Efficient one-pot synthesis of 2-arylbenzo[b]furans from 2-styrylphenols using CuBr2

Article abstract of DOI:10.1080/00397910903318716

A new route to the synthesis of 2-arylbenzo[b]furans has been developed. It involves homo/cross-McMurry coupling of salicylaldehyde/substituted salicylaldehydes/aromatic aldehydes to 2-styrylphenols, which undergo intramolecular cyclization with CuBr

Full text of DOI:10.1080/00397910903318716

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Efficient One-Pot Synthesis of 2-
Arylbenzo[b]furans from 2-Styrylphenols
Using CuBr2
Suchitra Bhatt a , Kshama Roy a & Sandip K. Nayak a
a Bio-organic Division, Bhabha Atomic Research Centre , Mumbai,
India
Published online: 09 Aug 2010.
To cite this article: Suchitra Bhatt , Kshama Roy & Sandip K. Nayak (2010) Efficient One-Pot
Synthesis of 2-Arylbenzo[b]furans from 2-Styrylphenols Using CuBr2 , Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:18, 2736-2746,
DOI: 10.1080/00397910903318716
To link to this article: http://dx.doi.org/10.1080/00397910903318716
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Synthetic Communications1, 40: 2736–2746, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903318716
EFFICIENT ONE-POT SYNTHESIS OF
2-ARYLBENZO[b]FURANS FROM
2-STYRYLPHENOLS USING CuBr2
Suchitra Bhatt, Kshama Roy, and Sandip K. Nayak
Bio-organic Division, Bhabha Atomic Research Centre, Mumbai, India
A new route to the synthesis of 2-arylbenzo[b]furans has been developed. It involves
homo/cross-McMurry coupling of salicylaldehyde/substituted salicylaldehydes/aromatic
aldehydes to 2-styrylphenols, which undergo intramolecular cyclization with CuBr2 in tetra-
hydrofuran at ambient temperature to afford 2-arylbenzo[b]furans in good yields.
Keywords: 2-Arylbenzo[b]furan; 2-styrylphenols; copper(II) bromide; McMurry coupling
INTRODUCTION
The benzo[b]furan motif is prevalent in a wide variety of biologically active
natural and manmade compounds.[1] Many 2-arylbenzo[b]furan derivatives exhibit
a broad range of biological activities including anticancer,[2] antiviral,[3] immuno-
suppressive,[4] antioxidative,[5] and anti-inflammatory[6] properties. This has led to
efforts to synthesize this class of compounds. A number of routes leading to differ-
ently substituted benzo[b]furans have been described in the literature, including
palladium-catalyzed annulations of 2-allyl-phenols and o-hydroxyarylacetylenes,[7,8]
palladium-catalyzed one-pot annulations of 2-hydroxyaryl iodides with alkynes,[9]
dehydrative cylization of a-phenoxyketones,[10] ring closure of 2-halo aromatic
ketones,[11] and intramolecular oxidative cyclization of 2-vinylphenols.[12] Some of
these methods involved multistep synthesis or are limited to a particular class of sub-
strate, use of expensive catalysts, and=or do not tolerate a variety of functional
groups. Therefore, there is still scope to develop a simple and convenient protocol
for the synthesis of benzo[b]furans. Herein, we report a novel and convenient proto-
col for the synthesis of 2-arylbenzo[b]furans from 2-styrylphenols in one pot using
CuBr2 at ambient temperature (Scheme 1).
RESULTS AND DISCUSSION
Earlier, synthesis of 2-aryl-3-alkylbenzo[b]furans by low-valent titanium (LVT)
reagent–mediated intramolecular reductive deoxygenation of ortho-aroyloxyacetophenones
Received July 2, 2009.
Address correspondence to Sandip K. Nayak, Bio-organic Division, Bhabha Atomic Research
Centre, Mumbai 400085, India. E-mail: sknayak@barc.gov.in
2736

SYNTHESIS OF BENZO[b]FURANS
2737
Scheme 1. Intramolecular oxidative cyclization of 2-styryl phenols to benzo[b]furans with CuBr2.
was reported from our laboratory.[13] However, reaction of ortho-aroyloxybenzalde-
hyde with LVT failed to yield to 2-arylbenzo[b]furans under identical reaction
conditions (Scheme 2), the cause of which is not clear to us. This prompted us to
develop an alternate convenient protocol for the synthesis of 2-aryl-benzo[b]furans.
