Continuous Photoflow Synthesis of Heterohelicenes

Abstract

Heterohelicenes continue to attract interest for their potential applications as organic chiral materials. To keep up with the demand for novel heterohelicene structures, expedient and scaleable synthetic procedures are required. We report a “Mallory” photocyclization methodology in continuous flow for the synthesis of thia-, oxa-, and azahelicenes. This procedure has been successfully scaled up to 9.8 mmol and can be applied to an iterative modular synthesis.

Helicenes are polyaromatic compounds, composed of ortho-fused aromatic rings, that are known for their unusual, screw-like chiral structure. This combination of helical chirality and polyaromatic structure results in both highly dissymmetric interaction with circularly polarized (CP) light and high charge transport. − Thus, helicenes have found applications as semiconductors in OFETs or for the emission or detection of CP light. , Perhaps the most intriguing application is the potential use of helicenes as spin-filters. Helicene enantiomers may be able to achieve spin-selective electron transport, − also known as the chiral induced spin selectivity (CISS) effect, opening up the potential for helicenes to be used in a variety of “spintronics” devices. ,

A common feature in many helicene designs is the inclusion of a heteroatom into the helical backbone. This is often highlighted by studies as being crucial in influencing the physical and optoelectronic properties of a helicene. − However, relatively few studies have been dedicated to investigating synthetic strategies toward these heterohelicenes. Existing examples include photochemical methodologies as applied to the synthesis of azahelicenes by the Caronna group , and a variety of thiahelicenes synthesized by the Wynberg group. − Mallory photocyclizations are one of the most common strategies to access heterohelicenes, but nonphotochemical methodologies such as [2+2+2] cycloisomerizations − are also often employed.

Photoflow methodologies are an often overlooked synthetic strategy for accessing heterohelicenes. Photoflow chemistry has practical advantages over batch chemistry, including straightforward scalability, shorter reaction times, and a safer reaction setup, which are desirable traits for industrial synthesis. , A handful of examples of helicenes and heterohelicenes synthesized in flow have been reported, but very few of these studies have explored the preparation of heterohelicenes by photocyclization. −

In this work, we report the Mallory photocyclization of a series of heterohelicenes using a photochemical flow reactor. Most substrates were synthesized with a 100 s residence time (corresponding to a 6 mL/min flow rate when using a 10 mL tubing coil), enabling throughputs of up to 195 mg of stilbene precursor/h. A further elaboration of the products to longer helicenes afforded nonsymmetric [6]­di­(thieno)­helicene 4b in 53% yield over three steps from stilbene 1b (Figure ).

1.

(A and B) Previous syntheses of heterohelicenes by Mallory photocyclization. (C) This work: photoflow synthesis of heterohelicenes. ^aFrom ref . ^bFrom ref .

The preparation of the heterostilbenes was achieved via a Wittig reaction between literature-known Wittig salts , and commercially available heteroaromatic aldehydes (Table S1). The resulting products are E/Z mixtures of stilbenes, but due to rapid photoisomerization, both isomers can be used in the cyclization. We used a Vapourtec UV-150 photochemical reactor and a 150 W (365 nm) UV lamp, a lab-scale setup that provides yields comparable to those of commercial pilot-scale systems while slightly underperforming commercial or 3D-printed lab-scale systems for photon-intensive applications. , Optimization of the cyclization of heterostilbene 1a (Table S2) to [4]­thienohelicene 2a was achieved in 94% yield (conditions A, Table ). The Mallory reaction proceeds through an initial 6π photocyclization step, after which an oxidant such as iodine or oxygen is required to complete the reaction via rearomatization.

1. Scope of the Mallory Photocyclization under Conditions A (stoichiometric iodine).

^aFrom ref .

^bWith a 60 W lamp at 40 °C. When using a 150 W lamp at 55 °C and a 2 mL/min flow rate, the yield was 48%.

^cAt a concentration of 0.5 mM.

^dWith a 60 W lamp in a 1:1 toluene:acetonitrile mixture at 40 °C.

^eFrom ref .

To illustrate the scope, we targeted heterohelicenes that were previously unknown or for which no Mallory reaction had been reported (cf. gray text in Table ). 2-Chloro-substituted [4]­thienohelicene 2b was obtained in 77% yield on a 0.2 mmol scale and was scaled up to a multigram scale (9.8 mmol) to afford 2b in 79% yield (see the Supporting Information (SI)). Furan-based helicenes 2c and 2d were obtained in lower yields of 74% and 57% respectively, compared to the corresponding [4]­thienohelicenes 2a and 2b. A less powerful 60 W lamp was found to be more optimal for the synthesis of 2d; the use of a 150 W lamp resulted in a lower yield of 48%. [6]­Thienohelicene 2e and [5]­thienohelicene 2f were obtained in 71% and 56% yields, respectively. A longer [7]­thienohelicene 2g was synthesized in a single step in 73% yield through a double-Mallory reaction, though the reaction mixture was diluted to 0.5 mM to accommodate the low solubility of heterostilbene precursor 1g in toluene. The mild conditions of the Mallory reaction provide an alternative synthesis of 2g, which was previously made via a thermal Newman–Kwart rearrangement. For quinolinyl substrate 2h, we found that the use of the 150 W lamp resulted in very low yields, but upon switching to a 60 W lamp, our yield of product 2h improved to 44%. 2h was previously prepared in batch by Caronna and co-workers with a yield of 82% over 36 h. We propose that a weaker lamp may reduce the conversion of desired product 2h into doubly cyclized perylene-like structure S2h′, which has been reported to be a typical side product of [5]­helicene synthesis via a Mallory photocyclization. Additionally, due to solubility issues of product 2h in toluene, we used a reaction mixture of equal parts toluene and acetonitrile.

