One-pot formation and derivatization of di- and triynes based on the Fritsch-Buttenberg-Wiechell rearrangement

Article abstract of DOI:10.1021/jo701810g

(Chemical Equation Presented) A divergent, one-pot synthesis of functionalized polyynes has been developed. Beginning with the appropriately substituted dibromoolefinic precursor, a carbenoid Fritsch-Buttenberg-Wiechell (FBW) rearrangement is used to gene

Full text of DOI:10.1021/jo701810g

One-Pot Formation and Derivatization of Di- and Triynes Based on
the Fritsch-Buttenberg-Wiechell Rearrangement
Thanh Luu,† Yasuhiro Morisaki,‡ Nina Cunningham,† and Rik R. Tykwinski*,†
Department of Chemistry, UniVersity of Alberta, Edmonton, Alberta T6G 2G2, Canada, and Department of
Polymer Chemistry, Graduate School of Engineering, Kyoto UniVersity, Katsura Nishikyo-ku,
Kyoto 615-8510, Japan
rik.tykwinski@ualberta.ca
ReceiVed August 17, 2007
A divergent, one-pot synthesis of functionalized polyynes has been developed. Beginning with the
appropriately substituted dibromoolefinic precursor, a carbenoid Fritsch-Buttenberg-Wiechell (FBW)
rearrangement is used to generate the lithium acetylide of a conjugated polyyne framework, and subsequent
trapping with carbon-based electrophiles provides for in situ formation of a wide range of di- and triynes.
The lithium acetylide formed from the FBW reaction can also undergo transmetalation to provide the
corresponding zinc, copper, tin, or platinum acetylides, leading to the divergent formation of symmetrical
and unsymmetrical conjugated acetylenes, as well as ynones.
Introduction
however, be problematic due to the fact that they often show
limited stability.7 Metal acetylides 1 (Scheme 1), on the other
hand, are often stable intermediates when kept in solution.
Although the most obvious route to an intermediate lithium
acetylide might be through a two-step approach consisting of
desilylation and lithiation (i.e., Scheme 1A), instability of the
terminal polyyne often renders such an approach impossible.
Thus, a number of methods have been developed for the in situ
generation of the metal acetylide 1, typically based on one of
two strategies. One approach relies on the derivatization of an
existing polyyne core through, for example, desilylation/
metalation of a 1-(trimethylsilyl)-1,3-butadiyne or -1,3,5-
hexatriyne (2 or 3) with MeLi-LiBr8-10 or Si-Sn11,12 exchange
mediated by TBAF (parts B and C, respectively, of Scheme 1).
The second approach utilizes an initial elimination reaction
using, for example, 1-halo-1-buten-3-ynes 413-17 or (Z)-1-
methoxy-1-buten-3-ynes 518,19 to construct a conjugated diyne,
Conjugated carbon-carbon triple bonds are important build-
ing blocks for organic chemistry because they are found in a
wide variety of natural products,1-3 and they can function as
carbon-rich scaffolds and organic materials.4 As well they can
be utilized as high-energy precursors for many cyclic and acyclic
derivatives.5 The synthesis of organic compounds containing
multiple carbon-carbon triple bonds can be challenging. Over
the years, a number of metal-catalyzed hetero- and homocou-
pling reactions have been developed for the formation of sp-
sp2 and sp-sp bonds, many of which have been refined and
applied to the synthesis of structurally diverse derivatives.6 The
use of terminal polyynes in these coupling reactions can,
† University of Alberta.
‡ Kyoto University.
(1) Shi Shun, A. L. K.; Tykwinski, R. R. Angew. Chem., Int. Ed. 2006,
45, 1034-1057.
(2) Chemistry and Biology of Naturally Occurring Acetylenes and Related
Compounds; Lam, J., Breteler, H., Arnason, T., Hansen, L., Eds.; Elsevier:
Amsterdam, 1988.
(7) For stable terminal diynes, see: West, K.; Wang, C.; Batsanov, A.
S.; Bryce, M. R. J. Org. Chem. 2006, 71, 8541-8544.
(8) Holmes, A. B.; Jennings-White, C. L. D.; Schulthess, A. H.; Akinde,
B.; Walton, D. R. M. J. Chem. Soc., Chem. Commun. 1979, 840-842.
(9) Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A. J. Organomet.
Chem. 2005, 690, 3004-3008.
(3) Bohlmann, F.; Burkhardt, T.; Zdero, C. Naturally Occuring Acety-
lenes; Academic Press: New York, 1973.
(4) Acetylene Chemistry: Chemistry, Biology, and Material Science;
Diederich, F., Stang, P. J., Tykwinski, R. R., Eds.; Wiley-VCH: Weinheim,
Germany, 2005.
