An isomerization-ring-closing metathesis strategy for the synthesis of substituted benzofurans

Article abstract of DOI:10.1016/j.tet.2005.05.090

Twelve substituted benzofurans were synthesized from their corresponding substituted 1-allyl-2-allyloxybenzenes using ruthenium-mediated C- and O-allyl isomerization followed by ring-closing metathesis.

Full text of DOI:10.1016/j.tet.2005.05.090

Tetrahedron 61 (2005) 7746–7755
An isomerization-ring-closing metathesis strategy for the
synthesis of substituted benzofurans
*
Willem A. L. van Otterlo, Garreth L. Morgans, Lee G. Madeley, Samuel Kuzvidza,
Simon S. Moleele, Natalie Thornton and Charles B. de Koning
School of Chemistry, Molecular Sciences Institute, University of the Witwatersrand, PO Wits 2050, Johannesburg, South Africa
Received 14 March 2005; revised 16 May 2005; accepted 26 May 2005
Available online 20 June 2005
Abstract—Twelve substituted benzofurans were synthesized from their corresponding substituted 1-allyl-2-allyloxybenzenes using
ruthenium-mediated C- and O-allyl isomerization followed by ring-closing metathesis.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
reported combinatorial approaches towards its synthesis.4
Relevant medicinal chemistry examples include compound
6, a potent and selective dopamine D-2 antagonist,5 and
compound 7, a k-selective agonist, with a potency 25 times
greater than morphine (Fig. 2).6
The 1-benzofuran skeleton 1 is a well known structural unit
in naturally occurring compounds (Fig. 1).1 Examples of
interesting natural products containing the benzofuran motif
include khellin 2, a potent coronary vasodilator, isolated
from the seeds of Ammi visnaga L.2a In addition, the
synthetic bis(khellin) analogue 3 has been used in the
treatment of atherosclerosis.2b Other examples include
the furocoumarin heraclenol 4 and the related compound,
byakangelicin 5, both isolated from the spring parsley
Cymopterus watsonii3a or the plant Ruta montana.3b
Figure 2.
Owing to the obvious interest in this class of compounds,7
many different approaches have been applied to their
synthesis,8 the most popular of these involving the use of
a palladium-catalyzed cyclization reaction.9 It is with this
interest in mind that we report here a novel approach to the
synthesis of benzofurans using a ruthenium-mediated
isomerization reaction followed by a ring-closing
metathesis (RCM) reaction.10
Figure 1.
The benzofuran building block has also been recognized as
a ‘bicyclic privileged structure’ and several groups have
In recent years, the application of RCM to the synthesis of
small ring systems has seen much activity and this research
has been extensively reviewed.11 The synthesis of
2-substituted benzofurans by titanium-mediated ester alkyl-
idenation followed by molybdenum alkylidene-catalysed
Keywords: Benzofurans; Isomerization; Ring-closing metathesis.
*
Corresponding author. Tel.: C27 11 717 6707; fax: C27 11 717 6749;
e-mail: willem@aurum.chem.wits.ac.za
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.05.090

W. A. L. van Otterlo et al. / Tetrahedron 61 (2005) 7746–7755
7747
RCM has been reported by Grubbs and co-workers in 1994.12
However, the application of ruthenium-mediated RCM to the
synthesis of benzofurans has only been reported twice
before.13 In 2003, we published a communication that
mentioned the synthesis of benzofuran using the bis-
isomerization of a C-allyl and O-allyl group, followed by a
RCM reaction (disconnection a, Fig. 3).13a The second report
is that by Wang and co-workers who published a ruthenium-
catalysed RCM approach to benzofurans in 2004.13b Their
approach involved the installation of an O-vinyl aryl ether by
way of a two-step alkylation-base-mediated elimination
(disconnection b, Fig. 3). Subsequent metathesis then afforded
the desired benzofurans.14 Of interest is that the use of an
isomerization reaction, normallyofanarylallyl group, prior to
RCM has seen an increase in synthetic approaches.14,15 Our
present paper describes the extension of our work in which 12
substituted benzofurans have been synthesized, some bearing
reactivefunctionalgroups, todemonstratethe feasibilityofthe
isomerization-RCM approach.16
Scheme 1. (a) K2CO3, allyl bromide, acetone; (b) microwave irradiation,
neat, 100 W, 180–220 8C; (c) 5% catalyst 13, toluene (or CH2Cl2 for 10b);
(d) 5% catalyst 14, toluene; For yields see Table 1.
11 as a mixture of geometrical isomers. These compounds
were not characterized any further and were used directly in
the next reaction. Fortunately, the crucial ruthenium-
mediated RCM reactions were mostly successful, using
the second generation Grubbs metathesis catalyst 14,
affording the substituted benzofurans 12 in unoptimized
yields ranging from 20 to 100%. From the 1H NMR spectra
it was clear that the expected compounds had been formed,
as shown by the presence of two sets of doublets at dZca.
6.8 ppm (3-H) and ca. 7.5 ppm (2-H) with coupling
constants of JZca. 2.2 Hz.
To the best of our knowledge, this isomerization-RCM
sequence to afford the substituted benzofurans is novel in
two aspects. Firstly, the isomerization of mixed C- and
O-allyl systems is unprecedented and secondly the RCM of
C-vinylic groups with O-vinylic groups has received little
attention to the best of our knowledge. Literature searches
have revealed that RCM using Grubbs’ catalysts on
Figure 3. (a) This work and that first described in Ref.13a (b) Wang’s
route.13b
2. Results and discussion
Variously substituted phenols 8 were initially converted into
their corresponding aryl allyl ethers using allyl bromide and
K2CO3. Subsequent microwave-assisted Claisen rearrange-
ments then gave the substituted phenols 9 in acceptable
yields over two steps (Scheme 1). These phenols were then
re-allylated to afford the corresponding 1-allyl-2-allyloxy-
benzenes 10 in moderate to excellent yields (see Table 1 for
respective yields). In the first important step, the two allyl
groups were isomerized with the dependable ruthenium-
based catalyst, [RuClH(CO)(PPh3)3] 13. This catalyst and
Table 1. Yields for Scheme 1
8/10a
10/11
11/12
a R1,R4ZOMe, R2,R3ZH
b R1,R3ZOMe, R2,R4ZH
c R1ZPh, R2,R3,R4ZH
31%
61%
48%
28%
36%
62%
45%
36%
50%
25%
85%
37%
99%
100%
98%
57%
82%
94%
85%
54%
86%
100%
100%
96%
63%
70%
50%
82%
92%
50%
70%
20%
92%
31%c
d R1ZCHO, R2,R3,R4ZH
e R1,R2,R4ZH, R3ZCHO
f R1ZNO2, R2,R3,R4ZH
g R1,R2,R4ZH, R3ZNO2
h R1ZOMe, R4ZCHO, R2,R3ZH
i R1,R2,R4ZH, R3Zt-butyl
j R1,R2,R4ZH, R3ZBr
its application to allyl group isomerization has been
17
´
popularized by the group of Krompiec, Kuznik, Pigulla
and their co-workers and application of their methodology
to our 1-allyl-2-allyloxybenzene substrates 10 readily
afforded the aryl enol ethers 11. The extent of reaction
was monitored by 1H NMR spectroscopy and once the
reaction was deemed to be complete, filtration through a
short silica gel plug afforded the bis-isomerized compounds
k R1-R2ZC6H4, R3,R4ZH
l R1,R2ZH, R3-R4ZC6H4
93%
b
a Yield over three steps.
b Compound not isolated.
c Yield over two steps.

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W. A. L. van Otterlo et al. / Tetrahedron 61 (2005) 7746–7755
substrates containing electron-rich vinylic olefins can be
problematic18,12b and we were satisfied at the reasonable
results afforded by the RCM of the bis-vinylic systems.
conventional silica gel chromatography. All solvents used
for reactions and chromatography were distilled prior to use.
All microwave reactions were performed in a CEM
Corporation Discover Focused Microwave Synthesis system.
