Tandem regioselective synthesis of tetrazoles and related heterocycles using iodine

Article abstract of DOI:10.1039/c0ob01007c

A one-pot, tandem process has been developed for the synthesis of a library of tetrazoles from aryl isothiocyanates. Condensation of aryl isothiocyanates with ammonia, and aryl amines (R-NH₂) provided mono, 1,3-disubstituted symmetrical and unsymmetrical thioureas, which on desulfurization with molecular iodine (I₂) led to formation of the corresponding heterocumulene (cyanamides or carbodiimides). The in situ generated heterocumulene on subsequent treatment with sodium azide at room temperature gave corresponding tetrazoles. The product regioselectivity for unsymmetrical 1,3-disubstituted thioureas was found to be correlated with the basicities (pK_a's) of the parent amines attached to the thiourea. Aryl-sec-alkyl unsymmetrical thioureas gave thioamido guanidino products rather than the 5-aminotetrazoles produced by HgCl₂ mediation of the reaction. Bis-thioureas derived from aryl isothiocyanates and hydrazine gave thiadiazoles exclusively.

Full text of DOI:10.1039/c0ob01007c

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PAPER
Tandem regioselective synthesis of tetrazoles and related heterocycles using
iodine†
Ramesh Yella, Nilufa Khatun, Saroj Kumar Rout and Bhisma K. Patel*
Received 10th November 2010, Accepted 7th February 2011
DOI: 10.1039/c0ob01007c
A one-pot, tandem process has been developed for the synthesis of a library of tetrazoles from aryl
isothiocyanates. Condensation of aryl isothiocyanates with ammonia, and aryl amines (R-NH2)
provided mono, 1,3-disubstituted symmetrical and unsymmetrical thioureas, which on desulfurization
with molecular iodine (I2) led to formation of the corresponding heterocumulene (cyanamides or
carbodiimides). The in situ generated heterocumulene on subsequent treatment with sodium azide at
room temperature gave corresponding tetrazoles. The product regioselectivity for unsymmetrical
1,3-disubstituted thioureas was found to be correlated with the basicities (pKa’s) of the parent amines
attached to the thiourea. Aryl-sec-alkyl unsymmetrical thioureas gave thioamido guanidino products
rather than the 5-aminotetrazoles produced by HgCl2 mediation of the reaction. Bis-thioureas derived
from aryl isothiocyanates and hydrazine gave thiadiazoles exclusively.
ing anti-allergic/anti-asthmatic,8 antiviral,9 anti-inflammatory,9
antineoplastic,10 and cognition disorder activities.11
Introduction
Few examples of aminotetrazoles having pharmacological,12
antiviral,13 and receptor modulator14 activities are shown in Fig.
1. They are also used in high energy density materials (HEDM)15
as ligands in coordination chemistry16 and in the preparation of
imidoylazides.17
In combinatorial chemistry, tandem reactions have gained vital
role in the construction of small molecule libraries. Usually,
they involve multiple chemical transformations in one synthetic
approach, and the advantage is that the intermediate need not
be stable enough to be isolated. Tandem reactions also provide
powerful methods to construct structurally complex molecules
containing biologically and pharmacologically important C–N
bonds from a relatively simple starting materials in a convergent
approach.1
Aminotetrazoles are an interesting class of heterocyclic com-
pounds that have not been found in the nature so far. They are
resistant to metabolic degradation as well as towards chemical
oxidants,2 and have found application in propellents,3a explosives3b
and as structural components of many biologically important
molecules.4 For a drug to be effective, it should be sufficiently
lipophilic in nature so as to pass through the cell membrane
effectively. Hansch has shown that anionic tetrazoles are at least
ten times more lipophilic than the corresponding carboxylates.5
Due to the tunable lipophilicity of various tetrazole derivatives;
it is possible to use them as “isosteric substituents” of various
functional groups. 5-Substituted (alkyl/aryl) tetrazoles (RCN4H)
in particular, may serve as “non-classical isosteres” for the
carboxylic acid moiety (RCO2H) in biologically active molecules.6,7
Additionally, aminotetrazoles are found in compounds hav-
Fig. 1 Some of the biologically important aminotetrazoles.
As shown in Scheme 1, many of these reported methods require
harsh reaction conditions, high temperature, and the use of toxic
reagents or metal salts. We regard the development of new methods
for aminotetrazole synthesis having qualities of reagent economy,
metal free conditions, and tandem or one-pot operation as being
highly desirable.
In recent years, molecular iodine (I2) has emerged as a useful
catalyst for various organic transformations because of its in-
expensive, non-toxic, readily available and eco-friendly nature.25
It has high tolerance to air and moisture that can be removed
from the reaction systems easily, and so has also been explored
as a useful reagent in organic synthesis.26 Our interest in the
thiophilic properties of hypervalent iodine reagents27 made us
Indian Institute of Technology Guwahati, Guwahati, 781 039, Assam, India.
E-mail: patel@iitg.ernet.in; Fax: +91-361-2690762; Tel: +91-361-2582307
† Electronic supplementary information (ESI) available: 1H and 13C
NMR spectra. CCDC reference numbers 787035–787038. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c0ob01007c
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Scheme 1 Available literature methods (I–VI) for the preparation of aminotetrazoles.18–24
envisage the development of an efficient three step tandem process
to construct the aminotetrazoles utilizing isothiocyanates. The
synthetic sequence for the proposed one-pot tandem process
can be accomplished by treating the organic isothiocyanates
with amines (ammonia, aryl or alkyl amine) to form the
corresponding thiourea. The in situ generated thiourea gives
cyanamides/carbodiimides in the medium when reacted with
molecular iodine in the presence of a base. Subsequent treatment
of the cyanamides/carbodiimides with sodium azide generates the
tetrazole.
optimized reaction condition [arylthiourea (1 equiv.), Et3N (3
equiv.), iodine (1.1 equiv.), DMF (2 mL)] for the synthesis of
various mono substituted tetrazoles.
