Synlett 2015; 26(01): 67-72
DOI: 10.1055/s-0034-1379600
cluster
© Georg Thieme Verlag Stuttgart · New York

Regio- and Diastereoselective Vinylogous Mannich Addition of 3-Alkenyl-2-oxindoles to α-Fluoroalkyl Aldimines

Yingle Liu
a  School of Chemistry and Pharmaceutical Engineering, Sichuan University of Science & Engineering, 180 Xueyuan Street, Huixing Lu, Zigong, Sichuan 643000, P. R. of China
b  College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Road, Shanghai 201620, P. R. of China
,
Yi Yang
a  School of Chemistry and Pharmaceutical Engineering, Sichuan University of Science & Engineering, 180 Xueyuan Street, Huixing Lu, Zigong, Sichuan 643000, P. R. of China
,
Yangen Huang
b  College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Road, Shanghai 201620, P. R. of China
,
Xiu-Hua Xu
c  Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China   Email: flq@mail.sioc.ac.cn
,
Feng-Ling Qing*
b  College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Road, Shanghai 201620, P. R. of China
c  Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, P. R. of China   Email: flq@mail.sioc.ac.cn
› Author Affiliations
Further Information

Publication History

Received: 24 September 2014

Accepted after revision: 03 November 2014

Publication Date:
20 November 2014 (online)

 


Abstract

An efficient asymmetric vinylogous Mannich (AVM) addition reaction of 3-alkenyl-2-oxindoles to α-fluoroalkyl aldimines has been developed. This reaction provided various optical active α-alkylidene-δ-amino-δ-fluoroalkyl oxindoles in excellent yields, complete γ-site ­regioselectivity, and excellent diastereoselectivities.


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The δ-amino-α,β-unsaturated carbonyl compounds represent an important class of units in modern organic and medicinal chemistry.[1] They are useful building blocks for the synthesis of various pharmaceuticals and biologically active natural products.[2] It is well known that fluorine-­containing compounds are considered as the extraordinarily promising drug candidates because the introduction of fluorine atom or fluorine-containing groups into organic compounds often significantly improves the chemical, physical, and biological properties of the parent compound.[3] [4] Especially, the fluoroalkyl-substituted molecules, such as trifluoromethylated and difluoromethylated compounds, have attracted increasing attention.[5] Thus, the incorporation of fluoroalkyl into δ-amino-α,β-unsaturated carbonyl compounds will provide novel fluorinated moieties, which might be applied in various research fields. Among them, δ-amino-δ-fluoroalkyl-α,β-unsaturated carbonyl compounds are particularly interesting, because the neighboring electron-withdrawing fluoroalkyl groups would change the basicity of imine groups, thus affecting their bioactivities. Normally, these compounds were prepared by vinylogous Mannich reactions.[6] In 1992, Tsukamoto and Kitazume reported the Lewis acid promoted reaction of fluorinated N,O-acetal with trimethylsilyloxyfuran (Scheme [1, a]).[7] The Lewis acid catalyzed vinylogous Mannich addition of trimethylsilyloxyfuran to fluorinated aldimines was disclosed by Crousse and co-workers in 2004 (Scheme [1, a]).[8] Shi’s group realized the first enantioselective vinylogous Mannich reaction of fluorinated aldimines bearing a chiral auxiliary [(S)-1-phenylethyl group] and siloxyfurans under the catalytic environment of silver acetate and axially chiral phosphine-oxazoline ligand (Scheme [1, b]).[9] Very recently, we developed a tunable and highly regio- and diastereoselective addition reaction of acyclic silyl dienolates to α-fluoroalkyl sulfinylimines, in which the Lewis acid TMSOTf was a critical parameter in the control of γ-site regioselectivity (Scheme [1, c]).[10] All the previous works need silylated substrates as the nucleophiles. From the point of atom and step economy, it is worthy to investigate the addition reactions directly using α,β-unsaturated carbonyl compounds as the nucleophiles. In light of the important pharmaceutical implications of the privileged structural motif oxindole,[11] herein we report a regio- and diastereoselective vinylogous Mannich addition of 3-alkenyl-2-oxindoles to α-fluoroalkyl aldimines to afford various chiral α-alkylidene-δ-amino-δ-fluoroalkyl oxindoles (Scheme [1, d]).

