Aryl N-Boc imines

A particularly successfiil case of BB catalyzed aza-Henry reaction is the addition of arylnitromethanes to aryl N-Boc imines promoted by chiral bis(amidines) [44], Reactions carried out in toluene at —78 C employing 5mol% of catalyst 36 afford the corresponding aza-Henry adducts in good yields and enantioselectivities and high diastereoselectivities. The methodology has been appHed to the synthesis of (-)-nutlin-3, a potent p53/MDM2 inhibitor (Scheme 29.19). 

The first aza-Henry reaction promoted by a hydrogen bond donor-based catalyst, that is, thiourea 37, was described by Jacobsen in 2005 [45]. The addition reaction of nitromethane and nitroethane to aryl N-Boc imines in the presence of catalyst 37 and diisopropylethylamine (DIPEA) proceeds in very good yields and high diastereo- and enantioselectivity (Scheme 29.20). 

On the other hand, results obtained in the addition of nitromethane to aryl N-Boc imines in the presence of triethylamine and using catalyst 39 (ee 65-91%) seem to indicate that the incorporation of two thiourea groups in a chiral platform, BINAM-based 39, neither improves the stereochemical outcome of the reaction nor the catalyst activily, even with higher catalyst loading (20mol%). Only the single-step synthesis of the catalyst 39 from commercially available materials could represent an advantage [47]. 

In contrast to catalysts 37-39, which are neutral species with dual hydrogen bond donor capability, catalysts such as 40-43 are ionic displaying a hydrogen bond donor site that better resemble the proton (H" ), which is probably the most common Lewis acid found in Nature. The pioneering work carried out by Johnston showed the effectiveness of the chiral proton-based structure 40 in the addition of nitromethane and nitroethane to aryl N-Boc imines (Scheme 29.22) [48]. As a... 

Catalyst 40 and 41 have been employed in the synthesis of a-substituted anti-a,P-diamino phosphonic acid derivatives [50] and 5-amino acids [51], respectively. Subsequent modifications of the reaction conditions and catalyst structure (catalyst 42 in Figure 29.4) allowed also the synthesis of a-substituted syn-a,P-diammo acid derivatives of phenylalanine [52]. Further studies, aimed at improving catalyst 40 activity by addition of over-stoichiometric amounts of triflic acid, led to catalysts such as 43, which showed increased effectiveness in promoting the addition of unactivated nitroalkanes to either electron-poor or -rich aryl N-Boc imines ]53]. Although it seems that this type of catalysis is performed by activation through hydrogen bond, the concurrent intervention of the basic nitrogen of the quinoUne moiety could not be mled out. 

Ketenes are attractive due to their remarkable reactivity and wide application in the synthesis of cyclic compounds. Ye et al. and Smith et al. have independently demonstrated that NHCs are efficient catalysts for the reactions of ketenes. In 2008, Ye and co-workers reported the synthesis of chiral NHCs 84 derived from l-pyrolutamic acid, which could catalyze the reaction of aryl(alkyl)ketenes with N-Boc imine to give the corresponding p-lactams in good yield with good diastereo- and high enantioselectivities (Scheme 7.69). More importantly, the NHC-catalyzed... 

Scheme 6.13 The in situ generation of N-Boc imines from a-carbamoyl sulfone derivatives followed by their enantioseiective arylation with arylboronic acids, as described by Ellman s group [18b].

Acetaldehyde 34, which is the simplest of all enolizable carbonyl compounds but highly reactive as an electrophile, is an inexpensive and versatile two-carbon nucleophile in enamine-based Mannich reactions. Mannich reactions of acetaldehyde as a donor with aryl or alkyl substituted N-Boc-imines 90 are effectively catalyzed by (S) -proline (13) in moderate yield but excellent enantioselectivity (Table 28.6, entries 1 and 2) [47]. Chemical yields are improved up to 87% when N-benzoyl (Bz)-imine is employed in the presence of diaryl prolinol silyl ether 85 with p-nitrobenzoic acid (entry 3) [48]. To suppress side reactions, such as self-aldol reactions, the moderate nucleophilicity of the axially chiral amino sulfonamide 23 is particularly useful for this type of Mannich reaction these conditions give the corresponding adducts 91 in good yield and excellent stereoselectivity (entries 4 and 5) [49]. 

The aza-Henry reaction promoted by catalyst 31 deserves special attention. This bifunctional catalyst, which displays an additional hydrogen bond donor, afforded the best results in terms of yield and selectivity for the addition of nitromethane, nitroethane, or 1-nitropropane to various aryl and heteroaryl N-Boc imines (Scheme 29.13) [37]. Reactions carried out in acetonitrile at -20°C, employing 10mol% catalyst, provided the highest stereoselectivities achieved so far. 

An interesting protocol to concurrently produce adjacent quaternary and tertiary stereogenic centers was described employing the bifunctional thiourea-secondary amine 34, which promotes the addition of methyl 2-nitropropanoate to aryl and heteroaryl N-Boc imines. In this particular case, the secondary amine N-H group present in the catalyst seemed to play an additional role other than merely acting as a Br0nsted base (Scheme 29.17) [41],... 

