synthesis and catalytic functionalization of biologically active indoles

Zn-Catalyzed Hydroamination of Terminal Alkynes
Table 3. Hydroamination of 1-octyne (2a) and phenylacetylene (2d) with
various substituted anilines 1. [a]
Entry Hydroamination product Yield
[%] [b]
1 58
2 67
3 66
4 51
5 67
6 95
7 97
8 91
9 [c]
10 77
[a] Reaction conditions: 1) alkyne 2 (1.5 mmol), aniline derivatives 1
(1.95 mmol), ZnACHTUNGTRENUNG(OTf) 2 (5 mol %), toluene (2 mL), 24 h, 120 8C; 2) reduction:
NaBH 3CN (3 mmol), ZnCl 2 (1.5 mmol), MeOH (8 mL), 20 h, room temperature.
[b] Yield of isolated product. [c] Dioxane (2 mL).
line derivatives led to the secondary amines 3l–p in yields of
up to 97 %. Notably, in contrast to most transition-metal-catalyzed
hydroamination reactions, nitro- and cyano-substituted
anilines are tolerated. For example, NO 2-substituted anilines
showed no reaction in titanium-catalyzed aminations [12] and
CN-substituted anilines reacted only in low yield. [13] In addition,
methoxy- and chloro-substituted anilines as well as 3-aminopyridine
gave the desired products in the presence of the zinc
catalyst. In all cases, over 99 % regioselectivity for the corresponding
Markovnikov isomer was observed. [14]
A significant advantage of the ZnACHTUNGTRENUNG(OTf) 2-catalyzed hydroamination
compared to similar Ti-catalyzed reactions is the reactiv-
93
ity of secondary amines (Scheme 4). For example, the preparation
of N-methyl-N-(1-phenylethyl)aniline (5a) and N-benzyl-N-
(1-phenylethyl)aniline (5b) proceeded to give the corresponding
tertiary amines in moderate to good yields.
Scheme 4. Zinc-catalyzed hydroamination of phenylacetylene (2d) with secondary
amines 4 (Bn = benzyl).
Conclusion
In summary, we have shown for the first time that easily available
zinc salts are active and practical catalysts for the intermolecular
hydroamination of terminal alkynes with anilines. The
reactions proceed in the presence of ZnACHTUNGTRENUNG(OTf) 2 with excellent
regioselectivity (>99 %) and with high yields. Notably, no expensive
catalyst and even no ligands are required for this
novel environmentally friendly reaction.
Experimental Section
All reactions were carried out under an argon atmosphere. Chemicals
were purchased from Aldrich, Fluka, and Acros and unless otherwise
noted were used without further purification. All compounds
were characterized by 1 H NMR and 13 C NMR spectroscopy,
low- and high-resolution mass spectrometry (MS and HRMS), and
FTIR spectroscopy. 1 H and 13 C NMR spectra were recorded on a
Bruker AV 300 spectrometer. 1 H NMR chemical shifts are reported
relative to the TMS signal, and the 13 C NMR chemical shifts are reported
relative to the center of solvent resonance (CDCl 3: d =
77.23 ppm ( 13 C)). EI mass spectra were recorded on an MAT 95XP
spectrometer (Thermo ELECTRON CORP.). GC was performed on a
Hewlett Packard HP 6890 chromatograph with a 30 m HP5 column.
IR spectra were recorded on a FT-IR Nicolet 6700 (Thermo ELEC-
TRON CORP.).
General Procedure for the Zinc-Catalyzed Hydroamination
Reaction
ZnACHTUNGTRENUNG(OTf) 2 (27.3 mg, 0.075 mmol) was dissolved in dry toluene or dry
dioxane (3 mL) in an ACE pressure tube under argon atmosphere.
Then aniline (1.95 mmol) and alkyne (1.5 mmol) were added to the
solution, and the reaction mixture was heated at 1208C for 24 h.
After cooling the mixture to room temperature, a suspension of
NaBH 3CN (188.5 mg, 3 mmol) and ZnCl 2 (204.4 mg, 1.5 mmol) in
methanol (8 mL) was added and the mixture was stirred for 20 h at
room temperature. Saturated Na 2CO 3 solution (15 mL) was added,
and the resulting mixture was extracted with CH 2Cl 2 (3 ”20 mL),
and the organic layer was dried over MgSO 4. The organic solvent
was removed in vacuo, and the amine product was purified by
column chromatography with hexane/ethyl acetate (9:1) as eluent.
ChemSusChem 2008, 1, 333 – 338 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemsuschem.org 335