Catalytic asymmetric homo-1,3-dipolar cycloadditions of azomethine ylides: diastereo- and enantioselective synthesis of imidazolidines

Download Catalytic asymmetric homo-1,3-dipolar cycloadditions of azomethine ylides: diastereo- and enantioselective synthesis of imidazolidines

Post on 25-Dec-2016

214 views

Category:

Documents

2 download

Embed Size (px)

TRANSCRIPT

  • Catalytic asymmetric homo-1,3-dipolar cyylides: diastereo- and enantioselective sy

    Ren-Yi Zhu, Cong-Shuai Wang, Fei Jiang, Feng Shi , ShSchool of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic C

    tricchiateenicto 9idazste

    azomethine ylides to unsaturated bonds haerful tool to access chiral nitrogenous hetexisted in numerous natural products and apharmaceutical relevance.1 As a result,

    d in thtron-de scaffoselect1,3-DCgen do

    at the precursorserated from alde-nitrogen

    es via homDCs under the catalysis of CPA, thus affording chiral imidazowith multiple stereogenic centers (Scheme 1). In this appazomethine ylides would act as both 1,3-dipoles and diphiles to perform diastereo- and enantioselective homo-1,3-DCs,which have not been reported so far during the development ofcatalytic asymmetric 1,3-DCs of azomethine ylides.

    Herein we report the rst catalytic asymmetric homo-1,3-DCsof azomethine ylides, which assemble aldehydes and 2-aminomal-onates in a highly ordered reaction sequence to efciently

    N R3R1

    R2

    H

    N

    NHR

    1

    R2

    R3

    ArR

    only a few enantioselectivetransformations are available

    Cat.*

    Cat.* **

    N

    Ar

    R*imineazomethine ylide

    imidazolidine

    pyrolidine

    (2)

    Corresponding author. Tel./fax: +86 (516) 83500065.E-mail address: fshi@jsnu.edu.cn (F. Shi).

    Tetrahedron: Asymmetry xxx (2014) xxxxxx

    Contents lists availab

    Tetrahedron:

    journal homepage: www.elstereoselective imidazolidines, we envisioned thof azomethine ylides, that is, the aldimines genhydes and amino-esters would serve as carbonAbonds to react with the same azomethine ylid

    EWGR4

    R5 R6

    NR1

    R2

    R3

    EWG

    R6

    R5 R4

    many enantioselectivetransformations are available**

    * *olefin

    (1)http://dx.doi.org/10.1016/j.tetasy.2014.03.0080957-4166/ 2014 Elsevier Ltd. All rights reserved.

    Please cite this article in press as: Zhu, R.-Y.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2014.03.008doubleo-1,3-lidinesroach,polaro-volves the use of imines derived from anilines and aldehydes asdipolarophiles as reported by Gong et al. and Wang et al. (Eq. 2).3

    as dipolarophiles.We have already established a series of 1,3-DCs of azomethine

    ylides to electron-decient olens7 or alkynes8 with excellentenantioselectivity using chiral phosphoric acids (CPAs)9 as cata-lysts. Inspired by this success and with the aim of synthesizing

    previous work on catalytic asymmetric 1,3-DCs:transformations have been develope1,3-DCs of azomethine ylides to electo the formation of chiral pyrolidinin sharp contrast, only a few enantifound for the catalytic asymmetricto electronically poor carbonAnitrove proven to be a pow-erocyclic motifs, whichrticial molecules withmany enantioselectivee catalytic asymmetricecient olens, leadingolds (Eq. 1).2 However,ive variants have beens of azomethine ylidesuble bonds, which in-

    natural products, bioactive compounds, and important catalystsor ligands in organic synthesis. For example, as illustrated inFigure 1, fumiquinazolines A and B I are natural alkaloids.4 Com-pounds IIIV possess antipyretic, anticonvulsant, and aldosereductase inhibitory activities, respectively.5 Compounds VVIIare well known organocatalysts or ligands, which have enabled avariety of enantioselective transformations.6 Therefore, this trans-formation is highly desirable for the stereoselective construction ofthe imidazolidine moiety and remains a challenge with regard tothe limited examples employing carbonAnitrogen double bonds1. Introduction

    Catalytic asymmetric 1,3-dipolar cycloadditions (1,3-DCs) of

    On the other hand, the catalytic asymmetric 1,3-DCs of azome-thine ylides to imines would allow for the creation of a chiral imi-dazolidine skeleton, which constitutes the core structure of manya r t i c l e i n f o

    Article history:Received 22 January 2014Accepted 7 March 2014Available online xxxx

    a b s t r a c t

    The rst catalytic asymmelished via SPINOL-derivedhydes and 2-aminomalonscaffolds with two stereog81% yield, all >20:1 dr, uptically important chiral imfour new bonds in a singlecloadditions of azomethinenthesis of imidazolidines

    u-Jiang Tuhemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, China

    homo-1,3-dipolar cycloadditions of azomethine ylides have been estab-ral phosphoric acid-catalyzed pseudo four-component reactions of alde-s, resulting in the stereoselective construction of chiral imidazolidinecenters in generally high yields and with good stereoselectivities (up to

    3% ee). This protocol provides easy access to synthetically and pharmaceu-olidines via the formation of one ring system, two stereogenic centers, andp.

