1,2,3-Triazole-Mediated Synthesis of 1-Methyleneisoquinolines: A Three-Step Synthesis of Papaverine and Analogues

Article abstract of DOI:10.1021/acs.orglett.0c01069

A metal-free three-step synthesis toward functionalized 1-methyleneisoquinolines from readily available substrates is reported. First, acetal-containing 1,2,3-triazoles were prepared via a high-yielding triazolization reaction and quantitatively converted into triazolo[5,1-a]isoquinolines. Next, the acid-promoted ring opening of these fused triazoles was studied in order to obtain coupling to a diverse scope of nucleophiles, including carbon nucleophiles such as veratrole. By means of non-nucleophilic strong acids under anhydrous conditions, a series of unprecedented isoquinolines and imidazo[5,1-a]isoquinolines was synthesized.

Full text of DOI:10.1021/acs.orglett.0c01069

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Letter
1,2,3-Triazole-Mediated Synthesis of 1‑Methyleneisoquinolines: A
Three-Step Synthesis of Papaverine and Analogues
Tomas Opsomer, Max Van Hoof, Andrea D’Angelo, and Wim Dehaen*
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ABSTRACT: A metal-free three-step synthesis toward function-
alized 1-methyleneisoquinolines from readily available substrates is
reported. First, acetal-containing 1,2,3-triazoles were prepared via a
high-yielding triazolization reaction and quantitatively converted
into triazolo[5,1-a]isoquinolines. Next, the acid-promoted ring
opening of these fused triazoles was studied in order to obtain
coupling to a diverse scope of nucleophiles, including carbon
nucleophiles such as veratrole. By means of non-nucleophilic
strong acids under anhydrous conditions, a series of unprecedented
isoquinolines and imidazo[5,1-a]isoquinolines was synthesized.
Scheme 1. Acid-Mediated Ring Opening Reactions of 1,2,3-
Triazolo[5,1-a]isoquinolines
soquinolines are a valuable class of N-containing hetero-
Icycles. In particular, 1-substituted isoquinolines have been
studied extensively, largely owing to their occurrence in many
biologically important alkaloids.1,2 Syntheses toward these
scaffolds are numerous, and improvements of existing
pathways as well as novel methods have been reported over
the past decades.3,4 However, in order to overcome limitations
such as restricted substitution patterns or the use of transition
metals, the development of alternative pathways for the rapid
construction of functionalized isoquinolines remains an area
with high level of interest.
Triazolo[5,1-a]isoquinolines can be put forward as potential
substrates for the synthesis of isoquinolines. This was originally
demonstrated by Jones, Abarca and co-workers, who studied
the denitrogenative ring opening of aryl-fused triazoles with
bromine, selenium dioxide, and acids.5 Yet, the scope of acid-
mediated ring opening reactions of triazoloisoquinolines has
mostly remained limited to 1-hydroxymethyl- and 1-acetox-
ymethylisoquinolines, resulting from reactions in aqueous
sulfuric acid and acetic acid, respectively (Scheme 1a).5f,g,6a−d
In recent years, alternative methods for the denitrogenative
ring opening of benzo-fused triazoles have received consid-
erable attention. The formation of rhodium and copper
carbenes has been utilized in transannulation reactions of
triazolopyridines,7 light-induced ring opening was possible for
3-aryl-1,2,3-triazolo[1,5-a]pyridine derivatives,8 and tetra-n-
butylammonium bromide (TBAB) has been applied in the
metal-free ring opening of pyridotriazoles in the presence of
anilines.9 Despite these advancements, ring opening reactions
of triazoloisoquinolines are underexplored, although they could
be of interest, especially when the substrates are easily
accessible. The reported methods for the construction of
1,2,3-triazolo[5,1-a]isoquinolines either start from 1-methyl-
isoquinolines,10 affording low product yields, or require
transition metal catalysis and advanced substrates that are
often not commercially available.6
A metal-free three-component reaction for the synthesis of
1,5-di-, fully substituted and even NH-1,2,3-triazoles, including
fused systems, was reported by our group in 2016.11 This
method was named “the triazolization reaction of ketones” and
combines a broad substrate scope with the advantage of using
readily available starting materials such as primary amines and
the recoverable 4-nitrophenyl azide as a dinitrogen source.
