Synthesis of the unique angular tricyclic chromone structure proposed for aspergillitine, and its relationship with alkaloid TMC-120B

Article abstract of DOI:10.1039/c2ob25067e

The synthesis of the tricyclic angular chromone structure originally assigned to aspergillitine is reported. The synthesis was achieved in 11 steps and 15% overall yield from 2,4-dihydroxypropiophenone, through the intermediacy of 2,3-dimethyl-7-hydroxych

Full text of DOI:10.1039/c2ob25067e

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PAPER
Synthesis of the unique angular tricyclic chromone structure proposed for
aspergillitine, and its relationship with alkaloid TMC-120B†
Sebastián O. Simonetti, Enrique L. Larghi, Andrea B. J. Bracca and Teodoro S. Kaufman*
Received 10th January 2012, Accepted 19th March 2012
DOI: 10.1039/c2ob25067e
The synthesis of the tricyclic angular chromone structure originally assigned to aspergillitine is reported.
The synthesis was achieved in 11 steps and 15% overall yield from 2,4-dihydroxypropiophenone, through
the intermediacy of 2,3-dimethyl-7-hydroxychromen-4-one. Construction of the nitrogen-bearing
heterocyclic ring entailed a Stille cross-coupling reaction with n-Bu3SnCH2CHvCH2, followed by
double bond isomerization, oximation of the chromone carbonyl, and a final microwave-assisted
electrocyclization of the thus formed 6π-electron aza-triene system.
In 2001, the group of Proksch obtained several heterocycles
from a strain of Aspergillus versicolor isolated from the marine
Introduction
The oceans cover around 70% of the planet’s surface and harbor
most of the biodiversity of our world, being a unique resource
that provides a diverse array of natural products, especially from
bacteria, cyanobacteria, fungi and invertebrates, including
bryozoans, sponges, tunicates and molluscs.
Therefore, the marine environment contains an immense trea-
sure of useful natural products awaiting discovery. Ecological
pressures, including predation and fight for survival, fouling of
the surface, competition for space, and continuously evolving
environmental conditions have led to the development of sec-
ondary metabolites with singular structures and diverse biologi-
cal activities.
On the other hand, emerging infectious diseases, growth of
antibiotic resistance and the continued fight against cancer have
all contributed to the increasing interest in the isolation of
marine natural products for assessing their potential usefulness
against these and other relevant conditions.
In general, marine sponges are known to produce chemicals
able to deter predators; many of these released by the diverse
microorganisms living within the tissues of the sponge.
In addition, fungi isolated from marine sponges and other
filter-feeding invertebrates have recently captured great scientific
attention;1a–c they relate to the local environment through
complex and specialized interactions and were proven to be the
single most prolific source of new bioactive natural products.1d–h
sponge Xestospongia exigua, collected along the coast line of
Bali (Indonesia).
They were termed aspergillitine (1) and aspergiones A–F (2a–
f), to which the original tricyclic angular 2,3-dimethylchromone
structures shown in Fig. 1 were attributed,2 on the basis of their
NMR spectral analyses. Aspergillitine exhibited moderate anti-
bacterial activity against Bacillus subtilis, being inactive against
Escherichia coli and Saccharomyces cerevisiae.
Structures 1 and 2a–f are unusual in several ways. First,
because Aspergillus versicolor has been extensively studied and
over the years it became the source of many interesting natural
products;3a however, chromones were not isolated before from
this fungus.3b–h
Secondly, because the 2,3-dimethylchromone motif is rare4a
and 2,3-dimethylchromones are uncommon as natural products,
exceptions being chromones 3a, isolated from the mycobiont of
the lichen Graphis scripta4b compound 3b, obtained from Thito-
nia diversifolia4c and Tussilago farfara,4d chromone 3c, isolated
from Ligularia microphylla,4e and chaetochromin D, a bis
(naphtho-γ-pyrone) derivative produced by the fungus Chaeto-
mium gracile.4f Interestingly, 2,3-dimethylchromones have been
employed as key intermediates for the synthesis of more
complex natural and other products.5
Finally, the structure assigned to aspergillitine contains a pyri-
dine ring instead of the pyrane-type heterocycle as found in
2a–f, which conveys to 1 an unprecedented tricyclic core,
especially in view that incorporation of nitrogen in fungal poly-
ketides is infrequent.
Taken together, aspergillitine (1) and the aspergiones display a
structural relationship analogous to that found between the
naphthoquinones bostrycoidin and fusarubin, and between their
intermediate metabolites, such as 6-deoxybostrycoidin (4) and
6-deoxy-3,4-anhydrofusarubin (4a).6
Institute of Chemistry of Rosario (IQUIR, CONICET-UNR) and School
of Biochemical and Pharmaceutical Sciences, National University of
Rosario, Suipacha 531, S2002LRK Rosario, Argentina.
E-mail: kaufman@iquir-conicet.gov.ar; Tel: +54-341-4370477
†Electronic supplementary information (ESI) available: Selected spectra
of intermediates and final product. See DOI: 10.1039/c2ob25067e
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Fig. 1 Chemical structures of aspergillitine (1), the aspergiones A–F (2a–2f, respectively), and related natural products, including the naturally-
occurring 2,3-dimethylchromones 3a–c, 6-deoxybostrycoidin (4), 6-deoxy-3,4-anhydrofusarubin (4a), ustusorane C (5a), (+)-pseudodeflectusin (5b),
and alkaloid TMC-120B (6).
Unrelated with Proksch’s group report, some isochromane
derivatives, including ustusorane C (5a)7a and pseudodeflectusin
(5b),7b were isolated from Aspergillus pseudodeflectus (a parasite
of the sea weed Sargassum fusiform) and Aspergillus ustus
094102, respectively. These tricycles displayed interesting cyto-
toxic activity against several human cancer cell lines.
Results and discussion
Two retrosynthetic analyses of structure 1, which resort to the
same key transformations in order to generate the A and C rings,
are detailed in Scheme 1. Strategy A pivoted on a B → AB →
ABC ring forming sequence.
Disconnection of the marked C–C and C–N bonds on ring C
unveiled the 7,8-disubstituted chromones 7a,b as suitable precur-
sors, from which 1 could be accessed by installing a suitable
three carbon atoms unit carrying an olefin moiety on 7-C, and a
properly substituted benzylidene-amino motif on 8-C to allow an
aza-triene cyclization.
In turn, chromones 7a,b could be made available from con-
veniently substituted propiophenones (8a,b) by means of a Kosta-
necki–Robinson synthesis. Properly functionalized propiophenones
should result from Friedel–Crafts acylation of phenols or Fries
rearrangement of their corresponding propionates.
On the other hand, strategy B was based on the installation of
the chromone ring at the end of the synthesis (B → BC → ABC).
We envisioned that 8-hydroxyisoquinoline derivatives 9,10
uncovered by disconnection of the marked C–C and C–O bonds,
would be suitable precursors of 1. In turn, these could be
accessed from 6-substituted salicylaldehyde derivatives 10.11
Interestingly, this B → BC → ABC approach has been employed
for the synthesis of the oxygen-bearing congeners, the asper-
giones A and B,7c–f as well as for their isomers, pseudodeflectu-
sin and ustusorane C.8e,f
In view of the previous analysis, strategy A was first explored
due to its original conception and the comparatively easier avail-
ability of the required starting materials. Thus, esterification of 3-
bromophenol (9a) with propionyl chloride (Scheme 2), followed
by an AlCl3-mediated Fries rearrangement of the resulting ester
11 furnished 61% of 4-bromopropiophenone derivative 8a.12 In
order to install the projected 8-formyl moiety,13 8a was next sub-
jected to a Williamson allylation giving 85% yield of allyl
phenyl ether 12, which once heated in refluxing ortho-dichloro-
benzene underwent a Claisen rearrangement to ortho-allyl
phenol 13a in 64% yield.
