Fused quinoline heterocycles IX: First example of a 3, 4-diamino-1H- pyrazolo[4, 3-c]quinoline and a 3-azido-1H-1, 2, 4, 5, 6, 6a-hexaazabenzo[a] indacene

Article abstract of DOI:10.1515/znb-2009-0813

4-Alkylamino-2-chloroquinoline-3-carbonitriles 4a - c react with NaN3 to give the corresponding tetrazolo[1, 5-a]quinoline-4-carbonitriles 5a - c which are converted into 2-amino-quinoline-3-carbonitriles 8a - c by reaction with PPh3 via an iminophosphora

Full text of DOI:10.1515/znb-2009-0813

Fused Quinoline Heterocycles IX:
First Example of a 3,4-Diamino-1H-pyrazolo[4,3-c]quinoline
and a 3-Azido-1H-1,2,4,5,6,6a-hexaazabenzo[a]indacene
Ramadan Ahmed Mekheimera, Afaf Mohamed Abdel Hameeda, Saeed Mohamed Refaeya,
Mohamed Ashry Ibrahima, Kamal Usef Sadeka, and Anamik Shahb
a Department of Chemistry, Faculty of Science, El-Minia University, El-Minia 61519, Egypt
b Department of Chemistry (FIST DST Funded & UGC SAP Sponsored), Saurashtra University,
Rajkot-360 005, India
Reprint requests to Dr. R. A. Mekheimer. E-mail: rmekh@yahoo.com
Z. Naturforsch. 2009, 64b, 973 – 979; received April 3, 2009
4-Alkylamino-2-chloroquinoline-3-carbonitriles 4a – c react with NaN3 to give the corresponding
tetrazolo[1,5-a]quinoline-4-carbonitriles 5a – c which are converted into 2-amino-quinoline-3-carbo-
nitriles 8a – c by reaction with PPh3 via an iminophosphorane and subsequent hydrolysis. On the
other hand, the new 3,4-diamino-1H-pyrazolo[4,3-c]quinoline (11) was prepared by fusion of the
aminoquinolines 8a – c with hydrazine hydrate. Diazotization of 11 followed by reaction with NaN3
yielded the novel tetracyclic ring system 3-azido-1H-1,2,4,5,6,6a-hexaazabenzo[a]indacene (13).
Key words: Aminoquinoline-3-carbonitriles, Heterocyclic Synthesis,
3,4-Diamino-1H-pyrazolo[4,3-c]quinoline
Introduction
Functionalized quinolines and their hetero-fused
analogs represent an important class of organic
molecules that have attracted a great deal of attention
from synthetic as well as medicinal chemists because
of their presence in numerous natural products along
with the wide spectrum of physiological activities dis-
played by these compounds [1]. Thus, 2-aminoquinol-
ines have recently been reported to be potent melanin-
concentrating hormone 1 receptor (MCH1R) antago-
nists [2 – 5]. Pyrazole derivatives exhibit pharmacolog-
ical activities such as hypotensive, antibacterial, anti-
inflammatory and antitumor properties [6].
Of special interest, 3-aminopyrazoles have recently 2, 4 R1
R2
a
b
c
4-methylpiperidino
CH3 CH3
been reported to display significant biological activi-
ties, being inhibitors of CDK2/cyclin A as antitumor
agents [7, 8] and strong anticonvulsants [9]. Thus, it
is envisioned that 3,4-diaminopyrazolo[4,3-c]-quinol-
ines, which contain both the 3-aminopyrazole and 2-
aminoquinolinemoieties, may afford unique biological
activities.
Although numerous elegant syntheses have been de-
veloped for pyrazolo[4,3-c]-quinoline derivatives, be-
cause of their great importance [10 – 21], to the best of
our knowledge, 3,4-diamino-1H-pyrazolo[4,3-c]quin-
oline 11 is unknown, due to the difficulties encoun-
Et
Et
Scheme 1.
tered to synthesize this tricyclic diamino compound
with two primary amino groups using the previously
known methodologies, providing the impetus to syn-
thesize this novel heterocyclic system.
