A mild and clean method for oxidative formation of amides from aldehydes and amines

Article abstract of DOI:10.1055/s-2008-1078218

A metal-free direct oxidative formation of amides from aldehydes and amines using a hypervalent iodine(III) reagent or an ion-supported hypervalent iodine(III) reagent as a recyclable oxidant under mild conditions is reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078218

LETTER
2529
A Mild and Clean Method for Oxidative Formation of Amides from Aldehydes
and Amines
CleanMethod
fo
h
O
xidative
F
e
ormationo
n
f
A
mides from
Ald
F
e
hydes andA
a
mines ng, Weixing Qian,* Weiliang Bao*
Department of Chemistry, Zhejiang University, Xi Xi Campus, Hangzhou, Zhejiang 310028, P. R. of China
Fax +86(571)88273814; E-mail: wlbao@css.zju.edu.cn
Received 16 April 2008
oxyiodo)benzene (DIB) is a popular one and has been ex-
Abstract: A metal-free direct oxidative formation of amides from
aldehydes and amines using a hypervalent iodine(III) reagent or an
ion-supported hypervalent iodine(III) reagent as a recyclable oxi-
dant under mild conditions is reported.
tensively studied.11 We have also been engaged in the
research of the applications of DIB, although our main in-
terest is the application of ion-supported hypervalent io-
dine compounds.12 In our previous work, ion-supported
hypervalent iodine compounds could efficiently oxidize
Key words: (diacetoxyiodo)benzene, ion-supported hypervalent
iodine(III) reagent, direct oxidative formation of amides, amines,
aldehydes
12
13
alcohols and thioethers. We found in the literature that
DIB was a favorable oxidant for the formation of the C–N
14
bond. We also noticed that the primary amines were not
easily oxidized by DIB.15 Herein we were prompted to
study the possibility of the direct oxidative formation of
amides from aldehydes and amines oxidized by hyperva-
lent DIB and its ion-supported analogue. Coincidently,
Chan and co-workers investigated oxidative sulfamida-
tion of aldehydes by using hypervalent iodine compounds
as oxidants and rhodium(II) as catalyst.16
The amide group is a ‘bio’ functionality in view of its
unique role in the peptides and is also a very important
motif in pharmaceuticals, agricultural chemicals and nat-
1
ural products. The treatment of activated derivatives of
acids such as acyl halides, acid anhydrides or activated es-
ters with ammonia or amines is the main route to obtain
2
the primary, secondary and tertiary amides. However,
such activated carboxylic acid derivatives are usually un-
stable. Other preparative methods of amides such as Rit-
Table 1 Optimization of the Oxidative Amidation of Aldehydes
with Amine in Different Solventsa
3
4
ter reaction, solid-phase synthesis, tin-radical-catalyzed
5
O
O
synthesis of a-methylene amides, hydrative amide syn-
DIB
6
thesis with terminal alkyne and azide, and formation of
H + H N
N
2
solvent, r.t.
H
amides from corresponding unactivated esters and
Cl
Cl
7
lactones were also reported. These routes are problematic
1
b
2b
3
b
because of the limited or inconvenient procedures or poor
atom economy. Direct oxidative formation of amides Entry
Solvent
Time (h)
Yield (%)b
from aldehydes and amines was reported, but this method
1
THF–H O (1:1)
36
36
36
36
36
20
15
17
24
38
42
40
2
used expensive transition metal catalysts and exhibited
8
poor substrate scope. Recently Li and co-workers devel-
2
3
4
5
MeCN
DCE
oped a direct oxidative strategy by using tert-butyl hydro-
9
peroxide (TBHP) as an oxidant; however there are still
some limitations. The amines must be converted to hydro-
chlorides to avoid oxidation and then liberated in situ by
neutralization with inorganic base, and metal-containing
CH Cl
2
2
CHCl3
catalyst, CuI–AgIO , was required. From both industrial
6
CHCl3
3
and green chemistry points of view, the exploitation of ef-
ficient and environmentally benign methods for this trans-
formation under mild reaction conditions is still
demanded.
a
Reaction conditions: 4-chlorobenzaldehyde (1.0 equiv), propan-1-
amine (1.0 equiv), DIB (1.1 equiv), solvent (1 mL).
b
Isolated yields based on 4-chlorobenzaldehyde.
