Studies Toward the Synthesis of Benzfuzed Azoles

I am forwarding his thesis entitled "Studies towards the synthesis of benzfuzed azoles" being presented for the Ph.D. The first two chapters describe the synthesis of 1-aryl-1H-benzotriazoles by copper-catalyzed C-N cross-coupling reactions and palladium-catalyzed C-H/C-N intramolecular activation reactions. The third chapter deals with the synthesis of N-aryl benzimidazoles via palladium-catalyzed intramolecular C-H amination, while the fourth chapter focuses on the PhI(OAc)2-promoted oxidative synthesis of benzfused azoles.

This procedure provides a simple route for the regioselective and efficient synthesis of functionalized 1-aryl-1H-benzotriazoles under external ligand-free conditions. This protocol is also applicable for the synthesis of both 2-unsubstituted and 2-alkyl/-aryl-substituted N-aryl-benzimidazoles.

Copper(I)-Catalyzed Synthesis of 1-Aryl-1H-benzotriazoles

Palladium-Catalyzed Synthseis of 1-Aryl-1H-benzo[d][1,2,3]triazoles

Palladium Catalyzed N-Arylation of 1H-Benzotriazoles

Copper-Catalyzed Synthesis of 1-Aryl-1H-benzo[d][1,2,3]triazoles

Copper Catalyzed N-Arylation of 1H-Benzotriazoles

1.3 1,3-Dipolar Cycloaddition Reactions

Synthesis of 1-Aryl-1H-benzotriazoles from 1,5-Diynes

Synthesis of 1-Aryl-1H-benzotriazoles via Benzyne Click Chemistry

One-Pot Synthesis of 1-Aryl-1H-benzotriazoles

Microwave Assisted Synthesis of 1-Aryl-1H-benzotriazoles

Present Study

Synthesis of 2-Halophenylimino-2-phenyl-hydrazines

We compared the catalytic activities of the copper sources and found that CuI is better than the others. In contrast, no product was obtained using Cu(OAc)2∙H2O, Cu(OTf)2 and CuO nanoparticles as catalyst. Control experiments confirmed that no product was obtained without the copper source.

Similarly, a series of 1c-o-substituted triazines underwent cyclization via intramolecular C-N coupling to afford the corresponding 2c-o-substituted 1-aryl-1H-benzotriazoles in 75–99%. These results clearly suggest that the protocol is simple, general and efficient for the direct synthesis of functionalized 1-aryl-1H-benzo[d][1,2,3]triazoles.

Table 1. Effect of Base on the Synthesis of 1-p-Tolyl-1H-benzo[d][1,2,3]triazole a

Synthesis of 2-(1H-Benzotriazol-1-yl)phenol: A Potassium Channel Activator

Proposed Catalytic Cycle Conclusion

Experimental Section
Characterization Data
References

The course of the reaction was monitored by TLC using ethyl acetate and hexane as eluent. After completion, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (25 ml). Drying (Na 2 SO 4 ) and evaporation of the solvent gave a residue which was purified by column chromatography on silica gel using 9:1 hexane and ethyl acetate as eluent.

The reaction mixture was then cooled to room temperature and diluted with ethyl acetate (15 mL). Drying (Na 2 SO 4 ) and evaporation of the solvent gave a residue which was purified by column chromatography on silica gel using ethyl acetate and hexane as eluent.

Palladium(II)-Catalyzed Synthesis of 1-Aryl-1H-benzotriazoles

Rhodium Catalyzed C-H Activation
Synthesis of Oxazolidinone Derivatives
Synthesis of 1H-Indole-2-carboxylates
Synthesis of Isoquinolones
C-H Amination of Chiral Sulfamate Ester
Intermolecular C-H Amination

Copper Catalyzed C-H Activation

Synthesis of 2-Substituted Benzimidazoles
Synthesis of of Pyrido[1,2-a]benzimidazoles
Synthesis of Imidazo/Benzimidazoquinazolinones
Copper(II)-Catalyzed Synthesis of 2-Arylbenzoxazoles

Palladium Catalyzed C-H Activation

Synthesis of Indazole Derivatives
Synthesis of Indole Derivatives
Synthesis of 2-Quinolinones
Synthesis of Indoline Derivatives
Synthesis of Indoline Derivatives
Synthesis of Carbazoles
Synthesis of 2-Substituted 1H-Benzo[d]imidazoles
Synthesis of Substituted 1H-Indoles
C-H Amination of N-Methoxyhydroxamic acids
C-H Amination of Alkenes and Cycloalkenes with Phthalimide
Allylic C-H Amination of Alkenes
Intramolecular C-H Amination Reaction
Allylic C-H Amination of Olefins
Synthesis of Indoline Compounds

