A concise microwave-assisted synthesis of 2-aminoimidazole marine sponge alkaloids of the isonaamines series

Article abstract of DOI:10.1055/s-2008-1078444

A short and efficient route to 1,4-substituted 2-aminoim-idazole alkaloids starting from the easily accessible 2-alkylami-nopyrimidines and α-bromo aldehydes is reported. The formation of the intermediate imidazo[l,2-a] pyrimidinium salts and subsequent cleavage were facilitated by microwave irradiation. Marine sponge alkaloids preclathridines A, C and isonaamines A, C, D were obtained in high yields using the optimized one-pot two-step procedure. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1078444

PAPER
2083
A Concise Microwave-Assisted Synthesis of 2-Aminoimidazole Marine Sponge
Alkaloids of the Isonaamines Series
M
icrowave-Assist
.
e
d
Synthesis
S
of 2-Aminoim
.
idazole
DerE
ivatives rmolat’ev,a V. L. Alifanov,b V. B. Rybakov,b E. V. Babaev,*b E. V. Van der Eycken*a
a
Laboratory for Organic and Microwave-Assisted Chemistry (LOMAC), University of Leuven,
Celestijnenlaan 200F, 3001 Leuven, Belgium
Fax +32(16)327990; E-mail: erik.vandereycken@chem.kuleuven.be
Department of Chemistry, Moscow State University, 119991 Moscow, Russia
Fax +7(495)9393929; E-mail: babaev@org.chem.msu.ru
b
Received 31 March 2008; revised 9 April 2008
The reported synthetic approaches to 1,4-dialkyl-2-ami-
noimidazoles 1 include quite a lengthy iminophospho-
rane-mediated synthesis from a-azido esters,4 the
condensation of poorly available a-amino ketones with
Abstract: A short and efficient route to 1,4-substituted 2-aminoim-
idazole alkaloids starting from the easily accessible 2-alkylami-
nopyrimidines and a-bromo aldehydes is reported. The formation of
the intermediate imidazo[1,2-a]pyrimidinium salts and subsequent
cleavage were facilitated by microwave irradiation. Marine sponge cyanamide,5,6 or a multistep derivatization of the protect-
ed imidazole core.7,8
alkaloids preclathridines A, C and isonaamines A, C, D were ob-
tained in high yields using the optimized one-pot two-step proce-
dure.
We have recently communicated a facile one-pot two-step
procedure for the synthesis of diversely substituted 2-ami-
Key words: natural products, ring opening, cleavage, imidazo[1,2-
a]pyrimidin-1-ium salts, 2-aminoimidazoles
noimidazoles from a-bromocarbonyl compounds and
substituted 2-aminopyrimidines.11 This methodology
could serve as a novel, practical, and general approach to
marine alkaloids of the family 1 (Table 1).
Marine sponges have been proven to be a source of bio-
Here, we report a short and efficient total synthesis of pre-
clathridine and isonaamine alkaloids 1a–e based on the
condensation of 2-aminopyrimidines 3 and a-bromo alde-
hydes 4 and subsequent cleavage of the intermediate imi-
logically active alkaloids and their metabolites. Among
the calcareous sponges, the genera Leucetta and Clathrina
are a rich source of imidazole alkaloids. Since the first dis-
covery of 2-aminoimidazole alkaloids in marine sponges
by Kashman’s group in 1987,1 a number of preclathridine
and isonaamine alkaloids, representing a family of 1,4-
substituted 2-aminoimidazoles 1 bearing one or two sub-
stituted benzyl moieties, has been isolated and synthe-
sized in the last two decades (Table 1).2 Many 2-
aminoimidazole alkaloids have been reported to have cy-
totoxic, antimicrobial, and antifungal properties.3
dazopyrimidinium salts
2
(Scheme 1). Although
heterocyclization reactions of a-bromo aldehydes are
hardly known due to their high reactivity, in our prelimi-
nary studies we were able to synthesize several 1,4-disub-
stituted 2-aminoimidazoles in high yields applying a one-
pot two-step microwave-assisted protocol.11
Table 1 1,4-Substituted 2-Aminoimidazole Marine Sponge Alkaloids
R2
N
N
H2N
R3
1
R1
Alkaloid
R1
R2
R3
Isolated
19929
Synthesis
1996,7 19994
1991,5 19994
19994
Preclathridine A (1c)
Preclathridine C (1i)
Isonaamine A (1j)
Isonaamine C (1e)
Isonaamine D (1g)
Isonaamine E (1f)
Me
-OCH2O-
Me
H
OH
19915
4-Hydroxybenzyl
4-Methoxybenzyl
4-Hydroxybenzyl
4-Methoxybenzyl
H
OH
19871a
19929
H
MeO
MeO
MeO
20038
H
19983d
200210
–
MeO
–
SYNTHESIS 2008, No. 13, pp 2083–2088
x
x.
x
x
.