    2014 Elsevier Ltd. All rights reserved.

    le at ScienceDirect

    Asymmetry

    sevier .com/locate / tetasy

  • an

    gens

    ort

    AsyNN

    TsSMe

    O

    O

    OR

    antipyretic

    N

    NNH

    O

    O

    Me

    N

    OH

    NH

    MeO

    H

    fumiquinazoline A and B

    NH

    NO

    Me

    Me

    Me

    Bn

    MacMillan's catalyst

    BnI

    II

    VJo

    Figure 1. Selected natural alkaloids, bioactive compounds, and imp

    this work: the first catalytic asymmetric homo-1,3-DCs

    N

    CO2R

    R1

    RO2C

    N

    CO2RCO2R

    R1

    +Homo-1,3-DCs

    CPAN

    NH

    CO2R

    CO2R

    RO2C

    RO2C R1

    R1*

    *

    CPA

    stereoselective formationof imidazolidines

    2 R.-Y. Zhu et al. / Tetrahedron:construct chiral imidazolidines with two stereogenic centers inhigh yields (up to 81%) and with good stereoselectivities (all>20:1 dr, up to 93% ee). This approach also takes advantage of apseudo four-component reaction, which forms one ring system,two stereogenic centers, and four new bonds in a single step.

    2. Results and discussion

    The initial experiments to test our hypothesis started with apseudo four-component reaction of 4-nitrobenzaldehyde 1a anddiethyl 2-aminomalonate 2a in the presence of various BINOL-de-rived CPAs 4 at 25 C in chloromethane (Table 1, entries 17).Although these reactions afforded the desired imidazolidineproduct 3aa, the yield was rather low, which indicated that thehomo-1,3-DCs of azomethine ylides were challenging because ofthe relatively low activity of azomethine ylides acting as dipolaro-philes. The preliminary screening of catalysts also revealed thatCPAs 4f and 4g could give product 3aawith higher enantioselectiv-ity than others (entries 6 and 7 vs 15). Changing CPA 4f to H8-BINOL-derived CPA 5a with the same 3,30-substituents of theBINOL backbone improved the enantioselectivity to 69% ee, butwithout any improvement in the yield (entry 8). Recently, SPI-NOL-derived CPAs have been recognized as a type of chiralBrnsted acids that possess higher capability in enantioselectivecontrol than their BINOL-based analogues.10 Hence, we changedthe H8-BINOL backbone of catalyst 5a to a SPINOL scaffold and em-ployed this type of spiro-CPA 6a to the same reaction. As expected,this structurally more rigid catalyst 6a enabled the model reactionto proceed in a much more efcient and enantioselective manner,affording imidazolidine 3aa in 68% yield and 87% ee (entry 9). Inthe presence of CPA 6a, the screening of molecular sieves (MS)

    R1 CHO + H2NCO2R

    CO2R

    Scheme 1. The design of catalytic asymmetric homo-1,3-DCs of azomethine ylides.

    Please cite this article in press as: Zhu, R.-Y.; et al. Tetrahedron: Asymmwere subsequently performed, which showed that 4 MS wasmuch superior to 3 and 5 MS, both in terms of reactivity andenantioselective control (entry 9 vs 10 and 11).

    Next, other reaction parameters including solvents, tempera-ture, and catalyst loading were optimized to further improve theenantioselectivity (Table 2). The screening of solvents (entries15) found that chloroform was the most suitable one, enablingthe model reaction to proceed in a high yield of 74% and with anexcellent enantioselectivity of 90% ee (entry 3). With regard tothe temperature (entries 6 and 7), we found that 40 C gave thebest performance in providing product 3aa in 76% yield and 91%ee (entry 6). However, increasing the catalyst loading was detri-mental to the enantioselectivity of the reaction without any obvi-ous improvements in the yields (entries 8 and 9). The most suitablereaction conditions are found in entry 6.

