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Tetrahedron Letters 50 (2009) 5218­5220

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Tetrahedron Letters
jo urn al h o mep ag e: www. el s evi er .co m/l oca t e/te tle t

Microwave-assisted synthesis of substituted 2-amino-1H-imidazoles from imidazo[1,2-a]pyrimidines
D. S. Ermolat'ev a, E. P. Svidritsky b, E. V. Babaev b, E. Van der Eycken
a b

a,*

Laboratory for Organic and Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium Chemistry Department, Moscow State University, Moscow 119992, Russia

article

info

abstract
An efficient method for the synthesis of mono and disubstituted 2 amino 1H imidazoles via microwave assisted hydrazinolysis of substituted imidazo[1,2 a]pyrimidines is reported. This protocol avoids strong acidic conditions and is superior to the classical cyclocondensation of a haloketones with N acetylguanidine. ñ 2009 Elsevier Ltd. All rights reserved.

Article history: Received 21 April 2009 Revised 24 June 2009 Accepted 29 June 2009 Available online 3 July 2009 Keywords: Imidazo[1,2-a]pyrimidines Substituted 2-amino-1H-imidazoles Microwave-assisted reaction Hydrazinolysis Ring cleavage

The 2 amino 1H imidazole motif, which is common in all mem bers of the oroidin family of marine sponge alkaloids,1 constitutes an important class of potent antagonists of serotonergic and hista minergic receptors.2 Very recently, it was demonstrated that natu rally occurring 2 amino 1H imidazoles and their synthetic analogues inhibit and disperse bacterial biofilms through a non bactericidal mechanism.3 Because of these interesting biological properties, numerous synthetic routes to 2 amino 1H imidazoles have been reported.4 Modern synthetic methods for accessing 1 unsubstituted 2 amino 1H imidazoles can be classified as heterocyclization of substituted or protected guanidines with 1,2 dielectrophiles,5 het eroaromatic nucleophilic substitution5c,6 and recyclization of 2 aminooxazoles.7 Although different substituted guanidines are readily available and can be prepared in situ (e.g., from cyanam ines8), the high basicity of guanidines together with non regiose lectivity of the reaction often leads to multiple products.9 Protection by acetyl5a and Boc groups5c requires, in turn, acidic deprotection conditions. Another procedure is the cyclocondensa tion of aldehydes and guanidine nitrate using sodium cyanide and supported aluminium oxide, which provides 2 aminoimidaz oles with identical substituents on positions 4 and 5 of the ring structure.10 An interesting microwave assisted protocol was developed by Lam and co workers for the construction of 2 amino 1H imida
* Corresponding author. Tel.: +32 16 327406; fax: +32 16 327990. E-mail address: erik.vandereycken@chem.kuleuven.be (E. Van der Eycken). 0040-4039/$ - see front matter ñ 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2009.06.128

zoles 1 from readily available N acetylguanidine (2) and a haloke tones 3 (Scheme 1, route A).4 Unfortunately, strong acidic conditions required for the deacetylation of the final products and limited availability of the starting 1,2 diaryl a haloketones significantly narrow the scope of the method. Recently, we described the microwave assisted procedure for the synthesis of polysubstituted 2 aminoimidazoles 1.11 This pro tocol is based on the cyclocondensation of 2 aminopyrimidines and a bromocarbonyl compounds 3 at elevated temperature, followed by the cleavage of the intermediary imidazo[1,2 a]pyrim idin 1 ium salts 4 with excess of hydrazine (Scheme 1, route B). In this approach to 1 substituted 2 aminoimidazoles we used readily available substituted 2 aminopyrimidines as the masked guani dine function for the construction of the imidazole ring.12 Herein we describe an alternative strategy for the synthesis of polysubstituted 2 amino 1H imidazoles 1. Due to the fact that the bicyclic system of the imidazo[1,2 a]pyrimidines 6 possesses an electron poor (p deficient) pyrimidine ring and an electron rich (p excessive) imidazole ring, we started our investigations by choosing imidazo[1,2 a]pyrimidines 6 as templates for the modu lar synthesis of 4,5 disubstituted 2 amino 1H imidazoles (Scheme 2). In our preliminary report13 we developed a new microwave as sisted Pd catalyzed synthesis of 2,3 disubstituted imidazo[1,2 a]pyrimidines 5 via a Heck type arylation of 2 substituted imidazo[1,2 a]pyrimidines 6. In this Letter, we report a facile and practical microwave assisted synthesis of 4(5) mono and 4,5 disubstituted 2 amino 1H imidazoles from the corresponding substituted imidazo[1,2 a]pyrimidines 5 and 6.


