In this approach, an appropriate diarylethene derivative is prepared, which is then cyclized, usually by photochemical methods, to obtain helicene; the diarylethene is generally obtained either by the Wittig reaction between a phosphonium salt and an aldehyde, or by Heck coupling through a vinyl derivative and an aryl halide. It is possible to devise the synthesis by incorporating starting materials containing the desired side groups.

The Wittig reaction is compatible with several functional groups, including multiple bonds, halogens, nitro, ether, ester, and acetal groups, which therefore may be present on the aldehyde moiety. The phosphorus ylide may contain multiple bonds and several functional groups; if it contains electron-withdrawing groups, it becomes more stable. This approach was adopted in many cases for carbohelicenes, for instance in [10], where 4-bromobenzaldehyde reacted with the appropriate four-ringed phosphonium ylide to obtain the diarylethene precursor of 2-Br-hexahelicene. For azahelicenes, the only additional limitation concerns the availability of the required commercial starting materials. One reported instance starts from 2-chloroquinoline-3-aldehyde (1) to obtain the symmetrical 6,9-dichloro-(2) and 6,9-dimethoxy-5,10-diaza[5]helicene (3) [11]. Both terms employed in the Wittig condensation originate from the same substituted quinolinaldehyde (Scheme 1); (1) is easily accessible by reacting acetanilide with POCl₃ in DMF at 80 °C [12]. By using differently substituted moieties, it is also possible to obtain the unsymmetrically substituted product.

Starting from 6,9-dichloro-5,10-diaza[5]helicene (2) it is possible to substitute chlorine atoms with several functional groups, as depicted in Scheme 2.

The substitution of chlorine atoms with chiral amines provides a way to separate diastereomers, in order to achieve an enantiomeric resolution. However, the five-ringed helicenic scaffold is readily racemized, and the presence of nitrogen substitution accelerates racemization compared to the parent compound [11].

In a modification of this approach, Harrowven and coworkers [13] prepared 6-chloro-5-aza[5]helicene (4) again by using (1) as the starting material, and reacting it with a phosphonium salt bearing an iodine atom, to be used for a non-photochemical radical coupling reaction (Scheme 3).

3-bromo-4-aza[6]helicene was also prepared following the Wittig condensation. The photochemical ring closure strategy [14] started from 6-bromo-2-pyridinecarboxaldehyde, which was condensed with benzo[g]phenanthren-3-ylmethyl triphenyl phosphonium bromide through the use of BuLi in THF to obtain the corresponding diarylethene in a 90% yield. This was then irradiated with visible light in toluene with I₂ (2 equiv.) and excess propylene oxide (PO) for 15 h to yield 3-bromo-4-aza[6]helicene in a 45% yield. In the same way, racemic 3-(2-pyridyl)-4-aza[6]helicene 5 was synthesized in two steps from 2,2′-bipyridine-6-carbaldehyde by the Wittig reaction with (benzo[g]phenanthren-3-ylmethyl)triphenyl phosphonium bromide followed by a photocyclization reaction (83% overall yield, Scheme 4) [15], and 3-(2-pyridyl)-4-aza[4]helicene was prepared by using (2-methylnaphthyl) triphenyl phosphonium bromide, with an overall yield of 61%.

These compounds were used to realize Pt complexes acting as chiroptical switches. The 2,2′-bipyridine unit is endowed with remarkable stability and exceptional coordination chemistry. Functionalized helical bipyridine systems exhibit, in addition to the usual azahelicene properties, a rich and high-affinity coordination chemistry with metals, a good acid/base and alkylation reactivity, and redox activity.

A chiroptical switch based on reversible Zn(II) complexation by the double azahelicene (6) was synthesized by the same research group through double photochemical cyclization (Scheme 5) [16].

The same group also synthesized a three-substituted 4-aza[6]helicene by preparing a diarylethene already bearing a dialkynyl substituent, which, after cyclization, was then reacted further to obtain a phosphole-substituted azahelicene, as reported in Scheme 6 [17].

A Br-substituted diaza[7]helicene (7) was prepared [18] through the Wittig condensation, as shown in Scheme 7.

Removal of the benzyloxy groups from (7) by TFA yields the corresponding brominated pyridinone 8 in a 63% yield. The bromine atom can be substituted with the COCH₃ group. Pd- and CuI-cocatalyzed coupling of TMS-acetylene with 7 yielded the corresponding ethynyl helicene, which, by treatment with trifluoroacetic acid, cleanly liberated the pyridinone hydrogen bond sites and simultaneously deprotected the TMS-acetylene moiety, generating the methyl ketone derivative analogous to 8 in a nearly quantitative yield.