Zoom Image
Scheme 1 Synthesis of δ-amino-α,β-unsaturated carbonyl compounds by vinylogous Mannich reactions

Initially, the reaction conditions were optimized using (SS )-N-tert-butanesulfinyl-3,3,3-trifluoroacetaldimine (1a)[12] and N-Boc-protected 3-alkylidene-2-oxindole 2a [13] as the model substrates (Table [1]). Treatment of the substrates with TMSOTf and Et3N gave only a silylated intermediate of 2a.[13d] The desired product 3a was not obtained (Table [1], entry 1). In view of the better nucleophilic properties of the metallic enolate intermediate in comparison to silyl enolate, LDA was chosen as the base. To our delight, the addition reaction happened in the presence of LDA, and 3a was obtained in moderate yield, with virtually complete γ-site selectivity (>99:1 γ/α) and good diastereoselectivity (94:6 dr, Z/E = 8:1; Table [1], entry 2). Considering the fact that the addition of Lewis acid might improve the yield and diastereoselectivity because of its coordination with sulfinylimine substrate,[14] different Lewis acids were then investigated. Among the three typical Lewis acids, Ti(Oi-Pr)4, AlMe3, and BF3·OEt2, Ti(Oi-Pr)4 showed the highest efficiency and sharply increased the yield of 3a from 60% to 98% (Table [1], entries 3–5). When the base was changed from LDA to KHMDS, 3a was obtained in similar yield with much higher Z/E ratio (Table [1], entry 6). Finally, different solvents including toluene, Et2O, and hexane were screened (Table [1], entries 7–9). However, no better result was obtained.

Zoom Image
Scheme 2 Vinylogous Mannich addition of 3-alkenyl-2-oxindoles to α-fluoroalkyl aldimines

With the optimized conditions in hand, the substrate scope of direct asymmetric vinylogous Mannich (AVM) reaction was surveyed.[15] [16] The results are summarized in Scheme [2]. Firstly, 3-alkylidene-2-oxindoles 2ad bearing diverse nitrogen protecting groups, Boc, Moc, Bn, and Me, reacted smoothly with 1a under identical conditions, affording the corresponding products 3ad in moderate to good yields and excellent stereoselectivities. Additionally, the reaction conditions displayed good compatibility with the substituent pattern on the phenyl ring of the 2-oxindole. The substrates 2eg, bearing electron-donating and electron-withdrawing groups, can be efficiently transformed to the corresponding products in excellent yields and stereoselectivities. Subsequently, the patterns of R3 in 3-alkylidene-2-oxindole 2hj having aromatic groups were tested as the substrates. The reactions proceeded well affording products 3hj in good yields and diastereoselectivities, although the Z/E ratios were comparably low. It was noteworthy that this protocol could be applied to difluoromethylated sulfinylimine 1b. The corresponding difluoromethylated products 3kn were conveniently obtained ­under the optimal reaction conditions. The 3-(propan-2-ylidene)benzofuran-2(3H)-one 2o [17] was also a suitable substrate for this reaction to furnish the product 3o in modest yield and good stereoselectivity.

The absolute configuration of these α-alkylidene-δ-amino-δ-fluoroalkyl oxindoles 3 was confirmed by X-ray crystallographic analysis of compounds 3d (Figure [1]).[18] Normally, a nonchelated transition-state model was involved in the addition reaction of nucleophiles to fluorinated sulfinylimines.[12] The stereochemical outcome observed in the present study could also be explained by the nonchelated transition-state model, in which the sulfinyl oxygen coordinates to Ti(Oi-Pr)4 and sterically shields the Re face of the imine. Thus, the Si attack from metallic enolate intermediates would produce adducts 3 with (C S ,S S )-configurations. The high Z/E ratios in compound 3 might be caused by the cyclic structure of nucleophilic enolate intermediates.[19] The accurate reaction mechanism still needs further investigation.

Table 1 Optimization of Reaction Conditionsa

Entry

Base

Lewis acid

Solvent

Temp (°C)

Yield (%)b

Z/E b

drb

1c

Et3N

TMSOTf

CH2Cl2

0 to r.t.

