Synthesis of furo[2,3-c]-2,7-naphthyridine derivatives via domino heterocyclization reaction

Article abstract of DOI:10.1016/j.tet.2005.07.074

2-Amino-4-cyanomethyl-6-dialkylamino-3,5-pyridinedicarbonitriles were found to react with substituted oxiranes yielding 5,6-diamino-8-dialkylamino-1, 2-dihydrofuro[2,3-c]-2,7-naphthyridine-9-carbonitriles. The oxirane ring was shown to be opened selective

Full text of DOI:10.1016/j.tet.2005.07.074

Tetrahedron 61 (2005) 9618–9623
Synthesis of furo[2,3-c]-2,7-naphthyridine derivatives via domino
heterocyclization reaction
b
c
Anton V. Tverdokhlebov,a, Alexander V. Zavada, Andrey A. Tolmachev,
*
Alexander N. Kostyuk,d Alexander N. Chernegad and Eduard B. Rusanovd
aEnamine Ltd Co., Alexandra Matrosova str. 23, 01103, Kiev, Ukraine
bChernigov State University of Technology, Shevchenko str. 95, 14027 Chernigov, Ukraine
cKiev National Taras Shevchenko University, Volodimirska str. 62, 01033 Kiev, Ukraine
dInstitute of Organic Chemistry NAS, Murmanska str. 5, 02094 Kiev, Ukraine
Received 14 May 2005; revised 5 July 2005; accepted 21 July 2005
Available online 8 August 2005
Abstract—2-Amino-4-cyanomethyl-6-dialkylamino-3,5-pyridinedicarbonitriles were found to react with substituted oxiranes yielding 5,6-
diamino-8-dialkylamino-1,2-dihydrofuro[2,3-c]-2,7-naphthyridine-9-carbonitriles. The oxirane ring was shown to be opened selectively
from the unsubstituted side and further cyclization occurred with participation of 3-CN, but not 5-CN of the starting pyridines. The
furonaphthyridines obtained were converted into 2-dialkylamino-5-methyl-9,10-dihydro-4H-furo[2,3-c]pyrimido[4,5,6-ij]-2,7-naphthyri-
dine-1-carbonitriles and 2-dialkylamino-5,6,9,10-tetrahydro-4H-spiro{furo[2,3-c]pyrimido[4,5,6-ij]-2,7-naphthyridine-5,10-cyclohexane}-
1-carbonitriles by treatment with acetic anhydride and cyclohexanone, respectively. The structure of prepared compounds was confirmed
unambiguously by X-ray crystallographic study.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
c]-2,7-naphthyridines, respectively.8,9 Continuing the
investigations in the field it would be interesting to elaborate
a domino synthesis of the corresponding furo analogues as
an alternative to the known stepwise procedure.1,2
Furo[2,3-c]-2,7-naphthyridine is a rare and uninvestigated
heterocyclic system. To date only four derivatives of this
framework have been reported.1,2 All were prepared
through the same three-step approach including the classic
Hantzsch pyridine synthesis using 2-nitrofuran-3-carbalde-
hyde, methyl acetoacetate and ammonia, further aromatiza-
tion of the dihydropyridine obtained and, finally, reduction
of the nitro group accompanied by intramolecular inter-
action of the amino group formed with the suitably situated
ester. The method is limited, first of all, by the single
applicable furancarbaldehyde and secondly, by the
Hantzsch synthesis restrictions.
2. Results and discussion
Malonodinitrile and ethyl cyanoacetate were reported to
react with epoxides yielding aminofurans 110–15 (Fig. 1).
When propenetricarbonitrile 2 (malonodinitrile dimer) was
used as starting material the intermediate furans of type 1 (X
is C(NH2)]C(CN)2) underwent further intramolecular
addition of the amino group to the nitrile resulting in
furopyridines 3.16 Thus, compounds 3 were obtained by
formation of the two rings at once via the domino sequence
including methylene alkylation and consecutive intra-
molecular additions of hydroxy and amino groups to
nitriles. Previously the readily available pyridines 4–6
Over recent years so-called domino reactions have got an
increasing importance in condensed heterocyclic
chemistry,3–7 since they allow creation of two or more
rings at once at the expense of sequential chemical
transformations, induced one by another. Recently the
domino principle based approaches were applied by us and
other researchers to preparation of pyrrolo- and thieno[2,3-
Keywords: Domino reactions; Furo[2,3-c]-2,7-naphthyridines; Nitriles;
Oxiranes; Spiro compounds.
*
Corresponding author. Tel./fax: C380 44 558 6553;
e-mail: atver@univ.kiev.ua
Figure 1. XZCN, CO2Et.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.07.074

A. V. Tverdokhlebov et al. / Tetrahedron 61 (2005) 9618–9623
9619
Scheme 1. R1Za: CH2Cl, b: C2H5, c: C6H5.
were shown to be suitable precursors of various 2,7-
naphthyridines.8,17 Like compound 2 derivatives 4–6
contain the same vicinal CH2CN groups moiety and CN
and therefore, their reaction with epoxides should occur
similarly and should afford the target furonaphthyridines.
