Facile, efficient and eco-friendly synthesis of 5-sulfenyl tetrazole derivatives of indoles and pyrroles

Article abstract of DOI:10.1016/j.tetlet.2014.01.101

A concise, two-step eco-friendly approach towards the synthesis of 5-sulfenyl tetrazole derivatives of indoles and pyrroles, is reported. The synthesis comprises the oxone-mediated thiocyanation of the starting heterocycles towards intermediate 3-thiocyanato indoles and 2-thiocyanato pyrroles, and their subsequent treatment with sodium azide in 2-propanol/water under zinc bromide promotion.

Full text of DOI:10.1016/j.tetlet.2014.01.101

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile, efficient and eco-friendly synthesis of 5-sulfenyl tetrazole
derivatives of indoles and pyrroles
a,
Bruna L. Kuhn a, Margiani P. Fortes a, Teodoro S. Kaufman b, , Claudio C. Silveira
⇑
⇑
a Departamento de Química, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
b Instituto de Química Rosario (IQUIR, CONICET-UNR) and FCByF—Universidad Nacional de Rosario, Suipacha 531, 2000 Rosario, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise, two-step eco-friendly approach towards the synthesis of 5-sulfenyl tetrazole derivatives of
indoles and pyrroles, is reported. The synthesis comprises the oxone-mediated thiocyanation of the start-
ing heterocycles towards intermediate 3-thiocyanato indoles and 2-thiocyanato pyrroles, and their sub-
sequent treatment with sodium azide in 2-propanol/water under zinc bromide promotion.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 24 December 2013
Revised 20 January 2014
Accepted 22 January 2014
Available online xxxx
Keywords:
5-Sulfenyl tetrazoles
Pyrrole and indole derivatives
Thiocyanation
Eco-friendly functionalization of
heterocycles
Zinc bromide promoted reaction
The tetrazoles are five-membered ring 6
p-heterocycles, con-
out by reaction with inorganic thiocyanate salts under assistance
by different acid catalysts or oxidants. Acids include montmoril-
lonite K-10,12a acid alumina,12b TsOH12c and Amberlyst-15,12d
taining four contiguous nitrogen atoms.1a They are not found in
Nature;1b however, tetrazole derivatives possess interesting appli-
cations in agriculture, pharmacy, photography and as components
of explosives. In medicinal chemistry, they are employed as
metabolically-stable carboxylic acid isosteres.2
while oxidants encompass HIO3,13a I2O5,13b I2/MeOH,13c CAN,13d
Mn(OAc)3,13e FeCl3,13f DDQ,13g H2O2
others.
and OxoneÒ,13i among
13h
5-Substituted tetrazoles are usually prepared by
a
[3+2]
5-Sulfenyl tetrazoles are a small and special group of tetrazoles
that can be found as a distinguished motif in active pharmaceutical
ingredients, such as cefamandol and latamoxef, and other poten-
tially bioactive molecules (Fig. 1).14
5-Sulfenyl tetrazoles have been occasionally synthesized from
thiocyanates and inorganic azides during studies on 5-substituted
tetrazoles.7a,b,9a
cycloaddition reaction between organic nitriles and hydrazoic
acid,3 commonly generated in situ from azides, including NaN3,4
TMSN3,5a,b tin5c,d and organoaluminium azides,5e,f and DPPA,5g
and protic or Lewis acids such as I2,6a NaHSO4/SiO2,6a TMSCl,6b
7d
Et3NÁHCl,6c NH4Cl,7a NH4Cl/LiCl,7b Cu2O,7c AlCl3 and FeCl3.4a An
intramolecular version has also been reported, employing an
organic azide moiety.8
In addition, 1-substituted 5-thiotetrazoles have been used as
capping agents for stabilization of gold nanoparticles,15a while
5-ethyl- and 5-benzyl-thio-1H-tetrazole are used as 1H-tetrazole
replacements in oligonucleotide synthesis.15b,c The sulfur atom of
the thioether group conveys better solubility and turns the tetra-
zole ring more acidic than the corresponding 5-alkyl tetrazoles,
improving their ability to act as activators.16
More recently, the use zinc promoters, especially ZnBr2 in
water-based solvents, has greatly simplified the synthesis.9 Varia-
tions including mesoporous ZnS nanospheres,10a Zn/Al hydrotal-
cite,10b Bu2SnO10c and ZnCl2 under solventless conditions have
also been reported.10d Ionic liquids10e and a catalyst-free method
in glycerol10f have been proposed as alternative media.
