Reaction between (Z)-Arylchlorooximes and α-Isocyanoacetamides: A procedure for the synthesis of Aryl-α-ketoamide amides

Article abstract of DOI:10.1021/jo5005444

(Z)-Arylchlorooximes and α-isocyanoacetamides undergo a smooth reaction to produce 1,3-oxazol-2-oxime derivatives in good yields. Opening of the oxazole ring and deoximation reaction give a facile access to aryl-α-ketoamide amides, a class of privileged s

Full text of DOI:10.1021/jo5005444

Article
pubs.acs.org/joc
Reaction between (Z)‑Arylchlorooximes and α‑Isocyanoacetamides:
A Procedure for the Synthesis of Aryl-α-ketoamide Amides
Mariateresa Giustiniano,*,† Valentina Mercalli,‡ Hilde Cassese,† Salvatore Di Maro,† Ubaldina Galli,‡
Ettore Novellino,† and Gian Cesare Tron*,‡
†Dipartimento di Farmacia, Universita
̀
di Napoli “Federico II”, via D. Montesano 49, 80131 Napoli, Italy
‡Dipartimento di Scienze del Farmaco, Universita
Novara, Italy
̀
degli Studi del Piemonte Orientale “A. Avogadro”, Largo Donegani 2, 28100
S
* Supporting Information
ABSTRACT: (Z)-Arylchlorooximes and α-isocyanoacetamides under-
go a smooth reaction to produce 1,3-oxazol-2-oxime derivatives in
good yields. Opening of the oxazole ring and deoximation reaction give
a facile access to aryl-α-ketoamide amides, a class of privileged scaffolds
in medicinal chemistry and important synthetic intermediates in
organic chemistry.
A drawback of the reaction between acyl chlorides and α-
INTRODUCTION
■
isocyanoacetamides3 was the lack of reactivity of the latter with
aroyl chlorides due to the concomitant reduced nucleophilicity
of the isocyano group and the reduced electrophilicity of the
aroyl chloride coupled with the impossibility for the latter to
generate the ketene intermediate.3
It is clear for all the organic chemists involved in the search for
novel isocyanide-mediated organic reactions1 that the discovery
of new suitable electrophilic partners for isocyanides can give a
direct access to novel two- or multicomponent transformations2
and consequently to an innovative way to synthesize known
molecular scaffolds or give access to unknown molecular
frameworks.
In this context, it is interesting to highlight the use of α-
isocyanoacetamides 2 along with acyl chlorides3 1 or
diazocarbonyl esters4 to give substituted 2-acyl-5-amino-
oxazoles 3. As 5-aminooxazoles are not stable under acid
conditions,5 the 2-acyl-5-aminooxazoles can be hydrolyzed to
give α-ketoamide amides 4 (Scheme 1).
Any attempts (higher temperatures, neat conditions, MW
heating) to react, in a productive way, an aroyl chloride with an
α-isocyanoacetamides failed.
Herein, we fill the gap by presenting our results on the
reaction between (Z)-chlorooximes10 and α-isocyanoaceta-
mides and its potential in the synthesis of medicinal relevant
aryl α-ketoamide amides.
RESULTS AND DISCUSSION
■
Our recent finding that nitrile N-oxide species (generated via
base dehydrochlorination of (Z)-chlorooximes 5, Huisgen’s in
situ method)11 are able to react in a stereoselective way with
isocyanides 7 under mild reaction conditions (TEA, room
temperature, dichloromethane) to give a nitrilium ion 8, which
can be further intercepted by a third nucleophile,12,13 has paved
the way for an extensive use of this reaction which, to our
surprise, has eluded chemists (Scheme 2).
Scheme 1. Reaction between Acyl Chlorides and α-
Isocyanoacetamides
A possible explanation of this missed opportunity might be
found in a 1965 paper14 where it was documented that nitrile
N-oxides 10 and isocyanides 11 react to give isocyanates 12 and
nitriles 13 according to the reaction reported in Scheme 3.
As no mechanism for this reaction was reported, we propose
the following scenario: the isocyanide 11 attacks, in a
stereoselective way,15,16 the electrophilic carbon of the nitrile
The latter are warhead scaffolds in medicinal chemistry due
to their activity as inhibitors, since they can react with the key
cysteine or lysine residues in protease,6 lipase,7 and histone
deacetylase,8 or to the fact that they constitute useful
intermediates for a variety of transformations in organic
chemistry.9
Received: March 14, 2014
© XXXX American Chemical Society
A
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Scheme 2. Proposed Scheme for the Formation of Novel MCRs via Nitrile N-Oxide Species
Scheme 3. Reported Reaction between Nitrile N-Oxides and
Isocyanides
N-oxide 10 to give the intermediate a. This intermediate is then
Figure 1. Intramolecular trapping of the nascent nitrilum ion.
intramolecularly intercepted by the oxygen of the nitrile N-
oxide to give the highly unstable 4H-1,2-oxazet-4-imine
derivative b17 which, by a retro [2 + 2] cycloaddition, provides
the corresponding cyanide 12 and isocyanate 13 (Scheme 4).
It appears evident, therefore, that the presence of a third
nucleophile in the reaction mixture can preclude the formation
diversity: the amide function derived from cyclic secondary
amines (as for 20, 30−32, 36, 37) or noncyclic secondary
amine (as for 35) and the α-substitution (methyl- or benzyl, 30
and 31, 32, respectively) (Figure 3).
Arylchlorooximes were synthesized by chlorination of the
corresponding oximes with N-chlorosuccinimide,20 while α-
isocyanoacetamides were easily accessible by amidation of the
of the high energy content 4H-1,2-oxazet-4-imine derivative17
b
driving the reaction toward another synthetic pathway as
reported by us.12,13,18
In addition, it is reasonable to assume that an isocyanide
containing an internal nucleophile can intramolecularly
intercept the nitrilium ion species generating a novel molecular
framework (Figure 1).
Inspired by pioneering work by Zhu, who demonstrated that
α-isocyanoacetamides 2 can take part in a three-component
reaction with aldehydes 15 and primary or secondary amines 16
to afford 5-aminooxazoles 17 (through interception of the
nitrilium ion by the oxygen atom of the amide),19 we reasoned
that α-isocyanoacetamides could, in principle, react with the
nitrile N-oxides and then intermolecularly intercept the nascent
nitrilium species (Figure 2).
As a starting point for our study, we chose the reaction
between (Z)-phenylchlooroxime 19 and the 4-
(isocyanoacetyl)morpholine 20. The reaction was carried out
without TEA and with 1 equiv of TEA in dichloromethane at
room temperature. To our delight, the reaction with 1 equiv of
TEA was complete after 2 h giving the desired compound 21 in
74% yield after column chromatography (Scheme 5).
Not surprisingly, when the reaction was carried out without
TEA we did not notice the formation of the desired product 21
and the syn-phenylchlorooxime 19 was recovered after column
chromatography.