2
0
0
8
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1078444; Art ID: Z07408SS
© Georg Thieme Verlag Stuttgart · New York

2084
D. S. Ermolat’ev et al.
PAPER
Table 2 Investigation of the Condensation under Conventional
N
Heating and Microwave Irradiation Conditionsa
NH2
N
R
3
Br –
N
N
+
R
H
N
N
N
R
+
N
N
N
N
Br
Br –
Ar
N
NHMe
Ar
+
N
1
O
2
Ar
+
3a
Me
N
Me
N
N
+
+
Br –
Bn
4
Br
Bn
O
OH
Scheme 1 Retrosynthetic analysis for the synthesis of 1,4-substitu-
2a
Bn
5a
4a
ted 2-aminoimidazoles
Entry
Temp (°C) Time (min) Power (W)b Ratio 5a:2ac
The crucial step in the synthesis of 2-aminoimidazoles
from 2-aminopyrimidines is the formation of imida-
zo[1,2-a]pyrimidin-1-ium salts 2 (Scheme 1).11 As a
proof of this concept, the cyclization step was initially op-
timized using 2-methylaminopyrimidine12 (3a) and 1.35
equivalents of 2-bromo-3-phenylpropanal (4a) as starting
materials (Table 2). At room temperature (or after reflux
in MeCN) we observed the formation of stable hydrate 5a
instead of the expected aromatic salt 2a. We carefully in-
vestigated the microwave-assisted dehydration of the in-
termediate salt 5a to the dehydrated salt 2a. A sealed vial
containing a solution of the starting compounds 3a and 4a
in acetonitrile was irradiated at 120–130 °C for 20–30
minutes (Table 2, entries 1–3). However, only trace
amounts of the desired 1-methyl-3-benzylimidazo[1,2-
a]pyrimidin-1-ium salt (2a) were observed next to the hy-
droxy salt 5a. Upon further increasing the temperature to
1
2
3
4
5
6
120
130
130
140
150
160
20
20
30
30
30
25
120
150
150
150
150
200
100:0
95:5
67:33
51:49
8:92
0:100
a All reactions were carried out on a 1 mmol scale of 2-methylami-
nopyrimidine (3a) with 2-bromo-3-phenylpropan-1-al (4a) (1.35
equiv) in MeCN (5 mL).
b Ceiling power of MW irradiation.
c Determined by 1H NMR spectroscopy.
a-bromo aldehydes 4a–d (Scheme 2). These were irradi-
ated together with 2-alkylaminopyrimidines 3a–c and 8 in
140 °C, a nearly equimolar mixture of salts 5a and 2a was acetonitrile at 80 °C for 10 minutes, and subsequently at
obtained (Table 2, entry 4). Increasing the ceiling temper- 160 °C for 25 minutes, leading to the desired intermedi-
ature to 160 °C and the maximum power to 200 W for 25 ates 2a–g. The final step – cleavage of the pyrimidine
minutes drove the reaction completely to the formation of fragment – was achieved by the addition of hydrazine hy-
the desired imidazo[1,2-a]pyrimidin-1-ium salt 2a as the drate (7 equiv) to the cooled reaction mixture, and irradi-
ation was continued at 100 °C for another 10 minutes. The
obtained 1,4-substituted 2-aminoimidazoles 1a–g were
isolated in good yields as shown in Table 3 (entries 1–7).
Remarkably, we observed almost complete loss of the
TBDMS group under the cleavage conditions (Table 3,
entry 7) and 2-aminoimidazole 1g was isolated in 58%
yield together with 5% of the protected counterpart 1h.
The 2-aminoimidazoles 1d and 1e were demethylated
with BBr3 to give preclathridine A (1i) and isonaamine A
(1j) in good yields (Table 3, entries 8 and 9).
sole reaction product (Table 2, entry 6).
Having optimized the microwave-assisted protocol for the
synthesis of 1,4-substituted 2-aminoimidazoles, we devel-
oped a short route for the related marine sponge alkaloids
from readily available starting materials. 2-Benzyl-
aminopyrimidine13 (3b) and 2-(4-methoxybenzyl)amino-
pyrimidine (3c) were prepared from the corresponding
amines and 2-chloropyrimidine (6) by microwave irradia-
tion (Scheme 2). Subsequent demethylation of the meth-
oxy group of compound 3c, followed by silyl protection
with tert-butyldimethylsilyl chloride, provided pyrimi-
dine 8.
Finally, the structure of synthetic isonaamine C (1e) was
unambiguously confirmed by single crystal X-ray crystal-
lography (Figure 1).18 Interestingly, two hydrogen bonds
(between amino groups and endocyclic nitrogen atoms)
link two aminoimidazole molecules in the crystal into
centrosymmetric dimers (with NH…N bond length 2.07
Å), similar to the effect we observed earlier19 for 2-amino-
1-methyl-5-(4-chlorophenyl)imidazole.
For the synthesis of a-bromo aldehydes, the substituted 3-
phenylpropanols 9a–d, which can be easily accessed from
the corresponding cinnamic acids,14 were oxidized to the
aldehydes 10a–d.15 Mild bromination16 of 10a–d using
0.5 equivalent of 5,5-dibromobarbituric acid (DBBA)17 at
room temperature resulted in the formation of the required
N
N
N
i
ii, iii
R
R = PMB
N
N
N
N
H
N
Cl
H
3b: R = Bn (89%)
3c: R = PMB (86%)
8
6
OTBDMS
Scheme 2 Reagents and conditions: (i) amine (1.3 equiv), Et3N (1.5 equiv), EtOH, MW 80 W, 120 °C, 5 min; (ii) BBr3 (5 equiv), CH2Cl2,
0 °C to r.t., 12 h (→ 7, 64%); (iii) TBDMSCl (1.25 equiv), imidazole (1.4 equiv), DMF, r.t., overnight (92%).
