Application of the thioimidate cyclopropane rearrangement to heterocyclic synthesis. Preparation of diaryl pyrrolines

Tetrahedron Letters

Volumn 46, Issue 49, 2005, Pages 8513-8516

  Chang, Ronald K ^a   Dipardo, Robert M ^a   Kuduk, Scott D ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Cross coupling; Cyclopropane rearrangement

Indexed keywords

CYCLOPROPANE DERIVATIVE; HETEROCYCLIC COMPOUND; IMIDE; PYRROLINE DERIVATIVE;

ARTICLE; CHEMICAL ANALYSIS; CHEMICAL STRUCTURE; GRIGNARD REACTION; REACTION ANALYSIS; STRUCTURE ANALYSIS;

EID: 27644470190     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2005.10.009     Document Type: Article

References (26)

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2. Thioamides were synthesized as in Ref. 1.
3. 3): 7.46-7.41 (m, 3H), 7.25 (m, 2H), 4.51 (t, J = 9.2 Hz, 1H), 4.44 (m, 1H), 4.27 (m, 1H), 3.06 (s, 3H), 2.90 (m, 1H), 2.47 (m, 1H).
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5. The disubstituted cyclopropyl thioamide 5m was prepared as in Ref. 1 and by use of a modification of the method described in Ref. 4.
6. Table 1, entry 12 details the rearrangement of optically pure (+)-trans-2-phenylcyclopropanecarbothioamide. The product was a mixture of 5-phenylpyrrolothiomethylimidate enantiomers. The scrambling of the benzylic center may arise because of the cationic nature of the ion pairs or double inversion via a second equivalent of iodide.
7. Nucleophilic addition of ammonia to the commercially available 3-oxabicyclo[3.1.0]hexane-2,4-dione gave the desired cis- aminocarbonylcyclopropane carboxylic acid 10. Benzylation and subsequent treatment with Lawesson's reagent provided the desired thioamide 11..
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20. We utilized 1,1-bis(diphenylphosphinoferrocene) palladium (II) dichloride as the favored catalyst over dichloro bis(triphenylphosphine) palladium (II). Although the latter gave slightly higher yields, triphenylphosphine oxide generated from the reaction may be difficult to separate from the desired product.
21. 9b,9c However, the reaction did not proceed in greater than 25% completion and the product was difficult to isolate.
22. 3): δ 7.73 (d, J = 7.1 Hz, 2H), 7.32-7.25 (m, 5H), 7.17 (t, J = 7.3 Hz, 1H), 7.12 (d, J = 7.3 Hz, 2H), 4.50 (d, J = 7.8 Hz, 1H), 4.13 (m, 2H), 2.58 (m, 1H), 1.99 (m, 1H).
23. Further investigations into the scope of the organomagnesium reagent with aliphatic and vinyl Grignard reagents failed to produce desired product. Yet, the use of an alternate aryl Grignard reagent such as 3-thienylmagnesium iodide provided the diaryl pyrroline 12 in 51% yield..
24. 13 The relative stereochemistry of 2,3-diphenyl pyrrolidine 13 was determined by NMR studies..
25. There are examples of uncatalyzed addition of Grignard reagents to thioethers in the literature, but the yields (26-32%) are generally low, see: W. Gessner, K. Takahashi, and A. Brossi Helv. Chim. Acta 70 1987 2003 2010
26. 1H NMR, which was not isolated.