Synthesis of N-Protected 1-Aminoalkylphosphonium Salts from Amides, Carbamates, Lactams, or Imides

This report describes the development and optimization of the one-pot method for the synthesis of N-protected 1-aminoalkylphosphonium salts based on the three-component coupling of aldehydes and either amides, carbamates, lactams, imides, or urea in the presence of triarylphosphonium salts. The proposed strategy is very efficient and easy to carry out even on a larger scale (20 g) in any typical laboratory. Most reactions occur at temperatures between 50 and 100 °C in a short time (1–2 h) without requiring any catalyst, and simple workup procedures afford good to excellent yields. The exceptions are condensations with imides, which require much higher temperatures (150–170 °C) and longer reaction times (even 30 h). The possibility of carrying out the synthesis under solvent-free conditions (neat reactions) is also demonstrated. It is especially important for less reactive substrates (imides), and reactions required high temperature (or generally harsher conditions). Finally, we prove the developed one-pot methodology can be successfully applied for the synthesis of structurally diverse N-protected 1-aminoalkylphosphonium salts. Mechanistic studies showed the intermediate products of described couplings are 1-hydroxyalkylphosphonium salts, not N-hydroxyalkylamides, -imides, etc., as initially expected.


■ INTRODUCTION
Phosphonium salts comprise a class of organic compounds that has enjoyed unwavering interest from the chemistry community for decades because of their applicability as reagents (e.g., ylide precursors), catalysts, or solvents (e.g., phosphonium ionic liquids (PILs)) in the synthesis of biologically active compounds. 1−8 Certain structural features of N-protected 1-aminoalkylphosphonium salts make them a very interesting and promising type of phosphonium compounds; however, their synthetic potential has not yet been fully elucidated. The presence of an acylamino group next to a positively charged phosphonium moiety permits the use of N-protected 1-aminoalkylphosphonium salts as very effective α-amidoalkylating agents (i.e., precursors of N-acylimines or N-acyliminium cations) in the αamidoalkylation reaction. It has been demonstrated that under appropriate conditions, N-protected 1-aminoalkylphosphonium salts readily react with both carbon-and heteronucleophiles, leading to the formation of new C−C and C− heteroatom bonds, respectively. 9−12 Moreover, the reactivity of these salts can be improved by imposing some structural modifications, especially within the phosphonium group. The introduction of electron-withdrawing substituents (e.g., Cl, CF 3 ) into the phosphonium moiety weakens the C α −P + bond, thereby facilitating its cleavage and promoting the generation of iminium-type cations, which are the proper α-amidoalkylating agents. This phenomenon highlights the possibility of conducting catalyst-free α-amidoalkylation, 13,14 which is an interesting alternative or complementary approach to those already described in the literature (mostly acid-catalyzed reactions). 15 −22 The most significant challenges regarding the use of phosphonium salts on a large scale involve difficulties with their preparation. So far, the most important methods are based on electrochemical alkoxylation (Scheme 1/I), which is very efficient (especially for electrochemical decarboxylative αalkoxylation of α-amino acid derivatives 5) but requires additional, sometimes expensive equipment and basic knowledge of electrochemistry. 23−35 Therefore, synthetic chemists are often reluctant to employ such strategies. There are several other interesting methods for the synthesis of N-protected 1aminoalkylphosphonium salts described in the literature. 36−39 However, in most cases, they are multistep, time-and laborconsuming, and have a narrow scope of application, which in practice is limited to N-acylaminomethylphosphonium salts (see also Table S1, Supporting Information). 20 To overcome these challenges, we have developed a novel, nonelectrochemical method for the preparation of N-protected 1-aminoalkylphosphonium salts. The proposed synthetic strategy is based on the one-pot reaction between aldehydes and either amides, carbamates, lactams, imides, or urea in the presence of triarylphosphonium tetrafluoroborates or bromides (Scheme 1/II).

