Ferric chloride-catalyzed decarboxylative alkylation of β-keto acids with benzylic alcohols - PDF

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Article SPECIAL TOPIC Iron Catalysis in Synthetic Organic Chemistry July 2012 Vol.57 No.19: doi: /s SPECIAL TOPICS: Ferric chloride-catalyzed decarboxylative alkylation

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Article SPECIAL TOPIC Iron Catalysis in Synthetic Organic Chemistry July 2012 Vol.57 No.19: doi: /s SPECIAL TOPICS: Ferric chloride-catalyzed decarboxylative alkylation of β-keto acids with benzylic alcohols YANG CuiFeng 1, SHEN Chen 1, LI HaiHua 1 TIAN ShiKai 1,2* 1 Joint Laboratory of Green Synthetic Chemistry, Department of Chemistry, University of Science and Technology of China, Hefei , China; 2 Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai , China Received December 22, 2011; accepted January 31, 2012; published online April 26, 2012 β-keto acids are unstable to heat, acids, and bases, and have rarely been employed as carbon nucleophiles for the formation of carbon-carbon bonds. In this context, an efficient decarboxylative alkylation reaction of β-keto acids with benzylic alcohols has been developed, for the first time, through sequential cleavage of carbon-oxygen and carbon-carbon bonds. In the presence of 10 mol% of ferric chloride, a range of β-keto acids smoothly undergo decarboxylative alkylation with benzylic alcohols to give structurally diverse unsymmetric ketones in moderate to excellent yields and with extremely high regioselectivity. Preliminary mechanistic studies indicate that the reaction proceeds through an S N 1 alkylation followed by decarboxylation. alkylation, benzylic alcohols, decarboxylation, ferric chloride, β-keto acids Citation: Yang C F, Shen C, Li H H, et al. Ferric chloride-catalyzed decarboxylative alkylation of β-keto acids with benzylic alcohols. Chin Sci Bull, 2012, 57: , doi: /s In sharp contrast to β-keto esters, β-keto acids have rarely been employed as carbon nucleophiles in the formation of carbon-carbon bonds. For a long time the synthetic applications of β-keto acids have been hampered by their instability to heat, acids, and bases [1,2]. Nevertheless, a few appropriate conditions have been reported for β-keto acids to undergo decarboxylative carbon-carbon bond-forming reactions with carbon electrophiles such as aldehydes [1 5], imines [6,7], electron-deficient alkenes [8 10], allylic acetates [11], 1,3-diene monoepoxides [12], and N-benzylic sulfonamides [13]. These biomimetic reactions have demonstrated that β-keto acids are able to serve as attractive surrogates of ketones for α-alkylation because of high reactivity and regioselectivity. In the course of investigating sp 3 carbon-nitrogen bond cleavage [13 20], we recently found that N-benzylic sulfonamides could serve as carbon electrophiles for the decarboxylative alkylation of β-keto acids [13]. Mechanistic studies show that benzyl cation intermediates are generated *Corresponding author ( through the acid-catalyzed cleavage of the carbon-nitrogen bonds of N-benzylic sulfonamides. Since benzyl cation intermediates can also be generated from benzyl alcohols [21 28], we envisioned that it would be possible to develop a decarboxylative alkylation reaction of β-keto acids with benzyl alcohols under appropriate acidic conditions, which would allow an alkylation/decarboxylation sequence. The proposed reaction would generate water and carbon dioxide as byproducts, which were not expected to accelerate the decomposition of β-keto acids through decarboxylation. Nevertheless, it is a formidable challenge to fine tune reaction conditions to cleave the carbon-oxygen bonds in benzylic alcohols prior to the carbon-carbon bonds in β-keto acids. 