One-pot synthesis of 5-amino-2,5-dihydro-1-benzoxepines: Access to pharmacologically active heterocyclic scaffolds

Article abstract of DOI:10.1021/acs.joc.5b00583

A one-pot multibond-forming process involving a thermally mediated Overman rearrangement and a ring closing metathesis reaction of allylic trichloroacetimidates bearing a 2-allyloxyaryl group has been developed for the synthesis of 5-amino-substituted 2,5-dihydro-1-benzoxepines. Chemoselective reduction and functionalization of these compounds allowed access to a range of pharmacologically active 5-amino-2,3,4,5-tetrahydro-1-benzoxepine scaffolds.

Full text of DOI:10.1021/acs.joc.5b00583

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Article
One-Pot Synthesis of 5-Amino-2,5-Dihydro-1-Benzoxepines:
Access to Pharmacologically Active Heterocyclic Scaffolds
Ewen D. D. Calder, Salaheddin A. I. Sharif, Fiona I. McGonagle, and Andrew Sutherland
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 07 Apr 2015
Downloaded from http://pubs.acs.org on April 7, 2015
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The Journal of Organic Chemistry
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OneꢀPot Synthesis of 5ꢀAminoꢀ2,5ꢀDihydroꢀ1ꢀ
Benzoxepines: Access to Pharmacologically Active
Heterocyclic Scaffolds
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Ewen D. D. Calder, Salaheddin A. I. Sharif, Fiona I. McGonagle and Andrew Sutherland*
WestCHEM, School of Chemistry, The Joseph Black Building, University of Glasgow,
Glasgow G12 8QQ, United Kingdom.
Andrew.Sutherland@glasgow.ac.uk
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
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TITLE RUNNING HEAD: Synthesis of 2,5ꢀDihydroꢀ1ꢀbenzoxepines
CORRESPONDING AUTHOR FOOTNOTE:
University of Glasgow
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Table of Contents Graphic:
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Abstract: A oneꢀpot multibond forming process involving a thermally mediated Overman
rearrangement and a ring closing metathesis reaction of allylic trichloroacetimidates bearing a 2ꢀ
allyloxyaryl group has been developed for the synthesis of 5ꢀaminoꢀsubstituted 2,5ꢀdihydroꢀ1ꢀ
benzoxepines. Chemoselective reduction and functionalization of these compounds allowed access to a
range of pharmacologically active 5ꢀaminoꢀ2,3,4,5ꢀtetrahydroꢀ1ꢀbenzoxepine scaffolds.
Keywords: Overman rearrangement, ring closing metathesis, 1ꢀbenzoxepines, synthetic building
blocks.
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INTRODUCTION
Dihydrobenzo[b]oxepines are an important class of sevenꢀmembered heterocyclic compound found as
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a key constituent in a variety of natural products and biologically active substances.1–3 In particular, 2,5ꢀ
dihydroꢀ1ꢀbenzoxepines such as radulanin A (1)4 and heliannuol B5 were isolated from liverwort and
sunflowers, respectively, while 2,3ꢀdihydroꢀ1ꢀbenzoxepines including pterulone (2) have been
recovered from various fungi and shown to possess antibiotic activity (Figure 1).1,3
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Figure 1. Structures of dihydroꢀ1ꢀbenzoxepine natural products (1 and 2) and biologically active
aminoꢀsubstituted 2,3,4,5ꢀtetrahydroꢀ1ꢀbenzoxepines (3 and 4).
As a result of their biological significance and interesting structures, various methods for the
preparation of these compounds have been reported. 2,3ꢀDihydroꢀ1ꢀbenzoxepines have been synthesized
by metal catalyzed formation of the oxepine ring using suitably derived phenol ethers and alkynes,6,7
and also via a Wittig homologation of 2ꢀ(chloromethyl)ꢀ2Hꢀchromenꢀ2ꢀol derivatives.8 A variety of
methods have also been reported for the preparation of 2,5ꢀdihydroꢀ1ꢀbenzoxepines.9–13 These include a
general approach involving the Claisen rearrangement of allyl phenyl ethers followed by Oꢀallylation
and a ring closing metathesis (RCM) reaction (Scheme 1a).11 This particular strategy has been utilized
for the total synthesis of a number of 2,5ꢀdihydroꢀ1ꢀbenzoxepine containing natural products.2,12,13
Building on the general strategy of using sigmatropic rearrangements in combination with RCM
reactions for the synthesis of mediumꢀsized heterocycles (Scheme 1a) and our previous work on the
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development of oneꢀpot multistep reactions,14–16 we were interested in developing an approach for the
synthesis of 5ꢀaminoꢀ2,5ꢀdihydroꢀ1ꢀbenzoxepines (Scheme 1b). Previous oneꢀpot methods developed by
our group for the preparation of sevenꢀmembered ring systems have encountered issues during the
metathesis step, such as the formation of dimeric products,14a and the requirement of forcing conditions
to form the sevenꢀmembered ring in good yields.15a In this current study, we wished to investigate
whether more rigid alkene derived allylic alcohols bearing an aromatic ring would prove to be more
suitable substrates for such a process, yielding a library of 5ꢀaminoꢀ2,5ꢀdihydroꢀ1ꢀbenzoxepines.
Subsequent oxidation or chemoselective reduction of the alkene moiety of these targets would then
allow access to functionalized 5ꢀaminoꢀ2,3,4,5ꢀtetrahydroꢀ1ꢀbenzoxepines that are present in a wide
range of pharmacologically active compounds (e.g. 3 and 4, Figure 1).17–20 We now report an efficient
synthesis of 5ꢀaminoꢀ2,5ꢀdihydrobenzoxepines from commercially available salicylaldehydes using a
oneꢀpot multibond forming process for introduction of the amine functionality and consecutive
formation of the oxepine ring. As well as demonstrating the general scope of this strategy, we also
explore the synthetic utility of 5ꢀaminoꢀ2,5ꢀdihydroꢀ1ꢀbenzoxepines for the preparation of 2,3,4,5ꢀ
tetrahydroꢀ1ꢀbenzoxepine targets.
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Scheme 1. 3,3-Sigmatropic rearrangement and RCM routes to 2,5-Dihydro-1-benzoxepines
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RESULTS AND DISCUSSION
The study began with the development of a general approach for the synthesis of (E)ꢀ(2ꢀ
allyloxy)cinnamyl alcohols from readily available salicylaldehydes (Scheme 2). OꢀAllylation of
salicylaldehydes 5a–l under standard conditions gave 2ꢀallyloxybenzaldehydes 6a–l and these were
subjected to a Horner–Wadsworth–Emmons (HWE) reaction with triethyl phosphonoacetate (TEPA)
under mild Masamune–Roush conditions.21 Reduction of the resulting (E)ꢀα,βꢀunsaturated esters 7a–l
with DIBALꢀH completed the threeꢀstep synthesis of (E)ꢀ(2ꢀallyloxy)cinnamyl alcohols 8a–l in high
overall yields.
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Scheme 2. Synthesis of Allylic Alcohols 8a–l
The oneꢀpot multibond forming process was then optimized for the synthesis of 5ꢀaminoꢀsubstituted
2,5ꢀdihydroꢀ1ꢀbenzoxepine 11a (Table 1). (E)ꢀ(2ꢀAllyloxy)cinnamyl alcohol 8a was converted to the
corresponding allylic trichloroacetimidate using trichloroacetonitrile and a catalytic amount of DBU,
and then subjected to an Overman rearrangement under thermal conditions (entry 1).22 Grubbs first
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generation catalyst was initially investigated for the RCM step and required a catalyst loading of 30 mol
% and a reaction time of 120 h for complete conversion.23 This gave 2,5ꢀdihydroꢀ1ꢀbenzoxepine 11a in
15% yield over the three steps. On analysis of the process, it was found that the typical workꢀup
procedure of allylic trichloroacetimidate formation by filtration of the reaction mixture through a plug of
silica gel, resulted in substantial decomposition of 9a. This is likely promoted by the presence of the
electronꢀrich orthoꢀether unit and the acidic nature of the silica gel. In subsequent studies of the oneꢀpot
process, this issue was overcome by simply performing the filtration using neutral alumina. Using this
modification, the oneꢀpot process was repeated and 11a was isolated in a significantly improved 63%
overall yield (entry 2). The use of a palladium(II)ꢀcatalyzed Overman rearrangement was next
investigated and while this transformation was conducted under mild conditions, 2,5ꢀdihydroꢀ1ꢀ
benzoxepine 11a was isolated in only 26% yield (entry 3). The low yield is likely due to a number of
factors such as a competing 1,3ꢀrearrangement as well as coordination of the palladium(II)ꢀcatalyst with
the allylic ether moiety preventing effective activation and rearrangement of the allylic
trichloroacetimidate.15a Finally, the use of a oneꢀpot process involving a thermally mediated Overman
rearrangement in combination with Grubbs second generation catalyst was examined and this resulted in
a substantial improvement of reaction conditions for the RCM step (entry 4).24 After 20 h, complete
conversion could be achieved using a 5 mol % catalyst loading, resulting in the isolation of 2,5ꢀdihydroꢀ
1ꢀbenzoxepine 11a in 68% yield from allylic alcohol 8a.
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Table 1.
Optimization of the One-Pot Process
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Entry
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Overman Rearrangement
K2CO3, 140 ºC
RCM Reaction
Yield (%)
Grubbs I (30 mol %), 120 h
Grubbs I (30 mol %), 120 h
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K2CO3, 140 ºC
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Pd(MeCN)2Cl2 (10 mol %), rt Grubbs I (30 mol %), 120 h
K2CO3, 140 ºC Grubbs II (5 mol %), 20 h
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a
Allylic trichloroacetimidate 9a was isolated by filtration of the reaction mixture through a plug of
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silica gel. Allylic trichloroacetimidate 9a was isolated by filtration of the reaction mixture through a
plug of neutral alumina.
Using these optimized conditions, the scope of the oneꢀpot process for the synthesis of a small library
of 5ꢀaminoꢀsubstituted 2,5ꢀdihydroꢀ1ꢀbenzoxepines was explored (Scheme 3). Overall, this approach
was found to be general for a range of substituents and substitution patterns. For example, comparison
of the same substituent at orthoꢀ, metaꢀ or paraꢀpositions showed no significant difference in reactivity,
giving the final products in comparable yields (11b/c/d and 11g/i). Substrates bearing strongly electronꢀ
deficient substituents did require extended reaction times for the Overman rearrangement, however,
these oneꢀpot processes still produced the corresponding 2,5ꢀdihydroꢀ1ꢀbenzoxepines in high yields
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(11f–j). Only products 11k and 11l were isolated in modest yields and this is likely due to the increased
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steric bulk associated with the aryl substituents.
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Scheme 3. Synthesis of 5-Amino-Substituted 2,5-Dihydro-1-benzoxepines 11a–l
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aThe Overman rearrangement required an extended reaction time (24 h, 11i and 11j; 48 h, 11h and 11k;
60 h, 11f and 11g). b7.5 mol % of Grubbs second generation catalyst was used for the RCM step.