Synthesis 2008, No. 13, 2083–2088 © Thieme Stuttgart · New York

PAPER
Microwave-Assisted Synthesis of 2-Aminoimidazole Derivatives
2085
R2
R3
R2
R2
OH
i
ii
O
O
Br
R3
R3
9a: R2, R3 = H
10a: R2, R3 = H (77%)
4a: R2 = R3 = H (85%)
9b: R2 = H, R3 = MeO
9c: R2 = MeO, R3 = MeO
9d: R2, R3 = -OCH2O-
10b: R2 = H, R3 = MeO (93%)
10c: R2 = MeO, R3 = MeO (97%)
10d: R2, R3 = -OCH2O- (86%)
4b: R2 = H, R3 = MeO (89%)
4c: R2 = R3 = MeO (87%)
4d: R2, R3 = -OCH2O- (67%)
N
R2
R3
N
+Br –
R1
R2
iii
iv
H2N
N
N
N
R1
R3
1a–g
2a–g
1d
1i
1e
1j
v
vi
Scheme 3 Reagents and conditions: (i) PCC (1.4 equiv), CH2Cl2, 0 °C, 3–4 h; (ii) DBBA (0.5 equiv), Et2O, HCl (cat.), r.t., 15–20 hr; (iii) 2-
alkylaminopyrimidines 3a–c and 8, DMAP (cat.), MeCN, MW 200 W, 80 °C, 10 min, then 160 °C, 25 min; (iv) hydrazine hydrate (7 equiv),
MW 100 W, 100 °C, 10 min; (v) BBr3 (5 equiv), CH2Cl2, 0 °C to r.t., 0.5 h; (vi) BBr3 (10 equiv), CH2Cl2, 0 °C to r.t., 1 h.
Table 3 2-Aminoimidazoles 1a–j Prepareda
In conclusion, we have applied a short and efficient mi-
crowave-assisted protocol for the preparation of the 1,4-
dialkyl-2-aminoimidazole-based marine sponge alka-
loids, using readily available substituted 2-aminopyrim-
idines as the masked guanidine function20 in the reaction
with a-bromo aldehydes. In addition to its simplicity, this
method provides high yields of products in short reaction
times. The microwave-assisted procedure would be of
great use in the synthesis of a range of 2-aminoimidazole-
based natural products.
Entry Product R1
R2
H
R3
Yield (%)b
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
Me
Bn
Bn
88
74
67
87
89
85
Bn
H
Me
-OCH2O-
Me
H
MeO
4-Methoxybenzyl
4-Methoxybenzyl
H
MeO
MeO
MeO
MeO
H
Melting points were determined using a Reichert-Jung Thermovar
apparatus or an Electrothermal 9200 digital melting point apparatus
1g
+
4-Hydroxybenzyl
+
58
+
5
1
and are uncorrected. H NMR spectra were recorded on a Bruker
Avance 300 (300/75.5 MHz) and 400 (400/100.5 MHz) instruments
1h
4-TBDMSObenzyl
1
using CDCl3 and DMSO-d6 as solvents. The H and 13C chemical
8
9
1i
1j
Me
H
H
OH
OH
55
71
shifts are reported in parts per million relative to tetramethylsilane
using the residual solvent signal as an internal reference. Mass spec-
tra were recorded by using a Kratos MS 50 TC, Kratos Mach III sys-
tem, and LCQ Advantage (Thermo Electron Corp.). The ion source
temperature was 150–250 °C, as required. High-resolution EI-mass
spectra were performed with a resolution of 10000. The low-resolu-
tion spectra were obtained with a HP5989A MS instrument. For
TLC, analytical TLC plates [Alugram SIL G/UV254 and 70–230
mesh silica gel (E. M. Merck)] were used.
4-Hydroxybenzyl
a Yields of 2-aminoimidazoles 1a–h given for the one-pot procedure,
starting from a-bromo aldehydes 4a–d.
b Isolated yield.
Microwave Experiments
A multimode Milestone MicroSYNTH microwave reactor (Labora-
tory Microwave Systems) was used in the standard configuration as
delivered, including proprietary software. Reaction temperatures
were monitored by an IR sensor on the outside wall of the reaction
vial and a fiber optic sensor inside the reaction vial. All experiments
were carried out in sealed microwave process vials (15, 50 mL). Af-
ter completion of the reaction, the vial was cooled to 25 °C via air
jet cooling before opening.
