Dipolarophiles intermolecular cycloadditions

The most general approach to synthesis of five-membered heterocyclic compounds involves cycloaddition of a 1,3-dipole to an appropriate unsaturated substrate, the dipolarophile. Intermolecular cycloadditions result in the formation of one new ring only. When the 1,3-dipole and the substrate are part of the same molecule, cycloaddition is intramolecular and leads to a new bicyclic system. Thus, intramolecular... 

I.3.4.2. Intermolecular Cycloaddition at C=X or X=Y Bonds Cycloaddition reactions of nitrile oxides to double bonds containing heteroatoms are well documented. In particular, there are several reviews concerning problems both of general (289) and individual aspects. They cover reactions of nitrile oxides with cumulene structures (290), stereo- and regiocontrol of 1,3-dipolar cycloadditions of imines and nitrile oxides by metal ions (291), cycloaddition reactions of o-benzoquinones (292, 293) and aromatic seleno aldehydes as dipolarophiles in reactions with nitrile oxides (294). 

Diazoalkenes always have the intervening chain attached on carbon. The dipole HOMO-dipolarophile LUMO interaction is usually dominant in intermolecular cycloadditions. Consequently, nonactivated al-kenes which have a relatively high-energy LUMO react poorly. Nevertheless, intramolecular cycloaddi-... 

Intermolecular cycloaddition also proceeds smoothly. The 2,8-dioxabicyclo-[3,2.1]octane core system 379 of zaragozic acid 380 was constructed by the intramolecular carbonyl ylide formation from 376 catalysed by Rh2(OAc)4, followed by intermolecular 1,3-dipolar cycloaddition of the electron-deficient dipolarophile 377 as shown by 378 as a single diastereomer out of four possible diastereomers [124],... 

Unsymmetrical dipolarophiles were found to undergo intermolecular cycloaddition with isomiinchnones with high regioselectivity [27]. For example, the decomposition of diazoimide 9 with Rh2(OAc)4 in the presence of methyl vinyl ketone resulted in the formation of two products identified as 27 and 28 in 27 %... 

The game is certainly not over, very recently catalytic enantioselective intermolecular cycloadditions of 2-diazo-3,6-diketoester of type 68 derived carbonyl ylides with alkene dipolarophiles have been developed [57]. Relying on chiral rhodium(II) clusters I and II, Hodgson et al. obtained very high enantioselectivities (up to 92% ee on 69) with norbornene as a trap, as disclosed in Scheme 31. 

Apart from alkyl acrylates, electron-deficient alkenes do not react with azine 6.136,137 Isolation of the zwitterionic intermediate (e.g.. 8) resulting from the first intermolecular cycloaddition allows a mixed crisscross addition, with the second cycloaddition performed between the dipole and various dipolarophiles.138-140... 

An important factor which could influence asymmetric induction would be that cycloaddition is faster than catalyst decomplexation from the ylide. Although the precise mechanism remains unclear, the high levels of enantios-election in intermolecular cycloadditions with dipolarophiles provide definite support for the intermediacy of a chiral rhodium(II)-associated carbonyl ylide involved in the cycloaddition step. These examples indicate that metal-catalyzed dipole formation followed by cycloaddition has the potential to be a powerful method for asymmetric synthesis. 

Hodgson, D.M. et al.. Catalytic enantio selective intermolecular cycloadditions of 2-diazo-3,6-dike-toester-derived carbonyl yhdes with alkene dipolarophiles, Proc. Natl. Acad. Sci. U.S.A., 101, 5450, 2004. 

Shen T, Wang T, Qin C, Jiao N (2013) Silver-catalyzed nitrogenation of alkynes a direct approach to nitriles through C=C bond cleavage. Angew Chem Int Ed 52(26) 6677-6680 Kadaba PK (1990) TriazoUnes XX. Vinyl azides as dipolarophiles in 1,3-dipolar cycloadditions intermolecular cycloaddition of hydrazoic acid and a-styryl azide to give a tetrazole. Synlett 6 349-351... 

For intramolecular cycloadditions with the dipolarophile attached to the C(3) center, the same facial selectivity rules apply as for the intermolecular cycloadditions (see below) [89]. However, if the tether is attached to an sp carbon, C(4) [126], C(5) [127], or C(6) [127], the tether directs the approach of the dipolarophile. 

The most extensively stodied double intermolecular cycloadditions involve vinyl ether dienophiles (F = -OR, Scheme 16.53) and unsaturated ester dipolarophiles (A = — CO2R)- In this case, the final product of hydrogenolysis is pyrrolizidinone (such as 250, Scheme 16.54), which may contain five of the six original stereogenic centers in the nitroso acetal. The pyrrolizidine is a common motif in many natural products and the double intermolecular cycloaddition of nitro olefins has been extensively employed for its construction in syntheses efforts. 

