Microwave-assisted cycloadditions of 2-alkynylbenzonitriles with sodium azide: selective synthesis of tetrazolo[5,1-a]pyridines and 4,5-disubstituted-2H-1,2,3-triazoles

Article abstract of DOI:10.1016/j.tet.2009.08.009

Under microwave irradiation (75 W), treatment of 2-alkynylbenzonitriles with 1.5 equiv of sodium azide in DMSO at 140 °C gave 4,5-disubstituted-2H-1,2,3-triazoles in 60-99% yields. Additionally, adding 8 equiv of ZnBr₂ and using 8 equiv of sodi

Full text of DOI:10.1016/j.tet.2009.08.009

Tetrahedron 65 (2009) 8367–8372
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Microwave-assisted cycloadditions of 2-alkynylbenzonitriles with sodium azide:
selective synthesis of tetrazolo[5,1-a]pyridines and 4,5-disubstituted-2H-1,2,3-
triazoles
,
Chih-Wei Tsai a, Shyh-Chyun Yang a, Ya-Ming Liu b, Ming-Jung Wu c
*
a Graduate Institute of Pharmaceutical Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan, ROC
b Faculty of medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung City 807, Taiwan, ROC
c Department of Chemistry, National Sun Yat-sen University, Kaohsiung City 804, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 June 2009
Received in revised form 3 August 2009
Accepted 6 August 2009
Available online 9 August 2009
Under microwave irradiation (75 W), treatment of 2-alkynylbenzonitriles with 1.5 equiv of sodium azide
in DMSO at 140 ꢀC gave 4,5-disubstituted-2H-1,2,3-triazoles in 60–99% yields. Additionally, adding
8 equiv of ZnBr2 and using 8 equiv of sodium azide in DMF at 100 ꢀC lead to the formation of tetra-
zolo[5,1-a]isoquinolines up to 87% yield.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Tetrazolo[5,1-a]pyridines
4,5-Disubstituted-2H-1,2,3-triazoles
1. Introduction
alkynes with unsubstituted azides, such as sodium azide, is lim-
ited.7 Normally, the reaction required longer time at high tem-
1,2,3-Triazoles are important molecules for pharmaceutical and
agricultural use.1 Recently, Shi reported that the N-2-aryl-2H-
1,2,3-triazoles have unique photonic properties.2 Therefore the
development of an efficient method for constructing substituted-
2H-1,2,3-triazoles has become an important synthetic organic
chemistry topic. The general synthetic method for synthesizing
1,2,3-triazoles involves the thermal 1,3-dipolar cycloaddition re-
action of organic azides with alkynes pioneered by Huisgen.3 The
drawbacks of this method are poor regioselectivity and long re-
action time. Improved methods were reported by the Sharpless
group with so-called ‘click chemistry’4 and by the Meldal group.5
They reported that cycloaddition reactions of terminal alkynes
with alkyl azides using Cu(I) as a catalyst can be performed under
mild conditions and give products with high yields and high
regioselectivities. However, these methods cannot be applied to
the internal alkynes.
perature to give the adducts in low to modest yields7b–d unless
there is a strong electron-withdrawing group attached to the al-
kyne terminus.7e–f
Tetrazolo[5,1-a]isoquinolines are also compounds with phar-
maceutical interest. It has been shown that these molecules
show good monoamine oxidase inhibition activity.8 Under ther-
mal or photochemical conditions, these compounds can be
converted to various heterocyclic compounds through pyr-
idylnitrene intermediates.9 However, the available methods for
synthesizing tetrazolo[5,1-a]isoquinolines and related molecules
are limited.9,10 Herein, we report efficient methods to selectively
synthesize 4,5-disubstituted-2H-1,2,3-triazoles and tetrazolo[5,1-
a]isoquinolines via reaction of 2-alkynylbenzonitriles with so-
dium azide.
Recently, the Weinreb group reported successful cycloadditions
of internal alkynes with alkyl azides over a ruthenium catalyst to
give 4,5-disubstituted triazoles.6 Still, a direct method to produce
4,5-disubstituted-1,2,3-triazoles by cycloadditions of internal
2. Results and discussion
The starting internal alkynes were prepared by the following
two routes: 2-(2-arylethynyl)benzonitriles 3a–k were prepared
by Sonogashira coupling of 2-ethynylbenzonitrile (1)11 with
various aryl iodides 2a–k in 40–81% yields (Scheme 1). The 2-
alkynylbenzonitriles 3l–n were synthesized by coupling of 2-
bromobenzonitrile (4) with alkynes 5a–c in 80–89% yields
(Scheme 1).
* Corresponding author. Tel.: þ886 7 5252000; fax: þ886 7 5253909.
E-mail address: mijuwu@faculty.nsysu.edu.tw (M.-J. Wu).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.009

8368
C.-W. Tsai et al. / Tetrahedron 65 (2009) 8367–8372
Ar
Use of microwave irradiation to enhance reaction rates has
Pd(PPh3)4
been known for years.13 Hallberg has applied this method to
prepare a variety of tetrazoles by the reaction of sodium azide
with corresponding nitriles.12a Fokin also found that micro-
wave irradiation could accelerate the reaction rate of ruthe-
nium-catalyzed cycloaddition reactions of substituted azides
with terminal alkynes.14 We carried out the reaction of 3a with
1.5 equiv of sodium azide in dimethyl sulfoxide under micro-
wave irradiation (75 W) at 140 ꢀC. The reaction went to com-
pletion within 10 min and produced the triazole adduct 6a in
98% yield. At the optimal reaction conditions, we then turned
our attention to the scope and generality of this method. Thus,
various substituted 2-alkynylbenzonitriles 3b–n were prepared
(Scheme 1) and submitted to the cycloaddition conditions to
afford the 4,5-disubstituted-2H-1,2,3-triazoles in 60–99% yields
(Table 2). The results show that all of the attempted reactions
were successfully completed under the optimal reaction con-
ditions. The reaction only required longer time when trazole
has a phenyl ring bearing electron-donating groups (Table 2,
entries 6–9). Triazoles with strong electron-withdrawing
group, such as a nitro group, resulted in slightly lower yields
but faster than the others (Table 2, entries 4 and 5). The ortho-
substituted phenyl rings and bulky tert-butyl group also gave
cycloadditon adducts in somewhat lower yields (Table 2, en-
tries 3, 5, 7, 9, and 14).
