Cycloaddition heterocyclic compounds

In the presence of a double bond at a suitable position, the CO insertion is followed by alkene insertion. In the intramolecular reaction of 552, different products, 553 and 554, are obtained by the use of diflerent catalytic spe-cies[408,409]. Pd(dba)2 in the absence of Ph,P affords 554. PdCl2(Ph3P)3 affords the spiro p-keto ester 553. The carbonylation of o-methallylbenzyl chloride (555) produced the benzoannulated enol lactone 556 by CO, alkene. and CO insertions. In addition, the cyclobutanone derivative 558 was obtained as a byproduct via the cycloaddition of the ketene intermediate 557[4I0]. Another type of intramolecular enone formation is used for the formation of the heterocyclic compounds 559[4l I]. The carbonylation of the I-iodo-1,4-diene 560 produces the cyclopentenone 561 by CO. alkene. and CO insertions[409,4l2]. 

A large fraction of the chemical reactions known are used to form heterocyclic compounds. Displacement reactions and cycloadditions are particularly important, and their rates are therefore of great practical interest. The same is true for the rates of reverse reactions — ring opening by displacements or retrocycloadditions. It was realized over the last 40 years that... 

Dipolar cycloaddUions. Interest in 1,3-dipolar cycloadditions increased dramatically during the past 20 years, largely because of the pioneering studies of Huisgen [7, 2] The versatility of this class of pericychc reactions in the synthesis of five-membered-ring heterocyclic compounds is comparable with that of the Diels-Alder reaction in the synthesis of six-membered-ring carbocyclic systems (equation 1)... 

Huisgen has reported in 1963 about a systematic treatment of the 1,3-dipolar cycloaddition reaction as a general principle for the construction of five-membered heterocycles. This reaction is the addition of a 1,3-dipolar species 1 to a multiple bond, e. g. a double bond 2 the resulting product 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 four non-dienic r-electrons. The 1,3-dipolar cycloaddition is thus An +2n cycloaddition reaction, as is the Diels-Alder reaction. 

Dihydro-1-vinylnaphthalene (67) as well as 3,4-dihydro-2-vinylnaphtha-lene (68) are more reactive than the corresponding aromatic dienes. Therefore they may also undergo cycloaddition reactions with low reactive dienophiles, thus showing a wider range of applications in organic synthesis. The cycloadditions of dienes 67 and 68 and of the 6-methoxy-2,4-dihydro-1-vinylnaphthalene 69 have been used extensively in the synthesis of steroids, heterocyclic compounds and polycyclic aromatic compounds. Some of the reactions of dienes 67-69 are summarized in Schemes 2.24, 2.25 and 2.26. In order to synthesize indeno[c]phenanthrenones, the cycloaddition of diene 67 with 3-bromoindan-l-one, which is a precursor of inden-l-one, was studied. Bromoindanone was prepared by treating commercially available indanone with NBS [64]. 

These dienes are valuable for the Diels-Alder based synthesis of dibenzofurans, dibenzothiophenes, carbazoles and other classes of complex polycyclic heterocyclic compounds. Scheme 2.32 summarizes some of the cycloadditions [81] of 2-vinylbenzofurans (80). 

Silylthioaldehydes 103, reactive dienophiles formed in situ from acetals according to a general method, are directly trapped with dienes to afford sulfur-containing heterocyclic compounds in good yield (Equation 2.29). Silylthioaldehydes are quite reactive in comparison with the aliphatic ones [102] which are rather inert in the cycloaddition reactions. 

Sauer J. The Structure-Reactivity Problem in Cycloaddition Reactions to Form Heterocyclic Compounds Khim. Geterotsikl. Soedin. 1995 1307-1322 Keywords structure-reactivity, heterocyciic compounds... 

Azides add to double bonds to give triazolines. This is one example of a large group of reactions ([3-l-2]-cycloadditions) in which five-membered heterocyclic compounds are prepared by addition of 1,3-dipolar compounds to double bonds (see Table 15.3). These are compounds that have a sequence of three atoms A—B—C,... 

