Double annulations of dihydroxy- and diacetoxy-dialkynylbenzenes. An efficient construction of benzodifurans

Article abstract of DOI:10.1016/j.tet.2007.10.051

An efficient synthetic route to construct disubstituted benzodifurans from dihydroxy- or diacetoxy-dialkynylbenzenes utilizing Cs₂CO₃ or Pd(OAc)₂/Cs₂CO₃ promoted double annulations is described. The s

Full text of DOI:10.1016/j.tet.2007.10.051

Available online at www.sciencedirect.com
Tetrahedron 63 (2007) 12877–12882
Double annulations of dihydroxy- and diacetoxy-
dialkynylbenzenes. An efficient construction of benzodifurans
b
b
Zhiqiang Liang,a,b Shengming Ma,a, Jihong Yu and Ruren Xu
*
aState Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, PR China
bState Key Laboratory of Inorganic Synthesis and Preparative Chemistry, Jilin University, Changchun 130012, PR China
Received 22 July 2007; revised 8 October 2007; accepted 12 October 2007
Available online 16 October 2007
Abstract—An efficient synthetic route to construct disubstituted benzodifurans from dihydroxy- or diacetoxy-dialkynylbenzenes utilizing
Cs2CO3 or Pd(OAc)2/Cs2CO3 promoted double annulations is described. The scope for the reaction in the presence of a catalytic amount
of Pd(OAc)2 is more general. In addition, it was observed that NaOH-promoted reaction of diacetoxy-dialkynylbenzenes may directly afford
in THF/MeOH/H2O at 80 ꢀC benzodifurans through hydrolysis and double cyclization in a one-pot manner. However, in most cases, the
reaction is less selective affording a mixture of the double cyclization products and monocyclization–hydrolysis products.
Ó 2007 Published by Elsevier Ltd.
1. Introduction
we also used double RCM reaction to construct bicyclic
quinolizidine alkaloids13 and tricyclic benzodipyran deriva-
tives.14 Here, we wish to report an efficient method for the
synthesis of disubstituted benzodifurans from the double
cyclization of dihydroxy- or diacetoxy-substituted dialky-
nylbenzenes.
Benzofurans and benzodifurans play a fundamental role in
organic chemistry and life science because of their presence
in natural products and their interesting chemical and phy-
siological properties.1,2 Benzofurans have been the subject
of extensive studies and numerous synthetic methods have
been developed.3,4 Compared to benzofurans, reports on
the synthetic methods for benzodifurans are limited:2,5
they were usually prepared from the reaction of p-benzoqui-
none with acetoacetic acid ester,6 aromatization of tetrahy-
drobenzodifuran,2c acid-catalyzed cyclocondensation of
resorcinol with benzoin or 2-chloro-1,2-diphenyl-ethan-
one,2d intramolecular aldol-type condensation reactions of
the appropriate products,2a,7 or concomitant photocycliza-
tion and photo-Fries rearrangement reactions of dibenzoyl-
dialkoxybenzene,5 etc. On the other hand, the additions of
heteroatom-centered nucleophiles to unsaturated carbon–
carbon bonds are important reactions.8 Such intramolecular
additions are efficient for the construction of heterocycles.9
For example, the metal-3 or base-catalyzed8 cyclization of
2-alkynylphenol or their derivatives presents an efficient
synthetic method for the preparation of benzofurans.
2. Results and discussion
2.1. Synthesis of starting materials 4a–g
Dibromide 1 and diiodide 214 were selected as the starting
materials. Their Sonogashira coupling with terminal alkynes
gave the corresponding products 3a–g in good yields. Subse-
quent hydrolysis with NaOH or LiOH in THF/MeOH/H2O
gave differently substituted dihydroxydialkynylbenzenes
4a–g.
2.2. Double cycloisomerization of dihydroxydialkynyl-
benzenes
In the beginning, the double cycloisomerization of 1,4-dihy-
droxy-2,5-di(1-hexynyl)benzene 4a was investigated. The
reaction of 4a under the condition reported by Knochel8 us-
ing Cs2CO3 instead of CsOH$H2O as the base afforded the
double cyclization product 5a in very poor yield (entry 1,
Table 1). When the solvent was changed to DMA, the yield
of 5a was improved to 60% (entry 2). By increasing the
amount of Cs2CO3 to 2 equiv, the yield of 5a was improved
to 76% (entry 3, Condition A). With 4 equiv of Cs2CO3, the
Recently, we reported bicyclic carbopalladation,10 double or
triple Suzuki coupling reaction,11 and triple cyclic Heck re-
actions12 affording fused bicyclic or tetracyclic compounds;
Keywords: Benzodifuran; Palladium; Base; Annulation.
