I₂-Promoted oxidative annulation of three different amines to access diverse biheteroaryls

Abstract

Utilizing tertiary alkylamines as reliable two-carbon building blocks, a concise and efficient route for the regioselective synthesis of biquinolines from 2-methylquinolines and arylamines has been established. This I₂-promoted approach enables a [4π + 2σ] annulation of three nucleophilic species via two kinds of transient enamines. The C(sp³)–H annulation strategy is also extended to other methylazaarenes toward constructing nonsymmetrical benzo[f]quinoline-containing biheteroaryls. Notably, the applicability of this process for the late-stage functionalization of complex molecules highlights its considerable potential for application in biorelevant areas.

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N-Heterocyclic frameworks found in natural products, pharmaceuticals, biologically active compounds, and functional materials frequently feature unsubstituted C=C bonds.¹ In fact, access to unsubstituted vinylene-embedded azaarenes could be accomplished by direct heteroannulations of ethylene or acetylene with suitable coupling partners. Nevertheless, the operational safety issues associated with these gaseous two-carbon reactants have made these processes extremely challenging.² Fortunately, several breakthrough molecules such as acrylic acid,³ vinyl acetate,⁴ vinylene carbonate,⁵ vinyl selinene,⁶ norbornadiene,⁷ and calcium carbide⁸ have been identified as effective and practical equivalents to facilitate the construction of vicinal unsubstituted N-heteroarenes through transition-metal-catalyzed ortho C–H bond activation/annulation reactions. Recently, certain general and inert solvents or additives have emerged as unique vinylene candidates in dehydrogenative annulation strategies. For example, the You team made a groundbreaking advancement by using 1,2-dichloroethane to generate ring-fused pyridiniums through a rhodium-catalyzed annulation between N-vinylpyridinium and alkynes.⁹ Li and Majee independently reported an iron-catalyzed α,β-dehydrogenation of ethanol and nitroethane for the formation of 3,4-unsubstituted 2-arylquinolines, respectively.¹⁰ Our group realized an NH₄I-mediated vinylation annulation of α-aminoazoles with triethylamine, establishing a versatile class of promising ethylene precursors for the synthesis of pharmaceutically significant azolo[1,5-a]pyrimidines (Scheme 1a).¹¹ In this context, we hypothesize that an ethylene annulation building block derived from triethylamine could be exploited in the C(sp³)–H annulation of methylazaarenes to enable efficient preparation of valuable biheteroaryls. Herein, we introduce the first example of an I₂-promoted oxidative annulation from three different and simple amines, providing a straightforward pathway to a variety of biheteroaryl molecules with good substrate and functional group compatibility.

Scheme 1 Introduction.

Biheteroaryls with quinoline cores are an important class of structures in bioactive molecules, chemical sensors, ligands, and organic materials.¹² Among these, 2,2′-biquinolines are associated with lead compounds and drug coordinates known for their anticancer, antimicrobial, and anti-neurodegenerative properties.¹³ However, current methods towards 2,2′-biquinolines have mostly been limited to nickel-catalyzed reductive couplings of 2-haloquinolines,¹⁴ metal-free deoxygenative dimerizations of quinoline N-oxides,¹⁵ and dipyridannulations of specific isocyanides¹⁶ and these traditional methods for accessing such biheteroaromatic compounds by homocoupling have a restricted substrate scope. Recently, C(sp³)–H bond heteroannulation of 2-methylquinolines has allowed for the development of novel approaches for enhancing functional and space diversity in the synthesis of challenging nonsymmetrical 2,2′-biquinoline derivatives. In 2017, the group of Yan first demonstrated a copper-catalyzed oxidative annulation of 2-methylquinolines and 2-vinylanilines to deliver 4-aryl-2,2′-biquinolines.¹⁷ Subsequently, Deng et al. skillfully employed 1,4-dioxane as a 2-(vinyloxy)ethan-1-ol source, achieving the successful implementation of oxidative annulation with 2-methylquinolines and arylamines.¹⁸ In the same year, Zhu and co-workers reported a one-pot tandem protocol for the synthesis of 2-heteroaryl-substituted quinolines, wherein 2-methylquinolines were converted into quinoline-2-carbaldehydes in the presence of iodine and DMSO (Scheme 1b).¹⁹ Driven by these achievements, we present a general strategy for the direct assembly of biomedically relevant nonsymmetrical 2,2′-biquinolines and related bis-azines such as isoquinoline, quinoxaline, pyridine, benzothiazole, benzo[d]oxazole, and 1H-benzo[d]imidazole-tethered benzo[f]quinolines in the presence of I₂ (Scheme 1c). Moreover, this mild quinolylation protocol unveils a [4π + 2σ] annulation involving methylazaarenes and arylamines with tertiary alkylamines as two-carbon cycloaddition units, offering a convenient avenue for the late-stage functionalization of natural products and pharmaceuticals.

