Borylation Directed Borylation of Indoles Using Pyrazabole Electrophiles: A One-Pot Route to C7-Borylated-Indolines

Abstract

Pyrazabole (1) is a readily accessible diboron compound that can be transformed into ditopic electrophiles. In 1 (and derivatives), the B⋅⋅⋅B separation is ca. 3 Å, appropriate for one boron centre bonding to N and one to the C7 of indoles and indolines. This suitable B⋅⋅⋅B separation enables double E-H (E=N/C) functionalisation of indoles and indolines. Specifically, the activation of 1 with HNTf₂ generates an electrophile that transforms N-H indoles and indolines into N/C7-diborylated indolines, with N-H borylation directing subsequent C7-H borylation. Indole reduction to indoline occurs before C-H borylation and our studies indicate this proceeds via hydroboration-C3-protodeboronation to produce an intermediate that then undergoes C7 borylation. The borylated products can be converted in situ into C7-BPin-N-H-indolines. Overall, this represents a transient directed C-H borylation to form useful C7-BPin-indolines.

Keywords: Boranes; C−H Borylation; Electrophilic Substitution; Indoles; Transient Directing Group.

Figure 1

Top: Established routes to achieve C7 borylation using a pre‐installed directing group. Middle: This work, borylation directed borylation. Bottom: A rare example of a diboron ditopic electrophile used in vicinal double C−H borylation.

Figure 2

Formation of 2,2‐(MeCN)₂ and 3 and bottom the solid‐state structures of 2 and the cationic portion of 2‐(MeCN)₂ (ellipsoids at 50 % probability). Selected metrics [Å] for 2: B1⋅⋅⋅B1′ 3.126(2), B1−N3 1.609(2), B1−N1 1.532(2). For 2‐(MeCN)₂ : B1⋅⋅⋅B2 2.974(4), N1−B1 1.530(4), B1−N5 1.565(4), B2−N6 1.569(4).

Scheme 1

The hydride affinity (relative to BEt₃) of [3]⁺ .

Figure 3

Scoping of N−H‐indole reduction/C7‐borylation using 3 (combining equimolar 1+2). a=Pinacol installation requires heating at 80 °C.

Scheme 2

L‐BH₃ reduction of indoles.

Figure 4

Reduction/C7‐borylation to form 7‐H/7‐Cl proceeding via 5‐H/5‐Cl and 6‐H/6‐Cl. Note an alternative isomer of 6 (from exchanging H/NTf₂ on the boron centres is also feasible (the ¹¹B NMR resonances are broad thus multiplicity from B−H coupling is not observed)). Bottom: Structure of the cationic portion of 7‐H (ellipsoids at 50 % probability). Selected bond lengths [Å] and angles [°]: B1−C13 1.602(4), B2−N5 1.578(3), B1⋅⋅⋅B2 2.858(4); C7‐N5‐C14 103.2(2), C14‐N5‐B2 119.2(2), B2‐N5‐C7 116.4(2).

Figure 5

Formation of 8, ellipsoids at 50 % probability. Selected bond lengths [Å]: B1⋅⋅⋅B2 3.071(2), N−B1 1.551(2), N5−B1 1.517(2), N6−B2 1.498(2).

Scheme 3

Formation of 7‐H from N−H‐indoline via 6‐H.

Figure 6

Hydroboration of N−Me‐indole with 3 to form 9. Right: Solid‐state structure of the cationic portion of 9 (ellipsoids at 50 % probability). Selected bond lengths and angles [Å/°]: B1⋅⋅⋅B2 2.829(3), B1−N1 1.664(2), B1−N2 1.532(2), B2−C2 1.660(2); B1‐N1‐C1 112.4(1), B2‐C2‐C1 112.1(1).

Scheme 4

Formation of 7‐H from N‐SiR₃‐indoles.