Aliphatic acetylenic homocoupling catalyzed by a novel combination of AgOTs-CuCl2-TMEDA and its application for the solid-phase synthesis of bis-benzo[b]furan-linked 1,3-diynes

Article abstract of DOI:10.1021/ol030009g

(Matrix presented) A novel catalytic system of AgOTs-CuCl ₂-TMEDA is described for the homocoupling of aliphatic acetylenes on solid support. It is the first observation that Ag^I's activating triple bond could facilitate Cu^II

Full text of DOI:10.1021/ol030009g

ORGANIC
LETTERS
2003
Vol. 5, No. 6
909-912
Aliphatic Acetylenic Homocoupling
Catalyzed by a Novel Combination of
AgOTs−CuCl2−TMEDA and Its
Application for the Solid-Phase
Synthesis of Bis-benzo[b]furan-Linked
1,3-Diynes
,†
,†
Yun Liao,* Reza Fathi,* and Zhen Yang†,‡
ViVoQuest, Inc., 711 ExecutiVe BouleVard, Valley Cottage, New York 10989, and
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of
Education, Department of Chemical Biology, College of Chemistry, Peking UniVersity,
Beijing, P. R. China 100871
r.fathi@ViVoquest.com
Received January 17, 2003
ABSTRACT
A novel catalytic system of AgOTs−CuCl2−TMEDA is described for the homocoupling of aliphatic acetylenes on solid support. It is the first
I
II
observation that Ag ’s activating triple bond could facilitate Cu -mediated oxidative acetylenic homocoupling. This study provides an efficient
way to synthesize a diversified symmetrical bis-benzo[b]furan-linked 1,3-diyne library on solid support.
As a powerful tool in molecular construction, acetylenic
homocoupling has been extensively studied1a since Glaser’s
pioneering work1b,c in 1869. The Glaser-Hay coupling1d and
the Eglinton-Galbraith method1e-g remain the most suc-
cessful techniques in addition to the recently improved
palladium-catalyzed homocoupling.1h,i
However, no study on polymer-supported aliphatic acety-
lenic homocoupling has hitherto been reported. During the
course of our systematic studies2a,b focusing on Pd- and Cu-
mediated couplings and domino reactions on macrobeads,2c
we primarily observed that the on-bead aromatic terminal
acetylenes easily undergo homocoupling under the Sono-
gashira conditions.2a This evidence confirmed our assumption
that polymer-supported acetylenic homocoupling could be
an important viable path to construct a symmetrical dimeric
scaffold,3a which is of significant interest due to its unique
† VivoQuest. Email: (Y.L.) y.liao@vivoquest.com
‡ Peking University.
(1) (a) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int.
Ed. 2000, 39, 2634-2657 and references therein. (b) Glaser, C. Ber. Dtsch.
Chem. Ges. 1869, 2, 422-424. (c) Glaser, C. Ann. Chem. Pharm. 1870,
154, 137-171. (d) Hay, A. S. J. Org. Chem. 1962, 27, 3320-3321. (e)
Eglinton, G.; Galbraith, A. R. Chem. Ind. (London) 1956, 737-738. (f) de
Meijere, A.; Kozhushkov, S. I. Top. Curr. Chem. 1999, 201, 1-42. (g)
Haley, M. M.; Pak, J. J.; Brand, S. C. Top. Curr. Chem. 1999, 201, 81-
130. (h) Liu, Q.; Burton, D. J. Tetrahedron Lett. 1997, 38, 4371-4374. (i)
Lei, A.; Srivastava, M.; Zhang, X. J. Org. Chem. 2002, 67, 1969-1971.
(2) (a) Liao, Y.; Fathi, R.; Reitman, M.; Zhang, Y.; Yang, Z. Tetrahedron
Lett. 2001, 42, 1815-1818. (b) Liao, Y.; Reitman, M.; Zhang, Y.; Fathi
R.; Yang, Z. Org. Lett. 2002, 4, 2607-2609. (c) Tallarico, J. A.; Depew,
K. M.; Pelish, H. E.; Westwood, N. J.; Lindsley, C. W.; Shair, M. D.;
Schreiber, S. L.; Foley, M. A. J. Comb. Chem. 2001, 3, 312-318.
10.1021/ol030009g CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/27/2003

