Additions to Imine Derivatives

Reactions of allylboronates with imines [119,120] and oximes [119,121-123] have also been documented. These reactions are attractive because they lead to homoallylic amines as products. They are much slower than similar reactions with aldehydes and the additions are often less selective. Prediction of their stereochemical outcome is complicated by the possibilities that they may proceed via boat-like transition states, and the imine or oxime substrate might undergo E-Z isomerization under the harsh conditions of the additions. Wuts and co-workers, however, observed that (E)-3-tri-alkylsilyl-substituted reagents like 85 are particularly effective for additions to N-ben-zyl imine derivatives (Equation 44) [124]. A few examples of enantioselective additions have been reported [125,126], one of the more successful being the addition of the 2-carboxyester allylboronate 86 to imine 87, yielding exo-methylene y-lactam 88 as a pure enantiomer (Equation 45) [127]. 

In the recent development of a one-pot borylation of allylic acetates (e.g., 37) followed by in situ addition to sidfonyl-imines, Szabo and co-workers observed that the palladium catalyst is required for the addition of the transient allylboronate 38 to the N-sulfonyl imine (Equation 46) [59]. The authors proposed the intermediacy of a bis-allylpalladium species to explain this result. These additions are highly regio- and stereoselective. 

Recently, Kobayashi and co-workers reported an interesting variant for the synthesis of homoallylic amines, dubbed an ammonia fixation reaction [128]. With this method, allylboronates are reacted with aldehydes in a solution of ethanolic ammonia. Despite the highly basic conditions, optically pure protected a-hydroxy aldehydes such as 89 can be employed without any observed racemization, and this approach was apphed to the synthesis of aminosugar derivatives via aminoalcohol product 90 (Equation 47). Unfortunately, the addition of a chiral camphor-based allylboronate to benzaldehyde led only to a low enantioselectivity (34% ee). Reactions with the ( )- and (2)-pinacol crotylboronates lead to the same diastereoselectivity seen in the corresponding reactions with aldehydes, affording the respective anti and syn products from a reaction mechanism that most likely involves the intermediacy of primary imines. 

Applications of Allylboronates in Tandem Reactions with Carbonyl Compounds 

Many recent advances in the synthetic applications of allylboronates have focused on the use of these reagents as key components of tandem reactions and one-pot sequential processes, including multicomponent processes. The following sections summarize some recent examples. 

---

To solve this problem, Pericas and co-workers have introduced a dual catalytic system consisting of a chiral amino alcohol 2, to control the enantioselectivity of the addition process, and a bulky silylating agent, to further activate the inline substrate (Scheme 1) [7]. When the 2/TIPSC1 system was used to promote the addition to imines derived from aromatic aldehydes, the addition reactions took place with good yield (63-75%) and high enantioselectivities (72-91%). Even in this case, a substoichiometric amount of chiral amino alcohol is required for a satisfactory result. 

In 1997, Kobayashi and colleagues reported the first truly catalytic enantioselective Mannich-type reactions of aldimines 24 with silyl enolates 37 using a novel chiral zirconium catalyst 38 prepared from zirconium (IV) fert-butoxide, 2 equivalents of (R)-6,6 -dibromo-l,l -bi-2-naphthol, and N-methylimidazole (Scheme 13) [27, 28], In addition to imines derived from aromatic aldehydes, those derived from heterocyclic aldehydes also worked well in this reaction, and good to high yields and enantiomeric excess were obtained. The hydroxy group of the 2-hydroxyphenylimine moiety, which coordinates to the zirconium as a bidentate ligand, is essential to obtain high selectivity in this method. 

Examples in Table 3 highlight 1,2-asymmetric additions to imine derivatives. Tanaka [25] reported the addition of alkyl Grignard reagents to the isoquinolines to yield a single enantiomer (see Table 3, entry 1). 

Addition to imines derived from aryl aldehydes has been investigated extensively and has been reviewed. The addition of Schiff base (18) to excess Grignard reagent (2 equiv.) provides a route to secondary amines (19 equation 1). As the size of R and branching of R increases, addition yields decrease (entries 1-3, Table l),>2.27,28 j d reduction products such as (20) are often generated. 

Intermolecular alkyl radical addition to imine derivatives was studied in aqueous media using indium as a single electron transfer radical initiator. The one-pot reaction based on radical addition to glyoxylic hydrazone provided a convenient method for preparing the a-amino acids. Indium-mediated radical addition to an electron-deficient C=C bond also proceeded effectively to provide a new carbon-carbon bond-forming method in aqueous media (Scheme 7.11).15... 

In an extensive investigation, Seebach has developed a deprotonative chiral auxiliary approach with an oxazolidinone to provide a reagent for enantioselec-tive formylation of aldehydes and ketones [ 14-16]. Lithiation-substitution of 20 gives a diasteromeric mixture of 21, as representative examples, with the major diastereoisomer formed in drs greater than 70 30, and up to 95 5 in most cases. The separated diastereoisomers were converted to highly enantioenriched products via the hemiaminal and hydrolysis, as shown in the representative examples in Scheme 6. Additions to imine derivatives were also foimd to be possible in this approach [14-16]. 

Chiral amines are commonly prepared by face-selective addition to imine derivatives or by enantioselective... 

Additions to Imine Derivatives Bearing N-Bound Auxiliaries... 

---