Imine-Enamine Tautomerism - Nucleophilic Reactions of Imines

Transcription

1 ImineEnamine Tautomerism ucleophilic Reactions of Imines AttaurRahman*, iqar Uddin Ahmad*, Mumtaz Sultana, usrat erveen, and ighat Sultana H. E. J. Research Institute of Chemistry, University of Karachi, Karaclii3, akistan Z. aturforsch. 3b, 5 (98); received September 5, 98 Enaminos, Ketimines, ucleophiles, Alkylation A reinvestigation of the reactivity of isopropylidene cyclohexylamine to methyl acrylate by GCMS analysis has shown that the major product is the ßaminoester (9) formed by the alkylation of cyclohexylamine which may be generated by a dimerisationelimination sequence. A number of other products resulting from and Calkylation of the ketimine have been identified. Tertiary enamines () are versatile intermediates in organic synthesis [, ] and have also been invoked as key intermediates in alkaloid biosynthesis [3]. Secondary enamines predominantly exist as the imine () rather than the enamine (3) and a mobile tautomeric equilibrium exists between these two forms [4], Our earlier studies on the naturally occurring ketimine harmaline (4) showed that ketimines are ambident nucleophiles and it was found possible to control the course of the reactions of harmaline ( or Calkylation) by adjusting the reaction conditions [5] (Scheme ). A report in the R,H Q c o r A, sk c=o S c h e m e.. (eak C0,Me 0 o., Fig. ) Recently fau and coworkers have repeated our work and confirmed the formation of the alkylated cyclohexylamine though they obtained this in low yields, and they account for its formation by a dimerisation elimination sequence (Scheme 3), re. HcJ* X ~ p p 3 Scheme 3. literature that exclusive Calkylation of ketimines occurs in reaction with electrophilic olefins [, ] was therefore contrary to our experience on the behaviour of harmaline which afford both and Calkylated products and led us to examine the behaviour of isopropylidene cyclohexylamine () with various electrophilic olefins. The major product isolated in each case was the alkylated cyclohexylamine which was thought to be formed by the alkylation of the ketimine, followed by hydrolysis during work up (Scheme ). * Reprint requests to rof. Dr. AttaurRahman or rof. Dr. iqar Uddin Ahmad /8/000005/$ 0.00/0 suiting in the formation of cyclohexylamine which then undergoes alkylation with methyl acrylate to afford 9 [9]. These findings have led us to undertake a reinvestigation of the reaction products obtained in this reaction by a GCMS analysis. Isopropylidene cyclohexylamine was prepared by the method of Campbell [0] and was refluxed with equimolar quantity of methyl acrylate in dry benzene for 4.5 h. GCMS analysis of the crude mixture revealed the presence of atleast twenty compounds. Out of these the fifteen major compounds have been identified. The mass spectra of all twenty compounds are tabulated in Table I and the relative percentages of these compounds are apparent from the GC plot (Fig. ). In agreement with our previous observation the predominant product (peak o. Fig. ) obtained was the /Samino ester (Scheme ) M+ = mje 85 and not the Calkylated product described by the French Dieses Werk wurde im Jahr 03 vom erlag Zeitschrift für aturforschung in Zusammenarbeit mit der MaxlanckGesellschaft zur Frderung der Wissenschaften e.. digitalisiert und unter folgender Lizenz verffentlicht: Creative Commons amensnennungkeine Bearbeitung 3.0 Deutschland Lizenz. This work has been digitalized and published in 03 by erlag Zeitschrift für aturforschung in cooperation with the Max lanck Society for the Advancement of Science under a Creative Commons AttributionoDerivs 3.0 Germany License. Zum ist eine Anpassung der Lizenzbedingungen (Entfall der Creative Commons Lizenzbedingung Keine Bearbeitung ) beabsichtigt, um eine achnutzung auch im Rahmen zukünftiger wissenschaftlicher utzungsformen zu ermglichen. On it is planned to change the License Conditions (the removal of the Creative Commons License condition no derivative works ). This is to allow reuse in the area of future scientific usage.