Alkenes are known to undergo bromination to their dibromides with CuBr2
(probably by the generation of bromine through disproportionation of CuBr2 to
CuBr and Br2).[14] We observed facile bromination of stilbene to dibromostilbene
in excellent yield (82%) with CuBr2 in acetonitrile at ambient temperature. Keeping
this in mind, we felt that the use of 2-styrylphenols (3) as a substrate for bromination
with CuBr2 may lead to the formation of 2-aryl-3-bromo-dihydrobenzofuran (5) by
the intramolecular nucleophilic addition of the sterically close phenolic OH group to
the unstable three-membered bromonium ion (4) formed during bromination of the
stilbene double bond. The intermediate 5, in principle, can be dehydrobrominated
with base to 2-arylbenzo[b]furan (6) (Scheme 3). To this end, (E)-1,2-bis-(2-hydroxy-
phenyl)ethene (3a) was prepared via LVT reagent–mediated reductive deoxygenation
(McMurry coupling) of 2-hydroxybenzaldehyde (1; R1 ¼ H) in good yield. Gratify-
ingly, when compound 3a was exposed to CuBr2 (2.1 equiv) in acetonitrile at ambient
temperature, a smooth reaction afforded 2-(2-hydroxyphenyl)benzo[b]furan (6a) as
the sole product in 70% yield (Table 1, entry 2). This necessarily means the formation
of the intermediate 5, which underwent in situ dehydrobromination without using any
base to afford 6a. It is important to note that use of excess of CuBr2 (5.0 equiv)
marginally improved the yield of 6a (75%) and that no nuclear brominated product
of the phenol ring of benzofuran (at C-2) was detected (Table 1, entry 3).
Scheme 2. Low-valent titanium–mediated intramolecular reductive deoxygenation of ortho-aroyloxy
aromatic aldehydes=ketones to benzo[b]furans.

2738
S. BHATT, K. ROY, AND S. K. NAYAK
Scheme 3. Proposed mechanism for the intramolecular cyclization of 2-styryl phenols to benzo[b]furans
with CuBr2.
Table 1. Optimization of reaction conditions for the conversion of 3a to 6a
Entry
Reaction conditions
Yielda (%) of 6a
1
2
CuBr2 (1.2 equiv)=ACN=rt=48 h
CuBr2 (2.1 equiv)=ACN=rt=5 h
CuBr2 (5.0 equiv)=ACN=rt=4 h
CuBr2 (2.1equiv)=ACN=reflux=3 h
CuBr2 (1.2 equiv)=THF=rt=48 h
CuBr2 (2.1 equiv)=THF=rt=4 h
29.0
70.0
75.0
70.0
47.0
74.0
78.0
72.0
—
3
4
5
6
7
CuBr2 (5.0 equiv)=THF=rt=4 h
8
CuBr2 (2.1equiv)=THF=reflux=2 h
CuCl2 (2.1 equiv)=ACN=rt=4 h
CuCl2 (2.1 equiv)=THF=rt=4 h
9
10
11
12
13
8.0
—
Cu(OAc)2 (2.1 equiv)=ACN=rt=24 h
Cu(OAc)2 (2.1 equiv)=THF=rt=24 h
CuBr2 (2.1 equiv) =ACN=KOH (2.0 equiv)=rt=16 h
—
27.0
aIsolated yield after column chromatography.
Table 2. Solvent optimization in the conversion of 3a to 6a with CuBr2 (2.1 equiv) at
ambient temperature
Entry
Solvent=time
Yielda (%) of 6a
1
2
3
4
5
6
7
CH3OH=24 h
C2H5OH=24 h
DMF=24 h
24
47
30
70
74
60
47
CH3CN=5 h
THF=4 h
DME=24 h
Ethyl acetate=24 h
aIsolated yield after column chromatography.

2739

2740

SYNTHESIS OF BENZO[b]FURANS
2741
During the screening of the various organic solvents for this transformation, it
was observed that both tetrahydrofuran (THF) and acetonitrile are equally efficient
in terms of both time and yield of the reaction (Table 2, entries 4 and 5). Moreover,
the combined effects of reagent stoichiometry, solvents, other copper(II) salts, and
temperature were also investigated (Tables 1 and 2). The best result was obtained with
CuBr2 (2.1 equiv)=THF=room temperature (rt) (Table 1, entry 6), and therefore, the
same conditions were used for all subsequent reactions. Also the use of potassium
hydroxide (KOH; for dehydrobromination) together with CuBr2 in this reaction
was found to be detrimental as evidenced by the poor yield of 6a (Table 1, entry 13).
To see the scope and limitation of this protocol, several 2-styrylphenols (3b–i)
were prepared by McMurry homo=cross-coupling of corresponding benzaldehydes
and subjected to CuBr2 in THF at ambient temperature. In all the cases, correspond-
ing benzo[b]furans (6b–i) were obtained in good yields (Table 3).
CONCLUSION
In summary, we have developed an easy and convenient protocol for the syn-
thesis of 2-arylbenzo[b]furans from 2-styrylphenols (prepared by McMurry coupling
of corresponding arylaldehydes) in one pot with CuBr2 in good yields. The present
protocol has several advantages, such as use of inexpensive reagent, experimental
simplicity, and rt reaction.
