Intramolecular 1,1-cydoaddition reactions

Bashiardes et al. [94] described an intramolecular cydoaddition reaction of unprotected carbohydrates 126, involving a nitrone ylide dipole 127 derived from the 1-aldehydic position, and an co-olefinic moiety constructed from the 6-hydroxyl function (Scheme 11.32). In this enantiomeric synthesis of novel bicyclic oxazoli-dines bearing a quaternary bridgehead, 128, a comparative study was performed of classical heating conditions and microwave-assisted cydoaddition, both in the same reaction medium, aqueous ethanol. All the examples provided products in yields which were improved from approximately 60% to 90%, basically because of the cleaner reactions. The reaction times were reduced from 48 h to just 1 h. 

An intramolecular [3 + 2]-cydoaddition reaction occurred at either the terminal or internal C=C bond in the following examples [77, 78] ... 

The expected intramolecular 1,3-dipolar cydoaddition product 171 was only a minor product (3%). The formation of major product 169 was explained through an intramolecular Michael reaction of the enolate ion. 

Coldham, I. and Hufton, R. (2005) Intramolecular dipolar cydoaddition reactions of azomethine ylides. Chemical Reviews, 105, 2765-2810. 

Dittami, J.P., Nie, X.-Y., Buntel, C.J., and Rigatti, S. (1990) Photoinitiated intramolecular ylide-alkene cydoaddition reaction. Tetrahedron Letters, 31, 3821-3824. 

Some straightforward, efficient cyclopentanellation procedures were developed recently. Addition of a malonic ester anion to a cyclopropane-1,1-dicarboxylic ester followed by a Dieckmann condensation (S. Danishefsky, 1974) or addition of ff-ketoester anions to a (l-phenylthiocyclopropyl)phosphonium cation followed by intramolecular Wittig reaction (J.P. Marino, 1975) produced cyclopentanones. Another procedure starts with a [2+2l-cydoaddition of dichloroketene to alkenes followed by regioselective ring expansion with di-azomethane. The resulting 2,2-dichlorocyclopentanones can be converted to a large variety of cyclopentane derivatives (A.E. Greene, 1979 J.-P. Deprfes, 1980). 

The authors reason that direct irradiation of (54) must induce bond fission to yield the radical pair (57) as well as yielding the cycloadduct. Rebonding within the radical pair (57) can yield (53) which would then undergo the photocycloaddition to yield the cycloadduct (55). Intramolecular cydoaddition is observed on irradiation of the enones (58). The reaction is both wavelength and temperature dependent. Irradiation through Pyrex brings about the formation of a cisitrans mixture of the alkene moiety as the main reaction. Low yields of the two adducts (59a) and (59b) are also formed under these conditions. When a quartz vessel is used the cycloaddition assumes major importance. From the results obtained it is clear that there is a preference for the formation of isomer (59a). Both the isomeric products arise from the biradical intermediate (60) which is formed by addition at the P carbon of the enone moiety and affords the more stable biradical. 

Intramolecular cydoaddition of furan has been performed successfully on a solid support in the presence of solvent under open-vessel or sealed-vessel microwave irradiation conditions. Whereas intramolecular reaction of furan 23 does not occur with classical heating [61], the reaction was performed sussessfully in 64% yield by using microwave activation (Scheme 11.6). 

Microwave-induced 1,3-dipolar cydoaddition reactions involving azomethine ylides have been widely reported in the literature. In 2002 many examples were described in a book chapter by de la Hoz [3j], which provides extensive coverage of the subject. The objective of this section is to highlight some of the most recent applications and trends in microwave synthesis, and to discuss the impact of this technology. Highly stereoselective intramolecular cycloadditions of azomethine ylides have been performed under solvent-free microwave conditions. 

