The synthesis of η2-β-vinylpyrrole complexes and their conversion to highly substituted indoles

Journal of the American Chemical Society

Volumn 118, Issue 30, 1996, Pages 7117-7127

  Hodges, L Mark ^a   Spera, Michael L ^a   Moody, Marcus W ^a   Harman, W Dean ^a  

^a UNIVERSITY OF VIRGINIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

INDOLE DERIVATIVE;

ARTICLE; DRUG SYNTHESIS; REACTION ANALYSIS; STEREOCHEMISTRY; TECHNIQUE;

EID: 0029780705     PISSN: 00027863     EISSN: None     Source Type: Journal    
DOI: 10.1021/ja961072m     Document Type: Article

References (71)

1. Couture, A.; Deniau, E.; Gimbert, Y.; Grandclaudon, P. J. Chem. Soc., Perkin Trans. I 1993, 2463, and references therein.
2. Brown, R. K. In Indoles Part One: The Chemistry of Heterocyclic Compounds, v. 25; Houlihan, W. J., Ed.; John Wiley & Sons: New York, 1972; Chapter 2.
3. For a review on indole syntheses using catalytic Pd(O) and Pd(II) salts, see: Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113.
4. (a) Fukuyama, T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994, 116, 3127.
5. (b) Fürstner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J. Org. Chem. 1994, 59, 5215.
6. For examples of intramolecular ring closures of a 2-substituted pyrroles, see: Ishibashi, H.; Akamatsu, S.; Iriyama, H.; Hanaoka, K.; Tabata, T.; Ikeda, M. Chem. Pharm. Bull. 1994, 42, 271. For other recent examples of this strategy, see: (a) Muratake, H.; Mikawa, A.; Seino, T.; Natsume, M. Chem. Pharm. Bull. 1994, 42, 846. (b) Muratake, H.; Mikawa, A.; Seino, T.; Natsume, M. Chem. Pharm. Bull. 1994, 42, 854. (c) Utsunomiya, I.; Muratake, H.; Natsume, M. Chem. Pharm. Bull. 1995, 43, 37.
7. For examples of intramolecular ring closures of a 2-substituted pyrroles, see: Ishibashi, H.; Akamatsu, S.; Iriyama, H.; Hanaoka, K.; Tabata, T.; Ikeda, M. Chem. Pharm. Bull. 1994, 42, 271. For other recent examples of this strategy, see: (a) Muratake, H.; Mikawa, A.; Seino, T.; Natsume, M. Chem. Pharm. Bull. 1994, 42, 846. (b) Muratake, H.; Mikawa, A.; Seino, T.; Natsume, M. Chem. Pharm. Bull. 1994, 42, 854. (c) Utsunomiya, I.; Muratake, H.; Natsume, M. Chem. Pharm. Bull. 1995, 43, 37.
8. For examples of intramolecular ring closures of a 2-substituted pyrroles, see: Ishibashi, H.; Akamatsu, S.; Iriyama, H.; Hanaoka, K.; Tabata, T.; Ikeda, M. Chem. Pharm. Bull. 1994, 42, 271. For other recent examples of this strategy, see: (a) Muratake, H.; Mikawa, A.; Seino, T.; Natsume, M. Chem. Pharm. Bull. 1994, 42, 846. (b) Muratake, H.; Mikawa, A.; Seino, T.; Natsume, M. Chem. Pharm. Bull. 1994, 42, 854. (c) Utsunomiya, I.; Muratake, H.; Natsume, M. Chem. Pharm. Bull. 1995, 43, 37.
9. For examples of intramolecular ring closures of a 2-substituted pyrroles, see: Ishibashi, H.; Akamatsu, S.; Iriyama, H.; Hanaoka, K.; Tabata, T.; Ikeda, M. Chem. Pharm. Bull. 1994, 42, 271. For other recent examples of this strategy, see: (a) Muratake, H.; Mikawa, A.; Seino, T.; Natsume, M. Chem. Pharm. Bull. 1994, 42, 846. (b) Muratake, H.; Mikawa, A.; Seino, T.; Natsume, M. Chem. Pharm. Bull. 1994, 42, 854. (c) Utsunomiya, I.; Muratake, H.; Natsume, M. Chem. Pharm. Bull. 1995, 43, 37.
10. For examples of Diels-Alder reactions with vinylpyrroles see: (a) Jones, R. A.; Saliente, T. A.; Arques, J. S. J. Chem. Soc., Perkin Trans. I 1984, 2541. (b) Jones, R. A.; Arques, J. S. Tetrahedron 1981, 37, 1597. (c) Jones, R. A.; Marriott, M. T. P.; Rosenthal, W. P.; Arques, J. S. J. Orig. Chem. 1980, 45, 4515. (d) Muchowski, J. M.; Scheller, M. E. Tetrahedron Lett. 1987, 28, 3453. For an example of a reaction between 2-vinylpyrrole and tetrachlorocyclopropene, see: Keil, J.; Massa, W.; Riedel, R.; Seitz, G.; Wocadlo, S. Tetrahedron Lett. 1994, 35, 7923.