(4-Methoxybenzyl)pyrimidin-2-ylamine (3c)
In a 50 mL microwave vial, 2-chloropyrimidine (3.43 g, 30 mmol),
4-methoxybenzylamine (5.35 g, 39 mmol, 1.3 equiv), and Et3N (6.2
mL, 45 mmol, 1.5 equiv) were successively dissolved in EtOH (20
mL). The reaction tube was sealed, and irradiated in the cavity of a
microwave reactor at a ceiling temperature of 120 °C at 80 W max-
imum power for 5 min. After the mixture was cooled with an air
flow for 15 min, it was diluted with H2O (100 mL), extracted with
CH2Cl2 (2 × 150 mL), and the combined organic extracts were dried
Figure 1 Crystal structure of isonaamine C
Synthesis 2008, No. 13, 2083–2088 © Thieme Stuttgart · New York

2086
D. S. Ermolat’ev et al.
PAPER
(Na2SO4). The solvent was removed under reduced pressure and the
residue was subjected to silica gel flash chromatography (0–5%
MeOH–CH2Cl2) to afford 5.55 g (86%) of 3c; colorless solid; mp
101–102 °C.
1H NMR (300 MHz, CDCl3): d = 8.26 (d, J = 4.8 Hz, 2 H), 7.26 (d,
J = 8.6 Hz, 2 H), 6.86 (d, J = 8.5 Hz, 2 H), 6.54 (t, J = 4.8 Hz, 1 H),
5.50 (br, 1 H), 4.56 (d, J = 5.7 Hz, 2 H), 3.81 (s, 3 H).
1H NMR (300 MHz, CDCl3): d = 8.97 (m, 1 H), 8.81 (m, 1 H), 7.42–
7.23 (m, 7 H), 5.32 (dd, J = 8.3, 1.8 Hz, 1 H), 4.93 (m, 1 H), 3.32 (s,
2 H), 3.08 (s, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 168.9, 154.8, 148.5, 135.0, 130.6
(2 ×), 129.6 (2 ×), 128.3, 111.6, 86.1, 68.7, 37.8, 28.9.
3-Benzyl-1-methylimidazo[1,2-a]pyrimidin-1-ium Bromide
(2a) (Table 2, Entry 6)
Colorless solid; mp 155–156 °C.
1H NMR (300 MHz, CDCl3): d = 9.28 (m, 1 H), 9.12 (m, 1 H), 8.16
(s, 1 H), 7.74 (dd, J = 6.3, 4.8 Hz, 1 H), 7.38–7.30 (m, 5 H), 4.46 (s,
2 H), 4.01 (s, 3 H).
13C NMR (75.5 MHz, CDCl3): d = 162.7, 159.3, 158.4 (2 ×), 131.6,
129.3 (2 ×), 114.4 (2 ×), 110.9, 55.7, 45.4.
HRMS-EI: m/z calcd for C16H21N3 [M]+: 215.1059; found:
215.1064.
4-(Pyrimidin-2-ylaminomethyl)phenol (7)
13C NMR (75.5 MHz, CDCl3): d = 157.9, 143.0, 137.2, 136.0, 129.7
(4 ×), 128.1, 125.1, 124.9, 114.4, 33.6, 29.1.
To a solution of 3c (3.23 g, 15 mmol) in CH2Cl2 (50 mL) at 0 °C was
added dropwise BBr3 (7.2 mL, 75 mmol, 5 equiv) and the mixture
was stirred at r.t. for 1 day. The mixture was cooled in an ice bath,
and then 6 N ammonia in MeOH (~60 mL) was added carefully. The
mixture was diluted with H2O (200 mL), extracted with EtOAc
(2 × 150 mL), and the combined organic extracts were dried
(Na2SO4). The solvent was removed under reduced pressure and the
residue was subjected to column chromatography on silica gel
(from 10% MeOH–CH2Cl2) to afford 1.93 g (64%) of 7; white solid;
mp 183–185 °C.
1H NMR (300 MHz, DMSO-d6): d = 9.22 (s, 1 H), 8.24 (d, J = 4.7
Hz, 2 H), 7.54 (t, J = 6.0 Hz, 1 H), 7.10 (d, J = 8.2 Hz, 2 H), 6.67 (d,
J = 8.2 Hz, 2 H), 6.54 (t, J = 4.8 Hz, 1 H), 4.36 (d, J = 6.3 Hz, 2 H).
13C NMR (75.5 MHz, DMSO-d6): d = 163.1, 158.9, 158.8, 156.9,
131.4, 129.3, 115.8, 110.9, 44.3.
DEPT NMR (75.5 MHz, CDCl3): d = 157.9, 137.2, 129.7 (4 ×),
128.1, 125.1, 114.4, 80.0, 33.6, 29.1.
3-Aryl-2-bromopropanals 4a–d; 2-Bromo-3-phenylpropanal
(4a); Typical Procedure
A solution of 10a (1.34 g, 10 mmol) in Et2O (10 mL) was added
dropwise to a solution of DBBA (1.45 g, 5 mmol, 5 equiv) in Et2O
(40 mL). Then, a 4 N solution of HCl in 1,4-dioxane (0.25 mL, 1
mmol) was added dropwise and the mixture was stirred for 15 h at
r.t. After partition of the mixture between Et2O (150 mL) and aq sat.
