Aza-Diels–Alder reaction explained

The Aza-Diels–Alder reaction is a modification of the Diels–Alder reaction wherein a nitrogen replaces sp2 carbon.[1] The nitrogen atom can be part of the diene or the dienophile.

Mechanism

The aza 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 exoposition. Thus, (E) imines, in which the lone pair and larger imine carbon substituent are cis, tend to give exo products.[2]

(2)When the imine nitrogen is protonated or coordinated to a strong Lewis acid, the mechanism shifts to a stepwise, Mannich-Michael pathway.[3] (3)

Attaching an electron-withdrawing group to the imine nitrogen increases the rate. The exo isomer usually predominates (particularly when cyclic dienes are used), although selectivities vary.[4]

(7)

Scope and limitations

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]

(6)

Asymmetric variants

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

(5)

In the enantioselective Diels–Alder (DA) reaction of an aniline, formaldehyde and a cyclohexenone catalyzed by (S)-proline even the diene is masked.[8]

In situ generated imines

The imine is often generated in situ from an amine and formaldehyde. An example is the reaction of cyclopentadiene with benzylamine to an aza norbornene..[9]

The catalytic cycle starts with the reactions of the aromatic amine with formaldehyde to the imine and the reaction of the ketone with proline to the diene. The second step, an endo trig cyclisation, is driven to one of the two possible enantiomers (99% ee) because the imine nitrogen atom forms a hydrogen bond with the carboxylic acid group of proline on the Si face. Hydrolysis of the final complex releases the product and regenerates the catalyst.

Tosylimines may be generated in situ from tosylisocyanate and aldehydes. Cycloadditions ofthese intermediates with dienes give single constitutional isomers, but proceed with moderate stereoselectivity.[10]

(8)Lewis-acid catalyzed reactions of sulfonyl imines also exhibit moderate stereoselectivity.[11] (9)Simple unactivated imines react with hydrocarbon dienes only with the help of a Lewis acid; however, both electron-richand electron-poor dienes 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.[12] (10)Vinylallenes react similarly in the presence of a Lewis acid, often with high diastereoselectivity.[13] (11)

Acyliminium substrates

Acyliminium ions also participate in cycloadditions. These cations are generated by removal of chloride from chloromethylated amides:[14]

The resulting acyl iminium cations serve as heterodienes as well as dienophile.

Use in natural products synthesis

The aza-Diels–Alder reaction has been applied to the synthesis of a number of alkaloid natural products. Danishefsky's diene is used to form a six-membered ring en route to phyllanthine.[15]

(12)

See also

Notes and References

  1. Book: Kobayashi, S.. Cycloaddition Reactions in Organic Synthesis. 2002. S.. Kobayashi. K. A.. Jørgensen. Catalytic Enantioselective Aza Diels-Alder Reactions. 187–210. 9783527301591. John Wiley & Sons.
  2. Whiting, A. . Windsor, C. M. . Tetrahedron. 1998. 54. 6035. 10.1016/S0040-4020(98)00284-1. What makes a neutral imino dieneophile undergo a thermal, non-catalysed, Diels-Alder reaction?. 22.
  3. Hermitage, S. . Jay, D. A. . Whiting, A. . Tetrahedron Lett.. 2002. 43. 9633. 10.1016/S0040-4039(02)02392-4. Evidence for the non-concerted \4+2]-cycloaddition of N-aryl imines when acting as both dienophiles and dienes under Lewis acid-catalysed conditions. 52.
  4. Corey, E. J. . Yuen, P.-W. . Tetrahedron Lett.. 1989. 30. 5825. 10.1016/S0040-4039(01)93481-1. A short, stereospecific route to chiral trans-2,6-disubstituted quinuclidines. 43.
  5. Waldmann, H. . Liebigs Ann. Chem.. 1989. 231–238. 10.1002/jlac.198919890145. Asymmetrische Hetero-Diels-Alder-Reaktionen in wäßriger Lösung unter Verwendung von Aminosäureestern als chiralen Auxiliaren. 1989. 3.
  6. Hedberg, C. . Pinho, P. . Roth, P. . Andersson, P. G. . J. Org. Chem.. 2000. 65. 2810–2. 10.1021/jo9916683. 10808461. Diels-Alder reaction of heterocyclic imine dienophiles. 9.
  7. Ishimaru, K. . Watanabe, K. . Yamamoto, Y. . Akiba, K.-Y. . Synlett. 1994. 495. 10.1055/s-1994-22902. Stereocontrol in \4+2]Type Cycloaddition of an Aldimine Derived from (S)-Ethyl Lactate with 2-Siloxy-1,3-butadienes. 1994. 7.
  8. Direct Catalytic Enantioselective Aza-Diels-Alder Reactions Henrik Sundén, Ismail Ibrahem, Lars Eriksson, Armando Córdova Angewandte Chemie International Edition 4877 2005 Abstract
  9. N-benzyl-2-azanorbornene. P. A.. Grieco. S. D.. Larsen. Organic Syntheses. 1990. 68. 206. 10.15227/orgsyn.068.0206.
  10. Schrader, T. . Steglich, W. . Synthesis. 1990. 1153. 10.1055/s-1990-27122. Phosphoranaloge von Aminosäuren IV.1Synthesen ungewöhnlicher 1-Aminophosphonsäuren über Diels-Alder-Reaktionen von (N-Acyliminomethyl)phosphonsäurediethylestern. 1990. 12.
  11. Krow, G. R. . Pyun, C. . Rodebaugh, R. . Marakowski, J. . Tetrahedron. 1974. 30. 2977. 10.1016/S0040-4020(01)97542-8. Heterodienophiles—V. 17.
  12. Bennett, D. M. . Okamoto, I.. Rick L. Danheiser . Danheiser, R. L. . Org. Lett.. 1999. 1. 641–4. 10.1021/ol9907217. 10823193. Hetero 4 + 2 cycloadditions of (trialkylsilyl)vinylketenes. Synthesis of alpha,beta-unsaturated delta-valerolactones and -lactams. 4.
  13. Regas, D. . Afonso, M. M. . Rodriguez, M. L. . Palenzuela, J. A. . J. Org. Chem.. 2003. 68. 7845–52. 10.1021/jo034480z. 14510565. Synthesis of octahydroquinolines through the Lewis acid catalyzed reaction of vinyl allenes and imines. 20.
  14. 10.1021/cr00097a008 . N-acyl imines and related hetero dienes in [4+2]-cycloaddition reactions . 1989 . Weinreb . Steven M. . Scola . Paul M. . Chemical Reviews . 89 . 7 . 1525–1534 .
  15. Han, G. . LaPorte, M. G. . Folmer, J. J. . Werner, K. M. . Weinreb, S. M. . J. Org. Chem.. 2000. 65. 6293–306. 10.1021/jo000260z. 11052071. Total syntheses of the Securinega alkaloids (+)-14,15-dihydronorsecurinine, (−)-norsecurinine, and phyllanthine. 20.

This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Aza-Diels–Alder reaction".

Except where otherwise indicated, Everything.Explained.Today is © Copyright 2009-2024, A B Cryer, All Rights Reserved. Cookie policy.