- Manganese-Catalyzed Anti-Markovnikov Hydroamination of Allyl Alcohols via Hydrogen-Borrowing Catalysis
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Controlling the selectivity in a hydroamination reaction is an extremely challenging yet highly desirable task for the diversification of amines. In this article, a selective formal anti-Markovnikov hydroamination of allyl alcohols is presented. It enables the versatile synthesis of valuable γ-amino alcohol building blocks. A phosphine-free Earth's abundant manganese(I) complex catalyzed the reaction under hydrogen-borrowing conditions. A vast range of aliphatic, aromatic amines, drug molecules, and natural product derivatives underwent successful hydroamination with primary and secondary allylic alcohols with excellent functional group tolerance (57 examples). The catalysis could be performed on a gram scale and has been applied for the synthesis of drug molecules. The mechanistic studies revealed the metal-ligand bifunctionality as well as hemilability of the ligand backbone as the key design principle for the success of this catalysis.
- Das, Kuhali,Sarkar, Koushik,Maji, Biplab
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p. 7060 - 7069
(2021/06/30)
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- Catalytic Formal Hydroamination of Allylic Alcohols Using Manganese PNP-Pincer Complexes
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Several manganese-PNP pincer catalysts for the formal hydroamination of allylic alcohols are presented. The resulting γ-amino alcohols are selectively obtained in high yields applying Mn-1 in a tandem process under mild conditions. (Figure presented.).
- Duarte de Almeida, Leandro,Bourriquen, Florian,Junge, Kathrin,Beller, Matthias
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p. 4177 - 4181
(2021/03/26)
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- Iron-Catalyzed Anti-Markovnikov Hydroamination and Hydroamidation of Allylic Alcohols
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Hydroamination allows for the direct access to synthetically important amines. Controlling the selectivity of the reaction with efficient, widely applicable, and economic catalysts remains challenging, however. This paper reports an iron-catalyzed formal anti-Markovnikov hydroamination and hydroamidation of allylic alcohols, which yields γ-amino and γ-amido alcohols, respectively. Homoallylic alcohol is also feasible. The catalytic system, consisting of a pincer Fe-PNP complex (1-4 mol %), a weak base, and a nonpolar solvent, features exclusive anti-Markovnikov selectivity, broad substrate scope (>70 examples), and good functional group tolerance. The reaction could be performed at gram scale and applied to the synthesis of drug molecules and heterocyclic compounds. When chiral substrates are used, the stereochemistry and enantiomeric excess are retained. Further application of the chemistry is seen in the functionalization of amino acids, natural products, and existing drugs. Mechanistic studies suggest that the reaction proceeds via two cooperating catalytic cycles, with the iron complex catalyzing a dehydrogenation/hydrogenation process while the amine substrate acts as an organocatalyst for the Michael addition step.
- Ma, Wei,Zhang, Xiaohui,Fan, Juan,Liu, Yuxuan,Tang, Weijun,Xue, Dong,Li, Chaoqun,Xiao, Jianliang,Wang, Chao
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supporting information
p. 13506 - 13515
(2019/09/09)
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- Novel Multitarget-Directed Ligands Aiming at Symptoms and Causes of Alzheimer's Disease
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Alzheimer's disease (AD) is a major public health problem, which is due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity of the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both the causes and symptoms of the disease. Here, we present new multitarget-directed ligands combining pharmacophore fragments that provide a blockade of serotonin 5-HT6 receptors, acetyl/butyrylcholinesterase inhibition, and amyloid β antiaggregation activity. Compound 12 has displayed balanced activity as an antagonist of 5-HT6 receptors (Ki = 18 nM) and noncompetitive inhibitor of cholinesterases (IC50hAChE = 14 nM, IC50eqBuChE = 22 nM). In further in vitro studies, compound 12 has shown amyloid β antiaggregation activity (IC50 = 1.27 μM) and ability to permeate through the blood-brain barrier. The presented findings may provide an excellent starting point for further studies and facilitate efforts to develop new effective anti-AD therapy.
- Wi?ckowska, Anna,Wichur, Tomasz,Godyń, Justyna,Bucki, Adam,Marcinkowska, Monika,Siwek, Agata,Wi?ckowski, Krzysztof,Zar?ba, Paula,Knez, Damijan,G?uch-Lutwin, Monika,Kazek, Grzegorz,Latacz, Gniewomir,Mika, Kamil,Ko?aczkowski, Marcin,Korabecny, Jan,Soukup, Ondrej,Benkova, Marketa,Kie?-Kononowicz, Katarzyna,Gobec, Stanislav,Malawska, Barbara
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p. 1195 - 1214
(2018/05/25)
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- Catalytic Asymmetric Synthesis of N-Chiral Amine Oxides
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Direct asymmetric synthesis of N-chiral amine oxides was accomplished (up to 91:9 e.r.) by means of a bimetallic titanium catalyst. A hydroxy group situated at the γ-position of the N stereocenter enables the desired N-oxidation through dynamic kinetic resolution of the trivalent amine substrates. The method was further extended to the kinetic resolution of racemic γ-amino alcohols with a preexisting stereocenter, giving an important class of enantioenriched (up to 99.9:0.1 e.r.) building blocks that are otherwise difficult to synthesize.
