Azide-Triggered Bicyclization of o-Alkynylisocyanobenzenes: Synthesis of Tetrazolo[1,5-a]quinolines

Article abstract of DOI:10.1002/ejoc.201901209

An efficient and rapid synthetic approach for the synthesis of tetrazolo[1,5-a]quinolines has been developed employing the reaction of o-alkynylisocyanobenzenes with sodium azide. The present strategy involved nucleophilic addition of azide to isocyanide followed by 6-endo cyclization. The reaction gives access to a collection of tetrazolo[1,5-a]quinolines with broad functional group in moderate to high yields under metal-, and base-free conditions.

Full text of DOI:10.1002/ejoc.201901209

DOI: 10.1002/ejoc.201901209
Full Paper
Annulation
Azide-Triggered Bicyclization of o-Alkynylisocyanobenzenes:
Synthesis of Tetrazolo[1,5-a]quinolines
Onnicha Khaikate,[a] Darunee Soorukram,[a] Pawaret Leowanawat,[a] Manat Pohmakotr,[a]
Vichai Reutrakul,[a] and Chutima Kuhakarn*[a]
Abstract: An efficient and rapid synthetic approach for the azide to isocyanide followed by 6-endo cyclization. The reaction
synthesis of tetrazolo[1,5-a]quinolines has been developed em- gives access to a collection of tetrazolo[1,5-a]quinolines with
ploying the reaction of o-alkynylisocyanobenzenes with sodium broad functional group in moderate to high yields under metal-,
azide. The present strategy involved nucleophilic addition of and base-free conditions.
Introduction
Nitrogen-containing heterocycles are prevalent structural mo-
tifs found in naturally occurring compounds and biologically
active molecules and they have been associated with the phar-
maceutical and agrochemical industries.[1] Among many privi-
leged classes of the aza-heterocycles, tetrazolo[1,5-a]quinolines
contain unique structural features and can be found in pharma-
ceutically relevant compounds exhibiting antibacterial,[2a]
anti-inflammatory,[2a] antimicrobial,[2b] anticancer,[2c] HMG-CoA
reductase inhibitory,[2d] antihypertensive[2e] and antituberculo-
sis[2f] activities (Figure 1). In addition to their pharmacological
significance, the tetrazolo[1,5-a]quinolines are also important
intermediates for the synthesis of indoxyl-fused pyridines,[3a]
quinolinotriazoles,[3b] 2-aminoquinolines,[3c] and α-carbol-
ines.[3d]
Due to the biological and synthetic utilities of tetrazolo-
Figure 1. Some selected examples of bioactive molecules containing tetraz-
olo[1,5-a]quinoline motif.
[1,5-a]quinolines, their syntheses received much attention and
are of particular interest. The previously reported methods to
access tetrazolo[1,5-a]quinolines involve the reaction of sodium
azide or TMSN3 with 2-chloroquinolines,[2,4] as well as other al-
ternative approaches starting from quinoline N-oxides,[5] 1-aryl-
tetrazoles,[3c,6] and other substrates.[7] Although there are sev-
eral approaches existing toward the synthesis of tetrazolo-
[1,5-a]quinoline scaffolds, the development of alternative syn-
thetic methods toward the preparation of tetrazolo[1,5-a]quin-
olines under mild and convenient experimental procedures is
still desirable.
tandem cyclization toward the synthesis of N-heterocycles.[9]
Recently, we reported the utilization of water, sulfinate sodium
salts, and ammonium thiocyanate as nucleophile to react with
o-alkynylisocyanobenzenes to access quinolin-2(1H)-ones, 2-
sulfonyl- and 2-thiocyanato quinolines, respectively.[10] As a part
of our on-going program, we now report the synthesis of tetraz-
olo[1,5-a]quinoline derivatives from the reaction of o-alkynyliso-
cyanobenzenes 2 and sodium azide (3) (Scheme 1).
Over the past few decades, nucleophile-triggered cyclization
of o-alkynylisocyanobenzenes has emerged as efficient and
atom-economical synthetic strategy for the synthesis of 2-sub-
stituted quinolines and indoles.[8] Our group interested in the
Scheme 1. Synthetic approach to access tetrazolo[1,5-a]quinolines 4.
[a] Department of Chemistry and Center of Excellence for Innovation in
Chemistry (PERCH-CIC), Faculty of Science, Mahidol University,
Rama VI Road, Bangkok 10400, Thailand
E-mail: chutima.kon@mahidol.ac.th
http://chemistry.sc.mahidol.ac.th/en/
Results and Discussion
Primarily, the reaction between o-(phenylethynyl)isocyano-
benzene (2a) and sodium azide (3) was examined under various
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901209.
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reaction parameters in order to screen for the optimum reac-
tion conditions and the results are summarized in Table 1. It
is worth to emphasize that 2a was readily obtained from its
corresponding N-(2-(phenylethynyl)phenyl)formamide (1a)
upon treatment with POCl3, iPr2NEt in CH2Cl2 at 0 °C for 0.5 h
(Step I).[11] Compound 2a is inherently unstable, therefore after
aqueous work-up, it was filtered through a short-path column
(aluminium oxide, Type E) eluted with EtOAc. After solvent re-
moval, the obtained crude compound 2a was treated with so-
dium azide (3, 2 equiv.) in DMF at room temperature (30–32 °C)
for overnight (18 h) (Table 1, entry 1) (Step II). Gratifyingly, the
desired 4-phenyltetrazolo[1,5-a]quinoline (4a) was obtained in
high yield (82 % yield). It is should be emphasized here that the
yield of 4a was based on the starting compound 1a. The yield
was not significantly improved at elevated temperature (60–
100 °C) (Table 1, entries 2–4). Additionally, an increase or de-
crease of the amount of sodium azide employed (1–3 equiva-
lents) did not have a profound effect on the yields of 4a
(Table 1, entry 1 vs. entries 5–7). Therefore, we decided to em-
ploy a slight excess amount of sodium azide with respect to
the starting compound 1a. After the reaction temperature and
the stoichiometry of sodium azide were chosen (room tempera-
ture and 1.5 equivalents, respectively), it was found that
the reaction time can be shortened from 18 h to 2 h (Table 1,
entry 1 vs. entries 8–10). Solvents, including dimethyl sulfoxide
(DMSO), toluene, dichloromethane (DCM) and water, were eval-
uated (Table 1, entries 11–14). Among solvents screened, only
DMSO gave comparable results to those obtained when DMF
was employed as the solvent; others failed to provide the ex-
pected product 4a. After extensive experimentation, the opti-
mal reaction conditions were identified as follows: 1 (0.5 mmol)
and sodium azide (3, 1.5 equiv.) in DMF at room temperature,
2 h (Table 1, entry 9).
