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Methods for the synthesis of α-heterocyclic/heteroarylα-aminophosphonic acids and their esters Tarik E. Ali* and Somaia M. Abdel-Kariem Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, Cairo, Egypt E-mail: [email protected] DOI: http://dx.doi.org/10.3998/ark.5550190.p009.112 Abstract This review describes a comprehensive account of methods which are commonly applied for the synthesis of α-heterocyclic/heteroaryl α-aminophosphonic acids and their esters. In the following order, protocols based on the methodologies listed below are discussed: (a) Pudovik reaction; (b) Kabachnik-Fields reaction and (c) Miscellaneous Methods. Keywords: α-Aminophosphonates, heterocycles, Kabachnik-Fields, Pudovik reactions

Table of Contents 1 2

3

4

Introduction Synthesis by Pudovik Reactions 2.1 Five-membered heterocycles with one heteroatom 2.2 Five-membered heterocycles with two heteroatoms 2.3 Six-membered heterocycles with one heteroatom Synthesis by Kabachnik-Fields Reactions 3.1 Five-membered heterocycles with one heteroatom 3.2 Five-membered heterocycles with two heteroatoms 3.3 Six-membered heterocycles with one heteroatom 3.4 Six-membered heterocycles with two or more heteroatoms 3.5 Macrocycles Miscellaneous Methods 4.1 From diethyl α-azido-α-(benzoylaminomethyl)phosphonate 4.2 Nucleophilic substitution reactions 4.3 Cycloaddition of α-alkylaminophosphonates 4.4 Reduction of α-hydroxyiminophosphonate 4.5 Hydrolysis of S-adenosyl-L-homocysteine derivative

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4.6 Curtius rearrangement of α-acylazidophosphonate 4.7 Addition of diethyl phosphite to chiral N-benzylnitrones 4.8 From phosphonyliminium salts 4.9 From oxazolyl phosphonates Conclusions References

1. Introduction α-Aminophosphonic acids are considered mimics of the corresponding α-aminocarboxylic acid.1 The phosphonic moiety has long been established as a bioisostere of a carboxylic unit. These features explain the large range of biological activities displayed by the members of this important class of compounds and the applications.2-5 They have been found in areas ranging from medicine to agriculture, for example, as antibiotics,6 enzyme inhibitors,7 anticancer agents8 and herbicides.9,10 These biological properties mostly are associated with the tetrahedral structure of the phosphonyl group acting as a “transition-state" analogue.11 Because of their ability to mimic transition states of hydrolysis, phosphonic acid derivatives having heterocycles at the α-positions have been shown to be inhibitors of various enzymes, including HIV-protease and human collagenase.12 At present, the literature concerning the synthesis and application of α-aminophosphonates is very extensive, comprising more than six thousand publications. Hence, several approaches13 have been developed for the synthesis of α-aminophosphonates. Two main pathways are: (i) the Pudovik reaction, where dialkyl phosphites are added to imines, and (ii) the Kabachnik-Fields three component reaction, in which a carbonyl, an amine and a di- or tri-alkyl phosphite react in a single-pot. In some reports, these reactions were carried out as straightforward one-pot procedures without any catalyst,14 but in most cases they were performed using catalysts.15 On the other hand, α-aminophosphonic acids and their esters bearing a heterocyclic moiety at the α-position are becoming the subject of growing interest. To our knowledge, there are several methods for the synthesis of α-heterocyclic/heteroaryl α-aminophosphonates (Figure 1). In connection with our work on the preparation of α-aminophosphonates containing heterocyclic systems,16-19 we report in this review article all the available synthetic methods of α-heterocyclic/heteroaryl α-aminophosphonates which were published until 2013. Ar NH Heterocycle or Heteroaryl

O OR P

H

OR

Figure 1. α-Heterocyclic/heteroaryl-α-aminophosphonic acids and their esters.

