Ring-closing metathesis for the synthesis of 2H- and 4H-chromenes

Article abstract of DOI:10.1016/j.tet.2005.08.020

Six 4H-chromenes were synthesized from substituted phenols using vinylstannylation and ring-closing metathesis (RCM) as key steps. In addition, a different approach involving amongst other steps, an aryl allyl isomerization and RCM afforded a set of seven 2H-chromenes from phenolic precursors.

Full text of DOI:10.1016/j.tet.2005.08.020

Tetrahedron 61 (2005) 9996–10006
Ring-closing metathesis for the synthesis of 2H-
and 4H-chromenes
*
Willem A. L. van Otterlo, E. Lindani Ngidi, Samuel Kuzvidza, Garreth L. Morgans,
Simon S. Moleele and Charles B. de Koning
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits, 2050 Johannesburg, South Africa
Received 31 May 2005; revised 20 July 2005; accepted 4 August 2005
Available online 26 August 2005
Abstract—Six 4H-chromenes were synthesized from substituted phenols using vinylstannylation and ring-closing metathesis (RCM) as
key steps. In addition, a different approach involving amongst other steps, an aryl allyl isomerization and RCM afforded a set of seven
2H-chromenes from phenolic precursors.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
of 4H-chromene examples, the literature abounds with vast
numbers of papers reporting the isolation and synthesis of
naturally occurring 2H-chromenes 3.1 Examples reported
recently include compounds 6 and 7, both isolated from the
leaf essential oil of Calyptranthes tricona (Fig. 2).4
Compounds in which a benzene and pyran ring are fused
together with various levels of saturation and oxidation are
very common in Nature.1 The 1-benzopyrans include
structural skeletons such as chromane 1, 4H-chromene 2
and 2H-chromene 3 as depicted in Figure 1.
Figure 2.
Figure 1.
The chromene skeletons have also elicited pharmaceutical
interest as structural elements in drug-like compounds.
Examples of artificial compounds bearing the 2H-chromene
motif include 6-fluoro-2H-chromene 8,5 which exhibited the
highest 5-HT1A receptor affinity among a series of novel
6-fluorochromane derivatives; and 6-substituted 2H-chro-
menyl compound 9,6 which was tested for potential
antidiabetic activity as a NaC-glucose co-transporter
inhibitor (Fig. 3). In addition, a series of hypoglycemic
benzenesulfonylsemicarbazides with potential application
in the treatment of diabetes mellitus included substituted
2H-chromene 10.7
As a class of compounds the 4H-chromenes 2 (also known
as 4H-1-benzopyrans) are rather unusual and only a few
examples of natural products containing this structure have
been isolated.2 An example of a naturally occurring
4H-chromene is 7-hydroxy-6-methoxy-4H-chromene 4,
which was efficiently synthesized by De Korte and co-
workers (Fig. 2).3 This natural product, which reportedly
has interesting organoleptic properties, was isolated from
the plant Wisteria sinensis along with the related compound,
6,7-dimethoxy-4H-chromene 5.2 In contrast to the paucity
In recent years, the ring-closing metathesis (RCM) reaction8
has been used to synthesize both the 2H-9 and
4H-chromene10 classes. Methodology for the synthesis of
the 2H-chromenes normally involves the RCM of an
Keywords: 2H-chromenes; 4H-chromenes; Ring-closing metathesis;
Isomerization.
*
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.2005.08.020

W. A. L. van Otterlo et al. / Tetrahedron 61 (2005) 9996–10006
9997
a copper-mediated procedure described in the literature.15
The crucial ruthenium-mediated RCM reactions on compounds
14 were highly successful, affording the 4H-chromenes 15
in 63–98% yield. It is known that RCM using Grubbs’
catalysts on substrates containing electron-rich vinylic
olefins can be problematic16 but that there are numerous
literature examples demonstrating the application of RCM
to alkyl vinyl ethers.16b,17,18 However, our results are
amongst the first describing the successful use of RCM on
substrates bearing phenolic vinyl ethers.9 g,h,10,19
As mentioned in the introduction, 4H-chromene 15a (Z5)
occurs naturally as a fragrance component from the plant
Wisteria sinensis and the spectra of our synthesized product
compared well to those obtained for the natural product.2
The other substituted 4H-chromenes that were synthesized
are described in Scheme 1 and Table 1 and it can be seen
that most of the reaction yields were in an acceptable range.
In addition, 4H-chromenes 15d and 15e, bearing a methyl
functionality at position 5 of the pyran ring, were also
obtained in good yields. Of interest was that relative to the
4-methyl-4H-chromenes 15b and 15d, the unsubstituted
chromenes 15a, 15c and 15e were much more prone to
decomposition. This was evident by the rapid darkening of
the oils, even within minutes under air, to afford deep green
or blue oils after a number of weeks, which were difficult to
characterize.
Figure 3.
o-allyloxystyrene [see disconnection (a) in Fig. 4]. On the
other hand the synthesis of the 4H-chromenes using RCM,
described only by ourselves in a communication11 and by
Lam and co-workers (one example),10 has been accom-
plished by the RCM between a vinyloxy group and an
arylallyl functionality (disconnection (b) in Fig. 4). In
addition, our research group has been interested in the use of
RCM and isomerization12 methodology towards the
synthesis of benzo-fused compounds.11,13
Figure 4.
In this publication we report in full novel syntheses to both
the 4H- and 2H-chromene structures using RCM as the key
step.11 This paper describes in detail how the 4H-chromenes
were synthesized by way of an O-vinylation followed by
RCM using the second generation Grubbs catalyst 11
(Fig. 5). In addition, we disclose the synthesis of a small set
of 2H-chromenes, which were obtained by first using a
versatile aryl allyl isomerization step followed by the usual
RCM reaction.14
Scheme 1. (a) K2CO3, allyl bromide, acetone, 60 8C; (b) 6 (180–240 8C),
neat; (c) Cu(OAc)2, Sn(vinyl)4, acetonitrile, O2, rt; (d) 5% catalyst 11,
toluene, 60 8C (for yields see Table 1 below).
3. Discussion: 2H-chromenes
The synthesis of a small set of substituted 2H-chromenes
required us to adopt a different approach. The 2-allyl-
phenols 17 were synthesised as before, making use of the
initial allylation of the substituted phenols 16 followed by a
Claisen rearrangement (Scheme 2 and Table 2). The next
step required the isomerization of the terminal alkene
groups of 17 to the thermodynamically more favoured
internal alkenes of the 2-(prop-1-enyl)phenols 18. This was
accomplished using the ruthenium-based catalyst,
[RuClH(CO)(PPh3)3], utilised by the group of Krompiec,
and co-workers for a variety of isomerization applications.20
For the most part, products 18 were obtained as a mixture of
E- and Z-isomers with the E-isomers predominating. The
only exception to this was that the isomerization of 1-allyl-
naphthalen-2-ol 17f predominantly afforded the Z-isomer
Figure 5.
2. Discussion: 4H-chromenes
Variably substituted phenols 12 were initially converted
into their corresponding aryl allyl ethers. Subsequent
thermal Claisen rearrangements then gave the substituted
phenols 13 in acceptable yields over two steps (Scheme 1
and Table 1). The compounds were then converted into the
respective aryl vinyl ethers 14, also in excellent yield, using

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W. A. L. van Otterlo et al. / Tetrahedron 61 (2005) 9996–10006
Table 1. Yields for Scheme 1
13a
13/14
14/15
a R1,R4,R5ZH; R2,R3ZOMe
b R1,R4ZH; R2,R3ZOMe; R5ZMe
c R1,R3ZOMe; R2,R4,R5ZH
d R1,R3ZOMe; R2,R4ZH; R5ZMe
e R1,R4ZOMe; R2,R3,R5ZH
f R1,R2ZH; R3,R4Zbenzo
45%b
65%b
91%c
42%c
63%d
90%e
98%
98%
99%
98%
99%
74%
90%
98%
80%
82%
85%
63%
a Yield over two steps.
b From compound 12a.
c From compound 12b.
d From compound 12c.
e From compound 12d.
modifications of the 2H-chromene skeletons should be
readily attainable.
It is of interest to note that most of the previous RCM
approaches to the 2H-chromene skeleton make use of an
O-allyl group cyclizing onto a styrene. The presence of the
styrene often necessitates an atom-inefficient Wittig
reaction on the corresponding benzaldehyde,9b,f a transition
metal-mediated vinylation of an aromatic halide9d,j or even
a ketone to enol silyl ether transformation.9g Our method-
ology is thus different in that it enables the use of very
simple precursors and reactions for the synthesis of the
2H-chromenes, utilizing the ruthenium-mediated isomeri-
zation as a key step.21
4. Conclusion
Scheme 2. (a) K2CO3, allyl bromide, acetone, 60 8C; (b) D (180–240 8C) or
microwave (150–200 8C), neat; (c) [RuCl(CO)(PPh3)3] (cat 1–4 mol%),
toluene, 80 8C; (d) 5% catalyst 11, toluene, rt K60 8C (for yields see
Table 2 below).
We have thus demonstrated a simple, versatile method of
synthesizing the 4H-chromene skeleton using as key steps a
copper-mediated aryl vinyl ether formation followed by a
ruthenium-mediated RCM reaction. In addition this paper
discloses our novel approach to the 2H-chromenes
involving an aryl allyl isomerization and a RCM reaction.
