Nitroalkanes as electrophiles: Synthesis of triazole-fused heterocycles with neuroblastoma differentiation activity

Article abstract of DOI:10.1039/d0ob01007c

We discovered a reaction of nitroalkanes with 2-hydrazinylquinolines, 2-hydrazinylpyridines and bis-2,4-dihydrazinylpyrimidines in polyphosphoric acid (PPA) affording 1,2,4-triazolo[4,3-a]quinolines, 1,2,4-triazolo[4,3-a]pyridines and bis[1,2,4]triazolo[4,3-a:4′,3′-c]pyrimidines, respectively. The reaction expands the scope of heterocyclic annulations involving phosphorylated nitronates, believed to be the electrophilic intermediates formed from nitroalkanes in PPA. Several of the synthesized triazoles showed promising anticancer activity by inducing differentiation in neuroblastoma cancer cells. Due to the urgent need for novel differentiation agents for neuroblastoma therapy, this finding warrants further evaluation of this class of compounds against neuroblastoma.

Full text of DOI:10.1039/d0ob01007c

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This article can be cited before page numbers have been issued, to do this please use: N. A. Aksenov, A.
V. Aksenov, N. K. Kirilov, N. Arutiunov, D. Aksenov, V. Maslivetc, Z. Zhao, L. Du, M. Rubin and A. Kornienko,
Org. Biomol. Chem., 2020, DOI: 10.1039/D0OB01007C.
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Number 47
21 December 2017
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DOI: 10.1039/D0OB01007C
Organic & Biomolecular Chemistry
ARTICLE
Received 00th
January 20xx,
Nitroalkanes as Electrophiles: Synthesis of Triazole-Fused
Heterocycles with Neuroblastoma Differentiation Activity
Nicolai A. Aksenov,a Alexander V. Aksenov,a Nikita K. Kirilov,a Nikolai A. Arutiunov,a Dmitrii A.
Aksenov,a Vladimir Maslivetc,b Zhenze Zhao,b Liqin Du,b Michael Rubin,a,c and Alexander
Kornienkob*
Accepted 00th
January 20xx
DOI:
We discovered
a reaction of nitroalkanes with 2-hydrazinylquinolines, 2-hydrazinylpyridines and bis-2,4-
10.1039/x0xx00000x
dihydrazinylpyrimidines in polyphosphoric acid (PPA) affording 1,2,4-triazolo[4,3-a]quinolines, 1,2,4-triazolo[4,3-a]pyridines
and bis[1,2,4]triazolo[4,3-a:4',3'-c]pyrimidines, respectively. The reaction expands the scope of heterocyclic annulations
involving phosphorylated nitronates, believed to be the electrophilic intermediates formed from nitroalkanes in PPA. Several
of the synthesized triazoles showed promising anticancer activity by inducing differentiation in neuroblastoma cancer cells.
Due to the urgent need for novel differentiation agents for neuroblastoma therapy, this finding warrants further evaluation
of this class of compounds against neuroblastoma.
www.rsc.org/
pentoxide in orthophosphoric acid.16 It was demonstrated that PPA
converts nitroalkanes, which are commonly used as nucleophiles at
Introduction
Heterocyclic scaffolds incorporating 1,2,4-triazoles have received
a great deal of attention in the medicinal chemistry community due
to their status as privileged medicinal scaffolds and their occurrence
in bioactive natural products and synthetic pharmaceutical agents.1-
the -carbon, into electrophilic phosphorylated nitronates (A,
Scheme 2). We have reported that such species can be effectively
employed in reactions with doubly nucleophilic substrates to form
benzimidazoles and benzoxazoles (B),17 indoloquinolines (C),18 and
oxadiazoles (D).19 Herein, we describe a newly developed synthetic
methodology to access triazole-fused heterocycles, such as 1,2,4-
triazolo[4,3-a]quinolines (E), using this approach. We also report the
results of biological studies, that led to the identification of several
triazoles that showed promising anti-tumor activity when tested
against neuroblastoma cancer cells.
5
Specifically, 1,2,4-triazolo[4,3-a]quinolines have been reported to
display a wide array of biological activities, including anticonvulsant,6
analgesic,7 antibacterial,8, 9 bromodomain inhibitory,10 histamine H4
receptor antagonistic,11 and cytotoxic,12 to name a few. Selected
examples, of biologically active 1,2,4-triazolo[4,3-a]quinolines are
shown in Scheme 1. These compounds are generally accessed via
cyclization of quinoline substrates bearing hydrazine substituents at
C-2, including cyclocondensation of hydrazides13,
or oxidative
14
cyclization of hydrazones8 (Scheme 1). The same type of heterocycles
can also be accessed by direct condensation of 2-
a
hydrazinylquinolines with carboxylic acid, but such processes
typically require harsh reaction conditions and provide marginal
yields.15
In recent years, our laboratories have been exploring the
reactivity of nitroalkanes in polyphosphoric acid (PPA), an ionic
liquid-like reaction medium prepared by dissolving phosphorous
Scheme 1. Examples of biologically active 1,2,4-triazolo[4,3-a]quinolines and main
methods utilized for their preparation
a. Department of Chemistry, North Caucasus Federal University, 1a Pushkin St.,
Stavropol 355009, Russian Federation
b. Department of Chemistry and Biochemistry, Texas State University, San Marcos, TX,
78666, USA, E-mail: a_k76@txstate.edu.
c. Department of Chemistry, University of Kansas, 1567 Irving Hill Rd., Lawrence, KS
66045-7582, USA.
Electronic Supplementary Information (ESI) available: Copies of 1H and 13C NMR spectra and
crystallographic data for CCDC 199548 and 1994533. See DOI: 10.1039/x0xx00000x
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R
NO2
smoothly, affording the corresponding triazoloquinolines 3ca-3ce
XH
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R3
and 3da-3de in good to excellent yields (SchDeOmI:e130).1.039/D0OB01007C
X
N
PPA
R3
NH2
R
Further demonstration of the reaction scope is shown in Scheme
4 using nitropropane as the electrophilic component. As can be seen,
methoxy groups at variable positions are well-tolerated (compounds
3fc, 3gc, 3hc, 3kc). So are aromatic (compounds 3ec, 3fc, 3gc, 3hc)
and amide (3jc) groups. Any position on the quinoline ring 3-8 can be
substituted successfully. We have also demonstrated that the
reaction can be performed on a multigram scale with a reduction of
the amount of PPA. Thus, combining 2.67 g of 2c with 1.59 g of
hydrazinylquinoline 1a in 10 g of PPA (1.5-fold reduction) gave 1.79
g of 3ac (91%, Scheme 3).
OPO(OH)2
N
R
X = NH, O
OPO(OH)2
B
A
R5HN
R5
R
N
R4
R6
N
H
R4
O
R6
N
C
O
NH2
R7
R7
R
N
H
N
N
D
After the successful development of the synthetic approach to
1,2,4-triazolo[4,3-a]quinolines, we wondered whether the presence
of the entire quinoline heterocyclic system in the starting material is
necessary. We reasoned that 2-hydrazinylpyridine (4, Scheme 5a),
containing the identical reactive moiety, should also be a good
substrate for this transformation. We were pleased to find that the
reactions of 4 with nitroalkanes 2a,c successfully provided the
corresponding triazolopyridines 5a,c in good yields (Scheme 5a).
Again, the reaction tolerates the presence of an aromatic group and
ester functionality, affording products 5e and 5g, respectively, albeit
in somewhat lower yields (Scheme 5a). Further, a double reaction of
dihydrazinylpyrimidine 6 with nitropropane 2c, allowed for the
efficient annulation of two triazole rings to yield bis[1,2,4]triazolo-
[4,3-a:4',3'-c]pyrimidines 7c (Scheme 5b). However, the reaction
with phenylnitromethane 2f was again low yielding providing 7f in
only 7% yield.
R2
N
R2
N
R1
R1
NH
N
NH2
N
E
R
Scheme 2. Construction of heterocyclic systems using nitroalkanes as electrophiles
Results and Discussion
Chemistry
Taking into account the binucleophilic nature of 2-
hydrazinylquinoline substrates, we wondered if heterocyclic scaffold
E could be accessed in the manner similar to the one that was
previously demonstrated for 1,3,4-oxadiazoles D (Scheme 2).19 To
test this idea, we pre-mixed 86% PPA with 3 equiv. of nitromethane
2a (Scheme 3) at 130 oC and added 2-hydrazinylquinoline 1a in
several portions over 1 h. TLC monitoring revealed the completion
of the reaction during the next 30 min. Simple aqueous work-up
including basification with ammonia and subsequent purification by
preparative column chromatography afforded 1,2,4-triazolo[4,3-
a]quinoline 3aa as a crystalline solid in 78% yield (Scheme 3). The
reaction of unsubstituted quinoline substrate 3a with higher
nitroalkanes (2b-e) can also be performed very efficiently providing
the corresponding triazoles 3ab-ae in high yields (Scheme 3). The
outcome of these reactions was unambiguously confirmed by single
crystal X-ray diffraction performed for the structures of 1,2,4-
triazolo[4,3-a]quinolines 3ab and 3ad (Fig. 1). It should be pointed
out that reaction involving phenylnitromethane (2f) proceeded
sluggishly providing very low yield of product 3af. One explanation
for this result is reduced electrophilicity of the corresponding
phosphorylated nitronate A (R = Ph, Scheme 2) due to resonance
effects. Introduction of methyl substituent at C-4 of quinoline
substrate was well tolerated, as reactions of 3b provided the
corresponding triazoles 3ba-3be in high yields (Scheme 3).
Transformation involving ethyl nitroacetate (2g) also proceeded
uneventfully allowing for an efficient access to triazole 3bg bearing
ester functionality at C-1 (Scheme 3). Next, the reactivity of
quinoline substrates 1c,d bearing Br or NO2 substituents at C-6 was
examined. Gratifyingly, the reactions involving nitromethane (2a) or
higher nitroalkanes (2b-e) as electrophilic components proceeded
Fig 1. X-ray structures of 1,2,4-triazolo[4,3-a]quinolines 3ab (CCDC # 1994548) and 3ad
(CCDC # 1994533). The thermal ellipsoids are shown at 50% probability.
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Scheme 3. Synthesis of 1,2,4-triazolo[4,3-a]quinolines using nitroalkanes as electrophiles
In a surprising deviation from this established reaction path, our
A putative mechanistic rationale of the featured trasformation is
attempt to incorporate a ketone function into the structure of the depicted in Scheme 7. We believe that after the initial attack of
triazole products by using -nitroacetophenones resulted in the loss hydrazine in 1a onto the electrophilic phosphorylated nitronates A,
of the carbonyl carbon (Scheme 6). Here, we found that 2 equivalents the adducts F undergo elimination of phosphoric acid to give the
of nitroacetophenones 8f, 8h and 8i per a hydrazine moiety in 1a, 1c amidine-type intermediates G (Scheme 7a). The 5-exo-trig intra-
(Scheme 6a) and 6 (Scheme 6b) gave the best results providing molecular nucleophilic cyclization of G followed by elimination of
excellent yields of triazoles 3af, 3ah, 3ai, 3ci and 7f. Curiously, the phosphorylhydroxylamine then leads to triazoles 3. When
successful syntheses of phenyl triazoles 3af and 7f mitigate the low nitroacetophenone is used as the source of the electrophilic
yielding reaction utilizing phenylnitromethane to produce these two component, the reaction takes a new path and the intramolecular
compounds (see Schemes 3 and 5b). Finally, we also showed that this cyclization occurs through the attack of the quinoline nitrogen onto
procedure can be scaled up and prepared 2.06 g (71%) of 3ai by the hydrazone moiety in J (Scheme 7b). The cyclization product K
combining 4.2
g
of nitroacetophenone 8i with 1.59
g
of then undergoes elimination of nitromethane to afford triazole 3af.
hydrazinylquinoline 1a in 10 g of PPA (1.5-fold reduction). The choice
of scaling up triazole 3ai was also based on a previous publication
reporting cytotoxic activity associated with this compound (see
Biology
Scheme 1).12 We therefore demonstrated that our methodology can Due to a diverse range of biological activities found in this class of
be used for large scale preparation of 1,2,4-triazolo[4,3- compounds, as mentioned in the Introduction, the triazole
a
a]quinolines with reported biological activities.
