Aldehydes enecarbamates

A catalytic asymmetric amination of enecarbamates has been attained using a chiral Cu(II) complex of diamine (210) as catalyst. Thus, azodicarboxylates have been shown to react with various enecarbamates (208) derived from aromatic and aliphatic ketones and aldehydes to provide acylimines (209) in good yields with high enantioselectivity (<99% ee). The catalyst loading required for high enantioselectivity was generally low (0.2 mol% in some cases).259... 

The formation of a carbon-carbon bond at the p-position of amines is made possible by the reaction of these enecarbamates with electrophiles. The acylation, Vilsmeyer reaction and hydroboration at the P-position of carbamates have been achieved by using this technique31. The syntheses of a derivative of hydrolulolidine 49 and nicotin-aldehyde 50 are shown below as typical examples. 

A diastereoselective synthesis of all. fy -2,3,6-trisubstitutcd tetrahydropyran-4-ones 1039 via an intramolecular Prins cyclization of enecarbamates 1038 with aldehydes is used during a formal synthesis of (+)-ratjadone (Equation 403) <2004JA12216>. Similarly, tetrahydropyran-4-ones bearing quaternary centres a-to the carbonyl are accessible via a Lewis acid-mediated Prins cyclization of silyl enol ether substrates <2004JA15662>. 

As shown in Scheme 33, the synthesis of the C1-C7 amide 160 began with a Hoppe crotyltitanation reaction between the aldehyde 17 and the (R)-crotyltitanium 163, prepared in situ (crotyl diisopropylcarbamate with sBuLi/(-)-sparteine/ Ti(0/Pr)4), to give O-enecarbamate 164 (>30 ldr) [166-169], Ozonolysis and HWE chain extension was followed by an Evans-Prunet 1,4-addition to install the C5-stereocentre to complete 160 [103], The synthesis of the C8-C14 subunit 161 started with an elegant installation of the C13-C14 (Z)-olefin. Deprotonation of the dihydrofuran 165, available in three steps from bromo alcohol 166, with fBuLi and transmetallation with Me2CuLi LiCN, and subsequent 1,2-cuprate transfer gave the... 

The total synthesis of amaryllidaceae alkaloid buflavin was achieved in the laboratory of A. Couture by utilizing a Horner-Wittig reaction between a biaryl aldehyde and a metalated carbamate. The diphenyl phosphine oxide carbamate was deprotonated with n-BuLi. To the resulting metalated carbamate was added the solution of the biaryl aldehyde in THF. The reaction afforded the corresponding (Z)- and ( )-enecarbamates in good yield and with high -selectivity. 

Lebrun and coworkers reported a convenient synthesis to a range of phenanthroindo- and quinolizidine natural products [62]. In this approach, the alkaloids (+)-antofine [( )-3] (n-1) and (+)-cryptopleurine [(+)-5] (n=2), were synthesized by Pictet-Spengler cyclization of 72 [2-arylmethyl-piperidine (n=2) and -pyrrolindine (n=l)], Scheme (7). The intermediate compounds were obtained by sequential iV-deprotection-reduction of the parent enecarbamates 71, which were obtained from Homer reaction of phosphorylated carbamates 70 with the appropriate aldehyde (69). 

Carbonyl reduction. Conversion of carboxylic acids to aldehydes can be achieved by DIBALH reduction of the derived trimethylsilyl esters. The cyclic carbonyl group of N-Boc pyrrolidinones is reduced and further treatment of the products with quinolinium camphorsulfonate delivers the enecarbamates. ... 

Several enamides, for example compound (72 Scheme 5), have been used as precursors to 1 -sub-stituted-2-pyridone derivatives (73) and pyridine-3-carbaldehyde derivatives (74 14-69%). Salt (1) promotes dehydration of tautomers (75b) of 2-acetylbenzamide derivatives (75a) to give enamides (76), which are converted by further reaction with salt U) into iminium salts (77). Hydrolysis of these salts yields aldehydes (78 81-99% Scheme 5). Enecarbamates, such as (79), give formylation products (80 26-94%) in the Vilsmeier-Haack reaction (Scheme 5). ... 

