Facile synthesis of 3-aryl benzofurans, 3-aryl benzothiophenes, 2-aryl indoles and their dimers

Article abstract of DOI:10.1080/00397911.2019.1611856

The preparation of 3-aryl benzofuran and benzothiophenes and their dimers at 2-position and, 2-aryl indoles and their 3-position dimers preparation is described.

Full text of DOI:10.1080/00397911.2019.1611856

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Facile synthesis of 3-aryl benzofurans, 3-aryl
benzothiophenes, 2-aryl indoles and their dimers
Pailla Umareddy & Veera Reddy Arava
To cite this article: Pailla Umareddy & Veera Reddy Arava (2019): Facile synthesis of 3-aryl
benzofurans, 3-aryl benzothiophenes, 2-aryl indoles and their dimers, Synthetic Communications,
DOI: 10.1080/00397911.2019.1611856
To link to this article: https://doi.org/10.1080/00397911.2019.1611856
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2019.1611856
Facile synthesis of 3-aryl benzofurans, 3-aryl
benzothiophenes, 2-aryl indoles and their dimers
Pailla Umareddy and Veera Reddy Arava
R&D Centre, Suven Life Sciences Ltd, Jeedimetla, Hyderabad, India
ABSTRACT
ARTICLE HISTORY
Received 21 February 2019
The preparation of 3-aryl benzofuran and benzothiophenes and their
dimers at 2-position and, 2-aryl indoles and their 3-position dimers
preparation is described.
KEYWORDS
Aluminum chloride;
3-aryl benzofurans;
3-aryl benzothiophenes;
2; 20-bis (3; 30-aryl
benzofurans and
thiophenes); 3;
GRAPHIC ABSTRACT
R
R
R
OCH3
X
FeCl3
AlCl3
30–bis (2; 20–aryl indoles);
ferric chloride
MDC
RT
X
4
H3CO
X
MDC
RT
H3CO
X
H3CO
O
R
5
3
H
N
R1
R
I2
Methanol
Ethylacetate
R
R1
R
R1
N
H
N
H
8
7
Introduction
Benzofurans are ubiquitous structural motifs in both natural products and synthetic
pharmaceuticals.[1] Benzofurans are attractive compounds due to their interesting prop-
erties.[2] They are widespread and have important biological activities, including antitu-
mor properties,[3] inhibition of protein phosphates 1B,[4] 5-HT2 and 5-HT3 antagonist
activity,[5a] inhibition of 5-lipoxygenase,[5b] and antifungal properties.[6a] Pharmaceutically,
these properties are convenient in the treatment of cancers[6b], cardiovascular diseases[6c]
,
type 2 diabetes[6d], migraines, dementia, and anxiety[6e]. In addition, benzofurans have
been reported as fluorescent markers for biomolecules.[7] In particular, benzofurans bearing
a 3-aryl substituent exhibit useful anticancer,[8] antiviral,[9] and immunomodulatory[10]
effects. Two examples are isoparvifuran,[11] an antifungal agent[12] and a promising antian-
drogenic agent.
CONTACT Veera Reddy Arava
reddyvenis@rediffmail.com
R&D Centre, Suven Life Sciences Ltd, Jeedimetla,
Hyderabad, India.
Supplemental data for this article can be accessed on the publisher’s website
ß 2019 Taylor & Francis Group, LLC

2
P. UMAREDDY AND V. R. ARAVA
HO
HO
OMe
O
O
HO
OH
OH
O
O
O
O
O
MeO
MeO
OH
Bisbenzofuran-2-ylmethanol.
Kynapcin-24,
Isoparvifuran
Figure 1. Kynapcin-24, bisbenzofuran-2-ylmethanol, isoparvifuran.
Benzofurans have been produced by a variety of methods[13] including cyclodehydra-
tion of aryl ketones,[14] palladium mediated Heck reactions,[15] radical reactions,[16]
Wittig and McMurry reactions.[17] The majority of methods are for selectively con-
structing benzofurans include the transition metal-catalyzed transformations.[18]
Although these transformations are efficient and general, two significant drawbacks are
usually the requirement of harsh conditions and the cost of the catalytic system.[18]
However, the bis benzofuran scaffold is much less studied, although it is present in a
number of biologically active molecules, for example, in kynapcin-24. The kynapsin-24,
whose first total synthesis was accomplished in 2009 by Yang et al.,[18,19] this act upon
prolyl endopeptidase, a protein engaged with Alzheimer’s infection (Figure 1).[20]
Other dimers of benzofurans, such as 2, 20 bis benzofurans exhibit also interesting
properties like antiprotozoal activities or antimicrobial effects.[21] Yet, only few syntheses
of bisbenzofuran derivatives have been published. They mainly involve the building of
two benzofuran units which need to be activated prior to connection by metal-catalyzed
coupling reaction, modified Castro reaction,[22] copper-mediated palladium-catalyzed
coupling[20] or BuLi/CuCl2 coupling.[23] The quick and efficient access to bisbenzofuran
derivatives from easily available starting material is, therefore, a challenging field of
investigations.
The 3, 30-Biindolyls are useful structural units that are frequently found in pharmaceut-
ical and functional materials.[24] accordingly syntheses and functionalization of 3,30-biin-
dolyls have attracted much attention over the decades.[25] The general method for the
preparation of 3,30-biindolyls involves the nucleophilic attack of indoles to isatin in the
presence of dimethylamine to give 3-(3-indoly)3-hydroxyoxindole. The subsequent reduc-
_
tion by stoichiometric NaBH4 and BF3 Et2O affords the desired products in moderate
yields.[26] For example, Chai reported the palladium catalyzed Suzuki–Miyaura cross-
coupling of the indolyl halides with indolyl boronic compounds to give dimers
efficiently.[27] However, the pre-functionalization of indoles to their halides or boronic
derivatives is required for these transformations. From both scientific and environmental
points of view, the development of a methodology for direct activation of C–H bond is of
great significance and metal catalyzed C–H bond functionalization has attracted much
attention currently[28]. Recently, Niu et al. reported the new method for the homo-cou-
pling of indoles with FeCl3 as a catalyst and molecular oxygen as the only oxidant.[29]
Results and discussion
In this paper, we would like to report the preparation of 3-aryl benzofurans, benzothio-
phenes, 2-aryl indoles, and their dimers.

