IMINO KETENIMINES ON AN ORTHO-BENZYLIC SCAFFOLD

Received: 20 August 2001 / Uploaded 21 August 2001
 
 

Introduction

Recently we have described the first examples of intramolecular [2+2] cycloaddition between imines and ketenimines supported on an ortho-benzylic scaffold [1]. Specifically in these cases we used as substrates imino-ketenimines 1, where the iminic nitrogen is on the benzylic position and the nitrogen of the ketenimine function is linked directly to the benzene ring. Compounds 1 underwent intramolecular [2+2] cycloaddition to give azeto[2,1-b]quinazolines 2 in a highly sterocontrolled manner.

As a further step in our study we considered if this type of cycloaddition could take place successfully interchanging the positions of the imine and ketenimine moieties on the ortho-benzylic scaffold: now the iminic nitrogen should be linked to the benzene ring and the nitrogen of the ketenimine fragment placed on the benzylic position. Imino-ketenimines 3 combine these structural requirements.

Results and Discussion

We envisaged that 3 could be prepared starting from 2-(azidomethyl)aniline 4 [2]. The reaction of 4 with aromatic aldehydes under standard conditions gave rise to imines 5. Sequential treatment of toluene solutions of these azido-imines with triphenylphosphane and methyl phenyl- or diphenyl ketene led to imino-ketenimines 3, which remained unaltered when kept at room temperature (reaction conditions for the conversion 1?2). However, when toluene solutions of compounds 3 were heated at reflux temperature the propanenitriles 6 were formed. Neither the formal [2+2] cycloadducts 7 nor the [4+2] products 8 were isolated or detected by analysis of the ¹H NMR spectra of the crude reaction mixtures.

An X-ray structure determination of compound 6a (R¹ = 4-O₂N-C₆H₄; R² = C₆H₅) confirmed the proposed structure. The relevant crystallographic data and structure refinement parameters are given in Table 2.

Singer and coworkers have demonstrated that N-benzyl-C,C-diphenyl ketenimines underwent [1,3] sigmatropic rearrangement of the benzyl group to the sp² carbon terminus of the ketenimine, to give propanenitriles, via radical intermediates [3]. Thus, the formation of compounds 6 should take place by the same mechanism.

When compared imino-ketenimines 1 and 3, both with an ortho-benzylic framework supporting the reactive functions, the inability of compounds 3 to experiment an intramolecular [2+2] cycloaddition imine-ketenimine can be rationalized on the basis of the stepwise mechanism reported for this type of cycloadditions [1c], by the less electrophilic character of the ketenimine fragment in the new imino-ketenimines 3 (N-alkyl ketenimines are less electrophilic than N-aryl [4]), combined with the presence of a less nucleophilic iminic nitrogen, now derived from an aniline instead of a benzylic amine (as in compounds 1).

Finally, propanenitriles 6 were used to prepare 2-amino-3,4-dihydroquinolines 9 by treatment with a catalytic amount of HCl in ethanol. Under this acidic conditions the imine undergo hydrolytic cleavage and the resulting amino group adds intramolecularly to the nitrile function, so leading to 9.

Conclusions

In summary, the positioning of the reactive functions of imino-ketenimines, where the N-atoms of both functionatilies are linked by an ortho-benzylic tether, strongly direct the course of their intramolecular evolution: [2+2] cycloaddition in one case (N-benzylic imines, previously reported) or [1,3] sigmatropic rearrangement (N-aryl imines, here disclosed).
 
 

Experimental Section

Imines 5 were obtained from 2-(azidomethyl)aniline by an standard procedure [5].

General procedure for the preparation of propanenitriles 6:

To a solution of triphenylphosphane (0.52 g, 2 mmol) in anhydrous Et₂O (10 mL) was added a solution of the azide 5 (2 mmol) in the same solvent (5 mL). The reaction mixture was stirred at room temperature for 4 h, and the solvent removed under reduced pressure. The crude material was dissolved in dry toluene (15 mL) and then the appropriate ketene (phenyl methyl or diphenyl ketene) (2 mmol) was added. The resultant mixture was stirred at room temperature for 15 min and then heated at reflux temperature for 1 h. After that, the solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column using hexanes/ethyl acetate (4:1) as eluent to give the propanenitriles 6.

3-{2-[4-(Nitrobenzylidene)amino]phenyl}-2,2-diphenylpropanenitrile 6a:

Yield 60%; m.p. 168 ºC (colourless prisms from diethyl ether). ¹H NMR (300 MHz, CDCl₃) d: 4.00 (s, 2 H), 6.84 (d, 1 H, J = 7.5 Hz), 7.15-7.33 (m, 13 H), 7.84 (d, 2 H, J = 8.7 Hz), 7.87 (s, 1 H), 8.26 (d, 2 H, J = 8.7 Hz). ¹³C NMR (75.4 MHz, CDCl₃) d: 39.78, 52.73 (s), 117.50, 122.31 (s), 123.84, 126.84, 127.71, 127.94, 128.49, 128.85, 129.43, 129.83 (s), 132.00, 140.27 (s), 141.77 (s), 149.11 (s), 150.28 (s), 156.17; IR (Nujol) n: 2237, 1627, 1517, 1343 cm^-1; MS m/z (%): 431 (M⁺, 29), 239 (100); C₂₈H₂₁N₃O₂ (431.48): calcd C, 77.94, H, 4.91, N, 9.74; found C, 78.12; H, 4.77; N, 9.81.

