Iodide-catalyzed amide synthesis from alcohols and amines

Article abstract of DOI:10.1039/c3ra43799j

An efficient method to prepare amides by a cascade strategy was developed. Using nBu₄NI or NaI as the catalyst and tert-butyl hydroperoxide as the oxidant, various alcohols reacted with N-hydroxysuccinimide or N-hydroxyphthalimide affording corresponding active esters in moderate to good yield. The resulting active esters were converted into amides smoothly in one pot. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra43799j

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DOI: 10.1039/C3RA43799J
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ARTICLE TYPE
Iodide-catalyzed Amide Synthesis from Alcohols and Amines
a
a
a
a
a
a
Gao Wang, Qing-Ying Yu, Jian Wang, Shan Wang, Shan-Yong Chen* and Xiao-Qi Yu*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
5
An efficient method to prepare amides by a cascade strategy was developed. Using nBu NI or NaI as the
4
catalyst and tertꢀbutyl hydroperoxide as the oxidant, various alcohols reacted with Nꢀhydroxysuccinimide
or Nꢀhydroxyphthalimide affording corresponding active esters in moderate to good yield. The resulted
active esters were converted into amides smoothly in one pot.
first metalꢀcatalyzed amidation reaction of aldehyde using Nꢀ
hydroxyimide as a dual promoter of aldehyde oxidation and
amines displacement. Barbas III groups reported the first
Introduction
8
1
1
2
2
0
5
0
5
Amide bond is one of the most abundant units in a wide range of
natural products, polymers, agrochemicals, and pharmaceuticals
with biologically relevant properties. The synthesis of amides
has therefore attracted considerable interest and a number of
methods have been devised. They are routinely prepared from the
acylation of amines with activated carboxylic acids, especially
with Nꢀhydroxyimide esters. Oxidative amidation of alcohols or
aldehydes are economically attractive alternatives to traditional
synthesis. Research during the past decade resulted in significant
organocatalytic amidation reaction of aldehyde using the same
9
4
0
strategy. We envisioned that an iodide reagent also could
1
catalyze the oxidation of alcohols into Nꢀhydroxyimide esters,
which facilitate the displacement of an amine. This tandem
strategy will alleviate structural dependence on amines.
2
Results and discussion
45
Our initial studies focused on the model reaction of
phenylmethanol 1a with Nꢀhydroxysuccinimide (NHS) 2a in
acetonitrile. Without a catalyst, no desired product was observed.
3
,4
progress in the field of amidation of aldehydes. Considering the
stability and the availability of alcohols, chemists have been
focusing on the direct conversion of alcohols and amines into
amides, which is more atomꢀeconomical and environmentally
benign. In spite of great progresses, the use of transitionꢀmetal
a
Table 1. Optimization of the reaction conditions
50
5
catalysts or the need for more than stoichiometric amounts of
6
hypervalent iodine (III) reagents limits the practical application
of this strategy.
Entry
Catalyst
Oxidant
Yield
1
2
3
4
5
6
7
8
ꢀ
aqueous TBHP
aqueous TBHP
aqueous TBHP
aqueous TBHP
aqueous TBHP
anhydrous TBHP
DTBP
N.D.
71%
82%
N.D.
N.D.
85%
N.D.
N.D.
NaI
nBu NI
4
I2
PhI(OAc)2
nBu NI
4
nBu NI
4
nBu NI
H O
2
4
2
b
9
nBu NI
anhydrous TBHP
anhydrous TBHP
80%
76%
4
c
1
0
nBu NI
4
Scheme 1. Methods to amidation of alcohols
a
1
a (0.5 mmol), NHS (0.75 mmol), catalyst (10 mol %), oxidant (4.0
3
0
b
equiv) in acetonitrile (2 mL) at 80 °C for 18 hours. Ethyl acetate as the
Wang et al developed an amide formation reaction of alcohol
with N,Nꢀdisubstituted formamides leading to N,Nꢀdisubstituted
amides without the use of a hypervalent iodine (III) reagent or a
c
solvent. Using 0.5 mmol of NHS. H O : 50% hydrogen peroxide in
water; DTBP: diꢀtertꢀbutylꢀperoxide.