Chemical syntheses of 5b and 2b unequivocally demonstrated
that the structure originally attributed to aspergione B (2b) was
incorrect, and suggestion was made to its reassignment as 5b.7c–e
Analogously, the synthesis of aspergiones A, B and ustusorane
C further confirmed the identity of Proksch’s aspergione A (2a)
with 5a.7f
Interestingly, the related alkaloid TMC-120B (6)8a–c was
repeatedly found in Aspergillus, including A. ustus (Bain.) Thom
& Church TC 1118, A. calidoustus and A. insuetus, fungi from
the rhizosphere of grass and indoor isolates, and also obtained
from Penicillium sp. PSU-F40, isolated from a gorgonian sea fan
of the genus Annella.8d This compound exhibited inhibitory
activity against the interleukin-5 mediated prolongation of
eosinophil survival, being a potential anti-inflammatory agent
and was totally synthesized,8e–g but connections between its
structure and the spectral data reported for aspergillitine were not
attempted.
Paralleling the relationship between aspergiones A and B (2a
and 2b) with ustusorane C and pseudodeflectusin (5a and 5b),
respectively, the proposed structure for aspergillitine (1) is identi-
cal with that of 6 concerning the isoquinoline moiety; however,
they differ in that ring A of 1 contains a 2,3-dimethyl-pyran-4-
one (2,3-dimethyl-γ-pyrone) motif, while ring A of 6 is the iso-
meric 3-isopropylidene-3H-furan-2-one.
We have previously studied the synthesis of natural products
of marine origin,9a,b and have also synthesized heterocycles car-
rying the 3-methylisoquinoline motif.9c Therefore, we decided to
undertake the synthesis of structure 1 with the double aim of
accessing a unique and unprecedented polycyclic structure,
while also contributing to reveal structural relationships between
the natural product isolated by the group of Proksch and com-
pound 6.
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Scheme 2 Reagents and conditions: (a) MeCH2COCl, Et3N, DMAP,
Et2O, 0 °C, 12 h (84%); (b) AlCl3, Δ (61%); (c) BrCH2CHvCH2,
K2CO3, EtOH, reflux (85%); (d) 1,2-Cl2–C6H4; Δ (64%); (e) Ac2O,
NaOAc, reflux; (f) Et3N, 115 °C, 14 h; (g) 1 M HCl (12% overall).
instability of the mesylate group to the reaction conditions, the
direct transformation of 17 was performed under the same con-
ditions, obtaining 50% of 7a.
Despite the slightly improved yields of 7a, the overall
sequence was deemed unsatisfactory and alternative formylation
strategies were sought. Interestingly, a simple modification of the
hydrolysis stage of the iminium intermediates, which included
the use of milder conditions (H2O, 100 °C) under an inert atmo-
sphere,14b led to increased yields of the 8-formyl derivative
(72%).
Attempts to triflate the phenolic hydroxyl of 7a with Tf2O
under assistance of organic bases (N,N-diisopropylethylamine,
2,4,6-lutidine) met with failure, and yields of 20 lower than 20%
were observed.18,19 Contrastingly, triflate 20 was cleanly
accessed in 95% yield by treatment of 7a with NaH and N-phe-
nyltriflimide in a THF–DMF solvent mixture.19
Scheme 1 Retrosynthetic analyses of aspergillitine (1).
Under the conventional procedure, which employs a mineral
acid hydrolysis final step, yields of 7a were around 20%.14a
Therefore, 7a was subjected to a Williamson allylation and the
resulting product (16), was submitted to Claisen rearrangement
affording 17 in 66% overall yield.
Finally, a three-step Kostanecki–Robinson synthesis of chro-
mones was carried out. Heating 13a with fused sodium acetate
in refluxing acetic anhydride afforded the corresponding acetate,
but did not trigger the expected Baker–Venkataraman rearrange-
ment; therefore, the latter transformation was carried out in Et3N
at 115 °C, and the product was cyclized under mild acid con-
ditions,15 furnishing 14, albeit in only 12% overall yield and
with poor mass balance.
In view of these results, the starting material was changed to
the commercially available propiophenone derivative 8b
(Scheme 3). When carried out on this ketone, the Kostanecki–
Robinson synthetic sequence afforded 56% yield of key chro-
mone intermediate 15,16 which was immediately subjected to a
Duff formylation.
Experiments towards the oxidative fission of the allyl moiety
were next carried out. Initially, and in order to avoid potential
overoxidation of the substrate, the phenol was protected as the
corresponding mesylate 18. However, treatment of 18 with cata-
lytic amounts of OsO4 and KIO4, in a t-BuOH:0.1 M phosphate
buffer, pH 8.0 (1 : 1) medium gave only 20% of aldehyde 7a,
presumably through the intermediacy of the readily enolizable
phenylacetaldehyde 19.17 Therefore, and considering the
Although there are scattered precedents suggesting that alde-
hyde 20 could withstand the conditions of the Stille cross-coup-
ling reaction,20 the palladium-catalyzed decarbonylation of
aromatic aldehydes and the Pd-catalyzed allylation of aldehydes
with allyltributyltin are well-documented transformations.21
In fact, when the transformation was attempted with n-
Bu3SnCH2CHvCH2, products resulting from 1,2-addition to the
20c
carbonyl were obtained when Pd(PPh3)2Cl2 was employed as
catalyst. On the other hand, use of Pd(PPh3)4 resulted in decar-
bonylation or complete degradation of the starting material.
Therefore, the carbonyl moiety of 20 was protected as the cor-
responding dimethyl acetal 21 in 97% yield with HC(OMe)3 and
catalytic amounts of camphorsulfonic acid in MeOH. This
allowed access to 22 in 36% yield with the use of Pd(PPh3)4 in
toluene. Nevertheless and to our great satisfaction, changing the
catalytic system to Pd(PPh3)2Cl2 in DMF settled the installation
of the 7-allyl moiety in 80% yield.22
Interestingly, it was observed that the acetal was readily hydro-
lyzed to 23 during acidic work-up and chromatography on silica
gel, and that prolonged reaction times afforded mixtures of the
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Scheme 4 Reagents and conditions: (a) 1. Pd(PPh3)2Cl2, LiCl, DMF,
Δ, 24 h; 2. H2O–THF, 80 °C, 2 h (75%, overall); (b) MeONH2·HCl,
NaOAc, EtOH, 50 °C, 12 h (85%); (c) 1,2-Cl2–C6H4, Microwaves,
180 °C, 30 min (80%).
of the protons of the methoxy group attached to the nitrogen
(δH = 4.04) upon irradiation of 12-H (δH = 8.59) in a NOE
experiment suggested that 24 was the syn methoxime.
The direct amino-Heck cyclization of the 1,3,6-azatriene
moiety under the conditions of Tsutsui and Narasaka, which
does not involve initial formation of π-allyl palladium species,
afforded 1 in a meager 18% yield.
Considering the literature precedents, where pyridine deriva-
tives were prepared from O-pentafluorobenzoyl oximes to avoid
side reactions, this outcome could be the result of the relatively
poor leaving group ability of the N-methoxy moiety of methox-
ime 24 and its reduced capability to suppress these unwanted
reactions.23
Therefore, isolated acetal 22 was subjected to isomerization
with Pd(PPh3)Cl2 in DMF (Scheme 4), affording 75% of alde-
hyde 25 after work-up and chromatography.24 Carrying out the
olefin isomerization on the acetal was relevant to the success of
the transformation, since subjecting aldehyde 23 to the same
reaction conditions resulted in its complete degradation to uni-
dentifiable products.
