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Synlett 2010(20): 3039-3044  
DOI: 10.1055/s-0030-1259058
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

N,N-Diisopropylformamidine (DIFA) Protection of Anilines in Metalation Reactions

Paul E. Zhichkin*, Sergiy G. Krasutsky, Ravi Krishnamoorthy
Medicinal Chemistry Department, AMRI, 26 Corporate Circle, P.O. Box 15098, Albany, NY 12212, USA
Fax: +1(518)5122079; e-Mail: paul.zhichkin@verizon.net;
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Publication History

Received 20 September 2010
Publication Date:
19 November 2010 (online)

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Abstract

A novel N,N-diisopropylformamidine (DIFA) protecting group for anilines was studied. Metalation is often metal-directed by this weakly coordinating and bulky group, making it complementary to ortho-metalation directed by tert-butylcarbamate and pivaloylamide groups and to regular electrophilic reactions of anilines. Importantly, DIFA is removed under nucleophilic conditions and is stable toward acids, thus being orthogonal to tert-butylcarbamate, N-tert-butylamide, and other acid-labile protecting groups.

Key words

protecting groups - regioselectivity - metalation - form­amidine

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10

An aliquot of the reaction mixture was quenched with 5% AcOH in H2O, and the HPLC areas of des-Br 2a or des-Br 2b were compared with those for decomposition products.

11

The anion of 2b obtained using n-BuLi had a half-life of only 1 h at -30 ˚C due to its reaction with 1-bromobutane, a side product of the metal-halogen exchange. After warming to r.t., N′-(4-butylphenyl)-N,N-diisopropylformamidine could be isolated in 90% yield (see Supporting Information for details).

13

See Supporting Information for detailed procedures.

15

No literature on DOM of derivatives of aminobenzoic acids could be found, and only two papers (see ref. 3) dealt with the lithiation of derivatives of aminoheteroarylcarboxylic acids.

17

Confirmed through NOE experiments with 9b and 9c (see Supporting Information).