A Straightforward Synthesis of 5-Methylaaptamine from Eugenol, Employing a 6π-Electrocyclization Reaction of a 1-Azatriene

Article abstract of DOI:10.1002/ejoc.201501566

Aaptamine, isolated from tropical marine sponges of the Demospongiae class, is the most prominent member of a growing family of natural products. Many aaptaminoids have been shown to have interesting biological activity. The efficient access to 5-methylaaptamine, an unnatural analogue of aaptamine, was achieved by using economic and naturally-occurring eugenol as the starting material. The synthesis involved the preparation of a 5-aminoeugenol derivative through successive nitration, O-methylation, and nitro group reduction reactions. An Elderfield-Johnson sequence was employed to synthesize the N-tosyl-5-allyl-7,8-dimethoxydihydro-1H-quinolin-4-one ring system. A catalytic double-bond isomerization followed by a carbonyl methoximation and 6-π electrocyclization of the 1-azatriene motif afforded the 2,3-dihydro-1H-benzo[de][1,6]naphthyridine tricyclic intermediate, which underwent a reductive desulfonylation and catalytic dehydrogenation to afford the target product.

Full text of DOI:10.1002/ejoc.201501566

DOI: 10.1002/ejoc.201501566
Full Paper
Natural Product Synthesis
A Straightforward Synthesis of 5-Methylaaptamine from
Eugenol, Employing a 6π-Electrocyclization Reaction of a
1
-Azatriene
[a]
[a]
[a]
Daniel A. Heredia, Enrique L. Larghi,* and Teodoro S. Kaufman*
Abstract: Aaptamine, isolated from tropical marine sponges of An Elderfield–Johnson sequence was employed to synthesize
the Demospongiae class, is the most prominent member of a the
N-tosyl-5-allyl-7,8-dimethoxydihydro-1H-quinolin-4-one
growing family of natural products. Many aaptaminoids have ring system. A catalytic double-bond isomerization followed by
been shown to have interesting biological activity. The efficient a carbonyl methoximation and 6-π electrocyclization of the 1-
access to 5-methylaaptamine, an unnatural analogue of aapt- azatriene motif afforded the 2,3-dihydro-1H-benzo[de]-
amine, was achieved by using economic and naturally-occur- [1,6]naphthyridine tricyclic intermediate, which underwent a re-
ring eugenol as the starting material. The synthesis involved the ductive desulfonylation and catalytic dehydrogenation to afford
preparation of a 5-aminoeugenol derivative through successive the target product.
nitration, O-methylation, and nitro group reduction reactions.
(Figure 1).[1a,5] Oxidized aaptaminoids such as 3a–3c,
morpholino derivative 4,
[5b,5d]
Introduction
[
5d]
and the zwitterionic aaptanone 5a
Tropical marine sponges of the Demospongiae class, especially
those of the genus Aaptos (family Suberitidae, order Hadrome-
rida) as well as those belonging to the genera Xestospongia,
Hymeniacidon/Suberites, Suberea, and Luffariella, are a rich
source of alkaloids collectively known as aaptaminoids, which
are characterized by their unusual 1H-benzo[de][1,6]naphthyr-
idine framework. From a biosynthetic viewpoint, these com-
pounds appear to be derivatives of aaptamine (1), the most
widespread and representative member of this class, and are
have also been reported. For structural elucidation purposes,
[6]
compound 5a was N-methylated to give 5b. Aaptaminoids
[5b,7]
that contain piperidine (i.e., 6), imidazole (i.e., 7 and 8),
and
[8]
piperazine (i.e., 9a–9d) rings fused to the original tricyclic
skeleton along with 5-substituted ketone 10 have also been
[8a]
discovered. In addition to hybrid aaptamine-type/bromoindole
alkaloids that have taurine- or histidine-derived residues (e.g.,
nakijinamines A–I), which were isolated from the Okinawan ma-
[9]
rine sponge Suberites species, dimeric compounds 12a, 12b,
[
1a]
[1]
formed by diversified substitution,
dimerization, and rear-
[1b]
1
4
3a, and 13b (suberitines A–D) reminiscent of lihouidine and
[
2]
rangement reactions.
[10]
,4′-binecatorone have been reported as well.
These natural products exhibit an ample array of prominent
biological activities, including α-adrenoreceptor blocking, anti-
neoplastic, antiviral, and antimicrobial properties.[ We previ-
In recent years, new biological properties of these natural
compounds have been found, which include their abilities to
3]
[
11]
[12]
produce pleiotropic effects,
act as proteasome inhibitors,
[
4a]
[
13]
ously performed a formal total synthesis of aaptamine
and,
nicotinic acetylcholine receptor ligands, and antiproliferative
and cancer-preventing agents,
sion, and protect kidney cells against cisplatin-induced cyto-
[
14]
in 2009, reviewed the isolation, syntheses, and biological activi-
inhibit liver cancer progres-
[
4b]
[
15]
ties of the aaptaminoid alkaloids.
[
16]
Since then, the continued interest in these heterocycles has toxicity. New insights have also been made about the mode
resulted in dramatic growth in the number of members of this of action of aaptamine and its congeners on cancer cells
family of compounds. In fact, 3-N-substituted 9-demethyl- as well as the structural features involved in the inhibition of
[
17]
[
18]
(
oxy)aaptamine derivatives 2a–2h have recently been isolated sortase A. Related tetracyclic compound 11 has been shown
from Aaptos marine sponges collected from the waters of Viet- to strongly bind DNA and behave as a cytotoxic and intercalat-
[
19]
nam, Indonesia, South China, and eastern Peninsular Malaysia ing agent.
However, most of these biological activity and molecular
biology studies regarding the search for molecular targets of
aaptamine and its congeners have been performed by employ-
ing compounds extracted from natural sources, which are often
scarce and difficult to access. The syntheses of unnatural oxy-
[
a] Instituto de Química Rosario (IQUIR, CONICET-UNR) and Facultad de
Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario,
Suipacha 531 (2000) Rosario, Argentina
E-mail: larghi@iquir-conicet.gov.ar
kaufman@iquir-conicet.gov.ar
http://tk-team-iquir.webnode.com/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201501566.
[
20]
genated aaptaminoids have been carried out,
and despite
that some naturally-occurring methylated aaptamines are
known, methyl analogues of natural products have also been
Eur. J. Org. Chem. 2016, 1397–1404
1397
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Results and Discussion
The retrosynthetic analysis shows the synthetic approach to-
[
24]
wards 1a (Scheme 1). Relying on our previous experience,
we propose that the B ring of the tricycle could be formed by
a 6π-electrocyclization reaction of a 1-azatriene, and, therefore,
the corresponding C–N bond disconnection was planned. The
chosen mode of assembly of the B ring imposes logistical de-
mands, different from those of previous syntheses of aaptamin-
oids, but has the compensatory advantage that, in principle, it
could lead to a new series of heterotricyclic compounds.
Scheme 1. Retrosynthetic analysis of 5-methylaaptamine (1a).
This building strategy mandates a late introduction of the C-
2
–C-3 double bond as a means to improve the electrophilicity
[
25a]
of the C-4 carbonyl
previous syntheses of aaptamine.
moiety and avoid some of the pitfalls of
[
21f,25b]
This approach revealed
imino derivative 15 as a suitable advanced intermediate of 1a.
Structural simplification, achieved by replacing parts of the 1-
azatriene components of 15 with a ketone and allylarene moi-
ety, uncovered dihydroquinolin-4-one 16 as a primary synthetic
subtarget.
Deepening the retrosynthetic analysis by disconnecting the
C-4–C-4a bond, we unveiled ꢀ-amino acid derivative 17 as a
suitable intermediate, which, in turn, should result from nitro
derivative 18. In the synthetic sense, this transformation should
involve the reduction of the nitro moiety and alkylation of the
resulting amine with a three-carbon chain.
Figure 1. New members of the aaptamine family.
The need of protecting groups as synthetic aids was also
prepared.[21] Recently, isolated ketone 10, a 5-substituted aapt- taken into account. Therefore, a nitrogen-protecting step was
amine derivative, and the 2-alkyl-substituted 7H-pyrido[4,3,2- planned at an early stage, and deprotection was considered at
[
4a]
kl]acridines (which contain a 1H-benzo[de][1,6]naphthyridine a late phase to enable access to 16
motif) have been synthesized as potential antitumor agents.
and ease the handling
[
22]
of the synthetic intermediates. The final disconnections that in-
In view of these precedents, the recent importance of aapt- volve the nitro moiety and the ortho ether motif exposed eu-
amine and its congeners, and the drawbacks of previous syn- genol (14) as the recommended starting material.
theses of the natural product, we sought to devise a short and
According to the retrosynthetic analysis, we initiated the syn-
efficient alternative pathway to a simple aaptamine analogue thesis with the selective ortho-nitration of eugenol (Scheme 2).
