1-Hydroxyalkylphosphonium Salts—Synthesis and Properties

An efficient and convenient method for the synthesis of 1-hydroxyalkylphosphonium salts is described. Reactions were carried out at room temperature, in a short time, and without chromatography for product isolation. The properties of the obtained phosphonium salts were examined and discussed. In this paper, primary attention was paid to the stability of phosphonium salts, depending on the structure of the aldehydes used as substrates in their preparation. Other conditions such as the type of solvent, temperature, and molar ratio of the substrates were also investigated. Finally, the high reactivity of 1-hydroxyalkylphosphonium salts was demonstrated in reactions with amide-type substrates and (hetero)aromatic compounds. The developed step-by-step procedure (with the isolation of 1-hydroxyphosphonium salts) was compared to the one-pot protocol (in situ formation of such phosphonium salts).


Introduction
Chemical compounds containing a phosphonium moiety play an increasingly important role in organic synthesis.They are already known not only for their use in the Wittig reaction as ylide precursors [1][2][3], but also as convenient building blocks used in many other reactions, especially various types of couplings [4][5][6][7][8].Moreover, they are successfully used as solvents and catalysts (PILs-phosphonium ionic liquids are good examples here) [9][10][11][12][13].Due to some specific properties, the presence of a phosphonium group can also influence the biological properties of the whole molecule (e.g., (TPP + )-based mitochondria-targeted compounds) [14].
Therefore, we present our research related to the synthesis and isolation of 1-hydroxyphosphonium salts as well as their properties, with particular emphasis on their stability, and reactivity with selected reagents.Scheme 1. 1-hydroxyalkylphosphonium salts 1: synthesis and applications.

Results and Discussion
Our journey to discover the properties of 1-hydroxyalkylphosphonium salts began with the synthesis of a wide range of such salts by slightly modifying the methods already described in the literature [6,24].To this end, we conducted two-component couplings of an aldehyde (aliphatic, aromatic, simple, and more complex) with triarylphosphonium salts in a molar ratio of 1:1 (see Table 1).We decided to use previously synthesized [24] or commercially available triarylphosphonium salts Ar3P•HX (HP + Ar3 X − ) in the reaction, rather than generating them in situ from the appropriate phosphines and acids.
In general, the reactions were carried out at room temperature, but in some cases (see paraformaldehyde) raising the temperature was necessary.The type of solvent affects the course of the reaction.Acetonitrile, chloroform, and dichloromethane (DCM) turned out to be the most effective.However, we also noticed that the use of THF leads to a complex reaction mixture (Table 1, entries 1-3).We demonstrated that the described procedure can be applied to a variety of phosphonium salts Ar3P•HX (HP + Ar3 X − ).The anion (X − ) does not play a significant role, while the triarylphosphonium group is crucial here.So far, we have not been able to obtain phosphonium salt derivatives of triarylphosphines substituted with electron-withdrawing substituents (e.g., P(3-C6H4Cl)3).Triphenylphosphonium salts and derivatives of triarylphosphines substituted with electron-donating substituents (PPh3 or P(4-C6H4OMe)3) can be synthesized without any problems (compare entries 5-7, Table 1).The reaction in which Ph3P•HBF4 was generated in situ using PPh3 and HBF4 (tetrafluoroboric acid diethyl ether complex) was also performed, but it turned out to be less efficient (92 vs. 86%-Table 1, entry 1).Therefore, we present our research related to the synthesis and isolation of 1-hydroxyphosphonium salts as well as their properties, with particular emphasis on their stability, and reactivity with selected reagents.

Results and Discussion
Our journey to discover the properties of 1-hydroxyalkylphosphonium salts began with the synthesis of a wide range of such salts by slightly modifying the methods already described in the literature [6,24].To this end, we conducted two-component couplings of an aldehyde (aliphatic, aromatic, simple, and more complex) with triarylphosphonium salts in a molar ratio of 1:1 (see Table 1).We decided to use previously synthesized [24] or commercially available triarylphosphonium salts Ar 3 P•HX (HP + Ar 3 X − ) in the reaction, rather than generating them in situ from the appropriate phosphines and acids.

