Phospha-Mannich reactions of RPH₂, R₂PH, and R₃P

Abstract

Phosphorus-based Mannich-type reactions (phospha-Mannich reactions) of primary or secondary phosphines with carbonyl compounds and amines (R₂NH, RNH₂, and NH₃) provide a powerful synthetic tool in the worldwide search for future ligands. The variety of amines and phosphines available allows for designing and fine-tuning water-soluble, chiral, macrocyclic, pincer, tripodal, photoactive, and etc., phosphine ligands with P–C–N linkage(s) (P,N-acetals). Aminized supports and amine-terminated dendrimers can easily be phosphine-functionalized by phospha-Mannich reactions, and used in reusable heterogeneous catalysts. If CH₂O is used as a C-component, its stable adducts with phosphines, that is, RP(CH₂OH)₂ and R₂PCH₂OH, are often used in syntheses of P,N-acetals as they are less toxic and non-pyrophoric analogs of the phosphines, whereas other carbonyl compounds are usually converted into imines or iminium salts. In phospha-Mannich reactions, tertiary phosphines form a P⁺–C–N linkage (P⁺,N-acetals) that can easily be broken by bases, realizing imine, or iminium cations, and are used as imine/iminium donors in organic syntheses.

Graphical abstract

Keywords:

• Hydroxymethyl phosphines
• aminomethyl phosphines
• PN-ligands
• P,N-acetals
• heterocycles
• macrocycles
• amines
• imines
• iminium salts
• immobilization
• hydrophosphination

Acknowledgments

We are indebted to Drs. Yulia B. Malysheva and Elena A. Zaburdaeva from the Nizhniy Novgorod State University, and Dr. Vladmir Malakhov from Ludwig-Maximilians-Universität München, for their help in the literature search. Photoshop brushes, developed by Zaen Bien (http://z-design.deviantart.com), were used for Graphical Abstract.

Funding

The research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Scheme 4. Reactions of PhPH₂ with tetraethylmethanediamine^[28] and Me₂NCH₂Cl.^[36]

Scheme 5. Preparation of P,N₂-acetals from P,O₂-acetals in the presence of KOH.^[37,38]

Scheme 6. Reaction of the dioxaborataphosphoniarinane 6 with Ph₂NH.^[39]

Scheme 7. Reaction of ω-diphosphino-alkanes with Et₂NH and CH₂O.^[41]

Scheme 8. Reaction of 1,2-bis(phosphino)benzene with CH₂O and secondary amines. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S2.

Scheme 9. Oxidative addition of PhPH₂ to N,N′-diamidocarbene.^[47]

Scheme 10. Reaction of dimethylformamide with PhP(SiMe₃)₂.^[49]

Scheme 11. Reaction of P,(OH)₂-acetals and N,N'-dialkylhydrazines.^[50]

Scheme 12. Reaction of P,(OH)₂-acetals with N,N'-bis(1-phenylethyl)ethane-1,2-diamine.^[51]

Scheme 13. Reaction of P,(OH)₂-acetals with N,N'-diphenylbenzidine and 4,4′-methylenebis(N-alkylanilines).^[52,53] Products, yields, ³¹P NMR shifts, are listed in Table S3.

Scheme 14. 1:2:3 Reactions of primary phosphines, primary amines, and CH₂O. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S4.

Scheme 15. Reaction of P,(NH)₂-acetals with CH₂O.^[50]

Scheme 16. Reaction of N-ethyl-2-phosphinoethanamine with aldehydes.^[71]

Scheme 17. Reaction of the 2-phosphinoethanamine 24 with excess CH₂O.^[72]

Scheme 18. Reaction of N-allyl-2-phosphinoethanamine with CH₂O.^[73]

Scheme 19. Synthesis of N-substituted benzazaphospholes via cyclo-PH,N-acetals.^[74,75]

Scheme 20. Reaction of N-neopentyl-2-phosphinoaniline with glyoxylic acid and p-toluidine.^[86]

Scheme 21. Reaction of N-tert-butylmethanimine with PhPH₂.^[90]

Scheme 22. Zr-catalyzed reaction of N-benzylideneaniline with the phosphine 34.^[91]

Scheme 23. Reaction of PhP(H)SiMe₃ with N-benzylideneaniline or N-benzylidenemethylamine.^[92]

Scheme 24. Reduction of the ethyl phosphinate 39 with BH₃·SMe₂ (Ar = 4-Br-C₆H₄).^[93]

Scheme 25. Preparation of 1,3,5-oxazaphosphinanes via a PH,NH-acetal.^[94]

Scheme 26. Cyclocondensation of 2-phosphinoethanamine and 2-phosphinoaniline with carbonyl compounds. Products, yields, and related references, are listed in Table S5.

