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Intermolecular reaction of nitroxide radicals with biradical intermediates generated from aromatic enediynes
Tetrahedron Letters, Vol. 36, No. 28, pp. 4951-4954, 1995
Pergamon
Elsevier Scieace lad Printed in Great Britain 0040-4039/95 $9.50+0.00
0040-4039(95)00967-1
Intermolecular Reaction Of Nitroxide Radicals With Biradical Intermediates Generated From Aromatic Enediynes Janet Wisniewski Grissom* and Gamini U. Gunawardena Departmentof Chemistry,Universityof Utah, Salt Lake City, LIT 84112
A~W~t: 1, 4-Dehydronaphthalenebiradicalsgeneratedby thermolysisof aromaticenediynescan be
trappedwith the nitroxideradical TEMPO. The isolatedproducts,however,are not the directtrapping productsbut 1,4-naphthoquinonesresultingfrom the homolysisof N-O bonds of trappingproducts. The potential clinical applications of antitumor antibiotics containing an enediyne substructure as the pharmacophore have stimulated tremendous interest in chemistry and biology of enediynes and related systems. 1 The focus of our work in the area has been the exploration of synthetic utility of enediynes and their relatives in the construction of polycyclic structures.2 In this report, we describe a new route to 1, 4-naphthoquinones via Bergrnan cyclization of aromatic enediynes. Numerous biologically and commercially important natural and unnatural products contain the 1, 4-naphthoquinone ring skeleton. 3, 4 Also, the ability of naphthoquinones to participate in a wide range of transformations has made them highly versatile synthetic intermediates.5 The intermolecular trapping of the transient 1, 4-dehydrobenzene biradical generated by thermal cyclization
of enediynes has been carded out with only a limited number of free-radical sources, namely, hydrogen, deuterium, halogen, and aryl groups (eq. 1).6, 7 This is largely due to the scarcity of reagents that could efficiently donate radicals to the dehydrobenzene biradical and, in the process, transform themselves into stable, neutral species, thereby avoiding the initiation of undesirable radical chain processes. Since the reaction between two radicals is essentially a termination step resulting in a neutral entity, use of preformed persistent or stable radicals is an attractive strategy for trapping transient radicals such as dehydrobenzene radicals generated in the Bergrnan cyclization.8, 9 Nitroxides are persistent radicals that react with a wide variety of carboncentered radicals at rates approaching diffusion control.9 The commercially available nitroxide TEMPO 1 (2,2, 6, 6-tetramethyl-l-piperidinyloxy, free radical) was chosen to examine the possibility of trapping 1, 4dehydrobenzene biradicals with nitroxide radicals to afford oxygenated aromatic systems. X radical source
(1) X X = H, D, CI, Br, Ar
A series of aromatic enediynes, 3a - f, was assembled from the corresponding 1, 2-diiodoarenes 2a - f v/a the well established palladium coupling protocol (eq. 2). 10 Diiodoarenes 2b - f were conveniently prepared by the n~thod of Suzuki 11 using commercially available arenes. 4951
4952
R R2~
l
~
I
v
1)
(2)
cat. Pd(Ph3P) 4 and CuI Et3N, RT
"I
2a - f
TMS
2) cat. K2CO3, MeOH, rt
3a R t, R2 = H 73%
3b R 1, R2 = Me 60% 3c R1, R2 = OMe 47% 3d RvR 2 = OCH20 60% 3e R1-R2 = (CH2)3 note 12 3fR 1 = Et, R2 = Me 71% Enediyne arenes 3 were heated in the presence of excess TEMPO in chlorobenzene (Scheme 1), and the results are given in Table 1.13 Our original intention was to isolate and further elaborate the direct trapping product,
bis-aryloxyamine4.
However, as is evident from the isolated products 5, homolytic cleavage of N-O
bonds of 4 occurs readily at the reaction temperature.
