Bis(enediyne) macrocycles: Synthesis, reactivity, and structural analysis

Article abstract of DOI:10.1016/S0040-4020(00)00932-7

We describe below the syntheses of five macrocycles possessing two enediyne warheads, along with the structural and thermal analyses of these bis(enediyne) compounds. The solid-state packing of compound 6 suggests the possibility for the molecule to undergo a topochemical diacetylene polymerization. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00932-7

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9581±9588
Bis(enediyne) Macrocycles: Synthesis, Reactivity,
and Structural Analysis
Heather S. Blanchette, Stephen C. Brand, Hitoshi Naruse, Timothy J. R. Weakley and
*
Michael M. Haley
Department of Chemistry, University of Oregon, Eugene, OR 97403-1253, USA
Received 1 September 2000; accepted 5 October 2000
AbstractÐWe describe below the syntheses of ®ve macrocycles possessing two enediyne warheads, along with the structural and thermal
analyses of these bis(enediyne) compounds. The solid-state packing of compound 6 suggests the possibility for the molecule to undergo a
topochemical diacetylene polymerization. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
system where products arising from Bergman chemistry
were detected.6 With this problem in mind, we embarked
on the preparation of systems having two independent
enediyne moieties. We report herein our work on the
synthesis, structural analysis, and thermal behavior of bis-
(enediyne) macrocycles 5±8, as well as work on related
system 9 (Fig. 2).7,8
In recent years the family of enediyne antibiotics has been
the subject of intense interest. A signi®cant body of research
has elucidated much of their chemical and biological
activity as anti-tumor agents.1 It is widely recognized that
the DNA-cleaving ability of these compounds is actuated by
the enediyne functional domain which undergoes either a
Bergman cyclization (Scheme 1) or Myers cyclization upon
activation to form a diradical species to in¯ict DNA
scissions.2 Anti-tumor, cytotoxic properties evolve from
the two radicals generated from the enediyne precursor.
In order to enhance the number of cytotoxic double-
stranded scissions on duplex DNA, we pursued structures
capable of generating four radicals (either simultaneously or
sequentially) and thus demonstrating greater anti-tumor
potential.
Macrocycle Synthesis
Bis(enediyne)s 5 and 6 were prepared in a straightforward
A search of the literature revealed a variety of molecules
capable of forming multiple diradicals (Fig. 1). These struc-
tures can be broken down into three fundamental motifs: (1)
molecules possessing two `independent' enediynes, e.g.
1;3,4; (2) molecules based on tetraethynylethene, e.g. 2;5
and (3) molecules containing a dec-5-en-1,3,7,9-tetrayne
moiety, e.g. 3.6 Although the thermal chemistry of each
class has been investigated, compound 4 was the only
Figure 1. Examples of different bis(enediyne) motifs.
Scheme 1. Bergman cyclization of a typical enediyne moiety.
Keywords: diynes; macrocycles; polyynes; annulenes.
* Corresponding author. Tel.: 1541-346-0456; fax: 1541-346-0487;
e-mail: haley@oregon.uoregon.edu
Figure 2. Target macrocycles 5±9.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00932-7

9582
H. S. Blanchette et al. / Tetrahedron 56 (2000) 9581±9588
resonances of 7, as these are shifted down®eld ca. 0.3±
0.5 ppm compared to the analogous resonances in 5.
Construction of macrocycle 8 is illustrated in Scheme 4.
Treatment of 1414 with the Grignard reagent prepared
from ethylmagnesium bromide and triisopropylsilylacetyl-
ene afforded bis-protected pentadiyne 15.15 Selective
desilylation using a catalytic amount of NaOH in 1:1
THF:MeOH followed by cross-coupling with excess cis-
1,2-dichloroethene gave compound 16. Removal of the tri-
isopropylsilyl group with Bu4NF furnished the deprotected
terminal alkyne. The ®nal cyclodimerization was accom-
plished by slow addition of deprotected 16 to a solution of
Pd(PPh3)4, CuI, and BuNH2. Macrocycle 8 was separated
from oligomeric material by preparative thin layer chroma-
tography and isolated in ca. 5% overall yield.
Scheme 2. Synthesis of macrocycles 5 and 6. (a) 1,5-hexadiyne (for 10) or
1,7-octadiyne (for 11), PdCl2(PPh3)2, CuI, Et3N, piperidine, 40±458C;
(b) Me3SiC;CH, PdCl2(PPh3)2, CuI, Et3N, piperidine, 1508C; (c) K2CO3,
MeOH, Et2O; (d) CuCl, O2, pyridine, DBU, 40±458C.
manner (Scheme 2). Two equivalents of 1-bromo-2-iodo-
benzene were attached to a diyne tether via established
Pd-catalyzed cross-coupling chemistry.9 Subsequent
addition of two equivalents of trimethylsilylacetylene fur-
nished tetraynes 10 and 11. The terminal alkynes were
desilylated with K2CO3 in MeOH and immediately
subjected to Cu-mediated oxidative coupling conditions10
to provide the desired macrocycles 5 and 6 as off-white
solids in 33 and 36% overall yield, respectively.
