Accessing the amide functionality by the mild and low-cost oxidation of imine

Article abstract of DOI:10.1016/j.tetlet.2009.02.174

Oxidation of imines using sodium chlorite under buffered conditions gave the corresponding amides in good to high yield. The reaction was generally fast and was completed within 5-40 min. As has been established in the corresponding oxidation of aldehyde, so-called Pinnick oxidation, the good functional group tolerance and the use of inexpensive reagents are the advantages of this protocol.

Full text of DOI:10.1016/j.tetlet.2009.02.174

Tetrahedron Letters 50 (2009) 3436–3438
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Accessing the amide functionality by the mild and low-cost oxidation of imine
*
Magdi A. Mohamed, Ken-ichi Yamada, Kiyoshi Tomioka
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Oxidation of imines using sodium chlorite under buffered conditions gave the corresponding amides in
good to high yield. The reaction was generally fast and was completed within 5–40 min. As has been
established in the corresponding oxidation of aldehyde, so-called Pinnick oxidation, the good functional
group tolerance and the use of inexpensive reagents are the advantages of this protocol.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 27 January 2009
Revised 20 February 2009
Accepted 23 February 2009
Available online 26 February 2009
The amide moiety is one of the most abundant functional
groups found in the chemical structures of polymers, natural prod-
ucts, and pharmaceuticals.1 Thus, the development of a new mild
and versatile method for amide formation is important and valu-
able. The most common way to form an amide bond is condensa-
tion of amines with activated carboxylic acid derivatives, such as
acyl chloride.2 For the cases where highly reactive carboxylic acid
derivatives should be avoided, however, alternative methods for
the preparation of an amide moiety have been developed.3 Oxida-
tion of secondary amines4 or imines5 has also been utilized for the
formation of amides. The oxidation of secondary amines to amides
has been achieved by using hypervalent iodines4a,c–e or permanga-
nate.4b The oxidation of imines proceeds under milder conditions,
such as transition metal catalysis,5a,b,e,g nickel peroxide,5d
m-CPBA,5f TBHP,5h and oxone.5i Because imines are readily pre-
pared from aldehydes and amines, this strategy seems versatile
and attractive. Recently, an efficient amide synthesis by catalytic
oxidative linkage of alcohols and amines has been reported.6
Oxidation of aldehyde to carboxylic acid by sodium chlorite un-
der buffered conditions was first reported by Lindgren and Nilsson
in 1973.7 This oxidation is now referred to as Pinnick oxidation be-
cause the generality of this oxidation was shown by Pinnick and
co-workers in 1981.8 During our investigation of an alkaloid syn-
thesis, we encountered difficulty in the oxidation of amine to
amide. After several attempts, we found that the oxidation under
the Pinnick conditions is applicable to imines to provide corre-
sponding amides in good to high yield. The required reagents were
inexpensive and less toxic and the reaction has a reasonable func-
tional group tolerance. Herein, we report this new protocol for
oxidation of imine.
NaClO2
NaH2PO4
2-methylbut-2-ene
+
N
NH
N
THF/H2O
rt
Cl
1a
2a
O
3
O
24 h
77%
13%
0%
68%
5 min
Scheme 1. Oxidation of isoquinoline 1a to isoquinolinone 2a and/or N-chloroiso-
quinolinone 3.
chlorite (0.92 mmol) were successively added to a solution of 1a
(0.18 mmol) in a mixture of 2-methylbut-2-ene, THF, and water
(1.8 mL each) at 0 °C. The solution was stirred at room temperature
for 24 h. After work-up, desired lactam 2a was obtained in 77%
yield. Silica gel TLC monitoring indicated that 1a was first con-
verted into a less polar intermediate within 5 min and then the
intermediate gradually transformed into more polar 2a for 24 h.
The intermediate, N-chloroamide 3 was obtained in 68% yield
along with 13% yield of 2a when the reaction was quenched after
5 min. It was found that 3 was convertible to 2a by the treatment
with 10% aqueous sodium thiosulfate; thus, the oxidation of 1 for
5 min, followed by dilution with ethyl acetate and a wash with
aqueous sodium thiosulfate, gave 2a in 98% yield (Table 1, entry 1).
This method was applicable to linear imines as well as to the
cyclic imine (Table 1).10 N-PMP imines (PMP = 4-methoxyphenyl)
were good substrates to give the products in good yields (entries
2–4). In the reaction of N-PMP cinnamaldehyde imine, N-PMP
cinnamamide was obtained in 67% yield, along with the corre-
sponding
a,b-epoxy amide in 11% yield. Using increased amount
First, oxidation of 3,4-dihydroisoquinoline (1a) was tested
(Scheme 1). The isoquinoline 1a was prepared from 1,2,3,4-tetra-
hydroisoquinoline by treatment with NCS followed by the addition
of DBU.9 Sodium dihydrogenphosphate (0.92 mmol) and sodium
of 2-methylbut-2-ene (50 equiv), the yield of the cinnamide was
improved to 73%, while almost the same amount of the epoxide
was produced (entry 4). An enolizable imine is also applicable to
this reaction to give the product in 85% yield (entry 5). Imine de-
rived from alkylamine gave the corresponding amide in 65% yield
along with the slight formation of dibenzoylimide (1%) (entry 6).
Electron-deficient N-tosyl imine gave the product in high yield
* Corresponding author. Tel.: +81 75 753 4553; fax: +81 75 753 4604.
E-mail address: tomioka@pharm.kyoto-u.ac.jp (K. Tomioka).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.02.174