o~/'N
R2
1 (3 equiv.) = 3
O
R2
R2
PhCI 150 - 160 °C
O 5 4
Scheme 1. Reaction of enediynes 3 with TEMPO Table 1. Reaction of Enediynes with TEMPO Substrate 3a 3b
3c 3d 3e 3f
R1
R2
H
H
Me Me OMe OMe -OCH20-(CH2)2Et Me
Product 5a
5b 5c 5d 5e 5f
Yield, % 65 60 57 50 14 00
4953
The failure of 3f to afford the expected product 5f as well as the poor yield of 5e obtained from the reaction of 3e is likely due to the presence of secondary benzylic hydrogens in the two substrates. In these cases, inter- or intramolecular hydrogen transfer to the intermediate biradical from secondary benzylic position(s) could compete efficiently with trapping the same with TEMPO, resulting in secondary benzylic radicals (Scheme 2). The secondary benzylic radicals could then react with TEMPO, but, since homolysis of the N-O bond of the resultant TEMPO adduct could not lead to any stable product, the overall outcome of the reaction would be the destruction of the substrate. The observation that 3f, when subjected to the similar conditions in the presence of excess 1, 4-cyclohexadiene in place of TEMPO (Scheme 2), gave 2-ethyl-3methylnaphthalene in 67% yield lends support to the above rationalization. Consistent with the stability trends of benzylic radicals, hydrogen transfer from primary benzylic radicals does not appear to be as efficient as that from secondary ones (cf. 3b and 3t").
A ~ Me"
~"~
3f
O"
O" N(R)21 I E M P O Y p
tI,4-c 11
-
destruction
O ,,
O. N(R)2
67%
Scheme 2. Proposed reaction of 3f with TEMPO and with 1, 4 - H D Nitroxide radicals are known to react with biradicals even at room temperature. 9a In sharp contrast to enediynes and enediyne arenes, enyne allenes cycloaromatize at temperatures as low as physiological temperature.2b, 14 The investigations of intercepting biradicals generated from enyne allenes with TEMPO at low temperature so the bis-TEMPO adduct could be isolated are currently underway. Acknowledgments: We gratefully acknowledge financial support from the National Institutes of Health (GM 49991-01) and the University of Utah for a faculty internship (GUG).
References and Notes 1. Reviews: a) Nicolaou, K. C. Chemistry in Britain 1994, 33. b) Nicolaou, K. C. Angew. Chem., lnt.Ed. Engl. 1993, 32, 1377. c) Nicolaou, K. C.; Smith, A. L.; Yue, E. W. Proc. Natl. Acad. Sci. USA 1993, 90, 5881. d) Nicolaou, K. C.; Smith, A. L. Acc. Chem. Res. 1992, 25, 497. e) Nicolaou, K. C.; Dal, W.-M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387. 2. a) Grissom, J. W.; Calkins, T. L.; McMillen, H. A.; Jiang, Y. J. Org. Chem. 1994, 59, 5833 and references cited therein, b) Grissom, J. W.; Huang, D. Ibid. 1994,59, 5114. c) Grissom, J. W.; Slattery, B. J. Tetrahedron Lett. 1994, 35, 5137. 3. Monographs: a) Thomson, R.H. Naturally Occurring Quinones, VoL 3; Chapman and Hall: London, 1987. b) Thomson, R. H. Naturally Occurring Quinones, Vol. 2; Academic Press: London, 1971.
4954
4.
5.
6. 7. 8. 9.
10. 11. 12. 13.
14.
Examples: a) Laatsch, H. Angew. Chem., Int. Ed. Engl. 1994, 33, 422. b) Meselhy, M. R.; Kadota, S.; Tsubono, K.; Kusai, A.; Hattori, M.; Namba, T. Tetrahedron Lett. 1994, 35, 583. c) O' Sullivan, P. L; Moreno, R.; Murphy, W. S. Ibid. 1992, 33, 535. d) Nomura, K.; Okazaki, K.; Hori, K.; Yoshii, E. J. Am. Chem. Soc. 1987, 109, 3402. e) Semmelhack, M. F.; Bozell, J. J.; Sato, T.; Wulff, W.; Spiess,E.; Zask, A. Ibid. 1982, 104, 5850. Examples: a) Chuang, C.-P.; Wang, S.-F. Tetrahedron Lett. 1994, 35, 4365. b) Singh, P. K.; Khanna, R. N. Ibid. 1994, 35, 3753. c) Bryce-Smith, D.; Evans, E. H.; Gilbert, A.; McNeill, H. S. J. Chem. Soc., Perkin Trans. 1 1992, 485. d) Shahlai, K.; Hart, H.; Bashir-Hashemi, A. J. Org. Chem. 1991, 56, 6912. a) Bergrnan, R. G. Acc. Chem. Res. 1973, 6, 25. b) Semmelhack, M. F.; Neu, T.; Foubelo, F. J. Org. Chem. 1994, 59, 5038. For an example of photolytically activated Bergman cycloaromatization reaction, see: Tun:o, N. J.; Evenzahav, A.; Nicolaou, K. C. Tetrahedron Lett. 1994, 35, 8089. For a discussion of persistent and stable radicals, see: Griller, D.; Ingold, K. U. Acc. Chem. Res. 1976, 9, 13. a) Adam, W.; Bottle, S. E. Tetrahedron Lett. 1991, 32, 1405. b) Bottle, S. E.; Busfield, W. K.; Thang, S. H.; Rizzardo, E.; Solomon, D. H. Eur. Polym. J. 1989, 25, 671. c)Beckwith, A. L. J.; Bowry, V. W.; Moad, G. J. Org. Chem. 1988, 53, 1632. d) Review: Keana, J. F. W. Chem. Rev. 1978, 78, 37. Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1980, 627. Suzuki, H.; Nakamura, K.; Goto, R. Bull. Chem. Soc. Japan 1966, 39, 128. Also, see: Hellberg, J.; Pelcman, M. E. Tetrahedron Lett. 1994, 35, 1769. In the preparation of 3e, crude 2e contaminated with 2-iodoindan was used. Endiyne arene 3e was isolated as an inseparable mixture of of 3e and 2-ethynylindan at 2.1:1 ratio, as determined by 1H NMR integration analysis. This mixture was used in the reaction with TEMPO. a) Typical procedure: Enediyne arene (0.5 mmol) and TEMPO (3 equiv.) were dissolved in chlorobenzene (ca. 0.07 M) in a screw-top pressure tube equipped with a magnetic bar. The solution was purged with nitrogen for 20 rain, and the tightly capped tube was heated with an oil bath pre-heated to 150 - 160 °C for 6 h and then cooled to room temperature. The solvent was removed in vacuo and the crude product was purified by flash chromatography on silica gel. b) Satisfactory 1H and 13C NMR, IR, and HRMS were obtained for all products. a) Myers, A. G.; Dragovich, P. S.; Kuo, E. Y.; J. Am. Chem. Soc. 1992, 114, 9369. b) Myers, A. G.; Kuo, E. Y.; Finney, N. S. Ibid. 1989, 111, 8057. c) Myers, A. G.; Dragovich, P. S. Ibid. 1989, 111, 9130.
(Received in USA 7 April 1995; revised 18 May 1995; accepted 26 May 1995)
Pergamon
Elsevier Scieace lad Printed in Great Britain 0040-4039/95 $9.50+0.00
0040-4039(95)00967-1
Intermolecular Reaction Of Nitroxide Radicals With Biradical Intermediates Generated From Aromatic Enediynes Janet Wisniewski Grissom* and Gamini U. Gunawardena Departmentof Chemistry,Universityof Utah, Salt Lake City, LIT 84112
A~W~t: 1, 4-Dehydronaphthalenebiradicalsgeneratedby thermolysisof aromaticenediynescan be
trappedwith the nitroxideradical TEMPO. The isolatedproducts,however,are not the directtrapping productsbut 1,4-naphthoquinonesresultingfrom the homolysisof N-O bonds of trappingproducts. The potential clinical applications of antitumor antibiotics containing an enediyne substructure as the pharmacophore have stimulated tremendous interest in chemistry and biology of enediynes and related systems. 1 The focus of our work in the area has been the exploration of synthetic utility of enediynes and their relatives in the construction of polycyclic structures.2 In this report, we describe a new route to 1, 4-naphthoquinones via Bergrnan cyclization of aromatic enediynes. Numerous biologically and commercially important natural and unnatural products contain the 1, 4-naphthoquinone ring skeleton. 3, 4 Also, the ability of naphthoquinones to participate in a wide range of transformations has made them highly versatile synthetic intermediates.5 The intermolecular trapping of the transient 1, 4-dehydrobenzene biradical generated by thermal cyclization
of enediynes has been carded out with only a limited number of free-radical sources, namely, hydrogen, deuterium, halogen, and aryl groups (eq. 1).6, 7 This is largely due to the scarcity of reagents that could efficiently donate radicals to the dehydrobenzene biradical and, in the process, transform themselves into stable, neutral species, thereby avoiding the initiation of undesirable radical chain processes. Since the reaction between two radicals is essentially a termination step resulting in a neutral entity, use of preformed persistent or stable radicals is an attractive strategy for trapping transient radicals such as dehydrobenzene radicals generated in the Bergrnan cyclization.8, 9 Nitroxides are persistent radicals that react with a wide variety of carboncentered radicals at rates approaching diffusion control.9 The commercially available nitroxide TEMPO 1 (2,2, 6, 6-tetramethyl-l-piperidinyloxy, free radical) was chosen to examine the possibility of trapping 1, 4dehydrobenzene biradicals with nitroxide radicals to afford oxygenated aromatic systems. X radical source