The metathesis cyclization methodology proved to be
efficient for electron rich arene substituents such as in the
synthesis of compounds 12a and 12b. Bulky groups ortho or
para to the phenol group also did not seem to hamper the
reaction (entries 12c and 12l). The electron-withdrawing
nitro (entries 12f and 12g) and aldehyde groups (entries 12d,
12e and 12h) also gave reasonable results. The advantage of
these groups being tolerated in this process is that they are
easily converted into a range of other functional groups, thus
allowing for further structural modification on the benzo-
furan skeleton. One of the few disappointing entries in the
tabulated results is entry 12j; the allylated 4-bromophenol
underwent extensive decomposition during the Claisen
reaction and also gave a low yield during the RCM
reaction (possibly further complicated by the high volatility
of the 5-bromobenzofuran product 12j). Finally, the
isomerization-RCM methodology also proved efficient in
synthesizing the two naphthofuran regioisomers 12l and
12k. Naphtho[2,1-b]furan 12k was synthesized using a
‘one-pot’ isomerization-RCM strategy where the inter-
mediate isomerized bis-allyl compound was not isolated.
However, in our hands this method led to a disappointing
yield of only 31%. In comparison, the synthesis of
naphtho[1,2-b]furan 12k over two separate steps from
2-allyl-1-allyloxynaphthalene 10k was highly successful
(85% over two steps). In most cases, the isomerization and
metathesis reactions were performed in toluene so that the
reaction times could be minimized (isomerization: over-
night; metathesis: 3–4 h). However, to prove that a lower
boiling point solvent could also be successfully used
compound 10b was isomerized in dichloromethane (48 h
at reflux) to afford 11b in quantitative yield. The RCM was
then performed at ambient temperature in toluene to afford
the required 5,7-dimethoxybenzofuran 12b in excellent yield.
4.1. Precursors for the synthesis of the substituted
benzofurans 12a-l
2,5-Dimethoxyphenol8a, 2,4-dimethoxyphenol 8b, biphenyl-
2-ol 8c, 2-hydroxybenzaldehyde 8d, 4-hydroxybenzaldehyde
8e, 2-nitrobenzene 8f, 4-nitrobenzene 8g, 3-hydroxy-4-
methoxybenzaldehyde 8h, 4-tert-butylphenol 8i,
4-bromophenol 8j, 2-naphthol 8k, 1-naphthol 8l were
allylated to afford 2-allyloxy-1,4-dimethoxybenzene 15 (see
below for experimental conditions), 1-allyloxy-2,4-
dimethoxybenzene,19a 2-allyloxybiphenyl 16 (see below for
experimental conditions), 2-allyloxybenzaldehyde,19b
1-allyloxybenzaldehyde,19c 1-allyloxy-2-nitrobenzene,19d
1-allyloxy-4-nitrobenzene,19e 3-allyloxy-4-methoxybenzal-
dehyde,19a 1-allyloxy-4-tert-butylbenzene,19f 1-allyloxy-4-
bromobenzene,19g
2-allyloxynaphthalene19h
and
1-allyloxynaphthalene,19i respectively. These compounds
were subjected to microwave-assisted Claisen rearrangement
at 180–220 8C to afford 2-allyl-3,6-dimethoxyphenol 9a (see
below for experimental conditions), 2-allyl-4,6-dimethoxy-
phenol 9b, 3-allylbiphenyl-2-ol 9c (see below for experi-
mental conditions), 3-allyl-2-hydroxybenzaldehyde 9d,19j
3-allyl-4-hydroxybenzaldehyde 9e (see below for experi-
mental conditions), 2-allyl-6-nitrophenol 9f,13b 2-allyl-4-
nitrophenol 9g (see below for experimental conditions),
2-allyl-3-hydroxy-4-methoxybenzaldehyde 9h,19d 2-allyl-4-
tert-butylphenol 9i,19f 2-allyl-4-bromophenol 9j,19f 1-allyl-
naphthalen-2-ol 9k19h and 2-allyl-naphthalen-1-ol 9l,19i
respectively.
4.1.1. 2-Allyloxy-1,4-dimethoxybenzene 15. Allyl
bromide (5.5 g, 45 mmol, 3.9 mL) and K2CO3 (9.5 g,
69 mmol) were added to 2,4-dimethoxyphenol 8a (5.0 g,
32 mmol) dissolved in dry acetone (500 mL). The reaction
mixture was then heated at reflux under N2 for 21 h. The
resulting crude residue was then passed through a silica gel
column (10% EtOAc/hexane) to afford 2-allyloxy-1,4-
dimethoxybenzene 15 as a light yellow oil (3.7 g, 60%).
3. Conclusion
We have thus demonstrated a simple, versatile method for
the synthesis of substituted benzofurans involving the novel
isomerization of C- and O-allyl functional groups followed
by a RCM reaction. The range of substituents tolerated by
the methodology is reasonable, with aldehyde and nitro
groups being important for further possible functional group
manipulations.
(Found: MC, 194.0942, C11H14O3 requires 194.0943). H
NMR (300 MHz, CDCl3): dZ3.75 (3H, s, OCH3), 3.82 (3H,
s, OCH3), 4.57–4.59 (2H, m, OCH2), 5.26–5.30 [1H, m,
1
ArCH2CH]C(H)H], 5.37–5.43 [1H,
m
ArCH2-
CH]C(H)H], 6.01–6.14 (1H, m, ArCH2CH]CH2), 6.40
(1H, dd, JZ8.7, 2.8 Hz, ArH), 6.52 (1H, d, JZ2.8 Hz,
ArH), 6.79 (1H, d, JZ8.8 Hz, ArH); 13C NMR (75 MHz,
CDCl3): dZ55.5 (OCH3), 56.6 (OCH3), 69.8 (OCH2), 102.2
(CH), 103.6 (CH), 112.6 (CH), 117.8 (CH), 133.3 (CH),
143.9 (C), 148.9 (C), 154.2 (C); nmax (CHCl3)/cmK1: 1610,
1602, 1510; MS: m/zZ195 (MCC1, 55%), 194 (MC, 90),
153(100), 125(90), 110(30), 79(35), 69(40), 52(40), 41(53).
4. Experimental
1H and 13C NMR spectra were recorded either on a Bruker
AC-200, Bruker 300 or Bruker DRX 400 spectrometer at the
frequency indicated. All 13C signals in the aromatic/alkene
region have been assigned as quaternary (C) or non-
quaternary (CH). Infrared spectra were recorded on either a
Bruker IFS 25 Fourier Transform spectrometer or on a
Bruker Vector 22 Fourier Transform spectrometer. Mass
spectra were recorded on a Kratos MS 9/50, VG 70E MS or
a VG 70 SEQ mass spectrometer. Macherey–Nagel
kieselgel 60 (particle size 0.063–0.200 mm) was used for
4.1.2. 2-Allyloxybiphenyl 16. Allyl bromide (6.37 mL,
8.9 g, 7.4 mmol) and K2CO3 (10.2 g, 7.4 mmol) were added
to biphenyl-2-ol 8c (5.0 g, 2.9 mmol) dissolved in acetone
(100 mL) and the reaction slurry was then stirred at 60 8C
for 20 h. After cooling, the base was removed by filtration
through a Celite plug and the solvent was removed under
reduced pressure. The brown residue was then purified using

W. A. L. van Otterlo et al. / Tetrahedron 61 (2005) 7746–7755
7749
silica gel column chromatography (EtOAc/hexane) to afford
compound 16 as a yellow oil (6.2 g, 100%). (Found: MC,
210.1054, C15H14O requires 210.1045). 1H NMR
(300 MHz, CDCl3): dZ4.50–4.52 (2H, m, ArOCH2-
CHCH2), 5.16–5.26 [1H, m, ArOCH2CHC(H)H], 5.27–
5.34 [1H, m, ArOCH2CHC(H)H], 5.90–6.02 (1H, m,
ArOCH2CHCH2), 6.94–7.04 (2H, m, 2!ArH), 7.19–7.45
(4H, m, 4!ArH), 7.54–7.57 (2H, m, 2!ArH); 13C NMR
(75 MHz, CDCl3): dZ69.1 (ArOCH2), 113.0 (CH), 116.8
(CH), 121.1 (CH), 126.8 (CH), 127.9 (2!CH), 128.5 (CH),
129.6 (2!CH), 130.9 (CH), 131.1 (C), 133.3 (CH), 138.5
(C), 155.4 (C); IR nmax (CHCl3)/cmK1: 1638, 1590, 1497,
1458, 1433; MS: m/zZ211 (17), 210 (MC, 100%), 195 (12),
191 (11), 181 (18), 168 (14), 167 (20), 165 (29), 153 (13),
152 (21), 139 (10), 115 (21), 77 (13).
