Pd-Catalyzed Oxidation of Aldimines to Amides

Article abstract of DOI:10.1055/s-0037-1610653

Methods for the synthesis of amides via the direct oxidation of imines are rarely reported. Here we report an efficient method for Pd-catalyzed oxidation of imines to amide derivatives by the use of cheap aqueous tert -butyl hydroperoxide as an oxidant through a Wacker-type reaction. This method is practically convenient and displays high functional group tolerance, allowing a variety of imines to transform into the corresponding amide derivatives in moderate to good yields.

Full text of DOI:10.1055/s-0037-1610653

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
Synlett
S. Gao et al.
Letter
Pd-Catalyzed Oxidation of Aldimines to Amides
Shanshan Gao
Yaorui Ma
R2
O
Pd(OAc)2, TBHP
R2
Weidong Chen
Junfei Luo*
N
N
H
2
1 examples
up to 85% yield
R1
R1
School of Materials Science and Chemical Engineering,
Ningbo University, 315211 Ningbo, P. R. of China
luojunfei@nbu.edu.cn
1
R
R
= Br, Cl, F, Me, NO2
2
= CF3, NO2, COMe, Br, Cl, F, Me, t-Bu, OCF3, OMe
Received: 19.06.2018
Accepted after revision: 17.07.2018
Published online: 21.08.2018
pathway proceeding through a hemiaminal intermediate
Scheme 1, a). For example, Song, Yang and co-workers have
(
DOI: 10.1055/s-0037-1610653; Art ID: st-2018-b0383-l
reported a copper-catalyzed amidation of aldehydes with
primary amines in which they propose hemiaminal forma-
tion, rather than imine formation. This hypothesis was
Abstract Methods for the synthesis of amides via the direct oxidation
of imines are rarely reported. Here we report an efficient method for
Pd-catalyzed oxidation of imines to amide derivatives by the use of
cheap aqueous tert-butyl hydroperoxide as an oxidant through a
Wacker-type reaction. This method is practically convenient and dis-
plays high functional group tolerance, allowing a variety of imines to
transform into the corresponding amide derivatives in moderate to
good yields.
8a
based on the fact that imine reagents displayed poor reac-
tivity under the standard reaction conditions. Indeed, the
imines formation is irreversible in the oxidative amidation
9
of aldehydes or alcohols. The formation of hemiaminal was
also suggested in the transition-metal-free procedures for
8f
TBHP-mediated oxidative amidation of aldehyde. Thus,
reports that describe the oxidative amination of imines
remains scarce. Imines are easy to access synthetic building
blocks, therefore, investigating their reactivity towards oxi-
dative amidation may reveal useful synthetic pathways and
unique reactivities.
Key words Pd-catalyzed, amides, imines, oxidation, tert-butyl hydro-
peroxide
The amide motif is one of the most important architec-
tures in organic chemistry; they represent the building
blocks of peptides and some polymer materials, and are fre-
quently found in natural products and drug molecules.1
Amides are generally synthesized by the coupling of car-
boxylic acids with amines, however, these methods require
the use of coupling agents such as carbodiimides and 1-hy-
a) The synthesis of amides through amidation of aldehydes
Ar2
Ar2
OH
O
Ar2
N
O
HN
Ar1
Ar1
NH2
Ar1
H
Ar1
NHAr2
2
droxybenzotriazoles, or activated carboxylic acid deriva-
undesired product
hemiaminal intermediate
3
tives. Methods that focus on the amination of nonactivated
b) Oxidation of imines to amides by m-CPBA and BF3·OEt2
4
carboxylic acids have also been developed. On the other
Ar1
O
I
Ar2
5
hand, the Schmidt reaction and the Beckmann rearrange-
BF3
Ar1
H
NHAr1
N
N
I
m-CPBA
BF3·OEt2
II
6
O
ment represent classical methods for the preparation of
O
Ar1
H
Ar
H
II
amides. More recently, transition-metal-mediated pro-
cedures have allowed for the preparation of amides from a
variety of reagents.7
A range of transition-metal-catalyzed and transition-
metal-free procedures for the oxidative amination of
1
2
NAr Ar
c) Cyanide-mediated oxidation of imines to amides
H
O
NaCN
Ar2
Ar2
Ar1
N
Ar1
N
[O]