1 Experimental 1.1 General information 1 H and 13 C NMR spectra were recorded using tetramethylsilane as an internal reference. Melting points were un- The Author(s) This article is published with open access at Springerlink.com csb.scichina.com 2378 Yang C F, et al. Chin Sci Bull July (2012) Vol.57 No.19 corrected. Alcohols [26,28] and β-keto acids [1,10,29] were prepared according to known procedures, and the rest of chemicals were purchased and used as received. The solvents were dried over anhydrous magnesium sulfate prior to use. 1.2 General procedure for the decarboxylative alkylation of β-keto acids with benzylic alcohols To a solution of benzylic alcohol 2 (0.20 mmol) in 1,2- dichloroethane (1.0 ml) at room temperature were added β-keto acid 1 (0.24 mmol) and ferric chloride (3.2 mg, 10 mol%). The resulting mixture was stirred at 60 C for 40 min, and cooled to room temperature. The mixture was purified by column chromatography on silica gel, eluting with petroleum ether/ethyl acetate (20:1), to give compound Characterization data Ketone 3o, white solid; m.p C; 1 H NMR (CDCl 3, 300 MHz) δ (m, 6H), (m, 2H), 4.92 (t, J = 7.5 Hz, 1H), 3.78 (s, 3H), 3.11 (d, J = 7.5 Hz, 2H), 2.27 (s, 3H), 2.06 (s, 3H); 13 C NMR (CDCl 3, 75 MHz) δ 207.4, 156.9, 140.5, 135.7, 132.6, 129.1, 127.9, 127.6, 120.7, 111.0, 55.5, 49.2, 39.3, 30.2, 21.1; IR (film) ν 3020, 1715, 1598, 1491, 1465 cm 1 ; HRMS (ESI) calcd. for C 18 H 21 O 2 (MH ) , found Ketone 3p, colorless oil; 1 H NMR (CDCl 3, 300 MHz) δ (m, 2H), (m, 6H), 4.78 (t, J = 6.9 Hz, 1H), (m, 2H), 3.17 (d, J = 6.9 Hz, 2H), (m, 2H), 1.96 (s, 3H); 13 C NMR (CDCl 3, 75 MHz) δ 206.4, 141.2, 139.3, 130.4, 129.3, 126.9, 126.3, 51.5, 46.6, 33.3, 30.6; IR (film) ν 3017, 2933, 1714, 1491, 1448 cm 1 ; HRMS (EI) calcd. for C 18 H 18 O (M) , found Ketone 3r, white solid; m.p C; 1 H NMR (CDCl 3, 300 MHz) δ (m, 4H), (m, 4H), 4.67 (t, J = 7.2 Hz, 1H), 2.86 (d, J = 7.2 Hz, 2H), 1.86 (s, 3H); 13 C NMR (CDCl 3, 75 MHz) δ 206.9, 137.6, 137.4, 132.7, 132.3, 130.0, 129.1, 127.1, 126.8, 126.4, 126.0, 45.5, 44.3, 30.9; IR (film) ν 3061, 2923, 1709, 1464, 1438 cm 1 ; HRMS (EI) calcd. for C 16 H 14 OS (M) , found Results and discussion Initially, the acidity of β-keto acid 1a itself was attempted to catalyze the decarboxylative alkylation of β-keto acid 1a with alcohol 2a in 1,2-dichloroethane (DCE) at room temperature (Table 1, entry 1). However, the alkylation reaction did not take place and β-keto acid 1a decomposed slowly to give acetophenone. Gratifyingly, the addition of 10 mol% of ferric chloride to the reaction mixture resulted in the formation of ketone 3a in 16% yield (Table 1, entry 2) [30], and moreover, the yield was dramatically improved to 83% Table 1 Optimization of reaction conditions a) Entry Catalyst Solvent Temperature ( C) Yield (%) b) 1 None DCE FeCl 3 DCE FeCl 3 DCE BiCl 3 DCE ZnCl 2 DCE 60 Trace 6 Cu(OTf) 2 DCE SnCl 2 DCE HCl DCE TsOH DCE H 2 