Convergent First Total Synthesis of Melovinone: A Densely Substituted 3-Methoxy-4-quinolone Isolated from Melochia tomentosa L

Article abstract of DOI:10.1055/s-0039-1690164

The first total synthesis of melovinone, a nonrutaceous 3-methoxy-4-quinolone alkaloid isolated from Melochia tomentosa L., is reported. The target was acquired in a convergent fashion through the Suzuki-Miyaura cross-coupling reaction between an ortho-nitrobenzoic acid acetonyl ester derivative prepared from vanillin and potassium 5-phenyl-1-pentyltrifluoroborate, obtained from β-phenethyl bromide. The coupling was followed by a chemoselective reduction of the nitro group and a microwave-Assisted and AcOH-promoted cyclization with rearrangement of the resulting acetonyl anthranilate. This afforded a pseudane intermediate, which was selectively methylated on the 3-OH. The synthetic pathway enabled to reach the objective in 11 steps and 18% overall yield. The ¹ H NMR spectra of the synthetic and natural product were in full agreement.

Full text of DOI:10.1055/s-0039-1690164

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–J
paper
A
en
A. A. Aguilar et al.
Paper
Synthesis
Convergent First Total Synthesis of Melovinone: A Densely Substi-
tuted 3-Methoxy-4-quinolone Isolated from Melochia tomentosa L.
Abel A. Arroyo Aguilara
Gabriela N. Ledesmaa
Bárbara Tirlonib
CHO
Br
O
O
Me
7 steps
+
O
Cl
HO
Me
O
OMe
MeO
NO2
+
O
4 steps
Teodoro S. Kaufman*a
0
0
0
0-0
0
0
3-3
1
7
3-
2
1
7
8
a-chloroacetone
vanillin
OMe
OMe
Me
Enrique L. Larghi*a
0
0
0
0-0
0
0
2-9
7
9
1-4
8
3
1
3 steps
MeO
N
H
BF3K
MeO
a Instituto de Química Rosario (IQUIR, CONICET-UNR) and
Facultad de Ciencias Bioquímicas y Farmacéuticas, Univer-
sidad Nacional de Rosario, Suipacha 531, 2000 Rosario,
Argentina
Br
melovinone
11 steps
18% overall yield
b-phenethyl bromide
potassium 5-phenyl-1-
pentyltrifluoroborate
larghi@iquir-conicet.gov.ar
kaufman@iquir-conicet.gov.ar
b Departamento de Química, Universidade Federal de Santa
Maria, 97105-900 Santa Maria, RS, Brazil
Received: 27.05.2019
Accepted after revision: 26.07.2019
Published online: 12.08.2019
5"
2"
3'
O
4"
3"
6"
O
2'
1'
4'
5
8
OMe
Me
4a
8a
OMe
3
6
1"
4
5'
DOI: 10.1055/s-0039-1690164; Art ID: ss-2019-m0298-op
2
Me
7
N
H
MeO
N
1
OMe H
2, melovinone
Abstract The first total synthesis of melovinone, a nonrutaceous 3-
methoxy-4-quinolone alkaloid isolated from Melochia tomentosa L., is
reported. The target was acquired in a convergent fashion through the
Suzuki–Miyaura cross-coupling reaction between an ortho-nitrobenzoic
acid acetonyl ester derivative prepared from vanillin and potassium 5-
phenyl-1-pentyltrifluoroborate, obtained from -phenethyl bromide.
The coupling was followed by a chemoselective reduction of the nitro
group and a microwave-assisted and AcOH-promoted cyclization with
rearrangement of the resulting acetonyl anthranilate. This afforded a
pseudane intermediate, which was selectively methylated on the 3-OH.
The synthetic pathway enabled to reach the objective in 11 steps and
18% overall yield. The 1H NMR spectra of the synthetic and natural
product were in full agreement.
1, melochinone
O
O
R1
MeO
O
O
OMe
Me
OMe
Me
OH
OH
N
H
N
H
R2
R3
4, waltherione B
3, R1 = OMe, R2 = R3 = H, waltherione A
5, R1 = R3 = OMe, R2 = H, 5'-methoxywaltherione A
6, R1 = H, R2 = R3 = OMe, helicterone A
R4
5
O
OMe
R3
H
R2
O
O
OR1
Me
N
3
R1 R2
9, R1 = H, =O, OH, OMe
N
H
Key words melovinone, total synthesis, natural products, nonruta-
ceous alkaloids, 3-methoxy-4-quinolones
R2 = H, =O, OMe
R3 = Me, CH2OH
7, R1 = Me, R2 = H, waltherione C
R4 = (CH2)7Me, (CH2)5Ph
8, R1 = β-glucosyl, R2 = OH, waltherione D
Figure 1 Chemical structures of melovinone (2) and related 4-quinolones
During the last decades, a small family of bioactive 3-
methoxy-4-quinolones has emerged; however, unlike the
structurally related rutaceous alkaloids, its members dis-
play a pendant C-5 (ar)alkyl group or a seven-membered
ring fused to C-5 and C-6, to form a cyclohepta[f]quinoli-
none core, decorated with an unsaturation or oxygen func-
tionalities.
grandidens4a–c and from the Chinese tree Helicteres angusti-
folia L., respectively.4d The waltheriones C (7) and D (8)
were isolated from M. odorata collected in Papua New
Guinea.4e The family was enlarged with the isolation of the
waltheriones E–Q and others5 from the roots of the Nigeri-
an plant Waltheria indica L., most of which share the com-
mon core 9.
Interestingly, the alkaloids 3, 5, and 7 inhibited the
growth of various nematodes.4a–c In addition, waltherione A
(3) has broad-spectrum antifungal activity,3b whereas com-
pound 7 exhibited potent and selective activity against Try-
panosoma cruzi,6a–c and cytotoxicity against P-388 murine
leukemia cells,4e,6a being also cancer chemopreventive,6d
and cytoprotective against HIV infection.4e Other waltheriones
The first examples (Figure 1) were melochinone (1),1a
and its plausible biogenetic precursor melovinone (2), iso-
lated from the Colombian shrub Melochia tomentosa L.
(Sterculiaceae).1b Recently, the related waltheriones A (3)2a
and B (4)2b were isolated from the root bark of Waltheria
douradinha St.-Hil. Waltherione A was also isolated from M.
chamaedrys A. St.-Hil, which grows in southern Brazil,3a and
from M. odorata L. f., harvested in New Caledonia.3b
In addition, 5′-methoxywaltherione A (5) and helict-
erone A (6) were obtained from the woody herb Triumfetta
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
A. A. Aguilar et al.
Paper
Synthesis
also behaved as potent antifungal and cytotoxic agents.5b
The bioactivities of the extracts of W. indica L. have been re-
cently reviewed.7
a successful scaffold to install the aralkyl side chain, where-
as the acetonyl ester could be easily accessible from the
formyl group and an activated acetone equivalent 14.
Further, it was inferred that the amine feature of the key
anthranilate could result from a nitro group, through func-
tional group interconversion. Therefore, the 2-nitrobenzal-
dehyde derivative 15 was assumed as a convenient forerun-
ner of 11. This approach offered the possibility to perform a
convergent synthesis of the natural product by joining 10
and 11, as well as a stepwise alternative, which should en-
tail coupling 11 to 13 and then react their coupling product
with a species like 12.
Additional simplifications were performed on 15, by
disconnecting both substituents ortho to the formyl moiety,
under the premise that the directing effects of the different
functional groups will enable the selective functionaliza-
tion of the aromatic ring. These thoughts uncovered the
economical and easily available vanillin (16) as a logical
starting point.
With the above strategy in mind, the synthesis of 2 be-
gan with the acetylation of vanillin (required to avoid or-
tho-phenol bromination)12 under conventional conditions
(Ac2O, DMAP), to give 17 in 93% yield (Scheme 2). Without
purification, this material was subjected to bromination
with Br2 and KBr in MeCN/H2O,13 providing the bromoarene
18 in almost quantitative yield. Next, basic hydrolysis of the
acetate 18 furnished the intermediate 19 (85% yield), which
was submitted to a Williamson O-methylation with MeI in
MeCN, employing Cs2CO3 as base, to afford the veratralde-
hyde derivative 20 in 72% overall yield from 18.