Present Study

Synthesis of Symmetrical Phenylimino-2-phenyl-hydrazines
Synthesis of Unsymmetrical Phenylimino-2-phenyl-hydrazines
Proposed Catalytic Cycle

Buchwald and co-workers developed a copper(II)-catalyzed synthesis of benzimidazoles from amidines via C-H functionalization followed by intramolecular C-N bond formation (Scheme 6).9. Hiroya and co-workers reported a palladium(II)-catalyzed C-H activation followed by intramolecular C-H amination for the synthesis of indazole derivatives (Scheme 10).13. Hartwig and co-workers developed Pd(dba)2-catalyzed intramolecular C-H amination of oxyesters to provide substituted 1H-indoles (Scheme 19).22.

Yu and co-workers described Pd(OAc)2-catalyzed intramolecular C-H amination of N-methoxyhydroxamic acids to provide β-, γ-, and δ-lactams (Scheme 20).23. Stahl and co-workers reported a Pd(II)-catalyzed aerobic oxidative intermolecular C-H amination of unactivated alkenes and cycloalkenes with phthalimide (Scheme 21).24.

Table 1. Optimization of Reaction Conditions a

Conclusion

Characterization Data

Palladium(II)-Catalyzed Synthesis of N-Aryl Benzimidazoles

Classical Methods of Synthesis of Benzimidazoles

Cross Coupling Methods for the Synthesis of Benzimidazoles

Some of these drawbacks have been overcome by the recent development in the transition metal-catalyzed cross-coupling reactions that enable the construction of the target heterocyclic frameworks under relatively milder conditions.

Copper Catalyzed Synthesis of Benzimidazoles

Synthesis of 2-Unsubstituted N-Aryl Benzimidazoles
Synthesis of N-Alkyl Benzimidazoles
Synthesis of Sterically hindered N-Aryl Benzimidazoles
Synthesis of 2-Fluoroalkyl Benzimidazoles
Synthesis of 2-Unsubstituted N-Aryl Benzimidazoles
Synthesis of Benzimadazoles from 1,2-Dihaloarenes
Synthesis of 2-Substituted Benzimidazoles
Synthesis of Substituted Benzimidazoles
Synthesis of N-Substituted Benzimidazoles
Copper Catalyzed One-Pot Three-Component Synthesis of Benzimidazoles

Kozlowski and co-workers described a mild, efficient copper diamine-based catalytic system for the coupling of benzimidazoles with substituted arylboronic acids in good to excellent yields. Wu and co-workers reported a copper(I)-catalyzed synthesis of 2-fluoroalkylbenzimidazoles via tandem C-N cross-coupling reaction between fluorinated imidoyl chlorides and primary amines (Scheme 5).11. Meijere and colleagues developed a CuBr-catalyzed synthesis of 2-unsubstituted N-arylbenzimidazoles from 2-bromoarylisocyanides and primary amines.

The protocol proceeds via cascade addition reaction between 2-bromoarylisocyanides followed by intramolecular C-N cross-coupling to provide the corresponding N-aryl benzimidazoles (Scheme 6).12. Deng and co-workers demonstrated a CuI/N,N'-dimethylethylenediamine (DMEDA) as an efficient catalytic system for the guanidinylation of aryl iodides. The catalytic system provides ready access to readily available 1,2-substituted benzimidazoles from 1,2-dihaloarenes and guanidines in a single step (Scheme 7).13.

Peng and co-workers successfully developed a straightforward intramolecular N-arylation method to provide the benzimidazole ring system. Our group demonstrated the synthesis of benzimidazoles and 2-aminobenzimidazoles via intramolecular cyclization of 2-bromoarylamidine derivatives using CuO nanoparticles in DMSO under air. The protocol proceeds via Cu(I)-catalyzed cascade intermolecular addition followed by intramolecular C-N coupling process (Scheme 10).16.

Palladium Catalyzed Synthesis of Benzimidazoles

Synthesis of 1,2-Disubstituted Benzimidazoles
Microwave Assisted Synthesis of Benzimidazoles
Regiospecific Synthesis of N-Aryl Benzimidazoles
Synthesis of 1,2-Disubstituted Benzimidazoles

They used the combination of palladium and triphenylphosphine as a catalytic system under microwave conditions in the presence of NaOH in aqueous DME (Scheme 13).19. This protocol involves a cascade amination of 2-bromoacetanilides followed by condensation to yield the corresponding N-arylbenzimidazoles (Scheme 14).20. U and co-workers described a Pd(OAc)2-catalyzed cascade intermolecular and intramolecular amination of 1,2-dihaloarenes with guanidines that enables regiospecific and modular synthesis of a library of structurally diverse 1,2-disubstituted benzimidazoles (Scheme 15). 21 .

