Synthesis and structure of condensed triazolo- and tetrazolopyrimidines

Article abstract of DOI:10.1016/j.tet.2013.10.015

Herein we present the synthesis of several new hydrazino derivatives of cyclopenta[c]pyridine, 5,6,7,8-tetrahydroisoquinoline and pyrano[3,4-c]pyridine from 3-oxo-4-cyano fused pyridine derivatives. The hydrazino derivatives obtained were used as starting materials for the synthesis of isomeric triazolopyrimidines as well as tetrazolopyrimidines. Furthermore, the rearrangement of triazolopyrimidines 7 into triazolopyrimidines 8 is also presented. In DMSO tetrazolopyrimidines 10 were shown to be in equilibrium with the relevant azidopyrimidines 9. The tetrazolopyrimidine structure was confirmed by X-ray crystallography. The synthesized compounds were tested for their antimicrobial activity.

Full text of DOI:10.1016/j.tet.2013.10.015

Tetrahedron 69 (2013) 10637e10643
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and structure of condensed triazolo- and
tetrazolopyrimidines
,
Samvel N. Sirakanyan a, Athina Geronikaki b, Domenico Spinelli c
*
,
Anush A. Hovakimyan a, Azat S. Noravyan a
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, Yerevan 0014, Armenia
b Aristotle University of Thessaloniki, School of Pharmacy, Thessaloniki 54124, Greece
c
ꢀ
Dipartimento di Chimica G. Ciamician, Universita degli Studi di Bologna, Bologna 40126, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 June 2013
Received in revised form 26 September 2013
Accepted 7 October 2013
Available online 18 October 2013
Herein we present the synthesis of several new hydrazino derivatives of cyclopenta[c]pyridine, 5,6,7,8-
tetrahydroisoquinoline and pyrano[3,4-c]pyridine from 3-oxo-4-cyano fused pyridine derivatives. The
hydrazino derivatives obtained were used as starting materials for the synthesis of isomeric tri-
azolopyrimidines as well as tetrazolopyrimidines. Furthermore, the rearrangement of triazolopyr-
imidines 7 into triazolopyrimidines 8 is also presented. In DMSO tetrazolopyrimidines 10 were shown to
be in equilibrium with the relevant azidopyrimidines 9. The tetrazolopyrimidine structure was confirmed
by X-ray crystallography. The synthesized compounds were tested for their antimicrobial activity.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Triazolopyrimidines
Tetrazolopyrimidines
Azidopyrimidines
Antimicrobial activity
1. Introduction
Thus, several and several derivatives of azolopyrimidines have
been synthesized.9,10 Their syntheses and reactivity have been
Heterocyclic chemistry continues to attract the attention of or-
ganic chemists: in fact more than half of the papers in organic
chemistry involve, directly or by using them as intermediates,
heterocyclic compounds. Moreover, because of their involvement
in several life processes (from the DNA-transfer of hereditary in-
formation to the oxygen transport by hemoglobin, to the chlor-
ophyllian synthesis, and so on), five- and six-membered rings
containing nitrogen in particular represent important elements for
the occurrence of life.1
In this framework, nitrogen-rich five-membered ring hetero-
cyclic compounds, such as triazoles and tetrazoles, as well as their
condensed derivatives are very attractive targets from both a the-
oretical and a synthetic point of view. Moreover, they have been
the subject of many chemical and biological studies on account of
their pharmacological properties, such as mitotic,2 hypotensive,3
anti-inflammatory,4,5 antimicrobial,6 antifungal,7 and analgesic
activity.8
discussed in some reviews.11
In view of the above observations and as a continuation of
earlier work from some of us on annulated furo[2,3-b]pyridines,12
herein we report an extension of the synthesis of the isomeric
triazolofuropyrimidines 7, 8, and of tetrazolofuropyrimidines 10 as
potential biologically active compounds. With respect to our earlier
work,12 we have introduced some structural modifications in the
rings of the starting materials 1 fused to pyridine, and also some
new substituents at C-2 of the pyridine ring with the aim of en-
larging the spectrum of molecules able to show pharmacological
activity.
2. Results and discussion
The 3-oxo derivatives of cyclopenta[c]pyridine13 1aec, 5,6,7,8-
tetrahydroisoquinoline14 1def, and of pyrano[3,4-c]pyridine15
1gej represent very useful starting substrates for the synthesis of
polycondensed heterocycles. In fact, the hydroxyl and cyano func-
tionalities at carbon 3 and 4 of the pyridine ring open the way to
condensationecyclization processes that make them interesting
starting compounds. By condensation with ethyl chloroacetate,
these compounds gave the relevant O-alkylated derivatives 2,
* Corresponding author. e-mail addresses: shnnr@mail.ru (S.N. Sirakanyan),
geronik@pharm.auth.gr (A. Geronikaki), domenico.spinelli@unibo.it (D. Spinelli).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.10.015

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S.N. Sirakanyan et al. / Tetrahedron 69 (2013) 10637e10643
whose cyclization by the action of a base (e.g., sodium ethoxide) led
to the condensed furo[2,3-b]pyridines 3.
The azideetetrazole equilibrium was also observed for com-
pounds 10. The 1H NMR spectra of compounds 10 in DMSO-d6 show
the expected double set of signals. The difference between the
signals is clearly evidenced looking at the chemical shifts of the CH
proton of the pyrimidine ring. Thus, the 1H NMR spectra of com-
pounds 10 showed signals at 8.78e8.89 ppm, for the azido forms 9,
and at 10.13e10.26 ppm, for the tetrazolo forms 10, respectively.
The ratios of the tautomers 9:10 in DMSO-d6 was found to be ap-
proximately 2:3.
The furan ring of 3 is decorated by the very versatile amino and
carboethoxy functional groups, thus allowing simple cyclo-
condensation with formamide into furo[3,2-d]pyrimidinones 4. In
turn, compounds 4 were reacted with phosphorus oxychloride to
give the chloro derivatives 5, containing an ‘activated’ chlorine
atom that could easily be displaced by nucleophiles.
In order to synthesize new pentacyclic systems condensed on
the [c] side of the pyrimidine ring, the new chloro compounds 5c,e,j
and the previously reported chloro derivatives 5a,b,d,fei12,16e20
were reacted with hydrazine hydrate to afford the corresponding
hydrazinofuro[3,2-d]pyrimidines 6 (Scheme 1).
It is noteworthy to mention that, in contrast, the IR spectra of
compounds 10 did not show the characteristic azide absorption
bands near the region at
n
2100e2200 cmꢀ1. For the final confir-
mation of the structure of compounds 10, we used also X-ray
O
N
R
R
X
N
OEt
( )n
R
R
NH2
OEt
( )n
O
OH
( )n
C2H5ONa
ClCH2CO2Et
R
R
R1
X
N
X
N
N
O
3
R1
R
R1
O
2
1
R
R
R
X
R
X
R
( )n
( )n
( )n
X
N
N
N
HCONH2
POCl3
N2H4.H2O
R1
R1
R1
NH
O
N
N
N
N
O
N
O
O
Cl
HN
H
4
6
5
N
H
1-6 a c. X = CH2, n = 0, R = H, a: R1= i-C3H7; b: R1 = i-C4H9; c: R1= Ph; d f.X =CH2,
n = 1, R = H, d: R1 = C3H7; e: R1 = i-C3H7; f: R1 = i-C4H9; g j. X = O, n = 1, R = Me, g:
R1 = C3H7; h: R1 = i-C3H7; i: R1 = i-C4H9; j: R1 = 2-furyl.
Scheme 1. Synthesis of hydrazinofuro[3,2-d]pyrimidines 6 from pyridine derivatives 1.
Starting from previously synthesized12,18,19 and new hydrazino
derivatives 6, novel pentacyclic annelated heterocycles, isomeric
triazolopyrimidines 7 and 8 (these last compounds could be formed
via the intermediates 7 as suggested by the observed 7 / 8 rear-
rangement), as well as tetrazolopyrimidines 10 were obtained by
reaction with triethyl orthoformate, formic acid, and nitrous acid,
respectively (Scheme 2).
