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.


General Considerations
All reactions were performed under inert conditions using standard Schlenk techniques or in an MBraun Unilab glovebox (< 0.1 ppm H2O / O2).
Unless otherwise stated, solvents were degassed with nitrogen, dried over activated aluminium oxide (Solvent Purification System: Inert PureSolv MD5 SPS) and stored over 3 Å molecular sieves in ampules equipped with J. Young's valves. Chlorobenzene, 1,2difluorobenzene and 1,2-dichlorobenzene were dried over calcium hydride, distilled and stored over 3 Å molecular sieves. Deuterated solvents (CDCl3, CD2Cl2, C6D6 and C6D5Br (99.6% D, Sigma Aldrich)) were dried and stored over 3 Å molecular sieves. All chemicals were, unless stated otherwise, purchased from commercial sources and used as received. BH3·SMe2 and BCl3 in DCM (1M) were transferred to ampules fitted with J. Young's valves prior to use.
NMR spectra ( 1 H, 1 H{ 11 B}, 2 H, 11 B, 11 B{ 1 H}H, 13 C{ 1 H} and 19 F) were recorded on Bruker Avance III 400 MHz, Bruker Avance III 500 MHz or Bruker PRO 500 MHz spectrometers. Chemical shifts (δ) are quoted in parts per million (ppm), coupling constants (J) are given in hertz (Hz) to the nearest 0.5 Hz, and as positive vales regardless of their real individual signs. 1 H and 13 C shifts are referenced to the appropriate residual solvent peak while 11 B and 19 F shifts are referenced relative to external BF3·Et2O and C6F6, respectively. Abbreviations used are s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), dd (doublet of doublets), dt (doublet of triplets), m (multiplet), br (broad). 13 C resonances of carbon atoms directly bonded to boron atoms were not always observed due to the quadrupolar relaxation effects. The observation of very broad signals at ca. 0 ppm in 11 B NMR spectra owes to the use of borosilicate glass NMR tubes and boron-containing parts in the NMR cavity. Unless otherwise stated, all NMR spectra were recorded at 20 °C.
Mass spectrometry was performed by the Scottish Instrumentation and Resource Centre for Advanced Mass Spectrometry (SIRCAMS) at the University of Edinburgh using electron impact (EI) or electrospray ionisation (ESI) techniques.

Synthesis of Pyrazabole (1)
Neat BH3·SMe2 (4.0 ml, 42.2 mmol) was slowly added to a solution of pyrazole (2.87 g, 42.2 mmol, 1 equiv.) in DCM (20 ml) at 0 °C. After the initial gas evolution stopped the reaction was heated for 18 hrs at 35 °C in an unpressurized system. All volatiles were removed in vacuo and the remaining white solid was sublimed (120 °C, 4x10 -2 mbar) to yield the product as a white powder in 50% yield (1.67 g, 10.45 mmol). Analytical data are in accordance with literature values. [1] 2.2 Synthesis of bis-NTf2 Pyrazabole (2) A solution of HNTf2 (5.62 g, 20 mmol, 2 equiv.) in DCM (30 ml) was added dropwise to a solution of pyrazabole (1.60 g, 10 mmol) in DCM (1 ml) leading to gas evolution and precipitation of a white solid. The suspension was filtered after stirring at room temperature for 16 hours. The obtained white solid was washed with DCM (3 x 5 ml) and dried in vacuo. The product was obtained as a white powder in 74% yield (5.294 g, 7.37 mmol). Crystals suitable for X-Ray diffraction analysis were obtained from a less concentrated reaction by dissolving HNTf2 (0.011 g, 0.039 mmol, 1.25 eq) and pyrazabole (0.005 g, 0.031 mmol) in DCM (0.5 ml) and letting it stand for 1 hour at room temperature. Very low solubility of 2 in polar, weakly-coordinating solvents resulted in poor NMR data (see below), 1,2-difluorobenzene gave the best (but still limited) solubility for solvents that did not react with 2, thus 11 B NMR data is reported in this solvent. Better NMR data could be obtained using MeCN-d3 but this coordinating solvent formed 2-(MeCN)2 (see next entry).

Synthesis of bis-MeCN Pyrazabole 2-(MeCN)2
Compound 2 [Tf2N(H)B(pyrazole)]2 (0.011 g, 0.015 mmol) was dissolved in MeCN-d3 (0.5 ml). Crystals suitable for X-Ray diffraction were obtained after removing all volatiles in vacuo, dissolving the solid in PhCl at 100 °C and cooling by 20 °C per day till 40 °C was reached. The sample was then kept at 40 °C for 3 days. The compound could not be observed by using (EI) mass spectrometry (only compound 2 was detected).

7-BPin Indoline (4a)
Compound 4a was prepared following General Procedure 1 with indole (0.035 g). Reaction was heated to 100 °C for 18 hours to effect C7-borylation, then to 50 °C for 18 hours to convert to the BPin product. The product was isolated as a white solid (0.057 g, 0.233 mmol, 78 %) with no further purification necessary.

