[538-51-2]  · C13H11N  · N-Phenylbenzylimine  · (MW 181.25)

(hetero Diels-Alder and cycloaddition reactions; stereospecific b-lactam synthesis; secondary amine and quinoline syntheses)

Alternate Name: N-benzylideneaniline.

Physical Data: mp 52-54 °C; bp 310 °C; fp >110 °C; d 1.038 g cm-3. Generally exists in the trans form; theoretical studies have shown that the cis-trans interconversion occurs by inversion rather than rotation.1

Solubility: sol ether, alcohol, chloroform, acetic anhydride, liquid SO2, NH3; insol H2O.

Form Supplied in: commercially available.

Analysis of Reagent Purity: IR.18

Purification: recrystallize from CS2 (pale yellow needles) or dilute alcohol (plates) and vacuum dry.

Handling, Storage, and Precautions: harmful and irritant. Use in a fume hood.

Cycloaddition Reactions.

The initial example of an imino compound participating as a dienophile was reported by Alder in 1943.2 Whilst full mechanistic details are not known, these [4 + 2] cycloadditions of C=N dienophiles (and also of N=N, N=O and C=O dienophiles) are believed to be HOMOdiene-LUMOdienophile controlled and concerted pericyclic processes. However, a dipolar mechanistic model is normally sufficient for quantitative predictions as to the regiochemical outcome of these reactions and may even be indicative of dipolar character in a concerted pericyclic transition state. Unless X and Y are very good at stabilizing carbanions, only intermediates (i) and (iii) need to be considered (eq 1). Imino Diels-Alder reactions show excellent syn stereoselectivity with respect to the diene component. Krow, however,3 states that lone pair inversion on the nitrogen in both the imine and product tetrahydropyridine leads to stereochemical ambiguities that are missing in all carbon Diels-Alder reactions. Using a cyclic imine tends to remove this problem.

Imine cycloaddition reactions have become generally well known,4 and there are also examples of iminium salts participating in these reactions.5 Electron-rich dienes (3), in considerable excess, react with imines under the influence of Lewis acids (eq 2).6,7 Only the one regioisomer (2) is detected in the product mixture and this is in keeping with the postulated mechanism in eq 1. The Danishefsky group has done considerable work in this field,6 with both catalyzed and uncatalyzed reactions and with differing imines and dienes. There are also examples of Aluminum Chloride, dialkylaluminium halides,8a Boron Trifluoride Etherate, and Zirconium(IV) Chloride catalyzing these cycloadditions.8b Finally, various studies have been performed on the effects of the nitrogen substituent on the reaction course and heterocycle conformation in these imino Diels-Alder reactions.8b

b-Lactam Synthesis.

Condensation Reactions.

Imines and silyl ketene acetals condense in the presence of a Trimethylsilyl Trifluoromethanesulfonate (TMSOTf) catalyst to give mainly anti-b-amino esters, which can be cyclized to give trans-b-lactams (eq 3).9 Table 1 shows some typical results obtained, mainly using N-phenylbenzylimine as the imine (5), but another imine is given for comparison.

All these examples involve an acid-catalyzed condensation between an isomeric mix of silyl ketene acetal and nonenolizable imines. The yields obtained are normally good, with a preference for the anti-isomer, irrespective of the starting geometry of the silyl ketene acetal. The isomeric products can be separated by silica gel chromatography. The utility of this reaction is that the anti-b-amino esters can be cyclized to the trans-b-lactam in excellent yields (eq 4).9

The one well known exception to this is the silyl ketene acetal (8) derived from ethyl 3-hydroxybutanoate, which reacts with N-phenylbenzylimine with syn selectivity and cyclizes to give the cis-b-lactam (9) (eq 5).10

Another group has performed similar reactions to form chiral trans-b-lactams with high stereoselectivity using Titanium(IV) Chloride (eq 6).11 The silyl ketene acetal (10) is derived from (1S,2R)-N-methylephedrine and in the presence of TiCl4 gives the trans-b-lactam (11) in 79% yield and 95% ee. There are also reports of Zinc Iodide being used to promote these reactions, with some degree of stereoselectivity.12

Transition Metal-Mediated.

