1-Aminoalkylphosphonium Derivatives: Smart Synthetic Equivalents of N-Acyliminium-Type Cations, and Maybe Something More: A Review

N-acyliminium-type cations are examples of highly reactive intermediates that are willingly used in organic synthesis in intra- or intermolecular α-amidoalkylation reactions. They are usually generated in situ from their corresponding precursors in the presence of acidic catalysts (Brønsted or Lewis acids). In this context, 1-aminoalkyltriarylphosphonium derivatives deserve particular attention. The positively charged phosphonium moiety located in the immediate vicinity of the N-acyl group significantly facilitates Cα-P+ bond breaking, even without the use of catalyst. Moreover, minor structural modifications of 1-aminoalkyltriarylphosphonium derivatives make it possible to modulate their reactivity in a simple way. Therefore, these types of compounds can be considered as smart synthetic equivalents of N-acyliminium-type cations. This review intends to familiarize a wide audience with the unique properties of 1-aminoalkyltriarylphosphonium derivatives and encourage their wider use in organic synthesis. Hence, the most important methods for the preparation of 1-aminoalkyltriarylphosphonium salts, as well as the area of their potential synthetic utilization, are demonstrated. In particular, the structure–reactivity correlations for the phosphonium salts are discussed. It was shown that 1-aminoalkyltriarylphosphonium salts are not only an interesting alternative to other α-amidoalkylating agents but also can be used in such important transformations as the Wittig reaction or heterocyclizations. Finally, the prospects and limitations of their further applications in synthesis and medicinal chemistry were considered.


Introduction
α-Amidoalkylation reactions play an increasingly important role in organic synthesis as convenient and effective methods for the formation of C-C and C-heteroatom bonds, particularly of the intramolecular type, allowing the synthesis of carbo-or heterocyclic systems. In most cases, N-acylimine 2 or N-acyliminium cations 3 are the correct αamidoalkylating agents and they are generated from precursors with the relevant structure 1 (Scheme 1) .
Many examples of α-amidoalkylating agent precursors and their applications in α-amidoalkylations have been reported in the literature. A brief summary is given in Table 1. Compared to the precursors described therein, 1-aminoalkylphosphonium derivatives are relatively unknown compounds. However, they have unique structural features Many examples of α-amidoalkylating agent precursors and their applications in αamidoalkylations have been reported in the literature. A brief summary is given in Table  1. Compared to the precursors described therein, 1-aminoalkylphosphonium derivatives are relatively unknown compounds. However, they have unique structural features which promote the generation of N-acyliminium-type cations. One of the most important is the presence of a positively charged phosphonium moiety (which easily departs as triarylphosphine PAr3) in the immediate vicinity of the acyl group.
Moreover, the reactivity of 1-aminoalkylphosphonium derivatives can be modulated by simple structural modifications, e.g., by changing the amino protecting group or by the introduction of electron-withdrawing substituents to the phosphonium moiety (replacing Ph3P by (3-C6H4Cl)3P or (4-C6H4CF3)3P; see Figure 1). Depending on the structure of the phosphonium salt used, the α-amidoalkylations may require a basic or acidic catalyst. However, the introduction of the abovementioned activating structural modifications allows one, in many cases, to conduct the reactions under milder and even catalyst-free conditions. Furthermore, such modifications not only affect the reactivity but also the course of the reaction (for example, to reduce side reactions), or even make it possible to change the type of reaction taking place (the α-amidoalkylation reaction vs the Wittig reaction).  Moreover, the reactivity of 1-aminoalkylphosphonium derivatives can be modulated by simple structural modifications, e.g., by changing the amino protecting group or by the introduction of electron-withdrawing substituents to the phosphonium moiety (replacing Ph 3 P by (3-C 6 H 4 Cl) 3 P or (4-C 6 H 4 CF 3 ) 3 P; see Figure 1). Depending on the structure of the phosphonium salt used, the α-amidoalkylations may require a basic or acidic catalyst. However, the introduction of the abovementioned activating structural modifications allows one, in many cases, to conduct the reactions under milder and even catalyst-free conditions. Furthermore, such modifications not only affect the reactivity but also the course of the reaction (for example, to reduce side reactions), or even make it possible to change the type of reaction taking place (the α-amidoalkylation reaction vs the Wittig reaction).

Scheme 1. The α-amidoalkylation reaction.
Many examples of α-amidoalkylating agent precursors and their applications in αamidoalkylations have been reported in the literature. A brief summary is given in Table  1. Compared to the precursors described therein, 1-aminoalkylphosphonium derivatives are relatively unknown compounds. However, they have unique structural features which promote the generation of N-acyliminium-type cations. One of the most important is the presence of a positively charged phosphonium moiety (which easily departs as triarylphosphine PAr3) in the immediate vicinity of the acyl group.
Moreover, the reactivity of 1-aminoalkylphosphonium derivatives can be modulated by simple structural modifications, e.g., by changing the amino protecting group or by the introduction of electron-withdrawing substituents to the phosphonium moiety (replacing Ph3P by (3-C6H4Cl)3P or (4-C6H4CF3)3P; see Figure 1). Depending on the structure of the phosphonium salt used, the α-amidoalkylations may require a basic or acidic catalyst. However, the introduction of the abovementioned activating structural modifications allows one, in many cases, to conduct the reactions under milder and even catalyst-free conditions. Furthermore, such modifications not only affect the reactivity but also the course of the reaction (for example, to reduce side reactions), or even make it possible to change the type of reaction taking place (the α-amidoalkylation reaction vs the Wittig reaction).  The main purpose of this review paper is to organize and disseminate current knowledge about 1-aminoalkylphosphonium derivatives. To help understand the presented issues, three classes of these P-compounds have been distinguished. Three separate chapters are dedicated to them, where general properties, the most important methods for preparation as well as synthetic applications are described. Particularly, the correlation between the structure and the reactivity of phosphonium derivatives I-III is discussed. Scheme 2 provides a classification and a brief summary of the chemistry of 1-aminoalkylphosphonium derivatives.
Molecules 2022, 27,1562 3 of 34 The main purpose of this review paper is to organize and disseminate current knowledge about 1-aminoalkylphosphonium derivatives. To help understand the presented issues, three classes of these P-compounds have been distinguished. Three separate chapters are dedicated to them, where general properties, the most important methods for preparation as well as synthetic applications are described. Particularly, the correlation between the structure and the reactivity of phosphonium derivatives I-III is discussed. Scheme 2 provides a classification and a brief summary of the chemistry of 1aminoalkylphosphonium derivatives. Scheme 2. Classification and reactivity of 1-aminoalkylphosphonium derivatives. Table 1. Summary of characteristics for the most important precursors of α-amidoalkylating agents 1.

