Mannich reactions borono

A series of functionalized 2,5-dihydrofurans was efficiently synthesized via an amine-promoted Petasis borono-Mannich reaction and a... 

Asymmetric synthesis of anti-1,2-amino alcohols via the borono-Mannich reaction a formal synthesis of (-)-swainsonine. 

N. Selander, A. Kipke, S. Sebehus, K. J. Szab6, J. Am. Chem. Soc. 2007, 129, 13723-13731. Petasis borono-Mannich reaction and allylation of carbonyl compounds via transient allyl boronates generated by palladium-catalyzed substitution of aUyl alcohols. An efficient one-pot route to stereodefmed a-amino acids and homoaUyl alcohols. 

A. Yazici, Pure Appl. Chem. 2008, 80, 751-762. Exploiting the borono-Mannich reaction in bioactive alkaloid synthesis. 

Scheme 6.39 General mechanism for the Petasis borono Mannich reaction [54].

Petasis Borono-Mannich Reaction Iminium Ions Lacking Neighboring Heteroatom Functionality... 

Scheme 7.1 Discovery of the Petasis borono-Mannich reaction using paraformaldehyde, amines and alkenylboronic acids.

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. 

Harwood and co-workers have reported the reaction of 3 and 2-furylboronic acid with aliphatic aldehydes (Scheme 7.2) [25,26). Adducts 4 were obtained in good yields and high diastereoselectivities, and are valuable intermediates for the formation of a-amino acids. This is an interesting reaction, since not only was it the first example of a stereoselective Petasis borono-Mannich reaction, but it also represents a rare example of the successfixl use of simple aliphatic aldehydes. Its success may be due to the... 

Scheme 7.2 Petasis borono-Mannich reaction of 2-furylboronic acid, aldehydes and secondary amines.

Synthetic Benefits of the Petasis Borono-Mannich Reaction... 

An inherent advantage of the Petasis borono-Mannich reaction is the ability to conduct reactions in a three-component fashion, since the imine or iminium ion intermediates can be formed in situ from the condensation of either primary or secondary amines with the corresponding aldehydes or ketones. The operational advantages of such a three-component coupling approach, combined with the practical benefits outlined above, render the Petasis borono-Mannich reaction particularly desirable for parallel synthesis applications and in the generation of combinatorial libraries. In-... 

There are no reports of detailed mechanistic studies on the Petasis borono-Mannich reaction. Nevertheless, some experimental observations have been made that provide a basic understanding of the reaction. These observations also provide some useful guidelines as to the types of substrates that are suitable for participation in the Petasis borono-Mannich reaction. 

Figure 7.3 Putative coordinated intermediates involved in Petasis borono-Mannich reactions of aldehydes possessing neighboring heteroatoms.

Microwave acceleration of reactions is a valuable tool for organic synthesis [39], and various specialized instruments are now commercially available. Tye and co-workers have reported the microwave-assisted Petasis borono-Mannich reaction of arylboron-ic acids and primary or secondary amines with either glyoxylic acid or salicylaldehyde [40]. Optimized reaction conditions employed didiloromethane as solvent, and microwave assisted heating at 120 °C for 10 min. Products were obtained in generally modest yields (10-83%), in part due to incomplete reaction conversion imder the reported conditions. 

A similar approach has been outlined by Petasis and Patel for the formation of piperazinones and benzopiperazinones, using either stepwise or one-pot" protocols (Scheme 7.5) [41], A sequential protocol was used for reactions of mono-Boc protected ethylenediamines, 1,2-cyclohexanediamines or 1,2-phenylenediamines 19. Standard conditions were used for the Petasis borono-Mannich reaction, followed by Boc... 

Portlock and co-workers have demonstrated the sequential use of a Petasis borono-Mannich reaction and an Ugi 4-component coupling reaction for the generation of dipeptide amides 24 (Scheme 7.6) [45]. Exchange of the solvent from dichloro-methane to MeOH was required between the Petasis borono-Mannich and Ugi reac-... 

Grigg and co-workers have used a sequential, one-pot Petasis borono-Mannich reaction with either Pd(0)-catalyzed carbonylative amination cyclization or Pd(0)-cat-alyzed allenylation/amination cyclization (Scheme 7.7) [46]. The overall approach results in the formation of a-amino acid derivatives of isoindolone 25 and 4-methylene-3,4 -dihydroisoquinoline 26. While this is the only reported example of a combination of a Petasis borono-Mannich reaction with a Pd(0)using other Pd(0) or transition metal catalyzed reactions is a very attractive strategy for the synthesis of complex molecules or combinatorial libraries. 

Scheme 7.8 Enantioselective synthesis of a-amino acids using a diastereoselective Petasis borono-Mannich reaction.

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. 

Scheme 7.9 Synthesis of ont/-1,2-amino alcohols using a diastere-oselective Petasis borono-Mannich reaction.

Petasis Borono-Mannich Reaction Iminium tons Possessing Neighboring Heteroatom Functionality 1291... 

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. 

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