One pot synthesis of α-ketoamides from ethylarenes and amines: a metal free difunctionalization strategy

Article abstract of DOI:10.1039/c6ob02361d

One-pot and metal free synthesis of α-ketoamides has been described through in situ generation of aryl ketones from easily available ethylarenes followed by amidation with various amines. This multiple oxidation protocol involves catalytic I₂-pyridine-TBHP (t-butyl hydroperoxide) mediated oxidative benzylic carbonylation and sequential NaI-TBHP mediated oxidative amidation without using any solvent.

Full text of DOI:10.1039/c6ob02361d

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COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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One Pot Synthesis of α-Ketoamides from Ethylarenes and
Amines: A Metal Free Difunctionalization Strategy†
Mani Ramanathan,a Chun-Kai Kuoa and Shiuh-Tzung Liua*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
One-pot and metal free synthesis of α-ketoamides has been described through in situ generation of aryl ketones from
easily available ethylarenes followed by amidation with various amines. This multiple oxidation protocol involves catalytic
I2-pyridine-TBHP (t-butyl hydroperoxide) mediated oxidative benzylic carbonylation and sequential NaI-TBHP mediated
www.rsc.org/
oxidative
amidation
without
using
any
solvent.
(B)
(A)
O
Ar
H
Ar
H
Introduction
I2-Py-TBHP
nBu4NI-TBHP
Ar
R1
+
N
+
α-Ketoamides, a structurally privileged core found in array of
biological compounds,1 pharmaceuticals,2 and natural
products,3 have received much attention due to the inherent
pharmacological and biological applications. Furthermore,
they also serve as versatile synthetic intermediates in
functional group transformation and synthesis. Thus, various
appealing synthetic approaches have been reported for this
motif in recent years. Even though, few review articles
summarize these synthetic methodologies,4-7 there is still a
growing interest in the development of one-pot preparation of
80 o
C
NaI-TBHP
This work
R1
O
R2
O
N
R1
N
R2
R2
Scheme 1 α-Ketoamides from ethylbenzenes
Results and discussion
Guided by the literature, we envisaged that the ethylbenzenes
could be transformed into corresponding phenacyl iodides 2a’
under catalytic I2-TBHP system,17 which might undergo
oxidative amidation leading to the desired α-ketoamides in a
one-pot fashion (Scheme 2A). Optimization studies with
ethylbenzene in the presence of 20 mol% of I2 and t-butyl
α-ketoamides from commercial chemicals.
A
variety of
styrene,9
precursors such as
acetophenone,8
phenylacetylene,10 1-arylethanol,11 phenylacetaldehyde,12
phenyl glyoxal,13 and 2-hydroxy-1-phenyl-ethanone,14 have
been achieved. Despite the aforementioned works, chemists
are interested in the development of efficient methods from
unfunctionalized molecules such as ethylbenzenes15 or
toluenes.16
o
hydroperoxide (TBHP) at 120 C followed by the treatment of
morpholine/TBHP led to the formation of 3a in trace yields
(Table 1, entry 1). Replacement of morpholine by piperidine
gave the desired product in trace amount. Upon extending the
reaction time to 12 h at 100 oC, we observed a slight increment
to 30% (Table 1, entry 3). These results prompted us to explore
this protocol with different solvents, time, and amount of
TBHP (Table 1, entries 4-10). Though, we performed the above
reactions carefully with the confirmation of the formation of
intermediate 2a’, yield of 3a could only be improved up to
Ethylbenzene is a commercially available substrate and has
been studied for the preparation of α-ketoamides.
A
pioneered work by Sun and co-workers showed that a range of
α-ketoamides can be prepared from ethylarenes and N,N-
dialkylformamides under n-Bu4NI/TBHP mediated oxidative
conditions (Scheme 1A).15 However, requirement of
formamide and limitation to N,N-dialkyl subsitutents with this
process drove us to improve the preparation of α-ketoamides
from ethylarenes and amines (Scheme 1B). Our approach
negates the requirement of N-formylated amine precursors
and exploits the greater number of commercially available
amines, thus expanding the diversity of α-ketoamide libraries.
55%.
O
I2-TBHP
I
TBHP
(A)
ꢀ
O
X
X
N
2a'
N
O
O
1a
(B)
I2-TBHP
pyridine
3a X = O
3b X =CH2
NaI-TBHP
ꢀ
2a
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Scheme 2 Synthetic approaches leading to α-ketoamides from ethylbenzene
attributed to the presence of multiple benzylic protons present
in the amino precursor. On the other hand, benzylamine
furnished the corresponding product under our optimized
conditions without any complications in 61% isolated yield
(Table 4, entry 4h). Although, the generality of this presented
method is applicable to variety of primary, secondary and
benzylic amines, despite our best efforts, no desired products
were obtained with 2,6-dimethyl piperidine, diisopropyl
amine, 2-hydroxy ethylamine and aniline. In the case of
aniline, we obtained a black unidentified solid, which was
presumably to be the polyanilines.
<<Table 1>>
It is known that the α-ketoamide 3a can be prepared from
acetophenone and morpholine.8 We then resumed our
approach by conversion of ethylbenzene into acetophenone
followed by the oxidative amidation in a one-pot fashion
(scheme 2B). By modification of Wang and co-workers’
procedure,18 we observed that ethylbenzene was transferred
into acetophenone with the treatment of a combination of I2-
pyridine-TBHP in a high conversion as monitored by the NMR
determination. Then, morpholine, NaI (20 mol%) and an extra
amount of TBHP were added to the above mixture for the
further reaction at the ambient temperature. To our delight,
this approach furnished 3a in good yield (table 2, entry 1). By
increasing the amount of NaI or with the use of I2, the yields of
3a were improved (table 2, entries 2-3). However, it reached
to the maximum when 60 mol% of NaI used (table 2, entry 4).
