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Preparation of bicyclic guanidines by the iodocyclization of alk-3-enyl-2-(substituted amino)-1-imidazolin-4-ones

Michihiko Noguchi, *a Hiroshi Okada,a Masanori Watanabe,a Hideki Moriyama,a Osamu Nakamuraa and Akikazu Kakehib

aDepartment of Applied Chemistry, Faculty of Engineering, Yamaguchi University, Tokiwadai, Ube 755, Japan
b Department of Chemistry and Material Engineering, Faculty of Engineering, Shinshu University, Wakasato, Nagano 380, Japan


The iodocyclization of 3-allyl-2-(substituted amino)-5-(unsubstituted)- and -5-(monosubstituted)-1-imidazolin-4-ones, which are suggested to be sensitive under such oxidative conditions, was examined; the 5-exo cyclization products, imidazo[1,2-a]imidazoles, were formed were similar to those of 5,5-dimethyl-1-imidazolin-4-ones. The scope and limitations of these cyclization are also discussed.


In previous papers,1,2 we reported a novel synthetic route to bicyclic guanidines, imidazo[1,2-a]imidazole and imidazo[1,2-a]pyrimidine, some derivatives of which showed hypoglycaemic activity.3 The guanidines were formed by the iodocyclization of alk-3-enyl-1 and alk-3-ynyl-2-(substituted amino)-1-imidazolin-4-ones.2 The regiochemistry of the iodocyclization was predicted by the frontier electron densities for nucleophile [fr(N)] of the LUMOs of the corresponding iodonium ion intermediates. The stereochemistry of the guanidines was interpreted in terms of the stereoselective formation of the iodonium ion and its successive opening by the intramolecular nitrogen nucleophile in an SN2 mode.1 We report here the iodocylization of some 5-(unsubstituted)- and 5-(monosubstituted)-alk-3-enyl-2-(substituted amino)-1-imidazolin-4-ones, which are suggested to be sensitive to such oxidative conditions. The scope and limitation of these cyclizations will be also discussed.

Iodocyclization of 3-Allyl-5-(unsubstituted)- (13) and 3-Allyl-5-(monosubstituted)-2-(substituted amino)-1-imidazolin-4-ones (14) and (15)

The imidazolin-4-ones 13-15 were obtained according to the reported procedures in fair to good yields (Scheme 1).1 The reaction of 3-allyl-2-anilino-1-imidazolin-4-one (13a) with iodine (3.0 equiv.) in dimethoxyethane (DME) at room temperature gave the 5-exo cyclization product, 2-iodomethyl-1-phenyl-2,3-dihydro-1H-imidazo[1,2-a]imidazol-5(6)-one (16a), in 47% yield. Utilizing potassium carbonate (K2CO3) as a scavenger of hydrogen iodide afforded an improvement of its yield up to 75%. The structure of 16a was established on the basis of its spectroscopic data in comparison with those of the related compounds previously reported.1,5

Similar reaction of 3-allyl-2-anilino-5-methyl- (14a) and 3-allyl-5-methyl-2-(tosylamino)-1-imidazolin-4-ones (14b) with iodine also gave 5-exo cyclization products 17a,b in good yields. Imidazoimidazoles 17a,b were obtained as mixtures of two diastereomers, respectively. The stereoselectivity of the cyclization was not as high as expected. Product 17a was not so stable and the treatment of 17a with DBU (2.0 equiv.) in refluxing toluene gave 6-methyl-2-methylene-1-phenyl-2,3-dihydro-1H-imidazo[1,2-a]imidazo-5(6H)-one (18) in 86% yield. Similar results were obtained in the reaction of 3-allyl-2-anilino-5-phenyl-1-imidazolin-4-ones (15a) with iodine; imidazoimidazole 19a was formed as a 1:2 mixture of two diastereomers.The reaction of 2-tosylamino substrate 15b with iodine gave a mixture of unidentified products together with 4-(hydroxymethyl)-1-(phenyloxalyl)-3-tosylimidazolidin-2-one (20) (Scheme 2). These results suggest that the iodocyclization of 5-(unsubstituted)- and 5-(monosubstituted) substrates 13-15 proceeds similarly to that of 5,5-dimethyl substrates and that some of the cyclization products are not so stable under the reaction conditions and/or purification procedures.

