Nickel-Catalyzed Annulations of ortho-Haloarylimines

Abstract

We report the discovery, development, and mechanism of a nickel-catalyzed annulation reaction between o-haloarylimines and electron-poor olefins. The reaction produces two adjacent anti stereocenters and a free secondary amine. Spirocycles are formed from cyclic imines. We characterized the key oxidative addition intermediate and identified a major path leading to competing homocoupling products. The activation energy of oxidative addition and the rate of oxidative addition complex isomerization were determined. The sensitivity of the reaction to reaction conditions was established in a quantitative manner and both the scope and limitations of the method are presented.

Graphical Abstract

1. INTRODUCTION

We previously reported the synthesis of a small collection of spirocyclic compounds and assessment of their biological activity through a phenomic profiling experiment.¹ Spiroindane pyrrolidines that served as scaffolds for synthetic elaboration were accessed as both syn and anti diastereomers through a photocycloaddition between phenylpyrrolinium perchlorate and electron-poor alkenes (Figure 1A).² One compound from this collection induced changes in cell morphology in a manner distinct from a panel of 12 diverse bioactive compounds with well-understood mechanisms of action and distinct from simple cytotoxicity.³

Figure 1.

Various ways of generating complexity from simple precursors. (A) Application of photocycloaddition to prepare syn- and anti-spiroindane pyrrolidines. (B) Nickel-catalyzed method complementary to panel (A) of synthesizing indanyl amines through the reductive coupling of ortho-haloaryl pyrrolines and olefins. (C) Nickel was superior to palladium, which forms too stable a complex upon oxidative addition (1, CCDC 2082427) (D). Treating o-bromophenylpyrroline, o-BPP, with stoichiometric nickel at elevated temperature leads to the formation of syn adduct 2, the homocoupled biaryl 3, and reduced 2-phenylpyrroline.

Here, we discuss the discovery, development, and mechanistic elucidation of a nickel-catalyzed reaction that yields anti-indanyl amines that encompass spiroindane pyrrolidines (Figure 1B). The reaction is a conjugate addition of an aryl group to an olefin followed by a reductive aldol addition onto a pendant imine.^4,5 The benefits of this complementary synthetic method are 4-fold: (1) it obviates the need for a large excess of olefin. Up to 80 equiv were used in the photochemical reaction while only 1−2 equiv are needed here, meaning that synthetically more valuable coupling partners can be used. (2) The method expands the scope of usable arenes. Under photochemical conditions, perturbation of the electronic structure of phenylpyrrolinium perchlorates that occurs as a consequence of aryl ring substitution led to a structurally intriguing but unpredictable variety of photoproducts.¹ (3) The Ni-catalyzed process allows selective preparation of the anti diastereomer. (4) Metal catalysis potentially opens the door to enantioenriched products through the inclusion of chiral ligands on nickel.⁶ Access to both enantiomers of biologically active compounds is instrumental for establishing the enantiospecificity associated with their effects and can aid in identifying the protein target(s) responsible for the observed activity.

2. RESULTS AND DISCUSSION

Seeking an alternative route to spiroindane pyrrolidines that would allow greater control over stereochemical outcomes, we sought to establish a two-step transition metal-catalyzed process similar to the one shown in Figure 2. Concessions to poor atom economy⁷ (added halogen) and “steppiness” would pay off, we thought, in the improved modularity that would come from controlling the reactivity of copper-containing intermediate with suitable ligands (Figure 2).⁸ We were surprised that attempts at Heck coupling between ortho-bromophenylpyrroline (o-BPP) and methyl acrylate with stoichiometric palladium led only to the isolation of a chromatographically stable, crystalline material. Subsequent X-ray diffraction analysis revealed it to be a 16-electron, square planar, oxidative addition complex 1 (CCDC 2082427, Figure 1C).⁹ Switching to a more electropositive group 10 metal¹⁰ and to one that exchanges ligands with greater ease,¹¹ nickel(0) in the form of Ni(COD)₂ yielded syn-spiroindane pyrrolidine, 2, together with the biaryl homodimer, 3, and some reduced (debrominated) 2-phenylpyrroline, instead (Figure 1D). Other sources of nickel, such as Ni(acac)₂ or NiBr₂ in combination with a variety of reductants or the recently developed “bench-stable” Ni(0),¹² were not competent as catalysts in this reaction.

