Architecture and synthesis of P,N-heterocyclic phosphine ligands

Diverse P,N-phosphine ligands reported to date have performed exceptionally well as auxiliary ligands in organometallic catalysis. Phosphines bearing 2-pyridyl moieties prominently feature in literature as compared to phosphines with five-membered N-heterocycles. This discussion seeks to paint a broad picture and consolidate different synthetic protocols and techniques for N-heterocyclic phosphine motifs. The introduction provides an account of P,N-phosphine ligands, and their structural and coordination benefits from combining heteroatoms with different basicity in one ligand. The body discusses the synthetic protocols which focus on P–C, P–N-bond formation, substrate and nucleophile types and different N-heterocycle construction strategies. Selected references are given in relation to the applications of the ligands.


Introduction
Phosphines constitute a large percentage of ligands in organometallic chemistry and over the years, they have received enormous attention. The main interest towards this class of compounds is attributed to aspects such as, the good electron-donating ability of the phosphorous atom, and the ease of optimizing steric and electronic properties. Additionally, properties like chirality can be conferred to the backbone of the ligands to generate C-stereogenic [1] and P-chirogenic [2] compounds. Furthermore, the 31 P-nucleus abundance allows the use of NMR for reaction monitoring and in situ speciation. In addition, phosphine ligands have found various applications as auxiliary ligands in organometallic transition-metal complexes. A great number have exhibited potential application in organic lightemitting devices (OLEDs) [3], medicine [4][5][6] and catalysis [1,7,8] among other fields (Table 1). There is a number of review articles in the literature [9][10][11] which explore deeper into the applications of P,N-heterocyclic phosphine ligands. Besides, the inclusion of other heteroatoms in the phosphine ligand skeleton opens up many possibilities for metal coordination [12]. Thus, their use in catalysis is the basis of this review article with the main focus on the synthesis of N-heterocyclic phosphines.  [14] metal organic frameworks [15] polymerization of lactides [16] alkene hydroxylation [17] addition reaction [18] ethylene oligomerization [19] synthesis of pyrazolines [20] triazolyl phosphines Suzuki cross coupling [21] asymmetric hydrogenation [22] luminescence [23] hydroformylation [24] pyrazolyl phosphines coordination polymers [25] Heck coupling [26] imidazolyl phosphines Suzuki coupling [27] hydroamination [28] OLEDs [29] ethylene oligomerization [30] amination [31] olefin metathesis [32] hydroformylation [33] pyrrolyl phosphines hydroformylation [34,35] ethylene polymerization [36] oxazolyl phosphines asymmetric cycloaddition [37] asymmetric hydrogenation [38] carbonylation of alkynes [39] allylic substitution [40] asymmetric addition [41] allylic amination [42,43] The presence of soft donor atoms such as phosphorus results in the formation of hemilabile ligands. These are multidentate ligands having hard P-donor and soft N-and/or O-donor atoms [44]. During catalysis the weakly coordinating hard donor atom detaches to give way for the incoming substrate to coordinate to the metal center [45]. This behavior also aids in ligands being able to stabilize low-valent metal states and promote oxidative addition reactions [45,46]. The complimentary effect of P and N can help stabilizing different catalytic species that are produced during catalytic transformations [11,47]. P,N-phosphine ligands can effect regioselective control, due to the trans-effect as exhibited in π-allyl metal complexes, where substitution occurs selectively on the end opposite to the phosphorus donor atom [48]. This is because the position trans to the heteroatom, with greater π-acceptor character, is more electrophilic than the one opposite the σ-donor atom [9]. One can modify this electronic imbalance by attaching vicinal heteroatoms. The π-acceptor character of phosphorus can be reinforced by the presence of oxygen and/or nitrogen whilst σ-donating potency of nitrogen can be manipulated by switching between sp 3 and sp 2 hybridization [9,49,50].
The synthesis of phosphines is quite delicate because when exposed to air, some of them are easily oxidized, hence the reactions are often conducted under inert conditions. Alternatively, the phosphine can be protected as a borane adduct and thereafter, the protecting group is ultimately removed to liberate the free ligand. This method has been developed by Imamoto et al. [51,52] were the phosphine boranes were prepared by reacting phosphines with sodium borohydride. Alternatively, the reduction of phosphine oxide byproducts with lithium tetrahydridoaluminate, calcium aluminum hydride , and hydrosilanes can also be used to regenerate the phosphine ligands. Hydrosilane reagents usually lead to stereoselective reduction products, hence, they are used for the synthesis of chiral phosphines from chiral oxides [53]. Lithium tetrahydridoaluminate is used for the reduction of achiral phosphines because its action on optically active phosphine oxides leads mainly to the optically inactive phosphines ascribed to pseudo rotation of the pentacoordinated transition intermediates [52]. Despite this, researchers have synthesized many efficient phosphine ligands, though fast and easy synthetic methods which are principal in the development of flexible ligands are still needed.