We have previously reported a versatile method
directed towards the synthesis of new polyfunction-
ally substituted pyrazolo[4,3-c]quinolines with poten-
c
0932–0776 / 09 / 0800–0973 $ 06.00 ꢀ 2009 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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R. A. Mekheimer et al. · Fused Quinoline Heterocycles
5, 6, 8 R1
R2
a
b
c
4-methylpiperidino
CH3 CH3
Et
Et
Scheme 2.
tial pharmaceutical activity [22 – 28]. In order to ex- sequently, this reaction was applied in the present in-
tend the synthetic scope of this method and in con- vestigation to synthesize 2,4-diaminoquinoline-3-carb-
tinuation of our search for more potent pyrazolo[4,3- onitriles 8a – c, which are considered to be very im-
c]quinolines, we planned to synthesize new pyrazolo portant intermediates for the synthesis of the desired
[4,3-c]quinolines with a primary amino group with the pyrazolo-[4,3-c]quinolines 11, by reduction of tetraz-
expectation that the introduction of an NH2 group into olo[1,5-a]quinoline-3-carbonitriles, via the formation
different positions of the basic pyrazoloquinoline sys- of a phosphazene intermediate, in good yields.
tem will increase its therapeutic index. In this paper, we
wish to report the synthesis of the title compounds, us-
ing the conveniently available 2,4-dichloroquinoline-
3-carbonitrile (1) [29] as starting material.
In an attempt to synthesize 2,4-diaminoquinoline-3-
carbonitriles 8a – c from the tetrazoloquinolines 5a –
c, we investigated the ring opening of the tetrazo-
lo ring in 5a – c by reaction with triphenylphos-
phine to give the corresponding open-chain phosph-
azenes 6a – c (Scheme 2). Refluxing tetrazoloquin-
olines 5a – c with triphenylphosphine in bromobenz-
ene, high stability was observed, and no phosphaz-
enes 6a – c were isolated, even upon heating for ex-
tended periods. Therefore, we repeated the reaction in
Results and Discussion
In our studies, compound 1 was reacted with sec-
ondary amines 2 in order to obtain the required key
intermediates 4 for subsequent pyrazole ring closure.
The reaction of 1 with an excess of the appropriate sec-
ondary amines 2a – c in DMF solution at r. t. did not
afford the 2-dialkylamino-4-chloroquinoline-3-carbo-
nitriles 3, but gave instead the expected isomeric 4-
dialkylamino-2-chloroquinoline-3-carbonitriles 4a – c,
where the nucleophilic substitution first takes place
at position 4 [29, 30] (Scheme 1). When the amino-
quinolines 4a – c ◦were reacted with sodium azide in
DMF at 75 – 80 C the ring-closed tetrazolo[1,5-a]-
quinolines 5a – c were isolated as the only reaction
products, instead of the tautomeric azidoquinolines 7
(Scheme 2). The IR spectra of 5a – c have no azido
band.
◦
a solvent of (some 20 C) higher boiling point than
bromobenzene, viz. 1,2-dichlorobenzene. Heating 5a –
c with triphenylphosphine in 1,2-dichlorobenzene at
reflux temperature for 5 h afforded the phosphazenes
6a – c, which could be hydrolyzed with a mixture of
acetic acid/water (5 : 1) to the corresponding new 2,4-
diaminoquinoline-3-carbonitriles 8a – c (Scheme 2).
Structural proof of 8a – c rests on elemental analyses
and spectroscopic data (see Experimental Section). An
examination of other possible routes to the aminoquin-
oline-3-carbonitriles 8a – c shows that the three-step
sequence via the phosphazene 6 is a superior method.
Aminoquinoline derivatives 8a – c can not be prepared
by direct amination due to numerous competing side
reactions.
The Staudinger reaction [31] is one of the most com-
mon methods for reducing organic azides to the corre-
sponding primary amines due to the chemoselectivity,
As the synthesis of the new pyrazolo[4,3-c]quinol-
mild reaction conditions and good yields [32]. Con- ine ring system is the main target of this program, we
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R. A. Mekheimer et al. · Fused Quinoline Heterocycles
975
Scheme 3.
