Copper-catalyzed C5-selective thio/selenocyanation of 8-aminoquinolines

Abstract

Copper-catalyzed direct C5-position thio/selenocyanation of quinolines using commercially available, inexpensive KSCN/SeCN as the thio/selenocyanation reagent was developed, which had good tolerance toward various aliphatic or aromatic 8-aminoquinoline derivatives. Importantly, the synthetic application of this protocol led to some useful compounds.

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Organic thiocyanates are a class of important compounds with diverse bioactivities such as antibacterial, antifouling and antitumor activities.¹ Meanwhile, the thiocyanate can be handily transformed to other common functional groups such as disulfides, thioethers, thiocarbamates and sulfonylcyanides.² Although many methods have been established to synthesize alkyl thiocyanates, the construction of aryl thiocyanates has not been fully developed. Generally, the thiocyanate group can be introduced to arenes by the traditional cross-coupling of thiocyanate sources with active aryl species such as aryl halides, aryl diazonium salt (Sandmeyer reaction), aryl metal reagents or arylboronic acids (Scheme 1, eq1).^2a,b,3 The cyanation of thiophenols, disulfides or aryl sulfonates is another approach for synthesizing aryl thiocyanates (eq2).^2a,b,4 Undoubtedly the aforementioned methods have made great synthesis contributions, whereas the toxicity and high cost of the reagent, unavailable starting materials, or undesired byproducts could limit their wide applications. Compared with those that feature prefunctionalized arenes, the direct aryl thiocyanation seems more attractive. In fact, this strategy has been applied to the thiocyanation of some active heteroaromatics such as indoles and imidazopyridines (eq3).⁵ However, to the best of our knowledge, the direct thiocyanation of inactive arenes has rarely been reported.

Scheme 1 Pathways to synthesize aryl thiocyanates.

Quinolines are important structural motifs widely present in bioactive compounds, pharmaceuticals and natural products.⁶ They often serve as ligands for coordination chemistry or directing groups for various metal-catalyzed reactions.⁷ They are also used as fluorescent probes for the detection of Zn²⁺ and Fe³⁺ or imaging fluorescence in living cells.⁸ Great progress has been made in the 2-, 3-, 4- and 8-position modifications of quinolines,⁹ and the C5-position functionalization of 8-aminoquinolines has recently received increasing attention.¹⁰ Stahl and co-workers initially reported the Cu-catalyzed C5-chlorination of 8-aminoquinoline.^10a After that, Fe-catalyzed allylation,^10b Cu-mediated/catalyzed halogenation,^10c,d chalcogenation,^10e sulfonylation,^10f–k amination,^10l trifluoromethylation,^10m selenylation,¹⁰ⁿ and Co-catalyzed nitration^10o have also been reported on the C5 position independently. Very recently, Wang and co-workers realized the Ni-catalyzed C5-position difluoroalkylation of 8-aminoquinoline.^10p

Given the importance of quinolines and thiocyanates, it is of great interest to combine the two ones into a single entity. Herein, we would like to report a general and efficient protocol for the preparation of quinoline aryl thiocyanates on the C5 position, using commercially available and inexpensive KSCN as the thiocyanation reagent (Scheme 1, eq4). Moreover, this protocol was expanded to the corresponding selenocyanation of quinolines (eq4).

Initially, N-(quinolin-8-yl)butanamide (1a) and KSCN (2a) were selected as the substrates to optimize the reaction conditions. Fortunately, after several trials, when the reaction was performed in 1,2-dichloroethane (DCE) using K₂S₂O₈ (2.0 equiv.) as an oxidant in the presence of a catalytic amount of CuI (20 mol%), N-(quinolin-5-thiocyanate-8-yl)butanamide (3a) was obtained in 62% yield (Table 1, entry 1). The structure of 3a was unambiguously confirmed using X-ray crystallography analysis. The control experiment reveals that CuI was essential for this transformation (entry 2). Then, several copper salts were tested. CuCl and CuI showed almost similar reactivities, whereas the use of the others resulted in either decreased yields (entries 3–7) or only traces of products (entries 8 and 9). Other metallic catalysts were also tested, but no desired product was obtained (entries 10–12). Based on these results, CuCl was selected as the optimal catalyst. The reaction hardly occurred when KSCN was replaced by NH₄SCN (entry 13). Then, a series of oxidants were screened (entries 14–17), but none of them matched the efficiency of K₂S₂O₈ except Na₂S₂O₈ (entry 18). Increasing the loading of CuCl to 0.5 equiv. led to a slightly low yield (54%, entry 19), which can be explained by the generation of C5-chlorinated byproduct.^10a,c,d The addition of 10 mol% TBAI (tetrabutylammonium iodide) improved the yield to 73% (entry 20). While TBAI was replaced with I₂, the yield decreased to 47% (entry 21). Both base and acid additives were found to be detrimental to this reaction (entries 22–26). The solvent and temperature screenings reveal that the use of DCE and 120 °C comprised the optimal conditions (see ESI†).

