From propargylic amides to functionalized oxazoles: Domino gold catalysis/oxidation by dioxygen

Article abstract of DOI:10.1021/jo301288w

A new, highly efficient, and atom-economic access to a series of functionalized 2,5-disubstituted oxazoles from propargylic amides is reported. A series of propargylic amides were transformed to the corresponding alkylideneoxazolines by a gold(I) catalyst. The next step was an autoxidation to hydroperoxides bearing the heteroaromatic oxazoles. Experiments addressing the reaction mechanism reveal a radical pathway for this autoxidation process. The hydroperoxides could conveniently be converted to the corresponding alcohols by reduction with sodium borohydride.

Full text of DOI:10.1021/jo301288w

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pubs.acs.org/joc
From Propargylic Amides to Functionalized Oxazoles: Domino Gold
Catalysis/Oxidation by Dioxygen
A. Stephen K. Hashmi,* Maria Camila Blanco Jaimes, Andreas M. Schuster, and Frank Rominger
Organisch-Chemisches Institut, Ruprecht-Karls-Universitat Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
̈
S
* Supporting Information
ABSTRACT: A new, highly efficient, and atom-economic access to a
series of functionalized 2,5-disubstituted oxazoles from propargylic amides
is reported. A series of propargylic amides were transformed to the
corresponding alkylideneoxazolines by a gold(I) catalyst. The next step
was an autoxidation to hydroperoxides bearing the heteroaromatic
oxazoles. Experiments addressing the reaction mechanism reveal a radical pathway for this autoxidation process. The
hydroperoxides could conveniently be converted to the corresponding alcohols by reduction with sodium borohydride.
Scheme 1. Gold-Catalyzed Cycloisomerization of
Nonterminal Propargylic Amides7
INTRODUCTION
■
Propargylic amides have been widely studied as effective and
versatile substrates for the synthesis of oxazoles,1−4 which occur
in different natural and non-natural compounds with biological
and pharmaceutical properties.5 This reaction can either be pro-
moted by harsh basic conditions2 or be catalyzed under much
milder conditions by palladium3 or gold.4 Gold has emerged in
the field of organic chemistry as a powerful tool and due to the
high selectivity as well as mild reaction conditions has become
one of the major topics in catalysis research.6 The mild
conditions of gold(I) catalysis provided the first access to
alkylideneoxazolines 2, the latter now for the first time can be
investigated as building blocks for synthesis.
Overall, there are only a few reports where oxidizing agents
are used to synthesize functionalized oxazoles.8,9 Saito and co-
workers8 described the oxidative cycloisomerization of propargylic
amides mediated by phenyliodine(III) diacetate (PIDA); and
recently, Zhang and co-workers9 reported the synthesis of 2,5-
disubstituted oxazoles via gold-catalyzed alkyne oxidation using
pyridine/quinoline N-oxides as oxidizing agents. While in hetero-
geneous gold catalysis oxidation by dioxygen is a dominating topic,
in homogeneous gold catalysis only a handful of homogeneous
gold-catalyzed reactions have been reported.
air, the initial product was converted to a different product.
This new product turned out to be the corresponding hydro-
peroxymethyl oxazole 4, which is formed as a result of a
spontaneous oxidation mediated by the oxygen present in the
air (Scheme 2). This is the first time such hydroperoxides are
Scheme 2. Gold Catalysis Followed by Autoxidation of the
Alkylideneoxazoline 2
The direct oxidation with dioxygen in the context of homo-
geneous gold catalysis has only been reported in two cases, the
oxidation of alcohols to aldehydes10 and the oxidative cleavage
of C−C double bonds after a 5-exo-dig cyclization (the latter
quite similar to the formation of 2).11
We wanted to study the new building blocks 2 in com-
bination with dioxygen in order to obtain functionalized
oxazoles from the combination gold(I) catalysis and oxidation
rather than methyloxazoles4a from gold(III) catalysis.
obtained from gold-catalyzed reactions, which usually are famous
for tolerating both water and air.12 Related autoxidations are only
reported in the literature in the presence of different metals or
radical initiators13 and none of these had been used for the
synthesis of oxazoles.
As mentioned above, the starting point of our investigation
was the unexpected product obtained in the gold-catalyzed
reaction of propargylic amides 1. The reaction was carried out
in dry tetrahydrofuran (THF) at room temperature. As soon as
the catalysis reaction was complete, the reaction flask was
opened and stirred in air. After 30 min, the only product
RESULTS AND DISCUSSION
■
We have recently reported the gold-catalyzed cycloisomeriza-
tion of nonterminal propargylic amides 1 to the corresponding
alkylideneoxazolines 2 and oxazines 3 (Scheme 1).7 When, after
completion of the catalysis, the reaction mixture was exposed to
Received: June 20, 2012
Published: July 17, 2012
© 2012 American Chemical Society
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isolated corresponded to the hydroperoxymethyloxazole 4. The
results obtained with this procedure are summarized in Table 1.
the derivative 6e gave a moderate yield (entry 5, 59%, char-
acterized by an X-ray crystal structure analysis14). The highest
yield was obtained with the derivative 3,5-dichloro-substituted
6l (entry 12, 91%), whereas the 4-n-butoxy-substituted 6b
(entry 2, 78%) showed the fastest transformation.
Table 1. Preparation of 2,5-Disubstituted Oxazoles 4
With the methyleneoxazolines 6 we could now investigate
the autoxidation process. First the conditions for the formation
of the hydroperoxymethyloxazole were optimized for substrate
6a (Table 3). Different solvents, substrate concentrations, and
temperatures were tested. When the reaction was performed in
THF at 50 °C (entries 1−4), it was possible to observe an in-
crease of the conversion with the concentration of the substrate
in the reaction mixture. When the reaction was performed at
room temperature no conversion was observed at all (entry 5),
suggesting that the initiation stage requires a relative high
energy of activation. We then decided to change the solvent in
order to investigate if the THF was directly initiating the oxida-
tion process by its capability to form peroxides in the presence
of oxygen.15 In CHCl3 (entry 6) and CCl4 0.5 M at 50 °C
(entry 8) the yields are comparable but the conversion is slower
than in THF. Interestingly, the reaction also took place in
absence of solvent (entry 10), indicating that molecular oxygen
is the main oxidizing agent that promotes the conversion, although
the presence of THF peroxide seems to accelerate the formation
of the hydroperoxide 7.
Additional mechanistic experiments are shown in Table 4.
The first experiment (entry 1) in the absence of oxygen con-
firms that the latter is the oxidizing agent of the process. Even
in the presence of molecular oxygen the oxidation does not take
place in the presence of the well-known radical inhibitor tert-
butylhydroxytoluene (BHT)16 (entry 2). On the other hand,
the reaction is accelerated by the presence of the radical
initiator azobisisobutyronitrile (AIBN)17 (entry 3). In this case,
85% of conversion was observed after only 8 h, in contrast to
the 24 h needed to obtain 95% of conversion without the AIBN
(Table 3, entry 4). From these results it is possible to conclude
that the oxidation of methyleneoxazolines 6 follows a radical
pathway, probably triggered by the combination of high tem-
perature and light and promoted by the presence of oxygen and
THF peroxides in the reaction flask.18
In order to study the reaction scope and to identify the
reaction pathway, we decided to work first with the terminal
propargylic amide 5a and to isolate its corresponding cyclo-
isomerizated product, the methyleneoxazoline 6a. The com-
pound 6a was then subjected to an atmosphere of dioxygen
in THF in the presence or absence of gold and stirred
overnight at 50 °C. Interestingly, in both cases the same
product was isolated (Scheme 3) and the reaction rate was
identical. Therefore, it was clear that gold played no role in
the second part of the conversion, the oxidation reaction of
the alkylideneoxazolines.
To explore the reaction scope, different electron-withdrawing
(EWG) and electron-donating groups (EDG) in the benzene
ring were investigated. The propargylic amides 5 were obtained
in high yields using known procedures.4 The gold-catalyzed
cycloisomerization of compounds 5 in most of the cases took
place at room temperature in the presence of 2 mol % of
Ph3PAuNTf2 (Table 2, entries 1−4, 6−10, 12, 13, and 15).
Only the formation of the 3,4,5-trimethoxy-substituted 6e
(entry 5), 3,5-dibromo-substituted 6k (entry 11), and 3-nitro-
subtituted 6n (entry 14) needed heating to 35 °C. Most of the
methyleneoxazolines 6 could be obtained in high yields; only
Scheme 4 depicts a possible pathway for the oxidation of
methyleneoxazolines 6 to peroxides 7. The first step would
correspond to the activation of methyleneoxazoline 6 by loss of
an H-radical, leading to the formation of the radical species A
which is a resonance structure of B. When the reaction is
carried out in THF an alternative pathway to form A, involving
Scheme 3. Oxidation of Methyleneoxazoline 6a Occurs with and without the Gold Catalyst
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Table 2. Gold-Catalyzed Reaction of Propargylic Amides 5
Table 3. Optimization of Reaction Conditions
a
temp
(°C)
conc
[6a]
reaction
Time
yield by
GC/MS (%)
yield
entry solvent
(%)
1
2
THF
THF
THF
THF
THF
CHCl3
CCl4
CCl4
CCl4
50
50
50
50
rt
0.01
0.10
0.30
0.50
0.50
0.50
0.05
0.50
0.50
20
20
20
24
48
24
60
48
48
48
5
58
64
95
0
85
87
92
3
4
5
6
50
50
50
rt
56
47
93
0
87
85
90
7
8
9
10
rt
78
90
a
Yield based on recovered starting material.
a
Table 4. Additional Control Experiments
b
c
external/oxidizing
agent
time
(h)
conv
yield
entry
solvent
(%)
(%)
d
1
2
3
THF
72
72
8
0
0
e
BHT /O2
THF
CCl4
f
AIBN /O2
85
75
a
b
c
d
[6a] = 0.50 M, 50 °C. Estimated by GC−MS analysis. Yields. Dry
e
conditions, in absence of oxygen. BHT: tert-butylhydroxytoluene,
10 mol %. AIBN: azobisisobutyronitrile, 10 mol %.
f
Scheme 4. Proposed Pathway for the Oxidation of 6
a
b
Yields. The reaction mixture was heated to 35 °C.
the peroxyl radical of THF D as a radical initiator, could be
operational. This pathway would explain the faster conversion
of 6 under those conditions. Once the radical species B is
formed, it would quickly react with O2 to give rise to peroxyl
radical C,18 which in turn would react with a new molecule of
methyleneoxazoline 6 removing its H-radical, thus forming the
isolated peroxide 7 and a new radical species A to continue the
oxidation process by achieving radical chain propagation.
With the proposed pathway of the oxidation (Scheme 4), the
reaction conditions optimized (Table 3, entry 4), and methyl-
eneoxazolines 6 synthesized (Table 2), we could now investigate
the scope of the oxidation and explore one of the possible
further transformations of peroxides 7. Table 5 summarizes
the results obtained with the different EWGs and EDGs in the
benzene ring of 6. In most of the cases, peroxides 7 were
obtained in high yields (96−72%). The derivatives 7h (entry 8)
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a
and the ease to generate the delocalized radical (represented
by the mesomers A/B) and thus exclusively depend on the
electronic density of the R group. Hammett constants (σ) offer
a valuable tool to quantify the electronic density associated to
this part of the molecule. According to the results obtained, a
consistent relationship between the σ values and the reaction
time could be established. The derivatives 7a−d (entries 1−4)
possessed the smallest values of σ and presented the shortest
reaction times (48−25 h) as well as the highest yields (96−
80%), indicating that the oxidation process is accelerated by
higher electronic density on the substrate. As expected,
derivatives bearing EWG, namely 7i−l (entries 9−12), showed
larger reaction (168−64 h) times while retaining high yields
(92−72%). The fact that nitro derivatives (entries 14−15) did
not react could be explained by taking into account the big
electron-withdrawing effect that nitro group perform in the
molecule, increasing the activation energy needed to start the
oxidation process. The derivative 7m (entry 13), bearing two
trifluoromethyl groups, could only be obtained after 8 days of
reaction in moderate yield. Into the series of EWG and EDG
investigated on the benzene ring in compounds 7, the sub-
stitution pattern in presents 7m, with an σ value of 0.83, con-
stitutes the minimum electronic density needed to accomplish
the oxidation process.
Table 5. Scope of the Reaction
1
The structure of peroxides 7 was first elucidated by the H
NMR spectra, especially due to the presence of a broad peak
between 9 and 11 ppm corresponding to the hydroperoxide
proton. To unequivocally confirm the presence of the peroxide
function, compounds 7 were reduced to their corresponding
alcohol derivatives 8. In all the cases, the reduction was
performed in high yields using NaBH4 as reducing agent in
methanol (Table 5). The appearance of the characteristic peak
1
for alcohols between 2 and 3 ppm in the H NMR confirmed
the structure of the reduced products and the peroxide
precursor as well. The easy reduction to alcohols also illustrates
the potential of the hydroperoxides 7 for organic synthesis.
Crystal structures were obtained for the peroxides 7f and 7m
and for the alcohol derivatives 8a, 8b and 8e.14 In 7f, the
conformation of the hydroperoxide with a dihedral angle
C−O−O−H of 92° resembles the conformation of hydrogen
peroxide (90°). This still allows the formation of dimers by two
intermolecular hydrogen bonds, each from the −OOH unit to
the oxazole nitrogen atom of a second molecule of 7f (Table 5).
Compound 7m shows a similar structural motive. By inter-
molecular hydrogen bonds between the −OH groups and the
oxazole nitrogen atoms, the carbinol 8a forms chains in the solid
state. The same is true for 8b and 8e.