■ RESULTS AND DISCUSSION
During the search for a new, general method for the preparation of N-protected 1-aminoalkylphosphonium salts, we turned our attention to the three-component condensations used for the synthesis of structurally related α-amido sulfones 12 or N-[1-(benzotriazo-1-yl)alkyl]amides 13 (Scheme 2). 16−18 The possibility of obtaining phosphonium salts directly from aldehydes and amides (carbamates, etc.) in the presence of an appropriately designed phosphorus-containing component, using a one-pot methodology seems very promising. Therefore, we selected the condensation of propionaldehyde, acetamide, and triphenylphosphonium tetrafluoroborate (in the molar ratio of 1:1:1) as the model reaction, and then performed it under various conditions (see Table 1).
Preliminary investigations indicated that the expected transformation occurred in acetonitrile at room temperature, although, when the reaction temperature was raised to 50°C,  Table 1). Changing the solvent to CHCl 3 or THF did not appreciably affect the course of the reaction (entries 3 and 4, Table 1). The one-pot transformation can be carried out in a solvent-free environment; however, a slight excess of propionaldehyde is required, relative to the amide in these cases (molar ratio of 1:1.2; entries 5 and 8, Table 1). It is also preferred to raise the temperature to 70°C because at 50°C the reaction is slow (see entry 5, Table 1). Besides, it was confirmed that N-acylaminoalkylphosphonium salt 1a can be obtained using triphenylphosphine in the presence of HBF 4 (tetrafluoroboric acid diethyl ether complex) instead of triphenylphosphonium tetrafluoroborate, but the yield of the reaction is much lower (49% vs 84%; compare entries 6 and 2, Table 1). Furthermore, it was demonstrated other triarylphosphonium salts including triphenylphosphonium bromide and tris(3-chlorophenyl)phosphonium tetrafluoroborate can be used in the synthesis (entries 7−10, Table  1). However, it seems the solventless methodology may have some limitations here (entry 11, Table 1).
Next, to evaluate the scope of the developed methodology, we conducted reactions between selected amides (entries 1− 19, Table 2), carbamates (entries 20−29, Table 2), imides (entries 35−41), and structurally diverse, simple or functionalized aldehydes in the presence of various triarylphosphonium salts. We also checked the possibility of using lactams (on the example of butyrolactam; entries 30−33, Table 2) and urea (entry 34, Table 2) as the nitrogen-containing component.
In general, aliphatic and aromatic (simple and functionalized) aldehydes, as well as paraformaldehyde, can be used in the one-pot reaction with good results. However, in the case of paraformaldehyde, it was necessary to increase the reaction temperature to 135°C in order to obtain sufficiently high yields.
The proposed one-pot methodology enables the production of triphenylphosphonium salts (Ar = Ph) as well as phosphonium salts, which are derivatives of triarylphosphines substituted with electron-donating or electron-withdrawing substituents (Ar = p-C 6 H 4 OMe or m-C 6 H 4 Cl; see, e.g., entries 4, 7, 9, or 36 in Table 2). The type of substituent influences the strength of the C α −P + bond, which has a significant impact on the reactivity of the obtained compounds, especially in the αamidoalkylation-type reaction. 13,14,24 Amides, carbamates, and lactams react with aldehydes under mild conditions, even at room temperature; however, a temperature of 50−100°C is usually required.
Urea, in turn, reacts with paraformaldehyde and triphenylphosphonium tetrafluoroborate (in the molar ratio of 1(urea):2:2) to form a bisphosphonium salt 15 (Scheme 4). When the molar ratio of substrates was 1:1:1, a mixture of phosphonium salts (the major product is bisphosphonium salt 15) was obtained, but attempts to separate them failed.
