Synthesis of α-Keto Amides by a Pyrrolidine/TEMPO-Mediated Oxidation of α-Keto Amines

Article abstract of DOI:10.1055/s-0035-1562541

A mild procedure has been developed for the synthesis of α-keto amides by α-oxidation of the corresponding α-keto amines mediated by pyrrolidine and TEMPO. The method can also be applied to the synthesis of α-keto thioamides and α-keto amidines.

Full text of DOI:10.1055/s-0035-1562541

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
L. Yu, P. Somfai
Letter
Synlett
Synthesis of α-Keto Amides by a Pyrrolidine/TEMPO-Mediated
Oxidation of α-Keto Amines
Lu Yu
pyrrolidine
TEMPO
Peter Somfai*
R2
N
O
PhN
O
R2
N
O
S
R2
N
O
R1
R3
R1
R3
Centre for Analysis and Synthesis, Department of Chemistry,
Lund University, 22100, Lund, Sweden
peter.somfai@chem.lu.se
R1
R3
r.t.
50 °C
N
S
Ph
r.t.
O2
thioamide
3 examples
up to 95% yield
α-imino ketone
3 examples
up to 60% yield
R2
N
O
R1
R3
O
α-keto amide
15 examples
up to 88% yield
Received: 04.05.2016
Accepted after revision: 29.07.2016
Published online: 16.08.2016
tion conditions, they involve complex procedures for the
preparation of the required starting materials, or they give a
limited range of the desired products. Therefore, the devel-
opment of an efficient and convenient method for the syn-
thesis α-keto amides from readily prepared starting materi-
als without the use of toxic reagents is a highly desirable
goal. The asymmetric organocatalytic oxidation of alde-
hydes and ketones via an enamine intermediate to give the
corresponding α-functionalized carbonyl derivatives has
proven to be a highly efficient process.12 In contrast, the
corresponding enamine-mediated oxidation of aldehydes
and ketones to give the corresponding α-carbonyl deriva-
tives has received considerable less attention, the only one
example being an autoxidation of an enamine derived from
an α,β-unsaturated ketone to give the corresponding 1,4-di-
one.13 Inspired by this observation, we became interested in
the possibility of preparing α-keto amides through an
enamine-mediated oxidation of readily available α-keto
amines, and here we describe our preliminary results in de-
tail. The method is also applicable to the synthesis of α-keto
thioamides or α-keto amidines.14,15
Amino ketone 1a was chosen as the model substrate,
and selected results from our optimization study are col-
lected in Table 1. Treatment of 1a with pyrrolidine (5 equiv.)
in CH2Cl2 under air resulted in the formation of α-keto am-
ide 2a in low yield (Table 1, entry 1); this, however, con-
firmed our original hypothesis. Repeating this reaction un-
der a balloon pressure of O2 resulted in a greatly improved
conversion, and 2a was isolated in 63% yield (entry 2).
TEMPO has been used as an oxygen source for asymmetric
α-oxyamination of aldehydes mediated by secondary
amines.16 When the oxidation of 1a was performed in the
presence of pyrrolidine, TEMPO (1 equiv), and O2, there was
no significant effect on the yield of 2a (entries 3), but the
reaction rate increased significantly (entries 2 and 3). The
same reaction repeated under a N2 atmosphere gave 2a in
DOI: 10.1055/s-0035-1562541; Art ID: st-2016-b0315-l
Abstract A mild procedure has been developed for the synthesis of
α-keto amides by α-oxidation of the corresponding α-keto amines
mediated by pyrrolidine and TEMPO. The method can also be applied to
the synthesis of α-keto thioamides and α-keto amidines.
