1-Amino-1,1-bisphosphonates. Fundamental syntheses and new developments

1-Amino-1,1-bisphosphonates have become increasingly important in different fields of chemistry, medicine and agriculture. The combination of the unique physical, chemical and biological properties of methylenebisphosphonate and aminophosphonate fragments opens wide possibilities for the design of biologically active compounds including therapeutic agents to treat bone disorders related to calcium metabolism, immunomodulators, anti-infectives and plant growth regulators. The scope of this review is to summarize the existing strategies for the preparation of diversely functionalized 1-amino-1,1-bisphosphonates and to illustrate their utility as synthetic building blocks.


Introduction and short overview of biomedical applications
Aminophosphonic acids are amino carboxylic acid mimetics in which the carboxylic group is substituted by phosphonic acid residue P(O)(OH)2. 1 On the other hand, geminal aminobisphosphonates, which are characterized by a P-C(N)-P backbone, besides that they are structural analogs of α-aminophosphonic acids, may also be considered as carbon analogs of endogenous pyrophosphate (PPi) which is a regulator of calcium metabolism in living systems.Historically, aminophosphonic acids were first mentioned in the literature in the early 1940s in patents describing the synthesis of aminomethanephosphonic acid, H2NCH2PO3H2. 2,3The first reports on 1-amino-1,1-bisphosphonic acids came a decade later. 4At the present time we know that aminomethylenebisphosphonates (AMBPs), R 2 R 3 NC(A)(PO3R 1 2)2, where R 1 = H, Alk; R 2 , R 3 = H, alkyl, aryl or heterocyclic group, and A = any substituent, have a broad spectrum of practical application.Along with 1-hydroxy-1,1-bisphosphonates, AMBPs are in clinical use as drugs to treat diseases associated with excessive osteoclast-mediated bone resorption such as osteoporosis, hypercalcemia, and Paget's disease [5][6][7][8] plus they display antiparasitic [9][10][11][12][13][14][15] antibacterial, 16,17 and herbicidal 18,19 activities.1][22] In addition to their activity against FPPS, some AMBPs also inhibit other biosynthesis pathway enzymes, such as squalene synthase, 23 δ´pyrroline-5-carboxylate reductase, 24 1-deoxyxylulose-5-phosphate reductoisomerase, 25 and T. cruzi hexokinase (TcHK). 26AMBPs are also of interest in the context of cancer therapy since they stimulate human γδ T cells containing the Vγ2Vδ2 T cell receptor to proliferate and release large amounts of TNFα and IFNγ, leading to potential uses in immunotherapy. 27Moreover, the high affinity of bisphosphonates for mineralized tissues has led to application of these compounds as radiodiagnostic tools and bone-targeting moieties for drug and protein delivery with or without a polymeric platform. 28Selected examples of AMBPs used as therapeutic agents, herbicides, radiodiagnostic tools and metal-chelating ligands are shown in Chart 1.Thus, cycloheptylaminomethylene-1,1-bisphosphonate 1 is a representative of the latest generation of antiosteoporotic drugs and commercialized as Incadronate. 6,29,30N-Pyridyl-substituted aminomethylenebisphosphonic acids such as 2, developed in Japan, constitute new class of promising herbicides. 18,19Compound 2 is also potent FPPS inhibitor 12 and both 2 and 3 are efficient inhibitors of bone resorption 21,31 .1-Amino-1,1-bisphosphonates 4 and 5 are potent inhibitors of enzymatic activity of Trypanosoma cruzi, the causative agent of Chagas' disease. 10,26In addition, bisphosphonate 4 turned out to be the potent inhibitor of acid sphingomyelinase (aSMase), an important drug target for a variety of diseases. 32isphosphonate 6 is a potent inhibitor of the methylerithritolphosphate (MEP) pathway enzyme deoxyxylulose-5-phosphate reductoisomerase which is used in the protozoan parasite Plasmodium falciparum, a causative agent of malaria. 11,25iphenyl aminomethylenebisphosphonate 7 represents useful new lead for the development of antiamebic drugs. 111-Amino-1,1-bisphosphonates such as 8 are of interest in the context of inhibitory activity on squalene synthetase, which plays an important role in the pathway of cholesterol biosynthesis. 33Lanthanide(III) complexes of macrocyclic DOTA-like ligand 9 (BPAMD) containing a monoamide bis(phosphonic acid) bone-seeking group have great potential for applications in magnetic resonance imaging, radiodiagnosis and radiotherapy. 34Dipodal and tripodal ligands such as 10 are particularly interesting for uranyl sequestration. 35][38][39] The structural origins of the biological activity of AMBPs are attributed to a favorable combination of acidic phosphonyl groups with a basic amino group attached to a common carbon.A consequence of this is that they may contain positively charged protonated nitrogen atom which decreases the net ligand charge when compared with non-nitrogen-containing bisphosphonate analogs.A close position of the nitrogen atom with respect of the bisphosphonate backbone results in an increase of the acidity of the phosphonate groups, thus allowing an efficient chelating of metal ions already at low pH values. 40,41In addition, the role of PO3H2 and R 1 R 2 N groups attached to a prochiral carbon probably consists in that they provide specific orientation of the molecule on the surface of a biological object via hydrogen bond formation.Pharmacophores, such as substituents A and R 2 , R 3 , may impart some physiologic activity to the molecule.Therefore, purposeful synthesis of functionalized aminobisphosphonate derivatives is of paramount importance in the search for compounds with a desirable biomedical profile.
As a result of the exceptionally interesting biological properties of bisphosphates, numerous books and reviews have been published that summarize biomedical 5,[42][43][44][45][46][47][48][49] and synthetic aspects 47,[50][51][52][53][54][55][56] of the chemistry of bisphosphonates.However, the chemistry AMBPs has never been reviewed systematically.In this account we highlight some fundamentals concerning synthesis of AMBPs, together with most significant achievements that have appeared in literature during the last 10 years.Literature coverage for the review extends up to July 2011.
1-Aminomethylene-1,1-bisphosphonates (AMBPs) can be prepared in a number of different ways depending on the nature of organic moieties. 1,9,11,47,50,51The most common methods are (a) synthesis from carboxylic acid amides, (b) synthesis from nitriles, (c) synthesis via threecomponent reaction involving an amine, triethyl orthoformate and diethyl phosphite, (d) synthesis from imines and related compounds, and (e) block-building syntheses.All these methods are treated in detail in the next sections.