Amidoalkylation (Selected Research or Review
Literature) a limited structural diversity, limited reactivity, parent compounds for the other α-amidoalkylating agents, activation with acidic catalysts, synthesis from amides (or imides) and aldehydes (mostly in situ)-only Nhydoxymethylamides (or -imides) can be easily isolated [3,4,[6][7][8][9][10][11][12] limited reactivity, high structural diversity, activation with acidic catalysts, main synthesis methods based on electrochemical alkoxylation [5][6][7][8][9][12][13][14] high reactivity, rather low yields in α-amidoalkylation reactions (lots of by-products), difficulties in the preparation, purification and storage [6][7][8][9]12] high reactivity (good leaving group), high structural diversity, activation with acidic catalysts, easy to use and storage, diverse methods of synthesis, broad scope of application [8,9,12,[16][17][18][19] Scheme 2. Classification and reactivity of 1-aminoalkylphosphonium derivatives. The main purpose of this review paper is to organize and disseminate current knowledge about 1-aminoalkylphosphonium derivatives. To help understand the presented issues, three classes of these P-compounds have been distinguished. Three separate chapters are dedicated to them, where general properties, the most important methods for preparation as well as synthetic applications are described. Particularly, the correlation between the structure and the reactivity of phosphonium derivatives I-III is discussed. Scheme 2 provides a classification and a brief summary of the chemistry of 1aminoalkylphosphonium derivatives. Scheme 2. Classification and reactivity of 1-aminoalkylphosphonium derivatives. Table 1. Summary of characteristics for the most important precursors of α-amidoalkylating agents 1.
chloromethylisocyanate or bromomethylisocyanate and further hydrolysis of the isocyanate group (Scheme 3, Method C) [30,31]. In analogous reactions, the corresponding triphenylphosphonium iodides (4a, R 1 = OR, X = I) were also obtained by adding methyl iodide in the first step of the synthesis [32]. The same authors also described reactions in which phosphonium salts 4a (R 1 = OR, X = Cl) were obtained by alkylation of triphenylphosphine with N-(chloromethyl)carbamates 10, that were previously generated from alcohol and methyl isocyanide (Scheme 3, Method D) [33]. In turn, Zinner and Fehlhammer described the two-stage method for the synthesis of 1-(N-formylamino)methyltriphenylphosphonium chloride 4a (R 1 = H, X = Cl). Initially, they conducted the alkylation of triphenylphosphine using trimethylsilyl isocyanide in the presence of hexachloroethane in THF. The acidic hydrolysis of indirectly formed isocyanomethyltriphenylphosphonium chloride 11 finally yielded the expected phosphonium salt 4a (Scheme 3, Method E) [34]. However, the authors did not report the yield of the hydrolysis step.
Only a few of the described methods for synthesizing 1-(N-acylamino)methyltriphenylphosphonium salts 4a were based on other approaches than the alkylation of triphenylphosphine by N-(halomethyl)amides, their precursors or related compounds. One of these methods involved the alkylation of methyl carbamate with hydroxymethyltriphenylphosphonium chloride 12, which resulted in the production of 1-(N-methoxycarbonyl)aminomethyltriphenylphosphonium chloride 4a (R 1 = OMe, X = Cl) in 73% yield (Scheme 3, Method F) [35]. Devlin and Walker demonstrated that the treatment of 2bromo-2-nitrostyrene 14 with triphenylphosphine in methanol gave the phosphonium salt 15 in 47% yield. The vacuum pyrolysis of salt 15 at 150 °C, reduction with NaHBF4 in methanol or refluxing in chloroform with addition of bromine led to a mixture containing 1-(N-benzoylamino)methyltriphenylphosphonium bromide 4a (R 1 = Ph, X = Br) as the main product (Scheme 3, Method G) [28,36]. Only a few of the described methods for synthesizing 1-(N-acylamino)methyltriphenyl phosphonium salts 4a were based on other approaches than the alkylation of triphenylphosphine by N-(halomethyl)amides, their precursors or related compounds. One of these methods involved the alkylation of methyl carbamate with hydroxymethyltriphenylphosphonium chloride 12, which resulted in the production of 1-(N-methoxycarbonyl)aminomethylt riphenylphosphonium chloride 4a (R 1 = OMe, X = Cl) in 73% yield (Scheme 3, Method F) [35]. Devlin and Walker demonstrated that the treatment of 2-bromo-2-nitrostyrene 14 with triphenylphosphine in methanol gave the phosphonium salt 15 in 47% yield. The vacuum pyrolysis of salt 15 at 150 • C, reduction with NaHBF 4 in methanol or refluxing in chloroform with addition of bromine led to a mixture containing 1-(N-benzoylamino)methyltriph enylphosphonium bromide 4a (R 1 = Ph, X = Br) as the main product (Scheme 3, Method G) [28,36].
There are few data available in the literature on the synthesis of 1-substituted phosphonium salts 4. In 1975, Drach et al. demonstrated that the reaction of triphenylphosphine with N-(1-benzoyl-1-chloromethyl)amides 16 led to triphenylphosphonium salts 17 with a benzoyl group at the 1-position. However, salts 17 turned out to be hygroscopic and unstable. Thus, the authors decided to transform them into more stable oxazolones 18 (Scheme 4) [37]. There are few data available in the literature on the synthesis of 1-substituted phosphonium salts 4. In 1975, Drach et al. demonstrated that the reaction of triphenylphosphine with N-(1-benzoyl-1-chloromethyl)amides 16 led to triphenylphosphonium salts 17 with a benzoyl group at the 1-position. However, salts 17 turned out to be hygroscopic and unstable. Thus, the authors decided to transform them into more stable oxazolones 18 (Scheme 4) [37]. Next, Drach et al. described the route for the synthesis of various 1-(N-acylamino)substituted vinylphosphonium salts 22, which was based on the condensation of triphenylphosphine with N-polychloroalkylamides 19 [38,39]. As reported by the authors, in the first step, the salts 20 were probably formed, which further split off hydrogen chloride, resulting in the formation of the corresponding vinylphosphonium salts 22, typically in yields above 90% (Scheme 5). 1-(N-acylamino)vinylphosphonium salts (AVPOSs) 22 are unique reagents for various types of heterocyclization, which was comprehensively discussed by Drach, Brovarets, and co-workers in 2002 [39]. At about the same time, Mazurkiewicz et al. started more extensive research on the synthesis of structurally diverse 1-(N-acylamino)alkyltriarylphosphonium salts 4. Wherein, the common feature of these methods was the raw materials, which was N-protected α-amino acids. The use of α-amino acids or their derivatives as substrates was greatly advantageous, due to almost unlimited availability and structural diversity of such compounds.
The first approach was based on using 4-triphenylphosphoranylidene-5(4H)-oxazolones 24 or 4-alkyl-4-triphenylphosphonio-5(4H)-oxazolones 25, obtained from glycine (Scheme 6) [40]. Phosphoranylidene-5(4H)-oxazolones 24, were hydrolyzed at room temperature in the presence of HBF4 to N-acyl-α-triphenylphosphonioglycines 26 (R 2 = H, Scheme 6/A). Similarly, phosphonium iodides 25 were exposed to water in the mixture of THF/DCM, but without any acidic catalyst. Under these conditions, compounds 25 were transformed, in a few days, into N-acyl-1-triphenylphosphonio-α-amino acids 26 (R 2 = Me, Scheme 6/B). In the next stage, 1-triphenylphosphonio-α-amino acids 26 were heated at 105-115 °C under reduced pressure (5 mmHg) or treated with diisopropylethylamine in DCM at 20 °C, which resulted in their decarboxylation to corresponding 1-(N-acylamino)alkyltriphenylphosphonium salts 4, usually in good yields (Scheme 6/C). The authors also showed, that in the case of hydrolysis of 4-alkyl-4-triphenylphosphonio-5(4H)oxazolones 25 with a bulky substituent in the 4-position, the reaction proceeded with simultaneous decarboxylation and gave the expected 1-(N-acylamino)alkyltriphenylphosphonium salts 4 in one reaction step (Scheme 6/D) [41,42]. Next, Drach et al. described the route for the synthesis of various 1-(N-acylamino)substituted vinylphosphonium salts 22, which was based on the condensation of triphenylphosphine with N-polychloroalkylamides 19 [38,39]. As reported by the authors, in the first step, the salts 20 were probably formed, which further split off hydrogen chloride, resulting in the formation of the corresponding vinylphosphonium salts 22, typically in yields above 90% (Scheme 5). 1-(N-acylamino)vinylphosphonium salts (AVPOSs) 22 are unique reagents for various types of heterocyclization, which was comprehensively discussed by Drach, Brovarets, and co-workers in 2002 [39]. There are few data available in the literature on the synthesis of 1-substituted phosphonium salts 4. In 1975, Drach et al. demonstrated that the reaction of triphenylphosphine with N-(1-benzoyl-1-chloromethyl)amides 16 led to triphenylphosphonium salts 17 with a benzoyl group at the 1-position. However, salts 17 turned out to be hygroscopic and unstable. Thus, the authors decided to transform them into more stable oxazolones 18 (Scheme 4) [37]. Next, Drach et al. described the route for the synthesis of various 1-(N-acylamino)substituted vinylphosphonium salts 22, which was based on the condensation of triphenylphosphine with N-polychloroalkylamides 19 [38,39]. As reported by the authors, in the first step, the salts 20 were probably formed, which further split off hydrogen chloride, resulting in the formation of the corresponding vinylphosphonium salts 22, typically in yields above 90% (Scheme 5). 1-(N-acylamino)vinylphosphonium salts (AVPOSs) 22 are unique reagents for various types of heterocyclization, which was comprehensively discussed by Drach, Brovarets, and co-workers in 2002 [39]. At about the same time, Mazurkiewicz et al. started more extensive research on the synthesis of structurally diverse 1-(N-acylamino)alkyltriarylphosphonium salts 4. Wherein, the common feature of these methods was the raw materials, which was N-protected α-amino acids. The use of α-amino acids or their derivatives as substrates was greatly advantageous, due to almost unlimited availability and structural diversity of such compounds.
