Modular Preparation of 5-Halomethyl-2-oxazolines via PhI(OAc)2-Promoted Intramolecular Halooxygenation of N-Allylcarboxamides

Article abstract of DOI:10.1021/acs.joc.5b01832

A new method for the construction of oxazoline moiety was detailed. Using (diacetoxyiodo)benzene (PIDA) as the reaction promoter and halotrimethylsilane as the halogen source, intramolecular halooxygenation and halothionation of N-allylcarboxamides/N-ally

Full text of DOI:10.1021/acs.joc.5b01832

Article
pubs.acs.org/joc
Modular Preparation of 5‑Halomethyl-2-oxazolines via
PhI(OAc)2‑Promoted Intramolecular Halooxygenation of
N‑Allylcarboxamides
Gong-Qing Liu,† Chun-Hua Yang,† and Yue-Ming Li*,†,‡
†State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research,
Nankai University, Tianjin 300071, People’s Republic of China
‡CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, People’s Republic of China
S
* Supporting Information
ABSTRACT: A new method for the construction of oxazoline moiety was detailed. Using (diacetoxyiodo)benzene (PIDA) as
the reaction promoter and halotrimethylsilane as the halogen source, intramolecular halooxygenation and halothionation of N-
allylcarboxamides/N-allylcarbothioamides proceeded readily, leading to the corresponding 5-halomethyloxazolines/5-
halomethylthiazolines in good to excellent isolated yields. The 5-halomethyl products could be converted to different
derivatives via conventional nucleophilic substitution methods. The reactions were carried out using easily available starting
materials, and did not need harsh reaction conditions. All these features made this reaction a viable method for the construction
of different oxazoline and thiazoline structures.
catalyzed hydroamination of propargylic tosylcarbamates
produced the corresponding oxazolones in good yields. The
latter compounds could be further functionalized via β-selective
Heck reactions, leading to a variety of biologically interesting
structures in good yields.20
It is our purpose to prepare structure-diversified oxazoline
products. In this paper, we wish to report a modular access to
2-oxazolines as a continuation of our program on the
cyclization of unactivated olefins.21
INTRODUCTION
■
2-Oxazoline (4,5-dihydrooxazole) structures1 are important
subunits in natural products2 or biologically active compounds
(Figure 1),3 and can be used as key skeletons in many
pharmaceuticals with antitumor,4 anticancer,5 antidepressive,6
antibacterial3a or cytotoxic activities.2b In addition, these
functional groups have also been widely used as key structures,7
protective groups,8 chiral ligands or chiral auxiliaries9 in organic
synthesis and asymmetric synthesis. To this end, different
methods have been developed for the construction of 2-
oxazoline structures from carboxylic acids,10 carboxylic esters,11
nitriles,12 aldehydes,13 olefins14 and β-hydroxyamides.15
RESULTS AND DISCUSSION
■
Recently, we have shown that (diacetoxyiodo)benzene (PIDA)
can be used to promote haloheterocyclization of different
unfunctionalized olefins (Scheme 1, eq 1).21 In the presence of
1.1 equiv of PIDA and suitable halogen sources, intramolecular
haloamidation (iodo-, bromo-, chloro-, and fluoroamidation),
haloetherification and halolactonization reactions could all be
realized, giving the corresponding halocyclization products in
good to excellent isolated yields. However, the workup process
was sometimes troublesome due to the use of excess amount of
halogen sources. Further, the scope of reaction was limited to
In addition, electrophile-mediated cyclization of allylbenza-
mide or allylbenzothioamide also produced oxazoline or
thiazoline derivatives in excellent yields. For example, using t-
butyl hypoiodite as the promoter, cyclization of N-alkeneyla-
mides produced a variety of N-heterocycles under very mild
conditions.16 The cyclization could also be realized with
chloramine-T/I2 system.17 Using BINAP compounds as
catalysts, enantioselective bromocyclization of allylic amides
was realized using NBS as the bromine source, and the
products were obtained in up to 99% ee.18 In the presence of
NBS, electrophilic cyclization of N-(buta-2,3-dienyl)amides was
also possible, and the corresponding oxazoline products were
obtained in good isolated yields.19 Finally, palladium(II)-
Received: August 7, 2015
© XXXX American Chemical Society
A
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Figure 1. Examples of bioactive 2-oxazoline-containing compounds.
atom of the carboxamide functional group might be increased
after the formation of an N-TMS intermediate.23
Scheme 1. PIDA-Promoted Intramolecular
Haloheterocyclization Reactions
The model reaction was carried out in dry dichloromethane
with 1.1 equiv of PIDA as the reaction promoter and 1.1 equiv
of TMSI as the iodine source. To our delight, the desired 5-
iodomethyl-2-phenyloxazoline 2a was isolated in 88% yield
after 24 h (Scheme 2, eq 1). The reaction did not take place in
the absence of PIDA (Scheme 2, eq 2).
Scheme 2. Proposed Intramolecular Halooxygenation of N-
Allylbenzamide
N-alkyl and N-sulfonamide substrates, and N-carboxamide
substrates failed to give desired products (Scheme 1, eq 2).
We reasoned that this might be due to the low reactivity of
the N-carboxamide nitrogen atom, and direct reaction should
be possible if the reactivity of the nitrogen atom could be
increased. Halotrimethylsilanes have been successfully used as
both reaction promoters and halogen sources in organic
reactions such as Prins reactions.22 Enlightened by these
literature results, an intramolecular iodooxygenation reaction
was proposed using N-allyl carboxamide 1a as the model
substrate and TMSI as halogen source. Compound 1a was
chosen based on the assumption that successful intramolecular
oxygenation of the substrate would lead to the formation of
oxazoline structures that could be used as important structures
in both organic chemistry and medicinal chemistry. TMSI was
used based on the assumption that the reactivity of the oxygen
Other carboxamide substrates 1b−1ae were then subjected
to the same reaction to test the scope of the reaction, and the
results were summerized in Scheme 3. As these results showed,
5-iodomethyl-2-aryloxazolines could be obtained in good to
excellent isolated yields. Electronic effects of the substituents on
the aryl groups showed less effect on the reactions, and
B
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a
Scheme 3. Synthesis of 5-Iodomethyl-2-oxazolines
a
Reaction conditions: substrate (0.5 mmol), PIDA (0.55 mmol), TMSI (0.55 mmol), CH2Cl2 (2 mL), rt, 24 h; 1.1 mmol of PIDA and 1.1 mmol of
TMSI were used for the preparation of 2q.
substrates with either electron-donating or electron-with-
drawing groups on aromatic rings could all be cyclized in
good isolated yields (2a−2o). Different substituents including
Me, MeO, tBu, −X, −CHO and −CN could be tolerated
during the reactions, and the corresponding 5-iodomethyl-2-
aryloxazolines could be obtained in 85−93% isolated yields
(2b−2o). Substrate 1p bearing 2-naphthyl group worked well
in the current reaction system, and the corresponding 2-(2′-
naphthyl)oxazoline 2p was obtained in high yield. Furthermore,
the current protocol was also applicable to the synthesis of
bis(oxazoline) compound 2q. Oxazoline structures bearing
heterocycles have been used as important functional groups in
antibiotic, antidiabetic and antihypertensive agents.3c,24 To this
end, structurally diversified heterocyclic oxazoline compounds
were also prepared using the same method. As shown in
Scheme 3, heterocyclic oxazoline compounds 2r−2aa could be
obtained in good isolated yields. Ferrocene and anthraquinone
ring could be tolerated during the reaction (2r and 2s). N-
Allylcarboxamides bearing nitrogen-containing heteroaryl
groups such as pyridinecarboxamides (1t−1v), 2-qinolinecar-
boxamide (1w), 2-indolecarboxamide (1x) and 2-pyrrolecar-
boxamide (1y) could all be cyclized under the optimal
conditions, giving products 2t−2y in satisfactory isolated
yields. Similarly, the furan- and thiophene-containing oxazoline
products 2z and 2aa could also be obtained in 90% and 81%
isolated yields, respectively. Substituents on CC double
bonds showed some impact on the reactions, but the products
could still be isolated in acceptable yields. Preparation of 5,6-
dihydro-4H-1,3-oxazine 2ae was also possible using N-
homoallylbenzamide as the starting material. No product was
obtained when N-allyl p-nitrobenzamide was subjected to the
C
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reaction possibly due to the low reactivity of the substrate
caused by the nitro group.
substrates with bulky adamantyl or t-butyl groups could also be
cyclized in satisfactory isolated yields (4e and 4f). Increasing
the length of the mainchain of the carboxamide also showed
less impact on the reactions (4h−4k), and reaction of palmitic
acid derivative 3k gave cyclization product 4k in 80% isolated
yield. Different phenylacetamide substrates also produced the
desired cyclization products 4l−4m in acceptable isolated
yields. Chiral substrate 3n gave acceptable isolated yields but
low diastereoselectivity. Finally, diallylmalonamide 3o produced
the corresponding bis(oxazoline) product 4o in good isolated
yield.
Further, cyclization of N-allyl amides of aliphatic carboxylic
acids were also tested. As Scheme 4 showed, intramolecular
cyclization of aliphatic N-allylcarboxamides 3a−3o proceeded
readily, giving the corresponding 5-iodomethyl-2-oxazoline
products 4a−4o in good isolated yields. Steric effects of the
amides showed less impact on the reactions (4a−4g), and
a
Scheme 4. Cyclization of Aliphatic N-Allylcarboxamides
To test the scalability of the current protocol, cyclization of
N-allylbenzamide 1b was carried out on gram scale, and the
product 2b was obtained in 86% yield after recrystallization
(Scheme 5). The structure of 2b was further confirmed by X-
ray diffraction experiment.25
To test the synthetic utility of current reaction, functional
group transformations of 2b were also pursued, and the C−I
bond in 2b provided an easy access to a variety of useful
functional groups (Scheme 6). For example, iodine atom in 2b
could be replaced by different nucleophiles such as azide (5a)
and acetate (5b) under mild conditions. Radical deiodination
could be realized via tributylstannane reduction. When
oxazoline 2b was treated with AIBN/nBu3SnH at 100 °C for
8 h, compound 5c could be obtained in almost quantitative
isolated yield. Furthermore, the oxazoline moiety in 2b could
also be easily hydrolyzed upon treatment with CF3CO2H in
THF at room temperature, leading to vicinal amino alcohol 5d
in satisfactory yield.
To get mechanistic insights into the reaction, NMR
experiments were also carried out to study the possible
interaction between the substrates and TMSI (Table 1). N-
Propyl p-methoxybenzamide (1′) was used to get a clean NMR
spectrum. When 1′ was allowed to mix with TMSI, significant
downfield shift was observed for the amide proton. Different
extents of downfield shifts were also observed for protons
adjacent to the amide functional group. This result indicated
that there existed a strong interaction between amide and
TMSI. As the largest downfield shift was observed for amide
NH and adjacent protons, it was reasonable to believe that the
interaction between TMSI and amide happened on the
nitrogen atom (Figure 2).23
a
Reaction conditions: substrate (0.5 mmol), PIDA (0.55 mmol),
TMSI (0.55 mmol), CH2Cl2 (2 mL), rt, 24 h; 1.1 mmol of PIDA and
1.1 mmol of TMSI were used for the preparation of 4o.
Scheme 5. Gram-Scale Synthesis of Oxazoline 2b
On the basis of the NMR study and previous literature
reports, a preliminary reaction pathway was proposed as shown
in Scheme 7. Interaction of the substrate with TMSI produced
Scheme 6. Derivatization of Oxazoline 2b
D
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silylated intermediate A23 which could be further tautomerized
to intermediate B. In the meanwhile, the CC double bond in
substrate was activated by PhI(OAc)2,26 and intramolecular
nucleophilic attack of oxygen atom on the iodinium three-
membered ring produced the intermediate D, which finally
gave halooxygenation product after workup.
Table 1. Chemical Shift Changes for N-Propyl 4-
Methoxybenzamide upon Addition of TMSI
a
After the synthesis of 5-iodomethyl-2-oxazolines, the
syntheses of 5-bromo- and 5-chloromethyl-2-oxazolines were
also studied using the same method. As shown in Scheme 8,
different 5-bromo- and 5-chloromethyl-2-oxazolines could be
obtained in good isolated yield using TMSBr or TMSCl as the
respective bromine or chlorine source.
In addition to 2-oxazolines, the sulfur analogues, the 2-
thiazolines, are also important substructures in bioactive
compounds.27 To this end, the current method was also
extended to the cyclization of carbothioamide substrate. When
N-allylbenzothioxamide was allowed to react under optimized
reaction conditions, 5-iodo- and 5-bromomethyl-2-thiazolines
were also obtained in good isolated yields (Scheme 9).
chemical shift
(ppm)
Ha
Hb
Hc
Hd
He
Hf
Hg
substrate
3.82
3.84
6.87
6.93
7.73
8.09
6.35
9.53
3.37
3.56
1.59
1.77
0.93
0.95
substrate +
TMSI
a
The experiments were carried out in CDCl3.
Figure 2. Interaction between TMSI and 1′.
