620-19-9Relevant articles and documents
Synthesis and evaluation of tetrahydroisoquinoline derivatives against Trypanosoma brucei rhodesiense
Cullen, Danica R.,Gallagher, Ashlee,Duncan, Caitlin L.,Pengon, Jutharat,Rattanajak, Roonglawan,Chaplin, Jason,Gunosewoyo, Hendra,Kamchonwongpaisan, Sumalee,Payne, Alan,Mocerino, Mauro
, (2021/10/07)
Human African Trypanosomiasis (HAT) is a neglected tropical disease caused by the parasitic protozoan Trypanosoma brucei (T. b.), and affects communities in sub-Saharan Africa. Previously, analogues of a tetrahydroisoquinoline scaffold were reported as having in vitro activity (IC50 = 0.25–70.5 μM) against T. b. rhodesiense. In this study the synthesis and antitrypanosomal activity of 80 compounds based around a core tetrahydroisoquinoline scaffold are reported. A detailed structure activity relationship was revealed, and five derivatives (two of which have been previously reported) with inhibition of T. b. rhodesiense growth in the sub-micromolar range were identified. Four of these (3c, 12b, 17b and 26a) were also found to have good selectivity over mammalian cells (SI > 50). Calculated logD values and preliminary ADME studies predict that these compounds are likely to have good absorption and metabolic stability, with the ability to passively permeate the blood brain barrier. This makes them excellent leads for a blood-brain barrier permeable antitrypanosomal scaffold.
N -Hydroxyphthalimide/benzoquinone-catalyzed chlorination of hydrocarbon C-H bond using N -chlorosuccinimide
Li, Zi-Hao,Fiser, Béla,Jiang, Biao-Lin,Li, Jian-Wei,Xu, Bao-Hua,Zhang, Suo-Jiang
supporting information, p. 3403 - 3408 (2019/04/01)
The direct chlorination of C-H bonds has received considerable attention in recent years. In this work, a metal-free protocol for hydrocarbon C-H bond chlorination with commercially available N-chlorosuccinimide (NCS) catalyzed by N-hydroxyphthalimide (NHPI) with 2,3-dicyano-5,6-dichlorobenzoquinone (DDQ) functioning as an external radical initiator is presented. Aliphatic and benzylic substituents and also heteroaromatic ones were found to be well tolerated. Both the experiments and theoretical analysis indicate that the reaction goes through a process wherein NHPI functions as a catalyst rather than as an initiator. On the other hand, the hydrogen abstraction of the C-H bond conducted by a PINO species rather than the highly reactive N-centered radicals rationalizes the high chemoselectivity of the monochlorination obtained by this protocol as the latter is reactive towards the C(sp3)-H bonds of the monochlorides. The present results could hold promise for further development of a nitroxy-radical system for the highly selective functionalization of the aliphatic and benzylic hydrocarbon C-H.
Mild Aliphatic and Benzylic Hydrocarbon C-H Bond Chlorination Using Trichloroisocyanuric Acid
Combe, Sascha H.,Hosseini, Abolfazl,Parra, Alejandro,Schreiner, Peter R.
, p. 2407 - 2413 (2017/03/11)
We present the controlled monochlorination of aliphatic and benzylic hydrocarbons with only 1 equiv of substrate at 25-30 °C using N-hydroxyphthalimide (NHPI) as radical initiator and commercially available trichloroisocyanuric acid (TCCA) as the chlorine source. Catalytic amounts of CBr4 reduced the reaction times considerably due to the formation of chain-carrying ·CBr3 radicals. Benzylic C-H chlorination affords moderate to good yields for arenes carrying electron-withdrawing (50-85%) or weakly electron-donating groups (31-73%); cyclic aliphatic substrates provide low yields (24-38%). The products could be synthesized on a gram scale followed by simple purification via distillation. We report the first direct side-chain chlorination of 3-methylbenzoate affording methyl 3-(chloromethyl)benzoate, which is an important building block for the synthesis of vasodilator taprostene.
