Domino C-N coupling/annulation versus C-N coupling/ hydroamination of 2-alkynyl-3-bromobenzothiophenes and 2-alkynyl-3-bromothiophenes. highly efficient synthesis of benzothieno[3,2-b]quinolines and thieno[3,2-b]pyrroles

Article abstract of DOI:10.1002/adsc.201000709

While the palladium-catalyzed reaction of 2-alkynyl-3-bromothiophenes with anilines afforded thienopyrroles by a domino C-N coupling/hydroamination process, the reaction of 2-alkynyl-3-bromobenzothiophenes with anilines resulted, under identical condition

Full text of DOI:10.1002/adsc.201000709

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DOI: 10.1002/adsc.201000709
À
À
Domino C N Coupling/Annulation versus C N Coupling/
Hydroamination of 2-Alkynyl-3-bromobenzothiophenes and
2-Alkynyl-3-bromothiophenes. Highly Efficient Synthesis of
Benzothieno
G
U
Ghazwan Ali Salman,a Munawar Hussain,a Viktor Iaroshenko,a
Alexander Villinger,a and Peter Langera,b,*
a
Institut fꢀr Chemie, Universitꢁt Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax : (+49)-381-498-6412; e-mail: peter.langer@uni-rostock.de
Leibniz-Institut fꢀr Katalyse e. V. an der Universitꢁt Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
b
Received: September 16, 2010; Revised: December 21, 2010; Published online: February 14, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000709.
Abstract: While the palladium-catalyzed reaction of
2-alkynyl-3-bromothiophenes with anilines afforded
tions of ortho-alkynylated aryl halides.[8] Buchwald
et al. reported the synthesis of pyrroles and pyrazoles
by a related strategy.[9,10]
À
thienopyrroles by a domino C N coupling/hydro-
amination process, the reaction of 2-alkynyl-3-bro-
The development of regioselective palladium-cata-
lyzed coupling reactions of dihalogenated heterocy-
cles is of considerable current interest.[11] In the
course of our own studies in this field,[12] we have
studied the reaction of 2-alkynyl-3-bromothiophenes
and 2-alkynyl-3-bromobenzothiophenes with anilines.
Herein, we report the results of our efforts. The reac-
tion of 2-alkynyl-3-bromothiophenes with anilines af-
mobenzothiophenes with anilines resulted, under
identical conditions, in the formation of benzothi-
À
G
tion process. The electronic character of the aniline
also has an influence on the product distribution.
Keywords: catalysis; cyclizations; heterocycles; pal-
ladium; regioselectivity
À
forded, as expected, thienopyrroles by a domino C N
coupling/hydroamination process. In contrast, the re-
action of 2-alkynyl-3-bromobenzothiophenes with ani-
lines surprisingly resulted in the formation of benzo-
À
thienoquinolines by a domino C N coupling/annula-
Nitrogen-containing heterocycles are of great impor- tion process. This type of palladium-catalyzed domino
tance in the field of medicinal chemistry and material reaction has, to the best of our knowledge, not been
sciences.[1] In recent years, transition metal-catalyzed previously reported and provides a convenient ap-
syntheses of heterocycles have been developed which proach to pharmacologically relevant molecules
nicely complement classic synthetic approaches be- which are not readily available by other methods. We
cause they proceed under mild conditions and show a believe that this type of cyclization is mechanistically
high degree of chemoselectivity and functional group interesting and has the potential to be extended to
tolerance.[2] A variety of palladium-catalyzed synthe- other heterocyclic systems in the future.
ses of indoles and carbazoles have been reported.[3]
Cryptolepsis sanguinolenta is a shrub found along
Ackermann and co-workers reported the synthesis of the west coast of Africa and is still being used signifi-
carbazoles and related molecules by palladium-cata- cantly in the traditional medicine in Ghana. Its strong
lyzed cyclization of 1,2-dihalides with anilines by antimalarial activity has been proved in clinical trials.
[5]
domino[4] N H/C H activation reactions. Stepwise Furthermore, it has been been shown to possess a
syntheses following this strategy have also been re- considerable antibiotic activity against Gram-positive
ported.[6] Ackermann et al. reported the synthesis of and Gram-negative bacteria. Major alkaloids, crypto-
indoles and various other ring systems by domino N- lepine (1) and quindoline (2), have been isolated
arylation/hydroamination reactions.[7] They also devel- along with some minor alkaloids from Cryptolepsis
oped an efficient approach to indoles by Pd- or Cu- sanguinolenta (Figure 1).[13] Benzothienoquinolines
À
À
À
catalyzed domino C N coupling/hydroamination reac- are sulfur analogues of these alkaloids and represent
Adv. Synth. Catal. 2011, 353, 331 – 336
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331

