Synthesis and thermal cyclization of an enediyne-sulfonamide

Article abstract of DOI:10.1016/j.tet.2003.11.078

The synthesis of an enediyne sulfonamide by alkylidene carbene rearrangement is reported. The compound cyclizes thermally to give the Bergman product, which was prepared independently for comparison. Like other σ-acceptor substituents at the enediyne alkyne termini, such as fluoride, oxonium or ammonium groups, the sulfonamide moiety enhances the reactivity for thermal Bergman cyclization as shown by the cyclization kinetic of the title compound.

Full text of DOI:10.1016/j.tet.2003.11.078

Tetrahedron 60 (2004) 1087–1092
Synthesis and thermal cyclization of an enediyne-sulfonamideq
*
¨
Michael Klein and Burkhard Konig
¨ ¨
Institut fur Organische Chemie, Universitat Regensburg, D-93040 Regensburg, Germany
Received 8 September 2003; revised 17 November 2003; accepted 25 November 2003
Abstract—The synthesis of an enediyne sulfonamide by alkylidene carbene rearrangement is reported. The compound cyclizes thermally to
give the Bergman product, which was prepared independently for comparison. Like other s-acceptor substituents at the enediyne alkyne
termini, such as fluoride, oxonium or ammonium groups, the sulfonamide moiety enhances the reactivity for thermal Bergman cyclization as
shown by the cyclization kinetic of the title compound.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
are stable and crystalline due to the strong electron acceptor
properties of the sulfone moiety.13 The required s-acceptor
effect of the nitrogen atom on the enediyne system remains,
while the p-donating character of the nitrogen atom is
reduced similar to an ammonium ion.14 For the synthesis of
sulfonamide benzoenediynes two general routes can be
envisaged: the coupling of an alkyne sulfonamide to a
1-bromo-2-ethynyl-benzene by the Sonogashira–Hagihara
method (see Scheme 1, route 1), or the formation of
the carbon–nitrogen bond by either copper-catalyzed
N-alkynylation of a sulfonamide15 (see Scheme 1, route 2)
or the reaction of alkynyl-phenyl-iodonium triflate salts
with sulfonamides16 (see Scheme 1, route 3). A
Sonogashira–Hagihara coupling of ethynyl sulfonamides
has not been reported in the literature so far and all of our
initial attempts to couple N-Ts,N-Bn-ethynylamine17 or its
tri-methyl-tin derivative to iodo- or bromoarenes in
transition-metal mediated processes failed under various
reaction conditions. The copper-catalyzed N-alkynylation
of sulfonamides was recently described to be less efficient
than the N-alkynylation of lactams.15 Therefore, the target
enediyne was prepared via the alkynyl-phenyl-iodonium
triflate salt.
Apart from the ring strain, the Bergman cyclization is quite
sensitive to substituent effects.1 Substituents at the alkyne
termini are generally more effective than at the vinyl
positions,2 but heteroarene anellation can have a large effect
on the energetics, too.3–5 Morokuma et al.6 have predicted
that electron acceptor substituents at the terminal alkyne
carbons of an enediyne should facilitate its thermal
cyclization. This prediction was narrowed to strong
s-acceptors and/or p-donors by Schreiner et al.7 A doubly
fluoro-substituted enediyne was expected to undergo an
exothermic Bergman cyclization, which was recently
confirmed experimentally by Sander et al.8 Other structures
predicted to show enhanced reactivity in thermal cycliza-
tions are enediynes with protonated yne-ol (onium-ion) or
protonated yne-amine (ammonium-ion) sub-structure.9
These structures are not stable and have, to the best of our
knowledge, not been reported in the literature so far. We
describe here the synthesis of the first stabilized enediyne
with yne-amine substructure and its properties in thermal
cyclization.10
Starting material 1 was prepared following a modified
literature procedure.18 The TMS-alkyne was transformed
with iodosobenzene into the phenyl iodonium triflate in 64%
yield. The iodonium salt was then reacted in toluene with
lithium N-Bn,N-Ts-amide to give sulfonated, benzylated
alkyneamide 4 in 46%. The same reaction in THF was much
less efficient. Mechanistically, this step consists most likely
of an addition of the lithium amide to the alkyne in b
position giving a alkyldiene-carbene iodonium ylide, which
eliminates phenyl iodide. The so formed alkylidene carbene
rearranges by movement of the bromoaryl moiety to 4. To
complete the enediyne system, an alkyne must be
introduced at the position of the remaining bromine
2. Results and discussion
Yne-amines are very sensitive to hydrolysis.11,12 This
prohibits the characterization and property investigation of
yne-amine substituted enediynes. Therefore yne-sulfona-
mide structures were selected as target compounds. They
q Supplementary data associated with this article can be found at doi:
10.1016/j.tet.2003.11.078
Keywords: Enediyne; Yne-amine; Carbene rearrangement; Thermal
cyclization.