decided to investigate the reaction of aminoquinolines termediates, and they present a broad range of chem-
8a – c with hydrazine hydrate with the hope of obtain- ical reactivity [35]. We therefore are interested in in-
ing the interesting pyrazolo[4,3-c]quinoline ring sys- vestigating the introduction of the azido group into
tem 11. Thus, refluxing these amines 8a – c with an the newly synthesized 3,4-diamino-1H-pyrazolo[4,3-
excess of hydrazine hydrate (80 %) for 5 h produced c]quinoline (11) with the expectation that the prod-
a solid product in excellent yield which was identi- ucts would be of potential biological interest. Thus,
fied as 3,4-diamino-1H-pyrazolo[4,3-c]quinoline (11) when compound 11 was reacted with sodium nitrite in
(Scheme 3). The structural assignment for 11 was a 70 % solution of H2SO4 at −5 ◦C, followed by reac-
established on the basis of consistent elemental and tion of the non-isolated pyrazoloquinoline diazonium
spectral data. The IR spectrum showed no cyano ab- sulfate with an aqueous solution of sodium azide, a
sorption at 2210 cm−1, but absorption bands at 3330 solid product was obtained for which the two valence-
and 3200 cm−1 which were assigned to NH and NH2 isomeric structures 12 and 13 can be written (see
amino functions. Moreover, the 1H NMR spectrum re- Scheme 3). It has been reported that tetrazoles fused
vealed the absence of alkyl protons and the presence of with five-membered heterocycles are generally in the
signals for two amino protons at C-3, two amino pro- azide form while tetrazoles fused with six-membered
tons at C-4, and a pyrazole NH proton in addition to heterocycles exist in the tetrazole form [36]. Thus, the
aromatic protons in their expected positions. The mass previously unreported 3-azido-1H-1,2,4,5,6,6a-hexa-
spectrum showed a molecular ion at m/z = 199. Forma- azabenzo[a]indacene structure 13 is proposed for the
tion of the pyrazoloquinoline 11 can be rationalized as isolated product. The structure of 13 was confirmed
follows: the alkyl amino group at position 4 of 4-alkyl- on the basis of its elemental analysis and spectral
aminoquinoline-3-carbonitriles 8a – c undergoes a nu- data. The IR spectrum of the reaction product showed
cleophilic substitution reaction with one molecule of an absorption band for the N3 group at 2130 cm−1
.
1
hydrazine to give the intermediate 10. Subsequent in- The H NMR spectrum displayed no amino protons
tramolecular cyclization via the attack of the NH2 of (NH2) and the presence of a singlet at δ = 14.47 ppm,
the hydrazino group at position 4 on the nitrile carbon assignable to the pyrazole NH in addition to four aro-
in the intermediate 10 yields the pyrazolo-fused com- matic protons at δ = 7.77– 8.44 ppm. Furthermore,
pound 11 (Scheme 3).
the structure assigned for this reaction product 13 was
fully supported by its mass spectrum, which showed a
molecular formula C10H5N9 (m/z = 251, [M]+).
In summary, the work described in this paper shows
Organic azides are well known as compounds with a
high level of biological activity and have proved valu-
able as one of the most important classes of drugs for
the treatment of cardiovascular diseases [33]. Some for the first time the synthesis of two previously unre-
heterocyclic azides were synthesized as antithrombotic ported tricyclic systems, namely 3,4-diamino-1H-pyr-
and blood pressure-lowering agents [34]. Furthermore, azolo[4,3-c]quinoline (11), with both amino groups
they are among the most versatile organic synthetic in- as primary amines, and 3-azido-1H-1,2,4,5,6,6a-hexa-
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R. A. Mekheimer et al. · Fused Quinoline Heterocycles
azabenzo[a]indacene (13), which are difficult to obtain 128.9, 132.9 (Ar-C), 148.1(C-8a), 149.9 (C-2), 162.7 (C-4). –
MS (EI, 70 eV): m/z (%) = 233 (27) [M, 37Cl]+, 231 (82)
by alternative routes, with the purpose of investigating
[M, 35Cl]+. – C12H10ClN3 (231.7): calcd. C 62.21, H 4.35,
in the future their biological activity.
Cl 15.30, N 18.14; found C 62.36, H 4.19, Cl 15.27, N 18.19.