Compounds 7 and 8 differed significantly in their physical
properties (melting points as well signals of the triazole ring CH
protons). For the triazole ring, proton signals in the 1H NMR spectra
of compounds 7 were displayed at 9.48e9.56 ppm, in contrast to
those in isomeric triazoles 8 where they were shifted up-field to
8.54e8.85 ppm, respectively.
analysis (Fig. 1). In particular, the X-ray analysis of compound 10a
showed that in the crystalline form, the latter exists only in the
tetrazolo structure.
Based on the knowledge that different azoles are in clinical use
as antimicrobials, due to their broad spectrum, high potency, and
low toxicity,28 the synthesized compounds were preliminarily
tested for their possible antimicrobial activity using agar diffusion
method.29,30 Gram-positive bacteria, such as Staphylococcus aureus
209p and Gram-negative bacilli (Shigella dysenteriae flexneri 6858,
Fscherichia coli 0e55), were used. As a reference drug, Furazolidone
was used because the structure of this drug is in some way com-
parable to those of the tested compound. This study revealed that
among the synthesized compounds only triazolopyrimidines (7e8)
showed weak antimicrobial activity with zone inhibition between
13 and 18 mm (Table 1), while tetrazolopyrimidines (10) were
completely inactive. The reference drug exhibited 24e25 mm zone
inhibition.
Previously, by carrying out the rearrangement in basic medium,21 we
successfully obtained the rearrangement of one isomer into the other. Next,
we carried out this rearrangement in acidic medium simply by heating
triazolopyrimidines 7 in formic acid to obtain the thermodynamically more
stable triazolopyrimidines 8 (Scheme 2). A possible mechanism for this
rearrangement in acidic medium,22 involves a sequence of ring opening and
ring closing reactions, as shown in Scheme 3 and previously suggested by
other authors.23,24
Moreover, treatment of hydrazino derivatives 6 with an aqueous
solution of sodium nitrite in acetic acid, led to the formation of
condensed tetrazolopyrimidines 10 in good yields. Heterocyclic
azides, especially the azidoazomethines, are known to exist in
equilibrium with the relevant tetrazole tautomers.25e27
3. Conclusions
In summary, by exploiting a known synthetic scheme12 we
have used some bicyclic derivatives of pyridine 1 decorated with
two reactive functionalities to obtain, by alkylation of the hy-
droxyl group some new ethers 2. These ethers undergo base ca-
talysis to give the relevant furo[2,3-b]pyridines 3, which in turn
react with formamide to afford furo[3,2-b]pyrimidinones 4. By

S.N. Sirakanyan et al. / Tetrahedron 69 (2013) 10637e10643
10639
R
X
R
R
R
X
( )n
( )n
N
N
N
N
HCOOH
R1
N
N
O
R1
N
N
O
N
N
8
7
R
R
CH(OC2H5)3
HCOOH
( )n
X
N
N
R1
N
6
N
H
O
H
N
H
NaNO2/CH3COOH
R
X
R
R
X
R
( )n
( )n
N
N
N
N
R1
N
N
R1
N
N
N
O
O
N3
9
10
7. a c. X = CH2, n = 0, R = H, a: R1 = i-C3H7; b: R1 = i-C4H9; c: R1 = Ph; d: X = CH2, n
= 1, R = H, R1= i-C3H7; e,f. X = O, n = 1, R = Me, e: R1 = C3H7; f: R1 = 2-furyl. 8. a,b. X
= CH2, n = 0, R = H, a: R1= i-C3H7; b: R1 = i-C4H9; c: X = CH2, n = 1, R = H, R1 = i-
C3H7; d,e. X = O, n = 1, R = Me, d: R1 = C3H7; e: R1 = 2-furyl. 9,10 a c. X = CH2, n = 0,
R = H, a: R1 = i-C3H7; b: R1 = i-C4H9; c: R1 = Ph; d f. X = CH2, n = 1, R = H, d: R1 =
C3H7; e: R1 = i-C3H7; f: R1 = i-C4H9; g-i. X = O, n = 1, R = Me, g: R1= i-C3H7; h: R1 = i-
C4H9; i: R1= 2-furyl.
Scheme 2. Reaction of 6 with triethyl orthoformate, formic acid, and nitrous acid, respectively.
Fig. 1. Single crystal X-ray structure of compound 10a.
Scheme 3. Mechanism proposed for the 7 / 8 rearrangement.
Very interestingly, no process occurs with yields lower than 70%.
All of the studied reactions occur with yields in the range from good
to excellent (average yield ca. 80%).
introducing a chlorine atom at C-7(8) of the pyrimidine ring, we
obtained the intermediates 5 able to give the hydrazino de-
rivatives 6, which represent intermediates able to furnish new
ring-closure reactions. By the reaction of 6 with triethyl ortho-
formate, formic acid, and nitrous acid, respectively, different
condensed 1,2,4-triazoles 7 and 8 as well as tetrazoles 10 were
eventually obtained. In DMSO solution, compounds 10 are in
equilibrium with the relevant azides 9 able, in principle, to give
further cyclization reactions.
4. Experimental section
4.1. General
1H NMR spectra were recorded in DMSO-d6 solution on a Varian
Mercury 300VX 300 MHz spectrometer. Chemical shifts are re-
ported as
d (parts per million) relative to TMS as the internal
standard. IR spectra were recorded on Nicolet Avatar 330-FT-IR

10640
S.N. Sirakanyan et al. / Tetrahedron 69 (2013) 10637e10643
Table 1
7.13 (dd, J¼3.5, 0.9 Hz, 1H, 3-CH fur.), 7.62 (dd, J¼1.7, 0.9 Hz, 1H, 5-
Antimicrobial activity of triazolopyrimidines 7 and 8
CH fur.). Anal. Calcd for C19H20N2O5: C 64.04; H 5.66; N 7.86%.
Found: C 63.91; H 5.53; N 7.98%.
Compound no
The diameter of growth inhibition zones (mm)
Staphylococcus aureus
Sh. dysenteriae
flexneri 6858
E. coli 0e55
4.3. General procedure for the synthesis of compounds 3c,e,j
209p
1
7a
7b
7c
7d
7e
7f
8a
8b
8c
8d
8e
14
14
14
16
14
15
14
13
16
15
14
16
18
13
14
16
18
16
15
14
15
15
16
15
16
14
15
15
13
15
12
15
14
18
15
15
18
16
16
14
18
16
18
16
To a solution of sodium ethoxide [253 mg (11 mmol) of sodium
in absolute ethanol (300 ml)] was added compound 2 (10 mmol).
The mixture was refluxed for 10e15 min, cooled, and poured onto
ice. The formed crystals were filtered off, washed with water, dried,
and recrystallized from ethanol.
4.3.1. Ethyl
[2,3-b]pyridine-2-carboxylate (3c). A pale yellow solid; yield 83%;
mp 168e170 ꢂC; IR /cmꢀ1: 3350, 3480 (NH2), 1650 (C]O). 1H NMR
(300 MHz, DMSO-d6)
1-amino-5-phenyl-7,8-dihydro-6H-cyclopenta[d]furo
n
d
1.42 (t, J¼7.1 Hz, 3H, CH2CH3), 2.17e2.27 (m,
2H, 7-CH2), 3.14 (t, J¼7.3 Hz, 2H, 6-CH2), 3.35 (t, J¼7.5 Hz, 2H, 8-CH2),
4.35 (q, J¼7.1 Hz, 2H, CH2CH3), 5.80 (br, 2H, NH2), 7.34e7.47 and
7.75e7.70 (both m, 3H and 2H, Ph). Anal. Calcd for C19H18N2O3: C
70.79; H 5.63; N 8.69%. Found: C 70.91; H 5.77; N 8.56%.
spectrophotometer and the reported wave numbers are given in
cmꢀ1. All melting points were determined in an open capillary and
are uncorrected. Elemental analyses were performed on a Carlo
Erba 1108 machine. Quoted values are in the range ꢁ0.4% of the
theoretical ones.