Using these already optimized conditions (1 equiv of TEA,
rt, DCM), the scope and limitations of this novel reaction were
explored. (Z)-Phenylchloroxime (19) or (Z)-phenylchlorox-
imes bearing electron-withdrawing (22, 26, 27, 28, 29) or
electron-donating (methyl- or methoxy-, 23 and 24, respec-
tively) substituents on the para position were chosen, as well as
one (Z)-heteroarylchloroxime with a thiophene ring (25). α-
Isocyanoacetamides (20, 30−37) exhibit two points of
corresponding α-isocyanomethyl ester using the Domling
̈
procedure;21 to obtain the α-substituted α-isocyanoacetamides
the alkylation was carried out in the presence of cesium
hydroxide.22
The reaction appeared to be quite general, not depending on
electronic factors, as (Z)-arylchloroximes bearing both electron-
withdrawing and electron-donating substituents reacted
smoothly with the different isocyanoacetamides giving the
desired 1,3-oxazol-2-oxime derivatives (38−54) in good yields
(ranging from 32% to 88%) (Figure 4).
When isocyanoacetamide 36 was used, TEA was not
necessary, as the basic nitrogen of piperazine was able to
trigger the formation of the nitrile N-oxide species. The
reaction failed when a secondary amide was present such as in
the isocyanoacetamides (33 and 34); anyway this behavior was
not unexpected as it was already reported by Zhu.19,23
1,3-Oxazol-2-oximes were not stable molecules with isomer-
ization of the oxime, especially when the oxazole ring was
substituted at the 4-position, and formation of decomposition
products. Although we have fully characterized them, they
cannot be stored for long time (even at 0 °C).
At the beginning, we attempted a one-pot procedure for the
conversion of 1,3-oxazol-2-oximes into aryl-α-ketoamides.
Hydrolysis of these intermediates in the presence of HCl, at
room temperature, afforded the oxime−dipeptide analogue 55,
favoring, at the same time, the partial isomerization of the
oxime. When the reaction was heated, we did observe the
hydrolysis of the oxime and also the formation of several
byproducts, which decrease the yield and make difficult the
chromatographic purification. For these reasons, we opted to
use milder catalysts as a Lewis acid, and we identified the
Scheme 4. Proposed Mechanism for the Formation of Isocyanates and Cyanides Starting from Nitrile N-Oxides and Isocyanides
B
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Figure 2. Comparison between Zhu’s work and the reaction described in this work.
We believe that this new protocol can find application in the
synthesis of tailored aryl α-ketoamide amides given their
importance in both organic and medicinal chemistry.
Scheme 5. Reaction between (Z)-Phenylchlorooxime and 4-
(Isocyanoacetyl)morpholine
EXPERIMENTAL SECTION
■
General Methods. Commercially available reagents and solvents
were used without further purification. Dichloromethane was dried by
distillation from P2O5 and stored over activated molecular sieves (4 Å).
When necessary, the reactions were performed in oven-dried glassware
under a positive pressure of dry nitrogen. Melting points were
determined in open glass capillaries and are uncorrected. All the
copper(II) chloride24 as the reagent of choice. After the
aminooxazole ring was opened with HCl,25 the deoximation
reaction in the presence of copper(II) chloride was carried out.
Both reactions proceeded well and only a purification step was
required (Scheme 6).
By using this protocol, we prepared different aryl-α-
ketoamide amides (57−73) in good yields (Figure 5).
compounds were characterized by IR. H and 13C APT NMR were
1
recorded on a 300 MHz. Mass spectrometry was equipped with an ESI
source and an ion-trap detector. HRMS were recorded on ORBITRAP
mass spectrometer equipped with an ESI source. Chemical shifts (δ)
are reported in parts per million (ppm) relative to the residual solvent
peak. Column chromatography was performed on silica gel (70−230
mesh ASTM) using the reported eluents. Thin-layer chromatography
(TLC) was carried out on 5 × 20 cm plates with a layer thickness of
0.25 mm (silica gel 60 F254). When necessary, they were developed
with KMnO4. Elemental analysis (C, H, N) of all of the new
compounds were within 0.4% of the calculated values. Chloroximes
19 and 22−29 are not new, and they were prepared following
literature procedure.20 Isocyanoacetamides 20 and 33−36 were
CONCLUSIONS
■
In conclusion a general and straightforward methodology to
prepare structurally diverse aryl α-ketoamide amides has been
demonstrated. It is important to highlight that the entire
sequence of reactions is realized under mild reaction conditions
avoiding the use of expensive coupling agents and using simple
and easily available starting materials ((Z)-arylchlorooximes
and α-isocyanoacetamides). This method is complementary to
those previously reported for the synthesis of alkyl α-ketoamide
amides.3
prepared following Domling’s procedure,21 while isocyanoacetam-
̈
mides 30−32 were prepared following Zhu’s procedure.22
Synthesis of 4-Benzyl-1-(isocyanoacetyl)piperidine (37).
Methyl isocyanoacetate (1 equiv) was reacted with 4-benzylpiperidine
(1 equiv) overnight under neat conditions. The solution was
evaporated and the crude was purified by column chromatography
1
Ex/EtOAc 7:3 to give 37 as amorphous solid (yield 75%): H NMR
Figure 3. Structure of (Z)-chlorooximes and α-isocyanoacetamides.
C
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Figure 4. Synthesized 1,3-oxazol-2-oxime derivatives.
Scheme 6. Acid Hydrolysis and Deoximation of 1,3-Oxazol-2-oximino Derivatives
(400 MHz, CDCl3) δ 7.26−7.09 (m, 5H), 4.45 (br d, 1H), 4.24 (br d,
2H), 3.45 (br d, 1H), 2.93 (br t, 1H), 2.51−2.49 (m, 3H), 1.73−1.64
(m, 3H), 1.17−1.10 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 160.7,
160.4, 139.7, 129.1, 128.3, 126.1, 45.6, 44.6, 42.8, 42.6, 37.7, 32.0, 31.3;
HRMS (ESI) m/z (M + H)+ calcd for C15H18N2O 242.1419, found
242.1422.
General Preparation of 1,3-Oxazol-2-oximes (21, 38−54).
The chlorooxime (1 equiv) was dissolved in dry dichloromethane, and
α-isocyanoacetamide (1 equiv) was added dropwise or portionwise at
room temperature. Finally, TEA (1 equiv) was added dropwise (the
reaction is slightly exothermic and on a large scale the addition should
be done at 0 °C), and the reaction was stirred at room temperature
under a nitrogen atmosphere until all the chlorooxime was consumed
(typically 2−3 h as judged by TLC). The reaction mixture was
concentrated under reduced pressure, and the crude material was
purified by column chromatography.
2H), 7.44−7.40 (m, 3H), 6.26 (br s, 1H), 3.78 (br t, 4H), 3.16 (br t,
4H); 13C NMR (75 MHz, CDCl3) δC 156.2, 146.9, 141.9, 133.0,
129.5, 128.4 (2C), 101.5, 65.8, 47.3; HRMS (ESI) m/z (M + Na)+
calcd for C14H15N3NaO3 296.1011, found 296.1012.
(Z)-(4-Chlorophenyl)(5-morpholinooxazol-2-yl)methanone
Oxime (38). Starting material: chlorooxime 150 mg (0.79 mmol),
isocyanoacetamide 122 mg (0.79 mmol). The crude material was
purified by column chromatography (PE/EtOAc 6:4) to give 187 mg
of product as a yellow solid (yield 78%): 1H NMR (300 MHz, CDCl3)
δH 7.60−7.56 (m, 2 H, AA′XX′), 7.44−7.36 (m, 2 H, AA′XX′), 6.26
(br s, 1H), 3.80−3.77 (m, 4H), 3.18−3.15 (m, 4H); 13C NMR (75
MHz, CDCl3) δC 156.2, 146.5, 141.0, 135.6, 131.5, 129.7, 128.7, 101.6,
65.7, 47.2; HRMS (ESI) m/z (M + H)+ calcd for C14H14ClN3O3
307.0724, found 307.0727.
