Sustainable Synthesis of 4,7‐Dihydro‐4,7‐ethano‐2H‐isoindoles—Key Building Blocks to Benzoporphyrins

ABSTRACT

Benzoporphyrins, π extended porphyrin analogues, exhibit remarkable potential for optoelectronic and theragnostic applications, yet have remained largely confined to fundamental studies owing to the challenging synthesis of masked isoindole precursors. Here, we report a concise, scalable three‐step synthesis of 4,7‐dihydro‐4,7‐ethano‐2H‐isoindole, a key building block of the benzoporphyrin framework. Subsequent functionalization affords the corresponding α‐ester derivative, enabling controlled access to diverse, lower‐symmetry benzoporphyrin architectures. Compared with previous multistep strategies, this scalable route markedly reduces cost, waste generation, and synthetic complexity, representing the most practical synthetic approach to date. This advance enhances the synthetic accessibility of benzoporphyrins and paves the way for their broader implementation in molecular materials and biomedical applications.

A facile and sustainable route to isoindole derivatives—key benzoporphyrin precursors—brings high‐ and low‐symmetry benzoporphyrins closer to practical application.

1. Introduction

Beyond verteporfin, a chlorin derivative labeled as “benzoporphyrin derivative monoacid” and clinically used for the photodynamic therapy of macular degeneration [1, 2], benzoporphyrins have received little attention on an industrial scale. Nevertheless, the exceptional photophysical and electronic properties of benzoporphyrins—including their efficiency in light harvesting [3, 4, 5], nonlinear optical response [6, 7, 8], near‐infrared emission [9, 10, 11], molecular sensing [12, 13, 14], and diverse energy‐conversion processes [15, 16, 17, 18]—have established them as highly versatile chromophores for optoelectronic [19, 20, 21, 22, 23] and theragnostic technologies [24, 25, 26, 27, 28]. In addition, the characteristic saddle‐shaped conformation of tetraaryltetrabenzoporphyrins provides a preorganized platform for nanoarchitectures and self‐assembled two‐dimensional superstructures, thereby expanding their utility in molecular electronics [29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39].

Although benzannulated 2H‐isoindole is structurally related to pyrrole, it exhibits markedly distinct chemical behavior. In particular, its propensity for 1H/2H tautomerization and rapid polymerization above −40°C precludes its application as a simple “pyrrole equivalent” in standard porphyrin syntheses [40], thereby limiting access to linearly π‐extended benzoporphyrins [41, 42, 43]. To address these challenges, several masked isoindole precursors have been introduced, including 4,5,6,7‐tetrahydro‐2H‐isoindole [44], 4,7‐dihydro‐2H‐isoindole [45], and 4,7‐dihydro‐4,7‐ethano‐2H‐isoindole (1) [46, 47, 48, 49, 50, 51, 52, 53]. A comparative overview of these strategies is provided in Supporting Note S1. Building on our previously established high‐yielding synthesis of tetrabenzoporphyrins [54], we identified 1 as a particularly suitable precursor; however, its multistep preparation remains a significant synthetic bottleneck.

As depicted in Figure 1, state‐of‐the‐art approaches toward 1 rely on the Diels–Alder reaction of functionalized acetylenes with 1,3‐cyclohexadiene. However, each of these routes (I–III) exhibits distinct limitations that hinder their suitability with perspective to industrial applications. For instance, the pioneering synthesis reported by Gorgues et al. [46, 47, 48] (route I) is lengthy and requires costly reagents, notably 4,4‐diethoxybut‐2‐ynal. In contrast, the methodology developed by Ono et al. [49, 50, 51, 52] (route II) affords high overall yields with stable intermediates but involves high material costs and resource‐intensive purification steps. The most recent advancement toward 1 is the modification of route I by Lim et al. [53] (route III), which streamlines the reaction sequence and reduces material costs, but introduces a low‐yielding bottleneck in the initial step.

FIGURE 1.

Synthesis of tetrabenzoporphyrins using 1. This work provides a new entry for the preparation of 1 using 2,5‐dimethoxy‐2,5‐dihydrofuran (2). Below listed, are the starting materials for the approaches of Gorgues (I [46, 47, 48]), Ono (II [49, 50, 51, 52]), and Lim (III [53]).

Herein, we report a conceptually distinct synthesis of masked isoindole 1, fundamentally departing from prior methodologies by starting from cheap, green, and readily available 2,5‐dimethoxy‐2,5‐dihydrofuran (2). By eliminating column chromatography through the use of alternative purification techniques such as crystallization, sublimation, and filtration, this approach affords significantly improved green metrics, cost efficiency, and operational practicability. All intermediates are bench‐stable, allowing convenient storage of decagram‐scale quantities. Furthermore, to expand the synthetic potential of 1, we developed a post‐functionalization protocol converting 1 into the corresponding α‐substituted ester—an intermediate previously accessible only via the cost‐intensive Ono route [49, 50, 51, 52], and a key precursor to lower‐symmetry benzoporphyrin analogues [55, 56, 57].