The same approach held for the Heck coupling, where both the alkene and the halogen-bearing moieties used to obtain the diarylethene could bear substituents. 14-methoxy-3-aza[6]helicene (9) was synthesized through a double Heck condensation-photochemical oxidation approach (Scheme 8) [19].

The Heck couplings were obtained by using excess of the commercially available vinylderivatives in the presence of 3 equiv. AcONa and 1% Hermann’s palladacycle [trans-di(μ-acetato)-bis[o-(di-o-tolylphosphino)-benzyl]dipalladium] as the catalyst in DMA. The -OCH₃ group can be easily transformed in -OH by treatment with a BBr₃ solution in CH₂Cl₂ at RT for 3 h, with an excellent yield. The hydroxy derivative could serve as N–O bidentate ligands in asymmetric synthesis or as building blocks for supramolecular architecture. Although not many instances have been described in the literature, this approach is quite general.

Only two successful syntheses of stilbenoid precursors by the photocyclization of amides have been described [20]. In the first, photochemical ring closure of the amide provides lactam 10, which is then converted to double helicene 11 by POCl₃ (Scheme 9).

In the second, the same research group obtained the dithienocondensated aza[4]helicene (Figure 1) by the same procedure; however, the yield of the last step with POCl₃ was moderate (39%).

This approach to the synthesis of helicenes involves intramolecular [2 + 2 + 2] alkyne cycloisomerization catalyzed by Co^I, Ni⁰, or Rh^I to provide the simultaneous formation of three or more cycles in a single step, giving access directly to the desired helicene, or to its tetrahydro derivative, to be oxidised in a subsequent step. This strategy has been extensively used for the synthesis of electron-rich systems, namely carbo- and oxa-helicenes [21], while only limited examples are reported for electron-poor pyridine moieties (Figure 2).

Most frequently, unsubstituted azahelicenes are prepared by this method [22]. Some attempts to apply this strategy to alkyl-substituted azahelicenes were only partially successful. Cycloisomerization of an azabiphenylylnaphthalene catalyzed by InCl₃ and PtCl₄ allowed for the synthesis of 6,10-dimethyl-2-aza-[6]helicene in an 80% yield [23], while the same reaction, applied to the synthesis of 6,10-dimethyl-2,14-diaza-[6]helicene, failed despite the screening of a number of different catalyzers. In another instance [24], diversely substituted 1-aza[6]helicenes are produced in gram scale, starting from methoxy-substituted azahelicene (12), obtained as in Scheme 10.

The methoxy group, which can be located either in position 14 (12a) or 15 (12b), can then be converted relatively easily and with fair to good yields into different functional groups (Scheme 11). Furthermore, the precursors to compounds 12 show atropoisomeric chirality and could be resolved into stable enantiomers, thus enabling the obtainment of compounds 12a,b with an enantiomeric excess of more than 90%.

The enantioselective synthesis of azahelicenes and S-shaped double azahelicenes has been achieved via the Au-catalyzed sequential intramolecular hydroarylation of alkynes [25]. By using the catalytic system indicated in Scheme 12, the azahelicenone 18 is obtained in very good yield with 69% ee starting from an achiral precursor. It is also possible to reduce the amount of the catalyzers by operating at 80 °C: in this case, although, the yield decreases to 80%, and the ee decreases to 56%. When a phenyl group is introduced as a substituent in place of 2-methoxyphenyl, both the yield and ee decrease substantially.

Following the same procedure, products analogous to 18 can be prepared, in which one or both terminal aromatic rings bear two methoxy groups in positions 1,3.

Starting from a product analogous to 18 in which the nitrogen atom bears a 4-methoxybenzyl group, treatment with CF₃COOH followed by reaction with POCl₃ and PhNMe₂ (-)-8-chloro-2-(2-methoxyphenyl)-7-aza[6]helicene 19 (Figure 3) obtained a 67% yield, with 74% ee. By using the same reaction strategy, it is also possible to obtain the S-shaped double azahelicene 20 represented in Figure 3, with >99% ee of the (+) enantiomer.

Double azahelicenes showed red shifts of absorption and emission maxima and higher quantum yields in the CHCl₃ solution compared with azahelicenes. The optical rotation values of double azahelicenes were smaller than those of the corresponding single azahelicenes.

