1-(Methyldithiocarbonyl)imidazole as Thiocarbonyl Transfer Reagent: A Facile One-Pot Three-Component Synthesis of 3,5- and 1,3,5-Substituted-2-Thiohydantoins

G. S. M. Sundaram; C. Venkatesh; H. Ila; H. Junjappa

doi:10.1055/s-2007-967987

Subscribe to RSS

Please copy the URL and add it into your RSS Feed Reader.

https://www.thieme-connect.de/rss/thieme/en/10.1055-s-00000083.xml

Share / Bookmark

Facebook X Linkedin Weibo

Download PDF

Synlett 2007(2): 0251-0254
DOI: 10.1055/s-2007-967987

LETTER

1-(Methyldithiocarbonyl)imidazole as Thiocarbonyl Transfer Reagent: A Facile One-Pot Three-Component Synthesis of 3,5- and 1,3,5-Substituted-2-Thiohydantoins

G. S. M. Sundaram, C. Venkatesh, H. Ila*, H. Junjappa
Department of Chemistry, Indian Institute of Technology, Kanpur-208016, India
Fax: +91(512)2597436; Fax: +91(512)2590260; e-Mail: hila@iitk.ac.in;

Further Information

Publication History

Received 7 September 2006
Publication Date:
24 January 2007 (online)

Abstract
Full Text
References

Permissions and Reprints All articles of this category

Abstract

An efficient three-component one-pot synthesis of 3,5- and 1,3,5-substituted 2-thiohydantoins employing easily accessible amino acid esters, primary amines and 1-(methyldithiocarbonyl)imidazole as thiocarbonyl transfer reagent has been reported.

Key words

thiohydantoins - multicomponent reactions - fused thiohydantoins - imidazole dithioate - amino acids

References and Notes

Selected references:
1a Brouillete WJ. Jestkov VP. Brown ML. Akhtar MS. DeLorey TM. Brown GB. J. Med. Chem. 1994, 37: 3289

Crossref Search in Google Scholar
1b Nefzi A. Giulianotti M. Truong L. Rattan S. Ostresh JM. Houghten RA. J. Comput. Chem. 2002, 4: 175 ; and references therein

Crossref Search in Google Scholar
1c Chazeau V. Cussac M. Boucherle A. Eur. J. Med. Chem. 1992, 27: 839

Crossref Search in Google Scholar
1d Scicinski JJ. Barker MD. Murray PJ. Jarvie EM. Bioorg. Med. Chem. Lett. 1998, 8: 3609

Crossref Search in Google Scholar
1e He S. Kuang R. Venkatraman R. Tu J. Truong TM. Chan HT. Groutas WC. Bioorg. Med. Chem. 2000, 8: 1713

Crossref Search in Google Scholar
1f Zhang D. Xing X. Cuny GD. J. Org. Chem. 2006, 71: 1750

Crossref Search in Google Scholar
1g Reyes S. Burgess K. J. Org. Chem. 2006, 71: 2507

Crossref Search in Google Scholar
2 Cherouvrier J.-P. Carreaux F. Bazureau JP. Tetrahedron Lett. 2002, 8745 ; and references therein

Crossref
3a Cremlyn RJ, Elias RS, Geoghagan MJA, and Braunholtz JL. inventors; Br. Patent 967166. ; Chem. Abstr. 1965, 62, 7768g

Crossref
3b Mizuno T. Kino T. Ito T. Miyata T. Synth. Commun. 2000, 30: 1675

Crossref Search in Google Scholar
3c Mappes CJ, Pommer E.-H, Rentzea C, and Zeeh B. inventors; US 4 198 423. ; Chem. Abstr. 1980, 93, 71784

Crossref
4a Edman P. Acta Chem. Scand. 1950, 4: 283

Crossref Search in Google Scholar
4b Edman P. Begg G. Eur. J. Biochem. 1967, 1: 80

Crossref Search in Google Scholar
4c Evindar G. Batey RA. Org. Lett. 2003, 5: 1201

