Two-photon photochemical generation of reactive enediyne

Article abstract of DOI:10.1021/jo061285m

p-Quinoid cyclopropenone-containing enediyne precursor (1) has been synthesized by monocyclopropanation of one of the triple bonds in p-dimethoxy-substituted 3,4-benzocyclodeca-1,5-diyne followed by oxidative demethylation. Cyclopropenone 1 is stable up t

Full text of DOI:10.1021/jo061285m

Two-Photon Photochemical Generation of Reactive Enediyne
Andrei Poloukhtine and Vladimir V. Popik*,†
Center for Photochemical Sciences, Bowling Green State UniVersity, Bowling Green, Ohio 43403
Vpopik@uga.edu
ReceiVed June 21, 2006
p-Quinoid cyclopropenone-containing enediyne precursor (1) has been synthesized by monocyclopro-
panation of one of the triple bonds in p-dimethoxy-substituted 3,4-benzocyclodeca-1,5-diyne followed
by oxidative demethylation. Cyclopropenone 1 is stable up to 90 °C but readily produces reactive enediyne
2 upon single-photon (Φ300nm ) 0.46) or two-photon (σ800nm ) 0.5 GM) photolysis. The photoproduct 2
undergoes Bergman cyclization at 40 °C with the lifetime of 88 h.
Introduction
very attractive idea as it allows for the spatial and temporal
control of the Bergman cyclization. The direct irradiation of
acyclic5,6 and cyclic7 enediynes, as well as of natural antibiotic
Dynemicin A,8 is known to cause light-induced cycloaromati-
zation. However, quantum and chemical yields of this process
are usually low. The efficiency of the photochemical Bergman
cyclization can be substantially improved by adjusting the
electronic properties of substituents9 and/or by using different
modes of excitation energy transfer, for example, MLCT.6 In
addition, several caged enediynes have been prepared, which
undergo conventional chemical activation after the photochemi-
cal uncaging step.10
The cytotoxicity of enediyne antitumor antibiotics is attributed
to the ability of the (Z)-3-ene-1,5-diyne fragment to undergo
Bergman1 cyclization. The p-benzyne diradical produced in
this reaction is believed to abstract hydrogen atoms from both
strands of DNA, ultimately causing double-strand DNA scis-
sion.2 These natural products are highly potent antineoplastic
agents, but their clinical use is hampered by inadequate anti-
tumor selectivity.2 The cycloaromatization of enediynes is also
employed in the development of novel potent nucleases3 and
p-phenylene polymers for microelectronic fabrication.4 The
photochemical triggering of enediyne cycloaromatization is a
(5) Kagan, J.; Wang, X.; Chen, X.; Lau, K. Y.; Batac, I. V.; Tuveson,
R. W.; Hudson, J. B. J. Photochem. Photobiol. B 1993, 21, 135. Turro, N.
J.; Evenzahav, A.; Nicolaou, K. C. Tetrahedron Lett. 1994, 35, 8089.
Kaneko, T.; Takahashi, M.; Hirama, M. Angew. Chem., Int. Ed. 1999, 38,
1267. Plourde, G., II; El-Shafey, A.; Fouad, F.; Purohit, A.; Jones, G. Bioorg.
Med. Chem. Lett. 2002, 12, 2985.
(6) Benites, P. J.; Holmberg, R. C.; Rawat, D. S.; Kraft, B. J.; Klein, L.
J.; Peters, D. G.; Thorp, H. H.; Zaleski, J. M. J. Am. Chem. Soc. 2003,
125, 6434. Kraft, B, J.; Coalter, N. L.; Nath, M.; Clark, A. E.; Siedle, A.
R.; Huffman, J. C.; Zaleski, J. M. Inorg. Chem. 2003, 42, 1663.
(7) Choy, N.; Blanco, B.; Wen, J.; Krishan, A.; Russell, K. C. Org. Lett.
2000, 2, 3761. Funk, R. L.; Young, E. R. R.; Williams, R. M.; Flanagan,
M. F.; Cecil, T. L. J. Am. Chem. Soc. 1996, 118, 3291.
† Current address: Department of Chemistry, the University of Georgia,
Athens, Georgia 30602.
(1) Bergman, R. G. Acc. Chem. Res. 1973, 6, 25.
(2) For recent reviews see: Enediyne Antibiotics as Antitumor Agents;
Borders, D. B., Doyle, T. W., Eds.; Marcel Dekker: New York, 1995. Jones,
G. B.; Fouad, F. S. Curr. Pharm. Des. 2002, 8, 2415. Nicolaou, K. C.;
Dai, W.-M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387. Nicolaou, K. C.;
Smith, A. L. Acc. Chem. Res. 1992, 25, 497. Danishefsky, S. J.; Shair, M.