    With the optimal reaction conditions in hand, we next investi-gated the substrate scope of the catalytic asymmetric homo-1,3-DCs of azomethine ylides. As shown in Table 3, this protocol wasamenable to a wide range of aromatic, heteroaromatic aldehydes1a1m and different amino-esters 2a,2b, providing chiral imidaz-olidines 3 with structural diversity in generally acceptable yieldsand with good stereoselectivities. Most of the electronically pooraldehydes proved to be suitable substrates in giving the homo-1,3-DCs with high enantioselectivities (8093% ee, entries 15, 8,

    O

    N

    N

    O

    O

    OEt

    Ph

    Me**

    ticonvulsant

    O

    NHHN

    O

    O

    F

    OH

    inhibiting aldose reductase

    NH

    NMe

    CO2HN

    HN

    NN

    NH

    Bn

    Ph

    Ph

    Ph

    Bn

    Ph

    PyBidine ligand

    III IV

    VI VII

    en's catalyst

    ant catalysts or ligands containing a chiral imidazolidine skeleton.

    mmetry xxx (2014) xxxxxx10, and 1417). Nevertheless, for some of the benzaldehydessubstituted with electron-withdrawing groups, the enantioselec-tivities were moderate (entries 6, 7, and 9), which indicated thatthe electronic nature of the substituents might have an effect onthe enantioselectivity. The position of the substituents alsoaffected the reactivity and enantioselectivity. For instance,p-nitrobenzaldehyde 1a exhibited a higher reactivity and enanti-oselectivity than its meta- or ortho-substituted counterparts1b,1c (entry 1 vs 2 and 3). Electronically neutral or electron richaldehydes 1k,1l could participate in the homo-1,3-DCs with goodyields, but the enantioselectivities were unsatisfactory (entries10 and 11), which was largely ascribed to the low reactivity of suchaldehydes in 1,3-DCs.8a,c Similarly, heteroaromatic aldehydes asexemplied by 1m could also take part in the reaction althoughthe yield and enantioselectivity were not satisfactory (entry 13).Aliphatic aldehydes such as 3-phenylpropanal could not be utilizedas suitable substrates to afford the homo-1,3-DC products, and justgenerated the corresponding azomethine ylide using the currentconditions. Moreover, when dimethyl 2-aminomalonate 2b wasused in the reaction, o-nitrobenzaldehyde 1c showed the highestcapability in terms of enantioselective control (93% ee), albeitwith moderate yield (entry 14). It should be noted that all of the

    etry (2014), http://dx.doi.org/10.1016/j.tetasy.2014.03.008

  • Table 2Further optimization of reaction conditionsa

    CHO

    + H2NCO2Et

    CO2Et2 2

    N

    NH

    CO2Et

    CO2Et

    EtO2C

    EtO2C

    10 mol% 6a, T oC

    1a 2a 3aa

    NO2

    NO2

    O2N

    solvent, 4 MS

    Entry Solvent T (C) Yieldb (%) drc eed (%)

    1 CH2Cl2 25 68 >20:1 872 DCE 25 69 >20:1 813 CHCl3 25 74 >20:1 904 CCl4 25 66 >20:1 665 PhCH3 25 35 >20:1 726 CHCl3 40 76 >20:1 917 CHCl3 55 76 >20:1 868e CHCl3 40 76 >20:1 869f CHCl3 40 79 >20:1 86

    a Unless otherwise indicated, the reaction was carried out on a 0.1 mmol scale ina solvent (1 mL) with 4 MS (100 mg) for 24 h, and the ratio of 1a/2a was 1.2:1.

    b Isolated yields.c The diastereomeric ratio (dr) was determined by 1H NMR.d The enantiomeric excess (ee) was determined by HPLC.e Catalyzed by 15 mol % 6a.f Catalyzed by 20 mol % 6a.

    Table 1Screening of catalysts and MSa

    CHO

    + H2NCO2Et

    CO2Et2 2

    N

    NH

    CO2Et

    CO2Et

    EtO2C

    EtO2C

    O

    OP

    O

    OH

    G

    G

    10 mol% 4-6, 25 oC

    1a 2a 3aa

    CH2Cl2, MS

    NO2

    NO2

    O2N

    4a, G = 4-ClC6H44b, G = 2-naphthyl4c, G = 1-naphthyl4d, G = Ph3Si4e, G = 9-anthracenyl4f, G = 9-phenanthrenyl4g, G = 2,4,6-(i-Pr)3C6H2

    O

    OP

    O

    OH

    G

    G

    5a, G = 9-phenanthrenyl

    OO

    G

    G

    P

    O

    OH

    6a, G = 9-phenanthrenyl

    Entry 4 MS () Yieldb (%) drc eed (%)

    1 4a 4 31 >20:1 432 4b 4 38 >20:1 33 4c 4 15 >20:1 204 4d 4 >20:1 5 4e 4 20 >20:1 486 4f 4 33 >20:1 527 4g 4 33 >20:1 658 5a 4 34 >20:1 699 6a 4 68 >20:1 87

    10 6a 3 34 >20:1 5311 6a 5 10 >20:1 56

    a Unless otherwise indicated, the reaction was carried out on a 0.1 mmol scale in CH2Cl2 (1 mL) with MS (100 mg) for 24 h, and the ratio of 1a/2a was 1.2:1.b Isolated yields.c The diastereomeric ratio (dr) was determined by 1H NMR spectroscopy.d The enantiomeric excess (ee) was determined by HPLC.