Figure 2.

Originally envisioned scheme for improving control over product stereochemistry.

Having found nickel(0) to be effective, we then undertook to understand the elementary steps of this transformation and to quantify the relevant parameters as a means of rendering it catalytic in nickel, improving diastereoselectivity, and minimizing the homocoupling by-product.

2.1. Oxidative Addition.

Oxidative addition is the canonical first step in reactions of aryl halides and transition metals in their low oxidation state.^13,14 Freshly prepared Ni(COD)₂ (from reduction of Ni(acac)₂ with DIBAL-H in the presence of 1,5-cyclooctadiene, COD)¹⁵ inserts readily into ortho-haloaryl pyrrolines at ambient temperature (Figure 3). With o-BPP, the reaction is quick and produces yellow complex 4 within a couple of minutes. We isolated this material and characterized it crystallographically (CCDC 2032845). A similar structure is obtained with the chloride (Figure 3, 5, CCDC 2039903), but the reaction is noticeably slower. Complexes derived in this way are square planar, diamagnetic, 16-electron Ni(II) species, and they are stable as solids even under ambient conditions. En route to their formation, the expulsion of the weakly bound COD ligands is apparent in the NMR spectrum. Signals corresponding to olefinic protons shift from 4.85 ppm for Ni(COD)₂ to 5.58 ppm for free COD. A characteristic peak in the ¹H NMR of 4 and 5 is the ortho aromatic proton of the substrate that acts as a neutral ligand. The geometry of these complexes in solid state, with Ni−H distance of 2.79 Å in 4 and 2.77 Å in 5, and Ni−H−C angles of 108° in both, is nearly ideal for favoring anagostic metal−hydrogen interactions, which are characteristic of d⁸ metals such as Ni(II) (Figure 3B, measurements in green).^16,17 The term anagostic distinguishes this type of electrostatic metal−hydrogen interaction from 3-center-2-electron interactions for which the term agostic applies. The consequence of anagostic interaction is the downfield shift of the proton in ¹H NMR, as was observed here (9.75 ppm for 4, and 9.83 ppm for 5).

Figure 3.

(A) Facile oxidative addition into aryl halides containing an o-imine ligand. (B) Crystal structures of 4 and 5. Carbon is shown in gray, nitrogen in purple, bromine in yellow, chlorine in lime, and nickel in green. Distances from Ni to ortho hydrogen (in ångstroms, shown in green) and Ni−H−C angles (in degrees) support the anagostic interaction, which results in the downfield shift of that proton in ¹H NMR.

Figure 5.

(A) Isomerization of 4 to 6 is monitored with a UV−vis spectrophotometer. (B) Oxidative addition complex, 4, isomerizes into a 2,2′-di(pyrrolin-2-yl)biphenyl nickel(II) bromide, 6, in polar solvents. Crystal structures of the complex 6 is shown on the right. Carbons are shown in gray, nitrogens in purple, bromides in yellow, and nickel in green. Isosbestic points are seen at around 300, 340, and 500 nm.

In contrast to o-BPP, the analogous ortho-iodophenylpyrroline yields a product that is not isolable, but that we could observe with atmospheric solid analysis probe mass spectrometry,¹⁸ and which was characterized in the crude NMR by both upfield (−10 ppm) and downfield (15 ppm) signals, suggestive of formation of paramagnetic species.

