A practical synthetic route to benzofuro[2,3-b] pyridine and trifluoromethyl-α-carbolines

Article abstract of DOI:10.1055/s-2008-1032042

In situ generated benzofuran-2-amine reacts with 1,3-CCC-dielectrophiles, such as CF₃-containing β-diketones, 3-formylchromone, methyl-2,4-dioxopentanoate and pentafluorobenzaldehyde, and the reaction leads to the formation of benzofuro[2,3-b]pyridine ring system. By using a similar approach 4-trifluoromethyl-α-carbolines were synthesized starting from indole-2-amine. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032042

LETTER
343
A Practical Synthetic Route to Benzofuro[2,3-b]pyridine and
Trifluoromethyl-a-carbolines
S
ynthesis of Benzo
i
furo[2
k
,3-
b
]pyridine
t
and
T
o
r
yl-
a
-carbolinesO. Iaroshenko,*a,b Ulrich Groth,a Nadiya V. Kryvokhyzha,c Samra Obeid,a Andrei A. Tolmachev,b,d
Thomas Wescha
a
Fachbereich Chemie, Universität Konstanz, Fach M-720, Universitätsstraße 10, 78457 Konstanz, Germany
Fax +49(7531)884424; E-mail: yva108@yahoo.co.uk
b
National Taras Shevchenko University, 62 Volodymyrska st., Kyiv 33, 01033, Ukraine
c
Department of Chemistry, University of Glasgow, University Avenue, Glasgow, G12 8QQ, UK
d
‘Enamine Ltd.’, 23 A. Matrosova st., 01103 Kyiv, Ukraine
Received 25 September 2007
Dedicated to Professor Wolfgang Pfleiderer on the occasion of his 80th birthday
are well-known inhibitors of ApoB-100-associated lipo-
protein production and/or release.12
Abstract: In situ generated benzofuran-2-amine reacts with 1,3-
CCC-dielectrophiles, such as CF3-containing b-diketones, 3-
formylchromone, methyl-2,4-dioxopentanoate and pentafluoro-
benzaldehyde, and the reaction leads to the formation of benzofu-
ro[2,3-b]pyridine ring system. By using a similar approach 4-
trifluoromethyl-a-carbolines were synthesized starting from indole-
2-amine.
In the present short communication we would like to de-
scribe a facile synthesis of 4-trifluoromethylbenzofu-
ro[2,3-b]pyridine and 4-trifluoromethyl-a-carbolines.
According to retrosynthetic analysis and previously
known properties of electron-rich aminoheterocycles one
can presume that benzofuro[2,3-b]pyridine and a-carbo-
line ring systems could be built up starting from benzofu-
ran-2-amine and indole-2-amine, and also a number of
corresponding fluorine-containing 1,3-dielectrophiles.
Key words: furanamine, indoleamine, pyridine, annulation, elec-
trophilic aromatic substitution
Small heterocyclic molecules play an important role in
modern pharmaceutical and medical chemistry.1 A major-
ity of drugs which came on the market during the last 25
years are small heterocycles;1 nearly 20% of newly devel-
oped products in the life sciences sector contain fluorine.
Three out of ten of the top selling pharmaceutical products
worldwide (1997) are fluorinated or trifluoromethylated
compounds.2
The method of constructing a pyridine ring on the basis of
electron-rich aminoheterocycles consisting of a NCC tri-
ad by fluorine-containing 1,3-CCC-dielectrophiles has
presently gained a wide popularity. A variety of con-
densed pyridines was synthesized by applying this meth-
od.13
According to literature, benzofuran-2-amine is not com-
mercially available. A few polycyclic derivatives contain-
ing the benzofuran-2-amine fragment14 were described
previously, but they are usually stabilized due to the pres-
ence of some electron-withdrawing groups. However,
some representatives like aplysinimine (5,7-dibromo-6-
methoxybenzofuran-2-amine) have been identified as one
of the metabolites from the sponge Aplysina (Verongia)
thiona.15
The 6,5,6-polycyclic heterocyclic systems are at present
under investigation, since, for example a-carbolines have
shown remarkable antitumor,3 anti-HIV4 and antiviral5
bioactivities. Some of the representatives are clinically
used as anti-Leukemia drugs.6 However, the most typical
bioproperties which attracted attention to the a-carbolines
are activities such as CDK-1, CDK-5 and GSK-3 kinase
inhibition.7 Some of the carbolines have an intensive clin-
ical application for the chemotherapeutical treatment of
hypertension.8 Isosteric analogues of a-carbolines con-
taining an oxygen atom in the position 9 are also under in-
vestigation. Recently, the synthesis of a novel selective
inhibitor of cyclin-dependent kinases (CDK) belonging to
the benzofuro[2,3-b]pyridine9 series was reported. Fur-
thermore, benzofuro[2,3-b]pyridines possess a wide vari-
ety of other biological and pharmacological properties,
the most attractive among them are small-sized cytostat-
ics.10 Insertion of fluorine-containing groups in the target
bioactive molecules usually increases the biological prop-
erties and typically improves the pharmacological activi-
ties.11 On the other hand, 4-trifluoromethyl-a-carbolines
O
NH2
O
O
NCO
2
1
O
N
O
N
H
H
3
20–30%
Scheme 1 Reagents and conditions: DMF, AcOH, reflux, 2–3 h,
without an external electrophile.
So far, no suitable precursor to generate benzofuran-2-
amine in situ is mentioned in the literature, whereas indol-
2-amine is commercially available and can be prepared ei-
SYNLETT 2008, No. 3, pp 0343–0346
Advanced online publication: 16.01.2008
DOI: 10.1055/s-2008-1032042; Art ID: G30207ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8

