One-pot Mannich/aza-Wittig/deaminative aromatization reactions for the synthesis of 1,2,3,4-tetrahydroacridines and cyclohepta[b]quinolines

Abstract

A one-pot synthesis for the preparation of 1,2,3,4-tetrahydroacridines involving a Zr(IV)-catalyzed Mannich reaction of o-azidobenzaldehydes and arylamines with cycloketones, followed by aza-Witting cyclization and deaminative aromatization, is developed. This method can be extended for the synthesis of cyclohepta[b]quinolines.

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Introduction

Acridine is a privileged ring which could be found in natural products, such as plakinidine A and B^1a and dercitin,^1b as well as drug molecules, such as amsacrine (cytotoxic, antiviral),^2a,b botiacrine (antiparkinasonian),^2c,d clomacran (tranquilizer),^2e,f and monometacrine (antidepressant),^2g,h antitumor agents,^3a acetylcholinesterase inhibitors,^3b anticancer agents,^3c and DNA binding agents (Fig. 1).^3d 1,2,3,4-Tetrahydroacridine is an analogue of partially reduced acridine. The development of efficient methods for the synthesis of 1,2,3,4-tetrahydroacridine is desirable.^3b,c,4 The Friedländer-type reaction between o-aminobenzaldehyde and cyclohexanone is a traditional approach for 1,2,3,4-tetrahydroacridines (Scheme 1, A).⁴ The Katritzky group developed a one-pot synthesis involving the addition of a Vilsmeier-type reagent (benzotriazole iminium salt) to N-arylcyclohexanimines, followed by cyclization and elimination reactions (Scheme 1, B).⁵ The Basavaiah group utilized Baylis–Hillman alcohols (B–H alcohols) derived from 2-nitrobenzaldehydes and cyclohex-2-enone for the synthesis of 1-acetoxy-1,2,3,4-tetrahydroacridines (Scheme 1, C).⁶ The Ramachary group reported the List–Lerner–Barbas aldol (LLB-A) reaction of 2-azidobenzaldehydes and cyclohexanones for the synthesis of 1,2,3,4-tetrahydroacridines (Scheme 2, A).⁷ The iminophosphorane intermediate generated from tributylphosphine and the azido group underwent an intramolecular aza-Wittig reaction, followed by dehydroxylative aromatization, to generate bioactive tetrahydroacridines.

Fig. 1 Representative bioactive acridine derivatives.

Scheme 1 Reported methods for 1,2,3,4-tetrahydroacridines.

Scheme 2 o-Azidobenzaldehyde-based aza-Wittig cyclization for quinolones.

Readily available o-azidobenzaldehydes are a versatile synthon for constructing nitrogen-containing heterocycles.⁸ We have utilized them in the synthesis of quinolines,⁹ tetrahydroquinolines,¹⁰ benzodiazepines,¹¹ benzodiazepinones,¹² triazo-fused benzodiazepines¹³ and dihydroquinazolinethiones.¹⁴ We have also reported the synthesis of 4-hydroxyquinolines through a cascade Knoevenagel reaction of 2-azidobenzaldehydes and α-fluoro-β-ketoesters and an intramolecular aza-Wittig reaction (Scheme 2, B)^9b and the construction of 4-aminoquinolines through a cascade Mannich reaction of 2-azidobenzaldehydes, amines and α-fluoro-β-ketoesters, followed by aza-Wittig cyclization (Scheme 2, C).^9c Literature survey reveals that there is no report on the deaminative aromatization for preparing quinolines after the intramolecular aza-Wittig reaction. We decided to explore the reaction of o-azidobenzaldehydes 1, amines 2 and cycloketones 3 in sequential Mannich/aza-Wittig/deaminative aromatization reactions to construct biologically interesting tetrahydroacridines 4 (Scheme 3).

Scheme 3 Synthetic path of this work.

Results and discussion

The development of reaction conditions was carried out using 2-azidobenzaldehyde 1a (1 equiv.), aniline 2a (1.05 equiv.) and cyclohexanone 3a (1.5 equiv.) as the substrates. The Mannich reaction catalysed by 15 mol% of ZrOCl₂·8H₂O was performed in MeCN (5 mL) at rt for 12 h following the literature procedures.¹⁵ Without isolation of the intermediate, the Mannich product was treated with PPh₃ (1.2 equiv.) for the intramolecular aza-Wittig reaction, followed by sequential deaminative aromatization at rt for 6 h to afford product 4a in 73% yield (Table 1, entry 1). Screening of a number of arylamines 2c–f indicated that 4-chloroaniline 2e is the best choice which gave product 4a in 87% yield (entries 2–6). Other conditions such as a higher reaction temperature and a prolonged reaction time failed to improve the yields (entries 7 and 8).

