Sonogashira Coupling and a-Carbonyl Arylation
FULL PAPER
Representative procedure for the synthesis of a-aryl compounds 7 [2-
(2,4-dinitrophenyl)-1-o-tolylethanone (7ab)]: Cs2CO3 (0.22 mmol,
1.1 equiv) was added to a mixture of nucleophile 3a (0.20 mmol, 1 equiv)
and electrophile 1a (0.24 mmol, 1.2 equiv) in acetone (2 mL). The mix-
ture was stirred at 48C for 48 h (completion judged by TLC). Aqueous
1n HCl (1.2 mL) was added and the mixture was stirred at RT until TLC
analysis indicated consumption of the nucleophile. The reaction mixture
was diluted with CH2Cl2, washed with a saturated aqueous solution of
Na2CO3, brine, and dried with MgSO4. The solvents were removed under
reduced pressure and the residue was purified by flash chromatography
(silica gel; 50% pentane/CH2Cl2) to afford 7ab as a yellow solid (69%
yield). M.p. 1308C. 1H NMR (CDCl3): d=8.99 (d, J=2.3 Hz, 1H), 8.46
(dd, J=8.4, 2.3 Hz, 1H), 7.85 (d, J=7.8 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H),
7.46 (app. t, J=7.5 Hz, 1H), 7.35 (app. t, J=7.5 Hz, 1H), 7.30 (d, J=
7.6 Hz, 1H), 4.80 (s, 2H), 2.47 ppm (s, 3H); 13C NMR (CDCl3): d=196.9,
149.1, 147.3, 139.4, 137.7, 136.0, 134.9, 132.4, 132.3, 128.7, 127.3, 125.9,
120.7, 46.6, 21.4 ppm; IR (neat): n˜ =3095, 2975, 2928, 1682 (s), 1605, 1531
result in the formation of either the formal Sonogashira or
a-arylation product, under mild basic or acidic conditions,
respectively, thus precluding any role for intermediate or-
ganometallic species. Taken together, the results presented
here show that these reactions can be worthy alternatives
and/or complements to metal-catalyzed cross-coupling reac-
tions.
Experimental Section
General: NMR spectra were acquired with a Varian AS 400 spectrometer
running at 400 MHz for 1H, 100 MHz for 13C, and 376 MHz for 19F.
Chemical shifts are reported in ppm relative to residual solvent signals
(CHCl3, d=7.26 ppm; acetone, d=2.05 ppm; DMSO, d=2.50 ppm) for
1H NMR spectra, relative to the central solvent resonance (CDCl3, d=
77.00 ppm; [D6]acetone, d=30.83 ppm; [D6]DMSO, d=39.43 ppm) for
13C NMR spectra and relative to an external standard (hexafluoroben-
zene in CDCl3, d=164.9 ppm) for 19F NMR spectra. 13C NMR spectra
were acquired in broadband decoupled mode. Mass spectra were record-
ed either with a micromass LCT spectrometer using electrospray (ES+)
ionization or by GC–MS (HP 5973 mass selective detector; electron
impact ionization, EI; 70 eV) with a HP 6890 gas chromatograph using a
chiral Chrompack CP Chiralsil-Dex Cb column. Analytical thin layer
chromatography (TLC) was performed by using precoated aluminum-
backed plates (Merck Kieselgel 60 F254) and visualized either by ultra-
violet irradiation or by using a KMnO4 dip. IR spectra were recorded
with a Perkin–Elmer Paragon 1000 FTIR spectrometer. Commercially
available reagents and solvents were used without further purification.
Purification of reaction products was carried out by flash chromatogra-
phy (FC) on silica gel 60 (230–400 mesh, Fluka) or Iatrobeads (6RS-
8060, Iatron Laboratories), as indicated. Nucleophiles 2a–n and 3a–o
were synthesized according to literature procedures.[22]
(s), 1459, 1350 (s), 1325, 1209, 1195, 978, 909, 835, 764, 729, 682 cmÀ1
;
HRMS: m/z calcd for C15H12N2NaO5: 323.0644 [M+Na+]; found:
323.0647.
Acknowledgements
This work was made possible by a grant from The Danish National Re-
search Foundation, the OChemSchool and the Carlsberg Foundation.
G.E.H. and D.G.A. are grateful for sabbatical support from Carleton Col-
lege.
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[7] For some recent examples, see: a) J. L. Bolliger, C. M. Frech, Adv.
Representative one-pot procedure for the synthesis of alkynes 6 (Method
A): 2,4-dinitro-1-(o-tolylethynyl)benzene (6ab): K2CO3 (0.24 mmol,
1.2 equiv) was added to
a mixture of nucleophile 2b (0.20 mmol,
1.0 equiv) and electrophile 1a (0.44 mmol, 2.2 equiv) in acetone (1.0 mL).
The mixture was stirred vigorously at 658C until NMR spectroscopy
analysis indicated consumption of the nucleophile. The crude reaction
mixture was concentrated under reduced pressure and purified by flash
chromatography (silica gel; 5% Et2O/hexanes) to afford alkyne 6ab as a
yellow solid in 86% yield.
Representative two-step procedure for the synthesis of alkynes
6
(Method B): Cs2CO3 (0.11 mmol, 1.1 equiv) was added to a mixture of
nucleophile 3b (0.10 mmol, 1.0 equiv) and electrophile 1a (0.12 mmol,
1.2 equiv) in acetone (1.0 mL). The mixture was stirred at 48C until
NMR spectroscopy analysis indicated consumption of the nucleophile.
The reaction mixture was diluted with CH2Cl2 and acidified with 1n
aqueous HCl. The aqueous phase was extracted three times with CH2Cl2
and the combined organic layers were washed with brine and dried over
Na2SO4. After filtering off the drying agent and concentrating under re-
duced pressure, the crude adduct 5ab was dissolved in acetone (2.5 mL)
and NaHCO3 (0.15 mmol, 1.5 equiv) was added. The mixture was stirred
vigorously at 458C until TLC analysis indicated consumption of adduct
5ab. The crude reaction mixture was concentrated under reduced pres-
sure and purified by flash chromatography (silica gel; 5% Et2O/hexanes)
to afford alkyne 6ab as a yellow solid (62% yield). M.p. 164–1678C.
1H NMR (CDCl3): d=8.95 (d, J=2.3 Hz, 1H), 8.43 (dd, J=8.6, 2.3 Hz,
1H), 7.90 (d, J=8.6 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.35 (app. t, J=
7.6 Hz, 1H), 7.28 (d, J=7.6 Hz, 1H), 7.23 ppm (app. t, J=7.5 Hz, 1H);
13C NMR (CDCl3): d=148.9, 146.1, 141.7, 135.7, 133.0, 130.5, 129.9,
126.9, 125.9, 125.2, 121.1, 120.5, 103.0, 87.6, 20.7 ppm; IR (neat): n˜ =3108,
2915, 1847, 1609, 1589, 1515, 1339 (s), 1144, 1053, 918, 905, 850, 832, 760,
738 cmÀ1; MS (EI): m/z (%): 282.0 (2) [M]+, 265 (41), 219 (92), 119 (94),
91 (100).
[10] For reviews, see: a) F. Bellina, R. Rossi, Chem. Rev. 2009, 109,
ASAP, DOI: 10.1021/cr9000836; b) A. C. B. Burtoloso, Synlett 2009,
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M. V. Troutman, M. Palucki, S. L. Buchwald, J. Am. Chem. Soc.
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ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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