D. J. Org. Chem. 1996, 61, 16.
(3) Dai, W.-M.; Lai, K. W.; Wu, A.; Hamaguchi, W.; Le, M. Y. H.;
Zhou, L.; Ishii, A.; Nishimoto, S. J. Med. Chem. 2002, 45, 758. Tunti-
wechapikul, W.; David, W. M.; Kumar, D.; Salazar, M.; Kerwin, S. M.
Biochemistry 2002, 41, 5283. Rawat, D. S.; Zaleski, J. M. J. Am. Chem.
Soc. 2001, 123, 9675. Jones, G. B.; Hynd, G.; Wright, J. M.; Purohit, A.;
Plourde, G., II; Huber, R. S.; Mathews, J. E.; Li, A.; Kilgore, M. W.; Bubley,
G. J.; Yancisin, M.; Brown, M. A. J. Org. Chem. 2001, 65, 3688. Takahashi,
T.; Tanaka, H.; Yamada, H.; Matsumoto, T.; Sugiura, Y. Angew. Chem.,
Int. Ed. Engl. 1977, 36, 1524.
(8) Shiraki, T.; Sugiura, Y. Biochemistry 1990, 29, 9795.
(9) Alabugin, I. V.; Manoharan, M. J. Phys. Chem. A 2003, 107, 3363.
Alabugin, I. V.; Manoharan, M.; Kovalenko, S. V. Org. Lett. 2002, 4, 1119.
Clark, A. E.; Davidson, E. R.; Zaleski, J. M. J. Am. Chem. Soc. 2001, 123,
2650.
(10) Nicolaou, K. C.; Dai, W.-M.; Wendeborn, S. V.; Smith, A. L.;
Torisawa, Y.; Maligres, P.; Hwang, C.-K. Angew. Chem., Int. Ed. Engl.
1991, 30, 1032. Wender, P. A.; Zercher, C. K.; Beckham, S.; Haubold,
E.-M. J. Org. Chem. 1993, 58, 5867. Basak, A.; Bdour, H. M.; Shain, J.
C.; Mandal, S.; Rudra, K. R.; Nag, S. Bioorg. Med. Chem. Lett. 2000, 10,
1321.
(4) Smith, D. W., Jr.; Babb, D. A.; Snelgrove, R. V.; Townsend, P. H.,
III; Martin, S. J. J. Am. Chem. Soc. 1998, 120, 9078. John, J. A.; Tour, J.
M. Tetrahedron 1997, 53, 15515. Chen, X.; Tolbert, L. M.; Hess, D. W.;
Henderson, C. Macromolecules 2001, 34, 4104. Shah, H. V.; Babb, D. A.;
Smith, D. W., Jr. Polymer 2000, 41, 4415.
10.1021/jo061285m CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/16/2006
J. Org. Chem. 2006, 71, 7417-7421
7417

Poloukhtine and Popik
SCHEME 1
Our group explores the alternative strategy: the in situ
photochemical generation of reactive enediynes from thermally
stable precursors. The photogenerated enediyne then undergoes
facile thermal Bergman reaction. Thus, replacement of one of
the triple bonds in an enediyne structure with a cyclopropenone
group produces thermally stable precursors.11 UV photolysis
of these compounds results in the decarbonylation of cyclopro-
penone moiety12 and the formation of reactive enediynes. UV
irradiation, however, is not compatible with many biomedical
applications, which require the use of light in a so-called
“phototherapeutic window”, a region of relative tissue transpar-
ency between 650 and 950 nm. The energy of red or NIR
photons, on the other hand, is not sufficient to trigger most
photochemical reactions. One of the approaches allowing for
the alleviation of this problem is to employ nonresonant two-
photon excitation (2PE). At high light fluxes chromophores
might simultaneously absorb two red/NIR photons producing
excited states the same as or similar to ones accessible by
excitation with UV light of twice the frequency.13 In addition,
2PE also allows for the 3-D spatial control of photoinduced
processes.14 While many efficient two-photon fluorophores have
been reported,15 the field of two-photon photochemistry remains
relatively unexplored.16 Even fewer examples of two-photon
induced activation or release of bilogicaly relevant structures
are known.17
SCHEME 2 a
a Reagents and conditions: (a) Me2SO4, K2CO3, acetone; (b) Br2, CHCl3,
77% (two steps); (c) HCtCSiMe3, Pd(PPh3)2Cl2, CuI, PPh3, piperidine;
(d) K2CO3, MeOH, 71% (two steps); (e) n-BuLi, I(CH2)4I, THF, HMPA,
-78 °C f rt, 42%; (f) CHCl3, n-BuLi, THF, -78 °C, 86%; (g) BBr3,
CH2Cl2, -78 °C f rt; (h) FeCl3, THF, 23% (two steps); (i) CAN in aq
acetonitrile, 81% (10) or 89% (9).
