Carbonyl- and carboxyl-substituted enediynes: Synthesis, computations, and thermal reactivity

Article abstract of DOI:10.1021/jo001417q

The influence of electron-withdrawing groups (carbonyl and carboxyl) at the alkyne termini on the reactivity of enediynes was investigated by a combination of experimental and computational techniques. While the general chemical reactivity of such enediynes, especially if non-benzannelated, is increased markedly, the thermal cyclization, giving rise to Bergman cyclization products, is changed little relative to the parent enediyne system. This is evident from kinetic measurements and from density functional theory (DFT, BLYP/6-31G* + thermal corrections) computations of the experimental systems which show that the Bergman cyclization barriers slightly (3-4 kcal/mol) increase, in contrast to earlier theoretical predictions. The effect on the endothermicities is large (ΔΔH_r = 7-12 kcal/mol). Hence, the increased reactivity of the substituted enediynes is entirely due to nucleophiles or radicals present in solution. This was demonstrated by quantitative experiments with diethylamine and tetramethyl piperidyl oxide (TEMPO) which both give fulvenes through 5-exo-dig cyclizations.

Full text of DOI:10.1021/jo001417q

1742
J . Org. Chem. 2001, 66, 1742-1746
Ca r bon yl- a n d Ca r boxyl-Su bstitu ted En ed iyn es: Syn th esis,
Com p u ta tion s, a n d Th er m a l Rea ctivity
Burkhard Ko¨nig,*,‡ Wolfgang Pitsch,‡ Michael Klein,‡ Rudolf Vasold,‡ Matthias Prall,§,| and
Peter R. Schreiner*,§,|
Institut fu¨r Organische Chemie, Universita¨t Regensburg, D-93040 Regensburg, Germany, Department of
Chemistry, University of Georgia, 1001 Cedar Street, Athens, Georgia 30602-2556, and
Institut fu¨r Organische Chemie, Universita¨t Go¨ttingen, D-37077 Go¨ttingen, Germany
prs@ chem.uga.edu
Received September 25, 2000
The influence of electron-withdrawing groups (carbonyl and carboxyl) at the alkyne termini on the
reactivity of enediynes was investigated by a combination of experimental and computational
techniques. While the general chemical reactivity of such enediynes, especially if non-benzannelated,
is increased markedly, the thermal cyclization, giving rise to Bergman cyclization products, is
changed little relative to the parent enediyne system. This is evident from kinetic measurements
and from density functional theory (DFT, BLYP/6-31G* + thermal corrections) computations of
the experimental systems which show that the Bergman cyclization barriers slightly (3-4 kcal/
mol) increase, in contrast to earlier theoretical predictions. The effect on the endothermicities is
large (∆∆Hr ) 7-12 kcal/mol). Hence, the increased reactivity of the substituted enediynes is entirely
due to nucleophiles or radicals present in solution. This was demonstrated by quantitative
experiments with diethylamine and tetramethyl piperidyl oxide (TEMPO) which both give fulvenes
through 5-exo-dig cyclizations.
In tr od u ction
considerably less attention. While Morokuma et al.6
theoretically predicted that replacement of the acetylenic
hydrogen atoms by generic electron-withdrawing sub-
stituents will lower the cyclization barriers, Schreiner
and Shaik detail in their recent valence-bond study that
only σ-electron-withdrawing substituents will be effec-
tive.7 Some experimental support for these predictions
comes from a study by Schmittel et al.8 who showed an
increase of thermal reactivity of 3,4-benzo-1,6-diphen-
ylenediynes by nitro substitution; chlorosubstitution at
the vinyl position (noting that chlorine is a weak σ-ac-
ceptor but a good π-donor) retards the rate of cyclization
owing to π-electron donation.9 Benzannelation at the site
of the double bond, i.e., benzoenediynes, increases the
endothermicity of the Bergman-cyclization significantly10
and even changes the rate-determining step of the overall
reaction.11 Replacement of the benzene ring of aromatic
Enediynes are highly potent antitumor-pharmacoph-
ores with an activity exceeding that of any other anti-
cancer drug by a factor of up to a 1000-fold.1 While this
serves well to cleave the DNA of tumor cells by Bergman-
cycloaromatization of the enediyne moiety to the active
species, the p-didehydrobenzene biradical (p-benzyne),
many other cells are also destroyed indiscriminately.
