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Synlett 2024; 35(09): 1019-1022
DOI: 10.1055/a-2204-9522
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Chemical Synthesis and Catalysis in Germany

Bidentate Lewis Acid-Catalyzed Inverse Electron-Demand Diels–Alder Reaction of Phthalazines and Cyclooctynes

Michel Große
a   Institute of Organic Chemistry, Justus Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany
b   Center of Material Research (LaMa/ZfM), Justus Liebig University, Heinrich-Buff-Ring 16, 35392 Giessen, Germany
,
Hermann A. Wegner∗
a   Institute of Organic Chemistry, Justus Liebig University, Heinrich-Buff-Ring 17, 35392 Giessen, Germany
b   Center of Material Research (LaMa/ZfM), Justus Liebig University, Heinrich-Buff-Ring 16, 35392 Giessen, Germany
› Author Affiliations

The authors acknowledge the LOEWE Program of Excellence of the Federal State of Hesse (LOEWE Focus Group PriOSS ‘Principles of On-Surface Synthesis’) for financial support.
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Abstract

Herein we report a method for facilitating the inverse-electron-demand Diels–Alder reaction of 1,2-diazines and cyclooctynes by utilizing a boron-based bidentate Lewis acid catalyst. Readily available electron-deficient and electron-rich phthalazines proved to be suitable substrates in this transformation. The described method enables the facile construction of diversely substituted polycyclic aromatic hydrocarbons fused to eight-membered carbocycles.


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Key words

cycloaddition - diazines - cyclooctyne - bidentate catalysis - polycyclic aromatic hydrocarbons - Diels–Alder reactions

The inverse-electron-demand Diels–Alder (IEDDA) reaction has emerged as a powerful and versatile synthetic tool for the construction of various complex molecular architectures.[1] This cycloaddition reaction has been utilized extensively in natural product total synthesis,[2] chemical biology,[3] and materials science.[1] In contrast to the requirements for normal-electron-demand Diels–Alder reactions, electron-poor dienes and electron-rich dienophiles are needed for IEDDA reactions to take place. As a commonly used diene, 1,2,4,5-tetrazine has found broad application in bioorthogonal chemistry and the construction of functional materials.[4] Due to the low-energy LUMO of this compound, cycloaddition reactions with tetrazine usually proceed rapidly and at low temperatures without the need for an additional catalyst.[5] By contrast, azines containing fewer nitrogen atoms require much harsher conditions or additional modes of activation to enable IEDDA reactions.[6]

In the past decade, we established the bidentate Lewis acid BDLA as an effective catalyst for the activation of phthalazines 1 for IEDDA reactions (Scheme [1]).[7] The boron-based catalyst acts by lowering the LUMO energy of the diazine through complexation, facilitating the cycloaddition with various dienophiles like enamines or enol ethers.[8] Through subsequent cycloreversion, N2 is released and, depending on the reaction conditions and the dienophile, different domino processes are initiated.[9] Another way to accelerate IEDDA reactions is by raising the HOMO energy level of the dienophile, which can be achieved not only by attaching electron-donating groups but also by implementing ring strain into cyclic dienophiles.[3b]

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Scheme 1 Basic principle of the BDLA-catalyzed IEDDA reaction

As demonstrated by Sauer et al., a change from open-chain alkynes to strained cyclooctyne (2) significantly increases the reaction rate of the cycloaddition with 1,2,4,5-tetrazine.[5] [10] Further fine-tuning of the HOMO–LUMO energy gap can be realized by installing different substituents at the cyclooctyne core.[11] Therefore, cyclooctyne derivatives have found broad application as highly reactive alkynes in bioorthogonal chemistry and materials science,[12] mostly with 1,2,4,5-tetrazines or 1,2,4-triazines as reaction partners. However, the IEDDA reaction of cyclooctynes with much less reactive 1,2-diazines has not been reported so far, to the best of our knowledge. Therefore, we envisaged to facilitate this reaction by making use of the bidentate Lewis acid catalyst BDLA.

To begin our investigation with a comparatively reactive 1,2-diazine, we subjected the electron-deficient nitrophthalazine 1b to the IEDDA reaction with cyclooctyne (2) (Table [1], entries 1–3) and analyzed the reactions by 1H NMR spectroscopy. In all cases, no formation of side products was observed and the NMR spectra of the crude reaction mixtures only showed signals of the desired product 3b and unreacted phthalazine 1b in varying ratios. In the presence of 5 mol% BDLA catalyst at 40 °C, 71% of the phthalazine was converted into the substituted naphthalene 3b. By contrast, only 43% conversion was observed without the catalyst, a result indicating that the BDLA indeed catalyzes the IEDDA reaction efficiently. Upon raising of the temperature to 80 °C, full conversion was observed and naphthalene 3b was isolated in 95% yield. A change of the 1,2-diazine to the electron-neutral phthalazine 1a resulted in only 50% conversion in the presence of the catalyst, even at a higher temperature of 100 °C (Table [1], entry 5). An increase in the amount of cyclooctyne (2) from 1.3 to 2.0 equivalents resulted in nearly full conversion and led to the isolation of naphthalene 3a in 86% yield (Table [1], entry 6).

Table 1 Optimization of the Reaction Conditionsa

Entry

R

Temp (°C)

Time (h)

3:1 b (yield)

1c

NO2

 40

72

 43:57

2

NO2

 40

72

 71:29

3

NO2

 80

24

>99:1 (95%)

4c

H

100

48

 33:77

5

H

100

48

 50:50

6d

H

100

48

 94:6 (86%)

a Reaction conditions: 1,2-Diazine 1a or b (0.10 mmol, 1.0 equiv), cyclooctyne (2; 0.13 mmol, 1.3 equiv), BDLA (5.0 μmol, 5.0 mol%), and 1,4-dioxane (1 mL).

b Ratio was determined by 1H NMR spectroscopy of the crude product. Yields of isolated products are given in brackets.

c Reaction performed without catalyst.

d Reaction performed with 2.0 equivalents of cyclooctyne.

