3+2 dipolar cycloaddition

3-dipolar cycloaddition (1,3-DC) is the reaction of a dipolarophile with a 1,3-dipolar compound to form a five-membered ring, which is a kind of MBFT. The earliest 1,3-DC reactions were described in the late nineteenth century to the early twentieth century, following the discovery of 1,3-dipoles. Mechanistic investigations and synthetic applications were established by Rolf Huisgen in the 1960s [2], Now, the chemistry of the 1,3-DC reaction has thus evolved for more than 100 years, and a variety of different 1,3-dipoles have been discovered, which has significantly advanced the development of the 1,3-DC reactions. After several decades of development, transition-metal-catalyzed, stereoselective 1,3-DC has become one of the most useful synthetic routes to the synthesis of the five-membered heterocycles. 

2 Targets with Two Heteroatoms 1,3-DC reaction was also widely used in the preparation of five-membered heterocycles with two heteroatoms. For instance. 

the chiral Cu and Ce catalysts were also applied in the 1,3-DC of nitrones in succession. By using a similar strategy, the corresponding isoxazolidine products 

3-DC of nitrile oxides and alkenes leads to the formation of 2-isoxazolines, which are useful building blocks in organic chemistry. While the diastereoselective nitrile oxide cycloadditions have been investigated extensively, the development of enantioselective variants is quite rare. 

In 2004, an elegant example of nitrile oxide cycloaddition to pyrazolidinone cro-tonates catalyzed by a chiral Lewis acid was described by Sibi and coworkers [17a]. 

The azide-alkyne Huisgen cycloaddition is a popular approach to access 

3- triazoles however, metal is required for the reaction. To eliminate the need for metal, organocatalytic approaches towards 1,2,3-triazoles have been investigated involving 1,3-dipolar cycloadditions between iminium ions and azides. Whereas activated ketones containing electron-withdrawing substituents have already been employed, the scope for these transformations has been limited. L-Proline serves as a bifunctional aminocatalyst in the 

Five-membered heterocycles through a cycloaddition reaction 

Huisgen has reported in 1963 about a systematic treatment of the 1,3-dipolar cycloaddition reaction as a general principle for the constmction of five-membered heterocycles. This reaction is the addition of a 1,3-dipolar species 1 to a mnltiple bond, e. g. a double bond 2 the resnlting prodnct is a heterocyclic compound 3. The 1,3-dipolar species can consist of carbon, nitrogen and oxygen atoms (seldom sulfur) in various combinations, and has fonr non-dienic jr-electrons. The 1,3-dipolar cycloaddition is thns a 4jr -I- 2jr cycloaddition reaction, as is the Diels-Alder reaction. 

Mechanistically the 1,3-dipolar cycloaddition reaction very likely is a concerted one-step process via a cyclic transition state. The transition state is less symmetric and more polar as for a Diels-Alder reaction however the symmetry of the frontier orbitals is similar. In order to describe the bonding of the 1,3-dipolar compound, e.g. diazomethane 4, several Lewis structures can be drawn that are resonance structures  

The cycloaddition reaction of diazomethane 4 and an olefin, e.g. methyl acrylate 5, leads to a dihydropyrazole derivative 6  

The shifting of electrons as shown in the scheme should be taken as a simplified depiction only. A more thorough understanding follows from consideration of the frontier orbitals and their coefficients this may then permit a prediction of the regiochemical course of the cycloaddition. 

Asymmetric 1,3-dipolar cycloaddition of azomethine ylides to electron-deficient olefins leads to chiral pyrroUdines, which are applied broadly in the synthesis of 

SCHEME 2.12 Phosphoric acid-catalyzed asymmetric cascade reaction between enamines and a, 3-unsaturated ketones. 

The same group also demonstrated an efficient asymmetric construction of spiro[pyrrolidin-3,3 -oxindole] derivatives 55 via a three-component 1,3-dipolar cycloaddition of methyleneindolinones 54 with aldehydes 3 and amino esters 49 in 

SCHEME 2.13 Phosphoric acid-catalyzed asymmetric 1,3-dipolar cycloaddition. 

