Multicomponent One-Pot Synthesis of 3-Tetrazolyl and 3-Imidazo[1,2-a]pyridin Tetrazolo[1,5-a]quinolines

Article abstract of DOI:10.1021/acs.joc.6b01576

A series of 18 3-tetrazolyl-tetrazolo[1,5-a]quinolines were synthesized in 21-90% yields via a novel one-pot Ugi-azide/S_NAr/ring-chain azido-tautomerization process. We report also the synthesis of 10 3-imidazo[1,2-a]pyridin-tetrazolo[1,5-a]quinolines in 28-94% yields via a novel one-pot Groebke-Blackburn-Bienaymé/S_NAr/ring-chain azido-tautomerization process. Both synthetic strategies involve the use of microwaves or ultrasound, and catalyst-free conditions. Finally, we show the synthesis of the tetrazolo[1,5-a]quinoline-3-carbaldehyde and tetrazolo[1,5-a]quinoline-3-dimethyl acetal at room temperature in methanol as solvent.

Full text of DOI:10.1021/acs.joc.6b01576

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Note
Multicomponent one pot synthesis of 3-tetrazolyl and
3-imidazo[1,2-a]pyridin tetrazolo[1,5-a]quinolines
Murali Venkata Basavanag Unnamatla, Alejandro Islas-Jácome, Andrea Quezada-
Soto, Sandra C. Ramírez-López, Marcos Flores-Alamo, and Rocio Gamez-Montano
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01576 • Publication Date (Web): 25 Aug 2016
Downloaded from http://pubs.acs.org on August 26, 2016
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Multicomponent one pot synthesis of 3-tetrazolyl and 3-imidazo[1,2-a]pyridin tetrazolo[1,5-a]quinolines
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M. V. Basavanag Unnamatla,† Alejandro Islas-Jácome,† Andrea Quezada-Soto,† Sandra C. Ramírez-López,† Marcos
Flores-Álamo,§ Rocío Gámez-Montaño†,*
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† Departamento de Química, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta S/N,
Col. Noria Alta, Guanajuato, C.P. 36050, Gto., México
§ Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior S/N, Ciudad Universitaria,
Coyoacán, C.P. 04510, CDMX, México.
* Corresponding author’s e-mail address: rociogm@ugto.mx
Table of Contents / Abstract Graphic
ABSTRACT
A series of eighteen 3-tetrazolyl-tetrazolo[1,5-a]quinolines were synthesized in 21 to 90% yields via a novel one pot
Ugi-azide / SNAr / ring-chain azido-tautomerization process. We report also the synthesis of ten 3-imidazo[1,2-
a]pyridin-tetrazolo[1,5-a]quinolines in 28 to 94% yields via a novel one pot Groebke-Blackburn-Bienaymé / SNAr /
ring-chain azido-tautomerization process. Both synthetic strategies involve the use of microwaves or ultrasound, and
catalyst-free conditions. Finally, we show the synthesis of the tetrazolo[1,5-a]quinoline-3-carbaldehyde and
tetrazolo[1,5-a]quinoline-3-dimethyl acetal at room temperature in methanol as solvent.
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Bis-heterocycles are compounds containing two fused, merged, linked, or bound heterocyclic moieties.1 These
molecules have attracted much attention of scientific community from various fields such as agrochemistry, materials
science, optics, medicinal chemistry, and others emerging areas.2,3 In this note, we report the one pot synthesis of
novel unsymmetrical bis–heterocycles containing the tetrazolo[1,5-a]quinoline core bound with either, 1,5-
disubstituted-tetrazole (1,5-DS-T) or imidazo[1,2-a]pyridine frameworks.
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Tetrazolo[1,5-a]quinoline is the core of various compounds with interesting pharmacological properties, for example,
anti-cancer,4 anti-fungal,5 anti-bacterial,6 and anti-inflammatory.6 Particularly, there is a tetrazolo[1,5-a]quinoline
bound with a tetrazole ring, which exhibited anti-allergic activity.7 Moreover, 1,5-DS-T’s are considered metabolic
resistant bioisosters of the cis-amide bond of peptides by adopting their effective biological conformations.8-9 Thus,
1,5-DS-T is the core of numerous bioactive products.10 As examples, Cefamandole and Latamoxeb, which are second-
and third-generation cephalosporin antibiotics, respectively.11 Besides, imidazo[1,2-a]pyridine framework is present
also in a plethora of drugs, but mainly in various treatments of brain diseases and CNS-related disorders.12 For
example, the zolpidem, which is the most prescribed drug for insomnia.13
The general method to synthesize tetrazolo[1,5-a]quinolines involves a two-step process SNAr / ring-chain azido-
tautomerization using as starting reagents sodium azide and 2-chloroquinolines prepared stepwise.14 Besides, 1,5-DS-
T are synthesized using click reactions between organic azides and nitriles, both usually synthesized stepwise.15 In
the same context, there are various reported methods to synthesize imidazo[1,2-a]pyridines, generally form precursors
prepared stepwise.16 However, the Ugi-azide and the interrupted variant of the Ugi-4CR known as Groebke-
Blackburn-Bienaymé (GBB) reaction are the current and most efficient methods to synthesize 1,5-DS-T17 and
imidazo[1,2-a]pyridines,18 respectively.
As far as we know, the synthesis of unsymmetrical bis-heterocycles containing the tetrazolo[1,5-a]quinoline
framework bound either, with 1,5-DS-T or imidazo[1,2-a]pyridine moieties have not been reported using MCR or
any other stepwise method. However, there is a previous work by Ghandi et al. describing the synthesis of 3-
tetrazolyl-2-chloroquinolines in 65 to 85% yields via Ugi-azide reaction (Scheme 1a).19
Thus, according to our ongoing program to develop Ugi-azide based methods toward bis-heterocycles containing 1,5-
DS-T rings,20-24 we report the first synthesis of 3-tetrazolyl-tetrazolo[1,5-a]quinolines and 3-imidazo[1,2-a]pyridin-
tetrazolo[1,5-a]quinolines via one pot Ugi-type / SNAr / ring-chain azido-tautomerization processes (Scheme 1b-c).
In the same context, we developed a new one pot method to synthesize the tetrazolo[1,5-a]quinoline-3-carbaldehyde
either, as aldehyde or protected as dimethyl acetal (Scheme 1d). This latter masked aldehyde can be used for further
transformations, in which the tetrazolo[1,5-a]quinoline system is required.
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Scheme 1. Synthetic strategies
The N-((1-cyclohexyl-1H-tetrazol-5-yl)(tetrazolo[1,5-a]quinolin-4-yl)methyl)prop-2-en-1-amine (1a) was selected
as model to optimize reaction conditions (Table 1). Thus, 2-chloroquinoline-3-carbaldehyde (2) was combined
sequentially with one equivalent of aniline (3a), two equivalents of azidotrimethyilsilane (4), and one equivalent of
cyclohexyl isocyanide (5a) using the Ugi-azide standard conditions (MeOH, rt) as starting point. The product 1a was
isolated in 18% yield, together with products 6a and 7 in 40 and 16% yields respectively (Entry 1, Table 1). Then,
we decided to study the effect of temperature because it has been reported that ring-chain azido-tautomerization is
favored to cyclic tautomer (tetrazole) by using high temperatures.25 Thus, the reaction was performed in methanol at
reflux, but the product 1a was synthesized in 55% yield, together with 6a and 7 in 10 and 4% yields respectively
(Entry 2, Table 1). In this context, we used microwaves (MW) as heat source in order to reduce the reaction time and
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eventually to increase the yields. The product 1a was synthesized in 75% yield without by-products (Entry 3, Table
1). Only traces of the corresponding Schiff base (formed by condensation of 2-chloroquinoline-3-carbaldehyde (2)
with aniline (3a)) were observed. A further experiment was performed increasing temperature to 110 °C by MW, but
the yield was 68% without by-products (Entry 4, Table 1). Finally, an experiment was performed using ultrasound
(US) irradiation (or sonication), but the yield was 44% without by-products (Entry 5, Table 1). It is important to
mention that a change in the order of addition was done (TMSN3 (4) after isocyanide 5a) using the optimal conditions
of Entry 3, but the yield remained without changes. This latter observation gave us elements to propose a plausible
reaction mechanism (See the supporting information for further details).
