Morpholino enamine

The N-basicity of the commonly used amines (pyrrolidine > piperidine > morpholine) drops by 2-3 orders of magnitude as a consequence of electron pair delocalization in the corresponding enamines. This effect is most pronounced in morpholino enamines (see table below). Furthermore there is a tendency of the five-membered ring to form an energetically favorable exocyclic double bond. This causes a much higher reactivity of pyrroUdino enamines as compared to the piperidino analogues towards electrophiles (G.A. Cook, 1969). 

The stereochemical assignment is based on the comparison of the product with the pure cis and trans isomers (128 and 129) of the enamine prepared by the base-catalyzed elimination of the mesitoate esters of the d/-erythro-2-(4-morpholino)-l,2-diphenylethanol (130) and the <7/-threo-2-(4-morpho-lino)-l,2-diphenylethanol (131). 

That aminals and enamines are in equilibrium under certain conditions has been demonstrated (38). l,l-Di(N-morpholino)ethane 18, when heated with excess diethylamine for 24 hr at 60 and then treated with 4-nitro-phenylazide, gave the triazole (19) in 80% yield. The authors contend that... 

The reaction of ketene with the enamine (113) is reported (88) to give l-morpholino-2-acetyl-l-cyclohexene i.e., the enamino ketone expected from acylation of (113). The pyrrolidine enamine (28), however, has been shown to react (73) with excess ketene to give the a-pyrone (124). On the... 

When chloral was usedasthealdehyde2equivalents reacted with 1 equivalent of the enamine (98) regardless of the ratio of reactants or order of addition to give 2,6-bis(trichloromethyl)-5,5-dimethyl-4-morpholino-/ i-dioxane (183) in 83 % yield (126). Hydrolysis of 183 with hydrochloric acid at room temperature gave the hemiaeetal (184), but when heated with acid, the aldol product (185) was formed. 

Acryloyl chloride can be used to cause ring enlargement with the production of a bicyclodiketone when it is treated with a cyclohexanone enamine. This is shown by the reaction of acryloyl chloride (25) with 1-N-morpholino-1-cyclohexene (26), affording diketone 27 upon hydrolysis (32,33). 

It has been reported that perfluoroisobutylene and perfluorocyclobutene undergo 1,2 cycloaddition with l-(N-morpholino)isobutylene in ether at room temperature to give the corresponding perfluorocyclobutane derivatives ]20a). Enamines of cyclic ketones produce only simple alkylation products when treated with these perfluoroolefins. 

Many acyclic enamines form thioamides when they are allowed to react with elemental sulfur at room temperature in dimethylformamide solvent 138). They also produce cyclic 1,3-dithiole by-products, which become main products at higher temperatures 135). For example, the reaction of l-(N-morpholino)-l-phenylethene (106) and sulfur in dimethylformamide solvent yields 1,3-dithiole 107. 

The mechanism of the cycloaddition of phenyl azide to norbornene has been shown to involve a concerted mechanism with a charge imbalance in the transition state (199). In a similar manner the cycloaddition of phenyl azide to enamines apparently proceeds by a concerted mechanism (194, 194a). This is shown by a rather large negative entropy of activation (—36 entropy units for l-(N-morpholino)cyclopentene in benzene solvent at 25°C), indicative of a highly ordered transition state. Varying solvents from those of small dielectric constants to those of large dielectric constants has... 

A mixture of 100 g (0.6 mole) of 1-morpholino-l-cyclohexene, 28.8 g (0,4 mole) of /3-propiolactone, and 100 ml of chlorobenzene is placed in a 500-ml round-bottom flask fitted with a condenser (drying tube). The mixture is refluxed for 4 hours. The solvent and excess enamine are removed by distillation at aspirator pressure. (The residue may be distilled to afford the pure morpholide, bp 187-18871 rnm, 1.5090.) Basic hydrolysis may be carried out on the undistilled morpholide. To the crude amide is added 400 ml of 10% sodium hydroxide solution. The mixture is cautiously brought to reflux, and refluxing is continued for 2 hours. The cooled reaction mixture is made acidic (pH 4) and is extracted three times with ether. The combined ether extracts are washed twice with 5 % hydrochloric acid solution and twice with water. The ethereal solution is dried (sodium sulfate), then filtered, and the solvent is removed (rotary evaporator). The residue may be recrystallized from petroleum ether-benzene, mp 64°. 

Preparation of diethyl 3-diphenylthiophosphoryl-2-morpholino-l-cyclohexenylphosphonous acid — Reaction of an enamine with a phosphorus halide and subsequent esterification... 

