Zinc chloride-promoted aryl bromide-alkyne cross-coupling reactions at room temperature

Article abstract of DOI:10.1021/jo902015w

(Chemical Equation Presented) Substoichiometric amounts of ZnCl₂ promote the room temperature, Pd/P(t-Bu)₃-catalyzed cross-coupling of aryl bromides with alkynes. Pd(I) dimer 1 is demonstrated to be a particularly active precatalyst for this reaction. The reaction is general for a wide variety of aryl bromides.

Full text of DOI:10.1021/jo902015w

pubs.acs.org/joc
been significant advancements in overcoming the above lim-
Zinc Chloride-Promoted Aryl Bromide-Alkyne
Cross-Coupling Reactions at Room Temperature
itations through two general strategies: the utilization of
novel, highly active Pd catalysts6 and developing methodo-
logies that are active in the absence of copper cocatalyst.7
However, while “copper-free Sonogashira” conditions pre-
vent CuI-mediated homocoupling,8 they can suffer from
lower rates compared to those for reactions promoted by
CuI.9 Alternative cocatalysts that do not display this side
reactivity are thus highly desirable. In this Note, we describe
conditions for aryl bromide-alkyne cross-coupling reac-
tions at room temperature, which utilize substoichiometric
amounts of inexpensive ZnCl2 in the presence of an active Pd
catalyst.10
Aaron D. Finke, Eric C. Elleby, Michael J. Boyd,
Haim Weissman, and Jeffrey S. Moore*
Department of Chemistry, University of Illinois
Urbana-Champaign, 600 South Mathews Avenue, Urbana,
Illinois 61801
jsmoore@illinois.edu
Received September 17, 2009
The yields for the room temperature coupling of the
relatively unreactive 4-bromoanisole with phenylacetylene,
both in the absence and the presence of ZnCl2, for selected
Pd precatalyst systems are described in Table 1. Many of these
Pd catalysts have been reported previously for aryl bromide-
alkyne cross-couplings. Gratifyingly, most of these previously
(6) Selected recent reports on utilizing active ligands for Pd-catalyzed
cross-coupling of aryl halides with alkynes: (a) Bohm, V. P. W.; Herrmann,
W. A. Eur. J. Org. Chem. 2000, 3679–3681. (b) Hundertmark, T.; Littke, A.
F.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729–1731. (c) McGuinness,
D. S.; Cavell, K. J. Organometallics 2000, 19, 741–748. (d) Netherton, M. R.;
Fu, G. C. Org. Lett. 2001, 3, 4295–4298. (e) Gelman, D.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2003, 42, 5993–5996. (f) Kollhofer, A.; Pullmann, T.;
Plenio, H. Angew. Chem., Int. Ed. 2003, 42, 1056–1058. (g) Soheili, A.;
Albaneze-Walker, J.; Murry, J. A.; Dormer, P. G.; Hughes, D. L. Org. Lett.
2003, 5, 4191–4194. (h) Feuerstein, M.; Berthiol, F.; Doucet, H.; Santelli, M.
Org. Biomol. Chem. 2003, 1, 2235–2237. (i) Datta, A.; Ebert, K.; Plenio, H.
Organometallics 2003, 22, 4685–4691. (j) Hierso, J. C.; Fihri, A.; Amardeil,
R.; Meunier, P.; Doucet, H.; Santelli, M.; Ivanov, V. V. Org. Lett. 2004, 6,
3473–3476. (k) Adjabeng, G.; Brenstrum, T.; Frampton, C. S.; Robertson, A.
J.; Hillhouse, J.; McNulty, J.; Capretta, A. J. Org. Chem. 2004, 69, 5082–
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Angew. Chem., Int. Ed. 2005, 44, 6173–6177. (n) Kollhofer, A.; Plenio, H.
Adv. Synth. Catal. 2005, 347, 1295–1300. (o) Shirakawa, E.; Kitabata, T.;
Otsuka, H.; Tsuchimoto, T. Tetrahedron 2005, 61, 9878–9885. (p) Bren-
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Rominger, F.; Dupont, J. Adv. Synth. Catal. 2006, 348, 133–141. (t) Ruiz,
Substoichiometric amounts of ZnCl2 promote the room
temperature, Pd/P(t-Bu)3-catalyzed cross-coupling of
aryl bromides with alkynes. Pd(I) dimer 1 is demonstrated
to be a particularly active precatalyst for this reaction.
