Practical synthesis of (Z)-polyaromatic and heteroaromatic vinylacetylenes

Article abstract of DOI:10.1021/ol0508173

(Chemical Equation Presented) Two synthetic routes to several (Z)-polyaromatic and heteroaromatic substituted vinylacetylenes are described. The nature of aryl- or heteroaryl-substituted carboxaldehyde used as starting material dictated the choice of Wittig salt employed. A very attractive way to construct polyaromatic and pyridine-containing enynes is the reaction of polyaromatic and pyridine-containing aldehydes with bromomethyltriphenylphosphonium bromide in the presence of potassium tert-butoxide followed by a Sonogashira desilylation procedure (method B).

Full text of DOI:10.1021/ol0508173

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2671-2673
Practical Synthesis of (Z)-Polyaromatic
and Heteroaromatic Vinylacetylenes
Anthony Hayford,* Joseph Kaloko, Jr., Salwa El-Kazaz, Gwen Bass,
Cheryl Harrison, and Thomas Corprew
Department of Chemistry, Thomas Harriot College of Arts and Sciences, East Carolina
UniVersity, Science and Technology Building, Suite 300,
GreenVille, North Carolina 27858-4343
hayforda@mail.ecu.edu
Received April 14, 2005
ABSTRACT
Two synthetic routes to several (Z)-polyaromatic and heteroaromatic substituted vinylacetylenes are described. The nature of aryl- or heteroaryl-
substituted carboxaldehyde used as starting material dictated the choice of Wittig salt employed. A very attractive way to construct polyaromatic
and pyridine-containing enynes is the reaction of polyaromatic and pyridine-containing aldehydes with bromomethyltriphenylphosphonium
bromide in the presence of potassium tert-butoxide followed by a Sonogashira desilylation procedure (method B).
Vinylacetylenes are useful in organic synthesis as important
precursors for regio- and stereoselective synthesis of con-
jugated π-systems, including dienic, diacetylenic, and sub-
stituted aromatic compounds.1 Such important structural units
are known to be integral parts of highly potent antitumor
antibiotics,1 antifungal agents,2 sex pheromones,3 and novel
conducting polymeric materials.4 As such, several excellent
synthetic methods have been reported for their preparation.
However, the vast majority of the reported methods are either
limited to simple aliphatic and carbocyclic aromatic sub-
strates or/and are tedious procedures not practical for
multigram-scale synthesis.1-5
Our laboratory has been interested in the synthesis of
geometrically pure (Z)-heteroaromatic and polyaromatic
vinylacetylenes as starting material in the synthesis of
benzofused heterocycles via their reaction with Fischer
carbene complexes.6 The preparation of substituted viny-
lacetylenes through palladium-catalyzed cross-coupling of
(Z)-vinylhalides, derived from aldehydes, with terminal
alkynes was attractive, since this method has proven to be
successful for the stereoselective synthesis of many enynes
containing diverse functional groups at ambient conditions.1a,7
In seeking a practical and general route for the transformation
(5) For further examples of direct access to (Z)-enynes, see: (a)
Brandsma, L.; PreparatiVe Acetylenic Chemistry, Elsevier: Armsterdam,
1988. (b) Bates, C. G.; Saejueng, P.; Venkataraman, D. Org. Lett. 2004, 6,
1441. (c) Karatholuvhu, M. S.; Fuchs, P. L. J. Am. Chem. Soc. 2004, 126,
14314. (d) Halbes, U.; Bertus, P.; Pale, P. Tetrahedron Lett. 2001, 44, 8641.
(e) Alami, M.; Crousse B.; Ferri, F. J. Organomet. Chem. 2001, 624, 114
and references therein. (f) Fossatelli, M.; Kerk, A. C.; Vasilevsky, S. F.;
Brandsma, L. Tetrahedron Lett. 1992, 33, 4229. (g) Holmes, A. B.; Pooley,
G. R. Tetrahedron 1992, 48, 7775.
(6) (a) Herndon, J. W.; Hayford, A. Organometallics 1995, 14, 155. (b)
Hayford, A. Reactions of Z-Phenylvinylacetylenes and Cyclopropylacety-
lenes with Fischer Carbene-Chromium Complexes, Ph.D. Thesis, Univer-
sity Of Maryland, College Park, MD, 1994. (c) Hayford, A.; Kaloko, J. Jr.;
Bass, G.; Aber, L. C.; Bailey, D. L. Synthesis and Benzannulation Reactions
of Heteroaromatic-Vinylacetylenes with Fischer Carbene Complexes,
Abstracts of Papers, 226th National Meeting of the American Chemical
Society, New York, September 7-11, 2003; American Chemical Society:
Washington, DC, 2003; Section CHED, Paper 0187.
(1) (a) Negishi, E.; Anastasia, L. Chem. ReV. 2003, 103, 1979. (b) Saito,
S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901. (c) Gung, W, B.; Kumi,
G. J. Org. Chem. 2004, 69, 3488. (d) Nicolaou, K. C.; Dai, W. M. Angew.
Chem., Int. Ed. Engl. 1991, 30, 1387. (e) Grissom, J. W.; Gunawardena,
G. U.; Klingberg, D.; Huang, D. Tetrahedron 1996, 52, 6453. (f) Myers,
A. G.; Kuo, E. Y.; Finney, N. S. J. Am. Chem. Soc. 1989, 111, 8057.
(2) (a) Faulkner, D. J. Nat. Prod. Rep. 2000. 17, 7. (b) Nussbaumer, P.;
Leitner, L.; Marz, K.; Stutz, A. J. Med. Chem. 1995, 38, 1831.
(3) (a) Rossi R.; Carpita, Quirici, M. G. Gaudenzi T. Tetrahedron 1982,
38, 631. (b) Guerrero, A.; Camps, F.; Coll, J.; Riba, M.; Einhorn, J.;
Descoins, Ch.; Lallemand, J. Y. Tetrahedron Lett. 1981, 22, 2013.
(4) (a) Nicolaou, K. C.; Smith, A. L. In Modern Acetylene Chemistry;
Stang, P. J., Diederich, F., Eds.; VCH: Weinheim, 1995. (b) Gobbi, L.;
Seiler, P.; Diederich, F. Angew. Chem., Int. Ed. 1999, 38, 674. (c) Hynd,
G.; Jones, G. B.; Plourde, G. W.; Wright, J. M. Tetrahedron Lett. 1999,
40, 4481.
10.1021/ol0508173 CCC: $30.25
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Published on Web 06/03/2005