An advantage of both approaches is that they require
substituted phenols as precursors. Since a wide variety of
these compounds are commercially available or readily
synthesized, it allows for a versatile approach to both classes
of 1-benzopyrans.
of 1-(prop-1-enyl)naphthalen-2-ol 18f after chromato-
graphy.20b A facile O-allylation on compounds 18a–g then
afforded the substituted 1-allyloxy-2-(prop-1-enyl)benzenes
19a–g in acceptable yields. Compounds 19a–g subsequently
underwent RCM with Grubbs’ second generation catalyst
11 to afford the desired 2H-chromenes 20a–g in acceptable
to good yields. The 2H-chromenes synthesized also
contained a range of functional groups in varied positions
on the aromatic portion, demonstrating the utility of
this methodology. In particular the use of the nitro group,
which can readily be reduced to an amine, and the
versatile aldehyde substituents mean that subsequent
5. Experimental
1H and 13C NMR spectra were recorded either on a Bruker
Table 2. Yields for Scheme 2
16/17a
17/18
18/19
19/20
a R1ZNO2; R2,R3,R4ZH
b R1,R2,R4ZH; R3ZNO2
c R1ZOMe; R2,R3ZH; R4ZCHO
d R1ZCHO; R2,R3,R4ZH
e R1,R2,R4ZH; R3ZCHO
f R1,R2ZH; R3,R4Zbenzob
g R1,R2,R3,R4ZH
84%
49%
68%
45%
41%
96%
96%
67%
89%
42%
84%
90%
71%
100%
81%
100%
64%
65%
86%
90%
100%
77%
80%
76%
45%c,d
80%f,g
90%
e
a Yields over two steps.
b For starting material 16a R1,R4ZH; R2,R3Zbenzo.
c Reaction on a 0.6 mmol scale.
d When reaction was repeated on a 0.3 mmol scale yield of 20f obtained was 82%.
e 2-Allylphenol purchased from Aldrich.
f
Yield O80% by 1H NMR spectroscopy.
g Reaction performed on NMR spectroscopy scale as described in Ref. 13a.

W. A. L. van Otterlo et al. / Tetrahedron 61 (2005) 9996–10006
9999
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). Infra-red 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 conven-
tional 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.
(37), 182 (100), 165 (55), 154 (90), 139 (57), 79 (50), 55
(92), 39 (80), 27 (50).
5.2.2. 2-Allyl-4,6-dimethoxyphenol 13c. 1-Allyloxy-
2,4-dimethoxybenzene (1.1 g, 5.7 mmol) was heated without
solvent at 220–236 8C for 45 min under a N2 atmosphere. The
resultantbrownresiduewasthensubjectedtosilicagelcolumn
chromatography (20% EtOAc/hexane) to afford 2-allyl-4,6-
dimethoxyphenol 13c (0.58 g, 53%) as a light yellow oily
material. (Found: MC, 194.0958, C11H14O3 requires
194.0943); 1H NMR (300 MHz, CDCl3): dZ3.39–3.41
(2H, m, ArCH2), 3.72 (3H, s, OCH3), 3.77 (3H, s, OCH3),
5.03–5.11 (2H, m, CH2CH]CH2), 5.50 (1H, s, OH), 5.92–
6.06 (1H, m, CH2CH]CH2), 6.35 (1H, d, JZ2.7 Hz, ArH),
6.46 (1H, d, JZ2.7 Hz, ArH); 13C NMR (75 MHz, CDCl3):
dZ33.9 (ArCH2), 55.4 (OCH3), 55.6 (OCH3), 97.1 (CH),
105.4 (CH), 115.3 (CH), 125.7 (C), 136.4 (CH), 137.4 (C),
146.8 (C), 152.7 (C); nmax (CHCl3)/cmK1: 3555 br, 1639,
1617, 1605, 1499, 1467, 1431; MS: m/zZ194 (MC, 100%),
179 (34), 161 (5), 151 (12), 137 (6), 133 (6), 119 (6), 91
(10), 69 (8), 65 (5).
5.1. Experimental part A: 4H-chromenes
5.2. Known precursors for the synthesis of the 4H-
chromenes 15a–f. 3,4-Dimethoxyphenol 12a was allylated
to afford 4-allyloxy-1,2-dimethoxybenzene.22a A Claisen
rearrangement was performed on this compound to afford
2-allyl-4,5-dimethoxyphenol 13a.22b Similarly, allylations
on 3,4-dimethoxyphenol 12a and 2,4-dimethoxyphenol 12b
with crotyl bromide afforded 4-(but-2-enyloxy)-1,2-
dimethoxybenzene 21 (see below for experimental details
and structure) and 1-(but-2-enyloxy)-2,4-dimethoxybenz-
ene,22c respectively, which were converted to 4,5-di-
methoxy-2-(1-methylallyl)phenol22d 13b and 2,4-di-
methoxy-6-(1-methylallyl)phenol22c 13d, respectively, by
way of the Claisen rearrangement. In a similar manner,
2-allyl-4,6-dimethoxyphenol 13c (see below for experimen-
tal details) and 2-allyl-3,6-dimethoxyphenol13e 13e were
synthesized from 2,4-dimethoxyphenol 12b and 2,5-
dimethoxyphenol13e 12c, respectively, by way of the
intermediate allyl ethers; 1-allyloxy-2,4-dimethoxy-
benzene22e and 2-allyloxy-1,4-dimethoxybenzene.13e In a
similar manner, 2-hydroxynaphthalene 12d was con-
verted into 2-allyloxynaphthalene22f and then into
1-allyl-naphthalen-2-ol22f 13f by way of thermal Claisen
rearrangement.
5.3. General procedure for the vinylation of substituted
2-allyl-phenols 13 to 1-allyl-2-vinyloxy-benzenes 14
Anhydrous Cu(OAc)2 (1.2 mol equiv) was added to a
thoroughly degassed solution of substituted 2-allylphenol
13 (ca. 1.0 mmol) in CH3CN (3.0 mL). The reaction vessel
was then fitted with an O2 balloon and tetravinyltin
(1.2 mol equiv) was added through a septum. The mixture
was left to react for 22 h at room temperature after, which
aqueous NH4OAc (0.3 M, 25 mL) was added. The aqueous
layer was then extracted with EtOAc (5!20 mL). The
combined organic extracts were dried with anhydrous
MgSO4, then filtered and the solvent removed in vacuo.
The resultant residue was purified by column chromato-
graphy (2–30% EtOAc/hexane) to afford the product 14. The
following compounds were prepared using this procedure:
5.2.1. 4-(But-2-enyloxy)-1,2-dimethoxybenzene 21.
Crotyl bromide (5.3 g, 39 mmol, 4.0 mL) and K2CO3
(8.1 g, 59 mmol) were added to 3,4-dimethoxyphenol 12a
(3.0 g, 18 mmol) dissolved in dry acetone (200 mL). The
reaction mixture was then heated at reflux under nitrogen for
21 h. The K2CO3 was removed by filtration and the solvent
was removed in vacuo. Purification by silica gel column
chromatography (10% EtOAc/hexane) afforded the product
4-(but-2-enyloxy)-1,2-dimethoxybenzene 21 as a clear
yellow oil (2.0 g, 53%, E:Z ratio 75:25). (Found: MC,
208.1099, C12H16O3 requires 208.1099); 1H NMR
(300 MHz, CDCl3, only E isomer characterized): dZ
1.71–1.75 (3H, m, CH3), 3.80 (3H, s, OCH3), 3.82 (3H, s,
OCH3), 4.37 (2H, br d, JZ5.8 Hz, OCH2), 5.66–5.78
5.3.1. 1-Allyl-4,5-dimethoxy-2-(vinyloxy)benzene 14a.
The product 14a (0.23 g, quantitative) was isolated as a
clear oil starting from substrate 13a (0.20 g, 1.0 mmol).
1
(Found: MC, 220.1100, C13H16O3 requires 220.1099); H
NMR (300 MHz, CDCl3): dZ3.30–3.32 (2H, d m, JZ
6.6 Hz, ArCH2), 3.84 (3H, s, OCH3), 3.85 (3H, s, OCH3),
4.26 [1H, dd, JZ6.2, 1.8 Hz, OCH]C(H)H], 4.47 [1H, dd,
JZ13.9, 1.8 Hz, OCH]C(H)H], 5.02–5.03 [1H, m, CH2-
CH]C(H)H], 5.06–5.08 [1H, m, CH2CH]C(H)H], 5.86–
5.97 (1H, m, CH2CH]CH2), 6.56 (1H, dd, JZ13.9, 6.2 Hz,
OCH]CH2), 6.57 (1H, s, ArH), 6.69 (1H, s, ArH); 13C
NMR (75 MHz, CDCl3): dZ33.5 (CH2), 56.0 (OCH3), 56.2
(OCH3), 92.1 (CH), 103.7 (CH), 112.9 (CH), 115.5 (CH),
122.3 (C), 136.9 (CH), 145.5 (C), 147.1 (C), 147.9 (C),
150.4 (CH); IR nmax (CHCl3)/cmK1 1635, 1609, 1510; MS:
m/zZ221 (MCCH, 18%), 220 (MC, 100%), 205 (22), 194
(93), 191 (23), 179 (56), 91 (20), 69 (23).
[1H, m, OCH2]CHCH(CH3)], 5.80–5.87 [1H,
m
OCH2CH]CH(CH3)], 6.37 (1H, dd, JZ8.7, 2.5 Hz, 5-H),
6.52 (1H, d, JZ2.5 Hz, 3-H), 6.73 (1H, d, JZ8.7 Hz, 6-H);
13C NMR (75 MHz, CDCl3, only E isomer characterized):
dZ17.5 (CH3), 55.4 (OCH3), 56.1 (OCH3), 68.8 (OCH2),
100.8 (CH), 103.7 (CH), 111.6 (CH), 126.0 (CH), 129.9
(CH), 143.2 (C), 149.6 (C), 153.1 (C); nmax (CHCl3)/cmK1
:
5.3.2. 1-(But-3-en-2-yl)-4,5-dimethoxy-2-(vinyloxy)ben-
zene 14b. The product 14b (0.22 g, quantitative) was
1610, 1602, 1511, 1454; MS: m/zZ208 (MC, 51%), 196

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W. A. L. van Otterlo et al. / Tetrahedron 61 (2005) 9996–10006
isolated as a light yellow oil starting from substrate 13b
6.3 Hz, OCH]CH2), 6.62 (1H, d, JZ8.9 Hz, ArH), 6.76
(1H, d, JZ8.9 Hz, ArH); 13C NMR (75 MHz, CDCl3): dZ
28.1 (CH2), 55.8 (OCH3), 56.4 (OCH3), 89.6 (CH), 106.8
(CH), 110.6 (CH), 114.8 (CH), 123.2 (C), 136.1 (CH), 143.1
(C), 146.2 (C), 151.2 (CH), 152.1 (C); IR nmax (CHCl3)/
cmK1 1639, 1490; MS: m/zZ221 (MCCH, 15%), 220
(MC, 100%), 205 (21), 192 (45), 191 (33), 177 (21), 149
(58), 91 (43), 57 (50), 41 (63).