* Corresponding author. Tel.: +86 21 54925147; fax: +86 21 64167510;
e-mail: masm@mail.sioc.ac.cn
0040–4020/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tet.2007.10.051

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Z. Liang et al. / Tetrahedron 63 (2007) 12877–12882
Table 2. Cycloisomerization of 4 to form disubstituted benzodifurans
Table 1. Double cycloisomerization of 4a under different reaction condi-
tions
Entry Substrate
Product
Yield of 5 (%)
C4H9
Condition Condition
A
OH
O
C4H9
cat. base
solvent
B
HO
O
O
C4H9
C6H13
C4H9
4a
5a
1
2
3
4
5
4b
4c
4d
4e
4f
73
73
O
C6H13
C4H9
Entry Catalyst
Solvent Base (equiv)
NMP Cs2CO3 (1)
DMA Cs2CO3 (1)
DMA Cs2CO3 (2)
DMA Cs2CO3 (4)
DMA KOtBu (2)
DMA NaOH (2)
DMA LiOH$H2O (2) 80
DMA Cs2CO3 (2)
DMA Cs2CO3 (2)
DMF Cs2CO3 (2)
DMA Cs2CO3 (4)
T (ꢀC) Yield of 5a (%)
5b
C4H9
O
O
O
O
O
1
2
—
—
80
80
80
80
80
80
8
60
76a
40
8
22
14
68
75
72
62
62
77b
16
63
3
4
—
—
5c
5
6
—
—
O
O
O
BnO
OBn
7
8
—
—
22
35
60
100
80
5d
9
—
—
PdCl2
10
11
12
13
Ph
Ph
80
80
80
Trace
12
Trace
44b
Pd(PPh3)2Cl2 DMA Cs2CO3 (4)
Pd(OAc)2 DMA Cs2CO3 (4)
5e
a
Defined as Condition A.
Defined as Condition B.
t
t
Bu
Bu
b
5f
yield of 5a dropped to 40% (entry 4). Other bases, such as
KOtBu, NaOH, or LiOH$H2O, did not work well in DMA
at 80 ꢀC (entries 5–7). The effect of the temperature on the
yield of 5a is not obvious (entries 8,9). The reaction of 4a
under the catalysis of 5 mol % PdCl2 in DMA at 80 ꢀC in
the presence of Cs2CO3 afforded the expected 5a in only
62% yield (entry 11); using PdCl2(PPh3)2 as the catalyst,
the result is the same (entry 12), however, it was observed
that by using Pd(OAc)2 the yield of 5a was improved to
77% (entry 13, Condition B).
C6H13
O
O
C6H13
6
4g
34a
50
5g
a
Cs2CO3 (4 equiv) was used.
PdCl2 (5 mol %) and K2CO3 (4 equiv) were used.
b
of the two phenyl-substituted furan units. The high-yielding
nature of Condition B may be explained by the fact that
Pd(OAc)2 coordinates and subsequently activates the C–C
triple bond, which may greatly facilitate the cyclization re-
actions.
Under the optimized Condition A, 1,4-dihydroxy-2,5-di-
alkynylbenzene 4b was converted to 5b in 73% yield (entry
1, Table 2). However, the yields for the double cyclization
of 1,5-dihydroxy-2,4-dialkynylbenzenes 4c–g were very
low. It is interesting to observe that under the Condition
B, the yields for 5c,d and 5f,g are obviously higher (entries
2, 3, 5, and 6). The product 5e was formed only in trace
amount under both conditions probably due to the instability
Interestingly, further study on hydrolysis of 3a indicated that
when the reaction was conducted at 0 ꢀC, the double hydro-
lysis product 4a was formed (Scheme 1). However, when the
reaction was conducted at 80 ꢀC, sequential hydrolysis–
double cyclization product 5a was formed in good yield
R
R
AcO
HO
AcO
Br
Br
Pd(PPh3)2Cl2, CuI
Et3N, DMF, 70 °C
NaOH, 0 °C
THF/MeOH/H2O
+
R
OAc
OH
OAc
R
R
1
R = Bu 3a (84%)
= Hex 3b (85%)
R = Bu 4a (80%)
= Hex 4b (68%)
AcO
I
OAc
HO
OH
AcO
OAc
Pd(PPh3)2Cl2, CuI
LiOH, 0 °C
THF/MeOH/H2O
+
R
Et3N, DMF,
40-50 °C
I
R
R
R
R
2
R = Bu
3c (87%)
R = Bu
4c (80%)
= CH2OBn 3d (75%)
= CH2OBn 4d (65%)
= Ph
= t-Bu
= Hex
3e (77%)
3f (55%)
3g (90%)
= Ph
= t-Bu
= Hex
4e (76%)
4f (73%)
4g (70%)
Scheme 1.

Z. Liang et al. / Tetrahedron 63 (2007) 12877–12882
Table 3. Sequential hydrolysis–double cyclization of 3 to form disubstituted
benzodifurans
12879
4. Experimental
4.1. Synthesis of starting materials
Entry Substrate
Product
Yielda (%)
62
O
O
O
C4H9
The starting materials 1, 2, 3a, 3c, 3d, 4a, 4c, and 4d were
prepared according to the literature procedures.14
1
2
3
3a
3b
3d
O
C4H9
5a
5b
5d
4.1.1. 2,5-Di(oct-10-ynyl)-1,4-diacetoxybenzene (3b).