(Z)-(4-Methyl-5-(pyrrolidin-1-yl)oxazol-2yl)phenylmethanone
Oxime (39). Starting material: chlorooxime 150 mg (0.96 mmol),
isocyanoacetamide 147 mg (0.96 mmol). The crude material was
purified by column chromatography (PE/EtOAc 7:3) to give 180 mg
(Z)-(5-Morpholinooxazol-2-yl)phenylmethanone Oxime (21).
Starting material: chlorooxime 150 mg (0.96 mmol), isocyanoaceta-
mide 148 mg (0.96 mmol). The crude material was purified by column
chromatography (PE/EtOAc 7:3) to give 195 mg of product as yellow
1
of product as yellow solid (yield 69%): H NMR (300 MHz, CDCl3)
δH 7.69−7.66 (m, 2H), 7.40−7.38 (m, 3H), 3.42−3.38 (m, 4H), 2.27
1
solid (yield 74%): H NMR (300 MHz, CDCl3) δH 7.66−7.62 (m,
(s, 3H), 1.95−1.91 (m, 4H); 13C NMR (75 MHz, CDCl3) δC 150.2,
D
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Figure 5. Synthesized aryl-α-ketoamides.
143.9, 141.4, 133.3, 129.2, 128.4, 128.3, 108.4, 48.8, 25.4, 11.7; HRMS
(ESI) m/z (M + H)+ calcd for C15H17N3O2 271.1321, found 271.1321.
(Z)-(4-Chlorophenyl)(4-methyl-5-(pyrrolidin-1-yl)oxazol-2-yl)-
methanone Oxime (40). Starting material: chlorooxime 150 mg (0.79
mmol), isocyanoacetamide 120 mg (0.79 mmol). The crude material
was purified by column chromatography (PE/EtOAc 6:4) to give 190
65.8, 47.3; HRMS (ESI) m/z (M + H)+ calcd for C12H13N3O3S
279.0678, found 279.0677.
(Z)-(4-Benzyl-5-morpholinooxazol-2-yl)phenylmethanone Oxime
(43). Starting material: chlorooxime 150 mg (0.96 mmol),
isocyanoacetamide 236 mg (0.96 mmol). The crude material was
purified by column chromatography (PE/EtOAc 7:3) to give 169 mg
of product as yellow oil (yield 55%). Mixture of E/Z isomers; signals
1
mg of product as orange solid (yield 79%): H NMR (300 MHz,
1
are referred to the main isomer: H NMR (300 MHz, CDCl3) δH
CDCl3) δH 7.65−7.62 (m, 2H, AA′XX′), 7.40−7.37 (m, 2H, AA′XX′),
3.45−3.43 (m, 4H), 2.29 (s, 3H), 1.98−1.92 (m, 4H); 13C NMR (75
MHz, CDCl3) δC 150.3, 143.7, 140.5, 135.3, 131.9, 129.8, 128.6, 108.5,
48.9, 25.5, 11.7; HRMS (ESI) m/z (M + H)+ calcd for C15H16ClN3O2
305.0931, found 305.0933.
7.69−7.66 (m, 2H), 7.45−7.39 (m, 3H), 7.35−7.21 (m, 5H), 3.94 (s,
2H), 3.75−3.71 (m, 4H), 3.10−3.06 (m, 4H); 13C NMR (75 MHz,
CDCl3) δC 151.2, 148.3, 141.9, 138.3, 132.8, 129.5, 128.7, 128.4, 128.3,
128.0, 126.7, 121.4, 66.5, 49.9, 31.80; HRMS (ESI) m/z (M + H)+
calcd for C21H21N3O3 363.1583, found 363.1583.
(Z)-(4-Methoxyphenyl)(5-morpholinooxazol-2-yl)methanone
Oxime (41). Starting material: chlorooxime 150 mg (0.81 mmol),
isocyanoacetamide 125 mg (0.81 mmol). The crude material was
purified by column chromatography (PE/EtOAc 5:5) to give 196 mg
(Z)-(4-Benzyl-5-morpholinooxazol-2-yl)(4-chlorophenyl)-
methanone Oxime (44). Starting material: chlorooxime 150 mg (0.79
mmol), isocyanoacetamide 193 mg (0.79 mmol). The crude material
was purified by column chromatography (PE/EtOAc 7:3) to give 200
mg of product as white solid (yield 64%). Mixture of E/Z isomers,
1
of product as yellow solid (yield 80%): H NMR (300 MHz, CDCl3)
δH 7.60−7.56 (m, 2H, AA′XX′), 6.97−6.91 (m, 2H, AA′XX′), 6.25 (br
s, 1H), 3.81−3.78 (m, 7H), 3.17−3.15 (m, 4H); 13C NMR (75 MHz,
CDCl3) δC 160.6, 156.1, 147.1, 141.5, 129.7, 125.5, 113.8, 101.5, 65.8,
55.4, 47.3; HRMS (ESI) m/z (M + Na)+ calcd for C15H17N3NaO4
326.1117, found 326.1120.
1
signals are referred to the main isomer: H NMR (300 MHz, CDCl3)
δH 7.65−7.58 (m, 2H), 7.43−7.36 (m, 2H), 7.32−7.18 (m, 5H), 3.96
(s, 2H), 3.75−3.67 (m, 4H), 3.09−3.06 (m, 4H); 13C NMR (75 MHz,
CDCl3) δC 151.3, 147.7, 141.2, 138.3, 135.5, 131.4, 129.6, 128.8,
128.59, 128.32, 126.65, 121.3, 66.6, 49.8, 31.81; HRMS (ESI) m/z (M
+ H)+calcd for C21H20ClN3O3 397.1193, found 397.1197.
(Z)-(5-(Benzylmethylamino)oxazol-2-yl)(4-methoxyphenyl)-
methanone Oxime (45). Starting material: chlorooxime 150 mg (0.81
mmol), isocyanoacetamide 152 mg (0.81 mmol). The crude material
was purified by column chromatography (PE/EtOAc 7:3) to give 210
mg product as yellow solid (yield 77%): 1H NMR (300 MHz, CDCl3)
δH 7.61−7.56 (m, 2H, AA′XX′), 7.37−7.27 (m, 3H), 7.25−7.19 (m,
2H), 6.94−6.90 (m, 2H, AA′XX′), 6.15 (br s, 1H), 4.37 (s, 2H), 3.85
(E)-(5-Morpholinooxazol-2-yl)(thiophene-2-yl)methanone Oxime
(42). Starting material: chlorooxime 150 mg (0.93 mmol),
isocyanoacetamide 143 mg (0.93 mmol). The crude material was
purified by column chromatography (PE/EtOAc 6:4) to give 108 mg
1
of product as brown solid (yield 42%): H NMR (300 MHz, CDCl3)
δH 7.60−7.58 (m, 1H), 7.36−7.34 (m, 1H), 7.10−7.06 (m, 1H), 6.26
(br s, 1H), 3.87−3.83 (m, 4H), 3.28−3.26 (m, 4H); 13C NMR (75
MHz, CDCl3) δC 156.2, 146.1, 137.1, 135.6, 127.6, 127.3, 127.2, 101.4,
E
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(s, 3H); 13C NMR (75 MHz, CDCl3) δC 160.5, 156.1, 145.8, 141.3,
136.1, 129.7, 128.8, 127.9, 127.7, 125.6, 113.7, 55.5, 55.3, 36.6; HRMS
(ESI) m/z (M + H)+ calcd for C19H19N3O3 337.1426, found 337.1426.