Improved Halogenation of Methyl Aromatics and Methyl Heteroaromatics: Unexpected Reactivity of Tetrahalogeno-diphenylglycolurils
Moretti, Florian,Poisson, Guillaume,Marsura, Alain
, p. 173 - 183 (2016/05/19)
1,3,4,6-Tetrachloro (TCDGU) and 1,3,4,6-tetrabromo-3α,6α-diphenylglycolurils smooth halogen oxidizers have been exploited in a new direction as reagents for free radical substitution toward some N-halosuccinimide nonreactive bis-heterocycles. An unexpected selectivity and reactivity were observed with methyl benzenes, methyl heterocycles, and methyl-bis-heterocycles of interest. A chemometric study has been performed to optimize five independent factors of the chlorination reaction with TCDGU. The predictive model was established either for the halogenation conversion and the ratio of monochlorination.
Iron catalyzed halogenation of benzylic aldehydes and ketones
Savela, Risto,W?rn?, Johan,Murzin, Dmitry Yu.,Leino, Reko
, p. 2406 - 2417 (2015/04/14)
A simple and efficient iron-catalyzed method for chlorination of aromatic carbonyl compounds is reported. By using 4-10 mol% Fe(iii) oxo acetate catalyst, prepared by solid state atmospheric oxidation of Fe(ii) acetate, in combination with triethylsilane and chlorotrimethylsilane, hydrosilylation of benzylic carbonyl compounds with subsequent chlorination is achieved within a few hours at room temperature. This new method is mild and rapid compared to the conventional two step approach involving reduction and chlorination reactions in separate stages. Development of synthetic methodology is also supplemented here by kinetic investigation of the reaction mechanism, which supports the tentative mechanisms suggested previously for similar reactions. This journal is
Regiospecific chlorination of xylenes using K-10 montmorrillonite clay
Thirumamagal,Narayanasamy, Sureshbabu,Venkatesan
scheme or table, p. 2820 - 2825 (2009/05/07)
Regiospecific chlorination of xylenes has been developed by employing NCS as a reagent and K-10 montmorrillonite clay as a solid support. Copyright Taylor & Francis Group, LLC.
Efficient synthesis of tolunitriles by selective ammoxidation
Xie, Guangyong,Zheng, Qiong,Huang, Chi,Chen, Yuanyin
, p. 1103 - 1107 (2007/10/03)
Tolunitriles have been efficiently synthesized by selective ammoxidation of methylbenzyl chlorides prepared with chlorination of xylenes. In comparison with ammoxidation of xylenes themselves, the reaction temperature of ammoxidation of methylbenzyl chlorides has been lowered more than 100°C and the selectivity forming mono-nitriles is almost 100%.
Interpretation of retention indices in gas chromatography for establishing structures of isomeric products of alkylarenes radical chlorination
Zenkevich
, p. 270 - 280 (2007/10/03)
By an example of previously uncharacterized products obtained by alkylarenes radical chlorination was demonstrated that combination of various interpretation methods applied to the retention indices (RI) in the gas chromatography on the standard nonpolar phases (comparison of RI of products and initial compounds, characteristics of succession of the chromatographic elution of the structural isomers with the use of estimation of molecular dynamic parameters, application of the additive schemes to RI calculation, and using of structural analogy CH3?Cl for testing the results obtained) permitted unambiguous identification of the structure even without data of mass spectrometry.