2
2
7
metal catalyst. However, nitrogen source is limited to preꢀ
With NaI as the catalyst and aqueous tertꢀbutyl hydroperoxide
(
3
5
formed formamides. Quite recently, Yamamoto et al reported the
TBHP 70 wt.% in water) as the oxidant, the desired active ester
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aa was isolated in 71% yield (Table 1, entry 2). We further 15 donating or weak electronꢀwithdrawing groups were well
found nBu NI was more effective than NaI (Entry 3 vs entry 2)
tolerated and provided the corresponding esters in high yields
(Table 2). Orthoꢀsubstituted benzyl alcohols (1h and 1i) also
provided the products in good yields. Electron effects influence
the reaction. Strong electronꢀwithdrawing substituents retarded
4
and iodine or PhI(OAc) was inactive.
2
Replacement of the aqueous TBHP with anhydrous TBHP (5.5
M in decane) led to a slightly increased yield (Entry 6 vs entry 3).
5
Other oxidants like H O or DTBP did not work for this 20 this reaction obviously. For example, when 4ꢀcynao benzyl
2
2
transformation (Entries 7, 8). Using ethyl acetate instead of
acetonitrile as the solvent, this reaction gave 3aa in slightly
decreased yield (Entry 9). Other solvents including toluene,
tetrahydrofuran, ethanol and 1,4ꢀdioxane were not suitable for
alcohol was coupled with NHS, low yield of 3ka was obtained.
The aromatic rings of the reaction substrates could also be
naphthyl, thienyl, and furyl rings (1j, 1l and 1m). Using aqueous
TBHP as the oxidant, most benzyl alcohols gave esters in
10
this reaction. Reducing the amount of NHS resulted in an obvious 25 decreased but acceptable yields. Insufficiently, alkyl alcohols
decreased yield (Entry 10 vs entry 6).
With the optimized conditions in hand, the substrate scope of
the reaction was investigated. Benzyl alcohols with electronꢀ
didn’t undergo such transformation, suggesting that an aromatic
functionality is necessary to stabilize the active species.
a
Table 2. Oxidative esterification of alcohols with NHS
30
Yield
Yield
(%)
Alcohol
Product
Alcohol
Product
(%)
8
5b
1
1
a
3aa
1h
1i
3ha
85
8
2
8
3b
b
3ba
3ca
3ia
3ja
73
84
8
6
1
c
90
1j
8
3b
1
1
1
1
d
e
f
3da
3ea
3fa
3ga
1k
1l
3ka
3la
26
53
35
30
7
6
9
2b
6
4
8
1b
1m
1n
3ma
3na
5
7
g
77
a
Standard conditions: alcohol (0.5 mmol), NHS (0.75 mmol), nBu
4
NI (10 mol %), anhydrous TBHP (4.0 equiv), acetonitrile (2 mL), 80
°
C, 18 hours. b Using aqueous TBHP (4.0 equiv) as the oxidant.
In support of the utility of this method, we conducted this
reaction on a gram scale using aqueous TBHP as the oxidant. As
shown in scheme 2, the product was obtained with good yield.
35
Scheme 2. Preparative scale experiment.
