Facile synthesis of fluorinated benzofuro- and benzothieno[2,3-b]pyridines, α-carbolines and nucleosides containing the α-carboline framework

Article abstract of DOI:10.1055/s-0029-1217396

Fluorinated benzofuro[2,3-b]pyridines, benzothieno[ 2,3-b]pyridines and 9H-pyrido[2,3-b]indoles (α-carbolines) were synthesized via regiospecific pyridine core annulation of a number of fluoro-containing 1,3-CCC- dielectrophiles to benzofuran-2-amine, benzothiophen-2-amine and 1H-indol-2-amine. Based on the 2,4-bis(trifluoromethyl)-9H-pyrido[2,3-b]indole thus synthesized, the preparative approach towards a set of nucleosides and nucleoside mimetics bearing the α-carboline framework was elaborated. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217396

PAPER
2393
Facile Synthesis of Fluorinated Benzofuro- and Benzothieno[2,3-b]pyridines,
a-Carbolines and Nucleosides Containing the a-Carboline Framework
F
luorinated Benzo
i
furo-/B
k
enzothieno[2
t
,3-
b
]
py
o
ridines and
r
a
-Carbolines O. Iaroshenko,*a,b Yan Wang,c Biao Zhang,c Dmitriy Volochnyuk,d Vyacheslav Ya. Sosnovskikhe
a
Enamine Ltd., 23 A. Matrosova st., 01103 Kyiv, Ukraine
Fax +380(44)5373253; E-mail: yaroshenko@enamine.net
b
c
d
e
National Taras Shevchenko University, 62 Volodymyrska st., 01033 Kiev 33, Ukraine
Fachbereich Chemie, Universität Konstanz, Fach M-720, Universitätsstr. 10, 78457 Konstanz, Germany
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, 02094 Kiev 94, Ukraine
Department of Chemistry, Ural State University, 51 Lenina Ave., 620083 Ekaterinburg, Russian Federation
Received 24 December 2008; revised 3 March 2009
Dedicated to Professor Volodymir Kovtunenko on the occasion of his 60th birthday
Our previous experience2 indicated that the optimal pre-
parative method leading to amines 10 (X = O, S) via gen-
eration in situ is based upon the Curtius rearrangement of
the commercially available acyl azides 8 to isocyanates 9
Abstract: Fluorinated
benzofuro[2,3-b]pyridines,
benzo-
thieno[2,3-b]pyridines and 9H-pyrido[2,3-b]indoles (a-carbolines)
were synthesized via regiospecific pyridine core annulation of a
number of fluoro-containing 1,3-CCC-dielectrophiles to benzofu-
ran-2-amine, benzothiophen-2-amine and 1H-indol-2-amine. Based (Scheme 1). The latter, after hydrolysis, form amines 10.
Very recently,2 we have conducted this reaction as a two-
step, two-pot process. Herein, we report a simplified one-
on the 2,4-bis(trifluoromethyl)-9H-pyrido[2,3-b]indole thus syn-
thesized, the preparative approach towards a set of nucleosides and
nucleoside mimetics bearing the a-carboline framework was elabo-
pot, two-step method starting directly from azides 8. It
rated.
was found that the formation of 10 can proceed directly
from 8 in acetic acid under intense reflux. Another ap-
proach to generate 10 in situ starts from ureas 11, prepared
Key words: pyridines, fluorine, annulation, functionalization, a-
carbolines, nucleosides
from the corresponding acyl azides 8 and anilines in boil-
ing toluene,3 by prolonged reflux in a mixture of acetic
Continuing our research on the functionalization of elec-
acid, acetic anhydride and N,N-dimethylformamide in the
tron-rich aminoheterocycles,1 with the purpose of synthe-
presence of the electrophile.
sizing a set of diverse a-carbolines and benzofuro- and
Benzofuran-2-amine and benzothiophen-2-amine (10,
benzothieno[2,3-b]pyridines, the reaction of 1H-indol-2-
X = O, S), generated in situ according to the previously
amine, benzofuran-2-amine and benzothiophen-2-amine
with a number of 1,3-CCC-dielectrophiles 1–7 (Figure 1)
was investigated in detail. Benzofuran-2-amine and ben-
zothiophen-2-amine are not stable; thus, they were not
mentioned procedure, react with a number of 1,3-CCC-di-
electrophiles 1–4 (Scheme 2). The reaction proceeds re-
giospecifically to form a set of fluorinated benzofuro[2,3-
b]pyridines 12 and [1]benzothieno[2,3-b]pyridines 13
isolated, neither in the pure form nor as a salt. In contrast,
bearing an electron-withdrawing substituent at the g-posi-
1H-indol-2-amine is a stable and commercially available
tion of the annulated pyridine core (Table 1). During a
reagent, which was used in the present study.
study of the reaction mixture by HPLC and 19F NMR
spectroscopy, insertion of the diazo group into the starting
RF
R
dielectrophile compound was revealed in the case of fast
O
CF3
addition of azide 8. Thus, side products of type 14 were
detected in the 19F NMR spectra of the reaction mixture,
as well as traces of initial acids as products of acyl azide
8 hydrolysis, which were observed by HPLC.
O
O
O
O
1 RF = CF3, R = Me, Ph, 2-thienyl, CF3
2 RF = CF3, R = OEt
5
3 RF = CF2Cl, R = Ph
4 RF = C2F5, CF2H, R = Me
Reaction of 1H-indol-2-amine (15) with dielectrophiles
1–4 in boiling acetic acid delivers 9H-pyrido[2,3-b]in-
doles 16 with an unsubstituted 9-position. Methylation of
the 9H-pyrido[2,3-b]indoles 16 with iodomethane readily
occurs at the 9-position of the carboline core. This reac-
tion proceeds smoothly in anhydrous dimethyl sulfoxide
at room temperature with 7 equivalents of potassium hy-
droxide and leads to the formation of the methylated prod-
ucts 17 in excellent yields (Scheme 3, Table 1).
O
F
F
F
F
H
CF3
F
O
O
6
7
Figure 1 Variety of 1,3-CCC-dielectrophiles used for pyridine ring
annulation
The cyclic dicarbonyl compounds 6 and 5 were no excep-
tion to the general rule. Thus, they are suitable for pyri-
SYNTHESIS 2009, No. 14, pp 2393–2402
Advanced online publication: 22.06.2009
x
x.
x
x
.
2
0
0
9
DOI: 10.1055/s-0029-1217396; Art ID: P14708SS
© Georg Thieme Verlag Stuttgart · New York

2394
V. O. Iaroshenko et al.
PAPER
N3
i
X
X
NH2
i
X
NCO
8
9
in situ
O
10
iii
ref. 3
ii
O
X
N
H
NHTol
11
Scheme 1 Reagents and conditions: i: AcOH, DMF, reflux; ii: ArNH2, toluene, reflux; iii: AcOH–Ac2O–DMF (1:1:1), intense reflux.
RF
systems. Now, their derivatives are well known for their
antitumour activity.4
1–4
Previously, pentafluorobenzaldehyde (7) was known as a
1,3-CCC-dielectrophile used for constructing heteroannu-
lated tetrafluoroquinolines.5 Aldehyde 7 reacts under
harsh conditions (AcOH, DMF, 135–145 °C) with amino-
heterocycles 10 and 15 affording the annulated tetra-
fluoroquinolines 20. The latter can be considered as
fluoro-containing isosteres of ellipticine and crypto-
tackiene. Measurement of the 13C NMR spectra of quino-
lines 20 was unsuccessful due to low solubility in organic
solvents such as dimethyl sulfoxide and N,N-dimethylfor-
mamide. When the reaction mixture was analyzed by
means of HPLC with mass detection, it was found that the
reaction proceeds in two different directions: one is via
cycloaddition by a CCN + CCC path to form the major
products 20, the other is by a CCN + C + CC path to de-
liver 21 as side products in small amounts (Scheme 5).
We have not isolated any of these side products, but they
were detected and clearly observed by HPLC. We have
started attempts to develop synthetic methods towards
compounds of type 21.
i
X
N
R
X
NH2
12 X = O
13 X = S
73–93%
10 (X = O, S)
Ph
CF3
O
O
O
O
O
12c, 13b;
CF3
Ph
ii
X
N
H
NHTol
N2
14
11
Scheme 2 Reagents and conditions: i: AcOH, DMF, reflux, 2–3 h;
ii: AcOH–Ac2O–DMF (1:1:1), intense reflux.
RF
1–4
i
N
H
NH2
N
H
N
R
15
16
81–89%
RF
The structure of the fluorine-containing condensed py-
ridines was proven by 1H, 13C and 19F NMR spectroscopy.
For the determination of the position of the polyfluoro-
alkyl group, 2D NMR methods including ROESY
measurements2 were applied to model compounds 12g,
13d and 16d.
ii
N
N
R
Me
90–93%
17
Scheme 3 Reagents and conditions: i: AcOH, reflux, 2 h; ii: MeI
(3 equiv), KOH (7 equiv), DMSO, r.t., 30 min, then 80 °C, 1.5 h.
CF3
6
dine ring annulation, which led to the formation of
polycyclic carboline 18 and 3-(3-hydroxypropyl)-4-(tri-
fluoromethyl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one
(19) (Scheme 4). However, it should be noted that in this
case a number of side products were detected during ex-
amination of the reaction mixture by 19F NMR spectros-
copy. Attempts to isolate these side products failed. a-
Carbolines 16–19 can easily be purified by flash chroma-
tography or by recrystallization from an appropriate sol-
vent.
N
H
N
64%
18
i
N
H
NH2
15
F3C
OH
5
The discovery of the alkaloids ellipticine and crypto-
tackiene, two naturally occurring pyridine analogues
(Scheme 5), has led to an intensification of the synthesis
and biological evaluation of similar polyheteroaromatic
O
N
H
N
H
19 74%
Scheme 4 Reagents and conditions: i: AcOH, reflux, 2 h.