We next determined the activation energy for the oxidative addition reaction leading to 4 and 5 (Figure 4). The solutions of reactants were kept at −78 °C before they were mixed in a J. Young tube, and the NMR spectra were acquired every 2−3 min with the probe held at a constant pre-equilibrated temperature. Formation of 4 was monitored at a temperature range from −50 to −20 °C, while the formation of 5 was monitored from 10 to 50 °C, reflecting the relative facility of the oxidative addition of bromide compared to chloride. We quantified the formation of the oxidative addition complexes 4 and 5 by integrating peaks at 9.75 and 9.83 ppm, respectively. Since COD is also the product of this reaction, its signal at 5.58 ppm in the NMR served as an additional, and more intense marker of the extent of the reaction (eight protons, four from two molecules of COD displaced). The magnitudes of these integrals as a function of time and temperature are shown in Figure 4A (and also the Supporting Information, Section S2). From this data, we computed the initial rates of the reactions. This was achieved by considering a truncated Taylor series expansion of product concentration (either COD or oxidative addition complex) at the initial time point. Initial rates are obtained from a least-squares fit of the polynomial data.^19,20 Using the Arrhenius equation, the activation energy for insertion into the C−Br bond was 11 kcal/mol, while insertion into the C−Cl bond was found to be 22 kcal/mol (Figure 4B). Good agreement was found between values for the activation energy obtained by monitoring COD or the oxidative addition product. Activation enthalpy for the insertion of phosphine and COD-ligated Ni(0) into the aryl C−Br bond without the ortho-coordinating ligand was previously found²¹ to be 24 kcal/mol with entropy being nearly zero. The significant lowering of the insertion barrier in the present case is attributable to the strongly coordinating imine.

Figure 4.

Determining the activation energy for oxidative addition of Ni(0) into the aryl halide bond of o-haloaryl pyrrolines. (A) Variable temperature NMR spectra were taken every 2−3 min. Samples were kept in J. Young tubes at indicated temperatures. Characteristic product peaks were fitted and integrated at each time point. (B) Arrhenius analysis gives activation energy from the initial reaction rates obtained at a range of temperatures. The least-squares linear fit to reciprocal temperature against logarithm of the initial rate gave an activation energy of 11 kcal/mol for bromide, and 21 kcal/mol for chloride from the slope parameter.

2.2. Isomerization of 4.

The oxidative addition complex 4 is stable as a solid and has a yellow color typical of a diamagnetic, square planar, 16-electron species, consistent with early observations in this field.^22,23 However, when we dissolved this complex in polar organic solvents [e.g., tetrahydrofuran (THF), acetonitrile, acetone, or chloroform], we observed a gradual color change from yellow to blue, which is more characteristic of a tetrahedral paramagnetic nickel species (Figure 5A). Slow solvent evaporation of the blue solution led to crystals of complex 6, which we analyzed through X-ray diffraction. This confirmed the structure to be a complex of 2,2’-di(pyrrolin-2-yl)biphenyl-coordinating NiBr₂ (6, CCDC 2033223). We also decomposed this complex, isolated the ligand 3 through chromatography on alumina, and characterized it spectroscopically; the NMR agreed with the di-imine ligand in structure 6. Although the ligand was isolable, it decomposes over a period of several hours.

The isomerization process, 4 → 6, was monitored with a UV−vis spectrophotometer, taking advantage of the convenient color change accompanying the conversion (Figure 5B). While the yellow complex has absorptions in UV and blue parts of the spectrum, the blue complex is characterized by a broad, weak absorption stretching from 500 to 700 nm, hence its blue color (Figure 5B inset). The absorption spectra taken at regular intervals during the isomerization showed three isosbestic points (at around 300, 340, and 500 nm), indicating direct conversion from one species to another.

