Novel synthesis of 4,4-difluoropyrido[4,3-b]indoles via intramolecular Heck reaction

Article abstract of DOI:10.1016/j.tetlet.2012.12.115

Various difluoropyridoindoles were synthesized via a palladium-catalyzed intramolecular Heck reaction as a key step. Thus, ortho-bromoanilines and difluoropiperidinone were treated with (PPh₃)₂PdCl ₂ and base in pyridine to give the regioselective cyclized heterocycles in modest to satisfactory yields. Copyright

Full text of DOI:10.1016/j.tetlet.2012.12.115

Tetrahedron Letters 54 (2013) 1424–1427
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel synthesis of 4,4-difluoropyrido[4,3-b]indoles via intramolecular
Heck reaction
⇑
M. Madaiah, M. K. Prashanth, H. D. Revanasiddappa
Department of Chemistry, University of Mysore, Manasagangothri, Mysore 570006, Karnataka, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Various difluoropyridoindoles were synthesized via a palladium-catalyzed intramolecular Heck reaction
as a key step. Thus, ortho-bromoanilines and difluoropiperidinone were treated with (PPh3)2PdCl2 and
base in pyridine to give the regioselective cyclized heterocycles in modest to satisfactory yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 15 November 2012
Revised 28 December 2012
Accepted 30 December 2012
Available online 5 January 2013
Keywords:
Difluoropyridoindole
Palladium
Heck reaction
Pyridine
Regioselective
Nitrogen-containing heterocycles are one of the most important
classes of medicinal compounds and are structural components of
many bioactive natural products and organic materials.1 Owing to
the numerous applications of indoles in pharmaceutical research,
the development of efficient and new synthetic protocols for their
synthesis has attracted the attention of many chemists. Conse-
quently, there is a strong driving force to design new and efficient
strategies for making carbon–nitrogen (C–N) bonds.2 And the un-
ique properties of fluorine, selective introduction of fluorine
atom(s), or fluorine-containing moieties into organic molecules of-
ten dramatically alter their stability, lipophilicity, bioavailability,
and biopotency. It is estimated that as many as 30–40% of agro-
chemicals and 20% of pharmaceuticals on the market contain fluo-
rine3 as a result, difluoropiperidinone and o-haloanilines are
included in the indole derivatives.
tween aniline and 2,3-dihalopyridine by heating in a screw-capped
sample vial at 145 °C for about 16 h.9 Sarvesh et al., have described
the synthesis of substituted pyrazolo[3,4-b]indoles involving a pal-
ladium coupling reaction with Pd(OAc)2, n-Bu4NBr, K2CO3 between
aniline and 1-aryl pyrazole heating (2–30 h at 140 °C).10 Nazaré
et al., have reported the synthesis of substituted pyridoindoles
involving a palladium coupling reaction with Pd[P(t-Bu)3]2 be-
tween chloroanilines and ketones by thermal heating in a sealed
tube (4–16 h at 140 °C).11
In contrast to the well documented Fischer indole reaction ap-
plied to the azaindoles synthesis,12–14 the Hegedus–Mori–Heck
reaction has never been reported for the preparation of difluoropy-
ridoindole. In this work, the authors have described the intramo-
lecular Heck cyclization of difluoropiperidinone and ortho-
bromoanilines which yields the corresponding 4,4-difluoropyri-
do[4,3-b]indoles.
To the best of our knowledge, a rapid and general synthesis of
the isomeric difluoropyridoindole from readily accessible starting
materials has not been described. As part of our medicinal chemis-
try research program, we needed an efficient route to difluoropy-
ridoindole compatible with sensitive groups such as secondary
amine. In this investigation, we wish to report for the first time a
rapid one pot synthesis of difluoropyridoindole compounds using
difluoropiperidinone employing sealed tube conditions via an
intramolecular Heck reaction.
Based on the results shown in Scheme 1, a systematic survey of
this reaction sequence to fused indoles was undertaken. The pre-
cursors required for the Heck reaction were prepared by nucleo-
philic substitution using 4-methoxy benzyl amine and
The intramolecular Heck reaction4 is an important and powerful
method for the construction of carbo- and heterocyclic com-
pounds. The synthesis of indoles using this reaction has also been
widely studied.5,6 The application of the Hegedus–Mori–Heck reac-
tion (intramolecular Heck reaction) to the synthesis of pyrido[3,2-
b]indole was first explored on enamines with NaHCO3 and
Pd(PPh3)4 in HMPA at 140 °C.7,8 Under these conditions, the scope
of this palladium-catalyzed cross-coupling was limited to the prep-
aration of 4-azaindoles. In a recent Letter, Joydev and others have
described the synthesis of substituted R-carbolines involving a pal-
ladium coupling reaction with Pd(OAc)2, PCy3ÁHBF4, DBU, DMA be-
⇑
Corresponding author. Tel.: +91 821 2419669.
E-mail address: hdrevanasiddappa@yahoo.com (H.D. Revanasiddappa).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.115

