Synthesis of Polysubstituted 3-Methylisoquinolines through the 6π-Electron Cyclization/Elimination of 1-Azatrienes derived from 1,1-Dimethylhydrazine

Article abstract of DOI:10.1002/ejoc.201801076

A convenient one pot microwave-assisted 6π-electron cyclization/aromatization approach toward 3-methylisoquinolines is reported. The starting 1-azatriene derivatives were prepared in situ by reaction of 2-propenylbenzaldehydes with 1,1-dimethylhydrazine, which exhibited superior performance when compared with other hydrazine derivatives. Minor amounts of the related 3,4-dihydro isoquinolines were formed concomitantly with the isoquinolines, and a mechanism for their generation was proposed. The reaction conditions were optimized, and its scope and limitations were explored. In general, the transformation proceeded in moderate to good yields.

Full text of DOI:10.1002/ejoc.201801076

A Journal of
Accepted Article
Title: Synthesis of polysubstituted 3-methyl isoquinolines through the
6π-electron cyclization/elimination of 1-azatrienes derived from
1,1-dimethylhydrazine
Authors: Didier F Vargas, Enrique L Larghi, and Teodoro S. Kaufman
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801076
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801076
Supported by

10.1002/ejoc.201801076
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
Synthetic methodology - heterocycles
Me
Me
Me
Me
Me2NNH2
+
Didier F. Vargas, Enrique L. Larghi* and
Teodoro S. Kaufman*
PhCF3
O
N
N
N
(MW)
R
R
R
R
NMe2
R1
R1
R1
R1
R= OH, OMe, OiPr, OBn,
OMs, OMOM. R1= H, Me
(minor by-product)
One-pot procedure with PhCF3 as eco-friendly multipurpose solvent
12 Examples: 10 Aldehydes (48-70% yield), 2 ketones
Page No. – Page No.
Synthesis of polysubstituted 3-methyl
The scope and limitations of the use of 1,1-dimethylhydrazine for accessing 3-methyl
isoquinolines from 2-propenylbenzaldehydes through a one-pot hydrazonation, 6π-
electron cyclization of 1-azatrienes and final elimination, were examined.
isoquinolines
through
the
6π-
electron cyclization/elimination of 1-
azatrienes derived from 1,1-dimethyl
hydrazine
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801076
European Journal of Organic Chemistry
FULL PAPER
Synthesis of polysubstituted 3-methylisoquinolines through the 6π-
electron cyclization/elimination of 1-azatrienes derived from 1,1-
dimethylhydrazine
Didier F. Vargas Vargas,[a] Enrique L. Larghi[a],* and Teodoro S. Kaufman[a],*
Abstract: A convenient one pot microwave-assisted 6π-electron
cyclization/aromatization approach toward 3-methylisoquinolines is
reported. The starting 1-azatriene derivatives were prepared in situ
by reaction of 2-propenylbenzaldehydes with 1,1-dimethylhydrazine,
which exhibited superior performance when compared with other
hydrazine derivatives. Minor amounts of the related 3,4-dihydro
isoquinolines were formed concomitantly with the isoquinolines, and
a mechanism for their generation was proposed. The reaction
conditions were optimized, and its scope and limitations were
explored. In general, the transformation proceeded in moderate to
good yields.
Further, despite the group of Hibino described the general
use of this methodology for the preparation of isoquinolines,[5a]
there are only scattered cases involving the syntheses of the
isoquinoline framework,[4d,5] and even less on natural products
containing this heterocyclic framework (Figure 1).[6]
Me
Me
O
MeO
Me
O
N
N
O
N
O
O
Me
Me
OMe O
Me
Aspergillitine
Me
TMC-120B
Scorpinone
O
Me
MeO
HO
Me
MeO
MeO
Me
Introduction
N
OR
N
N
O
Nitrogen heterocycles are recurrent structural motifs in important
natural products as well as within biologically and technologically
relevant compounds. Among them, the isoquinolines hold a
central position because they are widely distributed in nature
and their structural diversity and broad spectra of biological
activities keeps attracting considerable attention from different
perspectives. Currently, this heterocycle is considered a highly
relevant privileged scaffold in fields such as medicinal and
agricultural chemistry.[1]
Numerous approaches have been designed to access
isoquinoline derivatives. However, new additions to the multistep
synthesis armamentarium through the development of novel
reagents and routes toward these heterocycles, are always
welcomed, especially if readily accessible precursors are
employed.
O
Renierol
R= H,
Me
Cassiarin C
Renierol acetate
R= Ac,
2-Methyltriclisine
MeO
N
MeO
MeO
R
MeO
Me
O
OMe
N
MeO
O
N
MeO
H
N+
Me
5-Methylaaptamine Broussonpapyrine
OMe
Aaptamine
R= H,
R= Me,
(S)-Cryptostylline II
Figure 1. Chemical structures of some natural products and analogs, bearing
an isoquinoline motif, which have been synthesized employing the 6π-
electrocyclization reaction of 1-azatrienes.
The electrocyclization reactions are powerful tools that allow
the construction of ring compounds under straightforward,
elegant and atom-economic conditions. Although the basic
pericyclic reaction has been known for a number of years,[2]
recent reviews[ 3 ] suggest that the 6π-electrocyclizations of
azatrienes has comparatively fewer examples.[4]
The 3-substituted isoquinolines have recently conceited
great attention; hence, considerable efforts have been made
toward their synthesis and different methods have been devised
for that purpose.[7]
The sequential 6π-electrocyclization/elimination of 1-
azatrienes has been carried out with oximes,[8] oxime ethers[9]
and oxime esters as sources of the nitrogen atom, but also and
more scarcely with sulfonylimines[10] and silylimines.[11] Imines[12]
and alkylimines have also been employed, but only for the 6π-
electrocyclization stage.[ 13 ] Surprisingly, however, despite the
analogous hydrazone derivatives possess weak N–N bonds
similar to those of the oxime ethers/esters, there are scarce and
scattered examples on their use as part of 1-azatrienes involved
in this kind of reactions.[14]
[a]
Prof. T. S. Kaufman, Prof. E. L. Larghi, Quim. D. F. Vargas,
Instituto de Química Rosario IQUIR (CONICET-UNR), and Facultad
de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de
Rosario (UNR), Suipacha 531 (2000) Rosario, Argentina.
Tel./Fax: + 54-341-437-0477
E-mail: kaufman@iquir-conicet.gov.ar (TSK)
E-mail: larghi@iquir-conicet.gov.ar (ELL)
E-mail: vargas@iquir-conicet.gov.ar (DFV)
Group page: https://tk-team-iquir.webnode.com/
To the best of our knowledge, there are no precedents on
the cyclization of hydrazone-derived 1-azatrienes in which one
of the double bonds of the polyenic starting material belongs to
an isocyclic aromatic ring. In this scenario, the need of
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801076
European Journal of Organic Chemistry
FULL PAPER
dearomatization during the cyclization stage may favour side
reactions and affect the success of the transformation.
spectroscopic analysis. Compound 8a displayed the diagnostic
signal of the 3-methyl group as a doublet (δ 1.40 ppm), coupled
to H-3, which not unexpectedly was observed as a complex
signal (δ 3.56-3.69 ppm). On the other hand, the isoquinoline 7a
exhibited a characteristic singlet corresponding to the three
hydrogens of the methyl group (δ 2.69 ppm) and those of its
heterocyclic ring (δ 7.69 and 9.06 ppm).
Interestingly, to the best of our knowledge, 3,4-
dihydroisoquinolines have not been previously reported as side
products in similar cyclization reactions leading to the related
isoquinolines, including those which use methoximes as source
of the nitrogen atom.
Multistep organic synthesis benefits from the availability of
multiple alternatives for a given transformation. Therefore, in an
effort to broaden the scope of the 6π-electron cyclization of 1-
azatrienes toward polysubstituted 3-methylisoquinolines, herein
we wish to report on the use of 1,1-dimethylhydrazine as a
convenient and suitable nitrogen atom source for such reaction,
according to the general synthetic route (A→B→C) outlined in
Scheme 1. The scope and limitations of the transformation are
also examined and discussed.
This could be happened because they were not expected,
were formed in minute amounts or had a very different and
much higher polarity. For instance, in a typical TLC run in
EtOAc:EtOH (9:1, v/v), the Rf of the isoquinolines are ≅ 0.6,
whereas the Rf values of the related 3,4-dihydroisoquinolines are
< 0.2. A literature search revealed only a related report by the
group of Hibino, which disclosed that strong heating of an oxime
derivative of 2-methoxy-6-propenyl benzaldehyde afforded the
corresponding 4-methyl-4,5-dihydro benzo[d][1,2]oxazepine.[4d]
Therefore, in order to rule out the possibility of formation of
the analogous 4-methyl-4,5-dihydro-3λ2-benzo[d][1,2]diazepine,
the mass spectrum of the product was obtained; delightfully, the
characteristic peak of its molecular ion [M]+ at m/z = 205
confirmed its proposed identity as the 3,4-dihydroisoquinoline 8a.
Encouraged by this result, the use of 4-toluenesulfonyl
hydrazine was explored, with a frustrating outcome, since only
5% of the expected isoquinoline was recovered, and no 3,4-
dihydroisoquinoline was observed (entry 2). Interestingly, the
related N-sulfonylimines have been recently used in azatriene
6π-electrocyclization reactions toward 1,2-dihydropyridines.[15]
Scheme 1. Proposed general strategy toward the isoquinolines C.
Results and Discussion
To begin the study and in order to test the performance of
different hydrazine derivatives as suitable sources of the
required isoquinoline nitrogen atom, the ortho-propenyl
benzaldehyde derivative 5a was prepared as a model in a four-
steps protocol (Scheme 2) from isovanillin (1a).
To that end, 1a was submitted to a Williamson O-alkylation
with allyl bromide in refluxing EtOH, to which K2CO3 was added
as base, and the resulting allyl ether 2a, obtained in 93% yield,
was subjected to a Claisen rearrangement to afford 3a (90%
yield). This was followed by O-alkylation of the free phenol with
MeI/K2CO3 in EtOH (95% yield) and final isomerization of the
double bond of the resulting allyl derivative 4a, promoted by
catalytic amounts of RuClH(CO)(PPh3)3 in toluene at 80°C,
which afforded 5a in 90% yield (72% overall yield from 1a).