There are two main problems that prevent direct measurement of component concentrations from the spectroscopic data even when good standards are available: (1) the measurements are inherently noisy, and (2) the individual components in a mixture can interact in a way that alters their spectral characteristics compared to the pure components. To address the first problem, we performed a Fourier transform step through which the spectra were significantly denoised and the concentrations of pure components could be more clearly determined. This was achieved by excluding high-frequency Fourier coefficients that often capture noise in spectral measurements. For the second issue, we computed, from a set of experiments using standard mixtures, a calibration matrix that relates projections of the Fourier-transformed spectra to the known component concentrations in these mixtures. This approach enabled the analysis of interacting components, which typically prohibit a $na\ddot{i}ve$ implementation of Beer-Lambert assumption of simple additivity of absorptivities. By applying the techniques of chemometric factor analysis,²⁴ and full-spectrum quantitation²⁵ to spectra at different time points and over a range of initial concentrations (25−400 μM), we accurately determined the changes in concentration of both 4 and 6 over time (Figure 6A). Further analysis of initial rates as a function of initial concentrations gave a pseudo-first-order rate constant of 1.12 × 10⁻³ s⁻¹ for the process (Figure 6B).

Figure 6.

(A) Denoised spectra and a multicomponent standard calibration matrix allowed accurate determination of concentrations of 4 and 6 over time starting from varying initial concentrations. The red vertical line draws attention to a lengthening “induction” period for the formation of 6 with decreasing initial concentration. (B) Pseudo-first-order rate constant for the consumption of 4 calculated from fitting a line through log−log transformed data of initial concentrations against initial rates. (C) Evidence for o-BPP expulsion preceding the isomerization. Note different scales of the y-axes.

The spectra processed as above also provided evidence for the obligatory dissociation of the ancillary o-BPP ligand, which precedes the isomerization. This spike in free o-BPP is best observed at low initial concentrations, where its rise and subsequent fall is more apparent (Figure 6C) and the delay in the increase in the concentration of 6 is longer (note the red vertical line in Figure 6A). The equilibrium between 4 and the coordinatively unsaturated intermediate weakly stabilized by a solvent molecule (Figure 5A in square brackets) can be conjectured to occur during the induction period for the biaryl formation.²² During this period, the blue complex concentration does not increase, and the 14-electron intermediate can undergo disproportionation to Ni(I) and Ni(III) species. Adding excess o-BPP to 4 increases the length of the induction period from 5 to 25 min when 4 was kept at 100 μM, and o-BPP was added in 5-fold excess; it was 50 min when o-BPP was added in 10-fold excess.

2.3. Identification of the Reducing Agent.

Oxidative addition complex 4 is inert in the presence of excess electron-poor olefins such as methyl acrylate, but this was changed when we added an additional 0.5 equiv of Ni(COD)₂ to it and isolated 11% yield of 2, which suggested that 4 had to be reduced to Ni(I) prior to the addition of the acrylate. A similar outcome was observed on the inclusion of 2 equiv of strong 1-electron reductant decamethylcobaltocene, $\text{CoC}{\text{p}}_2^{\ast }$, E = −1.94 V vs Fc/Fc⁺,²⁶ to catalytic Ni(COD)₂ together with o-BPP and methyl acrylate. $\text{CoC}{\text{p}}_2^{\ast }$ has 19 electrons in its valence shell and readily produces a stable cobaltocenium cation ${\left[\text{Co}(\text{III})-\text{C}{\text{p}}_2^{\ast }\right]}^{+}$. These conditions yield spirocyclic products (syn and anti diastereomers) together with homocoupled biaryl, dehalogenated phenylpyrroline, and unreacted o-BPP. Implicating single-electron processes further is the ability of duroquinone to inhibit the reaction.²⁷ Notably, other reductants, including simple cobaltocene (Co(C₅H₅)₂, E = −1.33 V),²⁶ a variety of boron-, silicon-, tin-, or aluminum hydrides, manganese, iron, or zinc powder, SmI₂, sodium naphthalide, titanocene(III) chloride, hydrazine, or Hantsch ester, were unable to achieve the needed reduction. However, the very strongly reducing benzophenoneketyl radical anion (E = −2.3 V in THF, obtained from benzophenone and sodium metal) was a suitably strong reductant for the reaction. Nevertheless, we did not pursue it as a favored reductant due to issues with its preparation and stability. Preliminary cyclic voltammetry experiments on 4 suggest that the reduction of Ni(II) to Ni(I) requires currents at potentials more negative than −1.4 V, which matches the trend we observed with various reductants.

