New approach to the synthesis of 2,3-dihydrofuro[2,3-b]pyridine derivatives: double reduction and double heterocyclization of 2-(3-cyano-5-hydroxy-1,5-dihydro-2H-pyrrol-2-ylidene)malononitriles in the presence of sodium borohydride

Article abstract of DOI:10.1007/s10593-018-2287-x

[Figure not available: see fulltext.] The reaction of 2-(3-cyano-5-hydroxy-1,5-dihydro-2H-pyrrol-2-ylidene)malononitriles with an excess of sodium borohydride resulted in diastereoselective formation of 2,3-diaryl-substituted 4,6-diamino-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitriles. This process was accompanied by opening of the pyrrole ring in the starting compounds, followed by a double reduction and tandem closure of furan and pyridine rings.

Full text of DOI:10.1007/s10593-018-2287-x

DOI 10.1007/s10593-018-2287-x
Chemistry of Heterocyclic Compounds 2018, 54(4), 447–450
New approach to the synthesis of 2,3-dihydrofuro[2,3-b]pyridine deriva-
tives: double reduction and double heterocyclization of 2-(3-cyano-
5-hydroxy-1,5-dihydro-2H-pyrrol-2-ylidene)malononitriles
in the presence of sodium borohydride
Mikhail Yu. Belikov1*, Sergey V. Fedoseev1, Mikhail Yu. Ievlev1, Oleg V. Ershov1
1
Chuvash State University named after I. N. Ulyanov ,
15 Moskovsky Ave., Cheboksary 428015, Russia; е-mail: belikovmil@mail.ru
Translated from Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(4), 447–450
Submitted January 12, 2018
Accepted March 2, 2018
The reaction of 2-(3-cyano-5-hydroxy-1,5-dihydro-2H-pyrrol-2-ylidene)malononitriles with an excess of sodium borohydride resulted in
diastereoselective formation of 2,3-diaryl-substituted 4,6-diamino-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitriles. This process was
accompanied by opening of the pyrrole ring in the starting compounds, followed by a double reduction and tandem closure of furan and
pyridine rings.
Keywords: 2,3-dihydrofuro[2,3-b]pyridines, sodium borohydride, diastereoselectivity, reduction.
2,3-Dihydrofuro[2,3-b]pyridine derivatives 1 (Scheme 1)
have attracted an increasing attention of researchers over
recent years due to various types of biological activity that
have been observed for these fused heterocyclic systems.
For example, the structural moiety of 2,3-dihydrofuro[2,3-b]-
pyridine is a part of the naturally occurring nicotinic
receptor agonist phantasmidine,1,2 as well as synthetic
agonists of nicotinic receptors.3 Dihydrofuropyridine motif
is present in the structure of an aza analog of the
pharmaceutical compound ramelteon – a ligand of
melatonin receptors.4 Compounds of this group have also
shown promise for the treatment of Alzheimer's disease.5
For this reason, it is quite important to continue the
development of new methods for the synthesis of 2,3-di-
hydrofuro[2,3-b]pyridine derivatives.
One of previously published procedures for the synthesis
of fused [2,3-b]pyridine systems involves the assembly of
structures A on the basis of malononitrile dimer derivatives
(Scheme 1), in which the molecule contains both a propene-
1,3-dicarbonitrile fragment and a nucleophilic group at the
γ- or δ-position relative to the cyano group. Structures of
type А, as a rule, are formed in situ by the reactions of
substrates containing amino or hydroxy groups with
derivatives of malononitrile dimer. The use of this
approach allows to synthesize a broad range of [2,3-b]pyridi-
Scheme 1
nes that are fused with pyridine,6,7 pyran,8 or dihydrofuran9
rings.