Table 1. Selection of the nitrogen derivatizing agent for aldehyde 5a.[a]
Isolated yield (%)
Entry
No.
Time
(h)
IQ:DHIQ
ratio
R1
R2
IQ[b]
20
5
DHIQ[c]
Global
29
1
2
3
4
5
6
7
8
9
H
H
H
Ts
2
3
9
1:0.45
1:0
0
5
H
Boc
1.3
1
22
55
26
40
45
30
73
23
38
15
10
21
13
12
55
1:0.95
1:0.7
Scheme 2. Reagents and conditions: a) BrCH2CH=CH2, K2CO3, EtOH, reflux,
3 h (93%); b) 1,2-Cl2C6H4, 180°C, 20 h (90%); c) MeI, K2CO3, EtOH, reflux, 6 h
(95%); d) RuClH(CO)(PPh3)3, PhMe, 80°C, 24 h (90%).
H
C(O)NH2
C(O)NHPh
Ph
93
H
3
41
1:0.57
1:0.25
1:0.46
1:0.43
1:0.16
H
1.5
6
50
With compound 5a in hands, the next task was to find the
proper substituted hydrazine for derivatization of the model
aldehyde (Table 1), in order to obtain the most suitable substrate
for the cyclization. Luckily, the first attempt run with hydrazine
itself, proved successful (entry 1). However, it was observed that
the corresponding intermediate 6 afforded only a 29% combined
yield of isoquinoline derivatives, after heating 2 h at 180°C in
DMA, as a 1:0.45 separable mixture of the isoquinoline (IQ) 7a
and the related 3,4-dihydroisoquinoline (DHIQ) 8a.
Ac
Ph
Me
Ph
66
Ph
4
43
Me
2
85
[a] Reaction conditions: a) R1R2N-NH2, EtOH, rt, 1-2 h; b) MW, DMA, 180°C.
[b] IQ: Isoquinoline. [c] DHIQ: 3,4-Dihydroisoquinoline.
On the other hand, slightly better results were obtained
employing the Boc-hydrazine derivative (entry 3), which
The structures of the heterocycles were assessed by NMR
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10.1002/ejoc.201801076
European Journal of Organic Chemistry
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furnished 55% overall yield of
a
mixture of isoquinoline
difficult removability of the high boiling amides and diphenyl
ether, it was chosen as the reaction solvent for further
experiments.
derivatives, at the expense of a high IQ:DHIQ ratio (1:0.95).
Better success was observed with the semicarbazide
derived substrate, which gave 93% yield of heterocyclic products,
but still in a high IQ:DHIQ ratio (1:0.7), so that the yield of the
isoquinoline was only 55% (entry 4). Further, the performance of
the related phenylsemicarbazide derivative of entry 5 was also
non-satisfactory, furnishing only 41% of isoquinoline derivatives,
in a IQ:DHIQ ratio of 1:0.57.
Furthermore, two protocols were devised for the reaction. In
Method A, the hydrazone was prepared in EtOH; then the
solvent was removed and replaced with PhCF3 to carry out the
cyclization stage. In Method B, the whole hydrazonation/
cyclization/aromatizing elimination sequence was performed as
a one pot process in PhCF3. Both alternatives proved to furnish
essentially identical results (for 7a, 76% with Method A and 72%
using Method B; entries 6 and 7), being Method B preferred for
its comparative simplicity.
Suspecting that thermal stability of the nitrogen derivatives
could be one of the determinants of the rather poor performance
of some of the candidates, the transformation was carried out
with phenylhydrazine (entry 6).[16] Despite the moderate overall
yield observed (50%), the low IQ:DHIQ ratio obtained (1:0.25)
prompted us to test the related reagent N-acetyl
phenylhydrazine. A further yield improvement to 66% (entry 7)
was detected, but at the expense of an increase in the amount
of the 3,4-dihydroisoquinoline side product (IQ:DHIQ = 1:0.46).
These results were encouraging but not satisfactory;
therefore, the N-acetyl moiety was replaced by the thermally
more stable N-phenyl motif (entry 8). However, not unexpectedly,
the overall yield of heterocycles dropped to 43%, while
maintaining the IQ:DHIQ ratio essentially unchanged (1:0.43).
This meagre result was attributed to the high steric demand
of the bulky phenyl substituents and suggested to experiment
with 1,1-dimethylhydrazine (entry 9), the least sterically
demanding 1,1-disubstituted hydrazine. Delightfully, an 85%
overall yield of isoquinoline derivatives was recorded, combined
with a highly satisfactory IQ:DHIQ ratio of 1:0.16.
Table 2. Solvent selection for the cyclization reaction of 6a.
Isolated yield (%)
Entry
No.
IQ:DHIQ
ratio
Solvent
7a (IQ)
53
8a (DHIQ)
Global
62
1
2
3
4
5
6
7
Xylene[a]
NMP
9
3
1:0.16
1:0.04
1:0.16
1:0.24
1:0.14
1:0.08
1:0.11
67
70
MeCONMe2
Ph2O
73
12
18
10
6
85
74
92
1,2-Cl2C6H4
PhCF3
68
78
76
82
[b]
PhCF3
72
8
80
[a] Yields are based on recovered starting 1-azatriene (20%). [b] Method B
was used.
These experiments revealed that significant reactivity
differences could be observed in the cyclization processes,
depending on the nature of the substituents at the distal nitrogen
atom of the hydrazone. Lyaskovskyy et al. attempted to perform
the KtBuO-mediated hydrohydrazination of an ortho-alkynyl
phenylhydrazone, meeting with failure. However, they found that
using the analogous N-methyl hydrazone (prepared with MeNH-
NH2) afforded the expected product in moderate yield.[ 17 ]
Therefore, we choose Me2N-NH2 as the most suitable hydrazine
derivative for further system optimization.
Next, the selection of the most suitable reaction medium was
carried out, by running the model transformation in hydrocarbon,
amides, ethereal and halogenated solvents. The results, detailed
in Table 2, revealed that the use of xylene was unsatisfactory
(entry 1), mainly because of the poor solubility of the starting
material. The overall yield of the reaction, based on 20% of
recovered starting material, was only moderate. Employing high
boiling point N,N-disubstituted amides (entries 2 and 3) resulted
in improved yields and good IQ:DHIQ ratios. The use of NMP
gave low amounts of DHIQ, whereas the reaction run in DMA
afforded cyclized products in 85% combined yield.
Hence, the effect of the reaction temperature on the yield of
the isoquinolines and their accompanying 3,4-dihydro
isoquinolines was assessed next in DMA and PhCF3 employing
tightly closed systems under conventional heating and
employing microwaves irradiation (Table 3).
At 180°C, PhCF3 proved to be superior under both heating
conditions (entries 1 vs 4 and 2 vs 5). Further analysis revealed
that the microwaves-assisted transformations outperformed
those carried out under conventional heating (entries 1 vs 2 and
4 vs 5), and that heating at temperatures above 180 °C resulted
in diminished yields of the isoquinolines (entries 5-7). Hence, the
temperature of 180°C and microwave irradiation were judged as
optimal conditions.
At this point and given the extended use methoxime
derivatization for the 6π-electrocyclization of 1-azatrienes toward
pyridines, isoquinolines and β-carbolines, the performances of
methoxylamine and 1,1-dimethylhydrazine were compared in the
model reaction, at 180°C, in DMA and PhCF3 as solvents, and
running the transformations under microwave irradiation.
The results (Table 3) revealed that, under these conditions,
The latter result was outperformed by Ph2O (entry 4), mainly
at the expense of delivering higher amounts of DHIQ. On the
other side, ortho-dichlorobenzene furnished 68% yield of the IQ,
similar to NMP (entry 5), whereas the reaction in PhCF3 gave
the highest yields of isoquinoline (76%) and its IQ:DHIQ ratio
ranked among the best.
Benzotrifluoride (PhCF3) is a safe and modern replacement
of hydrocarbons and chlorinated solvents, which is very suitable
for microwave-assisted reactions, being also easy to recover
due to its comparatively low boiling point (102°C).[18] Taking into
account its performance in the transformation and the rather
despite requiring
a longer reaction time, the 1,1-dimethyl
hydrazine derivative outperformed its congener in both solvents
(entries 1 vs 8 and 4 vs 9, respectively), albeit at the expense of
longer reaction times.
In addition, the 3,4-dihydroisoquinoline 8a was also isolated
as a minor product from the cyclization of the tested methoxime
derivative (entries 8 and 9), in amounts comparable to those
furnished by the related 1,1-dimethyl hydrazone 6a. This
demonstrates for the first time that 3,4-dihydroisoquinolines are
also formed as by-products of the cyclization methoxime-based
1-azatrienes.
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10.1002/ejoc.201801076
European Journal of Organic Chemistry
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On the other hand, these experiments revealed that the
methoxime largely outperformed the 1,1-dimethylhydrazone
when a ketone was employed as the starting carbonyl (entries
10 and 11). However, considerable amounts of the 3,4-dihydro
isoquinoline side product were produced in both cases.
Once the model reaction was fully optimized with regards to
solvent, temperature and heating mode, the scope and
limitations of the transformation were explored with different
poly-substituted compounds.
benzyl-5-hydroxy-6-methoxy-3-methylisoquinoline (7h’, 11%
yield) was isolated along with the benzyl ethers 7h and 8h and
the isoquinoline 7f, the hydrolysis product of methanesulfonate
7j, was isolated together with the latter (10% yield).
Contrastingly however, the transformation was not satisfactory
for the hydrazones derived from ketones (entries k and l).
Table 4. Yields of the different intermediates and the isoquinoline products.
Table 3. Comparison of the performances of the cyclizations of methoximes
and 1,1-dimethylhydrazones.[a]
Isolated yield (%)
IQ DHIQ Total
Entry
No.
