Breaking the tert-Butyllithium Contact Ion Pair: A Gateway to Alternate Selectivity in Lithiation Reactions

Abstract

The effects of Lewis basic phosphoramides on the aggregate structure of t-BuLi have been investigated in detail by NMR and DFT methods. It was determined that hexamethylphosphoramide (HMPA) can shift the equilibrium of t-BuLi to include the triple ion pair (t-Bu–Li–t-Bu)⁻/HMPA₄Li⁺ which serves as a reservoir for the highly reactive separated ion pair t-Bu⁻/HMPA₄Li⁺. Because the Li-atom’s valences are saturated in this ion pair, the Lewis acidity is significantly decreased; in turn, the basicity is maximized which allowed for the typical directing effects within oxygen heterocycles to be overridden and for remote sp³ C–H bonds to be deprotonated. Furthermore, these newly accessed lithium aggregation states were leveraged to develop a simple γ-lithiation and capture protocol of chromane heterocycles with a variety of alkyl halide electrophiles in good yields.

Graphical Abstract

1. INTRODUCTION

The widespread application of organolithium reagents can be ascribed to their innate ability to predictably transform organic substrates into organolithium compounds, priming them to be further functionalized.^1,2 Throughout the evolution of these lithiation-substitution sequences, the generality of this approach has been well demonstrated for substrates that incorporate Lewis basic (directing) or anion stabilizing subunits.³ For example, directed α-lithiations of heterocycles emerged as a critical strategy for the synthesis of building blocks in drug discovery (Figure 1A).⁴Despite these achievements, the strong coordinating ability of the Li-ion with Lewis basic directing groups has precluded remote positions in heterocycles from being functionalized, which is a significant limitation.

Figure 1.

(A) Directed ortho lithiation strategies and applications in synthesis. (B) Traditional lithiation site selectivity of chromane heterocycles. (C) This work-breaking the carbon lithium bond to alter lithiation site selectivity in oxygen heterocycles.

Although there are numerous illustrations of employing Lewis basic ligands to switch from one directing group to another, very few lithiation reactions are able to suppress embedded heteroatoms altogether and activate weakly acidic positions.⁵ As part of our efforts to identify new avenues to synthesize organometallics, we sought to develop a lithiation protocol that could bypass precoordination of the Li-ion with oxygen heterocycles and allow for remote positions to be deprotonated through a direct bimolecular acid base reaction. In particular, chromanes and tetrahydrobenzoxepines, which are popular cores in pharmaceuticals, remain challenging to selectively functionalize at the benzylic position because the Lewis basic O atoms direct and control the site of functionalization (Figure 1B).^6,7

In this article, we describe a new scheme for lithiation reactions based on the concept of ion-pairing (Figure 1C). Specifically, we have found that Lewis basic phosphoramides can shift the equilibrium of strong organolithium reagents, such as t-BuLi, to include triple ion pairs (TIP) and separated ion pairs (SIP).⁸ In this system the Li-atom’s valences are saturated (L₄Li⁺//R⁻) which hinders coordination to heteroatoms and, in turn, allows for remote benzylic C–H bonds to be selectively lithiated. For example, the benzylic site of chromane can now be lithiated and trapped in preference to traditional ortho-aromatic sites. Moreover, the decreased Lewis acidity of the saturated Li-atom (L₄Li⁺) combined with the enhanced nucleophilicity of the newly formed benzylchromane anion allows for primary and secondary alkyl halide electrophiles bearing functional groups, such as epoxides, to be well tolerated.

2. BACKGROUND

A growing body of experimental and theoretical investigations on organolithium reagents have shown that Lewis bases, such as tetramethylethylenediamine (TMEDA) or hexamethylphosphoramide (HMPA),⁹ can lead to drastic changes in reactivity,¹⁰ regioselectivity,¹¹ and stereoselectivity¹² by shifting the aggregate–aggregate exchange equilibrium to include lower aggregation states. At the extreme end, contact ion pairs (CIP) have been shown to convert into triple ion pairs (TIP) and even into separated ion pairs (SIP) (Figure 2A).¹³ For instance, Reich demonstrated that additions of HMPA to various organolithium reagents bearing anion stabilizing groups such as dithiosubstituted 1,¹⁴ 2,¹⁵ or 3⁹ allowed for the conversion of CIP into TIP as well as SIP. Importantly, these mechanistic insights revealed that the regioselectivity of lithium dithiane additions to enones was a function of the ion pair structure, where the CIP (absence of HMPA) with an intact C–Li bond give 1,2-addition through a four-centered transition state, i.e., “induced proximity”, and the SIP (presence of HMPA) give predominantly 1,4-addition via an open transition state (Figure 2B).^9c Although this model system clearly indicated that CIP and SIP exhibit unique reactivity patterns and is likely to apply to similar organolithium compounds, it is difficult to predict if strong organolithium bases, such as t-BuLi, have access to appreciable concentrations of TIP and SIP under standard reaction conditions. In this context the ability to perform a similar aggregate structure–activity relationship study with t-BuLi to determine if the SIP t-Bu⁻/L₄Li⁺ can be accessed and used to bypass directing groups for the lithiation of chromane heterocycles at the benzylic position would be ideal; however, the high reactivity of the t-BuLi CIP and predicted higher reactivity of TIP and SIP make their observation difficult in practice.