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2. Synthesis by Pudovik Reaction 2.1. Five-membered heterocycles with one heteroatom The Schiff bases 1 were subjected to react in situ with diethyl phosphite in toluene at 110 °C to give the corresponding α-aminophosphonate esters 2. When diphenyl phosphite was used in the reaction with imines 1, the addition reaction took place even at room temperature, giving the diphenyl esters in high yields (Scheme 1).20 O

RO RO

H N

P H N

HP(O)(OR)2 Ph

X

X

R = Et, Ph, X= O, S 1

Ph

H

Toluene, Reflux 59 - 78 %

2

Scheme 1 Stereoselective synthesis of (5-hydroxymethylfuran-2-yl)-N-(α-methylbenzylaminophosphonates 4a,b was performed by the addition of dibenzyl phosphite to the N-(furylmethylene)-(R)-α-methylbenzylamine (3), resulting in diastereoisomeric esters (Scheme 2).21,22

HOCH2

P(O)(OCH2Ph)2

HP(O)(OCH2Ph)2 O N 3

HOCH2

Ph

O

H

Ph

HN Me

Me

4a

Major product , 77% + P(O)(OCH2Ph)2 HOCH2

O

H HN

4b

Ph Me

Minor product, 23%

Scheme 2 When the cyclic phosphonate 5 was reacted with the Schiff base 6 at 17 °C it afforded the corresponding α-(3-thienyl)-α-aminophosphonate 7. Reaction of phosphonate 5 (R=COOR) with the imine 6 required ultrasonic conditions to bring the reaction to completion (Scheme 3).23

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R O P

Toluene,

+

O H N

P

88 oC O

O

O

O

NMe

H

71 - 82 %

S

R 5

Me H

R 7

6

S

R = a) CH3, b) (CH3)2, d) COOR

Scheme 3 Reaction of the Schiff bases 8 with dialkyl phosphites in toluene at 85 oC provided the corresponding α-aminophosphonates 9 (Scheme 4).24 O HP(O)(OR)2 X N

R`

Toluene 85 oC

H

P

X HN

8

OR OR R`

9

X= O, S

R = C10H21, Bn

R`= t-Bu, i-Pr

Scheme 4 The diethyl phosphonate esters 11 were prepared by heating equimolar mixtures of diethyl phosphite and the corresponding Schiff base 10 in the absence of solvent at temperatures between 90 and 100 ºC (Scheme 5).25

X Ph

X

(EtO)2P(O)H

EtO OEt

Ph N

Ph

50 - 93 % X= O, S, NH

10

P N

Ph

H

O

H 11

Scheme 5 Similarly, addition of two equivalents of dimethyl phosphite to heterocyclic imine 12 in methanol afforded the α-(2-furyl)-α-aminophosphonate 13 (Scheme 6).26

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HN

N 2 equiv HP(O)(OMe)2

O H

O P(OMe)2

H

MeOH, reflux, 2 h

O 12

13

Scheme 6 Synthesis of cucurbitine phosphonic analogues 16 was performed through reaction of hydrazone intermediates 14 with triethyl phosphite in acidic media. Subsequent cleavage of N–N bonds gave aminophosphonic acid 16 and not the corresponding α-hydrazinophosphonate (cucurbitine analogue) (Scheme 7).27

H X

+

NH2

EtO P EtO

P(OEt)3

HO HO

NH2

P

X

X

X = O, S, NR`

14

O

O

NHR N

15

16

Scheme 7 4,4'-Bis[[(dialkoxyphosphonyl)-(2-furyl)methyl]amino]diphenyl (18) was prepared by addition of diethyl phosphite to N,N´-bis(furfurylidene)benzidine (17) in sodium ethoxide and stirring at room temperature for 3 hours (Scheme 8).28

O

O N

N

17

2 HP(O)(OR)2

O H

NaOEt 87 %

O

H

H

N

N

P(OR)2

O H O

P(OR)2

18 R = Et, i-Pr

Scheme 8 Similarly, addition of diethyl phosphite to the azomethine bonds of the bis-Schiff base 19 was carried out, affording 1,3-bis[N-[(diethoxyphosphonyl)-(2-furyl)methyl]amino]benzene (20). In this case NMR studies revealed that the reaction product is a mixture of the two possible diastereomeric forms: R,S (meso) and the enantiomeric pair R,R and S,S (Scheme 9).29

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H

N

N

H O

H

P EtO

O P

O OEt

O

OEt OEt

20 R,R

N

O

N

H

H

N

N

H O

2 HP(O)(OEt)2

O

NaOEt 51 %

EtO

19

H

P O OEt

O

O P OEt OEt

20 S,S

H

H

N

N

H O

H

P EtO

O OEt

O

O P OEt OEt

20 R,S

Scheme 9 Also, four bis(aminophosphonates) 25, 26, 27 and 28 were synthesized through addition of diethyl phosphite to the azomethine bonds of the furan-substituted bis(imines) 21–24. The addition of dialkyl (diaryl) phosphites to bis(imines) should lead to the formation of two diastereomeric forms, meso and racemic diastereomers. Thus, this synthesis in most cases occurs with high stereoselectivity, yielding as major product only one of the diastereomers, as previously obtained in similar reactions (Scheme 10).30,31 2 HP(O)(OEt)2

