Propylene oxide assisted sonogashira coupling reaction

Article abstract of DOI:10.1055/s-0028-1087368

A propylene oxide assisted base-free Sonogashira cross-coupling reaction has been developed. The unique feature of the current protocol has extended the scope of Sonogashira reaction to some base-sensitive substrates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087368

LETTER
3239
Propylene Oxide Assisted Sonogashira Coupling Reaction
P
ropylene Oxid
h
e
A
ssisted S
a
o
Coupling Re
l
action ong Tong,a Peng Gao,a,b Haibing Deng,a Lei Zhang,a Peng-Fei Xu,b Hongbin Zhai*a,b
a
Laboratory of Modern Synthetic Organic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. of China
State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou,
Gansu 730000, P. R. of China
b
Fax +86(21)64166128; E-mail: zhaih@mail.sioc.ac.cn
Received 5 June 2008
The feasibility of base-free Sonogashira coupling was
first tested on iodobenzene and phenylacetylene, with the
Batey Pd-carbene complex 1 (2.5 mol%), PPh3 (2.5
mol%) and CuI (5 mol%) as the catalysts. Reaction of the
above components in DMF in the presence of Et3N5a (3.6
equiv) at 25 °C for 48 hours afforded diphenylacetylene
(2a) in excellent yield (Table 1, entry 1), which proved the
activity of the catalysts. Replacement of Et3N with PO (0,
3, 5,5b and 10 equiv) gave 2a in 2.8%, 74%, 84%, and 81%
yields, respectively (entries 2–5), suggesting that five
equivalents of PO should be sufficient. In addition, lower
yield was obtained in THF or MeCN as the solvent, pre-
sumably due to relatively poorer solubility of the Pd cata-
lyst 1 (entries 6 and 7).
Abstract: A propylene oxide assisted base-free Sonogashira cross-
coupling reaction has been developed. The unique feature of the
current protocol has extended the scope of Sonogashira reaction to
some base-sensitive substrates.
Key words: base-free, propylene oxide, Sonogashira reaction
Sonogashira coupling reaction, first emerged in 1975,1 in-
volved cross-coupling of a terminal alkyne with an aryl or
alkenyl halide.2,3 The reaction has been most frequently
conducted in the presence of a catalytic amount of palla-
dium complex and copper(I) iodide. Natural products
chemistry and material science have witnessed the exten-
sive applications of this useful type of transformation to
constructing various interesting substituted and conjugat-
ed alkynes.2
Table 1 Sonogashira Coupling of Iodobenzene with Phenylacety-
lene under Different Conditions
The original Sonogashira reaction and most of the modi-
fied versions1–3 require the use of an organic or inorganic
base, which unavoidably causes problems in the case of
base-sensitive substrates. Since propylene oxide (PO) is a
well-known acid scavenger widely used in amino acid and
peptide chemistry, we envisioned that the commercially
available and inexpensive PO4 might be able to assist a
base-free Sonogashira reaction.
1 (2.5 mol%)
CuI (5 mol%)
Ph
Ph
Ph
PhI
+
Ph3P (2.5 mol%)
scavenger, solvent
25 °C, 48 h
2a
(2.0 mmol)
(2.2 mmol)
Entry
Solvent
Scavenger
Yield (%)a
1
2
3
4
5
6
7
DMF
DMF
DMF
DMF
DMF
THF
Et3N (3.6 equiv)
PO (0 equiv)
PO (3 equiv)
PO (5 equiv)
PO (10 equiv)
PO (5 equiv)
PO (5 equiv)
93
2.8
74
84
81
63
64
N-Carbamoyl-substituted heterocyclic carbene complex
of palladium(II) (1; Figure 1), developed by Batey and co-
workers in 2002, is of good thermal and hydrolytic stabil-
ity and can efficiently catalyze Sonogashira cross-cou-
pling of various aryl halides with terminal alkynes.3b
N
N
N
MeCN
O
a Isolated yield.