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Scheme 4. Further diversification in the synthesis of 1,2,4-triazolo[4,3-a]quinolines
Scheme 5. Synthesis of (a) 1,2,4-triazolo[4,3-a]pyridines and (b) bis[1,2,4]triazolo[4,3-a:4',3'-c]pyrimidines using nitroalkanes as electrophiles
heterocycles synthesized in the present study were added to a
neuroblastoma differentiation screen available in our Department.
Neuroblastoma is the 3rd most lethal pediatric cancer responsible for
15% of all childhood cancer-related deaths.20 It is believed to arise
from the failure of neural crest precursor cells to differentiate into
mature neurons during embryonic development, hence its occur-
rence primarily in children.21 The idea behind the differentiation
therapy is to guide malignant cells to a non-malignant state through
the restoration of native biochemical pathways rather than through
cell killing. Although chemotherapy and radiation are the major
forms of treatment for high-risk patients, the differentiation therapy
is employed post-chemotherapy and offers a milder treatment
approach to prevent tumor recurrance.22 The standard-of-care
differentiation therapy utilizes retinoic acids (RAs), all-trans-RA
(ATRA) or 13-cis-RA. However, resistance to RAs is common23, 24 and,
in the absence of alternatives, generates an urgent need to discover
structurally novel differentiating agents.
Scheme 6. Reactions with nitroacetophenones
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Our differentiation screen is based on quantifying neurVitieewoAurttigclreoOwnltinhe,
DOI: 10.1039/D0OB01007C
which is an established marker of differentiation and can be used to
quantify the potency of a compound. Compared with undifferen-
tiated neuroblastoma cells that are characteristically small and
circular with minimal projections, cells treated with ATRA show easily
detectable neurite outgrowth, which is quantifiable by measuring its
length against the cells body area.25 Fig. 2 shows a scatter plot of
normalized neurite lengths associated with the synthesized triazoles.
Compounds 3hc, 3ec, 3cb clearly stand out from the other members
of this compound collection by an effective induction of neurite
outgrowth in neuroblastoma BE(2)-C cells at the concentration of 25
 (Fig. 2). Two of these, 3hc and 3ec, are based on the 1,2,4-
triazolo[4,3-a]quinoline skeleton, possessing an aromatic
substituent at position 3 of the quinoline moiety, indicating that
further search for more potent compounds may need to include the
preparation of compounds having these structural features. The
induction of neurite outgrowth can also be observed visually in Fig 3,
in which the neurites are highlighted in pink in the images showing
neuroblastoma BE(2)-C cells treated with 3hc (Fig. 3b), 3ec (Fig 3c),
3cb (Fig. 3d) and ATRA (Fig. 3e). Fig. 3a shows cells treated with a
vehicle control.
Scheme 6. Proposed mechanisms for (a) formation of 1,2,4-triazolo[4,3-a]quinolines 3
and (b) reaction with nitroacetophenones using 1a and 8f as examples
Fig. 3. Compounds 3hc, 3ec, 3cb induce neurite outgrowth in BE(2)-C cells. Shown are
representative phase-contrast images for cells treated with (a) DMSO control, (b) 3hc (25
M), (c) 3ec (25 M), (d) 3cb (25 M) and (c) ATRA (2.5 M) for 4 days. Neurites are
highlighted in pink and cell bodies in yellow color.
Fig. 2. Effect of compounds on neurite outgrowth in neuroblastoma cell line BE(2)-C.
1,000 cells were treated with the compounds (25 M) for 4 days. Shown is the scatter
plot of normalized neurite lengths, sorted in ascending order, associated with individual
compounds. Black dashed line is the mean of all compounds tested. The error bars are
derived from 3 replicates.
Conclusion
The current investigation expands the spectrum of applications
of nitroalkanes in PPA for the construction of heterocycles with
useful biological properties. As in our previous work, we believe that
these reactions proceed via phosphorylated nitronates readily
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formed upon pre-mixing of nitro compounds with PPA. These 2-Hydrazinyl-3-phenylquinoline (1e). 2-chloro-3-phenylquinoline
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DOI: 10.1039/D0OB01007C
versatile intermediates readily react with bis-nucleophiles to result (959 mg, 4.00 mmol), hydrazine hydrate (88% solution in water, 2.3
in heterocyclic annulations, in this case leading to 1,2,4-triazolo[4,3- mL, 40.0 mmol) and ethanol (0.7 mL) were combined in a 30 mL G30
a]quinolines as well as 1,2,4-triazolo[4,3-a]pyridines and bis[1,2,4]- vial and covered with a septum. The vial was placed in a Monowave
triazolo[4,3-a:4',3'-c]pyrimidines. These triazole-based heterocyclic 300 microwave reactor, and mixture was heated to 160 °C over the
scaffolds are privileged structures in medicinal chemistry as course of 5 minutes (power did not exceed 135 watts), after which
demonstrated in the cited literature and the use of our simple atom this temperature was maintained for 1.5 hours (controlled by IR
economical methodology should further expand their biological sensor, MW power within 10 watts, 10–15 bar pressure). Resulting
applications. In our own evaluation of the synthesized triazoles, we mixture was poured into water (50 mL) and extracted with
found interesting activity of several triazoloquinolines in inducing dichloromethane (4 × 20 mL). Combined organic layers were
differentiation of neuroblastoma cancer cells. Since there is no concentrated in vacuo, crude product was purified by silica gel
alternative solution for patients carrying tumors resistant to RAs, the column chromatography (hexanes:ethanol:Et3N, 10:1:0.2, v/v)
standard-of-care neuroblastoma differentiation therapy agents, the followed by recrystallization form ethanol to afford 1e as a pale
discovery of such effects is exciting and warrants further yellow solid, m.p. = 111–112 °C (ethanol); yield 847 mg (3.60 mmol,
1
investigation of compounds possessing these properties as potential 90%). Rf = 0.38, hexanes/ethanol/Et3N (5:1:0.1, v/v). H NMR (400
anti-neuroblastoma therapies.
MHz, DMSO-d6) δ 7.80 (s, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 8.3
Hz, 1H), 7.56–7.52 (m, 1H), 7.50 (d, J = 4.1 Hz, 4H), 7.46–7.41 (m, 1H),
7.23 (t, J = 7.2 Hz, 1H), 7.02 (br, 1H), 4.45 (br.s, 2H). 13C NMR (101
MHz, DMSO-d6) δ 155.8, 146.5, 136.5, 136.2, 129.3, 128.9 (2C), 128.8
(2C), 128.1, 127.7, 125.4, 124.8, 123.6, 122.1. FTIR (ZnSe) ν (cm−1):
3309, 3253, 3183, 1774, 1615, 1508, 1486, 1244. HRMS (ES TOF, m/z)
calcd for C15H14N3+ ([M+H]+): 236.1186, found: 236.1182 (1.6 ppm).
Experimental part
1
General information. H and 13C NMR spectra were recorded on a
Bruker Avance-III spectrometer (400 or 100 MHz, respectively)
equipped with a BBO probe in CDCl3 or DMSO-d6, using TMS as an
internal standard. High-resolution mass spectra were obtained using
2-Hydrazinyl-3-(4-methoxyphenyl)quinoline (1f). Product 1f was
obtained via method described for compound 1e employing 2-
chloro-3-(4-methoxyphenyl)-quinoline (1.076 g, 4.0 mmol), and
purified by recrystallization form ethanol. Brown solid, m.p. 132–133
a
Bruker Maxis spectrometer (electrospray ionization, MeCN
solution, using HCO2Na−HCO2H for calibration). Melting points were
measured with a Stuart smp30 apparatus. All reactions were
performed in oven-dried flasks equipped with reflux condensers and
magnetic stir bars. All reactions were followed by thin-layer
chromatography (TLC) using Silufol UV-254 plates, which were
visualized under UV light (254 nm), with acetone, hexane/acetone,
or hexane/ethanol/acetone mixtures as eluent. Polyphosphoric acid
(86%) was obtained by dissolving precise amount of P2O5 in 85%
°C (ethanol); yield 853 mg (3.22 mmol, 82%). Rf
= 0.55,
1
EtOAc/hexane/Et3N (10:1:0.2, v/v). H NMR (400 MHz, DMSO-d6) δ
7.79–7.63 (m, 3H), 7.58–7.48 (m, 1H), 7.47–7.39 (m, 2H), 7.22 (td, J =
7.7, 6.7, 1.0 Hz, 1H), 7.08–7.00 (m, 2H), 7.01 (s, 1H), 4.52 (s, 2H), 3.81
(s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 159.1, 155.9, 146.2, 135.6,
130.0 (2C), 129.0, 128.5, 127.5, 125.2, 124.6, 123.6, 122.0, 114.3
(2C), 55.1. FTIR (ZnSe) ν (cm−1): 3270, 2928, 2855, 1744, 1611, 1505,
1419, 1246, 1178, 1031. HRMS (ES TOF, m/z) calcd for C16H16N3O+
([M+H]+): 266.1288, found: 266.1293 (2.1 ppm).
orthophosphoric acid according to the published protocol.26,
27
Hydrazines 1a,28 1b,29 1d,30 1i,31-33, 4,34 6,35 8i,36 6-bromo-2-chloro-4-
methylquinoline,37 2-chloro-6,7-dimethoxy-3-phenylquinoline,38 2-
chloro-3-(4-methoxyphenyl)-quinoline,39
2-chloro-3-
5-bromo-2-chloro-6,7-dimethoxy-3-
2-Hydrazinyl-6,7-dimethoxy-3-phenylquinoline (1g). Product 1g was
obtained via method described for compound 1e employing 2-
chloro-6,7-dimethoxy-3-phenylquinoline (1.196 g, 4.00 mmol), and
purified by recrystallization form ethanol. Yellow solid, m.p. 187–189
phenylquinoline,40
phenylquinoline,41 2-chloroquinoline-4-carboxamide,42 2-chloro-8-
methoxyquinoline,43 were synthesized according to the literature
methods. All other reagents and solvents were purchased from
commercial vendors and used as received.