(0.20 g, 1.0 mmol). (Found: MC, 234.1255, C14H18O3
1
requires 234.1256); H NMR (300 MHz, CDCl3): dZ1.29
(3H, d, JZ7.0 Hz, CH3) 3.77–3.81 [1H, m, CH(CH3)], 3.84
(3H, s, OCH3), 3.85 (3H, s, OCH3), 4.28 [1H, dd, JZ6.2,
1.7 Hz, OCH]C(H)H], 4.50 [1H, dd, JZ13.9, 1.7 Hz,
OCH]C(H)H], 5.02–5.07 [2H, m, CH(CH3)CH]CH2],
5.94–6.05 [1H, m, CH(CH3)CH]CH2], 6.56 (1H, dd, JZ
13.9, 6.2 Hz, OCH]CH2), 6.56 (1H, s, ArH), 6.69 (1H, s,
ArH); 13C NMR (75 MHz, CDCl3): dZ20.6 (CH3), 36.2
[CH(CH3)], 56.9 (OCH3), 57.1 (OCH3), 93.2 (CH), 104.6
(CH), 111.6 (CH), 114.0 (CH), 128.7 (C), 143.3 (CH), 146.5
(C), 147.5 (C), 148.6 (C), 151.5 (CH); IR nmax (CHCl3)/
cmK1 1639, 1609, 1509; MS: m/zZ235 (MCCH, 22%),
234 (MC, 100%), 219 (20), 205 (41), 192 (21), 191 (77),
176 (19), 161 (17), 91 (18), 77 (19), 27 (22).
5.3.6. 1-Allyl-2-(vinyloxy)naphthalene 14f. The product
14f (0.15 g, 74%) was isolated as a clear oil starting from
substrate 13f (0.18 g, 1.0 mmol). (Found: MC, 210.10445,
C15H14O requires 210.10447); 1H NMR (300 MHz,
CDCl3): dZ3.84 (2H, br d, JZ5.9 Hz, CH2), 4.34 [1H,
dd, JZ6.2, 1.7 Hz, OC]CH(H)], 4.55 [1H, dd, JZ13.9,
1.7 Hz, OC]CH(H)], 4.48 [1H, dd, JZ9.1, 1.6 Hz,
CH2CH]CH(H)], 5.03 (1H, br s, CH2CH]CH(H)],
5.95–6.09 (1H, m, CH2CH]CH2), 6.68 (1H, dd, JZ13.9,
6.2 Hz, OCH]CH2), 7.24 (1H, d, JZ9.0 Hz, ArH), 7.38–7.43
(1H, m, ArH), 7.47–7.52 (1H, m, ArH), 7.72 (1H, d, JZ8.9 Hz,
ArH), 7.80 (1H, d, JZ8.1 Hz, ArH), 7.98 (1H, d, JZ8.5 Hz,
ArH); 13C NMR (75 MHz, CDCl3): dZ29.5 (CH2), 93.2
(OCH]CH2), 115.5 (CH), 119.1 (CH), 124.1 (CH), 124.3
(ArC), 124.5 (CH), 126.4 (CH), 128.2 (CH), 128.5 (CH), 131.0
(ArC), 133.1 (ArC), 136.3 (CH), 150.1 (CH), 151.1 (ArC); IR
nmax (CHCl3)/cmK1: 1641, 1549, 1463; MS: m/zZ210 (MC,
100%), 181 (99), 165 (94), 152 (63), 128 (49), 115 (38), 77
(15), 63 (16).
5.3.3. 1-Allyl-3,5-dimethoxy-2-(vinyloxy)benzene 14c.
The product 14c (0.22 g, quantitative) was obtained as a
clear oil starting from substrate 13c (0.19 g, 1.0 mmol).
1
(Found: MC, 220.1099, C13H16O3 requires 220.1099); H
NMR (300 MHz, CDCl3): dZ3.32 (2H, d m, JZ6.7 Hz,
CH2), 3.77 (3H, s, OCH3), 3.81 (3H, s, OCH3), 4.12 [1H, dd,
JZ6.3, 1.9 Hz, OCH]C(H)H], 4.24 [1H, dd, JZ13.9,
1.9 Hz, OCH]C(H)H] 5.04–5.11 (2H, m, CH2CH]CH2),
5.85–5.96 (1H, m, CH2CH]CH2), 6.32 (1H, d, JZ2.8 Hz,
ArH), 6.39 (1H, d, JZ2.8 Hz, ArH), 6.53 (1H, dd, JZ13.9,
6.3 Hz, OCH]CH2); 13C NMR (75 MHz, CDCl3): dZ34.2
(CH2), 55.4 (OCH3), 55.9 (OCH3), 89.1 (CH), 98.3 (CH),
105.1 (CH), 116.1 (CH), 134.4 (C), 135.8 (C), 136.3 (CH),
151.5 (CH) 152.6 (C), 157.0 (C); IR nmax (CHCl3)/cmK1
1633, 1610, 1594, 1486; MS: m/zZ220 (MC, 100%), 206
(48), 196 (38), 191 (60), 181 (71), 177 (32), 149 (34), 69
(30), 57 (77), 43 (45).
5.4. General RCM procedure for the synthesis of
substituted 4H-chromenes 15 from 1-allyl-2-vinyloxy-
benzenes 14
Typically, Grubbs catalyst 11 (4 mol%) was added to a
degassed solution of the substituted 1-allyl-2-vinyloxy-
benzene 14 (ca. 0.5–1.0 mmol) dissolved in degassed,
distilled toluene (ca. 30 mL, ca. 0.020 M). The reaction
mixture was then heated at 60 8C for 1 h under a N2
atmosphere. After removal of the solvent under reduced
pressure the residue was purified by silica gel column
chromatography (5–20% EtOAc/hexane) to afford the
desired product 15. The following compounds were
obtained using this procedure:
5.3.4. 1-(But-3-en-2-yl)-3,5-dimethoxy-2-(vinyloxy)ben-
zene 14d. The product 14d (0.21 g, quantitative) was
isolated as a light yellow oil starting from substrate 13d
(0.20 g, 1.0 mmol). (Found: MC, 234.1255, C14H18O3
1
requires 234.1256); H NMR (300 MHz, CDCl3): dZ1.29
(3H, d, JZ7.0 Hz, CH3) 3.71–3.81 [1H, m under 2!OCH3,
CH(CH3)], 3.78 (3H, s, OCH3), 3.81 (3H, s, OCH3), 4.13
[1H, dd, JZ6.3, 1.8 Hz, OCH]C(H)H], 4.25 [1H, dd, JZ
13.9, 1.8 Hz, OCH]C(H)H], 5.02–5.09 [2H, m, CH(CH3)-
CH]CH2], 5.92–6.03 [1H, m, CH(CH3)CH]CH2], 6.31
(1H, d, JZ2.7 Hz, ArH), 6.38 (1H, d, JZ2.7 Hz, ArH), 6.55
(1H, dd, JZ13.9, 6.3, OCH]CH2); 13C NMR (75 MHz,
CDCl3): dZ19.9 (CH3), 35.8 [CH(CH3)], 55.5 (OCH3),
56.0 (OCH3), 89.3 (CH), 98.0 (CH), 103.1 (CH), 113.4
(CH), 135.3 (C), 139.9 (C), 142.2 (CH), 151.9 (CH), 152.5
(C), 157.1 (C); IR nmax (CHCl3)/cmK1 1640, 1610, 1600,
1487; MS: m/zZ235 (MCCH, 16%), 234 (MC, 100%),
219 (20), 207 (29), 205 (77), 192 (28), 191 (54), 149 (32).
5.4.1. 6,7-Dimethoxy-4H-chromene 15a (Z5).2,3 The
product 15a (0.12 g, 97%) was isolated as a light yellow
oil starting from substrate 14a (0.14 g, 0.64 mmol) and
Grubbs catalyst 11 (20 mg, 0.024 mmol, 4 mol%) in toluene
1
(30 mL, 0.020 M); H NMR (200 MHz, CDCl3): dZ3.31–
3.33 (2H, m, 4-H), 3.82 (6H, s, 2!OCH3), 4.86–4.93 (1H,
m, 3-H), 6.42 (1H, s, ArH), 6.46 (1H, s, ArH), 6.42–6.46
(1H, m, 2-H); 13C NMR (50 MHz, CDCl3): dZ22.7 (CH2),
55.8 (OCH3), 56.1 (OCH3), 99.7 (CH), 100.5 (CH), 110.2
(C), 111.2 (CH), 140.4 (CH), 144.7 (C), 144.8 (C), 148.0
(C).
5.3.5. 2-Allyl-1,4-dimethoxy-3-(vinyloxy)benzene 14e.
