Electron-Deficient Acetylenes as Three-Modal Adjuvants in SNH Reaction of Pyridinoids with Phosphorus Nucleophiles

Publications covering a new easy metal-free functionalization of pyridinoids (pyridines, quinolines, isoquinolines, acridine) under the action of the system of electron-deficient acetylenes (acetylenecarboxylic acid esters, acylacetylenes)/P-nucleophiles (phosphine chalcogenides, H-phosphonates) are reviewed. Special attention is focused on a SNH reaction of the regioselective cross-coupling of pyridines with secondary phosphine chalcogenides triggered by acylacetylenes to give 4-chalcogenophosphorylpyridines. In these processes, acetylenes act as three-modal adjuvants (i) activating the pyridine ring towards P-nucleophiles, (ii) deprotonating the P-H bond and (iii) facilitating the nucleophilic addition of the P-centered anion to a heterocyclic moiety followed by the release of the selectively reduced acetylenes (E-alkenes).

This review covers publications (since 1999) concerning the reactions of pyridinoids with PH-nucleophiles in the presence of electron-deficient acetylenes which act as trimodal (polarization/deprotonation/oxidation) catalyst-like adjuvants.

One-Step S N H Phosphorylation
In 2018, it was found that the regioselective oxidative cross-coupling reaction between pyridines 1a,b and secondary phosphine chalcogenides 2a-j was triggered and further driven by electrophilic acetylenes 3a-d to produce S N H products, phosphorylated pyridines 4a-n, and E-acylphenylethenes 5a-d (Scheme 1) [37]. The reaction tolerates a quite representative number of structurally diverse secondary phosphine chalcogenides (oxides, sulfides and selenides), having both aromatic and alkyl aromatic substituents. The reaction involves the reversible generation of 1,3-dipole A via a nucleophilic attack of pyridine nitrogen at the electron-deficient triple bond (Scheme 2) [37].
The intermediate A accepts a proton from the phosphine chalcogenides 2 to produce the P-centered anion, which regioselectively attacks position four of the pyridine ring delivering dihydropyridine B. Its aromatization occurs via the stereoselective elimination of E-acylphenylethenes 5 from isomerized intermediate B C. The elimination includes the transfer of the hydride anion from position two of dihydropyridine to emerging carbocation. The driving force of the elimination is likely a higher thermodynamic stability of the final products (phosphorylated pyridines 4 and conjugated functionalized ethenes 5) as compared to intermediates B C.
The mechanism is supported by the detection of the intermediate dihydropyridine 7a in a mixture ( 1 H and 31 P NMR) with the corresponding pyridine 4i, when pyridine 1a reacts (room temperature, MeCN, 4 h) with terminal furoylacetylene 6a (having no phenyl substituent in position two) and phosphine selenide 2i (Scheme 3).  The perdeuteropyridine (pyridine-d 5 ) with phosphine sulfide 2f and acetylene 3c afforded the isotopically labeled cross-coupling product, 4-[bis(2-phenylethyl)thiophosphoryl] pyridine-d 4 , in a 42% yield (for 50 h) [37]. The low yield and longer reaction time compared to those for non-deuterated pyridine (71%, 35 h) are likely due to the deuterium kinetic isotopic effect. Notably, 3-fluoropyridine appeared unable to undergo above cross-coupling, obviously because of its lower basicity/nucleophilicity (an electron-acceptor effect of the fluorine atom).
The above cross-coupling might open simple access to the related phosphines, soughtafter ligands for new catalytically active metal complexes, having been demonstrated by the reduction in selenophosphorylpyridine 4i to phosphine 9 (Scheme 5) [37]. The improved green route towards 4-chalcogenophosphorylpyridines 4 was also developed [38]. Therefore, it was found that the previously considered S N H cross-coupling of pyridine 1a and 3-methylpyridine 1b with bis(2-phenylethyl)phosphine oxide 2b or bis(2-phenylethyl)phosphine sulfide 2f in the presence of benzoylphenylacetylene 3c as an adjuvant can be realized in a solvent-free version for a much shorter time (5.5-7 h), similar to Scheme 1. This greener protocol for the synthesis of phosphorylated pyridines 4 is not only environmentally friendly, but in some cases provides better average yields.
