Synthesis of novel fluorescent 12a-aryl substituted indoxylisoquinolines via aryne-induced domino process

Article abstract of DOI:10.1039/c5ra25323c

A novel effective protocol towards indolo[2,1-a]isoquinolinones via aryne-induced migration of aryl-anion in aryloxy substituted 3,4-dihydroisoquinolines is reported. These novel 12a-aryl substituted indoxylisoquinolines exhibit fluorescence properties and are characterized by green-shifted spectra and moderate quantum yields.

Full text of DOI:10.1039/c5ra25323c

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RSC Adv., 2016, DOI: 10.1039/C5RA25323C.
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Synthesis of novel fluorescent 12a-aryl substituted
indoxylisoquinolines via aryne-induced domino process
A. V. Varlamov,a N. I. Guranova,a R. A. Novikov,b V. V. Ilyushenkova,a V. N. Khrustalev,a N. S.
Baleeva,c T. N. Borisova,a and L. G. Voskressensky*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
R3
O
MeO
R1
Abstract:
A novel effective protocol towards indolo[2,1-
N
Me
N
O
O
N
HO
OR
a]isoquinolinones via aryne-induced migration of aryl-anion in
aryloxy substituted 3,4-dihydroisoquinolines is reported. These
novel 12a-aryl substituted indoxylisoquinolines exhibit fluorescent
properties and are characterized by green-shifted spectra and
moderate quantum yields.
R4
MeO
R2
OR
Tubulin polymerization inhibitors,
estrogen receptor binding affinity,
antiviral, antitumor,
MeO
Nuevamine
+
R=Me, ( )-Cryptaustoline
-
R=-CH2- (+)-Cryptowoline
-
immunosupressive activity
Figure 1 Biologically active indolo[2,1-a]isoquinolines
Introduction
Reactive intermediates such as radicals, carbenes,
soft and neutral nucleophiles with the formation of zwitterions.10 If
nitrenes etc. became widely used in organic synthesis. In the substrate has an electrophilic site, especially carbonyl or imine
recent decades arynes, highly reactive intermediates, justly groups, then the anionic center of the zwitterion can attack it
converted from an object of purely theoretical interest into a furnishing a fused heterocyclic system.3f,4g, 5f,10h,i,11
reagent for synthesizing variously constructed N- and O-
We presumed that the interaction of dehydrobenzene and
containing heterocycles1 after the development of the derivatives thereof with the conjugated –N=C–C=O system in
synthetic method of Kobayashi et al.2 Although [2+
4
]
aryloxy substituted isoquinolines would lead to annulation of an
cycloaddition3 and 1,3-dipolar cycloaddition4 of arynes are indole moiety and construction of the attractive indoloisoquinoline
used most frequently for heterocycle synthesis the core.
nucleophilic addition to arynes is one of the oldest and still
Herein we describe an elegant and effective synthesis of
widely used approaches towards alkaloids and biologically indoxylisoquinolines through Michael addition/aryl-anion migration
active compounds.5 The indolo[2,1-a]isoquinolines are the domino protocol induced by arynes in 1-aryloxy substituted 3,4-
principal structural moieties of Cryptaustoline and dihydroisoquinolines.
Cryptowoline alkaloids,6 which along with their synthetic
analogs exhibit strong anticancer activity and affinity for
estrogen receptors.7The structure of indoxylisoquinoline is also
Results and discussion
The required for the current study 1-(3,4-diethoxybenzoyl)-
found in Nuevamine alkaloid (figure 1).8 However the methods 6,7-diethoxy-3,4-dihydriosoquinoline 1 was obtained via oxidation
for the construction of such heterocycle core are limited.9
The low-lying LUMO determines highly electrophilic nature of commercially available hydrochloride; compound
of drotaverine by atmospheric oxygen during its isolation from the
was also
2
received by oxidation protocol;12 1-benzoyl-3,3-dimethyl-
substituted analogs 3-5 were synthesized by the literature
methods13 (figure 2). Compounds 5a and 5b were obtained from 3-
methoxyphenyl 2-methylpropan-2-ol and represent an inseparable
mixture of regioisomers. Arynes 6a-h were studied in present work.
arynes and makes them react primarily with electron-rich atoms of
Me
MeO
MeO
EtO
EtO
Me
N
N
N
OEt
OEt
O
O
O
OMe
3
1
2
Me
Me
Me
MeO
Me
Me
Me
N
N
N
Me
OMe
O
O
O
4
5a
5b
OMe
Me
MeO
MeO
Me
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
MeO
6a
6b
6c
6d
6e
6f
6g
6h
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Journal Name
EtO
EtO
6
1
6f
85
N
Figure 2. Starting 1-aryloxy-3,4-dihydroisoquinolines and arynes.
OMe
O
EtO
OMe
Based on the literature data the most used condition for
generation of arynes is CsF in acetonitrile at room temperature. We
7f
OEt
87b
EtO
EtO
7
8
1
1
6g
6h
conducted the model experiment with drotaveraldine
1 and
N
benzyne 6a at aforesaid conditions. To our delight the reaction
proceeded smoothly to furnish an unusual indoxylisoquinoline 7a in
90% yield (scheme 1).
O
EtO
7gA
OEt
67c
EtO
EtO
N