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Table 1. Screening conditions
Yieldc (%)
Entry T (°C) t (h)
1a
18
55
75
68
44
6a
40
7
1
2
3
4
5
rt
85
85a
110a
60b
24
12
1
1
2
16
10
-
4
-
-
-
-
-
a
c
MW (100 W). b US (42 kHz).
Measured after purification.
By using optimal conditions for the two irradiation methods (MW and US), we synthesized the 3-tetrazolyl-
tetrazolo[1,5-a]quinolines 1a-r (Table 2). As seen, good substrate scope was found. The stereoelectronic nature of
substituents in starting materials varies from alkyl to aryl and benzyl substituents in isocyanide moiety. Besides,
amines with a variety in their stereoelectronic nature (aromatic, aliphatic, allylic, propargylic, benzylic and
heterocyclic) were also explored to synthesize a set of eighteen final products. With respect to MW heating method,
higher yields were observed for 3,4-dimethoxyphenethyl isocyanide derivatives (1f, 88 and 1l, 90%) while the lowest
was for the cyclohexyl isocyanide derivative (1r, 65 %), which contains furfuryl as substituent coming from the
amine moiety. As seen, similar results were found using US irradiation because higher yields were observed for 3,4-
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dimethoxyphenethyl isocyanide derivatives (1f, 51 and 1l, 54%), while the lowest was also for the cyclohexyl
isocyanide derivative (1r, 21 %) containing furfuryl ring. Overall, the yields obtained in MW assisted reactions were
higher (33-90%) with respect to those observed using sonication (21-54%). Besides, it is noteworthy that compounds
6a-r can be synthesized using only one equivalent of TMSN3 instead two, but the tetrazolo[1,5-a]quinoline-3-
dimethyl acetal 7 will be formed as by-product. Adequate crystals for X-ray analysis of compounds 1b (CCDC:
1431691) and 6b (CCDC: 1482686) were obtained.
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Table 2. Substrate scope
Compound R1
R2
Ph
Ph
Ph
Ph
Ph
Yieldi (%)
75
88
62
84
65
88
Yieldii (%)
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38
27
47
29
51
1a
1b
1c
1d
1e
1f
c-Hex
t-Bu
4-OMePh
Bn
4-OMeBn
3,4-diMePhEt Ph
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1h
1i
1j
1k
1l
c-Hex
t-Bu
4-OMePh
Bn
4-OMeBn
3,4-diMePhEt Allyl
Allyl
87
78
65
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81
90
44
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34
39
54
Allyl
Allyl
Allyl
Allyl
1m
1n
1o
1p
1q
1r
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
c-Hex
Propargyl
Bn
4-OMeBn
n-Bu
c-Hex
74
61
57
51
41
33
35
32
30
33
26
21
furfuryl
i MeOH [1 M], MW (85 °C, 100 W), 1 h.
ii MeOH [1 M], US (60 °C, 42 kHz), 2 h.
Continuing with our study, we selected the N-cyclohexyl-2-(tetrazolo[1,5-a]quinolin-4-yl)imidazo[1,2-a]pyridin-3-
amine (8a) as model to optimize the one pot process GBB / SNAr / ring-chain azido-tautomerization. Thus, 2-
chloroquinoline-3-carbaldehyde (2) was combined sequentially with one equivalent of all, 2-aminopyridine (9a),
cyclohexyl isocyanide (5a), and azidotrimethylsilane (4) in methanol [1 M] at room temperature (Entry 1, Table 3).
The bis-heterocycle 8a was isolated in 25% yield, together with product 10a and the tetrazolo[1,5-a]quinoline-3-
dimethyl acetal (7), in 30 and 18% yields respectively. It is noteworthy that adequate crystals for x-ray analysis of
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compound 8a (CCDC: 1470205) were obtained. Then, according to our previous observations, we decided to conduct
the process at reflux, but the compound 8a was synthesized in 82% yield after 12 hours without by-products (Entry
2, Table 3). The reaction was performed using microwaves as heat source, yielding 94% after 1 hour. A further
experiment was conducted increasing temperature to 110 °C, but the product 8a was isolated in 76% yield (Entry 4,
Table 3). Finally, an experiment was performed under US irradiation, but the yield was 47% without by-products
(Entry 5, Table 1). Besides, an experiment to synthesize exclusively the compound 10a was conducted using
conditions of entry 3, but without addition of trimethylsylilazide (4). Compound 10a was isolated in quantitative
yield. The plausible reaction mechanism can be found in the Supporting Information File.
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Table 3. Screening conditions
Yieldc (%)
Entry Solvent T (°C) t (h)
8a
25
10a 7a
1
2
3
4
5
MeOH
MeOH
MeOH
MeOH
MeOH
rt
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85a
110a
60b
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-
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-
82
94
76
47
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-
a MW (100 W). b US (42 kHz).
c Measured after purification.
By using optimized conditions for the two irradiation methods (MW and US), we synthesized the series of 3-
imidazo[1,2-a]pyridin-tetrazolo[1,5-a]quinolines 8a-l (Table 4). As seen, good to excellent yields were obtained (67-
94%) under MW heating conditions, and moderate to good yields (28-69%) under sonication. It is noteworthy that
products 8f and 8k could not be synthesized. We calculated minimal energy conformations for both compounds by
Density Functional Theory at M06–2X/6–311G(d) level of theory (See the supporting information for further details).
Compound 8f was not synthesized due to the steric hindrance between the bulky tert-butyl moiety and bromine atom
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coming from the 6-bromo-2-aminopyridine moiety. There is a previous study by us regarding this type of behavior
for the GBB reaction involving similar substituents.26 Respect to the non-synthesized product 8k, there is also a strong
steric strain between tetrazolo[1,5-a]quinoline moiety and the N-H coming from the isocyanide moiety.
Table 4. Substrate scope
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Compound R1
R3 R4
Yieldi (%)
Yieldii (%)
8a
8b
8c
8d
8e
8f
c-Hex
t-Bu
4-OMePh
Bn
c-Hex
t-Bu
H
H
H
H
Br
Br
Br
Br
H
H
H
H
H
H
H
H
H
94
86
79
91
89
0
47
55
44
54
69
0
31
34
59
28
0
8g
8h
8i
4-OMePh
Bn
c-Hex
t-Bu
67
77
OBn 75
OBn 65
8j
H
8k
8l
4-OMePh
Bn
H
OBn
0
H
OBn 69
32
i MeOH [1 M], MW (85 °C, 100 W), 1 h.
ii MeOH [1 M], US (60 °C, 42 kHz), 2 h.
To conclude the work, we show the synthesis of the tetrazolo[1,5-a]quinoline-3-dimethyl acetal (7) in quantitative
yield. 2-chloroquinoline-3-carbaldehyde (2) was used as starting reagent and methanol as solvent via SNAr / ring-
chain azido-tautomerization process with azidotrimethylsilane (4) to give the tetrazolo[1,5-a]quinoline-3-
carbaldehyde (11), which undergoes a hydrazoic acid-catalyzed protection of the aldehyde functional group via
nucleophilic addition (Scheme 2). As seen, tetrazolo[1,5-a]quinoline-3-cabaldehyde (11) can be prepared using 1
equiv. of TMSN3 in 1 hour and the tetrazolo[1,5-a]quinoline-3-dimethyl acetal (7) adding 1 equiv. more of TMSN3
to 11 in one hour more, or in one pot manner from 2-chloroquinoline-3-carbaldehyde (2)using 2 equiv. of TMSN3 in
2 hours. Protection of aldehyde moiety depends on the amount of HN3 (formed by proton exchange between MeOH
and TMSN3 (4)). Conditions to synthesize 7 are greener in comparison to current reported methodologies, which are
stepwise and involve the use of harsh conditions like high temperatures and metallic Lewis catalysts in longer reaction
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time.27 Adequate crystals for X-ray analysis of the tetrazolo[1,5-a]quinoline-3-dimethyl acetal (7) (CCDC: 1482685)
5
were obtained.