Figure 2.

(A) Generation of triple ion pairs and separated ion pairs from alkyllithium reagents using Lewis bases. (B) Altered reactivity observed between CIP and SIP in enone additions.

3. GOALS OF STUDY

The central goal of this project is to determine if Lewis bases, such as phosphoramides, can shift the equilibrium of strong organolithium reagents to include separated ion pairs and in turn allow for common directing effects within oxygen heterocycles to be overridden. While there are numerous examples of stabilized organolithium reagents converting into SIP as described above, there are no known literature reports that describe TIP or SIP with unstabilized organolithium reagents such as t-BuLi.¹⁶ We suspect that this is because TIP and SIP are likely present in only trace amounts and are too reactive for detection by routine spectroscopic methods. Our laboratory specializes in rapid-injection NMR (RI-NMR) spectroscopy which provides us the unique avenue to investigate these highly reactive chemical processes.¹⁷ The major advantage of RI-NMR over other physical techniques is that the reaction is performed inside the NMR spectrometer, allowing for structural and kinetic data to be directly linked. Specific goals of this study include (1) investigating if t-BuLi/Lewis base combinations can override the directing effects in common oxygen heterocycles allowing for remote sp³ C–H bonds to be selectively lithiated and functionalized, (2) harnessing any new found reactivity by developing a general method to functionalize remote positions in oxygen heterocycles, (3) fully characterizing the active aggregate structures of t-BuLi in the presence of Lewis bases, and (4) quantum mechanical simulation of the metalation process by computational modeling.

4. RESULTS

4.1. Lithiation of Oxygen Heterocycles: Effect of Phosphoramides on Chemoselectivity.

4.1.1. Preliminary Reactions of Tetrahydrofuran with Organolithiums and Phosphoramides.

Tetrahydrofuran (THF) has proven to be a particularly useful solvent for lithiation reactions due to its ability to deaggregate organolithiums which often leads to extreme enhancements (and on occasion decreases) in the reactivity.¹⁰ However, THF is also susceptible to lithiation with organolithiums, especially at higher temperatures.¹⁸ Typically, THF is lithiated alpha to oxygen which is then followed by a rapid reverse [3 + 2] cycloaddition yielding lithium enolate 5 and ethylene 6 (Figure 3A).¹⁹ Recent investigations of substituted tetrahydrofurans have revealed a dependence on the solvent medium and metalating agent for the reverse [3 + 2] rate.²⁰ In contrast, Clayden found that in the presence of HMPA, an alternate fragmentation product 8 could be obtained (Figure 3B).²¹ We wondered if these results indicated that the site selectivity for the lithiation of THF had been altered to favor a β-lithiation pathway (Figure 3C).²² While it is possible that this alternative lithiation product 7 could be formed through lithiation alpha to oxygen followed by carbene formation and a 1,2 hydride shift, another likely mechanism would proceed through a direct β-metalation and subsequent anti-Baldwin elimination pathway.²³

Figure 3.

Altered site selectivity for THF lithiation. (A) α-Lithiation and fragmentation of THF. (B) Clayden observed alternate fragmentation products using HMPA. (C) Proposed mechanism for the formation of 7. (D) Preliminary results for lithiation and trapping of THF-d₄.

To determine if lithiation was occurring directly at the β-position, THF isotopomer THF-d₄ was subjected to t-BuLi and 6.0 equiv of trispyrrolidinephosphoramide (TPPA); TPPA is a nonmutagenic alternative to HMPA and exhibits nearly identical reactivity patterns to HMPA (Figure 3D).^24,25 The only product that could be detected by high resolution electrospray ionization mass spectrometry (HR-ESI-MS) after trapping with benzoyl chloride was 11-d₃. This result strongly suggests that lithiation is taking place directly at the β-position and that the heteroatom within the THF substrate was no longer binding the Li-ion. Importantly, this represents a rare example of selectively removing a stronger C–H bond in the presence of weaker ones.²⁶

4.1.2. Exploring Site Selectivity of Lithiation with Oxygen Heterocycles and t-BuLi/Phosphoramides.

Given the ability to override the typical directing effects imparted by the oxygen atom within THF, other saturated oxygen heterocycles were evaluated to determine if the unique site selectivity for lithiation could be generalized (Figure 4 and Tables S3–S9). To investigate this possibility, oxygen heterocycles 12–18 were subjected independently to t-BuLi in the presence and absence of phosphoramides as well as to other standard metalation conditions for comparison (Figure 4 and Tables S3–S9).²⁷ It became apparent that the product distribution derived by the addition of phosphoramides was selective for the benzylic position whereas the parent alkyl lithium reagent resulted in exclusive ortho-methylation in all cases. For example, addition of t-BuLi to a mixture of chromane 12 and TPPA followed by the addition of methyl iodide was cleanly methylated at the benzylic position. Furthermore, when compared to Schlosser’s base (t-BuLi/KO-t-Bu),^5b the t-BuLi/phosphoramide combination proved to be much more selective for the benzylic position. To further highlight the high degree of selectivity, methyl chromane 13 was evaluated under the same conditions indicating that similar functional groups could be differentiated.

