Chemoselective Ullmann coupling at room temperature: A facile access to 2-aminobenzo[b] thiophenes

Article abstract of DOI:10.1039/c7cc03273k

Various functionalized 2-aminobenzo[b]thiophenes have been synthesized at room temperature by the Ullmann coupling reaction for the first time. The enantiospecific coupling reaction has been further demonstrated without loss of optical purity. The newly synthesized 2-anilino-3-cyano-benzo[b]thiophenes are transformed into 11-amino-benzothieno[2,3-b]quinolines in the presence of triflic acid.

Full text of DOI:10.1039/c7cc03273k

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DOI: 10.1039/C7CC03273K
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Chemoselective Ullmann Coupling at Room Temperature: A Facile
Access to 2-Aminobenzo[b]thiophenes
Manojkumar Janni, Annaram Thirupathi, Sahil Arora and S. Peruncheralathan*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Various
functionalized
2-aminobenzo[b]thiophenes
are
Transition metal-catalyzed Ullmann coupling has proven to
synthesized at room temperature by Ullman coupling reaction for be one of the powerful strategies for the synthesis of nitrogen-
the first time. The enantiospecific coupling reaction is further containing heterocycles.1a,8 However, these intramolecular
demonstrated without loss of optical purity. The newly synthesized copper-mediated coupling reactions are performed under
2
-anilino-3-cyano-benzo[b]thiophenes are transformed into 11- drastic conditions and therefore much efforts have been put to
9
amino-benzothieno[2,3-b]quinolines in the presence of trifilic acid. overcome these drawbacks. In comparison, the respective
10
sulfur-containing heterocycles are less explored and in
Development of a mild and practical cross-coupling reaction at
room temperature is of fundamental importance in the process
chemistry. There is always a need to design newer cross-
particular, synthesis of 2-aminobenzo[b]thiophenes are
scarcely reported. In 2014, Wong and co-workers reported the
11
1
synthesis of 2-aminobenzo[b]thiophenes through a palladium
coupling methods, in which reactions are performed in a
sustainable manner by using energy efficient methods and the
reaction can easily be tuned up to the industrial scale. In the
heterocyclic family, benzothiophenes are known as one of the
important classes of molecules. They have a rich history in the
field of medicinal chemistry and also received much attention
as optical devices for the development of electronic materials.2
Recently, 2-aminobenzo[b]thiophene cores are found suitable
12
catalyzed C─S coupling reaction at 140 °C. Recently, Gong and
co-workers demonstrated synthesis of 2,3-diamino-
benzo[b]thiophenes via copper catalyzed intramolecular C─S
13
bond formation under microwave irradiation at 100 °C.
Despite initiating from simple starting materials, both of these
methods suffer drawbacks such as very high temperature, low
yields, limited substrate scope, use of expensive ligand and
racemization. In continuation of our ongoing interest in
synthesis of highly substituted N-heterocycles with novel
3
in tubulin polymerization and as acetyl-CoA carboxylase
4
inhibitors. These are also used as well-known precursors for
14
physical properties, herein we report a mild and practical
5
the synthesis of drug raloxifene and its various analogues. In
method for the synthesis 2-aminobenzo[b]thiophenes which
literature, 2-aminobenzo[b]thiophene was first synthesized
involves a copper-catalyzed chemoselective intramolecular
from thiosalicylic acid that involved multistep synthesis at
15
Ullman reaction at room temperature for the first time. The
6
elevated temperature. Since then, several methods have been
newly synthesized 2-anilino-3-cyano-benzo[b]thiophenes are
further transformed into functionalized quinoline derivatives by
using Brønsted acid mediated Frieldal Craft reaction.
7
developed from various precursors. Despite good yields, these
methods have their own limitations such as requirement of high
reaction temperature, stoichiometric amount of the reagents
and limited substrate scope, in addition to that some cases
benzo[b]thiophene itself is used as a precursor. Therefore,
developing a newer catalytic method for synthesis of 2-
aminobenzo[b]thiophenes is highly desirable.
