Nickel-catalyzed enantioselective α-heteroarylation of ketones via C–F bond activation to construct all-carbon quaternary stereocenters

Nickel-catalyzed asymmetric α-heteroarylation of ketones with fluorinated heteroarenes is reported via C–F bond activation. A series of ketones and 2-fluoropyridine derivatives with different functional groups proceed well to provide the corresponding products containing all-carbon quaternary stereocenters in good yields (up to 99% yield) and high ee values (up to 99% ee). In addition, drug molecule donepezil could also be compatible under the reaction conditions to afford late-stage diversification of pharmaceuticals.

Over the past decade, transition metal-catalyzed organic uorine chemistry including C-F bond formation and cleavage has become a popular topic to be explored by organic chemists. 1,2 Compared with other carbon-halogen (C-I, C-Br, and C-Cl) bonds, catalytic C-F bond cleavage is a highly regioselective strategy to achieve late-stage functionalization of pharmaceuticals and construct diversied complex molecules. Although the C-F bond has high bond dissociation energy, transition metalcatalyzed C-F bond activation has still made some progress through the unremitting effort of organic chemists. 2,3 The transition metal-catalyzed C-F bond cleavage proceeds primarily through direct oxidative addition of low-valence metal complex to the C-F bond, 2c-e,4 uorine elimination of organic metal intermediates formed from uorinated alkenes, 2f,5 or photocatalytic SET-type radical deuorinative functionalization. 2a,b,6 C Ar -F bonds are arguably the strongest bonds that carbon can form. BDE (bond dissociation energy) of the C Ar -F bond was calculated in the ESI † and is shown in Scheme 1a. Due to the high bond dissociation energy of the C Ar -F bond (526 kJ mol −1 for uorobenzene), early examples of deuorinative functionalization of uoroarenes mainly focused on extremely electron decient uorides. 7 Recently, transition metal-catalyzed C-F bond cleavage of (hetero)aryl uoride has been widely developed to construct C-C and C-X (X = N, B, Si, etc) bonds with organometallic reagents, alkynes, amines, borylation reagents or silylboranes as the coupling partner (Scheme 1b). 8-12 So far, there are rare examples of transition metal-catalyzed C(sp 3 )-H/C Ar -F cross-coupling reactions, 13 let alone asymmetric transformations with aryl or heteroaryl uoride derivatives as coupling partners via C-F bond activation. Prompted by the nickel-catalyzed arylation of indanones with aryl triates, chlorides, pivalates or pyrimidyl ether as arylation reagents, 14 we develop herein the Nicatalyzed asymmetric a-heteroarylation of ketones via C-F bond activation to deliver all-carbon chiral quaternary carbon centers (Scheme 1c).
Under the optimized reaction conditions, the scope of uorinated heteroarene derivatives 2 with 2-methyl-2,3-dihydro-1Hinden-1-one 1a was examined (Scheme 2). A series of 2-uoropyridines with an electron-donating group (e.g., OMe, OBn, OCH 2 R, OAr, PPh 2 and Me) on the 6-position of the pyridine ring proceeded well to provide arylated products in moderate to good yields and excellent ee values (3aa-3ai). The arylated product 3ac involving a chiral morpholine moiety could be obtained in 48% yield, >20 : 1 dr and 92% ee, which might be used as a potential dopamine receptor 4 (D 4 R) antagonist. 15 Interestingly, the 2-uoro-6-aryloxypyridines just underwent deuorinative arylation to deliver the corresponding products in good enantioselectivities (3ad-3ag), in which C Ar -O bond cleavage did not occur as reported by our group recently. 14d The diphenyl phosphine group was also compatible with reaction conditions to give the desired product in 47% yield and a 90% ee value with the addition of MgBr 2 which probably assisted the coordination with pyridine or an indanone motif (3ah). 16 2-Fluoro-6-aryl-pyridine derivatives involving a series of functional groups such as Me, OMe, OCF 3 , CF 3 and CN all worked well to afford the corresponding products in good yields and excellent ee values (3aj-3ap). The absolute conguration of the major heteroarylation products was conrmed to be S-conguration by X-ray analysis of 3ap (CCDC 2156742). 17 The 2-thienyl substituted 2-uoropyridine derivative was also an effective coupling partner to deliver desired product 3aq in a good ee value. 2-Fluoropyridine derivatives without substituents on the 6-position could also couple well with 1a to provide the corresponding products (3ar). To our delight, the C-F bond activation is highly regioselective such that the cleavage only occurred at the 2-position of 2,4-diuorinated or 2,5-diuorinated pyridine, which is probably caused by the coordination-assistance of pyridine (3as-3at). 