The preparation of macrocycle 9, despite being a slight
variation of 8, proved to be a troublesome goal. Dichloride
17 was prepared by desilylating 16 and reacting the
unprotected species with a second equivalent of cis-
dichloroethene (Scheme 5). Addition of two equivalents
of trimethylsilylacetylene provided tetrayne 18. In situ
Owing to the reported instability of cis-hex-3-en-1,5-
diyne,11 compound 7 was assembled in an alternative
fashion (Scheme 3). Selective desilylation of 1212 with
K2CO3 in MeOH and subsequent Pd-catalyzed cross-
coupling with cis-1,2-dichloroethene afforded monoene
13. Desilylation with Bu4NF and intramolecular coupling
with copper salts gave macrocycle 7 as a pale yellow solid
in 29% overall yield. Unlike 5 and 6, the central ring in 7 is a
fully conjugated dehydrobenzo[14]annulene derivative.13
Upon closure, the molecule exhibited a marked down®eld
shift of the alkene proton resonance (dˆ6.70) compared to
the chemical shift of the analogous resonance in 13
(dˆ6.11). The presence of the diatropic ring current in the
14-membered macrocycle is also evident in the arene proton
protiodesilylation/oxidative dimerization16 furnished
a
yellow solid that rapidly decomposed to dark brown ®lm.
1
The H NMR and UV/Vis spectra of the crude material
showed evidence for the formation of macrocycle 9. Never-
theless, attempts at puri®cation led only to recovery of
polymeric materials.
Structural Analyses
Extensive studies on simple model enediynes have
suggested that the distance between the distal alkynyl
carbons (c´´´d distance) provides an approximate measure
of a molecule's ability to undergo Bergman chemistry.1,17
Experiments have shown that ideal c´´´d distances fall
Ê
between 3.15 and 3.31 A for cyclizations to occur at physio-
logical temperature. Smaller values are characteristic of
enediynes which are unstable at room temperature, while
larger values suggest heating is needed to cyclize the
molecules. Accordingly, molecular modeling of macro-
cycles 5±9 was employed to provide calculated c´´´d
distances; results utilizing semi-empirical methods are
shown in Table 1.18
Scheme 3. Synthesis of macrocycle 7. (a) K2CO3, MeOH, Et2O; (b) cis-1,2-
dichloroethene, Pd(PPh3)4, CuI, THF, BuNH2; (c) Bu4NF, EtOH, THF;
(d) Cu(OAc)2, CuCl, pyridine.
To support the calculations, we sought to obtain X-ray
Scheme 4. Synthesis of macrocycle 8. (a) i-Pr3SiC;C±MgBr, CuCl, THF;
(b) MeOH, THF, NaOH; (c) cis-1,2-dichloroethene, Pd(PPh3)4, CuI,
BuNH2; (d) Bu4NF, EtOH, THF; (e) Pd(PPh3)4, CuI, BuNH2
Scheme 5. Synthesis of macrocycle 9. (a) Bu4NF, EtOH, THF; (b) cis-1,2-
dichloroethene, Pd(PPh3)4, CuI, Et3N; (c) Me3SiC;CH, Pd(PPh3)4, CuI,
Et3N; (d) Cu(OAc)2, CuCl, K2CO3, pyridine, MeOH.

H. S. Blanchette et al. / Tetrahedron 56 (2000) 9581±9588
9583
Ê
Table 1. Calculated and experimental c´´´d distances for bis(enediynes) 1,
Ê
5±9 (A)
Table 2. Selected bond lengths (A) and bond angles (8) for bis(enediyne)s
6±8
Molecule
AM1
PM3
MNDO
Experimental
4.27a
Macrocycle 6
1
5
6
7
8
9
4.366
3.792
4.009
3.868
4.345
3.799
4.214
3.826
4.019
3.916
4.305
3.795
4.466
3.878
4.088
3.929
4.470
3.916
C1±C10
C1±C2
C2±C3
C3±C8
C8±C9
C9±C10
C10±C11
C11±C12
1.387(6)
1.192(4)
1.428(4)
1.407(4)
1.429(5)
1.181(4)
1.465(5)
1.532(4)
C10 ±C1±C2
C1±C2±C3
C2±C3±C8
C3±C8±C9
C8±C9±C10
C9±C10±C11
C10±C11±C12
177.5(2)
177.1(4)
119.1(3)
120.8(3)
176.4(4)
177.5(4)
114.1(3)
3.93
3.84
4.21
a Ref. 2a.
Macrocycle 7a
structures of our macrocycles. Fortunately, three of the four
stable systems provided crystals suitable for analysis. The
molecular structures of 6±8 are illustrated in Fig. 3; selected
bond lengths and bond angles are given in Table 2. As is
often the case, the experimentally determined c´´´d
distances of 6±8 are shorter than the values calculated at
semi-empirical levels, and are well outside the range of
C1±C22
C1±C2
C2±C3
C3±C8
C8±C9
C9±C10
C10±C11
C11±C12
1.374(3)
1.196(3)
1.424(3)
1.404(3)
1.433(3)
1.196(3)
1.415(3)
1.346(3)
C2±C1±C22
C1±C2±C3
C2±C3±C8
172.3(2)
170.2(2)
118.2(2)
121.3(2)
179.0(2)
171.9(2)
128.8(2)
C3±C8±C9
C8±C9±C10
C9±C10±C11
C10±C11±C12
Ê
3.15±3.31 A. Whereas macrocycles 6 and 8 are essentially
Macrocycle 8b
strain-free systems, 7 displayed a moderate degree of bend-
ing in the diacetylenic linkage, with the C±C triple bonds
deviating up to ca. 108 from linearity.