Terminal acylacetylenes 6a,b (2-furoyl-and benzoylacetylene) can also behave as adjuvants triggering and driving S N H cross-coupling of pyridines 1 with secondary phosphine chalcogenides 2 under similar conditions to afford 4-chalcogenophosphorylpyridines 4 in up to a 70% yield (Scheme 6). In the reaction, intermediate 1-acylvinyl-4-chalcogenophosphoryl dihydropyridines 7 were isolated (in 52-77% yields, see also Scheme 21 below), further undergoing the oxidative (relative to the dihydropyridine ring) elimination of vinyl ketone oligomers [39]. The cross-coupling starts with the prototropic shift in the 1,4-dihydropyridine ring to 1,2-isomers, from which the redox elimination of acylethenes takes place easier as a concerted step process. The moderate yields of the target products 4 and the presence of acylphosphorylethenes of phosphine chalcogenides to acylacetylenes in the reaction mixture were assigned [39] to the retro-aromatization of intermediates 7 to the starting pyridines. This likely resulted from the dissociation of the P-C bond and recombination of chalcogenophosphoryl anions with the leaving acylvinyl cations (Scheme 7). The reflux (80-85 • C, 96 h) of pyridine 1a, 3-phenyl-2-propynenitrile 10 and phosphine oxides 2a,b in MeCN led to the regioselective phosphorylation of pyridine to 4-phosphorylpyridines 4a,b in a 30-35% yield and 3-phenyl-2-propenenitrile oligomers (Scheme 8) [40]. All the above information has allowed for the generalization of a concept of trimodal (polarization/deprotonation/oxidation) adjuvant-like assistance of electron-deficient acetylenes in the S N H reaction of the pyridinoid heterocycles with PH-nucleophiles. This includes: (i) the repolarization of the pyridine ring, (ii) generation of phosphorus-centered anions by the deprotonation of the P-H bond and (iii) oxidation of the dihydropyridine ring.

N-Vinylated/C-Phosphorylated Pyridines: Delayed S N H Phosphorylation
As follows from the preceding Section, the possibility to stop the S N H phosphorylation of pyridines with secondary phosphine chalcogenides in the presence of electron-deficient acetylenes as adjuvants on the intermediate step, i.e., the formation of N-vinylated/ C(4)-phosphorylated 1,4-dihydropyridines, provided a novel efficient approach to the synthesis of earlier inaccessible richly functionalized dihydropyridines.
2-Methylpyridine 1c with methyl propiolate 11a and diphenylphosphine sulfide 2e gave dihydropyridine 12g in a 47% yield, along with Eand Z-isomers of diphenyl (methylpropenoate)phosphine sulfide 13 (content in the reaction mixture ≈ 30%, identified by 31 P NMR) (Scheme 10) [45]. The side formation of vinylphosphine sulfide 13 was expected from the known data that secondary phosphine chalcogenides added to acyl-and cyanoacetylenes in the presence of the base [54]. To rationalize the formation of monoadducts 13, 19 and 20, especially with 4-methylpyridine (Schemes 12 and 13), the two competitive initial reactions should be analyzed [47]; the protonation of pyridines by the P-H bond (Scheme 15, a) and nucleophilic attack of pyridine nitrogen to the triple bond of alkyl propiolates to generate zwitterions A (Scheme 15, b). Assumingly, the protonation of 4-methylpyridine as more basic than 2-and 3-methyl congeners (pK a 6.05, 5.96, 5.68, respectively) is preferred, particularly by the most acidic secondary phosphine selenide 2i (compared with other phosphine chalcogenides [55]). This is why a two-component interaction between phosphine chalcogenides and acetylenes 11 took over. 4-Methylpyridine, in this case, plays a role of a basic catalyst.
At the same time, because of the weaker acidity of the secondary phosphine oxide, zwitterion A is not neutralized with the proton (the phosphine oxide remaining intact), but further reacts with the second molecule of methyl propiolate as an electrophile to furnish the Acheson adduct [48].