The reaction is general for a wide variety of aryl bromides.
The Pd- and CuI-catalyzed cross-coupling reaction of aryl
and vinyl halides with terminal alkynes, known as the
Sonogashira or Hagihara-Sonogashira reaction,1-3 is one
of the most widely used and reliable methods of alkyne
functionalization. Nonetheless, Cu-mediated homodimeri-
zation of alkynes and the requirement of elevated tempera-
tures for the coupling of aryl bromides present a challenge to
the efficient preparation of acetylene-containing molecular
scaffolds free of chemical defects.4,5 Recently, there have
ꢀ
ꢀ
J.; Cutillas, N.; Lopez, F.; Lopez, G.; Bautista, D. Organometallics 2006, 25,
5768–5773. (u) Flackenstein, C. A.; Plenio, H. Chem.;Eur. J. 2007, 13,
2701–2716. (v) Kondolff, I.; Feuerstein, M.; Doucet, H.; Santelli, M. Tetra-
hedron 2007, 63, 9514–9521. (w) an der Heiden, M. R.; Plenio, H.; Immel, S.;
Burello, E.; Rothenberg, G.; Hoefsloot, H. C. J. Chem.;Eur. J. 2008, 14,
2857–2866. (x) Lipshutz, B. H.; Chung, D. W.; Rich, B. Org. Lett. 2008, 10,
3793–3796. (y) Brown, W. S.; Boykin, D. D.; Sonnier, M. Q. Jr.; Clark, W.
D.; Brown, F. V.; Shaughnessy, K. H. Synthesis 2008, 1965–1970. (z) Lee, D.;
Qiu, H.; Cho, M.; Lee, I.; Jin, M. Synlett 2008, 1657–1660.
(1) Marsden, J. A.; Haley, M. M. In Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; de Meijre, A., Diederich, F., Eds.; Wiley-VCH:
Weinheim, Germany, 2004; pp 317-394.
(2) Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979–2017.
(3) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467–4470.
(7) (a) For a review of recent advances in aryl halide-alkyne cross-
coupling, see: Doucet, H.; Hierso, J. C. Angew. Chem., Int. Ed. 2007, 46,
834–871. (b) For a critical review on alternative metal-catalyzed cross-
couplings of aryl halides and alkynes, see: Plenio, H. Angew. Chem., Int.
Ed. 2008, 47, 6954–6956.
(8) Alkynes in the presence of CuI, amine, and a stoichiometric oxidant
(Pd(II) or air) rapidly and quantitatively homocouple. This is the generally
accepted mechanism for reduction of some Pd(II) precatalysts in the Sono-
gashira reaction. See: Nguyen, P.; Yuan, Z.; Agocs, L.; Lesley, G.; Marder,
T. B. Inorg. Chim. Acta 1994, 220, 289-296 and references cited therein.
(9) In our experience, this observation holds true for couplings that utilize
amines as base. However, Buchwald et al. have reported that for certain
coupling conditions which utilize inorganic bases, CuI inhibits reactivity (see
ref 6e.).
(4) Selected reviews on the synthesis and applications of acetylene scaf-
folds: (a) Poly(arylene ethynylene)s: From Synthesis to Application; Weder,
C., Ed.; Springer: Berlin/Heidelberg, Germany, 2005; Vol. 177. (b) Bunz, U. H. F.
Chem. Rev. 2000, 100, 1605–1644. (c) McQuade, D. T.; Pullen, A. E.; Swager,
T. M. Chem. Rev. 2000, 100, 2537–2574. (d) Thomas, S. W.; Joly, G. D.; Swager,
T. M. Chem. Rev. 2007, 107, 1339–1386. (e) Hill, D. J.; Mio, M. J.; Prince, R. B.;
Hughes, T. S.; Moore, J. S. Chem. Rev. 2001, 101, 3893–4011. (f) Moore, J. S.
