Asymmetric allylic alkylation of Morita–Baylis–Hillman carbonates with α-fluoro-β-keto esters

  1. Lin Yan1,
  2. Zhiqiang Han1,
  3. Bo Zhu1,
  4. Caiyun Yang1,
  5. Choon-Hong Tan2,3 and
  6. Zhiyong Jiang1,2,3

1Institute of Chemical Biology, Henan University, Jinming Campus, Kaifeng, Henan, 475004, P. R. China
2Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province, Henan University, P. R. China
3Division of Chemistry and Biological Chemistry, Nanyang Technological University, 21 Nanyang Link, Singapore 637371

  1. Corresponding author email

This article is part of the Thematic Series "Transition-metal and organocatalysis in natural product synthesis".

Guest Editors: D. Y.-K. Chen and D. Ma
Beilstein J. Org. Chem. 2013, 9, 1853–1857. doi:10.3762/bjoc.9.216
Received 29 May 2013, Accepted 19 Aug 2013, Published 11 Sep 2013


In the presence of a commercially available Cinchona alkaloid as catalyst, the asymmetric allylic alkylation of Morita–Baylis–Hillman carbonates, with α-fluoro-β-keto esters as nucleophiles, have been successfully developed. A series of important fluorinated adducts, with chiral quaternary carbon centres containing a fluorine atom, was achieved in good yields (up to 93%), with good to excellent enantioselectivities (up to 96% ee) and moderate diastereoselectivities (up to 4:1 dr).

Keywords: allylic alkylation; asymmetric catalysis; fluorine; fluoro-β-keto esters; Morita–Baylis–Hillman carbonates; natural product


Fluorine is the most electronegative element in the periodic table, resulting in a highly polar C–F bond. This gives fluoro-organic compounds unique properties, compared with their parent compounds [1]. Due to the rareness of organofluorine compounds in nature, synthetic fluorinated compounds have been widely applied in numerous areas, including materials, agrochemicals, pharmaceuticals and fine chemicals [2-4]. In this context, the stereoselective introduction of fluorine atoms in molecules has become one of the most exciting and intense research areas in the recent years.

Lewis base-catalyzed asymmetric allylic alkylations (AAA) of Morita–Baylis–Hillman (MBH) adducts [5,6], such as acetates and carbonates, have become an attractive option to access various chiral C- [7-19], N- [20-25], O- [26-30], P- [31-33] and S-allylic [34] and spirocyclic compounds [35-37]. Several protocols have been established to introduce fluorine atoms in AAA of MBH adducts. For example, to introduce a CF3 group, Shibata and co-workers [13] and Jiang and co-workers [14] successively reported the asymmetric allylic trifluoromethylation of MBH adducts with Ruppert’s reagent [(trifluoromethyl)trimethylsilane, Me3SiCF3] in the presence of (DHQD)2PHAL as catalyst. In 2011, our research group [15], Shibata and co-workers [16] and Rios and co-workers [17] reported the addition of fluoromethyl(bisphenylsulfones) to MBH carbonates to access chiral monofluoromethyl derivatives. Furthermore, Rios and co-workers presented an asymmetric substitution of MBH carbonates with 2-fluoromalonates in good enantioselectivities [38]. Notably, the reaction between an achiral fluorocarbon nucleophile with MBH carbonates, to afford compounds with chiral quaternary carbon centres bearing a fluorine atom, remains a formidable task. Since 2009, we developed a highly enantioselective and diastereoselective guanidine-catalyzed conjugate addition and Mannich reaction of α-fluoro-β-ketoesters with excellent results [38-40]. Herein, we wish to report the first allylic alkylation of MBH carbonates with α-fluoro-β-ketoesters in excellent enantioselectivities and moderate diastereoselectivities, furnishing enantiopure fluorinated compounds with chiral quaternary carbon centres containing a fluorine atom.

