Synthesis of differentially protected/functionalised acetylenic building blocks from p-benzoquinone and their use in the synthesis of new enediynes

Article abstract of DOI:10.1039/b302323k

The synthesis of differentially protected/functionalized acetylenic building blocks from p-benzoquinone and their use in the synthesis of new enediynes was discussed. The diastereoisomers were separated by using column chromatography and characterized by

Full text of DOI:10.1039/b302323k

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Synthesis of differentially protected/functionalised acetylenic
building blocks from p-benzoquinone and their use in the synthesis
of new enediynes†
Sethuraman Sankararaman* and Manivannan Srinivasan
Department of Chemistry, Indian Institute of Technology Madras, Chennai – 600 036, India.
E-mail: sanka@iitm.ac.in; Fax: 91 44 22570545; Tel: 91 44 22578252
Received 3rd March 2003, Accepted 20th May 2003
First published as an Advance Article on the web 4th June 2003
Sequential addition of two different lithium acetylides to p-benzoquinone yielded diastereomeric mixtures of 1,4-
diethynylcyclohexa-2,5-diene-1,4-diols wherein the two ethynyl groups bear different protective/functional groups.
Selective deprotection to the terminal acetylene followed by Pd(0) mediated coupling with Z-1,2-dichloroethene
yielded new enediynes bearing cyclohexa-2,5-diene units.
yielded the diol 3 in 96% yield (Scheme 1).4 These results
Introduction
prompted us to investigate the sequential addition of two
different lithium acetylides to p-benzoquinone. Accordingly
one equivalent of lithium triisopropylsilylacetylide was added
at Ϫ78 ЊC to p-benzoquinone and the solution was stirred at
Ϫ30 ЊC for 5 h and cooled back to Ϫ78 ЊC. Addition of one
equivalent of lithium trimethylsilylacetylide to the same pot
followed by slow warming to rt over a period of 16 h yielded the
corresponding diol 4 as a mixture of Z and E isomers in the
ratio 1 : 2, respectively (Scheme 2).
The recent past has witnessed tremendous growth in acetylene
chemistry, fuelled by the discovery of new carbon–carbon bond
forming reactions mediated by metal complexes.1 Several novel
acetylenic building blocks have been synthesized.2 The building
block approach is very useful for molecular scaffolding for the
synthesis of n-cyclocarbons, dehydroannulenes, pericyclynes,
graphyne subunits, enediynes and cyclophynes, to name a few.3
Recently we have synthesized Z-1,4-diethynyl-1,4-dimethoxy-
cyclohexa-2,5-diene from p-benzoquinone and demonstrated
its use as an acetylenic building block for the synthesis of
macrocyclic compounds bearing acetylenic bridges.4 In the
building block approach it is often necessary to selectively pro-
tect the terminal acetylenes with various protecting groups so
that they can be deprotected at an appropriate step to carry out
carbon–carbon bond forming reactions.5 During the course of
our investigation we have developed methods for the sequen-
tial addition of differentially protected lithium acetylides to
p-benzoquinone for the synthesis of 1,4-diethynylcyclohexa-
2,5-diene systems bearing two acetylenic groups that are either
differentially protected or differentially functionalized at the
termini.6 Herein we report the synthesis of derivatives of cyclo-
hexa-2,5-diene bearing two acetylenic groups, selective depro-
tection of one of the acetylenic groups to the corresponding
terminal acetylene and subsequent coupling of the terminal
acetylene with Z-1,2-dichloroethene for the synthesis of new
enediynes. The derivatives of 1,4-diethynylcyclohexa-2,5-diene
reported in this article are potentially useful as acetylenic
building blocks for the synthesis of macrocycles and cyclo-
phanes bearing enediyne and acetylenic bridges.
Scheme 1
Results and discussion
Our investigation began with an interesting observation that the
addition of two equivalents of lithium trimethylsilylacetylide
to p-benzoquinone occurred stepwise. At Ϫ78 ЊC the reaction
stopped cleanly at the mono addition stage to yield dienone 2 as
the only product in nearly quantitative yield. It was necessary to
warm up the reaction mixture above Ϫ40 ЊC in order for the
second addition to take place to yield diol 3. The dienone 2 was
isolated in 93% yield as a colorless solid. Addition of two
equivalents of lithium trimethylsilylacetylide to the dienone 2 at
Ϫ78 ЊC and subsequent warming of the reaction mixture to rt
Scheme 2 (a) 1.0 eq. lithium triisopropylsilylacetylide, THF, 5 h,
Ϫ78 ЊC to Ϫ30 ЊC; (b) 1.0 eq. lithium trimethylsilylacetylide, THF,
Ϫ78 ЊC to rt, 16 h; (c) aq. NH4Cl.
