Diethylzinc/CuII-mediated alkylation of aromatic amines and related compounds

Article abstract of DOI:10.1016/S0040-4039(01)01775-0

A mild and efficient method for the N-alkylation of aromatic amines and related compounds is described. The approach developed herein utilizes, as the key step, a transmetallation between a cupric salt and the dialkylzinc species.

Full text of DOI:10.1016/S0040-4039(01)01775-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8301–8302
Diethylzinc/CuII-mediated alkylation of aromatic amines and
related compounds†
Ce´dric Brielles,a Jerry J. Harnettb and Eric Dorisa,*
aCEA/Saclay, Service des Mole´cules Marque´es, De´partement de Biologie Cellulaire et Mole´culaire,
91191 Gif sur Yvette Cedex, France
bInstitut Henri Beaufour, ZA de Courtaboeuf, 5 Av. du Canada, 91966 Les Ulis Cedex, France
Received 20 July 2001; revised 20 September 2001; accepted 21 September 2001
Abstract—A mild and efficient method for the N-alkylation of aromatic amines and related compounds is described. The
approach developed herein utilizes, as the key step, a transmetallation between a cupric salt and the dialkylzinc species. © 2001
Elsevier Science Ltd. All rights reserved.
1. Introduction
the key step, a transmetallation5 between diethylzinc
and the copperII species.6
Organozinc compounds are useful reagents which, since
their discovery in 1849, have mainly been involved in
nucleophilic addition reactions1 but also in cyclopropa-
nation processes as carbene precursors.2 The ability of
these ZnII species to interact with other metals by
transmetallation expanded the scope of organozinc
chemistry.3 However, to the best of our knowledge,
dialkylzinc reagents have not yet been reported to be
effective for the N-alkylation of organic compounds.
We found that, upon treatment with 3 equiv. of
diethylzinc and 3 equiv. of a CuII salt in CH2Cl2,
aromatic amines and derived substrates can be N-alky-
lated (Scheme 1).
To find out the scope and limitations of this novel
reaction, the diethylzinc/Cu(acac)2-mediated alkylation
was attempted on various substrates (Table 1). The
overall yields are in most cases satisfactory. The reac-
tion has successfully been extended to diversely substi-
tuted anilines (entries 1–5) but also to a hydrazone
(entry 7), a hydrazine (entry 8) and a hydroxylamine
O-benzyl ether derivative (entry 6). The reaction of a
bulky substrate (entry 5) and of methylated aniline
(entry 4), under our conditions, led to the formation of
the expected products albeit in moderate yields. The
nature of the substitution of the aromatic ring has also
been briefly studied, showing that electron-donating
substituents induced some loss in selectivity (entry 2).
While electron-withdrawing groups, on the other hand,
increased the selectivity of the alkylation process (entry
3). In both cases, the alkylated aniline derivatives were
obtained in comparable yields. Our attempts to alkylate
aliphatic amines (e.g. benzylamine) under the aforemen-
tioned conditions were unsuccessful. This is possibly
due to the formation of a strong complex between the
more basic amine and copper.
Amongst the various copper salts tested (CuI, CuBr2,
Cu(OAc)2, Cu(OPiv)2, Cu(OTf)2), cupric acetylaceto-
nate (Cu(acac)2) was found to be the most efficient in
effecting N-alkylation. The mechanism for this trans-
formation is probably analogous to that of the CuII/
AlIII-mediated alkylation of amines4 and involves, as
CuII
Ar-NHEt
Ar-NH2
+
ZnEt2
CH2Cl2
In conclusion, we have shown that diethylzinc, in the
presence of a copperII-based promoter, selectively alky-
lates selected aromatic amines and related compounds.
Scheme 1.
2. Typical experimental procedure
Keywords: alkylation; amine; copper; transmetallation; zinc.
* Corresponding author. E-mail: eric.doris@cea.fr
Dedicated to the memory of Sir Derek H. R. Barton who initiated
this work.
†
Under Ar, to a stirred solution of Cu(acac)2 (0.430 g, 3
equiv.) and aniline (0.051 mL, 0.55 mmol, 1 equiv.) in
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01775-0

8302
C. Brielles et al. / Tetrahedron Letters 42 (2001) 8301–8302
Table 1. Examples of alkylation of amines and related compounds
entry
products
yield (%)b
95
substrate
ratioa
90/10
Ph-NEt2
Ph-NH2
Ph-NHEt
1
2
MeOp-C6H4-NH2
O2Np-C6H4-NH2
MeOp-C6H4-NHEt
MeOp-C6H4-NEt2
65/35
83
O2Np-C6H4-NHEt
3
4
85
35
Ph-N(Me)Et
iPr
Ph-NH-Me
iPr
5
41
NH2
NHEt
iPr
iPr
N
NH2
NHEt
NEt2
15/85
65/35
67
60
6
7
Ph
Ph
Ph
O
Ph
O
Ph
O
Ph
Ph
N
NH2
NHEt
Ph
Ph
Ph
Ph
78
8
N NHEt
N
NH2
N NEt2
Ph
Ph
a
1
Determined by H NMR analysis of the crude reaction mixture. b Isolated yields.
6 mL of anhydrous CH2Cl2 was added dropwise, over a
period of 1 h, ZnEt2 (1.7 mL of a 1 M soln in hexane,
3 equiv.). The reaction was then quenched with 10%
HCl and made basic with 10% NaOH. The mixture was
filtered through a sintered glass funnel and the aqueous
layer was extracted three times with Et2O. The com-
bined organic layers were dried over Na2SO4, filtered,
and concentrated under reduced pressure. The crude
material was purified by column chromatography over
silica gel (hexane/AcOEt, 8/2).
Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 39, 8621–
8624.
3. (a) Knochel, P.; Rozema, M. J.; Tucker, C. E.; Rether-
ford, C.; Furlong, M.; AchyuthaRao, S. Pure Appl.
Chem. 1992, 64, 361–369; (b) Knochel, P.; Singer, R. D.
Chem. Rev. 1993, 93, 2117–2188; (c) For a recent exam-
ple, see: Kabir, S. M. H.; Hasegawa, M.; Kuwatani, Y.;
Yoshida, M.; Matsuyama, H.; Iyoda, M. J. Chem. Soc.,
Perkin Trans. 1 2001, 159–165.
4. Barton, D. H. R.; Doris, E. Tetrahedron Lett. 1996, 37,
3295–3298.
5. (a) Normant, J. F. Synthesis 1972, 63–80; (b) See also:
Houben-Weyl, Methoden der Organischen Chemie, Metal-
lorganische Verbindungen, Band 13/1; Mu¨ller, E., Ed.,
Thieme: Stuttgart, 1970.
References
1. (a) O’Brien, P. In Comprehensive Organometallic Chem-
istry II, Vol. 3, Wardell, J. L., Ed.; Pergamon, 1995;
Chapter 4; (b) For a recent example, see: Alexakis, A.;
Benhaim, C. Tetrahedron: Asymmetry 2001, 12, 1151–
1157.
2. (a) Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991,
56, 6974–6981; (b) Charette, A. B.; Lemay, J. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1090–1092; (c) Yang, Z.;
6. For mechanistic considerations in other CuII/metal sys-
tems, see: (a) Arnauld, T.; Barton, D. H. R; Doris, E.
Tetrahedron 1997, 53, 4137–4144; (b) Evans, D. A.;
Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937–2940; (c) Lam, P. Y. S.; Clark, C. G.; Saubern, S.;
Adams, J.; Averill, K. M.; Chan, D. M. T.; Combs, A.
Synlett 2000, 674–676.