Typical Procedure A. To a flame-dried reaction tube were
added sequentially 1 (500 mg, 1.42 mmol), PdCl2(PPh3)2
(48 mg, 0.07 mmol), CuI (28 mg, 0.15 mmol), DMF
(2 mL), Et3N (2 mL), and 1-octyne (625 mg, 5.68 mmol)
under Ar. After being stirred at 80 ꢀC under Ar for 11 h,
the reaction mixture was quenched with water, extracted
with Et2O, washed with brine, and dried over MgSO4. Evap-
oration and flash column chromatography on silica gel (pe-
troleum ether/ethyl acetate¼20:1) gave the coupling product
3b (498 mg, 85%) as a white solid, mp: 61–62 ꢀC (petroleum
C6H13
72
34
O
O
C6H13
OBn
BnO
Ph
Ph
O
O
4
3e
Trace
1
ether/ethyl ether). H NMR (300 MHz, CDCl3) d 7.10 (s,
5e
2H), 2.38 (t, J¼6.9 Hz, 4H), 2.28 (s, 6H), 1.60–1.48 (m,
4H), 1.46–1.22 (m, 12H), 0.88 (t, J¼6.9 Hz, 6H); 13C
NMR (75 MHz, CDCl3) d 168.4, 148.6, 126.1, 118.3, 97.5,
74.7, 31.2, 28.4, 22.4, 20.6, 19.4, 13.9; MS (MALDI) m/z:
433.4 (M+Na+); IR (neat) n (cmꢁ1): 2933, 2859, 2232,
1774, 1496, 1196, 1156; Anal. Calcd for C26H34O4: C,
76.06, H, 8.35; Found: C, 76.00, H, 8.48.
a
The reaction was conducted in THF/MeOH/H2O at 80 ꢀC using 6 equiv of
NaOH.
(entry 1, Table 3). The diacetates 3b and 3d may be
converted to the corresponding benzodifurans 5b and 5d
smoothly (entries 2 and 3). Product 5e was still formed in
only trace amount under this reaction condition (entry 4).
The following compounds were prepared according to
Procedure A.
To our surprise, in the reaction of 1,5-diacetoxy-2,4-di(1-al-
kynyl)benzene 3c, the desired double cyclization product 5c
was formed in 66% yield, in addition, the monocyclization–
hydrolysis product benzofuran 6c was also isolated in 16%
yield. Similarly, substrate 3g was converted to benzodifuran
5g and benzofuran 6g in 34 and 20% yields, respectively.15
However, the reaction of substrate 3f afforded monocycliza-
tion product benzofuran 6f in 31% yield as the only product.
4.1.2. 2,4-Bis(phenylethynyl)-1,5-diacetoxybenzene (3e).
The reaction of 2 (400 mg, 0.9 mmol), Et3N (3 mL), phenyl-
acetylene (550 mg, 5.39 mmol), PdCl2(PPh3)2 (13 mg,
0.019 mmol), and CuI (7 mg, 0.037 mmol) in DMF (3 mL)
afforded the coupling product 3e (275 mg, 77%) as a white
solid after being stirred at 50 ꢀC for 21.5 h under Ar, mp:
123–124 ꢀC (petroleum ether/ethyl ether). 1H NMR
AcO
OAc
OH
O
R
R
O
O
NaOH (6 equiv.)
R
+
THF/MeOH/H2O
80 °C
R
R
R
O
R = n-Bu 3c
t-Bu 3f
C6H13 3g
R = n-Bu 5c 66%
t-Bu 5f trace
C6H13 5g 34%
R = n-Bu 6c 16%
t-Bu 6f 31%
C6H13 6g 20%
3. Conclusion
(300 MHz, CDCl3) d 7.78 (s, 1H), 7.51–7.46 (m, 4H),
7.39–7.35 (m, 6H), 7.04 (s, 1H), 2.37 (s, 6H); 13C NMR
(75 MHz, CDCl3) d 168.2, 151.4, 136.4, 131.5, 128.7,
128.4, 122.5, 117.1, 115.5, 94.6, 82.9, 20.8; MS (EI) m/z
(%): 394 (M+, 3.5), 310 (100.0); IR (neat) n (cmꢁ1): 2222,
1774, 1502, 1369, 1189, 1146; Anal. Calcd for C26H18O4:
C, 79.17, H, 4.60; Found: C, 79.47, H, 4.65.
In summary, we have developed a convenient synthesis of
disubstituted benzodifurans in moderate to good yields by
usingaPd(OAc)2-catalyzeddoublecyclizationofdihydroxy-
bis(alkyl-substituted 1-alkynyl)benzenes and a one-pot
NaOH-mediated hydrolysis and double cyclization of diace-
toxybis(alkyl-substituted 1-alkynyl)benzenes. However, the
NaOH-mediated reaction of 1,5-diacetoxy-2,4-bis(alkyl-
substituted 1-alkynyl)benzenes afforded a mixture of the
double cyclization products and monocyclization–hydroly-
sis products in many cases. Further study in this area is being
conducted in our laboratory.