The product 14e (0.22 g, quantitative) was isolated as a
clear yellow oil starting from substrate 13e (0.19 g,
1.0 mmol). (Found: MC, 220.1099, C13H16O3 requires
5.4.2. 6,7-Dimethoxy-4-methyl-4H-chromene 15b. The
product 15b (0.15 g, 90%) was isolated as a dark yellow oil
(that rapidly turned green upon drying under vacuum)
starting from substrate 14b (0.19 g, 0.81 mmol) and Grubbs
catalyst 11 (27 mg, 0.031 mmol, 4 mol%) in toluene
(40 mL, 0.02 M). (Found: MC, 206.0940, C12H14O3
1
220.1099); H NMR (300 MHz, CDCl3): dZ3.37 (2H, d
m, JZ6.2 Hz, CH2), 3.77 (6H, s, 2!OCH3), 4.14 [1H, dd,
JZ6.3, 1.9 Hz, OCH]C(H)H], 4.30 [1H, dd, JZ13.9,
1.9 Hz, OCH]C(H)H], 4.92–5.01 (2H, m, CH2CH]CH2),
5.86–5.99 (1H, m, CH2CH]CH2), 6.56 (1H, dd, JZ13.9,
1
requires 206.0943); H NMR (300 MHz, CDCl3): dZ1.32

W. A. L. van Otterlo et al. / Tetrahedron 61 (2005) 9996–10006
10001
(3H, d, JZ6.9 Hz, CH3), 3.44–3.48 (1H, m, 4-H), 3.83 (3H,
s, OCH3), 3.84 (3H, s, OCH3), 4.84 (1H, dd, JZ6.2, 3.9 Hz,
3-H), 6.43 (1H, s, ArH), 6.43–6.46 (1H, m, 2-H), 6.58 (1H,
s, ArH); 13C NMR (75 MHz, CDCl3, 2 quaternary carbons
not observed in spectrum): dZ25.6 (CH3), 28.2 (4-C), 55.6
(OCH3), 56.0 (OCH3), 98.0 (CH), 102.8 (CH), 105.7 (CH),
14f (0.11 g, 0.50 mmol) and Grubbs catalyst 11 (18 mg,
0.021 mmol, 4 mol%) in toluene (35 mL, 0.014 M); 1H
NMR (300 MHz, CDCl3): dZ3.68 (2H, br d, JZ1.9 Hz,
1-H), 5.11–5.16 (1H, m, 2-H), 6.60 (1H, dt, JZ6.3, 1.9 Hz,
3-H), 7.07 (1H, d, JZ8.9 Hz, ArH), 7.39–7.44 (1H, m,
ArH), 7.50–7.61 (1H, m, ArH), 7.65–7.70 (2H, m, 2!ArH),
7.78 (1H, d, JZ8.0 Hz, 6-H).
126.4 (C), 139.3 (CH), 155.4 (C); IR nmax (CHCl3)/cmK1
:
1664, 1618, 1509, 1452, 1406; MS: m/zZ206 (MC, 17%),
192 (14), 191 (100), 181 (15), 175 (10), 147 (22).
5.5. Experimental part B: 2H-chromenes
5.4.3. 6,8-Dimethoxy-4H-chromene 15c. The product 15c
(0.12 g, 68%) was isolated as a yellow oil that darkened
rapidly with time, starting from substrate 14c (0.20 g,
0.91 mmol) and Grubbs catalyst 11 (30 mg, 0.035 mmol,
4 mol%) in toluene (30 mL, 0.030 M). (Found: MC,
192.0780, C11H12O3 requires 192.0786); 1H NMR
(300 MHz, CDCl3): dZ3.36 (2H, br s, 4-H), 3.75 (3H, s,
OCH3), 3.85 (3H, s, OCH3) 4.87–4.91 (1H, m, 3-H), 6.09
(1H, d, JZ2.5 Hz, ArH), 6.34 (1H, d, JZ2.5 Hz, ArH), 6.56
(1H, br d, JZ6.2 Hz, 2-H); 13C NMR (75 MHz, CDCl3):
dZ23.4 (4-C), 55.5 (OCH3), 55.9 (OCH3), 98.3 (CH), 99.4
(CH), 103.3 (CH), 120.5 (C), 135.3 (C), 140.6 (CH), 148.5
(C), 155.2 (C); IR nmax (CHCl3)/cmK1: 1664, 1601, 1491,
1457, 1428; MS: m/zZ192 (MC, 100%), 191 (83), 180 (10),
177 (25), 176 (14), 149 (42), 148 (11), 134 (10), 133 (11),
121 (12), 106 (11), 91 (11), 77 (13), 63 (10).
5.5.1. Known precursors for the synthesis of the 2H-
chromenes 20a–g. 2-Nitrophenol 16a, 4-Nitrophenol
16b, 3-hydroxy-4-methoxybenzaldehyde 16c, 2-hydroxy-
benzaldehyde 16d, 4-hydroxybenzaldehyde 16e and
2-hydroxynaphthalene 16f (Z12d) were all converted to
their allyl derivatives: 1-allyloxy-2-nitrobenzene,24a
1-allyloxy-4-nitrobenzene,24b 3-allyloxy-4-methoxybenzal-
dehyde,24c 2-allyloxybenzaldehyde,24d 4-allyloxybenzalde-
hyde,24e and 2-allyloxynaphthalene,22f respectively. A
Claisen rearrangement was performed on these compounds
to afford the rearranged products: 2-allyl-6-nitrophenol
17a,15b 2-allyl-4-nitrophenol 17b,13e 2-allyl-3-hydroxy-4-
methoxybenzaldehyde 17c,15b 3-allyl-2-hydroxybenzalde-
hyde 17d,24f 3-allyl-4-hydroxybenzaldehyde13e 17e and
1-allyl-naphthalen-2-ol22f 17f (Z13f), respectively.
2-Allylphenol 17g was purchased from Aldrich and used
without further purification.
5.4.4. 6,8-Dimethoxy-4-methyl-4H-chromene 15d. The
product 15d (0.16 g, 91%) was isolated as a yellow oil (that
rapidly turned green upon drying under vacuum) starting
from substrate 14d (0.20 g, 0.85 mmol) and Grubbs catalyst
11 (28 mg, 0.030 mmol, 4 mol%) in toluene (40 mL,
0.021 M). (Found: MC, 206.0943, C12H14O3 requires
5.6. General procedure for the isomerization of
substituted 2-allylphenols 17 to 2-(prop-1-enyl)phenols
18
Typically, substituted 2-allylphenol 17 (ca. 3 mmol) and
[RuClH(CO)(PPh3)3] (1–4 mol%) were dissolved in dis-
tilled, degassed toluene (5 mL). The reaction was heated at
65–90 8C for 24 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, 18
as a mixture of E/Z isomers (predominantly E, which were
then characterized by NMR spectroscopy). The following
compounds were prepared using this procedure:
1
206.0943); H NMR (300 MHz, CDCl3): dZ1.30 (3H, d,
JZ6.9 Hz, CH3), 3.42–3.48 (1H, m, 4-H), 3.73 (3H, s,
OCH3), 3.81 (3H, s, OCH3), 4.80–4.86 (1H, m, 3-H), 6.18
(1H, d, JZ2.6 Hz, ArH), 6.32 (1H, d, JZ2.6 Hz, ArH), 6.53
(1H, dd, JZ6.2, 0.8 Hz, 2-H); 13C NMR (75 MHz, CDCl3):
dZ26.0 (CH3), 28.5 (4-C), 55.8 (OCH3), 56.2 (OCH3), 98.4
(CH), 103.1 (CH), 106.1 (CH), 126.7 (C), 139.7 (CH), 140.9
(C), 148.7 (C), 155.8 (C); IR nmax (CHCl3)/cmK1: 1665,
1598, 1489; MS: m/zZ206 (MC, 45%), 192 (25), 191 (100),
181 (16).
5.6.1. 2-Nitro-6-(prop-1-enyl)phenol 18a. The product
18a (0.48 g, 96%, E:Z ratio 88:12) was obtained as an
yellow oil from 17a (0.50 g, 2.8 mmol). Found: MC,
179.0556, C9H9NO3 requires 179.0582); 1H NMR
(300 MHz, C6D6, only E isomer characterized, OH not
observed in spectrum): dZ1.63 (3H, dd, JZ6.7, 1.7 Hz,
CH3), 5.92–6.04 (1H, m, CH]CHCH3), 6.21–6.26 (1H, m,
ArH), 6.71 (1H, dd, JZ15.9, 1.6 Hz, CH]CHCH3), 7.10–
7.15 (1H, m, ArH), 7.53 (1H, dd, JZ8.5, 1.4 Hz, ArH),
11.02 (1H, s, OH); 13C NMR (75 MHz, C6D6, only E isomer
characterized, one quaternary carbon obscured in spec-
trum): dZ18.8 (CH3), 119.2 (CH), 123.1 (CH), 124.1 (CH),
129.0 (CH), 133.3 (CH), 137.1 (C), 152.4 (C); IR nmax
(CHCl3)/cmK1: 3205 br, 1655, 1605, 1539, 1443, 1333;
MS: m/zZ179 (MC, 21%), 162 (32), 149 (23), 132 (40),
131 (53), 103 (10), 81 (11), 77 (14), 69 (100), 55 (12), 43
(15), 41 (18).
5.4.5. 5,8-Dimethoxy-4H-chromene 15e. The product 15e
(0.14 g, 80%) was isolated as a light yellow oil starting from
substrate 14e (0.20 g, 0.91 mmol) and Grubbs catalyst 11
(30 mg, 0.035 mmol, 4 mol%) in toluene (30 mL, 0.030 M).
1
(Found: MC, 192.0785, C11H12O3 requires 192.0786); H
NMR (300 MHz, CDCl3): dZ3.22–3.24 (2H, m, 4-H), 3.74
(3H, s, OCH3), 3.82 (3H, s, OCH3), 4.92–4.97 (1H, m, 3-H),
6.39 (1H, d, JZ8.9 Hz, ArH), 6.53 (1H, dt, JZ6.3, 1.9 Hz,
2-H), 6.67 (1H, d, JZ8.9 Hz, ArH); 13C NMR (75 MHz,
CDCl3): dZ18.5 (4-C), 55.5 (OCH3), 56.3 (OCH3), 100.3
(CH), 102.9 (CH), 109.4 (CH), 110.4 (C), 139.9 (CH), 141.5
(C), 141.9 (C), 151.2 (C); IR nmax (CHCl3)/cmK1: 1676,
1640, 1599, 1494, 1454. MS: m/zZ193 (MCC1, 12%), 192
(100), 191 (40), 177 (62), 162 (16), 161 (35), 149 (10), 86
(20), 84 (32).