Review
Preparation of N-heterocyclic phosphines via P-C bond formation

Nucleophilic substitution of halogens
There are different methods that have been reported for the construction of the P-C bonds. Two approaches are possible using halogenated precursors. The first one is the organometalhalogen-phosphine route where the metalated organohalogen compound is reacted with the halogen phosphine. Alternatively, the metal phosphide can be reacted with an organohalogen compound leading to the desired product. The most commonly used trans-metalation reagents are Grignard [54] or organolithium reagents [55] and other suitable bases. The metalation reaction is prone to side reactions when carried out at higher tempera-  tures and as such, the reaction must be carried out below 0 °C. For example, pyridyllithium derivatives as intermediates can be subjected to deprotonation, substrate addition and pyridine formation due to lithium halogen elimination, halide migration, and ring-opening reactions [56,57]. Butylphosphines are also formed alongside the main product, and in most cases pure phosphine pyridines are obtained using column chromatography followed by extractions adding to the number of synthesis steps.
This method has proven handy in the synthesis of phosphine pyridyl-type ligands. Jasen et al. [58] reported on the synthesis of picoline analogs by reacting the organohalide 1 with a lithium phosphide generated from chlorodiphenylphosphine (2) (Scheme 1). The resulting phosphine ligands 3 were obtained in relatively good yields. Notably, a low isolated yield was reported when starting from 2-(4-chlorobutyl)pyridine (n = 4) and this was attributed to the competing cyclization reaction affording cyclic pyridinium salts. The prominent 2-(diphenylphosphine)pyridine (4) has proved to be an interesting building block for the assembly of homo and hetero-organometallic complexes. The 3-and 4-pyridylphosphine derivatives 5 have also been successfully used as templates for assembling supramolecular structures and coordination polymers [54,59]. Halogenated ring-fused pyridine reagents can also be used to generate bipyridyl-(6), quinolinyl-(7), phenanthrolinyl-(8) and terpyridinyl-(9) phosphine ligands ( Figure 1) [60].
Trofimov et al. [61,62] reported on an alternative reaction pathway using microwave heating for the synthesis of tris(2pyridyl)phosphine in which white and red phosphorus were used. On treating the red phosphorus with 2-bromopyridine in potassium hydroxide/dimethyl sulfoxide emulsion, pyridylphosphine was obtained in moderate yields. Traces of phosphine oxide were present as evidenced by the observation of two phosphorus peaks in the 15 P NMR spectrum.
An optimized method via Grignard reagents has been reported by Kluver et al. [54], by which the product was isolated in excellent yield (71%). It was noted that the magnesium ions increase the water partition coefficient of these compounds since they coordinate stronger to the nitrogen atoms as compared to lithium ions. In this case, common extraction with dichloromethane was not applicable, hence solid-liquid extraction with diethylamine was used. Low yields were reported for the 3-and 4-pyridyl analogs due to the difficulty associated with their extraction compared to their 2-pyridyl counterparts [54,55].
Dai and co-workers [63] also used the Grignard route to synthesize phosphine ligands that are stable to oxidation as described in Scheme 2. The organomagnesium intermediate 11 produced from 2-(N-piperidyl)bromobenzene (10) was trapped with appropriate halo-phosphine reagents to generate derivatives 12. The 2-(N-piperidyl)phenyl-substituted phosphine (X = CH 2 , n = 1) was obtained in relatively good yield while the 2-(Nmorpholinyl)phenyl derivatives (X = O, n = 1, 2, 3) were obtained in moderate yields. The reactions were complete within 3 h despite the fact that the Grignard substrate contains an ortho-substituent. This methodology was also faster than the metal-catalyzed phosphorylation route reported by the same authors.