0

2

LDA

THF

–78

60

8:1

94:6

3

LDA

Ti(Oi-Pr)4

THF

–78

98

6:1

94:6

4

LDA

AlMe3

THF

–78

58

12:1

92:8

5

LDA

BF3·OEt2

THF

–78

70

7:1

95:5

6

KHMDS

Ti(Oi-Pr)4

THF

–78

97

16:1

93:7

7

KHMDS

Ti(Oi-Pr)4

toluene

–78

87

12:1

93:7

8

KHMDS

Ti(Oi-Pr)4

Et2O

–78

41

2:1

94:6

9

KHMDS

Ti(Oi-Pr)4

hexane

–78

18

a Reactions were carried out using 1a (0.3 mmol), 2a (0.36 mmol, 1.2 equiv), base (0.36 mmol, 1.2 equiv), and Lewis acid (0.33 mmol, 1.1 equiv) in dry solvent (2.5 mL) for 12 h.

b Ratios and yields were determined by 19F NMR spectroscopy of the crude reaction mixture using benzotrifluoride as an internal standard.

c Base (0.33 mmol, 1.1 equiv) and Lewis acid (0.36 mmol, 1.2 equiv).

Zoom Image
Figure 1 X-ray crystal structure of 3d and proposed transition-state model

It should be mentioned that the N-tert-butylsulfinyl group can serve not only as an efficient chiral auxiliary, but also as an amine protecting group.[20] It could be readily cleaved under mild acidic conditions. After deprotection, the trifluoromethylated free amines 4 can be easily obtained in high yield (Scheme [3]).

Zoom Image
Scheme 3 Conversion of 3d into the free primary amine 4

In summary, we have demonstrated a practical and efficient approach to synthesize α-alkylidene-δ-amino-δ-fluoroalkyl oxindoles via a regio- and stereoselective vinylogous Mannich-type reaction of fluorinated N-tert-butanesulfinyl aldimines with 3-alkenyl-2-oxindoles. This protocol displayed broad substrate scope, good functional-group compatibility, and satisfactory stereocontrol. Further applications of this method for the preparation of new fluorinated bioactive molecules are in progress.


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Acknowledgment

We thank the National Natural Science Foundation of China (21421002, 21332010, 21272036) and the National Basic Research Program of China (2012CB21600) for financial support. Sichuan University of Science & Engineering (No. 2014RC07, 2012RC17), Zigong Science and Technology Bureau (No. 2013X02), Education Department of Sichuan Province (No. 14ZB0207) and Key Laboratory of Green Chemistry of Sichuan Institutes of Higher Education (No. LZJ1401) are also gratefully acknowledged for funding this work.

Supporting Information

  • References and Notes


    • For selected reviews, see:
    • 1a Casiraghi G, Zanardi F, Appendino G, Rassu G. Chem. Rev. 2000; 100: 1929
    • 1b Casiraghi G, Zanardi F, Battistini L, Rassu G. Synlett 2009; 1525
    • 1c Casiraghi G, Battistini L, Curti C, Rassu G, Zanardi F. Chem. Rev. 2011; 111: 3076
    • 1d Martin SF. Adv. Heterocycl. Chem. 2013; 110: 73

      For selected examples, see:
    • 2a Mohan S, Kerry PS, Bance N, Niikura M, Pinto BM. Angew. Chem. Int. Ed. 2014; 53: 1076
    • 2b Ren W, Wang Q, Zhu J. Angew. Chem. Int. Ed. 2014; 53: 1818
    • 2c Hickin JA, Ahmed A, Fucke K, Ashcroft M, Jones K. Chem. Commun. 2014; 50: 1238
    • 2d Abels F, Lindemann C, Schneider C. Chem. Eur. J. 2014; 20: 1964
    • 2e Sartori A, Dell’Amico L, Battistini L, Curti C, Rivara S, Pala D, Kerry PS, Pelosi G, Casiraghi G, Rassu G, Zanardi F. Org. Biomol. Chem. 2014; 12: 1561
    • 2f Suetsugu S, Nishiguchi H, Tsukano C, Takemoto Y. Org. Lett. 2014; 16: 996
    • 4a Müller K, Faeh C, Diederich F. Science 2007; 317: 1881
    • 4b Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
    • 4c Meanwell NA. J. Med. Chem. 2011; 54: 2529
    • 4d Wang J, Sánchez-Roselló M, Aceña JL, Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432