Constrastingly, few synthetic efforts to access these
compounds have been recorded to date. These include a
study toward 7,8a the elaboration of the oxabicyclic core of 7
and 8,8b and the total synthesis of waltherione F.8c,d
We are interested in the synthesis of heterocyclic natu-
ral products9 and the development of analogues, to assess
their structure and bioactivity profile.10 In pursuit of these
interests, herein we disclose the first total synthesis of
melovinone (2), based on the retrosynthetic analysis de-
picted in Scheme 1.
cross-coupling
Me
selective O-methylation
O
4
O
3
2
A
B
MeO
N
Me
MeO
H
Niementowski
quinoline synthesis
2
O
Me
esterification
alkylation
Y
O
X
+
O
H
MeO
N
10
MeO
PG
functional groups
interconversion
11
X
O
Y
Me
Y
+
14
12
13
selective halogenation
CHO
Y
CHO
Br
Br
HO
MeO
NO2
X = activating groups
Y = halogen
CHO
CHO
CHO
OMe
MeO selective nitration
c
b
PG = protecting group
15
16
RO
a
AcO
HO
OMe
16, R = H
17, R = Ac
OMe
18
OMe
19
Scheme 1 Retrosynthetic analysis of melovinone (2)
f
d
The initial disconnections of melovinone were carried
out at the C-3 methyl ether, the aralkyl side chain and be-
tween the C-3–C-4 and N–C-2 bonds of the B-ring. These
scissions were performed considering that a Niementowski
reaction11 could be a viable means toward the 3-hydroxy-
quinolone core, which could be further O-methylated at a
later stage. On the other hand, the side chain was strategi-
cally dissected, having in mind a cross-coupling reaction
between a properly substituted -phenylpentyl derivative
10 and an activated benzenoid. These speculations revealed
the anthranilate acetonyl ester 11 as a suitable precursor.
In turn, 10 was disconnected into the -phenethyl de-
rivative 12 and the allyl component 13, under the conjec-
ture that the -phenylpentyl moiety could result from the
alkylation of an activated form of -phenethyl halide 12
and a three-carbon atoms species like 13. An additional dis-
connection was also performed on the ester moiety of 11,
unveiling an ortho-halobenzaldehyde derivative as its prop-
er precursor, on the assumption that the haloarene could be
Br
Br
Br
CHO
CHO
NO2
CHO
g
HO
NO2
OMe
23
AcO
MeO
OMe
22
OMe
20
e
X
h
Me
O
Br
Br
O
Br
CHO
NO2
CO2H
NO2
O
j
i
MeO
MeO
NO2
MeO
OMe
21
OMe
25
OMe
24
Scheme 2 Reagents and conditions: a) Ac2O, DMAP, 40 °C, 2 h (93%); b)
Br2, KBr, MeCN/H2O (1:1 v/v), rt 12 h (95%); c) aq 3 M NaOH, rt (85%);
d) MeI, Cs2CO3, MeCN, reflux, 5 h (85%); e) HNO3 (d = 1.52 g·cm–3), 0–
6 °C, 10 min (polynitrated products); f) HNO3 (d = 1.52 g·cm–3), 0–6 °C,
10 min (99%); g) aq 0.5 M KOH, 1,4-dioxane, 40 °C, 1 h (81% from 18);
h) MeI, K2CO3, DMF, 50 °C 5 h (91%); i) CrO3, H2SO4, acetone, 0 °C → rt,
1 h (99%); j) 1. K2CO3, DMF, 40 °C, 1 h; 2. ClCH2C(O)Me, DMF, 20–50 °C,
1 h (99%).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

C
A. A. Aguilar et al.
Paper
Synthesis
The subsequent step involved installation of the nitro
moiety; however, when nitration of 20 was carried out with
red fuming nitric acid, only polynitrated materials were ob-
served and 21 could not be detected. Other nitration condi-
tions such as mixtures of HNO3 with H2SO4, AcOH and Ac2O
were also tested, but all of them met with failure.
Conjecturing that the acetate 18 should be a less reac-
tive substrate than the related methyl ether 20,14a,b the ni-
tration of the former with fuming HNO3 was explored, ob-
serving the exclusive formation of the desired nitro deriva-
tive 22 in 99% yield. Then, the acetate was hydrolyzed with
KOH in 1,4-dioxane and the resulting phenol 23 was meth-
ylated, providing the benzaldehyde 21 in 81% overall yield
from 18.14c,d
Next, the benzaldehyde 21 was conveniently oxidized
with Jones’ reagent to the related benzoic acid 24 in 99%
yield. The proper aromatic substitution pattern of 24 was
assessed by NMR spectroscopy and the molecular structure
was also confirmed by single crystal X-ray diffraction (Fig-
ure 2).15
b
R
28
26, R = Br
27, R= MgBr
a
c
d
BF3K
B(OH)2
30
29
Scheme 3 Reagents and conditions: a) Mg0, I2, Et2O, rt; b)
BrCH2CH=CH2, Et2O, 15 °C, 1 h (95% from 26); c) 1. 1.4 M BH3·SMe2 in
toluene, CCl4, 0 °C, 30 min. Then rt, 3 h; 2. aq 2 M HCl, H2O, rt (83%); d)
sat. aq KHF2, MeOH, rt, 3 h (22%).
Then, the terminal alkene was submitted to a hydrobo-
ration with excess BH3·SMe2 in CCl4,18a to afford 83% yield of
the alkylboronic acid intermediate 29 after acid hydroly-
sis.18b Final treatment of the latter with KHF2 in MeOH, gave
the required potassium 5-phenyl-1-pentyltrifluoroborate
(30).19 The Suzuki–Miyaura reaction of 30 with the bro-
moarene 25 was executed in the presence of the hindered
phosphine ligand di-tert-butyl phosphinoferrocene (dtbpf)
to minimize competitive -hydride elimination.20 The
transformation proceeded smoothly to afford the cross-
coupled product 31 in 93% yield (Scheme 4), accompanied
by 5% of the debrominated compound 32.
O
O
Me
O
O
Me
R
Br
a
b
O
O
MeO
NO2
MeO
NO2
OMe
OMe
25
31, R = -(CH2)5Ph
32, R = H
O
Me
O
N
O
OR
Me
c
O
MeO
MeO
NH2
OMe H
Figure 2 Molecular structure of 24. The displacement ellipsoids were
drawn at the 50% probability level and hydrogen atoms were omitted
for the sake of clarity, excepting the OH group.
OMe
34, R = H
33
d
2, R = Me, melovinone
Scheme 4 Reagents and conditions: a) Ph(CH2)5BF3K (30), Pd(AcO)2,
dtbpf, K2CO3, toluene/H2O (10:1), 80 °C 18 h (31, 93%; 32, 5%); b) Ni2B,
H2 (1 atm), 1 M HCl, MeOH, 70 °C, 30 min (81%); c) glacial AcOH, MW
(150 °C, 60 W), 25 min; d) MeI, i-PrOH, K2CO3, 50 °C, 3.5 h (40%, from
33).
Without additional purification, the acid 24 was treated
with chloroacetone and K2CO3 in DMF, to give the acetonyl
ester 25 in 99% yield, setting the stage for the installation of
the C-5 side chain. A Suzuki–Miyaura strategy was chosen
to fulfil the task, because this is a leading methodology
which tolerates a broad range of functional groups and is
increasingly used to create new Csp3–Csp2 bonds.16
Among different alternatives, the synthesis of the triflu-
oroborate salt 30 as the boron component was next under-
taken, through the intermediacy of 5-phenyl-1-pentene
(28). Therefore, -phenethyl bromide (26) was exposed to
Mg0 in Et2O to give the Grignard reagent 27, and this was
made to react with allyl bromide to afford 28 in 95% yield
(Scheme 3).17
Construction of the heterocyclic B-ring was subsequent-
ly undertaken. Hence, the reduction of the nitro group of 31
was pursued, with freshly prepared nickel boride in MeOH,
gently affording the acetonyl anthranilate 33 in 81% isolated
yield.21
Then, the latter was submitted to an intramolecular
Niementowski cyclization/rearrangement protocol,22 in-
volving the microwave irradiation (150 °C, 60 W) of a dilute
solution of the ester in glacial AcOH.
