Palladium-catalyzed coupling between aryl halides and trimethylsilylacetylene assisted by dimethylaminotrimethyltin

Article abstract of DOI:10.1002/cjoc.201190180

Palladium-catalyzed coupling between aryl halides, especially less reactive ones or N-heteroaryls, and trimethylsilylacetylene in the presence of dimethylaminotrimethyltin generated the coupled products in high yields. The reaction does not need CuI and base as auxiliary agents.

Full text of DOI:10.1002/cjoc.201190180

NOTE
Palladium-catalyzed Coupling between Aryl Halides and
Trimethylsilylacetylene Assisted by Dimethylaminotrimethyltin
Cai, Liangzhena(蔡良珍)
Yang, Dujuana(杨杜娟)
Sun, Zhonghuaa(孙忠华)
Tao, Xiaochun*,a(陶晓春)
Cai, Lishengb(蔡利生)
Pike, Victor W.b
a School of Chemical and Molecular Engineering, East China University of Science and Technology,
Shanghai 200237, China
b Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health,
Bethesda, MD 20892, U. S. A.
Palladium-catalyzed coupling between aryl halides, especially less reactive ones or N-heteroaryls, and
trimethylsilylacetylene in the presence of dimethylaminotrimethyltin generated the coupled products in high yields.
The reaction does not need CuI and base as auxiliary agents.
Keywords palladium catalysis, trimethylsilylacetylene, aryl halide, dimethylaminotrimethyltin, Sonogashira
coupling
Introduction
Results and discussion
Aryl acetylenes are important organic intermediates,1
which are widely used in biology, medicine, and materi-
als chemistry.2 In 1975, Sonogashira et al.3 reported the
coupling of aryl halides and terminal alkynes to generate
aryl alkynes in the presence of CuI, organic base and pal-
ladium catalyst. Because of the mild reaction conditions
and high chemical yields, the reaction becomes an im-
portant synthetic method for aryl alkynes.4 In recent years,
various improved catalyst systems were used to enhance
the efficiency and to expand the scope of Sonogashira
reaction.5
So far, the most useful aryl halides in Sonogashira re-
action are aryl iodides and aryl bromides.6 The most inert
aryl halides are aryl chlorides, electron-rich aryl bromides,
and those containing nitrogen heteroatoms. The yields of
aryl acetylenes produced from those aryl halides are sig-
nificantly reduced or not produced at all,7 and the reac-
tions are less studied.8 On the other hand, trimethylsily-
lacetylene is a commonly used reagent in Sonogashira
reaction. Its advantage is that after the coupling is com-
pleted, the trimethylsilyl group can be removed easily to
get terminal aryl acetylenes.9 However, compared with
alkyl or aryl acetylenes, trimethylsilylacetylene is less
reactive in this reaction, giving low yields.10
When we synthesized N-acetyl-5-ethynyl indoline
from N-acetyl-5-bromoindoline (Scheme 1), the classi-
cal Sonogashira reaction conditions were chosen for this
reaction.12 No products were observed when N-acetyl-
5-bromoindoline (2 mmol), trimethylsilylacetylene (2.4
mmol), Pd2(dba)3 (2 mol%), PPh3 (4 mol%), CuI (4
mol%), and Et3N (6 mL), were reacted at reflux for 8 h
(Table1, Entry 1). Other organic bases, such as
piperidine 13 also did not work.
Dimethylaminotrimethyltin (Me3SnNMe2) had been
used to activate substrate with acidic hydrogens, to form
tin reagent.14 Stille et al,15 used it to make alkynyltin
reagents, to couple with alkenylhalides. We reasoned
that dimethylaminotrimethyltin would react with termi-
nal alkynes to generate in situ alkynyltin reagents,
which would react with aryl halides, such as N-acetyl-5-
bromoindoline mentioned above, just as what happened
in Stille reaction. After dimethylaminotrimethyltin and
trimethylsilylacetylene were allowed to react for 20 min
in THF, N-acetyl-5-bromoindoline, Pd2(dba)3 and PPh3
were added, refluxed for 8 h, and then tetrabutyl ammo-
nium fluoride was added to remove trimethylsilyl,
N-acetyl-5-ethynyl-indoline was obtained in 30% (Table
1, Entry 2). Among the solvents and temperature exam-
ined (Table 1), the reaction in refluxing toluene gave the
best yield of 78% (Table 1, Entry 5). Therefore, we fur-
ther evaluated the reaction scope and limitation based on
these new reaction conditions.