3-dipolar eyeloaddition, also known as the Huisgen cycloaddition, is a elassie reaetion in organic chemistry consisting in the reaetion of a dipolar-ophile with a 1,3-dipolar compound that allows the produetion of various five-membered heteroeyeles. This reaction represents one of the most productive fields of modern synthetic organic chemistry. Most dipolarophiles are alkenes, alkynes, and molecules possessing related heteroatom functional 

Since catalysts immobilised on hydrophilic silica gel often give superior performances to their polymer-bound or polymer-incorporated analogues for multiple applications, Heckel and Seebach have immobilised TADDOL derivatives on hydrophobic controlled-pore glass (CPG) silica gel. Indeed, CPG is 

The development of more eiScient and environmentally friendly methodologies in asymmetric catalysis is a very important area of research in chemistry. 

An alternative that has received a great deal of attention in recent years is the immobilisation of a chiral catalyst on a nonsoluble support (polystyrene resins, silica gel, zeolites, etc.), thereby creating a chiral heterogeneous catalyst. Unlike homogeneous catalysts, these supported complexes can be recovered from the 

The existence of ketenes was established over a hundred years ago, and, in recent years, asymmetric synthesis based on [2 + 2] cycloadditions of ketenes with carbonyl compounds to form chiral p-lactones has been achieved with high yields and high stereoselectivities. In 1994, Miyano et al. reported the use of Ca-symmetric bis(sulfonamides) as ligands of trialkylaluminum complexes to promote the asymmetric [2 + 2] cycloaddition of ketenes with aldehydes. The corresponding oxetanones were obtained in good yields and enantioselectivities 

This fully documented reaction [11] resembles [,r4+ 2]-cycloaddition in that two (7 bonds are formed between adjacent C atoms of an olefin and the termini of 

The MOs of the cyclic product are set up in the conventional manner bonding below non-bonding below antibonding, and cr below tt, MOs of the same type being ordered according to the number of nodal planes. The five doubly-occupied MOs are seen to correlate smoothly across the diagram, so no reduction of symmetry below C2v is called for. 

The correspondence diagram for the cycloaddition of ozone and ethylene, which is the first step in the Criegee mechanism of the ozonolysis of olefins, [17], [3, pp. 1067-1070] is illustrated if Fig. 7.6. 

The right side of Fig. 7.6 is identical with that of Fig. 7.5, except for the fact that 3(62) is doubly occupied. The MOs of ozone are easily related to those of N3 the additional occupied MO, n3(ai), is a non-bonding orbital largely localized on the central atom, that is derived from 3, the in-plane member of N3 s degenerate pair of tt orbitals. The required 723(01) 3(62) correspondence implies that the ethylene molecule has to move above or below the molecular plane of O3 along a reaction path that can retain no more than symmetry. 

5 and 7.6 are consistent with the hypothesis, in support of which Huisgen [12,13] has marshalled a great deal of evidence from solvent, substituent and isotope effects, that both types of 1,3-dipolar cycloaddition generally take place in a single step. Stepwise cycloaddition, advocated by Firestone [14, 15], has also been observed [16], but can compete successfully with the concerted 

The high reactivity of ortho-benzyne is also evident in 1,3-dipolar cycloadditions. The reaction is an extremely useful route to benzo-fused five-membered ring heterocydes. For example, azides give benzotriazoles, diazo compounds give (after 

Although the vast majority of stepwise polar additions to ortho-benzyne involve nucleophilic attack on the aryne, electrophilic attack is also possible provided that the aryne is generated by a method that does not involve strongly basic conditions. Few such additions are synthetically useful, with the exception of the formation of 1,2-dihalobenzenes by reactions of ortho-benzynes with halogens, although alternative mechanisms initiated by nucleophilic attack of halide may be envisaged. Radical reactions of ortHo-benzyne, on the other hand, are extremely rare. 