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SYNTHETIC COMMUNICATIONSV
3
The syntheses of 3-aryl benzofurans and 3-aryl benzothiophenes were achieved by cyclo-
dehydration of aryloxyketones in the presence of aluminum chloride. Initially, we investi-
gated the reaction of 2-(3-Methoxy-phenoxy)-1-phenyl-ethanone (3a), with aluminum
chloride under the normal condition at room temperature. To our delight, the desired prod-
uct 5a was formed in 64% yield after 2 h. The diverse reagents inspected for the synthesis of
benzofurans and benzothiophenes are BF3.OEt2, PTSA, ZnCl2 and Eaton’s reagent, how-
ever, cyclodehydration was seen better with aluminum chloride (Scheme 1).
Further, we tried the cyclization reaction of 3a with ferric chloride. To our surprise,
the product formed in this reaction was a cyclized one but with one aromatic hydrogen
was absent in NMR and mass of the product was double of the expected one. More
careful observation of NMR and other spectral data confirmed that the product is dimer
4 (Scheme 2) (Optimised conditions are given in Table-2)(Scope of different aryl indole
are given Table-5) .
Later different parameters of the reaction were considered like mole proportion of
ferric chloride, time, temperature, and solvents (Table 1).
Contrasted with alternate strategies, our technique is straightforward and practical.
The compound 2 was prepared from 3-methoxy phenol or 3-methoxy thiophenol with
substituted phenacyl bromide in the presence of potassium carbonate to get 3. The ver-
satility of the reaction was studied with different phenacyl bromides and the products
are formed in excellent yields.
Monomers were only formed with AlCl3 on reaction with 3 and dimers were only
formed with FeCl3 on reaction with 3. The results were tabulated in Table 3
(Schemes 3–5).
The syntheses of 2-aryl indoles (7)29 was achieved by condensation of anilines with
haloacyl benzenes followed by cyclodehydration. Initially, we studied the reaction of
3-methoxy aniline (6a) and phenacylbromide (2a), with N, N-dimethyl aniline at
R
R
AlCl3
MDC
X
H3CO
H3CO
X
3
O
5
Scheme 1. Synthetic access of 3-aryl benzofurans and 3-aryl benzothiophenes by cyclodehydration.
R
R
OCH3
X
FeCl3
X
H3CO
H3CO
X
3
O
R
4
Scheme 2. Syntheses of 3-aryl benzofurans and 3-aryl benzothiophenes dimers.

4
P. UMAREDDY AND V. R. ARAVA
Table 1. Optimization of reactions conditions such as moles of aluminum chloride, reaction tempera-
ture, time and solvents.
Entry
AlCl3
Solvent
Temperature (0 ꢀC)
Time (h)
Yield%
a
b
c
D
E
F
G
H
I
1.0
1.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
MDC
MDC
MDC
MDC
MDC
EDC
CHCl3
THF
Toluene
Hexane
Dioxane
DMF
0–5
5–15
15–20
RT
reflux
RT
1.0
1.5
1.0
2.0
2.0
3
2.5
24
24
24
24
24
24
40
45
50
64
ND
48.7
38.5
ND
ND
ND
ND
ND
ND
RT
reflux
reflux
reflux
reflux
reflux
reflux
j
k
l
m
DMSO
Bold values significance the best yields.
Table 2. Optimization of reaction conditions and solvents were studied, but dichloromethane found
to be the best solvent with best yields.
Entry
FeCl3
Solvent
Temperature
Time(h)
Yield (%)
a
b
c
d
e
f
g
h
i
1.0
1.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
MDC
MDC
MDC
MDC
MDC
EDC
CHCl3
THF
Toluene
Hexane
Dioxane
DMF
0–5
5–15
15–20
RT
Reflux
RT
1.0
1.5
1.0
2.0
2.0
3
2.5
24
24
24
24
24
24
ND
25%
33%
64%
Decompose
25%
38%
ND
RT
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
ND
ND
ND
ND
j
k
l
m
DMSO
ND
Bold values significance the best yields.
120–140 ꢀC. To our delight, the desired product 7a was formed in 55% yield. The dif-
ferent reagents examined for the synthesis of 2-aryl indoles are aluminum chloride
and Eaton’s reagent but the product was not observed, while PPA gave low yields
(10–15% only).
Our process for 2,20-aryl-3,30-biindolyls (8) from 2-aryl indoles (7) is performed with
molecular iodine (I2) under normal conditions. The desired product (8) was formed in
85–90% excellent yields. First, we tried the synthesis of 8 from 7 with FeCl3 but the
product was not formed. Compared to the previous methods[30–34], our methodology is
superior (Scheme 6).
The versatility of the reaction was studied with different phenacyl bromides and dif-
ferent anilines. The results are given in Table 4. Under the similar condition, 5-methoxy
and 6-chloro indoles did not give dimers 8.
Conclusion
We have successfully developed a simple and an industrially feasible methodology
for the syntheses of 3-aryl benzofurans 3-aryl benzothiophenes, 2-aryl indoles and
their dimers.

