SeO2mediated efficient synthesis of amides and α-ketoamides of secondary amines with wide substrate scope

Article abstract of DOI:10.1016/j.tetlet.2016.06.129

SeO₂mediated oxidative amidation of acetophenones, phenylacetylenes, and phenylacetaldehydes to α-ketoamides and aldehydes to amides is reported. Amidation selectively proceeds with secondary amines. α-Ketoamide derivatives of natural products 16-dehydropregnenolone acetate (8), pregnenolone acetate (10), and progesterone (11) were synthesized.

Full text of DOI:10.1016/j.tetlet.2016.06.129

Accepted Manuscript
SeO2 mediated efficient synthesis of amides and α-ketoamides of secondary
amines with wide substrate scope
Samdarshi Meena, Rohit Singh, Ram A. Vishwakarma, Mushtaq A. Aga,
Shreyans K. Jain
PII:
S0040-4039(16)30815-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.06.129
TETL 47856
Reference:
Tetrahedron Letters
To appear in:
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Revised Date:
Accepted Date:
20 April 2016
28 June 2016
29 June 2016
Please cite this article as: Meena, S., Singh, R., Vishwakarma, R.A., Aga, M.A., Jain, S.K., SeO2 mediated efficient
synthesis of amides and α-ketoamides of secondary amines with wide substrate scope, Tetrahedron Letters (2016),
doi: http://dx.doi.org/10.1016/j.tetlet.2016.06.129
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Tetrahedron Letters
SeO2 mediated efficient synthesis of amides and α-ketoamides of secondary amines
with wide substrate scope
Samdarshi Meenaab, Rohit Singhbc, Ram A. Vishwakarmac, Mushtaq A. Agad* and Shreyans K. Jaina*
aNatural Products Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu-180001, India
bAcademy of Scientific & Innovative Research (AcSIR), CSIR Campus, CSIR Road, Taramani, Chennai– 600113, India
cMedicinal Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Canal Road, Jammu-180001, India
dNatural Products Chemistry Division, Indian Institute of Integrative Medicine (CSIR)Branch, Sanat Nagar, Srinagar-190005 India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
SeO2 mediated oxidative amidation of acetophenones, Phenylacetylenes,
phenylacetaldehydes to α-ketoamides and aldehydes to amides is reported.
Amidation selectively proceeds with secondary amines. α-Ketoamide derivatives
of natural products 16-dehydropregnenolone acetate (8), pregnenolone acetate (10)
and progesterone (11) were synthesized.
Available online
Keywords:
Selenium dioxide
Amide
α-ketoamide
Aldehyde
2013 Elsevier Ltd. All rights reserved.
Glyoxal
α-Ketoamide is an important functionality of various
entry 2-8 and 11). Again product formation was not observed
with primary amines (Table 2, entry 14 and 15).
bioactive molecules (anti-HIV, anti-tumor, anti-IBD and anti-
bacterial).1 pharmaceuticals (rapamycin, enzyme inhibitors) and
agrochemicals (FK506).2-4
Further this method was explored for the synthesis of natural
product derivatives of 16-dehydropregnenolone acetate,
progesterone and pregnenolone acetate. 16-dehydropregnenolone
acetate was treated with piperidine and morpholine under