Figure 4.

Site selectivity in the metalation of oxygen heterocycles. ^aYields determined by NMR relative to a trimethoxybenzene internal standard. ^bOxygen heterocycle (1.0 equiv) treated with t-BuLi (1.0 equiv) at −78 °C and then warmed to rt for 1 h before cooling to −78 °C and adding MeI (1.1 equiv). ^cOxygen heterocycle (1.0 equiv) treated with ligand and t-BuLi (1.0 equiv) at −78 °C for 10 min before adding MeI (1.1 equiv). ^dOxygen heterocycle (1.0 equiv) treated with ligand and n-BuLi (1.0) at at −78 °C for 1 h before adding MeI (1.1 equiv). ^eOxygen heterocycle (1.0 equiv) treated with ligand and n-BuLi (1.0) at at −78 °C for 10 min before adding MeI (1.1 equiv).

Although there are many examples of switching from one directing group to another under metalation conditions by employing various Lewis basic ligands, few protocols are able to selectively suppress the directing effects of multiple heteroatoms.^5a Therefore, we sought to evaluate the selectivity on a variety of chromane cores bearing additional heteroatomic groups to determine if they could also be overridden. Piperidine (14), fluoro (15), and chloro (16) substituted chromanes were selected and evaluated under the same conditions; vide infra (Figure 4). It became apparent that the product distribution derived by the addition of phosphoramides was complementary to the parent alkyllithium in all cases. Although Schlosser’s base exhibited very little site selectivity with 14 or 15, it was selective for ortho-metalation in 16.^5b

We next turned our attention toward other oxygen heterocycles to determine if the selectivity was unique to the chromane core. Benzoxepin 17 provided the 5-methyl product in excellent selectivity with the t-BuLi/phosphoramide combination. Interestingly, Schlosser’s base becomes more selective for ortho-metalation with 17 in comparison to 12. Moreover, oxane 18, a nonbenzofused system, was cleanly methylated at the benzylic site whereas neither t-BuLi or Schlosser’s base reacted.

Significantly, these results combined demonstrate that heteroatomic directing groups can be overridden and benzyl anions can be generated and captured within oxygen heterocycles. More explicitly, the direct synthesis of benzyl anions within oxygen heterocycles provides a powerful synthon in creating pharmaceutically relevant structures.²⁸ Accordingly, the focus of our investigations switched to determine the generality of this protocol by investigating the functional group compatibilities of the chromane substructure and alkyl halide coupling partners.

4.1.3. Lithiation and Alkylation of Chromanes at the Benzylic Position with Alkyl Halides.

The development of new methods for the construction of sp³–sp³ carbon–carbon bonds is of paramount importance. Lithiation-substitution sequences mirror contemporary transition metal catalyzed cross-coupling methodologies but are not as susceptible to detrimental isomerization or β-hydride elimination pathways (Figure 5).²⁹ After a brief optimization, chromane 12 was found to undergo alkylation at the 4-position with 1-bromooctane using 2.0 equiv of HMPA and 1.2 equiv of t-BuLi (Figure 5; Table S10). In addition, TPPA and HMPA were found to behave similarly in all cases (Table S10). This is particularly attractive in a practical sense as HMPA can then be replaced with nonmutagenic alternatives in applications that require it on larger scales.²⁵ Interestingly, t-BuLi/DMPU was found to provide the same site-selectivity as the t-BuLi/phosphoramide combination though the yields were inferior.³⁰

Figure 5.

Scope of the chromane γ-alkylation. Standard reactions conditions were carried out on 0.5 mmol scale employing 2.0 equiv of (a) HMPA or (b) TPPA. Yields reported are isolated yields of spectroscopically pure product and are an average of two runs. (c) DMPU was used in place of HMPA or TPPA, and NMR yields are provided. (d) Single run experiment. (e) Product contains ∼5% of an inseparable aromatic alkylated isomer. (f) 6.0 equiv of HMPA employed in the reaction with no annealing period.

With optimized reaction conditions in hand, primary alkyl halides were explored first; 1-bromooctane was found to furnish the product 19 in excellent yields. Likewise, methyl iodide was found to be similarly as effective to 19, providing yet another avenue to install methyl groups at unique locations which have great pharmaceutical significance.³¹ Furthermore, protected oxygen functionality was also found to provide the alkylated products 21, 22, and 23 in moderate to good yield. Of note, epichlorohydrin was also found to provide the product 24 in synthetically useful yields.