Cheletropic and other cydoaddition reactions conserve orbital symmetry and can occur both intramolecularly as well as tmermolecularly. Both versions are peri-cyclic reactions. The imermolecular set is discussed here (since reactions in that set may be viewed as addition reactions between two molecules). The m/ramolecular reactions, which can be considered rearrangements, will be treated in that section of this chapter. 

Kulkarni, Y.S., Niwa, M., Ron, E., and Snider, B.B. (1987) Synthesis of terpenes containing the bicydo[3.1.1]heptane ring system by the intramolecular [2+2] cydoaddition reaction of vinylketenes with alkenes preparation of chrysanthenone, P-pinene, P-cis-bergamotene, P-trans-bergamotene, P-copaene, and p-ylangene and lemnalol./. Org. Chem., 52,1568-1576. 

As was the case with reactions of vinylindoles, the most elaborate synthetic targets approached by the indole-2,3-quinodimethane route have been alka-loids[18]. The route has been applied to aspidospenna[l9 ] and kopsine[20] structures. The fundamental reaction pattern is illustrated in equation 16.7. An indole-2,3-quinodimethane is generated by W-acylation of an Ai-(pent-4-enyl)-imine of a 2-methyl-3-formylindole. Intramolecular 2 -P 4 cydoaddition then occurs. 

Mejla-Oneto and Padwa have explored intramolecular [3+2] cycloaddition reactions of push-pull dipoles across heteroaromatic jr-systems induced by microwave irradiation [465]. The push-pull dipoles were generated from the rhodium(II)-cata-lyzed reaction of a diazo imide precursor containing a tethered heteroaromatic ring. In the example shown in Scheme 6.276, microwave heating of a solution of the diazo imide precursor in dry benzene in the presence of a catalytic amount of rhodium I) pivalate and 4 A molecular sieves for 2 h at 70 °C produced a transient cyclic carbonyl ylide dipole, which spontaneously underwent cydoaddition across the tethered benzofuran Jt-system to form a pentacyclic structure related to alkaloids of the vindoline type. 

Bispropargyl ether 222 isomerized on treatment with tBuOK into the naphthalene 223 via the intramolecular [4+2]-cydoaddition of the phenylallene with the acetylene moiety. Similar reactions of enynyl propargyl ether 224 took place at room temperature to give two isomeric isobenzofurans, 225 and 226. The major product 226 presumably arises from the intramolecular [4 + 2]-cycloaddition of the bisallenyl ether, whereas the minor product 225 is formed by the [4 + 2]-cycloaddition of the monoallenyl ether [180]. 

The photochemical intramolecular [3 + 2] cydoaddition of arenes with a tethered alkene leads to polycydic compounds. This reaction is better suited to the synthesis of natural products than to intermolecular [3 + 2] cydoaddition. A carbonyl group in the tether fails to produce any good results, because this chromophore can quench the... 

The most characteristic photochemical reaction of aromatic compounds is their cydoaddition with alkenes. The intramolecular reaction is suitable for the synthesis of complex structures, such as those depicted in Scheme 9.49, where [3+2]-photocycloaddition leads to structures which resemble natural products (aphidico-line and stemoclinone). An interaction of the arene singlet excited state with the alkene ground state gives rise to the meta adduct [83, 84]. 

The combination of two successive [4+2] cydoadditions has already been described by Diels and Alder [la] for the reaction of dimethyl acetylenedicarboxylate with an excess of furan. A beautiful, more modem, example is the synthesis of pagodane (4-5) by Prinzbach [2], in which an intermolecular Diels-Alder reaction of 4-1 and 4-2 to give 4-3 is followed by an intramolecular cycloaddition. The obtained 4-4 is then transfonned into 4-5 (Scheme 4.1). 

