Iridium–CNP complex catalyzed cross-coupling of primary alcohols and secondary alcohols by a borrowing hydrogen strategy

Abstract

A highly efficient C–C bond formation has been developed through the cross-coupling of primary and secondary alcohols. The corresponding functionalized ketones were obtained with an iridium–CNP complex as a catalyst through the borrowing hydrogen strategy. The present methodology provides an easy alternative method to aldol reaction derivatives. More importantly, the complexes were also effective catalysts for the alkylation of an aromatic amine with a tertiary alkyl amine.

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The borrowing hydrogen reaction has attracted considerable attention over the past ten years, emerging as a promising new catalytic transformation that provides a useful alternative method to the conventional alkylation of amines with a more atom-efficient, greener process.^1,2 The borrowing hydrogen process usually involves the activation of alcohols through the removal of hydrogen to form aldehydes or ketones, which react with amines to form imines, followed by reduction using the hydrogen generated in a dehydrogenation step to obtain an N-alkylated amine product.^3,4 Compared to the reactions of alcohols with amines, the development of borrowing hydrogen reactions with respect to alcohols with alcohols is slower and more difficult, as it is burdened by the problems of low efficiency and high temperature.⁵ The cross-coupling reaction involves the following process: (1) successive dehydrogenation of two molecules of alcohol to the corresponding carbonyl compounds; (2) aldol condensation of the foregoing to form an unsaturated carbonyl compound (Scheme 1); and (3) reduction of the C–C double bond using the borrowed H₂ from one molecule of alcohol⁶ water and hydrogen are produced as byproducts, and the atom efficiency of this system is high.⁷

Scheme 1 C–C formation using the borrowing hydrogen strategy.

We recently reported on the phosphorescent benzothienyl iridium(III) complexes⁸ with catalytic activity enhanced by phosphine ligand and non-coordinating anion (Scheme 2).⁹ These complexes provide a very efficient alternative method for the alkylation of amines. Here, in this paper we report that the functionalized ketones were obtained with iridium–CNP complexes as catalysts through the borrowing hydrogen strategy.

Scheme 2 Benzothienyl skeleton phosphine ligand Ir(III) complexes.

In order to evaluate the influence of the various reported iridium catalysts, the reaction of benzyl alcohol (3a) with 1-phenylethanol (4a) was chosen as the model substrate for the optimization of catalytic activity and selectivity (Table 1). First, we examined the activity of those iridium complexes, whereby the results showed that the yield of the product (5a) increased with benzothienyl skeleton phosphine ligand iridium(III) complexes in the following order: 2b > 2d > 2c > 2a > 1b > 1a. It should be noted that nearly all the catalysts with non-coordinating anion gave excellent yields.

Table 1 Screening of optimized reaction conditions for benzyl alcohol (3a) with 1-phenylethanol (4a)^a

Entry	Catalyst	Base	Solvent	Yield^b (%)
a Reagents and conditions: benzyl alcohol (1.1 mmol), 1-phenylethanol (1 mmol), cat [Ir] loading (2 mol%), base (1 mmol), solvent (2 mL), 110 °C, 16 h, N2.b Isolated yield.
1	1a	K2CO3	Dioxane	32
2	1b	K2CO3	Dioxane	38
3	2a	K2CO3	Dioxane	52
4	2b	K2CO3	Dioxane	55
5	2c	K2CO3	Dioxane	54
6	2d	K2CO3	Dioxane	55
7	2b	K2CO3	DMSO	67
8	2b	K2CO3	DMF	65
9	2b	K2CO3	Toluene	74
10	2b	K2CO3	MeCN	64
11	2b	none	Toluene	45
12	2b	KOH	Toluene	69
13	2b	Et3N	Toluene	55
14	2b	Na2CO3	Toluene	66
15	2b	CsCO3	Toluene	89
16	2b	^tBuOK	Toluene	87
17	2a	CsCO3	Toluene	85
18	2c	CsCO3	Toluene	86
19	2d	CsCO3	Toluene	88

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The reaction conditions were further optimized through the use of various solvents. The yield of product was significantly lower in polar solvent, toluene was found to be the most suitable among the solvents tested. The blank test showed that bases played an important role in the reaction, so a number of bases were checked. The result of the comparison of alkaline carbonates suggested that the alcohol-dehydrogenation and aldol-condensation steps demand stronger basic sites. Cs₂CO₃ and ^tBuOK efficiently provided the C–C formation reaction, but Cs₂CO₃ was relatively more effective. Under the optimized conditions (benzyl alcohol (1.1 mmol), 1-phenylethanol (1 mmol), [Ir] loading (2 mol%), Cs₂CO₃ (1 mmol), toluene (2 mL), 110 °C, 16 h, under nitrogen), phenethyl phenylketone (5a) was formed at a yield of 89% with catalyst 2b, while 3a, 3c, 3d afforded more than 85% yield of the desired product.

