Copper-Catalysed Cascade Synthesis of Imidazolidine-Benzothiazole and Imidazolidine-Tetrazole Hybrid Heterocycles from Bis-thioureas by a Desulfurisation Strategy

Article abstract of DOI:10.1002/ejoc.201501096

The in situ generated bis-thioureas obtained by treating aryl/alkyl isothiocyanates with aliphatic 1,2-diamines, upon treatment with Cu^I or Cu^II salts, depending on their quantity and the reaction conditions, furnished either imidazo

Full text of DOI:10.1002/ejoc.201501096

FULL PAPER
DOI: 10.1002/ejoc.201501096
Copper-Catalysed Cascade Synthesis of Imidazolidine–Benzothiazole and
Imidazolidine–Tetrazole Hybrid Heterocycles from Bis-thioureas by a
Desulfurisation Strategy
Ganesh Majji,[a][‡] Santosh K. Sahoo,[a][‡] Nilufa Khatun,[a] and Bhisma K. Patel*[a]
Keywords: Synthetic methods / C–H activation / Desulfurisation / Nitrogen heterocycles / Sulfur heterocycles / Copper
The in situ generated bis-thioureas obtained by treating aryl/
alkyl isothiocyanates with aliphatic 1,2-diamines, upon treat-
ment with CuI or CuII salts, depending on their quantity and
the reaction conditions, furnished either imidazolidine-
carbothioamide (ImCAT) or imidazolidine–benzothiazole
(ImBT) hybrid molecules. The same reactions in the presence
of sodium azide yielded imidazolidine–tetrazoles (ImTets).
The products were obtained in good yields at room tempera-
ture with all these processes taking place in a single pot. This
is a perfect illustration of Cu salts serving as both desulfur-
ising as well as C–H activating agents at ambient tempera-
ture.
desulfurise arylthioureas to aryl cyanamides.[6a] The ability
of Cu salts to act as efficient desulfurising agents was also
revealed during the synthesis of amino-substituted tetraz-
oles, triazoles, oxadiazoles and thiadiazoles by the oxidative
desulfurisation of their respective thiourea precursors.[6b]
Besides these, there are two other examples of copper-cata-
lysed oxidative desulfurisation of thioamides and their sub-
sequent transformations.[7] A unique example of an amidic
oxygen functioning as a nucleophile in a Cu-catalysed oxi-
dative coupling of an imine C–H bond in the synthesis of
2,5-disubstituted [1,3,4]oxadiazole has been demonstrated
by us.[8] Although copper-catalysed intermolecular thiol-
ation by C–H activation are well documented in the litera-
ture,[9] the selective formation of C–S bonds has been little
reported. This is because of the catalyst poisoning caused
by sulfur compounds and the tendency of thioamidic sub-
strates towards oxidative dimerisation and oxidation to
amides.[7a,10]
Recently, hybrid molecules have gained remarkable im-
portance in drugs discovery and other biological applica-
tions. Benzothiazoles are broadly found in bioorganic and
medicinal chemistry with applications in drug discovery
and the treatment of diabetes,[11a] epilepsy,[11b–11d] inflam-
mation,[12a] amyotrophic lateral sclerosis,[12b] analgesia,[12c]
tuberculosis[12d] and viral infections.[12e] Similarly, imid-
azoline-containing molecules exhibit a considerable array of
biological activities.[13] Thus, combining these two impor-
tant pharmacophoric units, namely imidazolidine and
benzothiazole, would be useful from the point of view of
pharmaceutical properties. Taking cues from the desulfur-
ising[1,2,6,7] and C–H activating ability[5h,8,9] of Cu catalysts,
the construction of a hybrid molecule possessing an imid-
azolidine and a benzothiazole pharmacophore can be envis-
aged from bis-thioureas derived from aryl/alkyl isothiocya-
Introduction
The transformation of simple precursors into a diverse
array of multifunctional molecules in one pot is of para-
mount interest to both academic and industrial research.
