Expedient synthesis of xanthones and multi-functionalized chromones from 1,1-diacyl cyclopropanes

Article abstract of DOI:10.1016/j.tet.2018.04.003

We report the rapid synthesis of various cycloheptane-fused chromones and an oxepine fused flavone in 5 steps from the corresponding 2-hydroxy acetophenone. Furthermore, we describe the synthesis of xanthones, in moderate to good yield, from 2,3-disubstit

Full text of DOI:10.1016/j.tet.2018.04.003

Accepted Manuscript
Expedient synthesis of xanthones and multi-functionalized chromones from 1,1-diacyl
cyclopropanes
Sarah A. French, Mitchell R. Clark, Robert J. Smith, Thomasin Brind, Bill C. Hawkins
PII:
S0040-4020(18)30371-5
10.1016/j.tet.2018.04.003
TET 29418
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 February 2018
Revised Date: 29 March 2018
Accepted Date: 3 April 2018
Please cite this article as: French SA, Clark MR, Smith RJ, Brind T, Hawkins BC, Expedient synthesis of
xanthones and multi-functionalized chromones from 1,1-diacyl cyclopropanes, Tetrahedron (2018), doi:
10.1016/j.tet.2018.04.003.
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ACCEPTED MANUSCRIPT
Expedient Synthesis of Xanthones and Multi-Functionalized Chromones from 1,1-Diacyl
Cyclopropanes.
Sarah A. French, Mitchell R. Clark, Robert J. Smith, Thomasin Brind and Bill C. Hawkins
Department of Chemistry, University of Otago, Dunedin, New Zealand
bhawkins@chemistry.otago.ac.nz
Graphical Abstract
Abstract
We report the rapid synthesis of various cycloheptane-fused chromones and an oxepine fused
flavone in 5 steps from the corresponding 2-hydroxy acetophenone. Furthermore, we describe
the synthesis of xanthones, in moderate to good yield, from 2,3-disubstituted flavones using a
Friedel Crafts alkylation strategy.
Introduction
The rich chemical diversity of natural products and their often useful biological activity has
provided a wealth of structures that lend themselves to the discovery of potential medicines.
In fact, nearly 50% of all clinically used drugs are natural products or directly derived from
them.1 Within this, terrestrial natural products are the most explored, constituting the majority
of the naturally derived drugs on the market.2 Central to the continued success is the
development of organic synthetic methodology and its application to efficiently produce
these, and yet to be discovered, natural products and pharmaceutically optimized analogues.
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In humans, chromones, xanthones and more broadly, benzopyrans, have been shown to
possess a diverse range of biological activity such as antioxidant,3 antidiabetic,4 anticancer
and antibacterial properties.5-8 This has attracted a lot of attention from the biological and
synthetic chemistry disciplines, and as a result significant efforts have been invested into the
synthesis of chromone analogues to further investigate their biological properties.9-12 The
Moraceae are a large family of flowering plants (which includes fig and mulberry trees)
which have long been used in herbal medicines to treat a variety of illnesses. Studies on the
chemical constituents present in the root bark of this family has led to the identification of
numerous natural products, including many which contain a 2-phenyl chromone (flavone)
core. Of particular interest to us are the oxepine-fused flavones like neocyclomorusin (1,
Figure 1) which has been reported to possess anticancer13 and antimicrobial14 activities
amongst others.15-16 Another structurally related compound is microsphaerin D (2, Figure 1) a
hexacyclic natural product found in the soil anamorph Microspaeropsis sp. which was
isolated along with three other compounds (microsphaerin A-C). All four compounds were
shown to possess low µM activity against Methicillin-resistant Staphylococcus aureus
(MRSA).17
Figure 1. Antimicrobial natural products containing chromones.
A related benzopyran subclass which incorporates a further fused cyclohexane ring, of
varying degrees of saturation, are the xanthones (Figure 2), which are present in fungi and
higher plant families.18-19 Xanthones can be highly cytotoxic and have shown anti-
inflammatory, antimalarial and antimicrobial activities.19-21 Examples of bioactive xanthone
containing natural products include citreamicin η (3) which was isolated from a culture of
Micromonosporacitrea and is a potent antibiotic possessing an MIC value below 30 nM
against several gram positive strains of bacteria (Figure 2).22 Lysolipin I (4) is also a potent
antibacterial against a variety of multidrug resistant pathogens, originally isolated from
Streptomyces violaceoniger Tü 96.23 In recent years, structure-activity relationships (SAR) of
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the xanthone scaffold has been a focus of much research, with several promising xanthone
based compounds having been identified.24
Figure 2. Potent antibiotics containing a xanthone core.
While there are several well established methods to synthesize chromone structures all the
currently available methods have limitations (Scheme 1) and several sites on the scaffold
remain difficult to functionalize.7, 25 Significant limitations include: acidic reaction condition
are often required to drive the dehydration step of the intermediary lactol and long reaction
times with elevated temperatures are usually needed.26-27 Since these structures are present in
a plethora of biologically active natural and non-natural compounds, any new synthetic
methods which allows for the rapid generation of analogues would be highly valued.
Furthermore, if new methods allowed access to chemical space beyond the scope of the
current methodology they may prove to be a useful tool in furthering medicinal chemistry
programs.
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Scheme 1. Common methods to synthesis chromones.
Recently we reported a rapid, acid-free, method to access various 2,3-substituted chromones
from various 1,1-diacylcyclopropanes (Scheme 2).28 The reaction proceeds under ambient
temperature in 90 mins.
Scheme 2. Synthesis of 2,3-substituted chromones from 1,1-diacylcyclopropanes.
Results and Discussion
Herein we disclose our efforts to expand the reaction scope and also use these chromones as
intermediates for the construction of structurally diverse natural product inspired scaffolds.
Given the prevalence of bioactive natural products containing cyclohepta- and oxepine- fused
chromones (for example, see Figure 1), our first study was focussed on extending our
established chemistry to the synthesis of such structures. Given our previous success in
synthesizing cycloheptane-fused oxazinones (Scheme 3),29 we postulated that the
electronically similar chromone system may also undergo in situ formation of the divinyl
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cyclopropane 9 and a subsequent rearrangement would provide the cycloheptane-fused
chromone 11.