However, contrary to compound 2 there are two possibilities
of a ring closure in the intermediates 7 (Scheme 1) with
participation of 3-CN or 5-CN leading to the isomers 8–10
and 11, respectively. Moreover different directions of the
epoxide ring opening could not be excluded. Although in
most cases oxiranes were reported to react with active
methylenes from the less substituted side10–16,18–23 a few
examples of nucleophilic attack at the more substituted
side13,16,24–26 have also been noted. Hence the possible
furan moiety isomerism in the products should be taken into
consideration as well.
1-substituted isomers. Additional chemical transformations
were used to distinguish the structures 8–10 and 11. Thus,
the selected derivatives 8a, 9b, 10c were treated with acetic
anhydride and cyclohexanone (Scheme 2). Both reactions
resulted in a ring annulation and afforded fused heterocycles
12 and spirocyclic compound 13. The similar transform-
ations are well known for 1,8-naphthalenediamines27–31 and
have also been reported for certain 2,7-naphthyridine-1,8-
diamines.8,32 So the synthesis of derivatives 12,13 estab-
lishes the neighboring arrangement of the amino groups in
the prepared furonaphthyridines thus excluding the structure
11. Therefore the structures 8–10 should be assigned to the
obtained compounds.
Of course, an X-ray crystallographic study would be
desirable to determine the structures 8–10 undoubtedly.
Unfortunately, we failed to grow a suitable crystal from the
diamines 8–10, but it was obtained from the cyclo-
hexylidene derivative 13b. An X-ray study confirmed its
structure (Fig. 2) and therefore, proved the structure of the
diamine precursors 8–10 unambiguously.
Nevertheless, treatment of the pyridines 4–6 with sub-
stituted oxiranes in ethanol in the presence of K2CO3 was
found to give individual compounds isolated in 60–80%
yields. 1H and 13C NMR spectra of isomeric 4- and
5-substituted furans 1 were well documented.11–13 Com-
parison of the published data with the spectra of compounds
obtained in the aliphatic region revealed their close
resemblance with those of 5-substituted derivatives 1.
Hence the prepared compounds were assumed to be
2-substituted furonaphthyridines 8–10 or 11, but not the
It should be emphasized that there were no detectable
amounts of isomers in the reaction mixtures during
synthesis of 8–10. Hence the reaction occurs selectively
both on the steps of epoxide ring cleavage and the amino
group addition to nitrile. Considering the literature
Scheme 2.

9620
A. V. Tverdokhlebov et al. / Tetrahedron 61 (2005) 9618–9623
power and effectiveness of the domino strategy in
heterocyclic synthesis. Apparently, the present method
extends considerably the scope of furonaphthyridines
chemistry and has significant advantages in comparison
with the stepwise approach described.1,2
3. Experimental
The pyridines 4–6 were prepared as reported.17 Other
reagents were commercially available and were used
without additional purification. Ethanol was dried with
CaO. All melting points were determined in open capillary
tubes in a Thiele apparatus and are uncorrected. 1H and 13
C
NMR spectra were recorded on a Varian VXR-400
1
(400 MHz for H and 100 MHz for 13C) spectrometer in
DMSO-d6 solutions. Chemical shifts (d) are given in ppm
downfield from internal Me4Si. J values are in Hz. The
purity of all compounds prepared was checked by 1H NMR
and LC/MS on an Agilent 1100 instrument.
Figure 2. X-ray molecular structure of compound 13b (a solvate with two
molecules of acetonitrile) with the atom numbering used in the
crystallographic analysis. Crystallographic data (excluding structure
factors) for the structure in this paper, have been deposited with the
Cambridge Crystallographic Data Center as supplementary publication
number CCDC 270785. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
C44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
3.1. Furo[2,3-c]-2,7-naphthyridines 8–10. General
procedure
Powdered K2CO3 (0.41 g, 3 mmol) was added to a solution
of pyridine 4–6 (3 mmol) and corresponding epoxide
(3 mmol) in ethanol (5 mL). The resulting mixture was
refluxed for 1 h. After cooling the precipitate formed was
filtered and thoroughly washed with water to remove
inorganic materials. Recrystallization from an appropriate
solvent afforded compounds 8–10.
data10–16,18–23 the selectivity of the oxiranes opening is
expected. Additional steric hindrances at the active
methylene of the pyridines 4–6 produced by neighboring
nitriles seem only to uphold the selectivity. Predominant
reactivity of 3-CN versus 5-CN in the pyridines 4–6 and
related compounds was described earlier.8,17,32 Its reasons
werediscussed in detailin ourpreviouswork8 andarebelieved
to be the same in the present case. Also it is interesting to note
that the epichlorohydrine reacted clearly as epoxide saving the
chloromethyl group and yielding furonaphthyridines
8a,9a,10a. According to the literature both its reactions with
active methylenes with and without participation of the
chlorine are known.16,33 Furthermore, it should be stated that
derivatives 12,13 are the representatives of hitherto unknown
heterocyclic systems, namely furo[2,3-c]pyrimido[4,5,6-ij]-
2,7-naphthyridine an0d spiro{furo[2,3-c]pyrimido[4,5,6-ij]-
2,7-naphthyridine-5,1 -cyclohexane}.