Experiments with 6a applying both the gold catalyst and
oxygen in THF at the same time gave only a reduced yield of
35% of the product 7a. A control experiment with only the
substrate and oxygen in THF shows that the substrate is slowly
decomposing under these conditions by a radical pathway as
well. On one hand, this demonstrates that gold catalysis and
radical reactions in principle are compatible, on the other hand
competing side-reactions cause problems.
a
b
[6] = 0.50 M. Hammett constant associated with the substitution
partner in the benzene ring.19 Reaction time needed to reach
complete conversion of 6. Yields. No product was formed, just the
substrate was recovered.
c
d
e
and 7m (entry 13) could only be obtained in moderate yields
(64−37%). Nitro-substituted methyleneoxazoline 6n (entry
14) and 6o (entry 15) did not react under the employed
conditions even after 8 days of reaction. In order to understand
the behavior of the reaction as a function of the substituents in
the benzene ring, we decided to associate this substitution
pattern to the Hammett constants (σ) for meta- and para-
substituted benzoic acids.19 According to the proposed pathway
(Scheme 4), the activation stage would depend on the stability
CONCLUSIONS
■
This combination of a gold-catalyzed cycloisomerization to
otherwise inaccessible building blocks and their in situ trans-
formation to the corresponding hydroperoxides by a radical
reaction pathway nicely demonstrates the compability of gold
catalysis and radical reactions. The good yields obtained for a
wide range of substrates with different EDGs and EWGs nicely
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AgOTs (25.0 μmol, 5 mol %). Compound 4a (30 mg) was obtained as
a white solid (160 μmol, 32%). Rf = 0.62 (petroleum ether/ethyl
acetate 2:1). Mp: 78.3−79.5 °C. H NMR (300 MHz, CDCl3, 25 °C,
underline the applicability in synthesis, although the established
relationship between the electron-withdrawing/donating capa-
bility of the R group and the reaction rate revealed that the
oxidation process has a limitation when strong EWG are present
in the substrate. This methodology proved to be a novel access to
2,5-disubtituted oxazole derivatives in high yields and with high
atom economy. For the formation of the hydroperoxides, the
stepwise process is superior to the process applying oxygen during
the gold-catalyzed cycloisomerization.
1
TMS): δ = 11.1 (br s, OOH), 7.68−7.76 (m, 2H), 7.27−7.46 (m, 3H),
7.00 (s, 1H), 4.85 (t, J = 7.3 Hz, 1H), 1.76−2.12 (m, 2H), 0.99 (t, J =
7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 161.7 (s),
150.6 (s), 130.7 (d), 128.7 (d, 2C), 127.2 (d), 126.4 (d, 2 C), 126.4
̃
̃
(s), 80.1 (d), 23.8 (t), 10.3 (q). IR (neat): ν = 3160, 2972, 2936, 2879,
2850, 2253, 1685, 1548, 1485, 1450, 1376, 1334 cm−1. HRMS (EI(+),
70 eV): [C12H13O2N]+ calcd 203.0946, found 203.0946.
1-(2-Phenyl-1,3-oxazol-5-yl)butan-1-ol (4b).
EXPERIMENTAL SECTION
■
General Methods. Chemicals were used without further
purification. Dry dichloromethane and tetrahydrofuran were used.
Chemical shifts were referenced to residual solvent protons. Signal
multiplicity as follows: s (singlet), d (doublet), t (triplet), q (quartet),
qu (quintet), hept (heptate), m (multiplet). 13C assignment was achieved
via HSQC, HMBC, and DEPT135 spectra. For HRMS with EI or FAB a
magnetic sector field analyzer was used.
The reaction was carried out according to GP 1 with 101 mg of 1b
(500 μmol, 1 eq), 15.5 mg of (IPr)AuCl (25.0 μmol, 5 mol %), and
6.97 mg of AgOTs (25.0 μmol, 5 mol %) in 10 mL of dry THF.
Compound 4b (47 mg) was obtained as a white solid (233 μmol,
47%). Rf 1= 0.64 (petroleum ether/ethyl acetate 1:1). Mp: 64.7−
66.1 °C. HNMR (300 MHz, CDCl3, 25 °C, TMS): δ= 11.4 (br s,
OOH), 7.68 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.5 Hz, 1H), 7.29 (t, J =
7.5 Hz, 2H), 6.97 (s, 1H), 4.92 (t, J = 7.3 Hz, 1H), 1.93−2.03 (m,
1H), 1.71−1.81 (m, 1H), 1.30−1.54 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H).
13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ= 161.6 (s), 150.8 (s),
130.6 (d), 128.7 (d, 2C), 127.0 (d), 126.4 (d, 2C), 126.3 (s), 78.4 (d),
Compounds 1 and 2 are known and fully characterized.7a
General Procedure 1 (GP 1): Gold-Catalyzed Cycloisomeri-
zation of Propargylic Amides 1 and Direct Conversion in
Hydroperoxides 4. In a dry Schlenk flask, 5 mol % of the gold
catalyst and 5 mol % AgOTs were dissolved in dry THF and stirred for
1 h. N-Propargylamide 1 (1 equiv) was added, and the reaction was
stirred at room temperature for 16 h. After completion of the reaction,
the reaction flask was opened and stirred in air for another 30 min.
The crude product was absorbed on Celite by concentration of the
reaction mixture with Celite 545 in vacuum. The reaction mixture was
purified by column chromatography on silica.
General Procedure 2 (GP 2): Synthesis of Propargylic
Amides 5.4c,7a Propargylamine (1.0 equiv with respect to the acid
chloride) was dissolved in dry DCM, and 1 equiv of Et3N and 2 mol %
of DMAP were added. The reaction mixture was cooled to 0 °C, and
1 equiv of the acid chloride was added. The mixture was stirred for
15 min at 0 °C and then for 3 h at room temperature. After the reac-
tion was completed, water was added and then the mixture extracted
with DCM. The organic layer was dried over MgSO4, and the solvent
was removed in vacuo. The product was purified by column chro-
matography or by recrystallization.
̃
̃
32.4 (t), 19.0 (t), 13.9 (q). IR (neat): ν = 3156, 2962, 2935, 2873,
2253, 1548, 1485, 1450, 1380, 1359, 1330, 1133, 1103, 1070. HRMS
(EI (+), 70 eV): [C13H15O2N]+ calcd 217.1103, found 217.1102.
1-(2-Phenyl-1,3-oxazol-5-yl)pentan-1-ol (4c).
The reaction was carried out according to GP 1 with 108 mg of 1c
(500 μmol, 1 equiv), 15.5 mg of (IPr)AuCl (25.0 μmol, 5 mol %), and
6.97 mg of AgOTs (25.0 μmol, 5 mol %) in 10 mL of dry THF.
Compound 4c (52 mg) was obtained as a white solid (259 μmol,
52%). Rf1 = 0.66 (petroleum ether/ethyl acetate 1:1). Mp: 57.5−
59.2 °C. H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 11.38 (br s,
OOH), 7.64−7.72 (m, 2H), 7.34−7.42 (m, 1H), 7.26−7.33 (m, 2H),
6.97 (s, 1H), 4.90 (t, J = 7.3 Hz, 1H), 1.92− 2.07 (m, 1H), 1.72−1.88
(m, 1H), 1.24−1.48 (m, 4H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (75
MHz, CDCl3, 25 °C, TMS): δ = 161.6 (s), 150.8 (s), 130.6 (d), 128.7
(d, 2C), 127.0 (d), 126.4 (d, 2C), 126.3 (s), 78.7 (d), 30.0 (t), 27.9
General Procedure 3 (GP 3): Gold-Catalyzed Synthesis of
Dihydrooxazoles 6.4c,7a The starting propargylic amide was
dissolved in DCM, and then the gold catalyst (2 mol %) was added.
The mixture was stirred for the denounced time. After the reaction was
completed, the solvent was evaporated and the organic product
purified by column chromatography or by recrystallization.
General Procedure 4 (GP 4): Oxidation of Dihydrooxazoles
6. A solution 0.5 M of the dihydrooxazole in THF was prepared and
stirred for the prescribed time at 50 °C under O2 atmosphere. After
the reaction was completed, the solvent was evaporated and the organic
product purified by column chromatography or by recrystallization.
General Procedure 5 (GP 5): Reduction of Peroxides 7. The
corresponding peroxide was dissolved in methanol, and then NaBH4
was added dropwise to the solution during 1 h. After the solution was
stirred at room temperature for 2 h, water and a solution 1 M of
chlorhydric acid were added, and the mixture was stirred for another
1 h. Finally, the reaction mixture was extracted with dichloromethane,
the organic layer was dried over MgSO4, and the solvent was evaporated.
The organic product was purified by column chromatography or by
recrystallization.
̃
̃
(t), 22.5 (t), 14.0 (q). IR (neat): ν = 3160, 2958, 2932, 2871, 2253,
1547, 1485, 1466, 1450, 1380, 1333, 1133, 1071, 1026, 974. HRMS
(EI (+), 70 eV): [C14H17O2N]+ calcd 231.1259, found 231.1251.
3,4-Dimethoxy-N-(prop-2-ynyl)benzamide (5a).
3,4-Dimethoxy-N-(prop-2-ynyl)benzamide was prepared accord-
ing to GP 2. Propargylamine (0.066 g, 1.25 mmol), Et3N (0.12 g,
1.25 mmol), DMAP (3 mg, 2 mol %), and 3,4-dimethoxybenzoyl
chloride (0.25 g, 1.25 mmol) in 20 mL of DCM were employed.
Flash chromatography on silica gel (PE/EA, 1:1) delivered 0.24 g
(1.1 mmol, 88%) of 5a as a white solid. Rf = 0.12 (petroleum ether/
1
ethyl acetate 1:1). Mp: 147−148.5 °C. H NMR (300 MHz, acetone-
d6, 25 °C, TMS): δ = 7.95 (s, NH), 7.54 (dd, J = 6.9, 2.1 Hz, 1H), 7.52
(d, J = 2.2 Hz, 1H), 7.00 (d, J = 6.92 Hz, 1H), 4.17 (dd, J = 5.6, 2.5
Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 2.64 (t, J = 2.5 Hz, 1H). 13C NMR
(75 MHz, acetone-d6, 25 °C, TMS): δ = 166.6 (s), 153.1 (s), 150.0
1-(2-Phenyl-1,3-oxazol-5-yl)propan-1-ol (4a). The reaction
was carried out according to GP 1 with 93.6 mg of 1a (500 μmol, 1
equiv), 15.5 mg of (IPr)AuCl (25.0 μmol, 5 mol %), and 6.97 mg of
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(s), 127.7 (s), 121.3 (s), 111.7 (s), 111.7 (s), 81.7 (s), 71.7 (s), 56.11
3,4,5-Trimethoxy-N-(prop-2-ynyl)benzamide (5e).
−1
̃
(s, 2C), 29.4 (s). IR (neat): ν
̃
= 1585, 1603, 1637, 3252, 3410 cm .
MS (70 eV): m/z 219 (63) [M+], 188 (17) [M+ − CH3O•], 165 (100)
[M+ − C3H4N•]. HRMS (EI (+), 70 eV): [C12H13NO3]+ calcd
219.0895, found 219.0891.
4-Butoxy-N-(prop-2-ynyl)benzamide (5b).
3,4,5-Trimethoxy-N-(prop-2-ynyl)benzamide was prepared accord-
ing to the GP 2. Propargylamine (0.19 g, 3.53 mmol), Et3N (0.36 g,
3.53 mmol), DMAP (9 mg, 2 mol %), and 3,4,5-trimethoxybenzoyl
chloride (0.81 g, 3.53 mmol) in 20 mL of DCM were employed. Flash
chromatography on silica gel (PE/EA, 1:1) delivered 0.8 g of (3.21
mmol, 91%) 5e as a colorless solid. Rf = 0.3 (petroleum ether/ethyl
4-Butoxy-N-(prop-2-ynyl)benzamide was prepared according to GP 2.
Propargylamine (0.28 g, 5 mmol), Et3N (0.51 g, 5 mmol), DMAP
(12 mg, 2 mol %), and 4-butoxybenzoyl chloride (1.06 g, 5 mmol) in
30 mL of DCM were employed. Flash chromatography on silica gel
(PE/EA, 2:1) delivered 1.10 g (4.7 mmol, 94%) 5b as a white solid.
Rf = 0.26 (petroleum ether/ethyl acetate 2:1). Mp: 120.4−122.0 °C.
1H NMR (300 MHz, acetone-d6, 25 °C, TMS): δ = 7.89 (dd, J = 9.3,
2.5 Hz, 2H), 6.99 (dd, J = 9.3, 2.5, 2H), 4.18 (dd, J = 5.6, 2.5 Hz, 2H),
4.08 (t, J = 6.5 Hz, 2H), 2.65 (t, J = 2.9 Hz, 1H), 1.78 (qu, J = 6.5 Hz,
2H), 1.52 (qt, J = 6.5, 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H). 13C NMR
(75 MHz, acetone-d6, 25 °C, TMS): δ = 166.4 (s), 162.7 (s), 129.9 (s,
2C), 127.3 (s), 114.9 (s, 2C), 81.6 (s), 71.7 (s), 68.5 (s), 32.0 (s), 29.9
1
acetate 1:1). Mp: 153.0−154.3 °C. H NMR (300 MHz, acetone-d6,
25 °C, TMS): δ = 8.05 (s, NH), 7.26 (s, 2H), 4.17 (dd, J = 5.6, 2.5 Hz,
2H), 3.85 (s, 6H), 3.77 (s, 3H), 2.66 (t, J = 2.5 Hz, 1H). 13C NMR (75
MHz, acetone-d6, 25 °C, TMS): δ = 165.5 (s), 154.2 (s, 2C), 142.0
(s), 130.4 (s), 105.1 (s, 2C), 81.6 (s), 71.9 (s), 56.5 (s, 2C), 60.6 (s),
29.5 (s). IR (neat): ν
̃
= 1588, 1638, 2943, 3289, 3388 cm−1. MS
(70 eV): m/z 249 (100) [M+], 218 (9) [M+ − CH3O•], 195 (75)
[M+ − C3H4N•]. HRMS (EI (+), 70 eV): [C13H15NO4]+ calcd 249.1001,
found 249.1001.
