Tandem nitroalkene cycloaddition reactions

Recently, Denmark and coworkers have developed a new strategy for the construction of complex molecules using tandem [4+2]/[3+2]cycloaddition of nitroalkenes.149 In the review by Denmark, the definition of tandem reaction is described and tandem cascade cycloadditions, tandem consecutive cycloadditions, and tandem sequential cycloadditions are also defined. The use of nitroalkenes as heterodienes leads to the development of a general, high-yielding, and stereoselective method for the synthesis of cyclic nitronates (see Section 5.2). These dipoles undergo 1,3-dipolar cycloadditions. However, synthetic applications of this process are rare in contrast to the functionally equivalent cycloadditions of nitrile oxides. This is due to the lack of general methods for the preparation of nitronates and their instability. Thus, as illustrated in Scheme 8.29, the potential for a tandem process is formulated in the combination of [4+2] cycloaddition of a donor dienophile with [3+2]cycload-... 

Inter [4 +2]/intra [3+2] This type of tandem reaction using nitroalkenes has been explored most extensively. Four subfamilies of tandem cycloaddition exist, which arise from the four different points of attachment of the dipolarophilic tether. They are defined as fused, spiro, and bridged modes, as depicted in Scheme 8.37.149... 

Cyclic alkyl nitronates may be used in tandem [4+2]/[3+2] cycloadditions of nitroalkanes, and this reaction has been extensively studied by Denmark et al. (64,333-335). In recent work, they developed the silicon-tethered heterodiene-alkene 219 (Scheme 12.63). Steric hindrance and the fact that both the nitroalkene and the a,p-unsaturated ester in 219 are electron deficient renders the possibility of self-condensation. Instead, 219 reacts with the electron-rich chiral vinyl ether 220 in the presence of the catalyst 224 to form the intermediate chiral nitronate 221. The tandem reaction proceeds from 221 with an intramolecular 1,3-dipolar cycloaddition to form 222 with 93% de. Further synthetic steps led to the formation of ( )-detoxinine 223 (333). A similar type of tandem reaction has also been applied by Chattopadhyaya and co-workers (336), using 2, 3 -dideoxy-3 -nitro-2, 3 -didehydrothymidine as the starting material (336). 

P(p-FC6H4)3-catalyzed tandem reaction between ethyl-2,3-butadienoate and nitroalkenes leads to substituted cyclopentenes (Scheme 6.6). The reaction involves a [3-f2] cycloaddition and a subsequent umpolung addition. The asymmetric version of this tandem reaction can be achieved by using chiral phosphine, that is, (/ )-2,2 -bis(diphenylphosphino)-1,1 -binaphthyl (Binap) [8],... 

Hassner and coworkers have developed a one-pot tandem consecutive 1,4-addition intramolecular cycloaddition strategy for the construction of five- and six-membered heterocycles and carbocycles. Because nitroalkenes are good Michael acceptors for carbon, sulfur, oxygen, and nitrogen nucleophiles (see Section 4.1 on the Michael reaction), subsequent intramolecular silyl nitronate cycloaddition (ISOC) or intramolecular nitrile oxide cycloaddition (INOC) provides one-pot synthesis of fused isoxazolines (Scheme 8.26). The ISOC route is generally better than INOC route regarding stereoselectivity and generality. 

Hetero Diels-Alder reactions using nitroalkenes followed by 1,3-dipolar cycloadditions provide a useful strategy for the construction of polycyclic heterocycles, which are found in natural products. Denmark has coined the term tandem [4+2]/[3+2] cycloaddition of nitroalkenes for this type of reaction. The tandem [4+2]/[3+2] cycloaddition can be classified into four families as shown in Scheme 8.31, where A and D mean an electron acceptor and electron donor, respectively.149 In general, electron-rich alkenes are favored as dienophiles in [4+2] cycloadditions, whereas electron-deficient alkenes are preferred as dipolarophiles in [3+2] cycloadditions. 

