Imines reactions with silyl ketene acetals

Acylhydrazones, R CH=N-NHCOR , undergo stereoselective Mannich reactions with silyl ketene acetals to give j8-hydrazido esters, using activation by a chiral silicon Lewis acid. Alternatively, the use of silyl ketene imine gives a /3-hydrazido nitrile. Enantioselective (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) hydrazone alkylation of aldehydes and ketones is the subject of a computational study, providing a useful screening method for possible new candidates. " ... 

Diastereoselection is also observed in the catalyzed [titanium tetrachloride (TiCI4)13, trimethyl-silyltrifluoromethanesulfonate (TMSTf)l4, zinc iodide (Znl2)15] reactions of silyl ketene acetal 1 with imines 2, The ami configuration of the product 3 dominates. 

Table 4 Ratio of Diastereoisomers in the Lewis Acid Mediated Reactions of Silyl Ketene Acetals with Imines...

Enol silanes (181), as reported by Pilli and Russowsky, add to arylimines (182) in the presence of catalytic amounts of TMS-OTf to afford (V-aryl- 3-amino ketones (183 equation 20).144 The reaction is carried out by adding the enol silane to the imine in the presence of 15 mol % of TMS-OTf at 0 C in CH2CI2, followed by aqueous work-up. Yields range from 50% to 98% in a series of benzylideneaniline derivatives using the enol silanes derived from acetophenone and f-butyl methyl ketone. The extent to which the reaction may be limited to nonenolizable imines, as in the analogous TMS-OTf-promoted reactions of silyl ketene acetals (see Section 4.1.3.2.2.iii),135 136 is not reported. The authors describe some spectral characteristics of an insoluble material formed by treating benzylideneaniline with TMS-OTf in CHCb. The data are consistent with the derived N-silyliminium salt of (182), the putative reactive intermediate. 

The use of TMSOTf in the reaction of silyl ketene acetals with imines offers an improvement over other methods (such as Ti - or Zn -mediated processes) in that truly catalytic amounts of activator may be used (eq 17) this reaction may be used as the cmcial step in a general s5mthesis of 3-(l -hytIroxyethyl)-2-azetidinones (eq 18). ... 

Colvin and his coworkers [86] reported that reaction of N-silyl imines with silyl ketene acetals in the presence of either Znl2 or trimethylsilyl triflate and t-butyl alcohol, followed by in situ treatment of the intermediate N-silyl p-aminoesters with MeMgBr, produced JV-silyl-azetidin-2-ones in good yields. Following this procedure (Scheme 30), starting from the silyl ketene acetal 179 and the N-silyl imine 180, the p-lactam 181 was produced in 44% yield as a... 

As outlined in the previous paragraph, chiral Brpnsted base organocatalysts appear to be most effective when equipped with an additional Brpnsted acidic moiety, for example, hydrogen bond donors like (thio)urea. Apparently, both functionalities catalyze the asymmetric Mannich reaction in a cooperative fashion, that is, simultaneous activation of both the nucleophile and the electrophile. However, activation of the electrophile can also be accomplished with a single, enantiomerically pure Brpnsted acid. In this respect, readily available chiral phosphoric acids are most commonly applied [88-90]. In 2004, the groups of Akiyama and Terada independently from each other reported the first asymmetric Mannich reaction of silyl ketene acetals or acetyl acetone with imines utilizing chiral phosphoric acid catalysts, which... 

Equiv of the imine 2 is dissolved in the appropriate solvent and 1 cquiv of the silyl ketene acetal 1 is added, the mixture is cooled to —70 °C and 0.1 equiv of TMSTf is added. After 15 h the reaction is quenched with H.O. 10% aq NH40H is added to make the piT basic, and the reaction mixture is extracted with F.tOAc. The crude product (obtained after the usual workup) is subjected to silica gel chromatography (pet. cthcr/Et20) to give the pure /J-amino ester 3. 

Since then, efficient catalytic asymmetric methods have been developed for the addition of silyl enol ethers or silyl ketene acetals to imines with chiral metal catalysts [29-34], Recently, direct catalytic asymmetric Mannich reactions which do not require preformation of enolate equivalents have appeared. 