Acc. Chem. Res. 1997, 30, 402–413. (g) Martin, R. E.; Diederich, F. Angew.
Chem., Int. Ed. 1999, 38, 1350–1377.
(5) Previous work from our group on applications of arylene ethynylene
scaffolds: (a) Hartley, C. S.; Elliott, E. L.; Moore, J. S. J. Am. Chem. Soc.
2007, 129, 4512. (b) Smaldone, R. A.; Moore, J. S. Chem.;Eur. J. 2008, 14,
2650–2657. (c) Zang, L.; Che, Y.; Moore, J. S. Acc. Chem. Res. 2008, 41,
1596–1608. (d) Zhang, W.; Moore, J. S. Angew. Chem., Int. Ed. 2006, 45,
4416–4439.
(10) This is an optimization of a method we previously reported: Elliott,
E. L.; Ray, C. R.; Kraft, S.; Atkins, J. R.; Moore, J. S. J. Org. Chem. 2006, 71,
5282–5290.
DOI: 10.1021/jo902015w
r
Published on Web 10/27/2009
J. Org. Chem. 2009, 74, 8897–8900 8897
2009 American Chemical Society

Finke et al.
JOCNote
TABLE 1. Scope of Palladium Sources with and without ZnCl2
TABLE 2. Efficacy of Zinc Halides in Promotion of Cross-Couplinga
% yieldc
% yield of
diynec in 24 h
entry
ZnX2
none
ZnCl2
ZnBr2
ZnI2
costb ($/mol)
15 min
24 h
1
2
3
4
5
6
2
87
88
48
85
<1e
84
100
100
79
100
99
<1
0
0
0
0
29.71
84.22
142.36
1076.05
48.52
Zn(OTf)2
CuId
3
aReaction conditions: 4-bromoanisole (1.0 mmol), phenylacetylene
(1.0 mmol), 1 (0.01 mmol), zinc halide (0.1 mmol), THF (1.0 mL), HN(i-
Pr)2 (0.5 mL), rt. bCost for reagent grade salts (as of July 2009), Aldrich
Chemical Co. cGC yields. d1 mol % CuI used in lieu of zinc halide (see
text). eReaction is complete after 2 h.
aConversions by GC. bReaction conditions: 4-bromoanisole (1.0
mmol), phenylacetylene (1.0 mmol), Pd catalyst (0.02 mmol), THF
(1.0 mL), HN(i-Pr)2 (0.5 mL), rt. cReaction conditions: 4-bromoanisole
(1.0 mmol), phenylacetylene (1.0 mmol), Pd catalyst (0.02 mmol Pd),
ZnCl2 (0.1 mmol), THF (1.0 mL), HN(i-Pr)2 (0.5 mL), rt. dNo Pd
catalyst added.
iodides in the presence of Pd(PPh3)4.14 Notably, they
were able to couple the typically unreactive methyl pro-
piolate with iodobenzene at elevated temperatures.15
Furthermore, they demonstrated the relative inertness of
zinc halide-promoted alkyne cross-couplings to air and
moisture.16
The coupling of 4-bromoanisole with phenylacetylene
with 1 mol % 1 in THF/HN(i-Pr)2 was performed in the
presence of 10 mol % of various zinc halides (Table 2, entries
2-5). Using only 10 mol % of a zinc halide salt promotes
rapid cross-coupling at room temperature, indicating that
stoichiometric quantities are not needed. All Zn salts display
significant conversion after only 15 min. Strong inorganic
bases such as Cs2CO3 and NaOt-Bu, when used in lieu of
HN(i-Pr)2, lead to no product formation at room tempera-
ture. Furthermore, deliberate addition of 20 mol % of a
chloride source (LiCl or Bu4NCl) leads to no noticeable rate
enhancement.
The scope of the optimized conditions described above is
summarized in Table 3. A variety of aryl bromides couple
with alkynes rapidly with low catalyst loadings and at room
temperature.17 The reaction conditions tolerate many func-
tional groups, including esters, aldehydes, and nitro groups
(Table 3, entries 9-11, respectively). Heteroaryl bromides
such as 2-bromothiophene are tolerated (Table 3, entry 15).