(Z)-(5-(4-Methylpiperazin-1-yl)oxazol-2-yl)(p-tolyl)methanone
Oxime (46). Starting materials: chlorooxime 150 mg (0.88 mmol),
isocyanoacetamide 147 mg (0.88 mmol). The crude material was
purified by column chromatography (DCM/MeOH 95:5) to give 232
mg product as yellow solid (88% yield): 1H NMR (400 MHz, CDCl3)
δH 7.56 (d, J = 7.8 Hz, 2H), 7.23 (m, 2H) partially overlapped to the
solvent, 6.23 (s, 1H), 3.22 (br t, 4H), 2.50 (br t, 4H), 2.39 (s, 3H),
2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δC 156.2, 146.7, 142.0,
139.3, 130.4, 128.9, 128.1, 101.4, 53.6, 46.9, 46.0, 21.3; HRMS (ESI)
m/z (M + H)+ calcd for C16H20N4O2 300.1586, found 300.1590.
(Z)-(4-Chlorophenyl)-(5-(4-methylpiperazin-1-yl)oxazol-2-yl)-
methanone Oxime (47). Starting materials: chlorooxime 150 mg
(0.79 mmol), isocyanoacetamide 132 mg (0.79 mmol). The crude
material was purified by column chromatography (DCM/MeOH
material was purified by column chromatography (n-hexane/AcOEt
9:1) to give the product as yellow solid (177 mg, 59% yield): 1H NMR
(400 MHz, CDCl3) δH 8.18 (s, 1H), 7.89−7.85 (m, 3H), 7.79 (br d,
1H), 7.52−7.50 (m, 2H), 7.30−7.25 (m, 3H), 7.21 (br d, 1H), 7.13
(br d, 2H), 6.23 (s, 1H), 3.54 (br d, 2H), 2.79 (br t, 2H), 2.56 (br d,
2H), 1.72−1.70 (m, 3H), 1.38−1.29 (m, 2H); 13C NMR (100 MHz,
CDCl3) δC 156.5, 146.2, 141.7, 139.7, 133.6, 133.0, 130.5, 129.1, 128.5,
128.3, 128.2, 127.9, 127.6, 126.8, 126.4, 126.1, 125.6, 100.6, 47.5, 42.8,
37.3, 30.7; HRMS (ESI) m/z (M + H)+ calcd for C26H25N3O2
411.1947, found 411.1950.
(Z)-[1,1′-Biphenyl]-4-yl(5-(4-benzylpiperidin-1-yl)oxazol-2-yl)-
methanone Oxime (53). Starting materials: chlorooxime 150 mg
(0.65 mmol), isocyanoacetamide 158 mg (0.73 mmol). The crude
material was purified by column chromatography (n-hexane/AcOEt
1
9:1) to give the product as yellowish solid (142 mg, 50% yield): H
NMR (400 MHz, CDCl3) δH 7.76 (br d, 2H), 7.67−7.63 (m, 4H),
7.47−7.44 (m, 3H), 7.38 (br d, 1H), 7.31−7.27 (m, 2H), 7.22 (br d,
1H), 7.14 (br d, 2H), 6.22 (s, 1H), 3.56 (br d, 2H), 2.81 (br t, 2H),
2.58 (br d, 2H), 1.75−1.72 (m, 3H), 1.41−1.32 (m, 2H); 13C NMR
(100 MHz, CDCl3) δC 156.5, 146.2, 142.0, 141.4, 140.3, 139.7, 132.0,
129.1, 128.8, 128.7, 128.3, 127.6, 127.1, 127.0, 126.1, 100.6, 47.6, 42.9,
37.4, 30.7; HRMS (ESI) m/z (M + H)+ calcd for C26H25N3O2
411.1947, found 411.1948.
1
97:3) to give the product as yellow solid (195 mg, 77% yield): H
NMR (400 MHz, CDCl3) δH 7.57−7.55 (m, 2H, AA′XX′), 7.36−7.34
(m, 2H, AA′XX′), 6.23 (s, 1H), 3.23 (br t, 4H), 2.52 (br t, 4H), 2.33
(s, 3H); 13C NMR (100 MHz, CDCl3) δC 156.3, 146.2, 141.2, 135.3,
131.9, 129.5, 128.5, 101.7, 53.6, 46.9, 46.0; HRMS (ESI) m/z (M +
H)+ calcd for C15H17ClN4O2 320.1040, found 320.1042.
(Z)-(5-Morpholinooxazol-2-yl)-p-tolylmethanone Oxime (48).
Starting materials: chlorooxime 150 mg (0.88 mmol), isocyanoaceta-
mide 136 mg (0.88 mmol). The crude material was purified by column
chromatography (n-hexane/AcOEt 7:3) to give the product as yellow
solid (197 mg, 78% yield): 1H NMR (400 MHz, CDCl3) δH 7.54 (m,
2H, AA′XX′), 7.23 (m, 2H, AA′XX′), 6.26 (s, 1H), 3.80 (m, 4H), 3.17
(m, 4H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δC 156.0, 147.0,
141.7, 139.4, 130.0, 129.0, 128.2, 101.3, 65.7, 47.2, 21.3; HRMS (ESI)
m/z (M + H)+ calcd for C15H17N3O3 287.1270, found 287.1268.
(4-Benzyl-5-(pyrrolidin-1-yl)oxazol-2-yl)-p-tolylmethanone
Oxime (49). Starting materials: chlorooxime 150 mg (0.88 mmol),
isocyanoacetamide 202 mg (0.88 mmol). The crude material was
purified by column chromatography (n-hexane/AcOEt 7:3) to give the
product as yellow solid (168 mg, 53% yield). Mixture of E/Z isomers,
(Z)-(5-(Benzylmethylamino)oxazol-2-yl)(4-fluorophenyl)-
methanone Oxime (54). Starting material: chlorooxime 150 mg (0.87
mmol), isocyanoacetamide 163 mg (0.81 mmol). The crude material
was purified by column chromatography (PE/EtOAc 7:3) to give 198
mg product as yellow solid (yield 70%). Mixture of E/Z isomers,
1
signals are referred to the main isomer: H NMR (300 MHz, CDCl3)
δH 7.65−7.53 (m, 3H), 7.37−7.19 (m, 3H), 7.10−7.02 (m, 3H), 6.18
(br s, 1H), 4.38 (s, 2H), 2.90 (s, 3H); 13C NMR (75 MHz, CDCl3) δC
164.9, 161.7, 156.2, 140.8, 136.0, 131.8, 130.3, 128.7, 128.6, 127.8,
115.4, 99.5, 55.3, 36.6; HRMS (ESI) m/z (M + H)+ calcd for
C18H16FN3O2 325.1227, found 325.1229.
General Preparation of Aryl-α-ketoamide Amides 56−73.
