Sequential MCR via Staudinger/Aza-Wittig versus Cycloaddition Reaction to Access Diversely Functionalized 1-Amino-1H-Imidazole-2(3H)-Thiones

A multicomponent reaction (MCR) strategy, alternative to the known cycloaddition reaction, towards variously substituted 1-amino-1H-imidazole-2(3H)-thione derivatives has been successfully developed. The novel approach involves α-halohydrazones whose azidation process followed by tandem Staudinger/aza-Wittig reaction with CS2 in a sequential MCR regioselectively leads to the target compounds avoiding the formation of the regioisomer iminothiazoline heterocycle. The approach can be applied to a range of differently substituted α-halohydrazones bearing also electron-withdrawing groups confirming the wide scope and the substituent tolerance of the process for the synthesis of the target compounds. Interestingly, the concurrent presence of reactive functionalities in the scaffolds so obtained ensures post-modifications in view of N-bridgeheaded heterobicyclic structures.

Among imidazole derivatives, imidazole-2-thiones have been associated to a special class of biologically relevant thiourea derivatives [8] endowed with antithyroid [9], antiproliferative [10], matrix metalloproteinases (MPP) inhibitory [11] properties and can be used as building blocks for the synthesis of N-aminoimidazole with antiretroviral activity [12].
Even if this method appears robust, it seems to suffer of some limitations in terms of insertion of electron-withdrawing groups placed on the α-halohydrazone precursors of conjugated azoalkene intermediates.In this regard, for our research purposes, we tried to apply the Schantl's method reacting 2-chloro-N,N-dimethyl-3-oxobutanamide (A), potassiun thiocyanate (B) and tert-butyl hydrazinecarboxylate (C) in acetic acid to obtain the corresponding N-substituted 1-amino-1H-imidazole-2(3H)-thione derivative I but without success.As shown in Scheme 2, instead of the cycloaddition, a 5-exo-dig cyclization reaction leading to 2-iminothiazole II took place.This evidence is in agreement with the result obtained by Lagoja and coworkers where a pathway involving the key α-thiocyanatohydrazone intermediate D is invoked [12].Scheme 2. Pathway for the formation of 2-iminothiazoline heterocycle II.
The structure of the iminothiazoline II was confirmed by comparison of the spectral data of the same compound obtained by means of a different procedure previously described by some of us that foresees the conjugated hydrothiocyanation of the pertinent conjugated azoalkene in acidic medium followed by intramolecular cyclization [22].
Inspired by our previous experience [23], and in order to perform a complete regioselective-oriented method for the desired 1-amino-1H-imidazole-2(3H)-thiones I, we have planned a different strategy that avoids the use of bidentate-nucleophilic reagents such as the potassium thiocyanate.In the construction of I, three strategic disconnections between the N1-C2, C2-N3 and N3-C4 were hypothesized (Scheme 3).Even if this method appears robust, it seems to suffer of some limitations in terms of insertion of electron-withdrawing groups placed on the α-halohydrazone precursors of conjugated azoalkene intermediates.In this regard, for our research purposes, we tried to apply the Schantl's method reacting 2-chloro-N,N-dimethyl-3-oxobutanamide (A), potassiun thiocyanate (B) and tert-butyl hydrazinecarboxylate (C) in acetic acid to obtain the corresponding N-substituted 1-amino-1Himidazole-2(3H)-thione derivative I but without success.As shown in Scheme 2, instead of the cycloaddition, a 5-exo-dig cyclization reaction leading to 2-iminothiazole II took place.This evidence is in agreement with the result obtained by Lagoja and coworkers where a pathway involving the key α-thiocyanatohydrazone intermediate D is invoked [12].
Even if this method appears robust, it seems to suffer of some limitations in terms of insertion of electron-withdrawing groups placed on the α-halohydrazone precursors of conjugated azoalkene intermediates.In this regard, for our research purposes, we tried to apply the Schantl's method reacting 2-chloro-N,N-dimethyl-3-oxobutanamide (A), potassiun thiocyanate (B) and tert-butyl hydrazinecarboxylate (C) in acetic acid to obtain the corresponding N-substituted 1-amino-1H-imidazole-2(3H)-thione derivative I but without success.As shown in Scheme 2, instead of the cycloaddition, a 5-exo-dig cyclization reaction leading to 2-iminothiazole II took place.This evidence is in agreement with the result obtained by Lagoja and coworkers where a pathway involving the key α-thiocyanatohydrazone intermediate D is invoked [12].