5.4.6. 1H-Benzo[f]chromene 15f.23 The product 15f
(0.060 g, 63%) was isolated as a light-coloured semi-solid,
which darkened rapidly with time, starting from substrate
5.6.2. 4-Nitro-2-(prop-1-enyl)phenol 18b. The product
18b (0.17 g, 96%, E:Z ratio 87:13) was obtained as an

10002
W. A. L. van Otterlo et al. / Tetrahedron 61 (2005) 9996–10006
orange oil from 17b (0.18 g, 1.0 mmol). Found: MC,
179.0574, C9H9NO3 requires 179.0582); 1H NMR
(300 MHz, CDCl3, only E isomer characterized, OH not
observed in spectrum): dZ1.95 (3H, dd, JZ6.5, 1.6 Hz,
CH3), 6.32–6.41 (1H, m, CH]CHCH3), 6.57 (1H, dd, JZ
17.3, 1.4 Hz, CH]CHCH3), 6.88 (1H, d, JZ8.9 Hz, 6-H),
7.99 (1H, dd, JZ8.9, 2.7 Hz, 5-H), 8.23 (1H, d, JZ2.7 Hz,
3-H); 13C NMR (75 MHz, CDCl3, only E isomer charac-
terized): dZ18.9 (CH3), 115.8 (CH), 123.2 (CH), 123.4
(CH), 123.8 (CH), 125.8 (C), 131.2 (CH), 141.6 (C), 158.0
(C); IR nmax (CHCl3)/cmK1: 3384 br, 1655, 1614, 1583,
1519, 1493, 1434, 1338; MS: m/zZ179 (MC, 100%), 167
(18), 149 (14), 132 (11), 118 (12), 103 (10), 77 (18), 69 (15),
57 (20), 41 (13).
CDCl3, only E isomer characterized): dZ18.9 (CH3), 116.2
(CH), 124.2 (CH), 126.1 (C), 129.5 (C), 129.7 (CH), 129.7
(CH), 130.4 (CH), 158.7 (C), 191.9 (CHO); IR nmax
(CHCl3)/cmK1: 3260 br, 1670, 1586, 1501, 1436; MS: m/
zZ162 (MC, 100%), 133 (13), 115 (121), 105 (12), 91 (10),
77 (14), 65 (9), 51 (9), 39 (9).
5.6.6. 1-(Prop-1-enyl)naphthalen-2-ol 18f.25 The product
18f (0.42 g, 84%, E:Z ratio 33:67) was obtained as a clear oil
from 17f (0.5 g, 2.7 mmol). Found: MC, 184.0886,
1
C13H12O requires 184.0888; H NMR (300 MHz, CDCl3):
Z isomer dZ1.61 (3H, br d, JZ6.7 Hz, CH3), 5.44 (1H, s,
OH), 6.24–6.35 (1H, m, CH]CHCH3), 6.56 (1H, br d, JZ
11.0 Hz, CH]CHCH3), 7.20 (1H, d, JZ8.9 Hz, ArH),
7.30–7.35 (1H, m, ArH), 7.41–7.46 (1H, m, ArH), 7.70–7.82
(3H, m, 3!ArH): E isomer dZ2.05 (3H, br d, JZ6.4 Hz,
CH3), 5.86 (1H, s, OH), 6.06–6.18 (1H, m, CH]CHCH3),
6.66 (1H, br d, JZ16.3 Hz, CH]CHCH3), 7.19 (1H, d, JZ
8.7 Hz, ArH), 7.30–7.35 (1H, m, ArH), 7.41–7.46 (1H, m,
ArH), 7.66 (1H, d, JZ8.9 Hz, ArH), 7.70–7.82 (2H, m, 2!
ArH); 13C NMR (75 MHz, CDCl3): Z isomer dZ14.8
(CH3), 115.3 (C), 117.0 (CH), 122.6 (CH), 123.3 (CH),
124.0 (CH), 126.3 (CH and C), 128.2 (CH), 129.1 (CH),
132.6 (C), 133.7 (CH), 149.7 (C): E isomer (some signals
under those of Z isomer) dZ19.0 (CH3), 117.4 (CH), 123.7
(CH), 124.4 (CH), 128.7 (CH), 132.7 (C), 133.8 (CH), 150.3
(C); IR nmax (CHCl3)/cmK1: 3350 br, 1689, 1641, 1588,
1569, 1550, 1515, 1463, 1431; MS m/zZ185 (MCC1,
18%), 184 (100), 183 (37), 181 (11), 173 (14), 172 (17), 170
(15), 169 (94), 168 (10), 167 (14), 165 (257), 155 (12), 153
(11), 152 (14), 141 (18), 139 (13), 128 (14), 127 (13), 115
(23), 83 (15).
5.6.3. 3-Hydroxy-4-methoxy-2-(prop-1-enyl)benzal-
dehyde 18c. The product 18c (0.38 g, 67%, E:Z ratio
66:34) was obtained as an orange oil from 17c (0.57 g,
3.0 mmol). Found: MC, 192.0787, C11H12O3 requires
1
192.0786; H NMR (300 MHz, CDCl3): E isomer dZ1.99
(3H, dd, JZ6.9, 1.6 Hz, CH3), 3.97 (3H, s, OCH3), 5.95
(1H, s, OH), 6.05 (1H, dq, JZ15.9, 6.6 Hz, CH]CHCH3),
6.80 (1H, dd, JZ15.9, 1.7 Hz, CH]CHCH3), 6.86 (1H, d,
JZ8.5 Hz, 5-H), 7.48 (1H, d, JZ8.5 Hz, 6-H), 10.08 (1H, s,
CHO): Z isomer dZ1.59 (3H, dd, JZ6.6, 1.7 Hz, CH3),
3.98 (3H, s, OCH3), 5.81 (1H, s, OH), 6.17 (1H, dq, JZ11.3,
6.9 Hz, CH]CHCH3), 6.55 (1H, dd, JZ11.3, 1.6 Hz,
CH]CHCH3), 6.91 (1H, d, JZ8.6 Hz, 5-H), 7.54 (1H, d,
JZ8.6 Hz, 6-H), 10.02 (1H, s, CHO); 13C NMR (75 MHz,
CDCl3, only E isomer characterized): dZ19.7 (CH3), 56.6
(OCH3), 109.0 (CH), 122.2 (CH), 123.0 (CH), 128.6 (C),
132.7 (C), 136.4 (CH), 143.3 (C), 150.8 (C), 192.0 (CHO);
IR nmax (CHCl3)/cmK1: 3424 br, 1678, 1593, 1484, 1440;
MS m/zZ192 (MC, 83%), 177 (100), 162 (20), 103 (21), 91
(18), 77 (21).
5.6.7. 2-(Prop-1-enyl)-phenol 18g.26 The product 18g
(0.90 g, 90%, E:Z ratio 89:11) was obtained as an orange
oil from 17g (1.0 g, 7.5 mmol); NMR (300 MHz, CDCl3,
1
5.6.4. 2-Hydroxy-3-(prop-1-enyl)benzaldehyde 18d. The
product 18d (0.45 g, 89%, E:Z ratio 85:15) was obtained as
an orange oil from 17d (0.51 g, 3.5 mmol). Found: MC,
162.0653, C10H10O2 requires 162.0681); 1H NMR
(300 MHz, CDCl3, only E isomer characterized): dZ1.93
(3H, dd, JZ6.6, 1.6 Hz, CH3), 6.29–6.41 (1H, m,
CH]CHCH3), 6.70 (1H, dd, JZ15.9, 1.6 Hz,
CH]CHCH3), 6.94–6.99 (1H, m, ArH), 7.41 (1H, dd, JZ
7.6, 1.5 Hz, ArH), 7.62 (1H, d, JZ7.6 Hz, ArH), 9.87 (1H,
s, CHO), 11.43 (1H, s, OH); 13C NMR (75 MHz, CDCl3,
only E isomer characterized): dZ19.0 (CH3), 119.6 (CH),
120.6 (C), 123.9 (CH), 128.4 (CH), 132.2 (CH), 133.6 (CH),
only E isomer characterized): dZ1.90 (3H, dd, JZ6.6,
1.7 Hz, CH3), 5.06 (1H, br s, OH), 6.19 (1H, dq, JZ15.9,
6.6 Hz, CH]CHCH3), 6.58 (1H, br d, JZ15.9 Hz,
CH]CHCH3), 6.77 (1H, d, JZ8.0 Hz, ArH), 6.85–6.90
(1H, m, ArH), 7.05–7.11 (1H, m, ArH), 7.28 (1H, dd, JZ
7.6, 1.2 Hz, ArH); 13C NMR (75 MHz, CDCl3, only E
isomer characterized): dZ18.9 (CH3), 115.6 (CH), 120.9
(CH), 125.1 (C), 125.3 (CH), 127.4 (CH), 127.9 (CH), 128.3
(CH), 152.3 (C).
5.7. General procedure for the allylation of substituted
2-(prop-1-enyl)phenols 18 to afford 1-allyloxy-2-(prop-1-
enyl)benzenes 19
137.1 (C), 158.4 (C), 196.8 (CHO); IR nmax (CHCl3)/cmK1
:
3250 br, 1951, 1654, 1608, 1486, 1431; MS: m/zZ162
(MC, 100%), 144 (14), 133 (12), 121 (14), 115 (17), 103 (7),
91 (10), 77 (15), 57 (12), 43 (14), 41 (14).
