Synthesis of Tetrakis(amino)ethylene-Derived Organic Reductants via Thermal Decomposition of Tris(amino)methanes

Abstract

Tetrakis­(amino)­ethylene (TAE)-based reductants are valuable in organic transformations, such as cross-electrophile coupling, but are not widely utilized due to their high cost and complicated syntheses. Here, we report the one-pot synthesis of TAE-derived organic reductants via thermal decomposition of tris­(amino)­methanes. Specifically, the neat reaction of N,N-dimethylformamide dimethylacetal (DMF-DMA) with pyrrolidine or piperidine generates tetrakis­(pyrrolidino)­ethylene (TPyE) or tetrakis­(piperidino)­ethylene (TPiE) in one pot through the in situ generation of a tris­(amino)­methane intermediate. The synthesis and thermal decomposition of other tris­(amino)­methanes were also investigated.

Reductants are critical to a wide variety of organic reactions because they can either directly reduce organic substrates or control the oxidation state of catalysts. Electrons are often introduced into organic reactions using metal-based heterogeneous reductants, such as Zn or Mn, or via strategies centered on electro- or photochemistry. Although these methods have many advantages, they can be difficult to scale. Reductants based on simple organic molecules are an attractive alternative because, in principle, they are easily scalable, and their reduction potential can be readily tuned by structural modification. This tunability can enable highly selective transformations with broad functional group tolerance.

Tetrakis­(amino)­ethylene (TAE)-derived organic reductants, such as tetrakis­(dimethylamino)­ethylene (TDAE, Figure a) and tetraazafulvalenes (TAF), facilitate a wide range of transformations, including radical and anionic cyclizations, benzylic substitutions, di/trifluoromethylations, and reductions of haloarenes. Unlike TAFs, which tend to dissociate and form stable N-heterocyclic carbenes that can poison transition metal catalysts, TDAE has proven effective in metal-mediated transformations, such as Ni-catalyzed cross-electrophile coupling. Nevertheless, despite the many advantages of TDAE, it has not widely been used because of its high cost, extreme air-sensitivity, and challenging synthesis.

1.

a) Examples of organic reductants based on TAE (reduction potentials measured in DMF (vs Fc/Fc⁺; Fc = ferrocene). b) Our previous synthetic route to TPyE, TPiE, and TME. c) This work: New syntheses of TPyE and TPiE were performed via tris­(amino)­methanes.

To expand the utility of organic reductants in metal-mediated transformations, we previously developed new TAE-derived reductants by modifying the amino groups on the TAE scaffold (Figure a). These reductants are solids under ambient conditions and often air-stable and consequently easier to handle than TDAE, which is a liquid at room temperature. The new reductants also exhibited reduction potentials spanning nearly 500 mV. Unfortunately, the broad use of these new reductants was limited by low-yielding and irreproducible multistep syntheses (yields could be four times lower than those reported) using relatively expensive starting materials and reagents. In particular, the final step involving the deprotonation and dimerization of substituted-amidinium salts, A, was problematic due to (i) the incompatibility of many of the reductants with LDA, which led to complex crude mixtures, and (ii) unidentified side reactions that produced multiple side products, complicating isolation of the desired product (Figure b). Herein, we report the large-scale one-pot syntheses of tetrakis­(pyrrolidino)­ethylene (TPyE) and tetrakis­(piperidino)­ethylene (TPiE) in relatively high yields via the formation and thermal decomposition of tris­(amino)­methane intermediates from inexpensive starting materials (Figure c). We further explore the thermal decomposition of other tris­(amino)­methanes to assess the generality of our approach.

Reisman and co-workers have previously described the bulk synthesis of TDAE via the thermal decomposition of tris­(dimethyl)­aminomethane. We hypothesized that thermal decomposition of the appropriate tris­(amino)­methane could be used to synthesize our reductants. Initially, we synthesized tris­(pyrrolidino)­methane (1) (Figure a) via a relatively cumbersome route involving the reaction of pyrrolidino-amidinium salt (see A, Figure b for a general depiction) with deprotonated pyrrolidine (see S2). Subsequent heating of 1 at 180 °C for 18 h resulted in thermal decomposition to TPyE in 59% yield (27% overall yield) after recrystallization (see Table S1). Although this result was promising, it did not represent a significant improvement over our previous synthesis of TPyE because the route to 1 was inefficient. Therefore, we sought alternative routes to obtain 1.

2.

One-pot syntheses of a) TPyE and b) TPiE from DMF-DMA (B) and pyrrolidine or piperidine, respectively.

It has been demonstrated that tris­(amino)­methanes can be accessed through the reactions of either N,N-dialkylformamide dialkyl acetals (compounds with the general formula R₂N-CH­(OMe)) or ortho-esters (compounds with the general formula RC­(OR)₃) with secondary amines. However, these reactions often generate a mixture of products containing mono-, bis-, and tris­(amino)­methanes, which are challenging to separate. Nevertheless, we postulated that the generation of 1 in situ, even as a mixture, may allow the formation of TPyE in high yields via thermal decomposition.