Results and Discussion

In the preliminary experiments, we investigated the reaction of α-fluoro-β-ketoester 1a with MBH carbonate 2a as the model substrate, in the presence of several commercially available Cinchona alkaloids as Lewis base catalysts (Table 1). First, the reaction was conducted in the presence of quinine at 50 °C in dichloroethane (DCE) as the solvent (Table 1, entry 1). The desired adduct 3aa was obtained in 53% yield with poor enantio- and diastereoselectivity. Cinchonine provided similarly poor results (Table 1, entry 2). Next, we screened a series of C2-symmetric bis-Cinchona alkaloids as catalysts under the same conditions (Table 1, entries 3–7). (DHQD)2PHAL showed moderate catalytic activity; 3aa was obtained in 67% yield with 71% ee and 60:40 dr (entry 3). The effects of solvent were then investigated (Table 1, entries 8–18). The best-performing solvent was mesitylene with respect to enantio- and diastereoselectivity; providing 3aa in 78% yield with 89% ee and 71:29 dr (entry 18). The reaction temperature can be decreased to 25 °C and 67% yield of 3aa with 92% ee and 74:26 dr was obtained (entry 19). A slight increase in enantio- and diastereoselectivity could be obtained when the reaction temperature was decreased to 10 °C, but the reaction rate became too sluggish to be useful (Table 1, entry 20).

Table 1: Catalyst screeninga.

[Graphic 1]
Entry Catalyst Solvent Yield (%)b ee (%)c drc
1 quinine DCE 53 32 (27) 55:45
2 cinchonine DCE 59 21 (10) 55:45
3 (DHQD)2PHAL DCE 67 71 (57) 60:40
4 (DHQD)2AQN DCE 53 –5 (–5) 56:44
5 (DHQ)2PHAL DCE 64 –35 (–1) 52:48
6 (DHQ)2PYR DCE 60 –25 (–1) 59:41
7 (DHQ)2AQN DCE 47 –11 (–10) 55:45
8 (DHQD)2PHAL DCM 56 69 (55) 58:42
9 (DHQD)2PHAL toluene 78 85 (65) 67:33
10 (DHQD)2PHAL Et2O 59 45 (30) 55:45
11 (DHQD)2PHAL EA 58 55 (30) 55:45
12 (DHQD)2PHAL THF 61 31 (49) 63:37
13 (DHQD)2PHAL MeCN 57 49 (19) 65:35
14 (DHQD)2PHAL MeOH 63 35 (20) 60:40
15 (DHQD)2PHAL o-xylene 74 85 (65) 72:28
16 (DHQD)2PHAL m-xylene 65 87 (74) 70:30
17 (DHQD)2PHAL p-xylene 72 85 (55) 68:32
18 (DHQD)2PHAL mesitylene 78 89 (72) 71:29
19d (DHQD)2PHAL mesitylene 67 92 (69) 74:26
20e (DHQD)2PHAL mesitylene 45 94 (55) 75:25

aUnless otherwise noted, reactions were performed with 0.05 mmol of 1a, 0.15 of 2a, and 0.005 mmol of catalyst in 0.5 mL solvent. bYield of isolated product. cDetermined by HPLC methods. The data in parenthesis is the ee value of the minor diastereoisomer dThe reaction was conducted at 25 °C, 1.0 mmol scale in 1.0 mL of mesitylene. eThe reaction was conducted at 10 °C, 1.0 mmol scale in 1.0 mL of mesitylene.

Using the established conditions, allylic alkylations of α-fluoro-β-ketoesters 1b–g with MBH carbonate 2a were found to afford the products 3ba–ga in 67–79% yield with 88–96% ee and 3:1 to 4:1 dr (Table 2, entries 1–6). The results showed that the introduction of various aryl substituents in α-fluoro-β-ketoesters did not affect the reactivity and stereoselectivity. Subsequently, the scope of the allylic alkylation with respect to various MBH carbonates 2 and α-fluoro-β-ketoester 1a was investigated (Table 2, entries 7–20). The desired allylic alkylation adducts 3ab–o were achieved in moderate to good yields with good to excellent enantioselectivities and moderate diastereoselectivities. MBH carbonates (Table 2, 2b–k) with electron-withdrawing groups appended on the aromatic rings were more active than those (Table 2, 2l–m) with electron-neutral and donating groups. Excellent ee values with moderate dr values were obtained when the phenyl groups of MBH carbonates were replaced with hetereoaromatic groups, such as thiophene and furan (Table 2, 2n–o).

