- Microwave-Assisted Synthesis of 2-Substituted 2-Thiazolines and 5,6-Dihydro-4 H -1,3-thiazines
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An efficient and general method for the synthesis of 2-substituted thiazolines and 5,6-dihydro-4 H -1,3-thiazines is developed via microwave-assisted ring closure of ω-thioamidoalcohols promoted by ethyl polyphosphate (PPE). The cyclization reaction involves an S N 2-type mechanism and features the advantages of very short reaction times, high yields and a predictable stereochemical outcome. The acyclic precursors are prepared in high overall yields by an improved diacylation-thionation-saponification sequence from commercially available ω-amino alcohols. The whole process is metal-free and operationally simple.
- Bisceglia, Juan A.,Kilimciler, Natalia B.,Mancinelli, Michele,Mollo, María C.,Orelli, Liliana R.
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p. 1666 - 1679
(2020/06/01)
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- Microwave-Assisted Synthesis of 2-Aryl-2-oxazolines, 5,6-Dihydro-4H-1,3-oxazines, and 4,5,6,7-Tetrahydro-1,3-oxazepines
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The first general procedure for the synthesis of 5- to 7-membered cyclic iminoethers by microwave-assisted cyclization of ω-amido alcohols promoted by polyphosphoric acid (PPA) esters is presented. 2-Aryl-2-oxazolines and 5,6-dihydro-4H-1,3-oxazines were efficiently prepared using ethyl polyphosphate/CHCl3. Trimethylsilyl polyphosphate in solvent-free conditions allowed for the synthesis of hitherto-unreported 4,5,6,7-tetrahydro-1,3-oxazepines. The method involves good to excellent yields and short reaction times.The reaction mechanism and the role of PPA esters were investigated in a chiral substrate.
- Mollo, María C.,Orelli, Liliana R.
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supporting information
p. 6116 - 6119
(2016/12/09)
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- Carboxyl activation of 2-mercapto-4,6-dimethylpyrimidine through n-acyl-4,6-dimethylpyrimidine-2-thione: A chemical and spectrophotometric investigation
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2-Mercapto-4,6-dimethylpyrimidine, as effective carboxyl activating group, has been successfully proved by converting it into respective acyl derivatives and the subsequent conversion to the amides and esters respectively using amines, amino alcohols and alcohols. The aminolysis and esterification were monitored chemically and spectrophotometrically. This paved way to establish that the above mercaptopyrimidine derivative is an efficient carboxyl activating group applicable in solid phase peptide synthesis.
- Rajan
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p. 287 - 291
(2015/01/30)
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- Ammonium nitrate: A biodegradable and efficient catalyst for the direct amidation of esters under solvent-free conditions
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A simple, metal-free, and environment-friendly procedure is developed for the direct conversion of esters to amides using ammonium nitrate as a catalyst under solvent-free conditions. Aryls, heteroaryls, and aliphatic esters are easily converted to the corresponding amides in excellent isolated yields (85-99%). An enantiopure ester and amine were both shown to react without racemization. The methodology has been successfully applied to preparation of procainamide.
- Ramesh, Perla,Fadnavis, Nitin W.
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supporting information
p. 138 - 140
(2015/02/19)
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- Carboxyl activation of 3-mercapto-5,6-diphenyl-1,2,4-triazine through N-phenylacetyl-5,6-diphenyl-1,2,4-triazine-3-thione
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The carboxyl activation ability of 3-mercapto-5,6-diphenyl-1,2,4-triazine has been established by coverting it into N-phenylacetyl-5,6-diphenyl-1,2,4-triazine-3-thione and this was then subjected to aminolysis and esterification with amines and alcohols respectively and selective aminolysis with aminoalcohols-monitoring chemically and confirmed spectrophotometrically by UV-Visible scannings. It could be proved that 3- mercapto-5,6-diphenyl-1,2,4-triazine is an efficient carboxyl activating group which can be successfully applied in solid phase peptide synthesis.
