General and efficient oxidative amidation of benzyl alcohols with amines using diacetoxyiodobenzene and TBHP

Article abstract of DOI:10.1016/j.tetlet.2015.10.066

A facile oxidative coupling of alcohols and amines to construct amides was developed using DIB as a catalyst and aqueous tert-butyl hydroperoxide as an oxidant. Various secondary and tertiary amides were prepared in good yield utilizing inexpensive and readily available reagents under mild reaction condition. The reaction involved operational simplicity, metal free oxidation, and wide functional group tolerance as attractive features.

Full text of DOI:10.1016/j.tetlet.2015.10.066

Tetrahedron Letters xxx (2015) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
General and efficient oxidative amidation of benzyl alcohols
with amines using diacetoxyiodobenzene and TBHP
⇑
Yogesh B. Sutar, Saket B. Bhagat, Vikas N. Telvekar
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga, Mumbai 400 019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile oxidative coupling of alcohols and amines to construct amides was developed using DIB as a cat-
alyst and aqueous tert-butyl hydroperoxide as an oxidant. Various secondary and tertiary amides were
prepared in good yield utilizing inexpensive and readily available reagents under mild reaction condition.
The reaction involved operational simplicity, metal free oxidation, and wide functional group tolerance as
attractive features.
Received 10 September 2015
Revised 17 October 2015
Accepted 19 October 2015
Available online xxxx
Ó 2015 Published by Elsevier Ltd.
Keywords:
Alcohol
Oxidation
Amine
Iodine reagent
Amide
Amide is one of the most important functional groups found in
polymers, fine chemicals, pharmaceuticals, and natural products.1
The traditional synthetic approach used for amide formation
involves the reaction of an amine with activated carboxylic acid
derivatives2 or coupling with carboxylic acids mediated by cou-
pling reagents,3 which suffers from several common drawbacks
such as the use of highly hazardous reagents, harsh reaction condi-
tions, toxicity issues, poor atom-efficiency, and generation of
wastes that not only reduce process efficiency but also pose envi-
ronmental problems. This necessitates the development of efficient
methods for amide bond formation that circumvents these
problems.
To overcome these limitations in amide synthesis, an array of
novel methodologies have been developed, such as Beckmann
rearrangement,4 Staudinger reaction,5 the Schmidt reaction,6
amino carbonylation of haloarenes,7 transamidation of primary
amides,8 oxidative amidation of aldehydes,9 and aminolysis of
esters.10 Recently, oxidative amidation of alcohol using several
transition-metal based homogeneous and heterogeneous catalysts
like Zn,11 Au-Pd/resin,12 Au/DNA13 and MnO2(IV)–NaCN14 afford an
elegant alternative for direct access to amides. Also, metal free
oxidative amidation of alcohol to amides using I2/TBHP,15 I2/
H2O2,16 NaI/TBHP,17 and NH3/TBHP18 have previously been
reported. However, there still remains a challenge for the improve-
ment of these reported methods, because the preparations of cata-
O
DIB, TBHP
N
OH
HN
+
Acetonitrile, reflux
Scheme 1. Reaction between benzyl alcohol and aqueous dimethylamine in the
presence of DIB and TBHP.
lysts are time-consuming and precious metals have relatively high
cost.
In the course of the continuous research of our group on devel-
oping novel efficient strategies, we decided to explore amide bond
formation through aerobic oxidative coupling of alcohols and ami-
nes, using hypervalent iodine reagents, which offer the major
advantages of mild reaction conditions, high efficiency, and a wide
scope of substrates.
For our initial study, we carried out reaction between benzyl
alcohol and aqueous dimethylamine in the presence of diace-
toxyiodobenzene (DIB) and TBHP using acetonitrile as solvent
under reflux condition for 10 h. The desired product N,N-dimethyl-
benzamide was isolated in moderate yield (Scheme 1).
Varying combinations of different iodine reagents and oxidizing
agents were screened for this reaction and most of them provided
moderate to good yield of N,N-dimethylbenzamide (Table 1).
To exploit the importance of the catalyst system, the oxidative
amidation was carried out in the presence of only DIB (2.0 equiv,
Table 1, entry 15), however, the reaction failed to afford the pro-
duct in not more than 7% yield. It is also noteworthy to mention
⇑
Corresponding author. Tel.: +91 22 3361 2213; fax: +91 22 3361 1020.
E-mail address: vikastelvekar@rediffmail.com (V.N. Telvekar).
http://dx.doi.org/10.1016/j.tetlet.2015.10.066
0040-4039/Ó 2015 Published by Elsevier Ltd.
Please cite this article in press as: Sutar, Y. B.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.10.066