Table 1 Optimization of reaction conditions^a

Entry	Catalyst	Oxidant	Additive	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (20 mol%), oxidant (0.4 mmol), additive (0.4 mmol), DCE (2 mL) at 120 °C for 24 h. b Isolated yield. c 2.0 equiv. of NH4SCN instead of KSCN. d Under O2 atmosphere. e Copper catalyst (0.5 equiv.). f Additive (10 mol%).
1	CuI	K2S2O8	—	62
2	—	K2S2O8	—	0
3	CuBr	K2S2O8	—	54
4	CuCl	K2S2O8	—	65
5	CuSCN	K2S2O8	—	25
6	CuCl2	K2S2O8	—	45
7	CuBr2	K2S2O8	—	35
8	Cu(OAc)2	K2S2O8	—	Trace
9	Cu(OTf)2	K2S2O8	—	Trace
10	Pd(OAc)2	K2S2O8	—	0
11	Co(OAc)2	K2S2O8	—	0
12	NiCl2	K2S2O8	—	0
13^c	CuCl	K2S2O8	—	Trace
14	CuCl	(NH4)2S2O8	—	Trace
15	CuCl	Ag2CO3	—	0
16	CuCl	PhI(OAc)2	—	37
17^d	CuCl	O2	—	Trace
18	CuCl	Na2S2O8	—	61
19^e	CuCl	K2S2O8	—	54
20	CuCl	K 2 S 2 O 8	TBAI	73
21^f	CuCl	K2S2O8	I2	47
22	CuCl	K2S2O8	K2CO3	0
23	CuCl	K2S2O8	NaOAc	0
24	CuCl	K2S2O8	KH2PO4	58
25	CuCl	K2S2O8	AcOH	34
26	CuCl	K2S2O8	TsOH	Trace

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With the optimized reaction conditions (entry 20), diverse 8-aminoquinoline scaffolds were first examined (Table 2). The results demonstrate that all substrates with electron-donating groups such as methyl (3b, 3j) or methoxy (3g, 3i) at C3-, C4- or C6-position of quinoline were well tolerated, and the desired products were obtained in 78–88% yields. Comparatively, the substrates with electron-withdrawing groups such as chlorine (3c, 3h, 3k), bromine (3d) or ester (3e) showed a lower reactivity, resulting in 48–71% yields. Even when the substrate substituted with the strong electron-withdrawing cyanide group (3f), no product was obtained. These results indicate that the reaction was sensitive to the electron density on the quinoline ring and the electron-rich substrates had better reactivity than the corresponding electron-deficient ones. Moreover, several disubstituted 8-aminoquinolines also smoothly proceeded the reaction (3l–o, 52–73% yields). The substrates with C2 substituents gave 3p and 3q in 24% and 11% yields, respectively. The reaction could not occur if C7-substituted substrates were used (3r and 3s). These results indicate that C2 or C7 substituents affected the coordination process of the Cu catalyst with the substrates because of the steric hindrance, which may be one of the proofs of our proposed mechanism (Scheme 4).

Table 2 Reaction scope of 8-aminoquinoline scaffold^a

a Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), CuCl (20 mol%), K₂S₂O₈ (0.4 mmol), TBAI (10 mol%), DCE (2 mL) at 120 °C for 24 h. Isolated yields.

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We subsequently explored the substrate scope with respect to the acyl motifs of the aminoquinoline amides (Table 3). This protocol was amenable to both linear (3a) and branched (4a–d) aliphatic-acid-derived substrates. All N-(quinolin-8-yl)benzamides substituted by various electron-withdrawing or electron-donating groups were well tolerated in this reaction system (4e–i). The substrates derived from 3-methyl-2-butenoic acid and 2-furoic acid were also feasible for this reaction (4j and 4k).