Scheme 3. Synthesis of cycloheptadienes via a divinyl cyclopropane rearrangement
(DVCPR).
To this end, the known allylic alcohol 1228 was smoothly converted to the corresponding
allylic bromides 13 and 14 by treatment with phosphorous tribromide (Scheme 4). The
inconsequential mixture of bromides 13 and 14, which presumably arose from an SN2 and
SN2’ reaction pathway, respectively. Treatment of the mixture of bromides 13 and 14 with
potassium tert-butoxide at low temperature for 3 h, provided the cycloheptadiene fused
chromone 11 in a 64% yield. Attempts to improve the efficiency by mesylation of the allylic
alcohol and treatment of the crude residue with base did not result in an improved yield. The
established procedure was also used to synthesise both the cycloheptane-fused 7-
methoxychromone (19) as well as the cycloheptane-fused 6-bromochromone (20, Table 1).
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Scheme 4. Synthesis of the cycloheptane-fused chromone 11.
Significant decreases in isolated yield were observed upon increase in steric bulk at the 2-
position of the chromone. For example, extension from methyl to ethyl resulted in the
isolated yield of the corresponding cycloheptane-fused chromone 21, dropping from 64% to
16%, under the standard reaction conditions (Table 1). Likewise, the 2-benzylchromone
provided the cycloheptane 22 in low yield. This was attributed to significant 1,4- flagpole
interactions expected in the boat-like transition state (Figure 3). Efforts to optimise the
reaction via increased formation of the O (Z) enolate, thereby minimising 1,4-flagpole
interactions in the transition state, only resulted in modest increases in yield of the
corresponding cycloheptadienes (Table 1). Interestingly, under reversible enolate formation
conditions (sodium methoxide in methanol) a significant increase in the isolated yield of 21
and 22, to 40% and 38%, respectively, was observed. This suggests that the kinetic and
thermodynamic enolate is the O (Z) enolate with the O (E) enolate being unfavoured due to
steric clashing between the 2 and 3 substituents on the chromone. This reaction pathway was
inaccessible to 2-methylchromones disubstituted at the methyl group, as shown by exposure
of the 2-isopropylchromone 23 to the standard reaction conditions, which provided the
eliminated product 24 and no traces of the cycloheptyl adduct (Scheme 5).
Figure 3. 1,4-Flag pole interactions can be minimized through the O (Z) enolate.
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Table 1. Reaction scope of the divinyl cyclopropane rearrangement (DVCPR).
Scheme 5. Synthesis of 3-dienyl-2-isopropylchromone (24).
The rapid and facile entry into the substrate makes this method attractive for the synthesis of
cycloheptane-fused chromones. However, limitations in scope around the vinyl handles of the
incipient cyclopropane limit widespread adoption of this method.
Given the prevalence of natural products containing oxepine-fused flavones,13-16 like
neocyclomorusin (Figure 1), we next sought to apply our methodology to the synthesis of
such structures. Specifically access to the oxepine was envisaged through an intramolecular
Mitsunobu reaction on the precursor flavone, itself accessible from the vinyl cyclopropane 27
(Scheme 6).
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Scheme 6. Retrosynthetic analysis of the scaffold present in numerous bioactive compounds
isolated from Moraceae, including neocyclomorusin (1).
In a forward synthetic sense the vinyl cyclopropane substrate 27 was prepared from 2-
hydroxyacetophenone (28) in three steps using an adapted literature procedure (Scheme 7).28
Treatment of the crude vinylcyclopropane 27 with Pd(0) under the standard reaction
conditions provided the hydroxyl flavone 26 in a 50% overall yield from 2-
hydroxyacetophenone. The intramolecular Mitsunobu reaction on the flavone was achieved
using DEAD and triphenylphosphine to form the oxepine 25 and thereby the scaffold of
neocyclomorusin in 57%. This provides a general strategy to access this scaffold, which is
prevalent in numerous natural products. Efforts towards the synthesis of these compounds
remains ongoing and will be reported in due course.
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Scheme 7. Synthesis of an oxepine-fused flavone, a structure embedded in numerous natural
products.
Despite many bioactive xanthones being known there remains relatively few methods to
synthesise them.30-32 The most common method for synthesis of xanthones is through
benzophenone or diaryl ether intermediates with the subsequent ring closures requiring harsh
reaction conditions.33 Other methods include Hauser type cyclizations on chromones,34-35
coupling of arynes with benzoates,33 or more recently photochemical induced
electrocyclizations of flavone derivatives.36
In continuing efforts to expand our methodology to access bioactive natural product
scaffolds, we next examined the possibility of creating xanthones using an intramolecular
Friedel Crafts alkylation strategy (Scheme 8). After the unsuccessful screening of various
Lewis Acids (TMSI, BF3.OEt2, FeCl3, SnCl2 and ytterbium triflate) it was found that
treatment of a solution of the flavone 2828 in dichloromethane with three molar equivalents of
aluminium trichloride smoothly provided the corresponding xanthone 29 in 34%.
Scheme 8. Synthesis of xanthone 29.
With the reaction conditions established we next examined substrate scope. As expected the
more electron rich aromatic systems in the 2-position of the chromone underwent the Friedel
Crafts alkylation with increased efficiency providing the corresponding xanthones in good
yields (35, 33%, 37, 66% and 38, 40%, Table 2). While substitution on the benzene ring of
the chromone scaffold appeared to be tolerated with electron poor (32, 28%) and electron rich
(33, 62%) substituents. Interestingly, in the case of xanthone 35 the intermediate
dihydroxanthone could be isolated.37 However, no general procedure to enable routine
isolation of the dihydroxanthone was developed.
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Table 2. Substrate scope
O
O
1.5-5 equiv.