Crossref Search in Google Scholar
5a Lin M.-J. Sun C.-M. Tetrahedron Lett. 2003, 44: 8739

Search in Google Scholar
5b Mui M. Ganesan A. J. Org. Chem. 1997, 62: 3230

Search in Google Scholar
5c Zhang W. Lu Y. Org. Lett. 2003, 5: 2555 ; and references therein

Search in Google Scholar
5d Matthews J. Rivero RA. J. Org. Chem. 1997, 62: 6090

Search in Google Scholar
5e Wu S. Janusz JM. Tetrahedron Lett. 2000, 41: 1165

Search in Google Scholar
5f Lopez A. Trigo GG. Adv. Heterocycl. Chem. 1985, 38: 177

Search in Google Scholar
6 Blotny G. Synthesis 1983, 391

Thieme Connect
7 Mohanta PK. Dhar S. Samal SK. Ila H. Junjappa H. Tetrahedron 2000, 56: 629

Crossref Search in Google Scholar
For other thiocarbonyl transfer reagents, see:
8a Katritzky AR. Ledoux S. Witek RM. Nair SK. J. Org. Chem. 2004, 69: 2976 ; and references therein

Search in Google Scholar
8b Katritzky AR. Witek RM. Rodriguez-Garcia V. Mohapatra PP. Rogers JW. Cusido J. Abdel-Fattah AAA. Steel PJ. J. Org. Chem. 2005, 70: 7866

Search in Google Scholar
11 Optical rotation of 4o [α]_D ²⁵ -46.7 (c 0.225, MeOH) was compared with the reported value [α]_D ²⁵ -40.5 (c 0.225, MeOH). See: Poupaert JH. Cavalier R. Claesen MH. Dumont PA. J. Med. Chem. 1975, 18: 1268

Crossref Search in Google Scholar

9

General Procedure for the Preparation of 3,5-Substituted 2-Thiohydantoins 4.
A solution of l-amino acid ethyl ester hydrochloride salt 1 (2.0 mmol), amine 2 (2.0 mmol), 1-(methyldithio-carbonyl)imidazole 3 (0.32 g, 2.0 mmol) and Et₃N (0.58 mL, 4.2 mmol) in 15.0 mL of absolute EtOH was refluxed for 7-8 h (monitored by TLC). The reaction mixture was cooled to r.t. and concentrated under vacuo. The residue was dissolved in CHCl₃ (25 mL) and washed with H₂O (2 × 20 mL), brine (20 mL), dried (Na₂SO₄) and concentrated under reduced pressure to afford the crude 4a-t, which were purified by column chromatography over silica gel using hexane-EtOAc as eluent. All the newly synthesized thiohydantoins 4a,b,e,f,h-t, 7a-i and 10a-c were characterized with the help of spectral and analytical data.
( S )-3-Furan-2-ylmethyl-5-isobutyl-2-thioxo-imidazolidin-4-one (4f).
Yield 92% (0.46 g); white solid; mp 132-133 °C; R _f = 0.73 (5:1 hexane-EtOAc). IR (KBr): 3185, 3004, 2958, 1754, 1527, 1430, 1342, 1169, 738 cm^-1. [a]_D ²⁵ -2.6 (c 0.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 0.92 (d, J = 2.44 Hz, 3 H), 0.93 (d, J = 2.44 Hz, 3 H), 1.52-1.59 (m, 1 H), 1.71-1.83 (m, 2 H), 4.12 (dd, J = 9.34, 2.72 Hz, 1 H), 4.93 (d, J = 15.12 Hz, 1 H), 4.98 (d, J = 15.12 Hz, 1 H, CH₂), 6.27 (dd, J = 3.16, 1.96 Hz, 1 H), 6.35 (dd, J = 3.40 Hz, 1 H), 7.30 (d, J = 0.72 Hz, 1 H), 8.20 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 21.3, 22.9, 25.0, 37.4, 40.1, 57.9, 109.4, 110.3, 142.3, 148.5, 174.0, 182.9. MS-FAB: m/z (%) = 253 (100) [M + 1]. ESI-HRMS: m/z calcd for C₁₂H₁₆N₂O₂SNa: 275.0830 [M + Na]⁺; found: 275.0838.
( S )-3-[2-(3,4-Dimethoxyphenyl)ethyl]-5-isopropyl-2-thioxoimidazolidin-4-one (4i).
Yield 89% (0.57 g); colorless solid; mp 114-115 °C; R _f = 0.76 (5:1 hexane-EtOAc). IR (KBr): 3188, 2949, 1747, 1515, 1441, 1350, 1269, 1152, 1028 cm^-1. [α]_D ²⁵ -5.4 (c 0.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 0.82 (d, J = 6.84 Hz, 3 H), 1.01 (d, J = 7.08 Hz, 3 H), 2.13-2.24 (m, 1 H), 2.90 (t, J = 8.08 Hz, 2 H), 3.82 (s, 3 H), 3.86 (s, 3 H), 3.91 (dd, J = 4.04, 1.20 Hz, 1 H), 3.94-4.08 (m, 2 H), 6.76 (s, 1 H), 6.78 (dd, J = 4.40, 1.72 Hz, 2 H), 7.72 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 16.1, 18.6, 30.6, 33.0, 42.1, 55.8, 64.4, 111.1, 112.0, 120.9, 130.1, 147.7, 148.7, 173.3, 184.1. MS-FAB: m/z (%) = 323 (100) [M + 1]. ESI-HRMS: m/z calcd for C₁₆H₂₂N₂O₃SNa: 345.1249 [M + Na]⁺; found: 345.1215.

