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. 2026 Jan 5;28(2):607–611. doi: 10.1021/acs.orglett.5c04149

Generation of Mono- and Bisazabicyclic o‑Quinodimethanes through Polarity-Matched and -Mismatched 6π-Azaelectrocyclization: Access to Substituted Naphthalenes

Daniel J Lee 1, Majji Shankar 1, Ayush Acharya 1, Ramesh Giri 1,*
PMCID: PMC12814512  PMID: 41490479

Abstract

Herein, we demonstrate that 2-alkenylarylaldimines and aryl-1,2-bisaldimines undergo polarity-matched and -mismatched 6π-azacarbo- (6π-AEC) and 6π-aza-azaelectrocyclization (6π-AAEC), respectively, by nitrogen to carbon (azacarbo) and nitrogen to nitrogen (aza–aza) bond formations to generate transient monoazabicyclo- and previously unknown 1,2-bisazabicyclo-o-quinodimethane (o-QDM) intermediates. The monoazabicyclo-o-quinodimethanes engage in a Diels–Alder/retro-Diels–Alder reaction to form substituted dimethyl naphthalene-2,3-dicarboxylates, while the 1,2-bisazabicyclo-o-quinodimethanes react in a Diels–Alder/N–N bond scission reaction to generate 1,4-bis­(phenylamino)­naphthalene-2,3-dicarboxylates. While polarity-matched 6π-AECs have been explored, polarity-mismatched 6π-AAECs have not been studied due to their complications with the nucleophilic character of iminyl nitrogens at the bond-forming termini.

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The reactivity of o-quinodimethanes (o-QDM) has been exploited for the synthesis of complex molecules, including steroids, alkaloids, and polyaromatic hydrocarbons. − Such o-QDM progenitors are designed to form the reactive intermediate following a thermal, chemical, or photochemical stimulus. − Susceptible substrates utilized for the synthesis of naphthalenes include benzocyclobutanes, hydroxy acetals toward transient isobenzofurans, benzo­[c]­tellurophenes, and brominated o-xylenes, among others (Figure a). ,,− Recently, our lab has demonstrated a new method of accessing o-QDM intermediates through a polarity-matched thermal 6π-azacarboelectrocyclization (AEC) of styrenyl aldimines (Figure b). We now present the utilization of this styrenyl aldimine o-QDM progenitor for the synthesis of substituted naphthalenes through a Diels–Alder/retro-Diels–Alder reaction (DARDA) (Figure c).

1.

1

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(a) Established o-QDM progenitors for synthesizing substituted naphthalenes. (b) Polarity-matched 6π-AEC o-QDM progenitor featuring a dual-nature intermediate (prior work). (c) Polarity-matched 6π-AEC and polarity-mismatched 6π-AAEC o-QDM generation and utilization in the synthesis of substituted naphthalenes (this work).

Beyond the o-QDM intermediate, substituted naphthalenes are typically prepared through the Haworth synthesis, arene homologation, electrophilic alkyne annulation chemistry, metal-catalyzed cyclizations, and electrocyclizations of suitable precursors. −

Most of these methods rely on intramolecular chemistry and therefore require much more prefunctionalization than an intermolecular Diels–Alder reaction that is the primary route to synthesizing naphthalenes but may require postsynthetic modifications to reach target molecules. , Thermal 6π-electrocyclizations are atom-economic reactions capable of rapidly generating molecular complexity and are often used in the synthesis of natural products. − Introduction of heteroatoms such as nitrogen into the backbone of linear hexatrienes has been shown to increase the rate of electrocyclization, with 6π-AEC occurring spontaneously without catalysis in nature to form pyridine rings. ,− Slower to cyclize and less explored are azatrienes in which a double bond is incorporated into an aromatic ring. Such compounds have a higher kinetic barrier to AEC as they proceed through dearomatized o-QDM intermediate 1A (Figure ).

2.

2

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Proposed mechanism toward (a) naphthalene-2,3-dicarboxylates through polarity-matched 6π-AEC and (b) 1,4-(bisphenylamino)­naphthalene-2,3-dicarboxylates through polarity-mismatched 6π-AAEC.

