On the reactivity of 4-cyano-1,3-dichloro-7-methyl-5,6,7,8-tetrahydro-2,7- naphthyridine with several amines in different experimental conditions: Monosubstitution, disubstitution, and a new unexpected rearrangement

Article abstract of DOI:10.1016/j.tet.2014.05.070

The reactivity of 4-cyano-1,3-dichloro-7-methyl-5,6,7,8-tetrahydro-2,7- naphthyridine 1 with nucleophiles has been investigated. The different reactivity of the two chlorine atoms in 1 enabled us to obtain, by using different experimental conditions, the mono- and the di-amino-substituted derivatives of 5,6,7,8-tetrahydro-2,7-naphthyridines 2 and 3, respectively. Thus, by carrying out the reaction in a low-boiling solvent and in the presence of a quasi-stoichiometric amount of amine, the mono-substituted derivatives 2 were obtained, which under harsher conditions was transformed into the diamino derivatives 3 when using an excess of amine. During the synthesis of some diamino derivatives 3 a new rearrangement was observed with formation of 1-oxo derivatives of 3,4-dihydro-2,7-naphthyridines 4. The structure of the unexpected compounds 4 was confirmed by X-ray crystallography. A mechanism for the rearrangement is tentatively suggested.

Full text of DOI:10.1016/j.tet.2014.05.070

Tetrahedron xxx (2014) 1e12
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
On the reactivity of 4-cyano-1,3-dichloro-7-methyl-5,6,7,8-
tetrahydro-2,7-naphthyridine with several amines in different
experimental conditions: monosubstitution, disubstitution, and
a new unexpected rearrangement
,
d
Samvel N. Sirakanyan a, Viktor G. Kartsev b, Domenico Spinelli c , Athina Geronikaki ,
Azat S. Noravyan a, Anush A. Hovakimyan a, Henrik A. Panosyan e, Armen G. Ayvazyan e,
Rafael A. Tamazyan e
*
a The Scientific Technological Center of Organic and Pharmaceutical Chemistry, Armenian Academy of Science, Institute of Fine Organic Chemistry of A.L.
Mnjoyan, Ave. Azatutyan 26, 0014 Yerevan, Armenia
b InterBioScreen, a/ya 218, Moscow 119019, Russia
c
ꢀ
Dipartimento di Chimica G. Ciamician, Alma Mater Studiorum, Universita degli Studi di Bologna, Bologna 40126, Italy
d Aristotle University of Thessaloniki, School of Pharmacy, Thessaloniki 54124, Greece
e The Scientific Technological Center of Organic and Pharmaceutical Chemistry, Armenian Academy of Science, Molecule Structure Research Centre, Ave.
Azatutyan 26, 0014 Yerevan, Armenia
a r t i c l e i n f o
a b s t r a c t
Article history:
The reactivity of 4-cyano-1,3-dichloro-7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine 1 with nucleo-
philes has been investigated. The different reactivity of the two chlorine atoms in 1 enabled us to obtain,
by using different experimental conditions, the mono- and the di-amino-substituted derivatives of
5,6,7,8-tetrahydro-2,7-naphthyridines 2 and 3, respectively. Thus, by carrying out the reaction in a low-
boiling solvent and in the presence of a quasi-stoichiometric amount of amine, the mono-substituted
derivatives 2 were obtained, which under harsher conditions was transformed into the diamino de-
rivatives 3 when using an excess of amine. During the synthesis of some diamino derivatives 3 a new
rearrangement was observed with formation of 1-oxo derivatives of 3,4-dihydro-2,7-naphthyridines 4.
The structure of the unexpected compounds 4 was confirmed by X-ray crystallography. A mechanism for
the rearrangement is tentatively suggested.
Received 28 February 2014
Received in revised form 5 May 2014
Accepted 19 May 2014
Available online xxx
This article is dedicated to the memory of
Professor Alan R. Katritzky (1928e2014;
firstly Full Professor at the East Anglia Uni-
versity and then Kenan Professor of Organic
Chemistry at the Florida University). ARK
has been for more than 50 years the big
‘Magister’ in the field of Heterocyclic
Chemistry: his lectures, everywhere in the
world, have been able to open new horizons
to the audiences
Ó 2014 Published by Elsevier Ltd.
Keywords:
5,6,7,8-Tetrahydro-2,7-naphthyridines
Mono- and di-amino 2,7-naphthyridines
1-Oxo-3,4-dihydro-2,7-naphthyridines
Nucleophilic substitution
Ring-into-ring rearrangement
1. Introduction
The study of the derivatives of five- and six-membered het-
erocycles containing nitrogen represents a ‘key’ field in the study of
organic and biological chemistry.1 Their involvements in life pro-
cesses, their pharmacological activities, their large use as in-
termediates in organic syntheses, and their variegated reactivity
make the study of properties of these compounds an attractive
* Corresponding author. E-mail addresses: shnnr@mail.ru (S.N. Sirakanyan),
vkartsev@ibscreen.chg.ru (V.G. Kartsev), domenico.spinelli@unibo.it (D. Spinelli),
geronik@pharm.auth.gr (A. Geronikaki), henry@msrc.am (H.A. Panosyan).
0040-4020/$ e see front matter Ó 2014 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tet.2014.05.070
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S.N. Sirakanyan et al. / Tetrahedron xxx (2014) 1e12
research field. In this research area we have been involved in the
study of the reactivity of several five- and six-membered nitrogen-
containing derivatives.2,3
By lengthening the reaction times (5 h) we have extended the
scope of the nucleophilic substitution on compounds 2a, b, g.
Several other amines were used, which gave the relevant 1,3-
diamino-4-cyano-7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridines
(3het) again in very high yields (again, average yield, ca. 76%).
Thus, by exploiting the different reactivity with nucleophiles of
chlorine atoms at C-1 and C-3 of the dichloro derivative 1 both the
mono- and the di-amino derivatives (2 and 3, respectively) of 2,7-
naphthyridines were obtained in either ‘very high’ or ‘excellent’
yields.
Recently some of us have examined the reactivity of 1,3-
dichloro-4-cyano-7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine
with some nucleophiles.4e8 As a matter of fact this compound is
a very interesting substrate: it is decorated by several functional
groups (two chlorine atoms with different reactivity towards nu-
cleophiles, a cyano group, a pyridinic nitrogen, and a benzylic ni-
trogen), which in turn, reacting, for example, with nucleophiles
could furnish new functional groups able to open the way to new
heterocyclic systems. As a continuation of our previous studies we
have reported the synthesis of several 5-amino-6-cyano-9-methyl-
This easily controlled step by step substitution provided us the
opportunity, by varying the substituent at C-1 of the naphthyridine
ring, to synthesize
a large number of derivatives of 2,7-
7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a]-2,7-naphthyridines
some 5-amino-6-cyano-9-methyl-7,8,9,10-tetrahydro[1,2,4]tri-
and
naphthyridines (Scheme 2), which appear very promising from
a biological point of view.
azolo[5,1-a]-2,7-naphthyridines (Scheme 1) with excellent yields
In spite of the apparent simplicity of the reactions, the com-
pounds of series 3 were synthesized and isolated with some diffi-
(average yield, ca. 83%).4
Scheme 1. From 1,3-dichloro-4-cyano-7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine 1 to some triazolonaphthyridines.
In the field of condensed heterocyclic compounds the 2,7-
naphthyridine derivatives occupy an important place because of
their very large spectrum of biological activity, as evidenced by the
literature data9e13 and by the results of some our
investigations.14e17
culty not only because the final products are easily soluble in a large
number of solvents, but also because, in this kind of nucleophilic
substitution, sometimes an unexpected process is observed, which
does not lead to the expected products.
For example, if at C-1 the chlorine atom was substituted by the
cyclic amine pyrrolidine, as in 2a, the subsequent substitution of
the second chlorine atom by some primary amines (e.g., ethanol-
amine, in excess) in harsh experimental conditions (by
5 h refluxing) did not produce the target products 3a, but the un-
expected compound 4a (Scheme 3).
For this reason we have deeply investigated this aspect of the
reaction examining the behavior of some compounds 2 with dif-
ferent amines under variable experimental conditions to ascertain,
which factors determine the occurrence of this new reaction.
A well chosen series of targeted experiments has allowed to
understand that this new reaction is observed ‘only’ when: 1) the
C-1 of the 2,7-naphthyridine ring is substituted by a cyclic amine, 2)
the second amine substituting at the C-3 of the ring is a primary
amine, 3) the boiling temperature of this primary amine is not
lower than 145 ꢀC.
In all the remaining cases (cyclic amine at C-1 and C-3; acyclic
amine at C-1 and C-3, and acyclic amine at C-1 and cyclic amine at
C-3; or reaction carried out at temperature lower than 145 ꢀC) the
substitution reaction to provide product 3 proceeds as usual and no
unexpected rearrangement reaction was observed.
2. Results and discussion
2.1. Synthesis of 1-amino and 1,3-diamino 4-cyano-7-methyl-
5,6,7,8-tetrahydro-2,7-naphthyridines
Taking into account the above considerations we have now
enlarged our interest to the study of the behavior of 1,3-dichloro-4-
cyano-7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine
1
with
nitrogen-nucleophiles [a series of amines (primary and secondary,
cyclic and acyclic)] in different experimental conditions.18
Firstly we have tested the nucleophilic reactivity of 1 with some
secondary cyclic amines and with a primary amine in quite smooth
experimental conditions: i.e., by refluxing (5 h) in a low-boiling
solvent (methanol) and using a quasi-stoichiometric substrate:-
amine ratio (1:2.2; only a 10% excess has been used). In such a way
we were able to realize the monosubstitution of chlorine at C-1,
thus obtaining the relevant 1-amino-3-chloro-4-cyano-7-methyl-
5,6,7,8-tetrahydro-2,7-naphthyridines (2aeg) with excellent yields
(average yield, ca. 85%).