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Scheme 2. Synthesis of tetrazolo[1,5-a]quinoline-3-dimethyl acetal and its non-protected analog
As conclusions, methodologies herein described are sustainable processes with potential application in the synthesis
of bis-heterocycles containing the tetrazolo[1,5-a]quinoline framework from complex precursors prepared in situ in
one pot manner. The most important feature of this work lies in the development of novel strategies in which MCR
reactions as Ugi-azide and GBB were combined with cascade SNAr / ring-chain azido-tautomerization processes
taking place in mild and green conditions toward bis-heterocycles type tetrazolo[1,5-a]quinolines containing both,
1,5-DS-T and imidazo[1,2-a]pyridine moieties. The synthesis of bis-heterocycles involved the combination of three
processes: Ugi-type / SNAr / ring-chain azido tautomerization to introduce high complex substituents at C-5 position
of tetrazoles, C-3 of imidazo[1,2-a]pyridines and in C-3 of tetrazolo[1,5-a]quinolines. Reactions performed under
microwave heating conditions gave higher yields than those using sonication.
EXPERIMENTAL SECTION
1
General Information. H and 13C NMR spectra were acquired on 400 or 500 MHz spectrometers. The solvent for
NMR samples was CDCl3. Chemical shifts are reported in parts per million (δ/ppm). Internal reference for NMR
spectra is TMS at 0.00 ppm. Coupling constants are reported in Hertz (J/Hz). Multiplicities of the signals are reported
using the standard abbreviations: singlet (s), doublet (d), triplet (t), quartet (q) and multiplet (m). IR spectra were
recorded by ATR method using neat compounds. The wavelengths are reported in reciprocal centimeters (max /cm-
1). HRMS spectra were acquired via electrospray ionization ESI (+) and recorded via the TOF method. Reactions at
reflux were performed using a recirculation system mounted on a sand bath with electronic temperature control.
Microwave assisted reactions were performed in closed vessel mode using a CEM Discover™ monomodal MW
reactor without pressure sensor. Ultrasound irradiated reactions were performed using a recirculation system mounted
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into bath of a Branson 1510 sonicator cleaner working at 42 kHz ±6% frequencies. The reaction progress was
monitored by TLC and the spots were visualized under UV light (254 or 365 nm). Flash column chromatography was
performed using silica gel (230-400 mesh) and mixtures in different proportions of hexanes with ethyl acetate as
mobile phase. Melting points were determined on a Fisher-Johns apparatus and were uncorrected. Purity degree is
documented product-by-product qualitatively with copies of all NMR spectra. Commercially available reagents were
used without further purification. Solvents were distilled and dried according to standard procedures.
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Procedure (i) to synthesize the products 1a-r (MW): In a vial (10 mL) equipped with a magnetic stirring bar
containing a solution of 2-chloroquinoline-3-carbaldehyde (0.52 mmol, 1.0 equiv.) in anhydrous MeOH [1.0 M], were
added sequentially the corresponding amine (0.52 mmol, 1.0 equiv.), azidotrimethylsilane (1.56 mmol, 3.0 equiv.)
and the corresponding isocyanide (0.52 mmol, 1.0 equiv.). Then, the vial was closed and the reaction mixture was
MW-heated at 85 oC (100 W) for 1 hour. The solvent was removed until dryness and the crude was purified by silica-
gel column chromatography using mixtures of hexanes with ethyl acetate (7/3; v/v) to afford products 1a-r.
Procedure (ii) to synthesize the products 1a-r (US): In a round-bottomed flask (10 mL) equipped with condenser
containing a solution of 2-chloroquinoline-3-carbaldehyde (0.52 mmol, 1.0 equiv.) in anhydrous MeOH [1.0 M], were
added sequentially the corresponding amine (0.52 mmol, 1.0 equiv.), azidotrimethylsilane (1.56 mmol, 3.0 equiv.)
and the corresponding isocyanide (0.52 mmol, 1.0 equiv.). Then, the flask was closed and the reaction mixture was
sonicated at 60 oC (45 kHz) for 2 hours. Then, the solvent was removed until dryness and the crude was purified by
silica-gel column chromatography using mixtures of hexanes with ethyl acetate (7/3; v/v) to afford products 1a-r.
Procedure (i) to synthesize the products 8a-l (MW): In a vial (10 mL) equipped with a magnetic stirring bar
containing a solution of 2-chloroquinoline-3-carbaldehyde (0.51 mmol, 1.0 equiv.) in anhydrous MeOH [1 M], were
added sequentially the corresponding amine (0.52 mmol, 1.0 equiv.), the corresponding isocyanide (0.52 mmol, 1.0
equiv.), and azidotrimethylsilane (1.56 mmol, 3.0 equiv.). Then, the vial was closed and the reaction mixture was
MW-heated at 85 oC (100 W) for 1 hour. Then, the solvent was removed until dryness and the crude was purified by
silica-gel column chromatography using mixtures of hexanes with ethyl acetate (7/3; v/v) to afford products 8a-l.
Procedure (ii) to synthesize the products 8a-l (US): In a round-bottomed flask (10 mL) equipped with condenser
containing a solution of 2-chloroquinoline-3-carbaldehyde (0.51 mmol, 1.0 equiv.) in anhydrous MeOH [1 M], were
added sequentially the corresponding amine (0.52 mmol, 1.0 equiv.), the corresponding isocyanide (0.52 mmol, 1.0
equiv.), and azidotrimethylsilane (1.56 mmol, 3.0 equiv.). Then, the flask was closed and the reaction mixture was
sonicated at 60 oC (45 kHz) for 2 hours. Then, the solvent was removed until dryness and the crude was purified by
silica-gel column chromatography using mixtures of hexanes with ethyl acetate (7/3; v/v) to afford products 8a-l.
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Procedure to synthesize the product 7: In a round-bottomed flask (10 mL) equipped with a magnetic stirring bar
containing a solution of 2-chloroquinoline-3-carbaldehyde (0.52 mmol, 1.0 equiv.) in anhydrous MeOH [1.0 M] under
argon atmosphere at room temperature, were added 2 equiv. of azidotrimethylsilane (0.52 mmol, 1.0 equiv.). The
flask was closed and the reaction mixture was stirred at room temperature for 2 hours. Then, the solvent was removed
until dryness and the crude was recrystallized using a cold mixture of hexanes with diethyl ether (1/1; v/v) to afford
the product 7.
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N-((1-cyclohexyl-1H-tetrazol-5-yl)(tetrazolo[1,5-a]quinolin-4-yl)methyl)aniline (1a): Pale brown solid (83.0 mg,
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75%, MW) (45.4 mg, 41%, US); mp = 174–175 °C; Rf = 0.40 (Hexanes-AcOEt = 7/3 v/v); H NMR (500 MHz,
CDCl3): δ 8.69 (d, J = 8.4 Hz, 1H), 8.14 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.89–7.83 (m, 1H), 7.72–7.65 (m, 1H),
7.54–7.46 (m, 1H), 7.17–7.07 (m, 2H), 6.75–6.68 (m, 1H), 6.56 (d, J = 7.8 Hz, 1H), 5.71–5.67 (m, 1H), 5.62–5.57
(m, 1H), 3.75–3.64 (m, 1H), 1.97–1.92 (m, 1H), 1.75–1.70 (m, 1H), 1.62–1.56 (m, 2H), 1.55–1.47 (m, 2H), 1.39–
1.28 (m, 2H), 1.22–1.15 (m, 1H), 1.05–0.99 (m, 1H); 13C{1H} NMR (126 MHz, CDCl3): δ 153.4, 146.4, 144.7, 131.5,
131.3, 130.2, 129.7, 129.4, 128.3, 128.1, 123.9, 123.8, 123.6, 123.3, 119.8, 116.8, 116.7, 114.0, 58.7, 54.4, 33.5, 32.8,
25.2 (2), 24.8; FT-IR (ATR)vmax/cm-1 3287.4 (N-H), 1602.0 (C=N), 1256.1 (N-N=N); HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C23H24N9 426.2149; Found 426.2153.