To explore the scope of dienes in this transformation, we screened differently substituted 1,2-diazines (1c–l; Scheme [2]), most of which were readily available from the corresponding aldehydes by a one-pot procedure previously developed in our laboratory.[13] As expected, phthalazines carrying electron-withdrawing groups (1c, d, and e) gave the corresponding naphthalenes 3c, d, and e in very good to excellent yields after the IEDDA reaction at 80 °C.

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Scheme 2 Scope of 1,2-diazines in the IEDDA reaction with cyclooctyne (2)

Similarly, the substituted quinoline 3f was obtained from pyridopyridazine 1f in nearly quantitative yield under the same conditions. Benzo[g]phthalazine (1g) also smoothly underwent the IEDDA reaction to form the anthracene derivative 3g. However, the yield was diminished by the formation of a side product through Diels–Alder reaction of the excess cyclooctyne with the central ring of the newly formed anthracene. In the case of benzo[f]phthalazine (1h), low conversion was observed by 1H NMR spectroscopic analysis of the crude product mixture and the desired phenanthrene 3h was only isolated in 22% yield. This might be attributable to the greater resonance stabilization and aromatic character of phenanthrene in comparison with anthracene,[14] which results in lower reactivity of benzo[f]phthalazine (1h) relative to benzo[g]phthalazine (1g). Even the more electron-rich methyl- and methoxy-substituted phthalazines 1i and 1j underwent the IEDDA reaction to give the substituted naphthalenes 3i and 3j, respectively. However, 3.0 equivalents of cyclooctyne (2) were necessary to obtain satisfactory yields. Only in the cases of furopyridazine 1k and thienopyridazine 1l no product was formed, and the unreacted diazines were recovered. We rationalized this outcome by the lower aromatic character of furan and thiophene relative to that of benzene.[15] As a consequence, the initial cycloaddition step with either furopyridazine 1k or thienopyridazine 1l would lead to a greater net loss in aromaticity relative to the cycloaddition with phthalazine (1a).

As a readily available and versatile cyclooctyne derivative, bicyclo[6.1.0]non-4-yn-9-ylmethanol (BCN) has found broad application in bioorthogonal chemistry.[16] Therefore, we synthesized exo-BCN and subjected it to the IEDDA reaction with two different phthalazines (1a and 1c) (Table [2]). In accordance with the reported reactivity enhancement of cyclooctyne by cyclopropane annulation,[11] [17] exo-BCN proved to be much more reactive in the IEDDA reaction with phthalazines than 2. Hence, the reaction temperature could be lowered to 40 °C.

Table 2 IEDDA Reaction of Phthalazines (1) with exo-BCN a

Entry

R

Time (h)

4:1 b (Yield)

1c

F

48

 93:7 (80%)

2

F

48

>99:1 (90%)

3c

H

72

 38:62 (28%)

4

H

72

 66:44 (52%)

a Reaction conditions: phthalazine 1a or c (0.10 mmol, 1.0 equiv), exo-BCN (0.11 mmol, 1.1 equiv), BDLA (5.0 μmol, 5.0 mol%), and 1,4-dioxane (1 mL).

b Ratio was determined by 1H NMR spectroscopy of the crude product. Yields of isolated products are given in brackets.

c Reaction performed without catalyst.

With the electron-deficient difluorophthalazine 1c, over 90% conversion was achieved in the presence or absence of BDLA catalyst (Table [2], entries 1 and 2). However, with the much less reactive unsubstituted phthalazine (1a), the conversion was almost doubled by the use of the catalyst compared to that in the uncatalyzed reaction (Table [2], entries 3 and 4). Notably, BDLA was active even in the presence of the unprotected alcohol.

In summary, we have developed a convenient method for facilitating the IEDDA reaction of phthalazines 1 and cyclooctynes 2 or exo-BCN by employing the bidentate Lewis acid catalyst BDLA. Moderate to excellent yields can be achieved with various substituted phthalazines, including N-heterocyclic (1f) and benzophthalazines (1g,h). The presented method provides rapid access to (substituted) polycyclic aromatic hydrocarbons fused to eight-membered carbocycles, a class of compounds that has recently received considerable attention in materials science and chemical sensing.[18] [19] [20]


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors thank the Organic Chemistry Analytics Department (Institute of Organic Chemistry, Justus Liebig University, Heinrich-Buff-Ring 17, Giessen) for NMR spectroscopy and HRMS measurements.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2204-9522.
  • Supporting Information

Corresponding Author

Hermann A. Wegner
Institute of Organic Chemistry, Justus Liebig University
Heinrich-Buff-Ring 17, 35392 Giessen
Germany   

Hermann A. Wegner
Center of Material Research (LaMa/ZfM), Justus Liebig University
Heinrich-Buff-Ring 16, 35392 Giessen
Germany

Publication History

Received: 15 October 2023

Accepted after revision: 06 November 2023

Accepted Manuscript online:
06 November 2023

Article published online:
13 December 2023

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Zoom Image
Scheme 1 Basic principle of the BDLA-catalyzed IEDDA reaction
Zoom Image
Scheme 2 Scope of 1,2-diazines in the IEDDA reaction with cyclooctyne (2)