Scheme 2. Pathway for the formation of 2-iminothiazoline heterocycle II.
The structure of the iminothiazoline II was confirmed by comparison of the spectral data of the same compound obtained by means of a different procedure previously described by some of us that foresees the conjugated hydrothiocyanation of the pertinent conjugated azoalkene in acidic medium followed by intramolecular cyclization [22].
Inspired by our previous experience [23], and in order to perform a complete regioselective-oriented method for the desired 1-amino-1H-imidazole-2(3H)-thiones I, we have planned a different strategy that avoids the use of bidentate-nucleophilic reagents such as the potassium thiocyanate.In the construction of I, three strategic disconnections between the N1-C2, C2-N3 and N3-C4 were hypothesized (Scheme 3).The structure of the iminothiazoline II was confirmed by comparison of the spectral data of the same compound obtained by means of a different procedure previously described by some of us that foresees the conjugated hydrothiocyanation of the pertinent conjugated azoalkene in acidic medium followed by intramolecular cyclization [22].
Inspired by our previous experience [23], and in order to perform a complete regioselective-oriented method for the desired 1-amino-1H-imidazole-2(3H)-thiones I, we have planned a different strategy that avoids the use of bidentate-nucleophilic reagents such as the potassium thiocyanate.In the construction of I, three strategic disconnections between the N1-C2, C2-N3 and N3-C4 were hypothesized (Scheme 3).We reasoned that the azidation process of the pertinent α-halohydrazone derivative followed by tandem Staudinger/aza-Wittig reaction with CS2 could have been a successful route [24,25].
Motivated by this result, we aimed to develop a one-pot sequential multicomponent reaction (MCR) [32][33][34][35] as alternative method for regioselective synthesis of a new series of imidazole-2-thione-containing structures as suitable precursors for drug-like compounds [36].
Hence, our new approach to N-substituted 1-amino-1H-imidazole-2(3H)-thiones 5a-k (53%-85%) is depicted in Scheme 5.The whole process that permits the formation of the desired heterocycle can be easily checked by the complete disappearance of the pertinent α-azidohydrazone derivative and by the observation of Ph3P=S as byproduct (thin-layer chromatography (TLC) check, see Experimental Section).It is to be noted that for 5a, the efficiency of the reaction benefits by this latter protocol increasing the overall yield from 25% (obtained employing the step-by-step procedure) to 79% (Table 1).Moreover, the implemented strategy broadens the substitution patterns Scheme 3. Our hypothesized disconnection of 1-amino-1H-imidazole-2(3H)-thione I derivatives.
We reasoned that the azidation process of the pertinent α-halohydrazone derivative followed by tandem Staudinger/aza-Wittig reaction with CS 2 could have been a successful route [24,25].
We reasoned that the azidation process of the pertinent α-halohydrazone derivative followed by tandem Staudinger/aza-Wittig reaction with CS2 could have been a successful route [24,25].