It was noticed that the yield was decreased significantly when
we use diaklylamine under this conditions. By monitoring the
reaction under various temperature, we found that lowering
the reaction temperature down to 0 oC is the best choice (table
2, entry 7).
Table 3 α-Ketoamides prepared from ethylbenzene and various cyclic amines
O
O
O
O
N
N
N
O
O
O
3a (72%)
3b (64%)
3c (68%)
O
NH
O
N
O
NPh
N
N
N
O
O
O
3d (0%)
3e (70%)
3f (76%)
<<Table 2>>
OMe
Ph
O
S
With the optimized conditions, we contemplated the scope
of the reaction with various commercially and readily available
amines. Common cyclic secondary amines such as morpholine,
piperidine and pyrrolidine reacted well with ethylbenzene to
furnish the corresponding α-ketoamides in synthetically useful
yields (Table 3, entries 3a-3c). Though piperazine was an
unsuccessful partner in this oxidative transformation (Table 3,
entry 3d), mono N-methylated piperazines smoothly
converted to α-ketoamides (Table 3, entry 3e). Utilization of
mono-N-functionalized piperazines with divergent functional
groups such as N-ethoxycarbonyl, N-allyl, and N-(4-
methoxy)phenyl sulfonyl groups were well tolerated under the
reaction conditions and afforded the corresponding α-
ketoamides in good yields (Table 3, entries 3f-3j). Synthetically
O
N
Ph
O
N
O
N
N
O
O
3h (71%)c
3g (72%)b
O
O
N
O
N
OEt
N
N
O
O
3j (73%)
3i (68%)
a Reaction Conditions: 1a (1.88 mmol), I2 (0.09 mmol), pyridine (0.09 mmol), TBHP
(5.65 mmol), 80 oC for 10 h, then TBHP (5.65 mmol), NaI (1.13 mmol), cyclic
distinct α-ketoamides of these types are previously not amine (2.5 eq), rt, 6h; isolated yields. amine dissolved in MeCN (1 mL). c amine
b
dissolved in 1 mL MeCN/0.5 mL MeOH.
reported by any other known methods.
The applicability of this method was further extended to
acyclic primary and secondary amines with the amidation at 0
oC. Linear and heterocycle bound primary amines participated
well in this reaction to give the corresponding α-ketoamides in
appreciable yields (Table 4). In the case of n-hexylamine as the
reacting partner, not only the desired product 4a was
obtained, also trace amount of decarbonylated product was
isolated (Table 4, entry 4a’). Other classes of primary amines
such as isopropyl, t-butylamine were also participated to
afford the α-ketoamides in moderate yields (Table 4, entries
4b
~ 4d). Acyclic secondary amines reacted equally well as
their cyclic counterparts albeit in slightly lower yields (Table 4,
entries 4e-4f). Notably, dibenzylamine delivered the
corresponding α-ketoamide in minor amount together with
complicated entities (Table 4, entry 4g). This might be
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product in good yield (Table 5, entry 5g). We found that 3-acetoxy-
1-ethylbenzene led to 3-hydroxyacetophenone as sole product.
Attempts to prepare bis-α-ketoamide from p-diethylbenzene
resulted a mixture of oxidation products in various ratios. However,
1-(4-ethylphenyl)-2-morpholinoethane-1,2-dione (Table 5, entry 5h)
was isolated in 33% yield. 2-Ethylnaphthalene also participated in
the reaction very well and furnished 5i in good yield (Table 5, entry
5i). However, 4-nitro-1-ethylbenzene does not undergo such an
oxidative amidation. Instead, p-nitrobenzoic acid was obtained as
the major product with trace amount of p-nitroacetophenone.19
Table 4 α-Ketoamides prepared from ethylbenzene and various aliphatic amines
To further extend this practical application, we focused our
efforts to synthesize anti-HIV compound 5j, which was previously
prepared from Au/Pd catalysed double carbonylation of aryl halides
with carbon monoxide.20 We carried out a gram scale synthesis of 5j
from 2-ethylnaphthalene and N-benzoyl-piperazine under the
optimized conditions. To our delight this transformation proceeded
smoothly to furnish the desired product in moderate yield (Scheme
3), thus demonstating the applicability of this method for larger
scales via a metal free approach.
a
Reaction Conditions: ethylarene (1.88 mmol), I2 (0.09 mmol), pyridine (0.09
mmol), TBHP (5.65 mmol), 80 oC for 10 h, then TBHP (7.52 mmol), NaI (1.13
mmol), cyclic amine (2.5 eq), 0 oC, 12h; isolated yields.
To extend the synthetic utility of this method, we examined
various ethyl substituted arenes and heteroarenes to this
methodology (Table 5). It was found that ethylarenes with
methoxy groups and bromo substituents were tolerated under
the reaction conditions to afford the corresponding α-
ketoamides (Table 5, entries 5a-5c). Oxidative amidation of
ethylthiophene proceeded as well to give the desired product
(Table 5, entry 5d-5e), but not 2-ethylpyridine and 2-
ethylimidazole. Oxidation of 2-ethylpyridine gave 2-
pyridinecarboxylic acid as the only product.