Here, we report a new and effective Pd catalyzed
coupling between aryl halides and trimethylsilylacety-
lene in the presence of dimethylaminotrimethyltin, those
reagents involving electron-rich aryl halides or
N-heteroaryl halides. For example, many drugs contain
indoline structure, especially the 5-substituted indolines
as obesity and diabetes drugs.11
A variety of aryl halides have been reacted with
trimethylsilylacetylene under the same reaction condi-
tions described above (Scheme 2 and Table 2). Chemi-
*
E-mail: xctao@ecust.edu.cn; Tel.: 0086-021-64253519
Received October 11, 2010; revised December 18, 2010; accepted January 26, 2011.
Chin. J. Chem. 2011, 29, 1059— 1062
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Cai et al.
NOTE
Scheme 1
Table 1 Palladium-catalyzed coupling between N-acetyl-5-
eliminates the product and regenerates the palladium
catalyst, which reacts further with aryl halide, to com-
plete the catalytic cycle.
bromoindoline and trimethylsilyl-acetylenea
Entry
Co-Cat.
CuIc
Solvent
Et3N
Yieldb/%
1
2
3
4
5
—
30
50
70
78
Cnclusion
Me3SnNMe2
Me3SnNMe2
Me3SnNMe2
Me3SnNMe2
THF
In summary, we have successfully used dimethyl-
aminotrimethyltin as an auxiliary agent in the palla-
dium-catalyzed coupling between aryl halides and
trimethylsilylacetylene, to generate terminal aryl al-
kynes in high yields.
DMF
MeCN
Toluene
a
Reaction conditions: N-acetyl-5-bromoindoline (2 mmol),
Me3SiC≡CH (2.4 mmol), Me3SnNMe2 (2 mmol), Pd2(dba)3 (1
mol%), PPh3 (4 mol%), solvent (6 mL), reflux for 8 h under argon.
The deprotection conditions: Bu4NF (2 mmol) in CH2Cl2 (6 mL),
stirred at room temperature for 5 h. b Isolated yield. c CuI (4 mol%)
as auxiliary catalyst.
Table 2 Palladium-catalyzed coupling between various aryl
halides and trimethylsilylacetylenea
Entry
ArX
Product
Yieldb/%
cal yields from 67% to 92% have been obtained for aryl
bromides and aryl iodides, with both electron-donating
and electron-withdrawing substituents. For both N-ace-
tyl-5-bromoindoline and N-methyl-5-bromoindoline, the
coupling with trimethylsilylacetylene worked nicely, but
the latter gave lower yield, due to electron-donating
substituent. For typical substrates of Sonogashira reac-
tion, N-acetyl-p-iodoaniline and N,N-dimethyl-p-
iodoaniline gave high yields (Table 2, Entries 3 and 4).
Electron-donating aryl bromides also gave high yields
(Table 2, Entries 5—8). N,N-Dimethyl-4-bromoaniline
and 3,5-dimethoxy-1-bromobenzene gave 71% and 70%
of the products, respectively (Table 2, Entries 7 and 9).
In contrast, very small amount of products were ob-
tained using (PPh3)2PdCl2/PPh3 and CuI as catalysts in
piperidine at reflux for 10 h.16
1
78
1
2
3
2
67
3
4
92
82
4
3
Scheme 2
5
6
7
87
71
73
4
5
We propose the reaction mechanism as shown in
Scheme 3. Trimethylsilylacetylene reacts with di-
methylaminotrimethyltin to generate in situ the alkynyl-
tin reagent,17 which reacts with aryl palladium halide, to
form aryl alkynyl palladium and trimethyltinhalide. The
palladium intermediate rearranges to the cis form, and
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Palladium-catalyzed Coupling between Aryl Halides and Trimethylsilylacetylene
Continued
Yieldb/%
CDCl3 using an Bruker Advance 500 spectrometer at
500 MHz, with tetramethylsilane as an internal standard.
Mass spectra were obtained on a Waters Miscromass
GCT spectrometer. Melting points were obtained in
open capillary tubes and uncorrected.
