Cyclohexene enamines

Few racemic alkyl p-tolyl sulphoxides were prepared in rather low yields (16—40%) by the reaction of Grignard reagents with mixed anhydrides 108, 109 and compound HO formed in situ from p-toluenesulphinic acid and 3-phthalimidoxy-l,2-benzoisothiazole 1, 1-dioxide167 (equation 59). The mixed anhydrides 109 or 110 when reacted with cyclopen-tene and cyclohexene enamines 111 gave the corresponding a-ketocycloalkyl sulphoxides 112 in low yields (10-41%) along with small amounts of several by-products such as disulphides and thiosulphonates167 (equation 60). 

A vinyl isocyanate, which may be considered as a 1,4-dipolar system, will react with an enamine to give a pyridone. Octahydrophenanthridone results when cyclohexene isocyanate and a cyclohexene enamine are used (J.H. Rigby and H. Balasubramanian, J, org. Chem., 1984, 49, 4569). 

Oxidative dimerization of various 2-benzyloxy-2-thiazoline-5-ones (222) catalyzed by iodine and triethylamine is another example of the nucleophilic reactivity of the C-4 atom (469) (Scheme 112). Treatment of 212 with pyrrolidinocyclohexene yields the amide (223) (Scheme 113). The mechanism given for the formation of 223 is proposed by analogy with the reactivitx of oxazolones with enamines (4701. 4-Substituted 2-phenylthiazol-5(4Hi-ones react with A -morphoiino-l-cyclohexene in a similar manner (562j. Recently. Barret and Walker have studied the Michael addition products... 

Johnson and Whitehead have further shown that the reductive elimination of the pyrrolidine group from the pyrrolidine enamine of 2,4-dimethyl-cyclohexanone (16), which involved treating it with a mixture of lithium aluminum hydride and aluminum chloride (9), gave the trans isomer of 3,5-dimethyl-/l -cyclohexene (17) which on subsequent hydrogenation on a platinum catalyst led to the // onr-3,5-dimethylcyclohexane (18). 

The 2,2 -dialkylation of enamines has been used for the synthesis of novel bi- and trieyeloketones (id). Alkylation of 1-N-pyrrolidino-l-cyclohexene (28) with 1,4-diiodobutane gave a 15% yield of bicyelo[1.3.4]-10-decanone (35), while alkylation with o-xylylenedibromide gave a 31 % yield of 2,6-o-xylyleneeyelohexanone (36). 

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... 

Reaction of the morpholine or piperidine enamine of cyclopentanone, however, gives an unstable adduct which rearranges under the reaction conditions and an aqueous work-up to give the ring expanded ketone 2-chloro-2-cyclohexen-l-one (203) (138,139). 

At higher temperatures the mixture of 10 and methyl vinyl ketone yields the 1,4-carbocyclic compound as described previously. Methyl isopropenyl ketone (5), ethyl acetylacrylate (d), 2-cyclohexenone (21), and 1-acetyl-1-cyclohexene (22) also undergo this type of cyclization reaction with enamines at higher temperatures. This cycloalkylation reaction occurs with enamines made of strongly basic amines such as pyrrolidine, but the less reactive morpholine enamine combines with methyl vinyl ketone to give only a simple alkylated product (7). Chlorovinyl ketones yield pyrans when allowed to react with the enamines of either alicyclic ketones or aldehydes (23). 

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). 

Enamines have been observed to act both as dienophiles (46-48) and dienes (47,49) (dienamines in this case) in one-step, Diels-Alder type of 1,4 cycloadditions with acrylate esters and their vinylogs. This is illustrated by the reaction between l-(N-pyrrolidino)cyclohexene (34) and methyl t/-a i-2,4-pentadienoate (35), where the enamine acts as the dienophile to give the adduct 36 (47). In a competitive type of reaction, however, the... 

The reaction of an alicyclic enamine with benzyne intermediate yields simple arylation products and/or 1,2-cycloaddition products, depending upon the reaction conditions 102). This is illustrated by the reaction of l-(N-pyrrolidino)cyclohexene with benzyne (86) (obtained from fluoro-benzene and butyl lithium or o-bromofluorobenzene and lithium amalgam), which produces benzocyclobutene 87 102). 

Similarly, a-trichloromethylamines (522) were obtained by decomposition of trichloroacetic acid in morpholine enamines, but an amide ester was formed from sodium trichloroacetate and the imonium salt of pyrrolidino-cyclohexene (523). The product is presumably derived from opening of an intermediate dichloroaziridinium salt. 

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°. 

A novel ring closure was discovered by Stork (6) in which the pyrrolidine enamine of a cycloalkanone reacts with acrolein. The scheme illustrates the sequence in the case of 1-pyrrolidino-l-cyclohexene, and the cyclopentane compound was found to undergo the reaction analogously. The procedure details the preparation of the bicyclo adduct and its cleavage to 4-cyclooctenecarboxylic acid. 