°C (ethanol); yield: 1.015
g (3.44 mmol, 86%). Rf = 0.51,
1
acetone/hexane (1:4, v/v). H NMR (400 MHz, DMSO-d6) δ 7.70 (s,
1H), 7.53–7.46 (m, 4H), 7.45–7.37 (m, 1H), 7.21 (s, 1H), 7.13 (s, 1H),
6.67 (s, 1H), 4.33 (br.s, 2H), 3.89 (s, 3H), 3.83 (s, 3H). 13C NMR (101
MHz, DMSO-d6) δ 155.0, 151.8, 146.2, 142.7, 137.0, 135.2, 128.8
(2C), 128.8 (2C), 127.7, 122.0, 117.7, 106.8, 105.9, 55.5, 55.4. FTIR
(ZnSe) ν (cm−1): 3242, 2960, 1767, 1617, 1605, 1501, 1463, 1447,
6-Bromo-2-hydrazinyl-4-methylquinoline (1c). Hydrazine hydrate
(80% solution in water, 1.56 g, 25.0 mmol) was added to a solution
of 6-bromo-2-chloro-4-methylquinoline (1.28 g, 5.00 mmol) in 5 mL
of ethanol. The reaction mixture was stirred at reflux for 8 hours.
Then, the mixture was cooled to room temperature, the formed solid
presipitate was filtered off and recrystallized from ethanol to afford
1c as a pale orange crystalline solid, m.p. 174–175 °C (ethanol); yield
1.13 g (4.50 mmol, 90%). 1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 1H),
7.89 (d, J = 1.8 Hz, 1H), 7.58 (dd, J = 8.8, 2.0 Hz, 1H), 7.46 (d, J = 8.8
Hz, 1H), 6.74 (s, 1H), 4.32 (s, 2H), 2.46 (s, 3H). 13C NMR (101 MHz,
DMSO-d6) δ 159.7, 147.0, 143.4, 132.2, 128.4, 126.5, 125.6, 113.8,
112.2, 18.7. FTIR (ZnSe) ν (cm−1): 3269, 3003, 1892, 1750, 1689, 1620,
+
1433, 1363, 1234, 1204. HRMS (ES TOF, m/z) calcd for C17H18N3O2
([M+H]+): 296.1394, found: 296.1402 (2.9 ppm).
5-Bromo-2-hydrazinyl-6,7-dimethoxy-3-phenylquinoline
Product 1h was obtained via method described for compound 1e
employing 5-bromo-2-chloro-6,7-dimethoxy-3-phenylquinoline
(1h).
(1.51 g, 4.00 mmol), and purified by recrystallization from ethanol.
Pale brown solid, m.p. = 180–182 °C (ethanol); yield 1.20 g (3.21
mmol, 80%). Rf = 0.34, acetone/hexane (1:3, v/v). 1H NMR (400 MHz,
DMSO-d6) δ 7.72 (s, 1H), 7.54–7.35 (m, 5H), 7.19 (s, 1H), 7.16 (s, 1H),
4.44 (s, 2H), 3.95 (s, 3H), 3.78 (s, 3H). 13C NMR (101 MHz, DMSO-d6)
+
1559, 1506, 1422, 1341. HRMS (ES TOF, m/z) calcd for C10H11BrN3
([M+H]+): 252.0131, found: 252.0121 (3.9 ppm).
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δ 155.8, 154.9, 144.9, 143.1, 136.3, 134.3, 129.0 (2C), 128.8 (2C), hydrazines 1 or 4.00 mmol for reaction with 6) in a 10 mL Erlenmeyer
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128.2, 123.6, 116.5, 114.5, 106.5, 60.3, 56.1. FTIR (ZnSe) ν (cm−1): flask. This mixture was stirred and heDatOeId: 10t.1o03193/D00O°CB0, 10th07eCn
3319, 3246, 2935, 1608, 1550, 1505, 1484, 1461, 1426, 1395, 1230, corresponding hydrazine 1 or 6 (1.00 mmol) was added in several
+
1201, 1035, 1019. HRMS (ES TOF, m/z) calcd for C17H17BrN3O2
portions over a period of one hour. The resulting mixture was stirred
at 130 °C, and the reaction progress was monitored by TLC. Upon
completion (1 – 1.5 hours), postreaction work up and isolation was
performed in the same manner as described for Method A.
([M+H]+): 374.0499, found 374.0500 (0.5 ppm).
2-Hydrazinylquinoline-4-carboxamide (1j). Product 1j was obtained
according to the literature method by refluxing the mixture of 2-
chloroquinoline-4-carboxamide (826.5 mg, 4.00 mmol) and [1,2,4]Triazolo[4,3-a]quinoline (3aa).7 Product 3aa was obtained via
hydrazine hydrate (88% solution in water, 2.3 mL, 40.0 mmol) in Method A employing 2-hydrazinylquinoline (1a) (159 mg, 1.00 mmol)
ethanol (2 mL) for 30 minutes. Solvent was evaporated in vacuo, the and nitromethane (2a) (183 mg, 3.00 mmol), and purified by silica gel
residue was recrystallized from ethanol. Colorless solid, m.p. 209– column chromatography (ethanol/acetone/hexane, gradient 1:3:6 –
213 °C (ethanol); yield: 735 mg (3.64 mmol, 91%). Rf = 0.34, 1:4:5, v/v). Dark brown solid, m.p. 170–171 °C (acetone); yield: 132
1
acetone/hexane (1:1, v/v). H NMR (400 MHz, DMSO-d6) δ 8.22 (s, mg (0.78 mg, 78%). Rf = 0.31, acetone. 1H NMR (400 MHz, DMSO-d6)
1H), 8.12 (s, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.73 (s, 1H), 7.58 (d, J = 8.3 δ 9.96 (d, J = 0.5 Hz, 1H), 8.39 (d, J = 8.3 Hz, 1H), 7.96 (dd, J = 7.9, 1.0
Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 6.89 (s, 1H), Hz, 1H), 7.79–7.65 (m, 3H), 7.59–7.53 (dt, J = 7.6, 1.0 Hz, 1H). 13C NMR
4.38 (br.s, 2H). 13C NMR (101 MHz, DMSO-d6) δ 169.1, 158.5, 148.0, (101 MHz, DMSO-d6) δ 147.4, 136.4, 132.2, 129.9, 129.5, 129.1,
143.2, 129.4, 125.9, 125.4, 121.7, 119.8, 108.9. FTIR (ZnSe) ν (cm−1): 126.3, 123.0, 116.5, 114.1. FTIR (ZnSe) ν (cm−1): 2997, 2951, 1928,
3326, 3064, 1666, 1590, 1568, 1526, 1489, 1431, 1381, 1307, 1208. 1780, 1685, 1541, 1515, 1420, 1371, 1239, 1049. HRMS (ES TOF, m/z)
HRMS (ES TOF, m/z) calcd for C10H11N4O+ ([M+H]+): 203.0927, found: calcd for C10H8N3+ ([M+H]+): 170.0713, found: 170.0712 (0.6 ppm).
203.0938 (5.1 ppm).
1-Methyl-[1,2,4]triazolo[4,3-a]quinoline (3ab).44 Product 3ab was
2-Hydrazinyl-8-methoxyquinoline (1k). Product 1k was obtained via obtained via Method A employing 2-hydrazinylquinoline (1a) (159
method described for compound 1e employing 2-chloro-8- mg, 1.00 mmol) and nitroethane (2b) (225 mg, 3.00 mmol), and
methoxyquinoline (500.0 mg, 2.59 mmol), and purified by silica gel purified by silica gel column chromatography (acetone/hexane,
column chromatography (hexanes/ethanol/Et3N, gradient 15:1:1– gradient 1:1 – pure acetone, v/v). Yellow solid, m.p. 171–172 °C
1
10:10:1, v/v) followed by recrystallization form ethanol. Brown solid, (acetone); yield: 165 mg (0.90 mmol, 90%). Rf = 0.33, acetone. H
m.p. = 78–79 °C (ethanol); yield 222 mg (1.16 mmol, 45%). Rf = 0.37, NMR (400 MHz, CDCl3) δ 8.19 (dd, J = 8.5, 0.9 Hz, 1H), 7.78 (dd, J =
1
EtOAc/Et3N (20:1, v/v). H NMR (400 MHz, DMSO-d6) δ 8.14 (br. s., 7.8, 1.4 Hz, 1H), 7.64 (ddd, J = 8.5, 7.4, 1.4 Hz, 1H), 7.56 (d, J = 9.5 Hz,
1H), 7.86 (d, J = 9.0 Hz, 1H), 7.21 (dd, J = 8.0, 1.2 Hz, 1H), 7.09 (t, J = 1H), 7.52 (ddd, J = 7.8, 7.4, 0.9 Hz, 1H), 7.45 (d, J = 9.5 Hz, 1H), 3.12
7.8 Hz, 1H), 7.00 (dd, J = 7.8, 1.1 Hz, 1H), 6.93 (d, J = 9.0 Hz, 1H), 3.87 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 150.0, 146.4, 132.5, 129.5, 129.4,
(s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 158.5, 152.9, 138.4, 136.6, 129.3, 126.1, 124.6, 115.8, 115.3, 16.1. FTIR (ZnSe) ν (cm−1): 3000,
124.1, 121.4, 119.6, 111.1, 109.2, 55.4. FTIR (ZnSe) ν (cm−1): 3304, 2864, 2000, 1784, 1765, 1689, 1564, 1409, 1242, 1178, 1057. HRMS
2835, 1615, 1487,1423, 1350, 1256, 1097, 1029, 984, 824. HRMS (ES (ES TOF, m/z) calcd for C11H9N3Na+ ([M+Na]+): 206.0689, found:
TOF, m/z) calcd for C10H11N3NaO+ ([M+Na]+): 212.0790, found: 206.0687 (0.9 ppm).
212.0794 (2.1 ppm).
1-Ethyl-[1,2,4]triazolo[4,3-a]quinoline (3ac). Product 3ac was
obtained via Method A employing 2-hydrazinylquinoline (1a) (159
mg, 1.00 mmol) and 1-nitropropane (2c) (267 mg, 3.00 mmol), and
purified by silica gel column chromatography (ethanol/acetone/
General procedure for the synthesis of triazoles 3, 5, and 7
employing nitroalkanes 2 (method A).
hexane, gradient 1:3:6 –1:4:5, v/v). Dark brown solid, m.p. 127–128
Polyphosphoric acid (1.5 g, 86% P2O5) was combined with corresp-
°C (acetone); yield: 190 mg (0.97 mmol, 97%). Rf = 0.24, ethanol/
onding nitroalkane 2 (3.00 mmol) in a 10 mL Erlenmeyer flask. The
acetone/hexane (1:3:6, v/v). 1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J
mixture was stirred and heated to 130 °C, then corresponding
hydrazine 1, 4 or 6 (1.00 mmol) was added in several portions over a
period of one hour. The resulting mixture was stirred at 130 °C, and
the reaction progress was monitored by TLC analysis. Upon
completion (0.5 – 1.5 hours) the mixture was cooled to rt. Water (5
mL) and 25% aqueous NH4OH solution (3 mL) were added, and the
product was extracted with EtOAc (4 × 5 mL). Combined organic
extracts were dried over sodium sulfate, filtered, and concentrated
= 8.5, 0.9 Hz, 1H), 7.81 (dd, J = 7.8, 1.4 Hz, 1H), 7.67 (ddd, J = 8.5, 7.4,
1.4 Hz, 1H), 7.62 (d, J = 9.5 Hz, 1H), 7.52 (ddd, J = 7.8, 7.4, 0.9 Hz, 1H),
7.49 (d, J = 9.5 Hz, 1H), 3.48 (q, J = 7.4 Hz, 2H), 1.64 (t, J = 7.4 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 151.1, 150.0, 132.3, 129.5, 129.4, 129.4,
126.0, 124.7, 116.1, 115.3, 23.2, 11.4. FTIR (ZnSe) ν (cm−1): 3000,
2940, 1920, 1844, 1772, 1681, 1557, 1428, 1386, 1246, 1049, 943.
