Metal-Free Insertion Reactions of Diazo Carbonyls to Azlactones

Article abstract of DOI:10.1021/acs.joc.8b01683

Insertion reactions of diazo carbonyls to azlactones in basic conditions have been performed. The developed method allows the preparation of a wide range of oxazole derivatives in yields ranging from 74 to 98%. Different substituents on both azlactone rings and diazo carbonyls do not compromise the methodology, even those containing stereogenic centers. Isotopic labeling experiments revealed the mechanism may proceed through a rare diazo carbonyl activation by an ammonium salt derivative.

Full text of DOI:10.1021/acs.joc.8b01683

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Metal-free Insertion Reactions of Diazo carbonyls to Azlactones
Amanda C. De Mello, Patrícia Betoni Momo, Antonio Carlos Bender Burtoloso, and Giovanni Wilson Amarante
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01683 • Publication Date (Web): 22 Aug 2018
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Metalꢀfree Insertion Reactions of Diazo carbonyls to
Azlactones
*
Amanda C. de Mello‡, Patricia B. Momo§, Antonio C. B. Burtoloso§ , and
*
Giovanni W. Amarante‡
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‡ Department of Chemistry, Federal University of Juiz de Fora, 36036ꢀ900, Juiz de Fora, MG, Brazil.
§ Institute of Chemistry of São Carlos, University of São Paulo, 13560ꢀ970, São Carlos, SP, Brazil.
TOC Graphic
ABSTRACT
Insertion reactions of diazo carbonyls to azlactones in basic conditions have been
performed. The developed method allows the preparation of a wide range of oxazole
derivatives in yields ranging from 74 to 98%. Different substituents on both azlactone
rings and diazo carbonyls do not compromise the methodology, even those containing
stereogenic centers. Isotopic labelling experiments revealed the mechanism may
proceed through a rare diazo carbonyl activation by an ammonium salt derivative.
Keywords: diazo carbonyls; insertion reactions; azlactones; tertiary amines.
Since the synthesis of the first diazo compound by Theodor Curtius in 18831, the
chemistry involving substances containing a diazo group has been investigated and
explored extensively2–7. They are a remarkable class of compounds due to the range of
different transformations they can perform. Moreover, they are a powerful tool in bondꢀ
forming reactions8–10. Typically, the reactivity of diazo compounds is associated with metal
catalysis11–14 and, among others, great advances in insertion reactions have been reported
with rhodium and copper complexes catalysts15–20
.
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Recently, some studies brought new approaches in insertion reactions of diazo carbonyl
compounds in the absence of metal catalysts. To this end, different types of hydrogen
bonding donor derivatives were explored to the diazo compound protonation step21,22
including the use of strong Brønsted acid catalysts23.
,
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In the present study, an innovative metalꢀfree methodology for insertion reaction in
basic conditions is described. In addition, the use of azlactones24ꢀ26 lead us to oxazole
derivatives, which can present biological activity. It is important to mention that this
heterocycle moiety has been observed in different classes of pharmaceutical agents27–29
(Figure 1).
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BuschꢀPetersen & Corey, 2000
R2OOC
O
O
O
R1
R2
Rhodium Complex
X
X
O
R1
+
N2
X = C,O
21ꢀ76%
Bernardim et al., 2016
R2
R2
O
O
Brønsted acid
R3OH
+
OR1
OR1
OR3
25ꢀ90%
N2
This work
R2OC
O
O
O
O
Brønsted base
+
R1
R2
O
Ph
R1
N
N2
N
Ph
up to 98%
Figure 1. Selective examples of diazo carbonyls insertion reactions.
The studies began using CSA as a Brønsted acid catalyst in diazo insertion reactions.
However, this catalyst afforded traces of the desired product. Phenol has also been tried, but
failed. Notably, the use of triethylamine (1 equiv) in toluene, at room temperature, 24 h
reaction, led to the desired product in good yield (Table 1, entry 2). Nevertheless, to achieve
higher yields, several attempts varying the tertiary amine, solvents, reaction time,
temperature, concentration were carried out (Table 1). Further improvement was observed
when the reaction was carried out using 1 equiv of DIPEA in fluorobenzene (Table 1, entry
11). Longer reaction time gives lower yield (Table 1, entry 12). Perhaps, after 24 h, the
product is unstable in the crude reaction mixture or becomes a little bit more soluble. It is
important to mention, the product is filtered off from the crude reaction mixture.
Concentration at 0.3 mol Lꢀ1 gave the best yield (Table 1, entry 18). Note that the reaction
does not occur in the absence of the base.
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Table 1. Optimization of the insertion reaction conditionsa.
O
O
O
O
O
O
Ph
Additive
+
Ph
Ph
N2
N
N
8
9
Entry
1
additive (equiv)
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Benzene
conc (mol Lꢀ1)
temp (◦C) time (hour) yield (%)
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CSA (10 mol%)
TEA (1.0)
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.3
0.4
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
24
24
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24
24
24
24
24
24
24
24
48
8
Traces
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48
ꢀ
2
DABCO (1.0)
ꢀ
3
4
DMOA (1.0)
DMAP (1.0)
Pyridine (1.0)
DIPEA (1.0)
DIPEA (1.0)
DIPEA (1.0)
DIPEA (1.0)
DIPEA (1.0)
DIPEA (1.0)
DIPEA (1.0)
DIPEA (1.0)
DIPEA (0.5)
DIPEA (0.75)
DIPEA (1.0)
DIPEA (1.0)
71
66
17
82
53
37
87
73
49
73
77
69
71
97
87
5
6
7
8
9
Nitromethane
Fluorobenzene
Fluorobenzene
Fluorobenzene
Fluorobenzene
Fluorobenzene
Fluorobenzene
Fluorobenzene
Fluorobenzene
Fluorobenzene
10
11
12
13
14
15
16
17
18
8
0
24
24
24
24
24
r.t.
r.t.
r.t.
r.t.
19
a
Reactions were carried out using 1 equiv. of azlactone and 1.1 equiv. of diazo carbonyl
derivative.
In order to study the substrate scope of the methodology, a series of functionalized
azlactones were tested (Table 2). The reaction was found to tolerate different azlactones, for
example, the sterically bulky azlactones 1b and 1d provided the desired products 3b and 3d
in 95% and 84% yield. Besides, substitution on the aromatic ring does not adversely
influence the reaction outcome, e.g., products 3g and 3h. Unfortunately, the use of alkyl
group at C2ꢀposition on azlactone ring gave no product. Instead, basically azlactone
decomposition was observed.
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Table 2. Scope of insertion reactions of azlactonesa.
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a Reactions were carried out using a 0.3 mol L−1 solution of 1a−i in fluorobenzene, 1.1 equiv of 2 and 1
equiv of DIPEA. b Concentration of 0.2 mol L−1.