AlCl3, DCM
OH
R1
R1
RT, overnight
O
O
R2
R2
31
30
O
O
O
O
O
Br
O
O
33: 62%
32: 28%
34: 25%
O
O
O
O
O
O
O
O
O
37: 66%
35: 33%
36: 23%
O
O
O
38: 40%
O
Cognizant of the limitations of an alkyl chain in terms of future functionalization, we next
examined the use of a phenylcyclopropane as a replacement for the vinyl cyclopropane. To
this end the diketone 39 was treated with an in situ generated sulfonium ylide,38 to provide
the phenylcyclopropane 40 (Scheme 9). Deallylation, provided the free phenol (not shown)
which was subsequently heated at reflux in aqueous acid to afford the flavone 41 in a 30%
overall yield from 39. Treatment of the flavone 41 under the standard reaction conditions
smoothly provided the dihydroxanthone 42 in a 37% yield.
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Br
(Me)2S
Br
O
O
O
O
O
Ph
Ph
Ph
K2CO3
Ph
DCM/H2O
O
39
40
1. Pd(PPh3)4, K2CO3, MeOH
2. HCl(aq), acetone
30% from 39
O
O
O
OH
Ph
Ph
AlCl3, DCM
37%
O
41
42
Scheme 9. Synthesis of the pentacycle 42.
In conclusion, we have disclosed our efforts towards the synthesis of cycloheptane- and
oxepine-fused chromones present in numerous bioactive natural products. The syntheses are
relatively rapid, 5 steps from the 2-hydroxyacetophenone, and required only 2
chromatographic separations. Future efforts will focus on applying this methodology to the
synthesis of neocyclomorusin and microsphaerin A. Furthermore, we have shown that a
series of flavone can be readily converted into the corresponding xanthones in moderate to
good yield (23- 66%).
Experimental Section
General
Thin layer chromatography (tlc) was performed on ALUGRAM® aluminium-backed UV254
silica gel 60 (0.20 mm) plates. Compounds were visualized with either p-anisaldehyde or
20% w/w phosphomolybdic acid in ethanol. Column chromatography was performed using
silica gel 60. Infrared spectra were recorded on a Bruker Optics Alpha ATR FT-IR
spectrometer. High resolution mass-spectra (HRMS) were recorded on a Bruker microTOFQ
mass spectrometer using an electrospray ionisation (ESI) source in either the positive or
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1
negative modes. H NMR spectra were recorded at either 400 MHz on a Varian 400-MR
NMR system or at 500 MHz on a Varian 500 MHz AR premium shielded spectrometer. All
spectra were recorded from samples in CDCl3 at 25 °C in 5 mm NMR tubes. Chemical shifts
are reported relative to the residual chloroform singlet at δ 7.26 ppm. Resonances were
assigned as follows: chemical shift (multiplicity, coupling constant(s), number of protons,
assigned proton(s)). Multiplicity abbreviations are reported by the conventions: s (singlet), d
(doublet), dd (doublet of doublets), ddd (doublet of doublet of doublets), t (triplet), td (triplet
of doublets), q (quartet), qd `(quartet of doublets), m (multiplet). Proton decoupled 13C NMR
spectra were recorded at either 100 MHz on a Varian 400-MR NMR system or at 125 MHz
on a Varian 500 MHz AR premium shielded spectrometer under the same conditions as the
1H NMR spectra. Chemical shifts have been reported relative to the CDCl3 triplet at δ 77.16
ppm. Dichloromethane (CH2Cl2) was dried using a PURE SOLV MD-6 solvent purification
system. All other solvents and reagents were used as received. Melting points were measured
using a DigiMelt MPA 161.
Chromone procedure To a solution of 1,3-diketone (1 equiv) in DMSO at rt was added
K2CO3 (3 equiv) and trans-1,4-dibromo-2-butene (1.1 equiv) the suspension was stirred for
24 h. After this time the reaction was diluted with water and extracted with ethyl acetate (×3).
The combined organic extracts were washed with water (×3) and brine (×1), dried over
MgSO4, and reduced in vacuo to provide the desired cyclopropane. The residue was of
sufficient purity to be used in the next step. To a solution of cyclopropane (1 equiv) in
degassed MeOH was added Pd(PPh3)4 (0.05 equiv) with stirring for 5 min followed by the
addition of K2CO3 (2 equiv) with stirring for a further 45 min. 1M HCl was added and stirred
for 15 min then extracted with EtOAc (×2). The combined organic extracts were washed with
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water (×1) and brine (×1), dried, and reduced in vacuo. The crude residue was purified by
flash
Xanthone procedure. To the chromone (1 equiv) in DCM, AlCl3 (1.5 equiv) was added and
stirred at rt for 30 minutes. If starting material remained a further 1.5 equivalents of AlCl3
was added. This was repeated until all the starting material was consumed. The solution was
diluted with water and the aqueous phase was extracted with DCM. The combined organic
fractions were washed with water, dried over MgSO4, filtered and concentrated in vacuo. The
crude residue was purified by flash chromatography (typically 1:9−1:4 EtOAc/40−60 Pet.
Ether), yielding the desired xanthone.
Cycloheptadiene general procedure. To a solution of the appropriate chromone (1 equiv) in
THF at 0ᴼC was added tBuOK (1.3 equiv). The reaction was warmed to rt and stirred for 3 h.
The reaction mixture was then quenched with water and extracted with EtOAc which was
further washed with brine. The solvent was removed in vacuo to give the crude
cycloheptadiene which was be purified by silica gel column chromatography.
Cyclohept-11-ene[2,3]-benzopyran-4-one 11
Following the cycloheptadiene procedure, a mixture of the appropriate allylic bromides
t
(0.063 g, 0.22 mmol) was reacted with BuOK (0.032 g, 0.29 mmol) in dry THF (1 mL) to
give a crude residue which was then subjected to column chromatography elution with 1:19
to 1:9 EtOAc/petrol provided the title compound (30 mg, 64%) as a yellow oil: 1H NMR (400
MHz, CDCl3) δ 8.21 (m, 1H). 7.61 (m, 1H), 7.38 (m, 2H), 5.79 (m, 1H), 5.67 (m, 1H), 3.46
13
(m, 2H), 3.03 (m, 2H), 2.45 (m, 2H). C NMR (126 MHz, CDCl3) δ 176.8, 167.0, 156.0,
133.1, 128.9, 126.8, 126.2, 124.8, 122.9, 121.5, 117.8, 31.6, 24.9, 20.8. FTIR (ATR / cm-1):
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1608, 1464, 1141, 756. HRMS-ESI calculated for C14H12O2Na+ [M + Na]+ : 235.0730; found:
235.0745.
