Reactivity of 1,4-didehydronaphthalene toward organic hydrogen atom donors

Article abstract of DOI:10.1016/S0040-4039(00)00575-X

1,4-Didehydronaphthalene, generated by thermolysis of 1,2- diethynylbenzene, reacts with organic hydrogen atom donors via hydrogen atom abstraction. The resulting naphthyl radical undergoes the expected abstraction of a hydrogen atom from a second hydrogen atom donor molecule. Surprisingly, significant amounts of radical-radical recombination between the hydrogen donor radical product and the naphthyl radical were also observed for several donors. Further, in some cases, the hydrogen donor radical products also rapidly add to the uncyclized 1,2-diethynylbenzene. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00575-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 4019–4024
Reactivity of 1,4-didehydronaphthalene toward organic hydrogen
atom donors
Kami K. Thoen, Jason C. Thoen and Fatih M. Uckun ∗
Department of Chemistry, Drug Discovery Program, Hughes Institute, Roseville, MN 55113, USA
Received 20 December 1999; revised 5 April 2000; accepted 6 April 2000
Abstract
1,4-Didehydronaphthalene, generated by thermolysis of 1,2-diethynylbenzene, reacts with organic hydrogen
atom donors via hydrogen atom abstraction. The resulting naphthyl radical undergoes the expected abstraction of a
hydrogen atom from a second hydrogen atom donor molecule. Surprisingly, significant amounts of radical–radical
recombination between the hydrogen donor radical product and the naphthyl radical were also observed for
several donors. Further, in some cases, the hydrogen donor radical products also rapidly add to the uncyclized
1,2-diethynylbenzene. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: diyne; addition reactions; radicals and radical reactions; trapping reactions.
The transformation of (Z)-3-ene-1,5-hexadiyne into 1,4-didehydrobenzene (i.e. para-benzyne) was
first elucidated by Bergman and Jones in the 1970s.1 Despite the fundamental importance of 1,4-
didehydrobenzene to the understanding of the stability and reactivity of biradicals, this novel cyclization
process received little attention until the discovery that the antitumor activity of a new class of com-
pounds, including calicheamicin and esperamicin, was due to the presence of a biradical intermediate.2
These anticancer agents each possess an enediyne backbone which undergoes the Bergman cyclization
to yield a 1,4-σ,σ-biradical which subsequently abstracts a hydrogen atom from each strand of DNA.2,3
These lesions in the DNA lead to double-strand DNA cleavage and, ultimately, cell death.3 However,
the naturally occurring enediyne antibiotics have to date found limited clinical applicability due to their
high cytotoxicity to healthy as well as cancerous cells.4 Obviously, the rational design of new antitumor
drugs containing an enediyne backbone requires rigorous examination of the various factors controlling
the Bergman cyclizations and hydrogen atom abstraction reactions of these species.
Much research has been devoted to studying the Bergman cyclizations of various enediyne
compounds.5–15 Most of the studies have been performed using 1,4-cyclohexadiene as the hydrogen
atom donor, however; only a few isolated investigations have employed other hydrogen atom donors,
such as isopropanol and acetonitrile.1b,7,9,15b,c Such limited knowledge of the reactivities of the biradical
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00575-X
tetl 16854

