Palladium(0)-catalyzed Domino C?N Coupling/Hydroamination/C?H Arylation: Efficient Synthesis of Benzothieno[2′,3′:4,5]pyrrolo[1,2-f]phenanthridines

Article abstract of DOI:10.1002/adsc.201601285

Two new and efficient routes to benzothieno[2′,3′:4,5]pyrrolo[1,2-f]phenanthridines have been developed. Alkynylated benzothiophenes reacted with various anilines to the target compounds in a domino reaction consisting of a C?N coupling-, hydroamination-

Full text of DOI:10.1002/adsc.201601285

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DOI: 10.1002/adsc.201601285
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Palladium(0)-catalyzed Domino CÀN
Coupling/Hydroamination/CÀH Arylation: Efficient Synthesis of
Benzothieno[2’,3’:4,5]pyrrolo[1,2-f]phenanthridines
Ghazwan Ali Salman,a, b Ngo Nghia Pham,a, c, d Thang Ngoc Ngo,a Peter Ehlers,a, c
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Alexander Villinger,a and Peter Langera, c,*
a
¨
¨
Institut fur Chemie, Universitat Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax: (+49)-381-498-6412
Phone: (+49)-381-498-6410; e-mail: peter.langer@uni-rostock.de
b
c
Department of Chemistry, College of Science, University Al-Mustansiriyah, Baghdad, Iraq
Leibniz-Institut fꢀr Katalyse e. V. an der Universitꢁt Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Faculty of Chemistry, VNU University of Science Hanoi (VNU-HUS), 19 Le Thanh Tong, Hoan Kiem, Hanoi, Vietnam
d
Received: November 18, 2016; Revised: January 4, 2017; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201601285
the treatment of cancer.[2] Given its medicinal impor-
Abstract: Two new and efficient routes to benzo-
thieno[2’,3’:4,5]pyrrolo[1,2-f]phenanthridines have
tance, synthetic chemists were devoted to efficient
syntheses of this skeleton.[3] Consequently, a number
been developed. Alkynylated benzothiophenes re-
of further phenanthridine derivatives has been discov-
acted with various anilines to the target compounds
ered with promising biological properties, for example,
in a domino reaction consisting of a CÀN coupling-,
hydroamination- followed by a final, ring-closing
CÀH arylation step. Products were isolated in
moderate to good yields.
compound NK109 with antitumor activity (Figure 1).[4]
Beyond medicinal applications, phenanthridine pos-
sesses great potential to be employed in material
science, for example as fluorescent dyes.[5] In order to
explore even more promising candidates, synthetic
chemists have recently attempted to establish the
preparation of phenanthridine-fused heterocycles in-
cluding coumarin, pyrrole, purine, indole, imidazole,
benzoimidazole and quinazoline (cf. Figure 1).[6,7]
Despite a wide range of synthetically available
polycycles of phenanthridine fused with O- and N-
heterocycles, those fused with S-heterocycles have still
Keywords: heterocycles; palladium; cyclization; ho-
mogeneous catalysis; domino reaction
Introduction
41 Phenanthridine is a tricyclic heterocycle which has remained thus far unexplored. Their syntheses have
42 received increasing attention in medicinal science. been considered to be difficult and tedious. Fortu-
43 Previously, it has been explored to be incorporated in nately, with the development of innovative
44 the chemical structure of sanguinarine[1] (Figure 1) in palladiumÀcatalyzed crossÀcoupling reactions, new
45 Sanguinaria Canadensis. Further medicinal studies CÀC and CÀN bonds can be created in more elegant
46 related to sanguinarine have revealed its potential for and atom-economic fashion. Utilizing palladium cata-
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lysts, we have synthesized several complex fused
phenanthridines from 1,2-dihalobenzene and 2,3-diha-
lopyridine by sequential regioselective Sonogashira
and domino CÀN coupling/hydroamination/CÀH ary-
lation.[8,9] These results have tempted us to undertake
a further investigation of the synthesis of benzothieno
[2’,3’:4,5]pyrrolo-[1,2-f]phenanthridines from 2,3-di-
bromobenzothiophene.
Figure 1. Relevant phenanthridine- and benzothiophene-de-
rivatives.
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Results and Discussion
Next, we optimized the domino CÀN coupling/
hydroamination/CÀH arylation reaction of 3-bromo-2-
At first, we attempted to obtain 3-bromo-2-(arylethyn- (phenylethynyl)benzo[b]thiophene (1a) and 2-bro-
yl)benzo[b]thiophenes 1a–c as precursors for the moaniline (2a). Initially, our previously reported
domino CÀN coupling/hydroamination/CÀH arylation. conditions for the synthesis of indolo[1,2-f]phenanthri-
These compounds were synthesized by applying dines and azaindolo[1,2-f]phenanthridines were ap-
siteÀselective Sonogashira coupling of 2,3-dibromo- plied (Entry 1–2, Table 2).[8] Unfortunately, these two
benzothiophene with corresponding arylacetylenes in conditions led to the formation of the corresponding
high yields using previously reported reaction con- product in only 30% yield. Subsequently, we tested
10 ditions (Table 1).[10]
other monodentate (Entry 3–7, Table 2) and bidentate
ligands (Entry 8–10, Table 2) in the presence of the
palladium source Pd(OAc)2. We found that the
monodentate ligand PtBu3·HBF4 gave rise to the
formation of the desired product 3a in highest yield
(65%, Entry 10, Table 2). Afterwards, we checked the
robustness of these reaction conditions by varying the
palladium source, base, solvent and temperature.