NaHCO3 (100 mL), the organic layer was washed with H2O (50
mL) and brine (50 mL), dried (MgSO4), and concentrated under re-
duced pressure to give a light yellow oil. The crude product was pu-
rified by flash chromatography on neutral alumina (CH2Cl2–Et2O,
2:1) to afford 1.81 g (85%) of 4a; light oil.
HRMS-EI: m/z calcd for C16H21N3 [M]+: 201.0902; found:
201.0892.
1H NMR (300 MHz, CDCl3): d = 9.51 (s, 1 H), 7.38–7.24 (m, 5 H),
4.47 (m, 1 H), 3.55–3.48 (m, 1 H), 3.24–3.16 (m, 1 H).
[4-(tert-Butyldimethylsilyloxy)benzyl]pyrimidin-2-yl-amine (8)
To a solution of 7 (1.4 g, 7 mmol) in DMF (25 mL) were added
TBDMSCl (1.32 g, 8.75 mmol, 1.25 equiv) and imidazole (0.67 g,
9.8 mmol, 1.4 equiv), and the mixture was stirred overnight at r.t.
After partition of the mixture between Et2O (200 mL) and aq sat.
NaHCO3 (100 mL), the organic layer was washed with H2O (50
mL) and brine (50 mL), dried (MgSO4), and concentrated under re-
duced pressure. The crude product was purified by flash chromatog-
raphy on neutral alumina (CH2Cl2–Et2O, 4:1) to afford 2.03 g (92%)
of 8; colorless solid; mp 132–134 °C.
1H NMR (300 MHz, CDCl3): d = 8.28 (d, J = 4.2 Hz, 2 H), 7.21 (d,
J = 8.3 Hz, 2 H), 6.80 (d, J = 8.6 Hz, 2 H), 6.55 (t, J = 4.7 Hz, 1 H),
5.49 (br, 1 H), 4.56 (d, J = 5.5 Hz, 2 H), 0.99 (s, 9 H), 0.20 (s, 6 H).
13C NMR (75.5 MHz, CDCl3): d = 162.7, 158.4 (2 ×), 155.3, 132.1,
129.3 (2 ×), 120.6 (2 ×), 111.0, 45.5, 26.1 (3 ×), 18.6, – 4.0 (2 ×).
13C NMR (75.5 MHz, CDCl3): d = 192.3, 136.7, 129.7 (2 ×), 129.2
(2 ×), 127.8, 55.1, 38.4.
HRMS-EI: m/z calcd for C9H9BrO [M]+: 211.9837; found:
211.9850.
2-Bromo-3-(4-methoxyphenyl)propanal (4b)
Yield: 89%; light oil.
1H NMR (300 MHz, CDCl3): d = 9.49 (s, 1 H), 7.19 (d, J = 8.4 Hz,
2 H), 6.86 (d, J = 8.4 Hz, 2 H), 4.86 (m, 1 H), 3.73 (s, 1 H), 3.39 (m,
1 H), 3.14 (m, 1 H).
13C NMR (75.5 MHz, CDCl3): d = 192.5, 159.3, 130.8 (2 ×), 128.6,
114.6 (2 ×), 55.7, 55.4, 37.7.
HRMS-EI: m/z calcd for C10H11BrO2 [M]+: 241.9942; found:
241.9939.
HRMS-EI: m/z calcd for C16H21N3 [M]+: 315.1767; found:
315.1768.
2-Bromo-3-(3,4-dimethoxyphenyl)propanal (4c)
Yield: 87%; light oil.
1H NMR (300 MHz, CDCl3): d = 9.48 (s, 1 H), 6.92–6.74 (m, 3 H),
4.43 (m, 1 H), 3.87 (s, 3 H), 3.86 (s, 3 H), 3.46–3.39 (m, 1 H), 3.17–
3.10 (m, 1 H).
13C NMR (75.5 MHz, CDCl3): d = 192.5, 149.5, 148.8, 129.1,
121.9, 112.8, 111.7, 68.4, 56.3, 55.2, 38.1.
HRMS-EI: m/z calcd for C11H13BrO3 [M]+: 272.0048; found:
272.0043.
Compounds 2a and 5a
In a 15 mL microwave vial, 2-methylaminopyrimidine (3a; 109 mg,
1 mmol) and 2-bromo-3-phenylpropanal (4a; 288 mg, 1.35 mmol,
1.35 equiv) were successively dissolved in MeCN. The reaction
tube was flushed with argon, sealed, and irradiated in the cavity of
a microwave reactor at 80 W and at a ceiling temperature specified
in Table 2. After the mixture was cooled with an air flow for 10 min,
it was diluted with H2O (25 mL), and the precipitate was washed
with a 1:1 mixture Et2O–acetone (2 × 10 mL) and dried in vacuum.
3-(1,3-Benzodioxol-5-yl)-2-bromopropanal (4d)
Yield: 67%; light oil.
1H NMR (300 MHz, CDCl3): d = 9.48 (s, 1 H), 6.75–6.68 (m, 3 H),
6.01 (s, 2 H), 4.42 (m, 1 H), 3.64–3.50 (m, 1 H), 3.18–3.09 (m, 1 H).
3-Benzyl-2-hydroxy-1-methyl-1H,2H,3H-imidazo[1,2-a]pyrim-
idin-4-ium Bromide (5a) (Table 2, Entry 1)
White solid; mp 197–199 °C.