N-((1-(tert-butyl)-1H-tetrazol-5-yl)(tetrazolo[1,5-a]quinolin-4-yl)methyl)aniline (1b): White solid (183.0 mg,
1
88%, MW) (79.0 mg, 38%, US); mp = 166–168 °C; Rf = 0.36 (Hexanes-AcOEt = 7/3 v/v); H NMR (500 MHz,
CDCl3): δ 8.65 (d, J = 8.4 Hz, 1H), 8.24 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.89–7.83 (m, 1H), 7.71–7.65 (m, 1H),
7.21–7.14 (m, 2H), 6.92 (d, J = 8.7 Hz, 1H), 6.83–6.78 (m, 1H), 6.76 (d, J = 7.9 Hz, 2H), 4.93 (d, J = 8.9 Hz, 1H),
1.92 (s, 9H), 1.64 (bs, 1H); 13C{1H} NMR (126 MHz, CDCl3): δ 153.4, 146.7, 144.6, 131.3, 131.1, 130.4, 129.8,
129.7, 129.6, 128.7, 128.2, 123.9, 123.6, 119.9, 116.7, 113.8, 62.8, 49.2, 30.2; FT-IR (ATR)max/cm-1 3287 (N–H),
1602 (C=N), 1256 (N–N=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H22N9 400.1992; Found 400.1991.
Precursor of compound 1b: N-((2-chloro-1,2-dihydroquinolin-3-yl)(1-cyclohexyl-1H-tetrazol-5-yl)methyl)aniline
(6b): white solid (125.2 mg, ~100%, MW), mp = 201–202 °C; Rf = 0.30 (Hexanes-AcOEt = 7/3 v/v); 1H NMR (400
MHz, CDCl3): δ 8.32 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.80–7.71 (m, 2H), 7.58–7.49 (m, 1H), 7.21–7.13 (m, 2H),
6.83–6.77 (m, 1H), 6.73–6.66 (m, 2H), 6.56 (d, J = 8.9 Hz, 1H), 4.84 (d, J = 8.7 Hz, 1H), 1.79 (s, 9H); 13C NMR (101
MHz, CDCl3, TMS): δ 153.6, 149.1, 147.4, 144.7, 137.9, 131.1, 129.7, 129.6, 128.2, 128.1, 127.5, 127.2, 119.8,
113.9, 62.7, 51.1, 30.0; FT-IR (ATR)max/cm-1 3285 (N–H), 1598 (C=N), 1260 (N–N=N); HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C21H22ClN6 393.1588; Found 393.1580.
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N-((1-(4-methoxyphenyl)-1H-tetrazol-5-yl)(tetrazolo[1,5-a]quinolin-4-yl)methyl)aniline (1c): Brown solid (72.0
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mg, 62%, MW) (31.4 mg, 27%, US); mp = 68–70 °C; Rf = 0.33 (Hexanes-AcOEt = 7/3 v/v); H NMR (500 MHz,
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CDCl3): δ 8.90 (s, 1H), 8.66 (d, J = 8.3 Hz, 1H), 8.23 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.90–7.85 (m, 1H), 7.74–7.68
(m, 1H), 7.62–7.56 (m, 5H), 7.15–7.11 (m, 2H), 7.07 (d, J = 9.0 Hz, 4H), 7.03 (d, J = 9.0 Hz, 2H), 6.82–6.78 (m,
1H), 6.65 (d, J = 7.8 Hz, 2H), 6.54 (d, J = 9.0 Hz, 1H), 4.90 (d, J = 9.3 Hz, 1H), 3.89 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3): δ 161.3, 154.7, 144.7, 140.6, 131.4, 130.9, 129.8, 129.6, 129.5, 129.0, 128.9, 128.8, 128.2, 127.1,
125.8, 123.8, 122.9, 119.9, 116.6, 115.2, 115.0, 114.2, 55.7, 48.2; FT-IR (ATR)max/cm-1 3287 (N–H), 1602.8 (C=N),
1256.6 (N-N=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H20N9O 450.1785; Found 450.1787.
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N-((1-benzyl-1H-tetrazol-5-yl)(tetrazolo[1,5-a]quinolin-4-yl)methyl)aniline (1d): Orange solid (95.0 mg, 84%,
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MW) (53.2 mg, 47%, US); mp = 75–76 °C; Rf = 0.43 (Hexanes-AcOEt = 4/1 v/v); H NMR (500 MHz, CDCl3): δ
8.62 (d, J = 8.3 Hz, 1H), 8.05 (s, 1H), 7.92–7.82 (m, 2H), 7.70–7.65 (m, 1H), 7.16 (s, 5H), 7.12–7.08 (m, 2H), 6.80–
6.73 (m, 1H), 6.56 (d, J = 8.2 Hz, 2H), 6.45 (d, J = 7.9 Hz, 1H), 6.05 (d, J = 15.4 Hz, 1H), 5.89 (d, J = 15.4 Hz, 1H),
5.17 (d, J = 7.9 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3): δ 154.4, 146.6, 144.7, 133.1, 131.8, 131.4, 130.5, 129.7,
129.6, 129.1, 128.9, 128.5, 127.7, 123.9, 123.1, 120.0, 116.9, 114.1, 52.0, 48.9; FT-IR (ATR)vmax/cm-1 3287.1 (N-H),
1613.4 (C=N), 1288.5 (N-N=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H20N9 434.1836; found 434.1841.
N-((1-(4-methoxybenzyl)-1H-tetrazol-5-yl)(tetrazolo[1,5-a]quinolin-4-yl)methyl)aniline (1e): Orange solid (79.0
1
mg, 65%, MW) (35.2 mg, 29%, US); mp = 77–78 °C; Rf = 0.40 (Hexanes-AcOEt = 7/3 v/v); H NMR (500 MHz,
CDCl3): δ 8.91 (s, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.24 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.90–7.84 (m, 1H), 7.73–7.67
(m, 1H), 7.62–7.55 (m, 5H), 7.16–7.10 (m, 2H), 7.07 (d, J = 9.0 Hz, 4H), 7.03 (d, J = 9.0 Hz, 2H), 6.83–6.77 (m,
1H), 6.65 (d, J = 7.8 Hz, 2H), 6.53 (d, J = 8.7 Hz, 1H), 5.03 (d, J = 9.2 Hz, 1H), 3.89 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3): δ 154.2, 146.4, 144.6, 133.0, 131.6, 131.3, 130.3, 129.5, 129.4, 129.0, 128.8, 128.3, 127.6, 123.7,
123.0, 119.9, 116.7, 114.0, 113.6, 51.9, 48.8, 29.3; FT-IR (ATR)max/cm-1 3287 (N–H), 1613 (C=N), 1288 (N–N=N);
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C25H22N9O 464.1941; Found 464.1934.
N-((1-(3,4-dimethoxyphenethyl)-1H-tetrazol-5-yl)(tetrazolo[1,5-a]quinolin-4-yl)methyl)aniline (1f): Brown
solid (183.0 mg, 88%, MW) (106.1 mg, 51%, US); mp = 113–115 °C; Rf = 0.44 (Hexanes-AcOEt = 7/3 v/v); 1H NMR
(500 MHz, CDCl3): δ 8.62 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.89 (d, J = 8.02 Hz, 1H), 7.87–7.82 (m, 1H), 7.69–7.64
(m, 1H), 7.15–7.05 (m, 2H), 6.78–6.69 (m, 1H), 6.59–6.48 (m, 5H), 6.39–6.37 (m, 1H), 5.90 (d, J = 7.9 Hz, 1H), 5.30
(s, 1H), 5.12 (d, J = 7.9 Hz, 1H), 5.10–5.04 (m, 1H), 4.96–4.87 (m, 1H), 3.72 (s, 3H), 3.63 (s, 3H); 13C{1H} NMR
(126 MHz, CDCl3): δ 154.7, 149.2, 148.2, 146.4, 144.4, 131.5, 131.4, 130.3, 129.5, 129.4, 128.7, 128.3, 123.8, 123.0,
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120.7, 119.7, 116.7, 113.8, 111.7, 111.4, 55.8, 55.7, 49.9, 48.3, 36.0; FT-IR (ATR)max/cm-1 3287.2 (N–H), 1602.8
(C=N), 1256.6 (N–N=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C27H26N9O2 508.2203; Found 508.2208.