Experimental Section
2-Chloro-4-(diethylamino)quinoline-3-carbonitrile (4c)
All melting points were measured on a Gallenkamp appa-
◦
M. p. 134 – 136 C. Yield: 93 %. – IR: ν = 3050 (arom.
CH), 2976, 2928, 2885 (aliph. CH), 2210 (CN) cm−1. –
1H NMR (400 MHz, [D6]DMSO): δ = 1.17 (t, 6H, J =
7.0 Hz, 2CH3), 3.73 (q, 4H, J = 7.0 Hz, 2CH2), 7.67 (m,
1H Ar), 7.90 (m, 2H Ar), 8.11 (d, 1H, J = 8.4 Hz, 1
Ar). – 13C NMR (100 MHz, [D6]DMSO): δ = 13.3 (2 CH3),
47.4 (2 CH2), 99.4 (C-3), 116.3 (CN), 123.6 (C-4a), 125.9,
127.4, 129.0, 133.3 (Ar-C), 148.3 (C-8a), 149.3 (C-2), 163.4
(C-4). – MS (EI, 70 eV): m/z (%) = 261 (15) [M, 37Cl]+,
259 (46) [M, 35Cl]+. – C14H14ClN3 (259.7): calcd. C 64.74,
H 5.43, Cl 13.65, N 16.18; found C 64.56, H 5.59, Cl 13.77,
N 16.09.
ratus and are uncorrected. IR spectra were obtained with a
Shimadzu 470 spectrophotometer as dispersions in KBr. 1H
and 13C NMR spectra were recorded on a Bruker Avance II
spectrometer at 400 MHz for 1H and 100 MHz for 13C with
[D6]DMSO as solvent and TMS as an internal standard.
Chemical shifts (δ) are reported in ppm. Mass spectra were
performed on a Shimadzu GCMS-QP 2010 mass spectrome-
ter at 70 eV. Microanalyses were performed by the Microan-
alytical Data Unit at Cairo University, and analytical values
obtained were within 0.4 % of the calculated values. All
reagents were of commercial quality or were purified before
use, and the organic solvents were of analytical grade or pu-
rified by standard procedures.
General procedure for the preparation of 5-substituted tetr-
azolo[1,5-a]quinoline-4-carbonitriles 5a – c
General procedure for the preparation of 4-alkylamino-2-
chloroquinoline-3-carbonitriles 4a – c
Sodium azide (5.25 mmol) was added to a solution of 4a –
c (1.75 mmol) in DMF (15 mL). The reaction mixture was
stirred at 75 – 80 ◦C for 12 h. After cooling, the reaction mix-
ture was poured into cold water, and the precipitated product
was filtered, washed well with water, dried and recrystallized
from DMF to afford the tetrazoloquinolines 5a – c.
The appropriate sec. amines 2a – c (2.25 mmol) were
added to a solution of 1 (0.250 g, 1.12 mmol) in DMF (3 mL).
The reaction mixture was stirred for 30 min at r. t. and was
then poured into water (10 mL). The precipitated solid prod-
uct was isolated by suction and recrystallized from ethanol.
5-(4-Methylpiperidino)-tetrazolo[1,5-a]quinoline-4-carbo-
nitrile (5a)
2-Chloro-4-(4-methylpiperidino)quinoline-3-carbonitrile
(4a)
◦
◦
M. p. 243 – 244 C. Yield: 94 %. – IR: ν = 2951, 2865
M. p. 160 – 161 C. Yield: 96 %. – IR: ν = 3050 (arom.
(aliph. CH), 2210 (CN) cm−1. – 1H NMR (400 MHz,
[D6]DMSO): δ = 1.05 (d, 3H, J = 6 Hz, CH3), 1.54 (m, 2H,
CH2), 1.77 (m, 1H aliph.), 1.86 (m, 2H, CH2), 3.52 (m, 2H,
CH2), 3.89 (m, 2H, CH2), 7.83 (t, 1H, J = 8 Hz, 1H Ar), 8.05
(t,1H, J = 8 Hz, 1H Ar), 8.18 (d, 1H, J = 8.2 Hz, 1H Ar), 8.56
(d, 1H, J = 8.2 Hz, 1H Ar). – MS (EI, 70 eV): m/z (%) = 293
(13) [M+1]+, 292 (63) [M]+. – C16H16N6 (292.3): calcd.
C 65.74, H 5.52, N 28.75; found C 65.86, H 5.74, N 28.88.
