N/O acetal

N,O-acetal intermediate 172, y,<5-unsaturated amide 171. It is important to note that there is a correspondence between the stereochemistry at C-41 of the allylic alcohol substrate 173 and at C-37 of the amide product 171. Provided that the configuration of the hydroxyl-bearing carbon in 173 can be established as shown, then the subsequent suprafacial [3,3] sigmatropic rearrangement would ensure the stereospecific introduction of the C-37 side chain during the course of the Eschenmoser-Claisen rearrangement, stereochemistry is transferred from C-41 to C-37. Ketone 174, a potential intermediate for a synthesis of 173, could conceivably be fashioned in short order from epoxide 175. 

Treatment of N, O-acetals 42 in which the para position is unsubstituted, with a twofold excess of the corresponding amine HC1 in boiling 50% aqueous methanol gives rise to the bis(4-aminoaryl)methane derivative.62 43. This method is suitable only for 4-AT,AT-unsubstituted diarylamines (Eq. 5). 

Another example of an intramolecular cyclization initiated by reactions of an acyliminium ion [32] with an unactivated alkene has been published by Veenstra and coworkers. In their total synthesis of CGP 49823 (1-116), a potent NK antagonist [33], these authors treated the N,O-acetal 1-112 with 2 equiv. of chlorosulfonic acid in acetonitrile to afford acyliminium ion 1-113 (Scheme 1.29) [34]. This is qualified for a cyclization, creating piperidine cation 1-114, which is then trapped by... 

It is assumed that the overall process is initiated by a Michael addition of the 1,3-dicarbonyl compound onto the ci,(5-uri saturated carbonyl derivative. There follows the formation of either an aminal and an iminium intermediate which is followed by the formation of two N.O-acetals. 

The formation of an iminium ion as 2-530 is also proposed by Heaney and coworkers in the synthesis of a tetrahydro- 3-carboline 2-531 (Scheme 2.120) [282]. Herein, heating a solution of tryptamine (2-526) and the acetal 2-527 in the presence of 10 mol% of Sc(OTf)3 gives in the first step the N, O-acetal 2-528, which then leads to the lactam 2-529 and further to the iminium ion 2-530 by elimination of methanol. The last step is a well-known Pictet-Spengler type cyclization to give the final product 2-531 in 91% yield. 

Pd-catalyzed intramolecular etherification reactions of aliphatic alcohols have also been practiced in tandem with other bond-forming processes, such as a Pd-catalyzed allyltin addition to an aldehyde (Equation (32)).160 Similarly, a tandem C-N and G-O bond formation sequence occurs (Equation (33)) during the reactions of /3-amino alcohols with biscarbonates in the presence of the N,O-acetal-derived ligand 43.161-163... 

Hydroformylation in the presence of nucleophiles such as alcohols or amines leads to 0,0- or N,O-acetals, aminals, imines or enamines (Scheme 2). 

Hydroformylation of unsaturated amines offer a convenient synthetic access to cyclic AT.O-hemiacetals. If performed in the presence of alcohols or orthoesters AT,O-acetals are formed. With additional N-nucleophiles N,N-acetals are obtained. These compounds are synthetically attractive building blocks and were therefore used as a key step in the synthesis of various natural products [27,35]. Thus the synthesis of (+)-prosopinine starting from enantiopure (T)-scrinc leads to a cyclic N,O-acetal functionality with the required functionality for the attachment of the side chain (Scheme 6) [36]. 

Scheme 7 Formation of N,O-acetals under hydroformylation conditions...

Oxidative decarboxylation of a-amino carboxylic acid The electrochemical oxidation of Al-acyl-a-amino acids (96) in MeOH affords N, O-acetals (98) through acyliminium intermediates (97) (Scheme 36) [121]. 

The stereochemistry in the electrochemical oxidation of (96) yielding N, O-acetals (98) is of timely interest. The electrochemical oxidation of acyclic threonine derivative... 

Since the oxidation of (96) proceeds through the acyliminium ions (97) (Scheme 36), where the positive charge is stabilized by the adjacent nitrogen atom, it should lead to racemic acetals (98) from enantioenriched acids (96). In fact, the electrolysis of A/-benzoylated L-proline (113) gave racemic N, O-acetal (114) regardless of the anode material used (Scheme 41) [129]. 

Chiral N/O-acetals may racemize in the solid state when water of crystallization is present. Examples are the epimerizations of the oxazolidines 97 that contain water from their preparation by stereoselective condensation. Thus, the kinetically preferred products 97a,b (which are admixed to the thermodynamically more stable products 98a,b) epimerize within some weeks in the solid state to give enantiopure 98a,b [661 (Scheme 9). It appears that the N/O-acetal hydrolyses and recloses. Solid-state racemizations are quantitative if the 1 1 equilibrium between the enantiomers is obtained. Therefore they do not really fulfill the criterion of only one product. Numerous examples in the organo-metallic field are listed in [671 and [681. 

A further refunctionalization of the N,O-acetal 5-alkylhexahydropyrrolo[2,1-/>]oxazole allows for the elaboration of 2,5-dialkylated pyrrolidines by reaction with Grignard reagents74. 