The diastereoisomers were separated by column chromato-
graphy and characterized by spectroscopic data. Similarly,
sequential addition of one equivalent of lithium acetylide
derived from 3,3-diethoxypropyne followed by one equivalent
of lithium trimethylsilylacetylide yielded the corresponding diol
5 as a pair of Z and E isomers in the ratio 1 : 2, respectively
(Scheme 3). In the above two reactions reversal of the sequence
of addition of the two acetylides did not affect the yield of the
1
† Electronic supplementary information (ESI) available: 400 MHz H
NMR and 13C NMR spectra. See http://www.rsc.org/suppdata/ob/b3/
b302323k/
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 8 8 – 2 3 9 2
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
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TIPS group is unaffected. The terminal acetylenic hydrogen
appeared as a singlet at δ 2.55 ppm in the 1H-NMR spectra of
Z-8 and Z-9. The coupling of Z-8 and Z-9 with Z-1,2-dichloro-
ethene, mediated by Pd(PPh3)4 gave the corresponding enediyne
derivatives Z-10 (49%) and Z-11 (25%), respectively (Scheme 5).
The olefinic hydrogens of the newly formed enediyne moiety
appeared as a singlet at δ 5.75 ppm in Z-10 and at 5.81 ppm in
Z-11, respectively in the corresponding 1H-NMR spectrum.
Finally the deprotection of the TIPS groups in Z-10 was
effected by treating it with n-Bu4NF in THF to yield the ter-
minal acetylene Z-12 in 75% yield (Scheme 6). Attempted
deprotection of the acetal groups in Z-11 to the corresponding
aldehyde under a variety of conditions8 (98% HCOOH–CHCl3,
rt; 3 M HCl–THF, rt; LiBF4–MeCN, rt and DDQ–MeCN–
H2O, rt) was unsuccessful. Under strongly acidic conditions
the cyclohexadiene units in Z-11 underwent aromatization, the
products of which were not investigated further. Coupling of
Z-8 with excess Z-1,2-dichloroethene using Pd(PPh3)4 yielded
the corresponding mono coupled product 13. Deprotection of
the TIPS group using TBAF yielded the terminal acetylene
14 in 85% yield (Scheme 7). Both Z-12 and 14 are potentially
useful starting materials for the construction of acetylenic
macrocycles bearing cyclohexadiene moieties and enediyne and
polyyne bridging units which are being currently investigated in
our laboratory.
Scheme 3 (a) 1.0 eq. lithium 3,3-diethoxypropyne, THF, 5 h, Ϫ78 ЊC
to Ϫ30 ЊC; (b) 1.0 eq. lithium trimethylsilylacetylide, THF, Ϫ78 ЊC to rt,
16 h; (c) aq. NH4Cl.
diols. The isomer ratios reported for diols 3–5 are based on the
1H-NMR spectral integration of the cyclohexadiene protons.
The stereochemistry of the E isomer of diol 3 was established
by single crystal X-ray crystallographic data.7 The structure of
the E isomer of diol 3 in the crystal is shown in Fig. 1. During
the chromatographic separation of the diastereomers of 3, the
E isomer was eluted first followed by the Z isomer. During
our earlier studies, several derivatives of 3 also showed the same
trend during chromatographic separation, in that the E isomer
was always eluted first.4 In general the E isomer was less polar
than the Z isomer in this series of compounds. On the basis
of these observations, based on the chromatographic elution
order we have assigned the relative stereochemistry of the
diastereomers of diols 4 and 5. The Z isomer of diols 4 and 5
were converted to the corresponding methyl ethers Z-6 and Z-7
using NaH and methyl iodide in good yields (Scheme 4). The
methyl ethers were generally found to be more stable than the
diols towards acid catalyzed decomposition leading to aromatic
compounds. Therefore further transformations were carried out
with the methyl ether derivatives 6 and 7. In order to demon-
strate the synthetic utility of the acetylenic building blocks 6
and 7 where the acetylenic functional groups are differentially
protected in case of 6 and differentially functionalized in case
of 7, selective deprotection of the TMS group followed by Pd(0)
mediated Sonogashira coupling was taken up. The selective
deprotection of the TMS group proceeded smoothly in high
yields when Z-6 and Z-7 were treated with K2CO3 in MeOH
under nitrogen atmosphere to yield the corresponding terminal
acetylene Z-8 and Z-9, respectively. Under these conditions the
Scheme 5 (a) K2CO3, MeOH, rt, N2, 1 h; (b) Z-ClCH᎐CHCl,
᎐
Pd(PPh3)4, CuI, n-BuNH2, THF, rt, N2, 18 h.
