A serendipitous conversion of enaminolactone nitriles with primary amines: A new synthesis of substituted 2-aminopyridine derivatives

Article abstract of DOI:10.1016/j.tet.2012.10.108

In the course of our studies on Cerpegin analogues synthesis, a serendipitous reactivity of enaminolactone nitrile has been observed. Instead of expecting iminocerpegins, we have gained new class of substituted 2-aminopyridines. The methodology has been applied on a wide range of primary amines, as aliphatic, aromatic, heteroaromatic and also, diamines, hydrazines and chiral amines.

Full text of DOI:10.1016/j.tet.2012.10.108

Tetrahedron 69 (2013) 1234e1247
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A serendipitous conversion of enaminolactone nitriles with primary
amines: a new synthesis of substituted 2-aminopyridine derivatives
,
b
,
,
a
a,d
Nawel Cheikh a c, Didier Villemin a , Nathalie Bar , Jean-Franc¸ ois Lohier
,
*
Nourredine Choukchou-Braham b, Bachir Mostefa-Kara b, Jana Sopkova d
Laboratoire de Chimie Moleculaire et Thioorganique, UMR CNRS 6507, INC3M, FR 3038, ENSICAEN et Universite de Caen Basse-Normandie, 14050 Caen, France
Laboratoire de Catalyse et Synthese en Chimie Organique, Faculte des Sciences, Universite Abou-Bakr Belkaid, BP 119, 13000 Tlemcen, Algeria
Universite de Bechar, Faculte des Sciences et Technologies, BP 417, 08000 Bechar, Algeria
a
ꢀ
ꢀ
b
c
ꢁ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
d
ꢀ
ꢀ
Centre d’Etudes et de Recherche sur le Medicament de Normandie (CERMN), Universite de Caen, boulevard Henri Becquerel, F-14032 Caen, France
a r t i c l e i n f o
a b s t r a c t
Article history:
In the course of our studies on Cerpegin analogues synthesis, a serendipitous reactivity of enamino-
lactone nitrile has been observed. Instead of expecting iminocerpegins, we have gained new class of
substituted 2-aminopyridines. The methodology has been applied on a wide range of primary amines, as
aliphatic, aromatic, heteroaromatic and also, diamines, hydrazines and chiral amines.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 11 September 2012
Received in revised form 11 October 2012
Accepted 16 October 2012
Available online 21 November 2012
Keywords:
Cerpegin
2-Aminopyridine
Enaminolactone nitrile
Solvent free
1. Introduction
providing enaminolactone ester 3 with good yields. In a second
time, the reaction between enaminolactones 3 and various primary
The fascinating chemistry of enaminones and their derivatives
has attracted the attention of numerous researchers due to their
potential properties in the synthesis of heterocyclic compounds.1,2
They are known to react as diene ‘pushepull’ with nucleophilic or
electrophilic reagents and they can be good candidates for
cycloadditions.
Since the discovery of N,N-dimethylformamide diethylacetal
(DMFDEA), synthesized for the first time by Meerwein,3 several
applications of formamide acetals were appeared in literature, in
particular as formylating agent for the preparation of enamines
using usually active methylene ketones.4e6
amines were easily performed without solvent under thermal
heating leading to Cerpegin and derivatives.7
In this context and in continuation of our work, we were in-
terested to develop efficient and easy methods for the preparation
of new biologically active heterocyclic compounds, in particular
new Cerpegin analogues, starting from another class of furanones,
the butenolide nitriles.
2. Results and discussion
The synthesis of new analogues of Cerpegin begins by the
Recently, in a previous work, we have reported the successful
synthesis of Cerpegin and derivatives 1.7 The Cerpegin is an alkaloid
extracted from Ceropegia juncea in 1990,8 which is a plant used in
traditional Indian pharmacopeia and well-known for its tranquil-
lizing, anti-inflammatory, analgesic, and antiulcer properties.9 The
Cerpegin and derivatives 1 synthesis was based on two steps: ini-
tially, the reaction began with the condensation of butenolide ester
2 and DMFDEA at room temperature under solvent free conditions
preparation of butenolide nitriles 4. These latter were easily ob-
tained, in cascade reaction, from
a-hydroxyketones 5 and ethyl
cyanoacetate in the presence of base like EtONa/EtOH,7,10,11
K2CO3,12,13 or CsCO3.14 We have shown that these bases could be
favourably substituted by Al2O3/KF15,16 as basic support, less ex-
pensive and easy to prepare and to handle. The reaction was carried
out in solvent free conditions for 3 h and gave good yields (80e89%)
(Table 1).
In connection with our previous work shown in Scheme 1, and
in the aim of obtaining new analogues of Cerpegin like imino-
cerpegin 7, we have decided to perform the reaction of butenolide
* Corresponding author. Tel.: þ33 231 45 28 40; fax: þ33 231 45 28 77; e-mail
address: villemin@ensicaen.fr (D. Villemin).
nitriles 4 with DMFDEA in order to obtain corresponding
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.108

N. Cheikh et al. / Tetrahedron 69 (2013) 1234e1247
1235
Table 1
Preparation of butenolide nitrile 4aec
O
CN
CO2Et
CN
Al2O3/KF
R1
R2
+
R1
R2
without solvent, RT
OH
O
O
5a-c
4a: R1 = R2 = Me
4b: R1 = Me, R2 = Et
4c: R1 = R2 = -(CH2)5-
Entry
1
Hydroxyketone
Butenolide
Yield [%]
O
CN
O
5a
89
80
4a
OH
O
O
CN
5b
5c
4b
2
3
O
OH
O
O
CN
O
4c
86
OH
O
R
N
N
CO2Et
CO2Et
O
RNH2
DMFDEA
R1
R2
R1
R2
R1
R2
O
O
O
O
O
O
3
2
1
Cerpegin: R1 = R2 = R = Me
Scheme 1. Synthesis of Cerpegin and derivatives.
enaminolactone nitriles 6. These latter were expecting to be con-
vert in iminocerpegins 7 when treated with various primary
amines (Scheme 2).
The enaminobutenolide nitriles 6aec were obtained by conden-
sation of 4-methyl-5,5-dialkyl-2-oxo-2,5-dihydrofuran-3-carboni-
triles 4aec with dimethylformamide diethylacetal DMFDEA in stoi-
chiometric amounts. The reactions were performed without solvent
and at room temperature during 1 h. The reactions afforded good
yields of 6aec (66e81%). The results obtained for the preparation of
enaminobutenolide nitriles 6aec are reported in Table 2.
The values of the coupling constants (12.6, 13.0 Hz) in 1H NMR
showed the ‘E’ configuration of the double bond. Also, the X-ray
single-crystal diffraction analysis of 4-(2-(dimethylaminovinyl)-
2,5-dihydro-5,5-dimethyl-2-oxofuran-3-carbonitrile) 6a confirmed
N
R
N
CN
CN
NH
R1
R2
R1
R2
R1
R2
O
O
O
O
O
O
7
6
4
Scheme 2. Retrosynthetic scheme of preparation of iminocerpegin and derivatives.

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N. Cheikh et al. / Tetrahedron 69 (2013) 1234e1247
Table 2
Preparation of enaminobutenolide nitriles 6aec with DMFDEA under free solvent conditions
N
CN
CN
DMFDEA
R1
R1
R2
R2
O
O
without solvent, RT
O
O
4a: R1 = R2 = Me
6a: R1 = R2 = Me
4b: R1 = Me, R2 = Et
6b: R1 = Me, R2 = Et
6c: R1 = R2 = -(CH2)5-
4c: R1 = R2 = -(CH2)5-
Entry
Butenolide
Enaminobutenolide
Yield [%]
N
CN
4a
1
81
CN
O
6a
6b
O
O
O
O
N
N
CN
4b
2
66
CN
O
O
O
CN
O
3
73
4c
CN
O
6c
O
O
the configuration E for the double bond and moreover showed the
conformation ‘s-cis’ for the two carbonecarbon double bonds
(Fig. 1a and b).
The crystal packing of 9d displays one intramolecular NeH/O
hydrogen-bond between O2 and H2 and one intermolecular
NeH/..N hydrogen-bond (N3eH3/N1) leading to infinite helices
of aminopyridine along the b axis.
Furthermore, HMBC experiments of compound 9d have con-
firmed a correlation between the amine proton (NH) with a meth-
ylene carbon (CH2) in the structure of aminopyridine, which is not
possible with a structure of iminocerpegin.
Similarly, all the compounds prepared 9aeh from primary
amines were characterized by 1H and 13C NMR spectroscopy and
they showed similar results. So, the synthesis of 2-aminopyridines
instead of iminocerpegins seems to be general (Scheme 4).
These results could constitute a convenient and effective syn-
thesis of new 2-aminopyridines 9, which belong to a very impor-
tant class of heterocyclic compounds.
The class of 2-aminopyridine presents a wide range of applica-
tions that are receiving considerable attention in the literature. This
functional group, because of its chelating abilities, is commonly
used as ligands in inorganic and organometallic chemistry. Addi-
tionally, aminopyridines have been shown to be biologically active
molecules, they constitute an important class of heterocyclic
compounds founding in numerous natural and pharmaceutical
The diagram of the X-ray crystal showed that the substructure of
(CH3)2NCH]CHeC]CeCN is plane involving the pushepull diene
is conjugated. This effect was already found with the corresponding
ester derivative.7 The crystal packing of 6a shows two weak in-
termolecular CeH/X (N and O) hydrogen-bonds. The first one
occurs between N1 and H6 to form infinite columns of molecules
along a axis. Hydrogen-bond between O2 and H7 reinforces the
crystal structure in the b axis direction.
After the formation of enaminolactone 6aec, the next step was
the subsequent ring-closure to the iminocerpegin 7. The conden-
sation of enaminolactone nitriles with various primary amines was
carried out in stoichiometric amounts in solvent free conditions
and with thermal heating expecting the synthesis of iminocerpe-
gins 7 (Scheme 2).
Surprisingly, the X-ray diffraction analysis of the product ob-
tained by reaction between enaminolactone nitrile 6a and trypt-
amine 8d showed the formation of a 2-aminopyridine structure 9d
(Scheme 3 and Fig. 2) rather than the expected structure of imi-
nocerpegin 7 (Fig. 2).