R O

N

N X

R O

NaOEt 51 - 67 %

21-24

H

H

N

N

H

R O

R O

X P

R`O

H

O OR`

P O

OR` OR`

25-28

R = H, Me R` = Me, Et

X=

Scheme 10 Poly(oxyethylene)aminophosphonates 31 were synthesized through addition of poly (oxyethylene H-phosphonates) 29 to the azomethine bond of N-furfurylidene toluidine (30), according to Scheme 11. The polymer analogous reaction was carried out in the presence of

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catalytic CdI2, as well as without catalyst. In the presence of CdI2 the addition of P-H groups to the azomethine 30 proceeded with higher reaction rate compared to the non-catalyzed reaction and the poly (α-aminophosphonates) 31 were obtained in good yields in 3 hours. In the absence of catalyst the reaction time was longer, up to 15 hours (Scheme 11).32 O CH3O

P

O O(CH2CH2O)

P

x

H

O O(CH2CH2O)

P

x

H

H

29 dry benzene

OH

O

CdI2 N

37 - 90 %

CH3

30 O CH3O

P

O O(CH2CH2O)

P

x

O HN

H

CH3 X= 4, 13

O O(CH2CH2O)

P

x

O HN

H

CH3

OH O

HN

H

CH3

31

Scheme 11 Reaction of Schiff bases 32 with bis(trimethylsilyl)hydrogen phosphite in boiling benzene gave α-(3-indolyl)-α-aminophosphonates 33 in yields 90-93% (Scheme 12).33

Scheme 12 Reaction of the Schiff bases 34 with diethyl hydrogen phosphite via Pudovik reaction in refluxing toluene in the absence of catalyst afforded the corresponding α-aminophosphonates 35 (Scheme 13).34

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O EtO P EtO

(EtO)2P(O)H NH

N

F

4-6 h 82, 72 % O2N

N H

F

Toluene, reflux

O2N

34

NH

H

35

Scheme 13 2.2. Five-membered heterocycles with two heteroatoms The aldimines 36 were reacted directly with trimethyl phosphite in the presence of bromotrimethylsilane to form the α-(2-thiazolyl)-α-aminophosphonic silylated esters 37, as intermediates, which were then deprotected giving the α-(2-thiazolyl)-α-aminophosphonic acids 38 (Scheme 14).35 P(OMe)3

N N

N

Me3SiBr

N

R

S

CH2Cl2

H

Me3Si

S

H

P

O

36

N

MeOH

N

R

OSiMe3

S

65-70 %

P O 38

OSiMe3

37

R

OH

H

OH

R = n-Bu, Ph, CH2Ph

Scheme 14 Similarly, the reaction of imines 39 with tris(trimethylsilyl) phosphite (generated in situ from triethyl or trimethyl phosphite and bromotrimethylsilane) to give the silylated intermediates 40 which were then treated with methanol, producing the desired desilyated α-(imidazol-2-yl)-αaminophosphonic acids 41 (Scheme 15).36,37

N

i) P(OR`)3

N

P

H

N NR

39

O

N

ii) 5 TMSBr

H

OSiMe3 OSiMe3 NHR

37-85 %

O

N

MeOH

H

H 40

P

OH OH NHR

N 41

R = butyl, benzyl, 2-pyridyl, 3-pyridyl, 1-imidazolyl , 2-PyCH2, 3-PyCH2, 1-imidazole(CH2)3 R`= Me, Et

Scheme 15 The diethyl 1,3-benzodioxylphosphonate esters 43 were prepared by heating equimolar mixtures of diethyl phosphite and the corresponding Schiff base 42 in the absence of solvent at temperatures between 90 and 100 °C (Scheme 16).25

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O O

(EtO)2P(O)H

O EtO OEt

93 %

Ph

Ph

P N

N

H

Ph

Ph

O

H 43

42

Scheme 16 2.3. Six-membered heterocycles with one heteroatom Addition of diethyl phosphite to the Schiff base 44 at room temperature without a solvent in the presence of catalytic amounts of sodium ethoxide afforded diethyl [(N-benzylamino)(2pyridinyl)methyl]phosphonate (45) which underwent acidic hydrolysis to give the corresponding α-aminophosphonic acid 46 (Scheme 17).38 O P