3.1.1. 5,6-Diamino-2-chloromethyl-8-(1-piperidinyl)-1,2-
dihydrofuro[2,3-c]-2,7-naphthyridine-9-carbonitrile
(8a). Yield 71%. Mp 294–296 8C (from dioxane); dH 1.56–
1.61 (6H, m, NR2), 3.19 (1H, dd, J3Z6.8 Hz, J2Z15.6 Hz,
1-H), 3.54 (1H, dd, J3Z9.6 Hz, J2Z15.6 Hz, 1-H), 3.65
(4H, m, NR2), 3.87 (1H, dd, J3Z4.8 Hz, J2Z11.6 Hz,
CH2Cl), 3.96 (1H, dd, J3Z4.0 Hz, J2Z11.6 Hz, CH2Cl),
5.03 (1H, m, 2H), 6.46 (2H, s, NH2), 7.10 (2H, s, NH2). dC
24.5 (4-CNR2), 26.2 (3,5-CNR2), 31.3 (1-C), 47.8 (CH2Cl),
48.8 (2,6-CNR2), 68.1 (9-C), 79.7 (2-C), 92.5 (5a-C), 94.1
(9b-C), 121.2 (CN), 145.9 (9a-C), 159.4 (5-C), 159.8 (6-C),
162.3 (8-C), 167.4 (3a-C). Found: 56.78% C, 5.42% H,
9.80% Cl, 23.34% N; C17H19ClN6O requires 56.90% C,
5.34% H, 9.88% Cl, 23.42% N.
To resume, present investigations has resulted in a simple
and convenient synthesis of furo[2,3-c]-2,7-naphthyridine
derivatives 8–10 based on the domino principle. Moreover,
the derivatives of two novel heterocyclic frameworks 12,13
have been obtained by further ring annulations to the
compounds 8–10. The starting pyridines 4–6 are available in
quantitative yields by reaction of 2-amino-6-chloro-4-
cyanomethyl-3,5-pyridinedicarbonitrile with appropriate
secondary amines.17 The chloropyridine precursor, in turn,
was prepared from malonodinitrile and inorganic reagents
in two steps.32 Hence, the furonaphthyridines 8–10 and their
condensed derivatives 12,13 have been synthesized from
malonodinitrile in four and five steps, respectively. Other
reagents used, for example, epoxides, acetic anhydride and
cyclohexanone are also of general access. So the new
heterocycles 8–10,12,13 of high complexity degree have
been obtained, in fact, from simplest and cheapest sources
through the sequence of moderate length. This exhibits a
3.1.2. 5,6-Diamino-2-ethyl-8-(1-piperidinyl)-1,2-di-
hydrofuro[2,3-c]-2,7-naphthyridine-9-carbonitrile (8b).
Yield 81%. Mp 191–192 8C (from EtOH); dH 1.03 (3H, t,
JZ7.2 , CH3),1.66(6H,m,NR2),1.74(2H,m,CH2CH3),3.02
(1H, dd, J3Z6.4 Hz, J2Z15.2 Hz, 1-H), 3.54 (1H, dd, J3Z
10.0 Hz, J2Z15.2 Hz, 1-H), 3.66 (4H, m, NR2), 4.68 (1H, m,
2-H), 6.12 (2H, s, NH2), 6.69 (2H, s, NH2). dC 9.0 (CH3), 24.1
(3,5-CNR2), 25.2 (4-CNR2), 27.3 (CH2CH3), 34.9 (1-C), 47.1
(2,6-CNR2), 66.4 (9-C), 82.3 (2-C), 89.5 (5a-C), 92.1 (9b-C),
121.8 (CN), 146.0 (9a-C), 157.3 (6-C), 160.7 (5-C), 164.2
(8-C), 168.5 (3a-C). Found: 63.97% C, 6.53% H, 24.82% N;
C18H22N6O requires 63.89% C, 6.55% H, 24.83% N.
3.1.3. 5,6-Diamino-2-phenyl-8-(1-piperidinyl)-1,2-di-
hydrofuro[2,3-c]-2,7-naphthyridine-9-carbonitrile (8c).