(5) Larock, R. C. In Acetylene Chemistry: Chemistry, Biology, and
Material Science; Diederich, F., Stang, P. J., Tykwinski, R. R., Eds.; Wiley-
VCH: Weinheim, Germany, 2005; Chapter 2.
(6) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int. Ed.
2000, 39, 2632-2657.
(10) Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A. Tetrahedron
2006, 62, 5126-5132.
(11) Mukai, C.; Miyakoshi, N.; Hanaoka, M. J. Org. Chem. 2001, 66,
5875-5880.
(12) Warner, B. P.; Buchwald, S. L. J. Org. Chem. 1994, 59, 5822-
5823.
10.1021/jo701810g CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/14/2007
9622
J. Org. Chem. 2007, 72, 9622-9629

Formation and DeriVatization of Di- and Triynes
SCHEME 1
SCHEME 2
followed by metal acetylide formation (parts D and E, respec-
tively, of Scheme 1). In either case, the result is a nucleophilic
acetylide that can be subsequently derivatized, and both ap-
proaches have been quite successful for the formation of diynes.
Much less has been done to generalize these protocols to triynes,
although a recent report by Negishi and co-workers provides a
viable route to not only triynes, but tetra- and pentaynes as
well.20
We envisioned a one-pot, divergent route for the formation
and substitution of di- and triynes based on the R-elimination
of a 1,1-dibromoolefin, 6 (Scheme 2), to initiate a sequence
consisting of a Fritsch-Buttenberg-Wiechell (FBW) rearrange-
ment21-24 and deprotonation. The result would be a lithium
acetylide intermediate 7 that could then be trapped directly with
electrophiles to give diynes 8 or triynes 9. Alternatively, the
lithium acetylide could be subjected to transmetalation to give
(a) zinc acetylides 10 for Negishi coupling to provide R,ω-tolans
11, (b) copper acetylides 12 for Glaser-Hay homocoupling to
polyynes 13, (c) alkynylstannanes 14 for Stille coupling to
ynones 15, and (d) the stable platinum σ-acetylide complexes
16. We report herein the successful development of this
(13) Himbert, G.; Umbach, H.; Barz, M. Z. Naturforsch., B 1984, 39,
661-667.
(14) Negishi, E. I.; Okukado, N.; Lovich, S. F.; Luo, F. T. J. Org. Chem.
1984, 49, 2629-2632.
(15) Kende, A. S.; Smith, C. A. J. Org. Chem. 1988, 53, 2655-2657.
(16) Alami, M.; Crousse, B.; Linstrumelle, G. Tetrahedron Lett. 1995,
36, 3687-3690.
(17) See also: (a) Bartlome, A.; Sta¨mfli, U.; Neuenschwander, M. HelV.
Chim. Acta 1991, 74, 1264-1272. (b) Faul, D.; Himbert, G. Liebigs Ann.
Chem. 1986, 1466-1473. (c) Okuhara, K. J. Org. Chem. 1976, 41, 1487-
1494.
(21) Chalifoux, W. A.; Tykwinski, R. R. Chem. Rec. 2006, 6, 169-
182.
(22) Eisler, S.; Chahal, N.; McDonald, R.; Tykwinski, R. R. Chem.s
Eur. J. 2003, 9, 2542-2550.
(18) Stracker, E. C.; Zweifel, G. Tetrahedron Lett. 1990, 31, 6815-
6818.
(23) Eisler, S.; Tykwinski, R. R. J. Am. Chem. Soc. 2000, 122, 10736-
10737.
(19) Kwon, J. H.; Lee, S. T.; Shim, S. C.; Hoshino, M. J. Org. Chem.
1994, 59, 1108-1114.
(20) Me´tay, E.; Hu, Q.; Negishi, E. Org. Lett. 2006, 8, 5773-5776.
(24) Eisler, S.; Slepkov, A. D.; Elliott, E.; Luu, T.; McDonald, R.;
Hegmann, F. A.; Tykwinski, R. R. J. Am. Chem. Soc. 2005, 127, 2666-
2676.
J. Org. Chem, Vol. 72, No. 25, 2007 9623

Luu et al.
SCHEME 3
divergent process for the one-pot formation of polyynes and
describe its scope for the construction of substituted deriva-
tives.25
a trace amount of the desired diyne 8a was observed.29 The
major product formed in both cases was the terminal diyne 18,7
along with a trace of the protonated species 19 that resulted
from quenching of the carbenoid intermediate of the reaction.22
Thus, the presence of water does not completely prevent FBW
rearrangement to the diyne, but it does effectively prevent
trapping of the intermediate acetylide.
