Copper-catalyzed dehydrogenative γ-C(sp3)-H amination of saturated ketones for synthesis of polysubstituted anilines

Metal-catalyzed β-C-H functionalization of saturated carbonyls via dehydrogenative desaturation proved to be a powerful tool for simplifying synthesis of valuable β-substituted carbonyls. Here, we report a copper-catalyzed dehydrogenative γ-C(sp3)-H amination of saturated ketones that initiates the three-component coupling of saturated ketones, amines and N-substituted maleimides to construct polysubstituted anilines. The protocol presented herein enables both linear and α-branched butanones to couple a wide spectrum of amines and various N-substituted maleimides to produce diverse tetra- or penta-substituted anilines in fair-to-excellent yields with good functional group tolerance. The mechanism studies support that this ketone dehydrogenative γ-C(sp3)-H amination was triggered by the ketone α,β-dehydrogenation desaturation that activates the adjacent γ-C(sp3)-H bond towards functionalization. This α,β-dehydrogenation desaturation-triggered cascade sequence opens up a new avenue to the remote C(sp3)-H functionalization of saturated ketones and has the potential to enable the rapid syntheses of complex compounds from simple starting materials.

K etones, a large class of versatile and readily available substrates, conventionally participate in reactions with their electrophilic ipso-carbons or nucleophilic α-carbons 1 . Recently, the β-functionalization reactions of saturated ketones have been achieved by employing directing group-assisted Pdcatalyzed C(sp 3 )-H activation methods [2][3][4][5][6] , or the strategies of merging photoredox catalysis with organocatalysis 7,8 , or metalcatalyzed ketone α,β-dehydrogenation desaturation/the resultant enone coupling cascade sequence [9][10][11][12][13][14][15][16][17][18] . Despite these advances in the development of the approaches to reactions at β-carbons of ketones, for the direct γ-C(sp 3 )-H functionalization of saturated ketone, only a few of examples have been reported to date 2,19-21 . The first example is the Pd-catalyzed γ-arylation reaction of the ketone lacking any β-C(sp 3 )-H bond using glycine as a transient directing group (Fig. 1a), which was limited to only a single ketone substrate 2 . The other two examples for ketone γ-C(sp 3 )-H functionalization both involved the use of α-imino-oxy acids prepared from the condensation of ketones with α-aminoxy acids as starting materials: one was the auxiliary-assisted Pd-catalyzed γ-C(sp 3 )-H arylation reaction of α-imino-oxy acid with aryl iodides that afforded γ-arylated ketones after Mn-catalyzed removal of α-imino-oxy acid auxiliary (Fig. 1b) 19 ; the other was the photoredox-catalyzed cross-coupling between α-imino-oxy acid and radical trapping reagents that furnished, after treatment of the reaction products with water, the γ-functionalized ketones as final products (Fig. 1c) 20,21 . Notably, the metal-catalyzed remote C(sp 3 )-H functionalization, which is similar to ketone γ-C(sp 3 )-H functionalizaion in terms of the distance between the reaction position and functional group, has been accessible to a handful of carboxylic acid derivatives containing specific auxiliary directing groups [22][23][24][25][26][27] . These reactions of carboxylic acid derivatives disclosed that their appropriate auxiliary directing groups were essential for remote C(sp 3 )-H functionalization. However, the relatively low reactivity of ketones severely limits the scope of the directing groups that are pre-installed or in situ installed to saturated ketone frameworks, and therefore poses a great challenge to the development of transient directing group strategy for metal-catalyzed γ-C(sp 3 )-H functionalization of simple ketones. The metal-catalyzed methods for direct γ-functionalization of saturated ketones without the need for pre-installation of auxiliary directing group to ketone framework is highly desired, given that such methods would expand the reactivity patterns of ketones, streamline syntheses of value-added γ-functionalized ketones.