Key words oxidation, catalysis, amides, ketones, amines, thioamides
The α-keto amide is an important structural subunit
that can be found in several natural products and pharma-
ceuticals having interesting biological activities. For exam-
ple, the 19-membered cyclic peptides cyclotheonamides A
and B are potent thrombin inhibitors that have been isolat-
ed from marine sponges, whereas isoquinoline-1,3,4-trione
derivatives are prominent inhibitors of caspase-3, an attrac-
tive therapeutic target.1 The α-keto amide moiety has also
found use in several important transformations, such as the
Pd-catalyzed intramolecular nucleophilic addition of aryl
halides to give 3-hydroxyoxindoles or the stereoselective
synthesis of α-silyloxy β-amino amides through a three-
component coupling with [dimethyl(phenyl)silyl]lithium
and a chiral butanesulfinylimine.2 Consequently, several ex-
cellent transition-metal-catalyzed methods have been de-
scribed for the preparation of α-keto amides from aryl ha-
lides,3 α-carbonyl aldehydes,4 terminal alkynes,5 α-oxocar-
boxylic acids,6 acetophenone,7 or other starting materials.8
To circumvent some of the drawbacks associated with the
use of transition metals, such high cost, toxicity, and air or
moisture sensitivity, recent efforts in this area have focused
on developing transition-metal-free protocols. As a result,
interesting alternative methods have been developed that
use iodine, hypervalent iodine reagents,9 DMSO,10 or other
oxidants.11 However, all these metal-free protocols are im-
practical because they require toxic oxidants or harsh reac-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

B
L. Yu, P. Somfai
Letter
Synlett
only 3% yield (entry 4), indicating that TEMPO is not the ac-
tual oxidant in this reaction. Decreasing the amount of
TEMPO was beneficial and the optimal result, in terms of
both the yield and reaction rate, was obtained by using 0.1
equivalents of the additive (entries 5–7). Decreasing the
amount of pyrrolidine was, however, detrimental and re-
sulted in a lower yield of 2a (entries 7–10). Indeed, when
the reaction was performed without any added pyrrolidine,
no product was obtained, suggesting that the α-oxidation
proceeds through an enamine intermediate. The effect of
using other secondary amines to promote the reaction was
then investigated, but none of the alternatives investigated
was superior to pyrrolidine (entries 7 and 11–13). However,
the effect of the solvent on the yield of 2a was significant
(entries 7, 14–19). Whereas most solvents gave lower or
comparable yields to CH2Cl2, the use of MeCN gave α-keto
amide 2a in 83% yield, and this also defines the current best
conditions for this reaction.
The scope of the pyrrolidine-mediated TEMPO-cata-
lyzed oxidation of α-keto amines was then investigated
(Scheme 1).17,18 Various N-alkyl groups were well tolerated
in the oxidation reaction, giving the corresponding α-keto
amides 2a–c in high yields. On changing from aryl dialkyl
amines to trialkyl amines, the oxidation became signifi-
cantly slower, and the reaction temperature had to be
raised to 50 °C to achieve an acceptable conversion to prod-
ucts 2d and 2f. It appears that the reaction is sensitive to
substituents in the benzoyl moiety, as an electron-with-
drawing group resulted in a decreased yield of 2g, whereas
the presence of a p-bromo or p-methoxy substituent gave
the corresponding products 2h and 2i in 72 and 75% yield,
respectively. Substrate 1j containing a cinnamoyl moiety
gave 2j in 43% yield, whereas the corresponding methyl ke-
tone failed to give any of the desired oxidation product 2m.
Next, the effect of altering the substituent on the aniline
moiety was investigated and it was found that electron-do-
nating or weakly electron-withdrawing para-substituents
were tolerated (2k, 2l), whereas the para-nitro derivative
1n gave only a trace of 2n. Finally, attempts to oxidize in-
dole derivative 1o under the standard reaction conditions
failed to give the desired product 2o.
Table 1 Optimizing the Reaction Conditionsa
amine
TEMPO
O
O
N
N
Ph
Ph
Ph
Ph
solvent
r.t., O2
O
1a
2a
O
COOH
N
H
N
H
N
H
N
H
III
IV
I
II
Entry
Solvent
Amine (equiv)
TEMPO (equiv) Yieldb (%)
Encouraged by these results, we extended our investiga-
tion to include nitrosobenzene as the oxidant. As shown in
Scheme 2, oxidation of 1a, 1o, and 1h by using nitrosoben-
zene afforded amidines 2p–r in 41, 60, and 49% yield, re-
spectively.15 When elemental sulfur was used as the oxi-
dant, thioamides 2s–u were obtained in high yields.
In conclusion, we have developed a mild procedure
for the oxidation of α-keto amines to give the correspond-
ing α-keto amides, α-thioamides, or α-keto amidines. It is
believed that the reaction proceeds through an enamine in-
termediate that is subsequently oxidized by TEMPO or O2.
