Heterocyclic carbanions. Synthesis of 2-substituted imidazole and benzimidazoles and of 3-substituted pyrazoles by lithiation of N-(dialkylamino)methyl heterocycles

Katritzky, Alan R.; Rewcastle, Gordon W.; Fan, Wei

doi:10.1021/jo00259a014

Cited by 58 publications

(19 citation statements)

References 3 publications

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“…In this case, the iodoalkane is completely consumed during the reaction (except for C 16 ), and the excess unreacted 1-(tetrahydropyran-2-yl)pyrazole is readily removed by heating to 55-60 C under reduced pressure (0.1-0.2 mmHg) ( Table 1: entries 11,13,15,18,20,21). In this case, the iodoalkane is completely consumed during the reaction (except for C 16 ), and the excess unreacted 1-(tetrahydropyran-2-yl)pyrazole is readily removed by heating to 55-60 C under reduced pressure (0.1-0.2 mmHg) ( Table 1: entries 11,13,15,18,20,21).…”

Section: Methods Bmentioning

confidence: 99%

Green protection of pyrazole, thermal isomerization and deprotection of tetrahydropyranylpyrazoles, and high-yield, one-pot synthesis of 3(5)-alkylpyrazoles

Ahmed

Mezei

2015

RSC Adv.

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We report a new synthetic approach that opens up the possibility of large scale, one-pot pyrazole derivatization by a wide variety of functionalities, including alkyl, halogen, hydroxyl, amino, azido, carbonyl, and organo-element (e.g., B, Si, P) groups. The approach is illustrated by the highly efficient synthesis of fourteen 3(5)-alkylpyrazoles, including the novel isopentyl-and n-hexadecyl derivatives, as well as 1,6-bis(pyrazol-3(5)-yl)hexane. The value of the new approach lies in the discovery of a green (solvent-and catalyst-free, quantitative) protection of pyrazole, followed by a high-yield lithiation/ alkylation/deprotection sequence in the same pot. For the first time, the corresponding N-tetrahydropyran-2-yl (THP) intermediates have been isolated and characterized. Thermal isomerization of the 5-alkyl-1-(THP) to the 3-alkyl-1-(THP) isomer is shown to be an advantageous, green alternative to the acid-catalyzed, sequential protecting-group switching methodology in pyrazole chemistry. The X-ray crystal structures of 1,6-bis(pyrazol-3(5)-yl)hexane and 5-n-hexadecyl-1-(tetrahydropyran-2-yl)pyrazole reveal supramolecular architectures that shine light on the remarkable affinity for water and unexpected insolubility in organic solvents of alkylene-bridged bis(pyrazoles).3(5)-Alkylpyrazoles are obtained in high yield from pyrazole by a one-pot procedure. † Electronic supplementary information (ESI) available: 1 H NMR and 13 C NMR spectra of all intermediates and nal products, CIF les for 1,6-bis(pyrazol-3(5)-yl)hexane hydrate and 5-n-hexadecyl-1-(tetrahydropyran-2-yl)pyrazole. CCDC 1040198 and 1040199. For ESI and crystallographic data in CIF or other electronic format see Scheme 1 Current strategies for the synthesis of 3(5)-alkylpyrazoles (R ¼ alkyl group).Scheme 2 Synthesis of 3(5)-alkylpyrazoles by alkylation of pyrazole (DHP ¼ 3,4-dihydro-2H-pyran; R ¼ primary alkyl group; X ¼ I or Br).24082 | RSC Adv., 2015, 5, 24081-24093This journal is

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Section: Methods Bmentioning

confidence: 99%

Green protection of pyrazole, thermal isomerization and deprotection of tetrahydropyranylpyrazoles, and high-yield, one-pot synthesis of 3(5)-alkylpyrazoles

Ahmed

Mezei

2015

RSC Adv.

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“…[342,343] Phenyllithium, phenylsodium, 2-anisylsodium, and alkali metals have also been used with varying success to metallate the 2-position, and Grignard reagents can also be formed at that position with ethylmagnesium bromide. [348,349] In addition, the benzotriazol-1-ylmethyl group can act as both a protecting and an activating group in 2-lithiation as it increases the acidity of H2. [348,349] In addition, the benzotriazol-1-ylmethyl group can act as both a protecting and an activating group in 2-lithiation as it increases the acidity of H2.…”