Results and Discussion
Our journey to discover the properties of 1-hydroxyalkylphosphonium salts began with the synthesis of a wide range of such salts by slightly modifying the methods already described in the literature [6,24].To this end, we conducted two-component couplings of an aldehyde (aliphatic, aromatic, simple, and more complex) with triarylphosphonium salts in a molar ratio of 1:1 (see Table 1).We decided to use previously synthesized [24] or commercially available triarylphosphonium salts Ar3P•HX (HP + Ar3 X − ) in the reaction, rather than generating them in situ from the appropriate phosphines and acids.
In general, the reactions were carried out at room temperature, but in some cases (see paraformaldehyde) raising the temperature was necessary.The type of solvent affects the course of the reaction.Acetonitrile, chloroform, and dichloromethane (DCM) turned out to be the most effective.However, we also noticed that the use of THF leads to a complex reaction mixture (Table 1, entries 1-3).We demonstrated that the described procedure can be applied to a variety of phosphonium salts Ar3P•HX (HP + Ar3 X − ).The anion (X − ) does not play a significant role, while the triarylphosphonium group is crucial here.So far, we have not been able to obtain phosphonium salt derivatives of triarylphosphines substituted with electron-withdrawing substituents (e.g., P(3-C6H4Cl)3).Triphenylphosphonium salts and derivatives of triarylphosphines substituted with electron-donating substituents (PPh3 or P(4-C6H4OMe)3) can be synthesized without any problems (compare entries 5-7, Table 1).The reaction in which Ph3P•HBF4 was generated in situ using PPh3 and HBF4 (tetrafluoroboric acid diethyl ether complex) was also performed, but it turned out to be less efficient (92 vs. 86%-Table 1, entry 1).The reaction of aldehyde 2 and PPh 3 in the presence of HBF 4 (tetrafluoroboric acid diethyl ether complex, molar ratio of 1:1:1), c A mixture of products (estimated content of compound 1a based on 31 P{ 1 H} NMR is 76%), d A mixture of products (estimated content of compound 1d based on 1 H and 31 P{ 1 H} NMR is 31%), crystallization attempts failed.
In general, the reactions were carried out at room temperature, but in some cases (see paraformaldehyde) raising the temperature was necessary.The type of solvent affects the course of the reaction.Acetonitrile, chloroform, and dichloromethane (DCM) turned out to be the most effective.However, we also noticed that the use of THF leads to a complex reaction mixture (Table 1, entries 1-3).We demonstrated that the described procedure can be applied to a variety of phosphonium salts Ar 3 P•HX (HP + Ar 3 X − ).The anion (X − ) does not play a significant role, while the triarylphosphonium group is crucial here.So far, we have not been able to obtain phosphonium salt derivatives of triarylphosphines substituted with electron-withdrawing substituents (e.g., P(3-C 6 H 4 Cl) 3 ).Triphenylphosphonium salts and derivatives of triarylphosphines substituted with electron-donating substituents (PPh 3 or P(4-C 6 H 4 OMe) 3 ) can be synthesized without any problems (compare entries 5-7, Table 1).The reaction in which Ph 3 P•HBF 4 was generated in situ using PPh 3 and HBF 4 (tetrafluoroboric acid diethyl ether complex) was also performed, but it turned out to be less efficient (92 vs. 86%-Table 1, entry 1).
The structure of the aldehyde appears to be most important to the success of the reaction.The synthesis of pure products from aliphatic aldehydes does not cause any significant problems (see Table 2).Even the use of hydrated chloroacetaldehyde allowed the expected product to be obtained with a high yield (Table 2, entry 8).The reactions can also be scaled up and conducted at a gram-scale.We demonstrated this for the reaction of paraformaldehyde with Ph 3 P•HBr (Table 2, entry 5), obtaining 2.6 g of product 1h with a yield of 87%.The structure of the aldehyde appears to be most important to the success of the reaction.The synthesis of pure products from aliphatic aldehydes does not cause any significant problems (see Table 2).Even the use of hydrated chloroacetaldehyde allowed the expected product to be obtained with a high yield (Table 2, entry 8).The reactions can also be scaled up and conducted at a gram-scale.We demonstrated this for the reaction of paraformaldehyde with Ph3P•HBr (Table 2, entry 5), obtaining 2.6 g of product 1h with a yield of 87%.The salt 1k was obtained through evaporation of the solvent; crystallization attempts failed, d Aldehyde does not dissolve in acetonitrile-the reaction does not occur.
