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Synlett 2017; 28(14): 1801-1806
DOI: 10.1055/s-0036-1589033
letter
© Georg Thieme Verlag Stuttgart · New York

Thieme Chemistry Journals Awardees – Where Are They Now?
Chiral Sulfinamide Ligands and Pd-Catalyzed Asymmetric Allylic Alkylations of Ethyl 2-Fluoroacetoacetate

Mingzhu Zhao
a   Shanghai Key Lab of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Shanghai 200092, P. R. of China   Email: xmzhao08@mail.tongji.edu.cn
,
Yawei Tian
a   Shanghai Key Lab of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Shanghai 200092, P. R. of China   Email: xmzhao08@mail.tongji.edu.cn
,
Xiaoming Zhao*
a   Shanghai Key Lab of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Shanghai 200092, P. R. of China   Email: xmzhao08@mail.tongji.edu.cn
b   Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, P. R. of China
› Author Affiliations

Supported by: National Science Foundation of China 21272175 Supported by: Shanghai Science and Technology Commission 14DZ2261100
Further Information

Publication History

Received: 16 March 2017

Accepted after revision: 18 April 2017

Publication Date:
08 May 2017 (online)

 
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Abstract

New chiral sulfinamide ligands made from salicylic acids and chiral tert-butanesulfinamide was utilized in Pd-catalyzed asymmetric allylic substitutions of ethyl 2-fluoroacetoacetate, which afforded the fluorinated allyl products with up to 98% yield, 94% ee, and 2.2:1 dr. Both sulfoxide and hydroxyl group on the sulfanilamide ligands are ­crucial for enantiocontrol in the Pd-catalyzed allylic alkylations of ethyl 2-fluoroacetoacetate.


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Key words

sulfinamide ligand - allylation - palladium - enantioselectivity - fluorinated allylproduct

Chiral fluorinated compounds are of great importance with regard to pharmaceuticals and materials.[1] For example, drugs such as Clevudine,[2] Clofarabine,[3] Fluticasone Furoate,[4] and Difluprednate[5] contain a chiral fluorinated carbon center. Accordingly, new methods for the synthesis of chiral fluorinated compounds are highly desirable. A direct way to build a chiral fluorinated carbon center is by transition-metal-catalyzed asymmetric allylic substitutions of fluorinated methylene derivatives.[6] Several fluorinated methylene derivatives such as fluorobisphenylsulfonylmethane[7] and 2-fluoromalonate[8] have been applied in Pd[9] or Ir[10]-catalyzed allylation reactions or one-pot tandem substitution and Krapcho reaction,[11] whereas other fluorinated nucleophiles are less exploited. Organocatalytic enantioselective reactions have also been applied for the synthesis of chiral fluorinated compounds.[12]

Zoom Image
Xiaoming Zhaoobtained his Ph.D. from Daliang University of Technology in 1995. He conducted his postdoctoral research at the University of Florida (UF) and University of Southern California (USC) in the group of Prof G. K. Prakash and Prof G. A. Olah. He is currently a professor in Tongji University at Shanghai. His research group’s interests were recognized by the award of a Thieme Chemistry Journal Award in 2012 and focus on reaction design, asymmetric synthesis, and fluorine chemistry.

Chiral ligands are crucial for enantiocontrol in transition-metal-catalyzed allylic substitutions.[13] The design and synthesis of novel chiral ligands have therefore drawn considerable attention. Chiral dienes, alkene, and P- and/or N-hybrid ligands have been extensively investigated.[14] Dorta was the first to develop a chiral ligand with a sulfoxide[15] unit, which is suitable in asymmetric synthesis.[16] Recently, the sulfinamide-olefin hybrid ligands were independently developed by Liao,[17] Xu,[18] Du,[19] and Xia,[20] and these ligands show satisfactory catalytic performance. Chiral sulfinamide-pyridine ligands derived from either tert-butanesulfinamide or o-aniline sulfoxides were also synthesized and they are effective for Pd-catalyzed asymmetric allylic substitutions of dimethyl 2-fluoromalonate.[21] The development of chiral sulfinamide ligands for Pd-catalyzed allylation of fluorinated methylene derivatives is a less explored area in asymmetric catalysis. In this paper, we describe the synthesis of chiral sulfinamide ligands and the application of these ligands in Pd-catalyzed asymmetric allylations of ethyl 2-fluoroacetoacetate.