Synthesis 2009, No. 14, 2393–2402 © Thieme Stuttgart · New York

PAPER
Fluorinated Benzofuro-/Benzothieno[2,3-b]pyridines and a-Carbolines
2395
framework, starting from building blocks 22, 25, 28–32,
and carboline 16a, a method incorporating the corre-
sponding sugar (sugar analogues) was developed. For the
synthesis of carbocyclic nucleoside analogues, we used
the known N-glycosylation procedure. For the synthesis
of riboside 23, the silyl-Hilbert–Johnson reaction12 was
used. This reaction takes place in dichloromethane with
N,O-bis(trimethylsilyl)acetamide (BSA) and trimethyl-
silyl triflate as a catalyst. The subsequent acetyl moiety
cleavage with ammonia gave compound 24 in 67% yield
(Scheme 6).
F
F
F
F
F
7
10a,b, 15
i
X
N
Het
Het
N
20a X = O 72%
b X = S 74%
c X = NH 67%
21
Me
N
N
H
N
N
OAc
CF3
O
Me
Me
AcO
cryptotackiene
ellipticine
AcO
OAc
22
N
N
CF3
Scheme 5 Reagents and conditions: i: AcOH, DMF, reflux, 2–3 h.
O
i
23 R = Ac 75%
24 R = H 67%
RO
ii
The structure of compound 13d was unambiguously con-
firmed by a single crystal X-ray analysis (Figure 2) at 153
K. This compound crystallized in a monoclinic C2/c space
group. An asymmetric unit consists of one molecule of
13d, which multiplies in eight molecules per unit cell. The
heterocyclic system is completely planar. The crystal
packing of this compound is based on compact impale-
ment of 2D layers of 13d.
OR
RO
16a
CF3
BzO
Br
O
N
N
CF3
RO
BzO
iii
25
O
26 R = Bz 68%
27 R = H 53%
ii
RO
Scheme 6 Reagents and conditions: i: BSA, TMSOTf; ii: NH3,
MeOH, r.t., 12 h; iii: NaH, MeCN.
Carboline 26 bearing an acyclic sugar mimetic was syn-
thesized by the direct base-catalyzed alkylation of 16a
with halide 25 in the same way as described previously.13
Deprotection of the product 26 to diol 27 was conducted
with ammonia in methanol (Scheme 6).13
BnO
O
BnO
OH
RO
Cl
OH
Figure 2 Molecular structure of compound 13d
BnO
RO
28
29
30
R = 4-MeC6H4CO
Nucleoside mimetics6 have attracted attention due to the
discovery of some antiviral and antineoplastic agents
among them. Well-known acyclovir,7 an anti-inflammato-
ry agent, also contains a sugar-mimicking group. In na-
ture, the ‘salvage’ nucleoside synthesis pathway8 is an
important route for purine and pyrimidine nucleotide syn-
thesis. It shares the common approach of catalyzing the
addition of nucleobases to anomerically activated ribose.
A modification of this biosynthesis can be a potent tool for
assembling diverse fluorinated nucleosides.
OAc
AcO
OH
31
32
O
O
Me
Me
Figure 3 Variety of compounds used for deoxyriboside and carbo-
cyclic sugar synthesis
1-Chloro-3,5-di-O-p-toluoyl-2-deoxy-a-D-erythro-pento-
furanose (28) (Figure 3) reacts smoothly with carboline
16a under basic conditions (NaH in MeCN)13 to deliver
deoxyriboside 35. Cleavage of the protecting groups was
carried out with ammonia in methanol, giving the 2-
deoxy-a-D-erythro-pentofuranose 36 in 83% yield.
Nucleosides containing an a-carboline group are rare in
the literature; however, the known representatives, such
as rebeccamycin analogues containing one azaindole unit,
have been described as potent antiproliferative9 and
antitumour10 agents and kinase inhibitors.11
In the course of the synthesis of acyclic and carbocyclic
nucleoside analogues containing a fluorinated a-carboline
Concerning the synthesis of the carbocyclic nucleosides
34 and 37–41 (Scheme 7), direct coupling of the hetero-
Synthesis 2009, No. 14, 2393–2402 © Thieme Stuttgart · New York

2396
V. O. Iaroshenko et al.
PAPER
CF3
base 16a with the corresponding carbocyclic pseudo sugar
CF3
(Figure 3) was applied.
The Mitsunobu coupling reaction was recently used for
the synthesis of many carbocyclic nucleosides.14 We have
used this method for the synthesis of compounds 34, 38
and 40. Attachment of 31 to carboline 16a was carried out
according to the previously described procedure used for
the synthesis of carbocyclic AdoazaMet.14a After attach-
ment of the pseudo sugar group, oxidation of the double
bond was performed with sodium periodate and osmium
tetroxide in methanol–water, and reduction of the formed
aldehyde was carried out with sodium borohydride in
methanol. Deprotection of compound 33 was performed
in trifluoroacetic acid–water according to the procedure
described by us previously.1d Thus, the synthesis of 34
was performed from 16a and 31 as a one-pot, three-step
procedure, without isolation of the intermediate products.
N
N
CF3
N
N
CF3
O
RO
HO
RO
RO
OR
35 R = 4-MeC6H4CO 69%
36 R = H 83%
CF3
33 R = 2,2-isopropylidene 33%
ii
i
34 R = H 80%
CF3
N
N
CF3
N
N
CF3
RO
iii
37 R = Bn 37%
38 R = H 59%
RO
39 R = Bn 66%
40 R = H 57%
iii
RO
For the synthesis of 37, enantiomerically pure (1S,3S,4R)-
3-benzyloxy-4-(benzyloxymethyl)cyclopentanol (29), a
precursor for carbocyclic 2-deoxynucleoside analogues,
was condensed to carboline 16a in acetonitrile according
to a slightly modified Mitsunobu protocol.15 The resultant
b-isomer 37 was easily deprotected in one step by hydro-
genolysis in ethanol, leading to 38.
CF3
N
N
CF3
41 59%
HO
Scheme 7 Reagents and conditions: i: TFA–H2O (9:1), 45 min; ii:
NH3, MeOH, r.t., 12 h; iii: H2, 10% Pd/C, EtOH, r.t., 2–3 h.
Palladium-catalyzed allylation of a heterobase possessing
a free NH position is one of the highly useful strategies for
assembling carbocyclic nucleosides.16 We have success-
fully used this method for the synthesis of carbocyclic nu-
cleoside 41 from carboline 16a and cis-diacetate 32.
was coupled with a number of sugars, and carbocyclic and
acyclic sugar analogues, to give a set of diverse nucleo-
sides and nucleoside mimetics. Simple synthetic and puri-
fication procedures and high yields of the target
compounds enable the synthesis of functionally diverse a-
carbolines, which are interesting objects for medicinal
chemistry and drug discovery.
In conclusion, a convenient synthetic approach to fluori-
nated benzofuro[2,3-b]pyridines, benzothieno[2,3-b]py-
ridines and a-carbolines based on cycloaddition of
fluorine-containing 1,3-CCC-dielectrophiles to the corre-
sponding aminoheterocyclic moiety was developed. Also,
2,4-bis(trifluoromethyl)-9H-pyrido[2,3-b]indole
(16a)
Table 1 Yields,a Melting Points,b and 1H and 19F NMR Data of Compounds 12, 13, 16 and 17c
Compound R
RF
Yield Mp
1H NMR data
19F NMR data
(%)
(°C)
d (ppm)
d (ppm)
12a
12b
CF3
CF3
CF3
89
71–73
(CDCl3): 7.45 (td, J = 8.0, 1.4 Hz, 1 H), 7.62–7.68 (m, 2 H), 7.90 (CDCl3): –65.0, –68.3
(s, 1 H), 8.12 (d, J = 8.0 Hz, 1 H)
Me
Ph
90
115–117 (DMSO-d6): 2.68 (s, 3 H), 7.50 (t, J = 8.0 Hz, 1 H), 7.66 (t,
J = 8.0 Hz, 1 H), 7.73 (s, 1 H), 7.83 (d, J = 8.0 Hz, 1 H), 7.99 (d,
J = 8.0 Hz, 1 H)
(DMSO-d6): –63.5
12c
12d
CF3
88
93
131–132 (CF3CO2D): 7.09 (s, 1 H), 7.42–7.63 (m, 5 H), 7.86–7.99 (m, 3