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D
A. A. Aguilar et al.
Paper
Synthesis
Formation of the sought pseudane key intermediate 34
took place smoothly, as first evidenced during TLC monitor-
ing of the reaction, where the heterocycle exhibited a char-
acteristic fluorescence when irradiated with long wave-
length (365 nm) UV-light and a blue colored spot, when the
plate was sprayed with a FeCl3 solution.
Various alternative mechanisms have been suggested
for the classical Niementowski quinoline synthesis, all of
which involve N–C-2 and C-3–C-4 bond formation in differ-
ent order.23
Although the actual sequence of transformations lead-
ing to 34 remains unknown, a mechanistic picture can be
proposed on the basis of analogous processes22b,c (Scheme
5). The reaction could be initiated by protonation of the ke-
tone moiety of 33 and intramolecular nucleophilic attack
by the amino group on the protonated carbonyl i to afford a
1,4 oxazepin-5(1H)-one derivative ii after dehydrative cy-
clization.
ylpentyl side chain to the polysubstituted aromatic core 39
was obtained after developing and testing alternative strat-
egies based on other proven cross-coupling schemes, such
as the Sonogashira and Stille reactions.
In the first case, the model 35 was prepared by joining
25 with 1-octyne; however, the reaction product demon-
strated to be too unstable for further manipulation and had
to be abandoned (Scheme 6). On the other hand, in the
Stille-based strategy, it was expected to convert 25 into the
allylbenzene derivative 36, which after olefin cross-metath-
esis with 4-phenyl-1-butene (38) should provide the prop-
er intermediate 39. Therefore, as planned the bromoarene
25 was submitted to Stille cross-coupling conditions with
allyltributyltin in toluene under Pd(Ph3P)4 catalysis, afford-
ing the allylbenzenoid 36 in 92% yield.
O
O
Me
O
O
Me
O
Me
O
Br
Me
b
O
O
O
R
R
O
O
MeO
NO2
MeO
NO2
MeO
NO2
+H+
O
O
+
OMe
OMe
OMe
O
OH
25
36
37
MeO
NH2
MeO
NH2
..
-H2O
H+
MeO
MeO
Me
Me
a
33
i
Ph
c, d
38
H
O
Me
O
O
R
R
O
O
Me
H+
O
O
( )n
O
Me
..
MeO
MeO
N
N
O
O
Me
Me
MeO
MeO
H
iii
ii
MeO
NO2
MeO
NO2
OMe
R
R
O
OMe
35
O
H
OH
Me
OH
Me
39, n = 1
40, n = 0
MeO
N
H+
MeO
N
H
Scheme 6 Reagents and conditions: a) n-C6H13C≡CH, [Pd(PhP3)4], CuI,
DMF, 70 °C, 15 h (78%); b) CH2=CHCH2SnBu3, Pd(Ph3P)4, LiCl, toluene,
80 °C, 18 h (92%); c) 36, Grubbs II, toluene, 40 °C, 6 h (53%); d) 36,
Hoveyda–Grubbs II, 1,4-benzoquinone, CH2Cl2, reflux, 2.5 h (95%).
MeO
MeO
34
R = Ph(CH2)5
iv
Scheme 5 Proposed mechanism for the Niementowski type cycliza-
tion/rearrangement of 33 toward 34
Sadly enough, however, compound 36 proved to be too
labile, easily suffering partial isomerization to the related -
methylstyrenes 37. It was further observed that the reac-
tion was promoted by the acidity of the silica gel during the
chromatographic purification step, as well as by the residu-
al acidity of the CDCl3, as assessed when running long NMR
experiments in this solvent. These undesired by-products
were also detected when the Stille reaction was allowed to
proceed during extended periods of time, and its facile for-
mation was attributed to the presence of the electron-
withdrawing groups in 36.26
Subsequent formation of the oxa-azabicyclo[4.1.0] hep-
tadiene-type intermediate iii by intramolecular attack of
the enamine motif to the ester carbonyl under the assis-
tance of the free electronic pair of the nitrogen, could be
followed by rearrangement with concomitant oxirane ring
opening to the -hydroxyketonic intermediate iv, which in
turn could undergo a 1,3-proton shift to afford 34.
The chromatographic purification of 34 proved trouble-
some.24 Therefore, the crude material was carried forward
to the final methylation step (Scheme 4). Based on our ex-
perience on the selective alkylation of quinolones,8c,25 34
was treated with MeI and K2CO3 in anhydrous i-PrOH, and
the system was refluxed in a closed vessel for 3.5 hours, to
In an attempt to solve this drawback, the crude com-
pound 36 was carried to the next stage, the cross-metathe-
sis reaction with 4-phenyl-1-butene (38).27 However, TLC
monitoring of the reaction revealed a complex series of
spots, corresponding to compounds, which could not be
separated chromatographically. The mixture was examined
1
give 40% of melovinone (2). Delightfully its H NMR spec-
trum was in full agreement with that of the natural prod-
uct.1b
1
Additional confirmation of the suitability of the Suzuki–
Miyaura approach for the key step of joining of the -phen-
by H and 13C NMR spectroscopy, concluding that its com-
ponents included the desired product 39, and the
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

E
A. A. Aguilar et al.
Paper
Synthesis
corresponding lower homologue 40 (53% combined yield).
Furthermore, both compounds (39:40 = 1.8:1) were pres-
ent as mixtures of their geometric isomers, complicating
the analysis and their separation. Presumably, compound
40 arose from the cross-coupling reaction between 38 and
the -methylstyrenes 37.
Several experiments were carried out with the aim to
suppress this undesired reaction. These included changing
the catalyst (from Grubbs II to Hoveyda–Grubbs II)28a and
solvent (from toluene to CH2Cl2), as well as adding 1,4-ben-
zoquinone to inhibit the isomerization reaction.28b,c In addi-
tion, a ‘two-steps one-pot’ Stille–Grubbs protocol was also
explored.29 However, no significant improvements were ob-
served.
In conclusion, the first total synthesis of the nonruta-
ceous alkaloid melovinone was accomplished on 11 steps
and 18% overall yield from commercially available vanillin,
-chloroacetone and -phenethyl bromide, by means of a
convergent strategy, with minimum use of protecting
groups.
The sequence toward the natural product entailed the
preparation of the key 2-nitro-3,4-dimethoxy-6-bromo-
benzoic acid acetonyl ester, and its subsequent cross-cou-
pling under Suzuki–Miyaura conditions, with potassium 5-
phenylpentyl trifluoroborate and palladium catalysis, with
dtbpf as ligand.
employing gradient of solvent polarity techniques. All new com-
pounds gave single spots on TLC plates run in different hexane/EtOAc
and EtOAc/EtOH solvent systems.
The chromatographic spots were detected by exposure to 254 and
365 nm UV light, followed by spraying with Dragendorff reagent (Mu-
nier and Macheboeuf modification),31 with FeCl3 2.5% in H2O (to de-
tect pseudane like molecules) or with ethanolic p-anisaldehyde/H2SO4
reagent and final careful heating of the plates for improving selectivi-
ty.
The melting points were measured on an Ernst Leitz Wetzlar model
350 hot-stage microscope and are uncorrected. The FT-IR spectra
were acquired on a Shimadzu Prestige 21 spectrophotometer, with
the samples prepared as solid dispersions in KBr disks or as thin films
held between NaCl cells. The NMR spectra were acquired at 300.13
MHz (1H), 75.48 MHz (13C) MHz, 96.29 MHz (11B) and 282.38 MHz
(
19F) on a Bruker Avance 300 spectrometer in CDCl3 as solvent, unless
stated otherwise. The residual resonance of CHCl3 in CDCl3 (ref
1H = 7.26), BF3·OEt2 (ref 11B = 0.00) as well as the signals of CDCl3 (ref
13C = 77.16) and CFCl3 for (ref 19F = 0.00) were used as the corre-
sponding standards. Chemical shifts are reported in parts per million
in the  scale and J-values are given in hertz (Hz). In special cases,
NOE and 2D-NMR experiments (COSY, HMBC and HMQC) were also
employed. Pairs of signals marked with an asterisk or hash signs (* or
#) indicate that their assignments may be exchanged. Samples for
NMR spectra were dissolved in CDCl3 unless otherwise stated. The
high-resolution mass spectra were obtained with a Bruker microTOF-
Q IIT instrument (Bruker Daltonics, Billerica, MA) employing sodium
formate as reference. Detection of the ions was performed in electro-
spray ionization, positive ion mode unless otherwise stated.
