A divergent synthesis of substituted 2-aminoimidazoles from 2-aminopyrimidines

Article abstract of DOI:10.1021/jo8008758

(Chemical Equation Presented) A new divergent and efficient synthesis of substituted 2-aminoimidazoles 5 and 6 has been developed starting from the readily available 2-aminopyrimidines 1 and α-bromocarbonyl compounds 2, using conventional heating or microwave irradiation. Thus, the cleavage of 1,2,3-substituted imidazo[1,2-a]pyrimidin-1-ium salts 4 with hydrazine or secondary amines led to 1,4,5-trisubstituted 2-aminoimidazoles 5, when the hydrazinolysis of 2-hydroxy-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-4-ium salts 3, followed by a novel Dimroth-type rearrangement, resulted in formation of 2-amino-1H-imidazoles 6. The relevant pathway of transformations was identified by characterization of the intermediates.

Full text of DOI:10.1021/jo8008758

A Divergent Synthesis of Substituted 2-Aminoimidazoles from
2-Aminopyrimidines
Denis S. Ermolat’ev and Erik V. Van der Eycken*
Laboratory for Organic & MicrowaVe-Assisted Chemistry (LOMAC), Department of Chemistry, UniVersity
of LeuVen, Celestijnenlaan 200F, B-3001 LeuVen, Belgium
erik.Vandereycken@chem.kuleuVen.be
ReceiVed May 6, 2008
A new divergent and efficient synthesis of substituted 2-aminoimidazoles 5 and 6 has been developed
starting from the readily available 2-aminopyrimidines 1 and R-bromocarbonyl compounds 2, using
conventional heating or microwave irradiation. Thus, the cleavage of 1,2,3-substituted imidazo[1,2-
a]pyrimidin-1-ium salts 4 with hydrazine or secondary amines led to 1,4,5-trisubstituted 2-aminoimidazoles
5, when the hydrazinolysis of 2-hydroxy-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-4-ium salts 3, followed
by a novel Dimroth-type rearrangement, resulted in formation of 2-amino-1H-imidazoles 6. The relevant
pathway of transformations was identified by characterization of the intermediates.
Introduction
Because of these interesting biological activities, numerous
synthetic routes to 2-aminoimidazoles have been reported.
The class of 2-aminoimidazoles has recently been given
particular interest due to various biological properties of these
compounds and can be divided into 1-unsubstituted and
1-substituted2-aminoimidazolescaffolds.1-Unsubstituted2-amino-
1H-imidazole alkaloids and their metabolites, isolated from
marine sponge Hymeniacidon sp., have been reported as potent
antagonists of serotonergic1 and histaminergic2 receptors.
Naamine and isonaamine alkaloids from the marine sponge
Leucetta sp., as examples of 1-substituted 2-aminoimidazoles,
have been reported to possess antiviral and anticancer activity.3,4
Modern synthetic methods of accessing 1-unsubstituted
2-amino-1H-imidazoles can be roughly classified as heterocy-
clization of substituted or protected guanidines with 1,2-
(3) (a) Carmely, S.; Ilan, M.; Kashman, Y. Tetrahedron 1989, 45, 2193. (b)
Bedoya-Zurita, M.; Ahond, A.; Poupat, C.; Potier, P. Tetrahedron 1990, 45,
6713. (c) Gross, H.; Kehraus, S.; Koenig, G. M.; Woerheide, G.; Wright, A. D.
J. Nat. Prod. 2002, 65, 1190. (d) Hassan, W.; Edrada, R.; Ebel, R.; Wray, V.;
Berg, A.; Van Soest, R.; Wiryowidagdo, S.; Proksch, P. J. Nat. Prod 2004, 67,
817.
(4) (a) Copp, B. R.; Fairchild, C. R.; Cornell, L.; Casazza, A. M.; Robinson,
S.; Ireland, C. M. J. Med. Chem. 1998, 41, 3909. (b) Colson, G.; Raboult, L.;
Lavelle, F.; Zeaial, A. Biochem. Pharmacol. 1992, 43, 1717. (c) Pitts, W. J.;
Wityak, J.; Smallheer, J. M.; Tobin, A. E.; Jetter, J. W.; Buynitsky, J. S.; Harlow,
P. P.; Solomon, K. A.; Corjay, M. H.; Mousa, S. A.; Wexler, R. R.; Jadhav,
P. K. J. Med. Chem. 2000, 43, 27. (d) Batt, D. G.; Petraitis, J. J.; Houghton,
G. C.; Modi, D. P.; Cain, G. A.; Corjay, M. H.; Mousa, S. A.; Bouchard, P. J.;
Forsythe, M. S.; Harlow, P. P.; Barbera, F. A.; Spitz, S. M.; Wexler, R. R.;
Jadhav, P. K. J. Med. Chem. 2000, 43, 41.
* To whom correspondence should be addressed.
(1) Cafieri, F.; Fattorusso, E.; Mangoni, A.; Taglialatela-Scafati, O. Tetra-
hedron Lett. 1996, 37, 3587.
(2) Kobayashi, J.; Ohizumi, Y.; Nakamura, H.; Hirata, Y. Experientia 1986,
42, 1176.