Scheme 3 Reagents and conditions: (a) 1. Ac2O, NaOAc, Δ; 2. Et3N,
Δ; 3. HCl (56% overall); (b) 1. Hexamine, H2O, AcOH, 100 °C, 2.5 h
(72%); c) BrCH2CHvCH2, K2CO3, EtOH, reflux, 3 h (83%); (d) 1,2-
Cl2-C6H4; Δ, 36 h (80%); (e) MsCl, pyridine, CH2Cl2, 40 °C, 48 h
(93%); (f) OsO4, KIO4, t-BuOH:0.1 M phosphate buffer, pH 8.0 (1 : 1),
r.t., overnight (18 → 7a, 20%; 17 → 7a, 50%); (g) N-phenyltriflimide,
NaH, THF-DMF, r.t., 4 h (95%); (h) HC(OMe)3, CSA, MeOH, r.t., 24 h
(97%); (i) n-Bu3SnCHCH2vCH2, Pd(PPh3)2Cl2, LiCl, PPh3, BHT,
DMF, Δ, 18 h (80%); ( j) SiO2 (100%); (k) MeONH2·HCl, NaOAc,
EtOH, 50 °C, 12 h (76%); l) Pd(PPh3)4, n-Bu4NCl, Et3N, DMF, 80 °C
(18%).
Finally, oximation of 25 to the O-methyl oxime 26 (obtained
in 85% yield as a 4 : 1 syn : anti mixture of isomers) was fol-
lowed by a microwave-assisted 6π-electrocyclization,9c which
uneventfully provided 80% yield of tricyclic compound 1.
1
Table 1 shows the H NMR chemical shifts of the synthetic
structure 1, compared to the resonances reported by Proksch
et al. for their isolated isoquinoline derivative termed aspergilli-
tine, as well as the chemical shifts of synthetic8e–g and naturally-
occurring8a alkaloid TMC-120B.
It can be clearly observed that the chemical shifts of com-
pound 1 do not match those corresponding to aspergillitine as
the natural product isolated by Proksch et al. However, the reson-
ances disclosed in ref. 2b, closely match those of synthetic and
natural TMC-120B (ΔδH ≤ 0.08), so it can be concluded that the
1H NMR spectral data reported for Proksch’s aspergillitine and
latter and E-25, resulting from conjugative terminal olefin
isomerization.
Oximation of aldehyde 23 in the presence of excess methoxyl-
amine hydrochloride and sodium acetate as base furnished 76%
of oxime 24, as a single isomer. Enhancement of the resonance
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Table 1 Comparison among the 1H NMR chemicals shifts recorded for aspergillitine as the product isolated by Proksch et al. and synthetic structure
1, as well as those for natural and synthetic TMC-120B
Compound 1a
Proton (Synthetic)
number in CDCl3
Compound 1a
(Synthetic)
in DMSO-d6
Aspergillitine
(after Proksch)2b Synthetic)c Proton (6, Natural)8a
in DMSO-d6 in DMSO-d6 number in CDCl3
Δδ (vs. 1,
TMC-120Ba
Δδ (vs. 6, TMC-120Ba
Natural)c (6, Synthetic)8e,g Synthetic)c
in CDCl3 in CDCl3 in CDCl3
Δδ (vs. 6,
6
7
11
12
14
15
16
8.34 (d, J = 8.6) 8.12 (d, J = 8.5) 7.82 (d, J = 8.6) −0.30
7.61 (d, J = 8.6) 7.76 (d, J = 8.5) 7.38 (d, J = 8.6)b −0.38
4
5
9
6
10
12
13
7.80 (d, J = 8.5) +0.02
7.35 (d, J = 8.5) +0.03
7.83 (d, J = 8.6) −0.01
7.38 (d, J = 8.6) 0.00
9.77 (bs)
7.56 (bs)
2.79 (s)
2.59 (s)
2.14 (s)
9.70 (bs)
7.79 (bs)
2.76 (s)
2.56 (s)
2.00 (s)
9.54 (s)
7.60 (s)b
2.69 (s)
2.38 (s)
2.25 (s)
−0.16
−0.19
−0.07
−0.18
+0.25
9.52 (s)
7.52 (s)
2.74 (s)
2.43 (d, J = 0.7) −0.05
+0.02
+0.08
−0.05
9.57 (s)
7.56 (s)
2.76 (s)
2.45 (s)
2.26 (s)
−0.03
+0.04
−0.07
−0.07
−0.01
2.25 (d, J = 0.7)
0.00
a Atom numbering for 1 and 6 according to ref. 2b and 8a, respectively. b Possible typographic error in the original. c Chemical shift differences
between Proksch’s data and the compound of interest in the designated solvent.
Table 2 Comparison among the 13C NMR chemicals shifts recorded for aspergillitine as the product isolated by Proksch et al. and synthetic
structure 1, as well as those for natural TMC-120B
Compound 1
(Synthetic) in
CDCl3
Compound 1
(Synthetic) in
DMSO-d6
TMC-120B
TMC-120B
Carbon
No.a
Proksch’s data2b
in DMSO-d6
Δδb in
DMSO-d6
(6, Natural)8a in (6, Synthetic)8e,g
Proksch’s data2b
in DMSO-d6
c
CDCl3
in CDCl3
Δδb
2
3
3a
4
5
5a
6
7
8
9
9a
9b
10
11
12
13
14
15
16
161.1
118.9
162.3
118.6
144.4
133.8
+17.9
−15.2
145.6
182.1
119.3
124.1
120.5
141.3
119.5
156.7
145.6
182.3
119.4
124.2
120.6
141.4
119.6
156.7
144.4
181.0
118.4
123.5
120.9
140.5
119.1
156.4
+1.2
+1.3
+1.0
+0.7
−0.3
+0.9
+0.5
+0.3
177.0
124.2
176.2
123.4
181.0
118.4
−4.8
+5.0
126.3
122.6
139.3
117.3
125.9
119.1
139.1
117.1
123.5
120.9
140.5
113.5
+2.4
+1.8
−1.4
+3.6
146.2
114.6
164.0
24.7
133.7
17.5
146.2
114.6
164.0
24.7
133.9
17.6
145.4
113.5
163.0
24.0
133.8
16.6
+0.8
+1.1
+1.0
+0.7
−0.1
+1.0
+0.7
118.9
146.5
119.0
155.7
24.4
18.5
10.2
118.4
146.5
119.1
156.1
24.5
18.6
10.3
163.0
145.4
119.1
156.4
24.0
19.7
16.6
−44.6
+1.1
0.0
−0.3
+0.5
−1.1
−6.3
20.4
20.4
19.7
a Atom numbering for 1 and 6 are according to ref. 2b and 8a. b Differences between synthetic aspergillitine (1) and synthetic TMC-120B (6) with
regards to Proksch’s data. c Proksch’s original assignments were not taken into account in order to arrange data for comparison with TMC-120B
resonances.
those of alkaloid TMC-120B are in good agreement with each
other.
Analogously, Table 2 lists the 13C NMR chemical shifts of
synthetic 1, naturally occurring TMC-120B and synthetic 6, and
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Apparatus
the resonances reported for the tricyclic chromone alkaloid iso-
lated from Aspergillus versicolor. It can be clearly observed that
the latter data correctly fit structure 6.
Melting points were measured on an Ernst Leitz Wetzlar model
350 hot-stage microscope and are reported uncorrected. IR
spectra were recorded with a Shimadzu Prestige 21 spectropho-
tometer, as thin films held between NaCl cells or as solid disper-
sions in KBr disks. The 1H NMR spectra were acquired at
300.13 MHz on a Bruker Avance spectrometer. The peak for
CHCl3 in CDCl3 (δ 7.26) was used as the internal standard.
Chemical shifts are reported in parts per million on the δ scale
and J-values are given in Hertz. The 13C NMR spectra were
recorded at 75.48 MHz on a Bruker Avance spectrometer. The
peak for CDCl3 (δ 77.0) was used as the internal standard.
DEPT 135 and DEPT 90 experiments aided the interpretation
and assignment of the fully decoupled 13C NMR spectra. In
special cases, 2D-NMR experiments (COSY, HMBC and
HSQC) were also employed. Pairs of signals marked with
asterisk (*) indicate that their assignments may be exchanged.