+
ArI
CuI, nBuNH2
Et2O
CN
CN
1
3
2a-k
3a. Ar = C6H5 (85%)
3g. Ar = o-MeC6H4 (49%)
3b. Ar = p-CF3C6H4 (77%) 3h. Ar = p-MeOC6H4 (73%)
3c. Ar = o-CF3C6H4 (58%) 3i. Ar = o-MeOC6H4 (57%)
3d. Ar = p-NO2C6H4 (61%) 3j. Ar = 2-thienyl (63%)
3e. Ar = o-NO2C6H4 (81%) 3k. Ar = 2-pyridinyl (61%)
3f. Ar = p-MeC6H4 (40%)
R
Br
Pd(PPh3)4
+
CN
R
CuI, nBuNH2
CN
THF, 80 o
C
4
5
3l. R = n-butyl (89%)
3m. R = i-butyl (80%)
3n.R = t-butyl (86%)
Scheme 1. Synthesis of intermediates 3a–n.
Our initial attempt at the cycloaddition of an internal alkyne
with sodium azide was carried out by mixing compound 3a with
5 equiv of sodium azide in DMF at 80 ꢀC. We found that this re-
action requires 6 days to consume the starting material but gives
the corresponding triazole 6a in 98% yield (Table 1, entry 1).
Doubling the amount of sodium azide to 10 equiv did not accel-
erate the reaction rate (Table 1, entry 2). Addition of copper sul-
fate along with sodium ascorbate into the reaction mixture did
not improve the reaction (Table 1, entry 3). Magnesium bromide
was also employed; however, no significant improvement was
observed (Table 1, entry 4). Ammonium and zinc salts have been
used to promote and catalyze, respectively, the reaction of orga-
nonitriles with sodium azide to give tetrazoles in high yields.12
Therefore, we introduced ammonium chloride into the reaction
mixture, and the reaction gave tetrazolo[5,1-a]isoquinoline and
triazole adducts in 47% and 50% yields, respectively (Table 1, entry
5). However, when zinc bromide was introduced to the reaction
mixture, although the reaction still took place very slowly, tetra-
zolo[5,1-a]isoquinoline was obtained as the only product (Table 1,
entry 6). The high selectivity of the formation of tetrazolo[5,1-
a]isoquinoline is because of zinc bromide could coordinate and
activate the cyano group. Thus, sodium azide would react with the
cyano group first to form the tetrazole and followed by cyclization
to give the tetrazolo[5,1-a]isoquinoline. This exciting initial result
encourages us to continue the investigation of these cycloaddition
reactions.
Table 2
The result of the reactions of 3a–n with sodium azide by microwave irradiation
H
N
R
N
N
NaN3 (1.5eq)
NC
R
DMSO, 140 °C
75 W
CN
3
6
Entry
R
Time (min)
Isolated products/yields (%)
1
2
3
4
5
6
7
8
C6H5
10
4
10
5
6a/98
6b/99
6c/95
6d/72
6e/66
6f/96
6g/60
6h/99
6i/92
6j/87
6k/84
6l/99
6m/81
6n/70
p-CF3C6H4
o-CF3C6H4
p-NO2C6H4
o-NO2C6H4
p-MeC6H4
o-MeC6H4
p-MeOC6H4
o-MeOC6H4
2-Thienyl
2-Pyridinyl
n-Butyl
5
25
30
40
90
7
9
10
11
12
13
14
6
12
15
20
i-Butyl
tert-Butyl
Table 1
The result of the reactions of 3a with sodium azide using various additives
H
N
Previously, we found that the reaction of sodium azide with
3a in the presence of zinc bromide gave tetrazolo[5,1-a]iso-
quinoline 7a in good yield, albeit, in long reaction time. When
the reaction was carried out under microwave irradiation (75 W)
at 100 ꢀC, the reaction went to completion in 4 h and gave the
product 7a in 69% yield. The other substrates 3b–n were also
reacted under the described conditions. The results are sum-
marized in Table 3. Most of the substrates gave the desired
products in good to excellent yields (Table 3, entries 1–3, 5–9,
and 11–13). The only exceptions occurred for the phenyl ring
bearing a nitro group, which gave the tetrazoloisoquinoline ad-
duct 7d in 30% yield, (Table 3, entry 4) and for compound 3k
bearing the 2-pyridinyl group at the terminus alkyne, which was
consumed very quickly under this reaction condition, but was
mostly decomposed (Table 3, entry 10).
Ph
Ph
N
N
NaN3
+
NC
N
additives
Ph
N
N
7a
DMF, 80 °C
N
CN
3a
6a
Isolated yields (%)
Entry NaN3 (equiv) Additive
Time (d) 3a
6a
7a
1
2
3
4
5
6
5
10
5
10
10
10
None
None
6
10
6
6
10
6
0
0
0
19
46
30
98
95
86
50a
0
0
0
8
CuSO4/Sodium ascorbate
NH4Cl/LiCl (10 equiv)
ZnBr2 (10 equiv)
47a
86a
4a
MgBr2 (10 equiv)
95a
a
Yields are calculated base on recovered starting materials.

C.-W. Tsai et al. / Tetrahedron 65 (2009) 8367–8372
8369
2-(2-(2-(trifluoromethyl)phenyl)ethynyl)benzonitrile17 (3c), 2-(2-
(4-(methyl)phenyl)ethynyl)benzonitrile15 (3f), 2-(2-(4-methoxyp-
henyl)ethynyl)benzonitrile17 (3h), 2-(2-(2-methoxyphenyl)ethy-
nyl)benzonitrile17 (3i), 2-(2-(2-thienyl)ethynyl)benzonitrile18 (3j),
and 2-(2-(pyridin-2-yl)ethynyl)benzonitrile18 (3k).
