Hexadehydro Diels–Alder/Alkynyliodanation Cascade: A Highly Regioselective Entry to Polycyclic Aromatics

Abstract

We report here a cascade process integrating the hexadehydro Diels–Alder (HDDA) reaction with alkynyliodanation, enabling efficient synthesis of highly substituted aryl-λ³-iodanes. Heating a mixture of a tetrayne and an alkynylbenziodoxole induces regioselective insertion of the tetrayne-derived aryne into the alkynyl–iodine(III) bond, yielding a 1,4-dialkynyl-2-iodanyl-3-aryl(or alkyl)benzene derivative. The unique regiochemistry facilitates subsequent π-extension, allowing divergent access to polyaromatic frameworks, such as helicenes and cyclopenta[cd]pyrenes, underscoring the utility of aryne carboiodanation in complex aromatic synthesis.

The hexadehydro Diels–Alder (HDDA) reaction between 1,3-diynes and alkynes provides a powerful strategy for accessing highly substituted arynes, which, upon trapping with suitable reaction partners (arynophiles), facilitate the synthesis of densely substituted aromatic compounds.^1,2 The exceptional reactivity of tetraynes comprising tethered 1,3-diyne units in HDDA renders this methodology particularly appealing for constructing aromatic frameworks with extended π-conjugation. For instance, Hoye and co-workers demonstrated that HDDA-generated arynes can be efficiently intercepted by perylene, producing naphthoperylenes functionalized with an additional alkynyl substituent (Scheme 1a-1).³ Additionally, the same group designed a polyyne substrate that undergoes sequential HDDA reactions to produce a tetracyne intermediate, which subsequently engages in a decarbonylative [4 + 2] cycloaddition with cyclopentadienone, yielding a dibenzohexacene skeleton (Scheme 1a-2).⁴ While these transformations elegantly highlight the synthetic utility of HDDA, considerable opportunities remain to further exploit its potential for expanding the chemical space of polyaromatic compounds.⁵ In particular, there is a need for aryne-trapping reactions that not only extend π-conjugation but also introduce versatile functional handles for downstream π-extension.

Scheme 1. HDDA–Aryne Trapping Reactions for the Synthesis of Polycyclic Aromatic Hydrocarbons.

Recently, our group reported the distinctive reactivity of organo-λ³-iodanes as arynophiles, which emulate organometalloids in their interactions with the electrophilic triple bond of arynes.⁶ Specifically, benziodoxole (BX) compounds⁷ bearing alkynyl,⁸ electron-rich alkenyl,⁹ or electron-rich (hetero)aryl¹⁰ ligands undergo insertion of arynes generated through fluoride activation of ortho-silylaryl triflates,^2c,11 yielding ortho-functionalized aryl-BX derivatives (Scheme 1b). These carboiodanation reactions simultaneously introduce unsaturated organic substituent (R^π) and the BX group, the latter serving as a versatile nucleofugal leaving group for subsequent cross-coupling reactions. This dual functionality enables further installation of another π-substituent (R_π’), creating new opportunities to access doubly ortho-π-functionalized aromatic scaffolds. Inspired by the synthetic potential of arynophilic organobenziodoxoles and the unique structure of HDDA-derived polysubstituted arynes, we sought to explore their combination. Among various BX derivatives, we identified ethynylbenziodoxoles (EBXs) as particularly attractive due to the utility of alkynyl groups as versatile synthetic handles for π-extension in polycyclic aromatic systems.¹²

Herein, we describe a successful merger of HDDA and alkynyliodanation, culminating in the regioselective synthesis of fully substituted aryl-BX derivatives (Scheme 1c). Remarkably, the reaction proceeds with high, often exclusive, regioselectivity, predominantly affording 1,4-dialkynyl-2-iodanyl-3-aryl/alkyl benzene frameworks. This regioselectivity contrasts with predictions based on aryne distortion¹³ and the established role of EBXs as nucleophilic alkynyl donors in the carboiodanation reaction.^6a The well-defined substitution pattern of the products enables their application as key intermediates in target-oriented π-extension, as exemplified by the expedient construction of polyaromatic compounds such as helicenes and cyclopenta[cd]pyrenes.