The high resolution mass spectra were obtained with a Bruker
MicroTOF-Q II instrument (Bruker Daltonics, Billerica, MA).
Detection of the ions was performed in electrospray ionization,
positive ion mode. Microwave-assisted reactions were performed
in a CEM Discover microwave oven.
Taken together this means that both, the compound isolated
by Proksch et al. and TMC-120B should be the same compound,
and that structure 1 remains unobserved among natural products.
Conclusions
A concise synthesis of the proposed structure of aspergillitine
was completed in 11 steps and 15% overall yield from the
known 2,4-dihydroxypropiophenone (8b). The synthesis features
1
minimum use of protective groups. The H and 13C NMR spec-
troscopic data of the synthetic aspergillitine do not match those
reported by Proktsch et al. for the natural product.
Instead, our results confirm that the spectral data disclosed for
the nitrogen heterocycle by the group of Proksch are quite
similar to those recorded for the synthetic and natural alkaloid
TMC-120B (6). Therefore, the tricyclic structure originally
assigned to aspergillitine still remains unobserved in nature.
In view of its unique structural characteristics, including its
planar polysubstituted azacycle character and the presence of an
α,β-unsaturated carbonyl system, compound 1 may display bio-
logical activity, which will be informed in due course.
1-(4-Bromo-2-hydroxyphenyl)-propan-1-one (11). A solution
of 3-bromophenol (9a, 200 mg, 0.865 mmol) and anhydrous
Et3N (2 mL) in dry CH2Cl2 (1 mL) was cooled to 0 °C and
treated dropwise with propionyl chloride (0.120 mL,
1.18 mmol). The reaction was stirred overnight at room tempera-
ture, when the mixture was diluted with brine (5 mL) and the
aqueous phase was extracted with EtOAc (4 × 20 mL). The com-
bined organic extracts were dried over Na2SO4 and concentrated
under reduced pressure affording propionate 11 (166 mg, 84%),
Experimental section
General information
All the reactions were carried out under dry nitrogen or argon
atmospheres, employing oven-dried glassware. Anhydrous THF
and Et2O were obtained from a M. Braun solvent purification
and dispenser system; anhydrous DMF was obtained by heating
the PA grade product over BaO for 4 h, followed by distillation
under reduced pressure; absolute MeOH and EtOH were
accessed by refluxing the solvents over clean Mg/I2 and distilling
from the resulting magnesium alkoxides; anhydrous Et3N was
prepared by distillation of the commercial product from CaH2;
anhydrous CH2Cl2 and 1,2-dichlorobenzene were prepared by a
4 h reflux of the solvent over P2O5 followed by atmospheric
pressure distillation; anhydrous solvents were stored in dry
Young ampoules. All other reagents were used as received.
In the conventional work-up procedure, the reaction mixture
was diluted with brine (5–10 mL) and the products were
extracted with EtOAc (4–5 × 20 mL); the combined organic
extracts were then washed once with brine (5 mL), dried over
Na2SO4 and concentrated under reduced pressure. The residue
was subjected to flash column chromatography with Merck’s
silica gel 60 H.
Elution was carried out with hexane–EtOAc mixtures, under
positive pressure and employing gradient of solvent polarity
techniques. All new compounds gave single spots on TLC plates
(silica gel 60 GF254) run in different hexane–EtOAc and EtOAc–
EtOH solvent systems.
Chromatographic spots were detected by exposure to 254 nm
UV light, followed by spraying with 1% methanolic FeCl3, Dra-
gendorff reagent (Munier and Macheboeuf modification),25 or
with ethanolic p-anisaldehyde/sulfuric acid reagent and final
careful heating of the plates for improving selectivity.
1
as an oil. H NMR (δ): 1.26 (t, J = 7.2, 3H, 3′-H), 2.58 (q, J =
7.2, 2H, 2′-H), 7.03 (ddd, J = 1.0, 2.1 and 9.0, 1H, 6-H), 7.18
(dd, J = 9.0, 1H, 5-H), 7.29 (t, J = 2.1, 1H, 2-H) and 7.36 (ddd,
J = 1.0, 2.1 and 9.0, 1H, 4-H); 13C NMR (δ): 9.0 (3′-C), 27.7
(2′-C), 120.5 (6-C), 122.3 (C-3), 125.1 (2-C), 128.9 (4-C), 130.4
(5-C), 151.3 (1-C) and 172.5 (1′-C). Without further purification,
the oily product was mixed with AlCl3 (365.6 mg, 2.74 mmol)
and the mixture was briefly heated to 80 °C and then at 160 °C
for 3 h. The reaction was cooled to room temperature, diluted
with 1 M HCl (5 mL) and the products were extracted with
EtOAc (4 × 20 mL). The organic extracts were dried over
Na2SO4, concentrated under reduced pressure and chromato-
graphed affording propiophenone 8a (135.3 mg, 51%), as a
white solid, m.p.: 48–50 °C (EtOAc, lit.: 48–49 °C).12b IR (KBr,
ν): 3450, 2993, 2943, 1640, 1413, 1199, 960, 866 and
1
780 cm−1; H NMR (δ): 1.24 (t, J = 7.2, 3H, 3′-H), 3.00 (q, J =
7.2, 2H, 2′-H), 7.03 (dd, J = 1.9 and 8.5, 1H, 5-H), 7.18 (d, J =
1.9, 1H, 3-H) and 7.61 (d, J = 8.5, 1H, 6-H).
1-(2-Allyloxy-4-bromo-phenyl)-propan-1-one (12). A mixture
of propiophenone 8a (135.5 mg, 0.591 mmol) and K2CO3
(114.4 mg, 0.827 mmol) in absolute EtOH (3 mL) was treated
dropwise with freshly distilled allyl bromide (140.1 mg,
1.16 mmol) and the reaction was heated to reflux until complete
consumption of the starting phenol (3 h). The solvent was evap-
orated under reduced pressure, the residue was dissolved in water
and the product was extracted with EtOAc (5 × 20 mL). The
This journal is © The Royal Society of Chemistry 2012
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7-Hydroxy-2,3-dimethylchromen-4-one (15). A solution of
2,4-dihydroxypropiophenone 8b (2.00 g, 12.03 mmol) in Ac2O
(50 mL, 531.2 mmol) was treated with freshly fused NaOAc
(5.40 g, 60.15 mmol) and the mixture was heated under reflux
for 3 h. Excess Ac2O was distilled off under reduced pressure,
the residue was suspended in EtOAc and the remaining NaOAc
was filtered off in vacuo (P < 10 mmHg), furnishing a mixture
of acetates. The acetates were treated with anhydrous Et3N
(2 mL) and the mixture was heated overnight at 115 °C. The
reaction was cooled to room temperature, the solvent was
removed under reduced pressure and the residue was treated with
cold 1 M HCl (100 mL). The resulting suspension was stirred
for 6 h at 40 °C and the white precipitate formed was filtered
under reduced pressure and washed with cold water. Chromato-
graphy of the product afforded 15 (1.248 g, 56%) as a yellowish
solid, m.p.: 315–318 °C (EtOH–H2O, lit.: 315–317 °C).15 IR
combined organic phases were washed with brine (10 mL), dried
(Na2SO4) and concentrated under reduced pressure. Chromato-
graphy of the residue afforded O-allylpropiophenone 12
(135.6 mg, 85%) as a white solid, m.p.: 59–60 °C (EtOAc). IR
(KBr, ν): 3080, 2979, 2935, 2871, 1666, 1584, 1403, 1367,
1240, 1196, 1092, 999, 800 and 607 cm−1; 1H NMR (δ): 1.15 (t,
J = 7.2, 3H, 3′-H), 2.98 (q, J = 7.2, 2H, 2′-H), 4.62 (dt, J = 1.4
and 5.4, 2H, 1′′-H), 5.35 (ddd, J = 1.3, 2.7 and 10.5, 1H, 3′′-
Hcis), 5.43 (ddd, J = 1.3, 2.7 and 17.3, 1H, 3′′-Htrans), 6.06 (ddd,
J = 5.4, 10.5 and 17.3, 2′′-H), 7.09 (d, J = 1.6, 1H, 3-H), 7.14
(dd, J = 1.6 and 8.3, 1H, 5-H) and 7.57 (d, J = 8.3, 1H, 6-H);
13C NMR (δ): 8.4 (3′-C), 37.1 (2′-C), 69.8 (1′′-C), 116.3 (C-3),
118.7 (3′′-C), 124.1 (5-C), 127.2 (1-C), 127.5 (4-C), 131.7 (6-
C), 132.0 (2′′-C), 157.9 (2-C) and 202.2 (1′-C); HRMS: Found
+
m/z = 290.9982; C12H13BrNaO2 [M + Na] requires m/z =
290.9991.
