Synthesis of N-Aminated Salts of Aliphatic tert-Amines, (Trialkyl)amidines, and (Pentaalkyl)guanidines by Electrophilic Amination in an Ethereal Solvent

Abstract

The electrophilic amination of nitrogen-based nucleophiles, including strong organic bases, was conducted in an Et₂O solvent using O-(mesitylenesulfonyl)hydroxylamine. Aliphatic tert-amines and N,N,N′-(trialkyl)amidines rapidly formed precipitates of the corresponding aminated salts in high yields. The amination of the highly basic and sterically hindered N,N,N′,N′,N″-(pentaalkyl)guanidines was achieved under modified conditions, although the yields were moderate because of a competing side reaction caused by the acid–base equilibrium.

Introduction

The electrophilic amination (EA) of nucleophilic nitrogen atoms yields molecules containing a N–N bond. In particular, the EA of aliphatic tert-amines and iminic compounds, such as pyridines, is an important transformation reaction. This is because the resulting N-aminated products are useful precursors of amine imide derivatives, i.e., nitrogen ylides, which exhibit unique reactivities and properties.^1–5) Thus far, various reagents and routes for EA reactions are being developed^6–9) to overcome the drawbacks associated with the traditional chloramine (NH₂Cl) reagent,^10,11) including its low reactivity and handling difficulty (preparation in a diluted solution immediately before use). O-(Mesitylenesulfonyl)hydroxylamine (MSH)^12,13) is a commonly used EA reagent, whose utility was established by Tamura et al.^14–17) MSH offers the advantages of high reactivity and sufficient solubility in common organic solvents. Typically, the EA of tert-amines with MSH is conducted by mixing equimolar amounts of these compounds in CH₂Cl₂ at 0 °C.^15,16,18) Subsequently, the precipitate is filtered to afford a crude N-aminoammonium salt. Occasionally, the addition of Et₂O to the reaction mixture was required to facilitate the precipitation. Thereafter, the crude solid is recrystallized to obtain pure N-aminoammonium mesitylenesulfonate.

Herein, we report a facile procedure for the EA of aliphatic tert-amines with MSH using Et₂O as the solvent.¹⁹⁾ The precipitation of the corresponding N-aminoammonium salts occurred rapidly, owing to their low solubility in Et₂O. Further, we describe previously unknown MSH-mediated EA reactions involving strong, nitrogen-containing organic bases.

Results and Discussion

The EA of N-methylpyrrolidine (1a), N-methylpiperidine (1b), and quinuclidine (1c) (1.05 equivalent (equiv.) each) was conducted using freshly recrystallized MSH¹³⁾ (1 equiv.) in Et₂O at 0 °C (Table 1, entries 1–3). After filtration, compounds 2a–c were obtained in excellent yields (97–100%) and high purity. With Et₂O as the solvent, the experimental procedure was simplified and the yields of 2a–c were improved by 8–15%, compared with the reported yields in CH₂Cl₂ (88, 85, and 91%, respectively, after recrystallization).¹⁸⁾ Following this practical procedure, we conducted the EA reactions of N-methylmorpholine (1d), N-ethylpiperidine (1e), trimethylamine (1f), and triethylamine (1g) to obtain the corresponding N-aminoammonium salts (2d–g) in 89–99% yields (Table 1, entries 4–7). The resulting mesitylenesulfonate salts (2d–g) are new compounds, while the N-aminoammonium cations paired with different counter anions have been reported.^9,10,20,21)

Table 1. Electrophilic Amination of Aliphatic tert-Amines Using MSH in Et₂O

Thereafter, we focused on the EA of the iminic nitrogen atoms, whose basicity was enhanced by the conjugation with a dialkylamino group (Table 2). p-(Pyrrolidino)pyridine (3a, entry 1), whose basicity (pK_aH in MeCN: 18.4)²²⁾ is comparable to that of 1g (pK_aH in MeCN: 18.8),²²⁾ afforded the aminated salt, 4a, in 92% yield, under the reaction conditions listed in Table 1. N,N,N′-(Trialkyl)amidines, such as 1,5-diazabicyclo[4.3.0]non-5-ene (3b, entry 2) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3c, entry 3), are well-known strong organic bases with high basicities (pK_aH in MeCN = 23.9 and 24.3 for 3b and 3c, respectively).²²⁾ However, minimal attention has been paid to the EA of strong organic bases. To the best of our knowledge, only two reports have described the EA of N,N,N′-(trialkyl)amidines: chloramine-mediated EA for 3b²³⁾ or a series of 5-membered cyclic amidines.²⁴⁾ Our EA procedure using MSH in Et₂O effortlessly afforded 4b and 4c from 3b and 3c, respectively, in 95–97% yields (Table 2, entries 2–3).