Hence, the factors controlling the formation of biradicals
from enediynes need to be determined to fine-tune the
activity of these highly promising drugs. The chemistry
of enediynes and their thermal cyclization reactions were
studied intensively over the past decade.2 The parent
reaction is now well understood both experimentally3 and
theoretically.4
The relationship between ring strain in the unsatur-
ated system and its reactivity were examined in detail
in a number of model studies.4g,h,5 However, electronic
substituent effects on enediyne reactivity has received
(4) (a) Lindh, R.; Persson, B. J . J . Am. Chem. Soc. 1994, 116, 4963-
4969. (b) Lindh, R.; Lee, T. J .; Bernhardsson, A.; Persson, B. J .;
Karlstro¨m, G. J . Am. Chem. Soc. 1995, 117, 7186-7194. (c) Kraka,
E.; Cremer, D. J . Am. Chem. Soc. 1994, 116, 4929-4936. (d) Cramer,
C. J .; Nash, J . J .; Squires, R. R. Chem. Phys. Lett. 1997, 277, 311-
320. (e) Cramer, C. J . J . Am. Chem. Soc. 1998, 120, 6261-6269. (f)
Gra¨fenstein, J .; Kraka, E.; Cremer, D. Chem. Phys. Lett. 1998, 288,
593-602. (g) Schreiner, P. R. Chem. Commun. 1998, 483-484. (h)
Schreiner, P. R. J . Am. Chem. Soc. 1998, 120, 4184-4190. (i) Gra¨fen-
stein, J .; Hjerpe, A. M.; Kraka, E.; Cremer, D. J . Phys. Chem. A 2000,
104, 1748-1761. (k) Kraka, E.; Cremer, D. J . Am. Chem. Soc. 2000,
122, 8245-8264.
* Corresponding authors. B. Ko¨nig: Fax: Int +49-941-943-1717.
E-mail: Burkhard.koenig@chemie.uni-regensburg.de. P. R. Schreiner:
Fax: Int +1-706-542-9454.
‡ Institut fu¨r Organische Chemie, Universita¨t Regensburg, Ger-
many.
§ University of Georgia, Athens.
| Universita¨t Go¨ttingen.
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U.; Klingberg, D.; Huang, D. Tetrahedron 1996, 52, 6453-6518. (b)
Nicolaou, K. C.; Smith, A. L. The Enediyne Antibiotics in Modern
Acetylene Chemistry; Stang, P J .; Diederich, F., Eds.; VCH: Weinheim,
1995; pp 203-283. (c) Maier, M. E. Synlett 1995, 13-26. (d) Smith, A.
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Chem. Eur. J . 2000, 6, 1446-1454.
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A 2001, 105, in press.
10.1021/jo001417q CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/03/2001

Carbonyl- and Carboxyl-Substituted Enediynes
J . Org. Chem., Vol. 66, No. 5, 2001 1743
Sch em e 1
Sch em e 3
Sch em e 4
Sch em e 2
diynes by quinones/dihydroquinones12 or uracil hetero-
cycles13 considerably changes the rates for thermal cy-
clization which was explained broadly by changes of the
electronic contribution to cyclization. To explore the
effects of electron-withdrawing substituents, we synthe-
sized enediynes functionalized with two of such groups:
methyl carbonyl and ethyl carboxylate. In the present
paper we present their synthesis, cyclization reactions,
and computations addressing the effect of carbonyl
substitution on the reactivity of these enediynes.
diyne can be avoided by alternative synthetic routes
superior for the preparation of 8 and 12 (Schemes 3 and
4). Thus, direct conversion of 1,6-bis(trimethylsilyl)hexa-
3-ene-1,5-diyne (7) into 8 proceeds in 63% yield by
reaction with acetyl chloride in the presence of AlCl3.17
Compound 12 was obtained by palladium-catalyzed
coupling of ethyl propyonate, protected as its ortho-ester
1018 and subsequent hydrolysis in ethanol. Neat solutions
of 8 and 12 are not stable and polymerize within minutes;
CCl4 solutions were used to obtain spectroscopic data. To
avoid major side reactions during the thermal cyclization
only enediynes 5 and 6 were employed for the thermoly-
ses.