Scheme 3 Gram scale synthesis of anti-HIV agent 5j
Table 5 α-Ketoamides prepared from ethylarenesa
O
O
O
O
O
Conclusions
N
N
N
In summary, we have developed a convenient method for the
synthesis of a variety of α-ketoamides from available ethylarenes
and amines. This reaction proceeds in one-pot fashion under metal-
free conditions via sequential dehydrogenation of five sp3 C-H
bonds.21 A comprehensive scope and the tolerance of various
functional groups were demonstrated successfully. In addition, a
gram scale synthesis of anti-HIV agent is achieved in good yield,
illustrating the possibility for the industrial application.
O
O
Br
O
MeO
MeO
5a (74%)
5b (72%)
5c (67%)
O
O
O
O
O
N
N
N
O
NH
S
O
S
O
5f (58%)
5d (63%)
O
OtBu
O
5e (60%)
O
O
O
O
O
N
N
N
Experimental
O
O
O
Et
General information.
OEt
5h (33%)
5i (71%)
5g (68%)
1H and 13C NMR were recorded in a 400 MHZ spectrometer in
CDCl3 or DMSO-d6 solvents referenced to TMS. Ethylarenes
were commercially purchased and used without further
purification. Column Chromatography was performed using
silica gel 230-400 mesh. Analytical thin layer chromatography
(TLC) was performed using Merck-60 F-254 plates and
visualized using UV lamp (254-365 nm). In cases of known
a
Reaction Conditions: ethylarene (1.88 mmol), I2 (0.09 mmol), pyridine (0.09
mmol), TBHP (5.65 mmol), 80 oC for 10 h, then TBHP (5.65 mmol), NaI (1.13
mmol), cyclic amine (2.5 eq), r, 6 h; isolated yields.
It is notable that o-N-Boc substituted ethylbenzene provided the
corresponding α-ketoamide in 58% yield (Table 5, entry 5f), thus
illustrating the scope and compatibility of the presented reaction.
Presence of free phenolic hydroxyl group led to complicated results,
on the other hand, 3-alkoxy ethylbenzene afforded the desired
1
compounds, their H and 13C values were compared with the
literature reports. FT-IR were recorded on Thermo Scientific-
Nicolet iS5 spectrometer and reported in frequency of
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absorption (cm-1). Melting points were determined on a Fargo 1-phenyl-2-(4-phenylpiperazin-1-yl)ethane-1,2-dione (3f).25
MP-1D instrument.
Brown viscous oil (76%); Purified by chromatography
(EtOAc/Hexane 30%); 1H NMR (400 MHz, CDCl3): δ 7.89-7.87 (m,
<<Caution: TBHP is a dangerous and toxic chemical. It should
be handled carefully!>>
2H), 7.57-7.54 (m, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.18 (t, J = 8.0 Hz,
2H), 6.83-6.80 (m, 3H), 3.83 (t, J = 5.2 Hz, 2H), 3.42 (t, J = 5.2 Hz,
2H), 3.19 (t, J = 5.2Hz, 2H), 3.04 (t, J = 5.2 Hz, 2H); 13C NMR (100
General procedure for the preparation of α-Ketoamides.
Ethylarene (1 eq.), I2 (5 mol%), pyridine (5 mol%) andTBHP (3 eq., MHz): δ 191.2, 165.3, 150.6, 134.8, 133.0, 129.6, 129.2, 129.0,
70% aqueous solution) were added in a 20 mL sealed tube with a 120.8, 116.9, 49.8, 49.5, 45.7, 41.2; IR (KBr, cm-1) υC=O 1682, 1644;
Teflon lined screw cap. The reaction mixture was stirred in an oil HRMS (ESI) calcd. for C18H19N2O2 (M+H)+:295.1447; found 295.1451.
bath at 80 oC for 10h (stage 1). Then TBHP (3 eq. 70% aqueous
1-(4-((4-methoxyphenyl)sulfonyl)piperazin-1-yl)-2-phenylethane-
solution), NaI (0.6 eq.) and the corresponding cyclic secondary
1,2-dione (3g).
amine (2.5 eq.) were added sequentially and stirred at room
Yellow solid (72%); mp 154-155oC; Purified by chromatography
temperature for 6h. The reaction mixture was directly purified by a
(EtOAc/Hexane 50%); 1H NMR (400 MHz, CDCl3): δ 7.85-7.83 (m,
silica gel column chromatography hexane/ethyl acetate as eluent to
2H), 7.65-7.62 (m, 2H), 7.60-7.58 (m, 1H), 7.44 (t, J = 7.6 Hz, 2H),
give the corresponding α-ketoamides. In cases of acyclic primary,
6.99-6.95 (m, 2H), 3.84 (s, 3H), 3.82-3.80 (m, 2H), 3.40 (t, J = 5.2 Hz,
2H), 3.08 (t, J = 5.2 Hz, 2H), 2.98 (t, J = 4.8 Hz, 2H); 13C NMR (100
secondary and benzylic amines, reaction mixture was cooled down
to 0 oC after the stage 1. Then TBHP (4 eq., 70% aqueous solution),
MHz): δ 190.8, 165.2, 163.3, 135.0, 132.7, 129.7, 129.6, 129.0,
NaI (0.6 eq) and the corresponding amine (2.5 eq.) were added
sequentially and stirred at 0 oC for 10h. The purification step is
126.6, 114.5, 55.6, 55.5, 46.0, 45.6, 45.2, 40.6; IR (KBr, cm-1) υC=O
1680, 1651; HRMS (ESI) calcd. for C19H21N2O5S (M+H)+:389.1171;
similar to the above.
found 389.1198.
1-morpholino-2-phenylethane-1,2-dione (3a).22
1-(4-diphenylmethylpiperazin-1-yl)-2-phenylethane-1,2-dione
Pale Yellow Viscous Oil (72%); Purified by chromatography
(EtOAc/Hexane 30%); 1H NMR (400 MHz, CDCl3): δ 7.95-7.92 (m,
(3h).
