Astruc D. - Modern arene chemistry (2002)(en)

8.5 Synthesis of Specific Arenes 273

arene upon careful oxidation [67], most examples include an oxidative work-up of the reaction mixture and thus a ord the corresponding quinones. The reactions are typically performed in an ethereal solvent such as tert-butyl methyl ether or THF in the temperature range 45–70 C to induce the primary decarbonylation. Reflux conditions are beneficial in order to remove the carbon monoxide evolved. The reaction can be conveniently monitored by either thin-layer chromatography or infrared spectroscopy, which allows selection of the appropriate reaction time and temperature and prevents undesired decomposition of the arene tricarbonyl chromium. Most benzannulations are accompanied by a color change from red to orange or yellow. After consumption of the starting material, the reaction mixture is cooled to ambient temperature, and the benzannulation product may then be subjected to a protection protocol (for example, tert-butyldimethylsilyl chloride/triethylamine or tertbutyldimethylsilyl triflate/2,6-lutidine) in order to increase its stability towards oxidation. Alternatively, in situ protection can be carried out in the course of the benzannulation reaction. Demetalation of the benzannulation product may be achieved by substitution of the arene ligand by typical two-electron ligands such as acetonitrile, triphenylphosphine, or carbon monoxide; the latter, applied at a pressure of 40 bar, is especially attractive since it is a clean process that allows the recovery of hexacarbonyl chromium, which serves as starting material for the carbene complex. Oxidative cleavage of the chromium–arene bond is usually e ected by CAN (cerium(IV) ammonium nitrate) or, more selectively, by silver(I) oxide.

8.5

Synthesis of Specific Arenes

8.5.1

Biaryls

Biaryls merit special interest due to their axial element of chirality and are among the most widely used ligands in enantioselective synthesis and catalysis. Their coordination by a tricarbonyl chromium fragment following benzannulation provides an additional stereogenic element in terms of a chiral plane to the molecule [68]. Biaryl quinones are similarly relevant to natural product synthesis and enantioselective catalysis.

The binaphthohydroquinone skeleton is accessible by a double benzannulation of a biphenylbis(carbene) complex using two equivalents of alkyne. Application of one alkyne equivalent a ords the mono-benzannulated product; the second benzannulation step proceeds with distinctly lower yield [68a]. A complementary approach to biaryls is based on 1,3-dialkynes (for example, 64) which undergo a stepwise benzannulation sequence (for example, yielding 65 and 66) (Scheme 26) [68c]. A one-step protocol starting from the ethylene-bridged bis-carbene complex 67 a ords the conformationally less flexible biaryl 68, albeit in only moderate yield.

A bidirectional benzannulation strategy allows the extension of an existing biaryl skeleton. The BINOL-derived bis-carbene complex 69, accessible through a sequence of regioselective double ortho-lithiation/Fischer carbene complex synthesis, undergoes bidirectional benzannulation to give the dinuclear biphenanthrene complex 70. The optical induction exerted by the binaphthyl core is, however, only moderate; a mixture of C2- and C1-symmetrical bis(phenanthrohydroquinone) bis-chromium complexes is formed, in which the C2-

274 8 The Chromium-Templated Carbene Benzannulation Approach to Densely Functionalized Arenes

Scheme 26. Interand intramolecular approaches to binaphthyls.

symmetrical diastereomer predominates [68e]. The in situ benzannulation/oxidation sequence a ords the bis(phenanthroquinone) 71 in higher yield and in enantiopure form (Scheme 27).

The benzannulation reaction further allows the concomitant generation of an axial and chiral plane in a single reaction step (Scheme 28) [68f ]. The diastereomeric ratio of the benzannulation products depends on the protocol used for phenol protection. Thus, in situ protection gives the kinetic ratio of 74a : 74b ¼ 11 : 89, whereas a two-step benzannulation/ protection sequence results in thermodynamic control to give a ratio of 74a : 74b > 99 : 1. These results can be explained in terms of a possible or arrested rotation around the biaryl axis in the benzannulation product before protection to give either 74a or 74b.

8.5 Synthesis of Specific Arenes 275

Scheme 27. Synthesis of bis(phenanthroquinones) and -(hydroquinones).

8.5.2

Cyclophanes

Coordinated and uncoordinated cyclophanes receive considerable interest due to the influence of strain on aromaticity [69]. Benzannulation adds a mild synthetic strategy to the known synthetic methods for their production, especially for coordinated cyclophanes, which have been mostly synthesized by the harsher direct coordination of pre-assembled cyclophanes.