Thiocyanates are versatile chemical intermediates, which em-
body a strategically useful entry to various derivatives carrying
C–S bonds.11 Thiocyanation of heteroaromatics has been carried
4b
NH4Cl15,17 and ZnBr2 have been employed as promoters for
the synthesis of 5-thio- and 5-seleno tetrazoles; Et3NÁHCl18a and
magnetic Fe3O4 nanoparticles have also been used recently.18b
Additionally, 5-alkyl(aryl)thiotetrazoles, were advantageously pre-
pared in a toluene-water biphasic system under phase-transfer
catalysis which eased work-up operations,17b and further, Et2AlN3
was also used as a source of the azide ion.5e,f
⇑
Corresponding authors. Tel./fax: +55 55 3220 8754.
E-mail addresses: kaufman@iquir-conicet.gov.ar (T.S. Kaufman), silveira@
quimica.ufsm.br (C.C. Silveira).
http://dx.doi.org/10.1016/j.tetlet.2014.01.101
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kuhn, B. L.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.01.101

2
B. L. Kuhn et al. / Tetrahedron Letters xxx (2014) xxx–xxx
NH4SCN, employing oxone as oxidizing agent. Following an adap-
OH
CO2H
tation of the work of Wu13i and based on our previous results,20
the amount of NH4SCN was limited to 1 mmol/mmol of heterocy-
cle in order to avoid formation of polythiocyanated compounds.
In all cases (Table 1), the thiocyanation was efficient and fur-
nished the expected compounds in short times and with high reg-
ioselectivity. Only 3-substituted indoles and 2-substituted pyrroles
were obtained.21 In their infrared spectra, all compounds exhibited
the typical CN stretching band of the SCN moiety at 2100–
2200 cmÀ1 and a resonance at 110–113 ppm in the 13C NMR spec-
tra. The mechanism of the thiocyanation has been studied.13i
With the thiocyanato derivatives in hand, the next step was the
[3+2] cycloaddition towards the tetrazoles. This was attempted
under different conditions and later optimized, by systematically
changing the solvent, amount of NaN3 and promoter. The effects
of time and reaction temperature were also studied, with the re-
sults summarized in Table 2.
N
N
N
N
O
O
N
N
N
N
OMe
N
Me
HO
N
S
N
O
O
Me
H
H
N
S
S
Cl
O
CO2Na
CO2H
Cefamandol (antibiotic)
Latamoxef (antibiotic)
S
H
N
N
S
O
H
NO2
N
N
N
N
Cl
Cl
S
H
S
N
O
N
N
N
N
N
N
N
N
Antitubercular
Antiviral (HIV)
Analgesic
Figure 1. Examples of bioactive 5-sulfenyl tetrazoles.
Employing the protocols of the groups of Das6a (entry 1) and
Hallberg,22 low product yields and incomplete consumption of
the starting material were observed (entry 2). On the other hand,
use of glycerol as the reaction medium without promoter (entry
3)10f and water as the sole solvent9a gave no product (entry 4).
However, the approach reported by the group of Suresh babu4b
met with better luck, furnishing 89% of the expected heterocycle
(entry 5). Apparently, in this case the addition of 2-propanol was
a key for the success of transformation.
Based on this result, it was decided to investigate the substitu-
tion of ZnBr2 with ZnCl2, observing that this caused an increase of
the reaction time to 7 h, while reducing the yields to 53% (entry 6).
A decrease in the amount of solvent (from 30 to 10 mL) allowed
decreasing the reaction time while maintaining the yields (entry
7). Lowering the amount of NaN3 to 1.2 equiv and further decreas-
ing the amount of the solvent mixture to 6 mL/mmole of thiocya-
nate (entry 8) resulted in 94% yield of the tetrazole, after 2 h.