13C NMR (75.5 MHz, CDCl3): d = 192.0, 149.7, 148.5, 129.7,
121.6, 109.3, 108.7, 101.4, 58.7, 38.6.
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Microwave-Assisted Synthesis of 2-Aminoimidazole Derivatives
2087
HRMS-EI: m/z calcd for C10H9BrO3 [M]+: 255.9735; found:
255.9738.
1H NMR (300 MHz, DMSO-d6): d = 7.81 (br, 1 H), 7.13 (m, 4 H),
6.87 (d, J = 8.4 Hz, 2 H), 6.79 (d, J = 8.2 Hz, 2 H), 6.26 (s, 1 H),
6.12 (s, 1 H), 5.35 (s, 2 H), 4.76 (s, 2 H), 3.71 (s, 3 H), 3.69 (s, 3 H).
Microwave-Assisted Synthesis of 1a–g; 4-(4-Benzylbenzyl)-1-
methyl-1H-imidazol-2-ylamine (1a); Typical Procedure
13C NMR (75.5 MHz, DMSO-d6): d = 159.4, 158.2, 149.6, 137.2,
133.8, 130.8, 130.4 (2 ×), 129.7 (2 ×), 114.7 (2 ×), 114.3 (2 ×),
110.9, 105.1, 55.9, 55.8, 47.3, 34.6.
HRMS-EI: m/z calcd for C20H23N3O3 [M]+: 323.1634; found:
323.1631.
A 10 mL microwave vial was successively charged with MeCN (10
mL), 2-methylaminopyrimidine (3a; 435 mg, 4 mmol), 2-bromo-3-
phenylpropanal (4a; 1.15 g, 5.4 mmol, 1.35 equiv), and DMAP (5
mg, 0.04 mmol, 1 mol%). The reaction tube was sealed, and irradi-
ated in a microwave reactor first at a ceiling temperature of 80 °C at
200 W maximum power for 10 min, and then at 160 °C at 200 W
maximum power for 25 min. After the mixture was cooled with an
air flow for 15 min, hydrazine hydrate (1.4 mL of a 64% solution,
28 mmol 7 equiv) was added, and the mixture was irradiated for an-
other 10 min at a ceiling temperature of 100 °C at 100 W maximum
power. The mixture was diluted with CH2Cl2 (150 mL), the CH2Cl2
layer was washed with aq sat. NH4Cl (100 mL), brine (100 mL), and
H2O (2 × 100 mL) and dried (Na2SO4). After filtration and concen-
tration, the resulting residue was purified by column chromatogra-
phy (silica gel; CH2Cl2–MeOH, 9:1 with 3% Et3N) to afford 659 mg
(88%) of 1a; light yellow solid; mp 66–68 °C.
4-(3,4-Dimethoxybenzyl)-1-(4-methoxybenzyl)-1H-imidazol-2-
ylamine (1f)
Yield: 85%; brown oil.
1H NMR (300 MHz, DMSO-d6): d = 7.19 (d, J = 8.0 Hz, 2 H), 6.80
(m, 5 H), 6.17 (s, 1 H), 4.58 (br, 2 H), 4.24 (s, 2 H), 3.83 (s, 3 H),
3.80 (s, 3 H), 3.77 (s, 3 H), 3.68 (s, 2 H).
13C NMR (75.5 MHz, DMSO-d6): d = 158.9, 150.3, 148.8, 147.5,
131.8, 131.7, 130.5, 128.5, 120.7, 114.0, 112.1, 111.8, 111.2, 55.9,
55.8, 55.2, 47.2, 32.6.
DEPT NMR (75.5 MHz, DMSO-d6): d = 128.8, 121.0, 114.3,
112.5, 112.2, 11.6, 56.3, 56.2, 55.6, –47.5, –32.96.
HRMS-EI: m/z calcd for C20H23N3O3: [M]+: 353.1739; found:
1H NMR (300 MHz, CDCl3): d = 7.28 (m, 4 H), 7.18 (m, 1 H), 6.09
(s, 1 H), 4.16 (br, 2 H), 3.76 (s, 2 H), 3.30 (s, 3 H).
353.1736.
13C NMR (75 MHz, CDCl3): d = 148.1, 140.8, 137.4, 129.3 (2 ×),
128.7 (2 ×), 126.3, 113.3, 35.4, 31.6.
4-[2-Amino-4-(4-methoxybenzyl)-1H-imidazol-1-ylmethyl]phe-
nol (1g)
Yield: 58%; yellow solid; mp 155–157 °C.
HRMS-EI: m/z calcd for C11H13N3 [M]+: 187.1109; found:
187.1108.
1H NMR (300 MHz, DMSO-d6): d = 9.33 (br, 1 H), 7.11 (d, J = 8.6
Hz, 2 H), 7.02 (d, J = 8.2 Hz, 2 H), 6.79 (d, J = 8.6 Hz, 2 H), 6.70
(d, J = 8.2 Hz, 2 H), 6.10 (s, 1 H), 5.23 (s, 2H), 4.70 (s, 2 H), 3.70
(s, 3 H), 3.49 (s, 2 H).