4.3.2. Ethyl
quinoline-2-carboxylate (3e). A pale yellow solid; yield 75%; mp
101e103 ꢂC; IR /cmꢀ1: 3330, 3500 (NH2), 1660 (C]O). 1H NMR
(300 MHz, DMSO-d6)
1-amino-5-isopropyl-6,7,8,9-tetrahydrofuro[2,3-c]iso-
Compounds 2a,b, 3a,b, 4a,b,20 2d,f, 3d,f, 4d,f,12 2g,i, 3g,i, 4g,i,17
2h, 3h, 4h,16 5a,b,d,f,h,i12,16e20 had been already described.
Crystallographic data for the structure of 10a have been de-
posited with the Cambridge Crystallographic Data Center as sup-
plementary publication no. CCDC 959723.31 Copies of the data can
be obtained, 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).
n
d
1.23 (d, J¼6.6 Hz, 6H, CH(CH3)2), 1.40 (t,
J¼7.1 Hz, 3H, CH2CH3),1.80e1.92 (m, 4H, 7,8-CH2), 2.73e2.80 (m, 2H,
6-CH2), 3.15e3.23 (m, 2H, 9-CH2), 3.25 (spt, J¼6.6 Hz, 1H, CH(CH3)2),
4.32 (q, J¼7.1 Hz, 2H, CH2CH3), 5.66 (br s, 2H, NH2). Anal. Calcd for
C
17H22N2O3: C 67.53; H 7.33; N 9.26%. Found: C 67.66; H 7.51; N 9.39%.
4.3.3. Ethyl 1-amino-5-(2-furyl)-8,8-dimethyl-8,9-dihydro-6H-furo
4.2. General procedure for the synthesis of compounds 2c,e,j
[2,3-b]pyrano[4,3-d]pyridine-2-carboxylate (3j). A yellow solid;
yield 71%; mp 235 ꢂC; IR /cmꢀ1: 3332, 3520 (NH2), 1658 (C]O). 1H
n
Ethyl chloroacetate (134 mg, 11 mmol) was added dropwise
with stirring to a suspension of compound 1 (10 mmol) and po-
tassium carbonate (150 mg, 11 mmol) in absolute DMF (150 ml).
The reaction mixture was maintained at 75e80 ꢂC for 2 h, then
cooled to room temperature, and poured onto cold water. The
resulting crystals were filtered off, washed with water, dried, and
recrystallized from ethanol.
NMR (300 MHz, DMSO-d6)
d
1.33 (s, 6H, C(CH3)2), 1.41 (t, J¼7.1 Hz,
3H, CH2CH3), 3.18 (s, 2H, CH2), 4.34 (q, J¼7.1 Hz, 2H, CH2CH3), 5.07
(s, 2H, OCH2), 5.82 (br, 2H, NH2), 6.59 (dd, J¼3.4, 1.7 Hz, 1H, 4-CH
fur.), 7.12 (dd, J¼3.4, 0.8 Hz, 1H, 3-CH fur.), 7.69 (dd, J¼1.7, 0.8 Hz,
1H, 5-CH fur.). Anal. Calcd for C19H20N2O5: C 64.04; H 5.66; N 7.86%.
Found: C 63.91; H 5.78; N 7.99%.
4.4. General procedure for the synthesis of compounds 4c,e,j
4.2.1. Ethyl 2-(4-cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyr-
idin-3-yloxy) acetate (2c). A white solid; yield 84%; mp 129e131 ꢂC;
A mixture of compound 3 (10 mmol) and formamide (200 ml)
was refluxed for 4 h. After cooling, the separated crystals were
filtered off, washed with water, dried, and recrystallized from di-
methyl sulfoxide.
IR n
/cmꢀ1: 2215 (CN), 1678 (C]O). 1H NMR (300 MHz, DMSO-d6)
d
1.27 (t, J¼7.1 Hz, 3H, CH2CH3), 2.15e2.28 (m, 2H, 6-CH2), 3.13 (t,
J¼7.5 Hz, 2H, 7-CH2), 3.16 (t, J¼7.4 Hz, 2H, 5-CH2), 4.24 (q, J¼7.1 Hz,
2H, CH2CH3), 4.98 (s, 2H, OCH2), 7.41e7.48 (m, 3H, Ph), 7.73e7.78
(m, 2H, Ph). Anal. Calcd for C19H18N2O3: C 70.79, H 5.63, N 8.69%.
Found: C 70.63, H 5.75, N 8.81%.
4.4.1. 4-Phenyl-2,3,7,8-tetrahydro-1H-cyclopenta[40,50]pyrido
[30,20:4,5]furo[3,2-d]pyrimidine-7-one (4c). A gray solid; yield 74%; mp
>360 ꢂC; IR /cmꢀ1: 3340 (NH),1688 (C]O). 1H NMR (300 MHz, DMSO-d6)
n
4.2.2. Ethyl 2-(4-cyano-1-isopropyl-5,6,7,8-tetrahydro-3-
isoquinolinyloxy)acetate (2e). A white solid; yield 78%; mp
d
2.24e2.34 (m, 2H, 2-CH2), 3.23 (t, J¼7.3 Hz, 2H, 3-CH2), 3.43 (t, J¼7.5 Hz,
2H, 1-CH2), 7.38e7.51 and 7.82e7.86 (both m, 3H and 2H, Ph), 8.04 (s, 1H,
N]CH), 12.88 (br, 1H, NH). Anal. Calcd for C18H13N3O2: C 71.28; H 4.32; N
13.85. Found: C 71.13; H 4.21; N 13.97%.
90e92 ꢂC; IR
DMSO-d6)
n
/cmꢀ1: 2220 (CN), 1675 (C]O). 1H NMR (300 MHz,
1.13 (d, J¼6.6 Hz, 6H, CH(CH3)2), 1.28 (t, J¼7.1 Hz, 3H,
d
CH2CH3), 1.79e1.87 (m, 4H, 6,7-CH2), 2.65e2.70 (m, 2H, 8-CH2),
2.88e2.93 (m, 2H, 5-CH2), 3.16 (spt, J¼6.6 Hz, 1H, CH(CH3)2), 4.16 (q,
J¼7.1 Hz, 2H, CH2CH3), 4.87 (s, 2H, OCH2). Anal. Calcd for
4.4.2. 5-Isopropyl-1,2,3,4,8,9-hexahydropyrimido[40,50:4,5]furo[2,3-
c]isoquinolin-8-one (4e). A gray solid; yield 76%; mp 358e360 ꢂC;
IR
C
17H22N2O3: C 67.53; H 7.33; N 9.26%. Found: C 67.67; H 7.20; N
n
/cmꢀ1: 3320 (NH), 1678 (C]O). 1H NMR (300 MHz, DMSO-d6)
9.39%.
d
1.28 (d, J¼6.6 Hz, 6H, CH(CH3)2), 1.84e1.97 (m, 4H, 2,3-CH2),
2.82e2.87 (m, 2H, 4-CH2), 3.34 (spt, J¼6.6 Hz, 1H, CH(CH3)2),
3.34e3.39 (m, 2H, 1-CH2), 7.98 (s, 1H, N]CH), 12.78 (br, 1H, NH).
Anal. Calcd for C16H17N3O2: C 67.83; H 6.05; N 14.83%. Found: C
67.94; H 5.91; N 14.96%.