Brown viscous oil (71%); Purified by chromatography
2H), 7.60-7.61 (m, 1H), 7.52-7.48 (m, 2H), 3.17 (brs, H), 3.64-3.62
(EtOAc/Hexane 35%); 1H NMR (400 MHz, CDCl3): δ 7.86-7.84 (m,
(m, 2H), 3.37-3.34 (m, 2H); 13C NMR (100 MHz): δ 191.1, 165.4,
134.9, 133.0, 129.6, 129.0, 66.7, 66.6, 46.2, 41.6; IR (KBr, cm-1) υC=O
2H), 7.56-7.52 (m, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.31 (d, J = 7.2 Hz,
1683, 1652; HRMS (ESI) calcd. for C12H14NO3 (M+H)+: 220.0974;
4H), 7.21-7.17 (m, 4H), 7.12-7.08 (m, 2H), 4.20 (s, 1H), 3.70 (t, J =
5.2 Hz, 2H), 3.28 (t, J = 5.2 Hz, 2H), 2.44 (t, J = 5.2 Hz, 2H), 2.28 (t, J =
4.8 Hz, 2H); 13C NMR (100 MHz): δ , 191.5, 165.3, 141.8(2C), 134.7,
found 220.0984.
1-phenyl-2-(piperidin-1-yl)ethane-1,2-dione (3b). 23
133.1, 129.5 (2C), 128.9, 128.6 (2C), 127.7(2C), 127.2, 75.8, 51.8,
White solid (64%); mp 94-95oC; Purified by flash column 51.4, 46.0, 41.4. IR (KBr, cm-1) υC=O 1681, 1643; HRMS (ESI) calcd.
chromatography (EtOAc/Hexane 30%); 1H NMR (400 MHz, CDCl3): δ for C25H25N2O2 (M+H)+:385.1916; found 385.1919.
7.89 (d, J = 7.6 Hz, 2H), 7.57 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2
1-(4-allylpiperazin-1-yl)-2-phenylethane-1,2-dione (3i).
H), 3.64 (brs, 2H), 3.22 (t, J = 5.6 Hz, 2H), 1.63 (t, J = 2.8 Hz, 4H), 1.49
(d, J = 5.2 Hz, 2H); 13C NMR (100 MHz): δ 191.8, 165.3, 134.5, 133.1,
Brown viscous oil (68%); Purified by chromatography
(EtOAc/Hexane 30%); 1H NMR (400 MHz, CDCl3): δ 7.93-7.91 (m,
129.4, 128.8, 46.9, 42.0, 26.0, 25.3, 24.2; IR (KBr, cm-1) υC=O 1680,
1640; HRMS (ESI) calcd. for C13H16NO2 (M+H)+: 218.1181; found
2H), 7.61 (d, J = 7.2 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 5.85-5.75 (m,
1H), 5.19-5.13 (m, 2H), 3.76 (t, J = 5.2 Hz, 2H), 3.35 (t, J = 5.2 Hz,
218.1187.
2H), 3.0 (d, J = 6.8 Hz, 2H), 2.53 (t, J = 5.2 Hz, 2H), 2.38 (t, J = 4.8 Hz,
2H); 13C NMR (100 MHz): δ 191.4, 165.3, 134.7, 134.2, 133.1, 129.6,
1-phenyl-2-(pyrrolidin-1-yl)ethane-1,2-dione (3c). 22
Pale Yellow Viscous Oil (68%); Purified by flash column 129.0, 118.6, 61.4, 52.8, 52.4, 45.8, 41.2; IR (KBr, cm-1) υC=O 1682,
chromatography (EtOAc/Hexane 30%); 1H NMR (400 MHz, CDCl3): δ 1643; HRMS (ESI) calcd. for C15H19N2O2 (M+H)+:259.1447; found
7.95-7.93 (m, 2H), 7.59 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.2 Hz, 2H), 259.1445.
3.60 (t, J = 6.4 Hz, 2H), 3.37 (t, J = 6.4 Hz, 2H), 1.93-1.87 (m, 4H); 13
C
Ethyl 4-(2-oxo-2-phenylacetyl)piperazine-1-carboxylate (3j).
NMR (100 MHz): δ 191.4, 164.8, 134.5, 132.8, 129.7, 128.8, 46.5,
45.1, 25.8, 23.9; IR (KBr, cm-1) υC=O 1685, 1651; HRMS (ESI) calcd. for
C12H14NO2 (M+H)+: 204.1025; found 204.1034.
Brown viscous oil (73%); Purified by chromatography
(EtOAc/Hexane 30%); 1H NMR (400 MHz, CDCl3): δ 7.94-7.90 (m,
2H), 7.64-7.60 (m, 1H), 7.48 (t, J = 7.6 Hz, 2H), 4.12 (q, J = 7.2 Hz,
2H), 3.72 (t, J = 5.6 Hz, 2H), 3.58-3.56 (m, 2H), 3.46-3.43 (m, 2H),
1-(4-methylpiperazin-1-yl)-2-phenylethane-1,2-dione (3e).24
Pale yellow gummy solid (70%); Purified by chromatography 3.32-3.29 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz): δ
(EtOAc/Hexane 35%); 1H NMR (400 MHz, CDCl3): δ 7.87-7.85 (m, 191.0, 165.5, 155.1, 134.9, 132.9, 129.6, 129.0, 61.8, 45.6 (2C), 41.0
2H), 7.59-7.54 (m, 1H), 7.45-7.31 (m, 2H), 3.70 (t, J = 5.2 Hz, 2H), (2C), 14.5; IR (KBr, cm-1) υC=O 1732, 1697, 1645; HRMS (ESI) calcd.
