One-pot synthesis of symmetrical and unsymmetrical bisarylethynes by a modification of the sonogashira coupling reaction.

Article abstract of DOI:10.1021/ol026266n

A modification of the Sonogoshira coupling reaction employing an amidine base and a substoichiometric amount of water generates symmetrical and unsymmetrical bisarylethynylenes in one pot through in situ deprotection of trimethylsilylethynylene-added intermediates.

Full text of DOI:10.1021/ol026266n

ORGANIC
LETTERS
2002
Vol. 4, No. 19
3199-3202
One-Pot Synthesis of Symmetrical and
Unsymmetrical Bisarylethynes by a
Modification of the Sonogashira
Coupling Reaction
Matthew J. Mio,† Lucas C. Kopel,† Julia B. Braun,† Tendai L. Gadzikwa,†
,†
Kami L. Hull,† Ronald G. Brisbois,* Christopher J. Markworth,‡ and
,‡
Paul A. Grieco*
Department of Chemistry, Macalester College, 1600 Grand AVenue,
St. Paul, Minnesota 55105, and Department of Chemistry and Biochemistry,
Montana State UniVersity, Bozeman, Montana 59717
brisbois@macalester.edu
Received May 30, 2002
ABSTRACT
A modification of the Sonogoshira coupling reaction employing an amidine base and a substoichiometric amount of water generates symmetrical
and unsymmetrical bisarylethynylenes in one pot through in situ deprotection of trimethylsilylethynylene-added intermediates.
The Sonogashira palladium-catalyzed cross-coupling reac-
tion1 has proven to be a powerful method for the formation
of shape-persistent arylethynylenes.2 Whether employed in
the generation of scaffolds leading to molecular electronic
devices,3 dendrimers,4 dehydrobenzannulenes,5 foldamers,6
or polymers,7 the Sonogashira cross-coupling has proven to
be a reliable, high-yielding reaction that is tolerant of a wide
variety of functional groups. However, use of the Sonogash-
ira reaction to effect iterative synthesis often requires
systematic silane protection/deprotection of terminal ethy-
nylenes.8 Although a variety of strategies for in situ base-
mediated deprotection and cross coupling have been reported,
all such methods require prior installation of protecting
groups and/or supplementary reagents.9 Our immediate need
for efficient syntheses of a wide range of bisarylethynylenes10
derives from efforts focused on supramolecular self-as-
sembly, in which Co-mediated [2 + 2] annulation of alkynes
(8) (a) Eaborn, C.; Walton, D. R. M. J. Organomet. Chem. 1965, 4, 217.
(b) Eastmond, R.; Johnson, T. R.; Walton, D. R. M. Tetrahedron 1972, 28,
4601. (c) Hiyama, T. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter
10.
(9) (a) Denmark, S. E.; Sweis, R. J. Am. Chem. Soc. 2001, 123, 6439.
(b) Pugh, C.; Percec, V. J. Polym. Sci., Part A: Polym. Chem. 1990, 28,
1101. (c) Chow, H.-F.; Wan, C.-W.; Low, K.-H.; Yeung, Y.-Y. J. Org.
Chem. 2001, 66, 1910. (d) Shultz, D. A.; Gwaltney, K. P.; Lee, H. J. Org.
Chem. 1998, 63, 4034. (e) Yang, C.; Nolan, S. P. Organometallics 2002,
21, 1020.
(10) While several procedures for generating bisarylethynylenes using
alkynylmetal reagents are known, we only compare our method to similar
Pd- and Cu-based strategies. (a) Sonogashira, K. In Metal-Catalyzed Cross-
Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Wein-
heim, 1998; Chapter 5. (b) Modern Acetylene Chemistry; Stang, P. J.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, 1995.
† Macalester College.
‡ Montana State University.
(1) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467.
(2) Moore, J. S. Acc. Chem. Res. 1997, 30, 402.
(3) Tour, J. M. Acc. Chem. Res. 2000, 33, 791.
(4) (a) Pugh, V. J.; Hu, Q.-S.; Zuo, X.; Lewis, F. D.; Pu, L. J. Org.
Chem. 2001, 66, 6136. (b) Hu, Q.-S.; Pugh, V.; Sabat, M.; Pu, L. J. Org.
Chem. 1999, 64, 7528.
(5) Wan, W. B.; Haley, M. M. J. Org. Chem. 2001, 66, 3893.
(6) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S.
Chem. ReV. 2001, 101, 3893.
(7) Bunz, U. H. F. Chem. ReV. 2000, 100, 1605.
10.1021/ol026266n CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/30/2002

