Convenient Synthesis of Structurally Novel 1,3‐Disubstituted Azetidine Derivatives

Kharul, Rajendra K.; Goswami, Amitgiri; Gite, Archana; Godha, Atul K.; Jain, Mukul; Patel, Pankaj

doi:10.1080/00397910801982340

Cited by 10 publications

(5 citation statements)

References 6 publications

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“…5, 142.3, 139.0, 138.2, 132.2, 130.8, 130.3, 130.0, 130.0, 128.5, 128.3, 127.6, 127.2, 127.1, 126.9, 78.7, 59.6, 59.0, 58.3, 51.6, 43.6, 32.5, 30.2, 15.8 300 MHz, CDCl3): δ 7.43-7.17 (m, 15H), 4.34 (s, 1H), 3.71 (s, 2H), 3.57-3.49 (m, 3H), 2.78-2.75 (m, 2H); 13 C-NMR (75 MHz, CDCl3): δ 142.3, 140.0, 128. 6, 128.5, 128.3, 127.5, 127.2, 78.6, 61.9, 51.7, 48.4 (17). Purified using 0:1 to 3:7 EtOAc / hexanes as eluent to give as an oil (208 mg, 60% yield).…”

Section: Methodsmentioning

confidence: 99%

A Single-Step Synthesis of Azetidine-3-Amines

Wang¹,

Duncton²

2020

Preprint

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<div> <p>The azetidine group is frequently encountered within contemporary medicinal chemistry where it is viewed as a privileged structure. However, the introduction of an azetidine can be synthetically challenging. Herein, a straight-forward one step synthesis of azetidine-3-amines, starting from a bench stable, commercial material is presented. The reaction tolerates functional groups commonly encountered in biological-, medicinal- and agro-chemistry, and proceeds in moderate-to-high yield with secondary amines, and moderate-to-low yield with primary amines. The methodology compares favorably to recent alternative procedures and can be utilized in “any-stage” functionalization, including late-stage azetidinylation of approved drugs and other compounds with pharmacological activity.</p> </div>

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Section: Methodsmentioning

confidence: 99%

A Single-Step Synthesis of Azetidine-3-Amines

Wang¹,

Duncton²

2020

Preprint

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“…Bis(4-bromophenyl)methanol (3d). Compound 3d was synthesized by adapting a literature method 26 from bis(4-bromophenyl)methanone (10.2 g, 30.0 mmol) and NaBH 4 (2.55 g, 67.4 mmol) in anhydrous ethanol (65 mL) at 0 °C under argon. The product 3d (9.8 g, 95% yield) was recovered as a white solid.…”

Section: ■ Experimental Methodsmentioning

confidence: 99%

Elucidation of Structural Elements for Selectivity across Monoamine Transporters: Novel 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues

Okunola-Bakare¹,

Cao²,

Kopajtic³

et al. 2014

J. Med. Chem.

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2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil, (±)-1) is a unique dopamine uptake inhibitor that binds the dopamine transporter (DAT) differently than cocaine and may have potential for the treatment of psychostimulant abuse. To further investigate structural requirements for this divergent binding mode, novel thio- and sulfinylacetamide and ethanamine analogues of (±)-1 were synthesized wherein (1) the diphenyl rings were substituted with methyl, trifluoromethyl, and halogen substituents and (2) substituents were added to the terminal amide/amine nitrogen. Halogen substitution of the diphenyl rings of (±)-1 gave several amide analogues with improved binding affinity for DAT and robust selectivity over the serotonin transporter (SERT), whereas affinity improved at SERT over DAT for the p-halo-substituted amine analogues. Molecular docking studies, using a subset of analogues with DAT and SERT homology models, and functional data obtained with DAT (A480T) and SERT (T497A) mutants defined a role for TM10 in the substrate/inhibitor S1 binding sites of DAT and SERT.

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“…14,15 The resulting 1benzhydrylazetidinazetidine-3-amine products can be easily deprotected to the parent azetidine. 16,17 In other cases, it is also possible to transform the 1-benzyhydryl protecting group directly to a carbamoyl chloride. 18 One of us has prior experience of the amine displacement reaction with compound 1, 19 and also has an interest in the azetidine group within drug discovery.…”

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confidence: 99%

“… Recently, there has been a renewed interest in the synthesis of azetidine-3-amines, by modifying ring-opening conditions of azabicyclobutane (ABB) with amine nucleophiles in a strain-release reaction. , Other approaches to azetidine-3-amines are based upon reductive amination. , Yet another synthesis of azetidine-3-amines, which has been used sporadically, is the direct displacement of an azetidine electrophile with an amine nucleophile . This approach is more frequently encountered in the patent literature, with a direct displacement of 1-benzhydrylazetidin-3-yl methanesulfonate 1 being the most frequently encountered azetidine electrophile. , The resulting 1-benzhydrylazetidine-3-amine products can be easily deprotected to the parent azetidine. , In other cases, it is also possible to transform the 1-benzyhydryl protecting group directly to a carbamoyl chloride . One of us has prior experience of the amine displacement reaction with compound 1 and also has an interest in the azetidine group within drug discovery .…”

mentioning

confidence: 99%

A Single-Step Synthesis of Azetidine-3-amines

Wang¹,

Duncton

2020

J. Org. Chem.

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The azetidine group is frequently encountered within contemporary medicinal chemistry where it is viewed as a privileged structure. However, the introduction of an azetidine can be synthetically challenging. Herein, a straightforward one step synthesis of azetidine-3-amines, starting from a bench stable, commercial material is presented. The reaction tolerates functional groups commonly encountered in biological-, medicinal-and agro-chemistry, and proceeds in moderateto-high yield with secondary amines, and moderate-to-low yield with primary amines. The methodology compares favorably to recent alternative procedures and can be utilized in "any-stage" functionalization, including late-stage azetidinylation of approved drugs and other compounds with pharmacological activity. ASSOCIATED CONTENT Supporting Information. Expanded experimental procedures and analytical data (1 H, 13 C, 19 F NMR, HPLC) for all new compounds (PDF). The Supporting Information is available free of charge on the Internet at http://pubs.acs.org.

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Convenient Synthesis of Structurally Novel 1,3‐Disubstituted Azetidine Derivatives

Cited by 10 publications

References 6 publications

A Single-Step Synthesis of Azetidine-3-Amines

A Single-Step Synthesis of Azetidine-3-Amines

Elucidation of Structural Elements for Selectivity across Monoamine Transporters: Novel 2-[(Diphenylmethyl)sulfinyl]acetamide (Modafinil) Analogues

A Single-Step Synthesis of Azetidine-3-amines

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