- Rajan
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p. 119 - 126
(2019/01/21)
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- Umpolung Amide Synthesis using substoichiometric N-iodosuccinimide (NIS) and oxygen AS a terminal oxidant
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Umpolung Amide Synthesis (UmAS) provides direct access to amides from an α-bromo nitroalkane and an amine. Based on its mechanistic bifurcation after convergent C-N bond formation, depending on the absence or presence of oxygen, UmAS using substoichiometric N-iodosuccinimide (NIS) under aerobic conditions has been developed. In combination with the enantioselective preparation of α-bromo nitroalkane donors, this protocol realizes the goal of enantioselective α-amino amide and peptide synthesis based solely on catalytic methods.
- Schwieter, Kenneth E.,Shen, Bo,Shackleford, Jessica P.,Leighty, Matthew W.,Johnston, Jeffrey N.
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supporting information
p. 4714 - 4717
(2015/04/27)
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- Amidation of esters with amino alcohols using organobase catalysis
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A catalytic protocol for the base-mediated amidation of unactivated esters with amino alcohol derivatives is reported. Investigations into mechanistic aspects of the process indicate that the reaction involves an initial transesterification, followed by an intramolecular rearrangement. The reaction is highly general in nature and can be extended to include the synthesis of oxazolidinone systems through use of dimethyl carbonate.
- Caldwell, Nicola,Campbell, Peter S.,Jamieson, Craig,Potjewyd, Frances,Simpson, Iain,Watson, Allan J. B.
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p. 9347 - 9354
(2014/12/11)
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- Direct synthesis of amides from carboxylic acids and amines using B(OCH2CF3)3
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B(OCH2CF3)3, prepared from readily available B2O3 and 2,2,2-trifluoroethanol, is as an effective reagent for the direct amidation of a variety of carboxylic acids with a broad range of amines. In most cases, the amide products can be purified by a simple filtration procedure using commercially available resins, with no need for aqueous workup or chromatography. The amidation of N-protected amino acids with both primary and secondary amines proceeds effectively, with very low levels of racemization. B(OCH2CF3)3 can also be used for the formylation of a range of amines in good to excellent yield, via transamidation of dimethylformamide.
- Lanigan, Rachel M.,Starkov, Pavel,Sheppard, Tom D.
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p. 4512 - 4523
(2013/06/05)
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- Organobase-catalyzed amidation of esters with amino alcohols
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A base-mediated procedure for the amidation of unactivated esters with amino alcohols is reported. Optimization and exemplification of the catalytic process are described, furnishing products in 40-100% isolated yield.
- Caldwell, Nicola,Jamieson, Craig,Simpson, Iain,Tuttle, Tell
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supporting information
p. 2506 - 2509
(2013/06/27)
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- Borate esters as convenient reagents for direct amidation of carboxylic acids and transamidation of primary amides
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Simple borates serve as effective promoters for amide bond formation with a variety of carboxylic acids and amines. With trimethyl or tris(2,2,2- trifluoroethyl) borate, amides are obtained in good to excellent yield and high purity after a simple work-up procedure. Tris(2,2,2-trifluoroethyl) borate can also be used for the straightforward conversion of primary amides to secondary amides via transamidation. The Royal Society of Chemistry 2011.
- Starkov, Pavel,Sheppard, Tom D.
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supporting information; experimental part
p. 1320 - 1323
(2011/04/23)
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- Polymer-mounted N3=P(MeNCH2CH2) 3N: A green, efficient and recyclable catalyst for room-temperature transesterifications and amidations of unactivated esters
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Merrifield resin-supported N3P(MeNCH2CH 2)3N shows excellent activity in the transesterification of higher esters such as glyceryl tribenzoate to methyl esters. The catalyst was successfully cycled 20 times (albeit with an increase in reaction time) without compromising yield up to the 20th cycle. The catalyst also showed good performance in amidation reactions of unactivated esters with amino alcohols.
- Chintareddy, Venkat Reddy,Ho, Hung-An,Sadow, Aaron D.,Verkade, John G.