Mode/
Temp. (°C) (h)
Time
IQ:DHIQ
ratio
R/Y
Solvent
DMA
1
2
H/NMe2
H/NMe2
H/NMe2
H/NMe2
H/NMe2
H/NMe2
H/NMe2
H/OMe
H/OMe
MW/180
Δ/180
2
3
2
2
3
3
3
1
1
73
58
52
72
65
64
40
62
59
3
12
11
17
8
85
69
69
80
82
72
52
68
69
23
50
1:0.16
1:0.20
1:0.32
1:0.11
1:0.26
1:0.12
1:0.30
1:0.10
1:0.16
1:6.66
1:1.66
DMA
Isolated yield (%)
4
95
Entry
No.
Substitution pattern
2
93
3
90
5 (E:Z)[a]
90
7
8
3[b]
4[b]
5[b]
6[b]
7[b]
8
PhCF3
PhCF3
PhCF3
PhCF3
PhCF3
DMA
MW/160
MW/180
Δ/180
a
b
c
d
e
f
R1 = R2 = R3 = H; R4 =
OMe; R5= Me
72
8
(82:18)
R1 = R2 = R3 = R4 = H;
R5= Me
94
96
84
91
93
-
36
41
58
79
90
-
91
86
97
91
-
89
(80:20)
57
58
60
73
48
65
64
70
60
5
8[b]
15[c]
12
17
8
R1 = R3 = R4 = H; R2 =
OMe; R5= Me
85
(80:20)
Δ/200
R1 = R2 = R4 = H; R3 =
OMe; R5= Me
88
Δ/220
12
6
(78:22)
MW/180
MW/180
R1 = R2 = H; R3 = R4 =
OMe; R5= Me
93
(90:10)
13
9
PhCF3
10
20
20
R1 = R2 = R3 = R5 = H; R4
= OMe
89
37
10[c] Me/NMe2 PhCF3
11[d] Me/OMe PhCF3
MW/180 0.75
MW/180 0.75 30
(78:22)
g
h
i
R1 = R2 = R3 = H; R4 =
OMe; R5= iPr
-
80[d]
15
(79:21)
[a] Δ: Conventional heating (bath temperature); MW: Microwaves irradiation.
[b] The reactions were carried out as one-pot procedures following Method B.
[c] Starting material (10%) was recovered. [d] Some of the 1-azatriene
starting material (20%) was recovered.
R1 = R2 = R3 = H; R4 =
OMe; R5= Bn
-
-
-
85[d]
9[e]
(82:18)
R1 = R2 = R3 = H; R4 =
OMe; R5= MOM
-
-
-
79[d]
15
(80:20)
Taking into account that naturally-occurring isoquinolines
and related compounds are characterized by their oxygenated
functionalities (mainly phenols and phenyl ethers),[1g] the scope
of the method was probed by preparing the set of hydrazone
precursors shown in Table 4, which also contains details of the
outcome of their cyclization.
j
R1 = R2 = R3 = H; R4 =
OMe; R5= Ms
-
-
-
84[d]
(75:25)
22[f]
20[h]
20[g]
k
l
R1 = R5= Me; R2 = R3 =
R4 = H
93
97
44
87
90
89
88
(84:16)
R1 = R5 = Me; R2 = R3 =
H; R4 = OMe
95
(80:20)
3
Thus, the optimized conditions were applied to similarly
prepared 1-azatrienes, carrying aromatic rings functionalized
with a free phenol (6f), as well as with different ether [Me (6a-e),
iPr (6g), Bn (6h)], acetal (MOM, 6i) and ester moieties. It was
observed that the methyl ethers of entries a-e gave good to very
good isolated yields (57-73%) of the expected isoquinolines,
accompanied by 8-15% of the related 3,4-dihydroisoquinolines.
On the other hand, the hydrazone derived from phenol 5f
Reagents and conditions: a) BrCH2CH=CH2, K2CO3, EtOH, ∆; b) 1,2-Cl2C6H4,
180°C; c) MeI, K2CO3, EtOH, ∆, or BnCl, K2CO3, KI (cat.), EtOH, ∆, or
Me2CHBr, K2CO3, KI (cat.), EtOH, ∆, or MOMCl, DIPEA, CH2Cl2, r.t., 16 h, or
MsCl, pyridine, CH2Cl2, r.t., 2 h; d) RuClH(CO)(PPh3)3 (cat.), PhMe, 80°C; e)
R1R2NNH2, AcOH, PhCF3, rt; f) MW, 180°C.
[a] According to 1H NMR integration. [b] Some starting 1-azatriene (9%) was
recovered. [c] Some starting 1-azatriene (5%) was recovered. [d] Prepared
from phenol 5f. [e] 8-Benzyl-5-hydroxy-6-methoxy-3-methylisoquinoline (7h’)
was also isolated in 11% yield. [f] Compound 7f (10%) was also isolated. [g]
The hydrazone 6 was formed according to Method A. [h] Some starting
material (10%) was recovered.
withstood the reaction conditions (entry f), affording
a
comparative higher amount of the 3,4-dihydroisoquinoline (37%)
at the expense of a moderate yield of the isoquinoline (48%).
A similar trend was observed among the other ethers tested
(entries
g and h), as well as with the MOM and the
Prompted by these results, the possibility of installing a
methanesulfonate derivatives (entries i and j). However, 8-
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10.1002/ejoc.201801076
European Journal of Organic Chemistry
FULL PAPER
functionality other than a methyl group on C-3 was explored. To
analogous to different oxygen-based leaving groups derived
from oximes, which were found to play quite similar roles at the
elimination step.[5a]
that end, isovanillin (1a) was subjected to
a selective
bromination with NBS (Scheme 3) and the resulting
bromophenol 9 was O-methylated to furnish 10 in 75% overall
yield.[19a] Next, the formyl moiety of 10 was exposed to propane-
1,3-diol and Ce(OTf)3 promotion, employing (iPrO)3CH as
carbonyl activator and water scavenger,[19b,c] to afford 96% yield
of the 1,3-dioxane derivative 11.
Then, the latter was subjected to a Heck reaction with methyl
acrylate, which furnished the ortho-formyl cinnamate 12 in 82%
yield, after mild acid hydrolysis of the protecting group.19d One-
pot hydrazonation toward 13 and further exposure to thermal
cyclization finally gave isoquinoline 14, albeit in a rather poor
10% yield, revealing a limitation in the scope of this reaction.
This complements others previously found by the group of
Hibino.[5a]
Scheme 4. Proposed mechanism for the thermal cyclization of 6a to afford the
isoquinoline 7a and the 3,4-dihydroisoquinoline 8a.
In the competing Path b, the weak N–N bond could undergo
homolytic cleavage to generate the iminyl radical ii, which could
experience an intramolecular ring closure onto the olefinic
acceptor of the propenyl moiety to render the dihydropyridinyl-
type radical iii. In this case, 6-endo-trig is the favoured mode of
cyclization, probably because this also generates a resonance-
stabilized radical.[21a] Somehow, this is conceptually reminiscent
to the iminyl radical-mediated synthesis of quinoxalines by gas
phase thermolysis of 1,2,5-triazapentadienes; however, the
latter process seems to require more strenuous conditions
(600 °C and 10-2 mmHg) and has a lower performance.[21b,c]
Interestingly, it was previously informed that irradiation of 2-
vinylbenzaldehyde O-acetyloxime and (Z)-1-phenyl-4-hepten-1-
one O-acetyloxime, enabled the experimental verification that
iminyl radicals could evolve through cyclization to form six- or
five-membered ring products, respectively, depending on the
presence or absence of a phenyl group as a spacer.
Scheme 3. Reagents and conditions: a) NBS, CHCl3, reflux, 3 h (78%); MeI,
K2CO3, EtOH, reflux, 5 h (96%); b) Propane-1,3-diol, Ce(OTf)3, (iPrO)3CH,
hexane, r.t., overnight (96%); d) 1. H2C=CHCO2Me, Et3N, Pd(OAc)2, (o-Tol)3P,
DMF, 125°C, 24 h; 2. 2M HCl, THF, r.t., 4 h (82%); e) 1. H2NNMe2, AcOH,
PhCF3, r.t., 5 h; 2. MW, 180°C, 2 h (10%).
Although the exact details of the reaction mechanism remain
unknown, a mechanistic picture such as that shown in Scheme 4
can be drawn on the basis of literature precedents.
Under the thermal conditions, the starting ortho-propenyl
hydrazone 6a can react along two alternate paths. In Path a, the
1-azatriene could undergo the expected 6π-electrocyclization
process to afford the intermediate i, which in turn could suffer
the elimination of dimethylamine to furnish the isoquinoline 7a.
In turn, the intermediate iii could interact with the aminyl
radical or with the solvent and either capture H• to afford the 3,4-
dihydro isoquinoline 8a or undergo an H-atom transfer to
complete the oxidative cyclization process toward the
22
]
isoquinoline 7a.[
In analogous embodiments, the latter
Dimethylamine has been the by-product in
a cyclization/
transformation has also been described as a “6π-electron
cyclization” process.[23]
elimination sequence toward carbazoles, as well as in other
aromatizations,[ 20 ] and has been detected in the reaction
medium by its characteristic odour.
This reaction path is likely to involve a classical concerted
mechanism, which proceeds in a disrotatory mode. The aromatic
ring would ensure the initial s-cis-geometry of the azatriene;
however, the need to dearomatize the benzenoid ring during the
cyclization would turn it into a species with low reactivity, that
may favour secondary reactions and conspire against high
yields.
