Synthesis of 6,12-Methanodibenzo[ c, f]azocines and 4-Aryltetrahydroisoquinolines from Aromatic Aldehydes

Article abstract of DOI:10.1021/acs.orglett.9b04401

A methodology for the synthesis of 7,12-dihydro-5H-6,12-methanodibenzo[c,f]azocines from aromatic aldehydes and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine using catalysis by trifluoroacetic and perchloric acids is described. The developed protocol was applied for the synthesis of N-unsubstituted and N-methyl-4-aryltetrahydroisoquinolines.

Full text of DOI:10.1021/acs.orglett.9b04401

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of 6,12-Methanodibenzo[c,f ]azocines and
4‑Aryltetrahydroisoquinolines from Aromatic Aldehydes
Evgeny M. Buev, Maxim A. Stepanov, Vladimir S. Moshkin,* and Vyacheslav Y. Sosnovskikh
Institute of Natural Sciences and Mathematics, Ural Federal University, 620000 Ekaterinburg, Russian Federation
S
* Supporting Information
ABSTRACT: A methodology for the synthesis of 7,12-
dihydro-5H-6,12-methanodibenzo[c,f ]azocines from aromatic
aldehydes and N-(methoxymethyl)-N-(trimethylsilylmethyl)-
benzylamine using catalysis by trifluoroacetic and perchloric
acids is described. The developed protocol was applied for the
synthesis of N-unsubstituted and N-methyl-4-aryltetrahydroi-
soquinolines.
etrahydroisoquinoline is a well-known core structure of a
wide range of alkaloids and pharmaceuticals.1 A subgroup
of these alkaloids is represented by 4-aryl-1,2,3,4-tetrahydroi-
soquinolines.2 For instance, Amaryllidaceae alkaloids such as
(−)-cherylline (I) have been isolated from Crinum latifolium
and other Crinum species (Figure 1).3 Structurally close to the
between nitrogen and the partially hydrogenated 4-aryl moiety
is Amaryllidaceae alkaloid (−)-montanine IV exhibiting
anticancer activity and an affinity to serotonin transporter.7
In addition to natural bridged 4-aryltetrahydroisoquinolines
III and IV, similar dihydro-6,12-methanodibenzo[c,f]azocines
1 have garnered much interest in the scientific society (Scheme
1).8 Azocines 1 possess a bridging methylene link between the
T
Scheme 1. Synthetic Pathways to 6,12-
Methanodibenzo[c,f]azocines
Figure 1. Selected 4-aryltetrahydroisoquinolines and related mole-
cules.
4-aryl moiety and isoquinoline nitrogen that forms a strained
skeleton of tetracyclic structure resembling isopavine alkaloids.
Moreover, a number of works applied dibenzo[c,f]azocines 1
as scaffolds in the syntheses of isopavines via Stevens
rearrangement9 and (−)-cherylline via a Polonovski-type
reaction.10
Among the articles dedicated to the synthesis of
methanodibenzo[c,f ]azocines 1, the majority of rely on
intramolecular Friedel−Crafts double cyclization of N,N-
latter is the synthetic drug nomifensine (II), a monoamine
reuptake inhibitor possessing dual inhibition activity to
norepinephrine and dopamine, which was marketed as an
antidepressant in the 1970s−1980s.4 Considerable efforts were
made for the synthesis of drugs based on the nomifensine
structure.5 (−)-Amurensinine III found in Papaver species is
an alkaloid of the isopavine family that was investigated for the
treatment of Parkinson’s and Alzheimer’s diseases.6 Alkaloid
III also represents a constrained 4-aryltetrahydroisoquinoline
bearing the methylene link between C-1 and the veratryl
group. Another natural product bearing a different bridge
Received: December 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04401
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
dibenzyl aminoacetaldehydes8a,9,11 (Scheme 1a), their dialky-
lacetals,12 related ketones,13 and rarely N-benzyltetrahydroiso-
quinolines.14 There is also a single example of an opposite
approach to this synthesis via double Pictet−Spengler
cyclization of 2,2-diarylethan-1-amine (Scheme 1b).7a Upon
an examination of the azocine 1 structure, we envisioned
another possible retrosynthetic direction. This is the cleavage
of C(4a)−C(5) and C(11a)−C(12) bonds that leads to
synthon A bearing both iminium and benzylic carbocations
(Scheme 1c). In light of simple modification of synthon A by
an oxygen atom, 5-aryl-3-benzyloxazolidine 2 seems to be the
most appropriate synthetic equivalent for the synthesis of
dibenzo[c,f ]azocines 1. To the best of our knowledge, this type
of transformation has never been explored.