The next step was the examination of the nucleophilic reactivity
of some monosubstituted products (2aec) with some amines un-
der harsher experimental conditions: i.e., by refluxing (30 min) in
the absence of any solvent and using an excess of amine (sub-
strate:amine ratio¼1:5). Under these experimental conditions the
substitution of the chlorine at C-3 was also achieved. As a result the
2.2. On the structure of compounds 4
To gain information about the structure of these unexpected
products (e.g., 4b) the 1H NMR spectra of 4b was examined. The
presence of a one proton singlet at 5.34 ppm was observed, while
the signal of the CH2 group at C-8 seen in 3b at 3.34 ppm was ab-
sent. Moreover the triplet of the NH group of 3b in the region of
5.80 ppm was shifted to 9.12 ppm in 4b.
relevant
1,3-diamino-4-cyano-7-methyl-5,6,7,8-tetrahydro-2,7-
naphthyridines (3aeg) were obtained with very high yields (aver-
age yield ca. 76%).
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Scheme 2. Syntheses of 1-amino 2 and of 1,3-diamino 3 derivatives of 4-cyano-7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridines.
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S.N. Sirakanyan et al. / Tetrahedron xxx (2014) 1e12
Scheme 3. Synthesis of 6,8-diamino-2-methyl-3,4-dihydro-2,7-naphthyridines 4.
Looking at the IR spectrum, it was observed that the band of the
For example, the MS calculated for 3-[(2-hydroxypropyl)
amino]-7-methyl-1-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-
naphthyridine-4-carbonitrile 3b obtained from the relevant 3-
chloro-7-methyl-1-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-
naphthyridine-4-carbonitrile 2a by short treatment (30 min) with
1-amino-2-propanol (see Section 4.4) furnished the expected value
for the chemical formula C17H25N5O (MW 315).
In contrast, the product obtained from the same 3-chloro-7-
methyl-1-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-
carbonitrile 2a by treatment with 1-amino-2-propanol by long
refluxing (5 h, see Section 4.6, method A) furnished an MS value in
line with the chemical formula C16H24N4O2 (MW 304). This was
consistent with structure 4b.
nitrile group at 2220 cmꢁ1 was absent (this fact was confirmed also
by the absence of the signal of nitrile group in the 13C NMR spec-
trum: for example, compare the 13C NMR spectra of 3b and 4b)
while an absorption band at 1600 cmꢁ1 (suggesting the presence of
a carbonyl group of amidic cyclic type) was present.
The data gave us some nice information on the structure of the
obtained compound, indicating the presence of a cyclic system
condensed with the pyridine ring and at the same time the ‘dis-
appearance’ of the nitrile group and the ‘appearance’ of an amide
group.
Moreover to gain further information about the structure of
compounds 4 we have registered the mass spectra of some of them,
in every case observing molecular weights 11 units lower than
those of the expected compounds 3.
With the aim of determining with certainty the structure of the
compounds obtained X-ray crystallography was used. In two cases
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S.N. Sirakanyan et al. / Tetrahedron xxx (2014) 1e12
5
suitable crystals were obtained and their structures analyzed. The
obtained results (Fig. 1) clearly indicated that a rearrangement had
occurred via a ring-opening at the level of the C-8/Cpyr bond fol-
lowed by a recyclization process occurring by addition onto the
nitrile group.
According to the results reported in Section 2.1 compounds 3 are
considering as starting point. Benzylic-like protons at C-8, linked to
the pyridine ring and to N-7, show some acidic character, thus in
the experimental conditions (an excess of primary amine is pres-
ent) a proton abstraction from the methylene group could occur
Fig. 1. Single crystals X-ray structures of compounds 4b and 4e, respectively.
The structure determined by X-ray analysis for 4b (8-[(2-
hydroxypropyl)amino]-2-methyl-6-pyrrolidin-1-yl-3,4-dihydro-
2,7-naphthyridin-1(2H)-one) is in agreement with the above cited
data collected by using MS, 1H, and 13C NMR, and IR data.
Interestingly, the large shift of the signal of the NH group ob-
served in the 1H NMR spectra of 4b could be related to the hydrogen
bond arising from the interaction between the proton of the NeH
group and the oxygen of the carbonyl.
The chemical structure of compounds 4 and their syntheses are
reported in Scheme 3.
The structure of 4e determined by X-ray analysis confirmed the
previous observations.
2.3. NMR study on the formation of compounds 4
Fig. 2. Diagram of the change in the contents of the compounds 3b and 4b in the
For a better understanding of the reaction course, the reaction
mixture of compound 2b and 1-amino-2-propanol was examined
every 30 min starting from the beginning of the reaction till the end
of it (5 h). The analysis showed that after 25e30 min only the
product of substitution at C-3, that is, 3-[(2-hydroxypropyl)amino]-
7-methyl-1-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-naphthyridine-
4-carbonitrile 3b, was present in the reaction mixture.
The rearrangement occurred only when the reaction mixture
was heated further and the new compound 4b appeared in grad-
ually increasing quantity, while that of 3b obviously decreased.
After 5 h the rearrangement process was complete and only 4b was
present. The course of the reaction was followed by thin-layer
chromatography while the quantitative analysis was performed
by means of 1H NMR spectroscopy (Fig. 2).
reaction mixture determined by 1H NMR spectroscopy.
followed by the breaking of the C-8/Cpyr bond and then by a proton
addition (a protonated primary amine or in the instance of the
aminoalcohols their hydroxyls can act as acids) on the aromatic
carbon of the pyridine ring (path a) with formation of the zwit-
terionic intermediate A.
This zwitterion could assume a proton from one of the acids
present (see above) thus giving the indicated imminium cation B
(path b). In the presence of the large excess of the primary amine, B
could give (path c), by transamination (or by hydrolysis) and by
rotation around the indicated CeC bond, the amine C, having the
right geometry for a nucleophilic attack at the carbon of the nitrile
group.
Details of the 1H NMR analysis are shown in Figs. 3e5. The
spectra reported in Figs. 3 and 4, recorded 30 min and 5 h after the
start of the reaction are in agreement with the spectra of the
compounds 3b and 4b, respectively. A spectrum collected 2 h after
the beginning of the reaction (Fig. 5) showed the presence of both
3b and 4b (ca. 40 and 60%, respectively).
The attack (path d) was thermodynamically guided by the for-
mation of a six-membered ring1b and furnished the cyclic ketimine
D, which in turn, by hydrolysis gave the relevant cyclic amide 4
(path e).19,20
2.4. A hypothesis on the rearrangement mechanism
3. Conclusions
An attempt to describe and comment on the different steps of
the rearrangement, following the hypothesis that the reaction oc-
curred according to the tentative pathway in Scheme 4, is now
reported.
It has been found that the nucleophilic substitution with amines
in the series of 1-amino-3-chloro-5,6,7,8-tetrahydro-2,7-
naphthyridines 2 could proceed in different ways, depending on
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S.N. Sirakanyan et al. / Tetrahedron xxx (2014) 1e12
Fig. 3. 1H NMR spectrum of the compound 3b 30 min after the beginning of the reaction.
Fig. 4. 1H NMR spectrum of the compound 4b 5 h after the beginning of the reaction.
the structure of 2 and on the nature of the used amines (see
Schemes 2 and 3).
In some cases, a new and unexpected rearrangement was ob-
served (see Scheme 3) with formation of derivatives of 2-methyl-
3,4-dihydro-2,7-naphthyridin-1(2H)one 4, which could be in-
teresting from the biological point of view.
In fact, literature data showed that 1-oxo-2,7-naphthyridine
could provide high biological activity21,22 and this fact gives to
this rearrangement a practical significance. The same compounds
could be obtained in similar experimental conditions also from the
relevant 3.
A deep investigation of the course of the nucleophilic reaction
on 2 and 3 revealed that the rearrangement could occur only when
the three following conditions were satisfied: 1) the C-1 of the 2,7-
naphthyridine ring must be substituted by a cyclic amine; 2) the
amine at C-3 in 3 (or acting as nucleophile on 2) must be a primary
one; 3) the boiling points of the primary amine shall be above
145 ꢀC. This last requirement suggests that the rearrangement
process is characterized by a high activation energy barrier.
The structure of the unexpected compounds 4 obtained in the
rearrangement has been confirmed by X-ray structural analysis and
supported by MS, 1H, and 13C NMR, IR and elemental analysis.
It should be remarked that the average yield in all the processes
(both nucleophilic substitutions and rearrangements) was from
very good to excellent, ranging from 76 to 85%, while no process
occurred with yield lower than 70%.
4. Experimental section
4.1. General
1H and 13C NMR spectra were recorded in DMSO-d6 solution
(300 MHz for 1H and 75 MHz for 13C, respectively) on a Varian
Mercury 300VX spectrometer. Chemical shifts are reported as
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S.N. Sirakanyan et al. / Tetrahedron xxx (2014) 1e12
7
Fig. 5. 1H NMR spectrum of the mixture of the compounds 3bþ4b 2 h after the beginning of the reaction.
N
N
N
H
N
H
N
H
N
R3
R3
R3
NH2R1
a
b
.
.
