The hydroboration of enamines

This review describes the hydroboration of enamines in chronological order covering early work to give β-amino alcohols and reduction products and then our more recent work to give β-aminoorganoboranes and their subsequent conversion into β-amino alcohols, β-aminoboronic esters and acids


Introduction
The hydroboration of enamines affords β-(dialkylamino)alkylboranes which can be converted into the corresponding β-(dialkylamino)alkylboronate esters and acids, β-(dialkylamino)alkyl alcohols, and olefins.This review describes early studies of the hydroboration of enamines, and then covers our detailed study of enamine hydroboration and analytical methods developed to determine the enantiomeric excesses in asymmetric hydroboration of enamines.

The Early Years of Enamine Hydroboration
The first report of the hydroboration of an enamine appeared in 1961, when Stork reported that the hydroboration of an unspecified cyclohexanone enamine followed by oxidative cleavage of the borane with alkaline hydrogen peroxide afforded a racemic trans-2-hydroxycyclohexylamine 1 (Equation 1). 1 (1) Two years later, Marshall and Johnson 2 reported that when the pyrrolidine dieneamine 2 was reacted with diborane in THF and the resulting solution of the borane refluxed with acetic acid, 3β-pyrrolidinocholest-5-ene (3) was formed in 44% yield (Equation 2). (2) In an attempt to repeat the work of Marshall and Johnson with 1-(1-piperidino)cyclohexene (4), Lewis and Pearce reported, in a 1964 communication 3 and a 1969 full paper, 4 the isolation of 2-(1-piperidino)cyclohexaneboronic acid (6) in nearly quantitative yield (Equation 3).
(3) When compound 6 was refluxed with acetic or propionic acid in diglyme, cyclohexene was obtained.The intermediate borane 5 was unaffected when it was heated at reflux in diglyme, but was converted into cyclohexene when a carboxylic acid was added.The hydroboration/elimination procedure was applied to a variety of enamines of cyclic and acyclic ketones to give the corresponding alkenes in yields of greater than 85%.
(6) (7)  Similarly, hydroboration/oxidation of the pyrrolidine enamine of 2-methylcyclohexanone (15a, 15b) gave a 64% yield of a 63:37 mixture of the isomeric amino alcohols 16a and 16b, with no detectable amount of the tertiary alcohol 16c (Equation 8).(8)  In 1970, Gore and Barieux 7 reported, in the first of a series of six papers, that the hydroboration of the pyrrolidine enamine of dihydrotestosterone 17 with diborane in THF followed by treatment of the intermediate organoborane with refluxing methanol afforded an 80-85% yield of an 82:18 mixture of the isomeric aminosteroids 18a and 18b (Equation 9).0) In 1972, Barieux and Gore reported the results of further studies on the hydroboration of enamines of 3-ketosteroids. 11,12Hydroboration/oxidation of the enamines of 3-ketosteroids containing a 19-methyl group (19a, 19b) afforded, instead of the 2-amino-alcohols, a mixture of the corresponding isomeric aminosteroids (20a, 20b, Equation 11).(11)   In contrast, hydroboration/oxidation of the enamine of a 3-ketosteroid containing no 19methyl group, the pyrrolidine enamine of the benzoate of 5α-oestranol-17β-one-3 (21), afforded a 75% yield of an 82:18 mixture of the corresponding trans-amino alcohol 22 and the aminosteroid 23 (Equation 12).(12)   From this study, the authors concluded that in systems in which the amino group and the BH2 group are in the trans-diequatorial orientation, amino alcohols are the predominant products, and in systems in which the amino group and the BH2 group are in the trans-diaxial orientation the reduced products (aminosteroids) predominate.
In 1973, Franck et al. 13 described a synthesis of dehydroproline (27), the key step of which was the one-pot conversion of ketone 24 to olefin 26 via hydroboration/elimination of the enamine 25 (Equation 13).(13)   Three years later, Fruborg, Magnussen, and Thoren 14 reported the hydrogenolysis of a series of β-enamino methyl esters with BH3 in THF to give the corresponding α,β-unsaturated esters (Equation 14).(14)   In 1980, Mueller and Thompson 15 described the hydroboration of an enamine in the synthesis of the ladybug defensive agent hippodamine (28).Hydroboration/oxidation of the enamine 30, prepared stereoselectively in two steps from perhydroboraphenalene (29), gave a 95% yield of a 3:1 mixture of the alcohols 31 and 32, respectively (Equation 15).
When BMS in THF was used for the hydroboration of 39, we obtained, at equilibrium, a 70:30 mixture of 40 and 41 (Equation 34). 224) Similar results were obtained for the hydroboration of 4-(cyclohexylidenemethyl)morpholine (42) with BMS in THF (Equation 35).22 (35) In contrast to the morpholino-enamines, hydroboration of the corresponding pyrrolidinoenamines with BMS in THF at 25 o C gave a single monoalkylborane product ( Equations 36 and 37). 2 (36) (37) The hydroboration of aliphatic β,β-disubstituted enamines with 9-BBN was then investigated.Unlike 39, these enamines were hydroborated at 25 o C within 12 hours and gave a single monoalkylborane product (Equations 38 and 39). 228) (39) These trialkylboranes were stable toward methanol even at 65 o C, and were recovered unchanged (Equation 40).Fortunately, thermal decomposition of these trialkylboranes at 200 o C afforded the corresponding alkenes in moderate to excellent yields.Oxidation of these trialkylboranes using hydrogen peroxide and solid sodium hydroxide afforded the corresponding β-amino alcohols in good to excellent yields (Equation 40).22 (40) All of the monoalkylboranes obtained from β,β-disubstituted enamines and BMS reacted readily with methanol to form the corresponding dimethyl boronate esters.Only the dimethyl boronate esters obtained from phenyl-substituted β,β-disubstituted enamines underwent oxidative elimination with neutral hydrogen peroxide to afford the corresponding alkenes (Equation 41). 