Synthesis of Imidazole Derivatives by Cascade Reaction: Base-Mediated Addition/Alkyne Hydroamination of Propargylamines and Carbodiimides

Article abstract of DOI:10.1055/s-0034-1378787

A novel synthesis of 2-iminoimidazoles and 2-aminoimidazoles, via nucleophilic addition and a subsequent sodium hydroxide mediated intramolecular alkyne hydroamination from propargylamines and carbodiimides, is developed. This transition-metal-free cascad

Full text of DOI:10.1055/s-0034-1378787

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3473–3478
paper
3473
J.-H. Jia et al.
Paper
Synthesis
Synthesis of Imidazole Derivatives by Cascade Reaction: Base-
Mediated Addition/Alkyne Hydroamination of Propargylamines
and Carbodiimides
Jian-Hong Jia
Chao Yu
Meng Xu
Jia-Wei Ma
Hong-Wei Jin*
College of Chemical Engineering, Zhejiang University of
Technology, Hangzhou 310014, P. R. of China
jhwei828@zjut.edu.cn
Received: 16.02.2015
Accepted after revision: 04.06.2015
Published online: 12.08.2015
azoles can provide routes to construct these heterocy-
cles;6e,7 however, to the best of our knowledge, reports on
efficient metal-free syntheses of 2-aminoimidazoles are
rare.8 By comparison, only two related studies on imino-
imidazole synthesis, by Xie7b and Kunetskiy,9 have been de-
scribed. Herein, we report an efficient cascade synthesis of
2-iminoimidazoles and 2-aminoimidazoles via the nucleo-
philic addition of N-substituted propargylamines and prop-
argylamine, respectively, to carbodiimides, followed by a
rarely explored sodium hydroxide (NaOH) mediated alkyne
hydroamination.10
DOI: 10.1055/s-0034-1378787; Art ID: ss-2015-h0115-op
Abstract A novel synthesis of 2-iminoimidazoles and 2-aminoimidaz-
oles, via nucleophilic addition and a subsequent sodium hydroxide me-
diated intramolecular alkyne hydroamination from propargylamines
and carbodiimides, is developed. This transition-metal-free cascade
process represents an atom-economic and step-economic procedure
for the construction of imidazole derivatives with high regioselectivity
and moderate to good yields.
Key words alkyne hydroamination, transition-metal-free, carbodiim-
In a preliminary study of the reaction, N-benzylpropar-
gylamine (1a), as a model substrate, was reacted with N,N-
diphenylcarbodiimide (2a) in the presence of potassium
phosphate (K3PO4) (1.0 equiv) in dimethyl sulfoxide at 80 °C
(oil bath temperature) for two hours (Table 1).
ides, imidazole synthesis, cascade process
Organic synthesis represents one of the major activities
of organic chemists. An ideal synthesis always possesses
several advantages such as high atom economy with mini-
mum generation of waste, high step economy with less la-
bor-consuming procedures, cheap and readily available
starting materials and reagents, and so on.1 Atom economic
cascade processes provide the above benefits to synthetic
chemists developing simple and elegant routes toward tar-
get compounds.2 Unarguably, such straightforward and effi-
cient cascade reactions for the construction of diverse het-
erocycles are highly desirable.3
2-Iminoimidazoles and 2-aminoimidazoles are two im-
portant classes of nitrogen-containing heterocycles that are
found in various important organic intermediates, especial-
ly in the application of coordination chemistry,4 and phar-
maceutical chemistry.5 Although there are several conven-
tional methods to prepare 2-aminoimidazoles, for example,
the reactions of α-aminoketones with cyanamide or α-
haloketones with acetylated guanidine derivatives,6 these
synthetic strategies often suffer from problems with unsta-
ble substrates and low reaction yields. Lanthanum(III)-, sil-
ver(I)- and titanium-catalyzed syntheses of 2-aminoimid-
To our delight, the desired product 3a was obtained in
25% yield (Table 1, entry 1). After screening several other
bases (K2CO3, Na2CO3, Cs2CO3, DBU, NaOH, and KOH), the re-
sults showed that the basicity of the carbonates was too
weak, while that of potassium hydroxide (KOH) was too
strong to allow efficient reactions to take place (Table 1, en-
tries 2–7). Thus, sodium hydroxide was found to be the best
choice among the bases screened (Table 1, entry 6). Raising
or lowering the reaction temperature did not improve the
yield (Table 1, entries 8 and 9). Increasing the amount of
base did not improve the yield, whilst decreasing the
amount of sodium hydroxide also gave the desired product
in a poor yield (Table 1, entries 10 and 11). Lower yields of
product 3a were obtained on changing the solvent from di-
methyl sulfoxide to other solvents such as N,N-dimethyl-
formamide, acetonitrile, 1,4-dioxane and toluene (Table 1,
entries 12–15). Hence, the optimum conditions for this re-
action are sodium hydroxide (1.0 equiv) in dimethyl sulfox-
ide at 80 °C (Table 1, entry 6).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3473–3478

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Synthesis
Table 1 Optimization Studies for the Synthesis of 2-Iminoimidazole
ide (DCC), an aliphatic carbodiimide, was applied, the pro-
cess failed to afford the expected product, which may be
due to the low reactivity of aliphatic carbodiimides (Table
2, entry 20). We also attempted to expand the substrate
scope to 3-substituted propargylamines, but unfortunately,
the reaction failed to give the corresponding products. This
outcome might due to the steric hindrance of the branched
amines.
3aa
Ph
N
base
solvent
Bn
N
PhN
C
NPh
+
N
Ph
Bn NH
1a
2a
CH3
3a
Table 2 Synthesis of Various 2-Iminoimidazoles 3a
Entry
Base (equiv)
Solvent
Temp (°C) Yield (%)b
R2
1
2
3
4
5
6
7
8c
9
K3PO4 (1.0)
K2CO3 (1.0)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
80
80
80
80
80
80
80
60
100
80
80
80
80
80
80
25
30
19
37
18
82
53
58
80
78
58
74
39
23
40
R2
Na2CO3 (1.0)
Cs2CO3 (1.0)
DBU (1.0)
N
R1
NaOH
N
R1 NH
+
N
C N
N
R3
DMSO
80 °C, 2 h
R3
1
2
NaOH (1.0)
KOH (1.0)
3
NaOH (1.0)
NaOH (1.0)
NaOH (1.5)
NaOH (0.5)
NaOH (1.0)
NaOH (1.0)
NaOH (1.0)
NaOH (1.0)
Entry
R1
R2
R3
Yield (%)b
1
2
Bn (1a)
H
H
H
H
H
H
H
H
H
82 (3a)
76 (3b)
72 (3c)
71 (3d)
56 (3e)
62 (3f)
83 (3g)
–
10
Pr (1b)
H
H
H
H
H
H
H
11
12
13
14
15
3
n-Bu (1c)
s-Bu (1d)
i-Bu (1e)
4
MeCN
5
1,4-dioxane
toluene
6
c-Hex (1f)
n-Oct (1g)
Ph (1h)
n-Bu 1c
Bn 1a
7
a Reaction conditions: N-benzylpropargylamine (1a) (0.5 mmol), N,N-di-
phenylcarbodiimide (2a) (0.5 mmol), base (0.25–0.75 mmol), solvent (2
mL), 60–100 °C, 2 h. All reactions were performed in a sealed, pressurized
process vial.
8
9
4-Me
4-Cl
4-Me
36 (3h)
76 (3i)
78 (3j)
75 (3k)
80 (3l)
55 (3m)
75 (3n)
60 (3o)
66 (3p)
76 (3q)
60 (3r)
–
b Yield of isolated product 3a.
10
11
12
13
14
15
16
17
18
19
20
4-Cl
c The reaction time was 5 h.
Pr 1b
4-Cl
4-Cl
n-Bu 1c
i-Bu 1e
Bn 1a
4-Cl
4-Cl
With optimized reaction conditions in hand, the scope
of this cascade reaction was explored. As shown in Table
2,N,N-diphenylcarbodiimide (2a) reacted with N-alkyl-sub-
stituted propargylamines to give the corresponding prod-
ucts in moderate to good yields (Table 2, entries 1–7). How-
ever, as a result of the poor nucleophilicity of aryl amines,
carbodiimide 2a failed to react with phenyl-substituted
propargylamine 1h (Table 2, entry 8). The diphenylcarbo-
diimide 2b (R2 = R3 = 4-Me) with electron-donating methyl
groups is expected to have reduced eletrophilicity, and in-
deed afforded the corresponding product 3h in a relatively
low 36% yield (Table 2, entry 9). In contrast, the reactions of
carbodiimide 2c (R2 = R3 = 4-Cl), which possesses electron-
withdrawing chlorine groups, gave the desired products in
good yields (Table 2, entries 10–13). When unsymmetric
carbodiimides 2d (R2 = 2-Me, R3 = 4-NC) and 2e (R2 = H, R3 =
4-F3C) were applied, the cascade process led to the corre-
sponding products with high regioselectivities (Table 2, en-
tries 14–19). However, when N,N′-dicyclohexylcarbodiim-
4-Cl
4-Cl
2-Me
2-Me
2-Me
2-Me
2-Me
H
4-NC
4-NC
4-NC
4-NC
4-NC
4-F3C
Pr 1b
n-Bu 1c
i-Bu 1e
n-Oct 1g
Pr 1b
Bn 1a
cyclohexyl
cyclohexyl
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), NaOH (0.5 mmol),
DMSO (2 mL), 80 °C, 2 h. All reactions were performed in a sealed, pressur-
ized process vial.
b Yield of isolated products.
Encouraged by the obtained results, we next chose to
study propargylamine as the substrate. To our delight, the
corresponding 2-aminoimidazoles 4 were successfully con-
structed in moderate to good yields (Table 3).
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Table 3 One-Pot Synthesis of 2-Aminoimidazoles 4a
In conclusion, we have successfully developed an effi-
cient, sodium hydroxide mediated cascade process involv-
ing a nucleophilic addition/alkyne hydroamination for the
synthesis of 2-iminoimidazoles and 2-aminoimidazoles
from carbodiimides and propargylamines. The procedure
occurs with both high step- and atom-economy, and affords
substituted imidazoles in moderate to good yields. Further
applications of this methodology are being investigated in
our laboratory.
R2
R2
NH
NaOH
N
N
C N
+
H2N
N
R3
DMSO
80 °C, 2 h
1
2
R3
4
Entry
R2
R3
Product
Yield (%)b
All solvents were dried using standard procedures. Reactions were
followed by TLC using SILG/UV 254 silica gel plates, which were visu-
alized using a UV fluorescent lamp or by staining with I2. Melting
points were obtained using a SGW X-4 micro-melting point appara-
tus. 1H NMR and 13C NMR spectra were obtained on a Bruker 500 MHz
spectrometer. Coupling constants are reported in hertz (Hz). LRMS
and HRMS analyses were performed using a Thermo ITG 1100 mass
spectrometer under ESI or EI ionization.
1
2
3
4
H
H
4a
4b
4c
4d
65
61
53
80
4-Me
4-Me
4-MeO
4-Cl
4-MeO
4-Cl
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), NaOH (0.5 mmol),
DMSO (2 mL), 80 °C, 2 h. All reactions were performed in a sealed, pressur-
ized process vial.
b Yield of isolated products.
2-Iminoimidazoles 3; General Procedure
According to the above experimental results and a pre-
vious report,11 we have proposed a mechanism for this cas-
cade process (Scheme 1). The nucleophilic addition of prop-
argylamine 1 to carbodiimide 2 produced guanidine inter-
mediate A, the structure of which was confirmed by 1H
NMR spectroscopy. Intermediate A is thought to generate
guanidine anion B in the presence of sodium hydroxide.
Subsequent intramolecular alkyne hydroamination of B
gives the cyclic intermediate C. The intermediate C then
tautomerizes into the final product, 2-iminoimidazole 3.
The guanidine anion B, formed from the unsymmetric car-
bodiimides 2d or 2e, on reacting with the propargylamine
To a sealable test tube equipped with a magnetic stir bar were added
substituted propargylamine
1 (0.5 mmol), carbodiimide 2 (0.5
mmol), NaOH (0.5 mmol) and DMSO (2 mL). The mixture was allowed
to stir at 80 °C for 2 h. After completion of the reaction, the mixture
was cooled to r.t. Next, the mixture was diluted with sat. aq NH4Cl
solution (4 mL) and extracted with EtOAc (3 × 10 mL). The combined
organic phase was washed with brine (5 mL), dried over Na2SO4, fil-
tered and concentrated under vacuum. The residue was subjected to
preparative TLC (PE–EtOAc–Et3N, 10:1:3) on a silica gel plate to give
the pure product 3.
1-Benzyl-4-methyl-N,3-diphenyl-1,3-dihydro-2H-imidazol-2-
imine (3a)
Yield: 139 mg (82%); yellow oil.
generates
a more stable anion having an electron-
1H NMR (500 MHz, CDCl3): δ = 7.42–7.30 (m, 5 H), 7.20–7.15 (m, 2 H),
7.15–7.08 (m, 3 H), 6.87 (dd, J = 8.3, 7.4 Hz, 2 H), 6.66–6.59 (m, 2 H),
6.57–6.48 (m, 1 H), 6.04 (d, J = 1.3 Hz, 1 H), 4.91 (s, 2 H), 1.82 (d, J = 1.3
Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 149.9, 147.0, 137.5, 136.4, 128.7,
128.5, 128.2, 128.0, 127.8, 127.6, 127.1, 121.8, 121.3, 118.5, 109.8,
48.5, 11.2.
withdrawing group attached. Hence, this reaction can give
specific products with high regioselectivity.
R2
R3
R2
N
R1 NH
+
HN
N
C N
EI-MS: m/z = 339 [M]+.
HRMS (EI): m/z [M]+ calcd for C23H21N3: 339.1735; found: 339.1732.
R3
N R1
A
1
2
NaOH
4-Methyl-N,3-diphenyl-1-propyl-1,3-dihydro-2H-imidazol-2-
imine (3b)
R3
N
R3
R3
R2
R2
R2
Yield: 110 mg (76%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.19–7.14 (m, 2 H), 7.12–7.06 (m, 3 H),
6.87–6.82 (m, 2 H), 6.61–6.55 (m, 2 H), 6.53–6.47 (m, 1 H), 6.16 (d, J =
1.2 Hz, 1 H), 3.71–3.56 (m, 2 H), 1.86 (d, J = 1.2 Hz, 3 H), 1.73 (dt, J =
14.7, 7.4 Hz, 2 H), 0.93 (t, J = 7.4 Hz, 3 H).
N
N
N
N
N
N R1
N R1
N R1
13C NMR (125 MHz, CDCl3): δ = 149.8, 147.0, 136.3, 128.5, 128.0,
3
C
B
127.8, 127.1, 121.5, 121.2, 118.4, 110.4, 46.7, 22.3, 11.2, 11.1.
EI-MS: m/z = 291 [M]+.
Scheme 1 A proposed mechanism for the formation of products 3
HRMS (EI): m/z [M]+ calcd for C19H21N3: 291.1735; found: 291.1733.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3473–3478

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1-Butyl-4-methyl-N,3-diphenyl-1,3-dihydro-2H-imidazol-2-imine
(3c)
1H NMR (500 MHz, CDCl3): δ = 7.20–7.13 (m, 2 H), 7.09 (td, J = 6.9, 1.4
Hz, 3 H), 6.89–6.79 (m, 2 H), 6.61–6.55 (m, 2 H), 6.49 (tt, J = 7.4, 1.1
Hz, 1 H), 6.13 (d, J = 1.3 Hz, 1 H), 3.69–3.55 (m, 2 H), 1.85 (d, J = 1.3 Hz,
3 H), 1.75–1.64 (m, 2 H), 1.34–1.27 (m, 10 H), 0.90 (t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 150.2, 147.0, 136.4, 128.5, 127.9,
127.8, 127.0, 121.6, 120.8, 118.1, 110.1, 45.0, 31.7, 29.2, 29.1, 28.9,
26.6, 22.6, 14.0, 11.0.
Yield: 109 mg (72%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.16 (dd, J = 8.3, 7.0 Hz, 2 H), 7.11–7.06
(m, 3 H), 6.88–6.81 (m, 2 H), 6.58 (dd, J = 8.3, 1.0 Hz, 2 H), 6.49 (t, J =
7.3 Hz, 1 H), 6.13 (d, J = 1.3 Hz, 1 H), 3.70–3.54 (m, 2 H), 1.84 (d, J = 1.2
Hz, 3 H), 1.75–1.60 (m, 2 H), 1.39–1.31 (m, 2 H), 0.93 (t, J = 7.4 Hz, 3
H).
EI-MS: m/z = 362 [M + 1]+.
13C NMR (125 MHz, CDCl3): δ = 150.2, 147.0, 136.3, 128.4, 127.9,
HRMS (EI): m/z [M]+ calcd for C24H31N3: 361.2518; found: 361.2521.
127.7, 126.9, 121.6, 120.7, 118.0, 110.0, 44.6, 31.0, 19.7, 13.6, 11.0.
EI-MS: m/z = 306 [M + 1]+.
1-Butyl-4-methyl-N,3-di-p-tolyl-1,3-dihydro-2H-imidazol-2-
imine (3h)
HRMS (EI): m/z [M]+ calcd for C20H23N3: 305.1892; found: 305.1895.
Yield: 59 mg (36%); yellow oil.
1-(sec-Butyl)-4-methyl-N,3-diphenyl-1,3-dihydro-2H-imidazol-2-
imine (3d)
1H NMR (500 MHz, CDCl3): δ = 6.96 (s, 4 H), 6.67 (d, J = 8.0 Hz, 2 H),
6.49 (d, J = 8.1 Hz, 2 H), 6.07 (s, 1 H), 3.58 (t, J = 7.3 Hz, 2 H), 2.25 (s, 3
H), 2.12 (s, 3 H), 1.82 (s, 3 H), 1.65 (dt, J = 15.0, 7.5 Hz, 2 H), 1.31 (dd,
J = 15.1, 7.5 Hz, 2 H), 0.91 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 147.5, 147.1, 136.7, 133.8, 129.0,
128.4, 127.6, 127.2, 121.5, 120.9, 109.8, 44.8, 30.9, 20.9, 20.4, 19.8,
13.7, 10.9.
Yield: 108 mg (71%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.18–7.11 (m, 2 H), 7.09–7.04 (m, 3 H),
6.82 (dd, J = 8.2, 7.4 Hz, 2 H), 6.55 (dd, J = 8.4, 1.0 Hz, 2 H), 6.49–6.43
(m, 1 H), 6.18 (d, J = 1.2 Hz, 1 H), 4.45–4.35 (m, 1 H), 1.86 (d, J = 1.2 Hz,
3 H), 1.75–1.59 (m, 2 H), 1.32 (d, J = 6.8 Hz, 3 H), 0.94 (t, J = 7.4 Hz, 3
H).
EI-MS: m/z = 334 [M + 1]+.
13C NMR (125 MHz, CDCl3): δ = 150.6, 147.4, 136.5, 128.5, 128.0,
HRMS (EI): m/z [M]+ calcd for C22H27N3: 333.2205; found: 333.2211.
127.8, 126.9, 121.5, 121.3, 117.9, 106.2, 50.5, 29.3, 19.6, 11.3, 10.8.
EI-MS: m/z = 306 [M + 1]+.
1-Benzyl-N,3-bis(4-chlorophenyl)-4-methyl-1,3-dihydro-2H-imid-
azol-2-imine (3i)
HRMS (EI): m/z [M]+ calcd for C20H23N3: 305.1892; found: 305.1896.
Yield: 154 mg (76%); yellow oil.
1-Isobutyl-4-methyl-N,3-diphenyl-1,3-dihydro-2H-imidazol-2-
imine (3e)
1H NMR (500 MHz, CDCl3): δ = 7.39–7.34 (m, 2 H), 7.31 (t, J = 6.1 Hz, 3
H), 7.18 (d, J = 8.6 Hz, 2 H), 7.02 (d, J = 8.6 Hz, 2 H), 6.83 (d, J = 8.6 Hz,
2 H), 6.50 (d, J = 8.6 Hz, 2 H), 6.09 (d, J = 1.0 Hz, 1 H), 4.89 (s, 2 H), 1.81
(d, J = 0.9 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 147.8, 146.6, 136.7, 134.4, 133.5,
129.01, 128.98, 128.8, 128.13, 128.06, 127.9, 123.7, 122.6, 121.6,
110.7, 48.8, 10.9.
Yield: 85 mg (56%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.18–7.12 (m, 2 H), 7.08 (dd, J = 7.2, 5.3
Hz, 3 H), 6.83 (t, J = 7.8 Hz, 2 H), 6.55 (d, J = 7.4 Hz, 2 H), 6.48 (t, J = 7.3
Hz, 1 H), 6.14 (d, J = 1.0 Hz, 1 H), 3.52 (d, J = 7.4 Hz, 2 H), 2.11 (td, J =
13.7, 6.8 Hz, 1 H), 1.85 (d, J = 1.1 Hz, 3 H), 0.93 (d, J = 6.7 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 150.1, 147.2, 136.4, 128.4, 127.9,
127.7, 126.9, 121.6, 120.5, 118.0, 110.9, 52.2, 28.1, 19.9, 11.0.
ESI-MS: m/z = 408 [M + 1]+.
HRMS (EI): m/z [M]+ calcd for C23H19Cl2N3: 407.0956; found:
EI-MS: m/z = 306 [M + 1]+.
407.0960.
HRMS (EI): m/z [M]+ calcd for C20H23N3: 305.1892; found: 305.1890.
N,3-Bis(4-chlorophenyl)-4-methyl-1-propyl-1,3-dihydro-2H-imid-
azol-2-imine (3j)
1-Cyclohexyl-4-methyl-N,3-diphenyl-1,3-dihydro-2H-imidazol-2-
imine (3f)
Yield: 140 mg (78%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.12 (d, J = 8.6 Hz, 2 H), 6.97 (d, J = 8.6
Hz, 2 H), 6.78 (d, J = 8.6 Hz, 2 H), 6.44 (d, J = 8.6 Hz, 2 H), 6.13 (s, 1 H),
3.60–3.54 (m, 2 H), 1.79 (s, 3 H), 1.71–1.62 (m, 2 H), 0.87 (t, J = 7.4 Hz,
3 H).
13C NMR (125 MHz, CDCl3): δ = 148.2, 146.5, 134.4, 133.0, 128.74,
128.67, 127.7, 122.9, 122.3, 120.8, 110.7, 46.5, 22.0, 10.9, 10.7.
Yield: 102 mg (62%); pale yellow solid; mp 123–125 °C.
1H NMR (500 MHz, CDCl3): δ = 7.16–7.09 (m, 2 H), 7.09–7.02 (m, 3 H),
6.81 (t, J = 7.8 Hz, 2 H), 6.54 (d, J = 7.4 Hz, 2 H), 6.45 (t, J = 7.3 Hz, 1 H),
6.22 (d, J = 1.1 Hz, 1 H), 4.24–4.11 (m, 1 H), 2.07 (s, 2 H), 1.84 (d, J = 1.0
Hz, 5 H), 1.74–1.65 (m, 1 H), 1.46–1.34 (m, 4 H), 1.23–1.12 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 150.4, 146.7, 136.5, 128.5, 128.0,
127.8, 127.0, 121.5, 121.2, 118.1, 106.8, 52.6, 32.4, 25.6, 25.5, 11.2.
EI-MS: m/z = 360 [M + 1]+.
HRMS (EI): m/z [M]+ calcd for C19H19Cl2N3: 359.0956; found:
EI-MS: m/z = 332 [M + 1]+.
HRMS (EI): m/z [M]+ calcd for C22H25N3: 331.2048; found: 331.2043.
359.0949.
1-Butyl-N,3-bis(4-chlorophenyl)-4-methyl-1,3-dihydro-2H-imid-
azol-2-imine (3k)
4-Methyl-1-octyl-N,3-diphenyl-1,3-dihydro-2H-imidazol-2-imine
(3g)
Yield: 139 mg (75%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.20–7.10 (m, 2 H), 7.04–6.93 (m, 2 H),
6.88–6.75 (m, 2 H), 6.53–6.41 (m, 2 H), 6.15 (d, J = 1.2 Hz, 1 H), 3.62 (t,
Yield: 150 mg (83%); yellow oil.
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J = 7.3 Hz, 2 H), 1.83 (d, J = 1.2 Hz, 3 H), 1.70–1.60 (m, 2 H), 1.31 (dq,
J = 14.2, 7.1 Hz, 2 H), 0.90 (t, J = 7.4 Hz, 3 H).
HRMS (EI): m/z [M]+ calcd for C22H24N4: 344.2001; found: 344.2005.
13C NMR (125 MHz, CDCl3): δ = 148.2, 146.5, 134.3, 132.9, 128.7,
4-[3-Isobutyl-5-methyl-2-(o-tolylimino)-2,3-dihydro-1H-imidaz-
ol-1-yl]benzonitrile (3p)
128.6, 127.7, 122.8, 122.2, 120.8, 110.6, 44.7, 30.7, 19.5, 13.4, 10.6.
EI-MS: m/z = 374 [M + 1]+.
Yield: 113 mg (66%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.05–6.90 (m, 6 H), 6.40 (d, J = 8.6 Hz, 2
H), 6.20 (d, J = 1.1 Hz, 1 H), 3.46 (ddd, J = 31.4, 13.6, 7.4 Hz, 2 H), 2.04
(td, J = 13.7, 6.8 Hz, 1 H), 1.97 (s, 3 H), 1.71 (d, J = 1.0 Hz, 3 H), 0.86 (dd,
J = 10.6, 6.7 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 154.8, 146.8, 135.7, 134.1, 131.6,
130.6, 128.7, 128.4, 126.1, 121.3, 120.8, 120.6, 110.9, 97.8, 52.0, 27.9,
19.53, 19.50, 17.3, 10.0.
HRMS (EI): m/z [M]+ calcd for C20H21Cl2N3: 373.1113; found:
373.1118.
N,3-Bis(4-chlorophenyl)-1-isobutyl-4-methyl-1,3-dihydro-2H-im-
idazol-2-imine (3l)
Yield: 149 mg (80%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.18–7.09 (m, 2 H), 7.03–6.94 (m, 2 H),
6.84–6.74 (m, 2 H), 6.49–6.38 (m, 2 H), 6.13 (d, J = 1.2 Hz, 1 H), 3.46
(d, J = 7.4 Hz, 2 H), 2.05 (dt, J = 13.8, 6.9 Hz, 1 H), 1.82 (d, J = 1.2 Hz, 3
H), 0.89 (d, J = 6.7 Hz, 6 H).
EI-MS: m/z = 345 [M + 1]+.
HRMS (EI): m/z [M]+ calcd for C22H24N4: 344.2001; found: 344.1995.
13C NMR (125 MHz, CDCl3): δ = 148.1, 147.0, 134.5, 133.3, 128.97,
4-[5-Methyl-3-octyl-2-(o-tolylimino)-2,3-dihydro-1H-imidazol-1-
yl]benzonitrile (3q)
128.95, 128.0, 123.3, 122.5, 121.0, 111.7, 52.5, 28.2, 19.9, 10.9.
EI-MS: m/z = 374 [M + 1]+.
Yield: 152 mg (76%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.12–7.01 (m, 6 H), 6.48 (d, J = 8.6 Hz, 2
H), 6.28 (d, J = 0.9 Hz, 1 H), 3.77–3.61 (m, 2 H), 2.03 (s, 3 H), 1.79 (d, J =
1.0 Hz, 3 H), 1.75–1.66 (m, 2 H), 1.28 (dd, J = 14.9, 7.8 Hz, 10 H), 0.87
(t, J = 6.9 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 154.8, 146.8, 136.1, 134.2, 132.1,
130.9, 128.9, 128.8, 126.5, 122.1, 121.0, 120.7, 110.5, 98.5, 45.2, 31.7,
29.1, 29.0, 28.9, 26.4, 22.5, 17.6, 14.0, 10.4.
HRMS (EI): m/z [M]+ calcd for C20H21Cl2N3: 373.1113; found:
373.1115.
4-[3-Benzyl-5-methyl-2-(o-tolylimino)-2,3-dihydro-1H-imidazol-
1-yl]benzonitrile (3m)
Yield: 104 mg (55%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.39–7.30 (m, 5 H), 7.14–7.01 (m, 6 H),
6.55–6.47 (m, 2 H), 6.17 (d, J = 1.3 Hz, 1 H), 4.91 (q, J = 15.0 Hz, 2 H),
2.07 (s, 3 H), 1.76 (d, J = 1.3 Hz, 3 H).
ESI-MS: m/z = 401 [M + 1]+.
HRMS (EI): m/z [M]+ calcd for C26H32N4: 400.2627; found: 400.2630.
13C NMR (125 MHz, CDCl3): δ = 154.6, 146.7, 136.7, 136.1, 134.3,
132.1, 131.0, 129.1, 128.9, 128.8, 128.0, 127.9, 126.6, 122.3, 121.2,
121.0, 110.2, 99.1, 48.7, 17.7, 10.5.
4-Methyl-N-phenyl-1-propyl-3-[4-(trifluoromethyl)phenyl]-1,3-
dihydro-2H-imidazol-2-imine (3r)
EI-MS: m/z = 379 [M + 1]+.
Yield: 108 mg (60%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.21–7.16 (m, 2 H), 7.13 (dt, J = 9.6, 4.3
Hz, 1 H), 7.09 (dd, J = 5.3, 3.2 Hz, 2 H), 7.04 (d, J = 8.4 Hz, 2 H), 6.56 (d,
J = 8.3 Hz, 2 H), 6.31 (d, J = 1.0 Hz, 1 H), 3.84–3.57 (m, 2 H), 1.91 (d, J =
1.2 Hz, 3 H), 1.83–1.68 (m, 2 H), 0.95 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 152.6, 146.8, 135.4, 128.9, 127.9,
127.4, 125.3, 125.2 (q, JC–F = 3.6 Hz), 124.0, 122.3, 120.1, 111.1, 47.0,
22.4, 11.1, 10.9.
HRMS (EI): m/z [M]+ calcd for C25H22N4: 378.1844; found: 378.1837.
4-[5-Methyl-3-propyl-2-(o-tolylimino)-2,3-dihydro-1H-imidazol-
1-yl]benzonitrile (3n)
Yield: 123 mg (75%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.05–6.93 (m, 6 H), 6.47–6.37 (m, 2 H),
6.22 (d, J = 1.3 Hz, 1 H), 3.65–3.52 (m, 2 H), 1.96 (s, 3 H), 1.71 (d, J = 1.2
Hz, 3 H), 1.66 (dt, J = 14.6, 7.3 Hz, 2 H), 0.85 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 154.9, 146.8, 135.9, 134.1, 131.8,
130.7, 128.8, 128.5, 126.3, 121.8, 120.9, 120.6, 110.4, 98.0, 46.5, 22.1,
17.4, 10.9, 10.2.
EI-MS: m/z = 360 [M + 1]+.
HRMS (EI): m/z [M]+ calcd for C20H20F3N3: 359.1609; found: 359.1606.
2-Aminoimidazoles 4; General Procedure
EI-MS: m/z = 331 [M + 1]+.
HRMS (EI): m/z [M]+ calcd for C21H22N4: 330.1844; found: 330.1842.
In a sealable test tube equipped with a magnetic stir bar were added
propargylamine 1 (0.5 mmol), carbodiimide 2 (0.5 mmol), NaOH (0.5
mmol) and DMSO (2 mL). The mixture was allowed to stir at 80 °C for
2 h. After completion of the reaction, the mixture was cooled to r.t.
Next, the mixture was diluted with sat. aq NH4Cl solution (4 mL) and
extracted with EtOAc (3 × 10 mL). The combined organic phase was
washed with brine (5 mL), dried over Na2SO4, filtered and concentrat-
ed under vacuum. The residue was subjected to preparative TLC (PE–
Et3N, 10:1) on a silica gel plate to give the pure product 4.
4-[3-Butyl-5-methyl-2-(o-tolylimino)-2,3-dihydro-1H-imidazol-1-
yl]benzonitrile (3o)
Yield: 103 mg (60%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.10–6.97 (m, 6 H), 6.46 (d, J = 8.6 Hz, 2
H), 6.25 (d, J = 0.9 Hz, 1 H), 3.74–3.59 (m, 2 H), 2.01 (s, 3 H), 1.76 (s, 3
H), 1.71–1.61 (m, 2 H), 1.39–1.27 (m, 2 H), 0.91 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 155.1, 146.9, 136.0, 134.3, 131.9,
130.8, 128.9, 128.6, 126.4, 121.8, 121.0, 120.7, 110.3, 98.1, 44.7, 30.9,
19.6, 17.4, 13.5, 10.3.
5-Methyl-N,1-diphenyl-1H-imidazol-2-amine (4a)12
Yield: 81 mg (65%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.50–7.45 (m, 3 H), 7.28–7.25 (m, 2 H),
7.17 (d, J = 3.3 Hz, 4 H), 6.91–6.84 (m, 1 H), 6.67 (s, 1 H), 4.64 (s, 1 H),
2.00 (s, 3 H).
EI-MS: m/z = 345 [M + 1]+.
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13C NMR (125 MHz, CDCl3): δ = 143.8, 140.5, 134.4, 129.3, 129.0,
127.8, 124.7, 123.0, 121.6, 119.9, 117.6, 10.3.
References
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EI-MS: m/z = 250 [M + 1]+.
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5-Methyl-N,1-di-p-tolyl-1H-imidazol-2-amine (4b)7b
Yield: 84 mg (61%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.33 (s, 2 H), 7.21 (s, 2 H), 7.18 (d, J =
5.8 Hz, 2 H), 7.04 (d, J = 5.9 Hz, 2 H), 6.66 (s, 1 H), 5.67 (s, 1 H), 2.45 (d,
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Yield: 82 mg (53%); yellow oil.
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1H NMR (500 MHz, CDCl3): δ = 7.25 (d, J = 9.0 Hz, 2 H), 7.20 (d, J = 8.9
Hz, 2 H), 7.02 (d, J = 8.9 Hz, 2 H), 6.79 (d, J = 9.0 Hz, 2 H), 6.60 (d, J = 1.2
Hz, 1 H), 3.87 (s, 3 H), 3.75 (s, 3 H), 1.97 (d, J = 1.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 159.8, 154.2, 145.0, 134.7, 129.1,
127.4, 124.0, 121.4, 118.5, 115.2, 114.3, 55.53, 55.50, 10.1.
EI-MS: m/z = 310 [M + 1]+.
N,1-Bis(4-chlorophenyl)-5-methyl-1H-imidazol-2-amine (4d)12
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Yield: 127 mg (80%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.56–7.44 (m, 2 H), 7.27–7.13 (m, 6 H),
6.67 (s, 1 H), 5.75 (s, 1 H), 2.01 (d, J = 0.6 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 143.2, 140.0, 135.3, 133.4, 130.4,
129.1, 128.9, 125.5, 124.5, 122.6, 117.5, 10.2.
EI-MS: m/z = 318 [M + 1]+.
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Acknowledgment
We thank the National Natural Science Foundation of China (No.
21452001), and are very grateful for a grant from the Construction
Funds for Key Disciplines of the College in Zhejiang Province during
the 12th Five Year Plan Period.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378787.
S
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p
p
ortioInfgrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3473–3478