To further demonstrate the functional group compatibility, a selection of heterocycle containing electrophiles were then evaluated. Indole (25) and piperazine (26) substrates provided the product in good to excellent yields showcasing the ability to incorporate nitrogen heterocycles of broad pharmaceutical relevance.³² Quinone (27) and thiophene (28) substrates provided the corresponding trapped products in slightly reduced but synthetically useful yields presumably due to competitive lithiation of the more acidic protons in these scaffolds.

Next, a set of secondary alkyl halides were evaluated as shown in Figure 5. Five (29), six (30), and seven (31) membered bromocarbocycles all provided the alkylated products in moderate to good yields. Cyclopropyl bromide (32) resulted in no product formation presumably due to the large amount of I-strain associated with the transition state during substitution³³ Furthermore, oxacycles (33) and (34) also provided good yields of the desired alkylation products. Finally, acyclic secondary bromide (35) provided the product in suitable yields albeit with low diastereoselectivity. The ability to couple two secondary sp³ hybridized carbons is particularly attractive for the formation of three-dimensional products that are required for many pharmaceutical applications.³⁴

To complement the electrophile scope, substituted chromane heterocycles were also evaluated (Figure 5). Methyl chromane 36 was found to be alkylated exclusively at the benzylic position within the ring, and no competing side chain alkylation was observed.³⁵ Fluorinated and chlorinated chromanes 37 and 38 were found to provide the trapped products in good to excellent yields. Interestingly, brominated chromane 39 could also be trapped, albeit in low yields as a result of competition with lithium halogen exchange. Lithium–halogen exchange is known to be one of the fastest chemical processes for organolithium reagents and can be competitive with proton transfer from an acidic substrate.³⁶ The ability to detect any of the desired product 39 from the aryl bromide further highlights the speed of the lithiation (see section 4.2.1). Evaluation of the trapping of biaryl 40 resulted in slightly reduced yield but with exclusive selectivity for the benzylic position which highlights the ability to maintain selectivity in the presence of other ortho-directing aryl ethers. Piperidine functionalized chromane 41 also provided the product in excellent yields, showcasing the ability to override the influence of nitrogen directing groups as well. Furthermore, a fused pyridine heterocycle 42 was also tolerated under these conditions demonstrating how this method could be amenable to more complex product synthesis. The ability of phosphoramides to completely override the directing group present in each of these substrates clearly demonstrates the level of control the active lithium aggregate has on site selectivity. Therefore, the next phase of our investigations focused on determining the active lithiation species.

4.2. Effect of Phosphoramides on the Organolithium Aggregate Structure: An NMR and DFT Study.

Before embarking on an in-depth mechanistic analysis into the effects of phosphoramides on the t-BuLi aggregate structure, a critical aspect of the mechanism needed to be clarified. To rule out the possibility of a lithiated phosphoramide serving as the base or an anionic intermediate, HMPA isotopomer HMPA-d₁₈ was subjected under the standard lithiation conditions with chromane 12.³⁷ Under these conditions, only protic isobutene (44) could be detected by ¹H and ¹³C NMR spectroscopy, i.e., no deuterium exchange (Figures 6 and S34). This result strongly suggests that HMPA is coordinating the Li⁺ cation and not serving as a proton shuttle. Therefore, to better understand the origins for the observed site selectivity changes as described above, an in-depth NMR investigation into the aggregate structure of the active lithiation species was undertaken.

Figure 6.

No deuterium incorporation was observed when employing HMPA-d₁₈ and THF-d₈ under the standard reaction conditions.

Based on Reich’s previous studies, we hypothesized that the change in site selectivity in our system could be due to the formation of TIP or SIP. Such intermediates have never been observed with unstabilized alkyllithium reagents which is presumably due to their high reactivity.^9a Armed with our rapid-injection NMR (RI-NMR) apparatus, we set out to identify the active aggregation state at low temperature. Although the natural abundance ⁷Li isotope is observable by NMR spectroscopy, it possesses a large quadrupole moment as well as a 3/2 nuclear spin which often leads to line broadening and precludes the observation of J-couplings between nuclei (Figure S4). Therefore, to detect and gain structural information, the carbon–lithium bond requires the enrichment of both the quaternary carbon and Li-atom within the t-BuLi [((CH₃)₃¹³C–⁶Li] CIP-46.

The t-BuLi isotopomer 46 was effectively synthesized through reductive metalation using our newly developed ⁶Li-dendrites and ¹³C enriched (CH₃)₃¹³CCl 45 (Figure 7).³⁸To provide insight into the aggregate structure and composition of the active lithiation species formed by combining phosphoramides with t-BuLi, a series of ⁶Li, ³¹P, and ¹³C NMR spectroscopic experiments were performed by titrating HMPA (Reich’s method)^9a into solutions of doubly isotopically enriched CIP-46.