A four-membered ring fused to a benzyne has a sizable directing effect for the regioselective reactions with ketene silyl acetals, nucleophiles, and a-alkoxyfuran. Such findings open up an opportunity for selective syntheses of various interesting aromatic compounds. 

Nitrones have been generally prepared by the condensation of /V-hydroxylamines with carbonyl compounds (Eq. 8.40).63 There are a number of published procedures, including dehydrogenation of /V,/V-disubstituted hydroxylamines, / -alkylation of imines, and oxidation of secondary amines. Among them, the simplest method is the oxidation of secondary amines with H202 in the presence of catalytic amounts of Na2W04 this method is very useful for the preparation of cyclic nitrones (Eq. 8.41).64 

Reductions of y-nitroketones yield cyclic nitrones, which undergo inter- and intramolecular cycloaddition to various alkenes. The result of addition to acrylonitrile is shown in Eq. 8.42, in which a mixture of regio- and stereoisomers is formed.65 

Conjugated nitrones are formed by intramolecular reductive cyclizations of nitro groups onto ketones the resulting nitrones give starting materials for preparing azasteroids. An example is shown in Eq. 8.43.66 

Nitrones, reactive 1,3-dipoles, react with alkenes and alkynes to form isoxazolidines and isoxazolines, respectively. With monosubstituted olefinic dipolarophiles, 5-substituted isoxazolidines are generally formed predominantly however, with olefins bearing strongly electron-withdrawing groups, 4-substituted derivatives may also be formed.631 

The mechanism of 1,3-dipolar cycloaddition can be found in Ref. 63 and the references within. The reaction of nitrone with 1,2-disubstituted alkenes creates three contiguous asymmetric centers, in which the geometric relationship of the substituents of alkenes is retained. The synthetic utility of nitrone adducts is mainly due to their conversion into various important compounds. For instance, P-amino alcohols can be obtained from isoxazolidines by reduction with H2-Pd or Raney Ni with retention of configuration at the chiral center (Eq. 8.44). 

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Apart from the thoroughly studied aqueous Diels-Alder reaction, a limited number of other transformations have been reported to benefit considerably from the use of water. These include the aldol condensation , the benzoin condensation , the Baylis-Hillman reaction (tertiary-amine catalysed coupling of aldehydes with acrylic acid derivatives) and pericyclic reactions like the 1,3-dipolar cycloaddition and the Qaisen rearrangement (see below). These reactions have one thing in common a negative volume of activation. This observation has tempted many authors to propose hydrophobic effects as primary cause of ftie observed rate enhancements. 

Mechanistic investigations have focused on the two pericyclic reactions, probably as a consequence of the close mechanistic relation to the so successful aqueous Diels-Alder reaction. A kinetic inquest into the effect of water on several 1,3-dipolar cycloadditions has been performed by Steiner , van... 

The reaction of cyclohexene with the diazopyruvate 25 gives unexpectedly ethyl 3-cyclohexenyl malonate (26), involving Wolff rearrangement. No cyclo-propanation takes place[28]. 1,3-Dipolar cycloaddition takes place by the reaction of acrylonitrile with diazoacetate to afford the oxazole derivative 27[29]. Bis(trimethylstannyl)diazomethane (28) undergoes Pd(0)-catalyzed rearrangement to give the A -stannylcarbodiimide 29 under mild conditions[30]. 

A ver promising reactivity of A-2-thiazoline-4-one has been found recently. 5-Aryl-A-2-thiazoline-4-one (190) gives the 1.3-dipolar cycloaddition product (191) with methyl fumarate and methyl maleate... 

Dipolar cycloaddition reactions with azides, imines, and nitrile oxides afford synthetic routes to nitrogen-containing heterocycles (25—30). 

