A simple and efficient synthesis of dibenzothiophene via BF 3·OEt2-promoted intramolecular annulation

Article abstract of DOI:10.1055/s-0032-1318391

A simple and efficient protocol promoted by BF₃·OEt ₂ for synthesizing functionalized dibenzothiophenes (DBTs) has been demonstrated. The annulation condition can tolerate a variety of functional groups. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318391

LETTER
▌851
lAetteSr imple and Efficient Synthesis of Dibenzothiophene via BF3·OEt2-Promoted
Intramolecular Annulation
Simple and Efficient Synthesis of Dibenzothiophene
Xiaobo Shang,a Wanzhi Chen,*a Yingming Yao*b
a
Department of Chemistry, Zhejiang University, Xixi Campus, Hangzhou 310028, P. R. of China
Fax +86(571)88273314; E-mail: chenwzz@zju.edu.cn
b
College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. of China
Received: 30.01.2013; Accepted: 11.02.2013
desired dibenzothiophene after an in situ cyclization.10
Abstract: A simple and efficient protocol promoted by BF3·OEt2
Substituted DBT can be obtained through functionaliza-
for synthesizing functionalized dibenzothiophenes (DBTs) has been
tion of dibenzothiophene. For example, direct lithiation of
demonstrated. The annulation condition can tolerate a variety of
DBT at 4- and 6-positions and subsequent nucleophilic re-
action gave 4,6-disubstituted DBT.11 2,8-Disubstituted
DBT can be obtained through Suzuki coupling reaction of
2,8-dibromodibenzothiophene generated from bromina-
tion of DBT12 or Stille coupling reaction of 2,8-bis(stan-
nyl)DBT.2 However the known synthetic methods have
the drawbacks including the use of sensitive organometal-
lic compounds and multistep procedures. Transition-met-
al-catalyzed C–S formation reactions are promising but
their application would be restricted due to poisoning ef-
fect of sulfur. Thus the development of an efficient and
simple method for the synthesis of DBT derivatives is of
great importance.
functional groups.
Key words: dibenzothiophenes, cyclization, Lewis acid, triazene
Dibenzothiophene (DBT) derivatives naturally exist in
coal tar and occur widely in heavier fractions of petro-
leum.1 DBT has a high ionization potential and a large
bond gap which facilitate charge transfer and its planar
structure favors intermolecular interaction. Thus DBT is a
good conjugated unit for organic semiconductors.2 The
DBT unit is also a building block of selective estrogen
modulators.3 Moreover, DBT derivatives have found a
number of applications as agrochemicals, liquid crystals,
and photoactive compounds.4 Typically, dibenzothio-
phene itself can be prepared from biphenyl and sulfur in
the presence of anhydrous aluminum chloride.5 Lithiation
of 2-fluorophenyl 2-iodophenylthioether with t-BuLi and
further reaction with a suitable electrophile gives rise to
functionalized dibenzothiophene derivatives and the pro-
cess involves an anionic cyclization on a benzyne-teth-
ered aryllithium intermediate.6 To avoid the poisoning of
the transition metal catalysts by thiols and thiolates, a new
ring-closure procedure involving main-group benzothio-
lates was reported. Various condensed S-heterocycles
have been obtained regioselectively and the intermediates
are readily available through a palladium-catalyzed cross-
coupling method.7 The radical reduction of 2-(2-iodophe-
nyl)phenylthio derivatives with Bu3SnH in the presence
of catalytic Et3B as radical initiator also led to annulations
and gave benzothiophene.8 Most recently, a brilliant pal-
ladium-catalyzed double C–H activation was developed
using sulfoxide as a new traceless directing group, and a
number of polysubstituted dibenzothiophenes have been
regioselectively prepared.9 The newest efficient three-step
protocol for synthesizing functionalized dibenzothio-
phenes involves Suzuki–Miyaura coupling of an ortho-
functionalized aryl halide with a (2-fluorophenyl)boronic
acid to form biphenyl compound, Pd-catalyzed C–S cou-
pling of either a bromide or a triflate with ethyl 3-mercap-
topropionate followed by deprotection to generate the
Triazene compounds are versatile intermediates in organ-
ic synthesis.13 Triazene functionality (ArN = NNR2) can
be viewed as a synthetic equivalent of the diazonium salt.
This allows to replace the reactive diazonium salt by more
stable triazene, and thus make the reaction easy to han-
dle.14 It was reported that Lewis acid promoted the synthe-
sis of carbazoles, dibenzofurans and dihydrobenzofurans
from biaryltriazenes.15 Recently Friedel–Crafts arylation
using aryl triazenes has also been reported to form poly-
cyclic aromatic hydrocarbons.16 Here we propose the an-
nulation reaction of triazene bearing a methylthio group
leading to dibenzothiophene derivatives via Lewis acid
promoted intramolecular nucleophilic substitution.
We initially attempted the reaction of 2a in the presence
of two equivalents of BF3·OEt2 in CH2Cl2. At room tem-
perature, 3a could be obtained in 45% yield after stirring
for 15 minutes. The influence of reaction temperature and
solvents was examined and the results are summarized in
Table 1. The reaction could be performed in methanol,
DMF, and toluene affording 3a in low yields, while ace-
tonitrile is much better in which the yield could be in-
creased to 80% within four hours under the same
conditions. Surprisingly, the reaction did not proceed at
all in THF. Other Lewis acids such as Fe2(SO4)3, CuCl2,
NiBr2 and AcOAg were ineffective for the annulation re-
action of 2a when 0.5 equivalent of Lewis acid was em-
ployed. However, when the Lewis acid loading was
increased to 2.0 equivalents, CuCl2 and NiBr2 could pro-
mote the annulation with the yields of 78% and 35%, re-
spectively. Therefore, BF3·OEt2 (2.0 equiv) in acetonitrile
is more appropriate for the annulation reaction.
SYNLETT 2013, 24, 0851–0854
Advanced online publication: 14.03.2013
DOI: 10.1055/s-0032-1318391; Art ID: ST-2013-W0104-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
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5
2
1
4
1
4
3
7
-
2
0
9
6