Derivatives of 5ꢀaminoꢀsubstituted 2,3,4,5ꢀtetrahydroꢀ1ꢀbenzoxepines bearing aryl groups at the 8ꢀ
postion (e.g. 20, Scheme 4) have been shown to be potent inhibitors of acylꢀCoA cholesterol Oꢀacyl
transferase (ACAT), the enzyme responsible for intracellular esterification of cholesterol.19 Due to the
significant biological activity of these compounds, the scope of our oneꢀpot synthesis of 2,5ꢀdihydroꢀ1ꢀ
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benzoxepines was extended to investigate the rapid assembly of this type of oxepine skeleton (Scheme
4). Initially, SuzukiꢀMiyaura coupling of 4ꢀfluorophenylboronic acid (12) and methyl 2ꢀhydroxyꢀ4ꢀ
iodobenzoate (13) gave biaryl compound 14 in quantitative yield. Reduction of the ester with lithium
aluminium hydride and selective allylation of the phenol gave benzyl alcohol 15. This was then
subjected to a oneꢀpot Swern oxidation and HWE reaction, which gave (E)ꢀα,βꢀunsaturated ester 16 as
the sole product in 84% yield over the two steps. DIBALꢀH reduction of the ester then completed the
sixꢀstep synthesis of allylic alcohol 17. Formation of the corresponding allylic trichloroacetimidate and
application of the oneꢀpot Overman rearrangement and RCM process using the optimized conditions
proceeded smoothly, giving 2,5ꢀdihydroꢀ1ꢀbenzoxepine 18 in 98% yield. The synthesis of 18 in 61%
overall yield from commercially available benzoate 13 demonstrates the robust nature of the oneꢀpot
strategy for the synthesis of pharmacologically important 5ꢀaminoꢀsubstituted 2,5ꢀdihydroꢀ1ꢀ
benzoxepine building blocks.
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Having explored the scope of the oneꢀpot process, the next stage of this research programme
investigated the synthetic utility of these compounds for the preparation of biologically active scaffolds.
As 5ꢀaminoꢀsubstituted 2,3,4,5ꢀtetrahydroꢀ1ꢀbenzoxepines have wide ranging pharmacological
activities,17–20 chemoselective methods for their synthesis from 2,5ꢀdihydroꢀ1ꢀbenzoxepines were
developed. A method that would allow preparation of the ACAT inhibitor core by reduction of the
alkene moiety of 18 while retaining the trichloroacetamide as a protecting group was initially examined.
Standard hydrogenation conditions (10% Pd/C in an atmosphere of H2) gave 19 in 59% yield. However,
several byꢀproducts formed via reduction of the trichloromethyl group were also isolated. Instead, a
more selective reaction for the preparation of 19 was achieved using diimide, which was generated in
situ from pꢀtoluenesulfonyl hydrazide and potassium acetate (Scheme 4).25 This produced 2,3,4,5ꢀ
tetrahydroꢀ1ꢀbenzoxepine 19 more cleanly in 81% yield.
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Scheme 4. Synthesis of 5-Amino-Substituted 2,3,4,5-Tetrahydro-1-benzoxepine 19
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A synthesis of 8ꢀchloroꢀ5ꢀguanidinoꢀ2,3,4,5ꢀtetrahydroꢀ1ꢀbenzoxepine (4), a known hypotensive
agent was developed from 2,5ꢀdihydroꢀ1ꢀbenzoxepine 11i (Scheme 5).20 In this case, introduction of the
guanidine moiety required removal of the trichloroacetamide and so no effort was made to maintain this
group during reduction of the alkene. Hydrogenation of 11i under standard conditions resulted in
reduction of both the alkene and the trichloromethyl group giving 21 as the sole product in 94% yield.
Acid hydrolysis of the dichloromethylacetamide group required forcing conditions but did yield the
corresponding amine cleanly. This was coupled with commercially available N,N’ꢀbis(tertꢀ
butoxycarbonyl)ꢀ1Hꢀpyrazoleꢀ1ꢀcarboxamidine (22) in the presence of Hünig’s base and this gave
guanidine 23 in 75% yield over the two steps.26,27 Finally, removal of the Bocꢀprotecting groups using
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TFA completed the tenꢀstep synthesis of hypotensive agent 4 in 40% overall yield from commercially
available 4ꢀchloroꢀ2ꢀhydroxybenzaldehyde (5i).
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Scheme 5. Synthesis of 8-chloro-5-guanidino-2,3,4,5-tetrahydro-1-benzoxepine (4)
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A number of 5ꢀaminoꢀsubstituted 2,3,4,5ꢀtetrahydroꢀ1ꢀbenzoxepines bearing hydroxyl groups have
displayed pharmacological activity (e.g. 3, Figure 1).17a,17c,18 For this reason and the considerable
interest in the medicinal chemistry applications of the vicinal amino diol motif,28 the final stage of this
research programme explored the directed oxidation of 5ꢀaminoꢀsubstituted 2,5ꢀdihydroꢀ1ꢀbenzoxepines
for the preparation of synꢀ and antiꢀ3,4ꢀdiol analogues. While directed dihydroxylation29 and
epoxidation30 of a number of cyclic allylic trichloroacetamide systems has been described, we were
interested in the outcome of these reactions using 5ꢀaminoꢀsubstituted 2,5ꢀdihydroꢀ1ꢀbenzoxepines as
novel substrates. Reaction of 6ꢀmethoxyꢀ2,5ꢀdihydroꢀ1ꢀbenzoxepine 11b with osmium tetroxide and
TMEDA under Donohoe conditions gave the corresponding (3R*,4S*,5S*)ꢀdiol 24 in 74% yield
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(Scheme 6).29 Inspection of the H NMR spectra of the crude material from this reaction showed only
one diastereomer, with NOE experiments clearly demonstrated the synꢀrelationship of the vicinal amino
diol motif. This result suggests that the trichloroacetamide unit of the oxepine ring systems is able to
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facilitate a highly effective, directed dihydroxylation with the complex formed from osmium tetroxide
and TMEDA.
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Scheme 6. Dihydroxylation of 5-Amino-Substituted 2,5-Dihydro-1-benzoxepines
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aRatio of major (3R*,4S*,5S*)ꢀ25 and minor (3S*,4R*,5S*) epoxide diastereomers.
Directed epoxidation of 7ꢀchloroꢀ2,5ꢀdihydroꢀ1ꢀbenzoxepine 11g and subsequent acid mediated ring
opening for the preparation of the antiꢀ3,4ꢀdiol was next investigated and found to be less selective.
Treatment of 11g with mꢀCPBA gave the corresponding epoxide in a 12:1 diastereoselectivity (Scheme
6). Again NOE experiments confirmed the all synꢀdiastereomer 25 as the major product, formed via a
substrate directed process that is in agreement with Henbest’s rule.30,31 Without purification,
regioselective hydrolysis of epoxide 25 under acidic conditions gave after purification, the
(3S*,4S*,5S*)ꢀdiol 26 in good yield over the two steps. The difference in selectivity between the
dihydroxylation and epoxidation processes is likely a direct reflection of the ability of the reagents of
these reactions to undergo hydrogen bonding substrate directed reactions with the allylic
trichloroacetamide oxepine unit. Sevenꢀmembered heterocyclic ring systems such as azepanes bearing
an allylic trichloroacetamide moiety have demonstrated similar selectivity and overall yields for these
oxidation processes.15b
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CONCLUSIONS
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In summary, a general approach has been developed for the preparation of 2,5ꢀdihydroꢀ1ꢀ
benzoxepines. A threeꢀstep synthesis of 2ꢀallyloxycinnamyl alcohol derivatives from readily available
2ꢀhydroxybenzaldehydes was followed by imidate formation and a oneꢀpot Overman rearrangement and
RCM process, allowing access to a diverse library of 5ꢀaminoꢀ2,5ꢀdihydroꢀ1ꢀbenzoxepines in high
overall yields. Further functionalization of these privileged structures was explored. Chemoselective
reduction or substrate directed oxidation of the alkene moiety generated a series of 5ꢀaminoꢀ2,3,4,5ꢀ
tetrahydroꢀ1ꢀbenzoxepines, compounds which display a wide range of pharmacological activities. Work
is currently underway to extend the application of this oneꢀpot multibond forming reaction process for
the preparation of biologically relevant polycyclic classes of compounds.
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EXPERIMENTAL SECTION
All reagents and starting materials were obtained from commercial sources and used as received. All
dry solvents were purified using a solvent purification system. All reactions were performed under an
atmosphere of argon unless otherwise mentioned. Brine refers to a saturated solution of sodium
chloride. Flash column chromatography was performed using silica gel 60 (35–70 ꢀm). Aluminiumꢀ
backed plates preꢀcoated with silica gel 60F254 were used for thin layer chromatography and were
visualized with a UV lamp or by staining with potassium permanganate. 1H NMR spectra were recorded
on a NMR spectrometer at either 400 or 500 MHz and data are reported as follows: chemical shift in
ppm relative to tetramethylsilane as the internal standard, multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet or overlap of nonequivalent resonances, integration). 13C NMR spectra
were recorded on a NMR spectrometer at either 101 or 126 MHz and data are reported as follows:
chemical shift in ppm relative to tetramethylsilane or the solvent as internal standard (CDCl3, δ 77.0
ppm or CD3OD, δ 44.0 ppm), multiplicity with respect to hydrogen (deduced from DEPT experiments,
C, CH, CH2 or CH3). Infrared spectra were recorded on a FTIR spectrometer; wavenumbers are
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indicated in cm–1. Mass spectra were recorded using electron impact, chemical ionization or
electrospray techniques. HRMS spectra were recorded using a dualꢀfocusing magnetic analyzer mass
spectrometer. Melting points are uncorrected.
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2-Allyloxybenzaldehyde (6a).32 Allyl bromide (0.98 mL, 1.3 mmol) was added to a stirred solution
of 2ꢀhydroxybenzaldehyde (5a) (0.10 mL, 0.94 mmol) and potassium carbonate (0.26 g, 1.9 mmol) in
N,N’ꢀdimethylformamide (10 mL) and warmed to 70 °C for 2 h. The reaction was cooled to room
temperature, diluted with 5% aqueous lithium chloride solution (20 mL) and extracted with diethyl ether
(20 mL). The organic layer was washed with 5% aqueous lithium chloride solution (3 × 10 mL), brine
(10 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography
(elution with 20% diethyl ether in petroleum ether) gave 2ꢀallyloxybenzaldehyde (6a) (0.15 g, 99%) as a
colorless oil. Spectroscopic data was in accordance with literature values.32 1H NMR (400 MHz, CDCl3)
7
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δ
4.66 (dt, J = 5.1, 1.5 Hz, 2H), 5.34 (dq, J = 10.5, 1.5 Hz, 1H), 5.45 (dq, J = 17.3, 1.5 Hz, 1H), 6.08
(ddt, J = 17.3, 10.5, 5.1 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 7.03 (br t, J = 7.5 Hz, 1H), 7.53 (ddd, J = 8.4,
7.5, 1.9 Hz, 1H), 7.84 (dd, J = 7.5, 1.9 Hz, 1H), 10.54 (d, J = 0.7 Hz, 1H); 13C NMR (101 MHz, CDCl3)
δ
69.4 (CH2), 113.0 (CH), 118.2 (CH2), 121.0 (CH), 125.3 (C), 128.6 (CH), 132.6 (CH), 135.9 (CH),
161.1 (C), 189.9 (CH); MS (CI) m/z 163 (MH+, 100), 135 (34), 121 (8), 85 (12), 79 (11).
