Nonstereospecific 1,3-dipolar cycloadditions of azomethine ylides and enamines

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  • Pergamon Tetrahedmn 55 (1999) 9535-9558

    TETRAHEDRON

    Nonstereospecific 1,3-Dipolar Cycloadditions of Azomethine Ylides and Enamines

    Thomas B6hm, Andreas Weber, and Jiirgen Sauer*

    lnstitut fiir Organische Chemie der Universitlit Regensburg, D-93040 Regensburg, Germany

    Received 27 April 1999; accepted 10 June 1999

    Abstract: The combination of electron-poor azomethine ylides 3 (AMY-I) or 4 (AMY-II) with electron-rich enamines 5 results in nonstereospecific 1,3-dipolar cycloadditions, which are

    LUMOdipole-HOMOdipol~phile controlled reactions. This phenomenon can be explained only by a two-step mechanism via zwitterionic intermediates. 1999 Elsevier Science Ltd. All rights reserved.

    Keywords: Nonstereospecific cycloadditions; 1,3-Dipolar cycloadditions; Azomethine ylides; Enamines

    INTRODUC~ON

    According to the Woodward-Hoffmann rules 1,3-dipolar cycloadditions are expected to

    occur in a stereospecific suprafacial manner due to the symmetry of the participating molecular

    orbitals [1,2,3]. Nonconcerted nonstereospecific cycloadditions are not excluded completely but

    until 1986 there was lack of experimental evidence. Earlier reports on nonstereospecific

    cycloadditions of azomethine imines [4] had to be revised [5,6]. The first examples proved were

    reported by Huisgen's group [7,8,9], who found that electron-rich thiocarbonyl ylides combine

    with the electron-poor dipolarophiles dicyanomaleate and dicyanofumarate in a

    nonstereospecific manner. A zwitterionic intermediate in the course of a two-step, nonconcerted

    cycloaddition was offered as an explanation.

    Quite recently we reported on the synthesis of two new classes of coloured, stable

    azomethine ylides 3 and 4 derived from 3,4-diazanorcaradienes 1 and l-aza-l,3-

    cyclopentadienes [ 10,11,12]. These electron-poor 1,3-dipoles combine, as kinetic studies prove [10], in a LUMOdipole-HOMOdivol~phite controlled reaction preferentially with electron-rich

    "Fax: (intemat.) +49 941-943-4946, E-mail: elisabeth.liebl@chemie.uni-regensburg.de

    0040-4020/99/$ - see front matter 1999 Elsevier Science Ltd. All fights reserved. PII: S0040-4020(99)00517-7

  • 9536 7". BOhm et al. /Tetrahedron 55 (1999) 9535-9558

    dipolarophiles such as enolethers, enamines, ynamines and ketene aminals. These 1,3-dipolar

    cycloadditions, the electronic counterpart of Huisgen's system, turned out to occur in a

    nonstereospecific manner, too, as could be shown when (E)-l-N,N-dimethylanfino-l-propene was used as a dipolarophile [13].

    In this communication we show that for all 1,3-dipoles 3 (AMY-I) and 4 (AMY-II)

    nonstereospecific cycloadditions are observed when (E)-enamines 5 were used as dipolarophiles.

    RESULTS

    Azomethine ylides 3 are easily obtained when 3,4-diazanorcaradienes 1 are treated with

    tetracyanoethylene oxide 2 in inert solvents [ 10,14] in good to excellent yields (Scheme 1).

    O NC'f"--'~'CN CN R e CN R

    N CH 3 NC 2 CN NC" "N / "~ 3 1. Acetic acidp

    R R CH3 O

    1 3 4

    1/3/4 a b c d e

    R 4-CH30-CtH 4 4-CH3-CtH 4 C6H 5 4-CI-C6H 4 4-CF3-CeH 4

    Scheme 1. Reactions of 2,5-disubstituted 3,4-diazanorcaradienes 1 with tetracyanoethylene oxide (TCNEO) 2 and acid triggered transformation of the 2,5-disubstituted AMY-I 3 in acetic acid to azacyclopentadiene-ylides AMY-II 4.

    These coloured 1,3-dipoles 3 are transformed by heating in acetic acid and following

    hydrolysis again to coloured 1,3-dipoles 4 (AMY-II) in a multistep sequence passing different coloured intermediates (Scheme 2). Mechanistic studies are still lacking [11,14].