H
8
amines with aldehydes have also been reported. In these
d) Our work: Pd-catalyzed oxidation of imines to amides by TBHP
cases it is possible that the reaction proceeds though an
imine intermediate, however, investigations so far have
dismissed the formation of imines and instead propose a
H
O
Pd(OAc)2
TBHP
Ar2
Ar2
Ar1
N
Ar1
N
H
Scheme 1 Strategies for oxidation of imines to amides
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
Synlett
S. Gao et al.
Letter
Despite these significant developments of methods for
the synthesis of amides through transition-metal-catalyzed
direct oxidation of imines has yet to be realized. Imines,
often referred to as Schiff bases, are an important class of
synthetic reagents that are easily accessed via substitution
of carbonyl compounds. Rhee and co-workers reported an
efficient method for the synthesis of amides by oxidation of
aldimines in the presence of meta-chloroperoxybenzoic
Table 1 Optimization of Oxidation of Aldimine to Amidea
O
Pd(OAc)2, oxidant
N
N
solvent
H
1a
2a
Entry
Pd(OAc)
2
Oxidant (equiv)
(3.0)b
Oxone (3.0)
(3.0)
Solvent
Yield (%)
10
1
2
3
4
5
6
7
8
9
2
2
H
2
O
2
CH
CH
CH
CH
3
3
3
3
CN
CN
CN
CN
5
NR
NR
20
NR
8
acid (m-CPBA) and BF ·OEt . This procedure performed
3
2
well for the preparation of formamide derivatives, however,
the reaction was very sensitive to the electronics of the aryl
substituents and the preparation of benzamide products
proved more difficult (Scheme 1, b). A selective and more
general procedure has been developed by Cheon and co-
workers who reported a cyanide-mediated aerobic oxida-
2
K
2
S
2
O
8
TBHP (3.0)c
TBHP (3.0)c
2
2
DMSO
2
TBHP (3.0)c
TBHP (3.0)c
TBHP (3.0)c
2
H O
11
2
PhCH
DCE
DCE
DCE
DCE
DCE
DCE
DCE
3
13
25
32
33
85
84
18
NR
tion of imines (Scheme 1, c). However, the use of highly
toxic NaCN limits the application of this methodology.
Other methods for the oxidation of imines to amides by the
2
5
TBHP (3.0)c
use of potassium permanganate1 and sodium chlorite
2
13
TBHP (3.0)c
10
11
12
13
10
5
were also reported. The development of selective, efficient,
and scalable methods for the oxidation of imines to amides
are therefore warranted.
TBHP (6.0)c
TBHP (8.0)c
TBHP (6.0)c
–
5
–
Herein, we provide a new transformation of imines to
amide derivatives through a Pd-catalyzed Wacker-type oxi-
dation using cheap aqueous TBHP as an oxidant (Scheme 1,
d). This protocol is practical, convenient, displays high func-
tional group tolerance, and can be performed under air
without the requirement of any extra additive or ligand. A
variety of substituted aldimines have been examined and
found to be oxidized to the corresponding amides in mod-
erate to good yields.
14
5
a
Yields are of pure isolated products; the reactions were performed by
using 0.2 mmol of 1a, in 1.5 mL of solvent at 120 °C for 5 h.
b
3
0% wt H
2 2
O in water.
c
70% wt of TBHP in water.
With suitable conditions in hand, we then turned our
attention to the scope of the reaction. A variety of function-
al substituents, such as OCF , Me, t-Bu, F, COMe, on the ani-
3
N,1-Diphenylmethanimine (1a) was chosen as a model
line aromatic ring were tested and found to be compatible,
giving place to the corresponding amide products in mod-
erate to good yields (Scheme 2, 2b–f). Halogen substituents,
Cl and Br on aniline ring were also tested, leading to the
corresponding amides 2g and 2h in 65% and 58%, respec-
tively. These provide convenient handles for further func-
tionalizations. Satisfyingly, imine with the strong electron-
donating methoxy group on the aniline ring underwent this
oxidation process smoothly to furnish the amide product 2i
in 51% yield. However, the substrates with a hydroxyl group
provided only the recovered starting material and aldehyde
and aniline by the hydrolysis of imine (Scheme 2, 2j) Sub-
strates with strong electron-withdrawing trifluoromethyl
and nitro groups on the aniline ring gave the corresponding
amides 2k and 2l in 55% and 65% yields, respectively. Imine
with a chlorine atom or a methyl group at the ortho posi-
tion of aniline ring could still underwent oxidation process,
leading to amide product 2m and 2n in 56% and 50% yield,
respectively. The oxidation of N-cyclohexyl-1-phenylmeth-
animine was also tested, and the corresponding amide
product 2o was obtained in a synthetic useful yield. We
were then attempted to oxidize different functional substit-
uents on the aldehyde aromatic ring, and found that the
substrates with F, Cl, Br, Me, and NO2 groups could be
substrate, treated with Pd(OAc) (2 mol%) in the presence of
2
H O (3.0 equiv) in MeCN, heating at 120 °C for 5 h to pro-
2
2
vide the N-phenylbenzamide product (2a) in 5% yield
(
(
Table 1, entry 1). Other oxidants potassium persulfate
K S O ), Oxone, and TBHP were then tested, and TBHP was
2
2
8
found to be the most efficient oxidant, leading to the de-
sired product N-phenylbenzamide (2a) in 20% yield
Table 1, entry 4). Solvent screen showed that DCE was the
most suitable solvent among those tested (Table 1, entries
–8). Different catalyst loadings were also tested and it was
(
5
found that 5 mol% of Pd(OAc) was the most suitable cata-
2
lyst loading (Table 1, entries 9 and 10). Finally, the yield
could be significantly improved by increasing the amount of
TBHP to 6.0 equivalents (Table 1, entry 11). The control re-
action in the absence of Pd(OAc) was also tested and found
2
that 18% of amide product was obtained (Table 1, entry 13).