Synthesis from carboxylic acid amides
In 1972 Plöger et al. 57 have described the direct phosphonation of formamide with phosphorous acid or phosphorus trichloride in the presence of water.Mechanism of the reaction has not been studied, however such transformation must inevitably involve a number of stages, such as the formation of the intermediate 12, its dehydration and addition of another H3PO3 molecule (Scheme 1).In the optimized procedure, formamide are added to a mixture of H3PO3 and PCl3 and then heated for 7 h at 70-75 o C.After hydrolysis the compound 13 is isolated as the sole product in 30-44% yield. 58,59The formation of iminobis(methylenebisphosphonic acid), HN[CH(PO3H2)2]2, as minor product was also detected. 59Using N,N-dialkylformamides in place of formamide, dialkylaminomethylene-1,1-bisphosphonic acids 14 were synthesized in a similar manner to 13 (Scheme 2).Chen and co-workers 61 have developed a simple and convenient one-pot procedure for the synthesis of aminomethylene-1,1-bisphosphonic acids using primary and secondary amines as the starting materials.In this case amines are formylated by formic acid to give the intermediate formamides which directly react with PCl3/H2O to afford the corresponding bisphosphonic acids 14 (Scheme 3).
Primary, secondary and tertiary amides of alkanecarboxylic acids are also suitable substrates for bisphosphonation. 10,32,62 Worms and Blum reported the formation of AMBPs from diamides 18. 64 The outcome of reaction depends on the structure of a diamide.With n > 3, a mixture of bis-and tetraphosphonic acids 19 and 20 is obtained.However, with n = 2 or 3, only cyclic bisphosphonic acids 21 are formed (Scheme 5).

