Copper-catalyzed and iodide-promoted aerobic C–C bond cleavage/C–N bond formation toward the synthesis of amides

Abstract

A copper-catalyzed and iodide-promoted aerobic C–C bond cleavage/C–N bond formation reaction between ketone and simple amine was developed toward the synthesis of amides, which are useful synthetic intermediates in organic synthesis and important skeletons of biologically active molecules. Notably, the reaction conditions are very mild, and preliminary mechanistic investigations indicate that molecular oxygen might be involved in the C–C bond cleavage process.

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Amides are one of the most well-known and important classes of compounds for life, which exhibit extraordinary properties in the fields of chemistry and biology.¹ In particular, in recent years, with the development of the pharmaceutical industry, more and more researchers project amidation to be one of the most preferred reactions that require universal and sustainable alternatives.² To date, various amidation reactions have been intensively investigated (Scheme 1(a)).³ However, most of these methods involve corrosive reagents, toxic gas, sensitivity toward moisture and highly harsh conditions. Practical approaches to realize amidation under simple and mild conditions are still desirable.

Scheme 1 The synthesis of amides.

During the past years, C–C bond activation and functionalization have emerged as an attractive and powerful strategy for the generation of carbon–carbon and carbon–heteroatom bonds.⁴ Of which, the selective oxidative cleavage of C–C single bonds still remains a great challenge in chemistry and biology.⁵ In very recent times, several achievements about the oxidative C(CO)–C(alkyl) bond cleavage of ketones have been reported.⁶ With this strategy, some kinds of amides could be synthesized from ketones and amines via copper or iodine catalyzed (Scheme 1(b)).⁷ However, in these reactions, ammonia,^7a,7b,7d azide,^7f azoles^7c or aminopyridine^7e are usually chosen as reagents, more universal amine rarely has been reported up to now.⁸ Herein, we present a copper-catalyzed and iodide promoted aerobic C–C bond cleavage/C–N bond formation reaction between ketone and simple amine toward the synthesis of amides (Scheme 1(c)).

The combination of CuI and KI in NMP and H₂O (15 : 1) at 40 °C gave the best result for the reaction between 1a and 2a under 1 atm O₂ (Table 1, entry 1). With these conditions, a 60% yield of morpholino(phenyl)methanone (3aa) was obtained. CuI played a critical role in the reaction, since no 3aa was formed without CuI. Other cuprous salts, such as CuCl, CuBr were also effective (Table 1, entries 2–4). As to additives, KI gave the highest yield for this reaction (Table 1, entry 5), ⁿBu₄NI was also effective and afforded 3aa in 55% yield (Table 1, entry 7), but I₂ and NIS showed less efficiency in terms of chemical yields (Table 1, entries 6 and 8). In addition, H₂O was beneficial for the reaction, the yield of desired product was decreased to 38% without H₂O, MeOH and EtOH could also promote the reaction (Table 1, entries 9–11). Notably, this reaction did not proceed in the absence of molecular oxygen (Table 1, entry 12).

Table 1 Optimization of the reaction conditions^a

Entry	Variation from “standard conditions”	Yield of 3aa^b [%]
a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), KI (0.6 mmol), NMP (0.75 mL), H2O (0.05 mL), 40 °C, 24 h, under O2 (1 atm). b The yield was determined by GC analysis, calibrated using biphenyl as the internal standard, the yield in parenthesis was isolated yield.
1	None	62(60)
2	No CuI	0
3	CuCl, instead of CuI	50
4	CuBr, instead of CuI	55
5	No KI	37
6	I2, instead of KI	15
7	^nBuN4I, instead of KI	55
8	NIS, instead of KI	12
9	No H2O	38
10	MeOH, instead of H2O	54
11	EtOH, instead of H2O	55
12	N2, instead of O2	0

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With the above optimized reaction conditions in hand, we subsequently tested the aerobic amidation of aryl ketones and 2a, and the results are summarized in Table 2. All substrates proceeded well and afforded corresponding products in moderate yields. Aryl methyl ketones with electron-donating group such as methyl, methoxy (Table 2, 3fa, 3ha) and electron-withdrawing group such as trifluoromethyl, cyano (Table 2, 3ba, 3ga) could react with 2a smoothly to afford the desired products in moderate yields. It is noteworthy that F, Cl, Br and I substituents on the phenyl rings were well tolerated, which enabled a potential application in further functionalization (Table 2, 3ca, 3da, 3ea, 3ja, 3ka, 3la). In addition, 1-(naphthalen-2-yl)ethanone was also suitable substrate for this transformation (Table 2, 3ia).