*
Corresponding author. Tel.: þ49-941-943-4576; fax: þ49-941-943-1717;
e-mail address: burkhard.koenig@chemie.uni-regensburg.de
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.11.078

¨
M. Klein, B. Konig / Tetrahedron 60 (2004) 1087–1092
1088
Scheme 1.
Scheme 2.
Scheme 3.

¨
M. Klein, B. Konig / Tetrahedron 60 (2004) 1087–1092
1089
substituent. Standard Sonogashira–Hagihara coupling con-
ditions with TMS-acetylene lead to decomposition of 4, but
a base-free Stille-type coupling protocol with 5 gave ene-
diyne 6 in good yield. Finally, the TMS group was removed
with K2CO3 in MeOH/water to give 7 in moderate yield.19
Our attempts to prepare a twofold substituted enediyne-bis-
sulfonamide20 were not successful. The bis-iodoniumphenyl
triflate 9 did not undergo a twofold rearrangement if treated
with lithiated N-Bn,N-Ts-amine. Only compound 7 could be
identified as reaction product, although in poor yield. A
decreased ability of the substituted aryl moiety to undergo
the rearrangement from the alkylidene carbene to the alkyne
may explain the observation (Schemes 2 and 3).21
t¼44 min of the compound at this reaction temperature.23
For the parent enediyne system benzo-1,2-diyne an
activation energy for thermal cyclization of Ea¼105.1 kJ/
mol has been reported. This corresponds to a rate constant of
k¼9.77£1025 s21 and a half life of t¼118 min at 141 8C.
Although the steric hindrance for a cyclization is signifi-
cantly increased in 7 due to the large N-benzyl and N-tosyl
substituents,24 the reactivity of 7 is comparable or even
higher than that of benzo-1,2-diyne. This supports the
theoretical prediction7 that s-acceptor substituents at the
terminal alkyne carbon atoms of an enediyne increase
the thermal reactivity of the system. The alkyne sulfona-
mide substituent described here adds another option to
electronically modify thermal enediyne reactivity.
The thermal cyclization reaction of 7 was investigated by
heating solutions of the compound (c¼1.6£1022 mol/l) in
benzene/cyclohexadiene (ratio 2/1) to 141 8C. The conver-
sion of the starting material and product formation was
followed by HPLC analysis of the reaction mixture
(Scheme 4).22 The expected Bergman cyclization product
11 was synthesized independently from 12 for comparison
using standard transformations (see Scheme 5 and Section 3
for details).
3. Experimental
3.1. General
1
All H NMR spectra were recorded at 400 MHz, all 13C
NMR spectra at 100 MHz in CDCl3 unless otherwise stated.
The multiplicity of the 13C signals was determined with the
DEPT technique and quoted as: (þ) for CH3 or CH, (2) for
CH2 and (Cquat) for quaternary carbons. CC means column
chromatography on silica gel. PE means petrol ether with a
boiling range of 60–70 8C. EA means ethyl acetate. All
reactions were carried out under nitrogen atmosphere.
