Tetramethylpiperidide derivatives

If desired, the potassium salt can be converted into the allyllithium derivative by metal exchange with lithium bromide46. Butyllithium/potassium 2,2,6,6-tetramethylpiperidide depro-tonates isoprene without polymerization to give 2-methylene-3-butenyllithium47. 

Recently, optically active (+)-(R)-methy 1 tolyl sulfoxide 102, R = H was alkylated with a very high diastereoselectivity136. The sulfoxide was treated with either lithium diisopropy-lamide (LDA) or lithium tetramethylpiperidide (LTMP) to form the lithio-derivative, which upon subsequent reaction with lithium a-bromomethyl acrylate gave a mixture of two diastereomers of a-methylene-y-sulfinylcarboxylic acid 103. The use of the sterically highly hindered base, LTMP, gave the product with a higher diastereoselectivity. For example, the Sc4 Rc4 ratio was 95 5 when R was the methyl group. 

As first described by Krizan and Martin,6 the in situ trapping protocol, i.e., having the base and electrophile present in solution simultaneously, makes it possible to lithiate substrates that are not applicable in classical ortho-lithiation reactions.7 Later, Caron and Hawkins utilized the compatibility of lithium diisopropylamide and triisopropyl borate to synthesize arylboronic acid derivatives of bulky, electron deficient neopentyl benzoic acid esters.8 As this preparation illustrates, the use of lithium tetramethylpiperidide instead of lithium diisopropylamide broadens the scope of the reaction, and makes it possible to functionalize a simple alkyl benzoate.2... 

The analogous dimerization of alkynes over Fe(C0)5 is not applicable, so clearly a different route towards alkynylated derivatives of 25 was needed. Comparison of 25 to cymantrene suggests that metallation of the hydrocarbon ligand should be the route of choice for the synthesis of novel substituted cyclobutadienes. In the literature, addition of organolithium bases (MeLi, BuLi) to the CO ligands with concomitant rearrangement had been observed [25]. But the utilization of LiTMP (lithium tetramethylpiperidide, Hafner [26]) or sec-BuLi as effectively non-nucleophilic bases led to clean deprotonation of the cyclobuta-... 

The easily obtainable 1,2-dihydro-2-boranaphthalene 27 can be depro-tonated by lithium 2,2,6,6-tetramethylpiperidide (LiTMP) to give the 2-boratanaphthalene 28, characterized via its derivative 29 (Scheme 5) (26). 

Thus, 5-methoxypyrimidine 103 when treated with lithium tetramethylpiperidide (LTMP) and subsequently by tosyl azide led to formation of the 2-azido derivative 104, which spontaneously undergoes ring closure to 8-methoxytetrazolo[l,5-c]pyrimidine 105. 

The formation of tluorinated Q -hydroxy-jS-imino esters (180) by treatment of fluorinated imino ethers (179) with lithium 2,2,6,6-tetramethylpiperidide has been reported. A possible explanation for this interesting intramolecular rearrangement is proposed in Scheme 64. Acyclic imides derived from primary benzylic amines and amino acid esters have been found to undergo a novel nitrogen to carbon acyl migration via a base-generated carbanion to yield the corresponding a-amino... 

Since the first reports23 in 1963 on metalation of imines, a number of bases such as ethyl-1 or isopropylmagnesium bromide1 24, lithium9 and potassium diethylamide13, lithium diisopropyl-amide (LDA), lithium 2,2,6,6-tetramethylpiperidide (LTMP)9 10,13, and lithium bis(trimethylsi-lyl)amide13 have been successfully applied in the preparation of imine-derived azaenolates. The most common of these reagents is LDA which has been applied in deprotonation reactions of the whole palette of different imines. 

Thus, starting from the (—)-(S )-a-(methoxymethyl)benzeneethanaminc derived imines at low temperatures, (S )-2-methylcycloalkanones are obtained via the -azaenolates, whereas (R)-configurated products are obtained via the thermodynamically more stable Z-azaenolates by refluxing the anion solutions prior to alkylation. However, a high degree of enantiomeric excess is obtained only under thermodynamic conditions, presumably due to different selectives in the alkylation step (see Table 3). Variation of the base (/ert-butyllithium, lithium diethylamide, lithium 2,2,6,6-tetramethylpiperidide) and additives (hexamethylphosphoric triamide) did not improve the EjZ ratio (enantiomeric excess) significantly9. 

Aldehyde imines derived from alkoxyamines are metalated by LDA (0 °C, TIIF, 1 h6 or —23 °C, THF, 0.5 h13) and by potassium diethylamide, lithium bis(trimethylsily])amide and lithium 2,2,6,6-tetramethylpiperidide (—23 °C, THF, 2-4 h)1J. Nucleophilic bases such as alkyl- and aryllithium derivatives and, in some cases, alkylmagnesium bromides add to aldehyde imines. Best enantioselectivities are achieved with lithium 2,2,6,6-tetramethylpiperidide (LTMP)13. The... 

Buflavine [41]. 8-O-Demethylbuflavine, [41]. The ability of lithium tetramethylpiperidide to selectively deprotonate the methyl group of N,N-dimethylatylamides and the in situ capture of the resulting caibanion by a silyl chloride to form a,a-brs-silyl derivatives had been put to good use in a neat synthesis [42] of buflavine (147) and 8-O-demethylbuflavine (144) (Scheme 20). The a.a-disilylamide 148, thus secured from 149, was o-metallated and thence converted, by standard synthetic operations to the boronic acid 150. 

