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. 2018 Oct 5;20(19):6144-6147.
doi: 10.1021/acs.orglett.8b02615. Epub 2018 Sep 17.

Chiral Aniline Synthesis via Stereospecific C(sp3)-C(sp2) Coupling of Boronic Esters with Aryl Hydrazines

Venkataraman Ganesh  1 , Adam Noble  1 , Varinder K Aggarwal  1
Affiliations

Chiral Aniline Synthesis via Stereospecific C(sp3)-C(sp2) Coupling of Boronic Esters with Aryl Hydrazines

Venkataraman Ganesh et al. Org Lett. .

Abstract

An enantiospecific coupling between alkylboronic esters and lithiated aryl hydrazines is described. The reaction proceeds under transition-metal-free conditions and is promoted by acylation of a hydrazinyl arylboronate complex, which triggers a N-N bond cleavage with concomitant 1,2-metalate rearrangement. Judicious choice of the acylating agent enabled the synthesis of ortho- and para-substituted anilines with essentially complete enantiospecificity from a wide range of boronic ester substrates.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Chiral aniline drugs.
Figure 2
Figure 2
Electrophile-induced coupling reactions of arylboronate complexes.
Scheme 1
Scheme 1. Synthesis of Permethylated Bromophenyl Hydrazines
Scheme 2
Scheme 2. Scope of para-Bromoaryl Hydrazines
Reactions carried out with 4 (1.1 equiv), n-BuLi (1.1 equiv), 5 (0.18 mmol, 1.0 equiv), and TFAA (2.1 equiv). Yields are of isolated products after purification by flash column chromatography. Number in parentheses is the isolated yield on a 1.2 mmol scale.
Scheme 3
Scheme 3. Scope of ortho-Bromoaryl Hydrazines
Reactions carried out with 8 (1.1 equiv), n-BuLi (1.1 equiv), 5 (0.18 mmol, 1.0 equiv), and Me2Troc–Cl (2.1 equiv). Yields are of isolated products after purification by flash column chromatography. Reaction carried out using the corresponding aryl iodide.
Scheme 4
Scheme 4. Boronic Ester Scope
Prepared from para-bromophenyl hydrazine 4a and TFAA (see Scheme 2 for conditions). See Supporting Information for details. Prepared from ortho-bromophenyl hydrazine 8a and Me2Troc-Cl (see Scheme 3 for conditions). TFA = trifluoroacetyl. DMT = 2,2,2-trichloro-1,1-dimethylethoxycarbonyl.
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