Recently, the impressive development of hypervalent io-
dine chemistry is prevalent. However, investigations on
the reactivities of hypervalent iodine compounds and their
efficient use as metal-free reagents in organic synthesis is
Initially, DIB was utilized as the oxidant at room temper-
ature. A brief optimization on the solvent effects revealed
that the CHCl and CH Cl were good solvents. When
3
2
2
CHCl was used as the solvent, the reaction time could be
1
0
3
still undergoing investigations. Among them, (diacet-
reduced to 20 hours (Table 1). Traditionally, a metal cat-
alyst was required in the oxidative amidation reaction. In
our study, however, we observed the formation of 3b in
moderate yield without any metal catalyst when one
equivalent of amine and one equivalent of DIB were used
SYNLETT 2008, No. 16, pp 2529–2531
x
x
.x
x
.2
0
0
8
Advanced online publication: 22.08.2008
DOI: 10.1055/s-2008-1078218; Art ID: W06108ST
©
Georg Thieme Verlag Stuttgart · New York

2
530
C. Fang et al.
LETTER
Table 2 Oxidative Amidation of Aldehydes with Amine by DIBa
O
O
DIB
+
R'NH2
R'
R
H
solvent, r.t.
R
N
H
1a–l
2a,b
3a–n
Entry
Aldehyde
1a
R
Amine
2a
R¢
Time (h)
20
Product
3a
Yield (%)b
1
2
3
4
5
6
7
8
9
Ph
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
Bn
50
68
70
75
46
53
60
49
50
83
85
58
55
1b
4-ClC H
2a
20
3b
3c
6
4
1c
4-BrC H
2a
20
6
4
1d
4-IC H
2a
20
3d
3e
6
4
1e
2-ClC H
2a
20
6
4
1f
a-naphthalene
2a
20
3f
1g
4-MeC H
2a
20
3g
6
4
1h
4-MeOC H
2a
20
3h
3i
6
4
1i
3,4,5-(MeO) C H
2a
20
3
6
4
1
1
1
1
0
1
2
3
1j
3-O NC H
2a
36
3j
2
6
4
4
4
4
1k
4-O NC H
2a
36
3k
3l
2
6
1j
3-O NC H
2b
2b
36
2
6
1k
4-O NC H
Bn
36
3m
2
6
a
Reaction conditions: benzaldehyde (1.0 equiv), amine (1.3 equiv), DIB (1.5 equiv), solvent(1 mL).17
Isolated yields based on benzaldehyde.
b
+
–
(
entry 5). A copper catalyst such as CuI or CuBr was em- As ion-supported hypervalent DIB ([dibmim] [BF ] )
4
ployed in the comparing reactions, but it did not show any possesses the advantage of easy recovery and reuse, we
catalytic activity.
studied the effect of 1-(4-diacetoxyiodobenzyl)-3-meth-
+
–
ylimidazolium tetrafluoroborate ([dibmim] [BF ] ) in the
4
In order to increase the yield, we slowly added the DIB
into the mixture of aldehyde and amine, but the method
did not work. Through observation, we suggested that the
amine played an important role in determining the yield.