Scheme 9. Synthesis of 5-Iodo- and 5-Bromomethyl-2-
thiazolines
Scheme 7. Plausible Mechanism for Intramolecular
Halooxygenation Reaction
a
Scheme 8. Synthesis of 5-Bromo- and 5-Chloromethyl-2-oxazolines
a
Reaction conditions: substrate (0.5 mmol), PIDA (0.55 mmol), TMSBr/TMSCl (0.55 mmol), CH2Cl2 (2 mL), rt, 24 h.
E
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2-(4-tert-Butylphenyl)-5-(iodomethyl)-4,5-dihydrooxazole (2c,
New Compound). Compound 2c was obtained as a white solid in
93% yield (159 mg) after flash chromatography (Silica gel, petroleum
CONCLUSION
■
In summary, we have reported a practical method for modular
preparation of 5-halomethyloxazolines and 5-halomethylthiazo-
lines. Using 1.1 equiv of (diacetoxyiodo)benzene as the
reaction promoter and 1.1 equiv of TMSX (X = I, Br, and
Cl) as the halogen sources, 5-halomethyl-2-oxazoline/thiazoline
products could be obtained in good to excellent isolated yields.
The method has several features: (1) the easy availability of the
starting materials and environmentally benign procedure; (2)
the very mild reaction conditions without special precautions;
and (3) the wide scope of the substrates and good isolated
yields. We envisage that the current method will have
widespread application in organic and medicinal chemistry.
1
ether:ethyl acetate = 3:1). mp = 71−73 °C; H NMR (400 MHz,
CDCl3) δ = 7.79−7.77 (m, 2H), 7.36−7.34 (m, 2H), 4.74−4.67 (m,
1H), 4.08 (dd, J = 15.1, 9.5 Hz, 1H), 3.71 (dd, J = 15.1, 6.5 Hz, 1H),
3.36−3.09 (m, 2H), 1.24 (s, 9H). 13C NMR (100 MHz, CDCl3) δ =
163.6, 155.1 128.1, 125.4, 124.5, 78.2, 60.6, 35.0, 31.2, 7.9. IR 3049,
2945, 2861, 1719, 1648, 1573, 1460, 1263, 1073, 910, 812, 619 cm−1.
HRMS−ESI (m/z) [M + H]+ calcd for C14H18INO, 344.0511, found
344.0511.
4-(5-(Iodomethyl)-4,5-dihydrooxazol-2-yl)benzonitrile (2d, New
Compound). Compound 2d was obtained as a white solid in 93%
yield (144 mg) after flash chromatography (Silica gel, petroleum
1
ether:ethyl acetate = 3:1). mp = 97−98 °C; H NMR (400 MHz,
CDCl3) δ = 8.05−8.02(m, 2H), 7.73−7.71 (m, 2H), 4.85−4.83 (m,
1H), 4.22 (dd, J = 9.6, 3.8 Hz, 1H), 3.98−3.84 (m, 1H), 3.44−3.35
(m, 2H). 13C NMR (100 MHz, CDCl3) δ = 162.0, 132.2, 131.6, 128.8,
118.2, 114.9, 78.7, 61.0, 7.5. IR 3097, 2947, 2868, 2227, 1691, 1614,
1566, 1453, 1292, 1063, 965, 902, 619, 446 cm−1. HRMS−ESI (m/z)
[M + H]+ calcd for C11H9IN2O, 312.9838, found 312.9827.
EXPERIMENTAL SECTION
■
General Experimental Information. Reagents were used as
received without further purification unless otherwise indicated.
Solvents were dried and distilled prior to use. Reactions were
monitored with thin layer chromatography using silica gel GF254 plates.
Organic solutions were concentrated in vacuo with a rotavapor. Flash
column chromatography was performed using silica gel (200−300
meshes). Petroleum ether used had a boiling point range of 60−90 °C.
Melting points were measured on a digital melting point apparatus
without correction of the thermometer. Nuclear magnetic resonance
spectra were recorded at ambient temperature (unless otherwise
stated) at 400 MHz (100 MHz for 13C) in CDCl3. Chemical shifts
were reported in ppm (δ) using TMS as internal standard, and spin−
spin coupling constants (J) were given in Hz. Infrared (IR) spectra
were recorded with KBr pellet, and wavenumbers were given in cm−1.
High resolution mass spectrometry (HRMS) analyses were carried out
on an FTICR HR-ESI-MS. Substrates used were prepared by coupling
of carboxylic acids and allylamine described by Borhan et al.28
4-(5-(Iodomethyl)-4,5-dihydrooxazol-2-yl)benzaldehyde (2e,
New Compound). Compound 2e was obtained as a white solid in
87% yield (136 mg) after flash chromatography (Silica gel, petroleum
1
ether:ethyl acetate = 2:1). mp = 62−63 °C; H NMR (400 MHz,
CDCl3) δ = 10.00 (s, 1H), 8.04−8.02 (m, 2H), 7.87−7.85 (m, 2H),
4.86−4.67 (m, 1H), 4.18−4.12 (m, 1H), 3.80−3.75 (m, 1H), 3.36−
3.20 (m, 2H). 13C NMR (100 MHz, CDCl3) δ = 191.7, 162.6, 138.1,
132.7, 129.6, 128.8, 78.5, 61.0, 7.6. IR 3047, 2930, 2851, 2734, 1934,
1696, 1647, 1572, 1506, 1449, 1262, 1065, 966, 901, 839, 615, 480
cm−1. HRMS−ESI (m/z) [M + H]+ calcd for C11H10INO2, 315.9834,
found 315.9832.
2-(2-Fluorophenyl)-5-(iodomethyl)-4,5-dihydrooxazole (2f, New
Compound). Compound 2f was obtained as an oil in 84% yield (128
mg) after flash chromatography (Silica gel, petroleum ether:ethyl
1
acetate = 4:1). H NMR (400 MHz, CDCl3) δ = 7.78 (m, 1H), 7.36
General Procedure for Synthesis of 5-Halomethyl-2-oxazo-
lines. In a 10 mL sealed tube were added N-allylcarboxamides (0.5
mmol), PhI(OAc)2 (0.55 mmol), and TMSX (0.55 mmol) in dry
CH2Cl2 (2 mL). The reaction mixture was stirred at room temperature
for 24 h. CH2Cl2 (10 mL) was then added, and the mixture was
washed with aqueous Na2S2O3. The combined organic layer was dried
(MgSO4) and concentrated to give crude residue, which was purified
by flash column chromatography to give the corresponding products.
5-(Iodomethyl)-2-phenyl-4,5-dihydrooxazole (2a, Known Com-
pound, CAS: 200573-05-3). Compound 2a was obtained as an oil in
88% yield (126 mg) after flash chromatography (Silica gel, petroleum
ether:ethyl acetate = 5:1). 1H NMR (400 MHz, CDCl3) δ = 7.86−7.84
(m, 2H), 7.41−7.37 (m, 1H), 7.34−7.30 (m, 2H), 4.73−4.66 (m, 1H),
4.05 (dd, J = 15.2, 9.6 Hz, 1H), 3.70 (dd, J = 15.2, 6.6 Hz, 1H), 3.27
(dd, J = 10.3, 4.9 Hz, 1H), 3.21 (dd, J = 10.3, 7.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ = 163.5, 131.6, 128.4, 128.2, 127.4, 78.3, 60.7,
7.9. Spectral data are in good agreement with literature values.16,17
5-(Iodomethyl)-2-(4-methoxyphenyl)-4,5-dihydrooxazole (2b,
New Compound). Compound 2b was obtained as a white solid in
93% yield (147 mg) after flash chromatography (Silica gel, petroleum
(m, 1H), 7.17−6.82 (m, 2H), 4.72−4.65 (m, 1H), 4.13 (dd, J = 15.2,
9.9 Hz, 1H), 3.76 (dd, J = 15.2, 6.3 Hz, 1H), 3.30−3.22(m, 2H). 13C
NMR (100 MHz, CDCl3) δ = 162.5, 159.9 (d, J = 11.7 Hz), 133.1 (d,
J = 8.8 Hz), 131.0, 124.0 (d, J = 3.7 Hz), 116.7 (d, J = 21.8 Hz), 115.7
(d, J = 10.3 Hz), 77.7, 61.1, 7.8. 19F NMR (376 MHz, CDCl3) δ =
−109.2. IR 3040, 2934, 2964, 1726, 1655, 1620, 1597, 1496, 1177,
905, 816, 669 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for
C10H9FINO, 305.9791, found 305.9784.
2-(2-Bromophenyl)-5-(iodomethyl)-4,5-dihydrooxazole (2g, New
Compound). Compound 2g was obtained as an oil in 86% yield (157
mg) after flash chromatography (Silica gel, petroleum ether:ethyl
1
acetate = 3:1). H NMR (400 MHz, CDCl3) δ = 7.64 (d, J = 7.6 Hz,
1H), 7.56 (d, J = 7.6 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.5
Hz, 1H), 4.81−4.67 (m, 1H), 4.13 (dd, J = 15.2, 9.6 Hz, 1H), 3.78
(dd, J = 15.2, 6.5 Hz, 1H), 3.37−3.20 (m, 2H). 13C NMR (100 MHz,
CDCl3) δ = 162.7, 134.0, 131.9, 131.5, 129.2, 127.2, 121.9, 78.5, 61.0,
7.7. IR 3060, 2937, 2867, 1733, 1659, 1590, 1427, 1086, 958, 733
cm−1. HRMS−ESI (m/z) [M + H]+ calcd for C10H9BrINO, 365.8990,
found 365.8980.
1
ether:ethyl acetate = 3:1). mp = 104−106 °C; H NMR (400 MHz,
5-(Iodomethyl)-2-(2-iodophenyl)-4,5-dihydrooxazole (2h, New
Compound). Compound 2h was obtained as an oil in 92% yield
(189 mg) after flash chromatography (Silica gel, petroleum ether:ethyl
CDCl3) δ = 7.80−7.78 (m, 2H), 6.84−6.80 (m, 2H), 4.70−4.68 (m,
1H), 4.06 (dd, J = 14.9, 9.6 Hz, 1H), 3.75 (s, 3H), 3.68 (dd, J = 14.9,
6.3 Hz, 1H), 3.26−3.20 (m, 2H). 13C NMR (100 MHz, CDCl3) δ =
163.3, 162.2, 129.9, 119.9, 113.8, 78.2, 60.7, 55.4, 8.0. IR 3007, 2960,
2928, 1711, 1648, 1607, 1508, 1458, 1071, 966, 738 cm−1. HRMS−ESI
(m/z) [M + H]+ calcd for C11H12INO2, 317.9991, found 317.9984.
Crystal Data for 2b. C11H12INO2, M = 317.12, orthorhombic, a =
15.334(3) Å, b = 6.3606(13) Å, c = 23.307(5) Å, α = 90.00°, β =
90.00°, γ = 90.00°, V = 2273.2(8) Å3, T = 113(2) K, space group Pbca,
Z = 8, μ(Mo Kα) = 2.797 mm−1, 16784 reflections measured, 2721
independent reflections (Rint = 0.0599). The final R1 values were
0.0382 (I > 2σ(I)). The final wR(F2) values were 0.0857 (I > 2σ(I)).
The final R1 values were 0.0474 (all data). The final wR(F2) values
were 0.0911 (all data). The goodness of fit on F2 was 1.101.
1
acetate = 3:1). H NMR (400 MHz, CDCl3) δ = 7.95 (d, J = 7.7 Hz,
1H), 7.66 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 7.6
Hz, 1H), 4.87−4.83 (m, 1H), 4.23 (dd, J = 15.2, 9.6 Hz, 1H), 3.87
(dd, J = 15.2, 6.6 Hz, 1H), 3.43 (dd, J = 10.2, 4.9 Hz, 1H), 3.41−3.35
(m, 1H). 13C NMR (100 MHz, CDCl3) δ = 163.7, 140.6, 133.0, 131.9,
130.9, 127.9, 94.7, 78.7, 61.0, 7.8. IR 3055, 2937, 2865, 1730, 1660,
1584, 1467, 1328, 1083, 959, 764 cm−1. HRMS−ESI (m/z) [M + H]+
calcd for C10H9I2NO, 413.8852, found 413.8839.
2-(2-Chlorophenyl)-5-(iodomethyl)-4,5-dihydrooxazole (2i, New
Compound). Compound 2i was obtained as an oil in 91% yield (146
mg) after flash chromatography (Silica gel, petroleum ether:ethyl
1
acetate = 3:1). H NMR (400 MHz, CDCl3) δ = 7.70 (d, J = 7.9 Hz,
F
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1H), 7.37 (d, J = 7.9 Hz, 1H), 7.29−7.27 (m, 1H), 7.22 (t, J = 7.2 Hz,
1H), 4.79−4.64 (m, 1H), 4.14 (dd, J = 15.2, 9.8 Hz, 1H), 3.79 (dd, J =
15.2, 6.2 Hz, 1H), 3.36−3.22 (m, 2H). 13C NMR (100 MHz, CDCl3)
δ = 161.9, 133.5, 131.8, 131.4 130.8, 127.0, 126.6, 78.2, 61.1, 7.8. IR
3048, 2945, 2861, 1719, 1648, 1537, 1511, 1334, 1019, 910, 812, 677
cm−1. HRMS−ESI (m/z) [M + H]+ calcd for C10H9ClINO, 321.9496,
found 321.9495.