The intramolecular Heck reaction presented in Scheme 8 is also interesting and worthy of comment. Rawal s potentially general strategy for the stereocontrolled synthesis of the Strychnos alkaloids is predicated on the palladium-mediated intramolecular Heck reaction. In a concise synthesis of ( )-dehydrotubifoline [( )-40],22 Rawal et al. accomplished the conversion of compound 36 to the natural product under the conditions of Jeffery.23 In this ring-forming reaction, the a-alkenylpalladium(n) complex formed in the initial oxidative addition step engages the proximate cyclohexene double bond in a Heck cyclization, affording enamine 39 after syn /2-hydride elimination. The latter substance is a participant in a tautomeric equilibrium with imine ( )-40, which happens to be shifted substantially in favor of ( )-40. 

Apart from the role of substituents in determining regioselectivity, several other structural features affect the reactivity of dipolarophiles. Strain increases reactivity norbornene, for example, is consistently more reactive than cyclohexene in 1,3-DCA reactions. Conjugated functional groups usually increase reactivity. This increased reactivity has most often been demonstrated with electron-attracting substituents, but for some 1,3-dipoles, enol ethers, enamines, and other alkenes with donor substituents are also quite reactive. Some reactivity data for a series of alkenes with several 1,3-dipoles are given in Table 10.6 of Part A. Additional discussion of these reactivity trends can be found in Section 10.3.1 of Part A. 

Vinylamines (enamines) are reduced by alane, mono- and dichloroalane to saturated amines, and hydrogenolyzed to amines and alkenes [710]. Reduction is favored by dichloroalane while hydrogenolysis is favored by alane. Alane, chloroalane and dichloroalane gave the following results with -N-pyrrolidinylcyclohexene V-pyrrolidinylcyclohexane in 13, 15 and 22% yield, and pyrrolidine and cyclohexene in 80, 75 and 75% yields, respectively [710]. Saturated amines were also obtained by treatment of enamines with sodium borohydride [711], with sodium cyanoborohydride [103, 712] (Procedure 22, p. 210) and by heating for 1-2 hours at 50-70° with 87% or 9S% formic acid (yields 37-89%) [320]. 

An interesting alternative intramolecular cyclisation was discovered by Jprgensen and co-workers [187]. Although not strictly exploiting an enamine intermediate, the transformation represents a secondary amine catalysed Morita-Baylis-Hillman reaction leading to a series of highly functionalised cyclohexene products. Reaction of the Nazarov reagent 137 with a,P-unsaturated aldehydes in the presence of the diarylprolinol ether 30 led to the cyclohexene products 138 (49-68% yield 86-96% ee) via a tandem Michael/Morita-Baylis-Hillman reaction (Scheme 54). 

When (2S)-1-(1-cyclohexene-l-yl)-2-(methoxymethyl)pyrrolidine (206), enamine from cyclohexanone, and (S)-proline-derived (2S)-(methoxymethyl)pyrrolidine is added to the Knoevenagel condensation products (207), mainly one of the possible four diastereomers is formed. The diastereomeric purity was found to be excellent (d.s. > 90%) 203). The stereochemical course of this highly effective asymmetric synthesis allowed the synthesis of the optically active target molecules (208). A possible mechanism discussed by Blarer and Seebach 203). 

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. 

Kwart and Kahn have found that benzenesulfonyl azide forms a complex with freshly reduced copper powder.189 190 This copper azide complex decomposes at a lower temperature than the pure sulfonyl azide. In refluxing methanol, benzene-sulfonamide (27) is isolated as the major product. In the presence of dimethyl sulfoxide, N-benzenesulfonyldimethyl-sulfoximine (28) is obtained in almost quantitative yield. In cyclohexene solution benzenesulfonamide (29), N-benzenesul-fonyl-7-azabicyclo[4.1.0]heptane (30), and 1-cyclohexenylben-zenesulfonamide (31) are isolated as the main reaction products. According to the authors, Schemes VII and VIII represent an acceptable interpretation of the experimental data.189 190 In pure alcohol, the decomposition should occur by two competitive reactions (Scheme VII) producing benzenesulfonamide together with a ketone and oxidized copper. These last two products have indeed been observed in the reaction mixture. In the presence of DMSO, it seems that a copper-nitrene intermediate is formed which is trapped by DMSO. In cyclohexene solution, the authors have observed that the aziridine (30) disappears from the product composition when DMSO is added. The yield of enamine 31, however, is... 

In the case of enaminoketone (77) and /j-benzoquinone, there are two parallel reactions in the /3-position of the enamine 77 and in the 8-position of the tautomeric dienamine 77a [93MC40 94KFZ(2)36]. The first pathway (common in the Nenitzescu reaction) gives a dibenzofuran derivative (78), the second affords an unusual product—a jpiro[benzofuran-3,l cyclohexene] derivative (79). The likely pathways are indicated. The... 

The origin of the observed 1,4-asymmetric induction in Michael reactions of chiral imines (Scheme 28) has been rationalized by conformational transmission of chirality. Thus, the phenethylamine auxiliary forces the cyclohexene part of the intermediate enamine into a half-chair conformation (140) that is 0.8 kcal mol-1 lower in energy than (141). Axial attack as shown then leads to the major product the energy difference between (140) and (141) roughly correlates with the observed diastereoselectivity ( 9 l).105... 

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. 

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