+
HRMS (ES TOF, m/z) calcd for C12H12N3 ([M+H]+): 198.1026, found:
198.1023 (1.6 ppm).
in vacuo to afford crude product that was purified by silica gel column
chromatography.
1-Heptyl[1,2,4]triazolo[4,3-a]quinoline (3ad). Product 3ad was
obtained via Method A employing 2-hydrazinylquinoline (1a) (159
mg, 1.00 mmol) and 1-nitrooctane (2b) (477 mg, 3.00 mmol), and
General procedure for the synthesis of triazoles 3 and 7 employing purified by silica gel column chromatography (ethanol/acetone/
-nitroacetophenone (method B).
hexane, gradient 1:1 – pure acetone, v/v). Orange solid, m.p. 79–81
°C (acetone); yield: 227 mg (0.85 mmol, 85%). Rf = 0.32, acetone/
hexane (1:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 8.5 Hz, 1H),
Polyphosphoric acid (1.5 g, 86% P2O5) was combined with
correcponding α-nitroacetophenone 8 (2.00 mmol for reactions with
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7.69 (d, J = 7.3 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 9.5 Hz, 1H), 1-(2-Nitrophenyl)-[1,2,4]triazolo[4,3-a]quinoline (3aiV).iewPrAortdiculecOtn3linaei
7.42 (t, J = 7.5 Hz, 1H), 7.36 (d, J = 9.5 Hz, 1H), 3.32 (t, J = 7.7 Hz, 2H), was obtained via Method B employing 2-DhyOdI:ra10z.i1n0y3lq9/uDin0oOlBin0e10(017aC)
2.00–1.92 (m, 2H), 1.52–1.44 (m, 2H), 1.38–1.29 (m, 2H), 1.29–1.16 (159 mg, 1.00 mmol) and 2-nitro-1-(2-nitrophenyl)ethan-1-one (8i)
(m, 4H), 0.81 (t, J = 6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 150.0, (420 mg, 2.00 mmol). Product was purified by silica gel column
149.8, 132.2, 129.3, 129.2, 129.0, 125.8, 124.5, 115.9, 115.2, 31.6, chromatography (acetone/hexane, gradient 1:2 – 1:1, v/v). Yellow
29.4, 29.3, 28.9, 26.6, 22.5, 14.0. FTIR (ZnSe) ν (cm−1): 3022, 2948, solid, m.p. = 210–212 °C (acetone); yield 211 mg (0.73 mmol, 73%).
2882, 1678, 1637, 1546, 1496, 1451, 1414, 1249. HRMS (ES TOF, m/z) Rf = 0.37, hexane/acetone (1:1, v/v). 1H NMR (400 MHz, DMSO-d6) δ
calcd for C17H22N3+ ([M+H]+): 268.1808, found: 268.1802 (2.4 ppm).
8.43 (dd, J = 7.7, 1.7 Hz, 1H), 7.96–7.85 (m, 2H), 7.83 (d, J = 7.1 Hz,
1H), 7.80–7.73 (m, 2H), 7.65 (d, J = 9.6 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H),
7.37–7.29 (m, 1H), 7.15 (d, J = 8.5 Hz, 1H). 13C NMR (101 MHz, DMSO-
d6) δ 149.1, 148.1, 144.4, 135.1, 133.3, 132.8, 131.2, 130.4, 129.9,
129.8, 126.4, 125.6, 124.4, 124.0, 115.2, 114.5. FTIR (ZnSe) ν (cm−1):
3342, 2989, 2124, 1732, 1654, 1377, 1249, 1051, 1026, 993, 823.
HRMS (ES TOF, m/z) calcd for C16H11N4O2+ ([M+H]+): 291.0880, found:
291.0877 (1.1 ppm).
1-Benzyl-[1,2,4]triazolo[4,3-a]quinoline (3ae). Product 3ae was
obtained via Method A employing 2-hydrazinylquinoline (1a) (159
mg, 1.00 mmol) and (2-nitroethyl)benzene (2e) (453 mg, 3.00 mmol),
and purified by silica gel column chromatography (acetone/hexane,
gradient 1:3 – 1:1, v/v). Pale yellow solid, m.p. 172–174 °C (acetone);
yield: 238 mg, 92%. Rf = 0.31, acetone/hexane (1:1, v/v).1H NMR (400
MHz, CDCl3) δ: 7.99 (dd, J = 7.7, 1.4 Hz, 1H), 7.76 (dd, J = 7.4, 1.9 Hz,
1H), 7.67 (d, J = 9.5 Hz, 1H), 7.52 (d, J = 9.5 Hz, 1H), 7.50–7.42 (m, 2H), 5-Methyl-[1,2,4]triazolo[4,3-a]quinoline (3ba). Product 3ba was
7.30 (t, J = 7.3 Hz, 2H), 7.25–7.18 (m, 3H), 4.92 (s, 2H). 13C NMR (101 obtained via Method A employing 2-hydrazinyl-4-methylquinoline
MHz, CDCl3) δ: 150.5, 147.9, 135.3, 131.8, 129.7, 129.4, 129.4, 129.2 (1b) (173 mg, 1.00 mmol) and nitromethane (2a) (183 mg, 3.00
(2C), 128.2 (2C), 127.4, 126.1, 124.7, 116.7, 115.3, 34.7. FTIR (ZnSe) mmol), and purified by silica gel column chromatography (acetone/
ν (cm−1): 2917, 2864, 1920, 1780, 1644, 1560, 1447, 1318, 1239, hexane, gradient 1:2 – pure acetone, v/v). Dark brown solid, m.p.
+
1072, 996. HRMS (ES TOF, m/z) calcd for C17H14N3 ([M+H]+): 227–228 °C (acetone); yield: 150 mg (0.82 mmol, 82%). Rf = 0.3,
260.1182, found: 260.1185 (1.2 ppm).
acetone. 1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.00 (d, J = 8.2 Hz,
1H), 7.95 (dd, J = 8.1, 0.8 Hz, 1H), 7.72 (ddd, J = 8.2, 7.2, 1.1 Hz, 1H),
7.60 (ddd, J = 8.1, 7.2, 0.8 Hz, 1H), 7.53 (s, 1H), 2.64 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 148.1, 136.9, 134.3, 130.2, 129.8, 126.4, 126.2,
124.2, 115.8, 113.5, 19.6. FTIR (ZnSe) ν (cm−1): 1931, 1753, 1704,
1568, 1504, 1371, 1288, 1246, 1061. HRMS (ES TOF, m/z) calcd for
C11H10N3+ ([M+H]+): 184.0869, found: 184.0870 (0.3 ppm).
1-Phenyl-[1,2,4]triazolo[4,3-a]quinoline (3af).45 Product 3af was
independently obtained via Method A employing 2-hydrazinyl-
quinoline (1a) (159 mg, 1.00 mmol) and (nitromethyl)benzene (2а)
(411 mg, 3.00 mmol). Yield: 29 mg, (0.12 mmol, 12%). Alternatively,
the same compound was obtained via and Method B employing 2-
hydrazineylquinoline (1a) (159 mg, 1.00 mmol) and α-
nitroacetophenone (8f) (330 mg, 2.00 mmol). Yield 210 mg (0.86 1,5-Dimethyl-[1,2,4]triazolo[4,3-a]quinoline (3bb).46 Product 3bb
mmol, 86%). In each case, crude product was purified by silica gel was obtained via Method A employing 2-hydrazinyl-4-methylquin-
column chromatography (acetone/ hexane, gradient 1:2 – 3:2, v/v). oline (1b) (173 mg, 1.00 mmol) and nitroethane (2b) (225 mg, 3.00
The titled material was obtained as orange solid, m.p. 135–137 °C mmol), and purified by silica gel column chromatography (acetone/
(acetone); Rf = 0.34, acetone/hexane (3:2, v/v). 1H NMR (400 MHz, hexane, gradient 1:2 – pure acetone, v/v). Yellow solid, m.p. 194–195
CDCl3) δ 7.77 (dd, J = 7.8, 1.4 Hz, 1H), 7.69–7.64 (m, 3H), 7.62–7.54 °C (acetone); yield: 190 mg (0.86 mmol, 86%). Rf = 0.3, acetone/
(m, 4H), 7.52 (d, J = 8.6 Hz, 1H), 7.43 (ddd, J = 7.8, 7.2, 0.9 Hz, 1H), hexane/ethanol (1:3:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J =
7.31 (ddd, J = 8.6, 7.2, 1.4 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ: 149.9, 8.5 Hz, 1H), 7.93 (dd, J = 8.1, 1.1 Hz, 1H), 7.69 (ddd, J = 8.5, 7.3, 1.1
149.1, 131.9, 130.6, 130.0 (2C), 129.9, 129.5, 129.4, 129.2 (2C), Hz, 1H), 7.59 (dd, J = 8.1, 7.3 Hz, 1H), 7.49 (s, 1H), 3.13 (s, 3H), 2.60
129.1, 126.2, 124.7, 116.8, 115.1. FTIR (ZnSe) ν (cm−1): 3188, 3062, (s, 3H). 13C NMR (101 MHz, CDCl3) δ 149.4, 146.0, 137.0, 132.3, 129.4,
2924, 2858, 1666, 1623, 1448, 1399, 1221, 980. HRMS (ES TOF, m/z) 126.2, 126.2, 125.2, 116.1, 113.9, 19.8, 16.3. FTIR (ZnSe) ν (cm−1):
calcd for C16H12N3+ ([M+H]+): 246.1026, found: 246.1024 (0.6 ppm).
3031, 1920, 1780, 1681, 1628, 1560, 1504, 1458, 1416, 1371, 1246.
+
HRMS (ES TOF, m/z) calcd for C12H12N3 ([M+H]+): 198.1026, found:
1-(4-Methoxyphenyl)-[1,2,4]triazolo[4,3-a]quinoline (3ah). Product
3ah was obtained via Method B employing 2-hydrazinylquinoline
198.1028 (1.3 ppm).
(1a) (159 mg, 1.00 mmol) and 1-(4-methoxyphenyl)-2-nitroethan-1- 1-Ethyl-5-methyl-[1,2,4]triazolo[4,3-a]quinoline (3bc). Product 3bc
one (8h) (390 mg, 2.00 mmol). Product was purified by silica gel was obtained via Method A employing 2-hydrazinyl-4-methylquin-
column chromatography (acetone/hexanes, gradient 1:2 – 3:2, v/v). oline (1b) (173 mg, 1.00 mmol) and 1-nitropropane (2c) (267 mg, 3.00
Colorless solid, m.p. = 135–137 °C (acetone); yield 267 mg (0.97 mmol), and purified by silica gel column chromatography (acetone/
mmol, 97%). Rf 0.29, acetone/hexanes (3:2, v/v). 1H NMR (400 MHz, hexane, gradient 1:2 – pure acetone, v/v). Dark brown solid, m.p.