Gas-phase substituent effects in highly electron-deficient systems. II. stabilities of 1-aryl-2,2,2-trifluoroethyl cations based on chloride-transfer equilibria
Mishima, Masaaki,Inoue, Hiroki,Fujio, Mizue,Tsuno, Yuho
, p. 1163 - 1169 (2007/10/03)
The relative stabilities of 1-aryl-2,2,2-trifluoroethyl cations were determined based on the chloride ion-transfer equilibria in the gas phase. An application of the Yukawa-Tsuno equation to this substituent effect on the equilibrium constants gave a remarkably larger r+ of 1.53 and a ρ of-10.6, supporting our previous conclusion that the highly electron-deficient benzylic carbocation systems are characterized by extremely high resonance demands. This r+ value, furthermore, conformed a linear relationship between the r+ value and the relative stability of the unsubstituted member of the respective benzylic carbocations, clearly demonstrating a continuous spectrum of varying resonance demands characteristic of the stabilities of carbocations. The π-delocalization of the positive charge into the aryl π-system increases with the destabilization of a carbocation by the α-substituent(s) linked to the central carbon. In addition, the r + value of 1.53 for 1-aryl-2,2,2-trifluoroethyl cations was found to be in complete agreement with that for the solvolysis of 1-aryl-2,2,2- trifluoroethyl tosylates in 80% aq acetone. This reveals that the r+ value observed for this solvolysis must be the intrinsic resonance demand of a highly electron-deficient cationic transition state in the SN 1 ionizing process. The identity of the r+ value was consistent with our previous observation for other benzylic carbocation systems, indicating that the degree of the π-delocalization of the positive charge is identical between the cationic transition state and an intermediate cation for all benzylic systems, which cover a wide range of reactivity and stability of the carbocation. This leads us to the conclusion that the geometry of the transition state in the ionizing process of the SN1 solvolysis, which is a highly endothermic reaction, closely resembles the high-energy product, an intermediate cation.
Electrophilic Aromatic Substitution. 13.1 Kinetics and Spectroscopy of the Chloromethylation of Benzene and Toluene with Methoxyacetyl Chloride or Chloromethyl Methyl Ether and Aluminum Chloride in Nitromethane or Tin Tetrachloride in Dichloromethane. the Methoxymethyl Cation as a Remarkably Selective Common Electrophile
Dehaan, Franklin P.,Djaputra, Markus,Grinstaff, Mark W.,Kaufman, Craig R.,Keithly, James C.,Kumar, Amit,Kuwayama, Mark K.,Dale Macknet,Na, Jim,Patel, Bimal R.,Pinkerton, Michael J.,Tidwell, Jeffrey H.,Villahermosa, Randy M.
, p. 2694 - 2703 (2007/10/03)
Vacuum line kinetics studies have been made of the reaction in nitromethane between benzene and/or toluene, methoxyacetyl chloride (MAC), and AlCl3 to produce benzyl or xylyl chlorides, CO, and a CH3OH- AlCl3 complex. For both arenes, the rate law appears to be R = (k3/[AlCl3]0) [AlCl3]2-[MAC]. When chloromethyl methyl ether (CMME) is substituted for MAC, a similar rate law is obtained. Both chloromethylation reactions yielded similar, large kT/kB ratios (500-600) and similar product isomer distributions with low meta percentages (～0.4) which suggest CH3OCH2+ or the CH3OCH2+Al2Cl7 - ion pair as a common, remarkably selective, electrophile. The kinetics of MAC decomposition to CMME and CO in the presence of AlCl3 yielded the rate law R = k2[AlCl3]0[MAC]. Here AlCl3 is a catalyst (no CH3OH is formed), and thus the rate law is equivalent to the chloromethylation rate law. All three reactions have comparable reactivities, which is consistent with rate-determining production of the electrophile. Kinetics studies of benzene or toluene with SnCl4 and MAC or CMME in dichloromethane were also completed. With MAC and benzene the rate law is R = k3[SnCl4]0[MAC][benzene] and with toluene R = k2[SnCl4]0[MAC]. MAC decomposition, again followed by CO production, was unaffected by the presence of either aromatic and obeyed the rate law R = k2′ [SnCl4]0[MAC] where k2 ≈ k2′ Chloromethylation with CMME followed the rate law R = k3[SnCl4]0[CMME][arene] for benzene and toluene and produced a kT/kB ratio and product isomer distributions very similar to those determined with AlCl3 in nitromethane, further supporting a common electrophile. Low-temperature 13C and 119Sn FT-NMR and Raman spectroscopic studies suggest the existence of a weak 1:1 adduct between MAC and SnCl4 of the type RCXO → SnCl4, with electron donation to the metal through carboxy oxygen. Finally, an explanation is provided for the range of chloromethylation kT/kB values and product isomer percentages published in the literature.
