A simple and efficient synthesis of 2,3-diarylnaphthofurans using sequential hydroarylation/Heck oxyarylation

Article abstract of DOI:10.1021/ol400738r

An efficient and simple strategy has been developed for the synthesis of 2,3-diarylnaphthofurans using sequential hydroarylation of naphthols and alkynes in the presence of In(OTf)₃ under microwave irradiation followed by one-pot Heck-oxyarylat

Full text of DOI:10.1021/ol400738r

ORGANIC
LETTERS
2013
Vol. 15, No. 9
2190–2193
A Simple and Efficient Synthesis of
2,3-Diarylnaphthofurans Using Sequential
Hydroarylation/Heck Oxyarylation
V. Kameshwara Rao,† Ganesh M. Shelke,† Rakesh Tiwari,‡
Keykavous Parang,*,‡ and Anil Kumar*,†
Department of Chemistry, Birla Institute of Technology and Science, Pilani, Pilani-333
031, Rajasthan, India, and Department of Biomedical and Pharmaceutical Sciences,
College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881,
United States
anilkumar@pilani.bits-pilani.ac.in; kparang@uri.edu
Received March 19, 2013
ABSTRACT
An efficient and simple strategy has been developed for the synthesis of 2,3-diarylnaphthofurans using sequential hydroarylation of naphthols
and alkynes in the presence of In(OTf)3 under microwave irradiation followed by one-pot Heck-oxyarylation of generated 1-substituted-R-hydroxy
styrenes.
Benzofurans and naphthofurans are important classes
of heterocyclic compounds that are present as key struc-
tural motifs in many natural products, as well as in
synthetic pharmaceutical compounds.1,2 The biological
significance of these motifs has been clearly exemplified
by natural products and synthetic compounds, such as
Furomollugin,3 Viniferifuran,4 Anigopreissin A,5 and
7-methoxy-2-nitronaphtho[2,1-b]furan (R7000)6 (Figure 1).
Naphthofuran is a powerful paradigm in the development
and design of potentially active compounds for anticancer,1
regulators of the nuclear receptor HNF4R,7 and imaging
agents for β-amyloid plaques in the brain.8
† Birla Institute of Technology and Science.
‡ University of Rhode Island.
Figure 1. Structure of bioactive benzofuran and naphthofurans.
(1) Srivastava, V.; Negi, A. S.; Kumar, J. K.; Faridi, U.; Sisodia,
B. S.; Darokar, M. P.; Luqman, S.; Khanuja, S. P. S. Bioorg. Med. Chem.
Lett. 2006, 16, 911–914.
(2) Tatum, J. H.; Baker, R. A.; Berry, R. E. Phytochemistry 1987, 26,
2499–2500.
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1999, 37, 46–49.
Considerable attention has been directed toward the
synthesis of compounds with the benzofuran and
naphthofuran framework because of their remarkable
biological activities.9ꢀ16 Acardi et al. described the first
(4) Ito, J.; Takaya, Y.; Oshima, Y.; Niwa, M. Tetrahedron 1999, 55,
2529–2544.
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Choppin, S.; Colobert, F. Eur. J. Org. Chem. 2012, 188–192.
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Carcinogenesis 1986, 7, 1447–1450.
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Ed. 2012, 51, 3220–3224.
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(12) Prasada Rao Lingam, V. S.; Dahale, D. H.; Mukkanti, K.;
Gopalan, B.; Thomas, A. Tetrahedron Lett. 2012, 53, 5695–5698.
ꢀ
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S.; Bondon, A.; Barath, P.; Simonneaux, G.; Salbert, G. Bioorg. Med.
Chem. 2009, 17, 7021–7030.
r
10.1021/ol400738r
Published on Web 04/15/2013
2013 American Chemical Society

palladium-catalyzed intramolecular cyclization of aryl-
substituted alkynes possessing a hydroxyl group at the
ortho-position to the triple bond for the synthesis of 2,3-
diarylbenzofuran.17 Since then transition metal catalyzed
coupling/cyclization of suitably functionalized alkynes as
starting materials has been the focus for the synthesis of
2,3-diarylbenzofurans and 2,3-diarylnaphthofurans.18ꢀ21
A number of methods have been developed for the syn-
thesis of 2,3-diarylbenzofurans, but synthetic routes for
naphthofurans are limited11,14 and the synthesis of diver-
sified naphthofurans still presents a major challenge in
organic synthesis.