On the example of diethyl acetylenedicarboxylate 21a, pyridine 1a and bis(2-phenylethyl) phosphine selenide 2i, it was shown that internal acetylenes of such a type were less effective in the three-component reaction with pyridines and secondary phosphine chalcogenides [49]. Therefore, at an equimolar ratio of these reagents (room temperature, 1 h) E-isomer of N-ethenyl-1,4-dihydropyridine 22 was formed in a 17% yield (Scheme 16). Under these conditions, a competitive two-component reaction of the nucleophilic addition of secondary phosphine selenide 2i to electron-deficient acetylene 21a mainly proceeded to give E-monoadduct 23. Scheme 16. Reaction of pyridine, diethyl acetylenedicarboxylate and secondary phosphine selenide.
In these reactions, the stereoselectivity is probably a result of the steric screening of position two in the Z-configuration of adducts 24 (Scheme 17), while this is not the case in the E-configuration. Finally, due to the Z-E equilibrium, the addition proceeds as the E-selective process, i.e., to form only E-isomers of adducts 24. Scheme 17. Phosphorylation/vinylation of pyridines with diphenylphosphine oxide and acylacetylenes.
Although the yields of dihydropyridines 24 were from good to excellent (72-94%), the reaction time differed considerably (from 3 to 21 h), indicating a significant substituents effect in the pyridine ring on the process rate. Indeed, the faster process occurred for 2-and 3-methylpyridines (4 and 3 h), whereas 3-fluoropyridine required a longer time (20-21 h). Noteworthy, the reactivity of perdeuteropyridine and non-deuterated pyridine is roughly the same that follows from close yields of the corresponding products (79-85%) and reaction times (5-5.5 h). This means that no breaking/forming of C-D bonds is involved in these steps. The more donating substituents at the P atom, as in phosphine oxide (PhCH 2 CH 2 ) 2 P(O)H, preclude the phosphorylation [39] that agrees a lesser PH-acidity of these phosphine oxides [55].
The rearrangement was completed when 1,2-dihydroadducts 24a,b,e-i were heated (50-55 • C, 5-8.5 h) to produce 1,4-dihydroadducts and E-acylvinyl-4-phosphorylpyridines 25a-g [39]. These products were synthesized directly from pyridines 1a-d, phosphine oxide 2a and acetylenes 6a,b under the same conditions (Scheme 19) [39]. Fluoropyridine derivatives 24j,k turned out to be reluctantly relative to such a migration undergoing the backward aromatization to 3-fluoropyridine at a higher temperature (70-75 • C) or upon treatment with external oxidants (chloranil and DDQ). This was rationalized [39] in terms of an ion-pair interplay, including the cleavage of the C-P bond and exchange between pyridinium cation A and phosphine oxide anion (Scheme 20). Expectedly, the dissociation is easier the more stable the ions are (or ion-like species) formed. Consequently, the least sTable 3-fluoropyridinium cation or cation-like intermediate, due to the electron-withdrawing effect of fluorine substituent, should form in a lesser concentration, if any, and this is why the fluoro-containing 1,2-diadduct is not subjected to the rearrangement. Phosphine oxide anionic species migrate to position four to form the more thermodynamically stable 1,4-regioisomer 25. Scheme 20. Tentative dissociation of 1,2-dihydroadducts to ion pairs. The higher thermodynamic stability of 1-E-benzoylvinyl-4-diphenylphosphoryl-1,4dihydropyridine 25a (by 4.0 and 3.4 kcal/mol of enthalpy in the MeCN solution and gas phase, respectively, or by 5.0 and 4.8 kcal/mol of Gibbs free energy in the MeCN solution and gas phase, respectively) compared to the corresponding 1,2-dihydropyridine 24a was confirmed by quantum chemical calculations (B2PLYP/6-311 + G** // B3LYP/6-31 + G* + IEF PCM (B3LYP/6-31 + G*)) [39].
It was suggested [39] that 3-fluoropyridine generates the initial zwitterions A in negligible concentration (Scheme 22), which is not enough for further phosphorylation. Overall, these results are in keeping with the above pseudo ion-pair mechanism, which implies a faster transfer of more stable chalcogenophosphoryl anions.