2. Results and Discussion

2.1. Refinement of Routes II and III Toward 1

To improve the cost‐efficiency and green metrics of the existing syntheses toward 1, we reassessed the methods reported by Ono et al. (route II) and Lim et al. (route III). In route II, costs can be lowered by preparing the required starting materials from less expensive precursors, albeit at the expense of additional steps and increased synthetic effort. Green metrics were further improved by replacing selected chromatographic purifications with sublimation. Route III, already an optimized version of the pioneering procedure by Gorgues (route I), was enhanced in yield and sustainability by prolonging the Diels–Alder reaction to 68 h and distilling the product. The modifications leading to routes II* and III* are summarized in Supporting Note S2. Despite these improvements, neither route is sufficiently streamlined for application beyond an academic laboratory. We therefore developed an alternative pathway that uses inexpensive starting materials, provides bench‐stable intermediates, and relies on straightforward transformations in combination with benign purification procedures.

2.2. Novel Route to 1

To address the challenges outlined above, we devised a three‐step methodology starting from 2,5‐dimethoxy‐2,5‐dihydrofuran (2), an inexpensive derivative of furan—a bio‐based feedstock (Figure 2) [58, 59]. The literature‐known Diels–Alder reaction between 1,3‐cyclohexadiene and 2 proceeds under solvent‐free conditions [60]. The resulting cycloadduct (3) can be isolated as a mixture of diastereomers in 74% yield by fractional distillation, simultaneously allowing recovery of unreacted 2. Notably, compound 3 is bench‐stable and can be stored for several years without detectable degradation.

FIGURE 2.

Synthetic methodology toward 4,7‐dihydro‐4,7‐ethano‐2H‐isoindole 1: (a) cyclohexadiene, 150°C, 112 h, 74%, (b) KO ^t Bu, DMSO, rt, 1 h, 96%.

The most significant challenge in our sequence was step two, in which 3 undergoes condensation with arylsulfonamides to furnish the N‐protected masked 2H‐isoindole (4). The arylsulfonyl protecting group was selected for its electron‐withdrawing nature, which imparts resistance to oxidative polymerization and ensures that 4 is a bench‐stable intermediate. Various condensation conditions, listed in the table in Figure 2, were tested from which we conclude that the use of aqueous media in combination with Brønsted or Lewis acids—such as hydrochloric acid, acetic acid, or iron(III) chloride (entries 1–6)—is inefficient, either failing to produce any meaningful amounts of product, or yielding irreproducible results.

In contrast, switching to less polar organic solvents (entries 7–12) led to the first successful conversions, with boron trifluoride in toluene yielding detectable amounts of product. Even the use of inorganic P₄O₁₀ (Entry 10) showed successful transformations, however, substantially improved outcomes were obtained when using organic sulfonic acids such as camphorsulfonic acid (CSA) or p‐toluenesulfonic acid (pTSA) (entries 11 and 12).

Subsequent optimization identified tosylamide combined with 15 mol% pTSA monohydrate in toluene at 100°C as the most practical set of conditions (Entry 17). Notably, Entries 13–17 highlight the robustness of this condensation step: variations in the arylsulfonamide (phenyl vs. tolyl), the sulfonic acid employed (CSA vs. pTSA), the catalyst loading (5–15 mol%), the heating method (conventional vs. microwave), and even the reaction scale (sub‐gram to decagram) consistently afforded yields in the narrow range of 48%–53% with excellent reproducibility. Furthermore, purification is straightforward: the crude material is passed through a short silica plug to remove polar impurities, followed by precipitation from dichloromethane with n‐pentane to give pure, bench‐stable 4.

Deprotection of 4 to the desired masked isoindole 1 proceeds smoothly under basic conditions, delivering 1 in quantitative yield upon treatment with potassium tert‐butanolate in dimethyl sulfoxide at ambient temperature. In contrast, the corresponding N‐benzenesulfonyl analogue affords only 67% yield under identical conditions. This difference is consistent with two distinct deprotection mechanisms. For the tosyl derivative, deprotonation of the para‐methyl group generates a benzylic quinoid anion that promotes cleavage of the S─N bond. In the case of the benzenesulfonyl substituent, formation of the quinoid intermediate is not possible; instead, deprotection likely proceeds through the nucleophilic attack of tert‐butanolate at the sulfur atom followed by displacement of the amine nitrogen; a process that may be sterically disfavored by the bicyclic framework [61].