The Povarov reaction is a formal inverse-electron demand [4 + 2] cycloaddition between electron rich-alkenes, acting as dienophiles, and N-alkylidene anilines acting as electron-poor dienes. The primary Povarov cycloadduct is a tetrahydroquinoline that can be oxidized to the corresponding quinoline; therefore, it can be used to grant easy access to helical-shaped compounds (Scheme 13) [26].

Actually, the reaction depicted in Scheme 14 brings about the formation of the dihydroderivative 21, which cannot be further oxidized even in much harsher conditions (5 equiv. of DDQ, DMF, microwave 150 °C, 12 h).

The Pictet-Spengler reaction was used to prepare a functionalized aza[4]helicene as depicted in Scheme 15 [27].

The reaction can be performed by both electron-deficient and electron-rich aldehydes, resulting in an aryl substituent that can bear groups such as –OCH₃ or –NO₂. In this paper, the optical properties of the aza[4]helicenes were studied by UV spectroscopy, finding absorption bands in CH₂Cl₂ with maxima at 274–307 nm, with the presence of electron-withdrawing groups resulting in absorption at longer wavelengths than the electron-donating groups; the positions of the substituents had no obvious effect on the maximum of the absorption peak. In the fluorescent spectra, the emission maxima for the helicene skeleton were observed at about 400 nm, and the substituent groups and their positions had no obvious effect on the emission, while the fluorescence intensities were weak. The methoxy group onto the aromatic ring can be demethylated with 98% yield by BBr₃ in dichloromethane. This method could also be applied to azahelicenes with more than four rings.

The configurationally stable diaza[4]helicene 22 is prepared starting from the tris(2,6-dimethoxyphenyl)methyl cation following the strategy indicated in Scheme 16 [28].

R can be alkyl, phenyl, benzyl, -NH₂, -CH₂CH₂OH, or -CH₂CH₂ NH₂. Yields range from 80 to 97%. This synthetic procedure is general, modular, and highly tolerant to functional groups. Single enantiomers of the [4]helicenes were obtained by chromatographic resolution, with a high racemization barrier. These helical quinacridines are effective dyes showing interesting absorption and emission properties, that can be modulated as a function of pH. Their fluorescence is weak and they show relatively modest changes in emissive properties upon protonation.

Substituted 7,8-diaza[5]helicenes were prepared by oxidative ring closure of 1,1′-binaphthalene-2,2′-diamines (BINAMs, Scheme 17) [29].

t-BuOCl acts as bland oxidizing agent, while 2,6-lutidine serves as weak base to neutralize HCl generated in the process. The method is moderately tolerant to functional groups: R₁ can be H, CH₃, Br, Ph, and COOCH₃, while R₂ can be H, Br, or butyl. The reaction takes place at RT in 3 h with yields ranging between 44 and 91% [29]. For these diazahelicenes, UV–VIS absorption spectra were recorded, observing a red shift over the whole region upon the introduction of methyl or phenyl groups in the 3,3′ positions, while on the opposite side the introduction of 6,6′-n-Bu substituents caused a blue-shift of n–π * transitions (380–430 nm), while π–π * transitions (300–340 nm) were red-shifted. Cyclic voltammetry experiments were used to estimate the LUMO energies, which ranged from −2.92 to −3.13 eV.

A very recent paper [30] reported the synthesis of a substituted aza[7]helicene by ring expansion starting from a helical ketone, which was reacted with a carbanion to obtain a five-membered ring alcohol. This latter then undergoes ring expansion by reaction with NaN₃, with subsequent rearomatization/deprotonation to yield an aryl-substituted aza[7]helicene (Scheme 18).

A variety of mono- and poly-cyclic aryl moieties were attached to the aza[7]helicene with excellent yields through the use of an appropriate Grignard reagent; both electron-withdrawing and electron-donating substituents on the aryl ring were tolerated and even aliphatic chains could be introduced. The enantiomers were separated by chiral HPLC. Under the irradiation of UV light (365 nm), some of these compounds, notably those bearing Ph, n-Bu,p-OPh, and 7-(tert-butyl)pyren-2-yl, displayed a bright green luminescence. The quantum efficiency of the n-Bu-substituted derivative leaps to 18% in comparison to ∼7% for its aryl analogues. The longest absorption maximum in UV−VIS spectra is at ∼433 nm.