CH), 2928, 2850 (aliph. CH), 2210 (CN) cm−1. – 1H NMR
(400 MHz, [D6]DMSO): δ = 1.02 (d, 3H, J = 6.4 Hz, CH3),
1.46 (m, 2H, CH2), 1.71 (m, 1H, H aliph.), 1.76 (m, 2H,
CH2), 3.50 (m, 2H, CH2), 3.88 (m, 2H, CH2), 7.65 (m, 1H
Ar), 7.86 (m, 2H Ar), 8.04 (d, 1H, J = 8.5 Hz, 1H Ar). –
13C NMR (100 MHz, [D6]DMSO): δ = 21.9 (CH3), 30.0
(aliph. CH), 34.6 (2CH2), 53.4 (2CH2), 95.5 (C-3), 116.8
(CN), 122.1 (C-4a), 125.7, 127.1, 129.0, 133.2 (Ar-C), 148.2
(C-8a), 149.8 (C-2), 162.8 (C-4). – MS (EI, 70 eV): m/z (%) =
287 (36) [M, 37Cl]+, 285 (100) [M, 35Cl]+. – C16H16ClN3
(285.8): calcd. C 67.25, H 5.64, Cl 12.41, N 14.70; found
C 67.44, H 5.78, Cl 12.26, N 14.82.
5-(Dimethylamino)-tetrazolo[1,5-a]quinoline-4-carbonitrile
(5b)
◦
M. p. 208 – 209 C. Yield: 81 %. – IR: ν = 3088 (arom.
CH), 2951, 2928 (aliph. CH), 2210 (CN) cm−1. – 1H NMR
2-Chloro-4-(dimethylamino)quinoline-3-carbonitrile (4b)
(400 MHz, [D6]DMSO): δ = 3.44 (s, 6H, 2CH3), 7.79 (t,
◦
M. p. 187 – 188 C. Yield: 92 %. – IR: ν = 3050 (arom. 1H, J = 8 Hz, 1H Ar), 8.02 (t, 1H, J = 8 Hz, 1H Ar), 8.31
CH), 2928, 2850 (aliph. CH), 2210 (CN) cm−1. – 1H NMR (d, 1H, J = 8.5 Hz, 1H Ar), 8.51 (d, 1H, J = 8.5 Hz, 1H
(400 MHz, [D6]DMSO): δ = 3.41 (s, 6H, 2CH3), 7.60 (m, Ar). – 13C NMR (100 MHz, [D6]DMSO): δ = 45.2 (2CH3),
1H Ar), 7.83 (m, 2H Ar), 8.18 (d, 1H, J = 8.5 Hz, 1H 79.7 (C-4), 115.4 (CN), 117.0 (Ar-C), 120.5 (C-5a), 127.8,
Ar). – 13C NMR (100 MHz, [D6]DMSO): δ = 45.2 (2 128.9 (Ar-C), 131.6 (C-9a), 133.9 (Ar-C), 148.3 (C-3a),
CH3), 93.7 (C-3), 117.0 (CN), 121.4 (C-4a), 126.5, 126.6, 159.8 (C-5). – MS (EI, 70 eV): m/z (%) = 239 (6) [M+1]+,
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238 (37) [M]+. – C12H10N6 (238.3): calcd. C 60.50, H 4.23, (Ar-C), 149.6 (C-2), 162.4 (C-4). – MS (EI, 70 eV): m/z
N 35.27; found C 60.61, H 4.09, N 35.19.
(%) = 473 (12) [M+1]+, 472 (53) [M]+. – C30H25N4P
(472.5): calcd. C 76.26, H 5.33, N 11.86; found C 76.37,
H 5.20, N 12.02.