The use of silyl and dialkylamine as reagents
Organosilyl, silylphosphine derivatives, along with dialkylamines can also be used as alternative substrates to halogenbased reagents. These compounds are more stable nucleophiles compared to organometallic or metal phosphides generated through metalation processes. Hayashi et al. [66] used tris(trimethylsilyl)phosphine to control the nucleophilic substitution in the preparation of P,N-(phosphino)triazine ligands (Scheme 5). It was shown that the use of other nucleophiles failed to give controlled products, i.e., when lithium phosphide was used in a 1:1 ratio a mixture of products was obtained. A reaction between one molar equivalent of cyanuric chloride (25)  involved, and the reaction requires relatively longer times compared to the organometallic route.

Reaction of metal phosphides with cycloalkanes
Cyclopropane easily undergoes nucleophilic substitution reactions because of its high ring strain. Tan et al. [69] reported the diphenylphosphine (48) with n-BuLi and ethylene sulfide in tetrahydrofuran at very low temperatures.

Metal-proton exchange from α-C-H bond activation in heterocycles
The α-position to a heteroatom in a cyclic compound is activated because of the difference in electronegativity with carbon. This presents an opportunity to readily generate organometallic nucleophiles. Chelucci et al. [71] used this fact to synthesize the monoterpene-derived pyridylphosphine ligand 58 (Scheme 10).
The key step was a Kröhnke annulation reaction. The Kröhnke salt 52 was pre-synthesized from ethyl bromoacetate and pyridine and then reacted with (−)-pinocarvone (53) in the presence of ammonium acetate. The obtained keto intermediate 54 was then treated with triflic anhydride to afford the corresponding triflate 55. Microwave-assisted reduction of compound 55 with pyridinium chloride afforded the α-chloropyridine derivative 56, which was further catalytically dehalogenated with palladium on carbon and formic acid to generate the pyridine scaffold 57. Coupling of 57 with Ph 2 PCl·BH 3 resulted in the boronprotected ligand 58, which was deprotected with Et 3 N. Alternatively, 1,1'-bis(diphenylphosphino)ferrocene (dppf) with palladium(II) acetate was used to catalyze the reduction of 55 generating the pyridine scaffold 57. Subsequent lithiation and addition of chlorophosphine resulted in the desired ligand 58. However, the overall yield was lower than the yield obtained through the other method.
Imidazole can be regioselectively deprotonated at the more acidic The fast and clean alkyne-azide cycloaddition reaction has been applied successfully to prepare click-phosphine ligands [72]. The presence of three nitrogen atoms within the five-membered ring results in a high activation of the α-position and the highly acidic nature of the proton makes it easy for abstraction. Sharpless et al. [73] reported on the synthesis of 1,5-disubstituted triazoles and Liu et al. [74] used this procedure to synthesize triazolylphosphine ligands with the phosphorous substituent in the α-position (Scheme 12). For this, the aryl azide 64 was reacted with bromomagnesium acetylides 65 to generate magnesiumcontaining triazoles 66 which, upon quenching with ammonium chloride, afforded the triazoles 67. Lithiation followed by coupling with the appropriate chlorophosphines resulted in the desired 1,5-disubstitued triazolylphosphine ligands 68. The procedure could be performed in one pot by directly quenching the metalated triazole 66 with chlorophosphine. However, a separation of the triazole before phosphorylation makes purification of the final ligand easier [74].
The direct ortho-metalation of pyridyltriazole 69 and subsequent reaction with chlorophosphines gave the isomeric ligands 71 and 72 in different ratios governed by the phosphine substituents (Scheme 13) [75]. When the R-substituent is more electron donating, the pyridine nitrogen ortho to the phosphine becomes more nucleophilic and intermediate 70 undergoes ring closure to give compound 71 with the phosphanyl substitutent in the 7-position of the fused ring structure. On the contrary, when the substituent R is electron withdrawing the pyridine nitrogen furthest away from the phosphine is more nucleophilic and hence is attacked resulting in isomeric ligand 72. Thus triazolopyridines and quinolones can undergo ring-chain isomerism, which is dependent on the inductive and/or steric effects of the substituents present on the backbone [75,76].
The α-phosphorus methylene lithiation presents more prospects for the development of modified 1,3,5-triaaza-7-phosphaadamantane (PTA) ligands [77,78]. A chiral center is also introduced adjacent to the coordinating phosphorous [79].  [81] selectively obtained compound 80 when allowing the reaction mixture comprising compound 77 and 2.5 equiv n-BuLi in THF to warm to room temperature prior to reaction with chlorodiphenylphosphine at rt. On the other hand, when both steps, the lithiation and the introduction of the phosphine were performed at low temperature (−70 °C), compound 81 was obtained in 63% yield [80]. In both instances, the other isomer was present in minute quantities and could be separated by recrystallization.
Hybrid phosphine N-heterocyclic carbenes (NHCs) have proved to be versatile ligands in organometallic chemistry [82]. The synthesis of sterically crowded biaryl ligands is still a challenging task, especially under mild reaction conditions. The diphosphine complexes of imidazolylphosphines proved to be an alternative towards the coupling of sterically crowded biaryl ligands as they showed outstanding performances [8]. Phosphines with imidazole and imidazoline functional groups present some interesting features. The imidazolium functionality mimics active sites in biological molecules [83,84]. The ionic nature adds another dimension to the applicability of the catalysts in two-phase homogeneous catalysis because it allows easy recycling [85] and separation from the reaction mixture [8].
Carbon-halogen bonds are more activated than carbon-hydrogen bonds and hence the halogen is more labile and preferentially displaced. Brill et al. [86] took advantage of this fact by synthesizing a class of N-tethered phosphine imidazole ligands (Scheme 16, route A). The lithiation of the presynthesized chloromethylimidazolium iodide 82 and subsequent trapping with borane-protected di-tert-butylphosphine gave the imidazolium borane adduct 83a. The subsequent deprotection then furnished 83b in reasonable yields between 68 and 87%. Bis(diphenylphosphine)-substituted imidazoles were also synthesized by Karthik et al. [87] starting from the diiodoimidazole derivative 84. The lithium chloride mediated magnesium/ iodine exchange reaction of 84 followed by the addition of chlorodiphenylphosphine, afforded 1-methyl-4,5-bis(diphenylphosphino)imidazole (85). Finally, N-methylation gave the imidazolium salt derivative 86 in good yield (65%).