Ghazwan Ali Salman et al.
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Scheme 1. Synthesis of 7a–c. Reaction conditions: i, 6a–c
(1.0 equiv.), Pd
ACHTUGNTERN(NUNG PPh3)2Cl2 (5 mol%), CuI (10 mol%), tri-
AHCTUNGTRENNUNG
Table 1. Regioselective alkynylation of 2,3-dibromobenzo-
thiophene.
Figure 1. Alkaloids cryptolepine (1) and quindoline (2) iso-
lated from Cryptolepsis sanguinolenta and bioactive benzo-
thienoquinolines 3 and 4.
6, 7
R
Yield [%] of 7[a]
a
b
c
H
Me
OCH3
80
90
87
[a]
Yields of isolated products.
interesting target molecules, due to their broad spec-
trum of antimicrobial, anticancer and cytotoxic activi-
ties. For example, benzothienoquinoline 3 has been
reported to show antitumor activity in vivo, while de-
rivative 4 possesses significant cytotoxic activity.[14,15]
Due to their biological relevance, a number of syn-
theses of benzothienoquinolines have been reported.
Many of them represent modifications of the Pfitzing-
er synthesis which relies on the base-mediated cyclo-
condensation of isatin with ketones.[16] Recently, Zhu
et al. reported a multistep synthesis of benzothieno-
quinolines from substituted anthranilic acids, acyl
chlorides and thiophenols.[15] The above-mentioned
syntheses of thienopyrroles and benzothienoquino-
lines proceed under harsh conditions or require sever-
al synthetic steps. Therefore, the development of al- Scheme 2. Synthesis of 9a–m. Reaction conditions: i, 8a–m
(1.3 equiv.),
Pd
G
(10 mol%),
PACTHNGUTREN(UNG t-Bu)3·HBF4
ternative synthetic strategies is of considerable inter-
est.
(20 mol%), KO-t-Bu (2 equiv.), CuI (25 mol%), toluene,
1058C, 12 h.
The regioselective synthesis of 2-alkynyl-3-bromo-
thiophenes[17]
and
2-alkynyl-3-bromobenzothio-
phenes[18] by Sonogashira reactions of 2,3-dibromo-
thiophene and 2,3-dibromobenzothiophene with al-
kynes has been previously reported. The reaction of
2,3-dibromobenzothiophene (5) with alkynes 6, in the
Table 2. Synthesis of 9a–m.
8, R1
9
R2
R4
R5
Yield [%] of
9[a]
presence of PdACHTUNGTRENNUNG(PPh3)2Cl2 (5 mol%), afforded the
2-alkynyl-3-bromobenzothiophenes 7a–c (Scheme 1,
Table 1).
The palladium-catalyzed reaction of 2-alkynyl-3-
bromobenzothiophenes 7a–c with anilines 8a–m af-
forded the benzothienoquinolines 9a–m in 60–70%
yields (Scheme 2, Table 2). The synthesis of derivative
9j was optimized by variation of the reaction condi-
tions. The best yield of 9j was obtained when
a
b
c
d
e
f
g
h
i
H
H
H
H
H
H
H
CH3
CH3
CH3
OCH3
CH3
OCH3
H
H
H
H
H
H
H
OCH3
OCH3
H
H
H
H
OCH3
H
H
H
CH3
OCH3
H
H
H
OCH3
H
CH3
C2H5
OC2H5
H
H
OCH3
H
H
H
H
H
60
65
61
60
65
61
H
CH3
OCH3 67
H
H
H
H
H
H
70
64
60
63
60
55
j
k
l
OC2H5
Pd
G
PACTHNGUTRENNU(G t-
H
H
CF3
CH
F
ACHTUGNTERN(NUNG CH3)2
Bu)3·HBF4 (20 mol%) was used as the catalyst and
when KO-t-Bu (2 equiv.) and CuI (25 mol%) were
employed. The use of stoichiometric amounts of CuI
in the absence of a palladium catalyst failed to give
m
H
H
[a]
Yields of isolated products.
332
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Adv. Synth. Catal. 2011, 353, 331 – 336