Finally, the isolation of 1 is straightforward: the crude product is obtained by pouring the reaction mixture into water, after which washing and drying yield a solid that can be purified to analytical grade by sublimation under reduced pressure. Notably, the final deprotection step represents a substantial improvement over the otherwise efficient method of Ono, which requires temperatures exceeding 180°C and is therefore highly sensitive to user‐dependent variations; under such conditions, even brief exposure to small amounts of air frequently leads to product decomposition. In contrast, the present approach proceeds under mild conditions and avoids these shortcomings. Overall, this streamlined three‐step sequence affords 1 in 37.7% yield and offers clear advantages in operational simplicity, reduced waste generation, and cost efficiency.

2.3. Resource Management

Previous investigations have primarily emphasized improving synthetic efficiency, whereas the sustainability of these approaches has received considerably less attention. To address this gap, the following section presents a systematic evaluation of all synthetic pathways. Quantitative assessment of economic and environmental impact was carried out by a cost–waste analysis (Figure 3). Cost was estimated based on the reagents and materials required to produce the target compound on a decagram scale, while waste was quantified using the process mass intensity (PMI), defined as the ratio of total process mass to isolated product mass (see Supporting Note S3). For reference, industrially optimized processes typically achieve PMI values below 50, while bulk chemical production can reach values below 5 [62]. In case of high‐value target compounds, such as peptide‐based drugs, values can, however, often exceed values >1000 [63].

FIGURE 3.

Green metrics evaluation of the overall process to 1. (a) 2D bubble plot of cost versus PMI of the individual synthetic routes. The diameter of the bubbles represents the overall yield of the approaches. References to the established approaches: I [46, 48], II [51], II*, III [53], III* [54] (see Supporting Note S3 ). (b) Summary table of all routes. (c) Waste contribution of the individual routes; outer ring: relative contribution of reaction, work‐up and purification to the synthetic process; inner ring: waste type (i.e., organic, solid, aqueous waste, and chemicals).

Analysis of the reported routes I–III (Figure 3a) reveals a consistent trend. Transitioning from route I to route II markedly reduces cost from >900 to ∼80€/g, but at the expense of increased waste generation, driven mainly by extensive chromatographic purification. Our refined route II* improves cost‐efficiency; however, the additional steps result in PMI values of ∼2500 and are thus comparable to route II. Route III offers no meaningful improvement in cost or waste relative to II*, although it requires fewer working days [53]. In contrast, the modifications implemented in route III* provide a substantial reduction in waste and a modest decrease in cost. Still, with PMI values exceeding 1100 and production costs >20€/g, none of the published approaches achieve sustainable performances.

On the other hand, our developed route shows a clear improvement in both metrics, delivering the lowest waste generation and cost among all evaluated pathways (PMI = 609, cost = 15.9€/g). Because overall yield can skew these values, both PMI and cost were normalized to the isolated yield. As shown in Figure 3b, our route displays by far the lowest PMI and cost per percent yield, underscoring its superior overall efficiency—even when accounting for its lower total yield (37.7%) compared to routes II (68.1%) and II* (56.3%). Moreover, the reduction of waste through the elimination of extensive purification methods has a pronounced impact on solvent usage. As a result, the solvent intensity (SI), defined as the total mass of solvent used per mass of isolated product, is reduced to 296—more than a factor of two lower than the next most efficient approach (route I, 697).

To further contextualize the improvements, a detailed breakdown of waste sources is presented in Figure 3c. Routes I–III exhibit similar waste profiles, with organic solvent use and chromatographic purification as the main contributors. The refined routes II* and III* reduce chromatographic waste but still generate considerable solvent loads. In contrast, our methodology minimizes waste generation by avoiding column chromatography entirely, requiring only a single plug filtration, with the majority of waste arising from routine aqueous work‐up rather than purification.

2.4. Post‐Functionalization of 1 Toward α‐Ester Derivatives

While previous studies demonstrated the use of 1 in statistical condensations to form A₄‐ and lower‐symmetry porphyrins, as well as via biscarbinols for directed syntheses of defined opp‐A₂B₂ substitution patterns, preparation of other geometries typically requires dipyrromethane intermediates [64, 65, 66, 67]. However, exploiting 1 analogously to pyrrole for direct meso‐trans‐symmetric systems has remained elusive, because inexpensive pyrrole can serve as both reagent and solvent and is easily recovered—a strategy impractical for valuable 3,4‐disubstituted pyrroles or for 1 itself. Established alternatives generally introduce an α‐ester on the pyrrole scaffold [68, 69, 70, 71, 72], enabling condensation with an aldehyde to form a diester, which is then converted to the dipyrromethane upon decarboxylation. To date, installing the requisite α‐ester to 1 has required the Barton–Zard reaction, as employed in the process mass intensive Ono route II [49, 50, 51, 52].