4.2.3. Ethyl
2-[5-cyano-8-(2-furyl)-3,3-dimethyl-3,4-dihydro-1H-
pyrano[3,4-c]pyridin-6-yloxy]acetate (2j). A white solid; yield 81%;
mp 144e146 ꢂC; IR
(300 MHz, DMSO-d6)
n
/cmꢀ1: 2222 (CN), 1680 (C]O). 1H NMR
d
1.27 (t, J¼7.1 Hz, 3H, CH2CH3), 1.35 (s, 6H,
C(CH3)2), 2.91 (s, 2H, CH2), 4.23 (q, 2H, J¼7.1 Hz, OCH2CH3), 4.93 (s,
2H, CH2CO), 5.08 (s, 2H, OCH2), 6.56 (dd, J¼3.5,1.7 Hz,1H, 4-CH fur.),
4.4.3. 2,2-Dimethyl-5-(2-furyl)-1,4,8,9-tetrahydro-2H-pyrano
[400,300:40,50]pyrido[30,20:4,5]furo[3,2-d]pyrimidin-8-one (4j). A gray

S.N. Sirakanyan et al. / Tetrahedron 69 (2013) 10637e10643
10641
solid; yield 71%; mp 341e343 ꢂC; IR
n
/cmꢀ1: 3330 (NH), 1690 (C]
Calcd for C16H19N5O: C 64.63; H 6.44; N 23.55. Found: C 64.78; H
6.56; N 23.39%.
O). 1H NMR (300 MHz, DMSO-d6)
d
1.36 (s, 6H, C(CH3)2), 3.31 (s, 2H,
CH2), 5.15 (s, 2H, OCH2), 6.62 (dd, J¼3.4, 1.7 Hz, 1H, 4-CH fur.), 7.23
(d, J¼3.4 Hz, 1H, 3-CH fur.), 7.73 (d, J¼1.7 Hz, 1H, 5-CH fur.), 8.01 (s,
1H, N]CH), 12.84 (br, 1H, NH). Anal. Calcd for C18H15N3O4: C 64.09;
H 4.48; N 12.46%. Found: C 64.20; H 4.59; N 12.61%.
4.6.3. 4-Phenyl-2,3-dihydro-1H-cyclopenta[40,50]pyrido[30,20:4,5]furo
[3,2-d]pyrimidin-7-ylhydrazine (6c). An orange solid; yield 78%; mp
235e237 ꢂC; IR /cmꢀ1: 3084, 3120, 3309 (NH, NH2). 1H NMR
n
(300 MHz, DMSO-d6)
d
2.25e2.35 (m, 2H, 2-CH2), 3.24 (t, J¼7.3 Hz,
4.5. General procedure for the synthesis of compounds 5c,e,j
2H, 3-CH2), 3.47 (t, J¼7.5 Hz, 2H, 1-CH2), 4.47 (br, 2H, NH2),
7.38e7.50 (m, 3H, Ph) and 7.81e7.86 (m, 2H, Ph), 8.44 (s, 1H, N]
CH), 9.11 (br, 1H, NH). Anal. Calcd for C18H15N5O: C 68.13; H 4.76; N
22.07. Found: C 68.01; H 4.59; N 21.91%.
A mixture of compound 4 (10 mmol) and phosphorus oxy-
chloride (250 ml) was refluxed for 4 h. The excess of phosphorus
oxychloride was distilled off to give a dry residue. Ice water and
then ammonia solution were added. The separated crystals were
filtered off, washed with water, dried, and recrystallized from
ethanol.
4.6.4. 5-Isopropyl-1,2,3,4-tetrahydropyrimido[40,50:4,5]furo[2,3-c]
isoquinolin-8-ylhydrazine (6e). A brown solid; yield 83%; mp
208e210 ꢂC; IR /cmꢀ1: 3109, 3250, 3310 (NH, NH2). 1H NMR
n
(300 MHz, DMSO-d6)
d
1.27 (d, J¼6.6 Hz, 6H, CH(CH3)2), 1.86e2.00
4.5.1. 7-Chloro-4-phenyl-2,3-dihydro-1H-cyclopenta[40,50]pyrido
(m, 4H, 2,3-CH2), 2.86 (t, J¼5.8 Hz, 2H, 4-CH2), 3.34 (spt, J¼6.6 Hz,
1H, CH(CH3)2), 3.42 (t, J¼5.8 Hz, 2H, 1-CH2), 4.43 (br, 2H, NH2), 8.40
(s,1H, N]CH), 8.96 (br,1H, NH). Anal. Calcd for C16H19N5O: C 64.63;
H 6.44; N 23.55. Found: C 64.80; H 6.31; N 23.67%.
[30,20:4,5]furo[3,2-d]pyrimidine (5c). A pink solid; yield 75%; mp
206e207 ꢂC. 1H NMR (300 MHz, DMSO-d6)
d 2.31e2.41 (m, 2H, 2-
CH2), 3.31 (t, J¼7.3 Hz, 2H, 3-CH2), 3.53 (t, J¼7.5 Hz, 2H, 1-CH2),
7.44e7.55 and 7.89e7.93 (both m, 3H and 2H, Ph), 8.94 (s, 1H, N]
CH). Anal. Calcd for C18H12ClN3O: C 67.19; H 3.76; Cl 11.02; N 13.06%.
Found: C 67.01; H 3.59; Cl 10.91; N 13.18%.
4.6.5. 2,2-Dimethyl-5-propyl-1,4-dihydro-2H-pyrano[400,300:40,50]pyr-
ido[30,20:4,5]furo[3,2-d]pyrimidin-8-ylhydrazine (6g). An orange
solid; yield 74%; mp 200e201 ꢂC; IR /cmꢀ1: 3280, 3320 (NH, NH2).1H
n
4.5.2. 8-Chloro-5-isopropyl-1,2,3,4-tetrahydropyrimido[40,50:4,5]furo
NMR (300 MHz, DMSO-d6)
d
1.03 (t, J¼7.4 Hz, 3H, CH2CH3),1.34 (s, 6H,
[2,3-c]isoquinoline (5e). A pink solid; yield 78%; mp 130e132 ꢂC. 1H
C(CH3)2),1.83 (sextet, J¼7.4 Hz, 2H, CH2CH2CH3), 2.68 (t, J¼7.4 Hz, 2H,
CH2CH2CH3), 3.31 (s, 2H, CH2), 3.80 (br, 2H, NH2), 3.80 (s, 2H, OCH2),
8.40 (s, 1H, N]CH), 9.09 (br, 1H, NH). Anal. Calcd for C17H21N5O2: C
62.37; H 6.47; N 21.39. Found: C 62.51; H 6.54; N 21.21%.
NMR (300 MHz, DMSO-d6)
d
1.31 (d, J¼6.7 Hz, 6H, CH(CH3)2),
1.89e2.02 (m, 4H, 2,3-CH2), 2.87e2.92 (m, 2H, 4-CH2), 3.40 (spt,
J¼6.7 Hz, 1H, CH(CH3)2), 3.42e3.47 (m, 2H, 1-CH2), 8.88 (s, 1H, N]
CH). Anal. Calcd for C16H16ClN3O: C 63.68; H 5.34; Cl 11.75; N
13.92%. Found: C 63.79; H 5.23; Cl 11.62; N 14.10%.
4.6.6. 2,2-Dimethyl-5-(2-furyl)-1,4-dihydro-2H-pyrano[400,300:40,50]
pyrido[30,20:4,5]furo[3,2-d]pyrimidin-8-ylhydrazine (6j). A light or-
4.5.3. 8-Chloro-5-(2-furyl)-2,2-dimethyl-1,4-dihydro-2H-pyrano
[400,300:40,50]pyrido[30,20:4,5]furo[3,2-d]pyrimidine (5j). A light pink
solid; yield 80%; mp 260e262 ꢂC. 1H NMR (300 MHz, DMSO-d6)
ange solid; yield 81%; mp 285e289 ꢂC; IR /cmꢀ1: 3135, 3220, 3350
n
(NH, NH2). 1H NMR (300 MHz, DMSO-d6)
d 1.38 (s, 6H, C(CH3)2),
3.38 (s, 2H, CH2), 4.34 (br, 2H, NH2), 5.16 (s, 2H, OCH2), 6.62 (dd,
J¼3.4, 1.7 Hz, 1H, 4-CH fur.), 7.19 (dd, J¼3.4, 0.8 Hz, 1H, 3-CH fur.),
7.74 (dd, J¼1.7, 0.8 Hz, 1H, 5-CH fur), 8.42 (s, 1H, N]CH), 9.09 (br,
1H, NH). Anal. Calcd for C18H17N5O3: C 61.53; H 4.88; N 19.93.