Cyclohept-11-ene[2,3]-7-methoxy-benzopyran-4-one 19
To a solution of the appropriate allylic bromides (0.350 g, 1.08 mmol) in dry THF (4 mL)
t
o
was added BuOK (0.158 g, 1.41 mmol) at 0 C. The reaction mixture was warmed to room
temperature and left to stir for 3 h. The reaction was then quenched with aqueous ammonium
chloride and extracted with EtOAc. The organic layer was separated washed with brine
before the solvent was removed under reduced pressure to give a crude residue which was
then subjected to column chromatography elution with 1:19 to 1:9 EtOAc/petrol provided the
1
title compound 19 (0.160 g, 61%) as a light yellow oil: H NMR (400 MHz, CDCl3) δ 8.09
(d, J = 8.9 Hz, 1H), 6.91 (dd, J = 8.9, 2.4 Hz, 1H), 6.77 (m, 1H), 5.79 (m, 1H), 5.67 (m, 1H),
3.87 (m, 4H), 3.42 (m, 2H), 2.97 (m, 2H), 2.42 (m, 2H). 13C NMR (101 MHz, CDCl3) δ
176.04, 166.07, 163.50, 157.49, 128.74, 127.45, 126.90, 120.92, 116.76, 113.97, 99.86,
55.69, 31.35, 24.70, 20.51. FTIR (ATR / cm-1): 1606, 1437, 1118, 722, 538. HRMS-ESI
calculated for C15H14O3Na+ [M + Na]+: 265.0835; found: 265.0869.
Cyclohept-11-ene[2,3]-6-bromo-benzopyran-4-one 20
To a solution of the appropriate allylic bromides (0.150 g, 0.40 mmol) in dry THF (2 mL)
t
o
was added BuOK (0.09 g, 0.81 mmol) at 0 C. The reaction mixture was warmed to room
temperature and left to stir for 3 h. The reaction was then quenched with aqueous ammonium
chloride and extracted with EtOAc. The organic layer was separated washed with brine
before the solvent was removed under reduced pressure to give a crude residue which was
then subjected to column chromatography elution with 1:19 to 1:9 EtOAc/petrol provided the
title compound 20 (0.065 g, 55%) a light yellow oil:
1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 2.5 Hz, 1H), 7.69 (dd, J = 8.9, 2.5 Hz, 1H), 7.30
(d, J = 8.9 Hz, 1H), 5.80 (m, 1H), 5.69 (m, 1H), 3.44 (dd, J = 5.3, 2.4 Hz, 2H), 3.02 (m, 2H),
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2.45 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 175.24, 166.99, 154.57, 135.89, 128.80,
128.73, 126.55, 124.19, 121.61, 119.72, 117.98, 31.45, 24.64, 20.63. FTIR (ATR / cm-1):
2923, 1634, 1463, 816, 756. HRMS-ESI calculated for C14H11BrO2Na+ [M + Na]+ :
312.9942; found: 312.9936.
14-Methyl-cyclohept-11-ene[2,3]-7-methoxy-benzopyran-4-one 21
Following the cycloheptadiene procedure, a mixture of the appropriate allylic bromides
(0.260 g, 0.85 mmol) was reacted with tBuOK (0.124 g, 1.10 mmol) in dry THF (3 mL). The
reaction mixture was warmed to room temperature and left to stir for 3 h. The reaction was
then quenched with aqueous ammonium chloride and extracted with EtOAc. The organic
layer was separated washed with brine before the solvent was removed under reduced
pressure to give a crude residue which was then subjected to column chromatography elution
with 1:19 to 1:9 EtOAc/petrol provided the title compound 21 (30 mg, 16%) as a yellow oil.
1H NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 7.6 Hz, 1H), 7.38 (m,
2H), 5.83 (m, 1H) 5.65 (m, 1H),3.65 (m, 1H), 3.47 (m, 1H), 3.28 (m, 1H), 2.37 (m, 2H), 1.41
(d, J = 7.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 176.6, 168.4, 155.7, 132.8, 128.1, 127.0,
126.0, 124.6, 122.4, 120.6, 118.3, 117.6, 35.7, 20.7, 16.8. FTIR (ATR / cm-1): 1614, 1464,
757. HRMS-ESI calculated for C15H14O2Na+ [M + Na]+ : 249.0886; found: 249.0878.
14-Benzo-cyclohept-11-ene[2,3]-7-methoxy-benzopyran-4-one 22
Following the cycloheptadiene procedure, a solution of the appropriate allylic bromides
t
(0.330 mg, 0.89 mmol) was reacted with BuOK (0.130 g, 1.16 mmol) in dry THF (3 mL).
The reaction mixture was warmed to room temperature and left to stir for 3 h. The reaction
was then quenched with aqueous ammonium chloride and extracted with EtOAc. The organic
layer was separated washed with brine before the solvent was removed under reduced
pressure to give a crude residue which was then subjected to column chromatography elution
with 1:19 to 1:9 EtOAc/petrol provided the title compound 22 (0.040 g, 16%). 1H NMR (400
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MHz, CDCl3) δ 8.20 (dd, J = 8.0, 1.7 Hz, 1H), 7.55 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 7.32 (m,
6H), 7.22 (m, 1H), 5.79 (m, 1H), 5.74 (dt, J = 10.8, 5.5 Hz, 1H), 4.40 (dd, J = 7.3, 4.9 Hz,
13
1H), 3.47 (m, 2H), 2.82 (m, 2H). C NMR (101 MHz, CDCl3) δ 177.4, 166.5, 155.9, 140.4,
133.2, 129.6, 128.6, 128.2, 128.1, 127.2, 126.2, 124.8, 122.7, 121.5, 117.9, 47.4, 31.2, 20.6.