Cycliza tion s In d u ced by Nu cleop h iles a n d Ra d i-
ca ls. The instability of 12 prompted us to investigate its
chemical reactivity more closely. Treatment of 12 with
diethylamine in dichloromethane at room temperature
gave spontaneously a mixture of isomeric fulvenes, as
concluded from the NMR spectra of the reaction mix-
tures; isolation and purification was not possible due to
the instability of the products. These most likely form
via Michael addition of the amine followed by intramo-
lecular 5-exo-dig cyclization. The nonthermally induced
formation of fulvene structures from enediynes19 has been
previously reported20 and similarly rationalized by Whit-
lock et al. for the addition of bromine to 1,2-bis(phenyl-
ethynyl)benzene.21
Resu lts a n d Discu ssion
Syn th esis. The title compounds 5 and 6 were synthe-
sized (Schemes 1 and 2) by standard methods starting
from 1,2-dibromobenzene (1)14 which was converted into
1,2-diethynylbenzene15 (4) by an improved large-scale
procedure using Pd-catalyzed coupling of 1,1-dimethyl-
hydroxy-2-propyne (2-methylbut-3-yn-2-ol, 2) followed by
base-induced retro-Favorskii rearrangement of the re-
sulting suspension in hot mineral oil. Two-fold deproto-
nation of the terminal alkynes with butyllithium, reaction
with ethanal followed by Swern oxidation gave diketone
5. Reaction of bis-lithiated 4 with chloroethylformate
yielded the desired bis-ester 6.
The non-benzannelated compounds 8 and 12 are ac-
cessible in a similar fashion starting from 1,6-bis-lithio
hexa-3-ene-1,5-diyne.16 However, preparation and han-
dling of stock solutions of the volatile hexa-3-ene-1,5-
Much to our surprise, a fulvene is also formed when a
solution of 12 was heated in the presence of the stable
(11) (a) Kaneko, T.; Takahashi, M.; Hirama, M. Tetrahedron Lett.
1999, 40, 2015-2018. (b) Thoen, K. K.; Thoen, J . C.; Uckun, F. M.
Tetrahedron Lett. 2000, 41, 4019-4024.
(17) (a) Stang, P. J .; Dixit, V.; Schiavelli, M. D.; Drees, P. J . Am.
Chem. Soc. 1987, 109, 1150-1156. (b) Hanack, M.; Hassdenteufel, J .
R. Chem. Ber. 1982, 115, 764-771.
(18) Boche, G.; Bigalke, J . Tetrahedron Lett. 1984, 25, 955-958.
(19) The thermally induced cyclization of enediynes to fulvenes as
alternative pathways to the Bergman cyclization was first suggested
by Schreiner et al. in ref 10b.
(20) (a) Blum, J .; Baidossi, W.; Badrieh, Y.; Hoffman, R. E.;
Schumann, H. J . Org. Chem. 1995, 60, 4738-4742. (b) Mu¨ller, E.;
Heiss, J .; Sauerbier, M.; Streichfuss, D.; Thomas, R. Tetrahedron Lett.
1968, 1195-1200. (c) Blum, J .; Badrieh, Y.; Greenwald, A.; Schumann,
H. Chem. Ber. 1992, 125, 667-674.
(21) Whitlock, H. W.; J . Org. Chem. 1969, 34, 879-886. (b) Whitlock,
H. W.; Sandwick, P. E. J . Am. Chem. Soc. 1966, 88, 4525-4526.
(12) Semmelhack, M. F.; Neu, T.; Foubelo, F. J . Org. Chem. 1994,
59, 5038-5047.
(13) Kim, C.-S,; Dietz, C.; Russel, K. C. Chem. Eur. J . 2000, 6, 1555-
1558.
(14) Brandsma, L.; Preparative Acetylenic Chemistry, 2nd ed.;
Elsevier: Amsterdam, 1988.
(15) (a) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara,
N. Synthesis 1980, 627-630. (b) Torii, S.; Hase, T.; Kuroboshi, M.;
Amatore, C.; J utand, A.; Kawafuchi, H. Tetrahedron Lett. 1997, 38,
7391-7394.
(16) Danishefsky, S. J .; Yamashita, D. S.; Mantlo, N. B. Tetrahedron
Lett. 1988, 29, 4681-4684.

1744 J . Org. Chem., Vol. 66, No. 5, 2001
Ko¨nig et al.
Sch em e 5
them have the same mass as the trapped Bergman
product. These results indicate that carbonyl- and car-
boxyl-substitution of enediynes mainly undergo Bergman
cyclization but substitution opens reaction pathways
other than the well-established thermal C1-C6 cycliza-
tion.