Ozonation ofAlkenes. The most common ozone reaction involves the cleavage of olefinic carbon—carbon double bonds. Electrophilic attack by ozone on carbon—carbon double bonds is concerted and stereospecific (54). The modified three-step Criegee mechanism involves a 1,3-dipolar cycloaddition of ozone to an olefinic double bond via a transitory TT-complex (3) to form an initial unstable ozonide, a 1,2,3-trioxolane or molozonide (4), where R is hydrogen or alkyl. The molozonide rearranges via a 1,3-cycloreversion to a carbonyl fragment (5) and a peroxidic dipolar ion or zwitterion (6). 

Most ozonolysis reaction products are postulated to form by the reaction of the 1,3-zwitterion with the extmded carbonyl compound in a 1,3-dipolar cycloaddition reaction to produce stable 1,2,4-trioxanes (ozonides) (17) as shown with itself (dimerization) to form cycHc diperoxides (4) or with protic solvents, such as alcohols, carboxyUc acids, etc, to form a-substituted alkyl hydroperoxides. The latter can form other peroxidic products, depending on reactants, reaction conditions, and solvent. 

From Diazo Compounds via 1,3-Dipolar Cycloaddition. This method has been utilized widely in heterocychc chemistry. Pyrazohne (57) has been synthesized by reaction of ethyl diazoacetate (58) with a,P-unsaturated ester in the presence of pyridine (eq. 12) (42). 

Reaction of arninoacetonitrile hydrochloride with sodium nitrite provides diazoacetonittile (62). The product undergoes a 1,3-dipolar cycloaddition with diethyl fumarate to yield a pyrazoline intermediate, which without isolation reacts with ammonia in water to furnish the pyrazole [119741-54-7] (63) (eq. 14) (43). 

Other approaches to (36) make use of (37, R = CH ) and reaction with a tributylstannyl allene (60) or 3-siloxypentadiene (61). A chemicoen2ymatic synthesis for both thienamycia (2) and 1 -methyl analogues starts from the chiral monoester (38), derived by enzymatic hydrolysis of the dimethyl ester, and proceeding by way of the P-lactam (39, R = H or CH ) (62,63). (3)-Methyl-3-hydroxy-2-methylpropanoate [80657-57-4] (40), C H qO, has also been used as starting material for (36) (64), whereas 1,3-dipolar cycloaddition of a chiral nitrone with a crotonate ester affords the oxa2ohdine (41) which again can be converted to a suitable P-lactam precursor (65). 

The dipolar cycloaddition of 2-diazopropane to l-methyl-3-phenylpyridazin-6(l//)-one takes place through an unstable adduct which thermally decomposes to a 1,2-diazepinone, a pyridazinone and diazanorcaradiene derivative (Scheme 46). 

Pyrrole 1-oxides are known they undergo 1,3-dipolar cycloaddition with DMAD and with A-phenylmaleimide (80TL1833). 

The distinction between these two classes of reactions is semantic for the five-membered rings Diels-Alder reaction at the F/B positions in (269) (four atom fragment) is equivalent to 1,3-dipolar cycloaddition in (270) across the three-atom fragment, both providing the 47t-electron component of the cycloaddition. Oxazoles and isoxazoles and their polyaza analogues show reduced aromatic character and will undergo many cycloadditions, whereas fully nitrogenous azoles such as pyrazoles and imidazoles do not, except in certain isolated cases. 

Isoxazolidines sometimes undergo retro 1,3-dipolar cycloaddition to give back alkenes and nitrones (77AHC(2D207). 

Several five-membered ring systems readily available by 1,3-dipolar cycloadditions are shown in Scheme 10. The dotted line indicates how the system was constructed, the line bisecting the two new bonds being formed in the cycloaddition. The majority of chapters in these volumes make some reference to 1,3-dipolar cycloadditions. 

Scheme 10 Some five-membered ring systems available by 1,3-dipolar cycloadditions...