Scheme 7
Efficient phosphonylation of amides can also be achieved via Vilsmeier reagents (R 1 CONR 2 R 3 /POCl3).It should be noted that early findings by Gross 65 and Degenhardt 66 demonstrated that dimethylchloroformiminium chloride, [Me2N=CHCl] + Cl -(prepared from DMF and oxalyl chloride), could react with P(OEt)3 to give Me2N-CH(PO3Et)2.More recently, it was shown that treatment of the Vilsmeier reagents with 2 equivalents of trialkyl-or dialkyl phosphite provides simple and efficient route to AMBPs. 36,37,67,68The reactions proceed under very mild conditions (20 o C, 8-12 hours) and presumably involve the intermediate formation of phosphoryliminium chlorides, their transformation into corresponding phosphonyliminium chlorides and subsequent addition of the next dialkyl phosphite molecule (Scheme 8).Yields of products usually vary from 45 to 65%.Using sterically crowded amides such as MeC(O)NHR (R = t-Bu, sec-Bu) leads to bisphosphonate products in low yield, typically 20-30%. 38
Surprisingly, primary amides RC(O)NH2 (R = Me, PhCH2) did not react with POCl3 in the presence of P(OEt)3. 36On the other hand, when the Vilsmeier reagent PhCH2C(O)NMe2/POCl3 was treated with diethyl phosphite in a molar ratio of 1:2, the bisphosphonate 27 was formed in 37% yield. 68The addition into the reaction mixture of triethylamine initiates a different reaction pattern and gives rise to E-vinylphosphonates 28 (Scheme 9). 69Should also be noted that hydridophosphorane 29 reacts with the Vilsmeier reagents similar to dialkyl phosphites forming methylenebisphosphoranes 30 (Scheme 10). 67,69,70

Scheme 10
Tordo and co-workers 39 have succeeded in preparing alicyclic analogues of AMBPs in reasonable yield by the reaction of pyrrolidine-2-one and triethyl phosphite with POCl3 (Scheme 11).The oxidation of 31 with dimethyldioxirane, prepared in situ from oxone and acetone, led to the bisphosphonylated nitrone 32, which can be used in spin trap experiments.The same authors then extended this method to other trialkyl phosphites P(OR)3 ( R = i-Pr, Bu) and lactams. 37By applying the method to 2-azitidinone and 2-piperidone, bisphosphonates 33 and 34 have been obtained in 28% and 19% yields, correspondingly.Bisphosphonylation of N-methylpyrrolidine-2-one afforded the expected bisphosphonate in 17% yield.However, attempts to prepare the tetraphosphonylated product 35 from succinimide failed. 36A multinuclear magnetic resonance study ( 1 H, 13 C, 31

Synthesis from nitriles
By analogy with the synthesis of 1-amino-1,1-bisphosphonates from amides and phosphonating agents, aminobisphosphonic acids may be obtained from nitriles and phosphorous acid (H3PO3) or phosphorus trihalide (PCl3, PBr3) in the presence of water.Some preparative examples of the syntheses are given in Methods of Preparation of Chemicals and Drugs. 72In particular, 1aminoethylidene-1,1-bisphosphonic acid, H2NC(Me)(PO3H)2, is available from acetonitrile and H3PO3 73 , PBr3/H3PO3 72 or PCl3/H2O 74 in the presence of large excess of hydrogen chloride.It is assumed that hydrogen chloride activates acetonitrile and intermediately formed imines in the reaction with phosphorous acid (Scheme 12). 75Phosphonylation of acetonitrile has been carried out also with diethyl phosphite in the presence of PBr3 62 or hydrogen chloride 76 .In the last case, depending on the ratio of reagents and reaction conditions mono-, di-and tetraethyl esters of the corresponding bisphosphonic acid have been obtained.Cl -

Scheme 12
1-Aminoalkylidene-1,1-bisphosphonic acids 36-39 derived from fatty acids are most conveniently prepared by reacting the corresponding nitriles with H 3 PO 3 or PCl 3 /H 3 PO 3 /PhSO 3 H system (Scheme 13). 10Similarly, benzyl cyanide easily reacts with H3PO3 to give the bisphosphonic acid PhCH2C(NH2)(PO3H2)2.Also 4-nitrophenylacetonitrile has been successfully transformed to the corresponding bisphosphonic acid, this time by the reaction with H3PO3/PCl3. 77In contrast, under the standard reaction conditions benzonitrile exhibits very low reactivity toward phosphorous acid even in the presence of a large excess of hydrogen chloride.However, heating of PhCN and H3PO3 in the presence of AlCl3 at 180 o C followed by hydrolysis leads to the formation of the 1-aminobenzylidene-1,1-bisphosphonic acid in 80-90% yield. 78