Herein, we report a Cu-catalyzed dehydrogenative γ-amination reaction of saturated ketone that initiates a 2-amino furan formation/[4 + 2] cycloaddition of resultant 2-amino furan with N-substituted maleimide cascade sequence toward construction of polysubstituted anilines (Fig. 1d). The mechanism studies reveals that this Cu-catalyzed γ-amination reaction is triggered by ketone α,β-dehydrogenative desaturation, which activates the γ-C(sp 3 )-H bond of the resultant enone intermediate toward amination. Our findings demonstrate that the α,β-dehydrogenative desaturation triggered ketone γ-functionalization is viable even using nucleophilic amines as coupling partners. Since these polysubstituted anilines are readily converted to diverse valuable compounds 61,62 , this operationally simple, efficient method for the syntheses of polysubstituted anilines from simple substrates will attract the attentions from chemists working in a variety of research fields.
Substrate scope of secondary amines. Figure 3 demonstrates that the Cu-catalyzed three-component coupling reaction was compatible with a broad range of secondary amines using 1phenyl-1-butanone or α-phenyl-substituted 1-phenyl-1-butanone as a coupling partner. N-alkyl anilines furnished the corresponding products in good yields (5a-g). Besides, acyclic dialkyl amines afforded products in fair-to-excellent yields (5h-5n). Notably, an array of alicyclic amines with varying substitutents and substitution patterns, including methyl (5t and 5x), phenyl (5u and 5v), chloro (5w), ester (5y) groups were well tolerated in this reaction. Thiomorpholine (5q) was also suitable substrate and provided synthetically useful yields. To demonstrate the practicability of our method, the gram-scale reaction of 1h (1.61 g, 7.14 mmol) was conducted to afford the corresponding product (5o) in 70% yield (2.06 g). The three-component coupling reaction was also capable of modifying paroxetine containing the alicyclic amine moiety (5z), illustrating its potential in practical utilities.
Substrate scope of tertiary amines. Interestingly, tertiary amines could participate in this three-component coupling reaction via cleavage of C-N bond 67,68 , thus play the similar role to secondary amines (Fig. 4). Although the exact reason for the cleavage of C-N bond remains to be clarified, among the investigated tertiary amines, the C-N bond cleavage occurred preferentially either at more sterically accessible carbon atoms (entries 1, 2, 4, and 8) or at carbon atoms adjacent to substituents capable of stabilizing carbon radicals (entries 3 and 6). For example, diisopropyl ethylamine gave excellent yield (entry 1) via cleavage of C-N bond of less sterically hindered ethyl group while bulkier triisobutyl amines gave moderate yield (entry 5).
In addition, this three-component coupling reaction was compatible with the variation of substituent on nitrogen atom of maleimide. A series of N-substituents of maleimide, such as benzyl, aryl and alkyl groups, were tolerable for the reaction (See Supplementary Methods for details).
In the optimization studies, control experiments showed that p-TsOH could facilitate the reaction, but was less effective than Cu catalyst alone. In the reaction of 1-phenyl-1-butanone (1a) with diisopropylamine to form 6a (eq. 6, Fig. 5), the simultaneous use of Cu catalyst and p-TsOH gave 45% yield while 16% yield was obtained in the absence of Cu catalyst, which is consistent with the results obtained in optimization studies. In contrast, in the reactions of enone 6c with diisopropylamine (eq. 3, Fig. 5) or with diisopropylamine and N-ethyl maleimide (eq. 7, Fig. 5), p-TsOH alone gave the comparable yields to those obtained with the simultaneous use of Cu catalyst and p-TsOH. These results implicated that Cu catalyst was more active than p-TsOH in the catalysis of ketone α,β-dehydrogenation desaturation step and that p-TsOH as a catalyst was effective in the conversions of enone intermediates.
On the basis of the above investigations, a cascade sequence was proposed for the three-component coupling reaction (Fig. 5c). The cascade sequence may proceed through initial α,β-dehydrogenation desaturation to form α,β-enone, γ-C(sp 3 )-H oxidation of resultant α,β-enone to a γ-keto enal intermediate, amine-aldehyde condensation between γ-keto enal with secondary amine to form 2-amino furan via intramolecular cyclization of iminium species, and final cycloaddition of 2-amino furan to N-substituted maleimide to afford polysubstituted aniline after dehydration aromatization.

