Desulfurization strategy in the construction of azoles possessing additional nitrogen, oxygen or sulfur using a copper(I) catalyst

Article abstract of DOI:10.1002/adsc.201200408

A tandem and convergent approach to various N-, O-, or S-containing azoles has been developed by exploiting the thiophilic property of copper( I) iodide used in a catalytic quantity. The present protocol gives access to amino-substituted tetrazoles, triazoles, oxadiazoles and thiadiazoles via oxidative desulfurization of their respective precursors followed by inter- or intramolecular attack of suitable nucleophiles. For aminotetrazoles and triazoles an excellent regioselectivity has been achieved through proper tuning of the pKa values of the parent amines attached to unsymmetrical thioureas. The method represents an autocatalytic process in which copper( I) iodide gets converted to copper(II) sulfide which in turn transforms to active copper(II) oxide that effectively carries forward the catalytic cycle. The fate of the copper catalyst has also been studied using scanning electron microscopic (SEM) and energy-dispersive X-ray spectroscopic (EDS) analyses which give an insight into the mechanism for this catalytic process.

Full text of DOI:10.1002/adsc.201200408

FULL PAPERS
DOI: 10.1002/adsc.201200408
Desulfurization Strategy in the Construction of Azoles Possessing
Additional Nitrogen, Oxygen or Sulfur using a Copper(I) Catalyst
Srimanta Guin,a,b Saroj Kumar Rout,a,b Anupal Gogoi,a Shyamapada Nandi,a
Krishna Kanta Ghara,a and Bhisma K. Patela,*
a
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, Assam, India
Fax : (+91)-361-2690-9762; e-mail: patel@iitg.ernet.in
Both authors have contributed equally to this paper
b
Received: May 9, 2012; Revised: June 25, 2012; Published online: September 28, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200408.
Abstract: A tandem and convergent approach to var- represents an autocatalytic process in which cop-
ious N-, O-, or S-containing azoles has been devel- per(I) iodide gets converted to copper(II) sulfide
oped by exploiting the thiophilic property of cop- which in turn transforms to active copper(II) oxide
per(I) iodide used in a catalytic quantity. The present that effectively carries forward the catalytic cycle.
protocol gives access to amino-substituted tetrazoles, The fate of the copper catalyst has also been studied
triazoles, oxadiazoles and thiadiazoles via oxidative using scanning electron microscopic (SEM) and
desulfurization of their respective precursors fol- energy-dispersive X-ray spectroscopic (EDS) analy-
lowed by inter- or intramolecular attack of suitable ses which give an insight into the mechanism for this
nucleophiles. For aminotetrazoles and triazoles an catalytic process.
excellent regioselectivity has been achieved through
proper tuning of the pKa values of the parent amines Keywords: azoles; copper catalysis; oxidative desul-
attached to unsymmetrical thioureas. The method furization; tandem reactions
Introduction
metals such as mercury and lead salts in a stoichiomet-
ric quantity. In one of our recent studies we have
The interest in transition metal-catalyzed processes shown that a copper salt in a catalytic quantity with
for the synthesis of various N-, O-, or S-containing the assistance of a base could indeed bring about a de-
heterocyclic frameworks employing different strat- sulfurization in the synthesis of various aryl/alkyl cy-
egies has experienced an explosive development in anamides from monosubstituted thioureas.[5a] Prior to
recent years.[1] Among these protocols, the copper our report, other groups had also reported similar
salts serving as catalysts exhibited a promising poten- copper-catalyzed oxidative desulfurization of thio-
tial in the synthesis of heterocyclic cores, which is due
amides and subsequent transformations.[5b,c] With the
ACHTUNGTRENNUNG
to its multifaceted properties.[2] With the advent of acquired knowledge from this transformation, we en-
À
such copper-catalyzed strategies the formation of C
visaged that the mono- or disubstituted thioureas
C and C X (X=heteroatom) bonds could now be re- under our earlier reported condition[5a] would give the
alized to give access to structurally important mole- heterocumulenes (cyanamides or carbodiimides).
cules easily.[3] However, most of these methodologies Since these heterocumulenes are potent reactive in-
stand on the two pillars of the modern organic synthe- termediates to various nitrogen-containing heterocy-
À
sis: (a) cross-coupling[2,3a] and (b) oxidative C H func- cles, thus in a one-pot strategy we could generate the
À
tionalization[4] reactions. Despite the successful ex- heterocumulenes in situ via a Cu(I) mediated strate-
ploitation of such advantageous properties of copper gy[5a] which, upon trapping with suitable nucleophiles
toward a plethora of synthetic protocols, the basic fea- (inter- or intramolecularly), would lead to the forma-
ture that remained unexplored is its thiophilic charac- tion of our desired heterocycles (azoles). With this ra-
ter which could be utilized to the same effect as that tionale behind our strategy we probed the synthesis
of other thiophiles in bringing about oxidative desul- of various azoles via a tandem convergent approach
furization. To date the metals that are being explored (Scheme 1). Herein, we report our one-pot tandem
mostly as thiophiles are confined to toxic heavy strategies for the synthesis of 5-aminotetrazoles (path
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Scheme 1. Envisaged routes to various N-, O-, or S-containing azoles.