Thiophilic reagents such as diacetoxyiodobenzene (DIB),
bromine or its equivalent 1,1Ј-(ethane-1,2-diyl)dipyridinium
bis(tribromide) (EDPBT) have been reported to give vari-
ous N, O and S heterocycles and key organic intermediates
such as isothiocyanates, cyanamides and carbodiimides by
a desulfurisation strategy using substituted thioureas or its
analogues.[1] Other thiophilic reagents such as iodine also
serve as an equally efficient desulfurising agent giving
carbodiimides from 1,3-disubstituted thioureas[2a] and or-
ganic cyanamides from alkyl/aryl thioamides.[2b,2c] The
above-mentioned reagents are required in stoichiometric
amounts to achieve the desired transformations. In recent
years, transition-metal-catalysed tandem reactions have led
to the construction of heterocycles, polycycles and natural
products.[3] Among these reactions, copper-catalysed proto-
cols have emerged as vital tools in the synthesis of a wide
variety of heterocyclic frameworks.[4] As a part of our ongo-
ing research into Cu-catalysed processes, our group and
others have contributed a number of one-pot protocols for
the synthesis of various biologically important N, O and S
heterocycles.[5] Recently, we demonstrated that a catalytic
quantity of a Cu salt in the presence of a base can efficiently
[a] Department of Chemistry, Indian Institute of Technology
Guwahati,
Guwahati 781039, Assam, India
E-mail: patel@iitg.ernet.in
http://www.iitg.ac.in/patel/
[‡] Both authors have contributed equally to this paper.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201501096.
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Copper-Catalysed Synthesis of Hybrid Heterocycles
nates and aliphatic 1,2-diamines. If copper behaves as a methods require harsh reaction conditions, long reaction
thiophilic/desulfurising agent similarly to other thiophilic times, tedious work-up and the use of toxic metal salts. In
reagents such as DIB or iodine, the bis-thiourea would yield recent years, the oxidative desulfurisation strategy has be-
imidazolidinecarbothioamide (ImCAT) 1a, as shown in come an effective method for the synthesis of tetrazoles. An
Scheme 1. So far there are four methods reported in the oxidative-desulfurisation-based protocol for the construc-
literature for the synthesis of imidazolidinecarbothioamide tion of tetrazoles has been achieved by using toxic thio-
1a. The two classical methods for its synthesis involve the philic metals such as Pb and Hg salts.[22] In an attempt to
desulfurisation of bis-thioureas using a toxic mercuric avoid the use of toxic metals, two greener strategies, one by
salt[14] or the treatment of 2-methylamino-2-imidazoline our group using molecular iodine[2d] and the other using
with an isothiocyanate.[15] Recently, our group developed hypervalent iodine,[23] have been developed. In addition, Cu
two greener approaches, one using a slightly expensive rea- salts in catalytic quantities have been found to be effective
gent, diacetoxyiodobenzene (DIB),[1a] and the other using in the desulfurisation of thioureas, and this strategy has
an unconventional bis(tribromide) reagent, 1,1Ј-(ethane- been successfully employed for the synthesis of various
1,2-diyl)dipyridinium bis(tribromide) (EDPBT).[1b] Because azoles possessing additional N, O and S atoms.[6b]
Cu shows intramolecular as well as intermolecular C–H ac-
In all the above processes, various heterocycles have
tivation potential, the formation of benzothiazole by a C–H been constructed by the desulfurisation of thioureas/thio-
activation path to give imidazolidine–benzothiazole (ImBT) amides.[2d,5h,6b,22,23] As seen above, the mono-desulfur-
1Јa cannot be ruled out (Scheme 1, Strategy 1). Alterna- isation of bis-thioureas in the presence of copper salts gives
tively, if the thiophilic power of Cu prevails, it may activate imidazolidinecarbothioamides (ImCATs) in which one of
the sulfur towards an intramolecular electrophilic substitu- the thioamidic (thiourea) units remains intact. A second de-
tion reaction to form the benzothiazole skeleton, thus giv- sulfurisation of the ImCATs in the presence of an azido
ing the hybrid molecule imidazolidine–benzothiazole 1Јa, as nucleophile would give intermediate azido-imidazolidine
shown in Scheme 1 (Strategy 1). In fact, by using a stoichio- species that may undergo further intramolecular cyclo-
metric amount of various copper salts, the corresponding addition to provide imidazolidine–tetrazole hybrid hetero-
imidazolidine–copper complexes have been isolated.[5h]
cycles (Scheme 1).