C1±C10
C1±C2
C2±C3
C3±C4
1.333(4)
1.418(3)
1.188(3)
1.478(3)
C10 ±C1±C2
C1±C2±C3
C2±C3±C4
C3±C4±C30
123.9(1)
178.6(2)
178.3(2)
109.9(2)
The molecular packing of the three macrocycles varies
signi®cantly. Annulene 7 stacks in columns where the
diacetylenic linkage lies below the alkene moiety of next
macrocycle. This type of staggered stacking precludes the
possibility of a topochemical diacetylene polymerization, as
was observed in the corresponding tribenzo[14]annulene
a Average values of both halves of the molecule.
b One of two independent yet essentially identical molecules.
Figure 3. X-Ray crystal structures of molecules 6±8. Ellipsoids are shown at the 30% probability level.

9584
H. S. Blanchette et al. / Tetrahedron 56 (2000) 9581±9588
1
analog.19 In contrast, the columns of 6 juxtapose the
diyne units in the proper orientation required for a
1,4-polymerization. The diyne polymerization parameters
instrument (1H: 300.13 MHz, C: 75.5 MHz) and a Varian
Unity Inova (1H: 299.95 MHz, 1C: 75.43 MHz) using CDCl3
as solvent unless otherwise noted. Chemical shifts are
reported in ppm, with the residual protonated solvent
serving as an internal standard (CDCl3ˆ7.26,
CD2Cl2ˆ5.32). 13C NMR spectra are referenced to the
central resonance of either CDCl3 (77.00) or CD2Cl2
(54.00). Coupling constants are expressed in hertz. IR
spectra were recorded using a Nicolet Magna 550 FT-IR
spectrometer. UV±Vis spectra were obtained on a Cary 14
or an HP 8453 UV±Vis spectrophotometer. Melting points
were measured with a MelTemp II apparatus using a digital
thermometer and are uncorrected.
Ê
Ê
for 6 are dˆ5.09 A, gˆ448, and S1ˆ3.62 A, which are
quite close to the optimal range for such monomers
20
(d´5 A, g´458). The presence of the gem-dimethyl groups
Ê
causes compound 8 to pack loosely in the unusual C2/m
space group. The only close C±C contacts are between
the methyl group of one molecule and the distal alkyne
carbon of another.
Thermal Studies
Given the relatively large magnitude of the c´´´d distances
for our systems, it was expected that elevated temperatures
would be required to induce Bergman chemistry; this indeed
proved to be the case. Differential scanning calorimetry
(DSC) showed that macrocycles 5±8 underwent irreversible
exothermic reactions between 175 and 2258C, with 5 and 8
possessing secondary irreversible exothermic processes
between 300 and 3508C. Only macrocycle 6 melted prior
to decomposition, which unfortunately excludes the possi-
bility of a thermally-induced diacetylene polymerization. A
reasonable explanation for the broad exothermic reactions
in the DSC scans is thermally-induced cyclization of the
enediyne units with subsequent polymerization of the bulk
material.21 In contrast, the solution chemistry of our
molecules proved to be very complex. Numerous attempts
were made to isolate and characterize discreet, soluble
materials. Small-scale reactions, however, suggested the
formation of numerous products in approximately equal
amounts. For example, reaction of 6 only occurred in 1,4-
cyclohexadiene solution at a temperature greater than 2258C
and produced an inseparable mixture of products. Although
benzannelation to the enediyne core is known to retard
cycloaromatization,22 we were surprised by the high
stability of our macrocycles. Based on these results, further
cyclization experiments are not planned.
Commercially available reagents were used as received
unless otherwise noted. THF and Et2O were dried by distil-
lation under N2 from sodium and benzophenone. BuNH2,
Et3N, piperidine, and pyridine were dried by distillation
from calcium hydride. Solvents used in palladium mediated
coupling reactions were deoxygenated prior to use by 30±
45 min of Ar bubbling. Other reactions were carried out in
an inert atmosphere (dry N2 or Ar) when necessary. Flash
chromatographic puri®cation of crude products was accom-
plished using Whatman 230±400 mesh silica gel. Prepara-
tive chromatography was performed on a Chromatotron
using 1 or 2 mm silica gel plates (EM Science 60 PF254
containing gypsum) or on TLC plates (Analtech Silica Gel
GF, 20 cm£20 cm£1 mm).
1,6-Bis(20-(trimethylsilylethynyl)phenyl)-1,5-hexadiyne
(10). To a degassed solution of 1-bromo-2-iodobenzene
(3.73 g, 13.2 mmol) and PdCl2(PPh3)2 (0.109 g,
0.155 mmol) in Et3N (44 mL) and piperidine (11 mL) was
added CuI (0.058 g, 0.305 mmol) and 1,5-hexadiyne
(0.469 g, 6.0 mmol). The reaction was stirred under Ar for
18 h at 40±458C. After cooling, the mixture was diluted
with Et2O, ®ltered through Celite, and washed sequentially
with 10% HCl solution, saturated aqueous NaHCO3, and
brine. The ethereal solution was then dried (MgSO4),
®ltered, and concentrated. Flash chromatography (5:1
hexanes/CH2Cl2, Rfˆ0.32) afforded the desired bis(bromo-
phenyl)diyne as a clear, colorless oil (2.05 g, 88%) which
solidi®ed upon prolonged storage at 2208C. 1H NMR
(CD2Cl2) d 7.57 (dd, Jˆ8.1, 1.4 Hz, 2H), 7.47 (dd, Jˆ7.5,
1.8 Hz, 2H), 7.26 (td, Jˆ7.7, 1.4 Hz, 2H), 7.15 (td, Jˆ7.7,
1.8 Hz, 2H), 2.82 (s, 4H); 13C NMR d 133.42, 132.27,
128.91, 126.86, 125.66, 125.50, 93.25, 80.38, 19.86; IR
(neat) nˆ3069, 3054, 2226 cm21; UV±Vis (CH2Cl2)
Conclusions
In our pursuit of bis(enediyne) macrocycles capable of
undergoing multiple Bergman cyclization reactions, we
prepared carbocycles 5±8. Although these compounds
exhibited exothermic activity indicative of Bergman
cyclization followed by bulk polymerization, the higher
temperatures required to initiate the cyclizations were
consistent with the larger c´´´d distances re¯ected in the
corresponding crystal structures. Efforts to reduce the
macrocycle ring size by one carbon in the synthesis of
analog 9 were unfruitful because of the instability of the
resultant product. We are currently exploring the chemical
transformation of 5 and 6 into dehydrobenzoannulene
derivatives, as well as the polymerization behavior of the
macrocycles; these results will be presented in due course.
