Novel Syntheses of Variably Substituted Pyrrolo[2,3-d]thiazoles

Abstract

Pyrrolo[2,3-d]thiazoles are conveniently derived from the corresponding o-aminoalkynylthiazoles via microwave assisted 5-endo-dig cyclization. Methylene-bridged substituents in the 6-position are directly obtained from 5-exo-Heck cyclization based on the same iodoaminothiazole precursor. Further structural variety is accessible via Suzuki reaction of 2-chloroaminothiazoles prior to cyclization or post-cyclization modifications.

Key words

thiazoles - pyrroles - heterocycles - microwave irradiation

References

• 1 For a review of pyrrolo[2,1-b]thiazoles, see: Tverdokhlebov AV. Heterocycles  2007,  71:  761 
• 2 Nakamura T, Hioki T, Ohzeki K, and Hanaki N. inventors; US Patent Appl. US  20020058216.  ; Chem. Abstr. 2002, 136, 393179
• 3 Dekhtyar ML. Dyes Pigm.  2007,  74:  744 
• For examples of 2-acylpyrrole derivatives including pyrrolo[2,3-d]thiazoles, see:
• 4a Heffernan MLR, Dorsey JM, Fang QK, Foglesong RJ, Hopkins SC, Jones ML, Jones SW, Ogbu CO, Perales JB, Soukri M, Spear KL, and Varney MA. inventors; PCT Int. Appl. US  20080058395.  ; Chem. Abstr. 2008, 148, 278900
• 4b Barker AJ, Kettle JG, and Faull AW. inventors; PCT Int. Appl. WO  199940914. See also: ; Chem. Abstr. 1999, 131, 170342
• For the original synthesis of pyrrolo[3,2-d]thiazoles, see:
• 5a Shafiee A. Mazloumi A. Cohen VI. J. Heterocycl. Chem.  1979,  16:  1563 
• 5b Athmani S. Farhat MF. Iddon B. J. Chem. Soc., Perkin Trans. 1  1992,  973 
• 5c Sparey T. Abeywickrema P. Almond S. Brandon N. Byrne N. Campbell A. Hutson PH. Jacobson M. Jones B. Munshi S. Pascarella D. Pike A. Prasad GS. Sachs N. Sakatis M. Sardana V. Venkatramane S. Young MB. Bioorg. Med. Chem. Lett.  2008,  18:  3386 
• 6a Grehn L. Chem. Scr.  1978,  13:  78 
• 6b Rao KE. Padmanabhan S. Lown JW. Actual. Chim. Ther.  1993,  20:  159 
• 7 Koolman H. Heinrich T. Böttcher H. Rautenberg W. Reggelin M. Bioorg. Med. Chem. Lett.  2009,  19:  1879 
• For examples of indole syntheses, see:
• 8a Mackmann RL. Katz BA. Breitenbucher JG. Hui HC. Verner E. Luong C. Liu L. Sprengeler A. J. Med. Chem.  2001,  44:  3856 
• 8b Palimkar SS. Kumar PH. Lahoti RJ. Srinivasan KV. Tetrahedron  2006,  62:  5109 
• 8c Saejueng P. Bates CG. Venkataraman D. Synthesis  2005,  1706 
• 8d Lu BZ. Zhao W. Wei H.-X. Dufour M. Farina V. Senanayake CH. Org. Lett.  2006,  8:  3271 
• 8e Gomtsyan A. Didomenico S. Lee C.-H. Stewart AO. Bhagwat SS. Kowaluk EA. Jarvis MF. Bioorg. Med. Chem. Lett.  2004,  14:  4165 
• 8f For an explicit example of a Boc-protected iodoaniline being cyclized to the corresponding indole after Sonogashira coupling employing TBAF as base in a one-pot procedure, see: Suzuki N. Yasaki S. Yasuhara A. Sakamoto T. Chem. Pharm. Bull.  2003,  51:  1170 
• 8g For a discussion of aminopalladation/reductive elimination reactions for the syntheses of indoles, see: Arcadi A. Cacchi S. Marinelli F. Tetrahedron Lett.  1992,  33:  3915 
• 8h See also: Tyrell E. Whiteman L. Williams N. Synthesis  2009,  829 
• 9 Al-Shaar AHM. Gilmour DW. Lythgoe DJ. McClenaghan I. Ramsden CA. J. Chem. Soc., Perkin Trans. 1  1992,  2779 
• 10 The yields of 4- and 5-aminothiazoles are low and rapid decomposition to a black solid is particularly mentioned for the 4-aminothiazole, see: Diener H. Zollinger H. Can. J. Chem.  1986,  64:  1102 
• 11 Yang Y. Hörnfeldt A.-B. Gronowitz S. Chem. Scr.  1988,  28:  275 
• The syntheses of azaindoles via DBN-mediated cyclization of Boc-protected o-aminoalkynylpyridines are reported in:
• 13a Choi-Sledeski Y.-M. Kearney R. Poli G. Pauls H. Gardner C. Gong Y. Becker M. Davis R. Spada A. Liang G. Chu V. Brown K. Collussi D. Leadley R. Rebello S. Moxey P. Morgan S. Bentley R. Kasiewski C. Maignan S. Guilloteau J.-P. Mikol V. J. Med. Chem.  2003,  46:  681 
• 13b Harcken C. Ward Y. Thomson D. Riether D. Synlett  2005,  3121 
• 14 Sanz R. Guilarte V. Castraviejo MP. Synlett  2009,  3006 
• 15 Knochel and co-workers mention the importance of NMP as solvent in combination with t-BuOK to induce cyclization to the pyrrole moiety: Rodriguez AL. Koradin C. Dohle W. Knochel P. Angew. Chem. Int. Ed.  2000,  39:  2488 ; Angew. Chem. 2000, 112, 2607
• 17 Murphy BP, Glenn RW, Lim MI, Gardlik JM, Jones SD, Laidig WD, and Shaffer JD. inventors; PCT Int. Appl. WO  2005077324. Pyrrolo[3,2-d]thiazole as a keratin dyeing compound is claimed, but its synthesis is not explicitly stated, see: ; Chem. Abstr. 2005, 143, 234964
• 19 The formation of a black slurry residue is observed, probably due to polymerization.
• 23 Wensbo D. Gronowitz S. Tetrahedron  1995,  51:  10323 