344
V. O. Iaroshenko et al.
LETTER
ther from o-nitrophenylacetonitrile on reduction in a yield On the other hand, indole-2-amine16b is easily accessible
of >95%16a,b or by using some other procedures.16c–e
and its chemistry has previously been studied in detail. It
was observed that some of the 1,3-dielectrophiles reacted
in two different ways depending on the type of the electro-
phile and the medium.20a Reaction with tetracyanoethyl-
ene proceeded, for example, in isopropanol in presence of
triethylamine with annulation of the pyridine moiety onto
the CCN triade,20b whereas acetylacetone led to the forma-
tion of pyrimido[1,2-a]indoles,20c which are antiathero-
sclerotic agents.
We have started our investigations with a search for a con-
venient approach towards the preparation of benzofuran-
2-amine (2). For this purpose the hydrolysis of
isocyanates17a,b was investigated. Commercially available
2-isocyanatobenzofuran17c,d (1) decomposes in aqueous
acetic acid leading to the in situ formation of the desired
benzofuran-2-amine which in absence of an external elec-
trophile leads to the formation of the urea 3 in a yield of
20–30% (Scheme 1). The in situ generated aminohetero-
cycle 2 was then subjected to reactions with 1,3-dielectro-
philes, such as trifluoromethyl-1,3-diones. Cycloaddition
took place in the boiling acetic acid medium. It is interest-
ing to note that after decomposition of isocyanate 1 the
newly formed benzofuran-2-amine (2) reacted with di-
electrophiles forming benzofuro[2,3-b]pyridines18 as ma-
jor products (Scheme 2). According to the HPLC and 19F
NMR studies the reactions proceeded in a straightforward
manner, with formation of only one regioisomer, since
only 1,3-di(benzofuran-2-yl)urea (3) was detected as a
side product. This side reaction can be avoided by using
high dilution conditions.
F3C
R
CF3
O
O
4a,b
N
NH2
N
N
R
H
H
6
7a R = Me 84%
7b R = Ph 89%
Scheme 3 Reagents and conditions: AcOH, reflux, 1 h.
Indol-2-amine reacted with 1,3-diketones in aqueous ace-
tic acid media selectively forming pyrido[2,3-b]indoles 7
in good yields (Scheme 3). Pyridines 5 and 7 were isolat-
ed by preparative chromatography on silica gel.
CF3
F3C
R
Besides the fluorine-containing 1,3-diketones we have
utilized other popular building blocks such as methyl-2,4-
dioxopentanoate (8), 4-oxo-4H-chromene-3-carbalde-
hyde (10) and pentafluorobenzaldehyde (12; Scheme 4).
The interaction of compound 8 with 2 proceeded in much
the same fashion, like the reaction forming 5, delivering
methyl 2-methylbenzofuro[2,3-b]pyridine-4-carboxylate
(9) as the major product with 91% yield. Application of 4-
oxo-4H-chromene-3-carbaldehyde (10)21 led with the
good yield of 79% to 11 and pentafluorobenzaldehyde
(12) which was recently used in an application to the syn-
thesis of fluorinated riboflavin analogues,22 on a base of 6-
aminouracil, gave in 72% yield the corresponding polycy-
clic compound 13.23 Among the benzofuro[2,3-b]quino-
lines some were found to be inhibitors for application to
the prevention of cancer metastases.24
O
O
4
O
N
R
O
NH2
5
2
4a R = Me
4b R = Ph
4c R = OMe
4d R = 2-thienyl
4e R = CF3
5a R = Me
5b R = Ph
5c R = OH
5d R = 2-thienyl
5e R = CF3
Scheme 2 Reagents and conditions: DMF, AcOH, reflux, 2–3 h.
Table 1 Yields of 4-Trifluoromethylbenzofuro[2,3-b]pyridines
5a–e
Product
5a
R
Yield (%)a
Me
90
88
79
93
89
The linear structure of product 13 could be easily con-
firmed by ROESY experiments since the correlation of
the protons in 1-position (d = 9.35 ppm) and 11-position
(d = 8.40 ppm) could be observed in 7,8,9,10-tetrafluo-
robenzofuro[2,3-b]quinoline (13). For 9, likewise, the
correlation of the protons of methoxy group (d = 4.05
ppm) and proton in the 5-position of benzofuro[2,3-b]pyr-
idine ring (d = 8.71 ppm) was observed.
5b
Ph
5c
OH
5d
2-thienyl
CF3
5e
a Yields refer to pure isolated products.
The structure of model compounds 14 which were spe-
cially synthesized for the determination of the structure of
scaffolds 5 and 7, was also based on the ROESY measure-
ment, in which the correlation of the hydrogen atom in the
CHF2 group at d = 7.04 ppm (for 14a)25 and d = 7.11 ppm
(for 14b), which could be observed as a triplet (1JCF = 56
Hz), with the H-C(5) at d = 8.04 ppm (14a) and d = 8.11
ppm (14b) was the striking feature. Also other convincing
evidences of the formation of a-CF3 isomers for 5 and 7
were the chemical shifts of the CF3 group [d(19F) ≈ –64
The solution of the isocyanate 1 and the dielectrophile in
anhydrous DMF was added very slowly to the boiling
aqueous acetic acid.19 It is recommended to apply a 2:5 ra-
tio of 2-isocyanatobenzofuran and electrophile to obtain
an almost quantitative yield of benzofuro[2,3-b]pyridines
(Table 1). Benzofuran-2-amine (2), which was generated
in situ was very unstable and decomposed so fast that at-
tempts to isolate the pure heterobase or at least its proto-
nated form failed.
Synlett 2008, No. 3, 343–346 © Thieme Stuttgart · New York

