Benzoxetes and Benzothietes - Heterocyclic Analogues of Benzocyclobutene

Benzo-condensed four-ring heterocycles, such as benzoxetes 1 and benzothietes 3 represent multi-purpose starting compounds for the preparation of various higher heterocyclic ring systems. The thermal or photochemical valence isomerizations between the benzenoid forms 1,3 and the higher reactive o-quinoid structures 2,4 provide the basis for the synthetic applications. On the other hand, this valence isomerization impedes in particular the generation and storage of 1 because the thermal equilibrium 1 ⇆ 2 is completely on the side of 2. Thus, the number of erroneous or questionable benzoxete structures published to date is surprisingly high. On the contrary, the thermal equilibrium 3 ⇆ 4 is on the side of the benzothietes 3, which makes them easily accessible, especially by different flash vacuum pyrolysis techniques. The present article gives a survey of the preparations of 1 and 2, and tries to stimulate their use in synthetic projects. Naphtho-condensed and higher condensed compounds and compounds with an exocyclic C=O or S=O double bond (lactones, thiolactones, sulfoxides and sulfones) are not covered in this article.


2H-Benz[b]oxetes (1) and 2H-benzo[b]thietes
, the heterocyclic analogues of benzocyclobutene (5) are highly interesting compounds because of their strained molecular structures which enables an easy thermal or photochemical ring opening to the o-quinoid valence isomers 2, 4 and 6, respectively. The latter 8 electron systems are reactive species which participate in a variety of addition and OPEN ACCESS cycloaddition reactions. Figure 1 visualizes the thermal ring opening processes on the basis of ab initio calculations (HF/6-31G ** ) [1].
Early EHMO calculations revealed already an increasing tendency of the ring opening in the groundstate S 0 as well as in the electronically excited singlet state S 1 in the sequence CH 2 < S < O [2]. Semiempirical quantum mechanics (MNDO) showed then that the ring opening 34 is an endothermic process [3]-as in the carbocyclic case 56. The ring opening 12 however, is an exothermic reaction [4]: The corresponding enthalpy differences of −37.6 and +79.9 kJmol −1 , respectively, agree very well to the results of earlier [1] or more recent ab initio calculations [5,6].
The thermal ring opening of benzoxetes 1 to o-quinone methides 2 can occur already far below room temperature, whereas benzothietes 3 are stable at ambient temperatures and isomerize to o-thioquinone methides 4 in toluene at about 100 °C (G ± = 120.0 kJmol −1 ) [3]. The calculated activation barriers, shown in Figure 1, are somewhat too high. These features demonstrate the essential difference between 1 and 3 in synthetic applications: The benzoxetes 1 cannot normally be stored, and they or better their open valence isomers have to be freshly prepared and reacted in situ. The benzothietes 3 on the other hand, can be stored and can be opened thermally or photochemically whenever needed [3]. Another difference concerns the chemical behavior of 1/2 and 3/4 in the absence of reaction partners such as nucleophiles or dienophiles. o-Quinone methide 2 forms dimers, trimers and tetramers by repetitive Diels-Alder reactions [7][8][9][10][11][12]. Scheme 1 shows the [2+4]-or better [2+8] cycloadditions to the dimer 7. Apart from the exocyclic CC double bond, one of the endocyclic double bonds of 2 can also represent the 2 component [12]. The hetero-Diels-Alder adduct 7 can enter then a further [2+8] cycloaddition to yield the trimer 8, but 7 can also dimerize in a normal Diels-Alder reaction to the tetramer 9 [11].

Isolation of Benzoxetes
The first isolable benzoxetes were obtained by Adam et al. [12,16]. Scheme 3 demonstrates the mode of preparation. Low temperature oxidations of benzofurans 13a-o by dimethyldioxirane afford mixtures of the epoxides 14a-o and the o-quinone methides 15a-o in high yields. The ratio of the 14/15 equilibrium depends on the substituents varying from almost pure 14f to almost pure 15h. All these trienediones 15 have (Z)-configurations. Irradiation ( = 589 nm) of the 14/15 mixtures between −25 and −78 °C yields then in most cases the desired benzoxetes (conversion 95%). Exceptions are the systems 14/15b,f,k,l (R 1  H). Low-temperature irradiations are necessary because the o-quinone methides 15 can isomerize above 0 °C by 1.5-H shifts to phenols [12]. Moreover, the benzoxetes 16 revert thermally to the valence isomers 14/15. The Cl-containing compounds 16m-o exist at −10 °C for approximately 1h, the OCH 3 systems 16g-i are even more labile. The resulting o-quinone methides can then oligomerize, as discussed above. In the presence of enol ethers, compounds 15 yield 3,4-dihydro-2H-benzopyrans, as the example 17a reveals, and in the presence of methanol a tautomeric mixture of the hydroxyketones 18 and their hemiacetals 19 is obtained [12]. Scheme 3. The first successful approach to benzoxetes.
Recently a Chinese research group [17] reported the isolation of a 5-aryl-2-hydroxybenzoxete 20 from the stem of Caesalpinia decapetala ( Figure 2). Although the structure was carefully studied by NMR including HMBC measurements, the stability of 20 raises some doubts about the validity of the proposed structure [18][19][20].