[
26]
by starting from inexpensive and easily available starting mate- Of the various alternatives considered, the most efficient one
rials. Herein, we report the synthesis of 5-methylaaptamine (1a) involved the treatment of natural product 14 with solid NaNO3
from eugenol (14), a natural product and a versatile commodity and KHSO in CH Cl and the presence of wet (50 % w/w) sil-
4
2
2
[
26b]
chemical that has been widely employed in synthetic organic ica,
which efficiently provided 19 in 91 % yield after a quick
[
23]
chemistry.
filtration of the reaction mixture through a short pad of silica
Eur. J. Org. Chem. 2016, 1397–1404
www.eurjoc.org
1398
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
gel. Long reaction times severely diminished the yields, presum-
The basic hydrolysis of the ester moiety was next explored
ably as a result of the polymerization of the product. A William- by using LiOH in an EtOH/H O solvent mixture. Employing pre-
2
son-type O-methylation of 19 by treatment with MeI and K CO
viously optimized conditions (1.3 M LiOH in EtOH/H O, reflux
2
3
2
as the base in refluxing EtOH completed this phase and cleanly overnight)[4a] afforded an inseparable mixture of carboxylic
1
and quantitatively afforded the expected nitro derivative 18.
acids in combined 60 % yield. The H NMR spectrum of the
mixture revealed the presence of envisaged acid 23, which ac-
counted for 61 % of the acid product, accompanied by ꢀ-meth-
ylstyrene derivatives 24 (39 %), which resulted from the base-
catalyzed isomerization of the allyl moiety, as a mixture of geo-
metric isomers (E/Z, 4.8:1). In addition, considerable amounts of
25 (up to 30 %) were observed. Compound 25 corresponded
to the retro-Michael product and exhibited chromatographic
behavior similar to that of starting ester 22, which complicated
the assessment of the time of completion of the reaction.
Despite that compound 24 could be cyclized into the useful
intermediate 27 and the presence of side products 24 and 25
could be decreased by lowering the amount of base and reduc-
ing the reaction temperature and time, the transformation was
carried out with LiOH in EtOH/H O at a final concentration of
2
0
.64 M at room temperature for 3 h. Under these conditions,
the yield of the allyl derivative 23 improved to 88 % without
the formation of ꢀ-methylstyrene 24. Interestingly, a further de-
crease of the reaction temperature to 0 °C did not result in
additional improvements (83 % yield). This efficient access to
23 set the stage for the projected cyclization.
It was anticipated that a Friedel–Crafts-type cyclization of the
Scheme 2. Reagents and conditions: (a) NaNO
CH Cl , room temp., 5 h (91 %); (b) MeI, K
100 %); (c) Fe , CaCl
AcOH (cat.), reflux, 24 h (65 %); (e) TsCl, EtN(iPr)
4 h (100 %); (f) (1) LiOH (1.3 ), EtOH/H O, reflux, overnight; (2) HCl, pH = 5
23 (37 %), 24 (23 %), 25 (up to 30 %)]; (g) (1) LiOH (0.64 ), EtOH/H O, room
3
, KHSO
CO , EtOH, reflux, overnight
O (10:1), reflux, 24 h (98 %); (d) H C=CHCO Et,
, DMAP (cat.), CHCl , reflux,
4
, SiO
2
/H
2
O (50 % w/w),
carboxylic acid onto the electron-rich arene moiety should take
place with relative ease, despite steric hindrance from the allyl
moiety attached at the ortho position to the ring-closing site.
However, the likelihood of this substituent to engage in isomer-
ization and polymerization reactions under acidic conditions
imposed some limitations on the choice of the suitable cycliz-
ing agent. Fortunately, treatment of 23 with PPE cleanly af-
forded cyclized product 26. However, the use of freshly pre-
2
2
2
3
0
(
2
, EtOH/H
2
2
2
2
3
2
[
M
2
M
2
temp., 3 h; (2) HCl, pH = 5 (88 %); (h) polyphosphate ester (PPE), PhMe, room
temp., 3 h (80 %).
To build heterocyclic ring C according to the Elderfield–John-
[
31a,31b]
[
27]
pared reagent
was critical to achieve the best reaction
son sequence,
compound 18 was subjected to a selective
performance and reach yields as high as 80 %.
reduction with iron powder in EtOH/H O (10:1) in the presence
2
[
28]
Having secured an efficient route toward key intermediate
of CaCl2,
which smoothly furnished amine 20 in 98 % yield.
26, we focused on the next task, working towards the construc-
This was then heated in refluxing ethyl acrylate in the presence
of a catalytic amount of AcOH to provide aza-Michael adduct
tion of the 1-azatriene moiety, which was required to construct
the remaining B ring. To that end, quinolin-4-one derivative 26
2
1 in 65 % yield. Unfortunately, despite the exploration of dif-
[
31c]
was exposed to freshly prepared PdCl (MeCN)
1
in anhydrous
,2-dichloroethane at reflux to uneventfully give the expected
-methylstyrene 27 in 91 % yield (Scheme 3), the (E) configura-
ferent alternatives, including the use of graphene oxide as a
2
2
promoter as well as K CO3 and ꢀ-cyclodextrins in aqueous
2
ꢀ
media, no significant improvement to the yield could be
1
[
29]
tion of which was assigned by H NMR analysis of the coupling
achieved.
constant between the vinylic protons (J = 15.7 Hz).
The cyclization of 21 proved to be unsatisfactory, as it af-
[
30]
forded several products,
which were probably the result of
The submission of 26 to a reaction with methoxyamine
the insufficient activation of the carbonyl moiety. Therefore, in hydrochloride in refluxing EtOH, to which NaOAc was added,
an effort to ease the manipulation of the polar synthetic inter- afforded oxime 28. Interestingly, model reactions revealed that
mediate and minimize the appearance of side products, sec- the addition of catalytic amounts of CeCl ·7H O greatly im-
3
2
32]
[
ondary aniline 21 was protected, as planned, by treatment with proved the performance of this transformation.
Therefore, it
TsCl (Ts = p-tolylsulfonyl) in chloroform and the employment was not surprising that the addition of 10 % of the promoter
of N,N-diisopropylethylamine (DIPEA) as a base. Under these afforded 76 % of methoxime 28 as a single isomer, to which
conditions, the reaction to give the expected tosylamide was the syn configuration was assigned by the reciprocal NOE en-
rather slow. However, the addition of 4-(N,N-dimethylamino)- hancements for the signals of the methoxime methyl protons
pyridine (DMAP) as a catalyst strongly improved the perform- and the neighboring α-proton of the ꢀ-methylstyrene motif.
ance of the sulfonamidation to furnish quantitative yields of 22 Interestingly, H-2 and H-3, which appear as triplets at δ = 3.97
after 24 h.
and 2.75 ppm (J = 6.4 Hz), respectively, for compound 27, were
Eur. J. Org. Chem. 2016, 1397–1404
www.eurjoc.org
1399
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Although the yield of the reaction at 140 °C in 1,2-dichloro-
benzene could be considered satisfactory, further experiments
were carried out with DMA as the solvent. Microwave irradiation
of this reaction at 140 °C for 30 min afforded 55 % of 29
(
Table 1, Entry 5), whereas heating for 20 min at the same tem-
perature provided the sought-after tricycle 29 in 77 % yield
(
Table 1, Entry 6).
The acquisition of 29 prompted a study of the remaining
transformations for ring C, which included a desulfonylation
and the installation of the C-2–C-3 double bond. Initial attempts
to effect both reactions in a single step by an oxidative desulf-
onylation and subsequent double-bond isomerization with KF/
Al O under microwave irradiation and solvent-free conditions
2
3
[
33a]
(
180 °C, 90 min.)
were unsuccessful, and only unreacted
Scheme 3. Reagents and conditions: (a) PdCl
8 h (91 %); (b) H NOMe·HCl, NaOAc, CeCl ·7H
night (76 %); (c) dimethylacetamide (DMA), microwave (MW) irradiation
2
(MeCN)
2
, ClCH
2
CH
2
Cl, reflux,
starting material was recovered. The same outcome was ob-
served when 29 was subjected to thermal heating in the pres-
ence of KF/Al O (240 °C, 24 h). These results were attributed
1
2
3
2
O (cat.), EtOH, reflux, over-
2
3
(
(
140 °C), 20 min. (77 %); (d) sodium naphthalenide, 1,2-dimethoxyethane
DME), –78 °C (81 %); (e) 10 % Pd/C, nBuOH-PhMe, 160 °C, 48 h (85 %).
[
33b]
to the low acidity of the H-2 atom.
Therefore, a reductive detosylation approach was explored.