N. Cheikh et al. / Tetrahedron 69 (2013) 1234e1247
1237
In this work, 2-aminopyridines 9aeh were prepared from
a wide variety of primary amines as aliphatic, aromatic, and het-
erocyclic amines like tryptamine 8d and histamine 8e (Table 3).
These two latter were tested in the aim of gaining new structures,
which could exhibit pronounced biological activities.
Pleasingly, all the primary amines tested gave excellent yields
(75e95%) of the desired products under the conditions described
previously. The results in Table 3 show that this protocol can be
applied to a variety of substrates, thus demonstrating the wide
scope of this methodology.
Based on these results above, a possible mechanism for the
formation of 2-aminopyridine was depicted in Scheme 5. Firstly,
intermediate A was formed via an initial addition reaction be-
tween primary amines and the nitrile group of the enamino-
lactone 6.
A then underwent an intramolecular cyclization reaction be-
tween the nitrogen group of imine anion and the double bond of
the enamine accompanied by the departure of dimethylamine
(CH3)2NH. B was transformed in 2-substituted aminopyridines 9
after an aromatization step, which constitutes probably the driving
force of the reaction (Scheme 5).
The addition of primary amine can take on the carbon 2 (ad-
dition 1,2) or 4 (addition 1,4) or 6 (addition 1,6) on the system
aminodienenitrile of 6. All these additions are reversible (addition
of Michael on carbon 4 or carbon 6), however only the addition on
the nitrile group of the carbon 2 is followed by an intramolecular
ring formation. Moreover, in order to justify our mechanism, we
have done some computation. The amine is a hard nucleophile, so
we have used the chelpg obtained by DFT to determinate the more
electrophilic carbon. The carbon 2 of the nitrile (0.437) seems
more electrophilic than the carbon 4 (0.103) and the carbon 6
(0.050).
In view of the success of this approach, diamines were tested in
the aim of obtaining new original polycyclic compounds, bis(2-
aminopyridines). These dimer compounds were obtained by con-
densation of 1 equiv of diamines 10aef with 2 equiv of enamino-
lactone nitrile 6a,b. The mixture was refluxed in DMF during 6 h.
After removing of the solvent and purification by column chro-
matography, we afforded the new original bis-(2-aminopyridines)
11aeg in moderate to good yields (Table 4).
All the structures obtained present at least four cycles, many
suitable locating nitrogen and oxygen atoms, allowing them to be
very good chelating candidates.
Next, we have decided to study the extension of this
method with hydrazines 12a,b. In a similar manner to the forma-
tion of 2-aminopyridine, the enaminolactone nitriles 6a,b were
reacted with methylhydrazine 12a and hydrazine 12b under sol-
vent free conditions for giving new heterocyclic compounds con-
taining in their structure three atoms of nitrogen, named 2-
hydrazinopyridines 13aec in excellent yields (81e95%) as sum-
marized in Table 5.
The structure of the 4-(2-methylhydrazinyl)-1,1-dimethylfuro
[3,4-c]pyridin-3(1H)-one 13a was confirmed by X-ray crystallog-
raphy. The ORTEP diagram is shown in Fig. 3a.
The crystal packing of 13a is governed by two intramolecular
hydrogen-bonds: one between O2 and H2 to form a six-membered
ring and one between N1 and H3 to give a five-membered ring. The
structure also displays two NeH/H intermolecular H-bonds. In
fact, N3 acts as hydrogen-bond acceptor to H2 but as well as
hydrogen-bond donor, through H3, to N1 from another molecule to
give infinite columns along c axis.
Finally, all those important results have encouraged us for the
synthesis of new chiral substituted 2-aminopyridines. For this
reason, we thought of adding enantiopure chiral amines 14aei in
the same manner with enaminolactone nitrile 6a. The reaction
Fig. 1. a. Diagram of the X-ray crystal structure of compound 6a. b. The crystal packing
of 6a.
products that exhibit remarkable biological activities. For all these
reasons, 2-aminopyridines are valuable synthetic targets.
Today a number of synthetic routes have been reported for the
synthesis of 2-aminopyridines derivatives.17e24 Yet, a versatile
route for the synthesis of N-substituted 2-aminopyridines using
amines as nucleophilic agents under mild conditions is highly
desirable.
was refluxed in DMF for
6 h. The purification by column

1238
N. Cheikh et al. / Tetrahedron 69 (2013) 1234e1247
N
H
N
H
N
N
CN
N
H
+
without solvent
H2N
O
O
O
O
8d
6a
9d
Scheme 3. Synthesis of 2-aminopyridine 9d.
enantiomers from each other. This allowed us to deduce that the
operating conditions are not racemating.
We also have tested an aminoacid, -phenylalanine 14i as chiral
L
amine in the aim of gaining new 2-(aminoacids)pyridines. Sur-
prisingly, the product of the reaction was decarboxylated affording
an achiral compound 15i, restringing seemingly the interest of
reaction.
However, this example permits us to confirm our proposed
mechanism in Scheme 6: the observed decarboxylation step in-
volved the formation of an imino bond of the phenylalanine, which
can be shown in the intermediate C (Scheme 6).
The structures of the 4-(2-methylhydrazinyl)-1,1-dimethylfuro
[3,4-c]pyridin-3(1H)-one 15a and 15f were confirmed by X-ray
crystallography. The ORTEP diagrams are shown in Figs. 4 and 5.
From these results, we can conclude that using enantiopure
amines can serve to produce chiral auxiliaries or chiral ligands
useful in asymmetric synthesis.
3. Conclusion
In summary, we have successfully developed a novel and effi-
cient approach for the synthesis of new original heterocyclic
compounds of substituted 2-aminopyridines via the treatment of
enaminolactone nitriles with a wide variety of amines (primary
amines, diamines, alkylhydrazines, and chiral amines), under very
mild conditions. This method provides high yields of products with
high selectivity affording a useful and attractive strategy for the
preparation of chelating and biologically active 2-substituted
aminopyridines from available building blocks. To the best of our
knowledge there are no reports in literature for the synthesis of
these types of heterocyclic compounds.
Fig. 2. a. Diagram of the X-ray crystal structure of compound 9d. b. The crystal packing
of 9d.
4. Experimental section
4.1. General information
chromatography afforded new chiral 2-aminopyridines 15aei in
good yields (52e85%) (Table 6).
Melting points were recorded on a Kofler apparatus and were
uncorrected. IR spectra were obtained with solids or neat liquids
with a Fourier transform PerkineElmer Spectrum One with ATR
accessory. Only significant absorptions are listed. NMR spectra
were recorded at 250 MHz for 1H NMR and 62.9 MHz for 13C
NMR with a ‘Bruker AC 250’ spectroctrometer in 250 MHz, CDCl3
We have used commercially enantiopure primary amines to
prepare chiral 2-aminopyridines 15aei. As shown in Table 6, all the
products are optically active. The values of optical rotations of
phenylethylamine 15a and 15b are very interesting because
they are similar with opposite signs, explaining that they are
and DMSO-d6; d-values are in parts per million relative to tet-
ramethylsilane as an internal standard. Mass spectra were
recorded on a QTOF Micro (Waters), ionization electrospray
positive (ESI), lockspray PEG, infusion introduction (5 mL/min),
source temperature 80 ꢀC, desolvatation temperature 120 ꢀC.
N
R
NH
N
CN
RNH2
R1
R2
Al2O3/KF was prepared through
a protocol described by
R1
R2
Villemin.25
O
O
O
O
Computational details: full geometry optimization for 6a and
computation of chelpg have been performed at the B3LYP/6-31G(d)
level of theory, which is the implemented in Gaussian 03 Rev02
package of programs.
6
9
Scheme 4. Synthesis of 2-aminopyridines derivatives.

N. Cheikh et al. / Tetrahedron 69 (2013) 1234e1247
1239
Table 3
Preparation of substituted 2-aminopyridines 9aeh by reaction of enaminobutenolide nitriles 6a,b and primary amines 8aef under free solvent conditions
N
N
CN
NHR
RNH2
8a-f
R1
R2
R1
R2
O
O
O
O
6a: R1 = R2 = Me
9a-h
6b: R1 = Me, R2 = Et
Entry
1
Enaminolactone
RNH2
Product
Yield [%]
N
6a
NH2
95
86
87
N
H
8a
9a
9b
O
O
N
2
3
6a
6a
NH2
N
8b
H
O
O
N
9c
8c
N
H
NH2
O
O
O
H
N
N
NH2
4
6a
92
8d
9d
N
H
HN
N
O
N
N
N
NH
NH2
NH2
8e
5
6
7
8
6a
6a
6b
6b
94
75
86
87
N
H
HN
9e
O
O
O
N
NH
8f
N
N
H
HN
9f
O
N
9g
NH2
N
8b
H
O
O
H
N
N
NH2
8d
9h
N
H
HN
O
O
4.2. Synthesis of substituted 2-aminopyridines
cyanoacetate (2.26 g, 20 mmol) was adsorbed on KF-alumina (3 g)
and then stirred at room temperature without solvent for 3 h. The
mixture was extracted with diethylether (3ꢁ20 mL). The combined
organic layers were subsequently washed with water, dried on
4.2.1. General procedure 1 for the synthesis of butenolide nitriles
4aec. A mixture of -hydroxyketone 5aec (20 mmol) and ethyl
a