From the experimental results, it became obvious that
nearly no product was formed by employing Pd
(PPh3)4 instead of Pd(OAc)2 (Entry 11, Table 2) or by
using other bases (Entry 13–14, Table 2). On the other
hand, raising the reaction temperature to more than
1408C did not improve the reaction while reducing the
temperature to 1208C led to sluggish conversion to
the desired product (Entry 15, 16, Table 2) and
uncyclized product 4 was observed as a major product
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Table 1. Synthesis of 3-bromo-2-(arylethynyl)benzo[b]thio-
phenes 1a–c.
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R
1
Yielda
H
1a
1b
1c
80%
85%
87%
ÀMe
ÀOMe
a
Isolated yield
Table 2. Optimization study for the synthesis of benzo[4’,5’]thieno[2’,3’:4,5]pyrrolo[1,2-f]-phenanthridine 3a.
Entry
Pd-source
Ligand
Base
Yielda
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2
3
4
5
6
7
8
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd2dba3
Xantphos
Xantphos
dppf
dppe
XPhos
DavePhos
(S)-BINAP
SPhos
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
30%
trace
35%
42%
38%
40%
34%
30%
30%
65%
trace
55%
trace
trace
60%
trace
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PPh3
10
11
12
13
14
15b
16c
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
PtBu3·HBF4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
KOtBu
Cs2CO3
Cs2CO3
Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), Pd-source 10 mol%, ligand (0.02 mmol for monodentate ligands and
0.01 mmol for bidentate ligands), base (0.3 mmol), DMF (3 ml), 1408C, 24 h;
a
Isolated yield;
reaction was carried out at 1608C;
reaction was carried out at 1208C
b
c
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(detected by GC/MS) (Scheme 1). This means that a
Applying the above optimized conditions in the
temperature of 1408C is essential for the final CÀH reaction of 3-bromo-2-(arylethynyl)benzo[b]-thio-
arylation step. Interestingly, these conditions involve phenes 1a–c with 2-bromoaryl amines 2a–c, corre-
identical catalysts, base and solvent compared to those sponding benzothieno[2’,3’:4,5]pyrrolo-[1,2-f]phenan-
used in the synthesis of 1H-benzo[4,5]thieno[3,2-b] thridines 3a–o were afforded in 55% to 80% yield
pyrrole in our previous report, despite at a higher (Table 3). The highest yield was observed for the
temperature (140 versus 1058C).[10]
electron-rich system 3l (Table 3). However, there was
no clear trend observed for a relation between
chemical structure and yield.
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In another context, we envisaged an alternative
pathway to obtain benzothieno[2’,3’:4,5]pyrrolo-[1,2-f]
phenanthridines, in which further options to install
substituents on the products are available (Scheme 2,
3). Hence, we synthesized alkynyl-benzothiophene 7
by site-selective Sonogashira reaction.
Scheme 1. Formation of uncyclized intermediate 4.
Table 3. Synthesis of benzothieno[2’,3’:4,5]pyrrolo[1,2-f]phe-
nanthridines 3a–o.
Entry
R1
R2
3
Yield (%)a
Scheme 3. Proposed reaction pathway to benzothieno
[2’,3’:4,5]pyrrolo[1,2-f] phenanthridines.
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8
H
H
H
H
H
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
65
68
58
60
70
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58
75
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80
66
60
58
Me
Cl
F
iPr
H
Starting
from
3-bromo-2-((2-bromophenyl)
H
ethynyl)benzo[b]thiophene 7, we tested the above
reaction conditions with three different amines to
compare the results with those obtained from the
previous synthesis (Entry 1–3, Table 3 vs. Entry 1–3,
Table 4). To our delight, identical products were
afforded in comparable yields. Encouraged by these
results, we examined the scope of the reaction with
several other amines (Entry 4–8, Table 4). Benzothie-
no[2’,3’:4,5]pyrrolo[1,2-f]phenanthridines 9d–h were
furnished in moderate yields. The lowest yield was
observed by applying 4-(methylthio)aniline (Entry 8,
Table 4). Both electron-withdrawing and -donating
substituents were tolerated. The reaction performed
well even with the sterically hindered and electron-
Me
Me
Me
Me
Me
OMe
OMe
OMe
OMe
OMe
Me
F
9
Cl
iPr
Me
iPr
Cl
F
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15
H
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Reaction conditions: 1 (0.3 mmol), 2 (0.38 mmol), Pd(OAc)2
(0.03 mmol), PtBu3·HBF4 (0.06 mmol), Cs2CO3 (0.9 mmol),
DMF (4.0 mL), 1408C, 24 h.
a
Isolated yield.
