From propargylamides to oxazole derivatives: NIS-mediated cyclization and further oxidation by dioxygen

Article abstract of DOI:10.1021/jo5001719

NIS-mediated iodocyclization of N-sulfonyl propargylamides for the synthesis of various oxazolidines and iodoalkylidenedihydrooxazoles via a 5-exo-dig process is developed. The resulting iodoalkylidenedihydrooxazoles can be further transformed into the corresponding oxazoles in the presence of dioxygen.

Full text of DOI:10.1021/jo5001719

Article
pubs.acs.org/joc
From Propargylamides to Oxazole Derivatives: NIS-Mediated
Cyclization and Further Oxidation by Dioxygen
Yancheng Hu, Ruxia Yi, Chunxiang Wang, Xiaoyi Xin, Fan Wu, and Boshun Wan*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, People’s Republic of China
S
* Supporting Information
ABSTRACT: NIS-mediated iodocyclization of N-sulfonyl
propargylamides for the synthesis of various oxazolidines and
iodoalkylidenedihydrooxazoles via a 5-exo-dig process is
developed. The resulting iodoalkylidenedihydrooxazoles can
be further transformed into the corresponding oxazoles in the
presence of dioxygen.
Scheme 1. Our Studies on the Cyclization of
Propargylamides
INTRODUCTION
■
Propargylamides have been well studied as versatile and
effective building blocks for the synthesis of oxazoles in the
past decade,1−5 which occur in a wide range of bioactive natural
products, synthetic intermediates, and pharmaceuticals.6 As a
consequence, the cyclization of propargylamides has gained
considerable attention and significant progress has been made
in this area. In 2001, Cacchi and co-workers reported the first
Pd-catalyzed coupling−cyclization sequence for the synthesis of
oxazoles.2a Along with remarkable improvements in gold
catalysis, Hashmi and co-workers have made great contribu-
tions to the gold-catalyzed cyclization of propargylamides.3 On
the basis of these findings, the transformation of propargyla-
mides has been successfully realized with other transition-metal
catalysts4 or under basic conditions5 to date. Therefore, the
exploration of more efficient and environmentally benign
alternatives for the synthesis of oxazole derivatives is still highly
desirable. As is known, electrophilic iodocyclization of alkynes
has emerged as a very effective approach for the construction of
a variety of carbocyclic and heterocyclic ring systems.7 The
resulting halides can undergo other useful transformations,
transition-metal-catalyzed cross couplings in particular, which
makes them extremely versatile building blocks in organic
synthesis. Very recently, we have reported the silver- and base-
catalyzed cyclization of N-sulfonyl propargylamides into
oxazoles via sulfonyl migration.8 As a continuation of our
interest in the cyclization of N-sulfonyl propargylamides, we
envisioned that iodonium-triggered electrophilic cyclization of
propargylamides would give some significant finding. Herein,
we report the halogen-mediated regioselective cyclization of N-
sulfonyl propargylamides to provide various halogen-containing
oxazole derivatives through an intramolecular 5-exo-dig process,
which can be further transformed into the corresponding
oxazoles in the presence of dioxygen (Scheme 1).
RESULTS AND DISCUSSION
■
Our initial studies were carried out with N-tosyl propargyla-
mide 1a as the substrate and N-iodosuccinimide (NIS) as the
iodine source. Surprisingly, when substrate 1a was submitted to
the iodocyclization conditions in the presence of NIS in
dichloromethane (DCM) at room temperature, polyfunction-
alized oxazolidine 2a with an exocyclic double bond and a
quaternary carbon atom was obtained as the only product (62%
yield). The formation of 2a was unambiguously confirmed by
X-ray crystallography.9 After a brief optimization process,
including the solvents, additives, and temperatures, we observed
that the desired product 2a was afforded in an acceptable yield
with 1.2 equiv of NIS in dichloromethane at 40 °C (see the
Supporting Information). It is noteworthy that iodoalkylidene-
dihydrooxazole 3a, instead of oxazolidine 2a, was found to be
the only product (83% yield) when the solvent was changed to
N,N′-dimethylformamide (DMF). Therefore, this reaction
provided an appealing alternative for the synthesis of diversified
dihydrooxazoles 3.
With these results in hand, we further explored the substrate
scope of both iodocyclization reactions and the results are
shown in Table 1. For the R2 groups, phenyl rings with both
electron-withdrawing and electron-donating substituents were
well tolerated, providing the desired oxazole derivatives 2 and 3
Received: January 24, 2014
Published: March 12, 2014
© 2014 American Chemical Society
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yields (Table 1, entries 8−10). Notably, these two cyclization
reactions with naphthyl-derived substrate 1k proceeded well,
whereas furyl substrate 1l gave no desired products 2l and 3l.
However, when we tried to prepare 2-pyridyl substrate, we
failed to obtain the desired substrate.
Table 1. NIS-Mediated Cyclization of N-Tosyl
Propargylamides in DCM and DMF
a
Likewise, the scope of sulfonyl group in the substrate and
effects of other halogen sources were also examined. As
summarized in Scheme 2, N-phenylsulfonyl substrates were also
suitable for these two iodocyclization reactions, giving the
corresponding products 2 and 3 in 73−93% yield. When we
tried to prepare a more electron withdrawing sulfonyl substrate
such as the 2-nitrobenzenesulfonyl group, unfortunately, we
failed to obtain the desired substrate according to our reported
method. Moreover, N-bromosuccinimide (NBS) could also
trigger the cyclization of substrate 1a, albeit with lower yields
(2o, 16%; 3o, 60%). However, no products (2p and 3p) were
detected with N-chlorosuccinimide (NCS) as the halogen
source. These results could be explained by taking account into
the lower activity of NBS and NCS, increasing the activation
energy needed to start the cyclization process. To our delight,
treatment of 1a with 1,3-diiodo-5,5-dimethylhydantoin afforded
the desired oxazolidine 2q in 62% yield.
A plausible mechanism for the above two iodocyclization
reactions is depicted in Scheme 3. The reaction is initiated by
the coordination of 1 with I+, thereby enhancing the
electrophilicity of the alkyne moiety to generate intermediate
A. The activated triple bond then undergoes nucleophilic attack
by the carbonyl oxygen to form intermediate B via a 5-exo-dig
cyclization mode. Two different pathways are followed in the
next reaction step on the basis of the choice of solvents. In
DCM, the succinimide anion attacks the more electrophilic
carbon of the iminium ion to furnish the final product 2. In
contrast, the succinimide anion traps the tosyl group of
intermediate B to give the desired product 3 when the reaction
is carried out in the more polar solvent DMF.
yield, %
entry
1
R1, R2
2
3
1
1a
1b
1c
1d
1e
1f
C6H5, C6H5
77 (2a)
86 (2b)
82 (2c)
80 (2d)
80 (2e)
38 (2f)
0 (2g)
83 (3a)
67 (3b)
65 (3c)
59 (3d)
56 (3e)
0 (3f)
2
C6H5, m-F-C6H4
C6H5, p-Me-C6H4
C6H5, p-OMe-C6H4
C6H5, p-Cl-C6H4
C6H5, OEt
3
4
5
6
7
1g
1h
1i
C6H5, cyclopentyl
o-F-C6H4, C6H5
m-F-C6H4, C6H5
p-Br-C6H4, C6H5
2-naphthyl, C6H5
2-furyl, C6H5
0 (3g)
8
84 (2h)
94 (2i)
85 (2j)
88 (2k)
0 (2l)
83 (3h)
80 (3i)
38 (3j)
82 (3k)
0 (3l)
9
10
11
12
1j
1k
1l
a
The reactions were carried out with 1 (0.20 mmol) and NIS (1.2
eqiuv) in solvent (3.0 mL) for 2−12 h, unless otherwise stated.
in moderate to good yields (Table 1, entries 1−5).
Unfortunately, the ethoxyl-substituted substrate 1f afforded
the iodocyclization product 2f only in 38% yield, and the
desired dihydrooxazole 3f was not observed under the standard
conditions. When another aliphatic moiety such as cyclopentyl
was employed as R2, both reactions failed to undergo the
cyclization, probably due to the electronic nature of aliphatic
substituents (Table 1, entry 7). Meanwhile, other functional
groups such as −F and −Br in aromatic R1 substituents were
also compatible in these two iodocyclization reactions and
afforded the corresponding products 2 and 3 in satisfactory
To illustrate the synthetic potential of halogen-containing
heterocycles produced in these two cyclization reactions,
additional studies were conducted on their further trans-
a
Scheme 2. Scope of Sulfonyl Group and Effects of the Halogen Source
a
b
The reactions were carried out with 1 (0.20 mmol) and halogen source (1.2 eqiuv) in solvent (3.0 mL) for 2−12 h, unless otherwise stated. 80 °C
in DCE for 18 h.
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Scheme 3. Proposed Mechanism for the Cyclization of N-
Sulfonyl Propargylamide
Scheme 5. One-Pot and Gram-Scale Synthesis of Oxazoles
4a and 7a
combination of iodine radicals and hydroxyl radicals results in
the formation of HIO, which can easily decompose into oxygen,
iodine, and water.
formations. Gratifyingly, we found that iodoalkylidene-
dihydrooxazole 3a could be efficiently converted into function-
alized oxazole 4a just in the presence of dioxygen (1 atm). To
the best of our knowledge, there has been no report on the
oxidation of iodoalkylidenedihydrooxazoles before. Thus, the
substrate scope was investigated (Scheme 4). The results
revealed that various dihydrooxazoles 3 underwent the
oxidation reaction smoothly, giving the corresponding oxazoles
in acceptable yields (70−80%). Furthermore, iodoalkylidene-
dihydrooxazoles 6, which were generated from NIS-induced
cyclization of structurally simpler propargylamides 5,3b could
also participate in this reaction and produce oxazole-5-
carbaldehydes 7 in good yields. However, the oxidation
reactions of oxazolidine 2 did not take place under the same
conditions.
CONCLUSION
■
In summary, we have developed a NIS-mediated cyclization of
N-sulfonyl propargylamides for the synthesis of various
functionalized oxazolidines and iodoalkylidenedihydrooxazoles
via a 5-exo-dig process. Moreover, the resulting iodoalkylidene-
dihydrooxazoles can be further transformed into the corre-
sponding oxazoles in the presence of oxygen. This oxidation
reaction may serve as a powerful tool for the rapid and efficient
transformations of other halogen-containing heterocycles.
Futhermore, this process may find applications in the synthesis
of complex structures.
On the basis of the above results, we then tried to combine
the formation and oxidation of iodoalkylidenedihydrooxazoles
3 and 6 in one pot by adding dioxygen after NIS-triggered
cyclization of propargylamides 1 and 5 (Scheme 5). Thus, the
two-step one-pot reaction was accomplished successfully.
Additionally, the gram scale reactions were performed in a
one-pot sequence, affording the desired oxazoles 4a and 7a in
62% and 65% yields, respectively.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise stated, all reactions and
manipulations were carried out under an argon atmosphere using
standard Schlenk techniques or in an argon-filled glovebox. All
chemicals were obtained from commercial sources and were used
without further purification. Solvents were treated prior to use
according to the standard methods. Column chromatography was
carried out on silica gel (300−400 mesh) using a forced flow of eluent
at 0.3−0.5 bar pressure. NMR spectra were recorded at room
temperature in CDCl3 on 400 and 500 MHz spectrometers. The
Mechanistically (Scheme 6),3e,10 the radical intermediate C
and an iodine radical are formed by homolytic cleavage of the
C−I bond under heat conditions. Intermediate C then would
quickly react with oxygen to give the peroxyl radical species D,
followed by a six-membered-ring transition state to give the
radical species E, which is a resonance structure of F. Species F
releases a hydroxyl radical to afford the final product 4. The
1
chemical shifts for H NMR were recorded in ppm downfield from
tetramethylsilane (TMS) with CDCl3 (7.26 ppm) as the internal
standard. The chemical shifts for 13C NMR were recorded in ppm
downfield using the central peak of CDCl3 (77.16 ppm) as the internal
standard. Coupling constants (J) are reported in hertz and refer to
apparent peak multiplications.
a
Scheme 4. Oxidation of Iodoalkylidenedihydrooxazole
a
The reactions were carried out with 3 or 6 (0.20 mmol) in O2 atmosphere and DCE (2.0 mL) at 80 °C, unless otherwise stated.
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Scheme 6. Proposed Mechanism for the Oxidation of Iodoalkylidenedihydrooxazole
Characterization of Starting Materials. The N-sulfonyl
propargylamides were prepared following the procedure described in
the literature.8b 1a−c,e−l are known compounds.8b
69.1, 64.9, 29.4, 28.4, 21.3. HRMS (ESI-TOF): m/z calcd for
C35H27N2O7F2NaSI [M + Na]+ 807.0450, found 807.0463.
(E)-2-(2-(2,5-Dioxopyrrolidin-1-yl)-4-phenyl-2-(p-tolyl)-3-tosylox-
azolidin-5-ylidene)-2-iodoethyl 4-Methylbenzoate (2c). By following
the general procedure (0.20 mmol), the compound was obtained as a
4-(4-Methyl-N-tosylbenzamido)-4-phenylbut-2-yn-1-yl 4-Me-
thoxybenzoate (1d). By following the known procedure (0.40
mmol), the compound was obtained as a white solid: 170.1 mg,
71% yield, mp 112−113 °C. 1H NMR (500 MHz, acetone): δ 8.06 (d,
J = 8.7 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.6 Hz, 4H),
7.36 (d, J = 8.2 Hz, 2H), 7.30−7.23 (m, 3H), 7.09 (d, J = 8.7 Hz, 2H),
6.80 (d, J = 8.7 Hz, 2H), 6.34 (s, 1H), 5.04 (d, J = 1.6 Hz, 2H), 3.90
(s, 3H), 3.78 (s, 3H), 2.40 (s, 3H). 13C NMR (126 MHz, acetone): δ
170.1, 164.9, 163.9, 162.9, 144.8, 136.5, 135.9, 131.6, 131.0, 129.3,
128.7, 128.2, 128.1, 127.9, 127.4, 121.9, 113.9, 113.2, 82.15, 82.12,
55.1, 54.9, 53.7, 52.0, 20.6. HRMS (ESI-TOF): m/z calcd for
C34H32NO7NaS [M + Na]+ 621.1797, found 621.1803.
Representative Procedure for the Synthesis of Oxazolidines
2. In a 10 mL flame-dried Schlenk, N-sulfonyl propargylamide 1 (0.20
mmol) and halogen source (1.2 equiv) were introduced under argon
and dissolved in 2 mL of dry and degassed dichloromethane. The
resulting yellow solution was stirred at 40 °C for 2−3 h and quenched
with sodium thiosulfate solution. The aqueous layer was extracted with
Et2O, and the combined organic layers were washed twice with brine,
dried over MgSO4, filtered, and concentrated under reduced pressure.
Purification by flash chromatography on silica gel (petroleum ether/
EtOAc: 2/1) afforded the expected product.
(E)-2-(2-(2,5-Dioxopyrrolidin-1-yl)-2,4-diphenyl-3-tosyloxazoli-
din-5-ylidene)-2-iodoethyl Benzoate (2a). By following the general
procedure (0.20 mmol), the compound was obtained as a white solid:
115.3 mg, 77% yield, mp 192−193 °C. 1H NMR (500 MHz, CDCl3):
δ 7.99−7.92 (m, 2H), 7.70−7.26 (m, 13H), 6.55−6.45 (m, 2H), 5.96
(d, J = 1.5 Hz, 1H), 5.89−5.79 (m, 2H), 5.62 (d, J = 12.6 Hz, 1H),
4.30 (dd, J = 12.6, 1.6 Hz, 1H), 3.20−2.64 (m, 4H), 2.15 (s, 3H). 13C
NMR (126 MHz, CDCl3): δ 176.7, 175.5, 165.8, 153.7, 142.2, 138.3,
136.0, 133.4, 133.2, 131.0, 130.0, 129.6, 129.5, 128.6, 128.5, 128.4,
128.1, 126.4, 102.1, 74.1, 68.9, 64.5, 29.6, 28.3, 21.2. HRMS (ESI-
TOF): m/z calcd for C35H29N2O7NaSI [M + Na]+ 771.0638, found
771.0620.
1
white solid: 128.0 mg, 82% yield, mp 200−201 °C. H NMR (400
MHz, CDCl3): δ 7.84 (d, J = 8.0 Hz, 2H), 7.59−7.01 (m, 11H), 6.50
(d, J = 8.2 Hz, 2H), 5.94 (s, 1H), 5.89 (d, J = 8.2 Hz, 2H), 5.59 (d, J =
12.6 Hz, 1H), 4.28 (d, J = 12.5 Hz, 1H), 2.99−2.75 (m, 4H), 2.40 (s,
3H), 2.38 (s, 3H), 2.16 (s, 3H). 13C NMR (126 MHz, CDCl3): δ
177.0, 175.7, 165.8, 153.6, 144.0, 142.1, 139.7, 138.4, 136.1, 131.0,
130.5, 129.7, 129.2, 128.6, 128.4, 127.9, 127.3, 126.5, 102.2, 74.6, 68.8,
64.3, 29.5, 28.3, 21.8, 21.33, 21.28. HRMS (ESI-TOF): m/z calcd for
C37H33N2O7NaSI [M + Na]+ 799.0951, found 799.0960.
(E)-2-(2-(2,5-Dioxopyrrolidin-1-yl)-2-(4-methoxyphenyl)-4-phe-
nyl-3-tosyloxazolidin-5-ylidene)-2-iodoethyl 4-Methoxybenzoate
(2d). By following the general procedure (0.20 mmol), the compound
was obtained as a white solid: 129.1 mg, 80% yield, mp 166−167 °C.
1H NMR (500 MHz, CDCl3): δ 7.91 (d, J = 8.9 Hz, 2H), 7.49 (d, J =
7.1 Hz, 4H), 7.39−7.29 (m, 3H), 7.08−6.65 (m, 4H), 6.54 (d, J = 8.2
Hz, 2H), 5.93−5.91 (m, 3H), 5.58 (d, J = 12.6 Hz, 1H), 4.26 (dd, J =
12.6, 1.5 Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 3.21−2.68 (m, 4H), 2.17
(s, 3H). 13C NMR (126 MHz, CDCl3): δ 177.0, 175.6, 165.5, 163.7,
160.7, 153.53, 153.47, 142.2, 138.6, 136.3, 131.8, 131.1, 128.6, 128.5,
128.1, 126.6, 125.6, 122.6, 113.9, 113.0, 102.3, 74.8, 68.9, 64.2, 55.6,
29.7, 28.5, 21.3. HRMS (ESI-TOF): m/z calcd for C37H33N2O9NaSI
[M + Na]+ 831.0849, found 831.0832.
(E)-2-(2-(4-Chlorophenyl)-2-(2,5-dioxopyrrolidin-1-yl)-4-phenyl-
3-tosyloxazolidin-5-ylidene)-2-iodoethyl 4-Chlorobenzoate (2e). By
following the general procedure (0.20 mmol), the compound was
1
obtained as a white solid: 130.3 mg, 80% yield, mp 214−215 °C. H
NMR (500 MHz, CDCl3): δ 8.06−7.79 (m, 2H), 7.59−7.29 (m,
10H), 7.21 (s, 1H), 6.59 (d, J = 8.1 Hz, 2H), 5.96 (d, J = 1.4 Hz, 1H),
5.93 (d, J = 8.4 Hz, 2H), 5.59 (d, J = 12.6 Hz, 1H), 4.31 (dd, J = 12.6,
1.6 Hz, 1H), 3.01−2.78 (m, 4H), 2.19 (s, 3H). 13C NMR (126 MHz,
CDCl3): δ 176.8, 175.6, 165.1, 153.7, 142.7, 139.9, 138.2, 136.1, 135.9,
132.15, 131.12, 131.0, 129.0, 128.9, 128.6, 128.5, 128.3, 126.4, 101.6,
74.0, 69.0, 64.7, 29.5, 28.5, 21.4. HRMS (ESI-TOF): m/z calcd for
C35H27N2O7Cl2NaSI [M + Na]+ 838.9858, found 838.9840.
(E)-2-(2-(2,5-Dioxopyrrolidin-1-yl)-2-(3-fluorophenyl)-4-phenyl-3-
tosyloxazolidin-5-ylidene)-2-iodoethyl 3-Fluorobenzoate (2b). By
following the general procedure (0.20 mmol), the compound was
(E)-2-(2-(2,5-Dioxopyrrolidin-1-yl)-2-ethoxy-4-phenyl-3-tosyloxa-
zolidin-5-ylidene)-2-iodoethyl Ethyl Carbonate (2f). By following the
general procedure (0.20 mmol), the compound was obtained as a
1
obtained as a white solid: 135.8 mg, 86% yield, mp 119−120 °C. H
1
NMR (500 MHz, CDCl3): δ 7.85−7.71 (m, 1H), 7.62 (ddd, J = 9.2,
2.5, 1.5 Hz, 1H), 7.53−7.20 (m, 10H), 7.09 (t, J = 7.5 Hz, 1H), 6.56
(d, J = 8.1 Hz, 2H), 5.97 (s, 3H), 5.61 (d, J = 12.6 Hz, 1H), 4.32 (dd, J
= 12.6, 1.5 Hz, 1H), 3.37−2.61 (m, 4H), 2.17 (s, 3H). 13C NMR (126
MHz, CDCl3): δ 176.5, 175.6, 164.89, 164.87, 162.7 (d, J = 247.5 Hz),
153.8, 142.7, 138.2, 136.0, 132.2 (d, J = 7.4 Hz), 131.0, 130.3 (d, J =
7.7 Hz), 128.8, 128.6, 128.3, 126.4, 125.5 (d, J = 2.7 Hz), 120.4 (d, J =
21.3 Hz), 116.6 (d, J = 23.1 Hz), 116.6 (d, J = 21.1 Hz), 101.3, 73.6,
white solid: 50.7 mg, 38% yield, mp 102−103 °C. H NMR (500
MHz, CDCl3): δ 7.35−7.27 (m, 3H), 7.19 (t, J = 7.6 Hz, 2H), 6.98 (d,
J = 8.4 Hz, 2H), 6.86 (d, J = 8.2 Hz, 2H), 5.85 (s, 1H), 5.01 (d, J =
12.5 Hz, 1H), 4.77 (d, J = 12.3 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 3.86
(dq, J = 8.6, 7.0 Hz, 1H), 3.71 (dq, J = 8.7, 7.0 Hz, 1H), 2.76 (s, 4H),
2.28 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.19 (t, J = 7.0 Hz, 3H). 13C
NMR (126 MHz, CDCl3): δ 154.8, 153.8, 143.3, 137.3, 135.5, 131.0,
128.6, 128.4, 128.3, 128.1, 113.8, 69.0, 68.2, 65.4, 64.3, 62.8, 28.6, 21.6,
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1
14.4, 14.3. HRMS (ESI-TOF): m/z calcd for C27H29N2O9NaSI [M +
Na]+ 707.0536, found 707.0543.
204−205 °C. H NMR (400 MHz, CDCl3): δ 7.97 (dd, J = 8.8, 5.4
Hz, 2H), 7.67−7.43 (m, 4H), 7.42−7.28 (m, 3H), 7.20−6.69 (m, 7H),
6.07 (d, J = 7.5 Hz, 2H), 5.97 (d, J = 1.2 Hz, 1H), 5.58 (d, J = 12.6 Hz,
1H), 4.30 (dd, J = 12.6, 1.5 Hz, 1H), 3.41−2.54 (m, 4H). 13C NMR
(126 MHz, CDCl3): δ 176.9, 175.7, 166.0 (d, J = 254.8 Hz), 165.0,
163.5 (d, J = 250.3 Hz), 153.5, 141.1, 136.0, 132.3 (d, J = 9.3 Hz),
131.8, 131.0, 129.5 (d, J = 2.5 Hz), 128.9, 128.8, 128.7, 128.6, 127.7,
127.4, 126.3, 115.8 (d, J = 22.0 Hz), 101.7, 74.4, 69.0, 64.6, 29.7, 28.0.
HRMS (ESI-TOF): m/z calcd for C34H25F2N2O7NaSI [M + Na]+
793.0293, found 793.0278.
(E)-2-(2-(2,5-Dioxopyrrolidin-1-yl)-4-(2-fluorophenyl)-2-phenyl-3-
tosyloxazolidin-5-ylidene)-2-iodoethy Phenyl Carbonate (2h). By
following the general procedure (0.20 mmol), the compound was
obtained as a white solid: 129.6 mg, 84% yield, mp 188−189 °C. H
1
NMR (500 MHz, CDCl3): δ 8.04−7.83 (m, 2H), 7.64 (d, J = 7.5 Hz,
2H), 7.59−7.52 (m, 1H), 7.47−7.32 (m, 6H), 7.07−7.03 (m, 2H),
6.54 (d, J = 8.2 Hz, 2H), 6.09 (s, 1H), 5.88 (s, 2H), 5.62 (d, J = 12.6
Hz, 1H), 4.31 (dd, J = 12.6, 1.6 Hz, 1H), 3.00−2.84 (m, 4H), 2.16 (s,
3H). 13C NMR (126 MHz, CDCl3): δ 176.2, 165.8, 161.7 (d, J = 252.3
Hz), 152.7, 142.4, 138.3, 133.4, 133.2, 130.9 (d, J = 8.1 Hz), 130.1,
129.7, 129.5, 128.9, 128.5, 128.3, 128.0, 126.2, 124.1, 122.9, 115.9 (d, J
= 21.4 Hz), 102.6, 72.5, 64.7, 28.9, 21.3. HRMS (ESI-TOF): m/z calcd
for C35H28FN2O7NaSI [M + Na]+ 789.0544, found 789.0537.
(E)-2-(2-(2,5-Dioxopyrrolidin-1-yl)-4-(3-fluorophenyl)-2-phenyl-3-
tosyloxazolidin-5-ylidene)-2-iodoethyl Phenyl Carbonate (2i). By
following the general procedure (0.20 mmol), the compound was
obtained as a light yellow solid: 142.4 mg, 94% yield, mp 200−201 °C.
1H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 7.4 Hz, 2H), 7.57 (t, J =
7.4 Hz, 3H), 7.49−7.26 (m, 7H), 7.11 (d, J = 9.5 Hz, 1H), 7.04 (t, J =
8.0 Hz, 1H), 6.56 (d, J = 8.2 Hz, 2H), 5.93 (d, J = 8.6 Hz, 3H), 5.61
(d, J = 12.6 Hz, 1H), 4.31 (dd, J = 12.6, 1.2 Hz, 1H), 3.01− 2.76 (m,
4H), 2.17 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 176.6, 175.8,
165.9, 162.8 (d, J = 246.9 Hz), 153.1, 142.6, 138.4 (d, J = 6.9 Hz),
138.3, 133.4, 133.3, 130.0, 129.9 (d, J = 8.0 Hz), 129.7, 128.6, 128.2,
127.1, 126.4, 117.6 (d, J = 22.0 Hz), 115.7 (d, J = 21.2 Hz), 74.7, 68.3,
64.5, 29.6, 28.4, 21.3. HRMS (ESI-TOF): m/z calcd for
C35H28FN2O7NaSI [M + Na]+ 789.0544, found 789.0551.
(E)-2-Bromo-2-(2-(2,5-dioxopyrrolidin-1-yl)-2,4-diphenyl-3-tosy-
loxazolidin-5-ylidene)ethyl Phenyl Carbonate (2o). By following the
general procedure (0.20 mmol), the compound was obtained as a
1
white solid: 23.6 mg, 16% yield, mp 171−172 °C. H NMR (500
MHz, CDCl3): δ 8.02−7.89 (m, 2H), 7.78−7.52 (m, 3H), 7.51−7.27
(m, 10H), 6.51 (d, J = 8.0 Hz, 2H), 6.03 (d, J = 1.4 Hz, 1H), 5.86 (d, J
= 8.4 Hz, 2H), 5.64 (d, J = 12.7 Hz, 1H), 4.35 (dd, J = 12.7, 1.6 Hz,
1H), 3.02−2.78 (m, 4H), 2.16 (s, 3H). 13C NMR (126 MHz, CDCl3):
δ 176.2, 166.0, 152.4, 142.3, 138.4, 135.9, 133.5, 133.3, 130.5, 130.3,
130.1, 129.7, 129.6, 128.63, 128.59, 128.5, 128.2, 126.5, 102.5, 99.6,
67.4, 62.8, 28.4, 21.3. HRMS (ESI-TOF): m/z calcd for
C35H29N2O7NaSBr [M + Na]+ 723.0777, found 723.0779.
(E)-2-(2-(4,4-Dimethyl-2,5-dioxoimidazolidin-1-yl)-2,4-diphenyl-
3-tosyloxazolidin-5-ylidene)-2-iodoethyl Benzoate (2q). By follow-
ing the general procedure (0.20 mmol), the compound was obtained
as a white solid: 97.9 mg, 62% yield, mp 194−195 °C. 1H NMR (400
MHz, CDCl3): δ 7.99 (d, J = 7.4 Hz, 2H), 7.75−7.28 (m, 13H), 6.53
(d, J = 8.0 Hz, 2H), 6.00 (s, 1H), 5.89 (s, 2H), 5.64 (s, 1H), 5.38 (d, J
= 11.8 Hz, 1H), 4.80 (d, J = 11.9 Hz, 1H), 2.16 (s, 3H), 1.60−1.54 (m,
6H). 13C NMR (126 MHz, CDCl3): δ 176.0, 165.7, 154.7, 154.0,
142.4, 138.4, 136.1, 133.5, 133.2, 131.1, 130.14, 130.06, 129.9, 129.8,
128.7, 128.53, 128.47, 128.2, 126.6, 102.2, 68.9, 64.6, 58.8, 53.5, 29.8,
25.0, 21.3. HRMS (ESI-TOF): m/z calcd for C36H32N3O7NaSI [M +
Na]+ 800.0903, found 800.0917.
General Methods for the Synthesis of Iodoalkylidene-
dihydrooxazoles 3. N-Sulfonyl propargylamide 1 (0.20 mmol) and
the halogen source (1.2 equiv) were dissolved in 2 mL of dry and
degassed N,N′-dimethylformamide. The resulting yellow solution was
stirred at room temperature for 12−18 h and quenched with sodium
thiosulfate solution. The aqueous layer was extracted with Et2O, and
the combined organic layers were washed twice with brine, dried over
MgSO4, filtered, and concentrated under reduced pressure. Purifica-
tion by flash chromatography on silica gel (petroleum ether/EtOAc:
20/1) afforded the expected product.
(E)-2-(2,4-Diphenyloxazol-5(4H)-ylidene)-2-iodoethyl Benzoate
(3a). By following the general procedure (0.20 mmol), the compound
was obtained as a white solid: 82.2 mg, 83% yield, mp 111−112 °C. 1H
NMR (500 MHz, acetone): δ 8.14−8.01 (m, 4H), 7.69−7.60 (m, 2H),
7.57−7.50 (m, 4H), 7.46−7.31 (m, 5H), 5.89 (s, 1H), 5.39 (dd, J =
2.6, 1.3 Hz, 2H). 13C NMR (126 MHz, acetone): δ 165.3, 160.8,
158.1, 138.0, 133.3, 132.4, 130.0, 129.4, 128.8, 128.6, 128.5, 128.1,
128.0, 126.2, 76.3, 69.6, 65.7. HRMS (ESI-TOF): m/z calcd for
C24H19INO3 [M + H]+ 496.0410, found 496.0409.
(E)-2-(2-(3-Fluorophenyl)-4-phenyloxazol-5(4H)-ylidene)-2-io-
doethyl 3-Fluorobenzoate (3b). By following the general procedure
(0.20 mmol), the compound was obtained as a colorless oil: 71.2 mg,
67% yield. 1H NMR (500 MHz, acetone): δ 7.91 (d, J = 7.8 Hz, 2H),
7.79 (ddd, J = 9.5, 2.6, 1.5 Hz, 1H), 7.74 (ddd, J = 9.5, 2.6, 1.5 Hz,
1H), 7.59 (td, J = 8.1, 5.7 Hz, 2H), 7.49−7.33 (m, 7H), 5.91 (s, 1H),
5.42 (dd, J = 2.5, 1.3 Hz, 2H). 13C NMR (126 MHz, acetone): δ 164.2
(d, J = 2.9 Hz), 162.6 (d, J = 245.4 Hz), 162.5 (d, J = 245.6 Hz), 159.8
(d, J = 3.1 Hz), 158.0, 137.6, 132.3 (d, J = 7.5 Hz), 131.0 (d, J = 8.2
Hz), 130.8 (d, J = 7.9 Hz), 129.1, 128.7, 128.6, 128.5, 128.4, 128.3,
128.1, 125.5 (d, J = 2.8 Hz), 124.2 (d, J = 2.9 Hz), 120.2 (d, J = 21.3
Hz), 119.3 (d, J = 21.4 Hz), 115.9 (d, J = 23.3 Hz), 114.8 (d, J = 24.0
Hz), 76.3, 69.6, 66.1. HRMS (ESI-TOF): m/z calcd for
C24H16F2NO3NaI [M + Na]+ 554.0041, found 554.0038.
(E)-2-(4-(4-Bromophenyl)-2-(2,5-dioxopyrrolidin-1-yl)-2-phenyl-
3-tosyloxazolidin-5-ylidene)-2-iodoethyl Phenyl Carbonate (2j). By
following the general procedure (0.20 mmol), the compound was
1
obtained as a white solid: 141.2 mg, 85% yield, mp 127−128 °C. H
NMR (500 MHz, CDCl3): δ 8.13−7.79 (m, 2H), 7.73−7.49 (m, 3H),
7.54−7.29 (m, 9H), 6.58 (d, J = 8.1 Hz, 2H), 5.90 (d, J = 8.4 Hz, 3H),
5.61 (d, J = 12.6 Hz, 1H), 4.30 (dd, J = 12.6, 1.6 Hz, 1H), 3.02−2.77
(m, 4H), 2.20 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 176.4, 175.7,
165.8, 153.1, 142.6, 138.3, 135.1, 133.5, 133.3, 132.5, 131.6, 129.9,
129.6, 128.5, 128.4, 128.2, 126.3, 122.8, 102.2, 74.4, 68.2, 64.4, 28.5,
28.1, 21.3. HRMS (ESI-TOF): m/z calcd for C35H28BrN2O7NaSI [M
+ Na]+ 848.9743, found 848.9760.
(E)-2-(2-(2,5-Dioxopyrrolidin-1-yl)-4-(naphthalen-2-yl)-2-phenyl-
3-tosyloxazolidin-5-ylidene)-2-iodoethyl Phenyl Carbonate (2k). By
following the general procedure (0.20 mmol), the compound was
1
obtained as a white solid: 140.6 mg, 88% yield, mp 157−158 °C. H
NMR (500 MHz, CDCl3): δ 8.01 (s, 1H), 7.99−7.92 (m, 2H), 7.88−
7.75 (m, 2H), 7.69 (d, J = 8.2 Hz, 3H), 7.60−7.48 (m, 3H), 7.44 (dt, J
= 7.5, 3.8 Hz, 6H), 6.19 (d, J = 8.1 Hz, 2H), 6.11 (d, J = 1.2 Hz, 1H),
5.73 (d, J = 8.4 Hz, 2H), 5.66 (d, J = 12.5 Hz, 1H), 4.31 (dd, J = 12.5,
1.6 Hz, 1H), 3.00−2.82 (m, 4H), 2.00 (s, 3H). 13C NMR (126 MHz,
CDCl3): δ 176.2, 165.8, 153.4, 142.1, 138.2, 133.7, 133.2, 133.2, 132.9,
132.8, 131.7, 130.0, 129.7, 129.6, 128.5, 128.4, 128.3, 127.8, 127.6,
126.7, 126.33, 126.27, 102.2, 74.1, 69.1, 64.6, 28.7, 21.1. HRMS (ESI-
TOF): m/z calcd for C39H31N2O7NaSI [M + Na]+ 821.0794, found
821.0791.
(E)-2-(2-(2,5-Dioxopyrrolidin-1-yl)-2,4-diphenyl-3-
(phenylsulfonyl)oxazolidin-5-ylidene)-2-iodoethyl Phenyl Carbo-
nate (2m). By following the general procedure (0.20 mmol), the
compound was obtained as a white solid: 136.6 mg, 93% yield, mp
1
188−189 °C. H NMR (500 MHz, CDCl3): δ 8.07−7.86 (m, 2H),
7.70−7.29 (m, 13H), 7.08 (t, J = 7.4 Hz, 1H), 6.71 (dd, J = 8.3, 7.6 Hz,
2H), 5.99−5.95 (m, 3H), 5.63 (d, J = 12.6 Hz, 1H), 4.29 (dd, J = 12.6,
1.6 Hz, 1H), 3.03−2.79 (m, 4H). 13C NMR (126 MHz, CDCl3): δ
176.8, 175.6, 165.8, 153.5, 141.0, 135.9, 133.3, 133.2, 131.4, 130.9,
130.0, 129.6, 129.5, 128.6, 128.5, 128.4, 128.0, 127.4, 126.4, 126.2,
102.1, 74.3, 68.9, 64.4, 29.4, 28.4. HRMS (ESI-TOF): m/z calcd for
C34H27N2O7NaSI [M + Na]+ 757.0481, found 757.0466.
(E)-2-(2-(2,5-Dioxopyrrolidin-1-yl)-2-(4-fluorophenyl)-4-phenyl-3-
(phenylsulfonyl)oxazolidin-5-ylidene)-2-iodoethyl 4-Fluoroben-
zoate (2n). By following the general procedure (0.20 mmol), the
compound was obtained as a white solid: 112.6 mg, 73% yield, mp
(E)-2-Iodo-2-(4-phenyl-2-(p-tolyl)oxazol-5(4H)-ylidene)ethyl 4-
Methylbenzoate (3c). By following the general procedure (0.20
mmol), the compound was obtained as a light yellow solid: 68.0 mg,
3056
dx.doi.org/10.1021/jo5001719 | J. Org. Chem. 2014, 79, 3052−3059

The Journal of Organic Chemistry
Article
1
65% yield, mp 121−122 °C. H NMR (400 MHz, acetone): δ 7.95
80% yield. 1H NMR (400 MHz, acetone): δ 8.19−8.09 (m, 4H),
7.48−7.21 (m, 9H), 5.88 (s, 1H), 5.39 (t, J = 1.5 Hz, 2H). 13C NMR
(101 MHz, acetone): δ 165.8 (d, J = 252.1 Hz), 165.2 (d, J = 251.4
Hz), 164.4, 160.0, 158.2, 137.9, 132.35, 132.26, 130.9, 130.8, 128.6,
128.5, 128.0, 126.5 (d, J = 2.9 Hz), 122.8 (d, J = 3.0 Hz), 115.9 (d, J =
22.5 Hz), 115.7 (d, J = 22.4 Hz), 76.3, 69.6, 65.9. HRMS (ESI-TOF):
m/z calcd for C24H16F2NO3NaI [M + Na]+ 554.0041, found 554.0054.
(E)-2-Bromo-2-(2,4-diphenyloxazol-5(4H)-ylidene)ethyl Benzoate
(3o). By following the general procedure (0.20 mmol), the compound
was obtained as colorless oil: 53.3 mg, 60% yield. 1H NMR (400 MHz,
acetone): δ 8.19−8.01 (m, 4H), 7.73−7.61 (m, 2H), 7.59−7.51 (m,
4H), 7.47−7.17 (m, 5H), 5.99 (s, 1H), 5.41 (m, 2H). 13C NMR (101
MHz, acetone): δ 165.2, 160.7, 156.4, 137.4, 133.1, 132.2, 129.3,
128.6, 128.5, 128.4, 128.03, 128.01, 127.8, 125.9, 96.9, 74.5, 63.6.
HRMS (ESI-TOF): m/z calcd for C24H18BrNO3Na [M + Na]+
470.0368, found 470.0375.
(dd, J = 8.0, 5.0 Hz, 4H), 7.43−7.28 (m, 9H), 5.85 (s, 1H), 5.36 (s,
2H), 2.41 (s, 6H). 13C NMR (101 MHz, acetone): δ 165.3, 160.9,
158.1, 144.0, 142.9, 138.1, 129.5, 129.4, 129.2, 128.6, 128.5, 128.1,
127.9, 123.5, 76.3, 69.6, 65.6, 20.7. HRMS (ESI-TOF): m/z calcd for
C26H22NO3NaI [M + Na]+ 546.0542, found 546.0540.
(E)-2-Iodo-2-(2-(4-methoxyphenyl)-4-phenyloxazol-5(4H)-
ylidene)ethyl 4-Methoxybenzoate (3d). By following the general
procedure (0.20 mmol), the compound was obtained as a light yellow
1
solid: 65.6 mg, 59% yield, mp 145−146 °C. H NMR (500 MHz,
acetone): δ 8.36−7.65 (m, 4H), 7.45−7.29 (m, 5H), 7.15−6.94 (m,
4H), 5.83 (s, 1H), 5.52−5.16 (m, 2H), 3.89 (s, 6H). 13C NMR (126
MHz, acetone): δ 164.9, 163.8, 163.0, 160.6, 158.1, 138.3, 131.5,
123.0, 128.6, 128.5, 127.9, 122.2, 118.4, 114.1, 113.8, 76.2, 69.5, 65.4,
55.0. HRMS (ESI-TOF): m/z calcd for C26H22NO5NaI [M + Na]+
578.0440, found 578.0449.
Methods for the Synthesis of Iodomethylene-
dihydrooxazoles 6. In a dry Schlenk, propargylamide 5 (1.00
mmol) and NIS (1.2 equiv) were dissolved in 4 mL of freshly distilled
dichloromethane. The resulting mixture was stirred at room
temperature for 2 h and quenched with sodium thiosulfate solution.
The aqueous layer was extracted with Et2O, and the combined organic
layers were washed twice with brine, dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification by flash chromatog-
raphy on silica gel (petroleum ether/EtOAc: 20/1) afforded the
expected product.
(E)-5-(Iodomethylene)-2-phenyl-4,5-dihydrooxazole (6a). By fol-
lowing the general procedure (1.00 mmol), the compound was
obtained as a white solid: 256.5 mg, 90% yield, known compound.3b
1H NMR (400 MHz, CDCl3): δ 8.04−7.86 (m, 2H), 7.53 (t, J = 7.4
Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 5.78 (t, J = 3.2 Hz, 1H), 4.63 (d, J =
3.2 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 163.8, 157.8, 131.9,
128.4, 127.8, 126.3, 61.0, 47.0.
(E)-2-(3-Bromophenyl)-5-(iodomethylene)-4,5-dihydrooxazole
(6b). By following the general procedure (1.00 mmol), the compound
was obtained as a white solid: 313.1 mg, 86% yield, mp 122−123 °C.
1H NMR (400 MHz, CDCl3): δ 8.02 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H),
7.65−7.47 (m, 1H), 7.23 (t, J = 7.9 Hz, 1H), 5.71 (t, J = 3.1 Hz, 1H),
4.54 (d, J = 3.2 Hz, 2H). 13C NMR (101 MHz, CDCl3): δ 162.7,
157.7, 135.1, 131.1, 130.2, 128.6, 126.6, 122.8, 61.3, 47.8. HRMS (ESI-
TOF): m/z calcd for C10H8BrINO [M + H]+ 363.8834, found
363.8842.
Oxidation of Iodoalkylidenedihydrooxazoles. Iodoalkylidene-
dihydrooxazole 3 or 6 (0.20 mmol) was dissolved in DCE (2 mL), and
the resulting mixture was stirred at 80 °C under an O2 atmosphere
until the consumption of starting materials detected by TLC. After the
reaction was completed, the solvent was evaporated and the organic
product purified by column chromatography (petroleum ether/
EtOAc: 30/1).
2-(2,4-Diphenyloxazol-5-yl)-2-oxoethyl Benzoate (4a). By follow-
ing the general procedure (0.20 mmol), the compound was obtained
as a white solid: 53.8 mg, 70% yield, mp 151−152 °C. 1H NMR (400
MHz, CDCl3): δ 8.44−8.31 (m, 2H), 8.22 (d, J = 6.8 Hz, 2H), 8.17 (d,
J = 7.4 Hz, 2H), 7.66−7.50 (m, 4H), 7.53−7.38 (m, 5H), 5.58 (s, 2H).
13C NMR (101 MHz, CDCl3): δ 181.5, 166.1, 162.3, 148.9, 142.0,
133.6, 132.3, 130.7, 130.2, 129.9, 129.5, 129.4, 129.2, 128.6, 128.5,
127.7, 126.1, 66.9. HRMS (ESI-TOF): m/z calcd for C24H18NO4 [M
+ H]+ 384.1236, found 384.1242.
(E)-2-(2-(4-Chlorophenyl)-4-phenyloxazol-5(4H)-ylidene)-2-io-
doethyl 4-Chlorobenzoate (3e). By following the general procedure
(0.20 mmol), the compound was obtained as a light yellow solid: 63.1
mg, 56% yield, mp 138−139 °C. 1H NMR (400 MHz, acetone): δ 8.06
(dd, J = 8.7, 2.1 Hz, 4H), 7.58 (d, J = 8.6 Hz, 4H), 7.44−7.27 (m, 5H),
5.89 (s, 1H), 5.39 (s, 2H). 13C NMR (101 MHz, acetone): δ 164.4,
160.0, 158.0, 139.0, 138.0, 137.7, 131.1, 129.8, 129.0, 129.0, 128.9,
128.6, 128.5, 128.0, 125.0, 76.3, 69.5, 65.9. HRMS (ESI-TOF): m/z
calcd for C24H16Cl2NO3NaI [M + Na]+ 585.9450, found 585.9441.
(E)-2-(4-(2-Fluorophenyl)-2-phenyloxazol-5(4H)-ylidene)-2-io-
doethyl Benzoate (3h). By following the general procedure (0.20
mmol), the compound was obtained as a colorless oil: 85.3 mg, 83%
yield. 1H NMR (500 MHz, acetone): δ 8.10−8.07 (m, 2H), 8.07−8.04
(m, 2H), 7.72−7.61 (m, 2H), 7.60−7.50 (m, 4H), 7.48−7.37 (m, 2H),
7.25−7.14 (m, 2H), 6.10 (s, 1H), 5.39 (m, 2H). 13C NMR (126 MHz,
acetone): δ 165.3, 161.7, 161.0 (d, J = 247.3 Hz), 157.4, 133.3, 132.4,
130.7 (d, J = 3.2 Hz), 130.4 (d, J = 8.5 Hz), 130.0, 129.4, 128.8, 128.6,
128.15, 126.16, 125.3, 125.2, 124.7 (d, J = 3.4 Hz), 115.5 (d, J = 21.5
Hz), 70.8, 68.7, 65.6. HRMS (ESI-TOF): m/z calcd for
C24H17FNO3NaI [M + Na]+ 536.0135, found 536.0129.
(E)-2-(4-(3-Fluorophenyl)-2-phenyloxazol-5(4H)-ylidene)-2-io-
doethyl Benzoate (3i). By following the general procedure (0.20
mmol), the compound was obtained as a colorless oil: 82.1 mg, 80%
yield. 1H NMR (400 MHz, acetone): δ 8.12−8.02 (m, 4H), 7.70−7.60
(m, 2H), 7.54 (t, J = 7.7 Hz, 4H), 7.43 (td, J = 8.0, 6.0 Hz, 1H), 7.28
(d, J = 7.7 Hz, 1H), 7.25−7.18 (m, 1H), 7.11 (td, J = 8.3, 2.2 Hz, 1H),
5.94 (s, 1H), 5.40 (d, J = 1.2 Hz, 2H). 13C NMR (101 MHz, acetone):
δ 165.1, 162.7 (d, J = 244.5 Hz), 161.1, 157.4, 140.5, 140.4, 133.1,
132.3, 130.3 (d, J = 8.3 Hz), 129.3, 128.6, 128.4, 128.0, 126.0, 124.4
(d, J = 2.9 Hz), 115.2 (d, J = 22.3 Hz), 114.6 (d, J = 21.2 Hz), 75.51,
75.49, 70.0, 65.5. HRMS (ESI-TOF): m/z calcd for C24H17FNO3NaI
[M + Na]+ 536.0135, found 536.0141.
(E)-2-(4-(4-Bromophenyl)-2-phenyloxazol-5(4H)-ylidene)-2-io-
doethyl Benzoate (3j). By following the general procedure (0.20
mmol), the compound was obtained as a light yellow oil: 44.0 mg, 38%
yield. 1H NMR (500 MHz, acetone): δ 8.12−8.00 (m, 4H), 7.73−7.62
(m, 2H), 7.61−7.52 (m, 6H), 7.45−7.35 (m, 2H), 5.91 (s, 1H), 5.39
(dd, J = 1.2, 0.8 Hz, 2H). 13C NMR (126 MHz, acetone): δ 165.3,
161.2, 157.6, 137.4, 133.3, 132.5, 131.7, 130.6, 130.0, 129.4, 128.8,
128.6, 128.2, 126.1, 121.5, 75.5, 70.0, 65.7. HRMS (ESI-TOF): m/z
calcd for C24H18BrNO3I [M + H]+ 573.9515, found 573.9528.
(E)-2-Iodo-2-(4-(naphthalen-2-yl)-2-phenyloxazol-5(4H)-ylidene)-
ethyl Benzoate (3k). By following the general procedure (0.20 mmol),
the compound was obtained as a white solid: 89.4 mg, 82% yield, mp
2-oxo-2-(4-Phenyl-2-(p-tolyl)oxazol-5-yl)ethyl 4-Methylbenzoate
(4c). By following the general procedure (0.20 mmol), the compound
was obtained as a white solid: 65.9 mg, 80% yield, mp 172−173 °C. 1H
NMR (400 MHz, CDCl3): δ 8.43−8.32 (m, 2H), 8.11 (d, J = 8.1 Hz,
2H), 8.05 (d, J = 8.1 Hz, 2H), 7.55−7.42 (m, 3H), 7.35 (d, J = 8.0 Hz,
2H), 7.28 (m, 2H), 5.56 (s, 2H), 2.46 (s, 3H), 2.43 (s, 3H). 13C NMR
(126 MHz, CDCl3): δ 181.6, 166.2, 162.6, 148.9, 144.3, 143.0, 141.9,
130.7, 130.2, 130.1, 130.0, 129.5, 129.3, 128.5, 127.7, 126.8, 123.5,
66.8, 21.9. HRMS (ESI-TOF): m/z calcd for C26H22NO4 [M + H]+
412.1549, found 412.1539.
1
142−143 °C. H NMR (400 MHz, acetone): δ 8.17−8.06 (m, 4H),
8.00 (s, 1H), 7.90 (t, J = 7.5 Hz, 3H), 7.68−7.58 (m, 2H), 7.57−7.37
(m, 7H), 6.07 (s, 1H), 5.43 (s, 2H). 13C NMR (101 MHz, acetone): δ
165.2, 160.8, 157.8, 135.0, 133.3, 133.1, 133.0, 132.2, 129.9, 129.3,
128.6, 128.5, 128.4, 128.0, 127.85, 127.82, 127.5, 126.11, 126.10,
125.7, 76.3, 69.7, 65.7. HRMS (ESI-TOF): m/z calcd for
C28H20NO3NaI [M + Na]+ 568.0386, found 568.0393.
(E)-2-(2-(4-Fluorophenyl)-4-phenyloxazol-5(4H)-ylidene)-2-io-
doethyl 4-Fluorobenzoate (3n). By following the general procedure
(0.20 mmol), the compound was obtained as a colorless oil: 85.0 mg,
2-(2-(4-Methoxyphenyl)-4-phenyloxazol-5-yl)-2-oxoethyl 4-Me-
thoxybenzoate (4d). By following the general procedure (0.20
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Article
mmol), the compound was obtained as a white solid: 63.9 mg, 72%
yield, mp 157−158 °C. H NMR (500 MHz, CDCl3): δ 8.43−8.31
Notes
1
The authors declare no competing financial interest.
(m, 2H), 8.19−8.14 (m, 2H), 8.13−8.06 (m, 2H), 7.57−7.38 (m, 3H),
7.08−7.01 (m, 2H), 6.98−6.90 (m, 2H), 5.52 (s, 2H), 3.90 (s, 3H),
3.87 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 181.6, 165.8, 163.9,
163.0, 162.5, 148.9, 141.8, 132.3, 130.6, 130.1, 129.6, 129.5, 128.4,
121.9, 118.8, 114.7, 113.9, 66.7, 55.7, 55.6. HRMS (ESI-TOF): m/z
calcd for C26H22NO6 [M + H]+ 444.1447, found 444.1463.
ACKNOWLEDGMENTS
■
We acknowledge the financial support from the National
Natural Science Foundation of China (21172218).
2-(2-(4-Fluorophenyl)-4-phenyloxazol-5-yl)-2-oxoethyl 4-Fluoro-
benzoate (4n). By following the general procedure (0.20 mmol), the
compound was obtained as a white solid: 60.5 mg, 72% yield, mp
185−186 °C. H NMR (400 MHz, CDCl3): δ 8.41−8.29 (m, 2H),
8.23 (dd, J = 8.6, 5.3 Hz, 2H), 8.18 (dd, J = 8.6, 5.6 Hz, 2H), 7.53−
7.42 (m, 3H), 7.26−7.21 (m, 2H), 7.15 (t, J = 8.6 Hz, 2H), 5.56 (s,
2H). 13C NMR (126 MHz, CDCl3): δ 181.3, 166.3 (d, J = 254.8 Hz),
165.4 (d, J = 254.2 Hz), 165.2, 161.5, 149.0, 142.1, 132.8 (d, J = 9.4
Hz), 130.9, 130.0 (d, J = 8.9 Hz), 129.8, 129.5, 128.5, 125.7 (d, J = 2.9
Hz), 122.5 (d, J = 3.0 Hz), 116.6 (d, J = 22.4 Hz), 115.8 (d, J = 22.1
Hz), 66.9. HRMS (ESI-TOF): m/z calcd for C24H16F2NO4 [M + H]+
420.1047, found 420.1058.
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9.82 (s, 1H), 8.18 (d, J = 7.3 Hz, 2H), 7.96 (s, 1H), 7.57−7.47 (m,
3H). 13C NMR (101 MHz, CDCl3): δ 176.4, 165.6, 149.7, 139.2,
132.4, 129.2, 127.8, 126.0. HRMS (ESI-TOF): m/z calcd for
C10H8NO2 [M + H]+ 174.0555, found 174.0556.
2-(3-Bromophenyl)oxazole-5-carbaldehyde (7b). By following the
general procedure (0.50 mmol), the compound was obtained as a
1
white solid: 102.9 mg, 82% yield, mp 114−115 °C. H NMR (400
MHz, CDCl3): δ 9.84 (s, 1H), 8.33 (t, J = 1.6 Hz, 1H), 8.11 (d, J = 7.8
Hz, 1H), 7.96 (s, 1H), 7.80−7.62 (m, 1H), 7.39 (t, J = 7.9 Hz, 1H).
13C NMR (101 MHz, CDCl3): δ 176.4, 163.9, 149.9, 138.9, 135.3,
130.7, 130.6, 127.8, 126.3, 123.3. HRMS (ESI-TOF): m/z calcd for
C10H7BrNO2 [M + H]+ 251.9660, found 251.9658.
One-Pot and Gram-Scale Synthesis of Oxazoles 4a and 7a.
In a dry Schlenk, N-tosyl substrate 1a (5.0 mmol) and NIS (1.2 equiv)
were dissolved in 20 mL of freshly distilled DMF. The resulting
mixture was stirred at room temperature for 12 h and then stirred at
80 °C under an O2 atmosphere until the consumption of starting
materials detected by TLC. After that, the reaction was quenched with
sodium thiosulfate solution. The aqueous layer was extracted with
Et2O, and the combined organic layers were washed twice with brine,
dried over MgSO4, filtered, and concentrated under reduced pressure.
Purification by flash chromatography on silica gel (petroleum ether/
EtOAc: 30/1) afforded the expected product 4a (1.1924 g) in 62%
yield.
In a dry Schlenk, propargylamide 5a (15.0 mmol) and NIS (1.2
equiv) were dissolved in 40 mL of freshly distilled DCE. The resulting
mixture was stirred at room temperature for 2 h and then stirred at 80
°C under an O2 atmosphere until the consumption of starting
materials detected by TLC. After the reaction was completed, the
solvent was evaporated and the organic product purified by column
chromatography (petroleum ether/EtOAc: 30/1), giving the expected
product 7a (1.6932 g) in 65% yield.
ASSOCIATED CONTENT
■
S
* Supporting Information
Figures, tables, and a CIF file giving data for the NIS-mediated
1
cyclization of N-sulfonyl propargylamides, H and 13C NMR
spectra of all compounds, and crystallographic data for 2a. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail for B.W.: bswan@dicp.ac.cn.
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Zhu, H.-T.; Qiu, Y.-F.; Liu, X.-Y.; Liang, Y.-M. Org. Biomol. Chem.
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78, 4895. (b) Hu, Y. C.; Yi, R. X.; Wu, F.; Wan, B. S. J. Org. Chem.
2013, 78, 7714.
(9) For the molecular structure of 2a, please see the Supporting
Information.
(10) Li, S.; Li, Z. K.; Yuan, Y. F.; Li, Y. J.; Zhang, L. S.; Wu, Y. M.
Chem. Eur. J. 2013, 19, 1496.
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