[
33c]
Model detosylation reactions with low-valence titanium,
tivated magnesium powder in anhydrous MeOH,
ac-
[
33d]
and so-
observed as broad signals at δ = 3.67 and 2.74 ppm, respec- dium naphthalenide[33e] in ethereal solvents revealed the better
tively, for compound 28. Their mutual interactions were as- suitability of the latter two reagents. However, when 29 was
sessed by a total correlation spectroscopy (TOCSY) experiment, exposed to a 20-fold excess amount of activated Mg powder in
whereas the signal broadening was attributed to the vicinity of anhydrous MeOH, no product could be isolated from the reac-
the nitrogen functionalities.
tion mixture, despite the complete consumption of the starting
Access to the ꢀ-methylstyrene-methoxime 28 set the stage material was indicated by TLC analysis after 20 h. Thus, the
for the second cyclization, to complete the B ring of the target. reaction of 29 with sodium naphthalenide in anhydrous DME
As planned, this was performed by a 6π-electrocyclization reac- at –78 °C was explored. As anticipated, these conditions cleanly
tion under microwaves irradiation, which presumably proceeds furnished dihydroaaptamine analogue 31 in 81 % yield. Carry-
through intermediate 30. However, the successful outcome re- ing out the reaction at low temperature, slowly adding the re-
quired some optimization studies (Table 1). Initially, the reaction ducing agent, and using stoichiometric amounts of the latter
was carried out in 1,2-dichlorobenzene. Unexpectedly, a disap- ensured the best yields.
pointing 15 % yield of 29 was obtained when the transforma-
The final step, the dehydrogenation of 31, was performed
tion was performed at 180 °C for 30 min (Table 1, Entry 1). with 10 % Pd/C in toluene at reflux. To improve the solubility
Lowering the temperature to 160 °C for 20 min improved the of the substrate, n-butanol was added as a co-solvent. Under
yield to 50 % (Table 1, Entry 2). A further increase was observed these conditions, 5-methylaaptamine (1a) was obtained after
when the reaction was performed at 140 °C (Table 1, Entry 3), 48 h in 85 % yield.
but at 120 °C, the transformation required a longer time and a
better yield was not obtained (Table 1, Entry 4).
Conclusions
Table 1. Optimization of the 6π-electrocyclization of 28 to 29.
In summary, we have developed a practical and convenient ap-
proach towards the synthesis of 5-methylaaptamine (1a), an
unnatural analogue of the 1H-benzo[de][1,6]naphthyridine
alkaloid aaptamine (1). The synthesis was achieved in 12 steps
and 14.9 % overall yield from naturally occurring eugenol (14)
through the formation of 5-allyl-7,8-dimethoxyquinolin-2-one
26. The sequence also featured the double-bond isomerization
and methoximation of this key intermediate as well as an effi-
cient microwave-assisted 6π-electrocyclization reaction of the
1
-azatriene motif. A final reductive desulfonylation and Pd/C-
Entry
Solvent
Temp. [°C]
Time [min]
% Yield of 29
mediated dehydrogenation reaction completed the synthesis.
The double bond of the advanced intermediate is a useful start-
ing point for the diversification of the C-5 side chain, which
would enable the elaboration of the structure to give more
complex compounds. Work in this direction is in progress, and
the results will be disclosed in due course.
1
2
3
4
5
6
1,2-Cl
1,2-Cl
1,2-Cl
1,2-Cl
MeCONMe
MeCONMe
2
2
2
2
C
C
C
C
6
6
6
6
H
H
H
H
4
4
4
4
180
160
140
120
140
140
30
20
20
45
30
20
15
50
62
20
55
77
2
2
Eur. J. Org. Chem. 2016, 1397–1404
www.eurjoc.org
1400
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Experimental Section
5.26–4.96 (m, 2 H, CH
=CHCH Ar), 3.94 (s, 3 H, OCH -2), 3.36 (d, J =
2 2 3
13
6
.7 Hz, 2 H, CH =CHCH Ar) ppm. C NMR: δ = 149.9 (C-2), 144.9
2
2
General Methods: All the reactions were executed under anhy-
drous argon and employed oven-dried glassware and freshly dis-
tilled anhydrous solvents. Chlorinated solvents (1,2-Cl C H , 1,2-di-
(
C-1), 135.9 (CH =CHCH Ar), 133.6 (C-6), 131.2 (C-4), 118.6 (C-3),
2 2
1
17.2 (CH =CHCH Ar), 115.1 (C-5), 56.7 (OCH -2), 39.4 (CH =
2 2 3 2
2
6
4
CHCH Ar) ppm.
2
chloroethane, and CHCl ) were dried at reflux over P O (4 h) fol-
3
2 5
5
-Allyl-1,2-dimethoxy-3-nitrobenzene (18):[26d] A mixture of 6-
nitroeugenol (3.00 g, 14.34 mmol) and K CO (7.93 g, 57.4 mmol)
lowed by distillation at atmospheric pressure. Anhydrous CH Cl2
was obtained by using an MBraun solvent purification and dis-
penser system. Anhydrous DMA was prepared by distillation from
2
2
3
in absolute EtOH (150 mL) was stirred for 5 min under argon. MeI
(3.57 mL, 57.4 mmol) was then added, and the resulting suspension
was heated at reflux overnight. The solids were removed by filtra-
tion, and the filter cake was washed with EtOH (2 × 10 mL). The
combined filtrates were evaporated under reduced pressure, and
the residue was dissolved in EtOAc (50 mL). The resulting solution
0
dry BaO. Toluene and DME were distilled from Na /benzophenone
ketyl. Absolute EtOH was prepared by treatment with clean magne-
sium turnings and iodine and subsequent distillation from the re-
sulting magnesium ethoxide. Anhydrous solvents were transferred
by cannula and stored in dry Young ampoules that contained mo-
lecular sieves. All other reagents were used as received. The
progress of the reactions was monitored by TLC analysis (silica gel
was washed sequentially with a NaOH (2
brine (2 × 10 mL). Finally, the organic layer was dried with Na SO ,
M solution, 5 mL) and
2
4
and the solvent was removed in vacuo to afford 18 (3.20 g, 100 %)
as an orange oil. IR (film): ν˜ = 775, 920, 997, 1065, 1144, 1279, 1362,
6
0 GF254; various mixtures of hexane/EtOAc and EtOAc/EtOH). The
chromatographic spots were visualized by exposure to UV light
–
1 1
1462, 1537, 2849, 2939 cm . H NMR: δ = 7.14 (d, J = 1.9 Hz, 1 H,
(254 nm) and spraying with 1 % methanolic FeCl , Dragendorff rea-
3
34]
[
4-H), 6.92 (d, J = 1.9 Hz, 1 H, 6-H), 5.91 (ddt, J = 17.1, 10.5, and
.7 Hz, 1 H, CH =CHCH Ar), 5.19–5.03 (m, 2 H, CH =CHCH Ar), 3.94
gent (Munier and Macheboeuf modification),
ethanolic p-anis-
6
2
2
2
2
aldehyde/sulfuric acid reagent, or 1 % ethanolic ninhydrin followed
by careful heating to improve selectivity. For the conventional
workup procedure, the reaction mixture was diluted with brine, and
the products were extracted with EtOAc. The combined organic
extracts were then washed with brine (1×), dried with Na SO , and
(
s, 3 H, OCH -2), 3.90 (s, 3 H, OCH -1), 3.37 (d, J = 6.7 Hz, 2 H, CH =
3 3 2
13
CHCH Ar) ppm. C NMR: δ = 153.9 (C-1), 144.7 (C-3), 141.1 (C-2),
2
1
6
36.3 (C-5), 135.7 (CH =CHCH Ar), 117.2 (CH =CHCH Ar), 116.4 (C-
), 115.6 (C-4), 61.9 (OCH -2), 56.4 (OCH -1), 39.6 (CH2=
2 2 2 2
3
3
2
4
CHCH Ar) ppm.
2
concentrated under reduced pressure. The residue was purified by
flash column chromatography (silica gel 60 H, particle size: 63–
5-Allyl-2,3-dimethoxyphenylamine (20): CaCl (2.22 g, 20 mmol),
2
2
00 μm; polarity gradient with hexane/EtOAc and EtOAc/EtOH mix-
clean iron powder (3.35 g, 60 mmol), and H O (2 mL) were succes-
sively added to a solution of 18 (850 mg, 3.81 mmol) in EtOH
2
tures) under the positive pressure of N . Melting points were meas-
2
ured on an Ernst Leitz Wetzlar model 350 hot-stage microscope.