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5
Table 3. Scope of different phenacyl bromides.
S.NO
3
4
Yield%
68
5
Yield%
(With FeCl3 Dimers)
(With AlCl3 Monomers)
OCH3
O
a
O
H3CO
64
57
O
O
H3CO
H3CO
O
H3CO
3a
5a
4a
OCH3
OCH3
OCH3
62
50
O
H3CO
OCH3
O
O
b
3b
O
O
H3CO
5b
4b
4c
H3CO
Br
Br
Br
O
H3CO
OCH3
OCH3
O
O
c
3c
45
38
O
H3CO
H3CO
O
H3CO
H3CO
5c
Br
Cl
Cl
Cl
O
O
S
d
O
H3CO
O
O
S
40
55
O
O
3d
Cl
4d
5d
1
H3CO
H3CO
H3CO
H3CO
OCH3
OCH3
H3CO
H3CO
e
O
62
68
O
O
O
3e
5e
4e
OCH3
OCH3
f
S
H3CO
65
80
H3CO
H3CO
S
H3CO
3f
5f
S
4f
OCH3
S
OCH3
OCH3
g
S
H3CO
O
3g
70
S
H3CO
5g
4g
H3CO
Br
Br
Br
S
H3CO
OCH3
SCH3
S
55
62
O
h
i
3h
60
74
S
H3CO
H3CS
S
H3CO
H3CS
5h
4h
4i
Br
O
H3CS
O
O
3i
O
O
5i
Experimental
Materials and instruments
Most of the reagents used in this work were obtained from commercial suppliers and
were of LR/AR grade. Solvents were purified before use by standard procedures.
Melting points were determined using open capillary tubes on POLMON melting points

6
P. UMAREDDY AND V. R. ARAVA
R
R
R
OCH3
X
FeCl3
AlCl3
MDC
RT
MDC
RT
X
H3CO
X
H3CO
X
H3CO
O
3
R
5
4
Scheme 3. Transformation of 3 to 4 and 5.
Cl Cl
Al
Cl Cl
Al
Cl Cl
Al
Cl
H
O
O
O
Cl
HCl
O
X
H
O
X
O
X
3
Cl
H
O
X
O
X
5
Scheme 4. Proposed reaction mechanism for the formation of 3-aryl benzofuran (5) from 3.
3+
2+
Fe
Fe
O
X
FeCl3
O
X
O
O
X
5
O
X
O
3
H
X
O
X
-2H+
H
X
O
O
X
4
Scheme 5. Proposed reaction mechanism for the formation of dimer (4) from 3.
H
N
R1
R
O
N,N-dimethyl
aniline
I2
R
R
+
R1
R
R1
Br
Methanol
Ethylacetate
120-130°C
N
H
N
R1
NH2
H
8
6
2
7
Scheme 6. Syntheses of 2-aryl indoles and their dimers.

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SYNTHETIC COMMUNICATIONSV
7
Table 4. Optimization of reaction condition (equivalence of I2, temperature and time).
Entry
I2 (Eq)
Temperature
Time(h)
Yield (%)
a
b
c
0.1
0.2
0.5
0.6
0–55 ꢀC
0–55 ꢀC
0–55 ꢀC
RT
24.0
24.0
8.0
No reaction
No reaction
35%
d
2.0
90%
Bold values significance the best yields.
Table 5. Scope of different 2-aryl indoles.
S.NO
7
8
Yield%
90%
H
OCH3
N
a
N
H
H3CO
7a
N
H3CO
H
8a
H
OCH3
OCH3
N
H3CO
H3CO
OCH3
80%
85%
N
H3CO
H
b
7b
N
H
8b
H
OCH3
OCH3
N
H3CO
H3CO
N
H
c
H3CO
H3CO
7c
1
N
H
8c
H
OCH3
N
H3CO
H3CO
H3CO
H3CO
d
88%
OCH3
N
H
OCH3
OCH3
7d
N
H3CO
H
8d
H3CO
No reaction
No reaction
e
f
-
-
N
H
7e
N
Cl
H
7f
1
apparatus (Model-96) and are uncorrected. H (400 MHz) and 13C (100 MHz) NMR
spectra were recorded by using a Bruker 400 Spectrometer with TMS as an internal
standard. IR spectra were recorded on a Perkin-Elmer Spectrum 100 FTIR
Spectrophotometer as KBr pellets or with the neat products. Mass spectra were recorded
on an API 2000 LCMS/MS Applied Bio Systems MDS Sciex spectrometer. Microanalysis
was performed on a Perkin-Elmer 240CHN elemental analyzer. Analytical TLC was
conducted on E-Merck 60F254 aluminum-packed plates of silica gel (0.2 mm).

