Mannich reaction using boronic acids

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

In its most general form, the boronic acid Mannich or Petasis reaction18 involves the reaction of boronic acid 22, a carbonyl compound 8, and an amine 23 to produce secondary amines 24. If one uses a-keto acid 25 for the carbonyl component then the corresponding product from the Petasis reaction was a-amino acid 26. The key mechanistic step was proposed to occur intramolecularly with alkyl migration from intermediate boronate ester 28 formed from aminol 27. 

Functionalized 2,5-dihydrofurans (21) have been prepared by a Petasis borono-Mannich reaction, using a 4-substituted l,2-oxaborol-2(5//)-ol and salicylaldehyde. ° The amine-catalysed process combines a boronic-acid-based Mannich reaction with an intramolecular Sj 2 cyclization. 

Nucleophiles other than hydride can be added to support-bound imines to yield amines. These include C,H-acidic compounds, alkynes, electron-rich heterocycles, organometallic compounds, boronic acids, and ketene acetals (Table 10.9). When basic reaction conditions are used, stoichiometric amounts of the imine must be prepared on the support (Entries 1-3, Table 10.9). Alternatively, if the carbon nucleophile is stable under acidic conditions, imines or iminium salts might be generated in situ, as, for instance, in the Mannich reaction. Few examples have been reported of Mannich reactions on insoluble supports, and most of these have been based on alkynes as C-nucleophiles. 

A further development of the Mannich reaction is the boronic Mannich reaction, which has been described extensively by Petasis and co-workers under conventional heating methods. Gupta et al. (Personal Chemistry, Uppsala, Sweden, internal report) have performed this reaction under microwave condition in acetonitrile (Scheme 5.11). A reaction time of 4 min at 120° C afforded the products in yields ranging from 25 to 100%. Alternative amines and boronic acids could be used, but the glyoxylic acid was essential for product formation. The major drawback with this reaction under microwave conditions at present is that the outcome is highly substrate dependent. 

Regardless of how it does take place, the fact that this addition is irreversible certainly imparts a clear advantage. In the classical Mannich, the reversibility of the final step limits the number of cases where the yields are synthetically useful. By comparison, the Boronic Acid Mannich Reaction permits a much broader scope of conversions to be carried out. 

Tertiary amines can serve as amine substrates for the boron-Mannich reaction, providing aromatic alkylation products of N,N-dialkyl-3-alkoxyanilines (Equation (125))573 and 1,3,5-alkoxy- or hydroxybenzenes (Equation (126)).574 The use of chiral diol esters of ( )-2-phenylethenylboronic acid for enantioselective alkylation resulted in 6-15% ee.575... 

Other Uses. Reagent 1 has been used for enantioselec-tive enolborination, albeit with poor (1.1 1) selectivity. Similar bis-sulfonamide-derived boron Lewis acids have been used for aldol additions, "" ester-Mannich reactions, Diels-Alder reactions, Ireland-Claisen reactions, and [2,3]-Wittig rearrangements. Similar bis-sulfonamide-derived aluminum Lewis acids have been used for aldol additions, Ehels-Alder... 

In addition to the very important palladium-catalysed reactions, boronic acids undergo a number of useful reactions that do not require transition-metal catalysis, particularly those involving electrophilic ipso-substitutions by carbon electrophiles. The Petasis reaction involves ip,y(9-replacement of boron under Mannich-like conditions and is successful with electron-rich heterocyclic boronic acids. A variety of quinolines and isoquinolines, activated by ethyl pyrocarbonate, have been used as the Mannich reagent . A Petasis reaction on indole 3-boronic acids under standard conditions was an efficient route to very high de a-indolylglycines. " ... 

Another device for bringing thiophenes into reaction with Mannich intermediates is to utilise thiophene boronic acids - the Petasis reaction primary aromatic amines can also be used as the amine component. ... 

The oxazaborolo-benzoxazaborininone derivatives 116 of resorcinar-ene were synthesized in 50—75% yields and in 98% de via a Mannich reaction with L-prohne followed by treatment with a boronic acid or ester (Scheme 38) (2003TA2787). Introduction of the electrophilic boron atom into this structure opens up a potential use for the catalysis of asymmetric reactions. The derivatives 116 were determined to exist as either crown or diamond conformers according to ID and 2D NMR experiments. Similar derivatives can also be prepared from (lS,2R)-ephedrine (2004MI75). 