A plausible reaction mechanism for this transformation has
been proposed as shown in Scheme 2. The intermediate cyanamide
(A) or (A¢) obtained from thiourea (2) (where R1 = H), has been
confirmed by its isolation and characterization. The precipitation
of elemental sulfur further supports our proposed mechanism.
The intermediate cyanamide (A) is attacked by the azide ion
giving the intermediate guanyl azide (B) which then undergoes
electrocyclization giving 1-aryl-1H-tetrazole-5-amine (3). In the
case of unsymmetrical thiourea an unsymmetrical guanyl azide B
or B¢ intermediate shall be generated. However protonation or flow
of the electron shall be on the nitrogen having more basicity (higher
pKa’s). This observation is consistent with our earlier reports on
regioselective reactions in unsymmetrical thioureas.27a,28a–c
Results and discussion
The development of the three step tandem process was carried out
using freshly prepared phenyl isothiocyanate (1a)26h,27b (1 equiv)
to which was added aqueous ammonia (25%, 1 mL) in an ice-
cold condition and the mixture was stirred for 20 min to give 1-
phenylthiourea (2a). The excess ammonia was removed in a rotary
evaporator to prevent the formation of nitrogen triiodide NI3.29
Subsequently, DMSO (2 mL) was admixed to the 1-phenylthiourea
(2a), and to which was added sequentially, NaN3 (2 equiv), I2
(1 equiv) followed by a drop wise addition of triethylamine (2
equiv) at room temperature. During this time the reaction was
exothermic. After complete addition of triethylamine the reaction
mixture was stirred for 14 h to convert the in situ generated
1-phenylthiourea (2a) to 1-phenyl-1H-tetrazole-5-amine (3a) in
moderate yield (55%). Other organic solvents such as chloroform,
tetrahydrofuran, toluene, acetonitrile, dioxane, ethanol etc. were
not effective in converting the cyanamide into the corresponding
tetrazole (3a) even at higher temperature as sodium azide remains
insoluble in these solvents. Additionally, the optimization of the
reaction conditions e.g. increase in the quantity of I2 from 1 to
1.1 equiv, Et3N from 2 to 3 equiv and switching the solvent from
DMSO to DMF reduced the time to 4 h and improved the yield
(75%) at room temperature. Therefore, we continued to use our
Scheme 2 Plausible mechanism for formation of 5-aminotetrazole 3.
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Table 1 Formation of 1-aryl-1H-tetrazole-5-amines from aryl
isothiocyanatesa,b
Isothiocyanate
Thiourea
Time/h
Productc
Yields (%)d
X = H (1a)
(2a)
(2b)
(2c)
(2d)
(2e)
(2f)
4.0
2.5
3
2.6
3.5
5
(3a)
(3b)
(3c)
(3d)
(3e)
(3f)
75
88
79
86
85
73
X = o-Cl (1b)
X = m-Cl (1c)
X = m-NO2 (1d)
X = p-Br (1e)
X = p-CH3 (1f)
a Reactions were carried out at room temperature in DMF. b Reactions
were monitored by TLC at an interval of 10 min. c Confirmed by IR, 1H
and 13C NMR. d Isolated yield.
Fig. 2 ORTEP view with the atomic numbering scheme of 3b.30
Employing this one-pot strategy, we have successfully prepared a
series of 1-aryl-1H-tetrazole-5-amine (3) from their corresponding
isothiocyanates (1) as shown in Table 1. Aryl isothiocyanates
containing weakly deactivating groups (Cl and Br) (1b), (1c) and
(1e) in their ortho, meta or para positions reacted efficiently to
afford the corresponding tetrazoles (3b), (3c) and (3e) in good
yields. Strongly deactivating group (-NO2) (1d) when present in
the m-position yielded the corresponding tetrazole (3d) in good
yield. Further, the structure of (3b) has been confirmed by X-ray
crystallographic analysis as shown in Fig. 2.30
Aryl isothiocyanate substituted with a weakly activating group
(p-CH3) (1f) also resulted in the corresponding tetrazole (3f) in
good yield, though it required longer reaction time compared
to the substrates possessing electron withdrawing groups (1b–e)
(Table 1).
elevated temperature. This of course is dependent on the nature of
the substituents attached to the aryl cyanamides. For substrates
having electron donating substituents, the formation of 1-aryl-
5-amino-1H-tetrazole (3) is favourable which goes via guanyl
azide intermediate (B). As the electronegativity of the substituent
increases, the product is shifted towards the 5-arylamino-1H-
tetrazole (3¢) which goes via guanyl azide intermediate (B¢). Very
recently, Katritzky et al. have investigated the tautomeric behavior
of N-(a-aminoalkyl) tetrazoles using NMR spectroscopy.31 Under
the present experimental condition which is carried out at room
temperature irrespective of the nature of the substituents present
(1a–1f) in the aryl cyanamide, exclusive formation of the 1-aryl-5-
amino-1H tetrazole (3a–3f) was observed (Table 1).
1,5-Disubstituted tetrazoles (7a–7f) were obtained by the reac-
tion of aryl isothiocyanates (1a–1f) and aryl amines (4a–4f) by a
similar mechanism as shown in Scheme 2. Symmetrical thioureas
containing moderately electron-withdrawing substituents such as
o-Cl, m-Cl, or p-Br and strongly electron-withdrawing substituent
m-NO2, all gave their corresponding tetrazoles (7b–7e) as shown
in Table 2 in good to excellent yields. The structure of one of
the products (7b) has been confirmed by X-ray crystallography
as shown in Fig. 3.32 This methodology was found to be equally
It may be mentioned here that formation of both the isomeric
products i.e. 1-aryl-5-amino-1H tetrazole (3) and 5-arylamino-
1H-tetrazole (3¢) (where R = Aryl, R¢ = H) from thiourea (2)
have been observed using hydrazoic acid and aryl cyanamide
under a thermal condition which is because of the thermal
isomerization of the intermediates (B) and (B¢) as shown in
Scheme 2.20c,d Recently, exclusive formation of one of the isomer
has been achieved using zeolite22b or ZnCl2
catalyst at an
22c
Table 2 Formation of aryl-(1-aryl-1H-tetrazol-5-yl)-amine from the in situ generated 1,3-diarylthioureaa,b
Isothiocyanate
Amine
Thiourea
Time/h
Productc
Yields (%)d
X = H (1a)
Y = H (4a)
(5a)
(5b)
(5c)
(5d)
(5e)
(5f)
4.5
2.6
3
2.8
3.6
8
(7a)
(7b)
(7c)
(7d)
(7e)
(7f)
75
85
80
81
78
74
X = o-Cl (1b)
X = m-Cl (1c)
X = m-NO2 (1d)
X = p-Br (1e)
X = p-CH3 (1f)
Y = o-Cl (4b)
Y = m-Cl (4c)
Y = m-NO2 (4d)
Y = p-Br (4e)
Y = p-CH3 (4f)
a Reactions carried out at room temperature in DMF solvent. b Reactions were monitored by TLC at an interval of 10 min. c Confirmed by IR and 1H
and 13C NMR. d Isolated yield.