      For selected reviews, see:
    • 5a Nie J, Guo H.-C, Cahard D, Ma J.-A. Chem. Rev. 2011; 111: 455
    • 5b Tomashenko OA, Grushin VV. Chem. Rev. 2011; 111: 4475
    • 5c Furuya T, Kamlet AS, Ritter T. Nature (London, U.K.) 2011; 473: 470
    • 5d Studer A. Angew. Chem. Int. Ed. 2012; 51: 8950
    • 5e Liang T, Neumann CN, Ritter T. Angew. Chem. Int. Ed. 2013; 52: 8214
    • 5f Merino E, Nevado C. Chem. Soc. Rev. 2014; 43: 6598
    • 6a Bur SK, Martin SF. Tetrahedron 2001; 57: 3221
    • 6b Martin SF. Acc. Chem. Res. 2002; 35: 895
    • 6c Karimi B, Enders D, Jafari E. Synthesis 2013; 45: 2769
  • 7 Tsukamoto T, Kitazume T. Chem. Lett. 1992; 21: 1377
  • 8 Spanedda MV, Ourévitch M, Crousse B, Bégué J.-P, Bonnet-Delpon D. Tetrahedron Lett. 2004; 45: 5023
    • 9a Zhao Q.-Y, Yuan Z.-L, Shi M. Tetrahedron: Asymmetry 2010; 21: 943
    • 9b Zhao Q.-Y, Yuan Z.-L, Shi M. Adv. Synth. Catal. 2011; 353: 637
  • 10 Liu Y, Liu J, Huang Y, Qing F.-L. Chem. Commun. 2013; 49: 7492

