obtained by simply adding one or two equiv. of the carbene
precursor. To our knowledge, all these results improve any
other value reported in the literature for this transformation, due
to the following reasons: (i) the reactions were carried out at
4,5,14
room temperature whereas other copper catalysts
as well as
usually required heating of the reaction mixture;
ii) an equimolar mixture of the amine and EDA has been
6,7
Rh
2
(OAc)
4
(5)
(
employed, therefore avoiding the excess of amine commonly
needed by other catalysts and (iii) the general quantitative yields
observed for primary and secondary, aliphatic or aromatic
amines finds no precedent either with copper- or rhodium-based
catalysts.
This exceptional catalytic activity has also been extended to
other diazo reagents. Thus, the use of ethyl diazopropionate
obtained in high yield (80%) as the result of the selective
insertion of the diazo group in one of the terminal amidic
nitrogen–hydrogen bonds.
X
In conclusion, the Tp Cu complexes promote the insertion of
diazo compounds into amine or amide N–H bonds in very high
yield and under very mild conditions. This heralds the
rediscovery of copper as a real alternative to rhodium-based
catalysts for this transformation.
We thank the MCYT for financial support (PB98-0958) and
the Universidad de Huelva for the Servicio de Resonancia
Magnética Nuclear. M. E. M. also thanks the MCYT for a
research studentship.
(
MEDA) or ethyl 2-phenyldiazoacetate (PhEDA) has allowed
the formation, with the intermediacy of Tp*Cu as the catalyst,
of alanine and phenylglycine derivatives (Scheme 1). The
reaction of equimolar amounts of morpholine and
CH
produced the corresponding insertion product in quantitative
yield. Similar results have been obtained with PhC(N )CO Et
80% yield), thus affording the phenylglycine derivative. This
3 2 2
C(N )CO Et in the presence of Tp*Cu (5% molar ratio)
2
2
Notes and references
(
procedure provides a route for the synthesis of amino acid
derivatives under very mild conditions and with no need for
excess of amine.
† General experimental procedure: the catalysts were prepared as in refs.
X
11c and 12b. A solution of the Tp Cu complex (0.05 mmol) in
1
,2-dichloroethane and pyrrolidine (2.5 mmol) was prepared under
nitrogen. The diazo compound (2.5 mmol of EDA) was added in one portion
and the mixture stirred until no diazo was detected by GC. Only in the case
of the primary amines, diphenylamine and amides a syringe pump was
employed to add the EDA for 1 h. Yields were determined after EDA
1
consumption by GC and also by H NMR.
1
M. P. Doyle, M. Anthony McKervey and Tao Ye, Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds, John Wiley &
Sons, New York, 1998.
2
(a) A. J. Hubert, A. F. Noels, A. J. Anciaux and P. H. Teyssie, Synthesis,
1
976, 600; (b) N. Petiniot, A. J. Anciaux, A. F. Noels, A. J. Hubert and
Scheme 1 Syntheses of Ala and Phg derivatives.
P. H. Teyssie, Tetrahedron Lett., 1978, 14, 1239; (c) A. Demonceau, A.
F. Noels, A. J. Hubert and P. H. Teyssie, J. Chem. Soc., Chem.
Commun., 1981, 688; (d) A. J. Anciaux, A. Demonceau, A. F. Noels, A.
J. Hubert, R. Warin and P. H. Teyssie, J. Org. Chem., 1981, 46, 873.
3 P. Yates, J. Am. Chem. Soc., 1952, 74, 5376.
4 T. Saegusa, Y. Ito, S. Kobayashi, K. Hirota and T. Shimizu,
Tetrahedron Lett., 1966, 6131.
As mentioned above, Moody et al. have recently applied the
insertion of diazocompounds into amide N–H bonds to generate
dipeptides, leading to an unprecedented route to this type of
9
compounds. In order to check the potential of our copper
system towards amide functionalisation, we have carried out a
competition experiment with equimolar amounts of pyrrolidine
and trimethylacetamide [eqn. (3)] in the presence of Tp*Cu
5
6
J.-F. Nicoud and H. B. Kagan, Tetrahedron Lett., 1971, 2065.
R. Paulissen, E. Hayez, A. J. Hubert and P. Teyssie, Tetrahedron Lett.,
1
974, 607.