To develop chiral sulfinamide ligands for asymmetric allylic substitutions of fluorinated methylene derivatives under Pd catalysis, we focused on the preparation of sulfinamide ligands derived from salicylic acid and (R)-tert-­butanesulfinamide according to the synthetic sequence shown in Scheme [1]. For example, sulfinamide ligand (R)-L1 was synthesized in 62% yield by an amidation reaction between an active amide, which was initially converted by a reaction of salicylic acid with N,N′-carbonyldiimidazole (CDI) in THF at 50 °C, with potassium (R)-tert-butanesulfinamide, made from treatment of (R)-tert-butanesulfinamide with potassium hydride (KH) in THF.[22] The molecular structure of (R)-L1 was established by its X-ray diffraction analysis (Figure [1]).[23] A range of the sulfinamide ligands L2–L6 was also synthesized by using a similar procedure (Figure [2]).[22]

Zoom Image
Scheme 1 Synthesis of chiral sulfinamide ligand (R)-L1
Zoom Image
Figure 1 The X-ray structure of (R)-L1
Zoom Image
Figure 2 Chiral ligands L used in this reaction

With the chiral sulfinamide ligands L1–L6 in hand, we then evaluated their catalytic performance. Thus, we chose a Pd-catalyzed allylic alkylation reaction between (E)-1,3-bis(3-chlorophenyl)allyl acetate (1a) and ethyl 2-fluoroacetoacetate (2a) as a model reaction. To our delight, the allylic products 3a were obtained in 95% yield with 45–56% ee and 1.5:1 dr with the assistance of the Pd complex formed from 4 mol% [Pd(C3H5)Cl]2 and 8 mol% (R)-L1 in THF at room temperature (Table [1], entry 1). Encouraged by these results, we then examined the use of various solvents. The solvent survey indicated that the use of dioxane resulted in the allylic products 3a in 62% yield with 73–76% ee and 1.6:1 dr (entry 2); CH2Cl2 gave 51% yield, and toluene was almost completely ineffective for this reaction (entries 3 and 4). Unexpectedly, when a mixture of THF and dioxane (1:1) was used, the allylic products 3a were afforded in 98% yield with 78–80% ee and 1.6:1 dr (entry 5). We next investigated the influence of the base on the efficiency, enantioselectivity, and diastereoselectivity of this allylation (entries 6–11). A range of bases such as K3PO4, t-BuOK, K2CO3, Cs2CO3, ­Na3PO4, CsF, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were tested. We found that K3PO4 was suitable, and t-BuOK, K2CO3 and Cs2CO3 resulted in good results (entries 6–8), but both Na3PO4 and CsF were unsuitable for this allylation reaction (entries 9 and 10). When DBU was used, the allylic products 3a were obtained with 97% yield but in racemic form (entry 11). Ligands play a significant role in Pd-catalyzed asymmetrical allyic alkylations.[13] Therefore, the set of chiral ligands L2–L4 was further explored. For instance, we modified the phenyl ring of L1 as a naphthyl group to give L2 and L3. The use of L2 resulted in similar outcomes to that of L1, whereas the use of L3 gave slight worse results than L2 (entry 5 vs. entry 12 vs. entry 13).