purified with column chromatography (5–20% EtOAc/
Hexane) to afford the desired product, 3-allyl-4-hydroxy-
benzaldehyde 9e (0.48 g, 41%) as a yellow oil. (Found: MC,
162.0684, C10H10O2 requires 162.0681). 1H NMR
(300 MHz, CDCl3): dZ3.47 (2H, br d, JZ7.5 Hz, ArCH2-
CHCH2), 5.13–5.19 (2H, m, ArCH2CH]CH2), 5.96–6.09
(1H, m, ArCH2CH]CH2), 6.97 (1H, d, JZ8.4 Hz, 5-H),
6.99 (1H, s under previous doublet, OH), 7.67–7.70 (2H, m,
2!ArH), 9.83 (1H, s, CHO); 13C NMR (75 MHz, CDCl3):
dZ32.7 (ArCH2), 115.4 (CH), 114.8 (CH), 125.2 (C), 127.9
(C), 129.2 (CH), 130.9 (CH), 133.8 (CH), 158.8 (C), 190.0
(CHO); IR nmax (CHCl3)/cmK1: 3256 br, 1687, 1593; m/zZ
163 (69%), 162 (MC, 100), 161 (90), 133 (55), 115 (38),
105 (49), 91 (37), 79 (36), 77 (50), 51 (31), 39 (33).
4.1.6. 2-Allyl-4-nitrophenol 9g. 4-Nitrophenol (1.17 g,
8.4 mmol) was irradiated with microwaves, (100 W,
215 8C, 15 min) to afford 2-allyl-4-nitrophenol 9g (0.62 g,
53%) after chromatography as a dark solid (mp 70–72 8C).
4.1.3. 2-Allyl-3,6-dimethoxyphenol 9a. 2-Allyloxy-1,4-
dimethoxybenzene 15 (1.0 g, 5.2 mmol) was heated without
solvent, under N2, at 220–240 8C for 40 min. The dark
brown residue was then subjected to purification by silica
gel chromatography (20% EtOAc/hexane) to afford 2-allyl-
3,6-dimethoxyphenol 9a as a light oily semi-solid (0.49,
49%). (Found: MC, 194.0943, C11H14O3 requires
1
(Found: MC, 179.0594, C9H9NO3 requires 179.0582). H
NMR (300 MHz, CDCl3): dZ3.47 (2H, br d, JZ6.3 Hz,
ArCH2CHCH2), 5.18–5.26 (2H, m, ArCH2CH]CH2),
5.94–6.08 (2H, m, ArOH and ArCH2CH]CH2), 6.89
(1H, dd, JZ9.4, 2.0 Hz, 3-H), 8.04–8.07 (2H, m, 2!
ArH); 13C NMR (75 MHz, CDCl3): dZ34.6 (ArCH2), 115.8
(CH), 118.0 (CH), 124.3 (CH), 126.4 (CH), 126.5 (C), 134.6
(CH), 141.6 (C), 159.8 (C); IR nmax (CHCl3)/cmK1: 1640,
1616, 1591, 1521, 1494, 1435; m/zZ180 (12%), 179 (MC,
100), 149 (7), 133 (12), 132 (12), 118 (11), 103 (12), 79
(14), 77 (24), 65 (10), 51 (11), 39 (12).
1
194.0943). H NMR (300 MHz, CDCl3): dZ3.43 (2H, br
d, JZ5.6 Hz, ArCH2CHCH2), 3.76 (3H, s, OCH3), 3.82
(3H, s, OCH3), 4.92–5.07 (2H, m, ArCH2CHCH2), 5.76
(1H, s, OH), 5.89–6.05 (1H, m, ArCH2CHCH2), 6.33 (1H, d,
JZ8.8 Hz, ArH), 6.65 (1H, d, JZ8.8 Hz, ArH); 13C NMR
(75 MHz, CDCl3): dZ27.4 (ArCH2), 55.8 (OCH3), 56.1
(OCH3), 100.9 (CH), 108.1 (CH), 114.1 (CH), 114.9 (C),
136.3 (CH), 141.0 (C), 144.2 (C), 152.4 (C); nmax (CHCl3)/
cmK1: 3506 br, 1639, 1601, 1493, 1464, 1440; MS: m/zZ
195 (MCC1.45%), 194 (MC, 91), 179 (100), 151 (84), 147
(50), 136 (35), 123 (24), 119 (26), 91 (46), 79 (22), 77 (26),
65 (20), 53 (30), 39 (20).
4.2. General procedure for the allylation of substituted
2-allylphenols to produce 1-allyl-2-allyloxybenzenes
Allyl bromide (2 mol equiv) and K2CO3 (2 mol equiv) were
added to the phenol 9 (ca. 3 mmol) dissolved in acetone
(100 mL) and the reaction slurry was then stirred at 60 8C
for 2 h. After cooling, the base was removed by filtration
and the solvent was removed under reduced pressure. The
brown residue was then purified using silica gel column
chromatography (EtOAc/hexane) to afford compound 10.
The following compounds were prepared using this
procedure:
4.1.4. 3-Allylbiphenyl-2-ol 9c. 2-Allyloxybiphenyl 16
(2.0 g, 9.5 mmol) was irradiated under microwave con-
ditions (power: 100 W, ramp time: 2 8C per min, tempera-
ture: 200 8C, maximum pressure 100 psi) in a pressure tube.
The irradiation was continued at 20 min intervals at, which
time the extent of the reaction was checked by TLC. After a
total irradiation time of 90 min the crude residue was
purified by silica gel column chromatography (10% EtOAc/
hexane) to afford the desired product 9c as a clear yellow oil
(1.2 g, 59%). (Found: MC, 210.1062, C15H14O requires
210.1045). 1H NMR (300 MHz, CDCl3): dZ3.47 (2H, br d,
JZ6.5 Hz, ArCH2CHCH2), 5.09–5.31 (2H, m, ArCH2-
CHCH2), 5.31 (1H, s, ArOH), 5.99–6.12 (1H, m, ArCH2-
CHCH2), 6.91–6.96 (1H, m, ArH), 7.11–7.15 (2H, m, 2!
ArH), 7.34–7.47 (5H, m, 5!ArH); 13C NMR (75 MHz,
CDCl3): dZ34.8 (ArCH2), 115.9 (CH), 120.5 (CH), 126.4
(C), 127.8 (CH), 128.2 (C), 128.4 (CH), 129.2 (3!CH),
129.3 (CH), 129.7 (CH), 136.6 (CH), 137.3 (C), 150.4 (C);
IR nmax (CHCl3)/cmK1: 3062, 3025, 1649, 1597, 1584,
1504, 1481, 1455, 1434; MS: m/zZ211 (12%), 210 (MC,
63), 195 (13), 178 (12), 176 (35), 169 (100), 168 (23), 163
(18), 141 (38), 139 (21), 115 (37), 41 (10).
4.2.1. 2-Allyl-3-allyloxy-1,4-dimethoxybenzene 10a. The
product 10a (0.53 g, 93%) was obtained as a clear oil from
9a (0.48 g, 2.4 mmol). (Found: MC, 234.1258, C14H18O
requires 234.1256). 1H NMR (300 MHz, CDCl3): dZ3.42–
3.45 (2H, m, ArCH2CHCH2), 3.77 (3H, s, OCH3), 3.80 (3H,
s, OCH3), 4.47–4.49 (2H, m, ArOCH2CHCH2), 4.92–5.01
(2H, m, ArCH2CHCH2), 5.20 [1H, dd, JZ10.3, 1.4 Hz,
ArOCH2CHC(H)H], 5.34–5.41 [1H, m, ArOCH2-
CHC(H)H], 5.90–6.16 (2H, m, ArOCH2CHCH2 and
ArCH2CHCH2), 6.56 (1H, d, JZ8.9 Hz, ArH), 6.73 (1H,
d, JZ8.9 Hz, ArH); 13C NMR (75 MHz, CDCl3): dZ28.3
(ArCH2), 56.0 (OCH3), 56.3 (OCH3), 73.9 (ArOCH2), 105.6
(CH), 110.2 (CH), 114.4 (CH), 116.9 (CH), 123.3 (C), 134.5
(CH), 137.0 (CH), 146.9 (C), 147.3 (C), 152.3 (C); IR nmax
(CHCl3)/cmK1: 1638, 1593, 1487, 1465, 1439; MS: m/zZ
234 (MC, 100%), 220 (21), 219 (39), 193 (94), 165 (44),
163 (33), 150 (26), 135 (23), 133 (26), 130 (62), 118 (18),
100 (18), 91 (28), 79 (22), 77 (27), 69 (97), 41 (31).