Scheme 27. Reaction of 3-aminopropylphosphine with salicylaldehyde.^[97]

Scheme 28. Cyclocondensation of 2-aminobenzylphosphine with carbonyl compounds.^[98]

Scheme 29. Cyclocondensation of 2-(2,3-dimethyl-3-phosphinobutan-2-yl)aniline with ketones.^[99]

Scheme 30. Reaction of bis(hydroxymethyl)mesitylphosphine and bis(4-amino-3-carboxyphenyl)methane.^[52]

Scheme 31. Acid-catalyzed reaction between 2-phosphinoanilines and aromatic aldehydes.

Scheme 32. Acid-catalyzed reactions of 2-phosphinoanilines with excess CH₂O.^[101,102]

Scheme 33. Reaction of pyridine-2,6-dicarbaldehyde with 4-methyl-2-phosphinoaniline.^[75,103]

Scheme 34. Reaction of t-BuPH2 with N-benzylidene-p-toluidine.^[108]

Scheme 35. Reaction of PhP(H)SiMe₃ with N-benzylidenemethylamine.^[92]

Scheme 36. Samarium-catalyzed diastereoselective addition of PhPH₂ to imines.^[109] Products, yields, and ³¹P NMR shifts, are listed in Table S6.

Scheme 37. Reaction of P,(OH)₂-acetals with primary amines. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S7.

Scheme 38. Reactions of PhP(CH₂OH)₂ with glycine.^[45]

Scheme 39. 3C-Phospha-Mannich reaction of PhPH₂ with 4-aminoacetophenone and glyoxylic acid.^[116]

Scheme 40. 3C-Phospha-Mannich reaction of CyPH₂ and i-BuPH₂ with primary amines and glyoxylic acid.^[88,116]

Scheme 41. Reaction of 1,4-bis[bis(hydroxymethyl)phosphinomethyl]benzene with aniline.^[118]

Scheme 42. Reaction of 4,4′-methylenedianiline with PhP(CH₂OH)₂.^[53]

Scheme 43. Reaction of the phosphonium salt PhP(CH₂OH)₃Cl with aniline.^[119]

Scheme 44. Hydrogel network from polypeptides and β-[tris(hydroxymethyl)phosphino]propionic acid.

Scheme 45. Example of peptide-functionalized P,(OH)₂-acetal, demonstrating no reactivity of amido, guanidino, and indole groups.^[133]

Scheme 46. Stepwise phospha-Mannich reactions of hydrazine with primary phosphines.^[137–139] Products, yields, and ³¹P NMR shifts, are listed in Table S8.

Scheme 47. Reaction of benzaldehyde azine with 1,2-diphosphinoethane or 1,2-diphosphinobenzene in the presence of HCl.^[137,139]

Scheme 48. Reaction of furfural azine with primary phosphines in the presence of acetyl chloride.^[137–139]

Scheme 49. Reaction of azines with primary phosphines in the presence of succinyl or phthaloyl chloride. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S9.

Scheme 50. Reaction of azines with 1,2-diphosphinoethane or 1,2-diphosphinobenzene in the presence of succinyl or phthaloyl chloride. Products, yields, and related references, are listed in Table S10.

Scheme 51. Reaction of PhP(CH₂OH)₂ and 1,2-phenylenediamine.^[156]

Scheme 52. 1:1 Reaction of P,(OH)₂-acetals with primary amines. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S11.

Scheme 53. Reaction of PhP(CH₂OH)₂ with excess aniline, and reaction of the resulted P,(NH)₂-acetal with P,(OH)₂-acetals.^[159]

Scheme 54. Synthesis of 1,3,5,7-tetraphenyl-1,3,5,7-tetrazocane from aniline and CH₂O.^[231,232]

Scheme 55. Syntheses of cyclo-P₂,N₂-acetals via alkylation of THP. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S12.