Table 3
The result of the reactions of 3a–n with sodium azide by microwave irradiation in
the presence of ZnBr2
R
NaN3 (8 eq)
ZnBr2 (8 eq)
R
N
N
DMF, 100 °C
75 W
CN
N
N
4.2.1. 2-(2-(4-Nitrophenyl)ethynyl)benzonitrile (3d). Yellow solid;
7
3
mp 133–134 ꢀC; 1H NMR (400 MHz, CDCl3):
d
8.24 (d, J¼8.8 Hz, 2H),
7.75 (d, J¼8.8 Hz, 2H), 7.72 (d, J¼7.6 Hz, 1H), 7.67 (d, J¼7.6 Hz, 1H),
Entry
R
Time (h)
Isolated products/yields (%)
7.62 (t, J¼7.6 Hz, 1H), 7.49 (t, J¼7.6 Hz, 1H); 13C NMR (100 MHz,
1
2
3
4
5
6
7
8
C6H5
4
3
3
0.5
5
5
6
5
7a/69
7b/85
7c/70
7d/30
7f/70
7g/63
7h/70
7i/68
7j/87
7k/0
CDCl3)
d 147.6, 132.8, 132.7, 132.6, 132.3, 129.3, 128.7, 125.9, 123.7,
p-CF3C6H4
o-CF3C6H4
p-NO2C6H4
p-MeC6H4
o-MeC6H4
117.2, 115.6, 93.4, 90.1; GC/MS (70 eV): m/z (%): 248 (100) [Mþ], 218
(49), 203 (28), 190 (39), 175 (16); HRMS (EI) calcd for C15H8N2O2
248.0586, found 248.0586. Anal. Calcd for C15H8N2O2: C, 72.58; H,
3.25; N, 11.28. Found: C, 72.68; H, 3.35; N, 11.25.
p-MeOC6H4
o-MeOC6H4
2-Thienyl
2-Pyridinyl
n-Butyl
4.2.2. 2-(2-(2-Nitrophenyl)ethynyl)benzonitrile (3e). Brown solid;
9
2
mp 143–144 ꢀC; 1H NMR (400 MHz, CDCl3):
d
8.13 (d, J¼8.4 Hz, 1H),
10
11
12
13
5 (min)
5
2
2
7l/85
7m/73
7n/83
7.86 (d, J¼7.6 Hz,1H), 7.73–7.59 (m, 4H), 7.54 (t, J¼7.6 Hz,1H), 7.48 (t,
i-Butyl
tert-Butyl
J¼7.6 Hz,1H); 13C NMR (100 MHz, CDCl3)
d 149.2,135.4,133.2,132.8,
132.7, 132.5, 129.6, 129.2, 126.2, 124.8, 117.6, 117.3, 115.4, 92.5, 90.8;
GC/MS (70 eV): m/z (%): 248 (21) [Mþ], 231 (30), 220 (60), 201 (21),
192 (34), 176 (24), 164 (36), 130 (100), 102 (36); HRMS (EI) calcd for
C15H8N2O2 248.0586, found 248.0586. Anal. Calcd for C15H8N2O2: C,
72.58; H, 3.25; N, 11.28. Found: C, 72.55; H, 3.35; N, 11.25.
3. Conclusion
In conclusion, we have developed methods for selectively
synthesizing 4,5-disubstituted-2H-1,2,3-triazoles and tetrazolo[5,1-
a]isoquinolines by the reactions of 2-alkynylbezonitriles with
sodium azide. Moreover, the reaction rate can be accelerated by
microwave irradiation. It is known that reactions of internal alkynes
with unsubstituted azides always require long reaction times.
Herein, we have demonstrated that use of microwave irradiation to
assist these cycloaddition reactions is an efficient method for directly
preparing a variety of 4,5-disubstituted-2H-1,2,3-triazoles.
4.2.3. 2-(2-(2-(Methyl)phenyl)ethynyl)benzonitrile (3g). White solid;
mp 77–78 ꢀC; 1H NMR (200 MHz, CDCl3):
d
7.72–7.52 (m, 4H),
7.45–7.38 (m, 1H), 7.26–7.15 (m, 3H), 2.59 (s, 3H); 13C NMR (50 MHz,
CDCl3) 140.9, 132.7, 132.4, 132.3, 132.2, 129.6, 129.3, 128.1, 127.5,
d
125.6, 121.8, 117.7, 114.9, 94.9, 89.2, 20.9; GC/MS (70 eV): m/z (%): 217
(100) [Mþ], 191 (12), 189 (14); HRMS (EI) calcd for C16H11N 217.0891,
found 217.0892. Anal. Calcd for C16H11N: C, 88.45; H, 5.10; N, 6.45.
Found: C, 88.34; H, 5.10; N, 6.40.
4. Experimental section
4.3. General procedure for cross-coupling reaction (3l–n)
4.1. Microwave irradiation experiments
To a degassed solution of each 1-alkyne (5a–c) (2.0 mmol) in
THF (20 mL) containing CuI (0.54 mmol) and n-BuNH2 (5.0 mrnol)
All microwave irradiation experiments were carried out in a ded-
icated monomode microwave reactor Synthwave 402 (Prolabo), op-
erating at a frequency of 2455 MHz with continuous irradiation
power from 0 to 300 W utilizing the standard absorbance level of
300 W maximum power. The machine was used in the standard
configuration as delivered, including proprietary software. The re-
actions were carried out in 10 mL glass vials, which can be exposed to
a maximum of 250 ꢀC. The temperature was measured with an IR
sensor on the outer surface of the process vial. After the irradiation
period, the reaction vessel was cooled to ambient temperature.
was added
a degassed solution of 2-bromobenzonitrile (4)
(2.0 mmol) containing Pd(PPh3)4 (0.14 mmol) in THF (20 mL). The
resulting solution was stirred at 80 ꢀC for 4 h and quenched with
saturated aqueous NH4Cl solution. The aqueous layer was extracted
with EtOAc (30 mLꢁ3) and the combined organic extracts were
washed with saturated aqueous Na2CO3 solution (40 mL) and dried
over anhydrous MgSO4. After filtration and removal of solvent
under reduced pressure, the residue was purified by column
chromatography on silica gel (hexanes as eluent) to give the desired
products 3l–n, in yields indicated as in (Scheme 1).
4.2. General procedure for cross-coupling reaction (3a–k)
The following compounds, prepared by the above procedure,
have been previously reported: 2-(hex-1-ynyl)benzonitrile15 (3l)
and 2-(3,3-dimethylbut-1-ynyl)benzonitrile18 (3n).