Analogous to the use of chiral acetals one can employ chiral N,O-acetals, accessible from a, -unsatu-rated aldehydes and certain chiral amino alcohols, to prepare optically active -substituted aldehydes via subsequent Sn2 addition and hydrolysis. However, the situation is more complicated in this case, since the N,0-acetal center constitutes a new stereogenic center which has to be selectively established. The addition of organocopper compounds to a, -ethylenic oxazolidine derivatives prepared from unsaturated aldehydes and ephedrine was studied.70-78 The (diastereo) selectivities were rather low (<50% ee after hydrolysis) in most cases, the highest value being 80% ee in a single case.73 There is a strong solvent effect in these reactions, e.g. in the addition of lithium dimethylcuprate to the ( )-cinnamaldehyde-derived oxazolidine (70 Scheme 28) 73 the (fl)-aldehyde (71) is formed preferentially in polar solvents, while the (S)-enantiomer [ent-71) is the major product in nonpolar solvents like hexane. This approach was utilized in the preparation of citronellal (80% ee) from crotonaldehyde (40% overall yield).78... 

The reaction of N,O-acetal 311 in the presence of NEt3 under the same conditions gives ring-opening siloxymethylation product 312 arising from exclusive C—O cleavage... 

Harayama Y, Yoshida M, Kamimura D, Wada Y, Kita Y (2006) The Efficient Direct Synthesis of N.O-Acetal Compounds as Key Intermediates of Discorhabdin A Oxidative Fragmentation Reaction of a-Amino Acids or P-Amino Alcohols by Using Hypervalent Iodine(III) Reagents. Chem Eur J 12 4893... 

The electrosynthesis of N,O-acetals was investigated by Hoechst 250). However, this route cannot compete with the anodic methoxylation of carboxamides. 

This type of C-H carbonylation is also feasible at C-H bonds in five-membered N-heteroaromatics, such as imidazoles 3 (Scheme 2), thiazoles 5, oxazoles 6, and pyr-azoles 7 [3], Functional group compatibility was extensively studied in the reaction of 3, and it was found that a variety of functional groups, for example ketone, ester, cy-ano, acetal, N, O-acetal, ketal, and silyl groups, were tolerated under the reaction conditions, indicating that C-H carbonylation reactions have now reached a satisfactory level in organic synthesis. The reactivity of the five-membered N-heteroaromatics is significantly affected by the pK, of conjugate acid of the N-heteroaro-... 

Substituted pipecolic acid derivatives can be accessed from a suitably protected allylglycine derivative by first use of a palladium-catalyzed N, O-acetal formation followed by RCM.43 Treatment of 19 with boron trifluoride etherate followed by a variety of nucleophiles formed the corresponding substituted products 20 and 21 (Scheme 28.12). 

An entirely different reaction occurred when 2-(4-diazo-3-oxobutyl)-benzoxazole (239) was treated with Rh(II) octanoate. In addition to undergoing dipolar cycloaddition to produce cycloadduct 241 (20%), the highly stabilized dipole (i.e., 240) formed from the benzoxazole loses a proton to produce the cyclic ketene N,O-acetal 242. This compound reacts further with the activated 7t-bond of DMAD to give zwitterion 243. The anionic portion of 243 then adds to the adjacent carbonyl group, producing a new zwitterionic intermediate 244. In the presence of water, this species is converted to the observed phenolic lactam 245. 

The structural core of (-)-adaline was prepared by a lithium-activated SN2-type alkynylation of an enantiomerically-enriched tricyclic N, O-acetal followed by reduction, Ar-formylation (80, R = CHO), and RCM using the MC2 <02OL2469> (Scheme 61). Yields were only slightly lower with the GMC. RCM fails with the HC1 salt of 80 (R =H2C1), presumably because of a diequatorial arrangement of the 2,6-dialkenyl substituents in that derivative. 

Triazines are generally more reactive in [2+4] cycloaddition in comparison with 1,2,3-triazines. A wide variety of dienophiles can be employed enamines, enaminones, vinyl silyl ethers, vinyl thioethers, cyclic ketene N,O-acetals, A-phenylmaleimide, 6-dimethylaminopentafulvene, 2-alkylidene-imidazolidines (cyclic ketene aminals), cyclic vinyl ethers, arynes, benzocyclopropene, acetylenes, and alkenes such as ethylene, (Z)-but-2-ene, cyclopentene, cyclooctene, bicyclo[2.2.1]hept-2-ene, hexa-1,5-diene, cycloocta-1,5-diene, diallyl ether, cyclododeca-l,5,9-triene, di-(3-methylcyclopropen-3-yl), and norbornadiene. 

In the presence of boron trifluoride catalyst, primary allylic alcohols 100 add to ynamines 101 at 30 °C to afford ketene N, O-acetals 102 and the rearrangement products 103 in good yields (equation 21)85. 

Ketene N, O-acetals are converted to 1,1-enediamines when reacted with amines. For example, compound 45 has been prepared by substitution of the methoxy with amine (equation 16)79. Symmetric 1,1-enediamines are obtained when both the alkoxy and the amino substituents are displaced by the amine employed81. In this way, the reaction between ketene N, O-acetals 50 and piperidine leads to 1,1-dipipefidinoethylene (35) (equation 17)81. Alternatively, 35 can be prepared from the reaction of piperidine with triethyl orthoacetate82,83 or with ethoxyacetylene84, reactions which probably proceed via a ketene TV, 0-acetal intermediate. 

Investigation of the reaction of l,l-bis(dimethylamino)ethylene 4, ketene N,S- or N,O-acetals, with 1,2,4-triazines and 1,2,4,5-tetrazines has been conducted by Muller and Sauer164. Unlike ketene, N,S- or AT,O-acetals, 1,1-enediamine 4 leads to both... 

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