optimized reaction condition36 to obtain α-ketoamide derivatives
8 (65%) and 9 (70%) respectively. 2-Me-piperidine 10 (70%)
derivative of pregnenolone acetate was obtained as mixture of
two diastereoisomers of equal ratio (Epimers), as the 2-Me-
piperidine was a racemic mixture. Method was extended to
synthesize α-ketoamide derivative 11 of progesterone with
piperidine (Figure 1).
α-Ketoamides are synthesized from diverse substrates such as
methyl-ketones,5-10 aldehydes/arylglyox-als,11-16 -ketoacids,17-20
terminal alkynes,21-24 cyanamides,25 carbamoyl stannane/ silane
with acid chlorides,26-28 addition of aroyl to aryl-acetamides,29
2,2-dibromo-1-aryl ethanones30 and double carbonylation of aryl
iodides.31-33 Usually in these oxidative amidation, a co-oxidant is
required. Recent advances in catalytic synthesis of α-ketoamides
has been reviewed recently.1
Shaw et al, synthesized a series of various α-ketoamides from
arylglyoxals and secondary amines by using SeO2.13 Selenium
dioxide is common oxidant and reported for synthesis of
arylglyoxals from acetophenones34 and phenylacetylenes.35
Keeping in view the above findings, it was reasoned to explore
SeO2 for synthesis of α-ketoamides from acetophenones and
amides from arylaldehydes.
Oxidation of phenylacetylene with SeO2 under acidic condition
produces
phenylglyoxal,35
therefore
we
selected
phenylacetylenes as another substrate for synthesis of α-
ketoamides. Reaction of Phenylacetylene (5a) and piperidine
(2d) under mild acidic condition (conc. H2SO4, 10 mol %) was
carried out to produce α-ketoamide 6a in good yield (Table 2,
entry 1). Catalytic amount of acid (10 mol %) improved the yield
however low yield (<20%) was observed in absence of acid even
after 30h. The substitution of alkynes with both electron
withdrawing and electron donating groups were well tolerated
(Table 2, entry 9, 10, 12 and 13). Further the methodology was
extended on phenylacetaldehyde (7) with secondary amines to
obtain α-ketoamide products in good yield (Table 3, entry 1, and
2) whereas no product formation was observed with primary
amines. We concluded that these reaction conditions are not
suitable for weak nucleophiles such as aromatic amines and
primary amines, though in recent investigations by Ahmed and
co-worker synthesized α-carbonylamide of various weak
nucleophiles amine using SeO2-pyridine as a versatile reagent for
In order to investigate SeO2 mediated amidation, a model
reaction of benzaldehyde with diethylamine was selected. Use of
one equivalent of SeO2 and diethylamine (2a) in dioxane at 80 oC
gave the desired product 3a in 90% yield (Table 1, entry 1).
Among the different amines screened, secondary amines
provided encouraging results with high yields 88-92% (Table 1,
3b-d) and no product formation was observed with primary
amines probably due to their week nucleophilicity (Table 1, 3e
and 3f). Next we explored SeO2 mediated amidation for α-
36
ketoamide from acetophenone (4a)
and piperidine (2d) to
obtain 6a (Table 2, entry 1). Different substituted acetophenones
were explored to obtain α-ketoamide in good yield (Table 2,

