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DOI: 10.1039/D1GC04686A (Communication) Green Chem., 2022, 24, 2772-2776

Thermoneutral synthesis of spiro-1,4-cyclohexadienes by visible-light-driven dearomatization of benzylmalonates†

Quan-Qing Zhao , Julia Rehbein and Oliver Reiser *
Institut für Organische Chemie, Universität Regensburg, Universitätsstrasse 31, 93053, Germany. E-mail: oliver.reiser@chemie.uni-regensburg.de

Received 15th December 2021 , Accepted 7th February 2022

First published on 7th February 2022

Abstract

A visible-light-driven dearomatization of unactivated arenes with perfect atom economy to access spiro-1,4-cyclohexadienes is disclosed. Calculations suggest that the overall process is approximately thermoneutral, showcasing the special opportunities of light-driven processes to develop sustainable transformations that defy thermodynamic requirements.

Photocatalysis enables chemical reactions by accessing excited states or radical intermediates of appropriate precursors,1 nevertheless, such transformations are by and large thermodynamically favored. Representative examples are photochemical ATRA reactions2 or “uphill catalysis” [4 + 2]-cycloadditions,3 in which the overall exchange of weak π-bonds for strong σ-bonds is the thermodynamic driving force. However, photochemical activation might also allow thermodynamically less favored processes to proceed (Scheme 1a) as demonstrated for E/Z-isomerization of alkenes4 or [2 + 2]-cycloadditions, culminating in the synthesis of Dewar benzenes from arenes,5 in which the products cannot absorb the light-energy offered to revert back to the starting materials.
image file: d1gc04686a-s1.tif
Scheme 1 Thermoneutral reactions via photocatalysis aiming at the dearomatization of arenes. PC = photocatalyst, SM = starting material, P = product.

The hydrogenation of benzene to 1,4-cyclohexadiene6 is an endergonic process (ΔRG = 12.9 kcal mol−1, M06-2X/G-311 + G**, see ESI†) due to the thermodynamically unfavorable dearomatization of the product (Scheme 1b). Known as Birch reduction,7 this reaction becomes thermodynamically possible (ΔRG = −0.1 kcal mol−1, M06-2X/G-311 + G**, see ESI†) by the coupling of a second, exergonic process, i.e. employing stoichiometric amounts of lithium metal in liquid ammonia as the terminal reducing reagent in combination with a proton source. More recently, visible light-driven photoredox catalysis has been recognized to offer new opportunities for the dearomatization of arenes under mild conditions.8 Despite these elegant reports, the synthesis of 1,4-cyclohexadienes by dearomatization of unactivated arenes, especially without the coupling to high-energy reagents or preactivation of the substrates, is still underdeveloped, reflecting the challenge to suppress alternative reaction pathways that will result in rearomatization and thus thermodynamically more favorable products.

We report here the dearomatizative coupling of benzylmalonates and alkynes to spiroanellated 1,4-cyclohexadienes, which proceeds via activation with light with perfect atom economy in high yields, despite the fact that the overall process is close to being thermodynamically neutral (Scheme 1d). No preactivation of the substrates or employment of stoichiometric high-energy reagents, being the traditional approach to drive thermoneutral transformations, is necessary.

Related to our study, in 1992 Santi and co-workers described a cascade cyclization between diethyl benzylmalonate and alkynes (Scheme 1c).9 Under high temperature conditions and using Mn(OAc)3 as overstoichiometric oxidant, dihydronaphthalenes were obtained via generation of a malonate radical, followed by addition to an alkyne and cyclization into the benzylic arene group.9a When malonates bearing an activating substituent in 4-position (4-F or 4-MeO) were used, spiro[4,5]-decanones were obtained in which oxidation of the arene moiety had taken place.9b Zhang and co-workers achieved a visible-light driven photoredox catalytic version to obtain the same spiro[4,5]-decanones, however, in this case the preactivation of the malonate by bromination was required.10

Based on this precedent, we questioned if a photocatalytic dearomatization of both unactivated arenes and malonates could also be developed. Through this way, novel 1,4-cyclohexadienes should become accessible with perfect atom economy in a redox neutral and, according to our calculations (M06-2X/6-311 + G** level; see ESI†), close to thermoneutral fashion. To achieve this goal, we envisioned that an initial one-electron oxidation of the malonate to its corresponding radical and after coupling onto an alkyne and cyclization a one electron reduction of a 1,4-cyclohexadienyl radical would be the necessary key steps.