Scheme 1a
Table 1. Relative Efficiency of Various Methods for the
On-Bead Aliphatic Homocoupling of E2 to F2
E2/F 2
(conv, %)
entry
acetylenic homocoupling conditions
1
2
3
4
5
6
7
8
9
PdII/Pd0, CuI, oxidants, bases, solvents, rt
Cu(OAc)2, pyridine (DBU), rt to 80 °C
CuCl or CuI, O2, TMEDA or dipyridyl
CuCl2, CuI, TMEDA, DBU, CH2Cl2, rt
CuCl2, CuI, AgOAc, TMEDA, DBU CH2Cl2, rt
CuCl2, CuI, AgOTf, TMEDA, DBU CH2Cl2, rt
CuCl2, CuI, AgOTs, TMEDA, DBu CH2Cl2, rt
Cu Cl2, AgOTs, TMEDA, DBU, CH2Cl2, r t
Cu(OTf)2, TMEDA, DBU, CH2Cl2, rt
>60:40 (<10)
>50:50 (<25)
>70:30 (<20)
50:50 (<20)
50:50 (45)
40:60 (55)
5:85 (85)
5:85 (85)
100:0 (0)
10
11
12
Cu(OTs)2, TMEDA, DBU, CH2Cl2, rt
Cu(OTs)2, AgOTs, TMEDA, DBU CH2Cl2, rt
AgOTs, TMEDA, DBU, CH2Cl2, rt
100:0 (0)
100:0 (0)
100:0 (0)
neither the Pd-catalyzed methods1h,i,2a (entry 1 in Table 1)
nor the Eglinton-Galbraith method1e-g and Glaser-Hay
coupling1d as well as their many variants (entries 2-4 in
Table 1) could provide any results with acceptable purities/
yields. Prolonging the reaction time only resulted in even
poorer purities and yields. This drawback of the on-bead
aliphatic acetylenic homocoupling in comparison with its
aromatic counterpart2a may derive from the aliphatic terminal
alkyne’s lower acidity, but higher instability of its diyne
product toward transition metals.6 Furthermore, the inef-
ficiency was “amplified” by the on-bead reaction which
usually is more sluggish and much slower than the solution-
phase reaction.7
a Conditions: (1) CO balloon, CF3CH2OH, Pd(PPh3)2Cl2-dppp
(1.2 equiv), CsOAc, DMF, 45 °C, 24 h; (2) Superbase D, alkynol
Cj, THF, rt, 48 h; (3) CuCl2 (1.1 equiv), AgOTs (1.1 equiv),
TMEDA (N,N,N,N-tetramethylethylenediamine), DBU, CH2Cl2, rt,
17 h; (4) HF/Py 5% in THF, rt, 1 h; TMSOMe, 0.5 h.
AgI could activate the terminal carbon-hydrogen bond
by forming a π-complex with the triple bond.8a However,
there is no report regarding the role of AgI in facilitating
acetylene homocoupling. We screened three AgI salts and
observed a clear activation tendency in the following order:
AgOAc < AgOTf < AgOTs (entries 5-7 in Table 1). In
the case of AgOTs, the on-bead homocoupling preceded
function as a modulator of cellular processes3b and its
potential contribution to protein interaction by providing an
extra binding domain.3c Unfortunately, none of the known
methods1 being tested are applicable for the on-bead aliphatic
acetylenic homocoupling. This challenge had not been
realized until we developed a unique AgOTs-CuCl2-
TMEDA combination that proved to be a superior system
in both solution and solid phase, thereby providing the
possibility for the acetylenic homocoupling on solid support.
Considering the frequent occurrence of di- and oligoacety-
lene moieties,4a,b as well as benzofuran skeleton4c,d in natural