We demonstrated the feasibility and utility of the 6π-AEC of 2-alkenylarylaldimines by capturing the dearomatized, reactive o-QDM intermediate with dienophiles in a [4 + 2] cycloaddition reaction as well as the reduction of the diradical form toward tetrahydroisoquinolines, revealing the dual nature of this intermediate (Figure b). However, when subjecting 2-alkenylarylaldimines to an alkyne, dimethyl acetylenedicarboxylate (DMAD), we observed new reactivity through a DARDA reaction (Figure a). Already containing 8π-electrons, intermediate 1B is primed to undergo a retro-Diels–Alder reaction to yield substituted, 10π-aromatic, dimethyl naphthalene-2,3-dicarboxylates in 71% yield (Table , entry 1), further adding to the utility of this o-QDM progenitor. The imine was generated in situ and subjected to the reaction. However, the product was formed in a much lower yield (23%).

1. Optimization of the AEC Diels–Alder/Retro-Diels–Alder Reaction .

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entry variation from the standard conditions yield of 1 (%)
1 none 71 (63)
2 inert atmosphere 67
3 1 equiv of BHT or TEMPO 47, 41
4 toluene, THF, or dioxane instead of DCE 41, 33, 41
5 DMSO, DMF, or MeCN instead of DCE 38, 61, 57
6 1 equiv of Lewis acid polymers
7 1 equiv of NEt3, KOtBu, or Cs2CO3 32, 15, 27
8 60 or 140 °C and 440 nm instead of 100 °C 0, 45, 0
9 0.1 or 0.4 M DCE 61, 59
10 5 mmol (1 g) 46
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a

On a 0.1 mmol scale in 0.5 mL of solvent.

b

Yields were determined by 1H NMR using 1,3,5-trimethoxybenzene as the internal standard.

Upon optimization of the DARDA reaction (Table ), we find no sensitivity to atmosphere and limited dampening of yield with incorporation of radical scavengers BHT and TEMPO, unlike our prior work, suggesting that the reaction proceeds only through an o-QDM intermediate (entries 2 and 3). The polarity of the solvent has a subtle effect on the yield; however, there is no discernible trend indicating limited charge build-up throughout the reaction, consistent with concerted cycloaddition chemistry (entries 4 and 5). Lewis acids promote polymerization of the starting material; other additives, including Lewis bases, decrease the yield of naphthalene-2,3-dicarboxylate 1 (entries 6 and 7). The DARDA reaction requires a minimum temperature of 100 °C to form the desired product and does not proceed under 440 nm light (entry 8). Deviating from the standard 0.2 M concentration moderately impacts the yield, and we find the reaction to be scalable to a 1 g scale with some loss of yield (entries 9 and 10). These experiments are consistent with an o-QDM intermediate that is intercepted by DMAD forming a bridged complex 1B that likely rapidly undergoes a retro-Diels–Alder reaction to generate aromatic and planar naphthalene-2,3-dicarboxylates (Figure a).

Like most successful 6π-AECs, 2-alkenylarylaldimines are geometrically and electronically oriented in a manner that allows a favorable, polarity-matched electrocyclization to generate the reactive o-QDM intermediate (Figure a). Such compounds feature a slightly negatively charged imine nitrogen head meeting with a slightly positively charged tail, which lowers the barrier to electrocyclization. Unexplored has been utilizing polarity-mismatched aryl hexatrienes for 6π-aza-azaelectrocyclizations (AAEC), such as 1,2-bisarylaldimines that are not isolable, in a sequential one-pot method (Figure b). Competing forces are at play with two nitrogen atoms embedded in the 1,6-diazatriene theoretically having a lower kinetic barrier to AAEC while the negatively polarized head electrostatically opposes electrocyclization with the negatively polarized tail. In such molecules, nucleophilic cyclization is polarity favored forming thermodynamic products, isoindolinimines and isoindolinones, irreversibly that must be avoided (Figure b). Despite this serous challenge, we also report a sequential one-pot method toward 1,4-bis­(phenylamino)­naphthalene-2,3-dicarboxylates through an unstable 1,2-bisarylaldimine that undergoes an unexplored polarity-mismatched 6π-AAEC.