Our goal was to modify this approach in order to enable
its use for the synthesis of new 2,3-dihydrofuro[2,3-b]-
pyridine derivatives, which would be difficult to obtain
otherwise. The salient features of the modified approach
include creating the conditions for the formation of
structures of type А, in which the hydroxy group is formed
from a preexisting functional group, instead of an
intermolecular process, as described before.6–9
2-(3-Cyano-5-hydroxy-1,5-dihydro-2H-pyrrol-2-ylidene)-
malononitriles 3 were selected as suitable substrates for the
synthesis of derivatives 1 (Schemes 2, 3). Compounds 3
were synthesized by our recently discovered rearrangement
0009-3122/18/54(4)-0447©2018 Springer Science+Business Media, LLC
447

Chemistry of Heterocyclic Compounds 2018, 54(4), 447–450
Scheme 3
of 4-oxoalkane-1,1,2,2-tetracarbonitriles 4 in acetic acid in
the presence of ammonium acetate (Scheme 3).10,11 The
specific selection of these compounds was associated with
their structural features: pyrroles 3 contain a hemiaminal
moiety which points to the existence of these structures in
an equilibrium with the open-chain form 3'.
Ar2
Ar2
Ar1
HO
CN
CN
CN
AcONH4
AcOH
Ar1
CN
CN
CN
N
H
O NC
4a–e
3a–e
Scheme 2
R2
R1
H2N
R2
CN
CN
CN
Ar2
Ar1
NaBH4 (4 equiv)
CN
CN
CN
CN
R1
90% EtOH
rt, 0.5–1 h
NH2
N
H
3
HO
N
O H2N
3'
O
5a–e
Table 1. Yields of compounds 5a–e
Stable compounds analogous to the structures 3',
which lack a carbonyl group, have been described in the
literature quite frequently.6–8 The open-chain structure 3'
contains both a carbonyl group that potentially can be
reduced to a nucleophilic hydroxyl group and cyano groups
at β- and δ-positions, therefore pyrroles 3 can be expected
to undergo a cascade of reactions analogous to that
described for the synthesis of condensed pyridines 2
(Scheme 1). The presence of a masked hydroxy group in
combination with cyano groups in structure 3' represents
the main difference of our approach in this work compared
to the process for the formation of structures 2 that is
illustrated in Scheme 1. We should also note that, in
contrast to the previously known routes of synthesis,6–9
malononitrile dimer was not used as starting material in
this work.
Compound
Ar(Het)1
Ar(Het)2
Ph
Yield, %
72
Ph
Ph
5a
54
59
68
53
5b
5c
5d
5e
During the development of our synthetic approach, we
studied the possibility of reducing the carbonyl group in
structures 3' with sodium borohydride. We found that the
treatment of pyrroles 3a–e with a fourfold excess of NaBH4
in aqueous ethanol resulted in a complex transformation
leading to 2,3-diaryl-substituted 4,6-diamino-2,3-dihydro-
furo[2,3-b]pyridine-5-carbonitriles 5a–e in 53–72% yields
(Scheme 3, Table 1).
no published data were available on 2,3-diaryl-substituted
2,3-dihydrofuro[2,3-b]pyridines. The closest structural
analogs of compounds 5a–e, which were thoroughly
described in the literature, were derivatives of 2,3-diaryl-
2,3-dihydrobenzofuran. In the case of such structures it was
shown that the spin-spin coupling constants for geminal
protons at aryl (hetaryl) substituents at the cis position were
8.7–10.2 Hz12 (8.0 Hz according to other data13). The spin-
spin coupling constants for compounds having a trans
configuration were 4.3–5.9,13 5.7–5.9,14 7.5,15 or 5–8 Hz.16
According to our data, the spin-spin coupling constants of
8.0–8.3 Hz between the protons of dihydrofuran ring in
compounds 5 can correspond to either cis- or trans-
isomers. In order to solve this issue, we performed an
additional structural study of compound 5а by using
NOESY experiments. It has been previously shown16 that
NOESY spectra acquired for the trans-isomers of 2,3-di-
aryl-2,3-dihydrobenzofurans lacked correlation between
the protons bonded to the С-2 and С-3 carbon atoms of the
furan ring, while these protons showed cross peaks with the
ortho protons of both the geminal and vicinal aryl
substituents. NOESY spectrum of compound 5а featured a
cross peak between the proton bonded to the С-2 carbon
atom (6.02 ppm) and the proton at the С-3 carbon atom
(4.70 ppm) of the furan ring (Fig. 1). Besides that, the
proton at the С-3 carbon atom showed a correlation with
the ortho proton (6.67 ppm) of the adjacent phenyl ring А,
as well as there was a correlation of the hydrogen atom at
The structure of compounds 5a–e was confirmed using
1
the data of IR, H and 13C NMR spectroscopy and mass
spectrometry. An important feature of the process leading
to the formation of heterocyclic products 5 was its
diastereoselectivity: structure 5 contains two asymmetric
centers, but diastereomeric mixture was not obtained
according to the data of NMR spectroscopy. The signals of
protons bonded to the С-2 and С-3 atoms of the
heterocyclic system were observed in the chemical shift
range of 4.50–6.02 ppm as two doublets with spin-spin
coupling constants of 8.0–8.3 Hz. In addition to that,
1H NMR spectra of compounds 5a–e contained characte-
ristic singlet signals of protons belonging to two amino
groups at 6.10–6.48 ppm. 13C NMR spectra contained three
characteristic signals of α- and γ-carbon atoms of pyridine
ring at 153.9–169.8 ppm, as well as a signal of the cyano
group carbon atom at 117 ppm.
