Letter pubs.acs.org/OrgLett
A Ligand-Directed Catalytic Regioselective Hydrocarboxylation of Aryl Olefins with Pd and Formic Acid Wei Liu,† Wenlong Ren,† Jingfu Li,† Yuan Shi,† Wenju Chang,† and Yian Shi*,†,‡ †
State Key Laboratory of Coordination Chemistry, Collaborative Innovation Center of Chemistry for Life Sciences, Center for Multimolecular Organic Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, China ‡ Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States S Supporting Information *
ABSTRACT: An effective Pd-catalyzed hydrocarboxylation of aryl olefins with Ac2O and formic acid is described. A variety of 2and 3-arylpropanoic acids can be regioselectively formed by the judicious choice of ligand without the use of toxic CO gas.
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tigated. The ligand was found to be highly crucial to the regioselectivity. Either 2-arylpropanoic or 3-arylpropanoic acids can be obtained regioselectively by the judicious choice of ligand (Scheme 1). Herein, we report our preliminary results on this subject.
arboxylic acids are a class of organic compounds of great importance in pharmaceuticals and fine chemicals. For example, a number of 2-arylpropanoic acids are effective nonsteroidal anti-inflammatory agents including ibuprofen, naproxen, and loxoprofen (Figure 1).1 Regioselective hydro-
Scheme 1. Pd-Catalyzed Regioselective Hydrocarboxylation without CO
Figure 1. Medicinally important 2-arylpropanoic acids.
carboxylation of olefins provides a straightforward approach to carboxylic acids. Traditionally, this process involves the use of toxic and flammable CO under high pressure and/or high temperature,2,3 which may limit its use in laboratories. Thus, it would be highly desirable to develop effective, mild, and operationally simple hydrocarboxylation processes with nongaseous CO surrogates.4 However, prior to our studies,5 only limited examples of such reaction were reported primarily with formic acid or esters as a CO source and Ir or Rh as a catalyst at high temperature (>100 °C).6 As part of our efforts in developing CO-free hydrocarbonylation reactions, we have recently found that carboxylic acids can be formed by direct addition of HCOOH to olefins with a Pd catalyst in the presence of HCOOPh5a,c,e or Ac2O.5b In this reaction process, HCOOPh and Ac2O can also be used in catalytic amounts.5a−c,7 The hydrocaboxylation of styrene was also investigated with our previous conditions. The corresponding carboxylic acids were isolated in 96% yield, but only with a 1:2 b/l ratio.5b For this class of olefins, it is clear that the regioselectivity obtained is not synthetically useful and remains to be solved. To address this issue, various reaction parameters were subsequently inves© XXXX American Chemical Society
Styrene (1a) was used as the test substrate for initial studies. Various ligands were investigated with 2.0 equiv of HCOOH and 1.0 equiv of Ac2O in the presence of 5 mol % Pd(OAc)2 in toluene at 80 °C (Table 1, entries 1−18). The ligand was found to be an important factor for both reactivity and regioselectivity. Among the ligands examined, the highest regioselectivity for the branched acid (2a) (15:1 b/l ratio) was obtained with tris[4(trifluoromethyl)phenyl]phosphine (L3) (Table 1, entry 4). Among the solvents tested, toluene was found to be the best solvent in terms of the b/l ratio (Table 1, entry 4 vs entries 19− 23). A higher yield and selectivity were obtained when the amount of HCOOH was increased to 3.0 equiv (Table 1, entry 24 vs entry 4). The yield was slightly increased when the amount of Ac2O was reduced to 20 mol % (Table 1, entry 25 vs entry 24). The yield was further increased with a lower reaction temperature (65 °C) (Table 1, entry 26) and prolonged reaction Received: February 20, 2017
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DOI: 10.1021/acs.orglett.7b00507 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Studies on Reaction Conditionsa
entry
ligand
solvent
yield (%)b (2a:3a)c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24d 25e 26e,f 27e,g 28h 29i
PPh3 L1 L2 L3 L4 P(m-tolyl)3 P(o-tolyl)3 L5 L6 L7 L8 dppe dppp dppb dppf L9 L10 L11 L3 L3 L3 L3 L3 L3 L3 L3 L3 L8 L8
toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene toluene hexane DCM dioxane EtOAc THF toluene toluene toluene toluene toluene toluene