The key step of the present methodology is copper-
catalyzed intramolecular Ullmann coupling of thioamides
required thioamides were prepared by treating anion of 2-
bromoaryl acetonitriles with substituted isothiocyanates in
moderate to good yields (Scheme S1, ESI†). All newly
synthesized α-cyano-α-(2-bromoaryl)thioamide derivatives
were characterized by spectral and analytical data. After having
the thioamides in our hand, the thioanilide 3a was chosen as
3. The
3
1
2
3
School of Chemical Sciences, National Institute of Science Education and Research
Bhubaneswar, HBNI, Jatni, Khurda – 752050, Odisha, India. Fax: +91-674-2494004;
Tel: +91-674-2494173; E-mail: peru@niser.ac.in
3
model substrate for chemoselective intramolecular Ullmann
cross-coupling process (C─S vs C─N). Initial experiment was
performed with CuI affording only 13% of the product along
†
Electronic Supplementary Information (ESI) available: [Experimental procedures
and spectral characterization of compounds 3, 4, 6, 7, 8 and 9. Copies of 1H &
13
C
NMR Spectra of all compounds. The X-ray data were also deposited with the CCDC
(entries 1545244 & 1545245)]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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with 79% of the starting material 3a (Table 1, Entry 1). This
product was characterized as 2-anilino-3-cyano-
13.
CuBr
Cu(OAc)
CuBr
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
Et N
DMF
88
View Article Online
3
DOI: 10.1039/C7CC03273K
1
1
4.
5.
2
Et
Et
Et
Et
3
3
3
3
N
N
N
N
DMF
79
benzo[b]thiophene (4a) by spectral and analytical data analysis.
Further, X-ray analysis was used to confirm the identity of the
product (Table 2). Interestingly, when 1,10-phenanthroline was
used as a ligand in this approach, yield of the coupling reaction
was significantly increased. Thus, the thioanilide 3a was
completely consumed within 2 hours in the presence of 1,10-
phenanthroline, and the expected 2-anilino-3-cyano-
benzo[b]thiophene (4a) was isolated as sole product in 72%
yield (Table 1, Entry 2), without the formation of C─N coupled
DMSO
84
16.
7.
CuBr
CH
3
CN
63
1
CuBr
Toluene
15 (64)c
aReaction conditions: 3a (0.5 mmol), Copper salt (5 mol%), ligand (10 mol%), base (1.5
equiv), solvent (2.0 mL), room temperature, 2 h. Isolated yields. The parenthesis is yield
of recovered starting material. TMEDA-N,N,N’,N’-Tetramethylethylene diamine; BINAM-
,1’-Bi-naphthyl-2,2’-diamine.
b
c
1
product. Various inorganic bases such as Cs
2 3
CO , K
2
CO
3
and
With the optimized conditions in our hand, we studied
KOH were screened to optimize this coupling reaction. These series of thioamides 3b-o for the chemoselective Ullmann
conditions afforded the product 4a ranging from 65-76% yields reaction. The 4-methoxy substituted N-phenyl thioamide
(
(
Table 1, Entries 3-5). However, organic bases such as DMAP derivative 3b was smoothly transformed to 2-(4-anisidinyl)-3-
N,N’-dimethylaminopyridine) and triethylamine were found to cyano-benzo[b]thiophene (4b) in 78% yield (Table 2). Similarly
improve the yield of 4a (Table 1, Entries 6-7). For further fine 3-cyano-2-(4-thioanisidinyl)-benzo[b]thiophene
(4c
)
was
tuning the reaction, a set of ligands, 2,2’-bipyridine, TMEDA, obtained from the corresponding thioamide 3c in excellent
BINAM and L-proline were screened and found to be less yields (94%, Table 2). However, 4-chloro substituted N-phenyl
beneficial when compared with 1,10-phenanthroline (Table 1, thioamide 3d afforded 4d only in 66% yield (Table 2). On the
Entries 8-11). Next, various copper salts were studied for the other hand, 3-methoxy substituted N-phenyl thioamide 3e was
Ullmann coupling reaction. CuBr was found to give a better yield converted to 2-(3-anisidinyl)-3-cyano-benzo[b]thiophene (4e
as compared with CuCl and Cu(OAc)
(Table 1, Entries 12-14) in very good yields. This reaction was further extended for
and chosen for further studies. Finally, the solvent effect on synthesis of 2-alkyl substituted amino-3-cyano-
Ullmann process was also examined with DMSO, CH
CN and benzo[b]thiophenes 4f and 4g respectively (Table 2). The N-
)
2
3
toluene. Among these, DMSO was compared with DMF in terms isopropyl substituted thioamide 3f gave an excellent yield of
of conversion and yields of benzo[b]thiophene 4a (Table 1, benzo[b]thiophene 4f (Table 2). Interestingly, 2-[2-(N-
Entries 15-17). These results clearly showed that the Ullmann morpholine)ethylamino]-3-cyano-benzo[b]thiophene (4g) was
coupling is highly chemoselective because copper thiolate is
more nucleophilic than the corresponding amide.
