Amide-Type Substrates in the Synthesis of N -Protected 1-Aminomethylphosphonium Salts

: Herein we describe the development and optimization of a two-step procedure for the synthesis of N -protected 1-aminomethylphosphonium salts from imides, amides, carbamates, or lactams. Our “step-by-step” methodology involves the transformation of amide-type substrates to the corresponding hydroxymethyl derivatives, followed by the substitution of the hydroxyl group with a phosphonium moiety. The ﬁrst step of the described synthesis was conducted based on well-known protocols for hydroxymethylation with formaldehyde or paraformaldehyde. In turn, the second (substitution) stage required optimization studies. In general, reactions of amide, carbamate, and lactam derivatives occurred at a temperature of 70 ◦ C in a relatively short time (1 h). On the other hand, N -hydroxymethylimides reacted with triarylphosphonium salts at a much higher temperature (135 ◦ C) and over longer reaction times (as much as 30 h). However, the proposed strategy is very efﬁcient, especially when NaBr is used as a catalyst. Moreover, a simple work-up procedure involving only crystallization afforded good to excellent yields (up to 99%).

Interesting exceptions are N-protected 1-aminoalkylphosphonium salts 2. This particular structure, especially the presence of a positively charged triarylphosphonium group (which easily departs as a triarylphosphine) in the direct vicinity of the N-acylamino group, facilitates the formation of N-acyliminium-type cations [16,29]. Besides, the reactivity of compounds 2 can be increased by structural modifications within the phosphonium moiety, e.g., by the introduction of electron-withdrawing substituents, which reduce the C α -P + bond strength and makes it even easier to break [30][31][32]. This procedure makes it possible to conduct α-amidoalkylations under mild conditions without the need for any catalyst [30][31][32][33].
Applications of N-protected 1-aminoalkylphosphonium salts 2 as α-amidoalkylating agents are widely reported in the literature, e.g., in the synthesis of phosphorus analogs of amino acids [34][35][36] or β-amino carbonyl compounds [33] (extremely valuable because of high and multidirectional biological activity). However, the possibilities for their synthetic In the last few years, we have described some general and very efficient protocols fo the synthesis of N-protected 1-aminoalkylphosphonium salts (Scheme 2, pathways A [29 and E [40]). However, they have some limitations in the preparation of N-protected am nomethylphosphonium salts, especially imidomethylphosphonium salts (see results an discussion).
In the literature, there are also several methods dedicated almost exclusively to th synthesis of N-protected aminomethylphosphonium salts, but in most cases, they have quite narrow range of applicability and allow for the formation of only one class of phos phonium salts, e.g., N-imidomethylphosphonium salts (Scheme 2, pathway B, if R 1 , R = -C6H4CO-) [39,41], N-alkoxycarbonylaminomethylphosphonium salts (Scheme 2, path way C) [42,43], ureidomethylphosphonium salts (Scheme 2, pathway D) [44], or N-acyla minomethylphosphonium salts (Scheme 2, pathways F [45] and G [46,47]). Moreover, the are often time-consuming and labor-intensive or require the use of toxic or troublesom reagents (not readily available or inconvenient to use) [16].
In this context, we would like to present our research on the two-step preparation o N-protected 1-aminomethylphosphonium salts from amides, carbamates, lactams, or im ides. It can be considered as an interesting complement to previously described method especially for the synthesis of imidoalkylphosphonium salts. Scheme 1. Generation of N-acylimines and N-acyliminium cations in α-amidoalkylations.
In the last few years, we have described some general and very efficient protocols for the synthesis of N-protected 1-aminoalkylphosphonium salts (Scheme 2, pathways A [29] and E [40]). However, they have some limitations in the preparation of N-protected aminomethylphosphonium salts, especially imidomethylphosphonium salts (see results and discussion).

Results and Discussion
In 2017, we reported the synthesis of 1-imidoalkylphosphonium salts and their application as α-imidoalkylating agents [32]. During the implementation of this work, we stumbled upon a problem with obtaining imidomethylphosphonium derivatives. At that time, the generally proposed method for synthesizing 1-imidoalkylphosphonium salts Scheme 2. Selected methods for the synthesis of N-protected 1-aminoalkyphosphonium salts 2. In the literature, there are also several methods dedicated almost exclusively to the synthesis of N-protected aminomethylphosphonium salts, but in most cases, they have a quite narrow range of applicability and allow for the formation of only one class of phosphonium salts, e.g., N-imidomethylphosphonium salts (Scheme 2, pathway B, if R 1 , R 2 = -C 6 H 4 CO-) [39,41], N-alkoxycarbonylaminomethylphosphonium salts (Scheme 2, pathway C) [42,43], ureidomethylphosphonium salts (Scheme 2, pathway D) [44], or Nacylaminomethylphosphonium salts (Scheme 2, pathways F [45] and G [46,47]). Moreover, they are often time-consuming and labor-intensive or require the use of toxic or troublesome reagents (not readily available or inconvenient to use) [16].
In this context, we would like to present our research on the two-step preparation of N-protected 1-aminomethylphosphonium salts from amides, carbamates, lactams, or imides. It can be considered as an interesting complement to previously described methods, especially for the synthesis of imidoalkylphosphonium salts.