10.1021/jo8008758 CCC: $40.75
Published on Web 07/26/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6691–6697 6691

Ermolat’ev and Van der Eycken
SCHEME 1
R-bromocarbonyl compounds 2 at 130-150 °C, followed by
the cleavage of the intermediary imidazo[1,2-a]pyrimidin-1-ium
salts with an excess of hydrazine. We have recently re-examined
this chemistry and present here a full account that addresses
(1) the isolation and characterization of the intermediates in the
synthesis of 1-substituted 2-aminoimidazoles, (2) the evaluation
of the scope and limitations of the microwave-assisted protocol
to a series of substrates related to the reported18 marine sponge
alkaloids, and (3) the development of a new approach for the
synthesis of 2-amino-1H-imidazoles via a novel Dimroth-type
rearrangement.
Results and Discussion
dielectrophiles,5 heteroaromatic nucleophilic substitution,5c,6 and
recyclization of 2-aminooxazoles.7 Although different substituted
guanidines are readily available and can be prepared in situ (e.g.,
from cyanamines8), the high basicity of guanidines together with
nonregioselectivity often leads to multiple products.9 Protection
by acetyl5a and Boc groups5c requires, in turn, acidic deprotec-
tion conditions. Another procedure is the cyclocondensation of
aldehydes and guanidine nitrate using sodium cyanide and
supported aluminum oxide, which provides 2-aminoimidazoles
with identical substituents on positions 4 and 5 of the ring
structure.10 However, only a few approaches describe the direct
synthesis of 1-substituted 2-aminoimidazoles, in particular,
1,4,5-trisubstituted 2-aminoimidazoles 5 (Scheme 1). The earli-
est method involves condensation of R-aminocarbonyl com-
pounds 7 with cyanamide 8, isothioureas, or their synthetic
equivalents (route A) and appears to be the most popular method
for the direct construction of the 2-aminoimidazole ring.11,12
However, this reaction is strongly pH-sensitive and can lead to
the self-condensation of R-amino aldehydes or ketones 7
resulting in the formation of symmetrical pyrazines.13 Other
general applicable strategies related to route A are the imino-
phosphorane-mediated cyclization of R-azido esters14 and the
ammonolysis of 2-amino-1,3-oxazol-3-ium salts.15 Route B
involves sequential functionalization of 1,2-diprotected imida-
zole ring 9 with different electrophiles and was realized by Ohta
and co-workers in the total synthesis of marine sponge alka-
loids.16
We found that the cyclocondensation of 2-aminopyrimidines
1 with R-bromoacetophenones 2 first led to stable 2-hydroxy-
2,3-dihydroimidazo[1,2-a]pyrimidin-4-ium bromides 3 (Table
1). The bicyclic nature of the structures 3 clearly followed from
1H NMR data clearly indicating the multiplet of the methylene
fragments, as well as from 13C NMR spectra. Simultaneous ring
closure to bicyclic hydrates was previously observed in other
similar cases, e.g., for the cyclocondensation between R-bromo
ketones and 2-alkylaminopyridines.19 Remarkably, we never
observed the formation of monocyclic N-phenacylpyrimidin-1-
ium salts,20 and our attempts to quaternize 2-dialkylaminopy-
rimidines (e.g., 2-(dimethylamino)pyrimidine and 2-(pyrrolidin-
1-yl)pyrimidine) with different R-bromoacetophenones were not
successful.
The salts 3a-g were obtained in good and high yields (Table
1), and only for sterically hindered 2-aminopyrimidines did the
yields slightly decrease (entries 4, 6, and 7). Dehydration of
the salts 3a-g was successfully achieved by short (15 min)
heating in polyphosphoric acid at 150 °C. The corresponding
imidazo[1,2-a]pyrimidin-1-ium salts 4a-g were isolated and
characterized as perchlorates, and in most cases, the yields were
almost quantitative (Table 1).
The structures of aromatic salts 4 were completely consistent
1
with their H, 13C, and DEPT NMR data. The cleavage of the
imidazo[1,2-a]pyrimidin-1-ium salts 4a-g was successfully
performed using 3.5 equiv of piperidine in refluxing acetonitrile
(Table 1). The reaction was completed in 45 min, and the
resulting 2-aminoimidazoles 5a-g were isolated after flash
chromatography (CH2Cl2-MeOH, 9:1 v/v) in good yields
(Table 1, entries 1-7).
In a preliminary report,17 we described the microwave-assisted
procedure for the synthesis of 1,4,5-substituted 2-aminoimida-
zoles 5 (Scheme 1, route C). This one-pot, two-step protocol is
based on the cyclocondensation of 2-aminopyrimidines 1 and
Careful investigation of the pyrimidine ring cleavage in salts
4 along with isolation and characterization of the intermediates
have been performed using piperidine or morpholine as nu-
cleophiles. It was found that imidazo[1,2-a]pyrimidin-1-ium salts
4a-g undergo ring-opening reaction at room temperature within
3 min in the presence of 3.5 equiv of secondary amine, giving
new deeply colored azabutadienes 10a-g in high yields (Table
1, entries 1-7). The imidazo[1,2-a]pyrimidin-1-ium salts 4,
bearing bulky substituents R1 at the N-1 position, were found
to be much more reactive toward nucleophilic attack and are
thermally unstable (Table 1, entries 10d-g).