11. For examples of Diels-Alder reactions with vinylpyrroles see: (a) Jones, R. A.; Saliente, T. A.; Arques, J. S. J. Chem. Soc., Perkin Trans. I 1984, 2541. (b) Jones, R. A.; Arques, J. S. Tetrahedron 1981, 37, 1597. (c) Jones, R. A.; Marriott, M. T. P.; Rosenthal, W. P.; Arques, J. S. J. Orig. Chem. 1980, 45, 4515. (d) Muchowski, J. M.; Scheller, M. E. Tetrahedron Lett. 1987, 28, 3453. For an example of a reaction between 2-vinylpyrrole and tetrachlorocyclopropene, see: Keil, J.; Massa, W.; Riedel, R.; Seitz, G.; Wocadlo, S. Tetrahedron Lett. 1994, 35, 7923.
12. For examples of Diels-Alder reactions with vinylpyrroles see: (a) Jones, R. A.; Saliente, T. A.; Arques, J. S. J. Chem. Soc., Perkin Trans. I 1984, 2541. (b) Jones, R. A.; Arques, J. S. Tetrahedron 1981, 37, 1597. (c) Jones, R. A.; Marriott, M. T. P.; Rosenthal, W. P.; Arques, J. S. J. Orig. Chem. 1980, 45, 4515. (d) Muchowski, J. M.; Scheller, M. E. Tetrahedron Lett. 1987, 28, 3453. For an example of a reaction between 2-vinylpyrrole and tetrachlorocyclopropene, see: Keil, J.; Massa, W.; Riedel, R.; Seitz, G.; Wocadlo, S. Tetrahedron Lett. 1994, 35, 7923.
13. For examples of Diels-Alder reactions with vinylpyrroles see: (a) Jones, R. A.; Saliente, T. A.; Arques, J. S. J. Chem. Soc., Perkin Trans. I 1984, 2541. (b) Jones, R. A.; Arques, J. S. Tetrahedron 1981, 37, 1597. (c) Jones, R. A.; Marriott, M. T. P.; Rosenthal, W. P.; Arques, J. S. J. Orig. Chem. 1980, 45, 4515. (d) Muchowski, J. M.; Scheller, M. E. Tetrahedron Lett. 1987, 28, 3453. For an example of a reaction between 2-vinylpyrrole and tetrachlorocyclopropene, see: Keil, J.; Massa, W.; Riedel, R.; Seitz, G.; Wocadlo, S. Tetrahedron Lett. 1994, 35, 7923.
14. For examples of Diels-Alder reactions with vinylpyrroles see: (a) Jones, R. A.; Saliente, T. A.; Arques, J. S. J. Chem. Soc., Perkin Trans. I 1984, 2541. (b) Jones, R. A.; Arques, J. S. Tetrahedron 1981, 37, 1597. (c) Jones, R. A.; Marriott, M. T. P.; Rosenthal, W. P.; Arques, J. S. J. Orig. Chem. 1980, 45, 4515. (d) Muchowski, J. M.; Scheller, M. E. Tetrahedron Lett. 1987, 28, 3453. For an example of a reaction between 2-vinylpyrrole and tetrachlorocyclopropene, see: Keil, J.; Massa, W.; Riedel, R.; Seitz, G.; Wocadlo, S. Tetrahedron Lett. 1994, 35, 7923.
15. For a recent synthesis of 3-vinylpyrrole: Settambolo, R.; Lazzaroni, R.; Messeri, T.; Mazzetti, M.; Salvadori, P. J. Org. Chem. 1993, 58, 7899. and references therein.
16. (a) Hodge, L. M.; Moody, M. W.; Harman, W. D. J. Am. Chem. Soc. 1994, 116, 7931.
17. (b) Hodges, L. M.; Gonzalez, J.; Koontz, J. I.; Myers, W. H.; Harman, W. D. J. Org. Chem. 1995, 60, 2125.
18. While the reaction does appear to work for pinacolone (tert-butyl methyl ketone) as well, the yield is compromised by significant amounts of protonation at C(3).
19. Myers, W. H.; Koontz, J. I.; Harman, W. D. J. Am. Chem. Soc. 1992, 114, 5614.
20. a ̃ 12). Attempts to synthesize the azafulvenium complex using catalytic base fail since any azafulvenium complex that is formed is deprotonated quickly relative to the elimination of remaining starting material, thus consuming any base present.
21. The 3H-pyrrolium complex (the product of C(3) protonation) is the only product isolated, possibly due to water contamination.
