Iodine-Catalyzed Synthesis of Chiral 4-Imidazolidinones Using α-Amino Acid Derivatives via Dehydrogenative N-H/C(sp3)-H Coupling

Article abstract of DOI:10.1021/acs.joc.9b01154

An efficient method for the asymmetric synthesis of 4-imidazolidinones via an iodine-catalyzed intramolecular N-H/C(sp³)-H activation of readily available and abundant feedstocks, amino acids, and amines is described. The reaction proceeded under visible light irradiation to afford a variety of 4-imidazolidinone derivatives under mild conditions in moderate to excellent yields. Secondary and tertiary C(sp³)-H bonds were aminated, and various functional groups were tolerated.

Full text of DOI:10.1021/acs.joc.9b01154

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Article
Iodine-Catalyzed Synthesis of Chiral 4-Imidazolidinones Using #-
Amino Acid Derivatives via Dehydrogenative N-H/C(sp3)-H Coupling
Kyalo Stephen Kanyiva, Marina Tane, and Takanori Shibata
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01154 • Publication Date (Web): 17 Jul 2019
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The Journal of Organic Chemistry
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Iodine-Catalyzed Synthesis of Chiral 4-Imidazolidinones
Using α-Amino Acid Derivatives via Dehydrogenative N-
H/C(sp3)-H Coupling
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Kyalo Stephen Kanyiva,†,* Marina Tane,‡ Takanori Shibata‡,*
† Global Center of Science and Engineering, School of Advanced Science and Engineering, Waseda University,
3-4-1 Okubo, Shinjuku, Tokyo 169-8555, Japan
‡ Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University,
3-4-1 Okubo, Shinjuku, Tokyo 169-8555, Japan
Supporting Information Placeholder
[Paste publication-size TOC graphic here]
ABSTRACT: An efficient method for the asymmetric synthesis of 4-
imidazolidinones via an iodine-catalyzed intramolecular N-H/C(sp3)-H
activation of readily available and abundant feedstocks, amino acids
and amines is described. The reaction proceeded under visible light
irradiation to afford a variety of 4-imidazolidinone derivatives under
mild conditions in moderate to excellent yields. Both benzylic,
secondary and tertiary C(sp3)-H bonds were aminated, and various
functional groups were tolerated.
INTRODUCTION
F
Ph
Ph
N
N
CO2Me
N
N
4-Imidazolidinone derivatives are important organic
molecules with various interesting biological properties,
including antitumor, anticonvulsant, anti-inflammatory
and antiviral activities.1 The 4-imidazolidinone skeleton is
also present in drugs such as spiperone, NNC 63-0532
and hetacillin (Figure 1). In addition, 4-imidazolidinones
are important organocatalysts, as shown by the
pioneering work of MacMillan and coworkers in Diels-
Alder reactions and other reactions.2 The 4-
imidazolidinone skeleton is also found in natural
products such as oxaline and neoxaline,3 and it is a
useful synthetic intermediate in organic chemistry.
O
HN
N
O
O
Spiperone
NNC 63-0532
(nociceptoid drug)
(drug for schizophrenia)
H
N
Ph
H
H
N
O
N
S
N
N
O
Ph
O
Ph
N
N
O
O
H
CO2H
Hetacillin
(-lactam antibiotic)
MacMillan organocatalysts
Figure 1. Examples of useful compounds containing 4-
imidazolidinone skeleton
Based on this background, various reactions have been
developed for the synthesis of 4-imidazolidinones,4-7
especially achiral derivatives.4 Considerable effort has
been devoted to synthesizing chiral 4-imidazolinones.
The most common method is the condensation of a
protected amino acid with a carbonyl compound followed
by intramolecular cyclization in the presence of a
stoichiometric or catalytic amounts of Brønsted acid
(Scheme 1(a)).5 Although this is a powerful method,
some substrates undergo racemization, thus limiting
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applicability.5b The other common strategy is the use of
the synthesis of nitrogen-containing five-membered
1
2
3
4
5
6
7
8
Lewis acid catalysts such as FeCl3, Sm(OTf)3 and
Yb(OTf)3.6 Although excellent enantioselectivities were
often obtained, reactions done using this method are
sometimes low yielding. Synthesis of chiral 4-
imidazolidinones was also reported using N-acyl
dipeptide esters in presence of tert-butyl peroxide as
oxidant and KI as catalyst (Scheme 1b).7 During the
heterocycles, is a good example that utilizes iodine to
form a C-N bond. The original strongly acidic reaction
conditions were not compatible with a variety of
functional and protecting groups. The modification by
Kimura using the photolysis of N-chloroamines,12
followed by those of Suárez13 and Fan,14 which use
molecular iodine and hypervalent iodine, allowed mild
reaction conditions. These modifications made the
reaction tolerant to various synthetically important
functional groups. Recently, the Muñiz group
demonstrated that this transformation can be carried out
using catalytic iodine under light irradiation to synthesize
pyrrolidine derivatives.15 Based on this precedent and
our ongoing interest in using amino acids as precursors
and templates for efficient organic synthesis,16 we herein
demonstrate the iodine-catalyzed synthesis of 4-
imidazolidinone derivatives using substrates prepared
enantioselective addition of organozinc reagents to α-
aldiminoesters,
Kozlowski
reported
that
4-
9
imidazolidinones were obtained mostly as minor
products.8a Pattarawarapan and Phakhodee also
reported a two-step reaction for the synthesis of 2-imino-
4-imidazolidinones.8b Recently, a highly enantioselective
C(sp3)-H amination of aliphatic azides using a chiral-Ru
catalyst was demonstrated for the synthesis of 4-
imidazolidinones by Houk and Meggers groups.8c Given
the importance of chiral 4-imidazolidinones, the
development of new and efficient approaches for their
synthesis is highly desired. This paper describes a
simple and catalytic metal-free protocol for the
preparation of chiral 4-imidazolinones from readily
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from readily available α-amino acids and alkylamines.
RESULTS AND DISCUSSION
available materials, α-amino acids and amines under
mild conditions (Scheme 1(c)).
Our initial studies focused on the intramolecular
dehydrogenative N-H/C(sp3)-H coupling of propanamide
1a, which was readily prepared from L-phenylalanine
and dibenzylamine. When 1a was treated with a catalytic
amount of iodine (10 mol%) and PhI(OAc)2
[(diacetoxyiodo)benzene] (1.2 equiv) as an oxidant in
DCE and the mixture was stirred on the benchtop under
the overhead fluorescent light on the ceiling for 5 h, only
trace amounts of the desired 4-imidazolidinone 2a were
observed (Table 1, entry 1). To our delight, when the
(a) Use of Brønsted acid or Lewis acid catalyst
Brønsted acid
or Lewis acid cat.
H
O
R1
R2
R3
N
O
R1
+
NHMe
R2 R3
N
NH2
O
(b) Use of KI catalyst and TBHP as an oxidant
R1
O
KI cat.
TBHP
O
R2
H
R2
O
oxidant
was
changed
to
PIFA
N
N
Ph
Ph
R3O2C
R1
N
[bis(trifluoroacetoxy)iodobenzene], the reaction efficiency
improved, and a diastereomeric mixture of 2a (3.8:1)
was obtained in 53% isolated yield. The diastereomers
were separated by preparative TLC, and their structures
H
N
H
CO2R3
O
(c) This work: Use of I2 catalyst and PIFA as an oxidant
1
were determined by NOE analyses and H-NMR charts
PG
in the literature as a reference.17 Other hypervalent
iodine reagents such as Koser’s reagent (entry 3) and
PhI(mCBA)2 [mCBA = m-chlorobenzoic acid] (entry 4),
which showed the best performance in the synthesis of
pyrrolidines by Muñiz and coworkers,15 gave low yields.
A bulkier leaving group on the hypervalent iodine was
also ineffective (entry 5). In comparison with THF, MeCN
and toluene, DCE gave higher yields possibly due to the
higher solubility of the hypervalent iodine (entries 6-8).
When the reaction was carried out under 12 W or 27 W
fluorescent light irradiation, the yield improved to 83%
(entries 9 and 10). Since a small amount of starting
material remained in entry 10, we increased the loading
of the iodine catalyst to 20 mol% and carried out the
reaction for 8 h, which increased the yield of desired
product 2a to 92% (entry 11). A reaction carried out
using 1.0 equiv of PIFA resulted in reduced yield (81%,
entry 12). The scalability of the reaction was also
demonstrated by reactions run for 24 h using 1.0 mmol
(0.50 g) or 2.1 mmol (1.05 g) that gave the desired
product in 88% and 76% yields, respectively, after
purification by flash silica gel chromatography (entry 13
I2 cat.
PIFA
PG
N
HN
R3
R3
O
H
R1
light irradiation
R1
N
N
O
R2
R2
Scheme 1. Methods for the synthesis of chiral 4-
imidazolidinones
Dehydrogenative N-H/C-H bond coupling is an attractive
strategy for the formation of C-N bonds, which are
ubiquitous in organic compounds. Although N-H/C(sp2)-
H bond couplings have been well studied,9 the more
challenging N-H/C(sp3)-H bond formations remain
relatively underdeveloped. N-H/C(sp3)-H bond couplings
are mainly realized using stoichiometric or catalytic
transition metals, but their toxicity, cost and difficult
purification from the target compounds have driven the
development of alternative methods. Accordingly, metal-
free dehydrogenative N-H/C(sp3)-H couplings are
attractive in terms of greenness and cost-efficiency.10
The Hofmann-Löffler-Freytag reaction,11 which allows
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The Journal of Organic Chemistry
and 14). As a control experiment, a reaction carried out
in darkness did not proceed at all (entry 15).
namely, D-α-phenylglycine (1i) and α,α-dimethylglycine
1
2
3
4
5
6
7
8
(1j), also underwent dehydrogenative C-N bond
formation to give desired products 2i and 2j in 63% and
77% yields, respectively. All these reactions proceeded
cleanly, and apart from the desired 4-imidazolidinone
product, the unreacted starting materials were easily
recovered by preparative TLC.
Table 1. Optimization of the reaction conditionsa
I2 (10 mol%)
PhI(A)(B) (1.2 equiv)
Ts
TsHN
N
Ph
Ph
Ph
solvent, 0 ºC, 5 h
Ph
N
O
N
O
Bn
Bn
9
1a
2a
10
11
12
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Entry PhI(A)(B)
Solvent
DCE
Yield (%)b anti/sync
1
PhI(OAc)2
PIFA
Traces
53
N.D.
3.8:1
3.4:1
4.0:1
2.3:1
2.4:1
--
2
DCE
3
PhI(OH)(OTs) DCE
7
4
PhI(mCBA)2
PhI(OPiv)2
PIFA
DCE
DCE
THF
8
5
18
6
16
7
PIFA
MeCN
toluene
DCE
DCE
DCE
DCE
DCE
DCE
DCE
N.R.
35
8
PIFA
6.1:1
4.3:1
4.3:1
4.3:1
4.3:1
4.3:1
4.3:1
--
9d
10e
11f
PIFA
83
PIFA
83
PIFA
92
12f,g PIFA
13f,h PIFA
14 f,i PIFA
81
Table 2. Scope of α-amino acid derivatives a
88
I2 (20 mol%)
PIFA (1.2 equiv)
R1
R1
R2
Ts
N
76
TsHN
N
R2
15j
PIFA
N.R.
Ph
27 W light lamp
DCE, 0 ºC, 8 h
N
a
Ph
O
Conditions: 1a (0.10 mmol), I2 (10 mol%), PhI(A)(B)
O
Bn
Bn
b
(1.2 equiv), solvent (0.70 mL) at 0 °C for 5 h. Isolated
1b - 1j
2b - 2j
c
d
yields.
Determined by 1H NMR.
Using a 12 W
fluorescent light. e Using a 27 W fluorescent light. f Using
Ts
N
Ts
N
Ts
a 27 W fluorescent light lamp, I2 (20 mol%), 8 h. g Using
N
h
Ph
Ph
Ph
PIFA (1.0 equiv). Done using 1.0 mmol scale (0.50 g)
N
N
N
of 1a for 24 h. i Done using 2.1 mmol scale (1.05 g) of 1a
O
O
O
Bn
Bn
Bn
j
for 24 h.
Conducted under darkness. DCE: 1,2-
2c, 96%
2d, 75%
2b, 90%
dichloroethane, MeCN: acetonitrile. N.R.: No reaction,
N.D.: Not determined.
(anti:syn = 1.7:1)
(anti:syn = 6.7:1)
Ts
Ts
CO2Me
Ts
N
N
N
OH
Ph
Ph
Ph
With the optimal conditions in hand (Table 1, entry 11),
the generality of the reaction was investigated first by
N
N
N
O
O
O
Bn
Bn
Bn
2e, 79%
(anti:syn = 8.1:1)
2f, 84%
(anti:syn = 2.4:1)
2g, 48%
(anti:syn = 11:1)b
using substrates prepared from various α-amino acids
and dibenzylamine (Table 2). A reaction carried out
using glycine derivative 1b afforded desired 4-
imidazolidinone 2b in 90% yield under the optimized
Ts
N
Ts
N
Ts
N
Ph
O
Ph
Ph
Ph
OTs
N
conditions. Substrates derived from alkyl-containing α-
N
O
N
O
Bn
Bn
Bn
amino acids, such as alanine, leucine and valine, gave
corresponding products 2c-2e in 75-96% yields. When
protected glutamic acid substrate 1f was reacted under
the iodine-catalyzed irradiation conditions, 2f was
obtained in high yield. The hydroxyl group of serine was
tolerated under the oxidative coupling conditions, and 1g
reacted to afford desired product 2g in moderate yield.
On the other hand, the tosyl-protected tyrosine derivative
gave 4-imidazolidinone 2h in a good yield. Two
substrates prepared from unnatural amino acids,
2h, 77%
(anti:syn = 4:1)
2i, 63%
(anti:syn = 1.9:1)
2j, 77%
a Conditions: 1 (0.10 mmol), I2 (20 mol%), PIFA (1.2 equiv),
DCE (0.70 mL) at 0 ºC for 8 h under 27 W fluorescent lamp
irradiation. b Using 12 W fluorescent lamp irradiation for 5 h.
Next, substrates derived from other types of alkyl amines
were examined as well (Table 3). Interestingly,
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substrates containing both benzylic and primary C(sp3)–
I2 (20 mol%)
PIFA (1.2 equiv)
PG
HN
PG
N
1
2
H bonds reacted regioselectively at the benzylic position.
Thus, corresponding products 2k and 2l were obtained
in excellent yields and the methyl group remained
unreacted. Similar observations were recently reported
by Muñiz and coworkers.18 As observed in the reaction
of dimethylamide substrate 1m, the primary C(sp3)-H
bonds were unreactive under the current reaction
conditions. A secondary C(sp3)–H bond of a substrate
derived from dibutylamine also participated in the
intramolecular C–N bond formation reaction to afford the
five-membered heterocycle 2n as the only product in
59% yield. The secondary C(sp3)–H bonds of piperidine
and morpholine derivatives (1o and 1p) were also
aminated to give fused heterocyclic compounds 2o and
2p in moderate yields. A seven-membered cyclic amine
derivative, which was prepared from azepane, also
reacted smoothly to afford 2q in 78% yield. The
dehydrogenative formation of such fused diazabicycles
under the metal-free conditions is remarkable owing to
their biological and synthetic significance.19 The
congested C(sp3)–H bonds of the iso-propyl group in 1r
and cyclohexylamide 1s were also selectively aminated
to give products 2r and 2s in 94% and 82% yields,
respectively. To compare the reactivity of secondary
C(sp3)–H bond and tertiary C(sp3)–H bond in our
R1
R2
R1
R2
27 W light lamp
DCE, 0 ºC, 24 h
N
3
N
O
O
R3
R3
4
5
6
7
8
9
1k - 1v
2k - 2v
Ts
N
Ts
N
Ph
F3C
N
N
O
O
Me
Me
10
11
12
13
14
15
16
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20
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2k, 91%
2l, 92%
(anti:syn = 1.6:1)
(anti:syn = 1.2:1)
Ts
Ts
N
TsN
N
N
O
N
N
O
O
Me
Bu
2n, 59%
(anti:syn = 1.1:1)
2o, 42%
2m, N.D.
(anti:syn = 1.8:1)
TsN
Ts
N
TsN
O
N
O
N
O
N
O
i-Pr
reaction,
we
subjected
(S)-N-hexyl-N-
2p, 44%
(anti:syn = 2.1:1)
2q, 78%
(anti:syn = 1.2:1)
2r, 94%
isopropylpropanamide 1t to the reaction conditions.
Interestingly, the reaction was selective to the tertiary
C(sp3)–H bond activation (1t, 69%) compared with the
secondary C(sp3)–H bond activation (1t’, 12%). Finally,
unlike the tosyl group, the reactions carried out with
Ts
N
NTs
N
TsN
+
O
N
N
O
substrates
containing
mesitylsulfonyl
and
2-
Me
i-Pr
O
nitrophenylsulfonyl (nosyl) groups also proceeded to give
corresponding products 2u and 2v in 92% and 62%
yields.
2s, 82%
2t, 69%
2t’, 12%
O2N
Table 3. Scope of amines and sulfonyl groups a
O
O
S
N
S
O
O
N
Ph
N
Ph
N
O
O
Bn
Bn
2v, 62%
(anti:syn = 4.6:1)
2u, 92%
(anti:syn = 2.6:1)b
a
Conditions: 1 (0.10 mmol), I2 (20 mol%), PIFA (1.2
equiv), solvent (0.70 mL) at 0 °C for 8 h under 27 W
fluorescent lamp irradiation. b Done for 8 h.
Based
on
the
reported
literatures,14,15,18,20
a
representative mechanism using substrate 1a is
demonstrated in Figure 2. The reaction mechanism is
initiated by the reaction of iodine with PIFA to give
trifluoroacetyl hypoiodite {I(OCOCF3)}, which serves as
the reactive catalytic species. The hypoiodite then reacts
with sulfonamide 1a to give an iodoamide intermediate A
with concomitant formation of CF3CO2H. The nitrogen-
iodine bond of A undergoes light-induced homolytic
cleavage to generate amidyl radical B, which is
stabilized by the electron-withdrawing tosyl group.
Amidyl radical B then traps the benzylic hydrogen to
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Removal of tosyl group
afford benzylic radical C, which couples with the iodine
H
N
1
2
3
4
5
6
7
8
Mg (20 equiv)
ultrasonic
Ts
N
radical to give benzyl iodide species D. Species D is
oxidized by the external oxidant (PIFA) to afford E.
Cyclization to form the desired 4-imidazolidinone 2a
occurs via nucleophilic attack of the benzylic position by
the nitrogen and elimination of I(OCOCF3) and
CF3CO2H. The fact that a superstoichiometric amount of
oxidant was necessary to afford high yields of desired
the 4-imidazolidinone means that cyclization of D prior to
oxidation is not feasible.15,18 Thus, although a catalytic
amount of iodine was sufficient to provide a high yield of
2a, 1.2 equiv of PIFA was consumed in the catalytic
cycle
Ph
Ph
Eq. 1
Ph
Ph
MeOH, rt
30 min
N
N
O
O
Bn
Bn
3, 98%
2a
Synthesis of tetrahydropyrimidin-4-one using -amino acid derivative
Ph
Ph
I2 (20 mol%)
PIFA (1.2 equiv)
9
TsN
Ph
TsHN
Ph
Eq. 2
10
11
12
13
14
15
16
17
18
19
20
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42
43
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46
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50
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52
53
54
55
56
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58
59
60
27 W light lamp
DCE, 0 ºC, 24 h
N
O
N
O
Bn
Bn
4 (racemic)
5, 65%
I2
PhI(OCOCF3)2
PhI
+
CONCLUSIONS
2a
+
CF3CO2H
1a
I(OCOCF3)
We have demonstrated the synthesis of 4-
imidazolidiones using an iodine-catalyzed
CF3CO2H
dehydrogenative N-H/C(sp3)-H coupling under light
irradiation in moderate to excellent yields. The reaction is
selective for benzylic C-H bonds over primary C-H
bonds. Fused heterocyclic compounds, as well as a
tetrahydropyrimidinone derivative were accessed from
readily available starting materials.
I
TsHN
Ph
TsN
(F3COCO)2I
Ph
N
O
Ph
E
Bn
Ph
N
O
Bn
A
PhI
h
PhI(OCOCF3)2
EXPERIMENTAL SECTION
I
General Information. Unless otherwise mentioned, all
reactions were carried out in an argon atmosphere. 1H NMR
spectra were recorded on JEOL AL-500 (500 MHz)
spectrometers. The chemical shifts were reported in parts
per million (δ) relative to internal TMS (0 ppm) for CDCl3.
The peak patterns are indicated as follows: s, singlet; d,
doublet; dd, doublet of doublets; t, triplet; m, multiplets; q,
quartet; br, broad. The coupling constants, J, are reported in
hertz (Hz). 13C{1H} NMR spectra were obtained by JEOL
AL-500 (125 MHz) spectrometer and referenced to the
internal solvent signal (central peak is 77.0 ppm in CDCl3 or
central peak is 39.5 ppm in DMSO-d6). CDCl3 or DMSO was
use as an NMR solvent. 19F NMR spectra were obtained by
JEOL AL-5000 (470 MHz) spectrum, and trifluoroacetic acid
was used as an external standard. High-resolution mass
spectra (HRMS) were measured on a TOFMS using JMS-
T100CS with the ESI (electro spray ionization) method and
DART (direct analysis in real time) method.22 Preparative
thin-layer chromatography (PTLC) was performed with silica
gel-precoated glass plates (Wakogel B-5F) prepared in our
laboratory. Flash column chromatography was performed
over silica gel 200-300. Light source was a bulb bought
from YAMAZEN (EFD30ED/27PR-E26 27W). All reagents
were weighed and handled in air and backfilled with argon
at room temperature. All reagents were purchased from
Wako, Kanto, Aldrich, TCI, and Strem and used without
further purification.
TsHN
N
TsN
N
Ph
O
Ph
I
Ph
Ph
O
Bn
Bn
B
D
TsHN
Ph
I
Ph
N
O
Bn
C
Figure 2. Plausible reaction mechanism
The tosyl group of 2a was readily removed using
magnesium turnings in methanol at rt to give deprotected
4-imidazolidinone 3 in almost quantitative yield (Eq. 1).21
To underscore the utility of the catalytic reaction, the
reaction conditions were applied to synthesize
tetrahydropyrimidin-4-one derivative from a substrate
a
prepared from racemic β-phenyl alanine and
dibenzylamine. The reaction of
4
under the
dehydrogenative iodine catalysis gave diazaheterocyclic
compound 5 in 65% yield (Eq. 2).
General procedure for the synthesis of starting
materials.
Experimental procedure for the synthesis of (S)-N,N-
Dibenzyl-2-((4-methylphenyl)sulfonamido)-3-
phenylpropanamide (1a). Step 1. A 50 mL dry two-necked
pear-shaped flask equipped with a magnetic stirred was
charged with L-phenylalanine (909 mg, 5.5 mmol) and
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1
H2O/THF (2/1, 30 mL), then cooled to 0 ºC. p-Tosylchloride
(953 mg, 1.0 equiv) was added in one portion, and the
solution was stirred overnight while warming gradually to rt.
The crude solution was evaporated and extracted with
diethyl ether. The aqueous layer was acidified with 1N HCl
solution to pH 2-3, then extracted with ethyl acetate (×3).
The combined organic layers were dried over Na2SO4, and
evaporated under reduced pressure. The crude tosyl-L-
phenylalanine was dried and used in the next step without
further purification.
(61%, 564 mg). H NMR δ 7.68 (d, J = 7.8 Hz, 2H), 7.21-
7.33 (m, 8H), 6.99-7.04 (m, 2H), 6.87-6.92 (m, 2H), 5.80-
5.86 (br, 1H), 4.76 (d, J = 14.8 Hz, 1H), 4.32 (d, J = 16.6
Hz, 1H), 4.13-4.21 (m, 2H), 4.08 (d, J = 14.8 Hz, 1H), 2.43
(s, 3H), 1.87-1.98 (m, 1H), 1.51-1.60 (m, 1H), 1.19-1.28 (m,
1H), 0.86 (d, J = 6.7 Hz, 3H), 0.73 (d, J = 6.5 Hz, 3H);
13C{1H} NMR δ 172.5, 143.4, 137.3, 136.5, 135.4, 129.7,
129.1, 128.8, 128.4, 128.1, 127.1, 127.5, 127.0, 51.9, 49.4,
48.5, 43.3, 24.1, 23.5, 21.7, 20.8; HRMS (ESI, positive)
calcd for C27H32N2NaO3S [M+Na]+ 487.2031; found
487.2025.
1
2
3
4
5
6
7
8
9
Step 2. A portion of the crude tosyl-L-phenylalanine (319 mg,
1.0 mmol) obtained above was dissolved in toluene (10 mL)
and SOCl2 (0.36 mL, 5.0 equiv) was added, then the
solution was heated at 70 ºC (oil bath temperature). The
obtained solution was cooled to room temperature, followed
by evaporation of toluene under reduced pressure. To the
crude acyl chloride was added dichloromethane (7.5 mL)
and dibenzylamine (0.22 mL, 2.0 equiv), and stirred at rt for
24 h. 1N HCl was added to the solution, then washed with
NaHCO3. The organic layers were dried over Na2SO4,
evaporated, then the residue was purified by column
chromatography on silica gel (toluene/ethyl acetate = 9/1, Rf
= 0.4) to afford title compound as a white solid (70%, 347
mg): mp 92 ºC; 1H NMR δ 7.57 (d, J = 7.7 Hz, 2H), 7.20-
7.35 (m, 6H), 7.05-7.19 (m, 7H), 6.91 (d, J = 7.5 Hz, 2H),
6.83 (d, J = 7.2 Hz, 2 H), 5.80-5.88 (br, 1H), 4.70 (d, J =
14.5 Hz, 1H), 4.39-4.47 (q, J = 7.2 Hz, 1H), 4.22 (t, J = 7.3
Hz, 2H), 4.04 (d, J = 16.8 Hz, 1H), 2.92-3.00 (m, 1H), 2.81-
2.88 (m, 1H), 2.39 (s, 3H); 13C{1H} NMR δ 171.4, 143.4,
137.6, 136.3, 135.7, 135.5, 129.7, 129.7, 129.1, 128.9,
128.7, 128.6, 128.0, 127.8, 127.2, 127.1, 54.5, 49.5, 48.6,
40.7, 21.7 (two aromatic peaks are overlapping); HRMS
(ESI, positive) calcd for C30H30N2NaO3S [M+Na]+ 521.1875;
found 521.1870.
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
(S)-N,N-Dibenzyl-3-methyl-2-((4-
methylphenyl)sulfonamido)butanamide (1e). Isolated by
flash column chromatography (hexane/ethyl acetate = 2/1,
Rf = 0.5). The title compound was obtained as yellow oil
1
(79%, 710 mg): H NMR δ 7.71 (d, J = 7.8 Hz, 2H), 7.22-
7.33 (m, 8H), 6.95-7.01 (m, 2H), 6.79 (d, J = 7.4 Hz, 2H),
5.90-6.01 (br, 1H), 4.81 (d, J = 14.8 Hz, 1H), 4.36 (d, J =
16.2 Hz, 1H), 4.06-4.13 (m, 2H), 3.93 (d, J = 14.8 Hz, 1H),
2.45 (s, 3H), 1.87-1.97 (m, 1H), 1.01 (d, J = 6.7 Hz, 3H),
0.88 (d, J = 6.7 Hz, 3H); 13C{1H} NMR δ 171.0, 143.4,
137.3, 136.5, 135.2, 129.8, 129.1, 128.8, 128.4, 128.2,
127.7, 127.5, 127.2, 58.0, 49.6, 47.8, 31.3, 21.8, 20.1, 15.9;
HRMS (ESI, positive) calcd for C26H30N2NaO3S [M+Na]+
473.1869; found 473.1868.
Methyl
(S)-5-(dibenzylamino)-4-((4-
methylphenyl)sulfonamido)-5-oxopentanoate (1f). Isolated
by flash column chromatography (hexane/ethyl acetate =
7/3, Rf = 0.5). The title compound was obtained as a white
1
solid (95%, 705 mg): mp 94 ºC; H NMR δ 7.66 (d, J = 7.8
Hz, 2H), 7.20-7.32 (m, 8H), 6.93-7.00 (m, 2H), 6.83 (d, J =
7.3 Hz, 2H), 6.04 (d, J = 7.7 Hz, 1H), 4.79 (d, J = 14.8 Hz,
1H), 4.69 (d, J = 16.2 Hz, 1H), 4.30-4.37 (m, 1H), 4.21 (d, J
= 16.2 Hz, 1H), 3.97 (d, J = 14.8 Hz, 1H), 3.63 (s, 3H), 2.74-
2.83 (m, 1H), 2.42-2.50 (m, 4H), 1.97-2.06 (m, 1H), 1.62-
1.72 (m, 1H); 13C{1H} NMR δ 173.8, 171.5, 143.5, 136.9,
136.3, 135.5, 129.9, 129.0, 128.8, 128.2, 128.0, 127.7,
127.4, 127.3, 52.4, 51.8, 49.3, 47.9, 29.2, 28.7, 21.8; HRMS
(ESI, positive) calcd for C27H31N2O5S [M+H]+ 495.1948;
found 495.1944.
N,N-Dibenzyl-2-((4-methylphenyl)sulfonamido)acetamide
(1b).
Isolated
by
recrystallization
from
dichloromethane/hexane. The title compound was obtained
1
as a white solid (88%, 1.08 g): mp 136 ºC; H NMR δ 7.70
(d, J = 7.8 Hz, 2H), 7.23-7.36 (m, 8H), 7.03-7.09 (m, 2H),
6.93-6.99 (m, 2H), 5.82-5.90 (br, 1H), 4.51 (s, 2H), 4.25 (s,
2H), 3.84 (s, 2H), 2.43 (s, 3 H); 13C{1H} NMR δ 167.7,
143.7, 136.2, 136.1, 135.0, 129.9, 129.3, 128.8, 128.4,
128.1, 127.9, 127.5, 126.5, 49.1, 49.0, 43.9, 21.7; HRMS
(ESI, positive) calcd for C23H24N2NaO3S [M+Na]+ 431.1400;
found 431.1399.
(S)-N,N-Dibenzyl-3-hydroxy-2-((4-
methylphenyl)sulfonamido)propanamide (1g). Isolated by
flash column chromatography (toluene/ethyl acetate = 4/1,
Rf = 0.3). The title compound was obtained as a white solid
1
(6%, 78 mg): mp 160 ºC; H NMR δ 7.72 (d, J = 7.8 Hz,
(S)-N,N-Dibenzyl-2-((4-
2H), 7.39 (m, 10H), 7.18-7.00 (m, 2H), 6.95-6.88 (m, 2H),
4.62 (d, J = 15.0 Hz, 1H), 4.45-4.24 (m, 4H), 3.65 (dd, J =
7.2, 4.0 Hz, 1H), 3.61 (dd, J = 7.2, 4.0 Hz, 1H), 2.21 (s, 3H);
13C{1H} NMR using DMSO-d6 δ 170.7, 143.1, 139.2, 137.4,
136.9, 130.0, 129.1, 128.9, 128.0, 127.9, 127.6, 127.5,
127.0, 62.7, 54.5, 49.9, 48.2, 21.5; HRMS (ESI, positive)
calcd for C24H26N2NaO4S [M+Na]+ 461.1505; found
461.1506.
methylphenyl)sulfonamido)propanamide (1c). Isolated by
flash column chromatography (hexane/ethyl acetate = 1/1,
Rf = 0.6). The title compound was obtained as a white solid
1
(78%, 1.64 g): mp 144 ºC; H NMR δ 7.70 (d, J = 7.8 Hz,
2H), 7.24-7.29 (m, 8H), 7.01-7.03 (m, 2H), 6.87 (d, J = 7.4
Hz, 2H), 5.97-6.04 (br, 1H), 4.75 (d, J = 14.8 Hz, 1H), 4.36
(d, J = 16.5 Hz, 1H), 4.29 (quint, J = 6.9 Hz, 1H), 4.18 (d, J
= 16.5 Hz, 1H), 4.11 (d, J = 14.8 Hz, 1H), 2.44 (s, 3H), 1.37
(d, J = 6.9 Hz, 3H); 13C{1H} NMR δ 172.3, 143.4, 137.5,
136.3, 135.2, 129.8, 129.1, 128.8, 128.2, 128.1, 127.8,
127.2, 126.9, 49.5, 49.2, 48.2, 21.7, 21.2; HRMS (ESI,
positive) calcd for C24H26N2NaO3S [M+Na]+ 445.1552; found
445.1557.
(S)-4-(3-(Dibenzylamino)-2-((4-methylphenyl)sulfonamido)-
3-oxopropyl)phenyl
4-methylbenzenesulfonate
(1h).
Isolated by flash column chromatography (hexane/ethyl
acetate = 2/1, Rf = 0.5). The title compound was obtained
as yellow oil (64%, 847 mg): 1H NMR δ 7.63 (d, J = 7.3 Hz,
2H), 7.55 (d, J = 7.3 Hz, 2H), 7.38-7.20 (m, 8H), 7.29-7.04
(m, 4H), 6.83 (d, J = 7.2 Hz, 2H), 6.78 (d, J = 7.3 Hz, 2H),
6.64 (d, J = 7.2 Hz, 2H), 6.10-5.96 (br, 1H), 4.63 (d, J = 15.0
Hz, 1H), 4.35 (q, J = 7.2 Hz, 1H), 4.12-4.04 (br, 3H), 2.84
(dd, J = 7.1, 7.1 Hz, 1H), 2.77 (dd, J = 7.1, 7.1 Hz, 1H), 2.42
(S)-N,N-Dibenzyl-4-methyl-2-((4-
methylphenyl)sulfonamido)pentanamide (1d). Isolated by
flash column chromatography (hexane/ethyl acetate = 3/1,
Rf = 0.4). The title compound was obtained as yellow oil
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(s, 3H), 2.40 (s, 3H); 13C{1H} NMR δ 171.2, 148.7, 145.5,
compound exists as tautomer. The coupling of F makes the
1
2
3
4
143.6, 137.3, 136.2, 135.5, 134.8, 132.4, 130.9, 129.9,
129.8, 129.2, 128.8, 128.6, 128.1, 127.9, 127.1, 126.9,
122.4, 54.3, 49.7, 49.0, 39.9, 21.8, 21.7 (two aromatic
carbon peaks are overlapping); HRMS (ESI, positive) calcd
for C37H36N2NaO6S2 [M+Na]+ 691.1907; found 691.1901.
aromatic carbons difficult to read); 19F NMR δ -62.5; HRMS
(ESI, positive) calcd for C19H21F3N2O3S [M+H]+ 415.1298;
found 415.1290.
(S)-N,N-Dimethyl-2-((4-
5
6
7
8
methylphenyl)sulfonamido)propanamide (1m). Isolated by
flash column chromatography (hexane/ethyl acetate = 1/1,
Rf = 0.5). The title compound was obtained as yellow solid
(S)-N,N-Dibenzyl-2-((4-methylphenyl)sulfonamido)-2-
phenylacetamide (1i). Isolated by flash column
chromatography (hexane/ethyl acetate = 2/1, Rf = 0.5). The
title compound was obtained as a white solid (39%, 574
1
(65%, 350 mg): mp 94 ºC; H NMR δ 7.70 (d, J = 7.9 Hz,
2H), 7.25 (d, J = 7.9 Hz, 2H), 5.76-5.82 (br, 1H), 4.14-4.23
(m, 1H), 2.82 (s, 3H), 2.71 (s, 3H), 2.41 (s, 3H), 1.24 (d, J =
7.2, 3H); 13C{1H} NMR δ 171.4, 143.6, 137.1, 129.5, 127.3,
48.0, 36.8, 35.7, 21.6, 19.9; HRMS (ESI, positive) calcd for
C12H19N2O3S [M+H]+ 271.1111; found 271.1107.
9
1
mg): mp 124 ºC; H NMR δ 7.57 (d, J = 7.9 Hz, 2H), 7.08-
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
7.34 (m, 13H), 6.94-7.02 (m, 2H), 6.72 (d, J = 7.4 Hz, 2H),
6.50-6.60 (br, 1H), 5.21 (s, 1H), 4.80 (d, J = 14.8 Hz, 1H),
4.29 (d, J = 16.6 Hz, 1H), 4.11 (d, J = 14.8 Hz, 1H), 4.01 (d,
J = 16.6 Hz, 1H), 2.40 (s, 3H); 13C{1H} NMR δ 169.5, 143.2,
137.6, 136.5, 136.2, 135.0, 129.6, 129.3, 129.0, 128.8,
128.7, 128.3, 128.0, 127.9, 127.7, 127.3, 126.9, 58.0, 49.5,
48.6, 21.7; HRMS (ESI, positive) calcd for C29H28N2NaO3S
[M+Na]+ 507.1713; found 507.1714.
(S)-N,N-Dibutyl-2-((4-
methylphenyl)sulfonamido)propanamide (1n). Isolated by
flash column chromatography (hexane/ethyl acetate = 1/1,
Rf = 0.5). The title compound was obtained as a white solid
1
(80%, 650 mg): mp 54 ºC; H NMR δ 7.70 (d, J = 7.8 Hz,
N,N-Dibenzyl-2-methyl-2-((4-
2H), 7.25 (d, J = 7.8 Hz, 2H), 5.93 (d, J = 7.9 Hz, 1H), 4.04-
4.11 (m, 1H), 3.17-3.25 (m, 1H), 2.95-3.09 (m, 3H), 2.40 (s,
3H), 1.11-1.37 (m, 11H), 0.83-0.92 (m, 6H); 13C{1H} NMR δ
171.1, 143.4, 137.3, 129.7, 127.3, 48.9, 47.3, 46.0, 31.0,
29.6, 21.6, 21.1, 20.1, 20.0, 13.9, 13.8; HRMS (ESI,
positive) calcd for C18H31N2O3S [M+H]+ 355.2050; found
355.2047.
methylphenyl)sulfonamido)propanamide (1j). Isolated by
flash column chromatography (hexane/ethyl acetate = 7/3,
Rf = 0.3). The title compound was obtained as a brown solid
1
(37%, 122 mg): mp 130 ºC; H NMR δ 7.68 (d, J = 7.8 Hz,
2H), 7.23-7.36 (m, 6H), 7.19 (d, J = 7.8 Hz, 2H), 7.08-7.16
(m, 4H), 5.91-5.98 (m, 1H), 4.40-4.75 (br, 4H), 2.39 (s, 3H),
1.54 (s, 6H); 13C{1H} NMR δ 173.3, 143.3, 140.1, 136.5,
129.7, 128.9, 127.6, 127.1, 60.8, 50.0, 26.8, 21.6 (two
aromatic carbon peaks are overlapping); HRMS (ESI,
positive) calcd for C25H28N2NaO3S [M+Na]+ 459.1713; found
459.1712.
(S)-4-Methyl-N-(1-oxo-1-(piperidin-1-yl)propan-2-
yl)benzenesulfonamide (1o). Isolated by flash column
chromatography (hexane/ethyl acetate = 1/1, Rf = 0.4). The
title compound was obtained as a light brown solid (75%,
466 mg): mp 93 ºC; 1H NMR δ 7.71 (d, J = 7.8 Hz, 2H), 7.27
(d, J = 8.3 Hz, 2H), 5.94 (d, J = 7.9 Hz, 1H), 4.08-4.19 (m,
1H), 3.41-3.48 (m, 1H), 3.08-3.26 (m, 3H), 2.40 (s, 3H),
1.38-1.60 (m, 4H), 1.13-1.32 (m, 5H); 13C{1H} NMR δ 169.5,
143.5, 137.0, 129.6, 127.5, 48.8, 46.3, 43.4, 26.1, 25.2,
24.3, 21.6, 20.5; HRMS (ESI, positive) calcd for
C15H23N2O3S [M+H]+ 311.1424; found 311.1420.
(S)-N-Benzyl-N-methyl-2-((4-
methylphenyl)sulfonamido)propanamide (1k). Isolated by
flash column chromatography (hexane/ethyl acetate = 3/2,
Rf = 0.5). The title compound was obtained as a brown solid
1
(63%, 218 mg): mp 122 ºC; H NMR δ 7.74 (d, J = 7.9 Hz,
0.67×2H), 7.69 (d, J = 7.9 Hz, 0.33×2H), 7.20-7.28 (m, 5H),
6.96-7.03 (m, 0.67×2H), 6.90-6.96 (m, 0.33×2H), 6.25-6.39
(m, 1H), 4.24-4.40 (m, 3H), 2.71-2.78 (m, 3H), 2.36-2.42 (m,
3H), 1.26-1.36 (m, 3H); 13C{1H} NMR δ 171.9, 171.8, 143.5,
143.4, 137.5, 137.4, 136.4, 135.7, 129.7, 129.0, 128.7,
127.9, 127.6, 127.2, 126.7, 52.9, 51.2, 49.0, 48.9, 34.3,
34.1, 21.7, 21.6, 20.7, 20.0 (more carbon peaks were
observed because the compound exists as a mixture of
tautomers). HRMS (ESI, positive) calcd for C18H23N2O3S
[M+H]+ 347.1424; found 347.1420.
(S)-4-Methyl-N-(1-morpholino-1-oxopropan-2-
yl)benzenesulfonamide (1p). Isolated by flash column
chromatography (hexane/ethyl acetate = 1/3, Rf = 0.6). The
title compound was obtained as a white solid (81%, 507
mg): mp 112 ºC; 1H NMR δ 7.71 (d, J = 7.9 Hz, 2H), 7.29 (d,
J = 7.9 Hz, 2H), 5.81 (br, 1H), 4.20-4.12 (m, 1H), 3.54-3.62
(m, 2H), 3.22-3.48 (m, 6H), 2.42 (s, 3H), 1.28 (d, J = 7.0 Hz,
3H); 13C{1H} NMR δ 170.1, 143.7, 137.0, 129.7, 127.5, 66.6,
66.3, 48.6, 45.7, 42.5, 21.6, 20.2; HRMS (ESI, positive)
calcd for C14H21N2O4S [M+H]+ 313.1217; found 313.1212.
(S)-N-Methyl-2-((4-methylphenyl)sulfonamido)-N-(4-
(trifluoromethyl)benzyl)propanamide (1l). Isolated by flash
column chromatography (hexane/ethyl acetate = 1/1, Rf =
0.5). The title compound was obtained as a white solid
(S)-N-(1-(Azepan-1-yl)-1-oxopropan-2-yl)-4-
methylbenzenesulfonamide (1q). Isolated by flash column
chromatography (hexane/ethyl acetate = 1/1, Rf = 0.4). The
title compound was obtained as a yellow solid (88%, 571
mg): mp 94 ºC; 1H NMR δ 7.72 (d, J = 7.9 Hz, 2H), 7.26 (d,
J = 7.9 Hz, 2H), 5.94 (d, J = 9.1 Hz, 1H), 4.06-4.13 (m, 1H),
3.53-3.60 (m, 1H), 3.25-3.32 (m, 1H), 3.11-3.18 (m, 1H),
2.93-3.00 (m, 1H), 2.39 (s, 3H), 1.34-1.66 (m, 6H), 1.32 (d,
J = 7.2 Hz, 3H), 1.11-1.28 (m, 2H); 13C{1H} NMR δ 171.1,
143.5, 137.1, 129.6, 127.5, 49.0, 47.3, 46.1, 28.9, 27.2,
27.0, 26.3, 21.5, 20.7; HRMS (ESI, positive) calcd for
C16H25N2O3S [M+H]+ 325.1580; found 325.1574.
1
(65%, 135 mg): mp 132 ºC; H NMR δ 7.74 (d, J = 7.8 Hz,
0.77×2H), 7.68 (d, J = 7.8 Hz, 0.23×2H), 7.53 (d, J = 7.8 Hz,
2H), 7.28 (d, J = 7.8 Hz, 2H + 0.23×2H), 7.09 (d, J = 8.0 Hz,
0.77×2H), 7.03 (d, J = 8.0 Hz, 0.23×2H), 5.87-5.77 (m, 1H),
4.50 (d, J = 15.0 Hz, 1H), 4.41 (d, J = 15.0 Hz, 0.23×1H),
4.35 (d, J = 15.0 Hz, 0.77×1H), 4.25-4.32 (m, 0.77×1H),
4.18-4.24 (m, 0.23×1H), 2.81 (s, 0.77×3H), 2.77 (s,
0.23×3H), 2.42 (s, 0.77×3H), 2.41 (s, 0.23×3H), 1.35 (s,
0.77×3H), 1.33 (s, 0.23×3H); 13C{1H} NMR δ 172.2, 172.0,
143.6, 140.5, 139.7, 137.4, 137.4, 130.2, 130.0, 129.8,
129.7, 128.0, 127.3, 127.2, 126.9, 126.0 (J = 2.5 Hz),
125.125.7 (J = 3.8 Hz), 125.2, 125.1, 123.0, 122.9, 52.5,
51.0, 49.0, 48.9, 34.6, 34.2, 21.7, 21.6, 20.9, 20.1 (the
(S)-N,N-Diisopropyl-2-((4-
methylphenyl)sulfonamido)propanamide (1r). Isolated by
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flash column chromatography (hexane/ethyl acetate = 3/2,
7.22 (m, 6H), 7.04-7.00 (m, 4H), 6.78-7.55 (br, 1H), 4.71 (d,
1
2
3
4
5
6
7
8
Rf = 0.6). The title compound was obtained as a yellow solid
(64%, 517 mg): mp 108 ºC; H NMR δ 7.73 (d, J = 7.9 Hz,
J = 14.6 Hz, 1H), 4.60 (q, J = 6.9 Hz, 1H), 4.44 (d, J = 16.0
Hz, 1H), 4.31 (d, J = 16.0 Hz, 1H), 4.12 (d, J = 14.6 Hz, 1H),
1.42 (d, J = 6.7 Hz, 3H); 13C{1H} NMR δ 171.8, 147.9,
136.4, 135.5, 134.8, 133.6, 132.9, 130.2, 129.2, 128.9,
128.2, 127.8, 126.9, 125.8, 50.5, 49.6, 48.4, 20.8 (two
aromatic carbon peaks are overlapping); HRMS (ESI,
positive) calcd for C23H24N3O5S [M+H]+ 454.1431; found
454.1425.
1
2H), 7.25 (d, J = 8.2 Hz, 2H), 6.23 (d, J = 7.9 Hz, 1H), 4.02-
4.10 (m, 1H), 3.66-3.75 (sept, J = 7.3 Hz, 1H), 3.15-3.27 (m,
1H), 2.37 (s, 3H), 1.28 (d, J = 7.3 Hz, 3H), 1.22 (d, J = 7.3
Hz, 3H), 1.08 (d, J = 7.3 Hz, 3H), 0.98 (d, J = 7.3 Hz, 3H),
0.91 (d, J = 7.3 Hz, 3H); 13C{1H} NMR δ 169.7, 143.3, 136.9,
129.6, 127.4, 49.7, 48.3, 45.9, 21.4, 20.8, 20.3, 20.3, 20.0,
19.9; HRMS (ESI, positive) calcd for C16H27N2O3S [M+H]+
327.1737; found 327.1733.
N,N-Dibenzyl-3-((4-methylphenyl)sulfonamido)-3-
9
phenylpropanamide (4). Isolated by flash column
chromatography (dichloromethane/ethyl acetate = 19/1, Rf =
0.6). The title compound was obtained as a white solid
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
(S)-N-Cyclohexyl-N-methyl-2-((4-
methylphenyl)sulfonamido)propanamide (1s). Isolated by
flash column chromatography (hexane/ethyl acetate = 1/1,
Rf = 0.5). The title compound was obtained as a white solid
1
(32%, 317 mg). mp 100 ºC; H NMR δ 7.62 (d, J = 8.2 Hz,
2H), 7.22-7.30 (m, 6H), 7.12-7.21 (m, 5H), 7.06-7.11 (m,
2H), 6.98-7.04 (m, 2H), 6.83-6.89 (m, 3H), 4.71-4.77 (m,
1H), 4.52 (d, J = 14.7 Hz, 1H), 4.39 (d, J = 14.7 Hz, 1H),
4.18 (s, 2H), 2.97 (dd, J = 7.0, 3.7 Hz 1H), 2.72 (dd, J = 7.0,
3.7 Hz 1H),
1
(35%, 118 mg): mp 86 ºC; H NMR δ 7.70 (d, J = 7.9 Hz,
2H), 7.25 (d, J = 7.9 Hz, 2H), 5.92 (d, J = 7.6 Hz, 0.40×1H),
5.82 (d, J = 8.7 Hz, 0.60×1H), 4.09-4.18 (m, 1H), 3.98-4.06
(m, 0.60×1H), 3.20-3.28 (m, 0.40×1H), 2.64 (s, 0.60×3H),
2.59 (s, 0.40×3H), 2.35-2.41 (m, 3H), 1.55-1.87 (m, 4H),
1.40-1.52 (m, 1H), 1.18-1.35 (m, 1.17 (m, 8H); 13C{1H} NMR
δ 171.1, 170.9, 143.5, 143.5, 137.1, 136.9, 129.6, 129.6,
127.4, 127.4, 56.4, 53.2, 49.4, 49.1, 30.8, 30.5, 29.7, 29.2,
29.0, 27.7, 25.7, 25.6, 25.5, 25.5, 25.5, 25.2, 21.6, 21.5,
21.2, 20.0 (more carbon peaks were observed because the
compound exists as a mixture of tautomers); HRMS (ESI,
positive) calcd for C17H27N2O3S [M+H]+ 339.1737; found
339.1732 .
2.36 (s, 3H); 13C{1H} NMR δ 171.2, 143.1, 140.0, 137.9,
136.7, 135.9, 129.5, 129.1, 128.7, 128.5, 128.3, 127.8,
127.7, 127.6, 127.3, 126.8, 126.3, 55.0, 50.1, 48.5, 38.8,
21.6; HRMS (ESI, positive) calcd for C30H31N2O3S [M+H]+
499.2050; found 499.2039.
General procedure for the synthesis of 4-
imidazolidinones:
methylphenyl)sulfonamido)-3-phenylpropanamide (1a) (49.9
mg, 0.10 mmol), bis(trifluoroacetoxy)iodobenzene
(S)-N,N-Dibenzyl-2-((4-
(S)-N-Hexyl-N-isopropyl-2-((4-
(PhIOCOCF3) (51.6 mg, 0.120 mmol), and iodine (5.1 mg,
0.020 mmol), were placed into a Schlenk tube equipped
with a magnetic stirring bar. The Schlenk tube was
evacuated and backfilled with argon (×3). To the reaction
vessel was added dichloroethane (0.70 mL). The Schlenk
was capped and the solution was stirred for 8 h at 0 ºC (ice
bath temperature) under 27 W fluorescent light irradiation.
The crude material was then purified using preparative TLC
to obtain (2S,5S)-3,5-dibenzyl-2-phenyl-1-tosylimidazolidin-
4-one (2a) as major diastereomer and (2R,5S)-3,5-dibenzyl-
methylphenyl)sulfonamido)propanamide (1t). Isolated by
flash column chromatography (hexane/ethyl acetate = 2/1,
Rf = 0.4). The title compound was obtained as brown oil
(59%, 523 mg). 1H NMR δ 7.74-7.66 (m, 2H), 7.29-7.21 (m,
2H), 6.00 (d, J = 7.2 Hz, 0.59×1H); 5.89 (d, J = 7.2 Hz,
0.41×1H); 4.20-4.28 (m, 0.41×1H); 4.10-4.19 (m, 0.59×1H);
3.97-4.06 (m, 0.41×1H); 3.71-3.81 (m, 0.59×1H); 2.80-3.01
(m, 2H), 2.36-2.42 (m, 3H), 1.09-1.36 (m, 12.77H), 1.02 (d,
J = 7.2 Hz, 0.41×3H), 0.83-.097 (m, 6H); 13C{1H} NMR δ
171.3, 170.4, 143.4, 143.3, 137.3, 137.0, 129.6, 129.6,
127.4, 127.4, 49.4, 49.2, 47.9, 47.0, 43.6, 41.5, 31.6, 31.4,
31.1, 29.0, 27.0, 26.8, 22.7, 22.6, 21.5, 21.5, 21.1, 21.1,
21.0, 20.9, 20.1, 14.1, 14.1 (the compound exists as a
mixture of tautomers); HRMS (ESI, positive) calcd for
C19H33N2O3S [M+H]+ 369.2206; found 369.2204
2-phenyl-1-tosylimidazolidin-4-one
diastereomer.
(2a’)
as
minor
(2S,5S)-3,5-Dibenzyl-2-phenyl-1-tosylimidazolidin-4-one
(2a). Isolated by PTLC (Rf = 0.5; toluene/ethyl acetate =
9/1) as a white solid (75%, 37.2 mg): mp 157 ºC; 1H NMR δ
7.55-7.62 (m, 2H), 7.32-7.40 (m, 3H), 7.20-7.30 (m, 1H),
7.12-7.19 (m, 1H), 7.00-7.10 (m, 4H), 6.83-6.95 (m, 4H),
6.67-6.78 (m, 2H), 6.19 (d, J = 7.5 Hz, 2H), 5.21 (d, J = 2.6
Hz, 1H), 4.84 (d, J = 15.0 Hz, 1H), 4.60 (s, 1H), 3.96 (dd, J
= 7.7, 3.0 Hz, 1H), 3.36 (dd, J = 7.7, 3.0 Hz, 1H), 2.98 (d, J
= 15.0 Hz, 1H), 2.33 (s, 3H); 13C{1H} NMR δ 167.9, 143.1,
136.6, 135.2, 133.7, 133.6, 131.4, 129.7, 129.1, 128.9,
128.6, 128.6, 128.5, 127.9, 127.7, 127.1, 126.6, 76.2, 62.1,
43.4, 37.5, 21.5; HRMS (ESI, positive) calcd for
(S)-N,N-Dibenzyl-2-((2,4,6-
trimethylphenyl)sulfonamido)propanamide (1u). Isolated by
flash column chromatography (hexane/ethyl acetate = 2/1,
Rf = 0.5). The title compound was obtained as yellow oil
(72%, 649 mg). 1H NMR δ 7.23-7.31 (m, 6H), 7.01-7.05 (m,
2H), 6.91-6.94 (m, 2H), 6.87-6.91 (m, 2H), 6.02 (br, J = 7.9
Hz, 1 H), 4.71 (d, J = 14.5 Hz, 1H), 4.34 (d, J = 16.3 Hz,
1H), 4.22-4.29 (m, 1H), 4.20 (d, J = 14.5 Hz, 1H), 4.15 (d, J
= 16.3 Hz, 1H), 2.61 (s, 6H), 2.31 (s, 3H), 1.33 (d, J = 7.2
Hz, 3H); 13C{1H} NMR δ 172.6, 142.2, 139.1, 136.4, 135.3,
134.5, 132.1, 129.1, 128.8, 128.2, 128.1, 127.8, 126.7,
49.5, 48.8, 48.3, 22.9, 21.2, 21.1; HRMS (ESI, positive)
calcd for C26H31N2O3S [M+H]+ 451.2050; found 451.2046.
C30H29N2O3S [M+H]+ 497.1893; found 497.1887. [α]31
–
D
12.0 (c = 0.34, CHCl3).
(2R,5S)-3,5-Dibenzyl-2-phenyl-1-tosylimidazolidin-4-one
(2a’). Isolated by PTLC (Rf = 0.6; toluene/ethyl acetate =
9/1) as colorless oil (17%, 8.4 mg): 1H NMR δ 7.46-7.51 (m,
2H), 7.19-7.35 (m, 9H), 7.12-7.19 (m, 2H), 7.03-7.10 (m,
2H), 6.72 (d, J = 7.3 Hz, 2H), 6.30 (d, J = 7.3 Hz, 2H), 5.34
(s, 1H), 4.86 (d, J = 15.0 Hz, 1H), 4.31-4.36 (m, 1H), 3.47
(dd, J = 7.7, 3.0 Hz, 1H), 3.34 (dd, J = 7.7, 3.0 Hz, 1H), 1H),
3.19 (d, J = 15.0 Hz, 1H), 2.45 (s, 3H); 13C{1H} NMR δ
(S)-N,N-Dimethyl-2-((2-
nitrophenyl)sulfonamido)propanamide (1v). Isolated by flash
column chromatography (hexane/ethyl acetate = 1/1, Rf =
0.5). The title compound was obtained as yellow oil (83%,
378 mg): 1H NMR δ 7.90 (dd, J = 7.7, 7.7 Hz, 2H), 7.71 (dd,
J = 7.7, 7.7 Hz, 1H), 7.60 (dd, J = 7.7, 7.7 Hz, 1H), 7.38-
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168.0, 144.6, 136.1, 135.9, 134.6, 132.8, 131.3, 130.1,
Hz, 0.11×1H), 3.16 (d, J = 14.7 Hz, 0.89×1H), 2.94-3.04 (m,
1
2
3
4
5
6
7
8
129.4, 128.7, 128.7, 128.6, 128.2, 128.1, 127.9, 127.0,
75.5, 62.6, 43.9, 37.4, 21.7 (two aromatic carbon peaks are
overlapping); HRMS (ESI, positive) calcd for C30H29N2O3S
[M+H]+ 497.1893; found 497.1886.
1H), 2.41 (s, 0.11×3H), 2.32 (s, 0.89×3H), 1.34 (d, J = 7.2
Hz, 0.89×3H), 1.15 (d, J = 7.2 Hz, 0.11×3H), 1.12 (d, J = 7.2
Hz, 0.11×3H), 1.04 (d, J = 6.8 Hz, 0.89×3H); 13C{1H} NMR δ
168.1, 143.1, 136.6, 134.8, 134.5, 130.1, 129.7, 129.1,
128.9, 128.9, 128.8, 128.7, 128.6, 128.6, 128.2, 128.1,
127.9, 127.7, 126.7, 76.1, 74.8, 66.2, 65.2, 44.2, 43.6, 31.5,
29.8, 21.7, 21.5, 19.7, 18.6, 18.4, 15.5 (some peaks of the
minor diastereomer could not be observed); HRMS (ESI,
positive) calcd for C26H29N2O3S [M+H]+ 449.1893; found
449.1891.
3-Benzyl-2-phenyl-1-tosylimidazolidin-4-one (2b). Isolated
by PTLC (Rf = 0.2; toluene/ethyl acetate = 9/1) as a white
1
solid (90%, 36.6 mg): mp 102 ºC; H NMR δ 7.33-7.43 (m,
5H), 7.23-7.33 (m, 3H), 7.17-7.23 (m, 2H), 7.14 (d, J = 7.9
Hz, 2H), 6.89 (d, J = 7.4 Hz, 2H), 5.67 (s, 1H), 4.98 (d, J =
15.0 Hz, 1H), 4.06-4.19 (m, 2H), 3.32 (d, J = 15.0 Hz, 1H),
2.41 (s, 3H); 13C{1H} NMR δ 167.0, 144.3, 136.2, 134.5,
134.0, 130.0, 130.0, 129.2, 129.0, 128.4, 128.2, 127.5,
127.4, 76.0, 49.3, 43.8, 21.7; HRMS (ESI, positive) calcd for
C23H22N2NaO3S [M+Na]+ 429.1243; found 429.1240.
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
Methyl 3-((4S)-1-benzyl-5-oxo-2-phenyl-3-tosylimidazolidin-
4-yl)propanoate (2f). Isolated by PTLC (Rf
dichloromethane/ethyl acetate 19/1) as
=
0.6;
=
a
yellow
diastereomeric mixture in solid form (84%, 41.4 mg).
1
Physical properties of the mixture are shown. H NMR δ
(S)-N,N-Dibenzyl-2-((4-
7.24-7.48 (m, 5H), 7.12-7.22 (m, 3H), 7.00-7.08 (m,
0.70×2H), 6.81-6.96 (m, 0.70×3H + 0.30×6H), 6.73-6.80 (m,
0.70×1H), 5.68 (br, 0.70×1H), 5.59 (br, 0.30×1H), 5.03 (d, J
= 14.6 Hz, 0.70×1H), 4.96 (d, J = 14.6 Hz, 0.30×1H), 4.20-
4.30 (m, 1H), 3.70 (s, 0.70×3H), 3.68 (s, 0.30×3H), 3.35 (d,
J = 14.6 Hz, 0.30×1H), 3.25 (d, J = 14.6 Hz, 0.70×1H), 2.53-
2.80 (m, 0.70×3H + 0.30×3H), 2.22-2.45 (m, 0.30×2H +
1H), 2.29 (s, 0.70×3H), 2.14-2.23 (m, 0.30×1H); 13C{1H}
NMR δ 173.3, 173.2, 169.2, 168.4, 144.5, 143.3, 136.5,
135.5, 134.6, 134.5, 134.2, 133.2, 130.2, 129.9, 129.9,
129.3, 129.2, 129.1, 128.9, 128.8, 128.7, 128.5, 128.4,
128.0, 127.8, 127.6, 126.8, 76.0, 75.3, 59.7, 59.0, 51.8,
51.8, 44.0, 43.9, 29.6, 29.2, 28.1, 27.0, 21.7, 21.5 (two
aromatic peaks are overlapping); HRMS (ESI, positive)
calcd for C27H29N2O5S [M+H]+ 493.1792; found 493.1786.
methylphenyl)sulfonamido)propanamide (2c). Isolated by
PTLC (Rf = 0.4; hexane/ethyl acetate = 7/3) as a yellow
diastereomeric mixture in solid form (96%, 40.4 mg).
1
Physical properties of the mixture are shown. H NMR δ
7.36-7.46 (m, 4H), 7.13-7.35 (m, 6H), 7.01-7.07 (m,
0.38×2H), 6.88-6.97 (m, 2H), 6.82 (d, J = 7.6 Hz, 0.62×2H),
5.69 (s, 0.38×1H), 5.58 (s, 0.62×1H), 5.03 (d, J = 15.0 Hz,
0.38×1H), 4.99 (d, J = 15.0 Hz, 0.62×1H), 4.16-4.22 (m,
1H), 3.33 (d, J = 15.0 Hz, 0.62×1H), 3.27 (d, J = 15.0 Hz,
0.38×1H), 2.42 (s, 0.62×3H), 2.31 (s, 0.38×3H), 1.80 (d, J =
7.2 Hz, 0.38×3H), 1.65 (d, J = 7.2 Hz, 0.62×3H); 13C{1H}
NMR δ 170.1, 169.9, 144.3, 143.2, 136.8, 136.3, 134.7,
134.6, 134.5, 134.0, 130.0, 129.9, 129.8, 129.2, 129.1,
129.1, 128.9, 128.8, 128.7, 128.4, 128.3, 128.2, 128.0,
127.7, 127.7, 126.7, 75.6, 75.3, 57.0, 56.5, 43.9, 43.7, 21.7,
21.5, 20.1, 19.5 (8 pairs of aromatic carbons are
overlapping); HRMS (ESI, positive) calcd for C24H25N2O3S
[M+H]+ 421.1580; found 421.1578.
(2S,5S)-3-Benzyl-5-(hydroxymethyl)-2-phenyl-1-
tosylimidazolidin-4-one (2g). The major diastereomer was
isolated by PTLC (Rf = 0.3; hexane/ethyl acetate = 7/3) as a
white solid (44%, 19.2 mg): mp 132 ºC; 1H NMR δ 7.82 (d, J
= 7.8 Hz, 2H), 7.42-7.48 (m, 3H), 7.35 (d, J = 7.8 Hz, 2H)
7.20-7.30 (m, 5H), 7.02-7.06 (m, 2H), 5.72-5.77 (br, 1H),
5.70 (s, 1H), 5.38 (d, J = 15.2 Hz, 1H), 4.15-4.06 (m, 1H),
3.78-3.87 (m, 2H), 3.46 (d, J = 15.2 Hz, 1H), 2.44 (s, 3H);
13C{1H} NMR δ 166.1, 144.2, 135.3, 135.1, 130.1, 130.0,
129.2, 128.9, 128.1, 128.1, 127.8, 127.6, 87.0, 62.7, 51.4,
47.2, 21.7 (two aromatic peaks are overlapping); HRMS
(ESI, positive) calcd for C24H25N2O4S [M+H]+ 437.1530;
(5S)-3-Benzyl-5-isobutyl-2-phenyl-1-tosylimidazolidin-4-one
(2d). Isolated by PTLC (Rf = 0.5; hexane/ethyl acetate =
7/3) as a brown diastereomeric mixture in solid form (75%,
1
34.7 mg). Physical properties of the mixture are shown. H
NMR δ 7.40-7.47 (m, 0.87×1H), 7.27-7.25 (m, 3.91H ),
7.10-7.18 (m, 2H), 6.99-7.06 (m, 0.87×2H), 6.87-6.93 (m,
0.87×4H), 6.78-6.86 (m, 2H), 5.68 (s, 0.87×1H), 5.63 (s,
0.13×1H), 5.02 (d, J = 14.8 Hz, 0.87×1H), 4.99 (d, J = 14.8
Hz, 0.13×1H), 4.11-4.14 (m, 0.87×1H), 4.04-4.07 (m,
0.17×1H), 3.36 (d, J = 14.8 Hz, 0.13×1H), 3.22 (d, J = 14.8
Hz, 0.87×1H), 2.43 (s, 0.13×3H), 2.31 (s, 0.87×3H), 2.11-
2.23 (m, 0.87×3H), 2.03-2.06 (m, 0.13×1H), 1.82-1.91 (m,
0.13×1H), 1.69-1.72 (d, J = 7.3 Hz, 0.13×1H), 0.95-1.07 (m,
6H); 13C{1H} NMR δ 170.3, 169.7, 144.4, 143.0, 136.8,
136.3, 134.6, 134.5, 134.2, 133.7, 130.2, 129.8, 129.2,
129.1, 129.0, 128.9, 128.7, 128.7, 128.5, 128.3, 128.0,
127.7, 127.6, 127.4, 127.0, 126.7, 75.9, 75.3, 59.6, 59.2,
44.1, 44.0, 43.8, 40.7, 24.4, 24.1, 23.9, 22.8, 22.6, 22.5,
21.7, 21.5; HRMS (ESI, positive) calcd for C27H30N2NaO3S
[M+H]+ 485.1869; found 485.1871.
found 437.1522. [α]25D +118.4 (c = 0.68, CHCl3).
4-(((4S)-1-Benzyl-5-oxo-2-phenyl-3-tosylimidazolidin-4-
yl)methyl)phenyl 4-methylbenzenesulfonate (2h). Isolated
by PTLC (Rf = 0.5; toluene/ethyl acetate = 9/1) as a white
diastereomeric mixture in solid form (77%, 61.3 mg).
1
Physical properties of the mixture are shown. H NMR δ
7.69-7.76 (m, 2H), 7.44-7.51 (m, 2H), 7.02-7.35 (m, 9H),
6.80-6.95 (m, 5H), 6.67-6.77 (m, 2H), 6.39 (d, J = 7.6 Hz,
0.20×2H), 6.26 (d, J = 7.6 Hz, 0.80×2H), 5.33 (br, 0.20×1H),
5.18 (br, 0.80×1H), 4.84 (d, J = 15.2 Hz, 0.20×1H), 4.79 (d,
J = 15.2 Hz, 0.80×1H), 4.51-4.57 (br, 0.80×1H), 4.26-4.30
(br, 0.20×1H), 3.92-3.84 (m, 0.80×1H), 3.35-3.41 (m,
0.20×1H), 3.26-3.34 (m, 0.80×1H + 0.20×1H), 3.18 (d, J =
15.2 Hz, 0.20×1H), 2.99 (d, J = 15.2 Hz, 0.80×1H), 2.41-
2.49 (m, 0.80×3H + 0.20×6H), 2.31 (s, 0.80×3H); 13C{1H}
NMR δ 167.7, 167.5, 150.9, 149.1, 149.1, 145.5, 144.8,
143.3, 136.2, 135.9, 135.0, 134.4, 134.3, 133.6, 133.5,
132.6, 132.5, 130.2, 129.9, 129.8, 129.7, 129.2, 128.8,
128.7, 128.6, 128.2, 128.1, 128.1, 128.0, 127.9, 126.6,
122.4, 122.3, 76.2, 75.4, 62.4, 61.7, 44.0, 43.5, 36.7, 36.6,
(5S)-3-Benzyl-5-isopropyl-2-phenyl-1-tosylimidazolidin-4-
one (2e). Isolated by PTLC (Rf = 0.5; hexane/ethyl acetate
= 7/3) as a white diastereomeric mixture in solid form (79%,
1
35.4 mg). Physical properties of the mixture are shown. H
NMR δ 7.24-7.43 (m, 5H), 7.09-7.21 (m, 2H), 7.00-7.05 (m,
0.89×2H), 6.83-6.96 (m, 5H), , 6.80 (d, J = 7.3 Hz,
0.11×2H), 5.68 (s, 0.89×1H), 5.62 (s, 0.11×1H) 5.06 (s, J =
15.0 Hz, 0.89×1H), 5.01 (s, J = 15.0 Hz, 0.11×1H), 4.17 (s,
0.89×1H), 3.92 (d, J = 6.0 Hz, 0.11×1H), 3.42 (d, J = 14.7
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Page 10 of 14
21.8, 21.7, 21.5 (9 aromatic carbons and two aliphatic
PTLC (Rf = 0.6; hexane/ethyl acetate = 1/1) as a brown
1
2
3
4
5
6
7
8
carbons are overlapping); HRMS (ESI, positive) calcd for
solid (50%, 20.6 mg): mp 152 ºC; 1H NMR δ 7.63 (d, J = 7.6
Hz, 2H), 7.58 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 7.6 Hz, 2H),
7.23 (d, J = 7.6 Hz, 2H), 5.78-5.65 (br, 1H), 4.22-4.05 (m,
1H), 2.60 (s, 3H), 2.41 (s, 3H), 2.60 (s, 3H); 13C{1H} NMR δ
169.8, 144.9, 141.0, 134.2, 132.0 (q, J = 32.5 Hz), 130.0,
128.1, 127.8, 126.1 (q, J = 2.5 Hz), 123.8 (q, J = 2.5 Hz),
56.5, 27.3, 21.6, 19.9 (an aliphatic peak is overlapping with
one of CDCl3 peaks); 19F NMR δ -62.7; HRMS (ESI,
positive) calcd for C19H20F3N2O3S [M+H]+ 413.1141; found
C37H35N2O6S2 [M+H]+ 667.1931; found 667.1917.
(2R,5R)-3-Benzyl-2,5-diphenyl-1-tosylimidazolidin-4-one
(2i). Isolated by PTLC (Rf = 0.5; toluene/ethyl acetate = 9/1)
1
as a white solid (41%, 19.8 mg): mp 112 ºC; H NMR δ
7.30-7.40 (m, 9H), 7.23-7.28 (m, 2H), 7.09 (d, J = 7.3 Hz,
2H), 7.01-7.07 (m, 2H), 6.84-6.93 (m, 4H), 5.90 (s, 1H),
5.20 (s, 1H), 5.07 (d, J = 14.8 Hz, 1H), 3.27 (d, J = 14.8 Hz,
1H), 2.31 (s, 3H); 13C{1H} NMR δ 168.1, 143.2, 137.5,
136.5, 134.9, 134.8, 130.0, 129.1, 129.1, 128.9, 128.8,
128.6, 128.6, 128.4, 127.6, 126.9, 76.3, 65.0, 43.9, 21.5
(two aromatic peaks are overlapping); HRMS (ESI, positive)
calcd for C29H27N2O3S [M+H]+ 483.1737; found 483.1732.
413.1137. [α]28D –61.4 (c = 0.78, CHCl3).
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15
16
17
18
19
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21
22
23
24
25
26
27
28
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45
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56
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58
59
60
(2R,5S)-3,5-Dimethyl-1-tosyl-2-(4-
(trifluoromethyl)phenyl)imidazolidin-4-one (2l’). Isolated by
PTLC (Rf = 0.5; hexane/ethyl acetate = 1/1) as yellow oil (
41%, 16.9 mg): 1H NMR δ 7.41 (d, J = 7.6 Hz, 2H), 7.08 (d,
J = 7.6 Hz, 2H), 7.00-6.92 (m, 4H), 5.88 (s, 1H), 4.22 (q, J =
7.2Hz, 1H), 2.60 (s, 3H), 2.30 (s, 3H), 1.88 (d, J = 7.2Hz,
3H); 13C{1H} NMR δ 170.1, 143.7, 138.7, 136.6, 132.1 (q, J
= 32.5 Hz), 129.3, 128.8, 126.5, 125.7 (q, J = 2.5 Hz), 123.7
(q, J = 275 Hz), 56.7, 27.1, 21.4, 19.4 (one of the aliphatic
carbons was overlapping with one of CDCl3 peaks); 19F
[α]27D –139.3 (c = 0.68, CHCl3).
(2S,5S)-3-Benzyl-2,5-diphenyl-1-tosylimidazolidin-4-one
(2i’). Isolated by PTLC (Rf = 0.5; dichloromethane = 9/1) as
a white solid (22%, 10.6 mg): mp 114 ºC; 1H NMR δ 7.44-
7.52 (m, 2H), 7.35-7.45 (m, 3H), 7.20-7.35 (m, 10H), 7.06
(d, J = 7.9 Hz, 2H), 6.90 (d, J = 7.3 Hz, 2H), 5.81 (s, 1H),
5.25 (s, 1H), 5.00 (d, J = 14.8 Hz, 1H), 3.37 (d, J = 14.8 Hz,
1H), 2.38 (s, 3H); 13C{1H} NMR δ 167.8, 144.3, 136.1,
135.4, 134.6, 134.3, 130.0, 129.9, 129.0, 129.0, 128.6,
128.5, 128.3, 128.3, 128.2, 127.6, 127.3, 75.3, 63.7, 44.4,
21.7; HRMS (ESI, positive) calcd for C29H27N2O3S [M+H]+
483.1737; found 483.1732.
NMR
δ
-62.7; HRMS (ESI, positive) calcd for
C19H20F3N2O3S [M+H]+ 413.1141; found 413.1136.
(2S,5S)-3-Butyl-5-methyl-2-propyl-1-tosylimidazolidin-4-one
(2n). Isolated by PTLC (Rf = 0.5; hexane/ethyl acetate =
7/3) as a brown solid (31%, 14.0 mg): mp 80 ºC; 1H NMR δ
7.80-7.75 (m, 2H), 7.28-7.35 (m, 2H), 5.24 (s, 1H), 3.98 (q,
J = 7.0 Hz, 1H), 3.72-3.80 (m, 1H), 2.68-2.78 (m, 1H), 2.42
(s, 3H), 2.10-2.20 (m, 1H), 1.40-1.70 (m, 6H), 1.17-1.30 (m,
3H), 0.68-1.11 (m, 7H); 13C{1H} NMR δ 170.3, 143.9, 138.4,
129.9, 126.9, 73.5, 57.1, 39.6, 34.2, 29.0, 21.6, 20.0, 18.0,
14.7, 13.7, 13.5; HRMS (ESI, positive) calcd for
3-Benzyl-5,5-dimethyl-2-phenyl-1-tosylimidazolidin-4-one
(2j). Isolated by PTLC (Rf = 0.4; hexane/ethyl acetate = 7/3)
as a white solid (77%, 33.5 mg): mp 97 ºC; 1H NMR δ 7.22-
7.35 (m, 4H), 7.10-7.18 (d, 2H), 7.06 (d, J = 7.8 Hz, 2H),
6.96-7.02 (m, 4H), 6.88 (d, J = 8.2 Hz, 2H), 5.62 (s, 1H),
5.02 (d, J = 14.8 Hz, 1H), 3.21 (d, J = 14.8 Hz, 1H), 2.27 (s,
3H), 1.80 (d, J = 4.2 Hz, 6H); 13C{1H} NMR δ 172.6, 142.9,
138.5, 135.0, 134.6, 129.7, 129.0, 129.0, 128.9, 128.6,
128.3, 128.2, 127.2, 74.3, 65.3, 43.6, 25.9, 25.5, 21.4;
HRMS (ESI, positive) calcd for C25H27N2O3S [M+H]+
435.1737; found 435.1731.
C18H29N2O3S [M+H]+ 353.1893; found 353.1889. [α]25
D
+31.8 (c = 0.35, CHCl3).
(2R,5S)-3-Butyl-5-methyl-2-propyl-1-tosylimidazolidin-4-one
(2n’). Isolated by PTLC (Rf = 0.6; hexane/ethyl acetate =
1
7/3) as brown oil (28%, 12.7 mg): H NMR δ 7.80-7.63 (m,
2H), 7.28-7.37 (m, 2H), 5.24 (s, 1H), 3.98 (q, J = 7.0 Hz,
1H), 3.58-3.63 (m, 1H), 2.62-2.68 (m, 1H), 2.42 (s, 3H),
1.90-1.98 (m, 1H), 1.42-1.64 (m, 5H), 1.10-1.37 (m, 3H),
1.07-1.20 (m, 1H), 0.68-1.11 (m, 7H); 13C{1H} NMR δ 170.0,
144.7, 133.1, 130.2, 127.9, 73.3, 57.0, 39.6, 36.2, 28.8,
21.7, 19.7, 19.7, 15.9, 13.9, 13.7; HRMS (ESI, positive)
calcd for C18H29N2O3S [M+H]+ 353.1893; found 353.1889.
(2S,5S)-3,5-Dimethyl-2-phenyl-1-tosylimidazolidin-4-one
(2k). Isolated by PTLC (Rf = 0.6; hexane/ethyl acetate =
3/2) as a yellow solid (56%, 19.3 mg): mp 108 ºC; 1H NMR δ
7.54 (d, J = 7.8 Hz, 2H), 7.35-7.42 (m, 3H), 7.29-7.35 (m,
2H), 7.23 (d, J = 8.2 Hz, 2H), 5.71 (s, 1H), 4.18 (q, J = 7.0
Hz, 1H), 2.56 (s, 3H), 2.40 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H);
13C{1H} NMR δ 169.8, 144.5, 137.0, 134.7, 130.0, 129.8,
129.1, 127.7, 127.6, 77.6, 56.6, 27.3, 21.6, 19.9; HRMS
(ESI, positive) calcd for C18H21N2O3S [M+H]+ 345.1267;
(2S)-2-Methyl-1-tosylhexahydroimidazo[1,2-a]pyridin-3(2H)-
one (2o). Isolated by PTLC as a diastereomeric mixture in
solid form (Rf = 0.4; hexane/ethyl acetate = 3/2) as yellow
oil (42%, 13.0 mg). Physical properties of the
diastereomeric mixture are shown. 1H NMR δ 7.67-7.77 (m,
2H), 7.28-7.38 (m, 2H), 4.86-4.94 (m, 0.54×1H), 4.61 (d, J =
3.7 Hz, 10.2 Hz, 0.46×1H), 4.18-4.26 (m, 0.54×1H), 4.07-
4.15 (m, 0.46×1H), 4.00-4.07 (m, 0.54×1H), 3.87 (q, J = 6.8
Hz, 0.46×1H), 2.68-2.78 (m, 0.54×1H), 2.50-2.67 (m, 1H),
2.39-2.49 (m, 3H + 0.46×1H), 1.86-1.99 (m, 1H), 1.59-1.72
(m, 1H), 1.20-1.59 (m, 5H + 0.46×1H), 1.07-1.20 (m,
0.54×1H); 13C{1H} NMR δ 168.3, 168.1, 144.8, 144.0, 138.1,
133.3, 130.0, 129.9, 127.8, 127.2, 73.2, 72.9, 56.7, 56.3,
40.5, 40.4, 36.4, 32.8, 24.0, 24.0, 22.5, 22.4, 21.7, 21.6,
20.5, 18.2; HRMS (ESI, positive) calcd for C15H21N2O3S
[M+H]+ 309.1267; found 309.1260.
found 345.1264. [α]25D –72.5 (c = 0.69, CHCl3).
(2R,5S)-3,5-Dimethyl-2-phenyl-1-tosylimidazolidin-4-one
(2k’). Isolated by PTLC (Rf = 0.7; hexane/ethyl acetate =
3/2) as a white solid (35%, 12.1 mg): mp 134 ºC; 1H NMR δ
7.29-7.35 (m, 1H), 7.19 (dd, J = 7.7 Hz, 7.7 Hz, 2H), 7.03
(d, J = 7.7 Hz, 2H), 6.94-6.99 (m, 4H), 5.85 (s, 1H), 4.12 (q,
J = 7.0 Hz, 1H), 2.59 (s, 3H), 2.32 (s, 3H), 1.76 (d, J = 6.7
Hz, 3H); 13C{1H} NMR δ 170.1, 143.2, 136.3, 134.8, 129.8,
129.2, 128.8, 128.4, 126.8, 78.0, 56.3, 27.1, 21.5, 19.3;
HRMS (ESI, positive) calcd for C18H21N2O3S [M+H]+
345.1267; found 345.1263.
(2S,5S)-3,5-Dimethyl-1-tosyl-2-(4-
(trifluoromethyl)phenyl)imidazolidin-4-one (2l). Isolated by
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Hz, 1H), 3.22-3.12 (m, 1H), 3.10-3.02 (m, 1H), 2.43 (s, 3H),
1
2
3
4
5
6
7
8
(2S)-2-Methyl-1-tosylhexahydro-3H-imidazo[2,1-
c][1,4]oxazin-3-one (2p). Isolated by PLTC as
1.76 (s, 3H), 1.47-1.64 (m, 7H), 1.22-1.35 (m, 6H), 0.87 (t, J
= 7.2 Hz, 3H); 13C{1H} NMR δ 169.3, 143.9, 138.0, 129.8,
127.5, 81.4, 56.1, 40.5, 31.4, 29.9, 29.0, 26.9, 25.5, 22.6,
21.6, 20.4, 14.0; HRMS (ESI, positive) calcd for
a
diastereomeric mixture (Rf = 0.5; hexane/ethyl acetate =
1/1) as a brown solid (44%, 13.7 mg). Physical properties of
1
the mixture are shown. H NMR δ 7.71-7.77 (m, 2H), 7.32-
C19H31N2O3S [M+H]+ 367.2050; found 367.2047. [α]24
D
7.40 (m, 2H), 4.93-4.98 (m, 0.69×1H), 4.69-4.73 (m,
0.31×1H), 4.52-4.58 (m, 0.69×1H), 4.34-4.39 (m, 0.31×1H),
4.14-4.20 (m, 0.69×1H), 4.07-4.13 (m, 0.69×1H), 3.94-3.99
(m, 0.31×1H), 3.82-3.90 (m, 1H + 0.31×1H), 3.25-3.33 (m,
1H), 3.05-3.17 (m, 1H + 0.69×1H), 2.96-3.05 (m, 0.31×1H),
2.46 (s, 0.31×3H), 2.45 (s, 0.69×3H + 0.31×3H), 1.58 (d, J =
7.1 Hz, 0.31×3H), 1.45 (d, J = 6.8 Hz, 0.69×3H); 13C{1H}
NMR δ 168.4, 168.2, 145.2, 144.5, 137.4, 132.3, 130.4,
130.1, 128.0, 127.3, 73.9, 72.2, 68.9, 68.7, 65.8, 65.7, 57.0,
56.7, 40.7, 40.7, 21.7, 21.7, 20.3, 17.6; HRMS (ESI,
positive) calcd for C14H19N2O4S [M+H]+ 311.1060; found
311.1053.
+27.3 (c = 1.07, CHCl3).
(5S)-3-Benzyl-1-(mesitylsulfonyl)-5-methyl-2-
phenylimidazolidin-4-one (2u). Isolated by PTLC as a
diastereomeric mixture (Rf = 0.4; hexane/ethyl acetate =
4/1) of yellow oil (92%, 41.3 mg). Physical properties of the
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23
24
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26
27
28
29
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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
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60
1
mixture are shown. H NMR δ 7.25-7.34 (m, 4H), 7.18-7.24
(m, 1H + 0.30×1H), 7.14 (m, 0.30×1H), 6.95-7.09 (m, 3H),
6.91 (d, J = 7.2 Hz, 0.70×2H), 6.75 (s, 0.70×2H), 6.60 (s,
0.30×2H), 5.61 (s, 0.70×1H), 5.58 (s, 0.30×1H), 5.07 (d, J =
15.0 Hz, 0.70×1H), 5.03 (d, J = 15.0 Hz, 0.30×1H), 4.59 (q,
J = 7.0 Hz, 0.30×1H), 4.47 (q, J = 7.0 Hz, 0.70×1H), 3.39 (d,
J = 15.0 Hz, 0.70×1H), 3.19 (d, J = 15.0 Hz, 0.30×1H), 2.38
(s, 0.30×6H), 2.36 (s, 0.70×6H), 2.20 (s, 0.70×3H), 2.14 (s,
0.30×3H), 1.66 (d, J = 7.0 Hz, 0.30×3H), 1.40 (d, J = 7.0 Hz,
0.70×3H); 13C{1H} NMR δ 170.5, 170.5, 144.1, 142.7, 141.2,
139.5, 136.3, 135.1, 134.6, 134.5, 133.5, 132.0, 131.8,
130.6, 129.7, 129.4, 129.0, 128.6, 128.3, 128.2, 128.1,
127.4, 74.8, 74.3, 58.4, 55.4, 44.3, 43.5, 22.6, 22.6, 21.0,
20.8, 19.2, 17.4 (4 pairs of aromatic carbons are
overlapping); HRMS (ESI, positive) calcd for C26H29N2O3S
[M+H]+ 449.1893; found 449.1889.
(2S)-2-Methyl-1-tosyloctahydro-3H-imidazo[1,2-a]azepin-3-
one (2q). Isolated by flash column chromatography
(hexane/ethyl acetate = 1/1), Rf = 0.5). The title compound
was obtained as a white diastereomeric mixture in solid
form (78%, 24.2 mg). Physical properties of the mixture are
1
shown. H NMR δ 7.68-7.76 (m, 2H), 7.35 (d, J = 7.9 Hz,
0.45×2H), 7.31 (d, J = 7.9 Hz, 0.55×2H), 5.21-5.16 (m,
0.55×1H), 4.96-4.91 (m, 0.45×1H), 4.15 (q, J = 7.2 Hz,
0.55×1H), 3.88-3.78 (m, 1H), 3.70-3.61 (m, 0.45×1H), 2.98-
2.94 (m, 0.55×1H), 2.87-2.83 (m, 0.45×1H), 2.43 (s,
0.45×3H), 2.42 (s, 0.55×3H), 2.25-2.08 (m, 2H), 1.84-1.65
(m, 1H), 1.68-1.43 (m, 7H), 1.43-1.31 (m, 1H); 13C{1H} NMR
δ 170.1, 169.8, 144.8, 143.9, 138.6, 133.0, 130.3, 129.9,
128.0, 127.1, 75.2, 75.0, 57.0, 56.6, 42.1, 41.7, 38.6, 34.5,
29.0, 28.6, 26.7, 26.7, 23.0, 22.7, 21.7, 21.6, 20.3, 17.7;
HRMS (ESI, positive) calcd for C16H23N2O3S [M+H]+
323.1424; found 323.1418.
(2S,5S)-3-Benzyl-5-methyl-1-((2-nitrophenyl)sulfonyl)-2-
phenylimidazolidin-4-one (2v). Isolated by flash column
chromatography (hexane/ethyl acetate = 1/1), Rf = 0.5). The
title compound was obtained as yellow oil (51%, 22.9 mg)
yield). 1H NMR δ 7.66 (dd, J = 7.7, 7.7 Hz, 1H), 7.59 (d, J =
8.0 Hz, 1H), 7.46-7.53 (m, 2H), 7.36-7.43 (m, 3H), 7.21-7.32
(m, 5H), 6.97 (d, J = 7.8 Hz, 2H), 5.87 (s, 1H), 5.05 (d, J =
14.8 Hz, 1H), 4.41 (q, J = 6.9 Hz, 1H), 3.43 (d, J = 14.8 Hz,
1H), 1.70 (d, J = 6.9 Hz, 3H) 13C{1H} NMR δ 169.4, 136.1,
134.6, 134.5, 131.6, 130.5, 130.3, 130.1, 129.3, 129.0,
128.5, 128.2, 127.7, 124.3, 75.2, 57.0, 44.2, 19.9 (two
aromatic peaks are overlapping); HRMS (ESI, positive)
calcd for C23H22N3O5S [M+H]+ 452.1275; found 452.1276.
(S)-3-Isopropyl-2,2,5-trimethyl-1-tosylimidazolidin-4-one
(2r). Isolated by PTLC (Rf = 0.3; toluene/ethyl acetate = 9/1)
as yellow oil (94%, 34.7 mg). 1H NMR δ 7.74 (d, J = 7.9 Hz,
2H), 7.31 (d, J = 7.9 Hz, 2H), 3.88 (q, J = 7.0 Hz, 1H), 3.29
(sept, J = 6.8 Hz, 1H), 2.43 (s, 3H), 1.76 (s, 3H), 1.60 (s,
3H), 1.50 (d, J = 7.0 Hz, 3H), 1.43 (d, J = 7.0 Hz, 3H), 1.39
(d, J = 7.0 Hz, 3H); 13C{1H} NMR δ 168.7, 143.9, 137.9,
129.8, 127.5, 81.9, 56.2, 45.8, 29.5, 25.3, 21.6, 20.4, 20.1,
20.1; HRMS (ESI, positive) calcd for C16H25N2O3S [M+H]+
[α]27D –116.5 (c = 0.88, CHCl3).
(2R,5S)-3-Benzyl-5-methyl-1-((2-nitrophenyl)sulfonyl)-2-
phenylimidazolidin-4-one (2v’). Isolated by flash column
chromatography (toluene/ethyl acetate = 9/1, Rf = 0.2). The
title compound was obtained as a white solid (11%, 5.0 mg):
mp 168 ºC; 1H NMR δ 7.50 (d, J = 8.0 Hz, 1H), 7.42 (dd, J =
7.7, 7.7 Hz, 1H), 7.29-7.35 (m, 3H), 7.17-7.25 (m, 1H), 7.14-
7.6.98 (m, 7H), 6.85 (d, J = 8.0 Hz, 1H), 5.71 (s, 1H), 5.08
(d, J = 14.8 Hz, 1H), 4.86 (q, J = 7.0 Hz, 1H), 3.25 (d, J =
14.8 Hz, 1H), 1.77 (d, J = 7.0 Hz, 3H) 13C{1H} NMR δ 169.9,
134.8, 134.1, 133.9, 133.0, 131.1, 131.0, 130.4, 129.1,
129.0, 128.8, 128.4, 128.3, 123.8, 75.3, 58.6, 43.5, 19.9;
HRMS (ESI, positive) calcd for C23H22N3O5S [M+H]+
452.1275; found 452.1276.
325.1580; found 325.1574. [α]26D +31.8 (c = 0.98, CHCl3).
(S)-1,3-Dimethyl-4-tosyl-1,4-diazaspiro[4.5]decan-2-one
(2s). Isolated by flash column chromatography
(hexane/ethyl acetate = 1/1, Rf = 0.5). The title compound
was obtained as a white solid (82%, 27.6 mg): mp 100 ºC;
1H NMR δ 7.71 (d, J = 7.8 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H),
4.10 (q, J = 6.8 Hz, 1H), 3.11 (s, 3H), 2.86-2.76 (m, 1H),
2.70-2.61 (m, 1H), 2.42 (s, 3H), 2.08-2.01 (m, 1H), 1.98-
1.82 (m, 2H), 1.76-1.60 (m, 4H), 1.52 (d, J = 6.7 Hz, 3H),
1.43-1.55 (m, 1H); 13C{1H} NMR δ 170.1, 143.8, 139.2,
129.8, 127.1, 82.9, 56.8, 39.8, 33.8, 29.7, 23.8, 23.7, 23.6,
21.6, 21.1; HRMS (ESI, positive) calcd for C17H25N2O3S
[M+H]+ 337.1580; found 337.1575. [α]24 +38.7 (c = 0.64,
Gram-scale
methylphenyl)sulfonamido)-3-phenylpropanamide (1a) (1.05
g, 2.10 mmol), bis(trifluoroacetoxy)iodobenzene
reaction.
(S)-N,N-Dibenzyl-2-((4-
D
CHCl3).
(PhIOCOCF3) (1083 mg, 2.52 mmol, 1.2 equiv), iodine
(106.7 mg, 0.42 mmol, 20 mol%), were placed into a
Schlenk tube equipped with a magnetic stirring bar. The
Schlenk tube was evacuated and backfilled with argon (×3).
(S)-3-Hexyl-2,2,5-trimethyl-1-tosylimidazolidin-4-one
(2t).
Isolated by PTLC as yellow oil (Rf = 0.6; hexane/ethyl
1
acetate = 2/1) of yellow oil (69%, 25.3 mg). H NMR δ 7.74
(d, J = 7.8 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 3.98 (q, J = 7.2
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Page 12 of 14
(1) (a) Mehta, N. B.; Diuguid, C. A. R.; Soroko, F. E. Potential
To the reaction vessel was added dichloroethane (14.7 mL).
The Schlenk was capped and the solution was stirred for 24
h at 0 ºC (ice bath temperature) under 27 W fluorescent
light irradiation. The crude material was then purified using
silica gel chromatography to obtain a mixture of (2S,5S)-
3,5-dibenzyl-2-phenyl-1-tosylimidazolidin-4-one (2a) and
(2R,5S)-3,5-dibenzyl-2-phenyl-1-tosylimidazolidin-4-one
(2a’) in 76% (790.2 mg) yield.
Anticonvulsants. 1, 5-Benzylhydantoins. J. Med. Chem., 1981, 24,
465. (b) Chazeau, V.; Cussac, M.; Boucherle, A. Eur. J. Med. Chem.
1992, 27, 615. (c) Al-Obaid, A. M.; El-Subbagh, H. I.; Khodair, A. I.;
Elmazar, M. M. A. 5-Substituted-2-thiohydantoin Analogs as a Novel
Class of Antitumor Agents. Anti-Cancer Drugs 1996, 7, 873. (d)
Cordi, A.; Lacoste, J.-M.; Audinot, V.; Millan, M. Design, Synthesis
and Structure-activity Relationships of Novel Strychnine-insensitive
Glycine Receptor Ligands. Bioorg. & Med. Chem. Lett. 1999, 9,
1409. (e) Barrow, J. C.; Rittle, K. E.; Ngo, P. L.; Selnick, H. G.;
Graham, S. L.; Pitzenberger, S. M.; McGaughey, G. B.; Colussi, D.;
Lai, M.-T.; Huang, Q.; Tugusheva, K.; Espeseth, A. S.; Simon, A. J.;
Munshi, S. K.; Vacca, J. P. Design and Synthesis of 2,3,5-Substituted
Imidazolidin-4-one Inhibitors of BACE-1. ChemMedChem 2007, 2,
995.
(2) For a review, see: (a) Lerais, G.; MacMillan, D. W. C. Modern
Strategies in Organic Catalysis: The Advent and Development of
Iminium Activation. Aldrichim. Acta 2006, 39, 93. For examples, see:
(b) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. New
Strategies for Organic Catalysis: The First Highly Enantioselective
Organocatalytic Diels-Alder Reaction. J. Am. Chem. Soc. 2000, 122,
4243. (c) Jen, W. S.; Wiener, J. J. M; MacMillan, D. W. C. New
Strategies for Organic Catalysis: The First Enantioselective
Organocatalytic 1,3-Dipolar Cycloaddition. J. Am. Chem. Soc. 2000,
122, 9874. (d) Paras, N. A.; MacMillan, D. W. C. New Strategies for
Organic Catalysis: The First Enantioselective Organocatalytic
Friedel-Crafts Alkylation. J. Am. Chem. Soc. 2001, 123, 4370. (e)
Northrup, A. B., MacMillan, D. W. C. The First General
Enantioselective Catalytic Diels-Alder Reaction with Simple α,β-
Unsaturated Ketones. J. Am. Chem. Soc. 2002, 124, 2458. (f) Huang,
Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. W. C.
Enantioselective Organo-Cascade Catalysis. J. Am. Chem. Soc. 2005,
127, 15051. (g) Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C.
Enantioselective α-Trifluoromethylation of Aldehydes via Photoredox
Organocatalysis. J. Am. Chem. Soc. 2009, 131, 10875.
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Deprotection of tosyl group. Magnesium turnings (1.0 mmol,
20 equiv) were added to a solution of (2S,5S)-3,5-dibenzyl-
2-phenyl-1-tosylimidazolidin-4-one (2a) (0.05 mmol, 1.0
equiv) in dry methanol (0.25 mL). The reaction mixture was
placed in an ultrasound bath and subjected to ultrasonic
irradiation for 30 min at rt. The magnesium turnings were
then filtered off, and washed with methanol, then
concentrated under reduced pressure. The residue was
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60
purified
by
PTLC
to
give
(5S)-3,5-dibenzyl-2-
phenylimidazolidin-4-one (3) as white solid in 98% yield
(16.8 mg). The spectra data of compound 3 were matched
with those in the literature.17
3-Benzyl-2,6-diphenyl-1-tosyltetrahydropyrimidin-4(1H)-one
(5).
Isolated
by
flash
column
chromatography
(dichloromethane/ethyl acetate = 60/1), Rf = 0.5). The title
compound was obtained as a white solid (65%, 32.3 mg):
1
mp 174 ºC; H NMR δ 7.15-7.40 (m, 12H), 7.03-7.15 (m,
5H), 6.88-6.96 (m, 2H), 6.59 (s, 1H), 4.88-4.99 (m, 2H),
4.06 (d, J = 14.6 Hz, 1H), 2.66-2.75 (m, 1H), 2.37-2.47 (m,
4H); 13C{1H} NMR δ 168.5, 144.3, 140.0, 137.7, 135.9,
135.4, 130.1, 129.7, 129.0, 128.7, 128.4, 128.4, 128.3,
127.7, 127.7, 127.0, 126.8, 71.6, 57.4, 49.8, 37.8, 21.7;
HRMS (ESI, positive) calcd for C30H29N2O3S [M+H]+
497.1893; found 497.1884.
(3) Koizumi, Y.; Arai, M.; Tomoda, H.; Omura, S. Oxaline, a
Fungal Alkaloid, Arrests the Cell Cycle in M Phase by Inhibition of
Tubulin Polymerization. BioChim. Biophys. Acta, Mol. Cell Res.
2004, 1693, 47.
ASSOCIATED CONTENT
Supporting Information
(4) For a review, see: (a) Blackmore, T. R.; Thompson, P. E.
Imidazolidn-4-ones: Their Synthesis and Applications. Heterocycles
2011, 83, 1953. For recent examples on synthesis of achiral 4-
imidazolidinones, see: (b) Liu, J.; Zhao, M., Qian, K.; Zhang, X.; Lee,
K.-H.; Wu, J.; Liu,Y.-N.; Peng, S. Benzyl 1,2,3,5,11,11a-Hexahydro-
3,3-dimethyl-1-oxo-6H-imidazo[3’,4’:1,2]pyridine[3,4-b]indole-2-
substituted Acetates: One-pot-preparation, Antitumor Activity,
Docking Toward DNA and 3D QSAR Analysis. Bioorg. Med. Chem.
Lett. 2010, 18, 1910. (c) Ross, T. M.; Battista, K.; Bignan, G. C.;
Brenneman, D. E.; Connolly, P. J.; Liu, J.; Middleton, S. A.; Orsini,
M.; Reitz, A. B.; Rosenthal, D. I.; Scott, M. K.; Vaidya, A. H. A
Selective Small Molecule NOP (ORL-1-Receptor) Partial Agonist for
the Treatment of Anxiety. Bioorg. Med. Chem. Lett. 2015, 25, 602.
(d) Attoresi, C. I.; Bonifazi, E. L.; Ramírez, J. A.; Gola, G. F. One-
step Synthesis of N,N’-Substituted 4-Imidazolidinones by an
Isocyanide-based Pseudo-five-multicomponent Reaction. Org.
Biomol. Chem. 2018, 16, 8944. (e) Buev, E. M.; Moshkin, V. S.;
Sosnovskikh, V. Y. Reaction of N-Methylazomethine Ylide with
Aroyl Azide: Synthesis of Imidazolidin-4-ones. Tetrahedron Lett.
2019, 60, 773. (f) Liu, Y.; Wu, J.; Jin, Z.; Jiang, H. Synthesis of 1,2-
Fused Bicyclic Imidazolidin-4-ones by Redox-Neutral Cyclization
Reaction of Cyclic Amines and α-Ketoamides. Synlett 2018, 29, 1061.
(g) Eyilcim, O.; Issever, S.; Ocal, N.; Gronert, S.; Erden, I.
Imidazolidin-4-ones via (3+2) Cycloadditions of Aza-Oxyallyl
Cations onto (E)-N-Arylideneanilides. Tetrahedron Lett. 2018, 59,
3674. (h) Zhao, X.; Liang, S.; Fan, X.; Yang, T.; Yu, W. Iron-
Catalyzed Intramolecular C-H Amination of α-Azidyl Amides. Org.
Lett. 2019, 21, 1559.
The Supporting Information is available free of charge on
the ACS Publications website at DOI: 10.1021/acs.joc.
NMR spectra charts of the starting materials and products
are provided.
AUTHOR INFORMATION
Corresponding Authors
* E-mail: kanyiva.skm@aoni.waseda.jp
* E-mail: tshibata@waseda.jp
ORCID
Kyalo Stephen Kanyiva: 0000-0001-9546-8367
Takanori Shibata: 0000-0003-4436-8264
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank Ms. Shen Wenyin for some initial experiments.
This work was supported financially by a Grant-in-Aid for
Scientific Research (C) (No. 18K05114) from JSPS and
Waseda University grants for Special Research Projects
(Project Nos. 2018K-296 and 2018B-200).
(5) (a) Naef, R.; Seebach, D. Herstellung Enantiomerenreiner cis-
oder trans-Koncfigurierter 2-(tert-Butyl)-3-methylimidazolidin-4-one
aus den Aminosäuren (S)-Alanin, (S)-Phenylalanin, (R)-Phenylglycin,
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