Entry
8
ArX
Product
70
General procedure for the preparation of terminal
aryl alkynes
6
7
Took a 25 mL Schlenk flask, loaded with trimethyl-
silylacetylene (Me3SiC≡CH) (235 mg, 2.4 mmol), di-
methylaminotrimethyltin (Me3SnNMe2) (0.33 mL 2
mmol), and 6 mL toluene, under argon. The mixture was
stirred at room temperature for 20 min. Aryl halide (2
mmol), Pd2(dba)3 (10 mg, 0.1 mmol), and PPh3 (22 mg,
0.4 mmol) were added. The reaction mixture was re-
fluxed for 8 h. After the reaction completed and cooled
to room temperature, the mixture was filtered through a
2 cm length silica gel column. Toluene was recovered
by distillation. The solid was dissolved in 6 mL di-
chloromethane, then Bu4NF (528 mg, 2 mmol) was
added. The mixture was stirred at room temperature for
5 h. After the reaction completed, the reaction mixture
was washed with saline, and purified by silica gel col-
umn chromatography (petroleum ether/ ethyl acetate) to
obtain the products.
9
80
90
89
74
10
11
12
8
9
N-Acetyl-5-ethynyl indoline (1): Solid, m.p. 142—
1
144 ℃; H NMR (CDCl3, 500 MHz) δ: 2.23 (s, 3H),
3.01 (s, 1H), 3.18 (t, J＝8.5 Hz, 2H), 4.07 (t, J＝8.5 Hz,
2H), 7.29 (s, 1H), 7.34 (d, J＝8.1 Hz, 1H), 8.15 (d, J－＝
1
10
8.1 Hz, 1H); IR (KBr) ν: 3219, 2965, 2092, 1660 cm ;
MS m/z (%): 185 (M＋, 62), 143 (100), 115 (31). HRMS
calcd for C12H11NO 185.0841, found185.0842.
a
Reaction conditions: aryl halide (2 mmol), Me3SiC≡CH (2.4
mmol), Me3SnNMe2 (2 mmol), Pd2(dba)3 (1 mol%), PPh3 (4
mol%), toluene (6 mL), reflux for 8 h under argon. The deprotec-
tion conditions: Bu4NF (2 mmol) in CH2Cl2 (6 mL), stirred at
room temperature for 5 h. b Isolated yield.
N-Methyl-5-ethynyl indoline (2): Oil; 1H NMR
(CDCl3, 500 MHz) δ: 2.86 (s, 3H), 3.02 (t, J＝8.4 Hz,
2H), 3.03 (s, 1H), 3.44 (t, J＝8.4 Hz, 2H), 6.44 (d, J＝
8.0 Hz, 1H), 7.31—7.33 (m, 2H); IR (KBr) ν: 3288,
＋
－1
Scheme 3 The mechanism of palladium-catalyzed coupling of
aryl halides and trimethylsilylacetylene assisted by dimethylami-
notrimethyltin
2949, 2096, 1611 cm ; MS m/z (%): 157 (M , 100),
141 (20), 115 (30). HRMS calcd for C11H11N 157.0891,
found 157.0889.
4-Acetylaminophenyl acetylene (3): Solid, m.p. 115—
1
119 ℃ (Lit.18 122—123 ℃); H NMR (CDCl3, 500
MHz) δ: 2.18 (s, 3H), 3.04 (s, 1H), 7.41—7.49 (m, －4H);
1
IR (KBr) ν: 3435, 3207, 3033, 2105, 1685, 1274 cm .
4-Dimethylaminophenyl acetylene (4): Solid, m.p.
1
31—35 ℃ (Lit.16 33—35 ℃); H NMR (CDCl3, 500
MHz) δ: 2.96 (s, 1H), 2.98 (s, 6H), 6.60 (d, J＝8.7 Hz,
2H), 7.37 (d, J＝8.7 Hz, 2H); IR (KBr) ν: 3287, 2954,
－1
2100, 1610 cm .
4-Methoxyphenyl acetylene (5): Oil (Lit.19 28—29
℃); 1H NMR (CDCl3, 500 MHz) δ: 2.99 (s, 1H), 3.81 (s,
3H), 6.84 (d, J＝7.6 Hz, 2H), 7.43 (d,－J＝7.6 Hz, 2H);
1
IR (KBr) ν: 3310, 2954, 2110, 1266 cm .
3,5-Dimethoxyphenyl acetylene (6): Solid, m.p. 35—
39 ℃ (Lit.20 oil); 1H NMR (CDCl3, 500 MHz) δ: 3.04 (s,
1H), 3.78 (s, 6H), 6.47 (t, J＝2.4 Hz, 1H), 6.65 (d,－J＝
Experimental
All reagents and solvents were anhydrous, purchased
from commercial sources, and used without further pu-
rification. Products were purified by silica gel column
chromatography. 1H NMR spectra were recorded in
1
2.4 Hz, 2H); IR (KBr) ν: 3266, 3004, 2080, 1316 cm .
2-Methoxy-5-ethynyl pyridine (7): Oil (Lit.21 oil); 1H
NMR (CDCl3, 500 MHz) δ: 3.10 (s, 1H), 3.94 (s, 3H),
Chin. J. Chem. 2011, 29, 1059— 1062
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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1061

Cai et al.