To bypass this requirement and expand the utility of 1, we developed a two‐step, one‐pot sequence to the corresponding α‐ester 6, as outlined in Figure 4a. Compound 1 was first treated with trichloroacetyl chloride, followed by reaction with ethanol under mildly basic conditions to afford 6. Notably, the initial trichloroacetylation affords a mixture of two products. Density functional theory (DFT) calculations (Supporting Note S4) confirm that the desired C‐acetylated species (5a) arises through a kinetically favored intermediate during the addition, whereas the N‐acetylated regioisomer (5b) is derived from the thermodynamically preferred pathway. As the subsequent HCl elimination is irreversible, lowering the reaction temperature to −20°C favors the formation of 5a.

FIGURE 4.

Post‐functionalization of 1 to α‐ester 6 and their use towards various types of benzoporphyrins. (a) Two‐step one‐pot reaction sequence: (i) trichloroacetyl chloride, tetrahydrofuran, −20 °C, 5 h, not isolated; (ii) potassium carbonate, ethanol, reflux; 82% over both steps. (b) Single crystal x‐ray structures of synthesized benzoporphyrin derivatives (BP1–BP3) obtained by the directed synthesis through 6. Detailed description of the individual routes is provided in Supporting Note S5. (c) Green metrics analysis analogously to Figure 3.

Fortunately, 5b is unstable under the basic conditions of the second step and reverts to 1, which can be readily recovered. The crude mixture of 5a and 5b was therefore used directly in the second step. Heating this mixture in ethanol with potassium carbonate furnished the α‐ester (6), which was separated from residual 1 by a short silica plug filtration. Subsequent sublimation under vacuum afforded pure 6 in 82% yield over the two‐step sequence.

Examples and respective single crystal x‐ray structures of trans‐A₂ (BP1), and trans‐A₂B₂ tetrabenzoporphyrins (BP2) or syn‐dibenzoporphyrins (BP3) via the dipyrromethane approach are highlighted in Figure 4b. All synthesized benzoporphyrin examples (BP1–BP5) and their respective structural and electronic properties are described in Supporting Note S5.

Analogous to the green metrics analysis of 1, we evaluated our approach to 6 in comparison to the state‐of‐the‐art Ono methodology [49, 50, 51, 52]. While our route involves more synthetic steps overall, it benefits from the low waste generation achieved in the preceding steps toward 1. When considering only the post‐functionalization to 6 (Figure 4c), the PMI is reduced by nearly a factor of two, and the cost of 13.94€/g makes our method the most efficient. Eliminating extensive chromatographic purification further improves the waste profile, providing a more practical and sustainable strategy to access advanced π‐extended porphyrinoids. Nonetheless, if 6 is considered the target starting material, the overall route from 2 results in elevated PMI and SI values of 908 and 561, respectively, while only marginally reducing the cost to 13.7€/g. Consequently, post‐functionalization becomes particularly attractive when 1 is produced as a feedstock chemical and 6 is generated on demand.

3. Conclusion

In this work, we have established a fundamentally new approach to 4,7‐dihydro‐4,7‐ethano‐2H‐isoindole 1 and its α‐ester derivative 6, thereby allowing benzoporphyrins to emerge from the shadow of their previously laborious precursor syntheses. Beyond demonstrating the synthetic feasibility and robustness of the sequence, we achieved a substantial improvement in cost efficiency and key green‐metrics parameters, including the solvent and process mass intensity. Although these values remain well above current industrial standards, the progress achieved relative to state‐of‐the‐art methods brings complex benzoporphyrinoid scaffolds a meaningful step closer to practical application.

Further optimization will be necessary before benzoporphyrins can be widely adopted in practical applications—notably by replacing chlorinated solvents and other process aids with more sustainable alternatives. Nevertheless, this study represents a significant step in that direction. With the rapid advances in unconventional synthetic technologies, such as mechanochemical activation [73, 74] and continuous‐flow processing [75, 76, 77], it is likely that the wet‐chemical route described here can be further improved to maximize overall efficiency.

Conflicts of Interest

The authors do not have a conflict of interest.

Supporting information

Supplementary Information: The authors have cited additional references within the Supporting Information [78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95].

Dedicated to Professor Jonathan S. Lindsey on the occasion of his 70th birthday.

Gazetas L. P., Ruppel M., Richtzenhain C., Hampel F., Jux N., and Lungerich D., “Sustainable Synthesis of 4,7‐Dihydro‐4,7‐ethano‐2H‐isoindoles—Key Building Blocks to Benzoporphyrins.” Chemistry – A European Journal 32, no. 23 (2026): e70979. 10.1002/chem.70979