Table 1. Optimization of reaction conditions.[a]
Entry
3 (equiv.)
Solvent
Temp (°C)
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
2
2
2
2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
Toluene
DCM
H2O
r.t.
60
80
100
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
18
18
18
18
18
18
18
6
2
1
2
2
82
82
81
85
88
80
88
85
88
83
78
N.D.
N.D.
N.D.
1.5
1
3
1.5
1.5
1.5
1.5
1.5
1.5
1.5
9
10
11
12
13
14
2
2
[a] Reaction conditions: Step I: 1a (0.5 mmol), POCl3 (0.75 mmol), (iPr)2NEt
(4.0 mmol), CH2Cl2 (4 mL), 0 °C, 0.5 h; after aqueous work-up and evaporation
to dryness the crude mixture was diluted with EtOAc, filtered by a short-path
column chromatography (aluminium oxide, Type E) and eluted with EtOAc.
Step II: 2a (freshly prepared from 1a) was treated with NaN3 (3) in the solvent
(2 mL) under various reaction conditions. [b] Isolated yields after chromato-
graphic purification (SiO2 column chromatography).
Table 2. Reaction of o-alkynylisocyanobenzenes 2a–2h.[a]
After having the optimized reaction conditions in hand, we
next evaluated the generality of the present transformation on
structurally different o-alkynylisocyanobenzenes 2 (freshly pre-
pared from the corresponding formamides 1) and the results
are summarized in Table 2. First, the effect of the substitution
on the aryl ring attached with the isocyanide moiety of the o-
alkynylisocyanobenzenes 2 was evaluated. Substrates 2 bearing
a substituent located at the para position with respect to the
isocyanide moiety were first examined. The p-methyl-substi-
tuted substrate gave the corresponding product 4b in 66 %
yield. Substrates with para electron attracting substituent (CF3,
F, Cl, Br) yielded the corresponding products 4c–4f with the
yields ranging from 40 %–76 % yields. Unfortunately, under the
standard reaction conditions, the p-nitro substituted substrate
1g was consumed but did not provide the desired product.
Finally, the m-chloro substrate delivered product 4h in 44 %
yield.
[a] Reaction conditions: Step I: 1 (0.5 mmol), POCl3 (0.75 mmol), (iPr)2NEt
(4.0 mmol), CH2Cl2 (4 mL), 0 °C, 0.5–1 h; after aqueous work-up and evapora-
tion to dryness the crude mixture was diluted with EtOAc, filtered by a short-
path column chromatography (aluminium oxide, Type E) and eluted with
EtOAc. Step II: 2 (freshly prepared from 1), NaN3 (3, 1.5 equiv.) in DMF (2 mL),
r.t. (30–32 °C), 2 h. In parenthesis: isolated yields after chromatographic purifi-
cation (SiO2 column chromatography).
Next, the reactions of o-alkynylisocyanobenzenes 2 bearing
different substituent R on the alkynyl moiety were evaluated
and the results are summarized in Table 3. Substrates 2i–2n
bearing a substituent (R2) located at the para position with re-
spect to the arylethynyl moiety of 2 were first tested. Substrates
87 % yields, respectively. While the para-halogen-substituted
substrates 2k–2m delivered their corresponding products 4k–
4m in good to high yields, limitation was again observed with
the p-nitro substrate. The reactions of substrates with a substit-
uent at meta position (m-F, m-Cl, and m-Br) readily proceeded
2i and 2j with electron-donating groups in para position (CH3 and gave the corresponding products with the yields ranging
and OCH3) gave the desired products 4i and 4j in 82 % and from 59–71 % yields. Apparently, the steric effect on the reac-
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tion efficiency was noticed. Substrates 2r and 2s bearing sub- procedure, denitrogenation reaction of 4a took place in the
stituent at the ortho position (o-F and o-Cl) gave products 4r presence of Cu(OAc)2·H2O (2 equiv.) in DMF to provide 3-
and 4s in 54 % and 29 % yields, respectively. The steric effect phenylquinolin-2-amine (5) in 51 % yield (Scheme 3).[3c]
was further emphasized when 4t and 4u were obtained in
much lower yields (8 % and 16 % yields, respectively). Extend-
ing the reaction time from 2 h to 18 h raised the yield of 4t to
33 % yield. Although 4w was obtained in low yield (20 % yield)
when a terminal alkynyl substrate was employed, the present
reaction can accommodate o-alkylnylisocyanobenzenes bearing
Scheme 2. Gram-scale synthesis of 4-phenyltetrazolo[1,5-a]quinoline (4a).
heterocycle (R = 2-thienyl) and aliphatic substituent (R =
n-butyl, n-hexyl, isopentyl and cyclopropyl) and furnished the
corresponding products with the yields ranging from 53–76 %
yields.
Table 3. Reaction of o-alkynylisocyanobenzenes 2i–2z and 2a′.[a]
Scheme 3. Synthetic application of 4-phenyltetrazolo[1,5-a]quinoline (4a).
To gain better insight into the reaction mechanism, some
control experiments were carried out (Scheme 4). After an
aqueous work-up but without prior filtration through a short-
path column (aluminium oxide, Type E), a freshly prepared 2a
was allowed to react with sodium azide (3) under standard reac-
tion conditions (Scheme 4a). It was found that 2-chloro-3-
phenylquinoline (6) was competitively formed in 15 % yield and
4a was obtained in lower yield (68 % yield). Therefore, in this
work, it is necessary that the crude o-alkynylisocyanobenzenes
2 were filtered through a short-path aluminium oxide column
prior to treatment with sodium azide. As previously mentioned,
tetrazolo[1,5-a]quinolines can generally be prepared by the re-
[a] Reaction conditions: Step I: 1 (0.5 mmol), POCl3 (0.75 mmol), (iPr)2NEt
(4.0 mmol), CH2Cl2 (4 mL), 0 °C, 0.5–1 h; after aqueous work-up and evapora-
tion to dryness the crude mixture was diluted with EtOAc, filtered by a short-
path column chromatography (aluminium oxide, Type E) and eluted with
EtOAc. Step II: 2 (freshly prepared from 1), NaN3 (3, 1.5 equiv.) in DMF (2 mL),
r.t. (30–32 °C) for 2 h. In parenthesis: isolated yields after chromatographic
purification (SiO2 column chromatography). [b] Reaction time = 18 h.