3.29 (t, J = 5.2 Hz, 2H), 2.42 (t, J = 5.2 Hz, 2H), 2.28 (t, J = 5.2 Hz, 2H), for C15H19N2O4 (M+H)+:291.1345; found 291.1350.
2.25 (s, 3H); 13C NMR (100 MHz): δ 191.5, 165.4, 134.8, 133.0,
N-Hexyl-2-oxo-2-phenylacetamide (4a).8d
129.6, 129.0, 54.8, 54.4, 45.9, 45.7, 41.1; IR (KBr, cm-1) υC=O 1681,
1643; HRMS (ESI) calcd. for C13H17N2O2 (M+H)+: 233.1290; found
Pale yellow viscous oil (64%); Purified by chromatography
1
(EtOAc/Hexane 35%); H NMR (400 MHz, CDCl3): δ 8.29 (d, J = 8.0
233.1310.
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Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.12 (brs, 1H), 13.8, 13.5; IR (KBr, cm-1) υC=O 1680, 1637; HRMS (ESI) calcd. for
3.34 (q, J = 7.2 Hz, 2H), 1.59-1.52 (m, 2H), 1.36-1.22 (m, 6H), 0.85 (t, C16H24NO2 (M+H)+:262.1807; found 262.1811.
J = 6.8 Hz, 3H); 13C NMR (100 MHz): δ 187.9, 161.7, 134.2, 133.3,
N-Benzyl-2-oxo-2-phenylacetamide (4h).8h
131.1, 128.3, 39.4, 31.3, 29.2, 26.5, 22.4, 13.9; IR (KBr, cm-1) υC=O
Orange solid (61%); mp 91-92oC; Purified by chromatography
1686, 1670, 1521; HRMS (ESI) calcd. for C14H20NO2
(EtOAc/Hexane 30%); 1H NMR (400 MHz, CDCl3): δ 7.63-7.59 (m,
(M+H)+:234.1494; found 234.1508.
1H), 7.48-7.44 (m, 2H), 7.40 (brs, 1H), 7.39-7.28 (m, 5H), 8.35-8.33
(m, 2H), 4.55 (d, J = 6.0 Hz, 2H); 13C NMR (100 MHz): δ 187.5, 161.5,
N-Hexylbenzamide (4a’).26
Off-white solid (4%); Purified by chromatography (EtOAc/Hexane 137.1, 134.4, 133.3, 131.2, 128.8, 128.5, 127.9, 127.8, 43.5; IR (KBr,
30%); 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J = 7.2 Hz, 2H), 7.46-7.42 cm-1) υC=O 1678; HRMS (ESI) calcd. for C15H14NO2 (M+H)+:240.1025;
(m, 2H), 7.37 (t, J = 7.2 Hz, 2H), 6.23 (brs, 1H), 3.40 (q, J = 6.4 Hz, found 240.1029.
2H), 1.60-1.37 (m, 2H), 1.36-1.22 (m, 6H), 0.86 (t, J = 6.8 Hz, 3H); 13C
1-(4-Methoxyphenyl)-2-morpholinoethane-1,2-dione (5a).28
NMR (100 MHz): δ 167.5, 134.8, 131.1, 128.4, 126.8, 40.0, 31.4,
Brown solid (74%); mp 112-113oC; Purified by chromatography
(EtOAc/Hexane 35%); 1H NMR (400 MHz, CDCl3): δ 7.88(d, J = 9.2
29.6, 22.5, 13.9.
N-Isopropyl-2-oxo-2-phenylacetamide (4b).15
Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H), 3.73 (brs, 4H), 3.60 (t, J
Off-white solid (67%); mp 77-78oC; Purified by chromatography = 4.8 Hz, 2H), 3.33 (t, J = 4.8 Hz, 2H); 13C NMR (100 MHz): δ 189.7,
1
(EtOAc/Hexane 30%); H NMR (400 MHz, CDCl3): δ 8.30 (d, J = 7.6 165.7, 164.9, 132.0, 126.0, 114.3, 66.7, 66.6, 55.6, 55.5, 46.2, 41.4;
Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 6.90 (brs, 1H), IR (KBr, cm-1) υC=O 1688, 1644; HRMS (ESI) calcd. for C13H16NO4
4.19-4.07 (m, 1H), 1.23 (d, J = 6.4 Hz, 6H); 13C NMR (100 MHz): δ (M+H)+:250.1079; found 250.1091.
188.0, 160.9, 134.2, 133.4, 131.1, 128.4, 41.7, 22.4; IR (KBr, cm-
1-(4-Methoxyphenyl)-2-(pyrrolidin-1-yl)ethane-1,2-dione (5b).29
1) υC=O 1682, 1597; HRMS (ESI) calcd. for C11H14NO2
(M+H)+:192.1025; found 192.1030.
Pale yellow viscous oil (72%); Purified by chromatography
1
(EtOAc/Hexane 35%); H NMR (400 MHz, CDCl3): δ 7.93 (d, J = 8.8
N-(3-(1H-Imidazol-1-yl)propyl)-2-oxo-2-phenylacetamide (4c).