(DMSO-d6): –63.2
(DMSO-d6): –63.7
H), 8.20 (d, J = 7.8 Hz, 1 H)
2-thienyl CF3
177–179 (DMSO-d6): 7.23 (br s, 1 H), 7.51 (t, J = 7.8 Hz, 1 H), 7.65 (t,
J = 7.8 Hz, 1 H), 7.76–7.82 (m, 2 H), 7.79 (d, J = 3.2 Hz, 1 H),
8.10 (s, 1 H), 8.22 (s, 1 H)
12e
OH
CF3
79
174–175 (DMSO-d6): 7.05 (s, 1 H), 7.45 (t, J = 7.8 Hz, 1 H), 7.54 (t,
J = 7.8 Hz, 1 H), 7.76 (d, J = 7.8 Hz, 1 H), 7.86 (d, J = 7.8 Hz, 1
H), 12.70 (br s, 1 H)
(DMSO-d6): –64.0
Synthesis 2009, No. 14, 2393–2402 © Thieme Stuttgart · New York

PAPER
Fluorinated Benzofuro-/Benzothieno[2,3-b]pyridines and a-Carbolines
2397
Table 1 Yields,a Melting Points,b and 1H and 19F NMR Data of Compounds 12, 13, 16 and 17c (continued)
Compound R
RF
Yield Mp
(%) (°C)
1H NMR data
d (ppm)
19F NMR data
d (ppm)
12f
Ph
CF2Cl 79
119–120 (DMSO-d6): 7.52–7.55 (m, 4 H), 7.68 (d, J = 7.8 Hz, 1 H), 7.83
(d, J = 7.8 Hz, 1 H), 8.17 (d, J = 7.8 Hz, 1 H), 8.19 (s, 1 H), 8.30
(d, J = 7.8 Hz, 2 H)
12g
Me
CF2H 85
112–113 (CDCl3): 2.72 (s, 3 H), 7.04 (t, 2JHF = 56 Hz, 1 H), 7.31 (s, 1 H),
7.39 (t, J = 8.0 Hz, 1 H), 7.53 (t, J = 8.0 Hz, 1 H), 7.63 (d, J = 8.0
Hz, 1 H), 8.01 (d, J = 8.0 Hz, 1 H)
13a
13b
CF3
Ph
CF3
CF3
80
83
111–112 (CDCl3): 7.33 (t, J = 7.8 Hz, 1 H), 7.49 (t, J = 7.8 Hz, 1 H), 7.55
(d, J = 7.8 Hz, 1 H), 7.81 (s, 1 H), 8.21 (d, J = 7.8 Hz, 1 H)
178–179 (DMSO-d6): 7.30 (s, 1 H), 7.51–7.58 (m, 3 H), 7.61–7.67 (m, 3 (DMSO-d6): –63.1
H), 8.18 (dd, J = 7.8, 1.4 Hz, 1 H), 8.26 (dd, J = 7.8, 1.4 Hz, 1 H),
8.30 (d, J = 7.8 Hz, 1 H)
13c
13d
OH
Me
CF3
73
257–258 (DMSO-d6): 7.08 (s, 1 H), 7.42–7.59 (m, 3 H), 8.08 (m, 1 H),
(DMSO-d6): –62.4
12.60 (br s, 1 H)
CF2H 90
112–114 (CDCl3): 2.70 (s, 3 H), 7.02 (t, 2JHF = 56 Hz, 1 H), 7.37 (s, 1 H), (DMSO-d6): –115.3
7.39 (t, J = 7.8 Hz, 1 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.60 (d, J = 7.8 (d, 2JFH = 56 Hz)
Hz, 1 H), 8.07 (d, J = 7.8 Hz, 1 H)
16a
16b
16c
CF3
Me
Ph
CF3
CF3
CF3
86
84
89
211–213 (DMSO-d6): 7.37 (m, 2 H), 7.71 (d, J = 7.2 Hz, 1 H), 7.94 (s, 1
H), 8.21 (d, J = 7.2 Hz, 1 H), 13.00 (s, 1 H)
(DMSO-d6): –63.3,
–65.3
283
(DMSO-d6): 2.70 (s, 3 H), 7.30 (d, J = 7.2 Hz, 1 H), 7.43 (s, 1 H), (DMSO-d6): –63.2
7.59 (m, 2 H), 8.07 (d, J = 7.2 Hz, 1 H), 12.3 (s, 1 H)
287–290 (DMSO-d6): 7.33 (t, J = 7.8 Hz, 1 H), 7.44–7.57 (m, 4 H), 7.78 (t,
J = 7.8 Hz, 1 H), 8.00 (s, 1 H), 8.11 (d, J = 7.8 Hz, 2 H), 8.28 (d,
J = 7.8 Hz, 1 H), 12.19 (s, 1 H)
16d
16e
Me
Ph
CF2H 81
CF2Cl 85
C2F5 87
259
(DMSO-d6): 2.68 (s, 3 H), 7.25 (m, 2 H), 7.46 (t, J = 7.8 Hz, 1 H), (DMSO-d6): –115.7
7.53 (d, J = 7.8 Hz, 1 H), 7.64 (t, 2JHF = 56 Hz, 1 H), 8.09 (d,
J = 7.8 Hz, 1 H), 12.01 (s, 1 H)
(d, 2JFH = 56 Hz)
271
(DMSO-d6): 7.41 (t, J = 7.8 Hz, 1 H), 7.52–7.62 (m, 4 H), 7.70
(d, J = 7.8 Hz, 1 H), 7.78 (d, J = 7.8 Hz, 1 H), 8.02 (s, 1 H), 8.23
(d, J = 7.8 Hz, 1 H), 8.33 (d, J = 7.8 Hz, 1 H), 12.01 (s, 1 H)
(DMSO-d6): –51.7
16f
Me
222–224 (DMSO-d6): 2.73 (s, 3 H), 7.35 (t, J = 7.2 Hz, 1 H), 7.58 (s, 1 H),
7.65 (m, 2 H), 8.15 (d, J = 7.2 Hz, 1 H), 12.07 (s, 1 H)
17a
CF3
CF3
CF3
90
90
188–190 (DMSO-d6): 3.95 (s, 3 H), 7.36 (t, J = 7.8 Hz, 1 H), 7.49 (t,
J = 7.8 Hz, 1 H), 7.74 (d, J = 7.8 Hz, 1 H), 7.97 (s, 1 H), 8.09 (d,
J = 7.8 Hz, 1 H)
17b
17c
Ph
108
(CF3CO2D): 4.05 (s, 3 H), 7.39 (t, J = 7.2 Hz, 1 H), 7.55–7.76 (m,
5 H), 7.79 (d, J = 7.2 Hz, 1 H), 8.02 (s, 1 H), 8.15 (d, J = 7.2 Hz,
1 H), 8.34 (d, J = 7.2 Hz, 1 H)
Me
CF2H 93
217
(DMSO-d6): 2.69 (s, 3 H), 3.26 (s, 3 H), 7.25 (m, 2 H), 7.60–7.70 (DMSO-d6): –115.6
(m, 3 H), 8.14 (d, J = 7.8 Hz, 1 H)
(d, 2JFH = 56 Hz)
a Yields refer to pure isolated product.
b Melting points are uncorrected.
c Satisfactory microanalyses obtained: C 0.33; H 0.45; N 0.25.
All solvents were purified and dried by standard methods. NMR
spectra were recorded on Jeol JNM-LA 400, Varian VXR-300 or
Varian Mercury-400 spectrometers. 1H and 13C NMR spectra (300
and 100 MHz, respectively) were recorded using TMS as an internal
standard, and 19F NMR spectra (282 MHz) with CFCl3 as an internal
standard. Mass spectra were obtained on a Hewlett-Packard HP GC/
MS 5890/5972 instrument (EI, 70 eV) by GC inlet or on an MX-
1321 instrument (EI, 70 eV) by direct inlet. Column chromatogra-
phy was performed on silica gel (63–200 mesh, Merck). Silica gel
Merck 60F254 plates were used for TLC. Tetra-O-acetylated ribo-
furanose 22 is a commercially available reagent. Precursors 25,17
28,18 2919 and 3020 were synthesized according to previously de-
scribed procedures. Compound 31 was obtained from D-ribose fol-
lowing a multistep sequence.21 cis-3-Acetoxy-5-(acetoxymeth-
yl)cyclopentene (32) is available in two steps22 from rel-
(1R,4S,6R)-6-bromo-2-oxabicyclo[2.2.1]heptan-3-one.
Synthesis 2009, No. 14, 2393–2402 © Thieme Stuttgart · New York

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V. O. Iaroshenko et al.
PAPER
X-ray Crystallography of 13d
MS: m/z (%) = 320 (17) [M+ + 1], 319 (100) [M+].
C13H9F2NS, M = 249.27, monoclinic, a = 18.056(8) Å,
b = 13.388(9) Å, c = 11.900(6) Å, b = 129.53(6)°, V = 2219(2) Å3,
pale yellow cuboid with size 0.8 × 0.6 × 0.4 mm. Crystallographic
measurements were performed on a CAD4 Enraf-Nonius diffracto-
meter operating in the w-2q-scan mode (scanning rate ratio w/
2q = 1.2), 11.197 £ q £ 13.976, T = 153 K. The structure was solved
with direct methods using the SHELXS-97 program and refined
with the full-matrix least-squares method on F2 using the SHELXL-
97 program. Space group C2/c, Z = 8, Dc = 1.493 g·cm–3, m(Mo
Ka) = 0.292 mm–1, F(000) = 1024, 4474 reflections measured,
2179 unique (Rint = 0.0428), which were used in all calculations.
The final wR(F2) was 0.0925 (all data).
4-(Trifluoromethyl)benzofuro[2,3-b]pyridin-2(1H)-one (12e)
Yield: 0.99 g (79%); colourless solid; Rf = 0.75 (EtOAc–hexane,
1:1).
13C NMR (DMSO-d6): d = 102.6, 112.1, 118.7 (1JCF = 275 Hz),
121.2, 121.3, 124.2, 124.3, 127.6, 133.2 (2JCF = 35 Hz), 153.2,
162.5, 163.4.
MS: m/z (%) = 254 (11) [M+ + 1], 253 (100) [M+], 201 (29), 183
(81) [M+ – 1 – CF3], 133 (10).
4-(Chlorodifluoromethyl)-2-phenylbenzofuro[2,3-b]pyridine
(12f)
Crystallographic data for the structure 13d reported in this paper
have been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC 713529 and can be
obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK; Fax: +44(1223)336033; E-mail: depos-
it@ccdc.cam.ac.uk.
Yield: 1.30 g (79%); colourless solid; Rf = 0.6 (EtOAc–hexane,
1:2).
13C NMR (DMSO-d6): d = 110.7, 110.9 (t, JCF = 5.0 Hz), 112.2,
119.9, 124.5 (t, JCF = 3.8 Hz), 124.8, 124.9 (1JCF = 289 Hz), 127.6,
129.4, 130.2, 130.5, 137.3, 138.5 (2JCF = 27 Hz), 155.1, 155.2,
163.8.
MS: m/z (%) = 331 (33) [M+ + 2], 330 (22) [M+ + 1], 329 (100)
Benzofuro[2,3-b]pyridines 12, 20a and [1]Benzothieno[2,3-
b]pyridines 13, 20b; General Procedure
[M+], 295 (20), 294 (87), 245 (10) [M+ + 1 – CF2Cl], 146 (17).