Results and Discussion
The requisite precursors, terminal alkynes 6a-g, were
synthesized in good yield from the corresponding TMS-
protected enynes 17a-g11,22 (Scheme 3) via desilylation with
K2CO3 in methanol/THF. The most important aspect in the
preparation of compounds 6a-g is the purification process,
which must ensure that the terminal alkyne products are
absolutely anhydrous before being carried on to the deproto-
nation-rearrangement step to follow (vide infra). Typically, this
can be accomplished by passing the terminal alkyne product
through a short column of unactivated alumina before proceed-
ing to the FBW reaction.
Initial studies were aimed at optimizing the FBW/deproto-
nation and trapping sequence. It is known that the successful
formation of polyynes using an FBW reaction requires an apolar
solvent such as hexanes.22 In the present case, however, the
dibromoolefins 6a-g showed only minimal solubility in hex-
anes, especially upon cooling to the desired reaction temperature.
Optimization studies determined that this problem could be
circumvented if the dibromoolefin 6 (ca. 0.5-1 mmol) was
initially dissolved in ca. 2 mL of toluene and this solution then
diluted with ca. 10 mL of hexanes.26 In the second step of the
reaction, it was quickly discovered that addition of an electro-
phile directly to the solution of intermediate 7 in hexanes/toluene
typically gave a low yield of the desired products 8 or 9 (Scheme
2). It was surmised that the nonpolar reaction medium that
favored the FBW rearrangement concurrently disfavored the
subsequent reaction with an electrophile. This problem was
easily solved by adding the electrophile as an ethereal solution
to the intermediate 7.
The scope of this one-pot reaction was then explored, again
using precursor 6a as a model system and diynols as the first
targets. Both di- and triynols have been isolated from a range
of natural sources and show a vast array of biological
activity.1,3,30-33 They can also be challenging synthetic targets.34
Thus, dibromoolefin 6a was subjected to BuLi to generate the
lithium acetylide intermediate 7a, which was subsequently
trapped with a variety of carbonyl electrophiles, including
formaldehyde, aryl and alkyl aldehydes, ketones, and CO2. The
products 8b-i were isolated typically in good yields (57-95%)
following aqueous workup and chromatographic purification
(Table 1). The latter three examples (8g-i) are perhaps the most
noteworthy. Compound 8g represents a substrate that could
easily be carried on to the formation of the unsymmetrical
tetrayne via a sequence of oxidation, dibromoolefination, and
an FBW rearrangement,35 while 8h provides an interesting
building block for three-dimensional carbon-rich architectures.36
The formation of 8i demonstrates the potential of this protocol
for reactions with alkyl aldehydes with acidic R-protons.
The successful formation of unsymmetrical diynes then
directed efforts to the formation of triynes using an analogous
route. Gratifyingly, the reaction of dibromoolefin 6c with BuLi
at -20 °C followed by trapping with a variety of electrophiles
gave triyne derivatives 9a-e.37 While the overall yields of 54-
72% for these reactions might only be labeled as moderate, it
is worth emphasizing that, in a single step, the triyne core is
both constructed and functionalized. Thus, this method is nicely
complementary to existing routes of triyne formation such as
the Cadiot-Chodkiewicz reaction.38
During the initial optimization of this procedure, the effect
of adventitious water on the reaction was also probed (eq 1).
Using dry hexanes and toluene,27 the reaction of dibromoolefin
(29) “Wet” toluene and hexanes were arrived at by storing reagent grade
solvent over molecular sieves (4 Å) for 24 h.
(30) Biologically ActiVe Natural ProductssPotential Use in Agriculture;
Cutler, H., Ed.; American Chemical Society: Washington, DC, 1988; Vol.
380.
(31) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.;
Prinsep, M. R. Nat. Prod. Rep. 2003, 20, 1-48.
6a with BuLi at -20 °C followed by quenching with methyl
iodide gave 8a in 67% yield.28 Conversely, when the reaction
was repeated using either “wet” toluene or “wet” hexanes, only
(32) Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1-49.
(33) Meinwald, J.; Meinwald, Y. C.; Chalmers, A. M.; Eisner, T. Science
1968, 160, 890-892.
(34) Luu, T.; Tykwinski, R. R. J. Org. Chem. 2006, 71, 8982-8985.
(35) Luu, T.; Elliott, E.; Slepkov, A. D.; Eisler, S.; McDonald, R.;
Hegmann, F. A.; Tykwinski, R. R. Org. Lett. 2005, 7, 51-54.
(36) Manini, P.; Amrein, W.; Gramlich, V.; Diederich, F. Angew. Chem.,
Int. Ed. 2002, 41, 4339-4343.
(25) For a preliminary report of this work, see: Morisaki, Y.; Luu, T.;
Tykwinski, R. R. Org. Lett. 2006, 8, 689-692.