In recent years, the importance of aliphatic nitro compounds has greatly increased, due to the discovery of new selective transformations. These topics are discussed in the following chapters Stereoselective Henry reaction (chapter 3.3), Asymmetric Micheal additions (chapter 4.4), use of nitroalkenes as heterodienes in tandem [4+2]/[3+2] cycloadditions (chapter 8) and radical denitration (chapter 7.2). These reactions discovered in recent years constitute important tools in organic synthesis. They are discussed in more detail than the conventional reactions such as the Nef reaction, reduction to amines, synthesis of nitro sugars, alkylation and acylation (chapter 5). Concerning aromatic nitro chemistry, the preparation of substituted aromatic compounds via the SNAr reaction and nucleophilic aromatic substitution of hydrogen (VNS) are discussed (chapter 9). Preparation of heterocycles such as indoles, are covered (chapter 10). 

Intramolecular [3+ 2]-cycloaddition of six-membered cyclic nitronates was extensively studied by Prof. Denmark and coworkers for the tandem [4 + 2] [3 + 2] -cycloaddition reactions of nitroalkenes. Detailed considerations of this problem were summarized in two reviews (394a, b). Most data were comprehensively discussed in Reference 394b. It is unnecessary to repeat this information however, it is worthwhile to briefly review the available data. 

Reactions of Tandem [4 + 2][3 + 2] Cycloaddition of Conjugated Nitroalkenes and their Use in Organic Synthesis... 

This synthetic feat relies on an asymmetric Michael/Michael/Henry tandem sequence, resulting in a formal [24-24-2] cycloaddition. The generation of a chiral copper enolate, which undergoes two successive Michael additions on two nitroalkenes followed by ring closure with a Henry reaction, generates the expected adduct in a highly enantio- and diastereoselective manner (Scheme 7.14). 

This reaction was applied to the synthesis of natural polyhydroxylated in-dolizidines and pyrrolizidines [179]. For example, (H-)-epiaustralin, which is one of pyrrolizidine alkaloids produced by the plant Castanospermum australe, was synthesized through tandem inter[4 + 2]/intra[3 + 2] cycloaddition of silyl tethered nitroalkene and chiral vinyl ether promoted by MAPh (Scheme 6.151). Furthermore, tandem [4 + 2]/[3 + 2] cycloaddition of nitrocyclopentene and vinyl ether was used as a key step for the synthesis of 1-azafenestranes, a structurally unique family of compounds constructed by four fused cycles (Scheme 6.152) [180]. 

Sometimes, nitronates are involved in tandem [4+2]/[3+2] cycloaddition processes. That is, the first step consists on the formation of the nitronate (starting from a nitroalkene) and the second is the 1,3-dipolar cycloaddition between the nitronate and an electron-deficient alkene. This is the case of the next example. The reaction between nitroalkene 7 and 2,3-dimethyl-2-butene 8 in the presence of a Lewis acid and under the conditions indicated in Scheme 22.3 yields tricyclic adduct 9. 

Once we understand flie regio- and stereochemistry of the [3+2] cycloaddition reactions involving nitronates, the formulation of the tandem process proposed in Part 2 is not difficult. The starting compounds are a nitroalkene 7 (tethered to an a,P-unsaturated ester) and 2,3-dimethyl-2-butene 8, a simple unactivated alkene. The fragments of flie starting materials can be easily recognized in the structure of the reaction product 9, as indicated in Scheme 22.7. The nitroalkene skeleton has been drawn in red and the 2,3-dimethyl-2-butene in blue. Discoimection of bonds a and b in 9 leads back to nitronate intermediate 13. Disconnection of c and d bonds in 13 leads back to nitroalkene 7 and 2,3-dimethyl-2-butene 8 (Scheme 22.7). The overall reaction could be interpreted as a tandem intermolecular [4+2]/ intramolecular [3+2] cycloaddition. Next we will formulate the process step by step. 