Typically, substituted 2-(prop-1-enyl)phenol 18 (ca.
2.6 mmol) and allyl bromide (2 mol equiv) were dissolved
in acetone (10 mL) (or DMF for substrates containing an
aldehyde functionality) containing K2CO3 (2 mol equiv).
The resulting reaction mixture was then heated at reflux for
12–24 h (at 60 8C for DMF solutions). The reaction mixture
was then cooled and the solvent removed under reduced
pressure. H2O (50 cm3) was then added to the residue and
the organic material, extracted using CH2Cl2 (4!40 mL).
The organic layer was then separated and dried using
MgSO4 and then concentrated in vacuo. The organic residue
obtained was then purified by column chromatography (10–
30% EtOAc/hexane) to afford 19 as a mixture of E/Z
5.6.5. 4-Hydroxy-3-(prop-1-enyl)benzaldehyde 18e. The
product 18e (0.42 g, 42%, E:Z ratio 92:8) was obtained as a
yellow solid (mp 88–91 8C, recrystalized from CHCl3) from
17e (1.0 g, 6.2 mmol). Found: MC, 162.0680, C10H10O2
1
requires 162.0681); H NMR (300 MHz, CDCl3, only E
isomer characterized): dZ1.93 (3H, dd, JZ6.6, 1.7 Hz,
CH3), 6.27–6.37 (1H, m, CH]CHCH3), 6.64 (1H, d, JZ
15.9 Hz, CH]CHCH3), 6.96 (1H, d, JZ8.4 Hz, 5-H), 7.17
(1H, br s, OH), 7.65 (1H, dd, JZ8.4, 1.9 Hz, 6-H), 7.88 (1H,
d, JZ1.9 Hz, 2-H), 9.84 (1H, s, CHO); 13C NMR (75 MHz,

W. A. L. van Otterlo et al. / Tetrahedron 61 (2005) 9996–10006
10003
isomers (predominantly E, which were then characterized
by NMR spectroscopy). The following compounds were
prepared using this procedure:
10.05 (1H, s, CHO):ZisomerdZ1.55(3H, dd, JZ6.8, 1.7 Hz,
CH3), 3.94 (3H, s, OCH3), 4.41–4.46 (2H, m under E-isomer,
OCH2), 5.18–5.24 [1H, m under E-isomer, CH]C(H)H],
5.31 [1H, dd, JZ17.2, 1.5 Hz, CH]C(H)H], 6.00–6.14
(2H, m under E-isomer, CH2CH]CH3 and CH]CHCH3),
6.57 (1H, br d, JZ11.4 Hz, CH]CHCH3), 6.95 (1H, d, JZ
8.8 Hz, 5-H), 7.75 (1H, d, JZ8.7 Hz, 6-H), 9.99 (1H, s,
CHO);13C NMR (75 MHz, CDCl3, only E isomer charac-
terized): dZ19.1 (CH3), 55.8 (OCH3), 73.8 (OCH2), 110.4
(CH), 117.7 (CH), 117.8 (CH), 122.2 (CH), 125.9 (CH),
128.3 (C), 133.9 (C), 136.5 (CH), 145.0 (C), 157.0 (C),
191.4 (CHO); IR nmax (CHCl3)/cmK1: 1676, 1585, 1565,
1511, 1483, 1464, 1440, 1420; MS: m/zZ232 (MC, 37%),
191 (100), 175 (11), 164 (12), 163 (16), 148 (18), 135 (48),
119 (9), 103 (23), 91 (25), 77 (17), 65 (14), 41 (20).
5.7.1. 2-Allyloxy-1-nitro-3-(prop-1-enyl)benzene 19a.
The product 19a (0.25 g, 71%, E:Z ratio 90:10) was
obtained as an orange oil from 18a (0.18 g, 0.96 mmol).
(Found: MC, 219.0893, C12H13NO3 requires 219.0895); 1H
NMR (300 MHz, CDCl3, only E isomer characterized): dZ
1.93 (3H, dd, JZ6.6, 1.6 Hz, CH3), 4.49 (2H, br d, JZ
5.8 Hz, OCH2), 5.29 (1H, dd, JZ10.4, 1.2 Hz, CH]C(H)H),
5.39 (1H, dd, JZ17.1, 1.5 Hz, CH]C(H)H), 6.01–6.14 (1H,
m, CH2CH]CH2), 6.26–6.38 (1H, m, CH]CHCH3), 6.66
(1H, dd, JZ15.9, 1.5 Hz, CH]CHCH3), 7.12–7.17 (1H, m,
ArH), 7.60–7.66 (2H, m, 2!ArH); 13C NMR (75 MHz,
CDCl3, only E isomer characterized): dZ18.9 (CH3), 77.0
(OCH2 under CDCl3 signals), 105.3 (CH), 122.9 (CH), 123.5
(CH), 124.5 (CH), 130.4 (CH), 130.5 (CH), 134.1 (C), 143.6
(C). 144.0 (CH), 147.1 (C); IR nmax (CHCl3)/cmK1: 1670,
1655, 1602, 1531, 1444, 1359; MS: m/zZ220 (MCCH,
29%), 219 (MC, 44%), 204 (47), 190 (68), 186 (213), 172
(28), 162 (47), 132 (100), 115 (46), 103 (48), 77 (48), 39
(47).
5.7.4. 2-Allyloxy-3-(prop-1-enyl)benzaldehyde 19d. The
product 19d (0.53 g, quantitative, E:Z ratio 85:15) was
isolated as a yellow oil from 18d (0.43 g, 2.7 mmol). Found:
MC, 202.0997, C13H14O2 requires 202.0994); 1H NMR
(300 MHz, CDCl3, only E isomer characterized): dZ1.94
(3H, dd, JZ6.6, 1.7 Hz, CH3), 4.44–4.47 (2H, m, OCH2),
5.29–5.37 [1H, m, CH]C(H)H], 5.38–5.44 [1H, m,
CH]C(H)H], 6.07–6.15 (1H, m, OCH2CHCH2), 6.29–
6.36 (1H, m, ArCH]CH), 6.67 (1H, dd, JZ15.9, 1.5 Hz,
ArCH]CH), 7.15–7.20 (1H, m, ArH), 7.67–7.72 (2H, m,
2!ArH), 10.39 (1H, s, CHO); 13C NMR (75 MHz, CDCl3,
only E isomer characterized): dZ18.9 (CH3), 77.0 (OCH2),
118.7 (CH), 124.4 (CH), 124.5 (CH), 126.7 (CH), 128.6
(CH), 129.8 (C), 132.6 (CH), 132.7 (CH), 136.7 (C), 158.8
(C), 190.3 (CHO); IR nmax (CHCl3)/cmK1: 1684, 1590,
1445; MS: m/zZ202 (MC, 16%), 178 (16), 177 (84), 176
(15), 161 (39), 159 (21), 149 (100), 145 (18), 133 (27), 132
(24), 120 (37), 115 (17), 105 (38), 103 (16), 77 (35), 65 (21),
63 (15), 51 (27), 41 (54), 38 (34).
5.7.2. 1-Allyloxy-4-nitro-2-(prop-1-enyl)benzene 19b.
The product 19b (0.18 g, quantitative, E:Z ratio 70:30)
was obtained as an orange oil from 18b (0.15 g, 0.83 mmol).
1
Found: MC, 219.0905, C12H13NO3 requires 219.0895); H
NMR (300 MHz, CDCl3): E isomer dZ1.94 (3H, dd, JZ
6.6, 1.7 Hz, CH3), 4.66–4.68 (2H, m, OCH2), 5.35 [1H, dd,
JZ10.5, 1.3 Hz, CH]C(H)H], 5.44 [1H, dd, JZ17.3,
1.3 Hz, CH]C(H)H], 6.01–6.14 (1H, m, CH2CH]CH3),
6.38 (1H, dq, JZ15.9, 6.6 Hz, CH]CHCH3), 6.70 (1H, dd,
JZ15.9, 1.6 Hz, CH]CHCH3), 6.87 (1H, d, JZ9.1 Hz,
6-H), 8.05 (1H, dd, JZ9.1, 2.8 Hz, 5-H), 8.29 (1H, d, JZ
2.8 Hz, 3-H): Z isomer dZ1.87 (3H, dd, JZ7.2, 1.9 Hz,
CH3), 4.66–4.68 (2H, m, OCH2), 5.34 [1H, dd, JZ10.5,
1.4 Hz, CH]C(H)H], 5.40–5.46 [1H, m, CH]C(H)H],
5.91–6.11 (2H, m, CH2CH]CH3 and CH]CHCH3), 6.51
(1H, dd, JZ11.6, 1.7 Hz, CH]CHCH3), 6.91 (1H, d, JZ
9.0 Hz, 6-H), 8.12 (1H, dd, JZ9.0, 2.7 Hz, 5-H), 8.16 (1H,
d, JZ2.7 Hz, 3-H); 13C NMR (75 MHz, CDCl3): E isomer
dZ18.9 (CH3), 69.6 (OCH2), 111.4 (CH), 118.3 (CH),
121.9 (CH), 123.5 (CH), 123.8 (CH), 128.1 (C), 129.5 (CH),
132.0 (CH), 141.6 (C), 159.7 (C): Z isomer dZ14.6 (CH3),
69.5 (OCH2), 111.1 (CH), 118.2 (CH), 123.3 (CH), 124.0
(CH), 125.6 (CH), 127.2 (C), 129.3 (CH), 131.9 (CH), 141.0
(C), 160.9 (C); IR nmax (CHCl3)/cmK1: 1676, 1585, 1565,
1511; MS: m/zZ219 (MC, 48%), 190 (10), 178 (67), 161
(14), 133 (11), 132 (100), 131 (64), 103 (23), 78 (12), 77
(22), 63 (11), 51 (13), 41 (71), 39 (25).