Yield 62%. Mp 206–207 8C (from acetonitrile); dH 1.42

A. V. Tverdokhlebov et al. / Tetrahedron 61 (2005) 9618–9623
9621
(2H, m, NR2), 1.54 (4H, m, NR2), 3.48 (4H, m, NR2), 4.30
(1H, dd, J3Z1.4 Hz, J2Z8.8 Hz, 1-H), 4.79 (1H, dd, J3Z
8.4 Hz, J2Z8.8 Hz, 1-H), 5.00 (1H, dd, J3Z1.4 Hz, J3Z
8.4 Hz, 2-H), 6.63 (2H, s, NH2), 7.02 (2H, d, JZ7.6 Hz, 2,6-
HPh), 7.14 (2H, s, NH2), 7.17 (1H, t, JZ7.6 Hz, 4-HPh), 7.25
(2H, t, JZ7.6 Hz, 3,5-HPh). dC 24.1 (4-CNR2), 25.7 (3,5-
CNR2), 44.3 (1-C), 48.3 (2,6-CNR2), 67.8 (9-C), 77.4 (2-C),
92.2 (5a-C), 97.5 (9b-C), 120.2 (CN), 126.4 (4-CPh), 126.9
(3,5-CPh), 128.4 (2,6-CPh), 144.4 (1-CPh), 145.9 (9a-C),
159.2 (5-C), 160.0 (6-C), 161.9 (8-C), 168.4 (3a-C). Found:
68.50% C, 5.60% H, 21.80% N; C22H22N6O requires
68.38% C, 5.74% H, 21.75% N.
C), 121.2 (CN), 145.9 (9a-C), 158.8 (5-C), 159.3 (6-C),
160.1 (8-C), 167.1 (3a-C). Found: 55.34% C, 5.60% H,
10.43% Cl, 24.17 N; C16H19ClN6O requires 55.41% C,
5.52% H, 10.22% Cl, 24.23 N.
3.1.8. 5,6-Diamino-8-diethylamino-2-ethyl-1,2-dihydro-
furo[2,3-c]-2,7-naphthyridine-9-carbonitrile (10b).
Yield 83%. Mp 212–213 8C (from i-PrOH); dH 1.03 (3H,
t, JZ7.4 Hz, CH3), 1.23 (6H, t, JZ6.8 Hz, 2CH3), 1.74 (2H,
m, CH2CH3), 3.05 (1H, dd, J3Z6.8 Hz, J2Z15.2 Hz, 1-H),
3.57 (1H, dd, J3Z9.6 Hz, J Z15.2, 1-H), 3.63 (4H, q, JZ
6.8 Hz, NCH2), 4.66 (1H, m, 2-H), 6.07 (2H, s, NH2), 6.59
(2H, s, NH2). dC 9.5 (CH2CH3), 13.8 (CH3), 27.3 (CH2CH3),
33.0 (1-C), 44.0 (NCH2), 65.9 (9-C), 82.6 (2-C), 93.7 (9b-
C), 94.6 (5a-C), 120.1 (CN), 142.9 (9a-C), 158.4 (5-C),
162.2 (6-C), 162.4 (8-C), 167.0 (3a-C). Found: 62.40% C,
6.76% H, 25.83% N; C17H22N6O requires 62.56% C, 6.79%
H, 25.75% N.
3.1.4. 5,6-Diamino-2-chloromethyl-8-(4-morpholinyl)-1,
2-dihydrofuro[2,3-c]-2,7-naphthyridine-9-carbonitrile
(9a). Yield 73%. Mp O300 8C (from DMF); dH 3.19 (1H,
dd J3Z6.8 Hz, J2Z16.0 Hz, 1-H), 3.54 (1H, dd J3Z9.6 Hz,
J2Z16.0 Hz, 1-H), 3.65 (8H, m, NR2), 3.87 (1H, dd J3Z
4.4 Hz, J2Z11.2 Hz, CH2Cl), 3.95 (1H, dd J3Z3.6 Hz,
J2Z11.2 Hz, CH2Cl), 5.04 (1H, m, 2-H), 6.52 (2H, s, NH2),
7.21 (2H, s, NH2). dC 31.1 (1-C), 45.4 (CH2Cl), 46.1
(NCH2), 65.6 (OCH2), 69.7 (9-C), 79.0 (2-C), 93.0 (5a-C),
94.1 (9b-C), 119.1 (CN), 145.4 (9a-C), 158.6 (6-C), 159.0
(5-C), 162.9 (8-C), 165.4 (3a-C). Found: 53.48% C, 4.67%
H, 9.80% Cl, 23.34% N; C16H17ClN6O2 requires 53.26% C,
4.75% H, 9.83% Cl, 23.29% N.
3.1.9. 5,6-Diamino-8-diethylamino-2-phenyl-1,2-di-
hydrofuro[2,3-c]-2,7-naphthyridine-9-carbonitrile
(10c). Yield 79%. Mp 170–171 8C (from dioxane); dH 1.11
(6H, t, JZ7.0 Hz, 2CH3), 3.48 (4H, m, NCH2), 4.33 (1H,
dd, J3Z2.0 Hz, J2Z8.4 Hz, 1-H), 4.78 (1H, dd, J3Z8.8 Hz,
J2Z8.4 Hz, 1-H), 5.09 (1H, dd, J3Z8.8, 2.0 Hz, 2-H), 6.34
(2H, s, NH2), 6.61 (2H, s, NH2), 7.08–7.14 (3H, m, 2,6,4-
HPh), 7.22 (2H, dd, JZ7.6, 7.6 Hz, 3,5-HPh). dC 16.7 (CH3),
43.4 (NCH2), 44.9 (1-C), 67.1 (9-C), 78.6 (2-C), 93.0 (5a-
C), 98.3 (9b-C), 119.7 (CN), 126.9 (2,6-CPh), 127.1 (4-CPh),
127.2 (3,5-CPh), 146.5 (9a-C), 146.8 (1-CPh), 158.1 (5-C),
161.4 (6-C), 164.4 (8-C), 168.3 (3a-C). Found: 67.57% C,
5.81% H, 22.48% N; C21H22N6O requires 67.36% C, 5.92%
H, 22.44% N.