N-(Prop-2-ynyl)-2-naphthamide (5f).
(s), 19.9 (s), 14.1 (s). IR (neat): ν
̃
= 1639, 2953, 3301, 3320 cm−1. MS
(70 eV): m/z 231 (65) [M+], 177 (56) [M+ − C3H4N•], 121 (100)
+
[C7H4O2 ]. HRMS (EI (+), 70 eV): [C14H17NO2]+ calcd 231.1259,
found 231.1265.
N-(Prop-2-yn-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbox-
N-(Prop-2-ynyl)-2-naphthamide was prepared according to GP 2. of
Propargylamine (0.40 g, 7.34 mmol), Et3N (0.74 g, 7.34 mmol),
DMAP (18 mg, 2 mol %), and naphthoyl chloride (1.40 g, 7.34 mmol)
in 30 mL of DCM were employed. Flash chromatography on silica
gel (PE/EA, 1:1) delivered 1.39 g (6.6 mmol, 90%) of 5f as a
white solid. Rf = 0.28 (petroleum ether/ethyl acetate 1:1). 1H NMR
(300 MHz, acetone-d6, 25 °C, TMS): δ = 8.50 (s, 1H), 8.30 (s,
NH), 7.99 (m, 4H), 7.59 (m, 2H), 4.27 (dd, J = 5.6, 2.5 Hz, 2H),
2.71 (t, J = 2.5 Hz, 1H). The 1H NMR corresponds to that reported
in the literature.20
amide (5c).
N-(Prop-2-yn-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carboxamide
was prepared according to GP 2. 5,6,7,8-Tetrahydronaphthalene-2-
carbonyl chloride was prepared by heating at reflux 5,6,7,8-
tetrahydronaphthalene-2-carbonyl acid (0.352 g, 2.0 mmol) and
SOCl2 (4.72 g, 40 mmol); after 2 h, the excess of SOCl2 was
evaporated and the crude used in GP 2 without further purification.
Propargylamine (0.11 g, 2.00 mmol), Et3N (0.20 g, 2.00 mmol),
DMAP (5 mg, 2 mol %), and the chloride (0.389 g, 2.00 mmol) in
20 mL of DCM were employed. Flash chromatography on silica gel
(PE/EA, 2:1) delivered 0.36 g (1.70 mmol, 85%) 5c as a white
solid. Rf = 0.36 (petroleum ether/ethyl acetate 2:1). Mp: 113.3−
3-Methyl-N-(prop-2-ynyl)benzamide (5g).
3-Methyl-N-(prop-2-ynyl)benzamide was prepared according to the
GP 2. Propargylamine (0.11 g, 2.00 mmol), Et3N (0.20 g, 2.00 mmol),
DMAP (5 mg, 2 mol %), and 3-methylbenzoyl chloride (0.31 g, 2.00
mmol) in 20 mL of DCM were employed. Flash chromatography on
silica gel (PE/EA, 2:1) delivered 0.32 g (1.85 mmol, 93%) of 5g as a
1
114.7 °C. H NMR (300 MHz, acetone-d6, 25 °C, TMS): δ = 7.95
(s, NH), 7.61 (d, J = 1.8 Hz, 1H), 7.61 (dd, J = 8.4, 1.8 Hz, 1H),
7.11 (d, J = 8.4 Hz, 1H), 4.17 (dd, J = 5.6, 2.5 Hz, 2H), 2.78 (t, J =
6.5 Hz, 4H), 2.63 (t, J = 2.5 Hz, 1H), 1.79 (qu, J = 6.5 Hz, 4H). 13C
NMR (75 MHz, acetone-d6, 25 °C, TMS): δ = 167.1 (s), 141.5 (s),
137.8 (s), 132.5 (s), 129.9 (s), 128.9 (s), 125.2 (s), 81.7 (s), 71.7
1
white solid. Rf = 0.30 (petroleum ether/ethyl acetate 2:1). H NMR
(300 MHz, acetone-d6, 25 °C, TMS): δ = 8.01 (s, NH), 7.74 (s, 1H),
7.71 (m, 1H), 7.34 (m, 2H), 4.19 (dd, J = 5.5, 2.5 Hz, 2H), 2.65 (t, J =
2.5 Hz, 1H), 2.37 (s, 3H). The 1H NMR corresponds to that reported
in the literature.21
̃
(s), 29.9 (s), 29.3 (s, 2C), 23.7 (s, 2C). IR (neat): ν = 1535, 1571,
1612, 1641, 3309 cm−1. MS (70 eV): m/z 213 (52) [M+], 159
(100) [M+ − C3H4N•]. HRMS (EI (+), 70 eV): [C14H15NO]+ calcd
213.1154, found 213.1130.
N-(Prop-2-yn-1-yl)biphenyl-3-carboxamide (5h).
N-(Prop-2-yn-1-yl)benzamide (5d).
N-(Prop-2-yn-1-yl)benzamide was prepared according to GP 2.
Propargylamine (0.42 g, 3.0 mmol), Et3N (0.16 g, 3.0 mmol),
DMAP (6 mg, 2 mol %), and benzoyl chloride (0.36 g, 3.0 mmol)
in 20 mL of DCM were employed. Flash chromatography on silica
gel (PE/EA, 2:1) delivered 0.43 g (2.7 mmol, 90%) of 5d as a
white solid. Rf = 0.40 (petroleum ether/ethyl acetate 2:1). 1H NMR
(300 MHz, acetone-d6, 25 °C, TMS): δ = 8.05 (s, NH), 7.92
(m, 2H), 7.50 (m, 3H), 4.20 (dd, J = 5.6, 2.6 Hz, 2H), 2.65 (t, J =
2.6 Hz, 1H).
N-(Prop-2-yn-1-yl)biphenyl-3-carboxamide was prepared according to
GP 2. Propargylamine (0.083 g, 1.50 mmol), Et3N (0.15 g, 1.50 mmol),
DMAP (3 mg, 2 mol %), and (1,1′-biphenyl)-3-carbonyl chloride
(0.30 g, 1.50 mmol) in 20 mL of DCM were employed. Flash chro-
matography on silica gel (PE/EA, 3:1) delivered 0.32 g (1.36 mmol,
91%) of 5h as a white solid. Rf = 0.29 (petroleum ether/ethyl acetate
3:1). Mp: 116.8−117.1 °C. H NMR (300 MHz, acetone-d6, 25 °C,
TMS): δ = 8.24 (s, NH), 8.20 (t, J = 1.8 Hz, 1H), 7.93 (ddd, J = 7.8,
1.8, 1.2 Hz, 1H), 7.83 (ddd, J = 7.8, 1.8, 1.2 Hz, 1H), 7.71 (dt, J = 7.5,
1
4c,7a
1
The H NMR corresponds to that reported in the literature.
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1.8 Hz, 2H), 7.57 (t, J = 7.8 Hz, 1H), 7.49 (td, J = 7.5, 1.8 Hz, 2H),
7.38 (tt, J = 7.5, 1.8 Hz, 1H), 4.23 (dd, J = 5.6, 2.5 Hz, 2H), 2.67 (t, J =
2.5 Hz, 1H). 13C NMR (75 MHz, acetone-d6, 25 °C, TMS): δ = 166.9
(s), 142.1 (s), 141.1 (s), 140.0 (s), 130.6 (s), 129.9 (s), 129.8 (s, 2C),
128.6 (s), 127.9 (s, 2C), 127.2 (s), 126.5 (s), 81.5 (s), 71.9 (s), 29.5
3,5-Dichloro-N-(prop-2-ynyl)benzamide (5l).
(s). IR (neat): ν
̃
= 1583, 1604, 1645, 3286 cm−1. MS (70 eV): m/z
235 (100) [M+], 181 (89) [M+ − C3H4N•]. HRMS (EI (+), 70 eV):
[C16H13NO]+ calcd 235.0997, found 235.0988.
3-Chloro-N-(prop-2-ynyl)benzamide (5i).
3,5-Dichloro-N-(prop-2-ynyl)benzamide was prepared according to
GP 2. Propargylamine (0.14 g, 2.50 mmol), Et3N (0.30 g, 2.50 mmol),
DMAP (5 mg, 2 mol %), and 3,5-dichlorobenzoyl chloride (0.52 g,
2.50 mmol) in 20 mL of DCM were employed. Flash chromatography
on silica gel (PE/EA, 3:1) delivered 0.45 g (2.00 mmol, 80%) 5l as a
white solid. Rf = 0.46 (petroleum ether/ethyl acetate 3:1). Mp: 140.6−
142.0 °C. 1H NMR (300 MHz, acetone-d6, 25 °C, TMS): δ = 8.31 (s,
NH), 7.88 (d, J = 1.9 Hz, 2H), 7.66 (t, J = 1.9 Hz, 1H), 4.20 (dd, J =
5.5, 2.5 Hz, 2H), 2.71 (t, J = 2.5 Hz, 1H). 13C NMR (75 MHz,
acetone-d6, 25 °C, TMS): δ = 164.5 (s), 138.2 (s), 135.8 (s, 2C), 131.8
3-Chloro-N-(prop-2-ynyl)benzamide was prepared according to GP 2.
Propargylamine (0.11 g, 2.00 mmol), Et3N (0.20 g, 2.00 mmol), DMAP
(5 mg, 2 mol %), and 3-chlorobenzoyl chloride (0.35 g, 2.00 mmol) in
20 mL of DCM were employed. Flash chromatography on silica gel (PE/
EA, 2:1) delivered 0.35 g (1.80 mmol, 90%) of 5i as a white solid. Rf =
̃
(s), 127.0 (s, 2C), 80.8 (s), 72.4 (s), 29.8 (s). IR (neat): ν = 1544,
1566, 1642, 3281 cm−1. MS (70 eV): m/z 227 (41) [M+], 173 (100)
[M+ − C3H4N•]. HRMS (EI (+), 70 eV): [C10H7Cl2NO]+ calcd
226.9905, found 226.9925.
1
0.44 (petroleum ether/ethyl acetate 2:1). H NMR (300 MHz, acetone-
d6, 25 °C, TMS): δ = 8.20 (s, NH), 7.92 (s, 1H), 7.87 (d, J = 7.5 Hz,
1H), 7.58 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 4.20 (dd, J = 5.5,
2.5 Hz, 2H), 2.68 (t, J = 2.5 Hz, 1H). The 1H NMR corresponds to that
reported in the literature.22
3,5-Bis(trifluoromethyl)-N-(prop-2-ynyl)benzamide (5m).
4-Trifluoromethyl-N-(prop-2-ynyl)benzamide (5j).
3,5-Bis(trifluoromethyl)-N-(prop-2-ynyl)benzamide was prepared ac-
cording to GP 2. Propargylamine (0.11 g, 2.00 mmol), Et3N (0.20 g,
2.00 mmol), DMAP (5 mg, 2 mol %), and the chloride (0.55 g,
2.00 mmol) in 20 mL of DCM were employed. Flash chromatography
on silica gel (PE/EA, 4:1) delivered 0.52 g (1.76 mmol, 88%) of 5m as
a white solid. Rf = 0.64 (petroleum ether/ethyl acetate 4:1). Mp:
4-Trifluoromethyl-N-(prop-2-ynyl)benzamide was prepared accord-
ing to GP 2. Propargylamine (0.11 g, 2.00 mmol), Et3N (0.20 g,
2.00 mmol), DMAP (5 mg, 2 mol %), and 4-(trifluoromethyl)-
benzoyl chloride (0.42 g, 2.00 mmol) in 20 mL of DCM were em-
ployed. Flash chromatography on silica gel (PE/EA, 3:1) delivered
0.40 g (1.76 mmol, 88%) of 5j as a white solid. Rf = 0.38 (petroleum
ether/ethyl acetate 3:1). Mp: 146.5−147.0 °C. 1H NMR (300
MHz, acetone-d6, 25 °C, TMS): δ = 8.31 (s, NH), 8.12 (d, J =
8.2 Hz, 2H), 7.83 (d, J = 8.2 Hz, 2H), 4.22 (dd, J = 5.6, 2.5 Hz, 2H),
2.69 (t, J = 2.5 Hz, 1H). 13C NMR (75 MHz, acetone-d6, 25 °C,
TMS): δ = 165.8 (s), 133.4 (s), 133.0 (s), 131.7 (q, 1JC,F = 246.5 Hz),
129.0 (s, 2C), 126.3 (q, 3JC,F = 3.9 Hz, 2C), 81.1 (s), 72.2 (s), 29.7 (s).
1
88.9−89.6 °C. H NMR (300 MHz, acetone-d6, 25 °C, TMS): δ =
8.61 (s, NH), 8.55 (s, 2H), 8.26 (s, 1H), 4.29 (dd, J = 5.5, 2.6 Hz, 2H),
2.75 (t, J = 2.6 Hz, 1H). 13C NMR (75 MHz, acetone-d6, 25 °C,
2
TMS): δ = 164.3 (s), 137.5 (s), 132.4 (q, JC,F = 33.6 Hz, 2C), 125.8
3
3
1
(q, JC,F = 3.8 Hz, 2C), 125.7 (hept, JC,F = 3.9 Hz), 124.2 (q, JC,F
=
̃
272.2 Hz, 2C), 80.6 (s), 72.6 (s), 29.9 (s). IR (neat): ν = 1419, 1454,
1542, 1618, 1647, 3100, 3247 cm−1. MS (70 eV): m/z 295 (66) [M+],
241 (100) [M+ − C3H4N•], 213 (68) [C8H3F6]. HRMS (EI (+),
70 eV): [C12H7NOF6]+ calcd 295.0432, found 295.0409.
