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Experimental Section
General considerations
1H NMR and 1D proton decoupled 13C NMR spectra were recorded
in CDCl3 on a Brucker AC-300 spectrometer operating at 300 MHz
and 75 MHz, respectively. Chemical shifts, d, are given in ppm rela-
tive to TMS and coupling constants, J, in Hz. The measurements
were carried out using the standard pulse-sequences. The carbon
type (methyl, methylene, methine, or quaternary) was determined
by DEPT experiments. Mass spectra were recorded on a ZQ 2000
Waters spectrometer, equipped with the positive electrospray
mode (ES+). Chemicals were commercial products of the highest
available purity and were used as supplied. Reduced catalyst 1red
was synthesized in two steps from commercially available 2-nitro-
resorcinol.[22]
Representative experimental procedure for CuII/1ox-catalyzed
aerobic oxidative cross-coupling of two primary amines
Equimolar amounts of 4-methylbenzylamine 2a (2.5 mmol) and 1-
ethylpropylamine 3a (2.5 mmol), reduced organocatalyst 1red
(0.1 mmol, 4 mol%), and copper (II) acetate (0.01 mmol, 0.4 mol%)
were mixed in methanol (10 mL) in an air atmosphere. The reaction
mixture was stirred at room temperature (258C) for six hours.
Then, an additional aliquot of 1red (0.025 mmol, 1 mol%) was intro-
duced into the reaction mixture and the reaction was stirred for
roughly four hours. The progress of the reaction was monitored by
1H NMR spectroscopy. After completion of the reaction, the solvent
was evaporated at room temperature to give the cross-coupled
imine product 4a (97%) as an almost pure product as confirmed
Scheme 2. Tandem oxidative aza Diels–Alder reaction for the synthesis of di-
hydro-4-pyridones.
1
by H and 13C NMR spectroscopy (see the Supporting Information).
Imine 4a: 1H NMR (300 MHz, CDCl3, 258C, TMS): d=0.88 (t, J=
8 Hz, 6H, 2ꢁCH3), 1.70 (m, 4H, 2ꢁCH2), 2.43 (s, 3H, CH3), 2.91 (m,
1H, CH), 7.25 (d, J=7 Hz, 1H, 2ꢁCH, Ar), 7.68 (d, J=7 Hz, 1H, 2ꢁ
CH, Ar), 8.24 ppm (s, 1H, CH=N); 13C NMR (75 MHz, CDCl3, 258C,
TMS): d=11.1 (2ꢁCH3), 21.5 (CH3), 28.9 (2ꢁCH2), 75.2 (CH), 128.1
(2ꢁCH, Ar), 129.3 (2ꢁCH, Ar), 133.8 (Cq), 140.5 (Cq), 159.4 ppm
(CH=N); MS (ES+): m/z=190 [MH+].
The above procedure is generally representative for all the prod-
ucts shown in Tables 2 and 3. Any deviations from this protocol are
specified in the footnotes of the tables.
Representative procedure for CuII/1ox-catalyzed aerobic oxida-
tive synthesis of dihydro-4-pyridones derivatives
1-Cyclopropyl-N-(4-methoxyphenyl)methanimine 7 was prepared in
situ by mixing equimolar amounts of aminomethylcyclopropane 6
(1.25 mmol) and 4-methoxyaniline 3i (1.25 mmol), reduced organo-
catalyst 1red (0.05 mmol, 4 mol%), and copper(II) acetate
(0.005 mmol, 0.4 mol%) in methanol (5 mL) under ambient condi-
tions for six hours. Then, an additional aliquot of 1red
(0.0125 mmol, 1 mol%) was introduced into the reaction mixture
and the reaction was stirred for four hours. After roughly 60% of
aminomethylcyclopropane 6 had been converted into the cross-
coupled imine product 7 (see the NMR spectrum in the Supporting
Information), 2 mL of the resulting solution (which corresponds to
roughly 0.3 mmol of 7) was removed and Danishefsky’s diene 8
(0.6 mmol, 2 equiv) was added dropwise to it over 30 min. After
stirring for 1 h at room temperature (258C), another equivalent of
Danishefsky’s diene 8 (0.3 mmol) was added dropwise over 15 min
to the reaction mixture, which was stirred for 2 h at room tempera-
ture. The reaction mixture was then quenched with HCl (2 mL,
1.0m). The product was extracted with diethyl ether and the sol-
vent was evaporated under reduced pressure. The crude material
was purified by column chromatography with dichloromethane/
Scheme 3. Proposed overall two-step mechanism for the Cu(OAc)2/1ox-medi-
ated cross-coupling of primary amines.
through a transamination process, which leads to the homo-
coupled imine intermediate, followed by dynamic transimina-
tion. This atom-economical process, which proceeds at room
temperature, under ambient air, with equimolar amounts of
each coupling partner, and tolerates diverse functional groups,
generates with unprecedented selectivity cross-coupled
imines, which have been previously shown to have broad use
in organic synthesis. The mild reaction conditions used in this
work should be particularly favorable for using unstable alkyl-
imines in situ for further reactions.
Chem. Eur. J. 2015, 21, 1 – 7
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