To investigate the thermal reaction of compound 5 and
6 more closely we followed the reaction by kinetic
measurements using the previously described HPLC
assay.23 The determined half-life for compound 4 under
the employed conditions (162 °C, 100 equiv of cyclohexa-
diene in dichlorobenzene) of t1/2 ) 29 min is in good
agreement with reported values.3,23 The half-lifes for
compounds 5 and 6 under identical conditions, t1/2 ) 481
min and t1/2 ) 660 min, respectively, are longer which
shows that the terminal carbonyl- and carboxyl-substitu-
tion does not increase the thermal reactivity of the
enediyne system.24 On the contrary, the thermal reactiv-
ity is decreased (vide infra).25
Sch em e 6
Com p u ta tion s. To support and elucidate the experi-
mental findings further, we also computed the Bergman
and the five-membered ring closures for the parent as
well as for the carbonyl- and carboxyl-substituted ene-
diynes (Scheme 7). All calculations were performed with
Gaussian9826 using Becke’s pure gradient-corrected ex-
change functional27 and the Lee-Yang-Parr nonlocal
correlation functional28 (BLYP) with a 6-31G* basis set
which has shown to give good results for the parent
reaction and related biradical cyclizations.4h,i,7,10b,29
A
restricted approach was used for geometry optimizations,
energy evaluations and frequency analyses of the reac-
tants and transition structures (TS) of the Bergman
product, while the biradical products as well as the TS
of the five-membered ring closure were computed by an
unrestricted broken spin ansatz (BS-UBLYP).10b
As indicated in Table 1 the cyclization barriers for the
radical TEMPO (tetramethyl piperidyl oxide). From the
reaction mixture was isolated the TEMPO-substituted
fulvene 15 in 25% yield as a mixture of syn- and anti-
isomers (Scheme 5). A possible rationale for the formation
of 15 may be the reversible addition of TEMPO to the
triple bond followed by rapid 5-exo-dig cyclization and
trapping of the product by effective hydrogen abstrac-
tion.22
Th er m olyses. Solutions of compound 5 and 6 in
dichlorobenzene and 1,4-cyclohexadiene were heated in
sealed tubes to 200 °C for several hours. Analysis of the
crude reaction mixtures by GC/MS revealed the forma-
tion of the major reaction products 16 and 17 in 70 and
90% yield, respectively (Scheme 6). Preparative isolation
and spectroscopic characterization showed that both
enediynes underwent thermal C1-C6 Bergman cycliza-
tion. In the case of 5 hydrogenation of one of the triple
bonds gave the partially reduced starting material as a
reaction side product in ca. 20% yield. In contrast to the
thermal cyclization of 1,2-diethynylbenzene (4), which
under identical conditions gave naphthalene in more
than 99% yield as shown by GC/MS, the thermal reac-
tions of 5 and 6 are less clean giving rise to the formation
of 10-15 side products, in an overall amount of 10%. Due
to the very small amount of material of the individual
reaction side products, it was not possible to assign their
structures, but GC/MS analysis showed that some of
substituted enediynes are slightly higher (3-4 kcal mol-1
)
than that of the parent system; the endothermicities are
raised by ∼8 kcal mol-1 for the carbonyl and by ∼9 kcal
mol-1 for the carboxyl substituent. As shown previously,10
benzannelation merely affects the barrier heights for
Bergman cyclization (∆∆H‡ < 1 kcal mol-1) but the
biradical products become significantly more endothermic
(∆∆Hr ∼ 6-10 kcal mol-1). The barriers for substituted
benzannelated enediynes are virtually unchanged com-
(23) (a) Choy, N.; Kim, C.-S.; Ballestero, C.; Artigas, L.; Diez, C.;
Lichtenberger, F.; Shapiro, J .; Russel, K. C. Tetrahedron Lett. 2000,
41, 6955-6958. (b) Wisniewski-Grissom, J .; Calkins, T. L.; McMillen,
H. A.; J iang, Y. J . Org. Chem. 1994, 59, 5833-5835. (c) Kim, C.-S.;
Russel, K. C. J . Org. Chem. 1998, 63, 8229-8234.
(24) The corresponding rate constants are k ) 3.9 × 10-4 s-1 (4), k
) 2.4 × 10-5 s-1 (5), and k ) 1.7 × 10-5 s-1 (6).
(25) Differential scanning calorimetry measurements lead to the
same conclusion. Ko¨nig, B.; Kro¨ner, J . Unpublished results.
(26) Gaussian98: Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.;
Scuseria, G. E.; Robb, M. A.; Cheeseman, J . R.; Zakrzewski, V. G.;
Montgomery, J . A.; Stratmann, R. E.; Burant, J . C.; Dapprich, S.;
Millam, J . M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.;
Tomasi, J .; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli,
C.; Adamo, C.; Clifford, S.; Ochterski, J .; Petersson, G. A.; Ayala, P.
Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari,
K.; Foresman, J . B.; Cioslowski, J .; Ortiz, J . V.; Stefanov, B. B.; Liu,
G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R.
L.; Fox, D. J .; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara,
A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; J ohnson, B.; Chen,
W.; Wong, M. W.; Andres, J . L.; Gonzalez, C.; Head-Gordon, M.;
Replogle, E. S.; Pople, J . A. Gaussian, Inc.: Pittsburgh, PA, 1999.