Hz, 2H), 6.93 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H), 3.60 (t, J = 6.8 Hz, 2H),
Brown viscous oil (62%); Purified by chromatography 3.38 (t, J = 6.4 Hz, 2H), 1.93-1.87 (m, 4H); 13C NMR (100 MHz): δ
(EtOAc/Hexane 30%); 1H NMR (400 MHz, CDCl3): δ 8.28-8.26 (m, 190.2, 165.2, 164.7, 132.3, 125.9, 114.2, 55.6, 46.7, 45.1, 25.8, 24.0;
2H), 7.62-7.57 (m, 2H), 7.49 (brs, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.03 (s, IR (KBr, cm-1) υC=O 1672, 1636; HRMS (ESI) calcd. for C13H16NO3
1H), 6.94 (s, 1H), 4.02 (t, J = 6.8 Hz, 2H), 3.39 (q, J = 6.8 Hz, 2H), (M+H)+:234.1130; found 234.1149.
2.12-2.06 (m, 2H); 13C NMR (100 MHz): δ 187.5, 162.3, 137.1, 134.5,
1-(4-Bromophenyl)-2-morpholinoethane-1,2-dione (5c).13c
133.1, 131.1, 129.3, 128.5, 118.8, 44.5, 36.5, 30.8; IR (KBr, cm-1)
Off white solid; (67%); mp 135-136oC; Purified by chromatography
υ
C=O 1688, 1671; HRMS (ESI) calcd. for C14H16N3O2 (M+H)+:258.1243;
1
(EtOAc/Hexane 35%); H NMR (400 MHz, CDCl3): δ 7.80 (d, J = 8.4
found 258.1258.
Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 3.75 (s, 3H), 3.62 (t, J = 4.4 Hz, 2H),
3.34 (t, J = 4.4 Hz, 2H); 13C NMR (100 MHz): δ 189.8, 164.8, 132.4,
N-(tert-Butyl)-2-oxo-2-phenylacetamide (4d).27
Pale yellow viscous oil (56%); Purified by chromatography 131.8, 131.0, 130.4, 66.7, 66.6, 46.2, 41.6; IR (KBr, cm-1) υC=O 1683,
(EtOAc/Hexane 20%); H NMR (400 MHz, CDCl3): δ 8.28 (d, J = 8.0 1648; HRMS (ESI) calcd. for C12H13BrNO3 (M+H)+: 298.0079; found
1
Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 6.90 (brs, 1H), 298.0067.
1.43 (s, 9H); 13C NMR (100 MHz): δ 188.6, 161.1, 134.1, 133.4,
1-Morpholino-2-(thiophen-2-yl)ethane-1,2-dione (5d).28
131.2, 128.3, 51.6, 28.4; IR (KBr, cm-1) υC=O 1670, 1516; HRMS (ESI)
calcd. for C12H16NO2 (M+H)+:206.1181; found 206.1198.
Brown viscous oil (63%); Purified by chromatography
(EtOAc/Hexane 30%); 1H NMR (400 MHz, CDCl3): δ 7.77-7.75 (m,
N,N-Diethyl-2-oxo-2-phenylacetamide (4e).22
2H), 7.13 (t, J = 4.0 Hz, 1H), 3.70-3.69 (m, 4H), 3.60 (t, J = 4.8 Hz,
Pale yellow viscous oil (60%); Purified by chromatography 2H), 3.42 (t, J = 4.8 Hz, 2H); 13C NMR (100 MHz): δ 182.7, 164.2,
1
(EtOAc/Hexane 30%); H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 7.2 140.1, 136.7, 136.2, 128.6, 66.6, 66.5, 46.3, 41.8; IR (KBr, cm-1) υC=O
Hz, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 2H), 3.53 (q, J = 1729, 1656; HRMS (ESI) calcd. for C10H12NO3S (M+H)+:226.0538;
7.2 Hz, 2H), 3.21 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H), 1.12 (t, J found 226.0550.
= 7.2 Hz, 3H); 13C NMR (100 MHz): δ 191.5, 166.7, 134.5, 133.3,
1-(Piperidin-1-yl)-2-(thiophen-2-yl)ethane-1,2-dione (5e).8h
129.5, 128.9, 42.0, 38.8, 14.0, 12.8; IR (KBr, cm-1) υC=O 1681, 1637;
Brown solid (60%); mp 115-116oC; Purified by chromatography
HRMS (ESI) calcd. for C12H16NO2 (M+H)+:206.1181; found 206.1191.
(EtOAc/Hexane 30%); 1H NMR (400 MHz, CDCl3): δ 3.64 (t, J = 5.2
N,N-Dibutyl-2-oxo-2-phenylacetamide (4f).22
Hz, 2H), 3.34 (t, J = 5.2Hz, 2H), 1.69-1.65 (m, 5H), 1.56-1.53 (m, 2H);
Pale yellow viscous oil; (56%); Purified by chromatography 13C NMR (100 MHz): δ 184.1, 164.7, 140.8, 136.4, 136.0, 128.8,
(EtOAc/Hexane 30%); 1H NMR (400 MHz, CDCl3): δ 7.91-7.89 (m, 47.4, 42.7, 26.4, 25.6, 24.5; IR (KBr, cm-1) υC=O 1643; HRMS (ESI)
2H), 7.62-7.58 (m, 1H), 7.49-7.45 (m, 2H), 3.46 (t, J = 7.6 Hz, 2H), calcd. for C11H14NO2S (M+H)+:224.0745; found 224.0740.
3.11 (t, J = 7.6 Hz, 2 H), 1.67-1.60 (m, 2H), 1.54-1.47 (m, 3H), 1.41-
tert-Butyl (2-(2-morpholino-2-oxoacetyl)phenyl)carbamate (5f).