In order to get insights into the participation of a radical
mechanism, the reaction mixture containing 6a was treated with
2,6-di-tert-butyl-4-methylphenol (BHT, 10 mol%). It was
observed that the presence of this free radical inhibitor affected
the production the isoquinoline from 72% to 65% yield, whereas
access to the related 3,4-dihydroisoquinoline was more
drastically reduced from 8% to 2% yield. Further, when the
semicarbazide derivative (Table 1, entry 4) was employed as
starting material, the yields of the isoquinoline changed from
55% to 24%, whilst the yields of the 3,4-dihydroisoquinoline
The driving force of the last stage should be aromatization,
and dimethylamine is the only by-product of the reaction. This is
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10.1002/ejoc.201801076
European Journal of Organic Chemistry
FULL PAPER
distilled from Na0/benzophenone ketyl. 1,2-Dichlorobenzene was
obtained by a 3 h reflux of the AR product over P2O5 and further
distillation of the product under reduced pressure. The anhydrous
solvents were transferred via cannula and stored under argon in dry
Young ampoules containing activated 3Å molecular sieves. All of the
other solvents and reagents were used as received.
dropped drastically from 38% to 8%.
These results fully supported the hypothesis that the
generation of the 3,4-dihydroisoquinolines is a result of the
intervention of a radical-mediated cyclization process. On the
other hand, the observed outcome of the experiment also
unveiled that, to some extent, the isoquinoline may also have
been produced through a radical mechanism.
Accordingly, the by-products of this path are the highly
volatile Me2NH and H2C=NMe. The latter proved hard to be
detected by GC-MS; however, the related 1,1-dimethyl-2-
The reactions were monitored by TLC, using silica gel GF254 plates
supported on aluminium and run in different hexane-EtOAc or EtOAc-
EtOH solvent mixtures. The spots were revealed by exposure to UV light
(254 and 365 nm) and spraying with ethanolic p-anisaldehyde/sulfuric
acid reagent, followed by careful heating to improve selectivity; in
selected cases, the Dragendorff reagent (Munier and Macheboeuf
modification) was used.[25] The flash column chromatographies were run
with silica gel 60 H (particle size < 55 μm), eluting with hexane-EtOAc
and EtOAc-EtOH mixtures, under positive pressure and employing
gradient of solvent polarity techniques.
methylene
hydrazine
derivative
(H2C=N-NMe2)
was
unequivocally observed [m/z = 72 (M+)] in the presence of a
small excess of 1,1-dimethylhydrazine.[24]
Conclusions
Equipment
We have developed a convenient, efficient and atom-economical
one-pot synthesis of 3-methylisoquinolines from ortho-formyl β-
methylstyrenes, through their sequential hydrazonation with 1,1-
dimethylhydrazine in PhCF3, followed by a microwave-assisted
cyclization and final elimination with concomitant aromatization.
The scope and limitations of the reaction were examined. It
could be performed under conventional heating, but microwaves
irradiation reduced substantially the reaction times, providing
yields of isoquinolines similar to those obtained when the related
methoximes were employed. Further, the transformation is
compatible with free phenols and different ethers, as well as with
MOM and methanesulfonate protecting groups.
This is the first general example involving the 6π-electron
cyclization of 1-azatrienes derived from hydrazones, in which the
starting polyene incorporates one double bond belonging to an
homocyclic aromatic ring. The use of hydrazones enabled the
development of a one-pot process, which cannot be put in place
with the related methoximes, providing a simpler alternative to
the latter.
The melting points were measured on an Ernst Leitz Wetzlar model 350
hot-stage microscope and are informed uncorrected.
The FT-IR spectra were acquired on
a Shimadzu Prestige 21
spectrophotometer, with the samples prepared as solid dispersions in
KBr disks or as thin films held between NaCl cells.
The NMR spectroscopic data were recorded in CDCl3 with an FT-
NMR Bruker Avance 300 spectrometer at 300.13 MHz (for 1H NMR) and
75.48 MHz (13C NMR). The chemical shifts are reported in ppm on the δ
scale. TMS (δ = 0.0 ppm) was used as the internal standard (resonances
for CHCl3 in CDCl3 are δ = 7.26 and 77.16 ppm for 1H and 13C NMR,
respectively). The magnitude of the coupling constant (J) values are
given in Hertz. In special cases, NOE and 2D NMR experiments (COSY,
HSQC, TOCSY and HMBC) were also employed in order to aid
unequivocal signal assignment.
The GC–MS experiments were performed with
a Shimadzu
QP2010Plus instrument equipped with an AOC-20i autosampler. The
high-resolution mass spectra were obtained from ICYTAC (Córdoba,
Argentina) and UMYMFOR (Buenos Aires, Argentina) with Bruker
MicroTOF-Q II instruments. Detection of the ions was performed in
electrospray ionization, positive ion mode.
In addition, this is the first report on the presence of 3,4-
dihydroisoquinolines as side products, for which a mechanism of
formation was proposed. Furthermore, it included the first
disclosure of the generation of these heterocycles during the
cyclization of the more widely used methoxime-derived 1-
azatrienes.
The microwave-assisted reactions were carried out in
Discover microwave reactor.
a CEM
The fact that the isoquinolines may also be produced
through a radical-mediated process turns convenient to consider
this transformation as a 6π-electron cyclization.
General procedures for the sequential hydrazine condensation/6π-
electron cyclization/elimination toward isoquinolines
These are promising results in the field of the synthesis of
isoquinolines, which suggest that the optimized reaction will find
wide use in multistep syntheses of more complex molecules, as
an alternative or complement to existing methodologies.
Method A: A mixture of the carbonyl compound 5 (0.8 mmol), 1,1-
dimethylhydrazine (64 μL, 0.85 mmol), glacial AcOH (46 μL, 0.8 mmol)
and absolute EtOH (1,5 mL) was placed in a microwave tube and stirred
at room temperature for 3 h. Anhydrous MgSO4 (30 mg) and activated
powdered 3Å MS (30 mg) were employed for the less reactive substrates.
Upon completion of the reaction, assessed by TLC analysis, the solvent
was removed under reduced pressure and PhCF3 (1 mL) was added.
Argon was bubbled to create a suitable atmosphere and the mixture was
irradiated in the microwave reactor (180 °C, ca. 250 W) in 1 h cycles until
judged complete by TLC. After cooling to room temperature, the solvent
was recovered by distillation, and the oily residue was purified by
chromatography to afford the 3-methylisoquinoline (7a, 7k and 7l) and 3-
methyl-3,4-dihydroisoquinoline (8a, 8k and 8l) products.
Experimental Section
General information
All the reactions were carried out under anhydrous argon atmospheres,
using oven-dried glassware and freshly distilled anhydrous solvents.
Anhydrous EtOH was obtained by reaction of the AR reagent from
magnesium chips and iodine, followed by distillation of the solvent from
the so formed magnesium ethoxide. Anhydrous DMA, NMP and DMF
were prepared by reduced-pressure distillation from BaO. Xylene was
Method B: A mixture of the carbonyl compound 5 (0.8 mmol), 1,1-
dimethylhydrazine (64 μL, 0.85 mmol) and glacial AcOH (46 μL, 0.8
mmol) in PhCF3 (1 mL) was transferred to a microwave tube. Argon was
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10.1002/ejoc.201801076
European Journal of Organic Chemistry
FULL PAPER
bubbled, and the mixture was stirred at room temperature until TLC
analysis indicated complete aldehyde consumption (approx. 3 h). Then,
the vessel was irradiated (180 °C, ca. 250 W) in the microwave reactor in
1 h cycles until completeness, as judged by TLC. After cooling to room
temperature, the solvent was recovered by careful distillation under
atmospheric pressure, and the oily residue was purified by
chromatography to afford the 3-methylisoquinoline (7a-j) and 3-methyl-
3,4-dihydroisoquinoline (8a-j) products.
1.35 (d, J = 6.2, 6H, OCHMe2), 2.68 (s, 3H, Me), 3.98 (s, 3H, OMe), 4.62
(sept, J = 6.2, 1H, OCHMe2), 7.28 (d, J = 9.0, 1H, 7-H), 7.67 (d, J = 9.0,
1H, 8-H), 7.70 (q, J = 0.7, 1H, 4-H) and 9.04 (s, 1H, 1-H). 13C NMR δ:
22.8 (OCHMe2), 24.6 (Me), 56.6 (OMe), 75.5 (OCHMe2), 112.9 (C-4),
114.8 (C-7), 123.2 (C-8a), 124.0 (C-8), 133.8 (C-4a), 139.1 (C-5), 151.4
(C-3), 151.6 (C-1) and 151.9 (C-6). HRMS (ESI-TOF): Found m/z:
232.1334; C14H18NO2 ([M+H]+) requires m/z: 232.1338.
5-(Benzyloxy)-6-methoxy-3-methylisoquinoline (7h): Yield: 64%
5,6-Dimethoxy-3-methylisoquinoline (7a):[26] Yield: 76% (Method A);
72% (Method B). Off-white solid, m.p.: 83-85 °C. 1H NMR δ: 2.69 (s, 3H,
Me), 3.98 (s, 3H, OMe), 4.02 (s, 3H, OMe), 7.29 (d, J = 9.1, 1H, 7-H),
(Method B). Whitish solid, m.p.: 79-81 °C. IR (KBr, ṽ): 3033, 2922, 2843,
1618, 1589, 1485, 1311, 1261, 1107, 1056, 974, 808, 732 and 696 cm–1
.
1H NMR δ: 2.64 (s, 3H, Me), 4.02 (s, 3H, OMe), 5.15 (s, 2H, PhCH2O),
7.31 (d, J = 9.0, 1H, 7-H), 7.33-7.44 (m, 3H, ArH), 7.52 (dd, J = 1.7 and
8.0, 2H, ArH), 7.64 (q, J = 0.8, 1H, 4-H), 7.71 (d, J = 9.0, 1H, 8-H) and
9.05 (s, 1H, 1-H). 13C NMR δ: 24.5 (Me), 56.7 (OMe), 75.4 (PhCH2O),
112.4 (C-4), 114.8 (C-7), 123.2 (C-8a), 124.6 (C-8), 128.2 (ArC), 128.4
(ArC), 128.6 (ArC), 132.9 (C-4a), 137.6 (ArC), 139.9 (C-5), 151.6 (C-3),
151.7 (C-1) and 151.8 (C-6). HRMS (ESI-TOF): Found m/z: 280.1340;
7.69 (br s, 1H, 4-H), 7.70 (d, J = 9.1, 1H, 8-H) and 9.06 (s, 1H, 1-H). 13
C
NMR δ: 24.5 (Me), 56.6 (OMe), 61.2 (OMe), 112.1 (C-7), 114.8 (C-4),
123.2 (C-8a), 124.5 (C-8), 132.5 (C-4a), 141.1 (C-5), 151.7 (C-1 and C-6)
and 151.8 (C-3). GC-MS m/z (rel. int. %): 203 (M+, 72), 188 (57), 160
(100), 145 (47), 117 (38), 89 (40) and 76 (41).
