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81-82-3Relevant academic research and scientific papers
First aromatic amine organocatalysed activation of α,β-unsaturated ketones
Sonsona, Isaac G.,Marqués-López, Eugenia,Gimeno, M. Concepción,Herrera, Raquel P.
, p. 12233 - 12240 (2019/08/12)
This work provides an unprecedented example of a chiral aromatic amine used to activate α,β-unsaturated ketones in asymmetric aminocatalysis. Chiral aromatic diamine VII has been efficiently employed, as a proof of concept, in the Michael addition reaction between benzylideneacetones (1a-f) and coumarins (2a-d). The reaction gives rise to warfarin derivatives 3 with promising results using this family of catalysts for the first time. The additional studies performed supported the bifunctional mode of activation of the chiral catalyst VII and the covalent nature of the interactions between the catalyst VII and benzylideneacetones 1.
Green asymmetric synthesis of Warfarin and Coumachlor in pure water catalyzed by quinoline-derived 1,2-diamines
Kucherenko, Alexander S.,Kostenko, Alexey A.,Zhdankina, Galina M.,Kuznetsova, Olga Yu.,Zlotin, Sergei G.
supporting information, p. 754 - 759 (2018/02/14)
Simple enantiomerically pure C2-symmetric quinoline (isoquinoline)-derived 1,2-diamines were synthesized from the corresponding aldehydes via stereospecific diaza-Cope rearrangement with 2,2′-(1,2-diaminoethane-1,2-diyl)diphenol (HPEN). Efficient green synthesis of both enantiomers of the anticoagulant Warfarin and rodenticide Coumachlor was achieved in an aqueous medium via the asymmetric iminium-type Michael reaction in the presence of the catalysts 8e and (ent)-8e in combination with (R)- or (S)-mandelic acid, respectively. This procedure provides high enantioselectivity (up to 91% ee), which has never been attained for these bioactive compounds with the known catalysts under aqueous conditions. Nearly optically pure Warfarin (～99% ee) was prepared via a green isolation procedure, which included acidic precipitation of the crude product from a basic aqueous solution followed by single recrystallization. Furthermore, unlike the known primary amine-derived organocatalysts, the developed aqueous catalytic system does not produce parasitic byproducts and can be recovered and reused in the asymmetric reaction.
Asymmetric synthesis of warfarin and its analogs catalyzed by C 2-symmetric squaramide-based primary diamines
Kochetkov, Sergei V.,Kucherenko, Alexander S.,Zlotin, Sergei G.
supporting information, p. 6423 - 6429 (2018/09/25)
Novel C2-symmetric N,N′-bis(2-amino-1,2-diphenylethyl)squaramides with 1,2-di(pyridin-2-yl)ethane and 1,2-diphenylethane spacer groups were designed and applied as organocatalysts in asymmetric additions of 4-hydroxycoumarin and 4-hydroxy-6-methyl-2H-pyran-2-one to α,β-unsaturated ketones. Both enantiomers of the anticoagulant warfarin and its analogs were prepared in up to 96% yield and with 96% ee. Recyclability of the developed catalysts and synthetic utility of the prepared Michael adducts for asymmetric synthesis of potential chiral medications via acylation reactions were demonstrated.
Chiral primary amino amide alcohol organocatalyst for the asymmetric Michael addition of 4-hydroxycoumarin with α,β-unsaturated ketones
Kumagai, Jun,Kohari, Yoshihito,Seki, Chigusa,Uwai, Koji,Okuyama, Yuko,Kwon, Eunsang,Nakano, Hiroto
, p. 1124 - 1134 (2015/04/27)
Chiral primary amino amide organocatalysts were designed and synthesized as new organocatalysts for the enantioselective Michael addition of 4-hydroxycoumarin with α,β-unsaturated ketones to produce chiral warfarin (up to 56% ee with up to 92% yield).
Asymmetric synthesis of warfarin and its analogues on water
Rogozińska-Szymczak, Maria,Mlynarski, Jacek
, p. 813 - 820 (2014/06/23)
The asymmetric Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones on water without organic co-solvents is reported to be catalysed by organic primary amines. The application of enantiomerically pure (S,S)-diphenylethylenediamine affords a series of important pharmaceutically active compounds in good to excellent yields (73-98%) and with good enantioselectivities (up to 76% ee) via reactions accelerated by ultrasound. In particular, our developments led to an efficient protocol for the 'solids on water' formation of the anticoagulant warfarin in both enantiomeric forms. The presented scalable and environmentally friendly organocatalytic approach affords the target drug in enantiomerically pure form.
