Selenium dioxide-mediated synthesis of α-ketoamides from arylglyoxals and secondary amines

Article abstract of DOI:10.1016/j.tetlet.2012.05.136

A facile and expeditious synthetic approach for the synthesis of α-ketoamides 3 is described. A series of α-ketoamides 3 was synthesized via reaction of selenium dioxide-mediated oxidative amidation between arylglyoxals 1 and secondary amines 2, and accelerated with microwave irradiation. Our findings indicate that constrained amines, such as piperazine and piperidine exhibit higher conversions for this transformation. This reaction was explored by synthesizing a series of α-ketoamides 3 from various arylglyoxals 1 with cyclic and acyclic secondary amines 2.

Full text of DOI:10.1016/j.tetlet.2012.05.136

Tetrahedron Letters 53 (2012) 4151–4153
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Selenium dioxide-mediated synthesis of
and secondary amines
a-ketoamides from arylglyoxals
Arthur Y. Shaw a, Christine R. Denning a, Christopher Hulme a,b,
⇑
a Department of Pharmacology and Toxicology, College of Pharmacy, BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd., Oro Valley, AZ 85737, USA
b Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile and expeditious synthetic approach for the synthesis of a-ketoamides 3 is described. A series of
Received 12 April 2012
Revised 25 May 2012
Accepted 29 May 2012
Available online 7 June 2012
a-ketoamides 3 was synthesized via reaction of selenium dioxide-mediated oxidative amidation between
arylglyoxals 1 and secondary amines 2, and accelerated with microwave irradiation. Our findings indicate
that constrained amines, such as piperazine and piperidine exhibit higher conversions for this transfor-
mation. This reaction was explored by synthesizing a series of
a
-ketoamides 3 from various arylglyoxals 1
with cyclic and acyclic secondary amines 2.
Keywords:
Ó 2012 Elsevier Ltd. All rights reserved.
a-Ketoamides
Selenium dioxide
Microwave-assisted
Arylglyoxals
a
-Ketoamides1 are of great interest within the realms of medic-
O
O
R
N
SeO2
oxidative amidation
inal chemistry, and this structural scaffold represents a key frame-
H
Ar
RR'NH
+
Ar
R'
work of many biologically active agents in natural products such as
O
immunosuppressive drugs FK506 and rapamycin.2 Moreover,
a-
2
O
3
1
ketoamides have been developed as serine or cysteine protease
inhibitors,3 human cytosolic phospholipase A2 (GIVA PLA2) inhibi-
tors,4 androgen and estrogen receptor antagonists,5 p38 inhibitors,6
and cathepsin S inhibitors.7 Thanks to their pharmacological rele-
vance, a variety of synthetic methodologies to access them have
been developed, such as palladium-catalyzed amino(double)
carbonylation of organic halides8 and reactions of carbamoylstann-
ane and carbamoysilane with acid chlorides.9 Indeed more recently,
2,2-dibromoacetophenone was reported to undergo oxidative ami-
dation reaction with secondary amines via aerial oxidation with
moderate to good yields.10 Through efforts to develop an expedi-
Scheme 1. Synthesis of a-ketoamides 3 via oxidative amidation.
(entries 4, 5), no significant transformation was observed.11 We fur-
ther examined the oxidative amidation potential of pyridinum
dichromate (PDC) which resulted in slight improvement with 11%
conversion rate (entry 6).12 Subsequently, we turned our attention
to employ selenium dioxide as the oxidizing agent, Table 1 (entries
7–13). Encouragingly, the oxidative amidation product 3a was
significantly increased over all attempted aerial oxidations and
moreover, results suggested that reaction times were shortened
at higher temperatures (entries 10, 11). It was also noted that the
reaction could be completed in DCM or DCM/1,4-dioxane (3/1) with
comparable isolated yields (entries 9, 10). Compared to the above-
mentioned oxidative amidation of 2,2-dibromoacetophenone that
required 4 equiv. of secondary amines, this method dramatically
reduced the amount of required secondary amine for successful
SeO2-mediated oxidative amidation.13
tious and efficient protocol for the synthesis of
a-ketoamides 3,
we herein utilize commercially available arylglyoxal 1, an equal
oxidative status of 2,2-dibromoacetophenone, to undergo oxidative
amidation with secondary amines 2 mediated by selenium dioxide
under microwave irradiation to give the desired
Scheme 1.
