Ligand-, copper-, and amine-free sonogashira reaction of aryl iodides and bromides with terminal alkynes

Article abstract of DOI:10.1021/jo049325e

Conditions for an efficient ligand-, copper-, and amine-free palladium-catalyzed Sonogashira reaction of aryl iodides and bromides with terminal alkynes have been developed. Critical to the success of this new protocol is the use of tetrabutylammonium ace

Full text of DOI:10.1021/jo049325e

reaction of aryl bromides, but it was necessary to use air-
sensitive and pyrophoric P(t-Bu)3 as a ligand, although
the coupling did proceed with only 0.5 mol % of palladium
and ligand.8 It is worthy of note that P(t-Bu)3 can be
replaced with the air-stable [(t-Bu)3PH]BF4 in Sonogash-
ira couplings.9 Ryu described a Sonogashira method for
coupling aryl iodides in ionic liquids, but it required an
elevated temperature (60 °C) as well as the use of a
phosphine ligand.10 Recently, Na´jera has disclosed a
palladacycle catalyst for the cross-coupling of aryl iodides
and terminal alkynes.11 However, this methodology re-
quires relatively harsh conditions (110 °C) and a multi-
step synthesis of the catalyst. TBAF, TBAOH, and Ag2O
were used by Mori as activators for the Sonogashira
coupling of aryl iodides, but an elevated temperature (60
°C) and a phosphine-based palladium catalyst were
needed in all three cases.12 Moreover, use of a silver
catalyst not only would add cost to the catalyst but also
to expense of metal waste disposal/recovery. Astruc
described the use of a preformed Pd(II)-phosphine
catalyst for a Sonogashira coupling of aryl halides in neat
Et3N.13 Leadbeater has reported a copper-free Sonogash-
ira methodology for aryl iodides and activated aryl
bromides with the traditional palladium catalyst Pd-
(PPh3)2Cl2 (4 mol %) at 70 °C in neat piperidine.14
Interestingly, however, the observation was made that
under phosphine- and copper-free conditions, neither
palladium acetate nor palladium on charcoal catalyzed
the aforementioned reaction. More recently, a report by
Buchwald has appeared describing the coupling of aryl
chlorides and aryl tosylates with terminal alkynes,
utilizing a bulky biphenylphosphine ligand under copper-
and amine-free conditions.15
Liga n d -, Cop p er -, a n d Am in e-F r ee
Son oga sh ir a Rea ction of Ar yl Iod id es a n d
Br om id es w ith Ter m in a l Alk yn es
Sameer Urgaonkar and J ohn G. Verkade*
Department of Chemistry, Gilman Hall,
Iowa State University, Ames, Iowa 50011
jverkade@iastate.edu
Received April 21, 2004
Abstr a ct: Conditions for an efficient ligand-, copper-, and
amine-free palladium-catalyzed Sonogashira reaction of aryl
iodides and bromides with terminal alkynes have been
developed. Critical to the success of this new protocol is the
use of tetrabutylammonium acetate as the base. Noteworthy
features of this method are room-temperature conditions and
the tolerance of a broad range of functional groups in both
reaction partners.
The palladium-catalyzed reaction of aryl halides with
terminal alkynes, known as the Sonogashira reaction,
constitutes an important facet of alkyne as well as of
organopalladium chemistry.1,2 This reaction is generally
cocatalyzed by Cu(I), and an amine as a base and a
phosphine as a ligand for palladium are also typically
included.3 An important side reaction encountered with
the presence of a Cu(I) cocatalyst is the Glaser-type
oxidative dimerization of the alkyne.4 To address this
issue, several reports have described copper-free Sono-
gashira reactions, but none of them are free of an amine
and a ligand simultaneously, while also operating at room
temperature.5 For example, in 1986, Cacchi et al. re-
ported the coupling of enol triflates with terminal alkynes
under copper-free conditions, but a phosphine-ligated
palladium precursor and a temperature of 60 °C were
employed.6 In 1993, Linstrumelle published a paper on
the Pd-catalyzed coupling of aryl or vinyl halides (I, Br,
OTf) with terminal alkynes.7 In this report, only one
example of a phosphine- and copper-free (but not amine-
free) Sonogashira coupling of a vinyl iodide with a
terminal alkyne was described, and the coupling pro-
ceeded in only moderate yield (57%). For an aryl iodide
(only iodobenzene was used), a phosphine-ligated pal-
ladium source was included under copper-free conditions.
In both cases, 5 mol % palladium catalyst was employed.
Herrmann reported a procedure for the Sonogashira
From an industrial as well as an economic standpoint,
a ligandless and copper-free process would provide much
needed impetus to the development of improved catalyst
systems for Sonogashira couplings. Further, such a
process would be advantageous for synthetic chemists
who would generally prefer not to use expensive and
sensitive ligands. In addition, the elimination of amines
(generally used in large excess) would be welcome
because industrial wastes containing them would require
treatment for environmental purposes.
Our continuing interest in palladium-catalyzed organic
transformations16-18 prompted us to extend our attention
(8) Bo¨hm, V. P. W.; Herrmann, W. A. Eur. J . Org. Chem. 2000, 3679.
(9) Netherton, M. R.; Fu, G. C. Org. Lett. 2001, 3, 4295.
(10) Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu, I.
Org. Lett. 2002, 4, 1691.
(11) Alonso, D. A.; Na´jera, C.; Pacheco, M. C. Tetrahedron Lett. 2002,
43, 9365.
(12) Mori, A.; Kawashima, J .; Shimada, T.; Suguro, M.; Hirabayashi,
K.; Nishihara, Y. Org. Lett. 2000, 2, 2935.
(13) Me´ry, D.; Heuze´, K.; Astruc, D. Chem. Commun. 2003, 1934.
(14) Leadbeater, N. E.; Tominack, B. J . Tetrahedron Lett. 2003, 44,
8653.
(15) Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003, 42,
5993.
(16) (a) Urgaonkar, S.; Nagarajan, M.; Verkade, J . G. J . Org. Chem.
2003, 68, 452. (b) Urgaonkar, S.; Nagarajan, M.; Verkade, J . G. Org.
Lett. 2003, 5, 815. (c) Urgaonkar, S.; Xu, J .-H.; Verkade, J . G. J . Org.
Chem. 2003, 68, 8416.
(17) Urgaonkar, S.; Nagarajan, M.; Verkade, J . G. Tetrahedron Lett.
2002, 43, 8921.
(1) Stang, P. J . In Modern Acetylene Chemistry; Diederich, F., Ed.;
VCH: Weinheim, Germany, 1995.
(2) Sonogashira, K. In Metal-Catalyzed Reactions; Diederich, F.,
Stang, P. J ., Eds.; Wiley-VCH: NewYork, 1998.
(3) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 4467. (b) Sonogashira, K. J . Organomet. Chem. 2002, 653, 46.
(c) Rossi, R.; Carpita, A.; Bellina, F. Org. Prep. Proc. Ind. 1995, 129.
(d) Tykwinski, R. R. Angew. Chem., Int. Ed. 2003, 42, 1566.
(4) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int.
Ed. 2000, 39, 2632.
(5) It should be noted that the examples for copper-free procedures
listed in this paper are representative and not comprehensive.
(6) Cacchi, S.; Morera, E.; Ortar, G. Synthesis 1986, 320.
(7) Alami, M.; Ferri, F.; Linstrumelle, G. Tetrahedron Lett. 1993,
34, 6403.
(18) You, J .; Verkade, J . G. Angew. Chem., Int. Ed. 2003, 42, 5051.
10.1021/jo049325e CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/16/2004
5752
J . Org. Chem. 2004, 69, 5752-5755