Results and Discussion
This report describes the first two-photon induced generation
of reactive enediyne, as well as the Bergman cyclization of the
photoproduct (Scheme 1). We also report direct determination
of the two-photon absorption cross-section of the precursor 1.
Synthesis of Cyclopropenone 1. Cyclopropenone 1 was
prepared in eight steps starting from 2,3-dimethyl-1,4-hydro-
quinone (4). The methylation of hydroquinone 4 followed by
the bromination of the product 5 provided 1,2-dibromo-3,6-
dimethoxy-4,5-dimethylbenzene (6) in a good yield. The Pd-
(0)/Cu(I) mediated coupling of dibromide 6 with trimethylsilyl
acetylene in piperidine and the subsequent cleavage of
trimethylsilyl protection in methanol under basic conditions
afforded diacetylene 8 in 71% yield. The benzannulated
enediyne 9 has been prepared by the reaction of the dianion of
8 with 1,4-diiodobutane in THF-HMPA solvent. The crucial
monocyclopropanation step was achieved by the addition of
dichlorocarbene, generated in situ from chloroform and n-BuLi,
followed by the hydrolysis in concentrated hydrochloric acid
at -78 °C to form cyclopropenone 10 in excellent yield
(Scheme 2).
(11) Poloukhtine, A.; Popik, V. V. Chem. Commun. 2005, 617. Poloukh-
tine, A.; Popik, V. V. J. Org. Chem. 2005, 70, 1297.
(12) Poloukhtine, A.; Popik, V. V. J. Org. Chem. 2003, 68, 7833.
(13) Go¨ppert-Mayer, M. Ann. Phys. (Leipzig) 1931, 9, 273. Lakowicz,
J. R. Two-Photon And Non-Linear Induced Fluorescence; Plenum Press:
New York, 1991. Callis, P. R. Ann. Phys. ReV. Chem. 1997, 48, 271. Becker,
A.; Hessenius, C.; Licha, K.; Ebert, B.; Sukowski, U.; Semmler, W.;
Wiedenmann, B.; Gro¨tzinger, C. Nat. Biotechnol. 2001, 19, 327. Rubat,
M. Circ. Res. 2004, 95, 1154. Kauffman, J. F.; Turner, J. M.; Alabugin, I.
V.; Breiner, B.; Kovalenko, S. V.; Badaeva, E. A.; Masunov, A.; Tretiak,
S. J. Phys. Chem. A 2006, 110, 241.
(14) Ko¨nig, K. J. Microsc. 2000, 200, 2. Weissleder, R. Nat. Biotechnol.
2001, 19, 316. Brown, E. B.; Shear, J. B.; Adams, S. R.; Tsien, R. Y.;
Webb, W. W. Biophys. J. 1999, 76, 489.
(15) Yao, S.; Belfield, K. D. J. Org. Chem. 2005, 70, 5156. Yang, W.
J.; Kim, D. Y.; Jeong, M.-Y.; Kim, H. M.; Lee, Y. K.; Fang, X.; Jeon, S.-J.
Chemistry 2005, 11, 4198. Drobizhev, M.; Stepanenko, Y.; Dzenis, Y.;
Karotki, A.; Rebane, A.; Taylor, P. N.; Anderson, H. L. J. Am. Chem. Soc.
2004, 126, 15352. Pond, S. J. K.; Tsutsumi, O.; Rumi, M.; Kwon, O.; Zojer,
E.; Bredas, J.-L.; Marder, S. R.; Perry, J. W. J. Am. Chem. Soc., 2004,
126, 9291. Beverina, L.; Fu, J.; Leclercq, A.; Zojer, E.; Pacher, P.; Barlow,
S.; Van Stryland, E. W.; Hagan, D. J.; Bredas, J.-L.; Marder, S. R. J. Am.
Chem. Soc. 2005, 127, 7282.
(16) (a) Belfield, K. D. Spectrum 2001, 14, 1. (b) Marder, S. R.; et al.
Nature 1999, 398, 51. (c) Fedoryak, O. D.; Dore, T. M. Org. Let. 2002, 4,
3419. (d) Kim, H.-C.; Kreiling, S.; Greiner, A.; Hampp, N. Chem. Phys.
Lett. 2003, 372, 899. (e) Dyer, J.; Jockusch, S.; Balsanek, V.; Sames, D.;
Turro, N. J. J. Org. Chem. 2005, 70, 2143. (f) Goodwin, A. P.; Mynar, J.
