Carbamates deprotonation

In comparison to other vinylic compounds , the vinyl proton in 1-alkenyl carbamates, deprotonation has a very high kinetic acidity . After protection of the 4-hydroxy group in the homoaldol products by silylation, deprotonation (w-BuLi, TMEDA, diethyl ether or THF) of enol carbamate 384 is complete at —78 °C (equation 103), and the resulting vinyUithium 385 can be kept at this temperature without decomposition for several hours. Stannylation , silylation , methoxycarbonylation (with methyl chloroformate) ... 

The reactivity of the sec-BuLi complexes with the like-sparteine diamines has been studied for the reaction of N-Boc pyrolidine with trimethylchlorosilane Scheme 24.23 (Table 24.9) (141). These results indicate that the stereoelectronic structure of the diamine plays an important role in the reaction of carbamates deprotonation. 

The chiral information of stereogenic centers in the allyl moiety of the precursor is destroyed on deprotonation. While an i/3-bound ion pair with a planar carbon frame is a chiral compound, usually rapid racemization takes place by intra- or intermolecular migration of the cation from one face to the opposite one. The sole exceptions known at present are secondary 2-alkenyl carbamates with X = dialkylaminocarbonyloxy21, in which the cation is tied by the chelating ligand, see Section 1.3.3.3.1.2. 

An efficient kinetic resolution of racemic secondary allyl carbamates was accomplished by the jw-butyllithium-(-)-sparteine complex76 131. Whereas the R-enantiomer (80% ee) is recovered unchanged, the 5-enantiomer is deprotonated preferentially. 

Carbamates (R2NCOOR ) may be O or N bonded. Base-promoted isomerization of carbamates from the O- to the deprotonated A--bound form in pentaamminecobalt(III) complexes have been defined.986... 

Dieter developed a flexible two step synthesis of substituted pyrroles involving initial Beak deprotonation of /ert-butoxycarbonyl (Boc) amines 36 followed by addition of CuX-2LiCl (X = -Cl, -CN) to afford a-aminoalkylcuprates. Such cuprates undergo conjugate addition reactions to a,(3-alkynyl ketones affording a,(3-enones 37, which upon treatment with PhOH/TMSCl undergo carbamate deprotection and intramolecular cyclization to afford the pyrroles 38 . 

A second route to nonracemic /-oxygenated allylic stannanes utilizes an enantioselective deprotonation of allylic carbamates by BuLi in the presence of (—)-sparteine. The configurationally stable a-lithio carbamate intermediate undergoes enantioselective S/,-2 reaction with Bu3SnCl and Mc SnCI (Scheme 28)65. Once formed, the /-carbamoyloxy stannanes can be inverted by successive lithiation with. s-BuLi and stannation with R3SnCl (Scheme 29)65. The former reaction proceeds with S/.-2 retention and the latter by Sf2 inversion. Nonracemic allylic carbamates can also be used to prepare chiral stannanes. Deprotonation with. s-BuLi TMEDA proceeds stereospecifically with retention (Scheme 29)65. 

The reaction proceeds via electrogenerated cationic species as its seen with the nonfluorinated amines, carbamates, and amides (Scheme 6.14). However, the regiochemistry of this anodic methoxylation is not governed by the stability of the cationic intermediates B and B (thermodynamic control) since the main products are formed via the less stable intermediates B. Indeed, this remarkable promotion effect and unique regioselectivity can be explained mainly in terms of a-CH kinetic acidities of the cation radicals formed by one-electron oxidation of the amines since the stronger the acidity of the methylene hydrogen, the easier the deprotonation. 

A more recent application of this chemistry was reported by Oestreich and Hoppe [74] and involved the enantioselective deprotonation of the enyne carbamate ester 125 with sec-butyllithium in the presence of (-)-sparteine (Scheme 2.41). Removal of the pro-S hydrogen atom led to the corresponding organolithium intermediate, which then underwent a highly enantioselective intramolecular 1,4-addition to the enyne. Protonation of the resulting allenyllithium species 126 provided a 70 30 mixture of the two diastereomeric allenes 127. 

In recent years, Hoppe s group has considerably extended the isomerization-addition methodology, especially for the highly regio- and stereoselective synthesis of 1,2-alkadienyl carbamates. It involves deprotonation of alkynyl carbamates, transme-talation into a titanium species and subsequent reaction with carbonyl compounds [26-30]. This group recently described the preparation of enantiomerically enriched 4-hydroxyallenyl carbamates 22 by sparteine-mediated lithiation of alkynyl carbamates 20 [29]. Impressive examples of these transformations are summarized in Scheme 8.8. 

Hoppe and Gonschorrek also reported the interesting formation of an enyne structure [137]. Deprotonation of allenyl carbamates 242 bearing a benzoyloxy group caused a 1,4-elimination of lithium benzoate, furnishing 1-alkynyl carbamates 243 in moderate to good yield (Scheme 8.63). 