2
Tetrahedron
the oxidation of α-carbonylimines, of weak nucleophilic
followed by nucleophilic attack of amine to give the selenite
intermediate 13. Further oxidative decomposition of 13 led to the
final α-ketoamide product (Scheme 1).
amines.38
Table 1. SeO2 mediated amidation of arylaldehydes with secondary amines
Entry
R
2 (Amine)
3
Yieldb
90
85
88
92
00
00
1
2
3
4
5
6
Ph (1a)
Ph (1a)
Ph (1a)
2,6-Cl2C6H3 (1b)
Ph (1a)
Ph (1a)
Diethylamine (2a)
Pyrrolidine (2b)
4-Phenylpiperidine (2c)
4-Phenylpiperidine (2c)
Aniline
3a
3b
3c
3d
3e
3f
Tryptamine
Scheme 1. Plausible mechanism of amidation
aEquivalent amount of aldehyde (1, 1.0 mmol) with amine (2, 1.0 mmol) and SeO2
(1.0 mmol), heated at 80 °C/12 hr in dioxane. b isolated yield
To support mechanism, acetophenone (4a) and phenylacetylene
(5a) were treated with SeO2 to give phenylglyoxal (14) and
phenylglyoxylic acid (15) as products. In a separate set of
experiments phenylglyoxal (14) and phenylglyoxylic acid (15)
were treated with piperidine (2d) in presence of SeO2 under
optimized reaction condition. Reaction proceeded as expected,
product 6a was obtained only from phenylglyoxal (14) (Scheme
2). These experiments confirmed amidation proceeds through
aryl glyoxal intermediate and the phenylglyoxylic acid (15) was
obtained as byproduct on over oxidation of phenylglyoxal (14).
Table 2. SeO2 mediated α-ketoamides of acetophenones and phenylacetylene
with secondary amines
Entr
y
R
2 (Amine)
6
Yieldb
1
2
3
4
5
6
7
8
Ph (4a, 5a)
Ph (4a, 5a)
Ph (4a, 5a)
Ph (4a, 5a)
Piperidine (2d)
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
85,86
80,82
82,86
86,88
78,81
85,89
88,90
85
80
76
72
78
Morpholine (2e)
4-Phenylpiperidine (2c)
4-Ethylpiperidine (2f)
4-Benzylpiperidine (2g)
N-Methylpiperazine (2h)
Morpholine (2e)
Morpholine (2e)
4-Ethylpiperidine (2f)
Piperidine (2d)
4-Phenylpiperidine (2c)
Piperidine (2d)
Piperidine (2d)
Aniline
Tryptamine
Ph (4a, 5a)
2-ClC6H4 (4b, 5b)
2-ClC6H4 (4b, 5b)
2,6-Cl2C6H3 (4c)
4-FC6H4 (5c)
4-terBuC6H4 (5d)
2-OH,5-F C6H3 (4d)
4-CNC6H4 (5e)
4-NO2C6H4 (5f)
Ph (4a, 5a)
9
10
11
12
13
14
15
Scheme 2. Synthesis of α-ketoamides through phenyl-glyoxal intermediate.
75
00
00
In summary, a concise SeO2 mediated methodology for the
synthesis of amides from aryl aldehydes and α-ketoamides from
acetophenones and phenylacetylene was developed. Application
of method has been demonstrated on some natural product
derivative synthesis.
Ph (4a, 5a)
aEquivalent amount of acetophenones (4, 1.0 mmol) or alkyne (5, 1.0 mmol) with
amine (2, 1.0 mmol) and SeO2 (1.0 mmol) same as mentioned for table 1, in case
of substrate 5, 10 mole % of H2SO4 was added. bisolated yield
Acknowledgements
The authors, S.M. and SKJ thank UGC-RGNF and CSIR,
respectively for fellowship. The authors gratefully acknowledge
Dr. Deepika Singh for NMR and Mr. Manoj Kushwaha for mass
data acquisition of compounds. This study was supported by
program project grant of CSIR BSC0108, Govt. of India.
Figure 1. New α-ketoamide derivatives of 16-dehydropregnenolone acetate,
pregnenolone acetate and progesterone
Supplementary data
Table 3. SeO2 mediated α-ketoamides of phenylacetaldehydes with secondary
amines
Experimental procedures and NMR of compounds are
available in supplementary data. Supplementary data can be
found in the online version at http://sciencedirect.com.
References and notes
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2
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2 (Amine)
Piperidine (2d)
Morpholine (2e)
6
6a
6f
Yieldb
65
Ph (7a)
2,6-Cl2C6H3 (7b)
70
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experiments were performed using impervious clothing, gloves,
protective mask, and safety goggles. All the reactions were
performed under exhaust ventilation. SeO2 (1.0 mmol) was
added to a solution of arylaldeydes or phenylacetones or
terminal alkyne (1.0 mmol) in dioxan (1 ml) followed by the
addition of catalytic amount of H2SO4 (in case of alkyne only)
and amine (1.0 mmol). The reaction mixture was then heated at
80 oC for 10-12 h and the product formation was monitored by
TLC. After completion, reaction mixture was partioned with
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Tetrahedron
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SeO2 mediated efficient synthesis of amides and
α-ketoamides of secondary amines with wide
substrate scope
Samdarshi Meena, Rohit Singh, Ram A. Vishwakarma, Mushtaq A Aga* and Shreyans K. Jain*
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Highlights
 Amidation and α-ketoamidation of
aromatic aldehydes, aryl alkynes and
acetophenones
 Practical, single pot and good yielding
method
 Applicable for synthesis of derivative of
natural product