Scheme 56. Syntheses of cyclo-P₂,N₂-acetals from THP and activated olefins.^[237] Products, yields, and ³¹P NMR shifts, are listed in Table S13.

Scheme 57. One by-product from syntheses of cyclo-P₂,N₂-acetals from THP (R = n-Pr, Ar = Ph, X = PF6- or R = CH₂CH₂CO₂Et, Ar = 4-MeO-C₆H₄, X = BF4-).^[237]

Scheme 58. Reaction of 2,5-diphenyl-1,3,5,2-dioxaphosphaborinane with primary amines.^[229,240]

Scheme 59. Reaction of bis[3-bis(hydroxymethyl)phosphinopropyl]phenylphosphine with p-toluidine.^[203]

Scheme 60. Reaction of 1,4-bis[bis(hydroxymethyl)phosphinomethyl]benzene with primary amines.^[118]

Scheme 61. Reaction of P,(OH)₂-acetals with dianilines. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S14.

Scheme 62. Reaction of PhP(CH₂OH)₂ with N-alkyl-2,6-diamino-9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboximides.^[53,252]

Scheme 63. Functionalization of the cyclo-P₂,N₂-acetal, derived from 3-(4-aminophenyl)propionic acid, by coupling with amino acid esters.

Scheme 64. Synthesis of phosphonate substituted cyclo-P₂,N₂-acetal via a halogen-lithium exchange reaction.

Scheme 65. Preparation of a water-soluble Ni²⁺ complex.^[272]

Scheme 66. Expansion of cyclo-P₂,N₂-acetal to a 16-member, macrocyclic ligand in coordination sphere of Au.^[210,280]

Scheme 67. Reaction of P,(OH)₂-acetals with hydrazine.^[50]

Scheme 68. Reaction of PhP(CH₂OH)₂ with 3-phenyl-6,7-benzo-1,5,3-diazaphosphepane.^[156]

Scheme 69. Reactions of 1,2-diphosphinobenzene or 1,2-diphosphinoethane with CH₂O and primary amines. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S15.

Scheme 70. Rearrangement of the diazaphosphorinane 108 in the presence of Ph₂PCH₂OH (Ar = 4-Me-C₆H₄).^[70]

Scheme 71. Syntheses of P-alkyl- and P-aryl-PTA. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S16.

Scheme 72. Synthesis of P-methyl-PTA in the presence of ethylenediamine.^[287]

Scheme 73. Cleavage of a P–CH₂–N linkage within P-alkyl-PTA compounds with Na.^{[284,285,288]}

Scheme 74. Self-assembly of a 1,5-diaza-3,7-diphosphabicyclo[3.3.1]nonane in Fe coordination sphere.^[286,289]

Scheme 75. Types of phospha-Mannich reaction products from secondary phosphines, CH₂O, and monoamines or NH₃.

Scheme 76. Conversion of P,N-acetals into P,N⁺-acetals.^[290]

Scheme 77. Preparation of imidazolium-containing P,N⁺-acetals.^[291,292]

Scheme 78. Syntheses of imidazolium-containing mixed (P,N)(P,N⁺)-acetals (R = Ph, Cy).^[291]

Scheme 79. Syntheses of imidazolium-containing P,N⁺-acetals from N-chloromethyl imidazolium iodide.^[293] DABCO = 1,4-diazabicyclo[2.2.2]octane.

Scheme 80. Phospha-Mannich reaction of secondary phosphines with secondary amines and aldehydes. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S17.

Scheme 81. Phospha-Mannich reactions of Et₂NH with biphosphines.^[313,314]

Scheme 82. Synthetic path to P,N-acetals via a reaction of Ph₂P(S)H with formamides.^[315]

Scheme 83. Reaction of Ph₂PCH₂OH with phosphinamines.^[316]

Scheme 84. Phospha-Mannich reaction of secondary phosphines with bis(dimethylamino)methane. Products, yields, and related references, are listed in Table S19.

Scheme 85. Phospha-Mannich reactions of secondary phosphines or lithiated phosphines with iminium salts. Products, yields, and related references, are listed in Table S20.