N-((1-cyclohexyl-1H-tetrazol-5-yl)(tetrazolo[1,5-a]quinolin-4-yl)methyl)prop-2-en-1-amine (1g): White solid
(176.0 mg, 87%, MW) (89.0 mg, 44%, US); mp = 177–178 °C; Rf = 0.48 (Hexanes-AcOEt = 7/3 v/v); 1H NMR (400
MHz, CDCl3): δ 8.66 (d, J = 8.29 Hz, 1H), 8.18 (s, 1H), 7.99 (d, J = 7.98 Hz, 1H), 7.91–7.85 (m, 1H), 7.75–7.68 (m,
1H), 5.96–5.82 (m, 2H), 5.23–5.15 (m, 2H), 4.83–4.72 (m, 1H), 3.36–3.28 (m, 2H), 2.74 (bs, 1H), 2.18–2.05 (m, 2H),
2.03–1.88 (m, 4H), 1.57–1.42 (m, 2H), 1.39–1.27 (m, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 153.9, 146.9, 135.3,
131.6, 131.4, 130.4, 129.5, 128.5, 124.1, 123.9, 117.9, 116.9, 58.6, 51.2, 50.2, 33.5, 33.0, 25.5, 25.4, 24.9; FT-IR
(ATR) max/cm-1 3309 (N–H), 1615 (N=C), 1288 (N–N=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C20H24N9
390.2149; Found 390.2154.
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N-((1-(tert-butyl)-1H-tetrazol-5-yl)(tetrazolo[1,5-a]quinolin-4-yl)methyl)prop-2-en-1-amine (1h): White solid
(148.0 mg, 78%, MW) (56.9 mg, 30%, US); mp = 119–121 °C; Rf = 0.36 (Hexanes-AcOEt = 7/3; v/v); 1H NMR (500
MHz, CDCl3): δ 8.68 (d, J = 8.3 Hz, 2H), 8.09 (d, J = 7.7 Hz, 1H), 7.95–7.90 (m, 1H), 7.76–7.71 (m, 1H), 6.56 (s,
1H), 6.18–6.02 (m, 1H), 5.47–5.33 (m, 2H), 3.81 (bs, 1H), 3.46–3.37 (m, 1H), 1.78 (s, 9H); 13C{1H} NMR (126 MHz,
CDCl3): δ 154.2, 147.1, 135.3, 131.4, 131.4, 130.3, 129.4, 128.3, 124.7, 123.8, 117.7, 116.8, 62.2, 52.0, 50.5, 30.1;
FT-IR (ATR) vmax/cm-1 3335 (N–H), 1642 (N=H), 1273 (N–N=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C18H22N9 364.1992; Found 364.1997.
N-((1-(4-methoxyphenyl)-1H-tetrazol-5-yl)(tetrazolo[1,5-a]quinolin-4-yl)methyl)prop-2-en-1-amine
(1i):
Yellow solid (167.0 mg, 65%, MW) (74.5 mg, 29%, US); mp = 141–143 °C; Rf = 0.37 (Hexanes-AcOEt = 7/3 v/v);
1H NMR (500 MHz, CDCl3) δ 8.66 (d, J = 8.3 Hz, 1H), 8.24 (s, 1H), 8.00 (d, J = 7.9 Hz, 1H), 7.91–7.86 (m, 1H),
7.76–7.70 (m, 1H), 7.62 (d, J = 8.6 Hz, 2H), 7.04 (d, J = 8.6 Hz, 2H), 5.84 (s, 1H), 5.79–5.67 (m, 1H), 5.05–4.92 (m,
2H), 3.88 (s, 3H), 3.29–3.18 (m, 2H), 2.46 (s, 1H); 13C{1H} NMR (126 MHz, CDCl3) δ 161.5, 155.5, 146.9, 135.1,
131.6, 131.3, 130.5, 129.6, 128.4, 127.3, 126.3, 124.1, 123.9, 117.7, 116.9, 115.2, 55.9, 50.6, 50.1; FT-IR (ATR)

max/cm-1 3289 (N–H), 1614 (C=N), 1304 (N–N=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H20N9O
414.1785; Found 414.1789.
N-((1-benzyl-1H-tetrazol-5-yl)(tetrazolo[1,5-a]quinolin-4-yl)methyl)prop-2-en-1-amine (1j): Yellow solid
(154.0 mg, 74%, MW) (70.8 mg, 34%, US); mp = 128–130 °C; Rf = 0.42 (Hexanes-AcOEt = 4/1 v/v); 1H NMR (500
MHz, CDCl3): δ 8.61 (d, J = 8.1 Hz, 1H), 7.91–7.82 (m, 3H), 7.70–7.65 (m, 1H), 7.21–7.12 (m, 5H), 6.01 (d, J = 15.3
Hz, 1H), 5.83 (d, J = 15.3 Hz, 1H), 5.79–5.71 (m, 2H), 5.10–5.02 (m, 2H), 3.15–3.01 (m, 2H), 2.67 (s, 1H); 13C{1H}
NMR (126 MHz, CDCl3): δ 154.8, 146.7, 134.9, 133.5, 131.5, 131.3, 129.3, 128.9, 128.6, 128.2, 127.7, 123.7, 123.6,
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121.6, 117.5, 116.7, 51.6, 50.1, 41.9; FT-IR (ATR) vmax/cm-1 3064 (N–H), 1617 (C=N), 1274 (N–N=N); HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C21H20N9 398.1836; Found 398.1844.
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N-((1-(4-methoxybenzyl)-1H-tetrazol-5-yl)(tetrazolo[1,5-a]quinolin-4-yl)methyl)prop-2-en-1-amine (1k): Pale
yellow solid (90.0 mg, 81%, MW) (43.3 mg, 39%, US); mp = 137–138 °C; Rf = 0.42 (Hexanes-AcOEt = 7/3 v/v); 1H
NMR (500 MHz, CDCl3): δ 8.59 (d, J = 8.2 Hz, 1H), 7.85–7.81 (m, 2H), 7.76 (s, 1H), 7.69–7.64 (m, 1H), 7.07 (d, J
= 8.6 Hz, 2H), 6.57 (d, J = 8.6 Hz, 2H), 5.90 (d, J = 15.1 Hz, 1H), 5.83–5.74 (m, 2H), 5.67 (d, J = 8.6 Hz, 1H), 5.11–
5.09 (m, 1H), 5.08–5.05 (m, 1H), 3.63 (s, 3H), 3.12 (dq, J = 13.9, 6.0 Hz, 2H); 13C{1H} NMR (126 MHz, CDCl3): δ
159.8, 154.6, 146.8, 135.1, 131.5, 131.4, 130.2, 129.4, 129.3, 128.4, 125.3, 123.8, 123.6, 117.7, 116.7, 114.1, 55.3,
51.7, 51.3, 50.3; FT-IR (ATR)max/cm-1 3311 (N–H), 1613 (C=N), 1305 (N–N=N); HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C22H22N9O 428.1941; Found 428.1947.
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N-((1-(3,4-dimethoxyphenethyl)-1H-tetrazol-5-yl)(tetrazolo[1,5-a]quinolin-4-yl)methyl)prop-2-en-1-amine
(1l): Yellow solid (110.0 mg, 90%, MW) (66.0 mg, 54%, US); mp = 118–119 °C; Rf = 0.40 (Hexanes-AcOEt = 7/3
v/v); 1H NMR (500 MHz, CDCl3): δ 8.66 (d, J = 8.4 Hz, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.92–7.86 (m, 2H), 7.75–7.70
(m, 1H), 6.56–6.48 (m, 2H), 6.39–6.35 (m, 1H), 5.85–5.75 (m, 1H), 5.30 (s, 1H), 5.16–5.08 (m, 2H), 4.91–4.77 (m,
2H), 3.70 (s, 3H), 3.67 (s, 3H), 3.22 (t, J = 6.6 Hz, 2H), 3.13–3.00 (m, 2H); 13C{1H} NMR (126 MHz, CDCl3): δ
155.1, 149.2, 148.1, 146.7, 142.8, 135.2, 131.6, 130.4, 129.4, 128.9, 128.4, 123.9, 123.4, 120.9, 117.6, 116.9, 111.8,
111.3, 56.0, 55.9, 51.4, 50.2, 49.7, 35.9; FT-IR (ATR) vmax/cm-1 3287 (N–H), 1617 (C=N), 1290 (N–N=N); HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C24H26N9O2 472.2203; Found 472.2213.