Fig. 1 Structure of the E isomer of diol 3 in the crystal showing the H-
bonding between two molecules.
Scheme 6
Scheme 7 (a) Z-ClCH᎐CHCl, Pd(PPh3)4, CuI, n-BuNH2, THF, rt,
᎐
Scheme 4 (a) NaH, MeI, THF, Ϫ78 ЊC to rt, 16 h.
18 h; (b) TBAF, THF, rt, 0.5 h.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 8 8 – 2 3 9 2
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1-(3,3-Diethoxypropynyl)-4-trimethylsilanylethynylcyclohexa-
2,5-diene-1,4-diol (5)
Conclusion
We have shown that the addition of lithium acetylides to
p-benzoquinone occurs in a stepwise manner, thus providing a
method for the synthesis of cyclohexa-2,5-dienes bearing dif-
ferent ethynyl substituents. Sequential addition of two different
lithium acetylides to p-benzoquinone gave cyclohexa-2,5-diene-
1,4-diols bearing ethynyl groups with different protective/func-
tional groups. Using selective deprotection followed by Pd(0)
mediated coupling reaction we have prepared enediynes 10–12
and eneynes 13–14 that are potentially useful as acetylenic
building blocks.
It was prepared by following the procedure described for diol 4
from p-benzoquinone (12.6 g, 0.12 mol). Lithium 3,3-diethoxy-
propylide [prepared from n-BuLi (0.140 mol, 88 mL of a 1.6 M
solution in hexane) and 3,3-diethoxypropyne (15.0 g, 0.12 mol)]
was added first followed by the addition of lithium trimethyl-
silylacetylide [prepared from n-BuLi (0.140 mol, 88 mL of a
1.6 M solution in hexane) and trimethylsilylacetylene (11.5 g,
0.12 mol)] The tan colored crude product was separated by
column chromatography using silica gel and ether–hexane mix-
ture (3 : 7, v/v) as the eluant to yield first the pure E-isomer
(E-5) (16.7 g, 43%) followed by the Z-isomer (Z-5) (11.9 g,
30%). Z-5: viscous liquid; νmax (film)/cmϪ1 3355 (OH), 2176
Experimental
᎐
(C᎐C); δ (400 MHz) 5.80 (4H, s), 5.12 (1H, s), 3.55 and 3.40
᎐
H
General remarks
(4H, quartet of AB pattern, J 9.5 and 7.1), 3.2 (1H, br, s), 2.93
(1H, br, s), 1.06 (6H, t, J 7.1), 0.00 (9H, s); δC (100 MHz) 129.6
(d), 128.7 (d), 104.2 (s), 91.2 (d), 90.2 (s), 84.9 (s), 80.2 (s), 61.01
(s), 61.00 (t), 60.6 (s), 15.0 (q), Ϫ0.3 (q); m/z (EI) 334.1600 (Mϩ,
1%, C18H26SiO4 requires 334.16008), 317 (1), 301 (2), 255 (4),
246 (5), 231 (28), 215 (40), 191 (62), 73 (100); E-5: mp 88–90 ЊC;
1H and 13C NMR spectra (CDCl3 solution) were recorded
with a JEOL GSX-400 spectrometer at 400 MHz and 100 MHz
or on a Bruker AM-200 at 200 MHz and 50 MHz, respec-
tively. Chemical shifts are reported in ppm from TMS. Mass
spectra were recorded either on a Finnigan MAT 8439 or
νmax (KBr)/cmϪ1 3355 (OH), 2176 (C᎐C); δ (400 MHz) 5.88
᎐
a
Finnigan MAT 8230 spectrometer. IR spectra were
᎐
H
recorded either on a Nicolet 320 FTIR or on a Shimadzu IR470
spectrometer. All reactions were carried out under nitrogen
unless indicated otherwise. Column chromatography was per-
formed on silica gel (60–120 or 240–400 mesh) with various
mixtures of diethyl ether, ethyl acetate, and hexane. TLCs were
run on Macherey-Nagel polygram sil G/UV254 plates. Melting
points are uncorrected. THF was distilled from calcium
hydride.