However, reducing the amount of promoter and running the reac-
tion at 70 °C or room temperature (entries 9–11) proved non-
satisfactory.
N
Thiocyanation
Ar=
[3+2] cycloaddition
N
N
ArH
ArSCN
N
ArS
N
H
R2
N
R
R
R1
Scheme 1. Proposed reaction sequence towards 5-sulfenyl tetrazoles.
Taking into account our interest in the development of new ap-
proaches to the synthesis of polysubstituted nitrogen heterocycles
with potential as bioactive compounds, herein we wish to report
the synthesis of 5-sulfenyl tetrazole derivatives of indoles and pyr-
roles in a two-step sequence involving the thiocyanation of the
substituted heterocycles and the subsequent reaction of the result-
ing thiocyanates with NaN3 under ZnBr2 promotion, as shown in
Scheme 1.
The different starting indoles (1) were synthesized according to
the literature.19 The intermediate thiocyanates 3 and 4 were pre-
pared by reaction of the indoles and N-phenyl pyrroles (2)20 with
These tests demonstrated the need of stoichiometric amounts
of the promoter and high temperatures for satisfactory results
Table 1
Synthesis of thiocyanates 3 and 4 by reaction of indoles 1 and pyrroles 2 with NH4SCN and OxoneÒ in MeOH
4
SCN
R2
R332
4
R3
3
5
R2
1
2
6
1N
R1
N
N
N
R
R
SCN
7
R1
1
3
4
2
Entry No
R
R1
R2
R3
Prod. No
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
H
5-Br
5-(p-Tolyl)
H
H
H
H
H
H
H
Me
H
H
H
H
—
—
—
—
—
—
—
—
—
—
—
—
—
H
3a
3b
3c
3d
3e
3f
3g
3h
4a
4b
4c
4d
4e
1
3
4
2
2
5
3.5
3
2
0.5
1.5
1.5
1.5
93
90
80
91
96
95
90
95
89
92
92
90
90
H
H
H
H
Br
—
—
—
—
—
Me
n-C8H17
Ph
Me
—
—
—
—
—
9
10
11
12
13
4-OMe
4-Cl
3-Cl
2-Cl
a
Isolated yields after column chromatography.
Please cite this article in press as: Kuhn, B. L.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.01.101

B. L. Kuhn et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 2
Optimization of the synthesis of the 5-sulfenyl tetrazoles
SCN
N
S
N
Reaction Conditions
N
N
H
Time, Temperature, Solvent, Promoter
N
N
H
H
Entry No
Solvent (mL)
NaN3 (equiv)
Promoter (equiv)
Temp (°C)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
DMF (1.5)
DMF (1.0)
Glycerol (20)
H2O (10)
H2O/2-PrOH (1:1, 30)
H2O/2-PrOH (1:1, 10)
H2O/2-PrOH (1:1, 10)
H2O/2-PrOH (1:1, 6)
H2O/2-PrOH (1:1, 6)
H2O/2-PrOH (1:1, 6)
H2O/2-PrOH (1:1, 6)
1.5
1.1
1.2
1.1
2.5
2.5
2.5
1.2
1.2
1.2
1.2
I2 (0.06)
NH4Cl (1.2)
—
120
160
110
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
r.t.
4
0.25
6
5
5
7
4
2
3
76
64b
—
ZnBr2 (1.0)
ZnBr2 (1.0)
ZnCl2 (1.0)
ZnBr2 (1.0)
ZnBr2 (1.0)
ZnBr2 (0.5)
ZnBr2 (1.0)
ZnBr2 (1.0)
—
89
53
87
94
78
39
64
9
10
11
3
3
70
a
Isolated yields after column chromatography.
Performed under microwave irradiation.
b
and defined the optimum conditions as those employed in entry
8.23
and the yields remained good to excellent. No significant steric
(entry 13) nor electronic (entries 9–11) effects were observed.