LETTER
Synthesis of Benzofuro[2,3-b]pyridine and Trifluoromethyl-a-carbolines
345
MeO2C
Me
CO2Me
O
O
8
O
N
Me
O
O
O
9
91%
O
OH
10
O
NH2
O
F
O
N
2
F
F
70%
11
H
generated in situ
F
F
F
F
F
12
F
O
N
13
72%
CF2H
N
H
X
Me
14a X = O 78%
14b X = NH 81%
Scheme 4 Reagents and conditions: DMF, AcOH, reflux, 2–3 h.
ppm, CDCl3)] and C(4) [d(13C) ≈ 130–133 ppm, CDCl3)]
with the coupling constant 2JCF ≈ 35 Hz, while signals of
an a-CF3 group, for example in 5e could be expected at
d ≈ –67 ppm (19F NMR) and d ≈ 145 ppm (CDCl3) [for
(C2) in the 13C NMR spectra).
We are grateful to the Bayer AG, the Enamine Ltd., the Merck
KGaA and the Wacker AG for generous gifts of reagents. We also
thank Prof. Dr. V. Y. Sosnovskikh, Department of Chemistry, Ural
State University, for discussions on the obtained results, and for
help during the preparation of the manuscript.
As an extension of our investigations we have applied this
approach also to 2-isocyanatofuran with the either men-
tioned dielectrophiles, but our attempts to obtain any fu-
ro[2,3-b]pyridines which show unique pharmacological
activities,26 were unsuccessful. Unfortunately, even no
traces of the desired product could be detected during the
GC–MS and 19F NMR investigations of the reaction mix-
tures.
References and Notes
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In summary, a convenient synthetic approach to the a-car-
boline and benzofuro[2,3-b]pyridine ring systems was
elaborated on the basis of the commercially available 2-
isocyanatobenzofuran as a convenient source of benzofu-
ran-2-amine and indole-2-amine and a series of popular
1,3-CCC-dielectrophiles. The discovered method allowed
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Acknowledgment
V.I. thanks the DAAD, Euler program, for a fellowship and Dr. N.
Srivastava, the founder of Vishwa Nirmala Dharma (Sahaja Yoga).
Synlett 2008, No. 3, 343–346 © Thieme Stuttgart · New York