Table 1 Optimizing Conditions for Pd-Catalyzed Allylic Substitution of 2 a

Entry

L

Base

Solvent

Yield (%)b

dr (%)c

ee (%)d

 1

L1

K3PO4

THF

95

1.5:1

56, 45

 2

L1

K3PO4

dioxane

62

1.6:1

76, 73

 3

L1

K3PO4

CH2Cl2

51

–

 –

 4

L1

K3PO4

toluene

trace

–

 –

 5

L1

K3PO4

THF/dioxane

98

1.6:1

80, 78

 6

L1

t-BuOK

THF/dioxane

85

1.3:1

73, 74

 7

L1

K2CO3

THF/dioxane

92

1.4:1

79, 79

 8

L1

Cs2CO3

THF/dioxane

97

1.3:1

75, 70

 9

L1

Na3PO4

THF/dioxane

48

–

 –

10

L1

CsF

THF/dioxane

35

–

 –

11

L1

DBU

THF/dioxane

97

1:1

rac

12

L2

K3PO4

THF/dioxane

95

1.6:1

80, 78

13

L3

K3PO4

THF/dioxane

82

1.5:1

78, 77

14

L4

K3PO4

THF/dioxane

95

1.3:1

72, 72

15

L5

K3PO4

THF/dioxane

trace

–

 –

16

L6

K3PO4

THF/dioxane

62

1:1

rac

17

BINAP

K3PO4

THF/dioxane

93

1:1

24, 22

19

Chiralphos

K3PO4

THF/dioxane

95

1:1

25, 16

19

Trost

K3PO4

THF/dioxane

82

1:1

 6, 11

20e

L1

K3PO4

THF/dioxane

85

1.6:1

81, 79

20f

L1

K3PO4

THF/dioxane

n.r.

–

 –

a Reaction conditions: [Pd(C3H5)Cl]2 (4 mol%), L (8 mol%), 1a (0.1 mmol), 2 (0.3 mmol) and base (0.3 mmol) in solvent (2 mL) at room temperature under argon for 12 h.

b Isolated yield.

c The diastereomeric ratio was determined by 1H NMR spectroscopic analysis.

d Determined by chiral HPLC analysis, the ee of the major diastereomer is given first.

e The reaction was conducted at 0 °C.

f 2a′ instead of 2a was used.

The use of L4, with an electron-donating group (p-MeO) on the phenyl ring, led to somewhat worse results than those obtained with L1 (Table [1], entry 5 vs. entry 14). Ligand L5, in which the hydroxyl group was protected by a methyl group, gave a trace amount of product (entry 15). Ligand L6, without a hydroxyl group on the phenyl ring, afforded 3a in racemic form with only 62% yield (entry 16). These results indicated that the stereochemistry of the allylation reaction is predominantly governed by the sulfinamide fragment and the hydroxyl group. In contrast, well-known ligands such as (R)-BINAP,[24] (S,S)-Josiphos,[25] and (S,S)-DACH-naphthyl Trost ligand[26] were respectively tested and they gave good yields but poor stereoselectivities (entries 17–19). Lowering the temperature from 25 °C to zero slightly improved the enantioselectivity, but had a negative effect on this reaction yield (entry 20).

Having established the optimal reaction conditions (Table [1], entry 5), the generality and scope of the reaction between the various allylic substrates 1 and ethyl 2-fluoroacetoacetate (2a) was examined.[27] As shown in Scheme [2], the substituent pattern on the phenyl ring of the allylic acetates 1 had a significant influence on the yield, enantioselectivity, and diastereoselectivity. Allylic substrates 1a–c having an electron-withdrawing group at the 3-position (e.g., 3-Cl, 3-F, and 3-Br) on the phenyl ring led to the corresponding allylic products 3a–c in high yields with good to high enantioselectivity but reduced diastereoselectivities. Notably, (E)-1,3-di(3-bromophenyl)allyl acetate (1c) afforded the corresponding products 3c in 94% yield with 90–94% ee and 1.8:1 dr. The chirality induced in this reaction was strongly facilitated by both L1 and the allylic substrate. Allylic acetates 1d–f, with an electron-withdrawing group at the 4-position (e.g., 4-Cl, 4-F, and 4-Br) on the phenyl ring, provided allylic products 3d and 3f in high yields with 62–70% ee and dr ranging from 1.8:1 to 2.0:1; however, the yield of 3e was significantly lower than those of 3d and 3f (Scheme [2]). (E)-1,3-Diphenylallyl acetate (1g) gave rise to 3g in 62% yield with 76–83% ee and 2.2:1 dr. Allylic acetate 1h, with a weak electron-donating group at the 3-position (e.g., 3-Me) on the phenyl ring, resulted in the allylic products 3h in 52% yield with 70–77% ee and 1.6:1 dr. 2-Naphthyl-substituted allylic acetate 1i produced 3i in 91% with 61–67% ee and 1.8:1 dr. The reaction with (E)-1,3-ditolyl allylacetate 1j failed to proceed. These results imply that 2a is a weak nucleophile in this alllylation process and that the reaction depends strongly upon the nature of the substituent and the substitution pattern on the allylic substrate. Ethyl 2-fluoro-3-oxo-3-phenylpropanoate (2b) was also tested in the allylation reaction of 1a, but the corresponding product 3k was not obtained. More significantly, ethyl 3-oxobutanoate 2a′ was examined under the optimized conditions and it did not give the corresponding products 3a′, in contrast to its analogue 2a containing a fluorine atom (Table [1] and Scheme [2]).