To a degassed solution of 2-ethynylbenzonitrile (1) (2.0 mmol)
in Et2O (20 mL) containing CuI (0.54 mmol) and n-BuNH2
(5.0 mrnol) was added a degassed solution of aryl iodide (2a–k)
(2.0 mmol) containing Pd(PPh3)4 (0.14 mmol) in Et2O (20 mL). The
resulting solution was stirred for 4 h and quenched with saturated
aqueous NH4Cl solution. The aqueous layer was extracted with
EtOAc (30 mLꢁ3) and the combined organic extracts were washed
with saturated aqueous Na2CO3 solution (40 mL) and dried over
anhydrous MgSO4. After filtration and removal of solvent under
reduced pressure, the residue was purified by column chromato-
graphy on silica gel (hexanes as eluent) to give the desired products
3a–k, in yields indicated as in Eq. 1.
4.3.1. 2-(4-Methylpent-1-ynyl)benzonitrile (3m). Yellow liquid; 1H
NMR (400 MHz, CDCl3):
d
7.60 (d, J¼7.6 Hz, 1H), 7.53–7.48 (m, 2H),
7.37–7.32 (m,1H), 2.39 (d, J¼6.4 Hz, 2H),1.97 (sept, J¼6.4 Hz,1H),1.08
(d, J¼6.4 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d 132.4, 132.21, 132.16,
128.0,127.5,117.7,115.1, 96.8, 78.0, 28.6, 27.9, 21.9; GC/MS (70 eV): m/z
(%): 183 (20) [Mþ],141 (100),114 (47); MS (ESI): 206 [MþNa]þ; HRMS
(ESI) calcd for C13H13NNa [MþNa]þ 206.0946, found 206.0945.
4.4. General procedure for the microwave-assisted reactions
to synthesize 4,5-disubstituted triazoles
The following compounds, prepared by the above procedure,
have beenpreviously reported: 2-(2-(phenyl)ethynyl)benzonitrile15
(3a), 2-(2-(4-(trifluoromethyl)phenyl)ethynyl)benzonitrile16 (3b),
An appropriate 2-alkynylbenzonitrile (0.4 mmol) and sodium
azide (0.6 mmol) were suspended in DMSO (3 mL) in a 10 mL

8370
C.-W. Tsai et al. / Tetrahedron 65 (2009) 8367–8372
glass vial. The mixture was then irradiated for the time and
temperature indicated in Table 2, using an irradiation power of
75 W. After completion of the reaction, the vial was cooled to
25 ꢀC. The mixture was then diluted with water (20 mL), extrac-
ted with EtOAc (10 mLꢁ3), and dried over anhydrous MgSO4.
After filtration and removal of solvent under reduced pressure,
the residue was purified by column chromatography on silica gel
to furnish the product triazoles 6a–n, in yields indicated as in
Table 2.
117.7, 112.6, 21.2; GC/MS (70 eV): m/z (%): 260 (100) [Mþ], 233
(33), 231 (28), 204 (17); HRMS (EI) calcd for C16H12N4 260.1062,
found 260.1064.
4.4.7. 2-(5-o-Tolyl-2H-1,2,3-triazol-4-yl)benzonitrile(6g). Yellow liq-
uid; 1H NMR (400 MHz, CDCl3):
d
7.73 (dd, J¼7.6,1.6 Hz,1H), 7.49 (td,
J¼7.6, 1.6 Hz, 1H), 7.42 (td, J¼7.6, 1.6 Hz, 1H), 7.34–7.29 (m, 2H), 7.24
(dd, J¼7.6, 0.4 Hz, 1H), 7.19–7.17 (m, 2H), 2.12 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 143.4, 141.7, 137.2, 134.0, 132.7, 130.8, 130.4, 130.0,
129.2,128.62,128.56,126.0,118.1,111.7, 20.0; GC/MS (70 eV): m/z (%):
260 (40) [Mþ], 231 (100), 204 (28), 177 (8); HRMS (EI) calcd for
C16H12N4 260.1062, found 260.1061.
4.4.1. 2-(5-Phenyl-2H-1,2,3-triazol-4-yl)benzonitrile (6a). Yellow liq-
uid; 1H NMR (400 MHz, CDCl3):
d
7.77 (d, J¼8.0 Hz, 1H), 7.60 (t,
J¼8.0 Hz, 1H), 7.53 (d, J¼8.0 Hz, 1H), 7.50 (t, J¼8.0 Hz, 1H), 7.44 (d,
J¼8.0 Hz, 2H), 7.35–7.30 (m, 3H); 13C NMR (100 MHz, CDCl3)
d 143.6,
4.4.8. 2-(5-(4-Methoxyphenyl)-2H-1,2,3-triazol-4-yl)benzonitrile
(6h). Brown liquid; 1H NMR (400 MHz, CDCl3):
d
7.76 (d, J¼8.0 Hz,
140.3, 134.4, 133.7, 132.8, 130.9, 129.1, 128.9, 128.84, 128.82, 127.6,
117.7, 112.4; GC/MS (70 eV): m/z (%): 246 (100) [Mþ], 219 (30), 190
(27); HRMS (EI) calcd for C15H10N4 246.0905, found 246.0908.
1H), 7.60 (t, J¼8.0 Hz, 1H), 7.54–7.47 (m, 2H), 7.35 (d, J¼8.8 Hz, 1H),
6.85 (d, J¼8.8 Hz, 1H), 3.79 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
160.0, 143.2, 139.9, 134.6, 133.7, 132.7, 130.8, 129.0, 128.8, 121.4,
117.7, 114.3, 112.5, 55.2; GC/MS (70 eV): m/z (%): 276 (100) [Mþ], 233
(16), 205 (33), 178 (18), 151 (14); HRMS (EI) calcd for C16H12N4O
276.1011, found 276.1011.
4.4.2. 2-(5-(4-(Trifluoromethyl)phenyl)-2H-1,2,3-triazol-4-yl)benzo-
nitrile (6b). Yellow solid; mp 115–116 ꢀC; 1H NMR (400 MHz,
CDCl3):
d
7.81 (d, J¼8.0 Hz, 1H), 7.65 (t, J¼8.0 Hz, 1H), 7.59 (s, 4H),
7.57–7.51 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
143.3, 140.8, 133.9,
4.4.9. 2-(5-(2-Methoxyphenyl)-2H-1,2,3-triazol-4-yl)benzonitrile
133.2, 133.0, 130.8, 130.6, 129.4, 128.7, 127.9, 125.7, 123.8, 117.6,
112.5; GC/MS (70 eV): m/z (%): 314 (100) [Mþ], 288 (26), 258 (23),
190 (34); HRMS (EI) calcd for C16H9F3N4 314.0779, found 314.0780.