We commenced our study with the [3 + 2]-cycloaddition
reaction of N-benzylazomethine ylide derived from N-
(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (4) in
the presence of trifluoroacetic acid with veratraldehyde (3a),
which was selected as a model substrate to facilitate further
Pictet−Spengler reaction and to increase the stability of the
formed benzylic carbocation (Table 1). To our delight, readily
obtained N-benzyloxazolidine 5a was smoothly recyclized into
2,3-dimethoxy-6,12-methanodibenzo[c,f ]azocine 1a in 32%
yield by treatment with sulfuric acid (96%) at room
temperature for 2 h (Table 1, entry 1). The use of perchloric
acid (70%) led to an improvement in the reaction efficiency,
and azocine 1a was isolated in 44% yield (entry 5). After an
optimization of the recyclization conditions (entries 1−6), we
examined the possibility of a combination of cycloaddition and
recyclization stages in one experimentally simple process that
consisted of sequential catalysis by two acids without an
isolation of intermediate oxazolidine 5a (entries 7 and 8).
Thus, optimal conditions were treatment of the mixture of
veratraldehyde (3a) and azomethine ylide precursor 4 with
TFA (5 mol %) for 20 h and then with excess HClO4 (70%)
for 3 h. These allowed us to synthesize the target 6,12-
methanodibenzo[c,f]azocine 1a in 57% yield (entry 8). It
should be noted that catalysis of the observed domino-process
with only perchloric acid failed, apparently, due to the
sensitivity of azomethine ylides to strong acids and oxidizers
(entry 9). Despite that AlCl3 and FeCl3 were known to catalyze
Friedel−Crafts cyclization in the construction of dibenzoazo-
cines 1 (Scheme 1a),9,12d they did not cause the recyclization
of oxazolidine 5a (entries 10 and 11).
Encouraged by this operationally convenient methodology
for the synthesis of 6,12-methanodibenzo[c,f ]azocines 1, we
examined benzaldehyde under the optimized conditions found
for veratraldehyde; however, the intermediate 3-benzyl-5-
phenyloxazolidine was obtained. This result forced us to
increase the temperature of the recyclization stage. Thus,
treating the mixture with excess perchloric acid at 80 °C for 3 h
led to 7,12-dihydro-5H-6,12-methanodibenzo[c,f ]azocine (1b)
in 85% yield (Scheme 2). Under these conditions, 3-
Table 1. Optimization of the One-Pot Synthesis of 6,12-
Methanodibenzo[c,f]azocines
a
Scheme 2. Synthesis of 6,12-Methanodibenzo[c,f]azocines
yield
a
1a
(%)
entry
reaction conditions
b
1
2
3
4
5
6
7
5a, H2SO4 (96%), CH2Cl2, rt, 2 h
32
33
0
24
44
43
52
b
5a, H2SO4 (80%), CH2Cl2, rt, 2 h
b
5a, PPA, 90 °C, 1.5 h
a
Reaction conditions: 3 (1.0 mmol), 4 (1.5 mmol), TFA (10 mol %),
b
5a, HClO4 (65%), CH2Cl2, rt, 24 h
CH2Cl2, rt, 20 h, then 70% HClO4 (2 mL/1 mmol of aldehyde 3), rt
b
b
c
5a, HClO4 (70%), CH2Cl2, rt, 3 h
or 80 °C, 3 h. HClO4, 80 °C for 3 h. HClO4, 80 °C for 3 h, then at
rt for 120 h. Azocines 1e and 1e′ were obtained from 3-
bromobenzaldehyde as a mixture and were separated by column
b
5a, HClO4 (70%), CH2Cl2, rt, 24 h
3a (1.0 mmol), 4 (1.1 mmol), TFA (5 mol %), CH2Cl2, rt,
20 h, then 70% HClO4 (2 mL), rt, 4 h
c
d
e
chromatography. HClO4, 80 °C for 70 min. HClO4, rt for 3 h.
8
9
3a (1.0 mmol), 4 (1.5 mmol), TFA (10 mol %), CH2Cl2, rt,
57
c
20 h, then 70% HClO4 (2 mL), rt, 3 h
3a (1.0 mmol), 4 (1.1 mmol), HClO4 (3 mol %), CH2Cl2,
d
methylazocine 1c was obtained from p-tolualdehyde, while p-
isopropylbenzaldehyde provided the related 3-isopropylazocine
1d. The reaction of 3-bromobenzaldehyde resulted in the
formation of 2-bromoazocine 1e along with 4-bromoazocine
1e′ which were separated by column chromatography in 50
and 19% yields, respectively. In the case of 3-methoxybenzal-
dehyde, performing the recyclization at room temperature did
not lead to the complete conversion of intermediate
oxazolidine 5f into azocine 1f (the NMR ratio of the resulting
mixture 5f:1f was 30:70 correspondingly). This fact indicates
c
rt, 20 h, then 70% HClO4 (2 mL), rt, 3 h
5a, AlCl3 (4.0 mmol), CH2Cl2, 40 °C, 4 h
5a, FeCl3 (4.0 mmol), CH2Cl2, 40 °C, 3 h
b
10
11
d
e
b
a
Reactions were performed on 1.0 mmol of 3a. Isolated yields based
on a starting veratraldehyde (3a) are depicted. Crude oxazolidine 5a
was obtained using 3a (1.0 mmol), 4 (1.07 mmol), and TFA (5 mol
%) and was used further without purification. HClO4 (2 mL) was
added to the reaction mixture after 20 h. Complex mixture.
