Concise Synthesis of the ABC-Ring System of the Azafluoranthene, Tropoisoquinoline and Proaporphine Alkaloids: An Olefin Hydroacylation/Pomeranz-Fritsch Cyclization Approach

Article abstract of DOI:10.1055/s-0037-1611711

A straightforward approach toward a decorated cyclopenta[ ij ]isoquinoline embodying the ABC-ring system characteristic of the azafluoranthene (triclisine), tropoisoquinoline (pareitropone) and proaporphine (prodensiflorin B) alkaloids, is reported. The s

Full text of DOI:10.1055/s-0037-1611711

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–I
paper
A
en
D. F. Vargas et al.
Paper
Synthesis
Concise Synthesis of the ABC-Ring System of the Azafluoranthene,
Tropoisoquinoline and Proaporphine Alkaloids: An Olefin Hydro-
acylation/Pomeranz–Fritsch Cyclization Approach
MeO
MeO
MeO
Pomeranz–Fritsch
synthesis
Didier F. Vargas
0
0
0
0-0
0
0
1-6
7
6
9-
6
4
4
2
Hydroacylation
CHO
Enrique L. Larghi*
0
0
0
0-0
0
0
2-
9
7
9
1-4
8
3
1
N
O
MeO
HO
MeO
Teodoro S. Kaufman*
0
0
0
0-
0
0
0
3-3
1
7
3-2
1
7
8
MeO
MeO
Me
Me
Instituto de Química Rosario (IQUIR, CONICET-UNR) and Facultad
de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de
Rosario, Suipacha 531, 2000 Rosario, Argentina
larghi@iquir-conicet.gov.ar
MeO
HO
A
B
7 steps
MeO
N
6.8% overall yield
N
C
N
* Tricyclic common core
of different bioactive
natural products
MeO
kaufman@iquir-conicet.gov.ar
* Protecting-groups-free
synthesis
HO
O
* Endangered/precious metal-
free synthesis
Pareitropone
(tropoisoquinoline)
Triclisine
(azafluoranthene)
Prodensiflorin B
(proaporphine)
Received: 10.09.2018
Accepted after revision: 03.12.2018
Published online: 29.01.2019
rines A (2a) and D (2b) were recently reported from Acorus
tatarinowii Schott, A. graminei (Araceae),6 and the unusual
azafluoranthenic acid 2c (sarumine) was isolated from
Saruma henryi (Aristolochiaceae).7
DOI: 10.1055/s-0037-1611711; Art ID: ss-2018-m0611-op
Abstract A straightforward approach toward a decorated cyclopen-
ta[ij]isoquinoline embodying the ABC-ring system characteristic of the
azafluoranthene (triclisine), tropoisoquinoline (pareitropone) and
proaporphine (prodensiflorin B) alkaloids, is reported. The synthetic
sequence entailed a novel 40% KF/Al2O3-mediated hydroacylation of a
2-allyl-benzaldehyde derivative, obtained in two steps from isovanillin,
through O-allylation and Claisen rearrangement to assemble the AC-
ring system. This was followed by an O-methylation and a reductive
amination of the resulting indanone with aminoacetal. A modified
Pomeranz–Fritsch cyclization was next implemented to install ring B,
through sulfonamidation, followed by acid-promoted cyclization and
final desulfonylation in situ.
R1
R1
MeO
MeO
MeO
MeO
MeO
MeO
A
B
A
B
N
N
N
C
D
C
D
R1
R3
R2
R2
R2
O
2a R1 = OH, R2 = H
2b R1 = H, R2 = OH
2c R1 = H, R2 = CO2H
1a R1 = R3 = OMe, R2 = OH
1b R1 = OMe, R2 = OH, R3 = H
1c R1 = R3 = H, R2 = OH
1d R1 = R2 = OMe, R3 = H
1e R1 = R2 = R3 = OMe
1f R1 = R2 = R3 = H
3a R1 = R2 = H
3b R1 = OMe, R2 = OH
3c R1 = OMe, R2 = OMe
Key words natural products, azafluoranthenes, tropoisoquinolines
and proaporphines, alkaloids, hydroacylation, Pomeranz–Fritsch
cyclization
R1
MeO
MeO
O
A
B
N
N
N
O
MeO
HO
C
The extracts of many plants that are widely used in tra-
ditional medicine systems for treatment of various health
conditions, have been found to contain alkaloids that dis-
play relevant biological activities.1 The azafluoranthenes
are a small class of naturally occurring alkaloids that are
characterized by their unique indeno[1,2,3-ij]isoquinoline
motif.2 They differ in the pattern of their oxygen substitu-
ents. Phenolic members of this family are norimeluteine
(1a), norrufescine (1b) and telitoxine (1c), isolated from the
climbing shrubs Cissampelos pareira, Abuta rufescens, A.
imene, Telitoxicum peruvianum, T. glaziovii Stephania her-
nandifolia and Pericampylus glaucus.3,4 In addition, rufes-
cine (1d), imeluteine (1e) and triclisine (1f), isolated from
the Amazonian vines Abuta rufescens, A. imene and Triclisia
gilletii, respectively,5 are non-phenolic tetracycles that are
also included in this group (Figure 1). These heterocycles
were isolated from Menispermaceae; however, the tata-
R
R3
R
R1
D
R
O
R
O
HO
HO
R2
4a R-R = CH2-CH2, R1 = H
4b R-R = CH2-CH2, R1 = O
4c R-R = CH=CH, R1 = O
4d R-R = CH2-CH2
4e R-R = CH=CH
3d R1 = R2 = OMe, R3 = H
3e R1 = R3 = OMe, R2 = OH
3f R1 = R3 = H, R2 = OH
3g R1 = OMe, R2 = OH, R3 = H
Figure 1 Chemical structures of some natural products carrying the
cyclopenta[ij]isoquinoline motif
The azafluoranthenes exhibit promising antidepressant,
healing, cytotoxic, anti-HIV and antifungal activity;3d,8 in
addition, triclisine and rufescine have been predicted to
display a number of relevant biological activities.9 The in-
terest in these natural products has resulted in different
synthetic and medicinal chemistry endeavors.5a,10,11
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

B
D. F. Vargas et al.
Paper
Synthesis
Some azafluoranthenes have environmental impact, be-
ing considered air pollutants and priority contaminants,12
while others display potentially valuable technological ap-
plications in luminescent and electroluminescent devices.13
Analogously, the tropo- and tropolo-isoquinolines are a
biogenetically related reduced group of Menispermaceae
natural products, bearing a poly-substituted 9H-azule-
no[1,2,3-ij]isoquinoline framework, which differ in the dec-
oration of oxygenated functions along the molecular pe-
riphery.14 Pareitropone (3a), grandirubrine (3b), and
isoimerubrine (3c), as well as imerubrine (3d), the pareiru-
brines A (3e) and B (3f), and granditropone (3g),4b,15 are its
most recognized members.