Figure 7.

(A) Preparation of ⁶Li enriched dendrites. (B) Synthesis of (CH₃)₃¹³C⁶Li using ⁶Li-dendrites and (CH₃)₃¹³CCl.

4.2.1. NMR Investigations on the Effect of HMPA on the t-BuLi Aggregate Structure.

Initial attempts to prepare samples of t-BuLi in the presence of HMPA at −80 °C resulted only in the formation of the THF elimination product 7 as described earlier (see section 4.1.1).^9a To overcome this limitation, t-BuLi samples for HMPA titrations were prepared at lower temperatures, −115 °C (Figure 8).³⁹ The ⁶Li spectrum of the t-BuLi isotopomer 46 consisted of a single doublet (J_Li–C = 12.9 Hz) at 1.03 ppm and was assigned as the monomeric contact ion pair structure CIP-46a.^9a Furthermore, only one signal at 17.20 ppm was observed in ¹³C NMR spectrum bearing the characteristic 1:1:1 triplet (J_C–Li = 13.1 Hz). Upon addition of 1.0 equiv of HMPA, CIP-46a was partially converted to a new monomeric contact ion pair t-BuLi-HMPA₁ CIP-46b that was observable in the ⁶Li and ¹³C NMR spectra. This structural assignment for CIP-46b was supported by the observation of small (J_Li–P = 3 Hz) scalar couplings between the ⁶Li and HMPA at −130 °C (Figure S13).⁴⁰

Figure 8.

HMPA-d₁₈ titration of (CH₃)₃¹³C⁶Li in 3:2 THF-d₈:Et₂O at −125 ° C at 0.1 M.

Upon addition of 2.0 equiv of HMPA, two new species appeared in the ⁶Li NMR spectrum in a 1:1 ratio (Figure 8). One species, at 2.7 ppm, is clearly resolved into a 1:2:1 triplet (J_Li–C = 12.1 Hz) which is consistent with the formation of (R–Li–R)⁻ as triple ion pair TIP-46. The second species appeared at −0.36 ppm and is resolved into a quintet (J_Li–P = 2.8 Hz) and is consistent with the formation of the (HMPA)₄Li⁺ counterion within the TIP-46. Likewise, in the ¹³C NMR spectrum, a new C–Li contact ion is formed as indicated by the appearance of a second 1:1:1 triplet (J_C–Li = 12.1 Hz). Combining the observations from the two spectra together is most consistent with the formation of the (t-Bu)₂Li⁻/L₄Li⁺ triple ion pair TIP-46.⁴¹ Furthermore, increasing the concentration of HMPA to 3.0 equiv increases the fraction of the t-BuLi CIP-46 that is sequestered in this triple ion pair TIP-46 from 9% to 15% further indicating that HMPA has a role in the formation of this aggregate.^42,43 Of note, upon increasing the amount of HMPA from 1 to 2 (or 3) equiv, the observed monomeric contact ion pair could not be detected as a distinct species t-BuLi-HMPA_X CIP-46a-d (X = a, 0; b, 1; c, 2; d, 3) even at −125 °C. This is presumably due to increased rates of exchange between bound and free HMPA. Results from our computations described below indicate that each addition of HMPA decreases the Lewis acidity of the Li-cation within CIP-46 and likely leads to the observed increased rates of exchange.

4.2.2. Thermochemical Calculations of the Effect of HMPA on the t-BuLi Aggregate Structure.

To gain further insight into the various aggregates formed during the titration of t-BuLi with HMPA, vide infra, dispersion-corrected DFT in THF using the CPCM implicit solvation model was used to calculate the ground-state energies (Figure 9). Starting from CIP-46a, the loss of a THF solvent molecule from CIP-46a and concomitant coordination of an HMPA molecule to form CIP-46b was predicted to be exergonic. Interestingly, upon each subsequent coordination of HMPA to CIP-46b resulted in a highly exergonic downward cascade leading to TIP-46. Upon inspection of complexation interaction energies, it became clear that each addition of HMPA was weakening the t-Bu···Li interaction and lowering the C–Li bond order (see Supporting Information Figure S91). Importantly, the Lewis acidity of the (HMPA)₄Li⁺ counterion within TIP-46 is greatly increased, and as a result, this decreases the ability for ligand dissociation to occur and serves as a thermodynamic sink for TIP-46.

Figure 9.

Calculated equilibria for t-BuLi titration with HMPA at −125 °C. See Supporting Information for equilibria calculations at −80 °C.

The goal of the NMR studies described above was to identify the aggregate responsible for the observed change in metalation site selectivity within oxygen heterocycles. Although several newfound aggregates, such as CIP-46b and TIP-46, were observable at low temperatures (−125 °C) where interaggregate exchange is slow, the high reactivity of these samples precluded investigation at higher temperatures (>−110 °C) where interaggregate exchange is presumably rapid. As a result, to gain further insight into the unique selectivity observed during the deprotonation step, a thorough computational investigation was undertaken to determine the active metalation aggregate and origins of selectivity (section 4.3).