The feasibility of aerial oxidative amidation was initially investi-
gated in Table 1 (entries 1–3) and upon microwave irradiation of
phenylglyoxal 1a with 1-phenylpiperazine 2a in the absence of an
oxidizing agent, no appreciable oxidative amidation product was
found.10 Indeed when hydrogen peroxide was utilized as an oxidant
a-ketoamides 3,
With optimized conditions in hand, a series of oxidative amida-
tions of phenyglyoxal 1a with various secondary amines 2a–2l was
thus carried out, Table 2. Results revealed that the desired a-keto-
amides were obtained in moderate to good yields, the reactivity
domain being broad including acyclic amines, five-membered,
six-membered, and seven-membered cyclic amines. Interestingly,
⇑
Corresponding author.
E-mail address: hulme@pharmacy.arizona.edu (C. Hulme).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.136

4152
A. Y. Shaw et al. / Tetrahedron Letters 53 (2012) 4151–4153
Table 1
Synthesis of a
-ketoamide 3aa
O
O
N
oxidant
solvent
N
+
N
HN
O
1a
O
2a
3a
Entry
2a (equiv)
Oxidant
Solvent
Temp (°C)
Time (min)
Conversionb (%) 3a
1
2
3
4
5
6
7
8
1.0
1.5
2.0
1.5
1.3
1.5
1.5
1.0
1.5
1.5
1.5
1.5
Air
Air
Air
DCM
DCM
DCM
1,4-Dioxane
—
100
100
100
100
80
100
100
100
100
100
120
120
20
20
20
20
120
20
20
20
20
20
10
20
Trace
<5
<5
H2O2
H2O2
PDC
SeO2
SeO2
SeO2
SeO2
SeO2
SeO2
<5
NDc
DCM
1,4-Dioxane
11
(100)b (37)d
(100)b (51)d
(100)b (60)d
(100)b (60)d
(100)b (58)d
(100)b (60)d
DCM/1,4-dioxane (3/1)
DCM/1,4-dioxane (3/1)
DCM
DCM/1,4-dioxane (3/1)
DCM/1,4-dioxane (3/1)
9
10
11
12
a
All reactions were performed with phenylglyoxal 1a (1 mmol), 1-phenylpiperazine 2a in the absence and presence of oxidant (1 mmol) in the corresponding solvents
(4 mL). All reactions were carried out under microwave irradiation.
b
The conversion rate was determined by LC–MS using Evaporative Light Scattering (ELS) detection
Not detected from LC–MS analysis. The reaction performed in 1 mL of 50% hydrogen peroxide solution under conventional heating.
Isolated yield.
