Vinylphosphonium and 2-aminovinylphosphonium salts – preparation and applications in organic synthesis

The main synthetic routes towards vinylphosphonium salts and their wide applications in organic synthesis are discussed in this review. Particular attention is paid to the use of these compounds as building blocks for the synthesis of carbo- and heterocyclic systems after their prior transformation into the corresponding phosphorus ylides, followed by the intramolecular Wittig reaction with various types of nucleophiles containing a carbonyl function in their structures.


Introduction
Vinylphosphonium salts have been known for a long time, although significant interest in these compounds dates back to 1964, when Schweizer found that they can be converted to phosphorus ylides by the addition of a nucleophile to the carbon atom at the β-position of the vinyl group (Scheme 1) [1].
Particularly widely used in organic synthesis are reactions involving the addition of a nucleophile containing a carbonyl group in its molecule to vinylphosphonium salt. A phosphorus ylide thus generated undergoes a subsequent intramolecular Wittig reaction, leading to a carbo-or heterocyclic ring closure (Scheme 2) [1][2][3]. This reaction can be considered as a general method for the synthesis of carbo-and heterocyclic systems. Schweizer's discovery became the basis for the wide use of vinylphosphonium salts in organic synthesis while stimulating the development of methods for the synthesis of those compounds.
Wide synthetic application, particularly for the synthesis of heterocycles found also 2-aminovinylphosphonium salts and their derivatives. The preparation and synthetic use of these compounds were presented by Drach, Brovarets and Smolii in a comprehensive review in 2002 [4]. In this paper we will discuss only the last reports on the synthesis and properties of 2-aminovinylphosphonium salts and their derivatives that were not included in the above-mentioned review article.
Increasing interest in phosphonium salts is also due to their use in drug design. It was demonstrated in the last decade that lipophilic cations having a triphenylphosphonium residue in the structure can be used as effective carriers of anticancer drugs, antioxidants, or functional probes into the mitochondria [5][6][7][8]. Review 1. Synthesis of vinylphosphonium salts 1

.1. Alkylation of phosphines with alkyl halides
One of the most common methods for the preparation of vinylphosphonium salts 1 is the quaternization of vinylphosphines with alkyl halides. Shutt and Trippett were able to alkylate vinylphosphines with methyl iodide or benzyl iodide, although attempts to use other alkyl halides, including benzyl bromide, ethyl bromoacetate and ethyl iodoacetate, in the presence of aprotic solvents provided only β-phosphonioylides 2 or polymeric phosphonium salts that were amorphous and unable to crystallize. Such products may be formed as a result of a subsequent Michael-like addition of the starting phosphine to the initially obtained vinylphosphonium salt 1 (Scheme 3). The formation of the expected salt was faster than the side addition reaction only in reactions with methyl iodide and benzyl iodide [9].
A similar alkylation of isopropenyldiphenylphosphine with methyl iodide in ether solution under a nitrogen atmosphere leading to isopropenylmethyldiphenylphosphonium iodide (3) Scheme 3: Alkylation of diphenylvinylphosphine with methyl or benzyl iodide.
in a yield of 97% was described by Schweizer and Wehman (Scheme 4) [10]. Vinylphosphonium salts can also be prepared by alkylation of phosphines (usually triphenylphosphine) with allyl halide derivatives and isomerization of allylphosphonium salts 4 thus obtained under the influence of bases such as triethylamine or sodium carbonate (Scheme 5) [11][12][13].
Vinyl halides are relatively less reactive alkylating agents. However, the use of readily available vinyl triflates 5 for the alkylation of triphenylphosphine in THF solution in the presence of a catalytic amount of (Ph 3 P) 4 Pd (1-3 mol %) gave the expected vinylphosphonium salts in a yield of 62-89% and a high stereoselectivity (Scheme 6) [14,15].
The proposed mechanism of this reaction is as described in Scheme 7 [14,15].
Oxidative addition of the vinyl triflate to the catalyst results in complex 6 that upon reductive elimination (an added phosphine) provides the vinylphosphonium salt and regenerates the Pd(0) catalyst (Scheme 7). Scheme 6: Alkylation of triphenylphosphine with vinyl triflates in the presence of (Ph 3 P) 4 Pd. Scheme 8: β-Elimination of phenol from β-phenoxyethyltriphenylphosphonium bromide.

