Synthesis of dibenzothiophenes and related classes of heterocycles by using functionalized dithiocarbamates

Article abstract of DOI:10.1002/anie.201001025

Chemical Equation Presentation A round trip: Readily available dithiocarbamates can undergo ring closure to give functionalized sulfur heterocycles (see scheme). These heteroaromatic compounds can be further functionalized by directed alumination and subsequently trapped with various electrophiles.

Full text of DOI:10.1002/anie.201001025

Angewandte
Chemie
DOI: 10.1002/anie.201001025
Sulfur Heterocycles
Synthesis of Dibenzothiophenes and Related Classes of Heterocycles
by Using Functionalized Dithiocarbamates**
Marcel Kienle, Andreas Unsinn, and Paul Knochel*
Dibenzothiophenes, benzo[b]thiophenes, and benzo[c]thio-
phenes have found numerous applications as dyes, pharma-
ceuticals, agrochemicals, or as building blocks for the syn-
thesis of conducting polymers.[1,2] Several straightforward
strategies for the synthesis of such S heterocycles have been
reported.[3] Palladium-catalyzed ring closures leading to
S heterocycles are especially difficult, but were realized
recently, despite the deactivating effect of sulfur on transi-
tion-metal catalysts.[4,5] To avoid this poisoning of the
transition-metal catalysts by thiols and thiolates, we have
envisioned a ring-closure procedure involving main-group
benzothiolates such as 1 as precursors, which will provide an
intermediate such as 2 by an addition/elimination reaction.[6]
The elimination of Met-X should result in various dibenzo-
thiophenes of type 3 (Scheme 1).
and then transmetalated with ZnCl2. A subsequent Negishi
cross-coupling reaction[10–12] ([Pd(dba)2] (2 mol%; dba =
trans,trans-dibenzylideneacetone), tri-2-furylphosphine (tfp;
4 mol%, 508C, 1.5 h)) with functionalized 1-chloro-2-iodo-
benzene derivatives 9 then afforded the polysubstituted
biphenyls 10 in 75–92% yield. Br/Li exchange proved to be
superior (nBuLi (1.1 equiv), ꢀ958C, 30 min) as these biphen-
yls did not undergo complete Br/Mg exchange because of
steric hindrance. After transmetalation with the THF-soluble
magnesium complex MgCl2·LiCl,[13,14] the resulting aryl
magnesium species were treated with tetramethylthiuram
disulfide (Me2NC(S)S)2 (0.9 equiv, 08C to 258C, 1 h)[15] to
provide the biphenyl dithiocarbamates 7a–f in yields of 80–
94% (Scheme 2).
Scheme 1. Preparation of S heterocycles by an addition/elimination
reaction. FG=functional group, Met=K, X=Br, Cl.
Herein we report the successful synthesis of various
classes of S heterocycles of types 3 and 4[7] as well as
[1]benzothieno[3,2-b][1]benzothiophene 5[8] and the previ-
ously unknown [1]benzothieno[2,3-b][1]benzofuran
6
(Scheme 1), starting from readily available biaryls of type 7.
A Br/Mg or I/Mg exchange on the aryl bromides or iodides 8
was first carried out with iPrMgCl·LiCl[9] (ꢀ208C, 0.5–2 h)
Scheme 2. Preparation of the starting dithiocarbamates 7.
[*] Dr. M. Kienle, A. Unsinn, Prof. P. Knochel
Ludwig Maximilians-Universitꢀt Mꢁnchen, Department Chemie
Butenandtstrasse 5–13, Haus F, 81377 Mꢁnchen (Germany)
Fax: (+49)89-2180-77680
This synthesis was also extended to the preparation of
benzothiophenes 11a–d and benzofurans 12a/b. Thus, 3-
bromobenzothiophene (13a) was magnesiated with
iPrMgCl·LiCl[9] (1.1 equiv, ꢀ158C, 24 h) to the corresponding
magnesium derivative. Subsequent transmetalation with
ZnCl2 and a Negishi cross-coupling reaction[10–12] with 1-
bromo-2-iodobenzene derivatives 14 ([Pd(dba)2] (2 mol%),
tfp (4 mol%), 508C, 1.5 h) then resulted in the formation of
the 3-arylated benzothiophenes 15a–d (63–75% yield;
E-mail: paul.knochel@cup.uni-muenchen.de
[**] We thank the Fonds der Chemischen Industrie, the European
Research Council (ERC), and the Deutsche Forschungsgemein-
schaft (DFG) for financial support. We also thank BASF AG
(Ludwigshafen), W. C. Heraeus GmbH (Hanau), and Chemetall
GmbH (Frankfurt) for the generous gift of chemicals.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201001025.