5-(Diethylamino)-tetrazolo[1,5-a]quinoline-4-carbonitrile
(5c)
4-(Diethylamino)-2-[(triphenylphosphoranylidene)amino]
quinoline-3-carbonitrile (6c)
◦
M. p. 168 – 169 C. Yield: 96 %. – IR: ν = 3070 (arom.
CH), 2976, 2910 (aliph. CH), 2210 (CN) cm−1. – 1H NMR
(400 MHz, [D6]DMSO): δ = 1.23 (t, 6H, J = 7.0 Hz, 2CH3),
3.75 (q, 4H, J = 7.0 Hz, 2CH2), 7.83 (t, 1H, J = 8 Hz, 1H
Ar), 8.05 (t, 1H, J = 8 Hz, 1H Ar), 8.25 (d, 1H, J = 8 Hz, 1H
Ar), 8.56 (d, 1H, J = 8 Hz, 1H Ar). – 13C NMR (100 MHz,
[D6]DMSO): δ = 13.1 (2CH3), 47.5 (2CH2), 86.7 (C-4),
114.8 (CN), 117.1 (Ar-C), 122.0 (C-5a), 128.2, 128.3 (Ar-C),
131.8 (C-9a), 134.0 (Ar-C), 147.8 (C-3a), 159.8 (C-5). – MS
(EI, 70 eV): m/z (%) = 267 (6) [M+1]+, 266 (28) [M]+. –
C14H14N6 (266.3): calcd. C 63.14, H 5.30, N 31.56; found
C 63.26, H 5.39, N 31.47.
M. p. 210 – 211oC. Yield: 96 %. – IR: ν = 3056 (arom.
CH), 2976 (aliph. CH), 2210 (CN) cm−1. – 1H NMR
(400 MHz, [D6]DMSO): δ = 1.09 (t, 6H, J = 7.0 Hz,
2CH3), 3.53 (q, 4H, J = 7.0 Hz, 2CH2), 7.08 – 7.16 (m, 2H
Ar), 7.39 (m, 1H Ar), 7.53 – 7.64 (m, 9H Ar), 7.77 (d, 1H,
J = 7.5 Hz, 1H Ar), 7.90 – 7.95 (m, 6H Ar). – 13C NMR
(100 MHz, [D6]DMSO): δ = 13.3 (2CH3), 46.7 (2CH3), 98.2
(C-3), 118.7 (CN), 120.3 (C-4a), 121.6, 124.7, 126.1, 128.3,
128.7, 128.9, 129.3 (Ar-C), 131.2 (C-8a), 132.3, 133.0, 133.1
(Ar-C), 149.6 (C-2), 161.7 (C-4). – MS (EI, 70 eV): m/z
(%) = 501 (10) [M+1]+, 500 (42) [M]+. – C32H29N4P
(500.6): calcd. C 76.78, H 5.84, N 11.19; found C 76.59,
H 5.72, N 11.04.
General procedure for the preparation of 4-substituted-2-
[(triphenylphosphoranylidene)-amino]quinoline-3-carbo-
nitriles 6a – c
General procedure for the preparation of 4-substituted-2-
aminoquinoline-3-carbonitriles 8a – c
A mixture of 5a – c (1.72 mmol) and triphenylphosphine
(1.72 mmol) in 1,2-dichloro-benzene was heated under reflux
A solution of compounds 6a – c (0.950 mmol) in a mix-
for 5 h. After concentration and cooling to r. t., the resulting ture of AcOH (5 mL) and H2O (1 mL) was refluxed for 3 –
solid product was filtered off, washed with a small amount 5 h. After concentration and cooling to r. t., the resulting solid
of MeOH, dried and recrystallized from DMF to give com- product was collected by filtration, washed well with MeOH
pounds 6a – c.
to remove Ph3PO, dried and recrystallized from EtOH to give
compounds 8a, c. In the case of 8b, the reaction mixture was
◦
heated in a water bath at 60 C for 40 h, and then it was
4-(4-Methylpiperidino)-2-[(triphenylphosphoranylidene)
amino]quinoline-3-carbonitrile (6a)
worked up as described for 8a, c.
◦
M. p. 230 – 231 C. Yield: 89 %. – IR: ν = 3040 (arom.
2-Amino-4-(4-methylpiperidino)quinoline-3-carbonitrile
CH), 2912, 2848 (aliph. CH), 2210 (CN) cm−1. – 1H NMR
(400 MHz, [D6]DMSO): δ = 1.01 (d, 3H, J = 6.3 Hz, CH3),
1.43 (m, 2H, CH2), 1.66 (m, 1H aliph.), 1.77 (m, 2H, CH2),
3.37 (m, 2H, CH2), 3.58 (m, 2H, CH2), 7.10 (t, 2H, J = 8 Hz,
2H Ar), 7.39 (t, 1H, J = 7.5 Hz, 1H Ar), 7.55 – 7.63 (m, 9H
Ar), 7.70 (d, 1H, J = 8.2 Hz, 1H Ar), 7.89 – 7.94 (m, 6H
Ar). – MS (EI, 70 eV): m/z (%) = 527 (19) [M+1]+, 526
(68) [M]+. – C34H31N4P (526.6): calcd. C 77.55, H 5.93,
N 10.64; found C 77.64, H 5.79, N 10.72.