C
18H18NO2 ([M+H]+) requires m/z: 280.1338.
5-Methoxy-3-methylisoquinoline (7b): Yield 57% (Method B). Light
brown solid; m.p.: < 40 °C. IR (KBr, ṽ): 3057, 2935, 2837, 1589, 1429,
1465, 1330, 1282, 1199, 1003, 989, 879 and 752 cm–1
.
1H NMR δ: 2.70
8-Benzyl-5-hydroxy-6-methoxy-3-methylisoquinoline (7h’): Yield 11%
(Method B). Pale brownish solid, m.p.: 159-161 °C. IR (KBr, ṽ): 3020,
2918, 2841, 1618, 1597, 1456, 1361, 1242, 1147, 1068, 958, 860, 733
(s, 3H, Me), 3.98 (s, 3H, OMe), 6.93 (d, J = 7.5, 1H, 6-H), 7.39 (t, J = 8.0,
1H, 7-H), 7.48 (d, J = 8.0, 1H, 8-H), 7.82 (d, J = 0.7 1H, 4-H) and 9.11 (s,
1H, 1-H). 13C NMR δ: 24.4 (Me), 55.6 (OMe), 107.5 (C-6), 113.0 (C-4),
119.4 (C-8), 126.3 (C-7), 127.6 (C-8a), 129.2 (C-4a), 151.4 (C-1), 151.5
(C-3) and 154.1 (C-5). HRMS (ESI-TOF): Found m/z: 174.0919;
and 658 cm–1 1H NMR δ: 2.66 (s, 3H, Me), 3.96 (s, 3H, OMe), 4.45 (s,
.
2H, PhCH2O), 7.05 (s, 1H, 7-H), 7.13-7.29 (m, 5H, ArH), 7.66 (br s, 1H,
4-H) and 9.23 (s, 1H, 1-H). 13C NMR δ: 24.3 (Me), 38.1 (PhCH2O), 56.8
(OMe), 112.6 (C-4), 114.6 (C-7), 121.1 (C-8a), 126.4 (ArC), 128.2 (C-4a),
128.6 (ArC), 128.7 (ArC), 130.6 (C-8), 137.0 (C-5), 140.4 (ArC), 143.8
(C-6), 148.8 (C-1) and 150.7 (C-3). HRMS (ESI-TOF): Found m/z:
280.1326; C18H18NO2 ([M+H]+) requires m/z: 280.1338.
C
11H12NO ([M+H]+) requires m/z: 174.0919.
5,8-Dimethoxy-3-methylisoquinoline (7c):[26b,27] Yield: 58% (Method B).
Yellow oil. 1H NMR δ: 2.70 (s, 3H, Me), 3.93 (s, 3H, OMe), 3.95 (s, 3H,
OMe), 6.65 (d, J = 8.4, 1H, 6-H), 6.82 (d, J = 8.4, 1H, 7-H), 7.76 (br s, 1H,
4-H) and 9.46 (s, 1H, 1-H). 13C NMR δ: 24.5 (Me), 55.8 (OMe), 55.9
(OMe), 103.3 (C-6), 107.6 (C-7), 112.8 (C-4), 119.5 (C-4a), 130.1 (C-8a),
146.8 (C-1), 148.0 (C-5), 150.4 (C-8) and 152.3 (C-3).
6-Methoxy-5-(methoxymethoxy)-3-methylisoquinoline (7i): Yield:
70% (Method B). Whitish solid, m.p.: 53-55 °C. IR (KBr, ṽ): 2997, 2984,
2845, 1625, 1595, 1489, 1381, 1265, 1165, 1076, 962, 873, 779 and 696
cm–1 1H NMR δ: 2.69 (s, 3H, Me), 3.64 (s, 3H, OCH2OMe), 3.99 (s, 3H,
.
OMe), 5.28 (s, 2H, OCH2OMe), 7.30 (d, J = 9.0, 1H, 7-H), 7.72 (d, J = 9.0,
1H, 8-H), 7.74 (q, J = 0.7, 1H, 4-H) and 9.06 (s, 1H, 1-H). 13C NMR δ:
24.6 (Me), 56.6 (OMe), 57.9 (OCH2OMe), 99.1 (OCH2OMe), 112.3 (C-4),
114.6 (C-7), 123.2 (C-8a), 124.9 (C-8), 133.08 (C-4a), 137.9 (C-5), 151.4
(C-6), 151.7 (C-1) and 151.8 (C-3). HRMS (ESI-TOF): Found m/z:
234.1134; C13H16NO3 ([M+H]+) requires m/z: 234.1130.
5,7-Dimethoxy-3-methylisoquinoline (7d): Yield: 60% (Method B).
Brownish solid, m.p.: 52-54 °C. IR (KBr, ṽ): 2997, 2935, 2833, 1595,
1458, 1340, 1205, 1155, 1043, 999, 937 and 839 cm–1 1H NMR δ: 2.66
.
(s, 3H, Me), 3.91 (s, 3H, OMe), 3.96 (s, 3H, OMe), 6.60 (d, J = 2.1, 1H, 6-
H), 6.75 (d, J = 2.1, 1H, 8-H), 7.72 (br s, 1H, 4-H) and 9.0 (s, 1H, 1-H).
13C NMR δ: 24.2 (Me), 55.6 (OMe), 55.8 (OMe), 96.5 (C-8), 101.5 (C-6),
113.2 (C-4), 125.7 (C-8a), 128.2 (C-4a), 149.6 (C-3), 150.0 (C-1), 155.4
(C-5) and 158.4 (C-7). HRMS (ESI-TOF): Found m/z: 204.1025;
6-Methoxy-3-methylisoquinolin-5-yl methanesulfonate (7j): Yield:
60% (Method B). Whitish solid, m.p.: 156-158 °C. IR (KBr, ṽ): 3043, 3005,
2924, 2846, 1633, 1597, 1492, 1342, 1267, 1168, 1097, 985, 898, 781
C
12H14NO2 ([M+H]+) requires m/z: 204.1025.
and 626 cm–1 1H NMR δ: 2.71 (s, 3H, Me), 3.43 (s, 3H, OSO2Me), 4.06
.
5,6,7-Trimethoxy-3-methylisoquinoline (7e): Yield: 73% (Method B).
(s, 3H, OMe), 7.34 (d, J = 9.0, 1H, 7-H), 7.71 (q, J = 0.7, 1H, 4-H), 7.90
(d, J = 9.0, 1H, 8-H) and 9.09 (s, 1H, 1-H). 13C NMR δ: 24.8 (Me), 40.0
(OSO2Me), 56.7 (OMe), 112.0 (C-4), 113.7 (C-7), 122.8 (C-8a), 128.6 (C-
8), 131.1 (C-5), 133.0 (C-4a), 151.5 (C-1), 151.8 (C-6) and 153.6 (C-3).
HRMS (ESI-TOF): Found m/z: 268.0642; C12H14NO4S ([M+H]+) requires
m/z: 268.0644.
Colorless solid, m.p.: 63-65 °C. IR (KBr, ṽ): 2987, 2945, 2833, 1595,
1489, 1307, 1244, 1103, 1039, 999, 867 and 715 cm–1 1H NMR δ: 2.66
.
(s, 3H, Me), 3.97 (s, 3H, OMe), 3.99 (s, 3H, OMe), 4.02 (s, 3H, OMe),
6.99 (s, 1H, 8-H), 7.62 (s, 1H, 4-H) and 8.98 (s, 1H, 1-H). 13C NMR δ:
24.2 (Me), 56.1 (OMe), 61.3 (OMe), 61.5 (OMe), 101.5 (C-8), 112.7 (C-4),
124.0 (C-4a), 128.5 (C-8a), 144.4 (C-7), 146.3 (C-5), 149.8 (C-1), 149.9
(C-3) and 153.2 (C-6). HRMS (ESI-TOF): Found m/z: 234.1119;
C
13H16NO3 ([M+H]+) requires m/z: 234.1130.
5-Methoxy-1,3-dimethylisoquinoline (7k):[ 28 ] Yield: 5% (Method A).
Amber oil. 1H NMR δ: 2.67 (s, 3H, 3-Me), 2.92 (s, 3H, 1-Me), 4.0 (s, 3H,
OMe), 6.95 (d, J = 7.7, 1H, 6-H), 7.41 (t, J = 8.2, 1H, 7-H), 7.64 (d, J =
8.6, 1H, 8-H) and 7.74 (s, 1H, 4-H). 13C NMR δ: 22.8 (1-Me), 24.5 (3-Me),
55.7 (OMe), 107.2 (C-6), 111.5 (C-4), 117.6 (C-8), 125.9 (C-7), 126.4 (C-
8a), 129.4 (C-4a), 150.7 (C-3), 154.6 (C-5) and 157.5 (C-1).
5-Hydroxy-6-methoxy-3-methylisoquinoline (7f): Yield: 48% (Method
B). Whitish solid, m.p.: 156-158 °C. IR (KBr, ṽ): 2991, 2937, 2839, 1624,
1595, 1489, 1332, 1271, 1114, 1062, 943, 871, 777 and 696 cm–1 1H
.
NMR δ: 2.69 (s, 3H, Me), 3.98 (s, 3H, OMe), 7.26 (d, J = 8.9, 1H, 7-H),
7.50 (d, J = 8.9, 1H, 8-H), 7.77 (q, J = 0.7, 1H, 4-H) and 9.05 (s, 1H, 1-H).