Table 2 Copper catalyzed aerobic C–C bond cleavage/C–N bond formation reaction from 1 with 2^a

a 1 (0.5 mmol), 2 (1.0 mmol), KI (0.6 mmol), NMP (0.75 mL), H₂O (0.05 mL), 40 °C, 24 h, under O₂ (1 atm); yields shown are of isolated products. b GC yields, calibrated using biphenyl as the internal standard.

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Furthermore, we explored the reactions between acetophenone with other secondary amines. Preliminary results showed that piperidine 2b and N-methyl benzylamine 2d were good substrates, generating the target amides in 50% and 53% yields, respectively (Table 2, 3ab, 3ad). Di-n-butylamine 2c could also obtain desired product smoothly (Table 2, 3ac). Besides, primary amines such as n-butyl amine and aniline were also tested, but they were not compatible with this reaction.

To explore the mechanism of this transformation, some potential intermediates were subjected to the reaction system (Scheme 2). When benzaldehyde (4) and benzoic acid (5) were employed to react with 2a under the standard conditions, no 3aa was detected, which suggested that 4 and 5 were not the active intermediates for this reaction (eqn (1) and (2)). In addition, the reactions of the intermediates 6 and 8 with morpholine (2a) afforded amides in a very low yields (eqn (3) and (5)). These results indicated that they might not be involved in the transformation. Furthermore, 2-iodo-1-phenylethanone (7) was also investigated and the desired product was afforded in 30% yield, demonstrating that 7 might be an alternative intermediate (eqn (4)).

Scheme 2 Control experiments.

To further elucidate the mechanism, ¹⁸O isotope labeling experiments were performed. As shown in Scheme 3, only 1% of ¹⁸O-labeled 3aa was obtained when the reaction was performed under 1 atm ¹⁸O₂ (eqn (6)). 9% of ¹⁸O-labeled 3aa was observed when H₂¹⁸O instead of H₂O was employed for the transformation (eqn (7)). In addition, when the reaction was performed under both ¹⁸O₂ and H₂¹⁸O, also only 7% of ¹⁸O-labeled 3aa was detected (eqn (8)). These results indicated that the carbonyl oxygen atom of products should be from the ketones, rather than O₂ or H₂O.

Scheme 3 Isotope labeled control experiments.

Besides, when amine 2d was subjected to the standard conditions under 1 atm ¹⁸O₂ in the absence of H₂O, some interesting results were observed (eqn (9)). Firstly, except for the desired product 3ad, compound 9 was also detected by GC-MS, which was believed to be a cleavage byproduct in this transformation. Then, 2% of ¹⁸O-labeled 3ad and 84% of ¹⁸O-labeled 9 were detected, indicating that molecular oxygen might be involved in C–C bond cleavage process, but not be a part of the desired amides 3ad.

Based on the results of mechanistic investigations and literature reports,⁹ two possible pathways were proposed in Scheme 4. In the path A, initially, three sequential α-halogenations took place to afford the triiodoacetophenone I in the presence of Cu/O₂/KI. Then the compound I was attacked by the amines to form the intermediate II. Finally, the product 3 was obtained via the C–C bond cleavage and electron transfer of intermediate II. Alternatively, in path B, the intermediate III was formed by the nucleophilic addition of ketone with amine, which could further transform into the radical intermediate IV in the presence of Cu(II) and O₂via a single electron transfer (SET) process. Subsequently, the SET reduction and protonation of intermediate IV by Cu(I) and base(H⁺) generated hydroperoxide intermediate V. Then a series of rearrangement, and electron transfer happened, 3 and VI¹⁰ was afforded finally.

Scheme 4 Proposed mechanism.

In conclusion, we have demonstrated a novel copper-catalyzed and iodide promoted aerobic C–C bond cleavage/C–N bond formation reaction between ketone and amine under simple and mild conditions. Preliminary mechanistic investigations indicated that molecular oxygen might be involved in C–C bond cleavage process, but not be a part of the desired amides. Detailed mechanism research and the synthetic applications of this methodology are currently ongoing in our laboratory.

Acknowledgements

This work was supported by the 973 Program (2012CB725302), the National Natural Science Foundation of China (21390400, 21520102003, 21272180, 21302148), the Hubei Province Natural Science Foundation of China (2013CFA081), the Research Fund for the Doctoral Program of Higher Education of China (20120141130002), and the Ministry of Science and Technology of China (2012YQ120060). The Program of Introducing Talents of Discipline to Universities of China (111 Program) is also appreciated.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra02153k

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