Chapter 2
Reactions of Imines

2.1 Nucleophilic Addition Reactions

Nucleophilic addition reactions of imines are perhaps the most widely studied area within the chemical literature of chiral Brønsted acid catalysis. In fact, most transformations in this book would fall into this category, even though they may be known more formally by a named reaction. We have carefully chosen which specific reactions deserve to be grouped into their own category, and therefore in this section, we will cover the literature that does not fall discreetly in the upcoming subsections.

2.1.1 C-Nucleophiles

The construction of C-C bonds is an organic transformation that arguably has attracted the greatest level of attention from the synthetic community. This fundamental process is integral in the art of molecular assembly. Shortly following the seminal papers of chiral phosphoric acids by Akiyama and Terada as organocatalysts [1, 2], Terada developed the direct alkylation of N-acylimines 1b with a-diazoesters 1a catalyzed by PA 1 (Scheme 2.1) [1].

Scheme 2.1 Alkylation of a-diazoesters with imines by Terada [1].

The reaction with a variety of aromatic imines gave the corresponding products 1c in good yields and high enantiomeric excesses. The nature of the protecting group was found to have a modest effect on the level of selectivity; while alkyl-protected imines failed to demonstrate any reactivity, N-acyl imines bearing a 4-(NMe2)C6H4 substituent provided the highest selectivities. The products could be routinely transformed into ß-amino acid derivatives without any loss of enantiopurity.

The mechanism of the process is depicted in Scheme 2.2. Activation of the imine by the catalyst is proposed to occur by hydrogen-bonding interactions with the basic nitrogen atom; however, such interactions may also be occurring with the oxygen atom of the amide unit. Addition of the diazoester to the imine occurs followed by an intramolecular deprotonation by the phosphoryl oxygen to yield the product. In 2012, Peng showed that a-diazophosphonates could also be used as suitable coupling partners to imines in the presence of only 0.1 mol% of a chiral phosphoric acid [3].

Scheme 2.2 Mechanism of diazoester additions to imines [1].

The field of chiral Brønsted acids is largely dominated by phosphoric acids and, surprisingly, carboxylic acids, which constitute an important class of acids, rarely feature as asymmetric catalysts. Over the past few years, Maruoka has been one of the pioneers attempting to bring carboxylic acid catalysts to the market. His seminal work reported on the addition of diazo-substrates 2a to imines 2b in the presence of chiral dicarboxylic acid BA 1 (Scheme 2.3) [4, 5].

Scheme 2.3 Alkylation of diazoesters with imines by Maruoka [4].

The reaction proceeds under mild conditions and delivers the products 2c in comparable yields and enantioselectivities to those reported by Terada (cf. Scheme 2.1) using a phosphoric acid. The structure of the catalyst has been elucidated, and it shows that it possesses a wide dihedral angle (93.4°) when compared to a typical phosphoric acid catalyst (55°) [6]. This property coupled with the presence of internal hydrogen bonding is thought to be crucial for the efficient control of stereoselectivity. The scope of this methodology has been extended by Maruoka to include diazosulfone and hydrazone components [6, 7].

The nature of the substituent of diazo-coupling partners is known to dictate the course of reactivity, and in 2008, Maruoka discovered that by using diazoacetamides 3a with N-Boc imines 3b, the reaction proceeded to yield trans-aziridine products 3c in good yields and with high enantioselectivities (Scheme 2.4) [8]. Once again, a dicarboxylic acid (BA 2) was used, and this aza-Darzens reaction, as it is formally known, represents a useful expansion for the utility of this class of catalysts. Maruoka has also performed this reaction with diazoacyl oxazolidinones, which provides access to tri-substituted aziridines [9].

Scheme 2.4 Aziridination with imines by Maruoka [8].

A similar reaction was studied by Akiyama in 2009, who found that imines formed in situ from amine 3d and glyoxals 3e could react with diazoacetate 3f to give cis-aziridines 3g with high enantioselectivities (Scheme 2.5) [10]. Akiyama needed the use of just 2.5 mol% of PA 2, which interestingly provided the complementary diastereoisomer to Maruoka's work.