(5) (a) Little, T. L.; Webber, S. E. J. Org. Chem. 1994, 59, 7299. (b) Abou-
Jneid, R.; Ghoulami, S.; Martin, M.-T.; Dau, E. T. H.; Travert, N.; Al-Mourabit,
A. Org. Lett. 2004, 6, 3933. (c) Gore, V. K.; Ma, V. V.; Norman, M. H.;
Ognyanov, V. I.; Xi, N. US Patent US2006/0084640 A1, 2006.
(6) Stamford, A. W.; Craig, C. D.; Huang, Y. Int. Pat. WO 01/44201 A1,
2001.
(7) (a) Lamattina, J. L.; Mularski, C. J. Tetrahedron Lett. 1984, 25, 2957.
(b) Lamattina, J. L. Eur. Pat. Appl. EP 138464 A2, 1985.
(8) Katritzky, A. R.; Rogovoy, B. ArkiVoc 2005, 49, and references cited
therein.
(9) Beyer, H.; Pyl, T.; Lahmer, H. Chem. Ber. 1961, 94, 3217.
(10) Thangavel, N.; Murgesh, K. Asian J. Chem. 2005, 17, 2769.
(11) (a) Lawson, A. J. Chem. Soc. 1956, 307. (b) Storey, B. T.; Sullivan,
W. W.; Moyer, C. L. J. Org. Chem. 1964, 29, 3118. (c) Lencini, G. C.; Lazzari,
E. J. Heterocycl. Chem. 1966, 3, 152.
(12) Aberle, N.; Guillaume, L.; Watson, K. Org. Lett. 2006, 8, 419.
(13) (a) Lancini, G. C.; Lazzari, E. J. Heterocycl. Chem. 1966, 29, 3118. (b)
Cavalleri, B.; Ballotta, R.; Lancini, G. C. J. Heterocycl. Chem. 1972, 9, 979.
(14) Molina, P.; Fresneda, P.; Sanz, M. J. Org. Chem. 1999, 64, 2540.
(15) Moschny, T.; Hartmann, H. HelV. Chim. Acta 1999, 82, 1981.
(16) Ohta, S.; Tsuno, N.; Nakamura, S.; Taguchi, N.; Yamashita, M.;
Kawasaki, I.; Fujieda, M. Heterocycles 2000, 53, 1939.
(18) (a) Carmely, S.; Kashman, Y. Tetrahedron Lett. 1987, 28, 3003. (b)
Alvi, K. A.; Crews, P.; Loughhead, D. G. J. Nat. Prod. 1991, 54, 1509. (c) Fu,
X.; Schmitz, F. J.; Tanner, R. S.; Kelly-Borges, M. J. Nat. Prod 1998, 61, 384.
(19) (a) Bradsher, C. K.; Litzinger, E. F.; Zinn, M. F. J. Heterocycl. Chem.
1965, 2, 331. (b) Kuhla, D. E.; Watson, H. A. J. Heterocycl. Chem. 1978, 15,
1149.
(17) Ermolat’ev, D. S.; Babaev, E. V.; Van der Eycken, E. V. Org. Lett.
2006, 8, 5781.
(20) Smirnova, T. A.; Kurapov, P. B.; Vetrova, E. L.; Bass, A. G.; Nam,
N. L. IzV. TimiryazeVsk. S’kh. Akad. 2003, 4, 132.
6692 J. Org. Chem. Vol. 73, No. 17, 2008

Synthesis of Substituted 2-Aminoimidazoles
TABLE 1. Synthesis of 1,5-Substituted 2-Aminoimidazoles 5a-g and Azadienes 10a-g under Conventional Conditions
entry
compd
R1
R2
yield of 3a (%)b
yield of 4c (%)b
yield of 5d (%)b
yield of 10d (%)b
X
1
2
3
4
5
6
7
a
b
c
d
e
f
Me
Me
Bn
F
NO2
Cl
Ph
CN
Cl
88
89
75
63
74
67
48
93
95
83
94
97
81
44
86
89
84
51
80
75
95
67
98
89
91
76
84
79
CH2
CH2
CH2
CH2
CH2
O
i-Pr
cyclohexyl
cyclohexyl
cyclododecyl
g
NO2
O
a Reactions were run on a 6 mmol scale of 2-alkylaminopyrimidine 1 with 1.2 equiv of R-bromo ketone 2 in 12 mL of MeCN in the presence of
catalytic amounts of DMAP. b Isolated yields. c Reactions were run on a 3 mmol scale of salts 3. d Reactions were run on a 1 mmol scale of salts 4.
TABLE 2. NMR Data and NOE and HMBC Correlations of Azadiene 10ba
atom no.
δH (m, J in Hz)
7.12 (s)
δC (type)
NOESYb
18, 22
HMBC (δH to δC)
2
4
5
7
8
9
156.0 (C)
128.2 (CH)
129.4 (C)
2, 17
2, 9
8.74 (d, 10.1)
5.50 (dd, 13.6, 10.1)
6.90 (d, 12.8)
3.28 (br)
1.64 (br)
1.64 (br)
164.1 (CH)
98.2 (CH)
155.1 (CH)
25.5 (CH2)
24.0 (CH2)
24.0 (CH2)
30.8 (CH3)
137.5 (C)
9
11, 15
11, 15
8, 9
11, 13, 15
11, 12, 14, 15
18, 22
8
13
12, 14
11, 15
2, 5
11, 15
12, 14
13
16
17
3.68 (s, NCH3)
18, 22
19, 21
20
8.20 (d, 8.7)
7.52 (d, 8.7)
126.7 (CH)
124.2 (CH)
145.8 (C)
16, 19, 21
18, 22
17
b
a CDCl3, 400 MHz; δ are given in ppm. NOESY correlations reported as H to H atom number.
