A convenient eco-friendly system for the synthesis of 5-sulfenyl tetrazole derivatives of indoles and pyrroles employing CeCl3·7H 2O in PEG-400

Article abstract of DOI:10.1039/c4ra05625f

The use of CeCl₃·7H₂O in polyethyleneglycol 400 (PEG-400), as an efficient and eco-friendly promoter system for the convenient synthesis of 5-sulfenyl tetrazoles derived from indoles and pyrroles, is reported. The synthesis entails the [3 + 2] cycloaddition reaction of NaN₃ with 3-thiocyanato indoles (including 3,3′-di-thiocyanato- 1H,1H′,2,2′-biindoles) and 2-thiocyanato pyrroles. The thiocyanates were conveniently obtained by the oxone-mediated thiocyanation of differently substituted starting indoles, 1H,1H′,2,2′-biindoles and N-aryl pyrroles with NH₄SCN. The scope and limitations of the transformation were also studied. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra05625f

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A convenient eco-friendly system for the synthesis
of 5-sulfenyl tetrazole derivatives of indoles and
pyrroles employing CeCl3$7H2O in PEG-400†
Cite this: RSC Adv., 2014, 4, 34519
a
a
b
*
Margiani P. Fortes, Mariana M. Bassaco, Teodoro S. Kaufman
a
*
and Claudio C. Silveira
The use of CeCl3$7H2O in polyethyleneglycol 400 (PEG-400), as an efficient and eco-friendly promoter
system for the convenient synthesis of 5-sulfenyl tetrazoles derived from indoles and pyrroles, is
reported. The synthesis entails the [3 + 2] cycloaddition reaction of NaN3 with 3-thiocyanato indoles
(including 3,30-di-thiocyanato-1H,1H0,2,20-biindoles) and 2-thiocyanato pyrroles. The thiocyanates were
conveniently obtained by the oxone-mediated thiocyanation of differently substituted starting indoles,
1H,1H0,2,20-biindoles and N-aryl pyrroles with NH4SCN. The scope and limitations of the transformation
were also studied.
Received 11th June 2014
Accepted 29th July 2014
DOI: 10.1039/c4ra05625f
www.rsc.org/advances
On the other hand, the 5-sulfenyl tetrazole motif has also
been included in antibiotics (G),3g,h antiviral (H),3i analgesic (I)3j
and antitubercular (J)3k agents.
Introduction
The tetrazoles are azapyrrole-type ve-membered ring 6p-
heterocycles, containing four contiguous nitrogen atoms,1a
which have received much attention in recent years due to their
diverse technological uses and numerous applications in
biology. Tetrazoles are not found in Nature;1b however, due to
their acidic character, metabolic stability and close structural
similarity with carboxylic acids, they are considered isosteres of
the latter.2
The 5-sulfenyl tetrazoles are a small and special group of
tetrazoles that are progressively becoming more ubiquitous;
they can be found as a distinguished motif in active pharma-
ceutical ingredients and other potentially bioactive molecules
(Fig. 1).
The technological applications of 5-sulfenyl tetrazoles
include their use as 1H-tetrazole replacements in oligonucleo-
tide synthesis,4a,b due to the improved solubility and acidity
caused by the thioether moiety, which enhances their ability to
act as activators4c,d and promoters of phosphate ester hydro-
lysis.4e They are also suitable capping agents for the stabiliza-
tion of CdS and noble metal (Au, Ag, Pd, Pt) nanoparticles.4f,g
5-Thiotetrazoles have been employed as ligands,5a taking
advantage of their relative stability to oxidation and high coor-
dination ability.5b Their capacity to form stable complexes with
various metal ions is widely used in photo processes and for
protection of metals against corrosion.5c
Despite their usefulness, systematic research work devoted
to the synthesis of 5-sulfenyl tetrazoles as a class of molecules
has been rather scarce.6 In fact, a critical analysis of the litera-
ture revealed that besides the pioneering work of Lieber and
Enkoji,4c they have been mostly synthesized during studies on 5-
aryl(alkyl) tetrazoles, and together with the latter.7
Approaches to the synthesis of 5-alkyl(aryl)thiotetrazoles
include (a) the nucleophilic displacement of suitable leaving
groups with 5-tetrazoyl mercaptan or its tautomer;8a–e (b) the
reaction of isothiocyanates and azides, which yields tetrazole-
thiols/thiones, that can exist in different tautomeric forms;8e,f
(c) the reaction of substituted thiosemicarbazides with aralkyl
chlorides, followed by diazotization and reaction of the product
with a Friedel Cras catalyst;8g (d) the SNAr reaction of arylsul-
fonyl tetrazoles with thiophenols,8h and (e) the [3 + 2] cycload-
dition reaction between thiocyanates and sources of hydrazoic
acid, such as azides.
Their derivatives have been shown to act as leukotriene
antagonists (A–C)3a–c and acyl-CoA cholesterol acyltransferase
(ACAT) inhibitors (D),3d being potentially useful in therapies for
allergy and hypercholesterolemia, respectively.
Other compounds featuring a 5-sulfenyl tetrazole moiety,
such as D, were also found to be selective agonists of the EP4
subtype of prostaglandin E2 receptors,3e with application in the
treatment of glaucoma and other prostaglandin-mediated
conditions, as in the case of indole derivative F.3f
a
´
Departamento de Quımica, Universidade Federal de Santa Maria 97105-900, Santa
Maria, RS, Brazil. E-mail: silveira@quimica.ufsm.br; margiani.fortes@ufsm.br;
mariquimica@gmail.com; Fax: +55-55-3220-8754; Tel: +55-55-3220-8754
b
´
Instituto de Quımica Rosario (CONICET-UNR), Suipacha 531, S2002LRK, Rosario, SF,
Argentina. E-mail: kaufman@iquir-conicet.gov.ar; Fax: +54-341-4370477; Tel: +54-
341-4370477
† Electronic supplementary information (ESI) available: Selected spectra of
intermediates and nal product. See DOI: 10.1039/c4ra05625f
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however, Et2AlN3,9c aluminium azide9d and Bu3SnN3 (ref. 9e)
have also been employed.
The discovery of ZnBr2 as a stoichiometric promoter in
aqueous or hydroalcoholic medium, was a major breakthrough
in the synthesis tetrazoles in general,7c,10a,b which also impacted
on 5-sulfenyl tetrazole chemistry.9e,10c Since then, different zinc
derivatives, including ZnCl2, mesoporous ZnS nanospheres and
Zn/Al hydrotalcite have also been disclosed as suitable alter-
native promoters.11
Based on computational and experimental studies, Himo
et al.12a proved the role of Zn in the reaction between MeCN,
MeN3 and ZnBr2, demonstrating that the activation energy of the
reaction experiences a signicant decrease (4–11 kcal molꢀ1
)
when the nitrogen of the nitrile group is coordinated to the
metal ion. Furthermore, a recently reported organocatalyst
for the synthesis of tetrazoles also acts through nitrile
activation.12b
On the other hand, lanthanide salts are useful as promoters
and catalysts in organic synthesis.13 Some of them are inter-
esting because of their ready availability, ease of handling and
low toxicity, as well as for their air and water stability.14 Among
them, cerium compounds have found extensive use in organic
synthesis.15
During the past decade, CeCl3 has been continuously fasci-
nating the scientic community with regards to its exploitation
as promoter of a growing array of organic reactions.16a The salt,
which qualies as a “3E-catalyst” (eco-friendly, efficient and
economical),6e is a safe, non-toxic, inexpensive and water-
tolerant compound, which has been used in its anhydrous
and heptahydrate forms, associated with NaI16b–d and as a solid-
supported reagent.16e–h
We have focused our recent research in trying to develop new
applications for CeCl3$7H2O and related compounds, as a
means to nd cleaner and more efficient methodologies for
carrying out classical reactions. One of the keys to waste mini-
mization and environmental friendliness is the substitution of
stoichiometric amounts of reagents in these classical trans-
formations with lower loads of reagents, as well as the use of
cleaner or catalytic alternatives.
