Carbonylative Sonogashira coupling of terminal alkynes with aqueous ammonia

Article abstract of DOI:10.1021/ol035007a

(Matrix presented) Carbonylative coupling of phenylethyne with 4-methoxy-1-iodobenzene in the presence of 1 mol% PdCl₂(PPh ₃)₂, 2 equiv of 0.5 M aqueous ammonia, and CO (1 atm) gives the corresponding α,β-alkynyl ketone in

Full text of DOI:10.1021/ol035007a

ORGANIC
LETTERS
2
003
Vol. 5, No. 17
057-3060
Carbonylative Sonogashira Coupling of
Terminal Alkynes with Aqueous
Ammonia
3
Mohamed S. Mohamed Ahmed and Atsunori Mori*
Chemical Resources Laboratory, Tokyo Institute of Technology, 4259 Nagatsuta,
Yokohama 226-8503, Japan
amori@res.titech.ac.jp
Received June 5, 2003
ABSTRACT
2 3 2
Carbonylative coupling of phenylethyne with 4-methoxy-1-iodobenzene in the presence of 1 mol % PdCl (PPh ) , 2 equiv of 0.5 M aqueous
ammonia, and CO (1 atm) gives the corresponding r,â-alkynyl ketone in 72% isolated yield after stirring at room temperature for 41 h, while
noncarbonylative coupling product is not obtained.
Synthesis of R,â-alkynyl ketones attracts considerable interest
directed for the reaction of terminal alkynes despite advan-
tages in atom economy. Indeed, higher reaction temperature
and pressure of carbon monoxide have been necessary in
order to achieve the selective carbonylative coupling of
because of their appearance in a wide variety of biologically
1
active molecules and their key synthetic intermediates. A
common route to prepare the compounds involves the
2
12
reaction of alkynyl organometallic reagents such as silver,
terminal alkynes. Only a few examples involving the
1,3
4
5
6
7
8
11
copper, sodium, lithium, cadmium, zinc, silicon, and
tin with acid chlorides. An alternative synthetic method for
reaction with fluoride ion in excess Et
3
N
or use of highly
9
13
reactive iodinium salt as a substrate are shown to proceed
under mild conditions.
R,â-alkynyl ketones is the transition metal-catalyzed coupling
of terminal alkynes or the metalated derivatives with organic
halides in the presence of carbon monoxide. Although the
On the other hand, the Sonogashira-(Hagihara) reaction
is recognized as a noncarbonylative coupling of terminal
alkynes with organic halides and takes place in the presence
10
11
reaction of alkynylstannanes or alkynylsilanes is shown
to proceed with carbon monoxide, little effort has been
1
4
of Pd(0)/Cu(I) catalyst. The coupling reaction is a highly
effective method for introducing an alkynyl moiety into an
(
1) Chowdhury, C.; Kundu, N. G. Tetrahedron 1999, 55, 7011 and
references therein.
(10) (a) Goure, W. F.; Wright, M. E.; Davis, P. D.; Labadie, S. S.; Stille,
J. K. J. Am. Chem. Soc. 1984, 106, 6417. (b) Grisp, G. T.; Scott, W. J.;
Stille, J. K. J. Am. Chem. Soc. 1984, 106, 7500.
(
(
2) Davis, R. B.; Scheiber, D. H. J. Am. Chem. Soc. 1956, 78, 1675.
3) (a) Normant, J. F. Synthesis 1972, 63. (b) Logue, M. W.; Moore, G.
L. J. Org. Chem. 1975, 40, 131. (c) Bourgain, M.; Normant, J. F. Bull.
Soc. Chim. Fr. 1973, 2137.
(11) Arcadi, A.; Cacchi, S.; Marinelli, F.; Pace, P.; Sanzi, G. Synlett.
1995, 823.
(
4) Fontaine, M.; Chauvelier, J.; Barchewitz, P. Bull. Soc. Chim. Fr. 1962,
145.
5) (a) Schmidt, U.; Schwochau, M. Chem. Ber. 1964, 97, 1649. (b)
Compagnon, P. L.; Grosjean, B.; Lacour, M. Bull. Soc. Chim. Fr. 1975,
(12) (a) Kobayashi, T.; Tanaka, M. J. Chem. Soc., Chem. Commun. 1981,
333. (b) Tanaka, M.; Kobayashi, T.; Sakakura, T. Nippon Kagaku Kaishi
1985, 537; Chem. Abstr. 1986, 104, 129561d. (c) Delaude, L.; Masdeu, A.
M.; Alper, H. Synthesis 1994, 1149. (d) Fukuyama, T.; Yamaura, R.; Ryu,
I. Abstract 83rd Annual Meeting of Chemical Society of Japan, Tokyo,
2003; 3G544.
(13) Luo, S. J.; Liang, Y. M.; Liu, C. M.; Ma, Y. X. Synth. Commun.
2001, 31, 343.
(14) (a) Sonogashira, K. In Metal-Catalyzed Cross-Coupling Reaction;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998; Chapter
5, pp 203-229. (b) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467. (c) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
2
(
7
1
1
3
79.
(6) Yashina, O. G.; Zarva, T. V.; Vereshchagin, L. I. Zh. Org. Khim.
967, 3, 219; Chem. Abstr. 1967, 66, 94664g.
(
7) Vereshchagin, L. I.; Yashina, O. G.; Zarva, T. V. Zh. Org. Khim.
966, 2, 1895; Chem. Abstr. 1967, 66, 46070p.
8) (a) Birkofer, L.; Ritter, A.; Uhlenbrauck, H. Chem. Ber. 1963, 96,
280. (b) Walton, D. R. M.; Waugh, F. J. Organomet. Chem. 1972, 37, 45.
9) Logue, M. W.; Teng, K. J. Org. Chem. 1982, 47, 2549.
(
(
1
0.1021/ol035007a CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/01/2003