TABLE 1. Scr een in g of Ba ses for Son oga sh ir a Cou p lin g
of 4-Iod oa n isole a n d 5-Hexyn -1-ol
TABLE 2. Liga n d -, Cop p er -, a n d Am in e-F r ee
Son oga sh ir a Cou p lin gs of Ar yl Iod id es w ith
P h en yla cetylen e
entry
base
yielda (%)
1
2
3
Bu4NOAc
Cs2CO3
Et3N
93b
69
5
4
DBU
8
5
6
7
8
9
10
i-Pr2NEt
piperidine
i-Pr2NH
Na2CO3
NaO-t-Bu
NaOAc
5
5
10
30
0
25
a
b
Isolated yields (average of two runs). Reaction time was 6
h.
to the Sonogashira reaction. Herein we report for the first
time a room-temperature, general, and efficient proce-
dure for a ligand-, copper-, and amine-free Sonogashira
reaction of aryl iodides and bromides with terminal
alkynes using Pd(OAc)2 or Pd2(dba)3 as the catalyst and
tetrabutylammonium acetate as the base.
a
b
Isolated yields (average of two runs). 1 mol % of Pd(OAc)2
was employed. c Parenthesized yields were obtained with 3 mol
% of Pd(OAc)2.
For preliminary optimization of the reaction conditions,
we studied the reaction of electron-rich 4-iodoanisole and
5-hexyn-1-ol in the presence of 2 mol % of Pd(OAc)2 in
DMF at room temperature (Table 1). An important initial
goal was to find a suitable base that would effect the
desired reaction. Surprisingly, commonly used secondary
and tertiary amine bases such as triethylamine, DBU
(diazabicyclo[5.4.0]undec-7-ene), N-ethyldiisopropylamine
(i-Pr2NEt), piperidine, and diisopropylamine (i-Pr2NH)
as well as Na2CO3, NaO-t-Bu, and NaOAc gave inferior
results. Gratifyingly, however, both Cs2CO3 and Bu4-
NOAc were effective as bases, with Bu4NOAc being the
more reactive, allowing the reaction to be completed in
6 h. Among the solvents screened (THF, toluene, dioxane,
CH3CN, and DMF), DMF proved to be the most efficient.
Other palladium sources such as PdCl2, Pd2(dba)3, and
[(π-allyl)PdCl]2 were also effective catalysts for the
aforementioned reaction.
drawing groups were completed in 3 h the electron-
neutral and electron-rich aryl iodides reacted in 6 h.
In an effort to further expand the scope of our ligand-,
copper-, and amine-free Sonogashira reaction, we next
investigated the reaction of substituted aryl iodides with
a series of aliphatic terminal alkynes as summarized in
Table 3. The yields were generally higher than those
obtained when phenylacetylene was used as the reaction
partner. Unfunctionalized alkynes, for example, 1-octyne
in Table 3 (entries 2, 3, 6, and 13) as well as function-
alized alkynes bearing a hydroxy group (entries 4, 8, 10,
12, and 15), a chloride group (entry 14), a cyano group
(entry 18), or a TIPS group (entry 17) reacted efficiently
with various aryl iodides to afford the corresponding aryl
alkynes in excellent yields. Even a terminal alkyne with
an alkene functionality underwent Sonogashira coupling
in good yields (entries 1, 5, 7, 9, 11, and 16).
Using equimolar reagent concentrations, 2 mol % Pd-
(OAc)2, 1.5 equiv of Bu4NOAc, and DMF as the solvent
at room temperature, reactions of a series of substituted
aryl iodides were carried out via the palladium-catalyzed
Sonogashira reaction with phenylacetylene (Table 2).
Good to excellent yields were generally obtained under
these ligandless, copper- and amine-free conditions.
Functional groups such as carboxyethyl, keto, and nitro
were well tolerated (Table 1, entries 1-3). Aryl iodides
with electron-withdrawing groups gave higher yields
than those with electron-neutral or electron-rich groups,
and the coupling proceeded with substantially lower
palladium catalyst loading. The cross-coupling of steri-
cally hindered aryl iodides (2-iodotoluene and 2-iododani-
sole) also proceeded quite well (Table 1, entries 4 and 6).
As expected, no homocoupling product was detected by
GC under these conditions. It may be noted that while
the reactions of aryl iodides possessing electron-with-
The efficiency of aryl bromides as a coupling partner
under ligandless, copper- and amine-free conditions was
also studied (Table 4). Although Pd2(dba)3 was employed
as the catalyst in these reactions, Pd(OAc)2 was also
found to be a suitable palladium precursor. However, this
method was effective only for electron-deficient aryl
bromides and it required a slightly higher catalyst
loading (4 mol % Pd) to provide good to excellent yields
of the desired product. Thus, aryl bromides with nitro
(entries 1-3), keto (entry 4), and cyano (entries 5-7)
functional groups were smoothly coupled with a variety
of terminal alkynes. Unfortunately, the Sonogashira
couplings of electron-rich aryl bromides were sluggish
under these conditions.
Presently, the beneficial effect of Bu4NOAc in these
reactions is not clear. Undoubtedly, Bu4NOAc acts as a
mild base to deprotonate the most acidic hydrogen in the
J . Org. Chem, Vol. 69, No. 17, 2004 5753

