Synthesis of diynes and tetraynes from in situ desilylation/dimerization of acetylenes

Article abstract of DOI:10.1021/ol016414u

(equation presented) An efficient method for the in situ desilylation/oxidative dimerization of (trialkylsilyl)acetylenes is described. This protocol avoids the complications encountered with sensitive diynes by eliminating the deprotection and isolation steps. Various aromatic and alkyl diynes and tetraynes can be synthesized in a straightforward manner in good yields (82-99%) from TIPS-protected acetylenes. This method facilitates the efficient synthesis of novel tetrayne-bridged acetylenic cyclophanes 6 and 7 in a direct manner.

Full text of DOI:10.1021/ol016414u

ORGANIC
LETTERS
2001
Vol. 3, No. 18
2883-2886
Synthesis of Diynes and Tetraynes from
in Situ Desilylation/Dimerization of
Acetylenes
Matthew A. Heuft, Shawn K. Collins, Glenn P. A. Yap,† and Alex G. Fallis*
Department of Chemistry, UniVersity of Ottawa, 10 Marie Curie,
Ottawa, Ontario, Canada K1N 6N5
afallis@science.ottawa.ca
Received July 10, 2001
ABSTRACT
An efficient method for the in situ desilylation/oxidative dimerization of (trialkylsilyl)acetylenes is described. This protocol avoids the complications
encountered with sensitive diynes by eliminating the deprotection and isolation steps. Various aromatic and alkyl diynes and tetraynes can
be synthesized in a straightforward manner in good yields (82−99%) from TIPS-protected acetylenes. This method facilitates the efficient
synthesis of novel tetrayne-bridged acetylenic cyclophanes 6 and 7 in a direct manner.
The unique properties of polyynes and acetylenic arrays
continue to garner attention and increased research interest.1
In addition to their unusual electrical and optical properties,
they are encountered in numerous natural products and
display a wide range of potential applications in both biology
and material sciences. Consequently, research into the
synthesis of well-defined polyynes continues to expand. The
electronic properties and spectra of polyynes and polyyne
polymers2 have been studied for their interesting bathochro-
mic shifts.3 These shifts are proportional to the number of
acetylene linkages.4 R,ω-Diarylpolyynes display efficient
charge transfer through their conjugated polyyne bridges in
applications as dyes and pigments.5 The efficiency of the
energy and electron transfer processes have been examined,
as potential molecular wires and chemosensors, particularly
in polyyne-bridged porphyrin systems6 and bis(benzocrown
ethers).7
Polyyne segments in both natural8a and unnatural8b,c
products exhibit a wide range of biological activity. These
include potential as potent antiinflammatory,9a antibiotic9b
(caryoynencins), antitumor9c (panaxydol), and antibacterial9d
agents (falcarrindiol). Polyynes are also crucial components
for the construction of carbon-rich materials such as novel
dehydrobenzoannulenes10 and innovative acetylenic cyclo-
phanes with potential to act as precursors to fullerenes.11
The most common synthetic method for the assembly of
polyynes involves bond formation between two acetylenes
† Contact this author for enquiries regarding x-ray analysis.
(1) (a) Ginsburg, E. J.; Gorman, C. B.; Grubbs, R. H. In Modern
Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH: Weinheim,
1995. (b) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int.
Ed. 2000, 39, 2632. (c) Brandsma, L. PreparatiVe Acetylenic Chemistry;
Elsevier, Amsterdam. 1988.
(6) Maruyama, K.; Kawabata, S. Bull. Chem. Soc. Jpn. 1990, 63, 170.
(7) Lee, L.-H.; Lynch, V.; Lagow, R. J. J. Chem. Soc., Perkin Trans. 1
2000, 2805.
(2) (a) Shirakawa, H.; Louis, E. J.; MacDiarmid, A. G.; Chiang, C. K.;
Heeger, A. J. J. Chem. Soc., Chem. Commun. 1977, 578. (b) Chiang, C.
K.; Fincher, C. R. Jr.; Park, Y. W.; Heeger, A. J.; Shirakawa, H.; Louis, E.
