1,3-Dimethylpyrrolidine from

Considering the monoaminomercuration-demercuration of 1,4-hexadiene with /V-me-thylaniline leads to V-methyl-lV-(l-methylpent-3-enyl)aniline, the stereoselective synthesis of /V-alkoxycarbonyl or /V-tosyl s-2,5-dimethylpyrrolidine from the same diene has been explained172 on the basis of an initial amidomercuration reaction on the terminal bond followed by the second addition of mercury(II) salt to the internal double bond, on the less sterically hindered site (equation 171). 

There are two examples in which the carboxylic group is first reduced to an alcohol. In this manner a multistep transformation yielded kainic acid 7 with the correct configuration at all three chiral centers (82JA4978). A similar reaction afforded (-)- or (+ )-lram-2,5-dimethylpyrrolidine from L- or D-Ala (87TL2083). 

Similarly, amination of diols with ammonia and hydrogen leads to heterocyclic compounds via the amino alcohol intermediate. A promoted fused Fe catalyst afforded 93% 2,5-dimethylpyrrolidine from 2,5-hexanediol [11]. 

The 2,2-dimethylpyrrolidine may be recovered from the aqueous distillate in two ways (a) the distillate can be extracted continuously with ether 3 or (6) the distillate can be acidified with hydrochloric acid and concentrated to dryness under reduced pressure to give crude 2,2-dimethylpyrrolidine hydrochloride. The base is then liberated by adding an excess of saturated aqueous sodium hydroxide solution. The oily layer is separated. The... 

Dimethylpyrrolidine has been prepared by the hydrogenation of 5-amino-2,2-dimethylpyrroline-N-oxide or 5-imino-2,2-dimethylpyrrolidine in the presence of Raney nickel8 or by reduction with sodium and alcohol.8 This method is from unpublished work of the submitter. 

FIGURE 6. Circular dichroism spectra of (R)-2-methylpyrrolidine [(R)-109] (solid line) and (R)-1,2-dimethylpyrrolidine [(Rj-110] (dashed line) in hexane. Reproduced from Reference 94 by permission of Pergamon Press... 

A potential method for the preparation of novel amino acids via the highly selective addition of radicals to the glyoxylic oxime derivative of Oppolzer s camphor sultam (88) has been reported.181 Both Lewis acid and non-Lewis acid-mediated reaction conditions for the addition of alkyl radicals generated from alkyl iodides and Et3B/Bu3SnH were examined. A new chiral auxiliary based upon (R,R)-2,5-diphenylpyiTolidine has been used in the addition of phenylthiyl radicals to unsaturated methacrylamides. The selectivity was found to be better than that reported for the structurally related 2,5-dimethylpyrrolidine derivative.182... 

The [2+2] cycloaddition of aliphatic hydrazones derived from (2R, 5R)-1 -amino-2, 5-dimethylpyrrolidine to A-benzyl-iV-(benzyloxycarbonyl)aminoketene was reported to take place affording the corresponding (3-lactams in good yields when Pr2EtN was used as the base (Scheme 46), [124]. 

Couturier (94) obtained a rather good yield of cK-ephedrine by reacting a diketone, phenylpropanedione, with methylamine in the presence of Raney nickel. Schwoegler and Adkins (93), on reducing acetonylacetone in ammonia, received a 28% yield of 2,5-dimethylpyrrolidine and a 59% yield of 2,5-dimethylpyrrole. From acetylacetone a quantitative yield of acetamide was obtained. 

The use of an enamine derived from a chiral C2-symmetric amine such as (2R, 5R)-2,5-dimethylpyrrolidine leads to products 30 with high diastereoselectivity as well as high stereofacial selectivity (equation 7)32. In this case the radical addition is thought to take place from the relatively less hindered face of the enamine 29. 

Asymmetric Alkylations and Michael Additions. Asym-metne alkylation of the cyclohexanone enamine derived from (+)-tran.s-2,5-dimethylpyrrolidine has been studied (eq 4). Alkylation with lodomethane, n-propyl bromide, and Allyl Bromide afforded the corresponding 2-n-alkylcyclohexanones in yields of 50-80% and with enantiomeric purities of 66, 86, and 64%, respectively. 

Asymmetric Radical Reactions. Several reports have documented the utility of nonracemic fra/w-2,5-dimethylpyrrolidine as a chiral auxiliary in asymmetric radical reactions. For example, the addition of -hexyl, cyclohexyl, and f-butyl radicals to the chiral acrylamide of 4-oxopentenoic acid provided four diastere-omeric products resulting from a- and p-addition (eq 7). The isomers resulting from p-addition were formed with no diastereoselectivity however, the isomers resulting from a-addidon were formed in ratios of 16 1,24 1, and 49 1. Unfortunately, the application of this chemistry is limited due to the poor regioselectivity in the addition and difficulty in removal of the chiral auxiliary. 

