinath, R.; Haque, Sk. J.; Patel, B. K. J. Org. Chem.
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Chem. 2005, 70, 6556.
4. Naik, S.; Kavala, V.; Gopinath, R.; Patel, B. K. Arkivoc
2006, 21.
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2006, 8, 5397.
6. Scott, M. K.; Ross, T. M.; Lee, D. H. S.; Wang, H.-Y.;
Shank, R. P.; Wild, K. D.; Davis, C. B.; Crooke, J. J.;
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Commun. 1987, 223.
11. Caputo, R.; Ciriello, U.; Festa, P.; Guaragna, A.;
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2617.
Figure 2. ORTEP diagram with atom numbering of 16a.
two sequential losses of HBr. This process is associated
with aromatisation leading to 12b. Benzodithiin 12b was
also obtained from cyclohexenone 13 with just 1.1 equiv
of EDPBT suggesting the requirement of two bromine
equivalents for complete aromatisation as proposed in
Scheme 3. Both a-tetralone 14 and b-tetralone 15 were
converted to the same naphtho-1,4-dithiin 14a. In the
latter case, proton abstraction occurs from the benzylic
carbon which is more acidic, whereas in the former, pro-
ton abstraction occurs from the only available b-carbon.
Finally, 6-methoxytetralone 16 was converted into
naphtho-1,4-dithiin derivative 16a. The single crystal
X-ray structure of 16a is shown in Figure 2.
12. Caputo, R.; Palumbo, G.; Pedatella, S. Tetrahedron 1994,
50, 7265.
13. Nakayama, J.; Nakamura, Y.; Hoshino, M. Heterocycles
1985, 23, 1119.
In conclusion, we have developed a one-pot transforma-
tion of acyclic ketones to 1,4-dithiins and cyclic ketones
to 1,4-benzodithiins/1,4-naphthodithiins using the
recyclable reagent, 1,10-(ethane-1,2-diyl)dipyridinium
bistribromide (EDPBT).18 This method is simple,
convenient, mild and environmentally benign. An inter-
esting aspect of this method is that EDPBT acts as a
promoter in the formation of 1,3-dithiolane and as a
reagent in the ring expansion step. The spent reagent
can be recovered, regenerated and reused.3,4
14. (a) Yoshino, H.; Kawazoe, Y.; Taguchi, T. Synthesis 1974,
713; (b) Fransisco, C. G.; Friere, R.; Hernandez, R.;
Salazar, J. A.; Suarez, E. Tetrahedron Lett. 1984, 25, 1621;
(c) Caputo, R.; Ferreri, C.; Palumbo, G. Synthesis 1991,
223; (d) Tani, H.; Inamasu, T.; Tamura, R.; Suzuki, H.
Chem. Lett. 1990, 1323; (e) Tani, H.; Inamasu, T.;
Masumoto, K.; Tamura, R.; Shimizu, H.; Suzuki, H.
Phosphorus, Sulfur Silicon Relat. Elem. 1992, 67, 261; (f)
Karimi, B.; Hazarkhani, H. Synthesis 2003, 2547; (g)
Philip, C. B.; Ley, S. V.; Morton, J. A.; Williams, D. J. J.
Chem. Soc., Perkin Trans. 1 1981, 457; (h) Jeko, J.; Timar,
T.; Jaszberenyi, J. C. J. Org. Chem. 1991, 56, 6748; (i)
Shukla, V. G.; Salgaonkar, P. D.; Akamanchi, K. G.
Synlett 2005, 1483; (j) Jeko¨, J.; Timar, T.; Jaszberenyi, J.
C. J. Org. Chem. 1991, 56, 6747; (k) Arote, N. D.;
Telvekar, V. N.; Akamanchi, K. G. Synlett 2005, 2935.
15. (a) Firouzabadi, H.; Iranpoor, N.; Hazarkhani, H.;
Karimi, B. J. Org. Chem. 2002, 67, 2572; (b) Firouzabadi,
H.; Iranpoor, N.; Garzan, A.; Shaterian, H. R.; Ebrahi-
mzadeh, F. Eur. J. Org. Chem. 2005, 416.
16. Experimental procedure: To a solution of carbonyl com-
pound (5 mmol) in acetonitrile (10 mL) and 1,2-ethane-
dithiol (5.5 mmol) was added EDPBT (0.5 mmol). The
reaction mixture was stirred at room temperature. After
stirring for 30 min, an additional 2.5 mmol of EDPBT was
added to the reaction mixture and stirring was continued
at room temperature. The reaction progress was moni-
tored by TLC. After completion of the reaction, acetoni-
trile was evaporated and the reaction was quenched by
adding saturated NaHCO3 solution and the product was
extracted with ethyl acetate (2 · 25 mL). The organic layer
was separated and dried over anhydrous sodium sulfate
and concentrated. Further purification was accomplished
by column chromatography over a short column of silica
gel using a mixture of hexane, ethyl acetate as eluent. The
aqueous layer containing spent reagent was kept for
regeneration.3,4
Acknowledgements
B.K.P. and C.B.S. acknowledge the support for this
research from DST (SR/S1/OC-15/2006) and CSIR
(01/1946/04/EMR-II), New Delhi. S.M. and V.K.
acknowledge financial support to the institute. Thanks
are due to CIF IIT Guwahati, for NMR spectra and
DST FIST for XRD facilities.