HP(O)(OEt)2 N H

N 83-94 % 44

N

OEt OEt

H N

45

HCl / H2O

O P N H

OH OH

H N 46

Scheme 17 1-(N-Benzyl)-2-formyl-5-benzyloxy-pyridone 47 reacted with primary amines to obtain the corresponding imines 48. The imines then were treated with a mixture of trimethyl phosphite and bromotrimethylsilane, which caused in situ formation of tris(trimethylsilyl) phosphite, which instantly reacted with the imines, giving silylated phosphonate intermediates. Treatment of the intermediates with methanol caused removal of the silylated groups and the formation of the final α-(pyridinyl)-α-aminophosphonic acids 49 (Scheme 18).39

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O

O

PhCH2O

N

CHO

i) P(OMe)3 ii) Me3SiBr

PhCH2O

RNH2

CH2Ph NH

48- 84 %

CH2Ph

49 47

P

MeOH

N

CH2Ph

O H N

NR

CH2Cl2

PhCH2O

OH OH

R

48

R = Bu, Ph2CH, PhCH2

Scheme 18 A short and efficient synthesis of new 4-amino(piperidine/tetrahydropyran/ tetrahydrothiopyran)-4-phosphonic acids 52 in good yields was described via addition of triethyl phosphite in acidic medium to ketone imines 50 via α-aminophosphonates 51 (Scheme 19).27 O

NR H

EtO EtO

+

O NHR

P

NHR

HO P HO

P(OEt)3

X 50

X

X

51

52

X = O, S, NR`

Scheme 19 Some piperidine-incorporated α-aminophosphonates 54 were prepared in excellent yields by reacting imines 53 with triethyl phosphite in the presence of dilute HCl under ultrasound irradiation (Scheme 20).40 O H

3

N

H

R

P EtO

R1

2

H N

3

R

OEt

R

R1

2

R

P(OEt)3 , dil HCl r. t., 3-5 min ))))))) N 73-88 %

53

R1 = H, F R2 = H, F, OCH3, NO2 R3 = H, F, CH3, OCH3, OEt, Cl, NO2

N

54

Scheme 20 α-(3-Quinolinyl)-α-aminophosphonates 56 were prepared in quantitative yields by reacting imines 55 with triethyl phosphite in the presence of tetramethylsilyl chloride (TMSCl) at room

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temperature. The yields of the α-aminophosphonates using this process are in the range of 95– 98% (Scheme 21).41,42 R5

5

R R

R

4

1

R

N

R

R

OEt OEt P

1

r. t.

Cl

N

HN

P(OEt)3 / TMSCl

2

R

H

2

3

95 - 98 %

O

R1 = H, Me, OMe, OEt R3 =

R

H, Me, Et

3

56

R2= H, Me, OMe

R4=

H, Me

R5=

Cl

N R

55

4

H, F

Scheme 21 Nucleophilic addition of the silylated phosphorus ester to imines 57 proceeded easily at room temperature for 12 hours. The formed silylated phosphonic intermediates 58 were treated with methanol as a desilylating agent to produce the desired α-(quinolin-2, 3- and 4-yl)-α(amino)methylphosphonic acids 59 in good yields (Scheme 22).43 R 1) P(OMe)3

N

Me3Si

2) TMSBr CH2Cl2, r.t., 12 h

N

MeOH

OSiMe3

53 - 67 % N

N 57

N

OSiMe3 P

R

H

R N

H

OH P

OH

O

O 59

58

Scheme 22 The synthesized imines 60 were treated with triethyl phosphite in the presence of TMSCl at room temperature to afford the corresponding diethyl α-(tetrazoloquinolin-3-yl)-α-aminophosphonate 61 (Scheme 23).44 F R

EtO

F

O P

1

N

P(OEt)3

R

EtO

1

N H

2

R

N R

3

N

N N

TMSCl / r. t. 78 - 95 %

60

H

2

R

N R

3

N

N N

61

R1 = H, Me, OMe, OEt R2 = H, Me, OMe R3 = H, Me, Et, OMe

Scheme 23 Page 256

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The Schiff bases 62 reacted with dialkyl phosphite or trialkyl phosphite in presence or absence of solvent to give α-(chromon-3-yl)-α-aminophosphonates 63 (Scheme 24).18,45,46 R