N-((1-cyclohexyl-1H-tetrazol-5-yl)(tetrazolo[1,5-a]quinolin-4-yl)methyl)prop-2-yn-1-amine (1m): Pale yellow
solid (150.0 mg, 74%, MW) (71.0 mg, 35%, US); mp = 173–174 °C; Rf = 0.22 (Hexanes-AcOEt = 7/3 v/v); 1H NMR
(500 MHz, CDCl3): δ 8.68 (d, J = 8.4 Hz, 1H), 8.28 (s, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.93–7.88 (m, 1H), 7.76–7.72
(m, 1H), 6.17 (s, 1H), 4.99–4.90 (m, 1H), 3.63–3.52 (m, 1H), 2.88 (s, 1H), 2.32 (t, J = 2.4 Hz, 1H), 2.26–2.21 (m,
1H), 7.93–7.88 (m, 1H), 2.15–1.94 (m, 5H), 1.84–1.79 (m, 1H), 1.60–1.48 (m, 2H), 1.42–1.32 (m, 1H); 13C{1H}
NMR (126 MHz, CDCl3): δ 153.3, 146.6, 131.6, 131.5, 130.3, 129.4, 128.4, 123.8, 123.3, 116.8, 80.2, 73.3, 58.5,
50.3, 36.4, 33.3, 32.9, 25.4, 25.3, 24.9; FT-IR (ATR)max/cm-1 3340 (N-H), 1616 (N=H), 1279 (N-N=N); HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C20H22N9 388.1992; Found 388.1985.
N-benzyl-1-(1-cyclohexyl-1H-tetrazol-5-yl)-1-(tetrazolo[1,5-a]quinolin-4-yl)methanamine (1n): White solid
(140.0 mg, 61%, MW) (73.0 mg, 32%, US); Rf = 0.26 (Hexanes-AcOEt = 7/3 v/v); 1H NMR (500 MHz, CDCl3): δ
8.71 (d, J = 8.3 Hz, 1H), 8.23 (s, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.95–7.90 (m, 1H), 7.78–7.74 (m, 1H), 7.40–7.26 (m,
5H), 5.82 (s, 1H), 4.64–4.57 (m, 1H), 3.94 (d, J = 13.2 Hz, 1H), 3.83 (d, J = 13.2 Hz, 1H), 2.10–2.03 (m, 2H), 2.01–
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1.93 (m, 3H), 1.92–1.87 (m, 1H), 1.80–1.74 (m, 1H), 1.49–1.40 (m, 1H), 1.39–1.26 (m, 2H); 13C{1H} NMR (126
MHz, CDCl3): δ 153.7, 146.8, 138.2, 131.5, 131.4, 130.4, 129.4, 128.7, 128.6, 128.5, 128.4, 127.8, 127.3, 123.9,
123.8, 116.8, 58.3, 51.4, 51.0, 33.2, 32.9, 25.3, 25.2, 24.8; FT-IR (ATR)max/cm-1 3313 (N-H), 1597 (N=H), 1270 (N-
N=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H26N9 440.2305; Found 440.2298.
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1-(1-cyclohexyl-1H-tetrazol-5-yl)-N-(4-methoxybenzyl)-1-(tetrazolo[1,5-a]quinolin-4-yl)methanamine
(1o):
Pale yellow solid (141.0 mg, 57%, MW) (73.0 mg, 30%, US); Rf = 0.22 (Hexanes-AcOEt = 7/3 v/v); 1H NMR (500
MHz, CDCl3): δ 8.62 (d, J = 8.4 Hz, 1H), 8.12 (s, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.85–7.81 (m, 1H), 7.69–7.65 (m,
1H), 7.14 (d, J = 8.6 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 5.72 (s, 1H), 4.55–4.47 (m, 1H), 3.78 (d, J = 13.0 Hz, 1H),
3.72 (s, 3H), 3.66 (d, J = 13.0 Hz, 1H), 2.01–1.95 (m, 2H), 1.92–1.78 (m, 2H), 1.59–1.48 (m, 5H), 1.39–1.13 (m,
2H); 13C{1H} NMR (126 MHz, CDCl3): δ 159.2, 153.7, 146.8, 131.5, 131.3, 130.4, 130.2, 129.7, 129.4, 128.3, 123.9,
116.8, 114.1, 58.3, 55.3, 50.9, 50.7, 33.2, 32.9, 25.3, 25.2, 24.8; FT-IR (ATR)max/cm-1 3340 (N-H), 1616 (N=H),
1278 (N-N=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C25H28N9O 470.2411; Found 470.2400.
N-((1-cyclohexyl-1H-tetrazol-5-yl)(tetrazolo[1,5-a]quinolin-4-yl)methyl)butan-1-amine (1p): White solid (107.0
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mg, 51%, MW) (70.0 mg, 33%, US); Rf = 0.39 (Hexanes-AcOEt = 7/3 v/v); H NMR (500 MHz, CDCl3): δ 8.62–
8.68 (m, 1H), 8.11 (s, 1H), 7.95–7.91 (m, 1H), 7.84–7.79 (m, 1H), 7.68–7.63 (m, 1H), 5.79 (s, 1H), 4.79–4.72 (m,
1H), 2.64–2.62 (m, 2H), 2.11–2.04 (m, 1H), 2.03–1.97 (m, 1H), 1.96–1.83 (m, 4H), 1.75–1.69 (m, 1H), 1.50–1.34
(m, 4H), 1.33–1.23 (m, 3H), 0.82 (td, J = 7.3, 1.9, 0.8 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ 153.9, 146.8,
131.4, 131.2, 130.3, 129.4, 128.3, 124.1, 123.9, 116.8, 58.5, 52.4, 47.6, 33.4, 32.9, 32.0, 25.4, 25.3, 24.9, 20.3, 13.9;
FT-IR (ATR)max/cm-1 3340 (N-H), 1617 (N=H), 1277 (N-N=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C21H28N9 406.2462; Found 406.2452.
N-((1-cyclohexyl-1H-tetrazol-5-yl)(tetrazolo[1,5-a]quinolin-4-yl)methyl)cyclohexanamine (1q): Orange oil
(93.0 mg, 41%, MW) (58.0 mg, 26%, US); Rf = 0.35 (Hexanes-AcOEt = 7/3 v/v); 1H NMR (500 MHz, CDCl3): δ 8.61
(d, J = 8.4 Hz, 1H), 8.52 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.84–7.80 (m, 1H), 7.68–7.64 (m, 1H), 5.92 (s, 1H), 4.80–
4.73 (m, 1H), 4.47–4.40 (m, 2H), 2.42–2.35 (m, 1H), 2.23–2.17 (m, 5H), 2.12–2.05 (m, 1H), 1.97–1.84 (m, 4H),
1.76–1.69 (m, 4H), 1.47–1.37 (m, 3H), 1.29–1.07 (m, 2H); 13C{1H} NMR (126 MHz, CDCl3): δ 154.3, 146.8, 140.6,
131.4, 131.0, 130.3, 129.4, 128.3, 124.6, 123.9, 116.8, 58.8, 58.5, 49.2, 33.5, 33.4, 33.1, 33.0, 32.8, 25.8, 25.4, 25.3,
24.9, 24.8; FT-IR (ATR)max/cm-1 3340 (N-H), 1617 (N=H), 1276 (N-N=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C23H30N9 432.2618; Found 432.2611.
1-(1-cyclohexyl-1H-tetrazol-5-yl)-N-(furan-2-ylmethyl)-1-(tetrazolo[1,5-a]quinolin-4-yl)methanamine
(1r):
Red oil (75.0 mg, 33%, MW) (47.7 mg, 21%, US); Rf = 0.22 (Hexanes-AcOEt = 7/3 v/v); 1H NMR (500 MHz, CDCl3):
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δ 8.61 (d, J = 8.3 Hz, 1H), 8.15 (s, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.85–7.81 (m, 1H), 7.69–7.65 (m, 1H), 7.28–7.27
(m, 1H), 6.24–6.22 (m, 1H), 6.13 (d, J = 3.1 Hz, 1H), 5.81 (s, 1H), 4.63–4.57 (m, 1H), 3.86 (d, J = 14.6 Hz, 1H), 3.77
(d, J = 14.6 Hz, 1H), 2.04–1.95 (m, 1H), 1.94–1.81 (m, 4H), 1.73–1.68 (m, 1H), 1.44–1.33 (m, 2H), 1.30–1.22 (m,
1H), 0.86–0.76 (m, 1H); 13C{1H} NMR (126 MHz, CDCl3): δ 153.5, 151.9, 142.5, 131.5, 131.4, 130.4, 129.4, 128.4,
123.9, 123.6, 116.8, 110.5, 108.5, 58.4, 50.7, 43.9, 33.2, 32.9, 25.3 (2), 24.9; FT-IR (ATR)max/cm-1 3340 (N-H),
1616 (N=H), 1278 (N-N=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H24N9O 430.2098; Found 430.2087.