12

The 2,5-diiodothiazole as a side-product in the synthesis of thiazole 2a could only be observed in traces via mass spectrometry. When scaling this reaction up to a 35 mmol, CH₂Cl₂ as solvent and a reaction time of 18 h at r.t. were used to achieve comparable yields.

16

See supporting information for a detailed reaction parameter diagram.

18

The low yield can be attributed to decomposition processes due to the considerably intense and long-lasting irradiation of the reaction mixture.

20

Several conditions were tested for the Boc cleavage of 6a: TFA in CH₂Cl₂, ethanolic HCl in CH₂Cl₂ and heating with SiO₂, with the latter being the superior method. In all cases partial decompostion occurred and oxidation of the alkyne appeared as the major side reaction.

21

All tried standard halogenation conditions for thiazoles affected the alkyne, or led to decomposition: iodination with NIS in CH₂Cl₂, DME, or MeCN with or without addition of K₂CO₃ at ambient or elevated temperatures. Best yields were obtained with N-chlorosuccinimide as electrophile compared to CCl₄ and quenching the reaction mixture with n-BuOH compared to H₂O, respectively.

22

Attempted Suzuki-couplings after cyclization to the unprotected pyrrolothiazoles only led to traces of product after prolonged reaction times, probably due to the influence of the free pyrrole NH group.

24

Products resulting from 6-endo-cyclization could not be detected in any case.