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词条 Imine Diels–Alder reaction
释义

  1. Introduction

  2. Mechanism and stereochemistry

     Prevailing mechanism  Stereoselective variants 

  3. Scope and limitations

  4. Synthetic applications

  5. Comparison with other methods

  6. See also

  7. References

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, in refluxing solvents such as benzene or others typical for Diels–Alder reactions, or acid catalyzed, again using common Diels–Alder Lewis acids such as boron trifluoride or zinc chloride. 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.

(1)

Simple alkyl or aryl amines are often generated in situ by combining an amine hydrochloride with an aldehyde.

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]

(2)

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

(3)

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.

(4)

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)

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

(5)

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]

(7)

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]

(8)

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

(9)

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.[11]

(10)

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

(11)

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]

(12)

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]

(13)

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

(14)

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

(15)

See also

  • Oxo Diels–Alder reaction
  • Aza-Diels–Alder reaction

References

1. ^{{cite journal|author1=Heintzelman, G. R. |author2=Meigh, I. R. |author3=Mahajan, Y. R. |author4=Weinreb, S. M. |journal=Org. React.|year=2005|volume=65|pages= 141|doi=10.1002/0471264180.or065.02|title=Diels-Alder Reactions of Imino Dienophiles|isbn=0471264180}}
2. ^{{cite journal|author=Waldmann, H. |journal=Synthesis|year=1994|pages= 535|doi=10.1055/s-1994-25519|title=Asymmetric Hetero Diels-Alder Reactions|volume=1994|issue=6}}
3. ^{{cite journal|author1=Whiting, A. |author2=Windsor, C. M. |journal=Tetrahedron|year=1998|volume=54|pages= 6035|doi=10.1016/S0040-4020(98)00284-1|title=What makes a neutral imino dieneophile undergo a thermal, non-catalysed, Diels-Alder reaction?|issue=22}}
4. ^{{cite journal|author1=Hermitage, S. |author2=Jay, D. A. |author3=Whiting, A. |journal=Tetrahedron Lett.|year=2002|volume=43|pages= 9633|doi=10.1016/S0040-4039(02)02392-4|title=Evidence for the non-concerted \\4+2]-cycloaddition of N-aryl imines when acting as both dienophiles and dienes under Lewis acid-catalysed conditions|issue=52}}
5. ^{{cite journal|author=Waldmann, H. |journal=Liebigs Ann. Chem.|year=1989|pages= 231|doi=10.1002/jlac.198919890145|title=Asymmetrische Hetero-Diels-Alder-Reaktionen in wäßriger Lösung unter Verwendung von Aminosäureestern als chiralen Auxiliaren|volume=1989|issue=3}}
6. ^{{cite journal|author1=Hedberg, C. |author2=Pinho, P. |author3=Roth, P. |author4=Andersson, P. G. |journal=J. Org. Chem.|year=2000|volume=65|pages= 2810–2|doi=10.1021/jo9916683|pmid=10808461|title=Diels-Alder reaction of heterocyclic imine dienophiles|issue=9}}
7. ^{{cite journal|author1=Ishimaru, K. |author2=Watanabe, K. |author3=Yamamoto, Y. |author4=Akiba, K.-Y. |journal=Synlett|year=1994|pages= 495|doi=10.1055/s-1994-22902|title=Stereocontrol in \\4+2]Type Cycloaddition of an Aldimine Derived from (S)-Ethyl Lactate with 2-Siloxy-1,3-butadienes|volume=1994|issue=7}}
8. ^{{cite journal|author1=Corey, E. J. |author2=Yuen, P.-W. |journal=Tetrahedron Lett.|year=1989|volume=30|pages= 5825|doi=10.1016/S0040-4039(01)93481-1|title=A short, stereospecific route to chiral trans-2,6-disubstituted quinuclidines|issue=43}}
9. ^{{cite journal|author1=Schrader, T. |author2=Steglich, W. |journal=Synthesis|year=1990|pages= 1153|doi=10.1055/s-1990-27122|title=Phosphoranaloge von Aminosäuren IV.1Synthesen ungewöhnlicher 1-Aminophosphonsäuren über Diels-Alder-Reaktionen von (N-Acyliminomethyl)phosphonsäurediethylestern|volume=1990|issue=12}}
10. ^{{cite journal|author1=Krow, G. R. |author2=Pyun, C. |author3=Rodebaugh, R. |author4=Marakowski, J. |journal=Tetrahedron|year=1974|volume=30|pages= 2977|doi=10.1016/S0040-4020(01)97542-8|title=Heterodienophiles—V|issue=17}}
11. ^{{cite journal|author1=Bennett, D. M. |author2=Okamoto, I. |author3=Danheiser, R. L. |journal=Org. Lett.|year=1999|volume=1|pages= 641–4|doi=10.1021/ol9907217|pmid=10823193|title=Hetero 4 + 2 cycloadditions of (trialkylsilyl)vinylketenes. Synthesis of alpha,beta-unsaturated delta-valerolactones and -lactams|issue=4}}
12. ^{{cite journal|author1=Regas, D. |author2=Afonso, M. M. |author3=Rodriguez, M. L. |author4=Palenzuela, J. A. |journal=J. Org. Chem.|year=2003|volume=68|pages= 7845–52|doi=10.1021/jo034480z|pmid=14510565|title=Synthesis of octahydroquinolines through the Lewis acid catalyzed reaction of vinyl allenes and imines|issue=20}}
13. ^{{cite journal|author1=Han, G. |author2=LaPorte, M. G. |author3=Folmer, J. J. |author4=Werner, K. M. |author5=Weinreb, S. M. |journal=J. Org. Chem.|year=2000|volume=65|pages= 6293–306|doi=10.1021/jo000260z|pmid=11052071|title=Total syntheses of the Securinega alkaloids (+)-14,15-dihydronorsecurinine, (−)-norsecurinine, and phyllanthine|issue=20}}
14. ^{{cite journal|author1=Thyagarajan, G. |author2=May, E. L. |journal=J. Heterocycl. Chem.|year=1971|volume=8|pages= 465|doi=10.1002/jhet.5570080317|title=Improved synthesis of 2-benzyl-1,2,5,6-tetrahydropyridines, precursors of analgetic 6,7-benzomorphans|issue=3}}
15. ^{{cite journal|author1=Angle, S. R. |author2=Henry, R. M. |journal=J. Org. Chem.|year=1998|volume=63|pages= 7490–7497|doi=10.1021/jo980749g|pmid=11672402|title=Studies toward the Synthesis of (+)-Palustrine: The First Asymmetric Synthesis of (−)-Methyl Palustramate|issue=21}}
16. ^{{cite journal|author1=Deiters, A. |author2=Martin, S. F. |journal=Chem. Rev.|year=2004|volume=104|pages= 2199–238|doi=10.1021/cr0200872|pmid=15137789|title=Synthesis of oxygen- and nitrogen-containing heterocycles by ring-closing metathesis|issue=5}}
{{DEFAULTSORT:Imine Diels-Alder reaction}}

2 : Name reactions|Cycloadditions
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