Scheme 86. Phospha-Mannich reaction of Ph2PH with sodium (N-phenylthiomethyl)oxazolidine-4-carboxylate.^[323]

Scheme 87. Reaction of the tetramethylformamidinium cations with lithiated secondary phosphines.^[324]

Scheme 88. Disproportionation of the α-phosphino-methanediamines 134.^[324]

Scheme 89. Reaction of dimethylformamide dimethyl acetal with secondary phosphines.^[325]

Scheme 90. Phospha-Mannich reactions of secondary phosphines with morpholine and N-substituted piperazines. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S21.

Scheme 91. Phospha-Mannich reactions of secondary phosphines with L-proline and its derivatives. Products, yields, and related references, are listed in Table S22.

Scheme 92. Reactions of Ph₂PCH₂OH with piperazine-containing antibiotics. Products, yields, and related references, are listed in Table S23.

Scheme 93. P,N-acetals, derived from deacylated ketoconazole or aza-crowns.

Scheme 94. Reaction of 1-hydroxymethyl-(2R,5R)-2,5-dimethylphospholane with Me₂NH.^[345]

Scheme 95. Reaction of 8-hydroxymethyl-1,3,5,7-tetramethyl-2,4,6-trioxa-8-phosphaadamantane and secondary amines. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S24.

Scheme 96. Reaction of a mixture of P,OH-acetals with Et₂NH.^[299,346]

Scheme 97. Stepwise phospha-Mannich reaction of 5,6-dimethylbenzimidazole with secondary phosphines.^[347,348]

Scheme 98. Reaction of chloromethyl-3,5-dimethylpyrazole with Ph₂PLi.^[349]

Scheme 99. Syntheses of P,N-acetals from imidazoles and P(O),O-acetals. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S25.

Scheme 100. Syntheses of P,N-acetals via cyclocondensation of P(S),N-acetals.^[352]

Scheme 101. Syntheses of P,N-acetals from azidomethyl phosphine oxides (R = i-Pr, Cy, Ph).^[356,357]

Scheme 102. Reactions of 3,4-dimethyl-1-arylphospholes, pyrrolidine, and carbonyl compounds. Products and yields are listed in Table S26.^[359]

Scheme 103. Reaction of the methylhydrazone of 4-hydroxybenzaldehyde with Ph₂PCH₂OH.^[360]

Scheme 104. Hydrophosphination of the phenylhydrazone of benzaldehyde with α-carboxy secondary phosphines (R = H, Me).^[361]

Scheme 105. Phospha-Mannich reactions of secondary diamines with secondary phosphines. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S27.

Scheme 106. Reactions of chiral hexahydropyridazines with Ar₂PCH₂OH.^[368] Products, yields, and ³¹P NMR shifts, are listed in Table S28.

Scheme 107. Examples of P,N-acetals, derived from macrocyclic di- and tetra-amines.

Scheme 108. Syntheses of bis-P,N-acetals from 1,2-bis(isopropylphosphino) benzene.^[43]

Scheme 109. Reaction of 1,3-diaminopropane with Ph₂PH and p-CH₂O (1:2:3).^[371]

Scheme 110. Bis- and tetrakis-P,N-acetals derived from 1,8-diaminonaphthalene^[372] and 3,4,9,10-tetraaminoperylene,^[373] respectively.

Scheme 111. Preparation of bis-P,N-acetal from benzimidazole and Ph₂P(O)CH₂OTs.^[374] PMHS = polymethylhydrosiloxane.

Scheme 112. Reaction of 1,2-bis(diphenylphosphinoamino)benzene with p-CH₂O.^[375]

Scheme 113. Synthesis of peptide-based P,N-acetals on solid support (R = Me or i-Bu).^[376]

Scheme 114. An example of Ph₂P-terminated dendrimers.^[378]

Scheme 115. Oxidative addition of Ph₂PH to N-heterocyclic carbenes.^[48,382]

Scheme 116. Oxidative addition of secondary phosphines to N,N′-diamidocarbene.^[47]

Scheme 117. Synthesis of a P,N-acetal via C–H bond activation.^[384]

Scheme 118. Cu-catalyzed hydroamination of vinylphosphine boranes. Products and yields are listed in Table S29.^[385]

Scheme 119. Cyclocondensation of secondary phosphino-amines with carbonyl compounds. Products, yields, and related references, are listed in Table S30.