2-(3-Chlorophenyl)-5-(iodomethyl)-4,5-dihydrooxazole (2j, New
Compound). Compound 2j was obtained as an oil in 88% yield (141
mg) after flash chromatography (Silica gel, petroleum ether:ethyl
acetate = 3:1). 1H NMR (400 MHz, CDCl3) δ = 7.84−7.83 (m, 1H),
7.74 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.27 (t, J = 7.8 Hz,
1H), 4.83−4.63 (m, 1H), 4.10 (dd, J = 15.2, 9.6 Hz, 1H), 3.72 (dd, J =
15.2, 6.7 Hz, 1H), 3.38−3.22 (m, 2H). 13C NMR (100 MHz, CDCl3)
δ = 162.4, 134.4, 131.6, 129.8, 129.2, 128.3, 126.3, 78.5 60.8, 7.7. IR
3063, 2941, 2867, 1731, 1656, 1595, 1477, 1435, 1095, 1037, 961, 766,
677 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for C10H9ClINO,
321.9496, found 321.9492.
2-(4-Chlorophenyl)-5-(iodomethyl)-4,5-dihydrooxazole (2k, New
Compound). Compound 2k was obtained as an oil in 91% yield (146
mg) after flash chromatography (Silica gel, petroleum ether:ethyl
acetate = 2:1). 1H NMR (400 MHz, CDCl3) δ = 7.79−7.77 (m, 2H),
7.32−7.30 (m, 2H), 4.74−4.71 (m, 1H), 4.09 (dd, J = 14.7, 10.3 Hz,
1H), 3.71 (dd, J = 14.7, 5.9 Hz, 1H), 3.36−3.12 (m, 2H). 13C NMR
(100 MHz, CDCl3) δ = 162.7, 137.8, 129.6, 128.7, 125.9, 78.5, 60.7,
7.7. IR 3064, 2932, 2866, 1726, 1652, 1602, 1488, 1263, 1176, 756,
622 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for C10H9ClINO,
321.9496, found 321.9487.
5-(Iodomethyl)-2-(naphthalen-2-yl)-4,5-dihydrooxazole (2p,
New Compound). Compound 2p was obtained as a white solid in
86% yield (145 mg) after flash chromatography (Silica gel, petroleum
1
ether:ethyl acetate = 4:1). mp = 100−101 °C; H NMR (400 MHz,
CDCl3) δ = 8.32 (s, 1H), 7.91 (dd, J = 8.2, 1.4 Hz, 1H), 7.84−7.77
(m, 1H), 7.73 (t, J = 8.2 Hz, 2H), 7.49−7.33 (m, 2H), 4.76−4.62 (m,
1H), 4.09 (dd, J = 15.2, 9.5 Hz, 1H), 3.72 (dd, J = 15.2, 6.6 Hz, 1H),
3.29−3.19 (m, 2H). 13C NMR (100 MHz, CDCl3) δ = 163.6, 134.7,
132.6, 128.9, 128.8, 128.2, 127.8, 127.6, 126.6, 124.8, 124.7, 78.4, 60.9,
7.9. IR 3053, 2940, 2863, 1796, 1649, 1509, 1462, 1359, 1127, 1020,
954, 869, 752, 613, 476 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for
C14H12INO, 338.0042, found 338.0037.
2,2′-Bis[5-(iodomethyl)-4,5-dihydrooxazol-2-yl]biphenyl. (2q,
New Compound). Compound 2q was obtained as an oil in 83%
yield (237 mg) after flash chromatography (Silica gel, petroleum
ether:ethyl acetate = 1:1). 1H NMR (400 MHz, CDCl3) δ = 7.80−7.69
(m, 2H), 7.57−7.19 (m, 6H), 4.59−4.42 (m, 2H), 4.00−3.90 (m, 2H),
3.73−3.42 (m, 2H), 3.23−2.81 (m, 4H). 13C NMR (100 MHz,
CDCl3) δ = 164.2, 141.3, 130.6, 130.2, 129.3, 127.3, 78.9, 60.6, 7.0. IR
3057, 2934, 2866, 1722, 1654, 1457, 1330, 1178, 1076, 960, 761, 615,
459 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for C20H18I2N2O2,
572.9536, found 572.9534.
(5-Iodomethyl-4,5-dihydrooxazol-5-yl)ferrocene (2r, New Com-
pound). Compound 2r was obtained as a white solid in 81% yield
(160 mg) after flash chromatography (Silica gel, petroleum ether:ethyl
1
acetate = 2:1). mp = 96−98 °C; H NMR (400 MHz, CDCl3) δ =
4.71−4.67 (m, 2H), 4.66−4.58 (m, 1H), 4.30−4.27 (m, 2H), 4.21−
4.13 (m, 5H), 3.95 (dd, J = 14.7, 9.4 Hz, 1H), 3.60 (dd, J = 14.7, 6.6
Hz, 1H), 3.31 (dd, J = 10.3, 4.8 Hz, 1H), 3.25 (dd, J = 10.3, 6.9 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ = 166.4, 77.8, 70.5, 70.4, 69.7,
69.0, 68.9, 60.5, 7.9. IR 3326, 3099, 2926, 2855, 1652, 1576, 1473,
1263, 1155, 1021, 827, 729, 649, 510 cm−1. HRMS−ESI (m/z) [M +
H]+ calcd for C14H14FeINO, 395.9548, found 395.9544.
5-(Iodomethyl)-2-(o-tolyl)-4,5-dihydrooxazole (2l, New Com-
pound). Compound 2l was obtained as an oil in 90% yield (135
mg) after flash chromatography (Silica gel, petroleum ether:ethyl
1
acetate = 4:1). H NMR (400 MHz, CDCl3) δ = 7.72 (d, J = 7.5 Hz,
1H), 7.25 (t, J = 7.5 Hz, 1H), 7.18−7.07 (m, 2H), 4.67−4.60 (m, 1H),
4.10 (dd, J = 15.2, 9.6 Hz, 1H), 3.74 (dd, J = 15.2, 6.6 Hz, 1H), 3.35−
3.20 (m, 2H), 2.51 (s, 3H). 13C NMR (100 MHz, CDCl3) δ = 163.9,
138.9, 131.3, 130.8, 129.9, 126.8, 125.7, 77.4, 61.1, 22.0, 8.2. IR 3060,
2929, 2866, 1722, 1646, 1574, 1490, 1325, 1041, 901, 773, 730, 676,
612 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for C11H12INO,
302.0042, found 302.0038.
5-(Iodomethyl)-2-(m-tolyl)-4,5-dihydrooxazole (2m, New Com-
pound). Compound 2m was obtained as an oil in 90% yield (135 mg)
after flash chromatography (Silica gel, petroleum ether:ethyl acetate =
4:1). 1H NMR (400 MHz, CDCl3) δ = 7.80−7.43 (m, 2H), 7.28−7.10
(m, 2H), 4.73−4.67 (m, 1H), 4.07 (dd, J = 15.1, 9.5 Hz, 1H), 3.70
(dd, J = 15.1, 6.6 Hz, 1H), 3.29−3.20 (m, 2H), 2.30 (s, 3H). 13C NMR
(100 MHz, CDCl3) δ = 163.7, 138.2, 132.4, 128.8, 128.3, 127.3, 125.3,
78.2, 60.7, 21.4, 7.9. IR 3024, 2930, 2866, 1720, 1652, 1591, 1485,
1330, 1189, 1070, 964, 799, 710, 615, 465 cm−1. HRMS−ESI (m/z)
[M + H]+ calcd for C11H12INO, 302.0042, found 302.0033.
2-(5-(Iodomethyl)-4,5-dihydrooxazol-2-yl)anthracene-9,10-dione
(2s, New Compound). Compound 2s was obtained as a white solid in
73% yield (152 mg) after flash chromatography (Silica gel, petroleum
1
ether:ethyl acetate = 3:1). mp = 107−108 °C; H NMR (400 MHz,
CDCl3) δ = 8.74 (s, 1H), 8.35−8.18 (m, 4H), 7.83−7.68 (m, 2H),
4.91−4.71 (m, 1H), 4.20 (dd, J = 15.6, 9.6 Hz, 1H), 3.82 (dd, J = 15.6,
6.8 Hz, 1H), 3.37 (dd, J = 10.4, 4.6 Hz, 1H), 3.32 (dd, J = 10.4, 7.0 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ = 182.5, 182.3, 162.1, 135.1,
134.4, 134.3, 133.5, 133.4, 133.4, 133.3, 132.7, 127.5, 127.4, 127.3,
127.1, 78.7, 61.1, 7.5. IR 3068, 2956, 2864, 1729, 1671, 1591, 1486,
1293, 1020, 931, 802, 692, 464 cm−1. HRMS−ESI (m/z) [M + H]+
calcd for C18H12INO3, 417.9940, found 417.9927.
5-(Iodomethyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (2t, New
Compound). Compound 2t was obtained as an oil in 85% yield
(122 mg) after flash chromatography (Silica gel, petroleum ether:ethyl
acetate = 1:1). 1H NMR (400 MHz, CDCl3) δ = 8.63−8.62 (m, 1H),
7.96−7.94(m, 1H), 7.72−7.68 (m, 1H), 7.33−7.30 (m, 1H), 4.86−
4.75 (m, 1H), 4.17 (dd, J = 15.6, 9.6 Hz, 1H), 3.79 (dd, J = 15.6, 7.0
Hz, 1H), 3.38 (dd, J = 10.1, 4.1 Hz, 1H), 3.29 (dd, J = 10.1, 7.7 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ = 162.6, 149.7, 146.3, 136.7,
125.9, 123.9, 79.0, 61.0, 7.8. IR 3060, 2926, 2857, 1733, 1647, 1578,
1526, 1463, 1089, 926, 699, 622 cm−1. HRMS−ESI (m/z) [M + H]+
calcd for C9H9IN2O, 288.9838, found 288.9830.
5-(Iodomethyl)-2-(pyridin-3-yl)-4,5-dihydrooxazole (2u, New
Compound). Compound 2u was obtained as an oil in 83% yield
(119 mg) after flash chromatography (Silica gel, petroleum ether:ethyl
acetate = 1:1). 1H NMR (400 MHz, CDCl3) δ = 9.06−9.05 (m, 1H),
8.64−8.63 (m, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.29 (dd, J = 8.0, 4.9 Hz,
1H), 4.83−4.66 (m, 1H), 4.12 (dd, J = 15.4, 9.6 Hz, 1H), 3.74 (dd, J =
15.4, 6.7 Hz, 1H), 3.37−3.19 (m, 2H). 13C NMR (100 MHz, CDCl3)
δ = 161.5, 152.1, 149.3, 136.0, 123.6, 123.3, 78.4, 60.8, 7.7. IR 3045,
2937, 2869, 1729, 1655, 1592, 1478, 1192, 1079, 823, 704 cm−1.
HRMS−ESI (m/z) [M + H]+ calcd for C9H9IN2O, 288.9838, found
288.9843.
5-(Iodomethyl)-2-(p-tolyl)-4,5-dihydrooxazole (2n, New Com-
pound). Compound 2n was obtained as a white solid in 93% yield
(140 mg) after flash chromatography (Silica gel, petroleum ether:ethyl
1
acetate = 4:1). mp = 94−96 °C; H NMR (400 MHz, CDCl3) δ =
7.76−7.74 (m, 2H), 7.15−7.13 (m, 2H), 4.73−4.70 (m, 1H), 4.08 (dd,
J = 15.1, 9.6 Hz, 1H), 3.71 (dd, J = 15.1, 6.4 Hz, 1H), 3.29−3.23 (m,
2H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3) δ = 163.6, 142.0,
129.1, 128.2, 124.7, 78.2, 60.7, 21.6, 7.9. IR 3027, 2957, 2863, 1648,
1570, 1508, 1413, 1258, 1071, 966, 824, 789, 726 cm−1. HRMS−ESI
(m/z) [M + H]+ calcd for C11H12INO, 302.0042, found 302.0039.
2-(3,5-Dimethylphenyl)-5-(iodomethyl)-4,5-dihydrooxazole (2o,
New Compound). Compound 2o was obtained as an oil in 85%
yield (134 mg) after flash chromatography (Silica gel, petroleum
1
ether:ethyl acetate = 4:1). H NMR (400 MHz, CDCl3) δ = 7.47 (s,
2H), 7.02 (s, 1H), 4.71−4.64 (m, 1H), 4.05 (dd, J = 15.1, 9.6 Hz, 1H),
3.68 (dd, J = 15.1, 6.5 Hz, 1H), 3.27 (dd, J = 9.6, 4.5 Hz, 1H), 3.24−
3.16 (m, 1H), 2.25 (s, 6H). 13C NMR (100 MHz, CDCl3) δ = 163.9,
138.0, 133.3, 127.2, 126.0, 78.2, 60.7, 21.2, 7.9. IR 3007, 2924, 2864,
1770, 1651, 1602, 1531, 1453, 1209, 1097, 808, 679 cm−1. HRMS−ESI
(m/z) [M + H]+ calcd for C12H14INO, 316.0198, found 316.0195.
