Lithium diisopropylamide-Hexamethylphosphoric triamide

GABA HMG-CoA HMPA HT LDA LHMDS LTMP NADH NBH NBS NCS NIS NK NMP PMB PPA RaNi Red-Al RNA SEM SnAt TBAF TBDMS TBS Tf TFA TFP THF TIPS TMEDA TMG TMP TMS Tol-BINAP TTF y-aminobutyric acid hydroxymethylglutaryl coenzyme A hexamethylphosphoric triamide hydroxytryptamine (serotonin) lithium diisopropylamide lithium hexamethyldisilazane lithium 2,2,6,6-tetramethylpiperidine reduced nicotinamide adenine dinucleotide l,3-dibromo-5,5-dimethylhydantoin A-bromosuccinimide A-chlorosuccinimide A-iodosuccinimide neurokinin 1 -methyl-2-pyrrolidinone para-methoxybenzyl polyphosphoric acid Raney Nickel sodium bis(2-methoxyethoxy)aluminum hydride ribonucleic acid 2-(trimethylsilyl)ethoxymethyl nucleophilic substitution on an aromatic ring tetrabutylammonium fluoride tert-butyldimcthyisilyl fert-butyldimethylsilyl trifluoromethanesulfonyl (triflyl) trifluoroacetic acid tri-o-furylphosphine tetrahydrofuran triisopropylsilyl A, N,N ,N -tetramethy lethylenediamine tetramethyl guanidine tetramethylpiperidine trimethylsilyl 2,2 -bis(di-p-tolylphosphino)-l,r-binaphthyl tetrathiafulvalene... 

This important synthetic problem has been satisfactorily solved with the introduction of lithium dialkylamide bases. Lithium diisopropylamide (LDA, Creger s base ) has already been mentioned for the a-alkylation of acids by means of their dianions1. This method has been further improved through the use of hexamethylphosphoric triamide (HMPA)2 and then extended to the a-alkylation of esters3. Generally, LDA became the most widely used base for the preparation of lactone enolates. In some cases lithium amides of other secondary amines like cyclo-hexylisopropylamine, diethylamine or hexamethyldisilazane have been used. The sodium or potassium salts of the latter have also been used but only as exceptions (vide infra). Other methods for the preparation of y-Iactone enolates. e.g., in a tetrahydrofuran solution of potassium, containing K anions and K+ cations complexed by 18-crown-6, and their alkylation have been successfully demonstrated (yields 80 95 %)4 but they probably cannot compete with the simplicity and proven reliability of the lithium amide method. 

Tricyclic lactams, such as exo- and c r/n-3a,4,7,7a-tetrahydro-4,7-methano-2-phenyl-1 //-isoin-dolc-1,3(2//)-dione (4), have been transformed into their dianions by treatment with slightly more than two equivalents of lithium diisopropylamide in tetrahydrofuran, sometimes with hexamethylphosphoric triamide as cosolvent. Alkylation with iodomethane or the bifunctional 1,4-dibromobutane leads to dialkylated products2. 

The regioselectivity of the latter reaction is strongly dependent on the base used for deprotonation. Thus, reaction with lithium diisopropylamide in tetrahydrofuran/hexamethylphosphoric triamide results in selective endo metalation23 and leads to the bicyclic product 10. 

Intramolecular cyclization of 6-(mesyloxymethyl)bicyclo[4.4.0]dcc-l-cn-3-one using lithium diiso-propylamide produced almost exclusively the y-alkylation product tricyclo[5.3.1.01,6]undec-5-en-4-one (17), together with a trace amount of the 2-alkylation product tricyclo[5.3.1 016]undec-5-en-8-one (18).17 Surprisingly, the a-alkylation product 18 was the major product when the cyclization was carried out using potassium tert-butoxide.17 The preference for y-alkylation over a-alkylation can be rationalized by the Hammond postulate which favors y-alkylation due to the less reactant-like transition state when lithium diisopropylamide is used. Alternatively, when potassium /ert-butoxide and 18-crown-6 in hexamethylphosphoric triamide is used, the reactivity of the enolate anion is significantly enhanced. As a result, the transition state becomes reactant-like so that a-alkylation is the predominant process.17... 

BASF AG CRBPII dba DBN DBU DIBAL-H DMAP DMF DMF-DMA DMPU HMDS HMPA HMPT H-LR LDA LDE LRAT MCPBA MOM NMO NMP PCC PhH = Badische Anilin- Soda Fabrik AG = cellular retinol-binding protein type II r dibenzylideneacetone = 1,5-diazabicyclo[4.3.0]non-5-ene = l,8-diazabicyclo[5.4.0]undec-7-ene = diisobutylaluminium hydride = 4-dimethylaminopyridine = A V-dimethylformamide = A,V-dimethylformamide, dimethylacetal = 1,3 -dimethyl-3,4,5,6-tetrahydro-2( 1H)-pyrimidone = hexamethyldisilazane = hexamethylphosphoramide = hexamethylphosphorous triamide = Hoffmann-La Roche = lithium diisopropylamide = lithium diethylamide = lecithin retinol acyltransferase = m-chloroperbenzoic acid = methoxymethyl = iV-methylmorpholine oxide = l-methyl-2-pyrrolidinone = pyridinium chlorochromate = benzene... 

Lithium diisopropylamide, 257 Lithium hexamethyldisilazide, 257 Lithium hydride, 165 Lithium N-isopropylcyclohexylamide-Hexamethylphosphoric triamide, 227 Mercuration, 174 by other metals... 