M. A. Mohamed et al. / Tetrahedron Letters 50 (2009) 3436–3438
3437
Table 1
Oxidation of imines 1 to amides 2
NaClO2, NaH2PO4, 2-methylbut-2-ene
H
N
R
N
R
R'
R'
THF/H2O
rt
O
1
2
Entry
1b
1
Methoda
A
Time (min)
5
2/yield (%)
98
N
Ph
N
2
B
B
40
86
OMe
N
MeO2C
3
10
15
5
90
OMe
N
4c
5
B
A
B
B
73d
85
OMe
N
OMe
6
Ph
Ph
N
Ph
30
65e
85
N
7
480
Ts
a
See Ref. 10.
Without 2-methylbut-2-ene.
50 equiv of 2-methylbut-2-ene was used.
The corresponding
b
c
d
e
a,b-epoxy amide was obtained in 9% yield.
Dibenzoylimide was obtained in 1% yield.
but required prolonged reaction time (entry 7). It is worthy to note
that the functionalities, such as an electron-rich aromatic ring (en-
tries 2–5), ester (entry 3), and benzylic methylene (entry 6) were
compatible with the conditions of this oxidation. These results
clearly show the generality and the functional group tolerance of
this oxidation protocol.
The reaction can also be conducted in other solvents, such as
tert-butanol and 1,4-dioxane, which allowed the oxidation of 1a
to give 2a in 98% and 95% yields after 15 and 10 min, respectively.
should be operative. One is the oxidation of protonated imine to
give directly amide 2a (Scheme 2). This pathway produces hypo-
chlorous acid, which would initiate the other oxidation pathway
by chlorinating 1a. The oxidation of the produced N-chloroimini-
um gives N-chloroamide 3, which is then converted to 2a. The
chlorination step should be rate-determining because the reac-
tions of more electron-rich N-PMP and N-alkyl imines are much
faster than that of more electron-deficient N-tosyl imine (Table
1). Dibenzoylimide (Table 1, entry 6) is probably produced by
the oxidation of N-benzylidenebenzamide generated through
dehydrochlorination of the N-chloroamide intermediate that re-
sults from the second pathway.
The formation of N-chloroamide
3 as an initial product
(Scheme 1) implies that two pathways from imine to amide
The mechanism proposed in Scheme 2 indicates that a hypo-
chlorous acid scavenger, 2-methylbut-2-ene, should be unneces-
sary. Indeed, almost the same results were obtained in the
oxidation of isoquinoline 1a with and without 2-methylbut-2-
HClO2
NH
NH
1a
2a
3
H
Cl
+
O
O
–
ClO2
ClOH
ClOH
NaClO2
NaH2PO4
HClO2
–H2O
NCl
NCl
2-methylbut-2-ene
+
+
2a
4
+
H
Cl
NH
N
HO–
O
O
4%
68%
THF/H2O
rt, 20 h
Cl
5
4
5%
Scheme 2. Two plausible competing pathways for the oxidation of imines to
amides.
Scheme 3. Attempted direct oxidation of amine 4.