D. S. Ermolat'ev et al. / Tetrahedron Letters 50 (2009) 5218­5220

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NAc N H2N Br 2 + R1 = H R3 R2 3 O
Scheme 1. Synthesis of substituted 2-amino-1H-imidazoles.

NH2 A

R1 HN

N

R2 B N Br R3 R3 4 R2 N R1 OH

N H 1

N N H2N N H 1 R2 R2 5 R1 6 R1 ? N N Ref. 13 N

N

N

R1

Scheme 2. Retrosynthetic analysis of the synthesis of 4,5-disubstituted 2-amino-1H-imidazoles.

To optimize the procedure we first studied nucleophilic cleav age of 2 phenylimidazo[1,2 a]pyrimidine (6a) under a variety of conditions and compared microwave and conventional heating conditions. Hydrazine was found to be the most reactive bis nucle ophile among the cleaving agents, such as hydroxylamine and alkylamines, giving pyrazole as the only by product of pyrimidine ring cleavage.14 A possible mechanism of the cleavage was given in our previous work.11b In a typical procedure, a mixture of 2 pheny limidazo[1,2 a]pyrimidine (6a) and 20% hydrazine hydrate in a suitable solvent was irradiated in a sealed vial at 150 W maximum power or heated in an oil bath (Table 1). First, we tried the cleavage in MeCN under conventional heat ing. However, the reaction was found to be sluggish and after 12 h of heating at 80 °C only 38% of 2 amino 1H 4(5) phenylimi dazole (1a) was isolated next to a considerable amount of unre acted starting material (Table 1, entry 1). Increasing the

temperature to 140 °C afforded product 1a in 72% yield within 5h (Table 1, entry 4). Interestingly, the cleavage was found to pro ceed faster in ethanol, thus providing the desired product in 83% yield within only 2 h (Table 1, entry 5). At this point, after the con ventional heating attempts, we decided to carry out the cleavage of 2 phenylimidazo[1,2 a]pyrimidine (6a) under focused microwave irradiation. Unfortunately, irradiating the reaction mixture for 1 h at 80 °C provided the product in a disappointingly low yield of 13% isolated yield (Table 1, entry 6). However, contrary to the reac tion under conventional heating conditions, we found that at 100 °C ceiling temperature the reaction was much faster as moni tored by TLC (Table 1, entry 7). A further experiment performed at 120 °C improved substantially the yield of 2 amino 1H 4(5) phen ylimidazole (1a) and the reaction was completed within 30 min

Table 2 Microwave-assisted synthesis of 4(5)-substituted 2-amino-1H-imidazoles 1a­ka Table 1 Optimization of the conditions for the cleavage of 6a with hydrazine
a