This is probably due to the decomposition of imine to alde-
hyde and aniline, which could then undergo oxidative ami-
nation of aldehyde process in the presence of TBHP.8f How-
ever, no product was observed when the reaction was per-
formed without TBHP (Table 1, entry 14).
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
Synlett
S. Gao et al.
Letter
oxidized to the corresponding amides in moderate yields
Scheme 2, 2p–t). However, the strong methoxy group sub-
tion (Scheme 3, a). We also ran the reaction under a nitro-
18
(
gen atmosphere employing TBHP with OH , and we saw
2
stituted on the aldehyde ring did not provide the amide 2s,
with only starting material and hydrolyzed products were
obtained. This methodology is easily scalable. 86% isolated
yield of amide product 2a could be obtained by the treat-
ment of 1a (6.0 mmol, 1.09 g) under our standard condi-
tions without any modification.
some incorporation of 18O into the product. This suggests
that this oxygen may originate from water in the reaction.
a)
Ph
Pd(OAc)2 (5 mol%)
anhydrous TBHP (6.0 equiv)
Ph
NH
N
O
Ph
DCE, N , 120 °C, 5 h
2
Ph
1a
2a, trace
O
R1
Pd(OAc)2 (5 mol%)
TBHP, DCE
R1
b)
Ph
N
R2
N
Pd(OAc)2 (5 mol%)
Ph
O
Ph
R2
H
NH
Ph
NH
1
20 °C, 5 h
N
anhydrous TBHP (6.0 equiv)
18OH2 (6.0 equiv)
1
2
18O
Ph
Ph
18O-2a
a: 18O-2a = 9:4
2
a
OCF3
Me
DCE, N2, 120 °C, 5 h
1a
O
O
O
2
N
H
N
H
N
H
Scheme 3 Primary mechanism studies
2
2
2
a, 85% (86%b)
2b, 60%
2c, 52%
On the basis of the above observation, the catalytic cycle
may undergo the coordination of the Pd catalyst with C=N
double bond, which followed by the reaction with water to
form the Pd complex 4. β-Hydride elimination of 4 gives the
amide product, with the concomitant expulsion of Pd spe-
cies 5. Pd(0) species could be generated from 5 by the loss
of acetic acid.14 The catalytic cycle can be completed by the
oxidation of Pd(0) to Pd(II) catalyst in the presence of TBHP
tBu
F
COMe
O
O
O
N
H
N
H
N
H
d, 45%
2e, 75%
2f, 50%
Cl
Br
OMe
O
O
O
N
H
N
H
N
H
(Scheme 4). Alternatively, the formation of the hemiaminal
intermediate through the reaction between H O and imine
g, 65%
2h, 58%
2i, 51%
2
could also be possible. The intermediate would then coordi-
nate to Pd(II) species, which is followed by β-hydride elimi-
nation to give the amide product.1
OH
CF3
O
O
O
2,15
N
H
N
H
N
H
NO2
2k, 55%
2l, 65%
t
BuOH + H O
R1
2
2
j, 0%
2
N
II
R2
LnPd X2
O
O
O
1
tBuOOH + 2HX
N
N
H
N
H
H
LnPd0
X = OAc
R2
Cl
Me
N
X2LnPdII
HX
m, 56%
2n, 50%
2o, 30%
R1
18OH2
3
O
O
O
II
LnPd HX
5
N
H
N
H
N
LnXPdII
R2
H
O18
N
HX
Br
F
Me
H
2q, 66%
2r, 60%
R1
NHR2
H18
R1
2
p, 42%
O
2
4
O
O
O
Scheme 4 Proposed mechanism for Pd-catalyzed oxidation of imines
N
N
N
H
H
H
MeO
Cl
O2N
2
s, 58%
2
t, 58%
2u, trace
To be noted, if this classical Wacker-type mechanism
were in operation then the product should form from the
reaction of the substrate with stoichiometric palladium in
the presence of water. However, when trying this experi-
ment none of the desired product was formed. In addition,
the observation of unlabeled amide product 2a in the reac-
a
Scheme 2 Scope of the oxidation of imines to amides. Reaction
conditions: 1 (0.2 mmol), Pd(OAc) (0.01 mmol), TBHP (70% wt in H O,
.0 equiv) in DCE (1.5 mL), heated at 120 °C for 5 h; Yields are of pure
2
2
6
b
isolated products; 6.0 mmol of 1a was used.