+
+
N
N
N
N
N
N
-
Me
Me
Me
CH
CH2
H
N
3
N
N
R1
R1
R
R1
R
A
R
B
H
Me
Me
N
Me
N
N
.
.
N
H
N
NH
O
H
H
R3
c
H2O
N
N
R3
R3
e
d
N
H2O
-HCOH
N
N
N
R1
N
N
R
R1
R
R1
C
R
D
4
Scheme 4. Mechanism proposed for the synthesis of 4 from 3.
d
(parts per million) relative to TMS as internal standard. IR spectra
Center as supplementary publication for compound 4b CCDC
885576 and for 4e CCDC 884790. Copies of the dates can be ob-
tained, free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax. þ44-(0)1223-336033 or e-mail:
deposit@ccdc.cam.ac.uk).
were recorded on Nicolet Avatar 330-FT-IR spectrophotometer and
the reported wave numbers are given in cmꢁ1. Mass spectra (MS)
were recorded on a spectrometer ‘MX-1321A’ with direct entry of
matter into the ion source at ionization energy 60ev, m/z (Ipto, %). All
melting points were determined in an open capillary and are un-
corrected. Elemental analyses were performed on a Carlo Erba 1108
machine. Quoted values are in the range ꢂ0.4% of the theoretical
ones.
4.2. Procedure for the synthesis of compound 1
A mixture of 1,3-dihydroxy-7-methyl-5,6,7,8-tetrahydro-2,7-
naphthyridine-4-carbonitrile23 (20.5 g, 100 mmol) and phospho-
rus oxychloride (60 ml) was heated in a glass ampoule (180 ml) at
Crystallographic data for the structure of compounds 4b and 4e
have been deposited with the Cambridge Crystallographic Data
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S.N. Sirakanyan et al. / Tetrahedron xxx (2014) 1e12
180 ꢀC for 3 h. After cooling the mixture was poured onto ice and,
with stirring, neutralized with a solution of potassium hydroxide
(10%). The resulting crystals were filtered off, washed with water,
dried, and recrystallized from ethanol.
7.19e7.27 (both m, 3O and 2H, Ph). Anal. Calcd for C22H25ClN4: C
69.37; H 6.62; N 14.71. Found: C 69.44; H 6.75; N 14.66%.
4.3.6. 3-Chloro-1-[4-(diphenylmethyl)piperazin-1-yl]-7-methyl-
5,6,7,8-tetrahydro-2,7-naphthy-ridine-4-carbonitrile (2f). Reaction
of compound 1 with 1-(diphenylmethyl)piperazine gave a yellow
4.2.1. 1,3-Dichloro-7-methyl-5,6,7,8-tetrahydro-2,7-naphthyridine-
4-carbonitrile (1). A light-yellow solid; yield 71%; mp 132e134 ꢀC;
solid; mp 186e188 ꢀC; IR
DMSO-d6) d 2.37 (s, 3H, NCH3), 2.45e2.55 (m, 4O, CHN(CH2)2), 2.65
n
/cmꢁ1: 2218 (CN). 1H NMR (300 MHz,
IR
n
/cmꢁ1: 2218 (CN). 1H NMR (300 MHz, DMSO-d6)
d
2.48 (s, 3H,
CH3), 2.71 (t, J¼5.7 Hz, 2H, NCH2CH2), 3.05 (tt, J¼5.7, 1.3 Hz, 2O,
NCH2CH2), 3.50 (t, J¼1.3 Hz, 2H, NCH2). Anal. Calcd for C10H9Cl2N3: C
49.61, H 3.75, N 17.36. Found: C 49.50, H 3.67, N 17.22%.
(t, J¼6.0 Hz, 2H, NCH2CH2), 2.93 (t, J¼6.0 Hz, 2O, NCH2CH2), 3.21 (br
s, 2H, NCH2), 3.32e3.43 (m, 4O, N(CH2)2), 4.28 (s, 1H, CH), 7.15 (tt,
J¼7.3, 1.5 Hz, 2H, 40-CH, Ph), 7.21e7.29 (m, 4H, 30,50-CH, Ph),
7.38e7.44 (m, 4H, 20,60-CH, Ph). Anal. Calcd for C27H28ClN5: C 70.81;
H 6.16; N 15.29. Found: C 70.73; H 6.22; N 15.31%.
4.3. General procedure for the synthesis of compounds 2aeg
A mixture of dichloride 1 (1.21 g, 5 mmol) and the corre-
sponding amine (11 mmol) in absolute methanol (30 ml) was
refluxed for 5 h. The solvent was removed under vacuum and water
(50 ml) was added. The separated crystals were filtered off, washed
with water, dried, and recrystallized from ethanol.
4.3.7. 3-Chloro-1-[(2-hydroxypropyl)amino]-7-methyl-5,6,7,8-
tetrahydro-2,7-naphthyridine-4-carbonitrile (2g). Reaction of com-
pound 1 with 1-amino-2-propanol gave a pale yellow solid; mp
234e236 ꢀC; IR /cmꢁ1: 2221 (CN). 1H NMR (300 MHz, DMSO-d6)
n
d
1.11 (d, J¼6.3 Hz, 3H, CHCH3), 2.44 (s, 3H, NCH3), 2.55e2.67 (m,
2O, NCH2CH2), 2.79 (tt, J¼5.7, 1.5 Hz, 2O, NCH2CH2), 3.12e3.26 (m,
2H, NCH2), 3.19 (ddd, J¼13.3, 7.7, 5.0 Hz, 1H, NHCH2), 3.48 (ddd,
J¼13.3, 6.0, 4.0 Hz, 1H, NHCH2), 3.76e3.90 (m, 1H, CHCH3), 4.45 (d,
J¼4.6 Hz, 1H, OH), 6.61 (dd, J¼6.0, 5.0 Hz, 1H, NH). 13C NMR
4.3.1. 3-Chloro-7-methyl-1-pyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-
naphthyridine-4-carbonitrile (2a). Reaction of compound 1 with
pyrrolidine gave a yellow solid; mp 179e181 ꢀC; IR /cmꢁ1: 2213
n
(CN). 1H NMR (300 MHz, DMSO-d6)
d
1.88e2.00 (m, 4H, (CH2)2),
(75 MHz, DMSO-d6) d: 20.6, 27.9, 45.2, 48.6, 50.0, 51.4, 64.5, 94.7,
2.40 (s, 3H, NCH3), 2.62 (t, J¼6.0 Hz, 2H, NCH2CH2), 2.86 (tt, J¼6.0,
1.4 Hz, 2O, NCH2CH2), 3.48 (t, J¼1.4 Hz, 2H, NCH2), 3.57e3.69 (m,
4O, N(CH2)2). Anal. Calcd for C14H17ClN4: C 60.76; H 6.19; N 20.24.
Found: C 60.87; H 6.31; N 20.16%.
113.0, 114.9, 145.9, 149.2, 155.5. Anal. Calcd for C13H17ClN4O: C
55.61; H 6.10; N 19.96. Found: C 55.49; H 5.97; N 19.84%.
4.4. General procedure for the synthesis of compounds 3aeg
4.3.2. 3-Chloro-7-methyl-1-morpholin-4-yl-5,6,7,8-tetrahydro-2,7-
A mixture of compounds 2a, b, or c (5 mmol) and the corre-
sponding amine (25 mmol) was refluxed for 30 min. The reaction
mixture was cooled, water (50 ml) was added, and the separated
crystals were filtered off, washed with water, dried, and recrystal-
lized from ethanol.
naphthyridine-4-carbonitrile (2b). Reaction of compound 1 with
morpholine gave a yellow solid; mp 173e175 ꢀC; IR /cmꢁ1: 2214
n
(CN). 1H NMR (300 MHz, DMSO-d6)
d 2.42 (s, 3H, NCH3), 2.68 (t,
J¼6.1 Hz, 2H, NCH2CH2), 2.95 (t, J¼6.1 Hz, 2O, NCH2CH2), 3.28 (s, 2H,
NCH2), 3.29e3.37 (m, 4H, N(CH2)2), 3.68e3.78 (m, 4H, O(CH2)2).
Anal. Calcd for C14H17ClN4O: C 57.44; H 5.85; N 19.14. Found: C
57.52; H 5.92; N 19.32%.
4.4.1. 3-[(2-Hydroxyethyl)amino]-7-methyl-1-pyrrolidin-1-yl-
5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile (3a). Reaction
of compound 2a with 2-aminoethanol
168e170 ꢀC; IR /cmꢁ1: 3380, 3320 (NH), 2215 (CN). 1H NMR
(300 MHz, DMSO-d6) 1.85e1.95 (m, 4H, (CH2)2), 2.34 (s, 3H,
a yellow solid; mp
4.3.3. 3-Chloro-7-methyl-1-piperidin-1-yl-5,6,7,8-tetrahydro-2,7-
n
naphthyridine-4-carbonitrile (2c). Reaction of compound 1 with
d
piperidine gave a pale yellow solid; mp 148e150 ꢀC; IR
n
/cmꢁ1
:
NCH3), 2.58 (t, J¼5.8 Hz, 2H, NCH2CH2), 2.76 (t, J¼5.8 Hz, 2O,
NCH2CH2), 3.34 (br s, 2H, NCH2), 3.42e3.52 (m, 2H, NHCH2),
3.52e3.58 (m, 4O, N(CH2)2), 3.56e3.65 (m, 2H, CH2OH), 4.38 (t,
J¼5.4 Hz, 1H, OH), 5.96 (t, J¼5.3 Hz, 1H, NH). Anal. Calcd for
2215 (CN). 1H NMR (300 MHz, DMSO-d6)
d 1.65e1.71 (m, 6H,
(CH2)3), 2.41 (s, 3H, NCH3), 2.67 (t, J¼6.1 Hz, 2H, NCH2CH2), 2.93 (tt,
J¼6.1, 1.2 Hz, 2O, NCH2CH2), 3.25 (t, J¼1.2 Hz, 2H, NCH2), 3.25e3.33
(m, 4O, N(CH2)2). Anal. Calcd for C15H19ClN4: C 61.96; H 6.59; N
19.27. Found: C 61.89; H 6.65; N 19.33%.
C16H23N5O: C 63.76; H 7.69; N 23.24. Found: C 63.85; H 7.75; N
23.32%.