A 5-mL flask was charged sequentially with catalyst (15 mg, 25 pmol, 0.05 equiv) and anhydrous toluene (250 pL). 3-Pyridylaldehyde N-Boc imine (0.53 mmol, 1 equiv) was added in one portion with stirring. When the solution was homogeneous, the flask was immersed in a dry ice/acetone bath and cooled to —30 °C. Silyl ketene acetal (216 mg, 1.0 mmol, 2 equiv) was then added slowly along the flask wall over 10 min. The flask was sealed under a nitrogen atmosphere and stirred at -30 °C for 48 h. Excess silyl ketene acetal was quenched at -30 °C via the rapid addition of a 3 M solution of trifluoroacetic acid in toluene (500 pL cooled to -20 °C prior to addition). The reaction was allowed to warm to 5 °C,... 

The original assignment of the absolute configuration (3S) for products 12 based on a comparison of the optical rotation value with a reported one for the phenyl derivative [27] must be considered uncertain. It would contradict the preferred attack of the nucleophile from the unshielded back side and the stereoselectivity observed in the reaction of A -galactosyl imines 7 with prochiral bis-silyl ketene acetals [28]. N-Galactosyl P-amino acids 13 are produced from bis-silylketene acetals in high yields and excellent diastereoselectivity (Scheme 10). The configuration at the P-position is R. 

Yamamoto and co-workers found that 27 is an excellent chiral promoter not only for the aza Diels-Alder reaction of aldimines [40] but also for the stereoselective aldol-type reaction of aldimines with ketene silyl acetals [55]. The reaction of (5)-benzyli-dene a-methylbenzylamine with trimethylsilyl ketene acetal derived from terf-butyl acetate in the presence of (R)-27 produces the (R) adduct in > 92 % diastereomeric excess (de), whereas reaction with (5)-27 gives the adduct in 74 % de. In a similar way, (5)-butylidene a-methylbenzylamine, an aliphatic imine, can be converted to the (R)-)3-amino ester in 94 % de by use of (R)-27 (Eq. 73). 

The reaction of an acetylenic imine and silyl ketene acetal with (R)-27 as a Lewis acid catalyst produces the aldol adduct with extremely high anti selectivity anti syn = 40 1) it is converted to the /3-lactam by use of Ohno s method, which is transformed into the key intermediate for (-i-)-PS-5 (Eq. 74). 

BLA 28 is very useful in the double stereodifferentiation of aldol-type reactions of chiral imines [41], Reaction of (5)-benzylidene-a-methylbenzylamine with trimethyl-silyl ketene acetal derived from tert-butyl acetate in the presence of (R)-28 at -78 °C for 12 h provides the corresponding aldol-type adduct in 94 % de (Eq. 78). Including phenol in the reaction mixture does not influence the reactivity or the diastereoselec-tivity. The aldol-type reaction using yellow crystals of (R)-28.(5)-benzylidene-a-methylbenzylamine PhOH proceeds with unprecedented (> 99.5 0.5) diastereoselec-tivity (Eq. 79). In general, 28 is a more efficient chiral Lewis acid promoter than 27. 

The electron-rich nature of silyl ketene acetals enables their facile coupling with imines in the presence of a titanium salt [101,102]. Interesting results are obtained from comparison of the efficiency of a titanium salts of the type 71X4. Switching the halogen X from F to Cl to Br to I, uniformly increases the product yield and diaster-eoselectivity of the TiX4-catalyzed reaction between a ketene silyl acetal and an imine (Eq. 28) [103]. The finding illustrated by Eq. (28) was further applied to diastereose-lective carbon-carbon bond formation as shown in Eq. (29) [103]. More examples of the titanium-mediated reaction of ketene silyl acetals and imines or their derivatives, for example (N,6>)-acetals, are summarized in Table 3. 