EXPERIMENTAL
Melting points were determined using a Fisher-Johns melting-point apparatus
and are uncorrected. Infrared (IR) spectra were scanned with a Jasco Fourier trans-
form (FT)–IR 4100 spectrophotometer. The 1H and 13C NMR spectra were recorded
with a Bruker AC 200 spectrometer with tetramethylsilane (TMS) as internal stan-
dard. Mass spectra (MS) were recorded with a Micromass Q-TOF micro
(YA-105) instrument. Microanalysis was performed with Carlo Erba elemental ana-
lyzer (model 1110). Aromatic aldehydes, TiCl4, and CuBr2 were purchased from
Aldrich Chemical Co. (USA) and used without further purification. All the solvents
were dried following the standard procedure. All reactions were carried out under an
argon atmosphere.
Typical Procedure for the Homo-McMurry Coupling of
2-Hydroxybenzaldehyde to (E)-1,2-Bis-(2-hydrophenyl)ethene (3a)
TiCl4 (2.5 ml, 22.5 mmol) was added slowly to a stirred suspension of Zn pow-
der (2.90 g, 45 mmol) in dry THF (80 ml) at 0 ꢀC under argon. The suspension was
warmed to ambient temperature and then refluxed for 2.5 h. The black mixture
was cooled in an ice-water bath, and a solution of 2-hydroxybenzaldehyde (1.10 g,
9 mmol) in THF (10 ml) was added. Then, the mixture was further refluxed until
the aldehyde was totally consumed (monitored by thin-layer chromatography,
TLC). The reaction mixture was cooled to ambient temperature, diluted with ethyl
acetate, and quenched with cold aqueous 10% K2CO3 solution (10 ml). The mixture
was stirred for 1 h and filtered through celite. The filtrate was washed with water and

2742
S. BHATT, K. ROY, AND S. K. NAYAK
brine and then dried (Na2SO4). Solvent was removed in vacuo to get a thick oil,
which on purification by column chromatography (silica) yielded 3a (0.782 g,
82%). Solid; mp 188–190 ꢀC; IR (KBr): n ¼ 3363, 2945, 2833, 1600, 1457, 1027cmꢁ1
;
1H NMR (200 MHz, acetone-d6): d 6.83–6.91 (m, 4H), 7.03–7.06 (m, 2H), 7.52 (s,
2H), 7.58 (d, 2H, J ¼ 7.7 Hz), 8.90 (br s, 1H, OH); 13C NMR (50 MHz, acetone-d6):
d 115.2 119.3, 122.7, 124.6, 125.7, 127.7, 154.1; EIMS: m=z ¼ 212. Physical and spec-
tral data for compounds 3b, 3d, 3e, 3f, 3 h, 3i synthesized from the same procedure
described for 3a are given next.
Physical and Spectral Data for Compounds 3b, 3d, 3e, 3f, 3h, and 3i
(E)-1,2-Bis-(5-chloro-2-hydroxyphenyl)-ethene (3b). Solid; mp 185–186 ꢀC;
IR (KBr): n ¼ 3359, 3019, 1480, 1421 cmꢁ1; 1H NMR (200 MHz, acetone-d6): d 6.91
(d, 2H, J ¼ 8.6 Hz), 7.09 (d, 2H, J ¼ 8.6 Hz), 7.50 (s, 2H), 7.59 (s, 2H), 8.91 (br s, 2H,
OH); 13C NMR (50 MHz, acetone-d6): d 117.3, 123.5, 124.3, 125.8, 126.5, 128.0,
153.6; EIMS: m=z ¼ 283.
(E)-1,2-Bis-(5-tert-butyl-2-hydroxyphenyl)ethene (3d). Solid; mp 210–211 ꢀC;
1
IR (KBr): n ¼ 3424, 2950, 1642 cmꢁ1; H NMR (200 MHz, CDCl3): d 1.29 (s, 18H),
6.81 (d, 2H, J ¼ 8.4 Hz), 7.12 (m, 2H), 7.52 (s, 2H), 7.59 (d, 2H, J ¼ 2.0 Hz), 8.49 (bs,
2H, OH); 13C NMR (50 MHz, acetone-d6): d 30.9, 33.6, 115.2, 122.9, 123.6, 124.3,
125.0, 141.9, 152.3; EIMS: m=z ¼ 324. Anal. Calcd. for C22H28O2: C, 81.44; H,
8.70. Found: C, 81.28; H, 8.58.
(E)-1,2-Bis-(2-hydroxy-5-methylphenyl)-ethene (3e). Solid; mp 215–216 ꢀC;
IR (KBr): n ¼ 3346, 2945, 2832, 1450 cmꢁ1; 1H NMR (200 MHz, acetone-d6): d 2.24
(s, 6H), 6.83 (m, 4H), 7.40 (s, 2H), 7.49 (s, 2H), 8.45 (s, 2H, OH); 13C NMR
(50 MHz, acetone-d6): d 20.0, 115.8, 123.1, 125.1, 126.6, 128.7, 128.9, 152.8; EIMS:
m=z ¼ 240.