L.; Ma, Y.; Fleming, G. R.; Frechet, J. M. J J. Am. Chem. Soc. 2005, 127,
9952. (g) Urdabayev, N. K.; Popik, V. V. J. Am. Chem. Soc. 2004, 126,
4058.
The oxidative demethylation of the hydroqiunone moiety of
10 proved to be challenging. Complex mixtures of ring-open
products were formed under various conditions (e.g., AgO/
18
HNO3 or H2SO4/HNO319). Treatment of 10 with CAN in
aqueous acetonitrile20 resulted in clean formation of enediyne
2. Recognizing that the cyclopropenone group might be ex-
tremely sensitive to strong oxidants we turned our attention to
stepwise demethylation and oxidation protocols. Reaction of
cyclopropenone 10 with boron tribromide gave rise to hydro-
quinone 11, which in turn was oxidized by FeCl3 to produce
the cyclopropenone-containing enediyne precursor 1 in 23%
yield. Enediyne 2 was prepared by CAN oxidation of 9
(Scheme 2).
(17) Nikolenko, V.; Yuste, R.; Zayat, L.; Baraldo, L. M.; Etchenique,
R. Chem. Commun. 2005, 1752. Fedoryak, O. D.; Sul, J.-Y.; Haydon, P.
G.; Ellis-Davies, G. C. R. Chem. Commun. 2005, 3664. Zhao, Y. R.; Zheng,
Q.; Dankin, K.; Xu, K.; Martinez, M. L.; Li, W.-H. J. Am. Chem. Soc.
2004, 126, 4653. Lu, M.; Fedoryak, O. D.; Moister, B. R.; Dore, T. M.
Org. Lett. 2003, 5, 2119. Kiskin, N. I.; Chillingworth, R.; McCray, J. A.;
Piston, D.; Ogden, D. Eur. Biophys. J. 2002, 30, 588. Furuta, T.; Wang, S.
S. H.; Dantzker, J. L.; Dore, T. M.; Bybee, W. J.; Callaway, E. M.; Denk,
W.; Tsien R. Y. Proc. Natl. Acad. Sci. U.S.A. 1999, 96, 1193. Adams, S.
R.; Lev-Ram, V.; Tsien, R. Y. Chem. Biol. 1997, 4, 867.
Single-Photon Photochemistry of 1. The UV spectrum of
the cyclopropenone (1) in methanol shows a strong absorption
(18) Parker, K. A.; Spero, D. M.; Koziski, K. A. J. Org. Chem. 1987,
52, 183.
(19) Waterlot, C.; Haskiak, B.; Couturier, D. J. Chem. Res. Synop. 2000,
3, 106.
(20) Jacob, P.; Callery, P. S.; Shulgin, A. T.; Castagnoli, N. J. Org. Chem.
1976, 41, 3627.
7418 J. Org. Chem., Vol. 71, No. 19, 2006

Photochemical Generation of ReactiVe Enediyne
FIGURE 1. UV spectra of ca. 3 × 10-4 M methanol solutions of
cyclopropenone 1 (solid line) and enediyne 2 (dotted line). The insert
shows the spectral width of the Ti:sapphire laser pulse.
FIGURE 3. Decay of enediyne 2 in 2-propanol at 40 °C. The curve
represents the calculated fit to a single-exponential equation.
photon photolysis. The HPLC analysis of reaction mixtures was
unable to detect any byproducts in the former case.
The conversion of the starting material (in terms of molar
concentration, C) by the two-photon induced photoreaction can
be described by eq 1,
100 fs
2
C ) C exp(-σ -100 fs I0 dt νt)
(1)
∫
0
R
which has been derived from the differential form of Beer’s
law for the two-photon absorption.22 In eq 1 I2 is a squared
light flux (photons2 cm-4 s-2), which is integrated for the
duration of the laser pulse, ν represents the repetition rate, and
σR is a two-photon cross-section for the induction of photo-
decarbonylation reaction. The latter term can be further defined
as σR ) Φ2PE*σ, where Φ2PE is a fraction of two-photon excited
molecules that undergo chemical transformation, and σ is the
2PE cross-section of the substrate.
Least-squares fitting of the experimental data to the equation
(eq 1) gave us σR ) 0.222 ( 0.017 GM.23 To convert the
experimentally determined two-photon cross-section for the
induction of the photodecarbonylation reaction, σR, into the two-
photon absorption cross-sections of enediyne precursor 1, we
need to know the fraction of two-photon excited molecules that
undergo decarbonylation, Φ2PE. The excited state initially
populated upon two-photon excitation might be different from
that initially populated upon single-photon excitation. However,
according to Kasha’s rule, photochemical reactions generally
occur from the lowest singlet or triplet excited states regardless
of the excitation method and the initial exited state.24 Thus, we
can assume that the quantum yield of the two-photon initiated
FIGURE 2. Formation of enediyne 2 in the two-photon induced
decarbonylation of 1 mM methanol solutions of cyclopropenone 1. The
line shown was drawn with parameters obtained by the least-squares
fitting of the experimental data to eq 1. The insert illustrates the
dependence of the rate of the photochemical reaction on the pulse
energy. The line shows the fit of the data to a second-order polynomial
equation.