Interestingly, we also managed to obtain hydroxyalkylphosphonium salts from bisaldehyde systems (e.g., bromomalonaldehyde; see compound 1l) or unsaturated aldehydes (e.g., (E)-cinnamaldehyde; see compounds 1m and 1n).In both cases, we had to use an excess of triphenylphosphonium salt (the molar ratio of substrates 2:6 was 1:2); otherwise, complex reaction mixtures were obtained.Furthermore, in the reaction of bromomalonoaldehyde, we isolated only compound 1l, most likely due to the reductive dehalogenation that occurred (Scheme 2).
On the other hand, in the case of bulky aldehydes (R 1 = i-Pr) and especially aromatic aldehydes, we observed the incomplete conversion of substrates (see Figure 1, Tables 3  and 4).We assumed that equilibrium was reached and decided to investigate this phenomenon closely (see also Table S1, Supporting Information).Reactions between 1-naphthaldehyde and triarylphosphonium salts Ar3P•HX (HP + Ar3 X − ) were chosen as model reactions (see Figure 1 and Table 3).As we checked ( 1 H NMR and 31 P{ 1 H} NMR), the reaction Interestingly, we also managed to obtain hydroxyalkylphosphonium salts from bisaldehyde systems (e.g., bromomalonaldehyde; see compound 1l) or unsaturated aldehydes (e.g., (E)-cinnamaldehyde; see compounds 1m and 1n).In both cases, we had to use an excess of triphenylphosphonium salt (the molar ratio of substrates 2:6 was 1:2); otherwise, complex reaction mixtures were obtained.Furthermore, in the reaction of bromomalonoaldehyde, we isolated only compound 1l, most likely due to the reductive dehalogenation that occurred (Scheme 2).
On the other hand, in the case of bulky aldehydes (R 1 = i-Pr) and especially aromatic aldehydes, we observed the incomplete conversion of substrates (see Figure 1, Tables 3 and 4).We assumed that equilibrium was reached and decided to investigate this phenomenon closely (see also Table S1, Supporting Information).Reactions between 1-naphthaldehyde and triarylphosphonium salts Ar 3 P•HX (HP + Ar 3 X − ) were chosen as model reactions (see Figure 1 and Table 3).As we checked ( 1 H NMR and 31 P{ 1 H} NMR), the reaction initially proceeds very quickly (until about 5 min), after which the composition of the reaction mixture does not change at a given temperature (Table 3, entries 1-3).
initially proceeds very quickly (until about 5 min), after which the composition of the reaction mixture does not change at a given temperature (Table 3 initially proceeds very quickly (until about 5 min), after which the composition of the reaction mixture does not change at a given temperature (Table 3, entries 1-3).Coming back to the initial temperature (25 °C) returns it to the starting composition of the reaction mixture (e.g., compare entries 4-6, Table 3).The equilibrium state itself is slightly affected by the type of solvent used (see CD3CN vs. CDCl3, entries 4-6 and 13-15) and the counteranion of the phosphonium salt 6 (compare BF4 vs. TfO, entries 4-9).We also observed that the use of excess aldehyde 2o (2:1, 3:1, and 5:1; entries 16-19, Table 3) moves the reaction equilibrium toward product 1. a The composition of the reaction mixture was estimated based on 1 H and 31 P{ 1 H} NMR (see also Table S1, Supporting Information).
The presence of equilibria was confirmed for the reactions of structurally diverse aldehydes, mostly aromatic but sometimes also aliphatic (e.g., isobutyraldehyde, cyclohexanecarboaldehyde; see Table 4).Generally, in CD3CN the equilibrium is clearly shifted toward the 1-hydroxyalkylphosphonium salts.In CDCl3, it looks less favorable, most likely due to the acidic nature of this solvent.Furthermore, the (hetero)aromatic systems react less willingly, giving reaction mixtures with lower contents of 1-hydroxyalkylphosphonium salts 1.The composition of the reaction mixture was estimated by 1 H and 31 P{ 1 H} NMR (see also Table S1, Supporting Information), b A mixture of two diastereomers is formed at the ratio of 1:1.9.