(1) X X = H, D, CI, Br, Ar
A series of aromatic enediynes, 3a - f, was assembled from the corresponding 1, 2-diiodoarenes 2a - f v/a the well established palladium coupling protocol (eq. 2). 10 Diiodoarenes 2b - f were conveniently prepared by the n~thod of Suzuki 11 using commercially available arenes. 4951
4952
R R2~
l
~
I
v
1)
(2)
cat. Pd(Ph3P) 4 and CuI Et3N, RT
"I
2a - f
TMS
2) cat. K2CO3, MeOH, rt
3a R t, R2 = H 73%
3b R 1, R2 = Me 60% 3c R1, R2 = OMe 47% 3d RvR 2 = OCH20 60% 3e R1-R2 = (CH2)3 note 12 3fR 1 = Et, R2 = Me 71% Enediyne arenes 3 were heated in the presence of excess TEMPO in chlorobenzene (Scheme 1), and the results are given in Table 1.13 Our original intention was to isolate and further elaborate the direct trapping product,
bis-aryloxyamine4.
However, as is evident from the isolated products 5, homolytic cleavage of N-O
bonds of 4 occurs readily at the reaction temperature.
o~/'N
R2
1 (3 equiv.) = 3
O
R2
R2
PhCI 150 - 160 °C
O 5 4
Scheme 1. Reaction of enediynes 3 with TEMPO Table 1. Reaction of Enediynes with TEMPO Substrate 3a 3b
3c 3d 3e 3f
R1
R2
H
H
Me Me OMe OMe -OCH20-(CH2)2Et Me
Product 5a
5b 5c 5d 5e 5f
Yield, % 65 60 57 50 14 00
4953
The failure of 3f to afford the expected product 5f as well as the poor yield of 5e obtained from the reaction of 3e is likely due to the presence of secondary benzylic hydrogens in the two substrates. In these cases, inter- or intramolecular hydrogen transfer to the intermediate biradical from secondary benzylic position(s) could compete efficiently with trapping the same with TEMPO, resulting in secondary benzylic radicals (Scheme 2). The secondary benzylic radicals could then react with TEMPO, but, since homolysis of the N-O bond of the resultant TEMPO adduct could not lead to any stable product, the overall outcome of the reaction would be the destruction of the substrate. The observation that 3f, when subjected to the similar conditions in the presence of excess 1, 4-cyclohexadiene in place of TEMPO (Scheme 2), gave 2-ethyl-3methylnaphthalene in 67% yield lends support to the above rationalization. Consistent with the stability trends of benzylic radicals, hydrogen transfer from primary benzylic radicals does not appear to be as efficient as that from secondary ones (cf. 3b and 3t").
A ~ Me"
~"~
3f
O"
O" N(R)21 I E M P O Y p
tI,4-c 11
-
destruction
O ,,
O. N(R)2
67%
Scheme 2. Proposed reaction of 3f with TEMPO and with 1, 4 - H D Nitroxide radicals are known to react with biradicals even at room temperature. 9a In sharp contrast to enediynes and enediyne arenes, enyne allenes cycloaromatize at temperatures as low as physiological temperature.2b, 14 The investigations of intercepting biradicals generated from enyne allenes with TEMPO at low temperature so the bis-TEMPO adduct could be isolated are currently underway. Acknowledgments: We gratefully acknowledge financial support from the National Institutes of Health (GM 49991-01) and the University of Utah for a faculty internship (GUG).
References and Notes 1. Reviews: a) Nicolaou, K. C. Chemistry in Britain 1994, 33. b) Nicolaou, K. C. Angew. Chem., lnt.Ed. Engl. 1993, 32, 1377. c) Nicolaou, K. C.; Smith, A. L.; Yue, E. W. Proc. Natl. Acad. Sci. USA 1993, 90, 5881. d) Nicolaou, K. C.; Smith, A. L. Acc. Chem. Res. 1992, 25, 497. e) Nicolaou, K. C.; Dal, W.-M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387. 2. a) Grissom, J. W.; Calkins, T. L.; McMillen, H. A.; Jiang, Y. J. Org. Chem. 1994, 59, 5833 and references cited therein, b) Grissom, J. W.; Huang, D. Ibid. 1994,59, 5114. c) Grissom, J. W.; Slattery, B. J. Tetrahedron Lett. 1994, 35, 5137. 3. Monographs: a) Thomson, R.H. Naturally Occurring Quinones, VoL 3; Chapman and Hall: London, 1987. b) Thomson, R. H. Naturally Occurring Quinones, Vol. 2; Academic Press: London, 1971.