To a boiling soln of AcOH (300 mL) and H2O (10 mL; temperature
in the oil bath was ca. 145 °C), a mixture of the dielectrophile (5
mmol) and the acyl azide (12.5 mmol) in anhyd DMF (50 mL) was
added dropwise through the condenser. After the addition was com-
pleted, the mixture was refluxed for a further 3 h. The solvent was
evaporated, and the residue was purified by column chromatogra-
phy on silica gel or was recrystallized from an appropriate solvent.
4-(Difluoromethyl)-2-methylbenzofuro[2,3-b]pyridine (12g)
Yield: 0.99 g (85%); colourless solid; Rf = 0.5 (EtOAc–hexane,
1:2).
13C NMR (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.
MS: m/z (%) = 234 (15) [M+ + 1], 233 (100) [M+], 182 (16) [M+ –
CF2H].
2,4-Bis(trifluoromethyl)benzofuro[2,3-b]pyridine (12a)
Yield: 1.36 g (89%); colourless solid; Rf = 0.75 (EtOAc–hexane,
1:2).
7,8,9,10-Tetrafluorobenzofuro[2,3-b]quinoline (20a)
Yield: 1.05 g (72%); colourless solid; mp 235–237 °C (i-PrOH).
1H NMR (DMSO-d6): d = 7.55 (t, J = 8.0 Hz, 1 H), 7.74 (t, J = 8.0
Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 8.40 (d, J = 8.0 Hz, 1 H), 9.35
(s, 1 H).
13C NMR (CDCl3): d = 111.8, 112.5, 117.0 (q, JCF = 1.6 Hz), 118.8,
1
1
120.7 (q, JCF = 275 Hz), 122.2 (q, JCF = 275 Hz), 124.4
2
(q, JCF = 4.0 Hz), 124.8, 131.3, 133.0 (q, JCF = 35 Hz), 144.6
(q, 2JCF = 35 Hz), 156.1, 162.8.
MS: m/z (%) = 306 (15) [M+ + 1], 305 (100) [M+].
MS: m/z (%) = 292 (17) [M+ + 1], 291 (100) [M+], 262 (10), 145
(10).
2-Methyl-4-(trifluoromethyl)benzofuro[2,3-b]pyridine (12b)
Yield: 1.08 g (90%); colourless solid; Rf = 0.65 (EtOAc–hexane, 1:2).
2,4-Bis(trifluoromethyl)[1]benzothieno[2,3-b]pyridine (13a)
Yield: 1.28 g (80%); colourless solid; Rf = 0.55 (EtOAc–hexane,
1:3).
13C NMR (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.
1
13C NMR (CDCl3): d = 112.8, 121.1 (q, JCF = 275 Hz), 122.7 (q,
MS: m/z (%) = 252 (14) [M+ + 1], 251 (100) [M+], 210 (37), 182
1JCF = 275 Hz), 123.2, 126.0, 127.0 (q, JCF = 6.4 Hz), 127.7, 129.2,
129.6, 133.0 (q, 2JCF = 35 Hz), 140.1, 145.9 (q, 2JCF = 35 Hz), 164.1.
(41) [M+ – CF3].
MS: m/z (%) = 322 (15) [M+ + 1], 321 (100) [M+], 271 (12), 232
(13).
2-Phenyl-4-(trifluoromethyl)benzofuro[2,3-b]pyridine (12c)
Yield: 1.38 g (88%); colourless solid; Rf = 0.55 (EtOAc–hexane,
1:2).
2-Phenyl-4-(trifluoromethyl)[1]benzothieno[2,3-b]pyridine
(13b)
Yield: 1.37 g (83%); colourless solid; Rf = 0.70 (EtOAc–hexane,
13C NMR (DMSO-d6): d = 109.5, 112.1, 115.6, 119.5, 123.3, 123.7
(1JCF = 275 Hz), 124.8, 126.3, 126.5, 126.9, 129.8 (2JCF = 35 Hz),
133.3, 134.7, 154.4, 158.2, 163.4.
MS: m/z (%) = 314 (20) [M+ + 1], 313 (100) [M+], 263 (18), 261
(53), 236 (11), 77 (35).
1:2).
1
13C NMR (DMSO-d6): d = 112.1, 121.1 (q, JCF = 275 Hz), 123.2,
126.2, 126.5, 126.7, 127.0, 127.6, 129.0, 129.5, 130.7, 133.2 (q,
2JCF = 35 Hz), 135.1, 139.7, 144.1, 164.9.
2-(2-Thienyl)-4-(trifluoromethyl)benzofuro[2,3-b]pyridine
(12d)
MS: m/z (%) = 330 (27) [M+ + 1], 329 (100) [M+], 260 (16) [M+ –
CF3], 259 (13).
Yield: 1.48 g (93%); colourless solid; Rf = 0.4 (EtOAc–hexane,
1:2).
4-(Trifluoromethyl)[1]benzothieno[2,3-b]pyridin-2(1H)-one
(13c)
Yield: 0.98 g (73%); colourless solid; Rf = 0.45 (EtOAc–hexane,
13C NMR (DMSO-d6): d = 110.1, 112.8, 115.0, 119.0, 122.2, 123.3,
123.9 (1JCF = 275 Hz), 124.3, 127.0, 128.7, 130.0 (2JCF = 35 Hz),
130.7, 145.2, 154.2, 158.2, 163.0.
1:1).
Synthesis 2009, No. 14, 2393–2402 © Thieme Stuttgart · New York

PAPER
Fluorinated Benzofuro-/Benzothieno[2,3-b]pyridines and a-Carbolines
2399
13C NMR (DMSO-d6): d = 113.1, 116.6, 119.4, 121.1, 122.0 (q,
1JCF = 275 Hz), 125.6, 125.9, 133.7 (q, 2JCF = 35 Hz), 135.5, 138.9,
150.3, 163.7.
MS: m/z (%) = 233 (14) [M+ + 1], 232 (100) [M+], 231 (22) [M+ –
1].
4-(Chlorodifluoromethyl)-2-phenyl-9H-pyrido[2,3-b]indole
(16e)
Yield: 1.4 g (85%); colourless solid (recrystallized from EtOH).
MS: m/z (%) = 270 (15) [M+ + 1], 269 (100) [M+], 241 (51), 172
(15), 145 (13).
4-(Difluoromethyl)-2-methyl[1]benzothieno[2,3-b]pyridine
(13d)
Yield: 1.12 g (90%); colourless solid; Rf = 0.55 (EtOAc–hexane,
13C NMR (DMSO-d6): d = 106.0 (t, JCF = 3.2 Hz), 110.2, 110.9 (t,
JCF = 4.6 Hz), 120.0, 121.2, 121.9 (t, 1JCF = 286 Hz), 125.9, 126.6,
2
127.9, 130.0, 131.0 (t, JCF = 29 Hz), 132.7, 134.4, 140.9, 152.3,
1:2).
157.0.
13C NMR (CDCl3): d = 24.6, 112.4 (t, JCF = 240 Hz), 116.1 (t,
MS: m/z (%) = 330 (32) [M+ + 2], 329 (20) [M+ + 1], 328 (100)
1
3JCF = 8.0 Hz), 123.3, 123.5 (t, JCF = 4.1 Hz), 125.2 (t, JCF = 4.1
Hz), 125.5, 127.5, 131.4, 136.8 (t, JCF = 26 Hz), 138.2, 157.0,
[M+], 327 (23) [M+ – 1].
2
162.8.
2-Methyl-4-(perfluoroethyl)-9H-pyrido[2,3-b]indole (16f)
Yield: 1.31 g (87%); colourless solid (recrystallized from i-PrOH).
13C NMR (DMSO-d6): d = 25.1, 109.0 (t, JCF = 4.5 Hz), 111.9 (t,
JCF = 5.8 Hz), 112.7, 120.0, 125.0, 127.1, 127.3, 130.7, 131.0 (t,
2JCF = 25 Hz), 134.7, 142.0, 154.0, 158.0.
MS: m/z (%) = 250 (13) [M+ + 1], 249 (100) [M+].
7,8,9,10-Tetrafluoro[1]benzothieno[2,3-b]quinoline (20b)
Yield: 1.14 g (74%); colourless solid; mp 243–245 °C (i-PrOH).
1H NMR (100 °C, DMSO-d6): d = 7.60 (t, J = 7.8 Hz, 1 H), 7.67 (t,
J = 7.8 Hz, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 8.65 (d, J = 7.8 Hz, 1 H),
9.44 (s, 1 H).
MS: m/z (%) = 301 (17) [M+ + 1], 300 (100) [M+].
7-(Trifluoromethyl)-6,12-dihydro-5H-12,13-diazaindeno[1,2-
b]phenanthrene (18)
Yield: 1.08 g (64%); colourless solid; mp 207 °C (i-PrOH).
MS: m/z (%) = 308 (21) [M+ + 1], 307 (100) [M+].
9H-Pyrido[2,3-b]indoles 16, 18 and 19; General Procedure
A mixture of a dielectrophile (5 mmol) and 1H-indol-2-amine (15;
0.66 g, 5 mmol) in AcOH (30 mL) was refluxed under an inert at-
mosphere for 2 h. After evaporation of the volatiles, the residue was
purified by column chromatography on silica gel or was recrystal-
lized from an appropriate solvent.
1H NMR (DMSO-d6): d = 2.96 (br s, 2 H), 3.25 (br s, 2 H), 7.28 (t,
J = 7.8 Hz, 1 H), 7.38–7.45 (m, 3 H), 7.49–7.57 (m, 2 H), 8.16 (d,
J = 7.8 Hz, 1 H), 8.30 (d, J = 7.8 Hz, 1 H), 12.4 (s, 1 H).