Anal. Calcd for C16H9F3N4: C, 61.15; H, 2.89; N, 17.83. Found: C,
61.08; H, 2.85; N, 17.85.
(6i). Brown liquid; 1H NMR (200 MHz, CDCl3):
d
7.70 (d, J¼7.6 Hz,
1H), 7.60–7.37 (m, 3H), 7.29 (t, J¼7.6 Hz, 2H), 6.91 (t, J¼7.6 Hz, 2H);
13C NMR (50 MHz, CDCl3)
156.1, 141.1, 137.0, 135.6, 133.3, 132.4,
d
130.6, 130.2, 129.9, 128.3, 120.9, 117.6, 117.0, 112.0,111.4, 55.1; GC/MS
(70 eV): m/z (%): 276 (100) [Mþ], 248 (54), 233 (52), 219 (87), 205
(56), 190 (30), 178 (19); HRMS (EI) calcd for C16H12N4O 276.1011,
found 276.1010.
4.4.3. 2-(5-(2-(Trifluoromethyl)phenyl)-2H-1,2,3-triazol-4-yl)benzo-
nitrile (6c). Light yellow solid; mp 169–170 ꢀC; 1H NMR (400 MHz,
CDCl3): d 13.30 (br s,1H), 7.78–7.73 (m, 2H), 7.57–7.53 (m, 2H), 7.46–
4.4.10. 2-(5-(Thiophen-2-yl)-2H-1,2,3-triazol-4-yl)benzonitrile
7.36 (m, 3H), 7.19 (d, J¼7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
(6j). Absinthe-green liquid; 1H NMR (400 MHz, CDCl3):
d 7.82 (d,
d
142.1 (2), 134.1, 133.2, 132.8, 132.6, 131.8, 130.1, 129.9, 129.5, 128.8,
J¼8.0 Hz, 1H), 7.70–7.63 (m, 2H), 7.56 (t, J¼8.0 Hz, 1H), 7.32 (dd,
128.3, 126.8, 123.5, 118.2, 111.9; GC/MS (70 eV): m/z (%): 314 (100)
[Mþ], 288 (40), 265 (32), 245 (34), 239 (16), 190 (31), 167 (38), 88
(36); HRMS (EI) calcd for C16H9F3N4 314.0779, found 314.0781. Anal.
Calcd for C16H9F3N4: C, 61.15; H, 2.89; N, 17.83. Found: C, 61.18; H,
2.85; N, 17.83.
J¼5.2, 1.2 Hz,1H), 7.05 (dd, J¼4.0, 1.2 Hz, 1H), 6.98 (dd, J¼5.2, 4.0 Hz,
1H); 13C NMR (100 MHz, CDCl3)
d 139.9, 139.6, 133.9, 133.7, 132.8,
131.0, 130.8, 129.4, 127.6, 126.7, 126.4, 117.5, 113.0; GC/MS (70 eV):
m/z (%): 252 (100) [Mþ], 223 (16), 196 (20); HRMS (EI) calcd for
C13H8N4S 252.0470, found 252.0471.
4.4.4. 2-(5-(4-Nitrophenyl)-2H-1,2,3-triazol-4-yl)benzonitrile
4.4.11. 2-(5-(Pyridin-2-yl)-2H-1,2,3-triazol-4-yl)benzonitrile
(6d). Yellow solid; mp 205–206 ꢀC; 1H NMR (400 MHz, CD3OD):
(6k). Brown liquid; 1H NMR (400 MHz, CDCl3):
d 8.60 (s, 1H), 7.77–
7.63 (m, 6H), 7.51 (t, J¼7.6 Hz, 1H), 7.28 (s, 1H); 13C NMR (100 MHz,
d
8.2 (d, J¼8.8 Hz, 2H), 7.89 (d, J¼8.0 Hz, 1H), 7.80 (t, J¼8.0 Hz, 1H),
7.70–7.64 (m, 2H), 7.67 (d, J¼8.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3)
d 149.5, 148.6, 141.3, 137.2, 134.7, 133.4, 132.7, 131.2, 129.0,
123.6,122.2,117.8,113.0; GC/MS (70 eV): m/z (%): 247 (23) [Mþ], 246
(100), 219 (16), 218 (28), 192 (30), 191 (44), 164 (11); HRMS (EI)
calcd for C14H9N5 247.0858, found 247.0860.
CD3OD)
d 149.0, 138.0, 135.5, 134.9, 134.6, 132.3, 131.1, 129.2, 125.0,
118.2, 113.9; GC/MS (70 eV): m/z (%): 291 (100) [Mþ], 261 (55), 205
(19), 190 (59), 178 (30), 151 (15); HRMS (EI) calcd for C15H9N5O2
291.0756, found 291.0756. Anal. Calcd for C15H9N5O2: C, 61.85; H,
3.11; N, 24.04. Found: C, 61.83; H, 3.21; N, 24.10.
4.4.12. 2-(5-Butyl-2H-1,2,3-triazol-4-yl)benzonitrile (6l). Yellow solid;
mp 85–86 ꢀC; 1H NMR (400 MHz, CDCl3):
d 9.20 (br s, 1H), 7.80 (d,
4.4.5. 2-(5-(2-Nitrophenyl)-2H-1,2,3-triazol-4-yl)benzonitrile
J¼7.6 Hz, 1H), 7.69 (t, J¼7.6 Hz, 1H), 7.61 (d, J¼7.6 Hz, 1H), 7.52 (t,
J¼7.6 Hz, 1H), 2.82 (t, J¼7.6 Hz, 2H), 1.64 (quint, J¼7.6 Hz, 2H), 1.30
(sext, J¼7.6 Hz, 2H), 0.84 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
(6e). Orange solid; mp 181–182 ꢀC; 1H NMR (400 MHz, CDCl3):
d
13.00 (br s, 1H), 7.95 (d, J¼8.0 Hz, 1H), 7.73 (d, J¼8.0 Hz, 1H), 7.67
(t, J¼8.0 Hz, 1H), 7.60–7.52 (m, 3H), 7.47 (t, J¼8.0 Hz, 1H), 7.37 (d,
d
143.0, 141.0, 134.5, 133.6, 132.8, 130.4, 128.7, 118.1, 112.2, 30.7, 24.1,
J¼8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 148.8, 142.1, 141.9, 133.9,
22.2, 13.5; GC/MS (70 eV): m/z (%): 226 (2) [Mþ], 198 (27), 184 (100),
169 (13), 155 (55), 129 (29); HRMS (EI) calcd for C13H14N4 226.1218,
found 226.1219. Anal. Calcd for C13H14N4: C, 69.00; H, 6.24; N, 24.76.