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N. Cheikh et al. / Tetrahedron 69 (2013) 1234e1247
N
H
N
N
NH
NH
C
N
C
N
N
H
N
H
R
N
R
RNH2
N
N
R
R
O
O
O
O
O
O
O
O
O
O
A
B
9
6
Scheme 5. Plausible mechanism for the synthesis of 2-substituted aminopyridines 9.
Table 4
Preparation of bis-aminopyridines 11aeg from diamines 10aef
N
N
N
R1
NH2
R1
CN
H2N
10a-f
R2
R2
R1
R2
N
H
N
H
DMF, reflux
O
O
O
O
O
O
11a-g
6a-b
Entry
1
Product
Yield [%]
83
H2N
NH2
10a
N
N
NHHN
6a
6a
6a
6a
11a
H2N NH2
O
O
O
O
N
N
11b
10b
2
3
4
36
83
82
N
H
N
H2N
NH2
H
O
O
O
O
O
N
N
11c
NH2
( )
10c
N
H
4 N
H
H2N
O
O
O
N
N
10d
NH2
H2N
11d
N
N
H
H
O
O
O
O
N
N
5
6a
10e
52
NHHN
11e
H2N NH2
O
O
O
O
N
N
11f
10f
6
7
6a
6b
35
85
N
N
H2N
NH2
H
H
O
O
O
O
N
N
11g
10b
N
N
H2N
NH2
H
H
O
O
O
O

N. Cheikh et al. / Tetrahedron 69 (2013) 1234e1247
1241
Table 5
Synthesis of 2-hydrazinopyridines 13aec
N
NHR
NH
N
CN
RNHNH2 12a-b
R1
R1
R1
R2
without solvent
O
O
O
O
6a-b
13a-c
Entry
1
Enaminolactone
RNHNH2
N-Aminopyridine
Yield [%]
N
HN
NH
6a
CH3NHNH2
12a
12a
81
95
13a
O
O
N
HN
NH
2
3
6b
6b
CH3NHNH2
13b
13c
O
O
N
NH2
NH
NH2NH2
12b
90
O
O
MgSO4, and concentrated to obtain 2,5-dihydro-4,5,5-trimethyl-2-
on MgSO4. The solvent was removed under vacuum providing
oxofuran-3-carbonitrile 4aec.
a yellow solid of enaminolactone nitriles 6aec.
4.2.1.1. 2,5-Dihydro-4,5,5-trimethyl-2-oxofuran-3-carbonitrile
4a. The general procedure 1 using (2.04 g, 20 mmol) of 3-hydroxy-
3-methylbutan-2-one 5a gave (2.70 g, 89%) of 4a as white solid, mp
4.2.2.1. 4-(E)-2-(Dimethylaminovinyl)-2,5-dihydro-5,5-dimethyl-
2-oxofuran-3-carbonitrile 6a. The general procedure
2 using
(0.76 g, 5 mmol) of 2,5-dihydro-4,5,5-dimethyl-2-oxofuran-3-
carbonitrile 4a, gave (0.84 g, 81%) of 6a as yellow solid, mp
170e172 ꢀC. IR nmax (neat/cmꢂ1): 2208, 1721, 1624, 1556, 1205. 1H
60e61 ꢀC. IR nmax (cmꢂ1): 2239, 1763, 1651. 1H NMR (CDCl3)
d
2.32
(3H, s, CH3), 1.54 (6H, s, 2ꢁ CH3). 13C NMR (CDCl3)
d 184.8, 165.5,
110.7, 104.6, 88.4, 24.4, 13.9.
NMR (CDCl3)
d
8.08 (1H, d, 3J¼12.6 Hz, CH]CHeN), 4.76 (1H, d,
3J¼12.6 Hz, CH]CHeN), 3.26 (3H, s, NCH3), 3.01 (3H, s, NCH3), 1.48
4.2.1.2. 2,5-Dihydro-4-ethyl-5,5-trimethyl-2-oxofuran-3-carboni-
trile 4b. The general procedure 1 using (2.32 g, 20 mmol) of 3-
hydroxy-3-methylpentan-2-one 5b, gave (2.65, 80%) of 4b as vis-
cous liquid, bp 129 ꢀC/5 mtorr. IR nmax (cmꢂ1): 2239, 1764, 1650. 1H
(6H, s, 2ꢁ CH3). 13C NMR (CDCl3)
d 177.8, 169.3, 154.0, 116.4, 104.9,
86.7, 85.6, 46.2, 37.1, 26.5. MS m/z (% relative abundance): 207
(MþH, 30), 189 (68), 164 (100), 134 (95). HRMS (ES-QTOF) calcd for
C
11H14N2O2Na MþNa 229.0953. Found 229.0953.
NMR (CDCl3) d 2.29 (3H, s, C]CeCH3), 2.07e1.71 (2H, m, CH2), 1.53
(3H, s, CCH3), 0.83 (3H, t, 3J¼7.5 Hz, CH2CH3). 13C NMR (CDCl3)
4.2.2.2. 4-(E)-2-(Dimethylaminovinyl)-5-ethyl-2,5-dihydro-5-
d
184.3, 165.7, 110.6, 105.0, 90.9, 30.2, 22.9, 14.2, 7.1.
methyl-2-oxofuran-3-carbonitrile 6b. The general procedure 2 us-
ing (106 mg, 5 mmol) of 5-ethyl-2,5-dihydro-4,5-dimethyl-2-
oxofuran-3-carbonitrile 4b, gave (73 mg, 66%) of 6b as yellow
solid, mp 97e98 ꢀC. IR nmax (neat/cmꢂ1): 2202, 1716, 1622, 1556,
4.2.1.3. 2,5-Dihydro-4-methyl-5,5-pentamethylene-2-oxofuran-
3-carbonitrile 4c. The general procedure 1 using (2.84 g; 20 mmol)
of 1-(1-hydroxy-cyclohexyl)ethanone 5c, gave (3.30 g, 86%) of 4c
as white solid, mp 119e120 ꢀC. IR nmax (cmꢂ1): 2236, 1764, 1650.
1199. 1H NMR (CDCl3)
d
8.09 (1H, d, 3J¼12.5 Hz, CH]CHeN), 4.75
(1H, d, 3J¼13.0 Hz, CH]CHeN), 3.26 (3H, s, NCH3), 3.00 (3H, s,
NCH3), 1.94e1.65 (2H, m, CH2), 1.63 (3H, s, CCH3), 0.81 (3H, t,
1H NMR (CDCl3):
13C NMR (CDCl3)
14.0.
d
2.28 (3H, s, CH3), 1.34e1.22 (10H, m, 5ꢁ CH2).
d
184.4, 165.6, 110.6, 104.6, 89.9, 33.1, 24.1, 21.4,
3J¼7.2 Hz, CH2CH3). 13C NMR (CDCl3)
d 176.6, 169.6, 153.8, 116.3,
88.2, 86.6, 46.1, 37.1, 32.0, 25.4, 7.3. MS m/z (% relative abundance):
221 (MþH, 50), 203 (45), 191 (95), 175 (66), 148 (100). HRMS (ES-
QTOF) calcd for C12H16N2O2Na MþNa 243.1109. Found 243.1115.
4.2.2. General procedure 2 for the synthesis of 4-(E)-2-(dimethyla-
minovinyl)-2,5-dihydro-5,5-dialkyl-2-oxofuran-3-carbonitrile
6aec. DMFDEA (0.73 g, 5 mmol) was added to the 4-methyl-5,5-
dialkyl-2-oxo-2,5-dihydrofuran-3-carbonitrile 4aec (5 mmol).
The mixture was stirred at room temperature without solvent
during 1 h. Ethyl acetate (20 mL) was added to the crude reaction
mixture. The organic layer was washed with water, brine and dried
4.2.2.3. 4-(E)-2-(Dimethylaminovinyl)-2,5-dihydro-5,5-pentame-
thylene-2-oxofuran-3-carbonitrile 6c. The general procedure 2 using
(95 mg,
5 mmol) of 4-methyl-2,5-dihydro-4,5-dimethyl-5,5-
pentamethylene-2-oxofuran-3-carbonitrile 4c, gave (90 mg, 73%)
of 6c as yellow solid, mp 182e183 ꢀC. IR nmax (neat/cmꢂ1): 2202,