Reactions between pyrrolidine and trimethyl orthoformate (HC­(OMe)₃) or triethyl orthoformate (HC­(OEt)₃), respectively, required the presence of Brønsted acids to generate 1 in any significant yield (see Table S2). This is undesirable for a one-pot synthesis of TPyE, as TAE-derived reductants are basic. In contrast, reactions of N,N-dimethylformamide dimethyl acetal (DMF-DMA, Figure a, B) with pyrrolidine generated 1 without any acid. Further the reaction could be performed without any solvent. Continuous removal of MeOH using a Dean–Stark apparatus (identified by ¹H NMR spectroscopy) increased the rate of the reaction and provided a method to monitor conversion to 1 in real time.

We optimized the conditions to maximize the formation of 1 and settled on a procedure involving sequential heating at two different temperatures. Initially, due to the low boiling point of pyrrolidine (89 °C) and B (103 °C), the reaction was heated at 90 °C, before subsequent heating at 120 °C. Based on previous literature reports , and the collection of MeOH in the Dean–Stark apparatus, we propose that the reaction proceeds in a stepwise fashion with initial incorporation of pyrrolidine and loss of HNMe₂ to form intermediate C. Subsequently, C incorporates another equivalent of pyrrolidine and loses MeOH to form the 1,1′-(methoxymethylene)­dipyrrolidine (D), which is subsequently converted into 1 via the substitution of another equivalent of pyrrolidine. Consistent with this proposal, even after heating at 120 °C, the mixture contains both D and 1 in a 1:0.51 ratio (see S4) and 1 was never formed or isolated in a pure form from this reaction. Further, while tracking reaction progress, we did not observe C. Therefore, it is possible that 1 equiv of MeOH is lost before HNMe₂ rather than initial loss of HNMe₂ to form C.

Our inability to isolate 1 was not significant for the purpose of generating TPyE. When a mixture, containing 1 and D, was heated at 180 °C, conversion to TPyE was observed. Further after 16 h at 180 °C, TPyE was generated in high yield with no observable side products. The pyrrolidine that was formed in the thermal decomposition of 1 was collected in a Dean–Stark apparatus. Starting from B and pyrrolidine, we were able to generate TPyE in one pot via successive heating at three different temperatures, 90, 120, and 180 °C. Crude TPyE was purified via recrystallization from dry diethyl ether under an inert atmosphere, which resulted in an overall yield of 74% on a 20 g scale. The reaction was repeated on this scale three times with highly reproducible yields (±5%). Importantly, control experiments demonstrated that TPyE is stable at high temperatures (see S7).

The advantages of our new route compared to the previous method include (Figure b) the following: (i) The yield of TPyE is five times higher; (ii) the cost of the starting materials is significantly cheaper (<$1/gram versus $45/gram); (iii) no intermediates need to be isolated and all steps are performed in one pot; (iv) no solvent is required until the final purification; (v) it is reproducible.

Following the successful synthesis of TPyE, we modified the synthetic route to prepare TPiE (Figure c). This required reoptimization of the reaction conditions and a different purification procedure. For example, the second heating phase of the initial conversion of B and piperidine to form a mixture containing tris­(piperidino)­methane (2) and 1,1′-(methoxymethylene)­dipiperidine required heating at 130 °C instead of 120 °C for better conversion to 2. Further, the thermal decomposition of 2 to TPiE was more difficult than the decomposition of 1. In this case, heating at 230 °C was required. Similarly to TPyE synthesis, full conversion of B and piperidine to 2 did not occur after 3 h at 130 °C, but subsequent heating of the mixture to 230 °C resulted in efficient conversion to TPiE. However, 2 is isolable after heating B and piperidine at higher temperature (see Figure ), and subsequent heating of isolated 2 at 230 °C also gave TPiE. This strongly suggests that 2 is an intermediate in the one-pot preparation of TPiE from B and piperidine.

3.

Tris­(amino)­methane synthesis from DMF-DMA (B).

In the one-pot synthesis of TPiE, strict exclusion of water was essential to achieve a good yield, as moisture promotes formation of a formamide byproduct (see Scheme S2 for structures and the proposed mechanism). For instance, using piperidine, which had been exposed to ambient conditions for an extended period, resulted in significant formation of a formamide. Accordingly, piperidine was dried over KOH pellets or CaO prior to use, or anhydrous piperidine stored under inert atmosphere was utilized. Further, likely due to the elevated temperature required for TPiE synthesis, the reaction is sensitive to the size and shape of the reaction vessel, which are described in detail in the SI; see S6.

The purification of TPiE after thermal decomposition was challenging. Residual piperidine and trace byproducts, including colored impurities, impeded direct recrystallization efforts. Instead, a multistep purification strategy was used involving (i) initial organic extraction of crude TPiE using diethyl ether with basic water, (ii) washing of the organic layer with brine, (iii) a short flash column using basic alumina, and (iv) washing with acetone. Using this procedure, TPiE was generated in 52% yield, which was reproduced three times (±5% yield). Overall, the revised route affords substantial improvements in yield, cost, and scalability compared to previous methods. Disappointingly, implementing the new one-pot synthetic route with morpholine did not result in generation of TME (vide infra).