3438
M. A. Mohamed et al. / Tetrahedron Letters 50 (2009) 3436–3438
O
O
‘Advanced Molecular Transformations’ from MEXT, and Targeted
H
H
Proteins Research Program from JST. M.A.M. thanks MEXT for a
predoctoral scholarship.
PhI=O, TBAI
O
O
O
O
H
H
NH
N
CH2Cl2/H2O
rt, 1.5 h
57%
Supplementary data
6
7
OMe
OMe
O
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.02.174.
NaClO2, NaH2PO4
2-methylbut-2-ene
H
O
O
H
NH
THF/H2O
rt, 19 h
83%
References and notes
8
OMe O
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10. General procedures. Method A: An aqueous solution of NaH2PO4 (1.0 M, 1.5 mL,
1.5 mmol) was added to a mixture of 2-methylbut-2-ene (1.1 mL, 10 mol) and
NaClO2 (452 mg, 5.0 mmol) in THF (3.9 mL). To the resulting pale yellow
solution, was added a solution of imine 1 (1.0 mmol) in THF (1 mL + 0.25 mL
washing  2) dropwise over 5–10 min. The mixture was vigorously stirred
until disappearance of the starting imine was confirmed by TLC monitoring.
Then, the reaction mixture was diluted with EtOAc (30 mL) and washed with
water, 10% Na2S2O3, and brine (10 mL each). The organic layer was dried over
Na2SO4 and concentrated. The resulting crude material was purified by column
chromatography or recrystallization.
Scheme 4. Two-step oxidation of 6 to give 8.
ene. However, in the oxidation of the substrates having the
electron-rich PMP moiety, addition of 2-methylbut-2-ene was re-
quired to avoid chlorination of the aromatic ring. The a,b-epoxida-
tion, observed in entry 4, was probably due to conjugate addition
of chlorite because its production was independent of the amount
of 2-methylbut-2-ene, which seems to simply protect the PMP
moiety from chlorination.
Direct oxidation of amine 4 to amide 2a was attempted (Scheme
3). Unfortunately, the oxidation of amine to imine 1a was sluggish
and unclean, resulting in 2a in only 4% yield along with 5% yield of
N-chloroamine 5 and 68% recovery of 4 after 20 h.11
Finally, the developed method was applied in an Amaryllidaceae
alkaloid synthesis (Scheme 4).12 Although all the attempts to oxi-
dize tricyclic tetrahydroisoquinoline 6 or its protected derivatives
directly to lactam 8 failed,4 partial oxidation of 6 was accomplished
using iodosobenzene with tetrabutylammonium iodide4d to afford
dihydroisoquinoline 7. The following oxidation by the method gave
desired lactam 8 in 83% yield, while the permanganate oxidation5c
of 7 resulted in a complex mixture.
In summary, we have shown that the oxidation by sodium chlo-
rite under buffered conditions, so-called Pinnick oxidation widely
used for the oxidation of aldehyde to carboxylic acid, was applica-
ble to the formation of amide from imine. Because imine can be
prepared by condensation of aldehyde and amine or by oxidation
of secondary amine, this protocol provides a versatile two-step
synthesis of amide from amine. The functional group tolerance,
the mild buffered conditions, and the inexpensiveness of the
reagents make this protocol useful and valuable.
Acknowledgments
Method B: Imine 1 (1.0 mmol) was dissolved in THF (3.9 mL). 2-Methylbut-2-
ene (1.1 mL, 10 mol) and NaClO2 (452 mg, 5.0 mmol) were added to the
solution. An aqueous solution of NaH2PO4 (3.3 M, 1.5 mL, 5.0 mmol) was added
dropwise to the vigorously stirred mixture. The same work-up as Method A
was followed.
This research was partially supported by the 21st Century Cen-
ter of Excellence Program ‘Knowledge Information Infrastructure
for Genome Science’ and a Grant-in-Aid for Young Scientist (B)
from JSPS, a Grant-in-Aid for Scientific Research on Priority Areas
11. 10% Na2S2O3 washing was omitted in the work-up procedure.
12. The preparation of 6 is to be submitted elsewhere afterward.