Synthesis and characterization of novel polystyrene-supported TBD catalysts and their use in the Michael addition for the synthesis of Warfarin and its analogues
Alonzi, Matteo,Bracciale, Maria Paola,Broggi, Alessandra,Lanari, Daniela,Marrocchi, Assunta,Santarelli, Maria Laura,Vaccaro, Luigi
, p. 260 - 267 (2014/04/03)
In the search for efficient and polymeric supports for organic bases to be used in environmentally friendly media and conditions, novel polystyrene-bound 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) has been prepared and characterized. Their catalytic properties have been tested in the Michael additions of 4-hydroxycoumarin to α,β-unsaturated ketones as a representative useful process for the syntheses of 4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H- chromen-2-one (Warfarin), 4-hydroxy-3-(1-(4-nitrophenyl)-3-oxobutyl)-2H- chromen-2-one (Acenocumarol), 4-hydroxy-3-(1-(4-chlorophenyl)-3-oxobutyl) -2H-chromen-2-one (Coumachlor), and 4-hydroxy-3-(1-(4-methoxyphenyl)-3- oxobutyl)-2H-chromen-2-one. Products were obtained in high to quantitative conversion yields. The novel catalytic systems showed promising catalytic properties, and they could be all easily recovered by filtration and have been reused for three representative consecutive runs without any significant lowering of their activity.
Atom-economic synthesis of optically active warfarin anticoagulant over a chiral mof organocatalyst
Shi, Tao,Guo, Zhiwei,Yu, Huixian,Xie, Jianwu,Zhong, Yijun,Zhu, Weidong
supporting information, p. 2538 - 2543 (2013/10/21)
A novel chiral metal-organic framework (MOF) organocatalyst has been developed, based on readily available MIL-101 and the chiral primary diamine (1R,2R)-1,2-diphenylethylenediamine, by the post-synthetic modification. Over the developed chiral heterogeneous catalyst the asymmetric synthesis of (S)-warfarin with high enantioselectivity can be fulfilled on a gram-scale (2.8 g) with excellent yield (92%) at low cost, making the synthesis method an ideal alternative to existing methods. Copyright
Gas phase retro-Michael reaction resulting from dissociative protonation: Fragmentation of protonated warfarin in mass spectrometry
Zhang, Jia,Chai, Yunfeng,Jiang, Kezhi,Yang, Huameng,Pan, Yuanjiang,Sun, Cuirong
, p. 1059 - 1064 (2012/11/07)
A mass spectrometric study of protonated warfarin and its derivatives (compounds 1 to 5) has been performed. Losses of a substituted benzylideneacetone and a 4-hydroxycoumarin have been observed as a result of retro-Michael reaction. The added proton is initially localized between the two carbonyl oxygens through hydrogen bonding in the most thermodynamically favorable tautomer. Upon collisional activation, the added proton migrates to the C-3 of 4-hydroxycoumarin, which is called the dissociative protonation site, leading to the formation of the intermediate ion-neutral complex (INC). Within the INC, further proton transfer gives rise to a proton-bound complex. The cleavage of one hydrogen bond of the proton-bound complex produces the protonated 4-hydroxycoumarin, while the separation of the other hydrogen bond gives rise to the protonated benzylideneacetone. Theoretical calculations indicate that the 1, 5-proton transfer pathway is most thermodynamically favorable and support the existence of the INC. Both substituent effect and the kinetic method were utilized for explaining the relative abundances of protonated 4-hydroxycoumarin and protonated benzylideneacetone derivative. For monosubstituted warfarins, the electron-donating substituents favor the generation of protonated substituted benzylideneacetone, whereas the electron-withdrawing groups favor the formation of protonated 4-hydroxycoumarin. Copyright
Chiral primary amine tagged to ionic group as reusable organocatalyst for asymmetric Michael reactions of C-nucleophiles with α,β-unsaturated ketones
Kucherenko, Alexander S.,Siyutkin, Dmitry E.,Nigmatov, Albert G.,Chizhov, Alexander O.,Zlotin, Sergei G.
supporting information, p. 3078 - 3086 (2013/01/15)
The first primary amine-derived organocatalyst modified with an ionic group for asymmetric Michael reactions of C-nucleophiles with α,β- unsaturated ketones was synthesized. In the presence of this catalyst and an acidic co-catalyst (AcOH), hydroxycoumarin and its sulfur-containing analogue reacted with benzylideneacetone derivatives or cyclohexenone to afford the corresponding Michael adducts in high yields (up to 97%) and with reasonable enantioselectivity (up to 80%). The catalyst could be easily recovered and efficiently reused three times, afterwards, its activity and stereodifferentiating ability gradually declined. The analysis of recovered catalyst samples by ESI-MS allowed us to detect undesirable side reactions that poisoned the catalyst, and propose an approach for its reactivation. Copyright