3.1.5. 5,6-Diamino-2-ethyl-8-(4-morpholinyl)-1,2-di-
hydrofuro[2,3-c]-2,7-naphthyridine-9-carbonitrile (9b).
Yield 77%. Mp 263–264 8C (from EtOH); dH 0.94 (3H, t,
JZ7.4 Hz, CH3), 1.69 (2H, m, CH2CH3), 2.97 (1H, dd, J3Z
7.2 Hz, J2Z15.2 Hz, 1-H), 3.51 (1H, dd, J3Z9.6 Hz, J2Z
15.2 Hz, 1-H), 3.65 (8H, m, NR2), 4.71 (1H, m, 2-H), 6.46
(2H, s, NH2), 7.18 (2H, s, NH2). dC 9.2 (CH3), 28.7
(CH2CH3), 32.6 (1-C), 48.0 (NCH2), 66.2 (OCH2), 68.6
(9-C), 82.3 (2-C), 92.1 (5a-C), 94.4 (9b-C), 120.7 (CN),
145.3 (9a-C), 159.2 (5-C), 159.6 (6-C), 162.3 (8-C), 167.5
(3a-C). Found: 59.95% C, 5.96% H, 24.92% N;
C17H20N6O2 requires 59.99% C, 5.92% H, 24.69% N.
3.2. Furo[2,3-c]pyrimido[4,5,6-ij]-2,7-naphthyridines
12a–c. General procedure
A solution of the diamine 8a,9b,10c (2.5 mmol) in acetic
anhydride (3 mL) was heated at 100–110 8C for 1 h. After
cooling the precipitated solid was filtered, washed with
water and recrystallized from DMF to give derivatives
12a–c.
3.1.6. 5,6-Diamino-8-(4-morpholinyl)-2-phenyl-1,2-di-
hydrofuro[2,3-c]-2,7-naphthyridine-9-carbonitrile (9c).
Yield 65%. Mp 242–243 8C (from dioxane); dH 3.57 (8H,
m, NR2), 4.28 (1H, dd, J3Z1.6 Hz, J2Z10.4 Hz, 1-H), 4.79
(1H, dd, J3Z8.8 Hz, J2Z10.4 Hz, 1-H), 5.00 (1H, dd, J3Z
8.8,1.6 Hz, 2-H), 7.02 (2H, d, JZ7.6 Hz, 2,6-HPh), 7.13
(2H, s, NH2), 7.17 (3H, m, NH2, 4-HPh), 7.25 (2H, dd, JZ
7.6, 7.6 Hz, 3,5-HPh). dC 43.7 (1-C), 49.0 (NCH2), 64.9
(OCH2), 65.0 (9-C), 78.2 (2-C), 92.4 (5a-C), 97.0 (9b-C),
120.7 (CN), 124.3 (3,5-CPh), 125.6 (4-CPh), 128.0 (2,6-CPh),
144.7 (1-CPh), 147.6 (9a-C), 160.6 (5-C), 161.0 (6-C), 162.3
(8-C), 169.9 (3a-C). Found: 64.65% C, 5.14% H, 21.66% N;
C21H20N6O2 requires 64.94% C, 5.19% H, 21.64% N.
3.2.1. 9-Chloromethyl-5-methyl-2-(1-piperidinyl)-9,10-
dihydro-4H-furo[2,3-c]pyrimido[4,5,6-ij]-2,7-naphthyri-
dine-1-carbonitrile (12a). Yield 92%. Mp O300 8C (from
DMF); dH 1.63 (6H, m, NR2), 2.36 (3H, s, 5-CH3), 3.22 (1H,
dd J3Z7.2 Hz, J2Z16.0 Hz, 10-H), 3.57 (1H, dd J3Z
9.6 Hz, J2Z16.0 Hz, 10-H), 3.70 (4H, m, NR2), 3.95 (1H,
dd J3Z4.8 Hz, J2Z11.6 Hz, CH2Cl), 4.03 (1H, dd J3Z
4.0 Hz, J2Z11.6 Hz, CH2Cl), 5.15 (1H, m, 9-H), 12.84 (1H,
br s, NH). dC 24.6 (5-CH3), 24.7 (4-CNR2), 27.8 (3,5-CNR2),
32.6 (10-C), 46.3 (CH2Cl), 47.8 (2,6-CNR2), 74.6 (1-C), 86.1
(9-C), 103.0 (10a-C), 110.0 (10c-C), 121.1 (CN), 149.6
(10b-C), 151.7 (6a-C), 156.1 (3a-C), 162.8 (2-C), 168.0
(5-C), 168.7 (7a-C). Found: 59.81% C, 5.10% H, 9.39% Cl,
21.92% N; C19H19ClN6O requires 59.61% C, 5.00% H,
9.26% Cl, 21.95% N.