The 1,3-oxazol-2-oxime was dissolved in THF (0.8 M), concentrated
HCl (1 equiv; 2 equiv for oxazoles 46 and 47) was added, and the
reaction was stirred at room temperature for 30 min. The reaction
mixture was diluted with water and extracted with EtOAc (×3). The
organic phase was washed with NaHCO3 standard solution (×1) and
brine (×1), dried over sodium sulfate, filtered, and concentrated under
reduced pressure. The crude was dissolved in acetonitrile (0.25 M),
and water (55 equiv) and copper(II) chloride (2 equiv) were added.
The solution was stirred for 1 h at 75 °C. The reaction mixture was
diluted with water and extracted with EtOAc (×2). The organic phase
was washed with brine (×1), dried over sodium sulfate, filtered, and
concentrated under reduced pressure, and the crude material was
purified by column chromatography.
1
signals are referred to the main isomer: H NMR (400 MHz, CDCl3)
δH 7.61 (m, 2H, AA′XX′), 7.31−7.22 (m, 7H) partially overlapped to
the solvent, 3.99 (s, 2H), 3.42 (br t, 4H), 2.40 (s, 3H), 1.93 (br t, 4H);
13C NMR (100 MHz, CDCl3) δC 150.3, 144.3, 141.3, 140.0, 139.1,
130.3, 128.9, 128.6, 128.2, 128.1, 126.3, 110.7, 48.8, 31.8, 25.3, 21.3;
HRMS (ESI) m/z (M + H)+ calcd for C22H23N3O2 361.1790, found
361.1793.
(Z)-(4-Benzyl-5-(pyrrolidin-1-yl)oxazol-2-yl)phenylmethanone
Oxime (50). Starting materials: chlorooxime 150 mg (0.96 mmol),
isocyanoacetamide 219 mg (0.96 mmol). The crude material was
purified by column chromatography (n-hexane/AcOEt 7:3) to give the
product as yellow solid (233 mg, 70% yield). Mixture of E/Z isomers,
2-(4-Chlorophenyl)-N-(2-morpholino-2-oxoethyl)-2-oxoaceta-
mide (56). Starting material: 1,3-oxazol-2-oxime 150 mg (0.49 mmol).
The crude material was purified by column chromatography (PE/
1
signals are referred to the main isomer: H NMR (400 MHz, CDCl3)
δH 7.71 (br d, 2H), 7.63−7.57 (m, 1H), 7.43−7.41 (m, 3H), 7.33−
7.20 (m, 4H) partially overlapped to the solvent, 4.00 (s, 2H), 3.41 (br
t, 4H), 1.92 (br t, 4H); 13C NMR (100 MHz, CDCl3) δC 150.3, 144.1,
141.4, 140.0, 133.2, 129.1, 128.6, 128.3, 128.2, 128.1, 126.3, 110.7,
48.7, 31.8, 25.3; HRMS (ESI) m/z (M + H)+ calcd for C21H21N3O2
347.1634, found 347.1637.
(Z)-(5-(4-Benzylpiperidin-1-yl)oxazol-2-yl)(4-nitrophenyl)-
methanone Oxime (51). Starting materials: chlorooxime 150 mg
(0.75 mmol), isocyanoacetamide 182 mg (0.75 mmol). The crude
material was purified by column chromatography (n-hexane/AcOEt
9:1) to give the product as bright yellow solid (97 mg, 32% yield). 1H
NMR (400 MHz, CDCl3) δH 8.28 (d, J = 8.7 Hz, 2H), 7.89 (d, J = 8.6
Hz, 2H), 7.29−7.12 (m, 6H), 6.23 (s, 1H), 3.54 (br d, 2H), 2.83 (br t,
2H), 2.58 (br d, 2H), 1.77−1.73 (m, 3H), 1.39−1.33 (m, 2H); 13C
NMR (100 MHz, CDCl3) δC 156.5, 148.2, 145.2, 139.9, 139.5, 139.2,
129.1, 129.0, 128.3, 126.1, 123.5, 100.7, 47.5, 42.8, 37.3, 30.7; HRMS
(ESI) m/z (M + H)+ calcd for C22H22N4O4 406.1641, found 406.1646.
(Z)-(5-(4-Benzylpiperidin-1-yl)oxazol-2-yl)(naphthalen-2-yl)-
methanone Oxime (52). Starting materials: chlorooxime 150 mg
(0.73 mmol), isocyanoacetamide 178 mg (0.73 mmol). The crude
1
EtOAc 2:8) to give 100 mg of product as white solid (yield 66%): H
NMR (300 MHz, CDCl3) δH 8.21−8.18 (m, 2H, AA′XX′), 8.03 (br s,
NH), 7.41−7.38 (m, 2H, AA′XX′), 4.12 (d, J = 4.6 Hz, 2H), 3.65−
3.59 (m, 6H), 3.44.3.41 (m, 2H); 13C NMR (75 MHz, CDCl3) δC
185.8, 165.8, 161.9, 141.1, 132.4, 131.6, 128.9, 66.6, 66.3, 44.9, 42.4,
40.9; m/z 311 (M + H)+; IR νmax/cm−1 (KBr) 3239, 3096, 1670, 1652,
1533, 1465, 1246, 855; mp 122−123 °C. Anal. Calcd for
C14H15ClN2O4: C, 54.12; H, 4.87; N, 9.02. Found: C, 53.95; H,
4.80; N, 9.31.
N-(2-Morpholino-2-oxoethyl)-2-oxo-2-phenylacetamide (57).
Starting materials: 1,3-oxazol-2-oxime 150 mg (0.55 mmol). The
crude material was purified by column chromatography (n-hexane/
EtOAc 5:5) to give the product as yellowish solid (103 mg, 68%
1
yield): H NMR (400 MHz, CDCl3) δH 8.28 (br d, 2H), 7.93 (br s,
NH), 7.62 (br t, 1H), 7.47 (br t, 2H), 4.18 (d, J = 4.0 Hz, 2H), 3.72−
3.66 (m, 6H), 3.47−3.45 (m, 2H); 13C NMR (100 MHz, CDCl3) δC
187.1, 165.8, 162.2, 134.4, 133.1, 130.9, 128.5, 66.6, 66.3, 44.9, 42.3,
40.8; MS m/z 277 (M + H)+; IR νmax/cm−1 (KBr) 3380, 1687, 1667,
1642, 1505, 1474, 1275, 745; mp 164−165 °C. Anal. Calcd for
F
dx.doi.org/10.1021/jo5005444 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
C14H16N2O4: C, 60.86; H, 5.84; N, 10.14. Found: C, 60.95; H, 5.97;
N, 10.01.
4H); 13C NMR (75 MHz, CDCl3) δC 185.8, 169.0, 160.9, 141.3,
135.7, 132.6, 131.6, 129.7, 129.0, 128.9, 127.5, 66.5, 66.1, 49.8, 46.1,
42.4, 39.9; MS m/z 401 (M + H)+; IR νmax/cm−1 (KBr) 3246, 3064,
1665, 1617, 1586, 1476, 1218, 858; mp 128−129 °C. Anal. Cacld for
C21H21ClN2O4: C, 62.92; H, 5.28; N, 6.99. Found: C, 63.04; H, 5.46;
N, 6.74.
