Epoxides with enamines

A useful assortment of carbon-carbon bond forming reactions such as alkylation of enolates and enamines and carbon-oxygen bond forming reactions such as epoxidation with ylides have been described in this chapter. 

The reaction of terminal epoxides with hindered lithium amide bases followed by organometallic reagents generates alkenes <2004JA12250>. Related reactions are the formation of enamines <2004JA6870> from terminal epoxides, 2-ene-l,4-diols from terminal epoxides <20050L2305>, and allylamines from amino epoxides <20060L349>. 

The first synthesis of polyzonimine (119) was a synthesis of the racemate carried out by Smolanoff and co-workers in 1975 at the time of its isolation and structure elucidation (111). Oxidation of 3,3-dimethylcyclohexene (368) with meto-perchlorobenzoic acid followed by treatment of the epoxide with lithium bromide and HMPA in refluxing benzene gave the carboxal-dehyde 369. The morpholino enamine 370 was then subjected to Michael addition with nitro-ethylene, generated from 2-acetoxy-nitroethane, to afford a nitro aldehyde 37L Ketalization and reduction with Raney nickel then afforded ( )-119 in overall yield for the five steps of 22% (Scheme 45) (111). 

Having precursor 407 in hand. Brooks et al. were able to synthesize anguidine (376) in a further 17 steps. Thus, precursor 407 was converted into enamine 409, which was hydrolyzed to hydroxymethylene derivative 410. Michael reaction with butanone afforded the exo product 411. Followed by an intramolecular Michael aldol condensation, enone 412 was obtained, which was methylated to the allyl alcohol 413 using methyl iodide. Subsequent reduction with Ufliium aluminum hydride led to tetraol 414. This was converted to the triacetate and selectively deprotected to diol 415. Acid-catalyzed cycUzation and protection of the free OH group afforded the trichothecene skeleton 416. Afterwards, the acetal 416 was deprotected and the ketone was reacted in a Wittig reaction to the olefin, which was treated with TBAF to afford compound 417. Epoxidation with /n-CPBA, followed by acetylatiOTi and final mono-deprotection, afforded the trichothecene, anguidine (376) (Scheme 8.4). 

A remarkable synthetic route to enamines, based on the reaction of terminal epoxides with hindered lithium amides, has been disclosed by Hodgson and co-workers (2004JA6870). When racemic lithium 2,2,6-trisubstituted piperidine 26 (R = Et) is reacted with terminal epoxides 25, trisubstituted piperidine-derived enamines 27 are formed in yields of up to 83%. The latter exhibited efficient C-alkylation activity toward a... 

The first section of this chapter describes the preparation and several synthetic applications of a-fluoroalkyl P-sulfmyl enamines and imines the second deals with the chemistry of di- and trifluoropyruvaldehyde A, 5-ketals, stereochemically stable synthetic equivalents of P-di and P-trifluoro a-amino aldehydes, which can be prepared from the corresponding p-sulfinyl enamines the third overviews the preparation of chiral sulfinimines of trifluoropyruvate and their use to prepare a library of a-trifluoromethyl (Tfm) a-amino acids the fourth section is mainly dedicated to the asymmetric synthesis of monofluorinated amino compounds, using a miscellany of methods such as MifstmobuAike azidation of P-hydroxy sulfoxides, ring opening of fluoroalkyl epoxides with nitrogen-centered nucleophiles and 1,3-dipolar cycloadditions with chiral fluorinated dipolarophiles. 

Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

Reaction conditions depend on the reactants and usually involve acid or base catalysis. Examples of X include sulfate, acid sulfate, alkane- or arenesulfonate, chloride, bromide, hydroxyl, alkoxide, perchlorate, etc. RX can also be an alkyl orthoformate or alkyl carboxylate. The reaction of cycHc alkylating agents, eg, epoxides and a2iridines, with sodium or potassium salts of alkyl hydroperoxides also promotes formation of dialkyl peroxides (44,66). Olefinic alkylating agents include acycHc and cycHc olefinic hydrocarbons, vinyl and isopropenyl ethers, enamines, A[-vinylamides, vinyl sulfonates, divinyl sulfone, and a, P-unsaturated compounds, eg, methyl acrylate, mesityl oxide, acrylamide, and acrylonitrile (44,66). 