13C NMR (DMSO-d6): d = 26.9, 27.1, 107.3, 110.9, 111.5, 120.9,
121.2, 123.0 (q, 1JCF = 275 Hz), 125.0, 125.5, 127.0, 127.5, 129.7,
131.1, 132.2 (q, 2JCF = 35 Hz), 132.4, 137.1, 140.5, 152.2, 156.6.
19F NMR (DMSO-d6): d = –55.4.
2,4-Bis(trifluoromethyl)-9H-pyrido[2,3-b]indole (16a)
Yield: 1.31 g (86%); colourless solid (recrystallized from i-PrOH).
MS: m/z (%) = 339 (24) [M+ + 1], 338 (100) [M+], 337 (43) [M+ –
1], 269 (15) [M+ – CF3], 268 (24).
1
13C NMR (DMSO-d6): d = 107.5, 109.9, 121.2 (q, JCF = 275 Hz),
1
121.4, 122.2 (q, JCF = 275 Hz), 124.7 (q, JCF = 4.2 Hz), 129.5,
131.1 (q, 2JCF = 35 Hz), 135.1, 142.2, 144.1 (q, 2JCF = 35 Hz), 151.9,
3-(3-Hydroxypropyl)-4-(trifluoromethyl)-1,9-dihydro-2H-pyri-
do[2,3-b]indol-2-one (19)
Yield: 1.15 g (74%); colourless solid; mp 199–200 °C; Rf = 0.50
(EtOAc).
1H NMR (DMSO-d6): d = 1.95 (br s, 2 H), 3.15 (br s, 2 H), 4.18 (br
s, 2 H), 7.17 (t, J = 7.2 Hz, 1 H), 7.33 (t, J = 7.8 Hz, 1 H), 7.49 (d,
J = 7.8 Hz, 1 H), 7.91 (d, J = 7.2 Hz, 1 H), 11.92 (s, 1 H), 12.13 (s,
1 H).
157.0.
MS: m/z (%) = 305 (14) [M+ + 1], 304 (100) [M+], 285 (18), 284
(39).
2-Methyl-4-(trifluoromethyl)-9H-pyrido[2,3-b]indole (16b)
Yield: 1.05 g (84%); colourless solid (recrystallized from i-PrOH).
13C NMR (DMSO-d6): d = 24.9, 107.7 (q, JCF = 2.6 Hz), 110.6,
13C NMR (DMSO-d6): d = 20.6, 25.8, 62.6, 102.1, 110.3, 111.5,
1
110.9 (q, JCF = 5.0 Hz), 120.9, 121.2 (q, JCF = 275 Hz), 125.2,
1
2
125.5, 127.5, 130.1 (q, 2JCF = 35 Hz), 140.5, 152.2, 156.6.
MS: m/z (%) = 251 (12) [M+ + 1], 250 (100) [M+], 249 (31).
119.1, 121.4, 123.1 (q, JCF = 275 Hz), 123.3, 130.9 (q, JCF = 35
Hz), 137.7, 148.0, 161.6, 170.2.
19F NMR (DMSO-d6): d = –56.1.
MS: m/z (%) = 310 (12) [M+], 303 (23), 298 (56), 233 (15), 178
(100).
2-Phenyl-4-(trifluoromethyl)-9H-pyrido[2,3-b]indole (16c)
Yield: 1.38 g (89%); colourless solid (recrystallized from MeOH).
13C NMR (DMSO-d6): d = 106.5 (q, JCF = 2.8 Hz), 110.4 (q,
JCF = 4.6 Hz), 110.6, 120.7, 121.2 (q, 1JCF = 275 Hz), 121.9, 125.0,
9-Methyl-9H-pyrido[2,3-b]indoles 17; General Procedure for
the Methylation of Compounds 16
2
126.1, 127.5, 130.4, 130.8, 131.4 (q, JCF = 35 Hz), 134.1, 140.5,
To a mixture of a 9H-pyrido[2,3-b]indole 16 (2 mmol) and KOH
(0.39 g, 14 mmol) in anhyd DMSO (10 mL), MeI (0.42 g, 6 mmol)
in DMSO (5 mL) was added dropwise. After the addition of MeI,
the mixture was kept at r.t. for 30 min, and then at 80 °C for 1.5 h.
Then, the mixture was poured into H2O (75–100 mL) and left over-
night. The formed precipitate was collected by filtration, washed
with H2O (3 ×) and dried in air. The obtained sample was recrystal-
lized (i-PrOH).
152.8, 156.9.
MS: m/z (%) = 313 (32) [M+ + 1], 312 (100) [M+], 311 (15) [M+ –
1], 242 (16) [M+ – 1 – CF3], 156 (10).
4-(Difluoromethyl)-2-methyl-9H-pyrido[2,3-b]indole (16d)
Yield: 0.94 g (81%); colourless solid (recrystallized from i-PrOH).
13C NMR (DMSO-d6): d = 24.3, 111.2, 111.5 (1JCF = 240 Hz),
114.3, 118.5, 119.9, 123.1, 126.7, 134.8 (2JCF = 26 Hz), 138.9,
152.6, 155.6, 163.4.
9-Methyl-2,4-bis(trifluoromethyl)-9H-pyrido[2,3-b]indole (17a)
Yield: 0.48 g (75%); colourless solid.
19F NMR (DMSO-d6): d = –115.7 (d, 2JFH = 56 Hz).
Synthesis 2009, No. 14, 2393–2402 © Thieme Stuttgart · New York

2400
V. O. Iaroshenko et al.
PAPER
13C NMR (DMSO-d6): d = 28.2, 107.9 (q, JCF = 2.6 Hz), 110.6,
2-{[2,4-Bis(trifluoromethyl)-9H-pyrido[2,3-b]indol-9-yl]meth-
oxy}propane-1,3-diyl Dibenzoate (26)
Yield: 1.68 g (68%); yellow oil; Rf = 0.45 (EtOAc–hexane, 1:3).
1H NMR (DMSO-d6): d = 4.33 (m, 4 H), 4.80 (m, 1 H), 6.11 (br s,
2 H), 7.37 (m, 6 H), 7.67 (m, 2 H), 7.77 (d, J = 7.8 Hz, 1 H), 7.87
(d, J = 7.2 Hz, 4 H), 7.89 (s, 1 H), 8.01 (d, J = 7.8 Hz, 1 H).
1
110.8 (q, JCF = 5.0 Hz), 121.2 (q, JCF = 275 Hz), 121.4, 122.2 (q,
1JCF = 275 Hz), 124.0, 130.1, 131.4 (q, 2JCF = 35 Hz), 137.3, 142.9,
144.4 (q, 2JCF = 35 Hz), 150.8.
MS: m/z (%) = 319 (17) [M+ + 1], 318 (100) [M+], 299 (92), 132
(11).
13C NMR (DMSO-d6): d = 62.0, 72.5, 79.0, 107.0, 109.4, 121.2 (q,
9-Methyl-2-phenyl-4-(trifluoromethyl)-9H-pyrido[2,3-b]indole
(17b)
Yield: 0.59 g (90%); colourless solid.
1JCF = 275 Hz), 121.7, 122.4 (q, 1JCF = 275 Hz), 124.3 (q, JCF = 4.1
2
Hz), 128.2, 129.5, 129.6, 129.8, 130.7, 131.1 (q, JCF = 35 Hz),
2
133.5, 135.1, 135.2, 142.4, 144.0 (q, JCF = 35 Hz), 152.1, 154.9,
13C NMR (DMSO-d6): d = 27.7, 106.0 (q, JCF = 2.8 Hz), 110.7,
173.6, 173.7.
1
110.9 (q, JCF = 4.6 Hz), 120.7, 121.4 (q, JCF = 275 Hz), 121.7,
MS: m/z (%) = 616 (57) [M+], 495 (21), 494 (11), 385 (51), 333
(17), 331 (33), 284 (40), 283 (40), 105 (60), 77 (100).
2
125.1, 126.2, 127.9, 130.5, 130.4, 131.0 (q, JCF = 35 Hz), 134.5,
140.9, 153.1, 157.2.
MS: m/z (%) = 327 (21) [M+ + 1], 326 (100) [M+], 325 (58) [M+ –
1], 163 (11).
9-(3,5-Di-O-p-toluoyl-2-deoxy-a-D-ribofuranosyl)-2,4-bis(trif-
luoromethyl)-9H-pyrido[2,3-b]indole (35)
Yield: 1.81 g (69%); colourless solid; mp 97–100 °C; Rf = 0.85
(EtOAc–hexane, 1:3).
4-(Difluoromethyl)-2,9-dimethyl-9H-pyrido[2,3-b]indole (17c)
Yield: 0.46 g (93%); colourless solid.
13C NMR (DMSO-d6): d = 24.3, 28.5, 111.2, 111.5 (1JCF = 240 Hz),
114.3, 118.5, 119.9, 123.1, 126.7, 134.8 (2JCF = 26 Hz), 138.9,
152.6, 155.6, 163.4.
MS: m/z (%) = 247 (17) [M+ + 1], 246 (100) [M+], 245 (80) [M+ –
1], 195 (10).
1H NMR (DMSO-d6): d = 2.31 (s, 3 H), 2.40–2.47 (br m, 2 H), 2.45
(s, 3 H), 3.80 (br s, 2 H), 4.43 (m, 1 H), 4.49 (m, 1 H), 6.84 (t, J = 6.1
Hz, 1 H), 7.28 (d, J = 7.8 Hz, 2 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.37
(t, J = 7.8 Hz, 1 H), 7.53 (d, J = 7.8 Hz, 1 H), 7.77 (t, J = 7.8 Hz, 1
H), 7.90–7.95 (br m, 4 H), 8.03 (s, 1 H), 8.22 (d, J = 7.8 Hz, 1 H).