IR (neat): ν
̃
= 1547, 1580, 1642, 3309 cm−1. MS (70 eV): m/z 227
(61) [M+], 173 (100) [M+ − C3H4N•], 145 (92) [M+ − C4H4NO•].
HRMS (EI (+), 70 eV): [C11H8F3NO]+ calcd 227.0558, found
227.0555.
3-Nitro-N-(prop-2-ynyl)benzamide (5n).
3,5-Dibromo-N-(prop-2-ynyl)benzamide (5k).
3-Nitro-N-(prop-2-ynyl)benzamide was prepared according to GP 2.
Propargylamine (0.14 g, 2.50 mmol), Et3N (0.30 g, 2.50 mmol),
DMAP (5 mg, 2 mol %), and the chloride (0.46 g, 2.50 mmol) in 20 mL
of DCM were employed. Flash chromatography on silica gel (PE/EA,
2:1) delivered 0.41 g (2.00 mmol, 80%) of 5n as a light yellow solid. Rf =
0.46 (petroleum ether/ethyl acetate 2:1). Mp: 146.5−147.9 °C. 1H NMR
(300 MHz, acetone-d6, 25 °C, TMS): δ = 8.74 (t, J = 1.8 Hz, 1H), 8.51
(s, NH), 8.40 (dt, J = 8.0, 1.8 Hz, 1H), 8.35 (dt, J = 8.0, 1.8 Hz, 1H),
7.81 (t, J = 8.0 Hz, 1H), 4.25 (dd, J = 5.5, 2.5 Hz, 2H), 2.72 (t, J =
2.5 Hz, 1H). 13C NMR (75 MHz, acetone-d6, 25 °C, TMS): δ = 165.0
(s), 149.2 (s), 136.8 (s), 134.3 (s), 131.0 (s), 126.8 (s), 123.0 (s), 81.0
3,5-Dibromo-N-(prop-2-ynyl)benzamide was prepared according
to GP 2. 3,5-Dibromobenzoyl chloride was prepared by heating
at reflux 0.56 g (2.0 mmol) of 3,5-dibromobenzoic acid and 4.72 g
(40 mmol) of SOCl2 during 2 h, and the excess of SOCl2 was
evaporated and the crude used in GP 2 without further purification.
Propargylamine (0.11 g, 2.00 mmol), Et3N (0.20 g, 2.00 mmol),
DMAP (5 mg, 2 mol %), and the chloride (0.597 g, 2.00 mmol) in
20 mL of DCM were employed. Flash chromatography on silica gel
(PE/EA, 4:1) delivered 0.57 g (1.80 mmol, 90%) 5k as a white
solid. Rf = 0.52 (petroleum ether/ethyl acetate 4:1). Mp: 148−
(s), 72.3 (s), 29.8 (s). IR (neat): ν
̃
= 1529, 1579, 1649, 3299 cm−1. MS
(70 eV): m/z 204 (61) [M+], 150 (100) [M+ − C3H4N•]. HRMS (EI
(+), 70 eV): [C10H8N2O3]+ calcd 204.0535, found 204.0523.
1
149.1 °C. H NMR (300 MHz, acetone-d6, 25 °C, TMS): δ = 8.32
3,5-Dinitro-N-(prop-2-ynyl)benzamide (5o).
(s, NH), 8.06 (d, J = 1.8 Hz, 2H), 7.93 (t, J = 1.8 Hz, 1H), 4.20 (dd,
J = 5.5, 2.6 Hz, 2H), 2.70 (t, J = 2.6 Hz, 1H). 13C NMR (75 MHz,
acetone-d6, 25 °C, TMS): δ = 164.2 (s), 138.8 (s), 137.3 (s, 2C),
̃
130.3 (s, 2C), 123.6 (s), 80.8 (s), 72.4 (s), 29.8 (s). IR (neat): ν =
1543, 1555, 3277, 1586, 1634, 3064 cm−1. MS (70 eV): m/z 317
(48) [M+], 263 (100) [M+ − C3H4N•], 235 (54) [C6H3Br2].
HRMS (EI (+), 70 eV): [C10H7NO79Br2]+ calcd 314.8894, found
314.8921.
3,5-Dinitro-N-(prop-2-ynyl)benzamide was prepared according to GP
2. Propargylamine (0.11 g, 2.00 mmol), Et3N (0.20 g, 2.00 mmol),
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DMAP (4 mg, 2 mol %), and 3,5-dinitrobenzoylchloride (0.46 g,
2.00 mmol) in 20 mL of DCM were employed. Flash chromatography
on silica gel (PE/EA, 2:1) delivered 0.40 g (1.60 mmol, 80%) of 5o as
a light yellow solid. Rf = 0.50 (petroleum ether/ethyl acetate 2:1). Mp:
δ = 7.68 (d, J = 1.7 Hz, 1H), 7.66 (dd, J = 7.8, 1.7 Hz, 1H), 7.11 (d, J =
7.8 Hz, 1H), 4.79 (q, J = 2.6 Hz, 1H), 4.62 (t, J = 2.6 Hz, 2H), 4.34 (q,
J = 2.6, 1H), 2.80 (t, J = 6.4 Hz, 4H), 1.81 (qu, J = 6.4 Hz, 4H). 13C
NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 164.0 (s), 159.0 (s), 141.6
(s), 137.4 (s), 129.3 (s), 128.7 (s), 125.0 (s), 123.8 (s), 83.5 (s), 57.6
1
139.5−141.0 °C. H NMR (300 MHz, acetone-d6, 25 °C, TMS): δ =
9.12 (d, J = 1.9 Hz, 2H), 9.10 (t, J = 1.9 Hz, 1H), 8.85 (s, NH), 4.29
(dd, J = 5.4, 2.5 Hz, 2H), 2.76 (t, J = 2.5 Hz, 1H). 13C NMR (75 MHz,
acetone-d6, 25 °C, TMS): δ = 163.1 (s), 149.7 (s), 138.1 (s, 2C), 128.4
̃
(s), 29.5 (s, 2C), 22.9 (s, 2C). IR (neat): ν = 1495, 1647, 1688, 2931
cm−1. MS (70 eV): m/z 213 (100) [M+], 185 (22) [M+ − CO], 171
(66) [M+ − C2H2O•]. HRMS (EI (+), 70 eV): [C14H15NO]+ calcd
213.1154, found 213.1142.
̃
(s, 2C), 121.9 (s), 80.5 (s), 72.7 (s), 30.1 (s). IR (neat): ν = 1541,
1592, 1653, 3289 cm−1. MS (70 eV): m/z 249 (100) [M+], 195 (72)
[M+ − C3H4N•]. HRMS (EI (+), 70 eV): [C10H7N3O5]+ calcd 249.0386,
found 249.0382.
5-Methylene-2-phenyl-4,5-dihydrooxazole (6d).
2-(3,4-Dimethoxyphenyl)-5-methylene-4,5-dihydrooxazole
(6a).
5-Methylene-2-phenyl-4,5-dihydrooxazole was prepared according to
GP 3. Compound 5d (0.30 g, 1.87 mmol) and PPh3AuNTf2 (27 mg,
2 mol %) were employed (reaction time 12 h). Flash chromatography
on silica gel (PE/EA, 1:1) delivered 0.27 g (1.70 mmol, 91%) of 6d as
a light yellow viscous oil. Rf = 0.51 (petroleum ether/ethyl acetate
2-(3,4-Dimethoxyphenyl)-5-methylene-4,5-dihydrooxazole was pre-
pared according to GP 3. Compound 5a (0.24 g, 1.1 mmol) and
PPh3AuNTf2 (16 mg, 2 mol %) were employed (reaction time 20 h).
Flash chromatography on silica gel (PE/EA, 1:1) delivered 0.20 g
(0.91 mmol, 83%) of 6a as a white solid. Rf = 0.22 (petroleum ether/
ethyl acetate 1:1); mp 93.7−95.1 °C; 1H NMR (300 MHz, CDCl3, 25
°C, TMS): δ = 7.56 (dd, J = 8.4, 1.8 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H),
6.90 (d, J = 8.4 Hz, 1H), 4.80 (q, J = 2.8 Hz, 1H), 4.63 (t, J = 2.8 Hz,
2H), 4.34 (q, J = 2.8, 1H), 3.93 (s, 3H), 3.94 (s, 3H). 13C NMR
(75 MHz, CDCl3, 25 °C, TMS): δ = 163.7 (s), 159.1 (s), 152.2 (s),
149.0 (s), 121.8 (s), 119.5 (s), 110.6 (s), 110.5 (s), 83.7 (s), 57.8 (s),
1
1:1). H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.99 (m, 2H),
7.47 (m, 3H), 4.82 (q, J = 2.9 Hz, 1H), 4.65 (t, J = 2.9 Hz, 2H), 4.37
1
(q, J = 2.8, 1H). The H NMR corresponds to that reported in the
literature.4c,7a
5-Methylene-2-(3,4,5-trimethoxyphenyl)-4,5-dihydrooxa-
zole (6e).
56.2 (s), 56.1 (s). IR (neat): ν
̃
= 3085, 2965, 1649, 1605, 1514 cm−1.
MS (70 eV): m/z 219 (100) [M+], 191 (53) [M+ − CO], 177 (98)
[M+ − C2H2O•]. HRMS (EI (+), 70 eV): [C12H13NO3]+ calcd 219.0895,
found 219.0882.
5-Methylene-2-(3,4,5-trimethoxyphenyl)-4,5-dihydrooxazole was pre-
pared according to GP 3. Compound 5e (0.43 g, 1.7 mmol) and
PPh3AuNTf2 (25 mg, 2 mol %) were employed. The reaction was
stirred at 35 °C during 48 h. Flash chromatography on silica gel (PE/
EA, 1:1) delivered 0.25 g (1.0 mmol, 59%) of 6e as a white solid. Cry-
stals suitable for X-ray crystal structure analysis could be obtained.14
2-(4-Butoxyphenyl)-5-methylene-4,5-dihydrooxazole (6b).
1
Rf = 0.28 (petroleum ether/ethyl acetate 1:1). Mp: 70.0−71.1 °C. H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.22 (s, 2H), 4.82 (q, J =
2.8 Hz, 1H), 4.64 (t, J = 2.8 Hz, 2H), 4.36 (q, J = 2.8, 1H), 3.91 (s,
3H), 3.90 (s, 6H). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ =
163.7 (s), 159.0 (s), 153.3 (s, 2C), 141.4 (s), 122.0 (s), 105.3 (s, 2C),
2-(4-Butoxyphenyl)-5-methylene-4,5-dihydrooxazole was prepared ac-
cording to GP 3. Compound 5b (0.46 g, 2.0 mmol) and PPh3AuNTf2
(15 mg, 1 mol %) were employed (reaction time 6 h). Flash chroma-
tography on silica gel (PE/EA, 2:1) delivered 0.36 g (1.56 mmol, 78%)
of 6b as a white solid. Rf = 0.36 (petroleum ether/ethyl acetate 2:1).
̃
84.0 (s), 61.1 (s), 57.9 (s), 56.4 (s, 2C). IR (neat): ν = 1588, 1649,
1686, 2986, 3010 cm−1. MS (70 eV): m/z 249 (100) [M+], 221 (42)
[M+ − CO], 207 (66) [M+ − C2H2O•]. HRMS (EI (+), 70 eV):
[C13H15NO4]+ calcd 249.1001, found 249.1003.
1
Mp: 36.0−36.5 °C. H NMR (300 MHz, CDCl3, 25 °C, TMS): δ =
7.90 (dd, J = 9.2, 2.3 Hz, 2H), 6.92 (dd, J = 9.3, 2.3 Hz, 2H), 4.78 (q,
J = 2.8, 1H), 4.61 (t, J = 2.8 Hz, 2H), 4.33 (q, J = 2.8 Hz, 1H), 4.00 (t,
J = 6.5 Hz, 2H), 1.78 (qu, J = 6.5 Hz, 2H), 1.50 (qt, J = 7.4, 6.5 Hz,
2H), 0.93 (t, J = 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3, 25 °C,
TMS): δ = 163.6 (s), 162.1 (s), 159.1 (s), 129.7 (s, 2C), 118.9 (s),
114.4 (s, 2C), 83.3 (s), 67.9 (s), 57.7 (s), 31.2 (s), 19.2 (s), 13.8 (s).
5-Methylene-2-(naphthalen-2-yl)-4,5-dihydrooxazole (6f).
IR (neat): ν
̃
= 1609, 1652, 1691, 2872, 2936, 2960 cm−1. MS (70 eV):
m/z 231 (76) [M+], 189 (100) [M+ − C2H2O•], 175 (4) [M+ − C4H8•],
133 (94) [C8H7NO+]. HRMS (EI (+), 70 eV): [C14H17NO2]+ calcd
231.1259, found 231.1265.
5-Methylene-2-(naphthalen-2-yl)-4,5-dihydrooxazole was prepared
according to GP 3. Compound 5f (0.418 g, 2.0 mmol) and PPh3Au-
NTf2 (37 mg, 2 mol %) were employed (reaction time 24 h). Flash
chromatography on silica gel (PE/EA, 2:1) delivered 0.29 gr (1.39
mmol, 70%) 6f as a white solid. Rf = 0.46 (petroleum ether/ethyl
5-Methylene-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-4,5-di-
hydrooxazole (6c).