Results and Discussion
In 2017, we reported the synthesis of 1-imidoalkylphosphonium salts and their application as α-imidoalkylating agents [32]. During the implementation of this work, we stumbled upon a problem with obtaining imidomethylphosphonium derivatives. At that time, the generally proposed method for synthesizing 1-imidoalkylphosphonium salts was inefficient for imidomethylphosphonium salts (three steps, including electrochemical alkoxylation, and total yields below 10%).
Recently, we described a one-pot methodology for the synthesis of N-protected 1aminoalkylphosphonium salts based on the three-component coupling of aldehydes and either amides, carbamates, lactams, or imides in the presence of triarylphosphonium salts [40]. However, in this case, the preparation of imidomethylphosphonium salts also proved to be problematic. Condensations with imides required very high temperatures (150-170 • C) and often resulted in only trace amounts of products [40]. The low nucleophilicity of the nitrogen in imides seems to hinder the crucial stage of this synthesis, i.e., the reaction of imides with 1-hydroxymethylphosphonium salts 8 (which are rapidly formed in situ from aldehyde 6 and triarylphosphonium salts 7, Scheme 3, pathway I). Therefore, we decided to reverse the ongoing transformations and, in the first step, create N-hydroxymethylimides 9 from imides and aldehyde 6, and then treat them with triarylphosphonium salts 7 (Scheme 3, pathway II). Procedures for the preparation of hydroxymethyl derivatives 9 have been known for years [48][49][50][51][52][53][54], so we focused on tuning the conditions for the second step, where the hydroxyl group is substituted by the phosphonium moiety.
Preliminary studies indicated that the reaction required a relatively high temperature (135 °C), so this transformation was tested by fusing N-hydroxymethylimides 9 (phthalimide derivative 9a: R 1 , R 2 = -C6H4CO-and succinimide derivative 9b: R 1 , R 2 = -CH2CH2CO-, see Table 1) with triphenylphosphonium tetrafluoroborate (Ph3P•HBF4, 7a) at an elevated temperature (135 °C) and under reduced pressure (2000-2500 Pa). Moreover, there was a positive effect of NaBr addition (a bromide anion catalyst) on the reaction time and yield (compare entries 1 and 5 with 2-4 and 6, Table 1). The best results were obtained at 135 °C using 10 mol% NaBr as a catalyst. Next, we examined how the type of N-protecting group affects the course of the reaction. N-hydroxymethylbenzamide (9c: R 1 = Ph, R 2 = H, Table 1; commercially available) was reacted with triphenylphosphonium tetrafluoroborate 7a under the aforementioned conditions, yielding good results (Table 1, entry 7). Further investigations revealed that the reaction occurred at temperatures as low as 70 °C and that the addition of NaBr was not essential (Table 1, see entries 8 and 9), although it facilitated the reaction and led to higher yields (as much as 20% higher).
Next, we examined how the type of N-protecting group affects the course of the reaction. N-hydroxymethylbenzamide (9c: R 1 = Ph, R 2 = H, Table 1; commercially available) was reacted with triphenylphosphonium tetrafluoroborate 7a under the aforementioned conditions, yielding good results (Table 1, entry 7). Further investigations revealed that the reaction occurred at temperatures as low as 70 • C and that the addition of NaBr was not essential (Table 1, see entries 8 and 9), although it facilitated the reaction and led to higher yields (as much as 20% higher).
Based on the data obtained from the optimization process, we performed the reactions on a preparative scale and isolated the products using only crystallization (no chromatography was necessary). The results confirmed all our previous observations (see Table 2). To evaluate the scope of the developed methodology, we synthesized a number of hydroxymethyl derivatives of imides, amides, carbamates, or lactams 9, and reacted them with various types of triarylphosphonium salts 7 (Ar 3 P·HX).
Generally, to obtain imidomethylphosphonium tetrafluoroborates with good yields, it was necessary to conduct the reaction at a relatively high temperature (135 • C, 3 h) in the presence of 10 mol% NaBr as catalyst ( Table 2, compare entries 1-4). On the other hand, N-hydroxymethylamides, -carbamates, and -lactams reacted smoothly with triphenylphosphonium tetrafluoroborate 7a at 70 • C with good to very good yields (see Table 2, e.g., entries 12, 20, and 23).