Benzannulation is compatible with the construction of non-planar or strained aromatic rings. This is demonstrated by both the annulation of boat-like arene decks in [2.2]metacyclophanes and by an intramolecular benzannulation to form a hydroquinone deck itself. The first e ort concentrated on the annulation of the strained ethene bridge in the [2.2]para-

276 8 The Chromium-Templated Carbene Benzannulation Approach to Densely Functionalized Arenes

Scheme 28. Concomitant generation of a chiral axis and a planar axis.

cyclophane-based carbene complex 75, which resulted in a combined 40 % yield of hydroquinone derivatives 76a and 76b (Scheme 29) [70].

The non-planar boat-like arene deck in the [2.2]metacyclophane carbene complex 77 undergoes benzannulation to give a diastereomeric mixture of naphthalenophanes 78a and 78b; reflecting the steric shielding by the una ected benzene deck, the anti-diastereomer 78a is formed preferentially to the syn-diastereomer 78b (combined yield: 52 %) (Scheme 30) [71]. The steric influence of the benzene deck is further evident from a study of the hapto-

Scheme 29. Benzannulation of the ethene bridge in [2.2]paracyclophanes.

8.5 Synthesis of Specific Arenes 277

Scheme 30. Synthesis and haptotropic rearrangement of metabenzonaphthohydroquinonophane tricarbonylchromium complexes.

tropic migration of the chromium fragment along the naphthalene p-system. Whereas the anti-diastereoisomer 78a rearranges upon warming to 80 C to give 79a, the metal migration to the inner naphthalene ring in the syn-diastereomer 78b is hampered by the combined steric repulsion between the Cr(CO)3 fragment, the inner hydrogen of the benzene deck, and the benzylic hydrogen atoms of the ethylene bridges. Instead, demetalation occurs under identical conditions to give the uncoordinated naphthalenophane 79b. The benzannulation methodology provides a regiodefined access to chromium-labeled cyclophanes and is complementary to the complexation protocol using traditional chromium-transfer reagents such as Cr(CO)3(NH3)3 [72].

Even the distorted boat-like deck in [2.2]metacyclophanes can be constructed by an intramolecular version of the benzannulation. A suitable precursor bears a chromium vinylcarbene and an alkyne moiety linked to a meta-phenylene core by two-atom bridges, as shown for complexes 80. Benzannulation under the typical conditions a ords hydroquinonophanes 81 in fair yields (Scheme 31) [73]. Interestingly, the intramolecular benzannulation approach even tolerates heteroatom bridges, which impose both additional strain and helicity on the cyclophane skeleton [73b].

Another independent intramolecular approach to cyclophanes was based on a macrocyclization [74].

278 8 The Chromium-Templated Carbene Benzannulation Approach to Densely Functionalized Arenes

Scheme 31. An intramolecular benzannulation approach to [2.2]metaand [2.2](hetera)metacyclophanes.

8.5.3

Annulenes and Dendritic Molecules

The benzannulation technique is also applicable to the benzene homologation and functionalization of annulenes, as well to a quadruple arene modification of dendritic cores. The reaction of chromium carbene functionalized 1,6-methano[10]annulene 82 with 3-hexyne under standard conditions a orded a fair yield of the benzannulation product 83 after protection and oxidative work-up (Scheme 32) [75]. The chromium complex 84 evidently partly survived the oxidation conditions using FeIII; a syn-stereochemistry with respect to the Cr(CO)3 fragment and the methano bridge was suggested on the basis of NMR data, which is in contrast to the preferred formation of anti-annulation products bearing cyclophane skeletons [75b].

Scheme 32. Benzannulation of chromium [10]annulene carbenes.

8.5 Synthesis of Specific Arenes 279

The tetrafunctional alcohol pentaerythritol is a popular core in dendrimer chemistry; it has been modified into a tetrakis chromium phenylcarbene 85, which underwent a quadruple benzannulation upon reaction with 3-hexyne. The reaction proceeded with only moderate diastereoselectivity in terms of the planes of chirality formed; demetalation by mild oxidative work-up gave the tetrakis-hydroquinone derivative 86 (Scheme 33) [76].

Scheme 33. Quadruple benzannulation of chromium carbenes with a dendritic core.