4954
4.
5.
6. 7. 8. 9.
10. 11. 12. 13.
14.
Examples: a) Laatsch, H. Angew. Chem., Int. Ed. Engl. 1994, 33, 422. b) Meselhy, M. R.; Kadota, S.; Tsubono, K.; Kusai, A.; Hattori, M.; Namba, T. Tetrahedron Lett. 1994, 35, 583. c) O' Sullivan, P. L; Moreno, R.; Murphy, W. S. Ibid. 1992, 33, 535. d) Nomura, K.; Okazaki, K.; Hori, K.; Yoshii, E. J. Am. Chem. Soc. 1987, 109, 3402. e) Semmelhack, M. F.; Bozell, J. J.; Sato, T.; Wulff, W.; Spiess,E.; Zask, A. Ibid. 1982, 104, 5850. Examples: a) Chuang, C.-P.; Wang, S.-F. Tetrahedron Lett. 1994, 35, 4365. b) Singh, P. K.; Khanna, R. N. Ibid. 1994, 35, 3753. c) Bryce-Smith, D.; Evans, E. H.; Gilbert, A.; McNeill, H. S. J. Chem. Soc., Perkin Trans. 1 1992, 485. d) Shahlai, K.; Hart, H.; Bashir-Hashemi, A. J. Org. Chem. 1991, 56, 6912. a) Bergrnan, R. G. Acc. Chem. Res. 1973, 6, 25. b) Semmelhack, M. F.; Neu, T.; Foubelo, F. J. Org. Chem. 1994, 59, 5038. For an example of photolytically activated Bergman cycloaromatization reaction, see: Tun:o, N. J.; Evenzahav, A.; Nicolaou, K. C. Tetrahedron Lett. 1994, 35, 8089. For a discussion of persistent and stable radicals, see: Griller, D.; Ingold, K. U. Acc. Chem. Res. 1976, 9, 13. a) Adam, W.; Bottle, S. E. Tetrahedron Lett. 1991, 32, 1405. b) Bottle, S. E.; Busfield, W. K.; Thang, S. H.; Rizzardo, E.; Solomon, D. H. Eur. Polym. J. 1989, 25, 671. c)Beckwith, A. L. J.; Bowry, V. W.; Moad, G. J. Org. Chem. 1988, 53, 1632. d) Review: Keana, J. F. W. Chem. Rev. 1978, 78, 37. Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. Synthesis 1980, 627. Suzuki, H.; Nakamura, K.; Goto, R. Bull. Chem. Soc. Japan 1966, 39, 128. Also, see: Hellberg, J.; Pelcman, M. E. Tetrahedron Lett. 1994, 35, 1769. In the preparation of 3e, crude 2e contaminated with 2-iodoindan was used. Endiyne arene 3e was isolated as an inseparable mixture of of 3e and 2-ethynylindan at 2.1:1 ratio, as determined by 1H NMR integration analysis. This mixture was used in the reaction with TEMPO. a) Typical procedure: Enediyne arene (0.5 mmol) and TEMPO (3 equiv.) were dissolved in chlorobenzene (ca. 0.07 M) in a screw-top pressure tube equipped with a magnetic bar. The solution was purged with nitrogen for 20 rain, and the tightly capped tube was heated with an oil bath pre-heated to 150 - 160 °C for 6 h and then cooled to room temperature. The solvent was removed in vacuo and the crude product was purified by flash chromatography on silica gel. b) Satisfactory 1H and 13C NMR, IR, and HRMS were obtained for all products. a) Myers, A. G.; Dragovich, P. S.; Kuo, E. Y.; J. Am. Chem. Soc. 1992, 114, 9369. b) Myers, A. G.; Kuo, E. Y.; Finney, N. S. Ibid. 1989, 111, 8057. c) Myers, A. G.; Dragovich, P. S. Ibid. 1989, 111, 9130.
(Received in USA 7 April 1995; revised 18 May 1995; accepted 26 May 1995)