All the above information has evidenced two modalities of terminal acetylenes as catalysts/promoters (polarizing and deprotonating agents) in the S N H phosphorylation of pyridines with secondary phosphine chalcogenides: (i) the repolarization of the pyridine ring rendering it a cation-like character (Scheme 22) and (ii) producing P-centered anions by their deprotonation of the corresponding nucleophiles (Scheme 22). This gave the key intermediates, 2-and 4-phosphorylated acylvinylpyridines 24, 25 and 7 (Schemes 17, 19 and 21). The third modality of these electron-deficient acetylenes, i.e., to behave as inner oxidants, readily occurs at a high temperature.
This S N H phosphorylation was assumed to follow the mechanism shown in Scheme 22, i.e., via the reversible generation of zwitterions A-B, intermediate cations C-E and phosphoruscentered anions [45]. The latter is attached to either position four of the intermediate E pyridinium ring in the case of phosphine oxide 2a or position two of the intermediate D with less spatially encumbered phosphine oxide 2b to afford the final products 28a,b and 29. Finally, dihydropyridine formed oxidatively (relative to dihydropyridine moiety) releases (upon heating) phenylpropenenitrile as oligomers to deliver S N H substitution products 4. In the solid state, these 1,2-dihydropyridines 31a-c were stable at ambient temperature. However, in CDCl 3 , they rearranged to the corresponding 1,4-dihydropyridines 32a-c (Scheme 26) [67]. Earlier [52], the reaction of pyridine 1a, ethyl propiolate 11b and dialkyl H-phosphonates 35a-c in the presence of Al 2 O 3 as a catalyst was shown to afford 1,2-dihydropyridine phosphonates 36a-c (Scheme 29).

Scheme 29. Catalyst reaction between pyridines, alkyl propiolates and dialkyl H-phosphonates.
The outcome of the reaction depends on the pyridine ring substitution. Therefore, no reaction occurred with 2,6-1utidine, whereas, in the case of 4-dimethylamino-pyridine 1h (DMAP), 1,2-dihydropyridine phosphonate bis-adduct 36d, resulting from the addition of two ethyl propiolate moieties to the pyridinium ring, was obtained (Scheme 30) [52]. The electrophilic character of the unsaturated substrate was also important, since authors have never observed any of the expected reactions with acrylonitrile or ethyl acrylate. The dry medium process enhanced the addition rate and improved the yield with respect to the homogeneous medium.

S N H Phosphorylation of Quinolines and Isoquinolines
Quinolines 37a-d reacted with secondary phosphine oxides 2a,b,d and terminal acylacetylenes 6a,b (room temperature) [69] to yield N-acylvinyl-2-phosphoryldihydroquinolines 38 (Scheme 31), i.e., here, the first step of S N H phosphorylation (the reductive insertion of phosphine oxides 2a,b,d into the heterocyclic core) occurred. Under these conditions, oddly, only 1,2-adducts of acylacetylenes and phosphine oxides to quinolines were regioselectively formed with a complete regioselectivity of the enone moiety. All of these, together with much milder conditions, differ this reaction from that with pyridines [39]. Thus, the reaction stopped at the formation of the dihydro intermediates, i.e., a delayed S N H reaction took place here. The longest duration of the process (17 h) was observed for the bulkiest nucleophile (phosphine oxide 2d). The decisive role of the steric effect in such a reaction was noted for an internal acylacetylene, i.e., benzoylphenylacetylene 3c; the reaction occurred at 70-75 • C for 50 h to give the expected N-benzoylvinyl-2-diphenylphosphoryldihydroquinoline 39 and, unexpectedly, 2,4-bis(diphenylphosphoryl)tetrahydroquinoline 40a (Scheme 32), the latter being obviously formed without acylacetylene 3c [69]. The slowest phosphorylations (10, 12 h) were for 4-bromo-and 5-nitroisoquinolines 41c,d, particularly when bulkier bis(2-phenylethyl)phosphine oxide 2b was employed, confirming the considerable contribution of the nitrogen atom basicity and steric screening of the phosphorus-centered anion to the reaction outcome. Evidently, the process is accelerated when isoquinoline basicity increases and steric constrains from the phosphine oxide side reduce.