3.1.1. (2-Bromophenylethynyl)trimethylsilane (1). After
stirring a mixture of PdCl2(PPh3)2 (351 mg, 0.50 mmol),
CuI (191 mg, 1 mmol) and 1,2-dibromobenzene (1.21 ml,
2.36 g, 10 mmol), dissolved in 5 ml of THF and 5 ml of
triethylamine at room temperature for 10 min, ethynyl-
trimethylsilane (1.55 ml, 1.08 g, 10 mmol) was added. The
reaction mixture was stirred at 60 8C for 16 h. After cooling
to room temperature, the mixture was diluted with CH2Cl2,
and washed with aqueous NH4Cl. The combined organic
phases were dried over Na2SO4, the solvent was removed
and CC with hexanes gave 1 as a yellow oil (1.47 g, 58%).
Scheme 4.
The HPLC analysis confirmed the formation of 11 from 7,
by identical retention times, UV- and mass spectra to the
independently prepared material. A kinetic analysis of the
reaction following the consumption of the starting material
under pseudo first order conditions revealed a rate constant
of k¼2.66£1024 s21 which corresponds to a half life time of
Scheme 5.

¨
M. Klein, B. Konig / Tetrahedron 60 (2004) 1087–1092
1090
Rf¼0.34 (hexanes). All spectroscopic data are identical to
d¼0.19 (s, 9H, Si(CH3)3), 2.42 (s, 3H, CH3), 4.62 (s, 2H,
CH2), 7.12–7.46 (m, 11H), 7.76–7.84 (m, 2H). 13C NMR
(100 MHz, C6D6): d¼21.7 (þ), 56.2 (2), 70.5 (Cquat), 87.1
(Cquat), 98.1 (Cquat), 103.6 (Cquat), 124.2 (Cquat), 125.7
(Cquat), 126.9 (þ), 127.8 (þ), 128.1 (þ), 128.4 (þ), 128.6
(þ), 128.9 (þ), 129.7 (þ), 131.0 (þ), 132.7 (þ)), 134.6
(Cquat), 135.0 (Cquat), 144.6 (Cquat). MS (EI) m/z (%): 457
(24) [Mþ], 302 (13) [M2C7H7SO2þ], 91 (100). C27H27-
NO2SSi (457.15): calcd C 70.86 H 5.95 N 3.06; found C
70.02 H 6.17 N 2.98.
the ones reported in the literature.18
3.1.2. (2-Bromophenylethynyl)phenyliodonium triflate
(3). To a stirred suspension of iodosobenzene (1.57 g,
7.14 mmol) in 50 ml of CH2Cl2, TMS-OTf (1.39 ml, 1.59 g,
7.14 mmol) and then 1 (1.80 g, 7.14 mmol) were added via
syringe at 220 8C over 10 min. After warming to room
temperature, the reaction mixture was concentrated and
15 ml of cold ether was added. The precipitated solid was
filtered off and washed with cold ether. The residue was
dried under reduced pressure to give a colorless solid
3.1.5. N-Benzyl-N-(2-ethynyl-phenylethynyl)-4-methyl-
(156 mg,
(2.43 g, 64%). Mp: 94–95 8C. IR (KBr): n¼2929 cm21
,
benzenesulfonamide (7). Compound
6
˜
2859, 2374, 2342, 2165, 1688, 1634, 1465, 1436, 1263,
1178, 1037, 990, 755, 735, 678, 649, 580, 522. UV/Vis
0.34 mmol) was dissolved in 20 ml of methanol and
K2CO3 (140 mg, 1.01 mmol) was added. After stirring for
1 h at room temperature, the reaction mixture was diluted
with EtOAc and washed three times with H2O. The organic
phase was dried over Na2SO4 and the solvent was removed.