References and notes
1. (a) Chaudhuri, M. K.; Khan, A. T.; Patel, B. K.; Dey, D.;
Kharmawophlang, W.; Lakshmiprabha, T. R.; Mandal,
G. C. Tetrahedron Lett. 1998, 39, 8163; (b) Bora, U.; Bose,
G.; Chaudhuri, M. K.; Dhar, S. S.; Gopinath, R.; Khan,
A. T.; Patel, B. K. Org. Lett. 2000, 2, 247.
2. (a) Roy, R. K.; Bagaria, P.; Naik, S.; Kavala, V.; Patel, B.
K. J. Phys. Chem. A 2006, 110, 2181; (b) Roy, R. K.;
Usha, V.; Patel, B. K.; Hairo, K. J. Comp. Chem. 2006,
773; (c) Kavala, V.; Patel, B. K. Eur. J. Org. Chem. 2005,
441; (d) Naik, S.; Kavala, V.; Gopinath, R.; Patel, B. K.
Arkivoc 2006, 119; (e) Naik, S.; Gopinath, R.; Goswami,

S. Murru et al. / Tetrahedron Letters 48 (2007) 1007–1011
1011
17. (a) Esteban, G.; Lopez, B.; Plumet, J.; del Valle, A.
Heterocycles 1997, 45, 1921; (b) Hiroyuki, T.; Tokuo, I.;
Rui, T.; Hitomi, S. Chem. Lett. 1990, 1323; (c) Hiroyuki,
T.; Shunsuke, I.; Kazunori, M.; Noboru, O. Heterocycles
1993, 36, 1783; (d) Benito, A.; Joaquin, P.; Rodriguez-
Campos, I. M. Heterocycles 1986, 24, 141; (e) Verheijen, J.
H.; Klossterziel, H. Synthesis 1975, 451; (f) Cristau, H.-J.;
Bazbouz, A.; Morand, P.; Torreilles, E. Tetrahedron Lett.
1986, 27, 2965.
28.3, 30.5, 45.3, 111.8, 125.6, 128.1, 129.2, 137.7, 141.5.
mass (EI): 250 (M+). Compound 6a: 1H NMR (400 MHz,
CDCl3): d 1.83 (s, 3H), 3.28 (s, 4H), 7.21 (d, 2H,
J = 8.4 Hz), 7.29 (d, 2H, J = 8.4 Hz). 13C NMR
(100 MHz, CDCl3): d 22.4, 29.5, 29.8, 121.2, 121.3,
128.5, 131.0, 133.5, 138.4; mass (EI): 242 (M+). Com-
1
pound 16a: H NMR (400 MHz, CDCl3): d 3.35 (m, 4H),
3.90 (s, 3H), 7.05 (s, 1H), 7.16 (m, 2H) 7.39 (d, 1H,
J = 8.8 Hz), 8.05 (d, 1H, J = 9.2 Hz). 13C NMR
(100 MHz, CDCl3): d 29.5, 30.3, 55.6, 107.0, 118.7,
119.5, 124.2, 124.8, 126.6, 127.6, 130.8, 132.9, 157.3; mass
(EI): 248 (M+). Compound 11a: 1H NMR (400 MHz,
CDCl3): d 1.49 (m, 4H), 1.59 (m, 4H), 2.32 (t, 4H,
J = 6.4 Hz), 3.14 (s, 4H). 13C NMR (100 MHz, CDCl3): d
26.6, 29.5, 30.1, 34.3, 112.5; mass (EI): 200 (M+). CCDC
numbers for compounds 1a and 16a are CCDC 626301
and 626302, respectively. These data can be obtained free
of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/datarequest/cif.
18. Selected Spectral data. Compound 3a: 1H NMR
(400 MHz, CDCl3): d 3.27 (m, 2H), 3.32 (m, 2H), 6.54
(s, 1H), 7.30 (d, 1H, J = 8 Hz), 7.47 (t, 1H, J = 8 Hz), 7.80
(d, 1H, J = 8 Hz), 8.28 (s, 1H). 13C NMR (100 MHz,
CDCl3): d 27.3, 27.7, 116.0, 120.8, 122.3, 125.6, 129.4,
131.6, 141.8, 148.4; mass (EI): 239 (M+). Compound 4a:
1H NMR (400 MHz, CDCl3): d 0.88 (d, 6H, J = 6.4 Hz),
1.83 (m, 1H), 2.44 (d, 2H, J = 7.2 Hz), 3.20 (m, 2H), 3.27
(m, 2H), 6.33 (s, 1H), 7.06 (d, 2H, J = 8 Hz), 7.31 (d, 2H,
J = 8 Hz). 13C NMR (100 MHz, CDCl3): d 22.7, 27.1,