    (E)-l-Propenyl-amines 5k-o are obtained in high purity from N-allylamines by base catalyzed double bond migration; the (Z)-enamines 6 are the primary products [15], but can be readily isomerized to the (E)-isomers by mild acid catalysis.

    /CH, /CH, R__CH a R= --I~, k --I~ n

    R~ OH3 CeH s \ CH s

    5k-m 6k-m

    --N .._./O m

    Figure 1. 1-N-propenyl-substituted enamines with (E)-configuration (5) and (Z)-configuradon (6) used in cycloaddition reactions.

  • T. Bi~hm et aL /Tetrahedron 55 (1999) 9535-9558 9537

    The reaction of AMY-I 3b with approximately one equivalent enamine 5k in acetonitrile at

    20C results in almost quantitative formation of two diastereomeric cycloadducts 7b and 8b,

    which can be separated by flash column chromatography. NMR data and X-ray analysis (vide

    infra) prove the trans-configuration for 7b and the cis-configuration for 8b, in both adducts the

    dimethylamino group appears in endo-position.

    Table 1 summarizes all results for the combination of AMY-I 3a,b,d with the (E)-enanfine 5k (Scheme 2). The yields as well as the isomer ratio were obtained by NMR technique or

    HPLC analysis (see Experimental Section). Mo2N H 7 MozN_~%,,~ . H H

    CN R ~ ., CH3 '" %_ l.,,,, . .c NC N , / ~ CH3 Me= CH3CN NC

    N ~ " CH3 + =" ~ N ~ H + N H CHa N ,, H N ~ . ~ H

    3a,b,d 5k CH= R H3C'~ CH 3

    7a,b,d " t rans " 8a,b,d " c is " Scheme 2. Nonstemospccific !,3-dipolar cycloadditions of AMY-[ 3a,b,d with (E)-!-N,N-dimethylamino-1-propcne (Sk). Table 1. Data for the reaction of AMY-[ 3a,b,d with (E)-!-N,N-dimethylamino-!-propne (Sk) in acetoni~le at ambient conditions.

    AMY-I [lamol] R 5k [lxmol] t [h] % 7 + 8 7 : 8

    3a 300 4-CH30-C6H4 364 116 99 45 : 55 a)

    3b 287 4-CH3-C6H4 349 3 100 48 : 52 a)

    3d 430 4-C1-C6I-I4 539 3 100 45 : 55 b) a) Yield and ratio from HPLC analysis (conditions see Table 11); b) Yield and ratio from tH NMR: only signals of the two isomers, no quantitative internal standard.

    The isomer ratio 7b (trans-adduct) : 8b (cis-adduct) depends only scarcely on the polarity of

    the solvent used (CH3CN: 48 : 52, CHC13:52 : 48, acetone: 56 : 44, dioxane: 65 : 35, toluene:

    54 : 46). Acetonitrile is the top solvent with regard to the product yield obtainable; the yield 7b

    + 8b drops considerably passing to CHC13 (73%), acetone (43%), dioxane (80%), toluene

    (22%). For this reason all further cycloadditions were performed in acetonitrile.

    Within the limit of error use of higher temperature (70C; 7b : 8b = 46 : 54) and pressure

    (20C, 7 kbar; 7b : 8b = 49 : 51) do not influence the isomer ratio. Also changing suhstituent R in the dipole 3 is negligible with regard to the isomer ratio (Scheme 2, Table 1).

    All 1,3-dipolar cycloadditions presented in Table 1 are kineticaUy controlled reactions.

    Between 10-95 percentage conversion the isomer ratios do not change within the limit of error

    (HPLC). Even at 70C the adducts 7 and 8 are stable in acetonitrile for 116 hours (7b, 8b)

    respectively 210 hours (7a,d, 8a,d). In the presence of the highly reactive dipolarophile

    cyclooctyne [13] no trace of a trapping product of dipole 3b could be detected by HPLC.

  • 9538 T. Bi~hm et al. /Tetrahedron 55 (1999) 9535-9558

    The approximate 1 : 1 - ratio for the diastereomeric cycloadducts formed when enarnine 5k is used as dipolarophile is also observed for the combination of AMY-I with the pyrrolidino enamine 51 (Scheme 3, Table 2) and the morpholino enamine 5m (Scheme 4, Table 3). All cycloadditions with 5m are much slower compared to those of 5k and 51.

    oAe . N ~,, , ,~ " CHa

    3a-d 51 Ha CH3

    9a-d "trans" 10ad "cls"

    Scheme 3. Nonstereospeeific 1,3-dipolar eycloadditions of AMY-I 3a-d with (E)-l-N-propenyl-pyrrolidine (51). Table 2. Data for the reaction of AMY-I 3a-d with (E)-I-N-propenyl-pyrrolidine (51) in acetonitrile at ambient conditions.