2.4. Blocking the Homocoupling Side Reaction.

The homocoupling product arises from the isomerization reaction described above (Figures 5 and 6). The synthetic utility of the tandem coupling reaction with only Ni(COD)₂ and $\text{CoC}{\text{p}}_2^{\ast }$ leading to spirocyclic products was diminished by this major competing product, formation of which consumes two molecules of the starting material per homocoupling. From the previous observations, we understood that homocoupling to form biaryl products is slower in nonpolar solvents, so we performed the coupling reaction in benzene, toluene, or xylene. However, even in these solvents, at elevated temperatures, the amount of homocoupling was substantial. We reasoned that the homocoupled product forms because the starting material, o-BPP, is also a good ligand for nickel. If we could break up the interaction between nickel and substrate acting as a ligand, and instead promote interaction with the coupling partner (i.e., olefin), this would diminish the amount of homocoupled product. Initially, we attempted to displace the second substrate molecule with other ligands (phosphines, quinolines, pyridines), but this was unsuccessful (see also the Supporting Information, Section S4: “Ligand exchange studies” for successful displacements with other pyrrolines). Conversely, Lewis acids compatible with the reaction conditions proved effective, possibly because they either activated the Lewis basic carbonyls thus promoting the conjugate addition or disrupted the imine−nickel coordination, thereby detaching the second molecule of imine substrate from the reactive site. For example, triethylborane or trimethylaluminum both inhibited homocoupling entirely. However, they also acted as alkyl donors and caused ortho alkylation of the substrates with a displacement of halogen. This byproduct was usually observed in smaller amounts.

2.5. Optimizing Reaction Conditions.

To optimize reaction for cross-coupling, we sought to quantify the yield of each product as a function of reaction conditions. For this purpose, we developed a quantitative high-performance liquid chromatography (HPLC) method to measure the concentrations of syn- and anti-spiroindane pyrrolidines, 2 and 7, reduced (debrominated) 2-phenylpyrroline, unreacted o-BPP, and alkylated 2-ethylphenylpyrroline, 8 (Figure 7). This HPLC method allowed us to rapidly investigate 96 different reaction conditions. We used “mass balance” as a criterion for retaining only those reaction conditions in which we could account for between 75 and 120% of the starting material amount. The major source of excess or shortfall in mass balance stemmed from the occasional formation of side products that were not accounted for, or from the work-up step and the carry-over of the highly UV-absorbing Co-containing impurities from the aqueous phase. For this analytical method, the replicability was moderately satisfactory, with an average variation between determined yields of 28% between replicates (best for o-BPP, 14%, and worst for phenylpyrroline, 39%).

Figure 7.

Optimization of reaction conditions required accurate determination of concentrations of all products. (A) Structures of quantified compounds and their retention times. (B) High-performance liquid chromatography traces of standard mixtures at five different concentrations (0.3−5.0 mM) with a UV detector set to 254 or 220 nm. Compounds 2 and 7 do not have a strongly absorbing chromophore at 254 nm. (C) We determined the conversion factor between absorbance and concentration for each component from the range with linear dependence of absorbances on concentration as the slope of the line with forced zero crossing.