4.1.3. 2,4-Bis(tert-butylethynyl)-1,5-diacetoxybenzene
(3f). The reaction of 2 (2 g, 4.5 mmol), Et3N (5 mL), tert-
butylethyne (2.2 g, 26.8 mmol), PdCl2(PPh3)2 (63 mg,
0.09 mmol), and CuI (34 mg, 0.18 mmol) in DMF (5 mL)
afforded the coupling product 3f (0.879 g, 55%) as a white

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Z. Liang et al. / Tetrahedron 63 (2007) 12877–12882
solid after being stirred at 40 ꢀC for 12 h under Ar, mp: 108–
109 ꢀC (petroleum ether). 1H NMR (300 MHz, CDCl3)
d 7.49 (s, 1H), 6.84 (s, 1H), 2.28 (s, 6H), 1.27 (s, 18H);
13C NMR (75 MHz, CDCl3) d 167.9, 150.7, 136.3, 116.4,
116.0, 103.7, 72.8, 30.7, 28.0, 20.6; MS (EI) m/z (%): 354
(4.0), 270 (100); IR (neat) n (cmꢁ1): 2969, 2231, 1775,
1495, 1367, 1190, 1106; Anal. Calcd for C22H26O4: C,
74.55, H, 7.39; Found: C, 74.54, H, 7.36.
73%) as a white solid after being stirred at 0 ꢀC for
30 min, mp: 74–75 ꢀC (petroleum ether/ethyl ether). 1H
NMR (300 MHz, CDCl3) d 7.26 (s, 1H), 6.52 (s, 1H), 5.83
(br s, 2H), 1.32 (s, 18H); 13C NMR (75 MHz, CDCl3)
d 157.4, 133.9, 105.0, 102.9, 100.4, 72.0, 31.1, 28.3; MS
(EI) m/z (%): 270 (100.0); IR (neat) n (cmꢁ1): 3499, 2969,
2928, 1631, 1496, 1272; Anal. Calcd for C18H22O2: C,
79.96, H, 8.20; Found: C, 80.02, H, 8.15.
4.1.4. 2,4-Di(oct-10-ynyl)-1,5-diacetoxybenzene (3g). The
reaction of 2 (500 mg, 1.13 mmol), Et3N (2 mL), 1-octyne
(495 mg, 4.5 mmol), PdCl2(PPh3)2 (32 mg, 0.046 mmol),
and CuI (17 mg, 0.09 mmol) in DMF (2 mL) afforded the
coupling product 3g (412 mg, 90%) as an oil after being
4.1.8. 2,4-Di(oct-10-ynyl)-1,5-dihydroxybenzene (4g). The
reaction of 3g (300 mg, 0.73 mmol) and LiOH$H2O
(132 mg, 3.14 mmol) in a mixed solvent (MeOH/THF/
H2O¼1:1:1, 20 mL) afforded the product 4g (186 mg,
1
78%) as an oil after being stirred at 0 ꢀC for 30 min. H
1
stirred at 40 ꢀC for 3.5 h under Ar. H NMR (300 MHz,
NMR (300 MHz, CDCl3) d 7.24 (s, 1H), 6.52 (s, 1H), 5.92
(br s, 2H), 2.42 (t, J¼6.9 Hz, 4H), 1.64–1.52 (m, 4H),
1.50–1.22 (m, 12H), 0.90 (t, J¼6.9 Hz, 6H); 13C NMR
(75 MHz, CDCl3) d 157.6, 133.9, 103.0, 100.6, 96.7, 73.6,
31.3, 28.7, 28.6, 22.5, 19.5, 14.0; MS (EI) m/z (%): 326
(M+, 100); IR (neat) n (cmꢁ1): 3497, 2930, 2858, 1629,
1586, 1492, 1354, 1272, 1146; HRMS Calcd for
C22H30O2: 326.2246; Found: 326.2253.
CDCl3) d 7.48 (s, 1H), 6.86 (s, 1H), 2.38 (t, J¼6.9 Hz,
4H), 2.29 (s, 6H), 1.61–1.48 (m, 4H), 1.46–1.21 (m, 12H),
0.89 (t, J¼6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 168.2, 150.7, 136.6, 116.6, 116.0, 95.8, 74.2, 31.3, 28.5,
28.4, 22.5, 20.7, 19.4, 14.0; MS (EI) m/z (%): 410 (M+,
12.6), 326 (100); IR (neat) n (cmꢁ1): 2932, 2859, 2233,
1776, 1493, 1190, 1128; HRMS Calcd for C26H34O4Na+
(M+Na+): 433.2349; Found: 433.2357.
4.2. Double cycloisomerization of 4
4.1.5. 2,5-Di (oct-10-ynyl)-1,4-dihydroxybenzene (4b).
