Azahelicenes and other similar tri and tetracyclic helical molecules

The possibility of using a wide range of synthetic methods and the diverse properties resulted in an increased interest in azahelicenes and similar nitrogen bearing helical molecules. The aim of this paper is to provide an update to the recent reviews, while also including tri and tetracyclic helical molecules


Introduction
The helical intramolecular distortion of ortho annulated cyclic or heterocyclic compounds is caused by sterical overcrowding in the molecule due to the number of rings or to the number and volume of the ortho substituents.In the case of helicenes or heterohelicenes the minimum requirement for helicity to occur is the existence of five ortho annulated rings.
In 1971 Wynberg formally included phenanthrene and benzo[c]phenanthrene in the class of helicenes and stated that properly positioned substituents may infer helicity to the molecule. 1ately, the field of azahelicenes has received a great deal of interest.Several reviews on carbohelicenes are available, 3 as well as a comprehensive review on aza and azonia helicenes published by Sato and Arai. 2 This work will provide an update to the field of aza and azonia helicenes, including the related tri and tetracyclic helical molecules containing nitrogen atoms.
In the approach towards aza and polyaza helical molecules two main synthetic strategies are used.The first strategy, central linkage approach, consists in building the molecule from several ring systems connected via short chains and coupling these parts either using photocyclization or another coupling procedure.This is similar to the classical route for helicenes first reported by Newman in 1955 (Scheme 1). 4

Scheme 1
The second synthetic approach, ortho annulation or substituent insertion, uses formal helicenes such as phenanthrene or phenanthroline (and in some cases even benzene) as starting materials.The final helical system is obtained by building successive rings or inserting one or several bulky substituents in the ortho positions of the initial molecule (Scheme 2).  5 adapted the classical helicene synthesis of stilbene derivative photocyclization to obtain aza or diaza [5]helicenes.The key intermediates, ethylenes substituted in the 1-and 2-positions with quinoline or isoquinoline, 1, were synthesized using a Wittig condensation between the corresponding aldehydes and phosphonium salts.In the case of symmetrical ethylenes, the heterocyclic aldehydes were reduced to the corresponding alcohols, transformed into chlorides and used to obtain the corresponding phosphonium salts for the Wittig reaction.
The final stage, the photocyclization of ethylene derivatives 1 to mono or diaza [5]helicenes 2 takes place generally in very good yields and without the formation of corresponding nonhelical isomers (Scheme 3).
This pathway offers high yields, regioselectivity and can be applied in the synthesis of a wide range of aza and diaza [5]helicenes.However, some monoaza [5]helicenes could not be obtained using this method.The photochemical cyclization leading to 7-aza [5]helicene 4 was unsuccessful, whereas the attempt to obtain 2-aza [5]helicene gave the 7-azabenzo[ghi]perylene 3 as the only product (Scheme 4).In order to complete the series of monoaza [5]helicenes, Caronna et al. 6 revised their initial synthetic approach.As the final photocyclization step showed both high yields and regioselectivity, the method was applied on different key intermediates.Thus, instead of 1,2disubstituted ethylenes with naphthyl, quinoline or isoquinoline moieties, derivatives with three ortho-condensed rings on one side of the ethene and one ring on the other side were used.Also, the regioselectivity of the final photocyclization step was explained using ab initio computational methods.
Both possible approaches were investigated for the synthesis of 1-aza and 3-aza [5]helicene: using pyridine as the nitrogen bearing moiety and phenanthrene as the tricyclic ring system, and using benzene as the single ring and benzo[h]isoquinoline as the nitrogen bearing moiety.1-Aza [5]helicene 5 was obtained along with 3-aza [5]helicene 6 in a 9:1 and 1:9 ratio respectively, depending on the method used (Scheme 5). 6RKAT USA, Inc. Ben Hassine et al. 7 expanded the original synthesis published by Caronna for the unsubstituted 3-aza [6]helicene 7. The synthesis involves two Mizoroki-Heck coupling reactions, each followed by a photocyclization step, with an overall yield of 26% for compound 7 (Scheme 6).The final photocyclization step is not completely regioselective, a small amount of isomeric 1-aza [6]helicene 8 being isolated.In order to continue their series of azoniahelicenes, Sato and Arai 8 employed a double photocyclization of disubstituted ethylenes in the synthesis of hexa-and heptacyclic thiaazoniahelicenes 9 and 10.For both compounds, the first part of the synthesis involves obtaining the thiaazonia tetracyclic moiety and condensing it with benzaldehyde for helicene 9 or 2-naphthaldehyde for 10 (Scheme 7).Special attention should be given to the very versatile synthetic method developed by Castle and co-workers 9 , based on the condensation and subsequent photochemical cyclization of 2carboxoyl chloride-3-chloro 3,4-annulated thiopenes with aromatic amines.
ARKAT USA, Inc.By applying the photochemical approach on disubstituted D-camphor substituted benzodithiophene and thienoquinoline ethylenes, Osuga and co-workers 11 obtained optically pure (M) and (P) thiaazahelicenes 13.The disubstituted ethylenes were prepared via a Wittig condensation.The photochemical stage resulted in 37:63 diastereomeric ratio, and the products were separated using column chromatography on silica gel (Scheme 10).Their enantiomeric purity was measured using HPLC chromatography and their absolute configuration using circular dichroism.Harrowven and coworkers 12 developed a versatile synthetic method based on a Bu3SnH mediated coupling and selective homolysis of the carbon-iodine bond by 1,1'azobis(cyclohexanecarbonitrile) (VAZO).This method was successfully applied in the high yield synthesis of 6-chloro-5-aza [5]helicene 15, using cooperative ortho effects to control the regioselectivity of the Wittig reaction and a halide atom as a protecting group in the homolytic aromatic substitution (Scheme 12).Nakano et al. 13 used Pd complexes with xantphos and biphenyl-phosphine to catalyze coupling reactions on a variety of 2,2'-disubstituted 1,1'-diphenanthrenes.This synthesis could be applied only for obtaining the racemic aza [7]helicene 16 from the reaction of aniline with racemic 4,4'-biphenanthryl-3,3'-ylene ditriflate (Scheme 13).Later, a group led by Warabi 15 isolated and characterized new such compounds from the same marine source, thus expanding the class of dictyodendrins from A to E (Scheme 14).It is noteworthy that these compounds exhibit complete telomerase inhibitory action even at concentrations as low as 50 μg/L, making them suitable carcinostatics.Furstner and coworkers described the total synthesis of dictyodendrin B 18 16 and, in another paper, the total synthesis of dictyodendrins C and E. 17 The synthesis of dictyodendrin B consists of 13 steps, affording the target compound in an 8% overall yield.