100 (3:1) 100 (2:1) 100 (3:1) 47 (15:1) 0 87 (7:1) 0 57 (4:1) 34 (10:1) 10 (1:1) 82 (1:3) 13 (2:1) 35 (1:6) 83 (1:3) 100 (1:1) 72 (1:2) 100 (1:1) 21 (3:1) 75 (5:1) 89 (2:1) 66 (2:1) 9 (8:1) trace 61 (>20:1) 67 (>20:1) 74 (>20:1) 96 (>20:1) 55 (1:10) 75 (1:10)
were examined. The best result was obtained with L8. Linear acid 3a was formed in 75% yield with a 1:10 b/l ratio when the reaction was carried out with 5 mol % Pd(OAc)2, 20 mol % L8, 2.0 equiv of HCOOH, and 20 mol % Ac2O in toluene at 80 °C for 36 h (Table 1, entry 29). The generality for the reaction process was subsequently investigated. As shown in Table 2, the regioselective hydrocarboxylation with tris[4-(trifluoromethyl)phenyl]phosphine (L3) can be extended to a wide variety of aryl olefins, giving 2arylpropanoic acids in 45−91% yields with generally high b/l ratios (Table 2, entries 1−16). The aromatic groups can have various substituents including alkyl, phenyl, OR, and Cl groups. Ibuprofen (2c) and naproxen (2p) can be readily obtained with high yields and regioselectivities (Table 2, entries 3 and 16). A lower reactivity and regioselectivity obtained for o-methylstyrene were likely due to the steric hindrance of the ortho methyl group (Table 2, entry 11). As shown in Table 3, the regioselective hydrocarboxylation with tris(2-methoxyphenyl)phosphine (L8) can also be applied to various aryl olefins, giving the corresponding 3-arylpropanoic acids in 53−78% yields with b/l ratios ranging from 1:8 to 20:1 b/l ratio in the presence of 5 mol % Pd(OAc)2, 20 mol % L3, 3.0 equiv of HCOOH, and 20 mol % Ac2O in toluene at 65 °C for 48 h (Table 1, entry 27). With the optimized reaction conditions in hand for the branched acid, studies were also carried out to increase the regioselectivity for the linear acid (3a). Among the ligands examined, tris(2methoxyphenyl)phosphine (L8), dppp, and dppb appeared to be the most promising ligands for the linear acid (Table 1, entries 11, 13, and 14). With these ligands, various reaction conditions B
DOI: 10.1021/acs.orglett.7b00507 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 2. Hydrocarboxylation of Olefins for Branched Carboxylic Acidsa
Table 3. Hydrocarboxylation of Olefins for Linear Carboxylic Acidsa
a
The reactions were carried out with 1 (0.50 mmol), Pd(OAc)2 (0.025 mmol), L8 (0.10 mmol), HCOOH (1.0 mmol), and Ac2O (0.10 mmol) in toluene (0.50 mL) at 80 °C for 36 h. bIsolated yield of two regioisomers. cThe ratio of 2:3 was determined by the 1H NMR analysis of the crude reaction mixture.
o-MeO group and/or the coordination of the o-MeO group to the palladium, consequently facilitating the formation of linear acid 3.3j,8 In summary, we have developed an efficient Pd-catalyzed regioselective hydrocarboxylation of aryl olefins under mild reaction conditions. A variety of 2- and 3-arylpropanoic acids have been obtained in good yields with generally high regioselectivities by the judicious choice of ligand. The reaction process requires no handling of toxic CO gas and is operationally simple. The observation of the profound ligand effect on the regioselectivity provides new insights for the reaction process.
a The reactions were carried out with 1 (0.50 mmol), Pd(OAc)2 (0.025 mmol), L3 (0.10 mmol), HCOOH (1.50 mmol), and Ac2O (0.10 mmol) in toluene (0.50 mL) at 65 °C for 48 h. bIsolated yield of two regioisomers. cThe ratio of 2:3 was determined by the 1H NMR analysis of the crude reaction mixture.
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DOI: 10.1021/acs.orglett.7b00507 Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters
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Scheme 2. Proposed Catalytic Cycle for Hydrocarboxylation
Further efforts will be devoted to understanding the reaction mechanism, expanding the substrate scope, and developing an asymmetric hydrocarboxylation process.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00507. Experimental procedures, characterization data, NMR spectra (PDF) Crystallographic information (CIF, CIF)
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REFERENCES
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Scheme 3. Deuterium-Labeling Experiments
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Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Wei Liu: 0000-0003-3294-9360 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge the National Natural Science Foundation of China (21632005, 21472083). D
DOI: 10.1021/acs.orglett.7b00507 Org. Lett. XXXX, XXX, XXX−XXX
