Synthesis and Isomerization of 3-Pyrroline Enamines

Cook, A. Gilbert; Switek, Karen A.; Cutler, Kenneth A.; Witt, Allison

doi:10.2174/1570178043488734

Cited by 20 publications

(17 citation statements)

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“…They all show a preference for extended conjugation with the acyl carbonyl, overcoming the steric effect of the acyl group. The 2-or 5-methyl substituted cyclopentenyl system likewise does not show large isomer distribution differences between the amines [19].…”

Section: Discussion Of Resultsmentioning

confidence: 89%

Isomer Distribution of Succinylcyclohexenyl, Acetylcyclohexenyl and Acetylcyclopentenyl Enamines

Cook¹,

Folk

2008

LOC

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The isomeric distributions of some cyclohexenyl enamines substituted by succinyl or acetyl groups at either the 2-or 6-positions are reported as are the isomeric distributions of similarly substituted cyclopentenyl enamines. Correlation between the 13 C NMR chemical shifts in these enamines and isomer distribution is shown. Density functional molecular modeling is used to demonstrate resonance and electrostatic effects on isomeric distributions.One of the most common methods of synthesizing cyclohexenyl and cyclopentenyl enamines is to allow a cyclohexanone or a cyclopentanone compound to react with a secondary amine [1,2]. If the enamine is unsymmetrically substituted at the 2,6-positions (cyclohexenyl) or at the 2,5-positions (cyclopentenyl), two different isomers may be produced, namely tet and tri (Eq. 1) with the latter present as two different conformers in the cyclohexenyl case, tri ax (substituted X is pseudoaxial) and tri eq (substituted X is pseudoequatorial).We produced cyclohexenyl enamines with acetyl substituents in the 2-and 6-positions and cyclopentenyl enamines with acetyl substituents in the 2-and 5-positions in two different ways. They were synthesized by direct carbon acylation of the enamine [3,4] and by reaction of an acetylcycloalkanone with a secondary amine [5,6] (Scheme 1). We have found that the isomeric distributions of enaminoketones 1 and 2 are essentially the same for each of the two alternative methods of synthesis. We have further discovered that the second method (acetylcycloalkane with a secondary amine) also produces an amide. For example amide 5 is produced along with acylated cyclic enamines 1 and 2 when this method is used. Production of amides from enamines by the reaction of acyl halides with enamines has been reported before [7], but this reaction involves different reagents and so follows a different mechanistic pathway. These amides are probably produced by way of initial formation of pseudobase 3 or 4 followed by elimination of amide 5 in a retro condensation reaction. Further proof for this mechanism is shown by the appearance of significant amounts of simple cyclic ketones and simple enamines in the crude reaction products as determined by GC-MS. A similar reaction has been reported with the reaction of pyrrolidine with acetylacetone under microwave conditions [8]. The yields of amides represent the amount of alternate enaminoketone (with an exocyclic double bond due to attack of the acetyl carbonyl by the amine) which would have formed if the retro reaction to form amide 5 did not take place. + + 1 tet, n=1 1 tri, n=1 2 tet, n=0 2 tri, n=0 + + 3, n=1 4, n=0 5 + Scheme 1.The isomeric distributions of products for these reactions are given in Tables 1 and 2 along with the isomeric distribution of some previously unreported or erroneously reported enamines of 2-methyl-and 3-phenylcyclohexanones.The relative amounts of the isomers were determined by using 13 C NMR in CDCl 3 solvent with a long relaxation delay. The pseudo-equatorial and pseudo-axial configurational iden...

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Section: Discussion Of Resultsmentioning

confidence: 89%

Isomer Distribution of Succinylcyclohexenyl, Acetylcyclohexenyl and Acetylcyclopentenyl Enamines

Cook¹,

Folk

2008

LOC

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“…Since the amination reaction was facilitated by acids, a variety of acids with 10 mol% loading were screened accordingly. As shown, indeed an acid was beneficial to the reaction (entries [3][4][5][6][7][8][9]. The acid promoters significantly shortened the reaction times from 10 h to 10 min while achieving better yields.…”

Section: Resultsmentioning

confidence: 99%

“…Survey of literature revealed that Cook and coworkers reported a thermodynamic controlled condensation of 3-pyrroline with cyclohexanone at 140 °C in xylenes to produce N-cyclohexylpyrrole in 47% yield while other ketones provided even poorer yields [9]. Tunge and coworkers improved this reaction under milder conditions at 110 °C in toluene with benzoic acid as catalyst and N 2 as inert atmosphere in excellent yields [3b].…”

Section: Resultsmentioning

confidence: 99%

A new facile approach to N-alkylpyrroles from direct redox reaction of 4-hydroxy-l-proline with aldehydes

Zou¹,

ZeJun²,

Yu³

et al. 2011

Sci. China Chem.

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“…In addition, Cook et al proposed the formal 1,3-hydride shift in a conversion process between 3-pyrroline and ketones to N-substituted pyrroles. 13 In the literature we found only one similar reaction that yields 3-substituted pyrroles from 1 with imines under basic conditions; 14 Wittig et al reported that lithium pyrrolidine amide (12) reacted with benzophenone imine (13) to give 3-(diphenylmethyl)pyrrole (17) in 35% yield. The proposed reaction mechanism requires the oxidation of the amide by the imine 13 to produce 1-pyrroline (2), which is deprotonated and then reacts with another 13 to give 17 via 15 and 16 (Scheme 3).…”

Section: Chartmentioning

confidence: 99%

“…4 (R=o- 18.9, 19.4, 31.2, 51.3, 108.9, 119.4, 121.1, 122.6, 125.8, 125.9, 126.3, 127.7, 127.7, 129.2, 130.0, 130.2, 135.7, 136.2 ppm. 4 (R=2- 7, 48.0, 109.1, 118.8, 120.8, 123.1, 123.2, 124.2, 125.5, 125.9, 126.6, 126.9, 140.6, 145.8 .31 (dd, J = 3.2, 1.6 Hz, 1H), 6.54 (dd, J = 2.1, 1.7 Hz, 1H), 6.61 (dd, J = 2.4, 2.1 Hz, 1H), 7.30 (dd, J = 1.8, 0.6 Hz, 1H), 7.36 (dd, J = 1.8, 0.6 Hz, 1H) ppm; 13 C NMR (CDCl 3 ) δ = 26. 1, 46.0, 105.1, 108.1, 109.0, 110.1, 110.4, 118.8, 120.2, 120.7, 140.9, 142.6, 150.7, 155.8 22.5, 22.7, 26.5, 27.1, 29.2, 31.3, 31.4, 31.5, 31.8, 49.5, 107.7, 117.7, 120.0, 124.4 …”

Section: Chartmentioning

confidence: 99%

A facile non-oxidative method for synthesizing 1,3-disubstituted pyrroles from pyrrolidine and aldehydes

Oda

Fukuchi

Ito

et al. 2007

Tetrahedron Letters

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Synthesis and Isomerization of 3-Pyrroline Enamines

Cited by 20 publications

References 0 publications

Isomer Distribution of Succinylcyclohexenyl, Acetylcyclohexenyl and Acetylcyclopentenyl Enamines

Isomer Distribution of Succinylcyclohexenyl, Acetylcyclohexenyl and Acetylcyclopentenyl Enamines

A new facile approach to N-alkylpyrroles from direct redox reaction of 4-hydroxy-l-proline with aldehydes

A facile non-oxidative method for synthesizing 1,3-disubstituted pyrroles from pyrrolidine and aldehydes

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