4020
intermediates generated from simple enediynes renders the process of modifying the naturally occurring
enediynes in order to optimize their hydrogen atom abstraction capabilities (and thus DNA-cleaving
efficiencies) more difficult. Additionally, the ultimate goal is in vivo applicability of the enediyne
antitumor drugs, yet the reactions of enediynes toward different types of molecules found in the
human body are almost entirely unexplored. The focus of our work in this area has been to describe
the reactivity of the 1,4-didehydronaphthalene biradical intermediate in the Bergman cyclization of
1,2-diethynylbenzene (Scheme 1), a simple model of the naturally occurring enediyne antitumor
antibiotics. In this report, we examine the reactions of this species toward the hydrogen atom donors
tetrahydrofuran, isopropanol, cyclohexane, toluene, 1,4-cyclohexadiene and 3,4-dihydro-2H-pyran.
Scheme 1.
1,2-Diethynylbenzene (10 mM) was heated (165°C) in neat solvent until the starting material was
consumed; the results are given in Table 1. The expected hydrogen atom abstraction trapping product of
the 1,4-didehydronaphthalene biradical, naphthalene, was observed for each of the substrates examined.
Surprisingly, however, substantial amounts of other products were also observed for most of the reagents.
For example, reaction of 1,4-didehydronaphthalene with 1,4-cyclohexadiene yields naphthalene (36%)
as well as two adducts (1-(2,5-cyclohexadienyl)naphthalene and 1-(2,4-cyclohexadienyl)-naphthalene,
31%, Scheme 2). These results are especially unexpected for 1,4-cyclohexadiene, as numerous pub-
lications have reported exclusive abstraction of two hydrogen atoms by a para-benzyne-type biradical
for reactions involving this reagent.12,15,16 A few studies have previously mentioned the formation of
adducts upon thermolysis of an enediyne1b,5c,7,9,12 in various solvents, but this phenomenon has not
been thoroughly explored. The results described in this paper demonstrate unequivocally, however, the
propensity for 1,4-σ,σ-biradicals to undergo reactions other than simple abstraction of two hydrogen
atoms upon interaction with a wide range of different hydrogen atom donors.
Adduct formation between the 1,4-didehydronaphthalene biradical and the hydrogen atom donor likely
proceeds via an initial hydrogen atom abstraction, followed by recombination of the resulting radicals
(Scheme 2). This mechanism is supported by the lack of any products resulting from addition of two
solvent molecules to the biradical. In other words, if the first step of the reaction involves addition of the
biradical to the hydrogen atom donor, one would expect to observe at least some addition of a second
solvent molecule to the biradical (Table 1). Also, two distinct adducts are observed for the reactions with
1,4-cyclohexadiene and 3,4-dihydro-2H-pyran. These findings are in good agreement with the proposed
mechanism, as the initial hydrogen atom abstraction reaction would produce a delocalized hydrogen
donor radical, which can then undergo radical–radical recombination with the naphthyl radical to yield
two different adducts (Scheme 2).
Closer examination of the products of some of the reactions studied revealed that addition of the hydro-
gen donor radical (produced in the initial hydrogen atom abstraction reaction) to the uncyclized enediyne
occurs, competing with recombination to the naphthyl radical. For example, the reaction with tetrahy-
drofuran yields the 1,2-diethynylbenzene (1-(2-ethynylbenzene)-2-(2-tetrahydrofuranyl)ethylene, 42%,
Scheme 3) and 1,4-didehydronaphthalene adducts (1-(2-tetrahydrofuranyl)-naphthalene, 2%, Scheme 3)
as well as naphthalene (4%). Thus, for each molecule of naphthalene that is produced in the reaction of
1,4-didehydronaphthalene with tetrahydrofuran, two tetrahydrofuran-2-yl radicals are generated which
can subsequently react with the uncyclized enediyne. Significant amounts of addition to the enediyne

4021
Table 1
Product yields measured upon thermocyclization of 1,2-diethynylbenzene in the presence of various
hydrogen atom donors
were also observed for isopropanol, toluene and cyclohexane (Table 1). Reactions involving addition of
a radical to an alkene or alkyne are common,17 but have not been reported as a major reaction pathway
in prior studies entailing thermolysis of enediynes in the presence of hydrogen atom donors.
The observation of substantial amounts of addition products in these reactions has several practical
implications. First, the reactions of 1,4-σ,σ-biradicals with hydrogen atom donors are not necessarily

4022
Scheme 2.
dominated by abstraction of two hydrogen atoms, as is commonly believed. Further, in reactions where
addition of a hydrogen donor radical product to the uncyclized enediyne represents a significant reaction
pathway, reaction rates obtained by monitoring the disappearance of the enediyne will not reflect the
rate of Bergman cyclization or the rate of hydrogen atom abstraction. Instead, the consumption of the
enediyne via a non-biradical pathway will result in a faster apparent reaction rate. The addition of
the hydrogen donor radical to the uncyclized enediyne yields a vinyl radical which then abstracts a
hydrogen atom from the solvent, producing another hydrogen donor radical and initating a radical chain
reaction. Thus, a single initial hydrogen atom abstraction by the 1,4-didehydronaphthalene biradical can
ultimately cause the disappearance of many enediyne molecules. A better measure of the capability of
1,4-didehydronaphthalene to abstract hydrogen atoms from various solvents, then, may be the measured
rates of formation of naphthalene and biradical addition products; this hypothesis is currently under
investigation in our laboratory.
References
1. (a) Jones, R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660. (b) Bergman, R. G. Acc. Chem. Res. 1973, 6, 25.
2. (a) Lee, M. D.; Dunne, T. S.; Chang, C. C.; Ellestad, G. A.; Siegel, M. M.; Morton, G. O.; McGahren, W. J.; Borders, D. B.
J. Am. Chem. Soc. 1987, 109, 3466. (b) Nicolaou, K. C.; Smith, A. L. Acc. Chem. Res. 1992, 25, 497. (c) Gleiter, R.; Kratz,