22. Some protonation still takes place to give the parent 1-methyl-3H-pyrrolium complex as a byproduct. Protonation not observed with non-enolizable acetals (e.g., benzaldehyde dimethylacetal); see ref 8b.
23. The acetyl complex 4 has been reported previously. See ref 8b.
24. Complex 32 is prone to undergo either hydrolysis in wet acetone solution, or a linkage isomerization.
25. The Michael reaction between 2 and either DMAD or 4-phenyl-3-butyn-2-one is carried out in DMSO, where the enolate anion generated ring closes at C(2) to initially give a cyclobutene-substituted 2-pyrroline complex, the synthetic equivalent to a 2 + 2 cycloaddition reaction. These intermediates are subsequently ring opened in the presence of a proton source such as methanol or phenol to give the vinyl pyrrole complexes. For characterization of the cyclobutene intermediates from the reaction with DMAD (35) or 3-butyn-2-one (33), see ref 8b.
26. In many cases, a second reversible oxidation wave is observed at +0.5 V. attributed to an oxidation-promoted linkage isomerization of the osmium to the pendant double bond (see text).
27. When this reaction was attempted using < 10 mol% of oxidant at a similar concentration, only 20% conversion occurred after a 30 min reaction time. The dark green appearance of the product is probably due to an impurity.
28. Stereochemistry assigned through NOE data, which are reported in the experimental section.
29. This reaction is cleaner using the latter procedure. Use of both polar aprotic solvents and/or salts such as LiOTf have been shown to enhance the reactivity of similar electrophiles in the dipolar cycloaddition reaction of these pyrrole complexes. Gonzalez. J.; Koontz, J. I.; Hodges, L. M.; Nilsson, K. R.; Neely, L. K.; Myers, W. H.; Sabat, M.; Harman, W. D. J. Am. Chem. Soc. 1995, 117, 3405.
30. For a more detailed explanation of the determination of the stereochemistry, see the experimental and supporting information.
31. By convention, the osmium is drawn to coordinate the top face of the pyrrole ring. Note that since all of the complexes are racemic mixtures, this designation is done only to illustrate relative stereochemistry of the molecule.
32. DDQ has been used successfully to decomplex the metal from several classes of dihapto-Os(II) complexes including both 2- and 3-pyrrolines. 7-azanorbornenes, furans, anilines, phenols, anisoles, dienes, and olefins. See ref 8b and references therein.
33. The only significant impurities observed are dihydroindoles, which are easily removed by chromatography. While increasing the DDQ to three equivalents tends to prevent the observation of dihydroindoles, it fails to increase the yield and, in some cases, results in slightly lower yields of the indole.
34. Increasing the temperature beyond 165 °C does not increase the yield and, in some cases, causes decomposition of the indole.
35. This air stable adduct is synthesized directly from the 1-methylpyrrole complex (2) by protonation with triflic acid in methanol in an overall yield of 91% from 1-methylpyrrole. See refs 8b and 9. For details of the bench procedure, see the Experimental Section.
36. The air stability of 88 in solution is highly dependent on the solvent; 88 is least stable in DMAc solution outside of the box due to facile deprotonation by the solvent and subsequent rapid oxidation of the resulting 1-methylpyrrole complex. Solutions of 88 are stable in acetonitrile for 1-2 days, and in acidic acetonitrile, several days to a week.
