Hydroxy ketones from enamines

These differences in the control of the product stereochemistry have recently been investigated by molecular modeling techniques [60,154], From these studies, the relevance of the side-chain of isoleucine 476 (PDCS.c.) (Table 2) for the stereo-control during the formation of aromatic a-hydroxy ketones became obvious, since this side-chain may protect one site of the ot-carbanion/enamine 6 (Scheme 3) against the bulky aromatic cosubstrate. Nevertheless, the smaller methyl group of acetaldehyde can bind to both sites of the a-carbanion/en-amine. The preference for one of the two acetoin enantiomers has been interpre-tated in terms of different Boltzmann distributions between the two binding modes of the bound acetaldehyde [155],... 

Simple enamines cannot be deprotonated directly at the a-position due to their low acidity, but starting from a-chloroenamines 685, a-lithioenamines 686991 have been prepared by chlorine-lithium exchange using an arene-catalyzed lithiation992. The treatment of compounds 685 with an excess of lithium and a catalytic amount of 4,4 -di-tert-butylbiphenyl (DTBB) in THF at —90 °C allowed the preparation of intermediates 686, which were trapped with a variety of electrophiles (Scheme 177). For aldol reactions, the arene-catalyzed lithiation has to be performed in the presence of aldehydes (Barbier conditions) at —40 °C. These adducts were transformed into a-hydroxy ketones after acid hydrolysis with hydrochloric acid or silica gel. 

The sequence of reactions nicely points out the relative reactivity of carbonyl groups at positions 3, 11 and 17. Reaction of the triketone 29-2 with a controlled amount of pyrrolidine leads to the formation of the enamine from the most reactive ketone, that at C3 (30-1) (Scheme 5.30). Treatment of this intermediate with methylmagnesium bromide leads to exclusive addition to C17. Although the ketone at Cn is virtually inert to addition reactions, it is subject to reduction. Reaction of 30-2 with lithium aluminum hydride thus leads to the corresponding j8-hydroxy derivative. The enamine is then removed by acid hydrolysis (30-4). Reaction of the newly formed alcohol with /i-toluenesulfonyl... 

Woodward has now reported reliable procedures for the preparation of trimethylene and ethylene dithiotoluene-jp-sulphonates, reagents used in the formation of dithians and dithiolans from active methylene compounds, including those adjacent to a carbonyl group activated by prior hydroxy-methylene or enamine formation. Applications include carbon-carbon bond cleavage and ketone transposition (Scheme 148). 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

The reaction of NO with a wide variety of enamines, derived from the respective aldehydes and ketones can produce N-hydroxy-N-nitrosamine (Scheme 3.10) [137]. These compounds are relatively stable to thermal decomposition and do not release copious volumes of NO upon adding to concentrated mineral acids. However, on dissolution in aqueous buffer at pH 7.4 and 37 °C, a slow release of NO could be detected by the chemiluminescence method. 

The procedure for the preparation of a dithiolane from a hydroxy-methylene derivative of a ketone and ethylene dithiotosylate (ethane-1,2-dithiol di-p-toluenesulfonate) can be varied to produce dithianes when the latter reagent is replaced by trimethylene dithiotosylate.8,4 The dithiotosylates also react with enamine derivatives to produce dithiaspiro compounds.4,5... 

When Schiff s bases (242), derived from ketones and tm-butylamine, were reacted with dimethyl methoxymethylenemalonate in diphenyl ether at 80-130°C for 1-15 hr, then at 190-250°C for 1-3 hr, 2-hydroxy-3-pyridinecarboxylates (243) were obtained by a one-pot procedure. In the first step of the reaction, the beta-carbon of the enamine moiety was involved instead of the amino group (89JHC773). 

These are the most favourable of all and the precursors, such as the hydroxy acids, e.g. 15, cannot usually be isolated, though the carboxylate salts are stable. The only important thing is to get the oxidation level of the precursor right. Using cyclic amines as examples, a fully saturated ring 45 would come from an alkylation reaction on 46 X = a leaving group. Imines 47 or enamines 49 would come from aldehydes or ketones 48. 

Fig. 12.18. Hydroxyalkylation of an enamine (—> hydroxy-enamine C), followed by in-situ-dehydration (—> dienamine F) and acidic workup (—> ft,/i-unsatu rated ketone E). Since the enamine A is produced from cyclopentanone, the figure shows the second part of a two-step reaction, which is an alternative to the base-mediated crossed aldol condensation (see Section 13.4.1).

Archer and co-workers (84) have used the original Stillwell ellipticine synthesis (87), as later exploited by Gouyette et al. (88) to prepare the simple 9-hydroxy-6//-pyrido[4,3-fe]carbazole (158) (Scheme 27). V-Benzyl-4-piperidone was converted via enamine 154 to the enone 155. Hydrogenation gave a mixture of cis- and trawj-ketones 156 which were separately converted to indole 157 by Fischer indolization. Some of the nonlinear pyrido[3,4-c]carbazole (17%) was formed from the cis-ketone. Dehydrogenation and demethylation gave the desired 158. 

It turns out that one of the best ketones for these asymmetric crossed aldol reactions is hydroxy-acetone 96. Combination with isobutyraldehyde 89 gives an aldol that is also an anti-diol 97 with almost perfect selectivity.21 The proline enamine of hydroxyacetone is evidently formed preferentially on the hydroxy side. You will recall from chapter 25 that asymmetric synthesis of anti-diols is not as easy as that of syn diols. 

Reaction at the 4-position of a guaiacyl system through electrophilic substitution followed by a ring closure involving an enamine was achieved in the synthesis of 8-hydroxy-9-methoxy-4,6,11,11 a-tetrahydro-1 H-benzo[bJquinoizin-2(3H)-6-one in 68% yield from the acetal shown with methyl vinyl ketone in ether solution by interaction at ambient temperature during 24 hours (under nitrogen) followed by solvent removal and treatment with concentrated hydrochloric acid at 100 C for 30 mins (ref.72). 

The electron-withdrawing effect of the benzotriazole nucleus has profound effect on the diverse reactions that oenzotriazole-based synthons undergo. For example, carbanions of 1-methyl- and 2-methylbenzotriazole reacted with 2-(methylthio)benzo-thiazole to afford the 1-substituted-benzotriazole (91) and the corresponding 2-substituted benzotriazole [94H(38)1041]. Immonium cations derived from 1-hydroxy-methylbenzotriazole (92) are also effective acceptors for ketones, 1,3-dicarbonyl and select enamine synthons under Lewis acid reaction conditions [94JHC(31)917]. 

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