Aiming to extend this research to other important organic
processes such as addition and cycloaddition reactions, we have
recently reported several CeCl3-mediated useful trans-
formations.13c,17,18 We have also developed a study focused on
the synthesis of 5-sulfenyl tetrazoles and became interested in
these heterocycles.6a
Fig. 1 Some selected examples of bioactive 5-sulfenyl tetrazole
derivatives.
Being important structural motifs, the synthesis of 5-sulfenyl
tetrazole derivatives has been arousing continued attention
during the last decade. Therefore, we inquired into the appli-
cation of CeIII for the tetrazoylation of thiocyanates and herein
we report the use of CeCl3$7H2O in polyethyleneglycol 400 (PEG-
400) as a promoting system for the development of a mild,
efficient and eco-friendly synthesis of 5-sulfenyl tetrazole
derivatives (3, 6) of indoles (1) and pyrroles (4), based on the
[3 + 2] cycloaddition reaction of their corresponding thiocya-
nates (2, 5) with NaN3 (Scheme 1).
Unfortunately, each one of these approaches suffers from
some disadvantage, including long reaction times, the use of
toxic metals, polar aprotic solvents, expensive reagents, harsh
reaction conditions, water sensitivity or the use of stoichio-
metric amounts of promoters.
The [3 + 2] cycloaddition between thiocyanates and hydrazoic
acid is the most widely employed approach towards tetrazoles.
The reaction is promoted by protic and Lewis acids, including
Et3N$HCl,9a NH4Cl,6d magnetic Fe3O4 nanoparticles6e and ionic
liquids,9b while the main source of hydrazoic acid is NaN3;3i,6b,c
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The 2-PrOH : H2O (1 : 1) system was chosen as a starting
point, for its efficiency as reaction medium for the synthesis of
5-sulfenyl tetrazoles under zinc assistance.6a,f
Using 0.5 equiv. of CeCl3$7H2O under reux for 8 h, there
was a limited conversion of the starting material and the
product (3a) was isolated in only 18% yield (entry 1). When H2O
was used as solvent, the reaction also proceeded very slowly;
however, 25% of 3a was obtained aer a reux period of 8 h
(entry 2). In MeCN, which is effective for carrying out [3 + 2]
cycloadditions leading to pyrroles,18 no product was detected
(entry 3).
Considering our interest in developing environmentally
friendly processes, the transformation was next attempted in
glycerol19 and PEG-400.20 These solvents showed up as great
alternative reaction media to those commonly used in
synthesis, because they are miscible with water, easily acces-
sible, biodegradable, and of low toxicity.
Scheme 1 Proposed reaction sequence towards 5-sulfenyl tetrazoles.
When run in glycerol, the solvent of choice for the CeIII
-
promoted synthesis of 3,30-bis(indolyl)methanes,21 a 70% yield
of 3a was realized aer heating for 3 h at 110 ꢁC (entry 4). A
parallel blank reaction carried out in the absence of CeCl3
demonstrated the requirement of the salt to promote the
transformation (entry 5), since no product was observed aer 8
h.22 On the other side, the use of PEG-ꢁ400 as solvent produced
77% of 3a aer heating for 3 h at 110 C (entry 7).
The 5-sulfenyl tetrazoles are known to decompose at high
temperatures, reverting to the thiocyanates and hydrazoic acid;
this explains the low yields attained at high temperatures and/
or aer prolonged heating.4c Therefore, lowering the reaction
Results and discussion
Employing 1-methyl-3-thiocyanato-1H-indole (2a, 0.5 mmol) as
model heterocycle, the establishment of the optimum condi-
tions was performed, by reacting the latter with NaN3 (0.6
mmol, 1.2 equiv.) under promotion by CeCl3$7H2O. The effi-
ciency of the transformation was evaluated in different solvents
and under various reaction temperatures and amounts of
promoter (Table 1).
Table 1 Optimization of the synthesis of the 5-sulfenyl tetrazoles
Entry no.
Solvent
Promoter (equiv.)
Temp. (ꢁC)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
2-PrOH : H2O (1 : 1)
H2O
MeCN
Glycerol
Glycerol
Glycerol
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400
PEG-400 : H2O (10 : 1)
0.5
0.5
0.5
0.5
—
0.5
0.5
0.5
0.3
0.2
0.1
0.2
0.2
0.2
0.2
Reux
Reux
Reux
110
110
95
110
95
95
95
95
80
65
8
8
8
3
8
3
3
3
3
3
8
3
3
3.5
3.5
18
25
—
70
—
69
77
89
89
90
78
92
71
76b
29c
9
10
11
12
13
14
15
80
80
a
b
Isolated yields aer column chromatography. Carried out with anhydrous CeCl3; 18% of starting material was recovered (92% yield based on
recovered starting material). c Starting material (65%) was recovered.
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temperature to 95 ꢁC avoided some decomposition6d and (88–93%) aer 3–4 h (entries 1–8). In addition, the nature of the
afforded the product in an improved 89% yield (entry 8). substituents did not show any marked inuence on the
Interestingly, under the same conditions, glycerol furnished reactivity.
only 69% of 3a (entry 6). This result conrmed PEG-400 as the
solvent of choice for this transformation (entry 8 vs. entry 6).
On the other hand, the N-unsubstituted indoles furnished
slightly lower yields of product than the corresponding N-
PEG-400 has emerged as one of the suitable solutions in the substituted counterparts. This was ascribed in part to the lower
global chemical strategy to avoid volatile organic solvents, solubility of the starting materials 2i–l in PEG-400. For instance,
especially chlorinated ones, which may create environmental compound 2i gave only 74% of 3i aer heating for 4 hours,
problems. PEG-400 is an affordable, recyclable and eco-friendly exhibiting the presence of insoluble material in the reaction
solvent for metal-mediated transformations.23 It is miscible mixture (entry 9).
with water and many different organic solvents, and has
successfully been utilized in different CeCl3$7H2O-promoted solubility obstacle, affording 93% yield of 3i in 3 h (entry 10),
reactions.23d,e
and improved the yields of the corresponding 5-sulfenyl tetra-
The use of glycerol as an alternative solvent overcame the low
The amount of promoter was next optimized. Lowering the zoles derived from other N-unsubstituted indole thiocyanates
quantity of added CeCl3$7H2O to 0.3 equiv. afforded 89% of 3a (entries 12 and 14).