The present study commenced with an investigation of the thermal reaction between malonate ester-tethered tetrayne 1a and phenyl-EBX 2a (Scheme 2). Upon simply heating an acetonitrile solution of 1a and 2a (2 equiv) at 100 °C for 18 h, the desired HDDA/alkynyliodanation cascade took place smoothly, furnishing the polysubstituted aryl-BX 3aa as a single regioisomer in 65% isolated yield (74% by ¹H NMR; see Table S1 for optimization data). The molecular structure 3aa, representing the selective installation of the nucleophilic alkynyl ligand of 2a onto the aryne carbon distal from the phenyl substituent,¹⁴ was unambiguously established by X-ray crystallographic analysis. Due to the significant steric crowding around the BX group, 3aa was found to exhibit carbon–iodine atropisomerism with a certain degree of stability.¹⁵ In the ¹⁹F NMR spectrum, a pair of quartet signals corresponding to the two CF₃ groups remained distinct and were far from coalescence even at 145 °C (see Figure S3). However, we were unable to identify suitable conditions for its optical resolution by HPLC on a chiral stationary phase at this time. The regiochemistry of subsequent HDDA/alkynyliodanation products was assigned by analogy to 3aa. This assignment was further validated through the structures of downstream transformation products (vide infra).

Scheme 2. HDDA/Alkynyliodanation Cascade: Scope of EBXs and Tetraynes.

The reaction was performed using 0.1 mmol of 1 and 0.2 mmol (2 equiv) of 2. The regioisomer ratio (determined by ¹H NMR) is shown in the parentheses.

With the successful reaction using 1a and 2a in hand, we explored the scope of the HDDA/alkynyliodanation cascade (Scheme 2). First, a variety of (hetero)aryl- and alkyl-substituted EBXs underwent the desired cascade reaction with 1a to afford the multisubstituted aryl-BXs 3ab–3ah in moderate to good yields with exclusive regioselectivity, except in the case of para-methoxyphenyl EBX, which generated a minor regioisomer (ratio = 9:1). Next, diethyl malonate-tethered tetraynes bearing a series of aryl and alkyl termini readily participated in the reaction with 2a, yielding the corresponding products 3ba–3ea with consistently high to perfect regioselectivity. Finally, the malonate tether of the tetrayne could be replaced with alternative linking groups such as 1,3-indandione, fluorene, simple methylene, and tosylamide moieties, as demonstrated by the formation of regiochemically pure products 3fa–3ia.

To gain insight into the origin of the regioselectivity of the alkynyliodanation of HDDA-derived arynes, we performed DFT calculations on the reaction of the trimethylene-tethered tetrayne 1h and Ph-EBX (2a) to afford 3ha as a model case (Figure 1). The aryne generated from 1h (INT) is slightly distorted, with the bond angle at the carbon proximal to the phenyl substituent (α, 129.0°) being marginally wider than the distal angle (β, 126.6°), suggesting a moderate intrinsic preference for nucleophilic attack at the proximal carbon. However, the reaction between INT and PhEBX was found to prefer the transition state of alkynylation at the distal carbon (TS1) over that at the proximal carbon (TS2), albeit with a modest free energy difference of 1.1 kcal mol^–1. This result is qualitatively in accordance with the observed regioselective formation of 3ha. In both TS1 and TS2, the aryne skeleton undergoes deformation to accommodate the incoming alkynyl group as the nucleophilic center. Thus, the original distortion mode of INT is reversed in TS1 (α = 123.1°; β = 130.3°) and amplified in TS2 (α = 132.2°; β = 119.8°). Both transition states feature a four-centered geometry of the reaction center, with a comparable degree of polarization of the aryne carbons. Thus, the aryne carbon accepting the alkynyl group is slightly positive (NPA charge 0.07–0.08), while the other carbon is slightly negative (NPA charge −0.13). Despite the reversed aryne distortion in TS1, the distortion energy (ΔE_dist) of the aryne segment in the alkynyliodanation TSs was lower for TS1 (1.1 kcal mol^–1) than for TS2 (2.8 kcal mol^–1; see Figure S4).¹⁶ The larger aryne distortion energy in TS2 may be attributed to the steric repulsion between the phenyl substituent and the incoming phenylethynyl group of Ph-EBX, which significantly increases the torsional angle between the aryne and phenyl planes (54.3° in TS2 vs 31.6° in INT and 32.9° in TS1).