FTIR spectra were recorded on a Shimadzu Prestige 21 spectropho-
tometer as solid dispersions in KBr disks for solid samples or as thin
films held between NaCl cells for oily samples. The NMR spectro-
(20 mL), and the reaction mixture was stirred at reflux for 24 h. The
suspension was then filtered through Celite, and the filter cake was
washed with EtOH (20 mL). After the concentration of the combined
filtrates, the residue was redissolved in EtOAc (50 mL), and the re-
scopic data were recorded in CDCl , unless otherwise noted, with
3
sulting solution was successively washed with a NaOH (2
M solution,
1
an FT-NMR Bruker Avance 300 spectrometer at 300.13 MHz (for H
10 mL) and brine (10 mL). The organic phase was dried with anhy-
1
3
NMR) and 75.48 MHz ( C NMR). Chemical shifts are reported in
drous MgSO and filtered, and the solvent was removed under vac-
4
parts per million on the δ scale, and TMS was used as the internal
uum. The residue was purified by silica gel column chromatography
to afford 20 (722 mg, 98 %) as a reddish brown oil. IR (film): ν =
1
13
standard (for H NMR, CHCl : δ = 7.26 ppm and for C NMR CDCl3:
3
˜
δ = 77.0 ppm). The magnitude of the coupling constants (J) and
half-width (w1/2) values are given in Hertz. In special cases, NOE and
3
464, 3371, 2931, 1614, 1593, 1504, 1454, 1352, 1230, 1134, 1072,
–1 1
1002 cm . H NMR: δ = 6.23 (d, J = 1.9 Hz, 1 H, 6-H), 6.17 (d, J =
2
D NMR experiments [COSY, heteronuclear single quantum correla-
1
5
.9 Hz, 1 H, 4-H), 5.94 (ddt, J = 16.9, 10.0, 6.8 Hz, 1 H, CH =CHCH Ar),
2 2
tion (HSQC) spectroscopy, TOCSY, and HMBC spectroscopy) were
also employed. Pairs of signals marked with an asterisk (*) indicate
that the assignments may be exchanged. GC–MS experiments were
performed with a Shimadzu QP2010 Plus instrument equipped with
an AOC-20i autosampler, and high resolution mass spectra were
obtained with a Bruker MicroTOF-Q II instrument (Bruker Daltonics,
Billerica, MA). Detection of the ions was performed by electrospray
ionization in the positive ion mode. Microwave-assisted reactions
were carried out in a CEM Discover microwave oven.
.18–4.99 (m, 2 H, CH =CHCH Ar), 3.82 (br. s, 2 H, NH ), 3.83 (s, 3 H,
2
2
2
OCH -3), 3.80 (s, 3 H, OCH -2), 3.25 (d, J = 6.8 Hz, 2 H, CH =
3
3
2
13
CHCH Ar) ppm. C NMR: δ = 152.7 (C-3), 140.9 (C-1), 137.4 (CH2=
2
CHCH Ar), 136.2 (C-5), 134.1 (C-2), 115.6 (CH =CHCH Ar), 108.7 (C-6),
2
2
2
102.6 (C-4), 59.8 (OCH -2), 55.6 (OCH -3), 40.2 (CH =CHCH Ar) ppm.
3 3 2 2
+
HRMS: calcd. for C H NO [M + H] 194.1181; found 194.1176.
11
16
2
Ethyl 3-(5-Allyl-2,3-dimethoxyphenylamino)propionate (21):
Glacial AcOH (0.11 mL) was added to a stirred and degassed solu-
tion of 20 (260 mg, 1.35 mmol) in excess amount of neat ethyl
4
-Allyl-2-methoxy-6-nitrophenol (6-Nitroeugenol, 19):[26a] Eu- acrylate (4.3 mL), and the mixture was heated at reflux for 24 h.
genol (2.5 mL, 16.25 mmol) was added dropwise to a vigorously
stirred mixture of potassium bisulfate (7.95 g, 58.5 mmol), sodium
nitrate (5.33 g, 62.7 mmol), and wet silica gel (50 % w/w, 6.174 g)
suspended in CH Cl (50 mL). The reaction mixture was stirred at
The volatiles were then carefully evaporated, and the residue was
purified by flash column chromatography to give ꢀ-amino ester 21
(258 mg, 65 %) as a yellowish oil. IR (film): ν˜ = 3400, 2960, 2929,
–
1 1
1732, 1593, 1454, 1371, 1249, 1139 cm . H NMR: δ = 6.16 (s, 2 H,
4-H and 6-H), 5.96 (ddt, J = 16.8, 10.0 and 6.7 Hz, 1 H, CH2=
2
2
room temperature until TLC analysis (hexanes/EtOAc, 80:20) con-
firmed the complete consumption of the starting material (approxi- CHCH Ar), 5.15–5.01 (m, 2 H, CH =CHCH Ar), 4.56 (br. s, w =
2
2
2
1/2
mately 1.5 h). Then, the slurry that contained the crude reaction
9.6 Hz, 1 H, NH), 4.15 (q, J = 7.1 Hz, 2 H, OCH CH ), 3.82 (s, 3 H,
2
3
mixture was poured onto the top of a silica gel column (hexanes/ OCH -3), 3.75 (s, 3 H, OCH -2), 3.46 (t, J = 6.5 Hz, 2 H, CH CH CO Et),
3
3
2
2
2
EtOAc mixtures) to afford 19 (3.09 g, 91 %) as a yellow oil. IR (film):
3.29 (d, J = 6.7 Hz, 2 H, CH =CHCH Ar), 2.60 (t, J = 6.5 Hz, 2 H,
2 2
13
ν˜ = 764, 920, 1063, 1136, 1263, 1331, 1393, 1547, 2853, 2924, 3050– CH CH CO Et), 1.26 (t, J = 7.1 Hz, 3 H, OCH CH ) ppm. C NMR: δ =
2
2
2
2
3
–1 1
3
670 cm . H NMR: δ = 10.67 (s, 1 H, Ar-OH), 7.52 (s, 1 H, 5-H), 6.96
172.2 (C=O), 152.3 (C-3), 141.4 (C-1), 137.6 (CH =CHCH Ar), 136.4 (C-
2 2
(
s, 1 H, 3-H), 5.92 (ddt, J = 16.9, 10.5, and 6.7 Hz, 1 H, CH =CHCH Ar), 5), 133.9 (C-2), 115.6 (CH =CHCH Ar), 104.3 (C-6), 101.7 (C-4), 60.6
2
2
2
2
Eur. J. Org. Chem. 2016, 1397–1404
www.eurjoc.org
1401
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(
OCH CH ), 59.8 (OCH -2), 55.7 (OCH -3), 40.7 (CH =CHCH Ar), 39.3 129.4 (2 C, TsC-3 and TsC-5), 127.8 (2 C, TsC-2 and TsC-6), 122.2 (C-
2
3
3
3
2
2
(
CH CH CO Et), 34.3 (CH CH CO Et), 14.2 (OCH CH ) ppm. HRMS:
6), 116.3 (CH =CHCH Ar), 113.3 (C-4), 60.8 (OCH -2), 55.9 (OCH -3),
2
2
2
2
2
2
+
2
3
2 2 3 3
calcd. for C H NNaO [M + Na] 316.1519; found 316.1519.
46.6 (CH CH COOH), 39.6 (CH =CHCH Ar), 33.6 (CH CH COOH), 21.5
2 2 2 2 2 2
16
23
4
(
4
ArCH3 of Ts) ppm. HRMS: calcd. for C21H25NNaSO6 [M + Na]+
42.1295; found 442.1285.
Ethyl 3-[(5-Allyl-2,3-dimethoxyphenyl)-(4-tolylsulfonyl)amino]-
propionate (22): DIPEA (0.22 mL, 1.28 mmol), tosyl chloride
Preparation of Polyphosphate Ester (PPE):[31b] P2O5 (15 g) was
(
218 mg, 1.11 mmol), and DMAP (2 mg) were successively added to
a stirred solution of 21 (258 mg, 0.88 mmol) in anhydrous CHCl3
4 mL), and the mixture was kept at 0 °C in an ice water bath. The
added in one portion to a 2:1 mixture of anhydrous Et O (30 mL)
2
(
and anhydrous ethanol-free CHCl (15 mL), and the suspension was
3
cooling bath was removed, and when the reaction reached room
temperature, it was heated at reflux for 24 h. The solvent was then
vigorously stirred at reflux for 4 d. The resulting mixture was then
concentrated by using a rotary evaporator, and the polyphosphate
removed under reduced pressure, and the oily residue was purified ester was separated from the remaining volatiles under vacuum for
by chromatography to give 22 (393 mg, 100 %) as an oil. IR (film): 24 h. The residue was used without further treatment.
–
1 1
ν˜ = 2978, 2943, 1732, 1581, 1494, 1348, 1161 cm . H NMR: δ =
5
-Allyl-7,8-dimethoxy-1-(4-tolylsulfonyl)-2,3-dihydro-1H-quin-
7
2
.68 (d, J = 8.2 Hz, 2 H, 2-ArH and 6-ArH of Ts), 7.27 (d, J = 8.2 Hz,
H, 3-ArH and 5-ArH of Ts), 6.70 (d, J = 1.9 Hz, 1 H, 4-H), 6.38 (d,
olin-4-one (26): PPE (750 mg) was added to a stirred solution of
acid 23 (73 mg, 0.17 mmol) in toluene (4.5 mL), and the reaction
mixture was stirred at room temperature for 3 h. Then, crushed ice
was added, and the mixture was extracted with EtOAc (4 × 20 mL).