l
max(e) 247 (24,700), 259 (28,400), 283 (980), 292 (660)
79
nm; HRMS calcd for C18H Br81Br: 387.9363, found:
12
387.9365.
To a degassed solution of bis(bromophenyl)hexadiyne
(1.92 g, 5.0 mmol), PdCl2(PPh3)2 (0.213 g, 0.30 mmol),
and CuI (0.084 g, 0.44 mmol) in Et3N (30 mL) in a glass
pressure tube was added trimethylsilylacetylene (4.2 mL,
29.7 mmol) in piperidine (6 mL). The tube was sealed
under Ar and stirred for 3 d at 1508C. The cooled reaction
mixture was diluted with Et2O (100 mL), ®ltered through
Celite, and washed with chilled 10% HCl solution, saturated
aqueous NaHCO3, and brine. The organic phase was dried
(MgSO4) and concentrated. Repetitive chromatography
(¯ash column, 4:1 hexanes/CH2Cl2, Rfˆ0.25; preparative
Experimental
General
1H and 13C NMR spectra were acquired on a GE QE-300

H. S. Blanchette et al. / Tetrahedron 56 (2000) 9581±9588
9585
TLC, 3:1 cyclohexane/benzene) afforded 10 as a light
orange oil (1.04 g, 52%). H NMR (CD2Cl2) d 7.47±7.42
graphy (hexanes) gave 5 as a white crystalline solid
1
1
(179 mg, 72%). Mpˆ1408C (dec); H NMR d 7.43 (dd,
(m, 4H), 7.28±7.23 (m, 4H), 2.84 (s, 4H), 0.29 (s, 18H); 13C
NMR (CD2Cl2) d 132.60, 132.52, 128.83, 128.17, 126.87,
126.00, 104.09, 98.75, 93.25, 80.60, 20.60, 0.32; IR (neat)
nˆ3069, 2156 cm21; MS (EI, 70 eV) 422 (5, M1), 407 (10,
M12Me), 349 (49, M12SiMe3), 333 (54), 319 (38), 73
(100, SiMe3); HRMS calcd for C28H30Si2: 422.1886,
found: 422.1868.
Jˆ7.5, 1.2 Hz, 2H), 7.36 (dd, Jˆ7.5, 1.2 Hz, 2H), 7.32±
7.20 (m, 4H), 2.86 (s, 4H); 13C NMR (CD2Cl2) d 132.45,
130.49, 130.06, 129.61, 128.25, 124.83, 94.37, 85.45, 79.83,
79.67, 19.78; IR (KBr) nˆ3057, 2208 cm21; UV (CH2Cl2)
lmax (e) 252 (21,600), 266 (24,300), 313 (7,000), 324
(7,100), 335 (12,300), 360 (15,600) nm; MS (EI, 70 eV)
276 (100, M1), 274 (82), 248 (14); HRMS calcd for
C22H12: 276.0939, found: 276.0940.
1,8-Bis(20-(trimethylsilylethynyl)phenyl)-1,7-octadiyne
(11). Compound 11 was prepared in an analogous fashion to
10. Thus, use of 1,7-octadiyne (0.637 g, 6.0 mmol) in the
above procedure furnished the corresponding bis(bromo-
phenyl)diyne as a colorless, crystalline solid (1.93 g,
1,2,7,8-Dibenzocyclohexadeca-3,5,9,15-tetrayne
(6).
Tetrayne 11 was deprotected in an analogous fashion to
10. The resultant brown oil was used immediately in the
1
next step. H NMR d 7.47 (d, Jˆ7.7 Hz, 2H), 7.40 (d,
1
77%). Rfˆ0.31 (5:1 hexanes/CH2Cl2); H NMR (CD2Cl2)
Jˆ7.6 Hz, 2H), 7.29±7.18 (m, 4H), 3.32 (s, 2H), 2.55 (br
d 7.57 (dd, Jˆ8.1, 1.3 Hz, 2H), 7.44 (dd, Jˆ7.5, 1.7 Hz,
2H), 7.25 (td, Jˆ7.7, 1.3 Hz, 2H), 7.14 (td, Jˆ7.8, 1.7 Hz,
2H), 2.59±2.52 (m, 4H), 1.89±1.84 (m, 4H); 13C NMR d
133.18, 132.15, 128.59, 126.77, 125.89, 125.41, 94.86,
79.74, 27.45, 19.03; IR (KBr) nˆ3061, 2233 cm21; UV-
Vis (CH2Cl2) lmax (e) 247 (26,400), 258 (26,900), 283
(760) nm; HRMS calcd for C20H16Br2: 413.9619, found:
413.9626.
s, 4H), 1.88 (br s, 4H).