1242
N. Cheikh et al. / Tetrahedron 69 (2013) 1234e1247
4.2.3.1.1. 1,1-Dimethyl-4-(propylamino)furo[3,4-c]pyridin-3(1H)-
one 9a. The general procedure 3 using (300 mg,1.45 mmol) of 4-(E)-
2-(dimethylaminovinyl)-2,5-dihydro-5,5-dimethyl-2-oxofuran-3-
carbonitrile 6a and (86 mg, 1.45 mmol) of propylamine 8a
gave (303 mg, 95%) of 9a as viscous oil. IR nmax (neat/cmꢂ1):
3392, 1730, 1616, 1590, 1524. 1H NMR (CDCl3)
d 8.15 (1H, d,
3J¼5.2 Hz, CH]CHeN), 6.42 (1H, s large, NH), 6.39 (1H, d,
3J¼5.2 Hz, CH]CHeN), 3.39 (2H, td, 3J¼5.8 Hz, 3J¼7.1 Hz,
CH2CH2CH3), 1.57 (2H, sextuplet, 3J¼7.3 Hz, CH2CH3), 1.48 (6H, s,
2ꢁ CH3), 0.87 (3H, t, 3J¼7.3 Hz, CH2CH3). 13C NMR (CDCl3)
d 170.4,
165.6, 156.4, 154.5, 103.6, 102.7, 85.2, 42.3, 26.4, 22.8, 11.4. EIMS
m/z (% relative abundance): 221 (MþH, 67), 203 (100), 185 (52),
179 (58), 161 (89). HRMS (ES-QTOF) calcd for
C15H18NO3
C12H17N2O2 MþH 221.1290. Found 221.1294.
4.2.3.1.2. 4-(Allylamino)-1,1-dimethylfuro[3,4-c]pyridin-3(1H)-
one 9b. The general procedure 3 using (300 mg,1.45 mmol) of 4-(E)-
2-(dimethylaminovinyl)-2,5-dihydro-5,5-dimethyl-2-oxofuran-3-
carbonitrile 6a and (83 mg, 1.45 mmol) of allylamine 8b gave
(272 mg, 86%) of 9b as yellow solid, mp 82e84 ꢀC. IR nmax (neat/
cmꢂ1): 3396, 1732, 1617, 1592, 1524. 1H NMR (CDCl3)
d 8.26 (1H, d,
3J¼5.2 Hz, CH]CHeN), 6.42 (1H, s large, NH), 6.40 (1H, d, 3J¼5.1 Hz,
3
3
CH]CHeN), 5.96 (1H, ddt, Jtrans¼17.2 Hz, Jcis¼10.3 Hz,
3J¼5.4 Hz, CH]CHaHb), 5.26 (1H, dq, 3Jtrans¼17.2 Hz, 4J¼2J¼1.6 Hz,
CH]CHaHb), 5.14 (1H, dq, 3Jcis¼10.3 Hz, 4J¼2J¼1.6 Hz, CH]CHaHb),
4.19 (2H, tt, 3J¼5.4 Hz, 4J¼1.6 Hz, CH2CH]CH2), 1.59 (6H, s, 2ꢁ
CH3). 13C NMR (CDCl3)
d 170.3, 165.7, 156.1, 154.5, 134.3, 116.2,
104.0, 102.9, 85.6, 42.8, 26.5. EIMS m/z (% relative abundance): 219
(MþH, 75), 201 (100), 173 (24). HRMS (ES-QTOF) calcd for
C
C
12H15N2O2 MþH 219.1134. Found 219.1126. Anal. Calcd for
12H15N2O2: C, 66.04; H, 6.47; N, 12.84. Found: C, 66.12; H, 6.78; N,
12.98%.
4.2.3.1.3. 4-(Benzylamino)-1,1-dimethylfuro[3,4-c]pyridin-3(1H)-
one 9c. The general procedure 3 using (300 mg,1.45 mmol) of 4-(E)-
2-(dimethylaminovinyl)-2,5-dihydro-5,5-dimethyl-2-oxofuran-3-
carbonitrile 6a and (155 mg, 1.45 mmol) of benzylamine 8c gave
(338 mg, 87%) of 9c as yellow solid, mp 183e184 ꢀC. IR nmax (neat/
cmꢂ1): 3414, 1733, 1619, 1591, 1523. 1H NMR (CDCl3)
d 8.30 (1H, d,
3J¼5.2 Hz, CH]CHeN), 7.39e7.28 (5H, m, Harom), 6.83 (1H, s large,
NH), 6.53 (1H, d, 3J¼5.2 Hz, CH]CHeN), 4.78 (2H, d, 3J¼5.9 Hz,
CH2Ph), 1.61 (6H, s, 2ꢁ CH3). 13C NMR (CDCl3)
d 170.3, 165.6, 156.1,
154.5, 139.1, 128.9, 127.2, 126.6, 104.0, 103.0, 85.4, 44.2, 26.9. EIMS
m/z (% relative abundance): 269 (MþH, 33), 191 (12), 173 (10), 91
(100). HRMS (ES-QTOF) calcd for C16H17N2O2 MþH 269.1290.
Found 269.1292. Anal. Calcd for C16H17N2O2: C, 71.62; H, 6.01; N,
10.44. Found: C, 69.57; H, 6.15; N, 10.38%.
4.2.3.1.4. 4-(2-(1H-Indol-3-yl)ethylamino)-1,1-dimethylfuro[3,4-
c]pyridin-3(1H)-one 9d. The general procedure 3 using (300 mg,
1.45 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-
dimethyl-2-oxofuran-3-carbonitrile 6a and (232 mg, 1.45 mmol)
of tryptamine 8d gave (428 mg, 92%) of 9d as white solid, mp
161e163 ꢀC. IR nmax (neat/cmꢂ1): 3392, 3163, 1738, 1620, 1587, 1520.
Fig. 3. a. ORTEP diagram of the X-ray crystal structure of compound 13a. b. The crystal
packing of 13a.
1716, 1614, 1532, 1210. 1H NMR (CDCl3)
d
8.17 (1H, d, 3J¼12.7 Hz,
CH]CHeN), 4.72 (1H, d, 3J¼13.0 Hz, CH]CHeN), 3.25 (3H, s,
NCH3), 3.00 (3H, s, NCH3), 1.81e1.21 (10H, m, 5ꢁ CH2). 13C NMR
1H NMR (CDCl3)
d
8.30 (1H, d, 3J¼5.1 Hz, CH]CHeN), 8.17 (1H, s
large, NHindol), 7.64 (1H, d, 3J¼7.7 Hz, CHNH), 7.38e7.11 (4H,
m, Harom), 6.63 (1H, t, 3J¼4.6 Hz, NHCH2), 6.48 (1H, d, 3J¼5.1 Hz,
CH]CHeN), 3.87 (2H, td, 3J¼4.6 Hz, 3J¼6.9 Hz, NHCH2CH2), 3.13
(2H, t, 3J¼6.9 Hz, NHCH2CH2), 1.58 (6H, s, 2ꢁ CH3). 13C NMR (CDCl3)
(CDCl3)
d 177.6, 169.7, 154.1, 116.7, 104.0, 87.5, 87.0, 46.2, 37.1, 35.1,
24.6, 21.8. MS m/z (% relative abundance): 247 (MþH,100), 229 (80),
203 (50), 174 (59). HRMS (ES-QTOF) calcd for C14H18N2O2Na MþNa
269.1266. Found 269.1259.
d
170.4, 165.6, 156.3, 154.5, 136.5, 127.3, 122.2, 122.1, 119.34, 118.8,
4.2.3. Synthesis of 2-aminopyridine derivatives
113.0, 111.2, 103.7, 102.9, 85.3, 40.8, 26.4, 25.3. EIMS m/z (% relative
abundance): 322 (MþH, 42), 144 (100). HRMS (ES-QTOF) calcd for
4.2.3.1. General procedure 3 for the synthesis of 2-aminopyridines
9aeh. A mixture of 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-
5,5-dialkyl-2-oxofuran-3-carbonitrile 6a,b (1.45 mmol) and pri-
mary amine 8aeh (1.45 mmol) was heated until homogenization
and the heating was continued for 5 min. The crude product ob-
tained was washed several time with diethylether and purified by
column chromatography (silica gel, ethyl acetate/cyclohexane
(70:30)) to give 2-aminopyridines derivatives 9aeh.
C
19H20N3O2 MþH 322.1556. Found 322.1566. Anal. Calcd for
C19H20N3O2: C, 71.01; H, 5.96; N, 13.08. Found: C, 70.71; H, 6.28; N,
12.99%.
4.2.3.1.5. 4-(2-(1H-Imidazol-4-yl)ethylamino)-1,1-dimethylfuro
[3,4-c]pyridin-3(1H)-one 9e. The general procedure using
3
(300 mg, 1.45 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-
5,5-dimethyl-2-oxofuran-3-carbonitrile 6a and (161 mg,1.45 mmol)

N. Cheikh et al. / Tetrahedron 69 (2013) 1234e1247
1243
Table 6
Preparation of chiral substituted 2-aminopyridines 15aei
Entry
1.
RR0CHNH2
Product
Yield [%]
75
[a]
20 (c 1, CHCl3)
D
ꢂ111.0
þ112.4
2.
75
3.
4.
5.
76
75
71
þ31.3
þ48.6
ꢂ98.3
6.
85
þ80.0
7.
8.
9.
83
52
52
ꢂ244.7
ꢂ230.6
d
of histamine 8e gave (370 mg, 94%) of 9e as yellow solid, mp 150 ꢀC.
IR nmax (neat/cmꢂ1): 3395, 3120, 1735, 1671, 1620, 1592, 1527. 1H
(1H, d, 3J¼5.2 Hz, CH]CHeN), 3.84 (2H, td, 3J¼6.2 Hz, 3J¼6.7 Hz,
NHCH2CH2), 2.96 (2H, t, 3J¼6.7 Hz, NCH2CH2), 1.58 (6H, s, 2ꢁ CH3).
NMR (CDCl3)
d
8.27 (1H, d, 3J¼5.2 Hz, CH]CHeN), 7.58 (1H, s,
13C NMR (CDCl3)
d 170.4,165.7,156.2,154.4,135.3,135.0,116.6,103.9,
NHeCH]N), 6.88 (1H, s, C]CHeNH), 6.72 (1H, s large, NH), 6.49
103.0, 85.4, 40.4, 27.3, 26.4. EIMS m/z (% relative abundance): 273