4.3.4. 3-Chloro-7-methyl-1-(4-methylpiperidin-1-yl)-5,6,7,8-
tetrahydro-2,7-naphthyridine-4-carbonitrile (2d). Reaction of com-
pound 1 with 4-methylpiperidine gave a light-yellow solid; mp
4.4.2. 3-[(2-Hydroxypropyl)amino]-7-methyl-1-pyrrolidin-1-yl-
5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile (3b). Reaction
of compound 2a with 1-amino-2-propanol gave an orange solid;
157e159 ꢀC; IR
n
/cmꢁ1: 2215 (CN). 1H NMR (300 MHz, DMSO-d6)
mp 144e146 ꢀC; IR
(300 MHz, DMSO-d6)
n
/cmꢁ1: 3460, 3330 (NH), 2220 (CN). 1H NMR
d
1.00 (d, J¼6.4 Hz, 3H, CH3), 1.21e1.37 and 1.69e1.79 (m, 4H,
d
1.09 (d, J¼6.3 Hz, 3H, CHCH3), 1.86e1.96 (m,
CH(CH2)2), 1.56e1.70 (m, 1H, CH), 2.41 (s, 3H, NCH3), 2.68 (t,
J¼6.0 Hz, 2H, NCH2CH2), 2.86e2.92 (m, 2O, NCH2, C6H12N), 2.94 (br
t, J¼6.0 Hz, 2O, NCH2CH2), 3.25 (s, 2H, NCH2), 3.66e3.76 (m, 2O,
NCH2, C6H12N). Anal. Calcd for C16H21ClN4: C 63.04; H 6.94; N 18.38.
Found: C 63.11; H 6.87; N 18.46%.
4H, (CH2)2), 2.36 (s, 3H, NCH3), 2.56 (t, J¼5.8 Hz, 2H, NCH2CH2), 2.75
(t, J¼5.8 Hz, 2O, NCH2CH2), 3.11 (ddd, J¼13.3, 7.6, 4.7 Hz, 1H,
NHCH2), 3.34 (br s, 2H, NCH2), 3.49 (ddd, J¼13.3, 6.6, 3.6 Hz, 1H,
NHCH2), 3.51e3.59 (m, 4O, N(CH2)2), 3.71e3.87 (m,1H, CH), 4.46 (d,
J¼4.4 Hz, 1H, OH), 5.80 (dd, J¼6.6, 4.7 Hz, 1H, NH). 13C NMR
(75 MHz, DMSO-d6) d: 20.9, 24.9, 28.3, 45.5, 48.0, 49.1, 50.7, 55.1,
4.3.5. 1-(4-Benzylpiperidin-1-yl)-3-chloro-7-methyl-5,6,7,8-
65.4, 77.9, 104.9, 117.3, 147.1, 155.5, 157.3. MS: m/z (Ipto, %), [Mþ] 315.
315 (10), 297 (1), 240 (73), 244 (61). Anal. Calcd for C17H25N5O: C
64.74; H 7.99; N 22.20. Found: C 64.81; H 7.88; N 22.31%.
tetrahydro-2,7-naphthyridine-4-car-bonitrile
compound 1 with 4-benzylpiperidine gave a white solid; mp
128e130 ꢀC; IR /cmꢁ1: 2220 (CN). 1H NMR (300 MHz, DMSO-d6)
1.26e1.42 (m, 2H), and 1.70e1.85 (m, 3H, CH2CHCH2), 2.41 (s, 3H,
(2e). Reaction
of
n
d
4.4.3. 3-{[2-(Diethylamino)ethyl]amino}-7-methyl-1-pyrrolidin-1-
yl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile
(3c). Reaction of compound 2a with 2-diethylaminoethylamine
NCH3), 2.57 (d, J¼6.9 Hz, 2H, CH2Ph), 2.67 (t, J¼6.1 Hz, 2H,
NCH2CH2), 2.79e2.91 (m, 2O), and 3.65e3.76 (m, 2H, N(CH2)2), 2.93
(t, J¼6.1 Hz, 2O, NCH2CH2), 3.24 (br s, 2H, NCH2), 7.09e7.17 and
gave a pale yellow solid; mp 95e97 ꢀC; IR /cmꢁ1: 3390, 3332
n
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S.N. Sirakanyan et al. / Tetrahedron xxx (2014) 1e12
9
(NH), 2220 (CN).1H NMR (300 MHz, DMSO-d6)
d
1.02 (t, J¼7.1 Hz, 6H,
4.5.1. 7-Methyl-1,3-dipyrrolidin-1-yl-5,6,7,8-tetrahydro-2,7-
N(CH2CH3)2), 1.85e1.93 (m, 4H, (CH2)2), 2.34 (s, 3H, NCH3), 2.52 (q,
J¼7.1 Hz, 4H, N(CH2CH3)2), 2.54 (t, J¼6.0 Hz, 2O, NCH2CH2), 2.57 (t,
J¼6.5 Hz, 2H, NHCH2CH2), 2.73 (t, J¼6.0 Hz, 2H, NCH2CH2), 3.32 (s,
2O, NCH2), 3.37 (td, J¼6.5, 5.4 Hz, 2O, NHCH2), 3.50e3.60 (m, 4H,
N(CH2)2), 5.73 (t, J¼5.4 Hz, 1H, NH). Anal. Calcd for C20H32N6: C
67.38; H 9.05; N 23.57. Found: C 67.42; H 9.11; N 23.51%.
naphthyridine-4-carbonitrile (3h). Reaction of compound 2a with
pyrrolidine gave a gray solid; mp 154e156 ꢀC; IR /cmꢁ1: 2222 (CN).
n
1H NMR (300 MHz, DMSO-d6)
d 1.85e1.98 (m, 8H, 2(CH2)2), 2.36 (s,
3H, NCH3), 2.57 (t, J¼6.0 Hz, 2H, NCH2CH2), 2.76 (t, J¼6.0 Hz, 2O,
NCH2CH2), 3.33 (s, 2H, NCH2), 3.48e3.58 (m, 4O, N(CH2)2),
3.62e3.72 (m, 4O, N(CH2)2). Anal. Calcd for C18H25N5: C 69.42; H
8.09; N 22.49. Found: C 69.51; H 8.18; N 22.60%.
4.4.4. 7-Methyl-1-pyrrolidin-1-yl-3-[(tetrahydrofuran-2-ylmethyl)
amino]-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile
(3d). Reaction of compound 2a with 2-tetrahydrofurfurylamine
4.5.2. 7-Methyl-3-morpholin-4-yl-1-pyrrolidin-1-yl-5,6,7,8-
tetrahydro-2,7-naphthyridine-4-carbonitrile (3i). Reaction of com-
pound 2a with morpholine gave a yellow solid; mp 138e140 ꢀC; IR
gave a brown solid; mp 105e107 ꢀC; IR
n
/cmꢁ1: 3395, 3318 (NH),
2210 (CN). 1H NMR (300 MHz, DMSO-d6)
d
1.58e1.70 and 1.81e1.96
n d 1.85e1.98 (m,
/cmꢁ1: 2220 (CN). 1H NMR (300 MHz, DMSO-d6)
(both m, 1O and 7H, CHCH2CH2 and N(CH2)2), 2.35 (s, 3H, NCH3),
2.55 (t, J¼6.0 Hz, 2H, NCH2CH2), 2.74 (tt, J¼6.0, 1.3 Hz, 2O,
NCH2CH2), 3.34 (t, J¼1.3 Hz, 2O, NCH2), 3.35e3.50 (m, 2H, NHCH2),
3.52e3.60 (m, 4H, N(CH2)2), 3.62e3.72 and 3.78e3.88 (both m, 1H
and 1H, OCH2), 3.97e4.07 (m, 1H, OCH), 5.65 (t, J¼5.7 Hz, 1H, NH).
Anal. Calcd for C19H27N5O: C 66.83; H 7.97; N 20.51. Found: C 66.73;
H 7.88; N 20.59%.
4H, (CH2)2), 2.36 (s, 3H, NCH3), 2.55 (t, J¼6.0 Hz, 2H, NCH2CH2), 2.78
(t, J¼6.0 Hz, 2O, NCH2CH2), 3.38 (s, 2H, NCH2), 3.45e3.62 (m, 8O,
N(CH2)2 and N(CH2)2 of morpholine), 3.68e3.75 (m, 4O, O(CH2)2).
Anal. Calcd for C18H25N5O: C 66.03; H 7.70; N 21.39. Found: C 66.14;
H 7.81; N 21.52%.
