A Nonoxidative Passerini Pathway to α-Ketoamides

Article abstract of DOI:10.1055/s-0035-1560632

The Passerini adducts of cinnamaldehyde derivatives may be efficiently converted into α-ketoamides when heated with a base under microwave conditions.

Full text of DOI:10.1055/s-0035-1560632

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Georg Thieme Verlag Stuttgart · New York
2015, 26, 2537–2540
2537
letter
Synlett
A. B. Abdessalem et al.
Letter
A Nonoxidative Passerini Pathway to α-Ketoamides
Abdelbari Ben Abdessalema,b
Raoudha Abderrahim*b
Laurent El Kaïm*a
OAc
O
RNC
+
neat
r.t.
NHR
Cs2CO3
NHR
CHO
Ar
Ar
Ar
CF3CH2OH
AcOH
O
O
1
40 °C, MW
15 min
a
Laboratoire de Synthèse Organique, CNRS, Ecole Poly-
Ar = Ph, 4-MeOC6H4, 2-furyl, etc.
R = Cy, t-Bu, 4-ClC6H4CH2, etc.
technique, ENSTA ParisTech- UMR 7652, Universtité Paris-
Saclay, 828 Bd des Maréchaux, 91128 Palaiseau, France
laurent.elkaim@ensta-paristech.fr
9 examples, 44–93% yields
b
Département de Chimie, Faculté des Sciences de Bizerte,
Université de Carthage, Carthage, Tunisia
abderrahim.raoudha@gmail.com
Received: 29.07.2015
Accepted after revision: 24.08.2015
Published online: 15.10.2015
then successfully added to related Passerini adducts
13
(Scheme 1,B). During the evaluation of the scope of these
DOI: 10.1055/s-0035-1560632; Art ID: st-2015-d0589-l
additions, we obtained under forcing conditions with some
poorer nucleophiles a decomposition of the Passerini ad-
ducts with the formation of traces of α-ketoamides. The
same was observed under heating with a base in the ab-
sence of palladium catalyst (ketoamide 2a, Scheme 1,C). As
this reaction might afford a simple and convenient access to
ketoamides, we decided to study further this transforma-
tion.
Abstract The Passerini adducts of cinnamaldehyde derivatives may be
efficiently converted into α-ketoamides when heated with a base under
microwave conditions.
Key words Passerini, isocyanide, α-ketoamide
α-Ketoamides have been the object of considerable at-
tention both as synthetic intermediates and as targets in
medicinal chemistry. Indeed, the integration of an α-ke-
toamide unit into amino acid derivatives has led to the dis-
closure of important families of reversible proteases inhibi-
O
O
R NC
1
R2
NHR1
O
O
Cs2CO3
DMF
NHCy
+
Ph
Ar
H
2
Ar
R CO2H
1
2
O
tors such as the Hepatitis C virus serine protease, calpain,
O
traces
Ar = Ph, R1 = Cy, R2 = Me
3
R2 = Me
or the NS2B-NS3 Dengue virus protease. The α-ketoamide
function is also present as a key pharmacophore in FK-506
or Rapamycin, natural products with interesting immuno-
R2 = H
diethylmalonate
Cs2CO3
Pd(PPh3)4
cat.
4
MeO2C
CO2Me
suppressive activity. Among the various synthetic methods
NHR1
5
NHR1
Ar
available for their preparation, the use of isocyanide-based
Ar
O
coupling reactions has been particularly useful as the ke-
toamides may be obtained from readily available acyl chlo-
rides or aldehydes. Isocyanide addition to acyl chlorides
O
Scheme 1 Tsuji–Trost reactions of Passerini cinnamaldehyde
(
Nef isocyanide reaction) followed by hydrolysis affords one
6
of the most straightforward preparation of α-ketoamides
whereas the use of aldehydes in Passerini reactions7 re-
quires a final oxidation of an intermediate α-hydroxyam-
ide. α-Ketoamides have also been obtained via different
Ugi/oxidation sequences or through using directly hydrox-
ylamine as the amino partner in the Ugi coupling. Herein,
we wish to present a new conversion of cinnamaldehydes
into α-ketoamides via a Passerini/saponification sequence.
