Hydroboration of Enamines

The normal electronic effect of the dialkylamino group strongly directs the boron to the (3-carbon of the enamine. However, when the hydroborating agent initially complexes with nitrogen atom, the influence of the dialkylamino group is reversed (Fig. 5.6). 

Aromatic (3,(3-disubstituted enamines do not undergo hydroboration with 9-BBN. However, their counterpart aliphatic enamines are hydroborated at 25 °C within 12 h and also place the boron exclusively at the (3 position (Chart 5.9) [41,42], regardless of the greater steric requirement of 9-BBN and the size of the amine moiety of the enamine. Thus it is explained that 9-BBN attacks the enamine double bond without prior coordination with nitrogen atom, while BMS initially coordinates to the nitrogen atom to a varying degree prior to hydroboration reaction. 

These trialkylboranes of 9-BBN are stable compounds when stored under nitrogen. Even the cyclic derivatives do not undergo appreciable isomerization [45]. The B NMR chemical shifts of these are in the range of 6 12-15, indicating that their stability is attributed to the strong coordination of boron to the nitrogen atom. 

The morpholinenamines of heterocyclic ketones such as tetrahydro-4H-py-ran-4-one, tetrahydro-4H-thiopyran-4-one, and l-benzyl-4-piperidone undergo hydroboration, cleanly, with 1 equiv of 9-BBN to furnish the corresponding trialkylboranes (Chart 5.10) [8]. 

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Such functional groups as OR, OH, NH2, SMe, halogen, and COOR may be present in the molecule," but not groups that are reducible by borane. Hydroboration of enamines with 9-BBN provides an indirect method for reducing an aldehyde or ketone to an alkene, for example. 

Asymmetric hydroboration of enamines with chiral diboranes, followed by oxidation with hydrogen peroxide, in aqueous sodium hydroxide, gives /1-amino alcohols in good yields and high ee (equation 29)153. The products of this reaction are useful in medicinal applications and as synthons for further synthetic elaboration. 

Table 5.13 Directive effect in the hydroboration of enamines derived from 2-methylpentanal [41].

The hydroboration of enamine is remarkable regio- and chemoselective as the boron adds to the electron-rich enamine double bond. Consequently, hydroboration of enamines and the treatment of the resulting trialkylboranes with methanol afford the corresponding alkenes in excellent yield [13]. The process is a general procedure for the synthesis of terminal alkenes from aldehydes and internal or cyclic alkenes from ketones (Eq. 24.5). 

This general procedure for the synthesis of alkenes from the enamines, when applied to the acyclic enamines derived from the acyclic ketones by modification of hydroboration-elimination procedure, permits a facile, diastereospecific conversion to either (Z)- or (E)-alkene at will (A) The hydroboration of enamine with 9-BBN, followed by treatment with methanol gives (Z)-alkenes of 99% isomeric purity. (B) The hydroboration of the same enamine with borane-methylsulfide, followed by methanolysis and oxidation with neutral hydrogen peroxide gives ( )-alkenes of 99% isomeric purity (Scheme 24.2) [13a]. 

Hydrogenation of olefins, enols, or enamines with chiral tVilkinson type catalysts, e.g., Noyort hydrogenation. Hydroboration of olefins with chiral boranes. Sharpless epoxi-dation of allylic alcohols. 

Enamines - alkenes.1 Hydroboration of (E)-enamines of aldehydes or ke- ones with 9-BBN followed by methanolysis (retention) affords alkenes in 60-80%... 

Hydroboration-oxidation of enamines has been reported by Borowitz and Williams171 to furnish the corresponding trans amino alcohols (Scheme 119). 

A number of atypical reactions of enamines have been developed. For example, hydroboration-oxida-tion affords stereochemically defined, vicinal amino alcohols (equation 26). Similarly, enamines have been shown to undergo reaction with diazomethane to form substituted cyclopropanes. These materials can be further transformed to a alkylated ketones by thermolysis followed by hydrolysis (equation 27). ... 

The ketone 629 has been isolated from peony flowers. It had already been synthesized several times for example, by hydroboration of the enamine 630 of the isomeric ketone 627, then Cope elimination of the iV-oxide 631 of the amino alcohol. Chromyl acetate oxidation of 1,8-cineole (553) led first to 629 further oxidation gave diketones. Aspergillus niger also gave some 629, although the main products were the corresponding alcohols. ... 

Enamines of unsaturated aldehydes can be converted into the corresponding dienes for example, citronellal, a chiral aldehyde, gives the chiral non-conjugated diene, /f-citronellene, in 92% enantiomeric excess - (Scheme 172). The combination of the Lewis hydroboration procedure with the thallium acetate acetoxylation of enamines provides a means of converting enamines into acetoxycycloalkenes (Scheme 173). The hydroboration oxidation of enamines to give -aminoalcohols was first reported by Borowitz and Williams . Cw-l,2-addition of BH3 occurs, to give the trans-ji-ammocy-... 

Studies relating to the stereoselective hydroboration of polyfunctional alkenes continue to appear. Various vinyl substituted pyridines, thiophenes and furans have been reacted with representative hydroborating agents,11" and further aspects of the hydroboration of cyclic dienes have been disclosed.11 The asymmetric hydroboration of cyclic enol ethers and enamines (heterocyclic alkenes) provides access... 

Hydroboration of 1-haloalkenes (38, 39) and enol acetates places the boron atom predominantly at the a carbon. However, enol ethers (38) and enamines (40), regardless of the degree of substitution on the original double bond, give 1,2-disubstituted products. 

Turning now to the synthesis of isopavines, a required intermediate for this purpose is again an appropriately substituted 1,2-dihydro-A -methylbenzyl-isoquinoline. Hydroboration of the enamine system and oxidative work-up induce formation of a 4-hydroxybenzylisoquinoline which can be cyclized in acid to the isopavine skeleton. A recent example of such a synthesis leads to the new isopavine thalidine ... 

Fig. 5.5 Effect of ring size on the regiochemistry of hydroboration of cyclic amine enamines...

Trialkylboranes, obtained after the hydroboration of p,p-disubstituted en-amines on hydroboration [17] with 9-BBN, do not react with methanol under conditions that work well for a,(3-disubstituted enamine [13]. These trialkylboranes are even inert at 65 °C with methanol for 12 h and are recovered unchanged. However, thermal decomposition of these trialkylboranes affords the corresponding alkenes (Eq. 24.11). Consequently, when neat trialkylboranes are maintained at 200 C for 6 h, the alkenes are recovered in moderate to excellent yield by a simple distillation (Table 24.6) [17]. 

The dienamines derived from enals undergo hydroboration with 9-BBN, with high regio- and chemoselectivity at the enamine carbon-carbon double bond and place the boron atom on a carbon having higher electron density. The high selectivity is confirmed by the hydroboration of a 1 1 mixture of 1-hexene and 1-morpholino-l-octene with 1 equiv of 9-BBN. The reaction mixture affords, after the addition of methanol, a 1 1 mixture of 1-hexene and 1-octene, and no 1-hexanol is detected. Consequently, this process is used to convert unsaturated aldehydes to dienes. Thus, enamine of citronellal on hydroboration-elimination affords a chiral non-conjugated diene, p-citronellene (Scheme 24.5) [1]. 

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