The synthetic applicability of the present reaction to a gram-
scale reaction was also evaluated. Under standard reaction con-
ditions, 2a freshly prepared from 1a (1.11 g, 5 mmol) was
treated with sodium azide (0.49 g, 7.5 mmol) to provide 4a
(1.05 g, 85 % yields) (Scheme 2). Finally, synthetic utility of the
tetrazolo[1,5-a]quinoline adduct to access 2-aminoquinoline
was also demonstrated. By modifying the previously reported
Scheme 4. Control experiments.
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Scheme 5. Plausible reaction mechanisms.
action of 2-chloroquinolines and sodium azide.[2,4] In order to ate to good yields. The present method should be found as
exclude the possibility that 4a formed from 2-chloro-3-phenyl- an attractive synthetic approach for a direct diversification of
quinoline (6) under standard reaction conditions, 6 was treated tetrazolo[1,5-a]quinolines in both chemical and pharmaceutical
with NaN3 (1.5 equiv.) and the reaction was allowed to stand at research and other related disciplines.
room temperature for 2 h and 18 h (Scheme 4b). It was found
that 4a was not formed and 6 was recovered (93–96 % yields).
Experimental Section
General information. 1H NMR spectra were recorded with a Bruker
Thus, in the present work, formation of 4a from 6 can be ex-
cluded. Nevertheless, under forcing conditions (120 °C, 18 h), 6
can be converted to 4a in 91 % yield (Scheme 4c). Finally, when
AVANCE 400 spectrometer (400 MHz) in CDCl3 by using tetramethyl-
D2O (2 equiv.) was added into the reaction of 2a and 3, a mix- silane (δ = 0 ppm) or residual non-deuterated solvent peak as an
internal standard. 13C NMR spectra were recorded with a Bruker
AVANCE 400 (100 MHz) spectrometer. Infrared spectra were re-
corded with a Bruker ALPHA FT-IR spectrometer and only partial
data were listed. High-Resolution Mass Spectra (HRMS) were re-
corded with a Bruker micro TOF spectrometer in the ESI mode.
Melting points were recorded with a Sanyo Gallenkamp apparatus.
Reactions were monitored by Thin-Layer Chromatography and visu-
alized by UV and a solution of KMnO4. N-(2-Arylethynyl)phenyl)-
formamides and N-(2-alkylethynyl)phenyl)formamides were synthe-
sized according to literature procedures. The structures of known
compounds were confirmed by comparing their 1H NMR and 13C
NMR data with those in the literature. All reagents and solvents
were obtained from commercial sources and used without further
purification. Column chromatography was performed by using
Merck silica gel 60 (Art 7734).
ture of products [d1]-4a and 4a ([d1]-4a/4a = 9:1, 1H NMR anal-
ysis, see Supporting Information) was obtained (Scheme 4d).
The results imply that proton source from water or D2O served
as a proton donor.
According to the experimental results as well as control ex-
periments, two plausible reaction mechanisms were proposed
as shown in Scheme 5. In Route I, a [3+2] cycloaddition of the
azido anion to an isocyanide moiety in compound 2 occurs
leading to intermediate A. The intermediate A undergoes 6-
endo cyclization to provide intermediate B. Subsequent proto-
nation and isomerization will lead to the obtained tetrazolo-
[1,5-a]quinolines 4. An alternative mechanism (Route II) which
cannot be excluded involves nucleophilic addition of an azide
anion to the isocyano carbon atom to generate the correspond-
ing imidoyl anion intermediate C. Next, C undergoes 6-endo
cyclization leading to intermediate D. The subsequent protona-
tion generates E, in which the azido group undergoes ring-
chain azido-isomerization to furnish the tetrazolo[1,5-a]quinol-
ines 4.[4h,8,10]
General procedure for the synthesis of N-(2-(arylethynyl)phen-
yl)formamides and N-(2-(alkylethynyl)phenyl)formamides 1. To
a round-bottom flask filled with formic acid (1.5 mL) was added
Ac2O (2 mL) at room temperature, and the resulting mixture was
stirred for 10 min. To this mixture was added the solution of 2-
iodoaniline derivatives (10 mmol) in CH2Cl2 (10 mL) then the reac-
tion chamber was stirred for 2 h at room temperature. After comple-
tion, the reaction was quenched with H2O (5 mL) and the resulting
mixture was extracted with CH2Cl2 (3 × 10 mL). The combined or-
ganic layers were washed with brine (20 mL), dried (MgSO4), fil-
tered, and concentrated (aspirator). Crude product was purified by
column chromatography on silica gel (hexanes/ethyl acetate) to
yield the corresponding N-(2-iodoaryl)formamide. The obtained N-
(2-iodoaryl)formamide was subjected to coupling reaction in the
next step. To the two-neck flask containing N-(2-iodoaryl)forma-
mide (10 mmol), PdCl2(PPh3)2 (0.13 mmol), and CuI (0.1 mmol) was
added THF (10 mL) and NEt3 (10 mL) under argon atmosphere.
Conclusions
In summary, we have developed an alternative strategy for the
synthesis of tetrazolo[1,5-a]quinolines from the reaction of o-
alkynylisocyanobenzenes with sodium azide. The salient fea-
tures of the present method include the consecutive formation
of two heterocyclic rings via a one-pot process, mild reaction
conditions (room temperature), a broad scope, scalability as
well as the robustness of the reaction. Structurally different
kinds of tetrazolo[1,5-a]quinolines could be prepared in moder- Then, monosubstituted acetylene (11 mmol) was added dropwise
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to the reaction mixture. The reaction was allowed to stir at room
7.53 (m, 3H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 147.8, 133.2,
temperature under Ar atmosphere for overnight. After completion, 131.5, 130.5 (q, JC,F = 32.9 Hz), 130.1, 129.2, 128.8, 128.6, 128.5, 126.9
the reaction was quenched with dilute HCl solution (20 mL) and
the resulting mixture was extracted with ethyl acetate (3 × 20 mL).
The combined organic layers were washed with brine (20 mL), dried
with MgSO4, filtered, and concentrated (aspirator). Crude product
was purified by column chromatography on silica gel (hexane/ethyl
acetate) to provide the corresponding N-(2-(arylethynyl)phenyl)-
formamide or N-(2-(alkylethynyl)phenyl)formamide 1.
(q, JC,F = 3.3 Hz), 126.5 (q, JC,F = 3.9 Hz), 124.2, 123.4 (q, JC,F =
271.0 Hz), 117.9 ppm. HRMS (ESI-TOF) m/z: [M + Na]+ calcd. for
C16H9F3N4Na: 337.0672, found 337.0671.