5-(Iodomethyl)-2-(pyridin-4-yl)-4,5-dihydrooxazole (2v, New
Compound). Compound 2v was obtained as a white solid in 88%
yield (126 mg) after flash chromatography (Silica gel, petroleum
G
DOI: 10.1021/acs.joc.5b01832
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
ether:ethyl acetate = 1:1). mp = 103−104 °C; H NMR (400 MHz,
CDCl3) δ = 8.63−8.62 (m, 2H), 7.68−7.67 (m, 2H), 4.77−4.70 (m,
1H), 4.14−4.11 (m, 1H), 3.73 (dd, J = 15.6, 6.8 Hz, 1H), 3.35−3.17
(m, 2H). 13C NMR (100 MHz, CDCl3) δ = 161.7, 150.3, 134.7, 121.8,
78.5, 60.9, 7.7. IR 3033, 2933, 1710, 1652, 1598, 1497, 1452, 1082,
872, 690, 618 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for
C9H9IN2O, 288.9838, found 288.9829.
128.3, 127.9, 83.9, 65.7, 25.5, 14.2. IR 3060, 2972, 2929, 2864, 1649,
1579, 1449, 1348, 693 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for
C11H12INO, 302.0042, found 302.0041.
5-(Iodo(phenyl)methyl)-2-phenyl-4,5-dihydrooxazole (2ac, New
Compound). Compound 2ac was obtained as a white solid in 72%
yield (130 mg) after flash chromatography (Silica gel, petroleum
1
ether:ethyl acetate = 10:1). mp = 114−116 °C. H NMR (400 MHz,
CDCl3) δ = 7.83 (d, J = 7.6 Hz, 2H), 7.40−7.20 (m, 8H), 5.25 (d, J =
9.2 Hz, 1H), 4.27 (dd, J = 14.6, 8.9 Hz, 1H), 4.10−3.90 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ = 155.6, 138.3, 132.9, 131.0, 129.2, 128.7,
128.2, 127.3, 127.2, 82.0, 53.2, 24.7. IR 3032, 2904, 1657, 1338, 1256,
696 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for C16H14INO,
364.0198, found 364.0191.
5-(2-Iodopropan-2-yl)-2-phenyl-4,5-dihydrooxazole (2ad, New
Compound). Compound 2ad was obtained as an oil in 76% yield
(130 mg) after flash chromatography (Silica gel, petroleum ether:ethyl
acetate = 10:1). 1H NMR (400 MHz, CDCl3) δ = 7.80 (d, J = 7.4 Hz,
2H), 7.40−7.20 (m, 3H), 4.20 (dd, J = 8.5, 7.4 Hz, 1H), 3.95−3.90
(m, 2H), 1.50 (s, 3H), 1.45 (s, 3H). 13C NMR (100 MHz, CDCl3) δ =
155.2, 133.5, 130.7, 128.1, 127.1, 77.3, 52.3, 30.8, 28.9, 23.1. IR 2980,
1654, 1451, 1247, 1070, 696 cm−1. HRMS−ESI (m/z) [M + H]+ calcd
for C12H14INO, 316.0198, found 316.0197.
6-(Iodomethyl)-2-phenyl-5,6-dihydro-4H-1,3-oxazine (2ae,
Known Compound). Compound 2ae was obtained as an oil in 86%
yield (130 mg) after flash chromatography (Silica gel, petroleum
ether:ethyl acetate = 5:1). 1H NMR (400 MHz, CDCl3) δ = 7.93−7.92
(m, 2H), 7.39−7.26 (m, 3H), 4.30−4.17 (m, 1H), 3.71−3.55 (m, 2H),
3.38−3.25 (m, 2H), 2.13−2.11 (m, 1H), 1.83−1.67 (m, 1H). 13C
NMR (100 MHz, CDCl3) δ = 155.5, 133.4, 130.7, 128.2, 127.2, 73.8,
42.8, 27.4, 7.6. Spectral data are in good agreement with literature
values.16
5-(Iodomethyl)-2-(quinolin-2-yl)-4,5-dihydrooxazole (2w, New
Compound). Compound 2w was obtained as a white solid in 85%
yield (143 mg) after flash chromatography (Silica gel, petroleum
1
ether:ethyl acetate = 2:1). mp = 135−136 °C; H NMR (400 MHz,
CDCl3) δ = 8.18 (d, J = 8.6 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 8.05−
8.03 (m, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.67−7.65 (m, 1H), 7.49 (t, J =
7.5 Hz, 1H), 4.94−4.81 (m, 1H), 4.22 (dd, J = 15.2, 9.6 Hz, 1H),
3.90−3.75 (m, 1H), 3.43 (dd, J = 10.1, 3.9 Hz, 1H), 3.30 (dd, J = 10.1,
8.1 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ = 163.0, 147.6, 146.5,
136.8, 130.3, 130.1, 128.7, 128.0, 127.5, 120.6, 79.11, 61.1, 7.7. IR
3064, 2953, 2909, 1722, 1645, 1598, 1369, 1077, 966, 842, 763, 628,
595, 446 m−1. HRMS−ESI (m/z) [M + H]+ calcd for C13H11IN2O,
338.9994, found 338.9990.
2-(1H-Indol-3-yl)-5-(iodomethyl)-4,5-dihydrooxazole (2x, New
Compound). Compound 2x was obtained as an oil in 68% yield
(111 mg) after flash chromatography (Silica gel, petroleum ether:ethyl
1
acetate = 1:1). H NMR (400 MHz, CDCl3) δ = 9.60 (s, 1H), 8.20−
8.18 (m, 1H), 7.73 (s, 1H), 7.37−7.35 (m, 1H), 7.25−7.21 (m, 2H),
4.86−4.70 (m, 1H), 4.18 (dd, J = 14.5, 9.6 Hz, 1H), 3.81 (dd, J = 14.5,
6.4 Hz, 1H), 3.42−3.28 (m, 2H). 13C NMR (100 MHz, CDCl3) δ =
161.6, 136.2, 128.6, 125.4, 123.1, 121.6, 121.3, 111.7, 104.5, 77.5, 59.9,
7.9. IR 3061, 2933, 2868, 1644, 1533, 1443, 1373, 1162, 1080, 964,
881, 750, 638, 454 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for
C12H11IN2O, 326.9994, found 326.9988.
2-Cyclopropyl-5-(iodomethyl)-4,5-dihydrooxazole (4a, New
Compound). Compound 4a was obtained as an oil in 80% yield
(100 mg) after flash chromatography (Silica gel, petroleum ether:ethyl
acetate = 3:1). 1H NMR (400 MHz, CDCl3) δ = 4.52−4.45 (m, 1H),
3.85 (dd, J = 14.4, 9.5 Hz, 1H), 3.46 (dd, J = 14.4, 6.4 Hz, 1H), 3.21−
3.11 (m, 2H), 1.59−1.54 (m, 1H), 0.94−0.86 (m, 2H), 0.79 (m, 2H).
13C NMR (100 MHz, CDCl3) δ = 168.4, 77.6, 60.1, 8.7, 8.1, 6.9, 6.8.
IR 3115, 3008, 2930, 2853, 1726, 1625, 1260, 1085, 947, 742, 667
cm−1. HRMS−ESI (m/z) [M + H]+ calcd for C7H10INO, 251.9885,
found 251.9876.
2-Cyclobutyl-5-(iodomethyl)-4,5-dihydrooxazole (4b, New Com-
pound). Compound 4b was obtained as an oil in 77% yield (102 mg)
after flash chromatography (Silica gel, petroleum ether:ethyl acetate =
3:1). 1H NMR (400 MHz, CDCl3) δ= 4.61−4.55 (m, 1H), 3.95 (dd, J
= 14.5, 9.8 Hz, 1H), 3.58 (dd, J = 14.5, 6.4 Hz, 1H), 3.27 (d, J = 5.5
Hz, 2H), 3.20−3.07 (m, 1H), 2.38−2.15 (m, 4H), 2.10−1.81 (m, 2H).
13C NMR (100 MHz, CDCl3) δ = 169.7, 77.6, 60.2, 32.9, 25.8, 25.8,
18.7, 8.5. IR 3105, 2942, 2869, 1730, 1625, 1564, 1447, 1080, 997, 842,
742, 670 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for C8H12INO,
266.0042, found 266.0029.
2-Cyclopentyl-5-(iodomethyl)-4,5-dihydrooxazole (4c, New Com-
pound). Compound 4c was obtained as an oil in 89% yield (124 mg)
after flash chromatography (Silica gel, petroleum ether:ethyl acetate =
4:1). 1H NMR (400 MHz, CDCl3) δ = 4.51−4.47 (m, 1H), 3.86 (dd, J
= 14.5, 9.5 Hz, 1H), 3.49 (dd, J = 14.5, 6.3 Hz, 1H), 3.19 (d, J = 5.6
Hz, 2H), 2.68−2.64 (m, 1H), 1.90−1.80 (m, 2H), 1.78−1.68 (m, 4H),
1.62−1.45 (m, 2H). 13C NMR (100 MHz, CDCl3) δ= 170.7, 77.5,
60.1, 38.2, 30.3, 30.2, 25.7, 8.5. IR 3327, 2953, 2868, 1731, 1305 1087,
928, 807, 648 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for
C9H14INO, 280.0198, found 280.0185.
2-Cyclohexyl-5-(iodomethyl)-4,5-dihydrooxazole (4d, New Com-
pound). Compound 4d was obtained as an oil in 85% yield (124 mg)
after flash chromatography (Silica gel, petroleum ether:ethyl acetate =
2:1). 1H NMR (400 MHz, CDCl3) δ = 4.57−4.34 (m, 1H), 3.86 (dd, J
= 14.2, 9.8 Hz, 1H), 3.49 (dd, J = 14.2, 6.2 Hz, 1H), 3.19−3.17 (m,
2H), 2.22 (t, J = 11.1 Hz, 1H), 1.87 (s, 2H), 1.72−1.69 (m, 2H), 1.60
(d, J = 7.8 Hz, 1H), 1.46−1.27 (m, 2H), 1.30−1.12 (m, 3H). 13C
NMR (100 MHz, CDCl3) δ = 170.7, 77.2, 60.0, 37.4, 29.8, 29.7, 25.8,
25.6, 25.6, 8.5. IR 3319, 3083, 2929, 2855, 1732, 1626,
5-(Iodomethyl)-2-(1H-pyrrol-2-yl)-4,5-dihydrooxazole (2y, New
Compound). Compound 2y was obtained as a white solid in 63%
yield (87 mg) after flash chromatography (Silica gel, petroleum
1
ether:ethyl acetate = 1:1). mp = 123−124 °C; H NMR (400 MHz,
CDCl3) δ = 11.27 (s, 1H), 6.86 (s, 1H), 6.69 (d, J = 2.9 Hz, 1H), 6.16
(s, 1H), 4.75−4.68 (m, 1H), 4.08 (dd, J = 14.4, 9.3 Hz, 1H), 3.71 (dd,
J = 14.4, 6.5 Hz, 1H), 3.30 (dd, J = 10.2, 4.6 Hz, 1H), 3.22 (dd, J =
10.2, 7.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ = 158.9, 122.8,
119.5, 113.4, 109.6, 78.2, 59.8, 7.5. IR 3151, 3079, 2965, 2876, 1664,
1544, 1426, 1344, 1174, 959, 873, 762, 611, 476 cm−1. HRMS−ESI
(m/z) [M + H]+ calcd for C8H9IN2O, 276.9838, found 276.9830.
2-(Furan-2-yl)-5-(iodomethyl)-4,5-dihydrooxazole (2z, New Com-
pound). Compound 2z was obtained as an oil in 90% yield (124 mg)
after flash chromatography (Silica gel, petroleum ether:ethyl acetate =
1
3:1). H NMR (400 MHz, CDCl3) δ = 7.48−7.47 (m, 1H), 6.90−
6.89(m, 1H), 6.42 (dd, J = 3.4, 1.7 Hz, 1H), 4.75−4.71 (m, 1H), 4.10
(dd, J = 15.2, 9.4 Hz, 1H), 3.73 (dd, J = 15.2, 6.7 Hz, 1H), 3.30 (dd, J
= 10.3, 4.7 Hz, 1H), 3.23 (dd, J = 10.3, 7.3 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ = 155.8, 145.5, 142.6, 114.7, 111.6, 78.6, 60.6, 7.2. IR
3326, 3104, 2931, 2877, 1726, 1669, 1562, 1478, 1173, 1005, 937, 777,
616, 468 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for C8H8INO2,
277.9678, found 277.9670.
5-(Iodomethyl)-2-(5-methylthiophen-2-yl)-4,5-dihydrooxazole
(2aa, New Compound). Compound 2aa was obtained as an oil in
81% yield (124 mg) after flash chromatography (Silica gel, petroleum
1
ether:ethyl acetate = 4:1). H NMR (400 MHz, CDCl3) δ = 7.32 (s,
1H), 6.66 (s, 1H), 4.80−4.56 (m, 1H), 4.05 (dd, J = 14.9, 9.7 Hz, 1H),
3.68 (dd, J = 14.9, 6.3 Hz, 1H), 3.29 (dd, J = 9.4, 4.3 Hz, 1H), 3.24−
3.20(m, 1H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3) δ = 159.3,
145.5, 130.8, 127.4, 126.1, 78.7, 60.7, 15.7, 7.5. IR 3069, 2967, 2864,
1708, 1649, 1541, 1472, 1064, 1020, 965, 810, 691, 615 m−1. HRMS−
ESI (m/z) [M + H]+ calcd for C9H10INOS, 307.9606, found 307.9598.