346
V. O. Iaroshenko et al.
LETTER
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(d, 3JHH = 8.0 Hz, 1 H). 13C NMR (100.5 MHz, DMSO-d6):
d = 24.4, 109.8, 112.7, 115.5, 119.7, 123.4, 123.7 (1JCF = 275
Hz), 124.7, 126.7, 129.9 (2JCF = 35 Hz), 154.5, 158.1, 163.1.
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(%) = 242 (14) [M+ + 1], 241 (100) [M+], 210 (37), 182 (41).
Anal. Calcd for C13H8F3NO: C, 62.16; H, 3.21; N, 5.58.
Found: C, 62.18; H, 3.20; N, 5.57.
(19) General Procedure for the Synthesis of Furo[2,3-
b]pyridines 5, 9, 11, and benzofuro[2,3-b]quinoline 13:
To a boiling solution of AcOH (250 mL) and H2O (10 mL;
temperature in the oil bath was about 135 °), a mixture of a
dielectrophile (5 mmol) and 2-isocyanatobenzofuran (1.99
g, 12.5 mmol) in absolute DMF (50 mL) was dropped very
slowly through the condenser. After the addition was
completed the mixture was refluxed for further 3 h. After
evaporation of the solvent, the residue was subjected to
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7.74 (t, 3JHH = 8.0 Hz, 1 H), 7.81 (d, 3JHH = 8.0 Hz, 1 H), 8.40
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[M+ + 1], 291 (100) [M+], 262 (10), 145 (10). Anal. Calcd for
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(14a): colorless solid (0.99 g, 85%); mp 112–113 °C; Rf =
0.5 (EtOAc–hexane, 1:2). 1H NMR (400 MHz, CDCl3): d =
2.72 (s, 3 H), 7.04 (t, 2JHF = 56 Hz, 1 H), 7.31 (s, 1 H), 7.39
(t, 3JHH = 8.0 Hz, 1 H), 7.53 (t, 3JHH = 8.0 Hz, 1 H), 7.63 (d,
3JHH = 8.0 Hz, 1 H), 8.01 (d, 3JHH = 8.0 Hz, 1 H). 13C NMR
(100.5 MHz, CDCl3): d = 24.5, 110.8, 112.4 (1JCF = 240 Hz),
113.1, 115.5, 120.9, 123.4, 124.3, 128.6, 136.8 (2JCF = 26
Hz), 154.6, 157.0, 163.4. 19F NMR (376.2 MHz, DMSO-d6):
d = –115.3 (d, 2JHF = 56 Hz, 2 F). MS: m/z (%) = 234 (15)
[M+ + 1], 233 (100) [M+], 182 (16). Anal. Calcd for
C13H9F2NO: C, 66.95; H, 3.89; N, 6.01. Found: C, 66.94; H,
3.89; N, 6.02.
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3515. (c) Wang, X.-C.; Chai, L.-Q.; Wang, M.-G.; Quan, Z.-
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Xiang, J. S.; Di-Grandi, M. J.; Du, X.; Ipek, M.; Laakso, L.
M.; Li, J.; Li, W.; Rush, T. S.; Schmid, J.; Skotnicki, J. S.
Bioorg. Med. Chem. 2005, 13, 6629.
(18) 2-Methyl-4-(trifluoromethyl)benzofuro[2,3-b]pyridine
(5a): colorless solid (1.13 g, 90%); mp 115–117 °C; Rf =
0.65 (EtOAc–hexane, 1:2). 1H NMR (400 MHz, DMSO-d6):
d = 2.68 (s, 3 H), 7.50 (t, 3JHH = 8.0 Hz, 1 H), 7.66 (t, 3JHH
=
8.0 Hz, 1 H), 7.73 (s, 1 H), 7.83 (d, 3JHH = 8.0 Hz, 1 H), 7.99
Synlett 2008, No. 3, 343–346 © Thieme Stuttgart · New York

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