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group giving product of the type (9) or a reverse orientation giving
product (10) as shown in Scheme 3, eq 1.
Recently, we have found a good correlation between the
regioselective N-acylation and the pKa’s of the precursor amines
attached to the thioureas.27a A similar observation was also noticed
during the synthesis of thiazole-2-imine [or 2-iminothiazoline],28a
2-imino-4-thiazolidinone,28b and in the synthesis of thioamido
guanidines.28c The larger the difference in pKa’s between the
precursor amines in 1,3-disubstituted thioureas, the higher is
the regioselective N-acylation with preferential acylation taking
place towards the amine having lower pKa.27a Similarly, during
the formation of 2-imino-4-thiazolidinone, the amine having
lower pKa is part of the heterocyclic nitrogen and amine having
higher pKa contributes the imino nitrogen.28b Again, during the
formation of thioamido guanidino moiety resulted from aryl-sec-
alkyl thiourea with bromine or its equivalent, amine having the
lower pKa as part of the imino nitrogen, and amino having the
higher pKa contributed to the thioamidic nitrogen.28c We wanted to
see whether this is applicable for the synthesis of 1,5-disubstituted
tetrazoles as well.
After the formation of an unsymmetrical carbodiimide (8¢)
(Scheme 3, eq 1), the attack of an azide group to an unsymmetrical
carbodiimide would led to the flow of electron (protonation)
towards the amine having more basic nature (higher pKa) hence
path-a is more favourable (Scheme 3, eq 1), without affecting the
imine group on the other side. The resultant guanidyl intermediate
(C), Scheme 3, eq 1 undergoes electrocyclization giving product
of the type (9) where the amine having lower pKa goes to the ring
nitrogen and the other amine having higher pKa is part of the
exocyclic nitrogen.
Fig. 3 ORTEP view with the atomic numbering scheme of 7b.32
efficient with moderately electron-donating substituent p-Me at-
tached to symmetrical thiourea (7f) obtained from isothiocyanate
(1f) and amine (4f).
A noteworthy aspect is that the parent amines attached to
the in situ generated thioureas Table 1 (2a–e) and Table 2 (5a–
e) having lower pKa’s resulted in the formation of the intermediate
cyanamide or carbodiimide faster because of the facile N–H
deprotonation (Scheme 2) compared to the amine having higher
pKa’s. Once the intermediate cyanamide/carbodiimide is built up,
the attack by the azide ion is possibly the rate determining step.
The effect of electron withdrawing groups facilitates this and hence
faster formation of tetrazoles (3a–3e) and (7a–7e). The pKa of o-
Cl, m-NO2, m-Cl, p-Br, p-Me anilines and aniline are 2.65, 2.46,
3.46, 3.86, 5.08 and 4.63 respectively, which is clearly reflected in
their reactivity order as can be seen from Table 1 and Table 2
leading to the formation of heterocycles (3a–3e) and (7a–7e).
So far there are no literature reports on the regioselectivity in
the formation of 1,5-disubstituted tetrazole from 1,3-disubstituted
unsymmetrical thioureas (8). We were interested to investigate
the regioselectivity of tetrazole formation from unsymmetrical
thioureas (8) i.e. whether the amine having lower pKa would be
attached to the ring nitrogen or contribute to the exocyclic amino
The flow of electron (protonation) towards the amine having
less basic nature (lower pKa) (path-b) is less favourable (Scheme 3,
eq 1) and hence unlikely to generate the intermediate (C¢) leading
to the product type (10). This is illustrated using phenylcyclohexyl
carbodiimide (8¢g) as a typical example as shown in Scheme 3,
eq 2. The measured pKa of cyclohexyl amine and aniline are
10.66 and 4.63 respectively and hence product (9g) is expected
to form exclusively as shown in Scheme 3, eq 2 and it is indeed the
case.
As can be seen from Table 3, an unsymmetrical thiourea (8a)
containing an aniline and a p-methylaniline group attached to
Scheme 3 Regioselective product of unsymmetrical thiourea (8).
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Table 3 Regioselective formation of aryl-(1-aryl-1H-tetrazol-5-yl)-amine from unsymmetrical 1,3-diarylthioureaa,b
Thiourea
Carbodiimide
Time/h
Product(s)c
Yields (%)d,e
X = H, Y = p-CH3 (8a)
X = H, Y = o-OCH3 (8b)
X = p-Br, Y = p-OCH3 (8c)
X = p-Br, Y = H (8d)
(8¢a)
(8¢b)
(8¢c)
(8¢d)
(8¢e)
(8¢f)
(8¢g)
6
3
3
6
6
3
12
(9a):(10a)
(9b):(10b)
(9c):(10c)
(9d):(10d)
(9e):(10e)
(9f):(10f)
(9g):(10g)
75 (77 : 23)
84 (84 : 16)
77 (57 : 43)
80 (59 : 41)
72 (61 : 39)
88 (100 : 00)
35 (100 : 00)
X = m-NO2, Y = pCH3 (8e)
X = o-Cl, Y = H (8f)
X = H, Ar–Y = cyclohexyl (8g)
a Reactions carried out at room temperature in DMF solvent. b Reactions were monitored by TLC. c Confirmed by IR and 1H and 13C NMR. d Isolated
yield. e Ratio of regioisomers determined by1H NMR.