Table 2. Copper Mediated Ullmann Reaction of Thioamides 3 at Room
Temperature
a
Table 1. Optimization of the Ullmann Reaction of Thioamide 3a at Room
a-b
Temperature
Entry
Metal
Ligand
Base
Solvent
Yield of 4a
t
13 (79)c
72
1
2
3
4
5
6
7
8
.
.
.
.
.
.
.
.
CuI
CuI
CuI
CuI
CuI
CuI
CuI
-
KO Bu
DMF
DMF
DMF
DMF
DMF
DMF
DMF
t
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
1,10-Phen
KO Bu
Cs
2
CO
3
65
K
2
CO
3
73
KOH
DMAP
76
84
Et
Et
3
N
N
83
2,2’-
Bipyridine
CuI
3
DMF
77
9
1
1
1
.
CuI
CuI
TMEDA
BINAM
Et
Et
Et
Et
3
3
3
3
N
N
N
N
DMF
DMF
DMF
DMF
74
61
63
77
a
b
Isolated yields. The reaction was performed in one-pot.
0.
1.
2.
prepared from morpholine derived thioamide 3g in 78% yield
under similar reaction conditions (Table 2). The effect of
electron donating substituents at aryl ring of thioamide was also
CuI
L-Proline
1,10-Phen
CuCl
2
| J. Name., 2012, 00, 1-3
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studied. The thioamides having dimethoxy groups at aryl ring, expect the formation of four different produVcietwsAr(titcwle oOnlinSe-
h-j gave 77-80% yield of benzo[b]thiophenes 4h-j (Table 2). heterocycles and two N-heterocycles,DOSI:c1h0e.1m03e9/C47SC,C0E3S2I7†3)K.
Whereas, the methylene dioxy substituted thioamide 3k gave However, as previously mentioned, optimized coupling
8% yield of 4k (Table 2). Similarly 4-methoxy substituted N- conditions favor the formation of C─S bond over the C─N bond.
phenyl thioamide 3l afforded 4l in moderate yield. Interestingly, For example, when thioamide 6e was subjected to the
-anilino-3-cyano-5-nitro-benzo[b]thiophene 4m was optimized conditions and the reaction resulted the formation of
3
6
2
(
)
synthesized from 3m (Table 2). The α-cyano-α-(1-bromo-2- 2-aminobenzo[b]thiophene 7e in 83% yield, which was
naphthyl)-thioamide 3n was transformed to 2-anilino-3-cyano- confirmed by spectral analysis. Overall, the 5-membered ring
naphtha[1,2-b]thiophene (4n) in 82% yield under optimized formation was favored over the six-membered one and
reaction conditions. This reaction was further successfully exclusive formation of only S-heterocyclic compound was
applied to enantiomerically pure amino acid substituted observed. This simple experiment highlights the chemo- and
thioamides 3o-p for the formation of corresponding regioselective nature of the present coupling reaction. To
benzo[b]thiophene derivatives 4o-p in 72% and 65% yields with elaborate this idea, 3-aroyl-2-amino-benzo[b]thiophenes 7f and
>99% ee and 97% ee respectively. No racemization was 7g were synthesized from respective thioamides 6f and 6g. The
observed during the reaction conditions (Table 2). This formation of chemoselectively coupled 3-(2-bromoaroyl)-2-
experiment clearly supported that mildness of the newly amino-benzo[b]thiophene 7f was further confirmed by single
optimized Ullmann reaction.
crystal X-ray analysis (Table 4).
Table 4. Chemoselective Ullmann Reaction of Thioamides 6 with Two
Reactive Bromides
We next tuned our interest towards studies involving
thioamides derived from methyl 2-bromoaryl acetate (6a and
a
6
b) and α-(2-bromoaryl)ketones (6c and 6d). The required
thioamides were prepared from reaction of 2-bromo-benzyl
6
derivatives with isothiocyanates (Scheme 3S, ESI†). The
thioamides 6a and 6b derived from esters 5a and 5b were
smoothly transformed into 3-methyl carboxylate substituted 2-
aminobenzo[b]thiophenes 7a and 7b respectively in very good
yields (Table 3). We have also demonstrated the synthesis of 3-
aroyl substituted 2-aminobenzo[b]thiophenes from α-aroyl-α-
(2-bromoaryl)thioamides 6c-d (Table 3). Under optimized
reaction conditions, 6c-d afforded the respective 3-aroyl
substituted 2-amino-benzo[b]thiophenes 7c-d in very good to
excellent yields (Table 3).