The combined organic phases were dried with Na SO and concen-
J = 1.9 Hz, 1 H, 6-H), 5.86 (ddt, J = 17.0, 10.5, and 6.7 Hz, 1 H, CH2=
CHCH Ar), 5.16–4.93 (m, 2 H, CH =CHCH Ar), 4.01 (q, J = 7.1 Hz, 2
2
2
2
H, OCH CH ), 3.82 (t, J = 7.6 Hz, 2 H, CH CH CO Et), 3.83 (s, 3 H,
2
3
2
2
2
2
4
OCH -3), 3.71 (s, 3 H, OCH -2), 3.24 (d, J = 6.7 Hz, 2 H, CH =
3
3
2
trated under reduced pressure. The resulting residue was purified
by silica gel column chromatography to afford quinolone 26
CHCH Ar), 2.54 (t, J = 7.6 Hz, 2 H, CH CH COOEt), 2.42 (s, 3 H, ArCH
2
2
2
3
1
3
of Ts), 1.17 (t, J = 7.1 Hz, 3 H, OCH CH ) ppm. C NMR: δ = 171.2
2
3
(
56 mg, 80 %), as a white solid; m.p. 158–160 °C (hexanes/EtOAc).
(C=O), 153.2 (C-3), 145.7 (C-2), 143.2 (TsC-4), 137.3 (TsC-1), 136.7
–1 1
IR (KBr): ν˜ 2916, 1678, 1589, 1558, 1333, 1263, 1151, 764 cm . H
NMR: δ = 7.82 (d, J = 8.2 Hz, 2 H, 2-ArH and 6-ArH of Ts), 7.30 (d,
J = 8.2 Hz, 2 H, 3-ArH and 5-ArH of Ts), 6.72 (s, 1 H, 6-H), 5.98 (ddt,
J = 16.3, 13.2, and 6.5 Hz, 1 H, CH =CHCH Ar), 5.14–4.99 (m, 2 H,
(
CH =CHCH Ar), 135.0 (C-5), 131.6 (C-1), 129.4 (2 C, TsC-3 and TsC-
2
2
5
1
), 127.7 (2 C, TsC-2 and TsC-6), 122.4 (C-6), 116.2 (CH =CHCH Ar),
2 2
13.2 (C-4), 60.6 (OCH -2), 60.4 (OCH CH ), 55.9 (OCH -3), 46.8
3
2
3
3
2
2
(
(
[
CH CH COOEt), 39.7 (CH =CHCH Ar), 33.9 (CH CH COOEt), 21.5
2 2 2 2 2 2
CH =CHCH Ar), 3.98 (t, J = 6.3 Hz, 2 H, 2-H), 3.92 (s, 3 H, OCH -7),
2
2
3
ArCH of Ts), 14.1 (OCH CH ) ppm. HRMS: calcd. for C H NNaSO
6
3
2
3
23 29
3
.77 (d, J = 6.5 Hz, 2 H, CH =CHCH Ar), 3.51 (s, 3 H, OCH -8), 2.76
+
2 2 3
M + Na] 470.1608; found 470.1606.
-[(5-Allyl-2,3-dimethoxyphenyl)-(4-tolylsulfonyl)amino]prop-
ionic Acid (23): LiOH (10 % solution, 2 mL) was added to a stirred
suspension of ester 22 (230 mg, 0.51 mmol) in EtOH/H O (3:1,
13
(t, J = 6.3 Hz, 2 H, 3-H), 2.44 (s, 3 H, ArCH of Ts) ppm. C NMR: δ =
3
3
193.8 (C-4), 156.7 (C-7), 143.6 (TsC-4), 142.3 (C-8), 139.9 (C-4a), 138.1
(
TsC-1), 137.2 (C-8a), 137.0 (CH =CHCH Ar), 129.5 (2 C, TsC-3 and
2
2
2
TsC-5), 127.4 (2 C, TsC-2 and TsC-6), 121.3 (C-5), 115.9 (CH2=
1
1 mL). The reaction mixture was stirred at room temperature for
CHCH Ar), 113.0 (C-6), 60.2 (OCH -8), 55.9 (OCH -7), 46.5 (C-2), 40.1
2
3
3
3
h, and then it was acidified to pH = 5 to 6 by the addition of
(
C-3), 39.0 (CH =CHCH Ar), 21.6 (ArCH of Ts) ppm. HRMS: calcd. for
2 2 3
HCl (1
M). The EtOH was evaporated, and the remaining aqueous
+
C H NNaSO [M + Na] 424.1189; found 424.1180.
21
23
5
suspension was extracted with EtOAc (4 × 10 mL). The combined
organic layers were dried with Na SO and concentrated in vacuo.
[
31c]
Preparation of PdCl (MeCN) :
A suspension of PdCl (100 mg,
2
2
2
2
4
0.56 mmol) in MeCN (5 mL) was stirred at room temperature for
The residue was purified by column chromatography to give 5-allyl-
2
d. The resulting solid was removed by filtered, washed with Et O,
2
2
,3-dimethoxy-(4-tolylsulfonyl)phenylamine (25, 18 mg, 10 %) as a
and dried under vacuum. Recrystallization (MeCN/CH Cl /hexane,
2
2
white solid, and a further increase in the solvent polarity afforded
carboxylic acid 23 (190 mg, 88 %) as a pale yellow oil. Data for 25:
2:3:1 v/v/v furnished the catalyst as a yellow-orange solid.
M.p. 134–135 °C (hexanes/EtOAc). IR (KBr): ν˜ = 704, 995, 1088, 1169, 7,8-Dimethoxy-5-propenyl-1-(4-tolylsulfonyl)-2,3-dihydro-1H-
–
1 1
1
7
2
337, 1385, 1429, 1504, 1591, 2837, 2926, 3240 cm . H NMR: δ = quinolin-4-one (27): A stirred solution of 2,3-dihydro-1H-quinolone
.68 (d, J = 8.2 Hz, 2 H, 2-ArH and 6-ArH of Ts), 7.20 (d, J = 8.2 Hz, 26 (265 mg, 0.66 mmol) in anhydrous 1,2-dichloroethane (20 mL)
H, 3-ArH and 5-ArH of Ts), 7.12 (s, 1 H, NH), 7.05 (d, J = 1.6 Hz, 1 was treated with freshly prepared PdCl (MeCN)2 (18 mg,
2
H, 6-H), 6.43 (d, J = 1.6 Hz, 1 H, 4-H), 5.90 (ddt, J = 16.8, 10.2, and 0.07 mmol). The resulting solution was heated at reflux for 18 h,
.6 Hz, 1 H, CH =CHCH Ar), 5.18–4.90 (m, 2 H, CH =CHCH Ar), 3.77 the time for complete consumption of the starting material as con-
6
2
2
2
2
1
(s, 3 H, OCH -3), 3.53 (s, 3 H, OCH -2), 3.29 (d, J = 6.6 Hz, 2 H, CH = firmed by H NMR analysis of an aliquot of the reaction mixture.