2

OEt EtO O

O 1 R

R

H 66 - 88 %

O

2

1

HP(O)(OR)2 or P(OR)3

N

R

O

P N H

O

62

63 R = Me, Et, i-Pr, R1 = H, Me, R2 = H, 4-Cl, 4-OMe, 2-Me, 4-Me, 2-NO2, 4-NO2

Scheme 24 Fusing of the bis-phosphonic hydrazone 64 with diethyl phosphite at 80-100 °C in the presence of catalytic amounts of triethylamine produced N1,N5-bis[N-methyl(diethoxyphosphonyl)-1-[(4-oxo-4H-chromen-3-yl)]phosphonic dihydrazide (65) as the sole product (Scheme 25).47 O

O N

H H N P

H N N

O O

O

64 HP(O)(OEt)2 Et3N

78 %

80 - 100 oC EtO EtO P O

O

O

P N

H H N P

OEt OEt

O

H N N H

H O

O

O 65

Scheme 25 Similarly, the addition of diethyl phosphite to compounds 66 was carried out in dry benzene containing few drops of triethylamine as catalyst to yield the corresponding bis-(α-aminophosphonate) derivatives 67 (Scheme 26).47 Also, addition of diethyl phosphite to azomethine bonds of interesting compounds 68 and 69 on fusion at 80–100 °C in the presence of a catalytic amount of triethylamine yielded one diastereomeric form of tetraethyl 5,5'-(1,4-phenylene)bis-[[[(3-oxo-3-phenyl-2,3-dihydro-4H1,2,4,3-triazaphosphol-4-yl)amino](4-oxo-4H-chromen-3-yl)methyl]phosphonate] (70) and two diastereomeric forms of tetraethyl 5,5'-(1,4-phenylene)bis-[[[(3-oxo-3-phenyl-2,3-dihydro-4H1,2,4,3-triazaphosphol-4-yl)methylphosphoryl]amino](6-methyl-4-oxo-4H-chromen-3-yl)methyl] phosphonate] (71), respectively (Scheme 27).17

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O N

C N H2 n

O

O

66 69, 71 % n = 3, 4

HP(O)(OEt)2 Et3N 80 - 100 oC EtO

OEt

O P

OEt

H

N H

O

EtO

O O

P

C N H2 n H H O

O 67

Scheme 26 H N

Ph

N

N

H N

O

Ph P

P

O

N

N X

X

N

N O

O O

O 68, X= bond 69, X= -P(O)CH3

H3C

fusion at 80-100 0C

CH3

Excess (EtO)2P(O)H Et3N 69

68 H N

Ph O O P EtO

OEt

N

N

H N

Ph P

P N NH H

N

H

P

O

O H3C

OEt

N

H N

P O

EtO

O

OEt

Ph P

NH H

O

N

N P

O

OEt

O

N

P

O O

HN

H N

Ph

O

H3C

P

O O

HN H

P

OEt

OEt O

O O

O

CH3

H3C 70, One diastereomeric form (R, S) or racemic (R, R and S, S)

CH3

H3C 71, Two diastereomeric forms (R, S) and racemic (R, R and S, S)

Scheme 27

3. Synthesis by Kabachnik-Fields Reaction 3.1. Five-membered heterocycles with one heteroatom Three component one-pot reaction of heterocyclic aldehydes such as furan-2-carbaldehyde,

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thiophene-2-carbaldehyde and pyrrole-2-carbaldehyde with different amines such as butylamine, cyclohexylamine, aniline, benzylamine, 4-chloroaniline, 4-methoxyaniline, 4-fluoroaniline, 4-methoxyaniline, HMDS (1,1,1,3,3,3-hexamethyldisilazane), aminoalkylphosphonic acid and heteroaryl amines with dialkyl or trialkyl phosphites gave the corresponding α-heterocyclic-αaminophosphonates 72 in good to excellent yields under different reaction conditions (Scheme 28) (Table 1).10,20,48-68

X

CHO

+ RNH 2

HP(O)(OR`)2/ P(OR`)3 Reaction conditions 36 - 98 %

NHR H

X R`O P R`O

O

72

Scheme 28 Table 1. Conditions of reactions of furan-, thiophene-, or pyrrole-2-carbaldehyde and different amines with dialkyl or trialkyl phosphites to give the corresponding α-heterocyclic-αaminophosphonates 72 Entry

X

R in Scheme 28

R'

Reaction conditions

Ref.