(26) Pure toluene can also be used for the FBW/deprotonation. Due to
the higher boiling point of toluene, however, it is more difficult to remove
during product isolation, which can cause problems in cases where the di-
or triyne product shows limited thermal stability.
(27) Hexanes were dried by distillation from CaH2, and toluene was dried
by distillation from Na/benzophenone ketyl.
(28) Compound 8a has been isolated from a well-known Chinese folk
medicine derived from the shrub Yin Chen Hao; see: Tang, W.; Eisenbrand,
G. Chinese Drugs of Plant Origin; Springer: Berlin, 1992.
(37) Triyne 9c is a natural product isolated from several species, such
as Bidens pilosus, Bidens leucanthus, and Dahlia pinnata; see: (a)
Bohlmann, F.; Bornowski, H.; Kleine, K.-M. Chem. Ber. 1964, 97, 2135-
2138. (b) Bohlmann, F.; Arndt, C.; Kleine, K.-M.; Wotschokowsky, M.
Chem. Ber. 1965, 98, 1228-1232. (c) Bendixen, O.; Lam, J.; Kaufmann,
F. Phytochemistry 1969, 8, 1021-1024.
(38) Cadiot, P.; Chodkiewicz, W. In Chemistry of Acetylenes; Viehe, H.
G., Ed.; Marcel Dekker: New York, 1969; pp 597-647.
9624 J. Org. Chem., Vol. 72, No. 25, 2007

Formation and DeriVatization of Di- and Triynes
TABLE 1. One-Pot Formation of Di- and Triynes through
Trapping with Carbon-Based Electrophiles
FIGURE 1. ORTEP drawing of 9a (20% probability level). Selected
interatomic distances (Å): C1-C2, 1.4522(17); C2tC3, 1.1949(17);
C3-C4, 1.3685(17); C4tC5, 1.2067(16); C5-C6, 1.3665(17); C6t
C7, 1.2024(17); C7-C8, 1.4308(17). Selected interatomic angles (Å):
C1sC2tC3, 178.95(13); C2tC3sC4, 177.58(13); C3sC4tC5,
178.24(13); C4tC5sC6, 177.48(13); C5sC6tC7, 177.57(14); C6t
C7sC8, 178.12(13).
The product 9a (1-phenylhepta-1,3,5-triyne) is a particularly
interesting molecule that has been isolated as a natural product
from many plant species such as Bidens pilosa (Asteraceae)40
and several members of the Coreopsis family.3 This triyne has
significant insecticidal activity against the larvae of the army
worm Spodoptera frugiperda, and it has also exhibited antimi-
crobial and nematicidal activity, as well as phototoxicity toward
Aedes aegypti larvae.41 Since single crystals of 9a were easily
grown from a concentrated solution in CHCl3 at 4 °C, the X-ray
crystallographic analysis of the molecule was explored. The
molecular structure shows a slight bending of the CsCtC
bonds, with angles in the range of 177.6-179.0° (Figure 1).42
The solid-state packing of 9a shows no intermolecular close
contacts of <4 Å between neighboring triyne segments, which
precludes solid-state polymerization and likely contributes to
the observed stability of this molecule in the solid state.
Complementary to targeting di- or triynes with an alcohol in
the propargylic position through the reaction of an acetylide
with a carbonyl compound would be synthesis of the homopro-
pargylic alcohols through addition of an acetylide to an epoxide
(Table 2). Thus, the reaction of 6a with BuLi in pure toluene
at -20 °C gave lithium acetylide intermediate 7a, which was
then trapped with (S)-propylene oxide to produce (S)-8j as a
light yellow oil in 30% yield ([R]2D0 ) -9.3, c 1.3, MeOH).
The use of the Lewis acid catalyst BF3‚Et2O did little to improve
the yield43 and provided a 16% yield of (S)-8j in a ca. 5:1 ratio
with (S)-8k, the product resulting from addition at the more
hindered site of the epoxide. Similarly, the addition of (S)-
propylene oxide dissolved in a combination of DMSO and Et2O
to a solution of 7a did not improve the yield, giving (R)-8j in
only 20% yield. The product (R)-8j ([R]2D0 +6.4, c 0.55,
MeOH) shows spectral data and optical rotation identical to
those of pilosol A, a diyne isolated from B. pilosa, thus
confirming both the structure and (R)-stereochemistry for this
natural product.44 The reaction of acetylide 7a with the TBDMS
(R)-(+)-glycidyl ether was attempted using HMPA as an
An analogous reaction of alkyl-terminated dibromoolefins 6e
and 6f with paraformaldehyde produced the triynols 9f and 9g
in reasonable yields.39 Compound 9f was obtained as a white
crystalline solid, but slowly turned magenta in color when
exposed to light. Triyne 9g, on the other hand, was isolated as
a pale yellow oil that remained unchanged when exposed to
light. Finally, the lithium acetylide 7f generated from 6f reacted
with a highly conjugated diyne ketone to produce tertiary alcohol
9h as a stable brown oil in an excellent 82% yield.