Intramolecular C—H insertion of carbenoids derived from diazoacetamides provides one of the most convenient routes to y-lactams. However, synthetic application of this reaction may be restricted by the competitive formation of either )8-lactams through aliphatic C—H insertion of 5-lactams through aromatic cycloaddition, etc. The competition between aromatic cydoaddition and C—H insertion is profoundly influenced by the choice of the dirhodium(II) ligand. With diazoacetamide 116 (R = H), Rh2(cap)4 provides y-lactam 117 (R = H) and virtually no 118 (R = H) but Rh2 (acam)4, like Rh2(OAc)4, gives a mixture of the two products 117 and 118 (R = H). With the nitro derivative 116 (R = NO2), use of Rh2(acam)4 results in y-lactam 117 (R = NO2) in 90% yield (92JA1874 93JA8669). 

Based on the same principle, we developed a three-component synthesis of macrocydes starting from an azidoamide (30), an aldehyde (31), and an a-isocya-noacetamide (32) bearing a terminal triple bond (Scheme 5.11) [28]. The reaction involved a sequence of three-component synthesis of an oxazole followed by an intramolecular [3 + 2] cydoaddition. The azido and alkyne functions were not directly involved in the three-component construction of the oxazole, but reacted intramolecularly once the oxazole (34) had been assembled. The reaction created five chemical bonds with concurrent formation of one macrocycle, one oxazole, and one triazole. 

Tlie intramolecular nature of this cydoaddition helps lo make it a good reaction, an argument in favour of disconnections like (6a) and 6b). On the other hand, disconnections like 5> (3) + (4) allow us to find simple starting materials more quickly and these two contrary considerations require a balanced judgement. 

Mizuno and coworkers demonstrated an intramolecular version of [2 -I- 2] photo-cydoaddition using glass or poly(dimethoxysilane) (PDMS) microreactors (channel dimensions 100-300 pm wide, 40-50 pm deep) [27]. The reaction using a microreactor gave a better regioisomeric ratio than that with a batch reactor, since the possibility of the reverse reaction was reduced by a much shorter residence time, i.e. Imin, inside the microchannel (Scheme 6.11). 

Synthesis of 1,2-disubstituted indole frameworks 257 via a formal 4 - - 1 cydoaddition between a 4-carbon unit and a primary amine was recently developed by Ackermann (Scheme 9.90) [242]. Reactive intermediates, 2-(o-haloaryl)enam-ines 256 were generated via the Cu(I)-catalyzed hydroamination of the orfHo-halo-substituted phenylacetylenes 254 with primary amines 255. A subsequent Cu(I)-catalyzed intramolecular enamine arylation reaction gave the corresponding indoles 257 in good yields. The authors demonstrated that alkynyl chlorides 254 could also participate in this cascade double amination process, albeit with a substantially diminished efHdency. 

Iwasawa has reported the gold(III)-catalyzed reaction of N-(o-ethynylphenyl)imi-nes with electron-rich alkenes to form polycyclic indole derivatives [26]. As an example, reaction of N-[l-(l-pentynyl)phenyl]imine 28 and tert-butyl vinyl ether with a catalytic amount of AuBrs in toluene at room temperature led to isolation of the polycyclic indole 29 in 80% yield as a mixture of diastereomers (Scheme 11.3). Conversion of 28 to 29 presumably occurs via initial intramolecular hydroamination to form the gold carbene containing azomethine ylide 30 that undergoes intermo-lecular [3 + 2] cydoaddition with tert-butyl vinyl ether to form the carbene complex 31. 1,2-Migration of the 7t-propyl group to the metal-bound carbon atom coupled with deauration then forms 29. This transformation is also catalyzed efficiently by PtCl2 [26]. 

Intramolecular [2+2]-photocycloadditions of cycUc a,P-unsaturated enones with remote double bonds have been extensively used to synthesize a variety of interesting compounds, including natural products. An analysis of the mechanism of the additions has also been carried out. 2-Pyrones having pendant enes and dienes undergo synthetically useful photocycloaddition processes to give tricyclic lactones and lactone-bridged cyclooctadienes by [2+2]-and [4+4]-cydoadditions, respectively. The photochemical reactions... 

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