OTf
The key steps are the titanium catalyzed synthesis of the 2,3,7-trisubstituted indole ring and the photochemical cyclization and concomitant aromatization using Pd/C in nitrobenzene leading to the substituted pyrrolo[2,3-c]carbazole scaffold in multigram quantities.For compound 18, the final procedure, the exhaustive demethylation without removing the labile sulfate group was performed using BCl3/(n-Bu)4NI.Obtaining dictyodendrins C and E involves the same synthesis of the pyrrolo[2,3-c]carbazole system, followed by very selective chemical transformations to yield the desired substituents (Scheme 15).Alvarez et al. 18 recently put forward a similar synthesis for obtaining substituted pyrrolo[2,3-c]carbazole derivatives to that described by Furstner.The synthetic pathway is based on a Suzuki coupling leading either to 2-ethenyl-3-pyrrolo indole derivatives or to indole and pyrrole substituted ethylenes.The final photocyclization stage results in pyrrolo[2,3-c]carbazoles 19 in the case of pyrrole-substituted indoles or in isomeric 20 and 21 in the case of (E) pyrrole and indole substituted ethylene and (Z)-isomer, respectively (Scheme 16).Benin and coworkers 21 obtained the tricyclic helical 1,10-diheterosubstituted benzo[c]cinnoline 23 using a sequence of minimum 5 reactions, while also investigating alternate synthetic routes.The key intermediate, 2-amino-2',6-dinitro-6'-propylthiobiphenyl, was obtained via an Ullmann coupling followed by a selective reduction of one nitro group.The helical benzo[c]cinnoline 23 was obtained by reducing the two nitro groups with Raney Ni and cleaving the amino protecting group (Scheme 18).The helicity of this compound was evidenced using X-ray analysis.While investigating various synthetic methods for N,N'-dioxides, Rajca 22 obtained the conjoined double azahelicene 24.This chemical transformation was conducted in good yields via three homocouplings (a C-C and two N-N) between two molecules of diamine 25 in the presence of a twofold excess of benzoyl peroxide (Scheme 19).The stereostructure of compound 24 was determined using X-ray diffraction.recently applied a [2+2+2] cobalt catalyzed trimerization strategy for obtaining 1,14-diaza [5]helicene and 1-and 2-aza [6]helicene.
The key precursors for the [2+2+2] cyclotrimerization, aromatic triynes 26 were obtained from the corresponding bromopyridines upon treatment with lithiated 1-(triisopropylsilyl)-1-propyne and subsequent Sonogashira coupling.The [CpCo(CO)2] catalyzed trimerization resulted in the formation of tetrahydro derivatives, which were aromatized to 27 and 28 in the presence of MnO2 (Scheme 20).The fully aromatic 1-and 2-aza [6]helicenes enantiomers were separated using HPLC with chiral stationary phases and their absolute configurations were investigated using CD spectroscopy.Their helicity degree was ascertained by X-ray analysis of the corresponding Ag complexes.Recently, the authors used this approach to obtain a number of new penta and hexacyclic azahelicenes. 24RKAT USA, Inc. Compounds 33, 34, 35 and 36 were obtained while investigating the reaction between 6,8dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones and cyclooctylamine or cycloheptylamine, respectively, in the presence of AgPy2MnO4 as oxidant (Scheme 24). 28,29lthough no data on the helicity of these compounds was presented, comparison with other literature examples suggests a possible helical distortion.