N-Benzyl-2-(2-(4-methoxyphenyl)-2-oxoacetamido)-N-methyla-
cetamide (64). Starting material: 1,3-oxazol-2-oxime 150 mg (0.44
mmol). The crude material was purified by column chromatography
(PE/EtOAc 5:5) to give 133 mg of product as colorless oil (yield
88%). Mixture of rotamers, signals are referred to the main rotamer:
1H NMR (300 MHz, CDCl3) δH 8.35−8.31 (m, 2H), 8.05 (br s, NH),
7.38−7.14 (m, 5H), 6.94−6.89 (m, 2H), 4.61 (s, 2H), 4.24−4.20 (br t,
2H), 3.85 (s, 3H), 2.92 (s, 3H); 13C NMR (75 MHz, CDCl3) δC
185.4, 167.4, 164.7, 162.8, 136.4, 133.7, 129.2, 128.8, 127.8, 126.3,
113.9, 55.6, 51.3, 41.3, 33.7; MS m/z 341 (M + H)+; IR νmax/cm−1
(KBr) 3387, 3300, 1646, 1653, 1511, 1453, 1263, 1028. Anal. Calcd for
C19H20N2O4: C, 67.05; H, 5.92; N, 8.23. Found: C, 67.14; H, 6.12; N,
8.46.
N-(1-Morpholino-1-oxopropan-2-yl)-2-oxo-2-phenylacetamide
(58). Starting material: 1,3-oxazol-2-oxime 150 mg (0.55 mmol). The
crude material was purified by column chromatography (PE/EtOAc
3:7) to give 92 mg of product as yellow oil (yield 60%). Mixture of
1
rotamers, signals are referred to the main rotamer: H NMR (300
MHz, CDCl3) δH 8.20−8.17 (m, 2H), 8.03 (br d, NH), 7.56−7.38 (m,
3H), 4.80−4.72 (m, 1H), 3.64−3.35 (m, 4H), 1.98−1.78 (m, 4H),
1.39 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δC 187.5, 169.9,
161.6, 134.2, 133.23, 130.9, 128.4, 46.9, 46.4, 46.2, 26.0, 24.1, 17.9; MS
m/z 275 (M + H)+; IR νmax/cm−1 (KBr) 3253, 3062, 1638, 1667,
1510, 1449, 1264, 715. Anal. Calcd for C15H18N2O3: C, 65.68; H, 6.61;
N, 10.21. Found: C, 65.66; H, 6.65; N, 10.25.
2-(4-Chlorophenyl)-N-(1-morpholino-1-oxopropan-2-yl)-2-oxoa-
cetamide (59). Starting material: 1,3-oxazol-2-oxime 150 mg (0.49
mmol). The crude material was purified by column chromatography
(PE/EtOAc 4:6) to give 80 mg of product as colorless oil (yield 53%):
1H NMR (300 MHz, CDCl3) δH 8.25−8.23 (m, 2H, AA′XX′), 7.97
(br d, NH), 7.43−7.40 (m, 2H, AA′XX′), 4.77−4.72 (m, 1H), 3.66−
3.39 (m, 4H), 2.03−1.83 (m, 4H), 1.42 (d, J = 7.0 Hz, 3H);13C NMR
(75 MHz, CDCl3) δC 186.1, 169.9, 161.0, 141.1, 132.6, 131.8, 129.0,
47.1, 46.5, 46.3, 26.2, 24.2, 18.1; MS m/z 309 (M + H)+; IR νmax/cm−1
(KBr) 3239, 3062, 1670, 1668, 1586, 1455, 856. Anal. Calcd for
C15H17ClN2O3: C, 58.35; H, 5.55; N, 9.07. Found: C, 58.23; H, 5.21;
N, 9.2.
N-(2-(4-Methylpiperazin-1-yl)-2-oxoethyl)-2-oxo-2-p-tolylaceta-
mide (65). Starting material: 1,3-oxazol-2-oxime 150 mg (0.50 mmol).
The crude material was purified by column chromatography (DCM/
MeOH 97:3) to give the product as yellow solid (75 mg, 50% yield):
1H NMR (400 MHz, CDCl3) δH 8.19 (br d, 2H, AA′XX′), 7.92 (br s,
NH), 7.27−7.25 (m, 2H, AA′XX′) partially overlapped to the solvent,
4.17 (d, J = 4.2 Hz, 2H), 3.68 (br t, 2H), 3.47 (br t, 2H), 2.44 (br s,
7H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δC 186.8, 165.5,
162.5, 145.5, 131.0, 130.7, 129.2, 54.6, 54.3, 45.8, 44.3, 41.9, 40.9, 21.8;
MS m/z 304 (M + H)+; IR νmax/cm−1 (KBr) 3351, 3000, 1669, 1642,
1504, 1475, 1276, 789; mp 97−98 °C. Anal. Calcd for C16H21N3O3: C,
63.35; H, 6.98; N, 13.85. Found: C, 63.67; H, 7.12; N, 14.12.
2-(4-Chlorophenyl)-N-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-2-
oxoacetamide (66). Starting material: 1,3-oxazol-2-oxime 150 mg
(0.47 mmol). The crude material was purified by column
chromatography (DCM/MeOH 97:3) to give the product as yellowish
solid (64 mg, 42% yield): 1H NMR (400 MHz, CDCl3) δH 8.23 (d, J =
8.4 Hz, 2H, AA′XX′), 7.98 (br s, NH), 7.41 (d, J = 8.4 Hz, 2H,
AA′XX′), 4.12 (d,, J = 4.0 Hz 2H), 3.63 (br t, 2H), 3.43 (br t, 2H),
2.40−2.37 (m, 4H), 2.28 (s, 3H); 13C NMR (100 MHz, CDCl3) δC
185.7, 165.3, 161.7, 141.0, 132.4, 131.5, 128.8, 54.7, 54.4, 46.0, 44.4,
42.0, 40.9; MS m/z 324 (M + H)+; IR νmax/cm−1 (KBr) 3344, 1673,
1645, 1586, 1443, 1273, 857; mp 127−128 °C. Anal. Calcd for
C15H18ClN3O3: C, 55.64; H, 5.60; N, 12.98. Found: C, 55.54; H, 5.42;
N, 12.78.
2-(4-Methoxyphenyl)-N-(2-morpholino-2-oxoethyl)-2-oxoaceta-
mide (60). Starting material: 1,3-oxazol-2-oxime 150 mg (0.49 mmol).
The crude material was purified by column chromatography (PE/
1
EtOAc 2:8) to give 70 mg of product as white solid (yield 46%). H
NMR (300 MHz, CDCl3) δH 8.33−8.8.30 (m, 2H, AA′XX′), 7.97 (br
s, NH), 6.94−6.91 (m, 2H, AA′XX′), 4.16 (br d, 2H), 3.87 (s, 3H),
3.71−3.65 (m, 6H), 3.46−43 (m, 2H); 13C NMR (75 MHz, CDCl3)
δC 185.3, 165.9, 164.8, 162.8, 133.8, 126.3, 114.0, 66.8, 66.4, 55.7, 45.0,
42.4, 41.0; MS m/z 307 (M + H)+; IR νmax/cm−1 (KBr) 3349, 3078,
1682, 1647, 1594, 1474, 1257, 861; mp 169−169.5 °C. Anal. Calcd for
C15H18N2O5: C, 58.82; H, 5.92; N, 9.15. Found: C, 58.93; H, 6.24; N,
9.36.
