Letter Cite This: Org. Lett. 2017, 19, 6260-6263
pubs.acs.org/OrgLett
Palladium-Catalyzed Hydroaminocarbonylation of Alkynes with Tertiary Amines via C−N Bond Cleavage Bao Gao† and Hanmin Huang*,†,‡,§ †
Department of Chemistry, University of Science and Technology of China, Hefei 230026, P. R. China State Key Laboratory for Oxo synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou, 730000, P. R. China § State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou, 730000, P. R. China ‡
S Supporting Information *
ABSTRACT: An efficient strategy for the cleavage of the C− N bond of tertiary amines was developed with DTBP as an oxidant, in which the cleaved H atom and amine moiety were successfully transferred to the desired products. This strategy has enabled an efficient palladium-catalyzed hydroaminocarbonylation of alkynes with tertiary amines. Notably, the catalyst loading could be lowered from 5 to 0.1 mol %, which represents the lowest catalyst loading among the reported work on carbonylation via C−N bond activation. Scheme 1. Our Strategy for the Synthesis of α,β-Unsaturated Amides
α,β-Unsaturated amides are an important class of compounds and play an important role in natural products, pharmaceuticals, and fine chemicals.1 As a result, the development of new and efficient synthetic methods to these compounds has stimulated constant interest over the years, and a number of methods have been devised for their preparation.2 Notably, relevant reports on palladium-catalyzed hydroaminocarbonylation of alkynes with secondary and primary amines have shown promise, but this process requires the use of strong acids, a large amount of amines, and a special reaction medium, greatly limiting potential applications in organic synthesis.3 Moreover, the high coordination abilities of the secondary and primary amines to a transition metal would inhibit the desired reaction to some extent via formation of Werner complexes.4 Thus, it is highly interesting to develop an alternative synthetic method that can selectively access such scaffolds from simple starting materials under mild reaction conditions. Tertiary amines widely exist in natural products, pharmaceuticals, and synthetic compounds. The relative lower binding affinity of tertiary amine to a transition metal endows it to be an alternative amine source for C−N bond formation reactions.5 As such, the direct transformation of simple tertiary amines to complex nitrogen-containing molecules under metal catalysis via C−N bond activation has long been a synthetic aspiration but a great scientific challenge.6 In 2011, we have shown for the first time that tertiary amines could be used as amine sources for the oxidative C−H amination reactions via Cu-catalyzed oxidative C−N bond cleavage.7 Since that discovery, the employment of oxidative C−N bond activation in synthetic organic chemistry has been increasingly appreciated and a variety of C−N bond formation reactions, including oxidative aminocarbonylation of alkenes and aryl halides, have been developed with tertiary amines as amino sources via C−N bond cleavage (Scheme 1).8,9 In these reactions, the iminium ion produced via oxidative C−H bond cleavage was identified as a © 2017 American Chemical Society
key intermediate to liberate the amine moiety. The cleaved H atom was converted into H2O when oxygen or metallic oxides served as oxidants, which rendered the cleaved H atom impossible to be incorporated into the desired products. In this context, we envisioned that if an appropriate oxidant other than oxygen or metallic oxide is used, the incorporation of the cleaved H atom into the desired product would be expected through a hydrogen-transfer process. This kind of transformation would provide a new strategy for establishing C−N bond formation reactions by using tertiary amines as amine sources. However, such a transformation has not been reported thus far. In connection with our interests in C−N bond activation and carbonylation,10,11 herein, we report a palladiumcatalyzed hydroaminocarbonylation of alkynes with tertiary amines as nitrogen sources via C−N bond activation, in which the cleaved H atom was incorporated into the desired α,βunsaturated amides. Received: October 25, 2017 Published: November 7, 2017 6260
DOI: 10.1021/acs.orglett.7b03331 Org. Lett. 2017, 19, 6260−6263
Letter
Organic Letters
were assessed as well, yet variation of these parameters could not deliver better results (see Supporting Information (SI)). Finally, no desired product was observed in the absence of a palladium catalyst or DTBP. Having identified the optimum reaction conditions, we explored the substrate scope of this new reaction with a variety of substituted alkynes (Scheme 2). In all cases, aromatic alkynes
We commenced our studies by attempting the proposed carbonylation of phenylacetylene 1a with Et3N 2a in CH3CN at 120 °C under CO (20 atm). With Pd(Xantphos)Cl2 as a catalyst and NH4Cl as an additive, which could facilitate formation of palladium hydride, a series of oxidants were initially examined. It was found that DTBP was the most efficient oxidant, providing the desired product 3aa in 38% isolated yield. Other oxidants, such as TBHP, BQ, Na2S2O8, and Ag2O, were ineffective for this carbonylation. Encouraged by this primary result, a variety of commercially available ligands, including diphosphine and monophosphine, were evaluated with PdCl2 as a catalyst precursor, and the results revealed that some commonly used ligands, such as PPh3, DPPP, and DPPen, were ineffective for this carbonylation. To our delight, when DPEphos, BINAP, and dppf were introduced into the catalytic system, the desired product 3aa was obtained in moderate yield with high selectivity (only branched product 3aa was detected by GC-MS). Further optimization of the catalyst system disclosed that Pd(dcpf)Cl2 could deliver the carbonylative adduct 3aa in 77% isolated yield. To further improve the reaction efficiency, other commonly used ammonium salts, such as NH4Cl, NH4Br, and NH4F, were investigated, but it made no improvement on the yield of the reaction. The desired product could be obtained in 62% yield in the absence of NH4Cl, indicating that the cleaved H atom is transferred to the desired product (Table 1, entry 20). Moreover, the reaction temperature and the pressure of CO
Scheme 2. Scope of the Alkynesa
Table 1. Optimization of the Reaction Conditionsa
entry
[Pd]
oxidant
ligand
additive
yield (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Pd(Xantphos)Cl2 Pd(Xantphos)Cl2 Pd(Xantphos)Cl2 Pd(Xantphos)Cl2 Pd(Xantphos)Cl2 Pd(Xantphos)Cl2 Pd(Xantphos)Cl2 Pd(Xantphos)Cl2 Pd(Xantphos)Cl2 PdCl2 PdCl2 PdCl2 PdCl2 PdCl2 PdCl2 Pd(dcpf)Cl2 Pd(dcpf)Cl2 Pd(dcpf)Cl2 Pd(dcpf)Cl2 Pd(dcpf)Cl2 Pd(dcpf)Cl2
DTBP DCP TBHP BQ DDQ oxone Na2S2O8 K2S2O8 Ag2O DTBP DTBP DTBP DTBP DTBP DTBP DTBP DTBP DTBP DTBP DTBP − DTBP
− − − − − − − − − PPh3 DPPP DPPPen DPEPhos BINAP dppf − − − − − − −
NH4Cl NH4Cl NH4Cl NH4Cl NH4Cl NH4Cl NH4Cl NH4Cl NH4Cl NH4Cl NH4Cl NH4Cl NH4Cl NH4Cl NH4Cl NH4Cl NH4Br NH4I NH4F − NH4Cl NH4Cl
38