(4H, s), 5.11 (1H, s), 3.5 and 3.4 (4H, quartet of AB pattern,
J 9.5 and 7.1), 2.32 (1H, br, s), 2.20 (1H, br s), 1.06 (6H, t,
J 7.1), 0.00 (9H, s); δC (100 MHz) 130.1 (d), 129.3 (d), 104.4 (s),
91.1 (d), 90.2 (s), 84.9 (s), 80.3 (s), 61.1 (t), 61.0 (s), 15.0 (q),
Ϫ0.3 (q); m/z (EI) 335 (<1%), 334 (Mϩ,<1), 333 (1), 289
(Mϩ Ϫ OEt, 1), 246 (5), 231 (12), 215 (15), 191 (20), 169 (100),
73 (90).
General procedure for the methylation of diols 4 and 5
1-Triisopropylsilanylethynyl-4-trimethylsilanylethynylcyclohexa-
2,5-diene-1,4-diol (4)
The pure Z diol (Z-4 or Z-5) (0.02 mol) in THF (100 cm3) was
added to a stirred suspension of NaH (0.9 g, 0.04 mol) in THF
(200 cm3) at Ϫ78 ЊC. The yellow colored suspension was stirred
for 30 min at the same temperature. Methyl iodide (14.9 g,
6.6 cm3, 0.11 mol) was added drop wise from a syringe and the
resulting mixture was allowed to warm to room temperature
overnight (18 h). The reaction mixture was poured into ice cold
saturated NH4Cl solution (500 cm3). The organic layer was
separated and the aqueous portion was extracted with ether
(3 × 200 cm3). The combined organic extract was washed thor-
oughly with water (2 × 200 cm3) and finally with saturated brine
solution (200 cm3). After drying over MgSO4, solvent was
removed to give the crude product as a viscous liquid. It was
purified by column chromatography on silica gel with ether–
hexane mixture (1 : 4, v/v) to afford the dimethyl ether as a
colorless viscous liquid.
n-BuLi (38 cm3 of a 1.6 M solution in hexane, 0.06 mol)
was added to a stirred solution of triisopropylsilylacetylene
(11.0 g, 13.5 cm3, 0.06 mol) in dry THF (100 cm3) at Ϫ78 ЊC.
The resulting pale yellow solution was stirred for 45 min at the
same temperature. It was added drop wise using a stainless
steel needle to
a stirred yellow viscous suspension of
p-benzoquinone (5.93 g, 0.06 mol) in dry THF (300 cm3)
at Ϫ78 ЊC. The dark blue reaction mixture was stirred at
Ϫ30 ЊC for 5 h and then cooled to Ϫ78 ЊC. In another schlenck
flask lithium trimethylsilylacetylide was prepared from
n-BuLi (38 cm3 of a 1.6 M solution in hexane, 0.06 mol) and
trimethylsilylacetylene (5.93 g, 8.5 cm3, 0.06 mol) in dry THF
(100 cm3) at Ϫ78 ЊC. It was added drop wise using a stain-
less steel needle to the above dark blue reaction mixture
at Ϫ78 ЊC and allowed to attain 10 ЊC over a period of 16 h.
It was cooled to 0 ЊC and quenched with aqueous saturated
NH4Cl solution (300 cm3). The organic layer was separated
and the aqueous layer was extracted with CH2Cl2 (4 × 100 cm3).
The combined organic extract was washed with ice cold
water (200 cm3) followed by ice cold saturated brine solution
(200 cm3). After drying over MgSO4, solvent was removed and
the resulting solid product was separated by column chromato-
graphy using silica gel and ether–hexane mixture (3 : 7,
v/v) as the eluant to yield first the pure E-isomer (E-4) (10.8 g,
51%) followed by the Z-isomer (Z-4) (9.17 g, 43%). Z-4:
Z-1,4-Dimethoxy-1-(3,3-diethoxyprop-1-ynyl)-4-trimethyl-
silanylethynylcyclohexa-2,5-diene (Z-7). Yield (4.46 g, 82%),
viscous liquid, νmax (film)/cmϪ1 2977, 2899, 2166 (C᎐C); δH (400
᎐
᎐
MHz) 5.87 and 5.84 (4H, AAЈBBЈpattern, J 10.2), 5.15 (1H, s),
3.57 and 3.43 (4H, quartet of AB pattern, J 9.5 and 7.1), 3.13
(3H, s, OMe), 3.10 (3H, s, OMe), 1.05 (6H, t, J 7.1), 0.00 (9H,
s); δC (100 MHz) 129.4 (d), 128.7 (d), 102.8 (s), 91.2 (s), 91.1 (d),
83.3 (s), 81.3 (s), 66.6 (s), 66.2 (s), 60.9 (t), 51.7 (q), 51.5 (q), 15.1
(q), Ϫ0.3 (q); m/z (EI) 364 (1%), 363 (4), 362.2089 (Mϩ, 22,
C20H30SiO4 requires 362.1914), 331 (30), 317 (18), 289 (20), 273
(19), 255 (38), 241 (22), 227 (50), 183 (23), 113 (50), 103 (20), 73
(100).