I
Pd
N
I
After the initial success of base-free coupling of iodoben-
zene and phenylacetylene, additional substrates were in-
spected under the above reaction conditions [1 (2.5
mol%), CuI (5 mol%), PPh3 (2.5 mol%), PO (5 equiv),
DMF, 25 °C]. As shown in Table 2, iodobenzene reacted
in high yields with various terminal alkynes such as 1-
hexyne, propargyl alcohol, and 2-methyl-3-butyn-2-ol in
80–90% yields (entries 2–4). The coupling products of
substituted iodobenzenes (p-Me, p-MeO, and m-NO2)
N
Batey Pd-carbene complex (1)
Figure 1
SYNLETT 2008, No. 20, pp 3239–3241
Advanced online publication: 26.11.2008
1
6
.1
2
.2
0
0
8
DOI: 10.1055/s-0028-1087368; Art ID: W08708ST
© Georg Thieme Verlag Stuttgart · New York

3240
Z. Tong et al.
LETTER
Table 2 PO-Assisted Sonogashira Coupling of Aryl Iodides with
Table 3 PO-Assisted Sonogashira Coupling of Aryl Bromides with
Terminal Alkynesa
Terminal Alkynesa
1, CuI
1, CuI
Ph3P, PO
Ph3P, PO
R
ArI
ArBr
+
Ar
R
R
+
Ar
R
DMF, 25 °C, 48 h
DMF, 80 °C, 48 h
Entry Ar
R
Product
Yield (%)b
Entry
Ar
Ph
Ph
Ph
Ph
R
Product
2a3c
2b3b
2c3b
2d3c
2h7
Yield (%)b
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
2a3c
2b3b
2c3b
2d3c
2e6
84
80
90
86
78
83c
97
1
2
Ph
81
84
82
85
91
94
94
78
84
81
n-Bu
CH2OH
C(Me)2OH
Ph
n-Bu
3
CH2OH
4
C(Me)2OH
p-MeC6H4
5
p-OHCC6H4
p-AcC6H4
Ph
Ph
Ph
Ph
Ph
Ph
p-MeOC6H4
m-O2NC6H4
Ph
2f3c
2g7
6
2i3b
Ph
7
p-O2NC6H4
p-PhC6H4
2j3b
2k7
a The reaction of aryl iodide (2 mmol) and alkyne (110 mol%) was
carried out in degassed DMF with 1 (2.5 mol%), CuI (5 mol%), PPh3
(2.5 mol%), and PO (5 equiv) at 25 °C for 48 h.
b Isolated yield.
8
9
p-MeC6H4
3-quinolinyl
2e6
10
2l8
c The reaction was carried out at 50 °C.
a The reaction of aryl bromide (2 mmol) and alkyne (110 mol%) was
carried out in degassed DMF with 1 (2.5 mol%), CuI (5 mol%), PPh3
(2.5 mol%), and PO (5 equiv) at 80 °C for 48 h.
b Isolated yield.
with phenylacetylene were formed in 78–97% yields (en-
tries 5–7).
Next, PO-assisted Sonogashira coupling of aryl bromides
with 1-alkynes was investigated (Table 3). The cross-cou-
pling of bromobenzene with phenylacetylene was rather
sluggish at 25 or 50 °C. However, the reaction was re-
markably accelerated at 80 °C and diphenylacetylene was
furnished in 81% yield (entry 1). This protocol was then
applied to a series of other aryl bromides and terminal
alkynes. For instance, bromobenzene coupled efficiently
with 1-hexyne, propargyl alcohol, and 2-methyl-3-butyn-
2-ol in good yields (82–85%) at 80 °C in the presence of
PO (entries 2–4). Moreover, the cross-coupling reaction
of phenylacetylene with several aryl bromides other than
bromobenzene was scrutinized. For the bromobenzenes
with an electron-withdrawing group (such as formyl,
acetyl, and nitro) at the para position, the transformation
proceeded cleanly and gave rise to the internal alkynes in
91–94% yields (entries 5–7). Reaction of phenylacetylene
with bromobenzenes bearing a para substituent of phenyl
or methyl generated the corresponding products in 78%
and 84% yields, respectively (entries 8 and 9). Finally,
3-quinolinyl bromide, a weak base itself, reacted very lit-
tle with phenylacetylene without the aid of PO (or other
bases). In the presence of five equivalents of PO, the reac-
tion proceeded smoothly (entry 10).