at 298 nm (log ꢀ ) 3.99) and a somewhat weaker band at 393
nm (log ꢀ ) 3.06, Figure 1). The irradiation of 1 in methanol
with 300 nm broad-band lamps, as well as monochromatic 355
nm light from the frequency tripled Nd:YAG laser, results in
the rapid decarbonylation of the substrate and the formation of
enediyne 2. The quantum yield of this reaction at room
temperature is Φ ) 0.46 ( 0.04 at 300 nm in methanol.
Incomplete photolysis (up to 40% conversion) of the precursor
1 produces only the target enediyne 2. However, further
irradiation results in the formation of substantial amounts of
byproducts and reduces the isolated yield of 2 to 76%. The UV
spectrum of the product overlaps substantially with the starting
material (Figure 1), which makes us believe that the lower yield
of the complete conversion photolysis is due to a secondary
photochemical reaction.
Two-Photon Induced Generation of Enediyne 2. The
irradiation of 1 in methanol with 800 nm pulses from a Ti:
sapphire laser results in the same process as the UV photolysis,
i.e., decarbonylation of the cyclopropenone group and the
formation of enediyne 2. The progress of this reaction was
monitored by HPLC following the disappearance of starting
material 1, as well as the formation of 2 (Figure 2, Table S121).
It is interesting to note that the two-photon induced decarbo-
nylation of cyclopropenone 1 is much cleaner than the single-
process is equal to its single-photon counterpart, Φ2PE ) ΦSPE
.
The two-photon absorption cross-section of cyclopropenone 1
is, therefore, equal to σ2PE(800) ) σR(800)/ΦSPE ) 0.483 ( 0.058 GM.
Bergman Cyclization of 2,3(Octa-1,7-diyne-1,8-diyl)-5,6-
dimethylhydroqiunone 1,4-Dimethyl Ether (2). The enediyne
2 undergoes efficient Bergman cyclization upon heating in the
degassed benzene at 75 °C in the presence of 1,4-cyclohexa-
diene. The starting material is completely consumed within 4 h
producing 2,3-dimethyl-5,6,7,8-tetrahydroanthracene-1,4-dione
(3) in 87% yield (Scheme 1). The rate of Bergman cyclization
(22) Urdabaev, N. K.; Poloukhtine, A.; Popik, V. V. Chem. Commun.
2006, 454.
(23) GM ) 10-50 cm4 s photon-1 molecule-1
.
(24) Turro, N. J. Modern Molecular Photochemistry; University Science
(21) See the Supporting information.
Books: Sausalito, CA, 1991.
J. Org. Chem, Vol. 71, No. 19, 2006 7419

Poloukhtine and Popik
mL), and the resulting mixture was protected from light and stirred
for 60 min at room temperature. The reaction mixture was washed
with an aqueous solution of Na2S2O5 and water, dried over
anhydrous MgSO4, and concentrated. The residue was purified by
chromatography on silica gel (ethyl acetate-hexanes 1:20) to give
9 g (27.8 mmol, 77%) of 1,2-dibroro-3,6-dimethoxy-4,5-dimethyl-
benzane (6). Rf 0.55 (ethyl acetate-hexanes 1:5); mp 117-118 °C
(lit.27 mp 117-119 °C).
of 2 was measured in a 2-propanol solution at 40 °C. The
progress of the reaction was followed by HPLC (Figure 3).
The observed rate of Bergman cyclization of 2, k40°C ) (3.14
( 0.31) × 10-6 s-1, is much faster than that of the parent 3,4-
benzocyclodeca-1,5-diyne. The latter is stable below 50 °C and
cyclized at 84 °C with k ) 8 × 10-6 s-1 25
. Direct comparison
of these rates, however, should be done with caution because
the rate of enediyne cyclization is known to depend on the
solvent, as well as on the concentration and nature of hydrogen
donor.25
It is important to note that the starting cyclopropenone 1 is
perfectly stable at 40 °C and shows no signs of decomposition
up to 90 °C.
Conclusions. We have shown the feasibility of the in situ
two-photon induced generation of reactive enediynes using light
within the “phototherapeutic window”. The cyclopropenone-
containing enediyne precursor 1 is stable in the dark even at
elevated temperatures but undergoes efficient photodecarbonyl-
ation producing reactive enediyne 2. The latter undergoes
Bergman cyclization at biologically relevant temperatures. The
two-photon induced photochemical reaction of 1 is much cleaner
because it is not accompanied by the secondary photochemistry.
