LiHMDS amide

In 2002, Leadbeater and Torenius reported the base-catalyzed Michael addition of methyl acrylate to imidazole using ionic liquid-doped toluene as a reaction medium (Scheme 6.133 a) [190], A 75% product yield was obtained after 5 min of microwave irradiation at 200 °C employing equimolar amounts of Michael acceptor/donor and triethylamine base. As for the Diels-Alder reaction studied by the same group (see Scheme 6.91), l-(2-propyl)-3-methylimidazolium hexafluorophosphate (pmimPF6) was the ionic liquid utilized (see Table 4.3). Related microwave-promoted Michael additions studied by Jennings and coworkers involving indoles as heterocyclic amines are shown in Schemes 6.133 b [230] and 6.133 c [268], Here, either lithium bis(trimethylsilyl)amide (LiHMDS) or potassium tert-butoxide (KOtBu) was em-... 

Lithium bis(trimethylsilyl)amide (LiHMDS) Disilazane, 1,1,1,3,3,3-hexamethyl-, lithium salt (8) Silanamine, 1,1,1 -trimethyl-N-(trimethylsilyl)-, lithium salt (9) (4039-32-1)... 

The reaction of ethyl A-arylcarbamates 3 with l-bromo-3,3-dimethyl-2-buta-none or l-bromo-3-ethyl-3-methyl-2-pentanone 4 in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) results in the one-step synthesis of 3-aryl-5-ferf-butyl-2(3/T)-oxazolones 7 in fair to good yields (Fig. 5.2 Table 5.1, Fig. 5.3). This method is efficient for the preparation of bulky 5-substimted-2(37f)-oxazo-lones. 

LiHMDS lithium hexamethyldisilazane, lithium bis(trimethylsilyl)amide... 

EDC FDPP Fmoc HOBt LiHMDS MAMP MCPBA MeOPEG NCA NMP PAL PASP PBP PEG SASRIN TEA TFA TMAD N-Ethyl-N - [ 3 - (dimethy lamino)propy 1] -c arbodiimide hydrochloride Pentafluoro phenyldiphenyl phosphate 9 -Fluoreny lme thoxy c arbony 1 Hydroxybenzotriazol Lithium hexamethyldisilazane Merrifield, alpha methoxy phenyl resin w-Chloroperbenzoic acid Methoxy polyethylene glycol /V-Carboxv a-aminoacid anhydride /V - M e t h v 1 pyrrol i do n e Peptide amide linker Polymer assisted solution phase Penicillin-binding proteins Polyethylene glycol Super acid sensitive resin Triethylamine Trifluoroacetic acid Tetramethylamine azodicarboxylate. 

A well-defined diblock copolymer of meta- andpara-substituted poly(benz-amide) was also synthesized by this polymerization method (Scheme 97). Thus, ethyl 3-(octylamino)benzoate (26a) was polymerized with 2.2 equivalents of LiHMDS at 0 °C to give a prepolymer. A fresh feed of methyl 4-(octyl-... 

Eliminations of epoxides lead to allyl alcohols. For this reaction to take place, the strongly basic bulky lithium dialkylamides LDA (lithium diisopropylamide), LTMP (lithium tetramethylpiperidide) or LiHMDS (lithium hexamethyldisilazide) shown in Figure 4.18 are used. As for the amidine bases shown in Figure 4.17, the hulkiness of these amides guarantees that they are nonnucleophilic. They react, for example, with epoxides in chemoselective E2 reactions even when the epoxide contains a primary C atom that easily reacts with nucleophiles (see, e.g., Figure 4.18). 

Alkaline earth metal amides have a unique place in enolate chemistry in light of the preceding discussion. Yet, amides without steric demand—from NaNH2 to UNIT,—also are usually not suitable for the formation of enolates, since their nucleophilicities exceed their basicities. On the other hand, the amides LTMP, LDA, and LiHMDS (structures in Figure 4.18) are so bulky that they can never act as nucleophiles and always deprotonate C,H acids to the respective enolates. 