DMSO-d6) δ 7.11 (d, J = 7.3 Hz, 1H), 6.93 (d, J = 9.6 Hz, 1H), 6.85 (d, J 152–154 °C (acetone); yield: 187 mg (0.87 mmol, 87%). Rf = 0.28,
= 9.5 Hz, 1H), 6.77 (d, J = 8.6 Hz, 2H), 6.68–6.53 (m, 3H), 6.33 (d, J = acetone. 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.5 Hz, 1H), 7.94 (dd,
8.7 Hz, 2H), 3.03 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 160.7, 149.0, J = 8.1, 1.2 Hz, 1H), 7.70 (ddd, J = 8.5, 7.4, 1.2 Hz, 1H), 7.59 (ddd, J =
148.3, 131.5, 131.4(2C), 129.8, 129.5, 129.0, 126.0, 124.2, 121.5, 8.1, 7.4, 0.8 Hz, 1H), 7.53 (s, 1H), 3.47 (q, J = 7.3 Hz, 2H), 2.61 (s, 3H),
115.9, 114.6, 114.5(2C), 55.4. FTIR (ZnSe) ν (cm−1): 3172, 3078, 2548, 1.63 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 150.7, 148.6,
2048, 1680, 1613, 1563, 1536, 1479, 1444, 1400. HRMS (ES TOF, m/z) 139.0, 131.9, 130.0, 126.7, 126.5, 125.4, 116.6, 113.1, 23.5, 19.9,
calcd for C17H14N3O+ ([M+H]+): 276.1131, found 276.1135 (1.5 ppm). 11.3. FTIR (ZnSe) ν (cm−1): 2980, 2888, 2363, 2337, 1737, 1712, 1511,
1454, 1384, 1240, 1170, 1056, 991. HRMS (ES TOF, m/z) calcd for
C13H14N3+ ([M+H]+): 212.1182, found: 212.1183 (0.3 ppm).
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Organic & Biomolecular Chemistry
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1-Heptyl-5-methyl[1,2,4]triazolo[4,3-a]quinoline (3bd). Product 7-Bromo-1,5-dimethyl-[1,2,4]triazolo[4,3-a]quinolineView Article(O3nclbin)e.
3bd was obtained via Method A employing 2-hydrazinyl-4-methyl- Product 3cb was obtained via Method ADOemI: 1p0lo.1y0i3n9g/D60-ObBro0m10o0-72C-
quinoline (1b) (173 mg, 1.00 mmol) and 1-nitrooctane (2b) (477 mg, hydrazinyl-4-methylquinoline (1c) (252 mg, 1.00 mmol) and
3.00 mmol), and purified by silica gel column chromatography nitroethane (2b) (225 mg, 3.00 mmol), and purified by silica gel
(acetone/hexane, gradient 1:2 – 1:1, v/v). Orange solid, m.p. 121– column chromatography (acetone/ethanol, gradient 8:1 –4:1, v/v).
123 °C (acetone); yield: 244 mg (0.85 mmol, 85%). Rf = 0.53, acetone. Colorless solid, m.p. 172–174 °C (acetone); yield: 258 mg (0.93.
1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 8.4 Hz, 1H), 7.93 (dd, J = 8.0, mmol, 93%). Rf = 0.32, acetone/ethanol (4:1, v/v). 1H NMR (400 MHz,
0.9 Hz, 1H), 7.69 (ddd, J = 8.4, 7.4, 0.9 Hz, 1H), 7.58 (dd, J = 8.0, 7.4 CDCl3) δ 8.12 (d, J = 9.0 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.80 (dd, J =
Hz, 1H), 7.50 (s, 1H), 3.41 (t, J = 7.7 Hz, 2H), 2.60 (s, 3H), 2.10–1.94 9.0, 2.0 Hz, 1H), 7.55 (s, 1H), 3.12 (s, 3H), 2.60 (s, 3H). 13C NMR (101
(m, 2H), 1.60–1.48 (m, 2H), 1.46–1.36 (m, 2H), 1.33–1.13 (m, 4H), MHz, CDCl3) δ 149.2, 146.4, 136.0, 132.3, 131.1, 129.0, 127.1, 119.9,
0.87 (t, J = 6.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 149.8, 149.4, 117.6, 115.2, 19.8, 16.2. FTIR (ZnSe) ν (cm−1): 2929, 2864, 1931, 1840,
136.8, 132.2, 129.4, 126.2, 126.1, 125.4, 116.4, 114.1, 31.8, 29.7, 1769, 1674, 1666, 1628, 1560, 1507, 1428. HRMS (ES TOF, m/z) calcd
29.5, 29.1, 26.7, 22.7, 19.8, 14.2. FTIR (ZnSe) ν (cm−1): 3039, 2956, for C12H11BrN3+ ([M+H]+): 276.0131, found: 276.0136 (2.0 ppm).
2874, 2841, 1682, 1637, 1566, 1509, 1459. HRMS (ES TOF, m/z) calcd
7-Bromo-1-ethyl-5-methyl-[1,2,4]triazolo[4,3-a]quinoline
Product 3cc was obtained via Method A employing 6-bromo-2-
(3cc).
for C18H24N3+ ([M+H]+): 282.1965, found: 282.1971 (2.3 ppm).
1-Benzyl-5-methyl-[1,2,4]triazolo[4,3-a]quinoline (3be). Product hydrazinyl-4-methylquinoline (1c) (252 mg, 1.00 mmol) and 1-
3be was obtained via Method A employing 2-hydrazinyl-4-methyl- nitropropane (2c) (267 mg, 3.00 mmol), and purified by silica gel
quinoline (1b) (173 mg, 1.00 mmol) and (2-nitroethyl)benzene (2e) column chromatography (acetone/hexane, gradient 1:2 – pure
(453 mg, 3.00 mmol), and purified by silica gel column chromato- acetone, v/v). Colorless solid, m.p. 184–186 °C (acetone); yield: 116
graphy (acetone/hexane, gradient 1:2 – pure acetone, v/v). Yellow- mg (0.80 mmol, 80%). Rf = 0.26, acetone. 1H NMR (400 MHz, CDCl3)
brown solid, m.p. 125–126 °C (acetone); yield: 236 mg (0.90 mmol, δ: 8.01 (d, J = 9.0 Hz, 1H),7.99 (d, J = 2.1 Hz, 1H), 7.74 (dd, J = 9.0, 2.1
90%). Rf = 0.26, acetone. 1H NMR (400 MHz, CDCl3) δ 8.00–7.95 (m, Hz, 1H), 7.46 (s, 1H), 3.39 (q, J = 7.3 Hz, 2H), 2.54 (s, 3H), 1.61 (t, J =
1H), 7.89–7.82 (m, 1H), 7.51–7.43 (m, 3H), 7.28 (t, J = 7.3 Hz, 2H), 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ: 150.8, 149.5, 135.5, 132.1,
7.24–7.16 (m, 3H), 4.88 (s, 2H), 2.59 (s, 3H). 13C NMR (101 MHz, 131.1, 128.9, 127.2, 119.6, 117.9, 115.5, 23.4, 19.7, 11.4. FTIR (ZnSe)
CDCl3) δ 150.3, 147.5, 136.5, 135.3, 131.6, 129.2 (2C), 129.1, 128.2 ν (cm−1): 2978, 2940, 2861, 2366, 2343, 1920, 1780, 1674, 1553,
+
(2C), 127.3, 125.92, 125.88, 125.2, 116.9, 114.3, 34.8, 19.8. FTIR 1507, 1428, 1375. HRMS (ES TOF, m/z) calcd for C13H13BrN3
(ZnSe) ν (cm−1): 3028, 2884, 1685, 1632, 1519, 1453, 1414, 1383, ([M+H]+): 290.0287, found: 290.0285 (0.6 ppm).
+
1252, 1178. HRMS (ES TOF, m/z) calcd for C18H16N3 ([M+H]+):
7-Bromo-1-heptyl-5-methyl[1,2,4]triazolo[4,3-a]quinoline (3cd).
Product 3cd was obtained via Method A employing 6-bromo-2-
274.1339, found: 274.1341 (0.9 ppm).
Ethyl 5-methyl[1,2,4]triazolo[4,3-a]quinoline-1-carboxylate (3bg). hydrazineyl-4-methylquinoline (1c) (252 mg, 1.00 mmol) and 1-nitro-
Product 3bg was obtained via Method A employing 2-hydrazinyl-4- octane (2b) (477 mg, 3.00 mmol), and purified by silica gel column
methylquinoline (1b) (173 mg, 1.00 mmol) and ethyl 2-nitroacetate chromatography (acetone/hexane, gradient 1:2 – pure acetone, v/v).
(2g) (399 mg, 3.00 mmol), and purified by silica gel column chroma- Pale yellow solid, m.p. 115–116 °C (acetone); yield: 351 mg (0.98
tography (acetone/hexane, gradient 1:2 – 1:1, v/v). Orange solid, mmol, 98%). Rf = 0.29, acetone/hexane (1:1, v/v). 1H NMR (400 MHz,
m.p. 103–105 °C (acetone); yield: 232 mg, 91%. Rf = 0.49, acetone/ CDCl3) δ 8.00–7.96 (m, 2H), 7.75 (d, J = 8.5 Hz, 1H), 7.45 (s, 1H), 3.35
hexane (1:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.88 (d, J = 8.5 Hz, 1H), (t, J = 7.4 Hz, 2H), 2.54 (s, 3H), 2.10–1.89 (m, 2H), 1.58–1.48 (m, 2H),
8.00 (d, J = 8.0 Hz, 1H), 7.74 (dd, J = 8.5, 7.8 Hz, 1H), 7.71–7.63 (m, 1.45–1.34 (m, 2H), 1.36–1.20 (m, 4H), 0.87 (t, J = 6.32 Hz, 3H). 13C
2H), 4.64 (q, J = 7.1 Hz, 2H), 2.70 (s, 3H), 1.55 (t, J = 7.1 Hz, 3H). 13
C
NMR (101 MHz, CDCl3) δ 149.7, 149.5, 134.7, 131.8, 131.0, 128.7,
NMR (101 MHz, CDCl3) δ 159.7, 150.5, 141.6, 140.2, 131.2, 129.9, 127.0, 119.3, 117.7, 115.6, 31.7, 29.0, 29.4, 29.0, 26.5, 22.6, 19.5,
127.4, 125.9, 125.4, 119.7, 113.3, 63.5, 19.9, 14.3. FTIR (ZnSe) ν 14.0. FTIR (ZnSe) ν (cm−1): 3004, 2955, 2845, 1776, 1681, 1663, 1568,
+
(cm−1): 2930, 2851, 1716, 1640, 1435, 1323, 1201. HRMS (ES TOF, 1526, 1466, 1420. HRMS (ES TOF, m/z) calcd for C18H23BrN3
m/z) calcd for C14H13N3NaO2+ ([M+Na]+): 278.0900, found: 278.0905 ([M+H]+): 360.1070, found: 360.1073 (1.0 ppm).
(1.8 ppm).
1-Benzyl-5-methyl-7-bromo-[1,2,4]triazolo[4,3-a]quinoline (3ce).
