Iodine-mediated oxidation of ynamides: A facile access to N-monosubstituted α-ketoamides and α-ketoimides

Article abstract of DOI:10.1002/ejoc.201402538

An efficient iodine-mediated oxidation reaction for ynamides has been developed to produce N-monosubstituted α-ketoamides and α-ketoimides. This oxidative method, which exhibits good functional group tolerance, was performed under mild conditions without a metal catalyst.

Full text of DOI:10.1002/ejoc.201402538

FULL PAPER
DOI: 10.1002/ejoc.201402538
Iodine-Mediated Oxidation of Ynamides: A Facile Access to
N-Monosubstituted α-Ketoamides and α-Ketoimides
Hai Huang,[a] Guangke He,[a] Xiaolin Zhu,[a] Xiaodong Jin,[a] Shineng Qiu,[a] and
Hongjun Zhu*[a]
Keywords: Synthetic methods / Iodine / Oxidation / Amides / Alkynes
An efficient iodine-mediated oxidation reaction for ynamides
exhibits good functional group tolerance, was performed un-
has been developed to produce N-monosubstituted α- der mild conditions without a metal catalyst.
ketoamides and α-ketoimides. This oxidative method, which
instance, Li[5b] reported the Au-catalyzed oxidation of an
alkyne by employing diphenyl sulfoxide to produce 1,2-di-
Introduction
The syntheses of α-ketoamides and their derivatives have carbonyl compounds. However, these oxidative methods
attracted considerable attention, because they are biolo- have several limitations, such as the need for harsh oxidative
gically active compounds and have widespread applications conditions, expensive transition-metal catalysts, and high
as versatile building blocks in organic synthesis.[1,2] Various reaction temperatures,[5] thereby restricting their practical
methods have been developed for the syntheses of α- applications. Therefore, the development of efficient and
ketoamides, which include the amidation of α-keto acids,[3] convenient methods to synthesize N-monosubstituted α-
the double carbonylation of amines,[4] the oxidation of ketoamides and α-ketoimides under mild reaction condi-
ynamides,[5] and other chemical transformations.[6] The oxi- tions is necessary.
dation of ynamides is a straightforward method to produce
The use of inexpensive and less toxic iodine-containing
α-ketoamides because of the availability of a variety of reagents is attractive in organic synthesis.[8] Several reports
ynamides.[7] Most of the present oxidation methods, how- have described the syntheses of α-diketones by using the
ever, are performed in the presence of transition-metal cata- iodine-mediated oxidation reaction of alkynes.[9] For in-
lysts (e.g., Au and Rh)[5d–5j] and external oxidants.[5f] For stance, Zhao and co-workers reported a convenient ap-
Scheme 1. Iodine-mediated oxidation of ynamides (Boc = tert-butoxycarbonyl, TFA = trifluoroacetic acid).
[a] Department of Applied Chemistry, College of Sciences, Nanjing
proach to the preparation of α-diketones that involves the
Tech University,
reaction of alkynes with N-iodosuccinimide (NIS)/H2O at
70 °C [see Scheme 1, Equation (1)].[10] Despite these ad-
vances, there is no reported example[11] of the synthesis of
N-monosubstituted α-ketoamides[12] through the direct oxi-
Nanjing 211816, Peoples Republic of China
E-mail: zhuhj@njtech.edu.cn
http://lxy.njtech.edu.cn/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402538.
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Iodine-Mediated Oxidation of Ynamides
dation of ynamides. Herein, we report a facile and straight- gave the highest yield of 2a (see Table 1, Entries 9–12).
forward method based on the iodine/water-mediated oxi- Interestingly, this oxidation reaction was also promoted by
dation of ynamides to synthesize N-monosubstituted α- using I2 instead of NIS, and 1.5 equiv. of I2 was an optimal
ketoamides and α-ketoimides [see Scheme 1, Equation (2)]. amount for this transformation (see Table 1, Entry 13).
Employing the optimized reaction conditions (see
Table 1, Entry 13), we examined the scope and generality of
this transformation by using various ynamides that con-
Results and Discussion
tained a Boc group (see Table 2). Methyl and bromo sub-
stituents on the aryl ring of the ynamide were tolerated and
readily gave high yields of the corresponding N-monosub-
stituted α-ketoamide (see Table 2, Entries 2 and 3). Under
the optimized reaction conditions, various substrates that
contained ortho, meta, and para substituents on the N-aryl
ring of the ynamide were converted (in moderate to high
yields) into the corresponding N-monosubstituted α-keto-
amides (see Table 2, Entries 4–11). The yields decreased
with an electron-withdrawing group at the meta position
of the N-aryl ring (see Table 2, Entries 8–11). N-naphthyl-
substituted ynamide 1l was also used in this reaction, and
2l was produced in a yield of 54% (see Table 2, Entry 12).
In addition, a high yield was obtained by using alkyl-substi-
tuted ynamide 1m under the reaction conditions (see
Table 2, Entry 13). The structure of 2a was further con-
firmed by using single-crystal X-ray structure analysis (see
Figure 1).[14]
In the initial experiments, tert-butyl N-benzyl-N-(phenyl-
ethynyl)carbamate (1a)[7d] was treated with NIS and H2O
under N2. Because of the strong acidic environment during
the oxidative process, this reaction afforded the oxidation
product N-benzyl-2-oxo-2-phenylacetamide (2a) in 13%
yield by HPLC analysis, instead of the α-ketoimide tert-
butyl N-benzyl-N-(2-oxo-2-phenylacetyl)carbamate (2aЈ,
see Table 1, Entry 1).[13] The desired product 2a was ob-
tained in 56% yield when 1a was stirred with NIS in a mix-
ture of CH3CN and H2O in the air (see Table 1, Entry 2).
The yield improved from 56 to 80% by decreasing the
amount of 1a (see Table 1, Entry 3). In a control experiment
(i.e., without NIS), the target product was not produced
(see Table 1, Entry 4). Among the solvents screened,
CH3CN was superior to tetrahydrofuran (THF; 55% yield),
1,4-dioxane (60% yield), N,N-dimethylformamide (DMF;
43% yield), and dichloromethane (DCM; 22% yield; see
Table 1, Entry 3 vs. 5–8). In addition, solvents with poor
water solubility, such as DCM, provided unsatisfactory re-
sults. Given that amide groups hydrolyze under acidic con-
ditions, TFA was added to the reaction mixture. The target
product 2a was obtained in high yield by using TFA (see
Table 1, Entry 9). The employment of 1.5 equiv. of NIS
Table 2. Iodine-promoted oxidation of ynamides.[a]
Entry
R
R1
t [h] Product Isolated yield [%]
Table 1. Optimization of reaction conditions.[a]
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph (1a)
p-MeC6H4 (1b)
p-BrC6H4 (1c)
Bn
Bn
Bn
Ph (1d)
3
3
2a
2b
2c
2d
2e
2f
93
93
90
75
83
89
80
79
65
59
57
54
91
3
5
5
5
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
o-MeC6H4 (1e)
m-MeC6H4 (1f)
p-MeC6H4 (1g)
m-FC6H4 (1h)
m-ClC6H4 (1i)
m-BrC6H4 (1j)
m-CF3C6H4 (1k)
2-naphthyl (1l)
Ph
5
5
5
2g
2h
2i
Entry
Solvent
[I] [equiv.] Additive (equiv.) t [h] Yield [%]
8
2j
1
2[c]
3
4
5
CH3CN
CH3CN
CH3CN
CH3CN
THF
NIS (1.5)
NIS (1.5)
NIS (1.5)
–
–
–
–
–
3
3
3
3
3
3
4
12
3
3
13[b,c]
56
80
0
55
12
3
2k
2l
n-butyl (1m)
4
2m
NIS (1.5)
–
[a] Reagents and conditions: ynamide (0.2 mmol), I2 (1.5 equiv.),
TFA (1.0 equiv.), CH3CN (2.0 mL), H2O (0.5 mL), room temp., air.
6
1,4-dioxane NIS (1.5)
–
60
43
22
7
8
9
10
11
12
13
DMF
DCM
NIS (1.5)
NIS (1.5)
NIS (1.5)
NIS (0.5)
NIS (1.0)
NIS (2.0)
I2 (1.5)
–
–
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
TFA (1.0)
TFA (1.0)
TFA (1.0)
TFA (1.0)
TFA (1.0)
95 (93)[d]
28
3
3
3
57
92
94
[a] Reagents and conditions: 1a (0.2 mmol), NIS or I2, H2O
(0.5 mL), and solvent (2.0 mL) at room temp. in the air. Unless
otherwise noted, yields were determined by HPLC analysis of the
crude reaction mixture. [b] H2O (2.0 equiv.) was used under N2.
[c] 1a (0.3 mmol) was used. [d] Isolated yield.
Figure 1. Single-crystal X-ray structure of 2a.
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H. Huang, G. He, X. Zhu, X. Jin, S. Qiu, H. Zhu
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Table 3. Iodine-promoted oxidation of ynamides without Boc group.[a]
[a] Reagents and conditions: ynamine (0.3 mmol), I2 (1.5 equiv.), CH3CN (3.0 mL), H2O (0.75 mL), room temp., air. [b] Isolated yield.
Different alkynamide derivatives that did not contain a was converted into the corresponding α-ketoimide (see
Boc group were then investigated (see Table 3). Both N- Table 3, compound 2t) with a yield of only 34%, which was
(arylalkynyl)- and N-(alkylalkynyl)-substituted oxazolid- possibly because of the strong electron-withdrawing ability
inones were converted into the corresponding α-ketoimides of the sulfonyl group.
in moderate yields (see Table 3, Compounds 2n and 2o). To
To demonstrate the synthetic potential of this strategy,
examine the steric effects of 4-substituted oxazolidinones, 1a (1.23 g, 4 mmol) and 1p (1.05 g, 4 mmol) were employed
we used (S)-4-phenyl-3-(phenylethynyl)oxazolidin-2-one in the reaction under the optimal conditions, which could
(1p) and (S)-4-benzyl-3-(phenylethynyl)oxazolidin-2-one be scaled up to 4 mmol without a significant decrease in
(1q) as model substrates, which produced the corresponding the yield (see Scheme 2). In the large-scale reaction of 1p, it
products in yields of 74 and 75%, respectively (see Table 3, is noteworthy that alkenyl diiodo intermediate 2pЈ was also
compounds 2p and 2q). This indicates that the product yield obtained in 4% isolated yield.
is affected more by the electronics of the substrates than
To understand the reaction mechanism, control experi-
the steric hindrance of the 4-substituted oxazolidinones. In ments were conducted by using different amounts of H2O
addition, substituted indoles were also examined, and they [see Scheme 3, Equation (i)]. Compound 2a was not pro-
could be transformed into the corresponding products in duced under N2 or O2 in the absence of H2O [see Scheme 3,
moderate yields (see Table 3, compounds 2r and 2s). N- Equation (i), Entries 1 and 2]. Although the reaction did
Benzyl-4-methyl-N-(phenylethynyl)benzenesulfonamide (1t) proceed by using different amounts of H2O in the absence
Scheme 2. Scale-up experiment.
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Iodine-Mediated Oxidation of Ynamides
Scheme 3. Experiments for mechanistic study.
Figure 2. The HR mass spectra of 18O-labeled 2a.
of oxygen [see Scheme 3, Equation (i), Entries 3 and 4], the removal of the Boc group could not occur before the oxi-
desired product was obtained in a relatively low yield. By dation process. It is, however, not easy to determine the
contrast, the desired product was afforded in 93% yield un- point of deprotection under the present reaction conditions.
der the optimized reaction conditions [see Scheme 3, Equa-
By employing our experimental results and literature re-
tion (i), Entry 5]. These results reveal the important role of ports, we have proposed a mechanism for this oxidation re-
molecular oxygen and H2O in this oxidation system. The action (see Scheme 5). In the presence of iodine as a weak
transformation of 1a was then investigated by using of Lewis acid, 1 can produce iodonium intermediate A,[8a]
H218O to verify the presence of a double-and single-18O- which can undergo a nucleophilic attack by a hydroxy or
labeled product. The HR mass spectra showed a signal iodide anion to produce iodoenol intermediate B[16] or di-
from a double-18O-labeled product and one from a single- iodo compound C,[17] respectively. There is a high degree of
18O-labeled product. The α-ketone moiety of α-ketoamide regioselectivity with the formation of B because of the
2a can actively undergo oxygen exchange through the hemi- strong electron-donating effect of the nitrogen atom.[18]
ketal and H218O, especially under acidic conditions (see Through a keto/enol tautomerism, intermediate B can then
Figure 2).[15]
form α-iodo ketone intermediate D.[10,19]
Two control reactions were performed to further under-
Then, radical intermediate E and an iodine radical could
stand the mechanism of the oxidative process. The reaction be generated from D through a homolytic cleavage of the
of ynamide 1d with TFA (1.0 equiv.) in the absence of I2 or C–I bond. Upon treatment with O2, E can be converted
NIS in the air resulted in the formation of amide 3d in 76% into peroxy radical species F, which releases a hydroxyl radi-
yield, which demonstrates that deprotected ynamides are cal to afford α-ketoimides 2. The hydroxyl radical may com-
very sensitive toward hydrolysis[7a] [see Scheme 4, Equa- bine with the iodine radical to result in the formation of
tion (a)]. Under our optimized reaction conditions for the HIO.[20] The further hydrolysis of α-ketoimides 2 under
oxidative process, amide 3d could not produce the desired acidic conditions provides the N-monosubstituted α-keto-
α-ketoamide 2d [see Scheme 4, Equation (b)]. Therefore, the amides.
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H. Huang, G. He, X. Zhu, X. Jin, S. Qiu, H. Zhu
FULL PAPER
Scheme 4. Control reactions for mechanistic study.
Scheme 5. Proposed mechanism for this oxidation of ynamides.
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
Conclusions
We developed a new, efficient, and economical method
to synthesize α-ketoamides by using the iodine-mediated
oxidation of ynamides in air. This method not only provides
a general entry to N-monosubstituted α-ketoamides and α-
ketoimides but also broadens the application of iodine. Fur-
ther studies of alkynes and iodine-mediated C–C, C–N, and
C–O bond formations are being conducted in our labora-
tory, and the results will be reported in due course.
Ynamides Synthesis – Typical Procedure I
tert-Butyl N-(Phenylethynyl)-N-(o-tolyl)carbamate (1e): According
to a reported procedure.[7d] To a mixture of tert-butyl o-tolylcarb-
amate (1.63 g, 8 mmol), K3PO4 (3.21 g, 16 mmol), CuSO4·5H2O
(0.19 g, 0.8 mmol), and 1,10-phenanthroline (0.27 g, 1.6 mmol) in
a reaction vial was added a solution of (bromoethynyl)benzene[21]
(1.57 g, 8.8 mmol) in toluene (15 mL). The vial was capped and
then heated in an oil bath at 85 °C for 18 h, as the progress of the
reaction was monitored by TLC analysis. Upon completion, the
reaction mixture was cooled to room temperature and diluted with
EtOAc. The resulting mixture was filtered through Celite, and the
filtrate was concentrated in vacuo. The crude product was purified
by flash chromatography on a silica gel column [petroleum ether
(PE)/ethyl acetate (EtOAc)] to afford 1e (1.37 g, 56%) as a yellow
solid; m.p. 55–56 °C (n-hexane/ethyl acetate). 1H NMR (400 MHz,
CDCl3): δ = 7.39–7.31 (m, 3 H), 7.29–7.22 (m, 6 H), 2.36 (s, 3 H),
1.52 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.3, 138.4,
135.4, 131.0, 130.9, 128.4, 128.1, 127.5, 127.2, 126.9, 123.5, 83.8,
83.0, 69.3, 28.0, 17.5 ppm. MS (ESI): m/z (%) = 330 (100) [M +
Experimental Section
General Methods: Unless otherwise stated, all commercial reagents
were used without additional purification. The H and 13C NMR
1
spectroscopic data were recorded at 400 and 100 MHz, respectively,
with a Bruker Avance DPX spectrometer, and CDCl3 was used as
the solvent. The abbreviations that are used to describe the peak
patterns are: br. (broad), s (singlet), d (doublet), t (triplet), q (quar-
tet), and m (multiplet). Coupling constants are reported in Hertz
(Hz). Chemical shifts are reported in ppm relative to the internal
standard tetramethylsilane (δ = 0 ppm) for 1H NMR and deute-
rochloroform (δ = 77.00 ppm) for 13C NMR spectroscopy. Low-
resolution and high-resolution mass spectra were obtained by using
ESI ionization. Melting points were measured with a micro melting
point apparatus. HPLC analysis was performed with a Shimadzu
LC-20A high performance liquid chromatograph by using an exter-
Na]+. IR (KBr): ν = 3443, 2983, 1725, 1636, 1522, 1370, 1306,
˜
1155, 1006, 857, 762 cm–1. C20H21NO2 (307.39): calcd. C 78.15, H
6.89, N 4.56; found C 78.42, H 6.73, N 4.39.
tert-Butyl N-(Phenylethynyl)-N-(m-tolyl)carbamate (1f): Yellow so-
1
lid (0.98 g, 40% yield); m.p. 93–94 °C (n-hexane/ethyl acetate). H
1
2
nal standard method. CCDC-991283 (for 2pЈ), -991284 (for 2a) NMR (400 MHz, CDCl3): δ = 7.39 (dd, J = 1.6 Hz, J = 8.0 Hz,
and -993262 (for 2s) contain the supplementary crystallographic 2 H), 7.34 (s, 1 H), 7.32–7.23 (m, 5 H), 7.08 (d, J = 6.8 Hz, 1 H),
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Iodine-Mediated Oxidation of Ynamides
2.38 (s, 3 H), 1.57 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ tert-Butyl N-(Naphthalen-2-yl)-N-(phenylethynyl)carbamate (1l):
= 153.0, 139.5, 138.8, 130.8, 128.6, 128.2, 127.5, 127.3, 125.4, 123.4,
Yellow solid (1.51 g, 55% yield); m.p. 90–92 °C (n-hexane/ethyl
1
121.8, 83.8, 83.4, 70.0, 28.0, 21.4 ppm. MS (ESI): m/z (%) = 330
acetate). H NMR (400 MHz, CDCl3): δ = 8.00 (d, J = 2.0 Hz, 1
(100) [M + Na]+. IR (KBr): ν = 3412, 2975, 2923, 2257, 1737, 1606,
H), 7.88–7.82 (m, 3 H), 7.65 (dd, 1J = 2.0 Hz, J = 8.8 Hz, 1 H),
2
˜
1490, 1451, 1361, 1290, 1248, 1150, 1043, 852, 758 cm–1. 7.53–7.45 (m, 2 H), 7.44–7.40 (m, 2 H), 7.33–7.24 (m, 3 H), 1.59
C20H21NO2 (307.39): calcd. C 78.15, H 6.89, N 4.56; found C
78.16, H 7.02, N 4.31.
(s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 153.0, 137.1,
133.3, 131.8, 130.9, 128.6, 128.2, 127.9, 127.6, 127.4, 126.5, 126.1,
123.3, 122.7, 83.7, 83.6, 70.2, 28.0 ppm. MS (ESI): m/z (%) = 366
tert-Butyl N-(Phenylethynyl)-N-(p-tolyl)carbamate (1g): Yellow so-
(100) [M + Na]+. IR (KBr): ν = 3414, 3132, 3055, 2978, 2927, 2252,
˜
1
lid (1.25 g, 51% yield); m.p. 63–64 °C (n-hexane/ethyl acetate). H
1736, 1392, 1369, 1289, 1249, 1149, 1022, 855, 754 cm–1.
C23H21NO2 (343.42): calcd. C 80.44, H 6.16, N 4.08; found C
80.16, H 6.51, N 4.22.
NMR (400 MHz, CDCl3): δ = 7.42–7.36 (m, 4 H), 7.31–7.24 (m, 3
H), 7.19 (d, J = 8.0 Hz, 2 H), 2.36 (s, 3 H), 1.57 (s, 9 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 153.0, 137.1, 136.6, 130.8, 129.4,
128.2, 127.3, 124.6, 123.4, 83.9, 83.3, 69.8, 28.0, 21.0 ppm. MS
tert-Butyl N-(Hex-1-ynyl)-N-(phenyl)carbamate (1m): Colorless oil
(ESI): m/z (%) = 330 (100) [M + Na]+. IR (KBr): ν = 3414, 3127, (0.72 g, 33% yield). 1H NMR (400 MHz, CDCl3): δ = 7.48–7.43
˜
3058, 2977, 2926, 2251, 1733, 1511, 1365, 1300, 1147, 1006,
(m, 2 H), 7.38–7.32 (m, 2 H), 7.21 (t, J = 7.6 Hz, 1 H), 2.33 (t, J
755 cm–1. C20H21NO2 (307.39): calcd. C 78.15, H 6.89, N 4.56; = 6.8 Hz, 2 H), 1.58–1.40 (m, 13 H), 0.91 (t, J = 7.6 Hz, 3 H) ppm.
found C 78.33, H 6.92, N 4.58.
13C NMR (100 MHz, CDCl3): δ = 153.6, 140.2, 128.6, 126.2, 124.5,
82.9, 74.3, 69.2, 31.0, 28.0, 21.9, 18.2, 13.6 ppm. MS (ESI): m/z (%)
tert-Butyl N-(3-Fluorophenyl)-N-(phenylethynyl)carbamate (1h):
Yellow solid (1.42 g, 57% yield); m.p. 33–35 °C (n-hexane/ethyl
acetate). 1H NMR (400 MHz, CDCl3): δ = 7.44–7.27 (m, 8 H),
6.99–6.92 (m, 1 H), 1.58 (s, 9 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 152.4, 141.1, 130.9, 129.8, 129.7, 128.3, 127.6, 123.0,
= 296 (100) [M + Na]+. IR (KBr): ν = 3415, 3329, 3111, 3062,
˜
2945, 2863, 2256, 1712, 1580, 1523, 1468, 1388, 1300, 1023, 958,
745 cm–1. HRMS (ESI+): calcd. for C17H23NO2 [M + Na]+
296.1621; found 296.1617.
119.7 (d, J = 2.8 Hz), 113.3 (d, J = 21.4 Hz), 111.8 (d, J = 25.5 Hz), Oxidation of Ynamides with Boc Group – Typical Procedure II
84.0, 82.7, 70.9, 28.0 ppm. MS (ESI): m/z (%) = 334 (100) [M +
N-Benzyl-2-oxo-2-phenylacetamide (2a): The reaction of 1a
Na]+. IR (KBr): ν = 3415, 3083, 2979, 2930, 2246, 1738, 1601,
˜
(61.5 mg, 0.2 mmol), I2 (75.4 mg, 0.3 mmol), TFA (15 μL), and
CH3CN/H2O (4:1, 2.5 mL) was carried out at room temp. for 3 h,
as the progress of the reaction was monitored by TLC analysis.
Upon completion, the mixture was diluted with 5% Na2CO3 solu-
tion (10 mL). The resulting mixture was extracted with diethyl
ether (3ϫ 10 mL), and the combined extracts were dried with anhy-
1488, 1365, 1292, 1249, 1152, 902, 858, 755 cm–1. C19H18FNO2
(311.35): calcd. C 73.29, H 5.83, N 4.50; found C 73.51, H 5.96, N
4.67.
tert-Butyl N-(3-Chlorophenyl)-N-(phenylethynyl)carbamate (1i):
Yellow solid (1.44 g, 55% yield); m.p. 64–66 °C (n-hexane/ethyl
1
acetate). H NMR (400 MHz, CDCl3): δ = 7.60 (t, J = 2.0 Hz, 1 drous Na2SO4. The solvent was removed by evaporation under re-
1
2
H), 7.47 (d, J = 8.4 Hz, 1 H), 7.41 (dd, J = 2.0 Hz, J = 8.0 Hz,
duced pressure. The crude product was purified by flash
2 H), 7.35–7.27 (m, 4 H), 7.23 (d, J = 8.0 Hz, 1 H), 1.58 (s, 9 chromatography on a silica gel column (petroleum ether/ethyl acet-
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.5, 140.7, 134.3,
130.9, 129.7, 128.3, 127.6, 126.6, 124.6, 123.0, 122.5, 84.0, 82.7,
70.8, 28.0 ppm. MS (ESI): m/z (%) = 350 (100) [M + Na]+. IR
ate) to afford 2a (44.6 mg, 93% yield) as a light yellow solid; m.p.
125–126 °C (n-hexane/ethyl acetate). 1H NMR (400 MHz, CDCl3):
δ = 8.40–8.33 (m, 2 H), 7.66–7.60 (m, 1 H), 7.48 (t, J = 7.6 Hz, 2
(KBr): ν = 3453, 3111, 3081, 2976, 2930, 2256, 1738, 1588, 1475, H), 7.42 (br., 1 H), 7.39–7.27 (m, 5 H), 4.57 (d, J = 6.0 Hz, 2
˜
1310, 1287, 1152, 1095, 1023, 781, 751 cm–1. C19H18ClNO2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 187.5, 161.5, 137.1,
(327.81): calcd. C 69.62, H 5.53, N 4.27; found C 69.22, H 5.39, N
4.04.
134.4, 133.3, 131.2, 128.8, 128.5, 127.9, 127.8, 43.5 ppm. MS (ESI):
m/z (%) = 262 (100) [M + Na]+. IR (KBr): ν = 3248, 3068, 2928,
˜
1697, 1658, 1593, 1546, 1405, 1399, 1216, 1160, 1024, 886,
753 cm–1. C15H13NO2 (239.27): calcd. C 75.30, H 5.48, N 5.85;
found C 75.16, H 5.43, N 5.59.
tert-Butyl N-(3-Bromophenyl)-N-(phenylethynyl)carbamate (1j): Yel-
low solid (1.48 g, 50% yield); m.p. 65–66 °C (n-hexane/ethyl acet-
ate). H NMR (400 MHz, CDCl3): δ = 7.75 (t, J = 2.0 Hz, 1 H),
1
7.53–7.48 (m, 1 H), 7.44–7.36 (m, 3 H), 7.34–7.23 (m, 4 H), 1.58
N-Benzyl-2-oxo-2-(p-tolyl)acetamide (2b): The reaction of 1b
(s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.4, 140.8, (63.7 mg, 0.2 mmol), I2 (75.2 mg, 0.3 mmol), TFA (15 μL), and
131.0, 130.0, 129.5, 128.3, 127.6, 127.5, 123.0, 122.1, 84.0, 82.7,
CH3CN/H2O (4:1, 2.5 mL) at room temp. for 3 h afforded 2b
70.8, 28.0 ppm. MS (ESI): m/z (%) = 394 (100) [M + Na]+. IR
(46.4 mg, 93% yield) as a light yellow solid; m.p. 81–82 °C (n-hex-
1
(KBr): ν = 3452, 3110, 2975, 2254, 1738, 1473, 1308, 1285, 1150, ane/ethyl acetate). H NMR (400 MHz, CDCl3): δ = 8.29 (d, J =
˜
1021, 863, 750 cm–1. C19H18ClNO2 (327.81): calcd. C 61.30, H 4.87,
N 3.76; found C 61.25, H 4.62, N 4.02.
8.4 Hz, 2 H), 7.43 (br., 1 H), 7.39–7.25 (m, 7 H), 4.57 (d, J =
6.0 Hz, 2 H), 2.43 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 187.0, 161.8, 145.7, 137.1, 131.4, 130.8, 129.2, 128.8, 127.9, 127.8,
43.4, 21.9 ppm. MS (ESI): m/z (%) = 276 (100) [M + Na]+. IR
tert-Butyl
N-(Phenylethynyl)-N-[3-(trifluoromethyl)phenyl]carb-
amate (1k): Yellow solid (1.27 g, 44% yield); m.p. 61–62 °C (n-hex-
(KBr): ν = 3272, 3102, 2925, 1677, 1644, 1605, 1565, 1428, 1403,
˜
1
ane/ethyl acetate). H NMR (400 MHz, CDCl3): δ = 7.86 (s, 1 H),
1228, 1174, 1032, 938, 766 cm–1. C16H15NO2 (253.30): calcd. C
75.87, H 5.97, N 5.53; found C 75.73, H 5.68, N 5.71.
7.80–7.74 (m, 1 H), 7.53–7.48 (m, 2 H), 7.44–7.39 (m, 2 H), 7.35–
7.28 (m, 3 H), 1.59 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 152.4, 140.2, 131.2 (d, J = 32.3 Hz), 131.0, 129.3, 128.3, 127.7,
N-Benzyl-2-(4-bromophenyl)-2-oxoacetamide (2c): The reaction of
127.4, 123.8 (d, J = 270.2 Hz), 123.0 (q, J = 4.0 Hz), 122.9, 121.3 1c (74.8 mg, 0.2 mmol), I2 (74.9 mg, 0.3 mmol), TFA (15 μL), and
(q, J = 4.0 Hz), 84.2, 82.5, 71.0, 28.0 ppm. MS (ESI): m/z (%) =
CH3CN/H2O (4:1, 2.5 mL) at room temp. for 3 h afforded 2c
384 (100) [M + Na]+. IR (KBr): ν = 3414, 3129, 2984, 2254, 1736, (55.2 mg, 90% yield) as a light yellow solid; m.p. 114–115 °C (n-
˜
1453, 1397, 1325, 1278, 1157, 1124, 1068, 845, 749 cm–1. hexane/ethyl acetate). H NMR (400 MHz, CDCl3): δ = 8.30–8.25
1
C20H18F3NO2 (361.36): calcd. C 66.48, H 5.02, N 3.88; found C
66.17, H 5.36, N 4.11.
(m, 2 H), 7.66–7.61 (m, 2 H), 7.45 (br., 1 H), 7.40–7.28 (m, 5 H),
4.56 (d, J = 6.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
Eur. J. Org. Chem. 2014, 7174–7183
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7179

H. Huang, G. He, X. Zhu, X. Jin, S. Qiu, H. Zhu
FULL PAPER
186.3, 161.0, 136.9, 132.7, 132.0, 131.9, 130.2, 128.9, 127.9, 7.37–7.30 (m, 2 H), 6.94–6.87 (m, 1 H) ppm. 13C NMR (100 MHz,
43.5 ppm. MS (ESI): m/z (%) = 340 (100) [M + Na]+. IR (KBr): ν CDCl3): δ = 186.9, 163.0 (d, J = 243.9 Hz), 158.8, 138.0 (d, J =
˜
= 3263, 2927, 1659, 1582, 1530, 1398, 1311, 1224, 1066, 931,
797 cm–1. C15H12BrNO2 (318.17): calcd. C 56.62, H 3.80, N 4.40;
found C 56.79, H 3.63, N 4.51.
10.7 Hz), 134.8, 132.8, 131.5, 130.3 (d, J = 9.1 Hz), 128.6, 115.3 (d,
J = 3.0 Hz), 112.1 (d, J = 21.8 Hz), 107.4 (d, J = 26.5 Hz) ppm.
19F NMR (376 MHz, CDCl3): δ = –110.76 ppm. MS (ESI): m/z
(%) = 266 (100) [M + Na]+. IR (KBr): ν = 3345, 3107, 1691, 1654,
˜
2-Oxo-N,2-diphenylacetamide (2d): The reaction of 1d (60.4 mg,
0.2 mmol), I2 (76.1 mg, 0.3 mmol), TFA (15 μL), and CH3CN/H2O
(4:1, 2.5 mL) at room temp. for 5 h afforded 2d (34.7 mg, 75%
yield) as a light yellow solid; m.p. 44–46 °C (n-hexane/ethyl acet-
1594, 1540, 1446, 1401, 1296, 1270, 1159, 1132, 867, 775 cm–1.
C14H10FNO2 (243.24): calcd. C 69.13, H 4.14, N 5.76; found C
69.26, H 4.51, N 6.00.
1
ate). H NMR (400 MHz, CDCl3): δ = 8.97 (s, 1 H), 8.45–8.38 (m,
N-(3-Chlorophenyl)-2-oxo-2-phenylacetamide (2i): The reaction of 1i
(65.8 mg, 0.2 mmol), I2 (75.3 mg, 0.3 mmol), TFA (15 μL), and
CH3CN/H2O (4:1, 2.5 mL) at room temp. for 5 h afforded 2i
(34.0 mg, 65% yield) as a light yellow solid; m.p. 120–121 °C (n-
2 H), 7.75–7.62 (m, 2 H), 7.51 (t, J = 8.0 Hz, 2 H), 7.40 (t, J =
7.6 Hz, 2 H), 7.20 (t, J = 7.6 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 187.4, 158.8, 136.6, 134.6, 133.0, 131.4, 129.2, 128.5,
125.3, 119.9 ppm. MS (ESI): m/z (%) = 248 (94) [M + Na]+. IR
1
hexane/ethyl acetate). H NMR (400 MHz, CDCl3): δ = 9.00 (s, 1
(KBr): ν = 3414, 3230, 1688, 1653, 1590, 1520, 1438, 1366, 1258,
˜
H), 8.44–8.38 (m, 2 H), 7.87 (t, J = 2.0 Hz, 1 H), 7.70–7.64 (m, 1
H), 7.56–7.49 (m, 3 H), 7.32 (t, J = 8.0 Hz, 1 H), 7.20–7.15 (m, 1
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 186.9, 158.8, 137.7,
134.9, 134.8, 132.8, 131.5, 130.2, 128.6, 125.3, 120.0, 117.9 ppm.
1172, 1032, 922, 752 cm–1. C14H11NO2 (225.25): calcd. C 74.65, H
4.92, N 6.22; found C 74.73, H 4.96, N 5.98.
2-Oxo-2-phenyl-N-(o-tolyl)acetamide (2e): The reaction of 1e
(63.0 mg, 0.2 mmol), I2 (75.5 mg, 0.3 mmol), TFA (15 μL), and
CH3CN/H2O (4:1, 2.5 mL) at room temp. for 5 h afforded 2e
(40.6 mg, 83% yield) as a light yellow solid; m.p. 90–92 °C (n-hex-
MS (ESI): m/z (%) = 282 (100) [M + Na]+. IR (KBr): ν = 3417,
˜
3347, 3149, 1689, 1661, 1592, 1539, 1403, 1278, 1174, 737 cm–1.
C14H10ClNO2 (259.69): calcd. C 64.75, H 3.88, N 5.39; found C
64.89, H 4.01, N 5.16.
1
ane/ethyl acetate). H NMR (400 MHz, CDCl3): δ = 8.91 (s, 1 H),
8.44–8.39 (m, 2 H), 7.69–7.62 (m, 1 H), 7.57 (s, 1 H), 7.55–7.46 (m,
3 H), 7.28 (t, J = 8.0 Hz, 5 H), 7.02 (d, J = 7.6 Hz, 2 H), 2.39 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 187.4, 158.8, 139.2,
136.5, 134.6, 133.1, 131.5, 129.0, 128.5, 126.1, 120.5, 117.0,
N-(3-Bromophenyl)-2-oxo-2-phenylacetamide (2j): The reaction of 1j
(77.2 mg, 0.2 mmol), I2 (76.1 mg, 0.3 mmol), TFA (15 μL), and
CH3CN/H2O (4:1, 2.5 mL) at room temp. for 8 h afforded 2j
(37.1 mg, 59% yield) as a light yellow solid; m.p. 113–115 °C (n-
21.5 ppm. MS (ESI): m/z (%) = 262 (65) [M + Na]+. IR (KBr): ν
˜
1
hexane/ethyl acetate). H NMR (400 MHz, CDCl3): δ = 9.00 (s, 1
= 3415, 3234, 1697, 1667, 1587, 1535, 1454, 1400, 1278, 1172, 1041,
890, 745 cm–1. C15H13NO2 (239.27): calcd. C 75.30, H 5.48, N 5.85;
found C 75.49, H 5.53, N 6.09.
H), 8.44–8.39 (m, 2 H), 8.01 (t, J = 2.0 Hz, 1 H), 7.71–7.66 (m, 1
H), 7.66–7.55 (m, 1 H), 7.52 (t, J = 7.6 Hz, 2 H), 7.36–7.31 (m, 1
H), 7.29–7.23 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
186.8, 158.7, 137.8, 134.8, 132.8, 131.5, 130.5, 128.6, 128.3, 122.9,
122.8, 118.3 ppm. MS (ESI): m/z (%) = 326 (46) [M + Na]+. IR
2-Oxo-2-phenyl-N-(m-tolyl)acetamide (2f): The reaction of 1f
(61.0 mg, 0.2 mmol), I2 (75.1 mg, 0.3 mmol), TFA (15 μL), and
CH3CN/H2O (4:1, 2.5 mL) at room temp. for 5 h afforded 2f
(42.3 mg, 89% yield) as a light yellow solid; m.p. 93–94 °C (n-hex-
(KBr): ν = 3414, 3340, 3058, 2933, 1692, 1677, 1594, 1432, 1380,
˜
1323, 1214, 1143, 1083, 960, 784 cm–1. C14H10BrNO2 (304.14):
calcd. C 55.29, H 3.31, N 4.61; found C 55.43, H 3.21, N 4.83.
1
ane/ethyl acetate). H NMR (400 MHz, CDCl3): δ = 8.93 (s, 1 H),
8.47–8.41 (m, 2 H), 8.12 (d, J = 8.0 Hz, 1 H), 7.67 (t, J = 7.6 Hz,
1 H), 7.52 (t, J = 7.6 Hz, 2 H), 7.32–7.22 (m, 2 H), 7.18–7.11 (m,
1 H), 2.38 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 187.5,
158.8, 134.6, 134.5, 133.1, 131.5, 130.7, 128.6, 128.5, 126.9, 125.6,
121.6, 17.6 ppm. MS (ESI): m/z (%) = 262 (100) [M + Na]+. IR
2-Oxo-2-phenyl-N-[3-(trifluoromethyl)phenyl]acetamide (2k): The
reaction of 1k (72.5 mg, 0.2 mmol), I2 (74.6 mg, 0.3 mmol), TFA
(15 μL), and CH3CN/H2O (4:1, 2.5 mL) at room temp. for 12 h
afforded 2k (33.5 mg, 57% yield) as a light yellow solid; m.p. 89–
90 °C (n-hexane/ethyl acetate). 1H NMR (400 MHz, CDCl3): δ =
9.13 (s, 1 H), 8.45–8.40 (m, 2 H), 8.08 (s, 1 H), 7.86 (d, J = 8.0 Hz,
1 H), 7.71–7.65 (m, 1 H), 7.53 (t, J = 8.0 Hz, 3 H), 7.46 (d, J =
7.6 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 186.7, 158.9,
137.1, 134.9, 132.8, 131.8, 131.5, 129.8, 128.6, 122.9, 121.8 (q, J =
3.7 Hz), 116.7 (q, J = 3.6 Hz) ppm. 19F NMR (376 MHz, CDCl3):
δ = –62.78 ppm. MS (ESI): m/z (%) = 316 (100) [M + Na]+. IR
(KBr): ν = 3417, 3342, 2980, 1688, 1660, 1593, 1532, 1487, 1279,
˜
1187, 868, 745 cm–1. C15H13NO2 (239.27): calcd. C 75.30, H 5.48,
N 5.85; found C 75.16, H 5.61, N 6.11.
2-Oxo-2-phenyl-N-(p-tolyl)acetamide (2g): The reaction of 1g
(65.2 mg, 0.2 mmol), I2 (76.4 mg, 0.3 mmol), TFA (15 μL), and
CH3CN/H2O (4:1, 2.5 mL) at room temp. for 5 h afforded 2g
(40.6 mg, 80% yield) as a light yellow solid; m.p. 114–116 °C (n-
(KBr): ν = 3413, 3344, 3061, 1694, 1664, 1597, 1538, 1446, 1334,
˜
1
hexane/ethyl acetate). H NMR (400 MHz, CDCl3): δ = 8.90 (s, 1
1273, 1165, 1117, 1071, 997, 889, 743 cm–1. C15H10F3NO2 (293.24):
calcd. C 61.44, H 3.44, N 4.78; found C 61.36, H 3.71, N 4.67.
H), 8.44–8.39 (m, 2 H), 7.69–7.62 (m, 1 H), 7.59 (d, J = 8.4 Hz, 2
H), 7.51 (t, J = 8.0 Hz, 2 H), 7.20 (d, J = 8.0 Hz, 2 H), 2.35 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 187.5, 158.7, 135.0,
134.6, 134.0, 133.1, 131.4, 129.7, 128.5, 119.9, 21.0 ppm. MS (ESI):
N-(Naphthalen-2-yl)-2-oxo-2-phenylacetamide (2l): The reaction of
1l (68.6 mg, 0.2 mmol), I2 (75.8 mg, 0.3 mmol), TFA (15 μL), and
CH3CN/H2O (4:1, 2.5 mL) at room temp. for 4 h afforded 2l
(29.8 mg, 54% yield) as a light yellow solid; m.p. 143–144 °C (n-
m/z (%) = 262 (100) [M + Na]+. IR (KBr): ν = 3416, 3340, 3059,
˜
3025, 2911, 1694, 1670, 1591, 1536, 1404, 1281, 1167, 987, 819,
741 cm–1. C15H13NO2 (239.27): calcd. C 75.30, H 5.48, N 5.85;
found C 75.59, H 5.52, N 5.99.
1
hexane/ethyl acetate). H NMR (400 MHz, CDCl3): δ = 9.14 (s, 1
2
H), 8.46–8.43 (m, 3 H), 7.86 (dd, 1J = 4.0 Hz, J = 8.8 Hz, 2 H),
N-(3-Fluorophenyl)-2-oxo-2-phenylacetamide (2h): The reaction of 7.28 (d, J = 8.0 Hz, 1 H), 7.70–7.64 (m, 1 H), 7.60 (dd, 1J = 2.0 Hz,
1h (62.3 mg, 0.2 mmol), I2 (75.6 mg, 0.3 mmol), TFA (15 μL), and 2J = 8.8 Hz, 2 H), 7.56–7.42 (m, 4 H) ppm. 13C NMR (100 MHz,
CH3CN/H2O (4:1, 2.5 mL) at room temp. for 5 h afforded 2h
(38.2 mg, 79% yield) as a light yellow solid; m.p. 97–98 °C (n-hex-
ane/ethyl acetate). H NMR (400 MHz, CDCl3): δ = 9.03 (s, 1 H),
CDCl3): δ = 187.3, 158.9, 134.7, 134.0, 133.7, 133.0, 131.5, 131.0,
129.1, 128.6, 127.9, 127.6, 126.8, 125.5, 119.5, 117.1 ppm. MS
(ESI): m/z (%) = 298 (39) [M + Na]+. IR (KBr): ν = 3416, 3338,
1
˜
8.44–8.39 (m, 2 H), 7.72–7.64 (m, 2 H), 7.52 (t, J = 8.0 Hz, 2 H),
3135, 3050, 1668, 1663, 1597, 1541, 1505, 1399, 1276, 1226, 852,
7180
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 7174–7183

Iodine-Mediated Oxidation of Ynamides
741 cm–1. C18H13NO2 (275.31): calcd. C 78.53, H 4.76, N 5.09; 1022, 924, 745 cm–1. C17H13NO4 (295.29): calcd. C 69.15, H 4.44,
found C 78.71, H 4.76, N 5.17.
N 4.74; found C 69.51, H 4.13, N 5.15.
2-Oxo-N-phenylhexanamide (2m): The reaction of 1m (56.2 mg,
(S)-1-(4-Benzyl-2-oxooxazolidin-3-yl)-2-phenylethane-1,2-dione (2q):
0.2 mmol), I2 (74.8 mg, 0.3 mmol), TFA (15 μL), and CH3CN/H2O The reaction of 1q (84.5 mg, 0.3 mmol), I2 (113.6 mg, 0.45 mmol),
(4:1, 2.5 mL) at room temp. for 3 h afforded 2m (38.3 mg, 91% and H2O (0.75 mL) in CH3CN (3 mL) at room temp. for 5 h af-
yield) as a light yellow solid; m.p. 84–85 °C (n-hexane/ethyl acet-
ate). H NMR (400 MHz, CDCl3): δ = 8.76 (s, 1 H), 7.65 (d, J =
forded 2q (70.7 mg, 75% yield) as a white solid; m.p. 121–123 °C
(n-hexane/ethyl acetate). [α]2D0 = +75.3 (c = 1.01, CHCl3). 1H NMR
1
7.6 Hz, 2 H), 7.38 (t, J = 7.6 Hz, 2 H), 7.18 (t, J = 7.6 Hz, 1 H), (400 MHz, CDCl3): δ = 7.91–7.86 (m, 2 H), 7.69–7.63 (m, 1 H),
3.02 (t, J = 7.2 Hz, 2 H), 1.70–1.60 (m, 2 H), 1.45–1.34 (m, 2 H), 7.53 (t, J = 8.0 Hz, 2 H), 7.42–7.35 (m, 2 H), 7.35–7.21 (m, 3 H),
0.95 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 4.86–4.78 (m, 1 H), 4.42 (t, J = 9.2 Hz, 1 H), 4.34 (dd, 1J = 3.6 Hz,
1
2
199.5, 157.5, 136.3, 129.2, 125.2, 119.7, 36.1, 25.4, 22.2, 13.8 ppm.
2J = 9.6 Hz, 1 H), 3.55 (dd, J = 3.6 Hz, J = 13.6 Hz, 1 H), 2.99
(dd, 1J = 9.6 Hz, 2J = 4.0 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 187.5, 166.6, 153.0, 134.7, 134.3, 132.4, 129.5, 129.3,
129.2, 129.0, 127.7, 68.1, 54.1, 37.6 ppm. MS (ESI): m/z (%) = 332
MS (ESI): m/z (%) = 228 (25) [M + Na]+. IR (KBr): ν = 3415,
˜
3329, 3111, 3062, 2945, 2863, 1719, 1684, 1599, 1543, 1492, 1443,
1388, 1048, 911, 759 cm–1. C12H15NO2 (205.26): calcd. C 70.22, H
7.37, N 6.82; found C 70.52, H 7.62, N 7.08.
(100) [M + Na]+. IR (KBr): ν = 3441, 3131, 2923, 1790, 1691, 1597,
˜
1451, 1398, 1368, 1237, 1122, 1005, 740 cm–1. C18H15NO4 (309.32):
calcd. C 69.89, H 4.89, N 4.53; found C 69.63, H 5.12, N 4.71.
Oxidation of Ynamides without Boc Group – Typical Procedure III
1-(2-Oxooxazolidin-3-yl)-2-phenylethane-1,2-dione (2n): The reac-
tion of 1n (57.0 mg, 0.3 mmol), I2 (111.3 mg, 0.45 mmol), and H2O
(0.75 mL) in CH3CN (3 mL) was carried out at room temp. for 5 h,
as the progress of the reaction was monitored by TLC analysis.
Upon completion, the mixture was diluted with 5% Na2CO3 solu-
tion (10 mL). The resulting mixture was extracted with diethyl
ether (3ϫ 10 mL), and the combined extracts were dried with anhy-
drous Na2SO4. The solvent was removed by evaporation under re-
duced pressure. The crude product was purified by flash
chromatography on a silica gel column (petroleum ether/ethyl acet-
ate) to afford 2n (41.7 mg, 63% yield) as a white solid; m.p. 149–
Ethyl [1-(2-Oxo-2-phenylacetyl)-1H-indol-2-yl]carboxylate (2r): The
reaction of 1r (85.1 mg, 0.3 mmol), I2 (119.8 mg, 0.45 mmol), and
H2O (0.75 mL) in CH3CN (3 mL) at room temp. for 5 h afforded
2r (60.5 mg, 64% yield) as a white solid; m.p. 103–104 °C (n-hex-
1
ane/ethyl acetate). H NMR (400 MHz, CDCl3): δ = 8.38 (d, J =
8.4 Hz, 1 H), 8.19–8.14 (m, 2 H), 7.71–7.64 (m, 2 H), 7.60–7.50 (m,
3 H), 7.44 (s, 1 H), 7.38 (t, J = 7.2 Hz, 1 H), 4.13 (q, J = 7.2 Hz,
2 H), 1.21 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 185.1, 165.2, 161.6, 138.6, 134.1, 133.2, 130.5, 129.6, 128.6,
128.5, 127.9, 124.9, 122.7, 118.4, 116.0, 61.8, 14.0 ppm. MS (ESI):
m/z (%) = 344 (100) [M + Na]+. IR (KBr): ν = 3343, 3116, 2983,
˜
1
150 °C (n-hexane/ethyl acetate). H NMR (400 MHz, CDCl3): δ =
2932, 1692, 1680, 1548, 1444, 1397, 1340, 1267, 1205, 1143, 1044,
938, 753 cm–1. C19H15NO4 (321.33): calcd. C 71.02, H 4.71, N 4.36;
found C 71.56, H 4.49, N 4.70.
7.89 (d, J = 7.2 Hz, 2 H), 7.66 (t, J = 7.6 Hz, 1 H), 7.52 (t, J =
7.6 Hz, 2 H), 4.62 (t, J = 8.0 Hz, 2 H), 4.18 (t, J = 8.0 Hz, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 187.8, 166.4, 153.0,
134.8, 132.3, 129.3, 129.0, 64.0, 40.9 ppm. MS (ESI): m/z (%) =
1-(3-Acetyl-1H-indol-1-yl)-2-phenylethane-1,2-dione (2s): The reac-
242 (55) [M + Na]+. IR (KBr): ν = 3415, 3069, 2924, 2853, 1787, tion of 1s (78.1 mg, 0.3 mmol), I2 (112.5 mg, 0.45 mmol), and H2O
˜
1690, 1468, 1396, 1239, 1201, 1125, 1025, 966, 716 cm–1. C11H9NO4
(219.20): calcd. C 60.27, H 4.14, N 6.39; found C 60.31, H 4.19, N
6.15.
(0.75 mL) in CH3CN (3 mL) at room temp. for 5 h afforded 2s
(48.3 mg, 55% yield) as a white solid; m.p. 167–168 °C (n-hexane/
ethyl acetate). 1H NMR (400 MHz, CDCl3): δ = 8.50–8.36 (m, 2
H), 8.13–8.08 (m, 2 H), 7.93 (s, 1 H), 7.75 (t, J = 7.6 Hz, 1 H), 7.59
(t, J = 8.0 Hz, 2 H), 7.52–7.44 (m, 2 H), 2.51 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 193.6, 187.5, 164.0, 135.9, 135.7,
132.2, 131.1, 130.4, 129.3, 127.6, 126.7, 126.3, 123.6, 123.0, 116.2,
(S)-1-(2-Oxo-4-phenyloxazolidin-3-yl)hexane-1,2-dione (2o): The re-
action of 1o (71.2 mg, 0.3 mmol), I2 (114.2 mg, 0.45 mmol), and
H2O (0.75 mL) in CH3CN (3 mL) at room temp. for 5 h afforded
2o (43.5 mg, 54% yield) as a white solid; m.p. 63–64 °C (n-hexane/
ethyl acetate). [α]2D0 = +71.5 (c = 0.78, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 7.46–7.32 (m, 5 H), 5.39 (dd, 1J = 4.4 Hz, 2J = 8.8 Hz,
27.9 ppm. MS (ESI): m/z (%) = 314 (100) [M + Na]+. IR (KBr): ν
˜
= 3168, 2958, 2901, 1701, 1680, 1621, 1533, 1498, 1402, 1333, 1287,
1234, 1121, 1022, 878, 746 cm–1. C22H19NO4S (393.46): calcd. C
74.22, H 4.50, N 4.81; found C 74.21, H 4.72, N 4.61.
1
2
1 H), 4.86 (t, J = 8.8 Hz, 2 H), 4.41 (dd, J = 4.4 Hz, J = 8.8 Hz,
1 H), 2.79–2.62 (m, 2 H), 1.71–1.60 (m, 2 H), 1.43–1.31 (m, 2 H),
0.91 (t, J = 7.6 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = N-Benzyl-2-oxo-2-phenyl-N-tosylacetamide (2t): The reaction of 1t
197.2, 166.8, 153.7, 137.1, 129.4, 129.3, 125.9, 72.0, 56.5, 38.9, 24.3,
(107.3 mg, 0.3 mmol), I2 (114.2 mg, 0.45 mmol), and H2O
(0.75 mL) in CH3CN (3 mL) at room temp. for 5 h afforded 2t
22.0, 13.7 ppm. MS (ESI): m/z (%) = 298 (100) [M + Na]+. IR
(KBr): ν = 3425, 3112, 3024, 2948, 2903, 1788, 1676, 1501, 1438, (39.7 mg, 34% yield) as a white solid; m.p. 90–92 °C (n-hexane/
˜
1332, 1302, 1123, 1001, 836, 740 cm–1. C15H17NO4 (275.30): calcd.
C 65.44, H 6.22, N 5.09; found C 65.30, H 6.51, N 5.18.
ethyl acetate). 1H NMR (400 MHz, CDCl3): δ = 7.91–7.86 (m, 2
H), 7.75 (d, J = 8.4 Hz, 2 H), 7.66–7.60 (m, 1 H), 7.50 (t, J =
7.6 Hz, 2 H), 7.31–7.20 (m, 7 H), 4.98 (s, 2 H), 2.41 (s, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 187.7, 167.5, 145.6, 134.6, 134.4,
134.3, 132.8, 129.8, 129.6, 128.8, 128.5, 128.0, 127.8, 48.2,
(S)-1-(2-Oxo-4-phenyloxazolidin-3-yl)-2-phenylethane-1,2-dione
(2p): The reaction of 1p (77.3 mg, 0.3 mmol), I2 (111.2 mg,
0.45 mmol), and H2O (0.75 mL) in CH3CN (3 mL) at room temp.
for 5 h afforded 2p (64.3 mg, 74% yield) as a white solid; m.p. 127–
128 °C (n-hexane/ethyl acetate). [α]2D0 = +37.4 (c = 1.01, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.78 (d, J = 7.2 Hz, 2 H), 7.62
21.7 ppm. MS (ESI): m/z (%) = 416 (100) [M + Na]+. IR (KBr): ν
˜
= 3423, 3102, 3028, 1690, 1670, 1593, 1371, 1213, 1163, 1088, 1059,
931, 714 cm–1. C22H19NO4S (393.46): calcd. C 67.16, H 4.87, N
3.56; found C 67.01, H 4.59, N 3.37.
1
2
(t, J = 7.6 Hz, 1 H), 7.51–7.40 (m, 7 H), 5.53 (dd, J = 4.0 Hz, J
1
2
= 8.8 Hz, 1 H), 4.88 (t, J = 9.2 Hz, 1 H), 4.44 (dd, J = 4.0 Hz, J Large-Scale Reaction of Ynamide with Boc Group: The reaction of
= 8.8 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 187.3,
1a (1.25 g, 4 mmol), I2 (1.53 mg, 6.0 mmol), TFA (0.3 mL), and
165.9, 153.2, 137.4, 134.7, 132.3, 129.5, 129.3, 129.0, 126.0, 71.9,
CH3CN/H2O (4:1, 40 mL) was carried out at room temp. for 12 h,
56.6 ppm. MS (ESI): m/z (%) = 318 (100) [M + Na]+. IR (KBr): ν and the progress of the reaction was monitored by TLC analysis.
˜
= 3441, 3012, 2948, 1756, 1692, 1544, 1438, 1369, 1334, 1223, 1115,
Upon completion, the reaction mixture was then diluted by the
Eur. J. Org. Chem. 2014, 7174–7183
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7181

H. Huang, G. He, X. Zhu, X. Jin, S. Qiu, H. Zhu
FULL PAPER
addition of 5% Na2CO3 solution (15 mL), and the resulting mix-
ture was extracted with Et2O (3ϫ 20 mL). The combined organic
extracts were washed with brine (5 mL) and dried with anhydrous
Na2SO4. Filtration and concentration gave the crude product,
which was purified by chromatography on silica gel (PE/EtOAc,
10:1) to afford 2a (0.79 g, 83% yield) as a white solid.
18O-Labeling Experiments with 1a: An oven-dried Schlenk tube
with a magnetic stirrer bar was purged with oxygen, and 1a
(61.3 mg, 0.2 mmol), NIS (67.6 mg, 0.3 mmol), H218O (0.5 mL),
and dry CH3CN (2.0 mL) were added. The resulting solution was
stirred at room temp. for 3 h, and then the mixture was analyzed
by HRMS. The product was purified by chromatography on a silica
gel column and then analyzed by HRMS.
Large-Scale Reaction of Ynamide without Boc Group: The reaction
of 1p (1.05 g, 4 mmol), I2 (1.45 g, 6.0 mmol), and CH3CN/H2O
(4:1, 40 mL) was carried out at room temp. for 18 h, as the progress
of the reaction was monitored by TLC analysis. Upon completion,
the reaction mixture was then diluted by the addition of 5%
Na2CO3 solution (15 mL), and the resulting mixture was extracted
with Et2O (3ϫ 20 mL). The combined organic extracts were
washed with brine (5 mL) and dried with anhydrous Na2SO4. Fil-
tration and concentration gave the crude product, which was puri-
fied by chromatography on silica gel (PE/EtOAc, 2:1) to afforded
2p (0.83 g, 71% yield) as a white solid and (S,E)-3-(1,2-diiodo-2-
phenylethenyl)-4-phenyloxazolidin-2-one (2pЈ, 0.08 g, 4% yield) as
N,2-Diphenylacetamide (3d): The reaction of 1d (296.3 mg,
1 mmol), TFA (74 μL), and CH3CN/H2O (4:1, 10 mL) was carried
out at room temp. for 12 h, as the progress of the reaction was
monitored by TLC analysis. Upon completion, the reaction was
diluted by the addition of 5% Na2CO3 solution (15 mL), and the
resulting mixture was extracted with Et2O (3ϫ 20 mL). The com-
bined organic extracts were washed with brine (5 mL) and dried
with anhydrous Na2SO4. Filtration and concentration gave the
crude product, which was purified by chromatography on a silica
gel column (PE/EtOAc, 5:1) to afford 3d[22] (162.2 mg, 76% yield)
as a white solid; m.p. 116–117 °C (n-hexane/ethyl acetate). 1H
NMR (400 MHz, CDCl3): δ = 7.40 (t, J = 8.0 Hz, 4 H), 7.36–7.30
(m, 3 H), 7.27 (t, J = 7.6 Hz, 2 H), 7.16 (s, 1 H), 7.08 (t, J = 7.6 Hz,
2 H), 3.72 (s, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 169.0,
137.6, 134.4, 129.5, 129.2, 128.9, 127.7, 124.4, 119.8, 44.8 ppm.
HRMS (ESI+): calcd. for C14H13NO [M + Na]+ 234.0889; found
234.0884.
a white solid; m.p. 118–119 °C (n-hexane/ethyl acetate). [α]2D0
=
1
+10.5 (c = 1.02, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.67–
7.61 (m, 2 H), 7.49–7.43 (m, 3 H), 7.32–7.25 (m, 4 H), 7.11–7.06
(m, 2 H), 5.05 (dd, 1J = 8.8 Hz, 2J = 10.4 Hz, 1 H), 4.74 (t, J =
9.2 Hz, 1 H), 4.46 (dd, J = 8.8 Hz, J = 10.4 Hz, 1 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 152.5, 144.7, 133.8, 129.7, 129.1,
128.9, 128.8, 128.6, 128.4, 101.0, 93.5, 69.6, 63.8 ppm. MS (ESI):
1
2
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra of all compounds and X-
ray crystal structures of 2pЈ and 2s.
m/z (%) = 540 (100) [M + Na]+. IR (KBr): ν = 3418, 3139, 3054,
˜
1777, 1617, 1387, 1331, 1277, 1205, 1096, 1023, 868, 757 cm–1.
C17H13I2NO4 (549.10): calcd. C 39.49, H 2.53, N 2.71; found C
39.53, H 2.76, N 2.56.
Acknowledgments
Reaction Mechanism Studies
The authors greatly acknowledge the financial support, in part,
from the Natural Science Foundation of Jiangsu Provincial Univer-
sities (grant number 12KJB150011), the Jiangsu Provincial Tech-
nology Support Program (grant number BE2012363), and the Post-
graduate Innovation Fund of Jiangsu Province (2013, CXZZ13_
0459).
Entry 1: Starting material 1a was dried in vacuo over P2O5 for 1 d.
CH3CN was freshly distilled from CaH2 under N2. After distil-
lation, the anhydrous CH3CN was stored in a bottle over molecular
sieves (4 Å). An oven-dried Schlenk tube with a magnetic stirrer
bar was purged with oxygen, and 1a (61.2 mg, 0.2 mmol), NIS
(67.4 mg, 0.3 mmol), TFA (15 μL), and dry CH3CN (2.0 mL) were
added. The resulting solution was stirred at room temp. for 3 h,
and then the mixture was diluted to 50 mL by the addition of
CH3CN. The yield was determined by HPLC analysis using the
external standard method.
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standard method.
Entry 3: An oven-dried Schlenk tube with a magnetic stirrer bar
was purged with nitrogen, and 1a (61.6 mg, 0.2 mmol), NIS
(66.8 mg, 0.3 mmol), H2O (7.2 μL), TFA (15 μL), and dry CH3CN
(2.0 mL) were added. The resulting solution was stirred at room
temp. for 3 h, and then the mixture was diluted to 50 mL by the
addition of CH3CN. The yield was determined by HPLC analysis
using the external standard method.
Entry 4: An oven-dried Schlenk tube with a magnetic stirrer bar
was purged with nitrogen, and 1a (61.3 mg, 0.2 mmol), NIS
(67.6 mg, 0.3 mmol), H2O (0.5 mL), TFA (15 μL), and dry CH3CN
(2.0 mL) were added. The resulting solution was stirred at room
temp. for 3 h, and then the mixture was diluted to 50 mL by the
addition of CH3CN. The yield was determined by HPLC analysis
using the external standard method.
7182
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 7174–7183

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Received: May 5, 2014
Published Online: September 24, 2014
Eur. J. Org. Chem. 2014, 7174–7183
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