1244
N. Cheikh et al. / Tetrahedron 69 (2013) 1234e1247
H
N
H
N
Ph
NH
C
N
Ph
N
C
N
CO2H
N
N
N
H2N
CO2H
CO2H
Ph
H
- CO2
Ph
O
O
O
O
O
O
O
O
6
C
N
H
N
Ph
O
O
15i
Scheme 6. Plausible mechanism of preparation of compound 15i.
3J¼5.5 Hz, 3J¼6.3 Hz, NHCH2CH2), 2.88 (4H, t, 3J¼4.7 Hz,
CH2NHCH2), 2.58 (2H, t, 3J¼6.3 Hz, NHCH2CH2), 2.34 (4H, s large,
CH2NCH2), 2.17 (1H, s large, CH2NHCH2), 1.55 (6H, s, 2ꢁ CH3). 13C
NMR (CDCl3) d 170.2, 165.7, 156.2,154.4,103.6,103.0, 85.1, 57.9, 54.3,
46.1, 37.2, 26.5. EIMS m/z (% relative abundance): 291 (MþH, 57),
205 (100). HRMS (ES-QTOF) calcd for C15H23N4O2 MþH 291.1821.
Found 291.1818.
4.2.3.1.7. 4-(Allylamino)-1-ethyl-1-methylfuro[3,4-c]pyridin-
3(1H)-one 9g. The general procedure 3 using (319 mg, 1.45 mmol)
of 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-dimethyl-2-oxo-
furan-3-carbonitrile 6b and (86 mg, 1.45 mmol) of allylamine 8b
gave (289 mg, 86%) of 9g as viscous oil. IR nmax (neat/cmꢂ1): 3395,
1731, 1616, 1590, 1522. 1H NMR (CDCl3)
d
8.23 (1H, d, 3J¼5.1 Hz,
CH]CHeN), 6.55 (1H, s large, NH), 6.44 (1H, d, 3J¼5.1 Hz, CH]
CHeN), 5.94 (1H, ddt, 3Jtrans¼17.1 Hz, 3Jcis¼10.3 Hz, 3J¼5.4 Hz, CH]
CHaHb), 5.23 (1H, dq, 3Jtrans¼17.1 Hz, 4J¼2J¼1.3 Hz, CH]CHaHb), 5.12
(1H, dq, 3Jcis¼10.3 Hz, 4J¼2J¼1.3 Hz, CH]CHaHb), 4.18e4.14 (2H, m,
CH2CH]CH2), 1.88 (HA, HB ABq, JAB¼14.4 Hz, JABq¼7.3 Hz, CHHCH3),
1.53 (3H, s, CH3), 0.75 (3H, t, 3J¼7.3 Hz, CH2CH3). 13C NMR (CDCl3)
Fig. 4. ORTEP diagram of the X-ray crystal structure of compound 15a with thermal
ellipsoids at 50% probability.
d
170.6, 164.5, 156.1, 154.4, 134.4, 116.2, 104.4, 103.8, 88.1, 42.8, 32.1,
24.9, 7.8. EIMS m/z (% relative abundance): 233 (MþH, 94), 215
(100), 200 (12), 197 (23), 187 (24). HRMS (ES-QTOF) calcd for
C
13H17N2O2 MþH 233.1290. Found 233.1294.
4.2.3.1.8. 4-(2-(1H-Indol-3-yl)ethylamino)-1-ethyl-1-methylfuro
[3,4-c]pyridin-3(1H)-one 9h. The general procedure
3 using
(319 mg, 1.45 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-
dihydro-5,5-dimethyl-2-oxofuran-3-carbonitrile 6b and (161 mg,
1.45 mmol) of tryptamine 8d gave (422 mg, 87%) of 9h as yellow
solid. Mp 150 ꢀC. IR nmax (neat/cmꢂ1): 3392, 1738, 1620, 1587,
1520. 1H NMR (CDCl3)
d
8.29 (1H, d, 3J¼5.1 Hz, CH]CHeN), 8.14
(1H, s large, NHindol), 7.65 (1H, d, 3J¼7.6 Hz, C]CHeNH),
7.38e7.09 (4H, m, Harom), 6.63 (1H, s large, NH), 6.44 (1H, d,
3J¼5.1 Hz, CH]CHeN), 3.87 (2H, q, JNHCH ¼ JCH CH ¼6.8 Hz,
Fig. 5. ORTEP diagram of the X-ray crystal structure of compound 15f with thermal
ellipsoids at 50% probability.
2
2
2
NHCH2CH2), 3.13 (2H, t, 3J¼6.8 Hz, NCH2CH2), 1.91 (HA, HB ABq,
JAB¼14.4 Hz, JABq¼7.4 Hz, CHHCH3), 1.56 (3H, s, CH3), 0.79 (3H, t,
(MþH, 55), 191 (14), 179 (56), 95 (100). HRMS (ES-QTOF) calcd for
3J¼7.4 Hz, CH2CH3). 13C NMR (CDCl3)
d 170.7, 164.4, 156.3, 154.4,
C
14H17N4O2 MþH 273.1352. Found 273.1364.
136.5, 127.3, 122.2, 122.1, 119.3, 118.8, 113.0, 111.2, 103.9, 103.8, 87.9,
40.8, 32.1, 25.3, 24.9, 7.8. EIMS m/z (% relative abundance): 336
(MþH, 34), 144 (100). HRMS (ES-QTOF) calcd for C20H22N3O2 MþH
336.1712. Found 336.1703.
4.2.3.1.6. 4-(2-(Piperazin-1-yl)ethylamino)-1,1-dimethylfuro[3,4-
c]pyridine-3(1H)-one 9f. The general procedure 3 using (300 mg,
1.45 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-
dimethyl-2-oxofuran-3-carbonitrile 6a and (187 mg, 1.45 mmol)
of 2-(piperazin-1-yl)ethanamine 8f gave (315 mg, 75%) of 9f as
viscous oil. IR nmax (neat/cmꢂ1): 3394, 3340, 1736, 1671, 1618, 1589,
4.2.3.2. General procedure 4 for the synthesis of bis(2-aminopy-
ridines) 11aeg. To
a solution of 4-(2-dimethylaminovinyl)-5,5-
1523. 1H NMR (CDCl3)
d
8.22 (1H, d, 3J¼5.1 Hz, CH]CHeN), 6.90
dimethyl-2-oxo-2,5-dihydrofuran-3-carbonitrile 6a,b (2.90 mmol)
dissolved in DMF was added diamine 10aeh (1.45 mmol). The
(1H, s large, NH), 6.44 (1H, d, 3J¼5.1 Hz, CH]CHeN), 3.60 (2H, td,