1,2-Diethynyl-3,6-dimethoxy-4,5-dimethylbenzene (8).28 Pd-
(PPh3)2Cl2 (1 g, 1.43 mmol), CuI (0.36 g, 1.88 mmol), and
trimethylsilylacetylene (17.0 g, 173 mmol) were added to a degassed
solution of dibromide 6 (8 g, 24.70 mmol) in piperidine (ca. 120
mL) at room temperature. The reaction vessel was sealed and the
mixture was stirred for 24 h at 85 °C. After being cooled to room
temperature, the reaction mixture was filtered and concentrated in
a vacuum. The residue was dissolved in a ethyl acetate-hexanes
(1:30) mixture, passed through a short silica gel column, and
concentrated in a vacuum to give crude 1,4-dimethoxy-2,3-dimethyl-
5,6-bis(trimethylsilanylethynyl)benzene (7). Rf 0.36 (ethyl acetate-
1
hexanes 1:20); H NMR (300 MHz, CDCl3) δ 3.82 (s, 6 H), 2.16
(s, 6 H), 0.27 (s, 18 H); 13C NMR (75 MHz, CDCl3) δ 155.9, 132.5,
117.8, 102.3, 99.6, 60.5, 12.8, 0.0; MS calcd for C20H30 O2Si2 (M+)
358, found 358.
A methanol solution of crude diacetylene 7 was added to a stirred
suspension of K2CO3 (14 g, 100 mmol) in methanol (120 mL),
and the resulting mixture was stirred for 1 h at room temperature.
The reaction was quenched by saturated aqueous NH4Cl, and most
of the solvent was removed in a vacuum. Ethyl acetate was added
to the mixture, then the organic layer was separated, washed with
water and brine, dried over anhydrous MgSO4, and concentrated
in a vacuum. The residue was purified by chromatography on silica
gel (ethyl acetate-hexanes 1:25) to give 3.76 g of 8 (17.57 mmol,
71% over two steps) as a white powder. Rf 0.38 (ethyl acetate-
hexanes 1:5); 1H NMR (300 MHz, CDCl3) δ 3.81 (s, 6 H), 3.49 (s,
2 H), 2.17 (s, 6 H); 13C NMR (75 MHz, CDCl3) δ 156.2, 133.1,
117.2, 84.5, 78.3, 60.8, 12.9; MS calcd for C14H14 O2 (M+) 214,
found 214.
Experimental Section
Single-Photon Photochemistry. The preparative and analytical
photolyses of 1 were conducted in methanol solutions with a
Rayonet photoreactor. Preparative 300 nm irradiation of 1 in
methanol allowed us to isolate 2,3-(octa-1,7-diyne-1,8-diyl)-5,6-
dimethyl-1,4-benzoquinone (2), which was found to be identical
with the sample prepared independently. The quantum yield of the
photodecarbonylation reaction of 1 was measured in methanol
solutions by using ferrioxalate actinometry.26
Two-Photon Induced Enediyne Generation. TPE experiments
were conducted with 800 nm pulses generated by an amplified Ti:
sapphire laser operating at 1 kHz. The laser beam was attenuated
by a diaphragm with a 6.15 mm opening. The power output of the
laser after the diaphragm was 0.61 W, which was reduced to 0.55
W after passing through the sample. At the concentration of the
substrate used in these experiments the loss of energy after the
sample is mostly due to the losses on the phase boundaries, which
allows us to evaluate the laser power within the sample as 0.58 W
or 580 µJ per pulse-1. The shape of the laser pulse was determined
to be close to Gaussian with the half-height width of 94 fs. Using
these parameters we have calculated the distribution of light
intensity and squared light intensity within the pulse assuming ideal
Gaussian shape of the pulse. For the integration of the squared light
intensity we have selected the integration limits of (100 fs from
the center of the pulse, as the value of I2 at these extremes drops
to less than 0.2% of the maximum.