5-Methyl 7-BPin Indoline (4b)
Compound 4b was prepared following General Procedure 1 with 5-methylindole (0.039 g). Reaction was heated to 100 °C for 18 hours to effect C7-borylation, then to 50 °C for 18 hours to convert to the BPin product. The product was isolated as a yellow solid (0.059 g, 0.228 mmol, 76 %) with no further purification necessary.

2-Methyl 7-BPin Indoline (4d)
Compound 4d was prepared following General Procedure 1 with 2-methylindole (0.039 g). Reaction was stirred at room temperature for 1 hour (hydroboration step is slower for 2-substituted indoles), heated to 100 °C for 18 hours to effect C7-borylation, then to 50 °C for 18 hours to convert to the BPin product. The product was isolated as a yellow oil (0.067 g, 0.259 mmol, 86 %) with no further purification necessary.

6-Methyl 7-BPin Indoline (4e)
Compound 4e was prepared following General Procedure 1 with 6-methylindole (0.039 g). Reaction was heated to 100 °C for 18 hours to effect C7-borylation, then to 80 °C for 18 hours (PhCl instead of DCM) to convert to the BPin product. The product was isolated as a yellow oil (0.043 g, 0.166 mmol, 55 %) with no further purification necessary.

5-Chloro 7-BPin Indoline (4f)
Compound 4f was prepared following General Procedure 1 with 5-chloroindole (0.045 g). Reaction was heated to 100 °C for 2 hours to effect C7-borylation, then to 50 °C for 18 hours to convert to the BPin product. The product was isolated as an orange oil (0.067 g, 0.240 mmol, 80 %) with no further purification necessary. Note: the broad N-H resonance is not observed for this substrate in the 1 H NMR spectrum.

4-Fluoro 7-BPin Indoline (4g)
Compound 4g was prepared following General Procedure 1 with 4-fluoroindole (0.041 g). Reaction was heated to 100 °C for 2 hours to effect C7-borylation, then to 50 °C for 18 hours to convert to the BPin product. The product was isolated as a colourless oil (0.067 g, 0.255 mmol, 85 %) with no further purification necessary.

5-Methoxy 7-BPin Indoline (4i)
Compound 4i was prepared following General Procedure 1 with 5-(methoxy)indole (0.044 g). Reaction was heated to 100 °C for 2 hours to effect C7-borylation, then to 50 °C for 18 hours to convert to the BPin product. The product was isolated as a yellow oil (0.055 g, 0.200 mmol, 67 %) with no further purification necessary. Note: the broad N-H resonance is not observed for this substrate in the 1 H NMR spectrum.

NMR Spectra of Synthesised 7-BPin Indolines
A number of substrates have minor impurities in the 11 B NMR spectra, consistent with pyrazabole species. These are all less than 5% based on 11 B NMR spectroscopy and higher purity can be obtained for these substrates, if required, by column chromatography.
NMR Spectra of 7-BPin Indoline (4a):                                Spectra recorded in reaction solvent C6H5Cl. Note: reaction is slower in NMR tubes due to poor solubility of 2 (and lack of stirring / inversion when heating), hence it is not fully C7borylated after 2 hours 100 °C (though 7-Cl is the major product). Figure S63: Stacked 11 B NMR spectra of the C7-borylation of 5-chloroindole with 3. Spectra recorded in reaction solvent C6H5Cl. Note: reaction is slower in NMR tubes due to poor solubility of 2 (and lack of mixing), hence not fully C7-borylated after 2 hours 100 °C. Figure S64: Stacked 13 C{ 1 H} NMR spectra of the C7-borylation of 5-chloroindole with 3. Spectra recorded in reaction solvent C6H5Cl. Note: reaction is slower in NMR tubes due to poor solubility of 2, hence not fully C7-borylated after 2 hours 100 °C. Figure S65: Excerpt of stacked 13 C{ 1 H} NMR spectra of the C7-borylation of 5chloroindole with 3. Spectra recorded in reaction solvent C6H5Cl. Note: reaction is slower in NMR tubes due to poor solubility of 2, hence not fully C7-borylated after 2 hours 100 °C.

Compound 7-Cl
An ampule was charged with pyrazabole 1 (0.018 g, 0.11 mmol, 0.55 equiv.), bis-NTf2 pyrazabole 2 (0.079 g, 0.11 mmol, 0.55 equiv.) and 5-chloroindole (0.030 g, 0.1 mmol, 1 equiv.), then suspended in chlorobenzene (1.5 mL). The reaction was heated to 100 °C in a sealed ampule for 2 hours. The reaction was then concentrated, and the solvent replaced with CDCl3 for NMR characterisation. Note the broad N-H resonance observed for 7-H is not observed in the spectra of this congener, all other data are closely comparable between 7-H and 7-Cl supporting our formulation as 7-Cl.

Reactivity in the presence of a hindered base
In-situ NMR spectra of 7-H made using 2 / excess hindered base (2,6-ditertbutyl-4methylpyridine) after heating to 110 o C (note the reaction is extremely slow at r.t.) Figure S79: Partial 1 H NMR spectrum in PhCl (after heating 18 h at 110 o C). This shows the diagnostic resonances for the formation of 7-H (or a very close analogue with different substituents on B e.g. H/NTf2 exchange). Note the identical indoline region to that for 7-H shown in Fig. S54 -55. The intense singlets in the aliphatic region are due to the hindered base.