Initially, 2-methylquinoline (1a), naphthalen-2-amine (2a), and tripropylamine (3a) were selected as the model substrates (Table 1). Fortunately, the desired 2-methyl-3-(quinolin-2-yl)benzo[f]quinoline (4a) was isolated in 70% yield when the reaction was carried out in the presence of I₂ and DTBP in toluene at 110 °C (entry 4). However, replacing the iodine source with KI, TBAI, NIS, or NH₄I did not effectively promote the reaction and no Povarov product could be obtained without I₂ (entries 2 and 3). Other common oxidants including CHP, TBHP, TBPB, DCP, K₂S₂O₈, and DMSO also did not lead to any increase in the yield of 4a (entry 4). Surprisingly, the yield of such a biheteroaryl was improved to 85% in the absence of DTBP (entry 1). The C(sp³)–H bond functionalization of 2-methylquinolines often requires Brønsted acids to accelerate tautomerization,²⁰ and this dehydrogenative annulation reaction thus used a variety of Brønsted acids as additives. Unfortunately, the target product was produced in diminished yields (entry 5). Afterward, a survey of solvents suggested that while toluene remained the preferred choice for the model substrate pair, o-DCB, PhCl, and o-xylene were also relatively effective (entries 6 and 7). Further evaluation of temperatures failed to show better results (entries 8–10). Control experiments demonstrated that aerial oxygen as the oxidant was essential for facilitating this quinolylation process (entries 11 and 12). Performing the reaction by adjusting the loading of 3a, 1a, or molecular iodine no longer had a positive effect on the yield of 4a (entries 13–17).

Table 1 Optimization of the reaction conditions^a

Entry	Variation from standard conditions	Yield^b (%)
a Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), 3a (0.2 mmol), [I] (0.2 mmol), and solvent (2.0 mL) at 110 °C for 20 h in a sealed tube. b Isolated yields. c Oxidant (0.6 mmol). d Acid (0.2 mmol).
1	None	85
2	KI, TBAI, NIS, NH4I instead of I2	0–52
3	Without I2	0
4^c	Addition of CHP, TBHP, TBPB, DCP, K2S2O8, DMSO, or DTBP	26–70
5^d	Addition of CF3SO3H, CH3SO3H, CH3COOH, or PhCOOH	55–79
6	o-DCB, PhCl, o-xylene instead of toluene	63–81
7	DCE, THF, DMSO, CH3CN, DMF, NMP instead of toluene	18–43
8	120 °C instead of 110 °C	71
9	100 °C instead of 110 °C	78
10	80 °C instead of 110 °C	62
11	Under Ar	45
12	Under O2	87
13	With 0.4 mmol 3a	50
14	With 0.4 mmol 1a	86
15	With 0.2 mmol 1a	64
16	With 0.3 mmol I2	77
17	With 0.1 mmol I2	45

