One-pot synthesis of diarylalkynes using palladium-catalyzed sonogashira reaction and decarboxylative coupling of sp carbon and sp2 carbon

Article abstract of DOI:10.1021/ol703130y

Decarboxylative coupling of sp-sp² carbons is possible by palladium catalyst. Employing propiolic acid (1) as a difunctional alkyne, and using the consecutive reactions of the Sonogashira reaction and the decarboxylative coupling, unsymmetrically substituted diaryl alkynes were obtained in moderate to good yield.

Full text of DOI:10.1021/ol703130y

ORGANIC
LETTERS
2008
Vol. 10, No. 5
945-948
One-Pot Synthesis of Diarylalkynes
Using Palladium-Catalyzed Sonogashira
Reaction and Decarboxylative Coupling
of sp Carbon and sp2 Carbon
Jeongju Moon,† Miso Jeong,† Hyungoog Nam,† Jinhun Ju,† Joong Ho Moon,‡
Hyun Min Jung,§ and Sunwoo Lee*,†
Department of Chemistry, Chonnam National UniVersity, 300 Yongbong-dong, Buk-gu,
Gwangju, 500-757, Republic of Korea, ICx Nomadics, Inc., 215 First Street, Suite 105,
Cambridge, Massachusetts 02142, and AdVanced Materials DiVision, Korea Research
Institute of Chemical Technology, 100 Jang-dong, Yuseong-gu, Daejeon, 305-600,
Republic of Korea
sunwoo@chonnam.ac.kr
Received December 30, 2007
ABSTRACT
Decarboxylative coupling of sp-sp2 carbons is possible by palladium catalyst. Employing propiolic acid (1) as a difunctional alkyne, and using
the consecutive reactions of the Sonogashira reaction and the decarboxylative coupling, unsymmetrically substituted diaryl alkynes were
obtained in moderate to good yield.
The Sonogashira reaction of terminal alkynes with aryl or
alkenyl halides is the most straightforward and powerful
existing method for constructing C(sp)-C(sp2) bonds1 and
has been used for the synthesis of pharmaceuticals, natural
products, and advanced functional materials. Generally, the
Sonogashira reaction is carried out in the presence of a
palladium catalyst and copper iodide, using an amine as
solvent. Since its inception, many new developments related
to the Sonogashira reaction have been reported in chemical
literature, including improvements in the catalytic efficiency
of the process,2 copper- and/or amine-free versions,3 and the
ability to run the reaction in aqueous media or without
solvent.4 In order to synthesize unsymmetrically substituted
diaryl alkynes using the Sonogashira reaction, acetylenes
protected with silanes or other metals (Sn, Zn, and B) and
aryl halides activated by copper and a base are generally
required.5
However, these methods are not ideal because they require
relatively long synthetic procedures for the protection and
deprotection of alkynes, and thus are not economical. They
(2) (a) Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003, 42,
5993. (b) Ko¨llhfer, A.; Pullmann, T.; Plenio, H. AdV. Synth. Catal. 2005,
347, 1295. (c) Feuerstein, M.; Doucet, H.; Santelli, M. Tetrahedron Lett.
2005, 46, 1717.
(3) For selected examples, see: (a) Ljungdahl, T.; Pettersson, K.;
Albinsson, B.; Ma¨rtensson, J. J. Org. Chem. 2006, 71, 1677. (b) Li, P.-H.;
Wang, L. AdV. Synth. Catal. 2006, 348, 681. (c) Ruiz, J.; Cutillas, N.; Lopez,
F.; Lopez, G.; Bautista, D. Organometallics 2006, 25, 5768. (d) Gonzalez-
Arellano, C.; Abad, A.; Corma, A.; Garcia, H.; Iglesias, M.; Sanchez, F.
Angew. Chem., Int. Ed. 2007, 46, 1536.
(4) Marsden, J. A.; Haley, M. M. In Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH:
Weinheim, 2004; Chapter 6.
(5) We presented the related works in Poster Session 1 at Tetrahedron
50th Anniversary Meeting Challenges in Organic Chemistry, Eight Tetra-
hedron Symposium, 26-29 June 2007, Berlin, Germany, 2007; pp 1, 44.
† Chonnam National University.
‡ ICx Nomadics, Inc.
§ Korea Research Institute of Chemical Technology.
(1) For recent selected reviews, see: (a) Doucet, H.; Hierso, J.-C. Angew.
Chem., Int. Ed. 2007, 46, 834. (b) Sonogashira, K. J. Organomet. Chem.
2002, 653, 46. (c) Tykwinski, R. R. Angew. Chem., Int. Ed. 2003, 42, 1566.
(d) Jutand, A. Pure Appl. Chem. 2004, 76, 565.
10.1021/ol703130y CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/30/2008