1
1
Detailed analysis of the structure was performed for azab-
utadienes 10a-e using 2D correlation NMR spectroscopy. The
composition of the products was confirmed by HRMS. For
example, 13C NMR and DEPT spectra of the compound 10b
(Table 2) showed 18 carbons, indicating four quaternary carbons,
azabutadiene motif. Finally, the structure 10b was established
by NOESY and HMBC correlations (Table 2).
A possible mechanism for the pyrimidine ring cleavage upon
reaction of salts 4 with amines, involves the formation of
azabutadienes 10 (Scheme 2). Initially, the imidazo[1,2-a]py-
rimidin-1-ium salt 4 undergoes a nucleophilic attack by a first
molecule of amine at its C-5 position. After rearrangement of
the intermediate A and isomerization of the resulting B, (E,E)-
azabutadiene 10 is formed. Initiated by protonation, the azab-
utadiene intermediate C in turn undergoes 1,4-addition with a
1
eight methine, five methylene, and one methyl group. Its H
NMR spectrum was simple and showed signals for 21 protons,
comprising signals of protons of the piperidine, azadiene,
imidazole, and aryl moieties. The coupling constants in the 1H
NMR spectrum of 10b support the all-(E) configuration of the
J. Org. Chem. Vol. 73, No. 17, 2008 6693

Ermolat’ev and Van der Eycken
SCHEME 2. Proposed Mechanism for the Ring Opening and Cleavage Reaction of Imidazo[1,2-a]pyrimidin-1-ium Salts 4 with
Amines
TABLE 3. One-Pot Two-Step Microwave-Assisted Synthesis of 1,4-, 1,5-, and 1,4,5-Substituted 2-Aminoimidazolesa
entry
imidazole
R1
R2
R3
yield (%)b
1
2
3
4
5
6
7
8
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
5t
5u
5v
Me
Me
H
H
H
H
4-ClPh
4-CNPh
Ph
Ph
4-CF3Ph
H
H
H
H
H
4-FPh
4-BrPh
Ph
4-ClPh
4-ClPh
68
73
81
79
46
88
74
89
71
59
71
77
95
89
65
2′-BrBn
3,4-diMeOPh(CH2)2
4-MeOPh
Me
Bn
H
Bn
Bn
4-MeOPh
4-MeOBn
4-MeOBn
Me
Me
Ph
4-MePh
4-MePh
Me
Me
9
10
11
12
13
14
15
4-MeOBn
Pr
MeO(CH2)2
Cyclohexyl
i-Bu
Ph
a All reactions were carried out on a 10 mmol scale of 2-alkylaminopyrimidine 1 with 1.35 equiv of R-bromocarbonyl compound 2 in 20 mL of
MeCN. b Isolated yields.
second molecule of amine, finally resulting in the formation of
2-aminoimidazole 5 together with diazapentadienium salt 11.
Consistent with this mechanism, the corresponding imidazo[1,2-
a]pyrimidin-1-ium salts 4 can directly be cleaved to 2-ami-
noimidazoles 5 upon stirring with a large excess of secondary
amine (6 or more equiv) at room temperature, when the isolated
azabutadienes 10a-g appeared to be stable to 20 and more
equivalents of piperidine in refluxing acetonitrile for 1 h. In
contrary, azabutadienes 10a-g were quantitatively cleaved to
2-aminoimidazoles 5a-g in the presence of 1.5 equiv of
triethylamine hydrochloride salt (Table 1).
To avoid the isolation of the intermediates and the use of
strong acidic conditions in the synthesis of polysubstituted
2-aminoimidazoles 5, we have developed a general microwave-
assisted, one-pot, two-step procedure for the synthesis of 1,4-,
1,5-, and 1,4,5-substituted 2-aminoimidazoles (Table 3). Ap-
plying the optimized cyclization and dehydratation conditions,17
we were able to expand the scope of R-bromocarbonyl
compounds 2 from R-bromo acetophenones (entries 1-5) to
R-bromo aldehydes (entries 6-10) and 1,2-disubstituted R-bro-
mo ketones (entries 11-15). At the first step 2-aminopyrim-
idines 1 react with R-bromocarbonyl compounds 2 to give
imidazo[1,2-a]pyrimidin-1-ium salts 4 (Table 3). At the next
step, the cleavage of salts 4 was performed using excess
hydrazine hydrate at 100 °C. The reaction conditions also
allowed the incorporation of other functional groups, e.g.,
sensitive to acids 4-cyanophenyl (entry 2). The yields of
2-aminoimidazoles 5h-v varied from good to excellent. Het-
erocyclization reactions of R-bromo aldehydes are hardly known
due to their high reactivity. Nevertheless, we were even able to
generate the corresponding 1,4-disubstituted 2-aminoimidazoles
5m-q in high yields by applying our microwave-assisted
protocol (Table 3, entries 6-10). The compounds bearing two
aromatic substituents at positions 4 and 5 of the imidazole ring
precipitated directly from the reaction mixture as white crystals
(Table 3, entries 11-15).