The reaction mechanism for the synthesis of tetrazoles has been
discussed elsewhere. Pioneering research by Himo et al.,25a based
on computational and experimental studies, demonstrated the role
of Zn in the synthesis of tetrazoles. Using MeCN, MeN3 and ZnBr2,
they were able to prove that there is a significant decrease in the
activation energy of the reaction when the nitrogen of the nitrile
group is coordinated to the Lewis acid. Whereas binding of ZnII
to the azide ion gave calculated activation energy of 34 and
36 kcal molÀ1 for tetrahedral and octahedral coordinating zinc
ions, respectively, when ZnII was connected to the nitrogen atom
In order to assess the scope and limitations of the transforma-
tion, the 3-thiocyanato-1H-indoles prepared as shown in Table 1
were submitted to the optimized conditions, with the results dis-
played in Table 3. All tetrazole products are novel. Their structures
were fully characterized by 1H and 13C NMR analysis, FT-IR
spectroscopy and elemental analysis or HRMS.24 The tetrazole
carbon atoms displayed a characteristic signal in a very narrow
region (d 154–156 ppm) of the 13C NMR spectrum.
It was observed that the less substituted heterocycle (entry 1)
reacted more rapidly than its congeners. On the other hand, sub-
stituents exert a large influence. For the N-substituted compounds,
3e reacted faster than 3f but furnished comparatively lower yields
of product (entries 5 and 6). However, introduction of a 5-Br sub-
stituent improved the yields at the expense of an increase in the
reaction time (entries 5 and 8), compared with the non-methylated
analogue 3c (entry 2).
of the nitrile, the activation energy dropped to 25–30 kcal molÀ1
.
Activation of the nitrile substrate is also the basis of the mode of
action of a new organocatalyst for the synthesis of tetrazoles.6b
In conclusion, a two step synthesis of new 5-thio-tetrazoles de-
rived from 3-thiocyanato-1H-indoles and 2-thiocyanato-1-phenyl
pyrroles, is reported. The NH4SCN/oxone reagent combination
was employed for the thiocyanation stage, affording good to
excellent yields of the thiocyanate intermediates. The [3+2]
For the series of tetrazoles derived from 1-aryl-2-thiocyanato-
1H-pyrroles (4a–e), the reaction times were generally shorter
Table 3
Synthesis of 5-sulfenyl tetrazoles 5 and 6 by reaction of 3-indolyl (3) and 2-pyrrolyl (4) thiocyanates
N
H
4
N
N
3
2
R3
R3
N
SCN
3
S
4
1
5
N
N
R2
SCN
R2
S
2
N
6
R
1N
R1
N
R1
R
7
N
N
H
N
3
5
6
4
Entry No
R
R1
R2
R3
St. mat./prod. no
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
H
5-Br
5-(p-Tolyl)
H
H
H
H
5-Br
—
—
—
—
—
H
H
H
H
H
H
H
Me
H
H
H
H
—
—
—
—
—
—
—
—
—
—
—
—
—
H
3a/5a
3b/5b
3c/5c
3d/5d
3e/5e
3f/5f
3g/5g
3h/5h
4a/6a
4b/6b
4c/6c
4d/6d
4e/6e
2
3.5
4
4
3
4.5
4
4.5
2
3
3
94
92
87
87
83
95
90
97
89
95
81
96
92
Me
n-C8H17
Ph
Me
—
—
—
—
—
9
10
11
12
13
4-OMe
4-Cl
3-Cl
2
2
2-Cl
a
Isolated yields after column chromatography.
Please cite this article in press as: Kuhn, B. L.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.01.101

4
B. L. Kuhn et al. / Tetrahedron Letters xxx (2014) xxx–xxx
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Supplementary data
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21. Typical procedure for the synthesis of the thiocyanates: A magnetically stirred
mixture of the indole (1.0 mmol) and NH4SCN (114 mg, 1.5 mmol) in MeOH
(10 mL), was treated with Oxone (921 mg, 1.5 mmol), and the reaction was
stirred at room temperature until complete consumption of the starting
material (TLC). Water (30 mL) was added and the products were extracted with
EtOAc (3 Â 10 mL). The organic phase was dried (MgSO4), concentrated under
reduced pressure and the residue was purified by chromatography (hexane/
EtOAc, 90:10).