TABLE 3. Liga n d -, Cop p er -, a n d Am in e-F r ee Son oga sh ir a Cou p lin gs of Ar yl Iod id es w ith Alip h a tic Ter m in a l Alk yn esa
a
b
d
For reaction conditions, see Table 1. Isolated yields (average of two runs). c 1 mol % of Pd(OAc)2 was employed. Parenthesized
yields were obtained with 3 mol % of Pd(OAc)2. e Pd2(dba)3 was used in place of Pd(OAc)2.
alkyne. In addition, it may facilitate the reduction of Pd-
(OAc)2 to a catalytically active Pd(0) species. The latter
phenomenon has been observed previously by Calo´19 and
by Reetz20 and co-workers, who observed Pd nanoparticle
formation, albeit at elevated temperatures. However, we
have found that the reaction in Table 1 proceeds in the
presence of mercury, thus supporting a homogeneous
catalytic pathway.21 A particular role for the tetrabutyl-
ammonium cation seems to be precluded because we
found that Me4NOAc can be substituted for Bu4NOAc.
On the other hand as expected, the coupling of 4-iodoani-
sole and 5-hexyn-1-ol did not proceed in the presence of
Bu4NBr (TBAB). These results indicate that the acetate
anion in combination with a bulky cation plays a very
essential role in promoting such coupling reactions,
perhaps by providing a naked more reactive acetate
anion. Another possibility is that in the catalytic cycle,
the oxidative addition adduct ArPd(II)X, a 12 e- unstable
complex, could be stabilized by tetrabutylammonium
acetate to afford a 16 e- complex [ArPd(II)X3]2- 2Bu4N+
(X ) OAc, and/or I or Br) in which the metal center could
be expected to be more stable and more electrophilic thus
facilitating its complexation with an alkyne. Deprotona-
tion (by Bu4NOAc), isomerization, and product-forming
(19) Calo´, V.; Nacci, A.; Monopoli, A.; Laera, S.; Cioffi, N. J . Org.
Chem. 2003, 68, 2929.
(20) Reetz, M. T.; Maase, M. Adv. Mater. 1999, 11, 773.
(21) Widegren, J . A.; Bennett, M. A.; Finke, R. G. J . Am. Chem. Soc.
2003, 125, 10301.
5754 J . Org. Chem., Vol. 69, No. 17, 2004