13C NMR (75.5 MHz, DMSO-d6): d = 157.3, 156.6, 148.6, 136.2,
132.9, 129.6 (2 ×), 128.9 (2 ×), 128.2, 115.2 (2 ×), 113.4 (2 ×),
110.0, 55.0, 46.5, 33.7.
1-Benzyl-4-(4-benzylbenzyl)-1H-imidazol-2-ylamine (1b)
Yield: 74%; light yellow solid; mp 124–125 °C.
1H NMR (300 MHz, CDCl3): d = 7.30 (m, 7 H), 7.15 (m, 3 H), 6.19
(s, 1 H), 4.80 (s, 2 H), 4.19 (br, 2 H), 3.80 (s, 2 H).
13C NMR (75 MHz, CDCl3): d = 148.4, 140.8, 137.5, 136.8, 129.4,
128.7, 128.3, 127.2, 126.3, 112.8, 48.8, 35.4.
HRMS-EI: m/z calcd for C18H19N3O2 [M]+: 309.1477; found:
309.1482.
DEPT NMR (75 MHz, CDCl3): d = 129.4 (2 × 2), 129.3 (2 × 2),
128.7 (2 × 2), 128.4, 127.2 (2 × 2), 126.3, –48.9, –35.4.
HRMS-EI: m/z calcd for C17H17N3 [M]+: 263.1422; found:
1-[4-(tert-Butyldimethylsilyloxy)benzyl]-4-(4-methoxybenzyl)-
1H-imidazol-2-ylamine (1h)
263.1425.
Yield: 5%; white solid; mp 115–117 °C.
4-(1,3-Benzodioxol-5-ylmethyl)-1-methyl-1H-imidazol-2-yl-
1H NMR (300 MHz, DMSO-d6): d = 7.09 (m, 4 H), 6.80 (m, 4 H),
6.12 (s, 1 H), 5.30 (br, 2 H), 4.74 (s, 2 H), 3.69 (s, 3 H), 3.49 (s, 2
H), 0.93 (s, 9 H), 0.16 (s, 6 H).
13C NMR (75.5 MHz, DMSO-d6): d = 158.0, 155.8, 149.4, 137.7,
130.3, 129.9, 128.3, 120.7, 114.1, 113.9, 112.7, 108.1, 55.4, 48.3,
34.2, 25.8, 18.3, –4.3.
amine (1c)
Yield: 87%; yellow oil.
1H NMR (400 MHz, DMSO-d6): d = 6.78 (m, 2 H), 6.68 (dd,
J = 8.0, 0.9 Hz, 1 H), 6.19 (s, 1 H), 5.94 (s, 2 H), 5.45 (br, 2 H), 3.57
(s, 2 H), 2.67 (s, 3 H).
13C NMR (75.5 MHz, DMSO-d6): d = 151.7, 148.0, 146.3, 133.8,
121.9, 112.4, 109.6, 108.5, 107.0, 101.2, 33.6, 30.9.
HRMS-EI: m/z calcd for C12H13N3O2 [M]+: 231.1008; found:
HRMS-EI: m/z calcd for C24H23N3O2Si [M]+: 423.2342; found:
423.2353.
231.1008.
O-Demethylation of 2-Aminoimidazoles 1d,e; 4-(2-Amino-1-
methyl-1H-imidazol-4-ylmethyl)phenol (1i); Typical Procedure
To a solution of 1d (326 mg, 1.5 mmol) in anhyd CH2Cl2 (10 mL)
was added dropwise a 1 M solution of BBr3 in CH2Cl2 (7.5 mL per
methoxy group, 7.5 mmol, 5 equiv) at r.t. and the mixture was re-
fluxed for 1 h at 55 °C. The reaction vessel was cooled in an ice bath
and the reaction was quenched by the addition of 6 N ammonia in
MeOH (7 mL). After evaporation of the solvent, the residue was
subjected to column chromatography (20% MeOH–CH2Cl2) on sil-
ica gel basified with ammonia, to afford 167 mg (55%) of com-
pound 1i; yellow solid; mp 114–116 °C.
4-(4-Methoxybenzyl)-1-methyl-1H-imidazol-2-ylamine (1d)
Yield: 67%; light brown solid; mp 134–136 °C.
1H NMR (400 MHz, DMSO-d6): d = 7.11 (d, J = 8.4 Hz, 2 H), 6.80
(d, J = 8.4 Hz, 2 H), 6.12 (s, 1 H), 5.19 (br, 2 H), 3.70 (s, 3 H), 3.49
(s, 2 H), 3.22 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 157.9, 147.7, 136.9, 132.3,
129.8, 113.8, 112.7, 55.3, 33.9, 31.3.
HRMS-EI: m/z calcd for C12H15N3O [M]+: 217.1215; found:
263.1218.
1H NMR (300 MHz, DMSO-d6): d = 9.05 (br, 1 H), 6.99 (d, J = 8.4
Hz, 2 H), 6.62 (d, J = 8.4 Hz, 2 H), 6.10 (s, 1 H), 5.16 (s, 2H), 3.44
(s, 2 H), 3.22 (s, 3 H).