    • For selected reviews, see:
    • 11a Galliford CV, Scheidt KA. Angew. Chem. Int. Ed. 2007; 46: 8748
    • 11b Peddibhotla S. Curr. Bioact. Compd. 2009; 5: 20
    • 11c Zhou F, Liu Y.-L, Zhou J. Adv. Synth. Catal. 2010; 352: 1381
    • 12a Truong VL, Ménard MS, Dion I. Org. Lett. 2007; 9: 683
    • 12b Truong VL, Pfeiffer JY. Tetrahedron Lett. 2009; 50: 1633
    • 12c Mei H, Xiong Y, Han J, Pan Y. Org. Biomol. Chem. 2011; 9: 1402
    • 12d Zhang H, Li Y, Xu W, Zheng W, Zhou P, Sun Z. Org. Biomol. Chem. 2011; 9: 6502
    • 12e Shibata N, Nishimine T, Shibata N, Tokunaga E, Kawada K, Kagawa T, Sorochinskycde AE, Soloshonok VA. Chem. Commun. 2012; 48: 4124
    • 12f Turcheniuk KV, Poliashko KO, Kukhar VP, Rozhenko AB, Soloshonok VA, Sorochinsky AE. Chem. Commun. 2012; 48: 11519
    • 12g Röschenthaler G.-V, Kukhar VP, Kulik IB, Belik MY, Sorochinsky AE, Rusanov EB, Soloshonok VA. Tetrahedron Lett. 2012; 53: 539
    • 12h Mei H, Xie C, Wu L, Soloshonok VA, Han J, Pan Y. Org. Biomol. Chem. 2013; 11: 8018
    • 12i Shevchuk MV, Kukhar VP, Röschenthaler G.-V, Bassil BS, Kawada K, Soloshonok VA, Sorochinsky AE. RSC Adv. 2013; 3: 6479
    • 12j Xie C, Mei H, Wu L, Soloshonok VA, Han J, Pan Y. Eur. J. Org. Chem. 2014; 1445
    • 12k Mei H, Dai Y, Wu L, Soloshonok VA, Han J, Pan Y. Eur. J. Org. Chem. 2014; 2429
    • 12l Milcent T, Hao J, Kawada K, Soloshonok VA, Ongeri S, Crousse B. Eur. J. Org. Chem. 2014; 3072
    • 12m Xie C, Mei H, Wu L, Han J, Soloshonok VA, Pan Y. J. Fluorine Chem. 2014; 165: 67
    • 12n Wu L, Xie C, Mei H, Soloshonok VA, Han J, Pan Y. J. Org. Chem. 2014; 79: 7677
    • 12o Shibata N, Nishimine T, Shibata N, Tokunaga E, Kawada K, Kagawa T, Aceña JL, Sorochinsky AE, Soloshonok VA. Org. Biomol. Chem. 2014; 12: 1454
    • 12p Mei H, Xiong Y, Xie C, Soloshonok VA, Han J, Pan Y. Org. Biomol. Chem. 2014; 12: 2018
    • 12q Wu L, Xie C, Mei H, Soloshonok VA, Han J, Pan Y. Org. Biomol. Chem. 2014; 12: 4620
    • 12r Xie C, Wu L, Mei H, Soloshonok VA, Han J, Pan Y. Org. Biomol. Chem. 2014; 12: 7836
    • 12s Qian P, Xie C, Wu L, Mei H, Soloshonok VA, Han J, Pan Y. Org. Biomol. Chem. 2014; 12: 7909
    • 12t Xie C, Mei H, Wu L, Soloshonok VA, Han J, Pan Y. RSC Adv. 2014; 4: 4763
    • 12u Xie C, Wu L, Mei H, Soloshonok VA, Han J, Pan Y. Tetrahedron Lett. 2014; 55: 5908
    • 13a Curti C, Rassu G, Zambrano V, Pinna L, Pelosi G, Sartori A, Battistini L, Zanardi F, Casiraghi G. Angew. Chem. Int. Ed. 2012; 51: 6200
    • 13b Rassu G, Zambrano V, Tanca R, Sartori A, Battistini L, Zanardi F, Curti C, Casiraghi G. Eur. J. Org. Chem. 2012; 466
    • 13c Rassu G, Zambrano V, Pinna L, Curti C, Battistini L, Sartori A, Pelosi G, Zanardi F, Casiraghi G. Adv. Synth. Catal. 2013; 355: 1881
    • 13d Ranieri B, Sartori A, Curti C, Battistini L, Rassu G, Pelosi G, Casiraghi G, Zanardi F. Org. Lett. 2014; 16: 932
    • 13e Chen Q, Wang G, Jiang X, Xu Z, Lin L, Wang R. Org. Lett. 2014; 16: 1394
    • 14a Jiang W, Chen C, Marinkovic D, Tran JA, Chen CW, Arellano LM, White NS, Tucci FC. J. Org. Chem. 2005; 70: 8924
    • 14b Senanayake C, Lu BZ, Li N, Han Z, Bakale RP, Wald SA. Org. Lett. 2005; 7: 2599
    • 14c Larhed M, Arefalk A, Wannberg J, Hallberg A. J. Org. Chem. 2006; 71: 1265
  • 15 General Procedure for the Synthesis of α-Alkylidene-δ-amino-δ-fluoroalkyl OxindolesA solution of KHMDS (0.36 mL, 1 M solution in THF) was slowly added to a dried Scheck flask containing 3-alkenyl-2-oxindoles 2 (0.36 mmol) in THF (2.0 mL) at –78 °C under N2 atmosphere. After stirring at –78 °C for 1 h, the mixture of 1 (0.3 mmol) and Ti(Oi-Pr)4 (0.33 mmol) in THF (1.0 mL) was added dropwise, and the mixture was stirred for 12 h at –78 °C. Then sat. aq NH4Cl solution and H2O was added at –78 °C. The mixture was brought to r.t. After 5 min, the mixture was filtered through Celite, and the filtrate was extracted with EtOAc. The combined organic solution was dried over MgSO4. After the removal of volatile solvents under vacuum, the crude product was purified by silica gel column chromatography to give the required product.
  • 16 Analytical Data for Compound 3aMp 60–61 °C. [α]D 17.0 +187.7 (c 0.41, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 8.2 Hz, 1 H), 7.60 (d, J = 7.8 Hz, 1 H), 7.35 (t, J = 7.9 Hz, 1 H), 7.20 (t, J = 7.7 Hz, 1 H), 4.35 (dd, J = 24.4, 11.2 Hz, 2 H), 4.19–3.96 (m, 1 H), 2.62 (dd, J = 12.7, 3.8 Hz, 1 H), 2.43 (s, 3 H), 1.67 (s, 9 H), 1.06 (s, 9 H). 19F NMR (377 MHz, CDCl3): δ = –74.87 (d, J = 6.5 Hz, 3 F). 13C NMR (101 MHz, CDCl3): δ = 166.5, 152.0, 149.1, 138.3, 128.9, 125.6, 125.2 (q, J = 284.8 Hz), 124.1, 123.9, 123.2, 114.6, 84.6, 57.2, 56.4 (q, J = 30.2 Hz), 35.3, 28.1, 24.2, 22.2. IR (KBr): νmax = 3261, 3060, 2975, 1731, 1613, 1462, 1535, 1300, 1258, 1157, 1090, 841, 748 cm–1. MS (EI): m/z = 497.2 [M + Na]+. ESI-HRMS: m/z [M + Na]+ calcd for C22H29F3N2O4SNa: 497.1692; found: 497.1712.
  • 17 Trost BM, Cramer N, Silverman SM. J. Am. Chem. Soc. 2007; 129: 12396
  • 18 Further details of the crystal data can be obtained from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK (CCDC deposition No. 1011207).
  • 19 Vincent MA, Smith AC, Donnard M, Harford PJ, Haywood J, Hillier IH, Clayden J, Wheatley AE. H. Chem. Eur. J. 2012; 18: 11036
  • 20 Robak MT, Herbage MA, Ellman JA. Chem. Rev. 2010; 110: 3600

