Efficient one-pot, two-step, microwave-assisted procedure for the synthesis of polysubstituted 2-aminoimidazoles

Article abstract of DOI:10.1021/ol062421c

(Diagram presented) A microwave-assisted, one-pot, two-step protocol was developed for the construction of polysubstituted 2-aminoimidazoles. This process involves the sequential formation of imidazo[1,2-a]pyrimidinium salts from readily available 2-amino

Full text of DOI:10.1021/ol062421c

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5781-5784
Efficient One-Pot, Two-Step,
Microwave-Assisted Procedure for the
Synthesis of Polysubstituted
2-Aminoimidazoles
Denis S. Ermolat’ev,† Eugene V. Babaev,*,‡ 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, and
Combinatorial Chemistry Centre, Department of Chemistry, Moscow State UniVersity,
119992 Moscow, Russia
erik.Vandereycken@chem.kuleuVen.be; babaeV@org.chem.msu.su
Received October 2, 2006
ABSTRACT
A microwave-assisted, one-pot, two-step protocol was developed for the construction of polysubstituted 2-aminoimidazoles. This process
involves the sequential formation of imidazo[1,2-a]pyrimidinium salts from readily available 2-aminopyrimidines and
followed by opening of the pyrimidine ring with hydrazine.
r-bromocarbonyl compounds,
In the last decades, several marine alkaloids possessing a
2-aminoimidazole skeleton have been given particular at-
tention, as many of them demonstrate interesting biological
properties. The naamine alkaloids, for example, isolated from
the marine sponge Leucetta sp., have been reported to possess
antiviral and anticancer activity.1,2 These compounds are
usually substituted with benzyl or aryl groups at the 1, 4,
and/or 5 positions. Several approaches for the synthesis of
2-aminoimidazoles have been described in the literature. Ohta
and co-workers performed the synthesis of polysubstituted
2-aminoimidazoles via functionalization of the imidazole
ring.3 Other general applicable strategies involve the reaction
of R-diketones with guanidine,4 the reaction of R-halo
ketones with N-acetylguanidine,5 and the iminophosphorane-
mediated cyclization of R-azido esters.6 The condensation
of R-aminocarbonyl compounds with cyanamide or isothio-
ureas appears to be the most popular method for the direct
construction of the 2-aminoimidazole ring.7,8 However, this
reaction is strongly pH-sensitive and can lead to the self-
(2) (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.
(3) Ohta, S.; Tsuno, N.; Nakamura, S.; Taguchi, N.; Yamashita, M.;
Kawasaki, I.; Fujieda, M. Heterocycles 2000, 53, 1939.
(4) Nishimura, T.; Kitajima, K. J. Org. Chem. 1979, 44, 818.
(5) Little, T. L.; Webber, S. E. J. Org. Chem. 1994, 59, 7299.
(6) Molina P.; Fresneda P.; Sanz, M. J. Org. Chem. 1999, 64, 2540.
† University of Leuven.
‡ Moscow State University.
(1) (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.
10.1021/ol062421c CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/10/2006