2-Allyloxy-6-methoxybenzaldehyde (6b).32 The reaction was carried out as described for the
synthesis of 2ꢀallyloxybenzaldehyde (6a) using 2ꢀhydroxyꢀ6ꢀmethoxybenzaldehyde (5b) (0.500 g, 3.29
mmol). This gave 2ꢀallyloxyꢀ6ꢀmethoxybenzaldehyde (6b) (0.559 g, 88%) as a yellow oil.
Spectroscopic data was in accordance with literature values.32 1H NMR (400 MHz, CDCl3)
δ 3.90 (s,
3H), 4.63 (dt, J = 5.0, 1.4 Hz, 2H), 5.31 (dq, J = 10.4, 1.4 Hz, 1H), 5.48 (dq, J = 17.3, 1.4 Hz, 1H), 6.05
(ddt, J = 17.3, 10.4, 5.0 Hz, 1H), 6.56 (d, J = 8.5 Hz, 1H), 6.58 (d, J = 8.5 Hz, 1H), 7.42 (t, J = 8.5 Hz,
13
1H), 10.56 (s, 1H); C NMR (101 MHz, CDCl3)
δ 56.2 (CH3), 69.7 (CH2), 104.2 (CH), 105.3 (CH),
115.0 (C), 117.9 (CH2), 132.6 (CH), 135.8 (CH), 161.6 (C), 162.0 (C), 189.4 (CH); MS (ESI) m/z 215
(MNa+, 100), 187 (10), 174 (20), 137 (5).
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2-Allyloxy-5-methoxybenzaldehyde (6c).33 The reaction was carried out as described for the
synthesis of 2ꢀallyloxybenzaldehyde (6a) using 2ꢀhydroxyꢀ5ꢀmethoxybenzaldehyde (5c) (0.41 mL, 3.30
mmol). This gave 2ꢀallyloxyꢀ5ꢀmethoxybenzaldehyde (6c) (0.60 g, 96%) as a yellow oil. Spectroscopic
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5
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8
data was in accordance with literature values.33 1H NMR (400 MHz, CDCl3)
δ 3.80 (s, 3H), 4.61 (d, J =
9
5.2 Hz, 2H), 5.31 (dd, J = 10.6, 1.4 Hz, 1H), 5.43 (dd, J = 17.1, 1.4 Hz, 1H), 6.06 (ddt, J = 17.1, 10.6,
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5.2 Hz, 1H), 6.93 (d, J = 9.1 Hz, 1H), 7.11 (dd, J = 9.1, 3.3 Hz, 1H), 7.33 (d, J = 3.3 Hz, 1H), 10.49 (s,
13
1H); C NMR (101 MHz, CDCl3)
δ 56.0 (CH3), 70.2 (CH2), 110.4 (CH), 115.1 (CH), 118.1 (CH2),
123.6 (CH), 125.6 (C), 132.8 (CH), 154.0 (C), 155.9 (C), 189.6 (CH); MS (ESI) m/z 215 (MNa+, 40),
206 (30), 174 (100).
2-Allyloxy-4-methoxybenzaldehyde (6d).33 The reaction was carried out as described for the
synthesis of 2ꢀallyloxybenzaldehyde (6a) using 2ꢀhydroxyꢀ4ꢀmethoxybenzaldehyde (5d) (0.500 g, 3.29
mmol). This gave 2ꢀallyloxyꢀ4ꢀmethoxybenzaldehyde (6d) (0.583 g, 92%) as a colorless oil.
Spectroscopic data was in accordance with literature values.33 1H NMR (500 MHz, CDCl3)
δ 3.85 (s,
3H), 4.62 (dt, J = 5.1, 1.5 Hz, 2H), 5.33 (dq, J = 10.5, 1.5 Hz, 1H), 5.45 (dq, J = 17.3, 1.5 Hz, 1H), 6.06
(ddt, J = 17.3, 10.5, 5.1 Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 6.54 (ddd, J = 8.7, 2.2, 0.6 Hz, 1H), 7.81 (d, J
13
= 8.7 Hz, 1H), 10.35 (d, J = 0.6 Hz, 1H); C NMR (126 MHz, CDCl3)
δ 55.8 (CH3), 69.3 (CH2), 99.2
(CH), 106.2 (CH), 118.2 (CH2), 119.4 (C), 130.6 (CH), 132.4 (CH), 162.8 (C), 166.2 (C), 188.4 (CH);
MS (ESI) m/z 215 (MNa+, 100), 187 (7), 174 (7), 159 (3).
2-Allyloxy-5-methylbenzaldehyde (6e).33 The reaction was carried out as described for the synthesis
of 2ꢀallyloxybenzaldehyde (6a) using 2ꢀhydroxyꢀ5ꢀmethylbenzaldehyde (5e) (0.136 g, 1.00 mmol). This
gave 2ꢀallyloxyꢀ5ꢀmethylbenzaldehyde (6e) (0.173 g, 98%) as a colorless oil. Spectroscopic data was in
accordance with literature values.33 1H NMR (500 MHz, CDCl3)
δ 2.31 (s, 3H), 4.63 (dt, J = 5.2, 1.6 Hz,
2H), 5.32 (dq, J = 10.6, 1.6 Hz, 1H), 5.44 (dq, J = 17.3, 1.6 Hz, 1H), 6.07 (ddt, J = 17.3, 10.6, 5.2 Hz,
1H), 6.88 (d, J = 8.5 Hz, 1H), 7.33 (ddd, J = 8.5, 2.3, 0.6 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 10.51 (s,
1H); 13C NMR (126 MHz, CDCl3)
δ 20.3 (CH3), 69.3 (CH2), 113.0 (CH), 117.9 (CH2), 124.9 (C), 128.5
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(CH), 130.3 (C), 132.6 (CH), 136.5 (CH), 159.1 (C), 189.9 (CH); MS (ESI) m/z 199 (MNa+, 100), 190
(3), 185 (4), 171 (5), 158 (16), 136 (2).
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2-Allyloxy-5-nitrobenzaldehyde (6f).34 The reaction was carried out as described for the synthesis of
2ꢀallyloxybenzaldehyde (6a) using 2ꢀhydroxyꢀ5ꢀnitrobenzaldehyde (5f) (0.050 g, 0.32 mmol). This gave
2ꢀallyloxyꢀ5ꢀnitrobenzaldehyde (6f) (0.061 g, 98%) as a white solid. Mp 62–64 °C (lit.34 63–65 °C); 1H
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NMR (400 MHz, CDCl3)
δ 4.80 (dt, J = 5.3, 1.4 Hz, 2H), 5.41 (ddt, J = 10.7, 2.5, 1.4 Hz, 1H), 5.48
(ddt, J = 17.3, 2.5, 1.4 Hz, 1H), 6.08 (ddt, J = 17.3, 10.7, 5.3 Hz, 1H), 7.11 (d, J = 9.2 Hz, 1H), 8.39 (dd,
J = 9.2, 2.9 Hz, 1H), 8.67 (d, J = 2.9 Hz, 1H), 10.48 (s, 1H); 13C NMR (101 MHz, CDCl3)
δ
70.3 (CH2),
113.5 (CH), 119.6 (CH2), 124.7 (CH), 124.8 (C) 130.6 (CH), 131.1 (CH), 141.7 (C), 164.7 (C), 187.6
(CH); MS (CI) m/z 208 (MH+, 100), 178 (45), 168 (13), 138 (16), 113 (21), 97 (18), 81 (32), 69 (33).
2-Allyloxy-5-chlorobenzaldehyde (6g).35 The reaction was carried out as described for the synthesis
of 2ꢀallyloxybenzaldehyde (6a) using 2ꢀhydroxyꢀ5ꢀchlorobenzaldehyde (5g) (0.500 g, 3.18 mmol). This
gave 2ꢀallyloxyꢀ5ꢀchlorobenzaldehyde (6g) (0.61 g, 96%) as a white solid. Mp 99–101 °C (lit.35 101–
1
102 °C); H NMR (400 MHz, CDCl3)
δ 4.65 (dt, J = 5.2, 1.5 Hz, 2H), 5.35 (dq, J = 10.6, 1.5 Hz, 1H),
5.44 (dq, J = 17.3, 1.5 Hz, 1H), 6.06 (ddt, J = 17.3, 10.6, 5.2 Hz, 1H), 6.93 (d, J = 8.9 Hz, 1H), 7.47 (dd,
J = 8.9, 2.8 Hz, 1H), 7.79 (d, J = 2.8 Hz, 1H), 10.46 (s, 1H); 13C NMR (101 MHz, CDCl3)
δ
69.8 (CH2),
114.7 (CH), 118.7 (CH2), 126.1 (C), 126.7 (C), 128.1 (CH), 132.1 (CH), 135.4 (CH), 159.5 (C), 188.5
(CH); MS (CI) m/z 197 (MH+, 100), 169 (13), 157 (4), 81 (11), 69 (18).
2-Allyloxy-5-bromobenzaldehyde (6h).35 The reaction was carried out as described for the synthesis
of 2ꢀallyloxybenzaldehyde (6a) using 2ꢀhydroxyꢀ5ꢀbromobenzaldehyde (5h) (0.500 g, 2.49 mmol). This
gave 2ꢀallyloxyꢀ5ꢀbromobenzaldehyde (6h) (0.591 g, 99%) as a white solid. Mp 35–37 °C;
Spectroscopic data was in accordance with literature values.35 1H NMR (400 MHz, CDCl3)
δ 4.65 (dt, J
= 5.2, 1.5 Hz, 2H), 5.35 (dq, J = 10.6, 1.5 Hz, 1H), 5.44 (dq, J = 17.3, 1.5 Hz, 1H), 6.05 (ddt, J = 17.3,
10.6, 5.2 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 7.60 (dd, J = 8.9, 2.6 Hz, 1H), 7.93 (d, J = 2.6 Hz, 1H),
13
10.44 (s, 1H); C NMR (101 MHz, CDCl3)
δ 69.7 (CH2), 113.8 (C), 115.1 (CH), 118.7 (CH2), 126.6
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(C), 131.2 (CH), 132.1 (CH), 138.3 (CH), 160.0 (C), 188.4 (CH); MS (ESI) m/z 263 (MNa+, 75), 236
(22), 219 (70), 201 (14), 184 (27).