    AMY-I [~tmol] R 51 [lamol] t [h] % 9 + 10 9 : 10

    3a 444 4-CH30-C6H 4 705 72 100 45 : 55 a) 3b 461 4-CH3-C6H 4 705 36 100 44 : 56 a) 3c 473 C6H 5 676 24 63 53 : 47 b) 3d 171 4-CI-C6H4 214 10 89 54 : 46 c)

    a) Yield and ratio from 'H NMR: only signals of the two isomers, no quantitative internal standard; b) Yield and ratio from ~H NMR: OMS as quantitative internal standard; e) Yield: isolated mixture of isomers, ratio from 'H NMR.

    When we tried to prove the kinetic control for the systems of Scheme 4 (Table 3) quite unexpected but fully reproducable results were obtained which are not yet completely understood. As Figure 2 shows, only for the combination of 3a with the (E)-morpholino enamine 5m the adduct ratio trans : cis ( l l a : 12a) is constant between 5 and 95 percent conversion. In contrast, using the dipoles 3b and 3d, the amount of cis-adduct 12b and 12d increases by about 20 percent as the reaction proceeds. Under the conditions of the reaction both cycloadducts 12b and 12d are stable.

    The regiochemistry and stereochemistry could be proved beyond doubt by X-ray analysis for 7b and 8b [16]. The coupling constants of the tertiary protons H-5 and H-6 in 7b (12.4 Hz) for the trans-adduct and 8b (4.7 Hz) for the cis-adduct are in accordance with the Karplus rule. Table 4 and Table 5 summarize the corresponding coupling constants for all trans-adducts 7, 9, and 11 as well as for the cis-isomers 8, 10, and 12. The constancy of the chemical shifts and the coupling constants within the whole series offers an excellent structure proof for all adducts compared.

  • 1". BOhm et al. / Tetrahedron 55 (1999) 9535-9558 9539

    CNR

    N ,~H'~ CHa + R CH3

    3a-d 5m

    CH3CN NC-- L,R

    N~ H

    RN~ H~~C NCH3 3 I l a~ "trans" ! 2a

  • 9540 T. BOhm et al. /Tetrahedron 55 (1999) 9535-9558

    Table 4. ~H NMR data for the trans-cycloadducts of AMY-I 3a-d: chemical shifts 8 [ppm], coupling constants J [Hz], CDCI3, TMS, 250 or 400 MHz.

    No. R 8 (H-5) 8 (H-6) 8 (H-7) 3,/(H-5,H-6) 3j (H-6,H-7)

    7a 4-CH30-C6H 4 3.52 (d) 2.63 (dq) 0.96 (d) 12.3 6.7 7b 4-CH3-C6H 4 3.54 (d) 2.65 (dq) 0.96 (d) 12.4 6.7 7d 4-C1-C6H 4 3.48 (d) 2.66 (dq) 0.97 (d) 12.4 6.7 9a 4-CH30-C6H 4 3.76 (d) 2.66 (dq) 0.97 (d) 12.2 6.6 9b 4-CH3-C6H 4 3.78 (d) 2.67 (dq) 0.97 (d) 12.3 6.6 9c C6H 5 3.79 (d) 2.70 (dq) 0.99 (d) 12.3 6.5 9d 4-C1-C6H4 3.72 (d) 2.69 (dq) 0.98 (d) 12.3 6.6 11a 4-CH30-C6H 4 3.45 (d) 2.66 (dq) 1.01 (d) 12.4 6.6 l lb 4-CH3-C6H 4 3.47 (d) 2.67 (dq) 1.01 (d) 12.4 6.6 l lc C6H5 3.48 (d) 2.70 (dq) 1.03 (d) 12.4 6.7 l ld 4-C1-C6H4 3.41 (d) 2.69 (dq) 1.03 (d) 12.5 6.6

    Table 5. mH NMR data for the cis-cycloadducts of AMY-I 3a-d: chemical shifts 8 [ppm], coupling constants J [Hz], CDCI3, TMS, 250 or 400 MHz.

