A new synthesis of functionalized imidazol-2-ones

Article abstract of DOI:10.1016/S0040-4039(00)01070-4

The novel preparation of imidazol-2-ones in four steps from quinolines via an oxidative ring rearrangement is reported. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01070-4

Tetrahedron Letters 41 (2000) 6387±6391
A new synthesis of functionalized imidazol-2-ones
Sebastian Wendeborn,* Tammo Winkler and Ingrid Foisy
Novartis Crop Protection AG, CH-4002 Basel, Switzerland
Received 17 May 2000; accepted 23 June 2000
Abstract
The novel preparation of imidazol-2-ones in four steps from quinolines via an oxidative ring rearrangement
is reported. # 2000 Elsevier Science Ltd. All rights reserved.
The imidazol-2-one ring is a frequently occurring motive in many interesting, biologically
active, natural and non-natural molecules.1 5 In general, the starting point for the construction of
the imidazol-2-one skeleton is a coupling between an appropriately functionalized a-amino
carbonyl compound and isocyanate; the resulting intermediate is then cyclized to the corresponding
imidazol-2-one, preferentially employing acid catalysis.1,3,6 Alternatively, a-substituted carbonyl
derivatives with a leaving group may be reacted with substituted urea derivatives.5
Recently, we reported a convenient solid phase synthesis of substituted 2,3-dihydro-quinoline-
4-ones, which required the preparation of intermediates 1 bound to polystyrene (R1=O-linker-
polystyrene).7 In this paper, we report the synthesis of C(4) substituted derivatives of 1 in solution
and their conversion to substituted imidazol-2-ones by an elegant oxidative ring rearrangement
(Scheme 1).
Scheme 1.
* Corresponding author: Fax: +41 61 6975500; e-mail: sebastian.wendeborn@cp.novartis.com
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01070-4

6388
We envisioned that oxidative cleavage of the C(3) C(4) double bond of 1 would result in an
intermediate aldehyde 2, which would readily cyclize to form a substituted imidazol-2-one 3.
Herein, we demonstrate the generality of this transformation, which allows the convenient
synthesis of highly functionalized imidazol-2-ones. A number of representative quinolines 4±6
were readily prepared as shown in Scheme 2. The 4-ethoxyquinoline 4 was prepared via reaction
of 4-chloroquinoline with sodium ethoxide, while substituted quinolines 5 and 6 were easily
prepared through cuprate addition to 4-chloro-quinoline8 and a Suzuki coupling reaction of 4-
bromo-quinoline, respectively.9,10
Scheme 2. (a) Hal=Cl: 4 equiv. NaOEt, EtOH, dioxane, 80ꢀC, 24 h. (b) Hal=Cl: 4 equiv. CuBr, 8 equiv. MeMgCl,
THF, ^78ꢀC, 3 h then rt overnight. (c) Hal=Br: 3.4 equiv. K2CO3, 1.5 equiv. 4-methylbenzeneboronic acid, Pd(OAc)2
catalyst, dioxane/H2O (6:1), 100ꢀC, 2 h
Nucleophilic addition of a number of di€erent Grignard reagents to the CˆN double bond of
quinolines 4±6 in the presence of phenyl chloroformate provided functionalized dihydro
quinolines 7±11 (Scheme 3).7,11 Treatment of 7±11 with aliphatic or aromatic magnesium amides
(generated in situ by reacting the amine with 1 equiv. of ethylmagnesium bromide in THF at
room temperature) resulted in the clean exchange of the phenolate and formation of ureas 1.7
With compounds 1 in hand we were able to attempt their envisioned conversion to 3. Indeed,
Scheme 3. (a) 1.1 equiv. R2MgBr, 1.1 equiv. ClC(O)OPh, THF, ^78ꢀC, 0ꢀC, rt. (b) 3 equiv. R3NH2, 3 equiv. EtMgBr,
dioxane, 100ꢀC, 2 h. (c) O3, CH2Cl2, ^78ꢀC, then dimethyl sul®de, then 5% CF3COOH in CH2Cl2, 0.25 h

6389
when compounds 1a±m (see Table 1) were treated carefully with ozone at ^78ꢀC for 1±2 min,
followed by addition of excess dimethyl sul®de, concentration, and subsequent treatment with
CF3COOH (5% in CH2Cl2) cyclization ensued, and compounds 3a±m were obtained in moderate
to good yields (Table 1). For the success of this reaction it was crucial to avoid any excess of
ozone since it led to diminished yields of 3, presumably through overoxidation.12
Table 1
Yields of products 1a±m and 3a±m (Scheme 3). Yields refer to isolated compounds with satisfactory H NMR and
a
1
b
MS. Yields refer to transformation of 1!3
As can be seen in Scheme 3 and Table 1, the corresponding intermediates 7±11 and 1a±m were
obtained in good yields. In an attempt to improve the moderate yields of the oxidative ring
rearrangement (1!3), we also oxidized 1m via bishydroxylation with OsO4/NMO, followed by
treatment of the diol with NaIO4. However, 3m was obtained in comparable yield to the
ozonolysis protocol.
Interestingly, oxidation of enol ether 12 with 2 equiv. of mCPBA also resulted in formation of
imidazolone 3n, rather than the expected hydroxy ketone 13, a transformation that can be