Cobalt Catalyzed Synthesis of Benzimidazoles

Synthesis of Substituted Benzimidazoles

C-H Activation Methods for the Synthesis of Benzimidazoles .1 Palladium Catalyzed Synthesis of Benzimidazoles

Synthesis of 2-Substituted-1H-Benzo[d]imidazoles

Copper Catalyzed Synthesis of Benzimidazoles

Synthesis of Benzimidazoles from Amidines

Synthesis of 2-Aryl-N-Benzylbenzimidazoles

Present Study

Synthesis of Substrate Precursors Symmetrical 1,3-Diarylamidines

Synthesis of Unsymmetrical 1,3-Diarylamidines

Synthesis of Unsymmetrical 1,3-Diarylbenzimidines

The protocol was also compatible for the cyclization of N,N'- bis(aryl)acetamidines and N,N'-bis(aryl)benzamidines to provide 2-substituted aryl benzimidazoles (Table 2, entries 9–16). Additionally, unsymmetrical 1o-p N,N'-bis(aryl)benzamidines having methyl and nitro groups at the p-position of one of the phenyl rings can be cyclized to give the corresponding 1,2-diaryl 2o-p benzimidazoles in 80 -82% yield.

Plausible Catalytic Cycle

References

Recrystallization of 2n and 2p in CH2Cl2 afforded crystals whose structures were unambiguously confirmed by single-crystal X-ray analysis. Pd-catalyzed aerobic C-H oxidative amination of bis(aryl)amidines has been developed to afford N-aryl benzimidazoles. The reaction provided the general route for the synthesis of 2-unsubstituted N-aryl as well as 2-substituted alkyl/-aryl benzimidazoles.

Purification of the reaction products was performed by column chromatography using Rankem silica gel mesh). The resulting white solid was triturated with cold hexane (30 mL), collected by vacuum filtration and dried in vacuo to give the symmetrical N,N'-bis(aryl)formamidines 1a-g (80-90%) as a white solid fabric. The resulting white solid was triturated with cold hexane (30 mL), collected by vacuum filtration, and dried in vacuo to provide unsymmetrical N,N'-bis(aryl)formamidine 1 h (700 mg, 39.2%) as a white solid matter.

The resulting brown viscous oil was triturated in ice-cold hexane, and the resulting white solid was triturated with cold hexane (30 mL), collected by vacuum filtration, and dried in vacuo to afford symmetrical N,N'-bis(aryl)acetamidines 1i-n (70-80%) as a white solid. The resulting yellow viscous oil was extracted with ethyl acetate (3 x 20 ml) and dried over Na 2 SO 4 . The residue was purified by column chromatography on silica gel (60-120 mesh) using hexane and ethyl acetate (1:9) as eluent to give N,N'-bis(aryl)benzamidine 1o-p (50-60%) as yellow solid.

The progress of the reaction was monitored by TLC using ethyl acetate and hexane as eluent. After the appropriate time, the reaction mixture was cooled to room temperature and water (5 ml) was added. Drying (Na2SO4) and evaporation of the solvent gave a residue which was purified by column chromatography on silica gel using hexane and ethyl acetate as eluent to yield analytically pure N-arylbenzimidazoles.

Figure 2. ORTEP diagram of the single-crystal X-ray structure of 6-Isopropyl-1-(4- 6-Isopropyl-1-(4-isopropylphenyl)-1H-benzo[d]imidazole 2n

PhI(OAc) 2 -Promoted Oxidative Synthesis of Benzo-fuzed Azoles

Metal-Free C-H Functionalization/C-N Bond Formation

Intramolecular Diamination of Olefins

Synthesis of N-Substituted Indoles via PIFA Promoted C-H Activation

Intermolecuar Oxidative C-H Amination of Unactivated Arenes

Oxidation of Oximes to Nitrile Oxides

Enantioselective Diamination of Styrenes

Synthesis of Pyrrido[2,3-b]indole Derivatives

Intramolecular Aziridation of Alkenes

Cross-Amination of Arenes

Intermolecular Amination of Arenes

Synthesis of Benzannulated Compounds

Kikugawa and co-workers showed PIFA-based cyclization of N-acylaminophthalimides for the synthesis of benzannulated 3H-benzol-3-ones and 3H-benzoxazin-3-ones from N-acylaminophthalimides containing a phenoxy group. Michael and co-workers reported a metal-free oxidative cyclization of ureas to unactivated alkenes using iodosylbenzene and a Lewis acid promoter.