5.7.5. 4-Allyloxy-3-(prop-1-enyl)benzaldehyde 19e. The
product 19e (0.81 g, 64%, E:Z ratio 93:7) was obtained as an
orange oil from 18e (1.0 g, 6.2 mmol). Found: MC,
202.0993, C13H14O2 requires 202.0994); 1H NMR
(300 MHz, CDCl3, only E isomer characterized): dZ1.92
(3H, br d, JZ6.6 Hz, CH3), 4.65 (2H, br d, JZ5.1 Hz,
OCH2), 5.33 [1H, br d, JZ10.6 Hz, CH]C(H)H], 5.44 [1H,
br d, JZ17.3 Hz, CH]C(H)H], 6.01–6.15 (1H, m, OCH2-
CHCH2), 6.36 (1H, dq, JZ15.8, 6.6 Hz, ArCH]CH), 6.73
(1H, br d, JZ15.8 Hz, ArCH]CH), 6.94 (1H, d, JZ8.5 Hz,
5-H), 7.69 (1H, dd, JZ8.5, 1.7 Hz, 6-H), 7.93 (1H, d, JZ
1.7 Hz, 2-H), 9.88 (1H, s, CHO); 13C NMR (75 MHz,
CDCl3, only E isomer characterized): dZ18.9 (CH3), 69.2
(OCH2), 111.7 (CH), 118.1 (CH), 124.5 (CH), 127.9 (CH),
128.1 (C), 128.4 (CH), 129.8 (C), 130.3 (CH), 132.4 (CH),
159.9 (C), 191.1 (CHO); IR nmax (CHCl3)/cmK1: 1686,
1595, 1492; MS: m/zZ202 (MC, 58%), 173 (13), 161 (34),
159 (11), 133 (27), 115 (11), 106 (9), 105 (100), 103 (16), 79
(16), 77 (26), 51 (11), 41 (32), 39 (19).
5.7.3. 3-Allyloxy-4-methoxy-2-(prop-1-enyl)benzal-
dehyde 19c. The product 19c (0.13 g, 81%, E:Z ratio
74:26) was obtained as an orange oil from 18c (0.13 g,
0.68 mmol). (Found: MC, 232.1083, C14H16O3 requires
232.1099); 1H NMR (300 MHz, CDCl3): E isomer dZ1.98
(3H, dd, JZ6.6, 1.7 Hz, CH3), 3.92 (3H, s, OCH3), 4.41–4.46
(2H, m, OCH2), 5.22 [1H, br d, JZ10.1 Hz, CH]C(H)H],
5.34 [1H, dd, JZ17.2, 1.5 Hz, CH]C(H)H], 5.86 (1H, dq,
JZ15.9, 6.6 Hz, CH]CHCH3), 6.00–6.14 (1H, m, CH2-
CH]CH3), 6.73 (1H, dd, JZ15.9, 1.7 Hz, CH]CHCH3),
6.91 (1H, d, JZ8.7 Hz, 5-H), 7.71 (1H, d, JZ8.7 Hz, 6-H),
5.7.6. 2-(Allyloxy)-1-(prop-1-enyl)naphthalene 19f.25 The
product 19f (0.37 g, 65%, O95% Z isomer) was obtained as
a clear oil from 18f (0.30 g, 2.6 mmol). (Found: MC,
224.1204, C16H16O requires 224.1201); 1H NMR
(300 MHz, CDCl3, only Z isomer characterized): dZ1.52
(3H, dd, JZ6.8, 1.7 Hz, CH3), 4.65–4.68 (2H, m, OCH2),
5.23–5.27 (1H, m, CH]C(H)H), 5.38–5.45 [1H, m,

10004
W. A. L. van Otterlo et al. / Tetrahedron 61 (2005) 9996–10006
CH]C(H)H], 6.01–6.16 (2H, m, CHCH3 and CH2-
CH]CH2), 6.60 (1H, dd, JZ11.2, 1.1 Hz, CH]CHCH3),
7.26 (1H, d, JZ9.0 Hz, ArH), 7.31–7.36 (1H, m, ArH),
7.41–7.47 (1H, m, ArH), 7.74–7.79 (2H, m, 2!ArH), 7.86
(1H, d, JZ8.5 Hz, ArH); 13C NMR (75 MHz, CDCl3, only
Z isomer characterized): dZ15.4 (CH3), 70.2 (OCH2), 115.2
(CH), 117.1 (CH), 121.1 (C), 123.6 (CH), 125.1 (CH), 126.1
(CH), 128.0 (CH), 128.4 (CH), 129.1 (C), 129.7 (CH), 129.8
(CH), 132.7 (C), 133.9 (CH), 153.0 (C); IR nmax (CHCl3)/
cmK1: 1672, 1623, 1596, 1511, 1465, 1435; MS: m/zZ224
(MC, 85%), 183 (100), 165 (49), 155 (93), 139 (31), 115
(33), 41 (35).
from 19b (0.15 g, 0.68 mmol). This yellow solid (mp
decomposition O210 8C with sweating at ca. 116 8C)
decomposed rapidly (hours at room temperature) to a dark
brown solid in air. (Found: MC, 177.0434, C9H7O3N
requires 177.0426); 1H NMR (300 MHz, CDCl3): dZ4.99–
5.00 (2H, m, 2-H), 5.88 (1H, dt, JZ10.0, 3.3 Hz, 3-H), 6.43
(1H, d, JZ10.0 Hz, 4-H), 6.78 (1H, d, JZ8.9 Hz, 8-H), 7.83
(1H, d, JZ2.5 Hz, 5-H), 7.99 (1H, dd, JZ8.9, 2.5 Hz, 7-H);
13C NMR (75 MHz, CDCl3): dZ66.7 (2-C), 116.0 (CH),
121.7 (C), 122.1 (CH), 122.9 (CH), 123.6 (CH), 125.3 (CH),
141.8 (C), 159.5 (C); IR nmax (CHCl3)/cmK1: 1650, 1613,
1578, 1506, 1488, 1435; MS: m/zZ177 (MC, 99%), 176
(100), 131 (24), 130 (57), 103 (25), 102 (23), 77 (44), 74
(10), 69 (10), 63 (10), 51 (26).
5.7.7. 1-Allyloxy-2-(prop-1-enyl)benzene 19g. The
product 19g (0.45 g, 86%, E:Z ratio 90:10) was obtained
as a clear oil from 18g (0.40 g, 3.0 mmol). Found: MC,
174.1043, C12H14O requires 174.1045); 1H NMR
(300 MHz, CDCl3, only E isomer characterized): dZ1.89
(3H, dd, JZ6.7, 1.5 Hz, CH3), 4.54–4.55 (2H, m, OCH2),
5.27 [1H, dd, JZ10.5, 1.3 Hz, CH]C(H)H], 5.41 [1H, dd,
JZ17.3, 1.3 Hz, CH]C(H)H], 6.01–6.14 (1H, m,
CH]CH2), 6.16–6.29 (1H, m, CH]CH), 6.75 (1H, d,
JZ15.9 Hz, ArCH]CH), 6.81–6.92 (2H, m, 2!ArH),
7.11–7.16 (1H, m, ArH), 7.39 (1H, d, JZ7.6 Hz, ArH); 13C
NMR (75 MHz, CDCl3, only E isomer characterized): dZ
19.3 (CH3), 69.6 (OCH2), 112.8 (CH), 117.6 (CH), 121.3
(CH), 126.1 (CH), 126.7 (CH), 126.8 (CH), 128.0 (CH),
5.8.3. 8-Methoxy-2H-chromene-5-carbaldehyde 20c. The
product 20c (0.32 g, 77%) was obtained as an orange oil
from 19c (0.50 g, 2.2 mmol). (Found: MC, 190.0639,
C11H10O3 requires 190.0630); 1H NMR (300 MHz,
CDCl3): dZ3.95 (3H, s, OCH3), 4.86 (2H, dd, JZ3.8,
1.8 Hz, 2-H), 6.00 (1H, dt, JZ10.2, 3.8 Hz, 3-H), 6.89 (1H,
d, JZ8.5 Hz, ArH), 7.34 (1H, d, JZ8.5 Hz, ArH), 7.53 (1H,
dt, JZ10.2, 1.8 Hz, 4-H), 9.97 (1H, s, CHO); 13C NMR
(75 MHz, CDCl3): dZ56.0 (OCH3), 65.1 (2-C), 110.4 (CH),
121.4 (CH), 122.9 (C), 124.4 (CH), 124.4 (C), 128.8 (CH),
143.2 (C), 152.5 (C), 191.7 (CHO); IR nmax (CHCl3)/cmK1
:
1686, 1592, 1565, 1493, 1460, 1439, 1412; MS: m/zZ190
(MC, 100%), 189 (53), 175 (61), 161 (19), 147 (26), 119
(17), 91 (28), 65 (19).
130.6 (C), 134.0 (CH), 155.6 (C); IR nmax (CHCl3)/cmK1
:
1601; MS: m/zZ174 (MC, 51%), 145 (24), 133 (71), 121
(20), 105 (100), 91 (11), 77 (28), 65 (10), 51 (15), 41 (34),
39 (25).
5.8.4. 2H-Chromene-8-carbaldehyde 20d.28 The product
20d (0.21 g, 80%) was obtained as a light yellow oil from
19d (0.34 g, 1.67 mmol). (Found: MC, 160.0521, C10H8O2
5.8. General RCM procedure for the synthesis of
substituted 2H-chromenes 20 from 1-allyloxy-2-(prop-1-
enyl)benzenes 19
1
requires 160.0524); H NMR (300 MHz, CDCl3): dZ4.96
(2H, br s, 2-H), 5.81–5.86 (1H, m, 3-H), 6.42 (1H, br d, JZ
10.0 Hz, 4-H), 6.87–6.92 (1H, m, ArH), 7.13 (1H, d, JZ
7.2 Hz, ArH), 7.61 (1H, d, JZ7.8 Hz, ArH), 10.36 (1H, s,
CHO); 13C NMR (75 MHz, CDCl3): dZ66.0 (2-C), 120.9
(CH), 122.4 (CH), 123.0 (C), 123.5 (CH), 123.6 (C), 127.2
(CH), 132.2 (CH), 156.9 (C), 189.1 (CHO); IR nmax
(CHCl3)/cmK1: 1684, 1593, 1448, 1400; MS: m/zZ160
(MC, 80%), 159 (100), 148 (52), 120 (22), 118 (40), 103
(30), 102 (28), 91 (37), 89 (25), 77 (35), 63 (30), 57 (30), 55
(38), 51 (34), 41 (43), 39 (34).