TABLE 4. Liga n d -, Cop p er -, a n d Am in e-F r ee
Son oga sh ir a Cou p lin gs of Ar yl Br om id es w ith Ter m in a l
Alk yn es
nium acetate as the base is important for obtaining high
yields of arylalkynes. The methodology encompasses a
wide variety of functional groups, and it is worthwhile
noting that our protocol employs a relatively low pal-
ladium catalyst loading. To the best of our knowledge,
this is the first ligand-, copper-, and amine-free method
for the cross-coupling of aryl iodides and bromides with
terminal alkynes. These conditions render our protocol
potentially attractive for industrial as well as academic
applications of Sonogashira couplings.
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Son oga sh ir a Rea ction . An
oven-dried Schlenk flask equipped with a magnetic stirring bar
was charged with Bu4NOAc (1.5 mmol) and Pd(OAc)2 (1-3 mol
%) or Pd2(dba)3 (2 mol % for aryl bromides) inside a nitrogen-
filled glovebox. The flask was capped with a rubber septum, and
then it was removed from the glovebox. An aryl iodide or bromide
(1.0 mmol) and DMF (3 mL) were then successively added, and
after 5 min of stirring, the alkyne (1.0 mmol) was added. Stirring
was continued at room temperature under argon for the corre-
sponding reaction times indicated in the tables, after which time
the reaction mixture was diluted with water (10 mL) and
extracted with diethyl ether (4 × 10 mL). The combined ether
layers were dried over Na2SO4, filtered, concentrated, and
purified by alumina gel flash chromatography using hexanes or
hexanes/ether to elute the desired coupling product.
a
Isolated yields (average of two runs).
Ack n ow led gm en t. The National Science Founda-
tion is gratefully acknowledged for financial support of
this work in the form of a grant.
reductive elimination would constitute the remaining
steps of the catalytic cycle.
In summary, we have established that Pd(OAc)2 or Pd2-
(dba)3 catalyzes the Sonogashira reaction of aryl iodides
and bromides at room temperature in the absence of
ligand, amine, and Cu(I). The choice of tetrabutylammo-
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and complete characterization of compounds prepared.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O049325E
J . Org. Chem, Vol. 69, No. 17, 2004 5755