Simultaneous studies between groups in America and Britain have shown that the condensation of certain transition metal complexes with imines can give unprecedented asymmetric induction (eq 7).13,14 Previous studies had shown that the enolate (13) derived from (12) is sufficiently nucleophilic to react with electrophiles, of which readily available imines (from amines and aldehydes/ketones) are a good example, and that the resulting b-aminoacyl complexes are formed stereoselectively. The American group have also shown that the diethylaluminum enolate is also as effective as the lithium enolate, and in some cases leads to greater stereoselectivity, although the yields drop.14

Preparation of Secondary Amines.

The addition of a carbon nucleophile to imines is a useful preparative method for secondary amines.15 Alkyl organolithiums and Grignard reagents have been used to form secondary amines and considerable attention has been paid to forming allylated derivatives. The general reaction is shown in eq 8 and is an example of an indium-mediated Barbier-type allylation.

Quinoline Synthesis.

Treatment of N-phenylbenzylimine with diisopropyl peroxydicarbonate generates the arylimidoyl radical (18) which reacts with 1-alkynes to form 4-alkylquinolines (19) (eq 9). This is a useful route to substituted quinolines in high yields.16 There are other examples of imines being used in annulation reactions with a variety of promoting reagents.17

1. Boltin, V. A.; Boltin A. B. Khim. Fiz. 1983, 5, 698 (CA 1984, 101, 110 050c).
2. Alder, K. Neuer Methoden der Preparative Organischen Chemie Verlag Chemie: Weinheim, 1943.
3. Krow, G.; Rodebaugh, R.; Carmosin, R.; Figures, W.; Pannela, H.; DeVicaris, G.; Grippi, M. JACS 1973, 95, 5273.
4. For early reviews see: Weinreb, S. M.; Levin, J. I. H 1979, 12, 949; Weinreb, S. M.; Staib, R. R. T 1982, 38, 3087.
5. Bohme, A. T.; Hartke, K.; Muller, A. CB 1963, 96, 607.
6. Kerwin, J. F., Jr.; Danishefsky, S. TL 1982, 23, 3739, and references therein.
7. Weinreb, S. M.; Boger, D. L. Hetero Diels-Alder Methodology in Organic Synthesis; Academic: San Diego, 1987; Chapter 2.
8. (a) Midland, M. M.; McLoughlin, J. I. TL 1988, 29, 4653, and references therein. (b) Le Coz, L.; Veyrat-Martin, C.; Wartski, L.; Seyden-Penne, J.; Bois, C.; Philoche-Levisalles, M. JOC 1990, 55, 4870, and references within.
9. Guanti, G.; Narisano, E.; Banfi, L. TL 1987, 28, 4331.
10. FF 1989, 14, 334.
11. Gennari, C.; Venturini, I.; Gislon, G.; Schimprena, G. TL 1987, 28, 227.
12. Colvin, E. W.; McGarry, D. G. CC 1985, 539.
13. Broadley, K.; Davies, S. G. TL 1984, 25, 1743.
14. Liebeskind, L. S.; Welker, M. E.; Goedken, V. JACS 1984, 106, 441.
15. Beuchet, P.; Le Marrec, N.; Mosset, P. TL 1992, 33, 5959, and references therein.
16. Leardini, R.; Pedulli, G. F.; Tundo, A.; Zanardi, G. CC 1984, 1320.
17. Leardini, R.; Nanni, D.; Tundo, A.; Zanardi, G.; Ruggieri, F. JOC 1992, 57, 1842.
18. Pouchert, C. J. Aldrich Library of FT-IR Spectra; Aldrich: Milwaukee, 1989; Vol. 1, p 1162D.

Adrian P. Dobbs

King's College London, UK

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