(entry 9). The yield of 3a was 90% in the presence of 0.2 equiv. of
Not unexpectedly, the reaction with the 5-methoxy derivative
the salt (entry 10) and dropped to 78% when the promoter was 2k required 8 h. On the other hand, the outcome with the 5-(p-
present at a 0.1 equiv. level; the latter process also required 8 h tolyl) example 2l was better in PEG-400 than in glycerol (entries
of reaction time (entry 11).
15–16), while despite the lack of an N-substituent, the 2-methyl
Using the optimum amount of promoter, the transformation substituted compound 2m did not exhibit solubility problems
was further ne-tuned. When the reaction was performed at in PEG-400, affording 82% yield of 3m aer 4 h (entry 17).
ꢁ
80 C, the product was obtained in 92% yield (entry 12) while
Interestingly, thiocyanato-nitrile 2n, prepared by cyanation
additional reduction of the temperature to 65 ꢁC, exhibited a of 5-bromoindole (1j) followed by the usual thiocyanation
decrease in efficiency, reaching 71% yield aer 3 hours of conditions,27 yielded exclusively 87% of the tetrazole derivative
reaction (entry 13). Finally, the effects of adding water and using 3n (entry 18). The yield of 3n increased to 91% when the
anhydrous CeCl3 were explored. It was concluded that drying amounts of CeCl3$7H2O and NaN3 were doubled, suggesting the
the salt reduces the reaction rate, but has no marked incidence relative unability of the Cerium-based system to tetrazoylate
on the yield of the transformation (entry 14). On the other side, these benzonitriles.
addition of 10% water to PEG-400 furnished only 29% of 3a aer
3.5 h and most of the starting material (65%) was recovered zonitrile afforded 77% of 3a and none of 5-phenyltetrazole
(entry 15). (entry 19), conrming that thiocyanates are much more easily
A competition experiment between thiocyanate 2a and ben-
From these results it was concluded that, opposite to the use converted into the corresponding tetrazoles than the nitriles, in
of ZnBr2,6a there is no need of stoichiometric amounts of the agreement with the observation that the related cyanates
CeIII promoter or high reaction temperatures for satisfactory (nitriles attached to oxygen), react with NaN3 in H2O at room
outcomes. The conditions employed in entry 12 (heating at 80 ꢁC temperature, in the absence of a catalyst.28 In addition, another
for 3 h in PEG-400, in the presence of 0.2 equiv. CeCl3$7H2O), experiment proved that the CeIII in PEG-400 reagent system is
were considered optimum. Interestingly, the transformation more selective than the traditional ZnBr2 in reuxing H2O,
was efficient, without requiring special protection against which gave a 6.6 : 1 mixture of 3a and 5-phenylsulfenyl tetrazole
atmospheric oxygen or humidity.
(91% global yield) aer 24 h.
With the optimized reaction conditions for the synthesis of
The CeCl3$7H2O in PEG-400 reagent combination also
3a in hand, the scope and limitations of the transformation proved to be an effective promoting system for the synthesis of
were studied next, employing various thiocyanates derived from 5-sulfenyl tetrazole derivatives of N-aryl pyrroles (6a–c), which
indoles and N-phenyl pyrroles.
The starting indoles (1a–n) and the pyrroles employed (4a–c) sponding thiocyanates 5a–c aer 3 h (entries 20–22).
were synthesized according to the literature18,24 and properly
The structures of the products were conrmed by spectro-
were obtained in more than 90% yields from their corre-
characterized before use.25 Their corresponding thiocyanates scopic means, especially employing exhaustive 1H and 13C NMR
2a–n and 5a–c were prepared in high yields by reaction of the data analysis. The main evidence of the formation of the tet-
heterocycles with NH4SCN, using oxone as oxidizing agent. razoles was found in their 13C NMR spectra, where a deshield-
Based on our previous results,18 and adapting the work of Wu,26 ing effect of the representative thiocyanate carbon (originally
a limited excess of NH4SCN was employed in order to avoid resonating at 110–112 ppm) was observed aer the [3 + 2]
formation of poly-thiocyanated compounds. When the thiocy- cycloaddition. This resulted in a low intensity signal resonating
anates 2 and 5 were submitted to the CeIII-promoted [3 + 2] at approximately d ¼ 154–156 ppm, characteristic of the tetra-
cycloaddition reaction towards 5-sulfenyl tetrazoles, it was zole ring carbon atom. The other carbons exhibited only minor
observed that, in general, the products were obtained in good to variations in their resonances.
excellent yields and in short reaction times (Table 2).
On the other hand, the low resolution electron impact mass
The N-substituted indole derivatives carrying alkyl and aryl spectra of the 5-sulfenyl tetrazolic compounds in the series 3a–n
groups (2a–h) afforded the expected products in excellent yields and 6a–c also exhibited some common fragmentation patterns.
34522 | RSC Adv., 2014, 4, 34519–34530
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Table 2 Synthesis of 3-indolyl (2) and 2-pyrrolyl (5) thiocyanates and their transformation into 5-sulfenyl tetrazoles 3 and 6 mediated by
CeCl3$7H2O in PEG-400
Yieldb (%)
Entry no.
R
R1
R2
R3
St. mat./prod. no.
Timea (h)
2/5
3/6
1
2
3
4
5
6
7
8
H
Br
MeO
p-Tolyl
H
H
H
H
H
Me
Me
Me
Me
Ph
4-ClC6H4
4-MeOC6H4
n-C8H17
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
H
2a/3a
2b/3b
2c/3c
2d/3d
2e/3e
2f/3f
2g/3g
2h/3h
2i/3i
2i/3i
2j/3j
2j/3j
2k/3k
2k/3k
2l/3l
3
3
3
3
3
3.5
4
3.5
4
3
3
3
8
8
8
8
4
2
96
95
82
89
90
88
85
95
93
92
90
88
92
89
93
91
91
74
93c
80
96c
47
63c
78
52c
82
87
77d
90
92
94
9
10
11
12
13
14
15
16
17
18
19
20
21
22
H
Br
Br
87
83
84
MeO
MeO
p-Tolyl
p-Tolyl
H
CN
H
—
2l/3l
2m/3m
2n/3n
2a/3a
5a/6a
5b/6b
5c/6c
90
95
H
Me
—
—
—
3
3
3
3
89
92
92
—
—
MeO
Cl
a
b
Conditions: thiocyanate (0.5 mmol), NaN3 (0.6 mmol), CeCl3$7H2O (0.1 mmol), PEG-400 (0.5 mL), 80 ꢁC. Isolated yields aer column
chromatography. c In glycerol (0.5 mL). d Competition experiment in the presence of 1 equivalent of benzonitrile.
Besides the signal of the molecular ion M+, a characteristic [(M (71% yield) and the mono-substituted product (8a0, 19%), which
ꢀ 69)+ fragment was observed (commonly the base peak), rep- can be considered a reaction intermediate.
resenting the loss of the tetrazole ring.
According to the above observation, the reaction time was
In order to further explore the scope and limitations of this increased to 18 h, which allowed the isolation of 89% of 8a
CeIII-assisted 5-sulfenyltetrazole synthesis, the transformation (entry 2). Increasing the temperature to 45 ꢁC reduced the
was extended to the more complex 1,10-dimethyl-1H,10H-2,20- reaction time to 6 h, while keeping high the product yield (entry
biindole (7a).29 However, reaction of the latter with 3 equiv. of 3, 91%). Therefore, in view of the cleanliness of the trans-
both, NH4SCN and oxone, in MeOH at room temperature led to formation, its slow pace was overcome by submitting the reac-
the formation of two products aer 3 h (Table 3, entry 1). These tion mixture to reux during 1 h, which afforded 91% of the
were unequivocally identied as the expected di-thiocyanate 8a required di-thiocyanate (entry 4).