The power of this method could be also demonstrated concerning different diazo
compounds (Table 3). Electronꢀwithdrawing functionalities on the aromatic rings in both
the para and ortho positions gave the corresponding products 3n, 3o and 3p in high yields.
Electronꢀdonating group well tolerated the reaction conditions, affording products 3l and
3m with 87% and 76% yield, respectively. Diazo carbonyls bearing both aliphatic and
unsaturated groups were used to obtain the corresponding products in high yields. Although
the isolated yield was low, the current method was also applied to a secondary diazo
compound, leading to the corresponding product 3t with 21% yield.
It is important to mention that carbamate derivatives 3r and 3s were obtained in good
yields. Moreover, these compounds were submitted for enantiopurity determination, where
chiral HPLC analyses revealed the methodology preserved the chirality (see Supporting
Information). No racemization was observed up to 8 h of reaction.
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Table 3. Scope of insertion reactions in the presence of diazo carbonylsa.
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a Reactions were carried out using a 0.3 mol L−1 solution of 1a−i in fluorobenzene, 1.1 equiv of 2 and 1 equiv
b
of DIPEA. Reaction time was 8 h. [Caution: after this period, significant racemization process]. c Measured
by HPLC with enantiodiscriminating stationary phase. d Reaction in toluene at 90 °C.
A plausible mechanism is also proposed. The presence of an acidic hydrogen (pKa ≈ 9)
in azlactone ring suggests that DIPEA initially deprotonates it, leading to its conjugated
acid and the enolate form of the azlactone30 (Scheme 1, Chart A). Next, the forming
Brønsted acid (ammonium salt of DIPEA) protonates the diazo carbonyl derivative to give a
diazonium ion. Finally, nucleophilic displacement by the enolate leads to the product and
releases molecular nitrogen. To confirm if the ammonium salt of DIPEA could, in fact,
protonate the diazo carbonyl compound and activate it, deuterium studies were carriedꢀout.
First, an ammonium salt of DIPEA, prepared by the reaction between DIPEA and DCl, was
stirred in the presence of diazo compound 2a in fluorobenzene. The analysis of the product
revealed a 35% incorporation of deuterium on diazo 2a (Scheme 1, Chart B). This indicates
that, even being a weak Brønsted acid, the ammonium salt of DIPEA can in fact protonate
the diazo compound. It is worthꢀmentioning that stirring the deuterated azlactone of 1a
(60% deuterium) with diazo 2a did not furnished any of the desired product 3a nor
deuterated 2a, showing that the presence of the base DIPEA is crucial for the reaction to
proceed. Finally, performing the reaction with the same best condition depicted in Table 1
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(entry 18), using deuterated 1a (60% deuterium), led to the product 3a with 5% of
deuterium incorporation (of a maximum of 30%) (Scheme 1, Chart C).
Scheme 1. Mechanistical investigations
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In summary, an insertion reaction of diazo carbonyls to widely available azlactones has
been described. The metalꢀfree methodology was optimized and led to oxazole derivatives
in good to excellent yields. It is worth highlighting the great substrate scope, even diazo
carbonyls bearing stereogenic centers could be used (99% e.e. preserved). To the best of our
knowledge, for the first time, the use of basic conditions in an insertion reaction involving
diazo compounds and azlactones was demonstrated. Finally, isotopic labelling experiments
suggested a mechanism trough a rare DIPEA’s conjugated acid as responsible for the diazo
carbonyl protonation step, following by nucleophilic displacement.
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EXPERIMENTAL SECTION
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1. General Information. Unless otherwise noted, all reagents were obtained
commercially and used without further purification. Unless otherwise noted, all reaction
mixtures were carried out in a flameꢀdried vial under a positive pressure of dry nitrogen.
Analytical thinꢀlayer chromatography (TLC) was performed on precoated glassꢀbacked
TLC plates (silica gel 60 F254) and visualized by a UV lamp (254 nm). Yields refer to
chromatographically purified and spectroscopically pure compounds, unless stated
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1
otherwise. H and 13C spectra were recorded on a 300 MHz, 400 MHz and 500 MHz
1
spectrometer. Chemical shifts are reported in ppm. H NMR spectra are referenced to
13
13
CDCl3 (7.26 ppm), and C NMR spectra are referenced to CDCl3 (77.0 ppm). All C
spectra were measured with complete proton decoupling. Peak multiplicities are
designated by the following abbreviations: s, singlet; d, doublet; dd, doublet of doublets;
ddd, doublet of doublet of doublets; dq, doublet of quartets; ddt, doublet of doublet of
triplets; q, quartet; t, triplet; sex, sextet; sept, septet; m, multiplet; br, broad; and J,
coupling constants in hertz. High resolution mass spectra were acquired in the positiveꢀ
ion mode using a mass spectrometer equipped with an electrospray ionization source
HRMS (ESIꢀQTOF). Chiral HPLC analysis was carried out using instrument fitted with a
plate autosampler and a Chiralpak IA column.
2. General Procedure and Characterization Data for azlactones. Azlactones 1aꢀj
were prepared according to the literature method31,32. To a suspension of Nꢀbenzoyl
amino acid (1 equiv) in dry CH2Cl2 (0.1 mol Lꢀ1) under N2 at 0 °C was added EDC.HCl
(1.3 equiv). The crude was stirred for 1 h. The reaction mixture was diluted with an equal
volume of CH2Cl2, and washed successively with cold water (6x, 5 mL), then dried over
anhydrous Na2SO4 and concentrated under reduced pressure. In all cases, corresponding
products were obtained in a pure form and use without further purification.
4-methyl-2-phenyloxazol-5(4H)-one. The product 1a was obtained as a white solid (226.2
1
mg, 82%). H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 7.4 Hz, 2H), 7.58 (t, J = 7.4 Hz,
1H), 7.49 (t, J = 7.6 Hz, 2H), 4.45 (q, J = 7.6 Hz, 1H), 1.59 (d, J = 7.6 Hz, 3H). 13C{1H}
NMR (125 MHz, CDCl3) δ 179.0, 161.5, 132.7, 128.7, 127.8, 125.8, 61.0, 16.8.
4-isobutyl-2-phenyloxazol-5(4H)-one. The product 1b was obtained as a white solid (82.1
mg, 90%). 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J = 7.5 Hz, 2H), 7.60 – 7.46 (m, 3H),
4.42 (dd, J = 9.0, 5.7 Hz, 1H), 2.13 – 2.02 (m, 1H), 1.89 – 1.80 (m, 1H), 1.73 ꢀ 1.64 (m,
1H), 1.05 – 1.03 (m, 6H). 13C{1H} NMR (75 MHz, CDCl3) δ 179.1, 161.7, 133.0, 129.0,
128.8, 128.2, 127.3, 126.2, 64.1, 41.0, 25.4, 23.0, 22.3.
