yield (entry 7). Moreover, catalyst loading could be reduced
to 2 mol % without diminishing the yield (entry 8).
Therefore, all follow-up experiments were performed with
2 mol % catalyst loading. We also tested whether benzyl-
amine can be added at the beginning of this one-pot two-
step process; however, reaction did not work (entry 9).
Somehow the amine in the presence of HFIP interferes
with the oxidation process. It is therefore obvious that
attempted use of catalytic amounts of HFIP (20 mol %)
in the presence of benzylamine did not deliver the desired
amide (entry 10).
We were very surprised to learn that HFIP esters have so
far not been used as active esters in intermolecular amide
bond formations.14 It is important to note that for HFIP active
esters, the side product formed during amide bond formation
is HFIP, which is readily removed by simple evaporation.
In particular for industrial scale synthesis this might be a
big advantage over other commonly used active esters where
the side product formed during amidation must often be
removed by more sophisticated separation processes. More-
over, the organic oxidant 5 used is readily available and its
reduction product o,o′-di-tert-butyl-p-bisphenol can readily
be isolated and reoxidized in near quantitative yield to 5 by
using dioxygen.15 Hence O2 can formally be considered as
the terminal oxidant in these reactions. Moreover, 5 is readily
prepared by treatment of cheap o,o′-di-tert-butylphenol
(Aldrich $29.1 (U.S.)/500 g) with O2.11
Table 2. Oxidative Amidation: Variation of Aldehyde and
Amine Moiety under Optimized Conditions
compd yield
no.
entry
R1
R2
[%]
1
C6H5CHdCH
C6H5CHdCH
C6H5CHdCH
C6H5CHdCH
C6H5CHdCH
C6H5CHdCH
C6H5
CH3CH2CH2
(CH3)2CH
C6H11
CH2dCHCH2
C2H5OC(O)CH2
CH3OC(O)CH(CH3)
C6H5CH2
7b
7c
7d
7e
7f
7g
7h
7i
93
78
86
90
93
81
92
81
92
89
90
91
81
2a
3a
4
5b c
,
6a b c
7d
8
,
,
4-NO2C6H4
C6H5CH2
9
4-MeOC(O)C6H4 C6H5CH2
7j
10
11
12
4-CF3C6H4
3-ClC6H4
2-thienyl
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
7k
7l
7m
13b d 2-CH3C6H4
7n
,
a Amidation for 12 h. b Amidation at 65 °C. c 1.5 equiv of amine was
used. d Oxidation for 8 h.
were acylated in good yields (f 7f,g,p, 78-93%, see
Scheme 3). In these cases amidation were conducted with
1.5 equiv of amines at higher temperature (entries 5 and
6). Under the optimal amidation conditions no racemiza-
tion occurred, as for 7g an er > 99:1 was measured by
chiral HPLC. The aldehyde component could also be
varied as shown for amidation of benzaldehyde, p-
nitrobenzaldehyde, 4-CH3OC(O)C6H4, and p-(trifluoro-
methyl)benzaldehyde with benzylamine (f 7h-k, 81-92%,
entries 7-10). m-Chlorobenzaldehyde and 2-thiophen-
ecarbaldehyde also underwent clean oxidative amidation
under the same conditions (f 7l,m, 81-91%, entries 11
and 12). For o-tolylaldehyde a good yield of the amide
was achieved by applying higher temperature for the
amidation (f 7n, 81%, entry 13).
To study the scope of our method different amines were
tested in the one-pot amidation of different aldehydes under
optimized conditions by using 2 mol % catalyst loading
(Scheme 3, Table 2). Reactions worked well with propyl and
Scheme 3
.
Oxidative Amidation of Various Aldehydes Wih
Different Amines
As another method for oxidative C-N bond formation of
the aldehyde carbonyl C atom, we tested azides as nucleo-
philes to directly convert aldehydes under oxidative condi-
tions to acyl azides16 which are highly useful intermediates
for the preparation of a large number of materials in organic
chemistry. Acyl azides undergo thermal Curtius rearrange-
(13) Review: Be´gue´, J.-P.; Bonnet-Delpon, D.; Crousse, B. Synlett 2004,
18. HFIP as a solvent for epoxide opening: (a) Das, U.; Crousse, B.;
Kesavan, V.; Bonnet-Delpon, D.; Be´gue´, J.-P. J. Org. Chem. 2000, 65, 6749.
(b) Yagi, H.; Jerina, D. M. J. Org. Chem. 2007, 72, 6037. HFIP in
epoxidations: Berkessel, A.; Adrio, J. A. AdV. Synth. Catal. 2004, 346, 275.
(14) For HFIP-esters in transesterifications and lactamizations, see:
Sarkar, S. M.; Wanzala, E. N.; Shibahara, S.; Takahashi, K.; Ishihara, J.;
Hatakeyama, S. Chem. Commun. 2009, 39, 5907 and Nakano, A.; Takahashi,
K.; Ishihara, J.; Hatakeyama, S. Org. Lett. 2006, 8, 5357.
(15) (a) Bukharov, S. V.; Fazlieva, L. K.; Mukmeneva, N. A.; Akhm-
adullin, R. M.; Morozov, V. I. Russ. J. Gen. Chem. 2002, 72, 1805. (b)
Rathore, R.; Bosch, E.; Kochi, J. K. Tetrahedron Lett. 1994, 35, 1335.
(16) For NHC catalyzed oxidative azidation of aldehydes, see: Vora,
H. U.; Moncecchi, J. R.; Epstein, O.; Rovis, T. J. Org. Chem. 2008, 73,
9727. For azidation of aldehydes with external oxidants, see: (a) Lee, J. G.;
Kwak, K. H. Tetrahedron Lett. 1992, 33, 3165. (b) Chen, D. J.; Chen, Z. C.
Tetrahedron Lett. 2000, 41, 7361. (c) Elmorsy, S. S. Tetrahedron Lett. 1995,
36, 1341. (d) Bose, S. D.; Reddy, A. V. N. Tetrahedron Lett. 2003, 44,
3543.
allyl amine to give 7b and 7e in 93% and 90% yield,
respectively (entries 1 and 4). For the sterically more
hindered isopropyl and cyclohexyl amine amidation was
slower and reaction time was extended to 12 h (f 7c,d,
entries 2 and 3). The same conditions were optimal for
acylation of pyrrolidine (f 7o, 92%, Scheme 2). Amino acid
esters such as H-Gly-OEt, H-Ala-OMe, and H-Pro-OMe
1994
Org. Lett., Vol. 12, No. 9, 2010