The sources of these heterocycles were Abuta rufescens,
A. imene, A. concolor, A. grandifolia, and Cissampelos pareira.
The compounds exhibited cytotoxic properties and antileu-
kemic activity against P-388 cells,16 and a number of efforts
have been made towards their synthesis.17
In addition, proaporphine alkaloids that display a fully
aromatic isoquinoline framework, are rather scarce. This
family includes prodensiflorin B (4a), compound 4b and
their oxidized congeners including prooxocryptochine (4c),
grandine A (4d) and scortechiniine B (4e), which have been
isolated from various ethnobotanically relevant plants, such
as Thalictrum wangii B. Boivin (Ranunculaceae) and Crypto-
carya densiflora Blume (Lauraceae).18
MeO
MeO
MeO
MeO
MeO
HO
A
B
N
N
N
C
D
HO
Prodensiflorin B (4a)
O
Triclisine (1f)
Pareitropone (3a)
Structural simplification
Pomeranz–Fritsch type
isoquinoline synthesis
MeO
MeO
O
A
Me
N
O
MeO
C
Reductive
amination
O-Methylation
Me
Me
Intramolecular hydroacylation
5
6
MeO
HO
MeO
A
CHO
HO
Claisen rearrangement
CHO
Isovanillin (8)
7
Scheme 1 Structural simplification of triclisine (1f), pareitropone (3a),
and prodensiflorin B (4a) and retrosynthetic analysis of the resulting cy-
clopenta[ij]isoquinoline 5
The azafluoranthenes, tropoisoquinolines and proapor-
phines share a tricyclic cyclopenta[ij]isoquinoline frame-
work. We have previously disclosed an electrocyclization-
mediated approach to 2-methyltriclisine, an unnatural ana-
logue of the azafluoranthene alkaloid triclisine,19 as well as
modified Pomeranz–Fritsch cyclization-mediated syntheses
of the ABC ring system of the related stephaoxocane alka-
loids,20a and other alternatives affording analogues of the
latter.20b–e
In pursuit of our efforts towards the preparation of ana-
logues of isoquinoline-type natural products, herein we
wish to report a hydroacylation/Pomeranz–Fritsch cycliza-
tion approach for the synthesis of the ABC ring system char-
acteristic of the azafluoranthene, tropoisoquinoline, and
proaporphine alkaloids. The synthetic sequence was based
on the retrosynthetic analysis outlined in Scheme 1.
Initially, triclisine (1f), imerubrine (3d), and prodensi-
florin B (4a) were taken as models and structurally simpli-
fied, uncovering the tricycle 5 as the target; the latter was
then disconnected at the indicated C–C and C–N bonds of
the heterocyclic ring, unveiling the indanone 6 as a suitable
precursor, under the assumption that the heterocyclic ring
could be built through a reductive amination of the ketonic
scaffold, followed by a Pomeranz–Fritsch cyclization se-
quence. A similar indanone was recently employed to build
the tricyclic core of the unusual cyclopenta[de]isoquinoline
alkaloid delavatine A.21
Further analysis that suggested two strategic C–C and
C–O bond disconnections of 6, revealed the ortho-allyl
benzaldehyde 7 as a key intermediate. This was guided by
the conjecture that the indanone motif 6 could be accessed
through an atom economic intramolecular olefin hydroacy-
lation.
A final C–C bond disconnection of 7 proposed the instal-
lation of the allyl substituent through a Claisen rearrange-
ment. This required the inclusion of an O-methylation stage
and suggested the use of the inexpensive and easily avail-
able isovanillin (8) as starting material.
As planned, the synthesis commenced with the O-al-
lylation of isovanillin (8), followed by Claisen rearrange-
ment of the resulting allyl ether 9, to afford 89% overall
yield of the foreseen intermediate 7 (Scheme 2).
In turn, the proposed intramolecular hydroacylation to-
ward 10 was explored. This kind of reaction has been per-
formed primarily under promotion by transition-metal
complexes (mainly derived from expensive, rare elements)
and/or comparatively expensive N-heterocyclic carbenes.22
Fortunately, however, we have found that the use of 40%
KF/Al2O3 reagent23 can promote such transformation, in
moderate yields, providing that a free phenol is located
ortho to the allyl moiety.
Therefore, 2-allylbenzaldehyde 7 was exposed to 40%
w/w KF/Al2O3 and heated in ethylene glycol to 160 °C. Un-
der conventional thermal conditions and a 2:1 ratio (molar
relation between the amount of KF in the solid promoter
and compound 7), this afforded 30% yield of 10 after 2.5
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