  • References and Notes


    • For selected reviews, see:
    • 1a Casiraghi G, Zanardi F, Appendino G, Rassu G. Chem. Rev. 2000; 100: 1929
    • 1b Casiraghi G, Zanardi F, Battistini L, Rassu G. Synlett 2009; 1525
    • 1c Casiraghi G, Battistini L, Curti C, Rassu G, Zanardi F. Chem. Rev. 2011; 111: 3076
    • 1d Martin SF. Adv. Heterocycl. Chem. 2013; 110: 73

      For selected examples, see:
    • 2a Mohan S, Kerry PS, Bance N, Niikura M, Pinto BM. Angew. Chem. Int. Ed. 2014; 53: 1076
    • 2b Ren W, Wang Q, Zhu J. Angew. Chem. Int. Ed. 2014; 53: 1818
    • 2c Hickin JA, Ahmed A, Fucke K, Ashcroft M, Jones K. Chem. Commun. 2014; 50: 1238
    • 2d Abels F, Lindemann C, Schneider C. Chem. Eur. J. 2014; 20: 1964
    • 2e Sartori A, Dell’Amico L, Battistini L, Curti C, Rivara S, Pala D, Kerry PS, Pelosi G, Casiraghi G, Rassu G, Zanardi F. Org. Biomol. Chem. 2014; 12: 1561
    • 2f Suetsugu S, Nishiguchi H, Tsukano C, Takemoto Y. Org. Lett. 2014; 16: 996
    • 4a Müller K, Faeh C, Diederich F. Science 2007; 317: 1881
    • 4b Purser S, Moore PR, Swallow S, Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
    • 4c Meanwell NA. J. Med. Chem. 2011; 54: 2529
    • 4d Wang J, Sánchez-Roselló M, Aceña JL, Pozo C, Sorochinsky AE, Fustero S, Soloshonok VA, Liu H. Chem. Rev. 2014; 114: 2432

      For selected reviews, see:
    • 5a Nie J, Guo H.-C, Cahard D, Ma J.-A. Chem. Rev. 2011; 111: 455
    • 5b Tomashenko OA, Grushin VV. Chem. Rev. 2011; 111: 4475
    • 5c Furuya T, Kamlet AS, Ritter T. Nature (London, U.K.) 2011; 473: 470
    • 5d Studer A. Angew. Chem. Int. Ed. 2012; 51: 8950
    • 5e Liang T, Neumann CN, Ritter T. Angew. Chem. Int. Ed. 2013; 52: 8214
    • 5f Merino E, Nevado C. Chem. Soc. Rev. 2014; 43: 6598
    • 6a Bur SK, Martin SF. Tetrahedron 2001; 57: 3221
    • 6b Martin SF. Acc. Chem. Res. 2002; 35: 895
    • 6c Karimi B, Enders D, Jafari E. Synthesis 2013; 45: 2769
  • 7 Tsukamoto T, Kitazume T. Chem. Lett. 1992; 21: 1377
  • 8 Spanedda MV, Ourévitch M, Crousse B, Bégué J.-P, Bonnet-Delpon D. Tetrahedron Lett. 2004; 45: 5023
    • 9a Zhao Q.-Y, Yuan Z.-L, Shi M. Tetrahedron: Asymmetry 2010; 21: 943
    • 9b Zhao Q.-Y, Yuan Z.-L, Shi M. Adv. Synth. Catal. 2011; 353: 637
  • 10 Liu Y, Liu J, Huang Y, Qing F.-L. Chem. Commun. 2013; 49: 7492