Table 1 Optimization of reaction conditions^a

Entry	R-NH2 (2)	T (°C)	t (h)	4a (%)
a Reaction conditions: (1) 1a (0.5 mmol), 2 (0.525 mmol/1.05 eq.), 3a (0.75 mmol/1.5 equiv.), ZrOCl2·8H2O (0.075 mmol/0.15 eq.), MeCN (5 mL), rt, 12 h; (2) PPh3 (0.6 mmol/1.2 eq.), rt, 6 h. b Isolated yield based on 1a.
1	Ph-NH2, 2a	rt	6	73
2	Bn-NH2, 2b	rt	6	23
3	4-Me-Ph-NH2, 2c	rt	6	76
4	4-MeO-Ph-NH2, 2d	rt	6	81
5	4-Cl-Ph-NH2, 2e	rt	6	87
6	4-CO2Me-Ph-NH2, 2f	rt	6	80
7	4-Cl-Ph-NH2, 2e	105	6	85
8	4-Cl-Ph-NH2, 2e	rt	12	88

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The scope of this new reaction process was evaluated under the optimized conditions using different o-azidobenzaldehydes 1 and cyclohexanones 3 (Table 2). It was found that Cl and Br on the benzene ring of 1 and Me at the 4-position of cyclohexanone 3 had little impact on the product yields. For example, reactions of 3a with halogen-containing 1b, 1c and 1d proceeded smoothly to produce 4d, 4g and 4j in 91%, 80% and 84%, respectively (entries 4, 7 and 10). These products could be further derivatized through metal-catalysed cross-coupling reactions. The reaction of 4-substituted cyclohexanones 3 gave products 4e–f, 4h–4i and 4k–l in 78–86% yields (entries 5, 6, 8, 9, 10 and 12). Reactions of 1e bearing an electron donating group also afforded the corresponding products 4m–4o in 83–87% yields (entries 13–15). However, the reaction of 4,4-difluorocyclohexan-1-one 3d afforded products 4p–4s in relatively low yields of 53–63% (entries 16–19).

Table 2 Scope of the reaction of 1 with cyclohexanones 3a–d^a

Entry	Aldehyde 1	Cyclic ketone 3				4 (%)
	R^1	1	R^2	R^3	3
a Reaction conditions: (1) 1 (0.5 mmol), 2e (0.525 mmol/1.05 eq.), 3 (0.75 mmol/1.5 equiv.), ZrOCl2·8H2O (0.075 mmol/0.15 equiv.), MeCN (5 mL), rt, 12 h; (2) PPh3 (0.6 mmol/1.2 equiv.), rt, 6 h. b Isolated yield based on 1.
1	H	1a	H	H	3a	4a, 87
2	H	1a	H	Me	3b	4b, 84
3	H	1a	Me	Me	3c	4c, 85
4	5-Cl	1b	H	H	3a	4d, 91
5	5-Cl	1b	H	Me	3b	4e, 84
6	5-Cl	1b	Me	Me	3c	4f, 86
7	5-Br	1c	H	H	3a	4g, 80
8	5-Br	1c	H	Me	3b	4h, 82
9	5-Br	1c	Me	Me	3c	4i, 78
10	4-Cl	1d	H	H	3a	4j, 84
11	4-Cl	1d	H	Me	3b	4k, 85
12	4-Cl	1d	Me	Me	3c	4l, 79
13		1e	H	H	3a	4m, 87
14		1e	H	Me	3b	4n, 86
15		1e	Me	Me	3c	4o, 83
16	5-Cl	1b	F	F	3d	4p, 63
17	5-Br	1c	F	F	3d	4q, 56
18	4-Cl	1d	F	F	3d	4r, 60
19		1e	F	F	3d	4s, 53

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Other than 6-membered cyclic ketones, we also investigated the reaction of cycloheptanone 3e with 1a–d and obtained cyclohepta[b]quinolines 4t–4w in 51–60% yields. The lower yields from the reaction of cycloheptanone could have resulted from the steric effect of the 7-membered ring (Scheme 4, a). Under the same conditions, reaction 1a with cyclopentanone 3f (Scheme 4, b) or benzocyclohexanone 3g (Scheme 4, c) gave trace amounts of products 4x and 4y.

Scheme 4 Reaction with cyclic ketones 3e–g.

Control experiments were carried out to gain information for understanding the mechanism of the cascade reaction process and the role of aryl amines 2. Without using ZrOCl₂·8H₂O or in the presence of ZrOCl₂·8H₂O but without amines 2e, no product was detected from the reaction mixture. The results suggested that the formation of a Mannich base as a reaction intermediate is indispensable. A plausible mechanism to rationalize the formation of 4 is proposed (Scheme 5). The Mannich reaction of 1, 2 and 3 under the catalysis of ZrOCl₂·8H₂O provides intermediate A. Aza-Wittig cyclization of A in the presence of PPh₃ affords N-substituted-9-aminohexahydroacridine intermediate B, followed by in situ release of aryl amine 2 to give product 4.

Scheme 5 Proposed mechanism for the one-pot synthesis.

Conclusions

In summary, we have developed a 4-chloroaniline-mediated highly efficient and simple one-pot and two-step synthesis of 1,2,3,4-tetrahydroacridines and cyclohepta[b]quinolines using readily available o-azidobenzaldehydes and cycloketones. The reaction process involves sequential Zr(IV)-catalysed Mannich/intramolecular aza-Wittig/deaminative aromatization reactions to give the desired products in moderate to good yields. The one-pot reaction has green chemistry advantages of pot economy, resource efficiency, and elimination of the waste generated from intermediate purification.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful for financial support from the Program for Science and Technology Development of Henan (212102310883) and the Key Natural Science Research Program of Education Department of Henan (21B150013).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures, compound characterization, and NMR spectra. See DOI: https://doi.org/10.1039/d2nj04082d

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