7-Fluoro-4-phenyltetrazolo[1,5-a]quinoline (4d): pale brown
solid (100 mg, 76 % yield); m.p. 193.9–195.9 °C (from CH2Cl2/hex-
anes). IR (neat): ν = 3053, 1629, 1575, 1527, 1464 cm–1 1H NMR
.
˜
(CDCl3, 400 MHz): δ = 8.73–8.70 (m, 1H), 8.15 (d, J = 7.2 Hz, 2H),
8.01 (s, 1H), 7.68 (dd, J = 8.2, 2.6 Hz, 1H), 7.62–7.50 (m, 4H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 161.4 (d, JC,F = 248.1 Hz), 147.1,
133.5, 129.9, 129.1, 128.6, 128.5 (d, JC,F = 3.0 Hz), 128.0, 126.6, 125.9,
119.2 (d, JC,F = 24.4 Hz), 119.0, 113.8 (d, JC,F = 23.2 Hz) ppm. HRMS
(ESI-TOF) m/z: [M + H]+ calcd. for C15H10FN4: 265.0884, found
265.0881.
General procedure for the synthesis of o-alkynylisocyano-
benzenes 2. To a solution of N-(2-(arylethynyl)phenyl)formamide or
N-(2-(alkylethynyl)phenyl)formamide 1 (0.5 mmol) and diisopropyl-
ethylamine (0.70 mL, 4.0 mmol) in CH2Cl2 (4 mL) was added drop-
wise POCl3 (0.07 mL, 0.75 mmol) at 0 °C under argon atmosphere.
The reaction mixture was stirred at 0 °C for 0.5–1 h. After comple-
tion, the reaction was quenched with NaHCO3 (5 mL) and the result-
ing mixture was extracted with CH2Cl2 (3 × 10 mL). The combined
organic layers were washed with brine (20 mL), dried (MgSO4), fil-
tered, and concentrated (aspirator). The crude product was filtered
through a short-path column (aluminium oxide, Type E), eluted with
100 % ethyl acetate, and was concentrated (aspirator) to provide
the corresponding o-alkynylisocyanobenzene 2 which were subse-
quently used in the next step without prior purification.
7-Chloro-4-phenyltetrazolo[1,5-a]quinoline (4e): colorless nee-
dle (80 mg, 57 % yield); m.p. 228.5–230.4 °C (from CH2Cl2/hexanes).
IR (neat): ν = 3054, 1660, 1602, 1522, 1439 cm–1 1H NMR (CDCl3,
.
˜
400 MHz): δ = 8.66 (d, J = 9.2 Hz, 1H), 8.16–8.13 (m, 2H), 8.01 (d,
J = 2.0 Hz, 1H), 7.99 (s, 1H), 7.81 (dd, J = 8.8, 2.0 Hz, 1H), 7.60–7.50
(m, 3H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 147.3, 134.1, 133.4,
131.0, 129.9, 129.1, 128.6, 128.3, 128.2, 128.0, 125.5, 118.4 ppm.
HRMS (ESI-TOF) m/z: [M + H]+ calcd. for C15H10ClN4: 281.0589, found
281.0588.
General procedure for the synthesis of tetrazolo[1,5-a]quin-
oline derivatives 4. To a round-bottomed flask filled with o-alkyn-
ylisocyanobenzene 2 [freshly prepared from the corresponding
7-Bromo-4-phenyltetrazolo[1,5-a]quinoline (4f): white solid
(91 mg, 56 % yield); m.p. 243.7–245.2 °C (from CH2Cl2/hexanes). IR
(neat): ν = 3051, 1674, 1593, 1518, 1441 cm–1 1H NMR (CDCl3,
.
N-(2-(arylethynyl)phenyl)formamide
or
N-(2-(alkynyl)phenyl)-
˜
formamide (0.5 mmol)] was diluted with DMF (2 mL). To this mixture
was added sodium azide (0.049 g, 0.75 mmol, 1.5 equiv.). The reac-
tion mixture was stirred at room temperature for 2 h. After comple-
tion, the reaction mixture was diluted with H2O (5 mL) and the
resulting mixture was extracted with ethyl acetate (3 × 10 mL). The
combined organic layers were washed with brine (20 mL), dried
(MgSO4), filtered, and concentrated (aspirator). Crude product was
purified by column chromatography on silica gel (hexanes/ethyl
acetate or hexanes/dichloromethane) to yield the corresponding
tetrazolo[1,5-a]quinoline derivatives 4.
400 MHz): δ = 8.59 (d, J = 8.8 Hz, 1H), 8.18–8.13 (m, 3H), 7.98 (s,
1H), 7.95 (dd, J = 8.8, 2.0 Hz, 1H), 7.60–7.50 (m, 3H) ppm.13C NMR
(CDCl3, 100 MHz): δ = 147.3, 133.7, 133.4, 131.2, 130.0, 129.1, 128.7,
128.6, 128.1, 125.8, 121.8, 118.5 ppm. HRMS (ESI-TOF) m/z: [M +
Na]+ calcd. for C15H9NBrNa: 346.9903, found 346.9904.
8-Chloro-4-phenyltetrazolo[1,5-a]quinoline (4h): white solid
(62 mg, 44 % yield); m.p. 230.9–232.3 °C (from CH2Cl2/hexanes). IR
(neat): ν = 3046, 1659, 1601, 1520, 1448 cm–1 1H NMR (CDCl3,
.
˜
400 MHz): δ = 8.73 (d, J = 2.0 Hz, 1H), 8.16–8.13 (m, 2H), 8.05 (s,
1H), 7.97 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 8.4, 2.0 Hz, 1H), 7.60–7.50
(m, 3H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 147.4, 136.9, 133.5,
130.3, 130.1, 129.8, 129.1, 129.0, 128.7, 128.5, 126.9, 122.8,
116.9 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd. for C15H10ClN4:
281.0589, found 281.0591.
4-Phenyltetrazolo[1,5-a]quinoline (4a):[7c] white solid (108 mg,
88 % yield); m.p. 154.4–156.4 °C (from CH2Cl2/hexanes) (lit.[7c] m.p.
175 °C). IR (neat): ν = 3051, 1699, 1525, 1457, 1443 cm–1 1H NMR
.
˜
(CDCl3, 400 MHz): δ = 8.68 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 7.6 Hz,
2H), 8.06 (s, 1H), 8.00 (d, J = 7.6 Hz, 1H), 7.84 (t, J = 7.2 Hz, 1H), 7.70
(t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.51–7.47 (m, 1H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 147.3, 133.8, 130.6, 129.9, 129.54,
129.46, 129.0, 128.9, 128.5, 128.1, 126.5, 124.3, 116.8 ppm. HRMS
(ESI-TOF) m/z: [M + H]+ calcd. for C15H11N4: 247.0978, found
247.0980.