Couplings with imides required high temperatures (150− 170°C), which promoted undesirable side reactions and relatively low yields of the products (entries 35−41, Table 2). It seems that one of the crucial factors here is the lower nucleophilicity of the nitrogen in imides compared to amides (see mechanistic studies, vide infra). Finally, we have explored the possibility of conducting the reaction under solvent-free conditions (neat reactions). This methodology is very useful for less reactive substrates (imides and paraformaldehyde) requiring harsher reaction conditions (compare entries 40 and 41, Table 2). It is also important from the safety point of view because of high pressure in the reaction system when solvents are present (reactions with or without solvents are carried out in screw cap vials; see Experimental Section). Unfortunately, it was confirmed that the solventless procedure can not be used for the preparation of N-protected 1-aminoalkylphosphonium salts, which are derivatives of phosphines substituted with electron-withdrawing substituents (see entry 11, Table 1 and entry 37, Table 2).
In order to present the high practical utility of the developed methodology, we conducted the synthesis of phosphonium salt 1a on a larger 20 g-scale (Scheme 5). The reaction was carried Table 2. Conditions and Yields for the One-Pot Synthesis of N-Protected 1-Aminoalkylphosphonium Salts from Amides, Carbamates, Lactams, Imides, or Urea a Isolated yields. b The main reaction product is 2-carbamoylethyltriphenylphosphoniumtetrafluoroborate 14 (78%). c The main reaction product is 1,1′-(carbonyldimino)bis(methyltriphenylphosphonium) bis(tetrafluoroborate) 15 (84%; the molar ratio of substrates equals 1(urea): 2:2).

Scheme 4. Reaction of Urea with Formaldehyde (Generated in Situ from Paraformaldehyde) in the Presence of Triphenylphosphonium Tetrafluoroborate
The Journal of Organic Chemistry pubs.acs.org/joc Article in a round-bottom flask equipped with a reflux condenser. During the addition of the substrates, the mixture was cooled using an ice−water bath. After that, the reaction mixture was heated at 50°C for 2 h (after 1h the conversion was 85%). Finally, we isolated over 22 g of product 1a in 82% yield.
We assumed that the one-pot reaction proceeds via the intermediate formation of N-hydroxyalkyl derivatives 16, as shown in Figure 1.
However, monitoring the reaction of acetamide and propionaldehyde in the presence of triphenylphosphonium bromide by 1 H and 31 P NMR (Figure 1, II) revealed a different mechanism. Spectral analysis indicated that the new C−P bond was formed in the first stage (fast step) because the 1-Scheme 5. Reaction of Acetamide with Propionaldehyde in the Presence of Triphenylphosphonium Tetrafluoroborate on the 20 g-Scale Figure 1. A plausible mechanism for the one-pot synthesis of N-protected 1-aminoalkylphosphonium salts (I) proposed based on the analysis of 31 P NMR spectra (161.9 MHz/CDCl 3 ; ppm) acquired at different stages of the reaction between propionaldehyde, acetamide, and triphenylphosphonium bromide (II).
The Journal of Organic Chemistry pubs.acs.org/joc Article hydroxypropylphosphonium salt 11a (R 3 = Et, Ar = Ph, X = Br, Figure 1) appeared early in the reaction mixture (immediately after mixing substrates, already at room temperature). Compound 11a reacted with the acetamide in the second, slower step to generate the target 1-(N-acetylamino)propylphosphonium bromide 1b (R 1 = Me, R 2 = H, R 3 = Et; Ar = Ph, X = Br, Figure 1). It is worth noting that formation of N-(1-hydroxypropyl)acetamide 16a (R 1 = Me, R 2 = H, R 3 = Et; Figure 1) was not observed during the reaction. That was also confirmed by control reactions between acetamide and propionaldehyde without the addition of triphenylphosphonium salt. In this case, a small amount (about 10%) of the compound 16a was detected only after heating of substrates at 50°C for 1 h (the yield of 16a can be improved by adding KHCO 3 (10 mol %) to the reaction mixture); at room temperature compound 16a was not formed at all. To verify these observations and the associated mechanistic proposal, 1-hydroxypropyltriphenylphosphonium bromide 11a was synthesized and isolated following the reaction between propionaldehyde and triphenylphosphonium bromide in acetonitrile at room temperature (90% yield). Then, the reaction between salt 11a and acetamide at 50°C in acetonitrile afforded the expected 1-(N-acetylamino)propyltriphenylphosphonium bromide 1b with a 98% yield.