the thiourea gave the corresponding unsymmetrical carbodiimide
(8¢a) in situ, which when reacted with sodium azide furnish a
mixture of tetrazoles (9a) and (10a) in the ratio of 77 : 23. The
measured pKa of aniline and p-methylaniline are 4.63 and 5.08
respectively. Thus, as per the mechanism proposed, Scheme 3, eq
1, in the major product, the amine having lower pKa (aniline)
is a part of the heterocyclic nitrogen and the other amine (p-
methylaniline) attached to the thiourea having a higher pKa is
part of the other exocyclic nitrogen in tetrazoles skeleton (9)
and (10). This assumption is again demonstrated for another
unsymmetrical thiourea (8b) having aniline and o-methoxyaniline.
Earlier we have demonstrated that larger the difference between
the pKa’s of the amines attached to the thiourea, greater is the
regioselectivity.27a,28a,b In this case, the pKa difference between
the two amines, o-methoxyaniline (5.45) and aniline (4.63) is
0.82, hence, expected to give better selectivity. The ratio of the
product (9b) and (10b) formed was (84 : 16) which can be explained
based on the measured pKa¢s of the parent amines. The X-ray
crystallographic analysis of the major product (9b) as shown in
33
Fig. 4 clearly revealed the disposition of the phenyl group as
part of the ring nitrogen and the o-methoxy phenyl group attached
Fig. 4 ORTEP view with the atomic numbering scheme of 9b.33
to the exocyclic nitrogen. It may be mentioned here that the
regioisomeric mixture (9a) and (10a) could not be resolved in thin
layer chromatography (TLC) whereas the regioisomer (9b) and
(10b) are well separated by TLC. One of the regioisomer (9b) forms
intramolecular hydrogen bonding between exocyclic NH and the
o-methoxy group thereby reducing its polar character. Similar
intramolecular hydrogen bonding possibility does not exist in the
other isomer (10b) as shown in Scheme 4. The single crystal XRD
structure of the product (9b) shows the intramolecular hydrogen
˚
bonding N5H ◊ ◊ ◊ O with a bond length of 2.223 A as shown in
Fig. 4.
An anomaly to the proposed regioselective mechanism was
observed in the case of thiourea (8c) where the measured pKa
of p-methoxyaniline and p-bromoaniline are 5.37 and 3.84 respec-
tively, a difference of 1.53 units, thus expected to give a better
regioselectivity compared to the thioureas (8a) and (8b). However,
Scheme 4 Intramolecular H bonding in regioisomers 9b and 10b.
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Table 4 Reaction of in situ generated aryl-sec-alkyl thiourea with iodinea,b
Isothiocyanate
Sec-amine(s)
Thiourea
Product(s)c
Yields (%)d
X = H (1a)
(k)
(I)
(I)
(m)
(k)
(k)
(I)
(11a)
(11b)
(11c)
(11d)
(11e)
(11f)
(11g)
(11h)
(13a) 87
(13b) 93
(13c) 94
(13d) 91
(13e) 88
(13f) 86
(13g) 89
(13h) 60
(14a) 10
(14b) nde
(14c) nde
(14d) nde
(14e) nde
(14f) nde
(14g) nde
(14h) 14
X = H (1a)
X = o-Cl (1b)
X = o-Cl (1b)
X = m-NO2 (1d)
X = p-Br (1e)
X = p-Br (1e)
X = p-CH3 (1f)
(I)
a Reactions carried out at room temperature in EtOH solvent. b Reactions were monitored by TLC. c Confirmed by IR and 1H and 13C NMR. d Isolated
yield. e nd = not detected.
the ratio of product (9c : 10c) was found to be 57 : 43, less than
expected. This could be due to the possible interconversion of the
two intermediates there by loss in the regioselectivity.
added NaN3 (3 equiv), iodine (1.1 equiv) followed by a drop
wise addition of triethylamine (3 equiv) over a period of 10 min.
After the complete addition of triethylamine, the reaction mixture
was allowed to stir for an additional 3 h. TLC showed complete
disappearance of the intermediate thiourea and the formation
In the case of thiourea (8d), the pKa difference between the
two amines, aniline (4.63) and p-bromoaniline (3.84) is 0.79. The
ratio of the product (9d) and (10d) formed was 59 : 41 which can
be again explained based on the measured pKa’s of the amines.
