Palladium catalyzed syntheses of dibenzothiophenes by ring-closure of 2-iodinated diaryl thioether

Article abstract of DOI:10.3987/COM-16-13531

An efficient ring-closure of 2-iodinated diaryl thioethers at the presence of palladium catalyst to form dibenzothiophene is described. After the best condition was set up as Pd3(dba)2 as the catalyst, anhydrous Cu(OAc)2 as additive, PivONa.H2O as base, DMF as solvent, a series of dibenzothiophenes could be successfully obtained through this protocol in moderate to excellent yields.

Full text of DOI:10.3987/COM-16-13531

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HETEROCYCLES, Vol. 92, No. 10, 2016, pp. 1874 - 1881. © 2016 The Japan Institute of Heterocyclic Chemistry
Received, 13 July, 2016, Accepted, 6th September, 2016, Published online, 21st September, 2016
DOI: 10.3987/COM-16-13531
PALLADIUM CATALYZED SYNTHESES OF DIBENZOTHIOPHENES
BY RING-CLOSURE OF 2-IODINATED DIARYL THIOETHER
Ya-Fang Chen, Rui-Yue Ma, Lu-Nan Zhou, Zhenting Du,* and Tao Zhang*
College of Science, Northwest A&F University, Yangling 712100, Shaanxi
Province, P. R. China, E-mail: duzt@nwsuaf.edu.cn
Abstract – An efficient ring-closure of 2-iodinated diaryl thioethers at the
presence of palladium catalyst to form dibenzothiophene is described. After the
best condition was set up as Pd3(dba)2 as the catalyst, anhydrous Cu(OAc)2 as
additive, PivONa.H2O as base, DMF as solvent, a series of dibenzothiophenes
could be successfully obtained through this protocol in moderate to excellent
yields.
Heterocyclic compounds is a very important class of organic compounds, no matter natural or artificial
ones, many heterocyclic compounds have potential pharmacological activity. Of them, dibenzothiophene
(DBT) is a fused aromatic tricyclic system can be isolated from high-boiling petroleum derivatives
originally.1 However, because of the sufficient availability, DBTs have been explored to a much less
extent than other related analogues such as carbazole or dibenzofurans. In fact, only a few reports of to
construct the skeleton of dibenzothiophene are presented in literature. The oldest one was sulfur insertion
o
to biphenyl at the presence of anhydrous aluminum chloride at 250 C in spite of in low yields.2
Intriguingly, using aryne produced by lithiation by perilous tert-butyllithium and a suitable electrophile,
Sanz furnished a series of functional dibenzothiophenes.3 In order to avoid the poisoning the
tramsition-metal catalysis, using Negishi coupling and subsequent SNAr reaction Kienle gave an
alternative strategy to form dibenzothiophenes.4 Using similar Suzuki biphenyl forming strategy, Golding
and Jepsen disclosed microwave-mediated intramolecular SNAr substitution to prepare
dibenzothiophenes.5 Regardless of the structural uniquity, under the initiation of triethylboran, a radical
reduction of 2-(2-iodophenyl)phenylthio derivatives by Bu3SnH giving dibenzothiophene was also
efficient.6 A palladium-catalyzed double C–H bond activation and thio-rearrangement, a series of
polysubstituted dibenzothiophenes could be provided in moderate yields.7 Actually, a brilliant C–H bond
activation and then thiolation, several 2-brominated diaryl thioethers could be obtained. Based on these
diaryl thioethers, Saravanan gave a short report of palladium catalyzed intramolecular annulations to

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afford dibenzothiophenes in good yields.8 Other miscellaneous methods can be found in literature as
well.9 Despite these advancements, there are still some drawbacks such as using sensitive organometallic
reagents or expensive organoboranes, confinements in substrates, limited applicability, being lack of
expandability or unsteady yields. As a continuation in searching efficient and cost-effective methods to
build different heterocycles,10 we envisaged a palladium-catalyzed C–H bond activation/ring-closure to
form dibenzothiophene based on 2-diazonium tetrafluoroborate of diaryl thioether.
Scheme 1. Major present pathways of synthesis of dibenzothiophene
At first, as an expansion of our previous protocol,10e we were strongly interested in the palladium
catalyzed denitrogenation/ C–H bond activation/ring-closure to form dibenzothiophene based on
2-diazonium tetrafluoroborate of diaryl thioether, however, after changes in palladium, base, solvent, this
attempt of ring-closure route was proved fruitless.
Scheme 2. Attempt in synthesis of dibenzothiophene from 2-diazonium tetrafluoroborate of diaryl
thioether
Thereafter, a literature survey revealed that there was no such a ring-closure report from 2-iodinated
diaryl thioether at all. So, through a simple Sandmeyer reaction, the diazonium group could be
transformed into corresponding iodo derivatives smoothly. Next we checked the possibility of
ring-closure method based on the obtained (4-chlorophenyl) (2-iodophenyl) thioether at the condition of
PdCl2(MeCN)2 as catalyst and Cs2CO3 as base. First of all, in order to prevent the poisoning of palladium
catalyst, 20% equivalent of anhydrous Cu(OAc)2 was used as additive. At first we found that the nature of
reaction solvents seems to be crucial for this reaction. In non polar solvents such as dichloromethane
(Table 1, entry 1) and toluene (Table 1, entry 2), and more polar solvents such as THF (Table 1, entry 2),