13C NMR δ: 24.3 (Me), 55.8 (OMe), 112.3 (C-4), 113.2 (C-7), 119.9 (C-8),
123.0 (C-8a), 127.6 (C-4a), 138.5 (C-5), 144.7 (C-6), 150.6 (C-3) and
28a]
5,6-Dimethoxy-1,3-dimethylisoquinoline (7l):[26b,
Yield: 3%
(Method A). Pinkish oil. 1H NMR δ: 2.65 (s, 3H, 3-Me), 2.89 (s, 3H, 1-Me),
3.96 (s, 3H, OMe), 4.01 (s, 3H, OMe), 7.26 (d, J = 9.2, 1H, 7-H), 7.59 (s,
1H, 4-H) and 7.84 (dd, J = 1.0 and 9.2, 1H, 8-H). 13C NMR δ: 22.5 (1-Me),
24.7 (3-Me), 56.6 (OMe), 61.2 (OMe), 110.8 (C-4), 114.0 (C-7), 121.9 (C-
8a), 122.6 (C-8), 132.8 (C-4a), 141.5 (C-5), 150.6 (C-3), 151.3 (C-6) and
157.9 (C-1).
151.5 (C-1). HRMS (ESI-TOF): Found m/z: 190.0861;
([M+H]+) requires m/z: 190.0868.
C11H12NO2
5-Isopropoxy-6-methoxy-3-methylisoquinoline (7g): Yield: 65%
(Method B). Light amber oil. IR (NaCl, ṽ): 2974, 2929, 2841, 1624, 1593,
1487, 1381, 1263, 1107, 1058, 929, 873, 777 and 692 cm–1 1H NMR δ:
.
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10.1002/ejoc.201801076
European Journal of Organic Chemistry
FULL PAPER
5,6-Dimethoxy-3-methyl-3,4-dihydroisoquinoline (8a):[26b] Yield: 6%
(Method A); 8% (Method B). Amber oil. 1H NMR δ: 1.40 (d, J = 6.8, 3H,
Me), 2.39 (dd, J = 11.8 and 16.5, 1H, 4-HA), 2.97 (dd, J = 5.7 and 16.5,
1H, 4-HB), 3.56-3.69 (m, 1H, 3-H), 3.80 (s, 3H, OMe), 3.90 (s, 3H, OMe),
6.80 (d, J = 8.2, 1H, 7-H), 7.05 (d, J = 8.2, 1H, 8-H) and 8.21 (d, J = 2.6,
1H, 1-H). 13C NMR δ: 22.0 (Me), 26.4 (C-4), 52.0 (C-3), 55.8 (OMe), 60.7
(OMe), 109.8 (C-7), 122.5 (C-8a), 124.1 (C-8), 130.1 (C-4a), 145.6 (C-5),
155.2 (C-6) and 158.7 (C-1). GC-MS m/z (rel. int. %): 205 (M+, 85), 190
(100), 175 (13), 146 (13), 117 (6), 91 (13) and 77 (12).
3H, Me), 2.37 (dd, J = 11.2 and 16.2, 1H, 4-HA), 2.96 (dd, J = 6.0 and
16.2, 1H, 4-HB), 3.54-3.68 (m, 1H, 3-H), 3.87 (s, 3H, OMe), 4.41 (sept, J
= 6.2, 1H, OCHMe2), 6.79 (d, J = 8.2, 1H, 7-H), 7.02 (d, J = 8.2, 1H, 8-H)
and 8.20 (d, J = 2.6, 1H, 1-H). 13C NMR δ: 22.0 (3-Me), 22.6 (OCHMe2),
22.7 (OCHMe2), 27.2 (C-4), 52.2 (C-3), 55.8 (OMe), 75.0 (OCHMe2),
109.7 (C-7), 122.5 (C-4a), 123.6 (C-8), 130.8 (C-8a), 143.5 (C-5), 155.5
(C-6) and 158.9 (C-1). HRMS (ESI-TOF): Found m/z: 234.1481;
C
14H20NO2 ([M+H]+) requires m/z: 234.1494.
5-(Benzyloxy)-6-methoxy-3-methyl-3,4-dihydroisoquinoline
Yield 9% (Method B). Amber oil. IR (NaCl, ṽ): 3130, 2962, 2854, 1622,
1568, 1487, 1315, 1276, 1167, 1089, 976, 805, 742 and 698 cm–1 1H
(8h):
5-Methoxy-3-methyl-3,4-dihydroisoquinoline (8b): Yield 8% (Method
B). Amber brown oil. IR (NaCl, ṽ): 3001, 2960, 2837, 1633, 1573, 1469,
.
1315, 1261, 1112, 1045, 966, 777 and 666 cm–1
.
1H NMR δ: 1.41 (d, J =
NMR δ: 1.28 (d, J = 6.8, 3H, Me), 2.22 (dd, J = 11.5 and 16.5, 1H, 4-HA),
2.79 (dd, J = 5.7 and 16.5, 1H, 4-HB), 3.41-3.53 (m, 1H, 3-H), 3.92 (s, 3H,
OMe), 4.99 (s, 2H, PhCH2O), 6.83 (d, J = 8.2, 1H, 7-H), 7.05 (d, J = 8.2,
1H, 8-H), 7.32-7.44 (m, 5H, ArH) and 8.18 (d, J = 2.8, 1H, 1-H). 13C NMR
δ: 21.9 (Me), 26.7 (C-4), 52.0 (C-3), 55.9 (OMe), 74.9 (PhCH2O), 109.8
(C-7), 122.5 (C-8a), 124.2 (C-8), 128.3 (ArC), 128.5 (ArC), 128.7 (ArC),
130.6 (C-4a), 137.4 (ArC), 144.2 (C-5), 155.3 (C-6) and 159.8 (C-1).
HRMS (ESI-TOF): Found m/z: 282.1494; C18H20NO2 ([M+H]+) requires
m/z: 282.1494.
6.8, 3H, Me), 2.32 (dd, J = 12.1 and 16.8, 1H, 4-HA), 2.95 (dd, J = 6.3
and 16.8, 1H, 4-HB), 3.59-3.73 (m, 1H, 3-H), 3.85 (s, 3H, OMe), 6.93 (d, J
= 7.5, 1H, 8-H), 6.94 (d, J = 8.0, 1H, 6-H), 7.26 (t, J = 8.0, 1H, 7-H), and
8.28 (d, J = 2.7, 1H, 1-H). 13C NMR δ: 22.1 (Me), 25.5 (C-4), 52.3 (C-3),
55.7 (OMe), 113.3 (C-6), 119.8 (C-8), 124.4 (C-4a), 127.5 (C-7), 129.0
(C-8a), 156.0 (C-5) and 159.3 (C-1). HRMS (ESI-TOF): Found m/z:
176.1076; C11H14NO ([M+H]+) requires m/z: 176.1075.
5,8-Dimethoxy-3-methyl-3,4-dihydroisoquinoline (8c):[26b] Yield: 15%
(Method B). Light amber oil. 1H NMR δ: 1.40 (d, J = 6.8, 3H, Me), 2.25
(dd, J = 12.5 and 16.8, 1H, 4-HA), 2.90 (dd, J = 5.9 and 16.8, 1H, 4-HB),
3.50-3.64 (m, 1H, 3-H), 3.80 (s, 3H, OMe), 3.83 (s, 3H, OMe), 6.72 (d, J
= 8.9, 1H, 6-H), 6.88 (d, J = 8.9, 1H, 7-H) and 8.67 (d, J = 2.6, 1H, 1-H).
13C NMR δ: 22.1 (Me), 25.9 (C-4), 51.6 (C-3), 56.0 (OMe), 56.2 (OMe),
109.1 (C-6), 114.1 (C-7), 117.8 (C-8a), 126.5 (C-4a), 149.9 (C-5), 151.6
(C-8) and 154.8 (C-1).
6-Methoxy-5-(methoxymethoxy)-3-methyl-3,4-dihydroisoquinoline
(8i): Yield: 15% (Method B). Amber oil. IR (NaCl, ṽ): 2960, 2926, 2843,
1624, 1570, 1489, 1273, 1157, 1068, 960 and 804 cm–1 1H NMR δ: 1.39
.
(d, J = 6.8, 3H, Me), 2.43 (dd, J = 11.5 and 16.5, 1H, 4-HA), 3.02 (dd, J =
5.8 and 16.5, 1H, 4-HB), 3.57 (s, 3H, OCH2OMe), 3.55-3.71 (m, 1H, 3-H),
3.88 (s, 3H, OMe), 5.07 (d, J = 6.0, 1H, OCH2OMe), 5.10 (d, J = 6.0, 1H,
OCH2OMe), 6.81 (d, J = 8.2, 1H, 7-H), 7.06 (d, J = 8.2, 1H, 8-H) and 8.21
(d, J = 2.6, 1H, 1-H). 13C NMR δ: 22.0 (Me), 27.0 (C-4), 52.1 (C-3), 55.9
(OMe), 57.6 (OCH2OMe), 98.8 (OCH2OMe), 109.8 (C-7), 122.5 (C-8a),
124.4 (C-8), 130.5 (C-4a), 142.7 (C-5), 154.7 (C-6) and 158.7 (C-1).
HRMS (ESI-TOF): Found m/z: 236.1285; C13H18NO3 ([M+H]+) requires
m/z: 236.1287.
5,7-Dimethoxy-3-methyl-3,4-dihydroisoquinoline (8d): Yield: 12%
(Method B). Amber oil. IR (NaCl, ṽ): 2956, 2920, 2848, 1598, 1595, 1458,
1319, 1203, 1151, 1049, 908 and 839 cm–1 1H NMR δ: 1.40 (d, J = 6.8,
.
