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Synlett 2008(19): 2961-2964  
DOI: 10.1055/s-0028-1083626
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

N-Heterocyclic Carbenes of Indazole as Reagents: Indazol-3-ylidene-Mediated Syntheses of Amidines from Thiolactams of Pyrrolobenzodiazepines

Anika Lindner, Andreas Schmidt*
Institute of Organic Chemistry, Clausthal University of Technology, Leibnizstr. 6, 38678 Clausthal-Zellerfeld, Germany
Fax: +49(5323)723861; e-Mail: schmidt@ioc.tu-clausthal.de;
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Publication History

Received 5 August 2008
Publication Date:
12 November 2008 (online)

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Abstract

On decarboxylation, 1,2-dimethylindazolium-3-carboxylate forms in situ the N-heterocyclic carbene 1,2-dimethylindazol-3-ylidene, which proved to be a suitable reagent for amidinations of the monothiolactam of benzo[e]pyrrolo[1,2-a][1,4]diazepine. A comparison of this metal-free approach to amidines to HgCl2- and Bi(NO3)3-mediated reactions is presented.

Key Words

thiolactam - bismuth(III) nitrate - mercury(II) chloride - mesomeric betaine - decarboxylation

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General Procedure for the Synthesis of ( S )-11-(Butyl-amino)-2,3-dihydro-1 H -benzo[ e ]pyrrolo[1,2- a ][1,4]-diazepin-5-(11a H )-one (5a)
Method A
Thiolactam (4, 0.232 g, 1 mmol) was suspended in n-BuNH2 (4 mL) and heated to 60 ˚C. At this temperature HgCl2 (0.272 g, 1 mmol) was added, and the mixture was heated over a period of 1 h at reflux temperature. After cooling, the reaction mixture was filtered through a plug of Celite and washed with CHCl3. The filtrate was washed with aq Na2S2O3 and dried over Na2SO4. The solvent and excess amine were distilled off in vacuo. The residue was then chromatographed (SiO2, PE-EtOAc, 1:5).
Method B
Bi(NO3)3 (0.395 g, 1 mmol) was used.
Method C
Compound 1 (0.190 g, 1 mmol) was used and heated as described. Then, the reaction mixture was concentrated in vacuo and chromatographed. The amidine was obtained as a faintly yellow oil, respectively; [α]D 518 (c 1, CDCl3). ¹H NMR (200 MHz, CDCl3): δ = 0.96 (t, J = 7.17 Hz, 3 H,
16-H), 1.31-1.49 (m, 2 H, 15-H), 1.54-1.69 (m, 2 H, 14-H), 2.00-2.14 (m, 3 H, 1-H, 2-H), 2.18-2.30 (m, 1 H, 1-H), 3.34-3.48 (m, 2 H, 13-H), 3.51-3.64 (m, 1 H, 3-H), 3.82-3.94 (m, 1 H, 3-H), 4.02 (t, J = 4.93 Hz, 1 H, 11a-H), 4.76 (br s, 1 H, NH), 7.02-7.14 (m, 2 H, 7-H, 9-H), 7.35-7.44 (m, 1 H, 8-H), 7.93 (dd, J = 7.9, 1.4 Hz, 1 H, 6-H). ¹³C NMR (50 MHz, CDCl3): δ = 13.9 (C-16), 20.3 (C-15), 23.8 (C-2), 26.7 (C-1), 31.1 (C-14), 41.2 (C-13), 46.3 (C-3), 54.3 (C-11a), 122.1, 126.4, 126.8, 129.9, 131.5, 147.4, (6C, Carom.), 156.1 (C-11), 166.7 (C=O). IR (KBr) = 3345, 3057, 2956, 2871, 1607, 1536, 1456, 1412, 1337, 1236, 1202, 1148, 1034, 835, 762 cm-¹. MS (EI): m/z (%) = 271 (80) [M+], 242 (20), 229 (20), 215 (10), 199 (15), 187 (25), 173 (30), 160 (70), 146 (30), 119 (25), 90 (30), 70 (100). Anal. Calcd for C16H21N3O: C, 70.82; H, 7.80; N, 15.49. Found: C,70.58; H, 7.41; N, 14.91.

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Compound 5g exists as mixture of tautomers A and B in DMSO-d 6; a single-crystal X-ray structure analysis was performed of tautomer B.³7