NOTE
6.70 (d, J＝8.4 Hz, 1H), 7.61 (dd, J＝8.4, 2.2 Hz, 1H),
7
8
Doucet, H.; Hierso, J. C. Angew. Chem., Int. Ed. 2007, 46,
834.
8.31 (d, J＝2.2 Hz, 1H); IR (KBr) ν: 3304, 2959, 2100,
－1
1260 cm .
(a) Herrmann, W. A.; Ofele, K.; Preysing, D. V.; Schneider,
S. K. J. Organomet. Chem. 2003, 687, 229.
(b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41,
4176.
Gil-Moltó, J. G.; Nájera, C. Adv. Synth. Catal. 2006, 348,
1874.
3-Acetylamino-6-ethynyl pyridine (8): Solid, m.p.
1
193—195 ℃; H NMR (CDCl3, 500 MHz) δ: 2.23 (s,
3H), 3.12 (s, 1H), 7.41 (br, 1H), 7.47 (d, J＝8.6 Hz),
8.24 (dd, J＝8.6, 2.4 Hz, 1H), 8.47 (d, J＝2.4 Hz, 1H);
9
－1
IR (KBr) ν: 3435, 32＋07, 3033, 2105, 1685, 1274 cm ;
MS m/z (%): 160 (M , 32), 118 (100), 91 (15). HRMS
calcd for C9H8N2O 160.0637, found 160.0638.
10 Datta, A.; Ebert, K.; Plenio, H. Organometallics 2003, 22,
4685.
2-Dimethylamino-5-ethynyl pyridine (9): Oil, 1H
NMR (CDCl3, 500 MHz) δ: 3.06 (s, 1H), 3.10 (s, 6H),
6.43 (d, J＝8.8 Hz, 1H), 7.51 (dd, J＝8.8, 2.0 Hz, 1H),
8.24 (d, J＝2.0－Hz, 1H); IR (KBr) ν: 3219, 2950, 2105,
11 (a) Murphy, J. A.; Rasheed, F.; Gastaldi, S.; Ravishanker, T.;
Lewis, N. J. Chem. Soc., Perkin Trans. 1 1997, 1549.
(b) Mathvink, R. J.; Barritta, A. M.; Candelore, M. R.; Cas-
cieri, M. A.; Deng, L.; Tota, L.; Strader, C. D.; Wyvratt, M.
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1999, 9, 1869.
12 Thorand, S.; Krause, N. J. Org. Chem. 1998, 63, 8551.
13 Fukuyama, T.; Shinmen, M.; Nishitani, S.; Sato, M.; Ryu, I.
Org. Lett. 2002, 4, 1691.
＋
1
1603, 1262 cm ; MS m/z (%): 146 (M , 95), 131 (55),
117 (100), 102 (30). HRMS calcd for C9H10N2 146.0844,
found 146.0840.
3-Dimethylamino-6-ethynyl pyridine (10): Solid,
m.p. 76—78 ℃; 1H NMR (CDCl3, 500 MHz) δ: 2.99 (s,
6H), 3.02 (s, 1H), 6.84 (dd, J＝8.8, 3.2 Hz, 1H), 7.30 (d,
J＝8.4 Hz, 1H), 8.05 (d, J＝3.2 Hz, 1H); IR (KBr) ν:
14 (a) Cai, L.; Cuevas, J.; Temme, S.; Herman, M. M.; Da-
gostin, C.; Widdowson, D. A.; Innis, R. B.; Pike, V. W. J.
Med. Chem. 2007, 50, 4746.
－1
3257, 2925, 2088, 1585, 1221 cm ; MS m/z (%): 146
(M＋, 100), 130 (15), 117 (5). HRMS calcd for C9H10N2
146.0844, found 146.0842.
(b) Cai, L.; Liow, J. S.; Zoghbi, S. S.; Cuevas, J.; Baetas, C.;
Hong, J.; Shetty, H. U.; Seneca, N. M.; Brown, A. K.; Glad-
ding, R.; Temme, S. S.; Herman, M. M.; Innis, R. B.; Pike,
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Chin. J. Chem. 2011, 29, 1059— 1062