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Table 3 Optimization of the thiocyanation of 1H,10H-2,20-bisindoles (7)a
Entry no.
R
Temp. (ꢁC)
Time (h)
St. mat./prod. no.
Product yieldb (%)
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
H
Ph
Bu
H
Ambient
Ambient
45
Reux
Reux
Reux
Reux
Reux
Ambient
3
18
6
1
1
1
1
1
0.5
7a/8a
7a/8a
7a/8a
7a/8a
7b/8b
7c/8c
7d/8d
7e/8e
7e/8e
71 (+8a0, 19%)
89
91
91
87
81
94
<10
95c
H
a
b
Conditions: indole derivative (0.5 mmol), oxone (3 equiv.), NH4SCN (3 equiv.), MeOH (5 mL). Isolated yields aer column chromatography.
Carried out with CAN (6 equiv.) and NH4SCN (6 equiv.).
c
These optimized conditions were employed for the synthesis typical C^N stretching band of the SCN moiety at 2100–2200
of 1H,10H-2,20-biindole 3,30-di-thiocyanates 8b–d from the cor- cmꢀ1 in their infrared spectra.
responding 1H,10H-2,20-biindoles 7b–d,30 bearing different
substituents on the nitrogen atom.
With convenient routes towards the 3,30-di-thiocyanates 8a–e
in hands, the effectiveness of the CeIII-assisted 5-sulfenylte-
Unfortunately, the attempted di-thiocyanation of the related trazole synthesis was further tested with these heterocycles. The
di(1H-indol-2-yl)sulde (7e)30e under the optimized conditions results (Table 4) indicated that good to excellent yields could be
met with failure and a complex mixture of products was attained in 3 h under the optimized reaction conditions.
obtained, which included a minor amount of the expected 8e.
Interestingly, however, the N-unsubstituted biindole 8b
This outcome may be a result of the oxone-mediated oxidation afforded 49% of 9b (entry 2) in mixture with side products that
of the sulfur bridge to the sulfoxide and sulfone derivatives.31a exhibited low solubility in PEG-400, which precluded access of
Therefore, a milder and more selective approach was good yields of the heterocycle under the standardized condi-
selected, which employs ceric ammonium nitrate (CAN) as an tions. This seems to be a drawback of the proposed tetrazoy-
environmentally friendly oxidant; this cleanly furnished 95% of lating system, since 9b could be obtained employing ZnBr2 in
8e aer 30 min. at room temperature.31b
2-PrOH : H2O (1 : 1, v/v)6f in more satisfactory yield (entry 3).
Although the exact intimate details remain unknown, from
1
The H and 13C NMR spectra of the symmetric compounds
8a–e were relatively simple, exhibiting a single set of signals the mechanistic point of view, one can speculate that the CeIII
corresponding to both indole nuclei, consistent with the free salt coordinates with the nitrogen of the thiocyanate group in 2
rotation of these heterocyclic moieties around both, the indole– or 5, increasing the polarization of the C^N moiety and turning
indole and the indole–S bonds.
it prone to a nucleophilic attack by the azide anion (i) to furnish
On the other hand, besides the molecular ion peaks (M+) of ii. This should give way to formation of the intermediate Cer-
the di-thiocyanates, the major fragments observed in their mass iumIII tetrazolate (iii), as shown in Scheme 2. The formation of
spectra were those related to the loss of one or both SCN CeriumIII azide, that may drive the reaction, cannot be ruled
moieties [(M ꢀ 58)+ and (M ꢀ 116)+, respectively], the depriva- out. This has been included in the list of reagents capable of
tion of both SCN and CN groups [(M ꢀ 85)+] or the loss of SCN furnishing tetrazoles, under Zinc promotion.32
together with S [(M ꢀ 91)+]. The heterocycles exhibited the
In turn, iii may attract a proton from the reaction medium
or, most probably exchange with Na+, furnishing iv and
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Table 4 Synthesis of bis-(5-sulfenyl tetrazoles) 9a–e derived from
3,30-di-thiocyanates of 1H,10H-2,20-bis and di-indoles (8a–e)a
In conclusion, a facile and efficient synthesis of 5-sulfenyl-
tetrazoles (3a–m and 6a–c) from thiocyanates derived from
1H-indoles, and 1-phenyl pyrroles, under environmentally
friendly conditions, is reported. The transformation, which was
also successfully applied to bi- and di-indolyl di-thiocyanate
derivatives, yielding 9a–e, entailed a [3 + 2] cycloaddition reac-
tion with NaN3 in PEG-400 containing 20 mol% CeCl3$7H2O, as
a novel tetrazoylation promoter system.
The cycloaddition was optimized with regards to the reaction
time, temperature, concentration of the reactants and amount
of the promoter. Under the optimized conditions, the process
furnished good to excellent yields of the target heterocycles and
exhibited satisfactory level of generality. Access to the products
was accomplished cleanly and in short time, aer a simple
acidic workup to free the sodium tetrazolates. No special
protection against humidity was required, turning the proce-
dure amenable to use in synthetic organic chemistry.
Entry no.
R
X
Time (h)
St. mat./prod. no.
Yieldb (%)
1
2
3
4
5
6
Me
H
H
Ph
Bu
H
—
—
—
—
—
S
3
3
2
3.5
3.5
3
8a/9a
8b/9b
8b/9b
8c/9c
8d/9d
8e/9e
93
49
90c
85
96
80
Experimental section
General information
a
THF was reuxed over sodium metal utilizing benzophenone as
an indicator and distilled immediately before use. Acetonitrile
was distilled from CaH2 under argon and kept over molecular
sieves. The alcohols used as solvents were previously distilled.
DMF and DMSO were dried over molecular sieves. All other
reagents were used as received.
Conditions: substrate (0.25 mmol), NaN3 (0.6 mmol), CeCl3$7H2O (0.1
mmol), PEG-400 (1 mL), heated at 80 ꢁC. b Isolated yields aer column
chromatography. Carried out using substrate (0.25 mmol), NaN3 (0.6
mmol) and ZnBr2 (0.5 mmol) in 2-PrOH : H2O (1 : 1, 5 mL), at reux.
c
Column chromatography was performed with silica gel 60 H
(40–63 mm particle size, 230–400 mesh). Elution was carried out
with hexanes or hexanes–EtOAc mixtures. All new compounds
gave single spots on TLC plates (Whatman – AL SIL G/UV) run in
different solvent systems (hexanes or hexanes–EtOAc). Chro-
matographic spots were detected by exposure to 254 nm UV
light, as well as by treatment with iodine or with an acid solu-
tion of vanillin.
Apparatus
Melting points were measured on an MQAPF-301 (Micro-
´
quımica) instrument and are reported uncorrected. IR spectra
were recorded with a Shimadzu Prestige 21 spectrophotometer,
as thin lms held between NaCl cells or as solid dispersions in
KBr disks. The 1H NMR spectra were acquired at 200 or 400 MHz
on Bruker DPX 200 or DPX 400 spectrometers. The peak for
CHCl3 in CDCl3 (d 7.26) was used as the internal standard.