(E)-1,2-Bis-(5-bromo-2-hydroxyphenyl)-ethene (3f). Solid; mp 201–202 ꢀC;
IR (KBr): n ¼ 3333, 3019, 2400, 1478, 1215 cmꢁ1; 1H NMR (200 MHz, acetone-d6): d
6.87 (d, 2H, J ¼ 8.6 Hz), 7.21 (dd, 2H, J ¼ 2.6 Hz, 8.6 Hz), 7.47 (s, 2H), 7.71 (d, 2H,
J ¼ 2.4 Hz), 9.12 (s, 2H, OH); 13C NMR (50 MHz, acetone-d6): d 111.5 117.7, 123.3,
127.0, 128.8, 130.8, 154.0; EIMS: m=z ¼ 372.
(E)-1,2-Bis-(2’-hydroxy-5’-methoxyphenyl)-ethene (3h). Solid; mp 215–
1
217 ꢀC; IR (KBr): n ¼ 3389, 3020, 2400, 1602, 1507, 1498, 1215 cmꢁ1; H NMR
(200 MHz, acetone-d6): d 3.75 (s, 6H), 6.66–6.86 (m, 4H), 7.16 (d, 2H, J ¼ 2.9 Hz),
7.52 (s, 2H), 8.27 (br s, 2H, OH); 13C NMR (50 MHz, acetone-d6): 55.3, 110.9,
114.6, 116.8, 123.7, 125.8, 149.1, 153.6; m=z ¼ 272.
(E)-1,2-Bis-(2’-hydroxy-5’-phenylphenyl)-ethene (3i). Solid; mp 265–
;
1H NMR (200 MHz, C5D5N): d
267 ꢀC; IR (KBr): n ¼ 3331, 3020, 1603 cmꢁ1
7.28–7.58 (m, 10H), 7.71 (d, 4H, J ¼ 7.4 Hz), 8.30 (s, 2H), 8.46 (s, 2H), 12.2 (br s,
2H, OH); 13C NMR (50 MHz, pyridine-d5): d 117.1, 124.7, 125.6, 126.7, 126.8,
126.9, 127.5, 129.2, 132.8, 141.6, 156.4; EIMS: m=z ¼ 364. Anal. Calcd. for
C26H20O2: C, 85.69; H, 5.53. Found: C, 85.50; H, 5.35.

SYNTHESIS OF BENZO[b]FURANS
2743
Typical Procedure for the Cross-McMurry Coupling Between
2-Hydroxybenzaldehyde and 3,4-Methylenedioxy Benzaldehyde to
(E)-1-(2-Hydroxyphenyl)-2-(3,4-methylenedioxyphenyl)-ethene (3c)
TiCl4 (2.7 mL, 25 mmol) was added dropwise to a stirred suspension of Zn
powder (3.3 g, 70 mmol) in dry THF (80 ml) at 0 ꢀC under argon. The suspension
was warmed to ambient temperature and then refluxed for 2.5 h. The black mixture
was cooled in an ice-water bath, and a solution of 2-hydroxybenzaldehyde (0.67 g,
5.5 mmol) and 3,4-methylenedioxy benzaldehyde (0.69 g, 4.6 mmol) in THF
(30 mL) was added dropwise. Then, the mixture was further refluxed until the alde-
hyde was consumed (monitored by TLC). The reaction mixture was cooled to ambi-
ent temperature, diluted with ethyl acetate, and quenched with cold aqueous 10%
K2CO3 solution (7 ml). The mixture was stirred for 1 h and filtered through celite.
The filtrate was washed with water and brine and then dried (Na2SO4). The solvent
was removed in vacuo to get a residue, which on purification by column chromato-
graphy yielded (E)-3c (0.66 g, 60%) and (E)-3a (0.11 g, 9%). (E)-3c: solid; mp
153–154 ꢀC; IR (KBr): n ¼ 3366, 3015, 2945, 2833, 1505, 1490, 1446 cmꢁ1
;
1H
NMR (200 MHz, DMSO-d6): d 5.85 (s, 2H), 6.70–7.00 (m, 7H), 7.18 (d, 1H,
J ¼ 16.5 Hz), 7.38 (d, 1H, J ¼ 7.4 Hz), 9.91 (br s, 1H, OH); 13C NMR (50 MHz,
acetone-d6): d 101.8, 106.0, 109.3, 116.6, 120.5, 122.0, 122.7, 124.7, 127.1, 128.5,
129.3, 133.0, 147.5, 148.6, 155.3; EIMS: m=z ¼ 240.
