Transition metal-free intramolecular regioselective couplings of aliphatic and aromatic C-H bonds

Cross-dehydrogenative couplings of two different C-H bonds have emerged as an attractive goal in organic synthesis. However, achieving regioselective C-H activation is a great challenge because C-H bonds are ubiquitous in organic compounds. Actually, the regioselective couplings promoted by enzymes are a common occurrence in nature. Herein, we have developed simple, efficient and general transition metal-free intramolecular couplings of alphatic and aromatic C-H bonds. The protocol uses readily available aryl triazene as the radical initiator, cheap K2S2O8 as the oxidant, and the couplings were performed well with excellent tolerance of functional groups. Interestingly, α-carbon configuration of some amino acid residues in the substrates was kept after the reactions, and the couplings for substrates with substituted phenylalanine residues exhibited complete β-carbon diastereoselectivity for induction of the chiral α-carbon. Therefore, the present study should provide a novel strategy for regioselective cross-dehydrogenative couplings of two different C-H bonds.


Results and Discussion
Development of a method. At first, 2-N-Tz o -amino-N,3-dimethyl-N-phenylbutanamide (1a) was chosen as the model substrate to optimize the reaction conditions including catalysts, oxidants, additives, solvents and temperature under nitrogen atmosphere. When TEMPO was used as the oxidant, TFA or TfOH as the additive referencing to Baran's conditions 45 , the desired product (2a) was observed in only 6% and 7% yields using CH 3 NO 2 as the solvent (Table 1, entries 1 and 2). Interestingly, use of two equiv of K 2 S 2 O 8 as the oxidant led to a 50% yield in the absence of additive at 100 °C (Table 1, entry 3). Other solvents, CH 3 CN, 1,2-dichloroethane (DCE), toluene, dioxane, DMF and DMSO, were attempted (Table 1, entries 4-9), and CH 3 CN gave the highest yield (53%) ( Table 1, entry 4). In order to confirm whether trace amount of transition metals in the system mediate this reaction, the solvent in the resulting solution of entry 4 was removed by a rotary evaporator, and the residue was determined by ICP mass spectrometry. Mn, Pd, Rh, Cu, Fe, Ni, Pt, Au, Ag, Co and Cr almost were not observed (Data determined by ICP mass spectrometry on the residue after the solvent in the resulting solution of entry 4 was removed by a rotary evaporator: Mn (0.1 ppm), Pd (< 0.5 ppm), Rh (< 0.5 ppm), Cu (44.1 ppm), Fe (72.1 ppm), Ni (4.1 ppm), Pt (< 0.5 ppm), Au (8.3 ppm), Ag (11.6 ppm), Co (0.12 ppm) and Cr (2.11 ppm)). Structure of 2a containing L-valine residue was identified by NMR, and the result showed that configuration of the chiral α -carbon in 2a was retentive and no racemization was observed. Other oxidants were tested (  19), and increasing its amount to three equivalents gave a similar yield to entry 4 (see Table 1, entry 20). Three common transition-metal catalysts, Pd(OAc) 2 , CuBr 2 and AgNO 3 ( Table 1, entries [21][22][23], were added to the reaction system, respectively, and the results showed that addition of transition-metal catalysts did not improve efficiency of the reaction, which exhibits that the present reaction is a transition metal-free process. Reaction in air provided a lower yield (Table 1, entry 24). Therefore, the optimal conditions for the intramolecular coupling of aliphatic and aromatic C-H bonds are as follows: two equiv of K 2 S 2 O 8 as the oxidant, CH 3 CN as the solvent at 100 °C for 2 h under nitrogen atmosphere.

