New Methods for the Synthesis of 3-Amino-6,7-Dihydro-5H-Cyclopenta[c]Pyridine-4-Carbonitriles and Cyclopenta[d]Pyrazolo[3,4-b]Pyridines via a Smiles-type Rearrangement

Article abstract of DOI:10.1002/jhet.2693

By reaction with sodium ethoxide and as a function of their structures, 2-[(1-alkyl(aryl)-4-cyano-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)oxy]acetamides 11 gave 1-amino-5-alkyl(aryl)-7,8-dihydro-6H-cyclopenta[d]furo[2,3-b]pyridine-2-carboxamides 10 and/or 1-alkyl(aryl)-3-amino-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitriles 12.

Full text of DOI:10.1002/jhet.2693

Month 2016
New Methods for the Synthesis of 3-Amino-6,7-Dihydro-5H-Cyclopenta
[c]Pyridine-4-Carbonitriles and Cyclopenta[d]Pyrazolo[3,4-b]Pyridines via
a Smiles-type Rearrangement
a
b
c
a
*
*
Samvel N. Sirakanyan, Domenico Spinelli, Athina Geronikaki, and Anush A. Hovakimyan
aScientific Technological Center of Organic and Pharmaceutical Chemistry of National Academy of Science of Republic
of Armenia, Institute of Fine Organic Chemistry of A.L. Mnjoyan, Ave. Azatutyan 26, Yerevan 0014, Armenia
bDipartimento di Chimica G. Ciamician, Alma Mater Studiorum-Università di Bologna, Via F. Selmi 2, Bologna 40126,
Italy
cAristotle University of Thessaloniki, School of Pharmacy, Thessaloniki 54124, Greece
*
E-mail: domenico.spinelli@unibo.it; geronik@pharm.auth.gr
Received January 28, 2016
DOI 10.1002/jhet.2693
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
By reaction with sodium ethoxide and as a function of their structures, 2-[(1-alkyl(aryl)-4-cyano-6,7-dihydro-5H-
cyclopenta[c]pyridin-3-yl)oxy]acetamides 11 gave 1-amino-5-alkyl(aryl)-7,8-dihydro-6H-cyclopenta[d]furo[2,3-b]
pyridine-2-carboxamides 10 and/or 1-alkyl(aryl)-3-amino-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitriles 12.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
could give as a function of their structure, the ‘expected’
furo[2,3-c]isoquinoline-2-carboxamides 4, with very high
yields, but also the ‘unexpected’ 3-amino-4-cyano-5,6,7,8-
tetrahydroisoquinolines 5 via a Smiles-type rearrangement
(Scheme 2) depending on the structure of the amide group [4].
The first reaction pathway was characteristic for amides
deriving from aliphatic secondary amines or from aromatic
amines; the second occurred only with amides deriving
from aliphatic primary amines [4].
Interestingly, amides obtained from ammonia reacted by
both pathways with a prevalence of the second pathway on
the first one (ratio of products: ca. 3/1).
A very interesting behavior has been observed with some
2-[(1-akyl(aryl)-4-cyano-5,6,7,8-tetrahydroisoquinolin-3-yl)
oxy]acetohydrazides (in 3: R1 =H, R2 =NH2), which by the
action of sodium ethoxide or of hydrazine hydrate excess
The discovery of several biologically active derivatives
of condensed furo[2,3-b]pyridines has open the way to
the research of new methods for their preparation [1].
Therefore, there is a growing interest in synthetic method-
ologies that could give facile and reliable accesses to this
class of compounds [1]. In this research line, we have
reported a synthetic procedure for the preparation of con-
densed ethyl 5-alkyl(aryl)-1-amino-6,7,8,9-tetrahydrofuro
[2,3-c]isoquinoline-2-carboxylates 2 from ethyl [(1-alkyl
(aryl)-4-cyano-5,6,7,8-tetrahydroisoquinolin-3-yl)oxy]ace-
tates 1 by the action of sodium ethoxide (Scheme 1) [2–4].
Very interestingly, by applying the same kind of procedure
to some 2-[(1-alkyl(aryl)-4-cyano-5,6,7, 8-tetrahydroisoquinolin-
3-yl)oxy]acetamides 3, we have observed that these substrates
© 2016 Wiley Periodicals, Inc.

S. N. Sirakanyan, D. Spinelli, A. Geronikaki, and A. A. Hovakimyan
Vol 000
Scheme
1. Synthesis
of
ethyl
5-alkyl(aryl)-1-amino-6,7,8,9-
yields (Y =79–84%) 1-amino-7,8-dihydro-6H-cyclopenta
[d]furo[2,3-b]pyridine-2-carboxylates 9 [3,11] via a base-
promoted addition of the methylene of the acetate group
to the cyano group (Scheme 3).
tetrahydrofuro[2,3-c]isoquinoline-2-carboxylates (2).
Attempts to convert the ester group in cyclopenta[d]furo
[2,3-b]pyridine-2-carboxylates 9 into an amide group by
treatment with various amines in order to obtain conve-
nient synthons 10 for the synthesis of new annulated
furan[2,3-b]pyridine derivatives failed (Scheme 3).
Therefore, to overcome this problem, we have replaced the
ester group in 8 before cyclization by reacting it with amines.
Thus, the corresponding cyclopenta[c]pyridine-2-acetamides
11b,c,e,f,h–k,m,n,q,v in high yields (72–79%) in the case of
primary and secondary amines were obtained (Scheme 4,
Table 1). Using aromatic amines, diethylamine, and ammo-
nia, we were not able to obtain the relevant acetamides 11.
Luckily, we were able to obtain these compounds 11a,d,g,l,
o,p,r–u by direct alkylation of 3-oxo-cyclopenta[c]pyridines
7 with the appropriate chloroacetamides in high yields
(Y=78–89%; mean yield 84%) (Scheme 4).
gave the 5-alkyl(aryl)-1-amino-6,7,8,9-tetrahydro-3H-
pyrazolo[3,4-c]isoquinolines
6 (a new pyrazole ring
condensed to the pyridine ring has been built!) presumably
via the intermediate formation of 1-akyl(aryl)-4-cyano-3-
hydrazino-5,6,7,8-tetrahydroisoquinolines I, that was the
expected product of the Smiles rearrangement.
The aim of the present work is to enlarge the scope of
the previous reactivity to some cyclopenta[c]pyridin-
2-acetamides 11 (the cyclohexa ring is now substituted by
a cyclopenta one) to obtain novel and novel condensed
furo[2,3-b]pyridine derivatives.
This kind of research falls in our general interest in the
chemistry of nitrogen-containing heterocycles: in this field,
we have studied reactivity [5,6], reaction mechanisms
[6,7], synthetic applications [5,6], and biological activities
[8–10] of several and several penta-atomic and hexa-
atomic heterocycles.
Scheme 3. Synthesis of 1-amino-7,8-dihydro-6H-cyclopenta[d]furo[2,3-b]
pyridine-2-carboxylates 9 from 3-oxo-3,5,6,7-tetrahydro-2H-cyclopenta[c]
pyridine-4-carbonitriles 7.
RESULTS AND DISCUSSION
In order to obtain the ethyl [(1-alkyl-4-cyano-
6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)oxy]acetates 8,
[3,11] we have treated 1-alkyl-3-oxo-3,5,6,7-tetrahydro-
2H-cyclopenta[c]pyridine-4-carbonitriles 7 in DMF with
chloroacetic ester in the presence of potassium carbonate,
as previously reported [3,11]. Then, compound 8 by cycli-
zation in the presence of sodium ethoxide gave with high
Scheme 2. Synthesis of furo[2,3-c]isoquinoline-2-carboxamides 4 and of 3-amino-5,6,7,8-tetrahydroisoquinoline-4-carbonitriles 5 and of 5-akyl(aryl)-1-
amino-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c]isoquinolines 6.
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Cyclopenta[c]Pyridine-4-Carbonitriles and Cyclopenta[d]Pyrazolo[3,4-b]Pyridines
Scheme 5. Reactions of 2-[(1-alkyl(aryl)-4-cyano-6,7-dihydro-5H-cyclopenta
[c]pyridin-3-yl)oxy]acetamides 11 with sodium ethoxide: synthesis of
1-amino-5-alkyl(aryl)-7,8-dihydro-6H-cyclopenta[d]furo[2,3-b]pyridine-2-
carboxamides 10 and of 1-alkyl(aryl)-3-amino-6,7-dihydro-5H-cyclopenta
[c]pyridine-4-carbonitriles 12.
To obtain the amides 10, alkoxyacetamides 11 were
treated with sodium ethoxide in ethanol. In contrast to
alkoxy esters 8, treatment of alkoxyacetamides 11 with
sodium ethoxide could follow different pathways, depend-
ing on their chemical structure. In fact, the condensed
cyclopenta[d]furo[2,3-b]pyridine-2-carboxamides 10 were
obtained in good yields (Y = 55–65%; mean yield 60%)
only when the amine of the alkoxyacetamides 11 derived
from aromatic 11d,o,p,s,t,u, or from aliphatic secondary
amines 11e,f,j,k,q,r,v (Scheme 5, Table 2).
In contrast, the alkoxyacetamides derived from primary
aliphatic amines 11b,c,h,i,m,n gave by the action of
sodium ethoxide unexpected products: 3-amino-6,7-
dihydro-5H-cyclopenta[c]pyridine-4-carbonitriles 12 in
moderate yields (Y=48–60%; mean yield 52%). Their struc-
tures were assigned examining the IR and 1H NMR spectra.
Moreover, looking at the behavior of alkoxyacetamides
11a,g,l derived from ammonia, a mixture of amides 10a,
e,h and amines 12a,d,g was obtained (ratio was 1:10
(10a:12a), 1:1 (10e:12d) and 1:4 (10h:12g).
The structure of amines 12 was confirmed by an alterna-
tive synthesis from the appropriate chloro derivatives 13,
activated to nucleophilic aromatic substitutions (SNAr) by
reaction with the appropriate aliphatic primary amines or
ammonia (Scheme 5, Table 2). The formation of these
amino derivatives 12b,c,e,f,h,i, or mixture with
furopyridines indicated that a rearrangement took place un-
der the applied conditions.
Also on the basis of the results previously obtained by us
on studying the reactivity of 2-[(1-alkyl(aryl)-4-cyano-
5,6,7,8-tetrahydroisoquinolin-3-yl)oxy]acetamides 3 with
sodium ethoxide, we can say that a Smiles-type rearrange-
ment (an intramolecular nucleophilic substitution SNi, see
Introduction) occurred also in this instance. The structure
of 2-[(1-alkyl(aryl)-4-cyano-6,7-dihydro-5H-cyclopenta[c]
pyridin-3-yl)oxy]acetamides 11b,c,h,i,m,n and 11a,g,l
(deriving from primary aliphatic amines) allowed its oc-
currence. In fact the presence of an alkoxyacetamide group
(containing a potential nitrogen nucleophilic center, that
could be further activated by sodium ethoxide, and at the
same time of an oxygen atom, of ether type, potential leav-
ing group) in a substrate strongly activated towards aro-
matic nucleophilic substitutions (a nitrogen pyridine atom
and a cyano group are present) rendered possible Smiles
rearrangements [12–21]. The mechanism of this
rearrangement is well known and has been recalled in
our previous paper [4]. It easily occurred in both benzene
Scheme 4. Synthesis of 2-[(1-alkyl(aryl)-4-cyano-6,7-dihydro-5H-cyclopenta
[c]pyridin-3-yl)oxy]acetamides 11.