(27) Becke, A. D. Phys. Rev. A 1988, 38, 3098-3100.
(22) Our attempts to use other radical initiators, such as AIBN, to
induce the cyclization were not successful and gave only polymeric
products.
(28) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785-789.
(29) Schreiner, P. R.; Prall, M. J . Am. Chem. Soc. 1999, 121, 8615-
8627.

Carbonyl- and Carboxyl-Substituted Enediynes
J . Org. Chem., Vol. 66, No. 5, 2001 1745
Ta ble 1. BLYP /6-31G* Com p u ted ∆H298 Va lu es (k ca l
m ol-1) for th e Cycliza tion of Ca r bon yl-Su bstitu ted
En ed iyn es to Com p a r ed to th e P a r en t System
tion). The thermal reactivities of 5 and 6 are similar to
the parent system, but are overall even more unfavorable.
Hence, in agreement with our earlier theoretical predic-
tions, π-acceptors do not increase the thermal reactivity
of enediynes. The σ-acceptor ability of the subsituents
examined here apparently is outbalanced by the unfavor-
able π-effects. A study concerning σ-acceptors is currently
underway in our laboratories. The major effect of carbo-
nyl- and carboxyl-substitution is an increased tendency
of enediynes to undergo reactions other than the Berg-
man cyclization.
R )
H
CHO
COOMe
enediynes
Bergman TS
0.0
24.3a
7.3a
0.0
27.0
14.8
-
30.7
0.0
0.0
28.8
16.0
-
37.2
0.0
28.8
21.7
37.4
34.2
Bergman product
fulvene TS
fulvene product
benzo-enediynes
Bergman TS
Bergman product
fulvene TS
fulvene product
c
c
40.1b
40.5
0.0
23.6
13.2
36.3b
36.5
27.5
20.2
c
-
c
-
Exp er im en ta l Section
a
Experimental values33 at this temperature: barrier ) 28.2 kcal
mol-1, endothermicity ) 8.5 kcal mol-1 The relative energy of
b
Gen er a l. Melting points were taken on a hot-plate micro-
scope apparatus and are not corrected. NMR spectra were
recorded at 400 MHz (1H) and 100 MHz (13C) in [D]-chloroform
solutions unless otherwise stated. The multiplicity of the 13C
signals was determined with the DEPT technique and quoted
as: (+) for CH3 or CH, (-) for CH2 and (Cquat) for quaternary
carbons. CC means column chromatography; PE means petrol
ether with a boiling range of 60-70 °C.
the TS is lower than that of the product because of the inclusion
of ZPVEs, which are quite different for the two states. What this
means is that the fulvene product simply would not form because
there is no barrier for ring opening of the biradical product.
c Despite extensive efforts, these structures could not be located
due to the large endothermicities of the reactions.
Sch em e 7
1,2-Dieth yn ylben zen e (4). A solution of 330 (19.2 g, 80
mmol) in 2 mL of CH2Cl2 was added to 60 mL of mineral oil
and 2.5 g of finely grounded KOH. The reaction mixture was
heated in vacuo (200 Pa) to 160 °C, and the crude product was
collected in the cooled receiver. CC (PE) gave 4 (5.00 g) in 50%
yield.15
1,2-Bis(3-h yd r oxy-1-bu tyn yl)ben zen e. To a solution of
4 (511 mg, 4 mmol) in 20 mL of dry THF was added at -78 °C
MeLi (15 mL, 1.4 M, 21 mmol), and the mixture was stirred
for 10 min. Freshly distilled ethanal (7 mL, 5.5 g, 125 mmol)
was slowly added, and the reaction mixture was allowed to
warm to room temperature. Aqueous NH4Cl solution (30 mL)
was added, the reaction mixture was extracted with diethyl
ether (3 × 50 mL), and the combined organic phases were dried
over Na2SO4. CC (PE:Et2O ) 1:1; Rf ) 0.11) of the crude
product gave 460 mg (54%) of 1,2-bis(3-hydroxy-1-butynyl)-
benzene, as a colorless oil. 1H NMR: δ 7.31-7.26 (m, 2H),
pared to their respective parent systems. A possible
cyclization of enediynes to fulvenes apparently is not
viable for systems with electron-withdrawing substitu-
ents examined here.10b Despite extensive efforts, we were
unable to locate the transition structures for this type of
cyclization due to an enormous energy increase along this
reaction mode. This is emphasized by the vanishing
barrier (including thermal and ZPVE corrections) for the
parent case (R ) H) for both the enediyne and the
benzoenediyne (Table 1). Hence, fulvenes cannot form
thermally from the substituted enediynes described in
the present study.