In order to resolve the issue of cis or trans confi-
guration of protons at the С-2 and С-3 carbon atoms of
compounds 5a–e, we performed a literature survey on the
stereochemistry of analogous structures. It was found that
448

Chemistry of Heterocyclic Compounds 2018, 54(4), 447–450
Scheme 4
Ar2
CN
Red. 1
NaBH4
EtOH
CN
CN
3
Ar1
O
NH2
3'
H2N
CN
CN
H2N
CN
Ar2
Ar2
Red. 2
CN
Figure 1. Correlations in NOESY spectrum of compound 5а.
Ar1
CN
Ar1
CN
OH
O
A
B
the С-2 carbon atom with the ortho proton of the phenyl
substituent B (6.93–7.10 ppm). The proton at the С-3
carbon atom also gave a cross peak with the amino group
proton (6.13 ppm) at position 4 of the pyridine ring.
Thus, our obtained data on the spatial proximity between
certain protons in the molecule of compound 5а provide
evidence that heterocyclic products 5 are more likely to
form as cis-isomers. Such conclusion was also supported
by the absence of correlations between the 2-CH proton
and the ortho proton of the phenyl ring А, as well as
between the 3-CH proton and the ortho proton of the
phenyl ring В.
According to the structure of compounds 5a–e, their
molecular mass is higher by four atomic mass units
compared to the molecular mass of the starting pyrroles 3a–e.
The same was confirmed by mass spectral data, which
showed molecular ion peaks with the intensity of 18–100%.
This fact indicated that a double reduction of pyrroles 3a–e
had occurred by the action of sodium borohydride.
The relatively complex rearrangement of the starting
structures 3, accompanied by pyrrole ring opening and
tandem closure of furan and pyridine rings, was explained
by the cleavage of one N–C bond during the reaction and
the formation of two new O–C and N–C bonds. In the case
of the synthesis of compounds 5, the following sequence of
mechanistic steps can be proposed: base-catalyzed opening
of the hydroxypyrrole ring with the formation of ketone 3'
occurred during the first stage (Scheme 4). This was
followed by 1,4-reduction of α,β-unsaturated ketone moiety
to enol A, which was further converted through the ketone
form B and reduced to the γ-hydroxynitrile C. The process
concluded with a double heterocyclization: intramolecular
interaction of hydroxy and cyano groups produced
dihydrofuran D, in which the interaction of amino group
with cyano group led to the formation of the final
furopyridines 5a–e.
H2N
CN
CN
H2N
O
CN
CN
Ar2
Ar2
Ar1
5
Ar1
CN
NH2
OH
C
D
products reflected the tendency for pyrrole ring opening in
the starting compounds in basic media and pointed to their
possible use in directed cascade transformations.
Experimental
IR spectra were recorded on an FSM-1202 FTIR
spectrometer for thin layers of Nujol mulls. 1Н and
13C NMR spectra were acquired on a Bruker DRX-500
spectrometer (500 and 125 MHz, respectively) in DMSO-d6,
using TMS as internal standard. Thiophene ring protons are
denoted as "H Th". Mass spectra were recorded on a
Finnigan МАТ INCOS-50 instrument (EI ionization, 70 eV).