Moderately hindered aryl bromides such as 2-bromotoluene
couple rapidly at room temperature (Table 3, entries 6 and
12, respectively). However, very hindered aryl bromides
such as 2-bromomesitylene and 9-bromoanthracene do not
couple as rapidly at room temperature (Table 3, entries 11
reported catalysts, in the presence of 10 mol % ZnCl2, are
effective at promoting cross-coupling at room tempera-
ture, with high yields after 1 h. The less reactive Pd(PPh3)4
(Table 1, entry 2) is an ineffective catalyst at room tem-
perature. Pd(I) dimer 1 (Table 1, entry 6)11 displays the
highest activity in aryl bromide-alkyne cross-coupling of
the catalyst systems studied. Complex 1 is a highly active
catalyst that is more air-stable than other previously
reported Pd/P(t-Bu)3 precatalysts12 (see the Supporting
Information).
The necessity of a cocatalyst for rapid couplings, even in
the presence of a highly active Pd catalyst, is illustrated in
Tables 1 and 2. Pd catalysts which displayed high activity in
the presence of ZnCl2 were far less active in the absence of
ZnCl2 (Table 1, entries 3-7). Coupling in the presence of 1
mol % CuI (Table 2, entry 6) is complete in 2 h, but forms a
significant amount of diyne byproduct. We attribute the low
yield of the CuI-promoted coupling after 15 min to the
solubility of CuI, which is less soluble in the reaction mixture
than zinc halides.
The effect of zinc halide salts in alkyne cross-coupling
reactions is well-documented but underutilized.13 Anasta-
sia and Negishi reported that stoichiometric ZnBr2 pro-
moted room temperature coupling of alkynes with aryl
€
(11) (a) Werner, H.; Kuhn, A. J. Organomet. Chem. 1979, 179, 439–445.
(14) Anastasia, L.; Negishi, E. Org. Lett. 2001, 3, 3111–3113.
(15) Reactions with methyl propiolate under our conditions lead only to
decomposition/polymerization of the alkyne, regardless of the amine used.
We observe that this occurs in the absence of Pd catalyst or Zn salt, indicating
that even amine bases incapable of conjugate addition are capable of
promoting alkyne decomposition. The method reported here is thus unsui-
table for cross-couplings of propiolate esters.
(16) Our reaction conditions are insensitive to moisture, and drying of the
hygroscopic zinc salts is unnecessary. However, the air sensitivity of the Pd
catalysts requires these reactions be run under inert atmosphere with
degassed solvents.
(b) Denmark, S. E.; Baird, J. D. Org. Lett. 2006, 8, 793–795. (c) Denmark, S.
E.; Baird, J. D.; Regens, C. S. J. Org. Chem. 2008, 73, 1440–1455. (d)
Denmark, S. E.; Baird, J. D. Tetrahedron 2009, 65, 3120–3129.
(12) Stambuli, J. P.; Kuwano, R.; Hartwig, J. F. Angew. Chem., Int. Ed.
2002, 41, 4746–4748.
(13) Pioneering studies on effects of Zn salts on aryl halide-alkyne cross-
couplings: (a) Crisp, G. T.; Turner, P. D.; Stephens, K. A. J. Organomet.
Chem. 1998, 570, 219–224. (b) Eberhard, M. R.; Wang, Z. H.; Jensen, C. M.
Chem. Commun. 2002, 818–819. For implementation of Zn-promoted aryl
halide-alkyne cross-couplings, see: (a) Boydston, A. J.; Pagenkopf, B. L.
Angew. Chem., Int. Ed. 2004, 43, 6336–6338. (b) Grube, G. H.; Elliott, E. L.;
Steffens, R. J.; Jones, C. S.; Baldridge, K. K.; Siegel, J. S. Org. Lett. 2003, 5,
713–716. (c) Crisp, G. T.; Turner, P. D. Tetrahedron 2000, 56, 407–415.
(17) “Room temperature” in this context refers to the absence of external
heating. In reality, many of these reactions, particularly with electron-poor
aryl bromides, can be quite exothermic.