4-(p-Tolyl)tetrazolo[1,5-a]quinoline (4i): white solid (107 mg,
82 % yield); m.p. 159.9–161.8 °C (from CH2Cl2/hexanes). IR (neat):
1
ν = 3049, 1678, 1527, 1514, 1454, cm–1. H NMR (CDCl3, 400 MHz):
˜
δ = 8.62 (d, J = 8.4 Hz, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.98 (s, 1H), 7.94
(d, J = 8.0 Hz, 1H), 7.78 (t, J = 8.2 Hz, 1H), 7.66 (t, J = 7.2 Hz, 1H),
7.32 (d, J = 8.4 Hz, 2H), 2.42 (s, 3H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 147.2, 139.6, 130.8, 130.3, 129.6, 128.74, 128.70, 128.2, 128.0,
126.3, 124.3, 116.6, 21.3 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd.
for C16H13N4: 261.1135, found 261.1138.
7-Methyl-4-phenyltetrazolo[1,5-a]quinoline (4b): colorless nee-
dle (86 mg, 66 % yield); m.p. 177.5–179.3 °C (from CH2Cl2/hexanes).
IR (neat): ν = 3068, 1657, 1579, 1524, 1442 cm–1 1H NMR (CDCl3,
.
˜
400 MHz): δ = 8.37 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 7.2 Hz, 2H), 7.84
(s, 1H), 7.60 (s, 1H), 7.51–7.44 (m, 3H), 7.43–7.41 (m, 1H), 2.49 (s, 3H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 146.8, 138.3, 133.7, 131.9,
129.3, 129.1, 128.8, 128.3, 128.2, 127.7, 125.9, 124.1, 116.1, 21.3 ppm.
HRMS (ESI-TOF) m/z: [M + H]+ calcd. for C16H13N4: 261.1135, found
261.1137.
4-(4-Methoxyphenyl)tetrazolo[1,5-a]quinoline (4j): pale brown
solid (120 mg, 87 % yield); m.p. 164.0–165.9 °C (from CH2Cl2/hex-
anes). IR (neat): ν = 3073, 1681, 1605, 1511, 1452 cm–1 1H NMR
.
˜
(CDCl3, 400 MHz): δ = 8.69 (d, J = 8.0 Hz, 1H), 8.17–8.14 (m, 2H),
8.01– 7.98 (m, 2H), 7.82 (t, J = 8.4 Hz, 1H), 7.70 (t, J = 8.2 Hz, 1H),
7.10–7.08 (m, 2H), 3.90 (s, 3H) ppm. 13C NMR (CDCl3, 100 MHz): δ =
160.7, 147.3, 130.2, 129.8, 129.5, 128.7, 128.00, 127.96, 126.1, 126.0,
124.5, 116.7, 114.3, 55.4 ppm. HRMS (ESI-TOF) m/z: [M + Na]+ calcd.
for C16H12N2ONa: 299.0903, found 299.0905.
4-Phenyl-7-(trifluoromethyl)tetrazolo[1,5-a]quinoline (4c): pale
yellow needle (63 mg, 40 % yield); m.p. 226.0–228.0 °C (from
CH2Cl2/hexanes). IR (neat): ν = 3069, 1630, 1523, 1499, 1442 cm–1
.
˜
1H NMR (CDCl3, 400 MHz): δ = 8.86 (d, J = 8.8 Hz, 1H), 8.34 (s, 1H), 4-(4-Fluorophenyl)tetrazolo[1,5-a]quinoline (4k): pale brown
8.18 (d, J = 7.2 Hz, 2H), 8.14 (s, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.62–
solid (112 mg, 85 % yield); m.p. 230.0–231.4 °C (from CH2Cl2/hex-
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anes). IR (neat): ν = 3066, 1687, 1600, 1508, 1465 cm–1
(CDCl3, 400 MHz): δ = 8.72 (d, J = 8.4 Hz, 1H), 8.20–8.17 (m, 2H),
8.05–8.02 (m, 2H), 7.87 (d, J = 8.2 Hz, 1H), 7.74 (t, J = 7.2 Hz, 1H),
7.29–7.25 (m, 2H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 148.6 (d,
.
1H NMR 1H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 160.1 (d, JC,F = 248.9 Hz),
˜
147.2, 132.9 (d, JC,F = 6.0 Hz), 131.8, 131.2, 131.1, 130.1, 129.1, 128.1,
124.6 (d, JC,F = 3.5 Hz), 124.0, 121.7 (d, JC,F = 12.5 Hz), 120.9, 116.8,
116.4 (d, JC,F = 22.1 Hz) ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd.
for C15H10FN4: 265.0884, found 265.0883.
JC,F = 248.8 Hz), 147.2, 130.8, 130.5 (d, JC,F = 8.3 Hz), 130.0, 129.3,
128.9, 128.2, 125.6, 124.3, 116.9, 116.1 (d, JC,F = 21.6 Hz) ppm. HRMS
(ESI-TOF) m/z: [M + Na]+ calcd. for C15H9FN4Na: 287.0706, found
287.0703.
4-(2-Chlorophenyl)tetrazolo[1,5-a]quinoline (4s): pale yellow
solid (41 mg, 29 % yield); m.p. 182.5–183.2 °C (from CH2Cl2/hex-
anes). IR (neat): ν = 3074, 1620, 1523, 1483, 1458 cm–1 1H NMR
.
˜
4-(4-Chlorophenyl)tetrazolo[1,5-a]quinoline (4l): pale brown
(CDCl3, 400 MHz): δ = 8.74 (d, J = 8.4 Hz, 1H), 8.03–8.01 (m, 2H),
7.90 (t, J = 7.6 Hz, 1H), 7.74 (t, J = 7.4 Hz, 1H), 7.68–7.65 (m, 1H),
7.60–7.58 (m, 1H), 7.46–7.43 (m, 2H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 147.4, 133.3, 132.9, 131.8, 131.2, 130.6, 130.4, 129.1,
128.2, 127.1, 124.4, 123.9, 116.9 ppm. HRMS (ESI-TOF) m/z: [M + H]+
calcd. for C15H10ClN4: 281.0589, found 281.0588.
solid (95 mg, 68 % yield); m.p. 229.7–231.3 °C (from CH2Cl2/hex-
anes). IR (neat): ν = 3063, 1678, 1525, 1493, 1464 cm–1 1H NMR
.