4-isopropyl-2-phenyloxazol-5(4H)-one. The product 1c was obtained as a white solid
1
(86.3 mg, 85%). H NMR (500 MHz, CDCl3) δ 8.01ꢀ7.99 (m, 2H), 7.56 (dt, 1H, J =
6.7 Hz, J = 1.2 Hz), 7.48ꢀ7.45 (m, 2H), 4.27 (d, 1H, J = 4.6 Hz), 2.37 (sept, 1H, J = 6.9
13
Hz, J = 4.6 Hz), 1.14 (d, 3H, J = 6.9 Hz), 1.01 (d, 3H, J = 6.9 Hz). C{1H} NMR (125
MHz, CDCl3) δ 177.9, 161.7, 132.7, 128.8, 128.0, 126.0, 70.8, 31.3, 18.8, 17.6.
4-(sec-butyl)-2-phenyloxazol-5(4H)-one. The product 1d was obtained as a yellow oil
(186.0 mg, 84%). 1H NMR (500 MHz, CDCl3) δ (appeared as a mixture of diastereomers)
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8.02 ꢀ 7.99 (m, 2H), 7.58 – 7.55 (m, 1H), 7.50 – 7.46 (m, 2H), 4.39 (d, J = 4.5 Hz, 1H),
2.17 – 2.12 (m, 1H), 1.73 ꢀ 1.53 (m, 1H), 1.49 ꢀ 1.36 (m, 1H), 1.07 – 0.90 (m, 6H).
13C{1H} NMR (125 MHz, CDCl3) δ (appeared as a mixture of diastereomers) 178.7,
177.9, 161.8, 161.7, 132.8, 130.7, 129.0, 128.9, 128.0, 126.1, 69.9, 69.3, 37.9, 26.4, 25.1,
15.6, 14.6, 11.9, 11.8.
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4-benzyl-2-phenyloxazol-5(4H)-one. The product 1e was obtained as a white solid (89.4
mg, 89%). 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J = 4.0 Hz, 2H), 7.55 – 7.50 (m, 1H),
7.49 – 7.40 (m, 2H), 7.28 – 7.19 (m, 5H), 4.67 (dd, J = 6.6, 5.0 Hz, 1H), 3.36 (dd, J =
14.0, 4.8, 1H), 3.17 (dd, J = 14.0, 6.6 Hz, 1H). 13C{1H} NMR (75 MHz, CDCl3) δ 177.7,
161.9, 135.5, 132.6, 129.7, 128.9, 128.6, 128.0, 127.3, 126.0, 66.7, 37.5.
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4-allyl-2-phenyloxazol-5(4H)-one. The product 1f was obtained as a yellow oil (67.3 mg,
1
93%). H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 7.1 Hz, 2H), 7.60 (t, J = 7.5 Hz, 1H)
7.51 (t, J = 7.7 Hz, 2H), 5.82 (ddt, J = 17.4, 10.2, 6.9 Hz, 1H), 5.27 (dq, J = 17.1, 1.4 Hz,
1H), 5.19 (dd, J = 10.2, 1.4 Hz, 1H), 4.52 (dd, J = 7.5, 5.5 Hz, 1H), 2.84 (ddd, J = 14.1,
6.7, 5.5 Hz, 1H), 2.67 (ddd, J = 14.2, 7.5, 6.5 Hz, 1H). 13C{1H} NMR (125 MHz, CDCl3)
δ 177.7, 161.9, 132.8, 132.6, 131.4, 128.8, 128.0, 119.8, 65.4, 35.4.
4-methyl-2-(p-tolyl)oxazol-5(4H)-one. The product 1g was obtained as a white solid (74.0
1
mg, 98%). H NMR (500 MHz, CDCl3) δ 7.90 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.0 Hz,
2H), 4.46 (q, J = 7.5 Hz, 1H), 2.45 (s, 3H), 1.61 (d, J = 7.6 Hz, 3H). 13C{1H} NMR (125
MHz, CDCl3) δ 179.1, 161.6, 143.5, 129.6, 127.9, 123.1, 61.0, 21.7, 17.0.
2-(4-bromophenyl)-4-methyloxazol-5(4H)-one. The product 1h was obtained as a white
1
solid (70.9 mg, 93%). H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 8.5 Hz, 2H), 7.64 (d, J
13
= 8.5 Hz, 2H), 4.44 (q, J = 7.6 Hz, 1H), 1.59 (d, J = 7.6 Hz, 3H). C{1H} NMR (125
MHz, CDCl3) δ 178.6, 160.9, 132.2, 129.3, 127.7, 124.8, 61.2, 16.8.
4-(2-(methylthio)ethyl)-2-phenyloxazol-5(4H)-one. The product 1f was obtained as a
1
colorless oil (77.2 mg, 82%). H NMR (500 MHz, CDCl3) δ 7.99 (d, J = 7.5 Hz, 2H),
7.57 (t, J = 7.4 Hz, 1H) 7.48 (t, J = 7.6 Hz, 2H), 4.60 (t, J = 6.5 Hz, 1H), 2.73 (t, J = 7.1
13
Hz, 2H), 2.34 – 2.27 (m, 1H), 2.18 – 2.09 (m, 4H). C{1H} NMR (125 MHz, CDCl3) δ
178.6, 160.9, 132.2, 129.3, 127.7, 124.8, 61.2, 16.8.
3. General Procedure and Characterization Data for αꢀdiazoketones. αꢀdiazoketones
were prepared according to the literature method33ꢀ42. The corresponding acyl halides (8
mmol, 1 equiv) were added dropwise to ethereal solution of diazomethane (0.4 M, 20
mmol, 2.5 equiv, 50 mL) at 0 °C and the crude reaction mixture was warmed to room
temperature and stirred for 2 h. After that, the solvent was removed under vacuum and
the residue purified by flash column chromatography (hexane/EtOAC 9:1) to afford
diazoketones 2aꢀh. Diazoketones 2j and 2k were prepared via mixed anhydrides. To that,
NꢀCbz phenylalanine (10 mmol, 3.2 g) in dry Et2O (22 mL) and THF (22 mL) was stirred
at ꢀ20 °C under argon atmosphere. Then, triethylamine (10 mmol, 1 equiv, 1.4 mL) was
added followed by isobutyl chloroformate (10 mmol, 1 equiv, 1.3 mL). The solution was
stirred for 30 min and subsequently warmed to ꢀ10 °C. Then, an ethereal solution of
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diazomethane (0.4 M, 23 mmol, 2.3 equiv, 58 mL) was added via syringe pump for 30
min and the reactional mixture was stirred for 3 h while it was warmed to room
temperature. The solvent was removed under reduced pressure and the crude product was
diluted with Et2O (25 mL) and washed with H2O (25 mL), saturated aqueous NaHCO3
(25 ml), and brine (25 ml). The organic phase was dried with Na2SO4 and the volatiles
were removed under reduced pressure. The crude product was purified by flash column
chromatography (EtOAc–hexane 2:8–1:1).
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2-diazo-1-phenylethan-1-one. The product 2a was obtained as a yellow solid (1.0 g,
90%). 1H NMR (500 MHz, CDCl3)
δ 7.79 – 7.73 (m, 2H), 7.58 – 7.51 (m, 1H), 7.45 (m,
2H), 5.91 (s, 1H). 13C{1H} NMR (125 MHz, CDCl3) δ 186.3, 136.7, 132.7, 128.7, 126.7,
126.7, 54.2.
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1-diazopentan-2-one. The product 2b was obtained as a yellow oil (0.69 g, 77%). H
NMR (400 MHz, Benzeneꢀd6) δ 4.41 (s, 1H), 1.85 (t, J = 7.3 Hz, 2H), 1.53 – 1.41 (m,
2H), 0.75 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (126 MHz, Benzeneꢀd6) δ 193.3, 52.8, 42.7,
18.6, 13.8.
1-diazo-3,3-dimethylbutan-2-one. The product 2c was obtained as a yellow oil (0.87 g,
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86%). H NMR (500 MHz, CDCl3) δ 5.45 (s, 1H), 1.15 (s, 9H). 13C{1H} NMR (101
MHz, CDCl3) δ 201.3, 42.6, 27.1.
1-diazo-4-(3-methoxyphenyl)butan-2-one. The product 2d was obtained as a yellow oil
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(1.4 g, 85%). H NMR (500 MHz, CDCl3) δ 7.21 – 7.16 (m, 1H), 6.80 – 6.70 (m, 3H),
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5.22 (s, 1H), 3.76 (s, 3H), 2.94 – 2.87 (m, 2H), 2.67ꢀ2.53 (m, 2H). C{1H} NMR (125
MHz, CDCl3) δ 193.9, 159.7, 142.2, 129.5, 120.6, 114.1, 111.5, 55.1, 54.6, 42.2, 30.9.
2-diazo-1-(4-methoxyphenyl)ethenone. The product 2e was obtained as a yellow solid
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(0.82 g, 58%). H NMR (500 MHz, CDCl3) δ 7.77 – 7.71 (m, 2H), 6.95 – 6.90 (m, 2H),
5.85 (s, 1H), 3.86 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 185.2, 163.2, 132.2,
129.5, 128.7, 113.8, 55.4, 53.4.
1-(4-chlorophenyl)-2-diazoethanone. The product 2f was obtained as a yellow solid (1.1
g, 75%). 1H NMR (400 MHz, CDCl3) δ 7.73 – 7.67 (m, 2H), 7.45 – 7.39 (m, 2H), 5.87 (s,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 184.9, 139.0, 135.0, 129.0, 128.1, 54.4.
2-diazo-1-(4-nitrophenyl)ethanone. The product 2g was obtained as a yellow solid (1.0 g,
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68%). H NMR (500 MHz, CDCl3) δ 8.33 – 8.28 (m, 2H), 7.95 – 7.91 (m, 2H), 5.99 (s,
1H). 13C{1H} NMR (125 MHz, CDCl3) δ 184.0, 150.2, 141.4, 127.8, 123.9, 55.7.
1-(2-chlorophenyl)-2-diazoethanone. The product 2h was obtained as a yellow solid (1.4
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g, 95%). H NMR (400 MHz, CDCl3) δ 7.60ꢀ7.48 (m, 1H), 7.44 – 7.30 (m, 3H), 5.81 (s,
1H). 13C{1H} NMR (101 MHz, CDCl3) δ 186.6, 137.4, 131.8, 131.1, 130.5, 129.3, 127.0,
57.8.
Benzyl (S)-(4-diazo-3-oxo-1-phenylbutan-2-yl)carbamate. The product 2j was obtained as
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a pale yellow solid (1.8 g, 68%). H NMR (500 MHz, CDCl3) δ 7.40 – 7.09 (m, 10H),
5.39 (br s, 1H), 5.20 (s, 1H), 5.08 (s, 2H), 4.55 – 4.41 (m, 1H), 3.04 (d, J = 6.8 Hz, 2H).
13C{1H} NMR (125 MHz, CDCl3) δ 192.7, 155.7, 136.2, 136.0, 129.3, 128.7, 128.5,
128.2, 128.1, 127.1, 67.0, 58.9, 54.6, 38.5.
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Benzyl (R)-(4-diazo-3-oxo-1-phenylbutan-2-yl)carbamate. The product 2k was obtained
as a pale yellow solid (1.6 g, 63%). H NMR (500 MHz, CDCl3) δ 7.42 – 7.05 (m, 10H),
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5.48 – 5.38 (m, 1H), 5.21 (s, 1H), 5.07 (s, 2H), 4.54 – 4.42 (m, 1H), 3.03 (d, J = 6.7 Hz,
2H). 13C{1H} NMR (125 MHz, CDCl3) δ 192.7, 155.7, 136.1, 136.0, 129.3, 128.7, 128.5,
128.2, 128.0, 127.1, 67.0, 58.9, 54.6, 38.5.
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4. General Procedure and Characterization Data for (E)ꢀ1ꢀdiazoꢀ4ꢀphenylbutꢀ3ꢀenꢀ
2ꢀone. (E)-1-diazo-4-phenylbut-3-en-2-one was prepared according to the literature
method43. To a solution of diethyl 3ꢀdiazoꢀ2ꢀoxopropylphosphonate (400 mg, 1.81 mmol,
1 equiv.) and benzaldehyde (185 µL, 1.81 mmol, 1 equiv.) in EtOH (5 mL) at room
temperature was added 3.6 mL of 0.5 mol Lꢀ1 of NaOH solution (water:EtOH, 1:1) via
syringe pump during a period of 1 h. The mixture was stirred for further 30 min and then
the reaction was quenched by the addition of saturated NaCl (20 mL). The mixture was
extracted with CH2Cl2 (3 x 20 mL) and dried over MgSO4. The crude product was
purified by flash column chromatography (EtOAc/hexane 1:9) to afford unsaturated
diazoketone 2i (233.7 mg, 75%) as yellow solid. 1H NMR (500 MHz, CDCl3) δ 7.59 (d, J
= 15.8 Hz, 1H), 7.55ꢀ7.51 (m, 2H), 7.39ꢀ7.37 (m, 3H), 6.60 (d, J = 15.8 Hz, 1H), 5.45 (s,
1H). 13C{1H} NMR (125 MHz, CDCl3) δ 184.3, 140.7, 134.4, 130.3,128.9, 128.2, 123.7,
56.2.
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5. General Procedure and Characterization Data for Preparation of methyl 2ꢀdiazoꢀ
2ꢀphenylacetate. Methyl 2-diazo-2-phenylacetate was prepared according to the
literature method44. To a solution of methyl 2ꢀphenylacetate (1.50 g, 10 mmol, 1 equiv.)
and 4ꢀacetamidobenzenesulfonyl azide (pꢀABSA) (2.88 g, 12 mmol, 1.2 equiv.) in
anhydrous CH3CN (30 mL) 2.10 mL of 1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene (DBU) (14
mmol, 1.4 equiv.) was added. The reaction mixture was stirred at room temperature for
16 h. After this time, the reaction mixture was diluted with distilled water (20 mL)
followed by extraction with diethyl ether (3 × 10 mL). The organic phase was washed
with 10% NH4Cl solution (3 x 10 mL) and brine (3 x 10 mL), the combined organic
extracts were dried over MgSO4 and concentrated under reduced pressure. The residue
was purified by flash column chromatography to afford 2l (1.4 g, 81%) as an orange oil.
1H NMR (500 MHz, CDCl3) δ 7.51 – 7.45 (m, 2H), 7.42 – 7.35 (m, 2H), 7.22 – 7.15 (m,
1H), 3.87 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 165.6, 129.0, 125.8, 125.5, 124.0,
52.0.
6. General Procedure and Characterization Data for the insertion products. To a
solution of azlactone (0.1 mmol) and diazo compound (0.11 mmol, 1.1 equiv) in
fluorobenzene (0.33 mL, 0.3 mol L−1 ) was added the DIPEA (0.1 mmol, 1 equiv) at
room temperature for 24 h. After reaction completion, the precipitate formed was filtered
off under reduced pressure.
2-((4-methyl-2-phenyloxazol-5-yl)oxy)-1-phenylethan-1-one. The product 3a was
obtained as a white solid (28.6 mg, 97%), m.p. 96.8ꢀ98.7 °C .IR (ZnSe, cmꢀ1): 3419,
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3357, 3242, 2996, 2949, 1686, 1521, 1442, 1349, 1229, 838, 726, 688. H NMR (500
MHz, CDCl3) δ 8.06 (d, J = 6.8 Hz, 2H), 8.00 (d, J = 7.2 Hz, 2H), 7.66 (t, J = 7.5 Hz,
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1H), 7.54 (t, J = 7.7 Hz, 2H), 7.43 – 7.36 (m, 3H), 5.60 (s, 2H), 2.45 (s, 3H). C{1H}
NMR (125 MHz, CDCl3) δ 190.6, 161.1, 154.6, 134.4, 134.1, 130.9, 129.1, 129.1, 128.5,
128.2, 126.2, 54.5, 12.0. HRMS (ESIꢀQTOF) m/z: [M + Na]+ calcd for C18H15NO3Na
316.0944, found 316.0926.
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2-((4-isobutyl-2-phenyloxazol-5-yl)oxy)-1-phenylethan-1-one. The product 3b was
obtained as a white solid (31.8 mg, 95%), m.p. 71.2ꢀ72.6 °C. IR (ZnSe, cmꢀ1): 3060,
2960, 2929, 2873, 1693, 1596, 1481, 1445, 1349, 1226, 984, 751, 718, 689, 844. 1H NMR
(500 MHz, CDCl3) δ 8.08 (d, J = 7.0 Hz, 2H), 8.02 (d, J = 7.9 Hz, 2H), 7.67 (t, J = 7.4
Hz, 1H), 7.55 (t, J = 7.7 Hz, 2H), 7.44 – 7.36 (m, 3H), 5.61 (s, 2H), 2.57 (d, J = 7.3 Hz,
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2H), 2.29 – 2.20 (m, 1H), 1.01 (d, J = 6.6 Hz, 6H). C{1H} NMR (125 MHz, CDCl3) δ
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190.8, 161.3, 157.6, 134.4, 134.2, 131.1, 129.1, 129.0, 128.4, 128.2, 126.4, 54.3, 34.9,
27.9, 22.4. HRMS (ESIꢀQTOF) m/z: [M + Na] + calcd for C21H21NO3Na 358.1419, found
358.1415.
2-((4-isopropyl-2-phenyloxazol-5-yl)oxy)-1-phenylethan-1-one. The product 3c was
obtained as a white solid (30.8 mg, 96%), m.p. 145.6ꢀ148.2 °C. IR (ZnSe, cmꢀ1): 3063,
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2972, 2936, 2863, 1688, 1596, 1496, 1453, 1348, 1223, 838, 748, 680. H NMR (500
MHz, CDCl3) δ 8.08 (d, J = 6.9 Hz, 2H), 8.02 (d, J = 8.0 Hz, 2H), 7.66 (t, J = 7.5 Hz,
1H), 7.54 (t, J = 7.9 Hz, 2H), 7.44 – 7.33 (m, 3H), 5.62 (s, 2H), 2.90 (sept, J = 6.8 Hz,
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1H), 1.39 (d, J = 6.9 Hz, 6H). C{1H} NMR (125 MHz, CDCl3) δ 191.0, 162.8, 161.3,
134.3, 134.2, 131.3, 129.1, 128.9, 128.4, 128.1, 126.4, 54.2, 26.0, 21.4. HRMS (ESIꢀ
QTOF) m/z: [M + Na] + calcd for C20H19NO3Na 344.1257, found 344.1247.
2-((4-(sec-butyl)-2-phenyloxazol-5-yl)oxy)-1-phenylethan-1-one. The product 3d was
obtained as a white solid (28.2 mg, 84%), m.p. 88.8ꢀ91.9 °C. IR (ZnSe, cmꢀ1): 3063,
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2962, 2924, 2870, 1690, 1595, 1479, 1448, 1346, 1222, 986, 746, 684. H NMR (500
MHz, CDCl3) δ 8.08 (d, J = 7.2 Hz, 2H), 8.02 (d, J = 7.6 Hz, 2H), 7.66 (t, J = 7.2 Hz,
1H), 7.54 (t, J = 7.5 Hz, 2H), 7.42 – 7.36 (m, 3H), 5.67 (d, J = 17.8 Hz, 1H), 5.58 (d, J =
17.8 Hz, 1H), 2.70 – 2.60 (sex, J = 6.9 Hz,1H), 1.96 – 1.87 (m, 1H), 1.75 – 1.67 (m, 1H),
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1.37 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H). C{1H} NMR (125 MHz, CDCl3) δ
191.0, 162.2, 161.4, 134.3, 134.3, 131.3, 129.1, 128.9, 128.4, 128.2, 126.2, 54.2, 33.1,
28.9, 19.3, 12.0. HRMS (ESIꢀQTOF) m/z: [M + Na] + calcd for C21H21NO3Na 358.1419,
found 358.1406.