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acetonitrile (Table 1, entry 3), there was no desired product at all. To our pleasure, in DMF, only after 4.5
hours, a yield of 59% was obtained. Next, the different palladium catalysts were screened. Subsequent
experiments revealed that PdCl2(MeCN)2, Pd(OAc)2(PPh3)2 and Pd(OAc)2 gave more or less yields under
same other conditions (Table 1, entries 5-7). Pd(OCOCF3)2, which has strong electron withdrawing
counter-ion, a higher yield of 2-chlorodibenzothiophene than the previous ones could be obtained (Table
1, entry 8). At last, we tried to alter base, inorganic base K2CO3 (Table 1, entry 9) didn’t gave a positive
yield. Delightfully, if PivONa·H2O was used as base (Table 1, entry 10), the best result was given.
Finally, we set up the optimized reaction conditions that are DMF as solvent, 20% molar ratio Pd3(dba)2
as catalyst, 20% molar ratio anhydrous Cu(OAc)2 as additive, C5H11NaO3 as base at refluxing
temperature (Table 1, entry 11).
Table 1. Screening condition of ring-closure of 4-chlorophenyl-2’-iododiphenyl thioether
Yields
Entry Solvent
Base
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
PivONa·H2
O
Additive
Cu(OAc)2
Catalyst
T (oC)
39.8
Time˄h˅
(%)b
1
DCM
toluene
THF
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
72
49
72
54
4.5
12.5
4
0
2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
110
66
0
3
0
4
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
82
0
5
150
59
50
54
68
71
64
6
Pd(OAc)2(PPh3)2 150
7
Pd(OAc)2
Pd(OCOCF3)2
Pd2(dba)3
150
150
150
150
8
4.5
2
9
10
Pd2(dba)3
2
Pd2(dba)3
11
DMF
150
2
82
a Reaction conditions: unless otherwise noted, substrate (0.58 mmol, 1 equiv.), palladium catalyst (0.116
mmol, 0.2equiv.), anhydrous Cu(OAc)2 (0.116 mmol, 0.2equiv.), base (0.58 mmol, 1 equiv.), solvent (5
mL). b Isolated yields.

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Having established optimized reactions conditions, we next examined the scope of our protocol for the
synthesis of a variety of substituted dibenzothiophene, as shown in Table 2. Altogether 9 examples (Table
2) with different substituents, including halo (Table 2, entry 1), t-butyl (Table 2, entry 5), and methyl or
methoxy (Table 2, entry 3) groups were subjected to this protocol to afford diarylbenzothiophenes in
fairly good yields. It is worth noting that if naphthyl was included, tetracyclic structure of
benzo[b]naphtho[1,2-d]thiophene could be obtained efficiently (Table 2, entries 6-7). As for the
variations of R1, two kinds of substituents have been tested. As for the variations of R2, electron-neutral
(Table 2, entries 2-4, 9), electron-donating (Table 2, entry 8) and electron-deficient (Table 2, entry 1)
groups were good substrates for this reaction. Thus, all the products in our reactions listed in Table 2 were
easily characterized on the basis of physical and spectral data and also by comparison with authentic
samples.
Table 2. Pd-Catalyzed synthesis of substituted dibenzothiophenes
Entry
1
Substrate
Product
Yield (%)a
82
1a
2a
2
80
1b
2b
3
4
5
84
81
77
1c
2c
2d
1d
1e
2e