1c
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
I (5)
I (5)
I (5)
I (5)
I (5)
I (5)
I (5)
I (3)
I (1)
—
0
23
0
63 (11)d
66 (52)d
3
3
1
4e
5
1
0.7
0.4
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
62
6
68
7
69
8
45
9
13
10
11
12
13
14
15
16
17
18
19
0
II (5)
III (5)
IV (5)
I (5)
I (5)
I (5)
I (5)
I (5)
–
43
Acknowledgment
12
This work was supported by the Swedish Research Council, the Chi-
nese Scholarship Council, and Lund University. We thank Dr. K. Popov
for helpful discussions.
NR
45
46
DMSO
66
Supporting Information
1,4-dioxane
MeCN
44
Supporting information for this article is available online at
83
http://dx.doi.org/10.1055/s-0035-1562541.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
pyrrolidinef
64
a Reaction conditions: 1a (0.3 mmol), amine, TEMPO, stirring, O2 (balloon
pressure), solvent (1 mL), r.t., 20 h.
b Yields determined by GC analysis with naphthalene as an internal standard.
c Sealed tube under air, 20 h.
d Yield by GC analysis after 1.5 h.
e The reaction was performed under N2 with deoxygenated solvent.
f Pyrrolidine (1 mL) was used as the solvent.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

C
L. Yu, P. Somfai
Letter
Synlett
R2
N
O
pyrrolidine
TEMPO
R2
O
N
R1
R3
R1
R3
MeCN
r.t., O2
O
2
1
O
Bn
N
O
O
O
O
N
N
N
N
O
O
O
O
O
2d, 63%b
2e, 49%b
2a, 87%
2b, 87%
2c, 88%
O
O
O
O
O
O
N
N
N
N
O
N
O
O
O
O
NO2
Br
OMe
2f, 54%b
2g, 34%c
2i, 75%d
2h, 72%
2j, 43%
O
O
O
O
O
N
N
N
O
N
N
O
O
O
O
MeO
Br
O2N
2l, 80%d
2k, 79%
2m, trace
2n, trace
2o, no reaction
Scheme 1 Oxidation of α-keto amines 1 to give α-keto amides 2. Reaction conditions: 1 (0.3 mmol), pyrrolidine (1.5 mmol, 123 μL), TEMPO (0.03
mmol, 4.7 mg), MeCN (1 mL), under O2, r.t., 20 h. a Stirred at 50 °C for 20 h. b Stirred at –25 °C for 20 h. c Stirred at r.t. for 72 h.
R5
N
O
pyrrolidine
TEMPO
R.; Khanwalkar, H.; Germain, P.; Lemaire, G.; Rodríguez-Barrios,
F.; Gronemeyer, H.; de Lera, Á. R. Bioorg. Med. Chem. 2009, 17,
4345. (d) Stein, M. L.; Cui, H.; Beck, P.; Dubiella, C.; Voss, C.;
Krüger, A.; Schmidt, B.; Groll, M. Angew. Chem. Int. Ed. 2014, 53,
1679.
R5
N
O
R4
R4
Ar
Ar
MeCN
argon
X
1
2
(2) (a) Jia, Y.-X.; Katayev, D.; Kündig, E. P. Chem. Commun. 2010, 46,
130. (b) Sun, Z.; Liu, H.; Zeng, Y.-M.; Lu, C.-D.; Xu, Y.-J. Org. Lett.
2016, 18, 620.
O
O
(3) (a) Uozumi, Y.; Arii, T.; Watanabe, T. J. Org. Chem. 2001, 66,
5272. (b) Iizuka, M.; Kondo, Y. Chem. Commun. 2006, 1739.
(c) Liu, J.; Zhang, R.; Wang, S.; Sun, W.; Xia, C. Org. Lett. 2009, 11,
1321. (d) Wang, Y.; Yang, X.; Zhang, C.; Yu, J.; Liu, J.; Xia, C. Adv.
Synth. Catal. 2014, 356, 2539. (e) Zhang, C.; Liu, J.; Xia, C. Org.
Biomol. Chem. 2014, 12, 9702.
N
N
N
N
O
N
Br
N
2p, 41%
2q, 60%
2r, 49%
(4) Zhang, C.; Zong, X.; Zhang, L.; Jiao, N. Org. Lett. 2012, 14, 3280.
(5) (a) Sagadevan, A.; Ragupathi, A.; Lin, C.-C.; Hwu, J. R.; Hwang, K.
