A simple route to polysubstituted indoles exploiting azide induced furan ring opening

Article abstract of DOI:10.1021/ol5018504

A straightforward, efficient indole synthesis based on thermolysis of 2-(2-azidobenzyl)furans with attack of the formed nitrene moiety onto the ipso position of furan ring has been developed. The cyclization is accompanied by furan ring opening and affords indoles with a 2-acylvinyl substituent suitable for further modifications.

Full text of DOI:10.1021/ol5018504

Letter
pubs.acs.org/OrgLett
A Simple Route to Polysubstituted Indoles Exploiting Azide Induced
Furan Ring Opening
Vladimir T. Abaev,*,† Anastasiya T. Plieva,† Petrakis N. Chalikidi,† Maxim G. Uchuskin,‡
Igor V. Trushkov,§ and Alexander V. Butin*,‡,∥
†Department of Chemistry, North-Ossetian State University, Vatutina 46, Vladikavkaz 362025, Russian Federation
‡Department of Chemistry, Perm State University, Bukireva 15, Perm 614990, Russian Federation
§Department of Chemistry, M.V. Lomonosov Moscow State University, Leninskie gory 1-3, Moscow 119991, Russian Federation
∥Institute of Technical Chemistry UB RAS, academica Koroleva 3, Perm 614013, Russian Federation
S
* Supporting Information
ABSTRACT: A straightforward, efficient indole synthesis based on
thermolysis of 2-(2-azidobenzyl)furans with attack of the formed nitrene
moiety onto the ipso position of furan ring has been developed. The
cyclization is accompanied by furan ring opening and affords indoles with
a 2-acylvinyl substituent suitable for further modifications.
Scheme 1
ndoles belong to the most privileged heterocyclic structures.
To date, more than 4000 indole alkaloids were isolated from
I
different natural sources; there is a myriad of synthetic indole
derivatives demonstrating a broad range of physiological
activities. The indole scaffold is present in a multitude of
medicines, such as anticancer prodrug apaziquone,1 fluvastatin,2
which is utilized to treat hypercholesterolemia, (Figure 1), and
Figure 1. Examples of indole-based drugs.
only as components of complex mixtures due to nitrene attack
onto both ortho- and ipso-positions of a neighboring ring.10
However, we reasoned that the thermolysis of 2-(2-azido-
benzyl)furans 1 should afford indoles 2 selectively (Scheme 1)
because of the known tendency of furans to provide an α
carbon atom for reactions with electrophiles even if this
position is substituted; in the latter case the reaction is
accompanied by furan ring opening.11 2-(2-Azidobenzyl)furans
can be synthesized from 2-substituted furans which are easily
produced from furfural, one of the biomass platform molecules.
Here we report our investigation of this transformation of
inexpensive biomass processing products into indoles bearing
functionalities which can be further manipulated in a simple
and predictable manner for the syntheses of bioactive
compounds.
many others. New indole derivatives are continuously approved
for application in medicine. It stimulates the development of
novel methods for indole preparation and modification.3
Syntheses of the indole core bearing functional groups suitable
for further transformations are especially attractive approaches.
Organic azides are excellent sources of electrophilic nitrene
acting as a counterpart with an appropriate functionality in the
synthesis of heterocycles.4 In particular, indoles are synthesized
from azides by four principal methods: (1) thermolysis of 2-
arylvinyl azides (Hemetsberger−Knittel indole synthesis, path a
in Scheme 1);5 (2) transformation of 2-azidostyrenes under
heating6 or treatment with transition metal complexes7
(Sundberg synthesis, path b); (3) Au(I)-catalyzed cyclization
of (2-azidoaryl)acetylenes8 (path c); (4) related cyclization of
(2-azidoaryl)allenes (path d in Scheme 1).9
If there is a gap in conjugation between the azide group and
double bond, selectivity is lost as in the case of 2-
azidodiphenylmethanes which thermolysis produced indoles
Received: June 26, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
The preparation of 2-(2-azidobenzyl)furans 1 constitutes a
significant synthetic challenge in itself. Thus, diazotization/
azidation of the corresponding aniline was found to be efficient
for 1 bearing an ester group in the furan ring;12 however, failure
occurred for 2-(2-azidobenzyl)furans without an acceptor
substituent.13 To exclude strong mineral acid as a possible
reason for the tar formation, we employed nonaqueous
conditions (i-C5H11ONO, Me3SiCl, MeCN) to generate
diazonium ions, but only cinnolines were isolated (Scheme
2).14 So, we started with the development of approaches to
various 2-(2-azidobenzyl)furans 1.
Reoptimization of the reaction conditions revealed that the
utilization of polyphosphoric acid trimethylsilyl ester16 enables
products 1h−j to be obtained in high yields (Table 1, entries
9−13).