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6
7
53
52
1f
2f
1g
1h
2g
8
9
92
86
2h
1i
2i
a Isolated yields.
Scheme 3. A plausible mechanism of Pd-catalyzed synthesis of substituted dibenzothiophenes
A plausible mechanism of this intramolecular cyclization is given in Scheme 3. The conversion
commenced with the oxidative-addition of Pd (0) to give intermediate I. A replacement of iodo ion by

HETEROCYCLES, Vol. 92, No. 10, 2016
1879
PivO- anion would happen. With the help of bulky tert-butyl group, the complex would be more soluble
than using normal inorganic base. And then the C–H bond is activated and then PivOH is released.
Subsequent reductive elimination gives the dibenzothiophenes and and regenerates Pd (0) for next
catalytic cycle.
In conclusion, we have expanded our palladium catalyzed ring-closure methodologies to synthesize
different heterocycles. In this case, using ortho iodo diaryl thioether, we have established the optimized
conditions is that Pd3(dba)2 as the catalyst, anhydrous Cu(OAc)2 as additive, sodium pivalate hydrate as
base, DMF as solvent. At best conditions, we have obtained 9 different dibenzothiophenes which were
confirmed by NMR. Our method merits as such advantages, high yield, short reaction time,
cost-effectiveness and versatility in substrates.
EXPERIMENTAL SECTION
All the solvents and commercially available reagents were purchased from commercial sources and used
1
directly. H NMR and 13C NMR were recorded in CDCl3 at room temperature on the Bruker NMR
spectrometers (DRX 500) if not noted otherwise. The chemical-shifts scale is based on internal TMS and
the coupling constants, J are reported in Hertz (Hz). Standard flash chromatography was employed to
purify the crude reaction mixture using 200–300 mesh silica gel (Tsingdao Ocean Company, Tsingdao,
China) under a positive nitrogen pressure.
General procedure for the preparation of dibenzothiophenes from the 2-iodinated diphenylthioethers using
Pd3(dba)2: Under argon flush, a flask was charged with the substrates of diaryl thioethers (0.58 mmol),
DMF (10 mL), Pd3(dba)2 (105 mg, 0.115 mmol), Cu(OAc)2 (23 mg, 0.115 mmol) and sodium pivalate
hydrate (72 mg, 0.58 mmol), and then the mixture was maintained at 150 °C with stirring for 5 h under
argon atmosphere. After completion by TLC analysis, the reaction mixture was diluted with EtOAc and
water. The aqueous phase was extracted with EtOAc twice and the combined organic phases were washed
with brine and dried over MgSO4. Then solvent was evaporated under vacuum and the crude product was
purified by column chromatography on silica gel, eluting with a mixture of petroleum ether and EtOAc to
give dibenzothiophenes. Yields are listed in Table 2.
2-Chlorodibenzothiophene 2a: white solid, mp 123-124 oC; 1H NMR (500 MHz, DMSO-d6) δ: 8.51 (d,
13
J = 1.5 Hz, 1H), 8.43 (d, J = 7.0 Hz, 1H), 8.03-8.07 (m, 2H), 7.50-7.56 (m, 3H); C NMR (125 MHz,
DMSO-d6) δ: 139.91, 137.59, 137.15, 134.56, 130.39, 128.21, 127.40, 125.41, 125.12, 123.61, 123.08,
122.27.