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23. Typical procedure for the synthesis of the 5-sulfenyl tetrazoles: A stirred
mixture of the thiocyanate (1 mmol, 1.0 equiv) NaN3 (1.2 equiv) and ZnBr2
(1.0 equiv) in 2-PrOH/H2O (1:1, 6 mL) was refluxed until complete
consumption of the starting material (2–4.5 h). After cooling to room
temperature, the reaction was acidified with 1 M HCl (10 mL) and diluted
with EtOAc (15 mL). The aqueous phase was extracted with EtOAc (2 Â 20 mL)
and the combined organic layers were dried (MgSO4) and concentrated under
reduced pressure. The residue was purified by column chromatography
(hexane/EtOAc to EtOAc/MeOH 90:10).
24. Characterization of selected compounds: 1H and 13C NMR were run at 400 and
100 MHz, respectively, with the samples dissolved in DMSO-d6. 3-((1H-
Tetrazol-5-yl)thio)-1H-indole (5a). Beige solid, mp: 210.4–211.6 °C. IR (KBr,
m
): 3269, 2336, 1653, 1508, 1310, 1042, 746 and 604 cmÀ1 1H NMR d: 11.83 (s,
.
1H), 7.91 (d, 1H, J = 2.3 Hz), 7.55 (d, 1H, J = 8.0 Hz), 7.49 (d, 1H, J = 7.8 Hz),
7.23–7.20 (m, 1H) and 7.14–7.10 (m, 1H). 13C NMR d: 155.3, 136.6, 133.1,
128.3, 122.3, 120.4, 117.9, 112.9 and 94.0. EI-MS (m/z, rel int., %): 218 [(M+1)+,
2], 217 (M+, 5), 160 (29), 148 (100), 89 (19) and 77 (19). Anal. Calcd: C, 49.76;
H, 3.25. Found: C, 50.09; H, 3.55. 3-((1H-Tetrazol-5-yl)thio)-5-bromo-1
7. (a) Bazile, Y.; Bras, J. P.; De Cointet, P.; Nanthavong, S.; Pigerol, C.; Broll, M.;
Eymard, P.; Werbenec, J. P.; Fournier, J. Eur. J. Med. Chem. 1977, 12, 525–530; (b)
Finnegan, W. G.; Henry, R. A.; Lofquist, R. J. Am. Chem. Soc. 1958, 80,
3908–3911; (c) Jin, T.; Kitahara, F.; Kamijo, S.; Yamamoto, Y. Tetrahedron Lett.
2008, 49, 2824–2827; (d) Matthews, D. P.; Green, J. E.; Shuker, A. J. J. Comb.
Chem. 2000, 2, 19–23.
H-indole (5b). Beige solid, mp: 209.5–211.3 °C. IR (KBr,
m): 3274, 2364, 1566,
1309, 1217, 1109, 1033, 795 and 746 cmÀ1 1H NMR d: 12.00 (s, 1H), 7.93 (d,
.
1H, J = 2.5 Hz), 7.64 (s, 1H), 7.49 (d, 1H, J = 8.6 Hz) and 7.31 (dd, 1H, J = 8.6 Hz,
0.9 Hz). 13C NMR d: 155.1, 135.4, 134.6, 130.4, 125.0, 120.3, 114.5, 113.3 and
94.2. EI-MS (m/z, rel int.,%): 296 [(M+2)+, 34], 295 [(M+1)+, 4], 294 (M+, 31), 239
(64), 227 (97), 225 (100), 173 (40), 148 (37), 120 (52), 114 (16) and 45 (34).
HRMS obsd m/z: 317.9429; C9H6BrN5SNa [M+Na]+ requires m/z 317.9425. 3-
((1H-Tetrazol-5-yl)thio)-5-(p-tolyl)-1H-indole (5c). Brown solid, mp 213.3–
8. Demko, Z. P.; Sharpless, K. B. Org. Lett. 2001, 3, 4091–4094.
9. (a) Demko, P. Z.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945–7950; (b) Himo, F.;
Demko, Z. P.; Noodleman, L.; Sharpless, B. K. J. Am. Chem. Soc. 2002, 124, 12210–
12216; (c) Demko, Z. P.; Sharpless, K. B. Org. Lett. 2002, 4, 2525–2527.