organic molecule; however, use of a large excess of amine
as a solvent or a cosolvent has been key to the success of
Table 1. Carbonylative Coupling of 1 with Aryl Iodidesa
1
5
the reaction. Hence, we have been studying effective
16
% yield
activators for the Sonogashira reaction instead of an excess
use of amine of a high boiling point and found that use of
dilute aqueous ammonia for the Sonogashira coupling was
highly effective.17
I-aryl
time, h
3
4
I-C6H4-4-OMe
I-C6H4-2-OMe
I-C6H4-3-OMe
I-C6H4-4-Me
I-C6H5
(2a )
(2b)
(2c)
(2d )
(2e)
(2f)
41
24
51
47
25
34
25 (61)
12 (18)
72
76
81
64
76
50
0
4
0
0
0
1
Our interest has thus been turned to the reaction with
aqueous ammonia for the carbonylative coupling of terminal
alkynes. Herein, we report that palladium- or palladium/
copper-catalyzed carbonylative coupling of terminal alkynes
in aqueous ammonia proceeds at room temperature and
under an ambient pressure of carbon monoxide to afford
R,â-alkynyl ketones efficiently.
1
-iodonaphthalene
I-C6H4-4-COMeb
(2g)
(2i)
75 (53)
67 (62)
7 (23)
0 (29)
I-C6H4-4-Clb
a
Reaction conditions: 1 (0.6 mmol), 2 (0.5 mmol), CO (1 atm),
PdCl2(PPh3)2 (1 mol %), aqueous ammonia (2 mL of 0.5 M solution), and
THF (3 mL) at room temperature. b PdCl2(dppf) (5 mol %) was employed
as a catalyst. The results using PdCl2(PPh3)2 (1 mol %) are shown in
parentheses.
The carbonylative reaction was first examined with Et
as a solvent. However, treatment of phenylethyne (1) with
-methoxy-1-iodobenzene (2a) in the presence of 1 mol %
PdCl (PPh at room temperature under an ambient pressure
3
N
4
2
3 2
)
zene (2d), iodobenzene (2e), and 1-iodonaphthalene (2f)
resulted in giving the coupling products in good yields.
Although the reaction with 4-iodoacetophenone (2g) or
of carbon monoxide resulted in giving the carbonylative
coupling product 3a in only 11% yield accompanied by 1%
12
diarylethyne 4a. By contrast, when the reaction system was
changed to that using 2 equiv of aqueous ammonia (0.5 M)
in THF, remarkable rate enhancement and selective carbo-
nylative coupling took place to afford 72% yield of 3a as
shown in Scheme 1. However, addition of a catalytic amount
4
-iodo-1-chlorobenzene (2i), which possessed an electron-
withdrawing substituent, afforded the mixture of carbony-
lative and noncarbonylative coupling products 3 and 4, the
2
selectivity to give 3 was remarkably improved when PdCl -
1
2a,b
(dppf) (5 mol %)
was employed as a catalyst.
We next examined the carbonylative reaction of terminal
alkynes bearing an alkyl substituent. The reaction was found
to be slower than that of arylalkynes, whose relative reactivity
was similar to the noncarbonylative coupling reactions.
Considerably slower reaction of 1-octyne (5a) took place
with 4-methoxy-1-iodobenzene (2a) to afford 6a in 15% yield
after stirring for 86 h under the conditions of Table 1. By
contrast, addition of CuI to the reaction mixture was found
to enhance the rate to yield the carbonylative coup-
Scheme 1. Coupling of Phenylethyne (1) with Aqueous
Ammonia in the Presence of Carbon Monoxide
ling product 6a in 65% yield. Use of 5 mol % PdCl
2 3 2
(PPh )
with 2 mol % CuI further improved the yield of 6a to 81%
(Table 2).
The reaction of 1-octyne with 4-methyl-1-iodobenzene
2d) and 2-amino-1-iodobenzene (2h) also proceeded with
(
5
mol % palladium catalyst and 2 mol % CuI in THF in the
presence of 0.5 M aqueous ammonia (2 equiv) to yield 78
and 71% of the carbonylative coupling products, respectively.
The reaction of 1-iodonaphthalene also afforded the corre-
sponding alkynyl ketone 6f. The selectivity of carbonylative/
noncarbonylative coupling of 5a with aryl iodides bearing
an electron-withdrawing group such as 2g and 2i was found
to be better than that of phenylethyne (1). Other alkynes such
as 3,3-dimethylbutyne (5b), 2-methyl-3-butyn-2-ol (5c), and
of CuI to the reaction system was found to be less effective
in affording noncarbonylative coupling product 4a as a major
1
8
product.
Table 1 summarizes the results for the carbonylative
coupling of phenylethyne with various aryl iodides at room
temperature under an ambient pressure of carbon monoxide.
The reaction of 2-methoxy-1-iodobenzene (2b) and 3-meth-
oxy-1-iodobenzene (2c) also proceeded with 1 mol %
palladium catalyst in THF in the presence of 0.5 M aqueous
ammonia (2 equiv) to yield 76 and 81% of the carbonylative
coupling products, respectively. Use of 4-methyl-1-iodoben-
3
-butyn-1-ol (5d) also coupled with 2 to afford the corre-
sponding ynones in good to excellent yields, respectively.
(16) (a) Mori, A.; Kawashima, J.; Shimada, T.; Suguro, M.; Hirabayashi,
K.; Nishihara, Y. Org. Lett. 2000, 2, 2935. (b) Mori, A.; Shimada, T.; Kondo,
T.; Sekiguchi, A. Synlett 2001, 649. (c) Mori, A.; Kondo, T.; Kato, T.;
Nishihara, Y. Chem. Lett. 2001, 286.
(15) Recent studies on the improvement of Sonogashira coupling: (a)
Herrmann. W. A.; Reisinger, C.-P.; Spiegler, M. J. Organomet. Chem. 1998,
(17) Mori, A.; Mohamed Ahmed, M. S.; Sekiguchi, A.; Masui. K.; Koike,
T. Chem. Lett. 2002, 756.
5
57, 93. (b) B o¨ hm, V. P. W.; Herrmann, W. A. Eur. J. Org. Chem. 2000,
3
679. (c) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org.
(18) Addition of 2 mol % CuI to the reaction system of standard
Sonogashira conditions with CO also resulted in noncarbonylative coupling
to yield 70% of 4a and only 7% of 3a after stirring at room temperature
for 4 h.
Lett. 2000, 2, 1729. (d) K o¨ llhofer, A.; Pullmann, T.; Plenio, H. Angew.
Chem., Int. Ed. 2003, 42, 1056. (e) Tykwinski, R. R. Angew. Chem., Int.
Ed. 2003, 42, 1566.
3058
Org. Lett., Vol. 5, No. 17, 2003