4.5.3. 7-Methyl-3-piperidin-1-yl-1-pyrrolidin-1-yl-5,6,7,8-
tetrahydro-2,7-naphthyridine-4-carbonitrile (3j). Reaction of com-
4.4.5. 3-[(2-Hydroxypropyl)amino]-7-methyl-1-morpholin-4-yl-
5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile (3e). Reaction
of compound 2b with 1-amino-2-propanol gave a yellow solid; mp
pound 2a with piperidine gave a white solid; mp 145e147 ꢀC; IR
n/
cmꢁ1: 2221 (CN). 1H NMR (300 MHz, DMSO-d6)
d 1.55e1.68 (m, 6H,
(CH2)3), 1.85e1.95 (m, 4H, (CH2)2), 2.38 (s, 3H, NCH3), 2.58 (t,
J¼6.0 Hz, 2H, NCH2CH2), 2.76 (t, J¼6.0 Hz, 2O, NCH2CH2), 3.36 (s,
2H, NCH2), 3.45e3.62 (m, 8O, N(CH2)2 and N(CH2)2 of piperidine).
Anal. Calcd for C19H27N5: C 70.12; H 8.36; N 21.52. Found: C 70.01; H
8.47; N 21.39%.
129e131 ꢀC; IR
(300 MHz, DMSO-d6)
n
/cmꢁ1: 3500, 3290 (NH), 2211 (CN). 1H NMR
d
1.10 (d, J¼6.3 Hz, 3H, CH3), 2.37 (s, 3H,
NCH3), 2.59 (t, J¼6.1 Hz, 2H, NCH2CH2), 2.81 (t, J¼6.1 Hz, 2O,
NCH2CH2), 3.14 (ddd, J¼13.3, 7.5, 4.7 Hz, 1H, NHCH2), 3.16 (s, 2H,
NCH2), 3.13e3.23 (m, 4O, N(CH2)2), 3.49 (ddd, J¼13.3, 6.5, 3.8 Hz,
1H, NHCH2), 3.65e3.77 (m, 4O, O(CH2)2), 3.74e3.86 (m, 1H, CH),
4.47 (d, J¼4.5 Hz, 1H, OH), 6.04 (dd, J¼6.5, 4.7 Hz, 1H, NH). 13C NMR
4.5.4. 7-Methyl-1-morpholin-4-yl-3-pyrrolidin-1-yl-5,6,7,8-
tetrahydro-2,7-naphthyridine-4-carbonitrile (3k). Reaction of com-
(75 MHz, DMSO-d6)
d: 20.8, 28.1, 45.5, 48.1, 48.9, 51.3, 54.3, 65.1,
pound 2b with pyrrolidine gave
a pale yellow solid; mp
65.9, 82.2, 108.8, 116.3, 148.6, 156.6, 159.7. Anal. Calcd for
17H25N5O2: C 61.61; H 7.60; N 21.13. Found: C 61.72; H 7.68; N
139e141 ꢀC; IR /cmꢁ1: 2219 (CN). 1H NMR (300 MHz, DMSO-d6)
n
C
d
1.89e1.95 (m, 4H, (CH2)2), 2.35 (s, 3H, NCH3), 2.59 (t, J¼6.1 Hz, 2H,
21.22%.
NCH2CH2), 2.82 (t, J¼6.1 Hz, 2O, NCH2CH2), 3.19e3.32 (m, 6H, NCH2
and N(CH2)2 of morpholine), 3.60e3.75 (m, 8H, N(CH2)2 of pyrro-
lidine and O(CH2)2 of morpholine). Anal. Calcd for C18H25N5O: C
66.03; H 7.70; N 21.39. Found: C 66.16; H 7.84; N 21.25%.
4.4.6. 3-[(2-Hydroxyethyl)amino]-7-methyl-1-piperidin-1-yl-
5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile (3f). Reaction of
compound 2c with 2-aminoethanol gave a yellow solid; mp
156e158 ꢀC; IR
(300 MHz, DMSO-d6)
n
/cmꢁ1: 3378, 3170 (NH), 2192 (CN). 1H NMR
4.5.5. 7-Methyl-1,3-dimorpholin-4-yl-5,6,7,8-tetrahydro-2,7-
d
1.60e1.70 (m, 6H, (CH2)3), 2.36 (s, 3H, NCH3),
naphthyridine-4-carbonitrile (3l). Reaction of compound 2b with
2.59 (t, J¼6.0 Hz, 2H, NCH2CH2), 2.79 (t, J¼6.0 Hz, 2O, NCH2CH2), 3.14
(s, 2H, NCH2), 3.12e3.20 (m, 4O, N(CH2)2), 3.42e3.50 (m, 2H,
NHCH2), 3.52e3.60 (m, 2H, CH2OH), 4.38 (t, J¼5.4 Hz, 1H, OH), 5.98
(t, J¼5.3 Hz, 1H, NH). Anal. Calcd for C17H25N5O: C 64.73; H 7.99; N
22.20. Found: C 64.68; H 7.87; N 22.26%.
morpholine gave a white solid; mp 160e162 ꢀC; IR /cmꢁ1: 2221
n
(CN). 1H NMR (300 MHz, DMSO-d6)
d 2.38 (s, 3H, NCH3), 2.61 (t,
J¼6.1 Hz, 2H, NCH2CH2), 2.82 (t, J¼6.1 Hz, 2O, NCH2CH2), 3.15e3.35
(m, 8H, 2N(CH2)2), 3.45e3.68 (m, 4H, O(CH2)2), 3.65e3.75 (m, 6H,
NCH2 and O(CH2)2 of morpholine). Anal. Calcd for C18H25N5O2: C
62.95; H 7.34; N 20.39. Found: C 63.10; H 7.21; N 20.28%.
4.4.7. 3-{[1-(Hydroxymethyl)propyl]amino}-7-methyl-1-piperidin-
1-yl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile
(3g). Reaction of compound 2c with 2-amino-1-butanol gave an
4.5.6. 7-Methyl-3-[(3-methylbutyl)amino]-1-pyrrolidin-1-yl-5,6,7,8-
tetrahydro-2,7-naphthyridine-4-carbonitrile
compound 2a with isopentylamine gave a brown solid; mp
114e116 ꢀC; IR /cmꢁ1: 3398, 3321 (NH), 2220 (CN). 1H NMR
(300 MHz, DMSO-d6)
0.93 (d, J¼6.6 Hz, 6H, CH(CH3)2), 1.42e1.50
(3m). Reaction
of
orange solid; mp 111e113 ꢀC; IR
n
/cmꢁ1: 3378, 3312 (NH), 2218
0.93 (t, J¼7.5 Hz, 3H, CH3),
(CN). 1H NMR (300 MHz, DMSO-d6)
d
n
1.52e1.76 (both m, 2H and 6H, CH2CH3 and (CH2)3), 2.36 (s, 3H,
NCH3), 2.58 (t, J¼6.2 Hz, 2H, NCH2CH2), 2.78 (t, J¼6.2 Hz, 2O,
NCH2CH2), 3.09e3.25 (m, 6O, N(CH2)2 and NCH2), 3.45e358 (m, 2H,
CH2OH), 3.91e4.03 (m,1H, CH), 4.40 (dd, J¼5.6, 4.6 Hz,1H, OH), 5.53
(d, J¼7.6 Hz, 1H, NH). Anal. Calcd for C19H29N5O: C 66.44; H 8.51; N
20.39. Found: C 66.31; H 8.65; N 20.28%.
d
(m, 2H, CHCH2), 1.65 (sp, J¼6.6 Hz, 1H, CH(CH3)2), 1.87e1.93 (m, 4H,
(CH2)2), 2.36 (s, 3H, NCH3), 2.56 (t, J¼6.0 Hz, 2H, NCH2CH2), 2.73 (t,
J¼6.0 Hz, 2O, NCH2CH2), 3.32e3.40 (m, 2O, NHCH2), 3.35 (s, 2O,
NCH2), 3.52e3.58 (m, 4O, N(CH2)2), 5.71 (t, J¼5.7 Hz, 1H, NH). Anal.
Calcd for C19H29N5: C 69.69; H 8.93; N 21.39. Found: C 69.59; H
9.01; N 21.25%.
4.5. General procedure for the synthesis of compounds 3het
4.5.7. 3-[(2-Aminoethyl)amino]-7-methyl-1-pyrrolidin-1-yl-5,6,7,8-
tetrahydro-2,7-naphthyridine-4-carbonitrile (3n). Reaction of com-
pound 2a with ethylendiamine gave a pale yellow solid; mp
A mixture of compounds 2a, b, or g (5 mmol) and the corre-
sponding amine (25 mmol) was refluxed for 5 h. The reaction
mixture was cooled, water (50 ml) was added, and the separated
crystals were filtered off, washed with water, dried, and recrystal-
lized from ethanol.