Resulting products have already proven their utility in post-
Received: March 24, 2020
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© XXXX American Chemical Society
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triazolization cyclization strategies, namely, toward 3-aryl-
1,3a,6a-triazapentalenes,12 allocolchicine analogues,13 and
polycyclic dihydroindoles.14 In this work, acetal-containing
1,2,3-triazoles, derived from acetophenones, were cyclized to
efficiently afford triazolo[5,1-a]isoquinolines. The 8,9-dime-
thoxytriazoloisoquinoline was considered as a potential
precursor for the synthesis of the opiate papaverine, an
antispasmodic and vasodilator.15 Consequently, the acid-
mediated denitrogenative ring opening of triazoloisoquinolines
in the presence of nucleophiles was investigated, which led to
the metal-free synthesis of functionalized 1-methyleneisoqui-
nolines (Scheme 1b).
functionalized methylene substituent onto the isoquinoline
core.5f,g,6a−d In the search for conditions that could be applied
to a variety of nucleophiles, papaverine 6a was put forward as a
target structure. This challenging aim entailed the use of
veratrole as a nucleophile in initial experiments. Several acids
caused conversion of 5c at temperatures above 95 °C in polar
solvents. However, when taking no precautions to exclude
water from the reaction mixture, the 1-hydroxymethylisoquino-
line was formed as one of the major products. Therefore,
further experiments were carried out with anhydrous reagents
and in dry 1,2-dichloroethane, which was selected as a suitable
solvent. Based on experimental observations, it was clear that
strong acids of non-nucleophilic anions would be crucial to
obtain the desired outcome. Indeed, methanesulfonic acid,
triflic acid, triflimidic acid, and tetrafluoroboric acid diethyl
ether complex were tested and found able to induce a reaction
toward papaverine at 100 °C, albeit in very low yields
Dimethyl acetal-substituted triazoles 4a−e were successfully
prepared in a first step from the commercial amino-
acetaldehyde dimethyl acetal 2, 4-nitrophenyl azide 3 (4-
NPA) and acetophenones 1 (Scheme 2). The reaction
1
according to the H NMR spectra of the crude mixtures. Due
Scheme 2. Synthesis of 1,2,3-Triazolo[5,1-a]isoquinolines
a b
,
5a−f
to the complexity of the spectra and therefore inconclusive
results obtained from reactions with veratrole, the more
reactive 1-hexanol was employed as a nucleophile in order to
make a careful comparison between the different acids.
Fortunately, under unoptimized conditions, nearly quantitative
NMR yields of isoquinoline 7h resulted from reactions with
triflic acid and HBF4·OEt2. Methanesulfonic acid (10% NMR
yield of 7h) appeared to still be too nucleophilic, while the use
of triflimidic acid (71% NMR yield of 7h) resulted in a
significant amount of degradation. Fluoroboric acid forms an
insoluble salt with 5c in DCE, which slowly disappears in the
presence of 1-hexanol, but does not react with veratrole at 100
°C. A triflic acid-promoted reaction with veratrole under the
same unoptimized conditions attained full conversion after 15
h, but it produced a complex mixture with a negligible yield of
papaverine. Nevertheless, based on the results with hexanol, it
was kept in mind that a procedure, comprising the use of triflic
acid at 100 °C, could be the method of choice for
denitrogenative ring opening reactions of 5c with potent
nucleophiles.17
The reaction of 5c with veratrole and fluoroboric acid was
further examined at higher temperatures. This could facilitate
complete solvation of the reagents and, concomitantly, the
desired reaction progress. Effectively, it was found that
papaverine 6a was formed in a promising NMR yield of 41%
after 1.5 h at 150 °C under microwave irradiation. One major
side product was the regioisomer 6b, furnished in an NMR
yield of 15%. A subsequent optimization study was carried out
by means of quantitative NMR analysis with the amounts of
veratrole, acid, and solvent as variables (see the Supporting
Information). In this way, papaverine could be obtained in an
improved NMR yield of 64%, along with 24% of its
regioisomer 6b. Advantageously, the outcome of this reaction
under conventional heating (2.5 h) was similar, and respective
isolated yields of 53% and 24% were achieved for 6a and 6b.