Dipolar cycloaddition reactions of thioisoraunchnones (l,3-thiazolium-4-olates) have not been as extensively studied as those of munchnones (l,3-oxazolium-5-olates) despite offering rapid access to novel heterocyclic compounds. The cycloaddition of the thioisomunchnone (52) with trans-P-nitrostyrene results in the formation of two diastereoisomeric 4,5-dihydrothiophenes (53) and (54) via transient cycloadducts. These cycloadducts then undergo rearrangement under the reaction conditions <96JOC3738>. 

In Chapter 10 of Part A, the mechanistic classification of 1,3-dipolar cycloadditions as concerted cycloadditions was developed. Dipolar cycloaddition reactions are useful both for syntheses of heterocyclic compounds and for carbon-carbon bond formation. Table 6.2 lists some of the types of molecules that are capable of dipolar cycloaddition. These molecules, which are called 1,3-dipoles, have it electron systems that are isoelectronic with allyl or propargyl anions, consisting of two filled and one empty orbital. Each molecule has at least one charge-separated resonance structure with opposite charges in a 1,3-relationship, and it is this structural feature that leads to the name 1,3-dipolar cycloadditions for this class of reactions.136... 

Et2 group in 2-670. Since 2-670 contains both, a 1,3-dipole as well as a 1,3-dipolarophile moiety, it immediately undergoes a 1,3-dipolar cycloaddition to form the heterocyclic compound 2-671. 

Diels-Alder reactions are one of the most fundamental and useful reactions in synthetic organic chemistry. Various dienes and dienophiles have been employed for this useful reaction.1 Nitroalkenes take part in a host of Diels-Alder reactions in various ways, as outlined in Scheme 8.1. Various substituted nitroalkenes and dienes have been employed for this reaction without any substantial improvement in the original discovery of Alder and coworkers.2 Nitrodienes can also serve as 4ti-components for reverse electron demand in Diels-Alder reactions. Because the nitro group is converted into various functional groups, as discussed in Chapters 6 and 7, the Diels-Alder reaction of nitroalkenes has been frequently used in synthesis of complex natural products. Recently, Denmark and coworkers have developed [4+2] cycloaddition using nitroalkenes as heterodienes it provides an excellent method for the preparation of heterocyclic compounds, including pyrrolizidine alkaloids. This is discussed in Section 8.3. 

Since Huisgen s definition of the general concepts of 1,3-dipolar cycloaddition, this class of reaction has been used extensively in organic synthesis. Nitro compounds can participate in 1,3-dipolar cycloaddition as sources of 1,3-dipoles such as nitronates or nitroxides. Because the reaction of nitrones can be compared with that of nitronates, recent development of nitrones in organic synthesis is briefly summarized. 1,3-Dipolar cycloadditions to a double bond or a triple bond lead to five-membered heterocyclic compounds (Scheme 8.12). There are many excellent reviews on 1,3-dipolar cycloaddition, in particular, the monograph by Torssell covers this topic comprehensively. This chapter describes only recent progress in this field. Many papers have appeared after the comprehensive monograph by Torssell. Here, the natural product synthesis and asymmetric 1,3-dipolar cycloaddition are emphasized.630 Synthesis of pyrrolidine and -izidine alkaloids based on cycloaddition reactions are also discussed in this chapter. 

Intramolecular cycloadditions of chiral nitrones provide a useful tool for the preparation of bioactive heterocyclic compounds.63 Shing et al. demonstrated that 1,3-dipolar cycloaddition of nitrones derived from 3-0-allyl-hexoses is dependent only on the relative configuration at C-2,3, as shown in Scheme 8.16. Thus 3-0-allyl-D-glucose and -D-altrose (both with threo-configuration at C-2,3) produce oxepanes selectively, whereas 3-O-allyl-D-allose and -D-man-nose (both with erythro-configuration at C-2,3) give tetrahydropyranes selectively.80... 