J.; Gau, S. C.; MacDiarmid, A. G. Phys. ReV. Lett. 1977, 39, 1098.
(3) Akiyama, S.; Nakasuji, K.; Akashi, K.; Nakagawa, M. Tetrahedron
Lett. 1968, 24, 1121.
(4) Prabhakara, R.; Mathur, S. C.; Dube, D. C.; Tewari, D. P.; Banerjee,
M. Can. J. Chem. 1997, 75, 1041.
(5) Akiyama, S.; Nakashima, K.; Nakatsuji, S.; Nakagawa, M. Dyes Pigm.
1990, 13, 117.
(8) (a) Svirskaya, P. I.; Leznoff, C. C.; Roelofs, W. L. Synth. Commun.
1980, 10, 391.(b) Rodbotten, S.; Benneche, T.; Undhiem, K. Acta Chem.
Scand. 1997, 51, 873. (c) Hopf, H.; Krause, N. Tetrahedron Lett. 1985, 26,
3323.
(9) (a) Zeni, G.; Panatieri, R. B.; Lissner, E.; Menezes, P. H.; Braga, A.
L.; Stefani, H. A. Org. Lett. 2001, 3, 819. (b) Yamaguchi, M.; Park, H.-J.;
Hirama, M.; Torisu, K.; Nakamura, T.; Minami, H.; Nishihara, H.; Hriraoka,
T. Bull. Chem. Soc. Jpn. 1994, 67, 1717. (c) Lu, W.; Haji, G. Z.; Cai, J.
Tetrahedron Lett. 1998, 39, 9521. (d) Zheng, G.; Lu, W.; Cai, J. J. Nat.
Prod. 1999, 62, 626.
10.1021/ol016414u CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/15/2001

via oxidative coupling. Frequently, the classic protocols
developed by Hay,12 Glaser,13 and Eglinton14 are the methods
of choice, although newer combinations and modifications
have also been developed.15 Diederich and co-workers have
introduced a solution spray flash vacuum pyrolysis of suitable
precursors for the formation of even- and odd-numbered
polyynes.16
Table 1. Optimization of Copper and Fluoride Ion Mediated
Dimerization of (Triisopropylsilyl)acetylenes
The instability of simple and higher polyynes is a major
challenge in their preparation. They are highly sensitive to
polymerization and prone to rapid decomposition.17 Terminal
phenylbutadiynes are particularly sensitive.10 Recently, dif-
ferent protocols have been developed for the in situ one-pot
desilylation/dimerization of acetylenes. Mori and Hiyama and
co-workers18 employed CuCl in DMF under air or oxygen
with (trimethylsilyl)acetylene in the absence of fluoride ion
to afford high yields (80-100%) of the homocoupled
product. This procedure has also been applied to the synthesis
of unsymmetrically substituted diacetylenes when alkynyl-
trimethylsilanes are mixed with 1-chloroalkynes.19 Haley et
al. reported a different in situ one-pot desilylation/dimeriza-
tion strategy for the synthesis of tetrayne-linked dehydroben-
zoannulenes. This method combines standard Eglinton
coupling conditions with an excess of potassium carbonate
to effect the protodesilylation of trimethylsilyl (TMS)
protected acetylenes in good yields.20
fluorine-
entry [1] (mM) copper source
source
time (h) yield (%)
1
2
3
4
1a , 2.0
1a , 4.0
1a , 4.0
1a , 4.0
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
TBAF
1 equiv
TBAF
1 equiv
TBAF
1 equiv
TBAF
2 equiv
-
TBAF
1 equiv
CsF
1 equiv
TBAF
1 equiv
TBAF
1 equiv
4
4
3
2
2a , 68a
2a , 45a
2a , 42
2a , 45
5
6
1a , 4.0
1b, 2.0
CuF2
Cu(OAc)2
2
2
NRb
2b, 15-40
7
8
9
1b, 2.0
1b, 2.0
1b, 2.0
Cu(OAc)2
Cu(OAc)2
3
3
2
2b, 6
2b, 100c
2b, <5d
CuCl,
TMEDA
We have previously investigated the synthesis of a novel
family of acetylenic cyclophanes21 and wished to extend these
studies to tetrayne-bridged systems. Our synthesis of acety-
lenic precursors involved the use of triisopropylsilyl (TIPS)
protected phenylbutadiyne units. Deprotection and isolation
of the terminal acetylenes was not possible as the products
rapidly decomposed before oxidative coupling could occur.