˜
(CDCl3, 400 MHz): δ = 8.71 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.8 Hz,
2H), 8.08 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.88 (t, J = 7.8 Hz, 1H), 7.84
(t, J = 7.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 147.1, 135.8, 132.2, 131.0, 130.1, 129.8, 129.5, 129.3,
129.0, 128.3, 125.4, 124.3, 116.9 ppm. HRMS (ESI-TOF) m/z: [M + H]+
calcd. for C15H10ClN4: 281.0589, found 281.0588.
4-(2,4-Dimethylphenyl)tetrazolo[1,5-a]quinoline (4t): pale yel-
low solid (45 mg, 33 % yield); m.p. 166.0–168.0 °C (from CH2Cl2/
1
hexanes). IR (neat): ν = 3073, 1666, 1523, 1501, 1461 cm–1. H NMR
˜
4-(4-Bromophenyl)tetrazolo[1,5-a]quinoline (4m): colorless nee-
(CDCl3, 400 MHz): δ = 8.74 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.0 Hz,
1H), 7.88 (t, J = 7.2 Hz, 1H), 7.81 (s, 1H), 7.73 (t, J = 7.6 Hz, 1H), 7.34
(d, J = 7.6 Hz, 1H), 7.21 (s, 1H), 7.15 (d, J = 7.6 Hz, 1H), 2.41 (s, 3H),
2.26 (s, 3H) ppm 13C NMR (CDCl3, 100 MHz): δ = 147.7, 139.3, 136.5,
132.0, 131.6, 131.1, 130.6, 130.1, 128.8, 128.0, 127.6, 126.9, 124.2,
116.9, 21.2, 20.3 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd. for
dle (117 mg, 72 % yield); m.p. 235.5–237.5 °C (from CH2Cl2/hexanes).
IR (neat): ν = 3054, 1670, 1522, 1490, 1463 cm–1 1H NMR (CDCl3,
.
˜
400 MHz): δ = 8.71 (d, J = 8.4 Hz, 1H), 8.08–8.06 (m, 3H), 8.03 (d,
J = 8.0 Hz, 1H), 7.88 (t, J = 7.2 Hz, 1H), 7.76–7.69 (m, 3H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 147.0, 132.7, 132.2, 131.0, 130.0, 129.5,
129.0, 128.3, 125.4, 124.3, 124.1, 116.9 ppm. HRMS (ESI-TOF) m/z: [M
+ Na]+ calcd. for C15H9BrN4Na: 346.9908, found 346.9902.
C17H15N4: 275.1291, found 275.1293.
4-(Naphthalen-2-yl)tetrazolo[1,5-a]quinoline (4u): pale yellow
4-(3-Fluorophenyl)tetrazolo[1,5-a]quinoline (4o): white solid
solid (24 mg, 16 % yield); m.p. 183.9–185.9 °C (from CH2Cl2/hex-
(94 mg, 71 % yield); m.p. 208.9–209.8 °C (from CH2Cl2/hexanes). IR
anes). IR (neat): ν = 3046, 1687, 1523, 1507, 1449 cm–1 1H NMR
.
˜
(neat): ν = 3058, 1692, 1583, 1528, 1461 cm–1 1H NMR (CDCl3,
.
˜
(CDCl3, 400 MHz): δ = 8.80 (d, J = 8.4 Hz, 1H), 8.04–7.91 (m, 5H),
7.79–7.71 (m, 3H), 7.63 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.2 Hz, 1H),
7.47 (t, J = 7.6 Hz, 1H) ppm 13C NMR (CDCl3, 100 MHz): δ = 148.2,
134.0, 133.2, 131.8, 131.4, 131.0, 130.3, 129.9, 129.0, 128.7, 128.3,
128.2, 126.7, 126.3, 126.0, 125.3, 125.0, 124.2, 117.0 ppm. HRMS (ESI-
TOF) m/z: [M + H]+ calcd. for C19H13N4: 297.1135, found 297.1136.
400 MHz): δ = 8.63 (d, J = 8.0 Hz, 1H), 8.09 (s, 1H), 8.03 (d, J = 7.6 Hz,
1H), 7.98–7.97 (m, 1H), 7.96–7.92 (m, 2H), 7.75–7.71 (m, 1H), 7.54–
7.51 (m, 1H), 7.194–7.186 (m, 1H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 163.0 (d, JC,F = 245.1 Hz), 147.0, 135.8 (d, JC,F = 7.9 Hz), 131.1,
130.5 (d, JC,F = 8.3 Hz), 130.1, 129.9, 129.1, 128.3, 125.2, 124.2 (d,
J
C,F = 2.8 Hz), 124.1, 116.8, 116.5 (d, JC,F = 21.1 Hz), 115.6 (d, JC,F =
23.3 Hz) ppm. HRMS (ESI-TOF) m/z: [M + Na]+ calcd. for C15H9FN4Na:
4-(Thiophen-2-yl)tetrazolo[1,5-a]quinoline (4v): pale yellow solid
287.0703, found 287.0709.
(68 mg, 54 % yield); m.p. 179.4–180.5 °C (from CH2Cl2/hexanes). IR
(neat): ν = 3078, 1679, 1599, 1538, 1453 cm–1 1H NMR (CDCl3,
.
˜
4-(3-Chlorophenyl)tetrazolo[1,5-a]quinoline (4p): pale brown
400 MHz): δ = 8.52 (d, J = 8.0 Hz, 1H), 8.34 (dd, J = 3.8, 1.0 Hz, 1H),
7.93 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.72 (t, J = 8.4 Hz, 1H), 7.60 (t,
J = 8.2 Hz, 1H), 7.43 (dd, J = 5.0, 1.0 Hz, 1H), 7.17–7.15 (m, 1H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 146.0, 135.9, 130.3, 129.7, 129.3,
128.6, 128.5, 128.1, 127.4, 126.4, 124.1, 120.3, 116.6 ppm; HRMS
(ESI-TOF) m/z: [M + Na]+ calcd. for C13H8N4SNa: 275.0362, found
275.0364.
solid (97 mg, 69 % yield); m.p. 182.5–184.3 °C (from CH2Cl2/hex-
anes). IR (neat): ν = 3053, 1681, 1567, 1526, 1464 cm–1 1H NMR
.
˜
(CDCl3, 400 MHz): δ = 8.69 (d, J = 8.4 Hz, 1H), 8.12–8.08 (m, 3H),
8.03 (d, J = 8.0 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.73 (t, J = 7.6 Hz,
1H), 7.51–7.45 (m, 2H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 147.0,
135.5, 135.0, 131.1, 130.2, 130.1, 130.0, 129.6, 129.1, 128.4, 128.3,
126.8, 125.1, 124.1, 116.8 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd.
for C15H10ClN4: 281.0589, found 281.0586.