221) During our comprehensive investigation of the hydroboration of ,-disubstituted enamines we observed the formation of β-aminoalkylboranes and aminoboranes as byproducts (Equations 42 and 43). 232) (43) Additionally, during the hydroboration/oxidation of (E)-1-(4-morpholino)-2-phenyl-1propene (39) we observed the formation of not only the expected alkene and amino alcohol but also an unexpected byproduct, 2-phenyl-1-propanol (Equation 44).23 (44) Two possible mechanisms were proposed to account for these observed products (Equations 45 and 46).23 In the first mechanism (Equation 45), it was proposed that the α-aminoborane coordinates with borane, making the amine moiety a better leaving group.A hydride then migrates to displace the aminoborane product.In the second possible mechanism (Equation 46), the α-aminoborane was visualized to form a dimer, thereby making the amine moiety a better leaving group.Intramolecular hydride transfer then completes the rearrangement.23 In both mechanisms the key step was the formation of a tetravalent boron atom and a positively charged nitrogen atom.
(45) (46)  It was hypothesized that use of a stronger Lewis acid, such as BF3, might facilitate the rearrangement reaction by forming a stronger adduct with the amino group.This proved to be the case.Hydroboration of ,-disubstituted enamines with BH3 in THF generated from sodium borohydride and boron trifluoride etherate afforded the rearranged products in significantly improved yield (Figure 2).Non-oxidative workup of the rearrangement reaction mixture afforded the corresponding boronic acid derivatives in good yield (Equations 47 and 48). 237) (48) Thus, the hydroboration of a β,β-disubstituted aldehyde enamine followed by non-oxidative work-up with water provided a novel method of converting β-substituted aldehydes into the corresponding boronic acids (Equation 49).23 (49) In preparation for examining the hydroboration of enamines with asymmetric hydroboration reagents, the hydroboration of two other classes of enamines with BMS was examined.The hydroboration of the enamines of symmetrical dialkyl ketones (43) with BMS followed by methanolysis and oxidation with basic hydrogen peroxide or trimethylamine N-oxide afforded the corresponding threo-β-amino alcohols (44) in moderate yields (Equation 50, Figure 3). 24The crude amino alcohols were shown to contain small amounts (3-7%) of the corresponding reduction products (45).Hydroboration of enamines (46) derived from 2-norbornanone, with BMS in THF followed by methanolysis and oxidation with basic hydrogen peroxide, afforded moderate yields of the corresponding endo-3-(dialkylamino)-exo-2-norbornanols (47). 25Hydroboration of 46 with 9-BBN in THF followed by treatment with methanol afforded, instead of norbornene, 18,19,20 the corresponding endo-2-(dialkylamino)norbornanes (48, Equation 51). 25 (51) Nearly all of our previous studies on the hydroboration of enamines were conducted with BMS, an achiral hydroboration reagent.β-Mono-substituted and α,βand β,β-disubstituted enamines were employed as the substrates.3][24] The organoboranes derived from acyclic β-mono-substituted and α,β-disubstituted enamines, however, tended to undergo β-elimination. 16,20Also, the trialkylboranes derived from enamines and 9-BBN underwent a methanol-promoted elimination to the corresponding alkene. 18,19,20In order to better understand and suppress this elimination reaction, we conducted a study of the hydroboration of enamines with a variety of mono-and dialkylboranes. 26ydroboration of 1-(4-morpholino)cyclopentene with thexylborane followed by methanolysis and oxidation with H2O2/NaOH afforded trans-2-(4-morpholino)cyclopentanol in 77% yield (Equation 52). 262) Hydroboration/methanolysis/oxidation of the enamines derived from 2-methylcyclohexanone produced particularly interesting results.Borowitz 6 reported that hydroboration of the pyrrolidine enamine of 2-methylcyclohexanone (49) with BH3 .THF afforded a 64% yield of a 63:37 mixture of 50a and 50b.We repeated this reaction with BMS in THF and obtained a 55% yield of 50a and 50b in a ratio of 66:34.Surprisingly, hydroboration of 49 with thexylborane followed by methanolysis and oxidation afforded a 56% yield of a 12:88 mixture of 50a and 50b, essentially a total reversal of the results obtained with either BH3 .THF or BMS in THF (Equation 53). 26These results are summarized in Table 1.

Analytical Methods for Determination of the ee of β-Amino Alcohols
In our early studies, the enantiomeric excess (ee) of the β-amino alcohols obtained by the asymmetric hydroboration of 1-(dialkylamino)cyclohexenes was determined by derivatizing the sample with (1R)-(-)-menthyl chloroformate (61) and analyzing the resulting mixture of diastereomers obtained by capillary gas chromatography (GC). 26,28[33]

References and Notes
1. Stork, G. reported before the Organic Chemistry Division at the 140 th National Meeting of the American Chemical Society, Chicago, Ill., September 6, 1961.Since the hydroboration of

Figure 3 .
Figure 3. threo-β-Amino alcohols from enamines of symmetrical dialkyl ketones (yields shown are doe isolated and distilled products, except if otherwise specified).

Figure 4 .
Figure 4. Synthesis of enantiomerically enriched β-aminoalcohols from 1-(dialkylamino)cyclohexanones (isolated and distilled yields, % ee). a Hydroboration carried out at -40 o C. b Hydroboration carried out at 0 o C. c Hydroboration carried out at -30 o C. d Diisopinocampheylborane used as a complexing agent to retard the rate of hydroboration.