3H, Me), 2.25 (dd, J = 12.2 and 16.5, 1H, 4-HA), 2.86 (dd, J = 6.2 and
16.5, 1H, 4-HB), 3.59-3.69 (m, 1H, 3-H), 3.82 (s, 3H, OMe), 3.83 (s, 3H,
OMe), 6.46 (d, J = 2.1, 1H, 6-H), 6.86 (d, J = 2.1, 1H, 8-H) and 8.23 (d, J
= 2.8, 1H, 1-H). 13C NMR δ: 22.2 (Me), 25.1 (C-4), 52.8 (C-3), 55.7 (2 
OMe), 101.4 (C-8), 103.2 (C-6), 117.0 (C-4a), 129.2 (C-8a), 157.7 (C-5),
159.2 (C-1) and 159.7 (C-7). HRMS (ESI-TOF): Found m/z: 206.1167;
6-Methoxy-3-methyl-3,4-dihydroisoquinolin-5-yl methanesulfonate
(8j): Yield: 22% (Method B). Amber oil. IR (NaCl, ṽ): 3015, 2927, 2846,
1625, 1568, 1494, 1359, 1282, 1174, 1080, 972, 852, 736 and 692 cm–1
1H NMR δ: 1.39 (d, J = 6.9, 3H, Me), 2.53 (dd, J = 11.3 and 16.7, 1H, 4-
HA), 3.03 (dd, J = 5.8 and 16.7, 1H, 4-HB), 3.32 (s, 3H, OSO2Me), 3.63-
3.74 (m, 1H, 3-H), 3.93 (s, 3H, OMe), 6.89 (d, J = 8.3, 1H, 7-H), 7.23 (d,
J = 8.3, 1H, 8-H) and 8.24 (d, J = 2.6, 1H, 1-H). 13C NMR δ: 21.7 (Me),
27.3 (C-4), 39.8 (OSO2Me), 51.7 (C-3), 56.2 (OMe), 110.2 (C-7), 122.7
(C-8a), 127.2 (C-8), 132.6 (C-4a), 136.1 (C-5), 153.9 (C-6) and 157.8 (C-
.
C
12H16NO2 ([M+H]+) requires m/z: 206.1181.
5,6,7-Trimethoxy-3-methyl-3,4-dihydroisoquinoline (8e): Yield: 13%
(Method B). Amber oil. IR (NaCl, ṽ): 2962, 2929, 2846, 1598, 1573, 1415,
1330, 1244, 1120, 1031, 991 and 831 cm–1 1H NMR δ: 1.40 (d, J = 6.8,
.
3H, Me), 2.32 (dd, J = 12.1 and 16.5, 1H, 4-HA), 2.87 (dd, J = 5.8 and
16.5, 1H, 4-HB), 3.55-3.70 (m, 1H, 3-H), 3.85 (s, 3H, OMe), 3.87 (s, 3H,
OMe), 3.91 (s, 3H, OMe), 6.66 (s, 1H, 8-H) and 8.20 (d, J = 2.6, 1H, 1-H).
13C NMR δ: 22.9 (Me), 25.7 (C-4), 52.2 (C-3), 56.3 (OMe), 61.0 (OMe),
61.1 (OMe), 107.1 (C-8), 122.5 (C-8a), 123.8 (C-4a), 145.0 (C-6), 150.5
(C-5), 152.4 (C-7) and 158.7 (C-1). HRMS (ESI-TOF): Found m/z:
236.1290; C13H18NO3 ([M+H]+) requires m/z: 236.1287.
1). HRMS (ESI-TOF): Found m/z: 270.0786;
requires m/z: 270.0800.
C
12H16NO4S ([M+H]+)
5-Methoxy-1,3-dimethyl-3,4-dihydroisoquinoline (8k):[ 29 ] Yield: 20%
(Method A). Amber brown oil. 1H NMR δ: 1.39 (d, J = 6.8, 3H, 3-Me),
2.23 (dd, J = 12.7 and 16.5, 1H, 4-HA), 2.38 (d, J = 2.1, 3H, 1-Me), 2.94
(dd, J = 5.6 and 16.5, 1H, 4-HB), 3.41-3.53 (m, 1H, 3-H), 3.85 (s, 3H,
OMe), 6.95 (d, J = 8.0, 1H, 6-H), 7.13 (d, J = 7.6, 1H, 8-H) and 7.25 (t, J
= 8.0, 1H, 7-H). 13C NMR δ: 22.4 (3-Me), 23.8 (1-Me), 26.1 (C-4), 51.6
(C-3), 55.7 (OMe), 112.6 (C-6), 117.9 (C-8), 125.8 (C-4a), 127.0 (C-7),
130.2 (C-8a), 156.0 (C-5) and 163.5 (C-1).
5-Hydroxy-6-Methoxy-3-methyl-3,4-dihydroisoquinoline (8f): Yield:
37% (Method B). Light brown solid, m.p.: 146-148 °C. IR (KBr, ṽ): 3110,
2964, 2854, 1608, 1578, 1490, 1332, 1273, 1138, 1089, 947, 837 and
788 cm–1 1H NMR δ: 1.40 (d, J = 6.8, 3H, Me), 2.40 (dd, J = 11.5 and
.
16.5, 1H, 4-HA), 2.98 (dd, J = 6.0 and 16.5, 1H, 4-HB), 3.61-3.73 (m, 1H,
3-H), 3.92 (s, 3H, OMe), 5.26 (br s, 1H, OH), 6.76 (d, J = 8.2, 1H, 7-H),
6.87 (d, J = 8.2, 1H, 8-H) and 8.23 (d, J = 2.5, 1H, 1-H). 13C NMR δ: 21.6
(Me), 25.9 (C-4), 51.4 (C-3), 56.1 (OMe), 108.3 (C-7), 120.8 (C-8), 121.7
(C-4a), 122.1 (C-8a), 142.3 (C-5), 149.5 (C-6) and 159.5 (C-1). HRMS
(ESI-TOF): Found m/z: 192.1012; C11H14NO2 ([M+H]+) requires m/z:
192.1025.
5,6-Dimethoxy-1,3-dimethyl-3,4-dihydroisoquinoline (8l):[26b] Yield:
20% (Method A). Amber brown oil. 1H NMR δ: 1.38 (d, J = 6.8, 3H, 3-Me),
2.31 (dd, J = 12.1 and 16.1, 1H, 4-HA), 2.36 (d, J = 1.9, 3H, 1-Me), 2.97
(dd, J = 5.3 and 16.1, 1H, 4-HB), 3.41-3.56 (m, 1H, 3-H), 3.80 (s, 3H,
OMe), 3.90 (s, 3H, OMe), 6.79 (d, J = 8.5, 1H, 7-H) and 7.26 (d, J = 8.5,
1H, 8-H). 13C NMR δ: 22.3 (3-Me), 23.4 (1-Me), 27.1 (C-4), 51.6 (C-3),
55.8 (OMe), 60.7 (OMe), 109.4 (C-7), 122.2 (C-8), 123.5 (C-8a), 13.4 (C-
4a), 145.4 (C-5), 154.6 (C-6) and 163.1 (C-1).
5-Isopropoxy-6-methoxy-3-methyl-3,4-dihydroisoquinoline
Yield: 15% (Method B). Amber oil. IR (NaCl, ṽ): 2970, 2926, 2843, 1625,
1570, 1487, 1379, 1274, 1109, 1089, 924 and 801 cm–1 1H NMR δ: 1.26
(d, J = 6.2, 3H, OCHMe2), 1.29 (d, J = 6.2, 3H, OCHMe2), 1.37 (d, J = 6.8,
(8g):
.
Acknowledgements
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801076
European Journal of Organic Chemistry
FULL PAPER
The authors gratefully acknowledge Consejo Nacional de
Investigaciones Científicas y Técnicas (CONICET, PUE IQUIR-
[10] (a) T. Sakaguchi, T. Kobayashi, S. Hatano, H. Tsuchikawa, K. Fukase,
K. Tanaka, S. Katsumura, Chem. Asian J. 2009, 4, 1573-1577; (d) Y.
Maekawa, T. Sakaguchi, H. Tsuchikawa, S. Katsumura, Tetrahedron
Lett. 2012, 53, 837-841; (e) D. I. S. P. Resende, S. Guieu, C. G. Oliva,
A. M. S. Silva, Tetrahedron Lett. 2014, 55, 6585-6588.
2016) and Agencia Nacional de Promoción Científica
y
Tecnológica (ANPCyT, PICT 2014-0445) for financial support.
D.F.V. also thanks CONICET for his fellowship. As members of
IQUIR the authors thank the Agencia Santafesina de Ciencia,
[11] T. Kobayashi, S. Hatano, H. Tsuchikawa, S. Katsumura, Tetrahedron
Lett. 2008, 49, 4349-4351.
Tecnología
e
Innovación (ASACTeI) for awarding the
[12] Y. Kwon, M. Jeon, J. Y. Park, Y. H. Rhee, J. Park, RSC Adv. 2016, 6,
661-668.
institutional grant AC-2015-0005 (400 MHz NMR machine).
[13] (a) K. Tanaka, H. Mori, M. Yamamoto, S. Katsumura, J. Org. Chem.
2001, 66, 3099-3110; (b) Z. Vincze, Z. Mucsi, P. Scheiber, P. Nemes,
Eur. J. Org. Chem. 2008, 1092-1100; (c) H. M. Sklenicka, R. P. Hsung,
M. J. McLaughlin, L.-l. Wei, A. I. Gerasyuto, W. B. Brennessel, J. Am.
Chem. Soc. 2002, 124, 10435-10442; (d) A. Patel, J. R. Vella, Z.-X. Ma,
R. P. Hsung, K. N. Houk, J. Org. Chem. 2015, 80, 11888−11894.
[14] (a) T. L. Gilchrist, M. A. M. Healy, J. Chem. Soc. Perkin Trans. 1 1992,
749−750; (b) T. L. Gilchrist, M. A. M. Healy, Tetrahedron Lett. 1990, 31,
5807-5810; (c) T. L. Gilchrist, M. A. M. Healy, Tetrahedron 1993, 49,
2543-2556; (d) S. T. Staben, J. J. Kennedy-Smith, D. Huang, B. K.
Corkey, R. L. LaLonde, F. D. Toste, Angew. Chem. Int. Ed. 2006, 45,
5991-5994; (e) S. Yamamoto, J. Shirai, Y. Fukase, A. Sato, M. Kouno,
Y. Tomata, A. Ochida, K. Yonemori, T. Oda, T. Imada, T. Yukawa,
Patent EP 2975031, 2016.