161e163 ꢀC; IR
NMR (300 MHz, DMSO-d6)
(CH2)2), 2.35 (s, 3H, NCH3), 2.55 (t, J¼6.0 Hz, 2H, CH2NH2), 2.74 (t,
n
/cmꢁ1: 3480, 3350, 3320 (NH, NH2), 2215 (CN). 1H
d
1.26 (br, 2H, NH2), 1.87e1.93 (m, 4H,
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10
S.N. Sirakanyan et al. / Tetrahedron xxx (2014) 1e12
J¼5.9 Hz, 2H, NCH2CH2), 2.77 (t, J¼5.9 Hz, 2O, NCH2CH2), 3.33 (s,
2O, NCH2), 3.37 (q, J¼5.8 Hz, 2O, NHCH2), 3.52e3.59 (m, 4O,
N(CH2)2), 5.97 (br t, J¼5.5 Hz, 1H, NH). Anal. Calcd for C16H24N6: C
63.97; H 8.05; N 27.98. Found: C 63.85; H 8.15; N 28.18%.
compound 2g with morpholine gave
185e187 ꢀC; IR /cmꢁ1: 3389, 3308 (NH), 2219 (CN). 1H NMR
(300 MHz, DMSO-d6)
1.08 (d, J¼6.2 Hz, 3H, CHCH3), 2.41 (s, 3H,
a yellow solid; mp
n
d
NCH3), 2.53e2.63 (m, 2H, NCH2CH2), 2.66e2.76 (m, 2O, NCH2CH2),
3.17 (ddd, J¼13.3, 7.3, 4.9 Hz, 1O, NHCH2), 3.11 (d, J¼14.7 Hz, 1O,
NCH2), 3.16 (d, J¼14.7 Hz, 1O, NCH2), 3.44 (ddd, J¼13.3, 6.1, 4.2 Hz,
1O, NHCH2), 3.43e3.53 (m, 4O, N(CH2)2), 3.65e3.77 (m, 4O,
O(CH2)2), 3.76e3.88 (m, 1O, CHCH3), 4.41 (d, J¼4.4 Hz, 1H, OH), 6.11
(dd, J¼6.1, 4.9 Hz, 1H, NH). Anal. Calcd for C17H25N5O2: C 61.61; H
7.60; N 21.13. Found: C 61.51; H 7.52; N 21.21%.
4.5.8. 3-{[2-(Dimethylamino)ethyl]amino}-7-methyl-1-pyrrolidin-1-
yl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile
(3o). Reaction of compound 2a with 2-(dimethylamino)ethylamine
gave a gray solid; mp 149e151 ꢀC; IR
n
/cmꢁ1: 3393, 3335 (NH), 2222
1.88e1.94 (m, 4H, (CH2)2), 2.24
(CN). 1H NMR (300 MHz, DMSO-d6)
d
(s, 6H, N(CH3)2), 2.35(s, 3H, NCH3), 2.47 (t, J¼6.5 Hz, 2H, CH2N(CH3)2),
2.55 (t, J¼6.0 Hz, 2H, NCH2CH2), 2.74 (t, J¼6.0 Hz, 2O, NCH2CH2), 3.33
(s, 2O, NCH2), 3.43 (td, J¼6.5, 5.1 Hz, 2O, NHCH2), 3.53e3.60 (m, 4O,
N(CH2)2), 5.71 (br t, J¼5.1 Hz, 1H, NH). Anal. Calcd for C18H28N6: C
65.82; H 8.59; N 25.59. Found: C 65.91; H 8.47; N 25.70%.
4.6. General procedure for the synthesis of compounds 4aeg
A. A mixture of compound 2 (5 mmol) and the corresponding
amine (25 mmol) was refluxed for 5 h. The reaction mixture
was cooled, water (50 ml) was added, and the separated crys-
tals were filtered off, washed with water, dried, and recrystal-
lized from ethanol.
B. A mixture of compound 3 (5 mmol) and the corresponding
amine (25 mmol) was refluxed for 4.5 h. The product was
isolated as in method A.
4.5.9. 3-[(3-Methoxypropyl)amino]-7-methyl-1-pyrrolidin-1-yl-
5,6,7,8-tetrahydro-2,7-naphthyridine-4-car-bonitrile (3p). Reaction
of compound 2a with 3-methoxypropylamine gave a white solid;
mp 109e111 ꢀC; IR
(300 MHz, DMSO-d6)
n
/cmꢁ1: 3372 (NH), 2184 (CN). 1H NMR
1.76e1.85 (m, 2H, NHCH2CH2),1.87e1.93 (m,
d
4H, (CH2)2), 2.35 (s, 3H, NCH3), 2.55 (t, J¼6.0 Hz, 2H, NCH2CH2), 2.74
(t, J¼6.0 Hz, 2O, NCH2CH2), 3.29 (s, 3O, OCH3), 3.33 (s, 2O, NCH2),
3.38e3.45 (m, 4O, NHCH2 and CH2O), 3.53e3.59 (m, 4O, N(CH2)2),
5.91 (br t, J¼5.9 Hz, 1H, NH). Anal. Calcd for C18H27N5O: C 65.62; H
8.26; N 21.26. Found: C 65.73; H 8.15; N 21.37%.
4.6.1. 8-[(2-Hydroxyethyl)amino]-2-methyl-6-pyrrolidin-1-yl-3,4-
dihydro-2,7-naphthyridin-1(2H)-one (4a). Reaction of compound
2a or 3a with 2-aminoethanol gave a white solid; mp 147e149 ꢀC;
IR
d6)
n
/cmꢁ1: 3401, 3312 (NH), 1605 (CO). 1H NMR (300 MHz, DMSO-
4.5.10. 3-{[3-(Dimethylamino)propyl]amino}-7-methyl-1-pyrrolidin-
1-yl-5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile
(3q). Reaction of compound 2a with 3-(dimethylamino)-1-
d
1.92e2.04 (m, 4H, (CH2)2), 2.74 (t, J¼6.6 Hz, 2H, NCH2CH2),
2.95 (s, 3H, NCH3), 3.39 (t, J¼6.6 Hz, 2O, NCH2CH2), 3.42e3.52 (m,
6O, N(CH2)2 and NHCH2), 3.58 (m, 2H, CH2OH), 4.46 (t, J¼4.8 Hz,1H,
OH), 5.35 (s, 1H, CH), 9.08 (t, J¼5.1 Hz, 1H, NH). Anal. Calcd for
propylamine gave a light-yellow solid; mp 138e140 ꢀC; IR
n/
cmꢁ1: 3343 (NH), 2219 (CN). 1H NMR (300 MHz, DMSO-d6)
d
1.69
C15H22N4O2: C 62.05; H 7.64; N 19.30. Found: C 62.12; H 7.52; N
(q, J¼6.4 Hz, 2H, NHCH2CH2), 1.87e1.93 (m, 4H, (CH2)2), 2.20 (s, 6H,
N(CH3)2), 2.34 (t, J¼6.5 Hz, 2H, CH2N(CH3)2), 2.35 (s, 3H, NCH3), 2.55
(t, J¼6.0 Hz, 2H, NCH2CH2), 2.73 (t, J¼6.0 Hz, 2O, NCH2CH2), 3.32 (s,
2O, NCH2), 3.41 (td, J¼6.4, 5.2 Hz, 2O, NHCH2), 3.52e3.58 (m, 4O,
N(CH2)2), 6.54 (br t, J¼5.2 Hz, 1H, NH). Anal. Calcd for C19H30N6: C
66.63; H 8.83; N 24.54. Found: C 66.51; H 8.75; N 24.41%.
19.43%.
4.6.2. 8-[(2-Hydroxypropyl)amino]-2-methyl-6-pyrrolidin-1-yl-3,4-
dihydro-2,7-naphthyridin-1(2H)-one (4b). Reaction of compound
2a or 3a with 1-amino-2-propanol gave
166e168 ꢀC; IR /cmꢁ1: 3393, 3320 (NH), 1600 (CO). 1H NMR
(300 MHz, DMSO-d6)
1.10 (d, J¼6.3 Hz, 3H, CH3), 1.94e2.03 (m, 4H,
a lactic solid; mp
n
d
4.5.11. 1,3-Bis[(2-hydroxypropyl)amino]-7-methyl-5,6,7,8-
tetrahydro-2,7-naphthyridine-4-carbonitrile (3r). Reaction of com-
pound 2g with 1-amino-2-propanol gave a brown solid; mp
(CH2)2), 2.74 (t, J¼6.6 Hz, 2H, NCH2CH2), 2.88 (s, 3H, NCH3), 3.28
(ddd, J¼13.5, 6.8, 5.4 Hz, 1H, NHCH2), 3.39 (t, J¼6.6 Hz, 2O,
NCH2CH2), 3.44 (ddd, J¼13.5, 6.2, 4.1 Hz, 1H, NHCH2), 3.38e3.50 (m,
4O, N(CH2)2), 3.74e3.86 (m,1H, CH), 4.64 (d, J¼4.3 Hz,1H, OH), 5.34
(s, 1H, CH), 9.12 (dd, J¼6.2, 5.4 Hz, 1H, NH). 13C NMR (75 MHz,
193e195 ꢀC; IR
DMSO-d6)
n
/cmꢁ1: 3324 (NH), 2192 (CN). 1H NMR (300 MHz,
1.09 (d, J¼6.3 Hz, 3H, CHCH3), 1.09 (d, J¼6.3 Hz, 3H,
d
CHCH3), 2.40 (s, 3H, NCH3), 2.53e2.62 (m, 2H, NCH2CH2), 2.62e2.70
(m, 2O, NCH2CH2), 3.04e3.19 (m, 4O, NCH2, 2NHCH2), 3.42e3.53
(m, 2O, NHCH2), 3.73e3.88 (m, 2O, 2CHCH3), 4.45 (d, J¼4.1 Hz, 1H,
OH), 4.52 (d, J¼4.3 Hz, 1H, OH), 5.73e5.83 (m, 1H, NH), 5.88e5.98
(m, 1H, NH). Anal. Calcd for C16H25N5O2: C 60.17; H 7.89; N 21.93.
Found: C 60.04; H 7.98; N 22.02%.
DMSO-d6) d: 21.1, 25.5, 29.1, 34.9, 46.9, 47.6, 49.5, 70.1, 93.3, 95.0,
150.3, 157.1, 159.9, 167.5. MS: m/z (Ipto, %), [Mþ] 304. 304 (22), 259
(100), 229 (5). Anal. Calcd for C16H24N4O2: C 63.13; H 7.95; N 18.41.
