Imine Diels-Alder reaction

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The imine Diels-Alder reaction involves the transformation of all-carbon dienes and imine dienophiles into tetrahydropyridines.[1]

Introduction

Imines may be employed as dienophiles in hetero-Diels-Alder reactions. These reactions involve the lowest unoccupied molecular orbital (LUMO) of the imine, meaning that imines substituted with electron-withdrawing groups on nitrogen are the most reactive. The reaction may be thermal or acid catalyzed. It may proceed via a concerted, [4+2] cycloaddition mechanism, although in cases of extreme polarization, addition to the imine followed by nitrogen nucleophilic attack (the "Mannich-Michael" pathway) occurs.[2] Cyclic, acyclic, and tethered imines have all been employed in the reaction with success.

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Mechanism and Stereochemistry

Prevailing Mechanism

The imino Diels-Alder (IDA) reaction may occur either by a concerted or stepwise process. The lowest-energy transition state for the concerted process places the imine lone pair (or coordinated Lewis acid) in an exo position. Thus, (E) imines, in which the lone pair and larger imine carbon substituent are cis, tend to give exo products.[3]

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When the imine nitrogen is protonated or coordinated to a strong Lewis acid, the mechanism shifts to a stepwise, Mannich-Michael pathway.[4]

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Whatever the mechanism, the transition state of cyclization is highly polarized. Thus, the regiochemistry of cycloaddition can be predicted by considering the electron-withdrawing or -donating nature of substituents on the diene. The carbon bearing the largest coefficient in the HOMO of the diene forms a bond to the imine carbon.

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Stereoselective Variants

In many cases, cyclic dienes give higher diastereoselectivities than acyclic dienes. Use of amino-acid-based chiral auxiliaries, for instance, leads to good diastereoselectivities in reactions of cyclopentadiene, but not in reactions of acyclic dienes.[5]

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Chiral auxiliaries have been employed on either the imino nitrogen[6] or imino carbon[7] to effect diastereoselection.

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Scope and Limitations

Attaching an electron-withdrawing group to the imine nitrogen increases the reactivity of the imine. The exo isomer usually predominates (particularly when cyclic dienes are used), although selectivities vary.[8]

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Tosylimines may be generated in situ from tosylisocyanate and aldehydes. Cycloadditions of these intermediates with dienes give single constitutional isomers, but proceed with moderate stereoselectivity.[9]

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Lewis-acid catalyzed reactions of sulfonyl imines also exhibit moderate stereoselectivity.[10]

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Simple unactivated imines react with hydrocarbon dienophiles only with the help of a Lewis acid; however, both electron-rich and electron-poor dienophiles react with unactivated imines when heated. Vinylketenes, for instance, afford dihydropyridones upon [4+2] cycloaddition with imines. Regio- and stereoselectivity are unusually high in reactions of this class of dienes.[11]

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Vinylallenes react similarly in the presence of a Lewis acid, often with high diastereoselectivity.[12]

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Synthetic Applications

The IDA reaction has been applied to the synthesis of a number of alkaloid natural products. In this example, Danishefsky's diene is used to form a six-membered ring en route to phyllanthine.[13]

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Comparison with Other Methods

Several other methods can access the 1,2,5,6-tetrahydropyridine ring system afforded by IDA reactions. Partial reduction of pyridinium salts has been used, although regioselectivity issues arise when substituted pyridiniums are used.[14]

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A modified Ireland-Claisen rearrangement leads to tetrahydropyridines via a silyl ketene acetal intermediate.[15]

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Ring-closing olefin metathesis has also been used to establish the tetrahydropyridine ring system.[16]

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Experimental Conditions and Procedure

Typical Conditions

Because of the diversity of conditions associated with iDA reactions, generalization is difficult. Reactions may be thermal or involve the use of a Lewis acid. For the former, refluxing benzene is common, although reaction temperatures depend on the reactivity of substrates. Boron trifluoride etherate and zinc chloride are commonly used Lewis acids. Simple alkyl or aryl amines are often generated in situ by combining an amine hydrochloride with an aldehyde.

Example Procedure[17]

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To an ice-cooled solution of butyl (p-tolylsulfonylimino)acetate (22.2 g, 78.4 mmol) in dry benzene (36 mL) was added freshly distilled and dried (CaCl2) cyclopentadiene (5.18 g, 78.5 mmol). When the exothermic reaction began to subside, the reaction mixture was kept at room temperature for 12 hours and was then concentrated in vacuo. The oily residue was taken up in Et2O (50 mL) and washed with 5% NaHCO3 solution, dried (MgSO4), and the solvent was removed under reduced pressure. The residue, which solidified upon standing, was crystallized from Et2O-hexane (1:5), yielding 23.0 g (84%) of butyl 2-(p-tolylsulfonyl)-2-azabicyclo[2.2.1]hept-5-ene-exo-3-carboxylate as a colorless solid, mp 53–55°; IR (nujol) 1740, 1600 cm−1; Anal. Calcd for C18H23NO4S: C, 61.88; H, 6.64; N, 4.01. Found: C, 61.97; H, 6.59; N, 3.83. [1H NMR data was reported for the methyl ester, but not for the title compound. Methyl carboxylate analog: 1H NMR (CDCl</sub>3</sub>) δ 0.93 (t, J = 5 Hz, 3H), 2.5 (s, 3H), 3.33 (m, 1H), 3.53 (s, 1H), 4.13 (t, J = 6 Hz, 2H), 6.23 (m, 2H), 7.56 (m, 4H)].

References

  1. Heintzelman, G. R.; Meigh, I. R.; Mahajan, Y. R.; Weinreb, S. M. Org. React. 2005, 65, 141. doi: (10.1002/0471264180.or065.02)
  2. Waldmann, H. Synthesis 1994, 535.
  3. Whiting, A.; Windsor, C. M. Tetrahedron 1998, 54, 6035.
  4. Hermitage, S.; Jay, D. A.; Whiting, A. Tetrahedron Lett. 2002, 43, 9633.
  5. Waldmann, H. Liebigs Ann. Chem. 1989, 231.
  6. Hedberg, C.; Pinho, P.; Roth, P.; Andersson, P. G. J. Org. Chem. 2000, 65, 2810.
  7. Ishimaru, K.; Watanabe, K.; Yamamoto, Y.; Akiba, K.-Y. Synlett 1994, 495.
  8. Corey, E. J.; Yuen, P.-W. Tetrahedron Lett. 1989, 30, 5825.
  9. Schrader, T.; Steglich, W. Synthesis 1990, 1153.
  10. Krow, G. R.; Pyun, C.; Rodebaugh, R.; Marakowski, J. Tetrahedron 1974, 30, 2977.
  11. Bennett, D. M.; Okamoto, I.; Danheiser, R. L. Org. Lett. 1999, 1, 641.
  12. Regas, D.; Afonso, M. M.; Rodriguez, M. L.; Palenzuela, J. A. J. Org. Chem. 2003, 68, 7845.
  13. Han, G.; LaPorte, M. G.; Folmer, J. J.; Werner, K. M.; Weinreb, S. M. J. Org. Chem. 2000, 65, 6293.
  14. Thyagarajan, G.; May, E. L. J. Heterocycl. Chem. 1971, 8, 465.
  15. Angle, S. R.; Henry, R. M. J. Org. Chem. 1998, 63, 7490.
  16. Deiters, A.; Martin, S. F. Chem. Rev. 2004, 104, 2199.
  17. Barco, A.; Benetti, S.; Baraldi, P. G.; Moroder, F.; Pollini, G. P.; Simoni, D. Liebigs Ann. Chem. 1982, 960.