Consequently, we chose to develop an alternative desilyla-
tion/dimerization protocol using a fluoride source to effect
desilylation of TIPS-protected acetylenes.
a Substrate not added by syringe pump. b NR ) no reaction. c TBAF
added via syringe pump instead of substrate. d Benzene used as solvent.
Initially, the dimerization of model compounds 1a and 1b
(Table 1) was investigated. Compound 1a was stirred with
a fluoride source (TBAF)22 and Cu(OAc)2 in pyridine/ether
(3:1) for 4 h to give a 68% yield of the diyne product.
Doubling the concentration of 1a did not increase the yield
(entry 2). It appeared that the deprotected phenylbutadiyne
was polymerizing rapidly and thus competing with the
desired dimerization. Thus, controlled addition of substrate
1a via syringe pump was attempted (entry 3). Unfortunately,
under identical concentrations, yields comparable to those
without controlled addition were obtained. An increase in
the number of equivalents of fluoride ion also had no effect
(entry 4). Exposure of 1a to CuF2 as a combined source of
fluoride ion for desilylation and copper ion for oxidative
coupling also proved futile. Copper(II) fluoride is insoluble
in common organic solvents, and under heterogeneous
reaction conditions only the starting material was recovered.
Despite the modest yields, the dimerization of 1b was
investigated, but results were irreproducible and the yields
varied from 15 to 40%. Substitution of TBAF with CsF23 as
the fluoride source decreased the yield to 6% for the
corresponding tetrayne (entry 7), while altering the Cu source
using Hay’s conditions (entry 9) gave a 5% isolated yield.
These disappointing results appeared to be a consequence
(10) Haley, M. M.; Bell, M. L.; English, J. J.; Johnson, C. A.; Weakley,
T. J. R. J. Am. Chem. Soc. 1997, 119, 2956.
(11) (a) Haley, M. M.; Langsdorf, B. L. Chem. Commun. 1997, 1122.
(b) Rubin, Y.; Parker, T. C.; Khan, S. I.; Holliman, C. L.; McElvany, S.
W. J. Am. Chem. Soc. 1996, 118, 5308. (c) Tobe, Y.; Nakagawa, N.;
Naemura, K.; Wakabayashi, T.; Shida, T.; Achiba, Y. J. Am. Chem. Soc.
1998, 120, 4544. (d) Rubin, Y.; Parker, T. C.; Pastor, S. J.; Jalisatgi, S.;
Boulle, C.; Wilkins, C. L. Angew Chem., Int. Ed. 1998, 110, 1353. (e) Fallis,
A. G. Can. J. Chem. 1999, 77, 159.
(12) (a) Hay, A. S. J. Org. Chem. 1960, 25, 1275. (b) Hay, A. S. J. Org.
Chem. 1962, 27, 3320.
(13) (a) Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422. (b) Glaser, C.
Ann. Chem. Pharm. 1870, 154, 137.
(14) Eglinton, G.; Galbraith, A. R. Chem. Ind. (London) 1956, 737.
(15) (a) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem.,
Int. Ed. 2000, 39, 2632. For additional palladium-based alkyne coupling
methods, see: (b) Liu, Q.; Burton, D. J. Tetrahedron Lett. 1997, 38, 4371.
(c) Godt, A. J. Org. Chem. 1997, 62, 7471.
(16) Rubin, Y.; Lin, S. S.; Knobler, C. B.; Anthony, J.; Boldi, A. M.;
Diederich, F. J. Am. Chem. Soc. 1991, 113, 6943.