1

O, S, NH

Bu, PhCH2

Et, Ph, PhCH2

toluene, reflux

10

2

O

4-MeOC6H4

Et

NH4VO3/RT/stirring

49

3

O, S

Ph

Et

[bnmim][HSO4]/RT/stirring

50

4

O, S

Ph

Et

1-hexanesulfonic acid sodium salt/ultrasound

51

5

S

Ph

Me

AlCl3/CH3CN/RT

52

6

O, S

Ph, 4-FC6H4

Et

[bmim]BF4 or [bmim]PF6

54

7

O

Ph, 4-MeOC6H4

Et

10 mol %, GaI3/CH2Cl2/RT

55

No.

o

8

O

PhCH2

Et

LiClO4, 20 mol%, 60 C, 8 h

56

9

O, S

4-MeOC6H4

2-MeOC6H4

Zn(NTf2)2/10 mol%, CH2Cl2, -50 °C

57

10

O, S

[(Me3Si)2NH]

Et

I2 (10 mol%), solvent free

58

11

S

(CH2)nCOOH

Et

MeOH, Et3N

61

12

O

4-MeOC6H4

Me

Yttria-zirconia Lewis acid/ aq. CH3CN/60 °C

48

13

O, S

Ph

Et

14

O, S, NH

[(Me3Si)2NH]

Et

Al(OTf)3 (10 mol%)/ solvent free/ 80 °C

59

15

O, NH

Ph, 4-MeOC6H4

Et, PhCH2

H-β-zeolite, heat, MeCN

60

16

S

PhCH2

Et

toluene, reflux, 3h

20

17

S

Ph

Et

TiO2 (20 mol%), no solvent, 50 °C

62

18

O

Ph, 3-pyridinyl

Et

Metal oxide, ultrasound

63

19

O

Ph

Me

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Homogeneous sulphamic acid (0.7 mol%), neat/RT

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Table 1. Continued Entry No.

X

R in Scheme 28 4-phenoxyquinazolin-

R'

Reaction conditions

Et

[BMIM]Cl/ MW

65

Mg(ClO4)2 (5 mol%)

66

20

O

21

O, S

Ph

Me, Et

22

S

1-(furan-2-yl)methyl

Me

2-yl

Ref.

TMG (tetramethyl guanidine), toluene, 50-60 °C, 5-6 h

67

Dibenzo[d,f][1,3,2] 23

O, S

diazaphosphepin-6-yl

TMG, toluene, 60-70 °C, 4 h

Me, Et

68

6-oxide-

Refluxing thiophene-2-carbaldehyde with a mixture of urea and diethyl phosphite in dry toluene afforded the ureidophosphonate 73 as a major product (Scheme 29).69 O O S

CHO

+

dry toluene HP(O)(OEt)2

H2N

NH2

O H H N

H H P N EtO EtO

P OEt OEt

O 8 h , 54%

S

S

73

Scheme 29 Magnetic iron oxide nanoparticles coated with structurally variable α-heterocyclic-αaminophosphonates 75 have been obtained by one-pot three-component reaction of 2-aminopyridine iron oxide nanoparticle 74, heterocyclic aldehydes and diethyl phosphite (Scheme 30).70 R X CHO

+ N

NH2

R

HPO(OEt)2

X

N

74 = magnetic core

= silica coated nanoparticles

N H H

PO(OEt)2

75 X= O, S, N, R= H, NO2

Scheme 30 α-(Indol-2-yl or 3-yl)-α-aminopyridinylphosphonates 76 were obtained from the corresponding indole aldehydes, 2-aminopyridine and diethyl phosphite without any solvent (Scheme 31).71,72 Page 260

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HP(O)(OEt)2

CHO + N

N

P(O)(OEt)2

neat

NH2

N

R

N H H N

R = H, Me, CH2CH2CH3

R

76

Scheme 31 Diethyl α-(indol-3-yl)-α-aminophosphonates 77 were synthesized through the reaction of 3formylindole, diethyl phosphite and heterocyclic amines and/or ammonium carbonate or ammonium acetate under various reaction conditions (Scheme 32) (Table 2).58-60,68,73,74 Ar HN

CHO

+

HP(O)(OR)2 Ar

O

H

P

NH2

RO OR Conditions i-iv

N H

N H

74 - 93 %

77

Scheme 32 Table 2. Conditions reaction of 3-formylindole, diethyl phosphite and amines to give diethyl indolyl-α-aminophosphonates 77 Entry No.

Conditions

Amine

R

Ref.