13C NMR (DMSO-d6): d = 21.8, 22.0, 38.9, 62.0, 69.4, 81.7, 88.5,
108.1, 111.3, 121.2 (q, 1JCF = 275 Hz), 121.7, 122.1 (q, 1JCF = 275
Hz), 124.0 (q, JCF = 4.0 Hz), 125.3, 128.9, 129.1, 129.7, 131.4 (q,
1,2,3,4-Tetrafluoro-6H-indolo[2,3-b]quinoline (20c)
2
To a boiling soln of pentafluorobenzaldehyde (7; 0.98 g, 5 mmol) in
AcOH (40 mL; temperature of the oil bath was 135 °C) under an in-
ert atmosphere, a soln of 1H-indol-2-amine (15; 0.79 g, 6 mmol) in
anhyd DMF (15 mL) was added dropwise through the condenser.
After the addition was completed, the mixture was refluxed for a
further 2 h. Then, the solvent was evaporated and the residue was
recrystallized (MeOH).
2JCF = 35 Hz), 135.3, 137.7, 138.8, 143.0, 144.1 (q, JCF = 35 Hz),
153.0, 156.2, 169.3, 169.4.
MS: m/z (%) = 656 (41) [M+], 601 (10), 554 (13), 553 (11), 520
(100), 497 (22), 490 (17), 452 (14), 305 (50), 285 (67), 221 (33),
187 (11), 185 (13), 119 (53), 91 (77).
Compounds 24, 27 and 36; General Procedure for the Deprotec-
tion of Acylated Nucleosides
Yield: 0.97 g (67%); colourless solid; mp >320 °C (MeOH).
To a soln of the acylated nucleoside (1 mmol) in abs MeOH (5 mL),
a sat. soln of NH3 in MeOH (20 mL) was added dropwise at 0 °C.
The mixture was stirred for another 30 min and left overnight at r.t.
The solvent was removed under reduced pressure, and the formed
material was kept for the next 24 h on a vacuum line. The resultant
yellow material was purified by column chromatography on silica
gel.
1H NMR (CF3CO2D): d = 7.50 (t, J = 7.8 Hz, 1 H), 7.61 (d, J = 7.8
Hz, 1 H), 7.69 (t, J = 7.8 Hz, 1 H), 8.75 (d, J = 7.8 Hz, 1 H), 9.84 (s,
1 H).
MS: m/z (%) = 291 (25) [M+ + 1], 290 (100) [M+], 145 (12).
9-(Tri-O-acetyl-b-D-ribofuranosyl)-2,4-bis(trifluoromethyl)-
9H-pyrido[2,3-b]indole (23)
Compound 23 was prepared according to the classical silyl-Hilbert–
Johnson reaction.12 Purification was by column chromatography.
9-(b-D-Ribofuranosyl)-2,4-bis(trifluoromethyl)-9H-pyrido[2,3-
b]indole (24)
Yield: 0.29 g (67%); colourless solid; mp 201–205 °C; Rf = 0.65
(EtOAc).
Yield: 1.69 g (75%); colourless solid; mp 125–129 °C; Rf = 0.65
(EtOAc–hexane, 1:4).
1H NMR (DMSO-d6): d = 3.39 (m, 1 H), 3.60 (m, 1 H), 4.21 (q,
J = 4.1 Hz, 1 H), 4.37 (br s, 1 H), 4.44 (d, J = 4.1 Hz, 1 H), 5.15 (m,
1 H), 5.65 (br s, 2 H), 6.44 (d, J = 5.2 Hz, 1 H), 7.33 (t, J = 7.8 Hz,
1 H), 7.51 (t, J = 7.8 Hz, 1 H), 7.70 (d, J = 7.8 Hz, 1 H), 7.91 (s, 1
H), 8.01 (d, J = 7.8 Hz, 1 H).
1H NMR (DMSO-d6): d = 1.91–2.10 (br s, 9 H), 3.48 (m, 1 H), 3.69
(m, 1 H), 4.00 (q, J = 4.4 Hz, 1 H), 4.39 (br s, 1 H), 4.64 (d, J = 4.4
Hz, 1 H), 6.49 (d, J = 4.8 Hz, 1 H), 7.39–7.51 (m, 2 H), 7.70 (d,
J = 7.8 Hz, 1 H), 7.74 (s, 1 H), 8.07 (d, J = 7.8 Hz, 1 H).
13C NMR (DMSO-d6): d = 20.1, 20.3, 20.9, 63.7, 67.9, 73.0, 79.0,
13C NMR (DMSO-d6): d = 62.4, 67.0, 71.9, 77.3, 86.9, 99.9, 105.9,
88.9, 99.0, 105.9, 107.8, 121.2 (q, 1JCF = 275 Hz), 121.9, 122.2 (q,
1
1
2
1JCF = 275 Hz), 124.9 (q, JCF = 4.0 Hz), 129.9, 131.3 (q, JCF = 35
107.8, 121.2 (q, JCF = 275 Hz), 121.9, 122.2 (q, JCF = 275 Hz),
124.9 (q, JCF = 4.0 Hz), 129.9, 131.3 (q, 2JCF = 35 Hz), 142.7, 144.2
(q, 2JCF = 35 Hz), 154.1, 157.1.
2
Hz), 142.7, 144.2 (q, JCF = 35 Hz), 149.2, 153.1, 170.4, 170.6,
171.0.
MS: m/z (%) = 436 (13) [M+], 419 (21), 418 (17), 401 (30), 400
(13), 355 (11), 333 (17), 305 (100), 301 (11), 300 (27), 284 (47),
273 (15), 211 (10), 187 (14), 167 (10), 166 (15).
MS: m/z (%) = 562 (47) [M+], 560 (33) [M+ – 2], 502 (54), 490 (11),
459 (10), 458 (14), 401 (70), 400 (11), 388 (17), 387 (50), 386 (13),
305 (100), 284 (88), 211 (22), 57 (39), 43 (71).
2-{[2,4-Bis(trifluoromethyl)-9H-pyrido[2,3-b]indol-9-yl]meth-
oxy}propane-1,3-diol (27)
Yield: 0.22 g (53%); yellow oil; Rf = 0.25 (EtOAc–hexane, 1:2).
Compounds 26 and 35
For the synthesis of compounds 26 and 35, and their deprotection, a
literature method14 was used without change. Alkylation was con-
ducted with NaH in MeCN. Purification was by column chromatog-
raphy.
Synthesis 2009, No. 14, 2393–2402 © Thieme Stuttgart · New York

PAPER
Fluorinated Benzofuro-/Benzothieno[2,3-b]pyridines and a-Carbolines
2401
1H NMR (DMSO-d6): d = 4.25 (m, 4 H), 4.43 (br s, 2 H), 4.50 (m,
1 H), 5.91 (br s, 2 H), 7.39 (m, 2 H), 7.70 (t, J = 7.8 Hz, 1 H), 7.81
(s, 1 H), 8.01 (d, J = 7.8 Hz, 1 H).
MS: m/z (%) = 434 (13) [M+], 416 (43), 339 (100), 377 (17), 331
(14), 330 (11), 305 (50), 285 (41), 284 (22), 143 (15), 141 (10), 130
(19).
13C NMR (DMSO-d6): d = 60.8, 71.5, 81.3, 108.8, 109.5, 121.2 (q,
1JCF = 275 Hz), 121.3, 122.3 (q, 1JCF = 275 Hz), 124.5 (q, JCF = 4.2
Hz), 129.4, 131.1 (q, 2JCF = 35 Hz), 142.9, 143.9 (q, 2JCF = 35 Hz),
152.3, 155.0.
Compounds 37 and 39
Carbocyclic nucleosides 37 and 39 were obtained according to the
Mitsunobu protocol.16
A soln of DEAD (8.9 mmol) in anhyd MeCN was added dropwise
to a stirred, cooled soln (0 °C) of a carbocyclic sugar (3.7 mmol).
Then, a soln of carboline 16a (1.26 g, 4 mmol) and Ph3P (2.31 g, 8.8
mmol) in anhyd MeCN was added. The reaction mixture was stirred
at 0 °C for 1 h, then heated to r.t. and stirred for another 12 h. The
solvent was then removed under reduced pressure. The residue was
dried under reduced pressure for 12 h and purified by column chro-
matography on silica gel.
MS: m/z (%) = 408 (14) [M+], 406 (71), 401 (14), 389 (100), 304
(79), 285 (18), 284 (39), 47 (11).
9-(2-Deoxy-a-D-ribofuranosyl)-2,4-bis(trifluoromethyl)-9H-py-
rido[2,3-b]indole (36)
Yield: 0.35 g (83%); colourless solid; mp 189–193 °C; Rf = 0.25
(EtOAc–hexane, 1:1).
1H NMR (DMSO-d6): d = 2.35–2.49 (br m, 2 H), 3.67 (br s, 2 H),
4.33 (m, 1 H), 4.45 (m, 1 H), 5.27 (br s, 2 H), 6.59 (t, J = 5.8 Hz, 1
H), 7.51 (t, J = 7.8 Hz, 1 H), 7.62 (d, J = 7.8 Hz, 1 H), 7.79 (t,
J = 7.8 Hz, 1 H), 7.99 (s, 1 H), 8.15 (d, J = 7.8 Hz, 1 H).
9-[(1R,3S,4R)-3-Benzyloxy-4-(benzyloxymethyl)cyclopentyl]-
2,4-bis(trifluoromethyl)-9H-pyrido[2,3-b]indole (37)
Yield: 0.88 g (37%); yellow oil; Rf = 0.40 (EtOAc–hexane, 1:5).
1H NMR (DMSO-d6): d = 1.30–1.37 (m, 1 H), 1.75–1.84 (m, 1 H),
2.10–2.17 (m, 3 H), 3.30 (ddd, 2J = 10.8 Hz, 3J = 5.8, 5.3 Hz, 1 H),
3.43 (ddd, 2J = 10.8 Hz, 3J = 5.6, 5.3 Hz, 1 H), 4.00–4.05 (m, 1 H),
4.59–4.75 (m, 4 H), 5.00–5.05 (m, 1 H), 7.25–7.48 (m, 12 H), 7.82
(d, J = 7.8 Hz, 1 H), 7.93 (s, 1 H), 8.21 (d, J = 7.8 Hz, 1 H).
