N-Acylation of Oxazolidinones via Aerobic Oxidative NHC Catalysis

Article abstract of DOI:10.1021/acs.joc.8b01723

The first N-acylation of synthetically useful oxazolidinones with aldehydes using aerobic oxidative NHC catalysis is reported. The reaction offers a broad scope of functionalized oxazolidinones in good to excellent yields. Careful choice of electron transfer mediators proved pivotal to achieve efficient aerobic N-acylation, which has previously proven difficult using NHC catalysis. The methodology allows a mild entry to acylated oxazolidinones, avoiding the use of hazardous and reactive prefunctionalized substrates.

Full text of DOI:10.1021/acs.joc.8b01723

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Note
N-acylation of oxazolidinones via aerobic oxidative NHC catalysis
Linda Ta, Anton Axelsson, and Henrik Sundén
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01723 • Publication Date (Web): 29 Aug 2018
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The Journal of Organic Chemistry
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N-acylation of oxazolidinones via aerobic oxidative NHC catalysis
Linda Ta,‡ Anton Axelsson‡ and Henrik Sundén*
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Chemistry and Chemical Engineering, Chalmers University of Technology, Kemivägen 10, 412 96 Göteborg, Sweden.
KEYWORDS: N-heterocyclic carbene, Aerobic, Oxidation, Oxazolidinone, N-Acylation, ETM, Organocatalysis.
ABSTRACT: The first N-acylation of synthetically useful oxazolidinones with aldehydes using aerobic oxidative NHC catalysis is
reported. The reaction offers a broad scope of functionalized oxazolidinones in good to excellent yields. Careful choice of electron
transfer mediators (ETMs) proved pivotal to achieve efficient aerobic N-acylation, which have previously proven difficult using
NHC-catalysis. The methodology allows a mild entry to acylated oxazolidinones avoiding the use of hazardous and reactive prefunc-
tionalized substrates.
Functionalized oxazolidinones are important organic mole-
cules that exhibit interesting biological activities. The oxazoli-
dinone-moiety can, for example, be found in pharmaceuticals,
such as Locostatin, a Raf-kinase inhibitor and natural products
(Scheme 1a).1-5 Synthetically, N-acylated oxazolidinones have
mostly been used as chiral auxiliaries, first popularized by Ev-
ans and have been employed in different asymmetric transfor-
mations6-8 such as aldol,9 alkylation,10 Diels-Alder reactions11
and Michael additions12 and in total synthesis13-14 (Scheme 1a)
and still attracts considerable attention within the synthetic
community today.15-20
Scheme 1. a) Various uses for functionalized oxazolidinones.
b) Previous reports for N-acylation of oxazolidinones. c)
This approach.
a)Pharmaceuticals and natural products Versatile platform for
O
asymmetric synthesis
O
Evans' auxiliary
Winchinine A
N
N
O
O
O
Locostatin
N
O
O
O
Ph
R
Aldol
Alkylation
Diels-Alder
Michael addition
The general synthesis of N-acylated oxazolidinones proceeds
by deprotonation normally using a strong base, such as n-BuLi,
in combination with an acid chloride or anhydride (Scheme 1b).
However, the use of highly reactive substrates, which requires
special precautions as well as the usage of strong bases, capable
of epimerizing chiral oxazolidinones at the C-5 position limits
these protocols.21 Alternative methods includes the use of cou-
pling reagents,22 acyl fluorides,23 carbonylazoles,24 DMAP,25
metal catalysis,26 and electrochemistry.27 However, these pro-
cedures still requires highly reactive reagents, coupling rea-
gents, high reaction temperatures and reagents in excess in or-
der to drive the reaction to completion. Clearly, a more benign,
atom economical and facile acylation of oxazolidinones would
be highly desirable (Scheme 1c).
H
N
HN
O
N
R
R
Ceramide analog
O
O
C12H25
HO
b) General strategy (stoichiometric)
- Sensitive reagents
- Strong bases
O
O
O
O
O
R
O
R
HN
O
N
O
O
R
- Stoichiometric
- Byprod: Li-salts
or
+
Li-salts and C4H10
n-BuLi
Cl
c)
This strategy (catalytic aerobic)
O
O
O
O
NHC, O2
O
water
+
+
HN
OH
O
N
O
R
The use of N-heterocyclic carbene (NHC) catalysis has
emerged as an environmentally friendly method in lieu of tran-
sition metal catalysis, and displays a plethora of reaction path-
ways taking the field of organic synthesis forward.28-31 In com-
bination with an oxidant, NHC catalysis can utilize readily
available aldehydes as acyl donors via the acyl azolium inter-
mediate (Scheme 1c), thus circumventing the need to generate
sensitive activated acyl-donors in advance.
R
- Mild conditions
- Aerial O2
via
N
O2
N
R
R
- Catalytic
N
N
H2O
N
N
Breslow intermediate
- Byprod: water
The acyl azolium intermediate is generally formed via inter-
nal oxidation of the Breslow intermediate or by addition of an
external oxidant, such as the Kharasch oxidant 8 (Table 1). Con-
ventional methods has enabled the formation of numerous novel
methodologies,32-34 where O-nucleophiles are well investi-
gated,34-38 on the contrary, methodologies for acylation of N-
nucleophiles remain scarce.39-45 These methodologies suffer
from using 8 in stoichiometric amounts, generating stoichio-
metric quantities of waste in the downstream process.
Recently, we have shown that 8 can be replaced with aerial O2,
an oxidant that generates water as the sole by-product, using a
system of electron transfer mediators (ETMs) for the synthesis
of various esters and dihydropyranones.46-48 The system of
ETMs circumvents the high energy barriers normally associated
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with direct aerobic oxidation by creating a low energy pathway Table 1. Screening of reaction conditions.
Page 2 of 9
for the electrons to flow from the substrate to oxygen.49-54 It is
worth noting, that by using an ETM-system, one can typically
avoid side-reactions associated with aerobic NHC catalysis,
such as, acid formation, homo-coupling and internal redox re-
actions. This selectivity can be attributed to a kinetic preference
for oxidation of the homoenolate to the acyl azolium by the
ETMs.
1
2
3
4
5
6
7
8
O
Cat., Base
O
O
ETM, ETM'
Solvent
Ph
N
+
Ph
HN
O
O
O
1
2
3
air, RT
Cl
I
S
Mes
Mes
Cl
N
N
N
N
N
N
To combine NHC-catalyzed N-acylation and aerobic oxida-
tion have proven cumbersome, as noted in the reports by Con-
non and co-workers, where aerobic esterifications are possible
but amidations require the addition of a stochiometric oxidant
to be efficient.55 This incompatibility was also noted in the oxi-
dative acylation of indoles previously reported by our group,
where aerobic oxidation was only possible for one entry and re-
quired high loading of the ETM (25 mol%).45 Herein, we report
the aerobic oxidative NHC-catalyzed N-acylation of oxazoli-
dinones using aldehydes as mild acylation reagents.56 The reac-
tion can be carried out under ambient reaction conditions and
offers a broad scope of synthetically useful acylated oxazoli-
dinones.
