Alkenes as dipolarophiles

The intramolecular cycloaddition of a silyl nitronate bearing a dipolarophilic appendage provides easy access to fused, bicyclic isoxazolidines (22). This process, in general, is very facile, and has allowed the use of unfunctionalized alkenes as dipolarophiles (Table 2.39) (106,124). Thus, a silyl nitronate bearing an allyl group will undergo the [3 + 2] cycloaddition at room temperature over 15 h to provide the corresponding isoxazoline upon acidic workup in moderate yield. 

Reactants 294 with a six-atom linkage have been used as a route to pyrazolo [l,5-fl][5,l]benzoxocines (295 and 296). Using alkenes as dipolarophiles gave 295 in moderate-to-good yields (21-61%) (183), terminal alkynes gave 296 (21 7%) but only 7% was obtained for an example with a terminal methyl group (184). 

Using unsymmetric substituted alkenes as dipolarophiles, a mixture of 2- and 3-substituted 1-pyrrolines were obtained71. The thermolyses and the photolyses of several... 

Most of the efforts towards the stereocontrolled synthesis of 4,5-dihydroisoxazoles were based on the use of chiral alkenes as dipolarophiles. Among these, the reactions of chiral acyclic olefins featuring an allylic stereocenter are of interest from both the practical and theoretical points of view 1 25,1 37 - 157. (More recent examples can be found in references 356-387.)... 

Acceptor-CH-substituted pyridinium-N-betaines 15 (accessible in situ by deprotonation of the corresponding N-alkylpyridinium salts 14) undergo 1,3-dipolar cycloaddition with activated alkynes and alkenes as dipolarophiles. With alkynes, the cycloadducts (16/19) dehydrogenate spontaneously to indolizines, which are either of the 1,2,3-trisubstituted type 17 or (indicating a regioselective cycloaddition) of the 1,3-disubstituted type 18. With olefinic substrates, the presence of an oxidant for additional dehydrogenation of the primary cycloadduct (20 -> 17) is required [219] ... 

The 2n component 2, the so-called dipolarophile (analogously to the dieno-phile of the Diels-Alder reaction) can be an alkene or alkyne or a heteroatom derivative thereof. Generally those substrates will be reactive as dipolarophiles, that also are good dienophiles. 

The other reactant in a dipolar cycloaddition, usually an alkene or alkyne, is referred to as the dipolarophile. Other multiply bonded functional groups such as imine, azo, and nitroso can also act as dipolarophiles. The 1,3-dipolar cycloadditions involve four it electrons from the 1,3-dipole and two from the dipolarophile. As in the D-A reaction, the reactants approach one another in parallel planes to permit interaction between the tt and tt orbitals. 

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. 

Finally, it is important to mention that there are other related publications in which porphyrin macrocycles are not directly used as dipolarophiles but are transformed into new derivatives that can react with carbonyl ylides via ACE (alkene cyclobutene epoxide) reactions. This idea arose in 1997, when Russell and co-workers found that fused ester-activated cyclobutene epoxides 86 can be ring-opened to give carbonyl ylides 87, and that these can be trapped stereospecifically by ring-strained alicyclic dipolarophiles, such as 2,5-norbomadiene, to form hetero-bridged norbomanes 88 in good yields, through ACE transformations (Scheme 31) <97CC1023>. 

Dipolarophiles D5. Electron-deficient alkenes based on acrolein and its analogs are widely used as dipolarophiles. To carry out asymmetrical 1,3-dipolar cycloadditions between various nitrones and acrolein, the bis-titanium catalyst (543) (Fig. 2.37) was used as the chiral Lewis acid (Table 2.22) (754a). 

Dipolarophiles D12. Heteroatom substituted alkenes of general formula D12 have been sparingly used as dipolarophiles when compared to vinyl ethers Dll (see Fig. 2.33). Comparative studies between common heating and microwave... 