8898 J. Org. Chem. Vol. 74, No. 22, 2009

Finke et al.
JOCNote
TABLE 3. Aryl Bromide-Alkyne Cross-Couplings Promoted By Cata-
lytic ZnCl2
TABLE 4. Effects of Trace CuI in Cross-Couplinga
a
% yieldb
entry
ZnCl2 (mol %)
c
CuI (mol %)
c
1 h
2 h
24 h
entry
R
R0
Ph
time
yield (%)b
1
2
3
4
-
-
2
5
24
30
5
10
56
58
19
56
100
100
1
2
3
H
30 min
1 h
2 h
2 h
2 h
93
86
89
88
83
92
94
97
c
-
0.005
0.005
4-OMe
4-OMe
4-OMe
2-OMe
2-Me
4-COMe
3-(COOMe)
4-CHO
4-NO2
2,4,6-(Me)3
2-Ph
1-naphthyl
9-anthracyl
2-thienyl
4-Br
Ph
TMS
Bu
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
10
10
c
-
4
5c
6
aReaction conditions: 4-bromoanisole (1.0 mmol), phenylacetylene
(1.1 mmol), 1 (0.01 mmol), zinc halide (0.1 mmol) and/or CuI (5 ꢀ
10-5 mmol), THF (10.0 mL), HN(i-Pr)2 (3.0 mL), rt. Details are in
the Supporting Information. bGC yields, average of two runs. cNot
added.
1 h
7
8
9
20 min
30 min
20 min
20 min
16 h
2 h
1 h
5 h
1 h
3 h
94
96
10
11
12
13
14
15
16d
17
18
76 (90)
93
94
results are summarized in Table 4. To our surprise, even
small amounts of CuI can enhance the rate of coupling
(Table 4, entry 2). However, couplings were faster in the
presence of 10 mol % ZnCl2 (Table 4, entry 4), which, after
accounting for trace Cu contaminants in ZnCl2, contains 1/
100th the amount of Cu compared to entries 3 and 4. There
does not appear to be a significant rate enhancement when
trace CuI is added in the presence of 10 mol % ZnCl2. Thus,
we conclude that trace copper does not appear to be the
active catalyst. Mechanistic studies to delineate the role of
the zinc halide are currently underway.
86
91
88
92
4-OTf
3-OTf
30 min
30 min
93
aReaction conditions: aryl bromide (3.0 mmol), alkyne (3.0 mmol), 1
(0.03 mmol), ZnCl2 (0.3 mmol), THF (7.0 mL), HN(i-Pr)2 (3 mL), rt.
bYields are an average of two runs. Yields in parentheses are GC yields.
cThe alkyne was added over 2 h and stirred at rt for an additional 2 h. d2.0
equiv (6.0 mmol) of phenylacetylene was used. The product is 1,4-bis(2-
phenylethynyl)benzene.
In conclusion, we have developed optimized conditions
for a general and convenient aryl bromide-alkyne cross-
coupling method in which rates of coupling are significantly
enhanced by addition of catalytic ZnCl2, without promoting
diyne byproduct formation. These conditions present a
superior alternative to other “copper-free Sonogashira”
cross-couplings, by enhancing the rate of coupling via addi-
tion of an inexpensive cocatalyst that is less susceptible to
alkyne homocoupling.
and 14, respectively) but still give acceptable yields. Aryl
chlorides are unreactive at room temperature. Both 3- and
4-bromophenyltriflate exclusively couple with the bromide
over the triflate under the standard reaction conditions,
rapidly and in good yield (Table 3, entries 17 and 18).18
No triflate coupling products are detectable by GC.
This orthogonal reactivity has the potential for the rapid,
iterative preparation of unsymmetrical, conjugated architec-
tures.