Table 2. Electrophilic Amination of Iminic Nitrogen Atoms Conjugated with a Dialkylamino Group Using MSH in Et₂O

Next, we investigated the unprecedented EA reactions of N,N,N′,N′,N″-(pentaalkyl)guanidines²⁵⁾ (Chart 1). Barton’s base (3d, pK_aH in MeCN: 23.6)²²⁾ and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (3e, pK_aH in MeCN: 25.5),²²⁾ both of which were commercially sourced, were selected as the starting materials. When 3d was treated with MSH under the standard EA conditions, no precipitation occurred, unlike the case in the reactions described in Tables 1 and 2. The ¹H-NMR spectrum of the crude product, which was obtained by concentrating the reaction mixture, suggests that a significant amount of the protonated starting material (3d–H⁺) was formed along with the desired aminated salt (approx. 1 : 1 ratio). The EA of 3d was conducted at –78 °C to achieve improved selectivity (Chart 1A). However, a similar product ratio was achieved. After purification, the aminated salt (4d/Cl⁻) and the protonated salt (3d–H⁺/Cl⁻) were obtained in 31 and 32% yields, respectively. These compounds were isolated as chloride salts because anion exchange was necessary during the purification process, where 4d/Cl⁻ and 3d–H⁺/Cl⁻ were separated by preparative thin layer ion-pair chromatography^26,27) using a NaCl-treated silica gel plate (see Supplementary Materials for details). Then, 4d/Cl⁻ was converted to 4d/B(C₆F₅)₄⁻ by treating with LiB(C₆F₅)₄ (Chart 1B). This salt was isolated as a monohydrate in 87% yield. The structure of 4d/B(C₆F₅)₄⁻ was confirmed by single crystal X-ray structure analysis (CCDC 2114892, see Supplementary Materials for details). Thereafter, following the EA procedure for 3d, 3e was reacted with MSH to afford the aminated salt, 4e (Chart 1C). In this case, the precipitate formed in the reaction mixture was contaminated by a small amount of a byproduct, which was tentatively assigned as protonated 3e. Pure 4e was obtained in 66% yield after the recrystallization.

Chart 1. (A) Electrophilic Amination of 3d Using MSH; (B) Anion Exchange of 4d/Cl⁻; (C) Electrophilic Amination of 3e Using MSH

When strongly basic carbanions were reacted with the EA reagents, such as MSH and O-(2,4-dinitrophenyl)hydroxylamine (DPH), the competing protonation of the nucleophiles occurred as a side reaction.^28–30) The proposed mechanism for this side reaction involves the deprotonation of the EA reagents by the nucleophile, followed by the decomposition of the EA reagents to afford diimide. Since 3d, a strong base, could deprotonate MSH, the formation of 3d–H⁺ (Chart 1A) can be explained similarly. A plausible mechanism for this side reaction is shown in Chart 2. The diimide formed in the reaction mixture could be further disproportionated to N₂ and hydrazine. In contrast to 3d, 3b and 3c did not afford any protonated byproduct during their EA reactions (entries 2 and 3 in Table 2), irrespective of their comparable basicities (pK_aH in MeCN: 23.9–24.3) to that of 3d (23.6). These results are consistent with the higher nucleophilicities of 3b and 3c than that of 3d. The relative rate constants for the methylation at the iminic nitrogen atom sites in 3b, 3c, and 3d were reported to be 39 : 18 : 1.³¹⁾ Although the methylation rate constant of 3e was 3.4 times higher than that of 3d, the EA of 3e did not afford a very high yield (66%, Chart 1C). This result is attributed to the high basicity of 3e (pK_aH in MeCN: 25.5),²²⁾ which facilitated the deprotonation of MSH.

Chart 2. Plausible Reaction Mechanism for the Formation of 3d–H⁺

The EA of 3d was further examined using DPH instead of MSH (Chart 3). The results revealed that 4d/Cl⁻ was obtained in 49% yield after purification involving chloride anion exchange, although the reaction required a high heating temperature (approx. 75 °C in 1,4-dioxane). This result suggests that a mild EA reagent can partially suppress the side reaction caused by the acid–base equilibrium. However, the reaction selectivity was still unsatisfactory, as indicated by the ¹H-NMR signals corresponding to 3d–H⁺ (approx. 30% integral ratio to that of the desired aminated product) in the crude mixture.

Chart 3. Electrophilic N-Amination of 3d Using DPH

In addition to the strong organic bases, quinoline (3f, Chart 4) was subjected to the MSH-mediated EA in Et₂O, to demonstrate the applicability of this reaction to a weak organic base. The reaction between 3f (1.2 equiv.) and MSH (1 equiv.) at 0 °C afforded the N-aminated salt 4f^32–34) as a precipitate in 82% yield. The long reaction time (3 h) was attributed to the low basicity of 3f (pK_aH in MeCN: 12.0).²²⁾

Chart 4. Electrophilic N-Amination of 3f Using MSH in Et₂O

Conclusion

Here, we extended the substrate scope of MSH-mediated EA. The aminated salts of aliphatic tert-amines and N,N,N′-(trialkyl)amidines were rapidly precipitated in Et₂O. The EA reactions of the sterically hindered N,N,N′,N′,N″-(pentaalkyl)guanidines were more challenging because of the competing protonation side reaction. Nevertheless, we successfully isolated the corresponding aminated guanidinium salts in moderate yields. The N-aminated salts synthesized in this study will be useful for preparation of new amine imide derivatives.

Acknowledgments

This work was partially supported by JSPS KAKENHI, Grant Nos. 19K23798 and 21K15222.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

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