Table 3. Copper Mediated Ullmann Reaction of Thioamides 6 at Room
a
Temperature
aIsolated yields.
The newly synthesized benzo[b]thiophene core is decorated
with aniline and cyano groups at 2- and 3-positions,
respectively. We envisioned that the nitrile can be activated by
a Lewis acid, which could be in situ trapped by an intramolecular
attack of aniline moiety at its ortho position. The strategy works
well for the synthesis of 4-aminoquinoline ring over the
benzothiophene (Scheme 5S, ESI). To optimize this proposed
strategy, we screened a set of Lewis and Brønsted acids for
intramolecular Friedal-Craft reaction of 2-anilino-3-cyano-
benzo[b]thiophene (4a, Table 1S, ESI). Interestingly, we found
that in the presence of triflic acid (10 equiv), the
benzo[b]thiophene 4a was smoothly converted into the
corresponding 11-amino-benzothieno[2,3-b]quinoline (8a) in
aIsolated yields.
Next we focused on chemoselective Ullmann coupling
8
6% yield at room temperature. Using these optimized
1
reaction of thioamides 6e-f having two reactive bromides (Br
conditions, several benzo[b]thiophene derivatives were
4
2
vs Br , Table 4). Under the classic coupling conditions, we could
transformed into the corresponding benzothieno fused
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reaction at room temperature: (b) A. Shafir and S. L.
quinolines 8c-d, 8h, 8j,
& 8n in moderate to very good yields
View Article Online
Buchwald, J. Am. Chem. Soc. 2006, 128, 8742; (c) X. Xie, Y.
DOI: 10.1039/C7CC03273K
(Table 4). To the best of our knowledge, the 11-amino-
Chen and D. Ma, J. Am. Chem. Soc. 2006, 128, 16050; (d) F. Y.
benzothieno[2,3-b]quinoline core is not known and to date,
there is only one reported method for the synthesis of
benzothieno[2,3-b]quionoline by radical cyclization.
Kwong and S. L. Buchwald, Org. Lett. 2003, 5, 793.
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Review: (a) B. Wu and N. Yoshikai, Org. Biomol.
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C. Q. Ma and P. Bäuerle, M. Nakano, Acc. Chem. Res., 2014,
Table 5. Synthesis of 11-Amino-benzothieno[2,3-b]quinolines 8 via
Brønsted acid mediated Friedal Craft Annulation of 4a
47, 1493, 793; (d) B. Godoi, R. F. Schumacher and G. Zeni,
Chem. Rev. 2011, 111, 2937; (e) D. Alberico, M. E. Scott and
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Further, we also performed the deprotection of para-
methoxyphenyl (PMP) group of 2-amino-benzo[b]thiophene by
standard oxidative cleavage conditions. The 2-(4-anisidinyl)-3-
26, 1108.
8
9
Selected Reviews: (a) I. P. Beletskaya and A. V. Cheprakov,
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cyano-benzo[b]thiophene
ammonium nitrate (CAN) in CH
-cyano-benzo[b]thiophene ( ) in 57% yield (Scheme 1).
(
4b
3
)
was treated with ceric
2
CN/H O affording the 2-amino-
3
9
2
2
014, 79, 8507; (b) D. S. Surry and S. L. Buchwald, Chem. Sci.
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1
In conclusion, we have demonstrated the chemoselective
Ullmann reaction at room temperature for synthesis of 2-
aminobenzo[b]thiophenes for the first time. The present
protocol is mild and gives access to a variety of highly
functionalized benzo[b]thiophenes in good to excellent yields.
The potential application of the reaction was further extended
to (i) enantiospecific Ullmann reaction that occurred without
the loss of optical purity and (ii) a highly selective C─S bond
(
,
4254; (d) D. Ma, X. Lu, L. Shi, H. Zhang, Y. Jiang and X. Liu,
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hitherto unknown 11-amino-benzothieno[2,3-b]quinoline was
1
1
2 C. Hou, Q. He and C. Yang, Org. Lett. 2014, 16, 5040.
successfully synthesized by using Brønsted acid. Currently,
synthesis of 2-aminobenzo[b]thiophenes derivatives via C─H
fuctionalization are in progress in our laboratory.
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,
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Notes and references
1
5 L. Benati, R. Leardini, M. Minozzi, D. Nanni, P. Spagnolo and
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2
4
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DOI: 10.1039/C7CC03273K
TOC Graphic
Copper catalyzed Ullmann reaction has been used for the first time to study chemoselective and
enantiospecific intramolecular C─S bond formation at room temperature.