Found: C 61.68; H 4.71; N 20.12%.
d
1.39 (s, 6H, C(CH3)2), 3.39 (s, 2H, CH2), 5.20 (s, 2H, OCH2), 6.67 (dd,
J¼3.5, 1.8 Hz, 1H, 4-CH fur.), 7.36 (dd, J¼3.5, 0.8 Hz, 1H, 3-CH fur.),
7.81 (dd, J¼1.8, 0.8 Hz, 1H, 5-CH fur.), 8.91 (s, 1H, N]CH). Anal.
Calcd for C18H14ClN3O3: C 60.77; H 3.97; Cl 9.96; N 11.81%. Found: C
60.59; H 4.14; Cl 10.09; N 11.97%.
4.7. General procedure for the synthesis of compounds 7aef
4.6. General procedure for the synthesis of compounds
6aec,e,g,j
A mixture of compound 6 (0.1 mmol) and triethyl orthoformate
(25 ml) was refluxed for 1 h. The reaction mixture was cooled, the
separated crystals were filtered off, washed with water, dried, and
recrystallized from a mixture of ethanoledichloromethane (1:3).
A mixture of chloride 5 (1 mmol) and hydrazine hydrate
(500 mg, 10 mmol) in absolute ethanol (50 ml) was refluxed for
10 h. The reaction mixture was cooled, water (100 ml) was added,
and the separated crystals were filtered off, washed with water,
dried, and recrystallized from ethanol.
4.7.1. 10-Isopropyl-8,9-dihydro-7H-cyclopenta[40,50]pyrido[30,20:4,5]
furo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine (7a). A white solid; yield
84%; mp 286e288 ꢂC. 1H NMR (300 MHz, DMSO-d6)
d 1.34 (d,
4.6.1. 4-Isopropyl-2,3-dihydro-1H-cyclopenta[40,50]pyrido[30,20:4,5]
J¼6.2 Hz, 6H, CH(CH3)2), 2.29e2.39 (m, 2H, 8-CH2), 3.07 (t, J¼7.5 Hz,
2H, 9-CH2), 3.23 (spt, J¼6.7 Hz,1H, CH(CH3)2), 3.44 (t, J¼7.6 Hz, 2H, 7-
CH2), 9.48 (s,1H, 3-CH), 9.51 (s,1H, 5-CH). Anal. Calcd for C16H15N5O:
C 65.52; H 5.15; N 23.88. Found: C 65.69; H 5.01; N 24.01%.
furo[3,2-d]pyrimidin-7-ylhydrazine (6a). A white solid; yield 81%;
mp 247e249 ꢂC; IR /cmꢀ1: 3190, 3280, 3390 (NH, NH2). 1H NMR
n
(300 MHz, DMSO-d6)
d
1.30 (d, J¼6.7 Hz, 6H, CH(CH3)2), 2.25e2.36
(m, 2H, 2-CH2), 3.03 (t, J¼7.4 Hz, 2H, 3-CH2), 3.20 (spt, J¼6.7 Hz, 1H,
CH(CH3)2), 3.41 (t, J¼7.6 Hz, 2H, 1-CH2), 4.37 (br, 2H, NH2), 8.40 (s,
1H, N]CH), 8.98 (br, 1H, NH). Anal. Calcd for C15H17N5O: C 63.59; H
6.05; N 24.72%. Found: C 63.67; H 5.91; N 24.84%.
4.7.2. 10-Isobutyl-8,9-dihydro-7H-cyclopenta[40,50]pyrido[30,20:4,5]
furo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine (7b). A white solid; yield
87%; mp 254e256 ꢂC. 1H NMR (300 MHz, DMSO-d6)
d 1.00 (d,
J¼6.6 Hz, 6H, CH(CH3)2), 2.22e2.35 (m, 1H, CH(CH3)2), 2.28e2.38
(m, 2H, 8-CH2), 2.73 (d, J¼7.1 Hz, 2H, CHCH2), 3.04 (t, J¼7.4 Hz, 2H,
9-CH2), 3.45 (t, J¼7.6 Hz, 2H, 7-CH2), 9.48 (s, 1H, 3-CH), 9.51 (s, 1H,
5-CH). Anal. Calcd for C17H17N5O: C 66.43; H 5.57; N 22.79. Found: C
66.29; H 5.71; N 22.91%.
4.6.2. 4-Isobutyl-2,3-dihydro-1H-cyclopenta[40,50]pyrido[30,20:4,5]
furo[3,2-d]pyrimidin-7-ylhydrazine (6b). A white solid; yield 76%;
mp 244e246 ꢂC; IR /cmꢀ1: 3160, 3300, 3450 (NH, NH2). 1H NMR
n
(300 MHz, DMSO-d6)
d
0.98 (d, J¼6.6 Hz, 6H, CH(CH3)2), 2.17e2.27
(m, 1H, CH(CH3)2), 2.24e2.35 (m, 2H, 2-CH2), 2.69 (d, J¼7.1 Hz, 2H,
CHCH2), 3.00 (t, J¼7.4 Hz, 2H, 3-CH2), 3.42 (t, J¼7.5 Hz, 2H, 1-CH2),
4.41 (br, 2H, NH2), 8.40 (s, 1H, N]CH), 9.02 (br, 1H, NH). Anal.
4.7.3. 10-Phenyl-8,9-dihydro-7H-cyclopenta[40,50]pyrido[30,20:4,5]
furo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine (7c). An orange solid;

10642
S.N. Sirakanyan et al. / Tetrahedron 69 (2013) 10637e10643
yield 83%; mp 344 ꢂC. 1H NMR (300 MHz, DMSO-d6)
d
2.29e2.39
2H, 7-CH2), 8.54 (s, 1H, 2-CH), 9.63 (s, 1H, 5-CH). Anal. Calcd for
C17H17N5O: C 66.43; H 5.57; N 22.79. Found: C 66.55; H 5.41; N
22.65%.
(m, 2H, 8-CH2), 3.29 (t, J¼7.3 Hz, 2H, 9-CH2), 3.52 (t, J¼7.4 Hz, 2H, 7-
CH2), 7.40e7.53 (m, 3H, Ph) and 7.86e7.91 (m, 2H, Ph), 9.53 (s, 1H,
3-CH), 9.54 (s, 1H, 5-CH). Anal. Calcd for C19H13N5O: C 69.72; H
4.00; N 21.39. Found: C 69.84; H 4.18; N 21.22%.
4.8.4. 8,8-Dimethyl-11-propyl-7,10-dihydro-8H-pyrano[400,300:40,50]
pyrido[30,20:4,5]furo[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine
(8d). A
white solid; yield 81 (A)/75 (B)%; mp 245e247 ꢂC. 1H NMR
(300 MHz, DMSO-d6)
4.7.4. 11-Isopropyl-7,8,9,10-tetrahydro[1,2,4]triazolo[300,400:60,10]pyr-
imido[40,50:4,5]furo[2,3-c]isoquinoline (7d). A white solid; yield 79%;
d
1.06 (t, J¼7.3 Hz, 3H, CH2CH3), 1.37 (s, 6H,
mp 297e298 ꢂC. 1H NMR (300 MHz, DMSO-d6)
d
1.31 (d, J¼6.7 Hz,
C(CH3)2), 1.81e1.93 (m, 2H, CH2CH3), 2.71e2.77 (m, 2H,
CH2CH2CH3), 3.39 (s, 2H, CH2), 4.86 (s, 2H, OCH2), 8.57 (s, 1H, 2-CH),
9.66 (s, 1H, 5-CH). Anal. Calcd for C18H19N5O2: C 64.08; H 5.68; N
20.76. Found: C 63.91; H 5.55; N 20.91%.
6H, CH(CH3)2), 1.89e2.01 (m, 4H, 8,9-CH2), 2.87e2.92 (m, 2H, 10-
CH2), 3.38 (spt, J¼6.7 Hz, 1H, CH(CH3)2), 3.43e3.48 (m, 2H, 7-CH2),
9.47 (s, 1H, 3-CH), 9.50 (s, 1H, 5-CH). Anal. Calcd for C17H17N5O: C
66.43; H 5.57; N 22.79. Found: C 66.59; H 5.73; N 22.91%.