Table 1
2-[(1-Alkyl(aryl)-4-cyano-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)oxy]acetamides 11.
Compound
R
R1R2
Compound
R
R1R2
11a
11b
11c
11d
11e
11f
11g
11h
11i
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C4H9
i-C4H9
i-C4H9
i-C4H9
i-C4H9
R1 = R2 = H
11l
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
2-furyl
2-furyl
2-furyl
2-furyl
2-furyl
R1 = R2 = H
R1 = H, R2 = 2-furylmethyl
R1 = H, R2 = CH2Ph
R1 = H, R2 = Ph
11m
11n
11o
11p
11q
11r
11s
11t
R1 = H, R2 = 2-furylmethyl
R1 = H, R2 = CH2Ph
R1 = H, R2 = 2-CH3OC6H4
R1 = H, R2 = 3-CH3OC6H4
R1 + R2 = –(CH2)4–
R1 + R2 = –(CH2)4–
R1 + R2 = –(CH2)5–
R1 = R2 = H
R1 = R2 = C2H5
R1 = H, R2 = 2-furylmethyl
R1 = H, R2 = CH2Ph
R1 + R2 = –(CH2)4–
R1 + R2 = –(CH2)5–
R1 = H, R2 = 2-CH3OC6H4
R1 = H, R2 = 3-CH3OC6H4
R1 = H, R2 = 4-CH3COC6H4
R1 + R2 = –(CH2)5–
11j
11k
11u
11v
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. N. Sirakanyan, D. Spinelli, A. Geronikaki, and A. A. Hovakimyan
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Table 2
1-Amino-7,8-dihydro-6H-cyclopenta[d]furo[2,3-b]pyridine-2-carboxamides 10 and 3-amino-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carbonitriles 12.
Compound
R
R1R2
Compound
R
R1R2
10a
10b
10c
10d
10e
10f
10g
10h
10i
i-C3H7
i-C3H7
i-C3H7
i-C3H7
i-C4H9
i-C4H9
i-C4H9
C6H5
C6H5
C6H5
C6H5
2-furyl
2-furyl
R1 = R2 = H
10n
10o
10p
12a
12b
12c
12d
12e
12f
12g
12h
12i
2-furyl
2-furyl
2-furyl
i-C3H7
i-C3H7
i-C3H7
i-C4H9
i-C4H9
i-C4H9
C6H5
R1 = H, R2 = 3-CH3OC6H4
R1 = H, R2 = 4-CH3COC6H4
R1 + R2 = –(CH2)5–
R1 = R2 = H
R1 = H, R2 = Ph
R1 + R2 = –(CH2)4–
R1 + R2 = –(CH2)5–
R1 = R2 = H
R1 = H, R2 = 2-furylmethyl
R1 = H, R2 = CH2Ph
R1 = R2 = H
R1 + R2 = –(CH2)4–
R1 + R2 = –(CH2)5–
R1 = R2 = H
R1 = H, R2 = 2-furylmethyl
R1 = H, R2 = CH2Ph
R1 = R2 = H
R1 = H, R2 = 2-CH3OC6H4
R1 = H, R2 = 3-CH3OC6H4
R1 + R2 = –(CH2)4–
R1 = R2 = C2H5
10j
10k
10l
C6H5
C6H5
R1 = H, R2 = 2-furylmethyl
R1 = H, R2 = CH2Ph
—
10m
R1 = H, Rn = 2-CH3C6H4
—
—
and heterocyclic derivatives activated to SNAr processes,
furnishing an interesting method for introducing new func-
tionalities in aromatic systems (Scheme 6).
With these results in our hands to enlarge the scope of the
aforementioned rearrangement, we have synthesized in
excellent yields (Y=87–90%) some 4-cyano-6,7-dihydro-
5H-cyclopenta[c]pyridine-3-yl)oxy]acetohydrazides 14, by
behaved as the amides 11 deriving from primary aliphatic
amines before furnishing (presumably as intermediates)
the relevant 3-hydrazino-6,7-dihydro-5H-cyclopenta[c]
pyridine-4-carbonitriles 15. In turn, compounds 15 by
internal cyclization (nucleophilic addition of the amino
group of hydrazine functionality to the cyano group)
furnished the 5-alkyl(aryl)-3,6,7,8-tetrahydrocyclopenta
[d]pyrazolo[3,4-b]pyridin-1-amines 16 in high yields
(Y = 83–88%; mean yield 86%). Of course, hydrazides 14
by long refluxing (10 h) in ethanol with hydrazine hydrate
in excess gave directly compounds 16.
reacting
ethyl
[(1-alkyl(aryl)-4-cyano-6,7-dihydro-5H-
cyclopenta[c]pyridin-3-yl)oxy]acetates 8 with excess of
hydrazine hydrate (short refluxing: 15min) in ethanol
(Scheme 7).
By significant extention of the reaction times (10 h), we
have observed a completely different result. In fact, the
tested hydrazides 14 in these experimental conditions
The structure of compounds 16 has been ascertained by
spectroscopic data and definitively confirmed by alterna-
tive synthesis from chlorides 13 (Y = 89–92%) and hydra-
zine hydrate in excess by long refluxing (10 h).
Finally, we recall that in all these different experimental
conditions we have never observed the formation of 5-alkyl
(aryl)-1-amino-7,8-dihydro-6H-cyclopenta[d]furo[2,3-b]
pyridine-2-carbohydrazides 17.
Scheme 6. Smiles rearrangements.
Scheme 7. Synthesis of 5-alkyl(aryl)-3,6,7,8-tetrahydrocyclopenta[d]pyrazolo[3,4-b]pyridin-1-amines 16 from ethyl [(1-alkyl(aryl)-4-cyano-6,7-dihydro-
5H-cyclopenta[c]pyridin-3-yl)oxy]acetates 8, from 4-cyano-6,7-dihydro-5H-cyclopenta[c]pyridine-3-yl)oxy]acetohydrazides 14, or from chlorides 13.
Journal of Heterocyclic Chemistry
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Month 2016
Cyclopenta[c]Pyridine-4-Carbonitriles and Cyclopenta[d]Pyrazolo[3,4-b]Pyridines
CONCLUSIONS 11b,e,f,h,i,k,m–q,s–v) solutions on a Varian Mercury
300VX 300MHz spectrometer.
Continuing in our studies on the synthesis of furopyridines
and on the application of Smiles rearrangement in pyridine
derivatives, we have investigated the reactivity of sev-
eral 2-[(1-alkyl(aryl)-4-cyano-6,7-dihydro-5H-cyclopenta[c]
pyridin-3-yl)oxy]acetamides 11 with sodium ethoxide
observing an interesting variety of chemical behavior de-
pending on the nature of the tested acetamides 11.
The amides deriving from aliphatic secondary amines or
primary aromatic amines gave the expected cyclopenta[d]
furo[2,3-b]pyridines 10 in good yields.
The progress of the reactions as well as purity of com-
pounds was monitored by thin layer chromatography with
Silufol UV-254 precoated sheets using the systems:
chloroformÀethanol, 2:1 (Compounds 8d, 9d and 11a–v);
pyridineÀethanol, 1:3 (Compounds 10a–p and 14a–d);
chloroformÀacetoneÀhexane, 1:1:2 (Compound 12a–h);
pyridineÀhexaneÀethanol, 1:2:3 (Compound 16a–d). UV
light was used for detection.
Compounds 8a–c3,11 and 9a–c3,11 had been already
described.
In contrast, acetamides 11 deriving from aliphatic
primary amines furnished 3-amino-6,7-dihydro-5H-
cyclopenta[c]pyridine-4-carbonitriles 12 via a Smiles-type
rearrangement in moderate yields. Moreover, acetamides 11
deriving from ammonia gave a mixture of products deriving
from the occurrence of both the reaction pathways.
Finally, acetylhydrazides 14 behaved in the first step of the
reaction in a manner similar to acetamides deriving from ali-
phatic primary amines; in a second step, they gave 3,6,7,8-
tetrahydrocyclopenta[d]pyrazolo[3,4-b]pyridin-1-amines 16:
in fact, the intermediate 3-hydrazinocyclopenta[c]pyridines
15 by internal cyclization gave rice in high yields to the
formation of a pyrazole ring condensed on the pyridine one.
In summary, starting from 2-[4-cyano-6,7-dihydro-5H-
cyclopenta[c]pyridin-3-yl)oxy]acetamides, we have described
the synthesis of new cyclopenta[d]furo[2,3-b]pyridines 10, of
3-aminocyclopenta[c]pyridines 12 and of cyclopenta[d]
pyrazolo[3,4-b]pyridins 16.
We have observed results strictly parallel to those recently
evidenced by us studying the reactivity of some ethyl [(1-
alkyl-4-cyano-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)oxy]
acetates, 2-[4-cyano-6,7-dihydro-5H-cyclopenta[c]pyridin-
3-yl)oxy]acetamides and 4-cyano-6,7-dihydro-5H-cyclopenta
[c]pyridine-3-yl)oxy]acetohydrazides, showing that the
observed behavior had a general character that could be
applied also to other classes of homocyclic or heterocyclic
compounds.
General method of synthesis of ethyl [(1-alkyl(aryl)-4-
cyano-6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)oxy]acetates
8a–d.
To a suspension of cyclopenta[c]pyridine 7
(0.1 mol) and potassium carbonate (15 g, 0.11mol) in dry
DMF (150mL), chloroacetic acid ethyl ester (13.48 g,
0.11 mol) was added dropwise with stirring. The reaction
mixture was kept at 75–80°C for 2 h, cooled to r.t. and
poured into cold water. The formed crystals were filtered,
washed with water, dried and recrystallized from ethanol.
Ethyl [(4-cyano-1-(2-furyl)-6,7-dihydro-5H-cyclopenta[c]
pyridin-3-yl)oxy]acetate (8d). Yield 90%, mp 99–101°C
1
(from EtOH). IR (cmÀ1): 2222 (CN), 1668 (C = O). H
NMR (δ, ppm): 1.26 (t, J = 7.1 Hz, 3H, CH2CH3), 2.24
(m, 2H, 6-CH2), 3.09 (t, J = 7.7 Hz, 2H, 7-CH2), 3.25 (t,
J = 7.5 Hz, 2H, 5-CH2), 4.19 (q, J= 7.1 Hz, 2H, CH2CH3),
4.93 (s, 2H, OCH2), 6.59 (dd, J1 = 3.4, J2 = 1.7 Hz, 1H,
4-CH, furyl), 7.05 (dd, J1 =1.7, J2 = 0.8 Hz, 1H, 3-CH,
furyl), 7.70 (dd, J1 = 3.4, J2 = 0.8 Hz, 1H, 5-CH, furyl).
Anal. Calcd C17H16N2O4: C 65.38, H 5.16, N 8.97%.
Found: C 65.36, H 5.15, N 9.00%.