2 58 AttaurRahman, et al. ImineEnamine Tautomerism ucleophilic Reactions of Imines group. The formation of each product is rationalised in Schemes 3 to Table I (continued). eak os. Compounds 3 8* * * i L L L i Table I. eak os. Compounds Mass spectra mje 93 (M+, 0%), 9 (9%), 9 (98%), 85 (%), 83 (4%), 8 (3%), 5 (4%), 3 (0%), 55 (8%) m/e 98 (M+, 3%), 83 (8%), 8 (3%), 3 (%), 55 (00%) m/e 39 (M+, 8%), 38 (%), 5 (0%), (%), 0 (%), 98 (%), 9 (4%), 9 (84%), 84 (38%), 83 (84%), 8 (48%), 58 (00%), 54 (9%) m/e 5 (M+, %), 4 (4%), (34%), 0 (%), 9 (0%), 85 (3%), 4 (0%), 59 (88%) 55 (00%) m/e 9 (M+, 3%), 4 (00%), 50 (4%), 3 (3%), (0%), 08 (%), 9 (39%), 8 (88%), (3%), 55 (00%) m/e 85 (M+, 43%), 5 (0%), 4 (00%), 4 (3%), 9 (%), (%), 0 (%), 8 (%), 8 (8%), 5 (%) m/e 9 (M+, %), 04 (30%), 9 (%), (%), (4%), (8%), 0 (%), 95 (0%), 8 (00%), (4%), 55 (0%) m/e 5 (M+, %), 0 (4%), 94 (8%), 8 (%), (0%), 5 (40%), 39 (89%), 4 (4%), (5%), 9 (38%), 83 (00%), 0 (30%), 55 (00%) m/e 5 (M+, %), 50 (%), (%), 0 (4%), 9 (35%), 8 (0%), 4 (30%), 5 (4%), 8 (34%), 0 (%), 9 (34%), 8 (00%), (4%), 55 (%) m/e (M+, 5%), 8 (00%), 4 (4%), (%), 98 (9%), 5 (8%), 4 (4%), (5%), 84 (5%) Mass spoctra m/e 305 (M+, %), 90 (8%), (0%), 3 (0%), 04 (8%), (8%), 30 (%), 08 (0%), 8 (00%) m/e 3 (M+, %), 80 (%), 5 (4%), 4 (50%), 5 (%). 98 (0%), 8 (8%), 5 (8%), 4 (4%), 90 (%), 83 (00%) m/e 3 (M+, %), 5 (3%), 8 (%), 5 (8%), 38 (4%), 5 (30%), 5 (%), 98 (4%), 45 (4%), 38 (8%), 8 (00%), 9 (90%), 83 (55%), 5 (8%) m/e 35 (M+, 8%), 330 (3%), 30 (0%), 30 (8%), 8 (30%), 5 (%), 50 (%), 3 (5%), 4 (%), 9 (0%), 8 (5%), 4 (8%), 48 (0%), 08 (8%), 8 (00%), 5 (5%) m/e 35 (M+, %), 30 (5%), 8 (%), 5 (0%), 50 (3%), 94 (%), 5 (3%), 4 (3%), 83 (00%) m/e 35 (M+, 3%), 30 (%), 8 (8%), 50 (53%), (0%), 9 (%), 4 (8%), 3 (5%), 8 (00%), 9 (40%), 83 (3%), 5 (59%) m/e 35 (M+, %), 30 (8%), 8 (45%), 05 (98%), 38 (%), 9 (%), 9 (94%), 4 (3%), (8%), 3 (%), 0 (8%), 83 (8%), 5 (44%) m/e 3 (M+, 9%), 338 (%), 35 (%), 3 (%), 84 (5%), 5 (5%), 3 (8%), 5 (0%), 0 (5%), 8 (%), 50 (%), 8 (00%), 90 (44%), 83 (8%), 5 (45%) m/e 3 (M+, 5%), 35 (30%), 3 (%), 84 (3%), 3 (%), 38 (4%), 04 (%), 8 (3%), 5 (3%), 4 (30%), 83 (00%), 5 (48%) m/e 43 (M+, 8%), 43 (%), 40 (%), 34 (3%), 350 (4%), 33 (3%), 8 (0%), 50 (8%), 4 (3%), 8 (5%), 8 (49%), 49 (3%), 3 (94%), 08 (4%), 8 (45%) * The structural assignment of compounds have been made on the basis of mass spectral fragmentation. It was observed that inspite of careful distillation the ketimine () contained significant quantities of cyclohexylamine, which may be formed by an intramolecular dimerization reaction to afford followed by an intramolecular deamination to give the ketimine () and cyclohexylamine (3). The form

3 59AttaurRahman,et al. ImineEnamine Tautomerism ucleophilic Reactions of Imines ation of the alkylated cyclohexylamine (9) on reaction of the ketimine () with methyl acrylate may therefore be attributed to the direct attack of the cyclohexylamine present in the ketimine mixture with methyl acrylate. In another experiment isopropylidene cyclohexylamine was refluxed in benzene for 4.5 h. The crude mixture on GCMS analysis showed three products exhibiting parent ions at m/e 99, 39 and 9 which were identified as cyclohexylamine (3), ketimine () and the dimerized product () respectively. It