7-Bromo-5-methyl-[1,2,4]triazolo[4,3-a]quinoline (3ca). Product Product 3ce was obtained via Method A employing 2-hydrazinyl-4-
3ca was obtained via Method A employing 6-bromo-2-hydrazinyl-4- methylquinoline (1b) (173 mg, 1.00 mmol) and (2-nitroethyl)benzene
methylquinoline (1c) (252 mg, 1.00 mmol) and nitromethane (2a) (2e) (453 mg, 3.00 mmol), purified by silica gel column chromato-
(183 mg, 3.00 mmol), and purified by silica gel column chromato- graphy (acetone/hexane, gradient 1:2 – pure acetone, v/v). Colorless
graphy (acetone/hexane, gradient 1:2 –1:1, v/v). Dark violet solid, solid, m.p. 221–223 °C (acetone); yield: 272 mg (0.77 mmol, 77%). Rf
m.p. 280–282 °C (acetone); yield: 166 mg (0.63 mmol, 63%). Rf = 0.48, = 0.22, acetone/hexane (1:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.09
acetone. 1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.40 (d, J = 8.8 (d, J = 2.2 Hz, 1H), 7.95 (d, J = 9.1 Hz, 1H), 7.87 (s, 1H), 7.69 (dd, J =
Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.98 (dd, J = 8.8, 2.0 Hz, 1H), 7.63 (s, 9.1, 2.2 Hz, 1H), 7.36–7.27 (m, 3H), 7.16 (d, J = 6.9 Hz, 2H), 4.91 (s,
1H), 2.57 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 147.1, 136.3, 135.9, 2H), 2.66 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 148.0, 147.5, 133.7,
132.4, 129.2, 128.4, 125.4, 119.0, 118.9, 114.0, 18.8. FTIR (ZnSe) ν 133.2, 129.7, 129.6 (2C), 129.1, 128.1 (2C), 128.0, 127.0, 121.1,
(cm−1): 3110, 2921, 2857, 1947, 1837, 1750, 1674, 1651, 1564, 1469, 120.3, 118.8, 113.4, 34.6, 19.9. FTIR (ZnSe) ν (cm−1): 3000, 2864,
+
1375. HRMS (ES TOF, m/z) calcd for C11H9BrN3 ([M+H]+): 261.9974, 1776, 1655, 1553, 1507, 1379, 1254, 1053, 1004. HRMS (ES TOF, m/z)
found: 261.9968 (2.3 ppm).
calcd for C18H15BrN3+ ([M+H]+): 352.0444, found: 352.0443 (0.2 ppm).
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+
7-Bromo-5-methyl-1-(2-nitrophenyl)-[1,2,4]triazolo[4,3-
a]quinoline (3ci). Product 3ci was obtained via Method B employing 257.1032 (0.3 ppm).
6-bromo-2-hydrazinyl-4-methylquinoline (1c) (159 mg, 1.00 mmol)
(ES TOF, m/z) calcd for C13H13N4O2 ([M+H]+): 257V.1ie0w3A3rt,iclfeoOunnlinde:
DOI: 10.1039/D0OB01007C
1-Heptyl-5-methyl-7-nitro-[1,2,4]triazolo[4,3-a]quinoline
(3dd).
Product 3dd was obtained via Method A employing 2-hydrazinyl-4-
methyl-6-nitroquinoline (1d) (218 mg, 1.00 mmol) and 1-nitrooctane
(2b) (477 mg, 3.00 mmol), and purified by silica gel column chromato-
graphy (acetone/hexane, gradient 1:2 – pure acetone, v/v). Dark
brown solid, m.p. 131–133 °C (acetone); yield: 268 mg (0.82 mmol,
82%). Rf = 0.34, acetone/hexane (1:1, v/v). 1H NMR (400 MHz, CDCl3)
δ 8.86 (d, J = 2.4 Hz, 1H), 8.58 (dd, J = 9.1, 2.4 Hz, 1H), 8.36 (d, J = 9.1
Hz, 1H), 7.74 (s, 1H), 3.46 (t, J = 7.3 Hz, 2H), 2.74 (s, 3H), 2.08–2.05
(m, 2H), 1.61–1.54 (m, 2H), 1.43–1.40 (m, 2H), 1.36–1.28 (m, 4H),
0.89 (t, J = 6.0 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 150.2, 149.6,
144.7, 135.8, 135.5, 126.0, 123.6, 121.7, 117.2, 116.6, 31.7, 29.6,
29.4, 29.0, 26.5, 22.6, 19.6, 14.1. FTIR (ZnSe) ν (cm−1): 2864, 1776,
and 2-nitro-1-(2-nitrophenyl)ethan-1-one (8i) (420 mg, 2.00 mmol).
Product was purified by silica gel column chromatography
(acetone/hexanes, gradient 1:2 – 1:1, v/v). Yellow solid, m.p. = 263–
264 °C (acetone); yield 79 mg (0.70 mmol, 70%). Rf = 0.54, acetone.
1H NMR (400 MHz, DMSO-d6) δ 8.46 (dd, J = 7.8, 1.3 Hz, 1H), 8.21 (d,
J = 2.0 Hz, 1H), 8.12–8.00 (m, 2H), 7.96 (dd, J = 7.2, 1.6 Hz, 1H), 7.77
(s, 1H), 7.69 (dd, J = 9.0, 2.1 Hz, 1H), 7.15 (d, J = 9.0 Hz, 1H), 2.64 (s,
3H). 13C NMR (101 MHz, DMSO-d6) δ 148.8, 148.1, 144.2, 136.7,
135.2, 133.3, 132.9, 132.4, 130.1, 128.8, 126.3, 125.7, 124.1, 119.1,
117.6, 114.4, 19.0. FTIR (ZnSe) ν (cm−1): 2980, 2820, 1613, 1573,
1512, 1493, 1447, 1388, 1132, 743. HRMS (ES TOF, m/z) calcd for
C17H12BrN4O2+ ([M+H]+): 383.0133, found: 383.0138 (1.3 ppm).
5-Methyl-7-nitro-[1,2,4]triazolo[4,3-a]quinoline (3da). Product 3da 1681, 1655, 1545, 1515, 1469, 1333, 1250, 1114. HRMS (ES TOF, m/z)
+
was obtained via Method A employing 2-hydrazinyl-4-methyl-6- calcd for C18H23N4O2 ([M+H]+): 327.1816, found: 327.1815 (0.2
nitroquinoline (1d) (218 mg, 1.00 mmol) and nitromethane (2a) (183 ppm).
mg, 3.00 mmol), and purified by silica gel column chromatography
1-Benzyl-5-methyl-7-nitro-[1,2,4]triazolo[4,3-a]quinoline
(3de).
(acetone/hexane, gradient 1:2 – 1:1, v/v). Dark purple solid, m.p.
324–327 °C (acetone, with decomposion); yield: 138 mg (0.60 mmol,
60%). Rf = 0.30, acetone/hexane (1:1, v/v). 1H NMR (400 MHz, DMSO-
d6) δ 10.04 (s, 1H), 8.77 (d, J = 2.2 Hz, 1H), 8.68 (d, J = 9.1 Hz, 1H),
8.63 (dd, J = 9.1, 2.2 Hz, 1H), 7.77 (s, 1H), 2.68 (s, 3H). 13C NMR (101
MHz, DMSO-d6) δ 147.4, 144.9, 137.0, 136.6, 134.0, 124.3, 123.9,
121.8, 118.5, 114.9, 18.7. FTIR (ZnSe) ν (cm−1): 3099, 2989, 1916,
1787, 1685, 1564, 1534, 1511, 1469, 1390, 1201. HRMS (ES TOF, m/z)
Product 3de was obtained via Method A employing 2-hydrazinyl-4-
methyl-6-nitroquinoline (1d) (218 mg, 1.00 mmol) and (2-nitroethyl)-
benzene (2e) (453 mg, 3.00 mmol), and purified by silica gel column
chromatography (acetone/hexane, gradient 1:2 – pure acetone, v/v).
Yellow solid, m.p. 246–248 °C (acetone); yield: 246 mg (0.77 mmol,
77%). Rf = 0.36, acetone/hexane (1:1, v/v). 1H NMR (400 MHz, CDCl3)
δ 8.84 (d, J = 2.4 Hz, 1H), 8.41 (dd, J = 9.3, 2.4 Hz, 1H), 8.24 (d, J = 9.3
Hz, 1H), 7.91 (s, 1H), 7.40–7.27 (m, 3H), 7.19 (d, J = 7.1 Hz, 2H), 4.98
(s, 2H), 2.77 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 148.5, 148.2, 145.5,
134.4, 133.4, 129.9, 129.7 (2C), 128.2, 128.1 (2C), 126.0, 124.5,
+
calcd for C11H8N4NaO2 ([M+Na]+): 251.0539, found: 251.0538 (0.7
ppm).
1,5-Dimethyl-7-nitro-[1,2,4]triazolo[4,3-a]quinoline (3db). Product 122.0, 118.6, 114.6, 34.8, 20.0. FTIR (ZnSe) ν (cm−1): 3038, 2944,
3db was obtained via Method A employing 2-hydrazinyl-4-methyl-6- 1909, 1772, 1689, 1617, 1568, 1549, 1519, 1428, 1390, 1337. HRMS
nitroquinoline (1d) (218 mg, 1.00 mmol) and nitroethane (2b) (225 (ES TOF, m/z) calcd for C18H15N4O2 ([M+H]+): 319.1190, found:
+
mg, 3.00 mmol), and purified by silica gel column chromatography 319.1191 (0.4 ppm).
(gradient acetone/hexane 1:1 – ethanol/acetone/hexane, 1:2:2, v/v).
Yellow solid, m.p. >300 °C; yield: 234 mg (0.96 mmol, 96%). Rf = 0.31,
1-Ethyl-4-phenyl-[1,2,4]triazolo[4,3-a]quinoline (3ec). Product 3ec
was obtained via Method
A
employing 2-hydrazinyl-3-
ethanol/acetone/hexane (1:4:5, v/v). 1H NMR (400 MHz, DMSO-d6)
δ 8.72 (d, J = 2.2 Hz, 1H), 8.57 (d, J = 9.3 Hz, 1H), 8.54 (dd, J = 9.3, 2.2
Hz, 1H), 7.71 (d, J = 0.9 Hz, 1H), 3.07 (s, 3H), 2.65 (d, J = 0.9 Hz, 3H).
13C NMR (101 MHz, DMSO-d6) δ 149.1, 147.5, 144.8, 137.0, 135.9,
125.4, 124.2, 121.8, 119.0, 115.6, 19.2, 15.8. FTIR (ZnSe) ν (cm−1):
3114, 3034, 2932, 2857, 1844, 1780, 1697, 1560, 1515, 1401, 1356,
phenylquinoline (3e) (235 mg, 1.00 mmol) and 1-nitropropane (2c)
(267 mg, 3.00 mmol), and purified by silica gel column
chromatography (acetone/hexane, gradient 1:2 – 1:1, v/v). Orange
solid, m.p. = 73–74 °C (acetone); yield 242 mg (0.89 mmol, 89%). Rf =
0.46, acetone/ hexane (1:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.14 (d,
J = 8.4 Hz, 1H), 8.06 (d, J = 7.3 Hz, 2H), 7.80 (d, J = 7.7 Hz, 1H), 7.61 (t,
J = 7.7 Hz, 1H), 7.54 (s, 1H), 7.48 (t, J = 7.6 Hz, 3H), 7.42 (t, J = 7.2 Hz,
1H), 3.49 (q, J = 7.3 Hz, 2H), 1.63 (t, J = 7.3 Hz, 3H). 13C NMR (101
+
1220, 1057. HRMS (ES TOF, m/z) calcd for C12H11N4O2 ([M+H]+):
243.0877, found: 243.0874 (1.2 ppm).