8
P. UMAREDDY AND V. R. ARAVA
Developed plates were visualized by using UV light or in an iodine chamber. HPLC was
performed by using a Shimadzu 2010 instrument. The HRMS data of new compounds
are provided in supplementary info.
General procedure for syntheses of 4
To a stirred solution of FeCl3 (5.0 g, 0.030 mol) and DCM (50 mL) was added a solution
of 3 (5.0 g, 0.020 mol in 15 mL of DCM) at 5–10 ꢀC for 15 min. The mixture was stirred
at room temperature. After completion of the reaction (monitored by TLC) the reaction
mass was quenched into water and stirred for 30 min. The organic layer was separated
and the aqueous layer was extracted with DCM. The combined organic layer was
washed with 5% hydrazine hydrate solution and the solvent was evaporated to get 4
which were purified on silica gel column and the pure compound was isolated as
a solid.
6,6’-Dimethoxy-3,3’-diphenyl-[2,2’]bibenzofuranyl (4a)
MP: 162.4–164.8 ꢀC; yield 68%; IR (KBr in, cmꢁ1): 2829, 1621, 1489, 1272, 1105, 813,
695, 564; 1 H NMR (400 MHz, CDCl3) (d ppm): 7.50 (d, J ¼ 8.5 Hz, 1H), 7.33–7.32
(m, 2H), 7.26–7.25 (m, 3H), 7.05 (s, 1H), 6.93 (d, J ¼ 8.48 Hz, 1H), 3.88 (s, 3H, OCH3),
13C NMR (100 MHz, CDCl3) (d ppm): 158.97, 155.98, 141.61, 131.81, 129.16, 128.32,
127.30, 121.90, 121.48, 120.75, 112.52, 95.86, 55.80; HRMS (ESI): [M þ H]þ calcd. for
C30H22O4, 446.1518; found, 446.1517.
General procedure for syntheses of 8
To a stirred solution of 7 (10.0 g, 0.044 mol) and methanol (20 ml) and ethyl acetate
(20 ml) added molecular I2 (6.8 g, 0.026 mol), respectively at room temperature. The
mixture was maintained at room temperature. After completion of the reaction (moni-
tored by TLC) reaction mass was concentrated under vacuum and saturated Na2S2O3
(20 ml) were added, and the mixture was extracted with ethyl acetate (2 ꢂ 100 mL).
The combined organic layers were washed with brine and concentrated in vacuum.
The crude product was crystallized from methanol to afford the desired bis indole
product 8.
6,6’-Dimethoxy-2,2’-biphenyl-1H,1’H-[3,3’] biindolyl (8a)
MP: 158–161.5 ꢀC; Yield: 90%; IR (KBr in, cmꢁ1): 3399, 2937, 1717, 1624, 1447, 1254,
1
767; H NMR (400 MHz, DMSO) (d ppm): 8.23 (S, 1H, NH), 7.28 (d, J ¼ 7.2 Hz, 2H),
7.25–7.06 (m, 4H), 6.94 (s, 1H), 6.67–6.50 (dd, J1¼2.4 Hz, J2¼2.0 Hz, 1H), 3.80 (s, 3 H,
OCH3); 13C NMR (100 MHz, DMSO) (d ppm): 156.76, 137.09, 133.89, 133.23, 128.40,
126.66, 126.47, 124.43, 121.30, 109.66, 107.32, 94.56, 55.70; HRMS (ESI): [M þ H]þ
calcd. for C30H22N2O2, 444.1838; found, 444.1839.