was of interest to examine the gradual change in relative concentrations of the products when isopropylidene cyclohexylamine was refluxed for prolonged periods. Isopropylidene cyclohexylamine was refluxed directly (not benzene solution) for about 4.5 h and the aliquots drawn after every h were subjected to gas chromatography. It was found that concentration of cyclohexylamine increased with time of reflux Avhile that of ketimine decreased. The concentration of the dimerized increased at first but on prolonged refluxed it started decreasing, possibly due to decomposition. Table II. Time [h] A Cycloliexylamine (3) B C Ketimine () Deaminated product () It is apparent that the reaction of ketimines with electrophilic olefins is of rather limited utility as it does not result in the exclusive formation of a Calkylated product as originally claimed by fau et al. [, ] but rather in a very complex mixture of reaction products as demonstrated by us earlier [5]. Our previous observations [8] that the major product of the reaction mixture was the /5amino ester (9) stands confirmed b y the GCMS analysis although the mechanism for its formation appears to be a dimeriziti DU iea mi nation sequence followed b y alkylation (Scheme 3) [9] rather than the alkylationhydrolysis sequence earlier proposed by us (Scheme ). Experimental ote: GCMS analysis of all the compounds reported in this paper were carried out on a arian model 300 capillary gas Chromatograph attached with mass spectrometer MAT S. 0.5 //I of sample was injected each time, the column temperature was set at 40 C during injection and raised by 8 C/min to 40 C. Gas chromatography of all the compounds was done on Dani model 800 equipped with programmer for temp, control, and connected to F I D detector. The spiral glass column packed with 5 % OlOl chromosorb W A W was used for separation whereas nitrogen gas was used as carrier. The column temp, (using programme control) was set at 50 C during all injections and was increased by 5 C/mt to 80 C. The recorder speed was adjusted at 0. mm/s. I. reparation of isopropylidene cyclohexylamine () Cyclohexylamine (0 ml) and acetone (9 ml) were mixed at room temperature and a catalytic amount of HCl ( ml) was added. The reaction mixture A v a s kept for 4 h and was shaken exhuastively with potassium hydroxide pellets (500g). The water which separated out on shaking was removed. The organic layer was distilled off at atmospheric pressure. The fraction distilling at 8 to 80 C was carefully collected. The ketimine (50 ml) so obtained was stored under molecular sieve (Linde 0 A) and in a nitrogen atmosphere to prevent hydrolysis and oxidation. II. Reaction of isopropylidene with methyl acrylate cyclohexyl amine Equimolar amount of isopropylidene cyclohexylamine (0. mole) and methyl acrylate (0. mole) were refluxed in dry benzene (0 ml) for 4.5 h in strictly anhydrous conditions. The mixture was cooled down to room temperature and then submitted for GCMS analysis. The GC plot showed twenty peaks (Fig. ). The mass spectrum of each compound was recorded and is tabulated in Table I. Out of twenty compounds fifteen major compounds could be identified and their formation is rationalized in Schemes 3 to. YCOjMe Scheme U. 4 m / e 5 (eak o.8, Fig.)

