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Aza-Diels–Alder reaction

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Aza-Diels–Alder reaction
Named after Otto Diels
Kurt Alder
Reaction type Cycloaddition
Identifiers
RSC ontology ID RXNO:0000092

The Aza-Diels–Alder reaction involves the transformation of all-carbon dienes and imine dienophiles into tetrahydropyridines.[1] This organic reaction is a modification of the Diels–Alder reaction.[2] The nitrogen atom can be part of the diene or the dienophile.

Mechanism[edit]

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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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.[5]

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Scope and limitations[edit]

Stereoselective variants[edit]

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.[6]

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Asymmetric variants[edit]

Chiral auxiliaries have been employed on either the imino nitrogen[7] or imino carbon[8] to effect diastereoselection.

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In the enantioselective Diels–Alder (DA) reaction of an aniline, formaldehyde and a cyclohexenone catalyzed by (S)-proline even the diene is masked.[9]

S-proline enantioselective Aza Diels–Alder reaction
S-proline enantioselective Aza Diels–Alder reaction

In situ generated imines[edit]

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..[10]

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.

catalytic cycle for S-proline enantioselective Aza Diels–Alder reaction
catalytic cycle for S-proline enantioselective Aza Diels–Alder reaction

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.[11]

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Lewis-acid catalyzed reactions of sulfonyl imines also exhibit moderate stereoselectivity.[12]

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Simple unactivated imines react with hydrocarbon dienes only with the help of a Lewis acid; however, both electron-rich and 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.[13]

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Vinylallenes react similarly in the presence of a Lewis acid, often with high diastereoselectivity.[14]

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Acyliminium substrates[edit]

Acyliminium ions also participate in cycloadditions. These cations are generated by removal of chloride from chloromethylated amides:[15]

RCONRCH2Cl → RCONR/dCH+2 + Cl−

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

Use in natural products synthesis[edit]

The aza-Diels–Alder reaction 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.[16]

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The Aza Diels–Alder reaction, general scope
The Aza Diels–Alder reaction, general scope

See also[edit]

References[edit]

  1. ^ Heintzelman, G. R.; Meigh, I. R.; Mahajan, Y. R.; Weinreb, S. M. (2005). "Diels-Alder Reactions of Imino Dienophiles". Org. React. 65: 141–599. doi:10.1002/0471264180.or065.02. ISBN 0471264180.
  2. ^ Kobayashi, S. (2002). "Catalytic Enantioselective Aza Diels-Alder Reactions". In Kobayashi, S.; Jørgensen, K. A. (eds.). Cycloaddition Reactions in Organic Synthesis. John Wiley & Sons. pp. 187–210. ISBN 9783527301591.
  3. ^ Whiting, A.; Windsor, C. M. (1998). "What makes a neutral imino dieneophile undergo a thermal, non-catalysed, Diels-Alder reaction?". Tetrahedron. 54 (22): 6035. doi:10.1016/S0040-4020(98)00284-1.
  4. ^ Hermitage, S.; Jay, D. A.; Whiting, A. (2002). "Evidence for the non-concerted \4+2]-cycloaddition of N-aryl imines when acting as both dienophiles and dienes under Lewis acid-catalysed conditions". Tetrahedron Lett. 43 (52): 9633. doi:10.1016/S0040-4039(02)02392-4.
  5. ^ Corey, E. J.; Yuen, P.-W. (1989). "A short, stereospecific route to chiral trans-2,6-disubstituted quinuclidines". Tetrahedron Lett. 30 (43): 5825. doi:10.1016/S0040-4039(01)93481-1.
  6. ^ Waldmann, H. (1989). "Asymmetrische Hetero-Diels-Alder-Reaktionen in wäßriger Lösung unter Verwendung von Aminosäureestern als chiralen Auxiliaren". Liebigs Ann. Chem. 1989 (3): 231–238. doi:10.1002/jlac.198919890145.
  7. ^ Hedberg, C.; Pinho, P.; Roth, P.; Andersson, P. G. (2000). "Diels-Alder reaction of heterocyclic imine dienophiles". J. Org. Chem. 65 (9): 2810–2. doi:10.1021/jo9916683. PMID 10808461.
  8. ^ Ishimaru, K.; Watanabe, K.; Yamamoto, Y.; Akiba, K.-Y. (1994). "Stereocontrol in \4+2]Type Cycloaddition of an Aldimine Derived from (S)-Ethyl Lactate with 2-Siloxy-1,3-butadienes". Synlett. 1994 (7): 495. doi:10.1055/s-1994-22902.
  9. ^ Direct Catalytic Enantioselective Aza-Diels-Alder Reactions Henrik Sundén, Ismail Ibrahem, Lars Eriksson, Armando Córdova Angewandte Chemie International Edition 4877 2005 Abstract
  10. ^ Grieco, P. A.; Larsen, S. D. (1990). "N-benzyl-2-azanorbornene". Organic Syntheses. 68: 206. doi:10.15227/orgsyn.068.0206.
  11. ^ Schrader, T.; Steglich, W. (1990). "Phosphoranaloge von Aminosäuren IV.1Synthesen ungewöhnlicher 1-Aminophosphonsäuren über Diels-Alder-Reaktionen von (N-Acyliminomethyl)phosphonsäurediethylestern". Synthesis. 1990 (12): 1153. doi:10.1055/s-1990-27122.
  12. ^ Krow, G. R.; Pyun, C.; Rodebaugh, R.; Marakowski, J. (1974). "Heterodienophiles—V". Tetrahedron. 30 (17): 2977. doi:10.1016/S0040-4020(01)97542-8.
  13. ^ Bennett, D. M.; Okamoto, I.; Danheiser, R. L. (1999). "Hetero 4 + 2 cycloadditions of (trialkylsilyl)vinylketenes. Synthesis of alpha,beta-unsaturated delta-valerolactones and -lactams". Org. Lett. 1 (4): 641–4. doi:10.1021/ol9907217. PMID 10823193.
  14. ^ Regas, D.; Afonso, M. M.; Rodriguez, M. L.; Palenzuela, J. A. (2003). "Synthesis of octahydroquinolines through the Lewis acid catalyzed reaction of vinyl allenes and imines". J. Org. Chem. 68 (20): 7845–52. doi:10.1021/jo034480z. PMID 14510565.
  15. ^ Weinreb, Steven M.; Scola, Paul M. (1989). "N-acyl imines and related hetero dienes in [4+2]-cycloaddition reactions". Chemical Reviews. 89 (7): 1525–1534. doi:10.1021/cr00097a008.
  16. ^ Han, G.; LaPorte, M. G.; Folmer, J. J.; Werner, K. M.; Weinreb, S. M. (2000). "Total syntheses of the Securinega alkaloids (+)-14,15-dihydronorsecurinine, (−)-norsecurinine, and phyllanthine". J. Org. Chem. 65 (20): 6293–306. doi:10.1021/jo000260z. PMID 11052071.
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