4.1.5. 3-Allyl-4-hydroxybenzaldehyde 9e. 4-Allyloxy-
benzaldehyde (1.18 g, 8.8 mmol) was irradiated with
microwaves (50 W) in a pressurized capsule for 10 min to
a maximum temperature of 250 8C. The dark residue was

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1
4.2.2. 1-Allyl-2-allyloxy-3,5-dimethoxybenzene 10b. The
product 10b (1.0 g, 61%) was obtained as a yellow oil from
9b (1.4 g, 7.1 mmol). (Found: MC, 234.1258, C14H18O3
202.0994). H NMR (300 MHz, CDCl3): dZ3.45 (2H, br
d, JZ6.7 Hz, ArCH2CHCH2), 4.63–4.66 (2H, m, ArOCH2-
CHCH2), 5.07–5.13 (2H, m, ArCH2CHCH2), 5.32 [1H, dd,
JZ10.6, 1.4 Hz, ArOCH2CHC(H)H], 5.44 [1H, dd, JZ
17.3, 1.5 Hz, ArOCH2CHC(H)H], 5.95–6.11 (2H, m,
ArOCH2CHCH2 and ArCH2CHCH2), 6.83 (1H, d, JZ
8.2 Hz, ArH), 6.93 (1H, d, JZ8.2 Hz, ArH), 7.71 (1H, br s,
ArH), 9.86 (1H, s, CHO); 13C NMR (75 MHz, CDCl3): dZ
34.2 (ArCH2), 68.9 (ArOCH2), 111.2 (CH), 116.4 (CH),
117.7 (CH), 126.0 (C), 130.7 (CH), 131.0 (CH), 132.4 (CH),
133.1 (C), 135.7 (CH), 161.3 (C), 191.1 (CHO); IR nmax
(CHCl3)/cmK1: 1689, 1639, 1595, 1492; MS: m/zZ203
(12%), 202 (MC, 85), 162 (38), 161 (39), 159 (25), 135 (26),
133 (50), 132 (10), 115 (15), 105 (30), 103 (12), 91 (13), 79
(13), 77 (25), 51 (12), 41 (100), 39 (25).
1
requires 234.1256). H NMR (300 MHz, CDCl3): dZ3.39
(2H, br d, JZ6.6 Hz, ArCH2CHCH2), 3.76 (3H, s, OCH3),
3.82 (3H, s, OCH3), 4.40 (2H, br d, JZ5.7 Hz, ArOCH2-
CHCH2), 5.03–5.11 (2H, m, ArCH2CHCH2), 5.20 [1H, dd,
JZ10.4, 1.3 Hz, ArOCH2CHC(H)H], 5.35 [1H, br dd, JZ
17.2, 1.6 Hz, ArOCH2CHC(H)H], 5.88–6.15 (2H, m,
ArOCH2CHCH2 and ArCH2CHCH2), 6.29 (1H, d, JZ
2.9 Hz, ArH), 6.37 (1H, d, JZ2.9 Hz, ArH); 13C NMR
(75 MHz, CDCl3): dZ34.5 (ArCH2), 55.5 (OCH3), 55.7
(OCH3), 74.0 (ArOCH2), 98.2 (CH), 105.0 (CH), 115.7
(CH), 117.0 (CH), 134.2 (C), 134.5 (CH), 137.1 (CH), 139.8
(C), 153.4 (C), 156.0 (C); IR nmax (CHCl3)/cmK1: 1638,
1600, 1489, 1466, 1424; MS: m/zZ234 (MC, 20%), 193
(100), 165 (11), 161 (13), 135 (6), 133 (30), 118 (10), 105
(5), 91 (12), 79 (7), 65 (8), 41 (15).
4.2.6. 1-Allyl-2-allyloxy-3-nitrobenzene19d 10f. The
product 10f (0.13 g, 71%) was obtained as a dark orange
oil from 9f (0.15 g, 0.84 mmol). 1H NMR (300 MHz,
CDCl3): dZ3.42 (2H, d, JZ6.4 Hz, ArCH2CHCH2), 4.42
(2H, d, JZ5.8 Hz, ArOCH2CHCH2), 4.99–5.09 (2H, m,
ArCH2CHCH2), 5.22 [1H, br d, JZ10.4 Hz, ArOCH2-
CHC(H)H], 5.32 [1H, dd, JZ17.2, 1.5 Hz, ArOCH2-
CHC(H)H], 5.84–6.04 (2H, m, ArOCH2CHCH2 and
ArCH2CHCH2), 7.07–7.12 (1H, m, ArH), 7.37 (1H, d, JZ
7.7 Hz, ArH), 7.61 (1H, dd, JZ8.1, 1.6 Hz, ArH); 13C NMR
(75 MHz, CDCl3, one quaternary carbon not observed): dZ
30.9 (ArCH2), 76.0 (ArOCH2), 117.0 (CH), 118.7 (CH),
123.4 (CH), 123.9 (CH), 132.7 (CH), 134.9 (CH), 135.7 (C),
136.6 (C), 150.1 (C).
4.2.3. 3-Allyl-2-allyloxybiphenyl 10c. The product 10c
(0.67 g, 81%) was obtained as a light yellow oil from 9c
(0.69 g, 3.3 mmol). (Found: MC, 250.1360, C18H18O
1
requires 250.1358). H NMR (300 MHz, CDCl3): dZ3.49
(2H, br d, JZ6.6 Hz, ArCH2CHCH2), 3.91 (2H, br d, JZ
5.7 Hz, ArOCH2CHCH2), 5.04–5.14 (4H, m, ArCH2-
CHCH2 and ArOCH2CHCH2), 5.70–5.83 (1H, m, ArCH2-
CHCH2), 5.96–6.10 (1H, m, ArOCH2CHCH2), 7.09–7.29
(3H, m, 3!ArH), 7.32–7.42 (3H, m, 3!ArH), 7.56–7.59
(2H, m, 2!ArH); 13C NMR (75 MHz, CDCl3, one
quaternary carbon not observable in spectrum): dZ34.4
(ArCH2), 73.7 (ArOCH2), 115.8 (CH), 117.2 (CH), 124.1
(CH), 127.1 (CH), 128.2 (2!CH), 129.1 (2!CH), 129.2
(CH), 129.4 (CH), 133.8 (CH), 135.1 (C), 137.4 (CH), 138.9
(C), 154.3 (C); IR nmax (CHCl3)/cmK1: 1638, 1600, 1498,
1459, 1431; MS: m/zZ250 (MC, 55%), 235 (15), 221 (16),
214 (28), 209 (28), 194 (42), 181 (57), 178 (25), 175 (24),
168 (100), 166 (20), 165 (65), 153 (16), 152 (26), 139 (16),
132 (21), 115 (29), 77 (17), 41 (47).
