N-Dealkylation of aliphatic amines and selective synthesis of monoalkylated aryl amines

Article abstract of DOI:10.1039/b803114b

Highly selective alkyl transfer processes of mono-, di- and trialkyl amines in the presence of the Shvo catalyst have been realized; in addition, a general method for N-alkylation of aniline with di- and trialkyl amines is presented. The Royal Society of Chemistry.

Full text of DOI:10.1039/b803114b

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COMMUNICATION
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N-Dealkylation of aliphatic amines and selective synthesis of
monoalkylated aryl aminesw
¨
Dirk Hollmann, Sebastian Bahn, Annegret Tillack and Matthias Beller*
Received (in Cambridge, UK) 25th February 2008, Accepted 7th April 2008
First published as an Advance Article on the web 8th May 2008
DOI: 10.1039/b803114b
Highly selective alkyl transfer processes of mono-, di- and
trialkyl amines in the presence of the Shvo catalyst have been
realized; in addition, a general method for N-alkylation of
aniline with di- and trialkyl amines is presented.
Metabolic N-dealkylation is an important biotransformation
Scheme 1 Arylation of aliphatic amines using the Shvo catalyst 1.
in nature. Such processes are catalyzed by monooxygenases
such as Cytochrome P 450,1 although these enzymes are
mainly known for oxidation reactions such as hydrocarbon
hydroxylation and alkene epoxidation.2 Ever since the identi-
fication of the first dealkylation catalyst,3 the understanding
and the development of new systems is of significant interest,
albeit only a few methods are known.4
in tert-amyl alcohol gave the best results. Notably, a mixture
of mono-, di- and tri-n-hexylamine is also converted highly
selectively to give N-hexylaniline (Scheme 3).
We believe that the reaction proceeds through a hydrogen
borrowing mechanism as proposed by Williams,12 which
involves dehydrogenation of the amine, imine formation,
nucleophilic attack by the aniline, elimination of ammonia,
and final hydrogenation. To confirm this mechanism, a reac-
tion was carried out with labeled aniline-15N and dibenzyl-
amine. The resulting N-benzylaniline was obtained in 96%
isolated yield and showed 499% of 15N-labelling (Table 1,
entry 5).13
In recent years, the synthesis of aniline derivatives has
received high attention. Aromatic amines play an outstanding
role as biologically active compounds.5 In addition, for in-
dustry the development of improved syntheses is of enormous
interest. Among the various methods, the widely used
palladium- and copper-catalyzed aminations of aryl halides
(Buchwald–Hartwig aminations) became the most general
method to form C–N bonds of aromatic amines.6,7 Apart
from well established aryl halides, tosylates and triflates,
simple anilines constitute available and cheap substrates.
Recently, we have described the first arylation of aliphatic
amines with anilines leaving ammonia as the only side-product
(Scheme 1).8 In the presence of the so-called Shvo catalyst 19,10
a variety of functionalized anilines and primary amines react
smoothly to give the corresponding aryl amines in excellent
yields.11
Of note, in this alkyl transfer reactions the hydrogen donors
for the final hydrogenation step are the primary, secondary
and tertiary amines. Hence, no additional hydrogen or hydro-
gen transfer reagent is required in the process. Advantageously
there is no need for high-pressure equipment which is used
often in hydrogenation reactions such as reductive amination.
As shown in Scheme 4 under the reaction conditions,
equilibrium between the mono-, di- and trialkyl amines is
observed. All alkyl amines are converted into each other and
can be monitored until the reaction is finished (reversible
steps).14,15 However, by reaction of the respective imines or
iminium species with aniline, the corresponding N-hexylaniline
is formed in an irreversible step. Thus, reaction of
tri-n-hexylamine with aniline yields exclusively N-hexylaniline
and di-n-hexylamine. Then, the next alkyl group is transferred.
Finally, the reaction of n-hexylamine with aniline, results in
the formation of ammonia (irreversible step).
In this communication we present our new studies of the
dealkylation of aliphatic amines combined with the selective
synthesis of monoalkylated aniline derivates. For the first time
it is shown that starting from primary, secondary and tertiary
amines, a complete and selective transfer of all alkyl groups
takes place highly selectively.
As a starting point of our investigations we compared the
amination of aniline with n-hexylamine, di-n-hexylamine and
tri-n-hexylamine. To our surprise, all the different hexylamines
are converted in high yields (75–87%) to the same N-hexylani-
line (Scheme 2)! Especially remarkable is the activation and
alkyl transfer of the tertiary amine.
Next, we were interested in the generality of the dealkylation
process and their application in the N-alkylation of aniline
with various di- and trialkyl amines. Using polyalkylated
short-chain amines, this method provides a convenient access
Upon optimization we found that two equivalents of aniline
per hexyl group in the presence of 1 mol% of the Shvo catalyst
Leibniz-Institut fur Katalyse e.V. an der Universitat Rostock, Albert-
¨
¨
Einstein-Str. 29a, D-18059 Rostock, Germany.
E-mail: matthias.beller@catalysis.de; Tel: +49 381 1281 113
w Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b803114b
Scheme 2 Amination of aniline with different alkyl amines (isolated
yields are based on hexyl groups).
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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
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of alkyl groups) were dissolved in tert-amyl alcohol (0.5 ml) and
aniline (4 mmol). The pressure tube was fitted with a Teflon cap
and heated at 150 1C for 24 h. The solvent was removed in vacuo,
and the crude alkyl aryl amine product was easily purified by
column chromatography with pentane–ethyl acetate (20 : 1).
12. For an excellent review of the hydrogen borrowing methodology,
see: M. H. S. A. Hamid, P. A. Slatford and J. M. J. Williams, Adv.
Synth. Catal., 2007, 349, 1555.
13. Similar observations have been made in the amination of alcohols:
D. Hollmann, A. Tillack, D. Michalik, R. Jackstell and M. Beller,
Chem.–Asian J., 2007, 3, 403; A. Tillack, D. Hollmann,
D. Michalik and M. Beller, Tetrahedron Lett., 2006, 47, 8881;
M. H. S. A. Hamid and J. M. J. Williams, Chem. Commun., 2007,
725; G. Cami-Kobeci, P. A. Slatford, M. K. Whittlesey and J. M.
J. Williams, Bioorg. Med. Chem. Lett., 2005, 15, 535.
14. A. Miyazawa, K. Saitou, K. Tanaka, T. M. Gadda, M. Tashiro,
¨
G. K. S. Prakash and G. L. Olah, Tetrahedron Lett., 2006, 47,
1437.
15. C. W. Jung, J. D. Fellmann and P. E. Garrou, Organometallics,
1983, 2, 1042.
16. J. J. Li, Z. Wang and L. H. Mitchell, J. Org. Chem., 2007, 72,
3606.
17. M. Kreis, C. J. Friedmann and S. Braese, Chem.–Eur. J., 2005, 11,
7387.
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