Typical Procedure B. To the solution of 3b (340 mg,
0.82 mmol) in a mixed solvent (MeOH/THF/H2O¼1:1:1,
20 mL) was added NaOH (140 mg, 3.5 mmol) at 0 ꢀC. The
resulting solution was stirred at this temperature for
30 min as monitored by TLC. The mixture was neutralized
with aq HCl, extracted with ethyl ether, washed with brine,
and dried over MgSO4. Evaporation and flash column chro-
matography on silica gel (petroleum ether/ethyl acetate¼
10:1) gave 4b (184 mg, 68%) as a white solid, mp: 87–
4.2.1. 2,6-Dibutylbenzo[1,2-b:4,5-b0]difuran (5a). Typical
Procedure C: Condition A. To a reaction tube were added
sequentially 4a (50 mg, 0.19 mmol), Cs2CO3 (120 mg,
0.37 mmol), and DMA (2 mL). The reaction mixture was
stirred for 2.5 h at 80 ꢀC, quenched with water, extracted
with ether, and washed with brine. Evaporation and flash col-
umn chromatography on silica gel (petroleum ether) gave 5a
(38 mg, 76%) as a white solid, mp: 55–56 ꢀC (petroleum
ether). 1H NMR (300 MHz, CDCl3) d 7.43 (s, 2H), 6.40 (s,
2H), 2.77 (t, J¼7.8 Hz, 4H), 1.80–1.70 (m, 4H), 1.50–1.40
(m, 4H), 0.97 (t, J¼7.2 Hz, 6H); 13C NMR (75 MHz,
CDCl3) d 159.8, 151.6, 125.8, 101.9, 100.6, 29.7, 28.3,
22.3, 13.8; MS (EI) m/z (%): 270 (50.3), 227 (100.0); IR
(neat) n (cmꢁ1): 2960, 2932, 1606, 1437; Anal. Calcd for
C18H22O2: C, 79.96, H, 8.20; Found: C, 80.11, H, 8.18.
1
88 ꢀC (petroleum ether/ethyl ether). H NMR (300 MHz,
CDCl3) d 6.84 (s, 2H), 5.42 (s, 2H), 2.46 (t, J¼6.9 Hz,
4H), 1.64–1.55 (m, 4H), 1.47–1.26 (m, 12H), 0.90 (t,
J¼6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) d 149.8,
116.2, 111.2, 99.1, 74.5, 31.3, 28.59, 28.55, 22.5, 19.6,
14.0; MS (EI) m/z (%): 326 (M+, 100); IR (neat) n (cmꢁ1):
3309, 2928, 2859, 2225, 1422, 1193; Anal. Calcd for
C22H30O2: C, 80.94, H, 9.26; Found: C, 81.14, H, 9.27.
The following compounds were prepared according to
Condition A.
The following compounds were prepared according to
Procedure B.
4.2.2. 2,6-Dioctylbenzo[1,2-b:4,5-b0]difuran (5b). The re-
action of 4b (62 mg, 0.19 mmol) and Cs2CO3 (126 mg,
0.39 mmol) in DMA (2 mL) afforded the product 5b
(19 mg, 31%) as a white solid after being stirred at 80 ꢀC
for 5.5 h, mp: 62–63 ꢀC (petroleum ether). 1H NMR
(300 MHz, CDCl3) d 7.42 (s, 2H), 6.40 (s, 2H), 2.76 (t,
J¼7.8 Hz, 4H), 1.80–1.70 (m, 4H), 1.50–1.25 (m, 12H),
0.89 (t, J¼6.9 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 159.9, 151.6, 125.8, 101.9, 100.6, 31.6, 28.9, 28.7, 27.6,
22.6, 14.1; MS (EI) m/z (%): 326 (M+, 52.4), 255 (100);
IR (neat) n (cmꢁ1): 2930, 2848, 1603, 1470, 1437; Anal.
Calcd for C22H30O2: C, 80.94, H, 9.26; Found: C, 80.90,
H, 9.41.
4.1.6. 2,4-Bis(phenylethynyl)-1,5-dihydroxybenzene (4e).
The reaction of 3e (278 mg, 0.71 mmol) and LiOH (68 mg,
2.83 mmol) in a mixed solvent (MeOH/THF/H2O¼1:1:1,
10 mL) afforded the product 4e (198 mg, 91%) as a brown
solid after being stirred at 0 ꢀC for 35 min, mp: 114–
1
115 ꢀC (petroleum ether/ethyl ether). H NMR (300 MHz,
CDCl3) d 7.55–7.51 (m, 5H), 7.43–7.36 (m, 6H), 6.65 (s,
1H), 6.07 (s, 2H); 13C NMR (75 MHz, CDCl3) d 158.4,
134.6, 131.5, 128.7, 128.5, 122.3, 102.9, 101.4, 95.5, 82.0;
MS (EI) m/z (%): 310 (100.0); IR (neat) n (cmꢁ1): 3497,
1626, 1595, 1501, 1271; Anal. Calcd for C22H14O2: C,
85.14, H, 4.55; Found: C, 85.15, H, 4.65.