4.2.7. 1-Allyl-2-allyloxy-3-nitrobenzene 10g. The product
10g (0.24 g, 93%) was obtained as an orange oil from 12e
(0.21 g, 1.2 mmol). The HRMS molecular ion was not
observed as the expected mass of 219.0895 (C12H13NO3)
was obscured by a reference compound fragment (perfluoro-
tributylamine); however, the deallylated fragment was
evident: (Found: MC, 178.0517, C9H8NO3 requires
1
178.0504). H NMR (300 MHz, CDCl3): dZ3.45 (2H, br
4.2.4. 3-Allyl-2-allyloxybenzaldehyde 10d. The product
10d (0.27 g, 77%) was obtained as an clear oil from 9d
(0.31 g, 1.9 mmol). (Found: MC, 202.1001, C13H14O2
d, JZ6.7 Hz, ArCH2CHCH2), 4.65–4.67 (2H, m, ArOCH2-
CHCH2), 5.09–5.15 (2H, m, ArCH2CHCH2), 5.30–5.47
(2H, m, ArOCH2CHCH2), 5.91–6.11 (2H, m, ArOCH2-
CHCH2 and ArCH2CHCH2), 6.88 (1H, d, JZ8.9 Hz, 3-H),
8.06–8.13 (2H, m, 2!ArH); 13C NMR (75 MHz, CDCl3):
dZ34.1 (ArCH2), 69.3 (ArOCH2), 110.8 (CH), 117.0 (CH),
118.1 (CH), 123.9 (CH), 125.4 (CH), 130.1 (C), 132.0 (CH),
1
requires 202.0994). H NMR (300 MHz, CDCl3): dZ3.47
(2H, br d, JZ6.4 Hz, ArCH2CHCH2), 4.46 (2H, br d, JZ
5.7 Hz, ArOCH2CHCH2), 5.06–5.15 (2H, m, ArCH2-
CHCH2), 5.31 [1H, dd, JZ10.4, 1.0 Hz, ArOCH2-
CHC(H)H], 5.43 [1H, dd, JZ17.1, 1.4 Hz,
ArOCH2CHC(H)H], 5.91–6.16 (2H, m, ArOCH2CHCH2
and ArCH2CHCH2), 7.17–7.22 (1H, m, ArH), 7.47 (1H, dd,
JZ7.6, 1.6 Hz, ArH), 7.72 (1H, dd, JZ7.6, 1.6 Hz, ArH),
10.37 (1H, s, CHO); 13C NMR (75 MHz, CDCl3, assign-
ments with the same superscript may be interchanged): dZ
33.3 (ArCH2), 77.5 (ArOCH2), 116.5 (CH), 118.5 (CH),
124.6 (CH), 126.9 (CH), 129.6 (C),a 132.6 (CH),a 134.4
(C),b 136.3 (CH),b 136.8 (CH), 160.1 (C), 190.3 (CHO); IR
nmax (CHCl3)/cmK1: 1685, 1639, 1589, 1477, 1447; MS:
m/zZ218 (57%), 202 (MC, 58), 187 (22), 173 (20), 161
(75), 145 (35), 133 (77), 132 (80), 131 (89), 115 (50), 105
(43), 91 (33), 77 (52), 51 (31), 41 (100).
135.0 (CH), 141.3 (C), 161.2 (C); IR nmax (CHCl3)/cmK1
:
1640, 1611, 1590, 1519, 1455, 1425, 1341; MS: m/zZ219
(MC, 100%), 178 (13), 152 (4), 131 (29), 119 (5), 100 (8),
77 (9), 69 (70), 41 (71), 28 (69).
4.2.8. 2-Allyl-3-allyloxy-4-methoxybenzaldehyde 10h.
The product 10h (0.53 g, 93%) was obtained as a pale oil
from 9h (0.48 g, 2.4 mmol). (Found: MC, 232.1085,
C14H16O3 requires 232.1099). 1H NMR (300 MHz,
CDCl3): dZ3.88 (2H, br d, JZ5.8 Hz, ArCH2CHCH2),
3.93 (3H, s, OCH3), 4.47 (2H, br d, JZ5.7 Hz, ArOCH2-
CHCH2), 4.89–5.04 (2H, m, ArCH2CHCH2), 5.24 [1H, dd,
JZ10.7, 1.1 Hz, ArOCH2CHC(H)H], 5.38 [1H, dd, JZ
17.2, 1.4 Hz, ArOCH2CHC(H)H], 6.03–6.10 (2H, m,
ArOCH2CHCH2 and ArCH2CHCH2), 6.92 (1H, d, JZ
8.6 Hz, ArH), 7.65 (1H, d, JZ8.6 Hz, ArH), 10.06 (1H, s,
CHO); 13C NMR (75 MHz, CDCl3): dZ28.9 (ArCH2), 55.8
4.2.5. 3-Allyl-4-allyloxybenzaldehyde 10e. The product
10e (0.86 g, 89%) was obtained as a pale oil from 9e (0.90 g,
5.5 mmol). (Found: MC, 202.0988, C13H14O2 requires

W. A. L. van Otterlo et al. / Tetrahedron 61 (2005) 7746–7755
7751
(OCH3), 74.0 (ArOCH2), 109.8 (CH), 115.6 (CH), 117.5
(CH), 128.0 (C), 128.9 (CH), 133.9 (CH), 136.3 (CH), 137.0
(C), 146.1 (C), 157.5 (C), 190.9 (CHO); IR nmax (CHCl3)/
cmK1: 1682, 1586, 1441; MS: m/zZ232 (MC, 37%), 217
(24), 191 (100), 190 (10), 175 (11), 164 (12), 163 (16), 148
(18), 135 (46), 120 (10), 105 (31), 103 (23), 91 (25), 77 (17),
65 (14), 43 (12), 41 (20), 39 (16).
ArOCH2CHCH2), 4.98–5.03 (2H, m, ArCH2CHCH2), 5.26
[1H, dd, JZ10.5, 0.8 Hz, ArOCH2CHC(H)H], 5.43 [1H, br
d, JZ17.2 Hz, ArOCH2CHC(H)H], 5.98–6.13 (2H, m,
ArOCH2CHCH2 and ArCH2CHCH2), 7.24 (1H, d, JZ
9.2 Hz, ArH), 7.30–7.35 (1H, m, ArH), 7.43–7.48 (1H, m,
ArH), 7.71 (1H, d, JZ9.0 Hz, ArH), 7.77 (1H, d, JZ8.1 Hz,
ArH), 7.94 (1H, d, JZ8.5 Hz, ArH); 13C NMR (75 MHz,
CDCl3): dZ29.3 (ArCH2), 70.3 (ArOCH2), 114.9 (CH),
115.1 (CH), 117.1 (CH), 121.7 (C), 123.4 (CH), 123.6 (CH),
126.2 (CH), 127.9 (CH), 128.4 (CH), 129.4 (C), 133.2 (C),
4.2.9. 2-Allyl-1-allyloxy-4-tert-butylbenzene19f 10i. The
product 10i (0.57 g, 90%) was obtained as a yellow oil from
133.8 (CH), 136.7 (CH), 153.5 (C); IR nmax (CHCl3)/cmK1
:
1
9i (0.52 g, 2.7 mmol). H NMR (300 MHz, CDCl3): dZ
1640, 1593, 1549, 1513, 1463, 1429; MS: m/zZ225 (17%),
224 (MC, 100), 183 (60), 181 (22), 165 (30), 155 (62), 153
(22), 152 (16), 128 (17), 115 (13), 55 (6), 41 (8).
1.29 [9H, s, C(CH3)3], 3.41 (2H, br d, JZ6.6 Hz, ArCH2-
CHCH2), 4.50–4.53 (2H, m, ArOCH2CHCH2), 5.01–5.10
(2H, m, ArCH2CHCH2), 5.23 [1H, dd, JZ10.6, 1.6 Hz,
ArOCH2CHC(H)H], 5.41 [1H, dd, JZ17.3, 1.6 Hz,
ArOCH2CHC(H)H], 6.00–6.06 (2H, m, ArOCH2CHCH2
and ArCH2CHCH2), 6.76 (1H, d, JZ9.2 Hz, ArH), 7.15–
7.17 (2H, m, 2!ArH).