Complex mixture with an admixture of oxazolidine 5a.
b
c
d
e
B
DOI: 10.1021/acs.orglett.9b04401
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Letter
the insufficiency of one electron-donating group in the starting
substrate for completing the process under mild conditions (rt,
3 h). An improved result was obtained upon heating the
reaction mixture at 80 °C for 70 min, which provided 2-
methoxymethanodibenzo[c,f ]azocine 1f as a single regioisomer
in 62% yield. Considering the above, we performed the
reaction of p-anisaldehyde under heating conditions (70%
HClO4, 80 °C, 3 h) that allowed us to isolate 3-
methoxyazocine 1g in 60% yield. Electron-rich aldehydes
such as alkylated vanillins and 2,3,4-trimethoxybenzaldehyde
readily afforded products 1h−j at room temperature in 47−
71% yields. 2-Naphthaldehyde was also successfully trans-
formed into the pentacyclic piperidine 1k in 58% yield as a
single regioisomer under heating conditions. 3-Nitro- and 4-
(trifluoromethyl)benzaldehydes, containing electron-withdraw-
ing substituents, failed to give azocines 1l and 1m at 80 °C,
while intermediate N-benzyloxazolidines 5 and 2-(benzylami-
no)-1-arylethanols were the general products.
water and the Pictet−Spengler reaction of the formed iminium
cation H ultimately result in dibenzoazocine 1.
Upon a closer investigation of the developed methodology,
we examined the reaction of p-anisaldehyde at room
temperature (HClO4, rt, 3 h, Scheme 4). Surprisingly, the
a
Scheme 4. Reaction of 4-Substituted Benzaldehydes
a
Reaction conditions: 3 (1.0 mmol), 4 (1.5 mmol), TFA (0.1 mmol),
A proposed mechanism of the reaction is depicted in
Scheme 3. Initially, we assumed that acid-catalyzed ring-
CH2Cl2, rt, 20 h, then 70% HClO4 (2 mL/1 mmol of aldehyde 3), rt
or 80 °C, 3 h, then 37% HCl (2 mmol), MeOH, reflux, 1.5 h.
b
c
HClO4, rt for 3 h. HClO4, 80 °C for 3 h.
Scheme 3. Proposed Mechanism for the Acid-Promoted
Domino-Reaction of N-Benzyloxazolidines
reaction did not stop at the intermediate oxazolidine 5 but
resulted in the formation of N-unsubstituted 4-(4-anisyl)-
1,2,3,4-tetrahydroisoquinoline (6g) in 45% yield. Gratifyingly,
4-halogen-substituted benzaldehydes were successfully in-
volved in the same process upon heating at the recyclization
stage (HClO4, 80 °C, 3 h) that gave N-unsubstituted
tetrahydroisoquinolines 6n−p in 42−59% yields. In these
cases, para-substituents did not promote the final Pictet−
Spengler cyclization and hemiaminal G (Scheme 3) eliminated
formaldehyde to give 6 (see the detailed mechanism in the
Supporting Information).
Considering that 4-aryltetrahydroisoquinolines are inter-
mediates of the domino-transformation of N-benzyloxazoli-
dines 5 into dibenzo[c,f ]azocines 1, we were intrigued to find
other possibilities to stop the reaction on their formation
regardless of the substituents in the starting aromatic aldehyde.
In general, the solution to this problem is to prevent the final
Pictet−Spengler cyclization. Given that the active intermediate
of this reaction is an iminium cation, the simplest approach is
to suppress its formation. This, in turn, can be achieved by
depriving the nitrogen atom of the lone pair, and quaternary
ammonium salts prepared on the basis of oxazolidines 5 seem
to be quite suitable for this purpose.
The feasibility of this idea was first evaluated with 3-
methoxybenzaldehyde (Scheme 5). Crude N-benzyloxazoli-
dine 5 was obtained as usual, and then, it was treated with
methyl iodide to provide quaternary ammonium salt 7.
Heating the latter in HClO4 at 80 °C for 3 h led to N-
methyl-4-(3-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline
(8a) in 28% overall yield based on a starting aldehyde 3.