Zoom Image
Scheme 2 Scope of the reaction with allylic acetates 1 and ethyl 2-fluoroacetoacetate 2a. Reaction conditions: [Pd(C3H5)Cl]2 (4 mol%), (R)-L1 (8 mol%) 1 (0.1 mmol), 2 (0.3 mmol) and K3PO4 (0.3 mmol) in THF/dioxane (2 mL, 1:1) at room temperature under argon for about 12–24 h. Isolated yields are given. The diastereomeric ratio was determined by 1H NMR spectroscopic analysis. The ee was determined by chiral HPLC analysis.

These results strongly suggest that the fluorine atom on 2a interacts with the Pd complex, which may promote the Pd-catalyzed allylation process. The nature of this interaction is unclear and further studies are being undertaken to address this question.

The synthesis of α-fluorinated β-lactone has been attracting great attention over the last decade because of the importance of the β-lactone moiety in biological sciences and medicinal chemistry.[28] As an illustration of the application of this methodology, the reduction of the allylic products 3c with NaBH4 in EtOH gave 4 in 74% yields with 84% ee and 10:7:6:1 dr (Scheme [3]). The hydrolysis of 4 with NaOH following by an esterification in the presence of N,N-dicyclohexylcarbodiimide (DCC) and 4-(N,N-dimethylamino)pyridine (DMAP) in CH2Cl2 provided α-fluoro-β-lactone 5 in 52% yield with 17:1.6:1 dr. The ee value of 5 was not determined because of its low stability in the chiral HPLC system used.

Zoom Image
Scheme 3 Preparation of the α-fluoro-β-lactone

In summary, we have developed chiral sulfinamide ligands made from salicylic acid and (R)-tert-butanesulfinamide in a single step. The ligands are effective for Pd-catalyzed asymmetric allyllic alkylations of ethyl 2-fluoroacetoacetate. This method furnished the monofluorinated allyl products in high yields with moderate to high enantioselectivities but lower diastereoselectivities. This is the first example of a ligand endowed with a hydroxyl group on the phenyl ring in the mono-sulfinamide for enhancing catalytic activity and stereocontrol in Pd-catalyzed asymmetric allylations.


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Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr /10.1055/s-0036-1589033.
  • Supporting Information

  • References and Notes

    • 2a Chu CK. Cheng YC. Pai BS. Yao GQ. US Patent 5587362, 1996
      PubMed
    • 2b Marcellin P. Mommeja-Marin H. Sacks SL. Lau GK. Sereni D. Bronowicki JP. Mondou E. Hepatology 2004; 40: 140
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  • 5 Yamaguchi M. Yasueda SI. Isowaki A. Yamamoto M. Kimura M. Inada K. Ohtori A. Int. J. Pharm. 2005; 301: 121
    CrossrefPubMedSearch in Google Scholar
  • 7 FBSM was reported by Shibata and Hu, respectively, in 2006, see ref. 6a and: Ni C. Li Y. Hu J. J. Org. Chem. 2006; 71: 6829
    CrossrefPubMedSearch in Google Scholar