4.2.3. Effect of HMPA on the Benzyl Anion in Chromane.

To probe the aggregate structure of the lithiated chromane 43, ¹H, ¹³C, ⁷Li, and ³¹P NMR experiments were carried out. See Supporting Information for full details. Following Reich’s titration protocols, the ⁷Li NMR spectrum displayed a single signal that is resolved into a quintet (J_Li–P = 7.8 Hz) (Figure 10A). Furthermore, the P NMR spectrum displayed at least two new signals at (26.88 ppm, J_P–Li = 7.8 Hz) and (26.74 ppm, J_P–Li = 9.1 Hz) with resolved J-couplings (Figure 10A). The most consistent interpretation of these spectra is the formation of the (HMPA)₄Li⁺ and (HMPA)₃Li⁺ cations. Interestingly, the ¹³C NMR indicates a significant loss in aromaticity of the lithiated chromane intermediate 43 as seen by the significant upfield shifts of nearly all aromatic signals. The benzylic carbon moved from 27.9 to 58.9 ppm (Δ(¹³C) – 31 ppm) suggesting significant delocalization of anionic character into the aromatic ring. The combined NMR spectra are most consistent with the assignment of the lithiated chromane as SIP-43 in the presence of 6.0 equiv of HMPA (Figure 10A).

Figure 10.

(A) ⁷Li and ³¹P NMR spectra of lithiated chromane in THF-d₈ at −115 °C. (B) ¹H NMR spectra (RI-NMR) array of the injection of 1-bromooctane into the lithiated chromane in THF-d₈ at −80 °C. The injection of substrate was performed at the 2 s time point.

Using our rapid-injection NMR (RI-NMR) apparatus,^17d the nucleophilicity under standard reaction conditions of the SIP-43 was evaluated by injecting 1-bromooctane at −80 °C (Figure 10B). Although it was not possible to obtain an exact rate for the alkylation of SIP-43, it was fully consumed in less than a single scan (<1 s at −80 °C), highlighting the tremendous reactivity of the SIP in solution.

4.3. Computational Analysis of the Reaction Profile for Deprotonation with Phosphoramides: Benzylic Site Selectivity Explained.

Based on our empirical and NMR studies, there are three plausible scenarios that explain the role of phosphoramides in alternating the site selectivity (ortho vs benzyl) during the deprotonation event with the substrates described in section 4.1.1 (Figure 11). Therefore, to gain further insight into the deprotonation step, computational investigations were undertaken as detailed below. To facilitate our discussions, chromane 12 was chosen as a representative substrate in the calculations. For completeness, energy profiles (ground states, transition states, and products) for the metalation event for both ortho (TS-O) and benzyl (TS-B) positions of 12 were calculated using the dispersion-corrected DFT in tetrahydrofuran as solvent using the CPCM solvent model (see Supporting Information for full computational details; Figure 12).^44–47 This level of theory has been used previously in the characterization of methyllithium and tert-butyllithium oligomers.^45d All structural figures were generated with CYLview.⁴⁸

Figure 11.

Possible lithiation scenarios using chromane as an example substrate.

Figure 12.

(A) Comparison of energy profiles for the deprotonation step: ortho vs benzyl. (B) Transition-state structure CIP-46a-TS-O for directed ortho lithiation (no HMPA). (C) Transition-state structure SIP-46-TS-B for undirected benzyl lithiation (with HMPA).

We posit the following three scenarios: (1) a contact ion pair bearing HMPA ligands (CIP-46b, CIP-46c, or CIP-46d) is the active metalating species and is too sterically hindered to be influenced by directing effects, (2) TIP-46 has significantly reduced Lewis-acidity due to the steric bulk and donating nature of the ligands which both increases its basicity and prevents directing effects, or (3) TIP-46 serves as a reservoir for SIP-46 that, by lacking lithium, is not influenced by directing effects.

4.3.1. Scenario 1: Comparison of Energy Profiles for Metalation of Chromane with tert-Butyl Lithium Contact Ion Pairs.

The energy profiles (i.e., ortho vs benzyl selectivity) employing CIP-46a (no HMPA) are summarized in Figure 12. The activation energies for H-atom extraction for CIP-46a-TS-O and CIP-46a-TS-B are 16.4 and 18.6 kcal/mol, respectively, clearly reflecting a notable activation energy difference of 2.2 kcal/mol in favor of the ortho position. The next series employing a single HMPA molecule CIP-46b-TS-O (16.7 kcal/mol) vs CIP-46b-TS-B (20.7 kcal/mol) also favored the ortho pathway by 4.0 kcal/mol (Figure 12). The greater activation barrier for CIP-46b-TS-B over CIP-46b-TS-O can be attributed to higher distortion energy of the t-Bu fragment during the removal of the proton (see Supporting Information for further details). In addition, activation energies for proton removal for CIP-46c-TS-O and CIP-46c-TS-B (2 HMPA) are nearly identical at 12.6 and 13.2 kcal/mol, respectively, clearly predicting only a slight preference for the ortho position.