5-(Iodomethyl)-5-methyl-2-phenyl-4,5-dihydrooxazole (2ab,
New Compound). Compound 2ab was obtained as an oil in 80%
yield (120 mg) after flash chromatography (Silica gel, petroleum
ether:ethyl acetate = 5:1). 1H NMR (400 MHz, CDCl3) δ = 7.86 (d, J
= 7.4 Hz, 2H), 7.42 (t, J = 7.3 Hz, 1H), 7.33 (t, J = 7.4 Hz, 2H), 3.95
(d, J = 15.0 Hz, 1H), 3.77 (d, J = 15.0 Hz, 1H), 3.43−3.30 (m, 2H),
1.68 (s, 3H). 13C NMR (100 MHz, CDCl3) δ = 163.0, 131.6, 128.5,
H
DOI: 10.1021/acs.joc.5b01832
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Article
1535,1451,1207, 1130, 1028, 931, 657, 506 cm−1. HRMS−ESI (m/z)
1738, 1671, 1636, 1571, 1464, 1162, 1086, 871, 724, 664, 480 cm−1.
HRMS−ESI (m/z) [M + H]+ calcd for C19H36INO, 422.1920, found
422.1916.
[M + H]+ calcd for C10H16INO, 294.0355, found 294.0348.
5-(Iodomethyl)-2-adamantyl-4,5-dihydrooxazole (4e, New Com-
pound). Compound 4e was obtained as an oil in 73% yield (126 mg)
after flash chromatography (Silica gel, petroleum ether:ethyl acetate =
2:1). 1H NMR (400 MHz, CDCl3) δ = 4.47−4.40 (m, 1H), 3.86−3.82
(m, 1H), 3.62−3.39 (m, 1H), 3.17 (t, J = 4.9 Hz, 2H), 1.92−1.90 (m,
3H), 1.82 (s, 6H), 1.65 (s, 6H). 13C NMR (100 MHz, CDCl3) δ =
173.2, 76.9, 59.8, 39.4, 36.5, 35.3, 27.8, 8.6. IR 3226, 2906, 2852, 2668,
1726, 1227, 1181, 1059, 973, 733, 649, 475 cm−1. HRMS−ESI (m/z)
[M + H]+ calcd for C14H20INO, 346.0668, found 346.0665.
2-tert-Butyl-5-(iodomethyl)-4,5-dihydrooxazole (4f, New Com-
pound). Compound 4f was obtained as an oil in 78% yield (104 mg)
after flash chromatography (Silica gel, petroleum ether:ethyl acetate =
2:1). 1H NMR (400 MHz, CDCl3) δ = 4.52−4.46 (m, 1H), 3.86 (dd, J
= 14.3, 9.7 Hz, 1H), 3.50 (dd, J = 14.3, 6.1 Hz, 1H), 3.19 (d, J = 5.3
Hz, 2H), 1.16 (s, 9H). 13C NMR (100 MHz, CDCl3) δ = 173.7, 77.4,
60.0, 33.3, 27.7, 8.4. IR 3330, 2967, 1726, 1641, 1285, 1158, 1039, 993,
812, 772, 648, 586 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for
C8H14INO, 268.0198, found 268.0194.
5-(Iodomethyl)-2-(pentan-3-yl)-4,5-dihydrooxazole (4g, New
Compound). Compound 4g was obtained as an oil in 70% yield
(98 mg) after flash chromatography (Silica gel, petroleum ether:ethyl
acetate = 2:1). 1H NMR (400 MHz, CDCl3) δ = 4.58−4.42 (m, 1H),
3.88 (dd, J = 14.6, 9.5 Hz, 1H), 3.53 (dd, J = 14.6, 6.6 Hz, 1H), 3.21
(dd, J = 10.2, 4.8 Hz, 1H), 3.15 (dd, J = 10.2, 7.0 Hz, 1H), 2.24−2.12
(m, 1H), 1.61−1.41 (m, 4H), 0.87−0.83 (m, 6H). 13C NMR (100
MHz, CDCl3) δ = 169.9, 77.4, 59.7, 42.5, 25.1, 25.0, 11.8, 11.7, 8.0. IR
3323, 3088, 2963, 2875, 1734, 1629, 1264, 1138, 1087, 977, 804, 739,
651 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for C9H16INO,
282.0355, found 282.0349.
5-(Iodomethyl)-2-propyl-4,5-dihydrooxazole (4h, New Com-
pound). Compound 4h was obtained as an oil in 75% yield (95
mg) after flash chromatography (Silica gel, petroleum ether:ethyl
acetate = 4:1). 1H NMR (400 MHz, CDCl3) δ = 4.53−4.49 (m, 1H),
3.87 (dd, J = 14.2, 10.0 Hz, 1H), 3.49 (dd, J = 14.2, 6.4 Hz, 1H), 3.26−
3.11 (m, 2H), 2.19 (t, J = 7.3 Hz, 2H), 1.69−1.50 (m, 2H), 0.91 (t, J =
7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 167.5, 77.6, 60.2, 30.0,
19.3, 13.8, 8.2. IR 3323, 3096, 2959, 2874, 1737, 1635, 1259, 1174,
1093, 804, 746, 669, 499 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for
C7H12INO, 254.0042, found 254.0035.
5-(Iodomethyl)-2-(2-nitrobenzyl)-4,5-dihydrooxazole (4l, New
Compound). Compound 4l was obtained as an oil in 65% yield
(112 mg) after flash chromatography (Silica gel, petroleum ether:ethyl
acetate = 2:1). 1H NMR (400 MHz, CDCl3) δ = 8.01−7.99 (m, 1H),
7.54−7.51 (m, 1H), 7.42−7.32 (m, 2H), 4.66−4.47 (m, 1H), 3.92 (d, J
= 4.5 Hz, 2H), 3.85−3.76 (m, 1H), 3.47 (dd, J = 14.6, 6.5 Hz, 1H),
3.21 (dd, J = 14.6, 4.8 Hz, 1H), 3.15 (dd, J = 10.3, 7.0 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ = 164.6, 148.8, 133.5, 132.8, 130.2, 128.5,
125.3, 78.6, 60.2, 32.9, 7.6. IR 3312, 3067, 2926, 2864, 1742, 1648,
1525, 1348, 1076, 994, 861, 789, 718, 672, 545 cm−1. HRMS−ESI (m/
z) [M + H]+ calcd for C11H11IN2O3, 346.9893, found 346.9891.
2-(2-Chlorobenzyl)-5-(iodomethyl)-4,5-dihydrooxazole (4m, New
Compound). Compound 4m was obtained as an oil in 61% yield (102
mg) after flash chromatography (Silica gel, petroleum ether:ethyl
acetate = 1:1). 1H NMR (400 MHz, CDCl3) δ = 7.33−7.25 (m, 2H),
7.18−7.12 (m, 2H), 4.58−4.54 (m, 1H), 3.89 (dd, J = 14.7, 9.5 Hz,
1H), 3.67 (s, 2H), 3.53 (dd, J = 14.7, 6.5 Hz, 1H), 3.19 (dd, J = 10.3,
4.7 Hz, 1H), 3.15 (dd, J = 10.3, 7.0 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ = 164.9, 134.3, 132.9, 131.1, 129.6, 128.6, 126.9, 78.2, 60.4,
32.5, 7.7. IR 3320, 3063, 2926, 2859, 1740, 1645, 1532, 1475, 1326,
1254, 1048, 927, 869, 753, 687, 445 cm−1. HRMS−ESI (m/z) [M +
H]+ calcd for C11H11ClINO, 335.9652, found 335.9640.
5-(Iodomethyl)-2-((S)-1-tosylpyrrolidin-2-yl)-4,5-dihydrooxazole
(Diastereomeric Mixtures, dr = 2:1). Colorless oil. Major diaster-
eomer: (4n, new compound). Compound 4n was obtained as an oil in
74% yield (161 mg) after flash chromatography (Silica gel, petroleum
ether:ethyl acetate = 1:1). 1H NMR (400 MHz, CDCl3) δ = 7.66 (d, J
= 8.7 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 4.44−4.33 (m, 1H), 4.28 (dd,
J = 8.3, 3.6 Hz, 1H), 3.92−3.85 (m, 1H), 3.50−3.44 (m, 3H), 3.24−
3.14 (m, 3H), 2.36 (s, 3H), 2.08−1.96 (m, 3H), 1.72−1.55 (m, 1H).
13C NMR (100 MHz, CDCl3) δ = 172.8, 166.4, 143.6, 129.6, 127.6,
77.9, 60.0, 56.4, 48.9, 31.0, 24.46, 21.5, 8.8. IR 3322, 2945, 2879, 1748,
1654, 1529, 1451, 1341, 1159, 1001, 917, 730, 666, 589, 493 cm−1.
HRMS−ESI (m/z) [M + H]+ calcd for C15H19IN2O3S, 435.0239,
found 435.0228.
2,2′-(Propane-2,2-diyl)bis(5-(iodomethyl)-4,5-dihydrooxazole)
(4o, New Compound). Compound 4o was obtained as an oil in 83%
yield (191 mg) after flash chromatography (Silica gel, petroleum
ether:ethyl acetate = 2:1). 1H NMR (400 MHz, CDCl3) δ = 4.66−4.48
(m, 2H), 3.91 (dd, J = 14.7, 9.5 Hz, 2H), 3.61−3.53 (m, 2H), 3.27−
3.13 (m, 4H), 1.47 (s, 6H). 13C NMR (100 MHz, CDCl3) δ = 168.4,
78.4, 60.1, 38.8, 24.1, 7.9. IR 3322, 2938, 2868, 1734, 1532, 1263,
1133, 1078, 803, 705, 549 cm−1. HRMS−ESI (m/z) [M + H]+ calcd
for C11H16I2N2O2, 462.9379, found 462.9371.
General Procedure for Nucleophilic Substitution of 5-
Iodomethyl-2-oxazolines. 5-(Iodomethyl)-2-(4-methoxyphenyl)-
4,5-dihydrooxazole (2b) was dissolved in 2 mL of DMF, the
nucleophile of interest was added, and the reaction mixture was
stirred for a given time. Then 30 mL of CH2Cl2 was added, and the
reaction mixture was washed with water, dried over MgSO4, and
concentrated under reduced pressure. The crude product was purified
by silica gel column chromatography to give the corresponding
product.
5-(Azidomethyl)-2-(4-methoxyphenyl)-4,5-dihydrooxazole (5a,
New Compound). Compound 5a was obtained as an oil in 92%
yield (107 mg) after flash chromatography (Silica gel, petroleum
ether:ethyl acetate = 4:1). 1H NMR (400 MHz, CDCl3) δ = 7.92−7.90
(m, 2H), 6.94−6.92 (m, 2H), 4.93−4.82 (m, 1H), 4.13 (dd, J = 14.7,
9.8 Hz, 1H), 3.85 (s, 3H), 3.79 (dd, J = 14.7, 6.8 Hz, 1H), 3.51−3.37
(m, 2H). 13C NMR (100 MHz, CDCl3) δ = 163.5, 162.2, 129.9, 119.7,
113.7, 78.1, 57.7, 55.3, 54.0. IR 3065, 2937, 2870, 2102, 1721, 1651,
1609, 1513, 1458, 1028, 843, 677 cm−1. HRMS−ESI (m/z) [M + H]+
calcd for C11H12N4O2, 233.1039, found 233.1038.
5-(Iodomethyl)-2-pentyl-4,5-dihydrooxazole (4i, New Com-
pound). Compound 4i was obtained as an oil 76% yield (107 mg)
after flash chromatography (Silica gel, petroleum ether:ethyl acetate =
3:1). 1H NMR (400 MHz, CDCl3) δ = 4.57−4.42 (m, 1H), 3.87 (dd, J
= 14.5, 9.6 Hz, 1H), 3.49 (dd, J = 14.5, 6.6 Hz, 1H), 3.25−3.12 (m,
2H), 2.20 (t, J = 7.6 Hz, 2H), 1.63−1.51 (m, 2H), 1.37−1.19 (m, 4H),
0.83 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 167.8, 77.7,
60.1, 31.3, 28.0, 25.5, 22.3, 13.9, 8.0. IR 3297, 3091, 2932, 2864, 1738,
1635, 1166, 1020, 855, 730, 495 cm−1. HRMS−ESI (m/z) [M + H]+
calcd for C9H16INO, 282.0355, found 282.0341.
2-Heptyl-5-(iodomethyl)-4,5-dihydrooxazole (4j, New Com-
pound). Compound 4j was obtained as an oil in 81% yield (125
mg) after flash chromatography (Silica gel, petroleum ether:ethyl
acetate = 2:1). 1H NMR (400 MHz, CDCl3) δ = 4.53−4.49 (m, 1H),
3.87 (dd, J = 14.5, 9.6 Hz, 1H), 3.49 (dd, J = 14.5, 6.5 Hz, 1H), 3.26−
3.07 (m, 2H), 2.20 (t, J = 7.6 Hz, 2H), 1.65−1.53 (m, 2H), 1.31−1.17
(m, 8H), 0.81 (m, 3H). 13C NMR (100 MHz, CDCl3) δ = 167.7, 77.6,
60.2, 31.6, 29.1, 28.9, 28.1, 25.8, 22.6, 14.1, 8.1. IR 3323, 3085, 2927,
2857, 1740, 1259, 1084, 927, 804, 724, 649, 423 cm−1. HRMS−ESI
(m/z) [M + H]+ calcd for C11H20INO, 310.0668, found 310.0657.