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2-Allyloxy-4-chlorobenzaldehyde (6i). The reaction was carried out as described for the synthesis of
2ꢀallyloxybenzaldehyde (6a) using 4ꢀchloroꢀ2ꢀhydroxybenzaldehyde (5i) (0.936 g, 6.00 mmol). This
gave 2ꢀallyloxyꢀ4ꢀchlorobenzaldehyde (6i) (1.17 g, 100%) as a white solid. Mp 48–49 °C; IR (neat)
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2867, 1685, 1589, 1413, 1240, 1222, 996, 904 cm−1; 1H NMR (400 MHz, CDCl3)
δ 4.67 (dt, J = 5.2, 1.5
Hz, 2H), 5.39 (dq, J = 10.5, 1.5 Hz, 1H), 5.48 (dq, J = 17.2, 1.5 Hz, 1H), 6.08 (ddt, J = 17.2, 10.5, 5.2
Hz, 1H), 6.95 (d, J = 1.7 Hz, 1H), 7.03 (ddd, J = 8.3, 1.7, 0.7 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 10.46
13
(d, J = 0.7 Hz, 1H); C NMR (101 MHz, CDCl3)
δ 69.5 (CH2), 113.5 (CH), 118.6 (CH2), 121.4 (CH),
123.6 (C), 129.5 (CH), 131.7 (CH), 141.8 (C), 161.2 (C), 188.4 (CH); MS (EI) m/z 196 (M+, 44), 181
35
(9), 167 (38), 155 (100), 126 (25), 99 (27), 75 (14), 63 (26); HRMS (EI) calcd for C10H9 ClO2 (M+),
196.0291, found 196.0288.
2-Allyloxy-4,5-difluorobenzaldehyde (6j). The reaction was carried out as described for the
synthesis of 2ꢀallyloxybenzaldehyde (6a) using 4,5ꢀdifluoroꢀ2ꢀhydroxybenzaldehyde (5j) (0.079 g,
0.500 mmol). This gave 2ꢀallyloxyꢀ4,5ꢀdifluorobenzaldehyde (6j) (0.099 g, 100%) as a white solid. Mp
1
35–36 °C; IR (neat) 2872, 1686, 1604, 1511, 1434, 1323, 1203, 990, 893, 758 cm−1; H NMR (500
MHz, CDCl3)
δ 4.63 (dt, J = 5.2, 1.6 Hz, 2H), 5.38 (dq, J = 10.6, 1.6 Hz, 1H), 5.46 (dq, J = 17.3, 1.6
Hz, 1H), 6.05 (ddt, J = 17.3, 10.6, 5.2 Hz, 1H), 6.81 (dd, 3JHF = 11.5, 4JHF = 5.2 Hz, 1H), 7.66 (dd, 3JHF
4
5
13
= 11.5, JHF = 9.4 Hz, 1H), 10.39 (d, JHF = 3.1 Hz, 1H); C NMR (126 MHz, CDCl3)
δ 70.2 (CH2),
2
103.0 (d, 2JCF = 21.1 Hz, CH), 116.4 (dd, JCF = 18.5, 3JCF = 2.9 Hz, CH), 118.9 (CH2), 121.5 (t, 3JCF =
3.2 Hz, C), 131.6 (CH), 145.2 (dd, 1JCF = 244.6, 2JCF = 13.0 Hz, C), 154.9 (dd, 1JCF = 258.5, 2JCF = 14.5
3
4
Hz, C), 157.8 (dd, JCF = 8.2, JCF = 1.8 Hz, C), 187.2 (CH); MS (EI) m/z 198 (M+, 10), 156 (11), 119
(4), 101 (6), 84 (100); HRMS (EI) calcd for C10H8F2O2 (M+), 198.0492, found 198.0489.
2-Allyloxy-3-methoxy-5-nitrobenzaldehyde (6k). The reaction was carried out as described for the
synthesis of 2ꢀallyloxybenzaldehyde (6a) using 2ꢀhydroxyꢀ3ꢀmethoxyꢀ5ꢀnitrobenzaldehyde (5k) (0.197
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g, 1.00 mmol). This gave 2ꢀallyloxyꢀ3ꢀmethoxyꢀ5ꢀnitrobenzaldehyde (6k) (0.209 g, 88%) as a white
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3
solid. Mp 82–84 °C; IR (neat) 3101, 2898, 1695, 1684, 1583, 1527, 1480, 1336, 1278, 1230, 1091, 954,
4
5
6
938, 743 cm−1; 1H NMR (500 MHz, CDCl3)
δ 4.02 (s, 3H), 4.84 (dt, J = 6.2, 1.3 Hz, 2H), 5.32 (dq, J =
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8
9
10.3, 1.3 Hz, 1H), 5.38 (dq, J = 17.1, 1.3 Hz, 1H), 6.05 (ddt, J = 17.1, 10.3, 6.2 Hz, 1H), 7.96 (d, J = 2.7
Hz, 1H), 8.33 (d, J = 2.7 Hz, 1H), 10.43 (s, 1H); 13C NMR (126 MHz, CDCl3)
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δ
56.6 (CH3), 75.4 (CH2),
111.5 (CH), 115.0 (CH), 120.0 (CH2), 129.3 (C), 132.3 (CH), 143.6 (C), 153.3 (C), 155.8 (C), 188.2
(CH); MS (EI) m/z 237 (M+, 24), 220 (4), 196 (27), 180 (27), 150 (15), 122 (11), 84 (100); HRMS (EI)
calcd for C11H11NO5 (M+), 237.0637, found 237.0630.
2-Allyloxy-1-naphthaldehyde (6l).32 The reaction was carried out as described for the synthesis of 2ꢀ
allyloxybenzaldehyde (6a) using 2ꢀhydroxyꢀ1ꢀnaphthaldehyde (5l) (0.172 g, 1.00 mmol). This gave 2ꢀ
1
allyloxyꢀ1ꢀnaphthaldehyde (6l) (0.208 g, 98%) as a white solid. Mp 72–74 °C (lit.32 79–80 °C); H
NMR (400 MHz, CDCl3)
δ 4.83 (dt, J = 5.2, 1.6 Hz, 2H), 5.39 (dq, J = 10.6, 1.6 Hz, 1H), 5.50 (dq, J =
17.3, 1.6 Hz, 1H), 6.13 (ddt, J = 17.3, 10.6, 5.2 Hz, 1H), 7.30 (d, J = 9.3 Hz, 1H), 7.45 (ddd, J = 8.5,
8.4, 1.3 Hz, 1H), 7.65 (ddd, J = 8.5, 8.4, 1.3 Hz, 1H), 7.80 (br d, J = 8.4 Hz, 1H), 8.06 (d, J = 9.3 Hz,
1H), 9.31 (br d, J = 8.4 Hz, 1H), 10.98 (s, 1H); 13C NMR (101 MHz, CDCl3)
δ 69.9 (CH2), 113.7 (CH),
116.8 (C), 118.1 (CH2), 124.7 (CH), 124.9 (CH), 128.3 (CH), 128.5 (C), 129.7 (CH), 131.5 (C), 132.4
(CH), 137.4 (CH), 163.0 (C), 191.8 (CH); MS (ESI) m/z 235 (MNa+, 100), 218 (6), 194 (16).
Ethyl (2E)-3-(2’-allyloxyphenyl)prop-2-enoate (7a).36 Lithium bromide (0.47 g, 5.4 mmol) was
added to a solution of triethyl phosphonoacetate (0.91 mL, 4.6 mmol) and 1,8ꢀdiazabicyclo[5.4.0]undecꢀ
7ꢀene (0.68 mL, 4.6 mmol) in acetonitrile (20 mL) and stirred at room temperature for 0.5 h. 2ꢀ
Allyloxybenzaldehyde (6a) (0.22 g, 1.4 mmol) was added and the solution was stirred at room
temperature for 18 h. The reaction was quenched by the addition of a saturated solution of ammonium
chloride (30 mL), concentrated to half volume in vacuo and extracted with diethyl ether (3 × 30 mL).
The combined organic layers were washed with water (100 mL), brine (100 mL), dried (MgSO4),
filtered and concentrated in vacuo. Purification by column chromatography (elution with 20% diethyl
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ether in petroleum ether) gave ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenoate (7a) (0.30 g, 95%) as a
yellow oil. Spectroscopic data was in accordance with literature values.36 1H NMR (400 MHz, CDCl3)
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δ
5
6
7
8
1.34 (t, J = 7.1 Hz, 3H), 4.26 (q, J = 7.1 Hz, 2H), 4.62 (dt, J = 5.1, 1.5 Hz, 2H), 5.31 (dq, J = 10.6, 1.5
Hz, 1H), 5.43 (dq, J = 17.3, 1.5 Hz, 1H), 6.08 (ddt, J = 17.3, 10.6, 5.1 Hz, 1H), 6.53 (d, J = 16.2 Hz,
1H), 6.90 (d, J = 8.3 Hz, 1H), 6.96 (td, J = 7.7, 0.5 Hz, 1H), 7.29–7.35 (m, 1H), 7.52 (dd, J = 7.7, 1.7
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Hz, 1H), 8.05 (d, J = 16.2 Hz, 1H); 13C NMR (101 MHz, CDCl3)
δ 14.4 (CH3), 60.3 (CH2), 69.2 (CH2),
112.5 (CH), 117.7 (CH2), 118.8 (CH), 120.9 (CH), 123.8 (C), 128.8 (CH), 131.3 (CH), 132.9 (CH),
139.9 (CH), 157.3 (C), 167.5 (C); MS (EI) m/z 232 (M+, 38), 187 (42), 158 (78), 144 (59), 129 (61), 118
(97), 84 (100), 77 (19), 49 (99).
Ethyl (2E)-3-(2’-allyloxy-6’-methoxyphenyl)prop-2-enoate (7b). The reaction was carried out as
described for the synthesis of ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenoate (7a) using 2ꢀallyloxyꢀ6ꢀ
methoxybenzaldehyde (6b) (0.531 g, 2.76 mmol). This gave ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ6’ꢀ
methoxyphenyl)propꢀ2ꢀenoate (7b) (0.594 g, 85%) as a yellow oil. IR (neat) 2979, 1701, 1622, 1593,
1
1473, 1308, 1254, 1160, 1093 cm−1; H NMR (400 MHz, CDCl3)
δ 1.33 (t, J = 7.1 Hz, 3H), 3.88 (s,
3H), 4.26 (q, J = 7.1 Hz, 2H), 4.62 (dt, J = 5.1, 1.5 Hz, 2H), 5.30 (dq, J = 10.5, 1.5 Hz, 1H), 5.43 (dq, J
= 17.3, 1.5 Hz, 1H), 6.08 (ddt, J = 17.3, 10.5, 5.1 Hz, 1H), 6.54 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 8.4 Hz,
1H), 6.89 (d, J = 16.3 Hz, 1H), 7.23 (t, J = 8.4 Hz, 1H), 8.17 (d, J = 16.3 Hz, 1H); 13C NMR (126 MHz,
CDCl3)
δ 14.4 (CH3), 55.7 (CH3), 60.1 (CH2), 69.4 (CH2), 103.8 (CH), 105.0 (CH), 112.5 (C), 117.6
(CH2), 120.8 (CH), 131.1 (CH), 132.9 (CH), 135.4 (CH), 158.9 (C), 160.1 (C), 168.6 (C); MS (ESI) m/z
285 (MNa+, 100); HRMS (ESI) calcd for C15H18NaO4 (MNa+), 285.1097, found 285.1088.