Scheme 13
Dinitriles of malonic, succinic, glutaric, and adipic acids can also be used to give the diaminotetraphosphonic acids of the general formula 40 (Scheme 14). 77

Scheme 14
The harsh reaction conditions restrict application of the method for the synthesis of polyfunctional bisphosphonates.Nevertheless, some functionalized 1-aminoalkylidene-1,1bisphosphonates can be prepared from substituted nitriles.For example, benzimidazolylsubstituted bisphosphonic acid 41 has been synthesized by treatment of the N-(2cyanoethyl)benzimidazole with PBr3 and water in dioxane as solvent (Scheme 15). 79 Russian research group reported the conversion of cyanoacetic acid into bisphosphonic acid 42 (23%) upon treatment with PBr3 at 25 o C for 50 h followed by hydrolysis.In the standard reaction conditions (H3PO3, 200 o C) only decarboxylated 1-aminoethylidene-1,1-bisphosphonic acid could be isolated. 73From cyanoacetamide and PCl 3 /H 3 PO 3 the bisphosphonic acid 43 has been prepared in 36% yield. 77Reasonably good yield of the bisphosphonic acid 44 was obtained from 3-(dimethylamino)propionitrile while treating it with PBr3/H3PO4 mixture (Scheme 16). 6lum has studied the reaction of 3-oxonitriles 45 with a mixture of H3PO3 and PBr3.

Synthesis via three-component reaction involving an amine, triethyl orthoformate and diethyl phosphite
This route is based on the triethyl orthoformate promoted P-C-P bond formation reaction first reported by Suzuki 81 and further extended by Maier 82 and Ebetino et al. 83 The standard procedure for the synthesis of N-pyridylaminomethylene bisphosphonic 53 and bisphosphinic 54 acids developed by these authors consists in heating a mixture of triethyl orthoformate, an aminopyridine and diethyl phosphite or ethyl hydrogen alkylphosphinate, HP(O)(OEt)R, followed by aqueous hydrolysis (Scheme 19).It was later shown that a wide range of primary and secondary amines enter into this kind of reactions. 29,84An important variation, with the utilization of trialkyl phosphites [85][86][87] was also reported.Moreover, the biological importance of 1aminomethylene-1,1-bisphosphonates has prompted the developments of improved methodologies including synthesis under solvent-free conditions, 88 catalytic synthesis, 89 and activation with microwave irradiation. 88,90O

Scheme 19
The mechanism of three component condensation leading to AMBPs has been investigated by Kafarski and co-workers. 91On the basis of 31 P NMR technique and preparative experiments, they demonstrated that the reaction is quite complex and proceeds via a series of imine and aminophosphonate intermediates existing in kinetic and thermodynamic equilibrium (Scheme 20).
In spite of complex reaction pathway, the method appears to be fairly general and can be applied for the construction of various N-monosubstituted and N,N-disubstituted 1aminomethylenebisphosphonates bearing alkyl, cycloalkyl and aryl substituents at the nitrogen atom. 11,84,89Of recent studies, should be mentioned synthesis of non-carrier-added (nca) 131 Ilabeled bisphosphonic acid 57 by the reaction of the amine 55 with triethyl ortoformate and diethyl phosphite followed by iododesilylation (Scheme 21). 92Another recent example is threecomponent reaction between aminoadamantanes 58, triethyl ortoformate and diethyl phosphite which was used to obtain bisphosphonates 59.This conversion was carried out under microwave irradiation (400 W, 150 o C).Disubstituted adamantane 60 was also prepared according this procedure (Scheme 22).