The reaction is illustrated by the intramolecular cycloaddition of the nitrilimine (374) with the alkenic double bond separated from the dipole by three methylene units. The nitrilimine (374) was generated photochemically from the corresponding tetrazole (373) and the pyrrolidino[l,2-6]pyrazoline (375) was obtained in high yield 82JOC4256). Applications of a variety of these reactions will be found in Chapter 4.36. Other aspects of intramolecular 1,3-dipolar cycloadditions leading to complex, fused systems, especially when the 1,3-dipole and the dipolarophile are substituted into a benzene ring in the ortho positions, have been described (76AG(E)123). 

Just as in the Diels-Alder reaction, 1,4-dipolar cycloadditions lead to six-membered rings. Their principal use in five-membered heterocycles is for ring annulations giving [5,6] ring-fused systems. 

In this section, reactivity studies will be emphasized while in those devoted to synthesis (Section 4.04.3) theoretical calculations on reactions leading to the formation of pyrazoles (mainly 1,3-dipolar cycloadditions) will be discussed. It should be emphasized that the theoretical treatment of reactivity is a very complicated problem and for this reason, most of the calculations have been carried out on aromatic compounds, as they are the easiest to handle. In general, solvents are not taken into account thus, at the best, the situation described theoretically corresponds to reactions taking place in the gas phase. 

The synthesis of pyrazoles, indazoles and their derivatives generally follows classical methods, the two most important methods for practical purposes being the reaction between hydrazines and /3-difunctional compounds, and 1,3-dipolar cycloadditions (Section 4.04.3.1.2). Both procedures are well documented (64HC(20)l, 66AHC(6)327, 67HC(22)l) and thus the length of the sections in this part of the chapter reflects not only the number of publications dealing with a particular method but also its interest and novelty. 

Hart and Brewbaker have described the cyclization of l,3-bis(diazopropane) to pyrazole (Scheme 49) by a concerted, intramolecular 1,3-dipolar cycloaddition (69JA711). 

Since 1,3-dipolar cycloadditions of diazomethane are HOMO (diazomethane)-LUMO (dipolarophile) controlled, enamines and ynamines with their high LUMO energies do not react (79JA3647). However, introduction of carbonyl functions into diazomethane makes the reaction feasible in these cases. Thus methyl diazoacetate and 1-diethylaminopropyne furnished the aminopyrazole (620) in high yield. 

The theoretical interest that these reactions aroused was enormous. Presently 1,3-dipolar cycloadditions are one of the cornerstones of theoretical chemistry and many references are to be found in the publications quoted in Table 36. For some recent publications related to this chapter see (78JA5701, 79TL2621, JST(89)147). 

In these types of 1,3-dipolar cycloaddition only one of two possible isomers is obtained and the pyrazole functions have different orientations by the two methods. Another classical synthesis of pyrazoles (Section 4.04.3.2.l(ii)), the reaction between hydrazines and )3-diketones, has been used with success to prepare high molecular weight polypyrazoles (Scheme 65) (81MI40400). A-Arylation (Section 4.04.2.1.3(ix)) of 4,4 -dipyrazolyl with 1,4-diiodobenzene also yields polymeric pyrazoles (69RRC1263). 

A -Isoxazolines are readily available from the 1,3-dipolar cycloaddition of nitrile -oxides with alkenes and from the condensation reaction of ehones with hydroxylamine. Therefore, methods of conversion of -isoxazolines into isoxazoles are of particular interest and of synthetic importance. 

Heterocyclics of all sizes, as long as they are unsaturated, can serve as dipolarophiles and add to external 1,3-dipoles. Examples involving small rings are not numerous. Thiirene oxides add 1,3-dipoles, such as di azomethane, with subsequent loss of the sulfur moiety (Section 5.06.3.8). As one would expect, unsaturated large heterocyclics readily provide the two-atom component for 1,3-dipolar cycloadditions. Examples are found in the monograph chapters, such as those on azepines and thiepines (Sections 5.16.3.8.1 and 5.17.2.4.4). 

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