Cobalt-catalyzed double hydroboration of pyridines

Cobalt(ii) complexes were prepared from a modular phosphinopyridonate platform and applied to the hydroboration of pyridines. The synthetically useful, yet challenging, double hydroboration toward tetrahydropyridine derivatives was successfully performed with high activity and regiocontrol. This new method enabled the direct synthesis of N-heterocyclic allylic boronates from commercial pyridines and pinacolborane (HBpin). One-pot acetylation afforded the bench-stable borylated N-acetyl tetrahydropyridines in good yields. The synthetic utility of this procedure was demonstrated by a gram-scale double hydroboration–acetylation sequence followed by chemical diversification. Mechanistic experiments indicated metal–ligand cooperativity involving ligand-centered C–H activation and the intermediacy of a cobalt(iii) hydride species.


Introduction
Six-membered N-heterocycles such as piperidines and tetrahydropyridines are ubiquitous in natural products and pharmaceuticals (Scheme 1a). 1 Among the 1086 FDA-approved small-molecule drugs as of 2012, 59% contained N-heterocycles. 1 The availability of straight-forward, robust, and selective synthetic routes to such building blocks is of utmost interest for medicinal chemistry and drug design endeavours.The synthesis of densely functionalized N-heterocycles from inexpensive starting materials in one synthetic operation is especially attractive by virtue of the high gain of complexity and ample opportunities for further derivatization.Borylated tetrahydropyridines could fulll these criteria if they were accessible from pyridines by simple and selective addition reactions of borane reagents as the resultant C-B motif can easily be functionalized under various conditions (Scheme 1b).Typical methods of tetrahydropyridine boronate synthesis include the addition of organometallics to activated pyridine boronic esters, 2 Tsuji-Trost type allylic substitution of N-heterocyclic allyl alcohol derivatives with B 2 pin 2 , 3 or Pd-catalyzed borylation/isomerization of alkenyl nonaates. 4,5However, these procedures require multiple reaction steps either in the substrate preparation or follow-up reactions.The partial reduction of readily accessible pyridines with organoboranes could provide a most direct alternative approach to N-heterocyclic allyl boronates.Selective 1,2-and 1,4-monohydroborations of pyridines were studied in great detail with metal catalysts (Rh, 6 Ru, 7 La, 8 Zn, 9 Th, 10 Mg, [11][12][13] Mn, 14 Ni, 15,16 Fe, 17 Co 18 ) and organoboranes [19][20][21] as well as metal-free conditions [22][23][24] (Scheme 1c).The more challenging double hydroboration of pyridines to tetrahydropyridines, however, has remained mostly unsuccessful.Double hydro-boration of quinolines was achieved both in the presence of catalytic amounts of B(C 6 F 5 ) 3 , 25 with Rh 26 or Co 27 catalysts.To the best of our knowledge, there is only a single report on the catalytic double hydroboration of pyridine (Scheme 1c). 28The Rh-phosphine catalyst gave 1,2,3,4-tetrahydropyridine diboronate in good yield and moderate regiocontrol.No substrate scope beyond the parent pyridine was explored. 28ollowing this lead and our recent explorations of selective hydrofunctionalizations with 3d transition metal catalysts, 29a-e we aimed at the development of a base metal-catalyzed double hydroboration of pyridines.In light of the recent advances in metal-ligand cooperativity (MLC) of base metal catalysts, 30 we sought to exploit a dual activation approach that would enable metal-centered pyridine coordination, ligand-centered borane activation, and metal hydride formation without ligand dissociation.Such MLC scenario was utilized in the 1,2-selective hydroboration of pyridines with Fe and Ni catalysts. 15,172][33][34] We reasoned that such multifunctional behaviour of metal pyridonates may facilitate hydroborations of pyridines.Herein, we report the successful implementation of these mechanistic scenarios into the rst base metal-catalyzed double hydroboration of pyridines to tetrahydropyridines.
Complementing our current investigations into the coordination chemistry of 3d metal pyridonates, 34 cobalt complexes featuring a 2-pyridonate motif modied by 6-dialkylphosphine substituents were prepared.The regio-selective Co-catalyzed borylative reduction of pyridines enabled the synthesis of highly versatile N-heterocyclic allyl boronates (Scheme 1d), which can be converted into bench-stable N-acetyl tetrahydropyridinyl boronates and various further derivatives.