      • For the use of 2-fluoromalonate in Pd-catalyzed asymmetrical allylations, see:
    • 9a Kawasaki T. Kitazume T. Isr. J. Chem. 1999; 39: 129
      CrossrefSearch in Google Scholar
    • 9b Jiang B. Huang ZG. Cheng KJ. Tetrahedron: Asymmetry 2006; 17: 942
      CrossrefSearch in Google Scholar
    • 9c Shibatomi K. Muto T. Sumilkawa Y. Narayama A. Iwasa S. Synlett 2009; 241
      Thieme Connect
    • 9d For the use of FBSM in Pd-catalyzed asymmetrical allylations of symmetric di-substituted allylic substrates, see: Zhao X. Liu D. Zheng S. Gao N. Tetrahedron Lett. 2011; 52: 665
      CrossrefSearch in Google Scholar
  • 11 Zhu F. Xu PW. Zhou F. Wang CH. Zhou J. Org. Lett. 2015; 17: 972
    CrossrefPubMedSearch in Google Scholar
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  • 20 Chen Q. Chen C. Guo F. Xia W. Chem. Commun. 2013; 6433
    PubMed
  • 22 Typical Procedure for the Synthesis of (R)-L1 To a solution of salicylic acid (1.0 mmol) in THF (2.0 mL) was added 1,1′-carbonyldiimidazole (CDI; 1.0 mmol, 1.0 equiv) slowly at room temperature, then the reaction mixture was heated to 50 °C for 1.0 h. The solution was cooled to room temperature and concentrated to give the active amide. To a suspension of KH (30% in oil, 2.0 mmol, 2.0 equiv) in THF (5.0 mL) was added (R)-tert-butanesulfinamide (1.0 mmol) under argon at room temperature and the mixture was stirred for 0.5 h. The active amide was added and the mixture was stirred at 50 °C for 1.0 h. The reaction mixture was cooled to room temperature and acidified with aqueous HCl to pH >7, then the mixture was diluted with EtOAc (10 mL), washed with H2O (3 × 10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (EtOAc) to give the desired product (R)-L1 (149.4 mg, 62% yield) as a white solid; mp 144.6–145.9 °C; [α] d 25 –73.8 (c = 1.0, MeOH). 1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 7.8 Hz, 1 H), 7.39 (t, J = 7.4 Hz, 1 H), 7.01 (d, J = 8.1 Hz, 1 H), 6.88 (t, J = 7.5 Hz, 1 H), 1.36 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ = 168.94, 159.16, 135.22, 129.55, 119.79, 118.01, 115.40, 57.05, 22.26. IR (KBr): 3259, 2963, 2930, 2854, 1677, 1605, 1464, 1408, 1393, 1304, 1232, 1107, 1032 cm–1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H16NO3S: 242.0845; found: 242.0841
  • 23 CCDC-1499293, (R)-L1, contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures
  • 24 Takaya H. Mashima K. Koyano K. Yagi M. Kumobayashi H. Taketomi T. Noyori R. J. Org. Chem. 1986; 51: 629
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  • 27 Typical Procedure for Pd-Catalyzed Allylic Alkylation Reaction [Pd(C3H5)Cl]2 (0.004 mmol, 4 mol%), (R)-L1 (0.008 mmol, 8 mol%), and (E)-1,3-disubstituted allyl acetate 1 (0.1 mmol) were dissolved in THF/dioxane (2.0 mL, 1:1) in a dry Schlenk tube filled with argon. The reaction mixture was stirred for 30 min at room temperature, then ethyl 2-fluoroacetoacetate (2a; 0.3 mmol, 3.0 equiv) and K3PO4 (0.3 mmol, 3.0 equiv) were added. The reaction mixture was stirred at room temperature and the progress of the reaction was monitored by TLC. Upon completion, the mixture was filtered through Celite and the solvent was evaporated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate) to give the desired products 3a–i. (E)-Ethyl 2-Acetyl-3,5-bis(3-chlorophenyl)-2-fluoropent-4-enoate (3a): Colorless oil (39.8 mg, 98% yield). The diastereomeric ratio was 1.6:1 determined by 1H NMR spectroscopic analysis. The ee value of the major diastereomer was 80%, the minor diastereomer was 78%, determined by chiral HPLC [Daicel CHIRALCEL OJ-H (0.46 cm × 25 cm); hexane/i-PrOH = 98:2; flow rate = 1.0 mL/min; detection wavelength = 254 nm; tR (major) = 16.984, 19.423 min; tR (minor) = 21.968, 25.166 min]. 1H NMR (400 MHz, CDCl3, stereoisomeric mixture): δ = 7.42–7.17 (m, 13 H), 6.61–6.21 (m, 3.3 H), 4.52 (dd, J = 32.6, 8.8 Hz, 1.6 H), 4.37–4.16 (m, 2 H), 4.06 (m, 1.3 H), 2.32 (d, J = 5.7 Hz, 1.9 H), 2.01 (d, J = 5.6 Hz, 3 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.06 (t, J = 7.1 Hz, 1.9 H). 13C NMR (100 MHz, CDCl3, stereoisomeric mixture): δ = 201.32 (d, J = 29.8 Hz), 201.14 (d, J = 29.9 Hz), 164.66 (d, J = 25.7 Hz), 164.26 (d, J = 25.9 Hz), 139.01, 138.42, 138.10, 138.03, 134.60, 134.46, 133.61, 133.30, 130.04, 130.02, 129.85, 129.52 (d, J = 2.5 Hz), 129.19 (d, J = 2.6 Hz), 128.11, 128.06, 128.05, 128.00, 127.70 (d, J = 2.2 Hz), 127.12 (d, J = 2.6 Hz), 126.38, 126.33, 125.79, 125.75, 125.60, 125.55, 124.89, 124.80, 102.68 (d, J = 206.1 Hz), 102.52 (d, J = 207.9 Hz), 63.09, 62.84, 52.88 (d, J = 18.1 Hz), 52.82 (d, J = 18.2 Hz), 26.85, 26.84, 14.18, 13.77. 19F NMR (376 MHz, CDCl3, stereoisomeric mixture): δ = –174.49, –175.05. IR (KBr): 3064, 2982, 2932, 2854, 1754, 1734, 1594, 1570, 1476, 1431, 1356, 1246, 1205, 967, 913, 781, 742 cm–1. HRMS (ESI-TOF): m/z [M + Na]+ calcd. for C21H19Cl2FNaO3: 431.0587; found: 431.0592