mp 186–188 ЊC; νmax (KBr)/cmϪ1 3345 (OH), 2181, 2153 (C᎐C);
᎐
᎐
δH (400 MHz) 5.81 (4H, s), 2.34 (2H, br, s), 0.91 (21H, s),
0.00 (9H, s); δC (100 MHz) 129.3 (d), 129.0 (d), 104.3 (s),
100.0 (s), 89.9 (s), 86.7 (s), 61.3 (s), 61.25 (s), 18.5 (q), 11.0 (d),
Ϫ0.3 (q); m/z (EI) 388.2190 (Mϩ, 10%, C22H36Si2O2 requires
388.2254), 370 (20), 327 (58), 311 (40), 257 (42), 73 (100); E-4:
Z-1,4-Dimethoxy-1-triisopropyl-silanylethynyl-4-trimethyl-
silanylethynylcyclohexa-2,5-diene (Z-6). In case of Z-6, its for-
mation was confirmed only by 1H- and 13C-NMR spectral data.
After purification it was directly converted to Z-8 and com-
pound Z-8 was fully characterized. Yield Z-6 (91%) viscous
liquid, δH (400 MHz) 5.80 (4H, s), 3.12 (6H, s), 0.88 (21H, s),
0.00 (9H, s); δC (100 MHz) 129.5 (d), 127.1 (d), 104.7 (s), 102.7
mp 56–58 ЊC; νmax (KBr)/cmϪ1 3413 (OH), 2164 (C᎐C); δH (400
᎐
᎐
MHz) 5.86 (4H, s), 2.20 (1H, br s), 2.1 (s, 1H), 0.89 (21H, s),
0.00 (9H, s); δC (100 MHz) 130.3 (d), 129.9 (d), 107.2 (s)
104.9 (s), 90.2 (s), 86.8 (s), 61.5 (s), 61.47 (s), 18.8 (q), 11.3 (d),
Ϫ0.12 (q).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 8 8 – 2 3 9 2
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(s), 91.5 (s), 90.2 (s), 61.5 (s), 61.3 (s), 56.0 (q), 18.8 (q), 11.3 (d),
0.0 (q).
Although, the 1H and 13C NMR spectroscopic data are consist-
ent with the structure of enediyne Z-10, mass spectrum (EI) of
this substance did not show Mϩ ion. However, its desilylated
derivative, namely, enediyne Z-12 is fully characterized.
General procedure for the deprotection of the TMS group
To a stirred solution of the column purified dimethoxy deriv-
ative (Z-6 and Z-7) (0.01 mol) in degassed MeOH (200 cm3),
solid K2CO3 (5.45 g, 0.04 mol) was added under a nitrogen
atmosphere at room temperature and stirring was continued for
1 h. After completion of the reaction, about 150 cm3 of MeOH
was removed under reduced pressure then the resulting slurry
was poured into ice cold water (700 cm3) and extracted with
ether (3 × 100 cm3). The combined organic extract was washed
thoroughly with water (2 × 100 cm3) and once with saturated
brine solution (200 cm3). After drying over anhydrous MgSO4,
solvent was removed to get a yellow viscous liquid. The crude
product was column chromatographed on silica gel with ether–
hexane mixture (1 : 9, v/v) to afford the desilylated product as
colorless viscous liquids.
Z-1,6-Bis[Z-1,4-dimethoxy-4-(3,3-diethoxyprop-1-ynyl)cyclo-
hexa-2,5-dienyl]hexa-3-ene-1,5-diyne (Z-11). Yield (0.77 g, 1.3
mmol, 25% from 10.3 mmol of Z-9), viscous liquid, νmax (film)/
cmϪ1 2978, 2888, 2146 (C᎐C); δ (400 MHz) 6.03 and 5.97 (8H,
᎐
᎐
H
AAЈBBЈpattern, J 10.1), 5.81 (2H, s), 5.23 (2H, s), 3.63 and 3.50
(8H, quartet of AB pattern, J 9.5 and 7.1), 3.3 (6H, s), 3.23 (6H,
s), 1.14 (12H, t, J 7.1); δC (100 MHz) 129.1 (d), 128.5 (d), 120.0
(d), 94.8 (s), 91.2 (d), 83.33 (s), 83.29 (s), 81.4 (s), 66.7 (s), 66.2
(s), 60.9 (t), 51.9 (q), 51.7 (q), 15.0 (q). Although, the 1H and 13
C
NMR spectroscopic data are consistent with the structure of
enediyne Z-11, mass spectrum (EI) of this substance did not
show Mϩ ion.