Reactions between aldehydes and either N-alkylamides, carbamates, lactams, imides, or urea in the presence of Ar 3 P· HX also proceed in accordance with the new proposed mechanism. This was confirmed by the fact that the corresponding 1-hydroxyalkylphosphonium salts were detected in the intermediate stages of all these reactions.

■ CONCLUSIONS
Herein, we describe the development and optimization of an effective method for preparing N-protected 1-aminoalkylphosphonium salts, based on the one-pot reaction between aldehydes and either amides, carbamates, lactams, or imides in the presence of triarylphosphonium bromide or tetrafluoroborates (Ar 3 P·HX). The greatest advantages of this novel method include the versatility, simplicity of the reaction apparatus, high yields, and the ability to synthesize structurally diverse N-protected 1-aminoalkylphosphonium salts (i.e., compounds with a modified phosphonium moiety) even on a large scale (up to 20 g). The reaction proceeds under relatively mild conditions in a short time, and it can be carried out in various solvents such as acetonitrile, chloroform, THF, or in a solvent-free environment. Although some amides react at room temperature, it is preferable to perform the transformation at elevated temperature (between 50 and 100°C ). The use of paraformaldehyde as a substrate required a higher temperature (135°C), and the reaction with imides required much more severe conditions (150−170°C), extended reaction time (3−5 h), and was not very effective (29−70% yields).
This research revealed mechanistic insights regarding the examined transformations, including the unexpected formation of structurally interesting 1-hydroxyalkylphosphonium salts in the intermediate stage following the reaction of aldehydes with triarylphosphonium tetrafluoroborates or bromides. The 1hydroxyalkylphosphonium salts are stable and easily separable. The reaction mechanism was confirmed by isolating the intermediate 1-hydroxyalkylphosphonium salts and reacting them further with an amide to obtain the expected 1-(Nacylamino)alkylphosphonium salts.

■ EXPERIMENTAL SECTION
General Methods. Melting points were determined in capillaries using a Stuart Scientific SMP3 melting point apparatus and were uncorrected. Infrared (IR) spectra were measured on a Fourier transform (FT)-IR spectrophotometer (using an attenuated total reflectance (ATR) method). 1 H and 13 C{ 1 H} NMR (the proton decoupled 13 C NMR) were recorded at operating frequencies of 400 and 100 MHz, respectively, using tetramethylsilane (TMS) as the resonance shift standard. 31 P{ 1 H} NMR spectra were recorded at an operating frequency of 161.9 MHz without the resonance shift standard, with respect to H 3 PO 4 set as 0 ppm. All chemical shifts (δ) are reported in ppm and coupling constants (J) in Hz. Highresolution mass spectrometry (HR-MS) analyses were performed on a Waters Xevo G2 quadrupole time-of-flight (Q-TOF) mass spectrometer equipped with an electrospray ionization (ESI) source operating in the positive ion mode. The accurate mass and composition of molecular ion adducts were calculated using the MassLynx software incorporated within the instrument. Solvents (ACS grade) were stored over molecular sieves before use. All other commercially available reagents, including compounds 8, 9 and triphenylphosphonium bromide (10d) were purchased and then used as received, without purification or modifications. Triarylphosphonium tetrafluoroborates (10a−c) were synthesized based on our previously described procedure. 13 Synthesis of Triarylphosphonium Tetrafluoroborates 10 from Triarylphosphines (Ar 3 P) and Tetrafluoroboric Acid Diethyl Ether Complex (HBF 4 ·Et 2 O). The reaction was carried out in a round-bottom flask fitted with a calcium chloride drying tube. Tetrafluoroboric acid diethyl ether complex (HBF 4 ·Et 2 O; 1.36 cm 3 , 1.619 mg, 10 mmol) was added dropwise to a solution of triarylphosphine (10 mmol) in dichloromethane (10 cm 3 ) which was cooled with an ice−water bath. After the addition of the acid, the reaction mixture was stirred for an additional 2 h at room temperature. Triarylphosphonium tetrafluoroborate was then precipitated with diethyl ether. The resulting precipitate was separated by vacuum filtration, washed on a Buchner funnel with CH 2 Cl 2 /Et 2 O (5 cm 3 , 1:3 [v/v]) and dried.