(17) Patel, G. N.; Chance, R. R.; Turi, E. A.; Khanna, Y. P. J. Am. Chem.
Soc. 1978, 100, 6644.
(18) Ikegashira, K.; Nishihara, Y.; Hirabayashi, K.; Mori, A.; Hiyama,
T. Chem. Commun. 1997, 1039.
(19) Nishihara, Y.; Ikegashira, K.; Mori, A.; Hiyama, T. Tetrahedron
Lett. 1998, 39, 4075.
(20) Haley, M. M.; Bell, M. L.; Brand, S. C.; Kimball, D. B.; Pak, J. J.;
Wan, W. B. Tetrahedron Lett. 1997, 38, 7483.
(21) Collins, S. K.; Yap, G. P. A.; Fallis, A. G. Angew Chem., Int. Ed.
2000, 39, 385.(b) Collins, S. K.; Yap, G. P. A.; Fallis, A. G. Org. Lett.
2000, 2, 3189.
(22) (a) Oda, H.; Sato, M.; Morizawa, Y.; Oshima, K.; Nozaki, H.
Tetrahedron 1985, 41, 3257. (b) Johnson, T. R.; Walton, D. R. M.
Tetrahedron 1972, 28, 5221.
(23) (a) Chan, T. H.; Massuda, D. Tetrahedron Lett. 1975, 3383. (b)
Chan, T. H.; Ong, B. S. J. Org. Chem. 1978, 43, 2994.
2884
Org. Lett., Vol. 3, No. 18, 2001

of the large relative concentration of fluoride ion present in
solution, which hindered the dimerization. Consequently, a
THF solution of TBAF was added directly via syringe pump
(entry 8). The tetrayne was isolated in quantitative yield!
The generality of this method was established by inves-
tigation of the dimerization of compounds listed in Table 2.
similar to that of the system reported by Tykwinski and co-
workers25 for cross-conjugated polyenynes (Figure 1). The
Table 2. Examples of TBAF/Cu(OAc)2-Mediated Desilylation/
Oxidative Dimerization of Aromatic Acetylene and Butadiynes
Figure 1. View of the unit cell crystal packing for the 1,8-di(2-
bromophenyl)-1,3,5,7-octatetrayne (2d).
electron-rich m-N,N-dibutylaminophenyl diyne 1e formed the
corresponding tetrayne in 82%. Desilylation/dimerization of
1f afforded the known tetrayne 1,8-(1-naphthyl)octa-1,3,5,7-
tetrayne (2f, 96%), investigated previously for its interesting
spectral properties.3 Alkyl substituents were also compatible
with this synthetic protocol as 1g dimerized in 98% yield.
Heteroaromatic substituted polyynes may also be easily
prepared by this procedure. For example, 1h produced the
thiophene-tetrayne (2h) in 82% yield. An attempt to form
a hexayne product via this procedure failed. The anthracenyl
triyne 1i26 (entry 9) gave two red solid products upon
treatment with the TBAF/Cu(OAc)2 system that were spar-
ingly soluble in organic solvents. At present, these cannot
be properly identified and characterized.
It was of interest to apply this desilylation/dimerization
sequence to the synthesis of a novel acetylenic cyclophane
bearing tetrayne linkages (Scheme 1). In principle, it should
be possible to generate the target cyclophane 6 from the
dimerization of 5. Dibutyl amino groups were installed on
the “corner” phenyl rings in order to aid solubility, as done
previously with similar large macrocycles.27 Treatment of
compound 3 with nBuLi caused elimination of the chloride
ion to produce the diynyl anion which was transmetalated
(24) X-ray data for compound 2 has been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC
163717. Copies of the data may be obtained free of charge from CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (Fax: (+44) 1223-336-033.
E-mail: deposit@ccdc.cam.ac.uk).
(25) Zhao, Y.; McDonald, R.; Tykwinski, R. R. Chem. Commun. 2000,
77.