This computational analysis also demonstrates that the
increased chemical reactivity for the carbonyl- and car-
boxyl-substituted enediynes is not based on an increased
thermal sensitivity and must instead be due to the
presence of other reagents such as bases or radicals which
are able to induce the observed cyclizations.
6.80-6.76 (m, 2H), 4.77-4.71 (m, 2H), 1.50-1.48 (m, 6H); 13
C
NMR δ 24.4 (+), 24.5 (+), 58.9 (+), 58.9 (+), 83.0 (Cquat), 96.6
(Cquat), 126.3 (Cquat), 127.8 (+), 128.0 (+), 128.3 (+), 131.4 (+);
IR (KBr): ν ) 3330 cm-1, 2982, 3063, 1480, 1444, 1371, 1330,
759; UV/vis (CH3CN): λmax (lg ꢀ) ) 192 nm (4.055), 226 (4.494),
232 (4.648), 248 (4.010), 254 (4.068), 260 (4.121), 272 (4.069),
280 (3.319), 284 (3.064); MS (70 eV): m/z (%): 127 (100), 170
(48), 214 (2) [M+]. Anal. Calcd for C14H14O2 (214.1): C 78.47;
H 6.59. Found: C 78.57; H 6.61.
1,2-Bis(1-bu tyn -3-on yl)ben zen e (5). To a solution of
DMSO (313 mg, 4 mmol, 0.29 mL) in CH2Cl2 (5 mL) was added
at -78 °C oxalyl chloride (381 mg, 3 mmol, 0.26 mL), and the
mixture was stirred for 15 min. 1,2-Bis(3-hydroxy-1-butynyl)-
benzene (150 mg, 0.7 mmol) dissolved in CH2Cl2 (5 mL) was
added, the reaction mixture was stirred for 15 min at -78 °C,
triethylamine (810 mg, 8 mmol, 1.1 mL) was added, and the
mixture was allowed to warm to room temperature. Diethyl
ether (30 mL) and water (10 mL) were added, the mixture was
extracted with diethyl ether (3 × 30 mL), and the combined
organic phases were dried over NaSO4 and evaporated in a
vacuum. The crude product was purified by CC (PE:Et2O )
2:1; Rf ) 0.4) to yield 120 mg (82%) of 5, as a yellow solid, mp
Con clu sion s
Enediynes with carbonyl and carboxyl substitutents at
the terminal acetylenic carbon atoms were prepared by
reaction of the corresponding bis-lithium acetylides with
suitable electrophiles or palladium-catalyzed coupling of
propynoate-ortho-esters with 1,2-dihalides and subse-
quent hydrolysis. While enediynes 8 and 12 are not stable
as neat compounds due to their high tendency to poly-
merize, the benzannelated enediynes 5 and 6 were
isolated in pure form. Thermolysis of 5 and 6 in the
presence of a hydrogen donor yielded the hydrogen-
trapped products of a C1-C6 cyclization (Bergman reac-
1
3
35 °C. H NMR (200 MHz, C6D6) δ 2.09 (s, 6H), 6.68 (dd, J )
4
3
4
5.7 Hz, J ) 3.3 Hz, 2H), 7.07 (dd, J ) 5.8 Hz, J ) 3.3 Hz,
2H). 13C NMR (100 MHz, C6D6) δ 32.4 (+), 86.1 (Cquat), 92.7
(Cquat), 124.5 (Cquat), 130.2 (+), 133.4 (+), 183.0 (Cquat). IR
(KBr): ν ) 3450 cm-1, 2208, 2171, 1671, 1650, 1359, 1293.
UV/vIS (CH3CN): λmax (lg ꢀ) ) 198 nm (4.239), 228 (4.180),
240 (4.259), 244 (4.278), 250 (4.286), 256 (4.404), 292 (4.114),
304 (4.035), 320 (3.574), 330 (3.002). MS (EI, 70 eV) m/z (%):
167 (7) [M-COCH3+], 195 (100) [M-CH3+], 210 (72) [M+].
(30) Huynh, C.; Linstrumelle, G. Tetrahedron 1988, 44, 6337-6344.

1746 J . Org. Chem., Vol. 66, No. 5, 2001
Ko¨nig et al.
HRMS: C14H10O2: calcd 210.0680; found 210.0678. Anal. Calcd
for C14H10O2 (210.1): C 79.98; H 4.79. Found: C 79.99; H 4.78.