Noteworthy, the reaction with bis(2-phenylethyl)phosphine sulfide 2f gave, together with the anticipated N-acylvinyl-1-phosphorylated dihydroisoquinolines 43a,b, the adducts 44a,b of this phosphine chalcogenide to acylacetylenes (Scheme 34) [69]. The key steric influence on this tandem vinylation/phosphorylation of isoquinoline was particularly displayed in the reaction with internal acetylenes 3c,d. In this case, even at a higher temperature (70-75 • C), the process was about ten times slower and the stereoselectivity was lost; the reaction mixture contained 70-75% of the 45 Z-isomer, which was proved to be a kinetic product (Scheme 35). This mechanism is consistent with the experimental fact that the reaction with isoquinolines is more facile than that with quinolines; a higher basicity of isoquinoline compared to quinolines (pK a values 5.46 and 4.93, respectively) ensures a greater concentration of triggering intermediate A (Scheme 37). Thus, electron-withdrawing substituents in the isoquinoline ring slow down the reaction (Scheme 33). Additionally, a bulkier phosphine oxide 2b and internal acylacetylenes 3c,d significantly hamper the reaction due to steric hindrance for the generation of intermediates A and B. Consequently, the formation of E-isomers (with terminal acylacetylenes) and kinetic Z-isomers (in the case of internal acetylenes) is an expected result of steric prerequisites. The reaction regioselectivity is understood in terms of an anticipated stronger positive charge at the α position relative to the nitrogen atom, provided the process is a charge-controlled one [69]. Scheme 37. Plausible mechanism of tandem addition of acylacetylenes and secondary phosphine chalcogenides to (iso)quinolines.
The quantum chemical insight [69] (HF/6-311G**//B3LYP/6-311G**) reveals that positions two both in pyridine-and quinoline zwitterions are positively charged, while positions four are almost neutral. Meanwhile, the LUMO localization in position four of pyridine is higher than that in quinoline, the α positions have a much lower LUMO localization. It follows that the phosphorylation of pyridines activated by acylacetylenes is orbital controlled, while a similar reaction in quinoline or isoquinoline series depends on charge distribution. This theoretical assessment helps to understand the different behavior of pyridines and quinolines (isoquinolines) in acetylene-triggered/driven S N H phosphorylation; the complete aromatic substitution for the former and the delayed process on the dihydrointermediate step for the latter. With isoquinoline 41a, the reaction was more facile, taking 1.5-3 h, and more efficient to afford 1,2-dihydroisoquinolines 48a-f in up to a 93% yield (Scheme 39) [70]. In both cases (Schemes 38 and 39), the reaction was regio-and stereoselective providing 1,2-dihydroisomers of the E-configuration relative to the double bond. The authors also show [53] that isoquinoline 41a reacted with H-phosphonates 35a,b,d, and acetylenedicarboxylates 21a-c under solvent-free conditions at room temperature to give 1,2-dihydroisoquinolin-1-ylphosphonate derivatives 51 in good yields (Scheme 42). Recently [73,74], it was shown that the promoting role of electron-deficient acetylenes towards the quinoline core in S N H reactions can be simulated by the reactive P-H nucleophiles themselves via the reversible protonation of the pyridine nitrogen.
Indeed, the reaction of quinolines 37a-c with secondary phosphine oxides 2a,b without electron-deficient acetylenes followed by treatment with chloranil [73] led to 2,4-bisphosphorylquinolines 57a-c along with 4-phosphorylquinolines 58a-c (for phosphine oxide 2a) and 2,4-bisphosphorylquinolines 57d-f (with phosphine oxide 2b) (Scheme 46). The intermediates of this unique S N H reaction, bisphosphoryltetrahydroquinolines 40, were observed (NMR) upon the heating of quinolines with phosphine oxides without external oxidants [73]. These intermediates turned out to be stable and isolable in excellent yields (Scheme 47). The substituents in the quinoline ring slightly affected the reaction time (20-26 h for phosphine oxide 2a and 46-48 h for phosphine oxide 2b) and the yields of tetrahydroquinolines 40, which ranged 81-96% for phosphine oxide 2a and 70-76% for phosphine oxide 2b. A lowered reactivity for bis(2-phenylethyl)phosphine oxide 2b was assumed to be associated with the spatial interference of the voluminous substituent.