Masarwa et al. reported similar observations for many aromatic aldehydes.They were also unable to isolate 1-hydroxyalkylphosphonium salts either through crystallization or flash chromatography, but they did not provide any explanation for this problem [6].
The high reactivity of the 1-hydroxyalkylphosphonium salts generated in situ (onepot method) toward aromatic compounds or heteronucleophiles is well documented [6,24].Therefore, we decided to examine the reactivity of the isolated 1-hydroxyalkylphosphonium salts (step-by-step procedure); however, some in-house results for one-pot reactions are also presented for comparison (see Table 5, Scheme 3, and Table S2, Supporting Information).To this end, we used the reaction with (hetero)aromatic systems or amide-type substrates (amides/carbamates/lactams).
Both transformations required an elevated temperature of 120 °C and 50 °C, respectively.
In the case of the less activated aromatic systems (e.g., 1,3-dimethoxybenzene), their excess (1:2 or 1:5) had a positive effect on the reaction yields but made the work-up procedure more difficult (sometimes one crystallization was not enough).Our research showed that the one-pot methodology (without the isolation of 1-hydroxyalkylphosphonium salts) is slightly more efficient (Table 5, entries 1, 4, and 5).Information), b A mixture of two diastereomers is formed at the ratio of 1:1.9.
Next, we performed some temperature tests using NMR (VT techniques) and determined the composition of the reaction mixture after increasing the temperature every 10 degrees (from 25 • C to 45 • C and back to 25 • C, see Figure 1 and Table 3).Regardless of the type of phosphonium salt used (anion X or phosphonium moiety Ar 3 P), increasing the temperature shifts the equilibrium towards the substrates (see entries 4-15 and Figure 1).Coming back to the initial temperature (25 • C) returns it to the starting composition of the reaction mixture (e.g., compare entries 4-6, Table 3).The equilibrium state itself is slightly affected by the type of solvent used (see CD 3 CN vs. CDCl 3 , entries 4-6 and 13-15) and the counteranion of the phosphonium salt 6 (compare BF 4 vs.TfO, entries 4-9).We also observed that the use of excess aldehyde 2o (2:1, 3:1, and 5:1; entries 16-19, Table 3) moves the reaction equilibrium toward product 1.
The presence of equilibria was confirmed for the reactions of structurally diverse aldehydes, mostly aromatic but sometimes also aliphatic (e.g., isobutyraldehyde, cyclohexanecarboaldehyde; see Table 4).Generally, in CD 3 CN the equilibrium is clearly shifted toward the 1-hydroxyalkylphosphonium salts.In CDCl 3 , it looks less favorable, most likely due to the acidic nature of this solvent.Furthermore, the (hetero)aromatic systems react less willingly, giving reaction mixtures with lower contents of 1-hydroxyalkylphosphonium salts 1.
Masarwa et al. reported similar observations for many aromatic aldehydes.They were also unable to isolate 1-hydroxyalkylphosphonium salts either through crystallization or flash chromatography, but they did not provide any explanation for this problem [6].
The high reactivity of the 1-hydroxyalkylphosphonium salts generated in situ (one-pot method) toward aromatic compounds or heteronucleophiles is well documented [6,24].Therefore, we decided to examine the reactivity of the isolated 1-hydroxyalkylphosphonium salts (step-by-step procedure); however, some in-house results for one-pot reactions are also presented for comparison (see Table 5, Scheme 3, and Table S2, Supporting Information).To this end, we used the reaction with (hetero)aromatic systems or amide-type substrates (amides/carbamates/lactams).
Table 5.The reaction of 1-hydroxyalkylphosphonium salts 1 with aromatic compounds-optimization of the conditions (step-by-step vs. one-pot protocol). tively.
In the case of the less activated aromatic systems (e.g., 1,3-dimethoxybenzene), their excess (1:2 or 1:5) had a positive effect on the reaction yields but made the work-up procedure more difficult (sometimes one crystallization was not enough).Our research showed that the one-pot methodology (without the isolation of 1-hydroxyalkylphosphonium salts) is slightly more efficient (Table 5, entries 1, 4, and 5).
Table 5.The reaction of 1-hydroxyalkylphosphonium salts 1 with aromatic compounds-optimization of the conditions (step-by-step vs. one-pot protocol).