The first approach was based on using 4-triphenylphosphoranylidene-5(4H)-oxazolones 24 or 4-alkyl-4-triphenylphosphonio-5(4H)-oxazolones 25, obtained from glycine (Scheme 6) [40]. Phosphoranylidene-5(4H)-oxazolones 24, were hydrolyzed at room temperature in the presence of HBF 4 to N-acyl-α-triphenylphosphonioglycines 26 (R 2 = H, Scheme 6/A). Similarly, phosphonium iodides 25 were exposed to water in the mixture of THF/DCM, but without any acidic catalyst. Under these conditions, compounds 25 were transformed, in a few days, into N-acyl-1-triphenylphosphonio-α-amino acids 26 (R 2 = Me, Scheme 6/B). In the next stage, 1-triphenylphosphonio-α-amino acids 26 were heated at 105-115 • C under reduced pressure (5 mmHg) or treated with diisopropylethylamine in DCM at 20 • C, which resulted in their decarboxylation to corresponding 1-(Nacylamino)alkyltriphenylphosphonium salts 4, usually in good yields (Scheme 6/C). The authors also showed, that in the case of hydrolysis of 4-alkyl-4-triphenylphosphonio-5(4H)oxazolones 25 with a bulky substituent in the 4-position, the reaction proceeded with simultaneous decarboxylation and gave the expected 1-(N-acylamino)alkyltriphenylphosphonium salts 4 in one reaction step (Scheme 6/D) [41,42]. The first, three-stage method begins with the appropriate protection of α-amino acid functional groups (the NH2 group and other groups susceptible to electrochemical oxidation). Next, electrochemical decarboxylative α-methoxylation (or more generally, alkoxylation) takes place. As the authors noted, the electrochemical oxidations could be carried out in methanol with the addition of sodium methoxide as a base or in the presence of a solid-supported base (SiO2-Pip); wherein the latter process (based on a solid-supported base) proceeded in excellent yields and had a less complicated work-up. Recently, a simpler and even more efficient, standardized method for preparation of N,O-acetals 30 using the commercially available ElectraSyn 2.0 setup (graphite electrodes, Et3N as a base, room temp.) was described [45].
The last step is the substitution of the methoxy group in the reaction of N,O-acetals 30 with various types of phosphonium salts (Ar3P·HX, Scheme 7; Method A). The proposed method allows high yields (up to 99%) to be obtained not only for the simplest 1-(N-acylamino)alkylphosphonium salts 4 (e.g., R 2 = H), but also for much more complex structure, including derivatives of phosphine with various substituents (Ar = Ph, 3- The first, three-stage method begins with the appropriate protection of α-amino acid functional groups (the NH2 group and other groups susceptible to electrochemical oxidation). Next, electrochemical decarboxylative α-methoxylation (or more generally, alkoxylation) takes place. As the authors noted, the electrochemical oxidations could be carried out in methanol with the addition of sodium methoxide as a base or in the presence of a solid-supported base (SiO2-Pip); wherein the latter process (based on a solid-supported base) proceeded in excellent yields and had a less complicated work-up. Recently, a simpler and even more efficient, standardized method for preparation of N,O-acetals 30 using the commercially available ElectraSyn 2.0 setup (graphite electrodes, Et3N as a base, room temp.) was described [45].
The last step is the substitution of the methoxy group in the reaction of N,O-acetals 30 with various types of phosphonium salts (Ar3P·HX, Scheme 7; Method A). The proposed method allows high yields (up to 99%) to be obtained not only for the simplest 1-(N-acylamino)alkylphosphonium salts 4 (e.g., R 2 = H), but also for much more complex structure, including derivatives of phosphine with various substituents (Ar = Ph, 3-Scheme 7. Modern strategy in the synthesis of 1-(N-acylamino)alkylphosphonium salts 4; Method A-Synthesis based on the electrochemical alkoxylation; Method B-Non-electrochemical synthesis based on the one-pot, three components coupling.
The first, three-stage method begins with the appropriate protection of α-amino acid functional groups (the NH 2 group and other groups susceptible to electrochemical oxidation). Next, electrochemical decarboxylative α-methoxylation (or more generally, alkoxylation) takes place. As the authors noted, the electrochemical oxidations could be carried out in methanol with the addition of sodium methoxide as a base or in the presence of a solid-supported base (SiO 2 -Pip); wherein the latter process (based on a solid-supported base) proceeded in excellent yields and had a less complicated work-up. Recently, a simpler and even more efficient, standardized method for preparation of N,O-acetals 30 using the commercially available ElectraSyn 2.0 setup (graphite electrodes, Et 3 N as a base, room temp.) was described [45].
The last step is the substitution of the methoxy group in the reaction of N,O-acetals 30 with various types of phosphonium salts (Ar 3 P·HX, Scheme 7; Method A). The proposed method allows high yields (up to 99%) to be obtained not only for the simplest 1-(N-acylamino)alkylphosphonium salts 4 (e.g., R 2 = H), but also for much more complex structure, including derivatives of phosphine with various substituents (Ar = Ph, 3-C 6 H 4 Cl, 4-C 6 H 4 CF 3 ) [43,46]. Moreover, the raw material base can be expanded, since N-methoxyalkyl derivatives can be obtained by electrochemical oxidation of amides, carbamates or lactams. However, this is a less efficient process and an aqueous work-up of the reaction mixture is necessary [47].
In 2021, a procedure for the prepartion of N-protected aminoalkylphosphonium salts (including 1-(N-acylamino)alkylphosphonium ones) in one reaction step from aldehydes and either amides, carbamates, lactams, or urea in the presence of phosphonium salts 33 -Ar 3 P·HX (Scheme 7; Method B) was described [44]. Using a one-pot methodology, the simple work-up of the reaction mixture (no chromatography) makes 1-(Nacylamino)alkylphosphonium salts obtainable in high yields under relatively mild conditions (even at room temperature, but usually at 50 • C for 1 h). So far, it is the only general method of obtaining N-protected aminoalkylphosphonium salts without the use of electrochemical techniques [44]. Mechanistic studies showed that in the first step of the transformation, aldehydes and phosphonium salts (Ar 3 P·HX) form 1-hydroxyalkylphosphonium salts 34, which then react with amide-type substrates 31 to give the desired 1-(N-acylamino)alkylp hosphonium salts 4 in good to excellent yields [44].
Next, it was shown that by conducting the reaction step-by-step and changing the order of the reacting compounds, 1-(N-acylamino)alkylphosphonium salts 4 could also be obtained. However, the procedure is effective only for formaldehyde (or paraformaldehyde). Hydroxymethylamides 35, already mentioned in the introduction (see also Table 1), are generated during such a transformation (Scheme 8). This method works well for the synthesis of N-protected aminomethyltriarylphosphonium salts 4a, but requires a catalyst (NaBr) and elevated temperatures (70-135 • C) [48]. C6H4Cl, 4-C6H4CF3) [43,46]. Moreover, the raw material base can be expanded, since Nmethoxyalkyl derivatives can be obtained by electrochemical oxidation of amides, carbamates or lactams. However, this is a less efficient process and an aqueous work-up of the reaction mixture is necessary [47]. In 2021, a procedure for the prepartion of N-protected aminoalkylphosphonium salts (including 1-(N-acylamino)alkylphosphonium ones) in one reaction step from aldehydes and either amides, carbamates, lactams, or urea in the presence of phosphonium salts 33 -Ar3P·HX (Scheme 7; Method B) was described [44]. Using a one-pot methodology, the simple work-up of the reaction mixture (no chromatography) makes 1-(N-acylamino)alkylphosphonium salts obtainable in high yields under relatively mild conditions (even at room temperature, but usually at 50 °C for 1 h). So far, it is the only general method of obtaining N-protected aminoalkylphosphonium salts without the use of electrochemical techniques [44]. Mechanistic studies showed that in the first step of the transformation, aldehydes and phosphonium salts (Ar3P·HX) form 1-hydroxyalkylphosphonium salts 34, which then react with amide-type substrates 31 to give the desired 1-(N-acylamino)alkylphosphonium salts 4 in good to excellent yields [44].
Next, it was shown that by conducting the reaction step-by-step and changing the order of the reacting compounds, 1-(N-acylamino)alkylphosphonium salts 4 could also be obtained. However, the procedure is effective only for formaldehyde (or paraformaldehyde). Hydroxymethylamides 35, already mentioned in the introduction (see also Table  1), are generated during such a transformation (Scheme 8). This method works well for the synthesis of N-protected aminomethyltriarylphosphonium salts 4a, but requires a catalyst (NaBr) and elevated temperatures (70-135 °C) [48].