To gain more insight into the thermal decomposition of tris­(amino)­methanes and prepare new reductants, we explored the reaction of B with selected secondary cyclic amines (Figure ). We selected amines that were commercially available and relatively low cost, as these would be optimal for eventual reductant synthesis. Electron-withdrawing substituents at the 4-position of piperidine favored tris­(amino)­methane formation. Morpholine, thiomorpholine, and difluoropiperidine generated the corresponding tris­(amino)­methanes, 3, 4, and 5, respectively, at room temperature in good yields. In these reactions, the tris­(amino)­methanes precipitated from the reaction mixture (unlike 1) and filtration resulted in the isolation of pure material. A higher number of equivalents of amine were required for difluoropiperidine, presumably because it is a less reactive nucleophile. In all cases, it is important to dry the amines in these reactions to prevent the formation of a formamide-based byproduct.

For amines lacking highly electron-withdrawing groups, elevated temperatures were required to generate tris­(amino)­methanes. Given the boiling point of B is 103 °C, we utilized a procedure involving sequential heating at 90 °C, 120 °C, and 180 °C to avoid the loss of starting material. Using this procedure, the isolated tris­(amino)­methanes 2, 6, and 7 were generated in reasonable yields starting from piperidine, 4-trifluoromethylpiperidine, and indoline, respectively. The isolation of 2 is particularly notable, as it cannot be isolated as an intermediate in the one-pot synthesis of TPiE. A list of amines that we were unable to successfully use to form tris­(amino)­methane products is provided in the SI; see S8.

We initially studied the thermal decomposition of 3 to synthesize TME. Unfortunately, at elevated temperatures, it melts and then evaporates and deposits around the top of the flask before undergoing thermal decomposition. Consequently, there was negligible conversion to TME. Several different approaches, such as the addition of high-boiling solvents or substoichiometric amounts of acids, were employed to address this challenge but were unsuccessful (see Table S3). A slight improvement was observed when 3 was heated at 200 °C for 20 h in a pressure tube (bomb flask), which allowed the entire flask to be heated, preventing deposition (Figure ). This resulted in a 13% yield of TME, which is not an improvement in yield compared with our original synthesis (Figure b).

4.

a) Thermal decomposition of tris­(amino)­methanes in a pressure tube. b) Solid-state structure of T^fPiE with thermal ellipsoids at 50%. Hydrogen atoms have been omitted for clarity. Selected bond lengths (Å) and angles (deg): C(1)–C(1′) 1.357(3), N(1)–C(1) 1.405(2), N(2)–C(1) 1.405(2), N(1)–C(1)–N(2) 112.76(14), N(1)–C(1)–C(1′) 123.64 (10). The cyclic voltammogram of T^fPiE was recorded in DMF with 0.1 M TBAPF₆ as the supporting electrolyte at 100 mV/s. E° = −0.79 V, following the IUPAC convention.

The thermal decomposition of 5 suffered from the same deposition problems as those of 3 when performed in standard glassware. However, heating in a pressure tube at 220 °C for 36 h resulted in a 60% isolated yield of the new reductant, T^fPiE, which was characterized using X-ray crystallography (Figure b). The solid-state structure indicates a CC bond distance of 1.357(3) Å, which is comparable to the CC bond distance in TME. The reduction potential of T^fPiE is 790 mV vs Fc⁺/Fc (Fc = ferrocene) in DMF, which makes it the weakest reductant among available TAE-derived reductants. This may be important for obtaining high selectivity in organic transformations.

Unfortunately, thermal decomposition of 4 and 7 led to complex reaction mixtures, which did not appear to contain any of the desired TAE. In contrast, a significant amount of unreacted 6 was observed after heating at 230 °C along with several unidentified peaks. These results show that thermal decomposition to generate TAEs is not general for all tris­(amino)­methanes.

In summary, we have developed an optimized, low-cost, one-pot synthesis of TAE-derived reductants that substantially improves the yield, scalability, and reproducibility compared to our previous route. This route relies on in situ generation of tris­(amino)­methanes. Although this method works well for the synthesis of TPyE and TPiE, it cannot currently be used for TME, likely because of reactor design issues, as opposed to chemical feasibility. Flow chemistry represents a potential alternative to TME synthesis. We also demonstrated that thermal decomposition of the appropriate tris­(amino)­methane can be used to generate the new reductant T^fPiE. Future mechanistic studies will explore the underlying reasons why certain tris­(amino)­methanes undergo more facile thermal decomposition to TAE derivatives compared to others. Overall, our new method should lower the barrier to accessing some TAE-based reductants, enabling their broader use in organic transformations.

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.6c00699.

• Experimental procedures, characterization, and spectral data (PDF)

‡.

S.K. and X.J. contributed equally.

The authors declare no competing financial interest.