FTIR (ATR / cm-1): 3232, 1615, 1466, 1073, 756, 698. HRMS-ESI calculated for
C20H16O2Na+ [M + Na]+ : 311.1043; found: 311.1017.
2-Isopropyl-3-(2’hydroxy-3’-buten-1’-yl)-benzopyran-4-one 23
Following the chromone general procedure 1, to a suspension of the appropriate diketone
(0.687 g, 2.79 mmol) and K2CO3 (1.16 g, 8.37 mmol) in DMSO (7 mL) was added trans-1,4-
dibromo-2-butene (0.629 g, 3.35 mmol) with stirring for 24 hours. Upon completion the
reaction was worked up and the crude residue was dried, redissolved in MeOH (10 mL) and
degassed. To this solution was added of K2CO3 (1.29 g, 9.31 mmol) and Pd(PPh3)4 (0.179 g,
0.16 mmol) with stirring for 45 min. After this time the reaction was diluted with 1M HCl
stirred for a further 15 min then extracted with EtOAc. Following work up crude residue was
purified by silica gel column chromatography (1:9-1:3 EtOAc:40-60 pet. Ether) to provide
the title compound (230 mg, 26%). 1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 8.0, 1.7 Hz,
1H), 7.64 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 7.39 (m, 2H), 5.93 (ddd, J = 17.1, 10.4, 5.9 Hz,
1H), 5.28 (dt, J = 17.1, 1.5 Hz, 1H), 5.10 (dt, J = 10.4, 1.4 Hz, 1H), 4.36 (m, 1H), 3.28 (p, J
= 6.8 Hz, 1H), 2.85 (m, 2H), 1.33 (d, J = 6.8 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 179.9,
170.8, 155.9, 140.6, 133.4, 125.8, 124.7, 122.5, 117.5, 116.2, 114.5, 72.8, 32.5, 30.5, 20.2,
19.8. FTIR (ATR / cm-1): 3413, 1619, 1466, 758. HRMS-ESI calculated for C16H18O3Na+ [M
+ Na]+: 281.1148; found: 281.1144.
2-Isopropyl-3-(1’,3’-butadiene)-benzopyran-4-one 24
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To a mixture of the appropriate allylic bromides (0.200 g, 0.62 mmol) in THF (2 mL) was
added tBuOK (0.090 mg, 0.81 mmol) the solution was stirred for 3 h before being quenched
with water (5 mL). Ethyl acetate (10 mL) was added and the organic layer was collected and
concentrated in vacuo to provide a crude residue. Subjection of the crude residue column
1
chromatography using 1:9 EtOAc/Pet Ether provided 24 (0.020 g, 13%) as a clear oil: H
NMR (400 MHz, CDCl3) δ 8.22 (d, J = 7.7 Hz, 1H), 7.63 (d, J = 6.5 Hz, 1H), 7.36 (m, 3H),
6.48 (m, 2H), 5.36 (d, J = 16.9 Hz, 1H), 5.19 (d, J = 9.8 Hz, 1H), 3.46 (h, J = 6.8 Hz, 1H),
13
1.35 (d, J = 6.9 Hz, 6H). C NMR (101 MHz, CDCl3) δ 177.1, 170.2, 155.2, 138.0, 136.1,
135.6, 133.0, 126.0, 124.7, 123.1, 122.8, 117.9, 117.4, 116.6, 30.2, 20.0. FTIR (ATR / cm-1):
1614, 1464, 1069, 758. HRMS-ESI calculated for C16H16O2Na+ [M + Na]+ : 263.1043; found:
263.1023.
2-(2’-Phenol)-3-(2’’-hydroxy-buten-1’’-yl)-benzopyran-4-one 26
Following the chromone general procedure 1, to a suspension of 1,3-bis(2-allyloxyphenyl)-
1,3-propandione (1.85 g, 5.50 mmol) and K2CO3 (2.28 g, 16.5 mmol) in DMSO (20 mL) was
added trans-1,4-dibromo-2-butene (1.18 g, 5.50 mmol) with stirring for 24 hours. Upon
completion the reaction was worked up and crude residue was dried, redissolved in MeOH
(20 mL) and degassed. To this solution was added of K2CO3 (2.61 g, 18.9 mmol) and
Pd(PPh3)4 (0.437 g, 0.378 mmol) with stirring for 45 min. After this time the reaction was
diluted with 1M HCl stirred for a further 15 min then extracted with EtOAc. Following work
up the crude residue was purified by silica gel column chromatography (1:4-2:3 EtOAc:40-60
pet. Ether) to provide the title compound (830 mg, 50%).Melting point: 162-166ᴼC. 1H NMR
(500 MHz, CDCl3) δ 8.23 (ddd, J = 7.9, 1.6, 0.52 Hz, 1H), 7.67 (ddd, J = 8.5, 7.1, 1.7 Hz,
1H), 7.44 - 7.39 (m, 3H), 7.30 (dd, J = 7.6, 1.6 Hz, 1H), 7.08 - 7.02 (m, 2H), 5.86 (ddd, J =
17.1, 10.4, 6.1 Hz, 1H), 5.30 (dt, J = 17.1, 1.3 Hz, 1H), 5.10 (dt, J = 10.4, 1.3 Hz, 1H), 4.80
13
(m, 1H), 2.92 (dd, J = 14.4, 3.3 Hz, 1H), 2.39 (dd, J = 14.3, 10.0 Hz, 1H). C NMR (126
17

ACCEPTED MANUSCRIPT
MHz, CDCl3) δ 181.5, 163.4, 159.2, 156.1, 142.8, 136.5, 134.7, 132.7, 128.4, 127.7, 125.5,
123.7, 123.3, 122.9, 121.2, 118.1, 73.5, 37.0. FTIR (ATR / cm-1): 3475, 3062, 2927, 2870,
-
1611, 1590, 1425, 999, 926, 753. HRMS-ESI calculated for C19H15O4 [M]-: 307.0976; found:
307.0957.
