Enantioselective Copper-Catalyzed Cyanation of Remote C(sp3)-H Bonds Enabled by 1,5-Hydrogen Atom Transfer.

The direct functionalization of C(sp3)-H bonds has led to the development of methods to access molecules or intermediates from basic chemicals in an atom- and step-economic fashion. Nevertheless, achieving high levels of chemo-, regio-, and enantioselectivity in these reactions remains challenging due to the ubiquity and low reactivity of C(sp3)-H bonds. Herein, we report an unprecedented protocol for enantioselective cyanation of remote C(sp3)-H bonds. With chiral Box-Cu complex as the catalyst, the reaction of N-fluorosulfonamide furnishes the corresponding products in excellent yields and high enantiomeric excess (ee) under mild reaction conditions. A radical relay pathway involving 1,5-hydrogen atom transfer (1,5-HAT) of N-center radicals followed by enantioselective cyanation of the in situ-formed benzyl radicals is proposed. This enantioselective copper-catalyzed cyanation thus offers insights into an efficient way for the synthesis of bioactive molecules for drug discovery.

Introduction

Synthesizing functional molecules in a rapid, efficient, and convenient manner still represents a significant challenge in organic synthesis (McMurry et al., 2011, Gutekunst and Baran, 2011, Yamaguchi et al., 2012, Karimov and Hartwig, 2018). The past several decades have witnessed the renaissance of C-H bond functionalization, which thus offers a unique solution for facile synthesis of functional molecules from basic chemicals (Giri et al., 2009, Colby et al., 2010, Lyons and Sanford, 2010, Newhouse and Baran, 2011, Sun et al., 2011, Wencel-Delord et al., 2011, Wendlandt et al., 2011, Liu et al., 2015, Davies and Morton, 2016, Rao and Shi, 2016, Liang and Jiao, 2017, Yang et al., 2017, Dong et al., 2017, Gensch et al., 2018). Specifically, the direct functionalization of C(sp3)-H bonds has led to the development of methods to access molecules or intermediates from simple starting materials in an atom- and step-economic fashion (Zhang et al., 2011, Baudoin, 2011, Rouquet and Chatani, 2013, Xie et al., 2014, Liu and Groves, 2015, He et al., 2016, He et al., 2017, Hartwig, 2016, Yi et al., 2017, Saint-Denis et al., 2018). Nevertheless, achieving high levels of chemo-, regio-, and enantioselectivity in these reactions remains challenging due to the ubiquity and low reactivity of C(sp3)-H bonds. To date, one efficient approach to asymmetric C(sp3)-H functionalization was the enantioselective insertion of chiral metallocarbene (Davies and Beckwith, 2003, Doyle et al., 2010, Davies and Morton, 2011, Davies and Manning, 2008, Lu and Zhang, 2011, Zheng and You, 2014, Schafer and Blakey, 2015, Newton et al., 2017) or metallonitrene (Davies and Manning, 2008, Lu and Zhang, 2011, Zheng and You, 2014, Schafer and Blakey, 2015, Newton et al., 2017, Müller and Fruit, 2003, Collet et al., 2011) species in situ generated into C-H bonds. The other known approach was transition-metal-catalyzed C(sp3)-H activation, which involves a stereocontrolled C-H cleavage to generate an enantioenriched organometallic intermediate for further functionalization (Saint-Denis et al., 2018). Despite recent advances in both approaches, the efficient and practical methods for enantioselective functionalization of remote C(sp3)-H bonds are still less developed.