We commenced our studies with readily available diethyl 2-benzylmalonate (1a) and phenylacetylene (2a) as model substrates (Table 1). After extensive screening (for details see ESI†), the desired spiro-1,4-cyclohexadiene 3aa was obtained in 96% yield by employing Ir(ppy)2dtbbpyPF6 as photocatalyst (PC, 2 mol%) under blue LED irradiation (Table 1, entry 1).

Table 1 Optimization of the reaction conditionsa

image file: d1gc04686a-u1.tif
Entry Variation from the standard conditions Yieldb (%)
a Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol, 2.0 equiv.), Ir(ppy)2dtbbpyPF6 (2 mol%), K3PO4 (1.0 equiv.) in CH3CN (2 mL), N2, rt, 24 h. b Yields were determined by NMR analysis with 1,3,5-trimethoxybenzene as an internal standard. c Isolated yield in parentheses.
1 None 99 (96)c
2 4CzIPN instead of Ir(ppy)2dtbbpyPF6 nd
3 Cu(dmp)2Cl2 instead of Ir(ppy)2dtbbpyPF6 nd
4 Mes-Acr-MeBF4 nd
5 0.8 equiv. of K3PO4 78
6 0.5 equiv. of K3PO4 74
7 Without PC nd
8 Without irradiation of visible light nd
9 Without base nd

Other photocatalysts that are known to be efficient for processes that require an initial one electron oxidation such as 4CzIPN,11 Mes-Acr-MeBF41f or Cu(II)-complexes such as Cu(dmp)2Cl2,12 did not promote the transformation (Table 1, entries 2–4). Besides acetonitrile, only DMF or DMSO as solvents were met with some success, while nonpolar solvents or THF did not result in the formation of 3aa. The addition of a base was found to be required, and compared to other inorganic or organic bases, K3PO4 (1 equiv.) proved to be by far superior, which can also be employed in substoichiometric quantities, however, with somewhat reduced yields (Table 1, entries 5 and 6). Control experiments revealed that each component, i.e. photocatalyst, visible-light-irradiation and base is essential for the success of the reactions (Table 1, entries 7–9).

With the optimized reaction conditions in hand, we next explored the scope of the reaction (Table 2 and Scheme 2). With few exceptions, high yields with good functional group tolerance were observed for a representative selection of the two components employed. Besides the two ester groups in the malonate, exchanging one for a keto group (3ea, 3fa) was possible, however, displacing both ester groups for this functionality or substitution by nitrile groups (1h) was unsuccessful. The benzylic group in 1 tolerated substitution in meta-position as demonstrated for 3ca and 3da, while para substitution (1i, 1j) was not possible most likely as a consequence of steric and electronic effects to access this position for the final hydrogen transfer. Moreover, ortho-substitution (1k) was not successful, reflecting the severe steric hindrance of the resulting product.


image file: d1gc04686a-s2.tif
Scheme 2 Synthetic applications. (a) Reaction conditions: 1a (5.0 mmol, 1.0 equiv.), 2a (15 mmol, 3.0 equiv.), Ir(ppy)2dtbbpyPF6 (2 mol%), and K3PO4 (1.0 equiv.) in CH3CN (100 mL), N2, rt, 48 h. (b) Reaction conditions: a: Pd/C (10 mol%), NH4HCO2, methanol, 25 °C, N2, 20 h, quantitative yield of 4; b: LiAlH4 (5.0 equiv.), Et2O (4 mL), 35 °C, N2, 20 h, quantitative yield of 5; c: 3,4-dimethoxythiophene (1.0 equiv.), p-TSA (10 mol%), toluene, 24 h, reflux, 41% yield of 6; d: Ru(bpy)3Cl2·6H2O (2 mol%), CH3CN (2 mL), blue LED, air, 53 h, 33% (brsm) yield of 7.
Table 2 Substrate scopea
a Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol, 2.0 equiv.), Ir(ppy)2dtbbpyPF6 (2 mol%), and K3PO4 (1.0 equiv.) in CH3CN (2 mL), N2, rt, 24 h. b 3.0 equiv. of 2a, 48 h. c 10 equiv. of 2, 24 h.
image file: d1gc04686a-u2.tif

A wide variety of substituents in the aryl ring of the alkyne component (electron donating and accepting groups in ortho, meta, para position) could be employed (3ab–3ar), but also substitution by naphthyl (3as) or pyridyl (3at, 3au) was met with success (77–98% yield). Notably, phenylacetylene 2p bearing an unprotected hydroxyl group which might be sensitive to the photocatalytic system, was amenable for the process to give rise to 3ap in 71% yield. 1,3-Diethynylbenzene having two reactive alkyne functionalities gave the monoadduct 3av in good yield (61%) along with the twofold adduct 3av′ (18%). Also, alkyl substituted alkynes can be engaged in this transformation, as demonstrated with the synthesis of 3aw. Finally, a late-stage functionalization of a steroid derivative was achieved with the synthesis of 3ax. X-ray structure analysis of 3ad unambiguously confirmed the structure of all products.13