2’-Ethene-benzooxapine[5’,4’,-b]-benzopyran-4-one 25
o
To a solution of triphenylphosphine (1.28 g, 4.9 mmol) in THF (10 mL) maintained at 0 C
was added diethylazodicarboxylate (0.847 g, 4.86 mmol), followed by addition of chromone
26 (1.25 g, 4.05 mmol) in THF (10 mL). The reaction was heated to 50 °C with stirring until
consumption of starting material (as indicated by TLC, ~2 hours). Solvent was removed in
vacuo and the crude residue purified by column chromatography (1:4 - 3:2 EtOAc:Pet Ether)
to provide the title compound as a yellow solid (673 mg, 57%). Melting point: 116-118ᴼC. 1H
NMR (500 MHz, CDCl3) δ 8.27 (ddd, 1H, J = 8.0, 1.7, 0.4 Hz), 7.90 (dd, 1H, J = 7.9, 1.7
Hz), 7.69 (ddd, 1H, J = 8.4, 7.1, 1.7 Hz), 7.53 (ddd, 1H, J = 8.5, 1.0, 0.4 Hz), 7.47 (ddd, 1H,
J = 8.2, 7.4, 1.7 Hz), 7.42 (ddd, 1H, J = 8.0, 7.1, 1.0 Hz), 7.27 (ddd, 2H, J = 7.9, 7.4, 1.2
Hz), 7.18 (dd, 1H, J = 8.2, 1.1 Hz), 6.05 (ddd, 1H, J = 17.2, 10.6, 5.8 Hz), 5.4 (dt, 1H, J =
17.2, 1.3 Hz), 5.25 (dt, 1H, J = 10.6, 1.3 Hz), 5.14 (m, 1H), 3.19 (dd, 1H, J = 15.4, 4.0 Hz),
13
2.79 (dd, 1H, J = 15.4, 8.1 Hz). C NMR (126 MHz, CDCl3) δ 177.0, 159.3, 156.4, 156.1,
136.9, 133.7, 133.7, 132.5, 128.5, 126.3, 126.0, 125.1, 123.6, 122.9, 118.8, 118.1, 116.8,
88.7, 28.1. FTIR (ATR / cm-1): 3080, 3013, 2922, 2854, 1632, 1605, 1565, 991, 935, 755.
HRMS-ESI calculated for C19H14O3Na+ [M+Na]+: 313.0835; found: 313.0841.
1’-Ethyl-naptha[4’,3’-b]-benzopyran-4-one 29
Following the xanthone general procedure, to a solution of the appropriate chromone (85 mg,
0.291 mmol) in dry DCM (2 mL) was added AlCl3 (58 mg, 0.436 mmol) and stirred over
night at room temperature. The crude residue was purified by flash chromatography (1:4
EtOAc/40-60 Pet. Ether) to afford the title compound 29 (27 mg, 34%) as a pale yellow oil.
18

ACCEPTED MANUSCRIPT
1H NMR (500 MHz, CDCl3) δ 8.74 (dd, J = 8.2, 1.4 Hz, 1H), 8.42 (dd, J = 7.9, 1.6 Hz, 1H),
8.14 (d, J = 7.9 Hz, 2H), 7.77 (dddd, J = 8.4, 6.7, 5.1, 1.6 Hz, 2H), 7.74 – 7.67 (m, 2H), 7.45
13
(td, J = 7.5, 7.1, 1.2 Hz, 1H), 3.16 (q, J = 7.5 Hz, 2H), 1.44 (t, J = 7.7 Hz, 3H). C NMR
(126 MHz, CDCl3) δ 177.1, 155.9, 152.7, 136.5, 135.4, 134.3, 129.6, 126.74, 126.6, 124.6,
124.4, 124.4, 123.7, 122.6, 119.5, 118.2, 117.4, 25.7, 14.8. FTIR (ATR / cm-1); 2969, 1721,
1626, 1468, 1434, 754. HRMS-ESI calculated for C19H15O2 [M+H]+: 275.1067; found:
275.1057.
1’-Ethyl-naptha[4’,3’-b]-6-bromo-benzopyran-4-one 32
Following the xanthone general procedure, to a solution of the appropriate chromone (38 mg,
0.102 mmol) in dry DCM (2 mL) was added AlCl3 (68 mg, 0.512 mmol) and stirred over
night at room temperature. The crude residue was purified by flash chromatography (1:4
1
EtOAc/40-60 Pet. Ether) to afford the title compound 32 (8 mg, 28%) as a brown oil. H
NMR (400 MHz, CDCl3) δ 8.71 – 8.66 (m, 1H), 8.52 (d, J = 2.5 Hz, 1H), 8.13 (d, J = 8.3 Hz,
1H), 8.08 (s, 1H), 7.84 (dd, J = 8.9, 2.5 Hz, 1H), 7.77 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.73 –
7.68 (m, 1H), 7.58 (d, J = 8.9 Hz, 1H), 3.15 (q, J = 7.5 Hz, 2H), 1.44 (t, J = 7.5 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ 175.8, 154.6, 152.7, 137.2, 137.0, 135.5, 129.9, 129.2, 126.7,
124.4, 124.4, 123.9, 123.6, 120.2, 119.3, 117.7, 117.1, 25.7, 14.7. FTIR (ATR / cm-1); 2965,
1628, 1465, 1444. HRMS-ESI calculated for C19H13BrNaO2 [M+Na]+: 374.9991; found:
374.9957.
1’-Ethyl-naptha[4’,3’-b]-7-methoxy-benzopyran-4-one 33
Following the xanthone general procedure, to a solution of the appropriate chromone (80 mg,
0.248 mmol) in dry DCM (2 mL) was added AlCl3 (165 mg, 1.241 mmol) and stirred over
night at room temperature. The crude residue was purified by flash chromatography (1:4
EtOAc/40-60 Pet. Ether) to afford the title compound 33 (50 mg, 62%) as a pale yellow oil.