N N R1

N

N

Ph

N

20% N2H4
N N

N

20% N2H4/EtOH MW, 120 °C

H2N N H 1b-k

H2N N H 1a
Entry 1 2 3 4 5 6 7 8 9 10 11

Solvent

6b-k

R1
R
1

6a
Ph
Entry 1 2 3 4 5 6 7 8 9 10
a b c

Product 1a 1b 1c 1d 1e 1f 1g 1h 1i 1j 1k

Time (min) 10 25 10 10 10 20 15 15 20 5 5

Yield (%) 89 79 93 88 87 80 88 64 89 87 93

b

Conditions

Solvent MeCN MeCN MeCN MeCN EtOH MeCN MeCN MeCN EtOH Dioxane

Temperature (°C) 80 100 120 140 140 80 100 120 120 120

Time (h) 12 12 5 5 2 1 1 0.5 0.5 0.5

Yield (%) 38 45 69 72 83 13 55 85 91 47

c

D

MWb

Ph p-MeOPh p-FPh p-ClPh p-BrPh p-MePh p-MeSO2Ph p-NO2Ph Biphenyl-4-yl CONHBn CONHPh

All reactions were performed on a 0.5-mmol scale in 3 mL of solvent. All the microwave experiments were performed at 150 W maximum power. All yields are isolated yields.

a All reactions were performed on a 5-mmol scale in 12 mL of solvent. All the microwave experiments were performed at a ceiling temperature of 120 °C and 150 W maximum power. b All yields are isolated yields.


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D. S. Ermolat'ev et al. / Tetrahedron Letters 50 (2009) 5218­5220

Table 3 Microwave-assisted synthesis of 4,5-disubstituted 2-amino-1H-imidazoles 1l­w

N N N N 20% N2H4/EtOH MW, 110 °C 10 min R2 5a-m
Entry 1 2 3 4 5 6 7 8 9 10 11 12

R

1

H2N N H 1l-w R2

R1
R R

Product 1l 1m 1n 1o 1p 1q 1r 1s 1t 1u 1v 1w

1

2

Yield 68 83 95 94 83 89 88 94 88 89 61 84

a,b

(%)

Ph p-ClPh p-ClPh p-MePh Ph p-FPh Ph Ph p-MeOPh p-MeSO2Ph CONHPh CONHBn

p-ClPh p-FPh p-CF3Ph p-ClPh p-MeOPh p-FPh p-CF3Ph o-FPh p-MeSO2Ph p-CF3Ph p-FPh Ph

Finally, we have applied the optimized protocol for the cleavage of 2,3 disubstituted imidazo[1,2 a]pyrimidines (Table 3). We sub jected 12 compounds 5a m to the microwave assisted hydrazinol ysis to afford the corresponding 4,5 disubstituted 2 amino 1H imidazoles 1l­w. Interestingly, all the reactions were completed within 10 min providing the products in high yields (Table 3). In a typical procedure, a mixture of 2,3 disubstituted imidazo[1,2 a]pyrimidines 5 and hydrazine hydrate in ethanol was irradiated in a sealed reaction vial at 150 W maximum power for 10 min at a ceiling temperature of 120 °C. The products were purified by column chromatography using 5 10% MeOH in CH2Cl2 as the eluent. In conclusion, we have developed a simple and practical proce dure for the preparation of 4(5) monosubstituted and 4,5 disubsti tuted 2 amino 1H imidazoles. We have investigated the cleavage of 2 arylimidazo[1,2 a]pyrimidines by hydrazine hydrate and found microwave irradiation to be very effective in this regard. A small library of 4(5) mono and 4,5 disubstituted 2 amino 1H imidazoles was synthesized for screening for potential antiviral activity. Acknowledgements Support was provided by the Research Fund of the University of Leuven and by the F.W.O. (Fund for Scientific Research Flanders (Belgium)). D.E. is grateful to the University of Leuven for obtaining a postdoctoral fellowship. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.tetlet.2009.06.128. References and notes
1. Hoffmann, H.; Lindel, T. Synthesis 2003, 1753­1783. 2. Olofson, A.; Yakushijin, K.; Horne, D. A. J. Org. Chem. 1998, 63, 1248­1253. 3. (a) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803­3805; (b) Richards, J. J.; Ballard, T. E.; Melander, M. Org. Biomol. Chem. 2008, 6, 1356­ 1363; (c) Richards, J. J.; Ballard, T. E.; Huigens, R. W.; Melander, M. ChemBioChem 2008, 14, 1267­1279; (d) Richards, J. J.; Huigens, R. W.; Ballard, T. E.; Basso, A.; Cavanagh, J.; Melander, M. Chem. Commun. 2008, 9, 1698­1700. 4. Soh, C. H.; Chui, W. K.; Lam, Y. J. Comb. Chem. 2008, 10, 118­122. and references cited herein. 5. (a) Little, T. L.; Webber, S. E. J. Org. Chem. 1994, 59, 7299­7305; (b) Abou-Jneid, R.; Ghoulami, S.; Martin, M.-T.; Dau, E. T. H.; Travert, N.; Al-Mourabit, A. Org. Lett. 2004, 6, 3933­3936; (c) Gore, V. K.; Ma, V. V.; Norman, M. H.; Ognyanov, V. I.; Xi, N. US Patent US 2006/0084640 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, 2957­2960; (b) Lamattina, J. L.; Eur. Pat. Appl. EP 138464 A2, 1985. 8. Katritzky, A. R.; Rogovoy, B. Arkivoc 2005, Part iv, 49­87. and references cited herein. 9. Beyer, H.; Pyl, T.; Lahmer, H. Chem. Ber. 1961, 94, 3217­3223. 10. Thangavel, N.; Murgesh, K. Asian J. Chem. 2005, 17, 2769­2772. 11. (a) Ermolatev, D. S.; Babaev, E. V.; Van der Eycken, E. Org. Lett. 2006, 8, 5781­ 5784; (b) Ermolat'ev, D. S.; Van der Eycken, E. J. Org. Chem. 2008, 73, 6691­ 6697. 12. Alifanov, V. L.; Babaev, E. V. Synthesis 2007, 2, 263­270. 13. Ermolat'ev, D. S.; GimÈnez, V. N.; Babaev, E. V.; Van der Eycken, E. J. Comb. Chem. 2006, 8, 659­663. 14. Fajgeli, S.; Stanovnik, B.; Tisler, M. Heterocycles 1986, 24, 379­386.