A primary mechanism for this transformation was in-
vestigated. The oxidation reaction was performed under
anhydrous conditions, and only trace of amide product was
obtained, which suggests water is necessary for the reac-
tion in the presence of 18OH indicates that the oxygen may
2
also originate from TBHP (Scheme 3, b). These results may
suggest a more complex mechanism is in operation and
that there are still plenty of other possible mechanisms.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
Synlett
S. Gao et al.
Letter
In conclusion, we report a method for Pd-catalyzed oxi-
dation of aldimines to amides by the use of cheap aqueous
J. Am. Chem. Soc. 2006, 128, 5695. (d) Lin, Y.-S.; Alper, H. Angew.
Chem. Int. Ed. 2001, 40, 779. (e) Uozumi, Y.; Arii, T.; Watanabe,
T. J. Org. Chem. 2001, 66, 5272. (f) Namayakkara, P.; Alper, H.
Chem. Commun. 2003, 2384. (g) Knapton, D.; Meyer, T. Y. Org.
Lett. 2004, 6, 687. (h) Uenoyama, Y.; Fukuyama, T.; Nobuta, O.;
Matsubara, H.; Ryu, I. Angew. Chem. Int. Ed. 2005, 44, 1075.
16
TBHP as an oxidant. This protocol provides an alternative
for the synthesis of amide derivatives from imines through
a Wacker–Tsuji oxidation process. The method is practically
convenient and display high functional group tolerance,
and it enriches the rarely reported methods for the trans-
formation of imines to amides.
(i) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317,
790. (j) Nordstrom, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc.
2008, 130, 17672. (k) Zhang, Y.; Chen, C.; Ghosh, S. C.; Li, Y.;
Hong, S. H. Organometallics 2010, 29, 1374. (l) Muthaiah, S.;
Ghosh, S. C.; Jee, J.-E.; Chen, C.; Zhang, J.; Hong, S. H. J. Org.
Chem. 2010, 75, 3002. (m) Kim, K.; Kang, B.; Hong, S. H. Tetrahe-
dron 2015, 71, 4565. (n) Islam, S. M.; Ghosh, K.; Roy, A. S.; Molla,
R. A. Appl. Organometal. Chem. 2014, 28, 900.
Funding Information
This research is sponsored by research funds of Ningbo University
(No. ZX2016000748) and the K. C. Wong Magna Fund in Ningbo
(8) (a) Ding, Y.; Zhang, X.; Zhang, D.; Chen, Y.; Wu, Z.; Wang, P.;
Xue, W.; Song, B.; Yang, S. Tetrahedron Lett. 2015, 56, 831.
University.
N
n
i
g
b
o
Unvieytrsi
Z(
X
2
0
1
6
0
0
0
7
4
8)
(b) Whittaker, A. M.; Dong, V. M. Angew. Chem. Int. Ed. 2015, 54,
1
312. (c) Mamaghani, M.; Shirini, F.; Sheykhan, M.;
Acknowledgment
Mohsenimehr, M. RSC Adv. 2015, 5, 44524. (d) Lu, S.-Y.; Badsara,
S. S.; Wu, Y.-C.; Reddy, D. M.; Lee, C.-F. Tetrahedron Lett. 2016,
We thank Dr Gregory Perry (Nagoya University) for useful discus-
sions.
57, 633. (e) Wu, Z.; Hull, K. L. Chem. Sci. 2016, 7, 969. (f) Ekoue-
Kovi, K.; Wolf, C. Org. Lett. 2007, 9, 3429.
(9) Zultanski, S. L.; Zhao, J.; Stahl, S. S. J. Am. Chem. Soc. 2016, 138,
6
416.
10) An, G.-i.; Kim, M.; Kim, J. Y.; Rhee, H. Tetrahedron Lett. 2003, 44,
183.
11) Seo, H.-A.; Cho, Y.-H.; Lee, Y.-S.; Cheon, C.-H. J. Org. Chem. 2015,
0, 11993.