Scheme 7:
Mechanism of alkylation of triphenylphosphine with vinyl triflates in the presence of (Ph 3 P) 4 Pd as catalyst.
1.2. β-Elimination of β-phenoxyalkyl-or α-haloalkylphosphonium salts Schweizer and Bach described the synthesis of vinyltriphenylphosphonium bromide (8) by heating a solution of the β-phenoxyethylphosphonium salt 7 in ethyl acetate. The final step of the reaction consisted in the β-elimination of the phenol molecule (Scheme 8) [16].
A similar reaction using β-phenoxyethylphosphonium salts 9 derived from benzyldiphenylphosphine or dibenzylphenylphosphine required an alkaline environment and gave the expected vinylphosphonium salts 10 in good yields (Scheme 9) [16]. Vinylphosphonium salt can also be synthesized by dehydrohalogenation of α-bromoethylphosphonium bromide 13 in the presence of lithium bromide in anhydrous dimethylformamide (Scheme 10). α-Bromoethylphosphonium salt 13 was obtained according to the three-step procedure, starting from the alkylation of triphenylphosphine with 1-bromoethylbenzene. The resulting phosphonium salt 11 was then deprotonated to the corresponding ylide 12, which in the last step was subjected to bromination to give the expected α-bromoethylphosphonium bromide 13 [10].

Peterson olefination of α-trimethylsilylphosphonium ylides with aldehydes
An interesting alternative pathway to vinylphosphonium salts, based on a Peterson-like olefination of α-trimethylsilyl phosphonium ylides 15, was described by McNulty and Das and by Łukaszewicz et al. The commercially readily available iodomethyltrimethylsilane was reacted with tributylphosphine at room temperature to give the corresponding α-trimethylsilylphosphonium salt 14. The latter salt was deprotonated in the presence of s-BuLi under kinetically controlled conditions, and the resulting ylide 15 reacted with aldehyde, providing tributylvinylphosphonium salt derivatives 17 in good yields via Peterson olefination through a silylated betaine 16. The alternatively possible Wittig reaction to vinylsilane 18 can be considered as a side reaction (Scheme 11) [17,18].
The transformation shown in Scheme 11 was proven to be a general reaction with the possible participation of both electronrich and electron-deficient aromatic aldehydes, giving the expected vinylphosphonium salts 17 with high yields and stereoselectivity, favoring the formation of an excess of E-isomers (Table 1) [17].

Electrochemical oxidative addition of triphenylphosphine to cycloalkenes
Another effective method for obtaining vinylphosphonium salts consists in the one-step electrochemical oxidation of triphenylphosphine in the presence of cycloalkenes. The synthesis of 1-cycloalkenetriphenylphosphonium salts 19 was carried out in the presence of 2,6-lutidine perchlorate and anhydrous potassium carbonate under a nitrogen atmosphere in dichloromethane solution on a graphite anode and a cathode of stainless steel at a constant current of 20 mA (Scheme 12). Depending on the cycloalkene used, the target vinylphosphonium salt was obtained in a yield of 53-66% [19].  Since the oxidation potential of cycloalkene is higher than that for triphenylphosphine, the suggested mechanism of formation of the final 1-cycloalkenetriphenylphosphonium salts 19 is analogous to the reactions of the radical cation of triphenylphosphine with other nucleophiles (Scheme 13) [19].