852
X. Shang et al.
LETTER
Under the optimized conditions, a number of triazenes The resulting dibenzothiophene 3m bearing the bromo
were subjected to the reaction, and the results are shown group is interesting since it offers opportunity for further
in Scheme 1. Triazene derivatives 2a–q containing elec- functionalization via metal-catalyzed cross-coupling re-
tron-withdrawing or electron-donating groups gave the actions (Scheme 2). For example, we were able to obtain
corresponding products in moderate to excellent yields. 4a–c in excellent yields using typical palladium-catalyzed
The reactivities of triazenes were sensitive to the substit- coupling between 3m and unsaturated compounds or or-
uents. The electron-deficient triazenes were found to be ganoboronic acid. In the UV/Vis absorption spectrum,
more reactive than electron-rich ones. Triazene 2b bear- compound 4a showed two peaks at λ = 346, 238 nm. The
ing a cyano group yielded dibenzothiophene in 88% yield. absorption at λ = 346 nm corresponds to the π → n* tran-
In the presence of BF3·OEt2, triazenes 3i–q bearing the sition band of the conjugated system. Compound 4b and
chalcone moiety could also be converted to the corre- 4c showed similar absorption to 4a.
sponding dibenzothiophenes in moderate to excellent
Decomposition of triazenes would generate either aryl
yields. It is well known that chalcone is abundant in plants
cations or aryl radicals.18 The annulation of triazene could
as a class of flavonoids and possesses a diverse array of
proceed via radical or cationic mechanism. In order to
pharmacological activities and is considered as a promis-
clarify the mechanism of the reaction, the influence of
radical scavengers was tested (Scheme 3). Addition of
ing template for drug design.17
2,6-di-tert-butyl-4-methylphenol (BHT) and 2,2,6,6-tet-
R1
S
S
Me
R2
N
N
BF3⋅OEt2 (2.0 equiv)
R1
N
R2
MeCN
3a–q
2a–q
S
S
S
R
Cl
3a: R = CO2Et, 80%
3b: R = CN, 88%
3c: R = Me, 51%
3d: R = H, 86%
3g: 46%
3h: 86%
3e: R = Cl, 57%
3f: R = COMe, 61%
S
Cl
S
R
Cl
O
S
3n: 58%
3i: R = H, 52%
3j: R = Cl, 64%
3k: R = OMe, 71%
3l: R = Me, 92%
3m: R = Br, 57%
O
3o: 81%
S
S
O
O
3p: 51%
3q: 43%
Scheme 1 Annulation of various diaryltriazenes promoted by BF3·OEt2. All reactions were carried out with triazene (1 mmol), BF3·OEt2 (2.0
equiv) in MeCN (40 mL) at 45 °C for 4 h. Yields are of isolated products after flash column chromatography.
Synlett 2013, 24, 851–854
© Georg Thieme Verlag Stuttgart · New York

