Cyclic Alkyne Approach to Heteroatom-Containing Polycyclic Aromatic Hydrocarbon Scaffolds

Abstract

We report a modular synthetic strategy for accessing heteroatom-containing polycyclic aromatic hydrocarbons (PAHs). Our approach relies on the controlled generation of transient heterocyclic alkynes and arynes. The strained intermediates undergo in situ trapping with readily accessible oxadiazinones. Four sequential pericyclic reactions occur, namely two Diels–Alder / retro-Diels–Alder sequences, which can be performed in a stepwise or one-pot fashion to assemble four new carbon–carbon (C–C) bonds. These studies underscore how the use of heterocyclic strained intermediates can be harnessed for the preparation of new organic materials.

Entry for the Table of Contents

We report a strained alkyne approach to access heteroatom- rich polycyclic aromatic hydrocarbons. This versatile synthetic platform allows for mild access to non-symmetric tricyclic cores through a sequential or one-pot reaction between two different strained alkynes and an oxidiazinone. In addition, we describe a rapid synthesis of a small molecule and polymeric donor–acceptor fluorophore.

Alkynes contained in small rings were once considered only intellectual curiosities. However, in recent years, strained cyclic alkynes have resurfaced and have been widely employed in synthetic methodology studies.^1,2,3,4 Additionally, such efforts have led to a greater understanding of aryne and cyclic alkyne reactivity and regioselectivities,^5,6,7 and a host of synthetic applications impacting catalysis,⁸ agrochemistry,⁹ pharmaceuticals, and academia.^10,11 A selection of important arynes and cyclic alkynes are shown in Figure 1.^{12,13,14,15,16,17,18,19}

Figure 1.

Arynes, cyclic alkynes, and heterocyclic variants, and 9,10-diphenylanthracene (1) and aza-derivatives 2–6.

One exciting application of arynes and cyclic alkynes lies in materials chemistry. Arynes have been employed in the synthesis of polymers and polycyclic aromatic hydrocarbons (PAHs),2,^20,21,22,23 with the latter having a remarkable impact on the materials science field.^24,25 PAHs have been used in widely-used devices, such as organic light-emitting diodes (OLEDs), field effect transistors (OFETs), and photovoltaics (OPVs).²⁶ An important subset of PAHs are 9,10-diphenylanthracene derivatives. The parent compound, 9,10-diphenylanthracene (1, Figure 1), has been widely studied since 1904²⁷ and has been used in blue glow sticks²⁸ and OLEDs.²⁹ Novel derivatives of 1 have been highly sought.³⁰ One promising ‘analoging’ approach is to prepare variants of 1 that bear heteroatoms in order to modulate the properties and potential applications of PAHs.^31,32,33 Heteroatoms may be included in the anthracene ring itself or on the C9/C10 substituents, as exemplified by 2^34,35,36,37 and 3,³⁸ respectively (Figure 1), which can impact material properties.³⁸ Compounds possessing heteroatoms on both the anthracene ring and C9/C10 substituents, such as 4, have also been prepared in the context of OLEDs.³⁹ Lastly, more exotic analogs of 1 and 2 are known where the C9/C10 substituents are replaced with heterocycles or substituted aromatics, as demonstrated by 5^34,37 and 6.⁴⁰ The majority of heteroatom-containing derivatives of 1 have been disclosed in the patent literature over the past 6 years and reflect a rapidly growing area of discovery.^41,42

Synthetic methods to rapidly generate novel heterocyclic PAHs remain limited. For example, the assembly of non-symmetric PAHs that possess multiple functional groups usually requires long linear sequences.³³ Additionally, approaches to arrive at het-anthracene cores typically necessitate harsh reaction conditions (e.g., high temperatures and strongly acidic or basic conditions).^33,13 Lastly, variation at C9 and C10 is primarily achieved via the use of strongly basic organometallic reagents or transition metal catalysis, and typically results in symmetric molecules or low yields.^31,43