a), 3-amino
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG[1,2,4]triazoles (path b), 2-amino- employed in bringing about the same transforma-
[1,3,4]oxadiazoles (path c), and 2,5-diamino- tion.[16] However, strictly adhering to the use of metal
A
catalysts, only Hg and Pb salts (stoichiometric quanti-
ty) have been exploited to generate the carbodiimide
intermediate via desulfurization of the corresponding
thiourea followed by attack of an azide ion to con-
struct the tetrazole core.[17] Thus, in an attempt to
Results and Discussion
Azoles occupy a central position in modern heterocy- avoid the use of such toxic and hazardous metal salts
clic chemistry pertaining to their importance in me- (Pb and Hg) and taking cues from our earlier
dicinal and pharmaceutical industries. They also find method, we wanted to invoke a copper salt in a cata-
diverse applications in agricultural and material re- lytic quantity to effect the transformation of thiourea
search.[6] As a privileged fragment, the aminotetra- to the intermediate carbodiimide or cyanamide.[5a]
zoles hold paramount significance from the stanpoint These carbodiimide or cyanamide intermediates
of their widespread applications in high energy densi- would subsequently lead to the formation of 5-amino-
ty materials,[7] as ligands in coordination chemistry,[8] tetrazole upon attack by an azide ion.
and as non-classical isosteres for the carboxylic acid
To initiate the investigation, phenyl isothiocyanate
moiety in biologically active molecules.[9] Further- (1 equiv.) in DMSO was treated with aniline
more, tetrazoles are reported to exhibit a wide scope (1 equiv.) and stirred at 808C for 10 min to give 1,3-
of biological activities which include antiallergic/anti- diphenylthiourea (1a). After complete formation of
asthmatic,[10] antiviral,[11] anti-inflammatory,[11] anti- 1,3-diphenylthiourea (1a) (judged by TLC), to this re-
neoplastic,[12] and cognition disorder[13] activities. The action mixture were added sequentially CuI
classical routes for the synthesis of 5-aminotetrazoles (10 mol%), NaOH pellets (2 equiv.) and NaN3
are grouped into four categories:[14] (a) amino group (1 equiv.) and the heating was continued for 5 h.
or ring functionalization of 5-aminotetrazole; (b) the These reaction conditions were chosen keeping our
substitution of a leaving group in the 5-position of tet- earlier catalytic synthesis of the cyanamides in
razole with amines; (c) reactions of aminoguanidine mind.[5a] However, this reaction was associated with
derivatives with sodium nitrite; and (d) various azide- the formation of a major amount of the correspond-
mediated tetrazole ring constructions from carbodi- ing urea as by-product along with a minor amount of
ACHTUNGTRENNUNGimides. Among these approaches, the attack of inor- aniline, probably by the decomposition of thiourea or
ganic azide to carbodiimide intermediate constitutes intermediate carbodiimide and only traces (<5%) of
one of the most useful methods for the synthesis of the expected 5-aminotetrazole (2a) (Table 1, entry 1).
aminotetrazoles. Relying on the aforesaid strategy re- It was obvious from this observation that the Cu(I)
cently we have developed a protocol for the regiose- salt does cause the desulfurization to form the inter-
lective synthesis of 5-aminotetrazoles using molecular mediate carbodiimide which is being attacked either
iodine as the thiophile.[15] Also the hypervalent iodine by hydroxide ion or the water present in ordinary
reagent, o-iodoxybenzoic acid, has been successfully DMSO to form the corresponding urea rather than
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Desulfurization Strategy in the Construction of Azoles Possessing Additional Nitrogen, Oxygen or Sulfur
Table 1. Screening of reaction conditions.
Entry
Catalyst (mol%)
NaN3 (equiv.)
Base (equiv.)
Solvent
Temperature
Time [h]
Yield [%][a]
1
2
3
4
5
6
7
8
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI(10)
CuI (10)
CuI (7.5)
CuI (5)
CuBr (10)
CuCl (10)
CuBr2 (10)
CuCl2·2H2O (10)
CuSO4·5H2O (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
none
1
1
1
1
1
1
2
3
4
3
3
3
3
3
3
3
3
3
3
3
3
NaOH (2)
K2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (3)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
DMSO
DMSO
DMSO
DMSO
808C
808C
808C
808C
808C
1008C
808C
808C
808C
808C
808C
808C
808C
808C
808C
808C
808C
808C
808C
808C
808C
5
5
5
5
5
5
5
5
5
5
5
7
10
7
7
12
10
15
12
15
24
<5
25
32
35
67
55
75
84
86
70
55
72
65
75
70
50
30
<5
20
<5
nd
DMSO (dry)
DMSO (dry)
DMSO (dry)
DMSO (dry)
DMSO (dry)
DMSO (dry)
DMSO (dry)
DMSO (dry)
DMSO (dry)
DMSO (dry)
DMSO (dry)
DMSO (dry)
DMF (dry)
toluene (dry)
dioxane (dry)
CH3CN (dry)
DMSO (dry)
9
10
11
12
13
14
15
16
17
18
19
20
21
[a]
Isolated yields.