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SYNTHETIC COMMUNICATIONSV
9
Supporting information
1
Full experimental detail, H and 13C NMR spectra, HRMS traces. This material can be
found via the “Supplementary Content” section of this article’s webpage.
Acknowledgment
We would like to thank Suven life sciences for providing excellent analytical facilities and our
CEO, Mr. Jasti for allowing us to publish this work.
Funding
Financial Support for This Work Was Provided by the Skaggs Institute for Chemical Biology, the
National Institutes of Health (USA), Doctoral Fellowships from the National Science Foundation
(S.A.S.) and the Department of Defense (J.A.P.), and Grants from Abbott, Amgen, Boehringer -
Ingelheim, Glaxo, Hoffmann - La Roche, DuPont, Merck, Novartis, Pfizer, and Schering Plough.
References
[1] (a) McCallion, G. D. An Efficient Synthesis and Substitution of 3-Aroyl-2-bromobenzo[b]-
furans. Curr. Org. Chem. 1999, 3, 67. DOI: 10.1021/jo701656z.(b) Kadieva, M. G.;
Oganesyan, E. T. Methods for the Synthesis of Benzofuran Derivatives (Review). Chem.
Heterocycl. Compd. 1997, 33, 1245. DOI: 10.1007/BF02320323. (c) Katritzky, A. R.; Rees,
C. W.; Scriven, E. F. V., Eds. Comp. Heterocycl. Chem. II. 1996, 2, 259. DOI: 10.
1021/jm9706123. (d) Dean, F. M.; Sargent, M. V. Furans and their Benzo Derivatives.
Comp. Heterocycl. Chem. 1984, 4, 531. DOI: 10.1016/B978-008096519-2.00060-6.
[2] (a) Hou, X. L.; Yang, Z.; Yeung, K. S.; Wong, H. N. C. Five-membered ring systems: fur-
ans and benzofurans. Prog. Heterocycl. Chem. 2008, 19, 176–207. DOI: 10.1016/S0959-
6380(08)80009-8. (b) Gribble, G. W.; Joule, J. A., Eds. Oxford: Elsevier, 2008, pp 176; and
previous volumes in the series. For recent work on benzofurans of pharmacological inter-
est, see. (c) Carlsson, B.; Singh, B. N.; Temciuc, M.; Nilsson, S.; Li, Y. L.; Mellin, C.;
Malm, J. Synthesis and Preliminary Characterization of
a Novel Antiarrhythmic
Compound (KB130015) with an Improved Toxicity Profile Compared with Amiodarone.
J. Med. Chem. 2002, 45, 623. DOI: 10.1021/jm001126%2B. DOI: 10.1021/jm001126þ. (d)
Flynn, B. L.; Hamel, E.; Jung, M. K. One-Pot Synthesis of Benzo[b]Furan and Indole
Inhibitors of Tubulin Polymerization. J. Med. Chem. 2002, 45, 2670. DOI: 10.1021/
jm020077t.
[3] Erber, S.; Ringshandl, R.; von Angerer, E. 2-Phenylbenzo[b]Furans: relationship between
Structure, Estrogen Receptor Affinity and Cytostatic Activity against Mammary Tumor
Cells. Anti-Cancer Drug Des. 1991, 6, 417.
[4] Malamas, M. S.; Sredy, J.; Moxham, C.; Katz, A.; Xu, W. X.; McDevitt, R.; Adebayo, F. O.;
Sawicki, D. R.; Seestaller, L.; Sullivan, D.; et al. Novel Benzofuran and Benzothiophene
Biphenyls as Inhibitors of Protein Tyrosine Phosphatase 1B with Antihyperglycemic
Properties. J. Med. Chem. 2000, 43, 1293. DOI: 10.1021/jm990560c.
[5] Watanabe, Y.; Yoshiwara, H.; Kanao, M. Syntheses of 4-(Benzo[b]Furan-2 or 3-yl)- and 4-
(Benzo[b]-Thiophen-3-yl)Piperidines with 5-HT 2 Antagonist Activity. J. Heterocycl.
Chem. 1993, 30, 445. DOI: 10.1002/jhet.5570300228.
[6] (a) McAllister, G. D.; Hartley, R. C.; Dawson, M. J.; Knaggs, A. R. Total Synthesis of
Moracin C. J. Chem. Soc, Perkin Trans. 1 1998, 20, 3453. DOI: 10.1039/a805026k.(b)
Dounya, S.; Van de Poll-Franse, L.; Pauline, V.; Myrthe, P. P.; Herk-Suke, V.; Susanne, S.;
Nina, R.; Trine, H.; Susanne, D.; Johan, D. J. Breast Cancer Res. Treat. 2017, 166(1),
259–266. DOI: 10.1007/s10549-017-4387-1.(c) Cermakova, P.; Johnell, K.; Fastbom, J.;