3-{2-[(4-Chlorobenzylidene)amino]phenyl}-2,2-diphenylpropanenitrile 6b:

Yield 71%; yellow oil; ¹H NMR (300 MHz, CDCl₃) d: 3.97 (s, 2 H), 6.78 (dd, 1 H, J = 1.4, 7.6 Hz), 7.09-7.39 (m, 17 H), 7.68 (s, 1 H); ¹³C NMR (75.4 MHz, CDCl₃) d: 39.55, 52.70 (s), 117.73, 122.47 (s), 125.99, 127.70, 127.83, 128.43, 128.72, 128.90, 129.36 (s), 130.02, 131.67, 134.98 (s), 137.03 (s), 140.30 (s), 150.89 (s), 157.32; IR (film) n: 2240, 1628 cm^-1; MS m/z (%): 420 (M⁺, 45), 288 (100); C₂₈H₂₁ClN₂ (420.94): calcd C, 79.89; H, 5.03; N, 6.65; found C, 79.67; H, 5.00; N, 6.83.

2-Methyl-3-{2-[(4-nitrobenzylidene)amino]phenyl}-2-phenylpropanenitrile 6c:

Yield 64%; yellow oil; ¹H NMR (300 MHz, CDCl₃) d: 1.83 (s, 3 H), 3.47 (s, 2 H), 6.88-6.93 (m, 1 H), 7.10-7.13 (m, 3 H), 7.16-7.34 (m, 5 H), 7.94 (d, 2 H, J = 8.7 Hz), 8.07 (s, 1 H), 8.31 (d, 2 H, J = 8.7 Hz); ¹³C NMR (75.4 MHz, CDCl₃) d: 26.18, 43.16, 43.62 (s), 117.54, 123.99, 124.34 (s), 126.01, 126.93, 127.77, 128.45, 128.80, 129.43, 130.39 (s), 131.74, 136.64 (s), 141.74 (s), 150.05 (s), 156.63, a quaternary carbon atom was not observed; IR (film) n: 2232, 1630 cm^-1; MS m/z (%): 369 (M⁺, 11), 239 (100); C₂₃H₁₉N₃O₂ (369.42): calcd 74.78; H, 5.18; N, 11.37; found C, 74.65; H, 5.01; N, 11.21.

General procedure for the preparation of the 2-aminoquinolines 9:

To a solution of the corresponding propanenitrile 6 (1 mmol) in ethanol (5 mL) was added a catalytic amount of hydrochloric acid. The mixture was heated at reflux temperature for 6 h. After cooling, 10% sodium hydroxide was added (15 mL). The resulting mixture was extracted with CH₂Cl₂ (3 x 15 mL), and the extracts were combined and dried over anhydrous MgSO₄. The solvent was removed under reduced pressure and the resulting oil was chromatographed on a silica gel column eluting with ethyl acetate/ methanol (3:2).

2-Amino-3,3-diphenyl-3,4-dihydroquinoline 9a: yield 91 % [6].

2-Amino-3-methyl-3-phenyl-3,4-dihydroquinoline 9b: yield 74% [6].

References

1. (a) Alajarín, M.; Molina, P.; Vidal, A. Tetrahedron Lett. 1996, 37, 8945. (b) Alajarín, M.; Molina, P.; Vidal, A.; Tovar, F. Tetrahedron 1997, 53, 13449. (c) Alajarín, M.; Vidal, A.; Tovar, F.; Arrieta, A.; Lecea, B.; Cossío, F Chem. Eur. J. 1999, 5, 1106.
2. Kreher, R.; Bergmann, U. Z. Naturforsch 1976, 31B, 222.
3. (a) Lee, K. -W.; Horowitz, N.; Ware, J.; Singer, L. A. J. Am. Chem. Soc. 1977, 99, 2622. (b) Newman, R. C.; Sylwester, A. P. J. Org. Chem. 1983, 48, 2285.
4. Barker, M. W.; McHenry, W. E. in The Chemistry of the Ketenes, Allenes and Related Compounds; Patai, S.; Ed. Wiley: Chichester, 1980, part 2, pp. 701.
5. Krechek, L.; Takimoto, H. J. Org. Chem. 1964, 29, 3630.
6. Makosza, A.; Kmiotek-Skar?y?ska, I.; Jawdosiuk, M. Synthesis 1977, 56.

Acknowledgements

This work was supported by the Dirección General de Enseñanza Superior (Projet PB95-1019), Fundación Séneca-CARM (Projet PB/2/FS/99), and Acedesa (a division of Takasago). F. Tovar also thanks the MEC for a fellowship.