4.8.5. 8,8-Dimethyl-11-(2-furyl)-7,10-dihydro-8H-pyrano[400,300:40,50]
4.7.5. 8,8-Dimethyl-11-propyl-7,10-dihydro-8H-pyrano[400,300:40,50]
pyrido[30,20:4,5]furo[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine
(8e). A
white solid; yield 70 (A)/67 (B)%; mp 343e345 ꢂC. 1H NMR
(300 MHz, DMSO-d6) 1.38 (s, 6H, S(CH3)2), 3.46 (s, 2H, CH2), 5.16
pyrido[30,20:4,5]furo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine
(7e). A
white solid; yield 87%; mp 265e267 ꢂC. 1H NMR (300 MHz, DMSO-
d6)
d
d
: 1.06 (t, J¼7.2 Hz, 3H, CH2CH3), 1.36 (s, 6H, S(CH3)2), 1.80e1.92
(s, 2H, OCH2), 6.77 (dd, 1H, J¼3.4, 1.7 Hz, 4-CH fur.), 7.29 (dd, 1H,
J¼3.4, 0.7 Hz, 3-CH fur.), 8.01 (dd, 1H, J¼1.7, 0.7 Hz, 5-CH fur.), 8.85
(s, 1H, 2-CH), 9.94 (s, 1H, 5-CH). Anal. Calcd for C19H15N5O3: C 63.15;
H 4.18; N 19.38. Found: C 63.03; H 4.29; N 19.20%.
(m, 2H, CH2CH3), 2.69e2.75 (m, 2H, CH2CH2CH3), 3.34 (s, 2H, CH2),
4.84 (s, 2H, OCH2), 9.51 (s, 1H, 3-CH), 9.51 (s, 1H, 5-CH). Anal.
Calcd for C18H19N5O2: C 64.08; H 5.68; N 20.76. Found: C 63.91; H
5.53; N 20.89%.
4.9. General procedure for the synthesis of compounds 10aei
4.7.6. 8,8-Dimethyl-11-(2-furyl)-7,10-dihydro-8H-pyrano[400,300:40,50]
pyrido[30,20:4,5]furo[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine
(7f). A
brown solid; yield 73%; mp >360 ꢂC. 1H NMR (300 MHz, DMSO-d6)
1.37 (s, 6H, S(CH3)2), 3.41 (s, 2H, CH2), 5.15 (s, 2H, OCH2), 6.76 (dd,
To an ice-cold solution of compound 6 (0.1 mmol) in acetic acid
(25 ml) a solution of sodium nitrite (obtained by dissolving sodium
nitrite [0.137 mg, 0.2 mmol] in the least amount of water) was
added dropwise with stirring in an ice-bath at 5 ꢂC. The reaction
mixture was maintained at room temperature for 12 h, and then
water (25 ml) was added. The resulting crystals were filtered off,
washed with water, dried, and recrystallized from a mixture of
ethanoledichloromethane (1:3).
d
J¼3.4, 1.7 Hz, 1H, 4-CH fur.), 7.26 (dd, J¼3.4, 0.7 Hz, 1H, 3-CH fur.),
7.99 (dd, J¼1.7, 0.7 Hz, 1H, 5-CH fur.), 9.56 (s, 1H, 3-CH), 9.64 (s, 1H,
5-CH). Anal. Calcd for C19H15N5O3: C 63.15; H 4.18; N 19.38. Found:
C 63.01; H 4.30; N 19.19%.
4.8. General procedures for the synthesis of compounds 8aee
4.9.1. 10-Isopropyl-8,9-dihydro-7H-cyclopenta[40,50]pyrido[30,20:4,5]
A. A mixture of compound 6 (0.1 mmol) and formic acid (25 ml)
was refluxed for 25 h. The reaction mixture was cooled, water
(100 ml) was added, and the separated crystals were filtered off,
washed with water, dried, and recrystallized from a mixture of
ethanoledichloromethane (1:3).
B. A mixture of compound 7 (0.1 mmol) and formic acid (25 ml)
was refluxed for 5 h. The product was isolated analogously to
method A.
furo[2,3-e][1,2,3,4]tetrazolo-[1,5-c]pyrimidine (10a). A white solid;
yield 87%; mp 201 ꢂC. 1H NMR (300 MHz, DMSO-d6)
d 1.32 (d,
J¼6.7 Hz, 2.4H, CH(CH3)2), 1.36 (d, J¼6.7 Hz, 3.6H, CH(CH3)2),
2.29e2.39 (m, 0.8H, CH2), 2.33e2.43 (m, 1.2H, CH2), 3.07 (t,
J¼7.4 Hz, 0.8H, CH2), 3.11 (t, J¼7.4 Hz, 1.2H, CH2), 3.26 (spt, J¼6.7 Hz,
0.4H, CH(CH3)2), 3.27 (spt, J¼6.7 Hz, 0.6H, CH(CH3)2), 3.45 (t,
J¼7.6 Hz, 0.8H, CH2), 3.52 (t, J¼7.6 Hz, 1.2H, CH2), 8.80 (s, 0.4H, N]
CH), 10.14 (s, 0.6H, N]CH). Anal. Calcd for C15H14N6O: C 61.22; H
4.79; N 28.55. Found: C 61.05; H 4.89; N 28.43%.
4.8.1. 10-Isopropyl-8,9-dihydro-7H-cyclopenta[40,50]pyrido[30,20:4,5]
furo[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (8a). A white solid; yield
4.9.2. 10-Isobutyl-8,9-dihydro-7H-cyclopenta[40,50]pyrido[30,20:4,5]
75 (A)/69 (B)%; mp 215e217 ꢂC. 1H NMR (300 MHz, DMSO-d6)
d
1.35
furo[2,3-e][1,2,3,4]tetrazolo[1,5-c]pyrimidine (10b). A white solid;
(d, J¼6.6 Hz, 6H, CH(CH3)2), 2.31e2.41 (m, 2H, 8-CH2), 3.08 (t,
J¼7.5 Hz, 2H, 9-CH2), 3.25 (spt, J¼6.6 Hz, 1H, CH(CH3)2), 3.49 (t,
J¼7.6 Hz, 2H, 7-CH2), 8.54 (s, 1H, 2-CH), 9.63 (s, 1H, 5-CH). Anal.
Calcd for C16H15N5O: C 65.52; H 5.15; N 23.88. Found: C 65.69; H
4.98; N 24.01%.
yield 85%; mp 180e181 ꢂC. 1H NMR (300 MHz, DMSO-d6)
d 0.98 (d,
J¼6.7 Hz, 2.4H, CH(CH3)2), 1.01 (d, J¼6.7 Hz, 3.6H, CH(CH3)2),
2.22e2.41 (m, 3H, CH2 and CH(CH3)2), 2.72 (d, J¼7.2 Hz, 0.8H,
CHCH2), 2.75 (d, J¼7.2 Hz,1.2H, CHCH2), 3.03 (t, J¼7.5 Hz, 0.8H, CH2),
3.07 (t, J¼7.5 Hz, 1.2H, CH2), 3.44 (t, J¼7.6 Hz, 0.8H, CH2), 3.51 (t,
J¼7.6 Hz, 1.2H, CH2), 8.79 (s, 0.4H, N]CH), 10.13 (s, 0.6H, N]CH).