The following two cases would affect the yields. One was
that the amine at relatively high concentration was oxi-
dized by DIB more readily. The other was that it con-
densed with aldehyde to form a Schiff base if the
substrates were mixed at once. Therefore, the amine was
slowly added into the reaction mixture in the presence of
two drops of water in order to reduce the Schiff base for-
mation. The molar ratio of aldehyde, amine and DIB was
direct oxidative amidation reaction. Because [dib-
+
–
mim] [BF ] was nearly insoluble in CHCl , a solvent
4
3
mixture of CHCl and MeCN (1:1) was used instead. The
3
+
–
yields of the reaction in the presence of [dibmim] [BF ]
4
were slightly lower than those from using DIB under the
same reaction (Table 3). Notably, this oxidant showed its
unique recyclable feature. By evaporating the reaction
solvents and adding diethyl ether which was almost im-
+
–
miscible with [dibmim] [BF ] , the products could be di-
4
rectly extracted from the reaction mixture and the oxidant
could be easily recovered and recycled.18
changed to 1.0:1.3:1.5. Indeed, the yield was significantly With regard to the reaction mechanism, one possible path-
improved. Using these optimized conditions, we explored way, as proposed by Wang and co-worker, would involve
the scope of the oxidative amidation reaction of aldehydes an oxidation of the imine to an oxaziridine, which would
1
a–k with amines 2a,b (Table 2). In terms of product in turn result in the cleavage of the N–O bond to form the
yields, the presence of electron-withdrawing groups in the target amide.19 We then tried to oxidize (4-chloroben-
aromatic aldehyde was favorable for the formation of zylidene)propanimine by DIB, and 35% of the desired
amides (Table 2, entries 2–4, 10, and 11), while electron- amide was formed after 20 hours. The other possible path-
donating groups made nearly no difference to the forma- way would be that nucleophilic addition of the amine to
tion of amides (entries 7–9). Reaction between sterically aldehyde would generate a carbinolamine intermediate,
hindered aldehyde 1e and amine 2a resulted in a lower which would get oxidized into the desired amide products
yield (Table 2, entry 5). When aliphatic aldehydes and by the hypervalent iodine(III) reagent or ion-supported
amines were mixed together, several products could be hypervalent iodine(III) reagent.
identified by TLC.
Synlett 2008, No. 16, 2529–2531 © Thieme Stuttgart · New York

LETTER
Clean Method for Oxidative Formation of Amides from Aldehydes and Amines
2531
Table 3 Oxidative Amidation of Aldehydes with Amine by [dib-
(7) (a) Trost, B. M.; Fleming, I. Comprehensive Organic
Synthesis, Vol. 6; Winterfeld, E., Ed.; Pergamon: Oxford,
+
–
mim] [BF ]
4
1
1
991. (b) Sheeham, J. C.; Hess, G. P. J. Am. Chem. Soc.
955, 77, 1067. (c) Lawrence, R. M.; Biller, S. A.;
O
O
+
–
[
dibmim] [BF4]
+
Fryszman, O. M.; Poss, M. A. Synthesis 1997, 553.
(8) (a) Tamaru, Y.; Yamada, Y.; Yoshida, Z. Synthesis 1983,
H2N
R
N
R
H
H
solvent, r.t.
4
(
2
74. (b) Naota, T.; Murahashi, S. Synlett 1991, 693.
c) Tillack, A.; Rudloff, I.; Beller, M. Eur. J. Org. Chem.
001, 523.
3
b–d,j,k
1b–d,j,k
2a
N
N
+
–
[
dibmim] [BF4] = Me
I(OAc)2
(9) Yoo, W.-J.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 13064.
(10) (a) Wirth, T. Angew. Chem. Int. Ed. 2005, 44, 3656.
BF4–
(
2
b) Richardson, R. D.; Wirth, T. Angew. Chem. Int. Ed.
006, 45, 4402.
11) (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2002, 102,
Entrya
R
Time (h)
20
Product
3b
Yield (%)b
(
1
2
3
4
4-ClC H4
62
65
65
70
72
6
2
1
523. (b) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96,
123.
4-BrC H4
20
20
36
36
3c
6
(
(
12) Qian, W. X.; Jin, E. L.; Bao, W. L.; Zhang, Y. M. Angew.
Chem. Int. Ed. 2005, 44, 952.
13) Qian, W. X.; Pei, L. Synlett 2006, 709.
4-IC H4
3d
6
3-NO C H
3j
2
6
4
4
(14) (a) Cui, Y.; He, C. Angew. Chem. Int. Ed. 2004, 43, 4210.
b) Davies, H. M. L.; Long, M. S. Angew. Chem. Int. Ed.
005, 44, 3518. (c) Espino, C. G.; Wehn, P. M.; Chow, J.;
(
5
4-NO C H
3k
2
6
2
a
Du Bois, J. J. Am. Chem. Soc. 2001, 123, 6935.
Reaction conditions: benzaldehyde (1.0 equiv), amine (1.3 equiv),
+
–
(d) Fleming, J. J.; Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc.
2003, 125, 2028. (e) Liang, J.-L.; Yuan, S.-X.; Huang, J.-S.;
Yu, W.-Y.; Che, C.-M. Angew. Chem. Int. Ed. 2002, 41,
[
dibmim] [BF ] (2.0 equiv), solvent (1 mL).
Isolated yields based on benzaldehyde.
