Hypervalent Iodine Mediated Oxidative Cyclization of Acrylamide N-Carbamates to 5,5-Disubstituted Oxazolidine-2,4-diones

Article abstract of DOI:10.1021/acs.joc.0c00581

A metal-free oxidative cyclization of N-Boc-acrylamides with (diacetoxyiodo)benzene in acetic acid produced 5,5-disubstituted oxazolidine-2,4-diones with the formation of a C-O bond in moderate to excellent yields. In addition, the reaction was diastereospecific with N-Boc-2,3-dimethylacrylamides and proceeded with phenyl migration in the case of an N-Boc-2-phenylacrylamide to generate a 5-acetoxy-5-benzyloxazolidine-2,4-dione.

Full text of DOI:10.1021/acs.joc.0c00581

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Note
Hypervalent Iodine Mediated Oxidative Cyclization of Acrylamide
N‑Carbamates to 5,5-Disubstituted Oxazolidine-2,4-diones
Anantha Lakshmi Duddupudi, Pankaj Pandey, Hien Vo, Colin L. Welsh, Robert J. Doerksen,
and Gregory D. Cuny*
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ABSTRACT: A metal-free oxidative cyclization of N-Boc-acrylamides with
(diacetoxyiodo)benzene in acetic acid produced 5,5-disubstituted oxazolidine-2,4-diones
with the formation of a C−O bond in moderate to excellent yields. In addition, the
reaction was diastereospecific with N-Boc-2,3-dimethylacrylamides and proceeded with
phenyl migration in the case of an N-Boc-2-phenylacrylamide to generate a 5-acetoxy-5-
benzyloxazolidine-2,4-dione.
n recent years, transition metal (TM) catalyzed and metal-
free oxidative cyclization via C−H activation of N-
aminooxylated oxindoles using a similar strategy.6 Alter-
natively, N-Boc acrylamides have been found to undergo
cyclization with the alkene generating a variety of 5,5′-
disubstituted oxazolidine-2,4-diones with the introduction of
C−F, C−N, and C−I bonds (Figure 1B).7−9 We now report
that metal-free hypervalent iodine mediated oxidative cycliza-
tion of N-Boc-acrylamides provides an efficient route to 5,5-
disubstituted oxazolidine-2,4-diones with the formation of a
C−O bond (Figure 1C).10 Furthermore, the reaction takes
place with an array of N-substituents, is diastereospecific with
N-Boc-2,3-dimethylacrylamides, and occurs with phenyl
migration in the case of an N-Boc-2-phenylacrylamide.
5,5-Disubstituted oxazolidine-2,4-diones are an interesting
class of heterocycles that has been recognized as a “privileged
medicinal chemistry scaffold”11 found in various pharmaco-
logically active compounds.12−14 For example, 5,5-disubsti-
tuted oxazolidine-2,4-diones have been reported as potent and
selective mineralocorticoid receptor antagonists with potential
use in the treatment of chronic kidney disease, hypertension,
and congestive heart failure.15−17 For these reasons, the
efficient construction of 5,5-disubstituted oxazolidine-2,4-
diones is of interest within the synthetic organic chemistry
community.
I
phenylacrylamides has emerged as an efficient method for
the construction of 3,3-disubstituted oxindoles (Figure 1A).1−3
For example, Jaegli et al. utilized Pd-catalysis to affect the
reaction rate, and this was further used in a spirooxindole
synthesis.4 In addition, Cao et al.5 reported a metal-free
example of this reaction, while Zhang et al. have generated
N-2,3-Dimethoxybenzyl-N-Boc-methacrylamide (1) was
selected as the initial substrate for this study. Exposure of
this material, at a concentration of 0.1 M in acetic acid, to 10
mol % Pd(OAc)2 and 2 equiv of PhI(OAc)2 at 100 °C for 3 h
generated 5,5-disubstituted oxazolidine-2,4-dione 2 as the
Received: March 16, 2020
Figure 1. Previous studies on (A) TM catalyzed and metal-free
oxidative cyclizations of N-phenylacrylamides and (B) Cyclizations of
N-Boc-acrylamides with the formation of C−F, C−N, and C−I
bonds. (C) Current study on metal-free oxidative cyclizations of N-
Boc-acrylamides producing 5,5-disubstituted oxazolidine-2,4-diones
with the introduction of a C−O bond.
https://dx.doi.org/10.1021/acs.joc.0c00581
© XXXX American Chemical Society
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A

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Note
a
Table 1. Analysis of Reaction Conditions and Reagents
Entry
Oxidant
Catalyst
Solvent
AcOH
AcOH
CH3CN
1,4-dioxane
AcOH
AcOH
AcOH
AcOH
AcOH
Temp (°C)
Time (h)
Yield of 2 (%)
1
2
3
4
5
6
7
8
9
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
Oxone
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
None
None
None
None
100
rt
3
70
75
24
27
72
2
2
16
3
100
100
100
100
100
100
100
100
<5
n.d.
22
b
K2S2O8
n.d.
71
83
48
84
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
c
6
3
d
10
AcOH
a
b
c
Reaction conditions: 1 (1.0 equiv), oxidant (2.0 equiv), catalyst (10 mol %) in solvent (0.1 M under argon). n.d. = not detected. 1.0 equiv.
Methyl carbamate of 1 used as substrate.
d
a
major product in 70% yield (Table 1, entry 1) with no
detection of the corresponding 3,3-disubstituted oxindole. In
order to confirm the structure assignment of 2 as a 5,5-
disubstituted oxazolidine-2,4-dione, a crystal structure was
obtained (cf. Figure S1). In addition, a minor overoxidized
product (<5%) was detected.18 Encouraged by these initial
results, a number of reaction parameters (e.g., solvent, oxidant,
temperature, and necessity of the palladium catalyst) were
examined. The reaction proceeded at room temperature,
although additional time was needed to achieve similar product
yield (entry 2). However, the reaction was adversely affected
when nonacidic less polar solvents (e.g., acetonitrile or 1,4-
dioxane) were used in place of acetic acid (entries 3 and 4).
Similarly, replacement of PhI(OAc)2 with other oxidants, such
as potassium peroxymonosulfate (e.g., Oxone) or potassium
persulfate, resulted in significantly lower product yields (entries
5 and 6). The reaction was conducted in the absence of a
palladium catalyst producing 2 in comparable yields (entries 7
and 8) demonstrating that the reaction proceeds in metal-free
conditions. Over-oxidation was observed in the absence of a
Pd-catalyst, but only during extended reaction time (entry 7).
Reducing the equivalents of PhI(OAc)2 was detrimental (entry
9). Finally, the methyl carbamate also gave a similar yield of 2
(entry 10).
Table 2. Reaction Substrate Scope: N-Substituents
a
Reaction conditions: PhI(OAc)2 (2 equiv) in AcOH (0.1 M) at 100
°C for 2−3 h. N-de-Boc starting material was isolated (80%).
b
Following an analysis of reaction conditions and reagents,
the structure−reactivity relationship (SRR) of the N-
substituent was explored. N-Benzyl groups with a 2- or 4-
methoxy (e.g., 3a and 3b) were well tolerated producing 4a
and 4b in good yields without generation of oxidized
byproducts as observed with substrate 1 (Table 2). Electron-
withdrawing groups in the 2- or 4-position of the N-benzyl, as
well as replacement of the benzyl with a heterocycle (e.g., 2-
thiophenylmethyl) or a fused aromatic hydrocarbon (e.g., 2-
naphthylmethyl), were well tolerated generating products 4c−
f, respectively, in good yields. The additional steric hindrance
on the benzylic carbon or extending the linker to a phenethyl
resulted in corresponding 5,5-disubstituted oxazolidine-2,4-
diones 4g and 4h in moderate yields. Finally, the attachment of
the phenyl group directly to the nitrogen was also tolerated (4i
and 4j). However, a similar substrate containing several
electron-withdrawing groups resulted in isolation of only the
corresponding N-de-Boc starting material.
