N-benzyl imines

Until now, few acyclic N-alkyl imines or the corresponding amines have been found to be of practical industrial importance. Most studies reported herein were carried out with model substrates, especially with the N-benzyl imine of acetophenone 5a and some analogues thereof (Fig. 34.7). One reason for this choice could be the easy preparation of a pure crystalline starting material, and another reason might be that the chiral primary amines can be obtained by hy-drogenolysis of the benzyl group. As can be seen in Table 34.4, there are several catalyst systems with fair to good ee-values and activities. 

Exploiting the Lewis basic phosphoryl oxygen of Im, Terada reported the direct alkylation of a-diazoesters with N-acyl imines to afford P-amino-a-diazoesters in high yields and ee s (Scheme 5.12) [23]. Earlier, Johnston had observed that catalytic TfOH promoted aziridine formation (Aza-Darzens reaction) between diazoacetates and N-benzyl imines [24]. The authors propose that aziridine formation is circumvented through C—H bond cleavage by the phosphoryl oxygen of 1 (Intermediate A). However, as noted by the authors, the low nucleophilicity of N-acyl imines might also be considered as the cause of this selective transformation. 

In the presence of 42 (2mol% loading), aliphahc and aromafic N-allyl as well as N-benzyl aldimines were efficiently converted after 20 h at -70 °C in toluene to the respective Strecker adducts and subsequently trifluoroacetylated to obtain the products 1-10 in good to excellent yields (65-99%) and ee values J7-97%) (Scheme 6.41). It turned out that N-benzyl imines could be used as substrates without significant difference in comparison to analogous N-allyl imines (e.g., N-benzyl adduct 8 85% yield, 87% ee N-allyl adduct 9 88% yield, 86% ee Scheme 6.41). 

In addition, acyclic aliphatic N-allyl imines and cycloalkylimines were acceptable starting materials for the asymmetric hydrocyanation and enantioselectivity of up to 95% ee was obtained by use of 10a as catalyst [10]. Representative examples of the range of substrates are summarized in Scheme 5.6. It should be added that as an alternative to the N-allyl imines the analogous N-benzyl imines can be efficiently used as starting material [10]. An optimized procedure for preparation of the catalyst 10a has recently been reported by the Jacobsen group [11]. 

Imines are, preferably, used in the N-Boc-protected form less electrophilic N-allyl and N-benzyl imines gave unsuccessful results [36], The tert-butyldimethyl-silyl ketene acetals are the most suitable silyl ketene acetal substrates. It should be added that a low temperature is required to suppress an undesired uncatalyzed reaction that leads to racemates. 

Table 6.27 Thiourea-catalyzed hydrophosphonylations of N-benzyl imines.

Yamamoto reported the first palladium catalyzed addition of allyltributyltin or allyltrimethylsilane to N benzyl imines [94]. Higher enantioselectivities are obtained if the reaction is performed in the presence of 1 equiv of water (Scheme 1.24). 

The [l- C]D-glucosamine has also been prepared using the aqueous solution obtained from the production of the cyanide ion. The N-benzyl imine of D-arabinose was... 

A tandem ring opening-cyclization reaction of 2-substituted 1,1-cyclopropane-diesters with N-benzyl imines in the presence of 5 mol% of Sc(OTf)3 was developed [149]. The 2,3,5-substituted pyrrolidines were obtained in moderate to high yields (42-98%) with high diaster eoselectivities (cis/trans = 8/1-30/1). 

Yamamoto and coworkers have also shown that tris(pentafluorophenyl)borane is a highly active catalyst for analogous imino-aldol reactions. Here, both the N-trialkylsilyl imines (72) (Equation 46) [44] and the N-benzyl imines (73) (Equation 47) [45] are applicable as electrophiles with ketene silyl acetals (74), and the reaction gives remarkably high yields of the N-benzyl imino-aldol adducts. 