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o
1
2-Methyldibenzothiophene 2b: white solid, mp 81-82 C, Lit.11 81-82oC; H NMR (500 MHz,
DMSO-d6) δ: 8.31-8.32 (m, 1H), 8.17 (s, 1H), 7.99-8.00 (m, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.48-7.50 (m,
13
2H), 7.34 (d, J = 8.0 Hz, 1H), 2.49 (s, 3H); C NMR (125 MHz, DMSO-d6) δ: 139.39, 136.04, 135.68,
135.39, 134.58, 128.94, 127.40, 125.09, 123.51, 123.14, 122.53, 122.36, 21.50.
o
1
2-tert-Butyldibenzothiophene 2c: white solid, mp 63-64 C; H NMR (500 MHz, CDCl3) δ: 8.15-8.18
(m, 2H), 7.81-7.83 (m, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.51 (dd, J = 8.5, 2.0 Hz, 1H), 7.41-7.44 (m, 2H),
13
1.43 (s, 9H); C NMR (125 MHz, CDCl3) δ: 147.73, 139.91, 136.55, 135.83, 135.44, 126.49, 124.90,
124.20, 122.90, 122.33, 121.45, 117.87, 34.88, 31.70.
o
o
1
Dibenzothiophene 2d: white solid, mp 99-100 C, Lit.11 99.7 C; H NMR (500 MHz, CDCl3) δ:
8.14-8.16 (m, 2H), 7.83-7.85 (m, 2H), 7.44-7.46 (m, 4H); 13C NMR (125 MHz, CDCl3) δ: 139.46, 135.57,
126.72, 124.37, 122.83, 121.60.
o
1
2-tert-Butyl-8-chlorodibenzothiophene 2e: white solid, mp 60-61 C; H NMR (500 MHz, CDCl3) δ:
8.13 (d, J = 2.0 Hz, 1H), 8.09 (d, J = 1.5 Hz, 1H), 7.72-7.77 (m, 2H), 7.54 (dd, J = 8.5, 2.0 Hz, 1H), 7.37
13
(dd, J = 8.5, 2.5 Hz, 1H), 1.43 (s, 9H); C NMR (125 MHz, CDCl3 δ: 148.10, 137.99, 137.31, 137.21,
134.46, 130.51, 126.69, 125.61, 123.86, 122.45, 121.37, 118.07, 34.91, 31.65.
o
1
Benzo[b]naphtho[1,2-d]thiophene 2f: white solid, mp 138-140 C, Lit.12 140 oC; H NMR (500 MHz,
CDCl3) δ: 9.00 (d, J =8.5 Hz, 1H), 8.85 (d, J = 8.0 Hz, 1H), 7.99-8.03 (m, 2H), 7.87-7.92 (m, 2H),
7.71-7.75 (m, 1H), 7.56-7.61 (m, 2H), 7.48-7.51 (m, 1H); 13C NMR (125 MHz, CDCl3) δ:139.78, 138.66,
136.76, 131.98, 130.70, 129.48, 129.09, 127.89, 127.17, 125.26, 124.93, 124.85, 124.76, 123.25, 123.23,
121.11.
o
1
Benzo[b]naphtho[1,2-d]-8-chlorothiophene 2g: white solid, mp 129-130 C; H NMR (500 MHz,
CDCl3) δ: 8.86 (d, J =8.5 Hz, 1H), 8.78 (d, J =2.0 Hz, 1H), 8.00 (d, J =8.5 Hz, 1H) 7.85-7.89 (m, 3H),
13
7.73 (td, J = 7.0, 1.5 Hz, 1H), 7.57-7.60 (m, 1H), 7.44 (dd, J = 8.5, 2.0 Hz, 1H); C NMR (125 MHz,
CDCl3) δ: 139.74, 137.87, 137.82, 131.93, 131.04, 130.47, 129.56, 128.56, 128.19, 127.52, 125.48,
125.22, 124.48, 123.99, 122.89, 120.95.
o
1
2-Methoxy-8-chlorodibenzothiophene 2h: white solid, mp 97-98 C; H NMR (500 MHz, CDCl3) δ:
8.05 (d, J =2.0 Hz, 1H), 7.69-7.74 (m, 2H), 7.54 (d, J =2.5 Hz, 1H), 7.38 (dd, J =8.5, 2.0 Hz, 1H), 7.10
13
(dd, J =9.0, 2.0 Hz, 1H), 3.93 (s, 3H); C NMR (125 MHz, CDCl3) δ: 157.82, 138.68, 136.83, 135.59,
132.08, 130.42, 126.90, 123.96, 123.60, 121.45, 116.77, 104.81, 55.73;
o
1
2-Methyl-8-chlorodibenzothiophene 2i: CAS: white solid, mp 112-113 C; H NMR (500 MHz,
DMSO-d6) δ: 8.44 (s, 1H), 8.25 (s, 1H), 8.02 (d, J =8.5 Hz, 1H), 7.90 (d, J =8.0 Hz, 1H), 7.51 (d, J =8.5
13
Hz, 1H), 7.37 (d, J =8.0 Hz, 1H), 2.49 (s, 3H); C NMR (125 MHz, DMSO-d6) δ: 1.38.50, 137.59,
137.51, 135.42, 135.29, 130.80, 130.16, 127.80, 125.72, 123.84, 123.70, 122.71, 22.00.

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ACKNOWLEDGEMENTS
Financial support from the National Natural Science Foundation of China (31301712) is greatly
appreciated. Zhenting Du would like to thank Opening Funds of Key Laboratory of Synthetic Chemistry
of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences for the
partial financial support. Zhenting Du would is deeply indebted to Hong-Li Zhang for his assistance in
acquiring NMR spectra.
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