    No. R 8 (n-5) 8 (n-6) 8 (n-7) 3,/(n-5,n-6) ~J (H-6,H-7)

    8a 4-CH30-C6H 4 2.94 (d) 2.73 (dq) 1.20 (d) 4.8 6.9 8b 4-CH3-C6H 4 2.94 (d) 2.75 (dq) 1.20 (d) 4.7 7.0 8d 4-C1-C6H 4 2.90 (d) 2.74 (dq) 1.21 (d) 4.8 7.0 10a 4-CH30-C6H 4 3.06 (d) 2.69 (dq) 1.21 (d) 4.8 7.0 10b 4-CH3-C6H 4 3.06 (d) 2.72 (dq) 1.22 (d) 4.7 7.0 10c C6H 5 3.06 (d) 2.75 (dq) 1.24 (d) 4.7 7.0 10d 4-C1-C6H , 3.02 (d) 2.70 (dq) 1.23 (d) 4.8 7.1 12a 4-CHaO-C6H 4 3.12 (d) 2.77 (dq) 1.18 (d) 4.6 7.0 12b 4-CH3-C6H 4 3.12 (d) 2.79 (dq) 1.18 (d) 4.7 6.9 12e C6H5 3.11 (d) 2.83 (dq) 1.21 (d) 4.7 7.0 12d 4-C1-C6H 4 3.07 (d) 2.78 (dq) 1.19 (d) 4.7 6.9

    Furthermore could be isolated the trans-adducts 13a and 17a-d as stable compounds, whereas the corresponding cis-adducts 14a and 18a-d gave labile oils. By combination of X-ray analysis for 13b [16] with the coupling constants for the tertiary protons H-1 and H-2 in 13b and 14b the regiochemistry and stereochemistry could be verified for both adducts unequivocally. In Table 9 and 10 the conclusive coupling constants H-l/H-2 are listed for all trans-adducts 13, 15, 17 and cis-adducts 14, 16, 18 as well. The Karplus rule is obeyed again, as shown by the X-ray analysis for adduct 13b [16].

  • T. B6hm et al. I Tetrahedron 55 (1999) 9535-9558 9541

    NC H3C. CH~ n e/Le.v,. + NC ~ \R Me2N~ CH 3

    R H

    CH3CN

    NC CH 3 NC CH 3

    MeaN 1\ / R MeaN 1\ / R H H /COIl 3 H

    4a,b 5k 13a,b "trans" 14a,b "cis"

    Scheme 5. Nonstereospecific 1,3-dipolar cycloadditions of AMY-II 4a,b with (E)-1-N,N-dimethylamino-1-propene (5k).

    Table 6. Data for the reaction of AMY-II 4a,b with (E)-1-N,N-dimethylamino-l-propen (5k) in acetonitrile at ambient conditions.

    AMY-I [ktmol] R 5k [mmol] t [h] %yield 13 + 14 13 : 14

    4a 783 4-CH30-C6H4 1.56 168 100 66:34 a) 4b 829 4-CH3-C6H4 1.76 4.5 98 45"55 b)

    a) Yield and ratio from tH NMR: OMS as quantitative internal standard; b) Yield and ratio from HPLC analysis.

    NC NC ~.iNc H3C .--CH 3 ,,,,~ + . H C~N~.I N R~ H3 H ~N~i .~ ~ , , , . ,.. ,,CH3

    4a-d 51 15a-d "trans" 16a-d "cis"

    Scheme 6. Nonstereospecific 1,3-dipolar cycloadditions of AMY-II 4a-d with (E)-l-N-propenyl-pyrrolidine (51).

    Table 7. Data for the reaction of AMY-II 4a-d with (E)-l-N-propenyl-pyrrolidine (51) in acetonitrile at ambient conditions.

    AMY-I [~tmol] R 51 [mmol] t [h] %yield 15 + 16 15 : 16 a)

    4a 247 4-CH30-C6H4 427 288 71 78:22 4b 395 4-CH3-C6H4 498 28 100 49:51 4c 318 C6H5 498 51 83 50:50 4d 335 4-C1-C6H4 498 24 100 44:56

    a) Yield and ratio from tH NMR: OMS as quantitative internal standard.

