Ligand-Free Pd-Catalyzed Double Carbonylation of Aryl Iodides with

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Ligand-Free Pd-Catalyzed Double Carbonylation of Aryl Iodides with Amines to alpha-Ketoamides under Atmospheric Pressure of Carbon Monoxide and at Room Temperature Hongyan Du, Qing Ruan, Minghao Qi, and Wei Han J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01249 • Publication Date (Web): 03 Jul 2015 Downloaded from http://pubs.acs.org on July 6, 2015

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The Journal of Organic Chemistry

Ligand-Free Pd-Catalyzed Double Carbonylation of Aryl Iodides with Amines to α-Ketoamides under Atmospheric Pressure of Carbon Monoxide and at Room Temperature Hongyan Du,† Qing Ruan,† Minghao Qi,† and Wei Han*,†,‡ †

Jiangsu Key Laboratory of Biofunctional Materials, Key Laboratory of Applied Photochemistry, School of Chemistry and Materials Science, Nanjing Normal University, Wenyuan Road NO.1, Nanjing 210023, China ‡ Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Nanjing 210023, China * Corresponding author’s email address: [email protected]; [email protected]

ABSTRACT: A general Pd-catalyzed double carbonylation of aryl iodides with secondary or primary amines to produce α-ketoamides at atmospheric CO pressure has been developed. This transformation proceeds successfully even at room temperature and in the absence of any ligand and additive. A wide range of aryl iodides and amines can be coupled to the desired α-ketoamides in high yields with excellent chemoselectivities. Importantly, the current methodology has been demonstrated to be applied in the synthesis of bioactive molecules and chiral α-ketoamides.

α-Ketoamides are important fragments in biologically active molecules, synthetic

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drugs, and pharmaceutically interesting compounds.1 Moreover, they frequently serve as useful building blocks for an array of functional group transformations.2 As a consequence, establishing a general, practical, and efficient approach to α-ketoamides having polyfunctional groups, is of significance. Palladium-catalyzed double carbonylation of aryl halides with amines is well known as a direct and efficient protocol for the synthesis of α-ketoamides.3,4 Generally, this transformation undergoes efficiently at a high pressure of carbon monoxide(≥10 bar) and/or an elevated temperature (≥80 oC).4,5 Moreover, the palladium catalysts are required to be modified by cost of ligands (often with phosphine ligands).2d,3b,5,6 These drawbacks have blocked the transfer of the advances to widespread applications, particularly in complex organic syntheses. In contrast, double carbonylation for α-ketoamides under ambient pressure of CO gas has been scarcely reported, likely due to inertness of CO and poor chemoselectivity.6,7 However, in these cases, the necessity to employ extra additives, such as a copper co-catalyst, a nucleophilic amine base, an air-sensitive phosphine, or Au-supported material. Most disadvantageous of all, aryl halide bearing a deactivating group such as halo, cyano, trifluoro, or an ester group in the aryl ring leads to a large amount of monocarbonylated side products.6,7 To the best of our knowledge, there is no report of general, ligand- and additive-free double carbonylations of aryl iodides under ambient conditions thus far. Recently, we demonstrated in situ generation of palladium nanoparticles in


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polyethylene glycol (PEG) without any additional ligand and additive. And this catalytic system achieved outstanding performance in carbonylative Suzuki coupling8 and hydrocarboxylation9 of aryl halides with CO gas under ambient conditions. In continuation of our research to employ this in situ generation of palladium nanoparticles system for other carbonylation, herein we disclose a ligand-free palladium-catalyzed double carbonylation for the synthesis of α-ketoamides by direct three-component coupling of various aryl iodides (including electron-deprived aryl iodides) and amines with CO gas at ambient pressure and temperature. The generality of this protocol is demonstrated here by synthesizing a typical set of α-ketoamide compounds (44 examples) with high yields and excellent selectivities. We

commenced

our

studies

by

investigating

the

reaction

between

1-chloro-4-iodobenzene 1a and cyclohexylamine 2a (1.0 equiv) employing Pd(OAc)2 as a catalyst and Na2CO3 as a base in PEG-400 at room temperature and atmospheric pressure of CO gas (Table 1). The reaction resulted in double carbonylated product 3aa in 74% yield with excellent selectivity (>95%) (entry 1). A screening of palladium sources revealed that Pd(OAc)2 is much better than PdCl2 (entry 2), and Pd/C is complete ineffective for the reaction (entry 3). Replacing PEG-400 with glycol, NHD-250 (polyethylene glycol dimethyl ether with an average molecular weight of 250 Da) , DMF, toluene, or 1,4-dioxane as the solvent resulted in poorer results (entries 4−8). Evaluation of several bases indicated that Na2CO3 was the optimal choice, albeit Na3PO4, and NEt3 were also efficient bases for this



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Table 1. Optimization of reaction conditions a

Ent

[Pd]

Base

Solvent

-ry

Yield

1

Pd(OAc)2

Na2CO3

PEG-400

74

2

PdCl2

Na2CO3

PEG-400

61

3

Pd/C

Na2CO3

PEG-400

-

4

Pd(OAc)2

Na2CO3

5

Pd(OAc)2

Na2CO3

NHD-250

40

6

Pd(OAc)2

Na2CO3

DMF

7

7

Pd(OAc)2

Na2CO3

Toluene

10

8

Pd(OAc)2

Na2CO3

Dioxane

25

9

Pd(OAc)2

NaHCO3

PEG-400

59

10

Pd(OAc)2

Na3PO4

PEG-400

72

11

Pd(OAc)2

NaF

PEG-400

67

12

Pd(OAc)2

DBU

PEG-400

99% ee using the HPLC conditions. (R)-2-(4-chlorophenyl)-N-(2-hydroxypropyl)-2-oxoacetamide

(3ao).