1
acetate 2:1). Mp: 53.7−54.0 °C. H NMR (300 MHz, CDCl3, 25 °C,
TMS): δ = 8.48 (s, 1H), 8.06 (dd, J = 8.5, 1.7 Hz, 1H), 7.93 (dd, J =
6.9, 2.6, 1H), 7.89 (d, J = 8.5 Hz, 1H), 7.87 (dd, J = 6.9, 2.7 Hz, 1H),
7.57 (td, J = 6.9, 2.6 Hz, 1H), 7.53 (td, J = 6.9, 2.6 Hz, 1H), 4.88 (q,
J = 2.8 Hz, 1H), 4.71 (t, J = 2.8 Hz, 2H), 4.40 (q, J = 2.8 Hz, 1H). 13C
NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 163.9 (s), 158.9 (s), 134.9
(s), 132.7 (s), 128.9 (s), 128.8 (s), 128.4 (s), 127.8 (s), 127.9 (s),
5-Methylene-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-4,5-dihydrooxazole
was prepared according to GP 3. Compound 5c (0.25 g, 1.17 mmol)
and PPh3AuNTf2 (16 mg, 2 mol %) were employed (reaction time
12 h). Flash chromatography on silica gel (PE/EA, 3:1) delivered 0.20 g
(0.94 mmol, 80%) 6c as a colorless viscous oil. Rf = 0.52 (petroleum
̃
126.7 (s), 124.2 (s), 124.0 (s), 83.8 (s), 57.9 (s). IR (neat): ν = 1650,
1686, 2834, 2926, 3051, 3436 cm−1. MS (70 eV): m/z 209 (77) [M+],
167 (100) [M+ − C2H2O•], 127 (56) [C10H7+]. HRMS (EI (+), 70 eV):
[C14H11NO]+ calcd 209.0841, found 209.0869.
1
ether/ethyl acetate 3:1). H NMR (300 MHz, CDCl3, 25 °C, TMS):
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5-Methylene-2-(m-tolyl)-4,5-dihydrooxazole (6g).
5-Methylene-2-(4-(trifluoromethyl)phenyl)-4,5-dihydrooxa-
zole (6j).
5-Methylene-2-(m-tolyl)-4,5-dihydrooxazole was prepared accord-
ing to GP 3. Compound 5g (0.25 g, 1.45 mmol) and PPh3AuNTf2
(21 mg, 2 mol %) were employed (reaction time 16 h). Flash
chromatography on silica gel (PE/EA, 2:1) delivered 0.20 g (1.16
mmol, 80%) of 6g as a pale yellow viscous oil. Rf = 0.44 (petroleum
5-Methylene-2-(4-(trifluoromethyl)phenyl)-4,5-dihydrooxazole was
prepared according to GP 3. Compound 5j (0.25 g, 1.10 mmol)
and PPh3AuNTf2 (16 mg, 2 mol %) were employed (reaction time
12 h). Flash chromatography on silica gel (PE/EA, 3:1) delivered
0.20 g (0.88 mmol, 88%) of 6j as a white solid. Rf = 0.62 (petroleum
1
ether/ethyl acetate 2:1). H NMR (300 MHz, CDCl3, 25 °C, TMS):
1
δ = 7.80 (s, 1H), 7.77 (td, J = 4.1, 1.2 Hz, 1H), 7.31 (dd, J = 4.2, 1.1 Hz,
2H), 4.80 (q, J = 2.8 Hz, 1H), 4.63 (t, J = 2.8 Hz, 2H), 4.35 (q, J = 2.8,
1H), 2.39 (s, 3H). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ =
164.0 (s), 159.0 (s), 138.4 (s), 132.7 (s), 128.7 (s), 128.5 (s), 126.7 (s),
ether/ethyl acetate 3:1). Mp: 48.1−49.0 °C. H NMR (300 MHz,
CDCl3, 25 °C, TMS): δ = 8.10 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 8.2 Hz,
2H), 4.85 (q, J = 2.8 Hz, 1H), 4.68 (t, J = 2.8 Hz, 2H), 4.41 (q, J = 2.8,
1H). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 162.6 (s), 158.5
2
1
̃
125.2 (s), 83.8 (s), 57.8 (s), 21.4 (s). IR (neat): ν = 1588, 1647, 1689,
(s), 133.4 (q, JC,F = 32.7 Hz), 131.7 (q, JC,F = 246.5 Hz), 128.4 (s,
2920 cm−1. MS (70 eV): m/z 173 (83) [M+], 145 (32) [M+ − CO], 131
(100) [M+ − C2H2O•]. HRMS (EI (+), 70 eV): [C11H11NO]+ calcd
173.0841, found 173.0835.
3
2C), 125.5 (q, JC,F = 3.8 Hz, 2C), 121.9 (s), 84.5 (s), 57.9 (s). IR
(neat): ν
̃
= 1618, 1649, 1674, 2921 cm−1. MS (70 eV): m/z 227 (28)
[M+], 199 (27) [M+ − CO], 185 (100) [M+ − C2H2O•]. HRMS (EI
(+), 70 eV): [C11H8F3NO]+ calcd 227.0558, found 227.0548.
2-(3,5-Dibromophenyl)-5-methylene-4,5-dihydrooxazole
(6k). 2-(3,5-Dibromophenyl)-5-methylene-4,5-dihydrooxazole was
2-((1,1′-Biphenyl)-3-yl)-5-methylene-4,5-dihydrooxazole
(6h).
prepared according to GP 3. Compound 5k (0.31 g, 0.98 mmol)
and PPh3AuNTf2 (14.4 mg, 2 mol %) were employed. The reaction
was stirred at 35 °C during 36 h. Flash chromatography on silica gel
(PE/EA, 3:1) delivered 0.25 g (0.79 mmol, 81%) of 6k as a white
solid. Rf 1= 0.66 (petroleum ether/ethyl acetate 3:1). Mp: 85.4−
86.3 °C. H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.06 (d, J =
1.7 Hz, 2H), 7.80 (t, J = 1.7 Hz, 1H), 4.84 (q, J = 2.8 Hz, 1H), 4.65 (t,
J = 2.8 Hz, 2H), 4.40 (q, J = 2.8, 1H). 13C NMR (75 MHz, CDCl3,
25 °C, TMS): δ = 161.3 (s), 158.3 (s), 137.1 (s), 130.0 (s, 2C), 129.7
2-((1,1′-Biphenyl)-3-yl)-5-methylene-4,5-dihydrooxazole was pre-
pared according to GP 3. Compound 5h (0.25 g, 1.06 mmol)
and PPh3AuNTf2 (16 mg, 2 mol %) were employed (reaction time
12 h). Flash chromatography on silica gel (PE/EA, 3:1) delivered
0.21 g (0.89 mmol, 84%) of 6h as a white solid. Rf = 0.51
1
(petroleum ether/ethyl acetate 3:1). Mp: 67.7−68.3 °C. H NMR
(300 MHz, CDCl3, 25 °C, TMS): δ = 8.22 (t, J = 1.8 Hz, 1H), 7.96
(dt, J = 7.7, 1.8 Hz, 1H), 7.75 (dt, J = 7.7, 1.8 Hz, 1H), 7.64 (dt, J =
7.5, 1.5 Hz, 2H), 7.52 (t, J = 7.7 Hz, 1H), 7.46 (td, J = 7.5, 1.5 Hz,
2H), 7.37 (tt, J = 7.5, 1.5 Hz, 1H), 4.84 (q, J = 2.8 Hz, 1H), 4.68
(t, J = 2.8 Hz, 2H), 4.38 (q, J = 2.8, 1H). 13C NMR (75 MHz,
CDCl3, 25 °C, TMS): δ = 163.9 (s), 159.0 (s), 141.7 (s), 140.3
(s), 130.6 (s), 129.1 (s), 129.0 (s, 2C), 127.9 (s), 127.4 (s), 127.3
̃
(s, 2C), 127.5 (s), 84.7 (s), 57.8 (s). IR (neat): ν = 1557, 1645, 1694,
2913 cm−1. MS (70 eV): m/z 317 (55) [M+], 289 (47) [M+ − CO],
275 (100) [M+ − C2H2O•]. HRMS (EI (+), 70 eV): [C10H7NO79Br2]+
calcd 314.8894, found 314.8880.
2-(3,5-Dichlorophenyl)-5-methylene-4,5-dihydrooxazole
(6l). 2-(3,5-Dichlorophenyl)-5-methylene-4,5-dihydrooxazole was
̃
(s, 2C), 126.9 (s), 126.8 (s), 84.0 (s), 57.9 (s). IR (neat): ν =
1586, 1601, 1654, 1688, 2851, 2905, 2919 cm−1. MS (70 eV): m/z
235 (100) [M+], 207 (60) [M+ − CO], 193 (100) [M+ − C2H2O•].
HRMS (EI (+), 70 eV): [C16H13NO]+ calcd 235.0997, found
235.1010.
2-(3-Chlorophenyl)-5-methylene-4,5-dihydrooxazole (6i).
prepared according to GP 3. Compound 5l (0.25 g, 1.10 mmol) and
PPh3AuNTf2 (16 mg, 2 mol %) were employed (reaction time 12 h).
Flash chromatography on silica gel (PE/EA, 3:1) delivered 0.23 g
(1.00 mmol, 91%) of 6l as a white solid. Rf = 0.59 (petroleum ether/
2-(3-Chlorophenyl)-5-methylene-4,5-dihydrooxazole was pre-
pared according to GP 3. Compound 5i (0.25 g, 1.29 mmol)
and PPh3AuNTf2 (19 mg, 2 mol %) were employed (reaction time
14 h). Flash chromatography on silica gel (PE/EA, 3:1) delivered
0.20 g (1.03 mmol, 80%) of 6i as a white solid. Rf = 0.6 (petroleum
1
ethyl acetate 3:1). Mp: 71.0−72.1 °C. H NMR (300 MHz, CDCl3,
25 °C, TMS): δ = 7.86 (d, J = 1.8 Hz, 2H), 7.50 (t, J = 1.8 Hz, 1H),
4.84 (q, J = 2.8 Hz, 1H), 4.65 (t, J = 2.8 Hz, 2H), 4.40 (q, J = 2.8, 1H).
13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 161.6 (s), 158.3 (s),
135.4 (s, 2C), 131.7 (s), 129.5 (s), 126.4 (s, 2C), 84.7 (s), 57.8 (s). IR
1
ether/ethyl acetate 3:1). Mp: 43.5−44.7 °C. H NMR (300 MHz,
CDCl3, 25 °C, TMS): δ = 7.96 (t, J = 1.8 Hz, 1H), 7.85 (dt, J =
7.9, 1.8 Hz, 1H), 7.48 (dt, J = 7.9, 1.8 Hz, 1H), 4.82 (q, J = 2.8 Hz,
1H), 4.64 (t, J = 2.8 Hz, 2H), 4.38 (q, J = 2.8, 1H). 13C NMR (75
MHz, CDCl3, 25 °C, TMS): δ = 162.7 (s), 158.7 (s), 134.8 (s),
132.0 (s), 129.9 (s), 128.6 (s), 128.2 (s), 126.2 (s), 84.4 (s), 57.9
(neat): ν
̃
= 1592, 1654, 1689, 2922 cm−1. MS (70 eV): m/z 227 (34)
[M+], 199 (29) [M+ − CO], 185 (100) [M+ − C2H2O•]. HRMS (EI
(+), 70 eV): [C10H7Cl2NO]+ calcd 226.9905, found 226.9915.
2-(3,5-Bis(trifluoromethyl)phenyl)-5-methylene-4,5-dihy-
drooxazole (6m). 2-(3,5-Bis(trifluoromethyl)phenyl)-5-methylene-
4,5-dihydrooxazole was prepared according to GP 3. Compound 5m
(0.30 g, 1.0 mmol) and PPh3AuNTf2 (15.0 mg, 2 mol %) were
employed (reaction time 12 h). Flash chromatography on silica gel
(s). IR (neat): ν
̃
= 1598, 1651, 1691, 2913 cm−1. MS (70 eV): m/z
193 (69) [M+], 165 (13) [M+ − CO], 151 (100) [M+ − C2H2O•].
HRMS (EI (+), 70 eV): [C10H8ClNO]+ calcd 193.0294, found
193.0280.
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(PE/EA, 4:1) delivered 0.26 g (0.88 mmol, 88%) of 6m as a white
solid. Rf = 0.78 (petroleum ether/ethyl acetate 4:1). Mp: 36.8−
37.4 °C. 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.44 (s, 2H),
8.02 (s, 1H), 4.91 (q, J = 2.8 Hz, 1H), 4.71 (t, J = 2.8 Hz, 2H), 4.46 (q,
J = 2.8, 1H). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 161.3 (s),
(d, J = 1.9 Hz, 1H), 7.08 (s, 1H), 6.82 (d, J = 8.9 Hz, 1H), 4.99 (s,
2H), 3.92 (s, 3H), 3.94 (s, 3H). 13C NMR (75 MHz, CDCl3, 25 °C,
TMS): δ = 163.3 (s), 151.4 (s), 149.1 (s), 147.0 (s), 128.8 (s), 120.0
(s), 119.3 (s), 110.9 (s), 109.2 (s), 68.4 (s), 56.2 (s), 56.1 (s). IR
(neat): ν
̃
= 1467, 1508, 1611, 2838, 2937, 3425 cm−1. MS (70 eV):
2
3
158.1 (s), 132.2 (q, JC,F = 33.6 Hz, 2C), 129.0 (s), 128.2 (q, JC,F
=
m/z 251 (1) [M+], 233 (100) [M+ − H2O•], 204 (52) [M+ − CH3O2•].
HRMS (EI (+), 70 eV): [C12H13NO5]+ calcd 251.0794, found 251.0810.
2-(4-Butoxyphenyl)-5-(hydroperoxymethyl)oxazole (7b).
3
1
3.8 Hz, 2C), 125.1 (hept, JC,F = 3.8 Hz), 122.9 (q, JC,F = 272 Hz,
̃
2C), 85.2 (s), 57.8 (s). IR (neat): ν = 1283, 1299, 1401, 1656, 1677
cm−1. MS (70 eV): m/z 295 (27) [M+], 267 (27) [M+ − CO], 253
(100) [M+ − C2H2O•]. HRMS (EI (+), 70 eV): [C12H7NOF6]+ calcd
295.0432, found 295.0431.
2-(3-Nitrophenyl)-5-methylene-4,5-dihydrooxazole (6n). 2-
(3-Nitrophenyl)-5-methylene-4,5-dihydrooxazole was prepared according
2-(4-Butoxyphenyl)-5-(hydroperoxymethyl)oxazole was obtained ac-
cording to GP 4 (reaction time 30 h). Dihydrooxazole (5.78 mg,
0.025 mmol) and 0.05 mL of THF were employed. Flash chromatography
on silica gel (PE/EA, 2:1) delivered 5.50 mg (0.024 mmol, 96%) of 7b
as a white solid. Rf = 0.16 (petroleum ether/ehyl acetate 2:1). Mp:
1
−119.1 °C. H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 9.75 (s,
to GP 3. Compound 5n (0.20 g, 0.98 mmol) and PPh3AuNTf2
(14 mg, 2 mol %) were employed. The reaction was stirred at 35 °C
during 48 h. Flash chromatography on silica gel (PE/EA, 2:1)
delivered 0.18 g (0.88 mmol, 90%) of 6n as a light yellow solid. Rf =
OOH), 7.72 (dd, J = 9.3, 2.3 Hz, 2H), 7.04 (s, 1H), 6.86 (dd, J = 9.3,
2.3 Hz, 2H), 4.96 (s, 2H), 4.01 (t, J = 6.5 Hz, 2H), 1.80 (qu, J =
6.5 Hz, 2H), 1.52 (qt, J = 7.4, 6.5 Hz, 2H), 1.00 (t, J = 7.4 Hz, 3H).
13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 162.6 (s), 161.3 (s),
145.8 (s), 128.4 (s), 128.2 (s, 2C), 118.9 (s), 114.6 (s, 2C), 68.2 (s),
1
0.44 (petroleum ether/ethyl acetate 2:1). Mp: 124.2−125.0 °C. H
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.82 (dd, J = 2.0, 1.2 Hz,
1H), 8.37 (ddd, J = 8.0, 2.0, 1.2 Hz, 1H), 8.32 (dt, J = 8.0, 1.3 Hz, 1H),
7.65 (t, J = 8.0 Hz, 1H), 4.89 (q, J = 2.8 Hz, 1H), 4.70 (t, J = 2.8 Hz,
2H), 4.44 (q, J = 2.8, 1H). 13C NMR (75 MHz, CDCl3, 25 °C, TMS):
δ = 161.8 (s), 158.4 (s), 149.2 (s), 133.6 (s), 129.7 (s), 128.6 (s),
̃
67.9 (s), 31.2 (s), 19.2 (s), 13.8 (s). IR (neat): ν = 1497, 1611, 2872,
2933, 2956, 3131, 3437 cm−1. MS (70 eV): m/z 263 (2) [M+], 245
+
+
(61) [M+ − H2O•], 189 (85) [C10H7NO3 ], 160 (100) [C9H6NO2 ].
HRMS (FAB (+), NBA): [C14H17NO4 + H]+ calcd 264.1236, found
264.1225.
̃
126.3 (s), 123.1 (s), 84.9 (s), 57.9 (s); IR (neat): ν = 1532, 1656,
1697, 2939 cm−1. MS (70 eV): m/z 204 (49) [M+], 176 (61) [M+ − CO],
162 (100) [M+ − C2H2O•]. HRMS (EI (+), 70 eV): [C10H8N2O3]+ calcd
204.0535, found 204.0557.
5-(Hydroperoxymethyl)-2-(5,6,7,8-tetrahydronaphthalen-2-
yl)oxazole (7c).
2-(3,5-Dinitrophenyl)-5-methylene-4,5-dihydrooxazole (6o).
2-(3,5-Dinitrophenyl)-5-methylene-4,5-dihydrooxazole was prepared
5-(Hydroperoxymethyl)-2-(5,6,7,8-tetrahydronaphthalen-2-yl)oxazole
was obtained according to GP 4 (reaction time 36 h). Dihydrooxazole
(63.9 mg, 0.30 mmol) and 0.6 mL of THF were employed. Flash chro-
matography on silica gel (PE/EA, 3:1) delivered 60.0 mg (0.24 mmol,
80%) of 7c as a viscous colorless oil. Rf = 0.24 (petroleum ether/ethyl
1
acetate 3:1). H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 9.78 (s,
according to GP 3. Compound 5o (0.28 g, 1.12 mmol) and PPh3-
AuNTf2 (16 mg, 2 mol %) were employed (reaction time 12 h). Flash
chromatography on silica gel (PE/EA, 3:1) delivered 0.23 g (0.924
mmol, 82.5%) of 6o as a light yellow solid. Rf = 0.42 (petroleum ether/
ethyl acetate 3:1). Mp: 131.2−132.6 °C. 1H NMR (300 MHz, CDCl3,
25 °C, TMS): δ = 9.18 (t, J = 2.0 Hz, 1H), 9.12 (d, J = 2.0 Hz, 2H),
4.96 (q, J = 2.8 Hz, 1H), 4.76 (t, J = 2.8 Hz, 2H), 4.51 (q, J = 2.8, 1H).
13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 160.1 (s), 157.9 (s),
148.7 (s), 130.5 (s, 2C), 127.9 (s, 2C), 121.2 (s), 86.0 (s), 58.1 (s). IR
OOH), 7.60 (d, J = 8.3 Hz, 1H), 7.55 (s, 1H), 7.11 (s, 1H), 7.09 (d,
J = 8.3 Hz, 1H), 5.00 (s, 2H), 2.77 (t, J = 6.5 Hz, 4H), 1.81 (qu, J =
6.5 Hz, 4H). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 163.1 (s),
146.8 (s), 140.4 (s), 137.6 (s), 129.5 (s), 128.7 (s), 127.2 (s), 123.7
̃
(s), 123.6 (s), 68.3 (s), 29.5 (s, 2C). 23.0 (s, 2C). IR (neat): ν = 1484,
1549, 1682, 2932 cm−1. MS (70 eV): m/z 245 (10) [M+], 228 (15)
•
[M+ − OH•], 229 (100) [M+ − H2O], 198 (44) [M+ − CH3O2 ], 170
(41) [C12H12N•]. HRMS (EI (+), 70 eV): [C14H15NO3]+ calcd
245.1052, found 245.1039.
(neat): ν
̃
= 1541, 1653, 1674, 3091 cm−1. MS (70 eV): m/z 249 (52)
5-(Hydroperoxymethyl)-2-phenyloxazole (7d).
[M+], 221 (74) [M+ − CO], 207 (100) [M+ − C2H2O•]. HRMS (EI
(+), 70 eV): [C10H7N3O5]+ calcd 249.0386, found 249.0377.
2-(3,4-Dimethoxyphenyl)-5-(hydroperoxymethyl)oxazole
(7a). 2-(3,4-Dimethoxyphenyl)-5-(hydroperoxymethyl)oxazole was
obtained according to GP 4 (reaction time 25 h). Dihydrooxazole
(10.95 mg, 0.05 mmol) and 0.1 mL of THF were employed. Flash
chromatography on silica gel (PE/EA, 1:1) delivered 10.0 mg (0.046
mmol, 92%) of 7a as a white solid. Rf = 0.1 (petroleum ether/ethyl
acetate 1:1). Mp: 118.0−118.8 °C. 1H NMR (300 MHz, CDCl3,
25 °C, TMS): δ = 9.78 (s, OOH), 7.37 (dd, J = 8.9, 1.9 Hz, 1H), 7.36
5-(Hydroperoxymethyl)-2-phenyloxazole was obtained according to
GP 4 (reaction time 48 h). Dihydrooxazole (79.53 mg, 0.50 mmol)
and 1.0 mL of THF were employed. Flash chromatography on silica
gel (PE/EA, 2:1) delivered 78.0 mg (0.41 mmol, 82%) of 7d as a white
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solid. Rf = 0.34 (petroleum ether/ethyl acetate 2:1). Mp: 87.0−
(s), 138.6 (s), 131.7 (s), 128.8 (s, 2C), 127.1 (s), 126.4 (s), 123.8 (s),
1
88.2 °C. H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 9.81 (s,
68.4 (s), 21.4 (s). IR (neat): ν
̃
= 1527, 1544, 2928, 2959, 3421 cm−1.
OOH), 7.84 (dd, J = 8.2, 1.5 Hz, 2H), 7.40 (m, 3H), 7.14 (s, 1H), 5.00
(s, 2H). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 162.4 (s),
147.5 (s), 130.9 (s), 128.8 (s, 2C), 128.6 (s), 126.5 (s, 2C), 126.3 (s),
MS (70 eV): m/z 205 (2) [M+], 187 (68) [M+ − H2O], 158 (90) [M+
− CH3O2*], 130 (100) [M+ − C2H3O3*]. HRMS (EI (+), 70 eV):
[C11H11NO3]+ calcd 205.0739, found 205.0741.
68.2 (s). IR (neat): ν
̃
= 1347, 1449, 1483, 1548, 2837, 2938, 3139 cm−1.
2-((1,1′-Biphenyl)-3-yl)-5-(hydroperoxymethyl)oxazole (7h).
MS (70 eV): m/z 191 (14) [M+], 174 (10) [M+ − OH•], 173 (68)
[M+ − H2O], 158 (91) [M+ − HO2], 144 (100) [M+ − CH3O2•].
HRMS (EI (+), 70 eV): [C10H9NO3]+ calcd 191.0582, found 191.0570.
5-(Hydroperoxymethyl)-2-(3,4,5-trimethoxyphenyl)oxazole
(7e). 5-(Hydroperoxymethyl)-2-(3,4,5-trimethoxyphenyl)oxazole was
2-((1,1′-Biphenyl)-3-yl)-5-(hydroperoxymethyl)oxazole was obtained
according to GP 4 (reaction time 60 h). Dihydrooxazole (58.8 mg,
0.25 mmol) and 0.5 mL of THF were employed. Flash chroma-
tography on silica gel (PE/EA, 2:1) delivered 43.0 mg (0.16 mmol,
64%) of 7h as a viscous oil. Rf = 0.32 (petroleum ether/ethyl acetate
2:1). 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 9.83 (s, OOH),
8.05 (t, J = 1.7 Hz, 1H), 7.78 (dt, J = 7.7, 1.7 Hz, 1H), 7.54 (m, 3H),
7.42 (m, 4H), 7.15 (s, 1H), 5.02 (s, 2H). 13C NMR (75 MHz, CDCl3,
25 °C, TMS): δ = 162.5 (s), 147.7 (s), 141.7 (s), 140.1 (s), 129.5 (s),
129.3 (s), 129.0 (s, 2C), 128.9 (s), 127.9 (s), 127.2 (s, 2C), 127.0 (s),
obtained according to GP 4 (reaction time 52 h). Dihydrooxazole
(12.46 mg, 0.05 mmol) and 0.1 mL of THF were employed. Flash chro-
matography on silica gel (PE/EA, 1:1) delivered 12.0 mg (0.043 mmol,
86%) 7e as a white solid. Rf = 0.22 (petroleum ether/ethyl acetate 1:1).
Mp: 156.5−157.0 °C. 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ =
11.22 (s, OOH), 7.31 (s, 2H), 7.26 (s, 1H), 5.01 (s, 2H), 3.92 (s, 6H),
3.79 (s, 3H). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 161.7 (s),
154.8 (s, 2C), 149.1 (s), 140.2 (s), 129.6 (s), 122.9 (s), 104.5 (s, 2C),
̃
125.3 (s), 125.1 (s), 68.2 (s). IR (neat): ν = 1457, 1477, 1542, 1684,
3160 cm−1. MS (70 eV): m/z 267 (5) [M+], 250 (20) [M+ − OH•],
•
249 (100) [M+ − H2O], 220 (84) [M+ − CH3O2 ], 192 (94)
̃
68.5 (s), 60.7 (s), 56.6 (s, 2C). IR (neat): ν = 1548, 1590, 2948, 3123,
[C14H10N•]. HRMS (EI (+), 70 eV): [C16H13NO3]+ calcd 267.0895,
found 267.0871.
•
3429 cm−1. MS (70 eV): m/z 281 (2) [M+], 266 (6)[M+ − CH3 ],
264 (17) [M+ − OH•], 263 (100) [M+ − H2O], 248 (35) [M+ −
H2O2]. HRMS (EI (+), 70 eV): [C13H15NO6]+ calcd 281.0899, found
281.0897.
2-(3-Chlorophenyl)-5-(hydroperoxymethyl)oxazole (7i).
5-(Hydroperoxymethyl)-2-(naphthalen-2-yl)oxazole (7f).
2-(3-Chlorophenyl)-5-(hydroperoxymethyl)oxazole was obtained ac-
cording to GP 4 (reaction time 64 h). Dihydrooxazole (48.38 mg,
0.25 mmol) and 0.5 mL of THF were employed. Flash chromato-
graphy on silica gel (PE/EA, 3:1) delivered 40.0 mg (0.18 mmol,
72%)of 7i as a white solid. Rf = 0.24 (petroleum ether/ethyl acetate
3:1). Mp: 121.8−122.2 °C. 1H NMR (300 MHz, CDCl3, 25 °C,
TMS): δ = 9.95 (s, OOH), 7.81 (t, J = 1.5 Hz, 1H), 7.79 (dt, J = 8.1,
1.5 Hz, 1H), 7.43 (dt, J = 8.1, 1.5 Hz, 1H), 7.36 (t, J = 8.1 Hz, 1H),
7.16 (s, 1H), 5.02 (s, 2H). 13C NMR (75 MHz, CDCl3, 25 °C, TMS):
δ = 161.2 (s), 148.0 (s), 135.1 (s), 131.0 (s), 130.3 (s), 129.1 (s), 128.2
5-(Hydroperoxymethyl)-2-(naphthalen-2-yl)oxazole was obtained ac-
cording to GP 4 (reaction time 60 h). Dihydrooxazole (10.45 mg,
0.05 mmol) and 0.1 mL of THF were employed. Flash chromatography
on silica gel (PE/EA, 2:1) delivered 25 mg (0.04 mmol, 80%) of 7f as a
white solid. Crystals suitable for X-ray crystal structure analysis could
be obtained.14 Rf = 0.2 (petroleum ether/ethyl acetate 2:1). Mp:
113.0−114.2 °C. 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 9.74
(s, OOH), 8.29 (s, 1H), 7.99 (dd, J = 8.6, 1.5 Hz, 1H), 7.83 (d, J =
8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 1H), 7.54 (td, J = 8.4, 1.1 Hz, 1H), 7.47
(td, J = 8.4, 1.2 Hz, 1H), 7.23 (s, 1H), 5.07 (s, 2H). 13C NMR
(75 MHz, CDCl3, 25 °C, TMS): δ = 163.0 (s), 162.7 (s), 147.4 (s),
133.5 (s), 132.9 (s), 129.1 (s), 128.8 (s), 128.6 (s), 127.8 (s), 127.5
̃
(s), 126.6 (s), 124.6 (s), 68.3 (s). IR (neat): ν = 1434, 1480, 1541, 1600,
3431 cm−1. MS (70 eV): m/z 225 (3) [M+], 208 (10) [M+ − OH•], 207
(71) [M+ − H2O], 178 (100) [M+ − CH3O2•], 150 (87) [C8H5ClN]+.
HRMS (EI (+), 70 eV): [C10H8ClNO3]+ calcd 225.0193, found 225.0167.
5-(Hydroperoxymethyl)-2-(4-(trifluoromethyl)phenyl)-
oxazole (7j).
̃
(s), 126.7 (s), 123.9 (s), 123.2 (s), 68.4 (s). IR (neat): ν = 1507, 1538,
1632, 3443 cm−1. MS (70 eV): m/z 241 (8) [M+], 223 (100) [M+ −
•
H2O•], 194 (76) [M+ − CH3O2 ]. HRMS (EI (+), 70 eV):
[C14H11NO3]+ calcd 241.0739, found 241.0728.
5-(Hydroperoxymethyl)-2-(m-tolyl)oxazole (7g).
5-(Hydroperoxymethyl)-2-(4-(trifluoromethyl)phenyl)oxazole was
obtained according to GP 4 (reaction time 66 h). Dihydrooxazole
(56.75 mg, 0.25 mmol) and 0.5 mL of THF were employed. Flash chro-
matography on silica gel (PE/EA, 1:1) delivered 60.0 mg (0.23 mmol,
92%) of 7j as a white solid. Rf = 0.22 (petroleum ether/ethyl acetate
1:1). Mp: 87.2−87.9 °C. 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ
= 10.0 (s, OOH), 7.95 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H),
7.20 (s, 1H), 5.04 (s, 2H). 13C NMR (75 MHz, CDCl3, 25 °C, TMS):
5-(Hydroperoxymethyl)-2-(m-tolyl)oxazole was obtained according to
GP 4 (reaction time 60 h). Dihydrooxazole (51.9 mg, 0.3 mmol) and
0.6 mL of THF were employed. Flash chromatography on silica gel
(PE/EA, 2:1) delivered 49.0 mg (0.24 mmol, 80%) of 7g as a pale
1
yellow viscous oil. Rf = 0.26 (petroleum ether/ethyl acetate 2:1). H
1
NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 9.80 (s, OOH), 7.66 (dt,
J = 7.6, 1.5 Hz, 1H), 7.61 (s, 1H), 7.26 (m, 2H), 7.11 (s, 1H), 4.99 (s,
2H). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 162.7 (s), 147.4
δ = 160.8 (s), 148.4 (s), 132.5 (s), 131.7 (q, JC,F =246.5 Hz), 129.0
(s), 126.6 (s, 2C), 125.8 (q, 3JC,F = 3.6 Hz, 2C), 121.7 (s), 68.1 (s). IR
(neat): ν
̃
= 1330, 1554, 2925, 3431 cm−1. MS (70 eV): m/z 259 (3)
6404
dx.doi.org/10.1021/jo301288w | J. Org. Chem. 2012, 77, 6394−6408

The Journal of Organic Chemistry
Featured Article
[M+], 242 (5) [M+ − OH•], 241 (27) [M+ − H2O], 212 (53) [M+ −
252 (83) [C10H4F6N•]. HRMS (EI (+), 70 eV): [C12H7F6NO3]+ calcd
327.0330, found 327.0316.
2-(3,4-Dimethoxyphenyl)-5-(hydroxymethyl)oxazole (8a).
•
CH3O2 ], 184 (100) [C9H5F3N•]. HRMS (EI (+), 70 eV):
[C11H8F3NO3]+ calcd 259.0456, found 259.0453.
2-(3,5-Dibromophenyl)-5-(hydroperoxymethyl)oxazole (7k).
2-(3,4-Dimethoxyphenyl)-5-(hydroxymethyl)oxazole was obtained
according to GP 5. Compound 7a (20 mg, 0.08 mmol), NaBH4
(4.5 mg, 0.12 mmol), and MeOH (5 mL) were employed. Flash chro-
matography on silica gel (PE/EA, 1:2) delivered 15 mg (0.065 mmol,
81%) of 8a as a white solid. Crystals suitable for X-ray crystal structure
analysis could be obtained.14
Rf = 0.11 (petroleum ether/ethyl acetate 1:2); mp 110.0−111.3 °C;
1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.61 (dd, J = 8.4,
1.9 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.05 (s, 1H), 6.92 (d, J = 8.4 Hz,
1H), 4.73 (s, 2H), 3.93 (s, 3H), 3.96 (s, 3H), 2.28 (s, OH); 13C NMR
(75 MHz, CDCl3, 25 °C, TMS): δ = 162.3 (s), 151.2 (s), 150.5 (s),
149.3 (s), 126.0 (s), 120.3 (s), 119.8 (s), 111.1 (s), 109.2 (s), 56.2 (s),
2-(3,5-Dibromophenyl)-5-(hydroperoxymethyl)oxazole was obtained
according to GP 4 (reaction time 104 h). Dihydrooxazole (47.6 mg,
0.15 mmol) and 0.3 mL of THF were employed. Flash chroma-
tography on silica gel (PE/EA, 2:1) delivered 40.0 mg (0.11 mmol,
73%) of 7k as a white solid. Rf = 0.58 (petroleum ether/ethyl acetate
2:1). Mp: 144.2−146.2 °C. 1H NMR (300 MHz, CDCl3, 25 °C,
TMS): δ = 9.11 (s, OOH), 8.04 (d, J = 1.8 Hz, 2H), 7.75 (t, J =
1.8 Hz, 1H), 7.22 (s, 1H), 5.05 (s, 2H). 13C NMR (75 MHz, CDCl3,
25 °C, TMS): δ = 159.6 (s), 148.3 (s), 136.1 (s), 129.7 (s), 129.2 (s),
̃
128.0 (s, 2C), 123.4 (s, 2C), 68.1 (s). IR (neat): ν = 1434, 1535, 1562,
1591, 2848, 3432 cm−1. MS (70 eV): m/z 349 (12) [M+], 332 (11)
[M+ − OH•], 331 (80) [M+ − H2O], 316 (72) [M+ − HO2], 302
̃
56.1 (s), 55.4 (s); IR (neat): ν = 1466, 1501, 1611, 2838, 2937, 3258,
•
(100) [M+ − CH3O2 ]. HRMS (EI (+), 70 eV): [C10H781Br2NO3]+
3428 cm−1; MS (70 eV): m/z 235 (100) [M+], 218 (25) [M+−OH•],
204 (21) [M+-CH3O•]; HRMS (EI (+), 70 eV): [C12H13NO4]+: calcd
235.0845, found 235.0861.
calcd 350.8752, found 350.8747.
2-(3,5-Dichlorophenyl)-5-(hydroperoxymethyl)oxazole (7l).
2-(4-butoxyphenyl)-5-(hydroxymethyl)oxazole 8b:
2-(3,5-Dichlorophenyl)-5-(hydroperoxymethyl)oxazole was obtained
according to GP 4 (reaction time 168 h). Dihydrooxazole (68.4 mg,
0.30 mmol) and 0.6 mL of THF were employed. Flash chromato-
graphy on silica gel (PE/EA, 3:1) delivered 62.0 mg (0.24 mmol, 80%)
of 7l as a white solid. Rf = 0.46 (petroleum ether/ethyl acetate 3:1).
Mp: 133.7−134.8 °C. 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ =
9.22 (s, OOH), 7.83 (d, J = 1.9 Hz, 2H), 7.44 (t, J = 1.9 Hz, 1H), 7.22
(s, 1H), 5.04 (s, 2H). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ =
159.9 (s), 148.2 (s), 135.7 (s, 2C), 130.6 (s), 129.3 (s), 129.2 (s), 124.7
2-(4-butoxyphenyl)-5-(hydroxymethyl)oxazole was obtained accord-
ing to GP 5. 40 mg (0.15 mmol) of 7b, 8.5 mg (0.23 mmol) of NaBH4
and 5 mL of MeOH were employed. Flash chromatography on silica
gel (PE/EA, 2:1) delivered 30 mg (0.12 mmol, 80%) 8b as a white
solid. Crystals suitable for X-ray crystal structure analysis could be
obtained.14 Rf = 0.1 (petroleum ether/ethyl acetate 2:1). Mp: 93.6−
94.5 °C. 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.95 (dd, J =
9.3, 2.4 Hz, 2H), 7.05 (s, 1H), 6.94 (dd, J = 9.3, 2.4 Hz, 2H), 4.72 (s,
2H), 4.01 (t, J = 6.5 Hz, 2H), 2.07 (s, OH), 1.79 (qu, J = 6.5 Hz, 2H),
1.51 (qt, J = 7.4, 6.5 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H). 13C NMR (75
MHz, CDCl3, 25 °C, TMS): δ = 162.5 (s), 161.2 (s), 150.3 (s), 128.2
(s, 2C), 126.1 (s), 120.0 (s), 114.8 (s, 2C), 68.0 (s), 55.5 (s), 31.4 (s),
(s, 2C), 68.1 (s). IR (neat): ν
̃
= 1442, 1538, 1572, 1594, 2935 cm−1. MS
(70 eV): m/z 259 (11) [M+], 242 (4) [M+ − OH•], 241 (28) [M+ −
H2O], 226 (100) [M+ − HO2•], 212 (50) [M+ − CH3O2•], 184 (63)
[C8H4Cl2N]. HRMS (EI (+), 70 eV): [C10H7Cl2NO3]+ calcd 258.9803,
found 258.9792.
̃
19.4 (s), 14.0 (s). IR (neat): ν = 1498, 1611, 2866, 2928, 2957, 3321
•
cm−1. MS (70 eV): m/z 247 (89) [M+], 191 (100) [M+ − C4H8 ],
+
160 (56) [C9H6NO2 ]. HRMS (EI (+), 70 eV): [C14H17NO3]+ calcd
2-(3,5-Bis(trifluoromethyl)phenyl)-5-(hydroperoxymethyl)-
247.1208, found 247.1212.
2-(5,6,7,8-Tetrahydronaphthalen-2-yl)-5-(hydroxymethyl)-
oxazole (8c).
oxazole (7m).
2-(3,5-Bis(trifluoromethyl)phenyl)-5-(hydroperoxymethyl)oxazole
was obtained according to GP 4 (reaction time 192 h, 8 days).
Dihydrooxazole (88.5 mg, 0.3 mmol) and 0.6 mL of THF were em-
ployed. Flash chromatography on silica gel (PE/EA, 3:1) delivered
37.0 mg (0.11 mmol, 37%) of 7m as a white solid. Crystals suitable for
X-ray crystal structure analysis could be obtained.14 Rf = 0.48 (petroleum
ether/ethyl acetate 3:1). Mp: 75.5−77.0 °C. 1H NMR (300 MHz, CDCl3,
25 °C, TMS): δ = 8.96 (s, OOH), 8.44 (s, 2H), 7.95 (s, 1H), 7.31 (s,
1H), 5.09 (s, 2H). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 159.6
2-(5,6,7,8-Tetrahydronaphthalen-2-yl)-5-(hydroxymethyl)oxazole was
obtained according to GP 5. compound 7c (20 mg, 0.082 mmol), NaBH4
(4.6 mg, 0.12 mmol), and MeOH (5 mL) were employed. Flash chro-
matography on silica gel (PE/EA, 2:1) delivered 15 mg (0.066 mmol,
80%) of 8c as a viscous oil. Rf = 0.18 (petroleum ether/ethyl acetate
1
2:1). H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.75 (s, 1H),
7.74 (d, J = 7.8 Hz, 1H), 7.14 (d, J = 7.8 Hz, 1H), 7.08 (s, 1H),
4.73 (s, 2H), 2.81 (m, 4H), 1.82 (m, 4H), 1.74 (s, OH). 13C NMR
(75 MHz, CDCl3, 25 °C, TMS): δ = 162.6 (s), 150.3 (s), 140.2 (s),
137.6 (s), 129.6 (s), 127.1 (s), 125.9 (s), 124.5 (s), 123.5 (s), 55.4 (s),
2
(s), 148.7 (s), 132.6 (q, JC,F = 34.1 Hz, 2C), 129.5 (s), 128.8 (s),
3
3
126.4 (q, JC,F =3.8 Hz, 2C), 123.9 (hept, JC,F = 3.8 Hz), 122.9 (q,
̃
29.5 (s, 2C), 23.0 (s, 2C). IR (neat): ν = 1496, 1551, 1618, 2854,
1JC,F = 272.9 Hz, 2C), 68.1 (s). IR (neat): ν
̃
= 1336, 1389, 1450, 1550,
2925, 3198, 3413 cm−1. MS (70 eV): m/z 229 (100) [M+], 198 (35)
[M+ − CH3O•], 170 (49) [C12H12N•]. HRMS (EI (+), 70 eV):
[C14H15NO2]+ calcd 229.1103, found 229.1113.