Results and Discussion
To test the feasibility of our proposed strategy 1
(Scheme 1), the in situ generated thiourea obtained by treat-
ing phenyl isothiocyanate (a) and ethylenediamine (1) was
treated with CuI (20 mol-%) and Na2CO3 (1 equiv.; Table 1,
entry 1) in an ethanolic medium and the reaction mixture
was stirred at room temperature under air. The thiophilic
salt CuI was chosen because of our recent success with it
during the catalytic synthesis of cyanamides from aryl-
thioamides.[6] The reaction mixture, however, was found not
to be so clean while monitoring by TLC; several N and S
donor atoms present in the expected product may form a
complex with the Cu salt.[5h] A control reaction was per-
formed in the absence of a copper catalyst and any other
additive, that is, by simply heating the bis-thiourea in eth-
anol at 80 °C; ImCAT was formed but in a yield of Ͻ10%
after 15 h. To characterise the product (ligand), the metal-
bound ligand was removed from the complex by treating
Scheme 1. Possible reaction path for the formation of ImCAT,
ImBT and ImTet.
On the other hand, there are only two instances in which the reaction mixture with an aqueous ammoniacal solution.
imidazolidine–tetrazole hybrid molecules have proven use- The organic products were extracted with EtOAc and the
ful, one in medicinal applications and the other in organo- major product, phenyl(phenylimino)imidazolidinecarbo-
catalysis.[16–20] The derivative 5-(4-benzyl-1-methylimid- thioamide (1a), was isolated in 58% yield along with traces
azolidin-2-yl)-1H-tetrazole has been used as an organocata- of imidazolidine–benzothiazole 1Јa (ImBT; ca. 5%).[5h] The
lyst in the asymmetric conjugate addition of nitroalk- formation of both these products (1a and 1Јa; Scheme 1)
anes.[20e] Thus, the development of efficient strategies for revealed that our strategy worked as expected. A decent
the synthesis of tetrazole derivatives is attractive due to conversion using a sub-stoichiometric amount of CuI sug-
their potential myriad of applications. Traditional methods gests the catalytic nature of the reagent.
for the synthesis of tetrazoles include the treatment of sec-
Initially, we optimised the reaction conditions so as to
ondary amides or thioamides with TMSN3/Et3N/HgII, achieve exclusively the intermediate imidazolidinecarbo-
PCl5/HN3 or TMSN3/Ph3P/DEAD.[21] However, these thioamide (ImCAT) 1a by using CuII salts as they are thio-
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Table 1. Screening of the reaction conditions for the desulfurisation of bis-thioureas.
Entry
Catalyst (mol-%)
CuI (20)
CuCl (20)
CuBr2 (20)
Base
Solvent
Time [h]
Temp. [°C]
Yield[a] [%]
1a
1Јa
1
2
3
4
5
6
7
8
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
THF
DMSO
MeOH
MeCN
EtOH
EtOH
MeCN
MeCN
12
12
12
12
12
12
12
12
12
12
12
12
12
12
12
28
28
28
28
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
58
61
75
38
46
68
69
48
85
76
69
56
58
68
86
13
8
5
3
2
CuO (20)
Cu(OH)2 (20)
n.d.
n.d.
5
CuSO4·5H2O (20)
Cu(OAc)2·2H2O (20)
Cu(NO3)2·3H2O (20)
CuCl2·2H2O (20)
CuCl2·2H2O (20)
CuCl2·2H2O (20)
CuCl2·2H2O (20)
CuCl2·2H2O (20)
CuCl2·2H2O (20)
CuCl2·2H2O (20)
CuCl2·2H2O (30)
CuCl2·2H2O (40)
CuCl2·2H2O (50)
CuCl2·2H2O (40)
5
n.d.
3
9
10
11
12
13
14
15
16
17
18
19
5
3
Et3N
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
n.d.