being attacked by a weak azide nucleophile. Replace- was observed (Table 1, entry 9). A decrease in the cat-
ment of NaOH with K2CO3 (2 equiv.) (Table 1, alyst loading to 7.5 and 5 mol% had negative effects
entry 2) or Cs2CO3 (2 equiv.) (Table 1, entry 3) made on the product yield (Table 1, entries 10 and 11). With
an improvement in the yield, it being slightly more this initial result in hand other reaction parameters
with Cs2CO3 (32%) in comparison to K2CO3 (25%). such as catalysts and solvents were varied to arrive at
Furthermore, an increase in the base quantity the optimum conditions required for this methodolo-
(3 equiv.) did not improve the yield (Table 1, entry 4). gy. The results are summarized in Table 1.
The methodology was thus disadvantageous with re-
As can be seen from Table 1, CuI (10 mol%) invari-
spect to the formation of urea as the major by-prod- ably proved to be superior to the other copper salts
uct. Hence the reaction was carried out in dry DMSO such as CuBr, CuCl, CuBr2, CuCl2·2H2O, and
under a nitrogen atmosphere to keep out any mois- CuSO4·5H2O both in terms of product yield and reac-
ture that could affect the yield. It was gratifying to tion time (Table 1, entries 12–16). Other anhydrous
observe that there was a substantial improvement in solvents examined such as DMF, toluene, dioxane and
the yield (67%) without the formation of urea by- CH3CN were unable to provide satisfactory yields as
product (Table 1, entry 5). The reaction carried out at compared to DMSO (Table 1, entries 17–20). Reac-
1008C had an adverse effect on the product yield due tions in these solvents either gave a multitudes of side
to possible decomposition of the substrate or inter- products or the starting material remained unreacted
mediate carbodiimide to aniline (Table 1, entry 6). under the reaction conditions. Notably, the reaction
Next the amount of sodium azide was increased to did not proceed at all in the absence of the metal cat-
2 equiv. and 3 equiv. from 1 equiv. and the best result alyst, thus implying the requirement of metal catalyst
was obtained with the latter (84%) (Table 1, entries 7 to effect the transformation (Table 1, entry 21).
and 8). With further increase in sodium azide quantity Therefore, for subsequent reactions we continued to
(4 equiv.) a marginal improvement (2%) in the yield use our optimized reaction conditions [disubstituted
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Scheme 2. Substrate scope for 5-aminotetrazoles.
thiourea (1 equiv.), Cs2CO3 (2 equiv.), NaN3 the formation of other by-products. Furthermore,
(3 equiv.), CuI (10 mol%) in anhydrous DMSO structure of the product (2f) has been confirmed by
(2 mL) under a nitrogen atmosphere].
X-ray crystallographic analysis as shown in Figure 1.
Notably, the reactions were superior in terms of
The optimized conditions were applied to various
in situ generated 1,3-diarylthioureas to explore the yield and shorter reaction time for thioureas bearing
scope and generality of this methodology. The results electron-withdrawing groups (1e–1j) in comparison to
shown in Scheme 2 attest that the methodology is those bearing electron-donating ones (1a–1d)
compatible to a wide range of functionalities giving (Scheme 2). Moreover, for unsymmetrical thioureas
moderate to excellent yields of the respective 5-ami- possessing aryl and alkyl moieties (1k) and (1l) exclu-
notetrazoles. Symmetrical thioureas bearing electron- sive formation of single regioisomers (2k) and (2l)
donating groups such as p-Me (1b), 3,4-di-Me (1c), p- was observed but the reactions were sluggish in con-
OMe (1d) all underwent the reaction smoothly to
give their respective 5-aminotetrazoles (2b–2d) in
good yields. Also for thioureas bearing moderately
electron-withdrawing substituents viz. p-F (1e), p-Cl
(1f), p-Br (1g), and strong electron-withdrawing sub-
stituents such as p-CF3 (1i) and m-NO2 (1j) under the
present conditions the reactions were very fast to give
excellent yields of the corresponding tetrazoles (2e–
2i). The only exception in the trend in yield was ob-
served with p-CN (1h) where the corresponding tetra-
zole (2h) was obtained in a moderate yield of 60%.