Elemental analysis was performed on a PerkinElmer 2400
CHN-analyzer. Melting points were determined on an
OptiMelt MPA100 apparatus. The reaction progress and
purity of the synthesized compounds were controlled by
TLC on Sorbfil PTSKh-AF-A-UF plates (eluent EtOAc–
hexane, 9:1, visualization under UV light, in iodine vapor,
or by thermal decomposition).
The starting compounds 3a–е were synthesized accord-
ing to a published procedure.10
Preparation of 2,3-diaryl-substituted 4,6-diamino-2,3-di-
hydrofuro[2,3-b]pyridine-5-carbonitriles 5а–е (General
method). NaBH4 (76 mg, 2 mmol) was added portionwise
with vigorous stirring to a suspension of pyrrole 3а–е
(0.5 mmol) in aqueous 90% EtOH solution (2–3 ml), while
keeping the temperature of the reaction mixture at or below
30°C. The obtained solution was stirred at room tempera-
ture for 0.5–1 h, then the mixture was cooled to 5–10°C,
maintained at this temperature for 1 h, and the precipitated
solid product was filtered off, washed with H2O (2 ml)
and cold (5–10°C) EtOH (2 ml). The product was dried at
reduced pressure over CaCl2.
It should be noted that using an equimolar amount of the
reducing agent also resulted in the formation of compounds
5, but in that case part of the starting pyrrole 3 remained in
the reaction mixture. This provided an indirect evidence
about the greater rate of reduction of the intermediate
structures A (B) compared to the reduction of the initial
ring opening product – ketone 3'.
4,6-Diamino-2,3-diphenyl-2,3-dihydrofuro[2,3-b]pyri-
dine-5-carbonitrile (5а). Yield 118 mg (72%), white
powder, mp 301–302°С (decomp.) (mp 305°С9). IR spectrum,
ν, cm–1: 3453, 3348 (NH2), 2191 (C≡N). 1H NMR
spectrum, δ, ppm (J, Hz): 4.70 (1H, d, J = 8.3, 3-CH); 6.02
(1H, d, J = 8.3, 2-CH); 6.13 (2H, s, NH2); 6.47 (2H, s,
NH2); 6.67 (2H, d, J = 7.0, H Ph); 6.93–7.10 (8H, m,
Thus, using the reduction of 2-(5-R1-4-R2-3-cyano-
5-hydroxy-1,5-dihydro-2H-pyrrol-2-ylidene)malononitriles
with an excess of sodium borohydride we demonstrated a
new method for diastereoselective synthesis of 2,3-di-
hydrofuro[2,3-b]pyridine derivatives. The formation of these
449

Chemistry of Heterocyclic Compounds 2018, 54(4), 447–450
H Ph). 13C NMR spectrum, δ, ppm: 48.4; 68.2; 86.2; 92.6;
IR spectrum, ν, cm–1: 3449, 3339 (NH2), 2199 (C≡N).
1H NMR spectrum, δ, ppm (J, Hz): 2.14 (3H, s, CH3); 2.26
(3H, s, CH3); 4.85 (1H, d, J = 8.0, 3-CH); 5.88 (1H, d,
J = 8.0, 2-CH); 6.06 (1H, s, H Th); 6.25 (2H, s, NH2); 6.39–
6.41 (1H, m, H Th); 6.48 (2H, s, NH2); 6.76–6.79 (1H, m,
H Th); 7.20–7.22 (1H, m, H Th). 13C NMR spectrum,
δ, ppm: 12.8; 14.7; 43.1; 68.2; 82.5; 92.7; 117.3; 124.9
(2С); 125.4; 126.4; 132.2; 132.5; 134.0; 142.5; 154.4;
162.8; 169.5. Mass spectrum, m/z (Irel, %): 368 [M]+ (18).
Found, %: C 58.51; H 4.46; N 15.04. C18H16N4OS2.
Calculated, %: C 58.67; H 4.38; N 15.20.
117.1; 124.9; 126.2; 127.0; 127.3; 128.5; 128.7; 136.6;
137.9; 154.1; 162.7; 169.8. Mass spectrum, m/z (Irel, %):
328 [M]+ (100). Found, %: C 73.01; H 4.97; N 16.93.