As an alternative tactic, hydrogen-atom abstraction via radical path has long been used as a powerful tool to activate the C(sp3)-H bonds. Of note is a radical relay strategy for enantioselective functionalization of allylic (Zhou and Andrus, 2002) and benzylic (Zhang et al., 2016, Zhang et al., 2019a, Zhang et al., 2019b, Zhang et al., 2019c, Wang et al., 2018) C-H bonds has recently been developed, in which a benzylic or allylic radical generated by hydrogen-atom abstraction underwent asymmetric functionalization by a chiral copper catalysis. Although inert C(sp3)-H bonds are almost impossible to distinguish from other aliphatic C-H bonds on the alkyl side chain, 1,n-hydrogen-atom transfer strategy offers us a reliable solution to selectively cleave the remote C(sp3)-H bonds in a high chemo- and regioselective path. Starting from the pioneering work of Hofmann (Hofmann, 1883), known as Hofmann–Lӧffler–Freytag (HLF) reaction with N-haloamines used as precursors to generate N-centered radical (Hofmann, 1883, Lӧffler and Freytag, 1909, Wolff, 1963, Neale, 1971, Mackiewicz and Furstoss, 1978), the selective cleavage of remote C(sp3)-H bonds via 1,5-HAT process is well documented (Robertson et al., 2001, Čeković, 2003, Chiba and Chen, 2014, Stateman et al., 2018, Chu and Rovis, 2016, Chu and Rovis, 2018, Martínez and Muñiz, 2015, Wappes et al., 2016, Choi et al., 2016, Xia et al., 2018, Na and Alexanian, 2018). Although the early examples utilize transition metal to facilitate electron transfer, to further expand the scope of this remote C(sp3)-H functionalization process, many domino processes involving a metal-catalyzed cross-coupling pathway have developed (Scheme 1A) (Zhou and Andrus, 2002, Zhang et al., 2016, Zhang et al., 2019a, Zhang et al., 2019b, Zhang et al., 2019c; Wang et al., 2018, Groendyke et al., 2016, Li et al., 2018, Liu et al., 2019, Bao et al., 2019). With the generation of N-centered radical initiating remote hydrogen transfer, the following cross-coupling reactions enabled by the recapture of in situ-generated carbon radical could be achieved with transition metals (Groendyke et al., 2016, Li et al., 2017, Li et al., 2018, Liu et al., 2019, Bao et al., 2019, Zhang et al., 2019a, Zhang et al., 2019b, Zhang et al., 2019c, Yu et al., 2014). As our continuous efforts on selective cleavage of remote aliphatic C(sp3)-H via a 1,5-HAT process (Scheme 1B) (Wang et al., 2017a, Wang et al., 2017b), we envisioned that the recapture of in situ-generated carbon radical of 1,5-HAT by chiral metal catalyst, followed by reductive elimination from the chiral metal complex would realize enantioselective C(sp3)–H functionalizations, thus providing a convenient entry to optically pure δ-cyano amines and their pharmaceutical derivatives (Figure 1) (Sugimoto et al., 2000, van de Waterbeemd et al., 2001, Abdel-Rahman et al., 2002). More recently, the remote C(sp3)-H functionalization was accomplished by the groups of Zhu (Bao et al., 2019) and Nagib (Zhang et al., 2019a, Zhang et al., 2019b, Zhang et al., 2019c), whereas the enantioselective remote C(sp3)-H cyanation reaction of excellent yield and high ee still remains as an unsolved problem.

Scheme 1

Enantioselective C(sp3)-H Functionalization via Reductive Elimination from Chiral Transition-Metal Catalyst

(A) Previous work: copper-catalyzed benzylic or allylic C-H functionaliztions.

(B) This work: copper-catalyzed remote C(sp3)-H cyanation enabled by 1,5-HAT.

(C) Proposed mechanism.

Figure 1

Pharmaceuticals Containing Chiral δ-cyano Amines and Their Derivatives

Herein, we described the first example of N-radical initiated enantioselective copper-catalyzed cyanation of remote C(sp3)-H bonds with excellent yield and high enantioselectivity (up to 95% ee). This asymmetric reaction has demonstrated high catalytic reactivity, excellent regio- and enantioselective control, low catalyst loading, mild conditions, and broad scope. The key to success is the recapture of the alkyl radical generated by selective cleavage of C(sp3)-H bond via 1,5-HAT with Box-Cu catalyst resulting in chiral copper cyanide for stereoselective reductive elimination (Wang et al., 2018). This radical relay strategy will offer a solution for regio- and enantioselective functionalization of remote C(sp3)-H bonds and provides an efficient way for facile synthesis of chiral δ-cyano amines and their pharmaceutical derivatives.