Cl
N
N
HO
N
9
Bn
Mes
MeO
6
4
5
7
10
11
12
13
14
15
16
17
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19
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21
22
23
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58
59
60
O
tBu
tBu
OMe
O
Co
N
O
N
O
O
tBu
tBu
O
8
9
10
Entry Cat. Solvent Base
ETM
ETM’ Yield
1.a
2.a
3.a
4
5
6
7
5
5
5
5
5
5
5
5
5
MeCN TBD
MeCN TBD
MeCN TBD
MeCN TBD
Anisole TBD
EtOAc TBD
8
8
8
8
8
8
8
8
8
8
8
9
FePc
FePc
FePc
FePc
FePc
FePc
FePc
FePc
47
53
32
0
The starting point for this study was a survey of different
NHC-precatalysts. Triazolium salts 4 and 5 were both good can-
didates (Table 1, entry 1 and 2) with 5 delivering 3 in slightly
higher yields (53% vs. 47%). Imidazolium salt 6 (entry 3) was
not as efficient in comparison (32%) and thiazolium salt 7 (en-
try 4) showed no activity in the reaction. Next, evaluations of
different solvents were made. Ethyl acetate (EtOAc) gave com-
parable results with acetonitrile (MeCN) delivering the product
in 55% yield (entry 6). On the other hand, dichloromethane
(DCM) (entry 7) and methyl ethyl ketone (MEK) (entry 8) re-
sulted in lower yields As EtOAc is considered a more sustaina-
ble and greener solvent alternative,57 it became the solvent of
choice. At this point the system was still not efficient enough.
The isolation of side-products such as γ-butyrolactone58 the sat-
urated N-acyloxazolidinone as well as cinnamic acid, indicated
a slow oxidation of the Breslow intermediate (Scheme 1c). Fur-
ther optimization with different bases and ETM-systems were
investigated. The most effective base proved to be DBU (entry
9) capable of delivering 3 in 90% yield, while the weaker or-
ganic base, triethylamine (TEA) (entry 10) failed to generate
any product at all. We also noted that it was possible to lower
the amount of NHC catalyst (from 5 mol% to 1 mol%), base
(from 0.5 eq. to 0.2 eq.). Furthermore, the reaction seemed to
be sensitive to changes in concentration; doubling the amount
of EtOAc (3.2 ml, 77% yield) give lower yields in comparison
with the optimized amount (1.6 ml, 90% yield). Different ETM-
systems (entry 11–12) were tested and showed that 8 together
with FePc were the most suited combination. With a stoichio-
metric amount of 8 the product was obtained in 84% yield, less
efficient in comparison with our developed aerobic method (en-
try 13). Reactions performed by excluding the different ETMs
and O2 showed that they are essential for an efficient reaction
(for full optimization of reaction conditions, see SI). The gen-
erality of the reaction was first investigated with regard to the
aldehyde reaction partner (Scheme 2). α,β-unsaturated alde-
hydes works well with both electron donating groups (com-
pounds 11–13, 16) and electron withdrawing groups (com-
pounds 14, 15, and 17) with both para- and orto-substitution on
the aromatic ring giving good yields. A gram-scale synthesis of
3 was also viable and could be obtained in 76% yield without
using any
4.a
5.a
6.a
7.a
8.a
9.b
10.b
11.b
12.b
13.b,d
24
55
35
32
DCM
MEK
TBD
TBD
EtOAc DBU
EtOAc TEA
EtOAc DBU
EtOAc DBU
FePc 90/89c
FePc
10
0
39
78
84
FePc
-
EtOAc DBU 8 (1 eq.)
Reaction conditions: a1 (1 eq.), 2 (1.5 eq.), cat (5 mol%), base (0.5
eq.), ETM (5 mol%), ETM’ (3 mol%), solvent (0.16 M).
bWith cat (1 mol%), base (0.2 eq.), ETM (3 mol%), ETM’ (2
mol%), solvent (0.31 M). cIsolated yield, 2 (1.3 eq.). dPerformed
under N2 with 8 (1 eq). Yield (%) was determined by 1H NMR
with durene as internal standard. FePc = Iron(II)phthalocyanine,
TBD = 1,5,7-triazabicyclo[4.4.0]dec-5-ene, DBU = 1,8-diazabi-
cyclo[5.4.0]undec-7-ene.
chromatography. An aldehyde bearing an anthracene-moiety
was converted to compound 18 in 87% yield. Moreover, a non-
aromatic α,β-unsaturated aldehyde was viable, generating 19 in
70% yield. It was also noted that α,β-unsaturated aldehydes
with electron donating groups on the aromatic ring required a
more electron-rich catalyst 4 to furnish the products. The ben-
zaldehydes, being less activated than their α,β-unsaturated
counterpart, required slightly higher loadings of catalyst 4.
Good yields were obtained with benzaldehydes containing elec-
tron donating groups (20, 21, 23, and 24) whereas electron poor
aldehyde gave compound 22 in acceptable yield (43%). The low
yield was attributed to the formation of the benzoic acid via di-
rect oxygenative oxidation of the Breslow intermediate with
O2.33 Saturated aliphatic aldehydes have proven difficult to in-
corporate in NHC-catalyzed N-acylations,39, 43-45, 55 however, it
was found that with an increased loading of DBU (0.8 eq.) cy-
clohexanecarboxaldehyde reacted smoothly delivering product
25 in 64% yield.
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The Journal of Organic Chemistry
Next the oxazolidinone-part was investigated (Scheme 3). Dif- Scheme 3. The scope of the reaction with different nucleo-
1
2
3
4
5
6
7
8
ferent chiral and achiral oxazolidinones were tested. The N-ac-
ylation of chiral oxazolidinones substituted at C-4 position
(compounds 26–29) gave products in good yields. Due to the
steric nature of the substituents, the reaction required an eleva-
tion of reaction temperature (60 °C) and a slight increase of
base. Reaction between the C-5 substituted oxazolidinone and
cinnamaldehyde delivered product 30 in 73% yield under nor-
mal reaction condition, leaving the primary alkyl chloride un-
scathed. Furthermore, it was also possible to incorporate 2-pyr-
rolidinone as nucleophile for the synthesis of two natural prod-
ucts, Piperlotine F (31) and Piperlotine G (32), a Nrf2 activator,
in moderate to good yields.59-60 Acyclic amides failed to deliver
the N-acylated product under the developed reaction condi-
tions.61
philes.
O
5, DBU
O
O
8, FePc
HN
R2
X
R1
N
R1
+
O
solvent
X
R3
air
R2
X = O or C
O
R3
O
O
O
9
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
R2
29, 52%a
26, R2 = Ph, 73%a
27, R2 = iPr, 50%a
28, R2 = Bn, 65%a
Scheme 2. The scope of the reaction with different alde-
hydes.