LETTER
Simple and Efficient Synthesis of Dibenzothiophene
853
Table 1 Optimization of the Reaction Conditions
Entry
Lewis acid
Equiv
Solvent
Temp (°C)
Time
Yield (%)
1
2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
Fe2(SO4)3
CuCl2
2.0
2.0
2.0
2.0
2.0
2.0
2.0
0.5
0.5
0.5
2.0
2.0
2.0
CH2Cl2
MeCN
MeOH
DMF
r.t.
45
45
45
45
45
45
45
45
45
45
45
45
15 min
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
45
80
3
65
4
trace
5
toluene
THF
40
6
no reaction
no reaction
no reaction
no reaction
no reaction
78
7
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
8
9
NiBr2
10
11
12
13
AcOAg
CuCl2
NiBr2
35
AcOAg
no reaction
ramethylpiperidinyloxy (TEMPO) to a mixture of 2d and amount of N-methylpyrrolidine has been confirmed by
BF3·OEt2 under the standard conditions, led to the forma- GC–MS.
tion of 3d in yields of 90% and 83%, respectively. Obvi-
ously, the reaction was not significantly affected by the
existence of the radical scavenger. Therefore the radical
N
N
N
mechanism can be excluded. We speculate that the annu-
lation proceeds via aryl cation (Scheme 4). The interac-
tion between the terminal nitrogen atom and Lewis acid
enhances the cleavage of the sp2 C–N bond and the forma-
tion of aryl cations with release of a molecule of N2. Sub-
sequent nucleophilic attack of the methylthio group
towards the positively charged arene generates a new C–
S bond. Elimination of a molecule of 1-methylpyrrolidine
gives the final product dibenzothiophene. A quantitative
BF3⋅OEt2 (2.0 equiv)
MeCN
45 °C, 4 h
SMe
S
2d
3d
with BHT(1.0 equiv), 90%
with TMEPO (1.0 equiv), 83%
without radical scavenger, 86%
Scheme 3 Annulation reaction in the presence of radical inhibitor
S
OMe
O
4a, 83%
S
S
Pd(OAc)2
Br
O
COOn-Bu
COOn-Bu
O
4b, 90%
S
3m
O
4c, 84%
Scheme 2 The coupling reaction of 3m
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 851–854

854
X. Shang et al.
LETTER
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LA
S
δ–
LA
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δ+ N
Me
S
Me
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+ Me+
– LA
S
+
– N2
Me
N
Scheme 4 Mechanism of the intramolecular annulation
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In summary, we have developed an efficient method for
the synthesis of dibenzothiophenes promoted by
BF3·OEt2.20 This approach works well to form various
dibenzothiophenes in moderate to excellent yields under
mild and transition-metal-free conditions. Extensions of
this methodology are currently being investigated in our
laboratories.
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Acknowledgment
The project is supported by the Natural Science Foundation of Chi-
na (No. 21072170).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
(20) Representative Procedure for the Synthesis of 3a:
BF3·OEt2 (2.0 equiv) was added dropwise to the stirred
solution of 2a (1 mmol) in anhyd MeCN at 45 °C. The
mixture was stirred for 4 h. After the completion of the
reaction detected by TLC, it was washed with sat. aq
NaHCO3 and extracted with EtOAc. The combined organic
extracts were dried over anhyd Na2SO4 and removed under
reduced pressure. The product was purified by column
chromatography to give 3a as a white solid (80% yield); mp
68–71 °C. 1H NMR (400 MHz, CDCl3): δ = 8.84 (s, 1 H),
8.22–8.26 (m, 1 H), 8.11–8.14 (m, 1 H), 7.84–7.90 (m, 2 H),
7.48–7.51 (m, 2 H), 4.46 (q, J = 6.8 Hz, 2 H), 1.47 (t, J = 7.2
Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 166.7, 144.2,
139.6, 135.5, 135.2, 127.3, 126.8, 124.8, 123.1, 122.8,
122.5, 121.9, 61.1, 14.4. IR (thin film): 3065, 2924, 1710,
1267, 1100, 1025 cm–1. MS (EI): m/z (%) = 256 (97) [M+],
241 (14), 228 (39), 211 (100), 183 (58), 139 (54). HRMS
(EI–TOF): m/z [M+] calcd for C15H12O2S: 256.0558; found:
256.0566.
References and Notes
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Synlett 2013, 24, 851–854
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