4.2.3. 2,6-Dibutylbenzo[1,2-b:5,4-b0]difuran (5c). The re-
action of 4c (50 mg, 0.19 mmol) and Cs2CO3 (120 mg,
0.37 mmol) in DMA (2 mL) afforded the product 5c
(8 mg, 16%) as a white solid after being stirred at 80 ꢀC
for 11 h, mp: 38 ꢀC (petroleum ether). 1H NMR
4.1.7. 2,4-Di(tert-butylethynyl)-1,5-dihydroxybenzene
(4f). The reaction of 3f (220 mg, 0.62 mmol) and LiOH
(59 mg, 2.46 mmol) in a mixed solvent (MeOH/THF/
H2O¼1:1:1, 10 mL) afforded the product 4f (122 mg,

Z. Liang et al. / Tetrahedron 63 (2007) 12877–12882
12881
(300 MHz, CDCl3) d 7.49 (s, 1H), 7.46 (s, 1H), 6.40 (s, 2H),
2.79 (t, J¼7.2 Hz, 4H), 1.82–1.72 (m, 4H), 1.50–1.42 (m,
4H), 0.99 (t, J¼7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 159.5, 152.3, 125.2, 109.1, 101.4, 93.5, 29.7, 28.3, 22.3,
13.8; MS (EI) m/z (%): 270 (M+, 34.5), 227 (100.0); IR
(neat) n (cmꢁ1): 2957, 2931, 1604, 1441; Anal. Calcd for
C18H22O2: C, 79.96, H, 8.20; Found: C, 80.36, H, 8.39.
0.009 mmol) and Cs2CO3 (200 mg, 0.61 mmol) in DMA
(2 mL) afforded 5b (38 mg, 73%) as a white solid after being
stirred at 80 ꢀC for 9 h.
4.2.9. 2,6-Dibutylbenzo[1,2-b:5,4-b0]difuran (5c). The
reaction of 4c (80 mg, 0.30 mmol), Pd(OAc)2 (4 mg,
0.018 mmol), and Cs2CO3 (387 mg, 1.19 mmol) in DMA
(2.5 mL) afforded 5c (50 mg, 63%) as a white solid after
being stirred at 80 ꢀC for 3 h.
4.2.4. 2,6-Bis(benzyloxymethyl)benzo[1,2-b:5,4-b0]-
difuran (5d). The reaction of 4d (50 mg, 0.13 mmol) and
Cs2CO3 (82 mg, 0.25 mmol) in DMA (2 mL) afforded
the product 5d (11 mg, 22%) as a white solid after being
stirred for 16 h at 80 ꢀC, mp: 72–73 ꢀC (petroleum ether/eth-
yl ether). 1H NMR (300 MHz, CDCl3) d 7.63 (s, 1H), 7.61 (s,
1H), 7.40–7.31 (m, 10H), 6.75 (s, 2H), 4.65 (s, 8H); 13C
NMR (75 MHz, CDCl3) d 154.5, 153.6, 137.6, 128.5,
128.0, 127.8, 124.8, 111.3, 105.7, 94.6, 72.3, 64.5; MS
(EI) m/z (%): 398 (M+, 3.3), 44 (100.0); IR (neat) n
(cmꢁ1): 2856, 1608, 1454, 1438, 1351; Anal. Calcd for
C26H22O4: C, 78.37, H, 5.57; Found: C, 78.45, H, 5.62.
4.2.10. 2,6-Bis(benzyloxymethyl)benzo[1,2-b:5,4-b0]-
difuran (5d). The reaction of 4d (120 mg, 0.3 mmol),
Pd(OAc)2 (3 mg, 0.013 mmol), and Cs2CO3 (391 mg,
1.2 mmol) in DMA (3 mL) afforded the product 5d
(42 mg, 35%) as a white solid after being stirred at 60 ꢀC
for 18 h.
4.2.11. 2,6-Di(tert-butyl)benzo[1,2-b:5,4-b0]difuran (5f).
The reaction of 4f (64 mg, 0.24 mmol), PdCl2 (2 mg,
0.011 mmol), and K2CO3 (121 mg, 0.88 mmol) in DMA
(2 mL) afforded the product 5f (28 mg, 44%) as a white solid
after being stirred at 80 ꢀC for 5 h.
4.2.5. 2,6-Di(tert-butyl)benzo[1,2-b:5,4-b0]difuran (5f).
The reaction of 4f (50 mg, 0.19 mmol) and Cs2CO3
(120 mg, 0.37 mmol) in DMA (2 mL) afforded the product
5f (6 mg, 12%) as a white solid after being stirred at 80 ꢀC
for 11 h, mp: 110–112 ꢀC (petroleum ether). 1H NMR
(300 MHz, CDCl3) d 7.46 (s, 1H), 7.45 (s, 1H), 6.35 (s,
2H), 1.38 (s, 18H); 13C NMR (75 MHz, CDCl3) d 167.2,
152.4, 125.1, 109.5, 98.6, 93.6, 33.0, 28.8; MS (EI) m/z
(%): 270 (M+, 31.6), 255(100); IR (neat) n (cmꢁ1): 2960,
2868, 1590, 1440, 1107; Anal. Calcd for C18H22O2: C,
79.96, H, 8.20; Found: C, 80.01, H, 8.49.