Upon inspection of energy profiles employing CIP-46d bearing three HMPA molecules, it becomes clear that the chromane 12 substrate can no longer bind the Li-cation, and as a result, the bimolecular proton extraction processes did not result in a realistic comparison to the other contact ion pairs described above. Because the three HMPA ligands are sterically demanding within CIP46d, the carbon–lithium bond distance became elongated (4.9 Å) during proton extraction and a result was reminiscent of the separated ion pair activation pathways described below (section 4.3.3). Combining our empirical, NMR and DFT mechanistic studies suggest that a contact ion pair ligated by HMPA is not responsible for the observed change in site selectivity.

4.3.2. Scenario 2: Comparison of Energy Profiles for Metalation of Chromane with Triple Ion TIP-53.

The second possibility also seems unlikely based on the energies of transition states TIP-46-TS-O and TIP-46-TS-B for proton extraction which are 17.2 and 18.0 kcal/mol, respectively. In this series the ortho position is slightly favored by 0.8 kcal/mol indicating that the process would favor the ortho position and likely to be unselective if TIP-46 were the dominant species. These combined observations lead us to investigate the possibility whereby TIP-46 dissociates into SIP-46 and monomeric CIP-46. Unfortunately, SIP-46 was completely undetectable during any of the HMPA NMR titrations carried out in this study. This is likely due to the high reactivity of this aggregate such that any SIP-46 generated reacts immediately, i.e., Curtin–Hammett conditions. Under such a scenario, the small amount of SIP-46 generated at any given time would be reacting under large excess of all possible substrates and provides a possible pathway for the observed site selectivity for the benzyl position.

4.3.3. Scenario 3: Comparison of Energy Profiles for Metalation of Chromane with Separated Ion Pair SIP-53.

In fact, the computed transition states for SIP-46-TS-O and SIP-46-TS-B were 11.3 and 6.9 kcal/mol, respectively, indicating that the benzylic position was predicted to be favored over the ortho position by 4.4 kcal/mol. The origin for the observed change in selectivity is the net result of the inability for the saturated (HMPA)₄Li⁺ cation to bind the oxygen atom within chromane 12 which does not allow for the t-Bu⁻ anion to be directed. Combining our results with the fact that SIP are known to be 10 orders of magnitude more reactive than TIP, as described by Reich et al.,⁴⁹ suggests that TIP-46 is the ground state complex and that SIP-46 is the active aggregate responsible for lithiation.

Of note, if an HMPA within the (HMPA)₄Li⁺ cation in SIP-46 were exchanged with the chromane 12 substrate, it would open an avenue for a Lewis acid catalyzed pathway (Figure 13). This effect is 2-fold: (1) it sterically shields the ortho position and (2) acidifies the benzyl position. Importantly, this Lewis acid catalyzed pathway raised the SIP-46-TS-O-CAT and lowered the SIP-46-TS-B-CAT to 13.3 and 5.5, respectively (Figure 13). Although the Lewis acid catalyzed pathway is predicted to have a lower barrier, we suspect that HMPA is likely inhibiting this pathway to some extent. Thus, the active species is likely a separated ion pair that proceeds through a combination of these two pathways. Our combined observations indicate that separated ion pairs are accessible with strong organolithiums and can serve as reactive intermediates.

Figure 13.

Comparison of energy profiles for the deprotonation step with separated ion pairs: Lewis acid vs non-Lewis acid catalyzed pathways.

5. SUMMARY

5.1. Observed Trends in Lithiation Site Selectivity.

It is clear from the earlier studies that the addition of phosphoramides changes the lithiation site selectivity for THF and other oxygen heterocycles. Because the oxygen atom within THF is electron withdrawing, the α hydrogen is known to be more acidic over the β hydrogen, indicating that pK_a values alone cannot explain the observed site selectivities for all the substrates surveyed.^20b,50 Thus, the selectivity for proton removal is likely the result of the summation of the localized steric, electronic, and stereoelectronic properties about each hydrogen atom. Since deprotonations of alkanes often exhibit late transition states, it is conceivable that small differences in the environments about the hydrogen atoms can lead to drastic changes in selectivity.⁵¹