(E)-1-(2-Hydroxyphenyl)-2-(4-methoxyphenyl)-ethene (3g). Compound
3 g was synthesized from the same procedure described for 3c. Solid; mp
148–149 ꢀC; IR (KBr): n ¼ 3440, 1601, 1517, 1260 cmꢁ1
;
1H NMR (200 MHz,
CDCl3): d 3.82 (s, 3H), 5.10 (br s, 1H, OH), 6.77–6.92 (m, 5H), 7.01–7.26 (m,
2H), 7.41–7.48 (m, 3H).
Typical Procedure for the Synthesis of 2-(2-Hydroxyphenyl)-
benzo[b]furan (6a) from 3a with CuBr2
CuBr2 (0.94 g, 4.2 mmol) was added to a solution of 3a (0.42 g, 2 mmol) in dry
THF (10 ml) under argon and stirred at ambient temperature for 4 h. The reaction
mixture was diluted with ethyl acetate and passed through celite. The filtrate was
washed with water and brine and then dried (Na2SO4). The solvent was removed
to get a thick oil, which on purification by column chromatography (silica) yielded
6a[15] (0.311 g, 74% yield). Solid; mp 97–98 ꢀC (lit. mp 98–99 ꢀC); IR (KBr): n ¼ 3535,
1
3063, 3016, 1482, 1466, 1449 cmꢁ1; H NMR (200 MHz, CDCl3): d 6.98–7.16 (m,
3H), 7.34–7.57 (m, 5H), 7.98 (d, 1H, J ¼ 7.6 Hz); 13C NMR (50 MHz, CDCl3): d
95.3, 111.0, 114.7, 117.3, 119.8, 120.2, 123.8, 125.6, 128.4, 129.3, 131.3, 149.1,
152.6, 153.9; EIMS: m=z ¼ 210.
Physical and Spectral Data for Unknown Compounds 6d, 6e, and
6i Synthesized from the Same Procedure Described for 6a
2-(5-tert-Butylbenzofuran-2-yl)-4-tert-butylphenꢁo1l (6d). Solid; mp 113–
115 ꢀC; IR (KBr): n ¼ 3528, 3018, 2964, 2905, 2869 cm
;
1H NMR (200 MHz,
CDCl3): d 1.43 (s, 9H), 1.47 (s, 9H), 6.99 (d, 1H, J ¼ 8.6 Hz), 7.19 (br s, 1H), 7.38

2744
S. BHATT, K. ROY, AND S. K. NAYAK
(dd, 2H, J ¼ 2.4, 8.6 Hz), 7.52 (d, 1H, J ¼ 8.6 Hz), 7.67 (d, 1H, J ¼ 2.4 Hz), 7.82 (d, 1H,
J ¼ 2.4 Hz); 13C NMR (50 MHz, CDCl3): d 31.4, 31.8, 34.1, 34.6, 103.6, 110.2, 115.7,
116.7, 117.1, 122.1, 123.5, 127.2, 128.4, 143.2, 146.2, 151.1, 152.2, 154.5; EIMS: m=
z ¼ 322. Anal. calcd. for C22H26O2: C, 81.95; H, 8.13. Found: C, 81.77; H, 8.02.
2-(5-Methylbenzofuran-2-yl)-4-methylphenol (6e). Solid; mp 93 ꢀC; IR
1
(KBr): n ¼ 3529, 3019, 2924, 1599, 1497, 1216 cmꢁ1; H NMR (200 MHz, CDCl3):
d 2.35 (s, 3H), 2.47 (s, 3H), 6.91 (d, 1H, J ¼ 8.3 Hz), 7.04–7.14 (m, 3H), 7.41 (d,
2H, J ¼ 9.0 Hz), 7.54 (d, 1H, J ¼ 1.7 Hz); 13C NMR (50 MHz, CDCl3): d 20.4,
21.2, 103.0, 110.4, 115.8, 117.1, 120.7, 125.5, 127.1, 128.7, 129.7, 130.7, 132.7,
151.1, 152.3, 154.4; EIMS: m=z ¼ 238. Anal. calcd. for C16H14O2: C, 80.65; H,
5.92. Found: C, 80.82; H, 5.74.
2-(5-Phenylbenzofuran-2-yl)-4-phenylphenol (6i). Solid; mp 125–126 ꢀC;
1
IR (KBr): n ¼ 3525, 3018, 1463, 1215 cmꢁ1; H NMR (200 MHz, CDCl3): d 7.08 (d,
1H, J ¼ 8.5 Hz), 7.24 (s, 1H), 7.38–7.69 (m, 13H), 7.81 (m, 1H), 8.02 (d, 1H, J ¼ 2.2 Hz);
;
13C NMR (50 MHz, CDCl3): d 104.2, 111.1, 116.5, 117.7, 119.5, 124.2, 125.7, 126.8,
127.0, 127.4, 128.8, 129.2, 134.1, 137.1, 140.4, 141.5, 152.9, 153.7, 154.6; EIMS:
m=z ¼ 362. Anal. calcd. for C26H18O2: C, 86.16; H, 5.01. Found: C, 86.02; H, 4.89.