Similar results have been achieved in the addition of chiral amide radicals to activated alkenes. For instance, a chiral amide radical, derived from (-)-tra i-2,5-dimethylpyrrolidine, adds in a 1,4-fashion to ethyl acrylate in 35% yield and with 12 1 diastereos-electivity (eq 8). Unfortunately, substantial amounts of higher oligomers are also formed. The radical telomerizadon of chiral acrylamides to afford nonracemic lower-order telomers (n= 1-5) has also been described. ... 

Asymmetric Pericyclic Reactions. Several reports illustrate the utility of fra/is-2,5-dimethylpyirolidine as a chiral auxiliary in asymmetric Claisen-type rearrangements, [4 + 2], and [2 + 2] cycloaddition reactions. The enantioselective Claisen-type rearrangement of N,0-ketene acetals derived from tram-2,5-dimethylpyrrolidine has been studied. For example, the rearrangement of the iV.O-ketene acetal, formed in situ by the reaction of A-propionyl-fra/w-(25,55)-dimethylpyrrolidine with ( )-crotyl alcohol, affords the [3,3]-rearrangement product in 50% yield and 10 1 diastereoselectivity (eq 9). 

Whitesell and Felman therefore concluded that an amine with a C2 axis of symmetry was required in order to ensure that the same side of the cyclohexene ring was shielded from attack whichever conformation of the enamine underwent alkylation. The en-antioselectivity was thereby considerably increased, but in the opposite chiral sense, by using the cyclohexanone enamine derived from ( + )-/mnj-2,5-dimethylpyrrolidine. This was assumed to have the S, S-configuration based on the results of the alkylation (Scheme 70). Optical yields of 82-93% ee were obtained. Also noteworthy was the low level of dialkylation observed (4-7%) and the fact that formation of enamine 77 was at least ten times faster using type 3A molecular sieves compared to 4A molecular sieves. Similar methodology has been applied to the alkylation of 4-substituted cyclohexanone enamines to give mainly the less stable trans disubstituted cyclohexanone s . 

The tributyltin hydride mediated macrocyclization of a long chain iodide bearing 2,5-dimethylpyrrolidine as chiral auxiliary gives four stcrcoisomcric products, two diastcrcomcrs resulting from exo and two from endo radical cyclization40. The endojexo product ratio is approximately 8 1, the two exo-products arc formed with no diastereoselectivity while the endo cyclization affords two enantiomers in a ratio of93 7. This indicates that asymmetric induction is only effective if attack occurs at the a-position of the chiral amide. 

Control of the configuration of the alkene center remote from an auxiliary group presents a challenge. For auxiliary groups such as the dimethylpyrrolidine amide the remote carbon of the alkene is beyond the reach of the auxiliary. Thus, addition of cyclohexyl radical to 10 proceeds without regioselectivity, and stereoselectivity is only observed for the products formed by addition to the end of the alkene bearing the auxiliary group [8]. 

Radicals such as 27 add to alkenes and abstract halogen from bromotrichloro-methane selectively [27], In each case, selectivities in excess of 10 1 are obtained and the observed product is as predicted based upon the proposed structure of the radical. The proximal methyl of the dimethylpyrrolidine protects one face of the radical from reaction. 

Several heterocyclic monoamines have also found applications (Section C.). Both enantiomers of 2,5-dimethylpyrrolidine 12 can be prepared from (7 )- or (S )-alaniiie in several steps20, but a more convenient access21 to the (27 ,53 )-enantiomer uses (2S,5S)-2.5-hexanedioI as the starting material, which is readily available by baker s yeast reduction of 2.5-hexanedione22. 

The hydroxyl radical rapidly reacted with the nitrone spin trap 5,5-dimethylpyrrolidine iV-oxide (DMPO). The effect of extracts from Cassia tora on DMPO-OH adduct formation was determined using an EPR spectrometer. Signal intensity of the DMPO-OH adduct decreased when the concentration of unroasted Cassia tora extracts was increased. At a same concentration (10 mg/mL), the scavenging effect of extracts firom Cassia tora on hydroxyl radicals was in the order of unroasted > 150 °C roasted > 200 °C roasted > 250 X roasted (22). This bend is also in agreemrat with the result that the antioxidant activity of the extracts of unroasted sanq>les was greater than tiiat of roasted samples. The scavenging activity of extracts from Cassia tora on hydroxyl radicals also increased witii an increase in the concentration. 

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