Given the optimized reaction conditions, we investigated the scope of the reaction with a series of secondary and primary alcohols (Table 2). The reactions of 1-phenylethanol with different types of aromatic alcohols occurred well, providing moderate to excellent yields (Table 2, entries 1–8). Chlorinated aromatic alcohol and electron-donating substituent were well tolerated in the reactions, while pyridyl-, furyl-, thienyl-heterocyclic alcohols could react under the optimal reaction conditions with the overall yield in 69–85%. Next, pyridyl heterocyclic alcohols with diverse phenylethanols were explored (Table 2, entries 9–13 and 15–16). Generally, phenylethanols possessing electron-donating groups gave the corresponding products in higher yields as compared to electron-poor ones, while benzyl alcohol with 1-[4-(trifluoromethyl)phenyl]ethanol afforded only 58% yield of the desired product. This, we believe, it is attributable to the trifluoromethyl strong electron-withdrawal (Table 2, entry 14).

Table 2 Iridium(III) complex 2b catalyzed reaction of primary and secondary alcohols^a

Entry	Primary alcohol	Secondary alcohol	Product	Yield^b (%)
a Reagents and conditions: primary alcohol (1.1 mmol), secondary alcohol (1 mmol), cat 3b (2 mol%), Cs2CO3 (1 mmol), toluene (2 mL), 110 °C, 16 h, N2.b Isolated yield.c Primary alcohol (10–15 mmol).d Primary alcohol (5 mmol).
1				5a, 89
2				5b, 97
3				5c, 81
4				5d, 85
5				5e, 82
6				5f, 78
7				5g, 74
8				5h, 69
9				5i, 73
10				5j, 81
11				5k, 79
12				5l, 82
13				5m, 78
14				5n, 58
15				5o, 63
16				5p, 73
17^c				5q, 46
18^c				5r, 31
19^c				5s, 62
20^d				5t, 59

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We were pleased that aliphatic alcohols were effective for this methodology. Of those, iso-octyl alcohol, 1-pentanol, n-propanol and isobutanol are representative (Table 2, entries 17–20). The corresponding target products were all separated smoothly, while the yields were significantly lower than those of aromatic alcohols.

In addition, we also explored the borrowing hydrogen reaction of an aromatic amine with a tertiary alkyl amine¹⁰ To our surprise, the substrate experiments showed that the reactions carried on smoothly and the desired products were separated with moderate to good yields (Table 3). When meta-substituted aniline was tried in this reaction, the product was also obtained with moderate yield (Table 3, entry 5). It should be noted that substrate containing a pyridine group showed only 58% yield (Table 3, entry 3).

Table 3 The alkylation of an aromatic amine with a tertiary alkyl amine by borrowing hydrogen strategy^a

Entry	Amine	Product	Yield^b (%)
a Conditions: 5 (1.0 mmol), triethylamine (20 mmol), 2b (2 mol%), Cs2CO3 (1.1 mmol), xylene (2 mL), 150 °C, 24 h, N2.b Isolated yield.
1			7a, 65
2			7b, 72
3			7c, 58
4			7d, 78
5			7e, 63

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Finally, a reaction pathway was proposed about this alkylation of an aromatic amine with a tertiary alkyl amine (Scheme 3). This transformation is a litter different from alkylation of two molecules of alcohols, despite the intermediate iminium ion is identical. Diethylamine is produced as a byproduct in this transformation,^10a,10c while there are water and H₂ as byproducts in alkylation of two molecules alcohols.

Scheme 3 The reaction pathway of alkylation of an aromatic amine with a tertiary alkyl amine.

Conclusions

In summary, highly efficient C–C bond formation was developed through the hydrogen autotransfer cross-coupling of secondary and primary alcohols. The corresponding functionalized ketones were obtained with iridium–CNP complex as a catalyst through the borrowing hydrogen strategy, and the substrate scope was wide. The present work is providing an easy step forward for the synthesis of ketones. The borrowing hydrogen reaction of an aromatic amine with a tertiary alkyl amine also works well.

Acknowledgements

We gratefully acknowledge financial support of this work by the National Natural Science Foundation of China (nos 21401080, 21371080), the Natural Science Foundation of Jiangsu Province of China (BK20130125), and MOE & SAFEA for the 111 Project (B13025).

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Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures, ¹H NMR, ¹³C NMR data for 5 and 7. See DOI: 10.1039/c4ra06474g

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