The moderate yield observed for cyano substrate (1h)
could be due to the interference of the cyano group
in the elecrocyclization with the azide ion leading to Figure 1. ORTEP view of (2f).[44]
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Desulfurization Strategy in the Construction of Azoles Possessing Additional Nitrogen, Oxygen or Sulfur
Scheme 3. Regioselective formation of product (2k).
trast to those of the diarylthioureas. These observa- veloped a protocol for the regioselective synthesis of
tions are consistent with our earlier report where the 3-aminoACTHNUTRGNEU[GN 1,2,4]triazoles mediated by molecular
aminotetrazoles have been synthesized using molecu- iodine.[27] A similar transformation has also been car-
lar iodine.[15] Formation of a single regioisomer could ried out by other groups using the hypervalent iodine
be judged from the pKa difference of the amines at- reagent o-iodoxybenzoic acid.[16] The usage of metal
tached to the unsymmetrical thioureas.[15] As a typical catalysts has been explored to accomplish the synthe-
illustration, substrate (1k) has been chosen as the sis of 3-aminoACHTNUTGRNEUNG
[1,2,4]triazoles employing mercury[26b]
model substrate. Thiourea (1k) underwent desulfuri- and silver[26d] salts as the thiophiles. Pertaining to the
zation upon treatment with CuI to give the unsym- metal-catalyzed synthesis, it would be of considerable
metrical carbodiimide (A) (Scheme 3). This carbodi- importance if the toxic and expensive metal salts used
ACHTUNGTRENNUNGimide intermediate (A) upon attack by the azide nu- in stoichiometric amounts could be substituted by
cleophile could lead to the formation of either gua- a copper salt in a catalytic quantity. Hence we pur-
nidyl intermediate (B) or (B’). However, the forma- sued the reaction with our pre-optimized conditions
tion of that guanidyl intermediate would be favoured by replacing sodium azide with formic acid hydrazide
(path-1) where the protonation occurs at the more (1 equiv.) with the in situ generated 1,3-diphenyl-
basic nitrogen (i.e., nitrogen attached to cyclohexyl
ACHTUNGTRENtNUNG hiourea (1a) as the model substrate. A fairly good
moiety) while the other nitrogen remains in the imine yield (65%) of the product (3a) was obtained under
form. The favoured intermediate (B) then undergoes the present conditions within a span of 4 h. An at-
an electrocyclization to give tetrazole (2k) exclusively. tempt to enhance the yield was carried out by increas-
As an extension of this study, we proceeded toward ing the quantity of formic acid hydrazide to 2 equiv.
the synthesis of another important heterocyclic scaf- and 2.5 equiv. A substantial improvement in yield of
fold viz. 3-aminoACTHNUTRGNEU[GN 1,2,4]triazole which could be ach- the product was observed with the latter (2.5 equiv.)
ieved through a sequential addition–dehydration path providing 90%. Further increase in the formic acid
upon reaction between carbodiimide and hydrazides hydrazide quantity provided no variation in yield.
(Scheme 1, path b). Triazoles display a wide array of Since it has been established earlier that CuI
biological activities in the field of medicinal and agro- (10 mol%) with the assistance of base Cs2CO3
chemicals. To exemplify their biological relevance, (2 equiv.) in dry DMSO serves the purpose to gener-
they serve as bioisosteres in lieu of amides and thio- ate the carbodiimide intermediate, so further optimi-
ACHTUNGTRENNUNG
amides,[18] are also present in potent pharmacophores zation was not carried out for the synthesis of 3-
which exhibit antifungal,[19] antimicrobial,[20] anti-in- amino
ACHTNUTRGNE[NUG 1,2,4]triazoles. For subsequent reactions the
flammatory,[21] antiviral,[22] antiasthmatic,[23] and anti- following conditions were applied [disubstituted thio-
proliferative[24] activities. Several efficient protocols urea (1 equiv.), Cs2CO3 (2 equiv.), RCONHNH2 (R=
have been developed for the synthesis of [1,2,4]tri- H, CH3) (2.5 equiv.), CuI (10 mol%) in anhydrous
ACHTUNGTRENNUNG
azoles that include both solid phase[25] and solution DMSO (2 mL) under a nitrogen atmosphere].
phase[26] synthesis. However, in all these methodolo-
Symmetrical thioureas bearing electron-donating
gies the [1,2,4]triazoles have different substitution groups such as p-Me (1b), p-OMe (1d), and p-OBu
patterns in the ring as well as in the exocyclic region. (1m) afforded excellent yields of their respective ami-
Thus focusing solely on the synthesis of 3-amino- notriazoles (3b), (3d) and (3m) in shorter reaction
ACHTUNGTRENNUNG[1,2,4]triazole where thiourea and hydrazides have times (Scheme 4). While those bearing electron-with-
been used as the precursors, not much has been dem- drawing groups viz. p-F (1e) and m-Br (1g) under-
onstrated in the literature. Very recently we have de- went reaction to give the corresponding products (3e)
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Scheme 4. Substrate scope for 3-aminoACTHNUTRGNEUNG[1,2,4]triazoles.
and (3g) in good yields, however in slightly lesser structure of the product (3e) has been further con-
yield and requiring longer reaction time as compared firmed by X-ray crystallographic analysis as shown in
to substrates possessing electron-donating ones. These Figure 2.