Encouraged by the illustrated biological and synthetic
interest in 1,2-diarylnaphtho[2,1-b]furans and prompted
by the recent results for metal catalyzed CꢀH activation
reactions, we envisaged a novel synthetic pathway to
2,3-diarylnaphthofurans starting from 2-naphthols (1),
aryl alkynes (2), and haloarenes (4). It was expected that
hydroarylation of 2 with 1 in the presence of Lewis acids will
generate R-hydroxy styrenes (3).22ꢀ27 Heck-oxyarylation of
3 with 4 will afford the desired 2,3-diarylnaphthofurans
(Scheme 1). We report herein a simple and efficient method
for the synthesis of 2,3-diarylnaphthofurans by sequential
hydroarylation/Heck-oxyarylation. To the best of our
knowledge, this is the first report of the synthesis of
diversified diarylnaphthofurans using sequential diarylation
reactions.
In our initial investigation, 2-naphthol (1a), phenylace-
tylene (2a), and iodobenzene (4a) were used as substrates
to form 2,3-diphenylnaphthofuran (5a) using Yb(OTf)3
as a catalyst for hydroarylation and Pd(OAc)2 for in situ
Heck-oxyarylation. This strategy was unsuccessful since
hydroarylation did not happen under these conditions.
Thus, first the reaction conditions for hydroarylation of 2a
with 1a to give 1-(1-phenylvinyl)naphthalen-2-ol (3a) were
optimized using different Lewis acid catalysts (Table 1).
Among the different metal triflates screened, Cu(OTf)2,
Sc(OTf)3, and Bi(OTf)3 afforded 3a in good to moderate
yields (30ꢀ81%, Table 1, entries 7ꢀ9). In the case of
Cu(OTf)2, the homocoupled product of 2a was also ob-
tained in 30% yield along with 3a. An excellent yield of 3a
(91%) was obtained by the use of In(OTf)3 (10 mol %)
under microwave irradiation in toluene (Table 1, entry 10).
Table 1. Optimization of Hydroarylation Conditions for 3a
mol
(%)
time
yielda
(%)
entry
catalyst
(min)
solvent
b,c
1
Yb(OTf)3
Y(OTf)3
10
10
10
10
10
10
10
10
10
10
10
5
40
40
40
40
40
40
40
40
40
40
20
40
20
20
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
ACN
ꢀ
2
trace
b
3
Ce(OTf)3
Ln(OTf)3
Gd(OTf)3
Zn(OTf)2
Cu(OTf)2
Sc(OTf)3
Bi(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
In(OTf)3
ꢀ
4
trace
10
5
6
trace
30
7
8
81
9
59
10
11
12
13
14
91 (76)c
66
Scheme 1. Retrosynthetic Analysis of 1,2-Diarylnaphthofurans
61
10
10
79
THF
71
a Isolated yield after MW irradiation for 40 min at 120 °C. b No
product was formed. c Thermal heating under reflux conditions for 10 h.
It is noteworthy to mention that when the hydroxyl
group of naphthol was converted to methoxy and acetoxy,
hydroarylation did not occur to give the corresponding
1-substituted-R-hydroxy styrene. It is expected that the
hydroarylation reaction proceeds through the mechanism
as proposed in literature.23,28
(13) Sakiyama, N.; Noguchi, K.; Tanaka, K. Angew. Chem., Int. Ed.
2012, 51, 5976–5980.
(14) Nicolaou, K. C.; Snyder, S. A.; Bigot, A.; Pfefferkorn, J. A.
Angew. Chem., Int. Ed. 2000, 39, 1093–1096.
(15) Hashmi, A. S. K.; Yang, W.; Rominger, F. Angew. Chem., Int.
Ed. 2011, 50, 5762–5765.
(16) Hashmi, A. S. K.; Yang, W.; Rominger, F. Chem.;Eur. J. 2012,
18, 6576–6580.