In a manner analogous to 10, desilylated 11 was intra-
molecularly cross-coupled. Puri®cation of the crude yellow
solid obtained ®rst by preparative TLC (2:1 cyclohexane/
CH2Cl2, Rfˆ0.35), then by radial chromatography (hexanes)
furnished 6 as a white crystalline solid (120 mg, 87%).
Mpˆ141.7±142.58C; 1H NMR (CD2Cl2) d 7.51 (dd,
Jˆ7.4, 1.4 Hz, 2H), 7.40 (dd, Jˆ7.7, 1.4 Hz, 2H), 7.34±
7.23 (m, 4H), 2.57±2.49 (m, 4H), 1.92±1.85 (m, 4H); 13C
NMR (CD2Cl2) d 132.64, 131.76, 129.54, 128.70, 127.95,
125.03, 96.09, 81.94, 79.89, 77.82, 29.02, 20.30; IR (KBr)
nˆ3061, 2226, 2144 cm21; UV (CH2Cl2) lmax (e) 249
(12,100), 264 (12,800), 309 (7,800), 330 (12,000), 353
(14,700) nm; MS (EI, 70 eV) 304 (100, M1), 303 (52),
302 (84), 300 (26), 289 (22), 276 (30); HRMS calcd for
C24H16: 304.1252, found: 304.1248.
Bis(bromophenyl)octadiyne (2.04 g, 5.0 mmol) was treated
as above. Chromatography over silica gel (hexanes/CH2Cl2,
20 to 35% CH2Cl2) gave 11 as an orange oil (1.19 g, 53%).
Rfˆ0.44 (4:1 hexanes/CH2Cl2); 1H NMR (CD2Cl2) d 7.45±
7.38 (m, 2H), 7.28±7.19 (m, 4H), 2.55 (br t, Jˆ6.3 Hz, 4H),
1.85 (m, 4H), 0.26 (s, 18H); 13C NMR (CD2Cl2) d 132.60,
132.39, 128.75, 127.83, 127.22, 125.87, 104.20, 98.47,
94.88, 79.89, 28.55, 19.64, 0.24; IR (neat) nˆ3062, 3024,
2231, 2159 cm21; UV±Vis (CH2Cl2) lmax (e) 240 (35,300),
265 (24,000), 279 (22,300), 297 (2,100), 309 (1,600) nm;
MS (EI, 70 eV) 450 (69, M1), 449 (70), 435 (17, M12Me),
422 (22), 407 (58), 73 (100, SiMe3); HRMS calcd for
C30H34Si2: 450.2199, found: 450.2207.
cis-1,6-Bis(20-(triisopropylsilylethynyl)phenyl)hex-3-en-
1,5-diyne (13). To a solution of diyne 1212 (2.13 g,
6.0 mmol) in MeOH (75 mL) and Et2O (15 mL) was
added anhydrous K2CO3 (415 mg, 3.0 mmol). After
stirring for 2 h, the mixture was diluted with Et2O,
washed with water, dried (MgSO4), and concentrated.
The resultant yellow oil was used immediately in the next
1,2,7,8-Dibenzocyclotetradeca-3,5,9,13-tetrayne (5). To a
solution of 10 (0.405 g, 0.96 mmol) in a mixture of MeOH
(15 mL) and Et2O (5 mL) was added K2CO3 (0.144 g,
1.04 mmol). After stirring for 3 h, the reaction mixture
was poured into Et2O (30 mL) and then washed with H2O
and brine. The organic layer was dried (MgSO4) and
concentrated to produce a brown oil which was immediately
1
step. H NMR d 7.51±7.47 (m, 4H), 7.29±7.24 (m, 4H),
3.26 (s, 1H), 1.15 (s, 21H); 13C NMR d 132.52, 132.42,
128.30, 127.89, 126.68, 124.94, 104.79, 95.28, 82.26,
81.03.
1
used in the next step. H NMR d 7.47 (d, Jˆ7.5 Hz, 2H),
To a degassed mixture of cis-1,2-dichloroethene (0.237 g,
2.5 mmol), CuI (0.024 g, 0.13 mmol), Pd(PPh3)4 (0.046 g,
0.04 mmol) and BuNH2 (2.0 mL) in dry THF (10 mL) was
added deprotected 12. After stirring for 18 h, the resultant
dark reaction mixture was poured into hexanes and washed
with 1 M HCl solution. The organic phase was dried
(MgSO4), concentrated, and chromatographed on silica gel
(hexanes) to give 13 as a pale yellow oil (0.619 g, 42%). 1H
NMR d 7.55±7.48 (m, 4H), 7.28±7.24 (m, 4H), 6.11 (s,
2H), 1.16 (s, 42H); 13C NMR d 1132.40, 132.20, 128.06,
127.92, 125.98, 125.85, 119.68, 105.08, 96.44, 96.44, 90.95,
18.77, 11.30; IR (neat) nˆ3061, 2156 cm21; MS (EI,
70 eV) 588 (8, M1), 545 (11, M12i-Pr), 503 (30), 461
(30), 274 (100, M122Sii-Pr3); HRMS calcd for
C40H52Si2: 588.3608, found: 588.3615.
