Imine with boron Lewis acids

Boron Lewis acids have been employed routinely to activate carbonyl and imine functionalities toward nucleophillic attack. This section describes examples of achiral and chiral Mukaiyama-aldol reactions as well as carbonyl addition chemistry that require activation with boron Lewis acids. 

Probably the most widely applicable asymmetric imine aziridination reaction reported to date is that of Wulff et al. These workers approached the reaction from a different perspective, utilizing the so-called vaulted , axially chiral boron Lewis acids VANOL and VAPOL [35] to mediate reactions between ethyl diazoacetate and N-benzhydrylimines (Scheme 4.29) [36]. The reactions proceed with impressive enantiocontrol, but there is a requirement that the benzhydryl substituent be present since this group is not an aziridine activator there is, therefore, a need for deprotection and attachment of a suitable activating group. Nonetheless, this method is a powerful one, with great potential for synthesis, as shown by the rapid synthesis of chloroamphenicol by the methodology [37]. 

The combination of metal tuning and double stereodifferentiation helps to prepare chelation and nonchelation products in the imine series7. In the case of an alkoxy substituent adjacent to the aldimino, the chelation product 10 is predominantly obtained with allylmagnesium chloride, chloromagnesium allyltriethylaluminate or allylzinc bromide, while the use of allyl-boronates or allyltitanium triisopropoxide, which lack the requisite Lewis acidity for chelation, gives 11 with good Cram selectivity. 

Inverting the orientation of the C4-N3 imine unit of a 2,3,1-diheterabotine gives a boron heterocycle with a markedly different chemical reactivity. In effect, the weakly basic oxime- or hydrazone-type imine nitrogen in the 2,3,1-diheteraborine is replaced by a much more basic imidate- or amidine-type imine nitrogen in the 2,4,1-diheteraborine. Likely, the Lewis acid tendency of the boron is enhanced by the ready protonation of this basic N4, and the formation of a stable borate-based zwitterion becomes thermodynamically favored. 

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. 

Imines may be activated by complexation with Lewis acids, but this also increases the acidity of a-hydrogen atoms. A combination of copper(i) halide and boron trifluoride etherate is a possible solution to the problem [6, 7]. Activation by trimethylsilyl triflate is also effective with aldimines (though not with ketimines) [7, 8]. 

Diphenyl-BINOL-derived chiral aluminum reagents are prepared in situ by addition of Ethylaluminum Dichloride or Diethylaluminum Chloride to 3,3 -diphenyl-BINOL. These chiral aluminum reagents promote the enantioselective Diels-Alder reaction of cyclopentadiene with the oxazolidone dienophile (eq 14). Endo products are obtained with a high level of asymmetric induction (>90% ee) however, a stoichiometric amount of the Lewis acid is required. The preparation and use of a C3 symmetric BINOL-derived boronate has been reported (eq 15). BINOL-B(OAr)3 complexes have recently been developed for the asymmetric Diels-Alder reaction with imines (eq 16). ... 

While aromatic aldimines of amino acid esters are readily accessible from benzaldehyde or related derivatives and amino acid esters with concomitant removal of water,the corresponding ketimines require harsher reaction conditions, e.g. the benzophenone imine of glycine methyl ester is formed in boiling xylene in the presence of boron trifluoride-diethyl ether complex as a Lewis acid in 82% yield.P l These or similar reaction conditions lead also to piperazine-2,5-dione (DKP) formation therefore milder reaction conditions have been developed such as the transimination with benzophenone imine in dichloromethane, which occurs at room temperature overnight in 80-95% yield (Scheme The N -diphen-... 