Found: C 63.22; H 7.87; N 18.52%.
4.6.3. 8-{[2-(Diethylamino)ethyl]amino}-2-methyl-6-pyrrolidin-1-
yl-3,4-dihydro-2,7-naphthyridin-1(2H)-one (4c). Reaction of com-
pound 2a or 3c with 2-diethylaminoethylamine gave a white solid;
4.5.12. 1-[(2-Hydroxypropyl)amino]-7-methyl-3-pyrrolidin-1-yl-
5,6,7,8-tetrahydro-2,7-naphthyridine-4-car-bonitrile (3s). Reaction
of compound 2g with pyrrolidine gave a light-yellow solid; mp
mp 117e119 ꢀC; IR
(300 MHz, DMSO-d6)
n
/cmꢁ1: 3399, 3350 (NH), 1601 (CO). 1H NMR
d
1.03 (t, J¼7.1 Hz, 6H, N(CH2CH3)2), 1.93e2.02
177e179 ꢀC; IR
(300 MHz, DMSO-d6)
n
/cmꢁ1: 3332, 3140 (NH), 2182 (CN). 1H NMR
(m, 4H, (CH2)2), 2.55 (q, J¼7.1 Hz, 4H, N(CH2CH3)2), 2.59 (t, J¼6.6 Hz,
2H, NCH2), 2.73 (t, J¼6.6 Hz, 2H, NCH2CH2), 2.94 (s, 3H, NCH3), 3.38
(t, J¼6.6 Hz, 2O, NCH2CH2), 3.38e3.52 (m, 6O, N(CH2)2 and NHCH2),
5.30 (s, 1H, CH), 8.92 (t, J¼5.5 Hz, 1H, NH). Anal. Calcd for
d
1.08 (d, J¼6.3 Hz, 3H, CHCH3), 1.89e2.00 (m,
4H, (CH2)2), 2.40 (s, 3H, NCH3), 2.53e2.61 (m, 2H, NCH2CH2),
2.64e2.72 (m, 2O, NCH2CH2), 3.08 (dt, J¼14.2, 1.3 Hz, 1O, NCH2),
3.12 (ddd, J¼13.3, 7.3, 4.8 Hz,1O, NHCH2), 3.13 (dt, J¼14.2,1.3 Hz,1O,
NCH2), 3.48 (ddd, J¼13.3, 6.2, 3.6 Hz,1O, NHCH2), 3.62e3.72 (m, 4O,
N(CH2)2), 3.76e3.88 (m, 1O, CHCH3), 4.40 (d, J¼4.3 Hz, 1H, OH), 5.85
(dd, J¼6.2, 4.8 Hz, 1H, NH). Anal. Calcd for C17H25N5O: C 64.73; H
7.99; N 22.20. Found: C 64.61; H 8.10; N 22.11%.
C19H31N5O: C 66.05; H 9.04; N 20.27. Found: C 66.13; H 9.11; N
20.19%.
4.6.4. 2-Methyl-6-pyrrolidin-1-yl-8-[(tetrahydrofuran-2-ylmethyl)
amino]-3,4-dihydro-2,7-naphthyridin-1(2H)-one (4d). Reaction of
compound 2a or 3d with 2-tetrahydrofurfurylamine gave a gray
4.5.13. 1-[(2-Hydroxypropyl)amino]-7-methyl-3-morpholin-4-yl-
5,6,7,8-tetrahydro-2,7-naphthyridine-4-carbonitrile (3t). Reaction of
solid; mp 158e160 ꢀC; IR
NMR (300 MHz, DMSO-d6)
n
/cmꢁ1: 3415, 3360 (NH), 1605 (CO). 1H
d 1.60e1.72 and 1.80e1.95 (both m, 1O
Please cite this article in press as: Sirakanyan, S. N.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.070

S.N. Sirakanyan et al. / Tetrahedron xxx (2014) 1e12
11
and 3H, CHCH2CH2), 1.94e2.03 (m, 4H, (CH2)2), 2.74 (t, J¼6.6 Hz, 2H,
NCH2CH2), 2.95 (s, 3H, NCH3), 3.39 (t, J¼6.6 Hz, 2O, NCH2CH2),
3.42e3.58 (m, 6O, N(CH2)2 and NHCH2), 3.62e3.72 and 3.81e3.91
(both m, 1H and 1H, OCH2), 3.95e4.06 (m, 1H, OCH), 5.32 (s, 1H,
CH), 9.00 (t, J¼5.6 Hz, 1H, NH). Anal. Calcd for C18H26N4O2: C 65.43;
H 7.93; N 16.96. Found: C 65.39; H 7.88; N 16.89%.
1H, CH), 9.04 (dd, J¼6.1, 5.5 Hz,1H, NH). Anal. Calcd for C17H26N4O2:
C 64.12; H 8.23; N 17.60. Found: C 64.19; H 8.31; N 17.71%.
4.7.3. 2-Methyl-8-[(2-morpholin-4-ylethyl)amino]-6-piperidin-1-yl-
3,4-dihydro-2,7-naphthyridin-1(2H)-one (4j). Reaction of com-
pound 2c with 2-morpholinoethylamine gave a yellow solid; yield
73%; mp 141e143 ꢀC; IR
NMR (300 MHz, DMSO-d6)
n
/cmꢁ1: 3415, 3310 (NH), 1604 (CO). 1H
d 1.54e1.71 (m, 6H, (CH2)3), 2.39e2.51
4.6.5. 8-[(2-Hydroxypropyl)amino]-2-methyl-6-morpholin-4-yl-3,4-
dihydro-2,7-naphthyridin-1(2H)-one (4e). Reaction of compound
2b or 3e with 1-amino-2-propanol gave a lactic solid; mp
(m, 4O, N(CH2)2), 2.54 (t, J¼6.6 Hz, 2H, NHCH2CH2), 2.73 (t,
J¼6.6 Hz, 2H, NCH2CH2), 2.95 (s, 3H, NCH3), 3.39 (t, J¼6.6 Hz, 2O,
NCH2CH2), 3.49 (td, J¼6.6, 5.3 Hz, 2O, NHCH2), 3.52e3.62 (m, 4O,
N(CH2)2), 3.57e3.67 (m, 4O, O(CH2)2), 5.58 (s, 1H, CH), 8.92 (d,
J¼5.3 Hz, 1H, NH). Anal. Calcd for C20H31N5O2: C 64.32; H 8.37; N
18.75. Found: C 64.43; H 8.42; N 18.66%.
143e145 ꢀC; IR
(300 MHz, DMSO-d6)
n
/cmꢁ1: 3408, 3316 (NH), 1604 (CO). 1H NMR
d
1.12 (d, J¼6.2 Hz, 3H, CH3), 2.75 (t, J¼6.6 Hz,
2H, NCH2CH2), 2.96 (s, 3H, NCH3), 3.27 (ddd, J¼13.3, 6.6, 5.3 Hz, 1H,
NHCH2), 3.38 (ddd, J¼13.3, 5.9, 4.8 Hz, 1H, NHCH2), 3.40 (t, J¼6.6 Hz,
2O, NCH2CH2), 3.46e3.56 (m, 4O, N(CH2)2), 3.63e3.73 (m, 4O,
O(CH2)2), 3.74e3.86 (m, 1H, CH), 4.33 (d, J¼4.6 Hz, 1H, OH), 5.61 (s,
1H, CH), 9.06 (dd, J¼5.9, 5.3 Hz, 1H, NH). MS: m/z (Ipto, %), [Mþ] 320.
320 (19), 275 (100), 245 (4). Anal. Calcd for C16H24N4O3: C 59.98; H
7.55; N 17.49. Found: C 59.85; H 7.46; N 17.38%.
4.7.4. 8-[(2-Hydroxypropyl)amino]-2-methyl-6-(4-methylpiperidin-
1-yl)-3,4-dihydro-2,7-naphthyridin-1(2H)-one (4k). Reaction of
compound 2d with 1-amino-2-propanol gave a lactic solid; yield
71%; mp 146e148 ꢀC; IR
NMR (300 MHz, DMSO-d6)
n
/cmꢁ1: 3420, 3345 (NH), 1600 (CO). 1H
d
0.96 (d, J¼6.2 Hz, 3H, (CH2)2CHCH3),
4.6.6. 8-[(2-Hydroxyethyl)amino]-2-methyl-6-piperidin-1-yl-3,4-
1.12 (d, J¼6.2 Hz, 3H, OHCHCH3), 1.10e1.21 and 1.55e1.72 (both m,
2H and 3H, CH(CH2)2), 2.73 (t, J¼6.6 Hz, 2H, NCH2CH2), 2.79 (td,
J¼12.5, 2.2 Hz, 2H), and 4.32 (td, J¼12.5, 2.9 Hz, 2H, N(CH2)2), 2.95
(s, 3H, NCH3), 3.25 (ddd, J¼13.2, 6.6, 5.3 Hz, 1H, NHCH2), 3.39 (t,
J¼6.6 Hz, 2H, NCH2CH2), 3.41 (ddd, J¼13.2, 6.0, 4.4 Hz, 1H, NHCH2),
3.74e3.86 (m, 1H, OHCH), 4.34 (d, J¼4.5 Hz, 1H, OH), 5.60 (s, 1H,
CH), 9.03 (br dd, J¼6.0, 5.3 Hz, 1H, NH). 13C NMR (75 MHz, DMSO-
dihydro-2,7-naphthyridin-1(2H)-one (4f). Reaction of compound 2c
or 3f with 2-aminoethanol gave a brown solid; mp 138e140 ꢀC; IR
n/
cmꢁ1: 3400, 3330 (NH), 1603 (CO). 1H NMR (300 MHz, DMSO-d6)
d
1.54e1.65 (m, 6H, (CH2)3), 2.73 (t, J¼6.6 Hz, 2H, NCH2CH2), 2.95 (s,
3H, NCH3), 3.39(t, J¼6.6 Hz, 2O, NCH2CH2), 3.41e3.51 (m, 2H, NHCH2),
3.52e3.62 (m, 6H, CH2OH, N(CH2)2), 4.28 (d, J¼5.3 Hz,1H, OH), 5.59 (s,
1H, CH), 8.99(t, J¼5.6 Hz,1H, NH). Anal. Calcd for C16H24N4O2: C 63.13;
H 7.95; N 18.41. Found: C 63.24; H 7.86; N 18.50%.