Scheme 23
Of great synthetic importance is the preparation of aminobisphosphonate 64, which are valuable precursor of a wide range of bisphosphonate conjugates.This compound is readily obtained from dibenzylamine, triethyl orthoformate and diethyl phosphite followed by debenzylation with cyclohexene or H2 and Pd/C as the catalyst. 94Known applications of 64 include the synthesis of the new macrocyclic DOTA-like ligand 66 containing a bis(phosphonic acid) pendant arm 34 and potential bone-targeting reagents 67-69 for bone tumors consisting of melphalan linked to a bisphosphonate moiety through an amide linkage (Scheme 24). 95

Synthesis from imines and related compounds
As mentioned in previous section, the three component reaction consisting of a primary amine, orthoformate and the half ester of phosphorous acid proceeds via a series of methyleneimine and alkoxymethylphosphonate intermediates.Not surprisingly, some methyleneimine derivatives can be used as independent substrates for the synthesis of specific types of aminobisphosphonates. Thus, Prishchenko et al. 96  A convenient methodology for the synthesis of γ-phosphono-α-aminobisphosphonates 77 was developed from 4-phosphono-1-aza-1,3-dienes 76 (Scheme 27).Double nucleophilic addition of silylated dialkylphosphites onto the azadienes 76 in the presence of sulfuric acid leads to compounds 77 in good yields.The regiochemistry of the reaction is dependent on the steric demand of the group on nitrogen.For example, in the case of the N-t-Bu derivative, a tandem 1,4 /1,2-addition of silylated phosphite leading to the α-aminophosphonate 78 was observed. 98In the reaction of imidoyl chloride 79 derived from FCH2C(O)NHC(O)CCl3 and PCl5 with diphenyl phosphite the substitution of chlorine atom by the phosphonate group is accompanied by the 1,2-addition to the C=N bond affording the bisphosphonate 80 (Scheme 28). 99Similar reactions have been described for trifluoroacetimidoyl chlorides F3CC(Cl)=NSO2Ar. 100

Scheme 28
In 1994, Shibuya and co-workers found a new synthetic route to conformationally constrained 1-aminomethyle-1,1-bisphosphonates via Beckmann rearrangement of oximes 81 in the presence of phosphorus nucleophiles [(EtO)3P or (EtO)2P(O)H] using POCl3 as a promoter (Scheme 29). 33In this reaction the phosphorus nucleophiles capture both the intermediate iminocarbocations and iminophosphonates to give bisphosphonate derivatives 82a-e.Bisphosphonylation reaction of aromatic oxime 83 gave the bisphosphonate 84 regioselectively with migration of the aromatic groups upon using (EtO)3P as a phosphorus reagent.Later a Chinese research group applied the same methodology as depicted in Scheme 29 to synthesize aminomethylene-1,1-bisphosphonates via one-pot reaction using ketones, hydroxylamine hydrochloride, phosphorus trichloride and water as starting materials. 101

Block building syntheses
In this group, a target aminomethylenebisphosphonate has been obtained from a pre-existing aminobisphosphonate molecule by synthetic adjustment such as acetylation, alkylation, phosphorylation, imination and other transformations.Such reactions open an effective route to bisphosphonate derivatives which can be used as precursors for the construction of bisphosphonated prodrugs and aminomethylenebisphosphonate conjugates.1-Aminomethylene-1,1-bisphosphonates can sometimes be easily converted into the bisphosphonic prodrugs by a simple coupling between the amine and carboxyl functions.Thus, gem-bisphosphonic methotrexate conjugate 87 used to treat animal models of Walker‫ۥ‬ s osteosarcoma has been prepared from acid 85 and bisphosphonate 64 followed by the coupling with 2,4-diamino-6-bromomethylpteridine.Hydrolysis of the phosphonic ester 86 took place via transsilylation with bromotrimethylsilane followed by methanolysis (Scheme 30).

Scheme 30
Similar amidation reaction was applied for the synthesis of estradiol-bisphosphonate conjugates (E2-BPs) 88-93 in which the linkers were sensitive to esterases, proteases, and acidic conditions on bones to act as bone-seeking E2 prodrugs.Among them, conjugate 93 (MCC-565) was found to be the most effective and specific for bones (Structure block 3). 103age 150 © ARKAT-USA, Inc.