    • For selected reviews, see:
    • 11a Galliford CV, Scheidt KA. Angew. Chem. Int. Ed. 2007; 46: 8748
    • 11b Peddibhotla S. Curr. Bioact. Compd. 2009; 5: 20
    • 11c Zhou F, Liu Y.-L, Zhou J. Adv. Synth. Catal. 2010; 352: 1381
    • 12a Truong VL, Ménard MS, Dion I. Org. Lett. 2007; 9: 683
    • 12b Truong VL, Pfeiffer JY. Tetrahedron Lett. 2009; 50: 1633
    • 12c Mei H, Xiong Y, Han J, Pan Y. Org. Biomol. Chem. 2011; 9: 1402
    • 12d Zhang H, Li Y, Xu W, Zheng W, Zhou P, Sun Z. Org. Biomol. Chem. 2011; 9: 6502
    • 12e Shibata N, Nishimine T, Shibata N, Tokunaga E, Kawada K, Kagawa T, Sorochinskycde AE, Soloshonok VA. Chem. Commun. 2012; 48: 4124
    • 12f Turcheniuk KV, Poliashko KO, Kukhar VP, Rozhenko AB, Soloshonok VA, Sorochinsky AE. Chem. Commun. 2012; 48: 11519
    • 12g Röschenthaler G.-V, Kukhar VP, Kulik IB, Belik MY, Sorochinsky AE, Rusanov EB, Soloshonok VA. Tetrahedron Lett. 2012; 53: 539
    • 12h Mei H, Xie C, Wu L, Soloshonok VA, Han J, Pan Y. Org. Biomol. Chem. 2013; 11: 8018
    • 12i Shevchuk MV, Kukhar VP, Röschenthaler G.-V, Bassil BS, Kawada K, Soloshonok VA, Sorochinsky AE. RSC Adv. 2013; 3: 6479
    • 12j Xie C, Mei H, Wu L, Soloshonok VA, Han J, Pan Y. Eur. J. Org. Chem. 2014; 1445
    • 12k Mei H, Dai Y, Wu L, Soloshonok VA, Han J, Pan Y. Eur. J. Org. Chem. 2014; 2429
    • 12l Milcent T, Hao J, Kawada K, Soloshonok VA, Ongeri S, Crousse B. Eur. J. Org. Chem. 2014; 3072
    • 12m Xie C, Mei H, Wu L, Han J, Soloshonok VA, Pan Y. J. Fluorine Chem. 2014; 165: 67
    • 12n Wu L, Xie C, Mei H, Soloshonok VA, Han J, Pan Y. J. Org. Chem. 2014; 79: 7677
    • 12o Shibata N, Nishimine T, Shibata N, Tokunaga E, Kawada K, Kagawa T, Aceña JL, Sorochinsky AE, Soloshonok VA. Org. Biomol. Chem. 2014; 12: 1454
    • 12p Mei H, Xiong Y, Xie C, Soloshonok VA, Han J, Pan Y. Org. Biomol. Chem. 2014; 12: 2018
    • 12q Wu L, Xie C, Mei H, Soloshonok VA, Han J, Pan Y. Org. Biomol. Chem. 2014; 12: 4620
    • 12r Xie C, Wu L, Mei H, Soloshonok VA, Han J, Pan Y. Org. Biomol. Chem. 2014; 12: 7836
    • 12s Qian P, Xie C, Wu L, Mei H, Soloshonok VA, Han J, Pan Y. Org. Biomol. Chem. 2014; 12: 7909
    • 12t Xie C, Mei H, Wu L, Soloshonok VA, Han J, Pan Y. RSC Adv. 2014; 4: 4763
    • 12u Xie C, Wu L, Mei H, Soloshonok VA, Han J, Pan Y. Tetrahedron Lett. 2014; 55: 5908
    • 13a Curti C, Rassu G, Zambrano V, Pinna L, Pelosi G, Sartori A, Battistini L, Zanardi F, Casiraghi G. Angew. Chem. Int. Ed. 2012; 51: 6200
    • 13b Rassu G, Zambrano V, Tanca R, Sartori A, Battistini L, Zanardi F, Curti C, Casiraghi G. Eur. J. Org. Chem. 2012; 466
    • 13c Rassu G, Zambrano V, Pinna L, Curti C, Battistini L, Sartori A, Pelosi G, Zanardi F, Casiraghi G. Adv. Synth. Catal. 2013; 355: 1881
    • 13d Ranieri B, Sartori A, Curti C, Battistini L, Rassu G, Pelosi G, Casiraghi G, Zanardi F. Org. Lett. 2014; 16: 932
    • 13e Chen Q, Wang G, Jiang X, Xu Z, Lin L, Wang R. Org. Lett. 2014; 16: 1394