(KBr, ν): 2923, 1610, 1573, 1445, 1400 and 1249 cm−1 1H
;
NMR (CDCl3-DMSO-d6, δ): 1.87 (s, 3H, 3-Me), 2.32 (s, 3H,
2-Me), 6.72 (d, J = 2.0, 1H, 8-H) 6.83 (dd, J = 2.0 and 8.8, 1H,
6-H), 7.81 (d, J = 8.8, 1H, 5-H) and 10.59 (s, 1H, OH); 13C NMR
(CDCl3-DMSO-d6, δ): 10.1 (3-Me), 18.6 (2-Me), 102.2 (8-C),
115.0 (6-C), 115.3 (C-3), 115.7 (4a-C), 127.2 (5-C), 157.5 (8a-C),
161.7 (2-C), 162.5 (7-C) and 176.3 (4-C); HRMS: Found
m/z = 203.0708; C12H11O3 [M + H]+ requires m/z = 203.0708.
1-(3-Allyl-4-bromo-2-hydroxyphenyl)-propan-1-one (13a). A
solution of 12 (135.6 mg, 0.504 mmol) in anhydrous o-dichloro-
benzene (3 mL) was purged with argon and heated under reflux
while stirring during 36 h. The mixture was left to attain room
temperature, the solvent was removed under reduced pressure
(10 mmHg) and the residue was chromatographed, affording 13a
(62 mg, 46%) as a white solid, m.p.: 222–224 °C (hexane–
EtOAc). IR (KBr, ν): 3709, 2980, 2940, 1637, 1585, 1431,
7-Allyloxy-2,3-dimethyl-chromen-4-one (16). Freshly distilled
allyl bromide (0.644 mL, 7.45 mmol) was added dropwise to a
mixture of chomone 15 (1.25 g, 6.77 mmol) and K2CO3
(3.274 g, 23.7 mmol) in absolute EtOH (10 mL). The reaction
was stirred under reflux during 3 h, when the solvent was
removed. The residue was suspended with brine (10 mL) and the
reaction products were extracted with EtOAc (4 × 20 mL). The
combined organic extracts were washed with brine (5 mL), dried
Na2SO4 and concentrated under reduced pressure. Chromato-
graphy of the residue furnished O-allylchromone 16 (1.253 g,
83%) as a white solid m.p.: 70–73 °C (hexane–EtOAc). IR
(KBr, ν): 2924, 2854, 1642, 1610, 1573, 1445, 1349, 1249,
1
1375, 1261, 1150, 1045, 933, 830 and 782 cm−1; H NMR (δ):
1.23 (t, J = 7.3, 3H, 3′-H), 3.00 (q, J = 7.3, 2H, 2′-H), 3.61 (d, J
= 6.0, 2H, 1′′-H), 5.04 (dd, J = 1.4 and 10.1, 1H, 3′′-Hcis), 5.08
(dd, J = 1.4 and 17.1, 1H, 3′′-Htrans), 5.93 (ddd, J = 6.0, 10.1
and 17.1, 1H, 2′′-H), 7.10 (d, J = 8.7, 1H, 5-H), 7.49 (d, J = 8.7,
1H, 6-H) and 12.49 (s, 1H, OH); 13C NMR (δ): 8.2 (3′-C), 31.7
(1′′-C),* 33.3 (2′-C),* 115.8 (3′′-C), 117.8 (1-C), 122.9 (5-C),
128.2 (6-C), 129.3 (C-3), 132.8 (4-C), 134.0 (2′′-C), 161.1 (2-C)
and 206.8 (1′-C); HRMS: Found m/z = 269.0167; C12H14BrO2
[M + H]+ requires m/z = 269.0172.
1
1187, 1017, 826 and 772 cm−1; H NMR (δ): 2.03 (s, 3H, 2-
8-Allyl-7-bromo-2,3-dimethylchromen-4-one (14). A solution
of propiophenone 13a (67.8 mg, 0.252 mmol) in a mixture of
Ac2O (0.272 mL, 2.67 mmol) and anhydrous Et3N (0.70 mL,
5.34 mmol) was stirred under reflux during 20 h. The solvent
was removed under reduced pressure (P < 10 mmHg) and the
residue was treated with 1 M HCl (3 mL) at 40 °C for 6 h. Then,
the solution was treated with brine (5 mL) and the reaction pro-
ducts were extracted with EtOAc (5 × 15 mL). The combined
organic extracts were washed with brine (5 mL), dried (Na2SO4)
and concentrated in vacuum. The residue was chromatographed,
affording chromone 14 (6 mg, 12%) as a solid, m.p.:
113–114 °C (EtOAc). IR (KBr, ν): 2922, 1643, 1591, 1418,
1358, 1184, 1001, 901 and 779 cm−1; 1H NMR (δ): 2.05 (s, 3H,
2-Me), 2.43 (s, 3H, 3-Me), 3.78 (d, J = 3.6, 2H, 1′-C), 5.07
(ddd, J = 1.6, 3.6 and 11.5, 1H, 3′′-Hcis), 5.08 (ddd, J = 1.6, 3.6
and 15.2, 1H, 3-H′′trans), 5.93 (ddd, J = 3.8, 11.5 and 15.2, 1H,
2′′-H), 7.54 (d, J = 8.5, 1H, 5-H) and 7.94 (d, J = 8.5, 1H, 6-H);
13C NMR (δ): 10.0 (3-Me), 18.5 (2-Me), 33.7 (1′-C), 116.4 (3′-
C), 117.1 (C-3), 121.8 (4a-C), 124.9 (6-C), 128.6 (5-C), 128.9
(7-C), 129.5 (8-C), 133.5 (2′-C), 154.1 (8a-C), 161.8 (2-C) and
177.7 (4-C); HRMS: Found m/z = 293.0169; C14H14BrO2
[M + H] + requires m/z = 293.0172.
Me), 2.38 (s, 3H, 3-Me), 4.61 (d, J = 5.2, 2H, 1′-H), 5.34 (dd, J
= 1.3, and 10.5, 1H, 3′-Hcis), 5.44 (dd, J = 1.3 and 17.2, 1H, 3′-
H
trans), 6.06 (ddd, J = 5.2, 10.5 and 17,2, 1H, 2′-H), 6.77 (d, J =
2.2, 1H, 8-H), 6.94 (dd, J = 2.2 and 8.9, 1H, 6-H) and 8.09 (d, J
= 8.9, 1H, 5-H); 13C NMR (δ): 10.0 (3-Me), 18.4 (2-Me), 69.2
(1′-C), 100.6 (8-C), 114.3 (6-C), 116.6 (C-3), 116.7 (4a-C),
118.4 (3′-C), 127.3 (5-C), 132.3 (2′-C), 157.4 (8a-C), 161.2 (2-
C), 162.4 (7-C) and 177.4 (4-C); HRMS: Found m/z =
231.1023; C14H15O3 [M + H]+ requires m/z = 231.1016.