Metalloenolates derived from a, /9 -unsaturated a-diketones undergo a cyclization reaction with lithium tetramethylpiperidide (LiTMP) to give a -hydroxycyclopente-nones, the first example of a base-induced Nazarov reaction (Scheme 51).85 If these reactions represent conrotations, they are the first such reactions to be described for enolates. 

N-Boc-4H-isoquinohne reacted quantitatively within 5 min with f-butyllithium in TMEDA to lead to the product silylated at the benzylic position.151 Another 4H-isoquinoline-type product has been silylated using lithium tetramethylpiperidide (LiTMP) in THF and the resulting compound has served as an intermediate in the synthesis of protoberberine.136,152 Interestingly, the intermediate lithium reagent did not react with the aldehyde group prior to silylation. A similar reaction has been done with the corresponding bromo derivative.153... 

In an unusual example of the epoxide moiety acting as a nucleophile, Hodgson and co-workers <02TL7895> have reported on a convenient method of deprotonating terminal oxiranes with lithium 2,2,6,6-tetramethylpiperidide (LTMP), followed by trapping of the anion with silyl-based electrophiles, to provide a,p-epoxysilanes in good yield. For example, chloro-epoxide 56 underwent clean conversion to epoxysilane 57 at 0 °C. This approach improves upon an earlier method, which employed sparteine derivatives at very low temperature (-90 °C) <01OL461>. 

The dianions of /S-enamino ketones react with a wide range of electrophiles such as alkyl halides, oxiranes, nitriles, esters, aldehydes and ketones37. Dalpozzo and coworkers reported the generation of the dianion derived from /S-enamino ketones with lithium 2,2,6,6-tetramethylpiperidide and the reaction of the dianion with nitroalkene (Scheme 24)38. The dianion underwent exclusive alkylation at the y-carbon atom to give the monoalkylated product in high yield. This reaction is useful for the introduction of a nitro group into a ketone side chain. 

Treatment of the sulfone 35 with three equivalents of butyllithium gave an intermediate selectively dimetalated at C-2 and the adjacent methyl group. Subsequent reactions of this species with aromatic or heteroaromatic esters, such as methyl thiophene-2-carboxylate, and final acid induced elimination of water, gave a series of thieno[ 3,2 -6] thiophene 1,1-dioxide systems, for example 36 <07S1827>. On the other hand, 3-methylthiophene undergoes selective deprotonation at C-5 upon treatment with lithium 2,2,6,6-tetramethylpiperidide (LiTMP), giving access to a 2,4-disubstituted thiophene derivatives <07JOC 1031>. 

Lithiation of 3-methylthiophene with lithium 2,2,6,6-tetramethylpiperidide is reported to be highly selective, giving the 5-lithio derivative <2007JOC1031>. 

The term amidolithium is the unambiguous name for the compounds RR NLi (R, R = alkyl, aryl, silyl, etc.) more often termed lithium amides. They derive their importance from the near-ubiquity of their bulkier members lithium diisopropy-lamide (LDA), lithium tetramethylpiperidide (LTMP), and lithium hexamethyldisilazide (LHMDS) in organic synthesis. Using such powerful but nonnucleophilic bases, many useful reactions may be performed, notably the enolization of ketones and esters, which can proceed both regio- and stereoselectively under kinetic control at low temperatures. ... 

BBN = 9-borabicyclo[3.3.1]nonyl cat = Catecholato cod = 1,5-cyclooctadiene coe = Cyclooctene Dur = Duryl = 2,3,5,6-tetramethylphenyl Fc = 1-ferrocenyl fc = l,l -ferrocenediyl Ipc = Isopinocampheyl (derived from (+)-a-pinene) Mes = Mesityl = 2,4,6-trimethylphenyl Np = 2-naphthyl OLED = Organic light-emitting diode Pf = Pentafluorophenyl pin = Pinacolato SCE = Standard calomel electrode thexyl = 2,3-dimethyl-2-butyl TMP = 2,2,6,6-tetramethylpiperidide tripyl = 2,4,6-tri-fro-propyl-phenyl. 

Regioselective lithiation on the benzene moiety of 4-substituted quinazolines occurs at position peri to the N1 ring nitrogen. Thus, treatment of 4-methoxyquinazolines 8 with an excess of lithium 2,2,6,6-tetramethylpiperidide (LTMP) at — 78 to 0 X followed by reaction with various electrophiles affords 8-substituted quinazoline derivatives 9. This regioselective lithiation provides easy access to a large range of substituted quinazolines which are not easily synthesized by other routes. ... 

Functionalization of the (3-position in the 1,3-dithiolane derivatives 475 was achieved via lithiation with LDA or lithium 2,2,6,6-tetramethylpiperidide (LTMP). The resulting (3-lithio derivatives were trapped with various electrophiles to form the corresponding (3-functionalized 1,3-dithiolanes 476 in 55-96% yields (Equation 57) <1998JOC6239, 1999PS689>. 

In order to introduce groups which cannot effect the elimination reaction, sterically hindered non-nucleophilic bases such as lithium diisopropylamide , lithium 2,2,4,4-tetramethylpiperidide or even t-BuO" can be used. Employing this technique, Szeimies and coworkers introduced thio and amino groups into the bridgehead position of bicyclobutane derivatives ... 

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