General method of synthesis of ethyl 1-amino-5-alkyl(aryl)-
7,8-dihydro-6H-cyclopenta[d]furo[2,3-b]pyridine-2-
carboxylates 9a–d.
To a solution of sodium ethoxide
[253 mg (11 mmol) of sodium in absolute ethanol
(300 mL)], compound 8 (10 mmol) was added. The
mixture was refluxed for 15–20min, cooled, and poured
onto ice. The formed crystals were filtered off, washed
with water, dried and recrystallized from ethanol.
Ethyl
1-amino-5-(2-furyl)-7,8-dihydro-6H-cyclopenta[d]
furo[2,3-b]pyridine-2-carboxylate (9d).
Yield 83%, mp
EXPERIMENTAL
240–242°C (from EtOH). IR (cmÀ1): 3535, 3280 (NH2),
1
1687 (C=O). H NMR (δ, ppm): 1.42 (t, J=7.1Hz, 3H,
All melting points were determined in an open capillary
and are uncorrected. Elemental analyses were performed
on a EuroEA3000 Elemental Analyzer.
CH2CH3), 2.27À2.40 (m, 2H, 7-CH2), 2.95 (t, J=7.5Hz,
2H, 6-CH2), 3.32 (t, J=7.5Hz, 2H, 8-CH2), 4.35 (q,
J=7.1Hz, 2H, CH2CH3), 5.75 (br, 2H, NH2), 6.61 (dd,
J1 =3.4, J2 =1.7Hz, 1H, 4-CH, furyl), 7.10 (dd, J1 =3.4,
J2 =0.8Hz, 1H, 3-CH, furyl.), 7.72 (dd, J1 =1.7,
J2 =0.8Hz, 1H, 5-CH, furyl.). Anal. Calcd C17H16N2O4: C
65.38, H 5.16, N 8.97%. Found: C 65.41, H 5.18, N 8.95%.
General method of synthesis of 1-amino-7,8-dihydro-6H-
cyclopenta[d]furo[2,3-b]pyridine-2-carboxamides 10a–p. To
a solution of sodium ethoxide [0.25g (0.011 mol) of
IR spectra were recorded on Nicolet Avatar 330-FT-IR
spectrophotometer, and the reported wave numbers are given
in cmÀ1. 1H NMR spectra were recorded in DMSO-d6 and
CDCl3 solutions on a Varian Mercury 300VX 300MHz
spectrometer. Chemical shifts are reported as δ (ppm)
relative to TMS as internal standard. 1H NMR spectra were
recorded in DMSO-d6 (Compounds 8d; 9d; 10a–p; 11a,c,
d,g,j,l,r; 12a–h; 14a–d; 16a–d) and CDCl3 (Compound
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S. N. Sirakanyan, D. Spinelli, A. Geronikaki, and A. A. Hovakimyan
Vol 000
sodium in absolute ethanol (30mL)], compound 11
(0.01mmol) was added. The mixture was refluxed for 2 h,
cooled, and poured onto ice water. The formed crystals
were filtered off, washed with water, dried and
recrystallized from ethanol.
2H, 8 (5)-CH2), 5.53 (10e) (br, 2H, NH2), 5.93 (12d)
(br, 2H, NH2), 6.89 (10e) (br, 2H, NH2).
5-Isobutyl-2-(pyrrolidin-1-ylcarbonyl)-7,8-dihydro-6H-
cyclopenta[d]furo[2,3-b]pyridin-1-amine (10f).
Yield
57%, mp 176–178°C(from EtOH). IR (cmÀ1): 3405, 3321
(NH2), 1650 (C=O). 1H NMR (δ, ppm): 0.95 (d,
J=6.6Hz, 6H, CH(CH3)2), 1.96 (br, 4H, 3,4-CH2,
C4H8N), 2.19 (m, 1H, CH(CH3)2), 2.21 (m, 2H, 7-CH2),
2.58 (d, J=7.1Hz, 2H, CHCH2), 2.90 (t, J=7.4Hz, 2H, 6-
CH2), 3.29 (t, J=7.6Hz, 2H, 8-CH2), 3.58 (br, 2H, NCH2),
3.99 (br, 2H, NCH2), 5.70 (br, 2H, NH2). Anal. Calcd
C19H25N3O2: C 69.70, H 7.70, N12.83%. Found: C 69.77,
H 7.67, N 12.87%.
1-Amino-5-isopropyl-7,8-dihydro-6H-cyclopenta[d]furo[2,3-b]
pyridine-2-carboxamide and 3-amino-1-isopropyl-6,7-dihydro-5
H-cyclopenta[c]pyridine-4-carbonitrile (10a and 12a). Yield
69%. IR (cmÀ1): 3190–3468 (NH, NH2), 2219 (CN), 1630
1
(C= O). H NMR (δ, ppm): 1.26 and 1.27 (d, J=6.7Hz,
6H, CH(CH3)2), 2.22 and 2.23 (m, 2H, 7 (6)-CH2), 2.93 and
2.94 (t, J= 7.4Hz, 2H, 6 (7)-CH2), 3.11 and 3.12 (spt,
J= 6.7 Hz, 1H, CH(CH3)2), 3.28 and 3.30 (t, J=7.4Hz, 2H,
8(5)-CH2), 5.51 (10a) (br 2H, NH2), 6.00 (12a) (br, 2H,
NH2), 6.89 (10a) (br, 2H, NH2).
5-Isobutyl-2-(piperidin-1-ylcarbonyl)-7,8-dihydro-6H-
cyclopenta[d]furo[2,3-b]pyridin-1-amine (10g).
Yield
61%, mp 72–73°C (from EtOH). IR (cmÀ1): 3367, 3330
(NH2), 1598 (C =O). 1H NMR (δ, ppm): 0.95 (d, J=6.6Hz,
6H, CH(CH3)2), 1.62–1.76 (m, 6H, 3,4,5-CH2, C5H10N),
2.19 (m, 1H, CH(CH3)2), 2.21 (m, 2H, 7-CH2), 2.58 (d,
J=7.1Hz, 2H, CHCH2), 2.90 (t, J=7.4Hz, 2H, 6-CH2),
3.29 (t, J=7.6Hz, 2H, 8-CH2), 3.81 (br, 4H, N(CH2)2), 5.72
(br, 2H, NH2). Anal. Calcd C20H27N3O2: C 70.35, H 7.97,
N12.31%. Found: C 70.41, H 7.95, N 12.35%.
1-Amino-5-isopropyl-N-phenyl-7,8-dihydro-6H-cyclopenta
[d]furo[2,3-b]pyridine-2-carboxamide (10b). Yield 55.7%,
mp 255–257°C (from EtOH). IR (cmÀ1): 3460, 3407, 3321
(NH, NH2), 1630 (C = O). 1H NMR (δ, ppm): 1.26 (d,
J=6.7Hz, 6H, CH(CH3)2), 2.25 (m, 2H, 7-CH2), 2.95 (t,
J=7.4 Hz, 2H, 6-CH2), 3.14 (spt, J= 6.7 Hz, 1H, CH(CH3)2),
3.32 (t, J= 7.6 Hz, 2H, 8-CH2), 5.75 (br, 2H, NH2), 6.98 (m,
1H, Ph), 7.19–7.27 (m, 2H, Ph), 7.84 (m, 2H, Ph), 9.55 (br,
1H, NH). Anal. Calcd C20H21N3O2: C 71.62, H 6.31,
N12.53%. Found: C 71.67, H 6.33, N 12.56%.
1-Amino-5-phenyl-7,8-dihydro-6H-cyclopenta[d]furo[2,3-b]
pyridine-2-carboxamide and 3-amino-1-phenyl-6,7-dihydro-5
H-cyclopenta[c]pyridine-4-carbonitrile (10h and 12g). Yield
69%. IR (cmÀ1): 3190–3469 (NH, NH2), 2218 (CN), 1588
5-Isopropyl-2-(pyrrolidin-1-ylcarbonyl)-7,8-dihydro-6H-
cyclopenta[d]furo[2,3-b]pyridin-1-amine (10c).
Yield
1
58.8%, mp 228–229°C (from EtOH). IR (cmÀ1): 3426,
(C=O). H NMR (δ, ppm):, 2.21 and 2.10 (m, 2H, 7 (6)-
1
CH2), 2.94–3.03 (12g) (m, 4H, 7,5-CH2), 3.13 (10h) (t,
J=7.2, 2H, 6-CH2), 3.34 (10h) (t, J=7.4, 2H, 8-CH2), 5.64
(10h) (br, 2H, NH2), 6.23 (12g) (br, 2H, NH2), 7.04 (10h)
(br, 2H, NH2), 7.32–7.47 (m, 3H, Ph), 7.68–7.79 (m, 2H, Ph).
1-Amino-N-(2-methoxyphenyl)-5-phenyl-7,8-dihydro-6H-
cyclopenta[d]furo[2,3-b]pyridine-2-carboxamide (10i). Yield
64%, mp 285–287°C (from EtOH). IR (cmÀ1): 3470, 3407,
3335 (NH2), 1616 (C=O). H NMR (δ, ppm): 1.25 (d,
J=6.7Hz, 6H, CH(CH3)2), 1.87–2.06 (br, 4H, 3,4-CH2
C4H8N), 2.22 (m, 2H, 7-CH2), 2.93 (t, J=7.4Hz, 2H,
6-CH2), 3.10 (spt, J=6.7Hz, 1H, CH(CH3)2), 3.28 (t,
J=7.5Hz, 2H, 8-CH2), 3.55 (br, 2H, NCH2), 4.04 (br, 2H,
NCH2), 5.70 (br, 2H, NH2). Anal. Calcd C18H23N3O2: C
68.99, H 7.40, N 13.41%. Found: C 69.03, H 7.41, N 13.44%.
5-Isopropyl-2-(piperidin-1-ylcarbonyl)-7,8-dihydro-6H-
1
3372 (NH, NH2), 1599 (C=O). H NMR (δ, ppm): 2.24
cyclopenta[d]furo[2,3-b]pyridin-1-amine (10d).
Yield
(m, 2H, 7-CH2), 3.16 (t, J=7.2Hz, 2H, 6-CH2), 3.38 (t,
J=7.5Hz, 2H, 8-CH2), 4.01 (s, 3H, OCH3), 5.88 (br, 2H,
NH2), 6.88–7.04 (m, 3H, C6H4), 8.42 (m, 1H, C6H4),
7.35–7.49 (m, 3H, Ph), 7.81 (m, 2H, Ph), 8.52 (br, 1H,
NH). Anal. Calcd C24H21N3O3: C 72.17, H 5.30,
N10.52%. Found: C 72.27, H 5.27, N 10.57%.
54.9%, mp 191–193°C (from EtOH). IR (cmÀ1): 3450,
1
3315 (NH2), 1625 (C=O). H NMR (δ, ppm): 1.26 (d,
J=6.7Hz, 6H, CH(CH3)2), 1.64–1.76 (m, 6H, 3,4,5-CH2
C5H10N), 2.22 (m, 2H, 7-CH2), 2.93 (t, J=7.4Hz, 2H, 6-
CH2), 3.11 (spt, J=6.7Hz, 1H, CH(CH3)2), 3.28 (t,
J=7.6Hz, 2H, 8-CH2), 3.79–3.85 (m, 4H, N(CH2)2), 5.73
(br, 2H, NH2). Anal. Calcd C19H25N3O2: C 69.70, H 7.70,
N 12.83%. Found: C 69.75, H 7.72, N 12.86%.