Next, the scope of the alkene was analyzed. For example,
alkene 5a generated 6a in quantitative yield (Table 3). The
SRR of the alkene geometry was also examined. The E-
substituted alkene substrate 5b underwent diastereospecific
reaction to generate 6b, albeit in only 27% yield. In addition to
the desired product, another 5,5-disubstituted oxazolidine-2,4-
dione 7a was generated in 44% yield. The Z-isomer 5c gave the
other diastereomer 6c in 42% yield, again with generation of 7a
in a similar yield. The trisubstituted alkene 5d and tetra-
substituted alkene 5e only yielded alkene products 7b and 7c,
respectively.
Assignment of the relative stereochemistry of 6b and 6c was
difficult to confirm via 1D, 2D, and NOE NMR experiments,
B
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Note
a
for both), 6RS matched 6b and 6SS matched 6c with 100%
probability when carbon-only or all chemical shift data were
used (cf. Tables S23−S24).
In order to verify the relative stereochemistry of these
materials, 6b was hydrolyzed with lithium hydroxide in THF/
MeOH/H2O to diol 8a (Scheme 1). The structure of 8a was
Table 3. Reaction Substrate Scope: Alkenes
Scheme 1. Synthesis of Dimethyl Ketals 9a and 9b
confirmed as rel-(R,S) by X-ray crystallography (cf. Figure S2).
Furthermore, this material was converted to dimethyl ketal 9a,
which by 1D-NOE experiments indicated the relative stereo-
chemistry was rel-(R,S). Diastereomer 6c was likewise
converted to diol 8b and then to dimethyl ketal 9b. 1D-
NOE experiments of 9b were consistent with the relative
a
b
Y: CH2(4-OMe)Ph. de-Boc starting material recovered.
so 1H and 13C NMR chemical shift calculations were
performed on the two diastereomers of interest, rel-(R,S)
and rel-(S,S), which for the calculations we labeled 6RS and
6SS, respectively. The gauge independent atomic orbital
(GIAO)19 method at the mPW1PW91/6-311+G(d,p) level
of theory20 was used for the chemical shift calculations, using
Boltzmann weighting for all low-energy conformations. CHCl3
was used as a solvent with the polarizable continuum solvent
model (PCM). The computed chemical shifts of 6RS and 6SS
were compared with the experimental values of 6b and 6c,
utilizing mean absolute error (MAE), CP321 and DP4+22
probability analyses (for DP4+, we used total or tDP4+ to be
the sum of the scaled, sDP4+, and unscaled, uDP4+, NMR
chemical shifts). The scaled chemical shifts were calculated by
applying empirical scaling using the slope and intercept of the
regression line obtained by plotting chemical shift values of 1H
and 13C (calculated vs experimental). This computational
approach has been reported for addressing the stereochemical
assignment of other isomeric compounds.23,24
Comparing the results (cf. Tables S1−S22, Supporting
Information) obtained with either tDP4+ probability analysis
or “scaled shift only” sDP4+ probability data of 6SS (96.86%
probability, Table S20) showed close agreement with the
experimental data of 6c, whereas sDP4+ also predicted 6RS to
match 6c (83.67% probability, Table S19), a confusing result.
The only case of DP4+ calculations in which 6RS matched
with experimental results for 6b was for sDP4+ carbon-only
data, and for these data 6SS matched with 6c as well. Similarly,
for scaled chemical shifts the carbon corrected mean absolute
error (CMAE) data of 6SS matched 6c, but the data of 6RS
did not match 6b. Moreover, tDP4+ probability analysis
predicted 6SS to match 6c with 99.78% probability but did not
predict 6RS calculated chemical shifts to match with 6b
experimental values. Finally, considering results from CP3 (a
method that simultaneously assigns structures for two
diastereomers when experimental chemical shifts are available
1
stereochemistry of rel-(S, S). H and 13C NMR chemical shift
calculations were performed for the two diastereomers of
interest, rel-(S,R) and rel-(S,S), which for the calculations we
labeled 8RS and 8SS, respectively. Comparing the results (cf.
Tables S17−S18 and S21−S22) obtained with DP4+
probability analysis and “scaled only” sDP4+ probability data,
sDP4+ chemical shift data for 8RS with 8a (53.06%
probability) and for 8SS with 8b (72.77% probability) showed
agreement, whereas the sDP4+ calculations for scaled carbon-
only data matched 8RS with 8a but 8SS also with 8b. In
addition, tDP4+ probability analysis predicted 8RS to match
8a with a 94.62% probability. The CMAE data for scaled
chemical shifts matched 8RS with 8a and 8SS with 8b. Unlike
for the 6b/6c assignment, for 8a/8b the CP3 probabilities (cf.
1
Tables S23−S24) were unhelpful. The CP3 H data and all
1
data (considering together both H and 13C data) predicted
that 8SS matched with 8a and 8RS matched with 8b, though
the CP3 13C only data did match correctly with what was
learned from the crystal structure of 8athat 8RS should
match with 8a and 8SS with 8b.
The diastereospecificity and formation of the alkene
byproducts observed in these reactions provide some insights
into the potential mechanism of this transformation.
Presumably the (diacetoxyiodo)benzene coordinates with the
alkene via intermediate A (Scheme 2) that can undergo
cyclization with loss of isobutylene to generate an intermediate
such as B. This is consistent with the stereochemical course
reported for the ICl-induced iodo-cyclization of similar N-Boc-
acrylamide substrates.9 This could be followed by SN2-like
substitution of PhI(OAc) with stereocenter inversion resulting
in 6b. Intermediate B could also undergo elimination
generating 7a.
Finally, the N-Boc-2-phenylacrylamide substrate 10 was
subjected to the same reaction conditions. However, the
phenyl-migration product 11 was generated in 75% yield
C
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Note
detection or visualizing agents (phosphomolybdic acid stain). Flash
chromatography was conducted with silica gel (230−400 mesh) using
a Teledyne ISCO CombiFalsh Rf instrument. NMR spectra were
recorded at room temperature using JEOL ECA-600 or 500 or 400
instruments (1H NMR at 600 or 500 or 400 MHz; 13C NMR at 150
or 125 or 100 MHz; 19F NMR at 564 MHz) with tetramethylsilane
(TMS) as an internal standard. Chemical shifts (δ) are given in parts
per million (ppm) with reference to solvent signals [1H NMR: CDCl3
(7.26 ppm), CD3OD (3.31 ppm), DMSO-d6 (2.50 ppm); 13C NMR:
CDCl3 (77.0 ppm), CD3OD (49.2 ppm), DMSO-d6 (39.5 ppm)].
Signal patterns are reported as s (singlet), d (doublet), t (triplet), q
(quartet), m (multiplet), and br (broad). Coupling constants (J) are
given in Hz. Nuclear Overhauser enhancement spectroscopy
(NOESY) spectra were obtained to observe correlations between
proton signals. High-resolution mass spectra (HRMS) were obtained
by the University of Texas at Austin mass spectrometry facility using
an ESI quadrupole mass spectrometer with a time-of-flight tube and
reported as m/z (relative intensity) for the molecular ion [M].
General Procedure A: Preparation of tert-Butyl Carbamates 1,
3a−h, 3k, 5a−e, and 10.26 To a solution of the corresponding
amine (1 equiv) in anhydrous dichloromethane was added Et3N (1.3
equiv) at 0 °C. Then the corresponding acryloyl chloride (1.0−1.5
equiv) was added slowly. The reaction mixture was allowed to warm
to room temperature and stirred for 2−4 h. After completion of the
reaction, water was added and the mixture was extracted with ethyl
acetate. The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, and filtered. The solvent was removed under
reduced pressure, and the crude compound was purified by
chromatography using hexane/ethyl acetate as eluent. To a solution
of the acrylamide (1 equiv) in anhydrous THF was added LiHMDS
(1.3 equiv, 1.0 M in THF) at −78 °C. The reaction mixture was
stirred for 20 min at this temperature. Then di-tert-butyl dicarbonate
(1.3 equiv dissolved in THF) was added slowly to the reaction
mixture, which was then allowed to warm to 0 °C. Stirring was
continued for 1−2 h. Reaction progress was monitored by TLC (30%
EtOAc/hexane). After reaction completion saturated NH4Cl solution
was added and the mixture was extracted twice with ethyl acetate. The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and filtered. The solvent was removed under
reduced pressure, and the crude compounds were purified by
chromatography using hexane/ethyl acetate as eluent to obtain
compounds 1, 3a−h, 3k, 5a−e, and 10.