N-(2-Morpholino-2-oxoethyl)-2-oxo-2-(thiophene-2-yl)-
acetamide (61). Starting material: 1,3-oxazol-2-oxime 150 mg (0.54
mmol). The crude material was purified by column chromatography
(PE/EtOAc 2:8) to give 85 mg of product as white solid (yield 56%):
1H NMR (300 MHz, CDCl3) δH 8.36 (d, J = 4.0 Hz, 1H), 8.19 (br s,
NH), 7.80 (d, J = 4.8 Hz, 1H), 7.18−7.15 (m, 1H), 4.15 (d, J = 4.5 Hz,
2H), 3.71−3.66 (m, 6H), 3.53−3.42 (m, 2H); 13C NMR (75 MHz,
CDCl3) δC 177.6, 165.7, 161.0, 138.5, 138.0, 136.9, 128.4, 66.6, 66.40,
42.5, 41.1, 40.7; MS m/z 283 (M + H)+; IR νmax/cm−1 (KBr) 3371,
3071, 1691, 1658, 1495, 1359, 1275, 737; mp 193−194 °C. Anal.
Calcd for C12H14N2O4S: C, 51.05; H, 5.00; N, 9.92. Found: C, 51.34;
H, 5.36; N, 10.10.
N-(1-Morpholino-1-oxo-3-phenylpropan-2-yl)-2-oxo-2-phenyla-
cetamide (62). Starting material: 1,3-oxazol-2-oxime 150 mg (0.41
mmol). The crude material was purified by column chromatography
(PE/EtOAc 4:6) to give 76 mg of product as white solid (yield 50%).
Mixture of rotamers, signals are referred to the main rotamer: 1H
NMR (300 MHz, CDCl3) δH 8.21 (d, J = 8.2 Hz, 2H), 7.87 (br d,
NH), 7.64−7.59 (br t, 1H), 7.52−7.38 (br t, 2H), 7.34−7.23 (m, 5H),
5.18 (br q, 1H), 3.62−3.44 (m, 6H), 3.16−2.94 (m, 4H); 13C NMR
(75 MHz, CDCl3) δC 187.4, 169.0, 161.6, 135.8, 134.5, 131.0, 129.7,
129.6, 128.8, 128.6, 127.4, 66.4, 66.0, 49.7, 46.1, 42.4, 39.8; MS m/z
367 (M + H)+; IR νmax/cm−1 (KBr) 3277, 3027, 1665, 1642, 1524,
1486, 1211; mp 151.5−152 °C. Anal. Calcd for C21H22N2O4: C, 68.84;
H, 6.05; N, 7.65. Found: C, 68.95; H, 6.40; N, 7.34.
N-(2-Morpholino-2-oxoethyl)-2-oxo-2-p-tolylacetamide (67).
Starting material: 1,3-oxazol-2-oxime 150 mg (0.52 mmol). The
crude material was purified by column chromatography (DCM/
MeOH 97:3) to give the product as yellow solid (98 mg, 65% yield):
1H NMR (400 MHz, CDCl3) δH 8.20 (d, J = 8.2 Hz, 2H), 7.92 (br s,
NH), 7.28−7.25 (m, 2H) partially overlapped to the solvent, 4.17 (d, J
= 4.0 Hz, 2H), 3.71−3.67 (m, 6H), 3.47−3.46 (m, 2H), 2.42 (s, 3H);
13C NMR (100 MHz, CDCl3) δC 186.6, 165.8, 162.4, 145.6, 131.1,
130.7, 129.2, 66.6, 66.3, 44.9, 42.3, 40.8, 21.8; MS m/z 291 (M + H)+;
IR νmax/cm−1 (KBr) 3430, 3423, 1695, 1660, 1494, 1276, 785; mp 83−
84 °C. Anal. Calcd for C15H18N2O4: C, 62.06; H, 6.25; N, 9.65.
Found: C, 62.34; H, 6.43; N, 9.78.
2-Oxo-N-(1-oxo-3-phenyl-1-(pyrrolidin-1-yl)propan-2-yl)-2-p-tol-
ylacetamide (68). Starting material: 1,3-oxazol-2-oxime 150 mg (0.41
mmol). The crude material was purified by column chromatography
(n-hexane/AcOEt 7:3) to give the product as a light yellow solid (78
mg, 52% yield): 1H NMR (400 MHz, CDCl3) δH 8.12 (d, J = 8.0 Hz,
2H), 7.79 (br d, NH), 7.28−7.23 (m, 7H), 4.95 (br q, 1H), 3.47−3.30
(m, 3H), 3.09 (d, J = 7.4 Hz, 2H), 2.69−2.63 (m, 1H), 2.40 (s, 3H),
1.80−1.55 (m, 4H); 13C NMR (100 MHz, CDCl3) mixture of
rotamers: δC 186.8, 168.6, 161.7, 145.5, 136.1, 132.0, 131.1, 130.7,
129.5, 128.5, 127.1, 52.4, 46.3, 45.8, 39.5, 25.8, 23.9, 21.8; MS m/z 365
(M + H)+; IR νmax/cm−1 (KBr) 3239, 3062, 1680, 1662, 1624, 1454,
1228, 763; mp 88−89 °C. Anal. Calcd for C22H24N2O3: C, 72.51; H,
6.64; N, 7.69. Found: C, 72.52; H, 6.65; N, 7.65.
2-(3-Chlorophenyl)-N-(1-morpholino-1-oxo-3-phenylpropan-2-
yl)-2-oxoacetamide (63). Starting material: 1,3-oxazol-2-oxime 150
mg (0.38 mmol). The crude material was purified by column
chromatography (PE/EtOAc 5:5) to give 78 mg of product as white
1
solid (yield 52%): H NMR (300 MHz, CDCl3) δH 8.19 (d, J = 8.1
Hz, 2H), 7.93 (br d, NH), 7.42 (br d, 2H), 7.34−7.22 (m, 5H), 5.16
(br q, 1H), 3.64−3.58 (m, 2H), 3.55−3.25 (m, 4H), 3.14−2.87 (m,
G
dx.doi.org/10.1021/jo5005444 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2-Oxo-N-(1-oxo-3-phenyl-1-(pyrrolidin-1-yl)propan-2-yl)-2-phe-
nylacetamide (69). Starting material: 1,3-oxazol-2-oxime 150 mg
(0.43 mmol). The crude material was purified by column
chromatography (n-hexane/AcOEt 7:3) to give the product as a
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
yellowish solid (110 mg, 73% yield): H NMR (400 MHz, CDCl3) δ
8.21 (d, J = 7.8 Hz, 2H), 7.76 (br d, NH), 7.60 (t, J = 7.4 Hz, 1H),
7.45 (t, J = 7.7 Hz, 2H), 7.31−7.25 (m, 6H), 4.96 (br q, 1H), 3.49−
3.36 (m, 3H), 3.10 (d, J = 7.4 Hz, 2H), 2.70−2.64 (m, 1H), 1.81−1.56
(m, 4H); 13C NMR (100 MHz, CDCl3) mixture of rotamers δC 187.4,
168.6, 161.6, 136.0, 134.2, 133.2, 130.8, 129.4, 128.8, 128.5, 128.4,
128.4, 127.0, 52.4, 46.3, 45.8, 39.4, 25.7, 23.9; MS m/z 351 (M + H)+;
IR νmax/cm−1 (KBr) 3240, 3062, 1682, 1664, 1621, 1555, 1454, 1222;
mp 118−119 °C. Anal. Calcd for C21H22N2O3: C, 71.98; H, 6.33; N,
7.99. Found: C, 72.21; H, 6.12; N, 8.21.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: mariateresa.giustiniano@unina.it.
