Preparation of bicyclic guanidines by the iodocyclization of
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
AbstractThe 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
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
(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
(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
(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
Scope and limitations of the iodocyclization of
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
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
- Watanabe, M.; Okada, H.; Teshima, T.; Noguchi, M.; Kakehi, A.
Tetrahedron 1996, 52, 2827.
Noguchi, M.; Okada, H.; Watanabe, M.; Okuda, K.; Nakamura, O.
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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,
For recent reviews on the iodocyclizations: Boivin, T. L. B.
Tetrahedron 1987, 43, 3309; Cardillo, G.; Orena, M.
Tetrahedron. 1990, 46, 3321.
Stewart, J. J. J. Comput. Chem. 1989, 10, 209.
"MOPAC program version 6, QCPE No. 455," 1990, Department of Chemistry,
Indiana University, Bloomington, IN 47405.
The reversibility of the three-membered halonium ion formation (containing
iodonium ion) has been detailed. As recent papers: Reitz, A. B.; Nortey, S.
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1987, 52, 4191; Labell, M.; Guindon, Y. J. Am. Chem. Soc.
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