Triphenylphosphonium tetrafluoroborate (10a).  One-Pot Reaction of Amides, Carbamates, Lactams, or Imides with Aldehydes in the Presence of Triarylphosphonium Salts. These one-pot reactions were carried out in a glass vial sealed with a screw-cap. The amide (carbamate, lactam, or imide; 1 mmol) and triarylphosphonium salt (bromide or tetrafluoroborate; 1 mmol) were added to a solution of aldehyde (1 mmol) in CH 3 CN (or The Journal of Organic Chemistry pubs.acs.org/joc Article CHCl 3 or THF; 0.65 cm 3 ). The obtained mixture was stirred vigorously and heated using an oil bath (time and temperature are given in Table 1 and 2). The N-protected 1-aminoalkylphosphonium salt was then precipitated with diethyl ether. Due to the relatively high concentration, the obtained N-protected 1-aminoalkylphosphonium salts often crystallized from the reaction mixture (especially from THF solutions). If necessary, the salt was recrystallized from CH 3 CN, CH 3 CN/Et 2 O, or CHCl 3 /Et 2 O.
One-Pot Reaction of Amides, Carbamates, Lactams, or Imides with Aldehydes in the Presence of Triarylphosphonium Salts without Solvent. These solvent-free reactions were carried out in a glass vial sealed with a screw-cap. Aldehyde (1.0 or 1.2 mmol in the case of a volatile aldehydes such as acetaldehyde or propionaldehyde), amide (carbamate, lactam, or imide; 1 mmol), and triarylphosphonium salt (bromide or tetrafluoroborate; 1.0 mmol) were added to the vial. The obtained mixture was heated using an oil bath (time and temperature are given in Table 1 and 2). The obtained crude 1-(N-acetylamino)alkylphosphonium salts were recrystallized from CH 3 CN/Et 2 O or CHCl 3 /Et 2 O.
One-Pot Reaction of Acetamide with Propionaldehyde and Triphenylphosphine in the Presence of HBF 4 . The one-pot reaction was carried out in a glass vial sealed with a screw-cap. Acetamide (14.8 mg, 0.25 mmol), triphenylphosphine (262.3 mg, 1 mmol), and HBF 4 ·Et 2 O (tetrafluoroboric acid diethyl ether complex, 0.1360 cm 3 , 161.9 mg, 1 mmol) were added to a solution of propionaldehyde (0.0717 cm 3 , 58.1 mg, 1 mmol) in CH 3 CN (0.65 cm 3 ). The obtained mixture was stirred vigorously and heated at 50°C for 1 h using an oil bath. The product was precipitated with diethyl ether to afford pure 1-(N-acetylamino)propyltriphenylphosphonium tetrafluoroborate in 49% yield.
One-Pot Reaction of Acetamide with Propionaldehyde in the Presence of Triphenylphosphonium Tetrafluoroborate on 20 g-Scale. The one-pot reaction was carried out in a 150 cm 3 round-bottom flask equipped with a reflux condenser. Acetamide (3.54 g, 60 mmol) and triphenylphosphonium tetrafluoroborate (21.01 g, 60 mmol) were added to a solution of propionaldehyde (4.3 cm 3 , 3.48 g, 60 mmol) in CH 3 CN (39 cm 3 ) which was cooled with an ice−water bath. Then, the obtained mixture was stirred vigorously and heated at 50°C for 2 h using an oil bath. After that, the product was precipitated with diethyl ether (40 cm 3  (N-Acetylamino)phenylmethyltriphenylphosphonium tetrafluoroborate (1e). 23  (N-Acetylamino)methyltriphenylphosphonium bromide (1h). 39