O
O
O
O
O
O
Cat., DBU
O
N
N
O
8, FePc
solvent
R
N
30, 73%b
R
+
O
R4
HN
O
O
31, R4 = H, 48%c,d
32, R4 = OMe, 61%c
air, RT
2
Cl
O
O
O
O
R
a
Reaction conditions: With cat 5 (1 mol%), DBU (0.4 eq.), 60
N
N
b
c
O
O
°C. With cat 5 (1 mol%). With cat 5 (1 mol%), 8 (5 mol%),
DBU (1.5 eq.), aldehyde (1 eq.), 2-pyrrolidinone (2 eq.). dWith
molecular sieves (4 Å, 0.2 g)
3, R = H, 89%a, (76%)d
11, R = p-OMe, 75%b
12, R = p-Me2N, 64%b
13, R = p-Me, 64%b
14, R = p-Cl, 67%a
18, 87%a
The postulated catalytic cycle (Scheme 4) starts with deproto-
nation of the NHC-precatalyst forming the active carbene spe-
cies I. The catalyst then adds to cinnamaldehyde 1 to give Bres-
low intermediate II. With the help of the linked ETM-system,
the Breslow intermediate is subsequently oxidized by O2 via a
multistep electron transfer step, to form the acyl azolium inter-
mediate III. In the last step, the deprotonated oxazolidinone IV
reacts with acyl azolium III forming 3 and regenerating the cat-
alyst. The synthetically useful N-acylated oxazolidinones were
also applied in the synthesis of a 2-chromanone-scaffold found
in the natural products of the calomelanol family (Scheme 5).62-
63 Compound 3 was reacted with phloroglucinol (33) in toluene
at 100 °C using montmorillonite K10 as catalyst giving com-
pound 34 in 87% yield through a tandem Friedel–Crafts alkyl-
ation lactonization.64-65
O
O
15, R = p-F, 86%a
N
N
O
19, 70%b
16, R = o-OMe, 81%b
17, R = o-NO2, 58%a
OMe O
O
O
O
O
N
O
O
O
21, 79%c
20, 63%c
Cl
O
O
N
O
O
N
O
O
Scheme 4. The proposed mechanism.
22, 43%c
23, 60%c
OH
oxidation
1/2 O2
ETM'red
O
O
N
O
O
ETMox
R
II
N
H2O
ETM'ox
N
ETMred
N
N
O
O
O
1
MeO
N
N
24, 60%c
25, 64%e
R
III
N
N
O
N
DBU
DBU
a
b
2
5
N
Reaction conditions: With cat 5 (1 mol%). With cat 4 (1
mol%). cWith cat 4 (4 mol%). dGram-scale synthesis. eWith cat
4 (5 mol%) and DBU (0.8 eq.).
O
N
I
IV
3
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General procedure 1. To a 4 ml vial equipped with a magnetic stir
Scheme 5. Synthesis of a dihydrocoumarin scaffold from 3
and phloroglucinol.
bar were added 1,4-dimethyl-4H-1,2,4-triazol-1-ium iodide (cat 5) (1.1
mg, 0.005 mmol, 0.01 eq.), iron(II)phthalocyanine (FePc) (5.7 mg, 0.01
mmol, 0.02 eq.), 3,3’,5,5’-tetra-tert-butyldiphenoquinone (8) (6.1 mg,
0.015 mmol, 0.03 eq.), 2-oxazolidinone (52 mg, 0.59 mmol, 1.3 eq.),
1
2
3
4
5
6
OH
cinnamaldehyde (62.1 mg, 0.47 mmol,
1 eq.), 1,8-diazabicy-
OH
Montmorillonite K10
clo[5.4.0]undec-7-ene (DBU) (15.4 µl, 0.10 mmol, 0.2 eq.) and ethyl
acetate (1.6 ml). The reaction mixture was stirred at room temperature,
+
3
o
toluene, 100 C
1
open to the atmosphere, monitored by H NMR until the reaction had
HO
OH
N2
7
8
9
reached completion. The product was purified with the biotage using
petroleum ether (40–60 °C)/ethyl acetate and dichloromethane gradi-
ent. (25ml/min, 100% petroleum ether → 20% ethyl acetate →100%
petroleum ether →100% dichloromethane). The product was obtained
as a lightly yellow solid (90.6 mg, 0.42 mmol, 89% yield). This proce-
dure was used for compounds 3, 14, 15, 17, 18, 30.
33
HO
O
O
34, 87% yield
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Reaction conditions: 3 (0.3 mmol), K10 (95.1 mg), phloroglu-
cinol 33 (1.1 eq.), PhMe (0.3 ml), 100 °C for 16 h.
General procedure 2. For the cinnamaldehydes containing electron
donating
substituents,
2-mesityl-6,7-dihydro-5H-pyrrolo[2,1-
In summary, the first aerobic oxidative NHC-catalyzed N-ac-
ylation of oxazolidinones and pyrrolidinone has been reported.
In combination with an ETM system the reaction uses molecu-
lar oxygen as a terminal oxidant in an atom efficient manner.
The reaction has a high functional group compatibility, provid-
ing a broad scope of N-acylated oxazolidinones. The method
was also used for the synthesis of two natural products, Piper-
lotine F and Piperlotine G. The acylated oxazolidinones were
further modified in the synthesis of a 2-chromanone using
montmorillonite K10 as catalyst. The developed methodology
offers a sustainable way of using readily available aldehydes as
acylation reagents circumventing the need for highly reactive
prefunctionalized substrates.
c][1,2,4]triazol-2-ium chloride (cat 4) (1.4 mg, 0.005 mmol, 0.01 eq.)
was used instead, for aromatic aldehydes 0.04 eq. of cat 4 was used. To
a 5 ml pear shaped flask was added 2-mesityl-6,7-dihydro-5H-pyr-
rolo[2,1-c][1,2,4]triazol-2-ium chloride (cat 4) (5.28 mg, 0.02 mmol,
0.04 eq.), iron(II)phthalocyanine (FePc) (5.7 mg, 0.01 mmol, 0.02 eq.),
3,3’,5,5’-tetra-tert-butyldiphenoquinone (8) (10.2 mg, 0.025 mmol,
0.05 eq.), 2-oxazolidinone (52.3 mg, 0.60 mmol, 1.2 eq.), 2-methox-
ybenzaldehyde (68.1 mg, 0.50 mmol, 1 eq.), 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU) (14.9 µl, 0.10 mmol, 0.2 eq.) and ethyl acetate (1.6
ml). The reaction mixture was stirred at room temperature, open to the
atmosphere, monitored by 1H NMR until the reaction had reached com-
pletion. The product was purified with the biotage using petroleum
ether (40–60 °C)/ethyl acetate and dichloromethane gradient.
(25ml/min, 100% petroleum ether → 20% ethyl acetate →100% petro-
leum ether →100% dichloromethane). The product was obtained as a
lightly yellow solid (87.9 mg, 0.397 mmol, 79% yield). This procedure
was used for compounds 11–13, 16, 19–25.
EXPERIMENTAL SECTION
General considerations. All solvents and reagents were purchased
from commercial suppliers and used without modifications unless oth-
erwise stated. NHC-precatalyst 4,66 and 5,67 were synthesized accord-
ing to literature procedures. Oxidant 3,3’,5,5’-tetra-tert-butyldipheno-
quinone (8) was synthesized according to literature procedure.68 4-
Methylcinnamaldehyde69 and ETM 1070-71 were synthesized according
to literature procedures.
General procedure 3. To a 5 ml pear shaped flask equipped with a
magnetic stir bar were added 1,4-dimethyl-4H-1,2,4-triazol-1-ium io-
dide (cat 5) (1.5 mg, 0.007 mmol, 0.001 eq.), iron(II)phthalocyanine
(FePc) (6 mg, 0.01 mmol, 0.02 eq.), 3,3’,5,5’-tetra-tert-butyldipheno-
quinone (8) (7.2 mg, 0.018 mmol, 0.03 eq.), (R)-(−)-4-phenyl-2-oxa-
zolidinone (82.4 mg, 0.51 mmol, 1 eq.), cinnamaldehyde (104.8 mg,
0.79 mmol, 1.6 eq.), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (30.2
µl, 0.20 mmol, 0.4 eq.) and ethyl acetate (1.6 ml). The reaction mixture
Purification was performed by an automated column chromatog-
raphy Biotage Isolera™ Spektra One with Biotage SNAP®-10 g KP-
sil column together with a 1 g samplet® cartridge. Thin layer chroma-
tography (TLC) was performed on Merck TLC plates pre-coated with
silica gel 60 F254 (Art 5715, 025 mm) and was visualized with UV-light
1
was stirred at 60 °C, open to the atmosphere, monitored by H NMR
until the reaction had reached completion. The product was purified
with the biotage using petroleum ether (40–60 °C)/ethyl acetate and
dichloromethane gradient. (25ml/min, 100 % petroleum ether → 20%
ethyl acetate →100% petroleum ether →100% dichloromethane). The
product was obtained as a yellow solid (107.9 mg, 0.37 mmol, 73%).
This procedure was used for compounds 26–29.
(254 nm) or Hanessian’s stain. NMR-spectra, 1H NMR (400 MHz), 13
C
NMR (101 MHz) and 19F NMR (376 MHz) were recorded on Varian
1
400. The chemical shifts for H and 13C NMR spectra are reported in
parts per million (ppm) relative to the residual peak from solvent CDCl3
or DMSO-d6 as the internal standard; 1H NMR at δ 7.26 ppm and 13C
NMR at δ 77.16 ppm for CDCl3, and 1H NMR at δ 2.50 ppm and 13C
NMR at δ 39.52 ppm for DMSO-d6. All coupling constants (J) are re-
ported in Hertz (Hz) and multiplicities are indicated by s (singlet), d
(doublet), dd (doublet of a doublet), appd (apparent doublet), t (triplet),
appt (apparent triplet) and m (multiplet).
FT-ATR-IR spectra were recorded on a Perkin-Elmer Spectrum
Frontier infrared spectrometer with pike-GladiATR™ module and re-
ported in wavenumber (cm−1) as follows: very strong (vs), s (strong)
and m (medium). Melting points were recorded on a Büchi Melting
Point B-545.High-resolution mass spectrometry (HRMS) was per-
formed on an Agilent 1290 infinity LC system equipped with an au-
toSampler tandem to an Agilent 6520 Accurate Mass Q-TOF LC/MS.
HRMS was analyzed with a column, with a 0.3 ml/min flow rate using
an isocratic method (10% MPA/90% MPB (Mobile Phase A: Water
with 0.04 % formic acid, Mobile Phase B: MeCN with 0.04% formic
acid)). All samples were initially analyzed using an ESI source in pos-
itive mode (scan range 100–1700 m/z). The samples were diluted to ca
10 µg/ml in MeCN. Ion source parameters were as follows: drying gas
10 L/min and temperature 275 °C and nebulizer pressure 40 psig.
General procedure 4. To a microwave vial was added 1,4-dimethyl-
4H-1,2,4-triazol-1-ium iodide (cat 5) (13.5 mg, 0.06 mmol, 0.01 eq.),
iron(II)phthalocyanine (FePc) (68.2 mg, 0.12 mmol, 0.02 eq.),
3,3’,5,5’-tetra-tert-butyldiphenoquinone (8) (80.2 mg, 0.20 mmol, 0.03
eq.), 2-pyrrolidinone (85.1 mg, 1 mmol, 2 eq.), 4-methoxycinnamalde-
hyde (81.1 mg, 0.5 mmol, 1 eq.), 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) (111.9 µl, 0.750 mmol, 1.5 eq.) and ethyl acetate (1.6 ml). The
reaction mixture was stirred at 60 °C, open to the atmosphere, moni-
tored by 1H NMR until the reaction had reached completion. The prod-
uct was purified with the biotage using petroleum ether (40–
60 °C)/ethyl acetate and dichloromethane gradient. (25ml/min, 100 %
petroleum ether → 20% ethyl acetate →100% petroleum ether →100%
dichloromethane). The product was obtained as a yellow solid (74.2
mg, 0.303 mmol, 61% yield). This procedure was used for Piperlotine
F and Piperlotine G.
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The Journal of Organic Chemistry
Gram-scale synthesis of 3.To a 50 ml pear shaped flask (opening
14/23) was added 1,4-dimethyl-4H-1,2,4-triazol-1-ium iodide (cat 5)
(1.1 mg, 0.005 mmol, 0.01 eq.), iron(II)phthalocyanine (FePc) (8.53
mg, 0.02 mmol, 0.03 eq.), 3,3’,5,5’-tetra-tert-butyldiphenoquinone (8)
(10.2 mg, 0.025 mmol, 0.05 eq.), 2-oxazolidinone (639.8 mg, 7.35
mmol, 1.2 eq.), cinnamaldehyde (797.3 mg, 6.0 mmol, 1 eq.), 1,8-di-
azabicyclo[5.4.0]undec-7-ene (DBU) (179.1 µl, 1.2 mmol, 0.2 eq.) and
ethyl acetate (15 ml).The mixture was stirred overnight at ambient tem-
(E)-3-(3-(4-(dimethylamino)phenyl)acryloyl)oxazolidin-2-one (12):
Was synthesized according to the general procedure with
1
2
3
4
5
6
7
8
2
4-(dimethylamino)cinnamaldehyde (90.3 mg, 0.505 mmol, 1 eq.) and
catalyst 4. The product was obtained as a red/brown solid (83.7 mg,
0.322 mmol, 64%), mp: 228–229 °C. 1H NMR (400 MHz, CDCl3) δ
7.84 (d, J = 15.6 Hz, 1H), 7.68 (d, J = 15.6 Hz, 1H), 7.57–7.49 (m, 2H),
6.71–6.64 (m, 2H), 4.46–4.39 (m, 2H), 4.17–4.09 (m, 2H), 3.04 (s, 6H).
13C NMR (101 MHz, CDCl3) δ 166.1, 153.9, 152.2, 147.3, 130.7,
122.6, 111.8, 110.9, 62.1, 43.1, 40.3. HRMS (ESI/Q-TOF) m/z
[M+H]+ calcd for C14H17N2O3 261.1239, found: 261.1241.
FTIR-ATR (νmax/cm−1): 1765 (s) (CO), 1661 (m) (CO).
1
perature in contact with air. A crude H NMR showed complete con-
sumption of aldehyde and clean formation of the product (a copy of the
crude 1H NMR can be found in the Supporting information). The mix-
ture was diluted with ethyl acetate (30 ml) and washed with water
(3´20 ml). The organic phase was collected and the volatiles were re-
moved under reduced pressure. The resulting solid was recrystallized
from heptane/ethyl acetate (1:1) yielding the product as a yellow solid
(995.1 mg, 4.5811 mmol, 76%).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(E)-3-(3-(p-tolyl)acryloyl)oxazolidin-2-one (13):
Was synthesized according to the general procedure 2 with 4-
methylcinnamaldehyde (74.1 mg, 0.507 mmol, 1 eq.) and catalyst 4.
The product was obtained as a yellow solid (75.3 mg, 0.326 mmol,
64%), mp: 172–173 °C. 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 2H),
7.52 (appd, J = 8.1 Hz, 2H), 7.20 (appd, J = 8.1 Hz, 2H), 4.49–4.41 (m,
2H), 4.17–4.09 (m, 2H), 2.38 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
165.7, 153.8, 146.5, 141.4, 131.9, 129.8, 128.8, 115.6, 62.2, 43.0, 21.7.
HRMS (ESI/Q-TOF) m/z [M+H]+ calcd for C13H14NO3 232.0974;
found 232.0973. FTIR-ATR (νmax/cm−1): 1767 (vs) (CO), 1674 (vs)
(CO).
Synthesis of 5,7-dihydroxy-4-phenylchroman-2-one (34). To a
microwave vial was added phloroglucinol (39.2 mg, 0.311 mmol, 1.1
eq.), 3-cinnamoyloxazolidin-2-one 3 (59.0 mg, 0.272 mmol, 1.0 eq.)
and montmorillonite K10 (95.1 mg) with a magnetic stir bar. The vial
was capped and evacuated and backfilled with N2 (×5 times). To this
was added toluene (0.3 ml) and the vial was then heated to 100 °C.
After 16 h the mixture was cooled to r.t. and subsequently filtered on a
frit to remove montmorillonite k10 and washed with EtOAc. The fil-
trate was washed with water (3×10 ml). The organic phase was col-
lected and the volatiles were removed under reduced pressure yielding
an oil. Two drops of DCM were added to induce precipitation. The re-
sulting solid was washed with DCM and water and then dried in vacuo.
The product was obtained as a white solid (60.8 mg, 0.237 mmol, 87%).
The NMR matches reported values.64 1H NMR (400 MHz, DMSO-d6)
δ 9.76 (s, 1H), 9.57 (s, 1H), 7.30–7.23 (m, 2H), 7.22–7.16 (m, 1H),
7.10–7.04 (m, 2H), 6.17 (d, J = 2.2 Hz, 1H), 6.03 (d, J = 2.1 Hz,
1H),4.47–4.40 (m, 1H), 3.20 (dd, J = 15.9, 7.1 Hz, 1H), 2.86–2.77 (m,
1H). 13C NMR (101 MHz, DMSO-d6) δ 167.8, 157.9, 155.4, 153.0,
142.5, 128.6, 126.7, 126.6, 103.0, 98.7, 94.7, 37.1, 33.7.
(E)-3-(3-(4-chlorophenyl)acrloyl)oxazolidin-2-one (14):
Was synthesized according to the general procedure 1 with 4-
chlorocinnamaldehyde (83.2 mg, 0.499 mmol, 1 eq.). The product was
obtained as a white solid (83.8 mg, 0.333 mmol, 67%), mp: 178–180
°C. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 15.7 Hz, 1H), 7.79
(d, J = 15.8 Hz, 1H), 7.57–7.51 (m, 2H), 7.39–7.33 (m, 2H), 4.49–4.42
(m, 2H), 4.16–4.10 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 165.3,
153.7, 144.9, 136.7, 133.1, 129.9, 129.3, 117.2, 62.3, 42.9. HRMS
(ESI/Q-TOF) m/z [M+H]+ calcd for C12H11ClNO3 252.0427; found
252.0428. FTIR-ATR (νmax/cm−1): 1766 (s) (CO), 1679 (s) (CO).
(E)-3-(3-(4-fluorophenyl)acryloyl)oxazolidin-2-one (15):
Was synthesized according to the general procedure 1 with 4-fluorocin-
namaldehyde (86.8 mg, 0.550 mmol, 1 eq.). The product was obtained
as a white solid (110.5 mg, 0.470 mmol, 86%), mp: 200–202 °C. The
NMR matches reported values.74 1H NMR (400 MHz, CDCl3) δ 7.84
(s, 2H), 7.65–7.58 (m, 2H), 7.13–7.05 (m, 2H), 4.50–4.43 (m, 2H),
4.18–4.11 (m, 2H).13C NMR (101 MHz, CDCl3) δ 165.4, 164.4 (d, 1JC-
F=250 Hz), 153.8, 145.1, 131.0 (d, 4JC-F=3.5 Hz), 130.8 (d, 3JC-F=8.6
Hz), 116.5 (d, JC-F=2.2 Hz), 116.2 (d, 2JC-F=22 Hz), 62.3, 43.0. 19F
NMR (376 MHz CDCl3) δ −108.85.
Synthesis of Chiral Oxazolidinone, (S)-4-isobutyloxazolidin-2-one.
To a microwave vial equipped with a magnetic stir bar was added L-
leucinol (474 µl, 3.56 mmol, 1 eq.) 1,5,7-triazabicyclo[4.4.0]dec-5-ene
(TBD) (102.1 mg, 0.73 mmol, 0.2 eq.) and dimethylcarbonate (7 ml)
which was sealed. The mixture was stirred to yield a homogeneous so-
lution and was heated to 100 °C. After 20 h the reaction mixture was
allowed to cool to room temperature and was washed with HCl (1M)
(10 ml), water (15 ml) and brine (15 ml). The organic phase was dried
over Na2SO4 and filtrated. The filtrate was concentrated to yield the
crude product as a yellow oil. The crude was purified using the biotage
using petroleum ether (40–60 °C)/ethyl acetate solvent mixture (petro-
leum ether 100% →70 % ethyl acetate). Obtained as a colorless oil
(350.8 mg, 2.45 mmol, 69% yield). The obtained data match the re-
ported ones reported in literature.72
(E)-3-(3-(2-methoxyphenyl)acryloyl)oxazolidin-2-one (16):
Was synthesized according to the general procedure 2 with 2-methox-
ycinnamaldehyde (81.6 mg, 0.503 mmol, 1 eq.) and catalyst 4 with ex-
clusion of light. The product was obtained as yellow solid (100.8 mg,
0.407 mmol, 81%). The NMR matches reported values.73 1H NMR
(400 MHz, CDCl3) δ 8.20 (d, J = 15.9 Hz, 1H), 7.97 (d, J = 15.9 Hz,
1H), 7.66–7.60 (m, 1H), 7.40–7.33 (m, 1H), 7.00–6.89 (m, 2H), 4.48–
4.40 (m, 2H), 4.17–4.10 (m, 2H), 3.90 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 166.0, 158.8, 153.8, 141.7, 132.1, 129.5, 123.7, 120.8, 117.0,
111.3, 62.2, 55.7, 43.0.
Characterization of Products
3-cinnamoyloxazolidin-2-one (3): Was synthesized according to the
general procedure 1 with cinnamaldehyde (62.1 mg, 0.470 mmol, 1
eq.). The product was obtained as faintly yellow solid (90.6 mg, 0.417
mmol, 89%). The NMR matches reported values.73 1H NMR (400
MHz, CDCl3) δ 7.92 (d, J = 15.7 Hz, 1H), 7.87 (d, J = 15.7 Hz, 1H),
7.64–7.60 (m, 2H), 7.43–7.37 (m, 3H), 4.49–4.44 (m, 2H), 4.17–4.12
(m, 2H). 13C NMR (101 MHz, CDCl3) δ 165.5, 15.7, 146.4, 134.6,
130.8, 129.0, 128.8, 116.7, 62.2, 43.0.
(E)-3-(3-(2-nitrophenyl)acryloyl)oxazolidin-2-one (17):
Was synthesized according to the general procedure 1 with 2-nitrocin-
namaldehyde (90.3 mg, 0.510 mmol, 1 eq.). The product was obtained
as yellow solid (78.0 mg, 0.298 mmol, 58%), mp: 177–178 °C. 1H
NMR (400 MHz, CDCl3) δ 8.27 (d, J = 15.9 Hz, 1H), 8.06–8.04 (m,
1), 7.82 (d, J = 16.0), 7.76–7.74 (m, 1H), 7.68–7.64 (m, H1), 7.57–7.53
(m, 1H), 4.49 (t, J = 7.9 Hz, 2H), 4.16 (J = 7.8). 13C NMR (101 MHz,
CDCl3) δ 164.4, 153.7, 148.6, 141.4, 133.7, 130.8, 130.6, 129.7, 125.0,
121.6, 62.4, 42.9. HRMS (ESI/Q-TOF) m/z [M+H]+ calcd for
C12H11N2O5 263.0668; found 263.0668. FTIR-ATR (νmax/cm−1): 1772
(s) (CO), 1718 (s) (CO).