Each reaction condition was characterized by 19 different reaction parameters. These were either numerical (e.g., concentrations of starting materials, catalyst, reducing agent) or categorical (e.g., the identity of Lewis acid, solvent, the type of workup). From these parameters, we constructed a 96 × 19 array of reaction conditions, A, which consisted of experiments in rows and reaction parameters in columns (Figure 8A). We also constructed the 96 × 5 yield array, b, which contained the HPLC-determined yields (Figure 7) of five compounds derived from o-BPP. From these arrays, we wanted to quantify (determine the unknown matrix x) how much each parameter contributes to the yields of the five measured compounds. This can be accomplished by finding the pseudoinverse of the condition matrix and multiplying the yield matrix with it: x = (A^TA)⁻¹A^Tb. This procedure finds the best fit of parameters (19-dimensional space) against measured yields (96-dimensional space) in the least-squares, linear regression sense. This analysis (Figure 8B) showed that the concentration of o-BPP (parameter 1) negatively affects the yield of the anti-spiroindane pyrrolidine, 7 (thick blue line). Therefore, lower concentrations favor the product formation. Concentrations of decamethylcobaltocene (parameter 3) and catalyst (parameter 5) both positively affected the yield of product, and this effect was more pronounced for the catalyst Ni(COD)₂, as could be expected. The concentration of Ni(COD)₂ also positively impacts the yield of a major byproduct (2-ethylphenylpyrroline, 8, purple line), but to a lesser extent. The concentration of Lewis acid was not a significant contributor to any of the yields (parameter 4), and the reaction seemed equally insensitive to the concentration of the olefin electrophile (parameter 2) provided that at least a stoichiometric amount is present. Among categorical variables, the identity of the Lewis acid (BEt₃, parameter 11) had the most profound effect. Other electronically similar Lewis acids (AlMe₃ or AlEt₃) were not effective, and neither were dicyclohexylboron triflate, BF₃· Et₂O, nor tris(pentafluorophenyl)borane. Parameter 14, toluene as the identity of the solvent, was the best choice with respect to yield of 7.

Figure 8.

Quantifying the effect of reaction parameters on yields of five major products of the reaction. (A) Mathematical model for finding the pseudoinverse of a conditions matrix and how the unknown parameters relate the condition matrix to the yield matrix. (B) Plot of quantitative contributions of 18 reaction parameters (one was discarded in the analysis) on yields of five analytes. The yield of anti-spiroindane is higher if the overall concentration is kept low, if there is more catalyst, and reducing agent, and if triethylborane is the Lewis acid and toluene the solvent.

Unsurprisingly, one factor that emerged from the analysis is the detrimental effect of water on the reaction outcomes. Adding molecular sieves into solvents overnight and drying the starting materials [as solutions in dichloromethane (DCM)] minimized the protic quench of the arylnickel species. We ran these reactions in the inert atmosphere of the glovebox, but we did not see any difference in the outcome whether solvents themselves were rigorously degassed or not.

2.6. Scope and Mechanism.

We prepared several imine substrates to investigate the influence of substrate structure on the outcome of the reaction. We also varied the nature of the electrophilic coupling partner, which allowed us to establish the limitations of this method. Figure 9 shows several products we prepared successfully via this method together with the ones that resisted its direct application. The nature of the coupling partners has a profound effect on the reaction. Esters are favored, and either methyl (Figure 9, entries 7, 10, 11, and 13) or benzyl esters (Figure 9, entries 12 and 15) were successfully coupled. Besides acrylates, acrylonitrile reacted similarly (Figure 9, entries 9, and 14), while N,N-dimethyl acrylamide and methyl vinyl ketone did not react. Substitution at the reacting double bond has a major impact on the reaction: neither β- nor α-substitution is tolerated. Thus, neither crotonates nor cinnamates gave the product. Substitution on the aromatic portion with the electron-donating methoxy substituent at two different positions did not inhibit the reaction (Figure 9, entries 10 and 11). However, the presence of an electron-withdrawing fluoride led to no product formation. Tetrahydropyridine was a suitable reactant, but the secondary amine product was isolated in only 15% yield with benzylacrylate as the coupling partner (Figure 9, entry 15), and 28% with acrylonitrile (Figure 9, entry 14).

Figure 9.