also produce an equivalent of metal complex as waste.
Therefore, it is vital to develop an environmentally friendly,
economical, and copper-free palladium catalytic system, such
as we describe here, to apply the Sonogashira reaction
intensively in chemical industry. Here, we introduce a
decarboxylative coupling method using propiolic acid (1) and
aryl halides with a copper-free palladium catalyst to produce
unsymmetrically substituted diaryl alkyne 3 (Scheme 1).
Table 1. Palladium-Catalyzed Decarboxylative Coupling
Reaction of Phenylpropiolic Acid and
4-tert-Butyl-bromobenzenea
base
(equiv)
convn
(%)
yield
(%)b
entry
ligand
PPh3
Pd/L
1
1/2
1/2
1/2
1/2
1/2
1/2
1/2
1/2
1/1.5
1/1
1/2
1/2
1/2
1/2
1/2
1/2
1/2
1/2
1/1
1/1
1/1
TBAF(2)
TBAF(2)
TBAF(2)
TBAF(2)
TBAF(2)
TBAF(2)
TBAF(2)
TBAF(2)
TBAF(2)
TBAF(2)
TBAF(2)
TBAF(2)
TBAF(1)
TBAF(2)
TBAI(2)
TBABr(2)
TBACl(2)
NEt3 (2)
TBAF(2)
TBAF(4)
TBAF(6)
56
54
51
88
70
64
55
100
80
62
100
100
90
27
15
11
13
0
78
19
14
28
45
30
54
22
97
67
53
72
68
53
15
2
Scheme 1. One-Pot Synthesis of Diarylalkynes from Propiolic
2
3
4
5
6
7
8
9
10
11d
12e
13
14f
15
16
17
18
19
20
21
Dppm
Dppe
Dppf
Xantphosc
PCy3
Acid
BiphPtBu2
PtBu3
PtBu3
PtBu3
PtBu3
PtBu3
PtBu3
PtBu3
PtBu3
PtBu3
PtBu3
PtBu3
Dppf
In devising this reaction, we first investigated the catalytic
applicability of the decarboxylative coupling of aryl bromide
and phenylpropiolic acid, since decarboxylative coupling of
sp carbon and sp2 carbon has never been reported.6 To the
best of our knowledge, decarboxylative cross-coupling has
so far only been reported for sp3-sp3, sp2-sp2, and sp-sp3
bond formation.7
0
0
0
48
70
88
We screened a variety of palladium sources, ligands, and
additives for use in the decarboxylative coupling of phenyl-
propiolic acid and 4-tert-butyl-bromobenzene. As shown in
Table 1, monodentate arylphosphines, such as PPh3, showed
very low yield. Among bidentate phosphine ligands, 1,1′-
bis(diphenylphosphino)ferrocene (dppf) afforded the highest
yield (entry 4). Among monodentate alkylphosphines, PtBu3
showed the best result (entry 8). Decreasing the ratio of
palladium to ligand to 1/1, the product yield was decreased
to 53% (entry 10). A palladium to ligand ratio of 1/2 was
found to provide the best conditions for obtaining the desired
product with high yield. Most palladium sources showed
good yields, but Pd2(dba)3 (dba ) dibenzylideneacetone)
yielded the best results (entry 8). The temperature required
for this reaction is above 90 °C, as inferior results were
obtained at 60 °C (entry 14). Decreasing the amount of TBAF
decreased the reaction yields (entry 13). Varying the base
used also had a significant effect on the reaction. Tetrabu-
tylammonium fluoride (TBAF) gave the product in 97%