Table 2. Carbonylative Coupling of Alkynes Bearing an Alkyl Substituent
product, % yielda
R-
I-aryl
PdCl2(PPh3)2, mol%
CuI, mol %
time, h
6
7
nC6H13- (5a )
I-C6H4-4-OMe (2a )
1
1
5
5
5
5
5
5
5
5
5
5
5
5
0
2
2
2
2
2
2
2
4
2
2
2
2
2
86
48
24
24
40
25
30
26
27
20
24
19
46
48
15b
65b
0
0
74 (81)b
0
0
0
0
5
4
I-C6H4-4-Me (2d )
I-C6H4-2-NH2 (2h )
78
71
60
47
70
1
-iodonaphthalene (2f)
I-C6H4-4-COMe (2g)
I-C6H4-4-Cl (2i)
I-C6H4-4-I (2j)
2a
c
c
0 (10d)
53 (8 ), 37 (9 )
87
77
69
55c
tBu-(5b)
0
0
0
0
0
2
2
e
f
HOC(CH3)2-(5c)
HO(CH2)2-(5d )
2a
2a
56
a
Isolated yield, unless noted. b IH NMR yield.
c
8:
9:
d
10:
The reaction of 1-octyne with 1,4-diiodobenzene (2j) using
PdCl (PPh (5 mol %) and CuI (4 mol %) in the presence
2
3 2
)
Scheme 2. Possible Explanation for Carbonylative/
of 0.5 M aqueous ammonia under an ambient pressure of
carbon monoxide afforded dicarbonylated product 8 and
monocarbonylated product 9 in 53 and 37% yields, respec-
tively, after stirring at room temperature for 27 h. Since the
product of the first coupling reaction is the electron-deficient
aryl iodide, the second coupling would be less selective in
accompanying noncarbonylative reaction, affording 9 with
the carbonylation leading to 8.
Noncarbonylative Coupling Reactions
In general, a palladium-catalyzed reaction in the presence
of carbon monoxide proceeds slower than that under an inert
atmosphere since CO serves as a strong ligand with electron-
12,19
withdrawing characteristics.
Nevertheless, it should be
pointed out that the carbonylative reaction took place under
ambient pressure and temperature. As shown in Scheme 2,
the key for the understanding of selective carbonylative
coupling would be the competition between transmetalation
and CO insertion toward intermediate aryl palladium iodide
species I, which is the resultant of the oxidative addition of
an aryl iodide to Pd(0). Since the Sonogashira reaction (with
Pd/Cu system) of a terminal alkyne bearing an aryl substitu-
ent is fast, transmetalation leading to II would be a preferable
pathway to the insertion of CO. As a result, the noncarbo-
nylative coupling would overcome the carbonylation when
an aryl alkyne is employed as a substrate. By contrast, since
the transmetalation of a terminal alkyne bearing alkyl
substituent would be slower, insertion of CO leading to III
is a major pathway even in the presence of CuI. Subsequent
transmetalation from copper to palladium and reductive
elimination afford the carbonylative coupling product. On
(19) Tsuji, J. In Palladium Reagents and Catalysts. InnoVation in Organic
Synthesis; Wiley: Chichester, 1995.
Org. Lett., Vol. 5, No. 17, 2003
3059