Synthesis of bis-Indole Pyrazabole 8
A solution of bis-NTf2 pyrazabole 2 (0.296 g, 0.409 mmol, 1 equiv.), indole (0.096 g, 0.818 mmol, 2 equiv.) and 2,6-di-tert-butyl-4-methyl-pyridine (0.168 g, 0.818 mmol, 2 equiv.) in dichloromethane (2 mL) was stirred at room temperature for 5 minutes. The volatiles were removed in vacuo, and the residue was extracted with toluene (2 x 5 mL). The extracts were combined and reduced to a third of the initial volume and left at room temperature. After 18 hours, the supernatant was filtered off the colourless crystals, and again reduced to a third of the initial volume to obtain a second batch. The isolated crystals from both batches were dried in vacuo to give the product as a colourless crystalline solid (0.056 g, 0.14 mmol, 34 %). X-ray quality crystals were grown by layering a dichloromethane solution with pentane.
In situ NMR Spectra of N-Pyrazabole Indoline Intermediate (6-H) Figure S86: 1 H NMR spectrum of key region of the reaction of N-H indoline, 2 and base in PhCl after 18 hours at room temperature. Note the two triplets of 2H intensity between 2.5 and 2.7 ppm are also observed in the N-H-indole / 3 reaction after 18 h at rt. The doublet at ca. 5 ppm is assigned to a pyrazabole resonance and is also observed in Fig S54. Other key resonances indicate formation of 7-H is occurring slowly at room temperature, while the intense singlets are due to the base.

Synthesis of N-TMS Indole
To a solution of indole (2.0 g, 17.06 mmol) in THF (5 mL) was added n-BuLi (11.8 mL, 1.6 M in hexanes, 19 mmol, 1.1 equiv.) dropwise at 0 °C. After stirring at 0 °C for 1 hour, chlorotrimethylsilane (2.6 mL, 20 mmol, 1.2 equiv.) was added dropwise. The resulting suspension was warmed to room temperature. The volatiles were removed in vacuo and the resulting slurry was extracted with pentane (2 x 5 mL). The combined pentane phases were concentrated, yielding the product as a colourless oil (3.025 g, 15.98 mmol, 94%). Analytical data are in accordance with literature values. [2] Figure S102: 1 H NMR spectrum of N-TMS-indole in CH2Cl2 (solvent suppression)

Synthesis of N-TIPS Indole
To a solution of indole (0.607 g, 5.18 mmol) in THF (20 mL) was added n-BuLi (2.9 mL, 1.6 M in hexanes, 4.6 mmol, 0.9 equiv.) dropwise at 0 °C. After stirring at 0 °C for 1 hour, chlorotrimethylsilane (0.88 mL, 4.1 mmol, 0.8 equiv.) was added dropwise. The resulting suspension was warmed to room temperature. After addition of water (20 mL), the reaction mixture was extracted with EtOAc (3 x 20 mL), and the combined organic phases dried in vacuo. The resulting residue was taken up in heptane (20 mL) and washed with MeOH (2 x 10 mL). The organic phase was dried over MgSO4, filtered and concentrated, yielding the product as a viscous colourless oil (0.810 g, 2.73 mmol, 67%). Analytical data are in accordance with literature values. [3]

Hydroboration of N-TMS Indole to 10
Combining a 1:1 mixture of 3 and TMS-indole led, after 1 h stirring at room temperature, to the clean hydroboration product analogous to 9. The assignment is based on comparison to product 9 which has a closely comparable NMR spectrum (excluding the TMS Vs Me change).

Computational Data
All calculations were performed using the Gaussian09 programme. [4] Geometry optimisations were completed with the DFT method using the M06-2X functional [5] and the 6-311G(d,p) basis set. All geometry optimizations were full, with no restrictions. Stationary points were characterized as minima by vibrational analysis. Solvent effects of the dichloromethane were introduced using the self consistent field approach, by means of the integral equation formalism polarizable continuum model (IEFPCM). [6] Pyrazabole N For data set 2 Bruker APEX3 software package was used for data collection, the applications SAINT 7 and SADABS 8 were used for the data reduction and absorption corrections of the data, respectively. For data sets 2-(MeCN)2, 7H, 8, and 9 the CrysAlisPro 9 software package was used for data collection, cell refinement and data reduction. The CrysAlisPro software package was used for empirical absorption corrections, which were applied using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. All further data processing was undertaken within the Olex2 software package. 10 The molecular structures of all compounds were solved with the ShelXT 11 structure solution program using Intrinsic Phasing and refined with the ShelXL 12-14 refinement package using Least Squares minimisation. Non-hydrogen atoms were refined anisotropically. Hydrogen atoms were all located in a difference map and repositioned geometrically.
Crystallographic data have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers 2114150 -2114154. Selected crystallographic data are presented in Table S1 and S2 and full details in cif format can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.uk/data_request/cif.