Ethyl (2E)-3-(2’-allyloxy-5’-methoxyphenyl)prop-2-enoate (7c). The reaction was carried out as
described for the synthesis of ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenoate (7a) using 2ꢀallyloxyꢀ5ꢀ
methoxybenzaldehyde (6c) (0.580 g, 3.02 mmol). This gave ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ5’ꢀ
methoxyphenyl)propꢀ2ꢀenoate (7c) (0.792 g, 100%) as a yellow oil. IR (neat) 2954, 1706, 1631, 1494,
1214, 1165, 1042, 862 cm−1; 1H NMR (400 MHz, CDCl3)
δ 1.34 (t, J = 7.1 Hz, 3H), 3.79 (s, 3H), 4.26
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(q, J = 7.1 Hz, 2H), 4.56 (dt, J = 5.2, 1.5 Hz, 2H), 5.29 (dq, J = 10.6, 1.5 Hz, 1H), 5.41 (dq, J = 17.3, 1.5
Hz, 1H), 6.06 (ddt, J = 17.3, 10.6, 5.2 Hz, 1H), 6.49 (d, J = 16.2 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.88
1
2
3
4
5
6
13
(dd, J = 8.8, 2.9 Hz, 1H), 7.05 (d, J = 2.9 Hz, 1H), 8.02 (d, J = 16.2 Hz, 1H); C NMR (126 MHz,
7
8
CDCl3)
δ 14.5 (CH3), 55.9 (CH3), 60.5 (CH2), 70.2 (CH2), 113.0 (CH), 114.4 (CH), 117.2 (CH), 117.8
9
(CH2), 119.1 (CH), 124.7 (C), 133.3 (CH), 139.8 (CH), 151.9 (C), 153.8 (C), 167.5 (C); MS (ESI) m/z
285 (MNa+, 100); HRMS (ESI) calcd for C15H18NaO4 (MNa+), 285.1097, found 285.1090.
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11
12
13
14
15
16
17
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Ethyl (2E)-3-(2’-allyloxy-4’-methoxyphenyl)prop-2-enoate (7d). The reaction was carried out as
described for the synthesis of ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenoate (7a) using 2ꢀallyloxyꢀ4ꢀ
methoxybenzaldehyde (6d) (0.580 g, 3.02 mmol). This gave ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ4’ꢀ
methoxyphenyl)propꢀ2ꢀenoate (7d) (0.79 g, 100%) as a yellow oil. IR (neat) 2980, 1701, 1601, 1505,
1300, 1252, 1155, 986 cm−1; 1H NMR (400 MHz, CDCl3)
δ 1.33 (t, J = 7.1 Hz, 3H), 3.82 (s, 3H), 4.24
(q, J = 7.1 Hz, 2H), 4.60 (dt, J = 5.2, 1.5 Hz, 2H), 5.32 (dq, J = 10.5, 1.5 Hz, 1H), 5.43 (dq, J = 17.3, 1.5
Hz, 1H), 6.08 (ddt, J = 17.3, 10.5, 5.2 Hz, 1H), 6.43 (d, J = 16.1 Hz, 1H), 6.44 (d, J = 2.4 Hz, 1H), 6.50
13
(dd, J = 8.6, 2.4 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 16.1 Hz, 1H); C NMR (101 MHz,
CDCl3)
δ 14.5 (CH3), 55.6 (CH3), 60.3 (CH2), 69.3 (CH2), 99.7 (CH), 105.6 (CH), 116.3 (C), 117.0
(CH2), 118.1 (CH), 130.3 (CH), 132.9 (CH), 140.0 (CH), 158.8 (C), 162.6 (C), 168.0 (C); MS (ESI) m/z
285 (MNa+, 100); HRMS (ESI) calcd for C15H18NaO4 (MNa+), 285.1097, found 285.1090.
Ethyl (2E)-3-(2’-allyloxy-5’-methylphenyl)prop-2-enoate (7e). The reaction was carried out as
described for the synthesis of ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenoate (7a) using 2ꢀallyloxyꢀ5ꢀ
methylbenzaldehyde (6e) (0.167 g, 0.950 mmol). This gave ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ5’ꢀ
methylphenyl)propꢀ2ꢀenoate (7e) (0.206 g, 88%) as a yellow oil. IR (neat) 3021, 1701, 1631, 1494,
1217, 1178, 750 cm−1; 1H NMR (400 MHz, CDCl3)
δ 1.33 (t, J = 7.1 Hz, 3H), 2.29 (s, 3H), 4.25 (q, J =
7.1 Hz, 2H), 4.59 (dt, J = 5.2, 1.6 Hz, 2H), 5.29 (dq, J = 10.6, 1.6 Hz, 1H), 5.41 (dq, J = 17.3, 1.6 Hz,
1H), 6.07 (ddt, J = 17.3, 10.6, 5.2 Hz, 1H), 6.51 (d, J = 16.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 7.11 (dd,
J = 8.4, 2.0 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 16.2 Hz, 1H); 13C NMR (101 MHz, CDCl3)
δ
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14.4 (CH3), 20.4 (CH3), 60.3 (CH2), 69.4 (CH2), 112.6 (CH), 117.6 (CH2), 118.6 (CH), 123.5 (C), 129.2
(CH), 130.1 (C), 131.8 (CH), 133.1 (CH), 140.0 (CH), 155.3 (C), 167.5 (C); MS (ESI) m/z 269 (MNa+,
100); HRMS (ESI) calcd for C15H18NaO3 (MNa+), 269.1148, found 269.1139.
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Ethyl (2E)-3-(2’-allyloxy-5’-nitrophenyl)prop-2-enoate (7f). The reaction was carried out as
described for the synthesis of ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenoate (7a) using 2ꢀallyloxyꢀ5ꢀ
nitrobenzaldehyde (6f) (0.049 g, 0.24 mmol). This gave ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ5’ꢀnitrophenyl)propꢀ
2ꢀenoate (7f) (0.060 g, 91%) as a white solid. Mp 64–65 °C; IR (neat) 2986, 1690, 1631, 1580, 1512,
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
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49
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58
59
60
1341, 1273, 1150, 1032, 872 cm–1; 1H NMR (500 MHz, CDCl3)
δ 1.35 (t, J = 7.1 Hz, 3H), 4.29 (q, J =
7.1 Hz, 2H), 4.74 (dt, J = 5.2, 1.5 Hz, 2H), 5.39 (dq, J = 10.6, 1.5 Hz, 1H), 5.45 (dq, J = 17.3, 1.5 Hz,
1H), 6.07 (ddt, J = 17.3, 10.6, 5.2 Hz, 1H), 6.61 (d, J = 16.2 Hz, 1H), 6.98 (d, J = 9.2 Hz, 1H), 7.98 (d, J
= 16.2 Hz, 1H), 8.22 (dd, J = 9.2, 2.8 Hz, 1H), 8.43 (d, J = 2.8 Hz, 1H); 13C NMR (126 MHz, CDCl3)
δ
14.3 (CH3), 60.7 (CH2), 70.0 (CH2), 112.2 (CH), 118.9 (CH2), 121.5 (CH), 124.0 (CH), 124.3 (C), 126.6
(CH), 131.5 (CH), 137.3 (CH), 141.4 (C), 161.4 (C), 166.5 (C); MS (ESI) m/z 300 (MNa+, 100); HRMS
(ESI) calcd for C14H15NNaO5 (MNa+), 300.0842, found 300.0829.
Ethyl (2E)-3-(2’-allyloxy-5’-chlorophenyl)prop-2-enoate (7g). The reaction was carried out as
described for the synthesis of ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenoate (7a) using 2ꢀallyloxyꢀ5ꢀ
chlorobenzaldehyde (6g) (0.595 g, 3.02 mmol). This gave ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ5’ꢀ
chlorophenyl)propꢀ2ꢀenoate (7g) (0.743 g, 92%) as a yellow oil. IR (neat) 2982, 1705, 1632, 1481,
1314, 1248, 1165, 1034, 984 cm–1; 1H NMR (500 MHz, CDCl3)
δ 1.33 (t, J = 7.1 Hz, 3H), 4.26 (q, J =
7.1 Hz, 2H), 4.60 (dt, J = 5.2, 1.4 Hz, 2H), 5.32 (dq, J = 10.5, 1.4 Hz, 1H), 5.41 (dq, J = 17.3, 1.4 Hz,
1H), 6.05 (ddt, J = 17.3, 10.5, 5.2 Hz, 1H), 6.49 (d, J = 16.2 Hz, 1H), 6.83 (d, J = 8.9 Hz, 1H), 7.25 (dd,
J = 8.9, 2.5 Hz, 1H), 7.48 (d, J = 2.5 Hz, 1H), 7.95 (d, J = 16.2 Hz, 1H); 13C NMR (126 MHz, CDCl3)
δ
14.5 (CH3), 60.6 (CH2), 69.7 (CH2), 114.0 (CH), 118.2 (CH2), 120.1 (CH), 125.4 (C), 126.1 (C), 128.3
(CH), 130.8 (CH), 132.6 (CH), 138.6 (CH), 155.8 (C), 167.2 (C); MS (ESI) m/z 289 (MNa+, 100);
HRMS (ESI) calcd for C14H1535ClNaO3 (MNa+), 289.0602, found 289.0610.
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Ethyl (2E)-3-(2’-allyloxy-5’-bromophenyl)prop-2-enoate (7h). The reaction was carried out as
described for the synthesis of ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenoate (7a) using 2ꢀallyloxyꢀ5ꢀ
bromobenzaldehyde (6h) (0.545 g, 2.26 mmol). This gave ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ5’ꢀ
1
2
3
4
5
6
7
8
bromophenyl)propꢀ2ꢀenoate (7h) (0.685 g, 97%) as a white solid. Mp <30 °C; IR (neat) 2986, 1688,
9
1
1628, 1489, 1300, 1275, 1175, 986 cm–1; H NMR (500 MHz, CDCl3)
δ 1.33 (t, J = 7.1 Hz, 3H), 4.26
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11
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59
60
(q, J = 7.1 Hz, 2H), 4.60 (dt, J = 5.2, 1.4 Hz, 2H), 5.32 (dq, J = 10.6, 1.4 Hz, 1H), 5.41 (dq, J = 17.3, 1.4
Hz, 1H), 6.05 (ddt, J = 17.3, 10.6, 5.2 Hz, 1H), 6.49 (d, J = 16.2 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 7.39
13
(dd, J = 8.8, 2.5 Hz, 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.94 (d, J = 16.2 Hz, 1H); C NMR (126 MHz,
CDCl3)
δ 14.5 (CH3), 60.6 (CH2), 69.6 (CH2), 113.3 (C), 114.4 (CH), 118.3 (CH2), 120.2 (CH), 125.9
(C), 131.2 (CH), 132.6 (CH), 133.8 (CH), 138.5 (CH), 156.3 (C), 167.2 (C); MS (ESI) m/z 333 (MNa+,
100); HRMS (ESI) calcd for C14H1579BrNaO3 (MNa+), 333.0097, found 333.0090.