Results and Discussion

Optimization of the Enantioselective Copper-Catalyzed Cyanation

Our initial investigation commenced with N-fluorosulfonamide1a used as the pilot substrate, along with trimethylsilyl cyanide (TMSCN) used as the coupling partner in the presence of a catalytic amount of Cu(MeCN)4PF6 (3 mol%) at room temperature. To our delight, the desired cyanation product 2a was obtained in 62% yield and 78% ee when chiral bis(oxazoline) ligand L1 was used (Entry 1, Table 1). To improve the enantioselectivity of this reaction, various chiral bis(oxazoline) ligands were next investigated. Gratifyingly, indanyl amino alcohol-derived bis(oxazoline) ligands (L2-L7) could afford almost the same good ee and normally satisfactory yield, whereas Pybox (L8) gave only trace amount of 2a (Entries 2–8). Lowering the reaction temperature to 10°C could further improve the ee to 90%, albeit with a relatively lower yield (52%, Entry 9). A careful investigation of various copper salts with the optimal bis(oxazoline) ligand (L6) were next performed, which indicated that a variety of Cu(I) and Cu(II) sources (Entries 10–12) gave higher ee, but with a low overall yield. Although a majority of H-abstraction byproduct of nitrogen was found after the reaction had run for 24 h, we proposed decreasing catalyst loading might improve the mass balance by reducing the amount of H-abstraction byproducts and allowing for a higher yield (Shu et al., 2017). As expected, lower catalyst loading to 1 mol% remarkably increased the yield to about 80% without a decline in ee (Entries 13–14).

Table 1

Optimization of Reaction Conditions

Entry	Cu cat.	Ligand	Solvent	Yield (%)	ee (%)
1	Cu(MeCN)4PF6	L1	DCM	62	78
2	Cu(MeCN)4PF6	L2	DCM	75	86
3	Cu(MeCN)4PF6	L3	DCM	33	87
4	Cu(MeCN)4PF6	L4	DCM	58	86
5	Cu(MeCN)4PF6	L5	DCM	70	87
6	Cu(MeCN)4PF6	L6	DCM	73	89
7	Cu(MeCN)4PF6	L7	DCM	33	87
8	Cu(MeCN)4PF6	L8	DCM	trace	–
9a	Cu(MeCN)4PF6	L6	DCM	52	90
10a	CuSCN	L6	DCM	43	92
11a	Cu(OAc)2	L6	DCM	43	92
12a	CuI	L6	DCM	30	92
13a,b	CuSCN	L6	DCM	81	91
14a,b	Cu(OAc)2	L6	DCM	78	92
15a,b	CuSCN	L6	MeCN	39	81
16a,b	CuSCN	L6	PhCl	84	88
17a,b	CuSCN	L6	DCE	99	90
18a,b	Cu(OAc)2	L6	DCE	91	90
19a,b,c	CuSCN	L6	DCE	92	91
20a,c,d	CuSCN	L6	DCE	98	91
21a,c,e	CuSCN	L6	DCE	99	92
22a,e,f	CuSCN	L6	DCE	64	92

Reaction conditions: 1a (0.1 mmol, 1.0 equiv), TMSCN (1.2 equiv), Cu cat. (3 mol%), L (3.6 mol%), solvent (1.0 mL), rt, 2 d, Ar. Yields were determined by 1HNMR analysis using CH2Br2 as internal standard. The ee values were determined by HPLC analysis on a chiral stationary phase.

DCM, dichloromethane; THF, tetrahydrofuran; DCE, 1,2-dichloroethane; Ac, acetyl.

10°C, 3 days.

Cu cat. (1 mol%), L6 (1.2 mol%).

Solvent (2.0 mL).

CuSCN (1 mol%), L6 (1.5 mol%).

CuSCN (1 mol%), L6 (2 mol%).

0°C.

To further improve the yield of this transformation, solvent effect was next studied with 1 mol% of CuSCN used as the catalyst, which showed DCE was the optimal solvent with excellent yield and a slightly lower ee (99% yield, 90% ee, Entry 17). Interestingly, a lower concentration and an enhancement of the ratio of ligand to copper salts (2/1) could slightly improve the ee to 92% (Entries 19–21), whereas further reducing the reaction temperature to 0°C resulted in an obvious drop in yield and 29% of 1a recovered from the reaction system (Entry 22). The absolute configuration of product 2a was assigned as (R) by single crystal X-ray diffraction.