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Scheme 4. Preparation of the S-heterocycle 5.
decompose under these conditions. An alternative radical
mechanism cannot be excluded.[19]
An isomeric structure of heterocycles of type 4, namely
the substituted [1]benzothieno[3,2-b][1]benzothiophene 5,
could be prepared by a slight modification of the procedure
shown in Scheme 1. Thus, a selective I/Mg exchange on 3-
bromo-2-iodo-benzothiophene (17; iPrMgCl·LiCl (1.1 equiv),
ꢀ408C, 1 h) followed by a transmetalation with ZnCl2 and
Scheme 3. Preparation of starting dithiocarbamates 11 and 12.
TMP=2,2,6,6-tetramethylpiperidyl.
Scheme 3). The magnesiation of compounds 15 with
TMPMgCl·LiCl[16] (1.1 equiv, 08C, 2 h) followed by a trapping
reaction with (Me2NC(S)S)2 (0.9 equiv, 08C to 258C, 12 h)
afforded the desired benzothienyl dithiocarbamates 11a–d in
80–90% yield. Similarly, 3-bromobenzofuran (13b) was
converted using the same two-step sequence into the benzo-
furyl dithiocarbamate (12a/b; 81–87%) via the intermediates
16a/b (76–80%; Scheme 3).
The chloro-substituted dithiocarbamates 7 were con-
verted by treatment with tBuOK (3.0 equiv, THF, 508C)
into the corresponding potassium thiolates, which undergo an
addition/elimination ring closure to provide the desired
functionalized dibenzothiophenes 3a–f in 71–96% yield
within 0.75–24 h (Table 1, entries 1–6). The rate of the
cyclization depends on the substitution pattern of both
aromatic rings. In general, electron-withdrawing substituents
on the ring bearing the leaving group (chloride) enhance the
reaction rates (entries 4 and 5). Microwave irradiation
dramatically accelerates the cyclization of 7c and 7 f. These
substrates do not undergo ring closure under thermal
conditions, but the reaction is complete after 45 minutes of
microwave irradiation (908C). Bromo-substituted precursors
such as 11a–d and 12a/b can also be used in such a ring-
closure reaction. Treatment with nBuLi (1.05 equiv, THF,
ꢀ208C) leads to a complete cyclization within 30 minutes at
ꢀ208C and furnishes the tetracyclic heterocyclic products 4a–
d in 78–90% yield (entries 7–10) and 6a/b in 72 and 76%
yield, respectively (entries 11 and 12). A possible mechanism
may involve a Br/Li exchange,[17] followed by a substitution
reaction of the intermediate aryl lithium compound on the
dithiocarbamate group to give the desired products as well as
dimethylthiocarbamoyllithium (LiC(S)NMe2),[18] which may
Scheme 5. Alumination and subsequent acylation, iodolysis, or Negishi
cross-coupling reaction to give the substituted heterocyles 22a/b, 23,
and 24.
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Table 1: Preparation of various S heterocycles of type 3, 4, and 6.