We targeted the synthesis of scaffold 7 through an ambitious approach, whereby ring fragments A–D could be united with formation of the central benzene ring (Figure 2a). This would enable access to a range of heterocyclic PAH scaffolds, with the possibility of accessing four quadrants of differentiation. In practice, we questioned if highly reactive arynes and cyclic alkynes (i.e., 8 and 10) could be used as building blocks A and B (Figure 2b). Heterocyclic strained intermediates (e.g. 8) would be used strategically to access the desired heteroatom-containing PAHs.⁴⁴ With regard to building blocks C and D, oxadiazinone 9 was identified as a versatile core scaffold. Oxadiazinones (diazapyrones) are easily prepared from simple precursors⁴⁵ and are known to readily undergo one or more Diels–Alder (DA) cycloaddition / retro-Diels–Alder (rDA) cycloaddition reactions (with sequential expulsion of N₂ and CO₂).⁴⁶ The success of this approach would hinge on uncovering a means to allow for the controlled generation and trapping of fragments 8 and 10 to ultimately deliver products 7 through the cascade of events suggested in Figure 2b. Key precedent stems from pioneering studies by Steglich in 1977,⁴⁷ which demonstrated the double addition of benzyne into oxadiazinones, in addition to the syntheses of conjugated materials by Nuckolls⁴⁸ and Wudl.⁴⁹ However, a notable limitation in all cases is the inability to introduce two different strained alkynes, instead delivering symmetric products with respect to building blocks A and B.⁵⁰

Figure 2.

Strategy to access 7.

We report the development of the synthetic sequence shown in Figure 2b, which provides a modular and rapid means to synthesize a diverse range of heteroatom-containing PAHs. The trapping of in situ-generated strained intermediates with oxadiazinones, demonstrated in both stepwise and one-pot fashions, furnishes the desired structural frameworks. Small molecule fluorophores can be accessed from this strategy. These studies demonstrate that heterocyclic strained intermediates can be leveraged for the preparation of new organic materials.

With the ultimate goal of synthesizing heterocyclic PAHs bearing four quadrants of differentiation, we first developed a stepwise variant (Figure 3). As mentioned above, arynes are known to undergo oxadiazinone trapping, but the intermediate benzopyrone directly undergoes trapping with a second equivalent of the aryne, precluding the opportunity to introduce two different strained alkyne fragments. When using benzyne in our initial studies, only double addition to form 1 was observed. We hypothesized that the intermediate benzopyrone was more reactive than the oxadiazinone, preventing isolation or second addition of a different aryne. We questioned if a cyclic alkyne could be used to isolate the corresponding pyrone intermediate based on prior studies by Sauer and co-workers using cyclooctyne.⁵¹ Thus, we used a heterocyclic alkyne derived from commercially available silyl triflate 11 (prepared in 3 steps from 4-methoxypyridine).¹³ Two key results (Figure 3) illustrate the ability to modulate the product distribution through alteration of the reaction stoichiometry. When silyl triflate 11 was employed in excess, the major products were adducts 14, consistent with the results previously seen in aryne/oxadiazinone reactions.^46,47,48 However, when a 1 : 2 ratio of 11 and 12 was utilized, the desired pyrones 13, arising from a single DA / rDA reaction, were isolated in 74% yield under optimized conditions, without formation of double addition products 14. Of note, pyrone 13 is produced as a mixture of regioisomers 13a and 13b. It was found that treatment of excess CsF under oxidative conditions selectively decomposed 13b leaving 13a untouched. Several points should be noted: a) our results provide the first example of a DA cycloaddition featuring an oxadiazinone and a strained intermediate derived from a Kobayashi silyl triflate precursor,⁵² b) the reactions occur under exceptionally mild reaction conditions, c) the desired reaction produces mixtures of pyrone isomers 13a and 13b, which may generally be viewed as both a strength and limitation (additional analogs, yet not selective), and d) isomer 13a, the key lynchpin to the success of our synthetic strategy, was ultimately accessible as a single isomer (33% yield from 11, see SI for details) and employed in subsequent experiments.

