Intermolecular cycloaddition reactions

Aminomethylindoles are particularly important synthetic intermediates. 3-Dimethyl-aminomethylindole (gramine) (153) and especially its quaternary salts readily undergo displacement reactions with nucleophiles (Scheme 60). Indole-2,3-quinodimethanes, generated from 2-methylgramine as shown in Scheme 61, undergo intermolecular cycloaddition reactions with dienophiles to yield carbazole derivatives (82T2745). 

IR spectroscopy, 2, 153 cycloaddition reactions, 1, 479 halogenation, 2, 203 hydrogenation, 2, 46 intermolecular cycloadditions, 2, 307 magnetic circular dichroism, 2, 129 N-oxides... 

The hetero Diels-Alder [4+2] cycloaddition (HDA reaction) is a very efficient methodology to perform pyrimidine-to-pyridine transformations. Normal (NHDA) and Inverse (IHDA) cycloaddition reactions, intramolecular as well as intermolecular, are reported, although the IHDA cycloadditions are more frequently observed. The NHDA reactions require an electron-rich heterocycle, which reacts with an electron-poor dienophile, while in the IHDA cycloadditions a n-electron-deficient heterocycle reacts with electron-rich dienophiles, such as 0,0- and 0,S-ketene acetals, S,S-ketene thioacetals, N,N-ketene acetals, enamines, enol ethers, ynamines, etc. 

The bicyclic system quinazoline undergoes intermolecular inverse cycloaddition reactions with enamines RRiNCR2=CHR3 (RRi=(CH2)3, R2 = Ph, R3 = H) yielding 2,3-disubstituted quinolines. 

The intramolecular variant leads to formation of more than one ring an interesting example is the formation of an intermediate in the synthesis of tetraasterane 16 by Musso and coworkers from 3,6-dihydrophthalic anhydride 15 by two subsequent [2 + 2] cycloaddition reactions, an intermolecular step followed by an intramolecular one ... 

Since the first demonstration of a cycloaddition reaction of a, /f-unsaturated sulfones in 1938 by Alder and coworkers85, a variety of a, /3-unsaturated sulfones have been prepared and used as dienophiles. For example, when a mixture of p-tolyl vinyl sulfone and 2,3-dimethylbutadiene in benzene is heated at 145-150 °C for 10 h in a sealed tube, crystals of the cycloadduct (134) are obtained (equation 102). Other examples of this intermolecular cycloaddition reaction are given in Table 12. 

Intermolecular [4C+2S] cycloaddition reactions where the diene moiety is contained in the carbene complex are less frequent than the [4S+2C] cycloadditions summarised in the previous section. However, 2-butadienylcarbene complexes, generated by a [2+2]/cyclobutene ring opening sequence, undergo Diels-Alder reactions with typical dienophiles [34,35] (Scheme 59). Also, Wulff et al. have described the application of pyranylidene complexes, obtained by a [3+3] cycloaddition reaction (see Sect. 2.8.1), in the inverse-electron-demand Diels-Alder reaction with enol ethers and enamines [87a]. Later, this strategy was applied to the synthesis of steroid-like ring skeletons [87b] (Scheme 59). 

Aryl- and alkenylcarbene complexes are known to react with alkynes through a [3C+2S+1C0] cycloaddition reaction to produce benzannulated compounds. This reaction, known as the Dotz reaction , is widely reviewed in Chap. Chromium-Templated Benzannulation Reactions , p. 123 of this book. However, simple alkyl-substituted carbene complexes react with excess of an alkyne (or with diynes) to produce a different benzannulated product which incorporates in its structure two molecules of the alkyne, a carbon monoxide ligand and the carbene carbon [128]. As referred to before, this [2S+2SH-1C+1C0] cycloaddition reaction can be carried out with diyne derivatives, showing these reactions give better yields than the corresponding intermolecular version (Scheme 80). 

Asymmetric induction in the intermolecular Diels-Alder cycloaddition reactions can be achieved with chirally modified dienes and dienophiles as well as with chiral Lewis-acid catalysts [54-56]. 

Given their extraordinary reactivity, one might assume that o-QMs offer plentiful applications as electrophiles in synthetic chemistry. However, unlike their more stable /tora-quinone methide (p-QM) cousin, the potential of o-QMs remains largely untapped. The reason resides with the propensity of these species to participate in undesired addition of the closest available nucleophile, which can be solvent or the o-QM itself. Methods for o-QM generation have therefore required a combination of low concentrations and high temperatures to mitigate and reverse undesired pathways and enable the redistribution into thermodynamically preferred and desired products. Hence, the principal uses for o-QMs have been as electrophilic heterodienes either in intramolecular cycloaddition reactions with nucleophilic alkenes under thermodynamic control or in intermolecular reactions under thermodynamic control where a large excess of a reactive nucleophile thwarts unwanted side reactions by its sheer vast presence. 

Jug and co-workers investigated the mechanism of cycloaddition reactions of indolizines to give substituted cycl[3,2,2]azines <1998JPO201>. Intermediates in this reaction are not isolated, giving evidence for a concerted [8+2] cycloaddition, which was consistent with results of previous theoretical calculations <1984CHEC(4)443>. Calculations were performed for a number of substituted ethenes <1998JPO201>. For methyl acrylate, acrylonitrile, and ethene, the concerted [8+2] mechanism seems favored. However, from both ab initio and semi-empirical calculations of transition states they concluded that reaction with nitroethene proceeded via a two-step intermolecular electrophilic addition/cyclization route, and dimethylaminoethene via an unprecedented two-step nucleophilic addition/cyclization mechanism (Equation 1). 