Entry
Molar Ratio Procedure Solvent Yield, % For more reactive substrates (1,3,5-trimethoxybenzene and indole), the stoichiometric ratio (1:1) is optimal, as it ensures high yields and an easier purification of the crude product (see Scheme 3).In special cases, e.g., when aqueous solutions of aldehydes are used (see chloroacetaldehyde, Scheme 3/compound 7d), the step-by-step procedure gives much better results.Water does not affect the formation of 1-hydroxyalkylphosphonium salts, but it hinders reactions with arenes.All in all, both methods allowed the synthesis of 1-arylalkylphosphonium salts 7a-g (R 1 = alkyl) at good to very good yields, and such compounds had not been synthesized in this way before.The only option for the synthesis of compounds 7h-l is the one-pot protocol because the isolation of the expected 1-hydroxyalkylphosphonium salt is not possible.
In comparison to the one-pot procedure proposed by Masarwa et al. (PPh3: TfOH: 2: (Het)ArH = 1.1:1.2:1:1,CH3CN, 45-80 °C, 15-24 h) [6], we used a different ratio of substrates (the lack of excess acid is crucial here; its excess can catalyze the reaction).Therefore, we had to increase the reaction temperature, but its duration was shortened, and the product purification became easier (simple crystallization, without chromatography).Furthermore, the use of Ar3P•HX seems to be safer and more convenient (solid and less aggressive reagents).
For reactions with amide-type substrates, we used analogous conditions to those in the case of the one-pot procedure we recently described [24].Transformations occurred similarly, with good yields.It is easy to notice that hydroxymethylphosphonium salts 1 (R 1 = H) are less reactive compared to phosphonium salts with a longer alkyl chain (e.g., R 1 = Et), which also is in agreement with the observations made previously (Scheme 4, see also Table S2, Supporting Information) [24].Both transformations required an elevated temperature of 120 • C and 50 • C, respectively.In the case of the less activated aromatic systems (e.g., 1,3-dimethoxybenzene), their excess (1:2 or 1:5) had a positive effect on the reaction yields but made the work-up procedure more difficult (sometimes one crystallization was not enough).Our research showed that the one-pot methodology (without the isolation of 1-hydroxyalkylphosphonium salts) is slightly more efficient (Table 5, entries 1, 4, and 5).
For more reactive substrates (1,3,5-trimethoxybenzene and indole), the stoichiometric ratio (1:1) is optimal, as it ensures high yields and an easier purification of the crude product (see Scheme 3).In special cases, e.g., when aqueous solutions of aldehydes are used (see chloroacetaldehyde, Scheme 3/compound 7d), the step-by-step procedure gives much better results.Water does not affect the formation of 1-hydroxyalkylphosphonium salts, but it hinders reactions with arenes.All in all, both methods allowed the synthesis of 1-arylalkylphosphonium salts 7a-g (R 1 = alkyl) at good to very good yields, and such compounds had not been synthesized in this way before.The only option for the synthesis of compounds 7h-l is the one-pot protocol because the isolation of the expected 1-hydroxyalkylphosphonium salt is not possible.
In comparison to the one-pot procedure proposed by Masarwa et al. (PPh 3 :TfOH:2: (Het)ArH = 1.1:1.2:1:1,CH 3 CN, 45-80 • C, 15-24 h) [6], we used a different ratio of substrates (the lack of excess acid is crucial here; its excess can catalyze the reaction).Therefore, we had to increase the reaction temperature, but its duration was shortened, and the product purification became easier (simple crystallization, without chromatography).Furthermore, the use of Ar 3 P•HX seems to be safer and more convenient (solid and less aggressive reagents).
For reactions with amide-type substrates, we used analogous conditions to those in the case of the one-pot procedure we recently described [24].Transformations occurred similarly, with good yields.It is easy to notice that hydroxymethylphosphonium salts 1 (R 1 = H) are less reactive compared to phosphonium salts with a longer alkyl chain (e.g., R 1 = Et), which also is in agreement with the observations made previously (Scheme 4, see also Table S2, Supporting Information) [24].Interestingly, the conducted research provided further evidence for the presence of equilibrium in the examined systems.The reactions of phosphonium salt 1a with acrylamide did not lead to the expected 1-(N-acylamino)alkylphosphonium salt 9f, but rather a complex mixture in which we identified the phosphonium salt 10 as one of the main products (about 30%).In turn, the phosphonium salt 1o (generated in situ) reacts under the same conditions to give 10 as the only reaction product.This can be explained by the course of the reaction proposed in Scheme 5.The addition to the double bond appears to occur more readily, causing the equilibrium to be shifted, limiting the formation of the desired product 9f.The 1-aryl-1-hydroxyalkylphosphonium salts (e.g., 1o) are much less stable, which means that there is more Ph3P•HBF4 in the system and thus the addition to the double bond is even more privileged.Interestingly, the conducted research provided further evidence for the presence of equilibrium in the examined systems.The reactions of phosphonium salt 1a with acrylamide did not lead to the expected 1-(N-acylamino)alkylphosphonium salt 9f, but rather a complex mixture in which we identified the phosphonium salt 10 as one of the main products (about 30%).In turn, the phosphonium salt 1o (generated in situ) reacts under the same conditions to give 10 as the only reaction product.This can be explained by the course of the reaction proposed in Scheme 5.The addition to the double bond appears to occur more readily, causing the equilibrium to be shifted, limiting the formation of the desired product 9f.The 1-aryl-1-hydroxyalkylphosphonium salts (e.g., 1o) are much less stable, which means that there is more Ph 3 P•HBF 4 in the system and thus the addition to the double bond is even more privileged.
Interestingly, the conducted research provided further evidence for the presence of equilibrium in the examined systems.The reactions of phosphonium salt 1a with acrylamide did not lead to the expected 1-(N-acylamino)alkylphosphonium salt 9f, but rather a complex mixture in which we identified the phosphonium salt 10 as one of the main products (about 30%).In turn, the phosphonium salt 1o (generated in situ) reacts under the same conditions to give 10 as the only reaction product.This can be explained by the course of the reaction proposed in Scheme 5.The addition to the double bond appears to occur more readily, causing the equilibrium to be shifted, limiting the formation of the desired product 9f.The 1-aryl-1-hydroxyalkylphosphonium salts (e.g., 1o) are much less stable, which means that there is more Ph3P•HBF4 in the system and thus the addition to the double bond is even more privileged.

