Formamidines lithiation

Regioselective lithiation of the formamidine 365 followed by tosylation afforded the corresponding 7-sulfone 367 which upon reaction with... 

Bicyclic structures of this type are more reactive than monocyclic or acyclic carbamates, indicating that a relatively rigid orientation of the carbonyl group is favorable to lithiation. Substituted formamidines can also be lithiated.60... 

The lithiation of 2,3-pyrrolines has received only moderate attention, but two different nitrogen protection systems have been found acceptable. Thus the terf-butylformamidine derivative metalates readily with either n-or t-butyllithium, and after reaction with a variety of electrophiles the formamidine group can be removed with hydrazine to give 2-substituted... 

Stereoselective alkylation of racemic lithiated 4- < r -butylpiperidines using formamidine or urethane activating groups is possible62. 

Meyers showed that the deprotonation of 7 displays no kinetic isotope effect - an observation consistent with rate-limiting formation of a formamidine-BuLi complex followed by deprotonation.8 A pre-lithiation complex analogous to 2 has furthermore been isolated in the formamidine series.9... 

Formamidines such as 81 may be lithiated with s-BuLi or r-BuLi and give stabilised organolithiums 82 which react with a wide range of electrophiles. Cleavage is much easier than cleavages in the amide series acidic methanolysis gives a secondary amine 83 while hydride reduction gives a tertiary amine 84.57... 

Formamidines also activate secondary centres towards lithiation, and have been used extensively in the synthesis of the benzylisoquinolines, where the lithiation takes place at a benzylic position. Formamidines bearing chiral substituents (for example the serine-derived 85) allow the introduction of asymmetry at such centres.58... 

Formamidines can also be used to promote the lithiation of vinylic centres a to nitrogen. 87 gives the organolithium 88 on treatment with r-BuLi. This is an acyl anion equivalent which adds to aldehydes to give, after hydrolysis, hydroxyketones 89.59... 

The potential for the use of the lithiated derivatives of formamidines 163 in synthesis meant they received a considerable amount of study during the 1980 s.73 75 However, only in 1991 was the question of their configurational stability finally resolved. It was already known that 166 and similar compounds had pyramidalised lithium-bearing carbon atoms75 and that they were formed by a highly diastereoselective deprotonation.73 74 However, the presence of the... 

Work in the reactions of alkyl halides with the more conventional Gilman cuprates has slackened considerably. Synthetically, alkylations have been performed employing alkynes as the second, disposable ligand in cuprates. In the transfer of vinyl groups, this allows aminomethylation or thiomethylation without the addition of HMPA or triethyl phosphite and without loss of alkene geometric integrity (equation 10)14. The addition of pentynylcopper to a-lithiated formamidines allows alkylation with primary alkyl iodides (equation ll)15. 

Although lithiated 1,2,3,4-tetrahydroisoquinoline reacts with aldehydes with little diastereoselectivity, the presence of MgBr2 dramatically enhances the selectivity. /-Isomers are obtained from 2-pivaloyl-1,2,3,4-tetrahydroisoquinoline in > % de, and a u-isomer predominantly from a formamidine. In Ae latter case, an organomagnesium reagent (3) formed by transmetalation was shown to be the reactive intermediate (Scheme 15). ... 

An interesting method for die synthesis of amines and the homologation of carbonyl compounds has been reported that utilizes the condensation of a lithiated formamidine with a carbonyl compound. 41 Typical examples are shown in Scheme 39. 

Similariy low face-selecdvity was found in die addition of lithiated formamidines of tetrahydroquin-oline, dihydroindole and p-carboline to benzaldehyde, although addition of the lithiated 3-car-boline to methyl chloropropyl ketone afforded an 8.5 1 selectivity (Scheme 48). Lithiated formamidines of pyrrolidine and piperidine also add to benzaldehyde in excellent yield, but the diastereoselectivity was not reported. ... 

Two protocols circumvent, or at least minimize, the SET processes discussed above. One is addition of HMPA to the lithiated formamidines prior to addition of the alkyl halides, while the second is transme-talation to a cuprate. Heterocycles having the C—Li bond in an allylic or benzylic position do not undergo SET at all. 

In 1981, several papers appeared detailing the alkylation of the 1-position of tetrahydroisoquinolines through the intermediacy of lithiated amides ° phosphoramides, and formamidines.- TTiese systems are discussed thoroughly in Beak s 1984 review, and so we will only provide one illustration of each in Scheme 13. 

Two asymmetric syntheses of phenethylisoquinolines have been reported. Simple exchange between isoquinoline 125 and imine 126 gave the chiral formamidine 127. Methylation of 127 with /ert-butyllithium gave the lithiated formamidine, which was alkylated with 3,4-dimethoxyphenethyl iodide and hydrazinolyzed to give the (S)-(-)-isoquinoline 128 in 95% enantiomeric excess (e.e.) (74). The e.e. of 128 was determined by chiral-column HPLC analysis, as developed by Pirkle and applied to chiral N-heterocycles and other amines (75). 

Gawley and coworkers have studied the alkylations of lithiated derivatives of aminooxazolines 53 and 4.13 [326, 400], while Meyers and co workers have developed alkylations of related derivatives of formamidines 5.4 and 4.14 [391, 392, 394, 1002, 1009], The formamidines must bear an alkoxy group (preferably /ert-BuO) on the carbon vicinal to the chiral substituent in order to observe a high asymmetric induction. The regjoselectivity of alkylations of allylic derivatives is often problematic, so the chemical yields of alkylated products formed from 53 and 5.4 are often poor. However, interesting results are obtained in alkylation of the bicyclic system 5.4 (R,R = (012)4), which is a precursor of an analgetic drug [400],... 

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