Figure 3.

Optimization to form pyrones 13. Cbz=benzylcarbamate, OTf=trifluoromethanesulfonate.

After establishing a suitable method to access pyrone 13a, we turned our attention toward introducing and modulating the B ring. Pyrone 13a readily undergoes a DA / rDA reaction sequence, with loss of CO₂, in the presence of arynes or non-aromatic cyclic alkynes (generated from silyl triflate precursors 15) at ambient temperature (Figure 4). In each case, the transformation proceeds with formation of two new C–C bonds and delivers non-symmetric heterocyclic PAH skeletons 16. Benzyne (17),⁵² 1,2-naphthalyne (19)⁵³ and 4,5-indolyne (21),¹⁸ performed well, giving rise to products 18, 20 and 22 in good yields (entries 1–3). Cyclic alkynes, which offer greater sp³-character and improved solubility of eventual products were also tested. Cyclohexyne (23), and heterocyclic strained cyclic alkynes 25¹³ and 26¹⁶ performed smoothly (entries 4–6).⁵⁴ With regard to regioselectivities (entries 2, 5, and 6), the major product likely arises from initial bond formation occurring between the more electron-rich carbon adjacent to the carbonyl group of the pyrone⁵⁵ and the more distorted carbon of the strained intermediate in a concerted asynchronous fashion.6^,13,16

Figure 4.

The second DA / rDA reaction using pyrone intermediate 13a. Conditions unless otherwise stated: CsF (5.0 equiv), CH₃CN (0.1 M), 14 h. For entries 2, 3, 5, and 6, the mixtures of regioisomers were not separable by column chromatography. Cbz=benzylcarbamate, OTf=trifluoromethanesulfonate.

We also sought to access products bearing differing C and D rings. As noted earlier, in most routes to 9,10-anthracene derivatives, the C and D rings are introduced through a double cross-coupling or by the double addition of an organometallic reagent, allowing for the formation of only symmetric products with limited functional group compatibility.^33,31 A series of differentially-substituted oxadiazinones were prepared using established chemistry⁴⁵ and subjected to silyl triflate 11 under our standard reaction conditions (Figure 5). The desired sequence took place to deliver pyrone isomers 28–31 in yields ranging from 66 to 84%. In all cases, it was possible to separate the depicted pyrone isomer (42 to 72% recovery of the single isomer from the mixture of isomers), which was then subjected to benzyne precursor 32 under our standard conditions. The desired products 33–36 were obtained in good to excellent yields. The D ring was varied to include different para substituents (33–35), such as a bromide (35) for use in cross-coupling. Also, a thiophene was incorporated to give 36, which is notable given the prevalence of thiophenes in organic electronics.³¹

Figure 5.

Variation of oxadiazinone. ^a Yield of the pyrone intermediates 28–31 (a and b isomers). Conditions for piperidyne cycloaddition: oxadiazinone 9 (2.0 equiv), silyl triflate 11 (1.0 equiv), CsF (2.0 equiv), CH₃CN (0.1 M), 14–18 h. ^b Recovery of pyrones 28a–31a from the mixtures of a and b isomers. See SI for details. ^c Yield of products 33–36. Conditions for benzyne cycloaddition: pyrone 28a–31a (1.0 equiv), silyl triflate 32 (2.0 equiv), CsF (5.0 equiv), CH₃CN (0.1 M), 18 h. Cbz=benzylcarbamate, OTf=trifluoromethanesulfonate.

A 3-component coupling of two different silyl triflates, 11 and 32, and oxadiazinone 12 was performed (Figure 6). Operationally, CsF was added to an equimolar solution of the three reactants, 18 was obtained in 56% yield along with pyrone intermediate 13 accounting for the remaining mass balance. Notably, the products of double piperidyne or benzyne addition were not observed, suggesting high selectivity for the controlled formation and reaction of the two strained intermediates. We posit that silyl triflate 11 more readily undergoes fluoride-mediated elimination to form the corresponding alkyne compared to benzyne precursor 32 as a result of the lower strain energy associated with 3,4-piperidyne compared to benzyne.⁵⁶ The transformation proceeds by way of 4 consecutive pericyclic reactions to create 4 new C–C bonds and deliver a heterocyclic PAH scaffold in one-pot.

