Cycloadditions formal

Stereochemical control of [2 + 2] cycloaddition is also achieved in transition metal catalyzed reactions of methylenecyclopropanes26 which, alternatively, can undergo [27t + 2a] cycloaddition, formally a [3 + 2] cycloaddition, leading to five-membered rings. These reactions are discussed in Sections 1.5.8.3.5.3. and D. 1.6.1.2.3. 

Sulfonium ylides may be added to C N double bonds to yield aziridines in a formal [1 -t-2]-cycloaddition. Alkyl azides are decomposed upon heating or irradiating to yield ni-trenes, which may also undergo [ 1 + 2 -cycloaddition reactions to yield highly strained hetero-cycles (A.G. Hortmann, 1972). 

The benzene derivative 401 by the intermolecular insertion of acrylate[278], A formal [2 + 2+2] cycloaddition takes place by the reaction of 2-iodonitroben-zene with the 1,6-enyne 402. The neopentylpalladium intermediate 403 undergoes 6-endo-lrig cyclization on to the aromatic ring to give 404[279],... 

Clearly, in the case of (66) two amide tautomers (72) and (73) are possible, but if both hydroxyl protons tautomerize to the nitrogen atoms one amide bond then becomes formally cross-conjugated and its normal resonance stabilization is not developed (c/. 74). Indeed, part of the driving force for the reactions may come from this feature, since once the cycloaddition (of 72 or 73) has occurred the double bond shift results in an intermediate imidic acid which should rapidly tautomerize. In addition, literature precedent suggests that betaines such as (74) may also be present and clearly this opens avenues for alternative mechanistic pathways. 

The Af-chlorosulfonyl-4-alkenyl-/3-lactams (119), formed by cycloaddition of CSI with the corresponding dienes, undergo a thermal rearrangement to give the formal [4 + 2]... 

Extrapolation from the known reactivity of cyclobutadiene would suggest that azetes should be highly reactive towards dimerization and as dienes and dienophiles in cycloaddition reactions and the presence of a polar C=N should impart additional reactivity towards attack by nucleophiles. Isolation of formal dimers of azetes has been claimed as evidence for the intermediacy of such species, but no clear reports of their interception in inter-molecular cycloaddition reactions or by nucleophiles have yet appeared. 

Adducts (278) and (279) are derived formally from addition of cw-acetoxy-butenone, whereas the starting material contained ca. 90% of the trans-isomer. Since irradiation of the latter leads to a mixture of 30% cis- and 70 % tra 5-enones, it is possible that (278) and (279) result from the addition to (276) of the more reactive cw-isomer formed by photochemical isomerization prior to cycloaddition. 

The dihydropyrones are not produced directly in the initial BINOL-titanium(IV)-cat-alyzed reaction. The major product at this stage is the Mukaiyama aldol product which is subsequently cyclized by treatment with TFA [19fj. The formal cycloaddition product 3d (97% ee) obtained from a-(benzyloxy)acetaldehyde is an important intermediate for compactin and mevinolin. Scheme 4.13 outlines how the structural subunit 13 is available in three steps via this cycloaddition approach [19 fj. 

The reaction of an alkyne 1 and an alkene 2 in the presence of dicobaltoctacar-bonyl to yield a cyclopentenone 3 is referred to as the Pauson-Khand reaction Formally it is a [2 + 2 + 1 ]-cycloaddition reaction. The dicobaltoctacarbonyl acts as coordinating agent as well as a source of carbon monoxide. 

Due to the presence of a heterocumulene unit, sulphines may be considered as a group of compounds which are able to undergo cycloaddition reactions. Reaction of sulphines with enamines and phosphorus ylides reported by Sheppard217 and Trippett218 and their coworkers may be considered formally as an example of [2 + 2] cycloaddition. In fact, Sheppard and Dickman217 obtained a 1 1 adduct from thiofluorenone S-oxide and 1-morpholinocyclohexene to which they assigned the dipolar sulphoxide structure 168. 