Scheme 2. Proposed Mechanism for the Conversion of 5b to
6b and 7a
a
a
R = CH2(4-OMe)Ph.
(Scheme 3). The structure of 11 was confirmed by X-ray
crystallography (cf. Figure S3). This reaction likely occurs via a
Scheme 3. Synthesis of 11
phenonium ion intermediate reminiscent of a similar reaction
of 4-aryl-4-pentenoic acids with a hypervalent iodine reagent
reported by Boye et al.25
In conclusion, a method for (diacetoxyiodo)benzene-
mediated oxidative cyclization of N-Boc-acrylamides in acetic
acid to produce 5,5-disubstituted oxazolidine-2,4-diones was
developed. The reaction scope was modestly broad with
respect to the amide N-substituents. In addition, the reaction
was diastereospecific with N-Boc-2,3-dimethylacrylamide sub-
strates. However, more highly substituted N-Boc-acrylamides
gave alkene-containing 5,5-disubstituted oxazolidine-2,4-dio-
nes. A proposed mechanism was provided that is consistent
with the observed diastereospecificity of the reaction and
formation of the alkene byproducts. Finally, in the case of an
N-Boc-2-phenylacrylamide substrate, phenyl migration was
observed generating a 5-acetoxy-5-benzyl oxazolidine-2,4-
dione. Hopefully, the results of this study will encourage
further examination of these reactions (e.g., employing more
reactive or catalytic hypervalent iodine reagents and expanding
the scope), as well as medicinal chemistry applications of the
products.
tert-Butyl (2,3-Dimethoxybenzyl)(methacryloyl)carbamate (1).
1
21%; colorless liquid; H NMR (400 MHz, CDCl3): δ 7.0 (t, J =
8.0 Hz, 1H), 6.80 (dd, J = 20.6 Hz, 8.2 Hz, 2H), 5.28 (s, 1H), 5.20 (s,
1H), 4.92 (s, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 2.04 (s, 3H), 1.40 (s,
9H). 13C{1H} NMR (100 MHz, CDCl3): δ 174.2, 153.4, 152.5, 146.7,
143.2, 131.5, 123.9, 119.4, 116.4, 111.2, 83.3, 60.4, 55.7, 43.2, 27.7,
19.3. HRMS (ESI): m/z [M + Na]+ calcd for C18H25NO5Na,
358.1625; found, 358.1634.
tert-Butyl Isobutyryl(4-methoxybenzyl)carbamate (3a). 69%;
1
yellow liquid; H NMR (400 MHz, CDCl3): δ 7.29 (d, J = 8.7 Hz,
2H), 6.83 (d, J = 8.7 Hz, 2H), 5.15 (s, 2H), 4.77 (s, 2H), 3.78 (s,
3H), 1.99 (s, 3H), 1.41 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3):
δ 174.2, 158.8, 153.4, 143.3, 129.8, 129.5, 116.2, 113.6, 83.3, 55.2,
47.5, 27.9, 19.2. HRMS (ESI): m/z [M + Na]+ calcd for
C17H23NO4Na, 328.1519; found, 328.1526.
tert-Butyl Isobutyryl(2-methoxybenzyl)carbamate (3b). 74%;
1
white solid; mp: 65−66 °C. H NMR (500 MHz, CDCl3): δ 7.22
(td, J = 8.0 Hz, 2.0 Hz, 1H), 7.15 (dd, J = 7.5 Hz, 1.5 Hz, 1H), 6.92−
6.89 (m, 1H), 6.85−6.83 (m, 1H), 5.27−5.26 (m, 1H), 5.20 (m, 1H),
4.86 (s, 2H), 3.80 (s, 3H), 2.02−2.04 (m, 3H), 1.38 (s, 9H). 13C{1H}
NMR (125 MHz, CDCl3): δ 174.2, 156.9, 153.5, 143.3, 128.1, 127.8,
125.9, 120.3, 116.5, 110.0, 83.0, 55.2, 43.6, 27.7, 19.3. HRMS (ESI):
m/z [M + Na]+ calcd for C17H23NO4Na, 328.1519; found, 328.1526.
tert-Butyl (4-Fluorobenzyl)(methacryloyl)carbamate (3c). 96%;
EXPERIMENTAL SECTION
■
General Information. All reactions involving air-sensitive
reagents were carried out with magnetic stirring and oven-dried
glassware with rubber septa under argon, unless otherwise stated. All
commercially available chemicals and reagent grade solvents were
used directly without further purification, unless otherwise specified.
Reactions were monitored by thin-layer chromatography (TLC) on
Baker-flex silica gel plates (IB2-F) using UV-light (254 and 365 nm)
1
yellow liquid; H NMR (400 MHz, CDCl3): δ 7.35−7.31 (m, 2H),
7.01−6.96 (m, 2H), 5.17−5.16 (m, 2H), 4.80−4.78 (m, 2H), 2.00 (s,
3H), 1.41 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ 173.9, 162.0
(d, JCF = 244.2 Hz), 153.2, 143.1, 133.4 (d, JCF = 2.9 Hz), 129.8 (d,
D
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JCF = 8.7 Hz), 116.3, 115.1 (d, JCF = 20.4 Hz), 83.7, 47.3, 27.6, 19.1.
19F NMR (564 MHz, CDCl3): δ −115.0 (s). HRMS (ESI): m/z [M +
Na]+ calcd for C16H20FNO3Na, 316.1319; found, 316.1317.
tert-Butyl (2-Fluorobenzyl)(methacryloyl)carbamate (3d). 23%;
9H); 13C{1H} NMR (125 MHz, CDCl3): δ 173.4, 158.8, 152.7,
134.8, 129.9, 129.8, 122.9, 113.6, 83.4, 55.2, 46.6, 27.7, 20.6, 14.2.
HRMS (ESI): m/z [M + Na]+ calcd for C18H25NO4Na, 342.1676;
found, 342.1686.
(E)-tert-Butyl 4-Methoxybenzyl(2-methylpent-2-enoyl)-
carbamate (5d). 87%; colorless liquid; 1H NMR (400 MHz,
CDCl3): δ 7.29 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.8 Hz, 2H), 5.77
(tq, J = 7.2 Hz, 1.6 Hz, 1H), 4.74 (s, 2H), 3.78 (s, 3H), 2.14−2.06
(m, 2H), 1.84 (m, 3H), 1.39 (s, 9H), 0.99 (t, J = 7.8 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 175.3, 158.7, 153.7, 135.8,
1
white solid; mp: 51−52 °C. H NMR (600 MHz, CDCl3): δ 7.28−
7.21 (m, 2H), 7.09 (t, J = 7.4 Hz, 1H), 7.03 (t, J = 9.3 Hz, 1H), 5.26
(s, 1H), 5.22 (s, 1H), 4.92 (s, 2H), 2.03 (s, 3H), 1.39 (s, 9H).
13C{1H} NMR (150 MHz, CDCl3): δ 174.2, 160.5 (d, JCF = 245.6
Hz), 153.1, 143.0, 129.2 (d, JCF = 4.3 Hz), 128.9 (d, JCF = 8.6 Hz),
124.8(d, JCF = 14.4 Hz), 124.1 (d, JCF = 2.9 Hz), 116.7, 115.2 (d, JCF
= 21.5 Hz), 83.6, 41.8 (d, JCF = 4.4 Hz), 27.7, 19.3. 19F NMR (564
MHz, CDCl3): δ −118.3 (s). HRMS (ESI): m/z [M + Na]+ calcd for
C16H20FNO3Na, 316.1319; found, 316.1317.
133.9, 130.1, 129.6, 113.6, 82.7, 55.2, 48.0, 27.8, 21.3, 13.5, 13.0.
HRMS (ESI): m/z [M + Na]+ calcd for C19H27NO4Na, 356.1832;
found, 356.1842.
tert-Butyl (2,3-Dimethylbut-2-enoyl)(4-methoxybenzyl)-
tert-Butyl Methacryloyl(thiophen-3-ylmethyl)carbamate (3e).
1
1
carbamate (5e). 95%; H NMR (400 MHz, CDCl3): δ 7.31 (d, J
81%; colorless liquid; H NMR (500 MHz, CDCl3): δ 7.25−7.22
= 8.8 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 4.83 (s, 2H), 3.78 (s, 3H),
1.79 (s, 3H), 1.66 (s, 3H), 1.57 (s, 3H), 1.41 (s, 9H); 13C{1H} NMR
(100 MHz, CDCl3): δ 174.5, 158.8, 152.8, 130.0, 129.8, 129.5, 128.0,
113.6, 82.7, 55.2, 46.7, 27.8, 21.3, 19.8, 16.2. HRMS (ESI): m/z [M +
Na]+ calcd for C19H27NO4Na, 356.1832; found, 356.1839.
(m, 2H), 7.10 (dd, J = 5.0 Hz, 1.5 Hz, 1H), 5.17−5.14 (m, 2H), 4.81
(s, 2H), 1.99 (s, 3H), 1.43 (s, 9H). 13C{1H} NMR (125 MHz,
CDCl3): δ 174.0, 153.2, 143.2, 138.1, 127.9, 125.5, 123.3, 116.3, 83.5,
43.2, 27.7, 19.2. HRMS (ESI): m/z [M + K]+ calcd for
C14H19NO3SK, 320.0717; found, 320.0720.
tert-Butyl 4-Methoxybenzyl(2-phenylacryloyl)carbamate (10).
tert-Butyl Methacryloyl(naphthalen-2-ylmethyl)carbamate (3f).
85%; pale yellow solid; mp 85−87 °C. 1H NMR (400 MHz, CDCl3):
δ 7.82−7.78 (m, 4H), 7.49−7.44 (m, 3H), 5.21−5.18 (m, 2H), 4.99
(s, 2H), 2.02 (s, 3H), 1.40 (s, 9H). 13C{1H} NMR (100 MHz,
CDCl3): δ 174.2, 153.4, 143.3, 135.1, 133.2, 132.7, 128.2, 127.9,
127.6, 127.0, 126.1, 126.0, 125.8, 116.5, 83.5, 48.3, 27.7, 19.3. HRMS
(ESI): m/z [M + Na]+ calcd for C20H23NO3Na, 348.1570; found,
348.1577.
1
61%; colorless liquid; H NMR (400 MHz, CDCl3): δ 7.36 (d, J =
8.4 Hz, 2H), 7.29−7.27 (m, 5H), 6.87 (d, J = 8.4 Hz, 2H), 5.68 (s,
1H), 5.48 (s, 1H), 4.88 (s, 2H), 3.80 (s, 3H), 1.18 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3): δ 172.4, 158.9, 152.7, 147.1, 136.0, 130.0,
129.7, 128.3, 128.2, 126.4, 115.9, 113.7, 83.6, 55.2, 47.5, 27.4. HRMS
(ESI): m/z [M + Na]+ calcd for C22H25NO4Na, 390.1676; found,
390.1683.
General Procedure B: Preparation of tert-Butyl Carbamates 3i−
j.8 To a solution of the corresponding amine, carboxylic acid (1.0
equiv each) and HOBt·H2O (0.3 equiv) in acetonitrile was added
EDC (1.2 equiv) at 0 °C. After 5 min, Et3N (1.0 equiv) was added
and the reaction mixture was allowed to warm slowly to room
temperature and then stir for 1 h. Reaction progress was monitored by
TLC (50% EtOAc/hexane). After reaction completion, water was
added and the mixture was extracted twice with ethyl acetate. The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and filtered. The solvent was removed under
reduced pressure, and the crude compound was purified by
chromatography using hexane/ethyl acetate as eluent. To a solution
of acrylamide (1.0 equiv) in anhydrous dichloromethane was added a
catalytic amount of DMAP. Then di-tert-butyl dicarbonate (2.0 equiv)
was added, and the reaction mixture was allowed to stir overnight at
room temperature. Reaction progress was monitored by TLC 30%
EtOAc/hexane. After reaction completion, water was added and the
mixture was extracted with dichloromethane. The combined organic
layers were washed with brine, dried over anhydrous Na2SO4, and
filtered. Solvent was removed under reduced pressure, and the crude
material was purified by chromatography to obtain 3i−j.
tert-Butyl Methacryloyl(2-phenylpropan-2-yl)carbamate (3g).
37%; yellow solid; mp 87−90 °C. H NMR (400 MHz, CDCl3): δ
7.49−7.47 (m, 2H), 7.33−7.29 (m, 2H), 7.22−7.18 (m, 1H), 5.77 (s,
1H), 5.50 (s, 1H), 2.0 (s, 3H), 1.76 (s, 6H), 1.28 (s, 9H); 13C{1H}
NMR (100 MHz, CDCl3): δ 174.1, 153.5, 147.7, 144.3, 128.1, 126.3,
124.8, 121.3, 82.4, 61.9, 29.2, 27.7, 18.6. HRMS (ESI): m/z [M +
Na]+ calcd for C18H25NO3Na, 326.1727; found, 326.1725.
1
tert-Butyl Methacryloyl(phenethyl)carbamate (3h). 89%; yellow
1
liquid; H NMR (400 MHz, CDCl3): δ 7.31−7.19 (m, 5H), 5.13 (s,
1H), 5.09 (s, 1H), 3.89 (t, J = 7.8 Hz, 2H), 2.90 (t, J = 7.8 Hz, 2H),
1.97 (s, 3H), 1.44 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ
174.2, 153.3, 143.4, 138.5, 129.0, 128.4, 126.4, 115.9, 83.7, 46.2, 34.9,
27.8, 19.3. HRMS (ESI): m/z [M + Na]+ calcd for C17H23NO3Na,
312.1570; found, 312.1576.
tert-Butyl (3-Chloro-4-cyanophenyl)(methacryloyl)carbamate
(3k). 77%; white solid; mp 105−107 °C 1H NMR (600 MHz,
CDCl3): δ 7.69 (dd, J = 8.2 Hz, 1.3 Hz, 1H), 7.36 (m, 1H), 7.19 (dt, J
= 8.3 Hz, 1.7 Hz, 1H), 5.61 (s, 1H), 5.51 (s, 1H), 2.07 (s, 3H), 1.47
(s, 9H); 13C{1H} NMR (150 MHz, CDCl3): δ 173.0, 152.0, 143.4,
142.4, 137.3, 134.2, 128.7, 126.0, 120.5, 115.5, 111.9, 85.1, 27.7, 18.7.
HRMS (ESI): m/z [M + Na]+ calcd for C16H17ClN2O3Na, 343.0820;
found, 343.0819.
tert-Butyl Methacryloyl(phenyl)carbamate (3i). 73%; white solid;
mp 65−67 °C. 1H NMR (500 MHz, CDCl3): δ 7.40 (br t, J = 7.8 Hz,
2H), 7.32 (br t, J = 7.5 Hz, 1H), 7.17−7.15 (m, 2H), 5.56 (s, 1H),
5.38 (s, 1H), 2.06 (s, 3H), 1.44 (s, 9H); 13C{1H} NMR (125 MHz,
CDCl3): δ 173.8, 153.2, 142.9, 138.6, 129.1, 127.7, 127.6, 118.6, 83.6,
27.8, 19.0. HRMS (ESI): m/z [M + Na]+ calcd for C15H19NO3Na,
284.1257; found, 284.1261.
tert-Butyl 4-Methoxybenzyl(2-methylenebutanoyl)carbamate
1
(5a). 79%; colorless liquid; H NMR (400 MHz, CDCl3): δ 7.29
(d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 5.16 (dt, J = 17.2 Hz,
1.6 Hz, 2H), 4.78 (s, 2H), 3.78 (s, 3H), 2.36 (qt, J = 7.2 Hz, 1.6 Hz,
2H), 1.40 (s, 9H), 1.08 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 174.1, 158.8, 153.4, 149.0, 129.9, 129.5, 113.9,
113.6, 83.2, 55.1, 47.5, 27.7, 25.5, 11.5. HRMS (ESI): m/z [M + Na]+
calcd for C18H25NO4Na, 342.1676; found, 342.1683.
tert-Butyl Methacryloyl(4-methoxyphenyl)carbamate (3j). 47%;
1
colorless viscous liquid. H NMR (600 MHz, CDCl3): δ 7.07 (d, J =
8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 5.51 (s, 1H), 5.34 (s, 1H), 3.80
(s, 3H), 2.05 (s, 3H), 1.43 (s, 9H); 13C{1H} NMR (150 MHz,
CDCl3): δ 173.9, 158.8, 153.4, 142.9, 131.2, 128.8, 118.2, 114.3, 83.4,
55.4, 27.7, 19.1. HRMS (ESI): m/z [M + Na]+ calcd for
C16H21NO4Na, 314.1363; found, 314.1371.
General Procedure C: Preparation of 5,5 Disubstituted
Oxazolidine-2,4-diones (2, 4a−j, 6a−c, 7a−c, and 11).4 To a
solution of the corresponding tert-butyl carbamate substrate (1.0
equiv) in acetic acid (0.1 M) at room temperature was added
(diacetoxyiodo)benzene (2.0 equiv). The reaction mixture was heated
in an oil bath to 100 °C for 2−3 h. Reaction progress was monitored
by TLC (30−40% EtOAc/hexane). Upon reaction completion, the
(E)-tert-Butyl 4-Methoxybenzyl(2-methylbut-2-enoyl)carbamate
(5b). 84%; colorless liquid; 1H NMR (500 MHz, CDCl3): δ 7.29 (d, J
= 8.5 Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 5.88 (qq, J = 7.0 Hz, 2.0 Hz,
1H), 4.74 (s, 2H), 3.78 (s, 3H), 1.84 (m, 3H), 1.70 (dd, J = 7.0 Hz,
1.0 Hz, 3H), 1.39 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3): δ
175.1, 158.8, 153.7, 135.5, 130.1, 129.6, 128.8, 113.6, 82.6, 55.2, 47.9,
27.8, 13.6, 13.3. HRMS (ESI): m/z [M + Na]+ calcd for
C18H25NO4Na, 342.1676; found, 342.1686.
(Z)-tert-Butyl 4-methoxybenzyl(2-methylbut-2-enoyl)carbamate
(5c). 85%; colorless liquid; 1H NMR (500 MHz, CDCl3): δ 7.31 (d, J
= 6.9 Hz, 2H), 6.83 (d, J = 6.9 Hz, 2H), 5.38−5.33 (m, 1H), 4.83 (s,
2H), 3.78 (s, 3H), 1.91 (s, 3H), 1.51 (d, J = 6.9 Hz, 3H), 1.43 (s,
E
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Note
volatiles were removed under reduced pressure and then the crude
materials were purified by chromatography.
was purified by chromatography (0−20% ethyl acetate in hexane) to
1
yield 4e (41.3 mg, 82%) as a white solid; mp 90 °C. H NMR 500
3-(2,3-Dimethoxybenzyl)-5-methyl-2,4-dioxooxazolidin-5-yl)-
methyl Acetate (2). Compound 2 was synthesized from 1 (50 mg,
0.15 mmol), PhI(OAc)2 (96 mg, 0.30 mmol), and acetic acid (1.49
mL, 0.1 M) according to general procedure C. The crude compound
was purified by chromatography (0−20% ethyl acetate in hexane) to
provide 2 (42.3 mg, 83%). White solid; mp 99−100 °C. 1H
NMR(500 MHz, CDCl3): δ 7.01−6.98 (m, 1H), 6.88−6.85 (m, 2H),
4.79 (s, 2H), 4.32 (dd, J = 54.0 Hz, 12.0 Hz, 2H), 3.91 (s, 3H), 3.85
(s, 3H), 1.96 (s, 3H), 1.58 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 173.1, 169.8, 154.2, 152.8, 147.2, 128.1, 124.1, 120.6,
112.5, 83.8, 65.1, 60.7, 55.8, 38.8, 20.4, 18.9. HRMS (ESI): m/z [M +
H]+ calcd for C16H20NO7, 338.1240; found, 338.1230.
(3-(4-Methoxybenzyl)-5-methyl-2,4-dioxooxazolidin-5-yl)methyl
Acetate (4a). Compound 4a was synthesized from 3a (50 mg, 0.16
mmol), PhI(OAc)2 (106 mg, 0.33 mmol), and acetic acid (1.64 mL,
0.1 M) according to general procedure C. The crude compound was
purified by chromatography (0−20% ethyl acetate in hexane) to yield
4a (40.7 mg, 81%) as a white solid; mp 103−105 °C. 1H NMR (400
MHz, CDCl3): δ 7.36 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H),
4.63 (dd, J = 34.8 Hz, 14.6 Hz, 2H), 4.27 (dd, J = 38.0 Hz, 12.4 Hz,
2H), 3.78 (s, 3H), 1.72 (s, 3H), 1.55 (s, 3H); 13C{1H} NMR (100
MHz, CDCl3): δ 172.9, 169.5, 159.6, 154.3, 130.2, 126.9, 114.0, 83.8,
65.0, 55.2, 43.3, 19.9, 18.4. HRMS (ESI): m/z [M + Na]+ calcd for
C15H17NO6Na, 330.0948; found, 330.0954.
MHz, CDCl3): δ 7.38−7.36 (m, 1H), 7.29−7.27 (m, 1H), 7.15−7.13
(m, 1H), 4.75 (dd, J = 14.5 Hz, 3.0 Hz, 1H), 4.67 (dd, J = 14.5 Hz,
2.5 Hz, 1H), 4.32 (dd, J = 12.0 Hz, 3.5 Hz, 1H), 4.23 (dd, J = 12.0
Hz, 3.5 Hz, 1H), 1.74 (d, J = 3.5 Hz, 3H), 1.56 (d, J = 2.5 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3): δ 172.6, 169.4, 154.1, 134.8,
127.7, 126.4, 124.9, 83.9, 65.0, 38.3, 19.9, 18.3. HRMS (ESI): m/z [M
+ Na]+ calcd for C12H13NO5SNa, 306.0407; found, 306.0406.
(5-Methyl-3-(naphthalen-2-ylmethyl)-2,4-dioxooxazolidin-5-yl)-
methyl Acetate (4f). Compound 4f was synthesized from 3f (50 mg,
0.15 mmol), PhI(OAc)2 (99 mg, 0.307 mmol), and acetic acid (1.5
mL, 0.1 M) according to general procedure C. The crude compound
was purified by chromatography (0−20% ethyl acetate in hexane) to
1
yield 4f (38 mg, 76%) as a white solid; mp 110−112 °C. H NMR
(500 MHz, CDCl3): δ 7.89 (s, 1H), 7.83−7.79 (m, 3H), 7.53−7.47
(m, 3H), 4.86 (dd, J = 42.0 Hz, 14.5 Hz, 2H), 4.27 (dd, J = 46.0 Hz,
13.0 Hz, 2H), 1.56 (s, 3H), 1.53 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3): δ 172.9, 169.5, 154.3, 133.1, 133.0, 132.0, 128.7, 128.1,
127.9, 127.6, 126.5, 126.1, 83.9, 65.0, 44.0, 19.8, 18.4. HRMS (ESI):
m/z [M + K]+ calcd for C18H17NO5K, 366.0738; found, 366.0743.
(5-Methyl-2,4-dioxo-3-(2-phenylpropan-2-yl)oxazolidin-5-yl)-
methyl Acetate (4g). Compound 4g was synthesized from 3g (50 mg,
0.16 mmol), PhI(OAc)2 (106 mg, 0.329 mmol), and acetic acid (1.65
mL, 0.1 M) according to general procedure C. The crude compound
was purified by chromatography (0−20% ethyl acetate in hexane) to
yield 4g (34 mg, 62%) as a white solid; mp 78−80 °C. 1H NMR (500
MHz, CDCl3): δ 7.37−7.32 (m, 4H), 7.28−7.25 (m, 1H), 4.28 (dd, J
= 82.5 Hz, 12.0 Hz, 2H), 2.07 (s, 3H), 1.97 (s, 6H), 1.52 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3): δ 173.8, 169.5, 153.7, 144.6,
(3-(2-Methoxybenzyl)-5-methyl-2,4-dioxooxazolidin-5-yl)methyl
Acetate (4b). Compound 4b was synthesized from 3b (50 mg, 0.16
mmol), PhI(OAc)2 (106 mg, 0.33 mmol), and acetic acid (1.64 mL,
0.1 M) according to general procedure C. The crude compound was
purified by chromatography (0−15% ethyl acetate in hexane) to yield
128.5, 127.3, 124.4, 81.6, 65.3, 62.8, 28.4, 27.8, 20.5, 18.9. HRMS
(ESI): m/z [M + K]+ calcd for C16H19NO5K, 344.0895; found,
344.0895.