(8a)
◦
M. p. 218 – 219 C. Yield: 75 %. – IR: ν = 3456, 3296,
3120 (NH2), 2940, 2848 (aliph. CH), 2210 (CN) cm−1. –
1H NMR (400 MHz, [D6]DMSO): δ = 1.01 (d, 3H, J =
6.4 Hz, CH3), 1.43 (m, 2H, CH2), 1.67 (m, 1H aliph.), 1.79
(m, 2H, CH2), 3.38 (m, 2H, CH2), 3.66 (m, 2H, CH2), 6.54
(s, 2H, NH2), 7.19 (t, 1H, J = 8 Hz, 1H Ar), 7.42 (d, 1H,
J = 8 Hz, 1H Ar), 7.54 (t, 1H, J = 8 Hz, 1H Ar), 7.76 (d,
1H, J = 8 Hz, 1H Ar). – 13C NMR (100 MHz, [D6]DMSO):
δ = 22.0 (CH3), 30.3 (aliph. CH), 34.6 (2CH2), 52.9 (2CH2),
84.6 (C-3), 117.7 (CN), 118.2 (C-4a), 121.7, 124.8, 126.5,
131.9 (Ar-C), 150.3 (C-8a), 157.6 (C-4), 162.6 (C-2). – MS
(EI, 70 eV): m/z (%) = 267 (18) [M+1]+, 266 (98) [M]+. –
C16H18N4 (266.3): calcd. C 72.15, H 6.81, N 21.04; found
C 72.27, H 6.69, N 21.15.
4-(Dimethylamino)-2-[(triphenylphosphoranylidene)amino]
quinoline-3-carbonitrile (6b)
◦
M. p. 206 – 208 C. Yield: 72 %. – IR: ν = 3070 (arom.
CH), 2912, 2850 (aliph. CH), 2210 (CN) cm−1. – 1H NMR
(400 MHz, [D6]DMSO): δ = 3.22 (s, 6H, 2CH3), 7.05 (m,
2H Ar), 7.35 – 7.38 (m, 1H Ar), 7.53 – 7.63 (m, 9H Ar),
7.77 (d, 1H, J = 8.4 Hz, 1H Ar), 7.89 – 7.94 (m, 6H Ar). –
13C NMR (100 MHz, [D6]DMSO): δ = 44.3 (2CH3), 92.8
2-Amino-4-(dimethylamino)quinoline-3-carbonitrile (8b)
◦
M. p. 208 – 209 C. Yield: 69 %. – IR: ν = 3400, 3300,
(C-3), 118.3 (CN), 119.3 (C-4a), 121.1, 125.3, 126.2, 128.4, 3150 (NH2), 2920 (aliph. CH), 2220 (CN) cm−1. – 1H NMR
128.7, 128.8, 128.9 (Ar-C), 131.0 (C-8a), 132.3, 133.0, 133.1 (400 MHz, [D6]DMSO): δ = 3.25 (s, 6H, 2CH3), 6.66 (s, 2H,
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978
R. A. Mekheimer et al. · Fused Quinoline Heterocycles
NH2), 7.19 (t, 1H, J = 7.8 Hz, 1H Ar), 7.49 (d, 1H, J = 8 Hz,
M. p. 326 – 328 ◦C (decomp.). – IR: ν = 3330, 3200 (NH,
1
1H Ar), 7.56 (t, 1H, J = 7.8 Hz, 1H Ar), 7.83 (d, 1H, J = 8 Hz, NH2) cm−1. – H NMR (400 MHz, [D6]DMSO): δ = 5.87
1H Ar). – MS (EI, 70 eV): m/z (%) = 213 (18) [M+1]+, 212 (s, 2H, NH2), 7.64 (m, 2H Ar), 8.01 (d, 1H, J = 7 Hz, 1H Ar),
(100) [M]+. – C12H12N4 (212.3): calcd. C 67.90, H 5.70, 8.25 (d, 1H, J = 7 Hz, 1H Ar), 9.11 (s, 2H, NH2), 12.82 (br
N 26.40; found C 67.78, H 5.88, N 26.53.