(40) Wat, C.-K.; Biswas, R. K.; Graham, E. A.; Bohm, L.; Towers, G.
H. N.; Waygood, E. R. J. Nat. Prod. 1979, 42, 103-111.
(41) Arnason, T.; Swain, T.; Wat, C.-K.; Graham, E. A.; Parington, S.;
Towers, G. H. N. Biochem. Syst. Ecol. 1981, 9, 63-68.
(42) Crystal data for 9a: C13H8, M ) 164.19, monoclinic space group
P21/n (an alternate setting of P21/c [No. 2]), Dc ) 1.158 g cm-3, a ) 6.1920-
(8) Å, b ) 7.7938(11) Å, c ) 19.640(3) Å, â ) 96.640(2)°, V ) 941.5(2)
Å3, Z ) 4, µ ) 0.066 mm-1. Final R(F) ) 0.0400, wR2(F2) ) 0.1163 for
(39) The product 9f (octa-2,4,6-triynol) has been isolated by Jones and
co-workers from the fungus Kuehneromyces mutabilis; see: (a) Hearn, M.
T. W.; Jones, E. R. H.; Pellatt, M. G.; Thaller, V.; Turner, J. L. J. Chem.
Soc., Perkin Trans. 1 1973, 2785-2788. (b) For a previous synthesis, see:
Luu, T.; Shi, W.; Lowary, T. L.; Tykwinski, R. R. Synthesis 2005, 3167-
3178.
2
2
119 variables and 1925 data with Fo2 g -3σ(Fo ) (1415 observations [Fo
2
g 2σ(Fo )]). CCDC 657101.
(43) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391-394.
(44) Chang, M.-H.; Wang, G.-J.; Kuo, Y.-H.; Lee, C.-K. J. Chin. Chem.
Soc. 2000, 47, 1131-1136.
J. Org. Chem, Vol. 72, No. 25, 2007 9625

Luu et al.
TABLE 2. Acetylide Addition to Epoxides
TABLE 3. One-Pot Formation and Negishi Coupling of Di- and
Triynes
a BF3‚OEt2 added, ∼5:1 ratio of 8j to 8k formed, not separated. b DMSO
added. c HMPA added. d NH3 added.
additive,45 but gave (R)-8l in only 22% yield. Given the limited
success of these addition reactions, only a single attempt was
made to form a triyne. Dibromoolefin 6e was used to provide
7e in toluene, and to this solution was added a mixture of excess
oxirane, ammonia, and THF at -20 °C. This procedure
ultimately gave a 58% yield of the triyne product 9i as a
colorless oil.46 Thus, the last set of conditions may ultimately
provide a general path to triyne homopropargylic alcohols, and
investigation of this possibility is ongoing.
Polyynes terminated with aryl groups are attractive synthetic
targets due to their potential as electronic and optical materials.35
The ease with which the polyyne framework of intermediate
acetylides 7 could be formed in situ suggested their use as
nucleophilic coupling partners in the formation of aryl polyynes
via the Negishi coupling reaction (Table 3).47 Thus, the
appropriate dibromoolefinic precursor 6 was reacted with BuLi
(2.2 equiv) at -40 °C in pure toluene to generate the lithium
acetylide 7. To ensure the rearrangement was complete, the
reaction mixture was warmed slowly to ca. -20 °C and then
recooled to -40 °C. To this mixture was added ZnCl2 (1.2
equiv, 0.5 M in THF) to effect transmetalation to the zinc
acetylide 10. The appropriate aryl iodide and Pd(PPh3)4 (5 mol
%) were added, and the mixture was heated at 70 °C for 20 h.
Workup and column chromatography provided diyne 11a and
triynes 11b-i. With the exception of 11g, the desired diaryl
polyynes were formed in generally good yields. In the reaction
of 10f with 4-iodo-N,N-dimethylaniline, the unfortunate low
yield of triyne 11g was not unexpected given the known issues
of Pd insertion into electron-rich C-I bonds.48 Finally, this
method could also be extended to multiple couplings, as
demonstrated by the Negishi reaction of 10a with 1,3-diiodo-
benzene to yield 11j in 64% yield.