Chiral ammonium betaines are a particular class of bifunctional BB-based catalysts that have been successfully applied in the aza-Henry reaction of N-Boc imines and a-substituted a-nitroesters [42]. The catalyst structure displays an intramolecular ion-pairing quaternary ammonium aryl-oxide and the mode of action may involve deprotonation of the pronucleophile by the basic anion to furnish and onium ion as its conjugate acid form. Catalyst loadings as low as lmol% produced the corresponding quaternary-tertiary aza-Henry adducts in excellent yields and enantioselectivities, albeit with low to moderate diastereoselectivities (Scheme 29.18). The lowest de s (up to 33%) were obtained with aliphatic N-Boc imines (R = CH2CH2Ph, -octyl). 

In 2008, the same group employed chiral dicarboxylic acid (R)-5 (5 mol%, R = 4- Bu-2,6-Me2-CgHj) as the catalyst in the asymmetric addition of aldehyde N,N-dialkylhydrazones 81 to aromatic iV-Boc-imines 11 in the presence of 4 A molecular sieves to provide a-amino hydrazones 176, valuable precursors of a-amino ketones, in good yields with excellent enantioselectivities (35-89%, 84-99% ee) (Scheme 74) [93], Aldehyde hydrazones are known as a class of acyl anion equivalents due to their aza-enamine structure. Their application in the field of asymmetric catalysis has been limited to the use of formaldehyde hydrazones (Scheme 30). Remarkably, the dicarboxylic acid-catalyzed method applied not only to formaldehyde hydrazone 81a (R = H) but also allowed for the use of various aryl-aldehyde hydrazones 81b (R = Ar) under shghtly modified conditions. Prior to this... 

Shortly thereafter, Terada demonstrated that the Mannich reaction between several N-Boc aryl imines and acetoacetone was effectively catalyzed by only 2 mol% of le (Scheme 5.2) [4]. In view of AMyama s work, this study is particularly significant because it suggested that le may act as a bifunctional catalyst [9] not only to form a chiral ion pair with the electrophile but also to activate the nucelo-phile through hydrogen bonding of the a-proton with Lewis basic phosphoryl oxygen. 

Dixon reported that saturated BINOL 45 sufficiently activates various N-Boc aryl imines toward Mannich reaction with acetophenone-derived enamines to yield P-amrno aryl ketones in good yields and enantioselectivities (Scheme 5.62) [116]. The same group applied a BINOL-derived tetraol catalyst to the addition of meth-yleneaminopyrroHdine to N-Boc aryl imines. Interestingly, appendage of two extra diarymethanol groups to the BINOL scaffold resulted in a marked increase in enantiomeric excess [117]. 

In Ught of the recent developments in thiourea, diol, and phosphoric-acid-mediated catalysis, far fewer studies have focused on the use of chiral carboxyhc acids as suitable hydrogen bond donors. To this end, Mamoka synthesized binaphthyl-derived dicarboxylic acid 49 which catalyzes the asymmetric Mannich reaction of N-Boc aryl imines and tert-diazoacetate (Scheme 5.65) [120]. The authors postulate that catalytic achvity is enhanced by the presence of an addihonal car-boxyhc acid moiety given that use of 2-napthoic acid as catalyst provided only trace amounts of product... 

The preparation of 3-aryl-A-(t-butoxycarbonyl)oxaziridines is readily accomplished by reaction of the A(-Boc-imines with lithium/n-chloroperbenzoate. ... 

N-acyl imines [144]. A slightly modified chiral Br0nsted acid 185 was found to catalytically induce addition of indoles to N-Boc-protected enecarbamates ISK) in high yields and enantioselectivities (Scheme 8.51) [145]. In a related study, Zhou demonstrated the use of a-aryl enamides to obtain optically enriched tertiary amine products [146]. 

Finally, Mukaiyama-Mannich-type reactions can also be induced and mediated by proton activation of the imine component, which thereby obtains a sufficient degree of reactivity to be attacked by highly nucleophilic silicon enolates. Thus, Wenzel and Jacobsen have shown that the specific protection by N-aryl substituents with a pendant ortho-hydioxy or ortho-methoxy chelating group is not required, if the acetate-derived sHyl ketene acetals 362 are reacted with simply BOC-protected aryl and hetaryl imines 361. Thus, P-amino esters 364 are obtained in excellent enantiomeric excess, if the reaction is catalyzed by the chiral urea derivative 363 that is assumedto act by activation through hydrogen bonding (Scheme 5.95) [181]. 

As mentioned above, the intrinsic non-directional nature of electrostatic interactions between substrates and monofunctional BB catalysts makes the development of highly selective processes in a predictable manner difficult. As an illustration, the few chiral guanidine organocatalysts that have been described that are capable of promohng the aza-Henry reaction between N-Boc aryl imines and nitromethane lead to the corresponding P-nitroamines in generally low enanhomeric excesses (20-70% ee) [43]. 

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