6694 J. Org. Chem. Vol. 73, No. 17, 2008

Synthesis of Substituted 2-Aminoimidazoles
TABLE 4. Microwave-Assisted Synthesis of 2-Amino-1H-imidazoles 6c-n
b
entry
producta
3
product
6
R1
R2
morpholin-4-ylcarbonyl
yield of 3 (%)c
yield of 6 (%)c
1
2
3
4
5
6
7
8
h
i
j
k
l
m
n
o
p
q
r
s
c
d
e
f
g
h
i
j
k
l
H
H
Et
H
H
H
H
H
H
H
H
Me
Me
Ph
4-tolyl
4-CNPh
4-NO2Ph
CONHEt
Morpholin-4-ylcarbonyl
3-NO2Ph
3-NO2Ph
4-NO2Ph
4-FPh
Ph
4-FPh
4-ClPh
4-ClPh
76
67
89
65
90
68
53
89
65
89
47
73
54
83
67
98
84
75
95
76
98
89
91
87
cyclopropyl
cyclohexyl
cyclododecyl
4-MeOBn
piperonyl
hexyl
MeO(CH2)2
homoveratryl
t-Bu
9
10
11
12
m
n
a All reactions were run on a 5 mmol scale of 2-alkylaminopyrimidine 1 with 1.2 equiv of R-bromo ketone 2 in 15 mL of MeCN in the presence of
catalytic amounts of DMAP. b All reactions were run on a 2 mmol scale of salt 3 in 5 mL of MeCN. c Isolated yields.
SCHEME 3. Formation of 2-Amino-1H-imidazoles 6a,b
FIGURE 1. HMBC and NOE correlations for compounds 6a and
6b.
1.2 equiv of R-bromo ketones 2 afforded 2-hydroxy-2,3-dihydro-
Next, we subjected the isolated intermediate 2-hydroxy-2,3-
1H-imidazo[1,2-a]pyrimidin-4-ium salts 3h-s in good or excel-
dihydroimidazo[1,2-a]pyrimidin-4-ium salts 3b and 3c to mi-
lent yields (Table 4). The cleavage step was performed under
crowave irradiation in the presence of 7 equiv of hydrazine
microwave irradiation at 100 °C, using 7 equiv of hydrazine
hydrate at 100 °C for 10 min (Scheme 3).
hydrate. The resulting 2-amino-1H-imidazoles 6c-n were
To our surprise, the cleavage of these salts resulted in the
obtained in high yields. Importantly, secondary and tertiary
formation of isomeric 2-amino-1H-imidazoles 6a and 6b.
amide functions survived cleavage conditions, and the corre-
Interestingly, no interconversion was observed between the
sponding 2-amino-1H-imidazoles 6e,f were obtained in 67% and
1-substituted 2-aminoimidazoles 5 and their 1-unsubstituted
98% yields, respectively (entries 3 and 4, Table 4).
isomers 6 under the reaction conditions applied. The structures
of two 2-amino-1H-imidazoles 6a and 6b were established by
All the intermediary salts 3h-s and the final 2-amino-1H-
imidazoles 6a-n were characterized by 1H and 13C NMR
NOESY and HMBC correlations (Figure 1).
spectroscopy. The composition of 2-amino-1H-imidazoles 6a-n
was also confirmed by HRMS.
Regarding the mechanism of the transformation of 2-hydroxy-
2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-4-iumsalts3into2-amino-
1
In the H NMR spectra of the products 6a,b, the chemical
shift of the endo-NHa of the imidazole ring is situated between
10.5-11.0 ppm while for the exo-NHb values between 4.3-6.5
ppm were detected.5a This observation, together with the
1H-imidazoles 6, we presume that the reaction proceeds via an
existence of Hb-Hc couplings, are proof for the proposed
unusual Dimroth-type rearrangement21 (Scheme 4).
2-amino-1H-imidazole structure. In the 13C NMR spectra of the
In the first step, the 2-hydroxy-2,3-dihydroimidazo[1,2-
a]pyrimidinium salt 3 undergoes cleavage of the pyrimidine ring,
resulting in the generation of pyrazole and 2-amino-5-hydroxy-
imidazolidine C, which is in equilibrium with the open form
D. This can cyclize again leading to the isomeric 2-amino-5(4)-
hydroxyimidazolidines E. Both isomers C and E were detected
products 6a-n (Scheme 3 and Table 4), the signals of C-4 and
C-5 of the imidazole ring appeared as broad peaks or were even
not detected, presumably, due to the fast proton exchange in
2-amino-1H-imidazoles between N-1 and N-3.5a
Hence, we started our investigation of this new reaction by
examining the heterocyclization of the parent 2-aminopyrim-
idines 1 with R-bromo ketones 2 at moderate temperature. The
optimized two-step protocol was successfully applied to syn-
thesize 12 substituted 2-amino-1H-imidazoles 6c-n (Table 4).
Irradiating an acetonitrile solution of 2-aminopyrimidines 1 with
(21) El Ashry, E. S. H.; El Kilany, Y.; Rashed, N.; Assafir, H. AdV.
