Synthesis of functionalized dibenzothiophenes- An efficient three-step approach based on Pd-catalyzed C-C and C-S bond formations

Article abstract of DOI:10.1002/ejoc.201001393

A novel and efficient three-step protocol for synthesizing functionalized dibenzothiophenes (DBTs) from common starting materials and by using palladium-catalyzed carbon-carbon and carbon-sulfur bond formations is presented. The reaction conditions offer significantly improved functional-group tolerance and regioselectivity as compared to previously reported methods. A flexible and concise three-step protocol for the synthesis of functionalized dibenzothiophenes DBTs from readily available starting materials is presented. The method is based on two palladium-catalyzed reactions to prepare the masked thiophenols 4followed by deprotection and in situ cyclization to form the DBT skeleton. This approach offers improved functional-group tolerance as well as regiocontrol in the synthesis of functionalized DBTs as compared to previously reported methods.

Full text of DOI:10.1002/ejoc.201001393

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201001393
Synthesis of Functionalized Dibenzothiophenes – An Efficient Three-Step
Approach Based on Pd-Catalyzed C–C and C–S Bond Formations
Tue Heesgaard Jepsen,[a,b] Mogens Larsen,*[b] Morten Jørgensen,[b] Katarzyna A. Solanko,[c]
Andrew D. Bond,[c] Anders Kadziola,[a] and Mogens Brøndsted Nielsen*[a]
Keywords: Dibenzothiophenes / Cross coupling / Palladium / Chromophores / C–H···F interactions
A novel and efficient three-step protocol for synthesizing
functionalized dibenzothiophenes (DBTs) from common
starting materials and by using palladium-catalyzed carbon–
carbon and carbon–sulfur bond formations is presented. The
reaction conditions offer significantly improved functional-
group tolerance and regioselectivity as compared to pre-
viously reported methods.
and anhydrous aluminum chloride at 250 °C.[6,7] One syn-
thesis of DBT involves an intramolecular Heck reaction of
aryl thioether followed by oxidation,[8] and another method
is based on cyclization of a diaryl thioether through a
benzyne intermediate,[9] leading to a mixture of regioiso-
mers. Also a few papers report cyclization of dibenzothio-
phene through radical reactions,[10–12] which result in low
yields due to the formation of by-products. A recent
method for preparing perfluorinated DBT derivatives is
based on sulfur insertion by nucleophilic aromatic substitu-
tion.[3b] In general, the existing methods for preparing func-
tionalized DBTs are often rather ineffective, non-selective,
or employ harsh conditions.
Introduction
Dibenzothiophene (DBT) is a commonly known aro-
matic tricyclic compound having a very old origin, since it
is naturally present in coal tar, and can be isolated from
high-boiling petroleum derivatives.[1] The DBT unit has re-
cently been part of the structure of selective estrogen modu-
lators,[2] and, in addition, DBT derivatives (including S,S-
dioxides) are targeted for organic electronics and materials
chemistry owing to their redox and optical properties.[3]
Yet, DBTs have been explored to a much lesser extent than
the related nitrogen and oxygen analogs (i.e., carbazoles
and dibenzofurans), which have been employed extensively
in both pharmaceutical and materials chemistry.[4]
Despite the applicability of DBT derivatives, only a few
methods for functionalizing these compounds are present
in the literature. The original method was to functionalize
DBT by electrophilic aromatic substitution. For example,
bromination of DBT provides 2,8-dibromodibenzo-
thiophene,[3a,3f,5] which can be employed for Suzuki cou-
plings,[3f] or after metal/halogen exchange be converted to
a bis(stannyl) derivative for Stille reactions.[3a] Direct lithi-
ation of DBT occurs at positions 4 and 6.[5b] Other methods
involve formation of the DBT skeleton, for example by de-
hydration of 2,2Ј-dihydroxybiphenyls with phosphorus
pentasulfide at 350 °C or reaction of biphenyl with sulfur
Results and Discussion
In this paper we report a new and efficient three-step
protocol for synthesizing functionalized DBT compounds
from 1-bromo-2-iodobenzenes or 2-haloaryl triflates. Our
protocol is inspired by existing methods for preparing di-
benzofurans and carbazoles[13,14] and by our own experi-
ence with the synthesis of promazines.[15] The use of rela-
tively mild reaction conditions furnishes this protocol with
good functional-group tolerance, complete regioselectivity,
and high yields. The protocol involves a palladium-cata-
lyzed formation of an aromatic C–S bond in the key step.
Methods for formation of biaryl thioethers from aryl ha-
lides and thiophenols are well established in the litera-
ture,[16–18] but relatively few H2S synthons are known for
this transformation. Bis(tributylstannyl) sulfide has been
coupled to aryl halides, but the stoichiometric use of a tin
reagent has major disadvantages.[19] Couplings with triiso-
propylsilanethiol (TIPS-SH) have also been reported,[20]
[a] Department of Chemistry, University of Copenhagen
Universitetsparken 5, 2100 Copenhagen Ø, Denmark
E-mail: mbn@kiku.dk
[b] Medicinal Chemistry Research, H. Lundbeck A/S
Ottiliavej 9, 2500 Valby, Denmark
[c] Department of Physics and Chemistry, University of Southern
Denmark
Campusvej 55, 5230 Odense M, Denmark
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001393.
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M. Larsen, M. B. Nielsen et al.
SHORT COMMUNICATION
and were extended by Hartwig to form non-symmetric bi-
aryl thioethers, albeit in three separate steps.[17] Various
mercaptopropionates have been coupled to aryl halides un-
der palladium catalysis to prepare thiophenols.[21] As we
have had good experiences with this transformation, ethyl
3-mercaptopropionate was chosen as H2S equivalent.
Scheme 1 summarizes our three-step DBT synthesis: (1)
Suzuki–Miyaura coupling[22,23] of an ortho-functionalized
aryl halide 1 with a (2-fluorophenyl)boronic acid 2 to form
biphenyl compound 3, (2) Pd-catalyzed C–S coupling of
either a bromide or a triflate with ethyl 3-mercaptopropi-
Scheme 1. Three-step protocol for the synthesis of the DBT com-
onate to give 4, and (3) deprotection to generate the desired pounds. A = CH, Y = Br, X = I: R = H (1a), R = Me (1b), R =
OMe (1c), R = F (1f), R = F (1g), R = CN (1h). A = CH, Y =