1

I2 (10 mol %)/ solvent-free

(Me3Si)2NH

Et

58

(Me3Si)2NH

Et

59

(NH4)2CO3 or NH4OAc

Et

73

PhNH2, 4-MeOC6H4NH2

Et

60

Et

74

Me, Et

68

2 3 4

Al(OTf)3(10 mol %), solventfree/ 80 °C Al(OTf)3(10 mol %), solventfree/ 100 °C β-zeolite

N

5

6

PEG / H2O / RT

Me

NH2

O

toluene / TMG /

O

60 -70 °C / 4h

O

O P NH2

α-(Indol-3-yl)-α-aminophosphonate 79 was synthesized by the reaction of an aromatic amine, 3-(4-formylphenyl)indole (78) and diethyl phosphite under MW conditions in the presence of Amberlyst-15 (Scheme 33).75

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NH2

Cl

CHO

+

HO

Amberlyst-15 H

MWI, 4-6 min

N H

Cl

OH

H N

HP(OEt)3

N H

78

P

OEt

Cl

OEt

O 79

Scheme 33 Various substituted anilines carrying either electron donating or electron withdrawing substituents, and also benzylamine, reacted with 9-ethyl-6-bromo-3-formylcarbazole (80) and diethyl phosphite in PEG-mediated reactions to give the desired α-(carbazol-3-yl)-α-aminophosphonates 81 in good yields. In this reaction PEG-400 not only acts as the solvent but also accelerates the imine formation and the nucleophilic addition of phosphite to the imine by increasing its electrophilicity through hydrogen bonding by its hydroxyl group with the imine nitrogen (Scheme 34).76 R HN CHO

Br

HP(O)(OEt)2 + R N

NH2

Br

H O P

PEG-400

EtO

OEt

100 oC N

Et

Et

80

81

R = Ph, PhCH2, 4-MeC6H4, 4-MeOC6H4, 4-ClC6H4, 4-BrC6H4, 4-FC6H4, 4-HOC6H4, 4-NO2C6H4, 4-NH2C6H4, 4-NCC6H4, 4-(Me)2CHC6H4, 4-Me-4-BrC6H3, 4-Cl-3-CF3C6H3

Scheme 34 3.2. Five-membered heterocycles with two heteroatoms In a one-pot synthesis, 3-formylpyrazole (82) reacted with benzyl carbamate and triphenyl phosphite in acetic acid to give α-(pyrazol-3-yl)-α-aminophosphonate 83 in moderate yield (Scheme 35).20

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AcOH, 2 h, 90 oC P(OPh)3

H

+ PhCH2OCONH2

N N

O

P OPh

O

O

N H

Ph

N

96 %

N

H

H

82

83

Scheme 35 1-Phenyl-3-aryl/heteroaryl-1H-pyrazol-4-carboxaldehyde (84) are reported to react with arylamines and dialkyl/diphenyl phosphites under Kabachnik-Fields reaction conditions in the presence or absence of catalysts to give the corresponding α-(pyrazol-4-yl)-α-aminophosphonates 85 (Scheme 36) (Table 3).77-80 O RO

CHO

Ar

+

N

NH2

N H H

reaction conditions

N

Ar`

RO

Ar

HP(O)(OR)2 Ar`

P

N N

Ph

Ph

84

85

Scheme 36 Table 3. Conditions of reactions of 1-phenyl-3-aryl/heteroaryl-1H-pyrazol-4-carboxaldehyde (84) with arylamines and dialkyl/diphenyl phosphites to give pyrazolyl-α-aminophosphonates 85 Entry No. 1

Ar

Ar´

R

Conditions

Ref.

Ph

Ph

Et

BF3.Et2O/70-80 °C

77

Et

MW(200W), 80 °C, 3 min

80

Ph

LiClO4, DCM, RT, 24-30 h

79

Me, Et

Toluene/ 110 °C

78

Ph, 4-MeC6H4, 4-ClC6H4, 2

4-ClC6H4

4-BrC6H4, 4-IC6H4, 4-FC6H4, 3-Cl-4-FC6H3, 3,4-Me2C6H3, 4-MeOC6H4, 4-EtOC6H4 Ph, 4-MeC6H4, 4-ClC6H4,

3

2-pyridyl

4-HOC6H4, 4-MeOC6H4, 4-Me2NC6H4,

4

Ph, 4-MeOC6H4

Ph, 4-MeC6H4, 2-MeC6H4, 4-MeOC6H4

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One-pot three-component reaction of bis-(4-formyl-3-phenyl-1H-pyrazol-1-yl)phosphine oxide (86), aniline and diethyl phosphite in the presence of BF3.Et2O at 80 °C under KabachnikFields reaction conditions produced an interesting type of bis(α-aminophosphonate) 87 (Scheme 37).81