Scope of the nickel-catalyzed tandem olefin coupling-imine addition. Isolated yields are shown for the compounds that were successfully synthesized. Whether aryl bromide or chloride was used as the reactant is indicated in the column heading. Products that were attempted but could not be prepared are shown in the rightmost gray area.

Notably, the outcome of the reaction is affected by a benzyl substituent. Exclusively, anti product is formed in 41% yield, but the quenching of the enolate prior to imine addition is also detected in significant amounts. Acyclic aldimine gave low yield under optimized reaction conditions (Figure 9, entry 13). This is partly explained by the instability of acyclic imine reactants. Sulfonylimines did not produce the expected products, and neither did the substrate that contained a free primary alcohol.

One significant attribute of this reaction is that the chloride substrates appear to give products in yields comparable (even slightly better) to more reactive bromides, even though the reactions took longer to reach completion (Figure 9, entries 7, 9, and 12).

Two plausible reaction mechanisms for this transformation are depicted in Figure 10.¹³ In both, the catalytic cycle is initiated by displacement of the labile COD ligand by two molecules of o-BPP. This ligand exchange (step a) places aryl bromide in proximity to Ni(0), which enables the facile oxidative addition to produce 16-electron species 2. In step b, 19-electron decamethylcobaltocene reduces the Ni−Br bond to produce cobaltocenium bromide and a 15-electron Ni(I) intermediate. Displacement of the pyrroline ligand by the π-ligating acrylate and tandem carbonickelation of the double bond produces species 4 in step c. Step d represents the enolate addition to imine and supports the syn stereochemistry of the cyclization observed in the absence of triethylborane. A second reduction of Ni(I) species 5 by a second equivalent of $\text{CoC}{\text{p}}_2^{\ast }$ regenerates Ni(0). The cobaltocenium amide exits the catalytic cycle and is quenched upon workup to produce the amine product and cobaltocenium hydroxide. The distinction in Scheme 2 is in the Ni(I)/Ni(III) step d, where π-complexed 8 undergoes 1,4-oxidative addition to produce 9. The second reduction now enables addition to the imine, and the reductive elimination of Ni(II) from 10 regenerates Ni(0) to commence the cycle anew together with 6, which is protio-quenched to 7 on workup.

Figure 10.

Plausible mechanisms for nickel-catalyzed tandem coupling-imine addition. Scheme 1 depicts the catalytic cycle where carbonickelation with Ni(I) is the key carbon−carbon bond-forming step, and Scheme 2 proposes Ni(I)/Ni(III) cycle. Steps are labeled in lower case italic letters, and intermediates are numbered in gray circles.

3. CONCLUSIONS

The development of synthetic methods (one reaction) and synthetic sequences (multiple reactions) expands the accessible chemical structure space, which in turn, and more importantly, expands chemical property space. Properties inscribed into structures of spiroindane pyrrolidines are responsible for the novel bioactivity we observed,¹ which is what motivated our research into better ways of preparing them. Regardless of the motivation, the rational approach we followed in developing this reaction stands in contrast to the purely empirical approaches more commonly taken. It relies on reducing the complexity of a multistep (but still “one-pot”) chemical reactions into its more elementary steps, quantitative measurements, of reaction parameters and product yields, and on building models based on these measurements. Fundamentals of chemical theory, in combination with the powerful mathematical apparatus of chemometrics and matrix methods, enable the creation of robust models, which can aid our understanding of complex phenomena such as chemical reactivity. In practice, the reaction described in this manuscript provides a more streamlined access to spiroindane pyrrolidines and indanyl amines, and it lays the foundation for further research into the effect of ligands on diastereo- and enantioselective syntheses. Electron paramagnetic resonance (EPR) studies of key intermediates, cyclic voltammetry-based experiments, and electroanalytic measurements are forthcoming together with the electrosynthetic alternatives to decamethylcobaltocene, and will be disclosed in due course.