C
D. F. Vargas et al.
Paper
Synthesis
Increasing the amount of promoter to a 4:1 ratio caused
diminished yields (Table 1, entry 6), and lowering the ratio
(1:1 or lower) also resulted in recovery of the starting mate-
rial after 30 min. Under the optimized conditions, 57% yield
of the 5-exo-trig cyclized product 10 was achieved (entry
3). No evidence of the endo cyclization isomer was observed
by NMR analysis of the crude reaction product. Although
the precise details of the reaction mechanism leading to in-
danone 10 remain unknown, a mechanistic picture like that
shown in Scheme 3 can be drawn on the basis of literature
precedents. It can be proposed that the reagent can abstract
a benzylic proton, generating the allyl anion intermediate
A. In turn, the latter can abstract the formyl hydrogen and
trigger the formation of the ketene derived anionic inter-
mediate B. Next, an intramolecular attack of the allyl car-
banion onto the carbonyl carbon of the ketene moiety, with
capture of a proton from the reagent would result in forma-
tion of the observed product 10. Notably, it has been re-
ported that the presence of ethylene glycol somehow pro-
tects allylphenols exposed to KF/Al2O3 from heat-mediated
deterioration.24
6
MeO
RO
MeO
HO
MeO
5
b
7
c
4
7a
O
CHO
CHO
RO
3a
1
3
2
Me
8 R = H
9 R = CH2CH=CH2
7
10 R = H
6 R = Me
a
d
OMe
OMe
OMe
OMe
e
MeO
MeO
MeO
+
(S)
(R)
N
N
R
MeO
R
(R)
(R)
Me
Me
(
(
)-11a R = H
(
(
)-11b R = H
)-12b R = Ts
f
f
)-12a R = Ts
Scheme 2 Reagents and conditions: (a) BrCH2CH=CH2, K2CO3, EtOH, re-
flux, 3 h; (b) MW (200 °C), 5 min (89% overall); (c) 40% KF/Al2O3, ethylene
glycol, MW, 160 °C, 30 min (57%); (d) MeI, K2CO3, EtOH, reflux, 2 h (82%);
(e) 1. H2NCH2CH(OMe)2 (6 equiv), AcOH (4.2 equiv), MgSO4, 3 Å MS,
EtOH, r.t., 20 h; 2. NaCNBH3, reflux, 24 h (11a, 44%; 11b, 43%); (f) TsCl,
iPr2NEt, CHCl3, reflux (11a→12a, 48 h, 83%; 11b→12b, 24 h, 95%).
hours (Table 1, entry 1) and no starting material could be
recovered. However, better results were obtained upon
brief microwave irradiation at the same temperature (en-
tries 2–5), with optimum yields being achieved in 30 min-
utes (entry 3). The relative amount of the promoter was
also optimized (entries 3, 6–9), with a 2:1 ratio (KF/Al2O3 to
7) providing the best reaction performance.
KF/Al2O3
(
),
KFAl
O
O
MW (160 °C)
OH
H
H
H
HO
MeO
MeO
O
H
O
H
H
H
KFAl
O
KFAl
KFAl
Table 1 Optimization of the Intramolecular Hydroacylation of 7
7
A
KFAl
ethylene glycol
160 °C, conditions
MeO
HO
MeO
HO
O
C
H
O
CHO
Me
H
H
MeO
MeO
Me
O
H
OH
7
10
H
KFAl
10
B
Entry
Heatingb
Time
(min)
Yield (%) Recovery
of 10
Ratio KF/Al2O3
to 7a
(%) of 7
Scheme 3 Proposed mechanism for the KF/Al2O3-promoted intramo-
lecular hydroacylation of ortho-allylbenzaldehyde 7 into indanone deriv-
ative 10
1
2
3
4
5
6
7
8
9
Thermal
MW
150
15
30
45
60
30
30
30
30
30
44
57
51
50
52
38
31
27
0
0
2:1
2:1
MW
0
2:1
Conventional alkylation of phenol 10 with MeI and
K2CO3 as base in refluxing EtOH furnished 6 in 82% yield. In-
terestingly, this compound has been prepared in an alter-
nate way in the context of examining the activity of E2020
(currently marketed as donepezil) and its analogues,25 as
potential candidates for treatment of mild to moderate cog-
nitive disorders of Alzheimer’s disease and related demen-
tias.
The indanone was then subjected to a reductive amina-
tion with aminoacetaldehyde dimethyl acetal, in the pres-
ence of anhydrous MgSO4 and 3Å molecular sieves, as water
scavengers. Acetic acid was added to promote condensation
toward the intermediate imine and cause further iminium
ion formation. The latter was selectively reduced with
MW
0
2:1
MW
0
2:1
MW
0
4:1
MW
0
1.5:1
1.0:1
0.5:1
MW
15
28
MW
a Molar ratio between the amount of KF and compound 7. The experiments
were carried out at a final concentration of 0.2 mmol of 7 in 1 mL of eth-
ylene glycol.
b MW: microwave heating.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

D
D. F. Vargas et al.
Paper
Synthesis
NaCNBH3 in refluxing EtOH,26 affording 87% of the expected
amine 11, as a ca. 1:1 mixture of diastereomers, which were
chromatographically separated, to provide 44% yield of (±)-
11a and 43% (±)-11b (87% combined yield).
Therefore, after screening different conditions, and in
light of our success with this alternative, the use of Lewis
acid promotion was examined (Scheme 4). Thus, (±)-12a
was exposed to SnCl4 in anhydrous CH2Cl2 at –60 °C. This
resulted in a series of unidentified products, along with (±)-
13a, which was obtained in 35% yield, as an inseparable
mixture of diastereomers,25b as stemmed from the charac-
teristic signals of the 4-OMe groups (δ = 3.33 and 3.45 ppm,
singlets) and the aromatic proton (δ = 6.58 and 6.75 ppm,
singlets) in the 1H NMR spectrum.
The relative stereochemistry of the amines (±)-11a,b
could not be deduced unambiguously from their 1H and 13
C
NMR spectra; therefore, it was investigated with the aid of
nuclear Overhauser effect (NOE) experiments. As shown in
Figure 2, these suggested that compound (±)-11a, which
displayed H-2 and H-3 signal enhancements but lacked sig-
nal increase of H-1 upon irradiation of Me-2, should be the
1,2-cis diastereomer. This was unequivocally confirmed by
examination of the amine (±)-11b, to which the 1,2-trans
stereochemistry should be attributed, after exhibiting
signal enhancements of H-1, H-2 and H-3 upon irradiation
of Me-2.