    • 14a Jiang W, Chen C, Marinkovic D, Tran JA, Chen CW, Arellano LM, White NS, Tucci FC. J. Org. Chem. 2005; 70: 8924
    • 14b Senanayake C, Lu BZ, Li N, Han Z, Bakale RP, Wald SA. Org. Lett. 2005; 7: 2599
    • 14c Larhed M, Arefalk A, Wannberg J, Hallberg A. J. Org. Chem. 2006; 71: 1265
  • 15 General Procedure for the Synthesis of α-Alkylidene-δ-amino-δ-fluoroalkyl OxindolesA solution of KHMDS (0.36 mL, 1 M solution in THF) was slowly added to a dried Scheck flask containing 3-alkenyl-2-oxindoles 2 (0.36 mmol) in THF (2.0 mL) at –78 °C under N2 atmosphere. After stirring at –78 °C for 1 h, the mixture of 1 (0.3 mmol) and Ti(Oi-Pr)4 (0.33 mmol) in THF (1.0 mL) was added dropwise, and the mixture was stirred for 12 h at –78 °C. Then sat. aq NH4Cl solution and H2O was added at –78 °C. The mixture was brought to r.t. After 5 min, the mixture was filtered through Celite, and the filtrate was extracted with EtOAc. The combined organic solution was dried over MgSO4. After the removal of volatile solvents under vacuum, the crude product was purified by silica gel column chromatography to give the required product.
  • 16 Analytical Data for Compound 3aMp 60–61 °C. [α]D 17.0 +187.7 (c 0.41, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.88 (d, J = 8.2 Hz, 1 H), 7.60 (d, J = 7.8 Hz, 1 H), 7.35 (t, J = 7.9 Hz, 1 H), 7.20 (t, J = 7.7 Hz, 1 H), 4.35 (dd, J = 24.4, 11.2 Hz, 2 H), 4.19–3.96 (m, 1 H), 2.62 (dd, J = 12.7, 3.8 Hz, 1 H), 2.43 (s, 3 H), 1.67 (s, 9 H), 1.06 (s, 9 H). 19F NMR (377 MHz, CDCl3): δ = –74.87 (d, J = 6.5 Hz, 3 F). 13C NMR (101 MHz, CDCl3): δ = 166.5, 152.0, 149.1, 138.3, 128.9, 125.6, 125.2 (q, J = 284.8 Hz), 124.1, 123.9, 123.2, 114.6, 84.6, 57.2, 56.4 (q, J = 30.2 Hz), 35.3, 28.1, 24.2, 22.2. IR (KBr): νmax = 3261, 3060, 2975, 1731, 1613, 1462, 1535, 1300, 1258, 1157, 1090, 841, 748 cm–1. MS (EI): m/z = 497.2 [M + Na]+. ESI-HRMS: m/z [M + Na]+ calcd for C22H29F3N2O4SNa: 497.1692; found: 497.1712.
  • 17 Trost BM, Cramer N, Silverman SM. J. Am. Chem. Soc. 2007; 129: 12396
  • 18 Further details of the crystal data can be obtained from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK (CCDC deposition No. 1011207).
  • 19 Vincent MA, Smith AC, Donnard M, Harford PJ, Haywood J, Hillier IH, Clayden J, Wheatley AE. H. Chem. Eur. J. 2012; 18: 11036
  • 20 Robak MT, Herbage MA, Ellman JA. Chem. Rev. 2010; 110: 3600

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Scheme 1 Synthesis of δ-amino-α,β-unsaturated carbonyl compounds by vinylogous Mannich reactions
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Scheme 2 Vinylogous Mannich addition of 3-alkenyl-2-oxindoles to α-fluoroalkyl aldimines
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Figure 1 X-ray crystal structure of 3d and proposed transition-state model
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Scheme 3 Conversion of 3d into the free primary amine 4