Z-1,6-Bis[Z-4-ethynyl-1,4-dimethoxycyclohexa-2,5-dienyl]hexa-
3-ene-1,5-diyne (Z-12)
Z-1,4-Dimethoxy-1-triisopropylsilanylethynyl-4-ethynylcyclo-
hexa-2,5-diene (Z-8). Yield (5.95 g, 0.017 mol, 85% from 0.02
EtOH (10 drops) and n-Bu4NF (1 M solution in THF, 1.5 cm3)
were added to the silyl protected enediyne Z-10 (1.27 g,
2.0 mmol) in dry THF (50 cm3) with stirring at room temper-
ature. After 0.5 h the reaction mixture was diluted with ether
(100 cm3), washed with water (100 cm3) followed by saturated
brine (2 × 100 cm3). The organic layer was dried over MgSO4,
and solvent was evaporated. The crude product was purified by
column chromatography on silica gel with ether–hexane mix-
ture (20 : 80, v/v) to afford Z-12 (0.53 g, 75%) as a colorless
mole of Z-6), colorless liquid, νmax (film)/cmϪ1 3311 (C᎐C–H),
᎐
᎐
᎐
2944, 2866, 2163 (C᎐C); δ (400 MHz) 6.12 and 6.03 (4H,
᎐
H
AAЈBBЈpattern, J 10.1), 3.38 (3H, s), 3.32 (3H, s), 2.55 (1H, s),
1.08 (21H, s); δC (100 MHz) 129.8 (d), 128.2 (d), 104.7 (s), 88.1
(s), 82.1 (d), 73.6 (s), 66.8 (s), 66.3 (s), 51.7 (q), 51.6 (q), 18.5 (q),
11.1 (d); m/z (EI) 346 (5%), 345 (10), 344.2084 (Mϩ, 38,
C21H32SiO2 requires 344.2173), 313 (Mϩ Ϫ OMe, 25), 286 (Mϩ
Ϫ CH(CH3)2, 30), 75 (100).
solid, mp 118–120 ЊC; νmax (KBr)/cmϪ1 3293 (C᎐C–H), 2936,
᎐
᎐
Z-1,4-Dimethoxy-1-(3,3-diethoxyprop-1-ynyl)-4-ethynylcyclo-
hexa-2,5-diene (Z-9). Yield (3.37 g, 0.009 mol, 90% from 0.01
᎐
2099 (C᎐C); δH (400 MHz) 6.04 and 5.97 (8H, AAЈBBЈpattern,
᎐
J 10.1), 5.83 (2H, s), 3.30 (6H, s), 3.24 (6H, s), 2.53 (2H, s);
δC (100 MHz) 129.2 (d), 128.6 (d), 120.0 (d), 94.7 (s), 83.3 (s),
82.1 (d), 74.2 (s), 66.6 (s), 66.1 (s), 51.8 (q), 51.6 (q); m/z (EI)
369.1320 (Mϩ Ϫ OCH3, 2%, C25H21O3 requires 369.1491), 338
(19), 307 (38), 276 (42), 263 (100), 250 (50).
mol of Z-7), colorless liquid, νmax (film)/cmϪ1 3288 (C᎐C–H),
᎐
᎐
᎐
2978, 2889, 2114 (C᎐C); δ (400 MHz) 5.99 and 5.96 (4H,
᎐
H
AAЈBBЈpattern, J 10.3), 5.22 (1H, s), 3.65 and 3.52 (4H, quar-
tet of AB pattern, J 9.5 and 7.1), 3.23 (3H, s), 3.22 (3H, s), 2.55
(1H, s), 1.14 (6H, t, J 7.1); δC (100 MHz) 128.8 (d), 128.7 (d),
90.9 (d), 82.8 (s), 81.6 (d), 81.3 (s), 74.1 (s), 65.9 (s), 65.8 (s),
60.6 (t), 51.4 (q), 51.3 (q), 14.8 (q); m/z (EI) 290 (Mϩ, 1%), 289
(2), 273 (5), 259 (Mϩ Ϫ OCH3, 18), 245 (Mϩ Ϫ OC2H5, 20), 231
(18), 217 (20), 201 (Mϩ Ϫ 2OC2H5, 20), 185 (Mϩ Ϫ CH(OEt)2,
40), 139 (100), 127 (40), 113 (65), 85 (28), 75 (30).