Chemical shis are reported in parts per million on the d scale
and J-values are given in Hertz. The 13C NMR spectra were
recorded at 50 or 100 MHz on Bruker DPX 200 or DPX 400
spectrometers. The central peaks of DMSO-d6 and CDCl3 (d 40.5
and 77.0, respectively) were used as internal standards.
The low resolution mass spectra were obtained in a Shi-
madzu QP2010 Plus GC-MS instrument. Fragments are
described with regards to their m/z ratios, in terms of relative
intensity (%) of their signals. The high resolution mass spectra
were obtained with a Bruker MicroTOF-Q II instrument (Bruker
Daltonics, Billerica, MA), using sodium formate. Detection of
the ions was performed in the electrospray ionization, positive
Scheme 2 Proposed reaction mechanism for the CeIII-promoted
synthesis of 5-sulfenyl tetrazoles.
regenerating the CeIII, which reenters into the cycle. Final
addition of HCl during the work-up frees the 5-sulfenyl tetrazole
(3, 6). That the reaction seems to run at a slower pace when
anhydrous CeCl3 is employed, probably reects that H2O also
plays a key role in the transformation, probably during the
stages of formation of ii or when iii is converted into iv.33
Interestingly enough, in some CeCl3-promoted reactions, the
presence of small amounts of water is essential for success,33b
and it has been speculated that this is related to the H2O-
mediated increase in Lewis acidity of the CeIII.33c
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ion mode. Elemental analyses were performed using a Perkin- 13C NMR (100 MHz, DMSO-d6) d: 155.0, 138.0, 137.2, 136.5,
Elmer analyzer model 2400 (Analytical Center; IQ-USP, SP, 135.7, 133.1, 129.2, 129.1, 126.4, 121.5, 115.5, 111.0, 93.3, 32.8
Brazil).
and 20.3. IR (KBr, n): 3446, 3102, 2915, 2857, 2695, 2667, 1617,
1513, 1476, 1448, 1364, 1304, 1239, 1150, 1117, 1035 and 801
cmꢀ1. EI-MS (m/z, rel. int., %): 322 [(M + 1)+, 8], 321 (M+, 38), 278
(36), 264 (48), 252 (100) and 43 (39). Anal. calc.: C, 63.53; H, 4.70.
Found: C, 63.56; H, 4.70%.
General procedure for the syntheses of the 5-sulfenyl tetrazole
derivatives 3a–m, 6a–c, and 9a–e
A stirred mixture of thiocyanate (2 or 5, 0.5 mmol), NaN3 (0.39 g,
3-((1H-Tetrazol-5-yl)thꢁio)-1-phenyl-1H-indoleꢁ (3e). Yellow
0.6 mmol) and CeCl3$7H2O (0.037 g, 0.1 mmol) in PEG-400 (0.5 solid, m.p.: 151.5–152.5 C (Lit.:6a 153.1–154.3 C); yield: 89%.
mL) was heated to 80 ꢁC (0.25 mmol thiocyanate and 1 mL PEG- 1H NMR (400 MHz, DMSO-d6) d: 8.21 (s, 1H), 7.64–7.58 (m, 6H),
400 were employed for the bi- and di-indole derivatives) in a test 7.50–7.47 (m, 1H) and 7.34–7.23 (m, 2H). 13C NMR (100 MHz,
tube, without special protection against moisture or atmo- DMSO-d6) d: 154.7, 137.9, 136.0, 135.3, 129.7, 129.1, 127.2,
spheric oxygen. The progress of the reaction was monitored by 124.2, 123.4, 121.5, 118.5, 111.0 and 96.9. IR (KBr, n): 3447, 3033,
TLC. Aer completion, a 2 M HCl solution (10 mL) was added 2885, 2531, 2331, 1598, 1517, 1498, 1457, 1230, 1016, 745 and
and the product was extracted with EtOAc (3 ꢂ 10 mL). The 695 cmꢀ1. EI-MS (m/z, rel. int., %): 293 (M+, 30), 236 (36), 224
organic layers were combined, dried over MgSO4 and concen- (100), 121 (21), 77 (41) and 51 (22).
trated under reduced pressure. The residue was puried by
3-((1H-Tetrazol-5-yl)thio)-1-(4-chlorophenyl)-1H-indole (3f).
1
ꢁ
precipitation with Et2O from an EtOAc solution or by column White solid, m.p.: 176–177 C; yield: 93%. H NMR (400 MHz,
chromatography, eluting with mixtures of hexanes and EtOAc. DMSO-d6) d: 8.25 (s, 1H), 7.70–7.66 (m, 4H), 7.61 (d, J ¼ 8.1, 1H),
For products 9b and 9e, the precipitate formed aer addition of 7.56 (d, J ¼ 7.8, 1H), 7.34–7.31 (m, 1H) and 7.27–7.24 (m, 1H).
2 M HCl solution was ltered, washed with water (3 ꢂ 10 mL) 13C NMR (100 MHz, DMSO-d6) d: 154.7, 136.7, 135.9, 135.4,
and dried under vacuum.
131.6, 129.7, 129.1, 126.0, 123.6, 121.7, 118.7, 111.1 and 97.4. IR
3-((1H-Tetrazol-5-yl)thio)-1-methyl-1H-indole (3a). Beige (KBr, n): 3437, 1627, 1614, 1594, 1514, 1493, 1454, 1226, 1091,
solid, m.p.: 179.5–180.5 C (Lit.:6a 179.9–181.4 C); yield: 92%. 1011, 832, and 743 cmꢀ1. EI-MS (m/z, rel. int., %): 329 [(M + 2)+,
1H NMR (400 MHz, DMSO-d6) d: 7.90 (s, 1H), 7.57 (d, J ¼ 8.2, 8], 328 [(M + 1)+, 5], 327 (M+, 25), 284 (18), 270 (43), 258 (100),
1H), 7.48 (d, J ¼ 7.9, 1H), 7.30–7.27 (m, 1H), 7.19–7.15 (m, 1H) 235 (13), 223 (28), 121 (36) and 77 (52). Anal. calc.: C, 54.96; H,
and 3.87 (s, 3H). 13C NMR (100 MHz, DMSO-d6) d: 155.3, 137.1, 3.07. Found: C, 55.51; H, 3.38%.
ꢁ
ꢁ
136.7, 128.6, 122.3, 120.5, 118.0, 110.6, 92.7 and 32.8. IR (KBr, n):
3-((1H-Tetrazol-5-yl)thio)-1-(4-methoxyphenyl)-1H-indole (3g).
1
3393, 3110, 2672, 2481, 1517, 1501, 1372, 1243, 1028 and 743 Light brown solid, m.p.: 165.2–166.5 ꢁC; yield: 91%. H NMR
cmꢀ1. EI-MS (m/z, rel. int., %): 232 [(M + 1)+, 5], 231 (M+, 33), 188 (400 MHz, DMSO-d6) d: 8.14 (s, 1H), 7.55 (d, J ¼ 8.6, 2H), 7.50 (d,
(10), 174 (27), 162 (100), 130 (11), 77 (17) and 45 (5).