condensation of R-aminoaldehydes or ketones resulting in
the formation of symmetrical pyrazines.9
the condensation in the first step was performed at elevated
temperature (>130 °C).
An alternative strategy for the synthesis of 2-aminoimi-
dazoles involves the formation of imidazo[1,2-a]pyrimidines,
followed by cleavage of the pyrimidine ring upon treatment
with strong nucleophiles as hydrazine or amines.10-14 How-
ever, this procedure yields only N-1-unsubstituted 2-ami-
noimidazoles.
On the contrary, when the corresponding N-1-substituted
imidazo[1,2-a]pyrimidinium salt should be cleaved, this
would result in the formation of N-1-substituted 2-aminoimi-
dazoles.15 We previously reported a new and convenient
three-step procedure for the synthesis of polysubstituted
2-aminoimidazoles 5 out of N-1-substituted imidazo[1,2-a]-
pyrimidinium salts 4, which are generated upon reaction of
2-aminopyrimidines 1 with R-bromoketones 2 (Scheme 1).16
As a result, we now wish to present an ameliorated and
convenient one-pot two-step protocol for the synthesis of
N-1-substituted 2-aminoimidazoles, applying microwave
irradiation.
We carefully investigated the dehydration of salt 3
resulting in the formation of salt 4 (Scheme 1) under
conventional heating conditions as well as upon microwave
irradiation. As a proof of concept, the condensation of
2-methylaminopyrimidine (1, R1 ) Me) and R-phenacyl
bromide (2, R2 ) H, R3 ) Ph) was studied (Table 1). A
Table 1. Investigation of the Condensation under Conventional
Heating and Microwave Irradiation Conditionsa
Scheme 1. Two-Step Conventional Synthesis of
2-Aminoimidazoles
time
3
4
entry conditions (min) T (°C) (yield, %)b (yield, %)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
30
60
30
60
30
60
30
60
30
60
30
60
30
60
30
60
80
80
64
77
81
85
68
53
45
43
88
85
48
45
12
traces
0
0
0
100
100
120
120
130
130
80
traces
traces
17
28
49
51
0
MW
80
0
100
100
120
120
130
130
33
35
79
84
98
97
The first step was performed at 80-100 °C resulting in the
formation of the hydroxy salt 3, which underwent water
elimination upon treatment with concentrated HBr or poly-
phosphoric acid at 140 °C, resulting in the formation of salt
4. Final treatment with aqueous hydrazine in acetonitrile at
80 °C yielded the N-1-substituted 2-aminoimidazole 5. We
have demonstrated that a considerable amount of the imi-
dazo[1,2-a]pyrimidinium salt 4 was directly formed when
0
a All reactions were carried out on a 1 mmol scale of 2-methylaminopy-
rimidine (1, R1 ) Me) with 1.35 equiv of R-phenacylbromide (2, R2 ) H,
R3 ) Ph) in 5 mL of acetonitrile. b Isolated yield after recrystallization from
acetonitrile.
sealed vial containing a solution of the starting compounds
1 and 2 in acetonitrile was heated at 80-100 °C for 30-60
min. However, only a trace amount of the desired 1-methyl-
(7) (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.
(8) Aberle, N.; Guillaume, L.; Watson, K. Org. Lett. 2006, 8, 419.
(9) (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.
(10) Casagrande, C.; Ferrini, R.; Miragoli, G.; Ferrari, G. Farmaco (Ed.
Sci.) 1972, 27, 715.
(11) Fajgelj, S.; Stanovnik, B.; Tisler, M. Heterocycles 1986, 24, 379.
(12) Commercon, A. France Patent 539229, 1993.
(16) (a) Babaev, E. V. Abstracts of Papers. 2nd International Conference
of Pure, Applied and Environmental Chemistry, 17-19 April 2000,
Yarmouk University, Irbid, Jordan, IL-5. (b) Rybakov, V. B.; Babaev, E.
V.; Belykh, E. N. Acta Crystallogr., Sect. E 2002, E58, o126-128 and
references therein. (c) Babaev, E. V.; Tsisevich, A. A.; Alifanov, V. L.;
Ermolat’ev, D. S. Book of Abstracts. 11th Blue Danube Symposium on
Heterocyclic Chemistry, Brno, Aug 28-Sep 1, 2005, OC-12. (d) Tsisevich
A. A. Ph.D. Thesis, Moscow University, 2006. (e) For use of our preparation
protocols and libraries in agrochemical screening, see also: Kurapov, P.
B.; Smirnova, T. A.; Vetrova, E. L.; Bass, A. G.; Babaev, E. V. Abstracts
of Papers. 1st Symposium of European Society of Combinatorial Chemistry
(EuroCombi-1), July 1-5, 2001, Budapest, Hungary, 63. Smirnova, T. A.;
Kurapov, P. B.; Vetrova, E. L.; Bass, A. G.; Nam, N. L. IzV. TimiryazeVsk.
S’kh. Akad. 2003, 4, 132 (in Russian).
(13) Pearson, N. R.; Kleschick, W. A.; Bartley, S. L. U.S. Patent Appl.
4731446, 1988.
(14) Grell, W.; Haaksma, E.; Binder, K.; Zimmermann, R.; Wienen, W.;
Hallermayer, G. German Patent DE 19548797, 1999.
(15) This method has previously been used in one single case, i.e. for
the synthesis of 1-methyl-2-aminoimidazole starting from imidazo[1,2-a]-
pyrimidine, by Paudler, W. W.; Helmick, L. S. J. Heterocycl. Chem. 1968,
5, 691.
5782
Org. Lett., Vol. 8, No. 25, 2006