37. Many of these indoles, particularly those prepared from N-phenylmaleimide, are highly fluorescent under long wave ultraviolet light (366 nm).
38. 2O.
39. (a) Capon, R. J.; MacLeod, J. K.; Scammells, P. J. Tetrahedron 1986, 42, 6545.
40. (b) Herb, R.; Carroll, A. R.; Yoshida, W. Y.; Scheuer, P. J.; Paul, V. J. Tetrahedron 1990, 46, 3089.
41. 3) δ 7.47 (s, 1H), 7.29 (d, J = 3.3 Hz, IH), 6.67 (d, J = 3.0 Hz, IH), 4.37 (s, 3H), 3.26 (s, 2H), 2.66 (s, 3H).
42. This alkyl-substituted benzyl protecting group was required to ensure that arene coordination did not occur during the complexation step.
43. Smith, A.; Utley, J. H. P. J. Chem. Soc., Chem. Commun. 1965, 427.
44. Suzuki, H.; Tsukuda, A.; Kondo, M.; Aizawa, M.; Senoo, Y.; Megumi, N.; Wantanabe, T.; Yokoyama, Y.; Murakami, Y. Tetrahedron Lett. 1995, 36, 1671.
45. 3) δ 7.47-7.25 (m, 6H). 6.91 (d, 7 = 3.3 Hz, 1H), 6.16 (d, J = 3.3 Hz, IH), 1.98 (s, 3H), 1.72 (s. 9H).
46. - anion being exchanged for triflate.
47. 2). Not all quaternary carbons are assigned.
48. For a review of vinylpyrroles, see: Trofimov, B. A. In Pyrroles Part Two: The Chemistry of Heterocyclic Compounds, v. 48; R. A. Jones, Ed.; John Wiley & Sons: 1992; Chapter 2, and references therein.
49. A common method for the synthesis of vinylpyrroles is formylation of the pyrrole ring followed by a Wittig reaction to introduce the double bond.
50. The only example in the literature to date of a cycloaddition with a 3-vinylpyrrole is for the case of 1-tert-butyl-3-vinylpyrrole. See ref 6c.
51. In related studies by Noland et al. substituted tetrahydrocarbazoles have been synthesized by Diels-Alder reactions with vinylindoles, which were prepared directly by electrophilic addition to the starting indole. Oxidation of the tetrahydrocarbazoles with two equivalents of DDQ gave the final carbazoles in high yield. See: (a) Noland, W. E., Walhstrom, M. J.; Konkel, M. J.; Brigham, M. E.; Trowbridge, A. G.; Konkel, L. M. C.; Gourneau, R. P.; Scholten, C. A.; Lee, N. H.; Condoluci, J. J.; Gac, T. S.; Pour, M. M.; Radford, P. M. J. Heterocycl. Chem. 1993, 30, 81, and references therein, (b) Noland, W. E.; Konkel, M. J.; Tempesta, M. S.; Cink, R. D.; Powers, D. M.; Schlemper, E. O.; Barnes, C. L. J. Heterocycl. Chem. 1993, 30, 183, and references therein.
52. In related studies by Noland et al. substituted tetrahydrocarbazoles have been synthesized by Diels-Alder reactions with vinylindoles, which were prepared directly by electrophilic addition to the starting indole. Oxidation of the tetrahydrocarbazoles with two equivalents of DDQ gave the final carbazoles in high yield. See: (a) Noland, W. E., Walhstrom, M. J.; Konkel, M. J.; Brigham, M. E.; Trowbridge, A. G.; Konkel, L. M. C.; Gourneau, R. P.; Scholten, C. A.; Lee, N. H.; Condoluci, J. J.; Gac, T. S.; Pour, M. M.; Radford, P. M. J. Heterocycl. Chem. 1993, 30, 81, and references therein, (b) Noland, W. E.; Konkel, M. J.; Tempesta, M. S.; Cink, R. D.; Powers, D. M.; Schlemper, E. O.; Barnes, C. L. J. Heterocycl. Chem. 1993, 30, 183, and references therein.
53. Although the use of methyl ethyl ketone results in a 1:1 ratio of structurally different vinylpyrroles, it has been demonstrated that both isomers convert cleanly to tetrahydroindoles with N-phenylmaleimide. Reaction of the mixture of vinylpyrrole complexes with 4-cyclopentene-1,3-dione followed by decomplexation would give a mixture of isomeric indoles, which in principle, could be separated. One of these isomers is the 4,5-dimethyl analog, which matches the substitution pattern for herbindole A. The other possesses a 4-ethyl substituent with a hydrogen at C(5), which matches the substitution pattern for trikentrin A.