Scheme 120. 3C-phospha-Mannich reaction of N-(1-phenyl-2-(phenylphosphino)ethyl)aniline with Et₂NH and CH₂O.^[387]

Scheme 121. Cyclocondensation of secondary phosphino-amines or 2-phosphinoanilines with glyoxylic and pyruvic acids. Products, yields, and related references, are listed in Table S31.

Scheme 122. Cyclocondensation of N-methyl-2-(phenylphosphino)aniline with HC(OMe)₃ and exchange of the OMe-group with other alcohols.^[395,396]

Scheme 123. Cyclocondensation of N-mesityl-2-(phenylphosphino)aniline with DMF-DMA.^[403]

Scheme 124. Pd-catalyzed P-arylation of N-neopentyl-1,3-benzazaphosphole.^[75,404] Products and yields are listed in Table S32.

Scheme 125. Reaction of N-alkylated 1,3-benzazaphospholes with t-BuLi [R = CH₂t-Bu, Ad, 2,6-(i-Pr)₂-C₆H₃].

Scheme 126. Reaction of secondary phosphines with imines, with or without solvents. Products, yields, and related references, are listed in Table S33.

Scheme 127. Reaction of secondary phosphines with N-benzylideneaniline in the presence of t-BuOK.^[416]

Scheme 128. Formation of P,NH-acetals from N-benzylidenebenzenesulfonamides.^[417]

Scheme 129. Hydrophosphination of imines with BH₃-protected Ph₂PH.^[419]

Scheme 130. Reactions of ferrocenylaldimines with Ph₂PLi in air (Ar = Ph, 4-Me-C₆H₄, 4-Cl-C₆H₄, 4-MeO-C₆H₄, 4-EtO-C₆H₄).^[421]

Scheme 131. Reaction of Et₂P–SiMe₃ with imines.^[422]

Scheme 132. Pd-catalyzed stereoselective hydrophosphination of N-tosylimines.^[423] Products, yields, and enantiomeric excess, are listed in Table S34.

Scheme 133. Stereoselective addition of Ph₂PH to ortho-substituted benzaldimines, coordinated to Cr(CO)₃ (R = Me, CH₂CO₂Me, Ph, C₆H₄-4-OMe; Y = Me, OMe, Cl).^[424] For simplicity, only formation of (R,R)-isomer is shown.

Scheme 134. 1,3-Azaphospholidin-5-ones from (phenylphosphino)acetic acid and imines. Products, yields, and related references, are listed in Table S35.

Scheme 135. 1,2,3,4-Tetrahydro-1,3-azaphosphinines from 4-(phenylphosphino)pentan-2-ones and imines.^[426] Products and yields are listed in Table S36.

Scheme 136. Preparation of P,NH-acetals from NH,O-acetals.^[429]

Scheme 137. Stepwise phospha-Mannich reaction of 4,4′-methylenedianiline with Ph₂PH.^[430]

Scheme 138. 2C-Phospha-Mannich reaction of aromatic amines with Ar₂PCH₂OH (Ar = Ph or 2-MeO-C₆H₄). Products, yields, ³¹P NMR shifts, and related references, are listed in Table S37.

Scheme 139. Preparation of P,NH-acetals via P(O),NH-intermediates.^[451]

Scheme 140. Reaction of Cy₂PCH₂OH with N-mesityl-1,2-ethylenediamine or N-mesityl-1,2-phenylenediamine.^[352]

Scheme 141. Reaction of 1-adamantylamine with Ph₂PCH₂OH.^[454]

Scheme 142. Reaction of 7-amino-1,3,5-triazaadamantane with Ph₂PCH₂OH.^[58]

Scheme 143. 3C-Phospha-Mannich reaction of Ph₂PH, bulky amines and benzaldehyde.^[295]

Scheme 144. Reaction of primary amines with 8-hydroxymethyl-1,3,5,7-tetramethyl-2,4,6-trioxa-8-phosphaadamantane. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S38.