Ethyl (2E)-3-(2’-allyloxy-4’-chlorophenyl)prop-2-eneoate (7i). The reaction was carried out as
described for the synthesis of ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenoate (7a) using 2ꢀallyloxyꢀ4ꢀ
chlorobenzaldehyde (6i) (0.150 g, 0.760 mmol). This gave ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ4’ꢀ
chlorophenyl)propꢀ2ꢀenoate (7i) (0.192 g, 94%) as an oil. IR (neat) 2989, 1707, 1632, 1592, 1486, 1312,
1178, 908, 732 cm−1; 1H NMR (500 MHz, CDCl3)
δ 1.35 (t, J = 7.1 Hz, 3H), 4.27 (q, J = 7.1 Hz, 2H),
4.63 (dt, J = 5.2, 1.3 Hz, 2H), 5.36 (dq, J = 17.2, 1.3 Hz, 1H), 5.46 (dq, J = 10.6, 1.3 Hz, 1H), 6.08 (ddt,
J = 17.2, 10.6, 5.2 Hz, 1H), 6.51 (d, J = 16.2 Hz, 1H), 6.91 (d, J = 1.9 Hz, 1H), 6.97 (dd, J = 8.3, 1.9 Hz,
13
1H), 7.45 (d, J = 8.3 Hz, 1H), 7.96 (d, J = 16.2 Hz, 1H); C NMR (126 MHz, CDCl3)
δ 14.3 (CH3),
60.4 (CH2), 69.5 (CH2), 113.1 (CH), 118.2 (CH2), 119.2 (CH), 121.1 (CH), 122.4 (C), 129.5 (CH),
132.2 (CH), 136.7 (C), 138.7 (CH), 157.6 (C), 167.2 (C); MS (ESI) m/z 289 (MNa+, 100); HRMS (ESI)
calcd for C14H1535ClNaO3 (MNa+), 289.0602, found 289.0595.
Ethyl (2E)-3-(2’-allyloxy-4’,5’-difluorophenyl)prop-2-enoate (7j). The reaction was carried out as
described for the synthesis of ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenoate (7a) using 2ꢀallyloxyꢀ4,5ꢀ
difluorobenzaldehyde (6j) (0.093 g, 0.470 mmol). This gave ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ4’,5’ꢀ
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difluorophenyl)propꢀ2ꢀenoate (7j) (0.117 g, 93%) as a white solid. Mp 52–53 °C; IR (neat) 2985, 1690,
1
2
3
4
1
1599, 1511, 1273, 1224, 1174, 987, 857 cm−1; H NMR (500 MHz, CDCl3)
δ 1.33 (t, J = 7.1 Hz, 3H),
5
6
4.26 (q, J = 7.1 Hz, 2H), 4.57 (dt, J = 5.2, 1.6 Hz, 2H), 5.34 (dq, J = 10.6, 1.6 Hz, 1H), 5.43 (dq, J =
7
8
3
17.3, 1.6 Hz, 1H), 6.04 (ddt, J = 17.3, 10.6, 5.2 Hz, 1H), 6.41 (d, J = 16.2 Hz, 1H), 6.72 (dd, JHF
=
9
4
3
4
5
11.5, JHF = 5.2 Hz, 1H), 7.32 (dd, JHF = 11.5, JHF = 9.0 Hz, 1H), 7.91 (dd, J = 16.2, JHF = 1.0 Hz,
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60
1H); 13C NMR (101 MHz, CDCl3) 14.3 (CH3), 60.5 (CH2), 70.2 (CH2), 102.6 (d, 2JCF = 20.9 Hz, CH),
δ
2
3
3
4
116.2 (dd, JCF = 18.6, JCF = 1.8 Hz, CH), 118.5 (CH2), 119.5 (CH), 120.1 (dd, JCF = 5.8, JCF = 4.3
1
2
1
Hz, C), 132.1 (CH), 137.7 (CH), 144.8 (dd, JCF = 241.6, JCF = 13.1 Hz, C), 151.5 (dd, JCF = 253.1,
2JCF = 14.0 Hz, C), 153.7 (dd, 3JCF = 7.3, 4JCF = 1.6 Hz, C), 167.0 (C); MS (ESI) m/z 291 (MNa+, 100);
HRMS (ESI) calcd for C14H14F2NaO3 (MNa+), 291.0803, found 291.0797.
Ethyl (2E)-3-(2’-allyloxy-3’-methoxy-5’-nitrophenyl)prop-2-enoate (7k). The reaction was carried
out as described for the synthesis of ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenoate (7a) using 2ꢀ
allyloxyꢀ3ꢀmethoxyꢀ5ꢀnitrobenzaldehyde (6k) (0.617 g, 2.60 mmol). This gave ethyl (2E)ꢀ3ꢀ(2’ꢀ
allyloxyꢀ3’ꢀmethoxyꢀ5’ꢀnitrophenyl)propꢀ2ꢀenoate (7k) (0.798 g, 100%) as a white solid. Mp 82–83 °C;
1
IR (neat) 3022, 1711, 1641, 1582, 1527, 1466, 1340, 1278, 1179, 979 cm−1; H NMR (500 MHz,
CDCl3)
δ 1.35 (t, J = 7.1 Hz, 3H), 3.97 (s, 3H), 4.28 (q, J = 7.1 Hz, 2H), 4.69 (dt, J = 6.1, 1.3 Hz, 2H),
5.28 (dq, J = 10.3, 1.3 Hz, 1H), 5.37 (dq, J = 17.2, 1.3 Hz, 1H), 6.05 (ddt, J = 17.2, 10.3, 6.1 Hz, 1H),
6.56 (d, J = 16.2 Hz, 1H), 7.77 (d, J = 2.6 Hz, 1H), 7.99 (d, J = 16.2 Hz, 1H), 8.10 (d, J = 2.6 Hz, 1H);
13C NMR (126 MHz, CDCl3)
δ 14.2 (CH3), 56.4 (CH3), 60.7 (CH2), 74.8 (CH2), 108.0 (CH), 114.9
(CH), 119.2 (CH2), 121.9 (CH), 129.1 (C), 132.9 (CH), 137.5 (CH), 143.7 (C), 151.8 (C), 153.1 (C),
166.3 (C); MS (ESI) m/z 330 (MNa+, 100); HRMS (ESI) calcd for C15H17NNaO6 (MNa+), 330.0948,
found 330.0934.
Ethyl (2E)-3-(2’-allyloxynaphthalen-1’-yl)prop-2-enoate (7l). The reaction was carried out as
described for the synthesis of ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenoate (7a) using 2ꢀallyloxyꢀ1ꢀ
naphthaldehyde (6l) (0.620 g, 2.94 mmol). This gave ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxynaphthalenꢀ1’ꢀyl)propꢀ2ꢀ
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enoate (7l) (0.760 g, 92%) as a white solid. Mp 46–48 °C; IR (neat) 2981, 1701, 1617, 1264, 1159, 907,
727 cm−1; 1H NMR (400 MHz, CDCl3)
1
2
3
4
δ
1.37 (t, J = 7.1 Hz, 3H), 4.32 (q, J = 7.1 Hz, 2H), 4.75 (dt, J =
5
6
7
8
5.2, 1.6 Hz, 2H), 5.31 (dq, J = 10.6, 1.6 Hz, 1H), 5.44 (dq, J = 17.3, 1.6 Hz, 1H), 6.10 (ddt, J = 17.3,
10.6, 5.2 Hz, 1H), 6.77 (d, J = 16.2 Hz, 1H), 7.25 (d, J = 9.3 Hz, 1H), 7.38 (ddd, J = 8.5, 8.4, 1.0 Hz,
9
1H), 7.52 (ddd, J = 8.5, 8.4, 1.0 Hz, 1H), 7.78 (dd, J = 8.4, 1.0 Hz, 1H), 7.81 (d, J = 9.3 Hz, 1H), 8.19
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60
13
(dd, J = 8.4, 1.0 Hz, 1H), 8.36 (d, J = 16.2 Hz, 1H); C NMR (101 MHz, CDCl3)
δ 14.4 (CH3), 60.4
(CH2), 70.0 (CH2), 114.3 (CH), 117.4 (C), 117.8 (CH2), 123.5 (CH), 123.7 (CH), 124.0 (CH), 127.3
(CH), 128.5 (CH), 129.1 (C), 131.3 (CH), 132.8 (C), 133.0 (CH), 137.7 (CH), 155.6 (C), 167.8 (C); MS
(ESI) m/z 305 (MNa+, 100); HRMS (ESI) calcd for C18H18NaO3 (MNa+), 305.1148, found 305.1139.
(2E)-3-(2’-Allyloxyphenyl)prop-2-en-1-ol (8a).36 Diisobutylaluminium hydride (3.21 mL, 1 M
solution in hexanes) was added dropwise with stirring, to a solution of ethyl (2E)ꢀ3ꢀ(2’ꢀ
vinylphenyl)propꢀ2ꢀenoate (7a) (0.298 g, 1.28 mmol), in diethyl ether (30 mL) at −78 °C. The solution
was stirred at −78 °C for 3 h, then allowed to return to room temperature over 15 h. The reaction was
quenched with 10% aqueous potassium sodium tartrate solution (30 mL), extracted with diethyl ether (2
× 20 mL), washed with water (100 mL), brine (100 mL), dried (MgSO4), filtered and concentrated in
vacuo. Purification by column chromatography (elution with 30% diethyl ether in petroleum ether) gave
(2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (8a) (0.211 g, 87%) as a white solid. Mp 44–46 °C;
Spectroscopic data was in accordance with literature values.36 1H NMR (400 MHz, CDCl3)
δ 1.41 (t, J =
5.9 Hz, 1H), 4.33 (td, J = 5.9, 0.8 Hz, 2H), 4.58 (dt, J = 5.2, 1.5 Hz, 2H), 5.29 (dq, J = 10.5, 1.5 Hz,
1H), 5.42 (dq, J = 17.3, 1.5 Hz, 1H), 6.08 (ddt, J = 17.3, 10.5, 5.2 Hz, 1H), 6.40 (dt, J = 16.0, 5.9 Hz,
1H), 6.87 (dd, J = 8.2, 0.8 Hz, 1H), 6.91–7.02 (m, 2H), 7.21 (ddd, J = 8.2, 7.5, 1.7 Hz, 1H), 7.46 (dd, J
13
= 7.5, 1.7 Hz, 1H); C NMR (101 MHz, CDCl3)
δ 64.5 (CH2), 69.4 (CH2), 112.5 (CH), 117.6 (CH2),
121.1 (CH), 126.2 (C), 126.4 (CH), 127.2 (CH), 128.8 (CH), 129.3 (CH), 133.5 (CH), 156.0 (C); MS
(EI) m/z 190 (M+, 57), 149 (59), 131 (92), 121 (60), 119 (46), 91 (100), 77 (40).
