A-amino ketone

The exploration of the chemistry of azirines has led to the discovery of several pyrrole syntheses. From a mechanistic viewpoint the simplest is based upon their ability to behave as a-amino ketone equivalents in reactions analogous to the Knorr pyrrole synthesis cf. Section 3.03.3.2.2), as illustrated in Schemes 91a and 91b for reactions with carbanions. Parallel reactions with enamines or a-keto phosphorus ylides can be effected with electron-deficient 2//-azirines (Scheme 91c). Conversely, electron-rich azirines react with electron deficient alkynes (Scheme 91d). 

Rearrangement of N.N-dimethyttiydrazone or tosylate derivatives of oxime to azirines and from there to a-amino ketones. 

The Knorr pyrrole synthesis involves the reaction between an a-amino ketone 1 and a second carbonyl compound 2, having a reactive a-methylene group, to give a pyrrole 3. The amine 1 is often generated in situ by reduction of an oximino group. 

A ketoxime tosylate 1 can be converted into an a-amino ketone 2 via the Neber rearrangement by treatment with a base—e.g. using an ethoxide or pyridine. Substituent R is usually aryl, but may as well be alkyl or H substituent R can be alkyl or aryl, but not H. 

An a-amino ketone, obtained by the Neber rearrangement, can be further converted into an oxime tosylate, and then subjected to the Neber conditions a ,a -diamino ketones can be prepared by this route. 

Systematic studies of additions to a-amino ketones are unavailable. One reason may be that the synthesis of enantiomerically pure a-amino ketones has been problematic, however, convenient preparations of various a-amino ketones are now known74-79. 

The addition of organometallic reagents to a-amino ketones e.g., 1 normally obeys Cram s rule the dominant diastereomer is the. syrc-compound81. 

Dagegen werden die a,/ -ungesattigten a-Amino ketone zu Vinyl-aminen reduziert z.B.8 ... 

Cyclische a-Amino-ketone erleiden bei der Elektroreduktion eine Strukturverande-rung l-Methyl-2-athyl-3-oxo-piperidin wandelt sich in 30%iger Schwefelsaure haupt-sachlich in 1 -Methyl-2-propyl-pyrrolidin um (an Cd bei 60°, 41% d.Th.). Daneben entste-hen an anderen Kathoden zusatzlich Methyl-heptyl-amin bzw. an Kupfer l-Methyl-2-pro-pyl-4,5-dihydro-pyrrol1 ... 

A similar microwave-assisted cyclization in the presence of ammonium acetate of an a-ketoamide, obtained by acylation of an a-aminoketone, was recently described for the synthesis of the antifungal agent Nortopsedin D [46]. The problem of the instabiUty of the a-amino ketones was successfully resolved by in situ acylation of the amine derived from Staudinger reaction of the azide 50 with a phosphine (Scheme 16). This ketoamide was... 

The reactions with a combination of (DHQ)2-PHAL [or (DHQD)2-PHAL] and /V-halosulfo-namides can be successfully applied to trans-olefins. Especially when the substrates are a,j3-unsaturated esters, high regioselectivity as well as good enantioselectivity is realized (Scheme 55).210,211 The use of an /V-halosulfonamide bearing a smaller A-substituent increases the enantioselectivity.211 n-Propanol/water (1 1) is the solvent of choice. Aminohydroxylation of silyl enol ethers has been successfully performed with DHQD-CL or (DHQD)2-PYR, to give the corresponding a-amino ketones.212... 

R,2S)-2-[(Ethoxycarbonyl)amino]-l-phenyl-l-propanol [Bronsted Acid Promoted Reduction of an a-Amino Ketone to an Erythro a-Hydroxy... 

The enantioseiective hydrogenation of a-amino ketones has been applied extensively to the synthesis of chiral drugs such as the / -agonist SR 58611 (Sanofi Cie). m-Chlorstyreneoxide was obtained via carbene-induced ring closure of the amino alcohol. Epoxide-opening by a chiral amine obtained via a ruthenium-catalyzed hydrogenation of an enamide has led to the desired compound where... 