observations are in contrast to reactivity trends ob-
Unsymmetrical aryl-alkylthioureas (1n) and (1o)
served during the formation of 5-aminotetrazoles dis- under the present reaction conditions gave single re-
cussed above but, however, are in good agreement gioisomers (3n) and (3o), respectively, though requir-
with our recently reported protocol on 3-amino- ing longer reaction times (Scheme 4). In these re-
ACHTUNGTRENNUNG
[1,2,4]triazole synthesis mediated by iodine.[27] The gioisomers the nitrogen atom having the higher pKa
forms part of the ring while the other nitrogen (lower
pKa) remains flanked as the exocyclic nitrogen of the
triazole core. The disposition of the nitrogen atoms in
aminotriazoles is in keeping with our recent report on
the regioselectivity,[27] that could be explained on the
basis of the pKa difference of the amines attached to
unsymmetrical thioureas. Noteworthy, again a reverse
trend is followed in the case of aminotriazoles
(Scheme 4) to that of aminotetrazoles (Scheme 2) in
terms of the regioselective disposition of the nitrogen
atoms attached to the unsymmetrical thioureas. As an
illustration of the regioselective formation of the ami-
notriazoles, substrate (1n) has been chosen as the
model substrate. As has been stated earlier the inter-
mediate carbodiimide (C) formed in situ from thiour-
ea (1n) upon the copper-catalyzed desulfurization un-
Figure 2. ORTEP view of (3e).[44]
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Desulfurization Strategy in the Construction of Azoles Possessing Additional Nitrogen, Oxygen or Sulfur
Scheme 5. Regioselective formation of product (3n).
dergoes a nucleophilic attack from formic acid hydra- zoles by replacing formic acid hydrazide with acetohy-
zide. This could lead to the possibility of intermedi- drazide. In these cases also all the in situ generated
ates (D) and (D’), which are tautomeric forms of each thioureas (1a), (1b), (1f) and (1g) underwent reac-
other (Scheme 5). However, the equilibrium would be tions smoothly to give fair yields of the products (3’a),
shifted toward (D) (path 3), due to favourable proto- (3’b), (3’f) and (3g), respectively. Worth mentioning is
nation at the more basic nitrogen than at the less that the same trend in yield was observed with aceto-
basic nitrogen (path 4). The intermediate (D) then hydrazide as was with formic acid hydrazide
undergoes a dehydrative cyclization to render the (Scheme 4).
aminotriazole regioisomer (3n) solely and no traces of
A plausible mechanism for the formation of amino-
the other regioisomer (3n’) was observed. Having suc- tetrazoles and aminotriazoles has been depicted in
cessfully synthesized the aminotriazoles, we focused Scheme 6. As demonstrated in our earlier report,[5a]
on the synthesis of 5-methyl-substituted aminotria- herein as well CuI after the first catalytic cycle is sup-
Scheme 6. Plausible mechanism for the formation of 5-aminotetrazole and 3-aminoACTHNUTRGNEUNG[1,2,4]triazole catalyzed by CuI.
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posed to get converted to CuS or forms an array of subjected to treatment of CuI (10 mol%) and Cs2CO3
polynuclear anions containing sulfur rings or (2 equiv.) in the same pot under the pre-optimized
a chain.[28] Under these conditions and temperature, conditions afforded an excellent yield (90%) of the
some of the in situ generated CuS gets converted/de- product (5a). A sub-optimization carried out with
composed to CuO. Thus the active CuO generated in thioACHTUNTRGNEUNGsemicarbazide (4a) revealed that K2CO3 (2 equiv.)
the reaction suffices for the purpose of oxidative de- worked as effectively as Cs2CO3 (2 equiv.). Addition-
sulfurization in the next catalytic cycles to give the in- ally, the reaction could be carried out in ordinary
termediate carbodiimide. In the case of 5-aminotetra- DMSO under normal atmospheric conditions rather
zole (Scheme 2, Scheme 3 and Scheme 6) the inter- than under a nitrogen atmosphere in anhydrous
mediate carbodiimide undergoes nucleophilic attack DMSO solvent. It was reasoned that since this reac-
by the azide ion to give a guanidyl kind of intermedi- tion goes via an intramolecular attack of the amidic
ate which on subsequent electrocyclization affords the oxygen, it is expected to be faster than the intermo-
5-aminotetrazole. During the formation of 3-amino- lecular attack of the water present in ordinary
ACHTUNGTRENNUNG[1,2,4]triazoles (Scheme 4), hydrazides are the active DMSO. However, other trials such as lowering of cat-
nucleophiles which attack the carbodiimide to give alyst loading or the temperature proved to be unsatis-
the acylureidrazone intermediate. Subsequent dehy- factory for the current methodology.
drative cyclization and aromatization leads to the for-
Thus having a standardized protocol in hand the
mation
of
3-amino
G
(Scheme 4, method was subsequently applied to various in situ
Scheme 5 and Scheme 6).
generated thiosemicarbazides to examine the general-
The success of this copper-mediated heterocycliza- ity and scope of the reaction (Scheme 7). Herein as
tion prompted us to apply the strategy to thiosemicar- well diverse functionalities have been tolerated giving
bazides (in situ generated), where a similar desulfuri- good to excellent yields of the desired 3-amino-
zation would generate intermediate carbodiimide.