3.1.7. 5,6-Diamino-2-chloromethyl-8-diethylamino-1,2-
dihydrofuro[2,3-c]-2,7-naphthyridine-9-carbonitrile
(10a). Yield 76%. Mp 300–301 8C (from dioxane); dH 1.23
(6H, t, JZ6.0 Hz, 2CH3), 3.29 (1H, dd, J3Z6.4 Hz, J2Z
15.6 Hz, 1-H), 3.63 (5H, m, NCH2, 1-H), 3.77 (1H, dd J3Z
4.4 Hz, J2Z10.8 Hz, CH2Cl), 3.83 (1H, dd J3Z3.2 Hz,
J2Z10.8 Hz, CH2Cl), 4.97 (1H, m, 2-H), 6.17 (2H, s, NH2),
6.64 (2H, s, NH2). dC 13.6 (CH3), 31.2 (1-C), 43.2 (NCH2),
47.5 (CH2Cl), 65.8 (9-C), 79.1 (2-C), 91.8 (5a-C), 93.7 (9b-
3.2.2. 9-Ethyl-5-methyl-2-(4-morpholinyl)-9,10-dihydro-
4H-furo[2,3-c]pyrimido[4,5,6-ij]-2,7-naphthyridine-1-
carbonitrile (12b). Yield 81%. Mp O300 8C (from DMF);
dH 0.97 (3H, t, JZ7.2 Hz, CH2CH3), 1.75 (2H, m,

9622
A. V. Tverdokhlebov et al. / Tetrahedron 61 (2005) 9618–9623
CH2CH3), 2.36 (3H, s, 5-CH3), 2.97 (1H, dd, J3Z8.0 Hz,
J2Z16.4 Hz, 10-H), 3.49 (1H, dd, J3Z9.2 Hz, J2Z16.4 Hz,
10-H), 3.69 (8H, m, NR2), 4.80 (1H, m, 9-H), 13.11 (1H, br
s, NH). dC 9.9 (CH2CH3), 22.9 (5-CH3), 31.1 (CH2CH3),
33.9 (10-C), 51.7 (NCH2), 69.0 (OCH2), 76.4 (1-C), 94.1
(9-C), 104.2 (10a-C), 108.7 (10c-C), 118.2 (CN), 147.1
(10b-C), 153.8 (6a-C), 156.3 (3a-C), 163.0 (2-C), 168.2
(5-C), 168.7 (7a-C). Found: 62.74% C, 5.40% H, 22.94% N;
C19H20N6O2 requires 62.62% C, 5.53% H, 23.06% N.
(10H, m, CH2CH3, 20,30,50,60-H), 2.96 (1H, dd, J3Z8.0 Hz,
J2Z14.8 Hz, 10-H), 3.48 (1H, dd, J3Z9.6 Hz, J2Z14.8 Hz,
10-H), 3.65 (4H, m, NR2), 3.71 (4H, m, NR2), 4.68 (1H, m,
9-H), 7.57 (1H, s, NH), 7.61 (1H, s, NH). dC 9.4 (CH2CH3),
22.7 (30,50-C), 22.8 (40-C), 31.3 (10-C), 33.2 (CH2CH3),
36.2 (20,60-C), 46.5 (NCH2), 67.6 (1-C), 68.0 (5-C), 68.6
(OCH2), 82.8 (9-C), 88.5 (10c-C), 92.3 (10a-C), 118.9 (CN),
142.7 (10b-C), 154.1 (6a-C), 155.5 (3a-C), 163.7 (2-C),
167.8 (7a-C). Found: 65.60% C, 6.63% H, 19.83% N;
C23H28N6O2 requires 65.69% C, 6.71% H, 19.98% N.
3.2.3. 2-Diethylamino-5-methyl-9-phenyl-9,10-dihydro-
4H-furo[2,3-c]pyrimido[4,5,6-ij]-2,7-naphthyridine-1-
carbonitrile (12c). Yield 93%. Mp O300 8C (from DMF);
dH 1.12 (6H, t, JZ6.8 Hz, 2CH3), 2.41 (3H, s, 5-CH3), 3.56
(4H, m, NCH2), 4.39 (1H, dd, J3Z1.2 Hz, J2Z8.8 Hz,
10-H), 4.93 (1H, dd, J3Z8.4 Hz, J2Z8.8 Hz, 10-H), 5.10
(1H, dd, J3Z8.4 Hz, 1.2,-H), 7.08 (2H, d, JZ8.0 Hz, 2,6-
HPh), 7.21 (1H, t, JZ8.0 Hz, 4-HPh), 7.29 (2H, dd, JZ8.0,
8.0 Hz, 3,5-HPh), 12.51 (1H, s, NH). dC 13.8 (CH3), 24.4
(5-CH3), 44.9 (10-C), 45.3 (NCH2), 77.0 (1-C), 89.1 (9-C),
104.8 (10a-C), 108.9 (10c-C), 116.7 (CN), 127.1 (3,5-CPh),
128.0 (2,6-CPh), 128.9 (4-CPh), 142.9 (1-CPh), 145.3 (10b-
C), 152.6 (6a-C), 156.0 (3a-C), 164.3 (2-C), 166.7 (5-C),
168.0 (7a-C). Found: 69.37% C, 5.35% H, 21.19% N;
C23H22N6O requires 69.33% C, 5.57% H, 21.09% N.