Semiempirical calculations show that the approach of the dipolarophile in a head-to-head manner is 5.91 kcal/mol more favorable than the head-to-tail orientation with electron-rich alkenes (93). This difference is manifest in the ground state of resulting cycloadducts where the head-to-head adduct is 6.6 kcal/mol more stable. Similarly, the head-to-head transition state is more favorable by 3.4 kcal/mol for electron-poor alkenes, and 7.4 kcal/mol for electron-rich alkenes as calculated with density functional theory (91). This preference is also carried over into the ground-state energies of the resulting cycloadducts. 

The many successful applications of nitrile oxide cycloadditions in synthesis are intimately linked with theory, both the simple FMO variety as well as the more sophisticated ab initio treatment, where the work of Sustmann and subsequently of Houk and his group has been seminal. We, the practitioners, have thus been supplied with a consistent view on the nature of 1,3-dipoles, their reactivity toward dipolarophiles, and the origin and interpretation of stereoselectivity of cycloaddition chemistry. It is of course desirable that our understanding of the relative reactivities of alkenes as well as of many 1,3-dipoles would be also improved, thereby leading to simple, extended recipes for the chemist practicing synthetics. We hope that this account will stimulate further advances in this field of cycloaddition chemistry and promote further uses of nitrile oxides in organic synthesis. 

Trifluoromethyl-substituted pyrazoles are easily obtained using trifluoromethyl-alkynes as dipolarophiles (Table 8.2, entry 9). Thus, treatment of 4,4,4-trifluorobut-2-ynoic acid with excess diazomethane gave methyl 4-(trifluoromethyl)pyrazole-4-carboxylate (45%) accompanied by its N - (32%) and -methylated (6.5%) derivatives (267). Another convenient route to CF3-substituted pyrazoles involves dipolar cycloaddition of appropriately CF3-substituted alkenes followed by eliminative aromatization (76,77,268). For example, the reaction of alkenes such as (CF3)2C=C(H)COAr with ethyl diazoacetate gave 4-aroyl-5-trifluoromethylpyra-zole-3-carboxylates (268). 

The direct cycloaddition adduct was oxidized, resulting in the hydroxylated isoxazoline product (316). Better selectivities were obtained in 1,3-dipolar cycloadditions of 204 with nitrile oxides (317,318). The 1,3-dipolar cycloadditions proceeded with concomitant loss of the boron group to give the isoxazoline products in up to 74% ee (318). The alkene 204 was also tested in reactions with nitrones. The reactions proceeded with poor yields, but high selectivities were observed in two cases (318). Gilbertson et al. (319) investigated the use of chiral ot,p-unsaturated hexacarbonyldiiron acyl complexes 205 as dipolarophiles in reactions with nitrones. Selectivities of up to >92% de were observed. The iron moiety was removed oxidatively after the cycloaddition and the thioester was hydrolyzed. 

Results of a similar study on the enantiospecific synthesis of a glycosidase inhibitor, using chiral (3-benzyloxy acrylamide, show that even electron-rich alkenes can serve as dipolarophiles. A large influence of the polarity of the solvent is observed the greater the polarity the greater is the diastereoselectivity. Thus, DMF and acetonitrile are found to be the best solvents. On the basis of these observations, the desired enantiomerically pure glycosidase inhibitor, (3R. 4R)-4-(hydroxymethyljpyrrolidin-3-ol, could be prepared in two steps in 87% overall yield.436... 

A 1,3-dipole is a compound of the type a—Het—b that may undergo 1,3-dipolar cycloadditions with multiply bonded systems and can best be described with a zwitterionic all-octet Lewis structure. An unsaturated system that undergoes 1,3-dipolar cycloadditions with 1,3-dipoles is called dipolarophile. Alkenes, alkynes, and their diverse hetero derivatives may react as dipolarophiles. Since there is a considerable variety of 1,3-dipoles—Table 15.2 shows... 

Alkynic esters participate as dipolarophiles in 1,3-dipolar cycloadditions and as dienophiles in Diels-Alder additions. They participate in [2+2] cycloadditions with alkenes, and they also undergo facile addition reactions with several nucleophiles to give (5,5)-fused heterocyclic ring systems (76AHC(19)279). 