yield, while other types of tetrabutylammonium salts afforded
no desired product or produced low yield (entries 15-17).
Triethylamine, which is typically employed to accelerate
the Sonogashira reaction, failed to give the desired product
Dppf
Dppf
100
100
a Reaction conditions; 1.0 mmol phenylpropiolic acid, 1.0 mmol 4-tert-
butyl-bromobenzene, 3 mL NMP, 5 mol % Pd (Pd2(dba)3). bYield was
determined by GC. c4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene.
dPd(OAc)2 was used instead of Pd2(dba)3. ePd(CH3CN)2Cl2 was used instead
of Pd2(dba)3 fReaction temperature is 60 °C.
under this reaction condition (entry 18). When dppf′ was
used as ligand, a palladium to ligand ratio of 1:1 showed
high yield of desired product. However, 6 equiv of TBAF
were required to obtain a high yield of product (entry 21). It
is noteworthy that this catalytic system produces no trace of
a diyne compound derived from the dimerization of alkynes,
a common byproduct that plagues Sonogashira reactions. In
addition, this reaction method could exclude the pheny-
lacetylene-added side product which is often produced when
phenylacetylene is used as an alkyne source.
Based on the reaction conditions of the decarboxylative
couplings, we attempted to expand this transformation to the
synthesis of unsymmetrically substituted diaryl alkynes from
propiolic acid. To achieve this goal, we first had to identify
appropriate reaction conditions for the synthesis of phenyl-
propiolic acid (step A), which is employed in the decar-
boxylative coupling (step B), from propiolic acid (1) and
aryl halides (Table 2).
(6) sp3-sp3 bond formation: (a) Waetzig, S. R.; Rayabarapu, D. K.;
Weaver, J. D.; Tunge, J. A. Angew. Chem., Int. Ed. 2006, 45, 4977. (b)
Burger, E. C.; Tunge, J. A. J. Am. Chem. Soc. 2006, 128, 10002. sp2-sp2
bond formation: (c) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006,
313, 662. (d) Becht, J.-M.; Catala, C.; Drian, C. L.; Wagner, A. Org. Lett.
2007, 9, 1781. (e) Goossen, L. J.; Rodr´ıguez, N.; Melzer, G.; Linder, C.;
Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824. sp-sp3 bond
formation: (f) Rayabarapu, D. K.; Tunge, J. A. J. Am. Chem. Soc. 2005,
127, 13510.
(7) For selected papers on the role of tetrabutylammonium ion in the
cross-coupling reactions: (a) Calo, V.; Nacci, A.; Monopoli, A.; Laera, S.;
Cioffi, N. J. Org. Chem. 2003, 68, 2929. (b) Reetz, M. T.; de Vries, J. G.
Chem. Commun. 2004, 1559.
Propiolic acid (1) and iodobenzene were reacted under
catalytic conditions with Pd2(dba)3 and PtBu3 at 90 °C. The
conversion of iodobenzene was 100%. However, the diphe-
nylacetylene (4a) was obtained as the major product (entry
1). Decreasing the reaction temperature caused a decrease
946
Org. Lett., Vol. 10, No. 5, 2008