Following

general procedure C, 3ao was isolated as a gray solid (98 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.8 Hz, 2 H), 7.56 (s, 1 H), 7.40 (d, J = 8.8 Hz, 2 H), 4.01–3.97 (m, 1 H), 3.52 (dd, J=12, 8 Hz, 1 H), 3.23 (dd, J = 12, 8 Hz, 1 H), 2.50 (s, 1 H), 1.22 ppm (d, J = 8 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 186.3, 162.1, 141.2, 132.6, 131.5, 128.9, 66.9, 46.6, 20.9 ppm; mp 87.0–87.5 °C; HRMS (ESI) m/z: [M + Na]+ calcd for C11H12ClNO3Na 264.0397; found 264.0399; IR νmax (KBr)/ cm-1 3401, 3246, 3100, 2966, 2933, 2875, 1682, 1653, 1636, 1584, 1447, 1376, 813, 737; chiral HPLC conditions: Chiralcel OD-H, (n-hexane/isopropanol, 80:20), flow rate = 1.0 mL/min, Rt = 23.0, and 24.1 min, respectively. Enantiomeric excess was determined to be >99% ee using the HPLC conditions. 1-(4-Benzoylpiperazin-1-yl)-2-(1-methyl-1H-indol-3-yl)ethane-1,2-dione

(3vp).20

Following general procedure B, 3vp was isolated as a white solid (122 mg, 65%). 1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1 H), 7.87 (s, 1 H), 7.36 (d, J = 22.4 Hz, 8 H),



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3.87–3.44 ppm (m, 11 H);

13

C NMR (100 MHz, CDCl3) δ 184.3, 170.6, 166.1, 139.6,

137.6, 134.9, 130.1, 128.6, 127.0, 126.0, 124.1, 123.4, 122.2, 113.2, 110.0, 45.9, 41.6, 33.8 ppm; mp 237.6–238.3 °C. (2S,3S,5S,6R)-2-(acetoxymethyl)-6-(4-(2-morpholino-2-oxoacetyl)phenoxy)tetrahy dro-2H-pyran-3,4,5-triyl triacetate (3wb). Following general procedure A, 3wb was isolated as a white oil (192 mg, 68%). 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 8.8 Hz, 2 H), 7.03 (d, J = 8.8 Hz, 2 H), 5.27 (t, J = 6.4 Hz, 2 H), 5.19 (d, J = 7.6 Hz, 1 H), 5.14 (t, J = 9.6 Hz, 1 H), 4.24 (dd, J=12.4, 5.2 Hz, 1 H), 4.13 (dd, J=12.4, 2 Hz, 1 H), 3.89 (ddd, J=10, 5.2, 2.4 Hz, 1 H), 3.76–3.69 (m, 4H), 3.61 (t, J =4 Hz, 2 H), 3.33 (t, J =4 Hz, 2 H), 2.02 (s, 3 H), 2.01 (s, 6 H), 2.00 ppm (s, 3 H);

13

C NMR (100 MHz, CDCl3) δ 189.6,

170.4, 170.1, 169.3, 169.2, 165.3, 161.5, 132.0, 128.1, 116.7, 97.8, 72.3, 72.2, 70.8, 67.9, 66.7, 66.6, 61.7, 46.2, 41.5, 20.6, 20.5 ppm; HRMS (ESI) m/z: [M + Na]+ calcd for C26H31NO13Na 588.1687; found 588.1668; IR νmax (KBr)/cm-1 2967, 2931, 2859, 1726, 1641, 1596, 1575, 1506, 1447, 1436, 1373, 1227, 1113, 1067, 1033, 847, 700.

Hg(0) Poisoning Test. As general procedure A, a reaction of 1-chloro-4-iodobenzene 1a (0.5 mmol, 122.9 mg), cyclohexylamine 2a (0.75 mmol, 58 µL), Pd(OAc)2 (0.01 mmol, 2.3 mg), sodium carbonate (1.0 mmol, 106.5 mg), and PEG-400 (2.0 mL), with the addition of Elemental mercury (1.0 mmol, 100equiv., 201 mg) (relative to palladium) was conducted. Following the reaction for 6 h at room temperature, the desired product 3aa was formed in a trace amount, suggesting that the reaction is completely inhibited by the introduction of Hg(0).


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Acknowledgements The work was sponsored by the Natural Science Foundation of China (21302099), the Natural Science Foundation of Jiangsu Province (BK2012449), the SRF for ROCS, SEM, and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Supporting Information. 1

H NMR and 13C NMR spectra for products. This material is available free of charge via

the Internet at http://pubs.acs.org.

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Ligand-Free Pd-Catalyzed Double Carbonylation of Aryl Iodides with

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