3 3 2
1
3
CHCH Ar), 2.35 (s, 3 H, ArCH of Ts) ppm. C NMR: δ = 151.9 (C-3),
Then, crushed ice was added, and the mixture was extracted with
2
3
1
1
43.8 (TsC-4), 136.9 (CH =CHCH Ar), 136.5 (OCH -2), 136.3 (TsC-1),* EtOAc (4 × 20 mL). The combined organic phases were dried with
2
2
3
36.1 (C-5),* 130.4 (C-1), 129.5 (2 C, TsC-3 and TsC-5), 127.2 (2 C,
Na SO4 and concentrated under reduced pressure. The resulting
2
TsC-2 and TsC-6), 116.1 (CH =CHCH Ar), 112.0 (C-6), 108.5 (C-4), 60.7 residue was purified by silica gel column chromatography to pro-
2
2
(
OCH -2), 55.7 (OCH -3), 40.2 (CH =CHCH Ar), 21.5 (ArCH of vide 27 (241 mg, 91 %) as a white solid; m.p. 178–180 °C (hexanes/
3 3 2 2 3
+
Ts) ppm. HRMS: calcd. for C H NNaSO [M + Na] 370.1084; found EtOAc). IR (KBr): ν˜ 2918, 2851, 1670, 1585, 1545, 1458, 1364, 1340,
1
8
21
4
–
1 1
3
1
2
70.1080. Data for 23: IR (film): ν˜ = 3700–2300, 2945, 1713, 1495, 1257, 1153, 1007, 758 cm . H NMR: δ = 7.83 (d, J = 8.2 Hz, 2 H, 2-
–1 1
346, 1240, 1161, 1128 cm . H NMR: δ = 7.67 (d, J = 8.2 Hz, 2 H, ArH and 6-ArH of Ts), 7.30 (d, J = 8.2 Hz, 2 H, 3-ArH and 5-ArH of
-ArH and 6-ArH of Ts), 7.27 (d, J = 8.2 Hz, 2 H, 3-ArH and 5-ArH of
Ts), 7.22 (d, J = 15.7 Hz, 1 H, CH CH=CHAr), 6.88 (s, 1 H, 6-H), 6.05
3
Ts), 6.71 (d, J = 1.7 Hz, 1 H, 4-H), 6.36 (d, J = 1.7 Hz, 1 H, 6-H), 5.85
ddt, J = 16.9, 10.4, and 6.7 Hz, 1 H, CH =CHCH Ar), 5.15–4.89 (m, 2
(dq, J = 15.7 and 6.7 Hz, 1 H, CH CH=CHAr), 3.97 (t, J = 6.4 Hz, 2 H,
3
(
2-H), 3.93 (s, 3 H, OCH -7), 3.51 (s, 3 H, OCH -8), 2.75 (t, J = 6.4 Hz,
2
2
3
3
H, CH =CHCH Ar), 3.83 (s, 3 H, OCH -3), 3.80 (t, J = 7.5 Hz, 2 H, 2 H, 3-H), 2.43 (s, 3 H, ArCH of Ts), 1.91 (dd, J = 6.7 and 1.4 Hz, 3
2
2
3
3
13
CH CH COOH), 3.72 (s, 3 H, OCH -2), 3.24 (d, J = 6.7 Hz, 2 H, CH =
H, CH CH=CHAr) ppm. C NMR: δ = 194.1 (C-4), 156.7 (C-7), 143.6
2
2
3
2
3
CHCH Ar), 2.59 (t, J = 7.5 Hz, 2 H, CH CH COOH), 2.42 (s, 3 H, ArCH
of Ts) ppm. C NMR: δ = 176.5 (C=O), 153.2 (C-3), 145.7 (C-2), 143.3
(TsC-4), 142.8 (C-8), 138.1 (TsC-1), 137.7 (C-4a), 136.6 (C-8a), 130.9
2
2
2
3
13
(CH CH=CHAr), 129.5 (2 C, TsC-3 and TsC-5), 128.7 (CH CH=CHAr),
3
3
(
TsC-4), 137.0 (TsC-1), 136.6 (CH =CHCH Ar), 135.2 (C-5), 131.5 (C-1), 127.3 (2 C, TsC-2 and TsC-6), 120.2 (C-5), 109.8 (C-6), 60.2 (OCH -8),
2
2
3
Eur. J. Org. Chem. 2016, 1397–1404
www.eurjoc.org
1402
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
5
5.9 (OCH -7), 46.4 (C-2), 40.0 (C-3), 21.6 (ArCH of Ts), 18.7 (CH CH=
13C NMR: δ = 156.6 (C-8), 154.9 (C-3a), 149.9 (C-5), 138.4 (C-9a),
3
3
3
+
CHAr) ppm. HRMS: calcd. for C H NNaO S [M + Na] 424.1189; 135.1 (C-6a), 131.2 (C-9), 115.8 (C-6), 111.4 (C-6b), 93.8 (C-7), 60.3
2
1
23
5
found 424.1183.
,8-Dimethoxy-5-propenyl-1-(4-tolylsulfonyl)-2,3-dihydro-1H-
quinolin-4-one O-Methyloxime (28): O-Methylhydroxylamine
hydrochloride (346 mg, 4.15 mmol), NaOAc (340 mg, 4.15 mmol), aaptamine, 1a): Pd/C (20 mol-% Pd, 14 mg) was added to a stirred
(OCH -9), 55.6 (OCH -8), 41.5 (C-2), 32.4 (C-3), 23.8 (ArCH -5) ppm.
3
3
3
+
HRMS: calcd. for C H N O [M + H] 245.1285; found 245.1293.
1
4 17 2 2
7
8,9-Dimethoxy-5-methyl-1H-1,4-diazaphenalene (5-Methyl-
and CeCl ·7H O (23 mg, 0.062 mmol) were successively added to a
stirred solution of 27 (250 mg, 0.62 mmol) in EtOH (5 mL), and
the mixture was heated at reflux overnight. Then, the solvent was
solution of 31 (15 mg, 0.06 mmol) in toluene/n-butanol (3:1,
1.1 mL). The mixture was heated at 160 °C for 48 h under argon
until the starting materials was completely consumed, as confirmed
3
2
evaporated, and the remaining solid was purified by chromatogra- by TLC analysis. After cooling to room temperature, the solids were
phy to yield 28 (204 mg, 76 %) as a white solid; m.p. 142–144 °C
removed by filtration through a short pad of Celite, and the crude
(
7
hexanes/EtOAc). IR (KBr): ν˜ 2934, 1595, 1493, 1340, 1157, 1047, product was purified by column chromatography to give 1a
–1 1
58 cm . H NMR: δ = 7.77 (d, J = 8.1 Hz, 2 H, 2-ArH and 6-ArH of
(12.7 mg, 85 %) as a clear oil. IR (film): ν˜ = 3700–3100, 2920, 2851,
–
1 1
Ts), 7.25 (d, J = 8.1 Hz, 2 H, 3-ArH and 5-ArH of Ts), 6.98 (d, J = 1643, 1634, 1557, 1470, 1393, 1248, 1121, 1040 cm . H NMR
1
5.7 Hz, 1 H, CH CH=CHAr), 6.97 (s, 1 H, 6-H), 6.04 (dq, J = 15.7 and
([D ]MeOH): 7.75 (d, J = 7.1 Hz, 1 H, 2-H), 6.92 (s, 1 H, 7-H), 6.64 (s,
4
3
6
.7 Hz, 1 H, CH CH=CHAr), 3.91 (s, 3 H, OCH -7), 3.87 (s, 3 H, Ar- 1 H, 6-H), 6.32 (d, J = 7.1 Hz, 1 H, 3-H), 4.02 (s, 3 H, OCH
3
-8), 3.90
]MeOH):
3
3
(s, 3 H, OCH
-9), 2.31 (s, 3 H, ArCH
-5) ppm. 13C NMR ([D
NOCH ), 3.68 (s, 3 H, OCH -8), 3.67 (br. s, w = 41.1, 2 H, 2-H), 2.74
3
3
4
3
3
1/2
(
br. s, w1/2 = 22.7 Hz, 2 H, 3-H), 2.42 (s, 3 H, ArCH of Ts), 1.87 (dd,
159.1 (C-8), 151.9 (C-3a), 142.4 (C-2), 140.8 (C-5), 135.1 (C-9a and C-
6a), 132.7 (C-9), 116.7 (C-6b), 112.3 (C-6), 101.3 (C-7), 98.9 (C-3), 61.2
3
1
3
J = 6.7 and 1.4 Hz, 3 H, CH CH=CHAr) ppm. C NMR: δ = 153.3 (C-
3
7
1
1
), 150.1 (C-4), 143.8 (C-8), 143.1 (TsC-4), 138.2 (TsC-1), 133.2 (C-8a),*
(OCH
3
-9), 56.9 (OCH
3
-8), 18.9 (ArCH
3
-5) ppm. HRMS: calcd. for
C H N O [M + H] 243.1128; found 243.1137.
14 15 2 2
+
32.9 (C-4a),* 131.1 (CH CH=CHAr), 129.4 (2 C, TsC-3 and TsC-5),
3
27.5 (2 C, TsC-2 and TsC-6), 125.8 (CH CH=CHAr), 119.5 (C-5), 109.8
3
(
C-6), 61.9 (ArNOCH ), 60.4 (OCH -8), 55.9 (OCH -7), 44.8 (C-2), 27.5
3 3 3
Acknowledgments
The authors are thank the Consejo Nacional de Investigaciones
(C-3), 21.5 (ArCH of Ts), 18.4 (CH CH=CHAr) ppm. HRMS: calcd. for
3
3
+
C H N NaO S [M + Na] 453.1455; found 453.1447.
22
26
2
5
8
,9-Dimethoxy-5-methyl-1-(4-tolylsulfonyl)-2,3-dihydro-1H-1,4- Científicas y Técnicas (CONICET), the Agencia Nacional de Prom-
diazaphenalene (29): A degassed solution of 28 (14 mg, oción Científica y Tecnológica (ANPCyT), and the Secretaría de
.03 mmol) in DMA (3 mL) was placed in a microwave oven and Ciencia y Técnica de la Universidad Nacional de Rosario (SECyT-
0
irradiated at 140 °C for 20 min. Then, the solvent was removed
under vacuum, and the solid residue was purified by chromatogra-
phy to give 29 (10 mg, 77 %) as a yellowish green solid; m.p. 174–
UNR) for the financial support (PIP number 2012-0471, PICT
number 06-2011-0399, and BIO-300). D. A. H. also acknowledges
CONICET for his fellowship.