Structure block 3. Estradiol-bisphosphonate conjugates (E2-BPs)
With regards to bisphosphonated benzoxazinorifamycin prodrugs for the prevention and treatment of osteomyelities, several approaches were applied one of which is summarized in Scheme 31. 104N-Protected amino alcohol 94 was treated with succinic anhydride to produce the succinic acid monoester, which was coupled with 1-aminomethylenebisphosphonate 64 under standard peptide-coupling conditions.The bisphosphonate intermediate 95 was then used in the condensation with the silylated rifamycin precursor 96 to provide bisphosphonated rifamycin prodrug 97.Effectiveness of the latter has been estimated by in vitro tests.
Lecouvey‫ۥ‬ s group has developed a method for the synthesis of new polydentate ligands for metal chelating therapy containing 1-hydroxy-2-pyridinone and bisphosphonate moieties linked via an amide function.Interestingly, the length of the carbon chain between the amino and the methylene bisphosphonate groups has a strong effect on the dealkylation of esters 98 by concentrated HCl.Refluxing 98a in concentrated HCl leads to the splitting of the amide bond and the formation of free 1-aminomethylenebisphosphonic acid.In contrast, when at least two carbon atoms are present between the amino group and the tetraethyl methylenebisphosphonate moiety as in ester 98b, dealkylation by concentrated HCl gives the mixed bisphosphonatehydroxy pyridonate ligand 99 in almost quantitative yield (Scheme 32). 105

Scheme 31
The synthesis of bisphosphonate diethylenetriaminepentaacetic acid (DPTA) derivative 100 was accomplished by treating aminobisphosphonate 64 with diethylenetriaminepentaacetic dianhydride in DMF at 50-60 o C followed by hydrolysis of 100 (Scheme 33).The DTPA conjugate 101 retains bone-binding character and is able to act as a carrier of cytotoxic radionuclides. 106O

Scheme 33
Catechol-bisphosphonate conjugates 104 for metal intoxication therapy were obtained by condensation of aminobisphosphonate 64 with dihydroxybenzaldehyde 102 followed by reduction with NaBH(OAc)3 prepared in situ.Hydrolysis of bisphosphonic esters 103 was carried out by using bromotrimethylsilane followed by methanolysis (Scheme 34). 107 variety of thioureido derivatives of methylenebisphosphonic acid was synthesized by the reaction of 1-aminomethylene-1,1-bisphosphonic acid with isothiocyanates (Scheme 35).In the free form the resulting compounds 105 are unstable, except for acid bearing 4dimethylaminophenyl substituent (R = 4-Me2NC6H4) which exists as an internal salt.However, thioureido derivatives could be isolated as disodium salts 106 108 and their herbicidal action 109 as well as effect on the activity of alkaline phosphatases from bovine small intestine mucosa and human placenta 110 were studied.It is worst mentioning that due to the partial double bond character of the SC-N bond thioureidobisphosphonates exist in solutions as mixtures of the E and Z isomers whose ratio is strongly pH-dependent. 111Substituted thioureidomethylenebisphosphonic acids react with haloketones to form thiazoles. [112][113][114] (HO)

Scheme 35
Isocyanatomethylenebisphosphonate 107 was demonstrated to be an interesting starting building block giving access to drugs for the treatment of metastatic bone cancer. 106For example, bisphosphonate conjugate with 5-fluorouracil was synthesized as outlined in Scheme 36.The urea linkage in compound 109 is possible functional group that may undergo biochemical cleavage to release the conjugated 5-fluorouracil and provide local concentration necessary for tumor therapy.Bisphosphonate conjugate 110 with the potential for targeted therapy for cancer patients was prepared using a reaction between the isocyanatobisphosphonate 107 and the potent anticancer drug gemcitabine (Gemzar ® ) (Scheme 37).

Scheme 37
The reaction of 1-aminomethylenebisphosphonate 64 with carbonyl compounds provides a very general route to bisphosphonated imines and various new aminophosphonate derivatives.For example, after condensation of 64 with aldehydes and cyclic ketones, the resulting imines 111 can be used as intermediates in the preparation of aminobisphosphonate derivatives 112 by reduction of the imino linkage with NaBH(OAc)3 (Scheme 38) as well as in the synthesis of 2aza-1,3-butadienes 113 by means of a Wadsworth-Emmons reaction (Scheme 39). 116The olefination reaction of imines 111 can be carried out using different bases including MeLi, BuLi and Bu t OLi but as might be expected a weaker base such as cerium carbonate in THF/Pr i OH provided good yields of azadienes 113.This methodology has been applied to the synthesis of azatrienes 114 and 115. 116