8
5
3
45
65
63
63
0
5
[a] n.d.: not detected.
philic, inexpensive, environmentally benign and easy to tive products 2b–2d. Similarly, moderately electron-with-
handle. Of the monovalent (CuCl) and divalent copper salts drawing p-Cl (e) and p-Br (f) as well as strongly electron-
[CuBr2, CuO, Cu(OH)2, CuSO4·5H2O, Cu(OAc)2·2H2O, withdrawing p-CF3 (g) groups in the aryl rings of isothiocy-
Cu(NO3)2·3H2O and CuCl2·2H2O, Table 1, entries 2–9] anate all gave excellent yields of their respective products
tested, the dihydrated salt of CuCl2 was found to be the best 2e–2g. It should be mentioned here that in general bis-thio-
(Table 1, entry 9). Ethanol was preferred over other solvents ureas derived from the rigid aliphatic cyclic 1,2-diamine (2)
such as MeOH, THF, DMSO and CH3CN (Table 1, en- gave superior yields in shorter reaction times than the bis-
tries 9–15) as it gave a better yield as well as being environ- thioureas derived from the conformationally flexible ethyl-
mental acceptable. The use of Na2CO3 (Table 1, entry 9) as enediamine (1; Table 2). Substrates possessing electron-do-
base gave better results than other bases such as K2CO3 nating substituents gave marginally better yields than sub-
and Et3N tested (Table 1, entries 10 and 11). Thus, solvent strates bearing electron-withdrawing groups (Table 2). The
EtOH, catalyst CuCl2·2H2O and Na2CO3 as base gave an bis-thioureas derived from o-phenylenediamine and aryl
isolated yield of 85% of 1a along with a trace (ca. 3%) isothiocyanates did not give the expected ImCAT products,
of 1Јa at room temperature under air after 12 h (Table 1, rather they gave benzimidazoles along with the expulsion
entry 9).
of the aryl isothiocyanate group, which is consistent with
Having optimised the reaction conditions, this strategy the results of our earlier work.[1a,1b]
was then applied to other in situ generated bis-diarylthio-
In the above cases, imidazolidinecarbothioamides
ureas derived from 1,2-ethylenediamine (1) and various aryl (ImCATs) were obtained as the major products (Table 2)
isothiocyanates (a–g) possessing electron-donating p-Me along with traces of imidazolidine–benzothiazoles (ImBTs)
(b), p-OMe (c) and 2,4-di-Me (d), moderately electron-with- (Table 1). When the reaction was prolonged, the yields of
drawing p-Cl (e) and p-Br (f) as well as strongly electron- the imidazolidine–benzothiazoles (ImBTs) increased, and
withdrawing p-CF3 (g) groups in the aryl rings; imidazol- were probably formed by a C–H activation path.[5h] Note
idinecarbothioamide (ImCAT) products 1a–1g were exclu- that there has not been a single report on the synthesis of
sively obtained, as shown in Table 2. Similarly, bis-dibenz- hybrid heterocycle imidazolidine–benzothiazoles (ImBTs),
ylthioureas derived from 1,2-ethylenediamine (1) and except for some of their copper complexes,[5h] thus the reac-
benzyl isothiocyanates h and i gave the corresponding imid- tion parameters were further optimised. The in situ gener-
azolidinecarbothioamides 1h and 1i, but in relatively low ated thiourea obtained by treating phenyl isothiocyanate (a)
yields (Table 2). The reaction of the cyclic aliphatic 1,2-di- and ethylenediamine (1) with 20 mol-% of CuCl2 gave imid-
amine, trans-1,2-diaminocyclohexane (2), with aryl isothio- azolidinecarbothioamide 1a (ImCAT) as the major product
cyanates bearing electron-donating p-Me (b), p-OMe (c) along with traces of ImBT 1Јa after 12 h. No substantial
and 2,4-di-Me (d) groups gave good yields of their respec- improvement in the yield of the latter product could be ob-
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Copper-Catalysed Synthesis of Hybrid Heterocycles
Table 2. One-pot synthesis of imidazolidinecarbothioamides (ImCATs) from aryl/alkyl isothiocyanates and 1,2-diamines.[a,b]
[a] Isolated yields are given. [b] The reactions were monitored by TLC and the products characterised by spectroscopic analysis.