C. Green Chem. 2015, 17, 1113. (b) Zhang, C.; Jiao, N. J. Am. Chem.
Soc. 2010, 132, 28.
(6) (a) Li, D.; Wang, M.; Liu, J.; Zhao, Q.; Wang, L. Chem. Commun.
2013, 49, 3640. (b) Wang, H.; Guo, L. N.; Duan, X.-H. Org. Biomol.
Chem. 2013, 11, 4573. (c) Guin, S.; Rout, S. K.; Gogoi, A.; Ali, W.;
Patel, B. K. Adv. Synth. Catal. 2014, 356, 2559.
(7) (a) Du, F.-T.; Ji, J.-X. Chem. Sci. 2012, 3, 460. (b) Zhang, J.; Wei, Y.;
Lin, S.; Liang, F.; Liu, P. Org. Biomol. Chem. 2012, 10, 9237.
(8) (a) El Kaim, L.; Gamez-Montaño, R.; Grimaud, L.; Ibarra-Rivera,
T. Chem. Commun. 2008, 1350. (b) Zhang, C.; Xu, Z.; Zhang, L.;
Jiao, N. Angew. Chem. Int. Ed. 2011, 50, 11088. (c) Xing, Q.; Shi,
L.; Lang, R.; Xia, C.; Li, F. Chem. Commun. 2012, 48, 11023.
(d) Tang, R.-Y.; Guo, X.-K.; Xiang, J.-N.; Li, J.-H. J. Org. Chem.
2013, 78, 11163. (e) Zhang, J.; Liu, Y.; Chiba, S.; Loh, T.-P. Chem.
Commun. 2013, 49, 11439. (f) Wan, J.-P.; Lin, Y.; Cao, X.; Liu, Y.;
Wei, L. Chem. Commun. 2016, 52, 1270.
Bn
N
O
O
O
O
N
S
N
S
S
2s, 95%a
2t, 87%a
2u, 75%a
Scheme 2 Conversion of α-keto amines 1 into amidines or thioamides.
Reaction conditions: 1 (0.3 mmol), nitrosobenzene (0.6 mmol, 64 mg),
pyrrolidine (0.3 mmol, 25 μL), TEMPO (0.03 mmol, 4.7 mg), MeCN (1
mL), under argon, r.t., 20 h. a A mixture of 1a (0.3 mmol), sulfur (10
equiv), pyrrolidine (1.5 mmol, 123 μL) and TEMPO (0.03 mmol, 4.7 mg)
in MeCN (1 mL) was stirred under argon at 50 °C for 20 h.
References and Notes
(1) (a) Fusetani, N.; Matsunaga, S.; Matsumoto, H.; Takebayashi, Y.
J. Am. Chem. Soc. 1990, 112, 7053. (b) Chen, Y.-H.; Zhang, Y.-H.;
Zhang, H.-J.; Liu, D.-Z.; Gu, M.; Li, J.-Y.; Wu, F.; Zhu, X.-Z.; Li, J.;
Nan, F.-J. J. Med. Chem. 2006, 49, 1613. (c) Álvarez, S.; Álvarez,
(9) (a) Lamani, M.; Prabhu, K. R. Chem. Eur. J. 2012, 18, 14638.
(b) Wei, W.; Shao, Y.; Hu, H.; Zhang, F.; Zhang, C.; Xu, Y.; Wan, X.
J. Org. Chem. 2012, 77, 7157. (c) Zhang, X.; Wang, L. Green Chem.
2012, 14, 2141. (d) Zhao, Q.; Miao, T.; Zhang, X.; Zhou, W.;
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

D
L. Yu, P. Somfai
Letter
Synlett
Wang, L. Org. Biomol. Chem. 2013, 11, 1867. (e) Deshidi, R.;
Kumar, M.; Devari, S.; Shah, B. A. Chem. Commun. 2014, 50,
9533. (f) Huang, H.; He, G.; Zhu, X.; Jin, X.; Qiu, S.; Zhu, H. Eur. J.
Org. Chem. 2014, 7174. (g) Liu, L.; Du, L.; Zhang-Negrerie, D.; Du,
Y.; Zhao, K. Org. Lett. 2014, 16, 5772. (h) Deshidi, R.; Devari, S.;
Shah, B. A. Eur. J. Org. Chem. 2015, 1428.
(15) Martinez-Ariza, G.; McConnell, N.; Hulme, C. Org. Lett. 2016, 18,
1864.