Heterocycl. Chem. 1999, 75, 79. (a) Wahren, M. Z. Chem. 1969, 9, 241. (b)
Brown, D. J. Mechanisms of Molecular Migrations; Thyagarajan, B. S., Ed.;
Wiley-Interscience: New York, 1968; Vol. 1, pp 209.
J. Org. Chem. Vol. 73, No. 17, 2008 6695

Ermolat’ev and Van der Eycken
SCHEME 4. Proposed Mechanism for the Dimroth-Type Rearrangement of
2-Hydroxy-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-4-ium Salts
130.1, 129.9 (×2), 128.7, 128.6 (×2), 127.9, 127.7 (×2), 127.5
(×2), 111.7, 92.3, 63.5, 47.2, 22.4, 20.7, 20.3; DEPT-135 (75.5
MHz, DMSO-d6) δ 167.6, 149.3, 129.9 (×2), 128.7, 128.6 (×2),
127.7 (×2), 127.5 (×2), 111.7, -63.5, 47.2, 20.7, 20.3; MS (m/z)
366 [(M - Br + CO)]+, 338 [(M - Br)]+, 230 [(M - Br - OH
- i-Pr)]+.
General Procedure for the Synthesis of 4a-g (with 4d as
an Example). A mixture of 84% polyphosphoric acid (3 g) and
3d (1.24 g, 3 mmol) was heated in 50 mL beaker upon intensive
stirring at 150 °C for 15 min. After being cooled to room
temperature, the resulting viscous mass was dissolved in 30 mL of
water, and 1 mL (10 mmol) of 70% HClO4 was added dropwise
upon mild stirring. The white precipitate was washed with distilled
water (3 × 10 mL) and ether (2 × 10 mL) until a neutral reaction
showed on pH paper and then dried over P2O5 to give salt 4d (1.17
g, 94% yield) as fine white crystals.
2-(1,1′-Biphenyl-4-yl)-1-isopropylimidazo[1,2-a]pyrimidin-1-
ium perchlorate (4d). mp 193-195 °C; 1H NMR (300 MHz,
DMSO-d6) δ 9.14 (br, 1H), 8.58 (br, 1H), 7.97 (d, J ) 7.2 Hz,
2H), 7.77 (m, 5H), 7.56-7.45 (m, 3H), 4.82 (t, J ) 6.4 Hz, 1H),
1.70 (d, J ) 6.4 Hz, 6H); 13C NMR (75.5 MHz, DMSO-d6) δ 157.7,
143.4, 142.8, 139.7, 139.4, 137.6, 131.6, 131.6 (×2), 130.1 (×2),
129.2, 128.5 (×2), 127.8 (×2), 125.3, 115.2, 112.3, 51.8, 21.3 (×2);
MS (m/z) 271 [(M - ClO4 - i-Pr)]+.
General Procedure for the Synthesis of 5a-g (with 5d as
an Example). To a solution of 4d (1 mmol, 414 mg) in acetonitrile
(10 mL) was added piperidine (168 µL, 3.5 mmol, 3.5 equiv), and
the reaction mixture was refluxed at 85 °C for 45 min upon vigorous
stirring. After being cooled to room temperature, the reaction
mixture was poured into water (100 mL) and extracted with
dichloromethane (2 × 100 mL). The combined organic extracts
were then washed with 3 M NH4Cl (1 × 100 mL), brine (2 × 100
mL), and water (2 × 100 mL). The organic phase was dried over
Na2SO4, and then the solvent was removed at reduced pressure and
the residue was subjected to the flash column chromatography (silica
gel; CH2Cl--MeOH, 9:1 v/v) to give 5d (141 mg, 56% yield) as
colorless crystals.
by mass spectrometry. Final dehydration upon microwave
irradiation results in the rearranged 2-amino-1H-imidazoles 6.
This dehydration step, as judged by mass spectra, was found to
be the slowest step of the transformation. While some 2-amino-
5(4)-hydroxyimidazolidines E lost water spontaneously at room
temperature, others required higher temperature upon microwave
irradiation. Therefore, all of the reactions were run at 100 °C,
preventing the sequence from stopping after the first step
(Scheme 4).
Conclusion
In summary, two novel and complimentary methods for the
synthesis of functionalized 1-substituted and 1-unsubstituted and
2-aminoimidazoles 5 and 6 have been developed, applying
2-aminopyrimidines 1 as protected and substituted guanidines
in a cyclocondensation reaction with R-bromo carbonyl com-
pounds. The cleavage of the intermediate imidazo[1,2-a]pyri-
midin-1-ium salts 4 with hydrazine hydrate gives access to 1,4,5-
substituted 2-aminoimidazoles 5, while the reaction with
secondary amines at room temperature leads to novel azabuta-
dienes 10. The cleavage of 2-hydroxy-2,3-dihydroimidazo[1,2-
a]pyrimidinium salts 3 by hydrazine is believed to be followed
by a Dimroth-type rearrangement via in situ generated 2-amino-
5-hydroxyimidazolidines, resulting in the formation of 2-amino-
1H-imidazoles 6. Finally, this general methodology provides
an efficient and practical route for the synthesis of analogues
of different bioactive marine alkaloids, possessing a 2-ami-
noimidazole skeleton. Further research is in progress.