3-(2-(Eth oxycar bon yleth yn yl)ph en yl)pr op-2-yn oic Acid
Eth yl Ester (6). To a solution of 4 (500 mg, 3.96 mmol) in 20
mL of THF was slowly added n-BuLi (5.3 mL, 7.9 mmol, 1.5
mol/L) at -35 °C. After stirring for 20 min, a solution of ethyl
formate (1.5 mL, 15.9 mmol) in 5 mL of THF was added
dropwise, and the reaction mixture was stirred for additional
30 min at this temperature, allowed to warm to room tem-
perature, and poured into 150 mL of aqueous NH4Cl solution.
The aqueous phase was extracted four times with Et2O (40
mL), the combined organic phases were dried over Na2SO4,
and the solvent was removed in a vacuum. The crude product
was purified by CC on silica (PE:Et2O 3:1) to yield 740 mg
(70%) of 6 (Rf ) 0.38) as a colorless solid; mp ) 46 °C. 1H NMR
δ 1.34 (t, 6H, CH3, J ) 7.12 Hz); 4.30 (q, 4H, CH2, J ) 7.12
Hz); 7.43 (2H, CH); 7.60 (2H, CH). 13C NMR δ 14.0 (+), 62.2
(-), 82.7 (Cquat), 84.7 (Cquat), 123.6 (Cquat), 130.2 (+), 133.4 (+);
153.6 (Cquat). IR (KBr): ν ) 2941 cm-1, 2213, 1705, 1194. UV
(CH3CN): λmax (lg ꢀ) ) 196 nm (4.311), 228 (sh, 4.391), 234
(4.473), 246 (4.462). MS (EI) (70 eV), m/z (%): 270 (22) [M+],
225 (36) [M - OCH2CH3+], 197 (24) [M - COOCH2CH3+], 126
(100). Anal. Calcd for C16H14O4 (270.28): C 71.10 H 5.22.
Found: C 71.11 H 5.26.
Dec-4-en ed i-3,6-yn e-2,9-d ion e (8). To a solution of 1,6-
bis-trimethylsilyl-3-ene-1,5-diyne (7) (0.22 g, 1 mmol) in 15 mL
of anhydrous CH2Cl2 was added acetyl chloride (0.39 g, 5.00
mmol) at -20 °C. AlCl3 (132 mg, 1 mmol) was added, and the
reaction mixture was stirred at -20 °C for 2 h. The solvent
was removed in vacuo, and the crude product was purified by
CC on silica (Rf ) 0.39; PE: Et2O 1:1) to give 8 (63%, 0.10 g),
as a rapidly decomposing oil; 1H NMR (400 MHz, benzene-d6)
δ 2.25 (s, 6H), 6.03 (s, 2H); MS (EI) (70 eV), m/z (%) 160 (57)
[M+], 145 (100) [M - CH3+].
product was chromatographed on silica (PE:Et2O 3:1; Rf )
0.23) to yield 46 mg (72%) of 12 as a colorless oil. 1H NMR
3
(400 MHz, C6D6) δ 0.79 (t, 6H, CH3, J ) 7.3 Hz), 3.79 (q, 4H,
CH2, 3J ) 7.3 Hz), 5.20 (s, 2H, CH). 13C NMR (100 MHz, C6D6)
δ 13.7 (+), 62.0 (-), 80.8 (Cquat), 89.5 (Cquat), 121.4 (+), 153.1
(Cquat).
E/Z-F u lven e 15. A mixture of 12 (100 mg, 0.45 mmol) and
TEMPO (702 mg, 4.5 mmol) in 80 mL of degassed toluene was
refluxed under N2 for 5 h, the solvent was removed in vacuo,
and the crude product was purified by CC (PE/Et2O 2:1) on
silica to yield 52 mg (30%) of 17 (Rf ) 0.35) as a red oil. 1H
3
NMR δ 1.03 (s, 6H), 1.28 (m, 12H), 1.58 (m, 6H), 4.14 (q, J )
3
7.3 Hz, 2H); 4.23 (q, J ) 7.3 Hz, 2H); 5.85 (d, J 3 ) 12.6 Hz,
3
1H); 6.25 (m, 1H); 7.81 (d, J ) 12.5 Hz, 1H). 13C NMR δ 14.0
(+), 14.3 (+), 16.9 (-), 21.9 (+), 31.8 (+), 39.5 (-), 59.8 (-),
60.8 (Cquat), 61.79 (-), 84.9 (Cquat), 87.2 (Cquat), 99.8 (+), 108.9
(+), 132.8 (+); 153.8 (Cquat), 166.9 (Cquat), 167.6, (Cquat). IR
(neat): ν ) 2935 cm-1, 2204, 1708. UV (CH3OH): λmax (lg ꢀ) )
206 nm (3.991), 282 (4.049), 306 (4.164), 374 (2.747). MS (EI)
(70 eV), m/z (%): 377 (14) [M+], 362 (100) [M - CH3], 348 (44)
[M - CH2CH3], 332 (6) [M - OCH2CH3]. C21H31NO5 (377.48):
HRMS: calcd 377.2202; found 377.2194.