An attempt was made to parlay this methodology toward the
cross-coupling of alkynyl iodides using a hybrid of the Negishi
and Cadiot-Chodkiewicz protocols (Scheme 4). Zinc acetylide
10c was formed from 6c and reacted with iodoalkyne 20 to
afford tetrayne 21 in 34% yield, as well as diyne 22 (24% yield),
the result of homocoupling of precursor 20. Competition
between the desired heterocoupling and the undesirable homo-
coupling is a well-known problem in Cadiot-Chodkiewicz-type
reactions,6 and attempts to reduce the byproduct were not
successful. Given the difficulty in separating the two products
chromatographically due to their similar polarities on common
supports, efforts toward optimizing this potentially useful
reaction were abandoned.
Transmetalation to Cu(I) was next explored toward effecting
oxidative homocoupling under Glaser-Hay conditions (Table
4). Intermediates 7a,b,g were generated from 6a,b,g under
standard conditions in toluene. To this mixture were added CuBr
(1 equiv) and TMEDA (17 equiv) to give copper acetylides
12a,b,g,49 and oxygen gas was then bubbled into the mixture
for 15 min. After TLC analysis revealed the reaction was
(45) Xie, X.; Yue, G.; Tang, S.; Huo, X.; Liang, Q.; She, X.; Pan, X.
Org. Lett. 2005, 7, 4057-4059.
(46) Triyne 8d is a natural product first isolated from the fungus Collybia
peronata and later from cultures of Lentinus edodes; see: (a) Higham, C.
A.; Jones, E. R. H.; Keeping, J. W.; Thaller, V. J. Chem. Soc., Perkin Trans.
1 1974, 1991-1994. (b) Tokimoto, K.; Fujita, T.; Takeda, Y.; Takaishi, Y.
Proc. Jpn. Acad. 1987, 63, 277-280.
(47) Negishi, E.; Zeng, X.; Tan, Z.; Qian, M.; Hu, Q.; Huang, Z. In
Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004; Chapter 15.
(48) Bre´fort, J. L.; Corriu, R. J. P.; Gerbier, P.; Gue´rin, C.; Henner, B.
J. L.; Jean, A.; Kuhlmann, T. Organometallics 1992, 11, 2500-2506.
9626 J. Org. Chem., Vol. 72, No. 25, 2007

Formation and DeriVatization of Di- and Triynes
SCHEME 4
TABLE 4. One-Pot Formation and Oxidative Homocoupling of Di-
and Triynes
TABLE 5. One-Pot Formation, Stannylation, and Stille Coupling
of Diynes
completed, the mixture was passed through a plug of alumina
to remove the insoluble salts, and the crude products were
purified by column chromatography to produce tetraynes 13a35
and 13b,50 as well as hexayne 13c24 (Table 4). By way of
comparison, the previous synthesis of 13c was also derived from
6g, but required two additional steps and provided an overall
yield of only 35%, whereas the current procedure provides 13c
in 68% yield and only one step.24
Conjugated ynones are desirable synthetic targets51 because
they are versatile precursors and are also known to possess
interesting biological activity.52 Thus, a one-pot protocol using
the Stille cross-coupling reaction based on transmetalation of
lithium acetylide 7 to the tin acetylide 14 was explored (Table
5). The dibromoolefin 6a or 6c was rearranged at -40 °C in
toluene and converted to the tin acetylide 14 via reaction with
Bu3SnCl. The reaction mixture was warmed to room temperature
to ensure complete transmetalation, and the acyl chloride
(dissolved in a minimal amount of CH2Cl2) was added, followed
by a catalytic amount of PdCl2(PPh3)2. After the reaction mixture
was refluxed overnight, workup gave the crude ynones 15a-
d, which could be isolated pure by column chromatography.
Stille coupling of the stannylacetylenes 14 was successful with
a variety of aryl acyl chlorides, ranging from electron-donating
to electron-withdrawing groups, although the yield for neutral
and electron-donating aryl acyl products 15a-c was slightly
higher than that with an electron-deficient aryl group, 15d.53,54
a Not isolated due to decomposition.
Compound 15e was derived from the combination of tin
species 14a and acetyl chloride and resulted in an unstable
orange oil in low yield. Attempts to extend this method to
triynones such as 15f were unsuccessful, and it was not possible
to isolate this product pure due to its instability, although TLC
analysis of the reaction mixture did suggest that 15f had been
formed.
Platinum acetylide complexes have recently been designed
for the formation of a wide range of carbon-rich oligomers,55
macrocycles,56 and supramolecular complexes.57 Thus, the final
transformation explored was the one-pot assembly of platinum
acetylides starting from precursors 6a,f,g (Table 6).58 The
general procedure was used to provide the lithium acetylide 7
in toluene, and to this intermediate was added CuI, followed
by PtCl2(PPh3)2. The reaction mixture was stirred at room
temperature for 12 h and then at 50 °C for 4 h. Using this
(49) Ruitenberg, K.; Kleijn, H.; Westmijze, H.; Meijer, J.; Vermeer, P.