d6) d: 21.0, 21.5, 28.5, 30.7, 33.3, 34.0, 44.3, 46.7, 47.7, 65.8, 91.2, 94.6,
149.4, 157.7, 157.9, 165.8. MS: m/z (Ipto, %), [Mþ] 332. 332 (27), 287
(100), 257 (7), 98 (2). Anal. Calcd for C18H28N4O2: C 65.03; H 8.49; N
16.85. Found: C 65.14; H 8.39; N 16.79%.
4.6.7. 8-{[1-(Hydroxymethyl)propyl]amino}-2-methyl-6-piperidin-
1-yl-3,4-dihydro-2,7-naphthyridin-1(2H)-one (4g). Reaction of
compound 2c or 3g with 2-amino-1-butanol gave a white solid; mp
4.7.5. 6-(4-Benzylpiperidin-1-yl)-8-{[1-(hydroxymethyl)propyl]
amino}-2-methyl-3,4-dihydro-2,7-naphthyri-din-1(2H)-one
(4l). Reaction of compound 2e with 2-amino-1-butanol gave
109e111 ꢀC; IR
(300 MHz, DMSO-d6)
CH2CH3, (CH2)3), 2.73 (t, J¼6.6 Hz, 2H, NCH2CH2), 2.95 (s, 3H, NCH3),
3.39 (t, J¼6.6 Hz, 2O, NCH2CH2); 3.42e3.58 (m, 6O, N(CH2)2 and
OHCH2), 3.91e4.02 (m,1H, CH), 4.21 (dd, J¼5.6, 4.6 Hz,1H, OH), 5.58
(s, 1H, CH), 8.92 (d, J¼7.6 Hz, 1H, NH). Anal. Calcd for C18H28N4O2: C
65.03; H 8.49; N 16.85. Found: C 65.11; H 8.40; N 16.72%.
n
/cmꢁ1: 3360, 3290 (NH), 1602 (CO). 1H NMR
d
0.96 (t, J¼7.5 Hz, 3H, CH3), 1.45e1.76 (m, 8H,
a white solid; yield 76%; mp 159e161 ꢀC; IR
n
/cmꢁ1: 3400, 3319
0.96 (t, J¼7.4 Hz,
(NH), 1601 (CO). 1H NMR (300 MHz, DMSO-d6)
d
3H, CH3), 1.15e1.29 (m, 2H), 1.45e1.59 (m, 1H), and 1.62e1.87 (m,
4H, CH2CHCH2, CH2CH3), 2.53 (d, J¼7.2 Hz, 2H, CH2Ph), 2.69e2.77
(m, 4H, NCH2CH2, N(CH2)2), 2.95 (s, 3H, NCH3), 3.39 (t, J¼6.6 Hz, 2O,
NCH2CH2), 3.37e3.55 (m, 2H, HOCH2), 3.88e4.00 (m, 1H, NHCH),
4.21 (dd, J¼5.6, 4.6 Hz, 1H, OH), 4.28e4.40 (m, 2H, N(CH2)2), 5.58 (s,
1H, CH), 7.07e7.16 and 7.18e7.26 (both m, 3H and 2H, Ph), 8.92 (d,
J¼7.6 Hz, 1H, NH). Anal. Calcd for C25H34N4O2: C 71.06; H 8.11; N
13.26. Found: C 71.14; H 8.21; N 13.34%.
4.7. General procedure for the synthesis of compounds 4hem
The A method of preparation of compounds 4aeg was used.
4.7.1. 8-{[1-(Hydroxymethyl)propyl]amino}-2-methyl-6-pyrrolidin-
1-yl-3,4-dihydro-2,7-naphthyridin-1(2H)-one (4h). Reaction of
compound 2a with 2-amino-1-butanol gave a white solid; mp
4.7.6. 6-[4-(Diphenylmethyl)piperazin-1-yl]-8-[(2-hydroxyethyl)
amino]-2-methyl-3,4-dihydro-2,7-naphthy-ridin-1(2H)-one
(4m). Reaction of compound 2f with 2-aminoethanol gave a brown
126e128 ꢀC; IR
DMSO-d6)
n
/cmꢁ1: 3239 (NH), 1610 (CO). 1H NMR (300 MHz,
d
0.97 (t, J¼7.4 Hz, 3H, CH3), 1.45e1.60 and 1.61e1.74
solid; yield 74%; mp 108e110 ꢀC; IR
n
/cmꢁ1: 3402, 3326 (NH), 1600
2.40e2.46 (m, 4O,
(both m, 1H and 1H, CH2CH3), 1.94e2.02 (m, 4H, (CH2)2), 2.74 (t,
J¼6.7 Hz, 2H, NCH2CH2), 2.95 (s, 3H, NCH3), 3.39 (t, J¼6.7 Hz, 2O,
NCH2CH2), 3.40e3.52 (m, 6O, N(CH2)2 and OHCH2), 3.93e4.04 (m,
1H, CH), 4.47 (t, J¼5.1 Hz, 1H, OH), 5.33 (s, 1H, CH), 9.00 (d, J¼7.2 Hz,
1H, NH). Anal. Calcd for C17H26N4O2: C 64.12; H 8.23; N 17.60.
Found: C 64.21; H 8.35; N 17.52%.
(CO). 1H NMR (300 MHz, DMSO-d6)
d
CHN(CH2)2), 2.73 (t, J¼6.6 Hz, 2H, NCH2CH2), 2.95 (s, 3H, NCH3),
3.38 (t, J¼6.6 Hz, 2O, NCH2CH2), 3.40 (q, J¼5.4 Hz, 2H, NHCH2), 3.51
(td, J¼5.4, 5.0 Hz, 2H, OHCH2), 3.54e3.59 (m, 4O, N(CH2)2), 4.25 (s,
1H, CH), 4.26 (t, J¼5.0 Hz, 1H, OH), 5.56 (s, 1H, CH), 7.15 (tt, J¼7.2,
1.4 Hz, 2H, 40-CH, Ph), 7.22e7.28 (m, 4H, 30,50-CH, Ph), 7.39e7.43 (m,
4H, 20,60-CH, Ph), 8.97 (t, J¼5.4 Hz, 1H, NH). 13C NMR (75 MHz,
4.7.2. 8-[(2-Hydroxypropyl)amino]-2-methyl-6-piperidin-1-yl-3,4-
DMSO-d6) d: 28.5, 34.0, 42.6, 44.0, 46.7, 51.2, 60.5, 75.4, 91.2, 95.3,
dihydro-2,7-naphthyridin-1(2H)-one (4i). Reaction of compound 2c
126.4, 127.3, 128.0, 142.1, 149.6, 157.4, 158.2, 165.8. Anal. Calcd for
C28H33N5O2: C 71.31; H 7.05; N 14.85. Found: C 71.25; H 7.12; N
14.96%.
with 1-amino-2-propanol gave
182e184 ꢀC; IR /cmꢁ1: 3360, 3280 (NH), 1600 (CO). 1H NMR
(300 MHz, DMSO-d6)
a
light-yellow solid; mp
n
d
1.12 (d, J¼6.3 Hz, 3H, CH3), 1.54e1.71 (m, 6H,
(CH2)3), 2.73 (t, J¼6.6 Hz, 2H, NCH2CH2), 2.95 (s, 3H, NCH3), 3.26
(ddd, J¼13.3, 6.6, 5.3 Hz, 1H, NHCH2), 3.39 (ddd, J¼13.3, 6.1, 4.5 Hz,
1H, NHCH2), 3.41 (t, J¼6.6 Hz, 2O, NCH2CH2), 3.50e3.60 (m, 4O,
N(CH2)2), 3.74e3.86 (m, 1H, CH), 4.33 (d, J¼4.6 Hz, 1H, OH), 5.59 (s,
References and notes
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Society: An Introduction to Heterocyclic Chemistry, Biochemistry and Applications;
Please cite this article in press as: Sirakanyan, S. N.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.070

12
S.N. Sirakanyan et al. / Tetrahedron xxx (2014) 1e12
J. Wiley & Sons, 2011; Eicher, T.; (b) Hauptmann, S.; Speicher, A. The Chemistry of
Heterocycles (Structure, Reactions, Syntheses, and Applications); Wiley-VCH, 2012.
11. Chowdhury, U. S. Tetrahedron 1990, 46, 7893e7900.
12. Reimann, E.; Renz, H. Monatsh. Chem. 1994, 125, 1397e1406.
13. Paronikyan, E. G.; Mirzoyan, G. V.; Noravyan, A. S.; Arzanunts, E. M.; Sukasyan,
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Please cite this article in press as: Sirakanyan, S. N.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.05.070