Preparation of N-heterocyclic phosphines via metal-catalyzed P-C/N bond formation
There is limited availability of certain N-containing precursors and hence they need to be synthesized through coupling of suitable pre-synthesized fragments. This, however, increases the  [90] and in case of the pyrazinyl derivative, sodium ethanethiolate [91] was used. The generated compounds 93 were then converted into triflate derivatives 94 by treatment with triflic anhydride in the presence of N,N-dimethyl-4-aminopyridine (DMAP) as the catalyst. Finally, the desired ligands were obtained by palladium-catalyzed phosphorylation with triphenylphosphine in DMF [92]. Resolution with palladium amine complexes and subsequent crystallization resulted in the enantiomerically pure ligands 95.
C 2 -Symmetric atropisomeric diphosphines are among a diverse family of privileged chiral ligands in asymmetric catalysis [12]. In these compounds, the C 2 axis of symmetry helps in increasing the selectivity of the formation of certain enantiomers by inhibiting other possible reaction pathways [93]. In particular, biarylphosphines and bidentate 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) with a greater π-density and sterically demanding groups, have been extensively used in catalytic reactions [94].

P-H Bond addition to unsaturated precursors
The addition of P-H to unsaturated organic compounds (hydrophosphination) presents an atom economical, efficient and green strategy for the preparation of phosphines. The process can be initiated thermally, chemically or by UV irradiation. Radicals can also be used in hydrophosphination reactions. For example, azobisisobutyronitrile (AIBN) can initiate the addition of secondary phosphines to N-vinylpyrroles under heating or UV irradiation resulting in regio-and chemospecific adducts. Using the same approach Trofimov et al. [96] reported on the selective synthesis of tertiary diorganyl pyrrolylphosphines 105 and 106 in high yields starting from the corresponding N-vinylpyrroles 103 and 104 (Scheme 19). The N-isopropenylpyrrole precursor 104 gave the adducts with 100% regioselectivity. More recently a solvent and catalyst-free method has been reported for vinylpyridines [97].