DBT unit 5 after in situ cyclization. This approach allows
OTHP, X = Br: R = OMe (1d), R = benzene-1,2-diyl (1j). A = CH,
for individual functionalization of each of the flanking aro-
Y = OMe, X = I: R = NO2 (1e). A = N, X = Br, Y = OTf: R = H
(1i). (a) 1 (1.0 equiv.), 2 (1.0 equiv.), [PdCl2(PPh3)2] (5 mol-%),
matic rings prior to the first step. The first step in the proto-
col is a Suzuki coupling on the ortho-functionalized aryl
halide 1 with an (ortho-fluorophenyl)boronic acid 2 in the
presence of potassium carbonate and [PdCl2(PPh3)2] in a
mixture of dimethoxyethane (DME) and water. The tem-
perature is kept at 80 °C to suppress the competing Wurtz–
K2CO3 (2.5 equiv.), DME/H2O at 80 °C for 5 h. (b) 3 (1.0 equiv.),
ethyl 3-mercaptopropionate (1.1 equiv.), [Pd2dba3] (5 mol-%),
dpephos (10 mol-%), K2CO3 (2.5 equiv.), toluene at either 110 °C
for 15 h with conventional heating or 180 °C under MW conditions
for 1 h. (c) 4 (1.0 equiv.), KOtBu (1.5 equiv.), THF at either 50 °C
with conventional heating for 8 h or 150 °C under MW conditions
Fittig-type reaction involving homocoupling of the iodo- for 30 min. Ph = phenyl, DME = 1,2-dimethoxyethane, dba = di-
benzylideneacetone, dpephos = bis[2-(diphenylphosphanyl)phenyl]
benzenes, which becomes significant at higher temperatures.
ether, MW = microwave, THF = tetrahydrofuran, THP = tetra-
The second step in the protocol is the sulfur-coupling reac-
hydropyranyl.
tion, which occurs by reaction of the bromo or triflate bi-
phenyl compounds 3 with ethyl 3-mercaptopropionate, in
the presence of Pd2(dba)3, dpephos, and potassium carbon-
As a testimony to the robustness of the sulfur coupling,
ate in toluene under an inert gas. This reaction has been the sterically hindered and electronically deactivated aryl
carried out either in a Schlenk tube at 110 °C for 15 h or in bromide 3c underwent conversion to 4c in 85% isolated
a closed vial under microwave conditions at 180 °C for 1 h, yield. The protocol was also readily expanded to the ex-
with comparable yields. The final reaction in the protocol tended π-system of 5j, which is interesting in the perspective
is a deprotection of the thioether with potassium tert-but- of materials science.
oxide in THF followed by a subsequent in situ intramolec-
The scope of the DBT synthesis is further illustrated by
ular nucleophilic aromatic substitution reaction. This reac- examples of bis(functionalized) DBTs prepared from the
tion can be performed either in a closed vial at 50 °C for functionalized (o-fluorophenyl)boronic acids, and bis-
8 h or under microwave conditions at 150 °C for 30 min, (functionalized) DBTs 5k and 5l were synthesized in excel-
again with comparable yields. When monitoring the depro- lent overall yields. Preliminary studies reveal that also aryl
tection/cyclization reaction by LCMS or GC–MS, relatively chlorides can be employed for the cyclization step with
large amounts of the thiophenol were observed, indicating comparable yields, which in addition enlarges the scope of
that the deprotection step is faster than the cyclization.[24]
Figure 1 summarizes the products and intermediates of
the protocol (cf. Scheme 3).
The C–C and the C–S bond-forming reactions are
the DBT synthesis, starting with the synthesis of biphenyls chemoselective owing to the higher reactivity of aryl iodides
3a–3l under Suzuki–Miyaura conditions. The THP ethers compared to aryl bromides and aryl triflates for palladium
3d and 3j and the methyl ether 3e were initially deprotected insertion. This induces the prospects of preparing two re-
with either aqueous HCl or HBr to furnish the phenols 6d, gioisomeric DBTs from the same starting material, which
6e, and 6j. The phenols were then treated with trifluoro- enlarges the scope of the protocol.
methanesulfonic anhydride and triethylamine in dichloro-
The synthesis of 5l is of particular interest since this
methane to provide triflates 7d, 7e, and 7j (cf. Scheme 2). molecule incorporates a donor and an acceptor substituent
Whereas the cyclization generally occurred in near-quanti- at each end of the DBT scaffold (push-pull chromophore).
tative yield, the yield of the sulfur coupling was more sub- The UV/Vis absorption spectrum of this compound in com-
strate-dependent, with yields ranging from 73% to Ͼ 95%. parison to selected compounds is shown in Figure 2. Com-
The overall protocol was applicable to both electron-rich pound 5l shows a very strong charge-transfer (CT) transi-
and electron-deficient systems, and we were able to isolate tion at λmax = 312 nm. The nitro-substituted DBT 5e also
5a in a total yield of 90% over three steps in multi-gram exhibits a CT of smaller intensity compared to that of 5l,
quantities (ca. 8 g), with reduced catalyst loading (1.5% but red-shifted (λmax = 345 nm).
Pd). Furthermore, the results demonstrate that the protocol
Single crystals of DBTs 5b–5d, 5f, 5g, 5j and 5l were ob-
is compatible with several potentially reactive functionali- tained from ethanol and subjected to X-ray crystallographic
ties such as pyridine nitrogen, nitro and cyano groups, as analysis (see Supporting Information).[25] The crystal struc-
well as an additional fluorine substituent.
ture of 5a has been reported previously.[26,27] Compound 5c
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Synthesis of Functionalized Dibenzothiophenes
Figure 1. Products and intermediates of the DBT synthesis. [a] The THP ethers 3d and 3j and the methyl ether 3e were subsequently
converted into the triflates 7d, 7e, and 7j in two steps (cf. Scheme 2). [b] Performed on a 45–50 mmol scale (1.5 mol-% Pd). * All yields
are isolated yields.
was found to be isomorphous with the previously reported position of DBT has no influence on the resulting crystal
methylthio analogue.[28] The structures of fluoro derivatives packing. The structure of 5g is closely comparable to 5a/5f,
5f and 5g are of interest in the context of the influence of but it displays a subtle distortion: the structure contains
organic fluorine on the packing of molecular crystals.[29] consistent 2-D sections (Figure 3), but adjacent sections are
The structure of 5f is isomorphous with unsubstituted DBT shifted by ca. 2.4 Å relative to each other in 5g compared
(5a), illustrating that introduction of one F atom at the 3- to 5a/5f. The local intermolecular interactions are of an
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55