1-Amino-5-isobutyl-7,8-dihydro-6H-cyclopenta[d]furo[2,3-b]
pyridine-2-carboxamide and 3-amino-1-isobutyl-6,7-dihydro-5
H-cyclopenta[c]pyridine-4-carbonitrile (10e and 12d). Yield
70%. IR (cmÀ1): 3195–3470 (NH, NH2), 2220 (CN),
1610 (C = O). 1H NMR (δ, ppm): 0.94 and 0.92 (d,
J = 6.6 Hz, 6H, CH(CH3)2), 2.17 and 2.09 (m, 1H, CH
(CH3)2), 2.21 and 2.08 (m, 2H, 7 (6)-CH2), 2.59 and
2.38 (d, J = 7.1 Hz, 2H, CHCH2), 2.89 and 2.76 (t,
J = 7.4 Hz, 2H, 6 (7)-CH2), 3.28 and 2.93 (t, J = 7.6 Hz,
1-Amino-N-(3-methoxyphenyl)-5-phenyl-7,8-dihydro-6H-
cyclopenta[d]furo[2,3-b]pyridine-2-carboxamide (10j). Yield
56%, mp 219–220°C (from EtOH). IR (cmÀ1): 3410, 3395,
1
3373 (NH, NH2), 1650 (C=O). H NMR (δ, ppm): 2.23
(m, 2H, 7-CH2), 3.16 (t, J=7.2Hz, 2H, 6-CH2), 3.38 (t,
J=7.4Hz, 2H, 8-CH2), 3.79 (s, 3H, OCH3), 5.87 (br, 2H,
NH2), 6.54 (ddd, J1 =8.2, J2 =2.5, J3 =0.7Hz, 1H, 4-CH,
C6H4), 7.13 (dd, J1 =8.2, J2 =8.1Hz, 1H, 5-CH, C6H4),
7.34–7.48 (m, 4H, 6-CH, C6H4, Ph), 7.59 (dd, J1 =2.5,
J2 =1.8Hz, 1H, 2-CH, C6H4), 7.75–7.8 (m, 2H, Ph), 9.65
(br, 1H, NH). Anal. Calcd C24H21N3O3: C 72.17, H 5.30,
N 10.52%. Found: C 72.27, H 5.33, N 10.48%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Cyclopenta[c]Pyridine-4-Carbonitriles and Cyclopenta[d]Pyrazolo[3,4-b]Pyridines
5-Phenyl-2-(pyrrolidin-1-ylcarbonyl)-7,8-dihydro-6H-cyclopenta
[d]furo[2,3-b]pyridin-1-amine (10k). Yield 60%, mp 201–203°C
(from EtOH). IR (cmÀ1): 3430, 3318 (NH2), 1620 (C= O). 1H
NMR (δ, ppm): 1.97 (br, 4H, 3,4-CH2 C4H8N), 2.22 (m, 2H,
7-CH2), 3.14 (t, J= 7.3 Hz, 2H, 6-CH2), 3.35 (t, J= 7.5 Hz, 2H,
8-CH2), 3.58 (br, 2H, NCH2), 4.02 (br, 2H, NCH2), 5.79 (br,
2H, NH2), 7.33–7.46 (m, 3H, Ph), 7.75–7.80 (m, 2H, Ph). Anal.
Calcd C21H21N3O2: C 72.60, H 6.09, N 12.10%. Found: C
72.69, H 6.10, N 12.07%.
J1 =1.8, J2 =0.8Hz, 1H, 5-CH, furyl), 7.83 (m, 2H, C6H4),
8.00 (m, 2H, C6H4), 10.03 (br, 1H, NH). Anal. Calcd
C23H19N3O4: C 68.82, H 4.77, N 10.47%. Found: C 68.93,
H 4.75, N 10.50%.
5-(2-Furyl)-2-(piperidin-1-ylcarbonyl)-7,8-dihydro-6H-
cyclopenta[d]furo[2,3-b]pyridin-1-amine (10p). Yield 60%,
m.p. 187–189°C (from EtOH). IR (cmÀ1): 3470, 3337
1
(NH2), 1618 (C=O). H NMR (δ, ppm): 1.64–1.78 (m,
6H, 3,4,5-CH2, C5H10N), 2.27 (m, 2H, 7-CH2), 3.28 (t,
J= 7.6 Hz, 2H, 6-CH2), 3.32 (t, J= 7.7 Hz, 2H, 8-CH2), 3.82
(m, 4H, N(CH2)2), 5.87 (br, 2H, NH2), 6.57 (dd, J1 =3.4,
J2 =1.8 Hz, 1H, 4-CH, furyl), 7.06 (dd, J1 =3.4, J2 =0.7Hz,
1H, 3-CH, furyl), 7.64 (dd, J1 =1.8, J2 = 0.7 Hz, 1H, 5-CH,
furyl). Anal. Calcd C20H21N3O3: C 68.36, H 6.02, N
11.96%. Found: C 68.48, H 6.04, N 12.00%.
General method of synthesis of 2-[(1-alkyl(aryl)-4-cyano-
6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)oxy]acetamides 11
b,c,e,f,h–k,m,n,q,v. A mixture of compound 8 (0.01mol)
and the appropriate amine (0.022mol) in absolute ethanol
(50mL) was refluxed for 10h. After cooling, water
(100mL) was added. The precipitate was filtered, washed
with water, dried and recrystallized from ethanol.
2-[(4-Cyano-1-isopropyl-6,7-dihydro-5H-cyclopenta[c]pyridin-
3-yl)oxy]-N-(2-furylmethyl)acetamide (11b). Yield 74%, mp
120–122°C (from EtOH). IR (cmÀ1): 3380, 3115 (NH),
2210 (CN), 1675 (C= O). 1H NMR (δ, ppm): 1.21 (d,
J=6.7Hz, 6H, CH(CH3)2), 2.21 (m, 2H, 6-CH2), 2.89 (t,
J=7.4Hz, 2H, 7-CH2), 3.00 (spt, J= 6.7Hz, 1H, CH(CH3)2),
3.08 (t, J=7.6Hz, 2H, 5-CH2), 4.54 (d, J=5.8Hz, 2H,
NHCH2), 4.93 (s, 2H, OCH2), 6.25 (dd, J1 =3.3,
J2 =0.9Hz, 1H, 3-CH, furyl), 6.31 (dd, J1 =3.3, J2 =1.9Hz,
1H, 4-CH, furyl), 6.78 (t, J=5.8Hz, 1H, NH), 7.35 (dd,
J1 =1.9, J2 =0.9Hz, 1H, 5-CH, furyl). Anal. Calcd
C19H21N3O3: C 67.24, H 6.24, N 12.38%. Found: C 67.36,
H 6.26, N 12.35%.
N-Benzyl-2-[(4-cyano-1-isopropyl-6,7-dihydro-5H-cyclopenta
[c]pyridin-3-yl)oxy]acetamide (11c). Yield 72%, mp 137–
139°C (from EtOH). IR (cmÀ1): 3398, 3120 (NH), 2219
(CN), 1654 (C = O). 1H NMR (δ, ppm): 1.16 (d,
J=6.7Hz, 6H, CH(CH3)2), 2.19 (m, 2H, 6-CH2), 2.89 (t,
J=7.5Hz, 2H, 7-CH2), 2.98 (spt, J=6.7Hz, 1H, CH
(CH3)2), 3.05 (t, J=7.6Hz, 2H, 5-CH2), 4.32 (d,
J=6.0Hz, 2H, NHCH2), 4.83 (s, 2H, OCH2), 7.14–7.28
(m, 5H, Ph), 8.18 (t, J= 6.0Hz, 1H, NH). Anal. Calcd
C21H23N3O2: C 72.18, H 6.63, N 12.03%. Found: C
72.04, H 6.60, N 11.99%.
1-Amino-N,N-diethyl-5-(2-furyl)-7,8-dihydro-6H-cyclopenta
[d]furo[2,3-b]pyridine-2-carboxamide (10l). Yield 64%, mp
184–186°C (from EtOH). IR (cmÀ1): 3416, 3328 (NH2),
1
1654 (C=O). H NMR (δ, ppm): 1.30 (t, J=6.9Hz, 6H,
2CH3), 2.27 (m, 2H, 7-CH2), 3.28 (t, J=7.4Hz, 2H,
6-CH2), 3.32 (t, J=7.6Hz, 2H, 8-CH2), 3.59–3.71 (m, 4H,
N(CH2)2), 5.81 (br, 2H, NH2), 6.57 (dd, J1 =3.4,
J2 =1.8Hz, 1H, 4-CH, furyl), 7.06 (dd, J1 =3.4, J2 =0.8Hz,
1H, 3-CH, furyl), 7.65 (dd, J1 =1.8, J2 =0.8Hz, 1H, 5-CH,
furyl). Anal. Calcd C19H21N3O3: C 67.24, H 6.24, N
12.38%. Found: C 67.29, H 6.25, N 12.41%.
1-Amino-5-(2-furyl)-N-(2-methoxyphenyl)-7,8-dihydro-6H-
cyclopenta[d]furo[2,3-b]pyridine-2-carboxamide (10m). Yield
63%, mp 268–270°C (from EtOH). IR (cmÀ1): 3405, 3370,
3325 (NH, NH2), 1635 (C=O). 1H NMR (δ, ppm): 2.29 (m,
2H, 7-CH2), 3.28 (t, J=7.6Hz, 2H, 6-CH2), 3.34 (t,
J=7.7Hz, 2H, 8-CH2), 4.02 (s, 3H, OCH3), 5.85 (br, 2H,
NH2), 6.59 (dd, J1 =3.4, J2 =1.7 Hz, 1H, 4-CH, furyl), 6.88–
7.02 (m, 3H, C6H4), 8.40 (m, 1H, C6H4), 7.09 (dd, J1 =3.4,
J2 =0.8 Hz, 1H, 3-CH, furyl), 7.67 (dd, J1 =1.7, J2 =0.8Hz,
1H, 5-CH, furyl), 8.48 (s, 1H, NH). Anal. Calcd
C22H19N3O4: C 67.86, H 4.92, N 10.79%. Found: C 67.94,
H 4.93, N 10.76%.
1-Amino-5-(2-furyl)-N-(3-methoxyphenyl)-7,8-dihydro-6H-
cyclopenta[d]furo[2,3-b]pyridine-2-carboxamide (10n). Yield
65%, mp 213–215°C (from EtOH). IR (cmÀ1): 3410, 3341,
1
3320 (NH, NH2), 1615 (C=O). H NMR (δ, ppm): 2.29
(m, 2H, 7-CH2), 3.29 (t, J=7.5Hz, 2H, 6-CH2), 3.34 (t,
J=7.6Hz, 2H, 8-CH2), 3.79 (s, 3H, OCH3), 5.83 (br, 2H,
NH2), 6.54 (dd, J1 =8.2, J2 =2.4Hz, 1H, 4-CH, C6H4),
6.57 (dd, J1 =3.3, J2 =1.7Hz, 1H, 4-CH, furyl), 7.01 (d,
J=3.3Hz, 1H, 3-CH, furyl), 7.12 (dd, J1 =8.2, J2 =8.0Hz,
1H, 5-CH, C6H4), 7.42 (dd, J1 =8.0, J2 =1.6Hz, 1H, 6-CH,
C6H4), 7.58 (dd, J1 =2.4, J2 =1.6Hz, 1H, 2-CH, C6H4),
7.66 (d, J=1.7Hz, 1H, 5-CH, furyl), 9.62 (br, 1H, NH).