Experimental Section
Representative Procedure for the Synthesis of 3a-g (with
3d as an Example). To a solution of 2-isopropylaminopyrimidine
(0.83 g, 6 mmol) and 1-(1,1′-biphenyl-4-yl)-2-bromoethanone (2.0
g, 7.2 mmol, 1.2 equiv) in acetonitrile (12 mL) was added
4-dimethylaminopyridine (6 mg, 0.05 mmol). After being stirred
at 85 °C for 5 h, the reaction mixture was diluted with acetone (20
mL), and the precipitate was filtered, washed with acetone (2 ×
20 mL) and ether (2 × 20 mL), and dried over P2O5 to give 3d
(1.78 g, 63% yield) as a white solid.
2-(1,1′-Biphenyl-4-yl)-2-hydroxy-1-isopropyl-2,3-dihydro-1H-
imidazo[1,2-a]pyrimidin-4-ium bromide (3d). mp 272-274 °C; 1H
NMR (300 MHz, DMSO-d6) δ 9.03 (m, 1H), 7.98 (s, 1H), 7.78
(m, 6H), 7.39 (m, 4H), 4.87 (dd, J ) 33.8, 14.6 Hz, 2H), 3.45 (m,
1H), 1.45 (d, J ) 6.4 Hz, 2H), 1.27 (d, J ) 6.4 Hz, 2H); 13C NMR
(75.5 MHz, DMSO-d6) δ 167.7, 154.8, 149.3, 141.7, 140.1, 138.7,
5-(1,1′-Biphenyl-4-yl)-1-isopropyl-1H-imidazol-2-amine (5d).
mp >350 °C dec; 1H NMR (300 MHz, DMSO-d6) δ 7.69 (m, 4H),
7.48-7.22 (m, 5H), 6.45 (s, 1H), 5.29 (br, 2H), 4.27 (m, 1H), 1.39
(d, J ) 5.8 Hz, 6H); 13C NMR (75.5 MHz, DMSO-d6) δ 151.1,
140.6, 139.1, 131.6, 129.9 (×2), 129.5 (×2), 128.5, 128.3, 127.7
(×2), 127.4 (×2), 124.5, 46.9, 21.5 (×2); HRMS-EI m/z [M]+ calcd
for C18H19N3 277.1579, found 277.1578.
General Procedure for the Synthesis of 10a-g (with 10d
as an Example). Perchlorate salt 4d (414 mg, 1 mmol) was
dissolved in acetonitrile (5 mL), piperidine (280 µL, 3.5 mmol,
3.5 equiv) was added to the solution dropwise, and the reaction
mixture was stirred for 10 min at room temperature. After 3 min,
6696 J. Org. Chem. Vol. 73, No. 17, 2008

Synthesis of Substituted 2-Aminoimidazoles
a deeply colored solid began to precipitate, and the reaction mixture
was poured in dichloromethane (100 mL), washed with water (4
× 100 mL) and brine (2 × 100 mL), and dried over Na2SO4. The
solvent was removed in vacuum, and the residue was subjected to
the flash chromatography on silica gel, using dichloromethane as
an eluent to give 10d (363 mg, 91% yield) as bright yellow needles.
5-(1,1′-Biphenyl-4-yl)-1-isopropyl-N-[(1E,2E)-3-piperidin-1-ylprop-
2-enylidene]-1H-imidazol-2-amine (10d). mp 219-221 °C; 1H NMR
(400 MHz, CDCl3) δ 8.70 (d, J ) 9.6 Hz, 1H), 7.62 (d, J ) 8.0
Hz, 6H), 7.42 (m, 6H), 7.32 (m, 1H), 6.83 (m, 2H), 5.50 (dd, J )
13.0, 9.8 Hz, 1H), 4.56 (m, 1H), 3.24 (br, 6H), 1.63 (br, 4H), 1.55
(d, J ) 6.6 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 162.0, 154.2,
153.8, 140.6, 140.0, 131.0, 130.8, 129.6 (×2), 128.8 (×2), 127.4
(×2), 127.1, 127.0 (×2), 125.2, 98.7, 47.4, 25.5, 24.1, 22.3 (×2);
DEPT-135 (100 MHz, CDCl3) δ 162.0, 153.8, 129.6 (×2), 128.8
(×2), 127.4, 127.1 (×2), 127.0 (×2), 125.2, 98.7, 47.4, 25.5, 24.1,
22.2 (×2); HRMS-EI m/z [M]+ calcd for C26H30N4 398.2471, found
398.2461.
General Procedure for the Microwave-Assisted Synthesis
of 5h-v (with 5h as an Example). In a 30 mL microwave vial
were successively brought dry acetonitrile (20 mL), 2-methylami-
nopyrimidine (1.09 g, 10 mmol), and 4-chlorophenacyl bromide
(3.15 g, 13.5 mmol). The reaction tube was sealed and irradiated a
microwave reactor at a ceiling temperature of 150 °C at 150 W
maximum power for 25 min. After the reaction mixture was cooled
with an air flow for 15 min, hydrazine hydrate (2.5 mL, 50 mmol
of a 64% solution) was added, and the mixture was irradiated at
100 W 100 °C for another 5 min at a ceiling temperature of 100
°C at 100 W maximum power. The reaction was worked up by
diluting with dichloromethane (300 mL), washing with satd NH4Cl
solution (150 mL), brine (150 mL), and water (2 × 150 mL), and
drying over anhydrous Na2SO4. After filtration and concentration,
the resulting residue was purified by column chromatography (silica
gel; CH2Cl2-MeOH, 9:1 v/v with 3% TEA) to afford 5h (1.41 g,
68% yield) as colorless plates.
was washed with acetone (25 mL), ether (20 mL) and dried in
vacuum to afford 3o (1.98 g, 89% yield) as a white powder.