Found: C, 69.03; H, 6.31; N, 24.42.
133.2, 133.0, 132.9, 132.7, 130.4, 130.2, 129.2, 124.9, 124.8, 117.6,
111.9; GC/MS (70 eV): m/z (%): 291 (9) [Mþ], 245 (100), 190 (35), 163
(7); HRMS (EI) calcd for C15H9N5O2 291.0756, found 291.0753. Anal.
Calcd for C15H9N5O2: C, 61.85; H, 3.11; N, 24.04. Found: C, 62.00; H,
3.12; N, 24.24.
4.4.13. 2-(5-Isobutyl-2H-1,2,3-triazol-4-yl)benzonitrile
(6m). Yellow oil; 1H NMR (400 MHz, CDCl3):
d
7.79 (dt, J¼8.0,
4.4.6. 2-(5-p-Tolyl-2H-1,2,3-triazol-4-yl)benzonitrile (6f). Light brown
0.8 Hz, 1H), 7.67 (td, J¼8.0, 1.2 Hz, 1H), 7.58 (dt, J¼8.0, 0.8 Hz,
1H), 7.50 (td, J¼8.0, 1.2 Hz, 1H), 2.70 (d, J¼7.2 Hz, 2H), 1.92
(sept, J¼7.2 Hz, 1H), 0.81 (d, J¼7.2 Hz, 6H); 13C NMR (100 MHz,
liquid; 1H NMR (200 MHz, CDCl3):
d
7.76 (d, J¼8.0 Hz, 1H), 7.60 (t,
J¼8.0 Hz, 1H), 7.57–7.45 (m, 2H), 7.32 (d, J¼8.4 Hz, 2H), 7.13 (d,
J¼8.4 Hz, 2H), 2.34 (s, 3H); 13C NMR (50 MHz, CDCl3)
d 143.5,
CDCl3)
d 142.2, 141.7, 134.8, 133.6, 132.8, 130.6, 128.7, 118.1,
112.4, 33.3, 28.5, 22.2; GC/MS (70 eV): m/z (%): 226 (2) [Mþ],
140.1, 138.8, 134.6, 133.7, 132.7, 130.9, 129.5, 128.8, 127.5, 126.2,

C.-W. Tsai et al. / Tetrahedron 65 (2009) 8367–8372
8371
211 (33), 198 (83), 184 (58), 156 (36), 155 (100), 129 (37); MS
(ESI): 227 [MþH]þ; HRMS (ESI) calcd for C13H15N4 [MþH]þ
227.1297, found 227.1299.
7.90 (m, 2H), 7.626 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
148.7, 148.6,
137.0, 132.6, 132.1, 131.7, 130.3, 130.1, 127.9, 125.4, 124.1, 119.5, 117.9;
MS (ESI): 292 [MþH]þ; HRMS (ESI) calcd for C15H10N5O2 [MþH]þ
292.0834, found 292.0832. Anal. Calcd for C15H9N5O2: C, 61.85;
H, 3.11; N, 24.04. Found: C, 61.81; H, 3.10; N, 24.00.
4.4.14. 2-(5-tert-Butyl-2H-1,2,3-triazol-4-yl)benzonitrile
(6n). White solid; mp 188–189 ꢀC; 1H NMR (400 MHz, CDCl3):
d
7.77 (dt, J¼8.0, 0.8 Hz, 1H), 7.66 (td, J¼8.0, 1.2 Hz, 1H), 7.54 (td,
4.5.5. 5-(4-(Methyl)phenyl)tetrazolo[5,1-a]isoquinoline (7f). Yellow
J¼8.0, 1.2 Hz, 1H), 7.51 (dt, J¼8.0, 0.8 Hz, 1H), 1.27 (s, 9H); 13C NMR
solid; mp 210–211 ꢀC; 1H NMR (200 MHz, CDCl3);
d
8.80 (d,
J¼9.2 Hz, 1H), 7.96–7.78 (m, 5H), 7.46 (s, 1H), 7.39 (d, J¼7.8 Hz,
1H), 2.48 (s, 3H); 13C NMR (50 MHz, CDCl3)
148.6, 140.7,
(100 MHz, CDCl3)
d 150.8, 140.2, 137.0, 132.8, 132.2, 132.0, 129.2,
117.5, 114.7, 31.6, 30.3; GC/MS (70 eV): m/z (%): 226 (2) [Mþ], 211
(100), 184 (13), 168 (21), 156 (11), 129 (14); MS (ESI): 227 [MþH]þ;
HRMS (ESI) calcd for C13H15N4 [MþH]þ 227.1297, found 227.1298.
Anal. Calcd for C13H14N4: C, 69.00; H, 6.24; N, 24.76. Found: C,
69.04; H, 6.31; N, 24.33.
d
135.2, 132.2, 131.6, 129.5, 129.0, 128.9, 128.2, 127.3, 125.1, 118.9,
115.7, 21.4; GC/MS (70 eV): m/z (%): 234 (100, M-26); MS
(ESI): 283 [MþNa]þ, 261 [MþH]þ; HRMS (ESI) calcd for
C16H12N4Na [MþNa]þ 283.0960, found 283.0958. Anal. Calcd
for C16H12N4: C, 73.83; H, 4.65; N, 21.52. Found: C, 73.83; H,
4.55; N, 21.52.
4.5. General procedure for the microwave-assisted reactions
to synthesize tetrazoloisoquinolines
4.5.6. 5-(2-(Methyl)phenyl)tetrazolo[5,1-a]isoquinoline (7g). Yellow
An appropriate 2-alkynylbenzonitrile (0.4 mmol), zinc bromide
(3.2 mmol), and sodium azide (3.2 mmol) were suspended in DMF
(3 mL) in a 10 mL glass vial. The mixture was then irradiated for the
time and temperature indicated in Table 3, using an irradiation
power of 75 W. After completion of the reaction, the vial was cooled
to 25 ꢀC. The mixture was then diluted with water (20 mL),
extracted with EtOAc (10 mLꢁ3), and dried over anhydrous MgSO4.