3.3.3. 2-Diethylamino-9-phenyl-5,6,9,10-tetrahydro-4H-
spiro{furo[2,3-c]pyrimido[4,5,6-ij]-2,7-naphthyridine-5,
10-cyclohexane}-1-carbonitrile (13c). Yield 87%. Mp
198–199 8C (from aqueous DMF); dH 1.06 (6H, t, 0 JZ
7.0 Hz, 2CH3), 1.28 (1H, m, 40-H), 1.40 (1H, m, 4 -H),
1.63–1.80 (8H, m, 20,30,50,60-H), 3.49 (4H, q, JZ7.0 Hz,
NCH2), 4.28 (1H, dd, J3Z2.0 Hz, J2Z8.8 Hz, 10-H), 4.80
(1H, dd, J3Z9.2 Hz, J2Z8.8 Hz, 10-H), 4.97 (1H, dd, J3Z
2.0, 9.2 Hz, 9-H), 7.04 (2H, d, JZ7.2 Hz, 2,6-HPh), 7.17
(1H, t, JZ7.2 Hz, 4-HPh), 7.26 (2H, t, JZ7.2 Hz, 3,5-HPh),
7.88 (2H, s, 2NH). dC 13.6 (CH3), 18.7 (30,50-C), 23.5 (40-
C), 37.8 (20,60-C), 43.7 (10-C), 43.9 (NCH2), 68.0 (1-C),
68.5 (5-C), 88.5 (10c-C), 89.1 (9-C), 91.5 (10a-C), 119.7
(CN), 125.2 (4-CPh), 127.2 (3,5-CPh), 130.8 (2,6-CPh), 141.2
(10b-C), 144.6 (1-CPh), 155.1 (6a-C), 159.5 (3a-C), 163.9
(2-C), 167.7 (7a-C). Found: 71.20% C, 6.51% H, 18.27% N;
C27H30N6O requires 71.34% C, 6.65% H, 18.49% N.
3.3. Spiro{furo[2,3-c]pyrimido[4,5,6-ij]-2,7-naphthyri-
dine-5,10-cyclohexanes} 13a–c. General procedure
A solution of the diamine 8a,9b,10c (2.5 mmol) in
cyclohexanone (3 mL) was heated at 100 8C for 2 h. After
cooling it was diluted with water resulting in a brown oil
separation. The liquid was decanted and the oil was
dissolved in ethanol (10 mL). Water (10 mL) was added
to ethanolic solution and a pale solid precipitated. It was
filtered and recrystallized from DMF–H2O (1:1 v/v) mixture
yielding compounds 13a–c. During the recrystallization, a
long heating time should be avoided.
References and notes
1. Goerlitzer, K.; Dobberkau, P. M. Pharmazie 1996, 51,
386–391.
2. Goerlitzer, K.; Dobberkau, P. M.; Ewert, H. J.; Heinrici, C.;
Bartke, U. Pharmazie 1997, 52, 575–578.
3. Langer, P.; Doring, M. Eur. J. Org. Chem. 2002, 221–234.
4. Padwa, A. Chem. Commun. 1998, 1417–1424.
5. Schobert, R.; Gordon, G. J. Curr. Org. Chem. 2002, 6,
1181–1196.
3.3.1. 9-Chloromethyl-2-(1-piperidinyl)-5,6,9,10-tetra-
hydro-4H-spiro{furo[2,3-c]pyrimido[4,5,6-ij]-2,7-
naphthyridine-5,10-cyclohexane}-1-carbonitrile (13a).
Yield 82%. Mp 186–187 8C (from aqueous DMF); dH 1.36
(1H, m, 40-H), 1.46 (1H, m, 40-H), 1.68 (12H, m, NR2,
20,30,50,60-H), 1.82 (2H, m, 20,60-H), 3.20 (1H, dd, J3Z
6.8 Hz, J2Z16.0 Hz 10-H), 3.52 (1H, dd, J3Z9.6 Hz, J2Z
16.0 Hz 10-H), 3.66 (4H, m, NR2), 3.78 (1H, dd, J3Z
5.2 Hz, J2Z11.2 Hz, CH2Cl), 3.84 (1H, dd, J3Z5.2 Hz,
J2Z11.2 Hz, CH2Cl), 4.98 (1H, m, 9-H), 7.58 (1H, s, NH),
7.60 (1H, s, NH). dC 20.9 (30,50-C), 24.6 (40-C), 25.1
(4-CNR2), 26.3 (3,5-CNR2), 30.6 (10-C), 37.3 (20,60-C), 47.7
(CH2Cl), 49.4 (2,6-CNR2), 68.5 (1-C), 68.7 (5-C), 79.9
(9-C), 89.8 (10c-C), 93.3 (10a-C), 121.0 (CN), 143.7 (10b-
C), 156.0 (6a-C), 156.2 (3a-C), 164.5 (2-C), 169.5 (7a-C).