products which possess intriguing biological activities,4c,d we
became increasingly interested in constructing a dimeric
benzofuran scaffold by exploring the acetylenic homocou-
pling on solid support for future combinatorial library
construction.
As illustrated in Scheme 1, the key intermediates Ei were
generated via a PdII-mediated cascade carbonylative
annulation2b of Ai to give activated esters Bi, followed by a
Verkade superbase D5 catalyzed transesterification with
various alkynols Cj.
The subsequent on-bead acetylenic homocoupling (Ei to
Fi) encountered unexpected difficulties. During the model
study (Cj ) 4-pentyn-1-ol, Ri ) tolyl, i ) 2, Scheme 1),
1
smoothly in a high conversion (85% based on H NMR
analysis, entry 7 in Table 1). The prominent activation effect
of the AgOTs may come from the much weaker coordinating
nature of OTs- than that of AcO- and TfO-, which makes
the cationic AgI more “naked”8b and facilitates its association
(4) (a) Hansen, L.; Boll, P. M. Phytochemistry 1986, 25, 285-293. (b)
Lu, W.; Haji, G. Z.; Aisa, A.; Cai, J. Tetrahedron Lett. 1998, 39, 9521-
9522. (c) Engler, T. A.; LaTessa, K. O.; Lyengar, R.; Chai, W.; Agrios, K.
Bioorg. Med. Chem. 1996, 4, 1755-1769. (d) Pieters, L.; Van Dyck, S.;
Gao, M.; Bai, R.; Hamel, E.; Vlietinck, A.; Lemiere, G. J. Med. Chem.
1999, 42, 5473-5481. (e) Donnelly, D. M. X.; Meegan, M. J. In
ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Ed.; Pergamon
Press: New York, 1984; Vol. 4. (f) Erber, S.; Ringshandl, R.; von Angerer,
E. Anti-Cancer Drug Des. 1991, 6, 417. (g) Malamas, M. S.; Sredy, J.;
Moxham, C.; Katz, A.; Xu, W. X.; McDevitt, R.; Adebayo, F. O.; Sawicki,
D. R.; Seestaller, L.; Sullivan, D.; Taylor, J. R. J. Med. Chem. 2000, 43,
1293. (h) Watanabe, Y.; Yoshiwara, H.; Kanao, M. J. Heterocycl. Chem.
1993, 30, 445. (i) McCallion, G. D. Curr. Org. Chem. 1999, 3, 67. (j) Yang,
Z.; Liu, H.-B.; Lee, C.-M.; Chang, H.-M.; Wong, H. N. C. J. Org. Chem.
1992, 57, 7248.
(5) Ilankumaran, P.; Verkade, J. G. J. Org. Chem. 1999, 64, 3086-3089.
(6) Rossi, R.; Carpita, A.; Bigelli, C. Tetrahedron Lett. 1985, 26, 523-
526.
(7) (a) Hudson, D. J. Comb. Chem. 1999, 1, 333-360; 403-456. (b)
Vaino, A. R.; Janda, K. D. J. Comb. Chem. 2000, 2, 579-596.
(8) (a) Ginnebaugh, J. P.; Maki, J. W.; Lewandos, G. S. J. Organomet
Chem. 1980, 190, 403-416. (b) Tsuji, J. Acc. Chem. Res. 1973, 6, 8-15.
(c) Jacobs, L. A.; Van Vuuren, C. P. J. Thermochim. Acta 1988, 127, 399-
402.
(3) (a) Clemons, P. A. Curr. Opin. Chem. Biol. 1999, 3, 112-115. (b)
Diver, S. T.; Schreiber, S. L. J. Am. Chem. Soc. 1997, 119, 5106-5109
and references therein. (c) Nicolaou, K. C.; Hughes, R.; Cho, S.-Y.;
Winssinger, N.; Smethurst, C.; Labischinski, H.; Endermann, R. Angew.
Chem., Int. Ed. 2000, 39, 3823-3828 and references therein.
910
Org. Lett., Vol. 5, No. 6, 2003