Couplings of aliphatic tertiary C-H and aromatic C-H bonds.
We investigated the scope of substrates containing L-and D-amino acid residues for intramolecular couplings of aliphatic tertiary C-H and aromatic C-H bonds (Fig. 2). When R 2 in the substrate was ethyl in stead of methyl in 1a, 2b was obtained in 65% yield. Various substitutes for R 1 were attempted. As shown in Fig. 2a, the substrate with p-Me relative to NR 2 on the aromatic ring provided higher yield than that with o-Me relative to NR 2 because of steric hindrance (compare 2c and 2d in Fig. 2a). Existence of piperidine in 2e was favor for the intramolcular coupling of aliphatic tertiary C-H and aromatic C-H bonds because N-Tz o -valine and aromatic C-H bond were on the same side of tetrahydroquinoline. NMR data exhibited that α -carbon configuration in the chiral amino acid residues is kept. In order to further ascertain structures of the newly synthesized products (2), 2k was made from the substrate with D-valine residue, its single crystal was prepared (see Supporting Information for details), and X-ray diffraction analysis showed that α -carbon configuration of D-valine residue in 2k was remained (Fig. 2b). The reactions showed good tolerance of functional groups including ether (see 2f in We also attempted substrates containing different R 3 and R 4 , and they afforded the reasonable yields (see 2l and 2m in Fig. 2a).

Couplings of benzylic C-H and aromatic C-H bonds.
Inspired by the excellent results above, we extended the substrate scope using substituted phenylalanine residues in 3 in stead of the above amino acid residues containing tertiary C-H bond in 1. As shown in Fig. 3a, the substrates with phenylalanine residue provided the reasonable yields under the standard conditions (see 4a-e in Fig. 3a), and those with electron-withdrawing groups at para-site of NMe on the aromatic ring exhibited higher reactivity (see 4d and 4e in Fig. 3a). We attempted other substrates with different substituted phenylalanine residues, and they also gave good results. The substrates containing electron-withdrawing groups on aromatic ring of phenylalanine residue (see 4l-q in Fig. 3a) afforded higher yields because of higher acidity of benzylic C-H than those containing electron-donating groups (see 4g and 4h in Fig. 3a). Similarly to 2k, single crystal of 4b was prepared, and its structure was identified by X-ray diffraction analysis (Fig. 3b)    amino acid residues, and they all were cis-form configuration. The couplings of benzylic C-H and aromatic C-H bonds exhibited excellent tolerance of functional groups including C-F bond (see 4i and 4q in Fig. 3a), C-Cl bond (see 4b in Fig. 3a), C-Br bond (see 4c and 4j in Fig. 3a), C-I bond (see 4k in Fig. 3a), trifluoromethyl (see 4d in Fig. 3a), esters (see 4e and 4h in Fig. 3a), ether (see 4g in Fig. 3a), nitrile (see 4l in Fig. 3a), nitro (see 4m-q in Fig. 3a).