1-Ethyl-5-methyl-7-nitro-[1,2,4]triazolo[4,3-a]quinoline
(3dc). MHz, CDCl3) δ 151.5, 149.5, 135.1, 131.6, 129.5, 128.98(2C), 128.96
Product 3dc was obtained via Method A employing 2-hydrazinyl-4- (2C), 128.6 (2C), 128.4, 126.6, 126.0, 125.1, 115.8, 23.2, 11.6. FTIR
methyl-6-nitroquinoline (1d) (218 mg, 1.00 mmol) and 1-nitro- (ZnSe) ν (cm−1): 3050, 2977, 2879, 1709, 1606, 1529, 1494, 1444,
+
propane (2c) (267 mg, 3.00 mmol), and purified by silica gel column 1332, 1227. HRMS (ES TOF, m/z) calcd for C18H16N3 ([M+H]+):
chromatography (acetone/hexane, gradient 1:2 – pure acetone, v/v). 274.1339, found: 274.1342 (1.3 ppm).
Yellow solid, m.p. 236–238 °C (acetone); yield: 230 mg (0.89 mmol,
1-Ethyl-4-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]quinoline (3fc).
89%). Rf = 0.31, acetone. 1H NMR (400 MHz, CDCl3) δ 8.83 (d, J = 2.4
Product 3fc was obtained via Method A employing 2-hydrazinyl-3-(4-
Hz, 1H), 8.54 (dd, J = 9.3, 2.4 Hz, 1H), 8.36 (d, J = 9.3 Hz, 1H), 7.65 (s,
methoxyphenyl)quinoline (1f) (265 mg, 1.00 mmol) and 1-
1H), 3.49 (q, J = 7.3 Hz, 2H), 2.71 (s, 3H), 1.67 (t, J = 7.3 Hz, 3H). 13
C
nitropropane (2c) (267 mg, 3.00 mmol), and purified by silica gel
column chromatography (acetone/hexane, gradient 1:2 – 1:1, v/v).
Yellow solid, m.p. = 146–147 °C (acetone); yield 239 mg, (0.79 mmol,
79%). Rf = 0.42, hexane/acetone (1:1, v/v). 1H NMR (400 MHz, CDCl3)
NMR (101 MHz, CDCl3) δ 151.1, 149.6, 144.8, 136.0, 135.7, 126.0,
123.7, 121.8, 117.3, 116.5, 23.5, 19.7, 11.2. FTIR (ZnSe) ν (cm−1):
1670, 1613, 1545, 1511, 1443, 1394, 1352, 1307, 1231, 1159. HRMS
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δ 8.19 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.7 Hz, 2H), 7.83 (d, J = 8.4 Hz, nitropropane (2c) (267 mg, 3.00 mmol), and purified by silica gel
View Article Online
1H), 7.65 (dd, J = 8.4, 7.5 Hz, 1H), 7.55 (s, 1H), 7.52 (dd, J = 8.5, 7.5 column chromatography (acetone/ethanol, DgrOaId: i1e0n.1t0:3p9u/Dre0aOcBe0t1o0n0e7C–
Hz, 1H), 7.03 (d, J = 8.7 Hz, 2H), 3.87 (s, 3H), 3.54 (q, J = 7.3 Hz, 2H), 1:2, v/v). Colorless solid, m.p. 302–303 °C (ethanol). yield: 206 mg
1.65 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 160.3, 151.4, (0.86 mmol, 86%). Rf = 0.23, acetone; Rf = 0.69, acetone/ethanol (1:2,
149.6, 131.3, 130.2 (2C), 129.3, 128.6, 127.9, 127.4, 126.0, 125.6, v/v). 1H NMR (400 MHz, DMSO-d6) δ 8.34 (d, J = 8.5 Hz, 1H), 8.30 (s,
125.3, 115.8, 114.0 (2C), 55.4, 23.1, 11.5. FTIR (ZnSe) ν (cm−1): 2857, 1H), 8.23 (dd, J = 8.2, 1.5 Hz, 1H), 7.89 (s, 1H), 7.82–7.72 (m, 2H), 7.61
1751, 1648, 1558, 1507, 1474, 1262, 1180, 1105, 1028, 989, 828. (t, J = 7.7 Hz, 1H), 3.49 (q, J = 7.3 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H). 13
HRMS (ES TOF, m/z) calcd for C19H18N3O+ ([M+H]+): 304.1444, found: NMR (101 MHz, DMSO-d6) δ 168.1, 151.3, 148.1, 135.1, 132.1, 129.9,
C
304.1447 (0.8 ppm).
127.5, 126.0, 121.3, 117.0, 113.6, 22.4, 11.2. FTIR (ZnSe) ν (cm−1):
3319, 3166, 2970, 1673, 1561, 1449, 1431, 1383, 1322, 1233. HRMS
(ES TOF, m/z) calcd for C13H13N4O+ ([M+H]+): 241.1084, found:
241.1087 (1.3 ppm). HRMS (ES TOF, m/z) calcd for C13H12N4NaO+
([M+Na]+): 263.0903, found: 263.0904 (0.2 ppm).
1-Ethyl-7,8-dimethoxy-4-phenyl-[1,2,4]triazolo[4,3-a]quinoline
(3gc). Product 3gc was obtained via Method A employing 2-
hydrazinyl-6,7-dimethoxy-3-phenylquinoline (1g) (295 mg, 1.00
mmol) and 1-nitropropane (2c) (267 mg, 3.00 mmol), and purified by
silica gel column chromatography (acetone/hexane, gradient 1:2 – 1-Ethyl-9-methoxy-[1,2,4]triazolo[4,3-a]quinoline (3kc). Product
1:1, v/v). Colorless solid, m.p. 197–198 °C (acetone); yield: 218 mg 3kc was obtained via Method employing 2-hydrazinyl-8-
A
(0.62 mmol, 62%). Rf = 0.49, acetone/hexane (1:1, v/v). 1H NMR (400 methoxyquinoline (1k) (189 mg, 1.00 mmol) and 1-nitropropane (2c)
MHz, DMSO-d6) δ 8.12 (dd, J = 8.7, 1.9 Hz, 2H), 7.89 (s, 1H), 7.71 (s, (267 mg, 3.00 mmol), and purified by silica gel column
1H), 7.58 (s, 1H), 7.53 (t, J = 7.5 Hz, 2H), 7.45 (t, J = 7.3 Hz, 1H), 3.99 chromatography (acetone/hexane, gradient: pure acetone–1:2, v/v).
(s, 3H), 3.89 (s, 3H), 3.56 (q, J = 7.3 Hz, 2H), 1.52 (t, J = 7.2 Hz, 3H). 13
C
Brown oil; yield 102 mg (0.45 mmol, 45%). Rf = 0.43, acetone. 1H NMR
NMR (101 MHz, DMSO-d6) δ 150.6, 150.6, 149.0, 147.6, 135.7, 129.0 (400 MHz, DMSO-d6) δ 7.64 (d, J = 9.4 Hz, 1H), 7.59 (d, J = 9.5 Hz, 1H),
(2C), 128.8 (2C), 128.8, 126.9, 126.2, 124.4, 118.5, 110.5, 99.9, 56.3, 7.57–7.51 (m, 2H), 7.41 (dd, J = 7.4, 2.1 Hz, 1H), 4.02 (s, 3H), 3.33 (q,
56.2, 22.4, 11.9. FTIR (ZnSe) ν (cm−1): 2921, 2844, 1625, 1533, 1489, J = 7.4 Hz, 2H), 1.26 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, DMSO-d6)
1454, 1379, 1252, 1229, 1152. HRMS (ES TOF, m/z) calcd for δ 153.5, 150.2, 149.2, 129.0, 127.0, 126.8, 121.8, 120.7, 115.4, 112.0,
C20H20N3O2+ ([M+H]+): 334.1550, found: 334.1541 (2.8 ppm).
55.5, 23.8, 12.5. FTIR (ZnSe) ν (cm−1): 2974, 1736, 1652, 1571, 1474,
1412, 1319, 1277, 1101, 954, 814. HRMS (ES TOF, m/z) calcd for
C13H14N3O+ ([M+H]+): 228.1131, found: 228.1136 (2.2 ppm).
6-Bromo-1-ethyl-7,8-dimethoxy-4-phenyl-[1,2,4]triazolo[4,3-
a]quinoline (3hc). Product 3hc was obtained via Method A
employing 5-bromo-2-hydrazinyl-6,7-dimethoxy-3-phenylquinoline [1,2,4]Triazolo[4,3-a]pyridine (5a).45 Product 5a was obtained via
(1h) (374 mg, 1.00 mmol) and 1-nitropropane (2c) (267 mg, 3.00 Method A employing 2-hydrazinylpyridine (4) (109 mg, 1.00 mmol)
mmol), and purified by silica gel column chromatography and nitromethane (2a) (183 mg, 3.00 mmol), and purified by silica gel
(acetone/hexane, gradient 1:4 – 1:2, v/v). Colorless solid, m.p. = 191– column chromatography (acetone/hexane, gradient 1:1 – pure
193 °C (acetone); yield: 341 mg,(0.83 mmol, 83%). Rf = 0.26, acetone, v/v). Yellow oil; yield: 83 mg (0.70 mmol, 70%). Rf = 0.38,
acetone/hexane (1:3, v/v). 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J acetone/hexane (1:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H),
= 7.1 Hz, 2H), 7.89 (s, 1H), 7.83 (s, 1H), 7.58–7.43 (m, 3H), 4.08 (s, 8.20 (d, J = 6.9 Hz, 1H), 7.63 (dd, J = 9.3, 0.6 Hz, 1H), 7.16 (ddd, J =
3H), 3.85 (s, 3H), 3.59 (d, J = 7.0 Hz, 2H), 1.53 (t, J = 6.7 Hz, 3H). 13
C
9.3, 6.6, 0.6 Hz, 1H), 6.76 (t, J = 6.6 Hz, 1H). 13C NMR (101 MHz, CDCl3)
NMR (101 MHz, DMSO-d6) δ 153.6, 151.0, 148.4, 144.7, 134.9, 129.0, δ 149.2, 135.7, 127.8, 123.8, 115.9, 114.1. FTIR (ZnSe) ν (cm−1): 3113,
128.9, 128.7 (2C), 128.6 (2C), 125.8, 124.6, 117.4, 117.4, 100.1, 60.3, 2985, 2886, 1736, 1649, 1546, 1517, 1455, 1368, 1253. HRMS (ES
56.4, 22.2, 11.3. FTIR (ZnSe) ν (cm−1): 2935, 1601, 1519, 1475, 1447, TOF, m/z) calcd for C6H6N3+ ([M+H]+): 120.0556, found: 120.0554 (2.2
1400, 1361, 1255, 1243, 1026, 708. HRMS (ES TOF, m/z) calcd for ppm).
C20H19BrN3O2+ ([M+H]+): 412.0655, found 412.0653 (0.6 ppm).