This on intramolecular nucleophillic attack by the formic acid hydrazide, acetohydrazide or benzohydra-
amidic oxygen could form 2-amino[1,3,4]oxadiazoles zide all underwent reactions smoothly to render the
(Scheme 1, path c). The aminooxadiazoles are recog- respective 3-amino[1,3,4]oxadiazoles. For thiosemicar-
ACHTUNGTREN[NUGN 1,3,4]oxadiazoles. Thiosemicarbazides obtained from
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
nized as biologically important pharmacophores due bazides bearing electron-donating substituents viz.3,4-
to their wide range of biological activities that include di-Me (4b), p-Me (4f and 4i), the reactions provided
analgesic,[29] anti-inflammatory,[29] anticonvulsant,[30] the desired products (5b), (5f) and (5i) in good yields
diuretic,[29] antineoplastic,[31] and muscle relaxant[32] (Scheme 7). However, for the electron-withdrawing
properties. Additionally, some exhibit insecticidal[33] ones viz. m-NO2 (4c), m-Cl (4g) and o-F (4j), excel-
and herbicidal[34] properties as well. However, their lent yields of the corresponding oxadiazoles (5c), (5g)
relevance is not restricted to the bioactivities alone. and (5j) were obtained in shorter reaction times as
Their potentialities have further extensions to well- compared to their electron-donating analogues. Naph-
defined applications in materials research particularly thyl thiosemicarbazide (4d) yielded oxadiazole (5d) in
in the field of organic electronics owing to their good decent yield under the present conditions. Also ali-
electron-transporting and hole-blocking abilities.[35] phatic thiosemicarbazide (4k) and chiral benzylthiose-
Such a wide spectrum of applications has led to the micarbazide (4l) gave their corresponding oxadiazoles
emergence of various protocols for the synthesis of 2- (5k) and (5l) in modest yields. The structure of (5i)
aminoACHTUNGTRENNUNG[1,3,4]oxadiazoles. The classical strategies that has further been confirmed by X-ray crystallographic
have been documented till date fall under two major analysis as shown in Figure 3.
heads: (a) cyclodehydration of semicarbazides[36] and
The reactivity order followed in the formation of
(b) cyclodesulfurization of thiosemicarbazides.[37] the oxadiazoles can be explained on the basis of the
Straightforward to the latter strategy, recently a mild dual role of electronic effects of the electron-with-
approach involving the mediation of molecular iodine drawing functionalities present in the aryl moiety.
has been reported by us,[38] while a similar transforma- Noteworthy is that the electron-withdrawing groups
À
tion has been carried out using the hypervalent iodine cause a faster deprotonation of aryl N H proton fol-
reagent o-iodoxybenzoic acid by another group.[16] lowed by a copper-mediated desulfurization to give
But a scrutiny of the metal-based transformations sug- the intermediate carbodiimide (Scheme 7 and
gest the use of toxic thiophilic Hg[39] and Pb[32] salts in Scheme 9). Additionally, the electron-withdrawing
stoichiometric quantity for the purpose of desulfuriza- effect increases the electrophilicity at the carbodiimi-
tion of the thiosemicarbazides. To do away with the dic carbon and thus facilitates the intramolecular
handling of such hazardous metal salts, a copper-cata- attack of the amidic O-atom to give the oxadiazoles.
lyzed method would be more appreciable. As a pri- These dual positive role exhibited by electron-with-
mary study, thiosemicarbazide (4a) obtained in situ drawing groups present in the aryl ring have a signifi-
[phenylisothiocyanate (1 equiv.) and formic acid hy- cant effect on the yield and the reaction time of the
drazide (1 equiv.) in anhydrous DMSO at 808C] when aforesaid reactions (Scheme 7).
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Desulfurization Strategy in the Construction of Azoles Possessing Additional Nitrogen, Oxygen or Sulfur
Scheme 7. Substrate scope for 2-aminoACTHNUTRGNEUNG[1,3,4]oxadiazoles.
thioureas have been rarely explored. The desulfuriza-
tion strategies to date use reagents such as chlor-
AHCTUNGTRENNUNG
anil,[43] bromonil,[43] iodine[15] and most recently the
hypervalent iodine reagent o-iodoxybenzoic acid[16]
but no metal-based catalytic transformation is report-
ed so far. In the present methodology, we have syn-
thesized various 2,5-diaminoACTHNUGTRNEUNG[1,3,4]thiadiazoles em-
ploying Cu(I) catalyst. The optimized conditions for
their synthesis are the same as those applied for the
Figure 3. ORTEP view of (5i).[44]
2-amino
Having a successful strategy in hand, we extended ized in Scheme 8.