C20H16N4O. Calculated, %: C 73.15; H 4.91; N 17.06.
4,6-Diamino-3-(2,5-dimethylthiophen-3-yl)-2-phenyl-
2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile
(5b).
Yield 98 mg (54%), white powder, mp 285–286°С
(decomp.). IR spectrum, ν, cm–1: 3462, 3341 (NH2), 2192
1
(C≡N). H NMR spectrum, δ, ppm (J, Hz): 1.83 (3H, s,
CH3); 2.17 (3H, s, CH3); 4.62 (1H, d, J = 8.2, 3-CH); 5.84
(1H, s, H Th); 5.86 (1H, d, J = 8.2, 2-CH); 6.12 (2H, s,
NH2); 6.44 (2H, s, NH2); 7.03–7.07 (2H, m, H Ph); 7.12–
7.17 (3H, m, H Ph). 13C NMR spectrum, δ, ppm: 12.5;
14.6; 41.8; 68.0; 86.2; 92.5; 117.2; 125.9; 126.5; 127.2;
127.4; 132.0; 133.1; 134.3; 136.5; 153.9; 162.5; 169.6.
Mass spectrum, m/z (Irel, %): 362 [M]+ (30). Found, %:
C 66.09; H 5.08; N 15.29. C20H18N4OS. Calculated, %:
C 66.28; H 5.01; N 15.46.
The reported study was funded by the Russian
Foundation for Basic Research (according to the research
project No. 16-33-60156 mol_a_dk).
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spectrum, δ, ppm (J, Hz): 1.87 (3H, s, CH3); 2.15 (3H, s,
CH3); 2.23 (3H, s, CH3); 2.27 (3H, s, CH3); 4.50 (1H, d,
J = 8.0, 3-CH); 5.80 (1H, d, J = 8.0, 2-CH); 5.87 (2H, br. s,
H Th); 6.10 (2H, s, NH2); 6.41 (2H, s, NH2). 13C NMR
spectrum, δ, ppm: 12.1; 12.4; 14.5; 14.6; 41.1; 68.0; 81.5;
92.5; 117.3; 125.1; 125.8; 132.5 (2C); 133.0; 133.1; 133.3;
133.9; 153.9; 162.5; 169.6. Mass spectrum, m/z (Irel, %):
396 [M]+ (21). Found, %: C 60.37; H 5.14; N 13.97.
C20H20N4OS2. Calculated, %: C 60.58; H 5.08; N 14.13.
4,6-Diamino-2-(5-chloro-2-methylthiophen-3-yl)-3-(2,5-
dimethylthiophen-3-yl)-2,3-dihydrofuro[2,3-b]pyridine-
5-carbonitrile (5d). Yield 142 mg (68%), white powder,
mp 245–246°С (decomp.). IR spectrum, ν, cm–1: 3446,
1
3352 (NH2), 2203 (C≡N). H NMR spectrum, δ, ppm
(J, Hz): 1.92 (3H, s, CH3); 2.24 (3H, s, CH3); 2.33 (3H, s,
CH3); 4.53 (1H, d, J = 8.0, 3-CH); 5.86 (1H, d, J = 8.0,
2-CH); 5.89 (1H, s, H Th); 6.08 (1H, s, H Th); 6.19 (2H, s,
NH2); 6.45 (2H, s, NH2). 13C NMR spectrum, δ, ppm: 12.4;
12.6; 14.7; 41.2; 68.3; 81.0; 92.4; 117.3; 122.7; 125.1;
125.2; 126.3; 132.7; 133.2; 133.8; 135.1; 154.1; 162.7;
169.5. Mass spectrum, m/z (Irel, %): 416 [M(35Cl)]+ (26).
Found, %: C 54.53; H 4.19; N 13.31. C19H17ClN4OS2.
Calculated, %: C 54.73; H 4.11; N 13.44.
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4,6-Diamino-2-(2,5-dimethylthiophen-3-yl)-3-(thiophen-
2-yl)-2,3-dihydrofuro[2,3-b]pyridine-5-carbonitrile (5e).
Yield 98 mg (53%), white powder, mp 185–186°С (decomp.).
450