The expected monoadducts were not isolated at all, i.e., they were more reactive than the starting quinolines. It was explained [73] by the aromaticity loss of the quinoline core after its first phosphorylation and the increased reactivity of the remaining double bond, which also became more electrophilic due to the effect of the phosphoryl substituent.
The above double phosphonylation of the isoquinoline ring also occurred [73] when H-phosphonates, e.g., bis(2,2,3,3-tetrafluoropropyl) phosphonate 30b, were employed as nucleophiles to afford the expected bisphosphonylated isoquinoline 60 in a 65% yield (Scheme 50). It was assumed [73] that the reaction began (Scheme 51) with the reversible protonation of quinoline 37's counterpart by the P-H bond of phosphine oxides 2 to produce ion pair A and, next, the monoadduct B, which is further phosphorylated to the most stable diadducts 40. Scheme 51. Tentative mechanism of catalyst-free double addition of secondary phosphine oxides to quinolines.

S N H Phosphorylation of Acridines
The attempt to transfer the above-considered (see Section 2.1) cross-coupling of pyridines with secondary phosphine chalcogenides [37] in the presence of electron-deficient acetylenes as adjuvants to acridine series has been undertaken. Unexpectedly, instead of the complete S N H reaction, a facile addition of secondary phosphine chalcogenides 2a-d,f-i to the 9,10-positions of acridine 61 took place to give 9-chalcogenophosphoryl-9,10-dihydroacridines 62a-h (Scheme 52) [75,76]. Surprisingly, this reaction did not require the presence of electron-deficient acetylenes. Scheme 52. Addition of secondary phosphine chalcogenides to acridine: synthesis of 9-chalcogenophosphoryl-9,10-dihydroacridines.
The substituents' character and the nature of chalcogene in phosphine chalcogenides significantly affect the yields of dihydroacridines and the process duration; selenides appeared to be most reactive, then, followed by sulfides and oxides (Scheme 52, 62h,e,b). This allowed suggesting that the proton accelerated the addition process since the selenides were the most acidic [55].
The reaction was shown to be applicable to dialkyl and diaryl H-phosphonates (Scheme 53) [75,77]. Acridine dihydro intermediates were unable to be oxidized (aromatized) by electrondeficient acetylenes such as benzoylphenylacetylene. In the case of dihydroacridines with thiophosphoryl substituents, the restoring of the starting acridine occurred and the eliminated phosphine sulfides added to acylacetylenes [75].
The anticipated S N H reaction was accomplished [75] by the oxidation of dihydroacridines 62a-d with a common external oxidant such as chloranil. The yields of aromatized products, 9-phosphorylacridines 64a-d reached 95% (Scheme 54). Tolerable to this reaction appeared to only be phosphoryl derivatives, while sulfur or selenium analogues gave complex mixtures of products. Scheme 54. Oxidative aromatization of 9-chalcogenophosphoryl-9,10-dihydroacridines with chloranil.
The resistance of acridine to a one-step S N H reaction in the presence of electrondeficient acetylenes was referred to the screening of the nitrogen atom by neighboring benzene ring protons precluding the approach of acetylenes to form the triggering zwitterions. Meanwhile [75], the proton acts as a competitive electrophile and readily attacks the electron lone pair of the acridine nitrogen. The key role of the proton in this mechanism is evidenced by the experiments (Scheme 52) showing that the reaction efficiency (yields and the process duration) improves for more acidic phosphine chalcogenides, as noted above. The carbon analogue of acridine, anthracene, which was not able to be protonated under the above conditions, did not add phosphine sulfide 2f as checked experimentally. The importance of steric requirements for the attack of secondary phosphine chalcogenides at position nine that follows from the mechanism proposed (Scheme 55) is also confirmed by the experimental results. In fact, higher yields and a shorter reaction time were observed [75] for less voluminous diphenylphosphine chalcogenides and otherwise (Scheme 52).