4
b
3
465.
In summary, we have developed a mild and efficient oxi-
dant for the formation of amides from aldehydes and
amines. The easy availability of the starting materials, the
simplicity and the high efficiency of the reaction proce-
dure, the recoverable and recyclable properties of the ox-
idants, as well as the mild reaction conditions should
render this protocol attractive to synthetic chemists.
(
15) Zhang, L.; Kauffman, G. S.; Pesti, J. A.; Yin, J. J. Org.
Chem. 1997, 62, 6918.
(16) Chan, J.; Baucom, K. D.; Murry, J. A. J. Am. Chem. Soc.
2007, 129, 14106.
(
17) All reagents and solvents were pure analytical grade
materials purchased from commercial sources and were used
without further purification, if not stated otherwise. All
melting points are uncorrected. The NMR spectra were
recorded in CDCl on a Bruker Avance 400 MHz instrument
3
with TMS as internal standard. TLC was carried out with 0.2
mm thick silica gel plates (GF254). The columns were hand
packed with silica gel 60 (200–300 mm). All products were
confirmed by H NMR and C NMR. Unknown compounds
were additionally confirmed by elemental analysis.
Typical Procedure for the Oxidative Amidation of
Aldehydes with Amines by DIB: A solution of aldehyde
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
1
13
Acknowledgment
This work was financially supported by the Natural Science Foun-
dation of China (No. 20572095).
(0.50 mmol, 1.0 equiv), DIB (0.75 mmol, 1.5 equiv), and
two drops of H O in CHCl (1 mL) was cooled to 0 °C under
2
3
an inert atmosphere (N ) and the amine (0.65 mmol, 1.3
2
equiv) was slowly added (about one drop in 1 h for 3 h). The
reaction vessel was capped and the reaction mixture was
stirred for 3 h at 0 °C and then for 17 h at r.t. The crude
reaction mixture was purified by column chromatography on
silica gel (EtOAc–hexane, 1:4).
References and Notes
(
(
(
1) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
243.
2) Katritzky, A. R.; He, H.-Y.; Suzuki, K. J. Org. Chem. 2000,
5, 8210.
3) (a) Mukhopadhyay, M.; Reddy, M. M.; Maikap, G. G.;
Iqbal, J. J. Org. Chem. 1995, 60, 2670. (b) Callens, E.;
Burtonb, A. J.; Barretta, A. G. M. Tetrahedron Lett. 2006,
2
6
3,4,5-Trimethoxy-N-propylbenzamide (Table 2, entry 9):
1
white solid; mp 108 °C. H NMR (400 MHz, CDCl ): d =
3
7.00 (s, 2 H), 6.25 (br, 1 H), 3.89 (s, 6 H), 3.87 (s, 3 H), 3.40
(q, J = 6.8 Hz, 2 H), 1.60–1.69 (m, 2 H), 0.98 (t, J = 8.0 Hz,
1
3
4
7, 8699.
4) (a) Liley, M. J.; Johnson, T.; Gibson, S. E. J. Org. Chem.
006, 71, 1322. (b) Perreux, L.; Loupy, A.; Volation, F.
3 H). C NMR (100 MHz, CDCl ): d = 167.3, 153.1, 140.7,
3
(
130.3, 104.3, 60.8, 56.2, 41.8, 22.9, 11.4. Anal. Calcd for
C H NO : C, 61.64; H, 7.56; N, 5.53; O, 25.27. Found: C,
2
1
3
19
4
Tetrahedron 2002, 58, 2155.
61.60; H, 7.65; N, 5.60.
(18) The ionic liquid [dibmim] [BF ] was recovered and
+
–
(
5) Uenoyama, Y.; Fukuyama, T.; Nobuta, O.; Matsubara, H.;
Ryu, I. Angew. Chem. Int. Ed. 2005, 44, 1075.
6) (a) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem.
Soc. 2005, 127, 16046. (b) Whiting, M.; Fokin, V. V.
Angew. Chem. Int. Ed. 2006, 45, 3157.
4
recycled in our previous work. Please refer to ref. 12.
(19) Gao, J.; Wang, G.-W. J. Org. Chem. 2008, 73, 2955.
(
Synlett 2008, No. 16, 2529–2531 © Thieme Stuttgart · New York