  • References and Notes

    • 2a Chu CK. Cheng YC. Pai BS. Yao GQ. US Patent 5587362, 1996
      PubMed
    • 2b Marcellin P. Mommeja-Marin H. Sacks SL. Lau GK. Sereni D. Bronowicki JP. Mondou E. Hepatology 2004; 40: 140
      Search in Google Scholar
  • 3 Montgomery JA. Shortnacy-Fowler AT. Clayton SD. Riordan JM. Secrist III JA. J. Med. Chem. 1992; 35: 397
    CrossrefPubMedSearch in Google Scholar
  • 4 Sorbera LA. Serradell N. Bolos J. Drugs Fut. 2007; 32: 12
    CrossrefSearch in Google Scholar
  • 5 Yamaguchi M. Yasueda SI. Isowaki A. Yamamoto M. Kimura M. Inada K. Ohtori A. Int. J. Pharm. 2005; 301: 121
    CrossrefPubMedSearch in Google Scholar
  • 7 FBSM was reported by Shibata and Hu, respectively, in 2006, see ref. 6a and: Ni C. Li Y. Hu J. J. Org. Chem. 2006; 71: 6829
    CrossrefPubMedSearch in Google Scholar

      • For the use of 2-fluoromalonate in Pd-catalyzed asymmetrical allylations, see:
    • 9a Kawasaki T. Kitazume T. Isr. J. Chem. 1999; 39: 129
      CrossrefSearch in Google Scholar
    • 9b Jiang B. Huang ZG. Cheng KJ. Tetrahedron: Asymmetry 2006; 17: 942
      CrossrefSearch in Google Scholar
    • 9c Shibatomi K. Muto T. Sumilkawa Y. Narayama A. Iwasa S. Synlett 2009; 241
      Thieme Connect
    • 9d For the use of FBSM in Pd-catalyzed asymmetrical allylations of symmetric di-substituted allylic substrates, see: Zhao X. Liu D. Zheng S. Gao N. Tetrahedron Lett. 2011; 52: 665
      CrossrefSearch in Google Scholar
  • 11 Zhu F. Xu PW. Zhou F. Wang CH. Zhou J. Org. Lett. 2015; 17: 972
    CrossrefPubMedSearch in Google Scholar
  • 19 Feng X. Wang Y. Wei B. Yang J. Du H. Org. Lett. 2011; 13: 3300
    CrossrefPubMedSearch in Google Scholar
  • 20 Chen Q. Chen C. Guo F. Xia W. Chem. Commun. 2013; 6433
    PubMed
  • 22 Typical Procedure for the Synthesis of (R)-L1 To a solution of salicylic acid (1.0 mmol) in THF (2.0 mL) was added 1,1′-carbonyldiimidazole (CDI; 1.0 mmol, 1.0 equiv) slowly at room temperature, then the reaction mixture was heated to 50 °C for 1.0 h. The solution was cooled to room temperature and concentrated to give the active amide. To a suspension of KH (30% in oil, 2.0 mmol, 2.0 equiv) in THF (5.0 mL) was added (R)-tert-butanesulfinamide (1.0 mmol) under argon at room temperature and the mixture was stirred for 0.5 h. The active amide was added and the mixture was stirred at 50 °C for 1.0 h. The reaction mixture was cooled to room temperature and acidified with aqueous HCl to pH >7, then the mixture was diluted with EtOAc (10 mL), washed with H2O (3 × 10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (EtOAc) to give the desired product (R)-L1 (149.4 mg, 62% yield) as a white solid; mp 144.6–145.9 °C; [α] d 25 –73.8 (c = 1.0, MeOH). 1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 7.8 Hz, 1 H), 7.39 (t, J = 7.4 Hz, 1 H), 7.01 (d, J = 8.1 Hz, 1 H), 6.88 (t, J = 7.5 Hz, 1 H), 1.36 (s, 9 H). 13C NMR (100 MHz, CDCl3): δ = 168.94, 159.16, 135.22, 129.55, 119.79, 118.01, 115.40, 57.05, 22.26. IR (KBr): 3259, 2963, 2930, 2854, 1677, 1605, 1464, 1408, 1393, 1304, 1232, 1107, 1032 cm–1. HRMS (ESI-TOF): m/z [M + H]+ calcd for C11H16NO3S: 242.0845; found: 242.0841