2-Fluoropyridine derivatives with functional groups such as CO 2 Me, OMe, Me or Ph on the 5-position of the pyridine ring were compatible with the reaction conditions to deliver the corresponding products in medium yields and good ee values, but 6-uoronicotinonitrile afforded the desired product in poor yield and enantioselectivity probably caused by the coordination of the cyano group with nickel (3au-3ay). Besides, 2-methyl-2,3-dihydro-1H-inden-1-one 1a could also effectively react with 2-uoropyrazine to provide the desired product in good enantioselectivity (3az). Next, we turn our attention to investigate the scope of ketones with 2-uoro-6-phenylpyridine 2j. Like described in Scheme 3, a series of 2-methyl-2,3-dihydro-1H-inden-1-one derivatives with electron-withdrawing or electron-donating groups (e.g., F, OMe and Me) on the phenyl ring all proceeded smoothly to deliver the corresponding products in good yields and excellent ee values (3bj-3gj). Indanone derivatives with various substituents (e.g., ethyl, n-pentyl, benzyl and allyl) at the a-position could well couple with 2-uoro-6-phenylpyridine to afford the corresponding products in moderate to good yields and excellent ee values (3hj-3lj). In particular, acetylcholinesterase inhibitor donepezil 1m, 18 for treating Alzheimer's and vascular dementia, was also compatible with the reaction conditions to provide the chiral a-heteroaryl substituted derivative 3mj in 65% yield and 93% ee. This transformation provided an effective methodology for the late-stage functionalization of donepezils. Besides, six-member cyclic ketones such as 2-methyl-3,4-dihydronaphthalen-1(2H)-one 1n could also proceed well with 2-uoro-6-phenylpyridine to afford desired product 3nj in 88% yield and 97% ee.
To evaluate the utility of this approach, a gram-scale reaction was carried out with 3 mmol of indanone 1a, and the coupling product 3ap could be obtained in 83% yield and 99% ee under the standard conditions. When the loading of the nickel catalyst decreased to 2.5 mol%, product 3ap could also be provided in medium yield and good enantioselectivity aer the optimization of the reaction conditions (Scheme 4a). The chiral a-heteroarylation product could be further transformed via functionalization of the carbonyl group (Scheme 4b). Coupling product 3ap could be reduced by NaBH 4 to deliver secondary alcohol 4 in excellent yield and enantioselectivity. Tertiary alcohol 5 was obtained in good diastereoselectivity via nucleophilic addition with phenylmagnesium bromide. Besides, the carbonyl group could be transformed into the C = X bond (X = C, N) by condensation with the Wittig reagent or hydroxylamine hydrochloride.
In order to explore the pathway of C-F bond cleavage, control experiments were explored (Table 2). When the reaction was carried out with 1a, 2a and NaO t Bu in dry anisole, almost no racemic 3aa and O-heteroarylation by-product 8 were obtained, but 1,4-dioxane could deliver 3aa and 8 in 13% yield and 14% yield, respectively (Table 2, entry 4-5). In addition, by-product 8 could not be further transformed into product 3aa in the presence of Ni(cod) 2 and L7 (Table S6 †). Control experiments indicated that the excellent enantioselectivity of this methodology was probably derived from the faster reaction rate of oxidative addition of the chiral nickel complex to the C-F bond than that of nucleophilic substitution. Besides, we also explored the existence of possible intermediates via 31 P NMR and HRMS (ESI †). When 2-uoropyridine was added to the mixture of Ni(cod) 2 and (S)-Ph-Garphos (L7), chiral complex Ni(L7)(cod) ( 31 P NMR, d = 33.32) was absolutely transformed into intermediate Ni(L7)(2-uoropyridine) ( 31 P NMR, d = 29.84). HRMS indicated that oxidative addition of nickel (0)  In summary, we have developed the nickel-catalyzed asymmetric a-heteroarylation of indanone derivatives with 2-uoropyridines via C-F bond activation. A series of ketones and 2-uoropyridine derivatives proceed smoothly to deliver the corresponding products containing all-carbon quaternary stereocenters in good yields and high ee values. Drug molecule donepezil could also be compatible with the reaction conditions to afford the desired product in excellent enantioselectivity. Further research on asymmetric C-F activation of diverse compounds is still underway.

Data availability
The datasets supporting this article have been uploaded as part of the ESI. †

Author contributions
X. Gu performed the experiments and prepared the ESI. † K. Liu repeated some experiments. L. Yang performed the DFT calculations. C. Xie ran some HRMS of intermediates. M. Li & J. W. conceived and directed the project, and wrote the paper.

Conflicts of interest
There are no conicts to declare.