Anal. Calcd for C16H16N6O: C 62.33; H 5.23; N 27.26. Found: C 62.21;
H 5.05; N 27.15%.
4.8.2. 10-Isobutyl-8,9-dihydro-7H-cyclopenta[40,50]pyrido[30,20:4,5]
furo[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine (8b). A white solid; yield
71 (A)/69 (B)%; mp 195e197 ꢂC. 1H NMR (300 MHz, DMSO-d6)
d 1.00
(d, J¼6.6 Hz, 6H, CH(CH3)2), 2.22e2.41 (m, 1H, CH(CH3)2), 2.22e2.41
(m, 2H, 8-CH2), 2.74 (d, J¼7.1 Hz, 2H, CHCH2), 3.05 (t, J¼7.4 Hz, 2H,
9-CH2), 3.49 (t, J¼7.5 Hz, 2H, 7-CH2), 8.55 (s, 1H, 2-CH), 9.63 (s, 1H,
5-CH). Anal. Calcd for C17H17N5O: C 66.43; H 5.57; N 22.79. Found: C
66.31; H 5.68; N 22.60%.
4.9.3. 10-Phenyl-8,9-dihydro-7H-cyclopenta[40,50]pyrido[30,20:4,5]
furo[2,3-e][1,2,3,4]tetrazolo[1,5-c]pyrimidine (10c). A white solid;
yield 84%; mp 220e222 ꢂC. 1H NMR (300 MHz, DMSO-d6)
d
2.30e2.41 (m, 2H, CH2), 3.27 (t, J¼7.2 Hz, 0.4H, CH2), 3.31 (t,
J¼7.2 Hz, 1.6H, CH2), 3.49 (t, J¼7.5 Hz, 0.4H, CH2), 3.57 (t, J¼7.5 Hz,
1.6H, CH2), 7.44e7.58 (m, 3H, Ph) and 7.86e7.95 (m, 2H, Ph), 8.89 (s,
0.2H, N]CH), 10.26 (s, 0.8H, N]CH). Anal. Calcd for C18H12N6O: C
65.85; H 3.68; N 25.60. Found: C 66.02; H 3.54; N 25.74%.
4.8.3. 11-Isopropyl-7,8,9,10-tetrahydro[1,2,4]triazolo[500,100:60,10]pyr-
imido[40,50:4,5]furo[2,3-c]isoquinoline (8c). A white solid; yield 75
(A)/68 (B)%; mp 199e201 ꢂC. 1H NMR (300 MHz, DMSO-d6)
d 1.32
(d, J¼6.7 Hz, 6H, CH(CH3)2), 1.92e2.03 (m, 4H, 8,9-CH2), 2.89e2.94
4.9.4. 11-Propyl-7,8,9,10-tetrahydro[1,2,3,4]tetrazolo[500,100:60,10]pyr-
imido[40,50:4,5]furo[2,3-c]isoquinoline (10d). A light brown solid;
(m, 2H, 10-CH2), 3.39 (spt, J¼6.7 Hz, 1H, CH(CH3)2), 3.48e3.53 (m,

S.N. Sirakanyan et al. / Tetrahedron 69 (2013) 10637e10643
10643
yield 87%; mp 128e129 ꢂC. 1H NMR (300 MHz, DMSO-d6)
d
1.05 (t,
4.10. Antimicrobial assay
J¼7.4 Hz,1.14H, CH3),1.07 (t, J¼7.4 Hz,1.86H, CH3),1.75e1.92 (m, 2H,
CH2CH3), 1.90e2.03 (m, 4H, C6H8), 2.78e2.88 (m, 4H, CH2),
3.37e3.45 (m, 0.76H, CH2), 3.45e3.54 (m, 1.24H, CH2), 8.78 (s,
0.38H, N]CH),10.13 (s, 0.62H, N]CH). Anal. Calcd for C16H16N6O: C
62.33; H 5.23; N 27.26. Found: C 62.51; H 5.40; N 27.09%.
The synthesized triazole and tetrazole derivatives were
examined for their antimicrobial activity against several bacteria
(S. aureus, 209p, 1; Sh. dysenteriae flexneri 6858, F. coli 0e55)
using the agar diffusion method. The preliminary antibacterial
activity of the synthesized compounds (data in Table 1) were
determined according to methods described in the literature.29,30
4.9.5. 11-Isopropyl-7,8,9,10-tetrahydro[1,2,3,4]tetrazolo[500,100:60,10]
pyrimido[40,50:4,5]furo[2,3-c]isoquinoline (10e). A white solid; yield
85%; mp 177e179 ꢂC. 1H NMR (300 MHz, DMSO-d6)
d 1.30 (d,
Acknowledgements
J¼6.7 Hz, 2.4H, CH(CH3)2), 1.33 (d, J¼6.7 Hz, 3.6H, CH(CH3)2),
1.91e2.02 (m, 4H, CH2), 2.89e2.95 (m, 2H, CH2), 3.40 (spt, J¼6.7 Hz,
0.4H, CH(CH3)2), 3.44 (spt, J¼6.7 Hz, 0.6H, CH(CH3)2), 3.42e3.47 (m,
0.8H, CH2), 3.50e3.56 (m, 1.2H, CH2), 8.80 (s, 0.4H, N]CH), 10.13 (s,
0.6 H, N]CH). Anal. Calcd for C16H16N6O: C 62.33; H 5.23; N 27.26.
Found: C 62.49; H 5.38; N 27.10%.
We thank R. A. Tamazyan and A. G. Ayvazyan for their support
concerning X-rays determination.
References and notes
1. Pozharskii, A. F.; Katritzky, A. R.; Soldatenkov, A. T. Heterocycles in Life and So-
ciety: an Introduction to Heterocyclic Chemistry, Biochemistry and Applications; J.
Wiley & Sons, 2011; and references therein.
2. Jackson, W. D.; Polaya, J. B. Aust. J. Sci. 1951, 13, 149e150.
3. Walker, H. A.; Wilson, S.; Atkins, E. C.; Garrett, H. E.; Richardson, A. R. J. Phar-
macol. Exp. Ther. 1951, 101, 368e378.
4. Hardmann, G. E.; Kathawala, F. G. U.S. Patent 4.053.600, 1977; Chem. Abstr. 1978,
88, 22970.
5. Rashad, A. E.; Heikal, O. A.; El-Nazhawy, A. O. H.; Abdel-Megeid, F. M. E. Het-
4.9.6. 11-Isobutyl-7,8,9,10-tetrahydro[1,2,3,4]tetrazolo[500,100:60,10]
pyrimido[40,50:4,5]furo[2,3-c]isoquinoline (10f). A white solid; yield
80%; mp 134e136 ꢂC. 1H NMR (300 MHz, DMSO-d6)
d 1.00 (d,
J¼6.6 Hz, 2.4H, CH(CH3)2), 1.03 (d, J¼6.6 Hz, 3.6H, CH(CH3)2),
1.91e2.01 (m, 4H, CH2), 2.26e2.38 (m, 1H, CH(CH3)2), 2.73 (d,
J¼7.0 Hz, 0.8H, CHCH2), 2.76 (d, J¼7.0 Hz,1.2H, CHCH2), 2.80e2.94 (m,
2H, CH2), 3.41e3.47 (m, 0.8H, CH2), 3.49e3.56 (m, 1.2H, CH2), 8.80 (s,
0.4H, N]CH), 10.14 (s, 0.6H, N]CH). Anal. Calcd for C17H18N6O: C
63.34; H 5.63; N 26.07. Found: C 63.50; H 5.51; N 26.18%.
eroat. Chem. 2005, 16, 226e234.
6. Hegab, M. I.; Hassan, N. A.; Rashad, A. E.; Fahmy, A. A.; Abdel-Megeid, F. M. E.
Phosphorus, Sulfur, and Silicon 2007, 182, 1535e1556; Holla, B. S.; Mahalinga, M.;
Karthikeyan, M. S.; Poojary, B.; Akberali, P. M.; Kumari, N. S. Eur. J. Med. Chem.