Scheme 24
Rozen and Dayan 30 obtained N,N'-phenanthrolinium dioxide 37 for the first time by treating 1,10-phenanthroline with fluorine in aqueous acetonitrile, the unstable compound HOF .CH3CN being the active oxygen donor (Scheme 25).The synthesis of this dioxide using other oxidizing reagents was unsuccessful.The torsion angle between the nitrogen atoms in the bay region, as measured by X-ray diffraction techniques, has a very high value of over 30 degrees.

The reactions of acetylenic esters with tricyclic azines.
A very convenient method for obtaining pentacyclic dipyrrolo compounds consists in treating phenanthroline derivatives with symmetrical acetylenic esters in methanol.The reaction yields the target dipyrrolo pentahelicenes in moderate yields. 44Recently, Maghsoodlou et al. 45  When applying the same reaction to 2,9-dimethyl- [1,10]phenanthroline, formation of the unexpected cyclobuta [4,5]pyrrolo[1,2-a][1,10]phenanthroline system 45 was observed instead of the normal dipyrrolo derivative (Scheme 29).The helical nature of this compound was ascertained using X-ray analysis. 46 Scheme 29 2.2.4 Helical molecules built from p-substituted benzene.While attempting to synthesize linear diazonia pentacene derivatives as DNA intercalators, Ihmels et al. 47 obtained the helical pentaphene derivatives 46 and 47.The formation of these unexpected compounds through a Nquaternization and a twofold acid-catalyzed cyclodehydration could be explained by a Wagner-Meerwein migration of a methyl group (Scheme 30).Although these compounds contain only three ortho condensed rings substituted with a single methyl group, they were found to possess helical distortion in solid state.Using the same reaction sequence on 1,7-bis(bromomethyl)naphthalene, the helical diazonia compound 48 was obtained as the major product, along with its planar isomer, 49 (Scheme 31).It is interesting to note that compared to the synthesis of derivatives 46 and 47, the absence of one or more methyl groups on the naphthalene ring system leads to a decrease in regioselectivity of the cyclodehydration reaction.Tanaka and coworkers 49,50 developed a very simple approach for obtaining 13,14dialkyldibenzo[b,j][4,7]-phenanthrolines 50 starting from the readily available materials N,N'diphenyl-p-phenylenediamine and n-alkyl carboxylic acids.The double condensation reaction is completely regioselective and takes place in the presence of ZnCl2 as the Lewis acid under heating or, more efficiently, microwave irradiation.The selectivity of this reaction was explained by semi-empirical molecular computations.Compounds 50 were subjected to chiral HPLC separation and racemization studies.It was shown that the methyl derivative racemized relatively quickly at room temperature, while the ethyl derivative was more stable.Furthermore, the dihydro derivatives 51 obtained by treating the fully aromatic compounds 50 with LiAlH4 were more stable towards racemization (Scheme 32).The helical chirality of these compounds was determined by X-ray analysis and their absolute configuration by circular dichroism (CD) experiments.