1
76 °C (EtOAc/EtOH). IR (KBr): ν˜ 2949, 1624, 1578, 1489, 1404, 1339,
–1 1
1
252, 1157, 769, 658 cm . H NMR: δ = 7.85 (d, J = 8.5 Hz, 2 H, 2-
Keywords: Natural products · Total synthesis · Cyclization ·
ArH and 6-ArH of Ts), 7.28 (d, J = 8.5 Hz, 2 H, 3-ArH and 5-ArH of
Ts), 7.22 (s, 1 H, 6-H), 6.88 (s, 1 H, 7-H), 4.09 (t, J = 5.8 Hz, 2 H, 2-H), Nitrogen heterocycles · Isomerization · Dehydrogenation
3
3
.97 (s, 3 H, OCH -8), 3.54 (s, 3 H, OCH -9), 3.31 (t, J = 5.8 Hz, 2 H,
3
3
13
-H), 2.60 (s, 3 H, ArCH -5), 2.42 (s, 3 H, ArCH of Ts) ppm. C NMR:
3
3
[
1] a) K. Shaari, K. C. Ling, Z. M. Rashid, T. P. Jean, F. Abas, S. M. Raof, Z.
Zainal, N. H. Lajis, H. Mohamad, A. M. Ali, Mar. Drugs 2009, 7, 1–8; b)
C. X. Liu, X. L. Tang, P. L. Li, G. Q. Li, Org. Lett. 2012, 14, 1994–1997.
2] A. Rudi, Y. Kashman, Tetrahedron Lett. 1993, 34, 4683–4684.
δ = 156.5 (C-8), 153.5 (C-3a), 150.7 (C-5), 143.3 (TsC-4), 143.0 (C-9),
1
9
7
5
3
38.7 (TsC-1), 134.3 (C-6a), 129.3 (2 C, TsC-3 and TsC-5), 127.2 (C-
a), 127.1 (2 C, TsC-2 and TsC-6), 116.1 (C-6), 115.4 (C-6b), 102.8 (C-
[
), 60.3 (OCH -9), 55.9 (OCH -8), 47.2 (C-2), 32.9 (C-3), 24.0 (ArCH -
3
3
3
[3] a) W. Li, L. Du, M. Li, Curr. Med. Chem. 2011, 18, 4923–4932; b) S. B.
Bharate, S. D. Sawant, P. P. Singh, R. A. Vishwakarma, Chem. Rev. 2013,
113, 6761–6815.
+
), 21.5 (ArCH of Ts) ppm. HRMS: calcd. for C H N O S [M + H]
3
21 23 2 4
99.1373; found 399.1369.
[
4] a) E. L. Larghi, B. V. Obrist, T. S. Kaufman, Tetrahedron 2008, 64, 5236–
Preparation of Sodium Naphthalenide:[33e] Sodium (120 mg,
.2 mmol) and sublimated naphthalene (0.72 g, 5.5 mmol) were
5
245; b) E. L. Larghi, M. L. Bohn, T. S. Kaufman, Tetrahedron 2009, 65,
5
4
257–4282.
successively added to DME (5 mL) under argon, and the mixture
was stirred at room temperature for 2 h to afford a dark green
solution, which was used without further treatment.
[
5] a) L. K. Shubina, A. I. Kalinovsky, S. N. Fedorov, O. S. Radchenko, V. A.
Denisenko, P. S. Dmitrenok, S. A. Dyshlovoy, V. B. Krasokhin, V. A. Stonik,
Nat. Prod. Commun. 2009, 4, 1085–1088; b) H.-B. Yu, F. Yang, F. Sun, G.-
Y. Ma, J.-H. Gan, W.-Z. Hu, B.-N. Han, W.-H. Jiao, H.-W. Lin, J. Nat. Prod.
8
(
(
,9-Dimethoxy-5-methyl-2,3-dihydro-1H-1,4-diazaphenalene
31): A vigorously stirred solution of the N-tosyl derivative 29
32 mg, 0.08 mmol) in DME (1 mL) was cooled to –78 °C and treated
2014, 77, 2124–2129; c) M. Arai, C. Han, Y. Yamano, A. Setiawan, M. Ko-
bayashi, J. Nat. Med. 2014, 68, 372–376; d) L. K. Shubina, T. N. Makarieva,
S. A. Dyshlovoy, S. N. Fedorov, P. S. Dmitrenok, V. A. Stonik, Nat. Prod.
Commun. 2010, 5, 1881–1884.
dropwise with a freshly prepared solution of sodium naphthalenide
until the dark green color of the reagent persisted for 5 min. The
reaction was quenched with water (1–3 drops), and the reaction
was left at –78 °C until the dark green color disappeared. The result-
ing suspension was dried with Na SO and concentrated under re-
[6] N. K. Utkina, V. A. Denisenko, M. A. Pushilin, Tetrahedron Lett. 2009, 50,
2580–2582.
[
[
7] L. Calcul, A. Longeon, A. A. Mourabit, M. Guyot, M.-L. Bourguet-Kon-
dracki, Tetrahedron 2003, 59, 6539–6544.
2
4
8] a) C.-D. Pham, R. Hartmann, W. E. G. Müller, N. de Voogd, D. Lai, P.
Proksch, J. Nat. Prod. 2013, 76, 103–106; b) H.-B. Yu, F. Yang, F. Sun, J. Li,
W.-H. Jiao, J.-H. Gan, W.-Z. Hu, H.-W. Lin, Mar. Drugs 2014, 12, 6003–6013.
9] a) Y. Takahashi, T. Kubota, A. Shibazaki, T. Gonoi, J. Fromont, J. Kobayashi,
Org. Lett. 2011, 13, 3016–3019; b) Y. Takahashi, N. Tanaka, T. Kubota, H.
Ishiyama, A. Shibazaki, T. Gonoi, J. Fromont, J. Kobayashi, Tetrahedron
2012, 68, 8545–8550.
duced pressure. The residue was purified by column chromatogra-
phy to afford 31 (16 mg, 81 %) as a yellowish oil. IR (film): ν˜ = 3600–
–
1 1
3
040, 2934, 2849, 1626, 1574, 1504, 1387, 1144, 1034 cm . H NMR:
[
δ = 7.11 (s, 1 H, 6-H), 6.41 (s, 1 H, 7-H), 4.16 (br. s, w1/2 = 35.1 Hz, 1
H, NH), 3.95 (s, 3 H, OCH -8), 3.84 (s, 3 H, OCH -9), 3.60 (t, J = 6.3 Hz,
3
3
2
H, 2-H), 3.27 (t, J = 6.3 Hz, 2 H, 3-H), 2.58 (s, 3 H, ArCH -5) ppm.
3
Eur. J. Org. Chem. 2016, 1397–1404
www.eurjoc.org
1403
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[
10] a) B. F. Bowden, B. J. McCool, R. H. Willis, J. Org. Chem. 2004, 69, 7791–
[23] a) T. S. Kaufman, J. Braz. Chem. Soc. 2015, 26, 1055–1085; b) P. R. R. Costa,
Quim. Nova 2000, 23, 357–369.
7793; b) J.-D. Klamann, B. Fugmann, W. P. Steglich, Phytochemistry 1989,
2
2
8, 3519–3522; c) J. Carstens, M. R. Heinrich, W. Steglich, Tetrahedron Lett.
013, 54, 5445–5447.
[24] C. C. Silveira, E. L. Larghi, S. R. Mendes, A. B. J. Bracca, F. Rinaldi, T. S.
Kaufman, Eur. J. Org. Chem. 2009, 4637–4645.
[
[
11] F. Stuhldreier, S. Kassel, L. Schumacher, S. Wesselborg, P. Proksch, G. Fritz,
Cancer Lett. 2015, 361, 39–48.
12] S. Tsukamoto, R. Yamanokuchi, M. Yoshitomi, K. Sato, T. Ikeda, H. Rotin-
sulu, R. E. P. Mangindaan, N. J. de Voogd, R. W. M. van Soest, H. Yokosawa,
Bioorg. Med. Chem. Lett. 2010, 20, 3341–3343.
[25] a) H. Cho, Y. Iwama, K. Okano, H. Tokuyama, Chem. Pharm. Bull. 2014,
62, 354–363; b) S. Hibino, E. Sugino, T. Choshi, K. Sato, J. Chem. Soc.
Perkin Trans. 1 1988, 2429–2432.
[
26] a) H. Carrasco, L. Espinoza, V. Cardile, C. Gallardo, W. Cardona, L. Lom-
bardo, K. Catalán, M. Cuellar, A. Russo, J. Braz. Chem. Soc. 2008, 19, 543–
[
[
[
[
13] D. Kudryavtsev, T. Makarieva, N. Utkina, E. Santalova, E. Kryukova, C.
5
48; b) I. M. Sudarma, N. Wazni, N. Wildawaty, E. Yuanita, I. W. Suana,
Methfessel, V. Tsetlin, V. Stonik, I. Kasheverov, Mar. Drugs 2014, 12, 1859–
Asian J. Chem. 2014, 26, 173–175; c) M. Egorov, B. Delpech, G. Aubert, T.