Scheme 145. Reaction of Ph₂PCH₂OH with hydrazones containing polyaromatic hydrocarbons.

Scheme 146. Reaction of Ph₂PCH₂OH with glycine N-(anthracen-2-yl)amide.^[132]

Scheme 147. Reaction of secondary phosphines with adducts of α-amino acids and CH₂O.^[298,457] Products and yields are listed in Table S39.

Scheme 148. Reaction of the Na salt of serine with Ph₂PH and excess CH₂O.^[323,457]

Scheme 149. 3C-Phospha-Mannich reaction of Ph₂PH, glyoxylic acid, and primary amines. Products and yields are listed in Table S40.

Scheme 150. Preparation of bis-P,NH-acetals from 1,2-phenylenediamines and 2 equiv. of R₂PCH₂OH. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S41.

Scheme 151. Reaction of tris(2-aminophenyl)amine with i-Pr₂PCH₂OH and preparation of metalloligands.^[490]

Scheme 152. Examples of bis- and tris-P,NH-acetals, obtained by phospha-Mannich reactions.

Scheme 153. Reaction of 1,3-bis((hydroxymethyl)phenylphosphino)propane with sodium 4-aminobenzenesulfonate.^[61]

Scheme 154. Immobilization of P,NH-acetals on the brominated Wang resin.^[415]

Scheme 155. Parallel synthesis of P,NH-acetals on solid support.^[415,502]

Scheme 156. Participation of P,NH-acetals in phospha-Mannich reactions.

Scheme 157. 3C-Phospha-Mannich reaction of a P,NH-acetal.^[90]

Scheme 158. 2C-Phospha-Mannich reaction of Ph₂PCH₂OH with P,NH-acetals. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S42.

Scheme 159. Reactions of N-naphthyl or N-quinolin P,NH-acetals with R2PCl. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S43.

Scheme 160. Condensation of secondary phosphines, primary amines, and CH₂O, leading to P₂,N-acetals. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S44.

Scheme 161. Reaction of 1-hydroxymethyl-2,5-dimethyl- or 2,5-diphenyl-phospholane with primary amines. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S45.

Scheme 162. Reaction of 8-hydroxymethyl-1,3,5,7-tetramethyl-2,4,6-trioxa-8-phosphaadamantane with primary amines. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S46.

Scheme 163. Reaction of 9-hydroxymethyl-9-phosphabicyclo[3.3.1]nonane with (R)-α-methylbenzylamine.^[299,346]

Scheme 164. Preparation of P₂,N-acetals by reduction of products from the Kabachnik-Fields reaction.

Scheme 165. Reactions of Ph₂PCH₂OH with 9-(3-aminopropyl)- and 9-(2-aminoethyl)-adenines.^[529]

Scheme 166. Reactions of α-amino acids, their salts, or esters, with CH₂O and secondary phosphines. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S47.

Scheme 167. Reaction of the oxazolidine derivative 252 with diarylphosphines (Ar = Ph, 4-Me-C₆H₄, 2-MeO-4-Me-C₆H₃).^[323]

Scheme 168. Reaction of glycine amides with Ph₂PCH₂OH. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S48.

Scheme 169. Preparation of diphosphine dioxides from ω-amino acids.^[571]

Scheme 170. Examples of β-cyclodextrin-modified P₂,N-acetals.^[574,575]

Scheme 171. Functionalization of the P₂,N-acetal, derived from 4-Br-aniline.^[576]

Scheme 172. Coupling alanine methyl ester to the COOH group of the P₂,N-acetal 295.^[565] HATU = 1-[bis-(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]-pyridinium 3-oxide hexafluorophosphate.

Scheme 173. Conversion of a phosphonate group of the P₂,N-acetal 297 into phosphonic acid one and grafting to a metal oxide surface.^[510]

Scheme 174. Phospha-Mannich reaction of hydrazine with Ph₂PCH₂OH.^[577]

Scheme 175. Reactions of mono- and di-substituted hydrazines with Ph₂PCH₂OH. Products, yields, and related references, are listed in Table S49.

Scheme 176. Reactions of hydrazones with Ph₂PCH₂OH.^[305]

Scheme 177. Phospha-Mannich reactions of aliphatic and aromatic diamines. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S50.