(26) Compound 1i was prepared from a Fritsch-Buttenberg-Wiechell
(FBW) rearrangement of the dibromide B derived from ketone A (recent
applications: Eisler, S.; Tykwinski, R. R. J. Am. Chem. Soc. 2000, 122,
10736).
Model compound 1b at various concentrations was exposed
to TBAF. A concentration of 1.7 mM afforded the isolated
tetrayne product (2b) in 73-77% yield. However, doubling
the concentration of 1b gave quantitative yields. The use of
a TMS silyl protected diyne (1c, entry 3) also gave, as
expected, the diaryl tetrayne in 93% yield. Substituent effects
were also investigated. Compound 1d, which has an electron-
withdrawing o-bromo phenyl, was dimerized in 98% yield.
X-ray crystallographic analysis established the structure of
the tetrayne (2d).24 This material displayed crystal packing
Org. Lett., Vol. 3, No. 18, 2001
2885

Sonogashira coupling of 4 with 1,4-diethynylbenzene pro-
duced the cyclophane precursor 5 in 39% yield. Compound
5 was subjected to the desilylation/dimerization protocol at
two separate concentrations. At the lower concentration, the
tetrayne-linked monomer product, 7, was the sole macrocycle
isolated in 46%. However, when the concentration of 5 was
increased, dimer 6 was formed in 5% yield, although
formation of 7 still dominated (26%).
Scheme 1. Synthesis of a Novel Acetylenic Cyclophane Using
an in Situ Desilylation/Dimerization Sequencea
In conclusion, we have developed an efficient method for
the in situ desilylation and oxidative dimerization of TIPS-
protected monoynes and diynes, based upon the addition of
a fluoride source to a solution of the substrate and a copper
salt. The optimized synthetic method [Cu(OAc)2 (3 equiv);
alkyne (3.3 mM) in a mixture of pyridine/ether (3:1); TBAF
(1 equiv) via syringe pump] afforded yields of diynes and
tetraynes in the range of 82-99% for various substituted
aromatic and alkyl systems. The method also provides an
expedient route to novel acetylenic cyclophanes. This method
should prove to be a valuable synthetic tool for the
construction of new polyyne-containing compounds.
Acknowledgment. We are grateful to the National
Sciences and Engineering Research Council of Canada for
financial support of this research. S. K. Collins and M. A.
Heuft thank NSERC and the University of Ottawa for
Graduate Scholarships.
1
Supporting Information Available: H NMR, 13C NMR,
and MS data for compounds 1a,b, 2a-e, and their corre-
sponding dimers and full characterization for 4, 5, 6, and 7.
This material is available free of charge via the Internet at
http://pubs.acs.org.
a (a) (i) nBuLi, THF, -78 °C, 5 min, (ii) ZnBr2, THF, 0 °C, 15
min, (iii) N,N-dibutyl-3-iodoaniline,24 Pd(PPh3)4, reflux, 15 h; (b)
BnNMe3ICl2, CaCO3, THF/MeOH (5:1), 4 h; (c) 1,4-diethynyl-
benzene, Pd(PPh3)2Cl2, CuI, NEt3, THF, reflux, 15 h; (d) Cu(OAc)2
(6 equiv), TBAF (1 equiv), pyridine/Et2O (3:1), 3 h.
OL016414U
(27) Pak, J. J.; Weakley, T. J. R.; Haley, M. M. J. Am. Chem. Soc. 1999,
121, 8182.
(28) (a) Sengupta, S.; Snieckus, V. J. Org. Chem. 1990, 55, 5680. (b)
Knochel, P.; Seebach, D. Tetrahedron Lett. 1982, 32, 3897.
(29) Kajigaeshi, S.; Kakinami, T.; Yamasaki, H.; Fujisaki, S.; Okamoto,
T. Bull. Chem. Soc. Jpn. 1988, 61, 600.
with ZnBr2 and subjected to palladium(0)-based coupling to
give the corresponding phenylbutadiyne product.28 Iodination
with BnNMe3ICl2 gave 4 in 57% yield over two steps.
29
2886
Org. Lett., Vol. 3, No. 18, 2001