- Bhadra, Sukalyan,Yamamoto, Hisashi
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supporting information
p. 13043 - 13046
(2016/10/30)
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- Structure-activity relationships of new 1-substitutedmethyl-4-[5-(N-methyl- N-propylamino)pentyloxy]piperidines and selected 1-[(N-substituted-N-methyl)-3- propyloxy]-5-(N-methy-l-N-propyl)-pentanediamines as H3-antagonists
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Novel, potent non-imidazole histamine H3 receptor antagonists have been prepared and in vitro tested as H3-receptor antagonists (the electrically evoked contraction of the guinea-pig jejunum). The present compounds contain a 4-hydroxypiperidine core, which behaves as a conformationally restricted version of the 3-amino-1-propanol moiety common to the many previously described non-imidazole H3 ligands. Detailed structure-activity studies revealed that 1-(2-benzofuranylmethyl)- 5c (pA 2 = 8.47 ± 0.05) and 1-(3-benzofuranylmethyl)-4-[5-(N-methyl- N-propyl)pentyloxy]piperidine 5d (pA2 = 8.15 ± 0.07) exhibit high potency for the H3 histamine receptor. In addition, the potency of selected 1-[(N-substituted-N-methyl)-3-propyloxy]-5-(N-methyl-N-propyl) pentanediamines as antagonist of the H3 histamine receptor was also evaluated. Replacement of the 4-hydroxypiperidine of the leads 7 and 5c by a highly flexible 3-(methylamino)propyloxy chain yields compounds 6a (pA 2 = 8.02) and 6b (pA2 = 6.23) with higher and lower potency than their piperidine analogues (7, pA2 = 7.79; 5c, pA 2 = 8.47), respectively. The histaminergic H1 antagonism of selected compounds 5c, 5d and 6a has been established on the isolated guinea-pig ileum by conventional methods; the pA2 values have compared with the potency of pyrilamine. None of them showed any H 1-antagonistic activity (pA2 2 = 8.5). The present compounds contain a 4-hydroxypiperidine core, which behaves as a conformationally restricted version of the 3-amino-1-propanol moiety common to the many previously described non-imidazole H3 ligands. Detailed structure-activity studies revealed that 1-(2-benzofuranylmethyl)- 5c (pA2 = 8.47 ± 0.05) and 1-(3-benzofuranylmethyl)-4-[5-(N-methyl-N-propyl)pentyloxy]piperidine 5d (pA2 = 8.15 ± 0.07) exhibit high potency for the H3 histamine receptor. Replacement of the 4-hydroxypiperidine of the leads 7 and 5c by a highly flexible 3-(methylamino)propyloxy chain yields compounds 6a (pA2 = 8.02) and 6b (pA2 = 6.23) with higher and lower potency than their piperidine analogues (7, pA2 = 7.79; 5c, pA 2 = 8.47), respectively.
- Maslowska-Lipowicz, Iwona,Walczynski, Krzysztof
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p. 106 - 118
(2014/01/17)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF 4-(N, N-DISUBSTITUTEDAMINO) BUTYRALDEHYDE ACETALS
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The invention disclosed in this application relates to an improved process for the preparation of compounds of formula (I): R1R2NCH2CH2CH2CH(OR3)2; wherein, R1 = R2 = C1-C16 alkyl; C3-C7 cycloalkyl; R1 = C1-C16 alkyl; R2 = C3-C7 cycloalkyl; NR1R2 = pyrrolidino, piperidino, morpholino, thiomorpholino, R1 = C1-C6 alkyl; R2 = ArCH2; Ar =4-R4-C6H4-, R4 = MeO, EtO, Me, Et, NMe2, NEt2, SMe, SEt, etc; R3=C1-C6 alkyl; C3-C7 cycloalkyl which comprises: (i) Reacting 3-(N, N-disubstitutedamino)propyl halide of formula (XXI): R1R2NCH2CH2CH2X; wherein, R1, R2 = as defined above, X = C1 or Br, with magnesium in the presence of a solvent to get the Grrgnard reagent 3-(N, N-disubstitutedamino)-propylmagnesium halide; (ii) Reacting the resulting 3-(N, N-disubstitutedamino) propylmagnesium halide (Grignard reagent) with the trisubstituted orthoformate of formula (XVII): HC(OR5)(OR3)2; wherein, R3 and R5 is same or different and represent C1 to C6 alkyl, C3 to C7 cycloalkyl OR R3 is as defined above and R5 represents phenyl radical; (iii) Filtering off the resultant reaction mixture and distilling the filtrate to isolate the compound of the formula (I). These substituted butyraldehyde derivatives of the formula (I) are very important building blocks for the synthesis of various tryptamine derivatives. In particular 4-(N, N-dimethylamino)butyraldehyde dimethyl or diethyl acetals are crucial intermediates for the synthesis of commercially available anti-migraine drugs, like sumatriptan, zolmitriptan, and rizatriptan.
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- Diesters of carbonic acid endowed with antiviral and anti-inflammatory activity
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Diesters of carbonic acid disubstituted with primary, secondary or tertiary amine groups, pharmaceutically acceptable salts thereof, and their use as antiviral and inti-inflammatory agents.
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- Omega-quaternary ammonium alkyl esters and thioesters of acidic nonsteroidal antiinflammatory drugs
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Quaternary ammonium alkyl esters and thioesters of acidic nonsteroidal anti-inflammatory drugs (NSAIDs) are disclosed. These esters and thioesters display the anti--inflammatory profile of the parent NSAIDs with greatly reduced gastrointestinal irritancy, providing a more favorable separation of therapeutic activity and toxicological side effects than the parent NSAIDs.
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