The residue was purified by CC with 9:1 hexanes/Et2O to
yield 7 as a light yellow oil (85 mg, 65%). Rf¼0.18 (9:1
1
(CH3CN): lmax (log 1)¼209 nm (3.873), 249 (3.520). H
NMR (250 MHz, CDCl3): d¼7.26–7.37 (m, 3H), 7.50–
7.69 (m, 5H), 8.16–8.21 (m, 2H). 13C NMR (60 MHz,
CDCl3): d¼36.4 (Cquat), 105.7 (Cquat), 117.3 (Cquat), 122.1
(Cquat), 126.6 (Cquat), 127.4 (þ), 130.3 (Cquat), 132.4 (þ),
132.5 (þ), 132.7 (þ), 132.8 (þ), 134.2 (þ), 135.1 (þ),
137.5 (þ). MS (ESI) m/z (%): 385 (97) [Mþ2CF3SO3], 383
(100) [Mþ2CF3SO3], 258 (18) [Mþ2CF3SO3–I], 256 (19)
[Mþ2CF3SO3–I]. C15H10BrF3IO3S (534.11): calcd C
33.80 H 1.70; found C 33.61 H 1.71.
hexanes/Et O). IR (film): n¼3283 cm21, 3065, 3033, 2925,
˜
2
2233, 2108, 1923, 1597, 1366, 1170, 1088, 1021, 799, 759,
653, 598. UV/Vis (CH3CN): lmax (log 1)¼227 nm (4.715),
254 (4.281), 261 (4.240). 1H NMR (300 MHz, CDCl3):
d¼2.43 (s, 3H, CH3), 3.12 (s, 1H, CH), 4.63 (s, 2H, CH2),
7.14–7.45 (m, 11H), 7.81–7.85 (m, 2H). 13C NMR
(75 MHz, CDCl3): d¼21.6 (þ), 55.9 (2), 70.2 (Cquat),
80.7 (Cquat), 82.2 (þ), 86.9 (Cquat), 123.3 (Cquat), 126.2
(Cquat), 127.0 (þ), 127.8 (þ), 128.3 (þ), 128.4 (þ), 128.5
(þ), 128.9 (þ), 129.7 (þ), 130.9 (þ), 132.4 (þ), 134.5
(Cquat), 134.8 (Cquat), 144.6 (Cquat). MS (EI, 70 eV) m/z (%):
91 (100) [C7H7þ], 155 (15) [CH3C6H4SO2þ], 230 (6)
[Mþ2CH3C6H4SO2], 385 (3) [Mþ]. HRMS C24H19NO2S:
calcd 385.1137; found 385.1138^0.8 ppm.
3.1.3. N-Benzyl-N-(2-bromophenylethynyl)-4-methyl-
benzenesulfonamide (4). To a solution of N-benzyl-4-
methylbenzene-sulfonamide (0.94 g, 3.58 mmol) in 50 ml
of toluene, n-buli (2.70 ml, 4.30 mmol, 1.6 M in hexane)
was added via syringe at 0 8C. After stirring for 30 min at
this temperature 3 (2.29 g, 4.30 mmol) was added in small
portions. The reaction mixture was stirred overnight, the
solvent was removed and the residue was dissolved in
Et2O. The organic phase was washed with H2O, brine and
was dried over Na2SO4. The solvent was removed and the
residue was chromatographed on silica gel with 7:3
hexanes/Et2O to give 4 as a colorless solid (0.72 g, 46%).
Rf¼0.34 (7:3 hexanes/Et2O). Mp: 87–88 8C. IR (KBr):
3.1.6. 2-Naphthyl-amine (13). 2-Nitronaphthalene (12,
2.00 g, 11.56 mmol) was dissolved in 50 ml of ethanol
and Pd/C (50 mg, 10% Pd) was added. The reaction mixture
was stirred at room temperature at a H2 pressure of 5 atm for
24 h. After filtration and removal of the solvent, the residue
was recrystallized from hexanes to give 13 as a yellow solid
(1.25 g, 76%). All spectroscopic data are identical to the
ones reported in the literature.25 Caution: Compound 13 is a
cancer inducing substance!
n¼2923 cm21, 2852, 2231, 1596, 1429, 1368, 1173, 762.