TMS
O
EtO
EtO
EtO
7h
OEt
OTf
N
N
EtO
EtO
EtO
MeO
MeO
9
2
2
3
6a
6f
73
77
93
CsF, MeCN, rt
OEt
OEt
N
O
O
EtO
O
1
7a
MeO
8a
Scheme 1. The model synthesis of indoxylisoquinoline
MeO
MeO
10
11
N
OMe
In order to minimize the reaction time we tried some other
conditions for aryne generation (see supporting information for
details), but however the yields were comparable or lower, except
benzyne 6h (entry 8), which gave indoxylisoquinoline 7h with good
yields only in case of microwave irradiation.
O
MeO
OMe
8b
6a
N
Further studies of scope and limitations of the reaction were
done in MeCN in the presence of CsF at room temperature, unless
otherwise defined (Table 1).
O
9a
12
3
6c
91
N
N
Table 1. The structure and the yield of indolo[2,1-a]isoquinolinones
Me
O
O
Entry
DIQ
a
Aryne
Product
Yield, %
Me
9bA
9bB
13
14
3
3
6f
94
72
EtO
EtO
1
1
1
6a
90
N
N
OMe
O
O
O
O
9c
OMe
EtO
7a
OEt
OEt
OEt
6g
EtO
EtO
EtO
EtO
2
6b
70
N
N
Me
N
N
O
O
O
EtO
9dA
9dB
EtO
Me
7bA
7bB
OEt
15
16
4
4
6a
6f
69
87
EtO
EtO
EtO
EtO
3
4
1
1
6c
75
N
N
N
Me
Me
O
O
10a
EtO
Me
EtO
7cA
7cB
OEt
6d
67b
EtO
EtO
N
N
Me
OMe
O
O
10b
OMe
EtO
MeO
7dA
OEt
17
5a 6a
5b
a:57
b:21
MeO
EtO
EtO
EtO
5
1
6e
80
N
N
N
MeO
N
EtO
EtO
OMe
O 11b
O 11a
O
O
EtO
OMe
7eA
7eB
OEt
OEt
aDIQ-dihydroisoquinoline. b only one isomer of possible two isomers was isolated c CsF,
2 | J. Name., 2012, 00, 1-3
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THF, 125oC, µW were used
Figure 3.The X-ray structure of 10a.
The reaction proceeds smoothly and well tolerates the
substituents in aryne moety. In case of compound 3 the target
indoxylisoquinolines were formed faster compared to ethoxy- and
methoxy substituted analogs and were precipitated from reaction
mixtures.
All synthesized in present work compounds displayed
fluorescent properties both in solid state and in solution. Recently
the fluorescent properties of indoloisoquinoline system were
discribed.17 In order to investigate the optical properties of
obtained compounds the absorbance and emission spectra were
recorded. It was found that the solutions of our
indoxylisoquinolines are characterized by green-shifted spectra,
except compound 7h, that demonstrated more red shift. The
It is noteworthy, that the unsymmetrical arynes 6d and 6g
regioselectivly gave only one isomer. The regioselectivity could be
explained in terms of the electronic and steric factors that favour
the nucleophilic attack on the less hindered position.3j,10h, 14
Based on the literature data3f,4g,5f,10a,b,h,j11 we suppose that the
reaction starts with the nucleophilic attack of the isoquinoline
nitrogen on generated in situ aryne leading to zwitterion A, the
anionic center of which attacks further carbonyl group, giving oxy-
anion B. Re-formation of the carbonyl group with subsequent
migration of aryl substituent to C-12a-position leads to formation of
indoloisoquinolinones 7-11 (scheme 2).
18
quantum yield with the use of p-HOBDI-BF2 as a standard was
calculated (Table 2).
Table 2 Spectral properties of indolo[2,1-a]isoquinolinones in MeCN
Compound
7a
Abs
Em
474
466
479
581
478
481
465
476
467
464
477
465
QY
399 (4200)a
389 (3600)
398 (6300)
463 (1700)
399 (3900)
397 (5500)
414 (4100)
413 (5500)
423 (4400)
413 (3800)
413 (4800)
413 (3600)
0.24
0.22
0.26
0.26
0.38
0.42
0.23
0.36
0.26
0.42
0.26
0.25
Migration of aryl anions during rearrangements of oxy-anions
has been reported. Benzylic rearrangements of α-diarylketones
through the action of bases15 and quasi-Favorskii rearrangements of
α-haloarylketones16 are some examples.
7dA
7f
7h
8a
8b
9a
R2
9c
R2
R1
R1
TMS
R1
R1
R2
9dA
10a
10b
11a
R4
R2
R4
N
OTf
N
O
1-5
O
A
R3
R3
aPeak maximum in nm (extinction coefficient in (mol cm)-1
)
R2
R2
R1
R1
R2
R2
N
N
R1
Conclusions
R1
R4
In summary, we developed a facile and efficient method
for the synthesis of a new class of fluorescent 12a-aryl
substituted indoxylisoquinolines through the interaction of
arynes with 1-aroyl-3,4-dihydroisoquinolines resulted in
annulation of an indolinone moiety that was accompanied by a
shift of the aryl substituent from the isoquinoline 1-carbonyl.
To the best of our knowledge this is the first example of the
aryne-induced aryl anion migration. Further studies on the
application of the present methodology along with the
investigation of biological properties are in progress.
O
R4
R3
O
R3
B
7-11
Scheme
2 Plausible mechanism for the formation of the indolo[2,1-
a]isoquinolines.
The structure of the product 10a was unambiguously established by
X-ray diffraction study and is shown in Figure 3 along with the
atomic numbering schemes.
Acknowledgments
This work was supported by RFBR grant №14-03-00311. This
research was carried out using equipment provided by the IBCH
core facility (CKP IBCH).
Notes and references
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R2
N
R2
N
TMS
OTf
R1
R1
CsF
R4
+
MeCN, rt
O
R3
O
R4
R3