Lithium 2,2,6,6-tetramethylpiperidide LTMP

The metallation, especially the lithiation, of pyridazines, mentioned briefly in CHEC-II(1996) <1996CHEC-11(6)1 >, has been developed extensively since 1995 by Queguiner and co-workers for the derivatization of pyridazines and benzopyridazines. The bases of choice are usually lithium 2,2,6,6-tetramethylpiperidide (LTMP) and lithium diisopropylamide (EDA). Special efforts have been made to achieve regioselective lithiations. 

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. 

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... 

Although the regioselectivity of the alkylation reaction is independent of the nature and the steric bulk of the electrophile, it is dependent on the steric bulk of the base used for deprotonation. Lithium diisopropylamide (LDA) is superior for endo deprotonation, whereas exo dcprotonation is best achieved with the sterically hindered lithium 2,2,6,6-tetramethylpiperidide (LTMP)11,16. 

As can be seen in the Table, lithium diisopropyl amide (IDA) is a satisfactory hase in cases where the carbon group (R) of a methyl ketone (RCOCH3) either is bulky or does not contain an a-roethylene or a-methine group. In the other cases, LDA is relatively ineffective. In such cases, however, the use of lithium 2,2,6,6-tetramethylpiperidide (LTMP) in place of LDA gives satisfactory results. The LTMP procedure appears to be the only documented method that is satisfactory for the conversion of the above-mentioned type. 

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>. 

Vinyl epoxides can also be ring-opened via an Sn2 sense, as exemplified in the macrocyclization of the epoxy-tethered cyclopentenone 76, which was induced to occur by treatment with lithium 2,2,6,6-tetramethylpiperidide (LTMP) followed by the mild Lewis acid diethylaluminum chloride in THF. The enolate attacked exclusively from the a-position of the... 

This asymmetric induction is strongly affected by the base. Asymmetric methylation of 32 occurred with retention of configuration when lithium 2,2,6,6-tetramethylpiperidide (LTMP) or LDA was used, while inversion of configuration was observed with potassium hexamethyldisilazide (KHMDS)... 

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. ... 

Quinoxalines bearing or//io-metalation directing 2-substituents react with lithium 2,2,6,6-tetramethylpiperidide (LTMP) to produce 2-substituted 3-lithioquinoxalines, which subsequently react with 7V-methoxy-7V-methylbenzamide to give 3-substituted 2-benzoylquinoxalines 20. ... 

In the enolization of 3-pentanone by lithium 2,2,6,6-tetramethylpiperidide (LTMP), kinetic ElZ selectivity normally obtained in THF at low temperature is only about 5 1, whereas in the presence of 0.3-0.4 equiv. LiCl, this ratio increases to 50-60 1. Surprisingly, with large quantities of LiCl (1 equiv.), the selectivity returned to ca 10 1 (Sch. 12) [46],... 

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>. 

The dihydro-1,2-azaboroles 4 <1996CHEC-II(3)753>, 2,5-dihydro-l,2-oxaboroles 14 <20040M5088>, and dihydro-1,2-thiaboroles 19-21 <20000M4681, 20000M4935> can be deprotonated by strong, bulky bases as in Equation (6), the most widely used bases being lithium diisopropylamide (LDA), lithium 2,2,6,6-tetramethylpiperidide (LTMP), and KN(SiMe3)2. 

Trimethylsilylcarbene can be generated in solution via a-elimination (Method B) from (chloro-methyl)trimethylsilane with lithium 2,2,6,6-tetramethylpiperidide (LTMP) (see Houben-Weyl Vol. E19b, p 1412). " The generation of this carbene in the presence of an alkene leads selectively to the corresponding cyclopropane 9. Although the yields of the reactions with several cyclic or acyclic alkenes are rather modest (23-33%), these cyclopropanations proceed stereo-specifically and with high diastereoselectivity (Table 1). 

The anion of 3-alkoxycarbonyl-3 f-azepines exhibits a reaction that is an allyl anion to cyclopropyl anion rearrangement (see Section 2.3.1.2.) and is also formally an azacyclohep-tatriene to azanorcaradiene rearrangement with an additional alkoxycarbonyl shift. Treatment of 13 (X-ray analysis) with lithium 2,2,6,6-tetramethylpiperidide (LTMP), followed by iod-omethane, provides 14 (X-ray analysis of picrate) in 50-60% yield. The mechanism as suggested by the authors is shown on the following page. 