After filtration and removal of solvent under reduced pressure, the
residue was purified by column chromatography on silica gel to
furnish the product tetrazoloisoquinolines 7a–m, in yields in-
dicated as in Table 3.
solid; mp 153–154 ꢀC; 1H NMR (400 MHz, CDCl3);
d 8.82 (d,
J¼8.0 Hz, 1H), 7.94 (d, J¼8.0 Hz, 1H), 7.88–7.81 (m, 2H), 7.51–7.46
(m, 2H), 7.42–7.34 (m, 2H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
148.1, 137.7, 134.8, 132.0, 131.6, 131.0, 130.6, 130.4, 130.3, 129.3,
127.4, 126.1, 125.1, 119.1, 117.4, 19.8; MS (ESI): 283 [MþNa]þ, 261
[MþH]þ; HRMS (ESI) calcd for C16H12N4Na [MþNa]þ 283.0960,
found 283.0958. Anal. Calcd for C16H12N4: C, 73.83; H, 4.65; N,
21.52. Found: C, 73.83; H, 4.63; N, 21.54.
4.5.7. 5-(4-Methoxyphenyl)tetrazolo[5,1-a]isoquinoline
(7h). Yellow solid; mp 195–196 ꢀC; 1H NMR (400 MHz, CDCl3);
d
8.78 (d, J¼8.0 Hz, 1H), 7.97 (d, J¼8.8 Hz, 2H), 7.92 (d, J¼8.0 Hz,
1H), 7.84–7.75 (m, 2H), 7.42 (s, 1H), 7.09 (d, J¼8.8 Hz, 2H), 3.91
(s, 3H); 13C NMR (100 MHz, CDCl3)
161.2, 148.6, 134.9, 132.3,
4.5.1. 5-Phenyltetrazolo[5,1-a]isoquinoline (7a). White solid; mp
210–211 ꢀC; 1H NMR (400 MHz, CDCl3);
d
8.81 (dd, J¼7.2, 1.6 Hz,
d
1H), 8.01–7.99 (m, 2H), 7.95 (dd, J¼7.2, 1.6 Hz, 1H), 7.87–7.79 (m,
131.6, 130.6, 128.9, 127.2, 125.1, 123.3, 118.7, 115.3, 114.2, 55.4;
MS (ESI): 299 [MþNa]þ, 277 [MþH]þ; HRMS (ESI) calcd for
C16H12N4ONa [MþNa]þ 299.0909, found 299.0911. Anal. Calcd
for C16H12N4O: C, 69.55; H, 4.38; N, 20.28. Found: C, 69.55; H,
4.38; N, 20.30.
2H), 7.62–7.56 (m, 3H), 7.49 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
148.6, 135.0, 132.2, 131.7, 131.0, 130.4, 129.3, 129.1, 128.8, 127.4,
125.1, 119.0, 116.3; GC/MS (70 eV): m/z (%): 220 (100, M-26), 194 (9),
165 (7); MS (ESI): 269 [MþNa]þ, 247 [MþH]þ; HRMS (ESI) calcd for
C15H10N4Na [MþNa]þ 269.0803, found 269.0805. Anal. Calcd for
C13H14N4: C, 73.16; H, 4.09; N, 22.75. Found: C, 73.12; H, 4.08; N,
22.46.
4.5.8. 5-(2-Methoxyphenyl)tetrazolo[5,1-a]isoquinoline (7i). Yellow
solid; mp 178–179 ꢀC; 1H NMR (400 MHz, CDCl3)
d 8.81 (d,
J¼7.2 Hz, 1H), 7.91 (d, J¼7.2 Hz, 1H), 7.85–7.80 (m, 2H), 7.59–7.53
4.5.2. 5-(4-(Trifluoromethyl)phenyl)tetrazolo[5,1-a]isoquinoline
(m, 2H), 7.39 (s, 1H), 7.14 (t, J¼8.0 Hz, 1H), 7.11 (d, J¼8.0 Hz, 1H),
(7b). Yellow solid; mp 182–183 ꢀC; 1H NMR (400 MHz, CDCl3);
3.78 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 157.8, 148.1, 132.7, 132.1,
d
8.83 (d, J¼8.0 Hz, 1H), 8.15 (d, J¼8.8 Hz, 2H), 7.99 (d, J¼8.0 Hz, 1H),
132.0, 131.4, 131.2, 129.1, 127.4, 125.1, 120.7, 120.4, 119.2, 117.5,
111.5, 55.6; MS (ESI): 299 [MþNa]þ, 277 [MþH]þ; HRMS (ESI)
calcd for C16H12N4ONa [MþNa]þ 299.0909, found 299.0910. Anal.
Calcd for C16H9N5O2: C, 69.55; H, 4.38; N, 20.28. Found: C, 69.60;
H, 4.40; N, 20.28.
7.91–7.84 (m, 4H), 7.55 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
148.6,
134.4, 133.5, 132.2, 132.0, 131.9, 129.9, 129.5, 127.7, 125.8, 125.3,
123.6, 119.3, 117.2; GC/MS (70 eV): m/z (%): 288 (100, M-26); MS
(ESI): 337 [MþNa]þ, 315 [MþH]þ; HRMS (ESI) calcd for
C16H9F3N4Na [MþNa]þ 337.0677, found 337.0674. Anal. Calcd for
C16H9F3N4: C, 61.15; H, 2.89; N, 17.83. Found: C, 61.08; H, 2.85; N,
17.85.
4.5.9. 5-(2-Thienyl)tetrazolo[5,1-a]isoquinoline (7j). Yellow solid;
mp 188–189 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.74 (d, J¼8.0 Hz,
1H), 8.31 (dd, J¼3.6, 1.2 Hz, 1H), 7.90 (d, J¼8.0 Hz, 1H), 7.82–7.73
(m, 2H), 7.64 (s, 1H), 7.56 (dd, J¼5.2, 1.2 Hz, 1H), 7.25 (dd, J¼5.2,
4.5.3. 5-(2-(Trifluoromethyl)phenyl)tetrazolo[5,1-a]isoquinoline
(7c). White solid; mp 200–201 ꢀC; 1H NMR (400 MHz, CDCl3);
3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 148.3, 132.1, 132.0,
d
8.83 (d, J¼8.4 Hz, 1H), 7.95–7.84 (m, 4H), 7.78–7.73 (m, 2H), 7.62
131.7, 130.2, 129.15, 129.11, 128.6, 128.2, 127.2, 125.0, 118.4,
113.9; MS (ESI): 275 [MþNa]þ; HRMS (ESI) calcd for
C13H8N4SNa [MþNa]þ 275.0367, found 275.0369. Anal. Calcd for
C13H8N4S: C, 61.89; H, 3.20; N, 22.21. Found: C, 61.88; H, 3.25;
N, 22.25.