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(2E)-3-(2’-Allyloxy-6’-methoxyphenyl)prop-2-en-1-ol (8b). The reaction was carried out as
described for the synthesis of (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (8a) using ethyl (2E)ꢀ3ꢀ(2’ꢀ
allyloxyꢀ6’ꢀmethoxyphenyl)propꢀ2ꢀenoate (7b) (0.569 g, 2.17 mmol). This gave (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ6’ꢀ
methoxyphenyl)propꢀ2ꢀenꢀ1ꢀol (8b) (0.427 g, 90%) as a colorless oil. IR (neat) 3372, 2953, 1584, 1470,
1
2
3
4
5
6
7
8
9
1251, 1200, 1112, 1079 cm−1; 1H NMR (500 MHz, CDCl3)
δ 1.41 (t, J = 5.9 Hz, 1H), 3.85 (s, 3H), 4.33
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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27
28
29
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31
32
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34
35
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47
48
49
50
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53
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55
56
57
58
59
60
(td, J = 5.9, 1.0 Hz, 2H), 4.58 (dt, J = 5.2, 1.5 Hz, 2H), 5.28 (dq, J = 10.5, 1.5 Hz, 1H), 5.42 (dq, J =
17.3, 1.5 Hz, 1H), 6.08 (ddt, J = 17.3, 10.5, 5.2 Hz, 1H), 6.55 (d, J = 8.3 Hz, 1H), 6.56 (d, J = 8.3 Hz,
13
1H), 6.82 (dt, J = 16.2, 5.9 Hz, 1H), 6.92 (br d, J = 16.2 Hz, 1H), 7.13 (t, J = 8.3 Hz, 1H); C NMR
(126 MHz, CDCl3)
δ 55.8 (CH3), 65.7 (CH2), 69.6 (CH2), 104.1 (CH), 105.4 (CH), 114.4 (C), 117.6
(CH2), 122.0 (CH), 128.3 (CH), 132.8 (CH), 133.5 (CH), 157.6 (C), 158.7 (C); MS (ESI) m/z 243
(MNa+, 100); HRMS (ESI) calcd for C13H16NaO3 (MNa+), 243.0992, found 243.0987.
(2E)-3-(2’-Allyloxy-5’-methoxyphenyl)prop-2-en-1-ol (8c). The reaction was carried out as
described for the synthesis of (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (8a) using ethyl (2E)ꢀ3ꢀ(2’ꢀ
allyloxyꢀ5’ꢀmethoxyphenyl)propꢀ2ꢀenoate (7c) (0.126 g, 2.94 mmol). This gave (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ5’ꢀ
methoxyphenyl)propꢀ2ꢀenꢀ1ꢀol (8c) (0.534 g, 83%) as a white solid. Mp 41–43 °C; IR (neat) 3387,
2915, 1585, 1493, 1424, 1213, 1123, 1011 cm−1; 1H NMR (500 MHz, CDCl3)
δ 1.48 (br s, 1H), 3.78 (s,
3H), 4.33 (br d, J = 5.7 Hz, 2H), 4.51 (dt, J = 5.2, 1.5 Hz, 2H), 5.27 (dq, J = 10.5, 1.5 Hz, 1H), 5.40 (dq,
J = 17.3, 1.5 Hz, 1H), 6.06 (ddt, J = 17.3, 10.5, 5.2 Hz, 1H), 6.38 (dt, J = 16.0, 5.7 Hz, 1H), 6.75 (dd, J
= 8.9, 3.0 Hz, 1H), 6.81 (d, J = 8.9 Hz, 1H), 6.94 (dt, J = 16.0, 1.3 Hz, 1H), 7.01 (d, J = 3.0 Hz, 1H); 13C
NMR (126 MHz, CDCl3)
δ 55.9 (CH3), 64.3 (CH2), 70.3 (CH2), 112.2 (CH), 114.0 (CH), 114.3 (CH),
117.5 (CH2), 126.2 (CH), 127.2 (C), 129.6 (CH), 133.7 (CH), 150.4 (C), 154.0 (C); MS (ESI) m/z 243
(MNa+, 100); HRMS (ESI) calcd for C13H16NaO3 (MNa+), 243.0992, found 243.0990.
(2E)-3-(2’-Allyloxy-4’-methoxyphenyl)prop-2-en-1-ol (8d). The reaction was carried out as
described for the synthesis of (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (8a) using ethyl (2E)ꢀ3ꢀ(2’ꢀ
allyloxyꢀ4’ꢀmethoxyphenyl)propꢀ2ꢀenoate (7d) (0.676 g, 2.58 mmol). This gave (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ4’ꢀ
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methoxyphenyl)propꢀ2ꢀenꢀ1ꢀol (8d) (0.566 g, 100%) as a white solid. Mp <30 °C; IR (neat) 3379, 2914,
1
2
3
4
1
1609, 1576, 1500, 1420, 1261, 1197, 1003 cm−1; H NMR (500 MHz, CDCl3)
δ 1.89 (s, 1H), 3.78 (s,
5
6
7
8
3H), 4.28 (dd, J = 6.1, 1.2 Hz, 2H), 4.53 (d, J = 5.2 Hz, 2H), 5.28 (dd, J = 10.5, 1.5 Hz, 1H), 5.41 (dd, J
= 17.3, 1.5 Hz, 1H), 6.06 (ddt, J = 17.3, 10.5, 5.2 Hz, 1H), 6.27 (dt, J = 16.0, 6.1 Hz, 1H), 6.42 (d, J =
9
13
2.4 Hz, 1H), 6.47 (dd, J = 8.5, 2.4 Hz, 1H), 6.86 (br d, J = 16.0 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H); C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(126 MHz, CDCl3)
δ 55.4 (CH3), 64.5 (CH2), 69.2 (CH2), 99.7 (CH), 105.3 (CH), 117.7 (CH2), 119.1
(C), 126.2 (CH), 127.1 (CH), 127.8 (CH), 133.2 (CH), 156.9 (C), 160.4 (C); MS (CI) m/z 221 (MH+,
18), 203 (100), 177 (3), 163 (2), 81 (5), 69 (7); HRMS (CI) calcd for C13H17O3 (MH+), 221.1178, found
221.1177.
(2E)-3-(2’-Allyloxy-5’-methylphenyl)prop-2-en-1-ol (8e). The reaction was carried out as described
for the synthesis of (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (8a) using ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ5’ꢀ
methylphenyl)propꢀ2ꢀenoate (7e) (0.198 g, 0.750 mmol). This gave (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ5’ꢀ
methylphenyl)propꢀ2ꢀenꢀ1ꢀol (8e) (0.164 g, 100%) as a colorless oil. IR (neat) 3370, 2922, 1494, 1243,
1220, 997, 909 cm−1; H NMR (500 MHz, CDCl3)
δ 1.39 (br s, 1H), 2.29 (s, 3H), 4.32 (d, J = 5.2 Hz,
1
2H), 4.54 (dt, J = 5.2, 1.6 Hz, 2H), 5.27 (dq, J = 10.6, 1.6 Hz, 1H), 5.40 (dq, J = 17.3, 1.6 Hz, 1H), 6.07
(ddt, J = 17.3, 10.6, 5.2 Hz, 1H), 6.38 (dt, J = 16.2, 5.2 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.94 (d, J =
13
16.2 Hz, 1H), 7.00 (dd, J = 8.3, 2.1 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H); C NMR (126 MHz, CDCl3)
δ
20.6 (CH3), 64.2 (CH2), 69.4 (CH2), 112.5 (CH), 117.4 (CH2), 125.8 (C), 126.1 (CH), 127.6 (CH), 129.1
(2 × CH), 130.1 (C), 133.6 (CH), 153.8 (C); MS (EI) m/z 204 (M+, 49), 163 (31), 145 (61), 133 (64),
105 (97), 84 (100), 77 (24), 69 (13); HRMS (EI) calcd for C13H16O2 (M+), 204.1150, found 204.1153.
(2E)-3-(2’-Allyloxy-5’-nitrophenyl)prop-2-en-1-ol (8f). The reaction was carried out as described
for the synthesis of (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (8a) using ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ5’ꢀ
nitrophenyl)propꢀ2ꢀenoate (7f) (0.629 g, 2.27 mmol). This gave (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ5’ꢀ
nitrophenyl)propꢀ2ꢀenꢀ1ꢀol (8f) (0.469 g, 88%) as a yellow solid. Mp 62–66 °C; IR (neat) 2864, 1611,
1508, 1335, 1246, 1078, 990 cm−1; 1H NMR (400 MHz, CDCl3)
δ
1.89 (br s, 1H), 4.37 (dd, J = 5.4, 1.7
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Hz, 2H), 4.67 (dt, J = 5.2, 1.5 Hz, 2H), 5.35 (dq, J = 10.6, 1.5 Hz, 1H), 5.43 (dq, J = 17.3, 1.5 Hz, 1H),
6.05 (ddt, J = 17.3, 10.6, 5.2 Hz, 1H), 6.49 (dt, J = 16.2, 5.4 Hz, 1H), 6.88 (d, J = 9.2 Hz, 1H), 6.92 (dt,
1
2
3
4
5
6
13
J = 16.2, 1.7 Hz, 1H), 8.08 (dd, J = 9.2, 2.8 Hz, 1H), 8.30 (d, J = 2.8 Hz, 1H); C NMR (101 MHz,
7
8
CDCl3)
δ 63.7 (CH2), 69.8 (CH2), 111.6 (CH), 118.8 (CH2), 122.6 (CH), 123.6 (CH), 124.5 (CH), 127.0
9
(C), 132.0 (CH), 132.3 (CH), 141.5 (C), 160.3 (C); MS (ESI) m/z 258 (MNa+, 100); HRMS (ESI) calcd
for C12H13NNaO4 (MNa+), 258.0737, found 258.0737.
10
11
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55
56
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58
59
60
(2E)-3-(2’-Allyloxy-5’-chlorophenyl)prop-2-en-1-ol (8g). The reaction was carried out as described
for the synthesis of (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (8a) using ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ5’ꢀ
chlorophenyl)propꢀ2ꢀenoate (7g) (0.126 g, 0.472 mmol). This gave (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ5’ꢀ
chlorophenyl)propꢀ2ꢀenꢀ1ꢀol (8g) (0.101 g, 95%) as a yellow oil. IR (neat) 3336, 2918, 1592, 1481,
1
1242, 1129, 1015, 970 cm−1; H NMR (500 MHz, CDCl3)
δ 2.24 (br s, 1H), 4.30 (dd, J = 5.7, 1.5 Hz,
2H), 4.51 (dt, J = 5.2, 1.4 Hz, 2H), 5.28 (dq, J = 10.6, 1.4 Hz, 1H), 5.39 (dq, J = 17.3, 1.4 Hz, 1H), 6.03
(ddt, J = 17.3, 10.6, 5.2 Hz, 1H), 6.34 (dt, J = 16.1, 5.7 Hz, 1H), 6.74 (d, J = 8.8 Hz, 1H), 6.87 (dt, J =
16.1, 1.5 Hz, 1H), 7.11 (dd, J = 8.8, 2.6 Hz, 1H), 7.37 (d, J = 2.6 Hz, 1H); 13C NMR (126 MHz, CDCl3)
δ
63.8 (CH2), 69.6 (CH2), 113.7 (CH), 117.8 (CH2), 124.7 (CH), 126.0 (C), 126.7 (CH), 127.8 (C),
128.1 (CH), 130.7 (CH), 133.0 (CH), 154.3 (C); MS (EI) m/z 224 (M+, 100), 183 (58), 165 (89), 155
(78), 125 (86), 91 (36), 63 (12); HRMS (EI) calcd for C12H1335ClO2 (M+), 224.0604, found 224.0606.