1H NMR (500 MHz, CDCl3) δ 8.69 (d, J = 8.3 Hz, 1H), 8.29 (d, J = 8.9 Hz, 1H), 8.14 – 8.10
19

ACCEPTED MANUSCRIPT
(m, 2H), 7.72 (ddd, J = 8.3, 7.0, 1.3 Hz, 1H), 7.65 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 7.03 (d, J
= 2.4 Hz, 1H), 6.98 (dd, J = 8.9, 2.4 Hz, 1H), 3.96 (s, 3H), 3.15 (q, J = 7.6 Hz, 2H), 1.44 (t, J
= 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 176.3, 164.7, 157.7, 152.5, 136.3, 135.1,
129.3, 128.1, 126.4, 124.5, 124.3, 123.4, 119.6, 117.3, 116.6, 113.8, 100.4, 56.0, 25.7, 14.8.
FTIR (ATR / cm-1); 2965, 1629, 1613, 1441, 788. HRMS-ESI calculated for C20H16NaO3
[M+Na]+: 327.0992; found: 327.0967.
1’-Ethyl-naptha[4’,3’-b]-6-methyl-benzopyran-4-one 34
Following the xanthone general procedure, to a solution of the appropriate chromone (30 mg,
0.10 mmol) in dry DCM (2 mL) was added AlCl3 (65 mg, 4.8 mmol) and stirred over night at
room temperature. The crude residue was purified by flash chromatography (1:4 EtOAc/40-
1
60 Pet. Ether) to afford the title compound 34 (7 mg, 25%) as a pale yellow oil. H NMR
(400 MHz, CDCl3) δ 8.72 (d, J = 8.4Hz, 1H), 8.21 – 8.18 (s, 1H), 8.13 (m, 2H), 7.75 (t, J =
7.7 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.58 (s, 2H), 3.15 (q, J = 7.5 Hz, 2H), 2.51 (s, 3H),
13
1.45 (t, J = 7.5 Hz, 3H). C NMR (101 MHz, CDCl3) δ 177.2, 154.2, 152.7, 136.3, 135.6,
135.4, 134.3, 129.5, 126.5, 126.0, 124.6, 124.4, 123.7, 122.3, 119.6, 118.0, 117.3, 25.7, 21.1,
14.8. FTIR (ATR / cm-1); 2923, 1651, 1627, 1487, 1447, 767. HRMS-ESI calculated for
C20H17O2 [M+H]+: 289.1223; found: 289.1211.
1’-Ethyl-8’-methyl-naptha[4’,3’-b]-benzopyran-4-one 35
Following the xanthone general procedure, to a solution of the appropriate chromone (31 mg,
0.102 mol) in dry DCM (2 mL) was added AlCl3 (68 mg, 0.512 mmol) and stirred over night
at room temperature. The crude residue was purified by flash chromatography (1:4
EtOAc/40-60 Pet. Ether) to afford the title compound 35 (10 mg, 33%) as a brown solid.
1
Melting point: 114 – 115ᴼC. H NMR (400 MHz, CDCl3) δ 8.62 (dd, J = 8.5, 2.0 Hz, 1H),
8.45 – 8.39 (m, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.77 (ddd, J = 8.6, 7.0, 1.6 Hz, 1H), 7.68 (dd,
J = 8.4, 1.4 Hz, 1H), 7.53 (dd, J = 8.6, 1.8 Hz, 1H), 7.44 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 3.14
20

ACCEPTED MANUSCRIPT
13
(q, J = 7.5 Hz, 2H), 2.63 (s, 3H), 1.45 (t, J = 7.5 Hz, 2H). C NMR (101 MHz, CDCl3) δ
177.1, 155.9, 152.9, 139.9, 135.9, 135.7, 134.2, 128.56, 126.7, 124.3, 123.8, 123.5, 122.7,
122.5, 119.6, 118.2, 116.8, 25.7, 22.5, 14.8. FTIR (ATR / cm-1); 2922, 2362, 1620, 1467,
1387, 760. HRMS-ESI calculated for C20H17O2 [M+H]+: 289.1223; found: 289.1207.
1’-Ethyl-6’,8’-dimethoxy-naptha[4’,3’-b]-benzopyran-4-one 36
Following the xanthone general procedure, to a solution of the appropriate chromone (100
mg, 0.28 mmol) in dry DCM (5 mL) was added AlCl3 (187 mg, 1.4 mmol) and stirred over
night at room temperature. The crude residue was purified by flash chromatography (1:3
1
EtOAc/40-60 Pet. Ether) to afford the title compound 36 (22 mg, 23%) as a yellow oil. H
NMR (400 MHz, CDCl3) δ 8.39 (d, J = 7.9 Hz, 1H), 8.17 (s, 1H), 7.76 – 7.69 (m, 1H), 7.63
(d, J = 8.4 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.00 (d, J = 2.2 Hz, 1H), 6.71 (d, J = 2.2 Hz,
13
1H), 4.10 (s, 3H), 3.99 (s, 3H), 3.05 (q, J = 7.5 Hz), 1.45 (t, J = 7.5 Hz). C NMR (126
MHz, CDCl3) δ 176.8, 161.3, 160.4, 155.9, 154.4, 139.4, 134.8, 133.9, 126.3, 124.1, 122.3,
121.4, 118.6, 116.4, 111.1, 99.4, 96.6, 56.5, 55.6, 26.5, 14.1. FTIR (ATR / cm-1): 2924, 1608,