10. (a) Lang, L.; Li, B.; Liu, W.; Jiang, L.; Xu, Z.; Yin, G. Chem. Commun. 2010,
448–450; (b) Lakshmi Kantam, M.; Shiva Kumar, K. B.; Phani Raja, K. J. Mol.
Catal. A. 2006, 247, 186–188; (c) Schulz, M. J.; Coatz, S. J.; Hlasta, D. J. Org. Lett.
2004, 6, 3265–3268; (d) Rostamizadeh, S.; Ghaieni, H.; Aryan, R.; Amani, A.
Chin. Chem. Lett. 2009, 20, 1311–1314; (e) Kanakaraju, S.; Prasanna, B.;
Chandramouli, G. V. P. J. Chem. 2013. art id 104690; (f) Nandre, K. P.; Salunke, J.
K.; Nandre, J. P.; Patil, V. S.; Borse, A. U.; Bhosale, S. V. Chin. Chem. Lett. 2012, 23,
161–164.
215.5 °C. IR (KBr, m .
): 3263, 2331, 1502, 1473, 1308, 1108, 1036 and 799 cmÀ1
1H NMR d: 11.81 (s, 1H), 7.90 (s, 1H), 7.65 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.52–
7.50 (m, 3H), 7.23 (d, 2H, J = 7.4 Hz), 2.33 (s, 3H). 13C NMR d: 154.9, 137.9,
135.6, 135.3, 133.2, 132.7, 128.9, 128.5, 126.1, 121.2, 115.1, 112.4, 94.3 and
20.1. EI-MS (m/z, rel int.,%): 308 [(M+1)+, 2], 307 (M+, 11), 277 (18), 238 (44),
173 (100), 11 (21), 77 (9) and 45 (21). Anal. Calcd: C, 62.58; H, 4.26. Found: C,
62.68; H, 4.68. 3-((1H-Tetrazol-5-yl)thio)-2-methyl-1H-indole (5d). Beige
11. (a) Newman, A. A. Chemistry and Biochemistry of Thiocyanic Acid and its
Derivatives, 1st ed.; Academic Press: USA, 1975; (b) Khazei, A.; Zolfigol, M. A.;
Safaiee, M.; Mohammad, M.; Donyadari, E.; Shiri, S. M.; Kruger, H. G. Catal.
Commun. 2012, 26, 34–38.
solid, mp: 184.5–185.7 °C. IR (KBr,
m
): 3339, 3052, 2332, 1546, 1518, 1314,
1035 and 742 cmÀ1
.
1H NMR d: 11.68 (s, 1H), 7.43–7.39 (m, 2H), 7.16–7.12 (m,
1H), 7.09–7.06 (m, 1H) and 2.52 (s, 3H). 13C NMR d: 155.2, 143.1, 135.5, 129.2,
121.4, 120.0, 117.1, 111.3, 91.3 and 11.6. EI-MS (m/z, rel int.,%): 233 [(M+2)+, 2],
233 [(M+1)+, 5], 231 (M+, 34), 174 (33), 162 (100), 130 (32), 118 (67) and 77
(27). HRMS obsd m/z: 254.0471; C10H9N5SNa [M+Na]+ requires m/z 254.0476.
3-((1H-Tetrazol-5-yl)thio)-1-methyl-1H-indole (5e). Beige solid, mp: 179.9–
12. (a) Chakrabarty, M.; Sarkar, S. Tetrahedron Lett. 2003, 44, 8131–8133; (b)
Murthy, Y. L. N.; Govindh, B.; Diwakar, B. S.; Nagalakshmi, K.; Venu, R. J. Iran.
Chem. Soc. 2011, 8, 292–297; (c) Das, B.; Kumar, A. S. Synth. Commun. 2010, 40,
337–341; (d) Raju, R. M.; Lenin, R. Lett. Org. Chem. 2010, 7, 392–395.
13. (a) Mahajan, U. S.; Akamanchi, K. G. Synth. Commun. 2009, 39, 2674–2682; (b)
Wu, J.; Wu, G.; Wu, L. Synth. Commun. 2008, 38, 2367–2373; (c) Nair, V.;
George, T. G.; Nair, L. G.; Panicker, S. B. Tetrahedron Lett. 1999, 40, 1195–1196;
(d) Yadav, J. S.; Reddy, B. V. S.; Shubashree, S.; Sadashiv, K. Tetrahedron Lett.