Remarkably, for the presumably less sterically demanding and more electrophilic acetylenecarboxylates, the nucleophilic attack of acridine nitrogen at the triple bond to generate carbanionic zwitterions is, in some cases, possible, as it was mentioned in earlier publications, wherein the three-component adducts with methanol or nitromethane were formed in 81% [78] and 1-8% [79] yields, respectively (Scheme 56). Apparently, in these reactions, acetylenes become competitive over protons due to the lower acidity of methanol or nitromethane as compared to phosphine chalcogenides 2 (pK a 29.9 and 17.2 for MeOH and MeNO 2 , respectively).
The anodic dehydroaromatization of 9-chalcogenophosphorylsubstituted 9,10-dihydroacridines expectedly proved to be a more efficient and environmentally benign compared to the chemical oxidation.
Indeed, in the case of dihydroacridines 62, 63, aromatization proceeded [77] with the saving of the phosphorus-containing substituents to afford the phosphorylated aromatic acridines 64b,c, 65a-d in high yields (81-89%) (Scheme 57). However, the decomposition of the starting dihydroacridines with phosphoryl sulfide and selenide substituents 62e,f,h with the cleavage of the C-P bond was observed (Scheme 57). Scheme 57. Electrochemical oxidation of dihydroacridines ( a Chemical oxidation yields [75]).
The cyclic voltammetry showed [77] differences in the behavior of dihydroacridines 62, 63. The phosphoryl derivatives 62b,c, 63a,b,d,e (X = O) gave an irreversible peak of two-electron oxidation, while in the case of compounds 62e,f,h containing sulfur and selenium (X = S, Se), the voltammogram had two one-electron oxidation peaks. From the quantum chemical calculations of the HOMO followed that the growth of the HOMO population corresponded to a decrease in E peak values [77].

Conclusions and Outlook
In this survey, the recent data on the nucleophilic substitution of hydrogen in the pyridine nucleus (S N H reaction) by PH-nucleophiles (phosphine chalcogenides, H-phosphonates) promoted by electron-deficient acetylenes were systematized and generalized. In these S N H reactions of a new type, electron-deficient acetylenes play a role of three-modal adjuvants triggering and further driving the whole process. The first modality of such acetylenic adjuvants consists of the activation of the pyridine ring by the reversible formation of 1,3(4)-dipolar donor-acceptor complexes with pyridinoids, which partially transfer their electron density over the anti-bonding orbital of the triple bond so that the repolarization of the system occurs; the former (basic) nucleophilic pyridine moiety now becomes electrophilic, while the acetylenic parts of the complexes acquire a vinyl carbanion character. The second modality is to abstract protons from the P-H bonds to generate N-vinyl ammonium-like cations and, correspondingly, P-centered anions further recombining to N-vinylphosphorylated dihydropyridinoids. The third modality is to aromatize the dihydropyridinoid intermediates by the internal redox elimination of the vinyl moieties, the former acetylenic counterpart, as functionalized alkenes of the E-configuration or their oligomers. In a number of cases, this S N H phosphorylation of pyridinoids can be retained on the step of dihydro intermediates, usually formed regio-and stereoselectively as 2-or 4-isomers having Eor Z-configuration of the functionalized vinyl substituents, depending on the structure of pyridinoids and the nature of PH-nucleophiles. From a synthetic and pharmaceutical view, such phosphorylated dihydroazines represent even a higher value than the corresponding aromatized phosphorylated products. It might be expected that this approach to promote the new type of S N H reaction can be extendable over other heterocycle/nucleophile/electrophilic acetylene triads. The keys to success of such an extension are (i) significant differences between nucleophilicity of heterocycles and electrophilicity of acetylenes, (ii) the moderate nucleophilicity of nucleophiles not enough for the addition to electrophilic acetylenes (two-component reaction), (iii) nucleophilicity of the anions formed after the abstraction of a proton from its neutral molecules should be appropriate for the addition to the heterocyclic ring activated by acetylenes and (iv) the dihydro intermediates should easily release the acetylenic counterpart (vinyl substituents) to complete the aromatization.