Scope and limitations of the iodocyclization of alk-2-enyl-5,5-dimethyl-2-(substituted amino)-1-imidazolin-4-ones

Next we focused on the scope of the iodocyclization of 1-imidazolin-4-ones; 3-(but-3-enyl)-1-imidazolin-4-ones 22a-c were also prepared by the reaction of ethyl 2-methyl-2-(N'-substituted carbodiimido)propionate1 with (but-3-enyl)amine (21). A similar iodocyclization of 22 gave 6-exo cyclization products, imidazo[1,2-a]pyrimidines 23, in good yields and in the reaction of 1-imidazolin-4-ones 22a and 22c, utilizing K2CO3 as a scavenger of hydrogen iodide afforded better yields (Scheme 3). The structures of imidazopyrimidines 23 were also confirmed by the conversion to the 7-exo methylene compounds 24 by the elimination of hydrogen iodide (Scheme 3). The regiochemistry of the iodocyclization was also consistent with the fr(N) obtained from the PM36 method in the MOPAC program;7 the values of fr(N) in the 6-exo cyclization were larger than those in the 7-endo cyclization in the corresponding iodonium ions 25 and 26 (Fig. 1).

The scope of the cyclization was further examined using the 2-tosylamino substrates, which are expected to be less reactive under the iodocyclization conditions. The iodocyclization of 3-(cyclohex-2-enyl)-5,5-dimethyl-2-tosylamino-1-imidazolin-4-one (27) gave 5-exo cyclization product 28 and 6-endo one 29 in 21 and 77% yields, respectively.

The structure of major product 29 was confirmed by X-ray crystallographic study and that of minor 28 was assigned using its spectroscopic data. These suggested that the formation of the iodonium ion 30 and its opening by the intramolecular tosylamino nitrogen proceeded in a highly stereoselective manner.

The similar reaction of 3-(3-methylbut-2-enyl) substrate 31 with iodine gave the unreacted 31 in recovery of 78%. The PM3 molecular orbital calculations of the iodonium ion 32 suggested the predominant formation of 6-endo cyclization product, although the energy difference between the frontier orbitals (dE= 6.475 eV) of the iodonium ion 32 was somewhat larger than those of 3-allyl substrate (dE= 5.720 eV)2 and 3-(but-3-enyl) substrate 26 (dE= 5.620 eV). The similar reaction of 31 in the presence of water gave iodohydrin 33 in 78% yield and the regiochemistry of the addition of hypoiodide was consistent with the PM3 calculation results. The treatment of 33 with DBU gave epoxide 34 in 75% yield. These results suggest that iodonium ion 32 is expected to form and that the successive nucleophilic attack of the amino nitrogen on the ion 32 is probably blocked because of serious steric interaction between both reaction sites.8


  1. Watanabe, M.; Okada, H.; Teshima, T.; Noguchi, M.; Kakehi, A. Tetrahedron 1996, 52, 2827.

    Noguchi, M.; Okada, H.; Watanabe, M.; Okuda, K.; Nakamura, O. Tetrahedron 1996, 52, 6581.

  2. Kosasayama, A.; Konno, T.; Higashi, K.; Ishikawa, F. Chem. Pharm. Bull. 1979, 27, 841. Also see references cited therein.
  3. For recent reviews on the synthetic utilities of carbodiimides: Molina, P.; Vilaplana, M. J. Synthesis 1994, 1197; Eguchi, S.; Matsushita, Y.; Yamashita, K. Org. Prep. Proced. Int. 1992, 24, 209; Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353.
  4. For recent reviews on the iodocyclizations: Boivin, T. L. B. Tetrahedron 1987, 43, 3309; Cardillo, G.; Orena, M. Tetrahedron. 1990, 46, 3321.
  5. Stewart, J. J. J. Comput. Chem. 1989, 10, 209.
  6. "MOPAC program version 6, QCPE No. 455," 1990, Department of Chemistry, Indiana University, Bloomington, IN 47405.
  7. The reversibility of the three-membered halonium ion formation (containing iodonium ion) has been detailed. As recent papers: Reitz, A. B.; Nortey, S. O.; Maryanoff, B. E.; Liotta, D.; Momahan, R. III. J. Org. Chem. 1987, 52, 4191; Labell, M.; Guindon, Y. J. Am. Chem. Soc. 1989, 111, 2204; Brown, R. S.; Slebocka-Tilk, H.; Bennet, A. J.; Bellucci, G.; Bianchini, R.; Ambrosetti, R. J. Am. Chem. Soc. 1990, 112, 6310; Brown, R. S.; Nagorski, R. W.; Bennet, A. J.; McClung, R. E. D.; Aarts, G. H. M.; Klobukowski, M.; McDonald, R.; Santarsiero, B. D. J. Am. Chem. Soc. 1994, 116, 2448. Also see the references cited therein.