ACKNOWLEDGMENT
One of the authors (S. B.) is thankful to the Department of Atomic Energy,
Government of India, for financial support in the form of a senior research fellowship.
REFERENCES
1. (a) Dean, F. M. The total synthesis of naturally occuring oxygen ring compounds. In The
Total Synthesis of Natural Products; J. Apsimon (Ed.); Wiley: New York, 1973; vol. 1,
p. 467; (b) Cagniant, P.; Cagniant, D. Recent advances in the chemistry of benzo[b]furan
and its derivatives, Part 1. Occurrence and synthesis. In Advances in Heterocyclic Chemis-
try; A. R. Katritzky, A. J. Boulton (Eds.); Academic Press: New York, 1975; vol.
18, p. 337; (c) Dean, F. M.; Sargent, M. V. Furans and their benzo derivatives. In
Comprehensive Heterocyclic Chemistry; A. R. Katritzky, C. W. Rees (Eds.); Pergamon
Press: Oxford, UK, 1984; vol. 4, p. 531; (d) Benassi, R. The furans and their benzo
derivatives. In Comprehensive Heterocyclic Chemistry II; A. R. Katritzky, C. W. Rees,
and E. F. V. Scriven (Eds.); Pergamon Press: Oxford, UK, 1996; vol. 2, p. 259.
2. (a) Navarro, E.; Alonso, S. J.; Trujillo, J.; Jorge, E.; Perez, C. General behavior, toxicity,
and cytotoxic activity of elenoside, a lignan from Justicia hyssopifolia. J. Nat. Prod. 2001,
64, 134; (b) Lambert, J. D.; Meyers, R. O.; Timmermann, B. N.; Dorr, R. T. Tetra-O-
methylnordihydroguaiaretic acid inhibits melanoma in vivo. Cancer Lett. 2001, 171, 47;
(c) Takasaki, M. T.; Komatsu, K.; Tokuda, H.; Nishino, H. Anti-tumor-promoting
activity of lignans from the aerial part of Saussurea medusa. Cancer Lett. 2000, 158, 53;
(d) Banskota, A.; Tezuka, Y.; Midorikawa, K.; Matsushige, K.; Kadota, S. Two novel
cytotoxic benzofuran derivatives from Brazilian propolis. J. Nat. Prod. 2000, 63, 1277;
(e) Lee, S. K.; Cui, B.; Mehta, R. R.; Kinghorn, A. D.; Pezzuto, J. M. Cytostatic mech-
anism and antitumor potential of novel 1H-cyclopenta[b]benzofuran lignans isolated from
Aglaia elliptica. Chem.-Biol. Interact. 1998, 115, 215; (f) Thompson, L. U.; Rickard, S. E.;
Orcheson, L. J.; Seidl, M. M. Flaxseed and its lignan and oil components reduce mam-
mary tumor growth at a late stage of carcinogenesis. Carcinogenesis 1996, 17, 1373;

SYNTHESIS OF BENZO[b]FURANS
2745
(g) Thompson, L. U.; Seidl, M. M.; Rickard, S. E.; Orcheson, L. J.; Fong, H. H. Antitumori-
genic effect of a mammalian lignan precursor from flaxseed. Nutr. Cancer 1996, 26, 159.
3. (a) Craigo, J.; Callahan, M.; Huang, R. C. C.; DeLucia, A. L. Inhibition of human papil-
lomavirus type 16 gene expression by nordihydroguaiaretic acid plant lignan derivatives.
Antiviral Res. 2000, 47, 19; (b) Cow, C.; Leung, C.; Charlton, J. L. Antiviral activity
of arylnaphthalene and aryldihydronaphthalene lignans. Can. J. Chem. 2000, 78, 553;
(c) Charlton, J. L. Antiviral activity of lignans. J. Nat. Prod. 1998, 61, 1447.
4. (a) Gordaliza, M.; Castro, M.; Del Corral, J. M.; Lopez-Vazquez, M.; Feliciano, A. S.;
Faircloth, G. T. In vivo immunosuppressive activity of some cyclolignans. Bioorg. Med.
Chem. Lett. 1997, 7, 2781; (b) Cho, J. Y.; Kim, A. R.; Yoo, E. S.; Baik, K. U.; Park,
M. H. Immunomodulatory effect of arctigenin, a lignan compound, on tumour necrosis
factor-a and nitric oxide production, and lymphocyte proliferation. J. Pharm. Pharmacol.
1999, 51, 1267.
5. (a) Maeda, S.; Masuda, H.; Tokoroyama, T. Studies on the preparation of bioactive lig-
nans by oxidative coupling reaction, I: Preparation and lipid peroxidation inhibitory effect
of benzofuran lignans related to schizotenuins. Chem. Pharm. Bull. 1994, 42, 2500; (b)
Lu, H.; Liu, G.-T. Anti-oxidant activity of dibenzocyclooctene lignans isolated from schi-
sandraceae. Planta Med. 1992, 58, 311; (c) Silva, D. H. S.; Pereira, F. C.; Zanoni, M. V.