M. Madaiah et al. / Tetrahedron Letters 54 (2013) 1424–1427
1425
O
O
N
O
O
a
N
H
O
N
O
b
O
N
O
N
NH2
O
1
2
c
O
O
O
O
O
O
N
F
f
N
N
O
e
O
d
F
O
O
O
O
O
N
F
F
F
F
F
F
O
3
6
4
5
Scheme 1. Synthesis of precursor required for the Heck reaction. Reagents and condition: (a) ethanol, rt, 16 h; (b) formaldehyde, benzotriazole, methanol, rt, 16 h; (c) zinc,
trimethylsilylchloride, ethylbromo difluoroacetate, tetrahydrofuran, rt, 18 h; (d) diisopropylamine, n-butyllithium, tetrahydrofuran, À78 °C, 16 h; (e) 18% HCl, reflux, 3 h; (f)
1-chloroethylchloroformate, 1,2-dichloroethane, 100 °C, 3 h; methanol, reflux, 6 h; triethylamine, boc anhydride, dichloromethane, rt, 18 h.
ethylacrylate in ethanol to give the ester 115 with good yields. Ester
1 was reacted with formaldehyde and benzotriazole in methanol
afforded the benzotriazole derivative 2,16,17 which on treatment
with ethyl bromodifluoro acetate in the presence of zinc and tri-
methylsilyl chloride afforded the difluoro-diester 3. Dieckmann
cyclization of 3 using diisopropylamine in tetrahydrofuran resulted
in the formation of keto-ester 4.18 Hydrolysis of keto-ester 4 fol-
lowed by decarboxylation using HCl gave the desired compound
5.19 The benzyl group was deprotected using 1-chloroethylchloro-
formate in 1,2-dichloroethane and methanol to form amine,20
which was protected with boc anhydride to get an amine 6 which
is having difluoro moiety in the piperidone ring as
difluoropiperidinone.21
Preliminary studies focused on optimization of the intramolec-
ular Heck reaction (8a–h) ? (9a–h). The enamine was selected as
the model substrate to explore the palladium catalyzed coupling
reaction (Scheme 2). Several palladium catalysts {Pd(OAc)2,
Pd(PPh3)4, (PPh3)2PdCl2}, bases (i-Pr2NEt, i-Pr2NH, NEt3, Cy2NMe),
solvent pyridine and temperature range (110–160 °C for 4–18 h)
were examined in degassed sealed tube reactions. Investigation
of the palladium source and the solvent effect revealed that
(PPh3)2PdCl2 and pyridine with diisopropylethylamine are the
most appropriate reagents to perform this intramolecular Heck
reaction under sealed tube.
From the above conditions, the Heck coupling was carried out
with boc protected difluoropiperidinone 6 and o-bromoanilines
(7a–h) in the presence of a catalytical amount of p-toluenesulfonic
acid in toluene as a solvent, resulting in the formation of the corre-
sponding imines.22,23 During the reaction, the imines undergo tau-
tomerism to form an enamine,4a,24 which is an active intermediate
to undergo Heck reaction. When the enamines (8a–h) were heated
at 120 °C with bis(triphenylphosphine) palladium(II)dichloride in
the presence of pyridine as solvent with diisopropylethylamine
as base resulted in the formation of difluoropyridoindoles (9a–h).
Under these conditions, yields of the desired tert-butyl 4,4-di-
fluoro-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate
derivatives ranged from 85% to 98%. Also, heating the reaction at a
higher temperature (above 120 °C) led to lower yields of difluoro-
pyridoindoles (9a–h) with increased decomposition.
O
(i) Condensation reaction
(ii) Heck reaction
O
R
O
N
Br
O
N
R
O
N
H
H2N
F
F
F
F
7(a-h)
6
9(a-h)
i
Condensation
ii
F
Heck reaction
R
O
O
O
Br
N
Br
N
O
N
R
N
H
F
F
F
8(a-h)
Scheme 2. One-pot synthesis of difluoropyridoindole (9a–h) from the reaction of 6 with (7a–h). Reagents and condition: (i) 2-bromo-aniline, para toluene sulfonic acid,
benzene, reflux, 3 h; (ii) dichloro-bis(triphenylphosphine) palladium(II), diisopropylethylamine, pyridine, 120 °C, 16 h.