the present protocol toward the synthesis of 2,5- All the bis-thioureas provided excellent to decent
diamino[1,3,4]thiadiazole from in situ generated bis- yields of the respective diaminothiadiazoles. For the
ACHTUNGTRENUN[NG 1,3,4]oxadiazoles. The results are summar-
ACHTUNGTRENNUNG
thiourea (Scheme 1, path d). The [1,3,4]thiadiazoles bis-arylthioureas having electron-donating substitu-
are important entities that are widely employed in ents (6b–6d) the yields of the products (7b–7d) were
drug discovery. There has been intense investigation superior to the bis-arylthioureas having electron-with-
on the biological activities of different classes of thia- drawing substituents (6e–6g) for which the product
diazole compounds, many of which are reported to be (7e–7g) yields were fairly decent (Scheme 8). Howev-
pharmacologically active. Of significance are their an- er for the bis-dialkyl thiourea (6h) the reaction was
ticonvulsant, anti-inflammatory, antioxidant, antimi- sluggish and the product (7h) yield was moderate. A
crobial, antituberculosis and antifungal properties.[40] probable reason for such reactivity trend could be
Recently, [1,3,4]thiadiazole cores have received much due to the attack of the sulfur nucleophile onto the
attention in material science due to their interesting carbodiimide facilitated by the electron-donating ef-
electronic and optical properties.[41] Various method- fects compared to the electron-withdrawing effects
ologies that exist in literature[42] for their synthesis are that cause the differences in yields and reaction time.
associated with number of drawbacks that impedes The structure of the product (7f) has further been
their applicability in the long run. Moreover, the confirmed by X-ray crystallographic analysis as shown
methods for the synthesis of 2,5-diamino- in Figure 4.
ACHTUNGTRENNUNG[1,3,4]thiadiazoles via oxidative desulfurization of bis-
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Scheme 8. Substrate scope for 2,5-diaminoACTHNUTRGENUG[N 1,3,4]thiadiazoles.
Figure 4. ORTEP view of (7f).[44]
An analogous mechanism is expected to operate in
the formation of 2-amino[1,3,4]oxadiazoles and 2,5-
diamino[1,3,4]-thiadiazoles where CuS and CuO gen-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
erated during the reaction carry forward the catalytic
cycle by an oxidative desulfurization as has been men-
tioned earlier. The carbodiimidic intermediate thus
formed undergoes an intramolecular nucleophilic
attack of amidic oxygen or thioamidic sulfur, followed
by aromatization to give 2-amino
ACHTUNGERTN[NUNG 1,3,4]oxadiazoles or
2,5-diamino[1,3,4]thiadiazoles as the case may be
ACHTUNGTRENNUNG
(Scheme 9).
The assumption that CuO and CuS are formed in
situ, which probably catalyzes the reaction further,
has been supported by the SEM and EDS analyses of
the sample obtained from one of the reactions. As
can been seen from Figure 5, there are clear indica-
Scheme 9. Plausible mechanism for the Cu catalyzed forma-
tion
of 2-amino
[1,3,4]oxadiazole
and
2,5-diamino-
AHCTUNGTREG[NNUN 1,3,4]thiadiazole.
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Desulfurization Strategy in the Construction of Azoles Possessing Additional Nitrogen, Oxygen or Sulfur
Figure 5. SEM and EDS analyses of the Cu salt.
tions for the existence of CuO and CuS in the SEM azide or hydrazide nucelophile to give 5-aminotetra-
picture. Some of the regions are rich in CuO (region zoles or 3-aminoACTHNUTRGNEU[GN 1,2,4]triazoles, respectively. Regiose-
B) while other parts contain fine fibrous CuS (region lective formation of tetrazoles and triazoles was ob-
A). Also treating the filtered Cu catalyst to the in situ served in the case of unsymmetrical thioureas. This
generated thiosemicarbazide 4a (Scheme 7) under the phenomenon is dependent on the pKa values of the
identical experimental conditions gave 2-amino- nitrogen atoms attached to the precursor thioureas. In
ACHTUNGTRENNUNG[1,3,4]oxadiazoles (5a) in 88% isolated yield thus sup- the second approach oxidative desulfurization of thio-
porting our proposed catalytic cycle. We believe the semicarbazides or bis-thioureas afforded the respec-
filtered catalyst should also be equally effective in tive carbodiimidic intermediates, which upon intramo-
bringing about all the above transformations.
lecular attack by an amidic O or a thioamidic S atoms
gave 2-amino[1,3,4]oxadiazoles or 2,5-diamino-
AHCTUNGTREG[NNNU 1,3,4]thiadiazoles. The fate of the copper catalyst at
AHCTUNGTRENNUNG
Conclusions
the end of reaction has also been studied using SEM
and EDS analysis. On a practical note, the use of
In conclusion, we have developed a tandem conver- a cheap copper salt in a catalytic amount replacing
gent synthesis of various N-, O-, and S-containing the toxic and expensive metal salts of Hg, Pb and Ag
azoles employing CuI in a catalytic quantity. This used in a stoichiometric quantity to give easy access
methodology involves two different approaches. In of such important heterocycles make this methodolo-
the first approach an oxidative desulfurization of thio- gy a suitable alternative for industrial applications
ureas by Cu catalyst gives intermediate carbodiimide and perhaps the best metal-based catalytic approach
which is followed by intermolecular attack by an reported so far.