Scope of the Enantioselective Copper-Catalyzed Cyanation

With the optimal reaction conditions in hand, we next explored the scope of this enantioselective cyanation of remote C(sp3)-H bonds (Figure 2). First, with respect to substituted benzenesulfonyl protecting groups (ArSO2), both electron-donating (1b-1c) and electron-withdrawing (1d-1e) substituents (R1) at para-position of the aryl rings gave the desired product in good to excellent yield along with excellent ee, among which para-CF3 substituted substrate performed best with 97% yield and 93% ee. Considering the common availability and low cost, benzenesulfonyl group was selected as the N-protecting group to investigate the substituent effect (R2) of the aromatic ring linked to the alkyl chain. A variety of N-fluorosulfonamides 1 installed with ortho-, meta-, and para-substituents on the aryl rings were smoothly cyanated on the benzylic position in this asymmetric catalytic system, furnishing the corresponding products 2 with satisfactory yields and high ee (up to 95%). Both electron-donating, including Me (2f, 2o, 2s), C5H11 (2h), Bu (2g), PhO (2j), and MeO (2p), and electron-withdrawing groups, including F (2t), Cl (2l, 2q), Br (2m), and CF3 (2n, 2r, 2u), were well compatible with the optimized conditions. Notably, Br (2m) as well as inert halides including F and Cl on the aromatic ring offered the synthetic potential for further transformations through transition-metal-catalyzed cross-coupling methods. Moreover, polycyclic arenes, such as naphthalene (2w-2x), and heteroaromatic ring, such as thiophene (2y), were well tolerated in this reaction with high ee and good yield. To our surprise, the incorporation of two methyl groups to the alkyl chain to induce the Thorpe-Ingold effect failed to give higher ee (2z), possibly because the increased steric hindrance of the methyl groups hampered the stereo control of chiral copper catalyst.

Figure 2

Substrate Scope of Enantioselective Copper-Catalyzed Remote C(sp3)-H Cyanation

Reaction conditions: 1 (0.2 mmol, 1.0 equiv), TMSCN (1.2 equiv), CuSCN (1 mol%), L6 (2 mol%), DCE (4.0 mL), 10°C, 3 d, Ar. Isolated yields. The ee values were determined by HPLC analysis on a chiral stationary phase.

Mechanistic Studies

To gain some insights into the mechanism of this asymmetric cyanation of remote C(sp3)-H bonds, we next carried out a series of control experiments. Firstly, the addition of 2.0 equiv of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) into the standard conditions completely inhibited the reaction, and 1a was 100% recovered from the reaction system (Scheme 2A), which was consistent with our previously noted hypothesis that this reaction may proceed via a radical path (Scheme 1). Although the coupling product of TEMPO and 1a was not isolated, compounds 4 and 6 had been designed and synthesized to trap the corresponding radicals. Accordingly, the subjection of alkene 4 into the reaction system afforded 5-exo cyclization product 5 in 62% yield, indicating an N-centered radical was involved in the catalytic cycle (Scheme 2B). Meanwhile, a radical clock experiment with 6 furnished the ring-opening product 7 in 73% yield, which suggested a carbon-centered radical generated via N-radical initiated 1,5-HAT (Scheme 2C). Secondly, competition experiments had been performed using N-fluorosulfonamide substrates with different substituents on respective aryl ring. Indeed, a competition experiment between 1c and 1e with para-OMe or CF3 groups on the aryl rings in the arylsulfonyl protecting groups showed that trifluoromethylated substrate reacted faster than methoxylated substrate (16% yield to 9% yield). On the other hand, the competition experiment between 1j and 1n with para-OPh or CF3 groups on the alkylated aryl rings afforded the desired products 2j and 2n in almost the same yields (15% and 17%, Scheme 2D). All these results indicated that a copper-involved single electron transfer process for the cleavage of N-F bond might be the rate-determining step (Zhang et al., 2016, Zhang et al., 2019a, Shu et al., 2017, Shekhar et al., 2018, Zhang et al., 2019b, Zhang et al., 2019c). It should be noted that besides our proposed mechanism as shown in Scheme 1C, an alternative mechanism involving the direct cyano group enantioselective transfer from chiral copper cyanide could not be excluded at this stage (Liu et al., 2018, Xiao et al., 2019).

Scheme 2

Mechanistic Studies

(A) The radical trapping experiment with TEMPO.

(B) N-radical trapping experiment.

(C) Radical clock experiment.

(D) Competition experiments.

Conclusion

In summary, we have developed a nitrogen-centered radical-initiated enantioselective copper-catalyzed cyanation of remote C(sp3)-H bonds with high yield and enantioselectivity (up to 95% ee). This method has demonstrated high catalytic reactivity, excellent regio- and enantioselective control, low catalyst loading, mild conditions, and broad scope. This radical relay strategy will offer a solution for region- and enantioselective functionalization of remote C(sp3)-H bonds and provides an efficient way for facile synthesis of chiral δ-cyano amines and their pharmaceutical derivatives. Mechanistic studies indicate that this transformation undergoes a radical relay pathway involving a 1,5-HAT process. Further exploration on enantioselective functionalizations of remote C(sp3)-H bonds are currently ongoing in our laboratory.

Limitations of the Study

Starting materials were cyanated only on the benzylic position under the current reaction conditions.

Methods

All methods can be found in the accompanying Transparent Methods supplemental file.