Building of the heterocyclic ring was accomplished by
the chemoselective nitro group reduction with Ni2B, a mi-
crowave-promoted cyclization of the so formed acetonyl
anthranilate and final methylation of the 3-OH moiety of
the resulting pseudane.
The convergent approach to access melovinone employ-
ing a Suzuki–Miyaura cross-coupling proved to be a highly
suitable alternative toward the total synthesis of the natu-
ral product. It paves the route toward acquisition of more
complex targets and may find application in the synthesis
of other members of this family of heterocycles, such as the
polycyclic waltheriones.
For single-crystal structure determination the data were collected
with a Bruker D8 Venture diffractometer. The equipment was operat-
ed using
a graphite monochromator with Mo-K radiation
( = 0.71073 Ǻ). The structure was solved by direct methods using
SHELXS and refined with SHELXL on F2 using anisotropic temperature
parameters for all non-hydrogen atoms.32 The positions of the hydro-
gen atoms were calculated starting from the idealized positions. Mi-
crowave-assisted reactions were performed in a CEM Discover micro-
wave oven.
4-Acetoxy-3-methoxybenzaldehyde (Acetylvanillin, 17)
A solution of vanillin (16; 4.0 g, 26.29 mmol) and DMAP (22 mg, 0.180
mmol) in Ac2O (5 mL) was heated at 40 °C during 2 h with vigorous
stirring. After verifying complete consumption of the starting materi-
al, the mixture was poured over crushed ice (30 g). The resulting
white precipitate was recovered by filtration and washed with H2O (3
× 100 mL). This solid material was dissolved in EtOAc (50 mL), the or-
ganic solution was successively washed with H2O (2 × 50 mL) and
brine (2 × 50 mL), dried (MgSO4) and concentrated to afford 17 as a
white solid; yield: 4.8 g (93%).
1H NMR (300 MHz, CDCl3):  = 9.94 (s, 1 H, CHO), 7.51 (d, J = 1.8 Hz, 1
H, H-2), 7.49 (dd, J = 7.8, 1.8 Hz, 1 H, H-6), 7.21 (d, J = 7.8 Hz, 1 H, H-5),
3.89 (s, 3 H, 3-OCH3), 2.34 (s, 3 H, 2′-CH3).
13C NMR (75 MHz, CDCl3):  = 191.2 (CHO), 168.5 (1′-CO2), 152.1 (C-
3), 145.1 (C-4), 135.4 (C-1), 124.9 (C-5), 123.5 (C-6), 111.0 (C-2), 56.2
(3-OCH3), 20.8 (2′-CH3).
All the reactions were carried out under dry N2 or argon atmospheres,
employing oven-dried glassware. Anhyd THF was obtained from a M.
Braun solvent purification and dispenser system; anhyd DMF was ob-
tained by heating the PA grade product over BaO for 4 h, followed by
distillation under reduced pressure; anhyd toluene, THF, and Et2O
were distilled from blue Na0/benzophenone ketyl; anhyd Et3N was
prepared by distillation of the commercial product from CaH2; anhyd
MeOH and 2-propanol were prepared by distillation after refluxing
the solvent for 24 h over I2-activated Mg0 turnings; anhydrous sol-
vents were stored in dry Young ampoules.30 EtOH refers to the 96°
product. All other solvents and reagents were used as received.
These data were in accordance with the literature values.33
Flash chromatographies were carried with silica gel 60 H (particle
size <55 m). Elution of the compounds was carried out with
hexanes/EtOAc or EtOAc/EtOH mixtures, under positive pressure and
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A. A. Aguilar et al.
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Synthesis
4-Acetoxy-6-bromo-3-methoxybenzaldehyde (18)
heated at 40 °C during 1 h. Once saponification was completed, the
mixture was driven to pH ~1 by addition of aq 6 M HCl (50 mL) and
the aqueous phase was extracted with Et2O (3 × 150 mL), the com-
bined organic phases were washed with brine (30 mL), and dried
(MgSO4). Removal of the solvent afforded the free phenol 23 as a pale
brown solid; yield: 2.40 g (81%). The 1H NMR spectrum was in agree-
ment with that of the solid obtained by application of Method A.
Br2 (9.52 g, 59.9 mmol) was cautiously dropped into a solution of 17
(3.90 g, 19.9 mmol) and KBr (8.03 g, 67.5 mmol) in MeCN/H2O (1:1,
v/v, 150 mL). The system was firmly closed and stirred for 20 h at rt,
when complete consumption of the starting material was assessed.
Then, the mixture was poured onto crushed ice (100 g), the solids
were filtered, washed with H2O, and further dissolved in EtOAc (300
mL). The organic solution was washed with H2O (250 mL) and brine (2
× 100 mL), and dried (MgSO4). The volatiles were removed in vacuo to
afford 18 as an orange solid; yield: 5.13 g (95%).
1H NMR (300 MHz, CDCl3):  = 10.27 (s, 1 H, CHO), 7.51 (s, 1 H, H-2),
7.36 (s, 1 H, H-5), 3.89 (s, 3 H, 3-OCH3), 2.33 (s, 3 H, 2′- CH3).
13C NMR (75 MHz, CDCl3):  = 191.0 (CHO), 168.1 (1′-CO2), 151.4 (C-
3), 145.1 (C-4), 131.7 (C-1), 128.1 (C-5), 118.0 (C-6), 112.3 (C-2), 56.4
(3-OCH3), 20.7 (2′-CH3).
6-Bromo-3,4-dimethoxy-2-nitrobenzaldehyde (21)
The phenol 23 (2.2 g, 8.03 mmol) was dissolved in anhyd DMF (25
mL) and the solution was sequentially treated with K2CO3 (2.2 g, 16.1
mmol) and MeI (2.5 mL, 40.0 mmol). The resulting slurry was heated
at 50 °C for 5 h under N2 atmosphere. Once complete consumption of
the starting material was assessed, the solids were filtered off, and
the remaining DMF solution was diluted with H2O (100 mL). The
products were extracted with Et2O (3 × 50 mL), the combined organic
phases were washed with aq 3 M NaOH (2 × 25 mL), H2O (3 × 30 mL)
and brine (30 mL), and dried (MgSO4). After filtration and concentra-
tion under reduced pressure, the veratraldehyde derivative 21 was
obtained as a yellow oil; yield: 2.12 g (91%).
1H NMR (300 MHz, CDCl3):  = 10.12 (s, 1 H, CHO), 7.23 (s, 3 H, H-5),
4.02 (s, 3 H, 4-OCH3), 3.91 (s, 3 H, 3-OCH3).
13C NMR (75 MHz, CDCl3):  = 187.5 (CHO), 158.6 (C-4), 145.1 (C-2),
141.1 (C-3), 123.1 (C-1),* 118.0 (C-5), 117.6 (C-6),* 62.3 (3-OCH3),
57.1 (4-OCH3).
These data were in accordance with the literature values.33
4-Acetoxy-6-bromo-3-methoxy-2-nitrobenzaldehyde (22)
The solid acetate 18 (524 mg, 1.92 mmol) was gradually added in
small portions over a period of 10 min and under vigorous stirring to
concd red fuming HNO3 (d = 1.52 g·cm–3, 1.9 mL) kept at 0–6 °C. Once
the addition was finished and the dissolution of the solid was visually
complete, the mixture was poured onto crushed ice (50 g). When the
ice melted, the products were extracted with Et2O (3 × 20 mL), and
the combined organic phases were washed with brine (30 mL) and
dried (MgSO4). After removal of the volatiles under reduced pressure,
the nitro derivative 22 was obtained as a bright yellow amorphous
solid; yield: 613 mg (99%).