In general, conjugated heterocyclic mesomeric betaines are associated with 1,3-dipoles and cross-conjugated heterocyclic mesomeric betaines are associated with 1,4-dipoles. The dipolar cycloaddition reactions of both types of heterocyclic mesomeric betaines have been widely investigated and its use for the preparation of a diverse variety of heterocyclic compounds was duly covered in CHEC-II(1996) <1996CHEC-II(8)747>. 

H(65)1889, 2005EJO3553>. Starting dihydro[l,2,4]triazolo[3, 4-4]benzo[l,2,4]triazines 482 readily react with aromatic aldehydes to yield iminium salts 483. These salts treated with a base (e.g., triethylamine) are deprotonated to reactive 1,3-dipolar azomethine imines 484. In contrast to related five-membered heterocycles, these compounds are relatively unstable on storage in the solid form and particularly in solution. Fortunately, this obstacle can be easily circumvented by their in situ preparation and subsequent 1,3-dipolar cycloaddition. These compounds can participate in 1,3-dipolar cycloadditions with both symmetric and nonsymmetric dipolarophiles to give the expected 1,3-cycloadducts in stereoselective manner. Selected examples are given in Scheme 82. 

Recently, much attention has been paid to hetero Diels-Alder reactions as powerful tools for the construction of heterocyclic compounds. For example, cycloaddition of 2,3-dimethylbuta-l,3-diene 41a with 1,2-thiazinylium salt 95, in acetonitrile at room temperature, resulted in the exclusive formation of product 76a resulting from cycloaddition across the C—S1 bond (see entry 1 in Table 15 and Equation 26) <1999TL1505>. Similarly, isoprene 41b and... 

The synthesis of biologically significant fluorinated heterocyclic compounds has been accomplished by 1,3-dipolar cycloaddition of nitrones to fluorinated dipolarophiles [51], This reaction was noticeably improved under solvent-free conditions and using microwave irradiation (Eq. (8) and Tab. 3.5). 

Cycloaddition of furan (5) has again been performed successfully under pressure and solvent-free conditions [12, 44], Usually, however, the cycloaddition of furan and heterocyclic compounds requires a Lewis-acid catalyst to give good yields. 

G. Mloston and H. Heimgartner, The chemistry of heterocyclic compounds, in Synthetic Application of 1,3-Dipolar Cycloaddition Chemistry toward Heterocyclic and Natural Products, A. Padwa, W.H. Pearson (eds), vol. 59, Wiley, New York, 2002. 

Benzonitrile oxide and mesitonitrile oxide undergo 1,3-dipolar cycloaddition reactions with 1,3,5-triphosphinines under mild conditions to afford fused heterocyclic compounds (Scheme 1.33), for example, 192 and 193. Oxaphosphazoles and oxadiphospholes have become accessible by thermal fragmentation reactions of such fused heterocyclic compounds (358). 

Regiospecilic intramolecular cycloadditions of nitrones to sulfur-substituted dienes, with 3-sulfolene precursors, has been realized (Scheme 2.217). The stereochemical outcome of these reactions is affected by the structure of the substituent (sulfide or sulfone) in the diene and by the chain length connecting the diene and nitrone (a) and (b) (see Scheme 2.211). The bicyclic products obtained from these reactions have been converted to interesting heterocyclic compounds (709). 

For reviews dealing with stereoselective 1,3-dipolar cycloaddition reactions, see (a) Martin JN, Jones RCF. In The Chemistry of Heterocyclic Compounds Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products, Padwa A, Pearson WH (Eds.), John Wiley Sons, New-York, Vol. 59, ch. 1, 1-81, 2002 ... 

Denmark SE, Cottell JJ. The Chemistry of Heterocyclic Compounds, Vol. 59 Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products, John Wiley Sons, 130-133, 2002. 

---