OMe
OMe
OMe
OMe
MeO
MeO
MeO
MeO
N
N
(S)
(R)
Ts
Ts
(R)
(R)
Me
Me
b
b
(
)-12b
(
)-12a
Me
O
Me
O
a
a
Me
H
O
H
Me
H
O
H
H
H
OMe
OMe
H
H
H
H
MeO
MeO
MeO
Me
H
H
N
H
N
H
H
H
Me
N
H
MeO
N
H
MeO
Ts
MeO
Ts
H
H
MeO
MeO
Me
11a
11b
Me
(
)-13a
( )-13b
4
3
Me
O
Me
3a
3b
c
MeO
MeO
5
2
Me
H
O
Me
O
O
N1
6
H
H
6a
8a
H
H
H
H
H
Me
8 Me
7
H
O
H
N
H
H
H
H
Me
H
H
H
N
MeO
MeO
5
O
O
S
S
MeO
MeO
O
Scheme 4 Reagents and conditions: (a) SnCl4, CH2Cl2, –60 °C, 1 h
(12a→13a, 35%; 12b→13b, 62%); (b) AlCl3, MeNO2, r.t., overnight
(12a→5, 15%; 12b→5, 3%) or 20% TFA in dioxane, 100 °C, 1.5 h
(12a→5, 45%); (c) KOtBu, pyridine, 100 °C, 30 min (63%).
Me
Me
12a
12b
Figure 2 Nuclear Overhauser effect (NOE) signal enhancements ob-
served in compounds 11a,b and 12a,b
On the other hand, the reaction of (±)-12a with AlCl3 in
nitromethane at room temperature proceeded smoothly to
give 5, which was isolated in 15% yield, through the one-pot
cyclization-aromatizing desulfonylation.29 Better perfor-
mance was achieved with 20% trifluoroacetic acid (TFA) in
refluxing dioxane, which gave compound 5 in 45% isolated
yield.30
Similar results were obtained with the 2,3-trans-substi-
tuted sulfonamidoacetal (±)-12b, which afforded 62% yield
of (±)-13b as a mixture of diastereomers when submitted to
reaction with SnCl4. Its characteristic signals in the 1H NMR
spectrum were singlets at δ = 3.32 and 3.38 ppm (4-OMe)
and signals of the aromatic proton as singlets at δ = 6.58
and 6.71 ppm. These results indicate that the relative ste-
reochemistry of the substituents on the five-membered
ring have no significant impact on the outcome of the cy-
clization stage. Without purification, (±)-13b was exposed
to KtBuO in refluxing pyridine, resulting in the isolation of 5
The amines 11a,b were individually submitted to a reac-
tion with tosyl chloride in refluxing chloroform, employing
DIPEA as HCl scavenger. This resulted in the acquisition of
12a and 12b in 83% and 95% yield, respectively. Analysis of
the NOE spectra of these sulfonamides confirmed previous
stereochemical assignments of their precursors. Irradiation
of H-1 of 12a resulted only in signal intensification of H-2,
whereas irradiation of H-1 of 12b augmented the signals of
Me-2 and H-3.
Subsequent exposure of the sulfonamidoacetals to cy-
clization under the conventional conditions of the Jackson
modification of the Pomeranz–Fritsch cyclization (6 N HCl,
dioxane, reflux)27 met with failure. This outcome was not
unexpected, probably being a result of the improper activa-
tion of the aromatic ring toward cyclization, due to the or-
tho-disubstituted condition of the methyl ether located in
the para position with regards to the cyclization site.26b,28
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

E
D. F. Vargas et al.
Paper
Synthesis
in 63% yield. This result contrasted markedly with those of
an attempt at cyclization with AlCl3 in nitromethane, which
gave only 3% yield of 5.
FOR (Buenos Aires, Argentina) with Bruker MicroTOF-Q II instru-
ments. Detection of the ions was performed in electrospray ioniza-
tion, positive ion mode. Microwave-assisted reactions were carried
out in a CEM-Discover microwave reactor system.
In conclusion, we have developed convenient syntheses
of two polysubstituted cyclopenta[ij]isoquinoline deriva-
tives, which embody the ABC-ring system of the azafluo-
ranthene, tropoisoquinoline, and proaporphine alkaloids.
The synthetic sequence toward 5 proceeded in seven steps
and 6.8% overall yield, from the easily available isovanillin.
The synthesis was executed without the use of rare transi-
tion-metal derivatives and did not require protecting
groups, and took place through the novel use of 40%
KF/Al2O3 as promoter of a key microwave-assisted intramo-
lecular hydroacylation to access an indanone key interme-
diate, embodying the AC-ring system of the natural prod-
ucts. This transformation was associated with a reductive
amination, followed by different modifications of the
Pomeranz–Fritsch isoquinoline synthesis protocol (TFA/di-
oxane, SnCl4-KtBuO, AlCl3/MeNO2), for the formation of the
remaining heterocyclic B-ring.
23
Preparation of 40% w/w KF/Al2O3
Al2O3 (7.5 g) was suspended in deionized water (38 mL) and magneti-
cally stirred for 5 minutes (pH of the liquid phase: 7.6). The mixture
was then treated with a solution of KF (5 g) in deionized water (38
mL, pH of the solution: 6.5). The resulting suspension was continu-
ously stirred until the pH of the liquid phase was 11.5–11.7. Most of
the water was then removed from the system by rotatory evapora-
tion, and the resulting wet solid mass was dried at 140–150 °C for 6 h
under reduced pressure (200 mbar). The so obtained solid mass was
ground in a mortar into a fine homogeneous powder.
2-Allyl-3-hydroxy-4-methoxybenzaldehyde (7)20a
A suspension of isovanillin (8, 500 mg, 3.3 mmol), allyl bromide
(0.363 mL, 4.2 mmol) and anhydrous K2CO3 (635 mg, 4.6 mmol) in ab-
solute EtOH (5 mL) was heated at reflux for 3 h. After completion of
the reaction, the solvent was evaporated, brine (5 mL) was added to
the residue, and the product was extracted with EtOAc (3 × 20 mL).
The combined organic phases were washed with brine (20 mL), dried
over MgSO4, filtered, and concentrated. A small sample of the result-
ing 3-allyloxy-4-methoxybenzaldehyde (9) was analyzed spectro-
scopically.
All the reactions were carried out under anhydrous argon atmo-
sphere, using oven-dried glassware and freshly distilled anhydrous
solvents. Anhydrous EtOH was obtained by reaction of the AR reagent
with magnesium turnings and a crystal of iodine, followed by distilla-
tion of the solvent from the so formed magnesium ethoxide. Anhy-
drous chloroform was obtained by a 4 h reflux of the AR product over
P2O5 and further distillation of the product. Anhydrous CH2Cl2 was
obtained from an M. Braun solvent purification and dispenser system.