Table 2: Allylic alkylation of α-fluoro-β-ketoesters 1 with MBH carbonates 2a.

[Graphic 2]
Entry Ar1, 1 Ar2, 2 Time (h) 3 Yield (%)b ee (%)c drd
1 p-FPh, 1b Ph, 2a 40 3ba 71 88 3:1
2 p-ClPh, 1c Ph, 2a 70 3ca 79 93 3:1
3 p-BrPh, 1d Ph, 2a 70 3da 75 96 3:1
4 m-BrPh, 1e Ph, 2a 70 3ea 72 90 3:1
5 3,5-Cl2Ph, 1f Ph, 2a 70 3fa 69 88 3:1
6 p-MePh, 1g Ph, 2a 50 3ga 67 94 4:1
7 Ph, 1a p-NO2Ph, 2b 70 3ab 91 95 3:1
8 Ph, 1a p-CF3Ph, 2c 70 3ac 65 87 4:1
9 Ph, 1a p-FPh, 2d 70 3ad 71 90 3:1
10 Ph, 1a p-ClPh, 2e 70 3ae 73 93 4:1
11 Ph, 1a p-BrPh, 2f 96 3af 64 91 4:1
12 Ph, 1a m-NO2Ph, 2g 96 3ag 93 95 3:1
13 Ph, 1a m-ClPh, 2h 70 3ah 81 91 3:1
14 Ph, 1a m-BrPh, 2i 70 3ai 78 90 4:1
15 Ph, 1a o-FPh, 2j 96 3aj 73 86 4:1
16 Ph, 1a o-ClPh, 2k 70 3ak 84 86 4:1
17 Ph, 1a p-MePh, 2l 70 3al 53 91 4:1
18 Ph, 1a p-MeOPh, 2m 70 3am 50 91 3:1
19 Ph, 1a 2-thienyl, 2n 90 3an 78 92 4:1
20 Ph, 1a 2-furyl, 2o 96 3ao 73 84 3:1

aReactions were performed with 0.1 mmol of 1, 0.3 mmol of 2, and 0.005 mmol of (DHQD)2PHAL in 1.0 mL mesitylene. bYield of isolated product. cDetermined by chiral HPLC on the major diastereoisomer. dDetermined by 1H NMR analysis.


We have developed an asymmetric allylic alkylation of MBH carbonates with α-fluoro-β-ketoesters, catalyzed by a commercially available Cinchona alkaloid. Several fluorinated adducts, with chiral quaternary carbon centres containing a fluorine atom, were successfully prepared in 50–93% yields with 84–96% ee and a dr of 3:1 to 4:1. The absolute configurations of adducts still have to be determined and will be reported in due course.


Representative procedure for the synthesis of 3aa: α-Fluoro-β-ketoester 1a (21.0 mg, 1.0 equiv, 0.1 mmol) and (DHQD)2PHAL (7.8 mg, 0.1 equiv, 0.01 mmol) were dissolved in mesitylene (1.0 mL) at 25 °C. After the addition of MBH carbonate 2a (3.0 equiv, 0.3 mmol) the reaction mixture was stirred at 25 °C. The reaction was monitored by TLC. After 96 hours, flash chromatography affords product 3aa (25.7 mg, 67% yield) as colorless oil.

Supporting Information

Supporting Information File 1: Experimental details and spectroscopic data.
Format: PDF Size: 2.2 MB Download


This work was supported by NSFC (nos. 21072044, 21202034), the Program for New Century Excellent Talents in University of the Ministry of Education (NCET-11-0938) and Excellent Youth Foundation of Henan Scientific Committee (114100510003). Z.J. also appreciates the generous financial support from Nanyang Technological University for the senior research fellow funding.


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