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Having established the optimized reaction conditions, we subsequently investigated the scope of this I₂-promoted [4π + 2σ] annulation with methylazaarenes (Scheme 2). A variety of substituents on the phenyl rings of 2-methylquinolines, regardless of whether they were electron-donating (Me and OMe), electron-withdrawing (NO₂, CO₂Et, and CO₂ⁱBu) or halo (F, Cl, and Br) groups, were well tolerated, affording the quinolylation products (4b–4f and 4h–4m) in 71–88% yields. Gratifyingly, cyclododecyl-containing 2-methylquinoline (1g) was also proven to be compatible with the reaction. In the case of 4-chloro-2-methylquinoline (1n), the relatively lower yield was presumably attributable to the reduced electron density on the pyridine ring, which had an adverse effect on the iodination process. To our delight, the π-system-expanded 3-methylbenzo[f]quinoline 1o was a suitable candidate to deliver the symmetrical 3,3′-bibenzo[f]quinoline skeleton in 85% yield. Meanwhile, 4-methylquinoline (1p) and 1-methylisoquinoline (1q) displayed reactivities similar to 2-methylquinoline. Further investigations revealed that mononuclear 2-methyl and 4-methyl feedstocks were excellent partners and gave rise to the corresponding pyridine–benzo[f]quinoline linked biheteroaryls (4s and 4t) in 85% and 87% yields, respectively. The C(sp³)–H annulation strategy was also extended to other 2-methylazaarenes featuring two heteroatoms, providing a straightforward access to various types of biheteroarene structural motifs (4r and 4u–4w). Given the intriguing versatility and practicality of this transformation, we conducted late-stage functionalization on several natural products and drug molecules. It is noteworthy that 2-methylquinolines derived from L-menthol, estrone, and vitamin E underwent successful modifications to yield the biheteroarene products. In addition, a larger scale experiment proceeded smoothly, with 1.0 mmol of starting material 2a under the standard conditions.

Scheme 2 Substrate scope of methylazaarenes. Reaction conditions: 1 (0.3 mmol), 2a (0.2 mmol), 3a (0.2 mmol), I₂ (0.2 mmol) and toluene (2.0 mL) at 110 °C in a sealed tube. Isolated yields. ^a 1 mmol scale based on 2a.

Next, we explored the generality of the dehydrogenative annulation strategy with respect to aromatic amines (Scheme 3). Naphthalen-2-amines with methoxyl, bromo, and formic ester groups at the C6 position exhibited good performance and generated the quinoline-substituted benzo[f]quinoline derivatives 4aa–4ac in good to excellent yields (75–90%). In comparison, the tetracyclic naphtho[2,3-f]quinoline 4ad was obtained in disappointing yields when the reaction was run with anthracen-2-amine. Instead of naphthalen-2-amine, when naphthalen-1-amine was used, 4ae was efficiently furnished in 82% yield. Remarkably, the versatility of this process was further demonstrated by the successful use of various anilines, which provided robust access to a series of nonsymmetrical 2,2′-biquinolines. Unsubstituted aniline, a challenging substrate in related research, reacted smoothly with 1a and 3a to form the methylated 2,2′-biquinoline 4af in 74% yield. Regarding monosubstituted anilines at the para position, the phenomenon wherein electron-rich groups such as methyl, methoxyl, and tertiary butyl favored the [4π + 2σ] cycloaddition step to give higher yields compared to the electron-poor substituent (2k) was observed. When meta-substituted arylamines were applied to this annulation procedure, only isomers 4ak and 4al were obtained successfully. Meanwhile, reactions using acyclic or cyclic disubstituted and trisubstituted anilines, characterized by enhanced nucleophilicity, also afforded the corresponding biquinoline derivatives in up to 85% yields (4am–4as). Unexpectedly, a methylene oxidation reaction occurred during such a quinoline annulation and permitted the integration of 9-fluorenone into the biheteroaryl structure (4aq). By utilizing this quinolylation of methylazaarenes, the unsubstituted N-biheterocycle 4at could be synthesized as well, wherein the unsubstituted C=C bond fragment favorably incorporated into the pyridine ring formed from triethylamine (3b). Moreover, efforts focused on testing other tertiary alkylamines (3c–3k), including triamylamine, trihexylamine, triheptylamine, trioctylamine, trinonylamine, tridecylamine, triundecylamine, tridodecylamine, and the bulky triisopentylamine. Much to our satisfaction, all these substrates showed consistent results with triethylamine in the established system, affording alkylation heteroannulation products (4au–4aac) in yields ranging from 77% to 85%.