Scheme 1
Table 1. Study of Symmetrical Bisarylethynylene Formation
under a Variety of Modified Sonogashira Reaction Conditionsa
yieldsb (%)
provides CpCoCb-bridged ligands or ligand precursors.11
Herein, we report on a modification of the Sonogashira
reaction that allows for the one-pot generation of symmetrical
(Scheme 1) and unsymmetrical bisarylethynylenes (Scheme
2). Central to the synthetic protocol is the utilization of an
entry
catalyst
base
DBU
solvent
7
8
9
1
2
3
4
5
6
7
8
9
10
11
12
13
14
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
benzene trace 99
0
0
0
0
0
0
DBU
DBU
DBU
DBU
DBU
TEA
toluene
dioxane
THF
DMF
CH3CN
8
5
6
4
92
95
94
96
trace 99
benzene 44
0
0
84
56
82
1
Scheme 2
DABCO benzene 18
DBN
GUAN
DBU
DBU
DBU
DBU
benzene 14
benzene 38
benzene
benzene
benzene
62 trace
91 trace
98 trace
93 trace
c
Pd2(dba)3
9
2
7
Pd(PPh3)4
PdCl2dppf
PdCl2(PhCN)3
d
benzene 85
9
5
a All reactions were carried out in the absence of light for 18 h with a
0.2 M solution of 1 in the indicated solvent using 6 mol % catalyst, 10 mol
% CuI, 6.0 equiv of base, 40 mol % water, and 0.5 equiv of trimethylsi-
lylethynylene (all relative to 1 equiv of 1). b GC yields based on 1. c 10
mol % PPh3 added. d 6 mol % P(t-Bu)3 added.
in yields ranging from 84% (DBN; Table 1, entry 9) to 62%
(GUAN; Table 1, entry 10). Interestingly, the terminal
ethynylene analogue of 9 was observed in trace amounts
when DBN was used in conjunction with no added water
(see the Supporting Information).13 Optimized results were
obtained with DBU, benzene, and 40 mol % water (Table
1, entry 1). Various palladium catalysts [PdCl2(PPh3)2, Pd2-
(dba)3/PPh3, Pd(PPh3)4, PdCl2dppf and PdCl2(PhCN)3/P(t-
Bu)3] were examined using these optimal reaction conditions.
Yields ranged from 90 to 99% (Table 1, entries 1, 11-14)
in all cases but PdCl2(PhCN)3/P(t-Bu)3. A survey of different
protecting alkylsilanes was also performed under optimized
reaction conditions, with data conforming to known reac-
tivities as they relate to steric bulk. Whereas excellent yields
were possible using DBU, benzene, and 30 mol % water
when trimethylsilylethynylene was used, triethylsilylethy-
nylene and tert-butyldimethylsilylethynylene gave only a
trace or none of product 8, respectively.
amidine base such as 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) and the presence of substoichiometric amounts of
water, in addition to Pd0 catalyst, CuI, and organic solvent.12
As outlined in Scheme 1 and detailed in Table 1 (entries
1-6), symmetrical bisarylethynylene 8 is produced in
excellent yield in a variety of solvents when 6.0 equiv of
DBU and 40 mol % water are used (along with 6 mol %
PdCl2(PPh3)2 and 10 mol % CuI). In addition to varying the
solvent, extensive studies were conducted to optimize these
reaction conditions for the formation of 8 by varying the
amount of added water, base, Pd0 catalyst, and the steric bulk
of the silane protecting group. Modulating the quantity of
added water between 0 and 100 mol % (relative to 1 equiv
of 7) showed a plateau effect at 40 mol %; thus, we chose
that amount for our protocol (see the Supporting Informa-
tion). The significance of DBU was demonstrated when
triethylamine (TEA) and DABCO were employed as the base
in benzene containing 40 mol % water: bisarylethynylene
8 was not be detected by GC analysis, and only standard
Sonogashira product 9 was obtained (Table 1, entries 7 and
8). Use of amidines 1,5-diazabicyclo[4.3.0]non-5-ene (DBN)
and 1,3,4,6,7,8-hexahydro-2H-pyrimido(1,2-a)pyrimidine
(GUAN) in benzene containing 40 mol % water provided 8
Based on these results and previous reports from the
literature,9 we conjectured that the operative coupling mech-
anism in the Sonogashira modification features a protode-
silylation to effect in situ silane deprotection. This conclusion
is based on three points: (1) Clearly, the in situ silane
deprotection step must be amidine base-dependent, but it is
also copper(I)-dependent. Reactions executed with no added
CuI resulted in complete recovery of starting material,
indicating Cu+ association is a reaction necessity and ruling
out nucleophilic activation involving silicon and the amidine
(11) Johannessen, S. C.; Brisbois, R. G.; Fischer, J. P.; Grieco, P. A.;
Counterman, A. E.; Clemmer, D. E. J. Am. Chem. Soc. 2001, 123, 3818.
(12) Use of DBU in Sonogashira-type couplings has been previously
reported: Bodwell, G. J.; Miller, D. O.; Vermeij, R. J. Org. Lett. 2001, 3,
2093.
3200
Org. Lett., Vol. 4, No. 19, 2002