The exact role of the zinc halide salt is unknown at this
time. However, previous mechanistic studies under similar
conditions propose an in situ zinc acetylide formation via
“soft” deprotonation of a zinc halide-alkyne complex.19
Recently, it was reported that trace copper in commercially
available iron salts acts as the active catalyst in C-O and
C-N bond formation reactions previously thought to be
iron-catalyzed.20 To address the possibilty that trace copper
in our zinc salts is responsible for the rate enhancement in our
reactions, trace metal copper analysis was performed by
ICP-MS.21 The coupling of 4-bromoanisole with phenylace-
tylene in the presence of trace amounts of CuI (0.005 mol %,
50 ppm) was compared to the use of 10 mol % ZnCl2; the
Experimental Section
General Procedure for the Preparation of Substituted Alkynes
with Catalytic ZnCl2 (Table 3, entry 2): 4-Methoxydiphenylace-
tylene. In a glovebox, a 20 mL vial with stirbar and PTFE/
silicone septum-lined cap was charged with, in order, 4-bromo-
anisole (0.561 g, 3 mmol, 1 equiv), ZnCl2 (41 mg, 0.3 mmol,
0.1 equiv), THF (7 mL), HN(i-Pr)2 (3 mL), and Pd(I) dimer 1
(21 mg, 0.03 mmol, 0.01 equiv). The solution was stirred to
dissolve the solids, and then phenylacetylene (0.306 g, 3 mmol,
1 equiv) was added. The vial was capped, removed from the
glovebox, and stirred at room temperature for 1h. The solution
was diluted with EtOAc and passed through a plug of silica gel
(10 g) and eluted with 100 mL of EtOAc to remove salts. The
solution was evaporated, and the residue was purified by
column chromatography (SiO2, 6:1 hexane:EtOAc) to give
the product in 90% yield (0.562 g). Pale yellow solid, mp
(18) (a) For examples of reverse selectivity (triflates preferential to
halides), see: Kamikawa, T.; Hayashi, T. J. Org. Chem. 1998, 63, 8922–
8925. Espino, G.; Kurbangalieva, A.; Brown, J. M. Chem. Commun. 2007,
1742–1744. (b) Pd/P(t-Bu)3 is selective for aryl chlorides over aryl triflates in
Suzuki cross-couplings: Littke, A. F.; Dai, C. Y.; Fu, G. C. J. Am. Chem.
Soc. 2000, 122, 4020–4028.
58-59 °C (lit.22 mp 58-61 °C); H NMR (500 MHz; CDCl3)
δ 7.53-7.51 (m, 2H), 7.50-7.47 (m, 2H), 7.36-7.32 (m, 3H),
6.90-6.88 (m, 2H), 3.83 (s, 3H); 13C NMR (126 MHz; CDCl3)
δ 159.7, 133.2, 131.6, 128.4, 128.1, 123.7, 115.5, 114.1, 89.5,
88.2, 55.4.
1
(19) Fassler, R.; Tomooka, C. S.; Frantz, D. E.; Carreira, E. M. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 5843–5845.
(20) See ref 7b and the following: Buchwald, S. L.; Bolm, C. Angew.
Chem., Int. Ed. 2009, 48, 5586–5587.
(21) The amounts of Cu (in ppm) of the zinc salts we used were as follows:
ZnCl2 (0.97 ppm); ZnBr2 (1.10 ppm); ZnI2 (1.23 ppm); Zn(OTf)2 (0.62 ppm).
(22) Colacino, E.; Daich, L.; Martinez, J.; Lamaty, F. Synlett 2007, 1279–
1283.
J. Org. Chem. Vol. 74, No. 22, 2009 8899

Finke et al.
JOCNote
Acknowledgment. This work was supported by the
National Science Foundation under NSF Award Nos.
CBET-0730667 and CHE-0642413. The authors grate-
fully acknowledge Dr. Scott Wilson at the George L. Clark
X-ray Facility for crystallographic analysis, Dr. Rudiger
Laufhutte of the Microanalysis Laboratory, University
of Illinois, Urbana-Champaign, for ICP-MS analysis, and
Dr. Qilong Shen, University of Illinois Urbana-Champaign,
for helpful discussions.
Supporting Information Available: Synthetic procedures,
spectroscopic characterization of compounds, and preparation
and handling of 1. This material is available free of charge via the
Internet at http://pubs.acs.org.
8900 J. Org. Chem. Vol. 74, No. 22, 2009