7.41 (d, Jˆ7.6 Hz, 2H), 7.28±7.18 (m, 4H), 3.26 (s, 2H),
2.83 (s, 4H).
To a solution of deprotected 10 in pyridine (80 mL) at 408C
was added CuCl (0.101 g, 1.02 mmol), DBU (165 mL,
1.10 mmol), and additional pyridine (10 mL) to complete
the transfer. O2 was bubbled through the mixture for
90 min while maintaining the temperature of the reaction
at 40±458C. After an additional 30 min of warming, the
mixture was concentrated (ca. 90%) in vacuo. To the slurry
was added a solution of KCN (54 mg, 0.82 mmol) and
NH4Cl (210 mg, 3.91 mmol) in water (2 mL) and the
mixture was stirred vigorously for 30 min. The ether
phase was washed with 2 M HCl solution, dried (MgSO4),
and concentrated. Puri®cation by preparative TLC (2:1
cyclohexane/CH2Cl2, Rfˆ0.41), then by radial chromato-
1,2,7,8-Dibenzocyclotetradeca-11-en-3,5,9,13-tetrayne

9586
H. S. Blanchette et al. / Tetrahedron 56 (2000) 9581±9588
(7). To a solution of 13 (0.589 g, 1.0 mmol) in dry THF
(15 mL) was added Bu4NF (1 M, 3.0 mL, 3.0 mmol) and
EtOH (2 mL). The solution was stirred for 2 h, then diluted
with Et2O. The mixture was washed with water, dried
(MgSO4), and concentrated. The resultant light brown oil
NaHCO3 solution. The organic phase was dried (MgSO4)
and concentrated to give a clear, colorless oil (3.56 g, 85%).
1H NMR d 2.19 (s, 1H), 1.53 (s, 6H), 1.11 (s, 21H); 13C
NMR d 31.26, 26.42, 7.37, 4.39.
1
was used immediately in the next step. H NMR d 7.56±
A mixture of cis-1,2-dichloroethene (0.50 g, 5.16 mmol),
CuI (0.047 g, 0.25 mmol), Pd(PPh3)4 (0.046 g, 0.040
mmol) and BuNH2 (0.5 mL) in dry THF (6 mL) was
degassed, then treated with deprotected 15 (0.46 g,
2.23 mmol). After stirring for 9 h, the resultant dark blue
reaction mixture was poured into hexanes and washed with
1 M HCl solution. The organic phase was dried (MgSO4),
concentrated, and chromatographed on silica gel (hexanes)
to give 16 as a clear, colorless oil (0.185 g, 30%). 1H NMR
d 6.34 (d, Jˆ7.5 Hz, 1H), 5.86 (d, Jˆ7.5 Hz, 1H), 1.58 (s,
6H), 1.08 (s, 21H); 13C NMR d 127.85, 112.09, 111.39,
101.77, 79.60, 73.61, 31.21, 27.50, 18.59, 11.22; IR (neat)
nˆ2223, 2173, 1600 cm21; MS (EI, 70 eV) 310 (2,
M1(37Cl)), 308 (2, M1(35Cl)), 267 (39, M1(37Cl)-i-Pr),
265 (100, M1(35Cl)-i-Pr), 237 (20), 205 (61), 199 (38);
HRMS calcd for C18H29ClSi: 308.1727, found: 308.1729.
7.49 (m, 4H), 7.35±7.27 (m, 4H), 6.20 (s, 2H); 13C NMR d
132.56, 128.40, 128.24, 126.07, 124.47, 119.64, 95.75,
91.01, 81.83, 81.59.
To a solution of CuCl (2.48 g, 25 mmol) and Cu(OAc)2
(6.01 g, 30 mmol) in pyridine (80 mL) heated at 408C was
added deprotected 13 dissolved in pyridine (5 mL) via
syringe pump (0.35 mL/h). Upon completion of addition,
the reaction mixture was stirred 6 h further and then con-
centrated in vacuo. The dark blue-green residue was
redissolved with CH2Cl2 and ®ltered through a pad of silica
gel. The ®ltered solution was concentrated and chromato-
graphed on silica gel (9:1 hexanes: CH2Cl2) to give 7 as a
beige crystalline solid (189 mg, 69%). Mpˆ1708C (dec); 1H
NMR d 7.92 (dd, Jˆ7.5, 1.8 Hz, 2H), 7.76 (dd, Jˆ6.9,
1.5 Hz, 2H), 7.58±7.47 (m, 4H), 6.70 (s, 2H); 13C NMR d
132.72, 129.41, 128.52, 128.45, 128.20, 123.12, 117.13,
97.42, 91.76, 85.24, 80.23; IR (KBr) nˆ3061, 2206, 2148,
1572 cm21; UV (CH2Cl2) lmax (e) 258 (12,700), 297
(33,500), 313 sh (26,200), 346 (20,900), 353 (18,900), 370
(13,000) nm; MS (EI, 70 eV) 276 (25), 275 (25), 274 (100,
M1), 272 (29); HRMS calcd for C22H10: 274.0783, found:
274.0782.