Scheme 2. Synthesis of 3-bromo-2-((2-bromophenyl)ethynyl)benzo[b]thiophene 7.
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poor 2-fluoroaniline (Entry 7, Table 4). However, hydroamination/CÀH arylation. The synthesis can also
there is no correlation between the chemical structure be carried out in a complementary pathway wherein
3
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and the reaction yield.
further choices of amines are available. Overall, these
methods are amendable to the generation of a large
product library for further biological- and material
applications.
Table 4. Alternative synthesis of benzothieno[2’,3’:4,5]pyrro-
lo[1,2-f]phenanthridines 9a–h.
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Experimental Section
General. All chemicals used are commercially available and
were used without further purification. Column chromatog-
raphy was performed using Merck Silicagel 60 (0.043–
0.06 mm). NMR data were recorded on Bruker AC 250,
Bruker ARX 300 and Bruker ARX 500 spectrometers.
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Entry
R3
9
Yielda
Gas chromatography-mass analysis was carried out on an
AgilentHP-5890 instrument with an Agilent HP-5973 Mass
Selective Detector (EI) and HP-5 capillary column using
helium carrier gas. ESI HR-MS measurements were per-
formed on an Agilent 1969 A TOF massÀspectrometer. For
High Resolution MS (HRMS), a Finnigan MAT95 XP was
used. Only the measurements with an average deviation
from the theoretical mass of Æ2mDa were accounted as
correct.
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8
H
4-Me
4-Cl
4-tBu
4-OMe
2-OMe
2-F
9a=3a
9b=3b
9c=3c
9d
9e
9f
60% (vs. 65%)
65% (vs. 68%)
50% (vs. 58%)
65%
60%
52%
9g
9h
55%
48%
4-SMe
Reaction conditions: 7 (0.3 mmol), 8 (0.38 mmol), Pd(OAc)2
(0.03 mmol), P(tBu)3.HBF4 (0.06 mmol), Cs2CO3 (0.9 mmol),
DMF (4 mL), 1408C, 24 h.
X-Ray crystallography was collected on a Bruker-Nonius
Apex X8 diffractometer. Infrared Spectra were recorded on
a Nicolet 550 FT-IR spectrometer with ATR sampling
technique.
a
Isolated yield.
Characterization data for the compounds can be found in the
electronic Supporting Information.
General Experimental Procedure. 3-Bromo-2-(phenylethyn-
yl)benzo[b]thiophene
1 (0.32 mmole), 2-bromoaniline 2
(1.2 equiv., 0.38 mmol), Pd(OAc)2 (10 mol%, 0.03 mmol), P
(tBu)3·HBF4 (20%, 0.06 mmol), and Cs2CO3 (3 equiv.,
0.96 mmol) were placed in a dried pressure tube equipped
with septum. Subsequently, dried and degassed DMF (4 mL)
was added under argon. The reaction was evacuated and
back-filled with argon three times and sealed by a Teflon
cap. The reaction mixture was allowed to stir at 1408C for
24 h. The reaction mixture was cooled to 208C, poured into
H2O and extracted with CH2Cl2 (33 25 mL). The combined
organic layers were dried (Na2SO4), and concentrated in
vacuo. The residue was purified by column chromatography
(flash silica gel, heptanes/EtOAc) to obtain compound 3. On
the other hand, compounds 1a, 1b, 1c, 7 were prepared
according to procedure described in literature.[12,13]
Figure 2. Crystal structure of 3 h.[11]
.
Finally, the structure of benzothieno[2’,3’:4,5]pyrro-
46 lo[1,2-f]phenanthridine 3h was independently con-
47 firmed by X-Ray crystal structure analysis (Figure 2).
48 Noticeably, the compound displays a distorted helical
49 instead of a planar structure, possibly due to the steric
50 repulsion between the rings (C10-C15) and (C17-C22).
51
Acknowledgement
G.A.S would like to thank Al-Mustansiriyah University
(www.uomustansiriyah.edu.iq) Baghdad-Iraq for its support
during the present work. Additionally, N.N.P acknowledges
DAAD for the scholarship.
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Conclusion
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54 In summary, we have developed a convenient syn-
55 thesis of benzothieno[2’,3’:4,5]pyrrolo[1,2-f]phenan-
56 thridines. The protocol involves a site-selective Sono-
57 gashira reaction followed by a cascade CÀN coupling/
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Palladium(0)-catalyzed Domino CÀN Coupling/Hydroa-
mination/CÀH Arylation: Efficient Synthesis of Benzo-
thieno[2’,3’:4,5]pyrrolo[1,2-f]phenanthridines
3
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Adv. Synth. Catal. 2017, 359, 1–6
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G. A. Salman, N. N. Pham, T. N. Ngo, P. Ehlers, A.
Villinger, P. Langer*
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