N-cyclohexyl-2-(tetrazolo[1,5-a]quinolin-4-yl)imidazo[1,2-a]pyridin-3-amine (8a): Yellow solid (188.2 mg,
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94%, MW) (94.1 mg, 47%, US); mp = 204-206 C; Rf = 0.19 (Hexanes-AcOEt = 7/3; v/v); 1H NMR (500 MHz,
CDCl3): δ 8.52 (s, 1H), 8.19 (d, J = 6.9 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.80–7.66 (m,
1H), 7.62–7.57 (m, 2H), 7.22–7.18 (m, 1H), 6.88–6.85 (m, 1H), 3.36 (d, J = 6.5 Hz, 1H), 2.69 (s, 1H), 1.72–1.66 (m,
2H), 1.60–1.53 (m, 2H), 1.47–1.42 (m, 1H), 1.08–0.99 (m, 4H), 0.95–0.83 (m, 1H); 13C{1H} NMR (126 MHz,
CDCl3): δ 149.0, 147.2, 141.9, 140.8, 133.6, 130.6, 128.6, 128.4, 127.9, 127.3, 127.2, 126.9, 124.2, 123.0, 117.6,
111.9, 56.6, 33.9, 25.6, 24.5; FT-IR (ATR)max/cm-1 3274 (N–H), 1632 (C=N); HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C22H21N7 384.1931; Found 384.1929.
Precursor of compound (8a): 2-(2-chloroquinolin-3-yl)-N-cyclohexylimidazo[1,2-a]pyridin-3-amine (10a): Brown
oil (125.4 mg, ~100%, MW); Rf = 0.30 (Hexanes-AcOEt = 7/3; v/v); 1H NMR (500 MHz, CDCl3) δ 8.51 (s, 1H),
8.17– 8.15 (m, 1H), 8.02–7.99 (m, 1H), 7.86–7.83 (m, 1H), 7.73–7.69 (m, 1H), 7.61–7.59 (m, 1H), 7.56–7.51
(m, 1H), 7.20–7.18 (m, 1H), 6.87–6.82 (m, 1H), 3.36 (s, 1H), 2.62 (s, 1H), 1.60 (s, 2H), 1.48 (s, 2H), 1.37 (s,
1H), 0.99–0.93 (m, 3H), 0.82–0.75 (m, 2H); 13C{1H} NMR (126 MHz, CDCl3) δ 148.7, 147.3, 141.3, 141.1,
130.9, 128.4, 128.1, 127.5, 127.1, 127.0, 125.4, 123.2, 117.1, 112.6, 56.6, 33.9, 25.5, 24.5; FT-IR (ATR)max/cm-
1 3275 (N–H), 1635 (C=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H22ClN4 377.1527; Found 377.1523.
N-(tert-butyl)-2-(tetrazolo[1,5-a]quinolin-4-yl)imidazo[1,2-a]pyridin-3-amine (8b): Yellow solid (172.0 mg,
o
86%, MW) (110.0 mg, 55%, US); mp = 146-148 C; Rf = 0.16 (Hexanes-AcOEt = 7/3; v/v); 1H NMR (500 MHz,
CDCl3) δ 8.58 (s, 1H), 8.37 (d, J = 6.9 Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.79–7.75 (m, 1H),
7.62–7.56 (m, 2H), 7.24–7.20 (m, 1H), 8.87–6.83 (m, 1H), 3.31 (s, 1H), 0.95 (s, 9H); 13C{1H} NMR (126 MHz,
CDCl3): δ 148.7, 147.3, 142.5, 141.0, 136.0, 130.6, 129.5, 128.4, 127.8, 127.5, 127.3, 125.5, 124.7, 123.8, 117.4,
111.7, 55.8, 30.1; FT-IR (ATR) max /cm-1 3291 (N–H), 1643 (C=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C20H20N7 358.1774; Found 358.1766.
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N-(4-methoxyphenyl)-2-(tetrazolo[1,5-a]quinolin-4-yl)imidazo[1,2-a]pyridin-3-amine (8c): Yellow solid (168.4
mg, 79%, MW) (93.8 mg, 44%, US); mp = 202-204 oC; Rf = 0.23 (Hexanes-AcOEt = 3/7; v/v); 1H NMR (500 MHz,
CDCl3): δ 9.15 (s, 1H), 9.06 (s, 1H), 8.61 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.91
(d, J = 6.8 Hz, 1H), 7.84–7.80 (m, 1H), 7.70–7.66 (m,1H), 7.52–7.47 (m, 1H), 7.01–6.97 (m, 1H), 6.65 (d, J = 8.9
Hz, 2H), 6.47 (d, J = 8.9 Hz, 2H), 3.61 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ 154.6, 145.8, 131.7, 130.1,
130.0, 128.7, 125.7, 124.6, 124.3, 116.9, 116.6, 115.8, 115.1, 55.6; FT-IR (ATR)max/cm-1 3285 (N–H), 1632(C=N);
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H17N7O 408.1567; Found 408.1559.
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N-benzyl-2-(tetrazolo[1,5-a]quinolin-4-yl)imidazo[1,2-a]pyridin-3-amine (8d): Orange solid (186.0 mg, 91%,
MW) (110.4 mg, 54%, US); mp = 113-115 oC; Rf = 0.12 (Hexanes-AcOEt = 7/3; v/v); 1H NMR (500 MHz, CDCl3)
δ 8.65 (d, J = 8.3 Hz, 1H), 8.54 (s, 1H), 8.26 (d, J = 6.8 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.84–7.80 (m, 1H), 7.72–
7.68 (m, 1H), 7.59 (d, J = 9.0 Hz, 1H), 7.27–7.22 (m, 1H), 6.91–6.84 (m, 5H), 6.78–6.72 (m, 2H), 4.02 (d, J = 7.2
Hz, 2H); 13C{1H} NMR (126 MHz, CDCl3): δ 146.0, 142.5, 138.5, 130.2, 129.9, 129.5, 129.0, 128.3, 128.2, 128.1,
128.0, 127.7, 126.8, 125.1, 124.6, 123.2, 120.1, 117.5, 116.4, 112.0, 52.5; FT-IR (ATR)max/cm-1 3267 (N–H), 1674
(C=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C23H17N7 392.1618; Found 392.1613.
5-bromo-N-cyclohexyl-2-(tetrazolo[1,5-a]quinolin-4-yl)imidazo[1,2-a]pyridin-3-amine (8e): Brown oil (178.3
mg, 89%, MW) (146.5 mg, 69%, US); Rf = 0.42 (Hexanes-AcOEt = 3/7; v/v); 1H NMR (500 MHz, CDCl3): 8.79–
8.72 (m, 2H), 8.10 (d, J = 7.9 Hz, 1H), 7.90–6.86 (m, 1H), 7.77–7.73 (m, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.06–7.00
(m, 2H), 5.96 (d, J = 9.3 Hz, 1H), 2.86–2.80 (m, 1H), 1.85–1.78 (m, 2H), 1.55–1.48 (m, 2H), 1.47–1.41 (m, 1H),
1.08–0.98 (m, 2H), 0.96–0.80 (m, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ 146.3, 144.5, 132.2, 132.1, 131.5, 130.6,
129.9, 129.3, 128.3, 125.0, 124.6, 120.6, 119.3, 117.1, 116.8, 113.2, 59.9, 32.6, 25.7, 25.3; FT-IR (ATR)max/cm-1
3258 (N–H), 1678 (C=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C22H20BrN7 462.1036; Found 462.1026.
