Homoallylamines

The reaction of crotyl organometallic compounds 1 with aldimines 2 results in linear 3 or branched 4 homoallylamines. 

Homoallylamines of type 4 contain two adjacent stereocenters therefore, two diastereomers, s.V)i-5 and anti-6, can be produced. 

The regioisomer 18 of isoxazoline 14 was also synthesized by an INOC reaction (Eq. 2). Homoallylamine 16 prepared by displacement of 4-bromo-l-butene... 

Iminium ions, generated in aqueous solution from secondary amines and formaldehyde, undergo a Barbier-type allylation mediated by tin, aluminum, and zinc. The reaction is catalyzed by copper and produces tertiary homoallylamines in up to 85% yield.67 The imines generated in situ from 2-pyridinecarboxaldehyde/2-quinolinecarboxaldehyde and aryl amines undergo indium-mediated Barbier allylation in aqueous media to provide homoallylic amines.68 Crotyl and cinnamyl bromides... 

Nakamura et al.100 found that in the presence of palladium catalysts imines undergo allylation readily, providing the corresponding homoallylamines with high yields. Thus, chiral palladium complex 157 has been synthesized and applied in the asymmetric allylation of imines using allyl tributyltin as the allylation reagent. In Scheme 3-54, moderate yield and up to 82% ee have been obtained with 157 as the chiral catalyst.101... 

Piperidines. Grieco et al. have described a general synthesis of piperidines by reaction of the acid salt of a primary amine with an allylsilane and 2 equiv. of formaldehyde in water. The reaction involves reaction of iminium ion (a), derived from the amine and formaldehyde, with the allylsilane to form a homoallylamine (b), which can form a second iminium ion (c), which cyclizes with capture of water to the piperidine. 

Another general synthesis of homoallylamines is the conversion of the trifluoroacetate of a primary or secondary amine into the corresponding inunonium salt by the action of aqueous formaldehyde, followed by successive treatment with allyltributylstannane and dilute hydrochloric acid e.g. equations 69 and 70 (TFA = CF3 CO2)195. 

TV-Glycosyl homoallylamines have been shown to undergo a stereocontrolled Lewis acid-catalyzed aza-Cope rearrangement to produce chain-extended amino sugars85. The reactions proceed in good to excellent yields with high stereoselectivity. Schiff base... 

The mechanism involves conversion of V-homoallylamine 116a to imine 117a via a Lewis acid-catalyzed cationic aza-Cope rearrangement (equation 61). Various Lewis acids were tested with yields ranging from 40-99% with high diastereoselectivities. 

Homoallylamines.1 In the presence of BF3 etherate or TiCl4 allyltributyltin (1) reacts with aldimines to give homoallylamines in moderate to high yield. Example ... 

A similar reaction occurs with crotyltributyltin to furnish mainly syn-p-methyl homoallylamines under controlled conditions in which the aldimine and the Lewis acid catalyst are allowed to complex for some time before addition of the reagent. Example ... 

Enantiomerically pure homoallylic amines are very important chiral building blocks for the synthesis of natural products. However, enantioselective methods for homoallylamine are quite undeveloped. In 1995, Itsuno and co-workers reported the first example of enantioselective allylation of an imine (Scheme 7) [13]. The reaction of N-trimethylsilylbenzaldimine 19 with a chiral allylboron reagent 20 in ether at -78 °C afforded the corresponding homoallylamine 22 in 73% ee. 

In the presence of molecular iodine, the C-C double bond of allylamines and homoallylamines can be activated towards nucleophilic attack by carbamate anion. Accordingly, iodoalkyloxazolidinones and iodoalkyloxazinanones have been prepared under mild conditions (ambient temperature, atmospheric C02 pressure) by the reaction of allylamines and homoallylamines with C02 and iodine via intramolecular cyclization [88],... 

The facile cyclopalladation of allylamine proceeds due to the chelating effect of the nitrogen. Carbopalladation of allylamine with malonate affords the chelating complex 203, which undergoes insertion of methyl vinyl ketone to form the amino enone 204 [124]. Homoallylamines and allyl sulfides behave similarly [125],... 

Homoallylamines such as 17 or 18 cannot be isomerized, similarly to cyclic Z enamines of the general formula 19. 

In this chapter, recent applications of (W)-phcnylglycine amide (1) in asymmetric synthesis are presented (Figure 25.2). The first section deals with diastereoselective Strecker reactions for the preparation of a-amino acids and derivatives, whereas the second section focuses on diastereoselective allylation of imines for preparation of enantiomerically pure homoallylamines. This latter class of compounds is a well-known intermediate for the synthesis of, for example, many types of amines, amino alcohols, and P-amino acids. The final section describes reduction of imines providing enantiomerically pure amines. (S)-3,3-Dimethyl-2-butylamine and (S)-l-aminoindane will be presented as leading examples. The results described in this chapter originate from a longstanding cooperation in the field of chiral technology development between DSM Pharma Chemicals and Syncom B.V. 