of both aromatic and heteroaromatic aldehydes to their
corresponding (Z)-vinylacetylenes, we have investigated a
stereoselective (method A) as well as a nonstereoselective
method (B) for their synthesis (Scheme 1).7,8
Table 2. Synthesis of π-Deficient Heteroaromatic
Vinylacetylenes via Method B
Scheme 1a
a Reagents and conditions: (i) CBr4, PPh3, CH2Cl2 or CH3CN,
0 °C; (ii) Bu2SnH, Pd(PPh3)4, CH2Cl2 or benzene, rt; (iii)
Br- +PPh3CH2Br, t-BuOK, THF, -78 °C; (iv) t-TMS, CuI,
Pd(PPh3)2Cl2, Et3N; (v) K2CO3, MeOH, 0 °C/rt.
Initial attempts to prepare both π-excessive and π-deficient
heteroaromatic substituted (Z)-vinyl bromides via the ste-
Table 1. Synthesis of π-Excessive Heteroaromatic
Vinylacetylenes via Method A
a Yields reported via method A (43-65%).8c b Unstable compound
rapidly decomposed on isolation. c Yields reported via method A (86%).8c
d Z/E ratio determined by separation of compounds after purification from
flash column chromatography.
terms of purity and isolated yields (0-71%) for O- and
N-functionalized bromoolefins. For example, significant
decomposition of pyridine-containing precursors was ob-
served under tributyltin hydride reduction conditions, and
heteroarylaldehydes with sensitive functional groups such
as pyrrole-2-carboxaldehyde failed to yield the expected
products. Furthermore, depending on the nature of the
heteroaromatic substrate and the synthetic strategy employed,
the reaction required a stoichiometric amount of expensive
and highly toxic [n-Bu3SnH] reagent (1.2-5 equiv) in the
hydrogenolysis step.8a-c In fact, the removal of the pervasive
stannous byproducts from the reaction mixtures was ex-
tremely difficult and greatly reduced the purity, stability and
overall yield of the reaction products. However, this problem
was greatly reduced by the addition of aqueous potassium
fluoride to the reaction mixture and also using finely ground
potassium fluoride as an additive to silica or basic alumina
reoselective tributyltin hydride reduction of gem-dibromide
heterocycles (method A)8a-c gave disappointing results in
(8) (a) Uenishi, J.; Kawahama, R.; Yonemitsu, O. Tetrahedron Lett. 1996,
37, 6759. (b) Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Tsuji, J. J. Org.
Chem. 1996, 61, 5716. (c) Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Tsuji,
J. J. Org. Chem. 1998, 63, 8965. (d) Herz, H. G.; Queiroz, M. J.; Maas, G.
Synthesis 1999, 6, 1013. (e) Matsumoto M.; Kuroda, K. Tetrahedron Lett.
1980, 21, 4021.
(7) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
50, 4467. (b) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N.
Synthesis 1980, 627. (c) Sakamoto, T.; Shiraiwa, M.; Kondo, Y.; Yamanaka,
H. Synthesis 1983, 312. (d) Sonogashira, K. In ComprehensiVe Organic
Chemistry; Fleming, I., Trost, B. M., Eds.; Pergamon: Oxford, 1991;
Vol. 3.
(9) Harrowven, D. C.; Guy, I. L. Chem. Commun. 2004, 1968 and
references therein.
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Org. Lett., Vol. 7, No. 13, 2005