Encouraged by the promising reaction with veratrole, the
optimized procedure was applied to some other nucleophilic
aromatic compounds (Scheme 3). For both naphthalene and
thiophene, mixtures of two regioisomers (6c,d and 6e,f) were
obtained in acceptable combined yields of 61 and 65%,
respectively. As one might expect, the α-positions of
naphthalene and thiophene were the most reactive sites. The
reaction of 5c with anisole was slow and gave an inseparable
mixture of products. However, starting from trimethoxytriazo-
loisoquinoline 5d, the reaction with anisole proceeded
a
Experimental conditions: 2.5 mmol of 1, 1.1 equiv of 2, 1.5 equiv of
3, 2.5 mL of toluene, 17 h; 1.2 mmol of 4 in 2.5 mL of aqueous
b
H2SO4 (80 wt %), 8 h. Isolated yields.
proceeded smoothly under acid-free conditions, although a
catalytic amount of acetic acid, as used in the optimized
triazolization procedure,11a was not found to have a significant
detrimental effect. Satisfyingly, the intermediate triazoles 4a−d
were then converted quantitatively via a modified Pomeranz−
Fritsch reaction,16 leading to the respective triazoloisoquino-
lines 5a−d (Scheme 2). Apart from several methoxy-
substituted acetophenones, 3′-fluoroacetophenone 1e was
applied as an additional example, resulting in a separable
mixture of two regioisomers (5e,f). By dissolving acetal 4e in a
small portion of MeOH prior to the addition of sulfuric acid,
an excellent combined yield of 96% was obtained.
Next, the acid-mediated denitrogenative ring opening of 8,9-
dimethoxytriazoloisoquinoline 5c was investigated. Previous
reports showed that 1,2,3-triazolo[1,5-a]isoquinolines can
react with a nucleophile upon ring opening, introducing a
B
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Scheme 3. Fluoroboric Acid-Mediated Ring Opening of
Scheme 4. Triflic Acid-Mediated Ring Opening of 1,2,3-
a b
,
1,2,3-Triazolo[5,1-a]isoquinolines toward Isoquinolines
Triazolo[5,1-a]isoquinolines toward Isoquinolines 7a−q
a b
,
6a−i
a
Experimental conditions: 0.44 mmol of 5c/5d, 7.5 mL of DCE.
b
c
Isolated yields. 0.88 mmol of 5b, 12 mL of DCE.
smoothly and two regioisomers (6g,h) could be isolated in
good yields. These results demonstrate the beneficial role of
the methoxy groups on the isoquinoline core in the ring
opening reaction. The 8-methoxytriazoloisoquinoline 5b
reacted much slower with veratrole compared to the
dimethoxy analogue 5c, which further substantiates the rate-
enhancing effect of the methoxy groups. The expected product
6i was isolated in only 18% yield, together with two side
products, which resulted from reaction with fluoride (6j) and
demethylation reactions (6k).
The reactions with 5c and 1-hexanol showed that the
denitrogenative ring opening of triazoloisoquinolines could be
carried out efficiently at 100 °C. Hence, for a selection of
stronger nucleophiles,17 the use of fewer equivalents of the
nucleophile in combination with milder conditions could be
considered. 1-Methylindole was chosen as a starting point.
Applying the optimized procedure with fluoroboric acid to this
nucleophile and 5c resulted in negligible conversion at 100 °C.
As anticipated, a suspension of the fluoroboric acid salt of 5c
was observed. In contrast, the homogeneous triflic acid-
mediated reaction was completed in 7 h, while the amount of
nucleophile could be reduced to three equivalents. By means of
this modified procedure, isoquinoline 7a was obtained in a
favorable yield of 80% (Scheme 4).
a
b
Experimental conditions: 0.44 mmol of 5c, 7.5 mL of DCE. Isolated
c
yields. Tetrabutylammonium chloride (3.92 equiv) was used as the
nucleophile.
Subsequently, the scope of nucleophiles of the triflic acid-
promoted ring opening was explored (Scheme 4). Reactions
with 1H-Indole and 9H-carbazole are interesting examples to
examine the regioselectivity. The reaction between 5c and 1H-
indole was clearly more delicate compared to the reaction with
its methylated analogue. Due to the difficult purification, 1-
(indol-3-yl)methylisoquinoline 7b was the only product that
could be isolated. On the other hand, from the reaction with
carbazole, a mixture of three regioisomers 7c−e was obtained
C
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a b
,
in an approximate 2:2:1 ratio and with a combined yield of
66%.
Scheme 5. Synthesis of Imidazo[5,1-a]isoquinolines 8
More N-containing heterocycles were tested. When the
parent 1,2,4-triazole was used, the reaction proceeded slowly,
which can be attributed to its basic properties. The reaction
was stopped after 8 h, and the expected product 7f could be
isolated in yield 25%, while 41% of the triazoloisoquinoline 5c
was recovered. Interestingly, the reaction with imidazole did
not show any conversion after 8 h. These results confirm that
only nucleophiles with a limited basicity fall within the scope of
this reaction. Correspondingly, ring opening of triazoloisoqui-
nolines in the presence of amines was not feasible under the
investigated conditions. Instead, one might propose a
substitution reaction with 1-chloromethylisoquinolines and
amines as an alternative pathway, which has already been
described in literature.18 The chloromethylisoquinoline 7g has
been successfully prepared in a very high yield via this
methodology, using tetrabutylammonium chloride as a
reactant.
a
Experimental conditions: 0.44 mmol of 5a/5c, 7.5 mL of DCE.