10
P. UMAREDDY AND V. R. ARAVA
Garcia-Ptacek, S.; Lund, L. H.; Winblad, B.; Eriksdotter, M.; Religa, D. Cardiovascular
Diseases in ꢃ30,000 Patients in the Swedish Dementia Registry. JAD. 2015, 48, 949–958.
DOI: 10.3233/JAD-150499. (d) Xiaohua, L.; Dalin, S.; Sean, X. L. Link between Type 2
Diabetes and Alzheimer’s Disease: From Epidemiology to Mechanism and Treatment. Clin.
Interv. Aging. 2015, 10, 549–560. DOI: 10.2147/CIA.S74042. (e) Chun-Ting, L.; Bei-Yu, W.;
Chiang, H.; Wang, L. Y.; Yan-Yuh, L.; Tsu-Kung, L.; Pao-Yen, L.; Wu-Fu, C.; Jen-Huai, C.;
Sheng-Feng, H.; et al. Decreased Risk of Dementia in Migraine Patients with Traditional
Chinese Medicine Use:
A Population-Based Cohort Study. Onco Target. 2017, 8,
79680–79692. DOI: 10.18632/oncotarget.19094.
[7] (a) Piloto, A. M.; Fonseca, A. S. C.; Costa, S. P. G.; Gonc¸alves, M. S. T. Carboxylic Fused
Furans for Amino Acid Fluorescent Labelling. Tetrahedron. 2006, 62, 9258. DOI: 10.1016/
j.tet.2006.07.003. (b) Piloto, A. M.; Costa, S. P. G.; Gonc¸alves, M. S. T. A Naphtho[2,1-
b]Furan as a New Fluorescent Label: synthesis and Spectral Characterisation. Tetrahedron
Lett. 2005, 46, 4757. DOI: 10.1016/j.tetlet.2005.05.035.
[8] (a) Babu, V. H.; Kumar, P. S.; Srinivasan, K. K.; Bhat, G. V. Synthesis, antitumor and anti-
bacterial activities of certain substituted pyrimidines bearing benzofuran. Indian J. Pharm.
Sci. 2004, 66, 647. (b) Hayakawa, I.; Shioya, R.; Agatsuma, T.; Furukawa, H.; Sugano, Y.
Thienopyridine and Benzofuran Derivatives as Potent anti-Tumor Agents Possessing
Different Structure–Activity Relationships. Bioorg. Med. Chem. Lett. 2004, 14, 3411. DOI:
10.1016/j.bmcl.2004.04.079.
[9] Abdel-Kader, M. S. Phenolic Constituents of Ononis Vaginalis Roots. Planta Med. 2001,
67, 388. DOI: 10.1055/s-2001-14325.
[10] Rahim, R. T.; Meissler, J. J., Jr.; Cowan, A.; Rogers, T. J.; Geller, E. B.; Gaughan, J.; Adler,
M. W.; Eisenstein, T. K. Administration of mu-, Kappa- or delta2-Receptor Agonists via
Osmotic Minipumps Suppresses Murine Splenic Antibody Responses. Internat.
Immunopharmacol. 2001, 1, 2001. DOI: 10.1016/S1567-5769(01)00128-X.
[11] (a) Frahm, A. W.; Muangnoicharoen, N. Arylbenzofurans from Dalbergia parviflora.
Phytochem. 1981, 20, 291. DOI: 10.1016/0031-9422(81)85109-6. (b) For a synthesis, see:
Mukherjee, S. K.; Walia, S.; Kulshrestha, S. K. Photochemistry of latifolin and some
related compounds.Tetrahedron. 1986, 42, 4817. DOI: 10.1016/S0040-4020(01)82062-7.
[12] Shirota, O.; Pathak, V.; Sekita, S.; Satake, M.; Nagashima, Y.; Hirayama, Y.; Hakamata, Y.;
Hayashi, T. Phenolic Constituents from Dalbergiacochinchinensis. J. Nat. Prod. 2003, 66,
1128. DOI: 10.1021/np0300683.
[13] (a) Mustafa, A. In Chemistry of Heterocyclic Compounds; Weissberger, A.; Taylor, E. C.,
Eds.; Wiley: New York, 1974; Vol. 29, pp 1–514. (b) Mustafa, A. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon
Press: Oxford, 1996; Vol. 2, pp 259.
[14] (a) Nicolaou, K. C.; Snyder, S. A.; Bigot, A.; Pfefferkorn, J. A. Solution and Solid-Phase
Synthesis of Functionalized 3-Arylbenzofurans by a Novel Cyclofragmentation – Release
Pathway. J. Angew. Chem. Int. Ed. 2000, 39, 1093. DOI: 10.1002/1521-3773(20001002)39.
DOI: 10.1002/(SICI)1521-3773(20000317)39:6<1093::AID-ANIE1093>3.0.CO;2-S. (b)
Habermann, J.; Ley, S. V.; Smits, R. Three-Step Synthesis of an Array of Substituted
Benzofurans Using Polymer-Supported Reagents. J. Chem. Soc, Perkin Trans. 1. 1999, 17,
2421. DOI: 10.1039/a904384e.
[15] Larock, R. C.; Stinn, D. E. Synthesis of Benzofurans via Palladium-Promoted Cyclization
of Ortho-Substituted Aryl Allyl Ethers. Tetrahedron Lett. 1988, 29, 4687. DOI: 10.1016/
S0040-4039(00)80581-X.
[16] Tae, J.; Kim, K. O. Synthesis of 2,3-Disubstituted Benzofurans from ortho -Acylphenols.
Synthesis. 2005, 2005, 387. DOI: 10.1055/s-2004-834951.
[17] (a) Twyman, L. J.; Allsop, D. A Short Synthesis of the b-Amyloid (Ab) Aggregation
Inhibitor 3-p-Toluoyl-2-[40-(3-Diethylaminopropoxy)-Phenyl]-Benzofuran. Tetrahedron
Lett. 1999, 40, 9383. DOI: 10.1016/S0040-4039(99)02030-4. (b) Ziegert, R. E.; Torang, J.;
Knepper, K.; Brase, S. The Recent Impact of Solid-Phase Synthesis on Medicinally
Relevant Benzoannelated Oxygen Heterocycles. J. Comb. Chem. 2005, 7, 147. DOI:

R
SYNTHETIC COMMUNICATIONSV
11
10.1021/cc049879v. (c) Zeni, G.; Larock, R. C. Synthesis of Heterocycles via Palladium-
Catalyzed Oxidative Addition. Chem. Rev. 2006, 106, 4644. DOI: 10.1021/cr0683966.(d)
Boswell, D. E.; Landis, P. S.; Givens, E. N.; Venuto, P. B. Catalytic Synthesis of
Benzofuran. Ind. Eng. Chem. Prod. Res. Dev. 1968, 7, 215. DOI: 10.1021/i360027a012. (e)
Kozikowski, A. P.; Ma, D.; Du, L.; Lewin, N. E.; Blumberg, P. M. Effect of Alteration of
the Heterocyclic Nucleus of Indolactam V on Its Isoform Selectivity for PKC. Palladium-
Catalyzed Route to Benzofuran Analogs of ILV. J. Am. Chem. Soc. 1995, 117, 6666. DOI:
10.1021/ja00130a003. (f) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. Gold Catalysis: On the
Phenol Synthesis. Org. Lett. 2001, 3, 3769. DOI: 10.1021/ol016734d. (g) Carril, M.;
SanMartin, R.; Tellitu, I.; Dominguez, E. On-Water Chemistry: Copper-Catalyzed
Straightforward Synthesis of Benzo[b]Furan Derivatives in Neat Water. Org. Lett. 2006, 8,
1467. DOI: 10.1021/ol060274c.
[18] Yang, L. Y.; Chang, C. F.; Huang, Y. C.; Lee, Y. J.; Hu, C. C.; Tseng, T. H. The First Total
Synthesis of Kynapcin-24 by Palladium Catalysis. Synthesis. 2009, 7, 1175. DOI: 10.1055/s-
0028-1087998.
[19] (a) Kim, S. I.; Park, I. H.; Song, K. S. Kynapcin-13 and -28, New Benzofuran Prolyl
Endopeptidase. Inhibitors from Polyozellus multiplex. J. Antibiot. 2002, 7, 623. DOI:
10.1002/chin.200301211. (b) Song, K. S.; Raskin, I. A Prolyl Endopeptidase-Inhibiting
Benzofuran Dimer from Polyozellusmultiflex. J. Nat. Prod. 2002, 65, 76. DOI: 10.1021/
np010194b.
[20] Bakunova, S. M.; Bakunov, S. A.; Wenzler, T.; Barszcz, T.; Werbovetz, K. A.; Brun, R.;
Hall, J. E.; Tidwell, R. R. Synthesis and in Vitro Antiprotozoal Activity of Bisbenzofuran
Cations. J. Med. Chem. 2007, 50, 5807. DOI: 10.1021/jm0708634.
[21] Kirilmis, C.; Koca, M.; C¸ukurovali, A.; Ahmedzade, M.; Kazaz, C. Synthesis, Reactivity
and Biological Activity of Novel Bisbenzofuran-2-yl-Methanone Derivatives. Molecules.
2005, 10, 1399. DOI: 10.3390/10111399.
[22] Janosik, T.; Bergman, J.; Stensland, B.; Stålhandske, C. Thionation of Bisindole Derivatives
with P4S10 or Elemental Sulfur. J. Chem. Soc, Perkin Trans. 1. 2002, 0, 330. DOI:
10.1039/b109840c.
ꢀ
[23] Benincori, T.; Brenna, E.; Sannicolo, F.; Trimarco, L.; Antognazza, P.; Cesarotti, E.;
Demartin, F.; Pilati, T. New Class of Chiral Diphosphine Ligands for Highly Efficient
Transition Metal-Catalyzed Stereoselective Reactions: The Bis(Diphenylphosphino) Five-
Membered Biheteroaryls. J. Org. Chem. 1996, 61, 6244. DOI: 10.1021/jo960211f.
[24] (a) Gribble, G. W.; Berthel, S. J. In: Studies in Natural Products Chemistry; Atta-ur-
Rahman, Ed. Elsevier: New York, 1993; Vol. 12, pp 365. (b) Pindur, U.; Kim, Y. S.;
Mehrabani, F. Advances in Indolo[2,3-a]Carbazole Chemistry: Design and Synthesis of
Protein Kinase C and Topoisomerase I Inhibitors. Curr. Med. Chem. 1999, 6, 29. DOI:
10.1002/chin.199918300. (c) Ito, S. A Chemist’s View of Melanogenesis. Pigment Cell Res.
2003, 16, 230. DOI: 10.1034/j.1600-0749.2003.00037.x. (d) Lather, V.; Kristam, R.; Saini,
J. S.; Kristam, R.; Karthikeyan, N. A.; Balaji, V. N. QSAR Models for Prediction of
Glycogen Synthase Kinase-3b Inhibitory Activity of Indirubin Derivatives. QSAR Comb.
Sci. 2008, 27, 718. DOI: 10.1002/qsar.200730052.
[25] (a) Greci, L.; Tommasi, G.; Astolfi, P.; Petrucci, R.; Marrosu, G.; Trazza, A.; Sgarabotto,
P.; Righi, L. Radical cations: reactions of 2-phenylindole with aromatic amines under
anodic oxidation. b-Scission of an amino alkoxy radical. J. Chem. Soc, Perkin Trans. 2.
2000, 2, 1749. DOI: 10.1039/a909035e. (b) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.;
Parisi, L. M. Palladium-Catalyzed Reaction of o -Alkynyltrifluoroacetanilides with 1-
Bromoalkynes. An Approach to 2-Substituted 3-Alkynylindoles and 2-Substituted 3-
Acylindoles. J. Org. Chem. 2005, 70, 6213. DOI: 10.1021/jo050517z.(c) Cacchi, S.; Fabrizi,
G.; Lamba, D.; Marinelli, F.; Parisi, L. M. 2-Substituted 3-Aryl- and 3-Heteroarylindoles
by the Palladium-Catalyzed Reaction of o-Trifluoroacetanilides with Aryl Bromides and
Triflates. Synthesis. 2003, 5, 728. DOI: 10.1055/s-2003-38079.