J ¼ 8.3, 1H), 7.31–7.27 (m, 1H), 7.24–7.21 (m, 1H), 7.16 (d, J ¼
3-((1H-Tetrazol-5-yl)thio)-5-bromo-1-methyl-1H-indole (3b). 8.6, 2H) and 3.85 (s, 3H). 13C NMR (100 MHz, DMSO-d6) d: 158.4,
Beige solid, m.p.: 203.6–204.6 C (Lit.:6a 205.5–207.0 C); yield: 154.9, 136.5, 135.7, 130.8, 128.9, 125.9, 123.3, 121.3, 118.5,
ꢁ
ꢁ
1
90%. H NMR (400 MHz, DMSO-d6) d: 7.94 (s, 1H), 7.62 (d, J ¼ 114.9, 111.0, 96.0 and 55.4. IR (KBr, n): 3437, 3109, 2924, 2841,
1.8, 1H), 7.56 (d, J ¼ 8.7, 1H), 7.40 (dd, J ¼ 8.7 and 1.8, 1H) and 2659, 2537, 2380, 1735, 1604, 1514, 1453, 1306, 1247, 1033, 839
3.86 (s, 3H). 13C NMR (100 MHz, DMSO-d6) d: 154.9, 138.0, and 746 cmꢀ1. EI-MS (m/z, rel. int., %): 324 [(M + 1)+, 5], 323 (M+,
135.9, 130.5, 124.8, 120.2, 113.4, 112.8, 92.8, 33.0. IR (KBr, n): 25), 280 (25), 280 (25), 266 (32), 254 (100), 223 (19), 210 (13) and
3274, 1734, 1496, 1308, 1217, 1109, 1032, 883 and 608 cmꢀ1. EI- 77 (23). Anal. calc.: C, 59.43, H, 4.05. Found: C, 59.65, H, 4.39%.
MS (m/z, rel. int., %): 311 [(M + 2)+, 35], 310 [(M + 1)+, 5], 309 (M+,
3-((1H-Tetrazol-5-yl)thio)-1-octyl-1H-indole (3h). Light brown
36), 254 (48), 253 (7), 252 (47), 242 (98), 241 (17), 240 (100), 162 solid, m.p.: 97.6–98.3 ꢁC (Lit.:6a 95.4–96.9 ꢁC); yield: 91%. 1H
(25), 117 (32), 77 (7). Anal. calc.: C, 51.93; H, 3.92. Found: C, NMR (400 MHz, CDCl3) d: 7.56 (d, J ¼ 7.9, 1H), 7.36 (s, 1H), 7.29
51.99; H, 3.99%.
(d, J ¼ 8.1, 1H), 7.25–7.21 (m, 1H), 7.19–7.15 (m, 1H), 3.99 (t, J ¼
3-((1H-Tetrazol-5-yl)thio)-5-methoxy-1-methyl-1H-indole (3c). 7.2, 2H), 1.78–1.76 (m, 2H), 1.27–1.22 (m, 10H) and 0.86 (t, J ¼
White solid, m.p.: 165.1–165.7 ꢁC; yield: 88%. 1H NMR (400 6.9, 3H). 13C NMR (100 MHz, CDCl3) d: 156.5, 136.7, 135.0,
MHz, DMSO-d6) d: 7.82 (s, 1H), 7.47 (d, J ¼ 8.5, 1H), 6.93–6.90 128.8, 123.0, 121.2, 118.8, 110.4, 93.1, 46.9, 31.7, 29.8, 29.1, 29.0,
(m, 2H), 3.82 (s, 3H) and 3.74 (s, 3H). 13C NMR (100 MHz, 26.8, 22.5 and 14.0. IR (KBr, n): 3443, 3106, 2953, 2923, 2853,
DMSO-d6) d: 155.2, 154.7, 137.0, 132.2, 129.4, 112.3, 111.5, 99.7, 2714, 2556, 2486, 1702, 1614, 1492, 1457, 1370, 1299, 1165, 1020
92.0, 55.3 and 32.9. IR (KBr, n): 3565, 3522, 3447, 3111, 3035, and 739 cmꢀ1. EI-MS (m/z, rel. int., %): 329 (M+, 34), 272 (58),
2999, 2915, 2712, 2533, 1622, 1513, 1490, 1424, 1370, 1221, 260 (59), 162 (100), 148 (20), 130 (29), 77 (9), 69 (23), 57 (26) and
1037, 870, 793, and 629 cmꢀ1. EI-MS (m/z, rel. int., %): 262 [(M + 41 (51).
1)+, 5], 261 (M+, 31), 218 (15), 204 (30) and 192 (100). HRMS
obsd. m/z: 262.0731; C11H12N5OS [(M + H)+] requires m/z: 209.0–210.6 ꢁC (Lit.:6a 210.4–211.6 ꢁC); yield: 74% (in glycerol: 3
262.0763.
h, 93%). 1H NMR (400 MHz, DMSO-d6) d: 11.76 (s, 1H), 7.88 (d, J
3-((1H-Tetrazol-5-yl)tio)-1H-indole (3i). Brown solid, m.p.:
3-((1H-Tetrazol-5-yl)thio)-1-methyl-5-(p-tolyl)-1H-indole (3d). ¼ 2.8, 1H), 7.51 (d, J ¼ 8.1, 1H), 7.45 (d, J ¼ 7.9, 1H), 7.21 (td, J ¼
Beige solid, m.p.: 198.5–199 ꢁC; yield: 92%. 1H NMR (400 MHz, 8.1 and 1.0, 1H), 7.12 (td, J ¼ 7.9 and 1.0, 1H). 13C NMR (100
DMSO-d6) d: 7.92 (s, 1H), 7.68 (s, 1H), 7.63 (d, J ¼ 8.6, 1H), 7.57– MHz, DMSO-d6) d: 155.2, 136.5, 132.9, 128.2, 122.2, 120.3, 117.8,
7.52 (m, 3H), 7.24 (d, J ¼ 8.0, 2H), 3.88 (s, 3H) and 2.32 (s, 3H). 112.3 and 94.0. IR (KBr, n) 3269, 2472, 2335, 1653, 1524, 1508,
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1309, 1041, 746 and 603 cmꢀ1. EI-MS (m/z, rel. int., %): 218 [(M + 1H NMR (400 MHz, DMSO-d6) d: 7.45–7.34 (m, 6H), 6.82 (dd, J ¼
1)+, 6], 217 (M+, 41), 160 (30), 148 (100), 121, (14), 89 (20), 77 (20) 3.6 and 1.7, 1H) and 6.40–6.39 (m, 1H). 13C NMR (100 MHz,
and 45 (11).
DMSO-d6) d: 155.0, 138.3, 128.7, 128.1, 127.7, 126.0, 121.6, 111.4
3-((1H-Tetrazol-5-yl)thio)-5-bromo-1H-indole (3j). Light and 109.8. IR (KBr, n): 3117, 2365, 1595, 1497, 1375, 1322, 1037,
brown solid, m.p.: 209.5–210.6 C (Lit.6a 209.5–211.3 C); yield: 765, 739 and 695 cmꢀ1. EI-MS (m/z, rel. int., %): 244 [(M + 1)+, 7],
ꢁ
ꢁ
80% (in glycerol: 3 h, 96%). H NMR (400 MHz, DMSO-d6) d: 243 (M+, 37), 186 (35), 174 (100), 130 (17), 115 (20), 77 (66), 71
1
11.99 (s, 1H), 7.95 (d, J ¼ 2.8, 1H), 7.61 (d, J ¼ 1.7, 1H), 7.48 (d, J (26), 51 (39) and 43 (19).