6390
rationalized by the mechanism outlined in Scheme 4. Thus, ring opening of intermediate epoxide
14 with mCPBA, followed by oxidative fragmentation of the C(3) C(4) bond of 15 could lead to
the formation of aldehyde 16, which could cyclize under the acidic conditions of the reaction to
produce 3n. The use of 1 equiv. of mCPBA gave similar results, but in addition to 3n, unreacted
12 was recovered due to incomplete reaction.
Scheme 4.
In summary, we have found a new and elegant synthesis for substituted imidazol-2-ones.
Starting from quinolines, substituted 1,2-dihydro-quinolines were synthesized in three steps.
These intermediates are then converted to imidazol-2-ones by the key transformation, an oxidative
ring rearrangement.13
References
1. Parmee, E. R.; Naylor, E. M.; Perkins, L.; Colandrea, V. J.; Ok, H. O.; Candelore, M. R.; Cascieri, M. A.; Deng,
L.; Feeney, W. P.; Forrest, M. J.; Hom, G. J.; MacIntyre, D. E.; Miller, R. R.; Stearns, R. A.; Strader, C. D.;
Tota, L.; Wyvratt, M. J.; Fisher, M. H.; Weber, A. E. Bioorg. Med. Chem. Lett. 1999, 9, 749.
2. Naylor, E. M.; Parmee, E. R.; Colandrea, V. J.; Perkins, L.; Brockunier, L.; Candelore, M. R.; Cascieri, M. A.;
Colwell Jr., L. F.; Deng, L.; Feeney, W. P.; Forrest, M. J.; Hom, G. J.; MacIntyre, D. E.; Strader, C. D.; Tota, L.;
Wang, P.-R.; Wyvratt, M. J.; Fisher, M. H.; Weber, A. E. Bioorg. Med. Chem. Lett. 1999, 9, 755.
3. Reitz, D. B.; Garland, D. J.; Olins, G. M.; Markos, C. S.; Gresk, C. J.; Litschgi, J. W.; McKinnis, B. R. Bioorg.
Med. Chem. Lett. 1994, 4, 111.
4. Reitz, D. B.; Garland, D. J.; Norton, M. B.; Collins, J. T.; Reinhard, E. J.; Manning, R. E.; Olins, G. M.; Chen, S. T.;
Palomo, M. A.; McMahon, E. G.; Koehler, K. F. Bioorg. Med. Chem. Lett. 1993, 3, 1055.
5. Carling, R. W.; Moore, K. W.; Moyes, C. R.; Jones, E. A.; Boner, K.; Emms, F.; Marwood, R.; Patel, S.;
Fletcher, A. E.; Beer, M.; Sohal, B.; Pike, A.; Leeson, P. D. J. Med. Chem. 1999, 42, 2706.
6. Coskun, N. Tetrahedron 1999, 55, 475.

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7. Wendeborn, S. Synlett 2000, 45.
8. Bell, T. W.; Hu, L.-Y.; Patel, S. V. J. Org. Chem. 1987, 52, 3847.
9. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513.
10. Wallow, T. I.; Novak, B. M. J. Org. Chem. 1994, 59, 5034.
11. (a) Fraenkel, G.; Cooper, J. W.; Fink, C. M. Angew. Chem., Int. Ed. Engl. 1970, 9, 523. (b) Comins, D. L.;
LaMunyon, D. H. Tetrahedron Lett. 1989, 30, 5053. (c) Comins, D. L.; Myoung, Y. C. J. Org. Chem. 1990, 55,
292.
12. (a) The use of several ozone indicators12b did not allow us to stop the ozonolysis prior to overoxidation taking
place. The intermediate ozonide appears to be very prone to overoxidation. In practice, the ozonolysis was
stopped every 10 s, and a small sample was treated with dimethyl sul®de and analyzed by TLC. Upon clean
conversion of all starting material, normally after 1±2 min, the reaction was worked up. (b) Veysoglu, T.;
Mitscher, L. A.; Swayze, J. K. Synthesis 1980, 807.
13. Typical procedure: Compound 1a (322 mg, 1 mmol) was dissolved in CH2Cl2 (30 ml) and cooled to ^78ꢀC. Ozone
was bubbled through the reaction mixture until all starting material was consumed, normally after 1±2 min.12
Dimethyl sul®de (0.1 ml) was added and the reaction mixture was stirred for 0.2 h at 25ꢀC. Tri¯uoroacetic acid
(1.5 ml) was added and the reaction mixture was stirred for 0.25 h at 25ꢀC, diluted with benzene, concentrated and
puri®ed by chromatography (SiO2, EtOAc:hexane (3:7)) to give compound 3a (158 mg).