Table 2. Synthesis of Unsymmetrically Substituted Diaryl
Alkynes from Propiolic Acida
Table 3. Synthesis of Unsymmetrical Diaryl Alkynesa
% Pdb, L,
temp yield (%)c
entry stepa equiv of TBAF (C°)
convn
2d 3a
4a
42
27
6
8
6
1
2
3
4
5
6
7
8f
9f
A
A
A
A
A
A
A
5, PtBu3, (2)
5, PtBu3, (2)
5, PtBu3, (2)
5, PtBu3, (4)
5, PtBu3, (6)
5, dppf, (2)
90
60
25
25
25
25
25
25, 90
25, 90
100
100
46
32
30
4
11
31
20
21
58
94
-
e
e
e
e
e
e
e
65
trace
trace
10, dppf, (2)
100
100
100
A+B 10, dppf, (2)
A+B 10, dppf, (6)
72 trace
90 trace
-
a Reaction conditions; step A: 1.0 mmol PhI, 1.0 mmol 1, 3 mL NMP,
Pd/L ) 1/2 (for entries 1-5), Pd/L ) 1/1 (for entries 6-9), TBAF were
reacted for 12 h; step B: after step A, 1.0 mmol 4-tBuC6H4Br was added
and reacted for 12 h. b Mol % of Pd (from Pd2(dba)3 with respect to PhI).
c Yield was determined by GC. d The product was converted to methyl ester
using BF3Et2O with methanol. e No subject. f Step A at 25 °C for 12 h and
step B at 90 °C for 12 h.
in both conversion and 4a yield, and the desired product yield
was increased but not sufficiently (entry 3). Using PtBu3 as
ligand and increasing the amount of TBAF to 6 equiv did
not increase the yield of 2 (entry 5). Replacing the ligand
PtBu3 with dppf, and increasing the mol % of the catalyst,
afforded phenylpropiolic acid in 94% yield as well as a trace
amount of 4a (entry 7). Based on these reaction conditions,
after the Sonogashira reaction of propiolic acid (1) and
iodobenzene, the decarboxylation using 4-tert-butyl-bro-
mobenzene proceeded at 90 °C to afford the unsymmetrically
diarylated acetylene 3a with 72% (entry 8) yield. A dramatic
improvement was observed when the amount of TBAF was
increased by up to 6 equiv (entry 9).
The scope of the one-pot synthesis of unsymmetrical diaryl
alkynes was explored. Aryl iodide was employed for the
Sonogashira reaction with propiolic acid (1). Next, aryl
bromide was employed for the decarboxylative coupling, and
the reaction was carried out at 90 °C. The results are
summarized in Table 3.
The one-pot reaction proceeded smoothly to produce
unsymmetric diarylalkynes in moderate to good yield.
Considering the reaction yields, electron-neutral and -rich
aryl iodides all seemed to be coupled with propiolic acid to
give the corresponding arylpropiolic acid. When using aryl
bromide as a partner for the decarboxylative coupling
reactions, all electron-neutral, -donating, and -withdrawing
substituents in the substrates afforded the desired coupled
products in good yields. In particular, 2-bromobiphenyl
afforded a 94% yield of the corresponding diarylalkynes
(entry 3). In our reaction, ortho-substituted aryl bromides
afforded high yields (entries 3-5 and 11). Moreover, a
sterically congested aryl bromide, such as bromomesitylene,
also gave the desired coupling products in 91% yield (entry
4). However, an electron-rich meta-substituted aryl bromide
showed low yield (entry 2). The heterocyclic bromides, such
as 3-bromopyridine and 2-bromothiophene, also react smoothly
in the decarboxylative couplings (entries 7, 8, 13, and 14).
a Reaction conditions: 1.0 equiv of aryl iodides, 1.0 equiv of propiolic
acid, 5 mol % Pd2(dba)3, 10 mol % dppf, 6.0 equiv of TBAF and NMP
(0.15 M halides) at room temperature for 12 h and 1.0 equiv of aryl bromides
at 90 °C for 12 h. Reaction time was not optimized. b Yield of isolated
product.
Symmetrical diarylalkynes were also obtained from propiolic
acid and 2 equiv of aryl bromide. Using PtBu3 as ligand,
only 2 equiv of TBAF are required for this reaction (Scheme
2).
Scheme 2. Synthesis of Symmetric Diaryl Alkynes
This reaction method has several advantages: (1) propiolic
acid (1) is relatively inexpensive compared to trimethylsi-
lylacetylene, which is widely used as an alkyne source. (2)
The byproduct is CO2, which makes the reaction environ-
mentally friendly. (3) Consecutive addition of different aryl
halides, without adding a second portion of palladium
Org. Lett., Vol. 10, No. 5, 2008
947

catalyst, followed by changing the temperature in the reaction
mixture yields an unsymmetrically substituted diaryl alkyne.
(4) No diyne byproduct was generated from the dimerization
of alkynes.
In summary, we demonstrate a simple synthetic method
for the one-pot synthesis of diarylalkynes using propiolic
acid (1). By modulating difunctional reactivity of the
propiolic acid at different temperatures, we successfully
coupled various aryl halides via a combination of the
Sonogashira reaction and decarboxylative coupling. This
method offers a new strategy to construct sp carbon and sp2
carbon bonds difunctionally that is very useful for hetero-
coupled alkyne derivatives. Synthetic applications for elu-
cidating conjugated oligomers and polymers, using the
difunctionality of propiolic acid in palladium-catalyzed
coupling, are under investigation.
Acknowledgment. This work was supported by Grant
No. R01-2005-000-10848-0 from the Basic Research Pro-
gram of the Korea Science & Engineering Foundation.
Supporting Information Available: Reaction procedures
and spectral and analytical data for reaction products. This
material is available free of charge via the Internet at
http://pubs.acs.org
OL703130Y
948
Org. Lett., Vol. 10, No. 5, 2008