Entry Substrate
T [8C][a]
Product[b]
Entry Substrate
T [8C][a]
Product[b]
1
2
7a
7b
50 (12)[c]
3a: 94%[b]
7
8
11a
11b
ꢀ20 (0.5)[e] 4a: 80%[b]
50 (18)[c]
3b: 81%[b]
ꢀ20 (0.5)[e] 4b: 90%[b]
3
4
5
6
7c
7d
7e
7 f
90 (0.75)[d] 3c: 78%[b]
9
11c
11d
12a
12b
ꢀ20 (0.5)[e] 4c: 83%[b]
ꢀ20 (0.5)[e] 4d: 78%[b]
ꢀ20 (0.5)[e] 6a: 72%[b]
ꢀ20 (0.5)[e] 6b: 76%[b]
50 (4)[c]
3d: 96%[b]
3e: 81%[b]
3 f: 71%[b]
10
11
12
50 (4)[c]
90 (0.75)d
[a] The reaction times (h) for the ring-closing reaction are given in parentheses. [b] Yield of the analytically pure isolated product. [c] KOtBu (3 equiv)
was used for the ring closure. [d] Microwave irradiation was used. [e] nBuLi (1.05 equiv) was used for the ring closure.
Negishi cross-coupling with 2,4-dichloroiodobenzene (9a)
provides the 2-arylated benzothiophene 18 in 82% yield. A
Br/Mg exchange of 18 with iPrMgCl·LiCl (1.1 equiv, ꢀ58C,
18 h) and subsequent quenching with (Me2NC(S)S)2 furnishes
19 in 76% yield. This dithiocarbamate undergoes a smooth
ring closure in the presence of tBuOK (3.0 equiv, THF, 508C,
18 h) to give the tetracyclic heterocycle 5 in 73% yield
(Scheme 4).
The S heterocycles prepared can be further functionalized
by a regioselective alumination by using the hindered
aluminum amide 20.[20,21] Thus, treatment of the O,S-tetracy-
clic compound 6a with 20 (1.0 equiv, THF, ꢀ208C, 2 h) led to
a regiospecific alumination at the a position to the furan unit
(left arrow in Scheme 5). This result arises from a preferential
complexation of the hindered aluminum base to the oxygen
atom. The resulting aluminum organometallic compound 21
was acylated (1: ZnCl2 (1.1 equiv); 2: CuCN·2LiCl
(1.1 equiv); 3: PhCOCl (1.1 equiv, ꢀ208C!258C, 4 h)) to
provide the ketone 22a in 71% yield. Furthermore, Negishi
cross-coupling of 21 (1: ZnCl2 (1.1 equiv); 2: [Pd(dba)2]
(5 mol%), tfp (10 mol%), ethyl 4-iodobenzoate (1.1 equiv,
508C, 8 h)) led to the arylated product 22b in 73% yield. It
was possible to regiospecifically metalate the heterocycles 4b
and 5 by using the same base. The substituents present in
those substrates (for example, a chloride or a methoxy group)
fully direct the alumination. Trapping either with iodine (1: 20
(1.0 equiv, 08C, 4 h) 2: ZnCl2 (1.1 equiv); 3: I2 (1.5 equiv ,
ꢀ208C!258C, 0.5 h)) or acylation (1: 20 (1.0 equiv, ꢀ408C,
2 h) 2: ZnCl2 (1.1 equiv); 3: CuCN·2LiCl (1.1 equiv); 4:
PhCOCl (1.1 equiv, ꢀ208C!258C, 4 h)) afforded the sub-
stituted heterocycles 23 and 24 in yields of 71 and 82%,
respectively (Scheme 5).
In summary, we have developed a cyclization reaction that
leads to various condensed S heterocycles. The precursors for
the ring-closing reaction are readily prepared by a palladium-
catalyzed cross-coupling method. We have also shown that
the newly formed S heterocycles can be regioselectively
functionalized using the hindered aluminum base 20. Further
extensions of this method for preparing material-relevant
compounds are currently underway.
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Communications
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dry THF (10 mL). This solution was then heated at 508C for 12 h.
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ether; 9:1) to give 3a (206 mg, 94%) as a colorless solid.
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Synthesis of 4a (Table 1, entry 7): A dry and argon-flushed 25 mL
Schlenk tube equipped with a magnetic stirring bar was charged with
a solution of 11a (408 mg, 1.0 mmol) in dry THF (10 mL) and cooled
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Received: February 18, 2010
Published online: May 31, 2010
Keywords: aluminum · amide bases · benzothiophene ·
.
cross-coupling · sulfur heterocycles
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