Oxidative Cyclization of Urea-Tethered Alkenes with Iodosylbenzene

Spirocyclization of Amides to N-Fused Spirolactams

Synthesis of Carbazoles from 2-Aryl Enaminones

Diastereoselective Aziridazation of B(pin)-Susbstituted Ally Alcohols

Metal-Free C-H Functionalization/C-O Bond Formation

Synthesis of Oxazoles from Enamines

Spirocyclization of Phenols

Synthesis of Spirofurans

Synthesis of 3,6-Dihydro-2H-pyran-2-ones

Metal-Free C-H Functionalization/C-C Bond Formation

Synthesis of 3-Hydroxy-2-oxindoles and Spiroindoles

Synthesis of Bipyrroles

Present Study

Benzo[d]imidazo[2,1-b]benzothiazole is an interesting platform for chemists with four fused rings found in many bioactive molecules, such as antibacterial agents (Figure 1, A), and plays a key role in the imaging of β - amyloid plaques in patients with Alzheimer's disease by positron emission tomography.27 Reports indicate that these core structures can be constructed from 2-iodobenzothiaozle or 2-mercaptobenzimidazole.24b The time-consuming, tedious multi-step synthesis of the preactivated substrate precursors and the requirement of elevated temperature (≥120 °C) limit the accessibility of these classical synthetic transformations. Thus, development of a general metal-free protocol that can be effective at ambient conditions for the construction of the above-described fused heterocyclic compounds and their analogs from the easily accessible broad-substrate precursors would be valuable in drug discovery. Increasing the amount of PIDA from 2.0 equiv to 4.0 equiv led to the formation of the objective 2a in 70% yield.

Next, the scope of the procedure was examined for the reactions of a series of substituted 1,3-diarylthiourea derivatives having electron-withdrawing and electron-donating substituents on the aryl rings (Table 2). Substrates 1b and 1f-g, which have 4-ethyl, 2,4-dimethyl, and 3,4-dimethyl substituents on the aryl rings, reacted to give benzo[d]imidazo-[2,1-b]benzothiazole 2b and 2e-f at high yields (entries 1, 7 and 8). In contrast, if both aryl rings are substituted with the nitro group 1o , the formation of benzimidazole 4h was not observed.

This may be due to the greater electron deficiency of the aryl ring which may be unable to react with the electron deficient nitrogen radical intermediate that may be involved in the reaction. These experimental results suggest that the nature of the solvent, oxidant, and substituent on the aryl ring is important for the target reaction. However, 1,3-diarylselenourea derivatives with alkyl substituents such as 4-ethyl, 4-methyl, and 2,4-dimethyl substituents on the aryl rings 1v-x readily underwent the formation of tandem C-N and C-Se bonds via C-H double activations to give the corresponding one.

For example, 1,3-diaryl isothiourea derivatives 1y-ab bearing methyl and isopropyl groups on the aryl rings readily reacted to give the corresponding 2-alkylthio N-aryl benzimidazoles 4m-p in 90-97%. Homolytic cleavage of B can lead to the formation of radical C, which could undergo cyclization to give. If R = EWG, 3 can be subjected to desulfurization in the presence of PhI(OAc)2 to give N-aryl benzimidazole 4.

Figure 1. Some Examples of Biologically Active Benzfuzed Azoles.

Reaction of 1,3-Di-p-Tolylthiourea with PIDA in Presence of TEMPO

References

The latter can react with the hypervalent iodine-centered radical (III) via single electron transfer (SET) to give the cyclohexadienyl cation E. If R = EDG, product 3 can undergo further reaction with PhI(OAc) 2 via F-I intermediates to afford product 2. A general metal-free protocol was developed for the synthesis of functionalized benzo[d]imidazo[2,1-b]benzothiazoles, benzimidazol-2-thiones, N-aryl benzimidazoles, and benzo[ d]imidazo[2,1 -b]benzoselenoazole 1,3-diarylthiourea/-selenourea derivs. using PIDA under ambient conditions.

This protocol can also be used for the construction of 2-alkylthio N-aryl benzimidazoles in quantitative yield. NMR spectra were recorded on DRX-400 Varian spectrometer using CDCl3 as solvent and Me4Si as internal standard. Progress of the reaction was monitored by TLC with ethyl acetate and hexane as eluent.

Drying (Na2SO4) and evaporation of the solvent yielded a residue which was purified by silica gel column chromatography using hexane and ethyl acetate as eluent to yield analytically pure products.

Figure 2. ORTEP diagram of the single-crystal X-ray structure of 3,9-dimethyl- 3,9-dimethyl-benzo[d]imidazo[2,1-b]benzothiazole 2a

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