Cycloaddition intermolecular

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). 

Cycloadditions resulting in ring-fused systems may be classified in two principal groups intramolecular and intermolecular cycloadditions. As the synthesis of the requisite precursor for an intramolecular cycloaddition is often more involved, more emphasis has been placed on those of an intermolecular nature. 

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... 

In Corey and Chaykovsky s initial investigation, a cyclic ylide 79 was observed from the reaction of ethyl cinnamate with ylide 1 in addition to 32% of cyclopropane 53. In a similar fashion, an intermolecular cycloaddition between 2-acyl-3,3-bis(methylthio)acrylnitrile 80 and 1 furnished 1-methylthiabenzene 1-oxide 81. Similar cases are found in transformations of ynone 82 to 1-arylthiabenzene 1-oxide 83 and N-cyanoimidate 84 to adduct ylide 85, which was subsequently transformed to 1-methyl-lX -4-thiazin-l-oxide 86. ... 

Introduction of an additional methyl group on the donor atom of TMM moiety gives a low 33% yield of the perhydroindans (49, X=H2) and (50, X=H2) with substantial production of the diene by-products [24]. However, it is still remarkable that the reaction works at all since the corresponding intermolecular cycloaddition failed. Incorporation of a carbonyl moiety adjacent to the donor carbon atom doubles the yield of the cycloadducts to 66% (Scheme 2.15). This so-called acyl effect works by making the donor carbon of the TMM unit "softer," thus facilitating the initial step of the conjugate addition, as well as inhibiting base-induced side reactions [22]. 

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. 

A complex sequence of pericyclic reactions, intramolecular and intermolecular cycloadditions and cycloreversions, was studied in an attempt to readily achieve bicyclic five-membered heterocycles, the methyl 4,6-dihydrothieno- and methyl-... 

Bicyclic [6.4.0]dodecane systems have been prepared [17] by catalyzed and photochemical intermolecular cycloaddition of the cyclooct-2-en-l-ones 10 and 1,3-butadiene (1) and by catalyzed intramolecular cycloaddition of trienone 11 (Scheme 3.4). 

Compounds in which a carbonyl or other nucleophilic functional group is close to a carbenoid carbon can react to give ylide intermediate.221 One example is the formation of carbonyl ylides that go on to react by 1,3-dipolar addition. Both intramolecular and intermolecular cycloadditions have been observed. 

In a recent publication, Perumal and coworkers [441] described the condensation of an aldehyde 2-863 with an aniline 2-864 to give an imine which is trapped by a dienophile. However, when using this approach an intermolecular cycloaddition takes place as the reaction is performed as a three-component process using enol ethers or cyclopentadiene as dienophiles (Scheme 2.192). When using enol ether 2-... 

Thus, isoxazolines are converted into y-amino alcohols and (3-hydroxy ketones stereoselec-tively. However, the intermolecular cycloaddition involving 1,2-unsymmetrically substituted alkenes such as trans-cinnamyl alcohol proceeds nonregioselectively to give a mixture of the two regioisomers (Eq. 8.63).98... 

No example of [2 + 2 + 1] intermolecular cycloaddition involving substituted MCPs has been reported so far. 

Bicycloheptanones formed by intermolecular cycloaddition of 2-cyclo-pentenones to olefins, as in (4.53) 465), are valuable synthons in organic chemistry 454a). 

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

Many pericyclic rearrangements show a pressure-induced acceleration which is characterized by a negative volume of activation157. The effect, which is usually smaller than that of intermolecular cycloadditions, may be explained with different packing coefficients of cyclic and acyclic states as already discussed for the pericyclic and stepwise cycloadditions. 

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. 

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). 

Three novel stereo- and regioselective schemes for the total synthesis of (+ )-brefeldin A 440 have been accomplished. Each of them exploit intermolec-ular nitrile oxide cycloaddition for constructing the open chain and introducing substituents, but differ in subsequent stages. The first (480) and the second (481) use intramolecular cycloaddition for the macrocycle closure. However, in the second scheme INOC is followed by C=C bond cis-trans-isomerization. In the third scheme (481) intermolecular cycloaddition is followed by ring closing metathesis as the key step. 

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). 

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. 

Intermolecular cycloadditions or Diels-Alder reactions have proved to be a successful route to several valuable intermediates for natural product syntheses. In creating new chiral centers, most of these reactions apply single asymmetric induction. As mentioned in Chapter 3, in the asymmetric synthesis of the octa-hydronaphthalene fragment, the Roush reaction is used twice. Subsequent intramolecular cyclization leads to the key intermediate, the aglycones, of several natural antitumor antibiotics. On the other hand, the Diels-Alder reaction of a dienophile-bearing chiral auxiliary can also be used intramolecularly to build... 

Based on the number of n electrons in polyenes, we can predict which type of intermolecular cycloadditions will be symmetry allowed. The close in energy the frontier orbitals are, the stronger will be the interaction between them and therefore the more easily the reaction will occur. The orbital coefficients at the interacting centres can also influence the rate and the direction of addition. 

Both inter- and intramolecular [5 + 2] cycloaddition modes have been utilized in the synthesis of natural products. Successful intermolecular cycloaddition depends on making an appropriate selection of solvent, supporting electrolyte, oxidation potential, and current density. This is nicely illustrated in Schemes 23 to 25. For example, in methanol the controlled potential oxidation of phenol (101) affords a high yield (87%) of (102), the adduct wherein methanol has intercepted the reactive intermediate [51]. In contrast, a constant current electrolysis conducted in acetonitrile rather than methanol, led to an 83% yield of quinone (103). 

Closely related to the already mentioned electrocyclizations of N-acyl thione S-imide (see Section 4.14.9.2) are some intermolecular cycloadditions involving this unusual class of 1,3-dipoles. Thus, the thione-S-imide intermediate (233) is probably involved in the formation of spirodithiazoline derivative (234) from the thione (235) and aryl azides <93HCA2147>. Also fluorenone-S-/ -tosylimide affords with carbonyl or thiocarbonyl compounds (R H) the corresponding oxathia- or dithia-zolidine derivatives (236) (Y = O or S) <80BCJ1023> (Scheme 44) (see also Section 4.14.6.1). 

It has long been recognized that nitrone cycloadditions may allow access to spirocyclic ring systems. Such systems are inherently difficult to synthesize by conventional methods, yet are a structural component of a number of biologically active natural materials. Two common strategies have emerged for spirocycle generation from exocyclic or endocyclic nitrones (Scheme 1.45). In the exocyclic version, the carbon atom (arrowed) of the nitrone C=N double bond of dipole 209 carries a cyclic substitutent and thus an intermolecular cycloaddition reaction will... 

---