B.; Yoshida, M. Lipophyllic antioxidants from Iryanthera juruensis fruits. Phytochemistry
2001, 57, 437.
6. (a) Day, S. H.; Chiu, N. Y.; Tsao, L. T.; Wang, J. P.; Lin, C. N. New lignan glycosides
with potent anti-inflammatory effect, isolated from Justicia ciliate. J. Nat. Prod. 2000,
63, 1560; (b) Borsato, M. L. C.; Grael, C. F. F.; Souza, G. E. P.; Lopes, N. P. Analgesic
activity of the lignans from Lychnophora ericoides. Phytochemistry 2000, 55, 809.
7. (a) Li, J. J.; Gribble, G. W. Palladium-catalyzed CꢁO bond formation. In Palladium in
Heterocyclic Chemistry; Pergamon: Amsterdam, 2000, vol. 20, chap. 1, p. 22; (b) Negishi,
E. I. Fundamental properties of palladium and patterns of the reactions of palladium and
its complexes. In Handbook of Organopalladium Chemistry for Organic Synthesis; E.
Negishi (Ed.); Wiley-Interscience: New York, 2002, vol. 2, p. 17; (c) Liao, Y.; Hu, Y.;
Wu, J.; Zhu, Q.; Donovan, M.; Fathi, R.; Yang, Z. Diversity oriented synthesis and
branching reaction pathway to generate natural product–like compounds. Curr. Med.
Chem. 2003, 10, 2285; (d) Zeni, G.; Larock, R. C. Synthesis of heterocycles via palladium
p-olefin and p-alkyne chemistry. Chem. Rev. 2004, 104, 2285; (e) Alonso, F.; Beletskaya,
I. P.; Yus, M. Transition-metal-catalyzed addition of heteroatom-hydrogen bonds to
alkynes. Chem. Rev. 2004, 104, 3079.
8. (a) Arcadi, A.; Cacchi, S.; Rosario, M. D.; Fabrizi, G.; Marinelli, F. Palladium-catalyzed
reaction of o-ethynylphenols, o-((trimethylsilyl)ethynyl)phenyl acetates, and o-alkynylphe-
nols with unsaturated triflates or halides: A route to 2-substituted-, 2,3-disubstituted-, and
2-substituted-3-acylbenzo[b]furans. J. Org. Chem. 1996, 61, 9280; (b) Chaplin, J. H.;
Flynn, B. L. A multi-component coupling approach to benzo[b]furans and indoles. Chem.
Commun. 2001, 1594; (c) 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; (d) Hu, Y.; Nawoschik, K. J.; Liao, Y.; Ma, J.; Fathi, R.; Yang, Z. Synthesis of
conformationally restricted 2,3-diarylbenzo[b]furan by the Pd-catalyzed annulation of
o-alkynylphenols: Exploring a combinatorial approach. J. Org. Chem. 2004, 69, 2235;
(e) Kondo, Y.; Shiga, F.; Murata, N.; Sakamoto, T.; Yamanaka, H. Condensed hetero-
aromatic ring systems, XXIV: Palladium-catalyzed cyclization of 2-substituted phenylace-
tylenes in the presence of carbon monoxide. Tetrahedron 1994, 50, 11803; (f) Nan, Y.;
Miao, H.; Yang, Z. A new complex of palladium-thiourea and carbon tetrabromide
catalyzed carbonylative annulation of o-hydroxylarylacetylenes: Efficient new synthetic
technology for the synthesis of 2,3-disubstituted benzo[b]furans. Org. Lett. 2000, 2, 297;

2746
S. BHATT, K. ROY, AND S. K. NAYAK
(g) Hu, Y.; Yang, Z. Palladium-mediated intramolecular carbonylative annulation of
o-alkynylphenols to synthesize benzo[b]furo[3,4-d]furan-1-ones. Org. Lett. 2001, 3, 1387;
(h) Hu, Y.; Zhang, Y.; Yang, Z.; Fathi, R. Palladium-catalyzed carbonylative annulations
of o-alkynylphenols: Syntheses of 2-substituted-3-aroyl-benzo[b]furans. J. Org. Chem.
2002, 67, 2365; (i) Liao, Y.; Fathi, R.; Yang, Z. Aliphatic acetylenic homocoupling cata-
lyzed by a novel combination of AgOTs-CuCl2-TMEDA and its application for the
solid-phase synthesis of bis-benzo[b]furan-linked 1,3-diynes. Org. Lett. 2003, 5, 909; (j)
Liao, Y.; Fathi, R.; Yang, Z. Convergent solid-phase synthesis of symmetrical benzo[b]-
furan’s dimerizer. J. Comb. Chem. 2003, 5, 79.