Tetrazolo[1,5-a]quinoline (4w):[5a–5b] pale yellow needle (17 mg,
20 % yield); m.p. 147.6–149.9 °C (from CH2Cl2/hexanes) (lit.[5a] m.p.
4-(3-Bromophenyl)tetrazolo[1,5-a]quinoline (4q): pale brown
156–157 °C). IR (neat): ν = 3075, 1697, 1529, 1448 cm–1 1H NMR
.
˜
solid (96 mg, 59 %); m.p. 226.0–227.9 °C (from CH2Cl2/hexanes). IR
(neat): ν = 3055, 1648, 1586, 1523, 1493 cm–1 1H NMR (CDCl3,
.
(CDCl3, 400 MHz): δ = 8.68 (d, J = 8.4 Hz, 1H), 7.98–7.94 (m, 2H),
7.89–7.84 (m, 2H), 7.71 (t, J = 7.6 Hz, 1H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 147.4, 133.3, 131.2, 130.8, 128.9, 128.0, 123.8, 116.8,
112.6 ppm. HRMS (ESI-TOF) m/z [M + Na]+ calcd. for C9H6N4Na:
193.0485, found 193.0487.
˜
400 MHz): δ = 8.68 (d, J = 8.4 Hz, 1H), 8.26 (s, 1H), 8.14 (d, J = 8.0 Hz,
1H), 8.06 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.73
(t, J = 7.6 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 147.0, 135.7, 132.5, 131.2,
131.1, 130.4, 130.1, 130.0, 129.1, 128.3, 127.3, 124.9, 124.1, 123.0,
116.8 ppm. HRMS (ESI-TOF) m/z: [M + Na]+ calcd. for C15H9BrN4Na:
346.9903, found 346.9906.
4-Butyltetrazolo[1,5-a]quinoline (4x): pale brown solid (60 mg,
53 % yield); m.p. 83.9–85.9 °C (from CH2Cl2/hexanes). IR (neat): ν =
˜
3058, 2961, 1691, 1614, 1529, 1461 cm–1. 1H NMR (CDCl3, 400 MHz):
δ = 8.57 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.74 (t, J =
8.4 Hz, 1H), 7.63 (t, J = 8.0 Hz, 2H), 3.11 (t, J = 7.8 Hz, 2H), 1.89–1.81
(m, 2H), 1.50–1.41 m, 2H), 0.68 (t, J = 7.4 Hz, 3H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 148.0, 129.8, 129.6, 129.5, 128.2, 128.1, 127.8,
124.3, 116.5, 31.0, 30.7, 22.4, 13.7 ppm. HRMS (ESI-TOF) m/z: [M +
Na]+ calcd. for C13H14N4Na: 249.1111, found 249.1107.
4-(2-Fluorophenyl)tetrazolo[1,5-a]quinoline (4r): colorless crystal
(71 mg, 54 % yield); m.p. 186.7–187.8 °C (from CH2Cl2/hexanes). IR
(neat): ν = 3085, 1618, 1527, 1491, 1461 cm–1 1H NMR (CDCl3,
.
˜
400 MHz): δ = 8.70 (d, J = 8.0 Hz, 1H), 8.13 (s, 1H), 8.08–8.04 (m,
1H), 8.00 (d, J = 8.0 Hz, 1H), 7.87 (t, J = 8.2 Hz, 1H), 7.72 (t, J =
7.2 Hz, 1H), 7.51–7.45 (m, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.30–7.25 (m,
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4-Hexyltetrazolo[1,5-a]quinoline (4y): pale yellow solid (97 mg,
(d, J = 8.8 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.74 (t, J = 7.6 Hz, 1H),
7.57 (t, J = 7.4 Hz, 1H), 7.54–7.43 (m, 5H) ppm. 13C NMR (CDCl3,
76 % yield); m.p. 73.4–75.2 °C (from CH2Cl2/hexanes). IR (neat): ν =
˜
3098, 2929, 1674, 1610, 1524, 1458 cm–1. 1H NMR (CDCl3, 400 MHz): 100 MHz): δ = 149.5, 146.8, 138.7, 137.5, 134.7, 130.3, 129.5, 128.2,
δ = 8.54 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.72 (t, J =
7.8 Hz, 1H), 7.63–7.59 (m, 2H), 3.08 (t, J = 7.8 Hz, 1H), 1.88–1.81 (m,
2H), 1.43–1.38 (m, 2H), 1.35–1.25 (m, 4H), 0.86–0.83 (m, 3H) ppm.
13C NMR (CDCl3, 100 MHz): δ = 148.0, 129.7, 129.5, 129.4, 128.1,
128.0, 127.7, 124.3, 116.4, 31.4, 31.2, 28.9, 28.5, 22.4, 13.9 ppm.
HRMS (ESI-TOF) m/z: [M + Na]+ calcd. for C15H18N4Na: 277.1424,
found 277.1422.
127.4, 127.2, 127.1 ppm. HRMS (ESI-TOF) m/z: [M + Na]+ calcd. for
C15H10ClNNa: 262.0394, found 262.0396.
General procedure for the synthesis of 4-phenyltetrazolo[1,5-a]-
quinoline-5-d ([d1]-4a). To the three-neck flask filled with o-(phe-
nylethynyl)isocyanobenzene (2a), freshly prepared from the corre-
sponding N-(2-(phenylethynyl)phenyl)formamide (1a, 0.5 mmol),
was diluted with dry DMF (2 mL) under argon atmosphere. To this
mixture was added sodium azide (0.75 mmol, 1.5 equiv.) and D2O
(0.018 mL, 2 equiv.). The reaction mixture was stirred at room tem-
perature for 2 h. After completion, the reaction mixture was diluted
with H2O (5 mL) and the resulting mixture was extracted with ethyl
acetate (3 × 10 mL). The combined organic layers were washed with
brine (20 mL), dried (MgSO4), filtered, and concentrated (aspirator).