Anal. Calcd C22H19N3O4: C 67.98, H 4.92, N 10.79%.
Found: C 67.89, H 4.94, N 10.77%.
N-(4-Acetylphenyl)-1-amino-5-(2-furyl)-7,8-dihydro-6H-
cyclopenta[d]furo[2,3-b]pyridine-2-carboxamide (10o). Yield
57%, mp 293–295°C (from EtOH). IR (cmÀ1): 3411, 3370,
1-Isopropyl-3-(2-oxo-2-pyrrolidin-1-ylethoxy)-6,7-dihydro-
5H-cyclopenta[c]pyridine-4-carbonitrile (11e). Yield 77%,
mp 156–158°C (from EtOH). IR (cmÀ1): 2210 (CN),
1
1
3318 (NH, NH2), 1590, 1675 (C =O). H NMR (δ, ppm):
1673 (C = O). H NMR (δ, ppm): 1.17 (d, 6H, J = 6.7Hz,
2.27 (m, 2H, 7-CH2), 2.52 (s, 3H, CH3), 3.27 (t, J=7.5Hz,
2H, 6-CH2), 3.33 (t, J= 7.7 Hz, 2H, 8-CH2), 5.94 (br, 2H,
NH2), 6.55 (dd, J1 =3.4, J2 =1.8Hz, 1H, 4-CH, furyl), 7.00
(dd, J1 =3.4, J2 =0.8Hz, 1H, 3-CH, furyl), 7.65 (dd,
CH(CH3)2), 1.87 and 2.02 (m, 2H and 2H, 3,4-CH2,
C4H8N), 2.17 (m, 2H, 6-CH2), 2.86 (t, J =7.4 Hz, 2H,
7-CH2), 2.97 (spt, J = 6.7 Hz, 1H, CH(CH3)2), 3.06 (t,
J = 7.6 Hz, 2H, 5-CH2), 3.50 (t, J= 6.9 Hz, 2H, NCH2),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. N. Sirakanyan, D. Spinelli, A. Geronikaki, and A. A. Hovakimyan
Vol 000
3.58 (t, J = 6.7Hz, 2H, NCH2), 4.94 (s, 2H, OCH2). Anal.
Calcd C18H23N3O2: C 68.99, H 7.40, N 13.41%. Found:
C 69.10, H 7.43, N 13.44%.
2H, CHCH2), 2.84 (t, J=7.4Hz, 2H, 7-CH2), 3.08 (t,
J=7.6Hz, 2H, 5-CH2), 3.45–3.56 (br, 4H, N(CH2)2), 5.05
(s, 2H, OCH2). Anal. Calcd C20H27N3O2: C 70.35, H
7.97, N 12.31%. Found: C 70.44, H 7.94, N 12.35%.
2-[(4-Cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-
1-Isopropyl-3-(2-oxo-2-piperidin-1-ylethoxy)-6,7-dihydro-5H-
cyclopenta[c]pyridine-4-carbonitrile (11f).
Yield 76%, mp
157–159°C (from EtOH). IR (cmÀ1): 2180 (CN), 1599
3-yl)oxy]-N-(2-furylmethyl)acetamide (11m).
Yield 76%,
1
(C= O). H NMR (δ, ppm): 1.20 (d, J= 6.7 Hz, 6H, CH
mp 178–180°C (from EtOH). IR (cmÀ1): 3407, 3329 (NH),
2209 (CN), 1590 (C=O). 1H NMR (δ, ppm): 2.22 (m, 2H,
6-CH2), 3.15 (t, 2H, J=7.5Hz, 7-CH2), 3.17 (t, J=7.1Hz,
2H, 5-CH2), 4.55 (d, J=5.8Hz, 2H, NHCH2), 5.02 (s, 2H,
OCH2), 6.24 (dd, J1 =3.2, J2 = 0.9 Hz, 1H, 3-CH, furyl),
6.29 (dd, J1 =3.2, J2 =1.8Hz, 1H, 4-CH, furyl), 6.82 (t,
J=5.8Hz, 1H, NH), 7.33 (dd, J1 =1.8, J2 =0.9Hz, 1H, 5-
CH, furyl), 7.43–7.51(m, 3H, Ph), 7.78–7.84 (m, 2H, Ph).
Anal. Calcd C22H19N3O3: C 70.76, H 5.13, N 11.25%.
Found: C 70.64, H 5.12, N 11.23%.
(CH3)2), 1.52–1.71 (m, 6H, 3,4,5-CH2 C5H10N), 2.18 (m,
2H, 6-CH2), 2.86 (t, J= 7.4 Hz, 2H, 7-CH2), 2.98 (spt,
J=6.7 Hz, 1H, CH(CH3)2), 3.06 (t, J= 7.6 Hz, 2H, 5-CH2),
3.46–3.57 (m, 4H, N(CH2)2), 5.04 (s, 2H, OCH2). Anal.
Calcd C19H25N3O2: C 69.70, H 7.70, N 12.83%. Found: C
69.81, H 7.73, N 12.80%.
2-[(4-Cyano-1-isobutyl-6,7-dihydro-5H-cyclopenta[c]pyridin-
3-yl)oxy]-N-(2-furylmethyl)acetamide (11h). Yield 78%, mp
142–144°C (from EtOH). IR (cmÀ1): 3310, 3140 (NH),
2220 (CN), 1655 (C=O). 1H NMR (δ, ppm): 0.93 (d,
J=6.6Hz, 6H, CH(CH3)2), 2.18 (m, 1H, CH(CH3)2), 2.19
(m, 2H, 6-CH2), 2.52 (d, J= 7.1Hz, 2H, CHCH2), 2.87 (t,
J=7.4Hz, 2H, 7-CH2), 3.08 (t, J=7.6Hz, 2H, 5-CH2), 4.54
(d, J= 5.7 Hz, 2H, NHCH2), 4.91 (s, 2H, OCH2), 6.25 (dd,
J1 =3.3, J2 = 0.8 Hz, 1H, 3-CH, furyl), 6.31 (dd, J1 =3.3,
J2 =1.9Hz, 1H, 4-CH, furyl), 6.79 (t, J= 5.7 Hz, 1H, NH),
7.35 (dd, J1 =1.9, J2 =0.8Hz, 1H, 5-CH, furyl). Anal. Calcd
C20H23N3O3: C 67.97, H 6.56, N 11.89%. Found: C 68.07,
H 6.57, N 11.91%.
N-Benzyl-2-[(4-cyano-1-phenyl-6,7-dihydro-5H-cyclopenta
[c]pyridin-3-yl)oxy]acetamide (11n).
Yield 79%, mp
194–196°C (from EtOH). IR (cmÀ1): 3401, 3216 (NH),
1
2219 (CN), 1655 (C = O). H NMR (δ, ppm): 2.22 (m,
2H, 6-CH2), 3.14 (t, J = 7.6 Hz, 2H, 7-CH2), 3.18 (t,
J = 7.3 Hz, 2H, 5-CH2), 4.56 (d, J= 6.0 Hz, 2H, NHCH2),
5.04 (s, 2H, OCH2), 6.80 (t, J = 6.0 Hz, 1H, NH), 7.22–
7.29 (m, 5H, Ph), 7.44–7.52 (m, 3H, Ph), 7.80–7.85 (m,
2H, Ph). Anal. Calcd C24H21N3O2: C 75.18, H 5.52, N
10.96%. Found: C 75.08, H 5.54, N 10.99%.
N-Benzyl-2-[(4-cyano-1-isobutyl-6,7-dihydro-5H-cyclopenta
[c]pyridin-3-yl)oxy]acetamide (11i). Yield 77%, mp 120–
122°C (from EtOH). IR (cmÀ1): 3307, 3144 (NH), 2219
(CN), 1669 (C=O). 1H NMR (δ, ppm): 0.94 (d, J=6.6Hz,
6H, CH(CH3)2), 2.17 (m, 1H, CH(CH3)2), 2.19 (m, 2H, 6-
CH2), 2.52 (d, J=7.1Hz, 2H, CHCH2), 2.87 (t, J=7.4Hz,
2H, 7-CH2), 3.08 (t, J=7.6Hz, 2H, 5-CH2), 4.55 (d,
J=6.0Hz, 2H, NHCH2), 4.93 (s, 2H, OCH2), 6.79 (t,
J=6.0Hz, 1H, NH), 7.23–7.36 (m, 5H, Ph). Anal. Calcd
C22H25N3O2: C 72.70, H 6.93, N 11.56%. Found: C 72.58,
H 6.91, N 11.52%.
3-(2-Oxo-2-pyrrolidin-1-ylethoxy)-1-phenyl-6,7-dihydro-5H-
cyclopenta[c]pyridine-4-carbonitrile (11q). Yield 78%, mp
203–205°C (from EtOH). IR (cmÀ1): 2220 (CN), 1665
1
(C=O). H NMR (δ, ppm): 1.85–2.07 (m, 4H, 3,4-CH2,
C4H8N), 2.21 (m, 2H, 6-CH2), 3.13 (t, J=7.3Hz, 2H,
7-CH2), 3.14 (t, J=7.5Hz, 2H, 5-CH2), 3.58 (br, 4H, N
(CH2)2), 5.03 (s, 2H, OCH2), 7.40–7.47 (m, 3H, Ph), 7.71–
7.76 (m, 2H, Ph). Anal. Calcd C21H21N3O2: C 72.60, H
6.09, N 12.10%. Found: C 72.68, H 6.08, N 12.12%.
1-(2-Furyl)-3-(2-oxo-2-piperidin-1-ylethoxy)-6,7-dihydro-
5H-cyclopenta[c]pyridine-4-carbonitrile (11v). Yield 77%,
mp 178–180°C (from EtOH). IR (cmÀ1): 2222 (CN), 1680
(C = O). 1H NMR (δ, ppm): 1.64–1.73 (m, 6H, 3,4,5-CH2,
C5H10N), 2.23 (m, 2H, 6-CH2), 3.09 (t, J = 7.7 Hz, 2H,
7-CH2), 3.24 (t, J= 7.5 Hz, 2H, 5-CH2), 3.51–3.57 (m,
4H, N(CH2)2), 5.09 (s, 2H, OCH2), 6.56 (dd, J1 = 3.4,
J2 = 1.7 Hz, 1H, 4-CH, furyl), 7.12 (d, J= 3.4 Hz, 1H,
3-CH, furyl), 7.58 (d, J =1.7 Hz, 1H, 5-CH, furyl). Anal.
Calcd C20H21N3O3: C 68.36, H 6.02, N 11.96%. Found:
C 68.28, H 6.03, N 11.93%.