4.
Step-by-step synthetic pathway for N-substituted Motivated by this result, we aimed to develop a one-pot sequential multicomponent reaction (MCR) [32][33][34][35] as alternative method for regioselective synthesis of a new series of imidazole-2-thione-containing structures as suitable precursors for drug-like compounds [36].
Hence, our new approach to N-substituted 1-amino-1H-imidazole-2(3H)-thiones 5a-k (53%-85%) is depicted in Scheme 5.The whole process that permits the formation of the desired heterocycle can be easily checked by the complete disappearance of the pertinent α-azidohydrazone derivative and by the observation of Ph3P=S as byproduct (thin-layer chromatography (TLC) check, see Experimental Section).It is to be noted that for 5a, the efficiency of the reaction benefits by this latter protocol increasing the overall yield from 25% (obtained employing the step-by-step procedure) to 79% (Table 1).Moreover, the implemented strategy broadens the substitution patterns Motivated by this result, we aimed to develop a one-pot sequential multicomponent reaction (MCR) [32][33][34][35] as alternative method for regioselective synthesis of a new series of imidazole-2thione-containing structures as suitable precursors for drug-like compounds [36].
Hence, our new approach to N-substituted 1-amino-1H-imidazole-2(3H)-thiones 5a-k (53%-85%) is depicted in Scheme 5.The whole process that permits the formation of the desired heterocycle can be easily checked by the complete disappearance of the pertinent α-azidohydrazone derivative and by the observation of Ph 3 P=S as byproduct (thin-layer chromatography (TLC) check, see Experimental Section).It is to be noted that for 5a, the efficiency of the reaction benefits by this latter protocol increasing the overall yield from 25% (obtained employing the step-by-step procedure) to 79% (Table 1).Moreover, the implemented strategy broadens the substitution patterns at the amino-N1 and at C4 of the heterocycle skeleton with electron-withdrawing groups (5a-e) and tolerates the aromatic (amino-N1) and aliphatic (C4) groups, as for 5j [15,17,18] (Table 1).
All 1 H NMR and 13 C NMR spectra were recorded at 400 and 100 MHz, respectively at 25 • C on a Bruker Ultrashield 400 spectrometer (Bruker, Billerica, MA, USA).Proton and carbon spectra were referenced internally to residual solvent signals as follows: δ = 2.50 ppm for proton (middle peak) and δ = 39.50 ppm for carbon (middle peak) in DMSO-d 6 and δ = 7.27 ppm for proton and δ = 77.00ppm for carbon (middle peak) in CDCl 3 .The following abbreviations are used to describe peak patterns where appropriate: s = singlet, d = doublet, t = triplet q = quartet, m = multiplet and br = broad signal.All coupling constants (J) are given in Hz.Copies of 1 H-NMR and 13 C-NMR spectra of compounds II, 2a, 3a, 5a-k, 7a-c, and 8a-c are in Supplementary Materials.FT-IR spectra were measured as Nujol mulls using a Nicolet Impact 400 (Thermo Scientific, Madison, WI, USA).Mass spectra were obtained by ESI-MS analyses performed on Thermo Scientific LCQ Fleet Ion Trap LC/MS and Xcalibur data System.High-resolution mass spectra (HRMS) were determined with ESI resource on a Waters Micromass QTOF instrument (Waters, Milford, MA, USA).Elemental analyses were within ±0.4 of the theoretical values (C, H, N).

3.2.
Step-By-Step Synthetic Method for 5a

Synthesis of tert-butyl 2-(3-azido-4-(dimethylamino)-4-oxobutan-2-ylidene) hydrazinecarboxylate (2a)
To the α-halohydrazone 1a (555.5 mg, 2.0 mmol) solved in THF (9.0 mL), an ice-cooled aqueous solution (1.0 mL, T = 4 • C) of NaN 3 (2.0 mmol, 130.02 mg) was added.The reaction mixture was stirred at room temperature until the disappearance of the starting 1a (TLC check).THF was removed under reduced pressure and the residue was diluted with water and extracted with CH 2 Cl 2 (3 × 15.0 mL).The combined organic layers were dried over anhydrous NaSO 4 and concentrated under reduced pressure.The crude reaction was purified by crystallization from Et 2 O affording the α-azido derivative 2a.Yield 70.0% (398.0 mg) as a white solid; Mp 120-124 0.65 Mmol of 3a (337.0 mg,) was solved in a mixture of THF:MeOH (4:1, 5.0 mL) heating.Then, 0.5 mL of CS 2 was added and the reaction was refluxed.The end of the reaction was defined (4.0 h) by the disappearance of 3a together with the formation of Ph 3 P=S as byproduct (monitored by TLC).After removal of the reaction solvents under reduced pressure, a first crop of 5a was obtained as white powder from a solution of THF/light petroleum ether.A further amount was be gained by column chromatography eluting with CH 2 Cl 2 /EtOAc mixtures.White powder from THF/light petroleum ether; yield 53% (103.4 mg); Mp 172-173 • C (dec.); 1 H-NMR (400 MHz, DMSO-d 6 ,) δ 1. 32 18.57.The partition of some signals here, as well as in the following cases, is due to the N1-amide rotameric effect [46].