The 1H NMR data were in accordance with the literature.14c
6-Bromo-3,4-dimethoxy-2-nitrobenzoic Acid (24)
1H NMR (300 MHz, CDCl3):  = 10.19 (s, 1 H, CHO), 7.63 (s, 1 H, H-5),
3.91 (s, 3 H, 3-OCH3), 2.39 (s, 3 H, 2′-CH3).
13C NMR (75 MHz, CDCl3):  = 187.4 (CHO), 167.2 (1′-CO2), 148.9 (C-
4), 145.1 (C-2), 144.2 (C-3), 130.6 (C-5), 123.0 (C-1), 120.6 (C-6), 63.2
(3-OCH3), 20.9 (2′- CH3).
A solution of the veratraldehyde derivative 23 (1.93 g, 6.80 mmol) in
acetone (50 mL) was cooled to 0 °C (ice bath) and Jones reagent (2.0
mL) was slowly added dropwise. The system was warmed to rt and
stirred for 1 h until the starting aldehyde was fully consumed. Then,
2-propanol was added in order to quench the excess of reagent, the
solvent was cautiously removed under vacuum, the remaining sus-
pension was treated with sat. aq Na2CO3 (5 mL) and extracted with
Et2O (3 × 50 mL). The organic phase was washed with brine (2 × 50
mL), dried (MgSO4) and the volatiles evaporated to give the benzoic
acid derivative 24 as a yellowish solid; yield: 2.0 g (99%); mp 197–
195 °C (from CHCl3/MeOH 9:1, v/v) (Lit.14d mp 199–198 °C (dil EtOH).
1H NMR (300 MHz, acetone-d6):  = 7.56 (s, 1 H, H-5), 4.07 (s, 3 H, 4-
OCH3), 3.94 (s, 3 H, 3-OCH3).
13C NMR (75 MHz, acetone-d6):  = 164.3 (CO2H), 155.8 (C-4), 146.3
(C-2), 141.5 (C-3), 121.6 (C-1), 120.3 (C-5), 115.5 (C-6), 63.2 (3-OCH3),
57.9 (4-OCH3).
These data were in accordance with the literature values.34
6-Bromo-4-hydroxy-3-methoxy-2-nitrobenzaldehyde (23)
Method A: The acetate 22 (600 mg, 1.88 mmol) was suspended in aq 3
M NaOH (10 mL). The system was heated at 40 °C for 1 h with vigor-
ous stirring under a N2 atmosphere. Once complete hydrolysis was
confirmed by TLC, the aqueous solution was washed with Et2O (2 ×
5.0 mL), then made acidic with aq 6 M HCl (ca. 5 mL), and the prod-
ucts were extracted with Et2O (3 × 50 mL). The combined organic
phases were washed with brine (25 mL), dried (MgSO4), and concen-
trated under vacuum. The desired phenol 23 was obtained as a pale
brownish solid; yield: 448 mg (86%).
Single crystals suitable for X-ray analysis were obtained after slow
solvent evaporation from a CHCl3/MeOH (9:1, v/v) solution.15
1H NMR (300 MHz, acetone-d6):  = 10.09 (s, 1 H, CHO), 7.46 (s, 1 H,
H-5), 3.94 (s, 3 H, 3-OCH3).
13C NMR (75 MHz, acetone-d6):  = 188.1 (CHO), 158.3 (C-4), 146.3 (C-
2′-Oxopropyl 6-Bromo-3,4-dimethoxy-2-nitrobenzoate (25)
The benzoic acid 24 (500 mg, 1.63 mmol) was dissolved in anhyd
DMF (5.0 mL) and treated with anhyd K2CO3 (293 mg, 2.12 mmol).
The system was heated at 40 °C for 1 h under argon, and treated with
freshly distilled -chloroacetone (328 L, 4.08 mmol) at 20 °C, over a
30 min period. The slurry was heated at 50 °C during additional 30
min, when it was poured onto crushed ice (10 g) and left during 10
min. The products were extracted with EtOAc (3 × 25 mL), the com-
bined organic phases were washed with brine (20 mL), dried (MgSO4)
and concentrated to dryness. The brownish oil obtained was chroma-
tographed to afford the acetonyl ester 25 as a brownish solid; yield:
585 mg (99%); mp 71–73 °C (from hexanes/EtOAc 1:1, v/v).
2), 140.7 (C-3), 123.2 (C-5), 123.1 (C-6), 117.7 (C-1), 62.6 (3-OCH3).
The spectroscopic data were in agreement with the literature.34
Method B: The bromoacetate 18 (2.98 g, 10.95 mmol) was portion-
wise added to concd red fuming HNO3 (d = 1.52 g·cm–3, 1.9 mL) at 0–
6 °C during a period of 10 min under vigorous stirring. Once the addi-
tion was finished and dissolution of the solid was complete, the
bright yellow solution was poured onto crushed ice (100 g). The prod-
uct was extracted with Et2O (3 × 250 mL), washed with brine (30 mL),
and dried (MgSO4). After removal of the volatiles, the thus obtained
solid nitro derivative was treated with aq 0.5 M KOH (150 mL) and
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A. A. Aguilar et al.
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Synthesis
IR (KBr): 2922, 2854, 1751, 1724, 1616, 1548, 1420, 1375, 1281, 1148,
1043, 718 cm–1
1H NMR (300 MHz, CDCl3):  = 7.26 (s, 1 H, H-5), 4.78 (s, 2 H, H-1′),
3.97 (s, 3 H, 4-OCH3), 3.95 (s, 3 H, 3-OCH3), 2.23 (s, 3 H, 3′-CH3).
13C NMR (75 MHz, CDCl3):  = 201.0 (C-2′), 162.4 (ArCO2CH2), 156.0
(C-4), 145.9 (C-2), 141.7 (C-3), 119.4 (C-1), 119.1 (C-5), 116.3 (C-6),
69.9 (C-1′), 62.5 (3-OCH3), 57.3 (4-OCH3), 26.6 (3′- CH3).
13C NMR (75 MHz, acetone-d6):  = 144.1 (Cipso), 129.1 (2 C, Cortho),
128.9 (2 C, Cmeta), 126.2 (Cpara), 36.8 (C-5), 34.1 (C-4), 32.9 (C-3), 26.2
(C-2). Note: the C-1 peak could not be observed in the 13C NMR spec-
trum.
19F NMR (282 MHz, acetone-d6):  = –141.1.
11B NMR (96 MHz, acetone-d6):  = 5.7.
HRMS (ESI, negative mode): m/z [M]– calcd for C12H18BO2: 205.1400,
found: 205.1390. The mass corresponds to the O-monomethylboro-
nate anion, resulting from solvolysis of 30 in the MeOH/HCO2NH4 me-
dium used for HRMS sample dissolution.
.
HRMS (ESI): m/z [M + Na]+ calcd for C12H12BrNO7Na: 383.9689; found:
383.9682.
Potassium 5-Phenyl-1-pentyltrifluoroborate (30)
2′-Oxopropyl 3,4-Dimethoxy-2-nitro-6-(5-phenylpentyl)benzoate
(31) and 2′-Oxopropyl 3,4-Dimethoxy-2-nitrobenzoate (32)
A solution of 2-phenyl-1-bromoethane (26; 2.07 mL, 15.1 mmol) in
anhyd Et2O (6.0 mL) was transferred to an addition funnel and slowly
added to a stirred suspension of Mg0 (405 mg, 16.5 mmol) in Et2O (2.0
mL) containing a crystal of I2 under argon. The reaction was initiated
by addition of an ethereal solution of phenethyl bromide (0.5 mL),
which caused the system to reflux; this condition was kept by contin-
uous dropping of the phenethyl bromide solution. Once the addition
was completed, the system was heated to reflux for an additional 1 h
period. Then, the reaction system was allowed to cool to rt, placed in
a cooled water-bath at 15 °C and the Grignard reagent 27 was treated
dropwise during 1 h with a recently distilled solution of allyl bromide
(1.8 mL, 15.2 mmol) in anhyd Et2O (6.0 mL). After this, sat. aq NH4Cl
(5.0 mL) was cautiously added to quench the reaction, and the aque-
ous phase was extracted with Et2O (3 × 5.0 mL). The combined organ-
ic phases were dried (MgSO4), the volatiles were evaporated off under
reduced pressure to afford 5-phenyl-1-pentene 28 as an oily residue;
yield: 2.36 g (95%).