base (see the Supporting Information). (2) Silicate pathways
for silane deprotection (both with and without added
Cu+)9a,d,e,14 are invalidated by the almost quantitative bisaryl-
ethyne product yields observed when reactions were per-
formed with substoichiometric (40 mol % relative to 7)
amounts of added water (Table 1). In addition, yields are
depressed when no water was purposefully added, suggesting
the involvement of adventitious moisture.15 (3) Bisarylethyne
yield suppression was observed under “protonless” reaction
conditions (mixtures of 7, 9, DBU, benzene, PdCl2(PPh3)2,
CuI, and no added trimethylsilylethynylene or water; see the
Supporting Information). Moreover, the addition of catalytic
HI16 to anhydrous reactions such as those listed in Table 1
show good yields of bisarylethyne 8 (see the Supporting
Information). Taken together, these three results indicate the
amidine base is acting as a proton shuttle. In support of this
determination, the literature reinforces the invocation of a
DBU salt in the organic reaction mixture,17 and DBU has
been used catalytically in the nucleophilic addition of
acyldiazomethanes to aldehydes and imines.18 Therefore, we
speculate that after proceeding through the commonly
accepted cross-coupling chemistry, the silane-protected aryl-
ethynylene converges with Cu+ and a water/DBU salt,
resulting in protodesilylation to yield the terminal ethynylene.
Consequently, the aryl-substituted terminal ethynylene is
resubmitted to the cross-coupling cycle, generating the
bisarylethynyl product after a second pass.
Table 2. Synthesis of Symmetrical Bisarylethynylenes from
Aryl Halides and Aryl Triflatesa
Using the optimized protocol detailed above (Scheme 1;
Table 1, entry 1), several symmetrical bisarylethynylenes
were prepared (Table 2). Similar procedures yielding such
symmetrical products have been reported; however, these
employ the in situ elimination of acetone under basic
conditions9b,c or the use of acetylene gas.19 Aryl iodides,
triflates, and bromides are all reactive and give rise to the
symmetrical bisarylethynylenes. Of particular note is the
substituent effect observed for both iodides and bromides.
Iodides with electron-withdrawing groups (acetyl, methoxy-
carbonyl, and trifluoromethyl) give excellent yields of their
respective bisarylethynes at room temperature. In contrast,
iodides with electron-donating groups such as methoxy and
a All reactions were carried out in the absence of light for 18 h with a
0.2 M solution of aryl halide/triflate in benzene using 6 mol % PdCl2(PPh3)2,
10 mol % CuI, 6.0 equiv of DBU, 40 mol % water, and 0.5 equiv of
trimethylsilylethynylene (all relative to 1 equiv of aryl halide/triflate).
b Isolated yield based on average of two runs. c From the precursor iodide.
d From the precursor bromide. e From the precursor triflate.
methyl require elevated temperatures (60 °C) to proceed in
good yield. The same applies to the more sterically hindered
o-iodohalide substrates; in comparison to reactions run at
60 °C, reduced yields were observed at room temperature.
Triflates follow this pattern as well. Aryl iodides 2-chloro-
5-iodopyridine, 1-iodonaphthalene, and 2-iodothiophene gave
high yields of their respective symmetrical bisarylethynylene
analogues at room temperature employing the standard
protocol. Additionally, room-temperature iodides are easily
scaled up into the 2 g range (see the Supporting Information).
In general, aryl bromides required elevated temperatures (80
°C) for complete conversion.20
(13) We ascribe this observation to the known comparison of the reaction
rates of DBU (faster) and DBN (slower) in elimination reactions. Ency-
clopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; John Wiley
& Sons: New York, 1995.
(14) (a) Correia, R.; DeShong, P. J. Org. Chem. 2001, 66, 7159. (b)
Manoso, A. S.; DeShong, P. J. Org. Chem. 2001, 66, 7449 and references
therein.
(15) Without intentional addition of water, we always isolated 8 as the
major product, although rigorously purified solvents and reagents were used
as well as careful syringe transfer techniques. For example, we observed
72% yield of 8 (by GC-MS analysis) using a 0.20 M benzene solution of
1 equiv of 1-bromo-3-iodobenzene (7), 6.0 equiv of DBU, 0.5 equiv of
trimethylsilylethynylene, 6.0 mol % PdCl2(PPh3)2, and 10 mol % CuI.
(16) Grieco, P. A.; Markworth, C. J. Tetrahedron Lett. 1999, 40, 665.
(17) Values of pKa in water for triethylamine (the most common base
used for Sonogashira couplings) have been measured at 10.8. In organic
solvents, this value is known to decrease (in DMSO, pKa ) 9.00). Bordwell,
F. G. Acc. Chem. Res. 1988, 21, 456. With DBU, on the other hand, the
exact opposite is observed. In water, the pKa of DBU has been measured
at 11.0. In DMSO, this value rises to 12.0, but a recent investigation of
this amidine in acetonitrile has produced a pKa of 24. Kalijurand, I.; Rodima,
T.; Leito, I.; Koppel, I. A.; Schwesinger, R. J. Org. Chem. 2000, 65, 6202.
(18) Jiang, N.; Wang, J. Tetrahedron Lett. 2002, 43, 1285.
Unsymmetrical bisarylethynylenes were also prepared
using a one-pot base toggle protocol (Scheme 2; Table 3).
Addition of benzene to a flask containing 6 mol % PdCl2-
(19) Li, C.-J.; Chen, D.-L.; Costello, C. W. Org. Process Res. DeV. 1997,
1, 325.
(20) 4-Bromobenzonitrile gave only a trace (<1%) of the bisarylethyne
product, and complete recovery of starting material was observed for
4-bromo-N,N-dimethylaniline and 4-bromobiphenyl. Other unsuccessful
attempts suggest that a detrimental single-electron-transfer pathway may
take precedence over cross-coupling in certain substrates. Two iodides we
investigated (1-iodo-4-nitrobenzene and 1-iodo-3,5-dinitrobenzene) and two
bromides (4-bromobenzophenone and 5-bromopyrimidine) gave no discern-
ible products when subjected to our reaction conditions.
Org. Lett., Vol. 4, No. 19, 2002
3201

