The direct conversion of carbamates to ureas using aluminum amides

Lee, Sang‐Hyuep; Matsushita, Hana; Clapham, Bruce; Janda, Kim D.

doi:10.1016/j.tet.2004.02.034

Cited by 52 publications

(18 citation statements)

References 20 publications

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“…Subsequent nucleophilic addition of the aromatic thiols 21 with ethyl chloroacetate or aralkyl chloride afforded the corresponding esters 22 and desired compounds 42–44 , respectively. The resulting esters readily underwent ester-amide exchange reaction upon treatment with substituted anilines in the presence of trimethylaluminum to afford the desired compounds 19 and 25–41 61 , 62 . Similarly, synthesis of 2,3-difuryl-quinoxaline derivatives 45 and 46 was carried out by condensation of 1,2-di(furan-2-yl)ethane-1,2-dione 23 with methyl 3,4-diaminobenzoate to provide 2,3-difuryl-quinoxaline ester 24 , which in turn was coupled with amines to provide corresponding amides 45 and 46 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Discovery of Mcl-1 inhibitors from integrated high throughput and virtual screening

Mady

Liao

Bajwa

et al. 2018

Sci Rep

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Protein-protein interactions (PPIs) represent important and promising therapeutic targets that are associated with the regulation of various molecular pathways, particularly in cancer. Although they were once considered “undruggable,” the recent advances in screening strategies, structure-based design, and elucidating the nature of hot spots on PPI interfaces, have led to the discovery and development of successful small-molecule inhibitors. In this report, we are describing an integrated high-throughput and computational screening approach to enable the discovery of small-molecule PPI inhibitors of the anti-apoptotic protein, Mcl-1. Applying this strategy, followed by biochemical, biophysical, and biological characterization, nineteen new chemical scaffolds were discovered and validated as Mcl-1 inhibitors. A novel series of Mcl-1 inhibitors was designed and synthesized based on the identified difuryl-triazine core scaffold and structure-activity studies were undertaken to improve the binding affinity to Mcl-1. Compounds with improved in vitro binding potency demonstrated on-target activity in cell-based studies. The obtained results demonstrate that structure-based analysis complements the experimental high-throughput screening in identifying novel PPI inhibitor scaffolds and guides follow-up medicinal chemistry efforts. Furthermore, our work provides an example that can be applied to the analysis of available screening data against numerous targets in the PubChem BioAssay Database, leading to the identification of promising lead compounds, fuelling drug discovery pipelines.

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Section: Resultsmentioning

confidence: 99%

Discovery of Mcl-1 inhibitors from integrated high throughput and virtual screening

Mady

Liao

Bajwa

et al. 2018

Sci Rep

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“…). HPLC reference standards were purchased from Sigma‐Aldrich with the exception of 4‐fluoro‐6‐methyl‐1‐[1‐tetrahydro‐2H‐pyran‐4‐yl)‐4‐piperidinyl]‐1,3‐dihydro‐2H‐benzimiadol‐2‐one, N , N ‐bis(phenylmethyl)urea, N , N ‐bis(1,3‐benzodioxol‐5‐ylmethyl)urea, N , N ‐bis(1‐methylethyl)urea, N ‐(1,3‐benzodioxol‐5‐ylmethyl)‐ N ‐(phenylmethyl)urea, N , N ‐dibutyl‐ N ‐(phenylmethyl)urea, N ‐(phenylmethyl)‐1‐piperidinecarboxamide, N ‐methyl‐ N , N ‐bis(phenylmethyl)urea, N , N ‐bis(2‐fluorophenyl)urea, N ‐phenyl‐1‐piperidinecarboxamide and N ‐2‐fluorophenyl‐1‐piperidinecarboxamide, which were synthesized according to the procedure below.…”

Section: Methodsmentioning

confidence: 99%

Palladium‐mediated oxidative carbonylation reactions for the synthesis of ¹¹C‐radiolabelled ureas

Kealey

Husbands

Bennacef

et al. 2013

Labelled Comp Radiopharmac

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Palladium(II)-mediated oxidative carbonylation reactions have been used to synthesize (11) C-radiolabelled ureas via the coupling of amines with [(11) C]carbon monoxide, in a one-pot process. Following trapping of (11) CO in a solution of copper(I) tris(3,5-dimethylpyrazolyl)borate, homocoupling reactions of primary aliphatic amines proceed in the presence of Pd(PPh3 )2 Cl2 to give the corresponding N,N-disubstituted [(11) C]ureas. Secondary amines do not produce the corresponding N,N,N,N-tetrasubsituted [(11) C]ureas under these conditions. This difference in reactivity allows for the formation of unsymmetrical N,N',N'-trisubstituted [(11) C]ureas using a mixture of a primary amine and a reactive secondary amine. The potential use of this method in positron emission tomography (PET) was demonstrated by the synthesis of the M1 muscarinic acetylcholine receptor radiotracer, [(11) C-carbonyl]GSK1034702.

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“…[72] Another method to mediate urea formation from carbamates is by performing the reaction in the presence of a stoichiometric amount of trimethylaluminum. [73] Under these conditions, carbamates of primary amines conventionally used as protecting groups, such as tert-butyl, benzyl, or allyl carbamates, are cleanly transformed into the corresponding ureas upon reaction with primary or secondary amines in yields of between 78 and 96% (Scheme 25). The reaction is performed at room temperature or 50 8 8C depending on whether a primary or secondary amine is used (110 8 8C in the case of diphenylamine) and is usually complete within 1.5-5 hours.…”

Section: Acyclic Unfunctionalized Ureasmentioning

confidence: 99%

“…Scheme 25 Urea Formation from Carbamates in the Presence of a Stoichiometric Amount of Trimethylaluminum[73] …”

mentioning

confidence: 99%

Acyclic and Cyclic Ureas (Update 2013)

Banert¹,

Dobbs²,

Hall³

et al. 2013

Knowledge Updates 2013/3

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The direct conversion of carbamates to ureas using aluminum amides

Cited by 52 publications

References 20 publications

Discovery of Mcl-1 inhibitors from integrated high throughput and virtual screening

Discovery of Mcl-1 inhibitors from integrated high throughput and virtual screening

Palladium‐mediated oxidative carbonylation reactions for the synthesis of ¹¹C‐radiolabelled ureas

Acyclic and Cyclic Ureas (Update 2013)

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The direct conversion of carbamates to ureas using aluminum amides

Cited by 52 publications

References 20 publications

Discovery of Mcl-1 inhibitors from integrated high throughput and virtual screening

Discovery of Mcl-1 inhibitors from integrated high throughput and virtual screening

Palladium‐mediated oxidative carbonylation reactions for the synthesis of 11C‐radiolabelled ureas

Acyclic and Cyclic Ureas (Update 2013)

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Palladium‐mediated oxidative carbonylation reactions for the synthesis of ¹¹C‐radiolabelled ureas