s, 1H, NH). – MS (EI, 70 eV): m/z (%) = 200 (14) [M+1]+,
199 (36) [M]+. – C10H9N5 (199.2): calcd. C 60.29, H 4.55,
N 35.16; found C 60.40, H 4.37, N 35.32.
2-Amino-4-(diethylamino)quinoline-3-carbonitrile (8c)
◦
M. p. 149 – 150 C. Yield: 73 %. – IR: ν = 3408, 3328,
3152 (NH2); 2960 (aliph. CH), 2210 (CN) cm−1. – 1H NMR
(400 MHz, [D6]DMSO): δ = 1.11 (t, 6H, J = 6.8 Hz, 2CH3),
3.57 (q, 4H, J = 6.8 Hz, 2CH2), 6.65 (s, 2H, NH2), 7.20 (t,
1H, J = 7.3 Hz, 1H Ar), 7.47 (d, 1H, J = 8.2 Hz, 1H Ar),
7.57 (t, 1H, J = 7.3 Hz, 1H Ar), 7.82 (d, 1H, J = 8.2 Hz, 1H
Ar). – 13C NMR (100 MHz, [D6]DMSO): δ = 13.3 (2CH3),
46.9 (2CH2), 89.2 (C-3), 117.2 (CN), 119.8 (C-4a), 121.9,
125.0, 126.4, 132.0 (Ar-C), 150.5 (C-8a), 157.4 (C-4), 162.4
(C-2). – MS (EI, 70 eV): m/z (%) = 241 (14) [M+1]+, 240
(80) [M]+. – C14H16N4 (240.3): calcd. C 69.97, H 6.71,
N 23.32; found C 70.13, H 6.59, N 23.47.
3-Azido-1H-1,2,4,5,6,6a-hexaazabenzo[a]indacene (13)
A solution of 11 (0.3 g, 1.51 mmol) in H2SO4 (4 mL,
70 %) was cooled until the temperature of the solution
was −5 ◦C and treated with sodium nitrite (0.313 g,
4.53 mmol) in water (1 mL). To the resulting solution of the
diazonium salt was added sodium azide (0.295 g, 4.53 mmol)
◦
in water (1 mL) and the mixture maintained at 0 to −5 C.
Stirring was then continued for 1 h at r. t. The resulting solid
product was collected by filtration and dissolved in H2O. The
solution was neutralized with dil. Na2CO3 solution, and the
precipitated solid product was collected by filtration, washed
well with H2O, dried and recrystallized from acetone to af-
ford compound 13.
3,4-Diamino-1H-pyrazolo[4,3-c]quinoline (11)
M. p. 196 – 197 ◦C (decomp.). Yield: 75 %. – IR: ν =
3200 (NH), 3008 (arom. CH), 2130 (N3) cm−1. – 1H NMR
(400 MHz, [D6]DMSO): δ = 7.77 (t, 1H, J = 7.5 Hz, 1H Ar),
7.87 (t, 1H, J = 7.5 Hz, 1H Ar), 8.25 (d, 1H, J = 8.0 Hz, 1H
Ar), 8.44 (d, 1H, J = 8.0 Hz, 1H Ar), 14.47 (s, 1H, pyrazole
NH). – MS (EI, 70 eV): m/z (%) = 251 (7) [M]+. – C10H5N9
(251.2): calcd. C 47.81, H 2.01, N 50.18; found C 48.02,
H 1.89, N 50.34.
A mixture of 8a – c (1.25 mmol) and hydrazine hydrate
(5 mL; 80 %) was refluxed for 5 h, until TLC showed the
disappearance of the starting compounds. After cooling, the
mixture was evaporated to dryness in vacuo. Water (3 mL)
was added to the remaining oily residue with scratching. The
resulting product was isolated by suction, washed with H2O,
dried and recrystallized from DMF. The product was ob-
tained in 80 – 86 % yield.
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