Synthesis of Pseudoazulenes

Considering the great variety of heterocyclic structures from which pseudoazulenes can be derived, it is hardly possible to generalize all the steps pertaining to their synthesis. The last steps, however, can be summarized, but even this classification, which is explained below in more detail, has some limitations. 

Yields of the deprotonation reactions are about 60 to 80% and are essentially dependent on the stability of the resulting pseudoazulene systems (see Section IV,A). 

Azalene salts 90 and 92 are obtained by quaternization of the corresponding heterocyclic bases with alkyl halides or tosylates. If the heterocyclic base contains several nitrogen atoms, alkylation can produce different quaternary salts. Quaternization, however, is surprisingly selective if certain conditions are met.205 Pyrrolo- and indolopyridines containing one pyridine-and one pyrrole-type nitrogen atom in their molecular lattice are (in aprotic solvents) almost exclusively alkylated at the nitrogen atom of the pyridine 

If the heterocyclic base contains several pyridine-type nitrogens select can also be observed. Indeno[l,2-b]quinoxalines, for example, are quaternized at the N-10 atom.110 The alkylation of heterocycles conta one pyrrole-type nitrogen and several pyridine-type nitrogens is appar selective (e.g., indolo[2,3-b]quinoxaline).201 The yields of quaternary however, are extremely low,201 even if phenacyl halides or a-halo ester used.207 Perhaps the resultant quaternary salts are dealkylated.200,207 

In many alkylations other side reactions can contribute to losses in yields of quaternary salts 90 and 92. Preferably, the quaternization is carr out in aprotic solvents because in protic solvents the heterocyclic base cl give rise to deprotonation of these salts (especially if Y = CH).58,59 Then, through substitution reactions the desired pseudoazulene products can produce substances with the quaternary salts that harden in the reaction medium (Eq. 1). 

These rules of alkylation have been summarized by Kermack.  

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In the presence of strong bases such as sodium amide, products (94) substituted at the pyrrole nitrogen are formed 167,183 jjjgy jjseigss for the synthesis of pseudoazulenes (see Scheme... 

Many of the pseudoazulenes summarized in Table I were prepared from the corresponding quaternary salts (90 and 92) by deprotonation reactions (Scheme 3). This type of synthesis is especially advantageous for azalenes and oxalenes, although thialenes are seldom prepared in this way (e.g., systems 37,107 51,137 and 67l76) because of the difficult synthesis of the corresponding thiopyrylium salts.204 However, with the exception of condensed compounds (e.g., systems 35,104,105 38,94 61,92 72,24-29,32-36 and 73,35,185,186 tjjjs approach also has disadvantages for the preparation of azalenes (93 X = NR) of the [c]-series. 

The functionalization of the five-membered ring can be promoted so that an intramolecular condensation to form the corresponding pseudoazulene becomes possible. The synthesis of compounds substituted in this way, however, is often difficult. 

Hafner s synthesis of azulene,216 the cyclopentadienyl anion can also be used to introduce the five-membered fragment. This anion reacts with heterocyclic quaternary salts in a complex manner the pseudoazulene, however, is obtained in one step. The total yields are only about 10%, but it is possible to use starting materials that are easily available in large quantities. This variant was applied to prepare 2H-cyclopenta[thiadiazolium salts145 and cyclopenta[c]thiopyranes (31) using N-methyl thiazoliumbromide.90... 

Information about absorption spectra of pseudoazulenes can be found in nearly every paper mentioned in Table I. In most cases the spectral data provide a comparison with the corresponding azulene. For unstable pseudoazulenes electronic spectra are also used to demonstrate the structure of the product of synthesis.53,83 104 113,116 123 184 188 192 Systematic investigations on absorption spectra of pseudoazulenes have been made 63 66 68 69 92 96 117,1 is... 

Pseudoazulenes 250 and 251 are Jt-isoelectronic with azulene 4, where the lone pair of electrons of a heteroatom in the six-membered ring is formally derived from one of double bonds at the seven-membered ring of the azulene skeleton. Therefore, these compounds should exhibit similar but specific properties in relation to azulene. Recently, it has been shown that a 5//-cyclopenta[c]quinolone derivative displays moderate-to-high inhibitory activity against cancer cells. This possible biological importance renewed interest in this class of compounds. Because some old reviews summarize the synthesis and the chemistry of pseudoazulenes [147], this section describes new synthetic methodologies published in the past two decades only. Because new azulene syntheses published during the past two decades are discussed in Sections 6.3.1.2 and 6.4.1, this section skips the azulene chemistry. 

Both methods explained above start from a molecular lattice already having the structure of the corresponding pseudoazulene system. The essential last step of a pseudoazulene synthesis, however, can also be to create... 

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