Butadienyl carbamates can be deprotonated with BuLi [8]. Subsequent treatment with Ti(OiPr)4 and acetaldehyde give the allenyl addition product in 73% yield as a 60 40 mixture of diastereomers (Eq. 9.10). 

Substrates with carbamate-protected [81, 82] and even free hydroxyl groups [69] reacted similarly in a deprotonation-reprotonation sequence, the latter even with retention of the -configuration of an alkene such as 46 (Scheme 1.19). The analogous (E)-alkene also delivers only E-product. 

While the examples outlined in the previous section all pertain to attack by a basic N-atom, another possibility is intramolecular attack by an acidic N-atom, i.e., a deprotonated amide. For example, in AT-(2-carbamoylphe-nyljcarbamalcs of model phenols (8.135, X = H, Cl, or MeO, Fig. 8.11), the deprotonated carboxamido group attacks the carbamate carbonyl C-atom to form a quinazoline-2,4-dione with release of the phenol [173]. In acidic media, formation of the quinazoline-2,4-dione is decreased by competitive breakdown of the intermediate to an anthranilate and C02 in addition to the phenol (not shown). 

N-(2-Hydroxypropyl)carbamates (8.139, Fig. 8.13,b) are prodrugs that resemble the A-(2-hydroxyphenyl)carbamates discussed above. Here, activation yielded the tranquilizer mephenoxalone (8.140, Fig. 8.13,b) and an alcohol or a phenol such as paracetamol. Other active oxazolidinones could be obtained by replacing the MeO group in 8.139 (Fig. 8.13, b) with another substituent. For this series, the mechanism of activation is not an intramolecular nucleophilic attack, but, rather, decomposition of the deprotonated carbamate group as shown in Fig. 8.7,b, Reaction b, with the intermediate isocyanate being trapped to form the oxazolidinone ring. 

Example Even a moderate voltage drop between nozzle and skimmer can cause the elimination of weakly bonded substituents such as CO2 in case of carbon dioxide-protected deprotonated A-heterocycles. In particular SnMes-substituted anions such as 2-(trismethylstannyl)pyrrole-A-carbamate exhibit variations in the [A-C02]7A ratio of up to a factor of 30 (Eig. 11.10). [76]... 

Better results were obtained for the carbamate of 163 (entry 3) [75, 80). Thus, deprotonation of the carbamate 163 with a lithium base, followed by complexation with copper iodide and treatment with one equivalent of an alkyllithium, provided exclusive y-alkylation. Double bond configuration was only partially maintained, however, giving 164 and 165 in a ratio of 89 11. The formation of both alkene isomers is explained in terms of two competing transition states 167 and 168 (Scheme 6.35). Minimization of allylic strain should to some extent favor transition state 167. Employing the enantiomerically enriched carbamate (R)-163 (82% ee) as the starting material, the proposed syn-attack of the organocopper nucleophile could then be as shown. Thus, after substitution and subsequent hydrogenation, R)-2-phenylpentane (169) was obtained in 64% ee [75]. 

S)-4-Phenyloxazolidine-2-one (98), (S)-4-phenyloxazolidine-2-thione (99) and (4R,5S)-4,5-diphenyloxazolidine-2-one (100) are very poor nucleophiles. A substoichiometric amount (10 mol%) of potassium hydride is necessary to generate a fraction of the potassium salt of 13 which has a sufficient nucleophilicity. This holds for the anions generated by deprotonation at the carbamate position and activation by addition of dibenzo-18-crown-6 to the reaction mixtime, and causes the Michael addition to be very slow at -78 °C. The best temperatme is -20 0 °C. The higher the temperature, the more decomposition product is formed dming the Michael addition. 

The carbamates 549 (R = OBu-f) behave similarly, though they must be lithiated with i-BuLi to avoid addition to the carbonyl group °. It is possible simply to use a lithium carbamate to protect an amino group during a lateral lithiation an initial deprotonation and carbonation generates the lithium carbamate 556, which is then deprotonated twice more by t-BuLi (Scheme 220). After electrophilic quench, acid hydrolysis of the carbamic... 

Configurational stability has also been confirmed for various metalated carbamates by Hoppe and coworkers. Remarkably, carbamate-protected alcohols such as 20 are deprotonated enantioselectively, when treated with i-butyllithium in the presence of (—)-sparteine. The lithium carbenoids like 21 (R = alkyl) thus generated turn out to retain their configuration (equation 11). Similar results have been obtained for a-lithiated amines and carbamate protected amines " . As a rule, dipole stabilization of the organolithium compounds in general also enhances the configurational stability of a-oxygen-substituted lithium carbenoids. 

SCHEME 24. (-)-Sparteine-induced deprotonation of allyl carbamate 170. Dynamic resolution by crystallization and enantioselective homoaldol reaction... 

---