Unlike other regioisomers, the isomers (9e) and (10e) derived from
thiourea (8e) could be separated by column chromatography and
the regioisomeric product ratios is in agreement with measured
pKa’s of the amine. However, when the pKa difference between
the amines attached to the thiourea is sufficiently large (<2
unit), only one of the regioisomer is obtained exclusively. This
has been demonstrated with two other unsymmetrical thioureas
(8f) and (8g). In the case of thiourea (8f), the pKa’s of the
parent amines, aniline and o-chloroaniline are respectively 4.63
and 2.65, a difference of 1.98, which gave exclusively one of the
regioisomer (9f). As discussed above, in the thiourea (8g), the
pKa’s of the parent amines, aniline and cyclohexylamine are 4.63
and 10.66 respectively, a difference of 6.03, which gave exclusively
one regioisomer (9g). The yield obtained in the case of thiourea
(8g) was much less (35%) which is because of the inability of
unsymmetrical thiourea (8g) to efficiently form corresponding
carbodiimide (8¢g) because of the presence of an aliphatic amine
in one side, an observation consistent with our recent report on
carbodiimide formation.26j
1
of a new product. Further, H NMR, 13C NMR analysis of the
product reveals the formation of a thioamido guanidine (13a) as
the major product (87%) along with 2-aminobenzothiazole (14a)
(10%) (Table 4). This observation is consistent with our recent
report on the formation of thioamido guanidino moiety rather
than the expected 2-aminobenzothiazole (Hugerschoff product)34
when the in situ generated thiourea, aryl-sec-alkyl thiourea was
treated with bromine or its equivalents.28c
The difference in the desulfurizing ability of HgCl2 and I2 is
quite evident. In the former, the intermediate imino S-HgCl 11¢
(Scheme 5, eq 1) is attacked by an azide ion directly giving guanidyl
azide intermediate E (Scheme 5, eq 1)20a whereas in the later case
the imino S–I intermediate is attacked by a second molecule of the
thiourea giving a disulfide intermediate F (Scheme 5, eq 2) which
rearrange to give the thioamido guinidino moiety (13) (Scheme
5, eq 2).28c However when the aryl ring is sufficiently activated,
it would prefer (G) an intramolecular electrophilic substitution
reaction to give Hugerschoff product i.e. aminobenzothiazole (14)
(Scheme 5, eq 2). It is pertinent to mention here that tetrazole
formation is not possible from N,N-disubstituted thiourea using
HgCl2 possibly because of the formation of bis-thiomercury(II)
complex.20a,35
After the successful synthesis of various tetrazoles from
mono substituted, symmetrical and unsymmetrical disubstituted
thioureas, we were interested to apply this strategy on thioureas
generated from isothiocyanates and alkyl sec-amines. Previously,
Batey et al. have successfully synthesized several tetrazoles using
mercuric chloride (HgCl2) as the desulfurizing agent.20a To scru-
tinize this, phenyl isothiocyanate (1a) (1 equiv) was treated with
piperidine (k) (1 equiv) to form the corresponding unsymmetrical
thiourea under our optimized reaction condition. To this was
As can be seen from Table 4, a range of aryl isothiocyanates
reacted with aliphatic secondary amines such as piperidine (k),
morpholine (l), pyrrolidine (m) to give the major product having
a thioamido guanidine skeleton in each case. Thiourea (11b)
obtained by the reaction of phenyl isothiocyanate (1a) and
morpholine (l) gave product (13b) in excellent yield. Similarly,
weakly deactivating substituents (Cl, Br) when present in the
ortho-position or para-position (1b) and (1e) reacts with secondary
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Table 5 Formation of thiadiazoles from in situ generated bis-diaryl thioureaa,b
Thiourea
Productc
Yields (%)d
X = H (15a)
(16a) nde
(16b) nde
(16c) nde
(16d) nde
(17a) 81
(17b) 79
(17c) 84
(17d) 87
X = m-Cl (15b)
X = p-Br (15c)
X = p-CH3 (15d)
a Reactions were carried out at room temperature in EtOH. b Reactions were monitored by TLC. c Confirmed by IR, 1H and 13C NMR. d Isolated yield.
e nd = not detected.
Scheme 5 Differential reactivity of aryl-sec-alkyl thiourea.
amines morpholine (l), pyrrolidine (m) and piperidine (k) to
give products (13c), (13d), (13f) and (13g) in good yields as
shown in Table 4. This method also worked equally effective for
aryl isothiocyanate bearing a strong electron withdrawing group
(-NO2) (1d) in its meta-position which on reaction with piperidine
k followed by the treatment with iodine gave (13e) as the only
isolated product.
Substrates (1b), (1d) and (1e) are moderately deactivating
in nature hence are less susceptible to intramolecular nucle-
ophilic substitution to give Hugerschoff reaction product 2-
aminobenzothiazole.36 Aryl isothiocyanate (1f) bearing moder-
ately activating groups (Me) in its para position gave no significant
amount (14%) of benzothiazole and the dominant product (60%)
was still the thioamido guanidine product (13h).
The success of this iodine mediated heterocyclization prompted
us to apply this strategy to bis-diarylthiourea (15), obtained by
reacting hydrazine hydrate (1 equiv) with phenyl isothiocyanate
(1a) (2 equiv), to yield a aryl/alkyl tetrazoylthiourea of the
type (16) as shown in Table 5. When the resultant in situ
generated bis-diarylthiourea (15) was treated with iodine, the
desired tetrazole derivative (16) was not observed at all; rather
thiadiazole (17) was the sole isolated product as shown in
Table 5.
The proposed mechanism for the formation of thiadiazole
(17) can be explained as shown in Scheme 6. The initial imino
S–I intermediate (H) (Scheme 6) obtained by the reaction of
bis-diarylthiourea (15) with iodine undergoes an intermolecular
attack by the adjacent soft sulfur atom on the imino carbon rather
than the attack by a hard nitrogen nucleophile and not by the
weak azido nucleophile thus forming a five membered ring with
the expulsion of sulfur. This is consistent with our recent proposed
mechanisms27a,28b,c and as proposed by others.37
Having a successful strategy in hand, we extended the present
protocol toward the synthesis of various thiadiazoles as shown in
Table 5. Aryl ring having mild electron withdrawing group (15b)
and (15c) as well as weakly activating group (15d) all gave the
desired products (17b–17d) in good yields. The structure of (17b)
has been further confirmed by X-ray crystallographic analysis as
shown in Fig. 5.38
Conclusions
In conclusion, we have developed an efficient tandem strategy
for the preparation of tetrazoles from the in situ generated
diverse mono and disubstituted symmetrical and unsymmetrical
thiourea starting from the corresponding aryl isothiocyanates. For
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Scheme 6 Mechanism for the formation of N2-N5 disubstituted thiadiazole.
Fig. 5 ORTEP view with the atomic numbering scheme of 17b.38
the first time, regioselective formation of tetrazoles have been
studied for unsymmetrical thioureas in which amine attached
to the thiourea having lower pKa is a part of the heterocyclic
nitrogen and the amine having higher pKa is the contributor to the
other exocyclic nitrogen. Further, aryl-sec-alkyl thiourea under
the present experimental condition gave thioamido guanidine and
not the expected tetrazole. Bis-thiourea resulted from hydrazine
and aryl isothiocyanate gave exclusively thiadiazole. Although
the overall isolated yields look moderate, considering that the
reactions are multiprocesses, the yields are in fact good to
excellent. Literature report enumerates a number of procedures
for the preparation of aminotetrazoles, however, the simplicity,
environmental acceptability and cost effectiveness of this iodine
makes this method more practical.