Quite recently, the same research group compared the electrophilicity of 6-nitro-tetrazolo[l,5- ]pyridine and 6,8-dini-trotetrazolo[l,5- ]pyridine 11 with a series of electron-deficient aromatic and heteroaromatic compounds <2005JOC6242>. As reference nucleophiles, fV-methylpyrrole, indole, fV-methylindole, and some morpholino enamines were used. The reactivity of the electrophiles studied followed the linear-free energy relationship defined by Mayr et al. <2003ACR66>. 

A large and interesting group of diacylenamines has been studied by NMR and IR spectroscopy (37). However, data have been recorded at room temperature only, and one of the conclusions seems questionable the morpholino enamines 19 are assumed to exist entirely in the EE form. As will be discussed later (Sect. 

The syntheses shown in Scheme 26 (71CB1573) are based on dibenzo-/3-tropolone (108) and its enamines. Condensation of 108 and benzoin in the presence of ammonia affords pyrrole 109. The morpholino enamine gives pyrazole 110 via benzoylation, hydrolytic elimination of morpholine, and cyclization, whereas diazo-group transfer onto the anilino enamine leads to triazole 111. Dione 108 and p-nitrophenylazide in one step give predominantly the p-nitro derivative of 111 (92G249). 

Application of the enamine-sulfene cycloaddition allowed the synthesis of 78 and 79 from the corresponding a,/l-unsaturated amines and sulfenes. Similarly, using enamine 80, the crystalline morpholino thietane dioxides (81) were produced. Elimination via the N-oxide gave the corresponding thiete dioxide, whereas reduction by LiAlH4 yielded the thietane 82. 

Azadienes of this sort were studied simultaneously by Mariano et al., who reacted mixtures of (1 ,3 ) and (1E, 3Z)-l-phenyl-2-aza-l,3-pentadiene 275 with several electron-rich alkenes, e.g., enamines and enol ethers (85JOC5678) (Scheme 61). They found the (l ,3 )-stereoisomer to be reactive in this process affording stereoselectively endo 276 or exo 277 piperidine cycloadducts in 5-39% yield, after reductive work-up with sodium borohydride. The stereochemistry of the resulting adducts is in agreement with an endo transition state in the case of dienophiles lacking a cis alkyl substituent at the /8-carbon (n-butyl vinyl ether, benzyl vinyl ether, and 1-morpholino cyclopentene), whereas an exo transition state was involved when dihydropyrane or c/s-propenyl benzyl ether were used. Finally, the authors reported that cyclohexene and dimethyl acetylenedi-carboxylate failed to react with these unactivated 2-azadienes. 

To a flask which was previously base-washed and dried is added 32 ml of 1.5 M potassium f-butoxide solution in dimethyl sulfoxide. (NOTE The potassium f-butoxide (MSA Research Corp.) is sublimed under 0.1 mm pressure at 155°-160°C, transferred to a brown bottle in a dry nitrogen atmosphere, sealed with a serum cap, dry dimethyl sulfoxide added, and the resulting solution only removed with a syringe.) To the latter solution is added 1.99 gm (0.0046 mole) of the mesitoate ester of < -f/ ra>-2-(4-morpholino)-l, 2-diphenyl-ethanol, the reaction is stirred for 3 hr at room temperature under a nitrogen atmosphere, and the mixture poured in 150 ml of ice-cold water. The resulting solution is extracted with ether, dried, and concentrated to afford 1.16 gm (94%) of crude enamine, m.p. 78°-81°C. The enamine is dissolved in the minimum amount of methanol at temperatures below 50°C, quickly cooled, and then filtered to afford 0.79 gm (65%), m.p. 103°-104°C. 

In the presence of magnesium bromide, cyclobutenecarbonitrile reacted with 1-morpholino-cy-cloalkenes to give exclusively the cycloadducts 23. Rather surprisingly, only cyclobutyl ketones 24 were obtained when cyclobutenecarbonitrile or methyl cyclobutenecarboxylate was reacted with other enamines under similar conditions.30... 

Enamines contain electron-rich double bonds and thus react readily with azides (in many cases at room temperature). Only one addition product is formed, namely a 5-amino-A2-triazoline, a result of electronic control.22 -223 Thus l-(p-nitrophenyl)-4-ethyl-5-morpholino-A2-triazoline (44) arises from the addition of p-nitrophenyl azide to 1-morpholino-l-butene (43). The addition products rearrange by heating into amidines (45).224... 