3-Ethyl-[1,2,4]triazolo[4,3-a]pyridine (5c).48 Product 5c was
1-Ethyl-4-nitro-[1,2,4]triazolo[4,3-a]quinoline (3ic). Product 3ic was obtained via Method A employing 2-hydrazinylpyridine (4) (109 mg,
obtained via Method A employing 2-hydrazineyl-3-nitroquinoline (1i) 1.00 mmol) and 1-nitropropane (2c) (267 mg, 3.00 mmol), and
(204 mg, 1.00 mmol) and 1-nitropropane (2c) (267 mg, 3.00 mmol), purified by silica gel column chromatography (acetone/hexane,
and purified by silica gel column chromatography (acetone/hexane, gradient 1:1 – pure acetone, v/v). Yellow solid, m.p. 121–123 °C
gradient 1:5 – 1:1, v/v). Brown solid, m.p. 219–221 °C (ethanol); yield: (acetone); yield: 99 mg (0.71 mmol, 71%). Rf = 0.28, acetone/hexane
165 mg (0.68 mmol, 68%). Rf = 0.22, EtOAc. 1H NMR (400 MHz, (1:1, v/v). 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 8.0 Hz, 1H), 7.70 (d,
DMSO-d6) δ 8.96 (d, J = 3.4 Hz, 1H), 8.40 (d, J = 4.9 Hz, 1H), 8.32 (d, J J = 8.0 Hz, 1H), 7.19 (t, J = 8.7 Hz, 1H), 6.81 (t, J = 8.0 Hz, 1H), 3.07 (d,
= 6.4 Hz, 1H), 7.98 (t, J = 7.5 Hz, 1H), 7.73 (t, J = 6.1 Hz, 1H), 3.51 (d, J J = 7.5 Hz, 2H), 1.49 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
= 4.3 Hz, 2H), 1.51 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 149.9, 147.8, 126.5, 121.8, 116.6, 113.5, 18.2, 10.9. FTIR (ZnSe) ν
152.3, 142.5, 134.9, 133.7, 133.3, 132.4, 129.6, 126.8, 121.4, 117.0, (cm−1): 2993, 2890, 1641, 1521, 1467, 1393, 1228, 1142, 1051. HRMS
22.3, 11.1. FTIR (ZnSe) ν (cm−1): 2991, 2943, 1740, 1633, 1607, 1568, (ES TOF, m/z) calcd for C8H10N3+ ([M+H]+): 148.0869, found: 148.0871
1505, 1451, 1383, 1320, 1283, 1243. HRMS (ES TOF, m/z) calcd for (1.0 ppm).
C12H11N4O2+ ([M+H]+): 243.0877, found: 243.0882 (2.1 ppm).
3-Benzyl[1,2,4]triazolo[4,3-a]pyridine (5e).47 Product 5e was
1-Ethyl-[1,2,4]triazolo[4,3-a]quinoline-5-carboxamide
Product 3jc was obtained via Method
(3jc). obtained via Method A employing 2-hydrazinylpyridine (4) (109 mg,
employing 2- 1.00 mmol) and (2-nitroethyl)benzene (2e) (453 mg, 3.00 mmol), and
A
hydrazinylquinoline-4-carboxamide (1j) (202 mg, 1.00 mmol) and 1- purified by silica gel column chromatography (acetone/hexane,
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gradient 1:1 – pure acetone, v/v). Yellow solid, m.p. 164–166 °C Erlenmeyer flask. This mixture was stirred and heated to 130 °C, then
View Article Online
DOI: 10.1039/D0OB01007C
(acetone); yield: 75 mg (0.41 mmol, 41%). Rf = 0.26, acetone/hexane 2-hydrazinylquinoline (1a) (1.59 g, 10.00 mmol) was added in several
(1:1, v/v). 1H NMR (400 MHz, CDCl3) δ: 7.76–7.71 (m, 2H), 7.33–7.17 portions over a period of one hour. The resulting mixture was stirred
(m, 6H), 6.72 (t, J = 6.7 Hz, 1H), 4.55 (s, 2H). 13C NMR (101 MHz, CDCl3) at 130 °C, and the reaction progress was monitored by TLC analysis.
δ: 150.2, 145.3, 134.5, 129.1 (2C), 128.4 (2C) , 127.4, 127.0, 122.3, Upon completion (1 – 1.5 hours) the mixture was cooled to rt. Water
116.5, 113.7, 31.3. FTIR (ZnSe) ν (cm−1): 3107, 3050, 2884, 2078, (50 mL) and 25% aqueous NH4OH solution (30 mL) were added, and
1777, 1694, 1650, 1611, 1563, 1501, 1471, 1431. HRMS (ES TOF, m/z) the product was extracted with EtOAc (4 × 50 mL). Combined organic
calcd for C13H12N3+ ([M+H]+): 210.1026, found: 210.1027 (0.5 ppm).
extracts were dried over sodium sulfate, filtered, and concentrated
in vacuo to afford crude product that was purified by silica gel column
chromatography (acetone/hexane, gradient 1:2 – 1:1, v/v). Yield 2.06
g (7.10 mmol, 71%).
Ethyl [1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (5g). Product 5g
was obtained via Method A employing 2-hydrazinylpyridine (4) (109
mg, 1.00 mmol) and 2-nitroacetate (2g) (399 mg, 3.00 mmol), and
purified by silica gel column chromatography (acetone/hexane, Procedure for gram-scale synthesis of triazole 3ac.
gradient 1:1 – pure acetone, v/v). Pale orange solid, m.p. 120–122 °C
(acetone); yield: 80 mg (0.42 mmol, 42%). Rf = 0.32, acetone/hexane
(1:1, v/v). 1H NMR (400 MHz, CDCl3) δ 9.14 (d, J = 7.0 Hz, 1H), 7.94 (d,
J = 9.2 Hz, 1H), 7.48 (dd, J = 8.6, 7.3 Hz, 1H), 7.11 (t, J = 7.3 Hz, 1H),
4.54 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
Polyphosphoric acid (10 g, 86% P2O5) was combined with 1-
nitropropane (2c) (2.67 g, 30.00 mmol) in a 25 mL Erlenmeyer flask.
The mixture was stirred and heated to 130 °C, then 2-
hydrazinylquinoline 1a (1.59 g, 10.00 mmol) was added in several
portions over a period of one hour. The resulting mixture was stirred
at 130 °C, and the reaction progress was monitored by TLC analysis.
Upon completion (0.5 – 1.5 hours) the mixture was cooled to rt.
Water (50 mL) and 25% aqueous NH4OH solution (30 mL) were
CDCl3) δ 158.4, 151.4, 137.8, 129.5, 126.0, 116.6, 116.2, 62.5, 14.4.
FTIR (ZnSe) ν (cm−1): 3003, 2924, 2858, 1980, 1699, 1636, 1455, 1316,
1237, 1052, 762. HRMS (ES TOF, m/z) calcd for C9H10N3O2+ ([M+H]+):
192.0768, found: 192.0769 (0.9 ppm).
added, and the product was extracted with EtOAc (4 × 50 mL).
3,9-Diethyl-5-methylbis[1,2,4]triazolo[4,3-a:4',3'-c]pyrimidine (7c). Combined organic extracts were dried over sodium sulfate, filtered,
Product 7c was obtained via Method A employing 2,4-dihydrazinyl- and concentrated in vacuo to afford crude product that was purified
6-methylpyrimidine (6) (154 mg, 1.00 mmol) and 1-nitropropane (2c) by silica gel column chromatography (ethanol/acetone/ hexane,
(267 mg, 3.00 mmol), and purified by silica gel column chromato- gradient 1:3:6 –1:4:5, v/v). Yield 1.79 g (9.08 mmol, 91 %).
graphy (acetone/hexane, gradient 1:1 – pure acetone, v/v). Off-white
solid, m.p. 204–205 °C (acetone); yield: 168 mg (0.73 mmol, 73%). Rf
= 0.44, acetone. 1H NMR (400 MHz, CDCl3) δ 6.80 (s, 1H), 3.49 (q, J =
Detection of neurite outgrowth.
Human neuroblastoma cell line BE(2)-C cells were grown in DMEM /
F-12 (Corning Cellgro) supplemented with 10% Equafetal bovine
serum (Atlas Biologicals). 1,000 cells were plated and treated in 96-
well plates with different concentration of compounds in triplicates
for 4 days. Cell images were taken under 20X magnification using
IncuCyte ZOOM Live Cell Imaging System (Essen BioScience). Neurite
7.5 Hz, 2H), 3.21 (q, J = 7.4 Hz, 2H), 2.77 (s, 3H), 1.52 (dt, J = 10.3, 7.4
Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 152.0, 150.9, 146.5, 143.2,
135.7, 101.8, 22.0, 20.3, 19.7, 11.9, 11.6. FTIR (ZnSe) ν (cm−1): 2984,
2879, 1781, 1724, 1698, 1650, 1545, 1506, 1466, 1431, 1379, 1340.
+
HRMS (ES TOF, m/z) calcd for C11H15N6 ([M+H]+): 231.1353, found:
lengths were analyzed in the acquired images using the neurite
231.1354 (0.4 ppm).
definition defined by NeuroTrack system (Essen BioScience) as
described previously.25
5-Methyl-3,9-diphenylbis([1,2,4]triazolo)[4,3-a:4',3'-c]pyrimidine
(7f). Product 7f was obtained via Method A employing 2,4-
dihydrazinyl-6-methylpyrimidine (6) (154 mg, 1.00 mmol) and
(nitromethyl)benzene (2f) (411 mg, 3.00 mmol), yield: 23 mg, (0.07
Conflicts of interest
mmol, 7%). Alternatively, the same compound was obtained via
There are no conflicts to declare.
Method B employing 2,4-dihydrazineyl-6-methylpyrimidine (6) (154
mg, 1.00 mmol) and α-nitroacetophenone (8f) (660 mg, 4.00 mmol),
228 mg (0.70 mmol, 70%). In each case the crude product was
purified by silica gel column chromatography (acetone/hexane,
Acknowledgements
This work was supported by the Russian Foundation for Basic
Research (grant #18-33-20021 mol_a_ved) and the Ministry of
Education and Science of the Russian Federation (grant #0795-2020-
0031). AK and LD acknowledge the National Institutes of Health
(grants 1R15CA227680-01A1 and 1R15CA213199-01A1).
gradient 1:2 – 1:1, v/v). Orange solid, m.p. 135–137 °C (acetone); Rf
= 0.71, acetone/hexane (1:1, v/v). 1H NMR (400 MHz, CDCl3) δ 8.38
(dd, J = 6.5, 3.1 Hz, 2H), 7.66–7.59 (m, 3H), 7.57 (d, J = 6.7 Hz, 2H),
7.54–7.50 (m, 3H), 6.92 (s, 1H), 2.25 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 165.9, 149.9, 149.1, 144.5, 138.4, 131.3, 131.0 (2C), 130.8,
129.6, 128.9 (2C), 128.7 (2C), 127.7 (2C) , 127.6, 103.1, 20.7. FTIR
(ZnSe) ν (cm−1): 2930, 2864, 1745, 1660, 1445, 1397, 1247. 973.
HRMS (ES TOF, m/z) calcd for C19H14N6Na+ ([M+Na]+): 349.1172,
found: 349.1179 (1.8 ppm).
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