10

General Procedure for the Preparation of 1,3,5-Trisubstituted 2-Thiohydantoins 7 and N-Substituted Fused 3-Thiohydantoins 10.
A solution of appropriate amine 2 (2.0 mmol) and 1-(methyl-dithiocarbonyl)imidazole (3, 0.32 g, 2.0 mmol) in 10 mL of absolute EtOH (or MeOH) was refluxed for 30 min. After the complete consumption of 3 (as shown by TLC), a mixture of appropriate N-substituted amino ester 6 (2.0 mmol) or l-proline methyl ester hydrochloride 9 (0.33 g, 2.0 mmol) and Et₃N (0.58 mL, 4.2 mmol) in 5 mL absolute EtOH (or MeOH) was added and the reaction mixture was further refluxed for 6-7 h (monitored by TLC). It was then worked up and purified as described above to afford the products 7a-i or 10a-c.
( S )-5-Benzyl-3-[2-(1 H -indol-3-yl)ethyl]-1-(4-methoxybenzyl)-2-thioxoimidazolidin-4-one (7c).
Yield 91% (0.85 g); yellow solid; mp 170-171 °C; R _f = 0.56 (5:1 hexane-EtOAc). IR (KBr): 3404, 2927, 1750, 1473, 1350, 1263, 739 cm^-1. [α]_D ²⁵ -13.1 (c 0.1, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 2.69-2.83 (m, 2 H), 2.92 (dd, J = 14.52, 5.40 Hz, 1 H), 3.12 (dd, J = 14.54, 4.40 Hz, 1 H), 3.77 (s, 3 H), 3.92-3.98 (m, 2 H), 4.00 (t, J = 4.64 Hz, 1 H), 4.15 (d, J = 14.88 Hz, 1 H), 5.87 (d, J = 14.88 Hz, 1 H), 6.81 (d, J = 8.52 Hz, 2 H), 6.98 (d, J = 1.96 Hz, 1 H), 7.05 (d, J = 7.46 Hz, 2 H), 7.07 (dd, J = 5.60, 2.20 Hz, 2 H), 7.10 (t, J = 7.84 Hz, 1 H), 7.17 (t, J = 8.08 Hz, 1 H), 7.24 (t, J = 7.32 Hz, 3 H), 7.31 (d, J = 7.56 Hz, 1 H), 7.74 (d, J = 7.80 Hz, 1 H), 8.0 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 22.9, 35.1, 42.3, 47.7, 55.2, 61.1, 111.0, 112.2, 114.2, 119.0, 119.4, 121.9, 122.1, 126.8, 127.4, 127.5, 128.6, 129.3, 129.6, 133.9, 136.0, 159.4, 172.7, 182.6. MS-FAB: m/z (%) = 470 (50) [M + 1], 121 (65). ESI-HRMS: m/z calcd for C₂₈H₂₇N₃O₂SNa: 492.1722 [M + Na]⁺; found: 492.1762.
( S )-1-Furan-2-ylmethyl-3-[2-(1 H -indol-3-yl)ethyl]-5-isopropyl-2-thioxoimidazolidin-4-one (7f).