3221 cm−1. MS (70 eV): m/z 327 (6) [M+], 310 (5) [M+ − OH•], 309
(24) [M+ − H2O], 294 (100) [M+ − HO2], 280 (39) [M+ − CH3O2•],
6405
dx.doi.org/10.1021/jo301288w | J. Org. Chem. 2012, 77, 6394−6408

The Journal of Organic Chemistry
2-Phenyl-5-(hydroxymethyl)oxazole (8d).
Featured Article
and MeOH (5 mL) were employed. Flash chromatography on silica
gel (PE/EA, 1:1) delivered 35 mg (0.19 mmol, 90%) of 8g as a white
solid. Rf = 0.16 (petroleum ether/ethyl acetate 1:1). Mp: 86.6−
87.5 °C. 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.87 (s, 1H),
7.83 (d, J = 7.6, 1.4 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 7.6
Hz, 1H), 7.11 (s, 1H), 4.74 (s, 2H), 2.41 (s, 3H), 1.93 (s, OH). 13C
NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 162.3 (s), 150.7 (s), 138.6
(s), 131.3 (s), 128.7 (s), 127.2 (s), 127.0 (s), 126.0 (s), 123.5 (s), 55.4
2-Phenyl-5-(hydroxymethyl)oxazole was obtained according to GP 5.
Compound 7d (45 mg (0.24 mmol), NaBH4 (13.36 mg, 0.36 mmol),
and MeOH (5 mL) were employed. Flash chromatography on silica
gel (PE/EA, 2:1) delivered 40 mg (0.23 mmol, 96%) of 8d as a white
solid. Rf = 0.20 (petroleum ether/ethyl acetate 2:1). Mp: 74.5−
(s), 21.3 (s). IR (neat): ν
̃
= 1549, 1611, 2847, 2922, 3101, 3175 cm−1.
MS (70 eV): m/z 189 (84) [M+], 158 (80) [M+ − CH3O•], 130 (100)
[C9H8N•]. HRMS (EI (+), 70 eV): [C11H11NO2]+ calcd 189.0790,
found 189.0787.
1
76.0 °C. H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.04 (m,
2-((1,1′-Biphenyl)-3-yl)-5-(hydroxymethyl)oxazole (8h).
2H), 7.46 (m, 3H), 7.12 (s, 1H), 4.75 (s, 2H), 1.73 (s, OH). 13C NMR
(75 MHz, CDCl3, 25 °C, TMS): δ = 162.4 (s), 150.9 (s), 130.7 (s),
̃
128.9 (s, 2C), 127.6 (s), 126.5 (s, 2C), 126.3 (s), 68.2 (s). IR (neat): ν =
1450, 1483, 1547, 1614, 2852, 3110, 3285 cm−1. MS (70 eV): m/z 175
(100) [M+], 144 (67) [M+ − CH3O•], 116 (80) [C8H6N•]. HRMS (EI
(+), 70 eV): [C10H9NO2]+ calcd 175.0633, found 175.0653.
2-(3,4,5-Trimethoxyphenyl)-5-(hydroxymethyl)oxazole (8e).
2-((1,1′-Biphenyl)-3-yl)-5-(hydroxymethyl)oxazole was obtained ac-
cording to GP 5. Compound 7h (26 mg, 0.10 mmol), NaBH4 (5.7 mg,
0.15 mmol), and MeOH (5 mL) were employed. Flash chromatog-
raphy on silica gel (PE/EA, 2:1) delivered 20 mg (0.08 mmol, 80%) of
8h as a very viscous oil. Rf = 0.35 (petroleum ether/ethyl acetate 2:1).
1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.28 (t, J = 1.7 Hz,
1H), 8.01 (dt, J = 7.7, 1.7 Hz, 1H), 7.68 (dt, J = 7.7, 1.7 Hz, 1H), 7.65
(dt, J = 7.5, 1.5 Hz, 2H), 7.53 (t, J = 7.7 Hz, 1H), 7.47 (td, J = 7.5, 1.5
Hz, 2H), 7.38 (tt, J = 7.5, 1.5 Hz, 1H), 7.13 (s, 1H), 4.76 (s, 2H), 2.14
(s, OH). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 162.1 (s),
150.9 (s), 141.9 (s), 140.2 (s), 129.3 (s), 129.2 (s), 128.9 (s, 2C),
127.7 (s), 127.2 (s, 2C), 126.1 (s), 125.2 (s), 125.1 (s), 55.4 (s, 2C).
2-(3,4,5-Trimethoxyphenyl)-5-(hydroxymethyl)oxazole was obtained ac-
cording to GP 5. Compound 7e (50 mg, 0.18 mmol), NaBH4 (10.2 mg,
0.27 mmol), and MeOH (5 mL) were employed. Flash chromatography
on silica gel (PE/EA, 1:2) delivered 40 mg (0.15 mmol, 83%) of 8e as a
white solid. Crystals suitable for X-ray crystal structure analysis could be
obtained.14 Rf = 0.12 (petroleum ether/ethyl acetate 1:2). Mp: 175.6−
176.6 °C. 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 7.24 (s, 2H),
7.08 (s, 1H), 4.73 (d, J = 4.6 Hz, 2H), 3.92 (s, 6H), 3.88 (s, 3H), 1.93 (t,
J = 4.6 Hz, OH). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 162.2
(s), 153.7 (s, 2C), 150.9 (s), 140.4 (s), 126.3 (s), 122.8 (s), 103.8 (s,
IR (neat): ν
̃
= 1477, 1543, 3034, 3143, 3210, 3276 cm−1. MS (70 eV):
m/z 251 (100) [M+], 220 (39) [M+ − H3O•], 192 (69) [C14H10N•].
HRMS (EI (+), 70 eV): [C16H13NO2]+ calcd 251.0946, found
251.0923.
̃
2C), 61.1 (s), 56.5 (s, 2C), 55.9 (s). IR (neat): ν = 1467, 1497, 1594,
2840, 2944, 3190, 3424 cm−1. MS (70 eV): m/z 265 (100) [M+], 250
(51) [M+ − CH3•], 248 (7) [M+ − OH•], 206 (18) [M+ − C2H3O2•].
HRMS (EI (+), 70 eV): [C13H15NO5]+ calcd 265.0950, found 265.0942.
2-(3-Chlorophenyl)-5-(hydroxymethyl)oxazole (8i).
2-(Naphthalen-2-yl)-5-(hydroxymethyl)oxazole (8f).
2-(3-Chlorophenyl)-5-(hydroxymethyl)oxazole was obtained accord-
ing to GP 5. Compound 7i (27 mg, 0.12 mmol), NaBH4 (6.8 mg, 0.18
mmol), and MeOH (5 mL) were employed. Flash chromatography on
silica gel (PE/EA, 2:1) delivered 23 mg (0.11 mmol, 92%) of 8i as a
white solid. Rf = 0.24 (petroleum ether/ethyl acetate 2:1). Mp: 106.0−
107.4 °C. 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.03 (t, J =
1.9 Hz, 1H), 7.92 (dt, J = 6.8, 1.9 Hz, 1H), 7.41 (m, 2H), 7.13 (s, 1H),
4.75 (s, 2H), 1.98 (s, OH). 13C NMR (75 MHz, CDCl3, 25 °C, TMS):
δ = 160.7 (s), 151.3 (s), 134.9 (s), 130.5 (s), 130.1 (s), 128.9 (s),
2-(Naphthalen-2-yl)-5-(hydroxymethyl)oxazole was obtained according to
GP 5. Compound 7f (10 mg, 0.04 mmol), NaBH4 (3 mg, 0.06 mmol),
and MeOH (2 mL) were employed. Flash chromatography on silica gel
(PE/EA, 2:1) delivered 8 mg (0.035 mmol, 88%) of 8f as a white solid. Rf
= 0.18 (petroleum ether/ethyl acetate 2:1). Mp: 98.6−99.2 °C. 1H NMR
(300 MHz, CDCl3, 25 °C, TMS): δ = 8.53 (s, 1H), 8.11 (dd, J = 8.6, 1.6
Hz, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.85 (m, 1H), 7.53 (m, 2H), 7.16 (s,
1H), 4.79 (s, 2H), 2.77 (s, OH). 13C NMR (75 MHz, CDCl3, 25 °C,
TMS): δ = 162.2 (s), 151.0 (s), 134.2 (s), 133.0 (s), 128.8 (s), 128.7 (s),
127.9 (s), 127.4 (s), 126.8 (s), 126.4 (s), 126.2 (s), 124.5 (s), 123.3 (s),
̃
126.5 (s), 126.2 (s), 124.4 (s), 55.3 (s). IR (neat): ν = 1477, 1544,
1601, 2917, 3103, 3222 cm−1. MS (70 eV): m/z 209 (100) [M+], 178
(84) [M+ − CH3O•], 150 (96) [C8H5ClN•]. HRMS (EI (+), 70 eV):
[C10H8ClNO2]+ calcd 209.0244, found 209.0246.
55.4 (s). IR (neat): ν
̃
= 1539, 1613, 1630, 3057, 3431 cm−1. MS (70 eV):
m/z 225 (100) [M+], 194 (32) [M+ − CH3O•], 166 (55) [C12H8N+].
2-(4-(Trifluoromethyl))-5-(hydroxymethyl)oxazole (8j).
HRMS (EI (+), 70 eV): [C14H11NO2]+ calcd 225.0790, found 225.0782.
2-(m-Tolyl)-5-(hydroxymethyl)oxazole (8g).
2-(4-(Trifluoromethyl))-5-(hydroxymethyl)oxazole was obtained ac-
cording to GP 5. Compound 7j (20 mg, 0.077 mmol), NaBH4 (4.4 mg,
0.12 mmol), and MeOH (5 mL) were employed. Flash chromatography
on silica gel (PE/EA, 2:1) delivered 18 mg (0.074 mmol, 96%) of 8j as
a white solid. Rf = 0.22 (petroleum ether/ethyl acetate 2:1). Mp:
2-(m-Tolyl)-5-(hydroxymethyl)oxazole was obtained according to GP
5. Compound 7g (44 mg, 0.21 mmol), NaBH4 (11.9 mg, 0.32 mmol),
6406
dx.doi.org/10.1021/jo301288w | J. Org. Chem. 2012, 77, 6394−6408

The Journal of Organic Chemistry
Featured Article
1
95.7−96.9 °C. H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.16
1453, 1625, 3411 cm−1. MS (70 eV): m/z 311 (58) [M+], 280 (35)
[M+ − CH3O•], 252 (100) [C10H4F6N•]. HRMS (EI (+), 70 eV):
[C12H7F6NO2]+ calcd 311.0381, found 311.0373.
(d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.18 (s, 1H), 4.78 (s,
2H), 1.77 (s, OH). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ =
1
160.8 (s), 148.0 (s), 132.5 (s), 131.7 (q, JC,F = 246.5 Hz), 129.0 (s),
3
126.6 (s, 2C), 125.8 (q, JC,F = 3.6 Hz, 2C), 121.7 (s), 55.3 (s). IR
ASSOCIATED CONTENT
■
(neat): ν
̃
= 1328, 1418, 1554, 1624, 2934, 3273, 3422 cm−1. MS
S
* Supporting Information
(70 eV): m/z 243 (87) [M+], 212 (55) [M+ − CH3O•], 184 (100)
[C9H5F3N•]. HRMS (EI (+), 70 eV): [C11H8F3NO2]+ calcd 243.0507,
found 243.0501.
1H NMR and 13C NMR spectra for compounds 4a−c, 5a−o,
6a−o, 7a−m, and 8a−m and X-ray data for compounds 6e,
7f,m, and 8a,b,e. This material is available free of charge via the
Internet at http://pubs.acs.org.
2-(3,5-Dibromophenyl)-5-(hydroxymethyl)oxazole (8k).
AUTHOR INFORMATION
Corresponding Author
*E-mail: hashmi@hashmi.de.
■
2-(3,5-Dibromophenyl)-5-(hydroxymethyl)oxazole was obtained ac-
cording to GP 5. Compound 7k (23 mg, 0.07 mmol), NaBH4 (3.74 mg,
0.1 mmol), and MeOH (2 mL) were employed. Flash chromatography
on silica gel (PE/EA, 2:1) delivered 20 mg (0.06 mmol, 86%) of 8k as a
white solid. Rf = 0.29 (petroleum ether/ethyl acetate 2:1). Mp: 141.4−
142.6 °C. 1H NMR (300 MHz, CDCl3, 25 °C, TMS): δ = 8.13 (d, J =
1.7 Hz, 2H), 7.74 (d, J = 1.7 Hz, 1H), 7.14 (s, 1H), 4.76 (s, 2H),
1.59 (s, OH). 13C NMR (75 MHz, CDCl3, 25 °C, TMS): δ = 159.0
(s), 151.4 (s), 135.5 (s), 130.1 (s), 127.7 (s, 2C), 126.2 (s), 123.1 (s,
ACKNOWLEDGMENTS
M.C.B.J. is grateful to the DAAD for a fellowship. Gold salts
were generously donated by Umicore AG & Co. KG.
■
REFERENCES
■
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̃
124.7 (s, 2C), 55.3 (s). IR (neat): ν = 1441, 1541, 1572, 1595, 3081,
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ethyl acetate 2:1). Mp: 80.8−82.0 °C. H NMR (300 MHz, CDCl3,
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̃
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6407
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