The formation of isoindolinone and isoindolinimine byproducts has been the main challenge when working with 1,2-bisarylaldimines and is the reason these compounds remain relatively unexplored. Prior work has demonstrated the sensitivity of bisarylaldimines to the solvent, pH, and temperature, indicating the adjustable parameters that can be accessed to avoid nucleophilic cyclization and promote the formation of the o-QDM intermediate to be captured with DMAD. As such, we determined that the polarity-mismatched 6π-AAEC of 1,2-bisarylaldimine was best performed at 150 °C or under a visible light LED at 440 nm in dioxane in the presence of AlCl3 (Table , entry 1). A survey of solvents with different polarities shows that nonpolar solvents give lower yields than polar aprotic solvents, with THF and dioxane giving the highest yields (entry 2). DMF and HFIP show no product formation likely due to hydrogen bonding, encouraging nucleophilic cyclization (entry 3). Various acids and bases were tested with bases showing no improvement in yield versus the control and no prevention of nucleophilic cyclization. While bases failed to prevent isoindolinone and isoindolinimine byproduct formation, Lewis acids AlCl3 and MgBr2 moderately reduce the level of nucleophilic cyclization, with 1 equiv of AlCl3 reducing the byproducts from a 24% to 8% yield and increasing the yield of 2 to 58% compared to 47% in its absence (entries 4 and 5). We also observed a temperature threshold of 100 °C that was required for the reaction to give any DA products (entry 6), suggesting the reaction is under kinetic control, with an optimal temperature of 150 °C. Higher concentrations reduce the yield by promoting side reactions (entry 7), and we find a limited effect on yields when radical scavengers BHT and TEMPO are introduced, suggesting no radicals are involved in the reaction (entry 8). Overall, it appears that the 6π-AAEC is reversible as we can intercept the o-QDM with DMAD but no other alkynes, in which case we find isoindolinimines and isoindolinones. The sensitivity of the reaction to solvent polarity, concentration, and Lewis acids suggests a possible acid-mediated proton shift from the bridged intermediate, establishing the aromatized diaminonaphthalene product.

2. Survey of Polarity-Mismatched AAEC and Diels–Alder Reaction Conditions .

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entry variation from the standard conditions yield of 2 (%)
1 none 58 (50)
2 THF, toluene, or DCE instead of dioxane 49, 31, 26
3 DMF or HFIP instead of dioxane 0
4 BF3Et2O, MgBr2, or AI(OTf)3 instead of AICI3 32, 54, trace
5 no AICI3, 2 equiv of AICI3, or 4 equiv of AICI3 47, 48, 22
6 RT, 60 °C, or 100 °C 0, 0, 16
7 0.2 or 0.5 M dioxane 51, 27
8 1 equiv of BHT or TEMPO 48, 46
9 one pot 42
10 390 nm instead of 440 nm 40
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a

On a 0.1 mmol scale in 0.5 mL of solvent.

b

Yields were determined by 1H NMR using 1,3,5-trimethoxybenzene as the internal standard.

Electrocyclizations can be promoted thermally or photochemically, giving opposite diastereochemical outcomes on hexatriene systems according to Woodward–Hoffmann rules. Interestingly, when the yellow 1,2-bisarylaldimine is subjected to 440 nm light, it undergoes a 6π-AAEC and DA reaction to form 2 in nearly the same NMR yield (52%) as under thermal conditions (58%) unlike 2-alkenylarylaldimines (Table , entry 8). Conveniently, the reaction can be performed in one pot thermally or photochemically, rather than the standard sequential one-pot reaction, leading to slightly diminished yields at 42% (entry 9). Higher-energy, 390 nm UV light also generates the product but in lower yield than 440 nm light (entry 10).