Following the optimized reaction conditions for the
hydroarylation, 1a and 7-methoxynaphthol (1b) were hy-
droarylated with different 4-substituted phenylacetylenes
(2aꢀc) in the presence of In(OTf)3 to give the correspond-
ing 1-substituted-R-hydroxy styrenes (3aꢀf) in high yields
(85ꢀ95%, Table 2).
(17) Arcadi, A.; Cacchi, S.; Del Rosario, M.; Fabrizi, G.; Marinelli,
F. J. Org. Chem. 1996, 61, 9280–9288.
(18) Colobert, F.; Castanet, A.-S.; Abillard, O. Eur. J. Org. Chem.
2005, 3334–3341.
(19) Bates, C. G.; Saejueng, P.; Murphy, J. M.; Venkataraman, D.
Org. Lett. 2002, 4, 4727–4729.
(20) G. Kundu, N.; Pal, M.; S. Mahanty, J.; De, M. J. Chem. Soc.,
Perkin Trans. 1 1997, 2815–2820.
The structures of 3aꢀf were confirmed by NMR and
high-resolution mass spectrometry (HRMS) (Supporting
Information). Vinylic CH2 protons for 3a resonated at δ
6.35 and 5.53 with a splitting constant of 1.5 Hz, and
the phenolic proton resonated at δ 5.61 as a singlet in the
1H NMR spectra. In the 13C NMR, a total of 16 carbons
(21) Larock, R. C.; Yum, E. K.; Doty, M. J.; Sham, K. K. C. J. Org.
Chem. 1995, 60, 3270–3271.
(22) Yamaguchi, M.; Hayashi, A.; Hirama, M. J. Am. Chem. Soc.
1995, 117, 1151–1152.
(23) J S Yadav, B. V. S. R. Synthesis 2009, 1301–1304.
(24) Yamaguchi, M.; Arisawa, M.; Omata, K.; Kabuto, K.; Hirama,
M.; Uchimaru, T. J. Org. Chem. 1998, 63, 7298–7305.
(25) Sarma, R.; Prajapati, D. Chem. Commun. 2011, 47, 9525–9527.
(26) Casiraghi, G.; Casnati, G.; Puglia, G.; Sartori, G.; Terenghi, G.
Synthesis 1977, 122–124.
(27) Mendoza, P. D.; Echavarren, A. M. Pure Appl. Chem. 2010, 82,
801–820.
(28) Yoon, M. Y.; Kim, J. H.; Choi, D. S.; Shin, U. S.; Lee, J. Y.;
Song, C. E. Adv. Synth. Catal. 2007, 349, 1725–1737.
Org. Lett., Vol. 15, No. 9, 2013
2191

appeared, which is as expected for the structure of 3a, and
a peak at 247.1126 for the [M þ H]þ ion in HRMS spectra
further confirmed the structure of 3a.
Table 3. Optimization of Heck-Oxyarylation Conditions for 5aa
yield
entry
catalyst
ligand
base
solvent
DMA
(%)b
Table 2. Synthesis of 1-Vinylnaphtholsa
1
Pd(OAc)2
Pd(OAc)2
PdCl2
ꢀ
Cs2CO3
18
2
PPh3
Cs2CO3 DMA
72
27
time
yield
(%)b
3
PPh3
Cs2CO3
Cs2CO3
Cs2CO3
KOH
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
entry
R1
R2
product
(min)
4
Pd(PPh3)2Cl2 PPh3
59
5
Pd(dba)2
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(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(dppf)Cl2
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Phenc
biPyd
(Tol)3P
TFPe
TCPf
64
1
2
3
4
5
6
H
H
H
H
3a
3b
3c
3d
3e
3f
40
40
30
35
35
30
91
92
95
86
85
86
6
15
4-CH3
4-OCH3
H
7
Et3N
trace
50
8
K2CO3
tBuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
7-OCH3
7-OCH3
7-OCH3
9
64
4-CH3
4-OCH3
10
11
12
13
14
15
16
17
18
48
Toluene 35
a Reaction conditions: 1 (1.39 mmol), 2 (1.66 mmol), In(OTf)3 (78 mg,
10 mol %), toluene (2 mL), MW at 120 °C, 30 psi. b Isolated yield.