the other hand, in the reactions without CuI to result in the
selective carbonylative coupling, the formation of II would
be much slower than that of acylpalladium III. As a result,
the selective carbonylative reaction is the major pathway
Acknowledgment. M.S.M.A. thanks Ministry of Educa-
tion, Culture, Sports, Science, and Technology, Japan, for
the financial support of graduate study program.
A
throughout IV . Alternatively, insertion of an arylalkyne to
Supporting Information Available: Experimental details
for the coupling reactions. This material is available free of
charge via the Internet at http://pubs.acs.org.
the acylpalladium species giving IV followed by â-hydrogen
B
elimination might be a plausible pathway.14
In conclusion, carbonylative coupling reaction of terminal
alkynes with aryl halides catalyzed by palladium or a
palladium/copper system took place at room temperature and
under an ambient pressure of carbon monoxide. The reaction
was found to proceed efficiently when dilute aqueous
ammonia was used as an additive. The effect of aqueous
ammonia is far superior to the use of an excess of tertiary
amine as a solvent, under which conditions higher reaction
temperature and CO pressure have to be applied to achieve
the selective carbonylative reaction. As a result, the protocol
using aqueous ammonia serves as a highly effective synthetic
OL035007A
(20) Typical preparation is as follows. To a clear pale yellow solution
of phenylethyne (66 µL, 0.6 mmol), 4-methoxy-1-iodobenzene (117 mg,
0
.5 mmol), and PdCl2(PPh3)2 (3.5 mg, 0.005 mmol) in THF (3 mL) was
added aqueous ammonia (0.5 M, 2 mL, 1.0 mmol) dropwise. The
atmosphere was replaced with carbon monoxide, and stirring was continued
at room temperature for 41 h. The resulting mixture was passed through a
Celite pad, and the filtrate was washed with brine. The aqueous layer was
extracted with diethyl ether (3 × 15 mL), and the combined organic layers
were dried over MgSO4 and concentrated in vacuo. The residue was purified
by flash chromatography eluting with hexanes/ethyl acetate (10/1) to give
85 mg of 1-(4-methoxyphenyl)-3-phenyl-2-propynone (72%).
2
0
method for a variety of R,â-alkynyl ketone derivatives.
3060
Org. Lett., Vol. 5, No. 17, 2003