A. Porcheddu et al.
of activated and electron-rich aniline derivatives, such as o/
m/p-toluidine and o/p-anisidine, proceeded smoothly and se-
lectively to give the corresponding mono-N-alkylated aniline
derivatives in nearly quantitative yields (Table 3, entries 5–
11).
Even the amination of aniline with a sterically hindered
substituent at the ortho position was found to be effective,
although a lower yield (66%; Table 3, entry 12) was ob-
served. The alkyl transfer reactions with o/p-halogenated
anilines were more problematic and gave only low yields
(Table 3, entries 13 and 14). The reaction of 3-trifluoro-
Scheme 2. Presumed mechanism for the arylation of tertiary amines.
A
elimination of the secondary amine 6. In the last step, the
starting Pd/C catalyst is regenerated and gives the desired
secondary aniline product 8.
In conclusion, we have developed a palladium-catalysed
N-alkylation of anilines with tertiary amines that occurs
under transfer-hydrogenation conditions. The reactions pro-
ceed smoothly and efficiently to give the corresponding N-
alkylanilines in good to excellent yields.
the alkylated aniline in a moderate yield (57%).
The amine coupling of 4-nitroaniline and 4-aminobenzoni-
trile (Table 3, entries 16 and 17) with different trialkyl-
ACHTUNGTRENNUNGamines showed no reaction even at higher temperatures or
increasing reaction times.
Finally, we explored the coupling of aniline with a set of
unsymmetrical tertiary amines; the results are summarized
in Table 4. In general, the reaction of trans alkylation gives
rise to a mixture of two N-alkylanilines (1 and 2, Table 4), in
Experimental Section
Table 4. N-Alkylation of aniline with unsymmetrical tertiary amines.
N-Propylaniline (Table 3, entry 1): 10% Pd/C (0.032 g, 0.03 mmol,
1.5 mol% relative to aniline), freshly distilled aniline (0.186 g, 182.5 mL,
2.0 mmol), freshly distilled tri-n-propylamine (0.430 g, 571 mL, 3 mmol)
and dry toluene (2.5 mL) was added to an argon-filled 10 mL pressure-re-
sistant vial equipped with rubber septum and an aluminium cap. The mix-
ture was put in the microwave apparatus (CEM Discover, 2.45 GHz,)
and irradiated at 1758C with stirring. After 1.5 h the reaction vessel was
cooled to room temperature and the palladium catalyst was filtered off.
The solvent was removed in vacuo and the crude product was easily puri-
fied by column chromatography with hexane/ethyl acetate (95/5) to
afford N-propylaniline as a pale yellow liquid (0.250 g, 1.84 mmol, 92%).
The analytical values agree well with the literature. 1H NMR (300 MHz,
CDCl3): d=7.23–7.16 (m, 2H), 6.74–6.68 (m, 1H), 6.64–6.61 (m, 2H),
3.64 (brs, 1H), 3.10 (t, J=7.2 Hz, 2H), 1.67 (sextuplet, J=7.5 Hz, 2H),
1.02 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=148.7,
129.4, 117.3, 112.9, 46.0, 23.0, 11.9 ppm; HRMS: m/z calcd for
[C9H13NH]+: 136.1126; found: 136.1118.
Entry[a]
R
R1
1 [%]
2 [%]
Yield [%][b]
1
2
3
4
5
6
Bu
Me
Bu
Et
iPr
Me
Me
Bu
Et
Bu
Me
iPr
75
45
77
42
–
25
55
23
58
100
–
76
71
78
73
59
70
100
[a] Reaction conditions: aniline (2 mmol), tri-n-propylamine (3 mmol),
10% Pd/C (1.5 mol%), toluene (2.5 mL), 1758C, 1.5 h. [b] Yield of isolat-
ed product after column chromatography is based on aniline residue.
which the major component is the N-alkylaniline with the
longest linear carbon chain bonded to the nitrogen atom.
For example, in the case of the reaction of aniline with N,N-
dimethylbutylamine (Table 4, entry 1) or N,N-dibutylmethyl-
amine (Table 4, entry 2), both the butyl and methyl groups
were transferred even if N-butylaniline was always obtained
as the major product. When N,N-dimethylisopropylamine or
N,N-diisopropylmethylamine were used (Table 4, entries 5
and 6) only methyl-group transfer occurred.
With regard to the mechanism of this reaction, we pro-
pose that the alkylation of aniline proceeds through a hydro-
gen-borrowing pathway, as previously postulated by the
groups of Murahashi, Beller and Williams (Scheme 2).[5,6,8]
Palladium is inserted into the carbon–hydrogen bond close
to the nitrogen of the alkylamine 3, promoting b-hydride
elimination, to give the highly reactive intermediate immini-
um ion 4.
Acknowledgements
This work was financially supported by the Universitꢀ degli Studi di Sas-
sari and MIUR (ROME) within the project PRIN: ꢃStructure and Activi-
ty Studies of DNA Quadruplex through the Exploitation of Synthetic
Oligonucleotides and Analoguesꢂ.
Keywords: alkylation · amines · anilines · heterogeneous
catalysis · microwave chemistry
[1] a) M. Negwer, Organic–Chemical Drugs and Their Synonyms (An
International Survey), 7th ed., Akademie Verlag, Berlin, 1994;
b) S. A. Lawrence, Amines: Synthesis, Properties, and Applications,
Cambridge University Press, Cambridge, 2004; c) The Chemistry of
Anilines, Vol. 1 (Ed.: Z. Rappoport), Wiley-Interscience, New York,
2007.
Nucleophilic attack by the incoming aniline on the imini-
um ion 4 forms an unstable aminoaminal 5 with subsequent
[2] M. B. Smith, J. March, Advanced Organic Chemistry, 5th ed., Wiley,
New York, 2001; p. 499–505.
84
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Chem. Eur. J. 2011, 17, 82 – 85