Elimination followed by nucleophilic addition to a strained C-C double bond was the main reaction sequence observed when a 1 3 mixture of (2-bromo-5-methyltetracy-clo[3.2.0.0 . 0 ]hept-l-yl)methanol and (7-bromo-5-methyltetracyclo[3.2.0.0 .0 ]hept-l-yl)methanol was allowed to react with a large excess of lithium aziridide. The main product, identified as 2-(aziridin-l-yl)-5-methyltetracyclo[3.2.0.0 -. 0" ]hept-l-yl methanol (13) and isolated in 21% yield, most likely results from aziridide attack on the intermediate lithium 5-methyltetracyclo[3.2.0.0 .0" ]hept-2(7)-en-l-yl)methoxide at C2. ° The other main product, 3-(aziridin-l-yl)-l-methyl-4-oxatetracyclo[4.3.0.0 .0 ]nonane (14), which was isolated in 15% yield, conceivably originates from the same intermediate as outlined above. Acyclo-propene intermediate was probably also formed when l-chloro-5-methyl-exo-6-phenyl-3-oxabicyclo[3.1.0]hex-2-one reacted with lithium 2,2,6,6-tetramethylpiperidide (LTMP) and gave 5-methyl-e.vo-6-phenyl-l-(2,2,6,6-tetramethyl-l-piperidyl)-3-oxabicyclo[3.1.0]hex-2-one (15) in 66% yield. 

These techniques will be discussed in Section 9.2, but an example is conversion of 3-pentanone to a 77 23 mixture of ( )- and (Z)-enolates by reaction with lithium diisopropylamide. When the enolate was formed by treatment with lithium 2,2,6,6-tetramethylpiperidide (LTMP), only slightly greater amounts of the ( ) -enolate were observed (86 14 E/Z). Addition of HMPA) to this reaction medium, however, led to a reversal of selectivity, favoring the (Z)-enolate (8 92). Under the best conditions, this ( /Z)-mixture will lead to a similar mixture of diastereomers in the products formed by reaction of the enolates. Some isomerization can occur in the deprotonation or condensation steps, and the product may isomerize under the reaction conditions. ... 

This section treats the lithiation of 1,2,3-triazines by lithium 2,2,6,6-tetramethylpiperidide (LTMP). The theoretical aspects of H/Li-exchange, especially for alkoxytriazines, have been discussed in Section 9.01.2.13, and the option to bypass the reluctance of 1,2,3-triazines to undergo electrophilic substitution by lithiation, followed by quenching with electrophiles, has been pointed out in Section 9.01.5.3. 

A hindered Hthium amide such as lithium 2,2,6,6-tetramethylpiperidide (LTMP) has proved to be effective in triggering a direct intramolecular cyclopropanation of the unsaturated terminal epoxide 31 to the tricycHc alcohol 32 (2010JOC2157). This strategy has been used successfully in a concise synthesis of (—)-cubelol (33) from (—)-menthone. Similarly, the naturally occurring (—)-10-epicubelol (34) can be prepared from (+)-menthone. Interestingly, whatever is the stereochemistry of the tethered alkene, the facial selectivity of cyclopropanation is controlled solely by the epoxide stereochemistry (Scheme 8). 

Robinson annulation although not extensively has been used in synthetic routes toward complex carbohydrate structures such as in the synthesis of 82. The starting ketone 80 reacts with (trimethylsilyl)but-3-en-2-one at -78 °C in the presence of lithium 2,2,6,6-tetramethylpiperidide (LTMP) base to give the alcohol 81. The a-methyl inverts to the axial position. The alcohol then produces the Robinson annulation adduct 82 in the presence of catalytic amount of methanolic potassium hydroxide in 58% yield. 

Nonnucleophibc (sterically hindered) lithium amides can be prepared by the simple reaction of the corresponding amines with -BuLi in nonpolar organic solvents (Fig. 26.3). Lithium amides are more soluble in hydrocarbons than their heavier element congeners (Na, K). LiN(i-Pr)j (LDA) is also cheaper than KN(/-Pr)2 (KDA) and is more widely used. Lithium amides, which have a much lower Lewis acid character than alkyllithiums, also form aggregates in solution [26-28]. They usually react under thermodynamic control according to a classic acid-base mechanism. The p a of diisopropylamine is 36 [8]. Lithium 2,2,6,6-tetramethylpiperidide (LTMP) is slightly more basic... 

Preparative Methods prepared in situ by lithiation of trimethylsi-lyldiazomethane using n-butyllithium prepared in situ by lithiation of trimethylsilyldiazomethane (TMSCHN2) using butyllithium, lithium diisopopylamide (LDA), or lithium 2,2,6,6-tetramethylpiperidide (LTMP). The lithium salt is easily converted to the corresponding magnesium bromide salt (eq 1). 

Furthermore, Vedso and Begtrup have demonstrated that ortho-lithiation, in situ borylation using lithium 2,2,6,6-tetramethylpiperidide (LTMP) in combination with triisopropylborate, is highly efficient and represents an experimentally straightforward preparation of ortho-substituted arylboronic esters such as 3 [4]. The mild reaction conditions allow the presence of functionalities such as ester or cyano groups or halogen substituents that are usually not compatible with the conditions used in directed metallation of arenes (Scheme 3.2). 

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