9. (a) Arcadi, A.; Marinelli, F.; Cacchi, S. Palladium-catalyzed reaction of 2-hydroxyaryl
and hydroxyheteroaryl halides with 1-alkynes: An improved route to the benzo[b]furan
ring system. Synthesis 1986, 749; (b) Kundu, N. G.; Pal, M.; Mahanty, J. S.; Dasgupta,
S. K. Palladium-catalysed heteroannulation of acetylenic compounds: A facile method
for the synthesis of benzofurans. J. Chem. Soc., Chem. Commun. 1992, 41; (c) Torii,S.;
Xu, L. H.; Okumoto, H. Novel synthesis of functionalized benzo[b]furans and homolo-
gues by use of a palladium-copper catalyst system. Synlett 1992, 515; (d) Candiani, I.;
Debernardinis, S.; Cabri, W.; Marchi, M.; Bedeschi, A.; Penco, S. A facile one-pot syn-
thesis of polyfunctionalized 2-unsubstituted benzo[b]furans. Synlett 1993, 269; (e) Larock,
R. C.; Yum, E. K.; Doty, M. J.; Sham, K. K. C. Synthesis of aromatic heterocycles via
palladium-catalyzed annulation of internal alkynes. J. Org. Chem. 1995, 60, 3270; (f)
Monteiro, N.; Arnold, A.; Balme, G. Palladium-catalyzed heteroannulation of o-alkynyl-
phenols with propargyl carbonates: A synthesis of 2-substituted-3-allenylbenzo[b]furans.
Synlett 1998, 1111; (g) Bishop, B. C.; Cottrell, I. F.; Hands, D. Synthesis of 3-hydroxyalk-
ylbenzo[b]furans via the palladium-catalysed heteroannulation of silyl-protected alkynols
with 2-iodophenol. Synthesis 1997, 1315; (h) Kundu, N. G.; Pal, M.; Mahanty, J. S.; De,
M. Palladium-catalysed heteroannulation with acetylenic compounds: Synthesis of benzo-
furans. J. Chem. Soc., Perkin Trans. 1 1997, 2815; (i) Lutjens, H.; Scammells, P. J.
Synthesis of 2-substituted 3-acylbenzo[b]furans via the palladium catalysed carbonylative
cyclisation of ortho-hydroxytolans. Synlett 1999, 1079.
10. (a) Shen, Q.; Peng, Q.; Shao, J.-L.; Liu, X.-L.; Huang, Z.-H.; Pu, X.-Z.; Ma, L.; Li, Y.-M.;
Chan, A. S. C.; Gu, L.-Q. Synthesis and biological evaluation of functionalized coumarins
as acetylcholinesterase inhibitors. Eur. J. Med. Chem. 2005, 40, 1307; (b) Mashraqui, S.
H.; Patil, M. B.; Sangvikar, Y.; Ashraf, M.; Mistry, H. D.; Daub, E. T. H.; Meetsma,
1
A. Synthesis and H NMR structural analysis of 11-aryl=heteroarylnaphtha[2,1-b]furans:
X-ray crystal structure of 11-(40-pyridyl)naphtho[2,1-b]furan. J. Heterocycl. Chem. 2005,
42, 947; (c) Santini, C.; Berger, G. D.; Han, W.; Mosley, R.; MacNaul, K.; Berger, J.;
Doebber, T.; Wu, M.; Moller, D. E.; Tolman, R. L.; Sahoo, S. P. Phenylacetic acid deri-
vatives as hPPAR agonists. Bioorg. Med. Chem. Lett. 2003, 13, 1277; (d) Jorgensen, M.;
Krebs, F. C.; Bechgaard, K. Easy access to 3,8-diaryldifurano[2,3-a:2’,30-f]naphthalenes:
A new extended aromatic system. J. Org. Chem. 2000, 65, 8783.
11. Chen, C.; Dormer, P. G. Synthesis of benzo[b]furans via CuI-catalyzed ring closure.
J. Org. Chem. 2005, 70, 6964.
12. Duan, X.-F.; Zeng, J.; Zhang, Z.-B.; Zi, G.-F. A facile two-step synthesis of 2-arylbenzo-
furans based on the selective cross-McMurry couplings. J. Org. Chem. 2007, 72, 10283.
13. Banerji, A.; Nayak, S. K. Synthesis of O-heterocycles via intramolecular reductive deox-
ygenation of o-aroyloxyacetophenones: One-step synthesis of benzofurans. J. Chem. Soc.,
Chem. Commun. 1990, 150.
14. Castro, C. E.; Gaughan, E. J.; Owsley, D. C. Cupric halide halogenations. J. Org. Chem.
1965, 30, 587.
15. Clerici, A.; Porta, O.; Arnone, A. Reduction of o-hydroxybenzaldehydes by aqueous titanium
trichloride: A new route to 2-(benzofuran-2-yl)phenols. J. Org. Chem. 1990, 55, 1240.