Scheme 8.
Step-by-step procedure for the synthesis of N-protected aminomethylphosphonium salts 4a.
The presented methods (Schemes 7 and 8) are based on a wide and diverse base of raw materials (α-amino acids, amide-type compounds, aldehydes), and provide easy access to structurally diverse 1-(N-acylamino)alkylphosphonium salts 4 also in the synthesis on a larger gram-scale [44,48].

Synthetic Utilization
Synthetic applications of 1-(N-acylamino)alkylphosphonium salts 4 are summarized in Figure 3. The high reactivity of such compounds is mainly related to the possibility of easy cleaving of the Cα-P + bond (Scheme 9).

Scheme 8.
Step-by-step procedure for the synthesis of N-protected aminomethylphosphonium salts 4a.
The presented methods (Schemes 7 and 8) are based on a wide and diverse base of raw materials (α-amino acids, amide-type compounds, aldehydes), and provide easy access to structurally diverse 1-(N-acylamino)alkylphosphonium salts 4 also in the synthesis on a larger gram-scale [44,48].

Synthetic Utilization
Synthetic applications of 1-(N-acylamino)alkylphosphonium salts 4 are summarized in Figure 3. The high reactivity of such compounds is mainly related to the possibility of easy cleaving of the C α -P + bond (Scheme 9).
The strength of the C α -P + bond can be further reduced by introducing electronwithdrawing substituents to the phosphonium moiety (Scheme 10, Ar = 3-C 6 H 4 Cl and 4-C 6 H 4 CF 3 ). The equilibrium in such systems was examined and described in 2018 [46]. As can be seen, it is shifted toward more stable and less reactive 1-(N-acylamino)alkylphosphon ium salts (reactivity: PS-CF 3 > PS-Cl > PS-H; stability: PS-CF 3 < PS-Cl < PS-H).
The ease of formation of iminium-type cations 3 from phosphonium salts 4 was essential in the α-amidoalkylation reactions of various types of nucleophiles (C-nucleophiles and heteronucleophiles). In many cases, the generation of such reactive intermediates can proceed without the use of any catalysts, which is an amazing advantage compared to other α-amidoalkylating agents described in the literature (e.g., N-(1-methoxyalkyl)amides, α-amido sulfones, or N-(benzotriazolylalkyl)amides) [12,20]. The strength of the Cα-P + bond can be further reduced by introducing electron-withdrawing substituents to the phosphonium moiety (Scheme 10, Ar = 3-C6H4Cl and 4-C6H4CF3). The equilibrium in such systems was examined and described in 2018 [46]. As can be seen, it is shifted toward more stable and less reactive 1-(N-acylamino)alkylphosphonium salts (reactivity: PS-CF3 > PS-Cl > PS-H; stability: PS-CF3 < PS-Cl < PS-H). The ease of formation of iminium-type cations 3 from phosphonium salts 4 was essential in the α-amidoalkylation reactions of various types of nucleophiles (C-nucleophiles and heteronucleophiles). In many cases, the generation of such reactive intermediates can proceed without the use of any catalysts, which is an amazing advantage compared to other α-amidoalkylating agents described in the literature (e.g., N-(1-methoxyalkyl)amides, α-amido sulfones, or N-(benzotriazolylalkyl)amides) [12,20].  The strength of the Cα-P + bond can be further reduced by introducing electron-withdrawing substituents to the phosphonium moiety (Scheme 10, Ar = 3-C6H4Cl and 4-C6H4CF3). The equilibrium in such systems was examined and described in 2018 [46]. As can be seen, it is shifted toward more stable and less reactive 1-(N-acylamino)alkylphosphonium salts (reactivity: PS-CF3 > PS-Cl > PS-H; stability: PS-CF3 < PS-Cl < PS-H). The ease of formation of iminium-type cations 3 from phosphonium salts 4 was essential in the α-amidoalkylation reactions of various types of nucleophiles (C-nucleophiles and heteronucleophiles). In many cases, the generation of such reactive intermediates can proceed without the use of any catalysts, which is an amazing advantage compared to other α-amidoalkylating agents described in the literature (e.g., N-(1-methoxyalkyl)amides, α-amido sulfones, or N-(benzotriazolylalkyl)amides) [12,20].  The strength of the Cα-P + bond can be further reduced by introducing electron-withdrawing substituents to the phosphonium moiety (Scheme 10, Ar = 3-C6H4Cl and 4-C6H4CF3). The equilibrium in such systems was examined and described in 2018 [46]. As can be seen, it is shifted toward more stable and less reactive 1-(N-acylamino)alkylphosphonium salts (reactivity: PS-CF3 > PS-Cl > PS-H; stability: PS-CF3 < PS-Cl < PS-H). The ease of formation of iminium-type cations 3 from phosphonium salts 4 was essential in the α-amidoalkylation reactions of various types of nucleophiles (C-nucleophiles and heteronucleophiles). In many cases, the generation of such reactive intermediates can proceed without the use of any catalysts, which is an amazing advantage compared to other α-amidoalkylating agents described in the literature (e.g., N-(1-methoxyalkyl)amides, α-amido sulfones, or N-(benzotriazolylalkyl)amides) [12,20]. One of the most widely described α-amidoalkylation reactions involving 1-(N-acylam ino)alkylphosphonium salts is the reaction with P-nucleophiles: phosphites, phosphonites, or phosphinites. The products of these transformations are called phosphorus analogs of α-amino acids 37 (more precisely: 1-aminoalkanephosphonic acid derivatives, 1-aminoalkanephosphinic acid derivatives, or 1-aminoalkylphosphine oxide derivatives), and they are extremely interesting in terms of their biological activity [49].
Initially, the Michaelis-Arbuzov-type reaction with a double catalytic system was used for the synthesis of such compounds. A base (e.g., the Hünig's base-(i-Pr) 2 EtN) facilitates the cleavage of the C α -P + bond and the formation of corresponding N-acylimine. In turn, the iodide anion (introduced as methyltriphenylphosphonium iodide) enables dealkylation of the intermediate alkoxyphosphonium salt 36 (Scheme 11) [50][51][52]. Further studies showed that the reaction could be carried out also under a catalytic-free conditions [46,52].
It was also possible, for the first time, to isolate and characterize one of the intermediates 36 (R 1 = t-Bu; R 2 = Me; R 3 , R 4 = OR = OEt, Scheme 11), thus proving the reaction mechanism [46]. and they are extremely interesting in terms of their biological activity [49].
Initially, the Michaelis-Arbuzov-type reaction with a double catalytic system was used for the synthesis of such compounds. A base (e.g., the Hünig's base-(i-Pr)2EtN) facilitates the cleavage of the Cα-P + bond and the formation of corresponding N-acylimine. In turn, the iodide anion (introduced as methyltriphenylphosphonium iodide) enables dealkylation of the intermediate alkoxyphosphonium salt 36 (Scheme 11) [50][51][52]. Further studies showed that the reaction could be carried out also under a catalytic-free conditions [46,52]. It was also possible, for the first time, to isolate and characterize one of the intermediates 36 (R 1 = t-Bu; R 2 = Me; R 3 , R 4 = OR = OEt, Scheme 11), thus proving the reaction mechanism [46]. Scheme 11. Michaelis-Arbuzov-type reaction of 1-(N-acylamino)alkylphosphonium salts 4 with Pnucleophiles.
Unfortunately, the major disadvantage of these reactions is the complete racemization of the products. However, two solutions were proposed to overcome this drawback. The first was enzymatic kinetic resolution of products using Penicillin G acylase from Escherichia coli (Scheme 12, Method A) [53,54]. The second was changing the synthetic approach and to conduct organocatalytic α-amidoalkylation of P-nucleophiles (e.g., dimethyl phosphite; Michaelis-Becker-type reaction) by 1-(N-acylamino)alkyltriphenylphosphonium salts in PTC systems using Cinchona alkaloid derivatives 38 and 39 as catalysts (Scheme 12, Method B) [55]. Scheme 11. Michaelis-Arbuzov-type reaction of 1-(N-acylamino)alkylphosphonium salts 4 with P-nucleophiles.
Unfortunately, the major disadvantage of these reactions is the complete racemization of the products. However, two solutions were proposed to overcome this drawback. The first was enzymatic kinetic resolution of products using Penicillin G acylase from Escherichia coli (Scheme 12, Method A) [53,54]. The second was changing the synthetic approach and to conduct organocatalytic α-amidoalkylation of P-nucleophiles (e.g., dimethyl phosphite; Michaelis-Becker-type reaction) by 1-(N-acylamino)alkyltriphenylphosphonium salts in PTC systems using Cinchona alkaloid derivatives 38 and 39 as catalysts (Scheme 12, Method B) [55].  Further research on phosphorus analogs of α-amino acids 37 revealed the possibility of transforming them into bisphosphoric acid esters 43, which also exhibit important biological activity (Scheme 13) [56,57]. Electrochemical alkoxylation of compounds 37 followed by substitution of the alkoxy group leads to 1-(N-acylamino)-1-triphenylphosphoniumalkylphosphonates 42. They can be also synthesized in a multi-stage procedure from imidate hydrochlorides 40 (Scheme 13).
As shown, the high reactivity of the phosphonium salts 42 can be used not only in the α-amidoalkylation reactions of phosphorus or carbon nucleophiles (Scheme 13, route A and B) but also in the elimination (Scheme 13; route C) or Wittig reaction (Scheme 13, route D) [57].
High reactivity of 1-(N-acylamino)alkylphosphonium salts 4 is also revealed in reactions with C-nucleophiles leading to the formation of β-aminocarbonyl systems 58 and 60.
High reactivity of 1-(N-acylamino)alkylphosphonium salts 4 is also revealed in reactions with C-nucleophiles leading to the formation of β-aminocarbonyl systems 58 and 60.
In the case of 1,3-dicarbonyl compounds 57 (dimethyl or diethyl malonate, ethyl acetoacetate, and ethyl 2-methylacetoacetate), it was necessary to use bases (DBU or LDA-lithium diisopropylamide) as catalysts to produce enolate anions [46,51]. However, the use of 1-(N-acylamino)alkyltriarylphosphonium salts 4 with a weakened C α -P + bond made it possible to conduct the reaction under slightly milder conditions (Scheme 16/A). This was similar in the reaction with 1-morpholinocyclohexene 59; replacing the triphenylphosphonium residue (Ar = Ph) with a triarylphosphonium group (Ar = 3-C 6 H 4 Cl or 4-C 6 H 4 CF 3 ) facilitates the transformation (Scheme 16B) [46,51]. In 2018, Adamek et al. examined the reactivity of 1-(N-acylamino)alkyltriarylphosphonium salts 4 towards various aromatic systems (Scheme 17/A). It was demonstrated that phosphonium salts 4 react with arenes or heteroarenes under non-catalytic conditions. Reactions of triphenylphosphonium salts 4 (Ar = Ph, Scheme 17) required an elevated temperature and led to the formation of 1-arylalkylphosphonium salts 63 (nonclassical α-amidoalkylation products). In turn, the use of 1-(N-acylamino)alkyltriarylphosphonium salts 4 with a weakened Cα-P + bond made it possible to carry out the transformations to the expected classical products-N-(1-arylalkyl)amides 62 at room temperature. Moreover, it was found that 1-arylalkylphosphonium salts 63 are formed from N-(1-arylalkyl)amides 62 in the consecutive-type reaction what is included in the plausible mechanism proposed by the authors (Scheme 17/B) [63]. In 2018, Adamek et al. examined the reactivity of 1-(N-acylamino)alkyltriarylphospho nium salts 4 towards various aromatic systems (Scheme 17/A). It was demonstrated that phosphonium salts 4 react with arenes or heteroarenes under non-catalytic conditions. Reactions of triphenylphosphonium salts 4 (Ar = Ph, Scheme 17) required an elevated temperature and led to the formation of 1-arylalkylphosphonium salts 63 (non-classical α-amidoalkylation products). In turn, the use of 1-(N-acylamino)alkyltriarylphosphonium salts 4 with a weakened C α -P + bond made it possible to carry out the transformations to the expected classical products-N-(1-arylalkyl)amides 62 at room temperature. Moreover, it was found that 1-arylalkylphosphonium salts 63 are formed from N-(1-arylalkyl)amides 62 in the consecutive-type reaction what is included in the plausible mechanism proposed by the authors (Scheme 17/B) [63].
The spontaneous generation of reactive N-acyliminium cations from 1-(N-acylamino) alkyltriarylphosphonium salts 4 (under catalyst-free conditions) was also used in reactions with silyl enolates 66 or 67, to provide N-protected β-amino esters 68, as well as N-protected β-amino ketones 69 in good to excellent yields (Scheme 18/A). As Październiok-Holewa et al. demonstrated, the process can be carried out in THF at 50 • C or 60 • C using conventional heating or microwave irradiation. The proposed mechanism of the transformation included, in the first stage, the formation of the reactive N-acyliminium cation 3, which further reacts with the silyl enolate to give silyloxy-substituted carbenium ion 70, which fast undergoes a desilylation reaction to give β-amino carbonyl compounds 68 or 69 (Scheme 18/B) [64]. The spontaneous generation of reactive N-acyliminium cations from 1-(N-acylamino)alkyltriarylphosphonium salts 4 (under catalyst-free conditions) was also used in reactions with silyl enolates 66 or 67, to provide N-protected β-amino esters 68, as well as N-protected β-amino ketones 69 in good to excellent yields (Scheme 18/A). As Październiok-Holewa et al. demonstrated, the process can be carried out in THF at 50 °C or 60 °C using conventional heating or microwave irradiation. The proposed mechanism of the transformation included, in the first stage, the formation of the reactive N-acyliminium cation 3, which further reacts with the silyl enolate to give silyloxy-substituted carbenium ion 70, which fast undergoes a desilylation reaction to give β-amino carbonyl compounds 68 or 69 (Scheme 18/B) [64]. 1-(N-acylamino)alkyltriarylphosphonium salts 4 are bifunctional compounds and their reactivity is not related only to the phosphonium moiety. Already in the 1980s, the transformation of N-acylaminomethyltriphenylphosphonium salts 4a into imidoyl chlorides 71 was described [26]. They turned out to be valuable reagents in cyclization reactions, in which heterocyclic systems such as oxazole, imidazole, tetrazole, or quinazolinone derivatives 72-76 can be obtained (Scheme 19/A-D) [26,65,66]. The presence of a triphenylphosphonium group enables further modification of the synthesized heterocycles, which was demonstrated in the example of the quinazolinones 75 (a structural motif of N-acylaminoalkylphosphonium salt can also be indicated here). These compounds undergo a reduction under mild conditions (Scheme 19/E). They can also be used as ylide precursors in the Wittig reaction with 4-nitrobenzaldehyde (Scheme 19/F) [26,65,66]. 1-(N-acylamino)alkyltriarylphosphonium salts 4 are bifunctional compounds and their reactivity is not related only to the phosphonium moiety. Already in the 1980s, the transformation of N-acylaminomethyltriphenylphosphonium salts 4a into imidoyl chlorides 71 was described [26]. They turned out to be valuable reagents in cyclization reactions, in which heterocyclic systems such as oxazole, imidazole, tetrazole, or quinazolinone derivatives 72-76 can be obtained (Scheme 19/A-D) [26,65,66]. The presence of a triphenylphosphonium group enables further modification of the synthesized heterocycles, which was demonstrated in the example of the quinazolinones 75 (a structural motif of N-acylaminoalkylphosphonium salt can also be indicated here). These compounds undergo a reduction under mild conditions (Scheme 19/E). They can also be used as ylide precursors in the Wittig reaction with 4-nitrobenzaldehyde (Scheme 19/F) [26,65,66].