2-((4-benzyl-2-phenyloxazol-5-yl)oxy)-1-phenylethan-1-one. The product 3e was obtained
as a white solid (33.5 mg, 91%) using the general procedure with concentration of 0.2
mol L−1 of azlactone in fluorobenzene, m.p. 159.7ꢀ161.2 °C. IR (ZnSe, cmꢀ1): 3080, 3059,
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3026, 2977, 2936, 1692, 1596, 1479, 1438, 1348, 1226, 841, 761, 716, 691. H NMR
(500 MHz, CDCl3) δ 8.11 (d, J = 7.0 Hz, 2H), 7.86 (d, J = 7.9 Hz, 2H), 7.64 (t, J = 7.3
Hz, 1H), 7.49 (t, J = 7.7 Hz, 2H), 7.46 – 7.36 (m, 3H), 7.30 – 7.16 (m, 5H), 5.37 (s, 2H),
4.22 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 190.7, 161.2, 156.2, 135.0, 134.3,
134.1, 130.9, 129.1, 129.0, 128.9, 128.6, 128.5, 128.0, 127.2, 126.3, 54.8, 32.7. HRMS
(ESIꢀQTOF) m/z: [M + Na] + calcd for C24H19NO3Na 392.1257, found 392.1261.
2-((4-allyl-2-phenyloxazol-5-yl)oxy)-1-phenylethan-1-one. The product 3f was obtained
as a light orange solid (27.3 mg, 86%), m.p. 126.7ꢀ128.0 °C. IR (ZnSe, cmꢀ1): 3067,
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2982, 2922, 1696, 1592, 1475, 1446, 1345, 1221, 922, 724, 684. H NMR (500 MHz,
CDCl3) δ 8.08 (d, J = 7.2 Hz, 2H), 7.99 (d, J = 7.5 Hz, 2H), 7.66 (t, J = 7.2 Hz, 1H), 7.54
(t, J = 7.5 Hz, 2H), 7.45 – 7.35 (m, 3H), 6.01 – 5.94 (m, 1H), 5.62 (s, 2H), 5.17 (d, J
=10.1 Hz, 1H), 5.13 (d, J =17.21 Hz, 1H), 3.58 (d, J = 5.8 Hz, 2H). 13C{1H} NMR (125
MHz, CDCl3) δ 190.8, 161.3, 155.5, 134.4, 134.2, 131.7, 130.9, 129.1, 128.5, 128.1,
126.3, 118.3, 54.6, 30.9. HRMS (ESIꢀQTOF) m/z: [M + Na] + calcd for C20H17NO3Na
342.1101, found 342.1084.
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2-((4-methyl-2-(p-tolyl)oxazol-5-yl)oxy)-1-phenylethan-1-one. The product 3g was
obtained as a white solid (25.5 mg, 83%), m.p. 156.4ꢀ157.6 °C. IR (ZnSe, cmꢀ1): 3064,
3037, 2934, 1695, 1592, 1492, 1452, 1338, 1222, 748, 688.1H NMR (500 MHz, CDCl3) δ
8.01 (d, J = 6.8 Hz, 2H), 7.94 (d, J = 8.2 Hz, 2H), 7.67 (t, J = 7.5 Hz, 1H), 7.54 (t, J = 7.6
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Hz, 2H), 7.22 (d, J = 7.4, 2H), 5.59 (s, 2H), 2.44 (s, 3H), 2.38 (s, 3H). C{1H} NMR
(125 MHz, CDCl3) δ 190.7, 161.2, 154.4, 139.0, 134.4, 134.1, 129.2, 129.1, 128.1, 126.1,
54.5, 21.3, 12.0. HRMS (ESIꢀQTOF) m/z: [M + Na] + calcd for C19H17NO3Na 330.1101,
found 330.1086.
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2-((2-(4-bromophenyl)-4-methyloxazol-5-yl)oxy)-1-phenylethan-1-one. The product 3h
was obtained as a white solid (21.2 mg, 91%) using the general procedure with
concentration of 0.2 mol L−1 of azlactone in fluorobenzene, m.p. 166.9ꢀ169.4 °C. IR
(ZnSe, cmꢀ1): 3033, 2920, 2854, 1695, 1593, 1485, 1452, 1405, 1225, 836, 685, 636.1H
NMR (500 MHz, CDCl3) δ 8.01 (d, J = 7.2 Hz, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.68 (t, J =
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7.5 Hz, 1H), 7.56 – 7.53 (m, 4H), 5.60 (s, 2H), 2.45 (s, 3H). C{1H} NMR (126 MHz,
CDCl3) δ 190.5, 160.3, 154.8, 134.5, 134.0, 131.7, 129.9, 129.1, 128.2, 127.8, 123.3,
+
54.5, 12.0. HRMS (ESIꢀQTOF) m/z: [M + Na] calcd for C18H14BrNO3Na 394.0049,
found 394.0051.
2-((4-(2-(methylthio)ethyl)-2-phenyloxazol-5-yl)oxy)-1-phenylethan-1-one. The product
3i was obtained as a white solid (31.5 mg, 94%), m.p. 108.7ꢀ110.3 °C. IR (ZnSe, cmꢀ1):
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3059, 2942, 2914, 2836, 1682, 1593, 1481, 1448, 1351, 1226, 929, 762, 691. H NMR
(500 MHz, CDCl3) δ 8.06 (d, J = 6.9 Hz, 2H), 8.02 (d, J = 8.1 Hz, 2H), 7.68 (t, J = 7.5
Hz, 1H), 7.55 (t, J = 7.8 Hz, 2H), 7.45 – 7.37 (m, 3H), 5.71 (s, 2H), 3.05 – 2.96 (m, 4H),
2.11 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 190.8, 161.3, 156.6, 134.4, 134.0,
130.9, 129.1, 128.5, 128.1, 126.3, 54.5, 32.0, 26.8, 15.9. HRMS (ESIꢀQTOF) m/z: [M +
Na]+ calcd for C20H19NO3SNa 376.0983, found 376.0980.
1-((4-methyl-2-phenyloxazol-5-yl)oxy)pentan-2-one. The product 3j was obtained as a
yellow solid (19.2 mg, 74%) after purification through a chromatography column
(elution: hexane/ethyl acetate, 3:1), m.p. 53.7ꢀ55.2 °C. IR (ZnSe, cmꢀ1): 3347, 3063,
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2962, 2929, 2874, 1722, 1668, 1519, 1442, 1356, 1112, 1036, 795, 722, 689. H NMR
(500 MHz, CDCl3) δ 8.04 (d, J = 6.9 Hz, 2H), 7.43 – 7.37 (m, 3H), 4.90 (s, 2H), 2.46 (t, J
= 7.3 Hz, 2H), 2.42 (s, 3H), 1.67 (sex, J = 7.4 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13C{1H}
NMR (125 MHz, CDCl3) δ 202.3, 161.2, 154.0, 130.8, 129.1, 128.5, 126.2, 57.0, 41.7,
16.7, 13.6, 11.9. HRMS (ESIꢀQTOF) m/z: [M + Na]+ calcd for C15H17NO3Na 282.1101,
found 282.1073.
3,3-dimethyl-1-((4-methyl-2-phenyloxazol-5-yl)oxy)butan-2-one. The product 3k was
obtained as a yellow oil (25.6 mg, 94%) after purification through a chromatography
column (elution: hexane/ethyl acetate, 3:1). IR (ZnSe, cmꢀ1): 3394, 3064, 2969, 2872,
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1722, 1673, 1523, 1478, 1443, 1352, 1109, 1064, 1006, 822, 725, 688. H NMR (500
MHz, CDCl3) δ 8.03 (d, J = 7.1 Hz, 2H), 7.42 – 7.35 (m, 3H), 5.11 (s, 2H), 2.36 (s, 3H),
1.28 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ 206.3, 160.9, 154.2, 130.9, 129.0,
128.4, 126.2, 52.6, 43.4, 26.1, 11.8. HRMS (ESIꢀQTOF) m/z: [M + Na]+ calcd for
C16H19NO3Na 296.1257, found 296.1235.
4-(3-methoxyphenyl)-1-((4-methyl-2-phenyloxazol-5-yl)oxy)butan-2-one. The product 3l
was obtained as a white solid (30.6 mg, 87%), m.p. 107.8ꢀ108.9 °C. IR (ZnSe, cmꢀ1):
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721, 691. H NMR (500 MHz, CDCl3) δ 8.03 (d, J = 6.8 Hz, 2H), 7.43 – 7.37 (m, 3H),
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7.20 (t, J = 7.9 Hz, 1H), 6.75 (d, J = 8.0 Hz, 2H), 6.71 (s, 1H), 4.85 (s, 2H), 3.77 (s, 3H),
2.94 (t, J = 7.3 Hz, 2H), 2.81 (t, J = 7.3 Hz, 2H), 2.33 (s, 3H). 13C{1H} NMR (125 MHz,
CDCl3) δ 201.6, 161.1, 159.8, 154.0, 141.6, 130.7, 129.7, 129.2, 128.5, 126.2, 120.6,
114.1, 111.7, 57.3, 55.1, 41.3, 29.4, 11.7. HRMS (ESIꢀQTOF) m/z: [M + Na]+ calcd for
C21H21NO4Na 374.1363, found 374.1361.
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1-(4-methoxyphenyl)-2-((4-methyl-2-phenyloxazol-5-yl)oxy)ethan-1-one. The product 3m
was obtained as a yellow solid (24.5 mg, 76%) after purification through a
chromatography column (elution: hexane/ethyl acetate, 3:1), m.p. 126.6ꢀ127.7 °C. IR
(ZnSe, cmꢀ1): 3367, 3059, 2924, 2844, 1685, 1596, 1512, 1441, 1353, 1311, 1165, 1016,
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984, 816, 719, 688. H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 7.3 Hz, 2H), 7.96 (d, J =
8.7 Hz, 2H), 7.42 – 7.35 (m, 3H), 6.97 (d, J = 8.7 Hz, 2H), 5.52 (s, 2H), 3.87 (s, 3H), 2.43
(s, 3H).13C{1H} NMR (125 MHz, CDCl3) δ 189.0, 164.4, 160.9, 154.6, 130.9, 130.5,
129.0, 128.4, 127.0, 126.2, 114.2, 55.6, 54.2, 12.0. HRMS (ESIꢀQTOF) m/z: [M + Na]+
calcd for C19H17NO4Na 346.1050, found 346.1039.
1-(4-chlorophenyl)-2-((4-methyl-2-phenyloxazol-5-yl)oxy)ethan-1-one. The product 3n
was obtained as a white solid (30.8 mg, 94%), m.p. 137.4ꢀ139.0 °C. IR (ZnSe, cmꢀ1):
3364, 3089, 2923, 1689, 1585, 1522, 1442, 1349, 1296, 1223, 1091, 988, 835, 722, 688.
1H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 6.9 Hz, 2H), 7.95 (d, J = 8.6 Hz, 2H), 7.51 (d,
J = 8.5 Hz, 2H), 7.44 – 7.36 (m, 3H), 5.55 (s, 2H), 2.44 (s, 3H). 13C{1H} NMR (125
MHz, CDCl3) δ 189.6, 161.2, 154.6, 141.1, 132.4, 130.8, 129.6, 129.5, 129.2, 128.5,
126.2, 54.4, 12.0. HRMS (ESIꢀQTOF) m/z: [M + Na]+ calcd for C18H14ClNO3Na
350.0554, found 350.0545.
2-((4-methyl-2-phenyloxazol-5-yl)oxy)-1-(4-nitrophenyl)ethan-1-one. The product 3o was
obtained as a yellow solid (31.5 mg, 93%), m.p. 162.8ꢀ164.4 °C. IR (ZnSe, cmꢀ1): 3067,
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2927, 2110, 1709, 1595, 1515, 1436, 1405, 1335, 1205, 1105, 984, 851, 719, 686. H
NMR (500 MHz, CDCl3) δ 8.37 (d, J = 8.8 Hz, 2H), 8.17 (d, J = 8.8 Hz, 2H), 8.04 (d, J =
13
6.8 Hz, 2H), 7.44 – 7.38 (m, 3H), 5.60 (s, 2H), 2.47 (s, 3H). C{1H} NMR (125 MHz,
CDCl3) δ 189.6, 161.4, 154.6, 151.0, 138.4, 130.7, 129.4, 129.3, 128.6, 126.2, 124.3,
54.7, 12.0. HRMS (ESIꢀQTOF) m/z: [M + Na]+ calcd for C18H14N2O5Na 361.0795, found
361.0790.
1-(2-chlorophenyl)-2-((4-methyl-2-phenyloxazol-5-yl)oxy)ethan-1-one. The product 3p
was obtained as an orange solid (32.1 mg, 98%), m.p. 103.7ꢀ105.5 °C. IR (ZnSe, cmꢀ1):
3057, 2924, 2853, 2106, 1700, 1585, 1523, 1472, 1436, 1351, 1209, 1101, 1065, 979,
1
834, 719, 688. H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 6.9 Hz, 2H), 7.66 (d, J = 7.6
Hz, 1H), 7.47 (d, J = 3.7 Hz, 2H), 7.43 – 7.36 (m, 4H), 5.55 (s, 2H), 2.48 (s, 3H).
13C{1H} NMR (125 MHz, CDCl3) δ 193.5, 161.1, 154.4, 135.6, 133.3, 131.5, 130.8,
130.1, 129.1, 128.5, 127.4, 126.2, 57.4, 12.0. HRMS (ESIꢀQTOF) m/z: [M + Na]+ calcd
for C18H14ClNO3Na 350.0554, found 350.0541.
(E)-1-((4-methyl-2-phenyloxazol-5-yl)oxy)-4-phenylbut-3-en-2-one. The product 3q was
obtained as a orange solid (24.3 mg, 76%) after purification through a chromatography
column (elution: hexane/ethyl acetate, 3:1), m.p. 143.7ꢀ144.6 °C. IR (ZnSe, cmꢀ1):3357,
3024, 2923, 2853, 1783, 1665, 1622, 1523, 1491, 1442, 1352, 1311, 1193, 1101, 1071,
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994, 829, 719, 685. H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 7.0 Hz, 2H), 7.77 (d, J =
16.1 Hz, 1H), 7.55 (d, J = 6.8 Hz, 2H), 7.45 – 7.38 (m, 6H), 6.77 (d, J = 16.1 Hz, 1H),
5.19 (s, 2H), 2.46 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 190.9, 161.2, 154.3,
145.8, 133.7, 131.4, 130.8, 129.1, 129.1, 128.7, 128.5, 126.2, 121.4, 56.2, 12.0. HRMS
(ESIꢀQTOF) m/z: [M + H]+ calcd for C20H18NO3 320.1281, found 320.1275.
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benzyl(R)-(4-((4-methyl-2-phenyloxazol-5-yl)oxy)-3-oxo-1-phenylbutan-2-yl)carbamate.
The product 3r was obtained as a white solid (40.2 mg, 85%) using the general
methodology for 8 h, m.p. 123.7ꢀ124.6 °C. IR (ZnSe, cmꢀ1):3306, 3033, 2923, 2856,
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1726, 1682, 1531, 1443, 1349, 1256, 1153, 1029, 979, 719, 688. H NMR (500 MHz,
CDCl3) δ 8.04 (d, J = 7.2 Hz, 2H), 7.42 – 7.28 (m, 11H), 7.16 (d, J = 7.0 Hz, 2H), 5.38
(d, J = 6.5 Hz, 1H), 5.10 (s, 2H), 5.05 (d, J = 18.2 Hz, 1H), 4.84 (d, J = 18.2 Hz, 1H),
4.57 (dd, J = 14.1, 7.1 Hz, 1H), 3.16 (dd, J = 13.9, 6.3 Hz, 1H), 3.03 (dd, J = 13.9, 7.7
13
Hz, 1H), 2.31 (s, 3H). C{1H} NMR (125 MHz, CDCl3) δ 190.9, 161.2, 154.3, 145.8,
133.7, 131.4, 130.8, 129.1, 129.1, 128.7, 128.5, 126.2, 121.4, 56.2, 12.0. HRMS (ESIꢀ
QTOF) m/z: [M + Na]+ calcd for C28H26N2O5Na 493.1734, found 493.1699.
benzyl(S)-(4-((4-methyl-2-phenyloxazol-5-yl)oxy)-3-oxo-1-phenylbutan-2-yl)carbamate.
The product 3s was obtained as a white solid (40.9 mg, 87%) using the general
methodology for 8 h, m.p. 125.4ꢀ127.3 °C. IR (ZnSe, cmꢀ1):3310, 3034, 2926, 2854,
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1725, 1670, 1528, 1446, 1345, 1273, 1155, 1036, 979, 721, 691. H NMR (500 MHz,
CDCl3) δ 8.03 (d, J = 7.2 Hz, 2H), 7.42 – 7.27 (m, 11H), 7.16 (d, J = 7.0 Hz, 2H), 5.40
(d, J = 6.6 Hz, 1H), 5.10 (s, 2H) 5.05 (d, J = 18.3 Hz, 1H), 4.84 (d, J = 18.2 Hz, 1H), 4.57
(dd, J = 13.9, 6.9 Hz, 1H), 3.15 (dd, J = 13.9, 6.4 Hz, 1H), 3.03 (dd, J = 13.9, 7.7 Hz,
1H), 2.31 (s, 3H).13C{1H} NMR (125 MHz, CDCl3) δ 201.2, 161.1, 156.1, 154.6, 135.8,
135.2, 130.7, 129.2, 129.1, 129.0, 128.6, 128.5, 128.4, 128.1, 127.5, 126.2, 67.4, 59.0,
55.8, 36.8, 11.6. HRMS (ESIꢀQTOF) m/z: [M + Na]+ calcd for C28H26N2O5Na 493.1734,
found 493.1754.
methyl 2-((4-methyl-2-phenyloxazol-5-yl)oxy)-2-phenylacetate. The product 3t was
obtained as a yellow solid (6.8 mg, 21%) using the general procedure with toluene at 90
°C after purification through a chromatography column (elution: hexane/ethyl acetate,
3:1), m.p. 79.9ꢀ81.7 °C. IR (ZnSe, cmꢀ1): 3064, 2953, 1748, 1653, 1521, 1442, 1345,
1
1269, 1212, 1171, 1109, 1002, 911, 724, 696. H NMR (500 MHz, CDCl3) δ 8.08 (d, J =
7.0 Hz, 2H), 7.43 – 7.37 (m, 8H), 6.24 (s, 1H), 3.86 (s, 3H), 2.33 (s, 3H).13C{1H} NMR
(125 MHz, CDCl3) δ 168.0, 160.7, 153.8, 133.1, 130.8, 129.2, 129.1, 128.9, 128.4, 128.4,
126.3, 65.2, 53.2, 12.8. HRMS (ESIꢀQTOF) m/z: [M + Na]+ calcd for C19H17NO4Na
346.1050, found 346.1035.
ethyl 2-((4-methyl-2-phenyloxazol-5-yl)oxy)acetate. The product 3u was obtained as a
white solid (6.9 mg, 26%), m.p. 84ꢀ86°C . IR (ATR, cmꢀ1): 2916, 2850, 1747, 1674,
1
1522, 1483, 1444, 1376, 1350, 1242, 1206, 1113, 1024, 727, 696. H NMR (400 MHz,
CDCl3) δ 8.11 – 8.00 (m, 2H), 7.48 – 7.34 (m, 3H), 4.91 (s, 2H), 4.27 (q, J = 7.2 Hz, 2H),
13
2.49 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H). C{1H} NMR (126 MHz, CDCl3) δ 166.6, 161.1,
154.1, 132.0, 130.8, 129.2, 128.6, 128.5, 127.4, 126.3, 62.3, 49.8, 14.1, 12.0. HRMS
(ESIꢀQTOF) m/z: [M + Na]+ calcd for C14H15NNaO4 284.0899, found 284.0876.
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Supporting information contains H and 13C{1H} NMR spectra, IR spectra, HPLC
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chromatograms, and mechanistic investigation. The supporting information is available
free of charge on the ACS Publications website at DOI:
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: antonio@iqsc.usp.br
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*Eꢀmail: giovanni.amarante@ufjf.edu.br; ORCID 0000ꢀ0003ꢀ1004ꢀ5395
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We would like to thank Brazilian agencies FAPEMIG (Fundação de Amparo à Pesquisa
do Estado de Minas Gerais), FAPESP (Fundação de Amparo à Pesquisa do Estado de São
Paulo), CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), CNPq
(Conselho Nacional de Desenvolvimento Científico e Tecnológico) and Rede Mineira de
Química for financial support.
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