Preparation of N-heterocyclic phosphines via P-Nbond formation
A P-N bond formation reaction is easier to be done than a P-C bond formation because the construction of the latter involves reaction conditions that are not suitable for multifunctionalized precursors. On the other hand, the installation of P-N bonds is usually done via a "one-pot synthesis" protocol. The quaternary salt byproduct that is formed when using an amine as the base can be easily separated by filtration. Bis(phosphine)amines with a P-N-P framework are more flexible to manipulate than diphosphines with a P-C-P framework [98]. The P-N-P cone angle and geometry on the phosphorus can be adjusted by changing the bulkiness of substituents around both, the N and P centers [99]. When reacting anilines and chlorophosphines under basic conditions they undergo P-N bond formation affording conventional aminophosphines [100,101]. A facile alternative method replaces the aniline with aminosilanes which produces trimethylchlorosilane as a byproduct which can be distilled off easily [102].
Bicyclic guanidine frameworks present an opportunity to form inflexible ligands that are inclined to exhibit a κ 2 -P,N-bonding mode in metal complexes. Dyer et al. [103] prepared cycloguanidine phosphine ligands (Scheme 20) using a one-pot procedure. First, the triazabicyclodecene 107 was metalated with n-butyllithium to give the intermediate 108 which was quenched with a chlorophosphine to produce the desired ligands 109 in excellent yields.
Besides substituents effects it has been reported that solvents may substantially influence reaction kinetics and product formation [102]. Biricik et al. [98] reported the preparation of polydentate aminophosphine 111 through a condensation-elimination-aminolysis reaction (Scheme 21). Reactions performed in diethyl ether and toluene resulted in bisphosphine imines and the reaction rates were low for anilines and analogous compounds. However, using dichloromethane proved to be a more suitable solvent because of higher product solubility and the Scheme 20: Synthesis of phosphine guanidinium ligands.
reactions could be followed using 31 P NMR spectroscopy [98,102]. The addition of four molar equivalents of Ph 2 PCl to a dichloromethane solution of 2,6-aminopyridine (110)  Phosphine hydrazine P-N and N-N bonds are labile and can easily reorganize in the presence of some transition elements [105]. This provides an easy method towards the preparation of phosphazenides and phosphineamides [106]. In this way, Kornev et al. [106] prepared  P-stereogenic phosphine ligands are difficult to synthesize because of low configurational stability and less availability of P-stereogenic precursors. However, asymmetric synthesis can be used as strategy to introduce stereogenic P-atoms into the ligand's backbone. The borane complexation approach is a unique stereoselective way for introducing a P-stereogenic center.
Benoit et al. [2] reported on the synthesis of 2-phenyl-1,3,2oxazaphosphorine ligands with a P-center and backbone chirality (Scheme 24). Spiro-1,3-amino alcohol compounds 124 were synthesized according to a literature procedure [107]. For the synthesis of the mono-N-methylated amino alcohol ligands a cooled solution of dichlorophenylphosphine was treated with triethylamine and mono-N-methylated spiro 1,3-amino alcohols 124. The mixture was equilibrated under reflux allowing P-center inversion and an uneven mixture of diastereoisomers 125 and 127 was obtained. Treating the mixture with borane·dimethyl sulfide gave a mixture of diastereoisomers in a ratio of 2:5. The major isomer (+)-125 was crystallized from Duplicating the same protocol with free amine spiro-amino alcohol derivative 124 gave compounds 125 and 127 (R = H) in low yields. An optimized procedure was used where dichlorophenylphosphine and borane·dimethyl sulfide in tetrahydrofuran were premixed at −78 °C. The temperature was then raised to 25 °C before neutralizing with triethylamine. Finally, spiro-1,3-amino alcohol was added and an equimolar mixture of compounds 125 and 127 was obtained with good yields. The dimeric ligands 126 and 128 were obtained by coupling each mono ligand in THF by first treating with potassium butoxide with subsequent addition of dibromomethane [2].