(d, J¼7.2 Hz, 1H), 7.38 (s, 1H); 13C NMR (100 MHz, CDCl3)
d 148.0,
132.3, 132.1, 131.8, 131.5, 131.0, 130.6, 130.1, 129.8, 129.1, 127.7, 126.8,
125.2, 123.4, 119.4, 118.3; GC/MS (70 eV): m/z (%): 288 (100, M-26),
247 (74), 222 (20), 207 (20); MS (ESI): 337 [MþNa]þ, 315 [MþH]þ;
HRMS (ESI) calcd for C16H9F3N4Na [MþNa]þ 337.0677, found
377.0675. Anal. Calcd for C16H9F3N4: C, 61.15; H, 2.89; N, 17.83.
Found: C, 61.08; H, 2.85; N, 17.85.
4.5.10. 5-Butyltetrazolo[5,1-a]isoquinoline (7l). White solid; mp
102–103 ꢀC; 1H NMR (400 MHz, CDCl3);
d
8.70 (d, J¼7.6 Hz, 1H),
7.84–7.70 (m, 3H), 7.15 (s, 1H), 3.28 (t, J¼7.6 Hz, 2H), 1.90 (quint,
4.5.4. 5-(4-Nitrophenyl)tetrazolo[5,1-a]isoquinoline (7d). Yellow solid;
J¼7.6 Hz, 2H), 1.50 (sext, 7.2 Hz, 2H), 0.99 (t, J¼7.2 Hz, 3H); 13C NMR
mp 240–241 ꢀC; 1H NMR (400 MHz, CDCl3)
d
8.85 (d, J¼9.2 Hz, 1H),
(100 MHz, CDCl3) d 148.0, 136.0, 132.1, 131.4, 128.5, 126.8, 124.9,
8.46 (d, J¼8.8 Hz, 2H), 8.24 (d, J¼8.8 Hz, 2H), 8.01 (d, J¼9.2 Hz, 1H),
118.5, 114.2, 30.4, 28.8, 22.3, 13.7; MS (ESI): 249 [MþNa]þ, 227

8372
C.-W. Tsai et al. / Tetrahedron 65 (2009) 8367–8372
[MþH]þ; HRMS (ESI) calcd for C13H14N4Na [MþNa]þ 249.1116,
found 249.1115. Anal. Calcd for C13H14N4: C, 69.00; H, 6.24; N, 24.76.
Found: C, 69.03; H, 6.31; N, 24.42.
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13. (a) Loupy, A. Microwaves in Organic Synthesis; Wiley-VCH Verlag GmbH & Co.
KGaA: Weinheim, 2002; (b) Suna, E.; Mutule, I. Top. Curr. Chem. 2006, 266, 49–101.
14. Rasmussen, L. K.; Boren, B. C.; Fokin, V. V. Org. Lett. 2007, 9, 5337–5339.
15. Wu, M. J.; Chang, L. J.; Wei, L. M.; Lin, C. F. Tetrahedron 1999, 55, 13193–13200.
16. Kleinpeter, E.; Schulenburg, A. J. Org. Chem. 2006, 71, 3869–3875.
17. Lin, C. F.; Yang, J. H.; Hsieh, P. C.; Lu, W. D.; Wu, M. J. J. Chin. Chem. Soc. 2001, 48,
211–214.
4.5.11. 5-(2-Methylpropyl)tetrazolo[5,1-a]isoquinoline (7m). White
solid; mp 71–72 ꢀC; 1H NMR (400 MHz, CDCl3):
d
8.72 (d, J¼8.0 Hz,
1H), 7.85 (d, J¼8.0 Hz, 1H), 7.79 (td, J¼8.0, 1.2 Hz, 1H), 7.74 (td,
J¼8.0, 1.2 Hz, 1H), 7.14 (s, 1H), 3.14 (d, J¼7.2 Hz, 2H), 2.41 (sept,
J¼7.2 Hz, 1H), 1.03 (d, J¼7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d
148.2, 135.1, 132.0, 131.4, 128.6, 126.8, 125.0, 118.6, 115.5, 40.0,
26.4, 22.4; GC/MS (70 eV): m/z (%): 226 (6) [Mþ], 198 (68), 183
(100), 155 (33), 128 (28); MS (ESI): 227 [MþH]þ; HRMS (ESI) calcd
for C13H15N4 [MþH]þ 227.1297, found 227.1298. Anal. Calcd for
C13H14N4: C, 69.00; H, 6.24; N, 24.76. Found: C, 69.00; H, 6.31; N,
24.57.
4.5.12. 5-(1,1-Dimethylethyl)tetrazolo[5,1-a]isoquinoline
(7n). White solid; mp 137–138 ꢀC; 1H NMR (400 MHz, CDCl3):
d
8.73 (dt, J¼7.6, 0.8 Hz, 1H), 7.86 (d, J¼7.6 Hz, 1H), 7.79 (td, J¼7.6,
1.2 Hz, 1H), 7.73 (td, J¼7.6, 1.2 Hz, 1H), 7.22 (s, 1H), 1.69 (s, 9H); 13C
NMR (100 MHz, CDCl3)
d 148.8, 143.8, 132.2, 131.4, 128.7, 127.2,
124.8, 118.7, 112.6, 35.9, 28.0; GC/MS (70 eV): m/z (%): 226 (4) [Mþ],
198 (54), 183 (100), 168 (15), 142 (32), 115 (19); MS (ESI): 227
[MþH]þ; HRMS (ESI) calcd for C13H15N4 [MþH]þ 227.1297, found
227.1299. Anal. Calcd for C13H14N4: C, 69.00; H, 6.24; N, 24.76.
Found: C, 69.04; H, 6.31; N, 24.43.
Acknowledgements
We thank the National Science Council of the Republic of China
for financial support.
18. Lu, W. D.; Lin, C. F.; Wang, C. J.; Wang, S. J.; Wu, M. J. Tetrahedron 2002, 58,
7315–7319.