Other methods of generating a-aminoketones in situ are common, if somewhat less general than the methods already described. 2-Nitrovinylpyrrolidine, which is readily available, yields 2,3-bis(3-aminopropyl)pyrazine on reduction and this almost certainly involves ring opening of the intermediate enamine to an a-aminoketone which then dimerizes under the reaction conditions (Scheme 59) (78TL2217). Nitroethylene derivatives have also served as a-aminoketone precursors via ammonolysis of the derived epoxides at elevated temperatures (Scheme 60) (76S53). Condensation of 1,1-disubstituted hydrazine derivatives with a-nitro-/3-ethoxyethylene derivatives has been used in the synthesis of l,4-dialkylamino-l,4-dihydropyrazines (Scheme 61) (77S136). 

To overcome this, the A -acetyl group is reduced with lithium aluminum hydride. The resulting basic enamine then reacts extremely rapidly and selectively with peracid. The derived epoxide is hydrolyzed very easily with alkali during the workup. 

Alkylation of enamines with epoxides or acetoxybromoalkanes provided intermediates for cyclic enol ethers (668) and branched chain sugars were obtained by enamine alkylation (669). Sodium enolates of vinylogous amides underwent carbon and nitrogen methylation (570), while vicinal endiamines formed bis-quaternary amonium salts (647). Reactions of enamines with a cyclopropenyl cation gave alkylated imonium products (57/), and 2-benzylidene-3-methylbenzothiazoline was shown to undergo enamine alkylation and acylation (572). A cyclic enamine was alkylated with methylbromoacetate and the product reduced with sodium borohydride to the key intermediate in a synthesis of the quebrachamine skeleton (57i). 

C. Reactions not involving P=0 or P=S Groups.—Enamine phosphine oxides (45) have been prepared by the addition of amines to 1-alkynyl-phosphine oxides, and the reactions of their anions with various electrophiles have been reported. - With ketones a Wittig-type reaction leads to the formation of a/3-unsaturated ketones, in 53—70% yield, while with epoxides cyclopropyl ketimines are formed. A Diels-Alder reaction of l-phenyl-A -phospholen-l-oxide (46) with 1,4-diacetoxybutadiene has been used in the preparation of l-phenyl-benzo[/>]phosphole (47), as... 

The racemic polyzonimine (19) is prepared as shown in Scheme 33. The expoxide (314) is rearranged to the aldehyde (315) by refluxing with LiBr-HMPA in benzene. Morpholine enamine (316) derived from 315 is condensed with nitroethylene, generated in situ from 2-acetoxynitroethane, to afford the nitroaldehyde (317). Ethylene acetalization, reduction over Raney nickel, and subsequent deacetalization give ( )-polyzonimine (19) in 22% overall yield from the epoxide (314) 113). 

The vast majority of organocatalytic reactions proceeds via covalent formation of the catalyst-substrate adduct to form an activated complex. Amine-based reactions are typical examples, in which amino acids, peptides, alkaloids and synthetic nitrogen-containing molecules are used as chiral catalysts. The main body of reactions includes reactions of the so-called generalized enamine cycle and charge accelerated reactions via the formation of iminium intermediates (see Chapters 2 and 3). Also, Morita-Baylis-Hillman reactions (see Chapter 5), carbene-mediated reactions (see Chapter 9), as well as asymmetric ylide reactions including epoxidation, cyclopropanation, and aziridination (see Chapter 10), and oxidation with the in situ generation of chiral dioxirane or oxaziridine catalysts (see Chapter 12), are typical examples. 

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