A cascade reaction sequence en route to 7-substituted 2-aminopyrrolo[1,2-a]pyrimidine-4,6-diones and the corresponding acrylic acid derivatives

Tetrahedron Letters

Volumn 48, Issue 41, 2007, Pages 7395-7398

  Gao, Ju ^a   Henry, Rodger F ^a   Pagano, Thomas G ^a   Duerst, Richard W ^a   Souers, Andrew J ^a  

^a ABBOTT LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6 AMINO 2 METHYLPYRIMIDIN 4(3H) ONE; ACRYLIC ACID DERIVATIVE; KETONE DERIVATIVE; OXYGEN; PYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ALKYLATION; ARTICLE; HYDROLYSIS; OXIDATION; POLYMERIZATION; REACTOR CASCADE; SYNTHESIS;

EID: 34548482932     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2007.08.003     Document Type: Article

References (11)

1. Ellingboe J., Alessi T., Millen J., Sredy J., King A., Prusiewicz C., Guzzo F., VanEngen D., and Bagli J. J. Med. Chem. 33 (1990) 2892-2899
2. The structurally similar 2-(dimethylamino)-7,8-diphenylpyrrolo[1,2-a]pyrimidine-4,6-dione was accessed in an alternative manner. See the following:. Banfield J.E., Fallon D., and Gatehouse B.M. Aust. J. Chem. 40 (1987) 1003-1009
3. The use of sodium hydride in DMF afforded a 2:1 mixture of 3 and 4. No products were observed when THF was used. See Ref. 1.
4. ROESY analysis demonstrated an NOE between the protons at C8 on the heterocycle and the ortho position on the phenyl ring for both structures 5 and 6. While definitive proof of structure 5 cannot be obtained via NMR, this analysis disproves the possibility of 5 being an alkene isomer of 6. Please see Supplementary data for details.
5. int = 0.1062); Data were processed using Saint + (BrukerAXS). The structure was solved by direct methods and expanded using Fourier techniques. Refinement was performed using SHELXTL. Crystallographic data for the structure have been deposited in the Cambridge Crystallographic Data Centre (deposition no. CCDC657980). Copies of these data can be obtained, free of charge on application to the CCDC via the Internet at www.ccdc.com.ac.uk/conts/retrieving.html.
6. Baraldi P.G., Preti D., Tabrizi M.A., Fruttarolo F., Romagnoli R., Zaid N.A., Moorman A.R., Merighi S., Stefania V., Katia B., and Borea P.A. J. Med. Chem. 14 (2005) 4607-4701
7. Elimination is possible at the 6 or 8 position within the five membered ring.
8. For a base-mediated oxidation using molecular oxygen see the following:. Tao Z.-F., Sowin T.J., and Lin N.-H. Tetrahedron Lett. 46 (2005) 7615-7618
9. All THF utilized in the reactions contained 250 ppm BHT. Since the formation of 5 in either THF or DMF involves an oxidative pathway, we do not suspect that the presence of BHT plays any role in the divergent pathways depicted in Scheme 5. However, further studies are required.
10. This transformation was also attempted in other solvents such as ethanol and acetonitrile; however, none of these provided the same results. This is primarily due to the limited solubility of the starting material 1 in these solvents.
11. With the exception of Entry 4, Table 2.