1-Imidoalkyltriarylphosphonium Salts
Structures of the 1-imidoalkylphosphonium salts 79 described in the literature are based on a phthalimide (A = 1,2-C6H4) or succinimide (A = (CH2)2) ring ( Figure 4). Two electron-withdrawing carbonyl groups connected to the nitrogen atom reduce the electron density at Cα, thus increasing its electrophilicity. In the α-position there may be hydrogen

1-Imidoalkyltriarylphosphonium Salts
Structures of the 1-imidoalkylphosphonium salts 79 described in the literature are based on a phthalimide (A = 1,2-C 6 H 4 ) or succinimide (A = (CH 2 ) 2 ) ring ( Figure 4). Two electron-withdrawing carbonyl groups connected to the nitrogen atom reduce the electron density at C α , thus increasing its electrophilicity. In the α-position there may be hydrogen (R 2 = H), alkyl (R 2 = Me, Et, i-Bu) or aryl (R 2 = Ph) substituent. C α is also directly bonded to the triarylphosphonium group PAr 3 (Ar = Ph, 4-C 6 H 4 Cl, 3-C 6 H 4 Cl, 4-C 6 H 4 CF 3 ), which is positively charged and can act as a nucleofugal group. Scheme 19. Synthesis of imidoyl chlorides 71 and their further transformations.

1-Imidoalkyltriarylphosphonium Salts
Structures of the 1-imidoalkylphosphonium salts 79 described in the literature are based on a phthalimide (A = 1,2-C6H4) or succinimide (A = (CH2)2) ring ( Figure 4). Two electron-withdrawing carbonyl groups connected to the nitrogen atom reduce the electron density at Cα, thus increasing its electrophilicity. In the α-position there may be hydrogen (R 2 = H), alkyl (R 2 = Me, Et, i-Bu) or aryl (R 2 = Ph) substituent. Cα is also directly bonded to the triarylphosphonium group PAr3 (Ar = Ph, 4-C6H4Cl, 3-C6H4Cl, 4-C6H4CF3), which is positively charged and can act as a nucleofugal group. In most cases, the 1-imidoalkylphosphonium salts are stable solids that can be stored under laboratory conditions for a long time. Interestingly, some of them also show biological activities such as cytotoxic or antimicrobial properties [67][68][69]. In most cases, the 1-imidoalkylphosphonium salts are stable solids that can be stored under laboratory conditions for a long time. Interestingly, some of them also show biological activities such as cytotoxic or antimicrobial properties [67][68][69].

Preparation
In general, there is not much information in the literature on the methods for synthesis of 1-imidoalkylphosphonium salts 79, and most of them concern the simplest onesimidomethylphosphonium salts (R 2 = H). To the best of our knowledge, the first attempt to prepare imidomethylphosphonium salts was reported in 1961 by Hellmann and Schumacher [70]. It consisted in the reaction of phthalimidomethyltrimethylammonium iodide with triphenylphosphine in methanol. Such a reaction was later used several times; however, the structure of the substrate and conditions were slightly modified (mainly the solvent, temperature, and reaction time, Table 2).

Preparation
In general, there is not much information in the literature on the metho sis of 1-imidoalkylphosphonium salts 79, and most of them concern the s imidomethylphosphonium salts (R 2 = H). To the best of our knowledge, th to prepare imidomethylphosphonium salts was reported in 1961 by Hellm macher [70]. It consisted in the reaction of phthalimidomethyltrimethylamm with triphenylphosphine in methanol. Such a reaction was later used sever ever, the structure of the substrate and conditions were slightly modified (m vent, temperature, and reaction time, Table 2).   N-(1-methoxyalkyl) a Compound 79 (X = Br) is also formed as a by-product in the reaction with Pd(PPh 3 ) 4 (rt, benzene).
After several decades, general methods for the synthesis of imidoalkylphosphonium salts appeared. The first one consisted of three stages: (A) the protection of amino group (from amino acids) by smelting phtalic, succinic or 1,8-naphthalic anhydride with the corresponding amino acid at 140-170 • C; (B) electrochemical decarboxylative α-methoxylation of 1-imidoalkanecarboxylic acids 81; (C) the displacement of the methoxy group by the triarylphosphine by smelting of the N-(1-methoxyalkyl)imides 82 with triarylphosphonium tetrafluoroborates in the presence of NaBr as catalyst (Scheme 20) [73].
After several decades, general methods for the synthesis of imidoalkylphosphonium salts appeared. The first one consisted of three stages: (A) the protection of amino group (from amino acids) by smelting phtalic, succinic or 1,8-naphthalic anhydride with the corresponding amino acid at 140-170 °C; (B) electrochemical decarboxylative α-methoxylation of 1-imidoalkanecarboxylic acids 81; (C) the displacement of the methoxy group by the triarylphosphine by smelting of the N-(1-methoxyalkyl)imides 82 with triarylphosphonium tetrafluoroborates in the presence of NaBr as catalyst (Scheme 20) [73]. As it was demonstrated, 1-imidomethylphosphonium salts 79 can also be obtained in the step-by-step procedure. This time, at first, formaldehyde (reactions with other aldehydes are ineffective) and imides form hydroxymethylimides 84 which, after isolation and purification, are reacted with triarylphosphonium salts 33 (Ar3P·HX) in the last stage (Scheme 22). The use of NaBr as a catalyst had a positive effect on the reaction (both on reaction time and yield) when Ar3P·HBF4 was used (for Ar3P·HBr no catalyst is needed) [48].

Scheme 22.
Step-by-step method for the synthesis of 1-imidoalkylphosphonium salts 79 from imides.
The last two methods allow for the fast synthesis of 1-imidoalkylphosphonium salts 79 (especially 1-imidomethylphosphonium salts) from readily available substrates, even on a larger scale (5-20 g). Besides, the advantage of both strategies is that they rely on nonelectrochemical procedures, thus they are an interesting complement to previously described method.

Synthetic Utilization
The most important synthetic applications of 1-imidoalkylphosphonium salts 79 are summarized in Figure 5. Due to certain structural features (dicarbonyl protecting group and thus no NH proton), 1-imidoalkylphosphonium salts 79 can be considered as poten- As it was demonstrated, 1-imidomethylphosphonium salts 79 can also be obtained in the step-by-step procedure. This time, at first, formaldehyde (reactions with other aldehydes are ineffective) and imides form hydroxymethylimides 84 which, after isolation and purification, are reacted with triarylphosphonium salts 33 (Ar 3 P·HX) in the last stage (Scheme 22). The use of NaBr as a catalyst had a positive effect on the reaction (both on reaction time and yield) when Ar 3 P·HBF 4 was used (for Ar 3 P·HBr no catalyst is needed) [48]. As it was demonstrated, 1-imidomethylphosphonium salts 79 can also be obtained in the step-by-step procedure. This time, at first, formaldehyde (reactions with other aldehydes are ineffective) and imides form hydroxymethylimides 84 which, after isolation and purification, are reacted with triarylphosphonium salts 33 (Ar3P·HX) in the last stage (Scheme 22). The use of NaBr as a catalyst had a positive effect on the reaction (both on reaction time and yield) when Ar3P·HBF4 was used (for Ar3P·HBr no catalyst is needed) [48].