(16) (a) Sibi, M. P.; Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124.
(b) Kano, T.; Mii, H.; Maruoka, K. Angew. Chem. Int. Ed. 2010, 49,
6638.
(17) N-(4-Methoxyphenyl)-N-methyl-2-oxo-2-phenylacetamide
(2k); Typical Procedure
(10) Mupparapu, N.; Khan, S.; Battula, S.; Kushwaha, M.; Gupta, A. P.;
Ahmed, Q. N.; Vishwakarma, R. A. Org. Lett. 2014, 16, 1152.
(11) (a) Yang, Z.; Zhang, Z.; Meanwell, N. A.; Kadow, J. F.; Wang, T.
Org. Lett. 2002, 4, 1103. (b) Song, B.; Wang, S.; Sun, C.; Deng, H.;
Xu, B. Tetrahedron Lett. 2007, 48, 8982. (c) Grassot, J. M.;
Masson, G.; Zhu, J. Angew. Chem. Int. Ed. 2008, 47, 947.
(d) Mossetti, R.; Pirali, T.; Tron, G. C.; Zhu, J. Org. Lett. 2010, 12,
820.
(12) (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471. (b) Kano, T.; Mii, H.; Maruoka, K. J. Am. Chem.
Soc. 2009, 131, 3450. (c) Jadhav, M. S.; Righi, P.; Marcantoni, E.;
Bencivenni, G. J. Org. Chem. 2012, 77, 2667. (d) Simonovich, S. P.;
Van Humbeck, J. F.; MacMillan, D. W. Chem. Sci. 2012, 3, 58.
(e) Abeykoon, G. A.; Chatterjee, S.; Chen, J. S. Org. Lett. 2014, 16,
3248. (f) Walaszek, D. J.; Rybicka-Jasińska, K.; Smoleń, S.;
Karczewski, M.; Gryko, D. Adv. Synth. Catal. 2015, 357, 2061.
(g) Lifchits, O.; Demoulin, N.; List, B. Angew. Chem. Int. Ed. 2011,
50, 9680.
Pyrrolidine (123 μL, 1.5 mmol) was added to a solution of
amino ketone 1k (76.5 mg, 0.3 mmol) and TEMPO (4.7 mg, 0.03
mmol) in MeCN (1 mL) under O2 (balloon pressure). The
mixture was then stirred at r.t. for 20 h (TLC monitoring) then
was concentrated. The residue was purified by column chroma-
tography [silica gel, heptane–EtOAc (5:1)] to give a slightly
yellow oil; yield: 63.4 mg (79%); 1H NMR (400 MHz, CDCl3): δ =
7.88–7.77 (m, 2 H), 7.58–7.49 (m, 1 H), 7.45–7.35 (m, 2 H),
7.08–7.00 (m, 2 H), 6.74–6.63 (m, 2 H), 3.68 (s, 3 H), 3.42 (s, 3
H); 13C NMR (100 MHz, CDCl3): δ = 191.1, 167.1, 158.9, 134.1,
133.5, 133.4, 129.2, 128.6, 128.3, 114.5, 55.2, 36.3; HRMS (ESI):
m/z [M + H]+ calcd for C16H16NO3: 270.1130; found: 270.1128.
(18) (3E)-N-Methyl-2-oxo-N,4-diphenylbut-3-enamide (2j)
Slightly yellow oil; yield: 34.6 mg (43%); 1H NMR (400 MHz,
CDCl3): δ = 7.60 (d, J = 16.3 Hz, 1 H), 7.56–7.49 (m, 2 H), 7.47–
7.37 (m, 3 H), 7.36–7.26 (m, 3 H), 7.23–7.16 (m, 2 H), 6.77 (d, J =
16.3 Hz, 1 H), 3.45 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ =
190.1, 167.0, 147.5, 141.7, 134.0, 131.3, 129.6, 129.0, 128.7,
128.1, 126.5, 123.4, 36.5; HRMS (ESI): m/z [M + H]+ calcd for
(13) Malhotra, S. K.; Hostynek, J. J.; Lundin, A. F. J. Am. Chem. Soc.
1968, 90, 6565.
(14) Li, H.-Z.; Xue, W.-J.; Wu, A.-X. Tetrahedron 2014, 70, 4645.
C17H16NO2: 266.1181; found: 266.1179.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D