4.3. General procedure for the isomerization of sub-
stituted 1-allyl-2-allyloxybenzenes to produce 1-(prop-1-
enyl)-2-(prop-1-enyloxy)benzenes
Typically, 1-allyl-2-allyloxybenzene 10 (ca. 1 mmol) and
[RuClH(CO)(PPh3)3] 13 (5 mol%) were dissolved in
distilled, degassed toluene (5 mL). The reaction was heated
at 65 8C for 14 h and the completion of the reaction was
confirmed by NMR spectroscopy of a crude sample. The
reaction solution was purified by filtration through a short
silica gel pad (5% EtOAc/hexane) and evaporated under
reduce pressure to afford the product, 11, as a mixture of E,Z
isomers. The following compounds, some, which were used
in the next reaction without further characterization, were
prepared using this procedure, unless otherwise mentioned:
4.2.10. 2-Allyl-1-allyloxy-4-bromobenzene 10j. The
product 10j (0.42 g, 25%) was obtained as a light yellow
oil from 9j (1.4 g, 6.6 mmol). (Found: MC, 252.0133,
C12H13OBr requires 252.0150). 1H NMR (300 MHz,
CDCl3): dZ3.37 (2H, br d, JZ6.7 Hz, ArCH2CHCH2),
4.50–4.52 (2H, m, ArOCH2CHCH2), 5.05–5.11 (2H, m,
ArCH2CHCH2), 5.27 [1H, dd, JZ10.6, 1.5 Hz, ArOCH2-
CHC(H)H], 5.40 [1H, dd, JZ17.3, 1.5 Hz, ArOCH2-
CHC(H)H], 5.88–6.09 (2H, m, ArOCH2CHCH2 and
ArCH2CHCH2), 6.70 (1H, dd, JZ5.6, 3.8 Hz, ArH), 7.25–
7.27 (2H, m, 2!ArH); 13C NMR (75 MHz, CDCl3): dZ
34.1 (ArCH2), 69.0 (ArOCH2), 112.9 (C), 113.3 (CH), 116.2
(CH), 117.3 (CH), 129.8 (CH), 131.3 (C), 132.5 (CH), 133.0
(CH), 136.0 (CH), 155.3 (C); IR nmax (CHCl3)/cmK1: 1638,
1591, 1487, 1455, 1424, 1410; MS: m/zZ254, (56%), 252
(MC, 56), 220 (31), 210 (37), 209 (20), 185 (18), 132 (100),
118 (19), 104 (33), 103 (17), 55 (14).
4.3.1. 1,4-Dimethoxy-2-(prop-1-enyl)-3-(prop-1-enyloxy)
benzene 11a. The product 11a (0.30 g, 99%) was obtained
as a dark oil from 10a (0.31 g, 1.3 mmol) and used without
further characterization.
4.3.2. 1,5-Dimethoxy-3-(prop-1-enyl)-2-(prop-1-enyloxy)
benzene 11b. 1-Allyl-2-allyloxy-3,5-dimethoxybenzene
10b (0.21 g, 0.91 mmol) and [RuClH(CO)(PPh3)3] 13
(5 mol%) were dissolved in distilled, degassed CH2Cl2
(10 mL). The reaction was stirred at 45 8C under N2 for 48 h
and the completion of the reaction was confirmed by NMR
spectroscopy of a crude sample. The reaction solution was
purified by filtration through a short silica gel pad (5%
EtOAc/hexane) to afford the product, 11b, after evaporation
of the solvent. Compound 11b (0.21 g, quantitative) was
obtained as a clear oil as a mixture of E,Z isomers.
4.2.11. 2-Allyl-1-allyloxynaphthalene 10k. The product
10k (0.86 g, 99%) was obtained as an yellow oil from 9k
(0.71 g, 3.9 mmol). (Found: MC, 224.1204, C16H16O
1
requires 224.1201). H NMR (300 MHz, CDCl3): dZ3.60
(2H, d, JZbr 6.4 Hz, ArCH2CHCH2), 4.50 (2H, dd, JZ5.9,
0.9 Hz, ArOCH2CHCH2), 5.07–5.13 (2H, m, ArCH2-
CHCH2), 5.32 [1H, br d, JZ10.4 Hz, ArOCH2CHC(H)H],
5.51 [1H, br d, JZ17.2 Hz, ArOCH2CHC(H)H], 5.97–6.10
(1H, m, ArCH2CHCH2), 6.14–6.27 (1H, m, ArOCH2-
CHCH2), 7.32 (1H, d, JZ8.5 Hz, ArH), 7.41–7.51 (2H,
m, 2!ArH), 7.57 (1H, d, JZ8.5 Hz, ArH), 7.81 (1H, d, JZ
7.8 Hz, ArH), 8.09 (1H, d, JZ8.1 Hz, ArH); 13C NMR
(75 MHz, CDCl3, one quaternary carbon not observable in
spectrum): dZ34.0 (ArCH2), 75.3 (ArOCH2), 115.9 (CH),
117.3 (CH), 122.1 (CH), 124.0 (CH), 125.5 (CH), 125.9
(CH), 127.9 (CH), 128.3 (CH), 128.4 (C), 133.8 (CH), 133.9
(C), 137.2 (CH), 152.2 (C); IR nmax (CHCl3)/cmK1: 1638,
1598, 1572, 1507, 1465; MS: m/zZ224 (MC, 61%), 184
(15), 183 (100), 182 (17), 181 (25), 165 (57), 154 (12), 153
(28), 152 (23), 139 (11), 128 (25), 127 (19), 115 (20), 41 (11).
4.3.3. 3-(Prop-1-enyl)-2-(prop-1-enyloxy)biphenyl 11c.
The product 11c (0.23 g, 98%) was obtained as a dark oil
from 10c (0.24 g, 0.94 mmol). (Found: MC, 250.1333,
C18H18O requires 250.1358); MS: m/zZ250 (MC, 100%),
236 (21), 235 (98), 221 (64), 208 (26), 207 (37), 194 (80),
191 (26), 179 (22), 178 (50), 168 (21), 166 (28), 165 (89),
152 (46), 115 (41).
4.3.4. 3-(Prop-1-enyl)-2-(prop-1-enyloxy)benzaldehyde
11d. The product 11d (0.13 g, 57%) was obtained as a
yellow oil from 10d (0.23 g, 1.1 mmol) and used without
further characterization.
4.2.12. 1-Allyl-2-allyloxynaphthalene 10l. The product 10l
(0.15 g, 41%) was obtained as a clear oil from 9l (0.30 g,
1.6 mmol). (Found: MC, 224.1212, C16H16O requires
1
224.1201). H NMR (300 MHz, CDCl3): dZ3.88 (2H, br
4.3.5. 3-(Prop-1-enyl)-4-(prop-1-enyloxy)benzaldehyde
11e. The product 11e (0.41 g, 82%) was obtained as a
d, JZ5.9 Hz, ArCH2CHCH2), 4.66 (2H, dd, JZ3.7, 1.3 Hz,

7752
W. A. L. van Otterlo et al. / Tetrahedron 61 (2005) 7746–7755
yellow oil from 10e (0.50 g, 2.5 mmol) and used without
further characterization.
from 11a (0.17 g, 0.71 mmol). (Found: MC, 178.0644,
C10H10O3 requires 178.0630). 1H NMR (300 MHz, CDCl3):
dZ3.89 (3H, s, OCH3), 3.96 (3H, s, OCH3), 6.53 (1H, d, JZ
8.5 Hz, ArH), 6.70 (1H, d, JZ8.5 Hz, ArH), 6.86 (1H, d,
JZ2.1 Hz, 3-H), 7.55 (1H, d, JZ2.1 Hz, 2-H); 13C NMR
(75 MHz, CDCl3, one quaternary carbon not observable in
spectrum): dZ55.8 (OCH3), 56.5 (OCH3), 102.7 (CH),
104.4 (CH), 106.8 (CH), 119.5 (C), 140.4 (C), 143.9 (CH),
147.6 (C); IR nmax (CHCl3)/cmK1: 1607, 1590, 1540, 1504,
1461; MS: m/zZ178 (MC, 65%), 163 (100), 135 (8), 120
(8), 92 (6), 76 (5), 63 (6).
4.3.6.
1-Nitro-3-(prop-1-enyl)-2-(prop-1-enyloxy)-
benzene 11f. The product 11f (0.47 g, 94%) was obtained
as a dark oil from 10f (0.50 g, 2.3 mmol). The compound
11f was purified by chromatography through a short silica
gel plug and was then immediately used in the subsequent
RCM reaction.
4.3.7.
4-Nitro-2-(prop-1-enyl)-1-(prop-1-enyloxy)-
benzene 11g. The product 11g (0.15 g, 85%) was obtained
as an orange oil from 10g (0.17 g, 0.79 mmol) and used
without further characterization.
4.4.2. 5,7-Dimethoxybenzofuran 12b. The product 12b
(0.16 g, 96%) was obtained as a clear oil from 11b (0.21 g,
0.91 mmol). RCM was done in toluene at room temperature
for 24 h with 6% catalyst 14. (Found: MC, 178.0639,
C10H10O3 requires 178.0630). 1H NMR (300 MHz, CDCl3):
dZ Found: MC, 178.0644, C10H10O3 requires 178.0630).