Matrix Isolation of Benzoxetes
Unsubstituted benzoxete 1, the parent compound, was first obtained by Tomioka et al. (Scheme 4) [1,21]. The masked diazo compound 21, developed by Eschenmoser [22], was used to produce the carbene 23 via the diazo system 22 at 10 K in an Ar matrix. The IR spectra revealed the formation of o-quinone methide (2) together with its valence isomer, benzoxete 1. Benzofuranone 24 provides another successful entry to the wavelength-dependent ratio 1/2.

Benzoxetes as Intermediates
Benzoxetes can be intermediates in various reactions. A quite new example is shown in Scheme 8 [26,27]. Benzyne or other arynes react with N,N-dialkylformamides or N,Ndialkylacetamides. Treatment of 40 with tributylammonium or cesium fluoride in acetonitrile generates the arynes 41, which undergo with carboxylic acid amides [2+2] cycloadditions to the benzoxetes 42. Their corresponding o-quinone methides 43 can be trapped by water to afford 44 [26], or with zinc organic compounds to form 45 [27], or by reactive methylene components to generate 46 [26] and 47 [26], respectively. The yields of 44-47 are moderate to good.
In contrast to the photochemical generation shown in Scheme 10, there is no thermal route 55  54. The compounds 54p,q are reaction products of 54g and have the structures 60p,q [48] (Figure 3).

Preparation of Benzothietes by Ring Contraction Reactions
The first successful synthesis of benzothietes was published in 1976 by Meier

Benzothietes by Cycloelimination Reactions
Several cycloelimination reactions of CO, CO 2 or SO 2 can be applied for the generation of benzothiete (Scheme 15). The parent compound 3 could be originally obtained by a multi-step degradation of 67b [3,59], but each of the elimination routes a)-c), shown in Scheme 15, provides a much easier route.

Scheme 15. Thermal or photochemical cycloelimination reactions leading to benzothiete.
The decarbonylation of 70 by flash-vacuum-pyrolysis (FVP) [14,62] and the decarboxylation of 71 by thermolysis in solution or FVP [63,64] look straightforward. Interestingly, the sulfone 72 does not eliminate SO 2 , and after a rearrangement CO 2 is split off [65,66]. In cold traps, 3 can be isolated in all these cases in yields up to 90%. The photodesulfonylation of 73 in benzene however, can only be used for trapping reactions of o-thiobenzoquinone methide 4 [67]. Substituted benzothietes (Scheme 16) can be obtained in high yields by FVP of the corresponding benzoxathiinones 71 [64].

Scheme 17. Preparation of unsubstituted benzothiete by flash-vacuum-pyrolysis of 2-mercaptobenzyl alcohol.
Fifty g of 3 per hour can be obtained in a suitable flow device [3]. Side products are not formed and the amount of unreacted starting material can be reduced by increasing the contact time [68]. Instead of the hydroxyl compound, o-chloromethylthiophenol can be used, too [3].  [69].
An unusual cyclization reaction was observed for 2,4,6-tris(trifluoromethyl)thiophenol [70]. The threefold elimination of HF led to benzothiete 81, whose structure was confirmed by a crystal structure analysis (Scheme 19). The reaction was performed in the presence of Ga(CH 3 ) 3 , whose role is not established.

Scheme 19.
Elimination of hydrogen fluoride for the preparation of a highly substituted benzothiete.

Synthetic Applications of Benzothietes
In contrast to the less stable benzoxetes, benzothietes are very useful for the preparation of S-heterocycles and benzene derivatives with SR groups. Two important reaction types have to be mentioned here, namely the cycloaddition of the corresponding thioquinone methides 4 as 8 components with 2 (or 4) components and the addition of nucleophiles to 4 (Scheme 21).

Scheme 21.
Addition and cycloaddition reactions of benzothiete/o-thioquinone methide.    [3] The reactivity and the regio-and stereoselectivity of all these reactions have been discussed in detail [3,93]. Finally the cycloaddition of benzothiete and fullerene C 60 shall be mentioned. The monoadduct 95a is generated in a yield of 54% [94] (Figure 5).  Dimerization of benzothiete 3 4  10 competes in all these reactions of 3 with dienophiles and nucleophiles. The less reactive the reaction partner is, the higher is the amount of 10. However, the portion of 10 is not completely lost, because FVP of 10 can lead back to 3.

Conclusions
Benzoxetes 1 and benzothietes 3 seem to be very similar compounds. Both have low activation barriers for the opening of the four-membered rings, but the thermal equilibrium is for the benzoxetes (1) on the side of the o-quinone methides 2, whereas it is for the o-thioquinone methides 4 on the side of the benzothietes 3.
The different energetic situation has far-reaching consequences for the preparation of these compounds and their applications. Very few examples of substituted benzoxetes 1 have been obtained by photochemical reactions at low temperatures. The number of questionable or erroneous benzoxete structures is surprisingly high. It is much easier to generate and apply their open valence isomers, the o-quinone methides 2 [99]. The benzothietes 3, on the other hand, can be prepared by various reactions including ring contractions, cycloeliminations, cyclizations and cycloadditions. The simple access to benzothietes 3 and their high reactivity in addition and cycloaddition reactions offers a variety of applications in the synthesis of benzo-condensed S-heterocycles (5-to 11-membered rings and macrocycles).