The addition reactions of aryl azides onto enamines bearing a carbonyl, sulfonyl, or nitro group in the 0 position with respect to the nitrogen atom have been investigated by Italian authors.240-241 The expected triazoline derivatives could not be isolated but were immediately converted into the corresponding 1,2,3-triazoles (49) and secondary amines. The reaction of p-nitrophenyl azide with l-benzoyl-2-morpholino-l-propene (48) is given as a typical example. 

Simpler alkenylmorpholines, such as 4-vinylmorpholine (148), would seem to be interesting heterocyclic monomers. While monomer (148) is unstable, substituted enamines such as 1-morpholino-l-butene (149) have been incorporated into copolymers with acrylonitrile. Copolymers containing up to 30% of units derived from monomer (148), however, may be prepared according to Scheme 45 (70MI11102). 

Enamines of cyclic ketones may also be used to prepare polyamides in a different type of condensation reaction (67MI11100). This polymerization involves reaction with diisocyanates (Scheme 46), with the enamine functioning as a difunctional reagent. Morpholino- and piperidino-enamines are the most effective monomers. 

Other classical synthetic approaches to 2-furanamine have failed, including the Curtius method and Beckmann rearrangement of 2-benzoylfuran oxime. However, hydrazinolysis of AT-(2-furyl)phthalimide, obtained from phthalimide and 2,5-dimethoxy-2,5-dihy-drofuran, gives 2-furanamine which was not isolated but detected by GLC-MS and H NMR spectroscopy. The latter reveals the absence of imino tautomers (75AP713). The chemistry of 2-dialkylamino-5-phenylfurans is typical of enamines protonation occurs on carbon to produce iminium salts. They are stable to base but afford 5-phenylfuran-2(3//)-one on hydrolysis with dilute acid. 2-Morpholino-5-phenylfuran couples with diazonium salts and affords Diels-Alder adducts with maleic anhydride and IV-phenylmaleimide (73JCS(P1)2523). 

Several groups have described syntheses of chromones which involve the use of enamines. Reaction of salicylaldehyde with 1-morpholinocyclohexene gives the chromanol which is readily oxidized to the chromone (66JOC1232). Other examples include the use of 1-morpholino-l-phenylethylene which gives flavene, whilst N-styrylmorpholine yields isoflavone. The enamine reaction is considered to proceed in the normal manner with subsequent cyclization involving the neighbouring phenolic group (Scheme 163). 

Schaefer and Weinberg have reported (126) that the deuterolysis of 4-t-butyl-1-morpholino cyclohexene (477) produced specifically 2-8-deuterio-4-1 -butyl-cyclohexanone (478). Malhotra and Johnson (148) have shown that the enamine of 2-methylcyclohexanone gives on hydrolysis the oU-deuteromethylcyclohexanone 481. This enamine is known to exist in conformation 479 with the methyl group axial. Consequently, axial protonation must have taken place on 479 to give first the imini urn ion 480 which was then hydrolyzed to 481. 

Table I Conversion of R1R2CO into Morpholino Enamines J. ...

Perfluoro-2-methyl-2-penten-3-yl isothiocyanate, which was prepared from perfluoro-2-methyl-2-pentene and KSCN in benzonitrile in high yield by direct substitution of fluorine, is a stable and versatile educt for heterocyclic synthesis. This a,p-unsaturated isothiocyanate reacted with enamines, such as 1-methylindole and 2-methyl-1-morpholino-l-propene, to yield 2-(l-methylindol-3-yl)-perfluro-4,5-dihydro-5,5-dimethyl-4-ethylidene-l,3-thiazole and its analogue in fair yield. [95H1015]... 

From a preparative point of view, the acylation of ketones via enamines is of particular interest. In comparison with pyrrolidine and piperidine enamines, the less reactive morpholine enamines give better yields, as found by Hiinig et al.2iZ j8-Diketones are the products of acylation with an acyl halide followed by acid hydrolysis, whereas with ethyl chloroformate, /J-ketoesters are obtained.212 Hiinig and his collaborators242-247 have used the acylation of 1-morpholino-l-cyclopentene and 1-morpholino-l-cyclohexene to lengthen the chains of acids by five and six carbon atoms, respectively. The reaction may... 

Treatment of 1-morpholino-l-cyclohexene with ketene gives l-morpholino-2-acetyl-l-cyclohexene251 as the main product, whereas enamines prepared from aliphatic aldehydes yield cyclo-butanones.252,253 Ketene may be generated directly in the reaction medium from acid chlorides and triethylamine. 

Irradiation of the piperidino and the morpholino derivatives (239) at 70°-100° produced the enamines (240), which on acid treatment gave the corresponding aminoaldehyde (241).127... 

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