  • 23 CCDC-1499293, (R)-L1, contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures
  • 24 Takaya H. Mashima K. Koyano K. Yagi M. Kumobayashi H. Taketomi T. Noyori R. J. Org. Chem. 1986; 51: 629
    CrossrefSearch in Google Scholar
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  • 27 Typical Procedure for Pd-Catalyzed Allylic Alkylation Reaction [Pd(C3H5)Cl]2 (0.004 mmol, 4 mol%), (R)-L1 (0.008 mmol, 8 mol%), and (E)-1,3-disubstituted allyl acetate 1 (0.1 mmol) were dissolved in THF/dioxane (2.0 mL, 1:1) in a dry Schlenk tube filled with argon. The reaction mixture was stirred for 30 min at room temperature, then ethyl 2-fluoroacetoacetate (2a; 0.3 mmol, 3.0 equiv) and K3PO4 (0.3 mmol, 3.0 equiv) were added. The reaction mixture was stirred at room temperature and the progress of the reaction was monitored by TLC. Upon completion, the mixture was filtered through Celite and the solvent was evaporated under vacuum. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate) to give the desired products 3a–i. (E)-Ethyl 2-Acetyl-3,5-bis(3-chlorophenyl)-2-fluoropent-4-enoate (3a): Colorless oil (39.8 mg, 98% yield). The diastereomeric ratio was 1.6:1 determined by 1H NMR spectroscopic analysis. The ee value of the major diastereomer was 80%, the minor diastereomer was 78%, determined by chiral HPLC [Daicel CHIRALCEL OJ-H (0.46 cm × 25 cm); hexane/i-PrOH = 98:2; flow rate = 1.0 mL/min; detection wavelength = 254 nm; tR (major) = 16.984, 19.423 min; tR (minor) = 21.968, 25.166 min]. 1H NMR (400 MHz, CDCl3, stereoisomeric mixture): δ = 7.42–7.17 (m, 13 H), 6.61–6.21 (m, 3.3 H), 4.52 (dd, J = 32.6, 8.8 Hz, 1.6 H), 4.37–4.16 (m, 2 H), 4.06 (m, 1.3 H), 2.32 (d, J = 5.7 Hz, 1.9 H), 2.01 (d, J = 5.6 Hz, 3 H), 1.27 (t, J = 7.1 Hz, 3 H), 1.06 (t, J = 7.1 Hz, 1.9 H). 13C NMR (100 MHz, CDCl3, stereoisomeric mixture): δ = 201.32 (d, J = 29.8 Hz), 201.14 (d, J = 29.9 Hz), 164.66 (d, J = 25.7 Hz), 164.26 (d, J = 25.9 Hz), 139.01, 138.42, 138.10, 138.03, 134.60, 134.46, 133.61, 133.30, 130.04, 130.02, 129.85, 129.52 (d, J = 2.5 Hz), 129.19 (d, J = 2.6 Hz), 128.11, 128.06, 128.05, 128.00, 127.70 (d, J = 2.2 Hz), 127.12 (d, J = 2.6 Hz), 126.38, 126.33, 125.79, 125.75, 125.60, 125.55, 124.89, 124.80, 102.68 (d, J = 206.1 Hz), 102.52 (d, J = 207.9 Hz), 63.09, 62.84, 52.88 (d, J = 18.1 Hz), 52.82 (d, J = 18.2 Hz), 26.85, 26.84, 14.18, 13.77. 19F NMR (376 MHz, CDCl3, stereoisomeric mixture): δ = –174.49, –175.05. IR (KBr): 3064, 2982, 2932, 2854, 1754, 1734, 1594, 1570, 1476, 1431, 1356, 1246, 1205, 967, 913, 781, 742 cm–1. HRMS (ESI-TOF): m/z [M + Na]+ calcd. for C21H19Cl2FNaO3: 431.0587; found: 431.0592