Isolated yields.
b
Fortunately, alcohols and thiols proved to be ideal substrates
for the triflic acid-mediated ring opening of triazoloisoquino-
line 5c. Very good yields of 87% or higher were afforded from
reactions with hexanol (7h), hexanethiol (7i), isopropyl
alcohol (7j), 2-propanethiol (7k), and ethyl thioglycolate
(7l). 1-Adamantanol (7m), on the contrary, gave a much lower
yield, and the reaction with 1-adamantanethiol did not yield
the expected product. The use of benzyl alcohol did also not
result in the desired reaction outcome. However, in case of
pentafluorobenzyl alcohol, the 1-methyleneisoquinoline 7n
could be easily purified in a reasonable yield of 64%. Products
from reactions with phenol (7p) and thiophenol (7o) were
obtained in very high yields, although phenol did not react
regioselectively. Benzylisoquinoline 7q, also known as the
alkaloid crykonisine, was isolated as a side product.
In the literature, examples of metal-free denitrogenative ring
opening reactions of triazolo[1,5-a]pyridines with nitriles have
been reported.19 These transannulation reactions are interest-
ing pathways toward various imidazopyridines. As a last part of
this work, the acid-mediated ring opening of triazoloisoquino-
lines in the presence of nitriles was evaluated and has, to the
best of our knowledge, not been explored to date. Pleasingly,
the condition with triflic acid at 100 °C provided a highly
effective method toward these fused systems (Scheme 5). For
both benzonitrile and aliphatic nitriles, the desired imidazoi-
soquinolines 8a−d were furnished in moderate to good yields
when using 10 equiv of nitrile. Also for the triflic acid-
promoted reaction, the absence of methoxy groups on the
triazoloisoquinoline resulted in a decreased yield, which is due
the slower reaction progress and concomitantly increased
degradation.
In conclusion, a triazolization/Pomeranz−Fritsch sequence
was successfully applied to generate 4,5-unsubstituted 1,2,3-
triazolo[5,1-a]isoquinolines in high yields. The use of readily
available starting materials can be seen as the major advantage.
Next, the acid-mediated denitrogenative ring opening reaction
of triazoloisoquinolines in the presence of nucleophiles was
studied. For two sets of nucleophiles, a respective procedure
has been put forward that allows for attaining conversion
toward the desired isoquinoline products. Interestingly, the
results proved that the methoxy groups on the phenyl ring of
the isoquinoline core have a rate-enhancing effect on the ring
opening reaction. The combination of the methods reported
herein provides access to papaverine and analogues as well as a
series of unprecedented functionalized (imidazo)isoquinolines.
It is believed that this methodology could be expanded to
other aryl methylene ketones, which may provide synthetic
access to diverse polyheterocyclic scaffolds.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01069.
Experimental procedures and characterization data;
NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Wim Dehaen − Molecular Design and Synthesis, Department of
Chemistry, KU Leuven, 3001 Leuven, Belgium; orcid.org/
0000-0002-9597-0629; Email: wim.dehaen@kuleuven.be
Authors
Tomas Opsomer − Molecular Design and Synthesis,
Department of Chemistry, KU Leuven, 3001 Leuven, Belgium;
orcid.org/0000-0002-8272-0292
Max Van Hoof − Molecular Design and Synthesis, Department
of Chemistry, KU Leuven, 3001 Leuven, Belgium;
orcid.org/0000-0001-5396-9892
Andrea D’Angelo − Molecular Design and Synthesis,
Department of Chemistry, KU Leuven, 3001 Leuven, Belgium
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01069
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
T.O. acknowledges the FWO-Vlaanderen for a PhD fellowship
(1154419N). W.D. acknowledges financial support from KU
Leuven (Project C14/19/78). The authors thank Karel
D
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(9) Lamaa, D.; Lin, H.-P.; Bzeih, T.; Retailleau, P.; Alami, M.;
Hamze, A. Eur. J. Org. Chem. 2019, 2019, 2602−2611.
Duerinckx and Bart Van Huffel for the assistance with the
NMR measurements and Prof. Dr. Jef Rozenski for the HRMS
measurements. Mass spectrometry was made possible by the
support of the Hercules Foundation of the Flemish Govern-
ment (Grant 20100225-7).
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