during chromatographic purification as described recently
by Harrowven and co-workers.9 Notably, the synthesis of
heteroaromatic substrates such as furan, benzofuran, and
thiophene vinylacetylenes (Table 1) was best accomplished
via method A.
It is worth noting that the conversion proceeded smoothly;
however, contrary to the π-deficient heteroaromatic series,
the similarities of Rf values of the π-excessive derivatives
did not permit efficient separation of the isomeric bromoole-
fins and 1,3-enyne derivatives. As such, the synthesis of the
desired (Z) electron-rich heteroaromatic enynes was conve-
niently carried out via the former alternative pathway
(method A).
Given the marginal and unreliable yields, as well as
workup procedural difficulties encountered with method A,
an alternative synthetic procedure, involving the Wittig
bromovinylation of aromatic and heteroaromatic aldehydes
with bromomethyltriphenylphosphonium bromide, was ex-
plored (method B).8e This protocol, which gave cleaner
reactions and satisfactory yields, led to the isolation of gram
quantities of several aryl- and heteroaryl-substituted enynes
with high Z/E stereoselectivity (Table 2). Thus, using method
B, a variety of substituted pyridine and quinoline vinyl-
bromides (2e-h) were effectively synthesized. In addition,
polyaromatic aldehydes naphthalene-2-carboxaldehyde (1i)
and fluorene-2-carboxaldehyde (1j) gave the corresponding
(Z) bromoolefins with selectivity as high as 100:0 (Z:E),
demonstrating the high efficiency of this method for both
π-deficient and aromatic substrates. Fortuitously, the polarity
of the predominantly (Z)-isomers was significantly different
from that of the (E)-isomers, as such allowing them to be
separated via chromatography. It is noteworthy that the
bromoolefins (2a-j) coupled well with trimethylsilylacetyl-
ene in the presence of CuI/Pd (II) catalyst in amine solvent
to give the (Z)-silylated vinylacetylenes in good to excellent
yields (Tables 1 and 2).7
In conclusion, the synthetic strategies depicted in Scheme
1 are extremely valuable and provide two alternative and
general pathways to predominantly (Z)-polyaromatic and
heteroaromatic enynes depending on precursors employed.
The synthetic utility of these methods is illustrated by
transformation of electron-rich (method A) and electron-
deficient heteroaromatic as well as aromatic carboxaldehydes
(method B) to their (Z)-vinylacetylenes in good to excellent
yields.
Acknowledgment. Many thanks are due to the Camille
and Henry Dreyfus Foundation, Inc. (Supplemental Grant-
SL-02-002) for partially supporting this work. We are also
thankful to Mr. Wittikar of University of Maryland at College
Park and Mr. Matt Lyndon of Mass Spectrometry Laboratory
at North Carolina State Uninversiy for the mass spectra data.
Supporting Information Available: Characterization
1
data. H NMR, and 13C NMR of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Attempts were also made to transform several electron-
rich heteroaromatic carbaldehydes (1a-d) to their corre-
sponding bromolefins and vinylacetylenes using method B.
OL0508173
Org. Lett., Vol. 7, No. 13, 2005
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