8-Allyl-7-hydroxy-2,3-dimethyl-chromen-4-one (17). Under a
nitrogen atmosphere, a solution of 16 (452 mg, 1.963 mmol) in
1,2-Cl2-C6H4 (2 mL) was heated under reflux for 36 h. The
solvent was removed under reduced pressure (P < 10 mmHg)
and the residue was chromatographed, furnishing 17 (361 mg,
80%) as a white solid, m.p.: 205–207 °C (hexane–EtOAc). IR
(KBr, ν): 3081, 2925, 2765, 1635, 1574, 1439, 1325, 1193,
1
1053 and 787 cm−1; H NMR (δ): 2.05 (s, 3H, 2-Me), 2.41 (s,
3H, 3-Me), 3.64 (d, J = 6.2, 2H, 1′-H), 5.12 (dd, J = 1.6 and
10.0, 1H, 3′-Hcis), 5.15 (dd, J = 1.6 and 17.2, 1H, 3′-Htrans),
6.00 (ddd, J = 6.2, 10.0 and 17.2, 1H, 2′-H), 6.26 (s, 1H, OH),
4130 | Org. Biomol. Chem., 2012, 10, 4124–4134
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6.90 (d, J = 8.7, 1H, 7-H) and 8.00 (d, J = 8.7, 1H, 6-H); 13C
NMR (δ): 9.9, (3-Me), 18.4, (2-Me), 27.1, (1′-C), 112.8, (5-C),
113.9 (4a-C), 114.8 (6-C), 115.6 (3′-C), 124.4 (C-3), 127.1
(8-C), 135.6 (2′-C), 155.5 (8a-C), 159.4 (2-C), 161.1 (7-C) and
178.0 (4-C); HRMS: Found m/z = 231.1023; C14H15O3
[M + H]+ requires m/z = 231.1016.
Trifluoromethanesulfonic acid 8-formyl-2,3-dimethyl-4-oxo-
4H-chromen-7-yl ester (20). Under a nitrogen atmosphere, NaH
(50% in mineral oil, 11.1 mg, 0.227 mmol) was added portion-
wise to a stirred solution of 7a (30 mg, 0.114 mmol) in a 1 : 1
THF : DMF mixture (1 mL), cooled in an ice-water bath. The
resulting suspension was stirred for 10 min, when a solution of
PhNTf2 (105.8 mg, 0.296 mmol) in THF (0.5 mL) was dropped
into the reaction via cannula and the resulting mixture was
stirred at room temperature during 4 h. Saturated NH4Cl solution
(5 mL) was added, the THF was removed under reduced
pressure and the residue was diluted with H2O (5 mL) and
extracted with EtOAc (4 × 20 mL). The combined organic
extracts were washed once with brine (10 mL), dried over
Na2SO4 and concentrated under reduced pressure. Chromato-
graphic purification of the residue provided triflate 20 (47 mg,
95%) as a yellowish solid, m.p.: 135–136 °C. IR (KBr, ν): 3072,
3047, 2930, 1705, 1640, 1597, 1431, 1319, 1216, 1140, 1058,
7-Hydroxy-2,3-dimethyl-4-oxo-4H-chromene-8-carbaldehyde
(7a). Method A: Under a nitrogen atmosphere, a mixture of 15
(28 mg, 0.147 mmol) and hexamine (103 mg, 0.735 mmol) in
glacial AcOH (2.7 mL) was treated with water (0.013 mL,
0.735 mmol) and stirred 2.5 h at 100 °C. The reaction was
allowed to cool to room temperature, when it was diluted with
cold brine (5 mL) and the products were extracted with EtOAc
(5 × 15 mL). The organic extracts were washed with brine
(5 mL), dried over Na2SO4 and concentrated under reduced
pressure. The residue was chromatographed furnishing aldehyde
7a (23 mg, 72%), as a white solid, m.p.: 180–182 °C (hexane–
EtOAc). IR (KBr, ν): 3443, 3084, 2959, 2922, 2853, 1670,
845, 811 and 759 cm−1 1H NMR (δ): 2.09 (s, 3H, 3-Me),
;
2.51 (s, 3H, 2-Me), 7.33 (d, J = 8.8, 1H, 6-H), 8.51 (d, J = 8.8,
1H, 5-H) and 10.66 (s, 1H, CHO); 13C NMR (δ): 9.9 (3-Me),
18.5 (2-Me), 117.7 (C-3) 118.6 (4a-C), 118.9 (6-C), 119.3 (q,
JC−F = 389, CF3), 122.8 (8-C), 133.6 (5-C), 150.4 (8a-C), 156.5
(7-C), 162.7 (2-C), 175.7 (4-C) and 184.3 (CHO); HRMS:
Found m/z = 351.0145; C12H11O4 [M + H]+ requires m/z =
351.0149.
1
1564, 1553, 1421, 1335, 1281, 1076 and 998 cm−1; H NMR
(δ): 2.06 (d, J = 0.5, 3H, 2-Me), 2.45 (d, J = 0.5, 3H, 3-Me),
6.95 (d, J = 8.9, 1H, 6-H), 8.32 (d, J = 8.9, 1H, 5-H), 10.54 (s,
1H, 1′-H) and 12.40 (s, 1H, OH); 13C NMR (δ): 9.9 (3-Me),
18.3 (2-Me), 108.3 (5-C), 115.2 (C-3), 115.7 (6-C), 118.1 (4a-
C), 135.3 (8-C), 157.6 (8a-C), 160.6 (7-C), 167.0 (2-C), 176.2
(4-C) and 192.3 (CHO); HRMS: Found m/z = 219.0652;
C12H11O4 [M + H]+ requires m/z = 219.0657.
Trifluoromethanesulfonic
acid
8-dimethoxymethyl-2,3-
dimethyl-4-oxo-4H-chromen-7-yl ester (21). Trimethyl ortho-
formate (0.090 mL, 0.821 mmol) and CSA (1 mg) were succes-
sively added to a solution of 20 (18 mg, 0.054 mmol) in
anhydrous MeOH (1 mL). The mixture was stirred 24 h at room
temperature when saturated KHCO3 (2 mL) was added, and the
reaction product was extracted with EtOAc (4 × 20 mL). The
combined organic extracts were dried (Na2SO4) and concentrated
under reduced pressure, leaving a residue which was purified
chromatographically to afford 21 (15 mg, 75%), as a pale
yellowish solid, m.p.: 125–127 °C (EtOAc). IR (KBr, ν): 3072,
2931, 1641, 1597, 1431, 1319, 1216, 1139, 1085, 846, 760 and
632 cm−1; 1H NMR (δ): 2.06 (s, 3H, 3-Me), 2.47 (s, 3H, 2-Me),
3.48 (s, 6H, 2 × OMe), 5.93 (s, 1H, O–CH–O), 7.26 (d, J = 8.8,
1H, 6-H) and 8.28 (d, J = 8.8, 1H, 5-H); 13C NMR (δ): 9.9 (3-
Me), 18.6 (2-Me), 55.1 (2C, 2 × OMe), 99.1 (O–CH–O), 117.7
(6-C), 118.7 (4a-C), 119.4 (q, JC−F = 387, CF3), 121.0 (C-3),
122.3 (8-C), 128.4 (5-C), 150.0 (8a-C), 153.9 (7-C), 162.5 (2-C)
and 176.6 (4-C). 19F NMR (δ): −73.9 (s, CF3SO3Ar); HRMS:
Found m/z = 397.0561; C15H16F3O7S [M + H]+ requires m/z =
397.0563.