1-Benzo[1,3]dioxol-5-ylmethyl-2-(4-fluorophenyl)-2-hydroxy-2,3-
dihydro-1H-imidazo[1,2-a]pyrimidin-4-ium bromide (3o). mp
238-240 °C; 1H NMR (300 MHz, DMSO-d6) δ 9.07 (m, 1H), 8.96
(m, 1H), 7.97 (s, 1H), 7.73 (m, 2H), 7.39 (t, J ) 5.2 Hz, 1H), 7.18
(t, J ) 8.6 Hz, 2H), 6.68 (d, J ) 7.7 Hz, 1H), 6.62 (s, 1H), 6.48
(d, J ) 7.8 Hz, 2H), 5.92 (d, J ) 3.2 Hz, 2H), 4.90 (s, 2H), 4.48
(d, J ) 15.9 Hz, 1H), 4.35 (d, J ) 15.8 Hz, 1H); 13C NMR (75.5
MHz, DMSO-d6) δ 168.5, 164.9, 161.7, 155.7, 149.3, 147.8, 147.2,
134.8, 130.7, 130.5, 130.3, 122.2, 115.9, 115.6, 112.7, 109.1, 108.6,
101.7, 91.3, 63.5, 44.5; MS (m/z) 366 [(M - Br)]+, 214 [(M - Br
- OH - piperonyl)]+.
General Procedure for the Microwave-Assisted Synthesis
of 6a-t (with 6j as an Example). To a suspension of salt 3 (2
mmol) in acetonitrile (5 mL) was added hydrazine hydrate (0.7
mL, 14 mmol of a 64% solution, 7 equiv), and the mixture was
irradiated in the sealed reaction tube for 10 min at a ceiling
temperature of 100 °C at 150 W maximum power. After the mixture
was cooled, hydrazine hydrate was evaporated with toluene (3 ×
20 mL). The resulting residue was purified by column chromatog-
raphy (silica gel; MeOH-DCM 1:4 v/v with 5% of 6 M NH3 in
MeOH) to afford 2-amino-1H-imidazole 6j (473 mg, 76% yield)
as an amorphous solid.
Benzo[1,3]dioxol-5-ylmethyl-[4-(4-fluorophenyl)-1H-imidazol-
2-yl]amine (6j). 1H NMR (300 MHz, DMSO-d6) δ 10.51 (br, 1H),
7.62 (t, J ) 7.0 Hz, 2H), 7.09 (d, J ) 8.6 Hz, 2H), 6.97 (d, J )
11.7 Hz, 2H), 6.85 (m, 2H), 6.22 (t, J ) 6.3 Hz, 1H), 5.96 (s, 2H);
13C NMR (75.5 MHz, DMSO-d6) δ 151.8, 148.8, 147.9, 146.8,
135.4, 132.0, 129.2, 126.0, 121.5, 116.1, 114.7, 108.9 (×2), 101.6
(×2), 63.9, 45.1; HRMS-EI: m/z [M]+ calcd for C17H14FN3O2
311.1070, found 311.1066.
Acknowledgment. Support was provided by the Research
Fund of the University of Leuven and by the FWO (Fund for
Scientific Research - Flanders (Belgium)). D.E. is grateful to
the University of Leuven for a scholarship. We are very thankful
to Prof. Eugene Babaev (Moscow State University) for a fruitful
discussion of this paper.
5-(4-Chlorophenyl)-1-methyl-1H-imidazol-2-amine (5h): mp
1
179-181 °C; H NMR (300 MHz, CDCl3) δ 7.49-7.34 (m, 4H),
6.70 (s, 1H), 4.05 (br, 2H), 3.40 (s, 3H); 13C NMR (75.5 MHz,
CDCl3) δ 152.8, 131.4, 130.8, 129.5 (×2), 128.9 (×2), 127.5, 124.6,
31.4; HR-MS (EI) C10H10ClN3 calcd 207.0563, found 207.0571.
General Procedure for the Microwave-Assisted Synthesis
of 3h-s (with 3o as an Example). In a 30 mL microwave vial
were successively brought acetonitrile (15 mL), N-(1,3-benzodioxol-
5-ylmethyl)pyrimidin-2-amine (1.15 g, 5 mmol), 4-fluorophenacyl
bromide (1.3 g, 6 mmol, 1.2 equiv), and a catalytic amount of
4-dimethylaminopyridine (6 mg, 0.05 mmol). The reaction tube was
sealed and irradiated in a microwave reactor at a ceiling temperature
of 80 °C at 150 W maximum power for 30 min. After the reaction
mixture was cooled with an air flow for 15 min, the precipitate
Supporting Information Available: Experimental details for
compounds 1; spectral and analytical data for compounds 1,
1
3-6, and 10; copies of H NMR and 13C NMR spectra of 1,
3-6, and 10; copies of 2D NMR (NOESY, HMBC) spectra
for 6a,b and 10a-e. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO8008758
J. Org. Chem. Vol. 73, No. 17, 2008 6697