2004, 45, 2951–2954; (e) Pan, X. Q.; Lei, M. Y.; Zou, J. P.; Zhang, W. Tetrahedron
Lett. 2009, 50, 347–349; (f) Yadav, J. S.; Reddy, B. V. S.; Krishna, A. D.; Reddy, C.
S.; Narsaiah, A. V. Synthesis 2005, 961–964; (g) Memarian, H. R.;
181.4 °C. IR (KBr, m .
): 3394, 3110, 2331, 1517, 1243, 1028 and 744 cmÀ1 1H
NMR d: 7.87 (s, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.29–7.26
(m, 1H), 7.18–7.14 (m, 1H) and 3.85 (s, 3H). 13C NMR d: 155.2, 137.1, 136.6,
128.6, 122.2, 120.4, 118.0, 110.5, 92.9 and 32.7. EI-MS (m/z, rel int.,%): 231 (M+,
4), 174 (27), 162 (100), 118 (15) and 77 (16). Anal. Calcd: C, 51.93; H, 3.92.
Found: C, 51.99; H, 3.99. 3-((1H-Tetrazol-5-yl)thio)-1-octyl-1H-indole (5f).
Yellow solid, mp: 95.4–96.9 °C. IR (KBr,
m
): 3444, 2953, 2923, 2852, 2713, 1613,
1508, 1492, 1457, 1299, 1165, 1020 and 738 cmÀ1
.
1H NMR d: 7.91 (s, 1H), 7.59
Please cite this article in press as: Kuhn, B. L.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.01.101

B. L. Kuhn et al. / Tetrahedron Letters xxx (2014) xxx–xxx
1595, 1498, 1322, 1038, 766 and 740 cmÀ1
5
(d, 1H, J = 8.1 Hz), 7.47 (d, 1H, J = 7.7 Hz), 7.27–7.23 (m, 1H), 7.16–7.12 (m, 1H),
4.22 (t, 2H, J = 6.8 Hz), 1.85–1.75 (m, 2H), 1.28–1.22 (m, 10H) and 0.85–0.83
(m, 3H). 13C NMR d: 155.1, 136.4, 135.5, 128.6, 122.1, 120.3, 118.1, 110.6, 93.0,
45.8, 30.9, 29.3, 28.3, 25.9, 21.7 and 13.6. EI-MS (m/z, rel int.,%): 331 [(M+2)+,
2], 330 [(M+1)+, 7], 329 (M+, 33), 272 (57), 260 (59), 162 (100), 130 (28), 77 (8),
57 (26) and 41 (50). Anal. Calcd: C, 61.97; H, 7.04. Found: C, 61.74; H, 7.23.
3-((1H-Tetrazol-5-yl)thio)-1-phenyl-1H-indole (5g). Yellow solid, mp:
.
1H NMR d: 7.45–7.34 (m, 6H), 6.82
(dd, J = 3.6 Hz, 1.6 Hz, 1H) and 6.40–6.38 (m, 1H). 13C NMR d: 155.0, 138.3,
128.7, 128.1, 127.7, 126.0, 121.6, 111.4 and 109.9. EI-MS (m/z, rel int.,%): 244
[(M+1)+, 2], 243 (M+, 6), 242 (37), 185 (34), 174 (45), 173 (100), 172 (48), 130
(16), 115 (19), 77 (65), 70 (26) and 51 (39). HRMS obsd m/z: 266.0465;
C
11H9N5SNa [M+Na]+ requires m/z 266.0476. 5-((1-(4-Methoxyphenyl)-1H-
pyrrol-2-yl)thio)-1H-tetrazole (6b). White solid, mp: 210.0–211.4 °C. IR (KBr,
153.1–154.3 °C. IR (KBr,
m
): 3033, 2331, 1598, 1499, 1457, 1231, 1017, 746
m
): 3012, 2360, 1517, 1250, 1039, 837 and 740 cmÀ1 1H NMR d: 7.27–7.24 (m,
.
and 695 cmÀ1
.