Scheme 3 Substrate scope of arylamines and tertiary alkylamines. Reaction conditions: 1a (0.3 mmol), 2 (0.2 mmol), 3 (0.2 mmol), I₂ (0.2 mmol) and toluene (2.0 mL) at 110 °C in a sealed tube. Isolated yields.

To elucidate the mechanism of this C(sp³)–H annulation reaction, a deuterium-labeling experiment with 3b-d₁₅ as the substrate was carried out and the expected deuterated product 4at-Dn was obtained with 100% and 25% deuterium incorporation at the β-C and γ-carbon atoms of the newly formed pyridine ring, respectively (Scheme 4a). Furthermore, the H/D exchange experiment confirmed that γ-selective deuteration reactions of two pyridine rings proceeded simultaneously. These results indicated that the mechanism involved the cleavage of three C(sp³)–D bonds and one C–N bond, showing that only the two C(sp³)–D bonds in the α,β-carbon atoms of triethylamine were effectively integrated into the biquinoline skeleton (Scheme 4b). When 2-(iodomethyl)quinoline (5) with 2a and 3a was subjected to the standard reaction conditions, product 4a was also achieved in 80% yield (Scheme 4c). Meanwhile, the [4π + 2σ] annulation of imine (6) and 3a proceeded well in the current system. Obviously, both heterobenzyl iodides and imines were recognized as potential intermediates during the transformation. However, the lack of I₂ rendered the reaction between 6 and 3a unsuccessful, highlighting the indispensability of I₂ in the [4π + 2σ] annulation procedure (Scheme 4d). Undoubtedly, the formation of a phenyl-substituted biheteroaryl (8) from N,N-diethyl-2-phenylethenamine (7) supported the idea that enamines generated from tertiary alkylamines through dual inert C(sp³)–C(sp³) bond dehydrogenation served as the actual intermediates for this [4π + 2σ] annulation (Scheme 4e). Furthermore, radical inhibition experiments ruled out a radical pathway (Scheme S1†).

Scheme 4 Mechanistic investigations and proposed mechanism.

Based on the above observations and relevant reports,²¹ a plausible mechanism for the C(sp³)–H annulation of three nucleophiles has been proposed (Scheme 4f). Under suitable pH conditions, 2-methylquinoline (1a) can be transformed into its more nucleophilic transient enamine counterpart 1a′, followed by iodination with I₂ to give the intermediate 2-(iodomethyl)quinoline (A). Subsequently, heterobenzyl iodide (A) undergoes nucleophilic amination directly with naphthalen-2-amine (2a) to generate the secondary amine intermediate B, which is further rapidly oxidized by I₂ to form the key imine intermediate 6. At the same time, the dehydrogenation of tripropylamine (3a) with I₂ and air easily results in the formation of a common imine-type intermediate (C). It is critical that I₂ and HI enable the aza-Diels–Alder reaction of 6 and the transient enamine (D) derived from the hidden tautomerization of C to afford the Povarov product E. Finally, the sequential deamination and oxidative aromatization can deliver the desired product 4a.

Conclusions

In conclusion, we have developed a [4π + 2σ] annulation approach that offers a general and complementary solution to a wide array of nonsymmetrical biheteroaryls under mild and metal-free conditions. The key to the oxidative annulation of three different nucleophiles is that molecular iodine establishes efficient transformations of methylazaarenes and linear alkyl tertiary amines into heterobenzyl iodide species and transient enamines, respectively. This C(sp³)–H annulation strategy exhibits outstanding compatibility with functional groups and heterocycles, is applicable to the late-stage functionalization of complex quinolines, and paves the way for the discovery of bioactive molecules and functional materials.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to the Natural Science Foundation of Henan Province (242300421356), the Key Research and Promotion Special Projects of Henan Provincial Science and Technology Department (242102320053) and Open Grant from Pingyuan Laboratory (2023PY-OP-0205) for financial support.

References

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2384037. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo01801j

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