À
À
Domino C N Coupling/Annulation versus C N Coupling/Hydroamination
the product. No reaction was observed when DMSO
The palladium-catalyzed reaction of 2-alkynyl-3-
and THF were used as solvents. In fact, toluene bromobenzothiophenes 7b, c with anilines 8a, n–p af-
proved to be the best solvent. The employment of di- forded separable mixtures of benzothienoquinolines
oxane afforded only trace amounts of product. Like- 9n–q and benzothienopyrroles 12a–d in 50–60 and 30–
wise, the use of Cs2CO3 instead of KO-t-Bu provided 40% yields, respectively (Scheme 3, Table 3). The re-
only traces of 9j. The use of SPhos, XPhos or P(Cy)3 actions were carried out under identical conditions as
instead of P
The best yield of 9j (60%) was obtained when
20 mol% of the ligand P(t-Bu)3·HBF4 was used. The substituents (nitro, ester, cyano), resulted in exclusive
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
yield decreased to 30% when only 10 mol% of the formation of benzothienopyrroles 12e–g. Thus, the
ligand was employed. The moderate yields of prod- electronic character of the starting materials seems to
ucts 9a–m can be explained by the fact that small have an influence on the product distribution. It is a
amounts of different side-products were formed (TLC striking observation that the combined yields of prod-
of the crude product) which resulted in some practical ucts 9n–q and 12a–g were higher than the yields of
difficulties during the chromatographic purification.
products 9a–m given in Table 2. This can be explained
The structures of all products were established by by the fact that several side products were formed
spectroscopic methods. The structure of 9a was inde- during the synthesis of 9a–m (resulting in a difficult
pendently confirmed by an X-ray crystal structure chromatographic purification), while the reactions
analysis (Figure 2).[19]
leading to those products listed in Table 3 proceeded
more cleanly and the chromatographic purification
was relatively easy.
The formation of benzothienoquinolines 9a–m can
À
be explained by a domino C N coupling/annulation
reaction and isomerization of
a
double bond
(Scheme 4). This type of reaction has, to the best of
our knowledge, not been previously reported. The for-
mation of 9a may proceed by initial palladium-cata-
À
lyzed C N coupling and subsequent annulation or by
Table 3. Synthesis of 9n–t and 12a–g.
Yield [%][a]
12
R1
R2
R3
R4
of 9
of 12
a
b
c
d
e
f
OCH3
CH3
CH3
OCH3
OCH3
OCH3
CH3
H
OCH3
OCH3
OCH3
Cl
H
CN
H
OCH3
H
H
H
60
53
50
55
0
30
35
40
32
78
84
45
OCH3
OCH3
H
NO2
H
H
H
0
0
g
H
CO2Me
[a]
Figure 2. Crystal structure of 9a.
Yields of isolated products.
Scheme 3. Synthesis of 9n–q and 12a–g. Reaction conditions: i, 8a, n–s (1.3 equiv.), Pd
(20 mol%), KO-t-Bu (2 equiv.), CuI (25 mol%), toluene, 1058C, 12 h.
ACHTUNGTRENUN(G OAc)2 (10 mol%), PACHTUGNTRNE(NUGN t-Bu)3·HBF4
Adv. Synth. Catal. 2011, 353, 331 – 336
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333

Ghazwan Ali Salman et al.
COMMUNICATIONS
Scheme 5. Synthesis of intermediate 10a. Reaction condi-
tions: i, 8p (1.3 equiv.), PdACTHNUTRGENNUG(OAc)2 (10 mol%), PACHUTGNTREN(NUGN t-Bu)3·HBF4
(20 mol%), KO-t-Bu (2 equiv.), CuI (25 mol%), toluene,
408C, 4 h.
of the one-pot synthesis of products 9 (and 12) is a
palladium-catalyzed process and not a thermal elec-
trocyclization.
2-Alkynyl-3-bromothiophenes 14a, b were regiose-
lectively prepared in very good yields by Sonogashira
reactions of 2,3-dibromothiophene (13) with alkynes
6a, d (Scheme 6, Table 4). The best yields were ob-
tained when PdACHTUNGTRNEUGN(PPh3)2Cl2 (5 mol%) was used.
The palladium-catalyzed reaction of 2-alkynyl-3-
bromothiophenes 14a, b with anilines 8a, c, d, e, g, n,
and t afforded the thienopyrroles 15a–h in 55–75%
yields (Scheme 7, Table 5).
In conclusion, we have studied the reaction of 2-al-
kynyl-3-bromothiophenes and 2-alkynyl-3-bromoben-
zothiophenes with anilines. While the reaction of 2-al-
kynyl-3-bromothiophenes with anilines afforded thi-
À
Scheme 4. Formation of 9a. Reaction conditions: i, 8a
(1.3 equiv.),
Pd
(OAc)2
(10 mol%),
PACTHNGUTREN(UNG t-Bu)3·HBF4
(20 mol%), KO-t-Bu (2 equiv.), CuI (25 mol%), toluene,
1058C, 12 h.
AHCTUNGTREGUNeNN nopyrroles by a domino C N coupling/hydroamina-
tion process, the reaction of 2-alkynyl-3-bromobenzo-
the opposite order of events. Buchwald and co-work- thiophenes with anilines resulted, under identical
À
ers showed that (copper-catalyzed) domino C N cou- conditions, in the formation of benzothienoquinolines
À
À
pling/hydroamination reactions proceed with the C N by a domino C N coupling/annulation process. The
coupling as the first step.[7] Therefore, we believe that type of starting material (both the heterocyclic moiety
this is the case also in our transformation. While the
À
C N coupling must proceed by palladium catalysis,
the subsequent annulation may proceed either by a
palladium-catalyzed or by a thermal process. A ther-
mal mechanism may involve intermediate 10b
(Scheme 4), its isomerization to a 5-aza-1,2,4,6-tet-
raene containing an allene unit and subsequent elec-
trocyclization.
To study the mechanism of the cyclization reaction,
we tried to isolate the intermediate 10 formed by ini-
tial C N coupling. The reaction of 7c with 8p, carried
out at at 408C (4 h) instead of 1058C (12 h), afforded
the desired product 10a (Scheme 5). Simple stirring of
a toluene solution of 10a at 1058C for 12 h, in the ab-
sence of a catalyst, failed to give any type of cycliza-
tion (decomposition). In contrast, a cyclization could
be successfully induced when the reaction was carried
out in the presence of PdACHTNUGTRENNUG(OAc)2 (10 mol%), PACHUTNGTREN(NUGN t-
Bu)3·HBF4 (20 mol%), KO-t-Bu (2 equiv.), and CuI
(25 mol%). This result shows that the cyclization step
Scheme 6. Synthesis of 14a, b. Reaction conditions: i, 6a, d
(1.0 equiv.), PdACHTUNGTRNEG(UN PPh3)2Cl2 (5 mol%), CuI (10 mol%), diiso-
propylamine (DIPA), 458C, 24 h.
À
Table 4. Regioselective alkynylation of 2,3-dibromothio-
phene.
6
14
R
Yield [%] of 14[a]
a
d
a
b
H
OCH3
75
80
[a]
Yields of isolated products.
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Adv. Synth. Catal. 2011, 353, 331 – 336