    NRX H3C .~ CH3 "."" j "~ '~

    NC" ~ "R i

    R H \ CH s

    4a-d 5m

    CH3CN im

    NC CH 3 NC CH 3

    ~O.. ~ 1\ / R ,------IN 1\ / R

    0- - " 17a-d "trans" 1~ "c/~"

    Scheme 7. Nonstereospecific 1,3-dipolar cycloadditions of AMY-II 4a-d with (E)-l-N-propenyl-morpholine (5m).

    Table 8. Data for the reaction of AMY-II 4a-d with (E)-1-N-propenyl-morpholine ($m) in aeetonitrile at ambient conditions.

    AMY-I [jxmol] R 5m [~tmol] t [d] %yield 17 + 18 17 : 18 a)

    4a 418 4-CH30-C6H4 500 28 95 67 : 33 4b 473 4-CH3-C6H4 625 33 100 70 : 30 4e 345 C6H5 460 39 96 62 : 38

    4d 458 4-C1-C6H4 601 2 87 69 : 31 a) Yield and ratio from ~H NMR: OMS as quantitative internal standard.

  • 9542 T. BiJhrn et aL /Tetrahedron 55 (1999) 9535-9558

    Table 9. ~H NMR data for the trans-cycloadducts of AMY-II 4a-d: chemical shifts 8 [ppm], coupling constants d [Hz], CDCI3, TMS, 250 or 400 MHz.

    No. R c5 (H-l) ~i (H-2) 8 (H-10) SJ(H-1,H-2) 3J(H-1,H-10)

    13a 4-CH30-C6H 4 2.90 (do,) 3.69 (d) 0.61 (d) 12.3 6.7 13b 4-CH3-C6H 4 2.90 (dq) 3.69 (d) 0.59 (d) 12.3 6.7 15a 4-CH30-C6H 4 2.95 (dq) 3.92 (d) 0.60 (d) 12.2 6.7 15b 4-CH3-C6H 4 2.96 (dq) 3.94 (d) 0.59 (d) 12.3 6.6 15c C6H 5 2.99 (dq) 3.95 (d) 0.58 (d) 12.1 6.7 15d 4-C1-C6H 4 2.96 (dq) 3.89 (d) 0.59 (d) 12.2 6.7 17a 4-CH30-C6H 4 2.93 (dq) 3.60 (d) 0.67 (d) 12.3 6.7 17b 4-CH3-C6H 4 2.92 (dq) 3.60 (d) 0.65 (d) 12.3 6.7 17c C6H 5 2.96 (dq) 3.63 (d) 0.66 (d) 12.3 6.7 17d 4-C1-C6H4 2.94 (dq) 3.57 (d) 0.67 (d) 12.3 6.7

    Table I0. ~H NMR data for the c/s-cycloadducts of AMY-II 4a-fl: chemical shifts 8 [ppm], coupling constants J [Hz], CDCI3, TMS, 250 or 400 MHz.

    No. R ~ (H-l) 8 (H-2) 8 (H-10) ~J(H-1,H-2) ~J(H-1,H-10)

    14a 4-CHaO-C6H 4 2.55 (dq) 3.27 (d) 1.39 (d) 5.5 7.5 14b 4-CH3-C6H 4 2.57 (dq) 3.27 (d) 1.39 (d) 5.4 7.3 16a 4-CH30-C6H 4 2.51 (dq) 3.37 (d) 1.39 (d) 5.5 7.5 16b 4-CH3-C6H 4 2.53 (dq) 3.38 (d) 1.40 (d) 5.5 7.1 16e C6H 5 2.56 (dq) 3.37 (d) 1.41 (d) 5.5 7.3 16d 4-CI-C6H 4 2.50 (dq) 3.32 (d) 1.39 (d) 5.5 7.3 18a 4-CH30-C6H 4 2.60 (dq) 3.45 (d) 1.36 (d) 5.5 7.3 18b 4-CH3-C6H 4 2.61 (dq) 3.44 (d) 1.36 (d) 5.5 7.3 18c C6Hs 2.64 (dq) 3.44 (d) 1.38 (d) 5.6 7.2 18d 4-C1-C6H4 ...a) 3.66 (d) 1.53 (d) 5.6 7.5 a) H-I signal covered by signals of the morpholino group

    The endo-configuration for the dimethylamino group is verified for 13b by X-ray analysis [16] and is assumed for all cis-adducts 14, 16, 18 by analogy to the reaction of AMY-I (vide supra).

    HPLC investigations showed for the c...

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