¼ 8.6, 1H) and 7.33 (dd, J ¼ 8.6 and 1.7, 1H). 13C NMR (100 MHz,
5-((1-(4-Methoxyphenyl)-1H-pyrrol-2-yl)thio)-1H-tetrazole (6b).
DMSO-d6) d: 155.0, 135.3, 134.6, 130.3, 124.9, 120.1, 114.4, 113.1 Beige solid, m.p.: 163.3–163.8 ꢁC; yield: 92%. 1H NMR (200
and 93.9. IR (KBr, n): 3274, 2502, 1566, 1496, 1308, 1217, 1109, MHz, DMSO-d6) d: 7.29–7.24 (m, 3H), 6.96 (d, J ¼ 8.8, 1H), 6.79
1032, 883, 870, 794, 746 and 608 cmꢀ1. EI-MS (m/z, rel. int., %): (dd, J ¼ 3.5 and 1.6, 1H), 6.38–6.35 (m, 1H) and 3.76 (s, 1H). 13
C
297 [(M + 2)+, 35], 296 [(M + 1)+, 4], 295 (M+, 31), 240 (65), 239 (9), NMR (100 MHz, DMSO-d6) d: 158.7, 155.1, 131.3, 128.4, 127.5,
238 (59), 228 (98), 227 (23), 226 (100), 173 (41), 159 (34), 148 (38), 121.2, 113.9, 111.5, 109.6 and 55.3. IR (KBr, n): 3117, 3011, 2360,
120 (52) and 45 (34).
1605, 1517, 1249, 1038, 837, 739 and 620 cmꢀ1. EI-MS (m/z, rel.
3-((1H-Tetrazol-5-yl)thio)-5-methoxy-1H-indole (3k). Brown int., %): 274 [(M + 1)+, 6], 273 (M+, 38), 230 (2), 216 (20), 204
solid, m.p.: 174.5–176.0 ꢁC; yield: 47% (in glycerol: 8 h; 63%). 1H (100), 189 (46), 173 (38), 92 (15) and 77 (21). HRMS obsd. m/z:
NMR (400 MHz, DMSO-d6) d: 11.64 (s, 1H), 7.81 (d, J ¼ 2.8, 1H), 274.0750; C12H12N5OS [(M + H)+] requires m/z: 274.0763.
7.40 (d, J ¼ 8.8, 1H), 6.91 (d, J ¼ 2.3, 1H), 6.85 (dd, J ¼ 8.8 and
5-((1-(4-Chlorophenyl)-1H-pyrrol-2-yl)thio)-1H-tetrazole (6c).
2.3, 1H) and 3.73 (s, 3H). 13C NMR (100 MHz, DMSO-d6) d: 155.2, Orange solid, m.p.: 170.9–171.9 ꢁC (Lit.:6a 171.2–173.1 ꢁC); yield:
154.4, 133.4, 131.4, 129.0, 113.1, 112.4, 99.5, 93.4 and 55.3. IR 94%. 1H NMR (400 MHz, DMSO-d6) d: 7.50 (d, J ¼ 8.8, 2H), 7.40
(KBr, n): 3407, 3263, 2898, 2832, 2696, 1626, 1584, 1490, 1300, (d, J ¼ 8.8, 2H), 7.35 (dd, J ¼ 3.0 and 1.8, 1H), 6.82 (dd, J ¼ 3.7
1210, 1033, 805 and 632 cmꢀ1. EI-MS (m/z, rel. int., %): 248 [(M + and 1.8, 1H) and 6.40 (dd, J ¼ 3.7 and 3.0, 1H). 13C NMR (100
1)+, 5], 247 (M+, 33), 204 (16), 190 (35), 189 (15), 180 (6), 179 (18), MHz, DMSO-d6) d: 154.9, 137.2, 132.3, 128.8, 128.2, 127.9, 121.9,
178 (100), 175 (8), 163 (21), 147 (11), 135 (23), 120 (6) and 43 (21). 111.6, 110.1. IR (KBr, n): 3128, 3010, 2696, 2620, 2361, 1493,
HRMS obsd. m/z: 248.0593; C10H10N5OS [(M + H)+] requires m/z: 1310, 1093, 1029, 837, 738 and 621 cmꢀ1. EI-MS (m/z, rel. int.,
248.0606.
3-((1H-Tetrazol-5-yl)thio)-5-(p-tolyl)-1H-indole (3l). Brown (19), 209 (19), 173 (100), 111 (14) and 75 (20).
%): 279 [(M + 2)+, 6], 278 [(M + 1)+, 3], 277 (M+, 19), 233 (6), 219
solid, m.p.: 210.3–214.0 ꢁC (Lit.:6a 213.3–215.5 C); yield: 78%
3,30-Bis((1H-tetrazol-5-yl)thio)-1,10-dimethyl-1H,10H-2,20-biin-
ꢁ
(in glycerol: 8 h; 52%). 1H NMR (400 MHz, DMSO-d6) d: 11.84 (s, dole (9a). White solid, m.p.: 265.9–268 ꢁC; yield: 93%. 1H NMR
1H), 7.93 (s, 1H), 7.68 (s, 1H), 7.60 (d, J ¼ 8.4, 1H), 7.52–7.49 (m, (400 MHz, DMSO-d6) d: 7.70 (d, J ¼ 8.0, 2H), 7.58 (d, J ¼ 7.8, 2H),
3H), 7.23 (d, J ¼ 7.5, 2H) and 2.32 (s, 3H). 13C NMR (100 MHz, 7.43–7.39 (m, 2H), 7.29–7.26 (m, 2H) and 3.67 (s, 6H). 13C NMR
DMSO-d6) d: 155.2, 138.2, 135.9, 135.6, 133.7, 133.0, 129.3, (100 MHz, DMSO-d6) d: 154.5, 137.6, 133.9, 128.1, 123.5, 121.2,
128.9, 126.5, 121.5, 115.4, 112.8, 94.5 and 20.4. IR (KBr, n): 3262, 118.6, 111.1, 99.0 and 31.2. IR (KBr, n): 3463, 3057, 2921, 2712,
2331, 1051, 1472, 1307, 1108, 1035 and 798 cmꢀ1. EI-MS (m/z, 1614, 1463, 1419, 1380, 1336, 1303, 1241, 1157, 1130, 1111, 1035
rel. int., %): 307 (M+, 11), 277 (19), 250 (18), 238 (44), 220 (18), and 745 cmꢀ1. EI-MS (m/z, rel. int., %): 417 (3), 374 (4), 322 (66),
209 (23), 173 (100), 111 (22), 102 (15), 77 (9), 71 (21) and 45 (22). 307 (9), 290 (56), 258 (8) and 43 (100). HRMS obsd. m/z:
3-((1H-Tetrazol-5-yl)thio)-2-methyl-1H-indole (3m). Light 483.0890; C20H16N10NaS2 [(M + Na)+] requires m/z: 483.0899.