Table 13.4 also shows that the deprotonation of isopropanol with LiHMDS is less than half as exothermic as the deprotonations with LDA or LTMP. Hence, LiHMDS is a much weaker base than the other two amides. This is due to the ability of the SiMe3 groups of LiHMDS to stabilize the negative charge in the a-position at the N atom. The mechanism of this stabilization might be the same as in the case of the isoelectronic triphenylphosphonium center in P ylides (Figure 11.1), that is, a combination of an inductive effect and anomeric effect. Because of its relatively low basicity, LiHMDS is employed for the preparation of enolates primarily when it is important to achieve high chemoselectivity. 

SCHEME 5.20 Use of the Ireland-Claisen rearrangement in C-sialylation. BOM, benzy-loxymethyl LiHMDS, lithium bis(trimethylsilyl)amide TMS, trimethylsilyl. 

SCHEME 59. Various types of solid-state mixed aggregates involving ketone lithium enolates (A) pinacolone enolate/lithium amide [LiHMDS/CH2C(OLi)Bu-i, 2 DME]230 (B) pentan-3-one enolate/2 chiral lithium amide232 (C) pinacolone enolate/lithium amide/LiBr [LiHMDS/2 Cl HCtOI.ijBu-f/LiBr, 2 TMEDA]235... 

The same approach was used with LiSIBP and LiBnPAT, upon incremental addition of LiHMDS in THF solution, as a potential model for the study of the alkylation of chiral amide-enolate aggregates. From the average values for ATagg (respectively, 560 and 760 M 1) and the values of the ratio LmXed/ (respectively, 100 and 20), the initial alkylation was estimated to involve 40% of monomeric enolate (although it represents less than 1% of the species in solution), a situation unsuitable for asymmetric synthesis (Scheme 83)256. 

In principle, C-terminal glycine units of a peptide chain 250 can be deprotonated selectively by strong lithium bases such as LiHMDS or LDA, without affecting other a-CH groups in the peptide backbone, because these units are protected by deprotonation of the adjacent amide NHs (251). Treatment of 251 with an electrophile (EX), followed by hydrolysis, leads to the peptide chain 252, a-substituted at the C-terminal glycine unit (equation 65). 

The nucleophilicity of silyl enol ethers has been examined. Base-induced formation of the enolate anion generally leads to a mixture of (E)- and (Z)-isomers, and dialkyl amide bases are used in most cases. The (EjZ ) stereoselectivity depends on the structure of the lithium dialkylamide base, with the highest EjZ) ratios obtained with LiTMP-butyllithium mixed aggregates in THF. ° The use of LiHMDS resulted in a reversal of the (E/Z) selectivity. In general, metallic (Z) enolates give the syn (or erythro) pair, and this reaction is highly useful for the diastereoselective synthesis of these products. 

T. Tsunoda and co-workers synthesized the antipode of naturai antibiotic antimycin Asb starting from (R)-(+)-methyibenzyiamine and utiiizing the asymmetric aza-Ciaisen rearrangement. The amide precursor was deprotonated with LiHMDS at iow temperature then the reaction mixture was refluxed for several hours to bring about the sigmatropic rearrangement. 

The 6Li, 15N and 13C NMR spectra of the a-aminoalkoxide-LiHMDS mixed dimer, where LiHMDS = lithium hexamethyldisilazide, showed the presence of a pair of conformers.7 6Li and 15N couplings and 6Li, ll HOESY data gave structural information for chiral lithium amides with chelating sulfide groups, e.g. (3).8... 

Verkade was able to aminate aryl bromides and chlorides where R1 contains an acidic proton (phenol, amide, or ketone) by simply using 2.4 equiv of LiHMDS rather than the usual 1.4 equiv. NaO/-Bu.46a This procedure works well for cyclic secondary amines and anilines of all types, but gives poor yields for primary aliphatic and secondary acyclic amines. 

The preparation of the methyl ketone required for the aldol coupling reaction was accomplished by using the asymmetric alkylation of the unsaturated amide 158 according to a protocol developed by Myers [112]. Asymmetric alkylation of 158 with ethyl iodide gave 159 which was reduced to the primary alcohol (LiNH2, BH3) and protected as a PMB ether to produce, after oxidative cleavage of the olefin, the methyl ketone 160 which was converted to the trimethylsilyl enol ether 161 (LiHMDS, TMSC1) (Scheme 31). 

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