served even after prolonging the reaction time to 48 h or by 28 h, the major product obtained upon aqueous ammonia-
heating the reaction mixture. This is because the catalyst cal work-up was found to be the imidazolidine–benzothi-
remained bound to ImBT in the form of a [Cu(ImBT)] azole (ImBT) 1Јa. The details of further optimisations are
complex.[5h]
shown in Table 1 (entries 16–19), and are very much sub-
However, upon increasing the quantity of the Cu salt to strate dependent, as is discussed below. It should be men-
40 mol-% and allowing the reaction to proceed for upto tioned here that 40 mol-% of the catalyst (CuCl2·2H2O) is
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essential for the reactions of thioureas derived from aryl reaction conditions, this strategy was then applied to other
isothiocyanates possessing electron-withdrawing groups in situ generated bis-diarylthioureas derived from acyclic di-
such as Cl (e) and Br (f), but for substrates possessing the amine 1 or cyclic 1,2-diamine 2 and various aryl isothiocya-
electron-donating groups Me (b), OMe (c) and di-Me (d), nates possessing electron-donating Me (b), OMe (c) and di-
the reaction proceeds efficiently with 20 mol-% of the cata- Me (d) and electron-withdrawing Cl (e) and Br (f) groups.
lyst. From these observations it is clear that in addition to All the in situ generated bis-diarylthioureas gave exclusively
the simple Cu salts, the [Cu(ImBT)] complexes[5h] also serve the corresponding imidazolidine–benzothiazoles (ImBTs)
as efficient catalysts for this transformation, particularly for 1Јa–1Јf and 2Јa–2Јf, as shown in Table 3. For the aryl iso-
the C–H activation step (Scheme 1). Having optimised the thiocyanate possessing the strongly electron-withdrawing
Table 3. One-pot synthesis of imidazolidine–benzothiazoles (ImBTs) from aryl isothiocyanates and 1,2-diamines.[a,b]
[a] Isolated yields are given. [b] The reactions were monitored by TLC and the products characterised by spectroscopic analysis. [c]
20 mol-% of CuCl2·2H2O was used. [d] 40 mol-% of CuCl2·2H2O was used. [e] A stoichiometric amount of CuCl2·2H2O was used.
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Copper-Catalysed Synthesis of Hybrid Heterocycles
group p-CF3 (g), a stoichiometric amount of CuCl2 was es- the product 1bx was confirmed by X-ray crystallographic
sential to achieve the conversion to 1Јg and 2Јg in modest analysis (Figure 1).[25] Similarly, bis-thioureas obtained
yields. For electron-poor substrates, a polar aprotic solvent from 1,2-ethylenediamine (1) and aryl isothiocyanates bear-
such as acetonitrile was found to be better than the polar ing the weakly deactivating substituents p-F, p-Cl, p-Br, p-
protic solvent ethanol. It is noteworthy that electron-rich I, m-Br and o-Br gave the corresponding imidazolidine–
substrates showed higher reactivity towards intramolecular tetrazoles 1ix, 1ex, 1fx, 1jx, 1kx and 1lx hybrid heterocycles
C–H activation than substrates with electron-withdrawing in excellent yields. The in situ generated 2,4-di-F- and p-
groups in the aryl ring (Table 3). These results are consis- CF3-substituted bis-thioureas also gave the imidazolidine–
tent with the observations of Buchwald and Nagasawa and tetrazoles 1mx and 1gx in yields of 63 and 83%, respec-
their co-workers for similar C–N and C–O bond-forming tively. As can be seen from Table 4, the yields obtained are
reactions.[24]
higher for substrates possessing electron-withdrawing
By using the conditions similar to those above and of groups than for substrates with electron-donating substitu-
our previous reports,[6b] we re-investigated the formation of ents. This trend in yields is consistent with the results of
imidazolidine–tetrazole (Strategy 2, Scheme 1). The treat- our earlier work in which tetrazole derivatives were synthe-
ment of phenyl isothiocyanate (a; 2 equiv.) with ethylenedi- sised from their mono-thiourea precursors.[6b] However, the
amine (1; 1 equiv.) in DMSO at 80 °C furnished the corre- in situ generated bis-thioureas derived from aryl isothio-
sponding bis-thiourea within 10 min. The in situ generated cyanates and 1,2-diaminocyclohexane (2) also furnished the
bis-thiourea provided N-phenyl-2-(phenylimino)imidazolid- corresponding hybrid heterocyclic scaffolds (2ax, 2bx, 2ix,
ine-1-carbothioamide (1a) on treatment with CuI (10 mol- 2fx and 2kx) in good yields. Here again, similar electronic
%) and Cs2CO3 (2 equiv.) for 3 h, as shown in Table 2. effects of the substituents on the phenyl ring were observed,
NaN3 (3 equiv.) was added to this reaction mixture and the as reflected by their yields (Table 4).