The reaction between furans and aldehydes is a stepwise
process, the intermediate being the corresponding aryl(furyl)-
methanol. Under that logic, the reaction of furans with other
diarylmethanols should also be an efficient method for the
synthesis of 2-(2-azidobenzyl)furans 1. We prepared a series of
2-azidobenzhydrols 5 and introduced them into the reaction
with 2-methylfuran (4a). This reaction was found to be
inefficient under the above-mentioned applied conditions.
However, utilization of BF3·OEt2 in CH2Cl2 allowed for
performing this condensation in reasonable to excellent yields
(Table 2, entries 1, 4−8). 1-(2-Azidoaryl)ethanol 5d with the
Scheme 2
Table 2. Synthesis of (2-Azidoaryl)difurylmethanes 1k−r
a
from 2-Azidobenzyl Alcohols 5 and Furans 4
One of the general methods for the synthesis of 2-(2-
substituted benzyl)furans is the Friedel−Crafts reaction of
furans with the corresponding benzaldehydes. Surprisingly, this
approach had not been reported for the substrates bearing the
azide moiety hitherto. The possible reason is the prejudice
about the instability of aryl azides in acidic media.15 After some
experimentation, 2-azidobenzaldehyde (3a) was found to react
with 2-methylfuran (4a) in the presence of HClO4 in dioxane
affording (2-azidophenyl)difurylmethane 1a in 76% yield
(Table 1, entry 1). Other 2-alkylfurans were also involved
b
entry
5
R2
R3
R6
R5
1
yield, %
1
2
3
4
5
6
7
8
a
a
a
b
c
d
e
f
H
H
Ph
Ph
Ph
Me
k
82
79
74
83
88
84
73
69
H
H
4-ClC6H4
l
c
H
H
CH2Pht
m
n
o
p
q
r
H
H
4-FC6H4
Ph
Me
Me
Me
Me
Me
Table 1. Synthesis of (2-Azidoaryl)difurylmethanes 1a−j
a
H
Cl
from 2-Azidobenzaldehydes 3 and Furans 4
OMe
OMe
OMe
OMe
Me
Ph
OCH2CH2O
Ph
a
Reaction conditions: benzyl alcohol 5 (10 mmol), furan 4 (20
mmol), BF3·OEt2 (15 mmol), and CH2Cl2 (25 mL), 5−10 °C.
b
c
Isolated yield. Pht = Phthalimido.
electron-enriched aromatic group also gave the corresponding
benzylfuran 1p in good yield (Table 2, entry 7). The furan 4e
with the masked aminomethyl substituent (Table 2, entry 3)
and 2-arylfuran 4d (entry 2) were also successfully introduced
into this condensation.
The starting 2-azidobenzaldehydes and 2-azidobenzyl alco-
hols can be prepared in a straightforward manner from
commercially available reagents. Thus, we have developed
efficient procedures for synthesis of 2-(2-azidobenzyl)furans 1
with a broad variety of substituents.
With a series of 2-(2-azidobenzyl)furans 1 in hand, we turned
our attention to their thermolysis producing 2. Screening
various solvents revealed that the heating of 1a under reflux in
PhBr, DMSO, DMF, Ph2O, and propionic acid afforded the
target indole 2a. However, significant tarring was found in these
solvents. Better results were obtained when the thermolysis was
carried out in p-xylene. (E)-2a was precipitated from the
reaction mixture and isolated in 52% yield by simple filtration.
Moreover, (Z)-2a was also obtained in 32% yield.
We believe that indole 2a formation proceeds through the
electrophilic attack of nitrene generated under thermolysis onto
the C(2) atom of the furan ring producing spiro zwitterionic
intermediate A (Scheme 3, path a). Then, furan ring opening
leads to 4-[3-furyl-3H-indol]but-3-en-2-one B aromatization
b
entry
3
R1
R2
R3
R4
R5
1
yield, %
1
2
a
a
a
b
c
d
e
f
H
H
H
H
Me
Et
a
b
c
d
e
f
76
79
75
84
88
92
85
89
85
83
H
H
H
H
3
H
H
H
H
t-Bu
Me
Me
Me
Me
Me
Me
Me
4
H
H
NO2
Br
H
5
H
H
H
6
OMe
Br
H
NO2
NO2
Me
H
H
7
H
H
g
h
i
8
OMe
OMe
OMe
H
OMe
H
9
g
h
OMe
H
10
H
OMe
j
a
Reaction conditions: (a) for 1a−g: aldehyde 3 (10 mmol), furan 4
(22 mmol), HClO4 (6 mmol), and 1,4-dioxane (10 mL), 5−10 °C;
(b) for 1h−j: aldehyde 3 (10 mmol), furan 4 (22 mmol), Me3SiPPA
b
(16.5 mmol), and CH2Cl2 (10 mL), 5−10 °C. Isolated yield.
into this reaction (Table 1, entries 2, 3). 2-Azidobenzaldehydes
3 with various substituents in the aromatic ring tolerated the
reaction conditions that allowed for synthesizing 2-(2-azido-
benzyl)furans 1a−g in good isolable yields. Nevertheless,
benzaldehydes 3f−h bearing two or more electron-releasing
substituents produced benzylfurans 1 in lower yields (50%−
60%) due to the partial destruction of the reaction products.