Elmer 2400 automatic carbon, hydrogen, nitrogen and sulfur
analyser. Melting points were recorded on Buchi B-545 melting
point apparatus and are uncorrected. IR spectra were recorded in
KBr or neat on a Nicolet Impact 410 spectrophotometer. Mass
data were obtained with a WATERS MS system, Q-tof premier
and data analyzed using Mass Lynx4.1.
Crystallographic analysis. Crystal data were collected with
Bruker Smart Apex-II CCD diffractometer using graphite by using
˚
graphite-monochromated Mo-Ka radiation (l = 0.71073 A) at 298
K. Cell parameters were retrieved using SMART 39 software and
refined with SAINT39 for all observed reflections. Data reduction
was performed with the SAINT software and corrected for
Lorentzian and polarization effects. Absorption corrections were
applied with the SADABS program.40 The structures were solved
by direct methods implemented in the SHELX-9741 program
and refined by full-matrix least-squares methods on F2. All non-
hydrogen atom positions were located in difference Fourier maps
and refined anisotropically. The hydrogen atoms were placed in
their geometrically generated positions. The crystals were isolated
in rectangular shape from ethyl acetate and hexane mixture at
room temperature.
Experimental
General remarks
Unless otherwise stated, all reagents were purchased from com-
mercial sources and used without further purification. Reaction
progress was monitored by TLC using Merck silica gel 60 F254
(0.25 mm) with detection by UV or iodine. Chromatography was
performed using Merck silica gel (60–120) mesh size with freshly
distilled solvents. Columns were typically packed as slurry and
equilibrated with the appropriate solvent system prior to use. 1H
NMR (400 MHz) and 13C NMR (100 MHz) spectra were recorded
on a Varian FT-400 MHz instrument using TMS as an internal
standard. Data are presented as follows: chemical shift (ppm),
multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet,
b = broad, br s = broad singlet, br m = broad multiplet, coupling
constant J (Hz). Elemental analyses were carried out on a Perkin–
General experimental procedure
General procedure for the preparation of 1-phenyl-1H-tetrazol-
5-ylamine (3a). Aqueous ammonia (25%, 2 mL) was added
to phenyl isothiocyanate 1a (270 mg, 2 mmol.) in an ice-cold
condition and the reaction mixture was stirred for 20 min at
room temperature. During this time complete formation of 1-
phenyl thiourea 2a was observed. Excess of ammonia was removed
in a rotary evaporator and the reaction mixture was admixed
with DMF (2 mL) followed by the sequential addition of NaN3
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(390 mg, 6 mmol.), I2 (559 mg, 2.2 mmol.) and a drop wise
addition of triethylamine (835 mL, 6 mmol.) over a period of 5 min.
During the addition of triethylamine the reaction was exothermic.
After complete addition of triethylamine, the reaction mixture
was stirred for an additional 3 h. Complete conversion of the
in situ generated 1-phenylthiourea 2a to 1-phenyl-1H-tetrazol-5-
ylamine 3a was observed by thin layer chromatography (TLC).
The reaction mixture was treated with a 5% hypo solution (5 mL)
and the product was extracted with ethylacetate (3 ¥ 10 mL).
The combined ethylacetate layer was washed with water (3 ¥
5 mL), dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The product was purified over a column of
silica gel (saturated with 1% triethyl amine) and eluted with (8 : 2
hexane/ethylacetate) to give 3a (242 mg, 75% yield). mp: 168 ◦C
(2-Methoxy-phenyl)-(1-phenyl-1H-tetrazol-5-yl)-amine
(9b).
◦
1
mp: 128–130 C; H NMR (400 MHz, CDCl3): d (ppm) 3.82 (s,
3H), 6.88 (d, J = 7.4 Hz, 1H), 7.04 (m, 2H), 7.26 (s, 1H), 7.63
(m, 4H), 8.38 (m, 1H); 13C NMR (100 MHz, CDCl3): d (ppm)
56.1, 110.1, 117.8, 121.7, 123.0, 124.4, 127.9, 130.5, 130.7, 133.2,
147.3, 151.4; IR (KBr): 3399, 3022, 2925, 1609, 1593, 1570, 1507,
1485, 1466, 1455, 1390, 1252, 1240, 1211, 1107, 1092, 1050, 1016,
765, 752 cm-1; Elemental analysis: C14H13N5O (267.28): calcd. C,
62.91; H, 4.90; N, 26.20; found: C, 62.96; H, 4.96; N, 26.11.
[1-(2-Methoxy-phenyl)-1H-tetrazol-5-yl]-phenyl-amine (10b).
mp: 178 ◦C; 1H NMR (400 MHz, CDCl3 + DMSO-d6): d (ppm)
3.87 (s, 3H), 7.02 (d, J = 6.0 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 7.32
(d, J = 6.0 Hz, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.54–7.65 (m, 3H),
8.30 (s, 1H); 13C NMR (100 MHz, CDCl3 + DMSO-d6): d (ppm)
55.7, 112.4, 118.1, 120.7, 122.1, 122.8, 128.2, 128.5, 131.7, 139.0,
152.7, 153.8; IR (KBr): 3250, 3200, 3168, 3115, 3088, 3052, 3012,
2971, 2926, 2842, 1614, 1574, 1532, 1499, 1471, 1406, 1384, 1318,
1305, 1280, 1260, 1240, 1185, 1163, 1113, 1087, 1043, 1020, 980,
785, 754 cm-1; Elemental analysis: C14H13N5O (267.28): calcd. C,
62.91; H, 4.90; N, 26.20; found: C, 62.95; H, 4.94; N, 26.08.
◦
(Lit.22a 162–163 C); H NMR (400 MHz, CDCl3 + DMSO-d6):
d (ppm) 6.82 (br s, 2H), 7.50–7.63 (m, 5H); 13C NMR (100 MHz,
CDCl3 + DMSO-d6): d (ppm) 123.6, 129.4, 129.8, 133.3, 154.2;
IR (KBr): 3411, 3321, 3160, 1632, 1597, 1570, 1560, 1504, 1456,
1324, 1128, 1067, 1017, 770, 755 cm-1; Elemental analysis: C7H7N5
(161.16): calcd. C, 52.17; H, 4.38; N, 43.45; found: C, 52.11; H,
4.42; N, 43.34.