Catalyst synthesis
Efficient 3d transition metal-catalyzed mono-hydroborations of pyridines have been accomplished with cyclopentadienyl metal complexes bearing hemilabile donor-functionalized phosphines. 15,17Upon employment of the modular ligand platform 6-phosphinomethyl-2-pyridone, we prepared heteroleptic cobalt(II) complexes of the general formula (h 5 -C 5 Me 5 )Co(R 2 PXN).We believed that a combination of the Lewis basic pyridonate with a strong-eld phosphine and a bulky spectator ligand would prohibit unwanted catalyst aggregation and coordinative saturation with substrate molecules while enabling dual activation of both substrates of the targeted hydroboration reaction, the borane and the pyridine (Schemes 2a and 2b).Complementing the literature-known diphenylphosphino complex Co1, 36 we varied the phosphine substituents to cover a wider structureactivity window.The di-iso-propyl (Co2) and di-tert-butyl (Co3) derivatives were prepared by a similar route involving sequential deprotonation of commercial 6-methyl-2(1H)-pyridone, phosphinylation, deprotonation, and substitution of the [Cp*CoCl] 2 dimer with the pyridonate (Scheme 2c).Single crystal structure analyses conrmed the expected k 2 -P,N chelating modes and pendent C]O moieties (Scheme 2d).The C-O bond distances (Co2: 1.243(7) Å; Co3: 1.245(9) Å) are consistent with a double bond character and align with the values of Co1 and related Ru and Ir phosphinopyridonates. [36][37][38] The bite angles (N-Co-P) and the bond lengths (Co-P, Co-N) of the phosphinopyridonate ligands increase in the series Ph 2 P < i Pr 2 P < t Bu 2 P.

Substrate scope
The optimized conditions were applied to a diverse set of pyridine derivatives in order to explore the scope of the double hydroboration reaction (Scheme 3).The parent pyridine underwent double hydroboration in 69% yield furnishing a mixture of two regioisomers (r.r.4/1).Remarkably, 4-substituted pyridines cleanly afforded a single isomer in the double hydroboration, i.e. the 1,3-di-boryl-1,2,3,6-tetrahydropyridines, in up to 89% yield.Treatment of the crude mixtures with acetic anhydride allowed one-pot conversions to the bench-stable N-acetyl allyl boronate derivatives.Alkyl, aryl, benzyl, triuoromethyl, and boronate functions were well tolerated.The bulky 4-tert-butylpyridine and the electron-rich 4-methoxypyridine enabled only single hydroborations (2s, 2s 0 and 2t), respectively.Acetylation of the

Thermodynamic and kinetic properties
The isolated N-acetyl tetrahydropyridine derivatives exist as two rotamers about the C-N amide bond in solution. 39 1H and 13 C-NMR spectra displayed two distinct set of signals; from temperature-gradient 1 H and 13 C-NMR analysis in toluene-d 8 between 27 °C and 100 °C the rotation barrier was determined to be ∼73.6 kJ mol −1 (from a modied Eyring analysis, see Schemes 4, S5 and S6 †). 40The compounds exhibited high thermal stability: Complete conservation of compound integrity and spectral data was observed when heating 4a to 100 °C under air for 6 h (Scheme S7 †).The N-heterocyclic allyl boronates were also stable toward silica gel and moisture, so that purication by ash chromatography did not require special handling procedures.This is surprising as cyclic allylic boronates were occasionally described as being unstable and difficult to isolate. 3,41,42Nevertheless, very minor amounts of unidentied pinacolato-boron species remained aer purications.Long-term storage of the N-acetyl tetrahydropyridines for two to four months under an atmosphere of air (both in solution and as an oily liquid) at −30 °C led to a slight increase in pinB-containing impurities with otherwise complete product integrity (NMR spectra, Schemes S8 and S9 †).The synthetic utility of the isolated N-acetyl tetrahydropyridines is evident from several literature reports on (allyl) boronate and tetrahydropyridine derivatizations. 2,35a-g The methallyl boronate 4a was isolated as a colorless oil from a gramscale reaction.Oxidation of 4a with sodium perborate cleanly afforded the N-heterocyclic allylic alcohol 5. Stereoselective allylboration of benzaldehyde proceeded with excellent diastereoselectivity (d.r.>99 : 1).NMR spectral data and single crystal Xray diffraction conrmed the formation of the syn-diastereomer (Scheme 4, right). 3,41Palladium-catalysed Suzuki-type arylative cross-coupling enabled the synthesis of the tetrahydropyridine 7.

Mechanistic studies
Various spectroscopic and preparative experiments were performed to gain insight into the nature of the catalytically active cobalt hydride species and the formation of pyridine-derived products.