Fmoc HMPA Ipc KHMDS LDA MCPBA MEM Mes MOM MS- NBS NCS NIS (+)-NLE PCC PDC Ph3P Pht PMB PNB europium 9-fluorenylmethoxycarbonyl hexamethylphosphoric triamide isopinocamphenyl potassium hexamethyldisilazanide lithium diisopropylamide 3- chloroperoxybenzoic acid (2-methoxyethoxy)methyl mesityl methoxymethyl molecular sieves iV-bromosuccinimide iV-chlorosuccinimide iV-iodosuccinimide positive non linear effect pyridinium chlorochromate pyridinium dichromate triphenylphosphane phthaloyl 4- methoxyphenyl 4-nitrobenzyl... 

Amide Enolates. The lithium (Z)-enolate can be generated from (5)-4-benzyl-3-propanoyl-2,2,5,5-tetra-methyloxazolidine and Lithium Diisopropylamide in THF at —78 °C. Its alkylations take place smoothly in the presence of Hexamethylphosphoric Triamide with high diastereoselec-tivity (eq 3), and its Michael additions to a,(3-unsaturated carbonyl compounds are also exclusively diastereoselective (eq 4). Synthetic applications have been made in the aldol reactions of the titanium (Z)-enolates of a-(alkylideneamino) esters. ... 

Synthesis of ketones. Stork and Maldonado6 have disclosed a new synthesis of ketones from aldehydes RCHO-> RCOR. The aldehyde is first converted into the cyanohydrin and then the hydroxyl group is protected by reaction with ethyl vinyl ether to give (1). This is then converted into the anion by reaction with lithium diisopropylamide under carefully controlled conditions, The base is generated from butyl-lithium and diisopropylamine in THF and then (1) in hexamethylphosphoric triamide... 

ALKYLATION Benzyltriethylammonium chloride. n-Butyl mercaptan. Dialkylcar-bonium fluoroborates. Diethoxycarboni-um fluoroborate. Dimethylcopperhthium. Ethyl vinyl ether. Dimethylformamide dimethyl acetal. Dimethyl sulflde. Dimeth-ylsulfonium methylide. Ethyl chlorofor-mate. Hexamethylphosphoric triamide. Lithium diisopropylamide. Lithium N-iso-propylcydohexylamide. O-Methyldiben-zofuranium fluoroborate. Methyl fluoro-sulfonate. Naththalene-Sodium. Palladi-um(II) chloride. 1,2,2,6,6-Pentamethyl-piperidine. Potassium hydroxide. Silver oxide. Sodium bis-2-methoxyethoxyalu-minum hydride. Sodium hydride. Thal-lous ethoxide. 

Cbz Cp DABCO DBU DDQ (DHQD)2CLB (DHQD)2PYR DMF DME DMPU DMSO Et Fmoc HMPA ia KHMDS LDA LiHMDS Me MEM Ms NaHMDS Ph Piv PMB Pr Py (saltmen)Mn(N) benzyloxy carbonyl p 5 -cyclopentadienyl l,4-diazabicyclo[2.2.2]octane l,8-diazabicyclo[5.4.0]undec-7-ene 2,3 -dichloro-5,6-dicyanobenzoquinone dihydroquinidinyl p-chlorobenzoale (see Chart 1) dihydroquinidinyl pyrimidine (see Chart 1) dimethylformamide dimethoxyethane l,3-dimethyl-3,4,5,6-tetrahydro-2(l//)-pyrimidinone dimethylsulfoxide ethyl 9-fluorenylmethoxy carbonyl hexamethylphosphoric triamide inverse addition potassium hexamethyldisilazide lithium diisopropylamide lithium hexamethyldisilazide methyl (2-methoxy ethoxy )methyl methanesulfonyl sodium hexamethyldisilazide phenyl pivaloyl p -methoxy benzyl propyl pyridine nitrido[A,A/-(l,l,2,2-tetramethyl) bis(salicylideneaminato)]manganese (see Chart 1)... 

The formation of ( )-enolates is favored in tetrahydrofuran alone, whereas addition of metalchelating solvents such as hexamethylphosphoric triamide, A,A, /V, Ar-tetranncthylcthylenedi-amine or l,4-dimethyltetrahydro-2(l//)-pyrimidinone reverses the enolate configuration to the (Z)-product. The best seleetivities were obtained with 45% l,3-dimethyltetrahydro-2(l//)-pyrimidinone. In comparison to lithium diisopropylamide in 23% hexamethylphosphoric triamide. slightly bulkier bases, i.e., lithium hexamethyldisilanazide, have proved to be more E selective256. 

GPI Glycosyl phosphatidylinositol HMPTA Hexamethylphosphoric triamide LDA Lithium diisopropylamide Lev Levulinyl mCPBA m-Chloroperbenzoic acid MEM Methoxyethoxymethyl Ment Menthyl... 

Borabicyclo[3.3. l]nonane Butylated hydroxytoluene 3,4-Dihydro-2//-pyran Diisobutylaluminum hydride V,jV-Dimethylformamide Dimethyl sulfoxide Hexamethylphosphoric triamide Lithium aluminum hydride Lithium diisopropylamide Minimum inhibitory concentration Pyridinium chlorochromate Pyridinium dichromate S-adenosylmethionine Tetrabutylammonium fluoride tert-Butyldimethylsilyl tert-Butyldimethylsilyl chloride Tetrahydrofuran Trimethylsilyl cyanide... 

LDA = lithium diisopropylamide MCPBA = m-chloroper-benzoic acid DMF = A,A-dimethylformamide HMPA = hexamethylphosphoric triamide. 

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