This reaction is therefore dipole-HO-controlled, and we can turn to the coefficients , the (eft)2 values, for the HOMO of the dipole from Table 6.1 and the coefficients of the LUMO of the dipolarophile from Fig. 6.22. Regioselectivity follows in the usual way from the large-large/small-small interaction 6.223, which has the carbon end of the dipole bonding to the ft carbon of the Z-substituted alkene, as observed. 

Application of azomethine ylides in dipolar cycloaddition reactions with alkenes provides a route to pyrrolidine derivatives, as illustrated by the generation of the intermediate 498, and its subsequent conversion to the target system 499 (Scheme 64) <1995TL9409>. The use of alkynes as dipolarophiles instead gives rise to 3-pyrrolines, which has been exploited in a route to indoloquinones <1997JOC4763>. 

Padwa and coworkers found that a-cyanoaminosilane 12a is a convenient synthon for azomethine ylide 15 which is extensively used in heterocyclic synthesis [7]. AgP has been adopted to generate the ylide 15 from 12a for the preparation of pyrrolidine derivative 14 (Sch. 4). Various dipolarophiles including A-phenylmaleimide (13) can be used for the cycloaddition. When iV-[(trimethylsilyl)methyl]-substituted indole 16 is reacted with AgP in the presence of maleimide 13, pyrrolo[l,2-a]indole 17 is formed in good yield, retaining the CN group [8]. A silver-bonded carbonium ion is assumed to be a reactive intermediate. Reaction of a cyano-substituted azomethine ylide, derived from (silylmethylamino)malononitrile 12b and AgP, with methyl propiolate (18) provides 3-carbomethoxy-A-benzylpyrrole (19) [9]. Epibatidine, a novel alkaloid, was successfully synthesized by employing the [3 + 2] cycloaddition of azomethine ylide with electron-deficient alkenes as a key step [10]. 

Acetyl- and 3-benzoylisoxazoles 389 (and isoxazolines) have been prepared by one-pot reactions of alkynes (and alkenes) with ammonium cerium(iv) nitrate (CAN(lv)) or ammonium cerium(lll) nitrate tetrahydrate (CAN(m))-formic acid, in acetone or acetophenone. These processes probably involve 1,3-dipolar cycloaddition of nitrile oxides produced via nitration of the carbonyl compound by cerium salts. The existence of nitrile oxides as reaction intermediates was proved by the formation of the dimer furoxan 390 when the above reaction was carried out in absence of any dipolarophile (Scheme 95) <2004T1671>. An analogous improved procedure has been applied to alkynyl glycosides as dipolarophiles for the preparation of carbohydrate isoxazoles <2006SL1739>. 

The solid phase synthesis of nitroso acetals via a resin-bound dipolarophile will be described first. It has already been mentioned that nitronates react much faster with electron-poor alkenes than with electron-rich alkenes. The reaction of the nitronate formed in situ with the resin-bound acrylate is therefore expected to be faster than its reaction with the enol ether in solution. An acrylate was selected as dipolarophile and coupled to the resin via an ester linkage, which allows the facile cleavage of the resin-bound nitroso acetals by several methods (hydrolysis, reduc-... 

A large variety of alkenes have been used as dipolarophiles, dienes, allylsilanes, ethyl and methyl acrylates, styrenes, methylene cyclopropanes, vinylketones, polyfunctionalized acrylates, etc., giving... 

Aryl-2,5-dihydro-l,2,3-triazines, also with electron-withdrawing substituents, are available via 1,3-dipolar cycloaddition of electron-poor dipolarophiles (DMAD, maleonitrile, etc.) to 1,2,3-triazole 1-oxides <1987CC706, 1990J(P1)3321> or 1,2,3-triazol-l-ium imides (Equations (126) and (127) Section 9.01.10). The electronic properties of the aryl groups introduced with the triazolium precursor may vary widely. If alkenes are used as dipolarophiles, thermolysis of the adducts has to be combined with oxidation by manganese dioxide <1993JCM78>. 

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