[4-(Z-4-Chlorobut-3-en-1-ynyl)-Z-1,4-dimethoxycyclohexa-2,5-
dienylethynyl]triisopropylsilane (13)
The acetylenic precursor Z-8 (2.9 g, 8.4 mmol) was treated with
Z-dichloroethene (1.87 g, 19.3 mmol) and the reaction was
carried out as described in the synthesis of compounds Z-10
and Z-11. Chromatographic purification of the crude product
on silica gel with ether–hexane mixture (1 : 9, v/v) gave 13 (1.53
General procedure for the synthesis of enediynes Z-10 and Z-11
(Z)-1,2-Dichloroethene (0.39 g, 4.02 mmol) was added to
a dry schlenck flask, containing tetrakis(triphenylphosphine)-
palladium(0) (0.193 g, 0.17 mmol) in dry THF (50 cm3). The
mixture was stirred at room temperature for 30 min. To the
clear yellow solution thus obtained the acetylenic substrate (Z-
8 and Z-9) (8.4 mmol) and n-butylamine (2 cm3) were added
and the resulting mixture was stirred well. After 30 min CuI
(0.175 g, 0.921 mmol) was added and stirring was continued for
18 h at room temperature. After completion of the reaction, ice
cold saturated aqueous NH4Cl (300 cm3) was added to the reac-
tion mixture and it was extracted with CH2Cl2 (4 × 100 cm3).
The combined organic extracts were washed with water (200
cm3) and saturated brine (200 cm3). The organic layer was dried
over MgSO4 and solvent was removed. The crude product was
purified by column chromatography on silica gel with ether–
hexane mixture (1 : 9 v/v in the case of Z-8 and 3 : 7 v/v in the
case of Z-9) to afford the enediyne as a viscous liquid.
g, 45%) as a viscous liquid, νmax (film)/cmϪ1 2944, 2886, 2163
᎐
(C᎐C); δ (400 MHz) 6.44 (1H, d, J 7.5), 6.11 and 6.06 (4H,
᎐
H
AAЈBBЈpattern, J 10.2), 5.88 (1H, d, J 7.5), 3.37 (3H, s), 3.36
(3H, s), 1.07 (21H, s); δC (100 MHz) 129.6 (d), 129.5 (d), 128.1
(d), 111.3 (d), 104.8 (s), 95.3 (s), 88.0 (s), 79.5 (s), 67.0 (s), 66.8
(s), 51.6 (q), 18.5 (q), 11.1 (d); m/z (EI) 408 (<1%), 407 (2),
406 (8), 405 (5), 404.1893 (Mϩ, 18, C23H33SiO235Cl requires
404.1939), 373 (10), 361 (80), 287 (78), 275 (60), 260 (100),
245 (79).
Z-4-(Z-4-Chlorobut-3-en-1-ynyl)-6-ethynyl-1,4-dimethoxycyclo-
hexa-2,5-diene (14)
Desilylation of 13 (1.42 g, 4.0 mmol) was carried out in dry
THF (50 cm3) using the same procedure as described in the case
of Z-12 using n-Bu4NF. The crude product was purified by
column chromatography on silica gel with ether–hexane mix-
ture (1 : 4, v/v) to afford 14 (0.74 g, 85%) as colorless viscous
liquid, νmax (film)/cmϪ1 3293 (C᎐C–H), 2938, 2115 (C᎐C);
᎐
᎐
Z-1,6-Bis[Z-1,4-dimethoxy-4-(triisopropylsilylethynyl)cyclo-
hexa-2,5-dienyl]hexa-3-ene-1,5-diyne (Z-10). Yield (1.41 g, 2
mmol, 49% from 8.4 mmol of Z-8), viscous liquid, νmax (film)/
᎐
᎐
δH (400 MHz) 6.45 (1H, d, J 7.49), 6.10 and 6.05 (4H, AAЈBBЈ-
pattern, J 10.1), 5.91 (1H, d, J 7.49), 3.37 (3H, s), 3.32 (3H, s),
2.61 (1H, s); δC (100 MHz) 129.5 (d), 129.1 (d), 128.1 (d), 111.3
(d), 81.9 (s), 81.6 (d), 80.0 (s), 73.7 (s), 66.7 (s), 66.5 (s), 51.74
(q), 51.70 (q); m/z (EI) 217 (Mϩ Ϫ OMe, 10%), 181 (100), 150
(80).
cmϪ1 2943, 2866, 2163 (C᎐C); δ (400 MHz) 5.98 (8H, s), 5.75
᎐
᎐
H
(2H, s), 3.30 (6H, s), 3.27 (6H, s), 0.98 (42H, s); δC (100 MHz)
128.8 (d), 127.9 (d), 119.6 (d), 104.7 (s), 94.6 (s), 87.6 (s), 82.7
(s), 66.6 (s), 66.5 (s), 51.5 (q), 51.3 (q), 18.2 (q), 10.8 (d).