Cresteil, M. C. García-Alvarez, P. Collina, C. Marazano, Org. Biomol. Chem.
1875.
14] a) V. A. Stonik, S. N. Fedorov, Mar. Drugs 2014, 12, 636–671; b) M. Jin, W.
Zhao, Y. Zhang, M. Kobayashi, H. Duan, D. Kong, Int. J. Mol. Sci. 2011, 12,
2014, 12, 1518–1524; d) M. Nakai, T. Enomiya, EP Patent 101223, 1984
[Chem. Abstr. 1984, 101, 54715].
7352–7359.
[
27] a) A. W. Konradi, G. Probst, D. L. Aubele, A. W. Garofalo, R. Hom, M. L.
Neitzel, C. M. Semko, A. P. Truong, U.S. Patent 21056, 2008; b) A. P.
Truong, D. L. Aubele, G. D. Probst, M. L. Neitzel, C. M. Semko, S. Bowers,
D. Dressen, R. K. Hom, A. W. Konradi, H. L. Sham, A. W. Garofalo, P. S.
Keim, J. Wu, M. S. Dappen, K. Wong, E. Goldbach, K. P. Quinn, J.-M. Sauer,
E. F. Brigham, W. Wallace, L. Nguyen, S. S. Hemphill, M. P. Bova, G. Basi,
Bioorg. Med. Chem. Lett. 2009, 19, 4920–4923; c) W. S. Johnson, E. L.
Woroch, B. G. Buell, J. Am. Chem. Soc. 1949, 71, 1901–1905.
15] Q.-l. Li, P.-p. Zhang, P.-q. Wang, H.-b. Yu, F. Sun, W.-z. Hu, W.-h. Wu, X.
Zhang, F. Chen, Z.-y. Chu, J.-p. Zhang, S.-s. Chen, H.-w. Lin, Anti-Cancer
Agents Med. Chem. 2015, 15, 291–297.
16] a) F. Funk, K. Krüger, C. Henninger, W. Wätjen, P. Proksch, J. Thomale, G.
Fritz, Anti-Cancer Drugs 2014, 25, 917–929; b) S. A. Dyshlovoy, S. Venz,
L. K. Shubina, S. N. Fedorov, R. Walther, C. Jacobsen, V. A. Stonik, C.
Bokemeyer, S. Balabanov, F. Honecker, J. Proteomics 2014, 96, 223–239.
17] a) S. A. Dyshlovoy, I. Naeth, S. Venz, M. Preukschas, H. Sievert, C. Jacob-
sen, L. K. Shubina, M. G. Salazar, C. Scharf, R. Walther, M. Krepstakies, P.
Priyadarshini, J. Hauber, S. N. Fedorov, C. Bokemeyer, V. A. Stonik, S. Bal-
abanov, F. Honecker, J. Proteome Res. 2012, 11, 2316–2330; b) S. A. Dysh-
lovoy, S. N. Fedorov, L. K. Shubina, A. S. Kuzmich, C. Bokemeyer, G. Keller-
von-Amsberg, F. Honecker, BioMed Res. Int. 2014, Article ID 469309.
18] Z. Lv, H. S. Wang, X. D. Niu, Chem. Phys. Lett. 2013, 585, 171–177.
19] a) A. Beauchard, A. Jaunet, L. Murillo, B. Baldeyrou, A. Lansiaux, J.-R. Chér-
ouvrier, L. Domona, L. Picot, C. Bailly, T. Besson, V. Thiéry, Eur. J. Med.
Chem. 2009, 44, 3858–3865; b) A. Beauchard, H. Chabane, S. Sinbandhit,
P. Guenot, V. Thiéry, T. Besson, Tetrahedron 2006, 62, 1895–1903.
20] G. Abbiati, A. Doda, M. Dell'Acqua, V. Pirovano, D. Facoetti, S. Rizzato, E.
Rossi, J. Org. Chem. 2012, 77, 10461–10467.
[
[
28] S. Chandrappa, K. Vinaya, T. Ramakrishnappa, K. S. Rangappa, Synlett
2010, 3019–3022.
[
29] a) S. Verma, H. P. Mungse, N. Kumar, S. Choudhary, S. L. Jain, B. Sain,
O. P. Khatri, Chem. Commun. 2011, 47, 12673–12675; b) K. Surendra, N.
Srilakshmi Krishnaveni, R. Sridhar, K. Rama Rao, Tetrahedron Lett. 2006,
4
7, 2125–2127; c) X.-J. Tang, Z.-L. Yan, W.-L. Chen, Y.-R. Gao, S. Mao, Y.-L.
[
[
Zhang, Y.-Q. Wang, Tetrahedron Lett. 2013, 54, 2669–2673.
[
30] K. I. Booker-Milburn, I. R. Dunkin, F. C. Kelly, A. I. Khalaf, D. A. Learmonth,
G. R. Proctor, D. I. C. Scopes, J. Chem. Soc. Perkin Trans. 1 1997, 3261–
3
273.
[
31] a) L. A. Dixon, Polyphosphate Ester, in: e-EROS Encyclopedia of Reagents
for Organic Synthesis, Wiley, Chichester, UK, 2001; b) M. Gerecke, A.
Brossi, Helv. Chim. Acta 1979, 62, 1549–1558; c) C. J. Mathews, P. J. Smith,
T. Welton, J. Mol. Catal. A 2003, 206, 77–82.
[
[
21] a) A. F. Coutinho, B. Chanas, T. M. L. Souza, I. C. P. P. Frugulhetti, R. A.
Epifanio, Heterocycles 2002, 57, 1265–1272; b) G. R. Pettit, H. Hoffmann,
D. L. Herald, J. McNulty, A. Murphy, K. C. Higgs, E. Hamel, N. E. Lewin,
L. V. Pearce, P. M. Blumberg, R. K. Pettit, J. C. Knight, J. Org. Chem. 2004,
[
32] a) J. M. dos Santos Filho, Eur. J. Org. Chem. 2014, 6325–6564; b) R. Lo-
khande, J. Sonawane, A. Roy, L. Ravishankar, Green Chem. Lett. Rev. 2011,
4
, 69–72; c) Z. Li, Z.-Y. Wang, W. Zhu, Y.-L. Xing, Y.-L. Zhao, Synth. Commun.
005, 35, 2325–2331.
33] a) C. C. Silveira, C. R. Bernardi, A. L. Braga, T. S. Kaufman, Synlett 2002,
6
6
9, 2251–2256; c) P. Molina, M. Alajarín, A. Vidal, J. Org. Chem. 1992, 57,
703–6711; d) P. Molina, A. Vidal, I. Barquero, Synthesis 1996, 1199–1202;
2
[
e) G. R. Pettit, H. Hoffmann, J. McNulty, K. C. Higgs, A. Murphy, D. J.
Molloy, D. L. Herald, M. D. Williams, R. K. Pettit, D. L. Doubek, J. N. A.
Hooper, L. Albright, J. M. Schmidt, J. C. Chapuis, L. P. Tackett, J. Nat. Prod.
9
1
06–910; b) Q. Meng, A. Thibblin, J. Am. Chem. Soc. 1997, 119, 1224–
229; c) N. Shohji, T. Kawaji, S. Okamoto, Org. Lett. 2011, 13, 2626–2629;
d) Y. Yoshitomi, H. Arai, K. Makino, Y. Hamada, Tetrahedron 2008, 64,
2004, 67, 506–509; f) A. J. Walz, R. J. Sundberg, J. Org. Chem. 2000, 65,
1
1568–11579; e) S. C. Bergmeier, P. P. Seth, Tetrahedron Lett. 1999, 40,
8001–8010.
6
181–6184.
[
22] a) D. J. Hagan, D. Chan, C. H. Schwalbe, M. F. G. Stevens, J. Chem. Soc.
Perkin Trans. 1 1998, 915–923; b) M. Julino, M. F. G. Stevens, J. Chem. Soc.
Perkin Trans. 1 1998, 1677–1684; c) M. J. Ellis, M. F. G. Stevens, J. Chem.
Soc. Perkin Trans. 1 2001, 3174–3179; d) M. J. Ellis, M. F. G. Stevens, J.
Chem. Res. Synop. 2003, 75–77; e) J. Stanslas, D. J. Hagan, M. J. Ellis, C.
Turner, J. Carmichael, W. Ward, T. R. Hammonds, M. F. G. Stevens, J. Med.
Chem. 2000, 43, 1563–1572.
[
34] H. Wagner, S. Bladt, V. Rickl, Drug Analysis: A Thin Layer Chromatography
Atlas, 2nd ed., Springer, Heidelberg, Germany, 2009, p. 360.
Received: December 13, 2015
Published Online: February 4, 2016
Eur. J. Org. Chem. 2016, 1397–1404
www.eurjoc.org
1404
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim