Dipolarophiles nitroalkenes

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. 

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... 

Di- and trisubstituted nitroalkenes tethered to dipolarophiles (unsaturated esters, nitriles) undergo tandem [4+2]/[3+2] cycloadditions with 2,3-dimethyl-2-butene or butyl vinyl ether in the presence of Lewis acids (Eq. 8.112). For the dimethylene tether, the E-configuration of the dipolarophile is preferred, and the products arise selectively from a syn-endo pathway.177... 

When a-tethered nitroalkenes bearing three or four methylene chains and ester-activated dipolarophiles react with vinyl ethers, spiro mode tandem cycloaddition takes place to give tricyclic spiro nitroso acetals in good yield and high diastereoselectivity (Scheme 8.46).184... 

The third cycloaddition substrate explored the feasibility of a vinyl nitro functionality as an activated dipolarophile (98, Scheme 1.9c). Preparation of nitroalkene oxidopyridinium betaine 98 began with silylenol ether 92, which was treated with methoxydioxolane in the presence of Lewis acid catalyst, TrC104, to afford keto dioxolane 93 in 58 % yield [47]. Ketone 93 then underwent a-nitration by treatment with /-BuONCL and KOt-Bu to provide nitro ketone 84 (91 %), which was then converted to the nitroalkene functionality via reduction under Luche conditions to... 

Clearly, the nitroalkene dipolarophile oxidoisoquinolinium betaine 123 is nonideal for the synthesis of the hetisine alkaloids, as mass throughput for the needed cycloadduct would be low, and conversion of the tertiary nitro group to carbon-based functionality, as would be required in the latter stages of the synthesis, could be problematic. On the other hand, an ene-nitrile dipolarophile has several potential advantages over nitroalkene dipolarophile. Most importantly, the ene-nitrile cycloadduct has carbon functionality installed at the C-10 position. Second, the conjugate addition byproduct pathway that occurs so readily for the nitroalkene oxidoisoquinolinium betaine 123 system (see Scheme 1.13) should be much slower... 

Individual aspects of nitrile oxide cycloaddition reactions were the subjects of some reviews (161 — 164). These aspects are as follows preparation of 5-hetero-substituted 4-methylene-4,5-dihydroisoxazoles by nitrile oxide cycloadditions to properly chosen dipolarophiles and reactivity of these isoxazolines (161), 1,3-dipolar cycloaddition reactions of isothiazol-3(2//)-one 1,1-dioxides, 3-alkoxy- and 3-(dialkylamino)isothiazole 1,1-dioxides with nitrile oxides (162), preparation of 4,5-dihydroisoxazoles via cycloaddition reactions of nitrile oxides with alkenes and subsequent conversion to a, 3-unsaturated ketones (163), and [2 + 3] cycloaddition reactions of nitroalkenes with aromatic nitrile oxides (164). 

The majority of asymmetric dipolar cycloadditions have been investigated in the context of the tandem [4 + 2]/[3 + 2]-nitroalkene cycloaddition. The chiral nitronate is prepared by using either a chiral nitroalkene, vinyl ether, or Lewis acid in the hrst cycloaddition. The acetal center at C(6) of the nitronate provides important steric and electronic effects that control the subsequent dipolar cycloaddition. Subsequently, in the cycloadditions of the chiral nitroalkenes 281 and 284, the dipolarophile approaches from the side distal to that of the substituent at C(4) and the acetal center at C(6) (Eq. 2.27 and Table 2.53) (90,215). 

In view of the multicomponent nature of the tandem [4 + 2] / [3 + 2] cycloaddition, the potential for a combinatorial approach to the synthesis of nitroso acetals has been investigated on solid-phase supports. The incorporation of either the dipolarophile or the starting nitroalkene on a Wang-type resin is compatible with the tandem cycloaddition promoted at high pressures (Schemes 2.28 and 2.29). The solid-supported nitroso acetals are subsequently liberated (in moderate yields from the staring nitroalkene) upon the addition of a catalytic amount of potassium cyanide in triethylamine and methanol or by reduction with lithium aluminum hydride (LAH) (261,264). 

Bicyclic nitroso acetals were able to be synthesised by employing ethyl vinyl ether (dienophile), styrene (dipolarophile) and the previously discussed resin-bound ni-troalkenes in a one-pot tandem [4+2]/[3+2]. As illustrated in Scheme 7.30, several aromatic and aliphatic substituents could be introduced to the bicyclic scaffold. Reductive cleavage of the cycloadducts with lithium aluminium hydride (LLAIH4) gave rise to the 3a-methyl alcohol substituted nitroso acetals in moderate overall yields. All these examples demonstrate that resin-bound nitroalkenes can be readily synthesised by microwave synthesis and thereafter can be used as starting materials, in a variety of high pressure-promoted cycloadditions. 

The Lewis acid-promoted tandem inter[4 + 2]/intra[3 + 2]-cycloaddition of the (fumaroyloxy)nitroalkene (124) with the chiral /i-silylvinyl ether (125) is the key step in the total synthesis of (+)-crotanecine (126), the necine base of a number of pyrrolizidine alkaloids (Scheme 46).237 The tandem inter[4 + 2]/intra[3 + 2]-cycload-ditions of nitroalkenes (127) with dipolarophiles attached to the /f-carbon of a vinyl ether (128) provides a method of asymmetric synthesis of highly functionalized aminocyclopentanes (129) (Scheme 47).238 trans-2-( 1 -Methyl-phenylethyl)cyclohex-anol has been developed as a new auxiliary in tandem 4 + 2/3 + 2-cycloadditions of nitroalkenes.239 The scope and limitations of the bridged mode tandem inter-[4 + 2]/intra[3 + 2]-cycloadditions involving simple penta-1,4-dienes are described in detail.240 A tandem intermolecular/intramolecular Diels-Alder cycloaddition was successfiilly used to synthesize a B/C cA-fused taxane nucleus (130) in 50% overall... 

The tandem double intramolecular 4 + 3/3 + 2-cycloaddition of the nitroalkene (10) produced the nitroso acetal (11) in 77% yield. Further functional group manipulations allowed for the conversion to the partial core (12) of the complex polycyclic alkaloid daphnilactone B in high yield (Scheme 3).6 The tandem intramolecular 4 + 2/3 + 2-cycloaddition cascade of 1,3,4-oxadiazoles (13) to polycyclic adducts (14) was investigated by considering the tethered initiating dienophile, the tethered dipolarophile, the 1,3,4-oxadiazole C(2) and C(5) substituents, the tether lengths and sites, and the central heterocycle (Scheme 4).7... 

The tandem inter-[4+2]/intra-[3+2] cycloaddition process involving dienylsilyloxy nitroalkene 540 and chiral vinyl ether 541 in the presence of methylaluminium bis(2,6-diphenylphenoxide) (MAPh) as Lewis acid afforded the single cycloadduct 542 in 66% yield. On a preparative scale, a lower yield (49%) of the purified product was obtained (Scheme 126) <2001JOC4276>. The two-atom linker between the nitronate and the dipolarophile moieties in 540 and the configuration of the chiral auxiliary phenylcyclohexanol could be chosen to obtain the adduct 542 with the relative and absolute configuration at the newly formed stereocenters, as required in the pyrrolizidine alkaloid (-l-)-l-epiaustraline. 

Tandem double intramolecular [4- -2]/[3- -2] cycloadditions were performed using nitroalkenes tethered to both the dienophile and the dipolarophile. For example, the [4-1-2] cycloaddition of the linear triene 544 was promoted by SnCU to afford a 3 2 mixture of545 and 546 rapidly. The intramolecular [34-2] cycloaddition was taken to completion by stirring the mixture in toluene at room temperature, and the polycyclic nitroso acetal 546 was then isolated as a single diastereoisomer in 87% overall yield (Scheme 128) <2003JOC8015>. 

The use of styrene as the dipolarophile in the reaction with either enol ether (10 or 14) and nitroalkene (31a or 31d) readily produced the corresponding nitroso acetals (33a, 33b and 33d), each as diastereomeric mixtures in 74, 65 and 77 % yield respectively (15 kbar, RT, 18 h. Scheme 9.11). 

The stereochemical limits of this type of domino reaction were also studied [8j. When l-phenyl-2-nitropropene 15b was used, the only product isolated was nitronate (16b). Nitroalkene 15b failed to react as a dipolarophile in the second cycloaddition with nitronate 16b, under even more extreme conditions (15 kbar, 50 °C, 96 h, Scheme 9.17). However, nitronate 16b reacted with y -nitrostyrene (15a) at 15 kbar, RT within 72 h completely regio- and stereoselectively producing the bicyclic nitroso acetal 49. 

Nitrostyrene (15a) can react as a dienophile in the Diels-Alder reaction with 2-alkoxy butadienes producing cyclic enol ethers (Scheme 9.23). By using an excess of nitrostyrene a domino reaction should take place with the in situ-generated enol ether. j -Nitrostyrene (15a) may react subsequently as a dienophile in the Diels-Alder reaction with a 2-alkoxy butadiene, as a heterodiene in the inverse Diels-Alder reaction of alkoxy cyclohexene which is formed primarily, and as a di-substituted dipolarophile in the 1,3-dipolar cycioaddition of the nitronate formed in the inverse Diels-Alder reaction. 2-Methoxy-l,3-butadiene (61) was selected for the Diels-Alder reaction, since it reacted in a completely regioselective manner with nitroalkenes. 

Since three building blocks are involved in the domino cydoaddition reactions, adaptation to the solid phase can be performed either with a resin-bound enol ether, a resin-bound nitroalkene or a resin-botmd dipolarophile (Scheme 9.26). Some applications of the latter two possibilities will be discussed in this section [27]. 

TS and the effect of the closer tert-butyl group would be more important. The high endo-selectivity observed in general was supported by energy calculations of the exo- and endo-TS. The endo-TS were lower in energy than their exo-analogues [47]. The computational analysis also predicted a probable concerted process when maleimides are involved in the 1,3-DCR, while a stepwise mechanism can be postulated for the other dipolarophiles, such as acrylates, fumarates, maleates, nitroalkenes, etc. In these last examples, the electrostatic interactions seem to be the responsible of the experimentally observed endo-selectivity. 

