A Copper- and Amine-Free Sonogashira Reaction Employing ...

Copper- and Amine-Free Sonogashira Reaction
SCHEME 3
cross-coupling product 3ec was isolated in 88% yield and
no Heck reaction product was detected (Table 4, entry
9). As expected, aryl halides with electron-withdrawing
groups are more reactive than those with electrondonating
groups; when bromoacetone and methyl 2-bromobenzoate
were employed, the reaction was complete
in 3 h (Table 4, entries 5 and 10).
The mechanism of the reaction is suggested as in
Scheme 3. The first step is the oxidative addition of Pd-
(0) with aryl halide. The application of electron-rich
aminophosphine ligands makes this step easier. The
second step is the activation of the terminal alkyne.
Because no copper salt was employed, and the bases are
not strong enough to subtract a proton from the alkyne,
a transmetalation step could be excluded. The terminal
alkyne C-H bond activation is acomplished by the
coordination of the alkyne to the ArPdX complex. Upon
coordination, the C-H bond is weakened, and HX is
removed from I in the presence of a base to form
arylalkynylpalladium species II, which undergoes reductive
elimination to afford the product III and regenerates
the catalyst. The electron-rich, and bulky, aminophosphine
ligands may play key roles in facilitating the
reductive elimination step.
In conclusion, we have developed an efficient, copperand
amine-free Sonogashira reaction with easily prepared,
air-stable aminophosphines as the ligands. The
mild reaction conditions, the obviation of copper salt as
cocatalyst and amine as solvent, and the utilization of
inorganic base are the most attractive features of the
reaction.
Experimental Section
Materials. THF was distilled from sodium-benzophenone
prior to use. K2CO3, K3PO4‚3H2O, KF, Pd(OAc)2, KOH, aryl
bromides, phenylacetylene, and hexyne were used directly as
obtained commercially unless otherwise noted. Other alkynes
were prepared according to the literature.
Preparation of Ligands. Caution: The aminophosphine
ligands may be toxious, no MSDS available. L1 was prepared
according to the literature, 16 while L2 was prepared according
to the process mentioned as follows: Under a nitrogen
atmosphere, a 100 mL three-necked flask was charged with
5-bromobenzo[1,3]dioxole (4.0 g, 20 mmol) in dry ether (15 mL)
and n-BuLi (15 mL, 1.6 M in hexanes, 24 mmol) was added
dropwise at -20 °C with stirring. The mixture was further
(16) Contreras, R.; Grevy, J. M.; Garcia-Hernandez, Z.; Gueizado-
Rodriguez, M.; Wrackmeyer, B. Heteroat. Chem. 2001, 12, 542-550.
stirred for 1hatthis temperature, and then i Pr2NPCl2 (2.0 g,
10 mmol) in dry ether (15 mL) was added dropwise in 2 h.
The reaction mixture was stirred overnight. Then the solvent
was evaporated under reduced pressure, and the residue was
purified by flash chromatography on Al2O3 to give L2 (1.53 g,
43%) as a colorless oil.
Data for L1. White solid. Mp: 69-70 °C. 1 H NMR (300
MHz, CDCl3): δ 7.53-7.47 (m, 4H), 7.34-7.30 (m, 6H), 3.39
(m, 2H), 1.08 (d, J ) 6.3 Hz, 12H). 13 C NMR (75 MHz, CDCl3):
δ 140.5 (d, J ) 19.8 Hz), 132.4 (d, J ) 20.3 Hz), 127.9, 127.9,
47.4 (d, J ) 8.3 Hz), 23.8 (d, J ) 7.1 Hz). 31 P NMR (121 MHz,
CDCl3): δ 38.2. MS (EI): m/z 285, 270, 242, 228, 194, 183,
108, 100. IR (KBr, cm -1 ): 3067, 2981, 2965, 1433, 1360, 1178,
1120.
Data for L2. Oil. 1 H NMR (300 MHz, CDCl3): δ 7.03-6.97
(m, 2H), 6.82-6.79 (m, 2H), 6.82-6.79 (m, 2H), 5.97 (s, 4H),
3.38 (m, 2H), 1.13 (d, J ) 6.0 Hz, 12H). 13 C NMR (75 MHz,
CDCl3): δ 147.5, 126.7, 126.4, 111.9, 111.6, 108.2, 100.8, 47.1,
23.8. 31 P NMR (121 MHz, CDCl3): δ 40.1. MS (EI): m/z (rel
intens) 373, 316, 273, 238. HRMS: m/z calcd for C20H24NO4P
373.1443, found 373.1466. IR (neat, cm -1 ): 2965, 2893, 1502,
1473, 1413, 1362, 1234, 1042.