A slurry composed by 2′-oxopropyl 6-bromo-3-methoxy-2-nitroben-
zoate (25; 80 mg, 0.22 mmol), potassium 5-phenyl-1-pentyltrifluo-
roborate (30; 89.8 mg; 0.35 mmol), K2CO3 (91.5 mg, 0.66 mmol),
Pd(OAc)2 (2.0 mg, 0.009 mmol), and dtbpf (6.3 mg, 0.013 mmol) in
toluene (2.4 mL) was purged with argon for 5 min. Freshly distilled
H2O (200 L, 0.011 mmol) was added, the tube was closed, and the
system was heated to 80 °C during 18 h. Once assessed that the start-
ing arene was fully consumed, the mixture was diluted with H2O (5
mL) and extracted with Et2O (3 × 30 mL). The organic phase was
washed with aq 1 M HCl (10 mL), brine (20 mL), and dried (MgSO4).
The volatiles were removed in vacuo and the remaining oily material
was chromatographed to afford the desired coupled product 31 as a
yellowish oil; yield: 120 mg (93%).
IR (NaCl): 3024, 2932, 2855, 1738, 1730, 1608, 1537, 1454, 1371,
1281, 1157, 1047, 700 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.31–7.14 (m, 5 H), 5.83 (ddt, J = 16.9,
10.2, 6.6 Hz, 1 H, H-1), 5.06–4.95 (m, 2 H, H-2), 2.62 (t, J = 7.7 Hz, 2 H,
H-5), 2.13–2.06 (m, 2 H, H-3), 1.77–1.67 (m, 2 H, H-4).
1H NMR (300 MHz, CDCl3):  = 7.30–7.16 (m, 5 H, C6H5), 6.84 (s, 1 H,
H-5), 4.74 (s, 2 H, H-1′), 3.93 (s, 3 H, 4-OCH3), 3.92 (s, 3 H, 3-OCH3),
2.85–2.80 (m, 2 H, H-1′′), 2.62 (td, J = 7.9, 2.6 Hz, 2 H, H-5′′), 2.18 (s, 3
H, C-3′), 1.71–1.58 (m, 4 H, H-2′′, H-4′′), 1.47–1.38 (m, 2 H, H-3′′).
13C NMR (75 MHz, CDCl3):  = 142.6 (Cipso), 138.8 (C-2), 128.6 (2 C,
C
ortho), 128.4 (2 C, Cmeta), 125.8 (Cpara), 114.8 (C-1), 35.5 (C-5), 33.4 (C-
13C NMR (75 MHz, CDCl3):  = 200.7 (C-2′), 163.7 (ArCO2CH2), 155.3
3), 30.8 (C-4).
(C-4), 145.8 (C-2), 142.6 (Cipso), 140.9 (C-6), 139.5 (C-3), 128.4 (2 C,
These data were in accordance with the literature,17a and the crude
material was used in the next step without further purification.
C
ortho),# 128.2 (2 C, Cmeta),# 125.6 (Cpara), 116.3 (C-1), 115.3 (C-5), 69.3
(C-1′), 62.3 (3-OCH3), 56.4 (4-OCH3), 35.8(C-5′′), 33.9 (C-1′′), 31.8 (C-
2′′), 31.2 (C-4′′), 29.1 (C-3′′), 26.1 (C-3′).
A recently titrated solution of BH3·SMe2 (1.4 M in toluene, 3.2 mL,
4.45 mmol) dissolved in anhyd CCl4 (5.0 mL) at 0 °C was treated drop-
wise during 30 min with a solution of alkene 28 (500 mg, 3.42 mmol)
in CCl4 (10 mL), while the diborane evolving from the reaction was
quenched by bubbling in an acetone/H2O solution. Once the addition
was completed, the reaction was warmed to rt, and stirred under an
argon atmosphere during an additional 3 h period, when the thus
formed alkylboranes were cautiously hydrolyzed at 0 °C by dropwise
addition of a solution of MeOH (2.0 mL) in CH2Cl2 (5.0 mL) over 30
min. Once the gas evolution ceased, aq 2 N HCl (3.42 mL) was added in
order to complete the boronic acid formation.20b The organic phase
was separated, washed with sat. aq NaHCO3 (5.0 mL) and brine (5.0
mL), dried (Na2SO4), and concentrated under reduced pressure until
dryness, to afford the crude boronic acid intermediate 29; yield: 549
mg (83%). This material (549 mg, 2.84 mmol) was dissolved in MeOH
(6.0 mL) and reacted with sat. aq KHF2 (4.3 mL) at rt during 3 h. The
volatiles were removed under vacuum to give a whitish solid materi-
al, which was extracted with hot acetone (4 × 5.0 mL). Evaporation of
the solvent furnished the desired potassium salt 30 as a white solid;
yield: 161.2 mg (22%); mp >200 °C (from acetone).
HRMS (ESI): m/z [M + Na]+ calcd for C23H27NO7Na: 452.1680; found:
452.1677.
Increasing solvent polarity gave the proto-debrominated benzoate 32
as a colorless solid; yield: 3.3 mg (5%); mp 87–89 °C (from hex-
anes/EtOAc 3:7, v/v).
IR (KBr): 2943, 2851, 1741, 1724, 1616, 1541, 1458, 1284, 1150, 1043,
893, 740 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.87 (d, J = 8.8 Hz, 1 H, H-6), 7.03 (d,
J = 8.8 Hz, 1 H, H-5), 4.80 (s, 2 H, H-1′′), 3.99 (s, 3 H, 3-OCH3), 3.92 (s, 3
H, 4-OCH3), 2.19 (s, 3 H, 3′-CH3).
13C NMR (75 MHz, CDCl3):  = 201.1 (C-2′), 162.0 (ArCO2CH2), 157.9
(C-3), 146.5 (C-2), 141.3 (C-4), 127.7 (C-6), 144.0 (C-1), 112.6 (C-5),
69.3 (C-1′), 62.7 (3-OCH3), 57.2 (4-OCH3), 26.3 (C-3′).
HRMS (ESI): m/z [M + Na]+ calcd for C12H13NO7Na: 306.5084; found:
306.5090.
2′-Oxopropyl 2-Amino-3,4-dimethoxy-6-(5-phenylpentyl)benzo-
ate (33)
IR (NaCl): 2922, 2853, 1300, 1082, 1058, 1031, 959, 741, 696 cm–1
.
A mixture of 31 (40.0 mg, 0.093 mmol) and freshly prepared Ni2B
(35.8 mg, 0.279 mmol) in anhyd MeOH (1.3 mL) was stirred while a
vigorous stream of H2 was bubbled in during 5 min. The reaction
1H NMR (300 MHz, acetone-d6):  = 7.26–7.10 (m, 5 H, C6H5), 2.56 (t,
J = 7.8 Hz, 2 H, H-5), 1.62–1.51 (m, 2 H, H-4), 1.32–1.27 (m, 4 H, H-2,
H-3), 0.17–0.14 (m, 2 H, H-1).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

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A. A. Aguilar et al.
Paper
Synthesis
mixture was treated with aq 1 M HCl (310 L, 0.31 mmol), and the
reaction tube was tightly closed and placed in a pre-heated bath at
70 °C for 30 min. After confirming the complete consumption of the
starting material, a 0.4% aq solution of NaHCO3 (5.0 mL) was added
and the products were extracted with EtOAc (3 × 10 mL). The com-
bined organic phases were washed with brine (10 mL), dried (MgSO4),
and concentrated under reduced pressure to afford the acetonyl an-
thranilate 33, which was used in the next step without further purifi-
cation; yield: 30 mg (81%).
The 1H NMR spectrum of 2 was in full agreement with that reported
by Kapadia et al. for the natural product.1b
13C NMR (75 MHz, CDCl3):  = 175.1 (C-4), 151.5 (C-7), 143.4 (Cipso),
142.0 (C-5), 141.2 (C-3), 138.2 (C-2), 134.7 (C-8a), 132.7 (C-8), 128.6
(2 C, Cortho), 128.3 (2 C, Cmeta), 125.6 (Cpara), 118.3 (C-4a), 110.4 (C-6),
61.2 (8-OCH3), 59.8 (3-OCH3), 56.2 (7-OCH3), 36.2 (C-5′), 35.9 (C-1′),
32.2 (C-2′), 31.7 (C-4′), 29.8 (C-3′), 15.2 (2-CH3).