Table 3 Reaction scope of the acyl motif^a

a Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), CuCl (20 mol%), K₂S₂O₈ (0.4 mmol), TBAI (10 mol%), DCE (2 mL) at 120 °C for 24 h. Isolated yields.

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Organic selenocyanates are also important precursors for the synthesis of many seleno-containing compounds and have been discovered with various bioactivities such as antioxidative, antitumor activities, etc.¹¹ Encouraged by the excellent performance of the current catalytic system, we explored the corresponding selenocyanation of 8-aminoquinoline derivatives using KSeCN as the selenocyanation reagent. To our delight, the desired selenocyanated products were obtained in moderate to good yields (Table 4). For C3- or C6-substituted 8-aminoquinolines, the substrates with electron-donating groups showed better reactivity than the corresponding ones with electron-withdrawing groups (e.g., 5avs.5b, 75% vs. 58%), which is similar to the thiocyanation process. The disubstituted substrates also showed good tolerance in this reaction system (5f, 68%). Typical linear or branched alkyl, olefinic or aromatic amide substitution all worked well under the standard reaction conditions (5g–5j).

Table 4 Reaction scope of the selenocyanation^a

a Reaction conditions: 1 (0.2 mmol), 2b (0.4 mmol), CuCl (20 mol%), K₂S₂O₈ (0.4 mmol), TBAI (10 mol%), DCE (2 mL) at 120 °C for 24 h. Isolated yields.

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To demonstrate the synthetic utility of the protocol, we conducted the reaction on a 10 mmol gram scale, and the desired product was obtained in 64% yield (Scheme 2). The amide bond can be easily broken without damaging the thiocyanate group of 3a to produce compound 6 in 91% yield.^10f The thiocyanate 3a can be oxidized to sulfinyl cyanide 7 in 86% yield^2h or transformed to thiocarbamate 8 in 82% yield.^2g In addition, the coupling of 3a with iodobenzene can produce the thioether 9 in 72% yield according to a modified method.^2e

Scheme 2 Gram scale and synthetic applications.

Furthermore, a series of control experiments were performed to explore the reaction mechanism as shown in Scheme 3. When the radical quencher TEMPO (2,2,6,6-tetramethylpiperidine-N-oxide) or BHT (2,6-di-tert-butyl-4-methylphenol) was added to the reaction system, the yield sharply decreased (Scheme 3a, 25% or trace). This empirical evidence reveals that a single-electron transfer (SET) process may be a key step in the catalytic system. The addition of substrates 1aa or 1ab instead of 1a to the reaction system led to the recovery of the corresponding starting materials (Scheme 3b). This result indicates that the thiocyanation was a direct functionalization process without the formation of chlorinated or iodinated intermediates.^10a,c,d A bidentate coordination model was obviously preferred based on the comparison of substrate 1a with 1ac, 1ad, 1ae (Scheme 3c).

Scheme 3 Control experiments.

Based on the above results and previous reports,¹⁰ we proposed a plausible reaction mechanism as shown in Scheme 4. First, a Cu(I)-quinoline complex A with bidentate nitrogen atom chelation was formed. With the assistance of TBAI, complex A was oxidized to a Cu(II) intermediate B by K₂S₂O₈. The deprotonation of B produced the amidate-Cu(II) intermediate C, which might experience an intramolecular SET process to produce a cationic radical D.^10h,n,o A radical coupling reaction of D and the SCN radical that was generated by the oxidation of KSCN in the presence of K₂S₂O₈ ^5d afforded the cationic intermediate E. Further deprotonation and ligand-exchange process produced the desired product 3a and regenerated the Cu(I) catalyst.

Scheme 4 Proposed mechanism.

In summary, an efficient method of copper-catalyzed direct C5-selective thio/selenocyanation of quinolines was developed. The protocol featured the use of commercially available and inexpensive KSCN/SeCN as the thio/selenocyanation reagent, which had good tolerance toward various aliphatic or aromatic 8-aminoquinoline derivatives. Besides, a direct thiocyanation was proposed. It should be noted that the thiocyanation product could be easily transformed to some useful compounds such as sulfinyl cyanide, thiocarbamate and thioether, which provides an alternative method to synthesize 5-thio-8-aminoquinoline derivatives.

Financial support from the National Natural Science Foundation (No. 81373280, 81673306), the Project Program of State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. SKLNMZZCX201404), and the Innovation project of Jiangsu Province (No. KYLX15_0633) is gratefully acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures, characterization of new compounds, and X-ray analysis. CCDC 1483507. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00590j

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