À
À
Domino C N Coupling/Annulation versus C N Coupling/Hydroamination
palladium-catalyzed attack of the ortho carbon atom
or of the nitrogen atom of the aniline to the alkyne.
The nucleophilicity of the aromatic carbon atom is re-
duced when electron-withdrawing substituents are
present and, thus, the cyclization proceeds via the
(more nucleophilic) nitrogen atom.
In conclusion, we have reported what are, to the
À
best of our knowledge, the first domino C N cou-
pling/annulation reactions. These reactions provide a
convenient approach to pharmacologically relevant
molecules which are not readily available by other
methods. A detailed study of the scope and limita-
tions and the isolation of an intermediate allowed us
to draw some conclusions regarding the mechanism of
cyclization.
Scheme 7. Synthesis of 15a–h. Reaction conditions: i, 8a, c,
d, e, g, n, t (1.2 equiv.), Pd(OAc)2 (10 mol%), P(t-Bu)3·HBF4
(20 mol%),KO-t-Bu (2.0 equiv.), CuI (25 mol%), toluene,
G
ACHTUNGTRENNUNG
908C, 12 h.
Experimental Section
Table 5. Synthesis of 15a–h.
General Procedure for the Synthesis of 9, 12 and 15
15 R1
R2
R3
R4
Yield [%] of 15[a]
In a pressure tube (glass bomb) a suspension of Pd
ACHTUNGTRENNUNG(OAc)2
a
b
c
d
e
f
H
H
H
H
OCH3
H
H
H
H
H
H
OCH3
OCH3
CH3
C2H5
OC2H5
OC2H5
H
H
H
H
H
H
65
64
60
65
75
(10 mol%), Pd(t-Bu)3·HBF4 (20 mol%), KO-t-Bu (2 equiv.)
AHCTUNGTRENNUNG
in toluene (5 mL) was purged with argon and stirred at
208C to give a brownish clear solution. To the stirred solu-
tion was added 7a–c or 14a, b (1.0 equiv.), aniline 8a–s
(1.3 equiv.) and CuI (25 mol%). The reaction mixture was
heated at 1058C for 12 h. The solution was cooled to 208C,
poured into H2O and CH2Cl2 (25 mL each), and the organic
and the aqueous layers were separated. The latter was ex-
tracted with CH2Cl2 (3ꢃ25 mL). The combined organic
layers were dried (Na2SO4), concentrated under vacuum,
and the residue was purified by chromatography (flash silica
gel, heptanes-EtOAc) to give 9 and/or 12 and 15.
OCH3 63
OCH3 60
H
g
h
H
H
OCH3 OCH3
NO2
H
55
[a]
Yields of isolated products.
and the aniline) plays an important role for the prod-
uct distribution. As mentioned above, Buchwald and
co-workers reported the synthesis of thienopyrroles
À
by copper-catalyzed domino C N coupling/hydroami-
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