Anhydrous 1,2-dichlorobenzene was prepared by refluxing the sol-
vent over CaH2 for 4 h, followed by distillation. The anhydrous sol-
vents were transferred by using a cannula and stored in dry Young
ampoules containing activated molecular sieves. All of the other sol-
vents and reagents were used as received.
IR (film): 2934, 2841, 1686, 1585, 1436, 1397, 1268, 1134, 1018, 932,
811, 757, 641 cm–1
.
1H NMR: δ = 3.96 (s, 3 H, OMe), 4.67 (dt, J = 1.3, 5.3 Hz, 2 H,
OCH2CH=CH2), 5.32 (dd, J = 1.3, 10.5 Hz, 1 H, OCH2CH=CH2cis), 5.44
(dd, J = 1.3, 17.3 Hz, 1 H, OCH2CH=CH2trans), 6.10 (dddd, J = 5.3, 10.5,
17.3 Hz, 1 H, OCH2CH=CH2), 6.99 (d, J = 8.1 Hz, 1 H, 5-H), 7.41 (d, J =
1.9 Hz, 1 H, 2-H), 7.47 (dd, J = 1.9, 8.1 Hz, 1 H, 6-H), 9.84 (s, 1 H, CHO).
13C NMR: δ = 56.1 (OMe), 69.6 (OCH2CH=CH2), 110.6 (C-5),* 110.8 (C-2),*
118.5 (OCH2CH=CH2), 126.7 (C-6), 129.9 (C-1), 132.4 (OCH2CH=CH2),
148.4 (C-3), 154.7 (C-4), 190.7 (CHO).
Without additional purification, the oily residue was transferred to a
microwave reaction tube, argon was bubbled to create a suitable at-
mosphere and the oil was irradiated in the microwave reactor (200 °C,
ca. 50 W, 5 min). After cooling, the resulting thick oil was purified by
silica gel column chromatography, furnishing 7.
The reactions were monitored by TLC, using silica gel GF254 plates
supported on aluminum and run in different hexane–EtOAc solvent
mixtures. The chromatographic spots were detected by exposure to
254 nm UV light, and by spraying with ethanolic p-anisaldehyde/sul-
furic acid reagent, 0.1% ninhydrin in EtOH or Dragendorff reagent, fol-
lowed by careful heating to improve selectivity. Flash column chro-
matography was performed with silica gel 60 H (particle size < 55
μm), eluting with hexane–EtOAc mixtures, under positive pressure
and employing gradient of solvent polarity techniques.
Yield: 564 mg (89% overall yield from 8); solid; mp 51–53 °C.
IR (KBr): 3425, 2954, 2850, 1679, 1600, 1575, 1492, 1345, 1279, 1165,
1084, 915, 804, 785, 656 cm–1
.
1H NMR: δ = 3.88 (dt, J = 1.7, 6.0 Hz, 2 H, ArCH2CH=CH2), 3.97 (s, 3 H,
OMe), 4.99 (ddt, J = 1.7, 1.7, 17.1 Hz, 1 H, ArCH2CH=CH2trans), 5.01 (ddt,
J = 1. 7, 1.7, 10.7 Hz, 1 H, ArCH2CH=CH2cis), 5.79 (s, 1 H, OH), 6.03 (ddt,
J = 6.0, 10.7, 17.1 Hz, 1 H, ArCH2CH=CH2), 6.88 (d, J = 8.4 Hz, 1 H, 5-H),
7.44 (d, J = 8.4 Hz, 1 H, 6-H), 10.07 (s, 1 H, CHO).
13C NMR: δ = 28.3 (ArCH2CH=CH2), 55.0 (OMe), 108.0 (C-5), 115.2
(ArCH2CH=CH2), 125.3 (C-6), 127.5 (C-1), 128.2 (C-2), 136.1
(ArCH2CH=CH2), 143.7 (C-3), 150.7 (C-4), 191.3 (CHO).
Melting points were measured with an Ernst Leitz Wetzlar model 350
hot-stage microscope and are uncorrected. FTIR spectra were ac-
quired with a Shimadzu Prestige 21 spectrophotometer, with the
samples prepared as solid dispersions in KBr disks or as thin films
held between NaCl cells. Nuclear magnetic resonance spectra were re-
corded with a Bruker Avance 300 NMR spectrometer, at 300.13 (1H)
and 75.48 (13C) MHz. CDCl3 was used as solvent, unless otherwise
noted, and the chemical shifts are reported in parts per million in the
δ scale. TMS was used as the internal standard (resonances of CHCl3 in
CDCl3: δ = 7.26 and 77.0 ppm for 1H and 13C NMR, respectively). Cou-
pling constants (J) are given in Hertz. Pairs of signals marked with as-
terisk (*) indicate that their assignments may be exchanged. Some 2D
NMR experiments (COSY, HSQC, HMBC) were performed concomi-
tantly to aid unambiguous signal assignment. High-resolution mass
spectra were obtained from ICYTAC (Córdoba, Argentina) and UMYM-
4-Hydroxy-5-methoxy-2-methyl-2,3-dihydro-1H-inden-1-one
(10)
A stirred mixture of 7 (100 mg, 0.52 mmol) and 40% KF/Al2O3 (64 mg)
in anhydrous ethylene glycol (2.6 mL), was placed in a microwave vial
and degassed under vacuum for 20 min. The suspension was then ir-
radiated in a microwave oven at 160 °C for 30 min. After cooling, gla-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

F
D. F. Vargas et al.
Paper
Synthesis
cial acetic acid (2 mL) was added to the reaction mixture and the sys-
tem was stirred for 45 min. Brine (5 mL) was added and the organic
products were extracted with EtOAc (3 × 20 mL). The combined or-
ganic phases were washed with water (10 mL) and brine (5 mL), dried
over MgSO4, filtered, and concentrated under reduced pressure. The
resulting residue was purified by column chromatography to give in-
danone 10.
Compound (±)-11a
Yield: 111 mg (44%); yellow oil.
IR (NaCl): 3300–3650, 3339, 2953, 2936, 2870, 2832, 1611, 1487,
1373, 1271, 1132, 1078, 968, 812, 721 cm–1
.