SO 4 DCE FeCl 3 CHCl FeCl 3 EtOAc FeCl 3 THF 60 Trace 14 FeCl 3 MeNO FeCl 3 MeCN c) FeCl 3 DCE a) Reaction conditions: β-keto acid 1a (0.24 mmol), alcohol 2a (0.20 mmol), catalyst (if any, 10 mol%), solvent (1.0 ml), 40 min. b) Isolated yield. c) 5 mol% of FeCl 3 was used. by elevating the temperature to 60 C (Table 1, entry 3). Diminished yields were obtained when switching the catalyst to some other Lewis acids or Brønsted acids, replacing 1,2-dichloroethane with a few other organic solvents, or lowering the catalyst loading (Table 1, entries 4 16). Under the optimized reaction conditions, a range of β-keto acids smoothly underwent decarboxylative alkylation with alcohol 2a to give structurally diverse unsymmetric ketones in moderate to excellent yields (Table 2). The R 1 group in the β-keto acid could be an alkyl, an aryl, or a heteroaryl group, and the R 2 group could be a hydrogen or an alkyl group. This reaction well tolerated electron-rich aromatic moieties (Table 2, entries 6 and 9), and moreover, no regioisomeric alkylation product was obtained from the reaction with β-keto acids 1b and 1c (Table 2, entries 2, 3). A variety of benzylic alcohols smoothly reacted with β-keto acid 1a in the presence of 10 mol% of ferric chloride to give the corresponding alkyl methyl ketones in good to excellent yields (Table 3). It is noteworthy that a few electron-donating groups were successfully introduced into the ketone products by employing the alcohols bearing such groups on the aromatic rings. Moreover, no rearrangement was observed for the carbon-carbon multiple bonds during the reaction (Table 3, entries 8 10). Nevertheless, this reaction was not applicable to less reactive benzylic alcohols such as benzyl alcohol and 1-phenylethanol. In addition, no decarboxylative alkylation product was obtained from the reaction of β-keto acid 1a with 2-cyclohexenol or cyclohexanol. It could be attributable to the relatively low stability Yang C F, et al. Chin Sci Bull July (2012) Vol.57 No Table 2 Decarboxylative alkylation of β-keto acids with alcohol 2a a) Table 3 Decarboxylative alkylation of β-keto acid 1a with benzylic alcohols a) Entry β-keto acid Product Yield (%) b) Entry Alcohol Product Yield (%) b) 1 1a, R 1 = Me 3a, R 1 = Me b, R 1 = (CH 2 ) 2 Me 3b, R 1 = (CH 2 ) 2 Me c, R 1 = CHMe 2 3c, R 1 = CHMe d, R 1 = CMe 3 3d, R 1 = CMe e, R 1 = Ph 3e, R 1 = Ph f, R 1 = 4-MeOC 6 H 4 3f, R 1 = 4-MeOC 6 H g, R 1 = 4-ClC 6 H 4 3g, R 1 = 4-ClC 6 H h, R 1 = 4-O 2 NC 6 H 4 3h, R 1 = 4-O 2 NC 6 H i, R 1 = 2-thienyl 3i, R 1 = 2-thienyl b, R = OMe 3l, R = OMe c, R = OH 3m, R = OH d, R = NMe 2 3n, R = NMe e, R = OMe 3o, R = OMe a) Reaction conditions: β-keto acid 1 (0.24 mmol), alcohol 2a (0.20 mmol), FeCl 3 (10 mol%), 1,2-dichloroethane (1.0 ml), 60 C, 40 min. b) Isolated yield. 5 2f, X = CH 2 CH 2 3p, X = CH 2 CH f, X = O 3q, X = O f, X = S 3r, X = S of the corresponding carbocations generated via carbonoxygen bond cleavage. We carried out 1 H NMR spectroscopic analysis of the mixture of β-keto acid 1e, alcohol 2a, and sulfuric acid (10 mol%) in deuterated chloroform at room temperature and identified three intermediates: ether 4a, β-keto acid 5a, and β-keto ester 6a (Figure 1). These intermediates were confirmed by ESI-MS spectroscopic analysis (Table 4). Nevertheless, the isolation of β-keto acid 5a and β-keto