Scheme 41
Free 1-aminomethylenebisphosphonic acids do not appear to participate readily in the reactions with aldehydes.Particularly, attempts to prepare imino derivatives from 1aminoethylidene-1,1-bisphosphonic acid H2N(Me)C(PO3H2)2 have not been successful.However, aromatic aldehydes could be iminated with tetrasodium salts H2N(Me)C(PO3Na2)2 to give the corresponding imino derivatives in moderate yields. 118minobisphosphonate 31 was recently used as an amine component in the multicomponent Petasis boronic acid Mannich reaction.The coupling of 31 with glyoxylic acid monohydrate and styryl-, aryl-or heterylboronic acid leads to amino acids 122 without detection of any intermediate products (Scheme 42).The method affords the useful access to polyfunctional molecules bearing both amino acid and aminophosphonic acid moieties. 119

Scheme 42
An interesting synthesis of bisphosphonates 125 substituted at the α-position both an amino and an allylic group has been proposed from 1-dimethylamino-1,1-bisphosphonate (Scheme 43).The key step of the synthesis was postulated [2,3]-Wittig rearrangement of the corresponding Nallylic ammonium salts 124 prepared by quaternization of the bisphosphonate 123 with allylic halides in the presence of AgBF4.The rearrangement has been realized by treatment of compounds 124 with NaH in THF.In the case of the prenyl derivative 124e, rearranged product 125 was not detected, and the bisphosphonate 123, stemming from the competitive process was the sole product of the reaction.

Scheme 43
The use of 1,1-bisphosphono-2-aza-1,3-dienes 126 for the synthesis of N-vinyl 2,2bisphosphonoaziridines 127 has been described by Stevens and co-workers. 121Treatment of the azadienes 126 with an excess of diazomethane in ether at room temperature yielded bisphosphonoaziridines 127 in 63-79% yields.As a side reaction, the formation of phosphonates 128 was also observed (Scheme 44).

Page 159
© ARKAT-USA, Inc.A useful method providing a direct entry to the anchoring of CH(PO3R2)2 moiety onto aromatic amines has been developed by Taran and co-workers. 35The method uses a bisphosphonate-metal-carbenoid N-H insertion reaction for which Rh2(NHCOCF3)4 was found to be an efficient catalyst.In general, the rhodium-catalyzed N-H insertion reaction of diazo compound 130 worked successfully with aromatic amines containing both electron-donating and electron-withdrawing substituents affording the desired aminobisphosphonates 131 in good yields.Moreover, the procedure is suitable for the construction of dipodal bisphosphonate ligands such as 132 by using diamines as starting materials (Scheme 46).However, attempts to apply this method on aliphatic amines failed.

Scheme 46
Although much more limited in scope, metal-mediated insertion of isocyanides to P(O)-H bond open a potentially useful route to bisphosphonate-like compounds.For example, the reaction of Ph2P(O)H with 2,6-dimethylphenylisocyanide in the presence of a catalytic amount of Pd2(dba)3 (5 mol %) in toluene predominantly produced the 1:1 adduct 133.However, when the catalyst Pd2(dba)3 was replaced with Ph(PPh3)3Cl, compound 135a was formed in 95% yield.Under similar conditions, other rhodium(I), but not rhodium(III) complexes, also produce compounds 135a-d selectively (Scheme 47).Alkylphosphine oxides, such as n-Bu2P(O)H only gave a trace amount of bisphosphorylated compounds. 123age 161 © ARKAT-USA, Inc.

Conclusions
It is evident from this account that 1-amino-1,1-bisphosphonates play an important role in organophosphorus chemistry and biochemistry.The last two decades have seen their increasing use in synthetic transformations directed towards the design of new drugs and biomedicals.Major advances have been made in the synthesis of N-heteryl-substituted bisphosphonates and the use of tetraethyl 1-aminomethylene-1,1-bisphosphonate in coupling reactions for the preparation of aminobisphosphonate conjugates.A major future goal remains to be the synthesis of a large diversity of functionalized, enantiomerically enriched aminobisphosphonates and bisphosphonate-containing amino acid mimetics.In our opinion, aminobisphosphonate-like pentacoordinated structures, which are directly mimics of transition state of phosphate hydrolysis, may be also very useful for biosciences.

Table of Contents
7115N) was performed on a series of new cyclic bisphosphonates.71 80Bisphosphonates 46 were obtained in modest yields and are valuable synthons for the synthesis of other types of bisphosphonic acids such as 47 and 48 (Scheme 17).