In addition to heterolysis of compounds of type (2), N-acyliminium intermediates (1) are also obtained by protonation of Af-acylimines (27) and by protonation of enamides or enecarbamates (28). The former method is mainly of theoretical interest, Ixcause /V-acylimines (27) are rather unstable compounds. The latter technique is occasionally applied, although compounds (28) are usually synthesized through elimination of HX from (2). Other preparatively very useful methods for the in situ generation of the N-acyliminium ion are the acid-mediated coupling of an aldehyde (or ketone) with a primary (or secondary) amide or a nitrile, and the thermal reaction between an acid chloride and an imine. ... 

Cycloaddition. In the presence of Dy(OTf)j aromatic aldehydes and arylamines form aldimines in situ, and then react as heterodienes toward enecarbamates. 

A chiral ligand mediated approach to lithiation-substitutions of allylic amines has also been well developed. Weisenburger and Beak demonstrated that lithiation of doubly protected allylic amines 141 in the presence of the chiral ligand (-)-sparteine (5), and substitution with a variety of electrophiles provided highly enantioenriched enecarbamate products 142 (Scheme 44) [100]. The authors demonstrated that the intermediate organolithium could be viewed as either an aldehyde P-homoenolate or y-lithioamine synthetic equivalent by hydrolysis or reduction and deprotection of the enecarbamates, respectively. 

Scheme 45) [101]. An additional a-lithiation/alkylation of the enecarbamate double bond allows access to ketone products 148 upon hydrolysis. Hydrolysis of the unsubstituted enecarbamate to the aldehyde 143, followed by oxidation and esterification provided the carboxylic acids and esters 146. 

These methodological studies served to demonstrate that reactions of an a-oxygenated crotyltitanium reagent and aldehyde lead to anft-homoallylic alcohol with a Z-O-enecarbamate group in a one-step sequence. We could take advantage of this functionality to give access either to the natural product or to synthetic analogues. 

The Homer-Wadsworth-Emmons (HWE) reaction of a lithiated (diphenylphosphinoyl)methyl amine with a biaryl aldehyde furnishes the corresponding enecarbamates, which serve as key intermediates for the synthesis of the Amaryllidaceae alkaloid buflavine (eq 44). ... 

The reaction of aldehydes, anilines and enecarbamates in dichlo-romethane in the presence of EtOH and a catalytic amount of the chiral phosphoric acid (225) afforded Mannich adducts which were in situ reduced to a ti-l,2-disubstituted 1,3-diamines (224) in excellent diastereoselectivity and enantioselectivity (Scheme 62). " ... 

Enantioselective organocatalyzed inverse-electron-demand hDA reactions of p,y-unsaturated a-keto esters with enecarbamates (14CEJ16753) or with allylsilanes (14AGE6131) led to 2-substituted 3,4-dihydro-2ff-pyrans and of a,P"Unsaturated aldehydes with acyl phosphonates gave access to... 

Hayashi, et al. developed an enantioselective formal aza [3+3] cycloaddition of a,p-unsaturated aldehydes and enamide (enecarbamate) providing tetrahydropyil-din-2-ol in excellent enantioselectivities and yield. Scheme 3.50 [66]. The reaction comprised four consecutive reactions ene reaction, isomerization of imine to enecarbamate, hydrolysis and hemiacetal formation. Noteworthy, examples of a,P-unsaturated aldehydes acting as enophile in intermolecular catalytic enantioselective ene reaction are rare, and the reaction developed by Hayashi represents one of the successful example in such category. 

Scheme 3.50 Organocatalytic formal aza [3+3] cycloaddition reactions of enecarbamates and a,p-unsaturated aldehydes...

The (/ )-BlNOL-based phosphoric acid catalyst 94 was recently applied in a related three-component Mannich-type reaction of aldehydes 2 with p-nitroaniline 95 and enecarbamates 96a-b by Masson and Zhu to obtain the corresponding amino-substituted N,0-acetals, which were reduced in situ to the fln -l,2-disubstituted 1,3-diamines 97a-f (Scheme 5.41) [57]. The reduced Mannich products were obtained in moderate to high yields (62-97%) and good to excellent ee. 

A practical approach using chiral Br0nsted acids for the enantioselective three-component Povarov reaction has been successfully developed by Zhu and co-workers recently/ When 10 mol% chiral acid 91 was used as catalyst, a reaction of aniline, aldehyde and enecarbamate 88 in one-pot gave tetrahydroquinoline derivatives in good yield and excellent enantioselectivities (up to > 99% ee). To illustrate the power of this novel catalytic enantioselective three-component Povarov reaction, toprcetrapib was prepared in only 4 steps, so far the most effective approach to this target. 