Typically, Grubbs catalyst 11 (4–6 mol%) was added to a
degassed solution of the substituted 1-allyl-2-vinyloxy-
benzene 19 (ca. 0.5–1.0 mmol) dissolved in degassed,
distilled toluene (ca. 30 mL, ca. 0.020 M). The reaction
mixture was then heated at 60 8C for 1 h under a N2
atmosphere. After removal of the solvent under reduced
pressure the residue was purified by silica gel column
chromatography (5–20% EtOAc/hexane) to afford the
desired product 20. The following compounds were
obtained using this procedure:
5.8.5. 2H-Chromene-6-carbaldehyde 20e. The product
20e (0.19 g, 76%) was obtained as an unstable orange oil
from 19e (0.31 g, 1.5 mmol). Found: MC, 160.0531,
C10H8O2 requires 160.0524); 1H NMR (300 MHz,
CDCl3): dZ4.97 (2H, dd, JZ3.3, 2.0 Hz, 2-H), 5.83 (1H,
dt, JZ10.0, 3.3 Hz, 3-H), 6.45 (1H, br d, JZ10.0 Hz, 4-H),
6.84 (1H, d, JZ8.3 Hz, 8-H), 7.47 (1H, d, JZ1.9 Hz, 5-H),
7.62 (1H, dd, JZ8.3, 1.9 Hz, 7-H), 9.82 (1H, s, CHO); 13C
NMR (75 MHz, CDCl3): dZ66.4 (2-C), 116.2 (CH), 117.8
(C), 122.1 (C), 122.7 (CH), 123.5 (CH), 127.8 (CH), 132.1
5.8.1. 8-Nitro-2H-chromene 20a.27 The product 20a
(0.14 g, 88%) was obtained as a light yellow oil from 19a
(0.20 g, 0.91 mmol). (Found: MC, 177.0431, C9H7O3N
1
requires 177.0426); H NMR (300 MHz, CDCl3): dZ5.00
(2H, dd, JZ3.4, 1.9 Hz, 2-H), 5.90 (1H, dt, JZ10.0, 3.4 Hz,
3-H), 6.45 (1H, dt, JZ10.0, 1.9 Hz, 4-H), 6.87–6.93 (1H, m,
ArH), 7.14 (1H, dd, JZ7.4, 1.4 Hz, ArH), 7.67 (1H, dd, JZ
8.3, 1.4 Hz, ArH); 13C NMR (75 MHz, CDCl3, one
quaternary carbon not observed in spectrum): dZ66.5 (2-
C), 120.4 (CH), 123.3 (CH), 123.4 (CH), 124.5 (C), 124.8
(CH), 130.9 (CH), 148.2 (C); IR nmax (CHCl3)/cmK1: 1609,
1527, 1477, 1343; MS: m/zZ177 (MC, 100%), 176 (81),
130 (41), 103 (24), 102 (20), 77 (14), 51 (6).
(CH), 159.0 (C), 190.7 (CHO); IR nmax (CHCl3)/cmK1
:
1686, 1595, 1578; MS: m/zZ160 (MC, 73%), 159 (100),
131 (33), 103 (19), 77 (25), 51 (18), 40 (10).
5.8.6. 3H-Benzo[f]chromene 20f.23,29 The product 20f
(0.086 g, 45%) was obtained as a yellow oil from 19f
(0.13 g, 0.58 mmol). The reaction was repeated on a smaller
scale (19f, 0.067 g, 0.30 mmol) to afford the product 20f
5.8.2. 6-Nitro-2H-chromene 20b. The product 20b
(0.12 g, quantitative) was obtained as a fluffy yellow solid

W. A. L. van Otterlo et al. / Tetrahedron 61 (2005) 9996–10006
10005
(0.055 g, 82%) in a better yield; 1H NMR (300 MHz,
CDCl3): dZ4.86 (2H, dd, JZ3.8, 1.7 Hz, 3-H), 5.91 (1H,
dt, JZ9.8, 3.8 Hz, 2-H), 7.06 (1H, d, JZ8.9 Hz, ArH), 7.13
(1H, d, JZ9.8 Hz, 1-H), 7.31–7.36 (1H, m, ArH), 7.44–7.50
(1H, m, ArH), 7.64 (1H, d, JZ8.9 Hz, ArH), 7.74 (1H, d,
JZ8.2 Hz, ArH), 7.92 (1H, d, JZ8.5 Hz, ArH).
2239–2258. (d) Deiters, A.; Martin, S. F. Chem. Rev. 2004,
104, 2199–2238.
9. (a) Harrity, J. P. A.; La, D. S.; Cefalo, D. R.; Visser, M. S.;
Hoveyda, A. H. J. Am. Chem. Soc. 1998, 120, 2343–2351. (b)
Chang, S.; Grubbs, R. H. J. Org. Chem. 1998, 63, 864–866. (c)
Ackermann, L.; Fu¨rstner, A.; Weskamp, T.; Kohl, F. J.;
Herrmann, W. A. Tetrahedron Lett. 1999, 40, 4787–4790. (d)
Hardouin, C.; Burgaud, L.; Valleix, A.; Doris, E. Tetrahedron
Lett. 2003, 44, 435–437. (e) For a similar RCM approach to a
2H-chromene example see: Gross, J. L. Tetrahedron Lett.
2003, 44, 8563–8565. (f) Doodeman, R.; Rutjes, F. P. J. T.;
Hiemstra, H. Tetrahedron Lett. 2000, 41, 5979–5983. (g)
Okada, A.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett.
2001, 42, 8023–8027. (h) Whitehead, A.; Moore, J. D.;
Hanson, P. R. Tetrahedron Lett. 2003, 44, 4275–4277. (i)
Fu¨rstner, A.; Guth, O.; Du¨ffels, A.; Seidel, G.; Liebl, M.;
Gabor, B.; Mynott, R. Chem. Eur. J. 2001, 7, 4811–4820. (j)
Wipf, P.; Weiner, W. S. J. Org. Chem. 1999, 64, 5321–5324.
(k) Fu¨rstner, A.; Hill, A. F.; Liebl, M.; Wilton-Ely, J. D. E. T.
Chem. Commun. 1999, 601–602. (l) Kinderman, S. S.;
Doodeman, R.; van Beijma, J. W.; Russcher, J. C.; Tjen,
K. C. M. F.; Kooistra, T. M.; Mohaselzadeh, H.; van
Maarseveen, J. H.; Hiemstra, H.; Schoemaker, H. E.; Rutjes,
F. P. J. T. Adv. Synth. Catal. 2002, 344, 736–748. (m) Harrity,
J. P. A.; Visser, M. S.; Gleason, J. D.; Hoveyda, A. H. J. Am.
Chem. Soc. 1997, 119, 1488–1489. (n) Fu¨rstner, A.; Liebl, M.;
Lehmann, C. W.; Picquet, M.; Kunz, R.; Bruneau, C.;
Touchard, D.; Dixneuf, P. H. Chem. Eur. J. 2000, 6,
1847–1857. (o) Lebel, H.; Paquet, V. J. Am. Chem. Soc.
2004, 126, 11152–11153.
5.8.7. 2H-Chromene 20g.29 This reaction was performed
on 19g (w20 mg) on a NMR spectroscopy scale in an
NMR tube using CDCl3 as solvent.13a The formation of
product 20g (conversion O80%) was confirmed by 1H
and 13C NMR spectroscopy and the spectra compared
well with that reported in the literature. 1H NMR
(300 MHz, CDCl3): dZ4.80 (2H, dd, JZ3.5, 1.9 Hz, 2-
H), 5.75 (1H, dt, JZ9.8, 3.5 Hz, 3-H), 6.40 (1H, br d,
JZ9.8 Hz, 4-H), 6.76 (1H, d, JZ8.0 Hz, ArH), 6.82–
6.87 (1H, m, ArH), 6.93–6.96 (1H, m, ArH), 7.05–7.11
(1H, m, ArH).
Acknowledgements
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). Prof. J. P. Michael is thanked
for many helpful discussions and Mr. L. G. Madeley
(Honours) and Ms. N. Thornton (Honours) are acknowl-
edged for preparing a number of synthetic precursors. We
also gratefully acknowledge the Mellon Postgraduate
Mentoring Programme (sponsored by the Andrew W.
Mellon Foundation) for generous funding for Mr. E. L.
Ngidi and 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.
10. Lam, P. Y. S.; Vincent, G.; Bonne, D.; Clark, C. G.
Tetrahedron Lett. 2003, 44, 4927–4931.
11. Preliminary communication: van Otterlo, W. A. L.; Ngidi,
E. L.; Coyanis, E. M.; de Koning, C. B. Tetrahedron Lett.
2003, 44, 311–313.
12. For a topical review including the relationship between
metathesis and isomerization processes see: Schmidt, B. Eur.
J. Org. Chem. 2004, 1865–1880.
13. For publications describing our previous isomerization-RCM
strategies and related papers see: (a) van Otterlo, W. A. L.;
Ngidi, E. L.; de Koning, C. B. Tetrahedron Lett. 2003, 44,
6483–6486. (b) van Otterlo, W. A. L.; Pathak, R.; de Koning,
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