Typical MCR Procedure for the Synthesis of N-Substituted 1-Amino-1H-Imidazole-2(3H)-Thione Derivatives 5a-k
To a round flask equipped with a magnetic stirring bar containing ice-cooled solution of NaN 3 (1.0 mmol, 65.01 mg) dissolved in 0.5 mL of H 2 O, the corresponding α-halohydrazone 1a-k (1.0 mmol) dissolved in THF (4.5 mL) was added.The mixture was stirred at room temperature until the disappearance of 1 (monitored by TLC).Upon completion, Na 2 SO 4 (0.5 g) , a solution of PPh 3 (1.1 mmol, 288.5 mg) in THF (1.0 mL) and CS 2 (1.0 mL) were added in sequence, and the mixture was refluxed for the appropriate reaction time (3.0-20.0h).The formation of the final products 5a-k was revealed by the complete disappearance of the spot corresponding to the α-azidohydrazone 2a-k as well as the detection of the byproduct Ph 3 P=S.The Na 2 SO 4 was filtered in vacuo and washed with THF (10.0 mL).The filtrate was concentrated under reduced pressure and the residue was purified by crystallization and/or by chromatography eluting with cyclohexane:EtOAc or CH 2 Cl 2 :EtOAc mixtures.The resulting products 5a-k were isolated by crystallization from the specific solvents (see below).According to this procedure, 5a was obtained in 79% (237.3 mg).To a suspension of the N-Boc-protected 1-amino-1H-imidazole-2(3H)-thione derivatives 5c,d,f (1.0 mmol) and K 2 CO 3 (1.0 mmol, 138 mg) in 10.0 mL of acetone, the corresponding α-halocarbonyl derivative 6a-c (1.0 mmol) was added.The reaction mixture was kept under magnetic stirring at room temperature.Upon completion (monitored by TLC) the solvent was removed, and the crude reaction mixture was quenched to neutrality with a solution of HCl 1N and extracted with EtOAc (30.0 mL).The organic layer was washed with brine and dried over anhydrous Na 2 SO 4 .The solvent was removed in vacuum and the crude extract was purified by crystallization or by column chromatography eluting with cyclohexane:ethyl acetate mixtures to furnish 7a-c derivatives in good yields (84%-93%).  1C-NMR (100 MHz, CDCl 3 ) δ 8.7, 12.9, 14.5, 28.0, 40.6, 41.6, 43.4, 82.5, 128.4, 128.5, 128.7, 130.9, 133.7, 135.3, 135.4, 139.9, 153.8, 164.5, 193.7     Derivative 7a,b (1.0 mmol) was solved in 5.0 mL of a solution of trifluoroacetic acid (TFA) and CH 2 Cl 2 (1:1).The reaction mixture was left at room temperature until the disappearance of the starting 7a,b (TLC check).Then, the solvent was removed under reduced pressure and the crude reaction mixture was quenched to neutrality with a saturated solution of Na 2 CO 3 and extracted with EtOAc (20.0 mL × 3).The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 .After the removal of the solvent, the crude extract was purified by crystallization or by column chromatography eluting with cyclohexane/ethyl acetate mixtures to furnish 8a,b derivatives.

a
Yield of isolated product 7a-c based on 6a-c; b Yield of isolated product 8a-c based on 7a-c.It is worthwhile to note that the proposed synthetic pathway can offer an alternative method for obtaining 2H-imidazo[2,1-b][1,3,4]thiadiazine derivatives 8 with respect to the ring transformation of α-(oxazol-2-ylthio) ketones 9 on treatment with hydrazine hydrate 10 [45], together with the possibility of wide diversification of the substituents at the different positions of the N-bridgeheaded heterobicyclic structures.As depicted in Scheme 7, a different disconnection for the assembly of the 2H-imidazo[2,1-b][1,3,4]thiadiazine scaffold can be envisaged.
a Overall yield of isolated product 5a from the step-by-step reaction based on 1a; b Overall yield of isolated products 5a-k from one-pot MCR based on 1a-k.
a Overall yield of isolated product 5a from the step-by-step reaction based on 1a; b Overall yield of isolated products 5a-k from one-pot MCR based on 1a-k.