An efficient enantioselective reductive amination of a-branched aldehydes (90) via d5namic kinetic resolution catalyzed by (89) has been described (Scheme 26). Reductive coupling of 1,3-enynes to heterocyclic aromatic aldehydes use an achiral rhodium-catalyst with a chiral Bronsted acid (89) as co-catalyst (Scheme 27). A highly efficient enantioselective aza-ene-type reaction of N-benzoylimines (91) with enecarbamates (92) has been achieved. The reaction can be performed at extremely low loading of the catalyst (93) without notable loss of enantioselectivity of P-aminoimines obtained (Scheme 28). ... 

Enamides and enecarbamates are considered as versatile synthetic building blocks in organic synthesis, but they have been rarely used as nucleophiles, presumably due to their lower reactivity compared with enamines and enols. In 2004, Kobayashi et al demonstrated the utility of enecarbamates as nucleophiles for C-C bond formation in asymmetric copper-catalysed reactions of aldehydes and aldimines. Later in 2005, these authors reported the enantioselective nickel-catalysed reactions of a simple diketone, such... 

On the other hand, Hayashi et al. have reported the highly enantio-selective formal [3 + 3] cycloaddition of a,p-unsaturated aldehydes with ene-carbamates catalysed by diphenylprolinol silyl ether as an organocatalyst. This reaction consisted of four consecutive reactions including an asymmetric ene reaction, an isomerisation from an imine into an enecarbamate, a hydrolysis and a hemiacetal formation in one pot to afford synthetically important chiral piperidine derivatives with excellent enantioselectivities of up to 99% ee, good yields and moderate to good diastereoselectivities, as shown in Scheme 6.22. 

Scheme 6.22 Formal [3 + 3] cycloadditions of a,P-unsaturated aldehydes with enecarbamates.

Terada, M. Soga, K. Momiyama, N. Enantioselective Activation of Aldehydes by Chiral Phosphoric Acid Catalysts in an Aza-Ene-Type Reaction between Glyoxate and Enecarbamate. Angew. Chem. Int. Ed. 2008, 47, 4122-4175. 

The first enantioselective, three-component Povarov reaction was reported in 2009 by Zhu. Anilines, aldehydes, and enecarbamates, acting as electron-rich olefins, afforded derivatives of 4-aminotetrahydroquinolines with excellent enantio (>99% ee) and diastereoselectivities (>99% cis), the reaction being catalyzed by a chiral phosphoric acid derived from Hg-BINOL 81. The reaction could be... 

Bi[l,2,3,4-tetrahydronaphthyl) derivatives. Masson and coworkers have described a highly stereoselective three-component Povarov reaction, catalysed by (R) and (S)-BINOL hydrogen phosphate derivative (195). A variety of aldehydes (190), enecarbamates (191), and aminosubstituted azines (192) participated in this reaction to afford the tetrahydropyrrolopyridines (193) and tetrahydropyrazolopyridines (194) with excellent enantioselectivities (84-99% ee) (Scheme 51). ... 

Chiral Brpnsted acids have also been shown to effectively catalyze the Mannich reaction between aldehydes, anilines, and enecarbamates [100]. Here, the application of enecarba-mates as nucleophilic species instead of ketones gives access to enantioenriched 1,3-diamines after subsequent reduction in situ with sodium cyanoborohydride. The potential of this approach was demonstrated by reacting various aromatic or aliphatic aldehydes and substituted enecarbamates with para-nitroaniline in the presence of the chiral phosphoric acid catalyst 150 (Scheme 11.34). 

Synthetically important chiral 1-monosubstituted 1,3-diamines (145) are synthesized in Mannich-t)fpe reactions of enecarbamates (140) with aromatic and aliphatic hemiaminal ethers (141) in the presence of phosphoric acid 95a. This process involves the highly reactive Mannich-t)fpe product (144), which is entrapped by a methanol molecule generated during the formation of the imine (143) derived from the hemiaminal ether (141) (Scheme 28.15) [72]. Similarly, diastereo- and enantio-enriched anti-l,2-disubstituted 1,3-diamines are prepared by the Mannich-type reaction of aldehydes, anilines, and enecarbamates in the presence of chiral phosphoric acid [73]. 

Scheme 42.27 Sequential three-component Mannich reaction of aldehydes 122, anilines 123, and enecarbamates 124 for the synthesis of 1,3-diamines 126.

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