ester 6a was not successful by chromatography on silica gel due to rapid decomposition. The 1 H NMR (400 M) spectra shown in Figure 1 clearly indicate the formation and the disappearance of these intermediates as the reaction progressed. Although acetophenone was detected in a significant amount in the reaction mixture, it could hardly be alkylated with alcohol 2a under our standard reaction conditions. Based on our experimental results, we propose the following reaction pathways for the catalytic decarboxylative alkylation of β-keto acids with benzylic alcohols (Scheme 1). Alcohol 2 is subjected to iron-catalyzed carbon-oxygen bond cleavage to give benzyl cation 7 [31 34], which reversibly reacts with alcohol 2 to generate ether 4 as an intermediate [21,35,36]. Benzyl cation 7 couples with β-keto acid 1 to give β-keto acid 5 via carbon-carbon bond-formation and 9 2j, R = Ph 3t, R = Ph k, R = (CH 2 ) 3 Me 3u, R = (CH 2 ) 3 Me 71 a) Reaction conditions: β-keto acid 1a (0.24 mmol), alcohol 2 (0.20 mmol), FeCl 3 (10 mol%), 1,2-dichloroethane (1.0 ml), 60 C, 40 min. b) Isolated yield. β-keto ester 8 via carbon-oxygen bond-formation. Decarboxylation of β-keto acid 5 leads to the formation of ketone product 3. Such an alkylation/decarboxylation sequence should account for the extremely high regioselectivity observed in the reaction (Table 2, entries 2 and 3). Alternatively, β-keto ester 6 is generated through S N 1 alkylation of β-keto ester 8 with alcohol 2, and is subsequently subjected to carbon-oxygen bond cleavage followed by decarboxylation to give ketone product 3. 3 Conclusion We have developed an unprecedented decarboxylative alkylation of β-keto acids with benzylic alcohols via catalytic cleavage of carbon-oxygen and carbon-carbon bonds. In the 2380 Yang C F, et al. Chin Sci Bull July (2012) Vol.57 No.19 Figure 1 1 H NMR (400 M) spectra recorded for the sulfuric acid-catalyzed reaction mixture of β-keto acid 1e and alcohol 2a in CDCl 3 at room temperature for 5 min, 1 h, 5 h, and 24 h (from top to bottom). Chemical shifts ( ) assigned for the protons of positions a: 4.06 (s), b: 5.70 (s), c: 5.40 (s), d: 3.74 (d, J = 7.2 Hz), e: 4.83 (t, J = 7.2 Hz), f: 2.61 (s), g: 5.84 (s), h: 5.45 (d, J = 11.6 Hz), i: 5.04 (d, J = 11.6 Hz), j: 5.51 (d, J = 12.0 Hz), k: 5.11 (d, J = 12.0 Hz), and l: 6.61 (s). Table 4 High resolution mass data of some intermediates Entry Species Mass (calcd.) Mass (found) Formula Error (ppm) 1 [4a H] C 26 H 23 O [5a Na] C 22 H 18 NaO [6a H] C 35 H 29 O presence of 10 mol% of ferric chloride, a range of β-keto acids smoothly undergo decarboxylative alkylation with benzylic alcohols to give structurally diverse unsymmetric ketones in moderate to excellent yields and with extremely high regioselectivity. Preliminary mechanistic studies indicate that the reaction proceeds through an S N 1 alkylation followed by decarboxylation. Scheme 1 Proposed reaction pathways. This work was supported by the National Natural Science Foundation of China ( , , and J ), the National Basic Research Program of China (2010CB833300), and the Program for Changjiang Scholars and Innovative Research Team in University (IRT1189). Yang C F, et al. Chin Sci Bull July (2012) Vol.57 No Grayson D H, Tuite M R J. Knoevenagel reactions with β-oxo acids. 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