1-Isobutyl-3-(2-oxo-2-pyrrolidin-1-ylethoxy)-6,7-dihydro-
5H-cyclopenta[c]pyridine-4-carbonitrile (11j).
Yield 74%,
mp 134–136°C (from EtOH). IR (cmÀ1): 2215 (CN), 1674
1
(C = O). H NMR (δ, ppm): 0.90 (d, J=6.6Hz, 6H, CH
(CH3)2), 1.85 and 2.01 (m, 2H and 2H, 3,4-CH2, C4H8N),
2.07 (m, 1H, CH(CH3)2), 2.17 (m, 2H, 6-CH2), 2.46 (d,
J=7.1Hz, 2H, CHCH2), 2.84 (t, J=7.5Hz, 2H, 7-CH2),
3.06 (t, J=7.6Hz, 2H, 5-CH2), 3.35 (t, J=6.9Hz, 2H,
NCH2), 3.52 (t, J= 6.7 Hz, 2H, NCH2), 4.92 (s, 2H, OCH2).
Anal. Calcd C19H25N3O2: C 69.70, H 7.70, N 12.83%.
Found: C 69.81, H 7.73, N 12.80%.
General method of synthesis of 2-[(1-alkyl(aryl)-4-cyano-
6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)oxy]acetamides 11
a,d,g,l,o,p,r,s,t,u.
To a suspension of cyclopenta[c]
1-Isobutyl-3-(2-oxo-2-piperidin-1-ylethoxy)-6,7-dihydro-
5H-cyclopenta[c]pyridine-4-carbonitrile (11k). Yield 75%,
mp 126–128°C (from EtOH). IR (cmÀ1): 2220 (CN),
1675 (C=O). H NMR (δ, ppm): 0.93 (d, J=6.6Hz, 6H,
CH(CH3)2), 1.69 (br, 6H, 3,4,5-CH2, C5H10N), 2.14 (m,
pyridine 7 (0.01 mol) and potassium carbonate (1.66 g,
0.012 mol) in dry DMF (20 mL), appropriate amide of
chloroacetic acid (0.012 mol) was added with stirring.
The reaction mixture was kept at 100°C for 2 h, cooled
to r.t. and poured into cold water. The formed crystals
1
1H, CH(CH3)2), 2.17 (m, 2H, 6-CH2), 2.50 (d, J=7.1Hz,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Cyclopenta[c]Pyridine-4-Carbonitriles and Cyclopenta[d]Pyrazolo[3,4-b]Pyridines
were filtered, washed with water, dried and recrystallized
from ethanol.
2-[(4-Cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-
3-yl)oxy]-N-(3-methoxyphenyl)acetamide (11p). Yield 83%,
mp 192–194°C (from EtOH). IR (cmÀ1): 3331, 3120,
2-[(4-Cyano-1-isopropyl-6,7-dihydro-5H-cyclopenta[c]pyridin-
3-yl)oxy]acetamide (11a). Yield 81%, mp 133–135°C (from
EtOH). IR (cmÀ1): 3410, 3150 (NH2), 2220 (CN), 1680
1
(NH), 2218 (CN), 1673 (C=O). H NMR (δ, ppm): 2.25
(m, 2H, 6-CH2), 3.18 (t, J=7.2Hz, 2H, 7-CH2), 3.19 (t,
J=7.6Hz, 2H, 5-CH2), 3.82 (s, 3H, OCH3), 5.09 (s, 2H,
OCH2), 6.68 (ddd, J1 =8.3, J2 =2.5, J3 =0.8Hz, 1H, 4-CH,
C6H4), 7.07 (ddd, J1 =8.0, J2 =1.8, J3 =0.8Hz, 1H, 6-CH,
C6H4), 7.23 (dd, J1 =8.3, J2 =8.0Hz, 1H, 5-CH, C6H4),
7.39 (dd, J1 =2.5, J2 =1.8Hz, 1H, 2-CH, C6H4), 7.44–7.52
(m, 3H, Ph), 7.80–7.86 (m, 2H, Ph), 8.30 (ш, 1H, NH).
Anal. Calcd C24H21N3O3: C 72.17, H 5.30, N 10.52%.
Found: C 72.06, H 5.29, N 10.56%.
2-{[4-Cyano-1-(2-furyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-
3-yl]oxy}-N,N-diethylacetamide (11r). Yield 78%, mp 171–
173°C (from EtOH). IR (cmÀ1): 2225 (CN), 1678 (C=O).
1H NMR (δ, ppm): 1.07 (t, J=7.1 Hz, 3H, CH3), 1.30 (t,
J=7.1 Hz, 3H, CH3), 2.22 (m, 2H, 6-CH2), 3.06 (t,
J=7.7 Hz, 2H, 7-CH2), 3.21 (t, J=7.5Hz, 2H, 5-CH2), 3.32
(q, J= 7.1Hz, 2H, NCH2), 3.39 (q, J= 7.1 Hz, 2H, NCH2),
5.07 (s, 2H, OCH2), 6.52 (dd, J1 =3.5, J2 =1.8Hz, 1H,
4-CH, furyl), 6.99 (dd, J1 =3.5, J2 =0.8 Hz, 1H, 3-CH,
furyl), 7.59 (dd, J1 =1.8, J2 = 0.8 Hz, 1H, 5-CH, furyl). Anal.
Calcd C19H21N3O3: C 67.24, H 6.24, N 12.38%. Found: C
67.12, H 6.21, N 12.40%.
1
(C= O). H NMR (δ, ppm): 1.20 (d, J= 6.7 Hz, 6H, CH
(CH3)2), 2.19 (m, 2H, 6-CH2), 2.89 (t, J=7.5Hz, 2H,
7-CH2), 3.02 (spt, J=6.7Hz, 1H, CH(CH3)2), 3.04 (t,
J=7.6Hz, 2H, 5-CH2), 4.73 (s, 2H, OCH2), 6.97 (br, 1H,
NH2), 7.04 (br, 1H, NH2). Anal. Calcd C14H17N3O2: C
64.85, H 6.61, N 16.20%. Found: C 64.98, H 6.63, N
16.24%.
2-[(4-Cyano-1-isopropyl-6,7-dihydro-5H-cyclopenta[c]pyridin-
3-yl)oxy]-N-phenylacetamide (11d). Yield 89%, mp 213–215°C
(from EtOH). IR (cmÀ1): 3410, 3129 (NH), 2210 (CN), 1673
1
(C= O). H NMR (δ, ppm): 1.12 (d, J=6.7Hz, 6H, CH
(CH3)2), 2.19 (m, 2H, 6-CH2), 2.87 (t, J=7.4Hz, 2H,
7-CH2), 2.95 (spt, J=6.7Hz, 1H, CH(CH3)2), 3.06 (t,
J=7.6Hz, 2H, 5-CH2), 4.91 (s, 2H, OCH2), 6.98 (m, 1H,
Ph) 7.18–7.25 (m, 2H, Ph), 7.54 (m, 2H, Ph), 9.76 (br, 1H,
NH). Anal. Calcd C20H21N3O2: C 71.62, H 6.31, N 12.53%.
Found: C 71.71, H 6.33, N 12.50%.
2-[(4-Cyano-1-isobutyl-6,7-dihydro-5H-cyclopenta[c]pyridin-
3-yl)oxy]acetamide (11g). Yield 83%, mp 128–130°C (from
EtOH). IR (cmÀ1): 3460, 3230 (NH2), 2230 (CN), 1590
1
(C=O). H NMR (δ, ppm): 0.93 (d, J=6.6 Hz, 6H, CH
2-{[4-Cyano-1-(2-furyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-
(CH3)2), 2.16 (m, 1H, CH(CH3)2), 2.18 (m, 2H, 6-CH2),
2.50 (d, J=7.1Hz, 2H, CHCH2), 2.86 (t, J=7.4Hz, 2H, 7-
CH2), 3.06 (t, J= 7.6 Hz, 2H, 5-CH2), 4.73 (s, 2H, OCH2),
6.91 (br, 1H, NH2), 7.05 (br, 1H, NH2). Anal. Calcd
C15H19N3O2: C 65.91, H 7.01, N 15.37%. Found: C 66.00,
H 6.99, N 15.41%.
3-yl]oxy}-N-(2-methoxyphenyl)acetamide (11s).
Yield 83%,
mp 210–212°C (from EtOH). IR (cmÀ1): 3359, 3330, (NH),
1
2209 (CN), 1658 (C= O). H NMR (δ, ppm): 2.26 (m, 2H,
6-CH2), 3.13 (t, J= 7.6Hz, 2H, 7-CH2), 3.29 (t, J=7.5Hz,
2H, 5-CH2), 3.95 (s, 3H, OCH3), 5.07 (s, 2H, OCH2), 6.58
(dd, J1 =3.5, J2 = 1.7Hz, 1H, 4-CH, furyl), 6.88 (dd,
J1 =8.0, J2 = 1.4 Hz, 1H, 3-CH, C6H4), 6.96 (ddd, J1 =7.9,
J2 =7.5, J3 = 1.4 Hz, 1H, 5-CH, C6H4), 7.06 (ddd, J1 =8.0,
J2 =7.5, J3 =1.7Hz, 1H, 4-CH, C6H4), 7.20 (dd, J1 =3.5,
J2 =0.7 Hz, 1H, 3-CH, furyl), 7.61 (dd, J1 =1.7, J2 =0.7Hz,
1H, 5-CH, furyl), 8.44 (dd, J1 =7.9, J2 = 1.7Hz, 1H, 6-CH,
C6H4), 9.11 (br, 1H, NH). Anal. Calcd C22H19N3O4: C
67.86, H 4.92, N 10.79%. Found: C 67.77, H 4.91, N 10.81%.
2-[(4-Cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-
3-yl)oxy]acetamide (11l).
Yield 86.6%, mp 225–227°C
(from EtOH). IR (cmÀ1): 3465, 3290 (NH2), 2220 (CN),
1
1640 (C=O). H NMR (δ, ppm): 2.20 (m, 2H, 6-CH2),
3.11 (t, J=7.6Hz, 2H, 7-CH2), 3.14 (t, J=7.2Hz, 2H,
5-CH2), 4.83 (s, 2H, OCH2), 6.92 (br, 1H, NH2), 7.01 (br,
1H, NH2), 7.35–7.46 (m, 3H, Ph), 7.76–7.82 (m, 2H, Ph).
Anal. Calcd C17H15N3O2: C 69.61, H 5.15, N 14.33%.
Found: C 69.72, H 5.13, N 14.30%.
2-{[4-Cyano-1-(2-furyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-
3-yl]oxy}-N-(3-methoxyphenyl)acetamide (11t).