5,5,12,12-Tetramethyl-1,8-cyclotetradecadien-3,6,10,13-
tetrayne (8). To a degassed solution of 16 (180 mg,
0.67 mmol) in dry THF (5 mL) was added Bu4NF
(340 mg, 1.45 mmol) and EtOH (2 mL). After stirring for
2 h, the reaction solution was diluted with petroleum ether
and washed with brine. The organic phase was dried
(MgSO4) and concentrated. The unstable pale yellow oil
1
was used immediately in the next step. H NMR d 6.36
(d, Jˆ7.5 Hz, 1H), 5.86 (d, Jˆ7.5 Hz, 1H), 2.25 (s, 1H),
3,3-Dimethyl-1-triisopropylsilyl-5-trimethylsilyl-1,4-
pentadiyne (15). A mixture of Mg turnings (0.54 g,
22.4 mmol), dry THF (10 mL), and a catalytic amount of
I2 was treated dropwise with a solution of bromoethane
(1.7 mL, 22.8 mmol) in dry THF (10 mL). After stirring
an additional 15 min, a solution of triisopropylsilylactetylene
(3.2 mL, 17.8 mmol) in dry THF (10 mL) was added over a
15 min period. The reaction was re¯uxed with stirring for
1 h, then cooled to ambient. Dry CuCl (0.20 g, 2.0 mmol)
was added and the mixture was stirred for 15 min. A solu-
tion of 3-chloro-3-methyl-1-trimethylsilyl-1-butyne (14)14
(3.77 g, 21.6 mmol) in dry THF (4 mL) was then added
dropwise to the reaction mixture. The suspension was
re¯uxed for 2 h. The cooled slurry was washed with a solu-
tion of NH4Cl (1.50 g, 28.0 mmol) and KCN (0.20 g,
3.07 mmol) in water (10 mL), followed by extraction of
the aqueous phase with Et2O. The combined organic phases
were washed with saturated NH4Cl solution, then water,
dried (MgSO4), and concentrated. The crude product was
®ltered through a thin cake of silica gel (petroleum ether).
Concentration in vacuo gave 15 as a clear, colorless oil
1.59 (s, 6H).
To a degassed solution of the deprotected enediyne in dry
THF (50 mL) was CuI (100 mg, 0.53 mmol), Pd(PPh3)4
(96 mg, 0.08 mmol), and BuNH2 (0.5 mL). The reaction
was stirred for 17 h at ambient. The mixture was poured
into saturated NH4Cl solution and extracted twice with
petroleum ether. The organic phase was ®ltered through a
pad of silica gel and concentrated. Puri®cation by prepara-
tive TLC (1:1 hexanes/CH2Cl2, Rfˆ0.51) gave 8 as an off-
1
white solid (28 mg, 18%). Mpˆ1758C (dec); H NMR d
5.77 (s, 4H), 1.63 (s, 12H); 13C NMR d 119.37, 100.60,
77.13, 30.72, 27.37; IR (KBr) nˆ3042, 2982, 2208,
1571 cm21; MS (EI, 70 eV) 232 (37, M1), 217 (46,
M12Me), 215 (55), 202 (100, M122Me); HRMS calcd
for C18H16: 232.1252, found: 232.1255.
1,9-Dichloro-5,5-dimethyl-1,8-nonadien-3,6-diyne (17).
To
a solution of desilylated precursor 16 (1.40 g,
9.17 mmol), generated as above, in dry THF (50 mL) was
added Pd(PPh3)4 (0.12 g, 0.10 mmol), CuI (0.103 g,
0.541 mmol), BuNH2 (3 mL, 30 mmol), and cis-dichloro-
ethene (3.12 g, 32 mmol). The reaction was stirred at
room temperature under N2 for 5.5 h. The mixture was
diluted with hexanes and washed twice with water. The
organic layer was dried (MgSO4) and concentrated to
yield a crude brown oil. Puri®cation on silica gel (petroleum
ether) afforded 17 as a pale yellow oil (2.0 g). An analyti-
cally pure sample was prepared by radial chromatography
(hexanes) to give a colorless oil. 1H NMR d 6.36 (d,
Jˆ7.5 Hz, 2H), 5.87 (d, Jˆ7.5 Hz, 2H), 1.63 (s, 6H); 13C
NMR d 128.21, 111.91, 100.92, 74.01, 30.90, 27.50; IR
1
(5.63 g, 90%). H NMR d 1.50 (s, 6H), 1.06 (br s, 21H),
0.14 (s, 9H); 13C NMR d 112.17, 110.06, 82.93, 79.26,
31.25, 27.41, 18.61, 11.27, 0.04; IR (neat) nˆ2167 cm21
;
MS (EI, 70 eV) 320 (6, M1), 305 (2, M12Me), 277 (100,
M12i-Pr), 235 (37), 73 (75); HRMS calcd for C19H36Si2:
320.2356, found: 320.2352.
1-Chloro-5,5-dimethyl-7-triisopropylsilylhept-1-en-3,6-
diyne (16). A solution of 15 (5.63 g, 20.2 mmol) in MeOH
(50 mL) and THF (50 mL) was stirred with 10% NaOH
solution (1 mL) for 6 h. The reaction mixture was diluted
with petroleum ether and washed with water and saturated

H. S. Blanchette et al. / Tetrahedron 56 (2000) 9581±9588
9587
(neat) nˆ3085, 2984, 2221, 1591 cm21; MS (EI, 70 eV) 216
(5, M1(37Cl)2), 214 (12, M1(35Cl37Cl)), 212 (16, M1(35Cl)2),
201 (6, M1(37Cl)2-Me), 199 (28, M1(35Cl37Cl)-Me), 197
(42, M1(35Cl)2-Me), 179 (24, M1(35Cl37Cl)-35Cl), 177 (76,
M1(35Cl)2-35Cl), 162 (40), 142 (68), 141 (100); HRMS calcd
for C11H10Cl2: 212.0160, found: 212.0166.
independent re¯ections scanned, 2546 re¯ections in re®ne-
ment (I´s(I)), 239 parameters, Rˆ0.088, Rwˆ0.092.