reaction was allowed to continue for a further 4 h. The ex-
pected imidazolidine–tetrazole 1ax was obtained in an iso-
lated yield of 32%. Encouraged by this result, a series of
optimisation reactions were performed to arrive at the
maximum possible yield. The use of K2CO3 as base was
found to be inferior (23%) and the organic base Et3N gave
an improved yield (40%). A further 8% improvement in the
yield (48%) was observed when the solvent was replaced
by DMF. Interestingly, when the reaction was performed at
60 °C, the product 1ax was isolated in 60% yield. However,
when the same reaction was carried out either at room tem-
perature or below 50 °C the yield was severely affected, giv-
ing yields of around 26%. The lower yield at low tempera-
ture is a consequence of thermodynamic parameters,
whereas the better yield at 60 °C is due to fewer competitive
Figure 1. ORTEP molecular diagram of the structure of 1bx.
reaction pathways as compared with at the higher tempera-
ture of 80 °C. An increase in the quantity of the base Et3N
(3 equiv.) resulted in an improved yield (70%). However,
the yield remained unaltered with further increases in the
quantity of base. The yield of the product dropped with a
Based on literature reports[5h,6b] and control experiments,
decrease in the amount of sodium azide (2 equiv., 63%) or a plausible mechanism for the formation of the imidazol-
catalyst (5 mol-%, 42%). The use of other Cu salts as cata- idine–tetrazoles is depicted in Scheme 2. One of the sulfur
lysts, such as Cu(OAc)2 (58%), CuCl2 (62%), CuSO4 5H2O atoms in the bis-thiourea is activated by the thiophilic Cu
(45%), CuBr2 (50%), CuCl (65%) and CuBr (63%), were salt. The imine carbon is then attack intramolecularly by
slightly inferior compared with CuI (70%). Thus, the most one of the thioamidic nitrogen atoms with the expulsion of
favourable conditions for the formation of 1ax are the use CuS to give imidazolidinecarbothioamide 1a, as shown in
of CuI (10 mol-%), Et3N (3 equiv.) and NaN3 (3 equiv.) in Scheme 2. The formation of both CuS and 1a was con-
DMF as solvent at 60 °C.
firmed by their isolation and characterisation.[6b] Under the
The optimised reaction conditions were then applied to present reaction conditions, the in situ generated CuS is
the synthesis of a diverse array of imidazolidine–tetrazoles converted into CuO, as has been observed earlier by us.[6b]
from the corresponding bis-thioureas. This methodology is This in situ generated CuO is equally effective in bringing
compatible with a wide range of functional groups, tolerat- about a similar desulfurisation.[6b] The treatment of isolated
ing both electron-donating and -withdrawing substituents. imidazolidinecarbothioamide 1a in the presence of NaN3
For example, bis-thioureas derived from 1,2-ethylenedi- under otherwise identical conditions gave product 1ax. The
amine (1) and aryl isothiocyanates possessing the electron- second sulfur atom in imidazolidinecarbothioamide 1a is
donating substituents p-Me and p-Bu gave the correspond- activated by the thiophilic Cu salt and is attacked by the
ing imidazolidine–tetrazoles 1bx and 1hx. The structure of external nucleophile azide (N3) to give an azido-imidazolid-
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Table 4. Substrate scope for the synthesis of imidazolidine–tetrazoles by oxidative double desulfurisation.[a]
[a] The reactions were monitored by TLC and the products characterised by spectroscopic analysis. The yields of the isolated pure
products are reported.
?ine species (Scheme 2). Intramolecular electrocyclisation of reaction path could be analogous to the one that has been
the azido-imidazolidine leads to the formation of the imid- proposed for a similar C–N coupling reaction by Brasche
azolidine–tetrazole hybrid heterocycle 1ax. Although we and Buchwald[24a] or for a C–O coupling reaction by
have not thoroughly investigated the reaction mechanism Nagasawa and co-workers[24b,24c] as well as our own
for the formation of the hybrid molecule 1Јa from 1a, the (Scheme 2).[1a,1b,5h]
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Copper-Catalysed Synthesis of Hybrid Heterocycles
Scheme 2. Proposed mechanism for the formation of ImCAT, ImBT and ImTet.
