Development of a new synthesis of [6]helicene precursors

The existing synthesis of the helicenes substrates 159 involved nine synthetic steps, functional group interconversions and had a relatively limited scope. Moreover, the variation of the aryl substituents at the 1- and 8-positions of the naphthalene core was difficult, namely due to the necessary installation of these groups early on in the sequence. Despite of this, modulation of the substituents at the periphery of the helicene most probably has a larger impact on their electronic structure and thus on the possible applications of this interesting class of compounds. Therefore, a modified procedure was envisaged according to the retrosynthetic analysis shown in Scheme 43. This is based on previously reported strategies for the synthesis of ortho alkynyl biphenyls reported by Gevorgyan^[223] and Lautens.^[224]

Starting from the commercially available 2,7-dihydroxynaphthalene and following a literature reported regioselective bromination at the 1 and 8 positions of the naphthalene with subsequent triflation of the free hydroxyl groups, a precursor 189 amenable to a chemoselective Sonogashira-Hagihara ethynylation followed by Suzuki-Miyaura coupling

would be obtained. This approach would be ideally placed to easily modulate the aromatic groups at the 1 and 8 positions of the naphthalene core, enabling the access to a larger scope of diyne substrates. Efforts would be made to incorporate heteroaromatics using this methodology and add heterohelicenes to the list of substrates amenable to this enantioselective hydroarylation.

Scheme 43. Disconnection approach to access substrates 159 from 2,7-dihydroxynaphthalene.

The proposed synthesis was started by the selective bromination at the 1- and 8- positions of commercially available 2,7-dihydroxynaphthalene with N-bromosuccinamide (NBS). This had been described in the literature using two sets of conditions, firstly by Whiting, using substoichiometric pyridine in chloroform^[225] and later by Pérez, carrying out the reaction in acetonitrile at 10 °C.^[226] Several variations of the conditions described were tried, including changing the order of reagents, method of addition and working with or without the exclusion of air and moisture. The best conditions in this study were found to be by adding NBS as a solid to a solution of 2,7-dihydroxynaphthalene at 10 °C under argon. This method afforded an approximately 70% pure product 190 as a mixture with other isomers. Dibromide 190 was reported to be unstable for purification by column chromatography but could be conveniently converted into stable bis-triflate 9. The latter was obtained in a yield of 26% over two steps.

In spite of a poor yield, low starting material costs and short preparation times mean that larger amounts of this intermediate could be accessed relatively quickly and used in the following steps.

4. Synthesis of new [6]helicene precursors

Scheme 44. Two-step sequence to prepare bis-triflate 189. Reagents and conditions: (a) 2,7-dihydroxynaphthalene (1.0 equiv.), NBS (2.0 equiv.), MeCN, 10 °C, 2 h; (b) crude 190 (1.0 equiv.), Tf2O (2.3 equiv.), pyridine (3.0 equiv.), CH2Cl2, 0 °C, 30 min.

The Sonogashira-Hagihara coupling proceeded chemoselectively to give the bis-alkynes 188a–c in moderate to good yields, with conservation of the two bromine substituents (Scheme 45). However, upon preparation of TMS-substituted diyne 188a, stirring of reaction mixture for longer than 1 h periods lead to the formation of additional side products, observable by GC-MS. Curiously, the selective mono-Sonogashira coupling of 189 to give TMS-substituted alkynylnaphthalene 191 could be carried out when using the less active palladium species PdCl2(PPh3)2.

Scheme 45. Sonogashira-Hagihara coupling to give alkynes 188a–c and 191. Reagents and conditions: (a) 189 (1.0 equiv.), arylacetylene (8–10 equiv.), Pd2Cl2(dppf) (5 mol%), CuI (10 mol%), Et3N/DMF, rt, 1–4 h; (b) 189 (1.0 equiv.), TMS-acetylene (2.0 equiv.), PdCl2(PPh3)2 (5 mol%), CuI (10 mol%), Et3N/DMF, rt, 16 h.