12
P. UMAREDDY AND V. R. ARAVA
[26] Desarbre, E.; Bergman, J. Synthesis of Symmetric and Non-Symmetric Indolo[2,3-
c]Carbazole Derivatives: preparation of Indolo[2,3-c]Pyrrolo[3,4-a]Carbazoles. J. Chem.
Soc, Perkin Trans. 1. 1998, 2009. DOI: 10.1039/a802852d.
[27] Duong, H. A.; Chua, S.; Huleatt, P. B.; Chai, C. L. L. Synthesis of Biindolyls via
Palladium-Catalyzed Reactions. J. Org. Chem. 2008, 73, 9177. DOI: 10.1021/jo801846b.
[28] (a) Sart, D. R.; Fagnou, K. The Catalytic Cross-Coupling of Unactivated Arenes. Science.
2007, 316, 1172. DOI: 10.1126/science.1141956. (b) Hull, K. L.; Sanford, M. S. Catalytic
and Highly Regioselective Cross-Coupling of Aromatic C ꢁ H Substrates. J. Am. Chem.
Soc. 2007, 129, 11904. DOI: 10.1021/ja074395z. (c) Seregin, I. V.; Ryabova, V.; Gevorgyan,
V. Direct Palladium-Catalyzed Alkynylation of N-Fused Heterocycles. J. Am. Chem. Soc.
2007, 129, 7742. DOI: 10.1021/ja072718l. (d) Lewis, J. C.; Bergman, R. G.; Ellman, J. A.
Direct Functionalization of Nitrogen Heterocycles via Rh-Catalyzed C ꢁ H Bond
Activation. Acc. Chem. Res. 2008, 41, 1013. DOI: 10.1021/ar800042p. (e) Kakiuchi, F.;
Murai, S. Catalytic C ꢁ H/Olefin Coupling. Acc. Chem. Res. 2002, 35, 826. DOI: 10.1021/
ar960318p. (f) Alberico, D.; Scott, M. E.; Lautens, M. Aryl ꢁ Aryl Bond Formation by
Transition-Metal-Catalyzed Direct Arylation. Chem. Rev. 2007, 107, 174. DOI: 10.1021/
cr0509760. (g) Roy, A. H.; Lenges, C. P.; Brookhart, M. Scope and Mechanism of the
Intermolecular Addition of Aromatic Aldehydes to Olefins Catalyzed by Rh(I) Olefin
Complexes. J. Am. Chem. Soc. 2007, 129, 2082. DOI: 10.1021/ja066509x.
[29] Mikolos, N.; Aron, P.; Andrea, V.; Istvan, B.; Laszlo, T. Synthesis of benz[5,6]azepino[4,3-
b]indoles by 1,7-electrocyclisation of azomethine ylides. Tetrahedron Lett. 2005, 46, 377.
DOI: 10.1016/j.tetlet.2004.11.127.
[30] Niu, T.; Zhang, Y. Iron-Catalyzed Oxidative Homo-Coupling of Indoles via C–H
Cleavage. Tetrahedron Lett. 2010, 51, 6847–6851. DOI: 10.1016/j.tetlet.2010.10.088.
[31] Kim, I.; Choi, J. A Versatile Approach to Oligostilbenoid Natural Products – Synthesis of
Permethylated Analogues of Viniferifuran, Malibatol A, and Shoreaphenol. Org. Biomol.
Chem. 2009, 7, 2788. DOI: 10.1039/b901911a.
[32] Zhang, W.; Sun, X.; Xia, P.; Huang, J.; Yu, G.; Wong, M. S.; Liu, Y.; Zhu, D. Novel
Butterfly-Shaped Fused Heteroacenes: Synthesis, Properties, and Device Performance of
Solution-Processed Field-Effect Transistors. Org. Lett. 2012, 14, 4382–4385. DOI: 10.1021/
ol301852m.
[33] Black, H. T.; Liu, S.; Sheares Ashby, V. Synthesis, Crystal Structures, and Electronic
Properties of Nonlinear Fused Thienoacene Semiconductors. Org. Lett. 2011, 13,
6492–6495. DOI: 10.1021/ol202662s.
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[34] Wirtanen, T.; Makela, M. K.; Sarfraz, J.; Ihalainen, P.; Hietala, S.; Melchionna, M.; Helaja,
J. Carbocatalysed Oxidative Csp2Csp2 Homocouplings of Benzo-Fused Heterocycles. Adv.
Synth. Catal. 2015, 357, 3718–3726. DOI: 10.1002/adsc.201500664.