Previously we demonstrated an interception of the in situ-generated o-QDM intermediate from 2-alkenylarylaldimines to generate bridged azabicycles. However, when using alkenyl dienophiles, the bridged, saturated, bicyclic products are not primed for a retro-Diels–Alder reaction as the product lacks aromatic stabilization energy. Such stabilization is found when using alkyne DMAD as a dienophile, which proceeds through a bridged bicyclic alkene, able to aromatize following a retro-Diels–Alder elimination forming substituted dimethyl naphthalene-2,3-dicarboxylates (Table A). This reaction tolerates electron rich (3 and 4) and poor o-styrenyl aldimines (5 and 6) as well as steric bulk (10–11). 2-Alkenylketimines (12) and α-methyl styrenyl aldimine (6) also form the desired products, with the substituents remaining on the naphthalene ring. Heterocyclic dimethyl benzo­[b]­thiophene-5,6-dicarboxylate (7) can be synthesized through our method, as well. 1,2-Bisarylaldimines have no precedent for undergoing 6π-AAEC, but we demonstrate here the formation of an o-QDM intermediate that can also be intercepted by DMAD to form a range of 1,4-bis­(phenylamino)­naphthalene-2,3-dicarboxylates. A condensation of phthalaldehyde with anilines yields an unstable 1,2-bisarylaldimine that can be filtered and advanced to the Diels–Alder step with DMAD in the presence of 1 equiv of AlCl3 in dioxane to generate the standard product (2) in 50% isolated yield (Table , entry 1). We are able to expand this scope (Table B) and isolate electron rich (13, 15 and 17) and electron poor (14) diaminonaphthalenes; however, sufficiently electron poor anilines promote the nucleophilic cyclization through the highly polarized imines. Electron rich alkyl amines also promote cyclization by creating a very nucleophilic imine nitrogen. Solubilizating and bulky anilines (15–18) are tolerated with naphthyl amine giving a moderate yield (16). Interestingly, benzylamine gave highest-yielding product 19 at 76% and was the only 1,2-bisaldimine to facilitate product formation with another alkyne (20). Functional groups such as OMe and Br on bisarylaldimine are also tolerated in the polarity-mismatched formulas (21 and 22, respectively). Such diaminonaphthalene compounds have been used as strongly reducing photocatalysts and biomolecule-sensing polymers wherein electronic tunability and a rapid synthesis may be desirable and can now be accessed through our method. ,

3. Scope of AEC DARDA and AAEC DA/N–N Cleavage Reactions .

graphic file with name ol5c04149_0005.jpg

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a

Isolated yields are reported.

b

On a 0.5 mmol scale in 5 mL of solvent.

c

On a 1.0 mmol scale in 10 mL of solvent.

We note the limitation on the types of alkynes that can be used in the current reaction and provide some explanations. The bisarylaldimines are not compatible with other alkynes, suggesting a slower Diels–Alder step with these worse dienophiles and a reversible 6π-AAEC judging by the evidence of formation on an o-QDM intermediate with DMAD and limited sensitivity to radical scavengers (Table entry 8). The 6π-AAEC was demonstrated to occur under thermal or photochemical conditions, achieving similar yields of the naphthalene products. The photochemical result being at ambient temperature is consistent with a fast Diels–Alder step between the o-QDM and DMAD. The Diels–Alder step in the polarity-mismatched reaction must be fast enough to intercept the transient o-QDM before it irreversibly forms the isoindolinone and isoindolinimine byproducts (Figure ). The Diels–Alder reaction of the polarity-matched reaction is generally fast, but the retro-Diels–Alder step does not proceed efficiently when other alkynes are used, leading to a mixture of bridged bicyclic, decomposition, and naphthalene products based on GC-MS and LC-MS.

In summary, the o-QDM intermediate has proven to be a versatile synthon for a variety of small molecules and organic materials. Recently, we have explored the formation of o-QDMs through 6π-AEC of 2-alkenylarylaldimines that are geometrically and electronically oriented in a manner to promote electrocyclizations with a negatively charged head cyclized with a positively charged tail. When submitted with DMAD, a Diels–Alder reaction proceeds through an intermediate primed for a retro-Diels–Alder reaction to form aromatized dimethyl naphthalene-2,3-dicarboxylates. We also explored a polarity-mismatched 6π-AAEC with 1,2-bisarylaldimines that have a propensity to form isoindolinimine and isoindolinone through nucleophilic cyclization. Despite the lack of precedent for such polarity-mismatched compounds to undergo 6π-AAEC, we find a Diels–Alder reaction occurs with DMAD to form 1,4-bis­(phenylamino)­naphthalene-2,3-dicarboxylates through an o-QDM intermediate judged by the procession of the reaction in the presence of BHT or TEMPO. While this reaction tolerates many anilines, it does not support alkyl amines, bisarylketimines, or any alkynes outside of DMAD.

Supplementary Material

ol5c04149_si_001.pdf (2.5MB, pdf)

Acknowledgments

The authors gratefully acknowledge the National Institute of General Medical Sciences (R35GM133438), the National Science Foundation (CHE-2102394), and The Pennsylvania State University for support of this work.

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

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.5c04149.

  • Experimental procedures, full characterization of products, and NMR spectra (PDF)

The authors declare no competing financial interest.

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Associated Data

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Supplementary Materials

ol5c04149_si_001.pdf (2.5MB, pdf)

Data Availability Statement

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

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