54. Remers, W. A. In Indoles Pari One: The Chemistry of Heterocyclic Compounds, v. 25; Houlihan, W. J., Ed.; John Wiley & Sons: New York, 1972; Chapter 1.
55. Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1994, 35, 2405, and references therein. For considerations on the synthesis and reactivity of 3-haloindoles, see: Powers, J. C., in Indoles Part Two: The Chemistry of Heterocyclic Compounds, v. 25; Houlihan, W. J. Ed.; John Wiley & Sons: New York, 1972; Chapter 5.
56. Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett. 1994, 35, 2405, and references therein. For considerations on the synthesis and reactivity of 3-haloindoles, see: Powers, J. C., in Indoles Part Two: The Chemistry of Heterocyclic Compounds, v. 25; Houlihan, W. J. Ed.; John Wiley & Sons: New York, 1972; Chapter 5.
57. Olefins and arenes are typically decomplexed from pentaammineosmium(II) by treatment of the metal with a one-electron oxidant such as DDQ or AgOTf.
58. 1H NMR spectrum and is an expected result in consideration of the known one-electron oxidation potential for 46 (0.29 V) and the reduction potential for DDQ (0.75 V).
59. This process is described in Hodges, L. M., Ph. D. Dissertation, University of Virginia, May 1995.
60. 3CN at 80 °C. In contrast, the 2-acetylpyrrole complex, isolated as a 3:1 mixture of carbonyl-bound and ring-bound isomers, will undergo a linkage isomerization to the carbonyl followed by substitution by solvent at room temperature.
61. Barcock, R. A.; Moorcroft, N. A.; Storr, R. C.; Young, J. H.; Fuller, L. S. Tetrahedron Lett. 1993, 34, 1187, and references therein.
62. Aumann, R.; Kuckert, E.; Krüger, C.; Angermund, K. Angew. Chem., Int. Ed. Engl. 1987, 26, 563.
63. Veith, M.; Zimmer, M.; Huch, V.; Denat, F.; Gaspard-Iloughmane, H.; Dubac, J. Organometallics 1993, 12, 1012.
64. In many cases, these groups are capable of supporting a positive charge as well as the pyrrole nitrogen, making the azafulvenium salts represent one resonance structure where a pyrrole possessing a positively charged substituent is the other. Examples of stabilizing groups include dialkylamino, cyclopentenyl, phenyl, and various sulfur-containing ring systems.
65. Sammes, M. P. In Pyrroles Part One: The Chemistry of Heterocyclic Compounds, v. 48; Jones, R. A., Ed.; John Wiley & Sons: 1990; Chapter 4, and references therein.
66. For a detailed explanation of general experimental methods, reagent preparation, and solvent purification, see supporting information.
67. Gonzalez, J.; Spera, M. L.; Nilsson, K. R.; Liu, R.; Chen, H.; Myers, W. H.; Harman, W. D. Manuscript in preparation.
68. The intermediate 3H-pyrrolium aldol adduct (8) has been isolated and characterized.
69. The presence of a light green color arises from formation of a small amount of the azafulvenium complex 20 during the reaction due to trace acid in the reaction mixture. This impurity is avoided by preparing the complex using excess methyl acrylate in DMAc solution (procedure 2).
70. When DMAc is used as the solvent for the reaction, filtration through silica gel facilitates the filtration of the tacky metal precipiate. Final column chromatography removes the last traces of DMAc.
71. 3/ethyl acetate as the mobile phase, especially if acetonitrile is the reaction solvent.