1,4-Bis-(4-methoxybenzyl)-1H-imidazol-2-ylamine (1e)
Yield: 89%; colorless solid; mp 139–141 °C.
Synthesis 2008, No. 13, 2083–2088 © Thieme Stuttgart · New York

2088
D. S. Ermolat’ev et al.
PAPER
(4) Molina, P.; Fresneda, P. M.; Sanz, M. A. J. Org. Chem.
13C NMR (75.5 MHz, DMSO-d6): d = 154.9, 147.6, 135.5, 129.8,
128.9, 114.5, 111.5, 32.9, 30.5.
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(5) Alvi, K. A.; Crews, P.; Loughhead, D. G. J. Nat. Prod. 1991,
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1993, 36, 3333.
(7) Kawasaki, I.; Taguchi, N.; Yoneda, Y.; Yamashita, M.;
Ohta, S. Heterocycles 1996, 43, 1375.
(8) Nakamura, S.; Kawasaki, I.; Yamashita, M.; Ohta, S.
Heterocycles 2003, 60, 583.
(9) Alvi, K. A.; Peters, B. M.; Hunter, L. M.; Crews, P.
Tetrahedron 1992, 49, 329.
(10) Gross, H.; Kehraus, S.; Koenig, G. M.; Woerheide, G.;
Wright, A. D. J. Nat. Prod. 2002, 5, 1190.
HRMS-EI: m/z calcd for C11H13N3O [M]+: 203.1059; found:
203.1059.
4-[2-Amino-1-(4-hydroxybenzyl)-1H-imidazol-4-ylmethyl]phe-
nol (1j)
Prepared from 1e, following the procedure given above; yield: 71%;
yellow solid; mp 125–127 °C.
1H NMR (400 MHz, DMSO-d6): d = 9.31 (br, 1 H), 9.03 (br, 1 H),
7.01 (d, J = 8.3 Hz, 2 H), 6.98 (d, J = 8.4 Hz, 2 H), 6.69 (d, J = 8.5
Hz, 2 H), 6.61 (d, J = 8.3 Hz, 2 H), 6.07 (s, 1 H), 5.21 (s, 2 H), 4.88
(s, 2 H), 3.43 (s, 2 H).
13C NMR (100.5 MHz, DMSO-d6): d = 156.7, 155.3, 148.5, 136.2,
130.9, 129.5 (2 ×), 128.9 (2 ×), 128.0, 115.2 (2 ×), 114.8 (2), 110.1,
46.6, 33.6.
(11) Ermolat’ev, D. S.; Babaev, E. V.; Van der Eycken, E. V.
Org. Lett. 2006, 8, 5781.
(12) Brown, D. J.; Hoerger, E.; Mason, S. F. J. Chem. Soc. 1955,
4035.
(13) Cherng, Y.-J. Tetrahedron 2002, 58, 887.
(14) Lal, K.; Ghosh, S.; Salomon, R. G. J. Org. Chem. 1987, 52,
1072.
(15) Pedrosa, R.; Andres, C.; Iglesias, J. M. J. Org. Chem. 2001,
66, 243.
(16) (a) Barnett, C. J.; Grubb, L. M. Tetrahedron Lett. 2000, 41,
9741. (b) Aso, K.; Imai, Y.; Yukishige, K.; Ootsu, K.;
Akimoto, H. Chem. Pharm. Bull. 2001, 49, 1280.
(17) Grundke, G.; Keese, W.; Rimpler, M. Chem. Ber. 1985, 118,
4288.
HRMS-EI: m/z calcd for C17H17N3O2 [M]+: 295.1321; found:
295.1327.
Acknowledgment
Support was provided by the Research Fund of the University of
Leuven. E.V. Van der Eycken thanks the F.W.O. [Fund for Scienti-
fic Research – Flanders (Belgium)]. DSE is grateful to the Univer-
sity of Leuven for obtaining a scholarship. EVB thanks the Russian
Foundation of Basic Research (RFBR Grant no. 05-03-39022-
GFEN_a.
(18) Crystallographic data for 1e reported in this paper have been
deposited with the Cambridge Crystallographic Data Centre
as supplementary publication No. CCDC 679428. Copies of
the data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB 2 1EZ, UK [fax:
+44(1223)336033 or E-mail: deposit@ccdc.cam.ac.uk].
Some selected crystallographic data: crystal system, space
group: crystal system triclinic; space group P1; cell
parameters: a = 5.8703(16), b = 9.0133(8), c = 16.155(2) Å;
a = 93.778(9), b = 91.640(10), g = 94.461(10)°; V = 849.843
Å3; Z = 2, Z¢ = 0; R-factor 4.9%.
(19) Rybakov, V. B.; Babaev, E. V.; Belykh, E. N. Acta
Crystallogr., Sect. E: Struct. Rep. Online 2002, 58, o126.
(20) For analogous methodology to use the readily available
pyrimidine-2-one as the masked urea function to prepare
2-aminooxazoles, see: Alifanov, V. L.; Babaev, E. V.
Synthesis 2007, 263.
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Synthesis 2008, No. 13, 2083–2088 © Thieme Stuttgart · New York