N. Cheikh et al. / Tetrahedron 69 (2013) 1234e1247
1245
mixture was refluxed for 3 h. The solvent was evaporated and the
residue obtained was purified by column chromatography (silica gel,
ethyl acetate (100)) to give bis(2-aminopyridines) 11aeg.
1732, 1615, 1592, 1520. 1H NMR (CDCl3)
d
8.26 (2H, d, 3J¼5.1 Hz, 2ꢁ
CH]CHeN), 6.82 (2H, d, 3J¼6.6 Hz, 2ꢁ NH), 6.38 (2H, d, 3J¼5.1 Hz,
2ꢁ CH]CHeN), 4.24 (2H, s large, 2ꢁ CH), 2.20 (2H, s large, 2ꢁ CH),
1.82 (2H, s large, 2ꢁ CH), 1.52 (12H, s, 4ꢁ CH3), 1.46 (4H, s large, 4ꢁ
4.2.3.2.1. 4-(2-(1,3-Dihydro-1,1-dimethyl-3-oxofuro[3,4-c]pyr-
idin-4-ylamino)ethylamino)-1,1-dimethylfuro[3,4-c]pyridin-3(1H)-
one 11a. The general procedure 4 using (600 mg, 2.90 mmol) of 4-
(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-dimethyl-2-oxofuran-
3-carbonitrile 6a and (87 mg,1.45 mmol) of ethane-1,2-diamine 10a
gave (460 mg, 83%) of 11a as white solid, mp 225e227 ꢀC. IR nmax
CH). 13C NMR (CDCl3)
d 169.8, 165.4, 156.2, 154.6, 103.5, 102.3, 84.7,
54.7, 32.6, 26.5, 26.4, 24.9. EIMS m/z (% relative abundance): 437
(MþH, 80), 259 (100). HRMS (ES-QTOF) calcd for C24H29N4O4 MþH
437.2189. Found 437.2188.
4.2.3.2.6. 4-(4-((4-(1,3-Dihydro-1,1-dimethyl-3-oxofuro[3,4-c]
pyridin-4-ylamino) cyclohexyl)methyl)cyclohexylamino)-1,1-
dimethylfuro[3,4-c]pyridin-3(1H)-one 11f. The general procedure 4
using (600 mg, 2.90 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-
dihydro-5,5-dimethyl-2-oxofuran-3-carbonitrile 6a and (305 mg,
1.45 mmol) of 4-((4-aminocyclohexyl)methyl)cyclohexanamine 10f
gave (270 mg, 35%) of 11f as white solid, mp 236 ꢀC. IR nmax (neat/
(neat/cmꢂ1): 3426, 1723, 1615, 1593, 1516. 1H NMR (CDCl3)
d 8.35
(2H, d, 3J¼5.1 Hz, 2ꢁ CH]CHeN), 7.13 (2H, s large, 2ꢁ NH), 6.52 (2H,
d, 3J¼5.1 Hz, 2ꢁ CH]CHeN), 3.85 (4H, m, 2ꢁ CH2), 1.59 (12H, s, 4ꢁ
CH3). 13C NMR (CDCl3)
d 170.1, 165.7, 156.4, 154.6, 104.1, 103.1, 85.2,
41.3, 26.5. EIMS m/z (% relative abundance): 383 (MþH, 83), 205
(100). HRMS (ES-QTOF) calcd for C20H23N4O4 MþH 383.1719. Found
383.1721.
4.2.3.2.2. 4-(3-(1,3-Dihydro-1,1-dimethyl-3-oxofuro[3,4-c]pyr-
idin-4-ylamino)propylamino)-1,1-dimethylfuro[3,4-c]pyridin-3(1H)-
one 11b. The general procedure 4 using (600 mg, 2.90 mmol) of 4-
(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-dimethyl-2-oxofuran-
3-carbonitrile 6a and (107 mg, 1.45 mmol) of propan-1,3-diamine
10b gave (488 mg, 85%) of 11b as white solid, mp 138e140 ꢀC. IR
nmax (neat/cmꢂ1): 3395, 1733, 1616, 1591, 1527. 1H NMR (CDCl3)
cmꢂ1): 3386, 1734, 1619, 1592, 1522. 1H NMR (CDCl3)
d 8.26 (2H, d,
3J¼5.1 Hz, 2ꢁ CH]CHeN), 6.45 (2H, d, 3J¼5.1 Hz, 2ꢁ CH]CHeN),
6.36 (2H, d, 3J¼8.1 Hz, 2ꢁ NH), 4.06e3.96 (2H, m, 2ꢁ CHNH),
2.13e1.65 (10H, m, 4ꢁ CH2, 2ꢁ CH), 1.59 (12H, s, 4ꢁ CH3), 1.35e1.04
(10H, m, 5ꢁ CH2). 13C NMR (CDCl3)
d 170.4, 165.7, 155.8, 154.6, 103.3,
102.5, 85.1, 49.6, 44.4, 33.9, 33.2, 32.2, 26.5. EIMS m/z (% relative
abundance): 533 (MþH, 100), 355 (70), 179 (84). HRMS (ES-QTOF)
calcd for C20H23N4O4 MþH 533.3128. Found 533.3108.
d
8.39 (2H, d, 3J¼5.1 Hz, 2ꢁ CH]CHeN), 7.07 (2H, s large, 2ꢁ NH),
4.2.3.2.7. 4-(3-(1-Ethyl-1,3-dihydro-1-methyl-3-oxofuro[3,4-c]
6.48 (2H, d, 3J¼5.1 Hz, 2ꢁ CH]CHeN), 3.68 (4H, q,
pyridin-4-ylamino)
propylamino)-1-ethyl-1-methylfuro[3,4-c]pyr-
3JCH NH
¼
3JCH CH ¼6.3 Hz, CH2CH2CH2), 1.92 (2H, m, CH2CH2CH2),
idin-3(1H)-one 11g. The general procedure 4 using (638 mg,
2.90 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-
dimethyl-2-oxofuran-3-carbonitrile 6b and (107 mg, 1.45 mmol)
of propane-1,2-diamine 10b gave (523 mg, 85%) of 11g as white
solid, mp 127e128 ꢀC; IR nmax (neat/cmꢂ1): 3396, 1733, 1616, 1590,
1.602 (12H, s, 4ꢁ CH3). 13C NMR (CDCl3)
d 170.4, 165.8, 156.6, 154.8,
2
2
103.7, 102.8, 85.2, 37.3, 30.1, 26.5. EIMS m/z (% relative abundance):
397 (MþH, 53), 219 (100). HRMS (ES-QTOF) calcd for C21H25N4O4
MþH 397.1876. Found 397.1864.
4.2.3.2.3. 4-(6-(1,3-Dihydro-1,1-dimethyl-3-oxofuro[3,4-c]pyr-
idin-4-ylamino)hexylamino)-1,1-dimethylfuro[3,4-c]pyridin-3(1H)-
one 11c. The general procedure 4 using (600 mg, 2.90 mmol) of 4-
(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-dimethyl-2-oxofuran-
3-carbonitrile 6a and (168 mg, 1.45 mmol) of hexane-1,6-diamine
10c gave (527 mg, 83%) of 11c as white solid, mp 130e132 ꢀC. IR
1527. 1H NMR (CDCl3)
d
8.37 (2H, d, 3J¼5.1 Hz, 2ꢁ CH]CHeN), 7.07
(2H, t, 3J¼6.0 Hz, 2ꢁ NH), 6.44 (2H, d, 3J¼5.1 Hz, 2ꢁ CH]CHeN),
3.68 (4H, q, JNHCH ¼ JCH CH ¼6.1 Hz, CH2CH2CH2), 2.03e1.75 (6H,
2
2
2
m, 2ꢁ CH2CH3, CH2CH2CH2), 1.55 (6H, s, 2ꢁ CH3), 0.78 (3H, t,
3J¼7.3 Hz, 2ꢁ CH2CH3). 13C NMR (CDCl3)
d 170.7, 164.6, 156.6, 154.7,
104.0, 103.7, 87.9, 37.3, 32.1, 30.1, 24.9, 7.8. EIMS m/z (% relative
abundance): 425 (MþH, 43), 233 (100). HRMS (ES-QTOF) calcd for
nmax (neat/cmꢂ1): 3396,1732,1619,1591,1526.1H NMR (CDCl3)
d 8.25
(2H, d, 3J¼5.1 Hz, 2ꢁ CH]CHeN), 6.48 (2H, s large, 2ꢁ NH), 6.46 (2H,
C23H29N4O4 MþH 425.2189. Found 425.2168.
d, 3J¼5.1 Hz, 2ꢁ CH]CHeN), 3.52 (4H, q, 3JCH NH
¼
3JCH CH ¼6.8 Hz,
2
2
2
2ꢁ NHCH2), 1.68e1.60 (4H, m, 2ꢁ CH2), 1.57 (12H, s, 4ꢁ CH3),
4.2.3.3. General procedure 5 for the synthesis of 2-hydrazino-
1.47e1.42 (4H, m, 2ꢁ CH2). 13C NMR (CDCl3)
d
170.5, 165.6, 156.4,
pyridines 13aec. A mixture of 4-(E)-2-(dimethylaminovinyl)-2,5-
dihydro-5,5-dialkyl-2-oxofuran-3-carbonitrile 6a,b (1.45 mmol)
and excess of hydrazine 12a,b (2 mmol) was heated until homoge-
nization and the heating was continued for 5 min. The crude
product obtained was washed several times with diethylether and
purified by column chromatography (silica gel, ethyl acetate/cyclo-
hexane (70:30)) to give 2-hydrazinopyridines 13aec.
154.5, 103.6, 102.7, 85.3, 40.5, 29.5, 26.7, 26.4. EIMS m/z (% relative
abundance): 439 (MþH, 100), 421 (29), 395 (16), 261 (59), 243 (14),
191 (28). HRMS (ES-QTOF) calcd for C24H31N4O4 MþH 439.2345.
Found 439.2326.
4.2.3.2.4. 4-((3-((1,3-Dihydro-1,1-dimethyl-3-oxofuro[3,4-c]pyr-
idin-4-ylamino) methyl)phenyl)methylamino)-1,1-dimethylfuro[3,4-
c]pyridin-3(1H)-one 11d. The general procedure 4 using (600 mg,
2.90 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-
dimethyl-2-oxofuran-3-carbonitrile 6a and (197 mg, 1.45 mmol)
of (3-(aminomethyl)phenyl)methanamine 10d gave (544 mg, 82%)
of 11d as yellow solid, mp 156e157 ꢀC. IR nmax (neat/cmꢂ1): 3395,
4.2.3.3.1. 4-(2-Methylhydrazinyl)-1,1-dimethylfuro[3,4-c]pyridin-
3(1H)-one 13a. The general procedure
5 using (300 mg,
1.45 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-
dimethyl-2-oxofuran-3-carbonitrile 6a and (92 mg, 2 mmol) of
methylhydrazine 12a gave (243 mg, 81%) of 13a as white solid, mp
150e152 ꢀC. IR nmax (neat/cmꢂ1): 3232, 1740, 1607, 1587. 1H NMR
1734, 1618, 1592, 1525. 1H NMR (CDCl3)
d
8.29 (2H, d, 3J¼5.1 Hz, 2ꢁ
CH]CHeN), 7.37e7.29 (4H, m, Harom), 6.83 (2H, s large, 2ꢁ NH),
(CDCl3)
d
8.29 (1H, d, 3J¼5.2 Hz, CH]CHeN), 7.70 (1H, s large, NH),
6.53 (2H, d, 3J¼5.1 Hz, 2ꢁ CH]CHeN), 4.76 (4H, d, 3J¼6.0 Hz, 2ꢁ
6.55 (1H, d, 3J¼5.2 Hz, CH]CHeN), 2.74 (1H, s, NHCH3), 1.59 (6H, s,
NHCH2), 1.61 (12H, s, 4ꢁ CH3). 13C NMR (CDCl3)
d
170.3, 165.6, 156.1,
2ꢁ CH3). 13C NMR (CDCl3)
d 170.0, 166.3, 156.7, 154.8, 105.2, 103.1,
154.5, 139.1, 128.9, 126.9, 126.6, 104.2, 103.0, 85.4, 44.2, 26.5. EIMS
m/z (% relative abundance): 459 (MþH, 14), 281 (100). HRMS (ES-
QTOF) calcd for C26H27N4O4 MþH 459.2032. Found 459.2009.
4.2.3.2.5. 4-((trans)-2-(1,3-Dihydro-1,1-dimethyl-3-oxofuran[3,4-
c]pyridin-4-yl-amino)cyclohexylamino)-1,1-dimethylfuro[3,4-c]pyr-
idin-3(1H)-one 11e. The general procedure 4 using (600 mg,
2.90 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-
dimethyl-2-oxofuran-3-carbonitrile 6a and (165 mg, 1.45 mmol)
of cyclohexane-1,2-diamine 10e gave (345 mg, 52%) of 11e as yel-
low solid, mp 205e206 ꢀC. IR nmax (neat/cmꢂ1): 3380,
86.1, 39.6, 26.8. EIMS m/z (% relative abundance): 208 (MþH, 45),190
(16), 178 (48), 163 (100), 148 (26). HRMS (ES-QTOF) calcd for
C
10H14N3O2 MþH 208.1086. Found 208.1078.
4.2.3.3.2. 4-(2-Methylhydrazinyl)-1-ethyl-1-methylfuro[3,4-c]
pyridin-3(1H)-one 13b. The general procedure 5 using (318 mg,
1.45 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-
dimethyl-2-oxofuran-3-carbonitrile 6b and (92 mg, 2 mmol) of
methylhydrazine 12a gave (304 mg, 95%) of 13b as white solid,
120e122 ꢀC. IR nmax (neat/cmꢂ1): 3394, 3304,1732,1610,1586,1515.
1H NMR (CDCl3)
d
8.24 (1H, d, 3J¼5.1 Hz, CH]CHeN), 6.57 (1H, d,