HRMS (ESI): m/z [M + H]+ calcd for C24H30NO4: 396.2169; found:
396.2164.
IR (NaCl): 3491, 3377, 3024, 2928, 2851, 1717, 1599, 1452, 1369,
1265, 1139, 1043, 804, 737 cm–1
.
2′-Oxopropyl 3,4-Dimethoxy-2-nitro-6-(oct-1-yn-1-yl)benzoate
(35)
1H NMR (300 MHz, CDCl3):  = 7.30–7.16 (m, 5 H, C6H5), 6.15 (s, 1 H,
H-5), 5.50 (br s, w = ~12.5 Hz, 2 H, NH2), 4.86 (s, 2 H, H-1′), 3.86 (s, 3
½
A mixture of [Pd(PPh3)4] (6.5 mg, 0.009 mmol), CuI (1.64 mg, 0.008
mmol), and 25 (50 mg, 0.170 mmol) in anhyd DMF (2.0 mL) contained
in a screw capped tube under argon was sequentially treated with
Et3N (100 mL, 0.715 mmol) and 1-octyne (36 mL, 0.210 mmol). The
system was purged with an intense stream of argon for 1 min, screw
capped, and placed in a preheated bath (70 °C) for 15 h. Then, the vol-
atiles were removed under reduced pressure and the remaining oily
residue was dissolved in EtOAc (10 mL) and filtered through a Florisil®
pad, affording the crude coupling product 35; yield: 53 mg (78%). This
oily material was unstable to chromatographic conditions.
H, 4-OCH3), 3.79 (s, 3 H, 3-OCH3), 2.79–2.74 (m, 2 H, H-1′′), 2.65-2.59
(m, 2 H, H-5′′), 2.20 (s, 3 H, H-3′), 1.69–1.56 (m, 4 H, H-2′′, H-3′′),
1.46–1.34 (m, 2 H, H-4′′).
13C NMR (75 MHz, CDCl3):  = 202.0 (C-2′′), 167.5 (ArCO2CH2), 154.3
(C-4), 144.0 (Cipso), 142.9 (C-2), 141.9 (C-6), 133.2 (C-3), 128.5 (2 C,
C
ortho),* 128.3 (2 C, Cmeta),* 125.7 (Cpara), 106.9 (C-1), 103.6 (C-5), 68.3
(C-1′), 59.8 (3-OCH3), 55.8 (4-OCH3), 36.0 (C-5′′), 35.8 (C-1′′), 32.0 (C-
2′′), 31.4 (C-4′′), 29.5 (C-3′′), 26.1 (C-3′).
HRMS (ESI): m/z [M + H]+ calcd for C23H30NO5: 400.2119; found
400.2105.
IR (NaCl): 2930, 2861, 2230, 1736, 1729, 1615, 1542, 1360, 1241,
1129, 820 cm–1
.
1H NMR (300 MHz, CDCl3):  = 7.07 (s, 1 H, H-5), 4.72 (s, 2 H, H-1′),
3.94 (s, 3 H, 4-OCH3), 3.93 (s, 3 H, 3-OCH3), 2.39 (t, J = 7.2 Hz, 2 H, H-
3′′), 2.21 (s, 2 H, H-3′), 1.44–1.25 (m, 6 H, H-4′′ to H-7′′), 0.89 (t, J = 6.9
Hz, 3 H, H-8′′).
13C NMR (75 MHz, CDCl3):  = 201.9 (C-2′), 162.7 (ArCO2CH2), 155.4
(C-4), 141.1 (C-2), 132.2 (C-3), 128.7 (C-6), 121.4 (C-1), 118.0 (C-5),
97.6 (C-2′′), 77.3 (C-1′′), 69.7 (C-1′), 62.6 (3-OCH3), 56.7 (4-OCH3),
31.4 (C-6′′), 28.7 (C-5′′), 28.4 (C-4′′), 26.5 (C-3′), 22.6 (C-7′′), 19.7 (C-
3′′), 14.1 (C-8′′).
3,7,8-Trimethoxy-2-methyl-5-(5′-phenyl-1′-pentyl)quinoline-
4(1H)-one (Melovinone, 2)
The anthranilate 33 (30.0 mg, 0.08 mmol) was weighed in a micro-
wave vial and dissolved in glacial AcOH (1.0 mL). The system gas
purged with argon, capped, and irradiated at 150 °C (power = 60 W)
for 25 min. The reaction was controlled by TLC, confirming complete
consumption of the starting material and product formation by its
characteristic fluorescence UV (360 nm), an orange spot after spray-
ing with the Dragendorff–Munier reagent and an intense blue colored
spot obtained after exposure to aq 1% FeCl3 solution. Removal of the
solvent under high vacuum gave the crude pseudane 34 as a solid,
which was used for the next step without purification; yield: 29 mg
(ca. 88%).
HRMS (ESI): m/z [M + Na]+ calcd for C20H25NO7Na: 414.1523; found
414.1520.
2′-Oxopropyl 6-Allyl-3,4-dimethoxy-2-nitrobenzoate (36) and 2′-
Oxopropyl(E)-3,4-Dimethoxy-2-nitro-6-(prop-1-en-1-yl)benzoate
(37)
HRMS (ESI): m/z [M + H]+ calcd for C23H28NO4: 382.2013; found:
382.2011.
Compound 34 (28.5 mg, 0.07 mmol) and K2CO3 (41.3 mg, 0.30 mmol)
were suspended in anhyd 2-propanol (1.4 mL) contained in a screw
capped tube. After purging with argon, the mixture was stirred for 15
min at rt, and further treated with MeI (95 L, 1.5 mmol). The reac-
tion vessel was tightly closed and heated at 50 °C for 3.5 h. The reac-
tion was then quenched with H2O (5 mL) and the products were ex-
tracted with EtOAc (3 × 10 mL). The combined organic phases were
washed with brine (15 mL), dried (MgSO4), and concentrated under
vacuum. The remaining oily material was chromatographed to afford
melovinone (2) as a white amorphous solid; yield: 10.8 mg (40% over-
all yield from anthranilate 33); mp 130–128 °C (from EtOAc/EtOH
~9:1) (Lit.1b mp 136–134 °C (from PE/benzene).
A mixture of bromoarene 25 (25 mg, 0.07 mmol), LiCl (11.7 mg, 0.280
mmol), Pd(Ph3P)4 (8.0 mg, 0.007 mmol), and allyltri(n-butyl)stannane
(40 L, 0.140 mmol) in anhyd toluene (1.5 mL) contained in a screw
capped tube was purged with argon for 5 min. The system was tightly
closed with a screw cap and placed in a preheated oil bath at 80 °C for
18 h. Then, the mixture was diluted with EtOAc (5.0 mL) and filtered
through Celite. The volatiles were removed under vacuum and the
oily residue was chromatographed to give the allylbenzene derivative
36 as a clear oil; yield: 12.3 mg (92%).
1H NMR (300 MHz, acetone-d6):  = 7.25 (s, 1 H, H-5), 5.96 (ddd,
J = 16.8, 10.3, 6.5 Hz, 1 H, H-2′′), 5.13 (dt, J = 10.3, 1.5 Hz, 1 H, H-3′′a),
5.09 (ddd, J = 16.8, 2.9, 1.5 Hz, 1 H, H-3′′b), 4.92 (s, 2 H, H-1′), 4.02 (s, 3
H, 4-OCH3), 3.90 (s, 3 H, 3-OCH3), 3.69 (dd, J = 6.5, 1.5 Hz, 2 H, H-1′′),
2.19 (s, 3 H, 3-CH3).
IR (NaCl): 3414, 2935, 2918, 2839, 1618, 1560, 1526, 1420, 1319,
1250, 1138, 1005, 899, 746, 698 cm–1
.