Scheme 178. Reaction of tert-butyl 3′,5′-bis(3-(4-aminophenyl)propyl)-[1,1′-biphenyl]-4-carboxylate with Ph₂PH and CH₂O.^[595]

Scheme 179. 2C-Phospha-Mannich reaction of the triamine 307 with P,OH-acetals.^[596,597]

Scheme 180. Examples of poly-P₂,N-acetals.^[598]

Scheme 181. Examples of Ph₂P-terminated dendrimers, derived from polypropylenimine hexadecaamine dendrimers.

Scheme 182. Examples of Ph₂P-terminated dendrimers, derived from NH₂-terminated PAMAM dendrimers.^[604]

Scheme 183. The first generation dendritic ligands on rink amide MBHA resin.^[606–608]

Scheme 184. Formation of P₂,N-acetal moieties on a peptide-based support.^[376]

Scheme 185. Reaction of hexachlorophosphazene with the phenolate 316.^[531]

Scheme 186. Immobilization of P₂,N-acetals on SiO₂-supports via the γ-aminopropyltriethoxysilane linker. MA = methyl acrylate, en = ethylenediamine.

Scheme 187. P₂,N-functionalized SiO₂-coated Fe₃O₄ nanoparticles.

Scheme 188. Anchoring a P₂,N-acetal on Fe₃O₄ magnetic nanoparticles.^[659,660]

Scheme 189. 2C-Phospha-Mannich reaction of Ph₂PCH₂OH with NH₂-groups of chitosan.^[661]

Scheme 190. Functionalization of an activated carbon support with P₂,N-acetals using ethylenediamine as a linker.^[663]

Scheme 191. Functionalization of an activated carbon support with P₂,N-acetals using 3-aminopropanol as a linker.^[530]

Scheme 192. Ph₂P-functionalized graphene oxide.^[665]

Scheme 193. Reactions of secondary 2-phosphinoethanamines or 3-phosphinopropan-1-amines with carbonyl compounds. Products, yields, and related references, are listed in Table S51.

Scheme 194. Reaction of 2-(phenylphosphino)ethanamine with salicylaldehyde.^[679]

Scheme 195. Reaction of 4-(phenylphosphino)butan-1-amine with carbonyl compounds.^[680]

Scheme 196. Reaction of γ-keto secondary phosphines with n-BuNH₂.^[426]

Scheme 197. Cyclocondensation of 2-(phenylphosphino)ethanamine with glyoxylic and α-keto acids.^[388,389]

Scheme 198. Cyclocondensation of P-alkylated 2-phosphinoanilines with cyclohexanone.^[96]

Scheme 199. Cyclocondensation of 2-((phenylphosphino)methyl)aniline with benzaldehyde.^[682]

Scheme 200. Preparation of ferrocene-containing P,NH-acetal.^[683]

Scheme 201. Cyclocondensation of bis-P,OH-acetals with primary amines. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S52.

Scheme 202. Cyclo-P₂,N-acetals, derived from 1,2-bis(phosphino)benzenes^[43] and bis(phosphino)carbaborane.^[699]

Scheme 203. Reaction of bis((hydroxymethyl)phenylphosphino)ethane with ethylenediamine.^[687]

Scheme 204. Macrocyclic P₄,N₂-acetals from bis-P,OH-acetals and primary amines. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S53.

Scheme 205. Reaction of m-xylylenediamine with 1,3-bis(mesitylphosphino)propane and CH₂O.^[720]

Scheme 206. Reaction of P,OH-acetals with NH₃. Products, yields, ³¹P NMR shifts, and related references, are listed in Table S54.

Scheme 207. Examples of P₃,N-acetals, derived from cyclic phosphines: 2,5-dimethyl- or 2,5-diphenyl-phospholane^[557] and 5H-benzo-[b]-phosphindole.^[308]

Scheme 208. Preparation of P₃,N-acetals from (ClCH₂)₃N.^[538,736]

Scheme 209. Reaction of Ph₂PH with hexafluoropropan-2-imine.^[737]

Scheme 210. Reaction of 4-phosphinobutan-2-ones with aldehydes in the presence of NH₃.^[426] Products and yields are listed in Table S55.