The relative reaction rates of the 1,3-dipolar cycloaddition reaction of phenyl azide to dipolarophiles containing the C=C bond can be predicted by using the Jaguar V. 3.0 ab initio electronic package. Thermodynamic analysis of the 1,3-dipolar cycloaddition of organic azides with conjugated nitroalkenes at 273-398 K shows that temperature does not affect the course of these reactions in the vapour phase. Density-functional procedures have been used to explain the regioselectivity displayed by the 1,3-dipolar cycloaddition of azides with substituted ethylenes. A density-functional theory study of the 1,3-dipolar cycloaddition of thionitroso compounds with fulminic acid and simple azides indicates that the additions are not stereospeciflc. ... 

In Fig. 15.1 we have represented the FMO in the transition state for the reaction between dipole 1 and nitroalkene 4. The preferred endo approach indicated by 8 is due to the stabilizing secondary bonding interactions between the Pz orbitals of the central nitrogen (-0.31) and endocyclic oxygen (+0.36) in the dipole, with the NO2 group of the dipolarophile (N -0.40 O +0.33, respectively). Although these interactions do not lead directly to new bonds, they lower the energy of the endo-transition state relatively to that of the exo-transition state 9, where these inteac-tions are absent. Hence, the enrfo-adduets are preferentially obtained. 

Although the [4- -2] cycloaddition of nitroalkenes is governed by inverse-electron-demand and requires an electron-rich 2ti-component, the [3 + 2] cycloadditions of nitronates engage both electron-rich and electron-poor dipolarophiles [118, 119]. Reactions with electron-poor dipolarophiles, however, are more facile [55]. It is difficult to compare the cycloaddition reactivity of different nitronates with dipolarophiles because nitronates are somewhat unstable. As a result, low yields of the nitroso acetals may reflect this instability rather than slow reaction rate. The example in Scheme 16.21 illustrates the higher reactivity of electron-deficient dipolarophiles in [3 - - 2] cycloadditions with nitronates [55]. In this competition experiment, nitro-styrene 44 undergoes inverse-electron-demand [4 + 2] cycloaddition selectively with the electron-rich ethyl vinyl ether even in the presence of dimethyl maleate. The intermediate nitronate reacts further with the electron-poor dimethyl maleate, even though both alkenes are present in large excess. The product 80 is isolated in 30% yield and... 

Nitronate Facial Selectivity in Intermolecular [3+2] Cycloadditions of Nitronates The majority of asymmetric dipolar cycloadditions of nitronates have been investigated in the context of the tandem [4 + 2]/[3 + 2] cycloadditions of nitroalkenes. With chiral, cyclic nitronates, the facial selectivity is primarily controlled by the steric environment that defines the diastereotopic faces of the nitronate. Nitronates obtained from [4 + 2] cycloadditions with vinyl ethers contain an acetal stereocenter that controls the approach of the dipolarophile. Nitronate 103 (Scheme 16.26) reacts with dimethyl maleate to produce predominantly nitroso acetal distal- QA through a distal approach of the dipolarophile [23]. The proximal approach provided the minor isomer with dr 7/l. Calculations suggest that the distal approach of the dipolarophile that leads directly to a chair-Uke conformation of the six-membered ring is slightly favored over the proximal approach [121]. 

Scheme 16.30 provides an easy visualization of the dipolarophile placement in the starting material for each of the four modes of the intramolecular [3 + 2] cycloadditions. Thus, to prepare a C(3)-tethered substrate 114 for the spiro mode of the [3 + 2] cycloaddition, the dipolarophile must be attached to the a-carbon of the nitroalkene 112. Alternatively, to prepare a C(4)-tethered substrate 117 for the fused... 

Selectivity in the Spiro Mode Intramolecular [3+2] Cycloadditions of Nitronates Placement of the tether at C(3)-position of the nitronate provides access to spiro mode dipolar cycloadditions (Scheme 16.31). Such nitronates are prepared by [4 + 2] cycloadditions of nitroalkenes bearing a dipolarophile attached at the a-carbon. Only (3-unsubstituted nitroalkenes of this type have been used for the tandem cycloadditions. As a consequence of their high electrophi-licity and low stability, such nitroalkenes have been prepared by nitromercuration. 

Selectivity in the Fused-Mode Intramolecular [3+2] Cycloadditions of Nitronates The most intensively investigated family of the intramolecular cycloadditions is the fused mode (Scheme 16.32) [76]. In this mode regio-, stereo-, and facial selectivity are completely governed by the tether, which is attached at C(4) of the nitronate. Such nitronates are prepared by [4 + 2] cycloadditions of nitroalkenes that bear the dipolarophile tethered at C(2). These nitroalkenes are typically prepared by a two-step procedure involving Henry reaction followed by dehydration [128]. Selenoxide elimination has been employed in the preparation of a P, 3-disubstituted nitroalkene [90]. Nitronates tethered at C (4) with two-carbon and three-carbon chains coimecting the... 

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