Scheme 33.13 Some applications of the enantioselective hydrogenation of a-amino ketones.

The two production processes using a-amino ketone substrates depicted in Figure 37.24 were developed by Boehringer-Ingelheim to improve on existing resolution syntheses for adrenaline and phenylephrine [94]. Unfortunately, few details are available but both processes are carried out with a Rh-mccpm catalyst with very high TONs and TOFs, albeit with medium ee-values of 88% which increase to >99% after precipitation of the free base. 

The hydrogenation of a-amino ketones was also a key step for the synthesis of three more pharma actives (Fig. 37.25). Roche [95] divulged a pilot process involving the hydrogenation/dynamic kinetic resolution of a cyclic a-amino ketone using an optimized MeO-biphep ligand. The Ru-catalyzed reaction was carried out on a 9-kg scale with excellent enantio- and diastereoselectivities, and very... 

Carbon monoxide rapidly inserts into the carbon—zirconium bond of alkyl- and alkenyl-zirconocene chlorides at low temperature with retention of configuration at carbon to give acylzirconocene chlorides 17 (Scheme 3.5). Acylzirconocene chlorides have found utility in synthesis, as described elsewhere in this volume [17]. Lewis acid catalyzed additions to enones, aldehydes, and imines, yielding a-keto allylic alcohols, a-hydroxy ketones, and a-amino ketones, respectively [18], and palladium-catalyzed addition to alkyl/aryl halides and a,[5-ynones [19] are examples. The acyl complex 18 formed by the insertion of carbon monoxide into dialkyl, alkylaryl, or diaryl zirconocenes may rearrange to a r 2-ketone complex 19 either thermally (particularly when R1 = R2 = Ph) or on addition of a Lewis acid [5,20,21]. The rearrangement proceeds through the less stable... 

Scheme 4.13. Conversion of an acyl zirconocene to a-hydroxy and a-amino ketones.

An extension of the strategy described for the reaction with aldehydes (Section 5.4.2) to imine derivatives might be expected to yield a-amino ketone compounds (Scheme 5.14), which are the constituents of a variety of biologically important molecules. 

Scheme 5.15. Lewis acid-catalyzed formation of an a-amino ketone.

Although the reactivity of acylzirconocene chlorides towards imine derivatives under Yb(OTf)3/TMSOTf (20 mol%, l l)-catalyzed conditions is not necessarily very high, the direct access to a-amino ketone derivatives indicates the usefulness of acylzirconocene chlorides as unmasked acyl anion donors. 

It is interesting to note that the reaction of N-salicylideneaniline, which possesses a free phenolic hydroxyl group at the ortho position in the benzylidene portion, with the acylzirconocene chloride gives the a-amino ketone in 67 % yield in the absence of any additive (Scheme 5.16) [23]. Similarly, N-(p-hydroxybenzylidene)aniline reacts with the acylzirconocene chloride to give the a-amino ketone in 58 % yield. The reaction of N-(m-hydroxyben-zylidene)aniline, however, gives the a-amino ketone in just 12 % yield. Neither N-(o-MeO-benzylidenejaniline nor N-(p-MeO-benzylidene)aniline gives an appreciable amount of product in the absence of additive. 

From a practical standpoint, this reaction is subject to many of the same limitations as cyclopropanation. Decomposition of the iodinane to toluenesulfonamide is competitive necessitating a high relative concentration of alkene. The use of a large excess of alkene is unnecessary if the concentration of the medium is kept relatively high (1 M in alkene). The exception to this statement is the use of more nucleophilic alkenes such as enolsilanes. Aziridination of acetophenone enolsilane proceeds in high yield at -20°C using only 1.5 equiv of alkene. It is significant to note that the products of these reactions are a-amino ketones (74). 

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