1466. HRMS-ESI calculated for C21H18NaO4 [M+Na]+: 357.1097; found: 357.1117.
1’-Ethyl-7’,9’-dimethoxy-naptha[4’,3’-b]-benzopyran-4-one 37
Following the xanthone general procedure, to a solution of the appropriate chromone (67 mg,
0.190 mmol) in dry DCM (2 mL) was added AlCl3 (127 mg, 0.951 mmol) and stirred over
night at room temperature. The crude residue was purified by flash chromatography (1:4
1
EtOAc/40-60 Pet. Ether) to afford the title compound 37 (42 mg, 66%) as brown solid. H
NMR (400 MHz, CDCl3) δ 8.39 (dd, J = 8.0, 1.6 Hz, 1H), 7.87 (s, 1H), 7.75 (ddd, J = 8.6,
7.0, 1.7 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 2.5 Hz, 1H), 7.42 (ddd, J = 8.0, 7.0,
1.2 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 4.04 (s, 3H), 3.96 (s, 3H), 3.30 (q, J = 7.3 Hz, 2H),
13
1.31 (t, J = 7.3 Hz, 3H). C NMR (101 MHz, CDCl3) δ 177.2, 159.0, 158.7, 156.0, 151.3,
137.9, 134.2, 134.2, 127.6, 126.7, 124.2, 123.3, 122.5, 119.1, 118.2, 117.9, 101.8, 94.5, 55.7,
21

ACCEPTED MANUSCRIPT
30.7, 16.9. FTIR (ATR / cm-1); 2930, 1612, 1557, 1467, 1208. HRMS-ESI calculated for
C21H19O4 [M+H]+: 335.1278; found: 335.1252.
1’-Ethyl-7’methoxy-naptha[4’,3’-b]-benzopyran-4-one 38
Following the xanthone general procedure, to a solution of the appropriate chromone (183
mg, 0.57 mmol) in dry DCM (2 mL) was added AlCl3 (378 mg, 2.83 mmol) and stirred over
night at room temperature. The crude residue was purified by flash chromatography (1:9
EtOAc/40-60 Pet. Ether) to afford a 81:19 mixture isomers of title compound 38 (70 mg,
40%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.41 (dd, J = 8.0, 1.7 Hz, 1H), 8.03
(d, J = 9.2 Hz, 1H), 7.98 (s, 1H), 7.96 (d, J = 2.7 Hz, 1H), 7.77 (ddd, J = 8.6, 6.9, 1.7 Hz,
1H), 7.69 (d, J = 7.9 Hz, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.38 (dd, J = 9.2, 2.7 Hz, 1H), 4.06 (s,
3H), 3.11 (q, J = 7.5 Hz, 2H), 1.42 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 177.3,
158.2, 155.9, 151.8, 136.4, 134.3, 130.6, 126.7, 126.0, 125.7, 124.3, 122.5, 121.2, 118.2,
117.9, 117.2, 102.5, 55.7, 25.8, 14.9. FTIR (ATR / cm-1): 2963, 1650, 1613, 1469, 759.
HRMS-ESI calculated for C20H16NaO3 [M+Na]+: 327.0992; found: 327.0977.
2-Benzo-3-(2’-hydroxy-2’-benzoethyl)-benzopyran-4-one 41
To a solution of the appropriate diketone (8.13 g, 29 mmol) in 1:1 DCM/H2O (80 mL) was
added K2CO3 (12.10 g, 87 mmol) and (2-bromo-1-phenyl ethyl)dimethyl sulphonium
bromide (10.0 g, 44 mmol) to stir for 24 h. Upon completion the reaction was worked up and
crude residue was dried, redissolved in MeOH (90 mL) and degassed. To this solution was
added of K2CO3 (12.2 g, 88 mmol) and Pd(PPh3)4 (0.57 g, 0.49 mmol) with stirring for 45
min. After this time the reaction was diluted with 1M HCl stirred for a further 15 min then
extracted with EtOAc. The crude extracts were refluxed overnight in 1M HCl:acetone (80
mL) then diluted with 1M HCl and extracted with DCM. Following work up the crude
residue was purified by flash chromatography (1:3 EtOAc/40−60 Pet. Ether) to afford the
1
title compound (2.65 g, 30%) as orange crystals. Melting point: 114 - 115ᴼC. H NMR (500
22

ACCEPTED MANUSCRIPT
MHz, CDCl3) δ 8.34 – 8.28 (dd, 1H), 7.71 (ddd, J = 8.6, 7.1, 1.6 Hz, 1H), 7.55 – 7.43 (m,
7H), 7.26 – 7.18 (m, 5H), 5.07 (dd, J = 8.6, 3.3 Hz, 1H), 3.07 (dd, J = 14.4, 8.6 Hz, 1H), 2.94
(dd, J = 14.5, 3.3 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 180.9, 164.5, 156.4, 144.9, 134.2,
133.0, 130.6, 129.0, 128.7, 128.6, 128.4, 127.3, 126.2, 125.7, 125.4, 122.8, 119.4, 118.1,
74.6, 36.9. FTIR (ATR / cm-1): 3417, 3060, 1617, 1387. HRMS-ESI calculated for
C23H18NaO3 [M+Na]+: 365.1148; found: 365.1125.
1’-Benzo-naptha[4’,3’-b]-benzopyran-4-one 42
Following the xanthone general procedure, to a solution 41 (101 mg, 0.29 mol) in dry DCM
(3 mL) was added AlCl3 (59 mg, 0.44 mmol) and stirred over night at room temperature. The
crude residue was purified by flash chromatography (1:3 EtOAc/40-60 Pet. Ether) to afford
1
the title compound 42 (37 mg, 39%) as pale white crystals. H NMR (500 MHz, CDCl3) δ
8.24 (dd, J = 7.9, 1.7 Hz, 1H), 8.08 (dd, J = 7.6, 1.6 Hz, 1H), 7.68 (ddd, J = 8.7, 7.1, 1.7 Hz,
1H), 7.58 (dd, J = 8.5, 1.0 Hz, 1H), 7.42 – 7.37 (m, 3H), 7.32 – 7.27 (m, 2H), 7.25 – 7.18 (m,
3H), 7.06 (d, J = 7.4 Hz, 1H), 4.33 – 4.27 (m, 1H), 3.32 (dd, J = 16.4, 6.9 Hz, 1H), 3.24 (dd,
J = 16.4, 9.1 Hz, 1H). NMR data were consistent with those found in the literature.39
Acknowledgements
The authors thank the University of Otago for funding and Prof. David Larsen (University of
Otago) for helpful discussions.
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