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 8 8 – 2 3 9 2
2391

View Article Online
Crystal data for compound E-3‡
acknowledged. We thank the Regional Sophisticated Instru-
mentation Centre, IIT, Madras for the spectral data.
Single crystals of E-3 suitable for X-ray diffraction were
obtained by crystallization of the column purified E-3 from a
mixture of ether–hexane. The sample was dissolved in mini-
mum amount of ether and then hexane was added until a slight
turbidity was seen. The resulting solution was left in the fridge
to obtain the crystals. C16 H24 O2 Si2, M = 304.53, Ortho-
rhombic, space group Pca2(1), a = 12.818(7), b = 10.012(5),
c = 29.263(14) Å, U = 3756(3) Å3, T = 115(2) K, Z = 8,
λ = 0.71073 Å, m = 0.188 mmϪ1, 18239 reflections measured,
5904 unique (Rint = 0.1206), final wR(F 2) [for 2540 reflections
with I > 2σ(I )] was 0.1745 and wR(F 2) was 0.2075 (all data),
refinement method was full-matrix least-squares on F 2 and
goodness of fit on F 2 was 0.846.
References
1 Modern Acetylene Chemistry, eds. P. J. Stang, and F. Diederich,
VCH, Weinheim, 1995; Metal Catalyzed Cross Coupling Reactions,
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2 H. Hopf, Classics in Hydrocarbon Chemistry, Wiley-VCH, Weinheim,
2000, ch. 15, pp. 457–472.
3 For recent reviews: F. Diederich, in Modern Acetylene Chemistry, eds.
P. J. Stang, and F. Diederich, VCH, Weinheim, 1995, ch. 13, pp. 443–
471; L. T. Scott, and J. M. Cooney, in Modern Acetylene Chemistry,
eds. P. J. Stang, and F. Diederich, VCH, Weinheim, 1995, ch. 9,
pp. 321–351; Y. Rubin, and F. Diederich, in Stimulating Concepts in
Chemistry, eds. F. Vogtle, J. F. Stoddart, M. Shibasaki, Wiley-VCH,
Weinheim, 2000, pp. 163–186; F. Diederich, Chem. Commun., 2001,
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and Y. Tobe, Chem. Soc. Rev, 1999, 28, 107.
Acknowledgments
4 M. Srinivasan, S. Sankararaman, H. Hopf and B. Varghese, Eur. J.
Org. Chem, 2003, 660.
5 J. Zhang, D. J. Pesak, J. L. Ludwick and J. S. Moore, J. Am. Chem.
Soc., 1994, 116, 4227; B. W. Wan, S. C. Brand, J. J. Pak and
M. M. Haley, Chem. Eur. J., 2000, 6, 2044.
6 For earlier reports on the addition of lithium acetylides to
p-benzoquinone see: W. Ried and H. J. Schmidt, Chem. Ber., 1957, 90,
2553; N. N. L. Madhavi, C. Bilton, J. A. K. Howard, F. H. Allen,
A. Nangia and G. R. Desiraju, New J. Chem., 2000, 24, 1 for addition
of organolithium reagents to p-benzoquinone see A. Fischer and
G. N. Henderson, Tetrahedron Lett, 1980, 701 and references cited
therein.
We thank the Volkswagen Stiftung, Hannover, Germany and
the Council of Scientific and Industrial Research, India for
financial support. We thank Professor H. Hopf, Institute of
Organic Chemistry, University of Braunschweig, Germany for
his constant support, encouragement and useful discussions
and Professor Mikhail Antipin, Director of the X-Ray Struc-
tural Center, INEOS, Russian Academy of Sciences, Moscow,
for the X-ray crystallographic data and structure refinement. A
graduate fellowship from IIT, Madras for MS is gratefully
7 The spectral data for both the isomers of 3 have been reported earlier
‡ CCDC reference numbers 202840. See http://www.rsc.org/suppdata/
ob/b3/b302323k/ for crystallographic data in .cif or other electronic
format.
in ref. 4.
8 T. W. Greene, and P. G. M. Wuts, Protective Groups in Organic
Synthesis, 3rd edn., John Wiley, New York, 1999, p. 299.
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 2 3 8 8 – 2 3 9 2
2392