Table 2. One-Pot, Two-Step, Microwave-Assisted Synthesis of 1,4-, 1,5-, and 1,4,5-Substituted 2-Aminoimidazolesa
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 acetonitrile.
b Isolated yield. c The condensation was performed at 130 °C within 15 min. d The condensation was performed at 150 °C within 25 min.
2-phenylimidazo[1,2-a]pyrimidinium salt (4{1}) was ob-
served next to the hydroxy salt 3{1} (Table 1, entries 3 and
4). On the contrary, upon microwave irradiation at a ceiling
temperature of 100 °C for 30 min, a mixture of salts 3{1}
and 4{1} was obtained in a ratio of 48:33 (Table 1, entry
11). Further increase of the temperature up to 130 °C
applying conventional heating led to a nearly equimolar
mixture of salts 3{1} and 4{1} (Table 1, entries 7 and 8).
Interestingly, using microwave irradiation at 130 °C for 30
min, we were able to drive the reaction completely to the
formation of the desired imidazo[1,2-a]pyrimidinium salt
4{1} (entry 15).
With these results in hand, we developed an elegant one-
pot, two-step, microwave-assisted protocol for the synthesis
Org. Lett., Vol. 8, No. 25, 2006
5783

of 1,4-, 1,5-, and 1,4,5-substituted 2-aminoimidazoles starting
from readily available 2-aminopyrimidines 1 and R-bro-
moketones 2 (Table 2). The reaction could visually be
followed, as after the start, the initially formed salt 3
precipitated from the reaction mixture and then slowly
dissolved at 130-150 °C, converting to the salt 4. Then 5
equiv of hydrazine (60%) were added and the mixture was
irradiated at a ceiling temperature of 100 °C for another 5
min. Upon completion, the reaction mixture was diluted with
water and extracted with dichloromethane. Side products
could easily be removed by washing the organic phase with
water, resulting in nearly pure compounds. Following this
protocol, a small library of variously substituted 2-aminoimi-
dazoles was generated, starting from readily available
R-bromocarbonyl compounds 2 and 2-aminopyrimidines 1
(Table 2).
The yields varied from good to excellent, although in some
cases lowered yields were observed (Table 2, entries 5, 12,
and 13) probably due to abstraction of the substituent R1
from the imidazole ring at high temperature. Interestingly,
applying conventional heating conditions, longer total reac-
tion times (up to 10-12 h) were necessary, resulting in lower
yields due to significant decomposition of the starting
compounds. Moreover, since the preparation of salts 4 under
conventional conditions involves the exposure of the inter-
mediates 3 and 4 to strong acids at elevated temperature
(Scheme 1), sensitive R1 substituents as cycloalkyl and
p-methoxybenzyl are not tolerated. Heterocyclization reac-
tions of R-bromoaldehydes are hardly known due to their
high reactivity. Nevertheless, we were able to generate the
corresponding 1,4-disubstituted 2-aminoimidazoles in high
yields by applying our microwave-assisted protocol (Table
2, entries 16-18). As the cyclization of R-bromoaldehydes
and 1,2-disubstituted R-bromoketones with 2-aminopyrim-
idines was found to be slow, the temperature of the first step
was raised to 150 °C and a longer irradiation time of 25
min was applied (Table 2, entries 16-27). The desired 1,4-
and 1,4,5-substituted 2-aminoimidazoles were isolated in
good yields (65-95%). The compounds bearing two aro-
matic substituents at positions 4 and 5 of the imidazole ring
precipitated directly from the reaction mixture as white
crystals (Table 2, entries 20, 23-24, and 27).
In conclusion, we have developed an efficient microwave-
assisted, one-pot, two-step protocol for the synthesis of 1,4-,
1,5-, and 1,4,5-substituted 2-aminoimidazoles from 2-ami-
nopyrimidines and R-bromoketones or R-bromoaldehydes,
applying the 2-aminopyrimidine ring as a protected guanidine
fragment. This procedure opens the way for the synthesis of
analogues of different bioactive marine alkaloids possessing
a 2-aminoimidazole skeleton.
Acknowledgment. E.V. thanks the F.W.O. (Fund for
Scientific Research - Flanders (Belgium)) and the Research
Fund of the University of Leuven for financial support. D.E.
is grateful to the University of Leuven for a scholarship. E.B.
thanks the RFBR for financial support (Grant No. 05-03-
39022GFEN).
Supporting Information Available: Spectroscopic data
for all new compounds prepared, as well as detailed
experimental procedures. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL062421C
5784
Org. Lett., Vol. 8, No. 25, 2006