    Table 3Substrate scope of the catalytic asymmetric homo-1,3-DCsa

    10 mol% 6a, 40 oC

    1 2 3

    CHCl3, 4 MS

    CHO

    + H2NCO2R

    CO2R2 2

    N

    NH

    CO2R

    CO2R

    RO2C

    RO2C

    R1 R1

    R1

    Entry 3 R1 1 R 2 Yieldb (%) drc eed (%)

    1 3aa 4-NO2 1a Et 2a 76 >20:1 912 3ba 3-NO2 1b Et 2a 66 >20:1 873 3ca 2-NO2 1c Et 2a 47 >20:1 894 3da 4-CN 1d Et 2a 81 >20:1 855 3ea 3-CN 1e Et 2a 68 >20:1 826 3fa 4-CO2Me 1f Et 2a 61 >20:1 477 3ga 4-CF3 1g Et 2a 36 >20:1 448 3ha 4-F 1h Et 2a 49 >20:1 879 3ia 2-F 1i Et 2a 45 >20:1 41

    10 3ja 4-F3-CN 1j Et 2a 51 >20:1 8711 3ka H 1k Et 2a 51 >20:1 2712 3la 4-MeO 1l Et 2a 62 >20:1 2313 3ma 2-Thiophenyl 1m Et 2a 38 >20:1 3714 3ab 4-NO2 1a Me 2b 72 >20:1 8415 3bb 3-NO2 1b Me 2b 75 >20:1 8316 3cb 2-NO2 1c Me 2b 45 >20:1 9317 3db 4-CN 1d Me 2b 77 >20:1 80

    a Unless otherwise indicated, the reaction was carried out on a 0.1 mmol scale inchloroform (1 mL) at 40 C with 4 MS (100 mg) for 24 h, and the ratio of 1/2 was1.2:1.

    b Isolated yields.c The diastereomeric ratio (dr) was determined by 1H NMR.d The enantiomeric excess (ee) was determined by HPLC.

    R.-Y. Zhu et al. / Tetrahedron: Asymmetry xxx (2014) xxxxxx 3

    Please cite this article in press as: Zhu, R.-Y.; et al. Tetrahedron: Asymmetry (2014), http://dx.doi.org/10.1016/j.tetasy.2014.03.008

  • gur

    AsyFigure 2. The absolute con

    O

    PO

    NRO2C R

    1CO2R

    R1

    9-Phen

    anthre

    nyl

    H

    4 R.-Y. Zhu et al. / Tetrahedron:reactions proceeded in a highly diastereoselective manner withmore than 20:1 dr due to the fact that only one diastereomer couldbe observed in the reaction.

    The absolute conguration of compound 3da was unambigu-ously determined to be (2S,5R) by single-crystal X-ray diffractionanalysis (Fig. 2).11 Moreover, the relative conguration of com-pound 3da was also conrmed to be cis by its X-ray structure.The relative and absolute congurations of other imidazolidines3 were assigned by analogy.

    Based on our experimental results and previous studies on thereaction mechanism,3a,7,12 we propose a possible reaction pathwayand transition state to explain the stereochemistry of this catalyticasymmetric homo-1,3-DCs of azomethine ylides. As illustrated inScheme 2, CPA 6a acted as a Brnsted acid/Lewis base bifunctionalcatalyst to simultaneously activate both the azomethine ylide andthe aldimine via hydrogen bonding interactions, which facilitatedsubsequent [3+2] cycloadditions. Due to the chiral environmentcreated by the (R)-SPINOL backbone and the bulky 6,60-(9-phen-anthrenyl)-substitutents of catalyst 6a, the homo-1,3-DCs of theazomethine ylides occurred in a diastereo- and enantioselectivemode, leading to the generation of the experimentally observed(2S,5R)-congured imidazolidines 3.

    3. Conclusion

    In conclusion, we have established the rst catalytic asymmet-ric homo-1,3-DCs of azomethine ylides generated in situfrom aldehydes and 2-aminomalonates. This approach utilized a

    O OCO2Et

    CO2EtN

    H

    9-Phenanthrenyl

    Scheme 2. Possible reaction pa

    Please cite this article in press as: Zhu, R.-Y.; et al. Tetrahedron: AsymmN

    NH

    CO2Et

    CO2Et

    EtO2C

    EtO2C

    (2S,5R)-3da

    CN

    NC

    15

    2 3

    4

    ation of imidazolidine 3da.

    N

    R1

    CO2...

Recommended

View more >