4 0 AttaurRahman et al. ImineEnamine Tautomerism ucleophilic Reactions of Imines J 4 H. H H H 5 m/e 5 (eak o.9, Fig.) MeO,C rc0 Me H Scheme. C0,Me m/e (eak o. 0. Rig. ) Scheme. MeO,C. m/e 35 (eak o., Fig.) T C0,Me rl C0Me C0,Me H Ö w Ö 4 4 m/e 3 Scheme. (eak o..fig.il C0Me in C0Me Me Me0C H QJj m/e 35 Ö 4 8 m/e 3 (eak o. 3, Fig.) C0Me eak o., Fig.) COjMe C0Me / H CO, Me 9 m/e 35 (eak o. 4, Fig.) m/e 3 3 peak o. 8,Fig. H H )LH H C0Me Y" illtco.me H \ c0 Me 0 C0Me m/e 35 (eak o. 5, Fig.] 4 T C0Me

5 AttaurRahman, et al. ImineEnamine Tautomerism ucleophilic Reactions of Imines 5 m/e 3 (eak o. 9. Fig ] C0Me H Ö Q,H vur?h m/e 43 (eak o. 0, Fig.l) COjMe The GC plot (Fig. ) shows the relative abundance of each product. eak o., which is the major peak in the plot, shows M + at 85 and was identified as the /?amino ester formed due to alkylation by cyclohexylamine. III. isopropylidene cyclohexylamine (blank reflux in benzene) Isopropylidene cyclohexylamine (5 ml) was refluxed in dry benzene (0 ml) for 4.5 h. The reaction mixture was subjected to GCMS analysis. The gas chromatograms showed three peaks exhibiting M+ ions at mje 99, 39 and 9 for cyclohexylamine, ketimine and deaminated product respectively. The major peak of the plot was of ketimine showing that ketimine predominates in the mixture. H Scheme A ( H rr m/e 9 ( eak o. 5, Fig. I. Isopropylidene cyclohexylamine (blank reflux without benzene) Isopropylidene cyclohexylamine was refluxed directly (without benzene) for h. The aliquots were drawn after every h during reflux so that six aliquots were collected each aliquot was subjected to gas chromatography under the same parameter. The percentage of each peak was calculated and are tabulated in Table II. [] G. Stork, R. Terrell, and J. Szmuszkovicz, J. Am. Chem. Soc., 00 (954). [] G. Stork and H. K. Handesman, J. Am. Chem. Soc. 8, 58 (95). [3] AttaurRahman and A. Basha, "The Biosynthesis of Indole Alkaloids", Oxford University ress, Oxford U. K., in press. [4] AttaurRahman and T. Burney, ak. J. Sei. and Ind. Res. 5(), 9 (9). [5] AttaurRahman, J. Chem. Soc. erkin 9, 3. [] M. fau and C. Ribior, Chem. Commun., (90). [] M. fau and C. Ribier, Bull. Soc. Chim. Fr., 584 (9). [8]. U. Ahmad, A. Basha, and AttaurRahman, Z. aturforsch. b, 584 (9). [9] M. fau and J. UghettoMonfrin, Tetrahedron 35, 899 (980). [0] K.. Campbell, A. H. Sommers, and B. K. Campbell, J. Am. Chem. Soc., 8 (944).