1426
M. Madaiah et al. / Tetrahedron Letters 54 (2013) 1424–1427
After the exploration of the reaction conditions, we focused our
ing materials required for our studies were prepared following lit-
erature procedures.7,8,25 Surprisingly, under these conditions and
with higher temperatures or longer reaction time, o-bromoanilines
attention on optimizing the isolation of the reaction product(s). It
was noted that on using an aqueous work-up for the isolation of
difluoropyridoindoles (9a–h), a lower yield than the conversion
determined by HPLC was obtained. Therefore, we thought of
non-aqueous work-up conditions since we suspected 9a–h to be
sparingly water-soluble. The optimized purification protocol in-
volves a direct column chromatography over silica gel (10–15%
EtoAc in hexane) of the reaction mixture followed by triturate with
hexane, to get the desired difluoropyridoindoles (9a–h).
Having established rapid and high yielding conditions for the
palladium cross-coupling of enamines (8a–h) to difluoropyridoin-
doles (9a–h), we wanted to examine the scope of this method. Ta-
ble 1 summarizes the results of difluoropyridoindole syntheses
starting from ortho-bromoanilines. Most of these condensed start-
remains unreacted in the presence of
difluoropiperidinone.
a small amount of
Having established the optimal reaction conditions, the scope of
this reaction was examined with respect to anilines by varying sys-
tematically the electronic properties of the aromatic ring. As
shown in Table 1, the reaction turned out to be very general and
is applicable to both electron-rich and electron-deficient o-bromo-
anilines. When meta and para methyl o-bromoanilines with elec-
tron releasing group in benzene ring increases the yield whereas
meta and para trifluoromethyl o-bromoanilines with electron with-
drawing group in benzene ring decreases the yield. Steric hin-
drance was also studied, when both 2-bromo-6-methylaniline
(7b) and 2-bromo-6-(trifluoromethyl)aniline (7f) were used to
produce less yield, thus, the use of 2 equiv of aniline was required
for the reaction of 9b and 9f. The product yield trends of the (ortho/
meta/para) methyl and trifluoromethyl derivatives may provide
some evidence that the reaction yield is influenced by substituent
electronic effects, the correlation could be considered over reach-
ing due to the small scale synthesis.
In conclusion, we have developed an efficient synthesis of
highly functionalized indoles by a palladium-catalyzed annulation
reaction between ortho-bromoanilines and difluoropiperidinone.
The intramolecular Heck reaction of enamines under sealed tube
conditions provides good yields of difluoropyridoindole. The pres-
ent method, therefore, provides general synthetic approaches for
these heterocylic frameworks and is compatible with a range of
electron-donating and electron-withdrawing substituents on the
aryl group. This methodology provided an array of difluoropyrido-
indole in modest to satisfactory yields and will facilitate the syn-
thesis of additional derivatives that can be used for various
applications, including screening for biological activities. This
method provides a new entry into interesting heterocycles con-
taining a piperidine ring. Finally, this Letter is the first to describe
the synthesis of difluoropyridoindole using difluoropiperidinone
compound via an intramolecular Heck reaction.
Table 1
Annulation reaction with acyclic ketones
Annulated precursor
Annulated producta
Yieldb (%)
Br
O
O
O
N
H2N
98
N
H
7a
F
F
9a
Br
H2N
7b
O
O
N
85
91
N
H
F
F
9b
Br
O
O
N
H2N
N
H
7c
F
F
9c
Br
O
N
H2N
92
91
7d
N
H
F
F
Acknowledgments
9d
The authors are grateful to the University of Mysore, Mysore for
providing laboratory facilities. One of the authors M.M. is thankful
to the University of Mysore, Mysore for providing necessary
facilities.
Br
O
O
O
H2N
O
O
N
7e
N
H
F
F
9e
Supplementary data
Br
N
Supplementary data (synthetic procedures and analytical data
for all products) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2012.12.115.
H2N
CF3
7f
86
88
CF3
N
H
F
F
9f
Br
References and notes
CF3
O
O
N
H2N
CF3
CF3
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a
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