Crude product was purified by column chromatography on silica
gel (hexanes/ethyl acetate) to synthesize the corresponding
4-phenyltetrazolo[1,5-a]quinoline-5-d ([d1]-4a). The mixture of
([d1]-4a) and 4a ([d1]-4a/4a = 9:1, 1H NMR analysis): pale yellow
4-Isopentyltetrazolo[1,5-a]quinoline (4z): pale brown solid
(73 mg, 61 % yield); m.p. 60.2–61.4 °C (from CH2Cl2/hexanes). IR
1
(neat): ν = 3060, 2955, 2865, 1689, 1613, 1534, 1465 cm–1. H NMR
˜
(CDCl3, 400 MHz): δ = 8.57 (d, J = 8.4 Hz, 1H), 7.86 (d, J = 7.6 Hz,
1H), 7.74 (t, J = 7.8 Hz, 1H), 7.65–7.61 (m, 2H), 3.11 (t, J = 8.0 Hz,
2H), 1.78–1.66 (m, 3H), 0.99 (d, J = 6.4 Hz, 6H); ppm. 13C NMR (CDCl3,
100 MHz): δ = 148.0, 129.8, 129.6, 129.3, 128.3, 128.2, 127.8, 124.3,
116.5, 37.6, 29.1, 27.8, 22.4 ppm. HRMS (ESI-TOF) m/z: [M + Na]+
calcd. for C14H16N4Na: 263.1267, found 263.1264.
4-Cyclopropyltetrazolo[1,5-a]quinoline (4a′): pale yellow solid
(57 mg, 54 % yield); m.p. 129.0–130.9 °C (from CH2Cl2/hexanes). IR
solid; IR (neat): ν = 3055, 1680, 1525, 1455, 1440 cm–1 1H NMR
.
˜
(CDCl3, 400 MHz): δ = 8.71 (d, J = 8.4 Hz, 1H), 8.16 (d, J = 7.6 Hz,
2H), 8.07 (s, 0.1H of 4a), 8.02 (d, J = 8.0 Hz, 1H), 7.85 (t, J = 7.4 Hz,
1H), 7.72 (t, J = 7.4 Hz, 1H), 7.59–7.55 (m, 2H), 7.52–7.48 (m, 1H);
13C NMR (CDCl3, 100 MHz): δ = 147.3, 133.8, 130.7, 130.0, 129.6,
129.0, 128.9, 128.5, 128.1, 126.5, 124.3, 116.8 ppm.
1
(neat): ν = 3098, 1670, 1525, 1458 cm–1. H NMR (CDCl3, 400 MHz):
˜
δ = 8.57 (d, J = 8.0 Hz, 1H), 7.82 (dd, J = 8.0, 1.2 Hz, 1H), 7.72 (t, J =
8.4 Hz, 1H), 7.61 (t, J = 8.2 Hz, 1H), 7.44 (s, 1H), 2.55–2.48 (m, 1H),
1.21–1.19 (m, 4H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 147.9, 130.0,
129.6, 129.2, 128.0, 127.8, 125.9, 124.3, 116.5, 12.4, 8.6 ppm. HRMS
(ESI-TOF) m/z: [M + Na]+ calcd. for C12H10N4Na: 233.0798, found
233.0799.
Acknowledgments
Synthesis of 3-phenylquinolin-2-amine (5).[12] To a round-bot-
tomed flask filled with 4-phenyltetrazolo[1,5-a]quinoline (4a)
(123 mg, 0.5 mmol) was diluted with DMF (2 mL). To this mixture
was added Cu(OAc)2·H2O (200 mg, 2 equiv.). The reaction mixture
was stirred at 130 °C for overnight. The reaction mixture was diluted
with H2O (5 mL) and the resulting mixture was extracted with EtOAc
(3 × 10 mL). The combined organic layers were washed with brine
(20 mL), dried (MgSO4), filtered, and concentrated (aspirator). Crude
product was purified by column chromatography on silica gel (3:2
v/v, hexanes/ethyl acetate) to yield the corresponding 3-phenyl-
quinolin-2-amine (5). Pale yellow solid (56 mg, 51 % yield); m.p.
We thank the Thailand Research Fund (BRG6180005 and
IRN58W0005), the Center of Excellence for Innovation in Chem-
istry (PERCH-CIC), Ministry of Higher Education, Science, Re-
search and Innovation for financial support. The Institute for
the Promotion of Teaching Science and Technology through
Science Achievement Scholarship of Thailand (SAST) for student
scholarships to O. K. is also gratefully acknowledged.
Keywords: Cyclization · Isocyanides · Nitrogen
heterocycles · Synthetic methods
148.7–150.5 °C (from CH2Cl2/hexanes). IR (neat): ν = 3455, 3100,
˜
1
1430 cm–1. H NMR (CDCl3, 400 MHz): δ = 7.77 (s, 1H), 7.69 (d, J =
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8.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.54–
7.47 (m, 4H), 7.44–7.40 (m, 1H), 7.28–7.24 (m, 1H), 5.13 (br s, 2H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 155.2, 147.0, 137.5, 137.3,
129.7, 129.1, 128.9, 128.2, 127.5, 125.4, 125.0, 124.1, 122.8 ppm.
HRMS (ESI-TOF) m/z: [M + H]+ calcd. for C15H13N2: 221.1073, found
221.1075.
Synthesis of 2-chloro-3-phenylquinoline (6).[8b,8c] To a round-
bottomed flask filled with o-alkynylisocyanobenzene (2a) [freshly
prepared from the corresponding N-(2-(phenylethynyl)phenyl)form-
amide (1a, 221 mg, 1 mmol)] was diluted with DMF (2 mL). To this
mixture was added tetrabutylammonium chloride (556 mg, 2
mmol). The reaction mixture was stirred at room temperature for
overnight. After completion, the reaction mixture was diluted with
H2O (5 mL) and the resulting mixture was extracted with ethyl acet-
ate (3 × 10 mL). The combined organic layers were washed with
brine (20 mL), dried (MgSO4), filtered, and concentrated (aspirator).
Crude product was purified by column chromatography on silica
gel (4:1 v/v, hexanes/ethyl acetate) to yield the corresponding
2-chloro-3-phenylquinoline (6). Pale yellow solid (184.6 mg, 77 %
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.
1H NMR (CDCl3, 400 MHz): δ = 8.09 (s, 1H), 8.07
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Received: August 17, 2019
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Annulation
O. Khaikate, D. Soorukram,
P. Leowanawat, M. Pohmakotr,
V. Reutrakul, C. Kuhakarn* .............. 1–9
Azide-Triggered Bicyclization of o-
Alkynylisocyanobenzenes: Synthesis
of Tetrazolo[1,5-a]quinolines
Anefficientsynthesisoftetrazolo[1,5-a]- proceeds through the nucleophilic ad-
quinolines employing the reaction of dition of the azide to the isocyanide
o-alkynylisocyanobenzenes with so- and a subsequent by 6-endo cycliza-
dium azide is described. The reaction tion.
DOI: 10.1002/ejoc.201901209
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