General Methods
Melting points were determined in capillaries and were uncorrected.The 1 H-and 13 C-NMR spectra were recorded at operating frequencies of 400 and 100 MHz, respectively, using TMS (tetramethylsilane) as the internal resonance shift standard.The 31 P-NMR spectra were recorded at an operating frequency of 161.9 MHz, with respect to H 3 PO 4 at zero ppm.All chemical shifts (δ) are reported in ppm and coupling constants (J) in Hz.Infrared (IR) spectra were measured on a Fourier transform (FT)-IR spectrophotometer (Attenuated Total Reflectance-ATR method).High-resolution mass spectrometry (HR-MS) analyses were performed using a Waters Xevo G2 Q-TOF mass spectrometer equipped with an ESI source operating in positive ion mode.The accurate mass and composition of the molecular ion adducts were calculated using the MassLynx 4.1 software incorporated within the instrument.Solvents (ACS grade) were stored over molecular sieves prior to use.All other commercially available reagents were used as received, without further purification or modifications.

Synthesis of 1-Hydroxyalkylphosphonium Salts
To an aldehyde (1.0 mmol) and a solvent (1 cm 3 ) placed in a glass vial sealed with a screw-cap, triarylphosphonium salt HP + Ar 3 X − (1 mmol) was added.The reaction was carried out under the conditions given in Table 1 and 2.Then, 1-hydroxyalkylphosphonium salts 1 were precipitated using Et 2 O.The crude 1-hydroxyalkylphosphonium salts 1 can also be obtained only via the evaporation of volatile components.