DMA
DMA
DMA
DMA
DMA
DMA
DMA
50
30
55
62
55
52
20
Next, the reaction conditions were standardized for
a one-pot sequential palladium-catalyzed cross-coupling
reaction and oxyarylation (Heck-oxyarylation) of 1-sub-
stituted-R-hydroxy styrenes (3) with haloarenes (4) to
afford the desired 2,3-disubstituted naphthofurans. The
model reaction performed with 3a using iodobenzene (4a)
in the presence of Pd(OAc)2 (5 mol %) and potassium
carbonate (2 equiv) in N,N-dimethylacetamide (DMA)
resulted in an 18% yield of 1,2-diphenylnaphtho[2,1-b]-
furan (5a) after 14 h at 140 °C. When triphenylphosphine
(PPh3) was used as a ligand in the above reaction, in
contrast to our earlier result, 5a was obtained in 50% yield.
Further optimization of the reaction conditions using
different palladium catalysts, ligands, bases, and solvents
(Table 3) led to improvement in the yield of 5a. The highest
yield of 5a (72%, entry 2) was obtained by using Pd(OAc)2
(5 mol %) in the presence of PPh3 and Cs2CO3 in DMA.
The yield of 5a was moderate to good (27ꢀ64%) with
other palladium catalysts such as PdCl2, Pd(PPh3)2Cl2,
Pd(dba)2, and Pd(dppf)Cl2 (Table 3, entries 2ꢀ4, 18).
The synthetic merit of the method was demonstrated by
varying the substrates for the reaction (Table 4). Various
haloarenes and R-hydroxy styrenes containing electron-
donating or -withdrawing groups could be used for
this reaction satisfactorily. For example, 1-(1-(4-methoxy-
phenyl)vinyl)-naphthalen-2-ol (3c) reacted with 4a to
give 5b in 68% yield (Table 4, entry 2) and 7-methoxy-
1-(1-(4-methoxyphenyl)vinyl)-naphthalen-2-ol (3f) reacted
with 4a to afford 5k in 65% yield (Table 4, entry 11).
Reaction of 3a with 4-nitroiodobenzene afforded corre-
sponding naphthofuran 5i in 51% yield (Table 4, entry 9).
The structures of all the synthesized 2,3-diarylnaphthofurans
(5aꢀn) were established by IR, NMR (1H and 13C), and
mass spectrometry data (Supporting Information). In the 1H
NMR of 5a, the peak for the vinylic methylene protons and
the phenolic proton of 3a disappeared, and only the signal
for the aromatic protons was observed. Similarly, in the IR
spectrum no peak was observed for the phenolic OH group.
The sequential hydroarylation/Heck-oxyarylation was
not limited to naphthol derivatives and was also applied to
the synthesis of 2,3-diarylbenzofurans from electron-rich
DMEDAg Cs2CO3
PPh3 Cs2CO3
h
a Reaction conditions: Catalyst (5 mol %), Ligand (10 mol %),
Base (2 equiv), Solvent (5 mL), 140 °C, 14 h. b Isolated yield. c Phen =
d
1,10-phenanthroline. biPy = 2,20-bipyridine. e TFP = Tri(2-furyl)-
phosphine. f TCP = Tricyclohexylphosphine. g DMEDA = N,N-Di-
methylethylenediamine (5 mol %). h Pd(dppf)Cl2
(diphenylphosphino)ferrocene]dichloropalladium(II), complex with DCM.
=
[1,10-Bis-
Table 4. Synthesis of 2,3-Diarylnaphthofuransa
time yieldb
entry
R1
R2
R3
product
(h)
(%)
1
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5a
5b
5c
5d
5e
5f
14
12
14
12
14
14
11
14
14
14
10
10
11
11
72
68
57
72
53
50
52
51
41
36
65
62
56
39
2
4-OCH3
4-CH3
H
3
4
4-OCH3
4-CH3
4-CH3
5
H
6
4-CH3
7
4-OCH3 4-CH3
5g
5h
5i
8
H
H
H
2-CH3
4-NO2
2,3-C4H4
H
9
10
11
12
13
14
5j
7-OCH3 4-OCH3
5k
5l
7-OCH3 4-OCH3 4-CH3
7-OCH3
H
4-CH3
4-CH3
5m
5n
7-OCH3 4-CH3
a Reaction conditions: 3 (0.81 mmol), 4 (0.975 mmol), Pd(OAc)2
(0.04 mmol), Ph3P (0.081 mmol), Cs2CO3 (1.63 mmol), DMA (5 mL),
140 °C, 14 h. b Isolated yield.