Section: Methods 2: Substitution By a Metalmentioning

confidence: 99%

“…[342,343] Such metallic groups are readily replaced by reaction (quenching) with alkyl and acyl halides, aldehydes and ketones, carbon dioxide, chlorotrimethylsilane, halogen sources, and reagents such as dimethylformamide (introduces a formyl group), disulfides, and tosyl cyanide. Protected benzimidazoles [with hemiaminal, [345] (dialkylamino)methyl, [349] benzyl, sulfonyl, and other suitable groups in the 1-position] are lithiated, then quenched with an electrophile before acid-catalyzed deprotection. [385] The lithiation process is outlined above (Section 12.4.4.2.1.2).…”

Section: Of Metalsmentioning

confidence: 99%

“…The reactions have to be carried out with dry apparatus and solvents, and often require specialized techniques, which are detailed in Wakefields monograph. [349] Scheme 52 shows some examples of 2-substituted benzimidazoles 104 made from 1-(hydroxymethyl)-2-lithiobenzimidazoles 103. Protected benzimidazoles [with hemiaminal, [345] (dialkylamino)methyl, [349] benzyl, sulfonyl, and other suitable groups in the 1-position] are lithiated, then quenched with an electrophile before acid-catalyzed deprotection.…”

Section: Of Metalsmentioning

confidence: 99%

See 1 more Smart Citation

Product Class 4: Benzimidazoles

Neier¹,

Bellus²

2002

Category 2, Hetarenes and Related Ring Systems

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“…In the first approach (Scheme 1, Method A), the N-1 was protected with the (N-dimethylamino)methyl group under Mannich reaction conditions [23] resulting in 2b. Then, the latter compound underwent smooth lithiation, which occurred regiospecifically at the 2-position of the imidazole ring, upon treatment with 1.6 M n-BuLi in the presence of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) in THF at À78 C, followed by electrophilic quenching with n-BuI [23,24]. Subsequent facile acidic hydrolysis of the protective group afforded the corresponding 2-butylimidazole (5b) in 85% yield.…”

Section: Chemistrymentioning

confidence: 99%

Rational design, efficient syntheses and biological evaluation of N , N ′-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers

Agelis

Resvani

Koukoulitsa

et al. 2013

European Journal of Medicinal Chemistry

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a b s t r a c tA series of symmetrically bis-substituted imidazole analogs bearing at the N-1 and N-3 two biphenyl moieties ortho substituted either with tetrazole or carboxylate functional groups was designed based on docking studies and utilizing for the first time an extra hydrophobic binding cleft of AT1 receptor. The synthesized analogs were evaluated for their in vitro antagonistic activities (pA 2 values) and binding affinities (elogIC 50 values) to the Angiotensin II AT1 receptor. Among them, the potassium (elogIC 50 ¼ 9.04) and the sodium (elogIC 50 ¼ 8.54) salts of 4-butyl-N,N 0 -bis{[2 0 -(2H-tetrazol-5-yl)biphenyl-4-yl]methyl} imidazolium bromide (12a and 12b, respectively) as well as its free acid 11 (elogIC 50 ¼ 9.46) and the 4-butyl-2-hydroxymethyl-N,N 0 -bis{[2 0 -(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (14) (elogIC 50 ¼ 8.37, pA 2 ¼ 8.58) showed high binding affinity to the AT1 receptor and high antagonistic activity (potency). The potency was similar or even superior to that of Losartan (elogIC 50 ¼ 8.25, pA 2 ¼ 8.25). On the contrary, 2-butyl-N,N 0 -bis{[2 0 -[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (27) (elogIC 50 ¼ 5.77) and 2-butyl-4-chloro-5-hydroxymethyl-N,N 0 -bis{[2 0 -[2H-tetrazol-5-yl)]biphenyl-4-yl] methyl}imidazolium bromide (30) (elogIC 50 ¼ 6.38) displayed very low binding affinity indicating that the orientation of the n-butyl group is of primary importance. Docking studies of the representative highly active 12b clearly showed that this molecule has an extra hydrophobic binding feature compared to prototype drug Losartan and it fits to the extra hydrophobic cavity. These results may contribute to the discovery and development of a new class of biologically active molecules through bis-alkylation of the imidazole ring by a convenient and cost effective synthetic strategy.

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Heterocyclic carbanions. Synthesis of 2-substituted imidazole and benzimidazoles and of 3-substituted pyrazoles by lithiation of N-(dialkylamino)methyl heterocycles

Cited by 58 publications

References 3 publications

Green protection of pyrazole, thermal isomerization and deprotection of tetrahydropyranylpyrazoles, and high-yield, one-pot synthesis of 3(5)-alkylpyrazoles

Green protection of pyrazole, thermal isomerization and deprotection of tetrahydropyranylpyrazoles, and high-yield, one-pot synthesis of 3(5)-alkylpyrazoles

Product Class 4: Benzimidazoles

Rational design, efficient syntheses and biological evaluation of N , N ′-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers

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