B
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Organic Letters
Letter
refluxing dodecane (210 °C). Under these conditions, (Z)-2a
was isolated in 60% yield while (E)-2a was obtained in 26%
yield. On the other hand, (E)-2a was exclusively obtained in
84% yield when products of 1a thermolysis in dodecane were
heated with 4-(dimethylamino)pyridine (DMAP) in refluxing
DMF to accelerate Z- to E-isomerization.19
Scheme 3. Possible Mechanism of Indoles 2 Formation
To determine the scope of the disclosed reaction, we
investigated the transformation of a series of 2-(2-azidobenzyl)-
furans 1 into the corresponding indoles using thermolysis in the
dodecane/DMAP-induced isomerization sequence (Scheme 4).
We found that 2-(2-acylvinyl)indoles 2a−j were isolated in
excellent yields and stereoselectivity independently of sub-
stitution pattern in the starting 1.
In conclusion, we proposed a conceptually new synthetic
approach to 2-(2-acylvinyl)indoles based on thermolysis of 2-
(2-azidobenzyl)furans in dodecane for 2−5 min and then in
DMF in the presence of DMAP. Indoles are obtained in
excellent yields and stereoselectivity. To realize this approach,
we developed methods for the preparation of a broad series of
starting 2-(2-azidobenzyl)furans from 2-azidobenzaldehydes or
2-azidobenzyl alcohols and 2-substituted furans. The latter are
direct products of biomass processing. The reported procedures
contribute to the solution of the vital problem of the biorefinery
and extend the utilization of the furan-based biomass platform
molecules for the production of valuable indoles. For example,
indole 2g can be straightforwardly transformed into fluvastatin
(Figure 1). The investigation of other transformations of the
synthesized indoles is in progress now.
which accomplishes (Z)-2a formation. A similar mechanism
was proposed earlier for the related thermolysis of compounds
wherein the 2-azidophenyl moiety was separated from another
(het)arene fragment by a one-atom linker.10b,12,17
The alternative mechanism consisting of aziridine C
formation (Scheme 3, path b) can be also considered by
analogy with mechanism proposed for (2-azidobenzyl)-
thiophenes thermolysis.18 However, in that case thieno[3,2-
b]quinolines were formed as a single products or along with
indoles. We did not identify furoquinoline derivatives D in the
reaction mixtures obtained after thermolysis of compounds 1.
So, we consider this mechanism to be unlikely.
(E)-2a is a secondary product resulting from isomerization of
the initially formed (Z)-2a. To manage the stereochemistry of
the reaction we reasoned that a higher temperature for the
nitrene generation should allow for shortening the reaction
time in favor of (Z)-isomers at the expense of (E)-ones. Indeed,
we found that only 2−3 min are sufficient for the full
conversion of 2-(2-azidobenzyl)furan 1a into indole 2a in the
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures as well as NMR, IR, MS spectra, and
elemental analyses are given in the Supporting Information.
a
,b
Scheme 4. Substrate Scope for 2-(2-Azidobenzyl)furan 1 into 2-(2-Acylvinyl)indole 2 Transformation
a
Reaction conditions: 2-Azidobenzylfuran 1 (3 mmol) was refluxed in dodecane (10−15 mL) for 2−5 min. Reaction mixture was evaporated in
b
vacuo to dryness; DMAP (0.15 mmol) and DMF (15 mL) were added; reaction mixture was refluxed for specified time. Isolated yield.
C
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Organic Letters
Letter
(14) Abaev, V. T.; Gutnov, A. V.; Butin, A. V.; Zavodnik, V. E.
Tetrahedron 2000, 56, 8933−8937.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: hampazero@mail.ru.
*E-mail: alexander_butin@mail.ru.
(16) Tsiunchik, F. A.; Abaev, V. T.; Butin, A. V. Chem. Heterocycl.
Compd. 2005, 41, 1476−1479.
Notes
(17) Hawkins, D. G.; Meth-Cohn, O. J. Chem. Soc., Perkin Trans. 1
1983, 2077−2087.
The authors declare no competing financial interest.
(18) Cliff, G. R.; Jones, G.; Woolard, J. McK. J. Chem. Soc., Perkin
Trans. 1 1974, 2072−2076.
ACKNOWLEDGMENTS
■
(19) (a) Konning, D.; Hiller, W.; Christmann, M. Org. Lett. 2012, 14,
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We thank the Russian Foundation for Basic Research (Project
13-03-01048), the Ministry of Education and Science of
Russian Federation (Project 4.246.2014/K), and the Ministry
of Education of the Perm Krai for support of this work.
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