2
Y. B. Sutar et al. / Tetrahedron Letters xxx (2015) xxx–xxx
Table 1
that in the presence of only TBHP (10.0 equiv, Table 1, entry 16),
Effect of iodine reagents and oxidizing agentsa
even after 10 h, the oxidative amidation failed to yield the product
above 20%. Thus, it was concluded that a combination of both, the
catalyst and the oxidant, in an adequate ratio is essential to obtain
the desired amide product.
Thus after analyzing different reaction conditions, it was
observed that in the case of secondary amines, the desired product
was obtained in good yield when 8 equivalent of TBHP and a cat-
alytic amount (20 mol %) of diacetoxyiodobenzene were used
(Table 1, entry 12).
We also attempted different solvents such as water, toluene,
ethanol, 1,4-dioxane, and tetrahydrofuran. However, all these reac-
tions gave lower yields than that in acetonitrile. Thus, it was
observed that 20 mol % DIB, 8 equiv of TBHP in acetonitrile at
reflux temperature was the optimal reaction condition to afford
the desired amide in good yield. It was interesting to know that
under similar conditions, when primary amine (phenylethylamine)
was reacted with benzyl alcohol, the desired product N-phenethyl-
benzamide was obtained in lower yield (52%). However, changing
Entry
Iodine regent (mol %)
Oxidizing agent (eq)
% Yieldb
1
2
3
4
5
6
7
8
I2 (10)
TBHP (5)
TBHP (5)
Oxone (5)
TBHP (5)
TBHP (5)
Benzyl peroxide (5)
H2O2 (5)
Oxone (5)
m-CPBA (5)
TBHP (5)
TBHP (5)
TBHP (8)
TBHP (10)
TBHP (8)
—
30
30
NR
45
46
17
10
7
PhI (10)
PhI (10)
IBX (10)
DMP (10)
DIB (10)
DIB (10)
DIB (10)
DIB (10)
DIB(10)
DIB(20)
DIB (20)
DIB (20)
DIB (25)
DIB (2 equiv)
—
9
8
10
11
12
13
14
15
16
61
76
86
87
85
7
TBHP (10)
20
a
Reaction conditions: 1.0 mmol of benzyl alcohol, 2.5 equiv aqueous N,N-
dimethylamine, oxidizing agent, iodine reagent in acetonitrile at reflux temperature.
b
Isolated yield.
Table 2
Synthesis of various amides using DIB and THBPa
Entry
1
Aryl alcohol
OH
Amine
Product
Yieldb (%)
86
O
HN
N
O
OH
HN
HN
N
2
3
88
78
Cl
Cl
O
OH
N
H3CO
H3CO
O
O
OH
OH
HN
HN
N
N
4
80
CH3
CH3
5
6
7
65
80
83
CH3
CH3
O
O
OH
HN
HN
N
H3C
H3C
OH
N
O2N
O
O2N
O
O
HN
HN
HN
8
9
72
79
OH
N
O
S
S
OH
OH
N
O
10
84
N
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Y. B. Sutar et al. / Tetrahedron Letters xxx (2015) xxx–xxx
3
Table 2 (continued)
Entry
Aryl alcohol
OH
Amine
Product
Yieldb (%)
88
O
O
HN
11
12
N
N
OH
OH
HN
O
88
81
O
O
O
OCH3
H
N
O
13
N
OCH3
NH2
OH
O
O
O
14c
15c
16c
74
69
74
NH
NH
NH
OH
OH
OH
NH2
NH2
H2N
17c
18c
67
NH
O
NH2
O
OH
69
65
NH
S
NH2
O
S
19c
OH
NH
a
Reaction conditions: 1 mmol of aryl alcohol, 2.5 mmol of amine, 8 mmol of THBP, and 20 mol % DIB in acetonitrile at 80 °C.
b
c
Isolated yields after column chromatography and structures were confirmed by comparison of IR, 1H NMR, and M.P. with literature reports.17,21
Water was used as a solvent instead of acetonitrile (entries 14–19).
the solvent from acetonitrile to water, afforded the desired product
in good yield (74%).
in moderate to good yields (Table 2, entries 14–19). Compound like
-proline also underwent amidation to provide the corresponding
L
To extend the scope and generality of this catalytic system, the
above optimized conditions were used for preparation of a variety
of substituted amides and results are summarized in Table 2.19
Various aromatic amides, bearing electron-withdrawing and
donating groups on the aromatic rings, could be obtained in good
to moderate yields from the corresponding aromatic alcohols
(Table 2, entries 2–7). It was also observed that the ortho substi-
tuted compound shows a lower yield, than corresponding meta
and para substituted derivatives, may be due to the presence of
steric hindrance (Table 2, entry 5). Heteroaromatic alcohols, such
as 2-thenyl alcohol and furfuryl alcohol, also reacted with aqueous
dimethylamine in the presence of DIB and TBHP to give the corre-
sponding N,N-dimethyl heteroaromatic amides in good to moder-
ate yields (Table 2, entries 8 and 9). The secondary cyclic amines,
like morpholine and piperidine, also gave the desired products in
good yield (Table 2, entries 11 and 12).
amides (Table 2, entry 13) in good yield.
It was observed that when aromatic amines, like aniline, were
reacted with benzyl alcohol, the corresponding amides were
obtained in a very low yield (20–25%). It is also noted that S-1-
phenylethylamine undergoes a similar transformation without
epimerization. This non-epimerization of
L-proline and S-1-
phenylethylamine, in the corresponding amides, was confirmed
by optical rotation data, which matches with the literature data.20
In conclusion, DIB and TBHP have been explored as an efficient
organocatalyst for oxidative amidation of various aryl alcohols,
bearing electron-withdrawing and electron-donating groups on
the aromatic rings, with amines for the synthesis of amides in good
yields. The present reaction is simple and environmentally benign,
and generates little waste. These novel cost-effective amide forma-
tion reactions provide practical alternatives for the synthesis of
amides under mild conditions.
The reaction of benzyl alcohol with primary amines, such as
phenylethylamine, n-butylamine,
a-methylbenzylamine, tert-
Acknowledgment
butylamine, and benzylamine, in the presence of DIB and TBHP
in water was then carried out. The results indicate that the
N-alkyl/alkylaryl benzamides from primary amines were obtained
Y.B.S. and S.B.B. are thankful to the University Grants Commis-
sion (UGC, New Delhi, India) for providing financial support.
Please cite this article in press as: Sutar, Y. B.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.10.066