4.2.12. 2,6-Dioctylbenzo[1,2-b:5,4-b0]difuran (5g). The
reaction of 4g (60 mg, 0.18 mmol), Pd(OAc)2 (2 mg,
0.009 mmol), and Cs2CO3 (240 mg, 0.74 mmol) in DMA
(2 mL) afforded the product 5g (30 mg, 50%) as a white
solid after being stirred at 80 ꢀC for 16.5 h.
4.3. Hydrolysis and double cyclization of 3
4.3.1. 2,6-Dibutylbenzo[1,2-b:4,5-b0]difuran (5a). Typical
Procedure E. To the solution of 3a (80 mg, 0.23 mmol) in
a mixed solvent (MeOH/THF/H2O¼1:1:1, 2 mL) was added
NaOH (62 mg, 1.55 mmol). After being stirred at 80 ꢀC for
4 h, the reaction mixture was quenched with water, extracted
with Et2O, washed with brine, and dried over MgSO4. Eva-
porationandflashcolumnchromatographyonsilicagel(petro-
leum ether) gave the product 5a (38 mg, 62%) as a white solid.
4.2.6. 2,6-Dioctylbenzo[1,2-b:5,4-b0]difuran (5g). The
reaction of 4g (50 mg, 0.15 mmol) and Cs2CO3 (200 mg,
0.61 mmol) in DMA (2 mL) afforded the product 5g
(17 mg, 34%) as a white solid after being stirred at 80 ꢀC
for 16.5 h, mp: 43–44 ꢀC (petroleum ether). 1H NMR
(300 MHz, CDCl3) d 7.48 (s, 1H), 7.46 (s, 1H), 6.40 (s,
2H), 2.77 (t, J¼7.5 Hz, 4H), 1.82–1.70 (m, 4H), 1.47–1.30
(m, 12H), 0.92 (t, J¼6.6 Hz, 6H); 13C NMR (75 MHz,
CDCl3) d 159.5, 152.3, 125.2, 109.1, 101.4, 93.5, 31.6,
28.9, 28.6, 27.6, 22.6, 14.1; MS (EI) m/z (%): 326 (M+,
50.2), 255 (100); IR (neat) n (cmꢁ1): 2929, 2858, 1604,
1441, 1131; Anal. Calcd for C22H30O2: C, 80.94, H, 9.26;
Found: C, 81.02, H, 9.45.
The following compounds were prepared according to Pro-
cedure E.
4.3.2. 2,6-Dioctylbenzo[1,2-b:4,5-b0]difuran (5b). The
reaction of 3b (80 mg, 0.20 mmol) and NaOH (50 mg,
1.25 mmol) in a mixed solvent (MeOH/THF/H2O¼1:1:1,
3 mL) afforded the product 5b (46 mg, 72%) as a white solid
after being stirred at 80 ꢀC for 17.5 h.
4.2.7. 2,6-Bisbutylbenzo[1,2-b:4,5-b0]difuran (5a). Typi-
cal Procedure D: Condition B. To a solution of 4a
(61 mg, 0.22 mmol) in DMA (2.5 mL) were added Pd(OAc)2
(3 mg, 0.013 mmol) and Cs2CO3 (290 mg, 0.89 mmol) in
open air. The reaction mixture was stirred for 9 h at 80 ꢀC,
quenched with water, neutralized with aq HCl, extracted
with ethyl acetate, washed with brine, and dried over
MgSO4. Evaporation and flash column chromatography on
silica gel (petroleum ether) gave 5a (47 mg, 77%) as a white
solid.
4.3.3. 2,6-Dibutylbenzo[1,2-b:5,4-b0]difuran (5c). The
reaction of 3c (85 mg, 0.24 mmol) and NaOH (55 mg,
1.38 mmol) in a mixed solvent (MeOH/THF/H2O¼1:1:1,
3 mL) afforded the product 5c (43 mg, 66%) as a white solid
and 6c (11 mg, 16%) as an oil after being stirred at 80 ꢀC for
11 h. Compound 6c: 1H NMR (300 MHz, CDCl3) d 12.60 (s,
1H), 7.87 (s, 1H), 6.94 (s, 1H), 6.29 (s, 1H), 3.02 (t, J¼7.5 Hz,
2H), 2.72 (t, J¼7.5 Hz, 2H), 1.78–1.62 (m, 4H), 1.48–1.26
(m, 6H), 1.00–0.88 (m, 6H); 13C NMR (75 MHz, CDCl3)
d 206.5, 160.70, 160.66, 159.3, 121.8, 121.7, 116.0, 101.4,
99.4, 38.4, 31.5, 29.5, 28.0, 24.6, 22.5, 22.2, 14.0, 13.8;
MS (EI) m/z (%): 288 (M+, 58.0), 217 (100); IR (neat) n
(cmꢁ1): 2957, 2929, 2860, 1643, 1610, 1463; HRMS Calcd
for C18H24O3: 288.1725; Found: 288.1721.