Substrate postfunctionalization and heterocycle construction
Some heterocyclic precursors can be readily obtained via accessible synthetic protocols. The nitrogen-containing compounds can be constructed and grafted on the phosphine precursor. Some available phosphines and organic precursors contain functional groups which can also be modified.  [109,110].
In these reactions the phosphine precursor can also be functionalized with appropriate groups for postfunctionalization. Detz et al. attached an alkyne to a phosphine which could easily be transformed to triazoles using click chemistry (Scheme 26) [111]. The click-phosphine ligands of type 136 were prepared by reacting phosphoacetylene 134 with different alkyl azides to generate the borane-protected ligand 135. The protection is necessary because it prevents the formation of iminophosphorane during the click reaction. The click-phosphine ligands 136 can be liberated in excellent yields by reacting the protected ligands 135 with DABCO [111,112]. A diverse library of ligands prepared in a similar manner can be obtained by varying the phosphine and the substituents around the skeleton. Some of the ligands prepared include compounds 137-140 shown in Figure 3 [111,112].
Phosphines with amine functional groups can easily undergo Mannich condensation reactions. Ferrocene-based Schiff base ligands containing pyridine-n-yl ring (n = 2, 3, 4) (Scheme 27) were synthesized by Hu et al. [113] through the Mannich condensation of ferrocenylphosphine amine 142 and the appropriate pyridine carboxaldehyde 143 in refluxing ethanol/magnesium sulfate solution . The targeted ferrocenylphosphine imines 144 were obtained in almost quantitative yield. The α-ferrocenylethyl(dimethyl)amine 141 can be synthesized from ferro-cenylethanol using phosgene and subsequent treatment with dimethylamine or, by using ferrocenyl(dimethylamino)acetonitrile. The phosphine group is introduced by ortho-lithiation of the ferrocenylamine followed by subsequent trapping with chlorophosphine [114,115].
Metallocenes have been used as ligand building blocks for many catalytic transformations. Especially, ferrocene has been used due to its high electron-donating capability and because it can be easily modified [118]. Furthermore, the ferrocenyl derivatives are reasonably stable and easily crystallize which makes purification much easier [119]. Ferrocene's distinctive attributes, like explicit geometry and conformational adaptability, can orientate donor atoms prior to coordination making it ideal for syntheses of chiral ligands [118]. In the recent decades, Ugi's amine has been one of the major interesting chiral ferrocenyl derivatives because the configuration at the α-ferrocenylmethyl position can be retained after nucleophilic substitution [115].
Drahonovsky et al. [120] conveniently modified ferrocene to synthesize a series of ferrocenyloxazole ligands as depicted in Scheme 29. The ligand can be prepared from readily available ferrocene (150). The ferrocenophane 151 was prepared via a stannylferrocenyl derivative that was reacted with the phosphide. Subsequent reaction with carbon dioxide and phenyllithium gives the phosphine ferrocene carboxylic acid 152 as the major reagent. Oxidation of the phosphine using hydrogen peroxide generated the phosphine oxide 153. In situ chlorination of the carboxylic acid followed by addition of the chiral amino alcohols gave the phosphoryl amido alcohols 154. Cyclization in the presence of tosyl chloride/triethylamine yielded the analogous ferrocenyl phosphoryl oxazoles 155, which were further reduced to give the corresponding phosphine oxazole ligands 156. The ferrocenylphosphine oxazole ligand 156 is a fascinating example which contains three metal-centered chiral elements which are conferred upon coordination with a metal [121].

Conclusion
In this review, the diversity of phosphine N-heterocyclic ligands and the variety of phosphine skeletons, which includes different five-and six-membered heterocycles and different coordinating sites has been reviewed. Different synthetic methods have been included which vary for different ligand systems. Some of the procedures satisfy more or less the following benchmarks, i.e., higher isolated yields and optical purity, allow variable substitution around the skeleton to adjust electronic and steric properties, use of low-priced and easily available reagents, mild and expedient reaction conditions, and few reaction steps. The motifs can also be chiral, and this is helpful in stereoselective synthesis. The introduction of different moieties can bring about enhanced properties like fluorescence, which can present possibilities for other interesting applications not only limited to organometallic catalysis. The combination of different heterocycles to make hybrid ligands can stimulate studies on their applicability in medicinal and OLEDs among other applications. In short, this review article presents the syntheses and architectures of phosphine N-heterocyclic ligands. Despite their success and many reported P,N-phosphine ligands, there is a need to designed new compounds to increase their library and to investigate other applications. It can be foreseen, that more probing and research on better synthetic protocols, which are fast, easy and greener, are needed. This is prime in the advancement of more flexible organometallic catalyst with novel applications.