8.5.4

Angular, Linear, and Other Fused Polycyclic Arenes

The benzannulation of naphthyl carbene complexes may be used as a direct route to functionalized phenanthrenes (Scheme 34) [37a]. While it is obvious that 1-naphthyl carbene complexes such as 87 lead to phenanthrenes 88 (see also Section 8.3.2, Scheme 19), chromium 2-naphthylcarbenes 89 o er two alternatives for annulation, giving either phenanthrene or anthracene derivatives. Generally, angular benzannulation a ording phenanthrenes 90 is favored over linear benzannulation to give anthracene derivatives 91. A rationale for this regiopreference is the higher electron density at C-1 compared with that at

280 8 The Chromium-Templated Carbene Benzannulation Approach to Densely Functionalized Arenes

Scheme 34. Benzannulation of 1- and 2-naphthyl carbene complexes.

C-3 of the naphthalene nucleus that controls the electrophilic ring-closure of the vinyl ketene intermediate; moreover, the degree of aromaticity of the angular rings in the phenanthrene skeleton exceeds that in the anthracene analogues. This regioselectivity observed in the benzannulation of chromium carbenes is paralleled by results observed for 2-naphthyl cyclobutenones [77] and for the palladium-catalyzed cyclocarbonylation of 2-naphthyl allyl acetates [78].

To date, reports of linear benzannulation are very limited [55b, 79]. One example referred to the annulation of a 2-naphthohydroquinoid chromium carbene, which was employed in the synthesis of anthracycline (see Section 8.6.2) [79]. Later, a complementary approach in this area started from 2-naphthylcyclopropenes which, in the presence of hexacarbonylmolybdenum, served as precursors for the vinyl ketenes required for linear annulation [55b].

The cycloaddition of naphthyl carbene complexes has found application in the synthesis of biphenanthryl derivatives (see Section 8.5.1) [68c, 68d].

An alternative route to oxygenated phenanthrenes is based on a photocyclization protocol; starting from chromium biphenylcarbene 92, methoxyphenanthrols 93a and 93b are obtained (Scheme 35) [60d]. The regioselectivity of the cyclization depends on the solvent used; while in THF the ortho product 93a is slightly favored, a marked 12 : 1 preference for para annulation is observed in toluene, giving 93b as the major isomer.

8.5 Synthesis of Specific Arenes 281

Scheme 35. Regioselective phenanthrene formation via photobenzannulation.

A similar competition of angular versus linear benzannulation has recently been observed in the dibenzofuran series (Scheme 36) [80]. The results obtained for carbene complex 94 suggest that the regiochemistry depends on the substitution pattern of the alkyne and, moreover, that this has an influence on whether or not the chromium fragment remains coordinated to the annulation product. When internal alkynes such as 3-hexyne or terminal alkynes bearing bulky alkyl substituents were used, the formation of angular-fused ben- zo[b]naphtho[1,2-d]furan tricarbonyl chromium complexes (95a, 95b) was accompanied by that of comparable amounts of uncoordinated benzo[b]naphtho[2,3-d]furans (96a, 96b) as linear annulation products. Diarylethynes such as tolane, however, gave exclusively the an-

Scheme 36. Angular versus linear benzannulations of dibenzofurylcarbene complex 94.

2828 The Chromium-Templated Carbene Benzannulation Approach to Densely Functionalized Arenes

gular annulation product 95c in moderate yield. Angular benzannulation may also hamper phenol protection with a bulky silyl group.

Apart from the construction of phenanthrenes, carbene complexes have also been used for the synthesis of more extended polycyclic arenes. An unusual dimerization of chromium coordinated ortho-ethynyl aryl carbenes results in the formation of chrysenes (Scheme 37)

[81].This unusual reaction course is presumably due to the rigid C2 bridge that links the carbene and alkyne moieties, and thus prevents a subsequent intramolecular alkyne insertion into the metal–carbene bond. Instead, a double intermolecular alkyne insertion favored by the weak chromium–alkyne bond is believed to occur forming a central ten-membered ring that may then rearrange to the fused arene system. For example, under typical benzannulation conditions, carbene complex 97 a ords an equimolar mixture of chrysene 98a and its monochromium complex 98b. The peri-interactions between the former alkyne substituent (in the 5- and 11-positions) and the aryl hydrogen induce helicity in the chrysene skeleton.

Scheme 37. Chromium-assisted dimerization of ortho-alkynylarylcarbene ligands to chrysenes.