C(3a)/C(4) relationship arises from the dipolarophile approach proximal to C(4) substituent on the corresponding nitronate (Scheme 16.32). Only two- and three-atom tethered substrates have been studied in these cycloadditions. The two-atom tether leads to the fra/i5-C(3)/C(3a) relationship because it can only fold endo- during the [3 + 2] cycloaddition. However, the three-atom tether is flexible enough to react via the ejto-transition structure and to provide the cis-C (3)/C(3a) relationship. As always, the dipolarophile configuration is preserved as the relationship between C(2) and C(3) in the nitroso acetal. Unlike the double intermolecular cycloadditions or the spiro mode, the trans—trans or cis—trans relationship is established between the substiments at C(3),... 

The tether between the nitronate and the dipolarophile is not restricted to carbon atoms the two- or three-atom tether may contain cleavable carboalkoxy or sUyloxy moieties (Figure 16.11). This strategy allows the directing power of the tether to introduce stereogenic centers at C(2), C(3), C (3a), and C(4). The tether may subsequentiy be cleaved to reveal stmctures (327, 328, 330, and 331) not accessible through the double intermolecular cycloadditions because of the propensity to create the all-cis relationship between C(2), C(3), C(3a), and C(4) as in 325. 

The intermolecular dimerization of nitrile oxides has been described as a procedure to prepare Fx with identical substituent both in the 3 and 4 position (Fig. 3). This procedure is a [3 -F 2] cycloaddition where one molecule of nitrile oxide acts as 1,3-dipole and the other as dipolarophile [24-26]. Yu et al. has studied this procedure in terms of theoretical calculus [27,28]. Rearrangement of isocyanates competes with the bimolecular dimerization, with the former becoming dominant at elevated temperatures. 

Recently, dipolarophile 1)13 (fumaronitrile) (777) has been used in the synthesis of indolizine lactone (677). Both, intermolecular and intramolecular cycloadditions were studied. Intermolecular 1,3-cycloaddition of nitrone (671) to D13 led to the formation of isoxazolidine (672). Subsequent deprotection and esterification of the obtained alcohol (673) with (674) gave isoxazolidine (675) in 65% yield. Ester (675), when refluxed in xylene for 10 min, after elimination of fumaronitrile by cyclo-reversion, underwent spontaneously intramolecular cycloaddition to give the tricyclic cycloadduct (676) in 84% yield (Scheme 2.291). 

Intramolecular [3+2]-Cycloaddition ofNitronates These reactions are more efficient than analogous intermolecular transformations of nitronates as [1,3]-dipoles, and, consequently, activation of the dipolarophilic fragment is not required. However, another problem arises, that is, the construction of the starting substrate combining the nitronate fragment and the C,C double bond in the required positions. 

Silyl nitronates containing chiral inductors have not been as yet used in intermolecular [3 + 2]-cycloaddition reactions. In this case, the facial discrimination was generally created by introducing chiral nonracemic fragments into dipolarophiles (see review 433). 

Elsewhere, Heaney et al. (313-315) found that alkenyloximes (e.g., 285), may react in a number of ways including formation of cyclic nitrones by the 1,3-APT reaction (Scheme 1.60). The benzodiazepinone nitrones (286) formed by the intramolecular 1,3-APT will undergo an intermolecular dipolar cycloaddition reaction with an external dipolarophile to afford five,seven,six-membered tricyclic adducts (287). Alternatively, the oximes may equilibrate to the corresponding N—H nitrones (288) and undergo intramolecular cycloaddition with the alkenyl function to afford five,six,six-membered tricyclic isoxazolidine adducts (289, R = H see also Section 1.11.2). In the presence of an electron-deficient alkene such as methyl vinyl ketone, the nitrogen of oxime 285 may be alkylated via the acyclic version of the 1,3-APT reaction and thus afford the N-alkylated nitrone 290 and the corresponding adduct 291. In more recent work, they prepared the related pyrimidodiazepine N-oxides by oxime-alkene cyclization for subsequent cycloaddition reactions (316). Related nitrones have been prepared by a number of workers by the more familiar route of condensation with alkylhydroxylamines (Scheme 1.67, Section 1.11.3). 

Much of the initial synthetically useful carbonyl ylide work originated from the Ibata group. Exploiting simple disubstituted aromatic diazoketo-esters and structurally diverse dipolarophiles, Ibata and co-workers (64—70) prepared several different cycloadducts 167-169 through an intermolecular ylide cycloaddition (Scheme 4.38). 

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