2005, 40, 1173e1178.
4.9.7. 8,8-Dimethyl-11-isopropyl-7,10-dihydro-8H-pyrano
[400,300:40,50]pyrido[30,20:4,5]furo[2,3-e][1,2,3,4]tetrazolo[1,5-c]pyrimi-
dine (10g). A white solid; yield 87%; mp 153e155 ꢂC. 1H NMR
7. Shalini, K.; Kumar, N.; Drabur, S.; Sharma, P. K. Beilstein J. Org. Chem. 2011, 7,
668e677.
8. Clark, R. L.; Pessolano, A. A.; Shen, T. Y. South African Patent 76.03163, 1977;
Chem. Abstr. 1978, 88, 22882.
9. Baeza, A.; Mendiola, J.; Burgos, C.; Alvarez-Builla, J.; Vaquero, J. J. Org. Chem.
2005, 70, 4879e4882.
10. Behbehani, H.; Ibrahim, H. M. Molecules 2012, 17, 6362e6385.
11. Stanovnik, B.; Svete, J. Chem. Rev. 2004, 104, 2433e2480.
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A. A. Chem. Heterocycl. Compd. 2013, 11, 1676e1683 and references therein.
13. Kamal El-Dean, A. M.; Abdel Hafez, A. A. Phosphorus, Sulfur Silicon Relat. Elem.
1989, 46, 1e6.
14. Paronikyan, E. G.; Sirakanyan, S. N.; Noravyan, A. S. Nitrogen-containing Het-
erocycles and Alkaloids; Iridium: Moscow, Russia, 2001, vol.1, pp 441e448.
15. Paronikyan, E. G.; Sirakanyan, S. N.; Lindeman, S. V.; Aleqsanyan, M. S.; Kar-
apetyan, A. A.; Noravyan, A. S.; Struchkov, Y. T. Chem. Heterocycl. Compd. 1989, 6,
1137e1142.
16. Sirakanyan, S. N.; Paronikyan, E. G.; Ghukasyan, M. S.; Noravyan, A. S. Chem.
Heterocycl. Compd. 2010, 6, 736e741.
17. Sirakanyan, S. N.; Hovakimyan, A. A.; Noravyan, A. S. Chem. J. Arm. 2011, 3,
401e410.
18. Sirakanyan, S. N.; Hovakimyan, A. A.; Noravyan, A. S.; Panosyan, G. A.; Merlani,
M. I. Georgian Chem. J. 2011, 4, 395e398.
19. Hovakimyan, A. A. Chem. J. Arm. 2012, 1, 69e76.
20. Sirakanyan, S. N.; Hovakimyan, A. A.; Noravyan, A. S.; Dzhagatspanyan, I. A.;
Shahkhatuni, A. A.; Nazaryan, I. M.; Akopyan, A. G. Pharm. Chem. J. 2013, 47,
8e11.
(300 MHz, DMSO-d6)
d
1.32 (d, J¼6.6 Hz, 2.4H, CH(CH3)2), 1.35 (d,
J¼6.6 Hz, 3.6H,CH(CH3)2), 1.36 (s, 2.4H, S(CH3)2), 1.38 (s, 3.6H,
S(CH3)2), 3.09 (spt, J¼6.6 Hz, 0.4H, CH(CH3)2), 3.13 (spt, J¼6.6 Hz,
0.6H, CH(CH3)2), 3.34 (s, 0.8H, CH2), 3.42 (s, 1.2H, CH2), 4.89 (s, 0.8H,
OCH2), 4.93 (s,1.2H, OCH2), 8.81 (s, 0.4H, N]CH),10.16 (s, 0.6 H, N]
CH). Anal. Calcd for C17H18N6O2: C 60.34; H 5.36; N 24.84. Found: C
60.21; H 5.48; N 24.96%.
4.9.8. 8,8-Dimethyl-11-isobutyl-7,10-dihydro-8H-pyrano[400,300:40,50]
pyrido[30,20:4,5]furo[2,3-e][1,2,3,4]tetrazolo[1,5-c]pyrimidine
(10h). A white solid; yield 78%; mp 145e147 ꢂC. 1H NMR (300 MHz,
DMSO-d6)
d
1.00 (d, J¼6.6 Hz, 2.4H, CH(CH3)2), 1.03 (d, J¼6.6 Hz,
3.6H, CH(CH3)2), 1.35 (s, 2.4H, S(CH3)2), 1.37 (s, 3.6H, S(CH3)2),
2.27e2.43 (m, 1H, CH(CH3)2), 2.62 (d, J¼7.1 Hz, 0.8H, CHCH2), 2.66
(d, J¼7.1 Hz, 1.2H, CHCH2), 3.34 (s, 0.8H, CH2), 3.42 (s, 1.2H, CH2),
4.83 (s, 0.8H, OCH2), 4.87 (s,1.2H, OCH2), 8.82 (s, 0.4H, N]CH),10.18
(s, 0.6H, N]CH).Anal. Calcd for C18H20N6O2: C 61.35; H 5.72; N
23.85. Found: C 61.21; H 5.63; N 24.00%.
21. Sirakanyan, S. N.; Avetisyan, N. G.; Noravyan, A. S. Chem. Heterocycl. Compd.
2012, 3, 470e475.
4.9.9. 8,8-Dimethyl-11-(2-furyl)-7,10-dihydro-8H-pyrano[400,300:40,50]
pyrido[30,20:4,5]furo[2,3-e][1,2,3,4]tetrazolo[1,5-c]pyrimidine (10i). A
pale brown solid; yield 75%; mp >360 ꢂC. 1H NMR (300 MHz,
22. Vorobyev, E. V. Author’s Summary of Dissertation for Candidate of Chemical
Sciences, Rostov-on-the-Don, 2006.
23. Katritzky, A. R.; Kingsland, M.; Tee, O. C. Chem. Commun. (London) 1968,
289e290.
24. Vereshchagina, N. N.; Postovskii, I. Y.; Mertsalov, S. L. Chem. Heterocycl. Compd.
1967, 3, 1096e1099.
25. Tisler, M. Synthesis 1973, 123e136.
26. Lowe-Ma, C. K.; Nissan, R. A.; Wilson, W. S. J. Org. Chem. 1990, 55, 3755e3761.
27. Shishoo, C. J.; Jain, K. S. J. Heterocycl. Chem. 1992, 29, 883e893.
28. Sheehan, D. J.; Hitchcock, C. A.; Sibley, C. M. Clin. Microbiol. Rev. 1999, 12, 40e79.
29. Bauer, A. W.; Kirby, W. M.; Sherris, J. C.; Turck, M. Am. J. Clin. Pathol. 1966, 39,
493e496.
DMSO-d6)
d 1.39 (s, 2.4H, S(CH3)2), 1.41 (s, 3.6H, S(CH3)2), 3.38 (s,
0.8H, CH2), 3.46 (s, 1.2H, CH2), 5.17 (s, 0.8H, OCH2), 5.20 (s, 1.2H,
OCH2), 6.65 (dd, J¼3.5, 1.7 Hz, 0.4H, CH), 6.66 (dd, J¼3.5, 1.7 Hz,
0.6H, CH), 7.29 (dd, J¼3.5, 0.7 Hz, 0.4H, CH fur.), 7.30 (dd, J¼3.5,
0.7 Hz, 0.6H, CH fur.), 7.78 (dd, J¼1.7, 0.7 Hz, 0.4H, CH fur.), 7.79 (dd,
J¼1.7, 0.7 Hz, 0.6H, CH fur.), 8.80 (s, 0.4H, N]CH), 10.17 (s, 0.6H, N]
CH). Anal. Calcd for C18H14N6O3: C 59.67; H 3.89; N 23.19. Found: C
59.59; H 4.02; N 23.27%.
30. Petersdorf, R. G.; Sherris, J. C. Am. J. Med. 1965, 39, 766e779.
31. Tamazyan, R. A.; Ayvazyan, A. G. work in progress.