Chiral homoallylamines are valuable intermediates for the preparation of compounds such as amines, P-amino acids, 1-amino-3,4-epoxides, and 1,3-amino alcohols.24 High 1,3-asymmetric induction has been achieved during the allylation of imines derived from chiral auxiliaries such as P-amino alcohols and a-amino acid esters.25 Drawbacks of these methods are the limited availability... 

These diastereomerically and enantiomerically enriched compounds are useful as intermediates for a variety of interesting building blocks such as 1-aminobutanes, nonprotected homoallylamines, [3-amino acids, and y-amino alcohols (Figure 25.5). The conversion to 1-aminobutanes and homoallylamines will be described. 

Catalytic hydrogenation of PGA-homoallylamines simultaneously reduced the double bond and removed the chiral auxiliary in one step. Some typical examples of enantiomerically pure (R)-aminobutanes 12 obtained are shown in Scheme 25.6. The nonoptimized yields varied between 49% and 88% with ee values of 94% to >98%. The high enantiomeric excesses of these chiral amines are in agreement with the equally high diastereoselectivity of the allylation reaction and lack of racemization of the phenylglycine amide moiety in any of the steps. Enantiomerically pure chiral (f )-a-propylpiperonylamine 12c is an important building block of the human leukocyte elastase inhibitor L-694,458 (13).28... 

Chiral homoallylamines are valuable synthons for the preparation of biologically active components including P-amino carboxylic acids or esters, obtained by oxidation of the ally lie functionality.1-29 Because removal of the chiral auxiliary by hydrogenation leads to the loss of the allylic functionality, we developed alternative routes for the conversion of the adduct into the unprotected homoallylamines. As a typical example, (f ,f )-PGA-homoallylamine derived from isobutyraldehyde Hi was used to develop the so-called mroStrecker and the decarbonylation method for the conversion of (R)-phenylglycine amide protected homoallylamines into /V-benzylidene protected homoallylamines 15 (Scheme 25.7). 

Conversions of PGA-functionalized homoallylamines into (3-amino acid derivatives34 and ami-noalcohols are being investigated. 

Catalytic hydrogenation of (R,S)-22 was unsatisfactory for removal of the chiral auxiliary. The regioselectivity of the TV-benzylation step (5% Pd-C, 5 bar H2, 40°C, EtOH, AcOH) gave a (S)-l-a m i ik > - in da n e/( W) - PG A ratio of 4 6. This means that 60% of the key intermediate was converted to the undesired product. Therefore, the retro-Strecker method, analogous to the homoallylamines case, was applied as an alternative. The initially 3-step method could be improved to an efficient one-pot procedure (Scheme 25.9). 

Carbohydrate-derived homoallylamines have been demonstrated as being useful chiral synthons for the stereoselective synthesis of P-amino acids. With allyltribu-tylstannane or allyltrimethylsilane as the nucleophiles, glycosyl imines form homoallylamines with high efficiency [29-31]. Promoted by SnCl4, the nucleophile al-lyltributylstannane attacks from the stoically less hindered side. 

The nucleophile attack of the allylstannane again proceeds at the unshielded Si-side of the imine and finally leads to the desired homoallylamines with (S)-config-uration. These homoallylamines (16) are detached from the carbohydrate auxiliary by acid-catalyzed hydrolysis, and can be converted into the enantiomerically pure P-amino acids (17) in a two-step procedure via oxidative degradation of the terminal double bond. 

The corresponding (/ )-homoallylamines are correspondingly synthesized from arabinosyl imines 18b or fucosyl imines 18a with high diastereoselectivity (> 25 1) [30,32], (Scheme 14). 

This aza-Cope-rearrangement is a common reaction type for glycosyl homoal-lylamines with high stereoselectivity and proceeds in excellent yields. D-Arabinosyl homoallylamines 19 and D-glucosyl homoallylamines 27 rearrange accordingly in the described way [41], (Scheme 18). 

Allyltriorganosilanes react with activated C-N double bonds such as iminium salts and Lewis acid-coordinated imines at the y-position to give homoallylamines.14,118 For example, in the presence of BF3, iV-acylimines generated in situ by the reaction of aldehydes or acetals with carbamates are efficiently allylated with allyltrimethylsilanes (Equation (26)).119,119a,12° The use of homochiral crotylsilanes such as 20 leads to highly diastereo- and enantioselective synthesis of homoallylamines (Equation (27)). a Allenylation of the iV-acylimines can be performed with propargylsi lanes. 

Trifluoromethylaldimine reacts with various allylic bromides, under Barbier conditions in the presence of indium in DMF, to provide the corresponding homoallylamines (Equation (57)).255 a-Methylene-y-butyro-lactams are prepared by the indium-mediated reaction of 2-(bromomethyl)acrylic acid with aldimines (Equation (58)).256... 

Indium-mediated reaction of enamines with allyl bromides gives homoallylamines. The addition of one equivalent of acetic acid accelerates the reaction. An analogous reaction of methyl bromoacetate in place of allylic bromides is also possible. The iminium salts formed by protonation of the enamines are considered to be the intermediates (Scheme 70).271 272... 

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