General Information
The structures of all compounds obtained were confirmed by spectroscopic methods (NMR, IR). 1 H, 13 C{ 1 H} (the proton decoupled 13 C NMR) and 31 P{ 1 H} NMR (the proton decoupled 31 P NMR) spectra were measured on Agilent NMR Magnet 400 at frequencies of 400, 100, and 161.9 MHz, respectively (Supplementary Materials). Tetramethylsilane (TMS) was used as the resonance shift standard ( 1 H and 13 C NMR). FT-IR spectra (ATR method) were recorded on an FT-IR spectrophotometer Nicolet 6700. High-resolution mass spectra (electrospray ionization) were recorded for unknown compounds on a Waters Xevo G2 quadrupole time-of-flight (Q-TOF) mass spectrometer. Melting points were determined (in capillaries) for crystalline substances and were uncorrected. Solvents (ACS grade) were stored over molecular sieves before use. All commercially available reagents, including compounds 5, 6, triphenylphosphonium bromide 7d, N-hydoxymethylbenzamide 9c, and N-hydroxymethylacetamide 9d were purchased and then used as received, without purification or modifications.

Synthesis of N-Protected Aminomethylphosphonium Salts 2
The N-(hydroxymethyl)imide, -amide, -carbamate or -lactam (1 mmol), triarylphosphonium bromide or tetrafluoroborate (Ar 3 P·HX, 1 mmol), and CHCl 3 (2.5 mL) were added to a 25 mL round-bottom flask. When necessary, the NaBr catalyst (which was previously heated at 60 • C under reduced pressure for a minimum of 1 h) was added to the mixture at a level of 5-20 mol% (see Tables 1 and 2). The solvent was then evaporated from the resulting mixture using a rotary evaporator. The residue was fused at 135 • C or 70 • C under reduced pressure for the time noted in Tables 1 and 2. The crude reaction product was dissolved in CH 3 CN or CH 2 Cl 2 and then, after removal of NaBr (by decantation), was precipitated with Et 2 O. If necessary, the crystallization was repeated.
3.2.3. 5g-Scale Synthesis of (N-phthalimido)methyltriphenylphosphonium Tetrafluoroborate (2a) N-(hydroxymethyl)phthalimide (2.30 g, 13 mmol), triphenylphosphonium tetrafluoroborate (4.55 g, 13 mmol), and CHCl 3 (25 mL) were added to a 100 mL round bottom flask. The NaBr (0.1338 g, 1.3 mmol, 10 mol%), which was previously heated at 60 • C under reduced pressure for a minimum of 1 h, was added to the mixture. The solvent was then evaporated from the resulting mixture using a rotary evaporator. The residue was fused at 135 • C under reduced pressure for 3h. The crude reaction product was dissolved in CH 3 CN and then, after removal of NaBr by decantation, was precipitated with Et 2 O to obtain 5.3 g of pure product 2a with a yield of 80%.

Conclusions
In this article, we describe the preparation of N-protected aminomethyltriarylphosphonium salts by a two-step synthesis from imides, amides, carbamates, or lactams. The first step of the synthesis, i.e., the hydroxymethylation of the substrates with formaldehyde (in the form of formalin or paraformaldehyde), is known and widely described in the literature. The second, crucial step-substitution of the hydroxyl group with a triarylphosphonium group-required some optimization. N-hydroxymethyl derivatives of amides, carbamates, and lactams reacted with triarylphosphonium salts under relatively mild conditions and in a short reaction time (70 • C, 1 h) to give the corresponding N-protected aminomethylphosphonium salts with good to very good yields (up to 99%). For N-hydroxymethylimides, more severe conditions were required (a higher temperature and longer reaction times: 135 • C, 3-30 h), but the products could also be effectively obtained (in up to 94% yield). In all cases, the use of NaBr as a catalyst had a positive effect on the course of the reaction. It is worth noting that the method also allows the synthesis of phosphonium salts with a modified structure of the triarylphosphonium moiety, not only triphenylphosphonium, but also tris(3-chlorophenyl)phosphonium or tris(4-methoxyphenyl)phosphonium salts. All these advantages make the developed protocol a good complementary alternative to the previously described literature methods for the synthesis of N-protected aminomethylphosphonium salts.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/ 10.3390/catal11050552/s1, Apparatus for the synthesis of N-protected aminomethylphosphonium salts 2. 1 H, 13 C{1H}, 31 P{1H} NMR, and IR spectra of N-protected aminomethylphosphonium salts 2. Supplementary data associated with this article can be found in the online version.

Data Availability Statement:
All data needed to support the conclusions in the paper are contained in the article.

Conflicts of Interest:
The authors declare no conflict of interest.