1H NMR (300 MHz, CDCl3): dZ3.83 (3H, s, OCH3), 3.97
(3H, s, OCH3), 6.45 (1H, d, JZ2.2 Hz, ArH), 6.63 (1H, d,
JZ2.2 Hz, ArH), 6.69 (1H, d, JZ2.0 Hz, 3-H), 7.58 (1H, d,
JZ2.0 Hz, 2-H); 13C NMR (75 MHz, CDCl3): dZ55.8
(OCH3), 56.0 (OCH3), 94.5 (CH), 97.0 (CH), 107.0 (CH),
128.7 (C), 139.7 (C), 145.4 (CH), 145.6 (C), 156.8 (C); IR
nmax (CHCl3)/cmK1: 1606, 1542, 1481, 1454, 1433; MS:
m/zZ179 (12%), 178 (MC, 100), 163 (15), 149 (8), 135
(33), 133 (6), 132 (6), 120 (8), 92 (7), 77 (5), 76 (5).
4.3.8. 4-Methoxy-2-(prop-1-enyl)-3-(prop-1-enyloxy)
benzaldehyde 11h. The product 11h (0.27 g, 54%) was
obtained as a light oil from 10h (0.50 g, 2.2 mmol). The
compound 11h was purified by chromatography through a
short silica gel plug and was then immediately used in the
subsequent RCM reaction.
4.3.9. 4-tert-Butyl-2-(prop-1-enyl)-1-(prop-1-enyloxy)
benzene 11i. The product 11i (0.19 g, 86%) was obtained
as a light oil from 10i (0.22 g, 0.97 mmol). (Found: MC,
230.1648, C16H22O requires 230.1671); MS: m/zZ230
(MC, 24%), 216 (17), 215 (100), 173 (7), 159 (13), 128 (8),
115 (11), 91 (9), 41 (13).
4.4.3. 7-Phenylbenzofuran 12c. The product 12c (0.051 g,
63%) was obtained as a yellow oil from 11c (0.10 g,
0.42 mmol). (Found: MC, 194.0711, C14H10O requires
4.3.10. 4-Bromo-2-(prop-1-enyl)-1-(prop-1-enyloxy)-
benzene 11j. The product 11j (0.23 g, 100%) was obtained
as a dark oil from 10j (0.23 g, 0.92 mmol). (Found: MC,
252.0150, C12H13OBr requires 252.0150); MS: m/zZ254
(52%), 252 (MC, 54), 239 (33), 237 (35), 225 (59), 223 (60),
218 (26), 210 (23), 198 (28), 196 (27), 173 (40), 158 (100),
145 (21), 144 (22), 132 (55), 130 (32), 116 (21), 115 (87),
103 (30), 89 (26), 69 (20), 63 (23), 41 (20).
1
194.0732). H NMR (300 MHz, CDCl3): dZ6.83 (1H, d,
JZ2.2 Hz, 3-H), 7.32–7.52 (5H, m, 5!ArH), 7.58 (1H, dd,
JZ7.7, 1.1 Hz, ArH), 7.67 (1H, d, JZ2.2 Hz, 2-H), 7.84–
7.87 (2H, m, 2!ArH); 13C NMR (75 MHz, CDCl3, one
quaternary carbon not observable in spectrum): dZ106.8
(CH), 120.4 (CH), 123.3 (CH), 123.8 (CH), 127.6 (CH),
128.5 (2!CH), 128.6 (2!CH), 129.3 (C), 136.5 (C), 145.0
(CH), 153.0 (C); IR nmax (CHCl3)/cmK1: 1668, 1596, 1542,
1499, 1474, 1451, 1412; MS: m/zZ195 (17%), 194 (MC,
100), 165 (53), 163 (10), 139 (12), 115 (9), 63 (7).
4.3.11. 2-(Prop-1-enyl)-1-(prop-1-enyloxy)naphthalene
11k. The product 11k (0.27 g, 93%) was obtained as a
dark yellow oil from 10k (0.29 g, 1.3 mmol). (Found: MC,
224.1205, C16H16O requires 224.1201; MS: m/zZ224 (MC,
64%), 219 (45), 213 (26), 210 (16), 209 (94), 196 (17), 195
(100), 194 (17), 183 (15), 182 (15), 181 (38), 168 (34), 165
(57), 155 (27), 153 (24), 152 (34), 141 (17), 139 (21), 128
(23), 127 (18), 115 (30).
4.4.4. Benzofuran-7-carbaldehyde21 12d. The product 12d
(0.048 g, 70%) was obtained as a clear oil from 11d
(0.095 g, 0.47 mmol). (Found: MC, 146.0374, C9H6O2
1
requires 146.0368). H NMR (300 MHz, CDCl3): dZ6.86
(1H, d, JZ2.2 Hz, 3-H), 7.36–7.41 (1H, m, ArH), 7.78 (1H,
d, JZ2.2 Hz, 2-H), 7.79–7.81 (1H, m, ArH), 7.87 (1H, dd,
JZ7.8, 1.0 Hz, ArH), 10.44 (1H, s, CHO); 13C NMR
(75 MHz, CDCl3): dZ106.3 (CH), 121.2 (C), 122.9 (CH),
126.2 (CH), 127.6 (CH), 129.1 (C), 146.2 (CH), 153.7 (C),
188.8 (CHO); IR nmax (CHCl3)/cmK1: 1699, 1607, 1541,
1477, 1431; MS: m/zZ146 (MC, 92%), 145 (100), 117 (33),
89 (44), 63 (33), 51 (7), 39 (12).
4.4. General procedure for the RCM of substituted
1-(prop-1-enyl)-2-(prop-1-enyloxy)benzenes to
benzofurans
Catalyst 14 (5 mol%) was added to compound 11 (ca.
0.5 mmol) dissolved in distilled degassed toluene (3–5 mL).
The reaction mixture was then stirred at 90 8C for 3 h under
N2. After cooling, the reaction mixture was filtered through
a Celite plug and the solvent was removed under vacuum.
The dark oil was further purified by column chromato-
graphy (10% EtOAc/hexane) to afford product 12. The
following compounds were prepared using this procedure
unless otherwise mentioned:
4.4.5. Benzofuran-5-carbaldehyde22 12e. The product 12e
(0.020 g, 50%) was obtained as a light coloured semi-solid
from 11e (0.060 g, 0.30 mmol). (Found: MC, 146.0369,
C10H8O2 requires 146.0369). 1H NMR (300 MHz, CDCl3):
dZ6.88–6.89 (1H, m, 3-H), 7.61 (1H, d, JZ8.5 Hz, 7-H),
7.72 (1H, d, JZ2.2 Hz, 2-H), 7.87 (1H, dd, JZ8.5, 1.6 Hz,
6-H), 8.14 (1H, d, JZ1.6 Hz, 4-H), 10.06 (1H, s, CHO); 13C
NMR (75 MHz, CDCl3): dZ107.6 (CH), 112.6 (CH), 125.0
4.4.1. 4,7-Dimethoxybenzofuran20 12a. The product 12a
(0.13 g, 100%) was obtained as a low melting point solid

W. A. L. van Otterlo et al. / Tetrahedron 61 (2005) 7746–7755
7753
(CH), 126.1 (CH), 128.4 (C), 132.7 (C), 147.1 (CH), 158.7
(C), 192.1 (CHO); IR nmax (CHCl3)/cmK1: 1693, 1609,
1587, 1540; MS: m/zZ146 (MC, 95%), 145 (100), 117 (53),
89 (35), 63 (22).
123.8 (CH), 127.1 (CH), 129.4 (C), 146.1 (CH), 153.7 (C);
MS: m/zZ198 (72%), 196 (MC, 43), 194 (30), 180 (23),
165 (19), 149 (22), 132 (46), 115 (24), 111 (30), 109 (22), 97
(43), 89 (38), 85 (50), 83 (57), 82 (20), 81 (35), 72 (35), 71
(60), 70 (25), 69 (62), 67 (24), 63 (33), 57 (100), 55 (81), 43
(92), 41 (64).