Scheme 22.
Step-by-step method for the synthesis of 1-imidoalkylphosphonium salts 79 from imides.
The last two methods allow for the fast synthesis of 1-imidoalkylphosphonium salts 79 (especially 1-imidomethylphosphonium salts) from readily available substrates, even on a larger scale (5-20 g). Besides, the advantage of both strategies is that they rely on nonelectrochemical procedures, thus they are an interesting complement to previously described method.

Synthetic Utilization
The most important synthetic applications of 1-imidoalkylphosphonium salts 79 are summarized in Figure 5. Due to certain structural features (dicarbonyl protecting group and thus no NH proton), 1-imidoalkylphosphonium salts 79 can be considered as potential precursors of ylides in the Wittig reaction. These properties of phthalimidomethyltri-

Scheme 22.
Step-by-step method for the synthesis of 1-imidoalkylphosphonium salts 79 from imides.
The last two methods allow for the fast synthesis of 1-imidoalkylphosphonium salts 79 (especially 1-imidomethylphosphonium salts) from readily available substrates, even on a larger scale (5-20 g). Besides, the advantage of both strategies is that they rely on non-electrochemical procedures, thus they are an interesting complement to previously described method.

Synthetic Utilization
The most important synthetic applications of 1-imidoalkylphosphonium salts 79 are summarized in Figure 5. Due to certain structural features (dicarbonyl protecting group and thus no NH proton), 1-imidoalkylphosphonium salts 79 can be considered as potential precursors of ylides in the Wittig reaction. These properties of phthalimidomethyltriphenylphosphonium bromide 79 were used by Tan and co-workers in the first stage of multi-step synthesis of compounds 85 and 86, which are known to modulate the activity of the TAAR 1 receptor (the trace amine-associated receptor 1, see Table 3) [72].  Recently, the possibilities of using 1-imidoalkylphosphonium salts in imidoalkylation reactions with carbon-or heteronucleophiles have been explored.
In 2017, the Friedel-Crafts-type reaction of 1-imidoalkylphosphonium salts with various aromatic compounds was described. N-(1-arylalkyl)imides 87 were the main products of these transformations (Scheme 23) [73].    Recently, the possibilities of using 1-imidoalkylphosphonium salts in imidoalkylation reactions with carbon-or heteronucleophiles have been explored.
In 2017, the Friedel-Crafts-type reaction of 1-imidoalkylphosphonium salts with various aromatic compounds was described. N-(1-arylalkyl)imides 87 were the main products of these transformations (Scheme 23) [73].  Recently, the possibilities of using 1-imidoalkylphosphonium salts in imidoalkylation reactions with carbon-or heteronucleophiles have been explored.
In 2017, the Friedel-Crafts-type reaction of 1-imidoalkylphosphonium salts with various aromatic compounds was described. N-(1-arylalkyl)imides 87 were the main products of these transformations (Scheme 23) [73].  Recently, the possibilities of using 1-imidoalkylphosphonium salts in imidoalkylation reactions with carbon-or heteronucleophiles have been explored.
In 2017, the Friedel-Crafts-type reaction of 1-imidoalkylphosphonium salts with various aromatic compounds was described. N-(1-arylalkyl)imides 87 were the main products of these transformations (Scheme 23) [73].  Recently, the possibilities of using 1-imidoalkylphosphonium salts in imidoalkylation reactions with carbon-or heteronucleophiles have been explored.
In 2017, the Friedel-Crafts-type reaction of 1-imidoalkylphosphonium salts with various aromatic compounds was described. N-(1-arylalkyl)imides 87 were the main products of these transformations (Scheme 23) [73].  Recently, the possibilities of using 1-imidoalkylphosphonium salts in imidoalkylation reactions with carbon-or heteronucleophiles have been explored.
In 2017, the Friedel-Crafts-type reaction of 1-imidoalkylphosphonium salts with various aromatic compounds was described. N-(1-arylalkyl)imides 87 were the main products of these transformations (Scheme 23) [73].  Recently, the possibilities of using 1-imidoalkylphosphonium salts in imidoalkylation reactions with carbon-or heteronucleophiles have been explored.
The presence of the dicarbonyl protection increases the electrophilicity of the C α . In addition, the use of phosphonium salts which were derivatives of triarylphosphines with electron-withdrawing substituents make it easier to cleave the C α -P + bond (first step of the reaction, Scheme 23). Such structural modifications facilitated reactions with aromatic systems, also with weakly activated anisole and toluene (see Scheme 23 and compare the relation between the required reaction temperature and the type of phosphonium moiety).
It is worth noting that, contrary to the reaction of the 1-(N-acylamino)alkylphosphonium salts 4 with arenes described in this review (Section 2.1.2), no consecutive reaction leading to the so-called non-classical α-amidoalkylation products (1-arylalkylphosphonium salts 63, see also Scheme 17) was observed. The only exception was the reaction of phosphonium salts 79-CF 3 with 1,3,5-trimethoxybenzene (Scheme 24). The presence of the dicarbonyl protection increases the electrophilicity of the Cα. In addition, the use of phosphonium salts which were derivatives of triarylphosphines with electron-withdrawing substituents make it easier to cleave the Cα-P + bond (first step of the reaction, Scheme 23). Such structural modifications facilitated reactions with aromatic systems, also with weakly activated anisole and toluene (see Scheme 23 and compare the relation between the required reaction temperature and the type of phosphonium moiety). It is worth noting that, contrary to the reaction of the 1-(N-acylamino)alkylphosphonium salts 4 with arenes described in this review (section 2.1.2), no consecutive reaction leading to the so-called non-classical α-amidoalkylation products (1-arylalkylphosphonium salts 63, see also Scheme 17) was observed. The only exception was the reaction of phosphonium salts 79-CF3 with 1,3,5-trimethoxybenzene (Scheme 24). Scheme 24. Unusual course of the reaction of 1-imidoalkylphosphonium salt 79-CF3 with a highly activated aromatic system-1,3,5-trimethoxybenzene.
1-Imidoalkylphosphonium salts have also been used in the synthesis of imidoalkanephosphonates, imidoalkanephosphinates, and imidoalkylphosphine oxides. The presence of the dicarbonyl protection increases the electrophilicity of the Cα. In addition, the use of phosphonium salts which were derivatives of triarylphosphines with electron-withdrawing substituents make it easier to cleave the Cα-P + bond (first step of the reaction, Scheme 23). Such structural modifications facilitated reactions with aromatic systems, also with weakly activated anisole and toluene (see Scheme 23 and compare the relation between the required reaction temperature and the type of phosphonium moiety). It is worth noting that, contrary to the reaction of the 1-(N-acylamino)alkylphosphonium salts 4 with arenes described in this review (section 2.1.2), no consecutive reaction leading to the so-called non-classical α-amidoalkylation products (1-arylalkylphosphonium salts 63, see also Scheme 17) was observed. The only exception was the reaction of phosphonium salts 79-CF3 with 1,3,5-trimethoxybenzene (Scheme 24).
1-Imidoalkylphosphonium salts have also been used in the synthesis of imidoalkanephosphonates, imidoalkanephosphinates, and imidoalkylphosphine oxides. Generally, these compounds exhibit interesting biological properties, including antibacterial and antifungal activities or can be used in the synthesis of many bioactive Scheme 24. Unusual course of the reaction of 1-imidoalkylphosphonium salt 79-CF 3 with a highly activated aromatic system-1,3,5-trimethoxybenzene.
1-Imidoalkylphosphonium salts have also been used in the synthesis of imidoalkanephosphonates, imidoalkanephosphinates, and imidoalkylphosphine oxides. Generally, these compounds exhibit interesting biological properties, including antibacterial and antifungal activities or can be used in the synthesis of many bioactive compounds such as phosphapeptides (acting as enzyme inhibitors), oligonucleotides, cytotoxic agents (for example Cryptophycin 52) or 2,4,5-imidazolidinetriones (herbicides and plant growth regulators) [74,75].
The strategy for preparation of P-compounds 90 from phosphonium salts 79 was based on the Michaelis-Arbuzov-type reaction with the appropriate phosphorus nucleophiles (Scheme 25) [76].
It was observed that the reactivity of phosphonium salts 79 strongly depends on their structure. Good yields were obtained only from 1-(N-phthalimido)alkylphosphonium salt derivatives of tris(3-chlorophenyl)phosphine and tris(4-trifluoromethylphenyl)phosphine. However, a relatively large excess of phosphorus nucleophile and the addition of methyltriphenylphosphonium iodide (MePPh3 + I -) as a catalyst that can facilitate the reaction were required (the most preferred molar ratio of reagents is 1:10:0.25 of phosphonium salt:P-nucleophile:catalyst).