4023
Scheme 3.
D. Angew. Chem. 1993, 105, 884. (d) Edo, K.; Mizugaki, M.; Koide, Y.; Seto, H.; Furihata, K.; Otake, N. Tetrahedron Lett.
1985, 26, 331. (e) Golik, J.; Clardy, J.; Dubay, G.; Groenewold, G.; Kawaguchi, H.; Konishi, M.; Krishman, B.; Ohkuma,
H.; Saitoh, K.; Doyle, T. W. J. Am. Chem. Soc. 1987, 109, 3461. (f) Golik, J.; Dubay, G.; Groenewold, G.; Kawaguchi, H.;
Konishi, M.; Krishman, B.; Ohkuma, H.; Saitoh, K.; Doyle, T. W. J. Am. Chem. Soc. 1987, 109, 3462. (g) Masataka, K.;
Ohkuma, H.; Matsumoto, K.; Takashi, T.; Kamei, H.; Miyaki, T.; Oki, T.; Kawaguchi, H. J. Anitbiot. 1989, 42, 1449.
3. Nicolaou, K. C.; Dai, W.-M. Ang. Chem. 1991, 103, 1453.
4. Enediyne Antibiotics as Antitumor Agents; Borders, D. B., Doyle, T. W., Eds.; Marcel Dekker: New York, 1995.
5. (a) Snyder, J. P. J. Am. Chem. Soc. 1989, 111, 7630. (b) Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J.;
Kumazawa, T. J. Am. Chem. Soc. 1988, 110, 7247. (c) Nicolaou, K. C.; Zuccarello, G.; Reimer, C.; Estevez, V. A.; Dai,
W.-M. J. Am. Chem. Soc. 1992, 114, 7360. (d) Maier, M. E. Synlett. 1995, 13. (e) Schreiner, P. R. Chem. Commun. 1998,
483. (f) Schreiner, P. R. J. Am. Chem. Soc. 1998, 120, 4184.
6. Schmittel, M.; Kiau, S. Chem. Lett. 1995, 953.
7. Hoffner, J.; Schottelius, M. J.; Feichtinger, D.; Chen, P. J. Am. Chem. Soc. 1998, 120, 376.
8. David, W. M.; Kerwin, S. M. J. Am. Chem. Soc. 1997, 119, 1464.
9. Kim, C.-S.; Russell, K. C. Tetrahedron Lett. 1999, 40, 3835.
10. Kim, C.-S.; Russell, K. C. J. Org. Chem. 1998, 63, 8229.
11. Maier, M. E.; Greiner, B. Liebigs Ann. Chem. 1992, 855.
12. Semmelhack, M. F.; Neu, T.; Foubelo, F. J. Org. Chem. 1994, 59, 5038.
13. Nicolaou, K. C.; Liu, A.; Zeng, Z.; McComb, S. J. Am. Chem. Soc. 1992, 114, 9279.
14. Meyers, A. G.; Dragovich, P. S. J. Am. Chem. Soc. 1992, 114, 5859.

4024
15. (a) Kaneko, T.; Takahashi, M.; Hirama, M. Tetrahedron Lett. 1999, 40, 2015. (b) Hirama, M. Pure Appl. Chem. 1997, 69,
525. (c) Iida, K.; Hirama, M. J. Am. Chem. Soc. 1995, 117, 8875.
16. See, for example: (a) Grissom, J. W.; Calkins, T. L.; McMillen, H. A.; Jiang, Y. J. Org. Chem. 1994, 59, 5833. (b) Choy,
N.; Russell, K. C. Heterocycles 1999, 1, 13. (c) Magnus, P.; Fortt, S.; Pitterna, T.; Snyder, J. P. J. Am. Chem. Soc. 1990,
112, 4986. (d) Schmittel, M.; Kiau, S. Chem. Lett. 1995, 953.
17. (a) For a review, see: Free Radicals, Vol. 1; Kochi, J. K., Ed.; Wiley: New York, 1973. (b) Westmoreland, P. R.; Dean, A.
M.; Howard, J. B.; Longwell, J. P. J. Phys. Chem. 1989, 93, 8171. (c) Dewar, M. J. S.; Gardiner Jr., W. C.; Frenklach, M.;
Oref, I. J. Am. Chem. Soc. 1987, 109, 4456.