Triphenylphosphine addition to a triple carbon-carbon bond of acetylenedicarboxylic acid esters
The addition of triphenylphosphine to acetylenedicarboxylic acid esters in the presence of a nucleophile is a frequently used method for the generation of unstable, highly reactive α,β-(dialkoxycarbonyl)vinylphosphonium salts 20 (Scheme 14) that are commonly used in further reactions without prior isolation [20][21][22][23][24][25][26][27][28]. Their generation and subsequent transformations are comprehensively discussed in section 2.3.2.
1.6. Synthesis and structure of 2-aminovinylphosphonium salts   The second method (procedure B) is based on the reaction of ylides with imidoyl iodides that are synthesized in situ from the corresponding imidoyl chlorides via the exchange of chlorine for iodine in the presence of sodium iodide (Scheme 15, X = I).
In the case of unstable or inaccessible imidoyl halides (Scheme 16) it is also possible to use an imidoylating agent in this reaction that is generated in situ from the amide or lactam by using dibromotriphenylphosphorane in the presence of triethylamine (procedure C). Spectral evidences were provided that both imidoyl bromide and N,N,N,N'-tetrasubstituted amidinium salt 23 could act in this reaction as an effective imidoylating agent [31].
Several years later, Schweizer et al. discovered that the nucleophilic addition of amines to 2-propynyltriphenylphosphonium bromide (24) involved propadienylphosphonium bromide (25)the tautomeric form of the starting phosphonium salt. The same authors carried out a series of nucleophilic additions of amines and hydrazine derivatives to 24 to obtain products with the proposed structure of 2-aminovinylphosphonium salts 27 in equilibrium with their tautomeric imine form 28 (Scheme 18). Depending on the nature of the substituent R, the enamine or the imine form predominated (Table 3) [33].  Scheme 20: Resonance structures of 2-aminovinylphosphonium salts and tautomeric equilibrium between aminovinylphosphonium and α-iminoalkylphosphonium cations.
In 2004 Mazurkiewicz and Fryczkowska discovered that the same type of compounds can be obtained in good or even very good yields by deacylation of 2-(N-acylamino)vinylphosphonium salts with methanol in the presence of DBU (Scheme 19) [34,35].
Spectroscopic properties (IR, 1 H and 13 C NMR) and X-ray data of the obtained 2-aminovinylphosphonium salts corresponded to the enamine tautomeric form with the domination of β-iminium ylide resonance structures. Furthermore, the authors did not observe an imine tautomeric form of the synthesized compounds as described by Schweizer ( 1 H NMR). The isotopic exchange of acidic protons using a D 2 O solution in CD 3 CN revealed that the isotopic exchange of a proton in the α-position was possible only in the presence of a strong base, such as, for example, DBU [34][35][36]. In the case of a real tautomeric equilibrium between aminovinylphosphonium and α-iminoalkylphosphonium cations, the isotopic exchange should occur easily (Scheme 20).
Borodkin et al. have recently reported a new method for the synthesis of 2-aminovinylphosphonium salts 30 by reaction of (formylmethyl)triphenylphosphonium chloride (29) with aromatic amines in isopropanol in yields of 47-91% (Scheme 21). The initially obtained imine form of the product underwent tautomerization to a more stable enamine form, usually in E-configuration. The obtained compounds, particularly the derivative containing a carboxylic group in ortho position of the aromatic ring, exhibited antimicrobial activity [37]. nucleophilic agents used in these reactions were usually prepared by reaction of sodium hydride or sodium ethoxide with a proper nucleophile, such as diethylamine, piperidine, pyrrole, ethanol, p-toluenesulfonamide, thiophenol and others. Depending on the reactants used, Zor E-stereoisomers of the products 32 were obtained, but most commonly the reactions resulted in a mixture of stereoisomers (Scheme 22). The yield of the reaction was dependent on the kind of substrate and ranged from 14 to 68% [38]. The reaction involving organocopper compounds as carbon nucleophiles (R 2 CuLi, where R = vinyl, butyl, phenyl) is another way of using vinylphosphonium bromide 8 in the intermolecular Wittig reactions (Scheme 23). Depending on the kind of substituent R and the aldehyde used, the yield of obtained compounds 33 was in the range of 25-80%. The reaction predominantly provided the Z-isomer of the alkene [39].

Vinylphosphonium salts in organic synthesis
An interesting pathway of generating ylides from vinylphosphonium salts turned out to be the reaction of the latter compounds with Grignard reagents in the presence of CuBr·H 2 O or CuBr·Ag 2 CO 3 (Scheme 24). The subsequent Wittig reaction allowed to obtain substituted alkenes 34 in a yield of 68-94% and in a good stereoselectivity. The configuration of products depended on the nature of the substituent in the phenyl group of the aldehyde. Electron-donating substituents favored the formation of E-isomers, while the presence of electron-withdrawing substituents made the formation of Z-isomers more favorable [40].
Vinylphosphonium salts can also be directly converted into the corresponding ylides by potassium tert-butoxide and subjected to the Wittig reaction as described by Yamamoto et al.

Vinylphosphonium salts in the intramolecular Wittig reaction
As was already mentioned, in 1964 Schweizer provided a general method for preparing carbo-and heterocyclic compounds 38 using vinylphosphonium salts [1,2]. The method consisted in the reaction of oxygen, nitrogen and carbon nucleophiles 36 containing a carbonyl group in the molecule with vinylphosphonium halides 37 (Scheme 26). In the following chapter this general method for preparing a variety of carboand heterocyclic systems using various types of nucleophilic agents is discussed in detail. 82-97% yield (Scheme 37) . The latter compounds were further used in the synthesis of natural compounds [50].

Deprotonated 2-aminovinylphosphonium salts in the
Wittig reaction: 2-Aminovinylphosphonium salts, which are the addition products of amines to 2-propynylphosphonium bromide [33] or can be obtained by deacylation of 2-(Nacylamino)vinylphosphonium salts [34,35], have been found to have several interesting synthetic applications, although they have only relatively recently become known. γ-Aminobutyric acid is a major neurotransmitter used to treat epilepsy [52]. Analogs of this acid displaying antitumor activity, such as hapalosin, dolastatins, and caliculins were found in natural marine products [53][54][55].
Palacios et al. also described the Wittig reactions of 2-aminovinylphosphonium salts with aldehydes and ketones in THF in the presence of K 2 CO 3 leading to allylamines 61, which are an important class of compounds due to their biological activities (Scheme 40) [56]. They are used, inter alia, as chemotherapeutic agents, enzyme inhibitors, and antifungal compounds [57][58][59]. The allylamine structure exists in numerous natural products [60]. Moreover, allylamines are widely used in the synthesis of compounds such as β-aminohydroxylamines, β-and γ-amino acids, pseudopeptides, spermidine derivatives or five-and six-membered heterocyclic systems [56].