As formal a, /i-unsaturated sulfones and sulfoxides, respectively, both thiirene dioxides (19) and thiirene oxides (18) should be capable, in principle, of undergoing cycloaddition reactions with either electron-rich olefins or serving as electrophilic dipolarophiles in 2 + 3 cycloadditions. The ultimate products in such cycloadditions are expected to be a consequence of rearrangements of the initially formed cycloadducts, and/or loss of sulfur dioxide (or sulfur monoxide) following the cycloaddition step, depending on the particular reaction conditions. The relative ease of the cycloaddition should provide some indication concerning the extent of the aromaticity in these systems2. 

Fischer-type carbene complexes, generally characterized by the formula (CO)5M=C(X)R (M=Cr, Mo, W X=7r-donor substitutent, R=alkyl, aryl or unsaturated alkenyl and alkynyl), have been known now for about 40 years. They have been widely used in synthetic reactions [37,51-58] and show a very good reactivity especially in cycloaddition reactions [59-64]. As described above, Fischer-type carbene complexes are characterized by a formal metal-carbon double bond to a low-valent transition metal which is usually stabilized by 7r-acceptor substituents such as CO, PPh3 or Cp. The electronic structure of the metal-carbene bond is of great interest because it determines the reactivity of the complex [65-68]. Several theoretical studies have addressed this problem by means of semiempirical [69-73], Hartree-Fock (HF) [74-79] and post-HF [80-83] calculations and lately also by density functional theory (DFT) calculations [67, 84-94]. Often these studies also compared Fischer-type and... 

The formation of a formal [3+2] cycloaddition product 56 upon reaction of the ethoxystyryltungsten complex 53 with 1-diethylaminopropyne, as observed... 

The formation of the tricarbonylchromium-complexed fulvene 81 from the 3-dimethylamino-3-(2 -trimethylsilyloxy-2 -propyl)propenylidene complex 80 and 1-pentyne also constitutes a formal [3+2] cycloaddition, although the mechanism is still obscure (Scheme 17) [76]. The rf-complex 81 must arise after an initial alkyne insertion, followed by cyclization, 1,2-shift of the dimethylamino group, and subsequent elimination of the trimethylsilyloxy moiety. Particularly conspicuous here are the alkyne insertion with opposite regioselectivity as compared to that in the Dotz reaction, and the migration of the dimethylamino functionality, which must occur by an intra- or intermo-lecular process. The mode of formation of the cyclopenta[Z ]pyran by-product 82 will be discussed in the next section. 

Reaction of the dihydropyranyl-substituted complex 83 with a conjugated internal alkynone 84 affords the Dotz-type formal [3+2+1] cycloadduct 86 in only 6% yield. The major product is the tricycle 85 as the result of a formal [3+4+1] cycloaddition with incorporation of the ynone carbonyl group (Scheme 18) [77]. 

The novel highly substituted spiro[4.4]nonatrienes 98 and 99 are produced by a [3+2+2+2] cocyclization with participation of three alkyne molecules and the (2 -dimethylamino-2 -trimethylsilyl)ethenylcarbene complex 96 (Scheme 20). This transformation is the first one ever observed involving threefold insertion of an alkyne and was first reported in 1999 by de Meijere et al. [81]. The structure of the product was eventually determined by X-ray crystal structure analysis of the quaternary ammonium iodide prepared from the regioisomer 98 (Ar=Ph) with methyl iodide. Interestingly, these formal [3+2+2+2] cycloaddition products are formed only from terminal arylacetylenes. In a control experiment with the complex 96 13C-labeled at the carbene carbon, the 13C label was found only at the spiro carbon atom of the products 98 and 99 [42]. 

Scheme 21 Formation of 5-(aminomethylene)cyclopentenones 101 and 2-(r-aminoalkenyl)-cyclopentenones 102 by formal [2+2+1] cycloadditions. Conditions A THF, 50-55 °C. B THF/ MeCN (9/1), 65 °C [82,83]. For further details see Table 4...

Scheme 23 Formation of tetrahydroazepinones 113 and methylenepyrrolidines 111 by a formal [5+2] cycloaddition with C-H activation [85]...

Scheme 24 Formation of a bisannelated methoxycyclooctatrienone 118 by a formal [5+2+1 ] cycloaddition [86,87]...