Similarly, 4-chlorobenzaldehyde gave rise to tetrahydroisoqui-
noline 8b in 47% overall yield.
Next, we intended to expand the variability of the developed
protocol for the construction of N-methyltetrahydroisoquino-
lines 8. Given the structure of the intermediate quaternary
ammonium salt 7 bearing benzyl and methyl groups, we
decided to change the order for the introduction of these
moieties into the molecule. Thus, the [3 + 2]-cycloaddition
reaction of 3-methoxybenzaldehyde with N-methylazomethine
ylide derived from sarcosine and formaldehyde provided 3-
methyl-5-(3-methoxyphenyl)oxazolidine (9a), which was read-
opening of oxazolidine 5 and the formation of iminium cation
C lead to Pictet−Spengler cyclization into tetrahydroisoqui-
nolin-4-ol D (Scheme 3, path A). Subsequent intramolecular
Friedel−Crafts reaction of the formed benzylic carbocation E
with the N-benzylic moiety results in the desired azocine 1.
However, the reaction of 5-(3-methoxyphenyl)-3-benzyloxazo-
lidine did not proceed well at room temperature despite the
favorable position of the electron-donating group that should
promote Pictet−Spengler cyclization into azocine 1f. In
comparison, 5-(3-methoxyphenyl)-3-methyloxazolidine was
readily recyclized into N-methyltetrahydroisoquinolin-4-ol of
type D under the treatment with HCl.15 This fact prompted us
to consider an alternative mechanism of the observed reaction
(path B). Apparently, in perchloric acid, in contrast to HCl, the
double protonation of oxazolidine 5 occurs (intermediate F,
Scheme 3). The formation of a benzylic carbocation and
intramolecular Friedel−Crafts reaction give 4-aryltetrahydroi-
soquinoline G bearing a hemiaminal group. The elimination of
C
DOI: 10.1021/acs.orglett.9b04401
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Letter
pressant and antiulcer activities,17 from 4-bromobenzaldehyde
in 43% overall yield. Related anisyl derivatives 8f and 8g were
obtained in 50 and 62% overall yields correspondingly.
Unexpectedly, o-ethoxybenzaldehyde gave 4-(2-
hydroxyphenyl)tetrahydroisoquinoline 8h in 17% overall
yield instead of the ethoxy-substituted product. This
apparently indicates an unfavorable effect of the bulky o-
substituent on the cyclization that causes a decrease in its rate
and hydrolysis of the EtO group to phenolic OH (see the
detailed mechanism in the Supporting Information).
Scheme 5. One-Pot Synthesis of N-Methyl-4-aryl-1,2,3,4-
tetrahydroisoquinolines 8 from N-Benzylazomethine Ylide
a
In conclusion, we developed a straightforward and flexible
approach to the construction of aza-polycycles from aromatic
aldehydes that consisted of the sequential [3 + 2]-cyclo-
addition of nonstabilized azomethine ylides and acid-catalyzed
recyclization of intermediate 5-aryloxazolidines. This new
method is of great value owing to its desirable features
including a rapid increase in molecular complexity, atom-
economy, and readily available materials, and it is expected to
find widespread use in the synthesis of 4-aryltetrahydroisoqui-
nolines as well as their constrained analogues6,12-
methanodibenzo[c,f]azocines.
a
Reaction conditions: 3 (1.0 mmol), 4 (1.5 mmol), TFA (10 mol%),
CH2Cl2, rt, 20 h, then MeI (3.0 mmol), PhMe, rt, 96 h, then 70%
HClO4 (2 mL/1 mmol of aldehyde 3), 80 °C, 3 h.
ily converted to quaternary ammonium salt 7a by treating with
benzyl chloride (Scheme 6). Pleasingly, its recyclization in
ASSOCIATED CONTENT
* Supporting Information
■
Scheme 6. One-Pot Synthesis of N-Methyl-4-aryl-1,2,3,4-
tetrahydroisoquinolines 8 from N-Methylazomethine Ylide
a
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04401.
Detailed experimental procedures and compound
characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mvslc@mail.ru.
ORCID
Vladimir S. Moshkin: 0000-0001-7673-1852
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by the Russian Science
Foundation (Grant 17-73-20070).
■
a
Reaction conditions: 3 (2.0 mmol), sarcosine (2.4 mmol),
paraformaldehyde (3.6 mmol of CH2O), PhH, 3 h, then ArCH2Cl
(2.2 mmol), PhMe, 55 °C, 72 h, then 70% HClO4 (2 mL/1 mmol of
aldehyde 3), 80 °C, 3 h. Overall yields based on starting aromatic
aldehydes 3 are depicted.
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DOI: 10.1021/acs.orglett.9b04401
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