In situ generation of α,β-di(alkoxycarbonyl)vinylphosphonium salts and their further transformations:
A significant number of reactions of acetylenedicarboxylic acid esters with triphenylphosphine and nucleophiles of a general NuH structure leading to reactive α,β-di(alkoxycarbonyl)vinylphosphonium salts 20 have been described (Scheme 41). Depending on the structure of the nucleophile used, the salts either convert into resonance-stabilized, relatively stable ylides 62 or undergo intramolecular nucleophilic substitution with the triphenylphos-phine departure to form products 63. The latter usually undergo further cyclization involving one of the alkoxycarbonyl groups. Ylides 62 also undergo some further transformations in certain cases.
Formation of resonance-stabilized phosphorus ylides and their further transformations: Phosphorus ylides are organic compounds that are being used increasingly more often in the synthesis of many naturally occurring compounds which exhibit biological and pharmaceutical activity [61].
A typical example of the generation of resonance-stabilized phosphorus ylides 65 comprises triphenylphosphine, dialkyl acetylenedicarboxylate, and arylsulfonic hydrazides providing the corresponding ylides in high yields of 90 to 95% as two rotational isomers 65' and 65'' (Scheme 42). The intermediate product, formed by the addition of triphenylphosphine to dialkyl acetylenedicarboxylate, is protonated here by arylsulfonic hydrazide as an NH-acid. The deprotonated form of the NH-acid as a nitrogen nucleophile then attacks the β-position of the vinylphosphonium salt 64, resulting in the expected resonance-stabilized ylide 65 [62].
The same kind of reaction with the participation of 2,4dihydroxybenzaldehyde or 2,4-dihydroxy-3-methylbenzaldehyde was applied in 2010 by Gryko and Flamigni et al. for the preparation of 6-formylcoumarin derivatives 109 that are used in the synthesis of dyads 111 consisting of coumarin and corrole units (Scheme 61). The latter synthesis took place by condensation of formylcoumarins 109 with 5-(pentafluorophenyl)dipyrromethane (110) [76].
The use of pyrocatechol or pyrogallol as reagents in reactions with the analogous mechanism resulted in the formation of mono-, di-, and tricyclic reaction products of phenol derivatives with one or two vinylphosphonium salt molecules (Scheme 62 and Scheme 63) [75].
In a similar reaction with 2-aminophenol, 1,4-benzoxazine derivative 113 was obtained in a yield of 70% [63]. According to the authors, the displacement of the triphenylphosphonium group resulted from the nucleophilic attack of the amine group of 2-aminophenol on the β-position of the vinylphosphonium salt 112, followed by the 1,2-cationotropic proton shift to the α-position and elimination of triphenylphosphine (Scheme 64) [63]. It seems, however, that the direct displacement of the triphenylphosphonium group by the attack of the amine group on the α-position of the vinylphosphonium salt is more probable.
Recently, an interesting one-pot condensation of acetylenedicarboxylates with phosphines and 1-nitroso-2-naphthol or 2-nitroso-1-naphthol leading to 1,4-benzoxazine derivatives was reported. The addition of triarylphosphine to an acetylenic ester followed by protonation of the adduct by the naphthol deriva-

Conclusion
Easily accessible vinylphosphonium salts are important reagents and building blocks in organic synthesis mainly due to the convenience of their transformation into reactive ylides by addition of a variety of nucleophiles, including carbon, nitrogen, sulfur, and oxygen nucleophiles. The addition of a bifunctional nucleophile with a carbonyl function to vinylphosphonium salts can be considered as a general method for a new ring closure to carboor heterocyclic systems of diversified size by the intramolecular Wittig reaction. Recently, significant attention attracts also highly reactive α,β-(dialkoxycarbonyl)vinylphosphonium salts, generated easily in situ from acetylenedicarboxylic acid diester, triarylphosphine and a nucleophile. Depending on the structure of the nucleophile used, the salts convert into the corresponding resonance-stabilized, relatively stable ylides or undergo intramolecular nucleophilic substitution with triphenylphosphine departure, usually followed by cyclization with the Scheme 70: Synthesis of 1,4-benzoxazine derivatives from acetylenedicarboxylates, phosphines, and 1-nitroso-2-naphthol or 2-nitroso-1-naphthol in the intramolecular Wittig-like cyclization.
engagement of one of the alkoxycarbonyl groups to carbo-or hetereocyclic systems. 2-Aminovinylphosphonium salts have also found several interesting synthetic applications, although they have become known relatively recently.