M. Larsen, M. B. Nielsen et al.
SHORT COMMUNICATION
Scheme 2. Synthesis of the triflates 7d, 7e, and 7j.
Scheme 3. Synthesis of DBT by employing aryl chlorides. (a), (b),
(c) Same conditions as in Scheme 1.
Figure 3. Overlay of the crystal structure of DBT[28] (red) and 5g
(blue), showing consistent 2-D sections shifted relative to each
other.
Figure 2. UV/Vis spectra of selected compounds in CHCl3.
Figure 4. Local intermolecular interactions in the crystal structures
of 5a and 5g.
Conclusions
edge-to-face type, and the relative shift in 5g serves appar-
ently to optimize the geometry of a C–H···F interaction
We have developed an efficient three-step protocol for
(Figure 4). Both 5f and 5g display disorder for the F-atom the synthesis of functionalised DBTs. The use of relatively
position, with a minor orientation (ca. 10% in both cases) mild reaction conditions offers significantly improved func-
corresponding to turning over the molecule about the axis tional-group tolerance and regioselectivity as compared to
passing through the S atom and the center of the opposite previously reported methods. We are currently in the pro-
C–C bond in the thiophene ring (see Supporting Infor- cess of enlarging the scope of the reaction to identify fur-
mation).
ther its utility and limitations.
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Synthesis of Functionalized Dibenzothiophenes
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Received: October 11, 2010
Published Online: November 17, 2010
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