(E)-3-(3-(4-methoxyphenyl)acryloyl)oxazolidin-2-one
(11):
Was synthesized according to the general procedure 2 with 4-methox-
ycinnamaldehyde (82.7 mg, 0.499 mmol, 1 eq.) and catalyst 4. The
product was obtained as white solid (93.2 mg, 0.377 mmol, 75%).
(stirred for 23 h).The NMR matches reported values.73 1H NMR (400
MHz, CDCl3) δ 7.84 (d, J = 15.7 Hz, 1H), 7.77 (d, J = 15.7 Hz, 1H),
7.62–7.54 (m, 2H), 6.95–6.88 (m, 2H), 4.49–4.40 (m, 2H), 4.18–4.09
(m, 2H), 3.85 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 165.7, 161.9,
153.8, 146.2, 130.6, 127.5, 114.5, 114.2, 62.2, 55.5, 43.0.
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The Journal of Organic Chemistry
Page 6 of 9
(E)-3-(3-(anthracen-9-yl)acryloyl)oxazolidin-2-one (18):
3-(4-Methoxybenzoyl)oxazolidin-2-one (24):
Was synthesized according to the general procedure 1 with 3-(9-an-
thryl)acrolein (116 mg, 0.499 mmol, 1 eq.). The product was obtained
as yellow solid (137.9 mg, 0.435 mmol, 87%), mp: 194–196 °C. H
NMR (400 MHz, CDCl3) δ 8.84 (d, J = 16.0 Hz, 1H), 8.48 (s, 1H),
8.38–8.27 (m, 2H), 8.04–7.98 (m, 2H), 7.85 (d, J = 16.0 Hz, 1H), 7.55–
7.45 (m, 4H), 4.54 (t, J = 8.0 Hz, 2H), 4.24 (t, J = 8.0 Hz, 2H). 13C
NMR (101 MHz, CDCl3) δ 165.2, 153.7, 143.2, 131.3, 129.7, 129.4,
129.0, 128.8, 126.6, 125.7, 125.5, 125.3, 62.4, 43.0. HRMS (ESI/Q-
TOF) m/z [M+H]+ calcd for C20H16NO3 318.1130; found 318.1129.
FTIR-ATR (νmax/cm−1): 1764 (vs) (CO), 1684 (s) (CO).
Was synthesized according to the general procedure 2 with 4-methox-
ybenzaldehyde (69.7 mg, 0.512 mmol, 1 eq.). The product was obtained
as white solid (72.7 mg, 0.329 mmol, 64%). The NMR matches re-
ported values.76 1H NMR (400 MHz, CDCl3) δ 7.73–7.66 (m, 2H),
6.9–6.88 (m, 2H), 4.48 (t, J = 7.9 Hz, 2H), 4.15 (t, J = 7.9 Hz, 2H), 3.86
(s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.2, 163.4, 153.7, 132.0,
124.6, 113.4, 62.4, 55.6, 44.1.
1
2
3
4
5
6
7
8
1
3-(Cyclohexanecarbonyl)oxazolidin-2-one (25): Was synthesized ac-
cording to a modified general procedure 2, with cyclohexanecarboxal-
dehyde (56.1 mg, 0.500 mmol, 1.0 eq.), 2-mesityl-6,7-dihydro-5H-pyr-
rolo[2,1-c][1,2,4]triazol-2-ium chloride (cat 4) (6.7 mg, 0.025 mmol,
0.05 eq) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (60 µl, 0.40
mmol, 0.8 eq.). The product was obtained as a faintly yellow oil (63.2
mg, 0.320 mmol, 64%).1H NMR (400 MHz, CDCl3) δ 4.39 (t, J = 8.2
Hz, 2H), 4.00 (t, J = 8.2 Hz, 2H), 3.54–3.46 (m, 1H), 1.91–1.85 (m,
2H), 1.81–1.75 (m, 2H), 1.72–1.66 (m, 1H), 1.47–1.33 (m, 4H), 1.29–
1,21 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 176.9, 153.3, 62.0, 42.9,
42.0, 29.2, 25.9, 25.6. HRMS (ESI/Q-TOF) m/z [M+H]+ calcd for
C10H16NO3 198.1130; found: 198.1125 . FTIR-ATR (νmax/cm−1): 1771
(vs)(CO), 1692 (vs) (CO).
9
3-((2E,4E)-hexa-2,4-dienoyl)oxazolidin-2-one (19):
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Was synthesized according to the general procedure 2 with sorbic al-
dehyde (58.1 µl, 0.500 mmol, 1 eq.) and catalyst 4 (0.02 eq.). The prod-
uct was obtained as a white solid (63.5 mg, 0.351 mmol, 70%). The
NMR matches reported values.75 1H NMR (400 MHz, CDCl3) δ 7.45
(dd, J = 15.2, 10.5 Hz, 1H), 7.20 (d, J = 15.1 Hz, 1H), 6.37–6.17 (m,
1H), 4.46–4.38 (m, 2H), 4.12–4.04 (m, 2H), 1.88 (d, J = 6.2 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 165.9, 153.7, 146.9, 141.4, 130.5,
117.6, 62.1, 42.9, 19.0.
3-(benzo[d][1,3]dioxole-5-carbonyl)oxazolidin-2-one (20):
Was synthesized according to the general procedure 2 with piperonal
(75.1 mg, 0.500 mmol, 1 eq.). The product was obtained as white solid
(74.1 mg, 0.315 mmol, 63%), mp: 150–153 °C. 1H NMR (400 MHz,
CDCl3) δ 7.31–7.29 (m, 1H), 7.16–7.14 (m, 1H), 6.85–6.83 (m, 1H),
6.04 (s, 2H), 4.48 (t, J = 7.8 Hz, 2H), 4.14 (t, J = 7.8 Hz, 2H). 13C NMR
(101 MHz, CDCl3) δ 168.9, 153.6, 151.6, 147.4, 126.2, 125.6, 109.8,
107.8, 102.0, 62.4, 44.1. HRMS (ESI/Q-TOF) m/z [M+H]+ calcd for
C11H9NO5 236.0559; found 236.0558. FTIR-ATR (νmax/cm−1): 1794
(s) (CO), 1671 (vs) (CO).
(R)-3-cinnamoyl-4-phenyloxazolidin-2-one (26):
Was synthesized according to the general procedure 3 with (R)-(−)-4-
phenyl-2-oxazolidinone (82.4 mg, 0.505 mmol, 1 eq.). The product was
obtained as a yellow solid (107.9 mg, 0.368 mmol, 73%).The NMR
matches reported values.77 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J =
15.8 Hz, 1H), 7.79 (d, J = 15.7 Hz, 1H), 7.63–7.55 (m, 2H), 7.44–7.30
(m, 8H), 5.56 (dd, J = 8.7, 3.9 Hz, 1H), 4.75 (t, J = 8.8 Hz, 1H), 4.33
(dd, J = 8.9, 3.9 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 164.8, 153.8,
146.7, 139.0, 134.5, 130.7, 129.2, 128.9, 128.7, 128.6, 126.0, 116.8,
70.0, 57.9. [α]ꢁꢀꢂ = −5.8 (c 0.01, CHCl3)
3-(2-methoxybenzoyl)oxazolidin-2-one (21):
Was synthesized according to the general procedure 2 with 2-methox-
ybenzaldehyde (68.1 mg, 0.500 mmol, 1 eq.). The product was obtained
as light yellow solid (87.9 mg, 0.397 mmol, 79%). The NMR matches
reported values.76 1H NMR (400 MHz, CDCl3) δ 7.47–7.40 (m, 1H),
7.35–7.30 (m, 1H), 7.04–6.98 (m, 1H), 6.94–6.89 (m, 1H), 4.44–4.36
(m, 2H), 4.18–4.11 (m, 2H), 3.81 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 167.8, 156.9, 152.5, 132.3, 128.7, 123.8, 120.5, 110.9, 62.1,
55.8, 42.9.
(R)-3-cinnamoyl-4-isopropyloxazolidin-2-one (27):
Was synthesized according to the general procedure 3 with (R)-(+)-4-
isopropyl-2-oxazolidinone (67.3 mg, 0.511 mmol, 1 eq.). The product
was obtained as a yellow oil (66.8 mg, 0.258 mmol, 50%). The NMR
matches reported values.23 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J =
15.7 Hz, 1H), 7.85 (d, J = 15.7 Hz, 1H), 7.65–7.59 (m, 2H), 7.43–7.36
(m, 3H), 4.60–4.52 (m, 1H), 4.35–4.22 (m, 2H), 2.52–2.40 (m, 1H),
0.96 (d, J = 7.0 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 165.3, 154.3, 146.3, 134.7, 130.7, 129.0, 128.7, 117.2, 63.5,
58.8, 28.6, 18.2, 14.8. [α]ꢁꢀꢂ = −89.2 (c 0.01, CHCl3)
3-(2-Chlorobenzoyl)oxazolidin-2-one (22):
Was synthesized according to the general procedure 2 with 2-chloro-
benzaldehyde (70.4 mg, 0.500 mmol, 1 eq.). The product was obtained
as faintly yellow solid (48.0 mg, 0.213 mmol, 43%), mp: 97–98 °C.
1H NMR (400 MHz, CDCl3) δ 7.44–7.38 (m, 2H), 7.36–7.30 (m, 2H),
4.51(t, J = 7.9 Hz, 2H), 4.22 (t, J = 7.79 Hz, 2H) 13C NMR (101 MHz,
CDCl3) δ 167.0, 152.3, 134.1, 131.5, 130.8, 129.5, 128.2, 126.9, 62.4,
42.6. HRMS (ESI/Q-TOF) m/z [M+H]+ calcd for C10H9ClNO3
226.0271; found 226.0273. FTIR-ATR (νmax/cm−1): 1775 (vs) (CO),
1686 (vs) (CO).
(R)-4-benzyl-3-cinnamoyloxazolidin-2-one (28):
Was synthesized according to the general procedure 3 with (R)-(+)-4-
benzyl-2-oxazolidinone (81.7 mg, 0.461 mmol, 1 eq.). The product was
obtained as off-white solid (91.9 mg, 0.299 mmol, 65%). The NMR
matches reported values.23 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J =
1.5 Hz, 2H), 7.67–7.62 (m, 2H), 7.44–7.39 (m, 3H), 7.38–7.32 (m, 2H),
7.31–7.27 (m, 1H), 7.26–7.22 (m, 2H), 4.85–4.76 (m, 1H), 4.29–4.19
(m, 2H), 3.38 (dd, J = 13.4, 3.3 Hz, 1H), 2.86 (dd, J = 13.4, 9.5 Hz,
1H). 13C NMR (101 MHz, CDCl3) δ 165.3, 153.7, 146.6, 135.5, 134.7,
130.9, 129.6, 129.1, 129.1, 128.8, 127.5, 117.1, 66.3, 55.6, 38.1. [α]ꢀꢁꢂ
= −63.3 (c 0.01, CHCl3).
3-(3,4-Methylbenzoyl)oxazolidin-2-one (23):
Was synthesized according to the general procedure 2 with 3,4-dime-
thylbenzaldehyde (67.1 mg, 0.500 mmol, 1 eq.). The product was ob-
tained as faintly yellow solid (65.5 mg, 0.300 mmol, 60%), mp: 143–
(S)-3-cinnamoyl-4-isobutyloxazolidin-2-one (29):
1
145 °C. H NMR (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.43–7.39 (m,
Was synthesized according to the general procedure 3 with (S)-(+)-4-
isobutyl-2-oxazolidinone (63.1 mg, 0.441 mmol, 1 eq.). The product
was obtained as a yellow oil (62.7 mg, 0.229 mmol, 52%). The NMR
matches reported values.78 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J =
15.7 Hz, 1H), 7.83 (d, J = 15.8 Hz, 1H), 7.65–7.56 (m, 2H), 7.43–7.34
(m, 3H), 4.65–4.56 (m, 1H), 4.42 (ddd, J = 8.7, 7.8, 0.9 Hz, 1H), 4.14
(dd, J = 8.7, 2.9 Hz, 1H), 1.91–1.82 (m, 1H), 1.70–1.60 (m, 1H), 1.58–
1.48 (m, 1H), 1.02–0.95 (m, 6H). 13C NMR (101 MHz, CDCl3) δ
165.2, 153.8, 146.2, 134.7, 130.7, 129.0, 128.7, 117.2, 67.8, 53.4, 41.7,
25.0, 23.6, 21.8. [α]ꢁꢀꢂ = +88.0 (c 0.01, CHCl3).
1H), 7.20–7.16 (m, 1H), 4.49 (t, J = 7.8 Hz, 2H), 4.16 (t, J = 7.7 Hz,
2H), 2.31 (s, 3H), 2.29 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 170.0,
153.5, 142.1, 136.5, 130.4, 130.1, 129.2, 127.0, 62.3, 44.0, 20.2, 19.8.
HRMS (ESI/Q-TOF) m/z [M+H]+ calcd for C12H13NO3 220.0974;
found 220.0974. FTIR-ATR (νmax/cm−1): 1758 (vs) (CO), 1671 (vs)
(CO).
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5. Li, Y.-T.; Gao, X.-D.; Zhang, W.; Huang, X.-J.; Zhang, D.-M.;
5-(chloromethyl)-3-cinnamoyloxazolidin-2-one (30):
Jiang, R.-W.; Wang, L.; Zhang, X.-Q.; Ye, W.-C., Winchinines A
and B, two unusual monoterpene indole alkaloids with a third
Was synthesized according to the general procedure 1 with cinnamal-
dehyde (103 mg, 0.0777 mmol, 1.5 eq.) and 5-chloromethyl-2-oxazol-
idinone (70.3 mg, 0.503 mmol, 1 eq.). The product was obtained as a
yellow solid (98.1 mg, 0.369 mmol, 73%), mp: 134–136 °C. 1H NMR
(400 MHz, CDCl3) δ 7.89 (s, 2H), 7.66–7.59 (m, 2H), 7.43–7.38 (m,
3H), 4.92–4.83 (m, 1H), 4.23 (dd, J = 11.6, 8.9 Hz, 1H), 4.06 (dd, J =
11.5, 5.8 Hz, 1H), 3.81–3.72 (m, 2H). 13C NMR (101 MHz, CDCl3) δ
165.3, 152.6, 146.9, 134.6, 131.0, 129.1, 128.8, 116.5, 71.7, 45.9, 44.7.
HRMS (ESI/Q-TOF) m/z [M+H]+ calcd for C13H12ClNO3 266.0584;
found 266.0584. FTIR-ATR (νmax/cm−1): 1771 (vs) (CO), 1679 (s)
(CO).
1
2
3
4
5
6
7
8
nitrogen atom from Winchia calophylla. RSC Adv. 2016,
6 (64),
59657-59660.
6. Ager, D. J.; Prakash, I.; Schaad, D. R., 1,2-Amino Alcohols and
Their Heterocyclic Derivatives as Chiral Auxiliaries in Asymmetric
Synthesis. Chem. Rev. 1996, 96 (2), 835-876.
7. Ager, D. J.; Prakash, I.; Schaad, D. R., Chiral Oxazolidinones in
Asymmetric Synthesis. Aldrichim. acta 1997, 30 (1), 3-12.
8. Zappia, G.; Cancelliere, G.; Gacs-Baitz, E.; Monache, G. D.;
Misiti, D.; Nevola, L.; Botta, B., Oxazolidin-2-one Ring, a Popular
Framework in Synthetic Organic Chemistry Part 2 [1]. Applications
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and Modifications. Curr. Org. Synth. 2007,
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condensations. 2. Erythro-selective chiral aldol condensations via
boron enolates. J. Am. Chem. Soc. 1981, 103 (8), 2127-2129.
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alkylation reactions of chiral imide enolates. A practical approach to
the enantioselective synthesis of α-substituted carboxylic acid
derivatives. J. Am. Chem. Soc. 1982, 104 (6), 1737-1739.
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Diels-Alder cycloaddition reactions. Chiral α,β-unsaturated
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auxiliaries in asymmetric aldol reactions applied to total synthesis.
Tetrahedron: Asymmetry 2013, 24 (19), 1149-1188.
Piperlotine-F, 1-cinnamoylpyrrolidin-2-one (31):
Was synthesized according to the general procedure 4 with cinnamal-
dehyde (66.1 mg, 0.500 mmol, 1 eq.) and molecular sieves (4Å, 0.2 g).
The product was obtained as faintly yellow solid (51.6 mg, 0.240
mmol, 48%). The NMR matches reported values.60 1H NMR (400
MHz, CDCl3) δ 7.93 (d, J = 16.0 Hz, 1H), 7.84 (d, J = 16.0 Hz. 1H),
7.65–7.58 (m, 2H), 7.40–7.35 (m, 3H), 3.92 (t, J = 7.5 Hz, 2H), 2.65 (t,
J = 8.0, 2H), 2.11–2.01 (m, 2H). 13C NMR (101 MHz, CDCl3) δ175.8,
166.4, 145.6, 135.0, 130.5, 129.0, 128.6, 119.1, 46.0, 34.1, 17.3.
Piperlotine-G, 1-(4-methoxycinnamoyl)pyrrolidin-2-one (32):
Was synthesized with 4-methoxycinnamaldehyde (81.1 mg, 0.500
mmol, 1 eq.). The product was obtained as faintly yellow solid (74.2
mg, 0.303 mmol, 61%). The NMR matches reported values.60 1H NMR
(400 MHz, CDCl3) δ 7.82 (s, 2H), 7.59–7.55 (m, 2H), 6.92–6.89 (m,
2H), 3.92 (appt, J = 7.2 Hz, 2H), 3.84 (s, 3H), 2.65 (t, J = 8.1 Hz, 2H),
2.11–2.03 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 175.8, 166.9,
161.6, 145.5, 130.4, 127.8, 116.6, 114.4, 55.5, 46.0, 34.2, 17.3.
14. Heravi, M. M.; Zadsirjan, V.; Farajpour, B., Applications of
oxazolidinones as chiral auxiliaries in the asymmetric alkylation
reaction applied to total synthesis. RSC Adv. 2016,
6 (36), 30498-
30551.
ASSOCIATED CONTENT
Supporting Information
15. Zheng, K.; Xie, C.; Hong, R., Concise synthesis and revision of
the proposed biogenesis of helicascolides. Tetrahedron Lett. 2017,
58 (47), 4459-4464.
The Supporting Information is available free of charge on the ACS
Publications website, including full optimization table and copies
of 1H NMR, 13C NMR, 19F NMR, COSY NMR, HSQC NMR, and
HMBC NMR.
16. Yang, X.; Zhao, Y.; Hsieh, M.-T.; Xin, G.; Wu, R.-T.; Hsu, P.-
L.; Horng, L.-Y.; Sung, H.-C.; Cheng, C.-H.; Lee, K.-H., Total
Synthesis of (+)-Medicarpin. J. Nat. Prod. 2017, 80 (12), 3284-3288.
17. Zhang, Z.; Collum, D. B., Evans Enolates: Structures and
Mechanisms Underlying the Aldol Addition of Oxazolidinone-
Derived Boron Enolates. J. Org. Chem. 2017, 82 (14), 7595-7601.
18. Dias, L. C.; Polo, E. C., Nhatrangin A: Total Syntheses of the
Proposed Structure and Six of Its Diastereoisomers. J. Org. Chem.
2017, 82 (8), 4072-4112.
AUTHOR INFORMATION
Corresponding Author
* sundenh@chalmers.se
19. Chatterjee, S.; Kuilya, T. K.; Goswami, R. K., Studies Directed
toward the Stereoselective Synthesis of Cytospolide E. ACS Omega
2018,
3 (1), 1041-1059.
20. Shiina, I.; Umezaki, Y.; Murata, T.; Suzuki, K.; Tonoi, T.,
Asymmetric Total Synthesis of (+)-Coprophilin. Synthesis 2018, 50
(06), 1301-1306.
21. Davies, S. G.; Doisneau, G. J. M., Base induced C-5
epimerisation of 4-methyl-5-phenyl oxazolidinones: Chiral
auxiliaries derived from norephedrine and norpseudoephedrine.
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
Tetrahedron: Asymmetry 1993,
4 (12), 2513-2516.
ACKNOWLEDGMENT
Funding from the Swedish Research Council (VR 2014-04664
and Formas 2016-00484) are gratefully acknowledged.
22. Andrade, C. K. Z.; Rocha, R. O.; Vercillo, O. E.; Silva, W. A.;
Matos, R. A. F., DCC/DMAP-Mediated Coupling of Carboxylic
Acids with Oxazolidinones and Thiazolidinethiones. Synlett 2003,
2003 (15), 2351-2352.
23. Schindler, C. S.; Forster, P. M.; Carreira, E. M., Facile
Formation of N-Acyl-oxazolidinone Derivatives Using Acid
Fluorides. Org. Lett. 2010, 12 (18), 4102-4105.
24. Heller, S. T.; Schultz, E. E.; Sarpong, R., Chemoselective N-
Acylation of Indoles and Oxazolidinones with Carbonylazoles.
Angew. Chem. Int. Ed. 2012, 51 (33), 8304-8308.
25. Ager, D. J.; Allen, D., R.; Schaad, D. R., Simple and Efficient N-
acylation Reactions of Chiral Oxazolidinone Auxiliaries. Synthesis
1996, (11), 1283-1285.
26. Zhang, J.; Hong, S. H., Direct N-Acylation of Lactams,
Oxazolidinones, and Imidazolidinones with Aldehydes by Shvo’s
Catalyst. Org. Lett. 2012, 14 (17), 4646-4649.
27. Chiarotto, I.; Feeney, M. M. M.; Feroci, M.; Inesi, A.,
Electrogenerated N-heterocyclic carbene: N-acylation of chiral
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