13C NMR (DMSO-d6): d = 38.9, 62.0, 69.4, 81.7, 88.5, 108.1,
1
1
111.3, 121.2 (q, JCF = 275 Hz), 121.7, 122.1 (q, JCF = 275 Hz),
124.0 (q, JCF = 4.4 Hz), 129.7, 131.4 (q, 2JCF = 35 Hz), 135.3, 143.0,
144.1 (q, 2JCF = 35 Hz), 153.0, 156.2.
MS: m/z (%) = 420 (24) [M+], 403 (18), 402 (100), 385 (10), 309
(19), 304 (82), 287 (12), 285 (10), 284 (22), 280 (17), 221 (20), 220
(37), 199 (11), 119 (12), 118 (11), 56 (14).
13C NMR (DMSO-d6): d = 31.7, 34.3, 51.0, 54.9, 65.0, 72.2, 73.1,
1
73.9, 106.9, 109.0, 121.1 (q, JCF = 275 Hz), 121.7, 122.3 (q,
1JCF = 275 Hz), 124.5, 127.3, 127.9, 128.7, 129.0, 131.2 (q,
2JCF = 35 Hz), 137.9, 138.1, 143.1, 144.3 (q, 2JCF = 35 Hz), 152.2,
154.4.
{(3aR,4R,6R,6aS)-6-[2,4-Bis(trifluoromethyl)-9H-pyrido[2,3-
b]indol-9-yl]-2,2-dimethyltetrahydro-3aH-cyclopen-
ta[d][1,3]dioxol-4-yl}methanol (33)
Compound 33 was synthesized from carboline 16a and 31 using the
Mitsunobu protocol, with subsequent oxidation of the double
bond.14a Purification was by column chromatography.
MS: m/z (%) = 598 (73) [M+], 504 (31), 491 (26), 490 (68), 467
(12), 377 (44), 321 (32), 304 (40), 285 (17), 278 (11), 261 (30), 204
(14), 191 (17), 161 (11), 91 (100).
Yield: 0.63 g (33%); colourless solid; mp 138–140 °C; Rf = 0.45
(EtOAc–hexane, 1:3).
9-[cis-3-(Benzyloxymethyl)cyclobutyl]-2,4-bis(trifluorometh-
yl)-9H-pyrido[2,3-b]indole (39)
1H NMR (DMSO-d6): d = 1.28 (s, 3 H), 1.50 (s, 3 H), 2.30 (m, 3 H),
3.47 (br s, 2 H), 4.55 (d, J = 4.1 Hz, 1 H), 4.80–4.86 (m, 2 H), 5.17
(d, J = 6.4 Hz, 1 H), 7.35 (m, 2 H), 7.71 (t, J = 7.8 Hz, 1 H), 7.77 (s,
1 H), 8.10 (d, J = 7.8 Hz, 1 H).
Yield: 1.17 g (66%); colourless solid; mp 116–118 °C; Rf = 0.85
(EtOAc–hexane, 1:3).
1H NMR (CDCl3): d = 1.90 (m, 2 H), 2.19 (m, 1 H), 2.59 (m, 2 H),
3.39 (d, J = 6.0 Hz, 2 H), 4.30 (s, 2 H), 6.03 (d, J = 6.6 Hz, 1 H),
7.29 (m, 5 H), 7.40 (t, J = 7.8 Hz, 1 H), 7.50 (d, J = 7.8 Hz, 1 H),
7.79 (t, J = 7.8 Hz, 1 H), 7.88 (s, 1 H), 8.13 (d, J = 7.8 Hz, 1 H).
13C NMR (DMSO-d6): d = 24.7, 27.1, 34.7, 47.8, 61.7, 61.9, 80.9,
1
82.3, 109.3, 110.1, 121.2 (q, JCF = 275 Hz), 121.9, 122.3 (q,
2
1JCF = 275 Hz), 124.9, 131.0 (q, JCF = 35 Hz), 142.4, 144.9 (q,
13C NMR (CDCl3): d = 25.5, 32.0, 66.7, 73.3, 74.7, 108.8, 109.5,
2JCF = 35 Hz), 152.4, 156.0.
1
1
121.0, 121.2 (q, JCF = 275 Hz), 121.3, 122.3 (q, JCF = 275 Hz),
124.5 (q, JCF = 4.2 Hz), 126.4, 127.7, 129.4, 131.1 (q, 2JCF = 35 Hz),
133.3, 136.7, 142.9, 143.9 (q, 2JCF = 35 Hz), 152.9, 156.3.
MS: m/z (%) = 474 (38) [M+], 457 (53), 441 (100), 402 (16), 304
(43), 285 (39), 171 (12), 166 (15), 162 (18), 161 (19), 155 (23), 153
(18), 147 (13), 43 (21).
MS: m/z (%) = 478 (59) [M+], 371 (79), 370 (90), 304 (100), 301
(15), 285 (59), 91 (90), 65 (11), 57 (41).
(1R,2S,3R,5R)-3-[2,4-Bis(trifluoromethyl)-9H-pyrido[2,3-b]in-
dol-9-yl]-5-(hydroxymethyl)cyclopentane-1,2-diol (34)
Deprotection of compound 33 was performed in TFA–H2O, accord-
ing to the procedure described previously.1d Purification was by col-
umn chromatography.
Compounds 38 and 40; General Procedure for Benzyl Group
Cleavage by Hydrogenation
The benzylated carbocyclic nucleoside (1 mmol) was dissolved in
EtOH and 10% Pd/C (70 mg) was added. The reaction mixture was
stirred under H2 at r.t. until complete conversion was observed by
TLC (ca. 2–3 h). The reaction mixture was filtered through a Celite®
pad which was washed with EtOH. The mother liquid was concen-
trated under reduced pressure and the residue was purified by col-
umn chromatography on silica gel.
Yield: 0.35 g (80%); colourless solid; mp 299–300 °C; Rf = 0.65
(EtOAc).
1H NMR (CDCl3): d = 1.60–1.70 (br s, 2 H), 1.99–2.04 (m, 1 H),
2.31 (m, 1 H), 3.43–3.51 (m, 2 H), 3.84 (m, 1 H), 4.38 (m, 1 H),
4.65–4.74 (m, 1 H), 4.85 (br t, J = 5.8 Hz, 1 H), 4.95 (d, J = 6.2 Hz,
1 H), 7.44 (t, J = 7.8 Hz, 1 H), 7.59 (d, J = 7.8 Hz, 1 H), 7.71 (t,
J = 7.8 Hz, 1 H), 7.84 (s, 1 H), 8.05 (d, J = 7.8 Hz, 1 H).
(1S,2R,4R)-4-[2,4-Bis(trifluoromethyl)-9H-pyrido[2,3-b]indol-
9-yl]-2-(hydroxymethyl)cyclopentanol (38)
Yield: 0.25 g (59%); colourless solid; mp 175–177 °C; Rf = 0.45
(EtOAc–hexane, 1:1).
1H NMR (DMSO-d6): d = 1.34–1.42 (m, 1 H), 1.70–1.81 (m, 1 H),
2.05–2.14 (m, 2 H), 2.17–2.25 (m, 1 H), 3.37 (ddd, J = 11.2 Hz,
13C NMR (DMSO-d6): d = 29.3, 45.1, 58.3, 63.0, 74.7, 77.3, 108.5,
1
1
111.9, 121.3 (q, JCF = 275 Hz), 121.9, 122.4 (q, JCF = 275 Hz),
124.0, 131.2 (q, 2JCF = 35 Hz), 141.7, 144.0 (q, 2JCF = 35 Hz), 153.1,
155.3.
2
Synthesis 2009, No. 14, 2393–2402 © Thieme Stuttgart · New York

2402
V. O. Iaroshenko et al.
PAPER
3
3J = 5.8, 5.0 Hz, 1 H), 3.57 (ddd, 2J = 11.2 Hz, J = 5.4, 5.0 Hz, 1
H), 4.07–4.12 (m, 1 H), 4.61 (t, J = 5.2 Hz, 1 H), 4.73 (d, J = 4.5 Hz,
1 H), 5.02–5.08 (m, 1 H), 7.39–7.50 (m, 2 H), 7.77 (d, J = 7.8 Hz, 1
H), 7.90 (s, 1 H), 8.08 (d, J = 7.8 Hz, 1 H).
U.; Brand, J.; Chernega, A. N.; Shivanyuk, A. N.;
Tolmachev, A. A. Synthesis 2008, 2337. (d) Iaroshenko, V.
O.; Sevenard, D. V.; Kotljarov, A.; Volochnyuk, D. M.;
Tolmachev, A. O.; Sosnovskikh, V. Ya. Synthesis 2009, 731.
(2) Iaroshenko, V. O.; Groth, U.; Kryvokhyzha, N. V.; Obeid,
S.; Tolmachev, A. A.; Wesch, T. Synlett 2008, 343.
(3) Shridhar, D. R.; Reddy Sastry, C. V.; Lal, K. B.; Bansal, O.
P.; Sondhi, S. M. J. Indian Chem. Soc. 1978, 55, 910.
(4) Sundaram, G. S. M.; Venkatesh, C.; Syam, K. U. K.; Ila, H.;
Junjappa, H. J. Org. Chem. 2004, 69, 5760.
(5) Abramov, M. A.; Ceulemans, E.; Jackers, C.;
Van der Auweraer, M.; Dehaen, W. Tetrahedron 2001, 57,
9123.
(6) (a) Simons, C.; Wu, Q.; Htar, T. T. Curr. Top. Med. Chem.
2005, 5, 1191. (b) Zapf, C. W.; Bloom, J. D.; Levin, J. I.
Annu. Rep. Med. Chem. 2007, 42, 281.