Hydrogenation of 2-isoxazolines over Raney nickel as catalyst and in the presence of acids often leads first to 1,3-hydroxyimines, and then, through hydrolysis, to 1,3-hydroxycarbonyl compounds. In some cases the stereochemical integrity of the starting material is maintained, but in others hydrolysis of the intermediate imines may cause scrambling of stereochemistry at the a-carbon atom. Rapid protonation of the imine function minimizes this possibility and the use of Lewis acids, such as boron trichloride or aluminum trichloride which release hydrochloric acid on contact with moist methanol, is frequently recommended. Boric acid serves a similar purpose and is effective in, for example, the stereocontrolled reductive ring opening of the 2-isoxazoline (135) en route to crispatic acid (136 Scheme 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]. 

Allylations of aldehydes and imines also constitute important carbon-carbon bond-forming reactions [14]. A range of metal-based Lewis acid catalysts have been reported. Hall and co-workers described the Bronsted acid-catalyzed allylation of aldehydes with allyl boronate (Equation 10.8) [15]. 

Of the various imines known to condense with active methylene compounds, a-arylimines have been the most widely used, especially in earlier work, because of their stability, ease of preparation and the absence of enolizable protons. Aliphatic imines containing enolizable protons have broader synthetic applications but their use is more restricted because they are prone to deprotonation and self aldol type condensations. As will be discussed, new methods utilizing Lewis acids and the less basic boron enolates have been devised to overcome the problem of deprotonation. Other innovations that have extended the scope of imine condensations include in situ methods for the preparation of elusive formaldehyde imines (CH2=NR2> and the utilization of A/-heterosubstituted imines (N = Si, O and S) for the synthesis of primary Mannich bases and A(-unsubstituted 3-lactams, available via hydrolysis or reduction of the N—X bond. 

In contrast with the more reactive crotyl reagents discussed above, crotyl-silanes, -stannanes and -boronates can be prepared in isomerically pure cis and trans forms for use in imine and aldehyde addition reactions. However, isomerization of these reagents under certain reaction conditions, particularly those requiring the presence of Lewis acids, cannot be ruled out. Nonetheless, in connection with a study involving aldehyde additions, Yamamoto et al. have shown that frans-crotyltri-n-butylstannane is stable to BF.vEt20 at -78 C. ... 

As shown in Fig. 8, two possibilities are conceivable for the addition step of the imine to the lanthanoid-phosphite complex Ha. To determine whether structure V or VI seems to be the more reasonable in the addition reaction of a dimethyl phosphite with the C=N double bond of cyclic imines, several hydrophos-phonylation experiments using different types of phosphites were carried out in the presence or absence of the Lewis acid boron trifluoride. As it was shown that a high level of Lewis acid activation of the imine is required independently from the nucleophilicity of the phosphorus nucleophile which was used, a transition state of type VI appeared to exist as the dominant transition state structure. 

An alternative approach to aziridine synthesis involves transfer of a carbenoid species to imines. Jacobsen achieved the first asymmetric aziridination of imines by transfer of copper carbenoids derived from copper bis-oxazohne catalysts and ethyl diazoacetate onto imines, but this process only proceeds with moderate yield and selectivity. Better results have been achieved by addition of ethyl diazoacetate to imines in the presence of enantiopure Lewis acids such as the boron-based catalysts prepared from vaulted biaryls such as VAPOL (4.154) and B(OPh)3. A range of aryl and alkyl N-benzylaldimines, for example (4.155) and (4.156), undergo aziridination to give ds-aziridines with high ee using this procedure. 

Alternative routes to pyrimidines, that avoid the later hydrogenation steps, were developed at Hoffmann-La Roche [46]. This alternative synthetic strategy is shown in Fig. 36. An amino-imine can be prepared in the same way, but this time it is not reacted with a substituted phenylmalonate. Instead an alkoxybenzaldehyde is subjected to a Wittig reaction with the phosphorus ylide of chloromethoxymethane to yield l-(4-al-koxyphenyl)-2-methoxyethane. Treatment with triethoxymethane in the presence of a Lewis acid such as boron trifluoride ether-ate gives the tetraethoxy derivative. Hydrolysis produces 2-(4-alkoxyphenyl)-3-me-thoxypropenal, reaction of this material with the imine results in the pyrimidine being formed directly. 

---