The following compounds were prepared according to
Procedure D.
4.2.8. 2,6-Bisoctylbenzo[1,2-b:4,5-b0]difuran (5b). The re-
action of 4b (52 mg, 0.16 mmol), Pd(OAc)2 (2 mg,

12882
Z. Liang et al. / Tetrahedron 63 (2007) 12877–12882
Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.;
Pergamon: Oxford, 1984; Vol. 4, pp 657–712; (c) Bird, C. W.
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E. F. V., Eds.; Pergamon: Oxford, 1993; Vol. 5, pp 129–142;
(d) Ono, M.; Kawashima, H.; Nonaka, A.; Kawai, T.;
Haratake, M.; Mori, H.; Kung, M. P.; Kung, H. F.; Saji, H.;
Nakayama, M. J. Med. Chem. 2006, 49, 2725.
4.3.4. 2,6-Bis(benzyloxymethyl)benzo[1,2-b:5,4-
b0]difuran (5d). The reaction of 3d (90 mg, 0.19 mmol)
and NaOH (50 mg, 1.25 mmol) in a mixed solvent
(MeOH/THF/H2O¼1:1:1, 2 mL) afforded the product 5d
(25 mg, 34%) as a white solid after being stirred at 80 ꢀC
for 11 h.
2. (a) Rene, L.; Buisson, J. P.; Royer, R.; Averbeck, D. Eur.
J. Med. Chem. Chim. Ther. 1977, 12, 31; (b) Royer, R.;
Bisagni, E.; Hudry, C.; Cheutin, A.; Desvoye, M. L. Bull.
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Orbaugh, D. M.; Parker, M. A.; Nichols, D. E. J. Med. Chem.
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4.3.5. 1-(2-tert-Butyl-6-hydroxybenzofuran-5-yl)-3,3-
dimethylbutan-1-one (6f). The reaction of 3f (80 mg,
0.23 mmol) and NaOH (70 mg, 1.75 mmol) in a mixed sol-
vent (MeOH/THF/H2O¼1:1:1, 2 mL) afforded the product
6f (20 mg, 33%) as an oil after being stirred at 80 ꢀC for
17 h. 1H NMR (300 MHz, CDCl3) d 12.89 (s, 1H), 7.88 (s,
1H), 6.95 (s, 1H), 6.27 (s, 1H), 2.88 (s, 2H), 1.35 (s, 9H),
1.09 (s, 9H); 13C NMR (75 MHz, CDCl3) d 206.4, 168.3,
161.1, 159.4, 123.0, 121.4, 117.3, 99.4, 98.7, 49.7, 32.9,
32.0, 30.3, 28.6; MS (ESI) m/z (%): 289.3 (M+H+); IR
(neat) n (cmꢁ1): 2962, 1638, 1605; HRMS Calcd for
C18H24O3: 288.1725; Found: 288.1732.
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4.3.6. 2,6-Dioctylbenzo[1,2-b:5,4-b0]difuran (5g). The
reaction of 3g (78 mg, 0.19 mmol) and NaOH (53 mg,
1.33 mmol) in a mixed solvent (MeOH/THF/H2O¼1:1:1,
3 mL) afforded the product 5g (21 mg, 34%) as a white solid
and 6g (13 mg, 20%) as an oil after being stirred at 80 ꢀC for
9 h. Compound 6g: 1H NMR (300 MHz, CDCl3) d 12.61 (s,
1H), 7.87 (s, 1H), 6.95 (s, 1H), 6.29 (s, 1H), 3.02 (t,
J¼7.5 Hz, 2H), 2.71 (t, J¼7.5 Hz, 2H), 1.79–1.68 (m, 4H),
1.46–1.18 (m, 14H), 0.89 (t, J¼6.6 Hz, 6H); 13C NMR
(75 MHz, CDCl3) d 206.5, 160.70, 160.68, 159.3, 121.8,
121.7, 116.0, 101.4, 99.4, 38.5, 31.7, 31.5, 29.3, 29.1,
28.8, 28.3, 27.4, 24.9, 22.6, 22.5, 14.09, 14.06; MS (EI)
m/z (%): 344 (M+, 57.1), 245 (100); IR (neat) n (cmꢁ1):
2927, 2855, 1642, 1605, 1460, 1132; HRMS Calcd for
C22H32O3: 344.2351; Found: 344.2354.
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Acknowledgements
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Financial support from the Major State Basic Research
Development Program (Grant No. 2006CB806105),
National NSF of China (Nos. 20172060, 200423001, and
20121202), and Shanghai Municipal Committee of Science
and Technology is greatly appreciated.
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690, 5389.
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J. Org. Chem. 2004, 69, 6305.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.10.051.
References and notes
14. Liang, Z.; Ma, S.; Yu, J.; Xu, R. Tetrahedron 2007, 63, 977.
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