1246
N. Cheikh et al. / Tetrahedron 69 (2013) 1234e1247
3J¼5.1 Hz, CH]CHeN), 5.82 (1H, s large, NH), 1.94 (HA, HB, ABq,
JAB¼14.5 Hz, JABq¼7.4 Hz, CHHCH3), 1.60 (1H, s large, NHCH3), 1.59
(3H, s, CH3), 0.80 (3H, t, 3J¼7.4 Hz, CH2CH3). 13C NMR (CDCl3)
251 (MþH, 40), 233 (27), 215 (22), 179 (100), 161 (43). HRMS (ES-
QTOF) calcd for C13H19N2O3 MþH 251.1396. Found 251.1398.
4.2.3.4.4. 4-((R)-2-Hydroxy-1-phenylethylamino)-1,1-dimethylfuro
d
169.9, 164.8, 156.3, 154.3, 105.2, 103.6, 88.5, 39.3, 32.1, 24.8,
[3,4-c]pyridin-3(1H)-one 15d. The general procedure 6 using
7.8. EIMS m/z (% relative abundance): 222 (MþH, 76), 204 (57), 186
(34), 174 (68), 163 (100), 162 (61), 158 (23), 147 (22), 143 (42). HRMS
(ES-QTOF) calcd for C11H16N3O2 MþH 222.1243. Found 222.1236.
4.2.3.3.3. 1-Ethyl-4-hydrazinyl-1-methylfuro[3,4-c]pyridin-3(1H)-
one 13c. The general procedure 5 using (318 mg, 1.45 mmol) of 4-
(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-dimethyl-2-
(300 mg, 1.45 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-
5,5-dimethyl-2-oxofuran-3-carbonitrile 6a and (199 mg, 1.45 mmol)
of (R)-2-amino-2-phenylethanol 14d gave (324 mg, 75%) of 15d as
white solid, mp 109e110 ꢀC, ½a D20
ꢃ
þ48.6 (c 1, CHCl3). IR nmax (neat/
cmꢂ1): 3480, 3382,1734,1617,1592,1519.1H NMR (CDCl3)
d
8.22 (1H,
d, 3J¼5.2 Hz, CH]CHeN), 7.42e7.30 (5H, m, Harom), 7.08 (1H, s large,
NH), 6.56 (1H, d, 3J¼5.2 Hz, CH]CHeN), 5.37 (1H, dt, 3J¼5.9 Hz,
NHCH), 3.98 (2H, d, 3J¼5.4 Hz, CH2OH), 3.76 (1H, s large, OH),1.62 (3H,
oxofuran-3-carbonitrile 6b and (64 mg, 2 mmol) of hydrazine 12b
gave (270 mg, 90%) of 13c as white solid, mp 190e192 ꢀC. IR nmax
(neat/cmꢂ1): 3281, 3149, 1723, 1651, 1542. 1H NMR (CDCl3)
d
7.64
s, CH3), 1.59 (3H, s, CH3). 13C NMR (CDCl3)
d 170.0, 165.9, 156.2, 153.9,
(1H, d, 3J¼6.9 Hz, CH]CHeN), 5.68 (1H, d, 3J¼6.9 Hz, CH]
CHeN), 4.99 (1H, s large, NH2), 1.84 (HA, HB, ABq, JAB¼14.4 Hz,
JABq¼7.3 Hz, CHHCH3), 1.65 (1H, s large, NH), 1.53 (3H, s, CH3), 0.82
139.3,129.0,128.0,126.7,104.7,103.6, 85.5, 60.4, 57.7, 26.4. EIMS m/z(%
relative abundance): 299 (MþH, 66), 179 (100). HRMS (ES-QTOF)
calcd for C17H19N2O3 MþH 299.1396. Found 299.1383.
(3H, t, 3J¼7.3 Hz, CH2CH3). 13C NMR (CDCl3)
d
169.9, 164.8, 156.3,
4.2.3.4.5. 4-((S)-1-Hydroxy-3-phenylpropan-2-ylamino)-1,1-
dimethylfuro[3,4-c]pyridin-3(1H)-one 15e. The general procedure 6
using (300 mg, 1.45 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-
dihydro-5,5-dimethyl-2-oxofuran-3-carbonitrile 6a and (219 mg,
1.45 mmol) of (S)-2-amino-3-phenylpropanol 14e gave (321 mg,
154.3, 105.2, 103.6, 85.6, 31.4, 24.2, 7.7. EIMS m/z (% relative
abundance): 208 (MþH, 100), 190 (94), 179 (50), 173 (30), 163
(54). HRMS (ES-QTOF) calcd for C10H14N3O2 MþH 208.1086.
Found 208.1093.
a 20
71%) of 15e as viscous oil, ½ ꢃD ꢂ98.3 (c 1, CHCl3). IR nmax (neat/
4.2.3.4. General procedure 6 for the synthesis of chiral 2-aminopyr-
cmꢂ1): 3425 (OH); 3378, 1731, 1615, 1590, 1518. 1H NMR (CDCl3)
idines 15aei. To
a
solution of 4-(2-dimethylaminovinyl)-5,5-
d
8.16 (1H, d, 3J¼5.2 Hz, CH]CHeN), 7.28e7.16 (5H, m, Harom), 6.69
dimethyl-2-oxo-2,5-dihydrofuran-3-carbonitrile 6a (300 mg,
1.45 mmol) dissolved in DMF was added chiral amine 14aei
(1.45 mmol). The mixture was refluxed for 3 h. The solvent was
evaporated and the residue obtained was purified by column
chromatography (silica gel, ethyl acetate/cyclohexane (70:30)) to
give chiral 2-aminopyridines 15aei.
4.2.3.4.1. 4-((R)-1-Phenylethylamino)-1,1-dimethylfuro[3,4-c]pyr-
idin-3(1H)-one 15a. The general procedure 6 using (300 mg,
1.45 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-
dimethyl-2-oxofuran-3-carbonitrile 6a and (175 mg, 1.45 mmol)
of (R)-1-phenyl-ethanamine 14a gave (307 mg, 75%) of 15a as white
(1H, d, 3J¼6.5 Hz, NH), 6.49 (1H, d, 3J¼5.2 Hz, CH]CHeN), 4.38 (1H,
0
0
m, CHNH), 4.18 (1H, s large, OH), 3.74 (2H, ABd, JHa Hb ¼11.1 Hz,
0
0
0
0
JHa CH¼6.4 Hz, JHb CH¼2.9 Hz, CHa Hb OH), 2.95 (2H, ABd,
JHaHb¼13.7 Hz, JHaCH¼7.7 Hz, JHbCH¼6.7 Hz, CHaHbPh),1.55 (6H, s, 2ꢁ
CH3). 13C NMR (CDCl3)
d 169.9, 165.9, 156.3, 153.7, 137.7, 129.3, 128.6,
126.7, 154.6, 104.4, 103.5, 85.4, 65.9, 55.3, 37.7, 26.4. EIMS m/z (%
relative abundance): 313 (MþH, 33), 295 (40), 179 (100), 161 (28),
133 (07), 117 (20), 91 (35). HRMS (ES-QTOF) calcd for C18H21N2O3
MþH 313.1552. Found 313.1563.
4.2.3.4.6. 4-((S)-1-Cyclohexylethylamino)-1,1-dimethylfuro[3,4-c]
pyridin-3(1H)-one 15f. The general procedure 6 using (300 mg,
1.45 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-
dimethyl-2-oxofuran-3-carbonitrile 6a and (184 mg, 1.45 mmol)
of (S)-1-cyclohexylethanamine 14f gave (355 mg, 85%) of 15f as
solid, mp 112e113 ꢀC; ½a D20
ꢃ
ꢂ111.0 (c 1, CHCl3). IR nmax (neat/cmꢂ1):
3393, 1734, 1618, 1591, 1519. 1H NMR (CDCl3)
d 8.24 (1H, d,
3J¼5.1 Hz, CH]CHeN), 7.43e7.21 (5H, m, Harom), 6.81 (1H, d,
3J¼7.6 Hz, NH), 6.48 (1H, d, 3J¼5.1 Hz, CH]CHeN), 5.46 (1H, quint,
white solid, mp 78e79 ꢀC, ½a D20
ꢃ
þ80.0 (c 1, CHCl3). IR nmax (neat/
3
JCHNH¼7.5 Hz, JCHCH ¼7.0 Hz, CHNH), 1.61 (3H, d, 3J¼7.0 Hz,
cmꢂ1): 3385, 1731, 1618, 1589, 1521. 1H NMR (CDCl3)
d 8.23 (1H, d,
3
3
CHCH3), 1.58 (6H, s, 2ꢁ CH3). 13C NMR (CDCl3)
d
170.2, 165.6, 155.6,
3J¼5.1 Hz, CH]CHeN), 6.44 (1H, s large, NH), 6.42 (1H, d, 3J¼5.1 Hz,
CH]CHeN), 4.16 (1H, m, CHNH), 1.85e1.61 (6H, m, 3ꢁ CH2), 1.58
(3H, s, CH3), 1.56 (3H, s, CH3), 1.45 (1H, m, CH(CH2)5), 1.18 (3H, d,
3J¼6.6 Hz, CHCH3), 1.26e1.03 (4H, m, 2ꢁ CH2). 13C NMR (CDCl3)
154.6, 143.9, 128.6, 127.13, 126.1, 103.9, 102.8, 85.3, 49.6, 26.4, 22.9.
EIMS m/z (% relative abundance): 283 (MþH, 82), 179 (100), 105
(15). HRMS (ES-QTOF) calcd for C17H19N2O2 MþH 283.1447. Found
283.1443.
d
170.6, 165.7, 156.3, 154.6, 103.2, 102.4, 85.1, 50.2, 43.2, 29.3, 29.0,
4.2.3.4.2. 4-((S)-1-Phenylethylamino)-1,1-dimethylfuro[3,4-c]pyr-
idin-3(1H)-one 15b. The general procedure 6 using (300 mg,
1.45 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-
dimethyl-2-oxofuran-3-carbonitrile 6a and (175 mg, 1.45 mmol)
of (S)-1-phenyl-ethanamine 14b gave (307 mg, 75%) of 15b as white
26.4, 26.2, 17.9. EIMS m/z (% relative abundance): 289 (MþH, 78),
179 (100), 161 (14). HRMS (ES-QTOF) calcd for C17H25N2O2 MþH
289.1916. Found 289.1911.
4.2.3.4.7. 4-((R)-1-(Naphthalen-3-yl)ethylamino)-1,1-dimethylfuro
[3,4-c]pyridin-3-(1H)-one 15g. The general procedure
6 using
solid, mp 110e111 ꢀC; ½a D20
ꢃ
þ112.4 (c 1, CHCl3). IR, 1H and 13C NMR
(300 mg, 1.45 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-
5,5-dimethyl-2-oxofuran-3-carbonitrile 6a and (248 mg, 1.45 mmol)
of (R)-1-(naphtalen-2-yl)ethanamine 14g gave (400 mg, 83%) of 15g
spectra and masse spectroscopy are similar to the described in
precedent Section 4.2.3.4.2.
4.2.3.4.3. 4-((R)-1-Hydroxybutan-2-ylamino)-1,1-dimethylfuro
as white solid, mp 162e164 ꢀC, ½a D20
ꢃ
ꢂ244.7 (c 1, CHCl3). IR nmax
[3,4-c]pyridin-3(1H)-one 15c. The general procedure
6
using
(neat/cmꢂ1): 3390, 1732, 1615, 1592, 1514. 1H NMR (CDCl3)
d 8.26 (1H,
(300 mg, 1.45 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-
5,5-dimethyl-2-oxofuran-3-carbonitrile 6a and (129 mg,
1.45 mmol) of (R)-2-aminobutanol 14c gave (275 mg, 76%) of 15c as
d, 3J¼5.1 Hz, CH]CHeN), 8.21e7.37 (7H, m, Harom), 6.87 (1H, d,
3J¼7.9 Hz, NH), 6.49 (1H, d, 3J¼5.1 Hz, CH]CHeN), 6.31 (1H, dq,
3J¼7.3 Hz, 3J¼6.8 Hz, CHNH), 1.76 (3H, d, 3J¼6.8 Hz, CHCH3), 1.61 (3H,
viscous oil, ½a 2D0
ꢃ
þ31.3 (c 1, CHCl3). IR nmax (neat/cmꢂ1): 3460, 3380,
s, CH3), 1.58 (3H, s, CH3). 13C NMR (CDCl3)
d 170.4, 165.6, 155.3, 154.7,
1730, 1615, 1588, 1520. 1H NMR (CDCl3)
d
8.18 (1H, d, 3J¼5.2 Hz,
139.4e122.3, 104.0, 102.8, 85.3, 45.6, 26.4, 22.0. EIMS m/z (% relative
abundance): 333 (MþH, 88), 205 (42),179 (100),155 (88). HRMS (ES-
QTOF) calcd for C21H20N2O2 MþH 333.1603. Found 333.1596.
4.2.3.4.8. 4-((1R,2R)-2-(1,3-Dihydro-1,1-dimethyl-3-oxofuran
[3,4-c]pyridin-4-ylamino)cyclohexylamino)-1,1-dimethylfuro[3,4-c]
pyridin-3(1H)-one 15h. The general procedure 6 using (600 mg,
2.90 mmol) of 4-(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-
CH]CHeN), 6.58 (1H, d, 3J¼6.1 Hz, NH), 6.51 (1H, d, 3J¼5.2 Hz, CH]
CHeN), 4.36 (1H, s large, OH), 4.05 (1H, m, CHNH), 3.72 (2H, ABd,
0
0
0
0
0
0
JHa Hb ¼11.0 Hz, JHa CH¼6.9 Hz, JHb CH¼2.9 Hz, CHa Hb OH), 1.70 (2H,
m, CH2CH3), 1.62 (3H, s, CH3), 1.59 (3H, s, CH3), 1.02 (3H, t, 3J¼7.4 Hz,
CH2CH3). 13C NMR (CDCl3)
d 170.5, 166.5, 157.1, 154.2, 104.7, 102.8,
85.7, 67.5, 56.2, 26.8, 25.0, 11.1. EIMS m/z (% relative abundance):