˜
UV/Vis (CH3CN): lmax (log 1)¼207 nm (4.996), 258
(4.144). 1H NMR: d¼2.44 (s, 3H, CH3), 4.63 (s, 2H,
CH2), 7.05–7.51 (m, 11H), 7.82–7.85 (m, 2H). 13C NMR:
d¼21.7 (þ), 55.8 (2), 70.6 (Cquat), 87.2 (Cquat), 124.4
(Cquat), 125.2 (Cquat), 126.9 (þ), 127.8 (þ), 128.4 (þ), 128.5
(þ), 128.6 (þ) 129.0 (þ), 129.8 (þ), 132.2 (þ), 132.5 (þ),
134.3 (Cquat), 134.7 (Cquat), 144.7 (Cquart). MS (CI) m/z (%):
459 (100)/457 (94) [MþNHþ4 ], 442 (39)/440 (37)
[MþHþ], 288 (37) [M2C7H7SO2þHþ]/286 (38)
[M2C7H7SO2þHþ]. C22H18BrNO2S (439.02): calcd C
60.01 H 4.12 N 3.18; found C 59.51 H 4.08 N 3.00.
3.1.7. 4-Methyl-(4-benzenesulfonyl)-N-naphthalen-2-
ylbenzenesulfonamide (14). A mixture of 13 (1.25 g,
8.74 mmol), 4-methyl-benzene-sulfonyl chloride (5.03 g,
26.4 mmol), triethylamine (9.00 ml, 6.48 g, 64 mmol) and
N,N-dimethyl-amino-pyridine (53 mg, 0.44 mmol) in 50 ml
of CH2Cl2 were stirred at room temperature for 4 h. The
reaction mixture was extracted with 1 N HCl, H2O and
brine. The combined organic phases were dried over
Na2SO4, the solvent was removed and the residue was
recrystallized from ethanol to give 14 as a colorless solid
3.1.4. N-Benzyl-4-methyl-N-(2-trimethylsilanyl-ethynyl-
phenyl-ethynylbenzenesulfonamide (6). To a solution of 4
(388 mg, 0.88 mmol), Pd(PPh3)4 (53 mg, 0.12 mmol) and
CuI (7 mg, 0.01 mmol) in 5 ml of THF, trimethylstannyl
ethynylsilane (116 mg, 0.30 mmol) was added, and the
reaction mixture was stirred at 60 8C for 2 d. The solvent
was removed and CC with 7:3 hexanes/Et2O gave 6, as a
light yellow oil (376 mg, 94%). Rf¼0.45 (7:3 hexanes/
(2.48 g, 63%). Mp: 165–166 8C. IR (KBr): n¼3061 cm21
,
2923, 2231, 1919, 1596, 1493, 1370, 1169, 1085, 928, 661,
˜
550, 482. UV/Vis (CH3CN): lmax (log 1)¼197 nm (5.097),
1
224 (5.074). H NMR (300 MHz, CDCl3): d¼2.48 (s, 6H,
CH3), 7.08 (dd, J¼8.7 Hz, J¼2.2 Hz, 1H), 7.31–7.38 (m,
4H), 7.48–7.60 (m, 3H), 7.74–7.89 (m, 7H). 13C NMR
(75 MHz, CDCl3): d¼21.8 (þ), 126.9 (þ), 127.7 (þ), 127.8
(þ), 128.3 (þ), 128.5 (þ), 128.7 (þ), 128.9 (Cquat), 129.0
Et O). IR (film): n¼3055 cm21, 2987, 2306, 2234, 1741,
˜
2
1265, 739. UV/Vis (CH3CN): lmax (log 1)¼230 nm (4.633),
246 (4.588), 288 (4.164). 1H NMR (250 MHz, CDCl3):

