Stabilizing N-tosyl-2-lithioindoles with bis(N,N′-dimethylaminoethyl) ether-a non-cryogenic procedure for lithiation of N-tosylindoles and subsequent addition to ketones

Tetrahedron Letters

Volumn 50, Issue 40, 2009, Pages 5667-5669

  Wu, Jiang Ping ^a   Sanyal, Sanjit ^a   Lu, Zhi Hui ^a   Senanayake, Chris H ^a  

^a BOEHRINGER INGELHEIM PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BIS(N,N' DIMETHYLAMINOETHYL) ETHER; ETHER DERIVATIVE; INDOLE DERIVATIVE; N TOSYL 2 LITHIOINDOLE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; LITHIATION; MOLECULAR STABILITY; REACTION ANALYSIS; SYNTHESIS; TEMPERATURE DEPENDENCE;

EID: 68749093986     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2009.07.120     Document Type: Article

References (21)

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13. (a) The 'in situ trapping' approach described in Reference 2 cannot be applied to our situation due to the reactivity of ketones toward LDA. (b) The procedure described in reference 3 was investigated using 2-butanone as the electrophile. No desired addition product was observed, likely due to ketone enolization under the reaction conditions.
14. In the absence of bis(N,N′-dimethylaminoethyl) ether, the HPLC trace of the reaction mixtures at -25 °C showed several pronounced peaks not fully identified. LC-MS analysis suggested that some peaks correspond to structures I and II. These side products were mostly suppressed by the addition of bis(N,N'-dimethylaminoethyl) ether.{A figure is presented}
15. The 'stabilizing' effects of TMEDA toward organolithium species are well documented, though the mechanism of these effects has been the topics of much discussion, see:. Shapiro R.H. Org. React. 23 (1976) 405
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19. (a) All reactions were run under nitrogen atmosphere in oven-dried flasks. (b) The examples in Tables 1 and 2 were run on scales of 2 g to 10 g. (c) Solvents used were commercial anhydrous solvents. (d) Bis(N,N′-dimethylaminoethyl) ether was purchased from Aldrich and dried over 4 Å molecular sieves to KF <300 ppm. Other reagents were used as purchased.
20. N-Boc indoles are not suitable substrates. When N-Boc 5-bromoindole was treated with LDA at -25 °C followed by addition of 2-butanone, multiple peaks were observed on HPLC, with <5A% of the desired addition product.{A figure is presented}
21. (a) The temperatures cited are internal temperatures unless otherwise stated. (b) All HPLC purities are area percentage measured at 254 nM.