brown solid, m.p.: 179.5–180.3 ꢁC (Lit.:6a 184.5–185.7 ꢁC); yield:
3,30-Bis((1H-tetrazol-5-yl)thio)-1H,10H-2,20-biindole
(9b).6f
82%. H NMR (400 MHz, DMSO-d6) d: 11.68 (s, 1H), 7.43–7.39 Brown solid, m.p.: 275 ꢁC (dec); yield: 49%. 1H NMR (400 MHz,
(m, 2H), 7.16–7.12 (m, 1H), 7.09–7.06 (m, 1H) and 2.53 (s, 3H). DMSO-d6) d: 12.21 (s, 2H), 7.59 (d, J ¼ 8.1, 2H), 7.45 (d, J ¼ 7.9,
13C NMR (100 MHz, DMSO-d6) d: 155.2, 143.1, 135.5, 129.2, 2H), 7.33–7.29 (m, 2H) and 7.19–7.16 (m, 2H). 13C NMR (100
121.5, 120.1, 117.1, 111.3, 91.1 and 11.6. IR (KBr, n): 3338, 3051, MHz, DMSO-d6) d: 154.6, 136.7, 133.2, 128.9, 123.5, 120.9, 118.5,
2332, 1546, 1518, 1313, 1234, 1034 and 741 cmꢀ1. EI-MS (m/z, 112.4 and 96.1. IR (KBr, n): 3379, 1614, 1517, 1448, 1339, 1079,
rel. int., %): 231 (M+, 34), 174 (34), 162 (100), 130 (33), 118 (68) 1037 and 744 cmꢀ1. HRMS obsd. m/z: 433.0753; C18H13N10S2
1
and 77 (27).
3-((1H-Tetrazol-5-yl)thio)-1H-indole-5-carbonitrile
[(M + H)+] requires m/z: 433.0766.
(3n).
3,30-Bis((1H-tetrazol-5-yl)thio)-1,10-diphenyl-1H,10H-2,20-biin-
Beige solid, m.p.: 190.6–192.0 ꢁC; yield: 87%. 1H NMR (400 dole (9c). Light brown solid, m.p.: 179.2–180.8 C; yield: 85%.
ꢁ
MHz, DMSO-d6) d: 12.32 (s, 1H), 8.11 (d, J ¼ 2.7, 1H), 7.97 (s, 1H NMR (400 MHz, DMSO-d6) d: 7.61–7.59 (m, 2H), 7.32–7.20
1H), 7.68 (d, J ¼ 8.5, 1H) and 7.57 (dd, J ¼ 1.5 and 8.5, 1H). 13
C
(m, 12H) and 6.80 (bs, 4H). 13C NMR (100 MHz, DMSO-d6) d:
NMR (100 MHz, DMSO-d6) d: 154.8, 138.4, 135.8, 128.3, 125.1, 154.4, 137.0, 135.7, 132.6, 129.1, 128.2, 127.5, 125.7, 124.7,
123.5, 120.0, 113.8, 102.7 and 95.8. IR (KBr, n): 3277, 3103, 2227, 122.1, 119.3, 111.0 and 103.6. IR (KBr, n): 3451, 3058, 2920, 1704,
1617, 1505, 1468, 1422, 1340, 1038, 913, 803, 705, 636, 421. EI- 1595, 1498, 1450, 1379, 1333, 748 and 697 cmꢀ1. EI-MS (m/z, rel.
MS (m/z, rel. int., %): 243 [(M + 1)+, 7], 242 (M+, 42), 214 (7), int., %): 446 (31), 414 (41), 380 (5) and 70 (100). HRMS obsd. m/z:
199 (25), 173 (100), 142 (23). Anal. calc.: C, 49.58; H, 2.50. Found: 607.1188; C30H20N10NaS2 [(M + Na)+] requires m/z: 607.1211.
C, 49.87; H, 2.80%.
3,30-Bis((1H-tetrazol-5-yl)thio)-1,10-dibutyl-1H,10H-2,20-biindole
5-((1-Phenyl-1H-pyrrolꢁ-2-yl)thio)1H-tetrazole ꢁ (6a). Yellow (9d). White solid, m.p.: 129.2–131.5 ꢁC; yield: 96%. 1H NMR (400
solid, m.p.: 157.9–158.5 C (Lit.:6a 160.1–161.4 C); yield: 90%. MHz, DMSO-d6) d: 7.73 (d, J ¼ 8.2, 2H), 7.54 (d, J ¼ 7.8, 2H),
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7.42–7.38 (m, 2H), 7.28–7.24 (m, 2H), 4.27–4.20 (m, 2H), 3.90–
3.82 (m, 2H), 1.56–1.46 (m, 2H), 1.40–1.29 (m, 2H), 1.13–1.00
(m, 4H) and 0.61 (t, J ¼ 7.2, 6H). 13C NMR (100 MHz, DMSO-d6)
d: 154.3, 137.0, 132.9, 128.4, 123.6, 121.2, 119.2, 111.6, 99.6,
44.6, 31.2, 19.1 and 13.1. IR (KBr, n): 3446, 3058, 2958, 2930,
2872, 1505, 1486, 1460, 1392, 1377, 1340, 1303, 1034, 1014 and
744 cmꢀ1. EI-MS (m/z, rel. int., %): 501 (2), 458 (3), 406 (100), 374
(29), 345 (98) and 44 (41). HRMS obsd. m/z: 567.1814;
2010, 20, 3692–3697; (h) T. Nishimura, Y. Yoshimura,
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C
26H28N10NaS2 [(M + Na)+] requires m/z: 567.1832.
Bis(3-((1H-tetrazol-5-yl)thio)-1H-indol-2-yl)sulde (9e).
Brown solid, m.p.: 250 ꢁC (dec.); yield: 80%. 1H NMR (400 MHz,
DMSO-d6) d: 12.10 (s, 2H), 7.44–7.40 (m, 4H), 7.25–7.22 (m, 2H)
and 7.16–7.12 (m, 2H). 13C NMR (100 MHz, DMSO-d6) d: 154.7,
137.1, 133.0, 128.8, 123.3, 121.0, 117.9, 112.0 and 99.7. IR (KBr,
n): 3458, 3423, 2901, 1622, 1495, 1342, 1309, 1230, 1043 and 744
cmꢀ1. HRMS obsd. m/z: 487.0288; C18H12N10NaS3 [(M + Na)+]
requires m/z: 487.0306.
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¨
´
Synthesis of 3,30-bis((1H-tetrazol-5-yl)thio)-1H,10H-2,20-biin-
dole (9b) employing ZnBr2 in 2-PrOH : H2O.6f A mixture of the
di-thiocyanato 7b (0.087 g, 0.25 mmol), ZnBr2 (0.112 g, 0.5
mmol) and NaN3 (0.081 g, 1.2 mmol) in a 1 : 1 mixture of 2-
PrOH and water (5 mL) was heated to reux for 2 h. Then, it was
allowed to return to room temperature and poured over a 4 M
HCl solution (5 mL); the resulting precipitate was ltered and
the residue was washed with water (3 ꢂ 10 mL) and dried under
vacuum to give 9b (97 mg, 90%) as a brown solid. The spectral
data were in agreement with those obtained from the reaction
of 8b with NaN3 in PEG-400, promoted by CeCl3$7H2O.
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Acknowledgements
The authors are thankful to MCT/CNPq and CAPES, for nan-
cial support. TSK also thanks CONICET and ANPCyT.
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