8. C18H16, Mrˆ232.32, colorless prism, 0.07£0.15£
0.32 mm, monoclinic, space group C2/m, aˆ10.3804(14),
Ê
bˆ14.6567(11), cˆ9.6200(13) A, bˆ93.334(11)8, Vˆ
1461.1(6) A , Zˆ4, rcalcˆ1.056 g cm23, MoKa radiation
Ê 3
(lˆ0.71073 A), mˆ0.553 cm21, F(000)ˆ496, Tˆ238C,
Ê
1,13-Bis(trimethylsilyl)-7,7-dimethyl-3,10-tridecadien-1,
5,8,12-tetrayne (18). A solution of dichloride 17 (generated
above) in THF (50 mL) was treated with Pd(PPh3)4 (0.16 g,
0.14 mmol), CuI (95 mg, 0.50 mmol), BuNH2 (4 mL,
40 mmol), and trimethylsilylacetylene (10 mL, 70 mmol).
After stirring for 25 h, the mixture was poured diluted
with petroleum ether and washed with NH4Cl solution.
The organic layer was dried (MgSO4) and concentrated.
Puri®cation by radial chromatography (hexanes) yielded
2umaxˆ508, 1345 independent re¯ections scanned, 897
re¯ections in re®nement (I´1.5s(I)), 122 parameters,
Rˆ0.044, Rwˆ0.042.
Acknowledgements
We thank The Camille and Henry Dreyfus Foundation
(Teacher-Scholar Award 1998±2003 to M. M. H.) and the
University of Oregon for support of this research. S. C. B.
acknowledges the Department of Education for a GAANN
Graduate Fellowship. H. N. was a Fuji-Silysia Chemical/
UO exchange scholar. We thank A. J. Boydston for his
help with the synthesis of compound 9.
1
18 as a light orange oil (1.26 g, 42% from 16). H NMR d
5.84 (AB d, Jˆ10.4 Hz, 2H), 5.79 (AB d, Jˆ10.4 Hz, 2H),
1.64 (s, 6H), 0.21 (s, 18H); 13C NMR d 120.79, 119.36,
102.39, 101.90, 100.91, 77.43, 31.25, 27.50, 20.10; IR
(neat) nˆ3045, 3027, 2214, 2143, 1571 cm21; MS (EI,
70 eV) 247 (18, M11H), 233 (20, M12Me), 73 (100,
SiMe3); HRMS calcd for C21H28Si2: 336.1730, found:
336.1728.
References
5,5-Dimethyl-1,8-cyclotridecadien-3,6,10,12-tetrayne (9).
To a solution of tetrayne 18 (56 mg, 0.17 mmol) dissolved
in pyridine (9 mL) and MeOH (9 mL) was added CuCl
(499 mg, 5 mmol), Cu(OAc)2 (915 mg, 5 mmol), and
K2CO3 (697 mg, 5 mmol). The mixture was stirred at
408C for 24 h. The dark blue-green solution was then diluted
with CH2Cl2, washed successively with 10% HCl solution,
saturated NaHCO3 solution, and water. The organic layer
was dried (MgSO4), ®ltered, and concentrated. Chromato-
graphy on silica gel (9:1 hexanes: CH2Cl2) gave 9 as an
unstable yellow solid that rapidly polymerized into an inso-
luble brown solid. 1H NMR (CD2Cl2) d 6.22 (d, Jˆ10.1 Hz,
2H), 5.92 (d, Jˆ10.1 Hz, 2H), 1.57 (s, 6H); UV (CH2Cl2)
lmax 259, 292, 316, 337, 362, 380 sh nm.
1. Inter alia: (a) Nicolaou, K. C.; Smith, A. L. In Modern Acetylene
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Enraf±Nonius CAD-4 Turbo diffractometer. Structure
re®nement (C atoms isotropic, H atoms riding) was accom-
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6. C24H16, Mrˆ304.39, colorless prism, 0.06£0.15£
0.50 mm, orthorhombic, space group P21212, aˆ
7. This work was presented in part at the American Chemical
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Abstract ORGN 133.
Ê
Ê 3
19.947(3), bˆ5.065(2), cˆ8.365 (1) A, Vˆ845.2(6) A ,
Zˆ2, rcalcˆ1.196 g cm23, MoKa radiation (lˆ0.71073 A),
Ê
mˆ0.629 cm21, F(000)ˆ320, Tˆ238C, 2umaxˆ508, 917
independent re¯ections scanned, 665 re¯ections in re®ne-
ment (I´s(I)), 100 parameters, Rˆ0.040, Rwˆ0.038.
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D. M.; Anthony, J. E. Org. Lett. 2000, 2, 961±963.
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Ê
Ê 3
bˆ12.540(3), cˆ17.043(3) A, Vˆ2905(2) A , Zˆ8,
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Ê
0.66 cm21
,
F(000)ˆ1136, Tˆ228C, 2umaxˆ508, 2895

9588
H. S. Blanchette et al. / Tetrahedron 56 (2000) 9581±9588
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È
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