Method B: Under an argon atmosphere, MsCl (0.014 mL,
0.174 mmol) was dropwise added to a stirred solution of 17
(20 mg, 0.087 mmol) and anhydrous pyridine (0.041 mL,
0.521 mmol) in dry CH2Cl2 (2 mL), cooled in an ice bath. The
reaction was stirred 48 h at 40 °C, when the solvent was evapor-
ated under reduced pressure. Brine (10 mL) was added and the
products were extracted with EtOAc (4 × 10 mL). The combined
organic phases were washed with brine (5 mL), dried (Na2SO4)
and concentrated under reduced pressure. Chromatography of the
residue afforded 18 (25 mg, 93%), as a light yellow oil. 1H
NMR (δ): 2.04 (s, 3H, 2-Me), 2.42 (s, 3H, 3-Me), 3.26 (s, 3H,
Me–SO3Ar), 3.69 (bd, J = 7.1, 2H, 1′-H), 5.07 (ddd, J = 1.6, 3.3
and 15.1, 1H, 3′-Htrans), 5.09 (ddd, J = 1.6, 3.3 and 11.8, 1H, 3′-
Hcis), 5.94 (ddd, J = 7.1, 11.8 and 15.1, 1H, 2′-H), 7.37 (d, J =
8.9, 1H, 6-H) and 8.12 (d, J = 8.9, 1H, 5-H). Without further
purification, KIO4 (419.3 mg, 1.82 mmol) was added with stir-
ring to a solution of 18 (25 mg, 0.081 mmol) in a 1 : 1 mixture
of t-BuOH and 0.1 M phosphate buffer, pH = 8.0 (3 mL), fol-
lowed by a 1% OsO4 solution in t-BuOH (0.166 mL,
0.0065 mmol). After stirring overnight at room temperature,
10% Na2SO3 (0.1 mL) was added, followed by brine (5 mL),
and the products were extracted with EtOAc (5 × 15 mL). The
combined organic extracts were washed with brine (5 mL), dried
over Na2SO4 and concentrated under reduced pressure. The
residue was chromatographed, furnishing 7a (3.6 mg, 20%)
which spectral data matched those of the product obtained by
Method A. When the same transformation was performed with
17 (100 mg, 0.081 mmol), improved yields of 7a (47 mg, 50%)
were obtained. Spectral data of the product were in agreement
with those recorded for the product obtained by application of
Method A.
7-Allyl-8-dimethoxymethyl-2,3-dimethyl-chromen-4-one (22).
Under an argon atmosphere, a stirred mixture of 21 (34 mg,
0.086 mmol) allyltributyltin (0.045 mL, 0.135 mmol) in anhy-
drous toluene (1.0 mL) was treated with Pd(PPh3)4 (19.8 mg,
0.011 mmol) and the reaction mixture was further stirred under
reflux for 36 h. The reaction was cooled to room temperature,
treated with brine NaCl (5 mL) and the reaction products were
extracted with EtOAc (5 × 15 mL). The combined organic
phases were washed once with brine NaCl (5 mL), dried
(Na2SO4) and concentrated under reduced pressure. Chromato-
graphy of the residue furnished 22 (9.1 mg, 36%) as a colorless
This journal is © The Royal Society of Chemistry 2012
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oil. IR (film, ν): 2957, 2872, 1633, 1427, 1215, 1143, 1049, 852
C), 154.5 (8a-C), 161.1 (2-C), and 177.7 (4-C); HRMS: Found
m/z = 272.1101; C16H17NNaO3 [M + H]+ requires m/z =
294.1090.
1
and 629 cm−1; H NMR (δ): 2.05 (s, 3H, 3-Me), 2.44 (s, 3H, 2-
Me), 3.45 (s, 6H, 2 × OMe), 3.80 (dt, J = 1.4 and 6.6, 1H, 1′-H),
5.07 (ddd, J = 1.4, 3.1 and 7.8, 1H, 3′-Hcis), 5.08 (ddd, J = 1.4,
3.1 and 18.9, 1H, 3′-Htrans), 5.94 (s, 1H, O–CH–O), 5.97 (ddd, J
= 6.6, 7.8 and 18.9, 1H, 2′-H), 7.23 (d, J = 8.3, 1H, 7-H) and
8.10 (d, J = 8.3, 1H, 6-H); 13C NMR (δ): 10.0 (3-Me), 18.6 (2-
Me), 37.4 (1′-C), 55.9 (2C, 2 × OMe), 101.2 (O–CH–O), 116.0
(3′-C), 120.5 (C-3), 124.4 (4a-C), 126.0 (5-C),* 127.5 (6-C),*
131.2 (8-C), 137.2 (2′-C), 146.0 (7-C), 153.9 (8a-C), 161.2 (2-
C) and 177.8 (4-C); HRMS: Found m/z = 289.1440; C17H21O4
[M + H]+ requires m/z = 289.1440.
(E)-2,3-Dimethyl-4-oxo-7-(1′propenyl)-4H-chromene-8-carbal-
dehyde (25). Under a nitrogen atmosphere, a solution of 22
(123 mg, 0.427 mmol) and LiCl (145 mg, 3.42 mmol) in DMF
(3 mL) was treated with Pd(PPh3)Cl2 (30 mg, 0.043 mmol) and
the mixture was heated at 130 °C during 48 h. The reaction was
diluted with EtOAc (40 mL), filtered through a short pad of
Celite and the filtrate was washed with saturated NaHCO3
(5 mL), brine (5 mL) and water (5 mL). The organic phase was
dried over Na2SO4, and concentrated under reduced pressure,
and the residue was chromatographed, furnishing 25 (70 mg,
70%), as an off-white solid, m.p. 106–107 °C (hexane–EtOAc).
IR (KBr, ν): 3419, 2956, 2848, 1653, 1398, 1096, 802, 692 and
7-Allyl-8-formyl-2,3-dimethyl-chromen-4-one (23). Under
a
nitrogen atmosphere, a solution of 21 (407 mg, 1.03 mmol),
anhydrous LiCl (348 mg, 8.13 mmol), PPh3 (134.7 mg,
0.513 mmol) and Pd(PPh3)2Cl2 (82 mg, 0.103 mmol) and BHT
(1 mg) in DMF (9 mL) was treated with allyltributyltin
(0.482 mL, 1.23 mmol) and the mixture was heated at 110 °C
during 14 h. The volatiles were removed under reduced pressure
and the residue was filtered through a short pad of Celite with
the aid of EtOAc (20 mL). A saturated solution of KF was added
(5 mL) and the product was extracted with EtOAc (4 × 20 mL).
The combined organic phases were washed once with brine
NaCl (5 mL), dried (Na2SO4) and concentrated under reduced
pressure. Chromatography of the residue gave 23 (144 mg,
60%), as an oil. IR (film, ν): 2955, 2924, 1695, 1632, 1603,
1
669 cm−1; H NMR (δ): 2.00 (dd, J = 1.7 and 15.6, 3H, 12-H),
2.08 (d, J = 0.6, 3H, 3-Me), 2.46 (d, J = 0.6, 3H, 2-Me), 6.45
(ddd, J = 6.8, 13.4 and 15.7, 1H, 11-H), 7.39 (dd, J = 1.7 and
15.6, 1H, 10-H), 7.54 (d, J = 8.5, 1H, 6-H), 8.38 (d, J = 8.5, 1H,
5-H) and 10.80 (s, 1H, 9-H); 13C NMR (δ): 9.9 (3-Me), 18.5 (2-
Me), 19.2 (12-C), 117.7 (3-C), 118.0 (11-C), 121.0 (4a-C),
123.2 (6-C), 128.0 (10-C), 130.7 (5-C), 140.9 (7-C), 144.8 (8-
C), 157.5 (8a-C), 161.5 (2-C), 178.9 (4-C) and 189.8 (9-C);
HRMS: Found m/z = 243.1010; C15H15O3 [M + H]+ requires
m/z = 240.1016.