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experimental part
p. 6523 - 6529
(2011/12/21)
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- Synthesis and anticonvulsant activity of N-(2-hydroxyethyl) cinnamamide derivatives
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A series of novel N-(2-hydroxyethyl) cinnamamide derivatives were synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). The MES test showed that compounds I(N-(2-hydroxyethyl) cinnamamide) and 1d ((E)-3-(3-fluorophenyl)-N-(2-hydroxyethyl)acrylamide) were found to possess better anticonvulsant activity but also had lower toxicity. In the anti-MES potency test, these compounds exhibited median effective dose (ED50) of 17.7 and 17.0 mg/kg, respectively, and median toxicity dose (TD50) of 154.9 and 211.1, respectively, resulting in a protective index (PI) of 8.8 and 12.4, respectively, which is much greater than the PI of the marked antiepileptic drug carbamazepine. To further investigate the effects of the anticonvulsant activity in several different models, compounds I and 1d were tested against convulsions induced by chemical substances, including pentylenetetrazole (PTZ), isoniazid, 3-mercaptopropionic acid, and thiosemicarbazide.
- Guan, Li-Ping,Wei, Cheng-Xi,Deng, Xian-Qing,Sui, Xin,Piao, Hu-Ri,Quan, Zhe-Shan
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experimental part
p. 3654 - 3657
(2009/12/04)
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- N-nitrosotolazoline: Decomposition studies of a typical N-nitrosoimidazoline
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N-Nitrosotolazoline (N-nitroso-2-benzylimidazoline), a N-nitrosated drug typical of N-nitrosoimidazolines, reacts readily with aqueous acid, nitrous acid, or N-acetylcysteine to produce highly electrophilic diazonium ions capable of alkylating cellular nucleophiles. The kinetics and mechanism of the acidic hydrolytic decomposition of N-nitrosotolazoline have been determined in mineral acids and buffers. The mechanism of decomposition in acidic buffer is proposed to involve the rapid reversible protonation of the imino nitrogen atom followed by slow general base-catalyzed addition of H2O to the 2-carbon of the imidazoline ring to give a tetrahedral intermediate, which is also a α-hydroxynitrosamine. Rapid decomposition of this species gives rise to the diazonium from which the products are derived by nucleophilic attack, elimination, and rearrangement. The proposed mechanism is supported by the observations of general acid catalysis, a negligible deuterium solvent kinetic isotope effect (kH/kD - 1.15) and ΔS≠ = -34 eu. In phosphate buffer at 30°C, the half-lives of N-nitrosotolazoline range from 5 min at pH 3.5 to 4 h at pH 6. The main reaction product of the hydrolytic decomposition is N-(2-hydroxyethyl)phenylacetamide. This and other products are consistent with the formation of a reactive diazonium ion intermediate. N-Nitrosotolazoline nitrosates 50 times more rapidly than tolazoline and results in a set of products derived from reactive diazonium ions but different from those produced from the hydrolytic decomposition of the substrate. N-Acetylcysteine increases the decomposition rate of N-nitrosotolazoline by 25 times at pH 7 and results in both N-denitrosation and induced decomposition to produce electrophiles. These data suggest that N-nitrosotolazoline shares the chemical properties of many known direct-acting mutagens and carcinogens.
- Loeppky, Richard N.,Shi, Jianzheng
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p. 308 - 318
(2008/12/22)
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- A diazonium ion cascade from the nitrosation of tolazoline, an imidazoline-containing drug
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Tolazoline (1-benzylimidazoline), a representative imidazoline-containing drug, reacts readily with nitrite in acetic acid to produce a complex product mixture. Fourteen compounds have been identified as products of this transformation when an 8-fold excess of HNO2 is used. The products, which include N-nitrosoamides, esters, alcohols, and phenylacetic acid, are rationalized as arising from a cascade of reactive diazonium ions. N-Nitrosotolazoline can be isolated from the nitrosation reaction in good yield when the mixture is extracted with CH2Cl2 as the transformation progresses. It nitrosates much more rapidly (50x) than tolazoline to give, among other products, the oxime [1-(N-nitroso-2-imidazolinyl) benzylidene]hydroxylamine, which can also be produced in good yield from the reaction of tolazoline with isopropyl nitrite. At low substrate and nitrite concentrations, the main reaction products are N-nitrosotolazoline, its decomposition product N-2-hydroxyethylphenylacetamide, the above-mentioned oxime, phenyl acetic acid, and 2-hydroxyethyl phenylacetate. The tolazoline nitrosation rate in three buffer systems has been determined at pH 3.4 and 37°C (kobs = 6.25 × 10-5 s-1 in 0.5 M acetate buffer with a 10 * [NO2-] = 250 mM). Because N-nitrosotolazoline exhibits the chemical properties of a direct-acting mutagen and carcinogen, we have used the rate data to estimate its level of formation at nitrite concentrations 3 mM. Cursory examination of the nitrosation chemistry of oxymetazoline, a related drug, is primarily focused at its electron-rich aromatic ring.