a All reactions were performed on a 0.5-mmol scale in 3­4 mL of solvent. All the microwave experiments were performed at a ceiling temperature of and 150 W maximum power. b All yields are isolated yields.

(Table 1, entry 8). Switching to ethanol the solvent resulted in an excellent yield of 91%. Curiously, the cleavage reaction proceeded comparatively slower in an apolar solvent as 1,4 dioxane giving the product 1a in only 47% yield (Table 1, entry 10). Thus, after optimizing the cleavage of 2 phenylimidazo[1,2 a]pyrimidine (6a) under microwave irradiation, we extended our strategy towards a series of 2 substituted imidazo[1,2 a]pyrimi dines (6a­k). All reactions were carried out on a 5 mmol scale in 20% hydrazine monohydrate solution in ethanol at a ceiling tem perature of 120 °C, applying microwave irradiation at 150 W max imum power (Table 2). The reactions proceeded smoothly with a very low amount of the starting material left and the products 1a­k were purified by column chromatography using 15 20% MeOH in CH2Cl2 as the eluent. The reaction times varied from 5 to 25 min depending on the nature of substituent R1 (Table 2). It was found that imidazo[1,2 a]pyrimidines bearing electron donat ing substituents, for example, p methoxyphenyl and p tolyl (Table 2, entries 2 and 6), require up to 25 min to drive the cleavage to completion. On the contrary, the cleavage of the imidazo[1,2 a]pyrimidines bearing electron withdrawing substituents was completed within 5 min (Table 2, entries 10 and 11). Importantly, the carboxamide function remained intact upon hydrazinolysis of the imidazo[1,2 a]pyrimidines and we have not observed any trace of transamination by products. The microwave assisted cleavage of 2 (p nitrophenyl)imi dazo[1,2 a]pyrimidine (6h) afforded the corresponding 2 amino 1H imidazole 1h in only 64% yield, probably due to the poor solu bility of the starting material (Table 2, entry 8).