phenols. Indeed, this catalytic system also proved viable
with 4-methoxyphenol (6). The reaction of 6 with 2a
using In(OTf)3 under microwave irradiation for 10 min
gave the corresponding R-hydroxystyrene (4-methoxy-
2-(1-phenylvinyl)phenol, 7) in 68% yield. The structure
of 7 was elucidated by IR, 1H NMR, 13C NMR, and mass
spectrometry. In the IR, a peak for the phenolic OH group
appeared in the region 3417ꢀ3525 cmꢀ1. In the 1H NMR,
the peak for the vinylic and phenolic protons appeared at
2192
Org. Lett., Vol. 15, No. 9, 2013

Scheme 2. Synthesis of 5-Methoxy-2,3-diphenylbenzofuran
Scheme 3. Tentative Proposed Mechanism for the
Heck-Oxyarylationa
a For clarity the ligands for Pd are omitted.
of alkene gives a five-membered oxygen-coordinated
palladium(II) complex (10). Thisintermediateonβ-hydride
elimination gives an intermediate with OPd(II)H (11).
Figure 2. ORTEP diagram of 8.
Intramolecular addition of the alkene of 11 to OPd(II)
H
givesthe six membered oxygen-coordinated Pd(II) complex
(12). Reductive elimination of 12 gives a tetrahydrofuran
derivative (13). Subsequent oxidation of 13 results in the
formation of naphthofuran (5)/benzofuran (8).
In conclusion, 2,3-diarylnaphthofurans were synthe-
sized by an efficient and general synthetic strategy in good
to high yields from easily available naphthols, alkynes, and
iodoarenes. An interesting feature of the method is that
it accommodates functional groups amenable to further
manipulation and with a rapid increase in molecular
complexity. Further studies are ongoing in our laboratory
to expand the synthetic utility of this versatile catalytic
system.
5.41 and 5.85 ppm as doublets and at 4.79 ppm as a singlet,
respectively. The reaction of 7 with 4a in the presence of
Pd(OAc)2 (5 mol %), PPh3, and Cs2CO3 gave 5-methoxy-
2,3-diphenylbenzofuran (8) in 75% yield (Scheme 2).
The structure of 8 was unambiguously elucidated by
1
spectroscopic analysis. The H NMR spectrum showed
only one singlet in the aliphatic region at 3.80 ppm for the
OCH3 group, and the integration for the aromatic region
was inaccordancewith the required13aromaticprotons of
8. The presence of a peak at 55.98 ppm of the OCH3 group,
along with another 16 carbons peaks in the 13C NMR and
the molecular ion peak at 323.1065 for the [M þ Na]þ ion
in the HRMS, confirmed the structure of 8. The structure
of 8 was further independently confirmed by an X-ray
crystal structure (CCDC 923801) (Figure 2). The two
aryl rings generate steric strain, and they are oriented in
different planes.
Based on the structure of the product obtained and
literature reports,29,30 the mechanism of the reaction is
tentatively proposed as shown in Scheme 3. It is expected
that initially 3 reacts with ArꢀPdꢀI to form an oxygen-
coordinated Pd(II)-aryl complex (9) which on insertion
Acknowledgment. The authors thank DST-FIST for
the focused microwave and UGC, New Delhi for financial
support via Grant No. 39-733/2010 (SR). V.K.R. thanks
CSIR, New Delhi for senior research fellowships.
Supporting Information Available. Experimental pro-
1
cedure, characterization data, and copies of the H and
13C NMR of the synthesized compounds 3, 5, 7, and 8.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(29) Zhu, C.; Falck, J. R. Angew. Chem., Int. Ed. 2011, 50, 6626–6629.
(30) Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Iazzetti, A.; Madec, D.;
Poli, G.; Prestat, G. Org. Biomol. Chem. 2011, 9, 8233–8236.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 9, 2013
2193