X
OH
PO
Cu
Ar
Ar-X
LnPd(II)
HX
X
oxid.
addn.
R
1
LnPd(0)
transmet.
Ar
LnPd(II)
H
R
red.
elimn.
CuX
Ar
R
R
Scheme 1 Mechanism of the coupling reaction
To demonstrate the advantage of the current protocol,
Sonogashira reaction of a terminal alkyne having a decon-
jugated enone unit (3) with iodobenzene was explored in
the presence of PO and Et3N as scavengers, respectively
(Table 4). After the reaction proceeded for 48 hours with
PO as the scavenger, both 4 and 5 were formed (80% com-
bined yield, 4/5 = 69:31), where 4 was the regular cou-
pling product and 5 resulted from both Sonogashira
coupling and carbon–carbon double bond shift (entry 2).
At shortened reaction time (24 h), the ratio of 4/5 was im-
proved to 94:6 while the combined yield dropped to 57%
(entry 1). In contrast, when reaction was run in Et3N–
DMF (1:1), conjugated enone 5 was obtained as the sole
product (entry 3). Even though in this case the double
bond shift could not be avoided completely with PO used
A plausible mechanism for the base-free Sonogashira
coupling reaction has been proposed, which follows the
expected oxidative addition, transmetallation, and reduc-
tive elimination pathway (Scheme 1). Here, the striking
feature lies in the fact that the Bronsted acid (HX), pro-
duced in the reaction, was scavenged by PO instead of
Et3N or other bases. The release of a halohydrin provides
a driving force for the catalytic cycle.
Synlett 2008, No. 20, 3239–3241 © Thieme Stuttgart · New York

LETTER
Propylene Oxide Assisted Sonogashira Coupling Reaction
3241
Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley: New
York, 1998, Chap. 5. (f) Brandsma, L.; Vasilevsky, S. F.;
Verkruijsse, H. D. Application of Transition Metal Catalysts
in Organic Synthesis; Springer-Verlag: Berlin, 1998, Chap.
10. (g) Nicolaou, K. C.; Sorensen, E. J. Classics in Total
Synthesis; Wiley-VCH: Weinheim Germany, 1996, 582.
(h) Tsuji, J. Palladium Reagents and Catalysts; Wiley:
Chichester, 1995, 168. (i) Rossi, R.; Carpita, A.; Bellina, F.
Org. Prep. Proced. Int. 1995, 27, 127. (j) Sonogashira, K.
In Comprehensive Organic Synthesis, Vol. 3; Trost, B. M.,
Ed.; Pergamon: New York, 1991, Chap. 2.4.
Table 4 PO-Assisted Sonogashira Coupling of Alkyne 3 with Iodo-
benzene
O
PhI (110 mol%), 1 (2.5 mol%)
CuI (5 mol%), Ph3P (2.5 mol%)
Ph
scavenger, DMF, r.t., 48 h
3
O
O
Ph
Ph
+
(3) For recent representative advances in Sonogashira or
Sonogashira-type cross-coupling, see: (a) Novak, Z.; Szabo,
A.; Repasi, J.; Kotschy, A. J. Org. Chem. 2003, 68, 3327.
(b) Batey, R. A.; Shen, M.; Lough, A. J. Org. Lett. 2002, 4,
1411. (c) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.;
Fu, G. C. Org. Lett. 2000, 2, 1729. (d) Alami, M.; Crousse,
B.; Ferri, F. J. Organomet. Chem. 2001, 624, 114.
(e) Soheili, A.; Albaneze-Walker, J.; Murry, J. A.; Dormer,
P. G.; Hughes, D. L. Org. Lett. 2003, 5, 4191. (f) Mori, A.;
Kawashima, J.; Shimada, T.; Suguro, M.; Hirabayashi, K.;
Nishihara, Y. Org. Lett. 2000, 2, 2935. (g) Anastasia, L.;
Negishi, E. Org. Lett. 2001, 3, 3111. (h) Cheng, J.; Sun, Y.;
Wang, F.; Guo, M.; Xu, J.-H.; Pan, Y.; Zhang, Z. J. Org.
Chem. 2004, 69, 5428. (i) Arques, A.; Aunon, D.; Molina, P.
Tetrahedron Lett. 2004, 45, 4337. (j) Ma, D.; Liu, F. Chem.