Scheme 211. Synthesis of the BH₃-protected P,NH₂- and P(O),NH₂-acetals.^[420]

Scheme 212. Synthesis of a P₂,NH-acetal from tert-butyl carbamate.^[727]

Scheme 213. Reaction of tertiary phosphines with aldehydes.

Scheme 214. Reaction of imines and iminium cations with tertiary phosphines.

Scheme 215. Formation of an imine and Ph₃P in reactions of ylides with PhN₃.^[741]

Scheme 216. Reaction of N-fluorosulfonylbenzaldimine with Ph₃P·HBr.^[412]

Scheme 217. Reaction of N-(bromo(phenyl)methyl)aniline with Et₂PPh.^[741] In the reference, N-(bromo(phenyl)methyl)aniline is presented as benzylidene aniline hydrobromide.

Scheme 218. Proposed equilibria in mixtures of a tertiary phosphine, a primary amine, and a carbonyl compound.

Scheme 219. 3C-Phospha-Mannich reaction of the phosphinoethyne 374 with Et₂NH and CH₂O.^[744]

Scheme 220. 3C-Phospha-Mannich reaction of phosphonium salts Ar₃P·HX with aldehydes and amides or carbamates.^[745] Products and yields are listed in Table S56.

Scheme 221. 3C-Phospha-Mannich reaction of phosphonium salts Ar3P·HX with aldehydes and lactams or imides.^[745] Products and yields are listed in Table S57.

Scheme 222. 2C-Phospha-Mannich reaction of P⁺,OH-acetals with methyl carbamate, 1,1- and 1,3-dimethylureas, and acetamide. Products, yields, and related references, are listed in Table S58.

Scheme 223. Cyclocondensation of 2-Ph₂P-aniline with benzaldehydes in the presence of acid.^[752]

Scheme 224. Cyclization of N-benzylidene-2-Ph₂P-aniline in the presence of BF₃·Et₂O.^[753]

Scheme 225. Reaction of hydrazine with 2-Ph₂P-benzaldehyde.^[754]

Scheme 226. Reactions of N-methoxymethyl cyclic ureas with Ph₃P in the presence of acids.

Scheme 227. Reaction of 3,5-dimethyl-1,3,5-oxadiazinan-4-one with Ph₃P in the presence of HBr.

Scheme 228. Reaction of N-(1-methoxyalkyl)imides with Ar₃P in the presence of HBF4.^[755] Products and yields are listed in Table S59.

Scheme 229. Reaction of N-(1-alkoxyalkyl)amides with phosphonium salt Ph₃P·HBF₄. Products, yields, and related references, are listed in Table S60.

Scheme 230. Replacement of Ph₃P within P⁺,NH-acetals with other nucleophiles.

Scheme 231. Syntheses of P⁺,N- and P⁺,NH-acetals from oxazol-5(4H)-ones.

Scheme 232. Reaction of iminium salts with tertiary phosphines. Products, yields, and related references, are listed in Table S61.

Scheme 233. Reactions of Ph3P with Me₂NCH₂Cl.

Scheme 234. Instability of P⁺,N-acetal triflates.^[791]

Scheme 235. Reaction of (2-i-Pr-phenyl)diphenylphosphine with the Alder’s dimer.^[791]

Scheme 236. Reaction of (C₂F₅)₃P with Me₂NCH₂F.^[792]

Scheme 237. Formation of P⁺,N-acetals during the penem synthesis.

Scheme 238. Reactions of N-chloro- or N-bromo-alkyl amides with Ph₃P. Products, yields, and related references, are listed in Table S62.

Scheme 239. Syntheses of oxazole derivatives from Ph₃P and N-(1-chloro-2-oxo-2-phenylethyl)amides.^[804]

Scheme 240. Reaction of Ph₃P with N-(1,2,2-trichloroethyl)amides^[805] or N-(1,2,2,2-tetrachloroethyl)amides.^[806]

Scheme 241. Reactions of chloro(isocyanato)methane with tertiary phosphines; action of alcohols on the products.^[808,809] Products and yield are listed in Table S63.

Scheme 242. Quaternization of PTA with MeOTf in acetone.^[810]

Scheme 243. Reaction of i-Pr₂PCH₂NMe₂ with MeBr.^[290]