The Nitro group in organic sysnthesis - Feuer

Scheme 8.6.

In intramolecular Diels-Alder reactions, two rings are formed in one step. The reaction has been used to synthesize a number of interesting ring systems.29 The intramolecular cyclization of (E)-1-nitrodeca-1,6,8-triene at 80 °C affords an endo cycloadduct with the trans ring fusion preferentially, as shown in Eq. 8.18. In contrast, (Z)-nitroalkenes produce a nearly 1:1 mixture of cisand trans-fused cycloadducts.30

Although Lewis acid-catalyzed-Diels-Alder reactions of enones are common, there are few reports on the catalysis of Diels-Alder reaction of nitroalkenes. The reaction of nitroalkenes with alkenes in the presence of Lewis acids undergoes a different course of reaction to give cyclic nitronates (see Section 8.3). Knochel reported an enhanced reactivity and selectivity of the intramolecular Diels-Alder reaction using silica gel as Lewis acid in hexane (Eq. 8.19).31

240 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

A concentrated solution of LiClO4 in diethyl ether has also been shown to activate the intramolecular Diels-Alder reactions (Eq. 8.20).32 The reaction proceeds at room temperature to give the adduct in good yield, whereas noncatalyzed reaction proceeds very slowly even at 80 °C (yield was 22% for 65 h).

Intramolecular Diels-Alder cyclizations of (E)-1-nitro-1,7,9-decatrienes under thermal conditions and Lewis acid conditions lead to the formation of decalin ring systems with excellent endo selectivity (Eq. 8.21). This strategy is used for preparing of the AB ring system of norzoanthamine.33

Oppolzer and Robbiani have reported highly stereoselective total syntheses of alkaloids such as chelidonine by an intramolecular o-quinodimethene/nitrostyrene-cycloaddition (Scheme 8.7).34 (Benzocyclobutane is used as a source of quinodimethene). The high regioand stereoselectivity in the intramolecular cycloaddition is remarkable; a strong preference for transition state, exo-NO2, over transition state, endo-NO2, is responsible for the stereoselectivity.

It has been known that aromatic heterocycles such as furan, thiophene, and pyrrole undergo Diels-Alder reactions despite their aromaticity and hence expected inertness. Furans have been especially used efficiently as dienes due to their electron-rich properties. Thiophenes and pyrroles are less reactive as dienes than furans. But pyrroles with N-electron-withdrawing substituents are efficient dienes. There exists a limited number of examples of five-membered, aromatic heterocycles acting as dienophiles in Diels-Alder reactions. Some nitro heteroaromatics serve as dienophiles in the Diels-Alder reactions. Heating a mixture of 1-(phenylsulfonyl)- 3-nitropyrrole and isoprene at 175 °C followed by oxidation results in the formation of indoles (see Eq. 8.22).35a N-Tosyl-3-nitroindole undergoes high-yielding Diels-Alder reactions with

8.24).37 Thus, nitroheterocycles are important synthons of five-membered heteroarynes in cycloaddition reactions, which are generally difficult to be generated.38

Microwave irradiation at solvent-free conditions induces pyrazoyl 2-azadienes to undergo Diels-Alder reactions with nitroalkenes, within 5–10 min good yields of pyrazolo[3,4-b]pyri- dines are obtained (see Eq. 8.25).39 Without irradiation the reaction produces only traces of products on classical heating.

3,7-Dinitro-11-oxatricyclo[6.2.1.01,6]undec-9-ene has been prepared by an intramolecular Diels-Alder reaction of the furan with a nitroalkene group as shown in Eq. 8.26. This tricyclic compound is a versatile synthetic tool for the preparation of ergot alkaloids.41

8.1 DIELS-ALDER REACTIONS 243

Amino-substituted dienes are also important dienophiles in Diels-Alder reactions. Recently, chiral and achiral 2-amino-1,3-dienes have been prepared to study their reactivity (see also asymmetric Diels-Alder reaction Section 8.1.2). The reaction of 2,3-diamino-1,3-butadienes with nitrostyrene gives unusual [3+2]carbocyclization products, 2-aminocyclopentanones, which are not formed by the direct cycloaddition but derived from the Michael addition products (see section discussing the Michael addition Section 4.1.3).42

A typical regioselectivity and endo/exo selectivity has been reported in the Diels-Alder reaction of 2-(N-acylamino)-1,3-diene with nitroalkenes (Eq. 8.27).43 Thus, exo products are predominantly formed, which is general for the Diels-Alder reaction of nitroalkenes with sterically hindered dienes.