1.34 (m, 2H), 1.20 (t, J = 7.6 Hz, 2H), 1.18-1.12 (m, 2H), 0.96 (t, J =
7.2 Hz, 3H), 0.78( t, J = 8.0 Hz, 3H); 13C NMR (100 MHz): δ 191.6,
Brown viscous Oil (58%); Purified by chromatography
(EtOAc/Hexane 30%); 1H NMR (400 MHz, CDCl3): δ 10.5 (brs, 1H),
167.0, 134.4, 133.3, 129.6, 128.9, 47.4, 44.0, 30.6, 29.4, 20.2, 19.7,
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
8.50 (dd, J = 8.6, 1.2 Hz, 1H), 7.61-7.53 (m, 2H), 7.04-6.99 (m, 1H),
3.74 (t, J = 1.9 Hz, 4H), 3.62-3.60 (m, 2H), 3.33-3.30 (m, 2H), 1.50 (d,
J = 2.6 Hz, 9 H); 13C NMR (100 MHz): δ 194.7, 164.7, 152.6, 143.4,
136.8, 133.4, 121.4, 119.1, 117.3, 81.1, 66.6, 46.3, 41.6, 28.2; IR
(KBr, cm-1) υC=O 1731, 1651, 1607; HRMS (ESI) calcd. for C17H23N2O5
(M+H)+:335.1607; found 335.1639.
Acknowledgements
We thank the Ministry of Science and Technology, Taiwan
(Grant No. MOST103-2113-M-002-002-MY3) for the financial
support. We also thank “National Taiwan University Mass
Spectrometry-based Proteomics Core Facility” for the
measurement of ESI mass data.
1-(3-ethoxyphenyl)-2-morpholinoethane-1,2-dione (5g).
Pale yellow viscous Oil (68%); Purified by chromatography
(EtOAc/Hexane 30%); 1H NMR (400 MHz, CDCl3): δ 7.46-7.43 (m,
2H), 7.37 (t, J = 8.0 Hz, 1H), 7.16-7.13 (m, 1H), 4.05 (q, J = 6.8 Hz,
2H), 3.756 (brs, 4H), 3.61 (t, J = 5.2 Hz, 2H), 3.33 (t, J = 4.8 Hz, 2H),
1.40 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz): δ 191.1, 165.4, 159.5,
134.3, 130.0, 122.5, 122.1, 113.5, 66.7, 66.6, 63.8, 46.2, 41.6, 14.6;
IR (KBr, cm-1) υC=O 1682, 1646; HRMS (ESI) calcd. for C14H18NO4
(M+H)+:264.1236; found 264.1259.
Notes and references
‡ Footnotes relating to the main text should appear here. These
might include comments relevant to but not central to the
matter under discussion, limited experimental and spectral data,
and crystallographic data.
1
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1-(4-ethylphenyl)-2-morpholinoethane-1,2-dione (5h).30
Pale yellow viscous Oil (33%); Purified by chromatography
1
(EtOAc/Hexane 30%); H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 8.0
Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 3.75 (brs, H), 3.61 (t, J = 4.8 Hz, 2H),
3.34 (t, J = 4.8 Hz, 2H), 2.70 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz,
3H); 13C NMR (100 MHz): δ 190.8, 165.6, 152.3, 130.8, 129.8, 128.6,
66.7, 66.6, 46.2, 41.5, 29.1, 14.9; IR (KBr, cm-1) υC=O 1677, 1646;
HRMS (ESI) calcd. for C14H18NO3 (M+H)+:248.1287; found 248.1290.
2
1-Morpholino-2-(naphthalen-2-yl)ethane-1,2-dione (5i).8c
Brown viscous Oil (71%); Purified by chromatography
(EtOAc/Hexane 30%); 1H NMR (400 MHz, CDCl3): δ 8.44 (s, 1H),
8.01-7.91 (m, 3H), 7.87 (d, J = 8.0 Hz, 1H), 7.65-7.61 (m, 1H), 7.58-
7.54 (m, 1H), 3.82 (brs, 4H), 3.64 (t, J = 4.4 Hz, 2H), 3.39 (t, J = 4.4
Hz, 2H): 13C NMR (100 MHz): δ 191.2, 165.5, 136.4, 133.0, 132.4,
130.4, 129.8, 129.5, 129.1, 127.9, 127.2, 123.5, 66.7, 66.6, 46.3,
41.7; IR (KBr, cm-1) υC=O 1674, 1645; HRMS (ESI) calcd. for C16H16NO3
(M+H)+:270.1130; found 270.1151.
3
(a) R. Finlayson, A. N. Pearce, M. J. Page, M. Kaiser, M.-L.
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4
5
1-(4-Benzoylpiperazin-1-yl)-2-(naphthalen-2-yl)ethane-1,2-dione
(5j).20
6
7
G. S. Singh and Z. Y. Desta, Chem. Rev., 2012, 112, 6104.
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2-Ethylnaphthalene (1 g, 6.40 mmol),I2 (81 mg, 0.03 mmol), pyridine
(26 mg, 0.03 mmol), TBHP (2.5 mL, 19.20 mmol, 70% aqueous
solution) were mixed in a 20 mL sealed tube. The reaction mixture
was stirred in an oil bath at 80 oC for 10 h. After confirming the
reaction progress by TLC, the reaction mixture was transferred to a
25 mL round bottomed flask. Then TBHP (2.5 mL, 19.20 mmol, 70%
aqueous solution), NaI (288 mg, 1.92 mmol) and a solution of
phenyl(piperazin-1-yl)methanone (3 g, 16.00 mmol) in acetonitrile
(2.5 mL) were added sequentially and stirred at room temperature
for 6 h. The volume of the reaction mixture reduced to half by
vacuum and purified by a silica gel column chromatography using
hexane/ethyl acetate as eluent (30% to 35%) to give 5j as a pale
brown solid. (1.25 g, 54%); mp 140-141oC; Purified by
8
Karuna, P. K. Niggula and S. Nagula, Green. Chem., 2016, 18
3439; (c) G. Shiyu, F. Zheng, Y. Zhao, L. Chengkou, D.
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Z. Zhang, J. Su, Z. Zha and Z. Wang, Chem. Commun, 2013,
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9
1
chromatography (EtOAc/Hexane 35%); HNMR (400 MHz, CDCl3): δ
8.43 (s, 1H), 8.00-7.91 (m, 3H), 7.87 (d, J = 8.0 Hz, 1H), 7.63 (d, J =
8.0 Hz, 1H), 7.56 (d, J = 7.2 Hz, 1H), 7.39 (brs, 5H), 3.83-3.69 (m, 4H),
3.42 (brs, 4H); 13C NMR (100 MHz): δ 191.0, 170.7, 165.7, 136.4,
134.8, 133.0, 132.4, 130.3, 130.2, 129.9, 129.6, 129.2, 128.7, 127.9,
127.2, 127.0, 123.5, 46.0, 41.5; IR (KBr, cm-1) υC=O 1674, 1641;
HRMS (ESI) calcd. for C23H21N2O3 (M+H)+:373.1552; found 373.1558.
10 R. Deshidi, M. Kumar, S. Devari and B. A. Shah, Chem.
Commun., 2014, 50, 9533.
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6 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6OB02361D
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ARTICLE
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Table 1 Optimization of the one pot oxidative amidation of ethylbenzene via phenacyl iodide 2a’
entry
1
2
3
4
5
6
7
8
Conditions for step 1
Conditions for step 2
yields
14%
trace
32%
47%
40%
47%
36%
49%
45%
55%
I2(20 mol%)/TBHP(3eq)/120 oC/1 h
morpholine(2.5 eq)/TBHP(3eq)/rt/12 h
piperidine(2.5 eq)/TBHP(3eq)/rt/12 h
piperidine(2.5 eq)/TBHP(3eq)/rt/12 h
piperidine(2.5 eq)/TBHP(3eq)/rt/12 h
piperidine(2.5 eq)/TBHP(3eq)/rt/12 h
morpholine(2.5 eq)/TBHP(3eq)/rt/12 h
morpholine(2.5 eq)/TBHP(3eq)/rt/12 h
morpholine(2.5 eq)/TBHP(3eq)/rt/12 h
morpholine(2.5 eq)/TBHP(3eq)/rt/12 h
morpholine(2.5 eq)/TBHP(3eq)/rt/12 h
I2(20 mol%)/TBHP(3eq)/120 oC/1 h
I2(20 mol%)/TBHP(3eq)/100 oC/12 h
I2(20 mol%)/TBHP(3eq)/100 oC/12 h/CH3CN
I2(20 mol%)/TBHP(3eq)/100 oC/12 h/dioxane
benzoyl peroxide (20 mol%)/I2(20 mol%)/TBHP(3eq)/100 oC/12 h/EtOAc
AIBN(20 mol%)/ I2(20 mol%)/TBHP(3eq)/100 oC/12 h/EtOAc
I2(20 mol%)/TBHP(3eq)/70 oC/12 h/250W hv
I2(20 mol%)/TBHP(10eq)/120 oC/1 h
9
10
I2(20 mol%)/TBHP(3eq)/65 oC/50 h
a
Reaction
conditions:
1a
(1.88
mmol)
no
solvent
used,
unless
noted;
Isolated
yields.
Table 2 Optimization of the one pot oxidative amidation of ethylbenzene via 2a
entry
Conditions for step 1
Conditions for step 2
yields
56%
1
2
3
4
5
6
7
8
9
I2(5 mol%)/pyridine (5 mol%)/TBHP(3eq)/80 oC/10 h
I2(5 mol%)/pyridine (5 mol%)/TBHP(3eq)/80 oC/10 h
I2(5 mol%)/pyridine (5 mol%)/TBHP(3eq)/80 oC/10 h
I2(5 mol%)/pyridine (5 mol%)/TBHP(3eq)/80 oC/10 h
I2(5 mol%)/pyridine (5 mol%)/TBHP(3eq)/80 oC/10 h
I2(5 mol%)/pyridine (5 mol%)/TBHP(3eq)/80 oC/10 h
I2(5 mol%)/pyridine (5 mol%)/TBHP(3eq)/80 oC/10 h
I2(5 mol%)/pyridine (5 mol%)/TBHP(3eq)/80 oC/10 h
I2(5 mol%)/pyridine (5 mol%)/TBHP(3eq)/80 oC/10 h
morpholine(2.5 eq)/NaI (20 mol%)/TBHP(3eq)/rt/12 h
morpholine(2.5 eq)/NaI (30 mol%)/TBHP(3eq)/rt/12 h
morpholine(2.5 eq)/I2 (30 mol%)/TBHP(3eq)/rt/12 h
morpholine(2.5 eq)/NaI (60 mol%)/TBHP(3eq)/rt/12 h
Et2NH(2.5 eq)/NaI (40 mol%)/TBHP(3eq)/rt/12 h
Et2NH(2.5 eq)/NaI (40 mol%)/TBHP(3eq)/10 oC/12 h
Et2NH(2.5 eq)/NaI (40 mol%)/TBHP(3eq)/0 oC /12 h
Et2NH(2.5 eq)/NaI (40 mol%)/TBHP(3eq)/- 5 oC/12 h
morpholine(2.5 eq)/TBHP(3eq)/rt/12 h
72%
68%
75%
31%
57%
65%
42%
51%
a
Reaction
conditions:
1a
(1.88
mmol)
no
solvent
was
used;
Isolated
yields.
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