Keywords: 6π-electron cyclization • nitrogen heterocycles • 3-
methylisoquinoline synthesis • benzotrifluoride • hydrazones
[1]
(a) J. W. Blunt, M. H. G. Munro in Dictionary of Natural Products,
Chapman and Hall, New York, USA, 2007; (b) J. D. Phillipson, M. F.
Roberts, M. H. Zenk in The Chemistry and Biology of Isoquinoline
Alkaloids, Springer, Heidelberg, Germany, 1985; (c) S. Bräse in
Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis,
Evaluation, RSC, London, UK, 2016, Chapter 7; (d) S. Hanessian in
Natural Products in Medicinal Chemistry, Wiley, New York, USA, 2014;
(e) L. Antkiewicz-Michaluk, H. Rommelspacher in Isoquinolines and
Beta-Carbolines as Neurotoxins and Neuroprotectants, Springer, New
York, USA, 2011; (f) J. Alvarez-Builla, J. J. Vaquero, J. Barluenga,
Modern Heterocyclic Chemistry, Wiley, New York, USA, 2011; (g) The
Simple Plant Isoquinolines (Eds.: A. Shulgin, W. E. Perry), Transform
Press, Berkeley, USA, 2003.
[15] D. I. S. P. Resende, S. Guieu, C. G. Oliva, A. M. S. Silva, Tetrahedron
Lett. 2014, 55, 6585-6588.
[16] (a) E. Shaban, I. Hossain, M.-Y. Wu, Y. Takemasa, S. Nagae, W. Peng,
H. Kawafuchi, T. Inokuchi, Heterocycles, 2014, 89, 171-182; (b) S.
Müller, B. List, Synthesis 2010, 2171-2178.
[2]
(a) D. F. Maynard, W. H Okamura, J. Org. Chem. 1995, 60, 1763-1771;
(b) K. Tanaka, H. Mori, M. Yamamoto, S. Katsumura, J. Org. Chem.
2001, 66, 3099-3110; (c) K. Tanaka, T. Kobayashi, H. Mori, S.
Katsumura, J. Org. Chem. 2004, 69, 5906-5925; (d) S. Fujita, T.
Sakaguchi, T. Kobayashi, H. Tsuchikawa, S. Katsumura, Org. Lett.
2013, 15, 2758-2761.
[17] V. Lyaskovskyy, R. Fröhlich, E.-U. Würthwein, Synlett, 2007, 2733-
2737.
[18] (a) A. Ogawa, D. P. Curran, J. Org. Chem. 1997, 62, 450-451; (b) J. J.
Maul, P. J. Ostrowski, G. A. Ublacker, B. Linclau, D. P. Curran in
Benzotrifluoride, Derivatives: Useful Solvents of Organic Synthesis and
Fluorous Synthesis in Modern Solvents in Organic Synthesis - Topics in
Current Chemistry (Ed. P. Knochel), Vol. 206, Ed.: Springer,
Heidelberg, 1999, pp. 79-105; (c) K. T. J. Loones, B. U. W. Maes, G.
Rombouts, S. Hostyn, G. Diels, Tetrahedron 2005, 61, 10338-10348.
[19] (a) M. Neumeyer, J. Kopp, R. Brückner, Eur. J. Org. Chem. 2017,
2883-2915; (b) F. Ono, H. Takenaka, T. Fujikawa, M. Mori, T. Sato,
Synthesis 2009, 1318-1322; (c) F. Ono, H. Takenaka, Y. Eguchi, M.
Endo, T. Sato, Synlett 2009, 487-489; (d) S. K. Meegalla, N. J. Taylor,
R. Rodrigo, J. Org. Chem. 1992, 57, 2422-2427.
[3]
[4]
S. Hibino, Yakugaku Zasshi 2016, 136, 607-648.
(a) M. L. Meketa, S. M. Weinreb, Y. Nakao, N. Fusetani, J. Org. Chem.
2007, 72, 4892-4899; (b) L. Meng, J. Org. Chem. 2016, 81, 7784-7789;
(c) K. Omura, T. Choshi, S. Watanabe, Y. Satoh, J. Nobuhiro, S. Hibino,
Chem. Pharm. Bull. 2008, 56, 237-238; (d) T. Choshi, T. Kumemura, J.
Nobuhiro, S. Hibino, Tetrahedron Lett. 2008, 49, 3725-3728; (e) T.
Kumemura, T. Choshi, A. Hirata, M. Sera, Y. Takahashi, J. Nobuhiro,
Hibino, Chem. Pharm. Bull. 2005, 53, 393-397; (f) Y. Li, T. Kobayashi,
S. Katsumura, Tetrahedron Lett. 2009, 50, 4482-4484.
[20] (a) R. Sureshbabu, R. Balamurugan, A. K. Mohanakrishnan,
Tetrahedron 2009, 65, 3582-3591; (b) K. T. Potts, E. B. Walsh, D.
Bhattacharjee, J. Org. Chem. 1987, 52, 2285-2292; (c) F. Palacios, D.
Aparicio, Y. Lopez, J. M. de los Santos, J. M. Ezpeleta, Tetrahedron
2006, 62, 1095-1101.
[5]
(a) S. Hibino, E. Sugino, Y. Adachi, K. Nomi, K. Sato, K. Fukumoto,
Heterocycles, 1989, 28, 275-282; (b) Y. Ishihara, S. Azuma, T. Choshi,
K. Kohno, K. Ono, H. Tsutsumi, T. Ishizu, S. Hibino, Tetrahedron 2011,
67, 1320-1333; (c) K. Umetsu, N. Asao, Tetrahedron Lett. 2008, 49,
2722-2725; (d) K. Kohno, S. Azuma, T. Choshi, J. Nobuhiro, S. Hibino,
Tetrahedron Lett. 2009, 50, 590-592; (e) T. Kumemura, T. Choshi, J.
Yukawa, A. Hirose, J. Nobuhiro, S. Hibino, Heterocycles 2005, 66, 87-
90.
[21] (a) K. Gilmore, R. K. Mohamed, I. V. Alabugin. WIREs Comput. Mol.
Sci. 2016, 6, 487-514; (b) H. McNab, E.-A. Murray, J. Chem. Soc.
Chem. Commun. 1981, 722-723; (c) H. McNab, J. Chem. Soc. Perkin
Trans. 1 1980, 2200-2204.
[6]
[7]
(a) N. Kuwabara, H. Hayashi, N. Hiramatsu, T. Choshi, T. Kumemura, J.
Nobuhiro, S. Hibino, Tetrahedron 2004, 60, 2943-2952; (b) D. F.
Vargas, E. L. Larghi, T. S. Kaufman, Nat. Prod. Rep. 2018, 35, 000-000.
Doi: 10.1039/C8NP00014J.
[22] (a) R. Alonso, P. J. Campos, M. A. Rodríguez, D. Sampedro, J. Org.
Chem. 2008, 73, 2234-2239; (b) R. T. McBurney, A. M. Z. Slawin, L. A.
Smart, Y. Yu, J. C. Walton, Chem. Commun. 2011, 47, 7974-7976; (c)
J. M. Pérez, P. López-Alvarado, E. Pascual-Alfonso, C. Avendaño, J. C.
Menéndez, Tetrahedron 2000, 56, 4575-4583.
(a) P. Zhao, F. Wang, K. Han, X. Li, Org. Lett. 2012, 14, 3400-3403; (b)
D. Zhao, F. Lied, F. Glorius, Chem. Sci. 2014, 5, 2869-2873; (c) H. Chu,
S. Sun, J.-T. Yu, J. Cheng, Chem. Commun. 2015, 51, 13327-13329;
(d) H. Jiang, X. An, K. Tong, T. Zheng, Y. Zhang, S. Yu, Angew. Chem.
Int. Ed. 2015, 54, 4055-4059.
[23] M. Austin, O. J. Egan, R. Tully, A. C. Pratt, Org. Biomol. Chem. 2007,
5, 3778-3786.
[24] Probably formed in situ as a result of the following reaction: H2C=NMe
+ H2N-NMe2 → MeNH2 + H2C=N-NMe2.
[8]
[9]
(a) K. Parthasarathy, C.-H. Cheng, J. Org. Chem. 2009, 74, 9359-9364;
(b) K. Parthasarathy, M. Jeganmohan, C.-H. Cheng, Org. Lett. 2008,
10, 325-328; (c) R. J. Olsen, Tetrahedron Lett. 1991, 32, 5235-5238;
(d) B. M. Trost, A. C. Gutierrez, Org. Lett. 2007, 9, 1473-1476.
(a) S. J. Markey, W. Lewis, C. J. Moody, Org. Lett. 2013, 15, 6306-
6308; (b) Z. Wróbel, Synlett 2001, 1927-1928; (c) T. D. Wahyuningsih,
N. Kumar, D. S. Black, Tetrahedron 2007, 63, 6713-6719; (d) K. A.
Clayton, D. S. Black, J. B. Harper, Tetrahedron 2007, 63, 10615-10621;
(e) D. Tejedor, G. Méndez-Abt, F. García-Tellado, Eur. J. Org. Chem.
2010, 6582-6587.
[25] H. Wagner, S. Bladt, V. Rickl in Drug Analysis:
A Thin Layer
Chromatography Atlas, 2nd Ed. 2009, pp. 360, Springer, Heidelberg,
Germany.
[26] (a) C.-K. Chan, Y.-L. Chan, M.-Y. Chang, Tetrahedron 2016, 72, 547-
554; (b) T. R. Govindachari, M. V. Lakshmikantham, Proc. Indian Acad.
Sci. A 1957, 46, 406-408.
[27] A. Coppola, D. Sucunza, C. Burgos, J. J. Vaquero, Org. Lett. 2015, 17,
78-81.
[28] (a) T. R. Govindachari, B. R. Pai, J. Org. Chem. 1953, 18, 1253-1262;
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10.1002/ejoc.201801076
European Journal of Organic Chemistry
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(b) W. Zielinski, Polish J. Chem. 1982, 56, 93-100.
[29] D. Behnke, D. Carcache, P. Ertl, M. Koller, D. Orain, Patent WO
2014/30128 A1, 2014.
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