Figure 1.

DFT-optimized structures of aryne generated via HDDA of 1h (INT) and transition states of alkynyliodanation with Ph-BEX (2a) leading to 3ha (TS1) and its regioisomer (TS2) (level: M06-2X/6-311++G(2df,2p)-SDD (for I)/SMD(MeCN)//M06-2X/6-31G(d)-SDD (for I)). The distances are shown in Å.

The fully substituted aryl-BX products obtained through the present cascade feature para-dialkynyl groups, aryl (or alkyl) groups, and iodanyl groups in a well-defined arrangement, rendering them valuable intermediates for the synthesis of polycyclic aromatic compounds (Scheme 3). To highlight this utility, preparative-scale (2 or 4 mmol) reactions of para-methoxyphenyl-capped tetraynes (1c and 1j) and para-methoxyphenyl-EBX (2f) were performed, successfully furnishing the desired products 3cf and 3jf, respectively, in good yields. Subsequent Suzuki–Miyaura coupling of 3cf or 3jf with 4-methoxyphenylboronic acid, 2-benzyloxyphenylboronic acid, and 4-phenanthrenylboronic acid afforded the corresponding 1,4-dialkynyl-2,3-diarylbenzene derivatives 4a–4c, respectively, in moderate yields. These products were further subjected to TFA-mediated electrophilic cyclization,¹⁷ furnishing symmetric [5]helicene 5a, unsymmetric [5]helicene 5b, and [7]helicene 5c. While symmetric 1,4-dialkynyl-2,3-diarylbenzene accessible through sequential double Sonogashira and Suzuki–Miyaura coupling reactions has previously been employed as a precursor for symmetric helicenes,^17,18 the present approach provides a versatile and flexible route to unsymmetrical helicenes.¹⁹ We are currently investigating alternative alkyne cyclization methods beyond the TFA-mediated protocol, aiming to expand the scope of substrate design. The reduction of the BX moiety of 3cf into monovalent iodine, followed by TFA-mediated cyclization of the left wing and subsequent Sonogashira coupling, afforded 3,4-dialkynylphenanthrene derivative 6. Cyclization of 6 under Pd/C-catalyzed, Me₃SiCl-mediated conditions²⁰ produced cyclopenta[cd]pyrene derivative 7 in good yield.²¹

Scheme 3. π-Extension of Polysubstituted Aryl-BXs for the Synthesis of Polycyclic Aromatic Compounds.

See the Supporting Information for the detailed reaction conditions.

In summary, we have established an efficient cascade process combining the HDDA reaction of tetrayne with alkynyliodanation of the resulting aryne. This methodology provides highly regioselective access to fully substituted aryl-λ³-iodanes featuring a 1,4-dialkynyl-2-iodanyl-3-aryl/alkyl benzene scaffold, which is difficult to obtain through conventional sequential cross-coupling starting from polyhalogenated benzene derivatives. The unique and well-defined functional group arrangement enables π-extension through robust cross-coupling and cyclization techniques, facilitating divergent synthesis of helical and planar polycyclic aromatics. Optical resolution of the helicene products and analysis of their chiroptical properties, along with further exploration of the utility of carboiodanation for the synthesis of complex polyaromatic systems, are currently underway.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.5c00956.

• Experimental procedures, spectral data of all new compounds, and DFT calculations (PDF)

Author Contributions

^# These authors contributed equally to this work.

The authors declare no competing financial interest.