- Loeppky, Richard N.,Shi, Jianzheng,Barnes, Charles L.,Geddam, Sailaja
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p. 295 - 307
(2008/12/22)
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- A convenient aminolysis of esters catalyzed by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) under solvent-free conditions
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Aminolysis of esters by using the organocatalyst 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) is reported. Secondary and tertiary amides were synthesized from alkyl or aryl esters with a variety of primary and secondary amines in good to excellent yields (60-94%) under solvent-free conditions (SFC).
- Sabot, Cyrille,Kumar, Kanduluru Ananda,Meunier, Stéphane,Mioskowski, Charles
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p. 3863 - 3866
(2008/02/02)
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- N-heterocyclic carbene-catalyzed amidation of unactivated esters with amino alcohols
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(Chemical Equation Presented) A catalytic amidation of unactivated esters with amino alcohols is described. A series of solution studies in addition to the first X-ray structure of a carbene-alcohol complex support a carbene-base nucleophile activation mechanism.
- Movassaghi, Mohammad,Schmidt, Michael A.
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p. 2453 - 2456
(2007/10/03)
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- New observations on peptide bond formation using CDMT
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The optimized formation of the peptide bond by means of 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) has been found to occur rapidly and essentially quantitatively in a one-pot, one-step procedure. This new method is effective for the coupling of a variety of reactive partners, including chiral amino acids (e.g. N-acetyl-L-leucine) without significant loss of configuration. Significant racemization was observed when the typical literature conditions were used, due to the formation of an azlactone intermediate which is configurationally unstable under the reaction conditions. A simpler, precipitative workup procedure is also disclosed in this report.
- Garrett, Christine E.,Jiang, Xinglong,Prasad, Kapa,Repi?, Oljan
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p. 4161 - 4165
(2007/10/03)
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- The acid-catalysed decomposition of N-nitrotolazoline
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Reaction of tolazoline with N2O4 yields N-nitrotolazoline, the prototypical nitroamidine. N-Nitrotolazoline undergoes acid-catalysed hydrolysis of the nitroamidine function to form N-(2hydroxyethyl)phenylacetamide. The observed pseudo-first-order rate constants, k0, have a non-linear dependence upon acidity, displaying saturation at higher acide concentrations consistent with a mechanism involving equilibrium protonation of N-nitrotolazoline prior to subsequent decomposition of the protonated intermediate. Reactions are subject neither to general acid-or base-catalysis nor to catalyss by thiocyanate ion. The solvent deuterium isotope effect for protonation was found to be 0.3, and for decomposition of the protonated intermediate, 1.7. A value of (-100 ± 5) J K-1 mol-1 was determined for ΔS? for the decomposition step. Thus, hydrolysis of the protonated intermediate involves rapid attack of a molecule of water at the amidine carbon atom followed by a slow, intramolecular rearrangement involving proton transfer.
- Iley, Jim,Norberto, Fatima,Sardinha, Paula
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p. 2207 - 2209
(2007/10/03)
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- 3-ACYL-2-(N-CYANOIMINO)THIAZOLIDINES AS AN ACYLATING AGENT. PREPARATION OF AMIDES, ESTERS, AND THIOESTERS
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3-Acyl-2-(N-cyanoimino)thiazolidines proved to be powerful acylating agents.They reacted easily with amines, alcohols and thiols to give the corresponding amides, esters and thioesters in good yields.
- Iwata, Chuzo,Watanabe, Mayumi,Okamoto, Shigeha,Fujimoto, Michitaro,Sakae, Masatoshi,et al.
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p. 323 - 326
(2007/10/02)
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