N. Cheikh et al. / Tetrahedron 69 (2013) 1234e1247
1247
6. (a) Michael, J. P.; de Koning, C. B.; Gravestock, D.; Hosken, G. D.; Howard, A. S.;
Jungmann, C. M.; Krause, R. W. M.; Parsons, A. S.; Pelly, S. C.; Stanbury, T. V. Pure
Appl. Chem. 1999, 71, 979e988; (b) Valla, A.; Valla, B.; Cartier, D.; Guillou, R.;
Labia, R.; Florent, L.; Charneau, S.; Schrevel, J.; Potier, P. Eur. J. Med. Chem. 2006,
41, 142e146.
7. (a) Villemin, D.; Cheikh, N.; Liao, L.; Bar, N.; Lohier, J. F.; Sopkova, J.; Choukchou-
Braham, N.; Mostefa-Kara, B. Tetrahedron 2012, 68, 4906e4918; (b) Villemin, D.;
Liao, L. Tetrahedron Lett. 1996, 37, 8733e8734.
8. (a) Sivakumar, K.; Eswaramurthy, K. S.; Sabramanian, K.; Natarajan, S. Acta
Crystallogr. 1990, 46, 839e841; (b) Adibatti, N. A.; Thirugnanasambantham, P.;
Kuilothungan, C.; Viswanathan, S.; Kameswean, L.; Balakrishna, K.; Sukumar, E.
Phytochemistry 1991, 30, 2449e2450.
9. (a) Usman, A. S.; Narayanaswamy, V. Indian J. Med. Res. 1970, 5, 10e15; (b)
Sukumar, E.; Gopal, R. H.; Rao, R. B.; Viswanathan, S.; Thirugnanasambantham,
P.; Vijayasekaran, V. Fitoterapia 1995, 66, 403e406; (c) Jong, Y. J.; Snell, E. E. J.
Biol. Chem. 1986, 261, 15112e15114.
dimethyl-2-oxofuran-3-carbonitrile 6a and (165 mg, 1.45 mmol) of
(1R,2R)-cyclohexane-1,2-diamine 14h gave (329 mg, 52%) of 15h as
yellow solid, mp 105e106 ꢀC, ½a D20
ꢃ
ꢂ230.6 (c 1, CHCl3). IR nmax (neat/
cmꢂ1): 3367, 1732, 1614, 1591, 1519. 1H NMR (CDCl3)
d
8.26 (2H, d,
3J¼5.1 Hz, 2ꢁ CH]CHeN), 6.82 (2H, d, 3J¼6.4 Hz, 2ꢁ NH), 6.37 (2H,
d, 3J¼5.1 Hz, 2ꢁ CH]CHeN), 4.24 (2H, s large, 2ꢁ CH), 2.19 (2H, s
large, 2ꢁ CH), 1.82 (2H, s large, 2ꢁ CH), 1.52 (6H, s, 2ꢁ CH3), 1.48
(6H, s, 2ꢁ CH3), 1.46 (4H, s large, 4ꢁ CH). 13C NMR (CDCl3)
d 169.8,
165.4, 156.2, 154.6, 103.5, 102.3, 84.7, 54.7, 32.6, 26.5, 24.9. EIMS m/z
(% relative abundance): 437 (MþH, 83), 259 (100), 179 (10). HRMS
(ES-QTOF) calcd for C24H29N4O4 MþH 437.2189. Found 437.2173.
4.2.3.4.9. 4-(Ethylamino)-1,1-dimethylfuro[3,4-c]pyridin-3(1H)-
one 15i. The general procedure 6 using (300 mg, 1.45 mmol) of 4-
(E)-2-(dimethylaminovinyl)-2,5-dihydro-5,5-dimethyl-2-oxofuran-
10. (a) Avetisyan, A. A.; Kagramanyan, A. A.; Melikyan, G. S. Armyanskii Khim. Zh.
1989, 42, 708e712; (b) Avetisyan, A. A.; Kagramanyan, A. A.; Melikyan, G. S.
Armyanskii Khim. Zh. 1985, 38, 335e336.
3-carbonitrile 6a and (239 mg, 1.45 mmol) of ( )-phenylalanine 14i
L
11. (a) This Work was a Part of the PhD thesis of Liang Liao, University of Caen,
gave (242 mg, 81%) of 15i as viscous oil, IR nmax (neat/cmꢂ1): 3675,
ꢀ
1999. (b) Maheut, G.; Liao, L.; Catel, J. M.; Jaffres, P. A.; Villemin, D. J. Chem. Educ.
3391, 1732, 1617, 1591, 1523. 1H NMR (CDCl3)
d
8.29 (H, d, 3J¼5.2 Hz,
2001, 78, 654e657.
12. Mostefa-Kara, B. PhD thesis, University of Paris 6, 1994.
CH]CHeN), 7.34e7.19 (5H, m, Harom), 6.58 (H, s large, NH), 6.49 (H,
13. Villemin, D.; Mostefa-Kara, B.; Bar, N.; Choukchou-Braham, N.; Cheikh, N.;
Benmeddah, A.; Hazimeh, H.; Ziani-Cherif, C. Lett. Org. Chem. 2006, 3, 558e559.
14. Cheikh, N. PhD thesis, University of Tlemcen: Algeria, 2008.
15. Villemin, D.; Cheikh, N.; Mostefa-Kara, B.; Bar, N.; Choukchou-Braham, N.; Didi,
M. A. Tetrahedron Lett. 2006, 47, 5519e5521.
d, 3J¼5.2 Hz, CH]CHeN), 3.79 (2H, q, JNHCH ¼ JCH CH ¼7.0 Hz,
2
2
2
NHCH2), 2.96 (2H, t, 3J¼7.0 Hz, NHCH2CH2), 1.59 (6H, s, 2ꢁ CH3). 13
C
NMR (CDCl3)
d 170.3, 165.6, 156.2, 154.5, 139.0, 128.8, 128.6, 126.5,
103.8, 102.9, 85.3, 42.0, 35.9, 26.4. EIMS m/z (% relative abundance):
283 (MþH, 100), 105 (88).
16. Pasumansky, L.; Hernandez, A. R.; Gamsey, S.; Goralski, C. T.; Singaram, B.
Tetrahedron Lett. 2004, 45, 6417e6420.
17. Abdel-Aziz, A. A. M.; El-Subbaghb, H. I.; Kunie, T. Bioorg. Med. Chem. 2005, 13,
4929e4935.
Supplementary data
18. Manna, F.; Chimenti, F.; Bolasco, A.; Bizzarri, B.; Filippelli, W.; Filippelli, A.;
Gagliardi, L. Eur. J. Med. Chem. 1999, 34, 245e254 and references cited therein.
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Fuhrmann, H.; Brenner, S.; Arndt, P.; Kempe, R. Inorg. Chem.1996, 35, 6742e6745.
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