Deprotonation-alkylation sequence

A deprotonation-alkylation sequence from tetrahydro-oxazolo[3,4- ]pyridin-5-ones or hexahydro-oxazolo[3,4-r ]pyridin-3-ones is an especially efficient method for diastereoselective functionalization, respectively, via the lactam enolate or... 

A versatile activating group for the removal of a-protons that are not benzylic is the carbamate fert-butoxycarbonyl, or t-Boc group, developed for this purpose by Beak and Lee in 1989. Its utility derives from the fact that the Boc group is easy to attach to a secondary amine, and easy to remove after a deprotonation/alkylation sequence. Moreover, stannylation affords a-amino-organostannanes that are themselves useful precursors of a-amino-organolithium compounds (Scheme 29) (see Section II). In a chiral pyrrolidine system, it has been shown that both deprotonation (H Li) and methylation (Li Me) occur with retention of configuration. 

The stereoelectronic effect of the RO-group is less pronounced, when bulkier electrophiles are employed (Table 3, entries 23,27,28), but is increased when the well solvating agent hexamethyl phosphorous amide (HMPA) is used as an additive 61,68). On the other hand, if one performs the deprotonation/alkylation sequence in the unpolar solvent pentane, a complete reversal of the stereochemical outcome provides the coproduct in excess (Eq. 35)61 Now a coordination of the lithium cation to the siloxy function might favour structures like 109 (or its oligomers) and cause predominant formation of cO-cyclopropanes. 

Although other deprotonated complexes are sometimes not as stable as [CpFe( 5-QMesCF )], they can be generated and used at low temperature to form the desired bonds [27e]. Using the base and electrophile in excess, the reactions can be carried out at room temperature because the deprotonated species immediately reacts with the electrophile in situ. This kind of deprotonation/alkylation sequence underpins the star and dendrimer construction described herein (vide infra). In this way, the complexes [FeCp( s-arene)][PF6] also act as proton reservoirs [33]. 

If deprotonation of a polymethylbenzene complex is carried out in the presence of an excess base and compatible electrophile such as an alkyl iodide or allyl- or benzyl bromide, the deprotonation-alkylation sequences spontaneously follow one another in situ until steric inhibition is reached. This reaction has been exploited with arene = CgMeg for the synthesis of star-shaped molecules (examples below) and living polymers and with arene = durene or mesitylene for the synthesis of dendritic cores (see for instance Chap. 21.2.2). 

The mechanism of this sequence is enlightening when contrasted with the mechanism of the formamidine auxiliary (Scheme 56). Scheme 59a illustrates the results of some deprotonation-alkylation experiments on deuteriated diastereomers. ° ° Two features of the product of these experiments were examined the diastereomer ratio and the percent deuterium incorporation. The deuterium incorporation in the product reveals that there is a preference for removal of the -proton. When deuterium is in the -position, this selectivity is opposed by the isotope effect, and the product has about half the original deuterium remaining. When deuterium is in the a-position, the selectivity for the -proton (imposed by the chiral auxiliary) and the isotope effect act in concert, and virtually all the... 

Scheme 12. Octa-alkylation, -allylation, or -benzylation of durene in high yields by a series of eight deprotonation/alkylation (or allylation or benzylation) sequences induced by the 12-electron activating group CpFe+ in a one-pot reaction under mild conditions.

Y two alkylation sequences (deprotonate, Sfj2) H3O 1 hydrolysis and heat f decarboxylation 0 ho- y ... 

The deprotonation and -alkylation sequence from 451 proceeded Without racemisation and resulted in the ketene thioaminal 452. At elevated temperature, 452 rearranged to provide thioamide 454. Proposed transition states 449 and 453 indicate that stereoelctronic effects play an important role in the reaction outcome. 

Compared with imidazol-2-yUdenes less attention has been paid to N,X-heterocychc carbenes pC = 0, S), mainly due to the instabihty of the free ligands which easily undergo dimerization processes.A probably better alternative would be to force the tautomerization of the coordinated azole ligand upon a deprotonation/protonation (or alkylation) sequence as that described earlier for N-alkyihmidazole Hgands. This method is illustrated in Scheme 36 for Mn(azole)(CO)3(bipy) (azole = oxazole, thiazole) complexes to afford the corresponding Prior to this work,... 

In the late 1970s, Enders pioneered an elegant method for ketone and aldehyde alkylation involving the use of metalated chiral hydrazones [92, 93). Extensive studies with the (S)-l-amino-2-methoxymethylpyrrolidine (SAMP, 150, Scheme 3.24) auxiliary and its enantiomer RAMP established these as superb chiral auxiliaries with numerous applications. In a typical alkylation sequence, a RAMP/SAMP hydrazine is condensed with an aldehyde or a ketone to form the corresponding hydrazone, such as 152. This can subsequently be deprotonated and the resulting enolate trapped with a variety of electrophilic reagents including alkyl halides, aldehydes, Michael acceptors, silyl triflates, and disulfides. The RAMP/SAMP hydrazine auxiliary may be removed by acidic hydrolysis or ozonolysis to reveal the alkylated... 

Oxathiane 101 is readily deprotonated using s-BuLi, and the resulting anion reacts with alkyl halides, ketones, and benzonitrile (85JOC657). The majority of work in this area, however, is due to Eliel and coworkers and has involved chiral 1,3-oxathianes as asymmetric acyl anion equivalents. In the earliest work it was demonstrated that the oxathianes 102 and 103, obtained in enantiomeri-cally pure form by a sequence involving resolution, could be deprotonated with butyllithium and added to benzaldehyde. The products were formed with poor selectivity at the new stereocenter, however, and oxidation followed by addition... 

For the C-H activation sequence, the different possibilities to be considered are shown in Scheme 5 (a) direct oxidative addition to square-planar Pt(II) to form a six-coordinate Pt(IV) intermediate and (b, c) mechanisms involving a Pt(II) alkane complex intermediate. In (b) the alkane complex is deprotonated (which is referred to as the electrophilic mechanism) while in (c) oxidative addition occurs to form a five-coordinate Pt(IV) species which is subsequently deprotonated to form the Pt(II) alkyl product. 

It is possible to deprotonate allylurethanes and to alkylate these anions re-giospecifically a to nitrogen. An application of this sequence has led to a novel synthesis of 2-butyl-4-pentylpyrrolidine (165). A salient feature of this approach is its stereoselectivity (> 95% trans), much better than the one obtained with the V-nitroso method (1 1 mixtures) (Scheme 16). 

Asymmetric alkylation. Deprotonation of (-)-l provides exclusively an (E)-enolate, which is alkylated to provide a single diastereomeric product. De-complexation by oxidation [Br, I2, Ce(IV)] in the presence of water provides the corresponding acid with the same configuration. This sequence has been used for synthesis of the drug (- )-captopril (3). In this case liberation of the acyl group in the presence of the amine provides the amide 2. 

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