Scheme 33
In order to obtain 5,10-diaza [5]helicene 53, terephthalic aldehyde was reacted with aniline in a 1:2 ratio, and the resulting diimine was subjected to photocyclization in the presence of sulfuric acid.The photocyclization step was not fully regioselective, since isomer 55 was obtained along with helicene 53 (Scheme 34). 51

Scheme 36
In their search for novel cationic dyes, Laursen and coworkers 53,54 obtained a number of helical dimethoxyquinacridinium derivatives.The synthetic pathway implies the reaction of stable carbocation 60 with aliphatic amines in the presence of N-methylpyrrolidone.In order to separate their enantiomeric counterparts, dimethoxyquinacridiniums 61 were treated with either acetonitrile and sodium hydride, or with (+)-(R)-methyl-p-tolylsulfoxide.The resulting diastereoisomers were separated by column chromatography.Upon treatment with HPF6 in acetone, the dimethoxyquinacridinium derivatives 61 were regenerated (Scheme 37).These compounds were studied extensively by circular dichroism and X-ray diffraction methods, showing a significant degree of helicity.[57] MeO OMe  58 The approach consists of a simple three step procedure, starting from 3,6diacetylated carbazole derivatives.These were transformed into their corresponding enolates upon treatment with triisopropylsilyl triflate (TIPSOTf).The enolates were reacted with 1,4benzoquinone, resulting in the target compounds 62, together with considerable amounts of isomeric 63 and traces of 64 (Scheme 38).Separation of 62 and 63 takes place readily, since the target helicenes are not soluble in pentanes, while their isomers are.The absolute configuration of derivatives 62 was ascertained by treatment with S)-(-)camphanoyl chloride, followed by chromatographic separation of the corresponding diastereoisomers and subsequent CD spectroscopy.2.2.7 Synthesis of expanded helicenes.By using a series of condensation reactions, Bell and Jousselin 60 obtained the expanded azahelicenes 65 and 66 in six and seven consecutive steps, respectively (Scheme 39).Purification of these compounds revealed that both expanded azahelicenes form 1:1 complexes with Na + ions.H-NMR studies indicated that although both the free compounds and their corresponding sodium complexes are prone to relatively fast racemization, the inclusion of the Na + ion in the molecular coil stabilizes the helical conformation to a small degree.

Properties
The helical nature of the above mentioned molecules was ascertained usually in solid state by Xray single crystal analysis.However, there are also a few examples of NMR studies on the helicity of such compounds. 37,43,60o our knowledge, no fully enantiomerically selective synthesis was reported to date, even though some synthetic methods offer a moderate enantiomeric excess. 11Enantiomeric separation was performed using either chiral column chromatography or a chiral complexation agent (for example TAPA), followed by standard chromatographic separation.
The racemization times and absolute configurations were determined using CD spectroscopy.][57] A comprehensive study of the circular dichroism properties of monoaza [5]helicenes was conducted by Caronna et al. 61,62 It was observed that although the studied compounds showed similar features to the parent [5]helicene, all of them had shorter racemization time and showed distinct features due to the presence of the nitrogen atom.
Ihmels and coworkers 63 showed that diazonia derivatives 46, 47 and 48 have a high binding selectivity for triple-helical DNA, most probably due to their double charge and helical molecular shape.To the best of our knowledge, such compounds are the only known examples of polycyclic aromatics acting as DNA intercalators without a functionalized side-chain attached to the ring system.
The proton affinities of 1-and 2-aza [6]helicene were measured using MS techniques and calculated using density functional molecular computations.The energies observed were comparable to those of classical "proton sponges", recommending the tested compounds as chiral superbases. 64yrrolophenanthrolines 38 were tested for thin film conductivity with good results, suggesting a possible use for nitrogen bearing helical aromatics in the field of optoelectronics. 65

Scheme 10 2.1.2 Sn and Pd mediated couplings. As
6he photochemical cyclization method could not be used for the synthesis of 2-aza[5]helicene 14, the only product formed being 7azabenzo[ghi]perylene 3, a different approach was used, a t-Bu3SnH mediated coupling (Scheme 11).6

2.2.5 Helical molecules built from 1,2,3-trisubstituted benzene.
52e reaction between 1bromo-2,6-di(carbomethoxy)-4-t-butyl benzene with diphenyl, 1-naphthylphenyl or 1,1'dinaphthyl amines in the presence of Cu resulted in triarylamines 56.Upon hydrolysis followed by treatment with oxalyl chloride and subsequent Friedel-Crafts acylation/cyclization in the presence of SnCl4, compounds 57, 58 and 59 were obtained in good yields (Scheme 36).The use of other Lewis acids such as FeCl3 for the acylation step led to a decrease in the regioselectivity of the cyclization.The helical distortion in compounds 57, 58 and 59, as determined by X-ray diffraction methods, increases progressively from 43 to 60 degrees.52