c
d
Table 2
Synthesis of a
-ketoamides 3b–3la
Table 3
Preparation of
O
a
-ketoamides 3m–3va
O
R
N
SeO2
O
O
R
N
+
NHRR'
SeO2
R'
O
+
DCM/1,4-dioxane (3/1)
NHRR'
2a-p
Ar
Ar
R'
O
DCM/1,4-dioxane (3/1)
1a
2a-2k
O
O
3a-3l
Yieldb (%) 3
1b-k
3m-v
Yield(%)b
Entry
2
Entry Ar
2
1
1-Phenylpiperazine (2a)
60 (3a)
26 (3b)
47 (3c)
45 (3d)
80 (3e)
3
2
3
4
N,N-Dicyclohexylamine (2b)
N-Methylbenzylamine (2c)
Pyrrolidine (2d)
1
6-Methoxy-2-naphthyl
(1b)
3-Br-Ph (1c)
3-NO2-Ph (1d)
Benzo[d][1,3]dioxol-5-yl 1-p-Tolylpiperazine (2m)
(1e)
3,4-di-MeO-Ph (1f)
1-Phenylpiperazine (2a)
49 (3m)
2
3
4
4-Benzylpiperidine (2j)
4-Benzylpiperidine (2j)
85 (3n)
66 (3o)
56 (3p)
5
6
1-(4-Fluorophenyl)piperazine (2e)
N,N-Dibenzylamine (2f)
c
ND (3f)
7
8
9
10
11
12
1-(2-Furoyl)piperazine (2g)
1-(Pyrrolidinocarbonylmethyl)-piperazine (2h)
t-Butyl piperazine-1-carboxylate (2i)
4-Benzylpiperidine (2j)
1-(4-Fluorobenzyl)-1,4-diazepane (2k)
1-(4-Pyridyl)-piperazine (2l)
62 (3g)
52 (3h)
70 (3i)
74 (3j)
43 (3k)
50 (3l)
5
6
1-p-Tolylpiperazine (2m)
62 (3q)
3,4,5-tri-MeO-Ph (1g)
1-(4-Methoxyphenyl)piperazine 71 (3r)
(2n)
7
4-F-Ph (1h)
1-(4-Methoxyphenyl)piperazine 57 (3s)
(2n)
4-Phenylpiperidine (2o)
4-Phenylpiperidine (2o)
1-(2-Fluorophenyl)piperazine
(2p)
a
All reactions were performed with phenylglyoxal (1 mmol), secondary amine 2
(1.5 mmol), selenium dioxide (1 mmol) in the solvents of DCM/1,4-dioxane (3 mL/
1 mL). All reactions were heated at 100 °C for 20 min under microwave irradiation.
8
9
10
4-NO2-Ph(1i)
3,4-di-F-Ph (1j)
4-OMe-Ph (1k)
56 (3t)
72 (3u)
68 (3v)
b
Isolated yield.
Not detected from [LC/MS] analysis.
c
a
All reactions were performed with arylglyoxal 1 (1 mmol), secondary amine 2
(1.5 mmol), selenium dioxide (1 mmol) in the solvents of DCM/1,4-dioxane (3 mL/
1 mL). All reactions were heated at 100 °C for 20 min under microwave irradiation.
b
Isolated yield.
acyclic secondary amines bearing flexible appendages such as 2b
(N,N-dicyclohexylamine), 2c (N-methyl-benzylamine), and 2f
(N,N-dibenzylamine) displayed poor reactivity with isolated yields
of 26%, 47%, and 0%, respectively.
addition of amine 2a to phenylglyoxal 1a,
none 4 is produced, which subsequently generates intermediate
5 upon reaction with SeO2. Internal rearrangement of 6 via pro-
a-hydroxyacetophe-
Furthermore, arylglyoxals 1b–j containing electron-donating
and electron-withdrawing substituents and secondary amines 2a–
p were examined and exhibited good scope of reaction, Table 3. Most
promising conversions were observed with substituted piperidines
ton transfer affords the desired
selanediol.
a-ketoamide 3a with release of
such as 2j and 2o, of which the
a-ketoamide 3n (Entry 2) was
In summary, we have successfully demonstrated a facile synthe-
sis of -ketoamides via the oxidative amidation of arylglyoxals with
secondary amines mediated by selenium dioxide and assisted by
microwave irradiation in moderate to good yields. The application
of this method to generate additional structural diversity will be
disclosed in the due course.
isolated in 85% yield. Highly noteworthy was the performance of
primary amines in this sequence which failed to give any apprecia-
ble oxidized product. The generality and scope of the amine inputs
were clearly confined to secondary amines.
The plausible mechanism of this selenium dioxide driven oxi-
dative amidation is depicted in Figure 1. Upon nucleophilic
a

A. Y. Shaw et al. / Tetrahedron Letters 53 (2012) 4151–4153
4153
O
O
N
HN
H
SeO2
N
N
O
DCM/1,4-dioxane
O
2a
1a
3a
Se
HO
OH
N
O
N
N
O
O
N
N
H
N
O
O
O
O
O
H
O
Se
O
Se
OH
Se
OH
4
5
6
Figure 1. Plausible mechanism to generate aryl a-ketoamide 3a.