N-acyl-1-phosphonio-α-amino Acid Esters
The general structural formula of N-acyl-1-phosphonio-α-amino acid esters 91 is shown in Figure 6. In most cases, structures of this kind of phosphonium salts described in the literature are based on a glycinate skeleton (R 2 = H), although derivatives of other proteinogenic and non-proteinogenic α-amino acids, containing in the α position alkyl (R 2 = Me, CH2OMe, CH2CN, CH2CH=CH2) or alkyl-aryl substituent (R 2 = CH2Ph, CH2Bt) are also known. Cα is most often directly bonded to the positively charged triphenylphosphonium group (R = Ph), and less often tributhylphosphonium group (R = Bu). In the structure of the phosphonium salts in question, the carboxyl group is protected as an ethyl or methyl ester (R 3 = Me, Et), while the protected amino group is present as an amide (R 1 = Me, t-Bu, Ph) or carbamate (R 1 = MeO, t-BuO, PhCH2O) moiety. The most common counterion to the positively charged phosphonium group is the tetrafluoroborate, bromide or iodide anion (X = BF4, Br, I). It was observed that the reactivity of phosphonium salts 79 strongly depends on their structure. Good yields were obtained only from 1-(N-phthalimido)alkylphosphonium salt derivatives of tris(3-chlorophenyl)phosphine and tris(4-trifluoromethylphenyl)phosphine. However, a relatively large excess of phosphorus nucleophile and the addition of methyltriphenylphosphonium iodide (MePPh 3 + I − ) as a catalyst that can facilitate the reaction were required (the most preferred molar ratio of reagents is 1:10:0.25 of phosphonium salt:P-nucleophile:catalyst).

N-acyl-1-phosphonio-α-amino Acid Esters
The general structural formula of N-acyl-1-phosphonio-α-amino acid esters 91 is shown in Figure 6. In most cases, structures of this kind of phosphonium salts described in the literature are based on a glycinate skeleton (R 2 = H), although derivatives of other proteinogenic and non-proteinogenic α-amino acids, containing in the α position alkyl (R 2 = Me, CH 2 OMe, CH 2 CN, CH 2 CH=CH 2 ) or alkyl-aryl substituent (R 2 = CH 2 Ph, CH 2 Bt) are also known. C α is most often directly bonded to the positively charged triphenylphosphonium group (R = Ph), and less often tributhylphosphonium group (R = Bu). In the structure of the phosphonium salts in question, the carboxyl group is protected as an ethyl or methyl ester (R 3 = Me, Et), while the protected amino group is present as an amide (R 1 = Me, t-Bu, Ph) or carbamate (R 1 = MeO, t-BuO, PhCH 2 O) moiety. The most common counterion to the positively charged phosphonium group is the tetrafluoroborate, bromide or iodide anion (X = BF 4 , Br, I).
The strategy for preparation of P-compounds 90 from phosphonium salts 79 was based on the Michaelis-Arbuzov-type reaction with the appropriate phosphorus nucleophiles (Scheme 25) [76]. It was observed that the reactivity of phosphonium salts 79 strongly depends on their structure. Good yields were obtained only from 1-(N-phthalimido)alkylphosphonium salt derivatives of tris(3-chlorophenyl)phosphine and tris(4-trifluoromethylphenyl)phosphine. However, a relatively large excess of phosphorus nucleophile and the addition of methyltriphenylphosphonium iodide (MePPh3 + I -) as a catalyst that can facilitate the reaction were required (the most preferred molar ratio of reagents is 1:10:0.25 of phosphonium salt:P-nucleophile:catalyst).

N-acyl-1-phosphonio-α-amino Acid Esters
The general structural formula of N-acyl-1-phosphonio-α-amino acid esters 91 is shown in Figure 6. In most cases, structures of this kind of phosphonium salts described in the literature are based on a glycinate skeleton (R 2 = H), although derivatives of other proteinogenic and non-proteinogenic α-amino acids, containing in the α position alkyl (R 2 = Me, CH2OMe, CH2CN, CH2CH=CH2) or alkyl-aryl substituent (R 2 = CH2Ph, CH2Bt) are also known. Cα is most often directly bonded to the positively charged triphenylphosphonium group (R = Ph), and less often tributhylphosphonium group (R = Bu). In the structure of the phosphonium salts in question, the carboxyl group is protected as an ethyl or methyl ester (R 3 = Me, Et), while the protected amino group is present as an amide (R 1 = Me, t-Bu, Ph) or carbamate (R 1 = MeO, t-BuO, PhCH2O) moiety. The most common counterion to the positively charged phosphonium group is the tetrafluoroborate, bromide or iodide anion (X = BF4, Br, I).

Preparation
For a wide group of compounds belonging to N-acyl-1-triphenylphosphonio-α-amino acid esters 91, N-acyl-1-triphenylphosphonioglycinates (R 2 = H) are the best known ones. They were prepared for the first time in 1983 by Kober and Steglich from ethyl N-acyl-1bromoglycinates 93 by their reaction with triphenylphosphine. The starting 1-bromoglycine derivatives 93 were previously obtained in situ in the reaction of photochemical bromination of N-acylglycine ethyl esters 92 with bromine or N-bromosuccinimide carried out in tetrachloromethane (Scheme 26) [77].
For a wide group of compounds belonging to N-acyl--triphenylphosphonio-αamino acid esters 91, N-acyl--triphenylphosphonioglycinates (R 2 = H) are the best known ones. They were prepared for the first time in 1983 by Kober and Steglich from ethyl Nacyl--bromoglycinates 93 by their reaction with triphenylphosphine. The starting -bromoglycine derivatives 93 were previously obtained in situ in the reaction of photochemical bromination of N-acylglycine ethyl esters 92 with bromine or N-bromosuccinimide carried out in tetrachloromethane (Scheme 26) [77]. However, the most convenient procedure for the synthesis of N-acyl--triphenylphosphonioglycinate tetrafluoroborates (91, X = BF4) is to treat a solution of phosphoranylidene-5(4H)-oxazolones 24 in methanol with an ethereal solution of tetrafluoroboric acid [78]. An alternative method for the synthesis of N-acyl--triphenylphosphonioglycinates with an iodide counterion (91, X = I) is a two-stage procedure that consists in the reaction of phosphoranylideneoxazolone 24 with acetyl iodide performed in acetonitrile, followed by the subsequent reaction of the acylation product with methanol [78,79]. Similarly, the synthesis of N-acyl--triphenylphosphonio-α-amino acids 91 with an alkyl substituent at the α-position (R 2 ≠ H) by alkylation of 4-phosphoranylidene-5(4H)-oxazolones 24 with alkyl halides [80], and the next opening of the oxazolone ring under the treatment with methanol or methanol in the presence of an acidic catalyst was also described (Scheme 27) [81]. However, the most convenient procedure for the synthesis of N-acyl-1-triphenylphos phonioglycinate tetrafluoroborates (91, X = BF 4 ) is to treat a solution of phosphoranylidene-5(4H)-oxazolones 24 in methanol with an ethereal solution of tetrafluoroboric acid [78]. An alternative method for the synthesis of N-acyl-1-triphenylphosphonioglycinates with an iodide counterion (91, X = I) is a two-stage procedure that consists in the reaction of phosphoranylideneoxazolone 24 with acetyl iodide performed in acetonitrile, followed by the subsequent reaction of the acylation product with methanol [78,79]. Similarly, the synthesis of N-acyl-1-triphenylphosphonio-α-amino acids 91 with an alkyl substituent at the α-position (R 2 = H) by alkylation of 4-phosphoranylidene-5(4H)-oxazolones 24 with alkyl halides [80], and the next opening of the oxazolone ring under the treatment with methanol or methanol in the presence of an acidic catalyst was also described (Scheme 27) [81]. In

Synthetic Utilization
N-Acyl--triphenylphosphonio-α-amino acid esters 91 are, in most cases, crystalline compounds, stable at room temperature, moderately sensitive to moisture, and well soluble in DCM and MeCN, but insoluble in diethyl ether. They can be easily purified by crystallization consisting of dissolution in DCM or MeCN at room temperature and precipitation with diethyl ether [78][79][80][81][82]. It is worth emphasizing that they are easily accessible from N-acylglycine even at kilogram scale (Schemes 26 and 27). All of these features of Nacyl--triphenylphosphonio-α-amino acid esters, as well as their diverse reactivity make these compounds interesting reagents in organic syntheses (Figure 7).