The overall result of this process is the formation of two new CT-bonds in addition to the generation of a new stereocaiter adjacent to the heteroatom, thereby constituting a tandem anionic—pericyclic ring-closure sequence. It can be considered formally an equivalent of a [3+3] cycloaddition in which the three carbons of aldehyde 2 have been added to the two carbons and one oxygen atom of pyrone 1 [3a,b,4,13,14]. The term [3+3] cycloaddition was adapted by us from Seebach s work describing a Stork-type carbo-[3+3] cycloaddition reaction between nitroalkenes and enamines [14]. 

As for any tandem cycloaddition sequence, four different permutations arise from the pairwise combinations of intermolecular and intramolecular events in each step (Figure 16.7). The double intermolecular variant involves three independent reaction partoers. The intra-[4 + 2]/inter-[3 + 2] variant requires that the dienophile, but not the dipolarophile, is connected to the nitroalkene. This variant and the next two variants can create additional complexity by adjusting the length and point of attachment of the tether to... 

In addition to the (3-aryl substituted nitroalkene 38, (3-cyclohexyl and (3-acyloxy nitroalkenes similarly participate in the C(5)-bridged-mode, tandem cycloadditions [77a]. Reactions with trisubstituted dienophiles have also been reported [94b]. 

Both Dienophile and Dipolarophile Attached to the Nitroalkene As illustrated in Figure 16.7, a tandem double intramolecular [4 + 2]/[3 + 2] cycloaddition of nitroalkenes requires that all three reaction partners (nitroalkene. 

The model studies demonstrated that an exo-(tether)-[4-1-2] cycloaddition on the a-unsubstimted nitroalkene, and the construction of the piperidine ring are possible. In the next stage of the synthesis the elements needed to create rings A, D, E, and F were installed in a suitable precursor. Thus, enantiopure nitroalkene (S)-165 (prepared as a 5/1 mixture of nitroalkene isomers, Scheme 16.83) [47, 147] undergoes tandem, double-intramolecular [4 + 2]/[3- -2] cycloaddition in the presence of SnCLj to provide an inseparable mixture of nitroso acetals 167. Assuming that the substrate does not isomerize prior to the [4 + 2] cycloaddition, the reaction proceeds via the cnt/o-(tether)-transi-tion stmcture. Calculations suggest that the reaction is... 

Compared to the cycloadditions of nitroalkenes, tandem cycloadditions of 1,3,4-oxadiazoles consist not of two, but of three elementary reactions. In the first step, a 1,3,4-oxadiazole 428 serves as an electron-poor heterodiene (4jt-component) and reacts thermally with an alkene dienophile (2jt-componait) by a [4-1-2] cycloaddition reaction. The preferred dienophile is electron-rich, unhindered, and strained. At the elevated temperatures required for the first step [169], the immediate product of this reaction, 430, is unstable and undergoes extrusion of dinitrogen by a [3 + 2] cycloreversion to form dipole 431 [170]. At the high temperatures required for its formation, 431 cannot be directly observed either and reacts by a [3 + 2] cycloaddition with an available dipolarophUe, which can be the same 27i-component that served as the dienophile or something else. Because none of the intermediates is isolated and no change in reaction conditions is required, tandem [4-f 2]/[3- -2] cycloadditions of 1,3,4-oxadiazoles are tandem cascade processes as defined earlier in this chapter. 

The tandem cycloaddition of nitroalkenes is a very complex process consisting of a number of elementary reactions. Multiple bonds, stereogenic centers, and rings are created. The connection between the starting materials and the final product is often not obvious. To simplify the retrosynthetic analysis, summary charts (e.g.. Figure 16.8) for most of the modes of the tandem cycloaddition of nitroalkenes were provided. Illustrations of how these charts can be used for retrosynthetic analysis (e.g.. Scheme 16.54) were also provided. For the most complex modes, such as double intramolecular cycloadditions, a similar chart would be too complex and of limited utility because of the myriad of theoretically possible tether lengths and placements. Moreover, only a handful of variants have been realized in practice. 

---