Commun. 2004, 1934. (k) Elangovan, A.; Wang, Y.-H.; Ho,
T.-I. Org. Lett. 2003, 5, 1841. (l) Thorand, S.; Krause, N.
J. Org. Chem. 1998, 63, 8551.
(4) To the best of our knowledge, PO has not been used in C–C
bond formation. For the sole relevant precedent (in C–S
bond formation), see: Moreau, X.; Campagne, J.-M.
J. Organomet. Chem. 2003, 687, 322.
(5) (a) For an example of Sonogashira reaction with Et3N as
both the solvent and the base in preparing diphenylacetylene,
see: Perner, R. J.; Gu, Y.-G.; Lee, C.-H.; Bayburt, E. K.;
McKie, J.; Alexander, K. M.; Kohlhaas, K. L.; Wismer,
C. T.; Mikusa, J.; Jarvis, M. F.; Kowaluk, E. A.; Bhagwat,
S. S. J. Med. Chem. 2003, 46, 5249. (b) General
Ph
Ph
4
5
Entry Scavenger
Time (h) 4/5
Yield [4 + 5 (%)]a
1
2
3
PO (5 equiv)
24
48
24
94:6
57
80
88
PO (5 equiv)
Et3N (excess)
69:31
0:100
a Isolated yield.
as the scavenger, our protocol should in general be a better
choice for base-sensitive substrates.
In conclusion, a PO-assisted Sonogashira cross-coupling
reaction has been developed. The unique base-free feature
of the current protocol has extended the scope of Sono-
gashira reaction to some base-sensitive substrates. Other
related transition-metal-catalyzed cross-coupling reac-
tions might also benefit from the current PO strategy. The
research results along these lines will be reported in due
course.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Procedure: The Batey Pd-carbene complex 1 (2.5 mol%),
CuI (5 mol%), Ph3P (2.5 mol%) and DMF (2 mL) were
added to a dry 10-mL septum-capped round-bottomed flask
under a nitrogen atmosphere. Aryl iodide (2 mmol), alkyne
(110 mol%), and PO (5 equiv) were then added to the above
mixture. While the mixture was stirred, the flask was cooled
to –78 °C, vacuumed, and charged with nitrogen. This
process was repeated for three times. After the mixture was
warmed to 25 °C, stirring was continued at that temperature
for 48 h. The mixture was diluted with H2O and extracted
with E2O. The organic extracts were combined, washed with
brine, dried (MgSO4), filtered, and concentrated to give a
residue, which was purified by flash column
Acknowledgment
Financial support was provided by the grants from NSFC
(90713007, 20772141, 20625204, 20632030), and MOST_863
(2006AA09Z405, 2006AA09Z446).
References and Notes
(1) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 50, 4467. (b) Cassar, L. J. Organomet. Chem.
1975, 93, 253. (c) Dieck, H. A.; Heck, F. R. J. Organomet.
Chem. 1975, 93, 259.
(2) For reviews, see: (a) Doucet, H.; Hierso, J.-C. Angew.
Chem. Int. Ed. 2007, 46, 834. (b) Chinchilla, R.; Najera, C.
Chem. Rev. 2007, 107, 874. (c) Wang, Y.-F.; Deng, W.; Liu,
L.; Guo, Q.-X. Chin. J. Org. Chem. 2005, 25, 8.
chromatography on silica gel.
(6) Ma, Y.; Song, C.; Jiang, W.; Wu, Q.; Wang, Y.; Liu, X.;
Andrus, M. B. Org. Lett. 2003, 5, 3317.
(7) Chow, H.-F.; Wan, C.-W.; Low, K.-H.; Yeung, Y.-Y. J. Org.
Chem. 2001, 66, 1910.
(8) Tang, B.-X.; Wang, F.; Li, J.-H.; Xie, Y.-X.; Zhang, M.-B.
J. Org. Chem. 2007, 72, 6294.
(d) Negishi, E.; Anastasia, L. Chem. Rev. 2003, 103, 1979.
(e) Sonogashira, K. In Metal-Catalyzed Cross-Coupling
Synlett 2008, No. 20, 3239–3241 © Thieme Stuttgart · New York

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