¨
M. Klein, B. Konig / Tetrahedron 60 (2004) 1087–1092
1091
8. Wenk, H. H.; Balster, A.; Sander, W.; Hrovat, D. A.; Borden,
W. T. Angew. Chem. Int. Ed. 2001, 40, 2295–2298.
(Cquat), 129.2 (þ), 129.4 (Cquat) 129.7 (þ), 130.0 (þ), 131.5
(þ), 131.8 (Cquat), 133.2 (þ), 133.7 (þ), 136.3 (Cquat), 136.7
(þ), 144.8 (Cquat), 145.2 (þ), 145.6 (Cquat). MS (EI, 70 eV)
m/z (%): 451 (81) [Mþ], 296 (100) [M2C7H7SO2þ], 1þ55
9. Amino-enediynes show a little lower reactivity than the parent
system in calculations. Because ammonium has no p-donor
and only s-acceptor properties, the ammonium-enediyne has a
relatively low barrier for cyclization and an almost thermo-
neutral reaction energy as predicted from calculations. Doubly
substituted bis-ammonium-enediynes are far less reactive,
because of the repulsion of the positively charged groups of
the ortho-ammonium substituents in the cyclization product.
See Ref. 7 for a systematic computational study.
þ
(10) [C7H7SO2 ], 139 (59) [C7H7SOþ], 91 (63) [C7H7 ].
C24H21NO4S2 (451.56): calcd C 63.84 H 4.69 N 3.10; found
C 63.79 H 4.71 N 3.11.
3.1.8. 4-Methyl-N-naphthalen-2-ylbenzenesulfonamide
(15). Sodium (1.20 g, 52.17 mmol) was added to 30 ml of
ethanol. After completion of the reaction, 14 (0.45 g,
1.00 mmol) was added and the reaction mixture was
refluxed for 2 h, then diluted with H2O and extracted with
EtOAc. The combined organic phases were dried over
Na2SO4, the solvent was removed and the residue was
recrystallized from ethanol to give 14 as a colorless solid
(0.21 g, 71%). All spectroscopic data are identical to the
ones reported in the literature.26
10. For a recent report on synthesis and thermal cyclization of
structurally
related
3-aza-3-ene-1,5-dienes,
see:
(a) Nadipuram, A. K.; David, W. M.; Kumar, D.; Kerwin,
S. M. Org. Lett. 2002, 4, 4543–4546. The nitrogen atom in
these enediynes is part of a imidazole ring and therefore of
different electronic influence. Enediynes with amide or amine
not adjacent to the alkyne termini: (b) Banfi, L.; Guanti, G.;
Rasparini, M. Eur. J. Org. Chem. 2003, 1319–1336. (c) Basak,
A.; Mandal, S.; Das, A. K.; Bertolasi, V. Bioorg. Med. Chem.
Lett. 2002, 12, 873–877.
3.1.9. N-Benzyl-4-methyl-N-naphthalen-2-ylbenzene-
sulfonamide (11). To a mixture of 15 (0.1 g, 0.34 mmol)
and benzyl bromide (0.12 ml, 0.17 g, 1.01 mmol) in 5 ml of
acetone, K2CO3 (0.14 g, 1.01 mmol) and KI (0.06 g,
0.34 mmol) were added and the reaction mixture was
refluxed for 3 d. After cooling to room temperature the
resulting precipitate was filtered off and washed with
acetone. The filtrate was evaporated and the residue was
recrystallized from ethanol to give 11 as a colorless solid
(0.10 g, 77%). All spectroscopic data are identical to the
ones reported in the literature.27
11. Brandsma, L. Preparative Acetylenic Chemistry; 2nd ed.
Elsevier: Amsterdam, 1988; p 187ff.
12. Brandsma, L. Recl. Trav. Chim. Trav. Chim. Pays-Bas 1971,
90, 1098–1100.
13. Witulski, B.; Stengel, T. Angew. Chem. Int. Ed. Engl. 1998,
37, 489–492.
14. The positive charge of the ammonium group should contribute
to the s-acceptor properties of the substituents. This effect is
missing in sulfonamides. Their activation effect on the
enediyne system is therefore expected to be smaller.
15. Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R. P.;
Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am.
Chem. Soc. 2003, 125, 2368–2369.
Acknowledgements
16. Witulski, B.; Stengel, T. Angew. Chem. Int. Ed. Engl. 1999,
38, 2426–2430.