General Procedure for Palladium-Catalyzed Copperand
Amine-Free Sonogashira Cross-Coupling Reaction.
Under a nitrogen atmosphere, a Schlenk reaction tube was
charged with alkyne substrate 1 (2.4 mmol), aryl bromide 2
(2 mmol), K2CO3 (828 mg, 6 mmol), Pd(OAc)2 (11 mg, 0.05
mmol), ligand (0.15 mmol), and THF (5 mL). The reaction tube
was purged with N2 in a dry ice bath. After the mixture was
heated at 65 °C for 8 h, the solvent was evaporated under
reduced pressure and the residue was purified by flash column
chromatography on silica gel to give the product 3.
Data for Hex-1-ynyl-2,6-dimethylbenzene (3bd). 1 H
NMR (300 MHz, CDCl3): δ 7.03-7.01 (m, 3H), 2.50 (t, J )
7.2 Hz, 2H), 2.54 (s, 6H), 1.62-1.52 (m, 4H), 0.95 (t, J ) 7.2
Hz, 3H). 13 C NMR (75 MHz, CDCl3): δ 139.9, 126.8, 126.5,
123.7, 98.9, 78.1, 31.1, 22.0, 21.1, 19.4, 13.6. MS (EI): m/z (rel
intens) 186, 157, 143, 142, 141, 129, 115. HRMS: m/z calcd
for C14H18 186.1409, found 186.1396. IR (neat, cm -1 ): 3022 (m),
2980 (s), 2924 (s), 2874 (m), 2226 (m), 1467 (s), 1378 (m), 769
(s), 734 (m).
Data for 2-Methyl-4-(1′-naphthalen-2-yl)but-3-yn-2-ol
(3gf). 1 H NMR (300 MHz, CDCl3): δ 8.35-8.31 (m, 1H), 7.85-
7.79 (m, 2H), 7.67-7.65 (m, 1H), 7.58-7.50 (m, 2H), 7.42-
7.37 (m, 1H), 2.70 (s, br, 1H), 1.76 (s, 6H). 13 C NMR (75 MHz,
CDCl3): δ 133.2, 133.0, 130.3, 128.6, 128.2, 126.7, 126.3, 125.9,
125.0, 120.2, 98.8, 80.1, 65.8, 31.6. MS (EI): m/z (rel intens)
210 (M + , 67), 209 (28), 195 (98), 165 (24), 152 (33), 86 (28), 84
(41), 43 (100). HRMS: m/z calcd for C15H14O 210.1045, found
210.1029. IR (neat, cm -1 ): 3368 (s), 3060 (m), 2983 (s), 2248
(m), 1396 (s), 1164 (s), 908 (s), 808 (s), 774 (s), 733 (s).
Data for 1,4-Bis(3-hydroxy-3-methylbut-1-ynyl)benzene
(3gg). 1 H NMR (300 MHz, CD3COCD3): δ 7.35 (s, 4H),
4.53 (s, br, 2H), 1.53 (s, 12H). 13 C NMR (75 MHz, CD3-
COCD3): δ 131.6, 123.2, 97.2, 80.6, 64.5, 31.3. MS (EI): m/z
(rel intens) 242 (M + , 12), 227 (47), 135 (15), 107 (47), 92 (17),
91 (24), 59 (16), 46 (21), 43 (100). HRMS: m/z calcd for
C16H18O2 242.1307, found 242.1329. IR (KBr, cm -1 ): 3339 (s),
2981 (s), 2983 (s), 1508 (m), 1362 (s), 1273 (s), 1187 (m), 1143
(s), 960 (s), 905 (s), 836 (s), 788 (m).
Deprotection of Acetone-Masked Alkynes. 17 To a solution
of 3gf (2.2 g, 10.5 mmol) in dry toluene (50 mL) was added
sodium hydroxide powder (400 mg, 10 mmol). The suspension
was refluxed till the starting material was consumed completely
(8 h). Brine (15 mL) was added, and the separated
toluene layer was dried (MgSO4). The solvent was evaporated
under reduced pressure, and the residue was purified by flash
(17) (a) Havens, S. J.; Hergenrother, P. M. J. Org. Chem. 1985, 50,
1763-1764. (b) Pourjavadi, A.; Marandi, G. B. J. Chem. Res., Synop.
2002, 11, 552-555. (c) Takalo, H.; Kankare, J.; Häenninen, E. Acta
Chem. Scand., Ser. B 1988, 42, 448-454.
J. Org. Chem, Vol. 69, No. 16, 2004 5431