Azirines Diels-Alder reactions

Lewis acid-mediated asymmetric Diels-Alder reactions between 2H-azirines 59, bearing chiral auxiliaries, with enophiles such as 60 afforded mixtures of bicyclic aziridine-2-carboxylates 61 (Scheme 3.20) [68]. 8-Phenylmenthol appeared to be the auxiliary of choice in this reaction in terms of yield and diastereoselectivity. 

Reduction of azirine-2-phosphonates 99 (Scheme 3.32) with NaBH4 in ethanol exclusively gave ris-aziridine-2-phosphonates 100 in 81-82 % yield [86, 87]. A Diels-Alder reaction between azirine-2-phosphonate 101 and trans-piperylene 102... 

Ab initio calculations on aza-Diels-Alder reactions of electron-deficient imines with buta-l,3-diene show that these reactions are HOMO (diene)-LUMO(dienophile)-controlled and that electron-deficient imines should be more reactive than alkyl-or aryl-imines. The Diels-Alder reaction of r-butyl 2//-azirine-3-carboxylate (80) proceeds with high diastereoselectivity with electron-rich dienes (81) (Scheme 28). The hetero-Diels-Alder additions of imines with sterically demanding dienes yield perhydroquinolines bearing an angular methyl group. The asymmetric hetero-Diels-Alder reaction between alkenyloxazolines and isocyanates produces diastereometri-cally pure oxazolo[3,2-c]pyrimidines. °... 

Reaction of l-azirine-3-methylaciylates (155) with imidazoles and pyrazoles under mild conditions results in the formation of 2-aza-1,3-dienes (156), which are useful as dienes in hetero Diels-Alder reactions with electron-deficient dienophiles <99JOC49>. When the related methyl 2-aryl-2ff-azirine-3-carboxylate (157) was used as fee substrate, reaction with an amine induced a ting opening by addition of the amino group onto fee C=N bond followed by cleavage to provide enediamine 158 <99JCS(P1)1305>. 

Most monoheterocycles with one cyclic double bond have been prepared by C-Z bond formation in which the Z atom acts as the nucleophile. However, for six-membered rings of this type, Diels-Alder reactions are especially important. Three-membered rings are also atypical azirines are often made by C-N bond formation from precursors in which N is electrophilic or has nitrene character, while oxirenes are but fleeting intermediates (CHEC 5.05.6.3). 

A novel route to optically active piperidines is the imino Diels-Alder reaction between the chiral 2//-azirine 49 and trans-1,3 - p c n t a d i c n c (Scheme 115) <20020L655>. The resulting strained intermediate was a single diastereomer and subsequent halogenation produced the 2,6-disubstituted piperidine. 

Aziridines can also be synthesized from their unsaturated azirine counterparts or existing aziridine rings. The first examples of enantiopure 2-substituted 2Z/-azirine 3-carboxylates 46 were prepared via dehydrochlorination of methyl 2-chloroaziridine-2-carboxylates. Bicyclic and tricyclic aziridines such as 47 were then generated via an aza-Diels-Alder reaction with the corresponding dienes <070L1707>. A related azomethine cycloaddition in the presence of an aziridine has also been reported <07JOC8506>. 

Activation of 3-alkyl and 3-phenyl-2H-aziiines by Lewis acids also promotes their participation in hetero Diels-Alder reactions with a variety of dienes. This methodology circumvents the previous requirement of needing an electron-withdrawing carboxyl moiety at the 3-position of the 2H-azirine ring (01TL9289). Thus, the reaction of 2H-azirine 125 with Danishefsky s diene gave the endo-cycloadduct 126... 

Highly diastereoselective Lewis acid mediated aza-Diels-Alder reactions of chiral auxiliary derivatized 2H-azirines have been studied (02T5983,03JOC9958,03CC1150). The cycloaddition proceeded with high diastereoselectivity (97% de), with the absolute stereochemistry of the major product confirmed by X-ray crystallography. Without the presence of a Lewis acid, no diastereoselectivity was obtained at room temperature. 

H-Azirines are excellent partners in aza-Diels-Alder reactions that occur at room temperature when the C = N bond is activated with a conjugated 0x0, alkoxycarbonyl or heteroaromatic group (05S555). For example, 3-(3-ferf-butyldimethylsilyloxy)buta-l,3-dienyl)oxazolidin-2-one (130) reacted with several electrophilic 2H-azirines of type 129 to furnish the expected [4- -2]-cycloadducts 131 in moderate to good yield (06T3095). 2H-Azirine 129b underwent smooth [4- -2]-cycloaddition with... 