2,3-(Octa-1,7-diyne-1,8-diyl)-5,6-dimethyl-1,4-hydroqui-
none Dimethyl Ether (9). n-BuLi (2.5 M solution in hexanes,
7.85 mL, 19.6 mmol) was added to a stirred solution of 1,2-
diethynyl-3,6-dimethoxy-4,5-dimethylbenzene (8) (2.0 g, 9.35
mmol) in THF (400 mL) and HMPA (20 mL) at -78 °C under
argon. After 2 h at this temperature, 1,4-diiobutane (2.91 g, 9.40
mmol) was added dropwise, then the reaction mixture was allowed
to reach room temperature and stirred for 24 h. The reaction was
quenched by addition of phosphate buffer, partially concentrated,
diluted with hexanes passed through a short silica gel column, and
concentrated in a vacuum. The residue was purified by chroma-
tography on silica gel (ethyl acetate-hexanes 1:30 f 1:25) to give
1.05 g (3.91 mmol, 42%) of 2,3-(octa-1,7-diyne-1,8-diyl)-5,6-
dimethylhydroquinone 1,4-dimethyl ether (9) as colorless crystals,
which decompose upon heating. Rf 0.40 (ethyl acetate-hexanes
1
1:5); H NMR (300 MHz, CDCl3) δ 3.85 (s, 6 H), 2.49 (m, 4 H),
1,2-Dibromo-3,6-dimethoxy-4,5-dimethylbenzene (6).27 A sus-
pension of 2,3-dimethyl-1,4-hydroquinone (4) (5 g, 36.23 mmol),
Me2SO4 (10.4 g, 72.46 mmol), and K2CO3 (25 g) in acetone (300
mL) was refluxed for 24 h under argon. The reaction mixture was
cooled to room temperature, filtered, and concentrated in a vacuum.
The oily residue was dissolved in ethyl acetate-hexanes (1:12)
mixture, passed through a short silica gel column, and concentrated
under vacuum to give 5.2 g of crude 2,3-dimethyl-1,4-dimethyl-
benzene (5).
2.16 (s, 6 H), 1.96 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 153.3,
130.8, 120.8, 102.4, 79.0, 60.8, 28.6, 21.9, 12.7; HRMS calcd for
C18H20O2 (M+) 268.1463, found 268.1462.
Cyclopropenone 10. A solution of n-BuLi (2.5 M solution in
hexanes, 2.34 mL, 5.87 mmol) was added dropwise over ca. 1.5 h
to a stirred solution of enediyne 9 and CHCl3 (0.8 g 6.67 mmol) in
THF at -78 °C. The resulting solution was stirred for 30 min,
quenched by 3 mL of concentrated HCl, and slowly warmed to
room temperature. Most THF was removed in a vacuum. The
reaction mixture was diluted with ether, washed with a saturated
solution of NaHCO3, water, and brine, dried over anhydrous
MgSO4, and concentrated. The residue was purified by chroma-
tography on silica gel (CH2Cl2-hexanes 1:5 f CH2Cl2 f ethyl
A solution of bromine (11 g, 68.3 mmol) in 50 mL of chloroform
was added dropwise to a solution of crude 5 in chloroform (100
(25) Semmelhack, M. F.; Neu, T.; Foubelo, F. J. Org. Chem. 1994, 59,
5038. Semmelhack, M. F.; Sarpong, R. J. Phys. Org. Chem. 2004, 17, 807.
(26) Murov, S. L.; Carmichael, I.; Hug, G. L. In Handbook of
Photochemistry; Marcel Dekker: New York, 1993; p 299.
(28) Nishinaga, T.; Miyata, Y.; Nodera, N.; Komatsu, K. Tetrahedron
2004, 60, 3375.
(27) Lawson, D.; McOmie, J.; West, D. J. Chem. Soc. C 1968, 2414.
7420 J. Org. Chem., Vol. 71, No. 19, 2006

Photochemical Generation of ReactiVe Enediyne
acetate) to give 0.353 g (1.19 mmol, 86% calculated on recovered
enediyne) of cyclopropenone 10 as dark orange oil, and 0.347 g
(1.29 mmol) of enediyne 9. Rf 0.42 (ethyl acetate); 1H NMR (300
MHz, CDCl3) δ 3.91, 3.89 (s, 6 H), 3.04 (t, J ) 6.6 Hz, 2 H), 2.52
(t, J ) 5.4 Hz, 2 H), 2.26 (s, 6 H), 2.09-2.05 (m, 2 H), 1.8-1.72
(m, 2 H); 13C NMR (75 MHz, CDCl3) δ 157.7, 156.6, 155.2, 154.3,
153.2, 136.4, 132.3, 120.8, 114.9, 102.0, 96.1, 78.9, 62.5, 61.0,
26.39, 26.41, 26.0, 18.8, 13.2, 12.8; IR (CCl4) 2934 (m), 2858 (w),
1840 (s), 1627 (s), 1461 (m), 1397 (m); HRMS calcd for C19H20
O3 (M+) 296.1412, found 296.1414.