Yield 82% (0.62 g); white solid; mp 143-144 °C; R _f = 0.56 (5:1 hexane-EtOAc). IR (KBr): 3332, 1712, 1466, 1356, 1288, 1258, 1222, 1148, 1005, 747 cm^-1. [a]_D ²⁵ -17.2 (c 0.1, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 0.76 (d, J = 6.84 Hz, 3 H), 1.14 (d, J = 7.08 Hz, 3 H), 2.34-2.41 (m, 1 H), 3.05-3.17 (m, 2 H), 3.77 (d, J = 3.40 Hz, 1 H), 4.09 (t, J = 8.32 Hz, 2 H), 4.42 (d, J = 15.60 Hz, 1 H), 5.67 (d, J = 15.60 Hz, 1 H), 6.34 (dd, J = 3.12, 1.96 Hz, 1 H), 6.37 (d, J = 3.16 Hz, 1 H), 7.07 (s, 1 H), 7.12 (dd, J = 7.08, 1.00 Hz, 1 H), 7.17 (dt, J = 7.94, 1.24 Hz, 1 H), 7.32 (d, J = 7.58 Hz, 1 H), 7.37 (d, J = 1.34 Hz, 1 H), 7.80 (d, J = 7.84 Hz, 1 H), 7.98 (br s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 15.6, 17.3, 23.5, 28.8, 41.1, 42.4, 65.8, 109.8, 110.6, 111.0, 112.2, 119.1, 119.4, 122.0, 122.2, 127.5, 136.1, 142.8, 148.5, 172.3, 182.7. MS-FAB: m/z (%) = 382 (100) [M + 1]. ESI-HRMS: m/z calcd for C₂₁H₂₃N₃O₂SNa: 404.1409 [M + Na]⁺; found: 404.1436.
( S )-2-Benzyl-3-thioxohexahydropyrrolo[1,2- c ]imidazol-1-one (10a).
Yield 92% (0.45 g); white solid; mp 80-81 °C; R _f = 0.70 (5:1 hexane-EtOAc). IR (KBr): 3055, 2971, 2932, 1741, 1457, 1346, 1246, 1263, 1222, 1167, 962 cm^-1. [a]_D ²⁵ -16.6 (c 0.1, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 1.55-1.63 (m, 1 H), 2.03-2.09 (m, 1 H), 2.11-2.22 (m, 2 H), 3.47 (ddd, J = 11.78, 8.68, 3.16 Hz, 1 H), 3.83-3.90 (m, 1 H), 4.09 (dd, J = 10.28, 6.84 Hz, 1 H), 4.83 (d, J = 14.64 Hz, 1 H), 4.93 (d, J = 14.64 Hz, 1 H), 7.15-7.24 (m, 3 H), 7.34-7.36 (m, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 26.6, 44.9, 48.2, 64.9, 127.7, 128.3, 128.5, 135.7, 173.3, 186.6. MS-FAB: m/z (%) = 247 (100) [M + 1]. ESI-HRMS: m/z calcd for C₁₃H₁₄N₂OSNa: 269.0724 [M + Na]⁺; found: 269.0723.

12

The optical purity was determined by chiral HPLC [Chiralcel OD column, hexane-2-PrOH, 9:1]; ee (%): 4a, 64; 4f, 58; 4g, 95; 7c, 58; 7f, >99; 10a, >99.