The vinylcyclopropane 144, bearing two electron-withdrawing groups, undergoes the intermolecular palladium-catalyzed [3 + 2]cycloaddition reaction of the Jt-allylpalladium intermediate 145 with a,/ -unsaturated esters or ketones to provide a useful method for forming the cyclopentane ring of 146 [74], (Scheme 51)... 

Click chemistry has been particularly active in various fields this year. For example, ample applications of click chemistry have been seen in carbohydrate chemistry. Various /weiido-oligosacchardies and amino acid glycoconjugates were synthesized via an intermolecular 1,3-dipolar cycloaddition reaction using easily accessible carbohydrate and amino acid derived azides and alkynes as building blocks <06JOC364>. The iterative copper(I)-catalyzed... 

In the intermolecular series, Diels-Alder cycloaddition of ethene to the pyrazi-none heterodiene led to the expected bicyclic cycloadduct (Scheme 6.95 b) [195], The details of this transformation, performed in pre-pressurized reaction vessels, are described in Section 4.3.2 [196], Similar cycloaddition reactions have also been studied on a solid phase (Scheme 7.58) [197]. 

The sesquiterpenes (+)-protoilludene471) (4.60) and ( )-modhepene472) (4.61) have also been synthesized via intermolecular cycloaddition reactions. 

Intermolecular Cycloaddition at the C=C Double Bond Addition at the C=C double bond is the main type of 1,3-cycloaddition reactions of nitrile oxides. The topic was treated in detail in Reference 157. Several reviews appeared, which are devoted to problems of regio- and stereoselectivity of cycloaddition reactions of nitrile oxides with alkenes. Two of them deal with both inter- and intramolecular reactions (158, 159). Important information on regio-and stereochemistry of intermolecular 1,3-dipolar cycloaddition of nitrile oxides to alkenes was summarized in Reference 160. 

An interesting antibody-catalyzed intermolecular asymmetric 1,3-dipolar cycloaddition reaction between 4-acetamidobenzonitrile N-oxide and N,N-dimethylacrylamide generating the corresponding 5-acylisoxazoline was observed (216). Reversed regioselectivity of nitrile oxide cycloaddition to a terminal alkene was reported in the reaction of 4-A rt-butylbenzonitrile oxide with 6A-acrylamido-6A-deoxy-p-cyclodextrin in aqueous solution, leading to the formation of the 4-substituted isoxazoline, in contrast to the predominance of the 5-substituted regioisomer from reactions of monosubstituted alkenes (217). 

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). 

Intermolecular Reactions Intermolecular 1,3-dipolar cycloaddition reactions of nitrones to olefins seem to be the most studied. They are widely used for the synthesis of different enantiomerically pure compounds, including biologically active ones. For example, two new glycosidase inhibitors have been obtained by the nitrone cycloaddition strategy (Fig. 2.32) (733). 

Cycloaddition of nitrone (508) to allyl alcohol at ambient temperature gave a mixture of four cycloadducts in a 23 5 4 1 ratio (Scheme 2.244). All of the adducts (509) are derived from the regiochemical approach opposite to the intramolecular pathway (Fig. 2.35). Formation of the cycloadduct in the intramolecular cycloaddition reaction is ascribed to a high preference for an endo-syn transition state, due to the constraint imposed by the short, three atom connecting chain (116). The major product in the intermolecular cycloaddition reaction was the exo-anti -(509) adduct (Scheme 2.244 and Fig. 2.35). 

I. Intermolecular [3+2]-Addition of Nitronates to Olefins Of all known types of nitronates (see Section 3.2), alkyl- and silyl nitronates as well as cyclic C5-C6 nitronates are involved in [3+ 2]-cycloaddition reactions. Detailed comparative kinetic studies for different types of nitronates have not been reported. However, a few data (162, 336, 337) allow one to deduce some sequences (Chart 3.10). 

Points b to d should be explained in more detail for intermolecular cycloaddition reactions of acyclic nitronates A with monosubstituted olefins. Regioselectivity of the process is determined by the character of the approach of olefin to the dipole (head-to-head or head-to-tail, (Chart 3.16, part (1)). In the former case, the substituent R is bound to the C-5 atom in the latter case, to the C-4 atom. 

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). 

In intramolecular [3+ 2]-cycloaddition reactions, silyl nitronates also lead to substantially higher stereoselectivity than intermolecular reactions (see, e.g., Scheme 3.178) (193). 

In addition to siloxy- and alkoxy-substituted VCPs, alkyl- and H-substituted VCPs are also effective in the intermolecular [5 + 2]-cycloaddition reaction (Scheme 11). In general, an increase in the steric bulk of the cyclopropane substituent (H vs. Me vs. Pr1) leads to increased reaction rates, putatively through preferential population of the more reactive as-oid arrangement of the vinyl and cyclopropane moieties.43... 

Cyclopropyl imines can be used as five-atom components in intermolecular [5 + 2]-cycloaddition reactions with dimethylacetylene dicarboxylate (DMAD) (Scheme 14).45 In this hetero-[5 + 2]-cycloaddition reaction, dihydroaze-pines are constructed from simple, readily available starting materials. The cyclopropyl imines can be preformed or made in situ by the condensation of cyclopropyl carboxaldehydes and amines. Although, thus far, DMAD is the only... 

Although cycloaddition reactions have yet to be observed for alkene radical cations generated by the fragmentation method, there is a very substantial literature covering this aspect of alkene radical cation chemistry when obtained by one-electron oxidation of alkenes [2-16,18-26,28-31]. Rate constants have been measured for cycloadditions of alkene and diene radical cations, generated oxidatively, in both the intra- and intermolecular modes and some examples are given in Table 4 [91,92]. 

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