40
2
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Unexpectedly, when the reaction was carried out with Nꢀ
hydroxyphthalimide (NHPI) 2b, under the above conditions only
7% of 3ab was isolated. After screening catalysts, bases and
solvents (see table S1 in the support information), we found NaI
was a good catalyst and a strong base was a good promoter. The
10
Employing the above experimental conditions, a series of
aromatic primary alcohols were efficiently oxidized to the
corresponding active esters. As shown in table 3, most benzyl
alcohols with electronꢀdonating or weak electronꢀwithdrawing
substituents provided NHPI esters in good yields. Steric effects
6
5
optimal reaction conditions were determined to be: 10 mol % of 15 influence this reaction obviously. For example, naphthalenylꢀ
NaI (catalyst), 0.4 equiv of KOH (base), 4 equiv of aqueous
TBHP (oxidant), 2 mL of ethyl acetate (solvent), reaction
temperature at 80°C under air atmosphere for 8 h.
methanol and orthoꢀchlorophenylmethanol provided the desired
product in low yield.
a
Table 3. Oxidative esterification of alcohols with NHPI
2
0
Yield
Yield
(%)
Alcohol
Product
Alcohol
Product
(%)
3
ab
bb
93
90
3hb
77
3
3ib
3jb
44
44
3
db
88
3
eb
89
74
3lb
92
47
3
fb
3mb
a
Conditions: alcohols (0.5 mmol), NHPI (0.75 mmol), NaI (10 mol %), KOH (0.4 eq), aqueous TBHP (4.0 equiv),
ethyl acetate (2 mL), 80 °C, 8 hours.
Next, we examined the amine displacement step (Table 4).
Treatment of the isolated NHPI ester 3ab with benzylamine
provided the expected amide 4a in moderate yield. In contrast,
NHS ester 3aa provide the desired amide 4a in high yield,
suggesting NHS ester is more reactive for the displacement of an
amine.
that the desired amide products were readilly obtained in good
yileds (Table 5). This oneꢀpot amidation of alcohols can be
applicable to primary amines, scondary amines and even
arylamines.
2
5
40
7, 9
In terms of the previous reports, a proposed mechanism is
ꢀ
shown in scheme 3. Alcohols are oxidized into aldehydes under I
/
TBHP system. Then Nꢀhydroxyimide attacks aldehydes to
3
0
Table 4. Examination of the amine displacement.
generate acetal A, which can be further oxidized to the product
esters. Last, active esters convert into amides smoothly in the
presence of amines.
45
Conclusions
Ester
Product
4a
Yield (%)
In conclusion, an efficient oneꢀpot oxidative amide synthesis
from benzyl alcohols and amines was developed. Using iodide as
the catalyst could avoid the use of stoichiometric amounts of
hypervalent iodine (III) reagents, thus reducing the resulted byꢀ
products. This metalꢀfree protocol provides a practical synthetic
tool for the construction of amides from benzyl alcohols.
3
aa
ab
95
62
3
4a
50
To further demonstrate its practical utility, we investigated
the feasibility of a oneꢀpot transformation of alcohols into amides.
When amines were added to the resulted mixtures, we discovered
3
5
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a
Table5. One pot synthesis of amides
O
N
H
Cl
4
a 90%
4b 80%
4e 70%
4
c 78%
4
d 65%
g 89%
4f 83%
4i 83%
4
4
h 69%
b
4
j 80%
4
l 80%
4
k 60%
a
3 4
Conditions: (1) alcohol (0.5 mmol), NHS (0.75 mmol), CH CN (2 mL), nBu NI (0.05 mmol) and anhydrous TBHP (4.0
equiv) 80 °C for 18h. (2) amine (0.75 mmol) at room temperature for 12 h. b The second step was performed at 50 C.
o
5
Scheme 3. A proposed mechanism for synthesis of amides
1
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Acknowledgements
This work was financially supported by the National Program on Key
Basic Research Project of China (973 Program, 2013CB328900) and the
National Science Foundation of China (Grant No. 21202107 and
2
5
1
0
2
1021001).
2
3
Notes and references
30
a
Key Laboratory of Green Chemistry & Technology, Ministry of
1
5
0
Education, College of Chemistry, Sichuan University, Chengdu 610064,
PR China. Fax: (86)-28-85415886; E-mail: chensy@scu.edu.cn or
xqyu@scu.edu.cn.
35
†
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
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A metal free prodecure for the syntheis of amides from benzyl alcohos and various aimines is
descripted.