(E)-2,3-Dimethyl-4-oxo-7-(1′-propenyl)-4H-chromene-8-carbal-
dehyde O-methyl-oxime (26). O-Methylhydroxylamine hydro-
chloride (259 mg, 3.1 mmol) and NaOAc (255 mg, 3.1 mmoL)
1
1416, 1182, 777 and 602 cm−1; H NMR (δ): 2.08 (s, 3H, 3-
Me), 2.47 (s, 3H, 2-Me), 3.88 (dt, J = 1.4 and 6.4, 2H, 9-H),
5.05 (ddd, J = 1.4, 3.3 and 16.7, 1H, 11-Htrans), 5.09 (ddd, J =
1.4, 2.8 and 10.3, 1H, 11-Hcis), 5.99 (ddd, J = 6.5, 10.2 and
16.7, 1H, 10-H), 7.30 (d, J = 8.2, 1H, 6-H), 8.33 (d, J = 8.2, 1H,
5-H) and 10.83 (s, 1H, 12-H); 13C NMR (δ): 9.9 (3-Me), 18.5
(2-Me), 37.8 (9-C), 116.9 (11-C), 117.7 (C-3), 121.3 (4a-C),
122.0 (7-C), 127.3 (6-C), 131.2 (5-C), 135.7 (10-C), 148.3 (8-
C), 157.7 (8a-C), 161.5 (2-C) 176.9 (4-C) and 189.5 (12-C);
HRMS: Found m/z = 243.1016; C15H15O3 [M + H]+ requires
m/z = 243.1021.
were successively added to
a solution of 25 (32 mg,
0.132 mmol) in absolute EtOH (3 mL) and the reaction was
stirred 14 h at 50 °C. The solvent was removed under reduced
pressure and the residue was chromatographed, affording 26
(30.6 mg, 85%) as a white solid, m.p.: 65–66 °C (hexane–
EtOAc). IR (KBr, ν): 2926, 2853, 1643, 1607, 1416, 1186,
1066, 966, 775 and 603 cm−1; Major isomer (syn)-1H NMR
(δ): 1.94 (dd, 3H, J = 1.8 and 6.7, 11-H), 2.05 (s, 3H, 3-Me),
2.42 (s, 3H, 2-Me), 4.06 (s, 3H, N-OMe), 6.38 (dd, 1H, J = 6.7
and 15.7, 10-H), 7.06 (dd, 1H, J = 1.8 and 15.7, 9-H), 7.51
(d, 1H, J = 8.5, 6-H), 8.07 (d, 1H, J = 8.5, 5-H) and 8.56 (s, 1H,
12-H); 13C NMR (δ): 10.0 (3-Me), 18.5 (2-Me),* 19.0 (11-C),*
62.3 (N-OMe), 117.2 (3-C), 122.7 (10-C), 123.1 (4a-C), 126.3
(6-C), 126.8 (8-C), 129.1 (5-C), 131.7 (9-C), 142.1 (7-C), 143.6
(12-C), 154.5 (8a-C), 161.6 (2-C) and 177.4 (4-C). HRMS:
Found m/z = 272.1281; C16H18NO3 [M + H]+ requires m/z =
272.1287.
(syn)-7-Allyl-2,3-dimethyl-4H-chromen-4-one-8-carbaldehyde
O-methyl-oxime (24). O-Methylhydroxylamine hydrochloride
(752 mg, 9.01 mmol) and NaOAc (739.5 mg, 9.01 mmol) were
successively added to a solution of 23 (93 mg, 0.384 mmol), in
absolute EtOH (3 mL) and the reaction was stirred 14 h at 50 °C.
The solvent was removed under reduced pressure, EtOAc (5 mL)
and brine (5 mL) were added and the reaction products were
extracted with EtOAc (4 × 20 mL). The combined organic
phases were washed with brine (5 mL), dried over Na2SO4 and
concentrated under reduced pressure. The residue was chromato-
graphed yielding 24 (80 mg, 77%), as an oil. IR (film, ν): 3377,
2,3,8-Trimethyl-4H-pyrano[3,2-h]isoquinolin-4-one
(1).
Method A: Under a nitrogen atmosphere, a solution of 22
(20 mg, 0.074 mmoL) and Bu4NCl (103 mg, 0.396 mmol) in
DMF (1.5 mL) was successively treated with Pd(PPh3)4 (8.6 mg,
0.0074 mmol) and Et3N (0.060 mL, 0.396 mmol) and the reac-
tion mixture was heated by 4 h at 80 °C. Then, the volatiles were
removed under reduced pressure (P < 10 mmHg), the residue
was dissolved in EtOAc (20 mL) and filtered through a short pad
of Celite. Brine (5 mL) was added to the filtrate and the product
was extracted with EtOAc (4 × 20 mL). The combined organic
phases were washed once with brine NaCl (5 mL), dried
(Na2SO4) and concentrated under reduced pressure.
1
2954, 2926, 1639, 1633, 1415, 1182, 1047 and 743 cm−1; H
NMR (δ): 2.05 (s, 3H, 3-Me), 2.42 (s, 3H, 2-Me), 3.78 (dt, J =
1.3 and 6.5, 2H, 9-H), 4.04 (s, 3H N-OMe), 5.06 (dd, J = 1.4
and 13.2, 1H, 11-Htrans), 5.09 (dd, 1H, J = 1.3 and 10.3, 11-
Hcis), 5.99 (ddd, J = 6.5, 10.3 and 13.2, 1H, 10-H), 7.28 (d, J =
8.4, 1H, 6-H), 8.12 (d, J = 8.4, 1H, 5-H), 8.59 (s, 1H, 12-H);
13C NMR (δ): 10.0 (3-Me), 18.6 (2-Me), 37.5 (9-C), 62.3
(N-OMe), 117.2 (11-C), 120.9 (C-3), 123.0 (7-C), 123.3 (4a-C),
126.3 (5-C), 129.1 (6-C), 131.7 (10-C), 142.1 (8-C), 143.7 (12-
4132 | Org. Biomol. Chem., 2012, 10, 4124–4134
This journal is © The Royal Society of Chemistry 2012

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Chromatography of the residue gave 1 (3 mg, 18%), as a solid.
The spectral data of 1 matched those obtained for the compound
accessed through Method B.
Method B: A solution of 26 (27 mg, 0,1 mmoL) in 1,2-
dichlorobenzene (2 mL) was placed in a microwave oven and
irradiated for 30 min at 180 °C. The solvent was removed under
reduced pressure and the residue was chromatographed, afford-
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(EtOAc). IR (KBr, ν): 3406, 2954, 2920, 2850, 1616, 1419,
1
1180, 1097, 1022, 923, 877, 798 and 746 cm−1; H NMR (δ):
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2.14 (s, 3H, 3-Me), 2.59 (s, 3H, 2-Me), 2.79 (s, 3H, 13-Me),
7.56 (bs, 1H, 12-H), 7.61 (d, J = 8.6, 1H, 7-H), 8.34 (d, J = 8.6,
1H, 6-H) and 9.77 (bs, 1H, 11-H); 13C NMR (δ): 10.2 (3-Me),
18.5 (2-Me), 24.4 (13-Me), 117.3 (9-C), 118.9 (10-C), 118.9 (3-
C), 119.0 (12-C), 122.6 (7-C), 124.2 (5-C), 126.3 (6-C), 139.3
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for spectral data in DMSO-d6, please see Tables 1 and 2;
HRMS: Found m/z = 243.1019; C15H14NO2 [M + H]+ requires
m/z = 240.1021.
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Acknowledgements
The authors gratefully acknowledge Secretaría de Ciencia y Tec-
nología de la UNR (SECyT-UNR), Consejo Nacional de Investi-
gaciones Científicas y Técnicas (CONICET), and Agencia
Nacional de Promoción Científica y Tecnológica (ANPCyT),
Projects BIO174, PIP No. 3294 and PICT No. 06-38165,
respectively, for financial support. S.O.S. also thanks CONICET
for his fellowship.
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