1H NMR dd: 8.22 (d, J = 0.9 Hz, 1H), 7.66–7.56 (m, 6H), 7.49–7.45
3H), 6.96 (d, J = 8.9 Hz, 2H), 6.78 (dd, J = 3.6 Hz, 1.7 Hz, 1H), 6.39–6.35 (m, 1H)
and 3.76 (s, 3H). 13C NMR d: 158.6, 155.1, 131.3, 128.4, 127.5, 121.2, 113.9,
111.5, 109.6 and 55.2. EI-MS (m/z, rel int.,%): 275 [(M+2)+, 2], 274 [(M+1)+, 6],
273 (M+, 37), 216 (20), 204 (100), 173 (37), 92 (15) and 77 (20). Anal. Calcd: C,
52.73; H, 4.06. Found: C, 52.86; H, 4.31. 5-((1-(4-Chlorophenyl)-1H-pyrrol-2-
(m, 1H), 7.33–7.29 (m, 1H) and 7.26–7.22 (m, 1H). 13C NMR d: 154.9, 137.9,
136.0, 135.5, 129.8, 129.1, 127.3, 124.2, 123.5, 121.6, 118.6, 111.1 and 96.9. EI-
MS (m/z, rel int.,%): 294 [(M+1)+, 5], 293 (M+, 29), 236 (36), 224 (100), 121 (21)
and 77 (40). HRMS obsd m/z: 316.0614; C15H11N5SNa [M+Na]+ requires m/z
316.0633. 3-((1H-Tetrazol-5-yl)thio)-5-bromo-1-methyl-1H-indole (5h). Beige
yl)thio)-1H-tetrazole (6c). Orange solid, mp: 171.2–173.1 °C. IR (KBr,
m): 3129,
solid, mp: 205.5–207.0 °C. IR (KBr,
m
): 3394, 1509, 1465, 1242, 795 and
3010, 2362, 1494, 1311, 1094, 837 and 739 cmÀ1 1H NMR d: 7.50 (d, J = 8.8 Hz,
.
614 cmÀ1
.
1H NMR d: 7.87 (s, 1H), 7.62 (d, J = 1.7 Hz, 1H), 7.52 (d, J = 8.7 Hz,
2H), 7.40 (d, J = 8.8, 2H), 7.35 (dd, 1H, J = 3.0 Hz, 1.8 Hz), 6.82 (dd, J = 3.7, 1.8,
1H) and 6.40 (dd, 1H, J = 3.7 Hz, 3.0 Hz). 13C NMR d: 155.0, 137.2, 132.4, 128.8
128.3, 127.9, 122.0, 111.6 and 110.2. EI-MS (m/z, rel int.,%): 279 [(M+2)+, 6],
278 [(M+1)+, 2], 277 (M+, 18), 219 (19), 173 (100), 111 (13) and 75 (19). HRMS
obsd m/z: 300.0074; C11H8ClN5SNa [M+Na]+ requires m/z 300.0087.
25. (a) Himo, F.; Demko, Z. P.; Noodleman, L.; Sharpless, B. K. J. Am. Chem. Soc.
2003, 125, 9983–9987.
1H), 7.36 (dd, J = 8.7 Hz, 1.8 Hz, 1H) and 3.82 (s, 3H). 13C NMR d: 155.2, 137.6,
135.8, 130.6, 124.7, 120.5, 113.2, 112.8, 94.3 and 33.0. EI-MS (m/z, rel int.,%):
310 [(M+2)+, 35], 309 [(M+1)+, 5], 308 (M+, 35), 253 (48), 241 (97), 239 (100),
162 (24), 117 (32) and 77 (7). HRMS obsd m/z: 331.9575; C10H8BrN5SNa
[M+Na]+ requires m/z 331.9581. 5-((1-Phenyl-1H-pyrrol-2-yl)thio)-1H-
tetrazole (6a). Yellow solid, mp: 160.1–161.4 °C. IR (KBr,
m): 3048, 2366,
Please cite this article in press as: Kuhn, B. L.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.01.101