Discussion
In summary, a Cu-catalyzed three-component coupling of saturated ketones, amines and N-substituted maleimides via dehydrogenative γ-C(sp 3 )-H amination of saturated ketones has been developed for syntheses of polysubstituted anilines. The dehydrogenative γ-C(sp 3 )-H amination of saturated ketones was triggered by the ketone α,β-dehydrogenation desaturation that activates the adjacent γ-C(sp 3 )-H bond. This α,β-dehydrogenation desaturation triggered sequence opens up a new avenue to the remote C(sp 3 )-H functionalization of saturated ketones, and has the potential to enable the rapid syntheses of complex compounds from readily available saturated ketones in a single operation. Efforts to develop other dehydrogenative γ-C(sp 3 )-H functionalization reactions 28,29,70 of ketones through clarifying reaction mechanism are underway in our group.

Methods
General procedure for ketones with secondary amines reaction. In a nitrogenfilled glovebox, a 25 mL Schlenk tube equipped with a stir bar was charged with Cu (OAc) 2 (7.26 mg, 0.04 mmol, 10 mol%), 2,2′-bipyridine (6.25 mg, 0.04 mmol, 10 mol%), N-substituted maleimide (0.6 mmol, 1.5 equiv.) and TEMPO (187.50 mg, 1.2 mmol, 3.0 equiv.). The tube was fitted with a rubber septum and moved out of the glove box. Then amine (0.4 mmol), ketone (0.8 mmol), p-Toluenesulfonic acid (6.88 mg, 0.04 mmol, 10 mol%, 12 wt% solution in pure acetic acid), and toluene (1.5 mL) were added in turn to the Schlenk tube through the rubber septum using syringes, and the septum was replaced with a Teflon screwcap under nitrogen flow. The reaction mixture was allowed to stir for 48 h at 120°C. After completion of the reaction, the reaction mixture was cooled to room temperature. Then the reaction mixture was diluted with ethyl acetate (10 mL), followed by filtration through a pad of silica gel with several washings. Then the filtrate was concentrated under reduced pressure, and purified by flash column chromatography on silica gel to provide the corresponding product.
General procedure for ketones with tertiary amines reaction. In a nitrogenfilled glovebox, a 25 mL Schlenk tube equipped with a stir bar was charged with Cu (OAc) 2 (7.26 mg, 0.04 mmol, 10 mol%), 2,2′-bipyridine (6.25 mg, 0.04 mmol, 10 mol%), TEMPO (187.50 mg, 1.2 mmol, 3 equiv), and N-substitutedmaleimide (75.08 mg, 0.6 mmol, 1.5 equiv). The tube was fitted with a rubber septum and moved out of the glove box. Then ketone (0.4 mmol), tertiary amine (0.8 mmol, 2.0 equiv.), p-Toluenesulfonic acid (6.88 mg, 0.04 mmol, 10 mol%, 12 wt% solution in pure acetic acid) and toluene (1.5 mL) were added in turn to the Schlenk tube through the rubber septum using syringes, and then the septum was replaced with a Teflon screwcap under nitrogen flow. The reaction mixture was stirred at 120°C for 48 h. Upon cooling to room temperature, the reaction mixture was diluted with 10 mL of ethyl acetate, followed by filtration through a pad of silica gel with several washings. The filtrate was concentrated under reduced pressure, and then purified by flash column chromatography on silica gel to provide the corresponding product.

Data availability
All data generated and analyzed during this study are included in this article and its Supplementary Information files, and are also available from the authors on reasonable request. Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition number 1905935 (4a), 1905936 (6b), and can be obtained free of charge from the CCDC via http://www.ccdc.cam.ac.uk/ data_request/cif.