Yield 82%,
mp 188–190°C (from EtOH). IR (cmÀ1): 3360, 3329,
2-[(4-Cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-
3-yl)oxy]-N-(2-methoxyphenyl)acetamide (11o). Yield 85%,
mp 196–198°C (from EtOH); IR (cmÀ1): 3316, 3130
1
(NH), 2210 (CN), 1660 (C=O). H NMR (δ, ppm): 2.27
(m, 2H, 6-CH2), 3.13 (t, J=7.7Hz, 2H, 7-CH2), 3.29 (t,
J=7.5Hz, 2H, 5-CH2), 3.82 (s, 3H, OCH3), 5.03 (s, 2H,
OCH2), 6.59 (dd, J1 =3.5, J2 =1.7Hz, 1H, 4-CH, furyl),
6.67 (ddd, J1 =8.2, J2 =2.5, J3 =0.9Hz, 1H, 4-CH, C6H4),
7.06 (ddd, J1 =8.0, J2 =2.0, J3 =0.9Hz, 1H, 6-CH, C6H4),
7.21 (dd, J1 =3.5, J2 =0.9Hz, 1H, 3-CH, furyl), 7.22 (dd,
J1 =8.2, J2 =8.0Hz, 1H, 5-CH, C6H4), 7.38 (dd, J1 =2.5,
J2 =2.0Hz, 1H, 2-CH, C6H4), 7.61 (dd, J1 =1.7,
J2 =0.9Hz, 1H, 5-CH, furyl), 8.29 (br, 1H, NH). Anal.
Calcd C22H19N3O4: C 67.86, H 4.92, N 10.79%. Found: C
67.76, H 4.91, N 10.77%.
1
(NH), 2210 (CN), 1675 (C=O). H NMR (δ, ppm): 2.24
(m, 2H, 6-CH2), 3.18 (t, J=7.6Hz, 2H, 7-CH2), 3.19 (t,
J=7.2Hz, 2H, 5-CH2), 3.97 (s, 3H, OCH3), 5.13 (s, 2H,
OCH2), 6.90 (dd, J1 =8.0, J2 =1.4Hz, 1H, 3-CH, C6H4),
6.97 (ddd, J1 =7.9, J2 =7.4, J3 =1.4Hz, 1H, 5-CH, C6H4),
7.07 (ddd, J1 =8.0, J2 =7.4, J3 =1.7Hz, 1H, 4-CH, C6H4),
7.44–7.52 (m, 3H, Ph), 7.85 (m, 2H, Ph), 8.45 (dd,
J1 =7.9, J2 =1.7Hz, 1H, 6-CH, C6H4), 9.15 (br, 1H, NH).
Anal. Calcd C24H21N3O3: C 72.17, H 5.30, N 10.52%.
Found: C 72.04, H 5.31, N 10.54%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. N. Sirakanyan, D. Spinelli, A. Geronikaki, and A. A. Hovakimyan
Vol 000
N-(4-Acetylphenyl)-2-{[4-cyano-1-(2-furyl)-6,7-dihydro-5H-
cyclopenta[c]pyridin-3-yl]oxy}acetamide (11u). Yield 85%,
mp 223–225°C (from EtOH). IR (cmÀ1): 3308, 3120 (NH),
Anal. Calcd C18H21N3O: C 73.19, H 7.17, N 14.23%.
Found: C 73.08, H 7.18, N 14.26%.
3-(Benzylamino)-1-isobutyl-6,7-dihydro-5H-cyclopenta[c]
pyridine-4-carbonitrile (12f). Yield 52 (A)/86 (B) %, mp
103–105°C (from EtOH). IR (cmÀ1): 3379 (NH), 2206
(CN). 1H NMR (δ, ppm): 0.85 (d, J= 6.6 Hz, 6H, CH
(CH3)2), 2.06 (m, 1H, CH(CH3)2), 2.07 (m, 2H, 6-CH2),
2.38 (d, J = 7.1 Hz, 2H, CHCH2), 2.74 (t, J = 7.3Hz, 2H,
7-CH2), 2.92 (t, J= 7.5 Hz, 2H, 5-CH2), 4.59 (d,
J = 6.9 Hz, 2H, NHCH2), 6.91 (t, J =6.9 Hz, 1H, NH),
7.13, (m, 1H, Ph), 7.18–7.24 (m, 2H, Ph), 7.28–7.33 (m,
2H, Ph). Anal. Calcd C20H23N3: C 78.65, H 7.59, N
13.76%. Found: C 78.75, H 7.60, N 13.74%.
3-[(2-Furylmethyl)amino]-1-phenyl-6,7-dihydro-5H-cyclopenta
[c]pyridine-4-carbonitrile (12 h). Yield 60(A)/89 (B) %, mp
173–175°C (from EtOH). IR (cmÀ1): 3380 (NH), 2208 (CN).
1H NMR (δ, ppm): 2.11 (m, 2H, 6-CH2), 2.99 (m, 2H,
7-CH2), 3.04 (m, 2H, 5-CH2), 4.67 (d, J=5.6Hz, 2H,
NHCH2), 6.19 (d, J=2.9 Hz, 1H, 5-CH, furyl), 6.27 (dd,
J1 =2.9, J2 =1.8Hz, 1H, 4-CH, furyl), 6.98 (t, J=5.6Hz, 1H,
NH), 7.33–7.44 (m, 4H, Ph), 7.75 (m, 1H, Ph), 7.77 (d, 1H,
J= 1.8Hz, 3-CH, furyl). Anal. Calcd C20H17N3O: C 76.17, H
5.43, N 13.32%. Found: 76.05, H 5.42, N 13.36%.
1
2218 (CN), 1580, 1673 (C=O). H NMR (δ, ppm): 2.28
(m, 2H, 6-CH2), 2.58 (s, 3H, CH3), 3.14 (t, J=7.7Hz, 2H,
7-CH2), 3.29 (t, J=7.5Hz, 2H, 5-CH2), 5.07 (s, 2H,
OCH2), 6.60 (dd, J1 =3.5, J2 =1.7Hz, 1H, 4-CH, furyl),
7.20 (dd, J1 =3.5, J2 =0.7Hz, 1H, 3-CH, furyl), 7.62 (dd,
J1 =1.7, J2 =0.7Hz, 1H, 5-CH, furyl), 7.73 (m, 2H, C6H4),
7.96 (m, 2H, C6H4), 8.55 (br, 1H, NH). Anal. Calcd
C23H19N3O4: C 68.82, H 4.77, N 10.47%. Found: C 68.90,
H 4.78, N 10.45%.
General methods of synthesis of 3-amino-1-alkyl(aryl)-6,7-
dihydro-5H-cyclopenta[c]pyridine-4-carbonitriles 12a–i
A. The same method for the preparation of compounds
10a–p.
B.
(For compounds 12b,c,e,f,h,i). A mixture of
chloride 13 (0.01 mol) and the appropriate amine
(0.1 mol) was refluxed for 5 h. After cooling, water
(100 mL) was added and the precipitate was filtered,
washed with water, dried and recrystallized from ethanol.
3-[(2-Furylmethyl)amino]-1-isopropyl-6,7-dihydro-5H-
cyclopenta[c]pyridine-4-carbonitrile (12b). Yield 50 (A)/
82 (B) %, mp 125–126°C (from EtOH). IR (cmÀ1): 3376 (NH),
3-(Benzylamino)-1-phenyl-6,7-dihydro-5H-cyclopenta[c]
pyridine-4-carbonitrile (12i). Yield 54 (A)/84 (B) %, mp
171–173°C (from EtOH). IR (cmÀ1): 3373 (NH), 2210
1
2203 (CN). H NMR (δ, ppm): 1.16 (d, J=6.7Hz, 6H, CH
(CH3)2), 2.09 (m, 2H, 6-CH2), 2.78 (t, J= 7.3 Hz, 2H, 7-CH2),
2.91 (spt, J= 6.7Hz, 1H, CH(CH3)2), 2.92 (t, J=7.5Hz, 2H,
5-CH2), 4.59 (d, J= 5.8 Hz, 2H, NHCH2), 6.14 (dd, J1=3.2,
J2 = 0.8 Hz, 1H, 3-CH, furyl), 6.24 (dd, J1 =3.2, J2 =1.8Hz,
1H, 4-CH, furyl), 6.77 (t, J= 5.8 Hz, 1H, NH), 7.32 (dd,
J1 =1.8, J2 = 0.8 Hz, 1H, 5-CH, furyl). Anal. Calcd
C17H19N3O: C 72.57, H 6.81, N 14.93%. Found: C 72.64, H
6.82, N 14.97%.
3-(Benzylamino)-1-isopropyl-6,7-dihydro-5H-cyclopenta[c]
pyridine-4-carbonitrile (12c). Yield 48 (A)/84 (B) %, mp
121–123°C (from EtOH). IR (cmÀ1): 3375 (NH), 2210 (CN).
1H NMR (δ, ppm): 1.11 (d, J= 6.7Hz, 6H, CH(CH3)2), 2.08
(m, 2H, 6-CH2), 2.77 (t, J= 7.3Hz, 2H, 7-CH2), 2.88 (spt,
J=6.7 Hz, 1H, CH(CH3)2), 2.91 (t, J=7.6Hz, 2H, 5-CH2),
4.60 (d, J= 5.9 Hz, 2H, NHCH2), 6.96 (t, J=5.9Hz, 1H,
NH), 7.12 (m, 1H, Ph), 7.18–7.24 (m, 2H, Ph), 7.33 (m, 2H,
Ph). Anal. Calcd C19H21N3: C 78.32, H 7.26, N 14.42%.
Found: C 78.41, H 7.28, N 14.39%.
1
(CN). H NMR (δ, ppm): 2.10 (m, 2H, 6-CH2), 2.99 (t,
J = 7.6 Hz, 2H, 7-CH2), 3.02 (t, J= 7.3 Hz, 2H, 5-CH2),
4.66 (d, J= 5.9 Hz, 2H, NHCH2), 7.15–7.28 (m, 4H, Ph
and NH), 7.32–7.38 (m, 5H, Ph), 7.63–7.68 (m, 2H, Ph).
Anal. Calcd C22H19N3: C 81.20, H 5.88, N 12.91%.
Found: C 81.30, H 5.90, N 12.94%.
General method of synthesis of 2-[(1-alkyl(aryl)-4-cyano-
6,7-dihydro-5H-cyclopenta[c]pyridin-3-yl)oxy]
acetohydrazides 14a–d.
A mixture of compound 8
(0.01 mol) and hydrazine hydrate (0.1 mol) in absolute
ethanol (50 mL) was refluxed for 15min. After cooling,
water (50 mL) was added, and the precipitate was filtered,
washed with water, dried and recrystallized from ethanol.
2-[(4-Cyano-1-isopropyl-6,7-dihydro-5H-cyclopenta[c]pyridin-
3-yl)oxy]acetohydrazide (14a). Yield 87%, mp 163–165°C
(from EtOH). IR (cmÀ1): 3470, 3330, 3240 (NH, NH2),
2219 (CN), 1589 (C =O). 1H NMR (δ, ppm): 1.19 (d,
J=6.7Hz, 6H, CH(CH3)2), 2.18 (m, 2H, 6-CH2), 2.88 (t,
J=7.6Hz, 2H, 7-CH2), 3.01 (spt, J=6.7Hz, 1H, CH(CH3)2),
3.04 (t, J=7.6Hz, 2H, 5-CH2), 3.98 (br s, 2H, NH2), 4.78 (s,
2H, OCH2), 9.05 (br s, 1H, NH). Anal. Calcd C14H18N4O2:
C 61.30, H 6.61, N 20.42%. Found: C 61.41, H 6.63, N
20.47%.