NMR Experiments (Studies of Equilibria)
A mixture of an aldehyde (0.1 mmol), a triarylphosphonium salt Ar 3 P•HX (0.1 mmol), and a deuterated solvent (0.65 cm 3 ) was placed in an NMR tube.The reaction was carried out under the conditions given in Tables 3 and 4. Changes in substrate and/or product concentrations were monitored via 1 H NMR and confirmed via 31

Reactions of 1-Hydroxyalkylphosphonium Salts with (hetero)arenes (Step-by-Step)
To a solution of 1-hydroxyalkylphosphonium salt (1.0 mmol) in CH 3 CN (1 cm 3 ) placed in a glass vial sealed with a screw-cap, a (hetero)aromatic compound (5, 2, or 1 mmol) was added.The reaction was carried out under the conditions given in Scheme 3.Then, the 1-arylalkylphosphonium salts 7 were precipitated using Et 2 O.

Conclusions
An efficient and convenient method for the preparation of 1-hydroxyalkylphosphonium salts was optimized and improved.This synthesis is based on the reaction of aldehydes

a
The yield was estimated based on 1 H and 31 P{ 1 H} NMR, b The isolated yields, c The reaction of aldehyde 2a, 1,3-dimethoxybenzene, and PPh 3 in the presence of HBF 4 (tetrafluoroboric acid diethyl ether complex).Molecules 2024, 29, x FOR PEER REVIEW 8 of 19

Scheme 4 .
Scheme 4. Conditions and results for the reaction of 1-hydroxyalkylphosphonium salts 1 with amide-type substrates.

Scheme 4 .
Scheme 4. Conditions and results for the reaction of 1-hydroxyalkylphosphonium salts 1 with amide-type substrates.

Entry Phosphonium Salts 1 Time, min Temp., • C Solvent Yield, % No. Ar X
a Only after solvent evaporation, no crystallization (crude salt), b
Only after solvent evaporation, no crystallization (crude salt), b The reaction of aldehyde 2 and PPh3 in the presence of HBF4 (tetrafluoroboric acid diethyl ether complex, molar ratio of 1:1:1), c A mixture of products (estimated content of compound 1a based on 31 P{ 1 H} NMR is 76%), d A mixture of products (estimated content of compound 1d based on 1 H and 31 P{ 1 H} NMR is 31%), crystallization attempts failed. a

Table 3 .
Equilibrium in the reaction of naphthaldehyde 2o and triarylphosphonium salts 6.

Table 3 .
Equilibrium in the reaction of naphthaldehyde 2o and triarylphosphonium salts 6.

Table 4 .
Equilibrium in the synthesis of 1-hydroxyalkylphosphonium salts 1

Table 4 .
Equilibrium in the synthesis of 1-hydroxyalkylphosphonium salts 1

Table 4 .
Equilibrium in the synthesis of 1-hydroxyalkylphosphonium salts 1

Table 4 .
Equilibrium in the synthesis of 1-hydroxyalkylphosphonium salts 1

Table 5 .
The reaction of 1-hydroxyalkylphosphonium salts 1 with aromatic compounds-optimization of the conditions (step-by-step vs. one-pot protocol).