Cobalt hydride complexes
Addition of pinacolborane (1.Co III H(PR 3 ) complexes. 45,46The more downeld resonance originates from the diamagnetic pyridyl monohydride complex Co6, which was isolated as a pure crystalline compound and characterized in solid state (XRD, elemental analysis) and solution (NMR, ESI-MS).Co6 features a cyclometalated k-C-pyridonate ligand that underwent ligand-C-H activation (Scheme 5).The slightly upeld hydride signal presumably is derived from a dihydrido cobalt complex and was tentatively assigned to complex Co7 (Scheme 5, see also Scheme S20 †).An identical reaction between Co2 and DBpin cleanly documented that the hydride resonance of Co6 is unaffected from the use of the isotopomeric borane reagent, so that this cobalt hydride is ligand-derived.The concomitantly formed Co7 showed strongly reduced intensity of the hydride resonance which supports the notion that the hydrido ligands are borane-derived (Scheme S25 †).This is further corroborated by the observed formation of Co7 (and minor amounts of other cobalt hydrides) from the reaction of pure Co6 with pinacolborane (Scheme S26 †).
Attempts to isolate pure Co7 were unsuccessful, but upon crystallization, a [Cp*Co]-capped derivative thereof was obtained, the dihydrido-bridged Co8 (Scheme 5).The Co-Co bond distance in Co8 of 2.420(4) Å suggests signicant metal-metal bonding. 43,47,48The residual electron density located between the cobalt centers of Co8 is consistent with bridging hydride ligands. 43The differences of model and diffraction data resulted in an uneven electron distribution among the Co ions, with higher electron density on the phosphino-bound cobalt ion (Co1) and lower electron density on the other center (Co2).This may be a strong argument for a Cp*(R 3 P)Co(I) fragment and a Cp*Co(III) cap, which could have formed via an intermediate cobalt(II) hydride species upon dinuclear disproportionation. 48Solutions of Co8 produced 1 H-NMR spectra displaying the resonances of Co6, Co7, L1Bpin, as well as unidentied paramagnetic species.We assume dynamic interconversions between several cobalt hydride species in solution (e.g.Co8 / Co6/Co7) and/or cocrystallization of different cobalt hydride complexes.Based on the isolated complexes and the collected spectroscopic data, we propose the following mechanism of cobalt hydride catalyst formation (Scheme 5): The pyridonate ligand in Co2 is believed to support borane activation via metal-ligand cooperativity (Co2a) yielding transient cobalt(II) hydride Co2b which dimerizes with another equivalent of Co2b to give Co2c.This bimetallic complex may engage in disproportionation to give the proposed dihydride species Co7 ( 1 H-NMR) and the short-lived Co6a.The hemilabile nature of the pyridonate ligand becomes evident by oxidative addition of the cobalt(I) centre into the ligand backbone to give Co6 (XRD, NMR, ESI-MS).However, the dimeric cobalt complex Co2c may also lose a phosphine ligand which results in the formation of Co8 (XRD).

Hydroboration products analysis
The cobalt monohydride complex Co6 was found to be equally active to Co2 in the catalytic double hydroboration of 4-phenylpyridine 1b, which again suggests rapid interconversion from Co2 to Co6.Full conversion of 4-phenylpyridine 1b to the tetrahydropyridine derivatives 3b and 3b 0 was observed when employing Co6 as catalyst (3 mol%).The stoichiometric reaction between Co6 and 1a resulted in rapid consumption of Co6 at room temperature (complete consumption at 50 °C, Scheme S27 †).This equimolar reaction did not lead to the formation of the mono-reduction product 2a.Addition of one equiv.HBpin to the Co6/pyridine reaction mixture afforded the monohydroboration product 2a and regeneration of the cobalt hydride complex Co6 as well as formation of Co7 (Schemes S27 and S28 †).Formation of the tetra-hydropyridine product 3a was only observed aer addition of a 2nd equiv.HBpin and heating to 50 °C (Scheme S28 †).When Co2 was reacted with one equiv.4-Benzylpyridine 1e and one or two equiv.HBpin at room temperature, only traces of Co6 were observed while the hydride signal of Co7 was rather unaffected (Schemes S30-S32 †).The formation of the mono/double hydro-boration products was associated with the same stoichiometry of HBpin addition.Reaction of the isotopomeric DBpin with 1b in the presence of 3 mol% Co2 led to deuteration in 2-and 6-positions of the tetrahydropyridine product (Schemes S33 and S34 †).Based on the collected analytical data and previously reported DFT studies, 27,28 we propose a mechanism for the Co-catalyzed double hydroboration of pyridines (Scheme 6a): The direct reaction of Co6 with pyridine substrates suggest rapid insertion into the Co-H bond to give the 2-hydropyridinyl complex Co6c.The borate function at the ligand is most likely only involved in the initiation steps but rather not operative in O-to-N boryl transfer onto the substrates.Thus, liberation of the monohydroboration product 2 is believed to occur via s-bond metathesis between Co6d and HBpin which also regenerates Co6.The 2nd hydroboration event commences with a regioselective insertion step of the Co-H bond of Co6 into the polarized C]C bond of the enamine motif within 2. The resultant Co6f may undergo another s-bond metathesis with HBpin to give the desired tetrahydropyridine derivative 3. The high regiocontrol of the second hydroboration is dictated by the polarity of the enamine-C]C bond, the lower sterics, and the formation of the thermodynamically more stable allyl boronate species (vs.alkyl boronate).The close mechanistic relationship between the precursor Co2 and the postulated catalyst species Co6 becomes also evident from kinetic reaction progress analyses (Scheme 6b).Under identical conditions, very similar reaction proles were observed that include identical reaction slopes of the 1st hydroboration event, very similar yields and lifetimes of the intermediate 1,2-dihydropyridine derivative, a signicantly slower 2nd hydroboration step, and comparable yields and selectivities of the nal product mixture.It is important to note, that the operation of a "hidden" BH 3 catalysis was largely excluded: 11 B NMR studies of various mixtures of HBpin with the Co2 and the pyridine under reaction conditions did not exhibit the characteristic upeld resonance of BH 3 $L, even in the presence of added TMEDA (N,N,N 0 ,N 0tetramethylethylenediamine, see Scheme S38 †). 49A similar stepwise hydroboration mechanism may be operative during the hydroboration of other polarized p-systems such as the cobalt pyridonate catalyzed hydroboration of CO 2 currently studied in our laboratory. 50