(0.2 mmol) were added to this heterogeneous reaction mixture and
the reaction mixture was stirred at room temperature under air.
The progress of the reaction was monitored by TLC by taking
Conclusions
The in situ generated bis-diarylthioureas derived from
aliphatic 1,2-diamines and aryl/alkyl isothiocyanates un- small aliquots, diluting with ethyl acetate and treatment with a few
drops of 30% aqueous ammonia. After shaking for 1 min, the
aqueous layer turned blue and the product present in the ethyl acet-
ate layer was spotted by TLC. After complete disappearance of the
starting thiourea, ethanol was removed under reduced pressure and
ethyl acetate (25 mL) was added followed by 30% aqueous ammo-
nia (5 mL). The resulting biphasic layer was stirred for 5 min. The
organic layer was then separated and dried with anhydrous Na2SO4
and concentrated under reduced pressure. The crude product so
obtained was purified over a short column of silica gel by using
EtOAc/hexane (2:8) as eluent to give the product 1a (260 mg, yield
85%). The identity and purity of the product was confirmed by
spectroscopic analysis.
dergo an efficient copper-catalysed cascade synthesis of
imidazolidine–benzothiazoles (ImBTs). This is a unique
demonstration of Cu salts serving both as a desulfurising
as well as a C–H activating agent at ambient temperature.
The double desulfurisation of bis-thiourea, catalysed by
CuI, leads to the construction of imidazolidine–tetrazoles
(ImTets) in a single operation. These hybrid heterocycles,
which possess two important pharmacophoric units, may
have potential applications in synthetic and pharmaceutical
chemistry.
General Procedure for the Preparation of (E)-N-[1-(Benzo[d]thiazol-
2-yl)imidazolin-2-ylidine]aniline (1Јa) Using CuCl2·2H2O as Cata-
lyst: A procedure similar to that used for the synthesis of 1a was
adopted except 0.4 mmol of CuCl2·2H2O was used instead of
0.2 mmol; yield 191 mg (65%).
Experimental Section
General Procedure for the Preparation of (E)-N-Phenyl-2-(phen-
ylimino)imidazolidine-1-carbothioamide (1a) Using CuCl2·2H2O as
Catalyst: Ethylenediamine (1; 60 mg, 1 mmol) was added to a solu-
tion of phenyl isothiocyanate (a; 270 mg, 2 mmol) in EtOH General Procedure for the Preparation of N-Phenyl-1-(1-phenyl-1H-
(10 mL) and the reaction mixture was stirred at room temperature. tetrazol-5-yl)-4,5-dihydro-1H-imidazol-2-amine (1ax) Using CuI as
The complete formation of bis-thiourea was observed within
20 min (monitored by TLC), and is associated with the formation
Catalyst: A mixture of 1,2-ethylenediamine (1; 60 mg, 1 mmol) and
phenyl isothiocyanate (a; 270 mg, 2 mmol) in DMF (2 mL) was
stirred in a pre-heated oil bath at 60 °C for 10 min. After the com-
of
a white precipitate. Na2CO3 (1 mmol) and CuCl2·2H2O
Eur. J. Org. Chem. 2015, 7534–7543
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7541

G. Majji, S. K. Sahoo, N. Khatun, B. K. Patel
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Acknowledgments
B. K. P. acknowledges the support of this research by the Depart-
ment of Science and Technology (DST), New Delhi (SB/S1/OC-53/
2013), and the Council of Scientific and Industrial Research
(CSIR) [02(0096)/12/EMR-II]. G. M. thanks the University Grants
Commission (UGC) and N. K. thanks CSIR for financial support.
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CCDC-1063526 (for 1bx) contains the supplementary crystal-
lographic 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. See also the Sup-
porting Information.
Received: August 24, 2015
Published Online: November 3, 2015
Eur. J. Org. Chem. 2015, 7534–7543
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7543