7
(a) M. C. Bagley, K. E. Bashford, C. L. Hesketh and C. J. Moody, J. Am.
Chem. Soc., 2000, 122, 3301; (b) M. Hrysatsak and T. Durst,
Heterocycles, 1987, 26, 2393; (c) T. Kametani, N. Kanaya, T.
Mochizuki and T. Honda, Heterocycles, 1982, 19, 1023; (d) G. Brooks,
T. T. Howarth and E. Hunt, J. Chem. Soc., Chem. Commun., 1981, 642;
(e) L. Cama and B. G. Christensen, Tetrahedron Lett., 1978, 4233.
(a) E. Aller, R. T. Buck, M. J. Drysdale, L. Ferris, D. Haigh, C. J.
Moody, N. D. Pearson and J. B. Sanghera, J. Chem. Soc., Perkin Trans.
(3)
(
1+20+50 ratio for [Cu]+[EDA]+[amine + amide], 0.05 mmol of
8
9
Tp*Cu, 1+1 amine+amide). After completion, NMR studies
revealed the existence of more than 95% (EDA-based) of the
amine-derivative, with only traces of the amide derivative being
detected. Since these transformations seem to occur through the
intermediacy of electrophilic metallocarbene species, this result
is in good agreement with the order of acidity of these N–H
bonds (amidic N–H > aminic N–H), therefore favoring the
more basic substrate. In the absence of amine, it was possible to
activate the N–H bonds of the trimethylacetamide. When
reacting this substrate with EDA under equimolar conditions,†
the insertion product was observed in 85% yield (diethyl
maleate and fumarate accounted for 100% of EDA) (eqn.
1
, 1996, 2879; (b) L. Ferris, D. Haigh and C. J. Moody, J. Chem. Soc.,
Perkin Trans. 1, 1996, 2885.
(a) C- J. Moody, L. Ferris, D. Haigh and E. Swann, Chem. Commun.,
1997, 2391; (b) R. T. Buck, P. A. Clarke, D. M. Coe, M. J. Drysdale, L.
Ferris, D. Haigh, C. J. Moody, N. D. Pearson and E. Swann, Chem. Eur.
J., 2000, 6, 2160; (c) M. C. Bagley, R. T. Buck, S. L. Hind and C. J.
Moody, J. Chem. Soc., Perkin Trans. 1, 1998, 591.
1
1
0 S. Trofimenko, Scorpionates, The Coordination Chemistry of Poly-
pyrazolylborate Ligands, Imperial College Press, London, 1999.
1 (a) P. J. Pérez, M. Brookhart and J. L. Templeton, Organometallics,
1993, 12, 261; (b) M. M. Díaz-Requejo, P. J. Pérez, M. Brookhart and
J. L. Templeton, Organometallics, 1997, 16, 4399; (c) M. M. Díaz-
Requejo, T. R. Belderrain, S. Trofimenko and P. J. Pérez, J. Am. Chem.
Soc., 2001, 123, 3167; (d) M. M. Díaz-Requejo, A. Caballero, T. R.
Belderrain, M. C. Nicasio, S. Trofimenko and P. J. Pérez, J. Am. Chem.
Soc., 2002, 124, 978.
(4)].
(4)
1
2 (a) M. M. Díaz-Requejo, T. R. Belderrain and P. J. Pérez, Chem.
Commun., 2000, 1853; (b) M. M. Díaz-Requejo, M. A. Mairena, T. R
Belderrain, M. C. Nicasio, S. Trofimenko and P. J. Pérez, Chem.
Commun., 2001, 1804.
In addition to plain amides, amino amides have also been
tested. Following Moody’s work, we have carried out the
reaction of an equimolar mixture of Z-gly-NH (Z = benzoy-
loxocarboxy protecting group) with the bulkier ethyl 2-phenyl-
diazoacetate [eqn. (5)]. in the presence of catalytic amounts of
Tp*Cu. The Z-gly-Phg-OEt dipeptide derivative has been
2
1
3 M. M. Díaz-Requejo, T. R. Belderrain, M. C. Nicasio, S. Trofimenko
and P. J. Pérez, J. Am. Chem. Soc., 2002, 124, 896.
14 G. S. Singh, S. B. Singh and K. N. Mehrotra, Bull. Chem. Soc. Jpn.,
1984, 57, 1667.
CHEM. COMMUN., 2002, 2998–2999
2999