Table 2. Results of the AgOTs/CuCl2/TMEDA-Promoted
On-Bead Aliphatic Acetylenic Homocoupling
Figure 1. Proposed mechanism of the acetylenic homocoupling.
with the acetylene, and as a consequence activates the triple
bond more efficiently.
To confirm the true active species, Cu(OTf)2 (entry 9),
Cu(OTs)2 (entry 10), and Cu(OTs)2/AgOTs (entries 11 and
12) were also tested. As a result, only the starting substrate
E2 was recovered in each case. This demonstrates that CuCl2
is required and its Cl- exchange with OTs- from AgOTs
may not occur since a soluble enthalpy-driven AgI-TMEDA
complex may be formed in CH2Cl2,8c which prevents AgCl
precipitation.
A plausible mechanism (Figure 1) of AgI-activated CuII-
catalyzed oxidative acetylenic homocoupling may start from
the π-complexing of AgI with the triple bond, activating the
terminal acetylene so as to accelerate the deprotonation by
the base, facilitating the further formation of a possible
dinuclear CuII acetylide complex,1a which collapses directly
to the homocoupling product and CuI. According to the
mechanism, CuI is not necessary as anticipated (entry 8).
To assess the general applicability of the combined
catalytic system AgOTs-CuCl2-TMEDA, eight on-bead
terminal alkynes Ei (Scheme 1) underwent smooth homo-
coupling to generate the corresponding Fi, and the results
are shown in Table 2.10 For the six products with a bridge
of 10 carbons in the center (F1-F6), the conversion/purity
is around 85% to 90%. For the product with a bridge of eight
carbons in the center (F7), the conversion/purity is a little
lower, around 70%. For the product with a bridge of eight
carbons in the center but containing branch substitution (F8),
the conversion remains 80%.
a Purity was estimated by 1H NMR analysis. b The same unreactive
impurity (10%) exists in both E8 and F8, which does not affect the
conversion (80%) but does decrease the purity (70%).
macrobeads and to avoid side reactions, a stoichiometric
amount of AgOTs-CuCl2 was utilized. Prolonging the
reaction time over 20 h in order to drive the homocoupling
to completion only resulted in lower conversion/yield partly
due to the instability of the aliphatic diyne. In homogeneous
solution-phase synthesis the homocoupling of 4-pentyn-1-
ol could be accomplished in almost quantitative yield in 1 h
at 20 °C by using 0.1 equiv of the AgOTs-CuCl2-TMEDA
under a balloon pressure of pure oxygen. In comparison, the
Pd-catalyzed method1i and the Hay coupling1d only led to
5% and 22% conversions, respectively, employing the similar
loading of catalysts in 1 h at 20 °C. The Eglinton-Galbraith
method1e-g gave a 90% yield in 1 h; however, excess Cu-
(OAc)2 had to be employed at 50 °C. Clearly, in comparison
with the old methods in both solid and solution phase, the
new system exhibited its superiority, which turned out to be
a determining factor in the case of the on-bead aliphatic
aecetylenic homocoupling in which the reaction rate is
extremely critical to influence the final purity and yield.
In summary, this paper describes a novel solid-supported
aliphatic acetylenic homocoupling by developing a novel
superior AgOTs-CuCl2-TMEDA system. Also, it is the first
observation that an AgI-activating triple bond could facilitate
1
All the results were confirmed by both LC-MS and H
NMR analyses. To accelerate the homocoupling on the
(9) Blackwell, H. E.; Clemons, P. A.; Schreiber, S. L. Org. Lett. 2001,
3, 1185-1188.
(10) The procedure for solid-phase synthesis is provided in the Supporting
Information, and a typical procedure for the solution-phase synthesis is
described below. The CuCl2 (13.4 mg, 0.1 equiv), AgOTs (27.9 mg, 0.1
equiv), TMEDA (0.1 mL), DBU (0.5 mL), and CH2Cl2 (2 mL) were mixed
under the balloon pressure of O2 and stirred for 0.5 h before the 4-pentyn-
1-ol (84 mg, 1.0 equiv) was added. The clear deep green solution was stirred
for another 1 h and filtered through a short plug of silica gel with ethyl
acetate. The filtrate was washed with a saturated NH4Cl solution. Removing
the ethyl acetate resulted in deca-4,6-diyne-1,10-diol as a colorless semisolid
(78 mg, 94% yield).
Org. Lett., Vol. 5, No. 6, 2003
911

CuII-mediated oxidative acetylenic homocoupling. We thereby
solved an obstacle in translating this classical reaction onto
the solid phase. Thus, we have developed a valuable
approach to potentially make diversified symmetrical mol-
ecules efficiently by means of the site-site interaction9
within the polymer. Indeed, the new system developed herein
allows diverse substitutions, as well as 1,3-diyne bridges with
different lengths and branches to be integrated into the final
scaffold, and as a result is capable of leading to generation
of a novel biologically interesting symmetrical bis-benzo-
[b]furan-linked 1,3-diyne molecules.
Supporting Information Available: Experimental pro-
cedures and NMR and LC-MS spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL030009G
912
Org. Lett., Vol. 5, No. 6, 2003