Cyclopropenone 1. A solution of BBr3 (1 M in CH2Cl2, 7 mL,
7 mmol) was added dropwise to a solution of dimethyl ether 10
(0.45 g, 1.52 mmol) in 80 mL of CH2Cl2 at -78 °C. The resulting
mixture was stirred for 4 h at -78 °C, slowly warmed to room
temperature, and stirred for another 4 h. Reaction was quenched
by water (50 mL), the organic layer was separated, and the aqueous
layer was extracted with CH2Cl2. The combined organic layers were
dried over anhydrous sodium sulfate and concentrated in a vacuum
to give 0.2 g of crude hydroquinone 11. 1H NMR (300 MHz,
CDCl3) δ 2.91 (t, J ) 6.6 Hz, 2 H), 2.52 (t, J ) 6.0 Hz, 2 H), 2.24,
2.23 (s, 6 H), 2.05-1.95 (m, 2 H), 1.83-1.75 (m, 2 H); MS calcd
for C17H16O3 (M+) 268, found 268.
Anhydrous FeCl3 was added to the solution of crude hydro-
quinone 11 in 30 mL of THF at room temperature. The reaction
mixture was stirred for 30 min, then quenched with water and ethyl
acetate. The organic layer was separated, washed with water and
brine, dried over anhydrous sodium sulfate, and concentrated in a
vacuum. The residue was purified by chromatography on silica gel
(ethyl acetate-hexanes 5:1) to give 92 mg (0.346 mmol, 23% over
two steps) of quinoid cyclopropenone 1 as a deep orange oil, which
crystallizes upon standing in the refridgerator. Rf )0.29 (ethyl
acetate); 1H NMR (300 MHz, CDCl3) δ 2.96 (t, J ) 6.6 Hz, 2 H),
2.55 (t, J ) 5.4 Hz, 2 H), 2.058, 2.045 (s, 6 H), 1.73-1.64 (m, 2
H); 13C NMR (75 MHz, CDCl3) δ 182.9, 182.2, 163.1, 157.2, 152.0,
141.9, 141.3, 133.7, 130.3, 117.2, 79.1, 27.1, 26.3, 26.05, 19.6,
12.62, 12.58; HRMS calcd for C17H14 O3 (M+) 266.0943, found
266.0931.
a stirred solution of CAN (1.63 g, 2.98 mmol) in 10 mL of a
acetonitrile-water mixture (1:1). The reaction mixture was stirred
for 45 min, then diluted with water and CH2Cl2. The organic layer
was separated, and the aqueous layer was extracted with 2 × 5
mL of CH2Cl2. Combined organic layers were washed with water
and dried over anhydrous sodium sulfate. The solvent was removed
in a vacuum to give 79 mg (0.332 mmol, 89%) of quinone 2 as
yellow crystalline material. Mp 118-120 °C dec. Rf 0.25 (EtOAc:
Hex 1:5); 1H NMR (300 MHz, CDCl3) δ 2.51 (s, b, 4 H), 2.00 (s,
6 H), 1.96-1.90 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 182.6,
140.8, 137.3, 114.9, 79.6, 28.2, 22.4, 12.5; HRMS calcd for C16H14
O2 (M+) 238.0994, found 238.0997.
2,3-Dimethyl-5,6,7,8-tetrahydroanthracene-1,4-dione (3). A
solution of 2 (0.087 g, 0.37 mmol) in benzene:1,4-cyclohaxadiene
(4:1, 15 mL) was degassed, the reaction vessel was sealed, and the
mixture was stirred for ∼5 h at 75 °C. After cooling and removing
the solvent, the residue was chromatographed on silica gel (ethyl
acetate-hexanes 1:1) to give 78 mg (0.33 mmol, 87%) of 3 as
yellow crystals. Mp 159-161 °C. Rf 0.25 (EtOAc:hexanes 1:5);
1H NMR (300 MHz, CDCl3) δ 7.73 (s, 2 H), 2.87 (m, 4 H), 2.15
(s, 6 H), 1.83 (m. 4 H); 13C NMR (75 MHz, CDCl3) δ 185.1, 143.5,
143.2, 129.7, 127.0, 29.7, 22.6, 12.8; HRMS calcd for C16H16 O2
(M+) 240.1150, found 240.1143.
Acknowledgment. Authors thank the National Institutes of
Health (grant CA91856-01A1) and the National Science Foun-
dation (grant CHE-0449478) for the support of this project, as
well as the Ohio Laboratory for Kinetic Spectroscopy for the
use of instrumentation and technical assistance. A.P. thanks the
McMaster Endowment for a research fellowship.
Supporting Information Available: Experimental details of
two-photon photolyses, complete ref 16b, and NMR spectra of
compounds 1-3 and 7-10. This material is available free of charge
via the Internet at http://pubs.acs.org.
2,3-(Octa-1,7-diyne-1,8-diyl)-5,6-dimethylquinone (2). A solu-
tion of 9 (0.1 g, 0.373 mmol) in 5 mL of acetonitrile was added to
JO061285M
J. Org. Chem, Vol. 71, No. 19, 2006 7421