Supporting Information
(
(
(
(
2
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610653.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
8
12) Larsen, J.; Jorgensen, K. A.; Christensen, D. J. Chem. Soc., Perkin
Trans. 1 1991, 1187.
13) Mohamed, M. A.; Yamada, K.-i.; Tomioka, K. Tetrahedron Lett.
2009, 50, 3436.
(14) (a) Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, S.; Sabel,
A. Angew. Chem., Int. Ed. Engl. 1962, 1, 80. (b) Clement, W. H.;
Selwitz, C. M. J. Org. Chem. 1964, 29, 241. (c) Tsuji, J. Synthesis
1984, 369. (d) Tsuji, J.; Trost, B. M.; Fleming, I. Comprehensive
References and Notes
(
(
(
1) Greenberg, A. The Amide Linkage: Selected Structural Aspects in
Chemistry, Biochemistry, and Materials Science; Wiley-Inter-
science: New York, 2000.
2) (a) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
2243. (b) Wipf, P. In Handbook of Reagents for Organic Synthesis;
Wiley and Sons: New York, 2005.
Organic Synthesis;7Vo.
l
Pergamon Press: New York, 1991, 449.
3) (a) Teichert, A.; Jantos, K.; Harms, K.; Studer, A. Org. Lett. 2004,
(15) Zhang, L.; Wang, W.; Wang, A.; Cui, Y.; Yang, X.; Huang, Y.; Liu,
X.; Liu, W.; Son, J.; Oji, H.; Zhang, T. Green Chem. 2013, 15, 2680.
(16) Typical Procedure for the Preparation of N-Phenylben-
zamide (2a)
6, 3477. (b) Shendage, D. M.; Froehlich, R.; Haufe, G. Org. Lett.
2004, 6, 3675. (c) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron
2005, 61, 10827. (d) Black, D. A.; Arndtsen, B. A. Org. Lett. 2006,
8, 1991. (e) Katritzky, A. R.; Cai, C.; Singh, S. K. J. Org. Chem.
2006, 71, 3375.
Pd(OAc)
(0.01 mmol), N,1-diphenylmethanimine (1a, 0.2
O, 6.0 equiv, 1.2 mmol), and
2
mmol), TBHP (70 % solution in H
2
(
4) (a) Lanigan, R. M.; Sheppard, T. D. Eur. J. Org. Chem. 2013, 33,
DCE (1.5 mL) were added to a vial. The reaction mixture was
stirred under 120 °C for 5 h. After that time, the reaction
7453. (b) Lundberg, H.; Tinnis, F.; Selander, N.; Adolfsson, H.
Chem. Soc. Rev. 2014, 42, 2714.
5) (a) Schmidt, R. F. Ber. Dtsch. Chem. Ges. 1924, 57, 704. (b) Yao, L.;
Aube, J. J. Am. Chem. Soc. 2007, 129, 2766.
mixture was quenched with saturated Na
sumption of residual TBHP) and extracted with EtOAc. The
organic layer was separated and dried with Na SO . Removal of
2 3
SO solution (con-
(
2
4
(
6) (a) Ramalingan, C.; Park, Y.-T. J. Org. Chem. 2007, 72, 4536.
solvent followed by flash column chromatographic purification
(b) Augustine, J. K.; Kumar, R.; Bombrun, A.; Mandal, A. B. Tetra-
(EtOAc/PE) afforded N-phenylbenzamide (2a) as a white solid
1
hedron Lett. 2011, 52, 1074.
(33.5 mg, yield 85%). H NMR (400 MHz, CDCl
3
): δ = 7.94 (br s, 1
(
7) (a) Martinelli, J. R.; Clark, T. P.; Watson, D. A.; Munday, R. H.;
Buchwald, S. L. Angew. Chem. Int. Ed. 2007, 46, 8460. (b) Chang,
J. W. W.; Chan, P. W. H. Angew. Chem. Int. Ed. 2008, 47, 1138.
H), 7.86 (d, J = 7.3 Hz, 2 H), 7.65 (d, J = 7.9 Hz, 2 H), 7.54 (t, J = 7.3
Hz, 1 H), 7.47 (t, J = 7.4 Hz, 2 H), 7.36 (t, J = 7.8 Hz, 2 H), 7.15 (t,
13
J = 7.4 Hz, 1 H) ppm. C NMR (101 MHz, CDCl
): δ = 165.7,
3
(c) Kolakowski, R. V.; Shangguan, N.; Sauers, R. R.; Williams, L. J.
137.9, 135.0, 131.9, 129.1, 128.8, 127.0, 124.6, 120.2 ppm.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D