1H NMR (300 MHz, CDCl3):  = 8.11 (br s, w = ~6.6 Hz, 1 H, NH), 7.29–
13C NMR (75 MHz, acetone-d6):  = 201.0 (C-2′), 164.4 (ArCO2CH2),
156.4 (C-4), 146.6 (C-2), 140.5 (C-3), 138.9 (C-6), 137.5 (C-2′′), 117.1
(C-1), 117.0 (C-5),* 116.9 (C-3′′), 70.2 (C-1′), 63.5 (3-OCH3), 57.5 (4-
OCH3), 38.4 (C-1′′), 26.0 (C-3′).
½
7.12 (m, 5 H, C6H5), 6.61 (s, 1 H, H-6), 3.97 (s, 3 H, 8-OCH3), 3.95 (s, 3
H, 7-OCH3), 3.85 (s, 3 H, 3-OCH3), 3.32 (dd, J = 6.2, 2.8 Hz, 2 H, H-1′),
2.60 (dd, J = 7.0, 1.9 Hz, 2 H, H-5′), 2.40 (s, 3 H, 2-CH3), 1.73–1.60 (m, 4
H, H-2′, H-4′), 1.56–1.46 (m, 2 H, H-3′).
HRMS (ESI): m/z [M + Na]+ calcd for C15H17NO7Na: 346.0897; found:
346.0900.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

I
A. A. Aguilar et al.
Paper
Synthesis
When longer reaction times were used or simply after standing some
time in solution, a mixture consisting by the allyl derivative and its
isomerized by-product 37 was observed (36:37 = ~10:1).
anhyd CH2Cl2 (2.0 mL). The mixture was further refluxed for 2.5 h.
Once the reaction was completed, the solution was filtered through a
cotton plug, the solids were washed with CH2Cl2, and the combined
organic solutions were evaporated to dryness. The resulting oil was
chromatographed, affording 39 and 40 as an inseparable mixture in a
1.8:1 molar ratio; yield: 50 mg (ca. 95%). The NMR spectra of 39 and
40 were in agreement with those of the product obtained after Meth-
od A.
37
1H NMR (300 MHz, CHCl3):  = 7.12 (s, 1 H, H-5), 6.86 (dqb, J = 15.6,
1.7 Hz, 1 H, H-1′′), 6.21 (dq, J = 15.6, 6.6 Hz, 1 H, H-2′′), 4.77 (s, 2 H, H-
1′), 3.97 (s, 3 H, 4-OCH3), 3.92 (s, 3 H, 3-OCH3), 2.20 (s, 3 H, H-3′), 1.93
(dd, J = 6.6, 1.7 Hz, 3 H, H-3′′).
13C NMR (75 MHz, CDCl3):  = 201.0 (C-2′), 163.7 (ArCO2CH2), 155.5
(C-4), 140.0 (C-6), 134.3 (C-3), 131.1 (C-2′′), 128.6 (C-2), 127.4 (C-1′′),
116.5 (C-1), 111.3 (C-5), 69.7 (C-1′), 62.5 (3-OCH3), 56.5 (4-OCH3),
26.3 (C-3′), 18.8 (C-3′′).
HRMS (ESI): m/z [M + Na]+ calcd for C15H17NO7Na: 346.0897; found:
346.0900.
Funding Information
The authors are indebted to Consejo Nacional de Investigaciones
Científicas y Técnicas (CONICET) (PUE-0006-2016) and Agencia Na-
cional de Promoción Científica y Tecnológica (ANPCyT) (PICT 2014-
0445 and PICT 2017-0149) for financial support. AAAA acknowledges
CONICET for his Doctoral fellowship. The authors also wish to thank
the Agencia Santafesina de Ciencia, Tecnología e Innovación Producti-
va (ASACTeI) for an institutional grant (AC 2015-0005) to Instituto de
2′-Oxopropyl (E)-3,4-Dimethoxy-2-nitro-6-(5-phenylpent-2-en-1-
yl)benzoate (39) and 2′-Oxopropyl (E)-3,4-Dimethoxy-2-nitro-6-
(4-phenylbut-1-en-1-yl)benzoate (40)
Química Rosario (IQUIR) for acquisition of a 400 MHz spectrometer.
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Method A: A solution of allylbenzene derivative 25 (20.3 mg, 0.063
mmol) and 4-phenyl-1-butene (38 L, 0.253 mmol) in anhyd toluene
(1.0 mL) was purged with argon and treated with Grubbs II catalyst
(2.7 mg, 0.003 mmol). The system was closed and heated at 40 °C for
6 h. Once the reaction was judged complete, the solution was filtered
through a cotton plug, washed with CH2Cl2, and evaporated to dry-
ness. The remaining oil was chromatographed affording an equimolar
inseparable mixture of 39 and 40; yield: 14.3 mg (53%).
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690164.
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References
39
1H NMR (300 MHz, acetone-d6):  = 7.35–7.09 (m, 4 H, Hortho, Hmeta),
7.23 (s, 1 H, H-5), 7.18–7.11 (m, 1 H, Hpara), 5.62 (m, 2 H, H-2′′, H-3′′),
4.90 (s, 2 H, H-1′), 3.97 (s, 3 H, 4-OCH3), 3.89 (s, 3 H, 3-OCH3) 3.60 (m,
2 H, H-1′′), 2.68 (t, J = 7.2 Hz, 2 H, H-5′′), 2.3 (m, 2 H, H-4′′), 2.17 (s, 3
H, H-3′).
13C NMR (75 MHz, acetone-d6):  = 201.1 (C-2′), 164.4 (ArCO2CH2),
156.3 (C-4), 146.5 (C-2), 142.7 (C-3), 139.6 (Cipso), 132.8 (C-3′′), 129.6
(C-6), 129.3 (2 C, Cmeta), 129.0 (2 C, Cortho, C-2′′), 127.4 (C-1), 126.6 (Cpa-
ra), 116.8 (C-5), 70.2 (C-1′), 62.5 (3- CH3O), 57.1 (4- CH3O), 37.1 (C-1′′),
36.4 (C-5′′), 35.0 (C-4′′), 26.0 (C-3′).
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HRMS (ESI): m/z [M + Na]+ calcd for C23H25NO7Na: 450.1523; found:
450.1518.
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M.; Cuendet, M.; Christen, P. J. Nat. Prod. 2014, 77, 2304.
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40
1H NMR (300 MHz, acetone-d6):  = 7.45 (s, 1 H, H-5), 7.35–7.09 (m, 4
H, Hortho, Hmeta), 7.18–7.11 (m, 1 H, Hpara), 7.02 (dt, J = 15.7, 1.5 Hz, 1 H,
H-1′′), 6.55 (m, 1 H, H-2′′), 4.92 (s, 2 H, H-1′), 4.05 (s, 3 H, 4-OCH3),
3.91 (s, 3 H, 3-OCH3), 2.80 (br s, w = ~3.2 Hz, 2 H, H-4′′), 2.52 (m, 2 H,
H-3′′), 2.17 (s, 3 H, H-3′).
13C NMR (75 MHz, acetone-d6):  = 201.2 (C-2′), 164.4 (ArCO2CH2),
156.3 (C-4), 146.2 (C-2), 142.5 (C-3), 140.1 (Cipso), 135.9 (C-2′′), 130.0
(C-6), 129.5 (2 C, Cmeta), 129.2 (2 C, Cortho), 127.4 (C-1′′), 126.7 (Cpara),
126.6 (C-1), 112.3 (C-5), 70.3 (C-1′), 62.6 (3- CH3O), 57.1 (4- CH3O),
35.9 (C-4′′), 35.7 (C-3′′), 26.0 (C-3′).
HRMS (ESI) m/z [M + Na]+ calcd for C22H23NO7Na: 436.1367; found:
436.1356.
½
Method B: A solution of Hoveyda–Grubbs II catalyst (5.0 mg, 0.006
mmol) in CH2Cl2 (2.0 mL) was infused at 2.5 mL/h into a refluxing
mixture of allylbenzene 36 (40 mg, 0.124 mmol), 4-phenyl-1-butene
(37 L, 0.248 mmol), and 1,4-benzoquinone (1.3 mg, 0.012 mmol) in
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–J

J
A. A. Aguilar et al.
Paper
Synthesis
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