Lanthanide triflates catalyze the Diels-Alder reaction of imines, generated from anilines and aldehydes, with both dienes and alkenes [26]. Thus N-benzyl-ideneaniline in the presence of Yb(OTf)3 (Scheme 6.16) reacts in organic solvent with open-chain dienes, such as Danishefsky s diene, to give tetrahy-dropyridine derivatives, while with cyclopentadiene and vinylethers and vinylthioethers it works like azadiene in both organic solvent and aqueous medium, affording tetrahydroquinoline derivatives. 

The asymmetric synthesis of 2,3-diamino acids can be accomplished by the addition of chiral enolates to prochiral imines. For example, reaction of morpholine-2-one 103, derived from (S)-phenylglycinol, with N-benzyl ben-zaldimine in the presence of pyridine and para-toluenesulfonic acid at high... 

The spiro compound 206 was prepared in five steps from (S)-l-naphthyl-ethylamine and was composed of a mixture of imine and enamine tautomers. Reduction of the imine function by sodium borohydride occurred on the less hindered si face, leading to the diamine with the R configuration of the newly formed stereo center, then the N-benzyl substituent was removed by hydrogenolysis to give 207 with good overall yield [98] (Scheme 30). 

The imine from benzaldehyde and benzyl amine (65 g, 0.33 mol) was added to phosphorous acid (27.3 g, 0.33 mol), and the mixture was stirred with heating. As the temperature reached 95 to 100°C, the entire mixture became a homogeneous liquid, which reacted vigorously as the temperature reached 115 to 120°C. After the reaction mixture became very viscous, it was allowed to cool, whereupon it condensed to a glass. The material was dissolved in aqueous sodium carbonate, which upon acidification precipitated pure N-benzyl a-aminobenzylphosphonic acid (90 g, 98%) of mp 233 to 234°C. The material exhibited analyses in accord with the proposed structure. 

The efficient addition-cyclization sequence described above could be successfully applied to the preparation of the polyhydroxylated y-amino acid (-)-detoxinine [73], The crucial key step in this fairly short synthesis is the chelate-controlled addition of lithiated benzyloxyallene 120 (R = Bn) to the chiral N-benzyl-substituted imine 121 as shown in Scheme 8.31. The required skeleton of the natural product was generated in good overall yield. 

Figure 6.16 Structure optimization of 42 in the asymmetric Strecker reaction of N-benzyl-protected 2-methylpropionaldehyde imine identified tertiary amide-functionalized Schiff base thiourea 47 as the most enantioselective catalyst stmcture.

Eine gewisse Sonderstellung nehmen die Nickel(ll)-Komplexe I3-4 der Imine von Glycin oder CR,J>)-Alanin mit (S)-2-[(N-Benzyl-prolyl)-amino]-benzaldehyds oder -benzophe-non6 ein In diesen sind das die optische Aktivitat induzierende Zentrum und die prochirale Gruppe gegenseitig starr angeordnet4 ... 

In einer Eintopf-Reaktion bilden racemische Aminosauren mit (S)-2-[(N -Benzyl-prolyl)-amino]-benzaldehyd bzw. -acetophenon und Kupfer(II)-Ionen diastereomere Imin-Kom-plexe im Verhaltnis 1 1 (vgl. S. 500) ... 

Additions to A-TMS imines proceeded analogously, except that the A-TMS grouping was cleaved under the reaction conditions (Table 24). The 1H NMR spectra of the NH aziridine products contained broad signals indicative of a mixture of N—H stereoisomers. However, upon N-benzylation, these products were converted to the previously prepared trans-aziridines, thereby confirming the expected anti selectivity of the addition. 

Carried out on a small multi-gram scale, the overall yield over the four recycle loops in the unoptimized process was 49% (based on the amount of racemate added throughout the investigation) compared to a traditional single-step resolution yield of -30% of the N-benzyl amine, demonstrating some improvement from an early stage. The product was isolated in 80-90% ee over each loop and required a final crystallization of the combined material from acetone to bring it up to the required specification. The main losses were to the imine, and, in a separate experiment, treatment of this under the SCRAM racemization conditions in the... 

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