Couplings of α-C-H bond of carbonyl and aromatic C-H bonds.
We further investigated intramolecular couplings of α -C-H bond of carbonyl and aromatic C-H bond for the substrates (5) containing aspartic acid derivatives. As shown in Fig. 4a, the examined substrates provided moderate to good yields. Unfortunately, the reactions led to racemization of α -carbon in aspartic acid residue because of unknown factors, and cisand trans-forms were observed through coupling constants between α -and β -C-H. Interestingly, cis-and trans-isomers were isolated by silicon gel column chromatography, and their structures were identified by 1 H NMR analysis. Single crystal of cis-isomers in 6m was prepared using similar procedures to 2k, and X-ray  diffraction analysis exhibited that two cis-forms were observed (Fig. 4b) (see Supporting Information for details). In addition, for substrates containing electron-withdrawing groups R 1 such as Cl, Br, CF 3 and ester, trans-form diastereomers were major products (see 6c-f in Fig. 4a), and that containing the bigger amide afforded major cis-form diastereomer (see 6l in Fig. 4a). The method also displayed good tolerance of functional groups including esters (see 6a-i in Fig. 4a), amides (all the substrates in Fig. 4a), C-Cl bond (see 6c in Fig. 4a), C-Br bond (see 6d in Fig. 4a), and CF 3 (see 6e in Fig. 4a). Mechanistic investigations. In order to explore mechanism on the couplings of aliphatic and aromatic C-H bonds, the following control experiments were performed. As shown in Fig. 5a, treatment of 2-N-Tz o -amino-N,3-dimethyl-N-phenylbutanamide (1a) with K 2 S 2 O 8 was performed in the presence of one equiv of 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO) under the standard conditions, and only 9%-yielded product (2a) was obtained. The result showed that the reaction could undergo a radical intermediate process.
Deuterium-labelling phenylalanine was prepared according to the previous procedure 48 , and intramolecular coupling of substrate 7 was carried out under the standard conditions (Fig. 5b). Pleasedly, product 8 was obtained in 47% yield, which implied transfer of deuterium from alphatic β-C-D bond to aromatic C-D bond. Therefore, a possible reaction mechanism for couplings of alphatic and aromatic C-H bonds is proposed in Fig. 5c. First, homolysis of K 2 S 2 O 8 yields radical F under heating condition, and treatment of substrate B with F provides radical cation H freeing anion G. Deprotonation of H by G gives radical J leaving I, and subsequent desorption of N-ethylideneethanamine (K) and N 2 leads to highly reactive aryl radical C. Intramolecular 1,6-H abstraction from alphatic C-H bond to aromatic C-H bond donates alphatic alkyl radical D, and cyclization of D affords radical L. Treatment of L with F produces cation M leaving G, and deprotonation of M in the presence of G provides the target product (E).
Application of the methods. In order to explore affect of position for hydrogen-transfer from alphatic C-H to aromatic C-H, compounds 9 was prepared and treated under the standard conditions. Pleasedly, product 10 was obtained in 40% yield (Fig. 6a). The result showed that 1,7-H abstraction is also feasible for the coupling of alphatic and aromatic C-H bonds. We attempted oxidation of 4k and 6k to lead to quinolinones. As shown in Fig. 6b, treatment of 4k or 6k with ten equiv of activated MnO 2 was performed in 1,2-dichloroethane (DCE) at 80 °C for 24 h, and the corresponding quinolinones 11 or 12 was obtained in 71% and 64% yields, respectively. Therefore, the present study is effective for synthesis of quinolinone derivatives.

Conclusion
We have developed simple, efficient and general transition metal-free intramolecular regioselective cross-dehydrogenative couplings of alphatic and aromatic C-H bonds. The protocol uses readily available aryl triazene as the radical initiator, cheap K 2 S 2 O 8 as the oxidant, and the couplings were performed well under mild conditions with excellent tolerance towards various functional groups. Interestingly, α-configuration of some amino acid residues in the substrates was kept after the reactions, and the couplings for substrates containing substituted phenylalanine residues exhibited complete β-carbon diastereoselectivity because of effect of ortho-site α-chiral carbon. Although the reactions for substrates containing aspartic acid derivatives gave cis-and trans-form racemates, the cis-and trans-isomers could be easily separated by silica gel column chromatography. The reaction mechanism indicated that initiation of reactions began in formation of aryl radicals from treatment of aryl triazenes with K 2 S 2 O 8 , in which aryl triazene seems to act as a radical initiator, and the reactions immediately process once K 2 S 2 O 8 starts. Therefore, the present method should provide a new strategy for intramolecular regioselective cross-dehydrogenative couplings of two different C-H bonds.

Methods
To a 25 mL Schlenk tube charged with a magnetic stirrer, 1, 3 or 5 (0.1 mmol), K 2 S 2 O 8 (0.2 mmol, 54 mg) and anhydrous MeCN (2.0 mL) were added. The tube was evacuated and back-filled with nitrogen for three cycles and then sealed. It was placed in a preheated oil bath at 100 °C, and the reaction was allowed to proceed for 2 hours. After completion of the reaction, the resulting mixture was filtered, and the filtrate was concentrated by a rotary evaporator. The residue was dissolved with EtOAc (3 mL), and the solution was washed with water (2 × 3 mL) and brine (2 × 3 mL), dried over MgSO 4 , filtered and concentrated by a rotary evaporation. The residue was purified with preparative TLC (silica gel, petroleum ether/EtOAc or dichloromethane/MeOH) to provide the target product (2, 4 or 6).