1H NMR: δ = 0.98 (d, J = 6.8 Hz, 3 H, Me-2), 1.47 (br s, w1/2 = 11.5 Hz,
1 H, NH), 2.56–2.69 (m, 1 H, H-2), 2.66 (dd, J = 5.2, 16.4 Hz, 1 H, H-3),
2.81 (d, J = 5.5 Hz, 2 H, NCH2-), 2.94 (dd, J = 8.4, 17.0 Hz, 1 H, H-3),
3.38 (s, 3 H, OMe, acetal), 3.40 (s, 3 H, OMe, acetal), 3.83 (s, 3 H, OMe-
4), 3.84 (s, 3 H, OMe-5), 3.99 (d, J = 5.8 Hz, 1 H, H-1), 4.50 (t, J = 5.5 Hz,
1 H, NCH2CH<), 6.74 (d, J = 8.1 Hz, 1 H, H-6), 6.98 (d, J = 8.1 Hz, 1 H, H-7).
Yield: 57 mg (57%); yellow solid; mp 135–138 °C.
IR (KBr): 3550–3040, 2967, 2930, 2880, 2849, 1694, 1607, 1501, 1439,
1364, 1279, 1184, 1078, 905, 820, 773, 669 cm–1
.
1H NMR: δ = 1.29 (d, J = 7.3 Hz, 1 H, Me-2), 2.63 (dd, J = 3.8, 16.9 Hz,
1 H, H-3), 2.71 (ddq, J = 3.8, 7.3, 7.5 Hz, 1 H, H-2), 3.34 (dd, J = 7.5,
16.9 Hz, 1 H, H-3), 3.95 (s, 3 H, OMe), 5.85 (br s, OH), 6.91 (d, J =
8.2 Hz, 1 H, H-6), 7.34 (d, J = 8.2 Hz, 1 H, H-7).
13C NMR: δ = 13.8 (Me-2), 35.5 (C-3), 38.4 (C-2), 49.4 (NCH2-), 54.1
(OMe, acetal), 54.2 (OMe, acetal), 56.2 (OMe-5), 60.4 (OMe-4), 65.1
(C-1), 104.5 (NCH2CH<), 110.8 (C-6), 119.6 (C-7), 135.4 (C-3a), 138.8
(C-7a), 145.7 (C-5), 151.8 (C-4).
13C NMR: δ = 16.7 (Me-2), 31.1 (C-3), 42.3 (C-2), 56.5 (OMe), 110.6 (C-
6), 116.5 (C-7), 130.8 (C-7a), 138.9 (C-3a), 142.2 (C-4), 151.1 (C-5),
208.5 (C-1).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H25NNaO4: 318.1681;
found: 318.1675.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H12NaO3: 215.0684;
Compound (±)-11b
found: 215.0681.
Increasing solvent polarity furnished (±)-11b.
Yield: 110 mg (43%); greenish yellow oil.
IR (NaCl): 2949, 2936, 2866, 2832, 1609, 1489, 1271, 1221, 1128,
4,5-Dimethoxy-2-methyl-2,3-dihydro-1H-inden-1-one (6)
A mixture of indanone 10 (216 mg, 1.1 mmol) and K2CO3 (304 mg, 2.2
mmol) in absolute EtOH (5 mL) was stirred for 10 min under argon.
MeI (0.205 mL, 3.3 mmol) was then added, and the resulting suspen-
sion was heated at reflux for 2 h. After completion of the reaction, the
solvent was removed under reduced pressure, brine (5 mL) was added
to the residue, and the products were extracted with EtOAc (3 × 15
mL). The combined organic phases were dried over MgSO4, filtered,
and concentrated under reduced pressure. The residue was purified
by column chromatography to afford compound 6.
1076, 964, 810 cm–1
.
1H NMR: δ = 1.15 (d, J = 6.8 Hz, 3 H, Me-2), 1.51 (br s, w1/2 = 14.5 Hz,
1 H, NH), 2.23–2.37 (m, 1 H, H-2), 2.44 (dd, J = 6.2, 16.0 Hz, 1 H, H-3),
2.80 (dd, J = 5.5, 12.0 Hz, 1 H, -NCH2-), 2.84 (dd, J = 5.5, 12.0 Hz, 1 H,
NCH2-), 3.20 (dd, J = 7.5, 16.0 Hz, 1 H, H-3), 3.38 (s, 6 H, 2 × OMe, ace-
tal), 3.73 (d, J = 5.5 Hz, 1 H, H-1), 3.83 (s, 3 H, OMe-4), 3.84 (s, 3 H,
OMe-5), 4.48 (t, J = 5.5 Hz, 1 H, NCH2CH<), 6.76 (d, J = 8.1 Hz, 1 H, H-6),
6.97 (d, J = 8.1 Hz, 1 H, H-7).
13C NMR: δ = 19.7 (Me-2), 35.7 (C-3), 41.3 (C-2), 48.3 (NCH2-), 54.0
(OMe, acetal), 54.2 (OMe, acetal), 56.3 (OMe-5), 60.3 (OMe-4), 70.1
(C-1), 104.6 (NCH2CH<), 111.3 (C-6), 119.5 (C-7), 135.7 (C-3a), 138.6
(C-7a), 145.5 (C-5), 151.9 (C-4).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C16H25NNaO4: 318.1681;
found: 318.1684.
Yield: 180 mg (82%); yellow solid; mp 72–75 °C.
IR (KBr): 2968, 2934, 2872, 2848, 1699, 1599, 1497, 1339, 1279, 1177,
1069, 978, 822, 775, 610 cm–1
.
1H NMR: δ = 1.29 (d, J = 7.2 Hz, 3 H, Me-2), 2.67 (dd, J = 4.0, 15.6 Hz,
1 H, H-3), 2.70 (ddq, J = 4.0, 7.2, 8.8 Hz, 1 H, H-2), 3.39 (dd, J = 8.8,
18.3 Hz, 1 H, H-3), 3.91 (s, 3 H, OMe-4), 3.94 (s, 3 H, OMe-3), 6.97 (d, J
= 8.3 Hz, 1 H, H-6), 7.52 (d, J = 8.3 Hz, 1 H, H-7).
13C NMR: δ = 16.6 (Me-2), 31.7 (C-3), 42.3 (C-2), 56.3 (OMe-5), 60.5
(OMe-4), 112.5 (C-6), 120.6 (C-7), 130.5 (C-7a), 145.5 (C-3a), 146.3
(C-4), 157.7 (C-5), 208.0 (C-1).