Scheme 25 Formation of 4-(1H)-pyridinylidene complexes 120 by a formal [4+2] cycloaddition [76,88]...

Aumann et al. showed that 1,2,4-tridonor-substituted naphthalenes, such as 126, are accessible from 3-donor-substituted propenylidenecarbene complexes 124 containing a (Z)-positioned 3-phenyl substituent and isocyanide (Scheme 26). These transformations constitute formal [5+1] cycloadditions [39, 89, 90]. Since isocyanides are strongly coordinating ligands on chromium, at least... 

Another interesting example is provided by the phenylethynylcarbene complex 173 and its reactions with five-, six-, and seven-membered cyclic enamines 174 to form bridgehead-substituted five-, six-, and seven-membered cycloalkane-annelated ethoxycyclopentadienes with high regioselectivity under mild reaction conditions (Scheme 38) [119,120]. In these transformations the phenylethynylcarbene complex 173 acts as a C3 building block in a formal [3+2] cycloaddition. Like in the Michael additions (reaction route F in Scheme 4), the cyclic electron-rich enamines 174 as nucleophiles attack the... 

The type of cycloaddition reaction is identified by the topological notation which will be used in a formal sense to describe the number of atoms provided... 

Stabilised sulphur ylides react with alkenylcarbene complexes to form a mixture of different products depending on the reaction conditions. However, at -40 °C the reaction results in the formation of almost equimolecular amounts of vinyl ethers and diastereomeric cyclopropane derivatives. These cyclopropane products are derived from a formal [2C+1S] cycloaddition reaction and the mechanism that explains its formation implies an initial 1,4-addition to form a zwitterionic intermediate followed by cyclisation. Oxidation of the formed complex renders the final products [30] (Scheme 8). 

Alkenylcarbene complexes react with in situ-generated iodomethyllithium or dibromomethyllithium, at low temperature, to produce cydopropylcarbene complexes in a formal [2C+1S] cycloaddition reaction. This reaction is highly diastereoselective and the use of chiral alkenylcarbene complexes derived from (-)-8-phenylmenthol has allowed the enantioselective synthesis of highly interesting 1,2-disubstituted and 1,2,3-trisubstituted cyclopropane derivatives [31] (Scheme 9). As in the precedent example, this reaction is supposed to proceed through an initial 1,4-addition of the corresponding halomethyllithium derivative to the alkenylcarbene complex, followed by a spontaneous y-elimi-nation of lithium halide to produce the final cydopropylcarbene complexes. 

The regioselectivity observed in these reactions can be correlated with the resonance structure shown in Fig. 2. The reaction with electron-rich or electron-poor alkynes leads to intermediates which are the expected on the basis of polarity matching. In Fig. 2 is represented the reaction with an ynone leading to a metalacycle intermediate (formal [4C+2S] cycloadduct) which produces the final products after a reductive elimination and subsequent isomerisation. Also, these reactions can proceed under photochemical conditions. Thus, Campos, Rodriguez et al. reported the cycloaddition reactions of iminocarbene complexes and alkynes [57,58], alkenes [57] and heteroatom-containing double bonds to give 2Ff-pyrrole, 1-pyrroline and triazoline derivatives, respectively [59]. 

The reaction of alkoxyarylcarbene complexes with alkynes mainly affords Dotz benzannulated [3C+2S+1C0] cycloadducts. However, uncommon reaction pathways of some alkoxyarylcarbene complexes in their reaction with alkynes leading to indene derivatives in a formal [3C+2S] cycloaddition process have been reported. For example, the reaction of methoxy(2,6-dimethylphenyl)chromium carbene complex with 1,2-diphenylacetylene at 100 °C gives rise to an unusual indene derivative where a sigmatropic 1,5-methyl shift is observed [60]. Moreover, a related (4-hydroxy-2,6-dimethylphenyl)carbene complex reacts in benzene at 100 °C with 3-hexyne to produce an indene derivative. However, the expected Dotz cycloadduct is obtained when the solvent is changed to acetonitrile [61] (Scheme 19). Also, Dotz et al. have shown that the introduction of an isocyanide ligand into the coordination sphere of the metal induces the preferential formation of indene derivatives [62]. 

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