7. Cai, J.; Robinson, J.; Belshaw, S.; Everett, K.; Fradera, X.; van Zeeland, M.; van
Berkom, L.; van Rijnsbergen, P.; Popplestone, L.; Baugh, M.; Dempster, M.;
Bruin, J.; Hamilton, W.; Kinghorn, E.; Westwood, P.; Kerr, J.; Rankovic, Z.;
Arbuckle, W.; Bennett, D. J.; Jones, P. S.; Long, C.; Martin, I.; Uitdehaag, J. C. M.;
Meulemans, T. Bioorg. Med. Chem. Lett. 2010, 20, 6890.
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12051; (b) Munreaki, L.; Yoshinori, K. J. Chem. Soc. Chem. Comm. 2006, 8, 1739.
9. (a) Hua, R.; Takeda, H.; Abe, Y.; Tanaka, M. J. Org. Chem. 2004, 69, 974; (b) Chen,
J.; Cunico, R. F. J. Org. Chem. 2004, 69, 5509.
10. Shanmugapriya, D.; Shankar, R.; Satyanarayana, G.; Dahanukar, V. H.; Syam
Kumar, U. K.; Vembu, N. Synlett 2008, 19, 2945.
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12. Chiou, A.; Verger, R.; Kokotos, G. Lipids 2001, 36, 535.
Acknowledgments
We would like to thank the Office of the Director, NIH, and the
National Institute of Mental Health for funding (1RC2MH090878-
01). Particular thanks to N. Schechter (PSM) for copy editing.
References and notes
1. For recent reviews, see: (a) Dugave, C. Curr. Org. Chem. 2002, 6, 1397; (b) Wang,
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13. General procedure for preparation of aryl
a-ketoamide 3. Compound 3a: To a
mixture of phenylglyoxal monohydrate 1a (152 mg, 1.0 mmol), 1-
phenylpiperazine 2a (251 mg, 1.5 mmol) in DCM (3 mL) and 1,4-dioxane
(1 mL), selenium dioxide (111 mg, 1.0 mmol) was added to the solution. The
resulting mixture was heated at 100 °C for 20 min under microwave
irradiation. The solution was diluted with DCM (5 mL), washed with
NaHCO3(sat) (10 mL) and brine (10 mL). The organic layer was dried over
MgSO4, evaporated in vacuo to obtain the crude product 3a. The crude residue
3a was transferred to a pre-packed column (2.5 g) and was purified using the
ISCOTM purification system (12 g silica gel flash column; eluent, ethyl acetate:
hexane = 0 to 40%). The fractions containing the product were collected and the
solvent was evaporated under reduced pressure and dried under high-vacuum
system to afford 3a (176 mg, 60%). 1H NMR (400 MHz, CDCl3) d 8.03–7.94 (m,
2H), 7.69–7.60 (m, 1H), 7.55–7.47 (m, 2H), 7.31–7.23 (m, 2H), 6.94–6.88 (m,
3H), 3.91 (dd, J = 6.0, 4.5 Hz, 2H), 3.54–3.48 (m, 2H), 3.30–3.25 (m, 2H), 3.13
(dd, J = 5.9, 4.4 Hz, 2H) ppm. 13C NMR (100 MHz, CDCl3) d 191.33, 165.41,
150.74, 134.88, 133.17, 129.68, 129.28, 129.09, 120.90, 116.96, 49.89, 49.58,
45.81, 41.27 ppm. HRMS (ESI) Calcd for C18H19N2O2 (M+H)+ 295.1442, Found
295.1441.
5. Bridgeman, E.; Cavill, J. L.; Schofield, D. J.; Wilkins, D. S.; Tomkinson, N. C. O.
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Lum, C.; Lundstroem, J.; Miller, S.; Nakanishi, H.; Roberts, E.; Saiah, E.; Sullivan,
R.; Urban, J.; Wang, Z.; Larson, C. J. Bioorg. Med. Chem. Lett. 2010, 20, 4819.