Preparative viability was demonstrated with the reaction of diethyl 1a and 2a on a 5 mmol scale, yielding 3aa on gram scale without loss of efficiency (95% yield, Scheme 2a). Moreover, a few synthetic transformations of the products were tested: exhaustive hydrogenation of 3aa gave rise to 4 in quantitative yield. Reduction of the ester moieties to the dialcohol 5 proceeded well with LiAlH4, which was further converted to the 3,4-dihydro-2H-thieno[3,4-b][1,4]dioxepin scaffold 6, which has gained attention in the area of material and photoelectrochemistry.14 In an attempt to connect this methodology to the one reported by Zhang and coworkers10 (cf.Scheme 1c), oxidation to cyclohexadienone 7 is possible albeit only with moderate conversion and yield.

To gain insight into the mechanism, the following experiments were conducted (Scheme 3). In the presence of two equivalents of the radical scavenger TEMPO, the reaction between 1a and 2a was largely inhibited and only 8% yield of 3aa was formed. In addition, the radical trapping products 3-I and 3-II were detected by HRMS (Scheme 3a), thus pointing to 2-I and 2-II (Scheme 4) as possible reaction intermediates. In the presence of allyl sulfone 8, being an especially effective radical acceptor,15 the product 3aa was not formed any longer but rather the allylated product 9 was obtained (Scheme 3b, 45%), supporting the formation of the benzylmalonate radical 1a-II (Scheme 4) as a key intermediate. Light on/off experiments in the reaction of 1a and 2a were conducted (Scheme 3c), which showed that the formation of 3aa immediately is halted in the absence of irradiation. In combination with the very low quantum yield (Φ = 0.00073) that was measured16 we suggest that a photoredox cycle (cf.Scheme 4) is operative, although a radical chain propagation pathway cannot be ruled out completely.17 Stern–Volmer analysis (Scheme 3d) revealed that only benzylmalonate 1a quenches the excited state of *[Ir(ppy)2dtbbpy]3+ to a significant extent, with a much higher rate constant in the presence of K3PO4. These data suggest that the reaction is initiated by a reductive quenching process, in which 1a undergoes deprotonation followed by oxidation of the resulting enolate by the excited photocatalyst *[Ir(ppy)2dtbbpy]3+.


image file: d1gc04686a-s3.tif
Scheme 3 Mechanistic studies.

image file: d1gc04686a-s4.tif
Scheme 4 Proposed mechanism.

Based on the above mechanistic studies and previous reports, a plausible reaction mechanism can be postulated (Scheme 4). After deprotonation of benzylmalonate 1a to generate the anionic intermediate 1a-I, single-electron oxidation mediated by the excited state of photocatalyst *[Ir(ppy)2dtbbpy]3+ generates the benzylmalonate radical 1a-II and the reduced state of the photocatalyst [Ir(ppy)2dtbbpy]2+. Subsequently, radical intermediate 1a-II adds to phenylacetylene 2a, furnishing the vinyl radical species 2a-I that has a sufficiently high reactivity for a dearomative 5-exo-trig cyclization to provide the radical species 2a-II. Finally, a single-electron reduction reaction of 2a-II mediated by the reduced state of photocatalyst [Ir(ppy)2dtbbpy]2+ regenerates the ground state of photocatalyst [Ir(ppy)2dtbbpy]3+ and the C-anionic intermediate 2a-III which upon protonation gives rise to 3aa.

In conclusion, a photoredox-catalyzed transformation involving enolate oxidation, formation of vinyl radicals and dearomatization of an unactivated arene moiety has been developed with complete atom economy, requiring no preactivation of stoichiometric reagents. The title reaction is a process that is thermodynamically allowed but lacks a significant driving force. To still obtain the product in high yields the reaction design requires the inclusion of irreversible steps. In this specific case both, the reduction of the radical 2a-II by the reduced PC and the protonation of the resulting anion 2a-III can be in principle considered as irreversible. Confirmation of these irreversible steps is supported by no reaction of the product 3aa under the catalysis conditions as well as by a PC*/3aa Stern–Volmer-plot, indicating insignificant quenching of the PC excited state by 3aa (see ESI†).

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to China Scholarship Council and Deutscher Akademischer Austauschdienst for a postdoctoral scholarship to QQZ. The project was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) − TRR 325444632635-A2.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2120296. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1gc04686a
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