3-[(2-Furylmethyl)amino]-1-isobutyl-6,7-dihydro-5H-
cyclopenta[c]pyridine-4-carbonitrile (12e). Yield 50 (A)/
87 (B) %, mp 92–93°C (from EtOH). IR (cmÀ1): 3370
1
(NH), 2211 (CN). H NMR (δ, ppm): 0.90 (d, J= 6.6 Hz,
6H, CH(CH3)2), 2.08 (m, 2H, 6-CH2), 2.13 (m, 1H, CH
(CH3)2), 2.42 (d, J = 7.1 Hz, 2H, CHCH2), 2.76 (t,
J =7.3 Hz, 2H, 7-CH2), 2.93 (t, J = 7.6 Hz, 2H, 5-CH2),
4.58 (d, J = 5.7 Hz, 2H, NHCH2), 6.12 (dd, J1 = 3.2,
J2 = 0.8Hz, 1H, 3-CH, furyl), 6.24 (dd, J1 = 3.2,
J2 = 1.9Hz, 1H, 4-CH, furyl), 6.71 (t, J = 5.7 Hz, 1H,
NH), 7.32 (dd, J1 =1.9, J2 = 0.8 Hz, 1H, 5-CH, furyl).
2-[(4-Cyano-1-isobutyl-6,7-dihydro-5H-cyclopenta[c]pyridin-
3-yl)oxy]acetohydrazide (14b). Yield 90%, mp 150–151°C
(from EtOH). IR (cmÀ1): 3445, 3326, 3210 (NH, NH2),
2205 (CN), 1656 (C=O). 1H NMR (δ, ppm): 0.92 (d,
J=6.6Hz, 6H, CH(CH3)2), 2.14 (m, 1H, CH(CH3)2), 2.17
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Cyclopenta[c]Pyridine-4-Carbonitriles and Cyclopenta[d]Pyrazolo[3,4-b]Pyridines
(m, 2H, 6-CH2), 2.49 (d, J= 6.7Hz, 2H, CHCH2), 2.85 (t,
J=7.5Hz, 2H, 7-CH2), 3.05 (t, J=7.6Hz, 2H, 5-CH2), 3.97
(br s, 2H, NH2), 4.78 (s, 2H, OCH2), 9.02 (br s, 1H, NH).
Anal. Calcd C15H20N4O2: C 62.48, H 6.99, N 19.43%.
Found: C 62.50, H 7.01, N 19.46%.
2-[(4-Cyano-1-phenyl-6,7-dihydro-5H-cyclopenta[c]pyridin-
3-yl)oxy]acetohydrazide (14c). Yield 88%, mp 223–225°C
(from EtOH). IR (cmÀ1): 3462, 3335, 3215 (NH, NH2),
2118 (CN), 1615 (C=O). 1H NMR (δ, ppm): 2.20 (m, 2H,
6-CH2), 3.11 (t, J=7.5Hz, 2H, 7-CH2), 3.15 (t, J=7.3Hz,
2H, 5-CH2), 4.09 (br s, 2H, NH2), 4.89 (s, 2H, OCH2),
7.39–7.50 (m, 3H, Ph), 7.77–7.81 (m, 2H, Ph), 9.17 (br s,
1H, NH). Anal. Calcd C17H16N4O2: C 66.22, H 5.23, N
18.17%. Found: C 66.32, H 5.25, N 18.20%.
(from EtOH). IR (cmÀ1): 3415, 3321, 3155 (NH, NH2). 1H
NMR (δ, ppm): 2.16 (m, 2H, 7-CH2), 3.08 (t, J=7.2Hz,
2H, 6-CH2), 3.29 (t, J=7.4Hz, 2H, 8-CH2), 4.78 (br, 2H,
NH2), 7.31–7.45 (m, 3H, Ph), 7.70–7.76 (m, 2H, Ph),
11.62 (br, 1H, NH). Anal. Calcd C15H14N4: C 71.98, H
5.64, N 22.38%. Found: C 71.86, H 5.62, N 22.40%.
5-(2-Furyl)-3,6,7,8-tetrahydrocyclopenta[d]pyrazolo[3,4-b]
pyridin-1-amine (16d).
Yield 87/89%, mp 302–303°C
(from EtOH). IR (cmÀ1): 3420, 3318, 3201 (NH, NH2).
1H NMR (δ, ppm): 2.27 (m, 2H, 7-CH2), 3.29 (t,
J = 7.7 Hz, 2H, 6-CH2), 3.34 (t, J= 7.5 Hz, 2H, 8-CH2),
4.58 (br, 2H, NH2), 6.58 (dd, J1 = 3.4, J2 = 1.7 Hz, 1H,
4-CH, furyl), 7.04 (dd, J1 =3.4, J2 = 0.8 Hz, 1H, 3-CH,
furyl), 7.67 (dd, J1 = 1.7, J2 = 0.8 Hz, 1H, 5-CH, furyl),
11.58 (br, 1H, NH). Anal. Calcd C13H12N4O: C 64.99, H
5.03, N 23.32%. Found: C 65.08, H 5.04, N 23.35%.
2-{[4-Cyano-1-(2-furyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-
3-yl]oxy}acetohydrazide (14d). Yield 89%, mp 233–235°C
(from EtOH). IR (cmÀ1): 3473, 3340, 3227 (NH, NH2),
1
2221 (CN), 1645 (C =O). H NMR (δ, ppm): 2.23 (m, 2H,
REFERENCES
6-CH2), 3.07 (t, J= 7.7Hz, 2H, 7-CH2), 3.23 (t, J=7.5Hz,
2H, 5-CH2), 4.04 (br s, 2H, NH2), 4.84 (s, 2H, OCH2), 6.61
(dd, J1 =3.5, J2 =1.7 Hz, 1H, 4-CH, furyl), 7.17 (dd,
J1 =3.5, J2 = 0.8Hz, 1H, 3-CH, furyl), 7.71 (dd, J1 =1.7,
J2 =0.8 Hz, 1H, 5-CH, furyl), 9.17 (br s, 1H, NH). Anal.
Calcd C15H14N4O3: C 60.40, H 4.73, N 18.78%. Found: C
60.31, H 4.74, N 18.80%.
General method of synthesis of 5-alkyl(aryl)-3,6,7,8-
tetrahydrocyclopenta[d]pyrazolo[3,4-b]pyridin-1-amines
16a–d. A mixture of compound 8 (or 13) (0.01mol) and
hydrazine hydrate (0.1mol) in absolute ethanol (50mL)
was refluxed for 10h. After cooling, water (50mL) was
added, and the precipitate was filtered, washed with water,
dried and recrystallized from ethanol.
[1] Sirakanyan, S. N.; Hovakimyan, A. A.; Noravyan, A. S. Russ
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[3] Sirakanyan, S. N.; Geronikaki, A.; Spinelli, D.; Hovakimyan,
A. A.; Noravyan, A. S. Tetrahedron 2013, 69, 10637.
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[6] Ruccia, M.; Vivona, N.; Spinelli, D. Mononuclear Heterocyclic
Rearrangements, Adv. Het. Chem; Academic Press, 1981; Vol 29, pp 141.
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[8] Viale, M.; Cordazzo, C.; Cosimelli, B.; De Totero, D.;
Castagnola, P.; Aiello, C.; Severi, E.; Petrillo, G.; Cianfriglia, M.;
Spinelli, D. J Med Chem 2009, 52, 259.
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Ciogli, A.; De Totero, D.; Spinelli, D. ACS Med Chem Lett 2013, 4, 694.
[10] Carosati, E.; Ioan, P.; Barrano, G. B.; Caccamese, S.;
Cosimelli, B.; Devlin, F. J.; Severi, E.; Spinelli, D.; Superchi, S.; Budriesi,
R. E. J Med Chem 2015, 92, 481.
5-Isopropyl-3,6,7,8-tetrahydrocyclopenta[d]pyrazolo[3,4-b]
pyridin-1-amine (16a).
Yield 83/91%, mp 264–266°C
(from EtOH). IR (cmÀ1): 3421, 3334, 3150 (NH, NH2). 1H
NMR (δ, ppm): 1.26 (d, J=6.7Hz, 6H, CH(CH3)2), 2.17
(m, 2H, 7-CH2), 2.91 (t, J=7.3Hz, 2H, 6-CH2), 3.11 (spt,
J=6.7Hz, 1H, CH(CH3)2), 3.22 (t, J=7.6Hz, 2H, 8-CH2),
4.65 (br, 2H, NH2), 11.46 (br, 1H, NH). Anal. Calcd
C12H16N4: C 66.64, H 7.46, N 25.90%. Found: C 66.75, H
7.49, N 25.94%.
[11] 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, 8.
[12] Gerasimova, T. N.; Kolchina, E. F. Russ Chem Rev 1995, 64, 133.
[13] Buchstaller, H. P.; Anlauf, U. Synthesis 2005, 4, 639.
[14] Mizuno, M.; Yamano, M. Org Synth 2007, 84, 325.
[15] Tian, X.; Wu, R. M.; Liu, G.; Li, Z. B.; Wei, H. L.; Yang, H.;
Shin, S. D.; Wang, L. Y.; Zuo, H. Arkivoc, 2011, X, 118.
[16] Wadia, M. S.; Patil, D. V. Synth Commun 2003, 33, 2725.
[17] Bonini, C.; Funicello, M.; Scialpi, R.; Spagnolo, P. Tetrahedron
2003, 59, 7515.
[18] Tyvorskii, V. I.; Bobrov, D. N.; Kulinkovich, O. G.; Tehrani,
K. A.; Kimpe, N. D. Tetrahedron 2001, 57, 2051.
[19] Bonini, C.; Cristiani, G.; Funicello, M.; Viggiani, L. Synth
Commun 2006, 36, 1983.
5-Isobutyl-3,6,7,8-tetrahydrocyclopenta[d]pyrazolo[3,4-b]
pyridin-1-amine (16b).
Yield 85/90%, mp 236–237°C
(from EtOH). IR (cmÀ1): 3471, 3338, 3160 (NH, NH2).
1H NMR (δ, ppm): 0.95 (d, J = 6.6 Hz, 6H, CH(CH3)2),
2.16 (m, 2H, 7-CH2), 2.18 (m, 1H, CH(CH3)2), 2.58 (d,
J =7.1 Hz, 2H, CHCH2), 2.89 (t, J= 7.3 Hz, 2H, 6-CH2),
3.22 (t, J = 7.5Hz, 2H, 8-CH2), 3.87 (br, 2H, NH2), 11.43
(br, 1H, NH). Anal. Calcd C13H18N4: C 67.80, H 7.88, N
24.33%. Found: C 67.90, H 7.86, N 24.30%.
[20] Sun, H.; Li, J.; Zhang, D.; Ma, C.; Liu, C. J Phys Org Chem
2008, 21, 215.
[21] Xie, Y.-S.; Vijaykumar, B. V. D.; Jang, K.; Choi, K.-M.; Zuo,
H.; Yoon, Y.-J.; Shin, D.-S. Tetrahedron Lett 2013, 54, 5151.
5-Phenyl-3,6,7,8-tetrahydrocyclopenta[d]pyrazolo[3,4-b]
pyridin-1-amine (16c).
Yield 88/92%, mp 299–300°C
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet