Microwave-assisted cascade cycloaddition for C-N bond formation: An approach to the construction of 1,4,5,6-tetrahydropyrimidine and 2-imidazoline derivatives

Article abstract of DOI:10.1055/s-0033-1339406

An efficient strategy for the synthesis of various 1,4,5,6- tetrahydropyrimidine and 2-imidazoline derivatives has been reported. The reactions proceeded from nitriles with ethylenediamine or 1,3-diaminopropane via cascade cycloaddition in the presence of CuL₂ (L = 2-hydroxy-2-phenylacetate) to afford the corresponding 1,4,5,6- tetrahydropyrimidine or 2-imidazoline derivatives under reflux conditions or microwave irradiation in excellent yields.

Full text of DOI:10.1055/s-0033-1339406

PAPER
▌2525
paper
Microwave-Assisted Cascade Cycloaddition for C–N Bond Formation:
An Approach to the Construction of 1,4,5,6-Tetrahydropyrimidine and
2-Imidazoline Derivatives
Cascade Cycloaddition for C–N Bond Formation
Shujuan An, Bing Yin, Ping Liu, Xiangnan Li, Chen Li, Jianli Li,* Zhen Shi
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education and College of
Chemistry & Materials Science, Northwest University, Xi’an Shaanxi 710069, P. R. of China
Fax +86(29)88308396; E-mail: lijianli@nwu.edu.cn
Received: 15.04.2013; Accepted after revision: 18.06.2013
R
CO2H
Abstract: An efficient strategy for the synthesis of various 1,4,5,6-
tetrahydropyrimidine and 2-imidazoline derivatives has been re-
ported. The reactions proceeded from nitriles with ethylenediamine
or 1,3-diaminopropane via cascade cycloaddition in the presence of
CuL2 (L = 2-hydroxy-2-phenylacetate) to afford the corresponding
1,4,5,6-tetrahydropyrimidine or 2-imidazoline derivatives under re-
flux conditions or microwave irradiation in excellent yields.
RC OEt
3
R
CN
N
R
R
TsN
RCO2Et
N
H
n
n = 1,2
Key words: catalysis, cycloaddition, nitrogen heterocycles, ni-
triles, synthesis
S
O
Ph
TsN
R
N
OEt
H
R
CHO
Nitrogen-containing heterocycles are ubiquitous subunits
in a variety of biologically active molecules and they are
also widely used in materials science, bioorganic chemis-
try, and organometallic chemistry.1 In particularly, 2-sub-
stituted 1,4,5,6-tetrahydropyrimidine and 2-imidazoline
derivatives have frequently been used as powerful build-
ing blocks in molecules with biological and pharmacolog-
ical activity.2 They have potential anthelmintic,
antidepressant, antibacterial, and fungicide activity, and
they are also used for the treatment of various diseases in-
cluding hypercholesterolemia, cancer, and AIDS related
opportunistic pathogens.3,4 The wide demand for diverse
1,4,5,6-tetrahydropyrimidine and 2-imidazoline deriva-
tives in various fields has promote the development differ-
ent synthetic methods. Many methods for the synthesis of
1,4,5,6-tetrahydropyrimidine and 2-imidazoline deriva-
tives are now available (Scheme 1).5,6 For example,
Prasad and co-workers described [4 + 2] cycloaddition of
2-aryl-N-tosylazetidines with nitriles in the presence of
boron trifluoride–diethyl ether complex for the synthesis
of tetrahydropyrimidines,7a and also contributed a proto-
col for the synthesis of 2-imidazolines derivatives with
boron trifluoride–diethyl ether complex or triethyloxoni-
um tetrafluoroborate as a catalyst for the [3+2] cycloaddi-
tion of aziridines with nitriles.7b
Scheme 1 General methods for the synthesis of 1,4,5,6-tetrahydro-
pyrimidines and 2-imidazolines
more expensive catalysts. Versatile and efficient methods
for the direct construction of tetrahydropyrimidine and
imidazoline rings remain highly desirable. Recently, cas-
cade reactions that are mediated by various catalysts have
made great progress in the synthesis of useful heterocyclic
compounds via C–X (X = N, O, S) bond formation.8–10
Our group performed copper-catalyzed reactions for the
synthesis of 2-thiazolines and 2-oxazolines.11 On the basis
of a previous study, we envision that cascade cycloaddi-
tion of a nitrile with a diamine would be a direct approach
for the construction of tetrahydropyrimidine and imidazo-
line rings in accordance with the principles of green
chemistry. Copper-catalyzed reactions have received con-
siderable attentions because of their efficiency and low
cost.12 However, to the best of our knowledge, the catalyt-
ic activity of copper has not been fully explored in this re-
action. In consequence, we explored the capability of
bis(2-hydroxy-κO-2-phenylacetato)copper(II) (CuL2) as
an inexpensive, reusable, and efficient catalyst for the
construction of 1,4,5,6-tetrahydropyrimidine or 2-imidaz-
oline derivatives from nitriles with ethylenediamine or
1,3-diaminopropane under reflux conditions or micro-
wave irradiation (Scheme 2).
Mohammadpoor-Baltork et al. reported that nano-silica
gel solid acid catalyzed cyclocondensation reaction of
arenecarbonitriles with 1,3-diaminopropane afforded the
corresponding tetrahydropyrimidines.7c However, these
procedures generally suffer from poor functional group
tolerance or low product yields, or they require the use of
To begin our study, 3-cyanopyridine (1b) and 1,3-diami-
nopropane (2) were chosen as model substrates to opti-
mize the reaction conditions. As can be seen from Table
1, screening various transition-metal catalysts (entries 1–
13) revealed that bis(2-hydroxy-κO-2-phenylacetato)cop-
per(II) (CuL2) displayed greater catalytic reactivity in the
reactions (entry 5); only 10% yield of the desired product
was obtained in the absence of CuL2 (entry 14). Moreover,
SYNTHESIS 2013, 45, 2525–2532
Advanced online publication: 24.07.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339406; Art ID: SS-2013-H0287-OP
© Georg Thieme Verlag Stuttgart · New York

2526
S. An et al.
PAPER
Scheme 2 Synthesis of 1,4,5,6-tetrahydropyrimidines and 2-imidazolines
Table 1 Optimization of the Reaction Conditionsa
several additives were tested including iodine, sulfur, and
DBU (entries 15–17); iodine performed better than other
additives (entry 16). Additionally, various bases were in-
vestigated (entries 18–20); sodium acetate is beneficial
N
catalyst, temp
CN
+
H2N
NH2
base, solvent
N
HN
N
2
3b
1b
for high reaction efficiency and low reagent cost (entry
20). Next, different temperatures were examined (entries
21–23), and 90 °C was found to be the optimal tempera-
ture (entry 22). Finally, solvent effects were also exam-
ined, and toluene proved to be the best solvent (entries
24–26). We also performed the reaction under microwave
irradiation and the desired product 3b was obtained in
26% yield in the absence of CuL2, and the yield increased
to 95% in the presence of CuL2 under the same conditions
(entries 27 and 28).
Entry Catalystb
Additive Base
Solvent Temp Yieldc
(°C) (%)
1
2
Co(L1)2
CoL2
Fe(L1)3
Mn(L1)2
CuL2
Cu(L1)2
Cu(L2)2
Cu(L3)2
Cu(L4)2
Cu(L5)2
Cu(IAA)2
CuC2O4
Cu(OAc)2
–
–
–
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
MeCN
EtOH
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
70
90
100
90
90
90
90
90
62
61
15
43
80
73
61
71
74
70
69
20
64
10
80
83
81
85
84
86
82
90
90
85
84
73
95
26
–
–
3
–
–
4
–
–
5
–
–
6
–
–
Using the optimized reaction conditions, we next explored
the substrate scope. The results of the reaction of various
nitriles with 1,3-diaminopropane (2) are summarized in
Table 2. These transformations displayed high functional
group tolerance. The nitriles possessing pyridyl, pyrimi-
dyl, thienyl, and pyrazinyl groups underwent the desired
reaction to give the corresponding 1,4,5,6-tetrahydropy-
rimidine products 3a–g in good yields (entries 1–7). In ad-
dition, nitriles with nitro, chloro, amino, and bromo
groups on the phenyl ring gave the corresponding 1,4,5,6-
tetrahydropyrimidines 3i–l in excellent yields in the reac-
tions (entries 9–12). An extensive investigation of the re-
action showed that dinitriles, such as phthalonitrile and
terephthalonitrile, were converted into the respective
monotetrahydropyrimidines 3m and 3n with excellent
chemoselectivity (entries 13–15). However, 2-aminophe-
nyl-substituted 3h and 4-tolyl-substituted 3p were ob-
tained in trace amounts (entries 8 and 16). It is noteworthy
that: (1) To the best of our knowledge, 3m, 3e, and 3f are
novel (entries 5, 6, and 12). (2) For electronic effects of
the transformation, we found that electron-deficient aro-
matic nitriles showed better reactivity and gave higher
yields than electron-rich aromatic nitriles. (3) Mixtures of
dinitriles (4 mmol) with double 1,3-diaminopropane (10
mmol) gave only monotetrahydropyrimidines. The trans-
formation of dinitriles into monotetrahydropyrimidines is
of practical significance because the remaining nitrile
group can be converted into other important functional
groups.
7
–
–
8
–
–
9
–
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27d
28d
–
–
–
–
–
–
–
–
–
–
CuL2
DBU
I2
S
–
CuL2
–
CuL2
–
CuL2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
K2CO3
NaHSO3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
CuL2
CuL2
CuL2
CuL2
CuL2
CuL2
CuL2
CuL2
NMP
CuL2
toluene
toluene
–
a Reaction conditions: 1b (4 mmol), 2 (5 mmol), base (1.1 mmol), ad-
ditive (0.4 mmol), catalyst (0.4 mmol), solvent (1 mL), 90 °C, 4 h.
b L = 2-hydroxy-2-phenylacetate; L1 = cinnamate; L2 = benzoate;
L3 = 3-nitrobenzoate; L4 = 4-nitrobenzoate; L5 = 4-hydroxybenzoate;
IAA = indole-3-acetate.
c The yield was determined by GC analysis with n-dodecane as the in-
For further examination of CuL2 in C–N bond formation,
ethylenediamine (4) was examined as the condensation ternal standard.
d The reactions performed at 90 °C under microwave irradiation with
800 W applied power for 20 min.
partner, and the results are given in Table 3. Satisfactorily,
the reactions afforded the corresponding 2-imidazolines 5
Synthesis 2013, 45, 2525–2532
© Georg Thieme Verlag Stuttgart · New York

PAPER
Cascade Cycloaddition for C–N Bond Formation
2527
Table 3 Copper-Catalyzed Synthesis of 2-Imidazolines under Re-
Table 2 Copper-Catalyzed Synthesis of 1,4,5,6-Tetrahydropyrimi-
flux Conditions and Microwave Irradiationa,b,c
dines under Reflux Conditions and Microwave Irradiationa,b
N
N
CuL2, NaOAc, I2
toluene, 90 °C
CuL2, NaOAc, I2
NH2
Ar
Ar CN
H2N
+
Ar
H2N
NH2
Ar CN
+
toluene, 90 °C
N
H
NH
3a–n
1
2
1
4
5a–j
Entry Product Ar
Time
Yield (%)
Entry Product Ar
Time
Yield (%)
Reflux MW
Reflux MW
Reflux MW
Reflux MW
1
2
3a
3b
3c
3d
3e
3f
2-pyridyl
3-pyridyl
4-pyridyl
Ph
6 h
4 h
4 h
6 h
6 h
6 h
6 h
10 h
6 h
6 h
6 h
6 h
4 h
4 h
4 h
10 h
25 min
82
85
95
97
90
88
89
92
1
2
5a
5b
5c
5d
5e
5f
3-pyridyl
4-pyridyl
Ph
4 h
4 h
4 h
4 h
20 min 86
20 min 90
20 min 90
20 min 80
92
93
93
86
–
20 min
20 min
25 min
25 min
25 min
25 min
90
3
95
3
4
85
4
2-thienyl
5
pyrimidin-2-yl
pyrazin-2-yl
2-thienyl
82
5
pyrimidin-2-yl 10 h
–
–
trace
trace
6
78
6
pyrazin-2-yl
4-ClC6H4
10 h
4 h
–
7
3g
3h
3i
85
7
5g
5h
5i
20 min 80
trace
87
8
2-H2NC6H4
3-H2NC6H4
4-ClC6H4
trace
65
8
2-NCC6H4
3-NCC6H4
4-NCC6H4
10 h
2 h
9
25 min
25 min
25 min
25 min
20 min
20 min
20 min
75
85
97
85
97
97
98
9
15 min 90
15 min 90
97
98
10
11
12
13
14
15
16
3j
80
10
5j
2 h
a Reaction conditions: nitrile 1 (4 mmol), diamine 4 (5 mmol),
NaOAc (1.1 mmol), I2 (0.4 mmol), CuL2 (0.4 mmol), toluene (1 mL),
3k
3l
4-O2NC6H4
4-BrC6H4
95
80
90 °C.
b All MW reactions were carried out at 90 °C, with 800 W applied
3m
3n
3o
3p
2-NCC6H4
3-NCC6H4
4-NCC6H4
4-MeC6H4
94
power.
c The yield was determined by GC analysis with n-dodecane as the in-
95
ternal standard.
95
trace
difficult to synthesize than their aryl analogues. There-
fore, the present method was only found to be effective for
the conversion of arenecarbonitriles to the corresponding
1,4,5,6-tetrahydropyrimidines and 2-imidazolines.
a Reaction conditions: nitrile 1 (4 mmol), diamine 2 (5 mmol), NaOAc
(1.1 mmol), I2 (0.4 mmol), CuL2 (0.4 mmol), toluene (1 mL), 90 °C.
b All MW reactions were carried out at 90 °C, with 800 W applied
power.
c The yield was determined by GC analysis with n-dodecane as the in-
ternal standard.
Microwave-assisted organic synthesis (MAOS) is a pow-
erful technique that is being used more frequently to ac-
celerate thermal organic reactions. The notable features of
the microwave approach are enhanced reaction rates, for-
mation of purer products in higher yields and easier ma-
nipulation.13 Therefore, we examined the effect of
microwave irradiation on the synthesis from the reaction
of nitriles with 1,3-diaminopropane (2) or ethylenedi-
amine (4), respective, in the presence of CuL2. Gratifying-
ly, the corresponding 1,4,5,6-tetrahydropyrimidines and
2-imidazolines were obtained in 75–98% yields within
10–25 minutes. The results are summarized in Table 2 and
Table 3.
with great efficiency. For heteroaryl-substituted 2-imid-
azolines, aromatic nitriles with pyridyl or thienyl worked
well, and the desired 2-imidazolines 5a–d were obtained
in 80–90% yields (entries 1–4). Surprisingly, 2-imidazo-
lines possessing pyrimidyl or pyrazinyl groups were ob-
tained in only trace amounts (entries 5 and 6). The
reactions of 4-chlorobenzonitrile with ethylenediamine
(4) produced the expected 2-imidazoline 5g in moderate
to good yield (entry 7). Finally, we investigated transfor-
mations of dinitriles to 2-imidazolines. The results dem-
onstrated that 2-imidazolines 5i and 5j were obtained in
good yields (entries 8 and 9), while phthalonitrile gave
trace amounts of product for the possible reason was that
the reaction was sensitive to steric hindrance by the sub-
stituent on the aromatic ring (entry 10). Meanwhile, al-
kanenitriles were also examined; 2-alkyl-1,4,5,6-
tetrahydropyrimidines and 2-alkylimidazolines are more
A possible mechanism for the synthesis of 1,4,5,6-tetrahy-
dropyrimidines and 2-imidazolines is depicted in Scheme
3. First, the nitrile is activated by CuL2 to give intermedi-
ate A. Nucleophilic addition of A with amine 2 or 4 pro-
vides B1 or B2. Intramolecular cycloaddition of B1 or B2
provides C1 or C2, intermediate C1 or C2 release [Cu] and
NH3 to afford target products T1 or T2.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2525–2532

2528
S. An et al.
PAPER
Ar
H
N
[Cu]
N
NH
H2N [Cu]
NH
Ar
Ar
HN
NH2
HN
T1
H2N
NH2
B1
C1
NH3
Ar CN
NH3
[Cu]
[Cu]
Ar
C
N
[Cu]
A
NH2
H
H2N
N
NH2 [Cu]
NH
[Cu]
NH2
Ar
Ar
HN
N
HN
Ar
C2
B2
N
H
T2
Scheme 3 Possible copper-catalyzed mechanism for the synthesis of 1,4,5,6-tetrahydropyrimidines and 2-imidazolines
For a better understanding, DFT14 calculations based on
the Fukui function f+ 14 [Equation 1 (a)] were performed
(r)
for the catalyst with B3LYP15 functional. Basis set of dou-
ble-ζ quality (6-31G** for C, H elements, 6-31+G* for O
element and SVP16 for Cu element) is used for the geom-
etry optimization and larger triple-ζ basis set (6-311G**
for C, H elements, 6-311+G* for O element, and TZVP17
for Cu element) is used for the following single point en-
ergy calculation. The optimized structure is proven to be
the local minimum based on the results of vibration anal-
ysis. All the calculations are performed with Gaussian 03
program.18 where N is the number of electrons, ν is the ex-
ternal potential, qX is the electronic population of atom X
in a molecule.
∂ρ(→r)
∂N
Figure 1 (a) The 3D representation of the Fukui function f+(r) of the
→
→
ƒ+
=
ρ(r)N+1
(1a)
(1b)
ρ(r)
=
isovalue of 0.002 a.u. (positive in red color and negative in green col-
–
N
(r)
or). (b) The condensed Fukui function f+ of copper and other sur-
ν
ν
(r)
qN+1 qN
ƒ+
=
–
rounding atoms.
X
X
(X)
Equation 1
Following the results of Fukui function, we further ex-
plored the frontier molecular orbitals involved in the inter-
action between the catalyst and benzonitrile, which is an
example of an aromatic nitriles. As shown in Figure 2, the
HOMO of benzonitrile has significant contribution from
the lone pair of the nitrogen atom. Correspondingly, the
LUMO of the catalyst is distributed mainly within the re-
gion around the copper atom. The small energy difference
(3.49 eV) between these two orbitals should facilitate the
electron transfer from the nitrogen atom to the copper
atom and thus the catalyst could active aromatic nitrile as
shown in Scheme 3.
The reactivity concerning nucleophilic attack has been
successfully described by the Fukui function f+
, e.g.,
19
(r)
nitrile attack in this work. As shown in Figure 1 (a), the
3D representation of f+(r) clearly demonstrates that the re-
gion around the copper atom possesses higher reactivity
than other parts of the catalyst. The condensed Fukui
function of individual atom [Figure 1 (b)], obtained from
NBO analysis,20 indicates that the copper atom should be
the first choice for the nitrile attack since its value of con-
densed Fukui function, 0.5073, is larger than those of oth-
er atoms by at least one magnitude. This theoretical
prediction supports the proposed reaction mechanism in
Scheme 3.
In summary, we have first demonstrated that CuL2 can be
used as a reusable and inexpensive catalyst for efficient
synthesis of 1,4,5,6-tetrahydropyrimidine or 2-imidazo-
line derivatives under either reflux conditions or micro-
wave irradiation. The mild reaction conditions, excellent
conversion, and high functional group tolerance have
Synthesis 2013, 45, 2525–2532
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PAPER
Cascade Cycloaddition for C–N Bond Formation
2529
2-(Pyridin-2-yl)-1,4,5,6-tetrahydropyrimidine (3a)5g
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc–MeOH, 3:1; Rf = 0.31) to provide
3a (3.28 mmol, 82%) as yellow oil.
IR (KBr): 3447, 3058, 2968, 1657, 1605, 1578, 1470, 1206, 741
cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.24 (d, J = 8.0 Hz, 1 H), 8.63 (d,
J = 4.5 Hz, 1 H), 8.05 (t, J = 7.8 Hz, 1 H), 7.58 (m, 1 H), 3.76 (t,
J = 5.7 Hz, 4 H), 2.14 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 154.97, 148.80, 142.48, 138.86,
128.10, 124.37, 39.17, 18.34.
MS (EI): m/z = 161 [M]+.
2-(Pyridin-3-yl)-1,4,5,6-tetrahydropyrimidine (3b)6b
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc–MeOH, 3:1; Rf = 0.35) to provide
3b (3.60 mmol, 90%) as a yellow solid; mp 97–98 °C.
IR (KBr): 3289, 2935, 1623, 1521, 1473, 1417, 1195, 709 cm–1.
Figure 2 The 3D representation and orbital energies of the frontier
molecular orbitals involved in the interaction between the catalyst and
benzonitrile
1H NMR (400 MHz, CDCl3): δ = 8.87 (s, 1 H), 8.64 (d, J = 4.8 Hz,
1 H), 8.02 (d, J = 7.9 Hz, 1 H), 7.34–7.31 (m, 1 H), 3.53 (t, J = 5.7
Hz, 4 H), 2.09–1.75 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 153.11, 150.59, 147.40, 134.14,
132.52, 123.18, 42.02, 20.40.
made the approach distinctly superior to other protocols
reported for the preparation of various 2-substituted
1,4,5,6-tetrahydropyrimidines and 2-imidazolines in a be-
nign manner.
MS (EI): m/z = 161 [M]+.
Column chromatography was performed with silica gel (200–300
mesh). Melting points were determined using a standard melting
point instrument and are uncorrected. 1H NMR spectra were record-
ed on 400 MHz instrument and 13C NMR spectra were recorded on
101 MHz instrument; internal standard TMS. IR spectra were re-
corded on a FT-IR spectrophotometer. The MS data were measured
on a GC-MS with electron ionization. All reactions were carried out
under an atmosphere of air.
2-(Pyridin-4-yl)-1,4,5,6-tetrahydropyrimidine (3c)6b
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc–MeOH, 3:1; Rf = 0.41) to provide 3c
(3.80 mmol, 95%) as a white solid; mp 97–99 °C.
IR (KBr): 3425, 2939, 1624, 1543, 1412, 1308, 1042, 835 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.66 (dd, J = 4.5, 1.6 Hz, 2 H),
7.57 (dd, J = 4.5, 1.6 Hz, 2 H), 3.55 (t, J = 4.0 Hz, 4 H), 1.93–1.87
(m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 152.70, 150.01, 144.47, 120.50,
42.23, 20.42.
Bis(2-Hydroxy-κO-2-phenylacetato)copper(II) (CuL2, L = 2-hy-
droxy-2-phenylacetate)
2-Hydroxy-2-phenylacetic acid (10 mmol) was slowly added to a
soln of NaOH [NaOH (8 mmol) in H2O (10 mL)] whilst stirring. To
the soln, an aq soln of CuCl2 [CuCl2·2 H2O (4 mmol) in H2O (14
mL)] was added, and the mixture was stirred for 5 min to give a blue
precipitate that was collected by filtration, washed with H2O, and
dried in vacuo to provide CuL2 (0.87 g, 92%). Single crystals suit-
able for X-ray diffraction were obtained by allowing Et2O to diffuse
into a saturated soln of CuL2 in MeCN.21
MS (EI): m/z = 161 [M]+.
2-Phenyl-1,4,5,6-tetrahydropyrimidine (3d)5g
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc–MeOH, 3:1; Rf = 0.42) to provide
3d (3.40 mmol, 85%) as a white solid; mp 85–88 °C.
IR (KBr): 3242, 2940, 2840, 1620, 1574, 1531, 1488, 1195, 784,
696 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.68 (dd, J = 7.6, 1.8 Hz, 2 H),
7.43–7.35 (m, 3 H), 3.54 (t, J = 6.0 Hz, 4 H), 1.91–1.85 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 154.51, 137.37, 129.64, 128.34,
125.99, 42.39, 20.77.
2-Aryl-1,4,5,6-tetrahydropyrimidines 3a–n or 2-Aryl-4,5-di-
hydro-1H-imidazoles 5a–j; General Procedure under Reflux
Conditions
A mixture of nitrile (4 mmol), ethylenediamine or 1,3-diaminopro-
pane (5 mmol), NaOAc (1.1 mmol), I2 (0.4 mmol), and CuL2 (0.4
mmol) was stirred at 90 °C for the appropriate time. The progress of
the reaction was monitored by TLC (EtOAc–MeOH, 3:1). After
completion of the reaction, the mixture was cooled to r.t., diluted
with CHCl3 (10 mL) and the catalyst was removed by filtration. The
solvent was evaporated, all compounds was purified by chromatog-
raphy (silica gel) to afford the pure product.
MS (EI): m/z = 160 [M]+.
2-(1,4,5,6-Tetrahydropyrimidin-2-yl)pyrimidine (3e)
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc–MeOH, 3:1; Rf = 0.35) to provide 3e
(3.28 mmol, 82%) as a yellow solid; mp 284–285 °C.
2-Aryl-1,4,5,6-tetrahydropyrimidines 3a–n or 2-Aryl-4,5-di-
hydro-1H-imidazoles 5a–j ; General Procedure under Micro-
wave Irradiation
IR (KBr): 3448, 3273, 3086, 2964, 1678, 1594, 1570, 1209, 715
cm–1.
A mixture of nitrile (4 mmol), ethylenediamine or 1,3-diaminopro-
pane (5 mmol), NaOAc (1.1 mmol), I2 (0.4 mmol), and CuL2 (0.4
mmol) was irradiated with microwave (800 W) for 10–25 min by
pulsed irradiation. At the end of the reaction (monitored by TLC,
EtOAc–MeOH, 3:1), the mixture was cooled to r.t., CHCl3 was then
added and the catalyst was filtered. Evaporation of the solvent gave
the almost pure product. Further purification was performed as for
the procedure used in the synthesis of imidazolines and tetrahydro-
pyrimidines under reflux conditions.
1H NMR (400 MHz, DMSO): δ = 9.15 (d, J = 4.9 Hz, 2 H), 7.92 (t,
J = 4.9 Hz, 1 H), 3.54 (t, J = 5.5 Hz, 4 H), 2.01–1.95 (m, 2 H).
13C NMR (101 MHz, DMSO): δ = 160.89, 155.82, 154.90, 127.41,
41.41, 20.08.
MS (EI): m/z = 162 [M]+.
HRMS (ESI): m/z [M + H]+ calcd for C8H11N4: 163.0984; found:
163.1038.
© Georg Thieme Verlag Stuttgart · New York
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PAPER
2-(4-Bromophenyl)-1,4,5,6-tetrahydropyrimidine (3l)5g
2-(Pyrazin-2-yl)-1,4,5,6-tetrahydropyrimidine (3f)
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc–MeOH, 3:1; Rf = 0.35) to provide 3f
(3.12 mmol, 78%) as a white solid; mp 114–116 °C.
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc–MeOH, 3:1; Rf = 0.29) to provide 3l
(3.20 mmol, 80%) as a white solid; mp 155–156 °C.
IR (KBr): 3361, 2950, 2929, 2849, 1630, 1573, 1469, 1155, 774
cm–1.
IR (KBr): 3424, 3284, 3124, 2997, 2647, 1608, 1536, 1175, 727
cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.41 (s, 1 H), 8.60 (d, J = 2.3 Hz,
1 H), 8.44 (d, J = 1.2 Hz, 1 H), 3.58 (s, 4 H), 1.87–1.91 (m, 2 H).
1H NMR (400 MHz, CD3OD): δ = 7.68 (d, J = 7.2 Hz, 2 H), 7.56 (d,
J = 8.0 Hz, 2 H), 3.51 (t, J = 4.0 Hz, 4 H), 1.99 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 150.53, 146.87, 145.10, 143.13,
13C NMR (101 MHz, CD3OD): δ = 159.57, 133.12, 129.88, 127.10,
141.85, 35.80, 20.66.
41.51, 20.16.
MS (EI): m/z = 162 [M]+.
MS (EI): m/z = 238 [M]+.
HRMS (ESI): m/z [M + H]+ calcd for C8H11N4: 163.0984; found:
163.1038.
2-(1,4,5,6-Tetrahydropyrimidin-2-yl)benzonitrile (3m)
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc; Rf = 0.35) to provide 3m (3.76
mmol, 94%) as a white solid; mp 142–144 °C.
2-(Thiophen-2-yl)-1,4,5,6-tetrahydropyrimidine (3g)6b
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc–MeOH, 3:1; Rf = 0.26) to provide
3g (3.40 mmol, 85%) as a yellow solid; mp 185–186 °C.
IR (KBr): 3429, 3211, 2957, 2851, 1643, 1472, 1427, 1360, 1093,
774, 712 cm–1.
IR (KBr): 3193, 3012, 2934, 2832, 1606, 1549, 1514, 1325, 1167,
712 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.35 (d, J = 4.0 Hz, 2 H), 7.03 (dd,
J = 6.4, 2.3 Hz, 1 H), 3.51 (t, J = 5.7 Hz, 4 H), 1.92–1.88 (m, 2 H).
1H NMR (400 MHz, CDCl3): δ = 7.89 (dd, J = 3.9, 2.6 Hz, 1 H),
7.76 (d, J = 3.2 Hz, 1 H), 7.64–7.58 (m, 2 H), 3.87 (t, J = 6.0 Hz, 2
H), 3.79 (t, J = 5.6 Hz, 2 H), 2.09–2.02 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 160.54, 151.90, 133.75, 131.74,
131.42, 130.80, 121.19, 120.76, 45.26, 37.59, 20.29.
MS (EI): m/z = 185 [M]+.
13C NMR (101 MHz, CDCl3): δ = 150.35, 140.50, 127.72, 127.19,
124.69, 41.83, 20.59.
MS (EI): m/z = 166 [M]+.
HRMS (ESI): m/z [M + H]+ calcd for C11H12N3: 186.1026; found:
186.1092.
3-(1,4,5,6-Tetrahydropyrimidin-2-yl)aniline (3i)22
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc–MeOH, 3:1; Rf = 0.30) to provide 3i
(2.60 mmol, 65%) as a yellow oil.
3-(1,4,5,6-Tetrahydropyrimidin-2-yl)benzonitrile (3n)7c
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc; Rf = 0.33) to provide 3n (3.80
mmol, 95%) as a white solid; mp 136–137 °C.
IR (KBr): 3308, 3208, 3125, 2996, 1644, 1629, 1593, 1495, 1046,
791, 719 cm–1.
1H NMR (400 MHz, DMSO): δ = 7.20 (t, J = 8.0 Hz, 1 H), 6.85–
6.80 (m, 3 H), 5.59 (s, 2 H), 3.43 (t, J = 4.0 Hz, 4 H), 1.94–1.92 (m,
2 H).
13C NMR (101 MHz, DMSO): δ = 162.67, 151.91, 132.26, 132.13,
120.69, 116.87, 114.40, 41.31, 20.45.
IR (KBr): 3424, 3117, 2996, 2777, 2233, 1648, 1617, 1449, 1103,
884, 807, 710 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.98 (s, 1 H), 7.91 (d, J = 7.8 Hz,
1 H), 7.68 (d, J = 7.6 Hz, 1 H), 7.50 (m, 1 H), 3.53 (t, J = 5.7 Hz, 4
H), 1.91–1.85 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 153.09, 138.37, 132.84, 130.55,
130.08, 129.11, 118.51, 112.14, 42.17, 20.48.
MS (EI): m/z = 185 [M]+.
MS (EI): m/z = 175 [M]+.
2-(4-Chlorophenyl)-1,4,5,6-tetrahydropyrimidine (3j)6b
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc–MeOH, 3:1; Rf = 0.36) to provide 3j
(3.20 mmol, 80%) as a white solid; mp 124–128 °C.
4-(1,4,5,6-Tetrahydropyrimidin-2-yl)benzonitrile (3o)7c
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc; Rf = 0.40) to provide 3o (3.80
mmol, 95%) as a white solid; mp 69–71 °C.
IR (KBr): 3178, 2952, 2853, 1623, 1541, 1488, 1194, 1036, 836
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.61 (d, J = 6.7 Hz, 2 H), 7.35 (d,
J = 8.1 Hz, 2 H), 3.51 (t, J = 4.0 Hz, 4 H), 1.92–1.85 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 154.69, 135.76, 134.83, 128.35,
127.70, 41.76, 20.31.
IR (KBr): 3431, 3052, 2361, 2232, 1630, 1504, 1401, 1199, 845
cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.79 (dd, J = 8.2, 3.6 Hz, 2 H),
7.68 (dd, J = 8.3, 4.2 Hz, 2 H), 3.54 (t, J = 4.0 Hz, 4 H), 1.92–1.85
(m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 153.29, 141.47, 132.10, 126.89,
118.57, 112.97, 42.27, 20.45.
MS (EI): m/z = 194 [M]+.
2-(4-Nitrophenyl)-1,4,5,6-tetrahydropyrimidine (3k)6b
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc–MeOH, 3:1; Rf = 0.42) to provide
3k (3.80 mmol, 95%) as a yellow solid; mp 140–142 °C.
MS (EI): m/z = 185 [M]+.
3-(4,5-Dihydro-1H-imidazol-2-yl)pyridine (5a)6f
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc–MeOH, 3:1; Rf = 0.35) to provide
5a (3.44 mmol, 86%) as a white solid; mp 102 °C.
IR (KBr): 3424, 3179, 2936, 2854, 1625, 1598, 1521, 1487, 1343,
1107, 861, 810 cm–1.
IR (KBr): 3160, 2938, 2854, 1609, 1587, 1513, 1485, 1277, 984,
706 cm–1.
1H NMR (400 MHz, DMSO): δ = 9.02 (s, 1 H), 8.66 (d, J = 3.6 Hz,
1 H), 8.18 (d, J = 7.8 Hz, 1 H), 7.48 (dd, J = 7.3, 5.0 Hz, 1 H), 3.65
(s, 4 H).
1H NMR (400 MHz, CDCl3): δ = 8.25 (d, J = 8.7 Hz, 2 H), 7.87 (d,
J = 8.7 Hz, 2 H), 3.57 (t, J = 5.7 Hz, 4 H), 1.92 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 152.95, 148.47, 143.10, 127.17,
123.55, 42.39, 20.44.
MS (EI): m/z = 205 [M]+.
Synthesis 2013, 45, 2525–2532
© Georg Thieme Verlag Stuttgart · New York

PAPER
Cascade Cycloaddition for C–N Bond Formation
2531
13C NMR (101 MHz, DMSO): δ = 166.88, 156.23, 153.30, 139.68,
MS (EI): m/z = 171 [M]+.
131.34, 128.59, 54.68.
MS (EI): m/z = 147 [M]+.
4-(4,5-Dihydro-1H-imidazol-2-yl)benzonitrile (5j)11b
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc–MeOH, 3:1; Rf = 0.42) to provide 5j
(3.6 mmol, 90%) as a white solid; mp 205 °C.
4-(4,5-Dihydro-1H-imidazol-2-yl)pyridine (5b)6f
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc–MeOH, 3:1; Rf = 0.40) to provide
5b (3.60 mmol, 90%) as a yellow solid; mp 134–135 °C.
IR (KBr): 3157, 2948, 2361, 2225, 1596, 1552, 1490, 1273, 1115,
849 cm–1.
IR (KBr): 3183, 2942, 2884, 1615, 1596, 1547, 1510, 1279, 686
cm–1.
1H NMR (400 MHz, DMSO): δ = 7.98 (d, J = 8.2 Hz, 2 H), 7.92 (d,
J = 8.1 Hz, 2 H), 3.65 (s, 4 H).
1H NMR (400 MHz, CDCl3): δ = 8.71 (dd, J = 4.5, 1.6 Hz, 2 H),
7.66 (dd, J = 4.5, 1.6 Hz, 2 H), 3.85 (s, 4 H).
13C NMR (101 MHz, DMSO): δ = 167.55, 139.82, 137.50, 132.99,
123.73, 117.80, 61.21.
13C NMR (101 MHz, CDCl3): δ = 150.06, 149.41, 121.18, 120.67,
MS (EI): m/z = 171 [M]+.
49.70.
MS (EI): m/z = 147 [M]+.
Acknowledgment
2-Phenyl-4,5-dihydro-1H-imidazole (5c)6f
The project was supported by National Natural Science Foundation
of China (NSFC 20972124; 21272184; 21103137), Shaanxi Provin-
cial Natural Science Fund Project (No. 2012JQ2007), Shaanxi Sci-
ence and Technology Coordination Innovation Engineering Project
(No.2011K12-77), Special Science Research Foundation of Educa-
tion Committee in Shaanxi Province (No.12JK0584), and the Chi-
nese National Innovation Experiment Program for University
Students (No. 201210697011).
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc–MeOH, 3:1; Rf = 0.38) to provide 5c
(3.60 mmol, 90%) as a white solid; mp 101 °C.
IR (KBr): 3201, 2929, 2868, 1611, 1598, 1573, 1508, 1270, 982,
696 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 8.0 Hz, 2 H), 7.45–
7.37 (m, 3 H), 3.78 (s, 4 H).
13C NMR (101 MHz, CDCl3): δ = 165.09, 130.83, 129.82, 128.43,
127.16, 49.79.
MS (EI): m/z = 146 [M]+.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
2-(Thiophen-2-yl)-4,5-dihydro-1H-imidazole (5d)6f
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc–MeOH, 3:1; Rf = 0.35) to provide
5d (3.20 mmol, 80%) as a white solid; mp 172–173 °C.
References
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5g (3.2 mmol, 80%) as a white solid; mp 187–188 °C.
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988, 838, 729 cm–1.
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3-(4,5-Dihydro-1H-imidazol-2-yl)benzonitrile (5i)11b
Following the general procedure, the product was obtained by chro-
matography (silica gel, EtOAc–MeOH, 3:1; Rf = 0.37) to provide 5i
(3.6 mmol, 90%) as a white solid; mp 105 °C.
IR (KBr): 3378, 2923, 2866, 2232, 1621, 1595, 1577, 1450, 1291,
988, 703 cm–1.
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13C NMR (101 MHz, DMSO): δ = 167.09, 138.99, 136.92, 136.67,
135.67, 134.85, 123.61, 116.61, 54.77.
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Synthesis 2013, 45, 2525–2532
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