Synthetic Utilization
N-Acyl-1-triphenylphosphonio-α-amino acid esters 91 are, in most cases, crystalline compounds, stable at room temperature, moderately sensitive to moisture, and well soluble in DCM and MeCN, but insoluble in diethyl ether. They can be easily purified by crystallization consisting of dissolution in DCM or MeCN at room temperature and precipitation with diethyl ether [78][79][80][81][82]. It is worth emphasizing that they are easily accessible from N-acylglycine even at kilogram scale (Schemes 26 and 27). All of these features of N-acyl-1-triphenylphosphonio-α-amino acid esters, as well as their diverse reactivity make these compounds interesting reagents in organic syntheses (Figure 7). The directions of N-acyl--triphenylphosphonio-α-amino acid esters reactivity, and thus, the possibility of their further applications, were recognized during comprehensive research on their behavior in the presence of organic bases [83]. Reactions of N-acyl-triphenylphosphonio-α-amino acid methyl esters 91 with DBU and triethylamine were investigated then as the crucial step of the base catalysed displacement of the triphenylphosphonium group by various nucleophiles. Initially, this was observed by Kober, and Steglich, and later confirmed by Mazurkiewicz and Grymel, that N-acyl--triphenylphosphonioglycinates 91, upon treatment with bases, were converted into a mixture of the corresponding N-acyliminoacetate 97 and N-acyl--triphenylphosphoranylideneglycinate 98. Both the iminoacetate 97 and the ylide 98 turned out to be highly reactive, instable compounds that remained in an equilibrium and reacted slowly with each other providing the fumaric acid derivative 99. In the case of N-acyl--triphenylphosphonio-α-amino acid esters 91 with the quaternary α-carbon, the α-substituted homologues of N-acyliminoacetate 97 can undergo further tautomerization into the corresponding enamine 100 (Scheme 29) [83]. The directions of N-acyl-1-triphenylphosphonio-α-amino acid esters reactivity, and thus, the possibility of their further applications, were recognized during comprehensive research on their behavior in the presence of organic bases [83]. Reactions of N-acyl-1triphenylphosphonio-α-amino acid methyl esters 91 with DBU and triethylamine were investigated then as the crucial step of the base catalysed displacement of the triphenylphosphonium group by various nucleophiles. Initially, this was observed by Kober, and Steglich, and later confirmed by Mazurkiewicz and Grymel, that N-acyl-1-triphenylphosphoniog lycinates 91, upon treatment with bases, were converted into a mixture of the corresponding N-acyliminoacetate 97 and N-acyl-1-triphenylphosphoranylideneglycinate 98. Both the iminoacetate 97 and the ylide 98 turned out to be highly reactive, instable compounds that remained in an equilibrium and reacted slowly with each other providing the fumaric acid derivative 99. In the case of N-acyl-1-triphenylphosphonio-α-amino acid esters 91 with the quaternary α-carbon, the α-substituted homologues of N-acyliminoacetate 97 can undergo further tautomerization into the corresponding enamine 100 (Scheme 29) [83]. ture of the corresponding N-acyliminoacetate 97 and N-acyl--triphenylphosphoranylideneglycinate 98. Both the iminoacetate 97 and the ylide 98 turned out to be highly reactive, instable compounds that remained in an equilibrium and reacted slowly with each other providing the fumaric acid derivative 99. In the case of N-acyl--triphenylphosphonio-α-amino acid esters 91 with the quaternary α-carbon, the α-substituted homologues of N-acyliminoacetate 97 can undergo further tautomerization into the corresponding enamine 100 (Scheme 29) [83]. N-acyl-1-triphenylphosphonio-α-amino acid esters 91 react easily with a wide variety of oxygen, sulphur and nitrogen nucleophiles including phenol (PhOH), mercaptans (t-BuSH, PhSH, PhCH 2 SH), imidazole, 4-nitroimidazole, pyrazole, benzotriazole, phthalimide, cyclohexylamine (Scheme 30) [78,81] and two kinds of carbon nucleophiles: enolates 103 of activated carbonyl compounds or enamines 105 (Scheme 31) [79]. Reactions were conducted in acetonitrile or methanol at room temperature in the presence of DBU or triethylamine, and the corresponding α-amino acid derivatives 102, 104, and 106 (including α,α-difunctionalized derivatives) were usually obtained in good to excellent yields [78,79,81]. This great interest in natural non-proteinogenic α-amino acids results from their diverse biological activities as antibiotics, pharmaceuticals, natural pesticides, and growth regulators, as well as their use in the synthesis of enzymes, hormones, new chemotherapeutics, synthetic immunostimulants, and other protein structured compounds [85,86]. The importance of α,α-disubstituted α-amino acids has been comprehensively discussed by many authors [87,88].
The crucial structural motif for N-acyl-1-triphenylphosphonio-α-amino acid esters (amino, phosphonium and carbonyl groups bonded to the same carbon atom) can be a part of more complex systems. In this regard, 3-triphenylphosphonio-2,5-piperazinedione 111, 114 can be considered as structurally similar compounds to the phosphonium salts 91. They can be obtained from dipeptides in multistep procedure described by Mazurkiewicz and Gorewoda in 2011 [102]. The retention of configuration (position 6) results in the formation of chiral glycine cation equivalents 111, 114 which can be used for a diastereoselective nucleophilic substitution of the triphenylphosphonium group with S-, N-, P-, and C-nucleophiles (Scheme 34). Reactions were conducted at 0 or 25 °C in the presence of a base (i-Pr2EtN or DBU) and were particularly effective (high yields and high de%) for the proline derivative 111 [102]. The crucial structural motif for N-acyl-1-triphenylphosphonio-α-amino acid esters (amino, phosphonium and carbonyl groups bonded to the same carbon atom) can be a part of more complex systems. In this regard, 3-triphenylphosphonio-2,5-piperazinedione 111, 114 can be considered as structurally similar compounds to the phosphonium salts 91. They can be obtained from dipeptides in multistep procedure described by Mazurkiewicz and Gorewoda in 2011 [102]. The retention of configuration (position 6) results in the formation of chiral glycine cation equivalents 111, 114 which can be used for a diastereoselective nucleophilic substitution of the triphenylphosphonium group with S-, N-, P-, and Cnucleophiles (Scheme 34). Reactions were conducted at 0 or 25 • C in the presence of a base (i-Pr 2 EtN or DBU) and were particularly effective (high yields and high de%) for the proline derivative 111 [102].

Conclusions
1-Aminoalkylphosphonium derivatives are, in most cases, crystalline compounds, stable at room temperature and well soluble in chloroform, dichloromethane or acetonitrile, which makes them easy to store (even for a long time) and convenient to use reagents. On the other hand, they show remarkable reactivity especially towards various kinds of nucleophiles (both carbon-and heteronucleophiles). Moreover, the structure of such phosphonium salts is easy to modify by changing the N-protecting group or introducing electron-withdrawing or electron-donating substituents to the phosphonium moiety by using appropriately modified phosphines in the key stage of the synthesis. It allows for the control and, more interestingly, the targeting of the reactivity of these phosphonium compounds (α-amidoalkylation reaction vs Wittig reaction).
All these factors make the 1-aminoalkylphosphonium derivatives an interesting group of "smart-reagents" with great potential as precursors of reactive intermediates such as N-acyliminium-type cations (generated without the need for any catalysts), or ylides. This was used in the synthesis of such compounds as phosphorus analogs of αamino acids, β-aminocarbonyl systems, 1-arylalkylphosphonium salts or α,β-dehydro-αamino acids, which are very important because of their valuable biological and chemical properties. However, most of the described reactions were intermolecular (did not lead to cyclization) and were not conducted in a stereocontrolled manner. These two aspects require further research because such transformations are of great importance in the synthesis of natural, biologically active compounds. It seems that, especially in this field, the easy ability to control the Cα-P + bond strength and introduce structural modifications within phosphonium salts may be crucial (Figure 8-new challenges/asymmetric synthesis/cyclization). Studies on cyclization and stereocontrol of reactions involving 1aminoalkylphosphonium salts are in progress.
It is worth adding that, not only many of the described compounds obtained from 1aminoalkylphosphonium salts derivatives, but also some phosphonium salts themselves show interesting biological properties. However, in this case, the area of potential application should also be much more explored. 1-Aminoalkylphosphonium salts derivatives can be an ideal tool for the modification of already known structures with proven biological activity. Furthermore, recent reports on mitochondria-targeted phosphonium salts inspire the design and synthesis of molecular hybrids or conjugates that will use the targeting properties of the triphenylphosphonium (TPP) group, its biological properties, or both ( Figure 8-new challenges/biological activity).

Conclusions
1-Aminoalkylphosphonium derivatives are, in most cases, crystalline compounds, stable at room temperature and well soluble in chloroform, dichloromethane or acetonitrile, which makes them easy to store (even for a long time) and convenient to use reagents. On the other hand, they show remarkable reactivity especially towards various kinds of nucleophiles (both carbon-and heteronucleophiles). Moreover, the structure of such phosphonium salts is easy to modify by changing the N-protecting group or introducing electron-withdrawing or electron-donating substituents to the phosphonium moiety by using appropriately modified phosphines in the key stage of the synthesis. It allows for the control and, more interestingly, the targeting of the reactivity of these phosphonium compounds (α-amidoalkylation reaction vs. Wittig reaction).
All these factors make the 1-aminoalkylphosphonium derivatives an interesting group of "smart-reagents" with great potential as precursors of reactive intermediates such as N-acyliminium-type cations (generated without the need for any catalysts), or ylides. This was used in the synthesis of such compounds as phosphorus analogs of α-amino acids, β-aminocarbonyl systems, 1-arylalkylphosphonium salts or α,β-dehydro-α-amino acids, which are very important because of their valuable biological and chemical properties. However, most of the described reactions were intermolecular (did not lead to cyclization) and were not conducted in a stereocontrolled manner. These two aspects require further research because such transformations are of great importance in the synthesis of natural, biologically active compounds. It seems that, especially in this field, the easy ability to control the C α -P + bond strength and introduce structural modifications within phosphonium salts may be crucial (Figure 8-new challenges/asymmetric synthesis/cyclization). Studies on cyclization and stereocontrol of reactions involving 1-aminoalkylphosphonium salts are in progress.
It is worth adding that, not only many of the described compounds obtained from 1-aminoalkylphosphonium salts derivatives, but also some phosphonium salts themselves show interesting biological properties. However, in this case, the area of potential application should also be much more explored. 1-Aminoalkylphosphonium salts derivatives can be an ideal tool for the modification of already known structures with proven biological activity. Furthermore, recent reports on mitochondria-targeted phosphonium salts inspire the design and synthesis of molecular hybrids or conjugates that will use the targeting properties of the triphenylphosphonium (TPP) group, its biological properties, or both ( Figure 8-new challenges/biological activity). We hope that the presented data will encourage further research on 1aminoalkylphosphonium salt derivatives and will contribute to discovering their full potential.