1
4b (47.6 mg, 94%) as a white solid; mp 82−83 °C. H NMR (400
MHz, CDCl3): δ 7.30−7.22 (m, 2H), 6.92−6.87 (m, 2H), 4.77 (s,
2H), 4.32 (dd, J = 50.8 Hz, 12.0 Hz, 2H), 3.84 (s, 3H), 1.95 (s, 3H),
1.57 (s, 3H);13C{1H} NMR (100 MHz, CDCl3): δ 172.8, 169.5,
157.0, 154.2, 129.4, 128.6, 122.2, 120.3, 110.5, 83.5, 64.9, 55.3, 39.1,
20.3, 18.7. HRMS (ESI): m/z [M + Na]+ calcd for C15H17NO6Na,
330.0948; found, 330.0954.
(5-Methyl-2,4-dioxo-3-phenethyloxazolidin-5-yl)methyl Acetate
(4h). Compound 4h was synthesized from 3h (50 mg, 0.17 mmol),
PhI(OAc)2 (111 mg, 0.34 mmol), and acetic acid (1.72 mL, 0.1 M)
according to general procedure C. The crude compound was purified
by chromatography (0−15% ethyl acetate in hexane) to yield 4h (38
1
(3-(4-Fluorobenzyl)-5-methyl-2,4-dioxooxazolodin-5-yl)methyl
Acetate (4c). Compound 4c was synthesized from 3c (50 mg, 0.17
mmol), PhI(OAc)2 (113 mg, 0.35 mmol), and acetic acid (1.70 mL,
0.1 M) according to general procedure C. The crude compound was
purified by chromatography (0−20% ethyl acetate in hexane) to yield
mg, 76%) as a white solid; mp 82−84 °C. H NMR (400 MHz,
CDCl3): δ 7.33−7.29 (m, 2H), 7.26−7.22 (m, 3H), 4.25 (dd, J = 58.4
Hz, 12.0 Hz, 2H), 3.82 (td, J = 7.6 Hz, 2.4 Hz, 2H), 2.99 (br t, J = 7.4
Hz, 2H), 1.99 (s, 3H), 1.43 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 172.9, 169.6, 154.2, 136.7, 128.8, 128.7, 127.0, 83.6, 64.8,
41.0, 33.2, 20.4, 18.6. HRMS (ESI): m/z [M + Na]+ calcd for
C15H17NO5Na, 314.1003; found, 314.0999.
1
4c (45 mg, 89%) as a white solid; mp 93 °C. H NMR (400 MHz,
CDCl3): δ 7.43−7.40 (m, 2H), 7.05−7.01 (m, 2H), 4.66 (dd, J = 36.0
Hz, 14.4 Hz, 2H), 4.28 (dd, J = 45.6 Hz, 12.4 Hz, 2H), 1.72 (s, 3H),
1.56 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 172.8, 169.4,
162.7 (d, JCF = 246.2 Hz), 154.1, 130.7 (d, JCF = 8.8 Hz), 130.6 (d, JCF
= 2.9 Hz), 115.7 (d, JCF = 21.4 Hz), 83.9, 65.0, 43.0, 20.0, 18.4. 19F
NMR (564 MHz, CDCl3): δ −112.9 (s). HRMS (ESI): m/z [M +
Na]+ calcd for C14H14FNO5Na, 318.0748; found, 318.0750.
(5-Methyl-2,4-dioxo-3-phenyloxazolidin-5-yl)methyl Acetate
(4i). Compound 4i was synthesized from 3i (50 mg, 0.19 mmol),
PhI(OAc)2 (123 mg, 0.381 mmol), and acetic acid (1.9 mL, 0.1 M)
according to general procedure C. The crude compound was purified
by chromatography (0−15% ethyl acetate in hexane) to yield 4i (37
1
mg, 74%) as a white solid; mp 118−120 °C. H NMR (500 MHz,
(3-(2-Fluorobenzyl)-5-methyl-2,4-dioxooxazolidin-5-yl)methyl
Acetate (4d). Compound 4d was synthesized from 3d (50 mg, 0.17
mmol), PhI(OAc)2 (113 mg, 0.35 mmol), and acetic acid (1.70 mL,
0.1 M) according to general procedure C. The crude compound was
purified by chromatography (0−20% ethyl acetate in hexane) to yield
CDCl3): δ 7.52 (br t, J = 7.5 Hz, 2H), 7.46−7.40 (m, 3H), 4.41 (dd, J
= 55.0 Hz, 12.0 Hz, 2H), 2.07 (s, 3H), 1.69 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3): δ 172.1, 169.5, 153.2, 130.7, 129.4, 129.1, 125.4,
83.5, 65.3, 20.4, 18.6. HRMS (ESI): m/z [M + Na]+ calcd for
C13H13NO5Na, 286.0686; found, 286.0686.
1
4d (44.3 mg, 88%) as a white solid; mp 94−95 °C. H NMR (400
(3-(4-Methoxyphenyl)-5-methyl-2,4-dioxooxazolidin-5-yl)methyl
Acetate (4j). Compound 4j was synthesized from 3j (180 mg, 0.618
mmol), PhI(OAc)2 (398 mg, 1.235 mmol), and acetic acid (6.18 mL,
0.1 M) according to general procedure C. The crude compound was
purified by chromatography (0−15% ethyl acetate in hexane) to yield
MHz, CDCl3): δ 7.41−7.35 (td, J = 7.2 Hz, 1.2 Hz, 1H), 7.34−7.28
(m, 1H), 7.14−7.05 (m, 2H), 4.80 (dd, J = 23.2 Hz, 14.8 Hz, 2H),
4.31 (dd, J = 52.4 Hz, 12.0 Hz, 2H), 1.88 (s, 3H), 1.59 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 172.6, 169.4, 160.5 (d, JCF
=
1
247.1 Hz), 153.9, 130.3 (d, JCF = 2.9 Hz), 130.2 (d, JCF = 8.8 Hz),
124.2 (d, JCF = 3.9 Hz), 121.3 (d, JCF = 14.6 Hz), 115.6 (d, JCF = 21.4
Hz), 83.9, 65.0, 37.6 (d, JCF = 4.9 Hz), 20.1, 18.5. 19F NMR (564
MHz, CDCl3): δ −116.8 (s). HRMS (ESI): m/z [M + Na]+ calcd for
C14H14FNO5Na, 318.0748; found, 318.0740.
(5-Methyl-2,4-dioxo-3-(thiophen-3-ylmethyl)oxazolidin-5-yl)-
methyl Acetate (4e). Compound 4e was synthesized from 3e (50 mg,
0.18 mmol), PhI(OAc)2 (144 mg, 0.45 mmol), and acetic acid (1.78
mL, 0.1 M) according to general procedure C. The crude compound
4j (150 mg, 82%) as an off-white solid; mp 111−113 °C. H NMR
(600 MHz, CDCl3): δ 7.30 (d, J = 9.0 Hz, 2H), 7.01 (d, J = 9.0 Hz,
2H), 4.40 (dd, J = 67.2 Hz, 12.0 Hz, 2H), 3.83 (s, 3H), 2.07 (s, 3H),
1.67 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 172.3, 169.5,
159.8, 153.5, 126.9, 123.2, 114.7, 83.5, 65.4, 55.5, 20.4, 18.7. HRMS
(ESI): m/z [M + Na]+ calcd for C14H15NO6Na, 316.0792; found,
316.0797.
(5-Ethyl-3-(4-methoxybenzyl)-2,4-dioxooxazolidin-5-yl)methyl
Acetate (6a). Compound 6a was synthesized from 5a (50 mg, 0.157
F
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mmol), PhI(OAc)2 (104 mg, 0.322 mmol), and acetic acid (1.57 mL,
0.1 M) according to general procedure C. The crude compound was
purified by chromatography (0−15% ethyl acetate in hexane) to yield
6a (48 mg, 99%) as a colorless liquid; 1H NMR (500 MHz, CDCl3):
δ 7.36 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 9.0 Hz, 2H), 4.64 (dd, J = 37.5
Hz, 14.5 Hz, 2H), 4.28 (dd, J = 59.0 Hz, 12.0 Hz, 2H), 3.77 (s, 3H),
1.94−1.85 (m, 2H), 1.73 (s, 3H), 0.88 (t, J = 7.0 Hz, 3H); 13C{1H}
NMR (125 MHz, CDCl3): δ 172.4, 169.5, 159.6, 154.6, 130.2, 126.9,
114.0, 87.0, 64.5, 55.2, 43.2, 25.2, 20.0, 6.5. HRMS (ESI): m/z [M +
Na]+ calcd for C16H19NO6Na, 344.1105; found, 344.1104.
rel-(R)-1-((S)-3-(4-Methoxybenzyl)-5-methyl-2,4-dioxazolidin-5-
yl)ethyl Acetate (6b). Compound 6b was synthesized from 5b (100
mg, 0.313 mmol), PhI(OAc)2 (201 mg, 0.62 mmol), and acetic acid
(3.13 mL, 0.1 M) according to general procedure C. The crude
compound was purified by chromatography (0−20% ethyl acetate in
hexane) to yield 6b (27 mg, 27%) as a colorless liquid and 7a (36 mg,
44%) as a colorless liquid. 1H NMR (600 MHz, CDCl3): δ 7.37 (d, J
= 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 5.07 (q, J = 6.6 Hz, 1H), 4.59
(dd, J = 20.4 Hz, 14.4 Hz, 2H), 3.76 (s, 3H), 1.52 (s, 3H), 1.50 (s,
3H), 1.32 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ
173.3, 169.1, 159.6, 154.6, 130.5, 127.0, 114.1, 86.4, 71.0, 55.3, 43.2,
20.1, 18.6, 13.4. HRMS (ESI): m/z [M + Na]+ calcd for
C16H19NO6Na, 344.1105; found, 344.1110.
mmol), PhI(OAc)2 (101 mg, 0.315 mmol), and acetic acid (1.57
mL, 0.1 M) according to general procedure C. The crude compound
was purified by chromatography (0−10% ethyl acetate in hexane) to
1
yield 11 (44 mg, 75%) as a white solid; mp 100−101 °C. H NMR
(500 MHz, CDCl3): δ 7.66−7.62 (m, 2H), 7.44−7.35 (m, 5H),
7.19−7.12 (m, 5H), 6.88−6.84 (m, 4H), 6.72−6.70 (m, 2H), 4.70−
4.66 (m, 1H), 4.60−4.57 (m, 1H), 4.55−4.52 (m, 1H), 4.45−4.42
(m, 1H), 4.37 (s, 2H), 3.78 (s, 3H), 3.77 (s, 3H), 3.31 (dd, J = 50.5
Hz, 18 Hz, 2H), 2.15 (s, 3H), 1.72 (s, 3H); 13C{1H} NMR (125
MHz, CDCl3): δ 171.1, 169.4, 168.8, 168.4, 159.6, 159.1, 154.1,
152.7, 131.4, 130.4, 130.2, 129.8, 129.5, 129.4, 129.0, 128.6, 128.1,
126.7, 125.9, 124.9, 114.0, 113.8, 99.9, 86.0, 66.4, 55.2, 55.1, 43.5,
43.1, 40.3, 20.4, 20.0. HRMS (ESI): m/z [M + K]+ calcd for
C20H19NO6K, 408.0844; found, 408.0853.
rel-(2S,3R)-2,3-Dihydroxy-N-(4-methoxybenzyl)-2-methyl-
butanamide (8a). To a solution of 6b (136 mg, 0.423 mmol) in THF
and MeOH (8 mL, 1:1) was added LiOH·H2O (480 mg, 11.42 mmol,
dissolved in 4.0 mL water) at room temperature. The reaction mixture
was stirred at room temperature overnight. Upon reaction
completion, volatiles were removed under reduced pressure and the
crude compound was extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over anhydrous Na2SO4,
and filtered. The solvent was evaporated, and the crude material was
purified by chromatography (0−50% ethyl acetate in hexane) to yield
3-(4-Methoxybenzyl)-5-methyl-5-vinyloxazolidine-2,4-dione
1
1
(7a). H NMR (400 MHz, CDCl3): δ 7.31 (d, J = 8.8 Hz, 2H), 6.85
8a (74 mg, 69%) as a white solid; mp 112−114 °C. H NMR (600
(d, J = 8.6 Hz, 2H), 5.92 (dd, J = 17.2 Hz, 10.8 Hz, 1H), 5.41 (dd, J =
75.2 Hz, 16.8 Hz, 1H), 4.59 (s, 2H), 3.78 (s, 3H), 1.61 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3): δ 173.4, 159.5, 154.3, 133.0,
MHz, CDCl3): δ 7.20 (d, J = 8.4 Hz, 2H), 7.12 (br s, 1H), 6.86 (d, J =
8.4 Hz, 2H), 4.39 (td, J = 15.6 Hz, 6.0 Hz, 2H), 4.11 (q, J = 6.6 Hz,
6.0 Hz, 1H), 3.79 (s, 3H), 3.21 (s, 1H), 2.76 (d, J = 6.0 Hz, 1H), 1.37
(s, 3H), 1.18 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3):
δ 175.7, 159.0, 130.0, 128.9, 114.1, 77.4, 71.3, 55.3, 42.7, 23.0, 16.7.
HRMS (ESI): m/z [M + Na]+ calcd for C13H19NO4Na, 276.1206;
found, 276.1213.
130.0, 126.8, 117.6, 114.1, 85.2, 55.2, 43.2, 22.5. HRMS (ESI): m/z
[M + Na]+ calcd for C14H15NO4Na, 284.0893; found, 284.0900.
rel-(S)-1-((S)-3-(4-Methoxybenzyl)-5-methyl-2,4-dioxo-
oxazolidin-5-yl)ethyl Acetate (6c). Compound 6c was synthesized
from 5c (100 mg, 0.313 mmol), PhI(OAc)2 (201 mg, 0.62 mmol),
and acetic acid (3.13 mL, 0.1 M) according to general procedure C.
The crude compound was purified by chromatography (0−20% ethyl
acetate in hexane) to yield 6c (42 mg, 42%) as a colorless liquid and
7a (34 mg, 42%) as a colorless liquid. 1H NMR (400 MHz, CDCl3): δ
7.36 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 5.12 (q, J = 6.4 Hz,
1H), 4.61 (dd, J = 48.6 Hz, 14.2 Hz, 2H), 3.78 (s, 3H), 1.75 (s, 3H),
1.54 (s, 3H), 1.30 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3): δ 172.6, 169.4, 159.5, 154.4, 130.2, 126.9, 114.0, 85.8, 71.9,
55.2, 43.1, 20.3, 18.8, 14.2. HRMS (ESI): m/z [M + Na]+ calcd for
C16H19NO6Na, 344.1105; found, 344.1110.
rel-(4S,5R)-N-(4-Methoxybenzyl)-2,2,4,5-tetramethyl-1,3-dioxo-
lane-4-carboxamide (9a).27 To a solution of 8a (35 mg, 0.14 mmol)
in 1.5 mL of CH2Cl2 was added 2,2-DMP (28 mg, 0.27 mmol) and a
catalytic amount of PTSA at room temperature. The reaction mixture
was stirred for 2 h. Upon reaction completion, sat. NaHCO3 solution
was added and the mixture was extracted with dichloromethane. The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and filtered. The filtrate was concentrated
under reduced pressure, and the crude material was purified by
chromatography (0−20% ethyl acetate in hexane) to yield 9a (39 mg,
97%) as a colorless liquid. 1H NMR (600 MHz, CDCl3): δ 7.19 (d, J
= 8.4 Hz, 2H), 7.02 (br s, 1H), 6.87 (d, J = 8.4 Hz, 2H), 4.36 (ddd, J
= 24.6 Hz, 17.4 Hz, 7.2 Hz, 2H), 4.17 (q, J = 7.20 Hz, 1H), 3.80 (s,
3H), 1.44 (s, 3H), 1.37 (d, J = 6.6 Hz, 3H), 1.33 (s, 6H); 13C{1H}
NMR (150 MHz, CDCl3): δ 173.4, 159.0, 130.1, 128.8, 114.1, 108.0,
83.4, 76.4, 55.2, 42.3, 28.2, 25.7, 19.5, 14.9. HRMS (ESI): m/z [M +
Na]+ calcd for C16H23NO4Na, 316.1519; found, 316.1522.
(E)-3-(4-Methoxybenzyl)-5-methyl-5-(prop-1-en-1-yl)-
oxazolidine-2,4-dione (7b). Compound 7b was synthesized from 5d
(100 mg, 0.30 mmol), PhI(OAc)2 (193 mg, 0.60 mmol), and acetic
acid (3.0 mL, 0.1 M) according to general procedure C. The crude
compound was purified by chromatography (0−10% ethyl acetate in
hexane) to yield 7b (42 mg, 51%) as a colorless liquid along with 4d
1
(12 mg, 17%). H NMR (500 MHz, CDCl3): δ 7.31 (d, J = 8.5 Hz,
rel-(2S,3S)-2,3-Dihydroxy-N-(4-methoxybenzyl)-2-methyl-
butanamide (8b). To a solution of 6c (70 mg, 0.42 mmol) in THF
and MeOH (4 mL, 1:1) was added LiOH·H2O (24 mg, 11.44 mmol,
dissolved in 2 mL water) at room temperature. The reaction mixture
was stirred at room temperature overnight. Upon reaction
completion, volatiles were removed under reduced pressure and the
crude material was extracted with ethyl acetate. The combined
organic layers were washed with brine, dried over anhydrous Na2SO4,
and filtered. The solvent was evaporated, and the crude compound
was purified by chromatography (0−50% ethyl acetate in hexane) to
2H), 6.85 (d, J = 8.5 Hz, 2H), 5.93−5.86 (dq, J = 15.5 Hz, 6.5 Hz,
1H), 5.54 (dq, J = 15.5 Hz, 2.0 Hz, 1H), 4.59 (s, 2H), 3.79 (s, 3H),
1.72 (dd, J = 7.0 Hz, 2.0 Hz, 3H), 1.58 (s, 3H); 13C{1H} NMR (125
MHz, CDCl3): δ 174.0, 159.5, 154.4, 130.0, 129.5, 126.9, 126.0,
114.1, 85.1 55.2, 43.2, 22.7, 17.7. HRMS (ESI): m/z [M + Na]+ calcd
for C15H17NO4Na, 298.1050; found, 298.1053.
3-(4-Methoxybenzyl)-5-methyl-5-(prop-1-en-2-yl)oxazolidine-
2,4-dione (7c). Compound 7c was synthesized from 5e (107 mg, 0.30
mmol), PhI(OAc)2 (193 mg, 0.60 mmol), and acetic acid (3.0 mL,
0.1 M) according to general procedure C. The crude compound was
purified by chromatography (0−15% ethyl acetate in hexane) to yield
7c (32 mg, 36%) as a colorless liquid; 1H NMR (500 MHz, CDCl4):
δ 7.32 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.21 (br s, 1H),
5.06−5.04 (m, 1H), 4.60 (s, 2H), 3.79, (s, 3H), 1.77 (t, J = 1.5 Hz,
3H), 1.65 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 173.5,
159.5, 154.5, 139.5, 130.0, 126.9, 114.8, 114.1, 87.0, 55.2, 43.2, 21.3,
18.1. HRMS (ESI): m/z [M + Na]+ calcd for C15H17NO4Na,
298.1050; found, 298.1051.
1
yield 8b (58 mg, 100%) as a colorless viscous liquid. H NMR (600
MHz, CDCl3): δ 7.22 (br s, 1H), 7.18 (d, J = 8.4 Hz, 2H), 6.85 (d, J =
8.4 Hz, 2H), 4.35 (ddd, J = 16.2 Hz, 15.6 Hz, 6.0 Hz, 2H), 3.94 (q, J
= 6.6 Hz, 1H), 3.78 (s, 3H), 3.30 (s, 1H), 3.13 (br s, 1H), 1.43 (s,
3H), 1.15 (d, J = 6.0 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ
174.9, 159.0, 129.9, 129.0, 114.0, 76.7, 71.4, 55.3, 42.6, 22.3, 17.2.
HRMS (ESI): m/z [M + Na]+ calcd for C13H19NO4Na, 276.1206;
found, 276.1213.
rel-(4S,5S)-N-(4-Methoxybenzyl)-2,2,4,5-tetramethyl-1,3-dioxo-
lane-4-carboxamide (9b). To a solution of 8b (40 mg, 0.158 mmol)
in 1.5 mL of CH2Cl2 was added 2, 2-DMP (33 mg, 0.316 mmol) and
5-Benzyl-3-(4-methoxybenzyl)-2,4-dioxooxazolidin-5yl Acetate
(11). Compound 11 was synthesized from 10 (58 mg, 0.157
G
https://dx.doi.org/10.1021/acs.joc.0c00581
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
a catalytic amount of PTSA at room temperature. The reaction
mixture was stirred for 2 h. Upon reaction completion, sat. NaHCO3
solution was added and the mixture was extracted with dichloro-
methane. The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, and filtered. The filtrate was concentrated
under reduced pressure, and the crude material was purified by
chromatography (0−20% ethyl acetate in hexane) to yield 9b (37 mg,
80%) as a colorless liquid. 1H NMR (600 MHz, CDCl3): δ 7.20 (d, J
= 8.4 Hz, 2H), 7.01 (br s, 1H), 6.86 (d, J = 8.4 Hz, 2H), 4.44 (dd, J =
6.6 Hz, 14.4 Hz, 1H), 4.31 (dd, J = 14.4 Hz, 5.4 Hz,1H), 4.13 (q, J =
6.6 Hz, 1H), 3.79 (s, 3H), 1.52 (s, 3H), 1.46 (s, 3H), 1.41 (s, 3H),
1.33 (d, J = 6.0 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3): δ 171.9,
159.0, 130.2, 128.8, 114.1, 108.4, 84.4, 80.5, 55.2, 42.6, 27.6, 25.7,
23.7, 16.0. HRMS (ESI): m/z [M + Na]+ calcd for C16H23NO4Na,
316.1519; found, 316.1522.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c00581
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Welch Foundation (E-1916-20170325) and NSF
CHE-1460568 and CHE-1757888 for financial support, the
Mississippi Center for Supercomputing Research and NSF
MRI 1338056 for providing access to supercomputer
resources, and Dr. James Korp (Department of Chemistry,
University of Houston) for solving the x-ray crystal structures
of 2, 8a, and 11. The authors would also like to recognize Dr.
Jeremy May (Department of Chemistry, University of
Houston) for insightful discussions regarding the proposed
reaction mechanism.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c00581.
1H, 13C NMR spectra of compounds 1, 2, 3a−k, 4a−j,
5a−e, 6a−c, 7a−c, 8a−b, 9a−b, 10, and 11; DP4+ and
CP3 experimental data (PDF)
Crystal structure data for compound 2 (CIF)
Crystal structure data for compound 8a (CIF)
Crystal structure data for compound 11 (CIF)
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AUTHOR INFORMATION
Corresponding Author
Gregory D. Cuny − Department of Pharmacological and
Pharmaceutical Sciences, College of Pharmacy, University of
Houston, Houston, Texas 77204-5000, United States;
orcid.org/0000-0002-3188-4748; Email: gdcuny@
central.uh.edu
■
Authors
Anantha Lakshmi Duddupudi − Department of
Pharmacological and Pharmaceutical Sciences, College of
Pharmacy, University of Houston, Houston, Texas 77204-5000,
United States
Pankaj Pandey − Department of BioMolecular Sciences, Division
of Medicinal Chemistry, School of Pharmacy, University of
Mississippi, University, Mississippi 38677-1848, United States;
orcid.org/0000-0001-9128-8254
Hien Vo − Department of Pharmacological and Pharmaceutical
Sciences, College of Pharmacy, University of Houston, Houston,
Texas 77204-5000, United States
Colin L. Welsh − Department of BioMolecular Sciences,
Division of Medicinal Chemistry, School of Pharmacy,
University of Mississippi, University, Mississippi 38677-1848,
United States
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Robert J. Doerksen − Department of BioMolecular Sciences,
Division of Medicinal Chemistry, School of Pharmacy,
University of Mississippi, University, Mississippi 38677-1848,
United States; orcid.org/0000-0002-3789-1842
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