J. R. Neth. Chem. Soc. 1982, 101, 405-409.
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Wan, W. B. Tetrahedron Lett. 1997, 38, 7483-7486.
(51) Walton, D. R. M.; Waugh, F. J. Organomet. Chem. 1972, 37, 45-
56.
(52) Chretien, R.; Wetroff, P.; Wetroff, G.; Thillay, L. U.S. Patent
3483257, 1969.
(53) Nash, B. W.; Thomas, D. A.; Warburton, W. K.; William, T. D. J.
Chem. Soc. 1965, 2983-2988.
(54) Fukumaru, T.; Awata, H.; Hamma, N.; Komatsu, T. Agric. Biol.
Chem. 1975, 39, 519-527.
(55) Liu, Y.; Jiang, S.; Glusac, K.; Powell, D. H.; Anderson, D. F.;
Schanze, K. S. J. Am. Chem. Soc. 2002, 124, 12412-12413.
(56) Campbell, K.; Kuehl, C. J.; Ferguson, M. J.; Stang, P. J.; Tykwinski,
R. R. J. Am. Chem. Soc. 2002, 124, 7266-7267.
(57) Kaiser, A.; Ba¨euerle, P. Top. Curr. Chem. 2005, 249, 127-201.
(58) For general reviews of metal polyynes, see: Szafert, S.; Gladysz,
J. A. Chem. ReV. 2003, 103, 4175-4205. Ren, T. Organometallics 2005,
24, 4854-4870.
J. Org. Chem, Vol. 72, No. 25, 2007 9627

Luu et al.
TABLE 6. Platinum Acetylide Formation from Di- and Triynes
was added BuLi (1.6 or 2.5 M in hexanes, 2.2 equiv) via syringe
over a period of ca. 1 min. The reaction mixture was allowed to
warm slowly to 0 °C and then cooled again to -20 °C. Et2O (10
mL) was added, followed by the addition of the electrophile
(dissolved in 2 mL of Et2O) via a cannula. The reaction mixture
was allowed to warm slowly to rt overnight. Saturated aqueous
NH4Cl (10 mL) and Et2O (10 mL) were added, and the organic
phase was separated, washed with saturated aqueous NaCl (2 ×
10 mL), and dried over MgSO4. Solvent removal and purification
by column chromatography (silica gel) gave the products 8a-i and
9a-h.
General Procedure for the One-Pot FBW-Negishi Reaction.
Dibromoolefin 6 (1.0 mmol) in toluene (10 mL) was cooled to
-40 °C under a N2 atmosphere. To this solution with stirring was
added BuLi (2.5 M in hexanes, 0.90 mL, 2.2 mmol) by syringe
over a period of ca. 5 min. The reaction mixture was allowed to
warm slowly to -20 °C and then cooled again to -40 °C. ZnCl2
(0.50 M in THF, 2.4 mL, 1.2 mmol) was added by syringe over a
period of ca. 5 min, the reaction mixture was allowed to warm
slowly to 0 °C, the aryl halide (1.1 mmol) and Pd(PPh3)4 (58 mg,
0.050 mmol) were added directly under a flow of N2, and this
mixture was heated to 70 °C. After being heated for 20 h, the
reaction mixture was cooled and filtered through a Celite column,
the solvent removed under reduced pressure, and the residue purified
by column chromatography to give the desired products 11a-j and
21.
General Procedure for the One-Pot FBW-Hay Reaction.
Dibromoolefin 6 (0.70 mmol) in toluene (10 mL) was cooled to
-40 °C under a N2 atmosphere. To this solution with stirring was
added BuLi (2.5 M in hexanes, 0.56 mL, 1.40 mmol) by syringe
over a period of ca. 5 min. The reaction mixture was allowed to
warm slowly to -20 °C. To this mixture with stirring were added
CuBr (0.6 mmol) and TMEDA (13 mmol), and oxygen was bubbled
through the solution for 15 min. The reaction mixture was allowed
to warm slowly to rt overnight, concentrated, filtered through a
plug of alumina, and purified by column chromatography to give
the desired products 13a-c.
procedure, tetrayne 16a was generated as a marginally soluble,
off-white solid in excellent yield. Compound 16b was synthe-
sized from precursor 6f as a soluble colorless solid in 82% yield.