N-((1R*,2R*)-4,5-Dimethoxy-2-methyl-2,3-dihydro-1H-inden-1-
yl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide [(±)-
12a]
To a stirred solution of amine (±)-11a (100 mg, 0.34 mmol) in anhy-
drous CHCl3 (5 mL) were successively added DIPEA (0.119 mL, 0.68
mmol) and tosyl chloride (117 mg, 0.61 mmol). The mixture was
heated under reflux for 48 h, when it was cooled to r.t., and most of
the organic solvent was removed under reduced pressure. The result-
ing residue was purified chromatographically to furnish the tosyl-
amide (±)-12a.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H14NaO3: 229.0841;
found: 229.0837.
(1R*,2R*)-N-(2,2-Dimethoxyethyl)-4,5-dimethoxy-2-methyl-2,3-
dihydro-1H-inden-1-amine [(±)-11a] and (1S*,2R*)-N-(2,2-Dime-
thoxyethyl)-4,5-dimethoxy-2-methyl-2,3-dihydro-1H-inden-1-
amine [(±)-11b]
Yield: 127 mg (83%); pale-yellow solid; mp 84–87 °C.
Aminoacetaldehyde dimethylacetal (0.549 mL, 5 mmol) and glacial
acetic acid (0.192 mL, 3.36 mmol) were successively added to a sus-
pension containing the indanone 6 (175 mg, 0.84 mmol), MgSO4 (50
mg), and activated 4 Å molecular sieves (50 mg) in absolute EtOH (6
mL). The mixture was stirred for 20 h at r.t., then NaCNBH3 (63 mg, 1
mmol) was carefully added. The resulting slurry was heated at reflux
for 24 h, then cooled to r.t. and the volatiles were removed in vacuum.
The resulting residue was purified by column chromatography to fur-
nish the expected amine (±)-11a.
IR (KBr): 2955, 2934, 2872, 2835, 1611, 1595, 1491, 1341, 1269, 1125,
1061, 970, 800, 791, 673 cm–1
.
1H NMR: δ = 1.16 (d, J = 6.6 Hz, 3 H, Me-2), 2.33 (dd, J = 9.3, 15.6 Hz,
1 H, H-3), 2.46 (s, 3 H, ArMe of Ts), 2.50–2.68 (m, 1 H, H-2), 2.82 (dd,
J = 7.6, 15.4 Hz, 1 H, NCH2-), 3.11 (dd, J = 8.1, 15.6 Hz, 1 H, H-3), 3.28
(dd, J = 3.0, 15.4 Hz, 1 H, NCH2-), 3.33 (s, 3 H, OMe, acetal), 3.46 (s, 3 H,
OMe, acetal), 3.76 (s, 3 H, OMe-5), 3.78 (s, 3 H, OMe-4), 4.66 (dd, J =
3.0, 7.6 Hz, 1 H, NCH2CH<), 4.83 (d, J = 8.8 Hz, 1 H, H-1), 5.77 (d, J =
8.0 Hz, 1 H, H-6), 6.47 (d, J = 8.0 Hz, 1 H, H-7), 7.33 (d, J = 8.0 Hz, 2 H,
H-3 and H-5 of Ts), 7.82 (d, J = 8.0 Hz, 2 H, H-2 and H-6 of Ts).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

G
D. F. Vargas et al.
Paper
Synthesis
13C NMR: δ = 17.6 (Me-2), 21.7 (Ar-Me of tosyl), 34.7 (C-3), 40.3 (C-2),
47.5 (NCH2-), 54.9 (OMe, acetal), 56.2 (OMe-5), 57.0 (OMe-acetal),
60.4 (OMe-4), 70.5 (C-1), 105.4 (NCH2CH<), 111.2 (C-7), 119.1 (C-6),
127.6 (Ar-2 and Ar-6 of tosyl), 129.9 (Ar-3 and Ar-5 of tosyl), 133.7 (C-
3a), 135.8 (C-7a), 137.6 (Ar-1 of tosyl), 143.6 (Ar-4 of tosyl), 145.3 (C-
4), 152.0 (C-5).
5,6-Dimethoxy-8-methyl-7,8-dihydrocyclopenta[ij]isoquinoline
(5) from (±)-12b
A stirred solution of tosylacetal (±)-12b (58 mg, 0.13 mmol) in CH2Cl2
(4 mL) was cooled to –78 °C, and treated dropwise with a freshly pre-
pared solution of SnCl4 in CH2Cl2 (0.370 mL, 0.26 mmol). After 1 h at
–78 °C, the reaction temperature was increased to –60 °C and the re-
sulting yellow mixture was further stirred for 2.5 h. The deep-red
mixture was slowly warmed to r.t., then the reaction was quenched
with saturated K2CO3 solution (1 mL). After 10 min stirring, brine (4
mL) was added and the organic products were extracted with EtOAc
(2 × 80 mL). The organic extracts were combined, dried over MgSO4,
concentrated under reduced pressure, and purified by chromatogra-
phy, furnishing the 1,2,3,4-tetrahydroisoquinolines (±)-13b (34 mg,
62%), as a diastereomeric mixture. Without further purification, (±)-
13b (32 mg, 0.07 mmol) was dissolved in freshly distilled pyridine (1
mL), potassium tert-butoxide (86 mg, 0.77 mmol) was added, and the
stirred reaction was heated to 100 °C for 30 min. Then, 10% NaOH
solution (1 mL) and brine (2 mL) were successively added, and the or-
ganic products were extracted with EtOAc (3 × 15 mL). The combined
organic phases were dried over MgSO4, filtered, and concentrated un-
der reduced pressure. The residue was purified by column chroma-
tography to afford compound 5 (9.6 mg, 63%), as a pale-yellowish oil
with the same spectroscopic characteristics as the compound ob-
tained from (±)-12a.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C23H31NNaO6S: 472.1770;
found: 472.1777.