4
Y. B. Sutar et al. / Tetrahedron Letters xxx (2015) xxx–xxx
and TBHP (70 wt % in H2O, 8.0 mmol) in acetonitrile (5 mL), was added DIB
References and notes
(0.2 mmol, 20 mol %) at room temperature. The reaction was allowed to stir at
reflux temperature for 5–6 h. After the reaction was complete, as indicated by
TLC, the mixture was cooled to room temperature. The volatiles were removed
under reduced pressure and 10 mL saturated solution of NaHCO3 was added.
The mixture was extracted with ethylacetate (3 Â 10 mL). The combined
organic phases were dried with Na2SO4 and evaporated under vacuum.
Purification of the residue by column chromatography (petroleum ether/
EtOAc) afforded the desired amide.
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C
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Morpholino(phenyl)methanone (Table 2, entry 12): Mp 66–69 °C (Lit. 21 68–
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= 3.37–3.85 (m, 8H), 7.48 (m, 5H); 13C NMR (CDCl3, TMS): d = 42.4, 48.2, 66.7,
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3310, 2957, 2931, 2871, 1635, 1577, 1540, 1435, 1376, 1074, 693 cmÀ1 1H
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(m, 2H), 3.40–3.46 (m, 2H), 7.23 (bs, 1H), 7.36–7.39 (m, 2H), 7.46–7.49 (m, 1H),
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128.3, 131.1, 134.7, 167.5; HRMS: calcd for
177.1204.
C11H15NO: 177.1154, found
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amine: To a mixture of aryl alcohol (1.0 mmol), appropriate amine (2.5 mmol)
Please cite this article in press as: Sutar, Y. B.; et al. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.10.066