The preparation of such dihydropyrans derivatives 21-23 modified at the C-6 position by a hydrophobic substituent (zsopentyl side chain) analogous to the oseltamivir side chain is summarized in Scheme 7. It uses the borono-Mannich Petasis reaction between an amine, ot-hydro)yaldehyde 25 and boronic acid 26. This reaction proceeds with remarkably high stereocontrol, producing 1,2-aminoalcohols with an a tf-configuration. The resulting acyclic aminoalcohol 24 is the key precursor to the functionalized cyclic dihydropyrans 21-23 with the proper functionality and stereochemistry at C4. 

Organoboron compounds have gained special attention and importance in the last years due to their use in different processes, but one of the most important and efficient protocols is the multicomponent Petasis-borono-Mannich (PBM) reaction [17-19]. In this approach, an amine, an aldehyde, and a boronic acid react to give access to a new amine... 

Ionic liquids [61], were found to accelerate the Petasis boron Mannich reaction of 2-hydroxy aryl aldehydes, secondary amines, and arylboronic acids, under mild conditions, by the group of Yadav [62]. As far as we are aware, these authors were the first (and only ) to report the use of ionic liquids in this reaction. The remarkable features of this procedure were the improvement of yields in the synthesis of the desired products, as well as enhanced reaction rates and the possibility of recycling the ionic liquid for up to five times without apparent loss in enantioselectivity. 

Subsequent to this, there have been numerous reports of the use of this reaction using alkenyl, alkynyl and arylboronic adds or esters in reactions with a range of amines and aldehydes. This reaction has been variously named the boronic Acid Mannich , boronic Mannich , boro-Mannich , Petasis boronic acid-Mannich , Petasis borono-Mannich , and Petasis" reaction. The more indusive term of Petasis borono-Mannich reaction will be used throughout this chapter. 

The use of chiral boronic esters in the Petasis borono-Mannich reaction has been reported to result in low levels of enantioselectivity of the adducts at room temperature (6-15% ee) [48]. Auxiliaries used in this study by Scobie and co-workers included pinanediol and tartaric acid derived alkenylboronates. Morpholine was the only secondary amine used, with the primary amine ethyl glycinate failing to react. 

Finn and Petasis have independently shown that salicylaldehyde is a suitable aldehyde for the Petasis borono-Mannich reaction, with alkenyl, aryl and heteroaryl-boronic acids (Equation 6) [30, 31]. The reaction works best for aliphatic secondary amines, as in the formation of 41 primary amines give modest yields of adducts 41. Benzaldehydes lacking ortho hydroxyl functionality do not react, with even ortho methoxy functionality being unsuitable, which is consistent with a tethering mechanism via putative intermediate 9 (Figure 7.3). Petasis and Boral reported that reactions occurred at room temperature over 24-36 h, using EtOH, MeOH or acetonitrile. 

Low stability of the functionalized allyl boronates may limit their synthetic application. Alternative progress towards a workable Petasis borono-Mannich reaction offers a new solution to this problem in situ generation and use of allylboronates [18]. This one-pot route to stereo-defined a-amino acids is outlined in Scheme 8.6. 

In recent years, catalytic asymmetric Mukaiyama aldol reactions have emerged as one of the most important C—C bond-forming reactions [35]. Among the various types of chiral Lewis acid catalysts used for the Mukaiyama aldol reactions, chirally modified boron derived from N-sulfonyl-fS)-tryptophan was effective for the reaction between aldehyde and silyl enol ether [36, 37]. By using polymer-supported N-sulfonyl-fS)-tryptophan synthesized by polymerization of the chiral monomer, the polymeric version of Yamamoto s oxazaborohdinone catalyst was prepared by treatment with 3,5-bis(trifluoromethyl)phenyl boron dichloride ]38]. The polymeric chiral Lewis acid catalyst 55 worked well in the asymmetric aldol reaction of benzaldehyde with silyl enol ether derived from acetophenone to give [i-hydroxyketone with up to 95% ee, as shown in Scheme 3.16. In addition to the Mukaiyama aldol reaction, a Mannich-type reaction and an allylation reaction of imine 58 were also asymmetrically catalyzed by the same polymeric catalyst ]38]. 

---