Following our interest in palladium-triggered transfor-
mation of multicomponent adducts derived from isocya-
nide, we recently became interested in the use of cinnamal-
dehyde in Passerini reactions and showed that the choice
of formic acid as acidic partner in the Passerini step afford-
ed suitable adducts for efficient Tsuji–Trost reduction
The formation of 2a may be explained by a two-step
process involving a saponification of the ester and an isom-
erization of the double bond. To improve the fragmentation
step the use of different combinations of protic solvent and
bases were explored. While the use of ethanol (with NaOEt,
K CO or Cs CO ) was rather deceiving giving either mix-
8
9
10
2
3
2
3
tures at higher temperature or unreacted starting material,
the choice of trifluroethanol as solvent was more gratifying.
When 1a was treated at room temperature with one equiv-
alent of Cs CO for 24 hours only the alcohol 3a was ob-
2
3
tained in 83% isolated yield (Scheme 2). When the reaction
was performed at 100 °C under microwave conditions (15
min) we were pleased to observe the formation of the ex-
pected 2a isolated in 55% yield along with a small amount
11
12
(Scheme 1,A). Different nucleophilic carbon species were
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538
Synlett
A. B. Abdessalem et al.
Letter
O
These conditions were selected to perform the conver-
O
O
OH
Cs2CO3
(1 equiv) Ph
NHCy
sion of various Passerini adducts 1 into ketoamides 2 (Table
NHCy
O
Me
+ Ph
1
4
1
). Several carboxylic acids were engaged in the Passerini
NHCy CF CH OH
O
O
3
2
Ph
3
a
2a
step to evaluate the influence of the ester moiety on the
yields of the ketoamide formation. Acetic acid appears to be
the best carboxylic acid partner for this sequence giving
higher yields those obtained with pivalic acid (Table 1, en-
try 1 versus entry 2) or benzoic acid (Table 1, entry 3 versus
entry 4). The ketoamide synthesis shows a strong depen-
dence on the nature of the N-amide substituent. N-Cyclo-
hexylamide (Table 1, entries 1, 2, 7, 8, 10 and 11) gave good
yields of ketoamides whereas an N-tert-butyl group led to
slightly lower yields (Table 1, entries 5 and 9) and a N-4-
chlorobenzyl group gave much lower yields (Table 1, entries
3 and 4).
1
a
3
a (%) 2a (%)
r.t., 24 h:
MW, 100 °C, 15 min: 16
MW, 120 °C, 15 min:
MW, 140 °C, 15 min:
83
–
55
59
93
–
–
Scheme 2 α-Ketoamide formation from Passerini adduct 1a
of 3a. Raising the temperature to 140 °C led to a complete
conversion to 2a obtained in 93% yield after a simple filtra-
tion on silica gel.
Table 1 Conversion of Various Passerini Adducts 1 into Ketoamides 2
R4
NHR2
2 3
Cs CO
(1 equiv)
R4
NHR2
O
2
R NC
R3
1
neat
R3
R CO2H
O
R1
+
r.t., 3 d
MW, 140 °C
15 min
CHO
O
R3
O
R4
O
1
2
Entry
1
1
Yield (%)
84
2
Yield (%)
93
NHCy
O
NHCy
O
Ph
Ph
O
O
O
O
O
O
O
2a
1
aa
NHCy
O
Ph
2
3
4
5
63
77
84
70
2a
83
53
28
82
O
O
1
ab
O
Ph
N
H
Ph
N
H
Me
Cl
O
Cl
O
O
O
2
b
1
ba
O
Ph
N
H
Ph
2b
Cl
1
bb
O
O
Ph
N
H
Ph
N
H
O
2c
1
c
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Synlett
A. B. Abdessalem et al.
Letter
Table 1 (continued)
Entry
1
Yield (%)
2
Yield (%)
O
O
Ph
Ph
N
N
H
O
H
O
6
7
79
44
O
MeO
MeO
OMe
O
OMe
1
d
2d
MeO
NHCy
O
NHCy
MeO
O
60
74
O
O
2e
1
1
1
e
O
O
O
O
NHCy
8
79
66
62
60
NHCy
75
70
92
68
O
O
O
2f
f
O
O
O
O
N
H
9
N
H
O
O
O
2g
g
O
O
Ph
NHCy
Ph
1
0
1
NHCy
O
OH
O
2h
1
1
h
O
O
NHCy
1
NHCy
O
OH
O
2i
i
The two-step sequence may be performed on various
cinnamaldehyde analogues as shown by the successful for-
mation of ketoamides from the 4-methoxyaryl derivative
The ability of related Ugi adducts of cinnamaldehyde to be
depronated at this position has already been reported in
various preparations of heterocycles.15 The inability of 1h to
be transformed into an α-ketoamide (Table 1, entry 10) may
probably be explained following the same line as even if an
aryl substituent should increase the acidity, the steric effect
of the methyl group on the double bond probably limits the
formation of a planar conjugated anion. Whenever the acid-
ity of alcohols 3 is not lowered by such factors, cesium car-
bonate is expected to be basic enough for the isomerization
of 3 into 2. This was further confirmed by the high-yielding
transformation of 3a into 2a under the same conditions
(Scheme 3).