(2E)-3-(2’-Allyloxy-5’-bromophenyl)prop-2-en-1-ol (8h). The reaction was carried out as described
for the synthesis of (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (8a) using ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ5’ꢀ
bromophenyl)propꢀ2ꢀenoate (7h) (0.075 g, 0.24 mmol). This gave (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ5’ꢀ
bromophenyl)propꢀ2ꢀenꢀ1ꢀol (8h) (0.058 g, 90%) as a white solid. Mp <30 °C; IR (neat) 3297, 2857,
1588, 1482, 1249, 1127, 1016, 974 cm−1; 1H NMR (500 MHz, CDCl3)
δ 2.07 (s, 1H), 4.30 (dd, J = 5.7,
1.4 Hz, 2H), 4.51 (dt, J = 5.2, 1.3 Hz, 2H), 5.28 (dq, J = 10.5, 1.3 Hz, 1H), 5.38 (dq, J = 17.2, 1.3 Hz,
1H), 6.03 (ddt, J = 17.2, 10.5, 5.2 Hz, 1H), 6.34 (dt, J = 16.1, 5.7 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H), 6.86
(dt, J = 16.1, 1.4 Hz, 1H), 7.25 (dd, J = 8.8, 2.5 Hz, 1H), 7.52 (d, J = 2.5 Hz, 1H); 13C NMR (126 MHz,
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CDCl3)
δ 63.9 (CH2), 69.5 (CH2), 113.4 (C), 114.1 (CH), 117.9 (CH2), 124.6 (CH), 128.3 (C), 129.6
1
2
3
4
5
6
7
8
(CH), 130.7 (CH), 131.1 (CH), 133.0 (CH), 154.8 (C); MS (EI) m/z 268 (M+, 65), 229 (40), 199 (50),
131 (20), 118 (100), 91 (27), 63 (11); HRMS (EI) calcd for C12H1379BrO2 (M+), 268.0099, found
268.0101.
9
(2E)-3-(2’-Allyloxy-4’-chlorophenyl)prop-2-en-1-ol (8i). The reaction was carried out as described
for the synthesis of (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (8a) using ethyl (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ4’ꢀ
chlorophenyl)propꢀ2ꢀenoate (7i) (0.193 g, 0.720 mmol). This gave (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ4’ꢀ
chlorophenyl)propꢀ2ꢀenꢀ1ꢀol (8i) (0.138 g, 85%) as a white solid. Mp 45–47 °C; IR (neat) 3350, 2869,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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26
27
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36
37
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39
40
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49
50
51
52
53
54
55
56
57
58
59
60
1590, 1485, 1408, 1245, 1226, 1015, 998, 972, 905, 730 cm−1; 1H NMR (400 MHz, CDCl3)
δ 1.59 (t, J
= 5.1 Hz, 1H), 4.34 (br t, J = 5.1 Hz, 2H), 4.57 (dt, J = 5.2, 1.4 Hz, 2H), 5.33 (dq, J = 10.6, 1.4 Hz, 1H),
5.44 (dq, J = 17.2, 1.4 Hz, 1H), 6.07 (ddt, J = 17.2, 10.6, 5.2 Hz, 1H), 6.38 (dt, J = 16.0, 5.1 Hz, 1H),
13
6.86 (d, J = 1.8 Hz, 1H), 6.88–6.94 (m, 2H), 7.37 (d, J = 8.3 Hz, 1H); C NMR (126 MHz, CDCl3)
δ
64.1 (CH2), 69.4 (CH2), 112.9 (CH), 118.0 (CH2), 121.0 (CH), 124.6 (C), 125.2 (CH), 127.7 (CH),
129.6 (CH), 132.6 (CH), 133.8 (C), 156.2 (C); MS (EI) m/z 224 (M+, 93), 183 (99), 165 (73), 155 (100),
125 (55), 120 (10), 91 (48), 77 (14); HRMS (EI) calcd for C12H1335ClO2 (M+), 224.0604, found
224.0600.
(2E)-3-(2’-Allyloxy-4’,5’-difluorophenyl)prop-2-en-1-ol (8j). The reaction was carried out as
described for the synthesis of (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (8a) using ethyl (2E)ꢀ3ꢀ(2’ꢀ
allyloxyꢀ4’,5’ꢀdifluoroꢀphenyl)propꢀ2ꢀenoate (7j) (0.090 g, 0.340 mmol). This gave (2E)ꢀ3ꢀ(2’ꢀallyloxyꢀ
4’,5’ꢀdifluorophenyl)propꢀ2ꢀenꢀ1ꢀol (8j) (0.071 g, 94%) as a yellow oil. IR (neat) 3341, 2867, 1610,
1507, 1422, 1192, 991, 969 cm−1; 1H NMR (400 MHz, CDCl3)
2H), 4.51 (dt, J = 5.2, 1.6 Hz, 2H), 5.31 (dq, J = 10.6, 1.6 Hz, 1H), 5.41 (dq, J = 17.3, 1.6 Hz, 1H), 6.03
δ 1.57 (br s, 1H), 4.32 (br d, J = 5.2 Hz,
3
4
(ddt, J = 17.3, 10.6, 5.2 Hz, 1H), 6.28 (dt, J = 16.0, 5.2 Hz, 1H), 6.67 (dd, JHF = 11.5, JHF = 5.2 Hz,
3
4
13
1H), 6.85 (dd, J = 16.0, 1.6 Hz, 1H), 7.23 (dd, JHF = 11.5, JHF = 9.0 Hz, 1H); C NMR (101 MHz,
2
CDCl3)
δ
63.9 (CH2), 70.1 (CH2), 102.5 (d, 2JCF = 20.8 Hz, CH), 114.7 (dd, JCF = 18.3, 3JCF = 1.4 Hz,
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3
4
4
CH), 118.1 (CH2), 122.5 (dd, JCF = 5.1, JCF = 3.8 Hz, C), 124.2 (CH), 129.9 (d, JCF = 2.2 Hz, CH),
1
2
3
1
2
1
2
132.6 (CH), 144.8 (dd, JCF = 240.5, JCF = 13.0 Hz, C), 149.7 (dd, JCF = 248.7, JCF = 13.9 Hz, C),
4
5
6
3
4
151.8 (dd, JCF = 7.1, JCF = 1.8 Hz, C); MS (EI) m/z 226 (M+, 79), 185 (74), 167 (100), 157 (60), 127
(94), 119 (22), 84 (97); HRMS (EI) calcd for C12H12F2O2 (M+), 226.0805, found 226.0806.
7
8
9
(2E)-3-(2’-Allyloxy-3’-methoxy-5’-nitrophenyl)prop-2-en-1-ol (8k). The reaction was carried out
as described for the synthesis of (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (8a) using ethyl (2E)ꢀ3ꢀ(2’ꢀ
allyloxyꢀ3’ꢀmethoxyꢀ5’ꢀnitrophenyl)propꢀ2ꢀenoate (7k) (0.798 g, 2.59 mmol). This gave (2E)ꢀ3ꢀ(2’ꢀ
allyloxyꢀ3’ꢀmethoxyꢀ5’ꢀnitrophenyl)propꢀ2ꢀenꢀ1ꢀol (8k) (0.604 g, 88%) as a white solid. Mp 58–60 °C;
IR (neat) 3267, 2933, 1657, 1579, 1511, 1471, 1336, 1265, 1210, 1104, 1071, 977 cm−1; 1H NMR (500
10
11
12
13
14
15
16
17
18
19
20
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22
23
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27
28
29
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32
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35
36
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MHz, CDCl3) δ 1.59 (t, J = 5.6 Hz, 1H), 3.95 (s, 3H), 4.38 (td, J = 5.6, 1.6 Hz, 2H), 4.60 (dt, J = 6.0, 1.3
Hz, 2H), 5.26 (dq, J = 10.5, 1.3 Hz, 1H), 5.37 (dq, J = 17.1, 1.3 Hz, 1H), 6.06 (ddt, J = 17.1, 10.5, 6.0
Hz, 1H), 6.50 (dt, J = 16.2, 5.6 Hz, 1H), 6.95 (dt, J = 16.2, 1.6 Hz, 1H), 7.66 (d, J = 2.6 Hz, 1H), 8.04
13
(d, J = 2.6 Hz, 1H); C NMR (126 MHz, CDCl3)
δ 56.2 (CH3), 63.4 (CH2), 74.4 (CH2), 105.9 (CH),
114.1 (CH), 118.6 (CH2), 123.4 (CH), 131.5 (C), 132.7 (CH), 133.3 (CH), 143.8 (C), 150.3 (C), 153.0
(C); MS (ESI) m/z 288 (MNa+, 100); HRMS (ESI) calcd for C13H15NNaO5 (MNa+), 288.0842, found
288.0837.
(2E)-3-(2’-Allyloxynaphthalen-1’-yl)prop-2-en-1-ol (8l). The reaction was carried out according to
the procedure described for the synthesis of (2E)ꢀ3ꢀ(2’ꢀallyloxyphenyl)propꢀ2ꢀenꢀ1ꢀol (8a) using ethyl
(2E)ꢀ3ꢀ(2’ꢀallyloxynaphthalenꢀ1’ꢀyl)propꢀ2ꢀenoate (7l) (0.760 g, 2.69 mmol). This gave (2E)ꢀ3ꢀ(2’ꢀ
allyloxynaphthalenꢀ1’ꢀyl)propꢀ2ꢀenꢀ1ꢀol (8l) (0.592 g, 92%) as a yellow solid. Mp 56–58 °C; IR (neat)
3391, 2865, 1591, 1510, 1217, 1011, 805 cm−1; 1H NMR (500 MHz, CDCl3)
δ 1.52 (t, J = 6.0 Hz, 1H),
4.47 (td, J = 6.0, 1.6 Hz, 2H), 4.70 (dt, J = 5.2, 1.6 Hz, 2H), 5.29 (dq, J = 10.5, 1.6 Hz, 1H), 5.44 (dq, J
= 17.3, 1.6 Hz, 1H), 6.10 (ddt, J = 17.3, 10.5, 5.2 Hz, 1H), 6.46 (dt, J = 16.2, 6.0 Hz, 1H), 7.04 (dt, J =
16.2, 1.6 Hz, 1H), 7.25 (d, J = 9.0 Hz, 1H), 7.35 (ddd, J = 8.5, 8.4, 1.0 Hz, 1H), 7.46 (ddd, J = 8.5, 8.4,
1.0 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.78 (dd, J = 8.4, 1.0 Hz, 1H), 8.16 (dd, J = 8.4, 1.0 Hz, 1H); 13C
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