5-bromo-N-(4-methoxyphenyl)-2-(tetrazolo[1,5-a]quinolin-4-yl)imidazo[1,2-a]pyridin-3-amine (8g): Yellow
oil (171.3 mg, 67%, MW) (79.3 mg, 31%, US); Rf = 0.32 (Hexanes-AcOEt = 7/3; v/v); 1H NMR (500 MHz, CDCl3):
8.70–8.67 (m, 2H), 8.04 (d, J = 8.0 Hz, 1H), 7.88–7.83 (m, 2H), 7.73–7.69 (m, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.16–
7.12 (m, 1H), 7.10–7.07 (m, 1H), 6.62 (d, J = 9.0 Hz, 2H), 6.35 (d, J = 9.0 Hz, 2H), 3.62 (s, 3H); 13C{1H} NMR (126
MHz, CDCl3): δ 153.3, 145.3, 141.9, 134.1, 132.3,131.1, 130.1, 129.3, 128.3, 126.4, 126.1, 124.4, 119.5, 119.3,
117.1, 116.7, 115.1, 114.7, 113.3, 55.5; FT-IR (ATR)max/cm-1 3217 (N–H), 1631 (C=N); HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C23H16BrN7O 486.0672; Found 486.0655.
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N-benzyl-5-bromo-2-(tetrazolo[1,5-a]quinolin-4-yl)imidazo[1,2-a]pyridin-3-amine (8h): Yellow oil (188.3 mg,
77%, MW) (83.1 mg, 34%, US); Rf = 0.27 (Hexanes-AcOEt = 1/1; v/v); 1H NMR (500 MHz, CDCl3):  8.64 (d, J =
8.3 Hz, 1H), 8.28 (s, 1H), 7.96 (d, J = 7.9 Hz, 1H), 7.86–7.82 (m, 1H), 7.73–7.68 (m, 1H), 7.58 (d, J = 8.6 Hz, 1H),
7.12–7.05 (m, 2H), 6.68–6.57 (m, 5H), 6.48–6.44 (m, 1H), 6.17–6.13 (m, 1H), 4.01 (d, J = 6.9 Hz, 2H); 13C{1H}
NMR (126 MHz, CDCl3): δ 145.9, 144.8, 137.7, 133.1, 131.4, 130.5, 129.6, 129.0, 128.5, 128.1, 127.3, 126.5, 125.2,
124.4, 119.8, 119.3, 117.1, 116.4, 113.1, 56.0; FT-IR (ATR)max/cm-1 3276 (N–H), 1624 (C=N); HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C23H16BrN7 470.0723; found 470.0722.
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8-(benzyloxy)-N-cyclohexyl-2-(tetrazolo[1,5-a]quinolin-4-yl)imidazo[1,2-a]pyridin-3-amine (8i): Yellow oil
(186.0 mg, 75%, MW) (146.3 mg, 59%, US); Rf = 0.63 (Hexanes-AcOEt = 7/3; v/v); 1H NMR (500 MHz, CDCl3): 
8.94 (s, 1H), 8.71 (d, J = 8.3 Hz, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.84–7.80 (m, 2H), 7.74–7.70 (m, 1H), 7.54 (d, J =
7.1 Hz, 2H), 7.43–7.38 (m, 2H), 7.36–7.32 (m, 1H), 6.67–6.63 (m, 1H), 6.52 (d, J = 8.9 Hz, 1H), 6.46 (d, J = 7.0 Hz,
1H), 5.44 (s, 2H), 2.76–2.68 (m, 1H), 1.80–1.75 (m, 2H), 1.62–1.56 (m, 3H), 1.49–1.43 (m, 1H), 1.28–1.24 (m, 2H),
1.14–1.01 (m, 3H), 0.90–0.82 (m, 1H); 13C{1H} NMR (126 MHz, CDCl3): δ 147.8, 137.1, 136.5, |135.7, 131.3, 130.9,
130.3, 129.4, 128.8, 128.3, 128.2, 127.3, 125.0, 120.5, 117.0, 116.8, 111.7, 103.0, 101.9, 70.9, 57.1, 34.0, 25.7, 25.3;
FT-IR (ATR)max/cm-1 3284 (N–H), 1672 (C=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C29H27N7O 490.2349;
Found 490.2344.
8-(benzyloxy)-N-(tert-butyl)-2-(tetrazolo[1,5-a]quinolin-4-yl)imidazo[1,2-a]pyridin-3-amine (8j): Yellow solid
(130.2 mg, 65%, MW) (56.1 mg, 28%, US); mp = 170-172 oC; Rf = 0.65 (Hexanes-AcOEt = 7/3; v/v); 1H NMR (500
MHz, CDCl3):  8.81 (s, 1H), 8.64 (d, J = 8.3 Hz, 1H), 8.07–7.97 (m, 2H), 7.80–7.76 (m, 1H), 7.67–7.64 (m, 1H),
7.48–7.45 (m, 2H), 7.34–7.23 (m, 4H), 6.58–6.55 (m, 1H), 6.40 (d, J = 7.4 Hz, 1H), 5.33 (s, 2H), 0.85 (s, 9H); 13C{1H}
NMR (126 MHz, CDCl3): δ 147.6, 146.5, 137.6, 136.3, 131.8, 131.7, 130.4, 129.8, 129.4, 129.3, 128.6, 128.2, 128.1,
127.4, 127.3, 124.7, 121.1, 117.7, 116.7, 111.2, 103.1, 70.8, 56.5, 29.5; FT-IR (ATR)max/cm-1 3269 (N–H), 1705
(C=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C27H25N7O 464.2193; Found 464.2203.
N-benzyl-8-(benzyloxy)-2-(tetrazolo[1,5-a]quinolin-4-yl)imidazo[1,2-a]pyridin-3-amine (8l): Yellow solid
(179.4 mg, 69%, MW) (83.2 mg, 32%, US); mp = 134-136 oC; Rf = 0.54 (Hexanes-AcOEt = 1/1; v/v); 1H NMR (500
MHz, CDCl3): 8.72–8.59 (m, 2H), 8.01 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 6.72 Hz, 1H), 7.83–7.79 (m, 1H), 7.71–
7.67 (m, 1H), 7.56–7.52 (m, 2H), 7.43–7.38 (m, 2H), 7.37–7.32 (m, 1H), 6.86–6.82 (m, 3H), 6.79–6.63 (m, 3H), 6.50
(d, J = 7.4 Hz, 1H), 4.00 (d, J = 7.2 Hz, 2H); 13C{1H} NMR (126 MHz, CDCl3): δ 148.0, 146.1, 138.6, 137.3, 136.4,
130.8, 130.2, 129.5, 129.2, 128.8, 128.4, 128.2 (2), 127.8, 127.4, 126.9, 124.8, 120.0, 116.5 (2), 112.0, 103.3, 71.0,
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52.7; FT-IR (ATR)max/cm-1 3284 (N–H), 1614 (C=N); HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C30H23N7O
498.2036; Found 498.2031.
4-(dimethoxymethyl)tetrazolo[1,5-a]quinoline (7): white solid (125.1 mg, ~100%); mp = 138-141 oC; Rf = 0.35
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(Hexanes-AcOEt = 7/3; v/v); H NMR (500 MHz, CDCl3): 8.69 (d, J = 8.4 Hz, 1H), 8.15 (s, 1H), 8.03–8.00 (m,
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1H), 7.90–7.87 (m, 1H), 7.75–7.71 (m, 1H), 6.03–6.01 (m, 1H), 3.55 (s, 7H); 13C{1H} NMR (126 MHz, CDCl3): δ
146.4, 131.3, 130.5, 130.2, 129.5, 128.1, 123.7, 123.5, 116.7, 99.3, 54.3; FT-IR (ATR)max/cm-1 1615 (C=N); HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C12H13N4O2 245.1033; Found 245.1023.
ASSOCIATED CONTENT
Supporting Information
The supporting Information is available free of charge on the ACS Publications website.
Copies of 1H and 13C NMR spectra for products 1a-r, 6b, 8a-l, 10a, and 7 (PDF)
X-ray analysis (ORTEP) for compound 1b, 6b, 8a, and 7 (PDF)
X-ray data for compound 1b, 6b, 8a, and 7 (CIF)
Plausible reaction mechanisms
Computational details
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
R.G.-M. is grateful for financial support from CIO-UG (009/2015), DAIP (859/2016) and CONACYT (CB-2011-
166747-Q) projects. A.I.-J (ID: I00247) and U.M.V.-B. (ID: 32510) thank UG. A.Q.-S. (707677/582770) and S.C.R.-
L. (701343/582679) acknowledge CONACYT-México for their scholarships. All authors kindly acknowledge
Laboratorio Nacional de Caracterización de Propiedades Fisicoquímicas y Estructura Molecular for the
instrumentation time provided (CONACYT-México, Project: 123732).
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