1
[1-(2-Chloro-phenyl)-1H-tetrazol-5-yl]-phenyl-amine (9f). mp:
132–134 ◦C; 1H NMR (400 MHz, CDCl3 + DMSO-d6): d (ppm)
5.93 (br s, 1H), 7.03 (d, J = 6.4 Hz, 1H), 7.30 (s, 2H), 7.53–7.66 (m,
5H), 8.93 (s, 1H); 13C NMR (100 MHz, CDCl3 + DMSO-d6): d
(ppm) 118.4, 122.4, 123.9, 124.8, 128.1, 128.5, 129.6, 130.5, 132.0,
139.1, 152.9; IR (KBr): 3241, 3078, 3038, 2997, 2926, 1603, 1614,
1593, 1529, 1489, 1454, 1318, 1245, 1120, 1087, 1077, 1020, 756,
748 cm-1; HRMS (ESI): 272.0703 (MH+).
Spectral data of selected compounds
1-◦(3-Chloro-phenyl)-1H-tetrazol-5-ylamine (3c). mp: 177–
179 C; 1H NMR (400 MHz, CDCl3 + DMSO-d6): d (ppm) 6.65
(br s, 2H), 7.27–7.70 (m, 4H); 13C NMR (100 MHz, CDCl3 +
DMSO-d6): d (ppm) 121.1, 122.9, 128.4, 130.3, 133.8, 134.1, 153.9;
IR (KBr): 3355, 3151, 1651, 1593, 1489, 1458, 1422, 1322, 1140,
1102, 1080, 866, 791 cm-1; Elemental analysis: C7H6ClN5 (195.60):
calcd. C, 42.98; H, 3.09; N, 35.80; found: C, 42.94; H, 3.03; N,
35.91.
N-((E)-Morpholino(phenylimino)methyl)-N-phen◦yl morpholine-
◦
1
4-carbothioamide (13b). mp: 150 C (Lit.28c 150 C), H NMR
(400 MHz, CDCl3): d (ppm) 2.62–3.80 (m, 16H), 6.81 (brm, 1H),
6.95–7.10 (m, 4H), 7.13 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 7.6 Hz, 2H),
7.28–7.48 (brm, 2H); 13C NMR (100 MHz, CDCl3): d (ppm) 46.8,
50.7, 65.5, 66.2, 120.4, 121.4, 122.2, 122.9, 124.8, 128.8, 129.8,
142.8, 149.3, 185.2; IR (KBr): 2979, 2904, 2894, 2856, 1634, 1586,
1485, 1453, 1351, 1301, 1277, 1239, 1206, 1157, 1109, 1062, 1022,
994, 937, 855, 765, 753 cm-1; HRMS (ESI): 411.1854 (MH+).
1-◦(3-Nitro-phenyl)-1H-tetrazol-5-ylamine (3d). mp: 161–
163 C; 1H NMR (400 MHz, CDCl3 + DMSO-d6): d (ppm) 7.12
(br s, 2H), 7.90 (t, J = 8.0 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 8.37
(d, J = 8.4 Hz, 1H), 8.40 (s, 1H); 13C NMR (100 MHz, CDCl3 +
DMSO-d6): d (ppm) 117.9, 122.9, 128.8, 130.4, 133.9, 147.9,
154.2; IR (KBr): 3318, 3142, 3091, 1660, 1596, 1574, 1532, 1497,
1351, 1307, 1139, 1079, 909, 813, 780, 743 cm-1; HRMS (ESI):
207.0630 (MH+).
N2,N5-Bis(3-chlorophenyl)-1,3,4-thiadiazole-2,5-diamine (17b).
(3-Chloro-phenyl)◦-[1-(3-chloro-phenyl)-1H-tetrazol-5-yl]-amine
(7c). mp: 143–145 C; 1H NMR (400 MHz, CDCl3): d (ppm) 6.62
(br s, 1H), 7.08 (d, J = 8.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.46 (m,
2H), 7.55–7.62 (m, 4H); 13C NMR (100 MHz, CDCl3 + DMSO-
d6): d (ppm) 116.6, 118.2, 122.1, 123.5, 125.2, 129.8, 130.9, 133.8,
134.7, 140.6, 151.8; IR (KBr): 3445, 2922, 2847, 1615, 1595, 1566,
1473, 1322, 1248, 1122, 1085, 834, 782 cm-1; Elemental analysis:
calcd. C13H9Cl2N5 (306.15): C, 51.00, H, 2.96, N, 22.88; found: C,
50.94, H, 2.92, N, 23.00.
◦
1
mp: 217–219 C; H NMR (400 MHz, CDCl3): d (ppm) 5.20
(br s, 1H), 6.90 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.74
(s, 2H), 9.69 (br s, 1H); 13C NMR (100 MHz, CDCl3): d (ppm)
114.7, 116.2, 120.3, 129.2, 133.5, 141.6, 155.6; IR (KBr): 3280,
3075, 1600, 1567, 1541, 1528, 1478, 1451, 1407, 1079, 773 cm-1;
Elemental analysis: C14H10Cl2N4 (337.23): calcd. C, 49.86; H, 2.99;
N, 16.61; S, 9.51; found: C, 49.81; H, 3.03; N, 16.66; S 9.46.
(3-Nitro-phenyl)-[◦1-(3-nitro-phenyl)-1H -tetrazol-5-yl]-amine
Acknowledgements
1
(7d). mp: 188–190 C; H NMR (400 MHz, CDCl3 + DMSO-
d6): d (ppm) 7.56 (t, J = 8.0 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.95
(t, J = 8.4 Hz, 1H), 8.05–8.13 (m, 2H), 8.47 (d, J = 8.0 Hz, 1H),
8.51 (s, 1H), 8.60 (s, 1H), 9.96 (br s, 1H); 13C NMR (100 MHz,
CDCl3 + DMSO-d6): d (ppm) 112.8, 116.6, 120.2, 123.8, 124.1,
129.4, 130.6, 131.0, 133.4, 140.2, 147.9, 148.2, 151.6; IR (KBr):
3444, 3258, 3089, 2925, 2857, 1622, 1574, 1524, 1393, 1353, 1245,
1119, 1081, 880, 803, 739 cm-1; HRMS (ESI): 328.0794 (MH+).