5-(Iodomethyl)-2-pentadecyl-4,5-dihydrooxazole (4k, New Com-
pound). Compound 4k was obtained as a white solid in 80% yield
(168 mg) after flash chromatography (Silica gel, petroleum ether:ethyl
1
acetate = 2:1). mp = 51−52 °C; H NMR (400 MHz, CDCl3) δ =
4.54−4.47 (m, 1H), 3.87 (dd, J = 14.5, 9.6 Hz, 1H), 3.49 (dd, J = 14.5,
6.5 Hz, 1H), 3.26−3.12 (m, 2H), 2.28−2.11 (m, 2H), 1.63−1.45 (m,
2H), 1.24−1.20 (m, 24H), 0.81 (m, 3H). 13C NMR (100 MHz,
CDCl3) δ = 167.7, 77.6, 60.2, 33.9, 31.9, 29.8, 29.7, 29.6, 29.5, 29.4,
29.3, 29.2, 28.1, 25.8, 25.6, 24.9, 22.7, 14.1, 8.1. IR 3323, 2920, 2855,
[2-(4-Methoxyphenyl)-4,5-dihydrooxazol-5-yl]methyl acetate
(5b, New Compound). Compound 5b was obtained as an oil in
75% yield (93 mg) after flash chromatography (Silica gel, petroleum
ether:ethyl acetate = 2:1). 1H NMR (400 MHz, CDCl3) δ = 7.82−7.80
I
DOI: 10.1021/acs.joc.5b01832
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Article
(m, 2H), 6.85−6.83 (m, 2H), 4.81−4.80 (m, 1H), 4.23 (d, J = 11.9
Hz, 1H), 4.14−4.00 (m, 2H), 3.77 (s, 3H), 3.71 (dd, J = 14.6, 7.3 Hz,
1H), 2.01 (s, 3H). 13C NMR (100 MHz, CDCl3) δ = 170.8, 163.8,
162.1, 129.9, 119.9, 113.7, 76.8, 65.2, 56.9, 55.3, 20.8. IR 3065, 2943,
2875, 1742, 1653, 1609, 1513, 1548, 1255, 1070, 845, 678 cm−1.
HRMS−ESI (m/z) [M + H]+ calcd for C13H15NO4, 250.1079, found
250.1079.
cm−1. HRMS−ESI (m/z) [M + H]+ calcd for C10H9BrINO, 365.8990,
found 365.8986.
5-(Bromomethyl)-2-(2-bromophenyl)-4,5-dihydrooxazole (6d,
New Compound). Compound 6d was obtained as an oil in 88%
yield (139 mg) after flash chromatography (Silica gel, petroleum
ether:ethyl acetate = 3:1). 1H NMR (400 MHz, CDCl3) δ = 7.63 (dd,
J = 7.6, 1.7 Hz, 1H), 7.56 (dd, J = 7.9, 1.0 Hz, 1H), 7.27 (td, J = 7.6,
1.0 Hz, 1H), 7.21 (td, J = 7.9, 1.7 Hz, 1H), 4.90−4.84 (m, 1H), 4.14
(dd, J = 15.2, 9.7 Hz, 1H), 3.97−3.82 (m, 1H), 3.59−3.35 (m, 2H).
13C NMR (100 MHz, CDCl3) δ = 162.8, 133.9, 131.9, 131.4, 129.1,
2-(4-Methoxyphenyl)-5-methyl-4,5-dihydrooxazole (5c, New
Compound). To a 100 mL flask was added tributyltinhydride (1.5
mmol), AIBN (0.025 mmol), 2b (0.5 mmol) and 20 mL of toluene.
The resulting solution was refluxed at 100 °C for 8 h. The residue
obtained by concentration was purified by flash column chromatog-
raphy to give the 5c as an oil (88 mg, 92% yield) after flash
127.2, 121.8, 78.0, 59.8, 33.2. IR 3053, 2933, 2868, 1734, 1655, 1472,
1246, 970, 837, 761 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for
C10H9Br2NO, 317.9129, found 317.9121.
1
chromatography (Silica gel, petroleum ether:ethyl acetate = 2:1). H
5-(Bromomethyl)-2-(4-chlorophenyl)-4,5-dihydrooxazole (6e,
New Compound). Compound 6e was obtained as a white solid in
90% yield (123 mg) after flash chromatography (Silica gel, petroleum
NMR (400 MHz, CDCl3) δ = 7.81−7.78 (m, 2H), 6.83−6.81 (m,
2H), 4.75−4.70 (m, 1H), 4.02 (dd, J = 14.2, 9.3 Hz, 1H), 3.74 (s, 3H),
3.53−3.48 (m, 1H), 1.32 (d, J = 6.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ = 163.6, 161.9, 129.8, 120.5, 113.6, 76.0, 61.5, 55.3, 21.1. IR
3066, 2966, 2867, 1710, 1645, 1579, 1511, 1457, 1256, 841, 742 cm−1.
HRMS−ESI (m/z) [M + H]+ calcd for C11H13NO2, 192.1025, found
192.1022.
1
ether:ethyl acetate = 4:1). mp = 65−66 °C; H NMR (400 MHz,
CDCl3) δ = 7.79−7.77 (m, 2H), 7.31−7.29 (m, 2H), 4.88−4.81 (m,
1H), 4.09 (dd, J = 15.2, 9.7 Hz, 1H), 3.91−3.76 (m, 1H), 3.46 (dd, J =
9.9, 4.3 Hz, 1H), 3.42 (dd, J = 9.9, 5.3 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ = 162.7, 137.7, 129.6, 128.7, 125.8, 78.0, 59.3, 33.6. IR 3070,
3011, 2951, 2873, 1722, 1647, 1488, 1262, 1075, 908, 845, 668 cm−1.
HRMS−ESI (m/z) [M + H]+ calcd for C10H9BrClNO, 273.9634,
found 273.9629.
N-2-Hydroxy-3-iodopropyl 4-methoxybenzamide (5d, New Com-
pound). To a solution of 2b (0.5 mmol) in THF was added
CF3COOH (5.0 equiv). The reaction mixture was stirred overnight at
room temperature. After completion of the reaction, the mixture was
quenched with saturated aqueous NaHCO3 and extracted with
CH2Cl2 (10 mL) for three times. The combined organic layer was
dried (MgSO4) and concentrated to give crude residue which was
purified by flash column chromatography to give compound 5d as a
white solid in 62% yield (104 mg) after flash chromatography (Silica
gel, petroleum ether:ethyl acetate = 2:1). mp = 110−112 °C; 1H NMR
(400 MHz, CDCl3) δ = 7.70−7.68 (m, 2H), 6.86−6.84 (m, 2H), 6.58
(brs, 1H), 4.13 (brs, 1H), 3.88−3.80 (m, 1H), 3.78 (s, 3H), 3.76−3.72
(m, 1H), 3.58−3.41 (m, 1H), 3.19 (d, J = 6.0 Hz, 2H). 13C NMR (100
MHz, CDCl3) δ = 168.8, 162.6, 128.9, 125.7, 113.9, 71.1, 55.4, 45.3,
10.1. IR 3314, 3064, 2925, 1712, 1621, 1548, 1433, 1089, 847, 677
cm−1. IR 3057, 2934, 2866, 1722, 1652, 1475, 1330, 1178, 960, 761,
615, 459 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for C11H14INO3,
336.0097, found 336.0086.
4-[5-(Bromomethyl)-4,5-dihydrooxazol-2-yl]benzonitrile (6f, New
Compound). Compound 6f was obtained as a white solid in 91% yield
(120 mg) after flash chromatography (Silica gel, petroleum ether:ethyl
1
acetate = 3:1). mp = 95−97 °C; H NMR (400 MHz, CDCl3) δ =
7.97−7.96 (m, 2H), 7.64−7.62 (m, 2H), 4.95−4.88 (m, 1H), 4.15 (dd,
J = 15.6, 9.8 Hz, 1H), 3.88 (dd, J = 15.6, 6.8 Hz, 1H), 3.49 (d, J = 5.3
Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 162.0, 132.1, 131.4, 128.7,
118.2, 114.8, 78.2, 59.4, 33.6. IR 3088, 3009, 2949, 2231, 1947, 1653,
1508, 1452, 1260, 1019, 908, 849, 665 cm−1. HRMS−ESI (m/z) [M +
H]+ calcd for C11H9BrN2O, 264.9977, found 264.9966.
4-(5-(Bromomethyl)-4,5-dihydrooxazol-2-yl)benzaldehyde (6g,
New Compound). Compound 6g was obtained as an oil in 83%
yield (111 mg) after flash chromatography (Silica gel, petroleum
1
ether:ethyl acetate = 3:1). H NMR (400 MHz, CDCl3) δ = 9.97 (s,
1H), 8.01−7.99 (m, 2H), 7.84−7.82 (m, 2H), 4.94−4.87 (m, 1H),
4.14 (dd, J = 15.5, 9.7 Hz, 1H), 3.87 (dd, J = 15.5, 6.8 Hz, 1H), 3.46
(d, J = 10.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 191.6, 162.6,
138.1, 132.5, 129.5, 128.8, 78.1, 59.4, 33.7. IR 2931, 2854, 1712, 1650,
1611, 1265, 843, 672 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for
C11H10BrNO2, 267.9973, found 267.9970.
5-(Bromomethyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole (6h, New
Compound). Compound 6h was obtained as an oil in 80% yield
(96 mg) after flash chromatography (Silica gel, petroleum ether:ethyl
acetate = 1:1). 1H NMR (400 MHz, CDCl3) δ = 8.65−8.64 (m, 1H),
7.97 (d, J = 7.9 Hz, 1H), 7.72 (t, J = 7.7 Hz, 1H), 7.38−7.27 (m, 1H),
5.06−4.82 (m, 1H), 4.19 (dd, J = 15.5, 9.7 Hz, 1H), 3.94 (dd, J = 15.5,
6.9 Hz, 1H), 3.56 (dd, J = 10.6, 4.2 Hz, 1H), 3.50 (dd, J = 10.3, 6.9 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ = 162.7, 149.7, 146.5, 136.7,
125.7, 123.9, 78.3, 59.4, 33.5. IR 3045, 2991, 2929, 1735, 1660, 1620,
1584, 1292, 1139, 753 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for
C9H9BrN2O, 240.9977, found 240.9975.
5-(Bromomethyl)-2-(furan-2-yl)-4,5-dihydrooxazole (6i, New
Compound). Compound 6i was obtained as an oil in 76% yield (87
mg) after flash chromatography (Silica gel, petroleum ether:ethyl
acetate = 4:1). 1H NMR (400 MHz, CDCl3) δ = 7.48 (s, 1H), 6.90 (d,
J = 3.3 Hz, 1H), 6.42 (d, J = 0.8 Hz, 1H), 4.87−4.83 (m, 1H), 4.11
(dd, J = 15.2, 9.5 Hz, 1H), 3.84 (dd, J = 15.2, 6.7 Hz, 1H), 3.47 (dd, J
= 10.7, 4.9 Hz, 1H), 3.43 (dd, J = 10.7, 6.4 Hz, 1H). 13C NMR (100
MHz, CDCl3) δ = 155.9, 145.4, 142.4, 114.9, 111.5, 78.0, 59.2, 33.2. IR
3047, 2929, 2856, 1726, 1669, 1625, 1474, 1396, 1175, 764 cm−1.
HRMS−ESI (m/z) [M + H]+ calcd for C8H8BrNO2, 229.9817, found
229.9814.
5-(Bromomethyl)-2-(p-tolyl)-4,5-dihydrooxazole (6a, New Com-
pound). Compound 6a was obtained as a white solid in 83% yield
(105 mg) after flash chromatography (Silica gel, petroleum ether:ethyl
1
acetate = 4:1). mp = 86−88 °C; H NMR (400 MHz, CDCl3) δ =
7.76−7.74 (m, 2H), 7.15−7.13 (m, 2H), 4.87−4.80 (m, 1H), 4.09 (dd,
J = 15.1, 9.6 Hz, 1H), 3.82 (dd, J = 15.1, 6.6 Hz, 1H), 3.47 (dd, J =
10.6, 5.0 Hz, 1H), 3.41 (dd, J = 10.6, 6.3 Hz, 1H), 2.31 (s, 3H). 13C
NMR (100 MHz, CDCl3) δ = 163.7, 141.9, 129.1, 128.1, 124.4, 77.7,
59.2, 33.8, 21.6. IR 3030, 2959, 2867, 1718, 1649, 1614, 1340, 1018,
900, 831, 726 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for
C11H12BrNO, 254.0181, found 254.0179.