3
3
2,3-Dia cetyln a p h th a len e (16). A solution of 5 (50 mg, 0.24
mmol) and 1 mL of 1,4-cyclohexadiene in 5 mL of dry toluene
was heated in a sealed tube to 190 °C for 3 h. The solvent was
removed in vacuo, and the crude reaction mixture was
analyzed by GC/MS. The major reaction product 16, and the
partially hydrogenated starting material was obtained as
inseparable 6:1 mixtures by CC (PE:Et2O, 2:1) in 80% isolated
yield. The spectroscopic data of 16 are identical to the reported
values.31 The structure of the partially hydrogenated starting
material was assigned from spectroscopic data and mass
spectrometry. Due to the small amount of material and the
very similar polarity compared with 16, it was not possible to
obtain this reaction side product in analytically pure form.
2,3-Dieth oxyca r bon yln a p h th a len e (17). A solution of 6
(50 mg, 0.2 mmol) and 1 mL of 1,4-cyclohexadiene in 5 mL of
dry toluene was heated in a sealed tube to 220 °C for 3 h. The
solvent was removed in vacuo, and the crude reaction mixture
was analyzed by GC/MS. The major reaction product 17 was
isolated by CC (PE:Et2O, 2:1) in 90% yield. The spectroscopic
data are identical with the reported values.32
1,2-Bis(3,3,3-tr ieth oxyp r op -1-yn yl)eth en e (11). To a so-
lution of Pd(PPh3)4 (831 mg, 0.72 mmol), CuI (344 mg, 1.81
mmol), 3,3,3-triethoxypropyne18 (4.66 g, 27.08 mmol), and 8
mL (81.2 mmol) of n-BuNH2 in 80 mL of toluene at 0 °C under
dinitrogen was added 1,2-dichloroethene (0.68 mL, 9 mmol)
dropwisely. The ice bath was removed, and the dark reaction
mixture was allowed to warm to room temperature and stirred
for additional 15 h. The reaction mixture was filtered through
a plug of Celite, the solvent was removed in vacuo, and the
residue was purified over silica (Et2O with 1% NEt3). The first
fraction (Rf ) 0.8) gave 1.49 g (45%) of 11 as a light yellow oil.
Ack n ow led gm en t. This work was supported by the
Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie.
3
1H NMR (200 MHz, acetone-d6) δ 1.16 (18H, CH3, t, J ) 7.1
Hz), 3.67 (12H, CH2, q, 3J ) 7.1 Hz), 5.99 (2H, CH, s). 13C NMR
(50 MHz, acetone-d6) δ 15.2 (+), 59.5 (-), 80.8 (Cquat), 92.6
(Cquat), 110.0 (Cquat), 121.0 (+). IR (neat): ν ) 2933 cm-1, 2224,
1391. UV (CH3OH): λmax (lg ꢀ) ) 192 nm (3.764), 260 (4.051),
272 (4.000), 234 (sh, 3.870). MS (EI) (70 eV), m/z (%): 323 (20)
[M - OEt+], 249 (88) [M - (OEt)2 - Et+], 221 (44) [M -
C(OEt)3+], 175 (100) [M - C(OEt)3 - OEt+], 147 (62) [C(O-
Et)3+].
Su p p or tin g In for m a tion Ava ila ble: Copies of proton,
carbon, and DEPT NMR spectra of compounds 6, 8, 11, 12,
and 15. All absolute energies and Cartesian coordinates for
computed structures. This material is available free of charge
via the Internet at http://pubs.acs.org.
J O001417Q
Oct-4-en e-2,6-d iyn ed oic Acid Dieth yl Ester (12). Com-
pound 11 (100 mg, 0.29 mmol) was dissolved in 50 mL of
EtOH/H2O (1:1), and two drops of TFA were added. The
reaction mixture was stirred for 1 h at room temperature,
extracted with ethyl acetate, washed with brine, and dried over
Na2SO4, and the solvent was removed in vacuo. The crude
(31) Rigaudy, J .; Baranne-Lafont, J .; Ranjon, A.; Casper, A. Bull.
Soc. Chim. Fr. 1984, 2 , 187-194.
(32) Pomerantz, M.; Dassanayake, N. L. J . Am. Chem. Soc. 1980,
102, 678-682.
(33) Roth, W. R.; Hopf, H.; Horn, C. Chem. Ber. 1994, 127, 1765-
1769.