Scheme 3
Table 3. Synthesis of Unsymmetrical Bisarylethynylenes from
Aryl Iodidesa
where the solid-phase generation of discrete oligomers is
inconvenient or expensive.21
a All reactions were carried out in the absence of light at room
temperature with a 0.2 M solution of the first aryl iodide (1 equiv) in benzene
using 6 mol % PdCl2(PPh3)2, 10 mol % CuI, 6.0 equiv of NEt3, and 1.05
equiv of trimethylsilylethynylene. After 18 h, 1.0 equiv of the second aryl
iodide, 12.0 equiv of DBU, and 40 mol % water were added (all relative to
1 equiv of first aryl iodide). Reactions were then allowed to stir an additional
18 h before workup. b Isolated yield based on an average of two runs.
In conclusion, we have demonstrated an innovative
modification for the Sonogashira coupling reaction to gener-
ate symmetrical and unsymmetrical bisarylethynes in one pot.
Combination of the amidine DBU as base and a substo-
ichiometric amount of water is critical to the featured
reactivity. Our continuing efforts are aimed at determining
the utility of our methodology in the efficient construction
of diverse oligo- and polymeric structures, encouraging
implications for which derive from convergent syntheses of
10 and 12. We shall report on such work in due course.
(PPh3)2, 10 mol % CuI, and a first aryl iodide 3 followed by
addition of 6.0 equiv of Et3N and trimethylsilylethynylene
provided standard Sonogashira product 4 in situ, after
vigorous stirring in the dark for 18 h. Sequential addition of
1.0 equiv of a second aryl iodide (5), 12.0 equiv of DBU,
and 40 mol % water (relative to 1 equiv 3) gave rise to
unsymmetrical bisarylethynylene 6 after 18 h at room
temperature (61-90% isolated yield; Table 3).
In addition, this one-pot base toggle procedure was
used to generate the symmetrical triarylethynylene 10,
prepared in 63% isolated yield from 1,4-diiodobenzene
(first aryl iodide) and 7 (second aryl iodide). Similarly,
tetraarylethynylene compound 12 was prepared in one pot
by using a combination base and temperature toggle pro-
cedure as illustrated in Scheme 3 in fair yield. Such
convergency is an excellent harbinger of applications
Acknowledgment. R.G.B. thanks the NSF for a Presi-
dential Faculty Fellowship Award (CHE 9350393). This
work was also supported by Macalester College through a
Faculty Startup Award. M.J.M. thanks Macalester College
for a postdoctoral fellowship. C.J.M. and P.A.G. thank the
National Institute of General Medical Sciences (GM 33605).
Supporting Information Available: General experimen-
tal details, general synthetic procedures, detailed results of
the optimization (water, solvent, base, catalyst, ethynylsilane)
study, and physical characterization data of all symmetrical
and unsymmetrical bisarylethynes. This material is available
free of charge via the Internet at http://pubs.acs.org.
(21) Huang, S.; Tour, J. M. J. Am. Chem. Soc. 1999, 121, 4908.
OL026266N
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