B. K. P acknowledges the support of this research by the Depart-
ment of Science and Technology (DST) (SR/S1/OC-79/2009),
New Delhi, and the Council of Scientific and Industrial Research
(CSIR) (01(2270)/08/EMR-II). RY, SKR and NK thank the
CSIR for fellowships. Thanks are due to Central Instruments
Facility (CIF) IIT Guwahati for Mass and NMR spectra, and
DST-FIST for XRD facility.
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30 Crystallographic description for 3b: C7H6ClN5, crystal dimension
(mm): 0.45 ¥ 0.35 ¥ 0.25, Mr = 195.62, monoclinic, space group
◦
˚
P21/c, a = 10.7905(4), b = 7.4830(3), c = 11.7242(4) A, a = g = 90 ,
◦
3,
b = 108.708(2) , V = 896.66(6) A , Z = 4, rcal = 1.449 mg m-3, m =
˚
0.384 mm-1, F(000) = 400, reflection collected/unique = 2232/1490,
refinement method = full-matrix least-squares on F2, final R indices
[I > 2sl ] R1 = 0.0547, wR2 = 0.1932, R indices (all data) R1 = 0.0726,
wR2 = 0.2112, goodness of fit = 1.022. CCDC-787036 (for 3b) contains
the supplementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
17 A. R. Modarresi-Alam, F. Khamooshi, M. Rostamizadeh, H. Keykha,
M. Nasrollahzadeh, H. R. Bijanzadeh and E. Kleinpeter, J. Mol.
Struct., 2007, 841, 61.
31 A. R. Katritzky, B. E-D. M. El-Gendy, B. Draghici, C. D. Hall and P.
J. Steel, J. Org. Chem., 2010, 75, 6468.
3244 | Org. Biomol. Chem., 2011, 9, 3235–3245
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32 Crystallographic data for 7b: C13H9Cl2N5, crystal dimension (mm):
35 R. Richter, J. Seiler, L. Beyer, O. Lindqvist and L. Anderson, Z. Anorg.
Allg. Chem., 1985, 522, 171.
36 (a) A. D. Jordan, C. Luo and B. Reitz, J. Org. Chem., 2003, 68, 8693;
(b) Z.-G. Le, J.-P. Xu, H.-Y. Rao and M. Ying, J. Heterocycl. Chem.,
2006, 43, 1123.
¯
0.21 ¥ 0.15 ¥ 0.12, Mr = 306.15, triclinic, space group P1,a = 7.3229(2),
◦
◦
˚
b = 9.8303(3), c = 10.1610(3) A,a = 81.772(2) ,b = 70.996(2) ,g =
◦
76.860(2) , V = 671.58(4) A , Z = 2, rcal = 1.514 mg m-3, m = 0.479 mm-1,
3
˚
F(000) = 312, reflection collected/unique = 3381/2756, refinement
method = full-matrix least-squares on F2, final R indices [I > 2sl ]
37 M.-H. Shih and C.-L. Wu, Tetrahedron, 2005, 61, 10917.
38 Crystallographic data for 17b: C14H10Cl2N4S, crystal dimension (mm):
0.30 ¥ 0.25 ¥ 0.20, Mr = 337.22, monoclinic, space group C◦ 2/c,
R1 = 0.0406, wR2 = 0.1172, R indices (all data): R1 = 0.0472, wR2
=
0.1242, goodness of fit = 1.079. CCDC-787037 (for 7b) contains the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
˚
a = 29.6523(10), b = 17.5907(10), c = 17.3440(7) A;a = g = 90 ,b =
◦
3
-3
-1
˚
108.649(3) , V = 8571.7(7)) A ; Z = 4, rc = 1.568 mg m , m = 0.093 mm ,
F(000) = 560; reflection collected/unique = 9883/2429,; refinement
method = full-matrix least-squares on F2; final R indices [I > 2s(I)]
33 Crystallographic data for 9b: C14H13N5O, crystal dimension (mm):
0.32 ¥ 0.24 ¥ 0.16, Mr = 267.29, monoclinic, space group P◦21/c,
R1 = 0.0345, wR2 = 0.1011, R indices (all data) R1 = 0.1132, wR2
=
˚
a = 10.8360(4), b = 16.3772(6), c = 7.6105(3) A; a = g = 90 ,b =
0.1412,goodness of fit = 0.947. CCDC-787035 (for 17b) contains the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
◦
3
107.280(2) , V = 1289.63(9) A , Z = 4, rcal = 1.377 mg m-3,m =
˚
0.093 mm-1, F(000) = 560, reflection collected/unique = 3221/1965,
refinement method = full-matrix least-squares on F2, final R indices
[I > 2sl ] R1 = 0.0442, wR2 = 0.1203, R indices (all data) R1
=
39 SMART, SAINT and XPREP, Siemens Analytical X-ray Instruments
Inc., Madison,Wisconsin, USA, 1995.
40 G. M. Sheldrick, SADABS: Empirical Absorption and Correction Soft-
ware, University of Gottingen, Institut fur Anorganische Chemieder
Universitat, Tammanstrasse 4, D-3400 Gottingen, Germany, 1999–
2003.
0.0672, wR2 = 0.1327, goodness of fit = 0.953. CCDC-787038 (for
9b) contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
34 (a) H. Hugerschoff, Ber. Dtsch. Chem. Ges., 1901, 34, 3130; (b) H.
41 G. M. Sheldrick, SHELXS-97, University of Gottingen, Germany,
Hugerschoff, Ber. Dtsch. Chem. Ges., 1903, 36, 3121.
1997.
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The Royal Society of Chemistry 2011
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