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FULL PAPERS
uct was purified over a column of silica gel and eluted with
(8:2, hexane/ethyl acetate) to give N-phenyl-1,3,4-oxadiazol-
2-amine (5a); yield: 145 mg (90%).
Experimental Section
General Procedure for the Synthesis of N,1-Diphenyl-
1H-tetrazol-5-amine (2a)
General Procedure for the Synthesis of N2,N5-
Diphenyl-1,3,4-thiadiazole-2,5-diamine (7a)
A mixture of aniline (93 mg, 1 mmol) and phenyl isothiocya-
nate (135 mg, 1 mmol) in anhydrous DMSO solvent (2 mL)
was stirred at preheated oil bath at 808C under a nitrogen
balloon for 10 min. After complete formation of diphenyl-
Phenyl isothiocyanate (270 mg, 2 mmol) upon treatment
with hydrazine hydrate (50 mg, 1 mmol) under neat condi-
tions gave bis-thiourea (6a). Subsequently CuI (19 mg,
0.1 mmol), K2CO3 (276 mg, 2 mmol) and DMSO solvent
(2 mL) were added to the bis-thiourea (6a) and the reaction
mixture was subjected to heating in a preheated oil bath at
808C for 6 h. The progress of the reaction was monitored by
TLC. After completion, the reaction mixture was cooled to
room temperature and diluted with ethyl acetate (10 mL).
Then the reaction mixture was filtered through a bed of
celite and washed with an additional amount of ethyl ace-
tate (20 mL). The filtrate was washed with water (3ꢁ5 mL).
The ethyl acetate layer was dried over anhydrous Na2SO4
and the solvent was removed under reduced pressure. The
crude product was purified over a column of silica gel and
eluted with (1:1, hexane/ethyl acetate) to give N2,N5-diphen-
yl-1,3,4-thiadiazole-2,5-diamine (7a); yield: 220 mg (82%).
ACHTUNGTRENNUNGthiourea (1a) to the reaction mixture were sequentially
added CuI (19 mg, 0.1 mmol), Cs2CO3 (650 mg, 2 mmol) and
NaN3 (195 mg, 3 mmol). The heating was continued and the
progress of the reaction was monitored by TLC. After 5 h,
the reaction mixture was cooled to room temperature and
diluted with ethyl acetate (10 mL). Then the reaction mix-
ture was filtered through a bed of celite and washed with an
additional amount of ethyl acetate (20 mL). The filtrate was
washed with water (3ꢁ5 mL). The ethyl acetate layer was
dried over anhydrous Na2SO4 and the solvent was removed
under reduced pressure. The crude product was purified
over a column of silica gel and eluted with (7:3, hexane/
ethyl acetate) to give N,1-diphenyl-1H-tetrazol-5-amine
(2a); yield: 199 mg (84%).
General Procedure for the Synthesis of N,4-Diphenyl-
4H-1,2,4-triazol-3-amine (3a)
A mixture of aniline (93 mg, 1 mmol) and phenyl isothiocya-
nate (135 mg, 1 mmol) in anhydrous DMSO solvent (2 mL)
was stirred at preheated oil bath at 808C under a nitrogen
balloon for 10 min. After complete formation of diphenyl-
Acknowledgements
We are grateful to the DST (SR/S1/OC-79/2009) and CSIR
[01ACTHUNRTGNEUNG(2270)/08/EMR-II] for funding. SG, SKR, AG thank the
CSIR for fellowships. Thanks are due to Arghya Basu and
Santosh Kumar Sahoo for crystallographic help and SEM
and EDS analyses. Thanks are also due to CIF, IIT Guwahati
for mass and NMR spectra.
ACHTUNGTRENNUNGthiourea (1a) to the reaction mixture were sequentially
added CuI (19 mg, 0.1 mmol), Cs2CO3 (650 mg, 2 mmol) and
NH2NHCHO (150 mg, 2.5 mmol). The heating was contin-
ued and the progress of the reaction was monitored by TLC.
After 4 h, the reaction mixture was cooled to room tempera-
ture and diluted with ethyl acetate (10 mL). Then the reac-
tion mixture was filtered through a bed of celite and washed
with an additional amount of ethyl acetate (20 mL). The fil-
trate was washed with water (3ꢁ5 mL). The ethyl acetate
layer was dried over anhydrous Na2SO4 and the solvent was
removed under reduced pressure. The crude product was
purified over a column of silica gel and eluted with (3:7,
hexane/ethyl acetate) to give N,4-diphenyl-4H-1,2,4-triazol-
3-amine (3a); yield: 212 mg (90%).
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Adv. Synth. Catal. 2012, 354, 2757 – 2770