1
e (Table 1, entry 7) or the substituted furans 1f and 1g (Ta-
ble 1, entries 8 and 9). Indications on the mechanism of the
reaction may be given from the attempted formation of α-
ketoamide from Passerini adduct 1i. Under our standard
conditions, allylic alcohol 3i was the only product we could
recover (Table 1, entry 11). This may be explained by the
higher acidity of aryl-substituted allyllic esters 1a–1g com-
pared to 1i. With the former Passerini adducts, Cs CO is ba-
2
3
sic enough to deprotonate the α-position of the amide lead-
ing to a migration of the double bond in the protic solvent.
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A. B. Abdessalem et al.
Letter
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OH
OH
Cs2CO3
NHCy
NHCy
Ph
2
a
Ph
CF3CH2OH
MW, 140°C
O
O
98%
3a
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(
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To conclude, we have proposed an alternative formation
of α-ketoamides using isocyanide-based multicomponent
reactions. Though the process is limited to the formation of
ketoamides substituted at the 4 position by aryl or het-
eroaryl groups, the addition of transition metals prone to
trigger allylic alcohol isomerization may be envisioned for
aliphatic derivatives.
(
(
(
7) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126. For reviews, see:
(
(
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Acknowledgment
(
10) Grassot, J. M.; Masson, G.; Zhu, J. Angew. Chem. Int. Ed. 2008, 47,
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We thank the University of Bizerte for a fellowship given to A.
Ben Abdessalem and we thank the ENSTA ParisTech for financial sup-
port
9
(
3
(
(
12) Dos Santos, A.; El Kaïm, L. Synlett 2014, 25, 1901.
13) Cordier, M.; Dos Santos, A.; El Kaïm, L.; Narboni, N. Chem.
Commun. 2015, 51, 6411.
Supporting Information
(
14) Typical Procedure for 2a: The Passerini adduct 1a (102 mg,
Supporting information for this article is available online at
0
.338 mmol) and Cs CO (1.0 equiv, 110 mg) were suspended in
2 3
http://dx.doi.org/10.1055/s-0035-1560632.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
trifluoroethanol (TFE; 3.0 mL) in a 10-mL reaction glass vial
containing a magnetic stir bar. The vial was flashed with argon,
sealed and irradiated with stirring (CEM Discover Microwave.
Settings: 140 °C, 150 W) during 15 min. Upon completion of the
reaction time, the vial was cooled to r.t. The reaction mixture
was diluted with H O (30 mL) and extracted with CH Cl (3 × 15
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2
2
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(
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CH Cl –petroleum ether, 20:80) gave 2a as a white solid (mp
2 2
8
6.0–86.5 °C) isolated in 93% yield (81 mg); R 0.6 (CH Cl –
f 2 2
1
petroleum ether, 80:20). H NMR (400 MHz, CDCl ): δ = 7.26–
3
7.30 (m, 2 H, H-Ar), 7.17–7.22 (m, 3 H, H-Ar), 6.82 (d, J = 6.3 Hz,
1 H, NH), 3.67–3.77 (m, 1 H), 3.28 (t, J = 7.5 Hz, 2 H), 2.93 (t, J =
7.5 Hz, 2 H), 1.87–1.91 (m, 2 H, H-Cy), 1.60–1.76 (m, 3 H, H-Cy),
1
.32–1.42 (m, 2 H, H-Cy), 1.13–1.25 (m, 3 H, H-Cy). 13C NMR
(
(
(
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(
100.6 MHz, CDCl ): δ = 198.8, 159.0, 140.5, 128.6, 128.5, 126.3,
3
4
2
1
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3
–1
682, 1522, 1498, 1453, 1373, 1116, 892 cm
.
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©
Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2537–2540