(7) (a) Brigden, D.; Fiddian, P.; Rosling, A. E.; Ravenscroft, T.
Antiviral Res. 1981, 1, 203. (b) De Clercq, E.; Naesens, L.;
De Bolle, L.; Schols, D.; Zhang, Y.; Neyts, J. Rev. Med.
Virol. 2001, 11, 381. (c) Abdel-Haq, N.; Chearskul, P.; Al-
Tatari, H.; Asmar, B. Indian J. Pediatr. 2006, 73, 313.
(8) (a) Rolfes, R. J. Biochem. Soc. Trans. 2006, 34, 786.
(b) Christopherson, R. J.; Lyons, S. D.; Wilson, P. K. Acc.
Chem. Res. 2002, 35, 961. (c) Manfredi, J. P.; Holmes, E.
W. Ann. Rev. Physiol. 1985, 47, 691. (d) Berens, R. L.;
Krug, E. C.; Marr, J. J. Biochemistry and Molecular Biology
of Parasites; Marr, J. J.; Müller, M., Eds.; Elsevier:
Amsterdam, 1995, 89.
(9) Marminon, C.; Pierre, A.; Pfeiffer, B.; Perez, V.; Leonce, S.;
Renard, P.; Prudhomme, M. Bioorg. Med. Chem. 2003, 11,
679.
(10) Prudhomme, M.; Marminon, C.; Routier, S.; Coudert, G.;
Merour, J.-Y.; Hickman, J.; Pierre, A.; Renard, P.; Pfeiffer,
B. Int. Patent WO 002563, 2003; Chem. Abstr. 2003, 138,
22877.
13C NMR (DMSO-d6): d = 31.7, 34.3, 51.0, 54.9, 65.0, 73.7, 106.9,
109.0, 121.1 (q, JCF = 275 Hz), 121.7, 122.3 (q, JCF = 275 Hz),
123.9, 124.5 (q, JCF = 4.2 Hz), 129.0, 131.2 (q, 2JCF = 35 Hz), 143.1,
144.3 (q, 2JCF = 35 Hz), 152.4, 153.9.
MS: m/z (%) = 418 (31) [M+], 417 (10), 401 (10), 399 (100), 389
(20), 388 (10), 340 (12), 339 (15), 299 (11), 285 (13), 251 (17), 209
(13), 189 (13), 111 (10).
1
1
{cis-3-[2,4-Bis(trifluoromethyl)-9H-pyrido[2,3-b]indol-9-yl]cy-
clobutyl}methanol (40)
Yield: 0.22 g (57%); colourless solid; mp 152–155 °C; Rf = 0.60
(EtOAc–hexane, 1:2).
1H NMR (DMSO-d6): d = 1.85 (m, 2 H), 2.01 (m, 1 H), 2.35 (m, 2
H), 3.37 (d, J = 5.2 Hz, 2 H), 4.60 (br s, 1 H), 5.01 (m, 1 H), 7.41 (t,
J = 7.8 Hz, 1 H), 7.67 (d, J = 7.8 Hz, 1 H), 7.70 (t, J = 7.8 Hz, 1 H),
7.91 (s, 1 H), 8.05 (d, J = 7.8 Hz, 1 H).
13C NMR (DMSO-d6): d = 27.1, 33.7, 63.0, 66.7, 108.9, 109.3,
121.2 (q, JCF = 275 Hz), 121.3, 122.2 (q, JCF = 275 Hz), 124.3,
129.5, 131.2 (q, 2JCF = 35 Hz), 133.3, 142.9, 143.7 (q, 2JCF = 35 Hz),
151.9, 154.0.
MS: m/z (%) = 388 (31) [M+], 387 (11), 353 (100), 305 (12), 299
(17), 245 (13), 207 (19), 189 (17), 167 (11), 158 (11), 131 (10), 57
(33).
1
1
{cis-4-[2,4-Bis(trifluoromethyl)-9H-pyrido[2,3-b]indol-9-yl]cy-
clopent-2-en-1-yl}methanol (41)
Under an inert atmosphere, carboline 16a (0.91 g, 3 mmol) was add-
ed to a stirred suspension of NaH (0.1 g, 4.4 mmol) in DMF (30 mL)
at r.t. The mixture was stirred at r.t. for 1 h, then cis-diacetate 32
(0.65 g, 3.3 mmol) and Pd(PPh3)4 (1.27 g, 1.1 mmol) were added.
The reaction vessel was protected from light by tin foil and the mix-
ture was heated to 60 °C for 2 h, then cooled to r.t. Abs MeOH
(2 mL) was added to the reaction mixture which was kept for 1 h at
r.t. The solvents were evaporated under reduced pressure and the
residue was purified by column chromatography on silica gel to fur-
nish product 41 as only the cis-isomer.
(11) Henon, H.; Messaoudi, S.; Anizon, F.; Aboab, B.;
Kucharczyk, N.; Leonce, S.; Golsteyn, R. M.; Pfeiffer, B.;
Prudhomme, M. Eur. J. Pharmacol. 2007, 554, 106.
(12) Vorbrüggen, H.; Ruh-Pohlenz, C. Handbook of Nucleoside
Synthesis; Wiley & Sons: New York, 2001.
(13) Hirao, I.; Mitsui, T.; Kimoto, M.; Yokoyama, S. J. Am.
Chem. Soc. 2007, 129, 15549.
(14) (a) Yang, M.; Ye, W.; Schneller, S. W. J. Org. Chem. 2004,
69, 3993. (b) Crimmins, M. T. Tetrahedron 1998, 54, 9229.
(15) Kaiwar, V.; Reese, C. B.; Gray, E. J.; Neidle, S. J. Chem.
Soc., Perkin Trans. 1 1995, 2281.
(16) Saville-Stones, E. A.; Lindell, S. D.; Jennings, N. S.; Head,
J. C.; Ford, M. J. J. Chem. Soc., Perkin Trans. 1 1991, 2603.
(17) Beauchamp, L. M. B.; Serling, L.; Kelsey, J. E.; Biron, K.;
Collins, K. P.; Selway, J.; Lin, J.-C.; Schaeffer, H. J. J. Med.
Chem. 1988, 31, 144.
(18) Hashmi, S. A. N.; Hu, X.; Immoos, C. E.; Lee, S. J.;
Grinstaff, M. W. Org. Lett. 2002, 4, 4571.
(19) Ludek, O. R.; Meier, C. Synthesis 2003, 2101.
(20) Kaiwar, V.; Reese, C. B.; Gray, E. J.; Neidle, S. J. Chem.
Soc., Perkin Trans. 1 1995, 2281.
(21) (a) Palmer, A. M.; Jager, V. Eur. J. Org. Chem. 2001, 1293.
(b) Paquette, L. A.; Bailey, S. J. Org. Chem. 1995, 60, 7849.
(c) Gallos, J. K.; Koftis, T. V.; Koumbis, A. E. J. Chem. Soc.,
Perkin Trans. 1 1994, 611. (d) Choi, W. J.; Park, J. G.; Yoo,
S. J.; Kim, H. O.; Moon, H. R.; Chun, M. W.; Jung, Y. H.;
Jeong, L. S. J. Org. Chem. 2001, 66, 6490. (e) Jin, Y. H.;
Wang, J.; Baker, R.; Huggins, J.; Chu, C. K. J. Org. Chem.
2003, 68, 9012.
Yield: 0.71 g (59%); colourless solid; mp 134–136 °C; Rf = 0.80
(EtOAc–hexane, 1:1).
1H NMR (DMSO-d6): d = 1.61 (dt, 2J = 11.8 Hz, 3J = 5.1 Hz, 1 H),
2
3
2.68 (dt, J = 13.0 Hz, J = 8.0 Hz, 1 H), 3.08 (m, 1 H), 3.41 (d,
J = 10.6 Hz, 2 H), 3.58 (br s, 1 H), 5.23–5.32 (m, 1 H), 5.81 (dt,
2J = 5.7 Hz, 3J = 2.2 Hz, 1 H), 6.11 (dt, 2J = 13.1 Hz, 3J = 2.5 Hz, 1
H), 7.37 (t, J = 7.8 Hz, 1 H), 7.50 (d, J = 7.8 Hz, 1 H), 7.79 (t,
J = 7.8 Hz, 1 H), 7.84 (s, 1 H), 8.10 (d, J = 7.8 Hz, 1 H).
13C NMR (DMSO-d6): d = 33.9, 48.1, 56.3, 66.1, 107.0, 109.6,
1
1
120.3, 121.2 (q, JCF = 275 Hz), 121.9, 122.3 (q, JCF = 275 Hz),
124.9 (q, JCF = 4.0 Hz), 129.0, 131.5 (q, 2JCF = 35 Hz), 132.7, 138.7,
142.9, 144.7 (q, 2JCF = 35 Hz), 154.1, 155.5.
MS: m/z (%) = 400 (41) [M+], 382 (70), 358 (13), 357 (100), 304
(20), 285 (35), 222 (23), 221 (10), 210 (12), 138 (35), 96 (14).
References
(1) (a) Iaroshenko, V. O.; Volochnyuk, D. M.; Wang, Y.; Vovk,
M. V.; Boiko, V. J.; Rusanov, E. B.; Groth, U. M.;
Tolmachev, A. A. Synthesis 2007, 3309. (b) Volochnyuk,
D. M.; Pushechnikov, A. O.; Krotko, D. G.; Sibgatulin, D.
A.; Kovalyova, S. A.; Tolmachev, A. A. Synthesis 2003,
1531. (c) Iaroshenko, V. O.; Volochnyuk, D. M.;
(22) Hodgson, D. M.; Witherington, J.; Moloney, B. A. J. Chem.
Soc., Perkin Trans. 1 1993, 1543.
Kryvokhyzha, N. V.; Martyloga, A.; Sevenard, D. V.; Groth,
Synthesis 2009, No. 14, 2393–2402 © Thieme Stuttgart · New York