Conclusions
The demand for highly functionalized and synthetically versatile platform molecules for the synthesis of biologically active compounds has prompted great interest in selective catalytic transformations.Six-membered N-heterocycles are an especially attractive class of building blocks for medicinal chemistry programs, yet, straight-forward synthetic routes that utilize commercial starting materials are rare.Based on a modular ligand platform and easily available substrates, an efficient cobalt-catalyzed double hydroboration of pyridines to tetrahydropyridines was developed.The catalyst was easily prepared from commercially available 6-methyl-2(1H)-pyridone by sequential deprotonation, phosphinylation, deprotonation, and salt metathesis with [Cp*CoCl] 2 Co4.The double hydroboration reaction afforded versatile N-heterocyclic allyl boronates that can be converted to bench-stable borylated N-acetyl tetrahydropyridines in a one-pot fashion.The double hydroboration of 4-substituted pyridines was found to occur in a regioselective manner with the formation of a single isomer.Remarkably, 1,2,3,6-tetrahydropyridines were the only reduced species formed with mostly full conversions of the intermediate 1,2-dihydropyridines and no onward hydroboration to the fully saturated piperidines.3-Substituted pyridines gave somewhat lower regiocontrol.7][28] Structural variation of the modular 2-pyridonate ligand enabled high activities of the iso-propyl derivative.The presumably formed cobalt(II) hydride complex Co2b underwent disproportionation to give cobalt(III) hydride complex Co6 that was found to be catalytically active.Hydride insertion of Co6 into the pyridinyl C]N and C]C bonds and s-bond metathesis with pinacolborane are believed to be key steps of the double hydroboration mechanism.The easy access to the pre-catalyst Co2 and the identication of Co6 as active catalyst species may prompt further studies into the exploration of base metal catalysts for polar hydrofunctionalization reactions of p-systems. 50

Scheme 1
Scheme 1 (a) Substituted piperidines and tetrahydropyridines as structural motifs in pharmaceuticals.(b) Synthetic utility of borylated tetrahydropyridines.(c) Methods of single and double hydroboration of pyridines.(d) New development of a cobalt pyridonate catalyzed double hydroboration of pyridines.

Scheme 6
Scheme 6 (a) Proposed mechanism of the cobalt-pyridonate catalyzed double hydroboration of pyridines.(b) Reaction progress analyses of the double hydroboration of 4-methylpyridine with catalytic Co2 and Co6, respectively.

Table 1
Catalytic activities of Co1-Co3 in the double hydroboration of pyridines a Minor amounts of deuorination were observed (to 3c, 12% yield).Isolation of 3-substituted N-acetyl tetrahydro-pyridines was generally plagued by the complexity of the crude product.The formation of minor species impeded with isolation.The cobalt pyridonate catalyst strongly discriminated between differing substitution patterns: While 3and 4-substituted pyridines were subjected to double hydroboration with a high preference for the allyl boronate motif, 2substituted pyridines (1l, 1m, 1n) exhibited no reactivity, neither in mono-hydroboration nor in double hydroboration.Quinoline 1o, isoquinoline 1p, and 3,4-lutidine 1q, on the other hand, underwent single hydroboration in 67-96% yield with no second hydroboration event occurring.Further substitution patterns that prohibited double hydroboration under the standard conditions were bulky tert-butyl groups, methoxy, sec-amine, halides, ester, nitrile, and vinyl groups (Scheme S4 †).