Scheme 3 Amination of aniline with a mixture of hexylamines
(isolated yields are based on hexyl groups).
Table 1 Amination of aniline with di- and trialkyl amines
Scheme 4 Equilibrium and selective transfer of alkyl groups.
Entry
Amine
Product
Yield (%)
Notes and references
1
2
Triethylamine
Dipropylamine
95
96
1. P. Hlavica, Drug Metab. Rev., 2002, 34, 451.
2. Review of P450 enzymes: D. Meyer, T. Leifels, L. Sbaragli and
W.-D. Woggon, Biochem. Biophys. Res. Commun., 2005, 338, 372;
W.-D. Woggon, Top. Curr. Chem., 1997, 184, 39; Cytochrome
P450 Structure, Mechanism and Biochemistry, ed. P Ortiz de
Montellano, Plenum Press, New York, London, 2nd edn, 1995.
3. T. Omura and R. J. Sato, J. Biol. Chem., 1964, 239, 2370.
4. In organic synthesis only a few dealkylation reactions are known:
for the von Braun reaction, Polonovski demethylation reaction,
and others, see: K. McCamley, J. A. Ripper, R. D. Singer and
R. J. Scammells, J. Org. Chem., 2003, 68, 9847, and references
therein.
3
Diisopropylamine
92
4
5
6
Dibenzylamine
Dibenzylamine
Tribenzylamine
98
92b
21c
7
Dicyclohexylamine
99
8
9
92
91
10
74
5. The Chemistry of Anilines, ed. Z Rappoport, Wiley-Interscience,
New York, 2007, vol. 1.
a
Reaction conditions: 1 mol% Shvo catalyst per alkyl group, 1 mmol
mono-, di- or trialkyl amine, 2 mmol aniline per alkyl group, 24 h,
tert-amyl alcohol, 150 1C. Isolated yields are based on alkyl groups.
6. For recent examples of palladium-catalyzed aminations, see:
E. M. Beccalli, G. Broggini, M. Martinelli and S. Sottocornola,
Chem. Rev., 2007, 107, 5318; C. A. Fleckenstein and H. Plenio,
Organometallics, 2007, 26, 2758; S. P. Nolan, Chem.–Eur. J., 2006,
12, 5142; J. F. Hartwig, Synlett, 2006, 1283; O. Navarro,
N. Marion, J. Mei, S. L. Buchwald, C. Mauger, G. Mignani and
U. Scholz, Adv. Synth. Catal., 2006, 348, 23; Q. Shen, S. Shekhar,
J. P. Stambuli and J. F. Hartwig, Angew. Chem., Int. Ed., 2005, 44,
1371. For reviews, see: B. Schlummer and U. Scholz, Adv. Synth.
Catal., 2004, 346, 1599; J. F. Hartwig, in Handbook of Organo-
palladium Chemistry for Organic Synthesis, ed. E.-I. Negishi,
Wiley-Interscience, New York, 2002, vol. 1, p. 1051; B. H. Yang
and S. L. Buchwald, J. Organomet. Chem., 1999, 576, 125.
7. Copper-catalyzed aminations of aryl halides, see: M. Taillefer,
N. Xia and N. Ouali, Angew. Chem., Int. Ed., 2007, 46, 934;
D. Jiang, H. Fu, Y. Jiang and Y. Zhao, J. Org. Chem., 2007, 72,
672; X. Guo, H. Rao, H. Fu, Y. Jiang and Y. Zhao, Adv. Synth.
Catal., 2006, 348, 2197; H. Zhang, Q. Qai and D. Ma, J. Org.
Chem., 2005, 70, 5164; I. P. Beletskaya and A. V. Cheprakov,
Coord. Chem. Rev., 2004, 248, 2337; S. V. Ley and A. W. Thomas,
Angew. Chem., Int. Ed., 2003, 42, 5400.
b
c
Aniline-15N; product content of 15N 4 99%. 78% recovered
tribenzylamine.
to monoalkylated anilines with short-chain alkyl groups. For
comparison, in the Buchwald–Hartwig reaction, these com-
pounds have to be synthesized from the corresponding volatile
amines using a sealed tube technique,16 benzylmethylamine or
methylammonium chloride.17
Instead of ethylamine (bp, 16.6 1C), propylamine (bp,
48 1C), isopropylamine (bp, 33.5 1C), we are able to use the
convenient non-volatile triethylamine, dipropylamine and
diisopropylamine (Table 1, entries 1–3). Excellent yields of
92–98% are observed. In addition, different alkyl amines and
aminoalkoxyethers are converted in excellent selectivity and
high yields (Table 1, entries 4, 5, 7–10). So far, only the full
conversion of tertiary benzylic amine poses a challenge
(Table 1, entry 6).
8. D. Hollmann, S. Bahn, A. Tillack and M. Beller, Angew. Chem.,
¨
Int. Ed., 2007, 46, 8291.
9. R. Karvembu, R. Prabhakaran and N. Natarajan, Coord. Chem.
Rev., 2005, 249, 911; Y. Shvo, D. Czarkie and Y. Rahamim,
J. Am. Chem. Soc., 1986, 108, 740; Y. Shvo and R. M. Laine,
J. Chem. Soc., Chem. Commun., 1980, 753.
10. A. Comas-Vives, G. Ujaque and A. Lledos, Organometallics,
2007, 26, 4135; J. S. M. Samec, A. H. Ell, J. B. Aberg,
In summary, we have presented the first selective N-alkyla-
tion with mono-, di- and trialkyl amines. This tool provides a
general access to the synthesis of monoalkylated aryl amines
via alkyl transfer and acts as a model for metabolic N-deal-
kylations. This novel reaction is highly atom efficient leaving
only ammonia as side-product and can be conveniently carried
out. Further applications with functionalized anilines as well
as other alkyl amines can be easily envisioned.
T. Privalov, L. Eriksson and J.-E. Backvall, J. Am. Chem. Soc.,
¨
and P. Brandt, Chem. Soc. Rev., 2006, 35, 237; J. B. Aberg, J. S.
¨
2006, 128, 14293; J. S. M. Samec, J.-E. Backvall, P. G. Andersson
M. Samec and J.-E. Backvall, Chem. Commun., 2006, 2771;
¨
C. P. Casey, G. A. Bikzhanova, Q. Cui and I. A. Guzei, J. Am.
Chem. Soc., 2005, 127, 14062; J. S. M. Samec, L. Mony and
J.-E. Backvall, Can. J. Chem., 2005, 83, 909; J. S. M. Samec,
¨
¨
A. H. Ell and J.-E. Backvall, Chem. Commun., 2004, 2748;
This work has been supported by the BMBF (Bundesminis-
C. P. Casey, S. W. Singer, D. R. Powell, R. K. Hayashi and
M. Kavana, J. Am. Chem. Soc., 2001, 123, 1090.
terium fur Bildung und Forschung), the Deutsche Forschungs-
¨
gemeinschaft (DFG BE 1931/16-1, Leibniz-price) and the state
of Mecklenburg-Vorpommern.
11. In an ACE-pressure tube under an argon atmosphere the Shvo
catalyst (0.02 mmol) and the corresponding alkyl amine (2 mmol
ꢀc
This journal is The Royal Society of Chemistry 2008
3200 | Chem. Commun., 2008, 3199–3201