This selectivity is best contextualized by revisiting the lithiation of some of the oxygen heterocycles presented earlier (Figure 14). In each of these substrates, there is at least one other site that is activated for alkylation. In chromane 12 for example, the ortho-aromatic site is activated for metalation in the absence of added ligands. Schlosser’s base is unable to overcome this activation and provides the methylated products as a mixture. By contrast, the t-BuLi/phosphoramide combination is able to completely override this directing effect. This is further demonstrated by examining chromanes that bear additional directing groups (14–16). Piperidine chromane 14 provides a product distribution that is similar to chromane under all examined conditions.⁵² Furthermore, the results with Schlosser’s base indicate that the site ortho to nitrogen is accessible though not favored, presumably due to the lower inductive withdrawing capability of nitrogen compared to oxygen. Metalation of fluorochromane 15 using the t-BuLi/phosphoramide combination demonstrates that the site selectivity is relatively insensitive to increased acidity in other positions on the substrate, whereas unassisted metalation results in selectivity ortho to oxygen, and Schlosser’s base results in metalation ortho to fluorine as it is more inductively withdrawing. Chlorochromane 16 on the other hand displays complete selectivity for the position ortho to oxygen with both t-BuLi and Schlosser’s base. This result falls directly in line with the trends summarized by Gschwend and Rodriguez⁵³ where Cl is an inferior ortho-director to OMe but a superior meta-director. These two features combined favor the observed site selectivity in directed metalation systems. The t-BuLi/phosphoramide combination is able to overcome this double directing effect and shows excellent selectivity for benzylic metalation. With each additional directing group surveyed, it becomes clear how sensitive standard metalating conditions are to the precise substitution of the substrate. By comparison, the t-BuLi/phosphoramide combination is relatively insensitive to the functionalization on the substrate. This is further demonstrated by examining benzoxepine 17. Despite what would appear to be a simple ring expansion, a strong change in selectivity is observed for Schlosser’s base while the t-BuLi/phosphoramide combination maintains exclusive selectivity for the benzylic position. Finally, metalation/trapping of oxane 18 is only possible through the t-BuLi/phosphoramide combination which would suggest that the mechanism for activation of the alkyllithium reagent must be unique to this combination. These results combined demonstrate the unique capability of the t-BuLi/phosphoramide system to override directing effects and enable the remote functionalization of oxygen heterocycles.

Figure 14.

Substrates that undergo selective benzylic lithiation.

5.2. Enhanced Functional Group Compatibility During Capturing Step.

While the change in site selectivity was the primary motivation of the study, it is worth commenting on the fact that the lithiated chromanes are far more nucleophilic than has been previously reported for similar organometallic reagents. Numerous reports throughout the past decades have detailed the direct alkylation of activated alkyl halide electrophiles with a variety of organolithium,⁵⁴ organosodium,⁵⁵ and organopotassium reagents.⁵⁶ Many of these reactions use catalytic or stoichiometric copper additives to further expand the scope of the transformation to less activated electrophiles. In this context, the direct trapping of secondary alkyl bromides from the SIP presented here is a significant departure from the current synthetic usage of alkyllithium reagents. Typically, to enable the coupling with unactivated secondary electrophiles, transmetalation to another organometallic is required to be compatible with modern cross-coupling methods. Considering this synthetic advantage, it is worth considering the exact cause for the increased reactivity. To understand a possible origin of the reactivity, it is worth contemplating two possible scenarios: alkylation from a CIP and alkylation from a SIP (Figure 15). Alkylation that proceeds from a CIP reagent generally requires the formation of a product-separated ion pair as described by Cram et al. (Figure 15A).⁵⁷ This separated ion pair must then reorganize to generate the CIP salt byproduct. Alternatively, if the lithium reagent starts as a separated ion pair, the lithium ion can be positioned such that during the capture step, a CIP can be formed immediately with minimal reorganization thus lowering the overall barrier of the transformation (Figure 15B).

Figure 15.

(A) Reaction pathway from CIP species. (B) Reaction pathway from SIP species.

The ability to trap secondary electrophiles with the SIP was unexpected as the direct trapping of secondary lithium reagents with unactivated secondary halides has not previously been reported. This result is likely indicative of the highly nucleophilic nature of benzylic anions and has not been exploited previously simply because the preparation of benzyl lithium reagents is challenging. The methods that are reliable often generate a stoichiometric alkoxide or sulfide byproduct that interferes with electrophile trapping.^6a,58 Regardless of the origin of the reactivity, the good yields observed with secondary electrophiles further emphasize how the enhanced nucleophilicity of separated anions can be leveraged for new reactivity to compliment other carbon–carbon bond forming reactions.⁵⁹

6. CONCLUSIONS

Given the long history and success of lithiation reactions, these initial observations of TIP generated from highly basic and localized organolithium reagents have confirmed that such species exist in the presence of sufficiently donating ligands. The ability to override the directing ability of embedded heteroatoms using the alternate aggregate structure provides a powerful entry point for the alkylation of oxygen heterocycles. Furthermore, it has been established that the highly nucleophilic SIP generated display tremendous reactivity toward alkyl electrophiles which challenges the traditional notions of carbon–carbon bond formation from organometallic reagents. The investigation and elucidation of the active lithium aggregates were crucial to understanding the origins of this reactivity and have the potential to reshape our approach to the lithiation of weakly acidic C–H bonds.