The total synthesis of frodosin B, which is a potentially useful drug for HIV, has been reported (Scheme 8.8). The key steps in the synthesis are a Friedel-Crafts reaction to form the sevenmembered ring and a Diels-Alder reaction of nitroethylene to build the six-membered ring, thereby fixing the double bond in the proper position.44

Resin-bound 2-aminobutadiene reacts with 1-nitro-2-arylethenes to give, after cleavage of the resin, nitrocyclohexanones in good yields with high purity (Eq. 8.28).45

The preparation of resin-bound nitroalkenes via a microwave-assisted Knoevenagel reaction of resin-bound nitroacetic acid with aryl and alkyl substituted aldehydes is reported. The potential of these resin-bound nitroalkenes for application in combinatorial chemistry is demonstrated by a Diels-Alder reaction with 2,3-dimethylbutadiene (Scheme 8.9). It is also used for one-pot three-component tandem [4+2]/[3+2] reactions with ethyl vinyl ether and styrene.46

8.1.2 Asymmetric Diels-Alder Reaction

Asymmetric Diels-Alder reactions have been performed by using either chiral dienophiles or chiral dienes in the presence or the absence of catalysts.47 The progress in this field is remarkable; catalytic asymmetric Diels-Alder reactions are generally carried out either by the use of chiral dienophiles or by the use of chiral dienes. Here, the reactions of chiral nitroalkenes with dienes or the reactions of nitroalkenes with chiral dienes are discussed. Many different chiral auxiliaries are now available, and some of them have been used in asymmetric Diels-Alder reactions of nitroalkenes.

8.1 DIELS-ALDER REACTIONS 247

section discussing Michael addition Section 4.2). The Diels-Alder reaction of the chiral nitroalkene with Danishefsky’s diene gives a diastereomeric mixture of the adduct. The exo-selectivity is general for this type of reaction, as discussed previously. The stereocontrol of newly created asymmetric carbons is not important because these isomers are converted into a single compound after aromatization of the resulting six-membered ring. Methylenation and reductive cyclization on treatment with CH2Br2 and Zn in the presence of TiCl4 give the lactam in 82% yield. The lactam is converted into the target compound via the processes shown in Scheme 8.11.

Clive and coworkers have reported a total synthesis of calicheamicinone, the aglycon of the antitumor agent calicheamicin γ1, starting from the Diels-Alder reaction of methyl 3-nitro- propenoate with ketene acetal (Eq. 8.32).54 An asymmetric Diels-Alder reaction between ketene acetal presented in Eq. 8.32 and 3-nitropropenoate derived from (–)-8-phenyl-menthol affords the optically pure adduct, which can be converted into either enantiomer of calicheamicinone (Eq. 8.33).55

(8.32)

Asymmetric Diels-Alder reactions using chiral sulfinylalkenes have been extensively studied by Koizumi and coworkers.55 Fuji and coworkers have extended this strategy to chiral 1-(alkyl- sulfinyl)-2-nitroalkenes. Such nitroalkenes react with reactive dienes such as Danishefsky’s dienes to produce an adduct with a high enantiomeric excess (ee) (see Eqs. 8.34 and 8.35).57

Simple dienes are not reactive enough toward chiral 1-(alkylsulfinyl)-2-nitroalkenes. To resolve this problem, the reaction of optically active 1-(alkylsulfinyl)-2-nitroalkenes with simple

248 CYCLOADDITION CHEMISTRY OF NITRO COMPOUNDS

dienes such as cyclopentadiene or 1,3-pentadiene has been carried in the presence of Lewis acids or under high pressure.58 In these reactions, the Z-sulfinyl dienophiles show high diastereoand endo/exo selectivity, as shown in Eq. 8.36.

attached to the C-1 position of the dienes is the most popular in asymmetric Diels-Alder reactions.59 In 1980, Trost reported high asymmetric induction in the Diels-Alder reaction using 1-(S)-O-methylmandeloxy-1,4-butadiene.59a However, the result obtained by Trost et al. has remained unique for more than a decade, at least in terms of enantioselectivity. The asymmetric Diels-Alder reaction of chiral diene-amines with nitroalkenes gives aminocyclohexenes with good diastereoselectivity (Eq. 8.37).60 The development in the area of chiral dienes is slow; it may be due to the difficulty of preparing these compounds.

Recently, the research groups of Enders (Eq. 8.38)61 and Barluenga (Eq. 8.39)62 reported on the cycloaddition of chiral 2-aminobutadiene and described elegant solutions to the stereochemistry problems (regio-, diastereo-, and enantioselectivity). The reaction of 2-[(S)-2- methoxymethyl]pyrrolidin-1-yl]buta-1,3-diene with various 2-aryl-1-nitroethenes produces after hydrolysis 5-aryl-2-methyl-substituted 4-nitrocyclohexanones in excellent enantiomeric purity (ee = 75–95%) and with high diastereoselectivity (ds = 75–95%).61