5-(Bromomethyl)-2-(4-methoxyphenyl)-4,5-dihydrooxazole (6b,
New Compound). Compound 6b was obtained as a white solid in
80% yield (108 mg) after flash chromatography (Silica gel, petroleum
1
ether:ethyl acetate = 4:1). mp = 82−84 °C; H NMR (400 MHz,
CDCl3) δ = 7.91−7.89 (m, 2H), 6.94−6.93 (m, 2H), 4.98−4.86 (m,
1H), 4.23−4.14 (m, 1H), 3.90 (dd, J = 15.0, 6.6 Hz, 1H), 3.86 (s, 3H),
3.56 (dd, J = 10.6, 5.0 Hz, 1H), 3.51 (dd, J = 10.6, 6.3 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ = 163.5, 162.2, 129.9, 128.9, 119.7, 113.7,
77.8, 59.0, 55.3, 33.7. IR 3013, 2927, 1713, 1648, 1607, 1510, 1260,
1104, 1026, 971, 843, 800, 740 cm−1. HRMS−ESI (m/z) [M + H]+
calcd for C11H12BrNO2, 270.0130, found 270.0125.
5-(Bromomethyl)-2-(2-iodophenyl)-4,5-dihydrooxazole (6c, New
Compound). Compound 6c was obtained as an oil in 83% yield (151
mg) after flash chromatography (Silica gel, petroleum ether:ethyl
1
acetate = 2:1). H NMR (400 MHz, CDCl3) δ = 7.87 (d, J = 7.9 Hz,
1H), 7.57 (dd, J = 7.9, 1.3 Hz, 1H), 7.31 (t, J = 7.3 Hz, 1H), 7.04 (td, J
= 7.9, 1.3 Hz, 1H), 4.90−4.87 (m, 1H), 4.15 (dd, J = 15.2, 9.7 Hz,
1H), 3.89 (dd, J = 15.2, 6.6 Hz, 1H), 3.57−3.40 (m, 2H). 13C NMR
(100 MHz, CDCl3) δ = 163.7, 140.6, 132.9, 131.8, 130.8, 127.9, 94.6,
78.2, 59.8, 33.6. IR 3053, 2931, 2867, 1732, 1657, 1584, 1089, 970, 762
5-(Bromomethyl)-2-(naphthalen-2-yl)-4,5-dihydrooxazole (6j,
New Compound). Compound 6j was obtained as a white solid in
85% yield (122 mg) after flash chromatography (Silica gel, petroleum
1
ether:ethyl acetate = 2:1). mp = 116−117 °C; H NMR (400 MHz,
J
DOI: 10.1021/acs.joc.5b01832
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
CDCl3) δ = 8.34 (s, 1H), 7.93 (dd, J = 8.6, 1.5 Hz, 1H), 7.83−7.78
(m, 1H), 7.78−7.72 (m, 2H), 7.50−7.28 (m, 2H), 4.88−4.83 (m, 1H),
4.12 (dd, J = 15.2, 9.6 Hz, 1H), 3.85 (dd, J = 15.2, 6.7 Hz, 1H), 3.48
(dd, J = 10.6, 5.0 Hz, 1H), 3.43 (dd, J = 10.6, 6.2 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ = 163.7, 134.9, 132.6, 128.9, 128.8, 128.2, 127.8,
127.7, 126.6, 124.7, 124.6, 78.0, 59.4, 33.8. IR 3057, 3011, 2957, 2872,
1715, 1649, 1575, 1464, 1296, 1194, 1055, 963, 757 cm−1. HRMS−ESI
(m/z) [M + H]+ calcd for C14H12BrNO, 290.0181, found 290.0178.
5-(Chloromethyl)-2-(p-tolyl)-4,5-dihydrooxazole (6a′, New Com-
pound). Compound 6a′ was obtained as a white solid in 77% yield (92
mg) after flash chromatography (Silica gel, petroleum ether:ethyl
5-(Chloromethyl)-2-(naphthalen-2-yl)-4,5-dihydrooxazole (6j′,
New Compound). Compound 6j′ was obtained as a white solid in
72% yield (88 mg) after flash chromatography (Silica gel, petroleum
ether:ethyl acetate = 2:1). mp = 99−100 °C; H NMR (400 MHz,
CDCl3) δ = 8.35 (s, 1H), 7.94−7.92 (m, 1H), 7.82−7.80 (m, 1H),
7.79−7.73 (m, 2H), 7.47−7.38 (m, 2H), 4.89−4.86 (m, 1H), 4.13 (dd,
J = 15.1, 9.7 Hz, 1H), 3.90 (dd, J = 15.1, 6.7 Hz, 1H), 3.62 (d, J = 5.4
Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 163.9, 134.8, 132.6, 128.9,
128.8, 128.2, 127.8, 127.6, 126.6, 124.6, 124.5, 78.3, 58.3, 45.5. IR
3058, 2957, 2875, 1728, 1649, 1568, 1461, 1231, 1056, 972, 828, 761
cm−1. HRMS−ESI (m/z) [M + H]+ calcd for C14H12ClNO, 246.0686,
found 246.0686.
1
1
acetate = 4:1). mp = 65−67 °C; H NMR (400 MHz, CDCl3) δ =
5-(Iodomethyl)-2-phenyl-4,5-dihydrothiazole (7a, Known Com-
pound, CAS: 906451-57-8). Compound 7a was obtained as an oil in
83% yield (126 mg) after flash chromatography (Silica gel, petroleum
ether:ethyl acetate = 5:1). 1H NMR (400 MHz, CDCl3) δ = 7.72−7.70
(m, 2H), 7.40−7.30 (m, 2H), 6.99 (t, J = 7.8 Hz, 1H), 4.50 (dd, J =
16.1, 2.0 Hz, 1H), 4.17 (dd, J = 16.1, 7.9 Hz, 1H), 4.10−4.09 (m, 1H),
3.25 (dd, J = 9.8, 4.7 Hz, 1H), 3.11 (t, J = 10.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3) δ = 166.7, 131.5, 130.3, 128.6, 128.4, 69.9, 51.6,
10.1. Spectral data are in good agreement with literature values.16
5-(Bromomethyl)-2-phenyl-4,5-dihydrothiazole (7b, New Com-
pound). Compound 7b was obtained as an oil in 71% yield (90 mg)
after flash chromatography (Silica gel, petroleum ether:ethyl acetate =
5:1). 1H NMR (400 MHz, CDCl3) δ = 7.75−7.69 (m, 1H), 7.62−7.57
(m, 1H), 7.38−7.29 (m, 2H), 7.03−6.96 (m, 1H), 4.61 (dd, J = 16.4,
2.4 Hz, 1H), 4.27−4.17 (m, 1H), 4.11−4.04 (m, 1H), 3.39 (dd, J =
10.1, 4.9 Hz, 1H), 3.26 (t, J = 10.1 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ = 166.5, 131.5, 130.3, 128.6, 128.4, 68.5, 51.2, 34.9. IR 3057,
2945, 2717, 1722, 1605, 1491, 1240, 1003, 944, 766, 688 cm−1.
HRMS−ESI (m/z) [M + H]+ calcd for C10H10BrNS, 255.9796, found
255.9796.
7.84−7.82 (m, 2H), 7.22−7.20 (m, 2H), 4.91−4.85 (m, 1H), 4.15 (dd,
J = 15.0, 9.7 Hz, 1H), 3.91 (dd, J = 15.0, 6.7 Hz, 1H), 3.66 (dd, J = 5.4,
1.6 Hz, 2H), 2.38 (s, 3H). 13C NMR (100 MHz, CDCl3) δ = 163.8,
141.9, 129.1, 128.1, 124.6, 78.0, 58.2, 45.5, 21.5. IR 3014, 2960, 2927,
1721, 1651, 1612, 1570, 1339, 1262, 1066, 904, 829, 748 cm−1.
HRMS−ESI (m/z) [M + H]+ calcd for C11H12ClNO, 210.0686, found
210.0685.
5-(Chloromethyl)-2-(4-methoxyphenyl)-4,5-dihydrooxazole (6b′,
New Compound). Compound 6b′ was obtained as an oil in 80% yield
(90 mg) after flash chromatography (Silica gel, petroleum ether:ethyl
acetate = 3:1). 1H NMR (400 MHz, CDCl3) δ = 7.82−7.80 (m, 2H),
6.85−6.83 (m, 2H), 4.84−4.80 (m, 1H), 4.08 (dd, J = 14.9, 9.6 Hz,
1H), 3.83 (dd, J = 14.9, 6.6 Hz, 1H), 3.77 (s, 3H), 3.60 (dd, J = 5.4,
3.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 163.5, 162.2, 129.9,
119.6, 113.7, 78.0, 58.1, 55.3, 45.5. IR 3010, 2940, 2873, 1718, 1650,
1610, 1259, 1174, 979, 904, 844, 677 cm−1. HRMS−ESI (m/z) [M +
H]+ calcd for C11H12ClNO2, 226.0635, found 226.0632.
2-(2-Bromophenyl)-5-(chloromethyl)-4,5-dihydrooxazole (6d′,
New Compound). Compound 6d′ was obtained as an oil in 80%
yield (109 mg) after flash chromatography (Silica gel, petroleum
ether:ethyl acetate = 2:1). 1H NMR (400 MHz, CDCl3) δ = 7.63 (dd,
J = 7.7, 1.7 Hz, 1H), 7.57 (dd, J = 7.7, 0.9 Hz, 1H), 7.33−7.16 (m,
2H), 4.90−4.84 (m, 1H), 4.14 (dd, J = 15.1, 9.8 Hz, 1H), 3.92 (dd, J =
15.1, 6.6 Hz, 1H), 3.64 (d, J = 3.0 Hz, 2H). 13C NMR (100 MHz,
CDCl3) δ = 163.0, 133.9, 131.9, 131.4, 129.0, 127.1, 121.8, 78.3, 58.5,
45.3. IR 3057, 2944, 2872, 1737, 1658, 1592, 1471, 1095, 842, 758
cm−1. HRMS−ESI (m/z) [M + H]+ calcd for C10H9BrClNO,
273.9634, found 273.9633.
5-(Chloromethyl)-2-(4-chlorophenyl)-4,5-dihydrooxazole (6e′,
New Compound). Compound 6e′ was obtained as an oil in 79%
yield (90 mg) after flash chromatography (Silica gel, petroleum
ether:ethyl acetate = 3:1). 1H NMR (400 MHz, CDCl3) δ = 7.84−7.81
(m, 2H), 7.34−7.32 (m, 2H), 4.94−4.87 (m, 1H), 4.15 (dd, J = 15.1,
9.6 Hz, 1H), 3.89 (dd, J = 15.1, 6.8 Hz, 1H), 3.63 (d, J = 5.2 Hz, 2H).
13C NMR (100 MHz, CDCl3) δ = 163.2, 138.0, 129.9, 128.9, 125.4,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01832.
■
S
Copies of NMR, IR and HRMS spectra for the obtained
compounds, X-ray structure for compound 2b. (PDF)
Crystal information file for compound 2b. (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: ymli@nankai.edu.cn.
■
Notes
78.5, 57.9, 45.3. IR 3052, 2949, 2873, 1723, 1649, 1599, 1540, 1264,
1094, 842, 731 cm−1. HRMS−ESI (m/z) [M + H]+ calcd for
C10H9Cl2NO, 230.0139, found 230.0140.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
4-[5-(Chloromethyl)-4,5-dihydrooxazol-2-yl]benzonitrile (6f′,
New Compound). Compound 6f′ was obtained as a white solid in
74% yield (81 mg) after flash chromatography (Silica gel, petroleum
We acknowledge the financial support from National Natural
Science Foundation of China (NSFC 20972072, NSFC
21272121). G.-Q. Liu acknowledges the support from The
Ph. D. Student Innovative Research Program of Nankai
University (68140001).
1
ether:ethyl acetate = 2:1). mp = 97−98 °C; H NMR (400 MHz,
CDCl3) δ = 7.97−7.95 (m, 2H), 7.64−7.62 (m, 2H), 4.94−4.90 (m,
1H), 4.14 (dd, J = 15.5, 9.8 Hz, 1H), 3.91 (dd, J = 15.5, 6.9 Hz, 1H),
3.70−3.57 (m, 2H). 13C NMR (100 MHz, CDCl3) δ = 162.1, 132.1,
131.3, 128.7, 118.2, 114.8, 78.6, 58.3, 45.4. IR 3088, 2590, 2875, 2231,
1736, 1653, 1505, 1417, 1070, 850, 668 cm−1. HRMS−ESI (m/z) [M
+ H]+ calcd for C11H9ClN2O, 221.0482, found 221.0476.
REFERENCES
■
(1) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297−2360.
(2) (a) Bode, H. B.; Irschik, H.; Wenzel, S. C.; Reichenbach, H.;
4-[5-(Chloromethyl)-4,5-dihydrooxazol-2-yl]benzaldehyde (6g′,
New Compound). Compound 6g′ was obtained as an oil in 75%
yield (84 mg) after flash chromatography (Silica gel, petroleum
ether:ethyl acetate = 3:1). 1H NMR (400 MHz, CDCl3) δ = 10.00 (s,
1H), 8.11−8.09 (m, 2H), 7.94−7.91 (m, 2H), 5.03−4.96 (m, 1H),
4.24 (dd, J = 15.4, 9.8 Hz, 1H), 3.95 (dd, J = 15.4, 6.9 Hz, 1H), 3.58
(dd, J = 5.1, 1.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ = 191.6,
162.9, 138.2, 132.3, 129.6, 128.9, 78.6, 58.2, 45.4. IR 3052, 2956, 2853,
1720, 1650, 1535, 1266, 1108, 852, 761, 695 cm−1. HRMS−ESI (m/z)
[M + H]+ calcd for C11H10ClNO2, 224.0478, found 224.0477.