*E-mail: giancesare.tron@unipmn.it.
Notes
■
The authors declare no competing financial interest.
N-(2-(4-Benzylpiperidin-1-yl)-2-oxoethyl)-2-(4-nitrophenyl)-2-ox-
oacetamide (70). Starting material: 1,3-oxazol-2-oxime 150 mg (0.37
mmol). The crude material was purified by column chromatography
(n-hexane/AcOEt 5:5) to give the product as a yellowish solid (100
mg, 66% yield): 1H NMR (400 MHz, CDCl3) δH 8.48 (d, J = 8.6 Hz,
2H), 8.31 (d, J = 8.8 Hz, 2H), 8.08 (br s, NH), 7.31−7.12 (m, 5H),
4.59 (br d, 1H), 4.17−4.14 (m, 2H), 3.72 (br d, 1H), 3.02 (br t, 1H),
2.58−2.55 (m, 2H), 1.83−1.76 (m, 3H), 1.21−1.15 (m, 3H); 13C
NMR (100 MHz, CDCl3) δC 185.5, 164.8, 160.8, 150.8, 139.6, 137.9,
132.1, 129.0, 128.4, 126.2, 123.4, 44.8, 42.8, 42.6, 41.0, 38.0, 32.2, 31.5;
MS m/z 410 (M + H)+; IR νmax/cm−1 (KBr) 3280, 1665, 1651, 1602,
1519; mp 78−79 °C. Anal. Calcd for C22H23N3O5: C, 64.54; H, 5.66;
N, 10.26. Found: C, 64.78; H, 5.84; N, 10.02.
N-(2-(4-Benzylpiperidin-1-yl)-2-oxoethyl)-2-(naphthalen-2-yl)-2-
oxoacetamide (71). Starting material: 1,3-oxazol-2-oxime 150 mg
(0.36 mmol). The crude material was purified by column
chromatography (n-hexane/AcOEt 5:5) to give the product as a
sticky solid (81 mg, 54% yield): 1H NMR (400 MHz, CDCl3) δH 9.06
(s, 1H), 8.18 (br d, AA′XX′, 1H), 8.06 (br s, NH), 7.98 (d, J = 8.1 Hz,
1H), 7.90−7.85 (m, 2H), 7.64−7.60 (m, 1H), 7.56−7.53 (m, 1H),
7.31−7.19 (m, 3H), 7.13 (br d, 2H), 4.60 (br d, 1H), 4.22−4.19 (m,
2H), 3.75 (br d, 1H), 3.01 (br t, 1H), 2.61−2.55 (m, 2H), 1.82−1.72
(m, 3H), 1.25−1.14 (m, 3H); 13C NMR (100 MHz, CDCl3) δC 186.9,
165.1, 162.3, 139.6, 136.1, 134.5, 132.3, 130.5, 130.2, 129.2, 129.0,
128.3, 128.3, 127.7, 126.7, 126.1, 125.1, 44.8, 42.8, 42.6, 41.0, 38.0,
32.2, 31.5; MS m/z 415 (M + H)+; IR νmax/cm−1 (KBr) 3280, 1665,
1651, 1602, 1519. Anal. Calcd for C26H26N2O3: C, 75.34; H, 6.32; N,
6.76. Found: C, 75.36; H, 6.46; N, 6.73.
ACKNOWLEDGMENTS
Financial support from Universita
gratefully acknowledged. M.G. acknowledges “Progetto Strain-
Regione Campania” for a fellowship.
■
̀
del Piemonte Orientale is
REFERENCES
■
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(9) Nucleophilic addition on carbonyl group, pinacol-type coupling,
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(10) Although we have used the term syn-chlorooximes in previous
works (see refs 12 and 13), according to the IUPAC gold book the
term syn should be replaced with (Z).
2-([1,1′-Biphenyl]-4-yl)-N-(2-(4-benzylpiperidin-1-yl)-2-oxoethyl)-
2-oxoacetamide (72). Starting material: 1,3-oxazol-2-oxime 150 mg
(0.34 mmol). The crude material was purified by column
chromatography (n-hexane/AcOEt 5:5) to give the product as a
1
white solid (112 mg, 75% yield): H NMR (400 MHz, CDCl3) δH
8.38 (br d, AA′XX′, 2H), 8.01 (br s, NH), 7.70 (br d, AA′XX′, 2H),
7.64 (br d, AA′XX′, 2H), 7.49−7.38 (m, 3H), 7.31−7.19 (m, 3H),
7.13 (br d, AA′XX′, 2H), 4.60 (br d, 1H), 4.24−4.12 (m, 2H), 3.74 (br
d, 1H), 3.01 (br t, 1H), 2.64−2.55 (m, 3H), 1.82−1.75 (m, 3H),
1.25−1.14 (m, 2H); 13C NMR (100 MHz, CDCl3) δC 186.7, 165.16,
162.3, 146.9, 139.7, 139.6, 132.0, 131.6, 129.0, 128.9, 128.4, 128.3,
127.3, 127.1, 126.1, 44.8, 42.8, 42.6, 41.0, 38.0, 32.2, 31.5; MS m/z 441
(M + H)+; IR νmax/cm−1 (KBr) 3364, 2919, 1682, 1628, 1475; mp
140−141 °C. Anal. Calcd for C28H28N2O3: C, 76.34; H, 6.41; N, 6.36.
Found: C, 76.29; H, 6.42; N, 6.78.
(11) Huisgen, R.; Mack, W. Tetrahedron Lett. 1961, 2, 583−586.
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4646.
N-Benzyl-2-(2-(4-fluorophenyl)-2-oxoacetamido)-N-methylaceta-
mide (73). Starting material: 1,3-oxazol-2-oxime 150 mg (0.46 mmol).
The crude material was purified by column chromatography (PE/
EtOAc 5:5) to give 106 mg of product as yellow oil (yield 70%).
Mixture of rotamers, signals are referred to the main rotamer: 1H
NMR (300 MHz, CDCl3) δH 8.37−8.29 (m, 2H), 8.11 (br s, NH),
7.34−7.21 (m, 4H), 7.19−7.05 (m, 3H), 4.59 (s, 2H), 4.20 (d, J = 4
Hz, 2H), 2.91 (s, 3H); 13C NMR (75 MHz, CDCl3) δC 185.4, 167.2,
164.8, 162.1, 136.4, 134.1, 129.7, 128.7, 128.1, 127.7, 115.9, 51.3, 41.2,
33.6; MS m/z 329 (M + H)+; IR νmax/cm−1 (KBr) 3377, 2926, 1647,
1595, 1230, 1089. Anal. Calcd for C18H17FN2O3: C, 65.84; H, 5.22; N,
8.53. Found: C, 65.52; H, 4.98; N, 8.76.
(15) As we used the term stereospecific in the previous papers (refs
12 and 13), an anonymous reviewer pointed out that, according to the
IUPAC gold book rules, for this reaction, the term stereoselective is
more appropriate and should be used. We thank the reviewer for the
suggestion.
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(a) Leandri, G.; Maioli, L.; Ruzzier, L. Boll. Sci. Fac. Chim. Ind. Bologna
H
dx.doi.org/10.1021/jo5005444 | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
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(25) When 1,3-oxazol-2-oxime (21) were directly reacted with
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The major product was
I
dx.doi.org/10.1021/jo5005444 | J. Org. Chem. XXXX, XXX, XXX−XXX