4.4.6. 7-Nitrobenzofuran5 12f. The product 12f (0.22 g,
82%) was obtained as a dark oily solid from 11f (0.36 g,
1
4.4.11. Naphtho[1,2-b]furan26 12k. The product 12k
(0.27 g, 92%) was obtained as a yellow oil from 11k
(0.39 g, 1.7 mmol). (Found: MC, 168.0573, C12H8O
1.6 mmol). H NMR (300 MHz, CDCl3): dZ6.94 (1H, d,
JZ2.2 Hz, 3-H), 7.36–7.41 (1H, m, ArH), 7.85 (1H, d, JZ
2.2 Hz, 2-H), 7.94 (1H, dd, JZ7.8, 0.8 Hz, ArH), 8.17 (1H,
d, JZ8.2 Hz, ArH); 13C NMR (75 MHz, CDCl3, one
quaternary carbon not observable in spectrum): dZ106.9
(CH), 120.9 (CH), 122.8 (CH), 126.5 (C), 128.2 (CH), 128.7
(C), 147.3 (CH); IR nmax (CHCl3)/cmK1: 1609, 1525, 1466,
1350.
1
requires 168.0575). H NMR (300 MHz, CDCl3): dZ6.89
(1H, d, JZ2.1 Hz, 3-H), 7.45–7.50 (1H, m, ArH), 7.52–7.61
(1H, m, ArH), 7.65 (2H, br s, 2!ArH), 7.75 (1H, d, JZ
2.1 Hz, 2-H), 7.92 (1H, d, JZ8.1 Hz, ArH), 8.31 (1H, d, JZ
8.1 Hz, ArH); 13C NMR (75 MHz, CDCl3): dZ107.6 (CH),
119.7 (CH), 120.0 (CH), 121.5 (C), 122.9 (C), 123.4 (CH),
125.1 (CH), 126.3 (CH), 128.3 (CH), 131.4 (C), 144.1 (CH),
150.6 (C); IR nmax (CHCl3)/cmK1: 1605, 1511, 1450; MS:
m/zZ168 (MC, 61%), 139 (26), 130 (47), 100 (11), 69 (76).
4.4.7. 5-Nitrobenzofuran23 12g. The product 12g (0.072 g,
92%) was obtained as a semi-solid from 11g (0.10 g,
0.48 mmol). The HRMS molecular ion was not found as the
expected mass of 163.0269 (C8H5NO3) was obscured by a
1
4.4.12. Naphtho[2,1-b]furan23 12l. Isomerization catalyst
13 (1 mol%) was added to compound 10l (0.13 g,
0.60 mmol) dissolved in distilled toluene (10 mL). The
reaction mixture was then stirred at 80 8C for 4 h under N2.
Catalyst 14 (5 mol%) was then added and the reaction
mixture was heated at 80 8C for 12 h. After cooling, the
reaction mixture was filtered through a Celite plug and the
solvent was removed under vacuum. The resultant dark oil
was further purified by column chromatography (2%
EtOAc/hexane) to afford product 12l (0.030 g, 31% over
reference compound fragment (perfluorotributylamine). H
NMR (300 MHz, CDCl3): dZ6.93 (1H, d, JZ2.3 Hz, 3-H),
7.57 (1H, d, JZ9.0 Hz, 7-H), 7.79 (1H, d, JZ2.2 Hz, 4-H),
8.22 (1H, dd, JZ9.0, 2.3 Hz, 6-H), 8.53 (1H, d, JZ2.2 Hz,
2-H); 13C NMR (75 MHz, CDCl3): dZ107.5 (CH), 111.7
(CH), 117.8 (CH), 120.1 (CH), 127.8 (C), 144.1 (C), 148.0
(CH), 157.6 (C); IR nmax (CHCl3)/cmK1: 1620, 1594, 1541,
1507, 1446, 1359; MS: m/zZ163 (MC, 100%), 149 (5), 133
(9), 117 (31), 105 (5), 89 (39), 69 (10), 63 (21), 43 (10).
1
4.4.8. 7-Methoxybenzofuran-4-carbaldehyde 12h. The
product 12h (0.09 g, 50%) was obtained as light oil from
11h (0.24 g, 0.10 mmol). (Found: MC, 176.0460, C10H8O3
two steps) as a pale oily semi-solid. H NMR (300 MHz,
CDCl3): dZ7.25 (1H, d, JZ2.1 Hz, 2-H), 7.46–7.51 (1H, m,
Ar-H), 7.56–7.61 (1H, m, Ar-H), 7.66 (1H, d, JZ9.0 Hz, Ar-
H), 7.73 (1H, d, JZ9.0 Hz, Ar-H), 7.76 (1H, d, JZ2.1 Hz,
3-H), 7.95 (1H, d, JZ8.1 Hz, Ar-H), 8.14 (1H, d, JZ8.1 Hz,
Ar-H); 13C NMR (75 MHz, CDCl3): dZ105.6 (CH), 112.5
(CH), 122.6 (C), 123.4 (CH), 124.5 (CH), 125.2 (CH), 126.3
(CH), 127.8(C),128.7(CH), 130.3(C),144.2(CH), 152.5(C);
IR nmax (CHCl3)/cmK1: 1628, 1582, 1516, 1458.
1
requires 176.0473). H NMR (300 MHz, CDCl3): dZ4.10
(3H, s, OCH3), 6.91 (1H, d, JZ8.2 Hz, 6-H), 7.53 (1H, d,
JZ2.0 Hz, 3-H), 7.68 (1H, d, JZ8.2 Hz, 5-H), 7.78 (1H, d,
JZ2.0 Hz, 2-H), 10.05 (1H, s, CHO); 13C NMR (75 MHz,
CDCl3): dZ56.4 (OCH3), 105.8 (CH), 107.2 (CH), 123.2
(C), 127.9 (C), 131.8 (CH), 144.4 (C), 147.5 (CH), 150.2
(C), 190.6 (CHO); IR nmax (CHCl3)/cmK1: 1684, 1624,
1540, 1500; MS: m/zZ176 (MC, 100%), 175 (83), 147 (12),
105 (8), 89 (9), 77 (10), 51 (8).
Acknowledgements
4.4.9. 5-tert-Butyl-benzofuran24 12i. The product 12i
(0.055 g, 70%) was obtained as a clear oil from 11i
(0.10 g, 0.44 mmol). (Found: MC, 174.1029, C12H14O
This work was supported by the National Research
Foundation (NRF, GUN 2053652), Pretoria, and the
University of the Witwatersrand (University and Science
Faculty Research Councils, Friedel Sellschop Award). Prof.
J. P. Michael is thanked for many helpful discussions. We
also gratefully acknowledge the Mellon Postgraduate
Mentoring Programme (sponsored by the Andrew W.
Mellon Foundation) for generous funding for Mr. S. S.
Moleele. Mr. R. Mampa and Mr. T. van der Merwe are also
thanked for providing the NMR and MS spectroscopy
services, respectively. A referee is thanked for drawing our
attention to relevant additional literature.
1
requires 174.1045). H NMR (300 MHz, CDCl3): dZ1.38
[9H, s, C(CH3)3], 6.73 (1H, d, JZ1.6 Hz, 3-H), 7.35 (1H,
dd, JZ8.7, 1.9 Hz, 6-H), 7.43 (1H, d, JZ8.7 Hz, 7-H),
7.58–7.60 (2H, m, 2-H and 4-H); 13C NMR (75 MHz,
CDCl3): dZ27.4 [C(CH3)3], 31.9 (3!CH3), 106.7 (CH),
110.6 (CH), 116.2 (C), 117.3 (CH), 122.2 (CH), 127.1 (C),
145.0 (CH), 145.8 (C); IR nmax (CHCl3)/cmK1: 1699, 1607,
1541; MS: m/zZ174 (MC, 23%), 160 (12), 159 (100), 115
(16), 91 (14), 89 (7), 77 (6), 63 (6), 63 (7), 40 (9).
4.4.10. 5-Bromobenzofuran25 12j. The product 12j
(0.021 g, 20%) was obtained as a yellow oil from 11j
(0.15 g, 0.59 mmol). (Found: MC, 195.9516, C8H5OBr
1
References and notes
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(1H, d, JZ2.1 Hz, 2-H), 7.73 (1H, br s, ArH); 13C NMR
(75 MHz, CDCl3): dZ106.0 (CH), 112.8 (CH), 115.7 (C),
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