Single crystals of 188b were grown by slowly cooling a hot ethyl acetate solution. The solid state structure is shown in Figure 28. The two bromine atoms, forced into close proximity due to their position on the naphthalene ring, display a large steric repulsion, bending the whole naphthalene core out of the plane and resulting in a torsional angle of 30.0° between the two bromine atoms.

Figure 28. Structure of diyne 188b in the solid state. Solvent molecules and counterions are omitted for clarity.

Thermal ellipsoids set at 50% probability, the numbering does not correspond to the IUPAC rules. Selected bond lengths (Å) and angles (°): C1–Br1 = 1.897(1), C2–Br2 = 1.889(1), Br1–C1–C2–Br2 = –29.96(7).

Finally, the Suzuki-Miyaura coupling of the precursors 188 was evaluated for a variety of aromatics and heteroaromatics (Table 5).

Table 5. Suzuki-Miyaura coupling with compounds 188b and 188c.

Entry 159 R¹ R² Yield (%)

1 159eb p-Tolyl 2-thienyl 51

2 159fb p-Tolyl 2-furanyl 88

3 159gb p-Tolyl 3-thienyl 57

4 159hb p-Tolyl 3-furanyl 45

5 159ib p-Tolyl 4-TMS-C6H4- 37

6 159jb p-Tolyl 4-BnO-C6H4- 46

7 159kb p-Tolyl 4-MeOCH2-C6H4- 54

8 159lb p-Tolyl 4-Ph-C6H4- 24

9 159mb p-Tolyl 3,5-(MeO)2-C6H3- 63

10 159nb p-Tolyl 3,5-Me2-C6H3- 34

11 159ag 4-MeO-C6H4- C6H5 53

12 159pg 4-MeO-C6H4- p-Tolyl 50

13 159ig 4-MeO-C6H4- 4-TMS-C6H4- 25

14 159qg 4-MeO-C6H4- 4-F-C6H4- 34

15 159ng 4-MeO-C6H4- 3,5-Me2-C6H3- 39

Reagents and conditions: (a) 188 (1.0 equiv.), ArB(OH)2 (3.0–4.3 equiv.), Cs2CO3 (3.0 equiv.), Pd2(dba)3 (4 mol%), Sphos (8 mol%), THF/H2O, 60 °C, 1–16 h.

C1 C2

Br1 Br2

188b

4. Synthesis of new [6]helicene precursors

water as solvent was found to improve conversion. A variety of aromatic and heteroaromatic groups could be incorporated, including thiophenes and furans. For these both, the 2- and 3-substituted thienyl- and furanylboronic acids were employed. In addition, para-functionalized aromatics, including 4-trimethylsilyl-, 4-benzyloxy-, 4-methoxymethyl-, 4-phenyl-, 4-methyl- and 4-fluorophenyl, as well as the meta-substituted 3,5-dimethoxy- and 3-5-dimethylphenyl, could also be installed. Single crystals suitable for X-ray diffraction, could be grown for the products 159eb, 159fb, 159gb and 159ib, confirming their structural identity (Figure 29).

Figure 29. Solid state structures of compounds 159eb (A), 159fb (B), 159gb (C) and 159ib (D). Solvent molecules and counterions are omitted for clarity. Thermal ellipsoids set at 50% probability.

Unfortunately, the Suzuki-Miyaura couplings were not completely selective. Despite full conversion being reached in almost all cases, the yields of the transformations remained mostly poor or moderate. No single major side product could be identified in the crude reaction mixtures, although one clue as to the types of additional products formed could be elucidated from the structure of deep red dinaphthopentalene 192, which crystallized from the crude reaction mixture upon preparation of 159kb (Figure 30). As they possess only 8 π-electrons, pentalenes are formally anti-aromatic. Typically, pentalenes exhibit a relatively small HOMO-LUMO gap, due to the propensity to accept or donate electrons to relieve their anti-aromaticity.^[138] While helicenes containing a pentalene subunit, to the best of our knowledge, have not been reported, the incorporation of anti-aromatic subunits into polyaromatic structures such as helicenes has been previously shown to significantly alter their electronic properties.^[143,228]

(A) (B)

(C) (D)

159eb 159fb

159gb 159ib

Figure 30. Solid state structure of 192. Solvent molecules and counter ions are omitted for clarity. Thermal ellipsoids set at 50% probability.