For some substrates, the best conditions used catalytic quantities of iodine (0.1 equiv) and an increased volume of THF (10 vol %) (conditions B, Table ). These conditions are likely to reduce the level of formation of the highly acidic hydrogen iodide side product, which may protonate N-heterocyclic products and cause the formation of a dark blue-black precipitate. , Under these conditions, the cyclization of thiazole-containing stilbene 1i led to a combined 61% yield of ring-closure products. However, desired [4]­thiazolohelicene 2i was obtained in only 35% yield, comparable to that of a similar thiazole-based helicene. The remaining mass balance of ring-closure products was side product S2i′ (see the SI), obtained in 26% yield after the ring opening of product 2i. No comparable ring opening was observed for [5]­oxazolohelicene 2k, which was synthesized in 40% yield. Chloro-substituted pyridohelicenes 2m and 2m′ were afforded in a 7:3 ratio (51% and 19% yields, respectively) in favor of more sterically hindered product 2m, which is the expected regioselectivity for Mallory cyclizations involving pyridine rings and has been explained through molecular orbital calculations. Similarly, [5]­thiadiazolohelicene 2n was obtained in 54% yield alongside 17% of linear side product 2n′, improving on the literature precedent where the ratio of the desired helicene to the linear product was 1:1. The synthesis of chloro-substituted pyrido[4]­helicene 2o was achieved in 78% yield. This higher yield compared to that of 2m is likely due to the chlorine atom blocking the alternative cyclization location, removing the possibility of a regioisomer.

2. Scope of the Mallory Photocyclization under Conditions B (catalytic iodine).

^aYield of ring-opened side product S2i′. See the SI for structure and characterization. Reaction performed on a 0.8 mmol scale.

^bReaction performed on a 0.8 mmol scale.

^cWith 0.19 equiv of I₂, 59 equiv of THF, and 1 mM toluene at 65 °C and a flow rate of 3.3 mL/min. Reaction performed on a 0.4 mmol scale.

^dFrom ref .

The cyclization of benzothiophene stilbene 1p afforded [7]­thienohelicene 2p in 56% yield alongside S-shaped side product S2p′ (see the SI) in 18% yield (Scheme ). The double cyclization of carbazole-based 1q afforded dibromo [7]­pyrrolohelicene 2q in 50% yield on a 0.32 mmol scale. The reaction was scaled to 1.0 mmol to afford 2q in 50% yield.

1. Synthesis of [7]­Heterohelicenes 2p and 2q .

^a For the structure of side product S2p′, see the SI.

For the sake of synthetic simplicity, most stilbene substrates were synthesized from naphthyl phosphonium salt S5a and a mono- or bicyclic aldehyde, affording [4]- or [5]­helicenes, respectively. While simple to synthesize, such short helicenes enantiomerize at room temperature unless bulky substituents are included. Longer helicenes can avoid this process. The enantiomerization half-life of [6]­helicene is 8 orders of magnitude longer than that of [5]­helicene. Thus, for chiral materials applications, longer helicenes, which can be resolved into their P- and M-enantiomers, are desirable.

As the synthesis of polyaromatic Wittig salts such as S5b (see the SI) often involves multiple steps, we considered other approaches to elongate a heterohelicene. First, the use of a bicyclic aldehyde in the formation of the stilbene precursor, such as in the case of 1f, 1p, and 1h, adds an extra ring compared to the corresponding stilbene containing monocyclic heteroaromatics at the cost of a reduced yield from alternative cyclization pathways (e.g., S2p′ (see the SI)). Second, double-Mallory cyclizations, such as those affording 2g and 2q, can quickly assemble large structures from simple starting materials. While stilbene 1g displayed a very low solubility in toluene, a similar problem was avoided for 1q by using the solubilizing 2-(trimethylsilyl)­ethoxymethyl (SEM) protecting group.

Finally, we decided to investigate a modular stepwise synthesis of longer helicenes. We performed further functionalizations on chloro-substituted [4]­thienohelicene 2b via Heck or Suzuki reactions, creating longer heterostilbene substrates (Scheme ). Using conditions A (Table ), we were pleased to synthesize [6]­thienohelicenes 4a and 4b in 80% and 87% yields, respectively, some our highest yields so far for a heterohelicene substrate.

2. Synthesis of [6]­Thienohelicenes 4a and 4b in Two Steps from 2b (Table ).

We have developed a robust Mallory photocyclization methodology in flow that is suitable for a wide range of heterohelicenes, as demonstrated by the synthesis of previously unreported thiahelicenes, azahelicenes, and oxahelicenes. Aryl halides such as [4]­thienohelicene 2b are tolerated and can be used to elongate the helicenes to longer, nonsymmetrical structures through a three-step Mallory–cross-coupling–Mallory sequence. We envision this strategy to also be applicable to aza- and oxahelicenes. While traditional Mallory reactions in batch can be difficult to scale up, our continuous flow methodology enables facile multigram syntheses with throughputs of up to 195 mg/h.

The data underlying this study are available in the published article, in its Supporting Information, and openly available in nmrXiv at 10.57992/nmrxiv.p146.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.6c00559.

• Experimental procedures, photoflow reactor specifications, structures not pictured in the manuscript, characterization data, and NMR spectra (PDF)

Conceptualization: K.L., C.P., and J.R.B. Funding acquisition: J.R.B. Investigation: K.L., C.P., S.S., Y.W., and J.M. Methodology: K.L., C.P., Y.W., and J.R.B. Supervision: J.R.B. Writing of the original draft: K.L. and J.R.B. Review and editing: all authors.

The authors declare no competing financial interest.

A previous version of this manuscript was published as a preprint on ChemRxiv.