Found: 62.76% C, 6.13% H, 8.10% Cl, 19.30% N;
C23H27ClN6O requires 62.93% C, 6.20% H, 8.08% Cl,
19.15% N.
6. Tietze, L. F. Chem. Rev. 1996, 96, 115–136.
7. Neuschultz, K.; Velker, J.; Neier, R. Synthesis 1998, 227–255.
8. Tverdokhlebov, A. V.; Resnyanska, E. V.; Zavada, A. V.;
Tolmachev, A. A.; Kostyuk, A. N.; Chernega, A. N.
Tetrahedron 2004, 60, 5777–5783.
9. Hirota, T.; Tomita, K.; Sasaki, K.; Okuda, K.; Yoshida, M.;
Kashino, S. Heterocycles 2001, 55, 741–752.
10. Morgenlie, S. Acta Chem. Scand. 1970, 24, 365–366.
11. Campaigne, E.; Ellis, R. L.; Bradford, M. J. Heterocycl. Chem.
1969, 6, 159–162.
12. Wamhoff, H.; Thiemig, H.-A. Chem. Ber. 1985, 118,
4473–4485.
13. Matsuda, T.; Yamagata, K.; Tomioka, Y.; Yamazaki, M.
Chem. Pharm. Bull. 1985, 33, 937–943.
14. Korte, F.; Trautner, K. Chem. Ber. 1962, 95, 281–294.
15. Glickman, S. A.; Cope, A. C. J. Am. Chem. Soc. 1945, 67,
1012–1016.
3.3.2. 9-Ethyl-2-(4-morpholinyl)-5,6,9,10-tetrahydro-
4H-spiro{furo[2,3-c]pyrimido[4,5,6-ij]-2,7-naphthyri-
dine-5,10-cyclohexane}-1-carbonitrile (13b). Yield 76%.
Mp 237 8C (from aqueous DMF); dH 1.04 (1H, t, JZ7.2 Hz,
CH3), 1.36 (1H, m, 40-H), 1.47 (1H, m, 40-H), 1.61–1.82
16. Ducker, J. W.; Williams, B. K. Aust. J. Chem. 1978, 31,
2327–2331.
17. Tverdokhlebov, A. V.; Resnyanska, E. V.; Tolmachev, A. A.;
Zavada, A. V. Monatsh. Chem. 2003, 134, 1045–1052.

A. V. Tverdokhlebov et al. / Tetrahedron 61 (2005) 9618–9623
9623
18. Suzuki, Y.; Nishimaki, R.; Ishikawa, M.; Murata, T.; Takao,
K.; Tadano, K. J. Org. Chem. 2000, 65, 8595–8607.
19. Easton, N. R.; Gardner, J. H.; Stevens, J. R. J. Am. Chem. Soc.
1947, 69, 2941–2942.
26. Achini, R.; Oppolzer, W. Tetrahedron Lett. 1975, 16,
369–372.
27. Sachs, F. Ber. Dtsch. Chem. Ges. 1906, 39, 3006–3028.
28. Leonard, N. J.; Hyson, A. M. J. Am. Chem. Soc. 1949, 71,
1961–1964.
20. Attenburrow, J.; Elks, J.; Hems, B. A.; Speyer, K. N. J. Chem.
Soc. 1949, 510–518.
29. Wasulko, W.; Noble, A. C.; Popp, F. D. J. Med. Chem. 1966, 9,
599–601.
21. Garcia, J. A.; Munoz, H.; Tamariz, J. Synth. Commun. 1983,
13, 569–574.
30. Zhitnikov, V. Ya.; Burmistrov, S. I. Izv. Vyssh. Uchebn. Zaved.
Khim. Khim. Tekhnol. 1969, 12, 1069–1071, Chem. Abstr.
1970, 72, 31757.
22. Munoz, A. H.; Tamariz, J.; Jiminez, R.; Garcia de la Mora, G.
J. Chem. Res. Synop. 1993, 68–69.
23. Schultz, E. M.; Robb, C. M.; Sprague, J. M. J. Am. Chem. Soc.
1947, 69, 2454–2459.
31. Yavari, I.; Mostafavi, H.; Tahmassebi, D.; Hekmat-Shoar, R.
Monatsh. Chem. 1997, 128, 675–679.
24. Benedetti, F.; Berti, F.; Risaliti, A. Tetrahedron Lett. 1993, 34,
6443–6446.
32. Atkinson, J. D.; Johnson, M. C. J. Chem. Soc. (C) 1968,
1252–1258.
25. Benedetti, F.; Berti, F.; Fabrissin, S.; Gianferrara, T. J. Org.
Chem. 1994, 59, 1518–1524.
33. Easton, N. R.; Fish, V. B. J. Org. Chem. 1953, 18, 1071–1074.