This year, following a consultation exercise involving members of the Editorial Board, and partly in the interest of getting the Volume published as soon as possible after the end of the year being reviewed, the Index is less comprehensive than formerly. It now includes only systematic heterocyclic ring system names. Thus, wherever a pyrrole is discussed, that would be indexed under pyrroles wherever pyrido[3,4-i]indoles are mentioned an indexed entry under that name will be found similarly aceanthryleno[l,2-e][l,2,4]triazines , azirines , 2f/-pyran-2-ones , 1,2,4-triazoles etc. etc. are listed. But, subjects like 4-ethyl-5-methylpyrrole , 5-acylazirines , 6-alkyl-2//-pyran-2-ones , 3-alkylamino-l,2,4-triazoles , are not listed as such in the Index. Diels-Alder reaction or Fleck coupling etc., are also not indexed. 

In contrast, treatment of the related 277-azirine-3-methylacrylate 785 with imidazoles and pyrazoles gave 2-aza-l,3-dienes 786 derived from a transient addition product (Scheme 189) <1999JOC49>. These dienes are useful in hetero-Diels-Alder reactions with electron-deficient dienophiles. 

Furan is an excellent diene in a wide variety of Diels-Alder reactions, providing oxabicyclic compounds with useful synthetic applications. However, Diels-Alder reactions with furans are often reversible and require a highly reactive dienophile in order to provide useful yields of the cycloadduct. As shown in Scheme 17, furans have now been shown to undergo synthetically useful Diels-Alder reactions with azirines. The reaction of furan with azirine 91 provides cycloadduct 92 in 100% yield <1998J(P1)299>. Aziridine 92, while crystalline, is moisture sensitive, decomposing to aziridine 93. An X-ray structure of 92 was obtained which confirmed the exo-natute of the cycloaddition reaction in contrast to the r/o-cycloadditions seen in the formation of 88 <2001J(P1)2969>. 

Azirine 91 has also heen shown to undergo a Diels-Alder reaction with diphenyl isobenzofuran to provide 94. The exo-isomct was reported to isomerize to the endo-isorac,i 95 upon heating, although no yields for this transformation were reported <2001J(P1)2969>. 

The pyridyl azirine 97 was prepared from mesitylsulfonyloxy oxime 96. This is one of the first examples of heteroaromatic substituted azirines reported. This azirine undergoes a Diels-Alder reaction with isobenzofuran to provide the rwn-cycloadduct 98 in 54% yield <2005S555>. In addition to isobenzofuran, this azirine undergoes cycloaddition with a number of different dienes, including cyclopentadiene (82%), 1-methoxy-butadiene (58%), and Danishefsky s diene (67%). 

In an effort to develop enantioselective methods for azirine cycloadditions, azirine 87 was added to chiral diene 99 <1998TL7579, 2003TL6561>. Diene 99 has previously shown facial selectivity in Diels-Alder reactions with a number of dienophiles. Reaction of Z equiv of azirine 87 with 99 provides aziridine 100 in excellent yield as a single isomer (Equation 24). 

The use of chiral esters has found some success in Diels-Alder reactions. Ester 101 was prepared and the enantioselectivity of this azirine with a series of dienes was examined <1999J(P1)1399, 2002J(P1)1911>. Regardless of the diene used, the cycloadducts with azirine 101 showed low diastereoselectivity (2 1 to 3 1). 

A chiral phosphonate-substituted azirine was prepared and its Diels-Alder reactions studied <20020L655>. Azirine 105 is prepared by the Swern oxidation of the corresponding aziridine as shown in Scheme 18. The Diels-Alder reaction of azirine 105 with Danishefsky s diene provides aziridine 106 in excellent yield as a single diastereomer. Note that the reaction time for azirines such as used by Gilchrist is only 15 min as compared to 8h with the phosphonate substituted azirines suggesting that the carboxylate-substituted azirines are much more reactive than the phosphonate-substituted azirines <19978271, 2001J(P1)2969, 2005S555>. 

Diels-Alder reactions of enantiomerically enriched 2H-azirine 3-phosphon-ates (281), a new class of chiral iminodienophiles, and dienes stereoselectively furnish optically pure, bicyclic aziridine adducts (282). Hydrogenation of (282) results in a ring opening that affords the first examples of optically pure quaternary piperidine phosphonates. Two step synthesis of an enantiomeric pure cyclic phosphite (283) and its application as a chiral phosphorus nucleophile in the asymmetric Michael addition to nitroalkenes (284) provides an efficient... 

Azirines constitute another class of neutral, electon-rich imines which will undergo [4 + 2] cycloadditions with certain types of dienes. As can be seen in the following discussion, the initial adducts of these reactions are often not isolable and that a Diels-Alder reaction has, in fact, occurred is sometimes inferred by mechanistic reasoning. 

---