Synthesis of Five-Membered Cyclic Guanidines via Cascade [3 + 2] Cycloaddition of α-Haloamides with Organo-cyanamides

Article abstract of DOI:10.1021/acs.joc.0c02932

The convenient preparation of N2-unprotected five-membered cyclic guanidines was achieved through a cascade [3 + 2] cycloaddition between organo-cyanamides and α-haloamides under mild conditions in good to excellent yields (up to 99%). The corresponding cyclic guanidines could be easily transformed into hydantoins via hydrolysis.

Full text of DOI:10.1021/acs.joc.0c02932

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Synthesis of Five-Membered Cyclic Guanidines via Cascade [3 + 2]
Cycloaddition of α‑Haloamides with Organo-cyanamides
Chuan-Chuan Wang,∥ Ya-Li Qu,∥ Xue-Hua Liu, Zhi-Wei Ma, Bo Yang, Zhi-Jing Liu, Xiao-Pei Chen,
and Ya-Jing Chen*
Cite This: J. Org. Chem. 2021, 86, 3546−3554
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ABSTRACT: The convenient preparation of N2-unprotected five-
membered cyclic guanidines was achieved through a cascade [3 + 2]
cycloaddition between organo-cyanamides and α-haloamides under mild
conditions in good to excellent yields (up to 99%). The corresponding
cyclic guanidines could be easily transformed into hydantoins via
hydrolysis.
efficient and practical procedures to construct cyclic guanidine
architectures has attracted considerable attention over the past
decades.
INTRODUCTION
■
Among the vast array of nitrogen-containing heterocycles,
cyclic guanidines are particularly fascinating motifs because of
their characteristic applications in many fields (Figure 1),
Traditional methods for synthesizing five-membered cyclic
guanidines include (i) cyclization guanidination of acyclic
guanidines or amino amidines; (ii) amination of 2-chloro-1,3-
imidazolium chloride; (iii) cycloguanidination of 1,2-diamine
derivatives; and (iv) cycloguanidination of amines with
guanidination reagents such as carbodiimides, thioureas, and
isothioureas.8 These classical methods for guanidine synthesis
often have drawbacks such as limited availability of starting
materials, low yields, harsh conditions, and generation of
undesired byproducts. Recently, transition-metal-promoted
intramolecular C−N bond formation via hydroamination,9
carboamination,10 diamination,11 and haloamination12 of N-
propargylguanidines or N-allylguanidines have become power-
ful synthetic strategies to construct cyclic guanidines (Scheme
1A, eq 1). Besides, cycloguanidination of alkenes has emerged
as an efficient route for the synthesis of five-membered cyclic
guanidines (Scheme 1A, eq 2).13 However, these approaches
always afford cyclic guanidines bearing protecting groups on
the N2 position, and it is sometimes quite challenging to
remove the protecting groups. In addition, Lin reported the
construction of 2-aminoimidazolidinone via the [3 + 2]
cycloaddition between chloroacetamide and 3,4-dichlorophe-
nylcyanamide sodium salt generated from 3,4-dichlorophenyl-
cyanamide using sodium metal in absolute ethanol (Scheme
Figure 1. Representative examples of natural compounds, synthetic
bioactive compounds, and organocatalysts containing cyclic guanidine
scaffolds.
including (i) serving as building blocks in various natural
products, pharmaceuticals, agrochemicals, and so on;1 (ii)
serving as organic superbases in many base-catalyzed
reactions;2 (iii) serving as good supporting ligands in
organometallic and coordination chemistry;3 and (iv) serving
as chiral guanidine catalysts in asymmetric synthesis.4 For
example, saxitoxin, isolated from the toxic mussels Mytilus
californianus, is an inhibitor of voltage-gated sodium channels.5
Palau’amine, a pyrrole-imidazole alkaloid isolated from the
marine sponge Stylotella agminata, has garnered much
attention due to its significant biological properties such as
immunosuppressive and antitumor activities.6 Imidacloprid is a
famous neonicotinoid insecticide for crop protection and
animal health usages.7 In consequence, the development of
Received: December 13, 2020
Published: February 4, 2021
https://dx.doi.org/10.1021/acs.joc.0c02932
© 2021 American Chemical Society
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a
Scheme 1. Previous Works and General Outline of the
Cycloaddition Strategy Employed Herein
Table 1. Optimization of the Reaction Conditions
b
entry
base
T (oC)
time (h)
yield (%)
1
2
3
4
5
6
TBAF
CsF
CsF/18-crown-6
K2CO3
KOH
Et3N
CsF/18-crown-6
CsF/18-crown-6
CsF/18-crown-6
CsF/18-crown-6
25
25
25
25
25
25
25
25
0
0.5
6
57
39
70
trace
trace
trace
68
64
96
89
0.5
24
24
24
0.5
4
c
7
8
d
9
10
1.5
4
−10
a
Unless otherwise specified, all reactions were performed with 0.26
mmol of 1a, 0.2 mmol of 2a, and 0.55 mmol of base in 2.0 mL of
b
CH3CN, and the molar ratio of CsF:18-crown-6 is 1:1. Isolated
c
d
yield. 2.0 mL of CH2Cl2 was used. 2.0 mL of THF was used.
96% yield at 0 °C albeit with prolonged reaction time (entry
9). A further decreased reaction temperature (−10 °C) had
detrimental effect (entry 10).
1A, eq 3).14 Nevertheless, further exploration of new methods
to construct N2-position unprotected cyclic guanidines under
mild conditions is still highly desirable.15
With the optimized conditions in hand, we then investigated
the scope and functional group tolerance for this novel
cyclization process with a variety of cyanamides 1 and α-
haloamides 2 in the presence of CsF:18-crown-6 (1:1, 2.75
equiv) at 0 °C in CH3CN (Scheme 2). At first, cyanamides 1
with diverse substituents were tested. Overall, the reactions
proceeded smoothly to give the desired cyclic guanidines 3b−
3n in good to excellent yields (Scheme 2A), and the reaction
seemed to be insensitive to the electronic features of the aryl
substituents on the cyanamides 1. For example, cyanamides 1
substituted by either electron-donating groups (−OMe, −Me)
(1l, 1m) or electron-withdrawing groups (−F, −Cl, −Br, −I,
−COOMe, −CN, −CF3) (1e−1k) on the para-position of the
phenyl ring all smoothly underwent the cascade [3 + 2]
cycloaddition with 2a, affording the desired products 3e−3m
in excellent yields. Moreover, the steric hindrance of the aryl
substituent showed no obvious influence for meta- and para-
substituted cyanamides 1. For example, cyanamides 1
substituted by the same methyl group on meta- or para-
position both could be successfully converted into the expected
products 3c or 3m in excellent yields. However, for ortho-
substituted cyanamide, the reaction yield seemed to be
sensitive to the steric hindrance of the substituent. For
example, o-F-substituted cyanamide 1b led to the desired cyclic
guanidine 3b in decreased yield, compared to p-F-substituted
cyanamide 1e. Additionally, ring-condensed naphthyl derived
cyanamide 1n was also an applicable substrate, offering the
corresponding cyclic guanidine 3n in 94% yield. Moreover, we
also studied the reactivity of N-tosylcyanamide 1 bearing an
alkyl substitute, such as n-butyl. Unfortunately, there was no
reaction under the current conditions, and the raw materials
were recovered.
More recently, Moses and Sharma found that N-tosyl-N-aryl
cyanamides (NCTS) could readily generate organo-cyanamide
anions via fluoride-promoted desulfonylation under mild
conditions.16 On the other hand, N-alkoxy α-haloamides
have emerged as attractive reactants in [3 + m] cycloadditions
for the synthesis of various nitrogen-containing heterocycles.17
Our previous work clearly demonstrated that N-alkoxy α-
haloamides could undergo [3 + 2] annulation via a tandem
addition/intramolecular SN2 cyclization procedure.18 Driven
by our strong interest in developing efficient cycloaddition
protocols to construct nitrogen-containing heterocycles,19 we
conceived that NCTS and α-haloamides could undergo a
cascade SN2/5-exo-dig cyclization sequence, building two new
C−N bonds and leading to five-membered cyclic guanidines
(Scheme 1B, eq 4).
RESULTS AND DISCUSSION
■
To evaluate the feasibility of this proposed cascade reaction, N-
tosyl-N-phenyl cyanamide 1a and N-benzyloxy α-bromoaceta-
mide 2a were elected to optimize the reaction conditions
(Table 1). Encouragingly, the target cyclic guanidine 3a could
be obtained in 57% yield while using TBAF as the base (entry
1). This elegant transformation validated the cascade cyclo-
addition pathway was a viable strategy for the synthesis of
cyclic guanidines. While replacing TBAF with CsF, the target
cyclic guanidine 3a was generated in a reduced yield (entry 2).
However, the addition of 18-crown-6 dramatically elevated the
yield to 70% and the reaction time could be reduced to 0.5 h
(entry 3). Unsuprisingly, only a trace amount of cyclic
guanidine 3a was obtained using nonfluorinated bases such
as K2CO3, KOH, and Et3N (Table 1, entries 4−6). Next, we
also investigated the influence of different solvent. Whether the
reaction was conducted in CH2Cl2 or THF, 3a was both
obtained in slightly lower yields (entries 7 and 8). To further
optimize the conditions, the reaction was conducted at a lower
temperature, and the desired product 3a could be obtained in
Inspired by these results, we next explored the scope and
limitation of various α-haloamides 2 (Scheme 2B). When α-
chloroacetamide was applied to this cycloaddition procedure,
the desired product 3a also could be obtained in 31% yield.
The substituent of α-substituted α-bromoamide 2 showed
significant impact on its reactivity. Unfortunately, when α-
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a
Scheme 2. Scope of the Reaction
Scheme 3. Gram-Scale Synthesis of 3a
icals.20 For example, phenytoin is an anticonvulsant and
antiarrhythmic drug that was first commercialized by Pfizer in
1951 (Scheme 4). Due to the importance of hydantoins in
a
Scheme 4. Hydrolysis of Cyclic Guanidines to Hydantoins
a
Unless otherwise noted, all reactions were performed with 0.3 mmol
of 3, 2.4 mmol of NaNO2, and 6.0 mmol of AcONa in 5.0 mL of 50%
b
AcOH at room temperature. The listed yield is isolated yield. The
structure was confirmed by X-ray diffraction analysis.
a
Unless otherwise noted, all reactions were performed with 0.26
mmol of 1, 0.2 mmol of 2, 0.55 mmol of CsF, and 0.55 mmol of 18-
crown-6 in 2.0 mL of CH3CN at 0 °C for 1.5 h. X = Br. The listed
medicinal chemistry, new approaches for their practical
preparation are strongly advised to supplement the existing
methods. Having successfully achieved the preparation of a
variety of cyclic guanidines, we next investigated their direct
conversion into hydantoins.
In order to access this key motif, 3a was treated with sodium
nitrite and sodium acetate in 50% acetic acid.21 To our delight,
the desired hydantoin 4a could be obtained in 73% yield. Then
a series of other hydantoins 4 were subsequently prepared in
acceptable yields following the same method (Scheme 4).
When using N-alkyl-substituted cyclic guanidines 3u and 3v as
substrates, the hydrolyzation process displayed obvious
decreased reactivities. For example, hydantoins 4u and 4v
only could be obtained in 27% and 45% yields, respectively,
along with a few unidentified byproducts. The structure of
hydantoin 4g was confirmed by single crystal X-ray diffraction
analysis (see the SI file).
Further transformations of hydantoin moieties are shown in
Scheme 5. Selective removal of Bn or BnO group from 4a was
achieved through hydrogenation over palladium−carbon or
reduction by SmI2, giving N−OH hydantoin derivative 5
(99%) or N−H hydantoin derivative 6 (91%), respectively.
In conclusion, we have developed a robust cascade [3 + 2]
cycloaddition between organo-cyanamide anions and α-
haloamides under mild conditions, thus affording a practical
and efficient route to synthesize five-membered cyclic
guanidines. Our fluoride-promoted [3 + 2] cycloaddition
reaction tolerates well a wide range of functional groups and
affords the desired products in good to excellent yields. Two
new C−N bonds could be formed in this transformation.
b
yield is isolated yield. The structure was confirmed by X-ray
diffraction analysis.
methyl α-bromoamide 2o and α,α-dimethyl α-bromoamide 2p
were used as the substrates, only a trace amount of the
corresponding products 3o and 3p could be obtained under
standard conditions, probably due to the steric hindrance and
the relatively lower reactivity. These results suggest that the
reaction occurs via a tandem intermolecular SN2/intra-
molecular 5-exo-dig cyclization process to generate five-
membered cyclic guanidines 3.18 Unsubstituted α-bromoace-
tamides 2 with different substituents (methyl, tert-butyl, 1-
naphthylmethylene) on the oxygen atom all could furnish the
desired products in excellent yields (3q−3s). To our delight,
N-alkyl protected α-bromoacetamides (2t−2x) could also
react with 1a, providing the desired cyclic guanidines 3t−3x in
excellent yields (93%−99%). Moreover, the structure of cyclic
guanidine 3g was confirmed by single crystal X-ray diffraction
analysis (see the SI file). Overall, the current cascade [3 + 2]
cycloaddition reaction could tolerate structurally diverse
substrates with different electronic features, offering a powerful
and practical approach to synthesize unprotected five-
membered cyclic guanidines.
To demonstrate the preparative utility of this cascade [3 +
2] cycloaddition, a gram-scale reaction was carried out under
the standard conditions, providing the desired cyclic guanidine
3a in a comparable yield (Scheme 3).
The hydantoin motifs are remarkable scaffolds since they are
widely spread in various natural products and pharmaceut-
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1
(2.8 g, 64% yield), mp 85−87 °C; H NMR (400 MHz, CDCl3) δ
7.72 (d, J = 8.4 Hz, 2H), 7.50−7.43 (m, 1H), 7.40−7.36 (m, 2H),
7.35−7.31 (m, 1H), 7.22 (t, J = 7.6 Hz, 1H), 7.16−7.09 (m, 1H),
2.49 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 158.1 (d,
1JC−F = 255.0 Hz), 147.1, 132.8, 132.7, 130.6, 130.4, 128.6, 125.3 (d,
Scheme 5. Transformations of Hydantoin 4a
3JC−F = 4.0 Hz), 121.8(d, JC−F = 13.0 Hz), 117.3 (d, JC−F = 19.0
2
2
Hz), 107.8, 22.0 ppm; 19F NMR (376 MHz, CDCl3) δ −118.9 ppm;
IR (KBr): v 3128, 2230, 1594, 1498, 1389, 1269, 1190, 1179, 911,
813, 766, 702, 676, 583, 543, 492 cm−1; HRMS (ESI) m/z: [M + H]+
calcd for C14H12FN2O2S 291.0598; found 291.0605.
N-Cyano-N-(m-tolyl)-4-methylbenzenesulfonamide (1c).22a This
compound was prepared via general procedure as white solid (2.3 g,
54% yield), mp 98−100 °C; 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J
= 8.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.24−7.18 (m, 2H), 7.03 (s,
1H), 6.97−6.92 (m, 1H), 2.47 (s, 3H), 2.33 (s, 3H) ppm.
N-Cyano-N-(3-nitrophenyl)-4-methylbenzenesulfonamide (1d).
This compound was prepared via general procedure as white solid
(2.5 g, 53%, yield), mp 134−136 °C; 1H NMR (400 MHz, CDCl3) δ
8.31−8.27 (m, 1H), 8.08 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.65−7.61
(m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 2.49 (s, 3H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ 148.9, 147.8, 135.9, 132.0, 131.9, 131.0, 130.8,
128.5, 124.7, 121.3, 107.8, 22.0 ppm; IR (KBr): v 3129, 2234, 1594,
1536, 1401, 1350, 1179, 1124, 1085, 847, 824, 745, 669, 587, 546
cm−1; HRMS (ESI) m/z: [M + Na]+ calcd for C14H11N3NaO4S
340.0362; found 340.0373.
N-Cyano-N-(4-fluorophenyl)-4-methylbenzenesulfonamide
(1e).22a This compound was prepared via general procedure as white
solid (3.7 g, 85% yield), mp 99−101 °C; 1H NMR (400 MHz,
CDCl3) δ 7.64 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H), 7.20−
7.14 (m, 2H), 7.11−7.03 (m, 2H), 2.48 (s, 3H) ppm.
N-(4-Chlorophenyl)-N-cyano-4-methylbenzenesulfonamide
(1f).22a This compound was prepared via general procedure as white
solid (3.9 g, 85% yield), mp 138−139 °C; 1H NMR (400 MHz,
CDCl3) δ 7.64 (d, J = 8.4 Hz, 2H), 7.39−7.33 (m, 4H), 7.16−7.12
(m, 2H), 2.48 (s, 3H) ppm.
N-(4-Bromophenyl)-N-cyano-4-methylbenzenesulfonamide
(1g).22a This compound was prepared via general procedure as white
solid (4.8 g, 91% yield), mp 143−145 °C; 1H NMR (400 MHz,
CDCl3) δ 7.64 (d, J = 8.4 Hz, 2H), 7.53−7.50 (m, 2H), 7.36 (d, J =
8.4 Hz, 2H), 7.09−7.06 (m, 2H), 2.48 (s, 3H) ppm.
N-Cyano-N-(4-iodophenyl)-4-methylbenzenesulfonamide (1h).
This compound was prepared via general procedure as white solid
(5.2 g, 87% yield), mp 155−157 °C; 1H NMR (400 MHz, CDCl3) δ
7.71 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz,
2H), 6.94 (d, J = 8.8 Hz, 2H), 2.48 (s, 3H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ 147.2, 139.2, 134.5, 132.1, 130.5, 128.5, 128.1, 108.3,
96.0 22.0 ppm; IR (KBr): v 3135, 2230, 1594, 1474, 1390, 1251,
1190, 1183, 1106, 1009, 903, 814, 703, 662, 583, 554, 536 cm−1;
HRMS (ESI) m/z: [M + H]+ calcd for C14H12IN2O2S 398.9659;
found 398.9665.
N-Cyano-N-(4-methylbenzoate)-4-methylbenzenesulfonamide
(1i). This compound was prepared via general procedure as white
solid (3.2 g, 65% yield), mp 121−123 °C; 1H NMR (400 MHz,
CDCl3) δ 8.05 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.37−
7.29 (m, 4H), 3.93 (s, 3H), 2.47 (s, 3H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ 165.7, 147.3, 138.4, 132.1, 131.4, 131.3, 130.5, 128.5,
125.7, 108.2, 52.7, 22.0 ppm; IR (KBr): v 3129, 2229, 1723, 1601,
1440, 1397, 1297, 1192, 1177, 1116, 906, 816, 768, 691, 664, 586,
561, 544 cm−1; HRMS (ESI) m/z: [M + Na]+ calcd for
C16H14N2NaO4S 353.0566; found 353.0579.
N-Cyano-N-(4-cyanophenyl)-4-methylbenzenesulfonamide (1j).
This compound was prepared via general procedure as white solid
(0.5 g, 11% yield), mp 129−131 °C; 1H NMR (400 MHz, CDCl3) δ
7.72−7.64 (m, 4H), 7.43−7.35 (m, 4H), 2.49 (s, 3H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 147.7, 138.5, 133.9, 131.9, 130.7, 128.4,
126.2, 117.4, 113.7, 107.7, 22.0 ppm; IR (KBr): v 3135, 2236, 2231,
1592, 1498, 1400, 1246, 1192, 1173, 1120, 894, 835, 819, 688, 597,
574, 555 cm−1; HRMS (ESI) m/z: [M + Na]+ calcd for
C15H11N3NaO2S 320.0464; found 320.0473.
Furthermore, subsequent hydrolysis of the cyclic guanidine
products could further offer the pharmacologically significant
hydantoins. Further expansion of new cycloaddition reactions
based on cyanamide anions generated from N-tosyl-N-aryl
cyanamides as well as investigation of the biological activities
of the produced cyclic guanidines and hydantoins are
underway in our laboratory.
EXPERIMENTAL SECTION
■
General Information. All reactions were performed in oven-dried
glassware with magnetic stirring. Unless otherwise stated, all reagents
were purchased from commercial suppliers and used without further
purification. All solvents were purified and dried according to
standard methods prior to use. Organic solutions were concentrated
1
under reduced pressure on a rotary evaporator or an oil pump. H
NMR, 13C{1H} NMR, and 19F NMR spectra were recorded at 400 or
600, 100, and 376 MHz, respectively, on a Bruker instrument.
Chemical shifts are reported in δ ppm referenced to an internal SiMe4
standard for 1H NMR and chloroform-d (δ 77.16), DMSO-d6 (δ
39.52) for 13C{1H} NMR. Data for 1H NMR are recorded as follows:
chemical shift (δ ppm), multiplicity (s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet), coupling constant (Hz), and integration. Data
for 13C{1H} NMR and 19F NMR are reported in terms of chemical
shift (δ, ppm). IR spectra were recorded using a ThermoFisher
NICOLET iS10 spectrometer (KBr disc). High-resolution mass
spectra (HRMS) were recorded on a Thermo Q-Exactive
Spectrometer (ESI source) or Waters Premier GC-TOF MS (EI
source). Reactions were monitored through thin-layer chromatog-
raphy (TLC) on silica gel-precoated glass plates. Flash column
chromatography was performed using silica gel (300−400 mesh).
α-Haloamides 2 were synthesized employing a literature
procedure.18
The Synthesis of N-tosyl-N-aryl Cyanamides 1. According to
reported methods,22 the aqueous solution of NaOCN (40 mmol, 30
mL) was added into a solution of ArNH2 in acetic acid (20 mmol, 30
mL) with continuous stirring at room temperature. The mixture was
stirred for 1 h and then concentrated under reduced pressure.
Afterward, the reaction mixture was poured into ice water (200 mL)
and stirred for additional 0.5 h. A large scale of precipitate was
therefore formed, which was then filtered, washed with water for three
times, and then recrystallized from MeOH-DCM. Finally, the pure
arylureas were isolated and used for the next step. The arylurea (15
mmol, 1 equiv) was dissolved by pyridine (10 mL, 1.5 M) in a dry
Schlenk flask. p-Toluenesulfonyl chloride (52 mmol, 3.5 equiv) was
added portionwise over several minutes at room temperature. Next,
the reaction mixture was stirred for additional 15 min and poured into
ice-cooled water (100 mL) with mechanical stirring. Precipitate
formed during mechanical stirring was filtered and washed with water.
The crude product was recrystallized from ethanol, and the pure titled
compound 1 was isolated as a white crystalline solid.
N-Cyano-N-phenyl-4-methylbenzenesulfonamide (1a).22a This
compound was prepared via general procedure as white solid (3.3 g,
81% yield), mp 85−86 °C; 1H NMR (400 MHz, CDCl3) δ 7.64−7.62
(m, 2H), 7.44−7.33 (m, 5H), 7.20−7.18 (m, 2H), 2.47 (s, 3H) ppm.
N-Cyano-N-(2-fluorophenyl)-4-methylbenzenesulfonamide (1b).
This compound was prepared via general procedure as white solid
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N-Cyano-N-(4-(trifluoromethyl)phenyl)-4-methylbenzenesulfo-
namide (1k).22a This compound was prepared via general procedure
as white solid (3.2 g, 63% yield), mp 98−99 °C; 1H NMR (400 MHz,
CDCl3) δ 7.68−7.62 (m, 4H), 7.41−7.34 (m, 4H), 2.48 (s, 3H) ppm.
N-Cyano-N-(4-methoxyphenyl)-4-methylbenzenesulfonamide
(1l).22a This compound was prepared via general procedure as white
1752, 1670, 1605, 1497, 1401, 1254, 1293, 1128, 1067, 808, 774, 743,
638, 616 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C17H18N3O2
296.1394; found 296.1380.
3-(Benzyloxy)-2-imino-1-(3-nitrophenyl)imidazolidin-4-one (3d).
This compound was prepared via the general procedure as white solid
(56 mg, 86% yield), purified by ethyl acetate:DCM = 1:50. Mp 165−
168 °C; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.10 (d, J = 7.6
Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.55−7.45 (m, 6H), 6.50 (s, 1H),
5.20 (s, 2H), 4.29 (s, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ
161.7, 149.1, 148.9, 140.3, 133.0, 130.2, 130.14, 130.11, 129.2, 123.5,
117.9, 112.6, 79.8, 48.1 ppm; IR (KBr): v 3290, 3132, 1753, 1672,
1616, 1525, 1488, 1401, 1349, 1244, 1173, 1128, 1080, 914, 858, 767,
738, 639, 615 cm−1; HRMS (ESI) m/z: [M + MeOH + H]+ calcd for
C17H19N4O5 359.1350; found 359.1329.
1
solid (3.5 g, 77% yield), mp 117−119 °C; H NMR (400 MHz,
CDCl3) δ 7.64 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.08−
7.04 (m, 2H), 6.87−6.83 (m, 2H), 3.81 (s, 3H), 2.48 (s, 3H) ppm.
N-Cyano-N-(p-tolyl)-4-methylbenzenesulfonamide (1m).22a This
compound was prepared via general procedure as white solid (3.7 g,
86% yield), mp 120−122 °C; 1H NMR (400 MHz, CDCl3) δ 7.64 (d,
J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H),
7.05 (d, J = 8.4 Hz, 2H), 2.47 (s, 3H), 2.36 (s, 3H) ppm.
N-Cyano-N-(naphthalen-2-yl)-4-methylbenzenesulfonamide
3-(Benzyloxy)-1-(4-fluorophenyl)-2-iminoimidazolidin-4-one
(3e). This compound was prepared via the general procedure as white
solid (57 mg, 95% yield), purified by ethyl acetate:hexane = 2:7. Mp
(1n). This compound was prepared via general procedure as white
1
solid (3.7 g, 77% yield), mp 124−126 °C; H NMR (400 MHz,
1
CDCl3) δ 7.87−7.76 (m, 3H), 7.72−7.67 (m, 1H), 7.66−7.61 (m,
2H), 7.60−7.53 (m, 2H), 7.34−7.28 (m, 2H), 7.27−7.24 (m, 1H),
2.46 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 146.9, 133.4,
133.2, 132.4, 131.9, 130.4, 130.2, 128.6, 128.4, 128.0, 127.9, 127.5,
126.0, 123.4, 108.9, 22.0 ppm; IR (KBr): v 3131, 2223, 1594, 1506,
1401, 1384, 1254, 1188, 1172, 964, 726, 865, 809, 755, 666, 601, 576,
549, 477 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C18H15N2O2S
323.0849; found 323.0856.
163−166 °C; H NMR (400 MHz, CDCl3) δ 7.66−7.53 (m, 2H),
7.52−7.46 (m, 2H), 7.45−7.38 (m, 3H), 7.06 (t, J = 8.4 Hz, 2H),
6.14 (s, 1H), 5.18 (s, 2H), 4.18 (s, 2H) ppm; 13C{1H} NMR (100
1
MHz, CDCl3) δ 162.5, 159.1 (d, JC−F = 252.0 Hz), 149.6, 135.2,
2
133.2, 130.1, 129.9, 129.0, 120.4, 116.0 (d, JC−F = 13.0 Hz), 79.6,
48.7 ppm; 19F NMR (376 MHz, CDCl3) δ −119 ppm; IR (KBr): v
3285, 3132, 1739, 1672, 1519, 1443, 1401, 1314, 1245, 1175, 1084,
1032, 910, 825, 759, 742, 696, 586, 504 cm−1; HRMS (ESI) m/z: [M
+ H]+ calcd for C16H15FN3O2 300.1143; found 300.1128.
General Procedure for Cascade [3 + 2] Cycloaddition. To a
10 mL test tube equipped with a magneton were sequentially added
N-tosyl-N-aryl cyanamide 1 (0.26 mmol, 1.3 equiv), α-haloamide 2
(0.2 mmol, 1 equiv), and MeCN (2.0 mL, 0.1 M). The reaction
mixture was then cooled to 0 °C in an ice water bath. Then, 18-
crown-6 (0.55 mmol, 2.75 equiv) and CsF (0.55 mmol, 2.75 equiv)
were added to the reaction mixture. The reaction mixture was stirred
for 0.5−2 h at 0 °C. Upon complete consumption of the starting
material detected by TLC, 200 mg of silica gel was added. Then, the
reaction mixture was concentrated and stored overnight at −20 °C to
make the impurity adjacent to the product disappear. Finally, the
resulting residue was purified by flash column chromatography
(hexane/EA) on silica gel to afford the pure product 3.
3-(Benzyloxy)-1-(4-chlorophenyl)-2-iminoimidazolidin-4-one
(3f). This compound was prepared via the general procedure as white
solid (52 mg, 83% yield), purified by ethyl acetate:hexane = 2:7. Mp
1
160−163 °C; H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz,
2H), 7.52−7.45 (m, 2H), 7.44−7.40 (m, 3H), 7.31 (d, J = 8.8 Hz,
2H), 6.25 (s, 1H), 5.17 (s, 2H), 4.18 (s, 2H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ 162.2, 149.3, 137.7, 133.1, 130.04, 129.98,
129.3, 129.1, 128.9, 119.7, 79.6, 48.3 ppm; IR (KBr): v 3294, 3135,
1743, 1670, 1606, 1500, 1441, 1401, 1241, 1172, 1101, 1080, 1209,
907, 821, 801, 744, 697, 572 cm−1; HRMS (ESI) m/z: [M + H]+
calcd for C16H15ClN3O2 316.0847; found 316.0834.
3-(Benzyloxy)-1-(4-bromophenyl)-2-iminoimidazolidin-4-one
(3g). This compound was prepared via the general procedure as white
solid (68 mg, 95% yield), purified by ethyl acetate:hexane = 2:9. Mp
3-(Benzyloxy)-2-imino-1-phenylimidazolidin-4-one (3a). This
compound was prepared via the general procedure as white solid
(54 mg, 96% yield), purified by ethyl acetate:hexane = 1:3. Mp 145−
1
166−168 °C; H NMR (400 MHz, CDCl3) δ 7.61−7.51 (m, 2H),
1
147 °C; H NMR (400 MHz, CDCl3) δ 7.70−7.55 (m, 2H), 7.55−
7.50−7.44 (m, 4H), 7.43−7.40 (m, 3H), 6.28 (s, 1H), 5.17 (s, 2H),
4.17 (s, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 162.2, 149.3,
138.2, 133.1, 132.2, 130.04, 129.99, 129.1, 119.8, 116.4, 79.6, 48.2
ppm; IR (KBr): v 3252, 3135, 1742, 1670, 1598, 1450, 1440, 1402,
1367, 1241, 1172, 1078, 1029, 820, 800, 745, 697, 615, 497 cm−1;
HRMS (ESI) m/z: [M + H]+ calcd for C16H1579BrN3O2 360.0342;
found 360.0325.
7.47 (m, 2H), 7.46−7.40 (m, 3H), 7.40−7.36 (m, 2H), 7.14−7.10
(m, 1H), 6.22 (s, 1H), 5.20 (s, 2H), 4.23 (s, 2H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 162.7, 149.6, 139.0, 133.2, 130.1, 129.9,
129.4, 129.0, 123.9, 118.8, 79.5, 48.5 ppm; IR (KBr): v 3284, 3135,
1740, 1672, 1601, 1505, 1436, 1401, 1308, 1240, 1174, 1085, 1403,
910, 834, 744, 697, 684, 501 cm−1; HRMS (ESI) m/z: [M + H]+
calcd for C16H16N3O2 282.1237; found 282.1225.
3-(Benzyloxy)-2-imino-1-(4-iodophenyl)imidazolidin-4-one (3h).
This compound was prepared via the general procedure as white solid
(67 mg, 83% yield), purified by ethyl acetate:hexane = 1:4. Mp 196−
3-(Benzyloxy)-1-(2-fluorophenyl)-2-iminoimidazolidin-4-one
(3b). This compound was prepared via the general procedure as white
solid (43 mg, 72% yield), purified by ethyl acetate:hexane = 4:5. Mp
1
198 °C; H NMR (400 MHz, CDCl3) δ 7.67−7.64 (m, 2H), 7.50−
1
99−101 °C; H NMR (400 MHz, CDCl3) δ 7.60−7.50 (m, 3H),
7.47 (m, 2H), 7.46−7.40 (m, 5H), 6.29 (m, 1H), 5.18 (s, 2H), 4.19
(s, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 162.2, 149.3,
138.9, 138.2, 133.1, 130.1, 130.0, 129.1, 120.3, 87.0, 79.7, 48.2 ppm;
IR (KBr): v 3298, 3130, 1769, 1673, 1589, 1493, 1441, 1401, 1248,
1179, 1128, 824, 794, 764, 747, 702, 638, 615, 505 cm−1; HRMS
(ESI) m/z: [M + H]+ calcd for C16H15IN3O2 408.0203; found
408.0183.
7.43−7.39 (m, 3H), 7.30−7.21 (m, 1H), 7.20−7.13 (m, 2H), 5.84 (s,
1H), 5.22 (s, 2H), 4.22 (s, 2H) ppm; 13C{1H} NMR (100 MHz,
1
CDCl3) δ 163.6, 160.2, 157.6 (d, JC−F = 244.0 Hz), 150.7, 133.3,
130.1, 129.8, 129.6 (d, 2JC−F = 20.0 Hz), 128.9, 128.1, 125.0 (d, 3JC−F
2
3
= 3.0 Hz), 117.1 (d, JC−F = 19.0 Hz), 79.3, 50.6 (d, JC−F = 5.0 Hz)
ppm; 19F NMR (376 MHz, CDCl3) δ −121.1 ppm; IR (KBr): v 3276,
3133, 1754, 1670, 1506, 1401, 1264, 1240, 1122, 1128, 1077, 837,
757, 694, 638, 617, 565 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for
C16H15FN3O2 300.1143; found 300.1127.
Methyl 4-(3-(Benzyloxy)-2-imino-4-oxoimidazolidin-1-yl)-
benzoate (3i). This compound was prepared via the general
procedure as white solid (56 mg, 83% yield), purified by ethyl
acetate:hexane = 2:5. Mp 191−193 °C; 1H NMR (400 MHz, CDCl3)
δ 8.03 (d, J = 8.8 Hz, 2H), 7.80−7.69 (m, 2H), 7.52−7.47 (m, 2H),
7.45−7.39 (m, 3H), 6.46 (s, 1H), 5.19 (s, 2H), 4.25 (s, 2H), 3.90 (s,
3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 166.6, 161.9, 149.1,
143.1, 133.1, 131.0, 130.1 (4C), 129.1, 124.7, 117.1, 79.7, 52.2, 48.1
ppm; IR (KBr): v 3129, 1747, 1676, 1609, 1519, 1401, 1249, 1128,
843, 826, 746, 697, 638, 615, 543 cm−1; HRMS (ESI) m/z: [M + H]+
calcd for C18H18N3O4 340.1292; found 340.1276.
3-(Benzyloxy)-2-imino-1-(m-tolyl)imidazolidin-4-one (3c). This
compound was prepared via the general procedure as white solid (52
mg, 88% yield), purified by ethyl acetate:hexane = 3:10. Mp 163−166
1
°C; H NMR (400 MHz, CDCl3) δ 7.54−7.48 (m, 2H), 7.44−7.32
(m, 5H), 7.26−7.22 (m, 1H), 6.92 (d, J = 7.2 Hz, 1H), 6.17 (s, 1H),
5.18 (s, 2H), 4.17 (s, 2H), 2.36 (s, 3H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ 162.8, 149.7, 139.4, 138.9, 133.3, 130.0, 129.8, 129.2,
129.0, 124.8, 119.6, 116.0, 79.5, 48.7, 21.8 ppm; IR (KBr): v 3132,
3550
https://dx.doi.org/10.1021/acs.joc.0c02932
J. Org. Chem. 2021, 86, 3546−3554

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
3-(Benzyloxy)-2-imino-1-(4-cyanophenyl)imidazolidin-4-one
(3j). This compound was prepared via the general procedure as white
solid (48 mg, 79% yield), purified by ethyl acetate:DCM = 1:50. Mp
163−166 °C; H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.4 Hz,
2H), 7.63 (d, J = 8.8 Hz, 2H), 7.52−7.47 (m, 2H), 7.46−7.40 (m,
3H), 6.53 (s, 1H), 5.19 (s, 2H), 4.23 (s, 2H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ 161.5, 148.9, 142.9, 133.4, 133.0, 130.14,
130.06, 129.1, 118.9, 117.7, 106.2, 79.8, 47.8 ppm; IR (KBr): v 3134,
2932, 1772, 1731, 1661, 1519, 1437, 1402, 1361, 1293, 1277, 1213,
1107, 904, 848, 763, 693 cm−1; HRMS (ESI) m/z: [M + H]+ calcd
for C17H15N4O2 307.1190; found 307.1175.
131 °C; 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 7.2 Hz, 2H), 7.39
(t, J = 7.6 Hz, 2H), 7.11 (t, J = 7.2 Hz, 1H), 6.36 (s, 1H), 4.24 (s,
2H), 1.45 (s, 9H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 165.1,
151.9, 139.3, 129.3, 123.6, 118.4, 87.9, 48.3, 27.6 ppm; IR (KBr): v
3301, 3133, 2989, 1757, 1677, 1600, 1503, 1440, 1403, 1369, 1309,
1227, 1174, 1078, 1041, 846, 748, 685, 643 cm−1; HRMS (ESI) m/z
[M + H]+ calcd for C13H18N3O2 248.1394; found 248.1381.
2-Imino-3-(naphthalen-1-ylmethoxy)-1-phenylimidazolidin-4-
one (3s). This compound was prepared via the general procedure as
white solid (53 mg, 80% yield), purified by ethyl acetate:hexane = 1:3.
Mp 120−121 °C; 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 8.4 Hz,
1H), 7.92 (t, J = 9.2 Hz, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.60−7.53 (m,
4H), 7.47 (t, J = 7.6 Hz, 1H), 7.36 (t, J = 7.6 Hz, 2H), 7.11 (t, J = 7.2
Hz, 1H), 6.11 (s, 1H), 5.67 (s, 2H), 4.24 (s, 2H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 162.8, 149.5, 139.0, 133.9, 132.4, 131.1,
129.8, 129.4, 129.2, 129.0, 127.5, 126.5, 125.3, 123.9, 123.8, 118.8,
77.3, 48.6 ppm; IR (KBr): v 3320, 3132, 1758, 1675, 1598, 1502,
1402, 1309, 1274, 1184, 1083, 1043, 928, 903, 801, 776, 752, 689,
637 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C20H18N3O2
332.1394; found 332.1375.
1
3-(Benzyloxy)-2-imino-1-(4-(trifluoromethyl)phenyl)-
imidazolidin-4-one (3k). This compound was prepared via the
general procedure as white solid (57 mg, 82% yield), purified by ethyl
acetate:hexane = 2:11. Mp 190−192 °C; 1H NMR (400 MHz,
CDCl3) δ 7.80 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.52−
7.47 (m, 2H), 7.46−7.40 (m, 3H), 6.43 (s, 1H), 5.20 (s, 2H), 4.25 (s,
2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 161.9, 149.2, 142.1,
133.1, 130.1 (3C), 129.1, 126.5 (q, 3JC−F = 4.0 Hz), 125.2 (q, 2JC−F
=
1
32.0 Hz), 124.2 (q, JC−F = 269.0 Hz), 117.6, 79.7, 48.1 ppm; 19F
NMR (376 MHz, CDCl3) δ −62.1 ppm; IR (KBr): v 3130, 1753,
1671, 1615, 1526, 1446, 1401, 1338, 1250, 1173, 1114, 1074, 844,
762, 745, 697, 638, 615 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for
C17H15F3N3O2 350.1111; found 350.1093.
3-(tert-Butyl)-2-imino-1-phenylimidazolidin-4-one (3t). This
compound was prepared via the general procedure as colorless oil
1
(43 mg, 93% yield), purified by ethyl acetate:hexane = 1:5. H NMR
(600 MHz, CDCl3) δ 7.43 (t, J = 7.8 Hz, 2H), 7.27 (d, J = 8.4 Hz,
2H), 7.24 (t, J = 7.8 Hz, 1H), 6.19 (s, 1H), 4.12 (s, 2H), 1.76 (s, 9H)
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 170.0, 156.1, 138.2, 129.9,
126.0, 123.6, 59.1, 52.5, 29.1 ppm; IR (KBr): v 3129, 2972, 1779,
1741, 1650, 1595, 1502, 1454, 1403, 1267, 1200, 1114, 1048, 912,
828, 800, 766, 716, 694, 646, 511 cm−1; HRMS (ESI) m/z: [M + H]+
calcd for C13H18N3O 232.1444; found 232.1437.
3-(Benzyloxy)-2-imino-1-(4-methoxyphenyl)imidazolidin-4-one
(3l). This compound was prepared via the general procedure as white
solid (54 mg, 87% yield), purified by ethyl acetate:hexane = 2:3. Mp
1
152−155 °C; H NMR (400 MHz, CDCl3) δ 7.55−7.48 (m, 2H),
7.47−7.39 (m, 5H), 6.92 (d, J = 8.8 Hz, 2H), 5.20 (s, 2H), 4.19 (s,
2H), 3.80 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 163.1,
156.7, 150.2, 133.3, 131.9, 130.0, 129.8, 128.9, 121.8, 114.7, 79.4,
55.6, 49.3 ppm; IR (KBr): v 3318, 3133, 2838, 1752, 1673, 1520,
1448, 1401, 1275, 1252, 1182, 1085, 1024, 949, 827, 746, 696, 616,
593 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C17H18N3O3
312.1343; found 312.1326.
3-Butyl-2-imino-1-phenylimidazolidin-4-one (3u). This com-
pound was prepared via the general procedure as white solid (45
mg, 98% yield), purified by ethyl acetate:hexane = 2:3. Mp 119−121
1
°C; H NMR (400 MHz, CDCl3) δ 7.50−7.30 (m, 4H), 7.25−7.21
(m, 1H), 5.96 (s, 1H), 4.26 (s, 2H), 3.67 (t, J = 7.6 Hz, 2H), 1.73−
1.66 (m, 2H), 1.46−1.36 (m, 2H), 0.97 (t, J = 7.6 Hz, 3H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 169.1, 154.5, 138.4, 129.9,
125.6, 122.5, 52.1, 39.5, 30.0, 20.3, 13.9 ppm; IR (KBr): v 3294, 3132,
2888, 1739, 1649, 1598, 1504, 1448, 1401, 1230, 1186, 1130, 1168,
925, 893, 755, 687, 642, 614, 473 cm−1; HRMS (ESI) m/z: [M + H]+
calcd for C13H18N3O 232.1444; found 232.1451.
3-(Benzyloxy)-2-imino-1-(p-tolyl)imidazolidin-4-one (3m). This
compound was prepared via the general procedure as white solid (47
mg, 80% yield), purified by ethyl acetate:hexane = 1:3. Mp 155−157
°C; 1H NMR (400 MHz, CDCl3) δ 7.55−7.35 (m, 7H), 7.17 (d, J =
8.0 Hz, 2H), 6.12 (s, 1H), 5.19 (s, 2H), 4.18 (s, 2H), 2.32 (s, 3H)
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 162.9, 149.8, 136.4, 133.7,
133.3, 130.1, 130.0, 129.9, 129.0, 119.2, 79.5, 48.8, 20.9 ppm; IR
(KBr): v 3282, 3132, 1738, 1673, 1623, 1520, 1441, 1401, 1241, 1172,
1128, 1084, 1031, 802, 696, 638, 616, 586, 502 cm−1; HRMS (ESI)
m/z: [M + H]+ calcd for C17H18N3O2 296.1394; found 296.1379.
3-(Benzyloxy)-2-imino-1-(naphthalen-2-yl)imidazolidin-4-one
(3n). This compound was prepared via the general procedure as white
solid (62 mg, 94% yield), purified by ethyl acetate:hexane = 2:7. Mp
189−192 °C; 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.85 (d, J
= 8.8 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.56−7.50 (m, 2H), 7.49−
7.39 (m, 5H), 6.30 (s, 1H), 5.22 (s, 2H), 4.34 (s, 2H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 162.7, 149.8, 136.7, 133.8, 133.3, 130.3,
130.1, 129.9, 129.3, 129.0, 127.7, 127.6, 126.9, 125.4, 119.0, 115.5,
79.6, 48.8 ppm; IR (KBr): v 3093, 3134, 1746, 1669, 1632, 1599,
1511, 1476, 1401, 1340, 1301, 1252, 1170, 1128, 1085, 1031, 909,
842, 740, 695, 476 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for
C20H18N3O2 332.1394; found 332.1375.
2-Imino-3-methoxy-1-phenylimidazolidin-4-one (3q). This com-
pound was prepared via the general procedure as white solid (34 mg,
83% yield), purified by ethyl acetate:hexane = 2:3. Mp 138−140 °C;
1H NMR (400 MHz, CDCl3) δ 7.63 (d, J = 7.6 Hz, 2H), 7.40 (t, J =
7.6 Hz, 2H), 7.14 (t, J = 7.6 Hz, 1H), 6.31 (s, 1H), 4.23 (s, 2H), 4.05
(s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) 162.3, 149.2, 138.8,
129.5, 124.1, 119.0, 65.0, 48.6 ppm; IR (KBr): v 3308, 3135, 2954,
1754, 1675, 1600, 1507, 1463, 1445, 1402, 1252, 1184, 957, 808, 762,
747, 691, 640, 508 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for
C10H12N3O2 206.0924; found 206.0914.
2-Imino-1,3-diphenylimidazolidin-4-one (3v). This compound
was prepared via the general procedure as white solid (50 mg, 99%
1
yield), purified by ethyl acetate:hexane = 1:2. Mp 169−171 °C; H
NMR (400 MHz, CDCl3) δ 7.75−7.60 (m, 2H), 7.57−7.53 (m, 2H),
7.50−7.47 (m, 1H), 7.45−7.36 (m, 4H), 7.19−7.12 (m, 1H), 5.94 (s,
1H), 4.46 (s, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 167.8,
153.5, 139.0, 131.4, 130.0, 129.5 (4C), 128.0, 124.3, 120.0, 51.4 ppm;
IR (KBr): v 3133, 1755, 1662, 1597, 1491, 1401, 1238, 1217, 1187,
1116, 752, 735, 700, 642, 615, 508 cm−1; HRMS (ESI) m/z: [M +
H]+ calcd for C15H14N3O 252.1131; found 252.1138.
3-Benzyl-2-imino-1-phenylimidazolidin-4-one (3w). This com-
pound was prepared via the general procedure as white solid (52 mg,
98% yield), purified by ethyl acetate:hexane = 2:3. Mp 178−180 °C;
1H NMR (400 MHz, CDCl3) δ 7.50−7.39 (m, 4H), 7.37−7.26 (m,
5H), 7.24−7.21 (m, 1H), 6.06 (s, 1H), 4.86 (s, 2H), 4.30 (s, 2H)
ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.0, 154.1, 138.3, 136.1,
129.9, 128.8, 128.5, 128.0, 125.7, 122.4, 52.2, 43.1 ppm; IR (KBr): v
3318, 3133, 1733, 1660, 1599, 1502, 1445, 1401, 1312, 1216, 1176,
1145, 1088, 927, 754, 738, 642, 615, 594, 480 cm−1; HRMS (ESI) m/
z: [M + H]+ calcd for C16H16N3O 266.1288; found 266.1277.
2-Imino-3-phenethyl-1-phenylimidazolidin-4-one (3x). This
compound was prepared via the general procedure as white solid
(55 mg, 99% yield), purified by ethyl acetate:hexane = 2:3. Mp 122−
1
124 °C; H NMR (400 MHz, CDCl3) δ 7.46−7.42 (m, 2H), 7.35−
7.28 (m, 6H), 7.26−7.20 (m, 2H), 5.37 (s, 1H), 4.21 (s, 2H), 3.92 (t,
J = 7.6 Hz, 2H), 3.03 (t, J = 7.6 Hz, 2H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ 168.9, 154.2, 138.24, 138.19, 130.0, 129.1, 128.6,
126.8, 125.9, 122.7, 52.2, 40.8, 33.8 ppm; IR (KBr): v 3339, 3131,
2904, 1726, 1660, 1596, 1504, 1459, 1433, 1388, 1313, 1276, 1217,
3-(tert-Butoxy)-2-imino-1-phenylimidazolidin-4-one (3r). This
compound was prepared via the general procedure as white solid
(43 mg, 87% yield), purified by ethyl acetate:hexane = 2:5. Mp 130−
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1189, 1145, 1066, 972, 894, 813, 770, 702, 642, 508 cm−1; HRMS
(ESI) m/z: [M + H]+ calcd for C17H18N3O 280.1444; found
280.1431.
Methyl 4-(3-(Benzyloxy)-2,4-dioxoimidazolidin-1-yl)benzoate
(4i). This compound was prepared via the general procedure as
yellow solid (73 mg, 72% yield), purified by DCM:hexane = 10:1. Mp
160−162 °C; H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.8 Hz,
1
General Procedure for the Synthesis of Hydantoins 4.21
Compound 3 (0.3 mmol, 1 equiv), 99% AcOH (2.5 mL, 0.12 M), and
sodium acetate (6 mmol, 20 equiv) were added into a 25 mL oven-
dried round-bottom flask equipped with a magneton. Then, an
aqueous solution of sodium nitrite (2.4 mmol, 8 equiv) in water (2.5
mL) was added dropwise at room temperature within 2−4 h. Upon
complete consumption of the starting material detected by TLC, the
reaction mixture was neutralized with saturated aqueous solution of
NaHCO3 and extracted with ethyl acetate. The ethyl acetate fraction
was separated, washed with brine, and dried over anhydrous Na2SO4.
The volatile components were then removed under vacuum, and the
residue was further purified by column chromatography on silica gel
to afford the desired hydantoins 4.
2H), 7.60 (d, J = 8.8 Hz, 2H), 7.55−7.50 (m, 2H), 7.42−7.37 (m,
3H), 5.20 (s, 2H), 4.25 (s, 2H), 3.91 (s, 3H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ 166.4, 162.4, 150.6, 141.2, 133.2, 131.2, 130.1,
129.7, 128.8, 126.2, 117.1, 79.8, 52.3, 47.5 ppm; IR (KBr): v 3130,
3033, 2927, 2852, 1771, 1731, 1611, 1519, 1437, 1401, 1294, 1277,
1213, 1197, 1175, 1107, 904, 764, 743, 693, 617 cm−1; HRMS (ESI)
m/z: [M + H]+ calcd for C18H17N2O5 341.1132; found 341.1141.
3-(Benzyloxy)-1-(4-(trifluoromethyl)phenyl)imidazolidine-2,4-
dione (4k). This compound was prepared via the general procedure as
white solid (85 mg, 81% yield), purified by DCM:hexane = 4:1. Mp
241−243 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 8.4 Hz,
2H), 7.79 (d, J = 8.4 Hz, 2H), 7.56−7.51 (m, 2H), 7.47−7.39 (m,
3H), 5.15 (s, 2H), 4.54 (s, 2H) ppm; 13C{1H} NMR (100 MHz,
DMSO-d6) δ 163.5, 150.8, 141.2, 133.9, 129.6, 129.1, 128.5, 126.3 (q,
3-(Benzyloxy)-1-phenylimidazolidine-2,4-dione (4a). This com-
pound was prepared via the general procedure as yellow solid (62 mg,
1
2
3JC−F = 4.0 Hz), 124.2 (q, JC−F = 270.0 Hz), 123.8 (q, JC−F = 32.0
Hz), 117.8, 78.9, 47.9 ppm; 19F NMR (376 MHz, DMSO-d6) δ
−62.30 ppm; IR (KBr): v 3129, 1793, 1735, 1616, 1525, 1433, 1401,
1340, 1310, 1219, 1116, 1075, 915, 837, 747, 616 cm−1; HRMS (ESI)
m/z: [M + H]+ calcd for C17H14F3N2O3 351.0951; found 351.0961.
3-(Benzyloxy)-1-(naphthalen-2-yl)imidazolidine-2,4-dione (4n).
This compound was prepared via the general procedure as white
solid (69 mg, 69% yield), purified by DCM:hexane = 10:1. Mp 175−
1
73% yield), purified by DCM:hexane = 10:1. Mp 149−151 °C; H
NMR (400 MHz, CDCl3) δ 7.56−7.47 (m, 4H), 7.44−7.36 (m, 5H),
7.20−7.16 (m, 1H), 5.20 (s, 2H), 4.20 (s, 2H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ 163.0, 150.7, 137.3, 133.4, 130.1, 129.59,
129.57, 128.7, 125.0, 118.3, 79.7, 47.8 ppm; IR (KBr): v 3133, 3024,
1784, 1731, 1600, 1504, 1436, 1401, 1217, 1114, 992, 951, 913, 703,
744, 700, 615 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for
C16H15N2O3 283.1077; found 283.1087.
1
177 °C; H NMR (400 MHz, CDCl3) δ 7.89−7.86 (m, 2H), 7.82−
3-(Benzyloxy)-1-(m-tolyl)imidazolidine-2,4-dione (4c). This com-
7.79 (m, 2H), 7.75 (s, 1H), 7.60−7.55 (m, 2H), 7.50−7.43 (m, 2H),
7.43−7.37 (m, 3H), 5.24 (s, 2H), 4.31 (s, 2H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ 163.0, 150.9, 135.0, 133.6, 133.4, 130.7, 130.1,
129.6 (2C), 128.8, 127.8, 127.7, 127.2, 125.8, 118.0, 115.1, 79.8, 48.0
ppm; IR (KBr): v 3129, 1781, 1729, 1631, 1600, 1513, 1475, 1432,
1402, 1245, 1217, 1183, 1108, 950, 914, 848, 744, 701, 575 cm−1;
HRMS (ESI) m/z: [M + H]+ calcd for C20H17N2O3 333.1234; found
333.1249.
pound was prepared via the general procedure as yellow solid (45 mg,
1
51% yield), purified by DCM:hexane = 7:1. Mp 170−172 °C; H
NMR (400 MHz, CDCl3) δ 7.54−7.50 (m, 2H), 7.40−7.35 (m, 4H),
7.29−7.24 (m, 2H), 7.02−6.96 (m, 1H), 5.20 (s, 2H), 4.18 (s, 2H),
2.37 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 163.1, 150.7,
139.6, 137.2, 133.4, 130.1, 129.6, 129.4, 128.7, 125.8, 119.0, 115.4,
79.7, 47.8, 21.8 ppm; IR (KBr): v 3130, 1784, 1729, 1608, 1585,
1494, 1433, 1402, 1305, 1225, 1191, 1114, 950, 911, 856, 779, 747,
701, 627 cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C17H17N2O3
297.1234; found 297.1243.
3-Butyl-1-phenylimidazolidine-2,4-dione (4u).23 This compound
was prepared via the general procedure as yellow solid (19 mg, 27%
yield), purified by ethyl acetate:hexane = 5:1 to 2:1. Mp 90−92 °C;
1H NMR (600 MHz, CDCl3) δ 7.56 (d, J = 7.8 Hz, 2H), 7.39 (t, J =
7.8 Hz, 2H), 7.15 (d, J = 7.8 Hz, 1H), 4.27 (s, 2H), 3.60 (t, J = 7.2
Hz, 2H), 1.68−1.63 (m, 2H), 1.41−1.36 (m, 2H), 0.96 (t, J = 7.2 Hz,
3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 168.6, 154.5, 137.7,
129.5, 124.5, 118.3, 49.8, 39.0, 30.2, 20.1, 13.7 ppm; HRMS (EI) m/
z: [M]+ calcd for C13H16N2O2 232.1206; found 232.1210.
3-(Benzyloxy)-1-(3-nitrophenyl)imidazolidine-2,4-dione (4d).
This compound was prepared via the general procedure as yellow
solid (85 mg, 87% yield), purified by DCM:hexane = 10:1. Mp 202−
1
204 °C; H NMR (600 MHz, CDCl3) δ 8.31 (t, J = 2.4 Hz, 1H),
8.05−8.01 (m, 2H), 7.59 (t, J = 8.4 Hz, 1H), 7.55−7.53 (m, 2H),
7.42−7.40 (m, 3H), 5.23 (s, 2H), 4.30 (s, 2H) ppm; 13C{1H} NMR
(100 MHz, DMSO-d6) δ 163.4, 151.0, 148.2, 138.8, 133.9, 130.6,
129.6, 129.1, 128.5, 123.7, 118.3, 112.4, 79.0, 48.1 ppm; IR (KBr): v
3135, 1784, 1728, 1618, 1532, 1491, 1432, 1401, 1351, 1278, 1215,
1122, 753, 738, 696, 641, 616 cm−1; HRMS (ESI) m/z: [M + Na]+
calcd for C16H13N3NaO5 350.0747; found 350.0759.
3-(Benzyloxy)-1-(4-chlorophenyl)imidazolidine-2,4-dione (4f).
This compound was prepared via the general procedure as yellow
solid (77 mg, 81% yield), purified by DCM:hexane = 10:1. Mp 174−
176 °C; 1H NMR (400 MHz, CDCl3) δ 7.56−7.50 (m, 2H), 7.46 (d,
J = 8.8 Hz, 2H), 7.41−7.38 (m, 3H), 7.35 (d, J = 8.8 Hz, 2H), 5.20 (s,
2H), 4.19 (s, 2H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 162.6,
150.7, 135.9, 133.3, 130.3, 130.1, 129.7, 129.6, 128.7, 119.4, 79.8, 47.7
ppm; IR (KBr): v 3134, 1787, 1732, 1601, 1497, 1401, 1302, 1297,
1219, 1184, 1112, 1095, 990, 914, 864, 864, 824, 750, 701, 582, 504
cm−1; HRMS (ESI) m/z: [M + H]+ calcd for C16H14ClN2O3
317.0687; found 317.0694.
1,3-Diphenylimidazolidine-2,4-dione (4v).24 This compound was
prepared via the general procedure as orange solid (34 mg, 45%
yield), purified by ethyl acetate:hexane = 5:1 to 2:1. Mp 137−139 °C;
1H NMR (600 MHz, CDCl3) δ 7.62 (d, J = 8.4 Hz, 2H), 7.52−7.48
(m, 2H), 7.47−7.40 (m, 5H), 7.22−7.18 (m, 1H), 4.48 (s, 2H) ppm;
13C{1H} NMR (100 MHz, CDCl3) δ 167.5, 153.3, 137.5, 131.4,
129.5, 129.3, 128.6, 126.4, 124.8, 118.7, 49.9 ppm; HRMS (EI) m/z:
[M]+ calcd for C15H12N2O2 252.0893; found 252.0895.
Procedure for the Synthesis of Compound 5.25 Palladium/
carbon catalyst (10 mg, 10% Pd on carbon) was added into the
solution of compound 4a (85 mg, 0.3 mmol) in dry THF (5 mL), and
the reaction mixture was stirred under H2 balloon for 4 h at room
temperature. Upon the complete consumption of 4a confirmed by
TLC, the reaction mixture was filtered through a Celite pad and
concentrated in vacuo, directly affording the desired compound 5 as
1
orange solid (57 mg, 99% yield). Mp 200−202 °C; H NMR (400
3-(Benzyloxy)-1-(4-bromophenyl)imidazolidine-2,4-dione (4g).
This compound was prepared via the general procedure as yellow
solid (90 mg, 83% yield), purified by DCM:hexane = 25:2. Mp 184−
MHz, DMSO-d6) δ 10.85 (s, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.40 (t, J
= 8.0 Hz, 2H), 7.14 (t, J = 7.6 Hz, 1H), 4.49 (s, 2H) ppm; 13C{1H}
NMR (100 MHz, DMSO-d6) δ 164.4, 152.0, 138.0, 129.1, 123.8,
118.0, 47.6 ppm. IR (KBr): v 3124, 3016, 2924, 1778, 1704, 1597,
1497, 1430, 1402, 1375, 1301, 1276, 1215, 1193, 1164, 1117, 853,
771, 758, 693, 640, 599 cm−1; HRMS (ESI) m/z: [M + Na]+ calcd for
C9H8N2NaO3 215.0427; found 215.0434.
1
185 °C; H NMR (400 MHz, CDCl3) δ 7.56−7.47 (m, 4H), 7.44−
7.36 (m, 5H), 5.20 (s, 2H), 4.18 (s, 2H) ppm; 13C{1H} NMR (100
MHz, CDCl3) δ 162.6, 150.6, 136.4, 133.3, 132.6, 130.1, 129.7, 128.8,
119.7, 117.9, 79.8, 47.6 ppm; IR (KBr): v 3132, 1793, 1732, 1594,
1494, 1441, 1402, 1297, 1115, 914, 765, 749, 735, 702, 638, 615
cm−1; HRMS (ESI) m/z: [M + Na]+ calcd for C16H1379BrN2NaO3
383.0002; found 383.0008.
Procedure for the Synthesis of Compound 6.26 After the
degasification of the solution of compound 4a (56 mg, 0.2 mmol)
dissolved in dry THF (1 mL), SmI2 (0.6 mmol) in THF (6 mL) was
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added dropwise at room temperature. After the addition, the mixture
was stirred for 6 h at room temperature. The mixture was diluted with
CH2Cl2 (20 mL), quenched with 10% aqueous solution of Na2S2O3
(5.5 mL), and extracted with CH2Cl2. The CH2Cl2 fraction was
separated and dried over anhydrous Na2SO4. The volatile solvent was
removed under vacuum and purified by column chromatography on
silica gel (ethyl acetate:hexane = 1:3) to afford the desired product 6
Author Contributions
∥These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
1
as white solid (32 mg, 91% yield). Mp 197−198 °C; H NMR (400
We acknowledge Prof. Chen-Guo Feng (Shanghai University
of Traditional Chinese Medicine) for his help in the
characterizations of compounds. We thank the financial
support from the Key Scientific and Technological Project of
Henan Province (grant nos. 202102110067 and
212102110439), Henan University of Animal Husbandry and
Economy (grant nos. 2019HNUAHEDF011 and
XKYCXJJ2020006), and the Natural Science Foundation of
Henan Province (grant nos. 202300410188 and
212300410152).
MHz, DMSO-d6) δ 11.18 (s, 1H), 7.59 (d, J = 8.0 Hz, 2H), 7.36 (t, J
= 7.6 Hz, 2H), 7.10 (t, J = 7.6 Hz, 1H), 4.43 (s, 2H) ppm; 13C{1H}
NMR (100 MHz, DMSO-d6) δ 170.5, 154.8, 138.2, 128.9, 123.3,
118.2, 50.9 ppm; HRMS (EI) m/z: [M]+ calcd for C9H8N2O2
176.0580; found 176.0575.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02932.
REFERENCES
Copies of NMR spectra for all new compounds and
crystallographic data (PDF)
■
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AUTHOR INFORMATION
■
Corresponding Author
Ya-Jing Chen − School of Pharmaceutical Sciences, Key
Laboratory of Advanced Drug Preparation Technologies,
Ministry of Education of China; Co-innovation Center of
Henan Province for New Drug R & D and Preclinical Safety,
Zhengzhou University, Zhengzhou 450001, Henan, China;
orcid.org/0000-0002-1624-0741; Email: chenyj@
zzu.edu.cn
Authors
Chuan-Chuan Wang − Faculty of Science, Henan University
of Animal Husbandry and Economy, Zhengzhou 450044,
Henan, China; College of Chemistry, Zhengzhou University,
Zhengzhou 450001, Henan, China
Ya-Li Qu − School of Pharmaceutical Sciences, Zhengzhou
University, Zhengzhou 450001, Henan, China
Xue-Hua Liu − School of Pharmaceutical Sciences, Zhengzhou
University, Zhengzhou 450001, Henan, China
Zhi-Wei Ma − Faculty of Science, Henan University of Animal
Husbandry and Economy, Zhengzhou 450044, Henan,
China
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Xiao-Pei Chen − Faculty of Science, Henan University of
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