Formation of the TIPS derivative 16c was also successful,
providing a marginally soluble product in 74% yield, although
all attempts to achieve a purity of >90% for this derivative
have been unsuccessful. The trans-stereochemistry of 16a-c
1
was easily established on the basis of the JPt-P coupling
constants observed in the 31P NMR spectra (CD2Cl2). Values
1
of JPt-P, 2570, 2525, and 2540 Hz, respectively, indicated
formation of the trans-isomer, whereas the cis-isomer would
1
show a smaller JPt-P, ∼2300 Hz.59
General Procedure for the One-Pot FBW-Stille Reaction.
Dibromoolefin 6 (0.70 mmol) in toluene (3.0 mL) was cooled to
-40 °C under a N2 atmosphere. To this solution with stirring was
added BuLi (2.5 M in hexanes, 0.65 mL, 1.6 mmol) by syringe
over a period of ca. 5 min. The reaction mixture was allowed to
warm slowly to -20 °C and then cooled again to -40 °C. Bu3-
SnCl (0.45 mL, d ) 1.2, 0.54 g, ca. 1.2 mmol) was added by syringe
over a period of 5 min and the mixture allowed to warm slowly to
rt and then stirred for 2 h. The acid chloride (0.70 mmol) and
PdCl2(PPh3)2 (25 mg, 0.035 mmol), both in CH2Cl2 (15 mL), were
added to the solution of the tin acetylide, and this mixture was
refluxed overnight. The reaction mixture was cooled to rt, aqueous
KF solution (30 mL) and ether (30 mL) were added, and the
mixture was stirred vigorously for 15 min. This solution was then
filtered through a Celite column and the organic phase separated,
washed with water, and dried over MgSO4. After the solvent
was removed under reduced pressure, the residue was purified by
column chromatography (silica gel) to give the desired products
15a-e.
General Procedure for the One-Pot Formation of Platinum
Acetylides. Dibromoolefin 6 (0.50 mmol) in toluene (5.0 mL) was
cooled to -40 °C under a N2 atmosphere. To this solution with
stirring was added BuLi (2.5 M in hexanes, 0.45 mL, 1.12 mmol)
dropwise by syringe over ca. 5 min. The reaction mixture was
allowed to warm slowly to -20 °C and then cooled again to -40
°C. CuI (125 mg, 0.656 mmol) was added directly under a flow of
N2, followed by PtCl2(PPh3)2 (199 mg, 0.252 mmol). The reaction
mixture was stirred at rt overnight and then at 50 °C for 4 h. After
the mixture was cooled, H2O (5 mL) and CH2Cl2 (5 mL) were
added, the organic phase was separated, washed with H2O, and
dried over MgSO4, and the solvent was removed under reduced
Conclusions
A one-pot protocol for the synthesis and derivatization of
di- and triynes has been developed based on an FBW rear-
rangement-deprotonation sequence. The main advantage of this
method is that, from a common dibromoolefinic precursor, a
substantial range of polyyne products can be achieved simply
through the choice of the electrophile introduced in the second
step of the reaction. The efforts to date have shown that carbon-
based electrophiles such as aldehydes, ketones, MeI, and CO2
work quite well, whereas the use of epoxide-based electrophiles
results in only low yields of the desired products. Use of an
electrophilic transition metal allows for transmetalation from
the initial lithium acetylide and the formation of zinc, copper,
tin, and platinum acetylides, which greatly increases the range
of products that may be achieved. Given the ease with which
this one-pot reaction sequence can be effected, the possibility
for structure-function analysis of di- and triynes for both
materials and medicine has been greatly expanded.
Experimental Section
General Procedure for One-Pot Trapping with Electrophiles.
Dibromoolefin 6 (0.5-1.0 mmol) was dissolved in toluene (2 mL),
and this mixture was then diluted with hexanes (10 mL) and cooled
to -20 °C under an Ar atmosphere. To this solution with stirring
(59) Campbell, K.; McDonald, R.; Ferguson, M. J.; Tykwinski, R. R. J.
Organomet. Chem. 2003, 683, 379-387.
9628 J. Org. Chem., Vol. 72, No. 25, 2007

Formation and DeriVatization of Di- and Triynes
pressure. Recrystallization from CH2Cl2 by the addition of MeOH
or hexanes or column chromatography gave the desired products
16a-c.
fellowship. We thank Dr. Michael Ferguson for the crystal
structure determination of compound 9a.
Supporting Information Available: Experimental and spec-
troscopic data for all new compounds and X-ray crystallographic
details for compound 9a. This material is available free of charge
via the Internet at http://pubs.acs.org.
Acknowledgment. This work has been generously supported
by the University of Alberta and the Natural Sciences and
Engineering Research Council of Canada (NSERC) through the
Discovery and Nano Innovation Platform (NanoIP) grant
programs. T.L. thanks the University of Alberta for a dissertation
JO701810G
J. Org. Chem, Vol. 72, No. 25, 2007 9629