N-((1S*,2R*)-4,5-Dimethoxy-2-methyl-2,3-dihydro-1H-inden-1-
yl)-N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide [(±)-12b]
By following the procedure employed for the preparation of (±)-12a,
amine (±)-11b (100 mg, 0.34 mmol) was dissolved in anhydrous CH-
Cl3 (5 mL) and treated with DIPEA (0.119 mL, 0.68 mmol) and tosyl
chloride (117 mg, 0.61 mmol), under reflux for 24 h, giving (±)-12b.
Yield: 145 mg (95%); white solid; mp 125–128 °C.
IR (KBr): 2961, 2936, 2886, 2837, 1603, 1489, 1339, 1273, 1161, 1074,
970, 822, 798, 675 cm–1
.
1H NMR: δ = 1.28 (d, J = 7.0 Hz, 3 H, Me-2), 2.48 (s, 3 H, ArMe of Ts),
2.54–2.67 (m, 1 H, H-2), 2.68–2.92 (m, 3 H, NCH2- and H-3), 3.00 (dd, J
= 8.1, 16.1 Hz, 1 H, H-3), 3.18 (s, 3 H, OMe, acetal), 3.24 (s, 3 H, OMe,
acetal), 3.78 (s, 3 H, OMe-5), 3.80 (s, 3 H, OMe-4), 4.21 (dd, J = 3.0,
6.6 Hz, 1 H, NCH2CH<), 5.17 (d, J = 7.7 Hz, 1 H, H-1), 5.93 (d, J = 8.2 Hz,
1 H, H-6), 6.55 (d, J = 8.2 Hz, 1 H, H-7), 7.35 (d, J = 8.1 Hz, 2 H, H-3 and
H-5 of Ts), 7.83 (br d, J = 7.2 Hz, 2 H, H-2 and H-6 of Ts).
Cyclization of Tosylacetals (±)-12a and (±)-12b with AlCl3
To a solution of AlCl3 (59 mg, 0.44 mmol) in MeNO2 (2 mL) at 0 °C was
added tosylacetal (±)-12a (50 mg, 0.11 mmol) in MeNO2 (1.5 mL)
dropwise. The resulting solution was stirred under argon at r.t. over-
night. The mixture was cooled to 0 °C, and the reaction was quenched
with saturated NaHCO3 solution (5 mL), and the mixture was extract-
ed with CH2Cl2 (3 × 15 mL). Combined organic layers were washed
with brine, dried over MgSO4, and concentrated in vacuo. The crude
residue was then purified by flash column chromatography to afford
5 (3.8 mg, 15%). Employing the same procedure on (±)-12b (59 mg,
0.44 mmol) gave 5 (0.8 mg, 3%). The spectroscopic data of the hetero-
cycles obtained from both tosylacetals were in full agreement with
those of the compound obtained by TFA-assisted cyclization of (±)-
12a.
13C NMR: δ = 14.3 (Me-2), 21.7 (Ar-Me of tosyl), 36.2 (C-3), 38.8 (C-2),
48.6 (NCH2-), 54.3 (OMe, acetal), 54.7 (OMe-5), 56.2 (OMe-acetal),
60.3 (OMe-4), 65.7 (C-1), 104.9 (NCH2CH<), 111.6 (C-7), 120.7 (C-6),
127.7 (Ar-2 and Ar-6 of tosyl), 129.7 (Ar-3 and Ar-5 of tosyl), 133.9 (C-
3a), 138.0 (C-7a), 138.5 (Ar-1 of tosyl), 143.3 (Ar-4 of tosyl), 145.2 (C-
4), 152.6 (C-5).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C23H31NNaO6S: 472.1770;
found: 472.1766.
5,6-Dimethoxy-8-methyl-7,8-dihydrocyclopenta[ij]isoquinoline (5)
from (±)-12a
The tosylacetal (±)-12a (32 mg, 0.07 mmol) was dissolved in dioxane
(1 mL), the resulting solution was treated with trifluoroacetic acid
(0.250 mL) and the mixture was heated at 105 °C for 1.5 h. The reac-
tion was then allowed to cool to r.t., 10 % NaHCO3 (3 mL) was added
and the organic products were extracted with EtOAc (2 × 80 mL). The
organic extracts were combined, dried over MgSO4, concentrated un-
der reduced pressure, and purified by chromatography, to give iso-
quinoline 5.
Funding Information
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET,
PUE IQUIR-2016) and Agencia Nacional de Promoción Científica y
Tecnológica (ANPCyT, PICT 2014-0445 and PICT 2017-0149).
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Yield: 7.2 mg (45%); pale-yellowish thick oil.
IR (NaCl): 3053, 2926, 2852, 2835, 1722, 1620, 1558, 1469, 1334,
Acknowledgment
1222, 1159, 1095, 963, 846, 736, 665 cm–1
.
1H NMR: δ = 1.52 (d, J = 7.1 Hz, 3 H, Me-8), 3.08 (dd, J = 3.2, 16.8 Hz,
1 H, H-7), 3.67 (ddq, J = 3.2, 7.1, 7.8 Hz, 1 H, H-8), 3.80 (dd, J = 7.9,
16.8 Hz, 1 H, H-7), 3.99 (s, 3 H, OMe-6), 4.07 (s, 3 H, OMe-5), 6.94 (s,
1 H, H-4), 7.25 (d, J = 5.9 Hz, 1 H, H-3), 8.32 (d, J = 5.9 Hz, 1 H, H-2).
The authors gratefully acknowledge the Agencia Santafesina de Cien-
cia, Tecnología e Innovación Productiva (ASaCTeI) for the institutional
grant AC 2015-0005 to IQUIR, used to acquire a 400 MHz NMR spec-
trometer. D.F.V. thanks CONICET for his doctoral fellowship.
13C NMR: δ = 19.9 (Me-8), 36.3 (C-7), 39.9 (C-8), 56.5 (OMe-6), 59.8
(OMe-5), 101.9 (C-4), 115.0 (C-3), 128.3 (C-3a),130.5 (C-3b), 131.2 (C-
6a), 144.6 (C-2), 145.2 (C-5), 157.6 (C-6), 171.1 (C-8a).
Supporting Information
HRMS (ESI-TOF): m/z [M + H]+ calcd for C14H16NO2: 230.1181; found:
Supporting information for this article is available online at
230.1178.
https://doi.org/10.1055/s-0037-1611711.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–I

H
D. F. Vargas et al.
Paper
Synthesis
References
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