Muller, R.; Hofle, G. J. Nat. Prod. 2003, 66, 1203−1206. (b) Tsuda,
̈
̈
M.; Yamakawa, M.; Oka, S.; Tanaka, Y.; Hoshino, Y.; Mikami, Y.; Sato,
A.; Fujiwara, H.; Ohizumi, Y.; Kobayashi, J. i. J. Nat. Prod. 2005, 68,
462−464. (c) Nicolaou, K. C.; Schlawe, D.; Kim, D. W.; Longbottom,
D. A.; de Noronha, R. G.; Lizos, D. E.; Manam, R. R.; Faulkner, D. J.
Chem. - Eur. J. 2005, 11, 6197−6211.
(3) (a) Onishi, H. R.; Pelak, B. A.; Gerckens, L. S.; Silver, L. L.;
Kahan, F. M.; Chen, M.-H.; Patchett, A. A.; Galloway, S. M.; Hyland,
S. A.; Anderson, M. S.; Raetz, C. R. H. Science 1996, 274, 980−982.
K
DOI: 10.1021/acs.joc.5b01832
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(b) Gwaltney, S. L., II; Jae, H.-S.; Kalvin, D. M.; Liu, G.; Sham, H. L.;
Li, Q.; Claiborne, A. K.; Wang, L.; Barr, K. J.; Woods, K. W.
Preparation of substituted oxazolines as antiproliferative agents.
WO2000006556A1, 2000. (c) Bergeron, R. J.; Xin, M. G.; Weimar,
W. R.; Smith, R. E.; Wiegand, J. J. Med. Chem. 2001, 44, 2469−2478.
(d) Li, Q.; Woods, K. W.; Claiborne, A.; Gwaltney, I. I. S. L.; Barr, K.
J.; Liu, G.; Gehrke, L.; Credo, R. B.; Hui, Y. H.; Lee, J.; Warner, R. B.;
Kovar, P.; Nukkala, M. A.; Zielinski, N. A.; Tahir, S. K.; Fitzgerald, M.;
Kim, K. H.; Marsh, K.; Frost, D.; Ng, S.-C.; Rosenberg, S.; Sham, H. L.
Bioorg. Med. Chem. Lett. 2002, 12, 465−469. (e) Celanire, S.; Talaga,
P.; Leurs, R.; Denonne, F.; Timmerman, H.; Lebon, F. Preparation of
oxazoline and thiazoline derivatives as histamine H3-receptor ligands
with numerous therapeutic uses. WO2006103057A1, 2006.
2007, 63, 1474−1480. (g) Xue, M.-X.; Guo, C.; Gong, L.-Z. Synlett
2009, 2009, 2191−2197.
(14) (a) Minakata, S.; Nishimura, M.; Takahashi, T.; Oderaotoshi, Y.;
Komatsu, M. Tetrahedron Lett. 2001, 42, 9019−9022. (b) Nishimura,
M.; Minakata, S.; Takahashi, T.; Oderaotoshi, Y.; Komatsu, M. J. Org.
Chem. 2002, 67, 2101−2110. (c) Minakata, S.; Morino, Y.; Ide, T.;
Oderaotoshi, Y.; Komatsu, M. Chem. Commun. 2007, 3279−3281.
(d) Hajra, S.; Bar, S.; Sinha, D.; Maji, B. J. Org. Chem. 2008, 73, 4320−
4322.
(15) (a) Vorbruggen, H.; Krolikiewicz, K. Tetrahedron Lett. 1981, 22,
̈
4471−4474. (b) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33,
907−910. (c) Wipf, P.; Venkatraman, S. Tetrahedron Lett. 1996, 37,
4659−4662. (d) Pirrung, M. C.; Tumey, L. N. J. Comb. Chem. 2000, 2,
675−680. (e) Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J.; Williams, D.
R. Org. Lett. 2000, 2, 1165−1168. (f) Wuts, P. G. M.; Northuis, J. M.;
(4) (a) Wipf, P.; Venkatraman, S. Synlett 1997, 1997, 1−10.
(b) Tsukamoto, M.; Murooka, K.; Nakajima, S.; Abe, S.; Suzuki, H.;
Hirano, K.; Kondo, H.; Kojiri, K.; Suda, H. J. Antibiot. 1997, 50, 815−
821. (c) Gemma, S.; Camodeca, C.; Brindisi, M.; Brogi, S.; Kukreja,
G.; Kunjir, S.; Gabellieri, E.; Lucantoni, L.; Habluetzel, A.; Taramelli,
D.; Basilico, N.; Gualdani, R.; Tadini-Buoninsegni, F.; Bartolommei,
G.; Moncelli, M. R.; Martin, R. E.; Summers, R. L.; Lamponi, S.;
Savini, L.; Fiorini, I.; Valoti, M.; Novellino, E.; Campiani, G.; Butini, S.
J. Med. Chem. 2012, 55, 10387−10404.
Kwan, T. A. J. Org. Chem. 2000, 65, 9223−9225. (g) Brandstatter, M.;
̈
Roth, F.; Luedtke, N. W. J. Org. Chem. 2015, 80, 40−51.
(16) Minakata, S.; Morino, Y.; Oderaotoshi, Y.; Komatsu, M. Org.
Lett. 2006, 8, 3335−3337.
(17) Morino, Y.; Hidaka, I.; Oderaotoshi, Y.; Komatsu, M.; Minakata,
S. Tetrahedron 2006, 62, 12247−12251.
(18) Kawato, Y.; Kubota, A.; Ono, H.; Egami, H.; Hamashima, Y.
Org. Lett. 2015, 17, 1244−1247.
(5) Wipf, P.; Fritch, P. C. Tetrahedron Lett. 1994, 35, 5397−5400.
(6) Vizi, E. S. Med. Res. Rev. 1986, 6, 431−449.
(19) Wang, N.; Chen, B.; Ma, S. Adv. Synth. Catal. 2014, 356, 485−
492.
(7) (a) Frump, J. A. Chem. Rev. 1971, 71, 483−506. (b) Zarantonello,
P.; Leslie, C. P.; Ferritto, R.; Kazmierski, W. M. Bioorg. Med. Chem.
Lett. 2002, 12, 561−565.
(20) Alamsetti, S. K.; Persson, A. K. Å.; Jiang, T.; Backvall, J.-E.
̈
Angew. Chem., Int. Ed. 2013, 52, 13745−13750.
(21) Liu, G.-Q.; Li, Y.-M. J. Org. Chem. 2014, 79, 10094−10109.
(22) (a) Sabitha, G.; Reddy, K. B.; Reddy, G.; Fatima, N.; Yadav, J. S.
Synlett 2005, 2347−2351. (b) Sabitha, G.; Reddy, K. B.; Bhikshapathi,
M.; Yadav, J. S. Tetrahedron Lett. 2006, 47, 2807−2810. (c) Elsworth,
J. D.; Willis, C. L. Chem. Commun. 2008, 1587−1589. (d) Clarisse, D.;
Pelotier, B.; Piva, O.; Fache, F. Chem. Commun. 2012, 48, 157−159.
(23) Saikia, U. P.; Baruah, D.; Pahari, P.; Borah, M. J.; Goswami, A.;
Konwar, D. Tetrahedron Lett. 2014, 55, 4328−4330.
(8) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons, Inc.: New York, 1999.
(b) Saravanan, P.; Corey, E. J. J. Org. Chem. 2003, 68, 2760−2764.
́
(9) (a) Gomez, M.; Muller, G.; Rocamora, M. Coord. Chem. Rev.
1999, 193−195, 769−835. (b) McManus, H. A.; Guiry, P. J. Chem.
Rev. 2004, 104, 4151−4202. (c) Desimoni, G.; Faita, G.; Jørgensen, K.
A. Chem. Rev. 2006, 106, 3561−3651. (d) Hargaden, G. C.; Guiry, P. J.
Chem. Rev. 2009, 109, 2505−2550.
(24) (a) Castellano, S.; Kuck, D.; Sala, M.; Novellino, E.; Lyko, F.;
Sbardella, G. J. Med. Chem. 2008, 51, 2321−2325. (b) Wuest, W. M.;
Sattely, E. S.; Walsh, C. T. J. Am. Chem. Soc. 2009, 131, 5056−5057.
(25) Please refer to Supporting Information for details.
(10) (a) Vorbruggen, H.; Krolikiewicz, K. Tetrahedron 1993, 49,
̈
9353−9372. (b) Marrero-Terrero, A. L.; Loupy, A. Synlett 1996, 1996,
245−246. (c) Cwik, A.; Hell, Z.; Hegedus, A.; Finta, Z.; Horvath, Z.
Tetrahedron Lett. 2002, 43, 3985−3987. (d) Rajaram, S.; Sigman, M. S.
Org. Lett. 2002, 4, 3399−3401. (e) Bandgar, B. P.; Pandit, S. S.
(26) (a) Tellitu, I.; Domínguez, E. Synlett 2012, 23, 2165−2175.
(b) Muniz, K. Pure Appl. Chem. 2013, 85, 755−761. (c) Romero, R.
̃
Tetrahedron Lett. 2003, 44, 2331−2333. (f) Vastila, P.; Pastor, I. M.;
̈
̈
M.; Woste, T. H.; Muniz, K. Chem. - Asian J. 2014, 9, 972−983.
̈
̃
Adolfsson, H. J. Org. Chem. 2005, 70, 2921−2929. (g) Kangani, C. O.;
Kelley, D. E. Tetrahedron Lett. 2005, 46, 8917−8920.
(d) Kishore Vandavasi, J.; Hu, W.-P.; Chandru Senadi, G.; Chen, H.-
T.; Chen, H.-Y.; Hsieh, K.-C.; Wang, J.-J. Adv. Synth. Catal. 2015, 357,
2788−2794.
(11) (a) Muller, D.; Umbricht, G.; Weber, B.; Pfaltz, A. Helv. Chim.
̈
Acta 1991, 74, 232−240. (b) Zhou, P.; Blubaum, J. E.; Burns, C. T.;
Natale, N. R. Tetrahedron Lett. 1997, 38, 7019−7020. (c) Kamata, K.;
Agata, I.; Meyers, A. I. J. Org. Chem. 1998, 63, 3113−3116.
(d) Ohshima, T.; Iwasaki, T.; Mashima, K. Chem. Commun. 2006,
2711−2713. (e) Ilkgul, B.; Gunes, D.; Sirkecioglu, O.; Bicak, N.
Tetrahedron Lett. 2010, 51, 5313−5315.
(27) (a) Gaumont, A.-C.; Gulea, M.; Levillain, J. Chem. Rev. 2009,
109, 1371−1401. (b) Just-Baringo, X.; Albericio, F.; Alvarez, M. Curr.
Top. Med. Chem. 2014, 14, 1244−1256.
(28) Jaganathan, A.; Garzan, A.; Whitehead, D. C.; Staples, R. J.;
Borhan, B. Angew. Chem., Int. Ed. 2011, 50, 2593−2596.
(12) (a) Bolm, C.; Weickhardt, K.; Zehnder, M.; Ranff, T. Chem. Ber.
1991, 124, 1173−1180. (b) Jnaneshwara, G. K.; Deshpande, V. H.;
Lalithambika, M.; Ravindranathan, T.; Bedekar, A. V. Tetrahedron Lett.
1998, 39, 459−462. (c) Mohammadpoor-Baltork, I.; Khosropour, A.
R.; Hojati, S. F. Synlett 2005, 2747−2750. (d) Mohammadpoor-
Baltork, I.; Mirkhani, V.; Moghadam, M.; Tangestaninejad, S.; Zolfigol,
M. A.; Abdollahi-Alibeik, M.; Khosropour, A. R.; Kargar, H.; Hojati, S.
F. Catal. Commun. 2008, 9, 894−901. (e) Mohammadpoor-Baltork, I.;
Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.; Hojati, S. F. Catal.
Commun. 2008, 9, 1153−1161. (f) Garg, P.; Chaudhary, S.; Milton, M.
D. J. Org. Chem. 2014, 79, 8668−8677. (g) Cai, A.-J.; Zheng, Y.; Ma, J.-
A. Chem. Commun. 2015, 51, 8946−8949.
(13) (a) Hayashi, T.; Sawamura, M.; Ito, Y. Tetrahedron 1992, 48,
1999−2012. (b) Badiang, J. G.; Aube,
́
J. J. Org. Chem. 1996, 61, 2484−
2487. (c) Benito-Garagorri, D.; Bocokic,
́
V.; Kirchner, K. Tetrahedron
Lett. 2006, 47, 8641−8644. (d) Chaudhry, P.; Schoenen, F.;
Neuenswander, B.; Lushington, G. H.; Aube, J. J. Comb. Chem.
2007, 9, 473−476. (e) Karade, N. N.; Tiwari, G. B.; Gampawar, S. V.
Synlett 2007, 2007, 1921−1924. (f) Ishihara, M.; Togo, H. Tetrahedron
L
DOI: 10.1021/acs.joc.5b01832
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