10.2 Product Class 2: Benzo[c]furan and Its Derivatives

H. Kwiecień

10.2.1 Product Subclass 1: Benzo[c]furans

The structure and numbering of the parent member of this product class, systematically named benzo[c]furan, are presented in ▶ Scheme 1. The ring system has also been named (with the same atom numbering) as isobenzofuran and 2-benzofuran. Chemical Abstracts uses the isobenzofuran name for 1; however, the systematic name is used as well. In the earlier literature, the skeleton was called 2-benzofurane.

There are no known naturally occurring compounds of the fully unsaturated ring system. The first synthesis of a stable benzo[c]furan, 1,3-diphenylbenzo[c]furan (2) (▶ Scheme 2), was reported in 1906.[1] The unstable parent compound 1 has been known since 1964, when its existence as a transient intermediate was first established by trapping it with a reactive dienophile and isolation as the Diels–Alder adduct.[2,3] In later work (1971), the elusive pure benzo[c]furan (1) was isolated and characterized.[4,5] Since that time, a wide variety of benzo[c]furan-related analogues substituted at the furan and/or benzene rings, as well as various annulated homologues of the parent compound, have been prepared. These benzo[c]furans are valuable substrates or intermediates for the synthesis of more complex molecules, which can be useful products for technical and biomedical applications. Some representative examples of such benzo[c]furans are given below.

The parent benzo[c]furan (1), a very reactive molecule, can be used as a precursor monomer for the preparation of polymeric thin films. The optical properties and surface-dependent growth characteristics of the poly(benzo[c]furan) obtained by chemical vapor deposition techniques can provide potential optical (such as components of optical waveguides) and microfluidic applications.[6] 4,7-Dimethoxybenzo[c]furan (3), isolated as a moderately stable crystalline solid, can be used in the synthesis of the anthra-9,10-quinone scaffold of the natural antitumor antibiotic dynemicin A (8) (▶ Scheme 3).[7,8] Diels–Alder reaction of the same benzo[c]furan, as well as its 4,5,7- and 4,6,7-analogues, is a key step in the total synthesis of racemic halenaquinone and racemic xestoquinones (12b-methyl-2,3-dihydro-1H-tetrapheno[5,4-bc]furan-6,8,11(12bH)-triones).[9,10] These pentacyclic marine quinones, which are isolated from tropical sponges, have significant and potentially valuable pharmacological properties and are powerful irreversible inhibitors of some cytoplasmic and receptor protein tyrosine kinases.

Other stable aryl- and methoxy-substituted benzo[c]furans (e.g., 4 and 5) can be used in the synthesis of natural lignans.[11,12] For example, 4,5,6-trimethoxy-1-(2,3,4-trimethoxyphenyl)benzo[c]furan (4) is the essential intermediate in the synthesis of racemic lirionol, a tetracyclic bridged natural lignin.[11] Benzo[c]furans bearing an aryl substituent at the C1 position are intermediates in the synthesis of diastereomeric switch molecules for the preparation of α-seleno esters that are used as precursors to farnesyltransferase inhibitors.[13]

1,3-Diphenylbenzo[c]furan (2) is known to be the most efficient agent for trapping singlet oxygen (1O2) and it and its derivatives have been employed in pharmacological studies.[14,15] For example, water-soluble derivatives of 1,3-diphenylbenzo[c]furan such as dyes 6 and 7 can be used as fluorescent scavengers for the detection of singlet oxygen in live mammalian cells (▶ Scheme 2).[14] Such dye scavengers decompose upon reaction with singlet oxygen and this is manifested as a decrease in the fluorescence intensity. The application of singlet oxygen in this context represents the first example of the formation of a cytotoxic drug (singlet oxygen) from a nontoxic prodrug (triplet oxygen) as a result of the chemical reaction of triplet oxygen with a specific endogenous ribonucleic acid in live mammalian cells.[16]

Benzo[c]furans such as 5,6- and 1,3-bis(trimethylsilyl)benzo[c]furans 9 and 10 (▶ Scheme 4) are well-known as isolable versatile building blocks for the synthesis of polycyclic linear hydrocarbons, namely acenes.[17–20] Acenes have been the subject of extensive studies owing to their potential applications in organic electronics. An example of acene synthesis from benzo[c]furan 9 via a Diels–Alder intermediate adduct is given in ▶ Scheme 5.[20] The stable, commercially available 1,3-diphenylbenzo[c]furan (2),[21] 4,7-dimethoxy-1,3-diphenylbenzo[c]furan (5),[22] and 4,9-bis[4-(trifluoromethyl)phenyl]naphtho[2,3-c]furan (11),[23] as well as annulated homologues of 1 such as naphtho[2,3-c]furan (12)[24] and naphtho[1,2-c]furan (13)[25] can also be used in the synthesis of various acenes.[23]

There are a few examples known of benzo[c]furans in which two furan units are fused to a common aromatic ring: the two benzo[c]difurans 14[26] and 15,[27] the two isomeric naphthodifurans 16[26] and 17,[28,29] and an example in which the furans are fused to opposite faces of a pyrene structure 18 (▶ Scheme 6).[30] These compounds and related examples have been used to prepare π-molecular switches,[31,32] linear polycyclic hydrocarbons,[27,32] and cyclophanes.[30,33] The in situ prepared (Diels–Alder) linear dibenzo[c]furan 19, for which a stable classical valence bond structure cannot be drawn (similar to 15), is a useful monomer for the synthesis of fullerene-type macromolecules.[34] Benzo[c]furan 20 is the only known molecule that contains three furan moieties, and with three sites available for Diels–Alder reactions, it is a potentially useful substrate for the synthesis of polymers and cyclophanes.[26]

1,3-Diaryl-substituted benzo[c]furans and homologous monomers[35,36] and dimers[37,38] can be used for the synthesis of compounds with photochromic or electrochromic properties as potentially useful materials for electronic devices. Aryl-substituted benzo[c]furan 21 is used as an electron-transport material in organic devices such as light-emitting diodes (▶ Scheme 7).[39] 1,3-Bis(4-methoxyphenyl)benzo[c]furan (22), a highly fluorescent compound, has been used as a dopant to fabricate efficient green luminescent devices.[40] Other aryl-substituted benzo[c]furans such as 23 can be applied for the synthesis of fluoranthene derivatives as electroluminescent emitters and for dye-sensitized solar cells.[41] Benzo[c]furans containing thiophene subunits (e.g., 24, R1 = H, OH, OMe, NMe2) can be used as push/pull-type near-infrared fluorophores.[42]

Because of their importance in synthetic organic chemistry, benzo[c]furans have been reviewed several times.[43–48] A comprehensive review of this product class was included in Houben–Weyl, Vol. E 6b/1, pp 163–216 (1994).

Benzo[c]furan is a Hückel aromatic 10-π species. Its structure can be represented as neutral oxygen-bridged ortho-quinodimethane 1 and mesomeric dipolar canonical forms 25 (▶ Scheme 8).

Although benzo[c]furan is a 10-π electronic system, the molecule does not possess the usual physical criteria of aromaticity. The aromaticity can be inferred on the basis of energetic (aromatic stabilization), geometric (aromatic bond length equalization), and magnetic properties (1H NMR chemical shifts or magnetic susceptibility exaltation and anisotropy). The resonance energy and nonalternating bond lengths of benzo[c]furan agree almost exactly with the experimentally...