Scheme 2.5 Aziridination with imines by Akiyama [10].

The mechanism of aziridination is shown in Scheme 2.6. The process commences in a similar manner to the addition reaction whereby activation of the imine occurs followed by addition of the diazo-nucleophile. It is proposed that the acidity of the a-proton is reduced due to the adjacent amide group (as opposed to an ester group) and, therefore, deprotonation is less favorable. Instead, the nitrogen attacks the a-carbon, eliminating N2 and forming the aziridine product. The acidity factor may well hold true for Maruoka's work, but Akiyama's aziridination process may be more reliant on a judicial choice of catalyst. This reaction has also received attention from Zhong, who utilized diazoacetamides with a phosphoric acid catalyst [11].

Scheme 2.6 Mechanism of aziridination with imines [8].

In 2006, Terada published an aza-ene-type reaction of enecarbamate 4a with imines 4b using a very low loading of 0.1 mol% of PA 1 (Scheme 2.7) [12]. The reaction efficiently yields 4c with high enantioselectivities. Noteworthy is that the reaction can be performed on a gram scale while employing a substrate:catalyst ratio of 1000 : 1 without any detrimental performance.

Scheme 2.7 Aza-ene reaction by Terada [12].

The mechanism of the aza-ene reaction is outlined in Scheme 2.8. It is proposed that the phosphoric acid plays a bifunctional role during the transition, which involves simultaneous activation of both the imine and the enamine partners. Subsequent addition followed by proton transfer yields the desired product and regenerates the catalyst.

Scheme 2.8 Mechanism of aza-ene reaction [12].

Terada has explored the scope of this reaction and extended it to prepare piperidines by the use of 2 equiv. of enamine [13]. A multicomponent variant whereby the imine is generated in situ has also been explored by Masson and Zhu, which provides access to 1,3-diamines in good yields and with high enantioselectivities [14]. Mechanistically related Friedländer condensation, involving the addition of enamines to imines, has been shown by Gong to be suitably catalyzed by a phosphoric acid [15]. More recently, cascade processes involving in situ generated enamines and imines coupling together in an intramolecular fashion have been shown by Shi [16, 17].

In 2011, Momiyama and Terada disclosed the use of a fluorinated phosphoric acid catalyst ([H8]-PA 3) to perform highly enantioselective Hosomi-Sakurai reactions of imines 5b with allyl silane 5a (Scheme 2.9) [18].

Scheme 2.9 Allylation of imines by Momiyama and Terada [18].

The reaction performs best when a stoichiometric amount of catalyst is used since the catalyst becomes silylated and hence is inactive after one cycle. It was, however, shown that, when a racemic phosphoric acid is used in conjunction with 20 mol% of [H8]-PA 3, satisfactory enantioselectivities of the products 5c could be achieved. List has also studied this reaction with disulfonimide catalyst BA 3 to deliver similar products 5g with good enantioselectivities (Scheme 2.10) [19].

Scheme 2.10 Allylation of imines by List [19].

The mechanism of the allylation is illustrated in Scheme 2.11. Activation of the imine occurs by hydrogen-bonding interactions with the phosphoric acid catalyst. This is followed by the attack by the allyl silane to form a ß-silyl carbocation, which is captured by the phosphate anion of the catalyst. This leads to the products and the silylated catalyst. In the nonstoichiometric variant, an achiral additive (usually an acid) would desilylate the catalyst and thus the process would become catalytic.

Scheme 2.11 Mechanism of allylation of imines [18].

Hydrazones are recognized for their nucleophilicity due to the resonance effect of the nitrogen's lone pair and serve as highly versatile synthetic intermediates. In 2007, Rueping demonstrated the coupling of hydrazones 6b with imines 6a in the presence of catalyst [H8]-PA 4 (Scheme 2.12) [20]. These mild conditions deliver the valuable products 6c with good selectivities.

Scheme 2.12 Hydrazone addition to imines by Rueping [20].

A similar approach has been described by Maruoka (Scheme 2.13), who showed the use of catalyst BA 1 to yield 6f with comparable enantiopurities [21]. Interestingly, although both groups employed the...