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Xiaoming Zhaoobtained his Ph.D. from Daliang University of Technology in 1995. He conducted his postdoctoral research at the University of Florida (UF) and University of Southern California (USC) in the group of Prof G. K. Prakash and Prof G. A. Olah. He is currently a professor in Tongji University at Shanghai. His research group’s interests were recognized by the award of a Thieme Chemistry Journal Award in 2012 and focus on reaction design, asymmetric synthesis, and fluorine chemistry.
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Scheme 1 Synthesis of chiral sulfinamide ligand (R)-L1
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Figure 1 The X-ray structure of (R)-L1
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Figure 2 Chiral ligands L used in this reaction
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Scheme 2 Scope of the reaction with allylic acetates 1 and ethyl 2-fluoroacetoacetate 2a. Reaction conditions: [Pd(C3H5)Cl]2 (4 mol%), (R)-L1 (8 mol%) 1 (0.1 mmol), 2 (0.3 mmol) and K3PO4 (0.3 mmol) in THF/dioxane (2 mL, 1:1) at room temperature under argon for about 12–24 h. Isolated yields are given. The diastereomeric ratio was determined by 1H NMR spectroscopic analysis. The ee was determined by chiral HPLC analysis.
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Scheme 3 Preparation of the α-fluoro-β-lactone