The authors thank the Fonds der chemi-schen Industrie for
support and Professor B. Witulski for advice in yne-amine
chemistry.
17. The alkyne was synthesized in two steps from TMS-ethynyl-
phenyliodonium triflate and N-Ts,N-Bz-amine, followed by
deprotection of the TMS group with fluoride. See supporting
information for details. Synthesis of the TMS-ethynyl-
phenyliodonium triflate, see: (a) Stang, P. J.; Zhdankin, V. V.
Chem. Rev. 1996, 96, 1123–1178. (b) Stang, P. J. In Modern
Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH:
Weinheim, 1995; pp 67–98.
References and notes
1. For one of the first experimental reports of electronic effects on
the Bergman cyclization, see: Schmittel, M.; Kiau, S. Chem.
Lett. 1995, 953–954.
18. Huynh, C.; Linstrumelle, G. Tetrahedron 1988, 44,
6337–6344.
2. (a) Jones, G. B.; Warner, P. M. J. Am. Chem. Soc. 2001, 123,
2134–2145. (b) Plourde, G. W., II; Warner, P. M.; Parrish,
D. A.; Jones, G. B. J. Org. Chem. 2002, 67, 5369–5374.
3. (a) Kim, C. S.; Russell, K. C. J. Org. Chem. 1998, 63,
8229–8234. (b) Kim, C. S.; Diez, C.; Russell, K. C. Chem.
Eur. J. 2000, 6, 1555–1558. (c) Nath, M.; Huffmann, J. C.;
Zaleski, J. M. Chem. Commun. 2003, 858–859.
19. Other conditions were tried: TBAF in THF/water gave only
very slow conversion and even poorer yield.
20. Theory predicts a significantly reduced thermal reactivity for a
bis-ammonium enediyne, because of strong repulsion of the
ortho ammonium moieties in the cyclization product. In the
case of a bis-sulfonamide at least the contribution from charge
to repulsion is omitted.
4. For a recent report on computer design of new enediyne based
anticancer drugs, see: Kraka, E.; Cremer, D. J. Am. Chem. Soc.
2000, 122, 8245–8264.
21. Compound 7 may have been obtained from 9 by one addition
of a lithium amide and rearrangement to the alkyne amide. The
second iodoniumphenyl moiety was hydrolyzed upon work up.
22. The analytical method follows previously described
procedures: (a) Choy, N.; Kim, C.-S.; Ballestero, C.; Artigas,
L.; Diez, C.; Lichtenberger, F.; Shapiro, J.; Russell, K. C.
Tetrahedron Lett. 2000, 41, 6955–6958. (b) Wisniewski
Grissom, J.; Calkins, T. L.; McMillen, H. A.; Jiang, Y. J. Org.
Chem. 1994, 59, 5833–5835. (c) Kim, C.-S.; Russell, K. C.
J. Org. Chem. 1998, 63, 8229–8234.
5. Effect of ortho-substituents in benzannelated enediynes:
(a) Alabugin, I. V.; Manoharan, M.; Kovalenko, S. V. Org.
Lett. 2002, 4, 1119–1122. (b) Alabugin, I. V.; Manoharan, M.
J. Phys. Chem. A 2003, 107, 3363–3371.
6. Koga, N.; Morokuma, K. J. Am. Chem. Soc. 1991, 113,
1907–1911.
7. Prall, M.; Wittkopp, A.; Fokin, A. A.; Schreiner, P. R.
J. Comput. Chem. 2001, 22, 1605–1614.

¨
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23. The derived rate constant describes the thermal conversion of
7. HPLC analyses showed that the Bergman cyclisation
product is the main product of the thermolysis. HPLC-MS
shows side products in minor amounts.
25. Roesler, A.; Pfleiderer, W. Helv. Chim. Acta 1997, 80,
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26. Hellwinkel, D.; Lenz, D. R. Chem. Ber. 1985, 118, 66–85.
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24. For a recent study on the effect of the steric influence of
functional groups at the termini of acylic enediynes on the
Bergman cyclization temperature, see: Rawat, D. S.; Zaleski,
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