Figure 6.

Three-component coupling of 11, 12, and 32. Conditions: silyl triflate 11 (1.0 equiv), oxadiazinone 12 (1.0 equiv), silyl triflate 32 (1.0 equiv), CsF (3.0 equiv), CH₃CN (0.1 M), 14 h. Cbz=benzylcarbamate, OTf=trifluoromethanesulfonate.

We pursued several synthetic applications with a focus on incorporating motifs commonly utilized in materials chemistry. As shown in Figure 7, we targeted a heterocyclic PAH scaffold reminiscent of 1. Oxadiazinone 37 was treated with silyl triflate 11 and CsF to furnish pyrone 38. Reaction with silyl triflate 39 afforded the corresponding product of the DA / rDA sequence. Silyl protection of the indole nitrogen provided separable isomers 40a and 40b. Removal of the Cbz-protecting group of 40a, followed by MnO₂-mediated oxidation gave 41a, which bears three heterocycles and a p-OMe-Ph motif. 41a exhibits pH-responsive fluorescence switching properties. Neutral 41a displays a blue fluorescence emission, whereas the protonated version, 42a, displays an orange fluorescence emission. Stimuli responsive materials are important for a host of materials-related applications such as pH fluorescence sensors^57,58 and solid-state fluorescent switches.⁵⁹

Figure 7.

Strategic synthesis of 40 and elaboration to pH-responsive fluorophore 41a. 40a and 41b are obtained as a 1:1 mixture of regioisomers. Cbz=benzylcarbamate, OTf=trifluoromethanesulfonate, TIPS=triisopropylsilyl.

We also carried out the one-pot, 3-component coupling of silyl triflates 11 and 32 with dichlorooxadiazinone 43 (Figure 8a). This transformation led to the controlled formation of dichloride 44 in 58% yield. 44 then underwent Pd-catalyzed borylation to give (bis)boronic ester 45. Subsequent coupling with 46 afforded donor–acceptor fluorophore 47, which was found to be solvatochromic,⁶⁰ indicative of a donor–acceptor system (Figure 8b).

Figure 8.

a. Three-component reaction toward 47 and 49. b. Solvatochromism of fluorophore 47. c. UV/Vis and fluorescence spectra in THF with oligomer 49 displaying red-shifted absorbance (black solid line) and emission (black dashed line) relative to 47 (gray solid and dashed lines). Cbz=benzylcarbamate, OTf=trifluoromethanesulfonate, pin=pinacol ester.

Bis(boronate) 45 could be employed as a building block for polymer synthesis (Figure 8a). Suzuki–Miyaura polymerization⁶¹ between diboronic ester 45 and 4,7-dibromobenzothiadiazole (48) provided donor–acceptor oligomer 49, which was found to have a polydispersity index (PDI) of 1.3 and a number average molecular weight (M_n) of 1.7 kDa. The donor–acceptor oligomer 49 displays a red-shifted absorbance and emission relative to 47 with a longest-wavelength absorption maximum of λ = 391 nm and an emission maximum of λ = 491 nm (Figure 8c). The chromatographic shifts can be attributed to the extended conjugation present in oligomer 49 compared to 47. These results demonstrate how a common adduct obtained from our methodology (i.e. 44) can be used to rapidly access donor–acceptor monomers and oligomers displaying differing photophysical properties.

We have discovered a modular synthetic platform that leverages strained cyclic alkynes and arynes to access new heteroatom-containing PAH scaffolds. Two strained intermediates are united with an oxadiazinone to rapidly construct 4 new C–C bonds. An array of heterocyclic PAH frameworks reminiscent of 1 can be accessed. These studies demonstrate that heterocyclic strained intermediates can be strategically harnessed for the preparation of new organic compounds with materials-related properties.