Asymmetric Mannich-type reactions provide useful routes for the synthesis of enantiomerically enriched P-amino ketones or esters [48a, 48b]. For the most part, these methods involve the use of chirally modified enolates or imines. Only a handful of examples has been reported on the reaction of imines with enolates of carboxylic acid derivatives or silyl ketene acetals in the presence of a stoichiometric amount of a chiral controller [49a, 49b, 49c]. Reports describing the use of a substoichiometric amount of the chiral agent are even more scarce. This section contains some of the most recent advances in the field of catalytic enantioselective additions of lithium enolates and silyl enol ethers of esters and ketones to imines. 

Saigo and coworkers have recently investigated the stereochemistry of the addition of silyl ketene acetals to N-sulfonyl imines [37]. In preliminary studies, the addition of E/Z mixtures of ketene silyl acetal 66 to an N-sulfonyl imine was investigated (Scheme 14). From these results, it appears that the major product of the reaction is always the anti isomer 67, and that the products 67 and 68 are both derived from the E isomer of 66 (ie, the Z isomer is totally unreactive). Since the ketene acetal 66 configuration was critical to the condensation reaction, the bis-silyl compounds 70 were investigated as an alternative (Scheme 15). It was found that this type of ketene acetal reacts stereoselectively with N-sulfonyl imines 69 using TiBr4 as catalyst. As can be seen from the data in Scheme 15, the anti products 71 predominated over the syn 72 in all cases. 

The TiCU-mediated reaction of enol silanes with imines was first introduced by Ojima and coworkers in 1977. The reaction was then extended to several similar substrates, i.e. nitrones, ot-methoxycarba-mates, aminals, 4-acetoxyazetidin-2-one, 40 anj to different Lewis acids, i.e. SnCU, TiCU-(0PH)2, catalytic ZnX2, catalytic TMSOTf, ° to give good yields of the addition products with low levels ( 80 20) or a complete lack of simple stereoselection. Moderate to good anti selectivities were reported in the addition of silyl ketene acetals to imines under particular reaction conditions (equation 9) significant results are summarized in Table 4. 

A -Methylephedrine-derived silyl ketene acetals react with imines in the presence of 2 mol equiv. of TiCU to give P-amino esters (equation 15) significant results are summarized in Table 7. With benzyl-ideneaniline the reaction is anti selective (entry 1), while with imino esters that chelate TiCU to give complexes such as (41), the reaction is syn selective (entries 2 and 3), in agreement with the general prin-... 

The Mannich reaction has been reviewed comprehensively by Blicke (1942), Reichert (1959), Hell-mann and Opitz (1960), and Tramontini (1973). These reviews also include synthetic applications of Mannich bases. Mechanistic studies of the Mannich reaction have been reviewed by Thompson (1968). Some variants of the Mannich reaction have been covered as subtopics in other reviews for example. Layer (1963) and Harada (1970) have reviewed general additions of stabilized carbanions to imines, while Bdhme and Haake (1976) have reviewed similar additions to methyleneiminium salts. In more specific reviews, Pai and coworkers (1984) have summarized stabilized carbanion additions to 3,4-dihy-droisoquinolines and 3,4-dihydroisoquinolinium salts in connection with the total synthesis of protober-berines and phthalide isoquinolines, and Evans et al. (1982) " have analyzed the stereochemical aspects of ester enolate and silyl ketene acetal additions to imines. 

Largely stimulated by the synthesis of 3-lactam antibiotics, there have been widespread investigations into the stereochemical aspects of imine condensations, mainly involving reactions of enolates of carboxylic acid derivatives or silyl ketene acetals. In analogy to the aldol condensation, stereoselectivity of imine condensations will be discussed in terms of two types in this chapter (i) simple dia-stereoselectivity or syn-anti selectivity, when the two reactants are each prochiral (equation 12) and (ii) diastereofacial selectivity, when a new chiral center is formed in the presence of a pre-existing chiral center in one of the reactants (e.g. equation 13). The term asymmetric induction may be used synonymously with diastereofacial selectivity when one of the chiral reactants is optically active. For a more explicit explanation of these terms, see Heathcock s review on the aldol condensation. ... 

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