The group of Don Tilley has reported the synthesis of dibenzopentalenes via the palladium-catalyzed homocoupling of ortho-alkynylaryl bromides under reductive conditions at high temperatures, with yields as high as 88%.^[229]

Scheme 46. Reductive homodimerization to give dibenzopentalenes. Reagents and conditions: (a) hydroquinone (2.0 equiv), Cs2CO3 (2.0 equiv), CsF (2.2 equiv.), Pd2(dba)3 (1.5 mol%), P(tBu)3 (6 mol%), 1,4-dioxane, 135

°C.^[229]

Presumably, the product 192 is formed through the mechanism shown below, which is based on the findings of the group of Don Tilley (Scheme 47). Firstly, a Suzuki coupling would take place, giving monobrominated intermediate 195. After oxidative addition to the second carbon-bromine bond, instead of proceeding through a second transmetalation, the Pd(II) species 196 would undergo a migratory insertion with a second equivalent of the intermediate 195. The vinyl palladium(II) species 197 would then participate in a second migratory insertion, completing the first cyclopentadiene ring and giving intermediate 198.

Finally, after oxidative addition to the closely proximal carbon-bromine bond in 198, reductive elimination from the resulting palladium (IV) species 199 would afford the

192

4. Synthesis of new [6]helicene precursors

192 may result from the lack of reductant in the reaction mixture, as the palladium(II) should be reduced back to palladium(0) to continue the catalytic cycle.

Scheme 47. Proposed mechanism for the formation of compound 192.

The solid-state structure of the product 192 suggests that the molecule may not yet be chiral, as the aromatic substituents in the two bay areas lie parallel to one another. Moreover, it can be considered as a potential substrate for a gold-catalyzed intramolecular hydroarylation, which would give the S-shaped fused double [5]helicene 200 (Scheme 48). The synthesis of fused helicenes and higher order polyaromatic structures has attracted a great deal of attention recently;[140,230,231] however to the best of our knowledge, only one example of an attempted enantioselective synthesis of a fused dihelicene^[232] as well as one example of a fused diheterohelicene^[208] have been reported up to now. If the compound 192 could be synthesized in better yield, it may offer an exciting entry to this emerging field of research.

Scheme 48. Possible transformation of 192 in gold(I)-catalyzed hydroarylation reactions.

4.3 Summary

In summary, a variety of new helicene precursors 159 were synthesised. Because the existing synthesis for helicene precursors 159 enabled modulation of the alkyne substituent;

a broad range of aromatic substituents were installed using this methodology, incorporating functional groups amenable to further transformations such as ethers, protected phenols, silanes and halogens. The alkyne was additonally brominated and silylated in the interest of further study.

In addition, a new synthetic route to diynes 159 was developed, which significantly lowered the number of synthetic steps required and allowed the introduction of a diverse range of aromatic and heteroaromatic groups directly onto the naphthalene core, which was a challenge when using the existing precursor synthesis. The new synthesis of 159 proceeded through a regioselective bromination of 2,7-dihydroxynaphthalene, followed by triflation, chemoselective Sonogashira-Hagihara coupling and finally Suzuki-Miyaura coupling. The final Suzuki-Miyaura coupling however, gave trace amounts of side products, one of which could be identified as the dinaphtho pentalene 192. This is likely formed via a palladium catalysed, reductive dimerisation reaction, which if it could be optimsied further may provide an entry towards fused dihelicenes with an anti-aromatic core.