OHC

O N

Ph

CHO

N

P

PhNH2 / HP(O)(OEt)2

N N

H

Ph

O

O

EtO

P

EtO

OEt

Ph

Ph

O

N H H

BF3.Et2O / 80 oC 72 %

Ph

86

OEt

P

N N

P

H

N N

H

N H

Ph

87

Scheme 37 Reaction of 6-amino-6λ5-dibenzo[d,f][1,3,2]dioxaphosphepin-6-oxide (88) with 2-formylimidazole (89) and dialkyl phosphites in dry toluene in the presence of tetramethylguanidine (TMG) as a catalyst at 60–70 °C for 4 hours afforded dimethyl/diethyl(6-oxo-6λ5-dibenzo[d,f] [1,3,2]dioxaphosphepin-6-ylamino)-(1H-2-imidazolyl)methylphosphonates (90) in good yields (Scheme 38).68

O

P O

HP(O)(OR)2

O NH2

Toluene/TMG

N

+ N H

CHO

O

OR

O P

OR

P

60-70 oC/ 4h R= Me, Et

O

O

N H H N

89.6, 91.6 % 88

89

H N

90

Scheme 38 Substituted α-(benzodioxol-5-yl)-α-aminophosphonates 91 could be prepared under various mild conditions by reaction of veratraldehyde, and dialkyl phosphites (Scheme 39).82-85 Three-component Mannich type reactions starting from aldehydes or ketones, amines and phosphites have proved to be a facile method for the preparation of various α-aminoalkylphosphonate compounds. A rapid method for the synthesis of N-phosphoramino-αaminophosphonate 92 involved reacting veratraldehyde with diethyl phosphoramidate and a cyclic trivalent chlorophosphite at 50–60 °C neat, without solvent or catalyst, for an appropriate time (Scheme 40).86

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CHO

O

+

O

HP(O)(OR)2 Ar

O

O

P

NH2 reaction conditions i-iv

RO OR

O

25 - 50 % 91

i) MgSO4 / Me3SiCl ii) Tween-20 / 30-80 oC, water iii) Neat/ solvent free iv) KH2PO4 / RT R= Et, PhCH2 Ar = Ph, PhCH2, p-ClC6H4, cyclohexyl, N N N

N

NC

Scheme 39 O

O OEt OEt

CHO

O

P H2N

+

+

Cl P

O

O O

O solvent free O catalyst free 90 % P EtO N EtO H H

P

O O

O 92

Scheme 40 Reaction between 2-formylbenzimidazole (93), 2-amino-5-methyloxazole (94), and diethyl phosphite by stirring equimolar quantities in a variety of solvents at ambient temperature gave a low yield of the desired α-aminophosphonate 95 in all the experiments. The best result was obtained when the reaction was carried out using PEG in water (Scheme 41).74

PEG / H2O

N

N CHO

N H 93

HP(O)(OR)2

+ O

NH2

HN

H

N

r. t. 74 - 84 %

94

N O

P

N H RO OR

O 95

R = Me, Et

Scheme 41

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3.3. Six-membered heterocycles with one heteroatom The action of tris(trimethylsilyl)phosphite on the aldimine formed in situ from 2-formylchromone (96) and benzylamine yielded (N-benzylamino)chromon-2-ylmethanephosphonic acid (97) (Scheme 42).87 O

O 1) PhCH2NH2 2) P(OSiMe3)3 CHO

O

O H

OH

P

3) MeOH/Chloroform

O

OH

31 %

NHCH2Ph

97

96

Scheme 42 3-Formylchromones (98) reacted easily with amines and dialkyl phosphites or trialkyl phosphites under different reaction conditions to form the α-(chromon-3-yl)-α-aminophosphonates 99 in moderate to high yields (Scheme 43).46,48 OR

O O R

1

CHO HP(O)(OR)2 or P(OR)3

+ R3NH2 2

98

R

OR

1

NHR

R = H, Me, Et, Ph

R1=

H, Cl, Me

R2

3

H

Reaction conditions i-ii 42 - 99 %

O R

P

O

O R

2

99

= H, Cl

R3 = Ph, PhCH2, PhCH2OCO, 4-MeC6H4, 2-MeOC6H4, 4-MeOC6H4, 4-ClC6H4, 2-NO2C6H4, 4-NO2C6H4 Reaction condition: i) AcOH or Yttria-Zirconia Lewis acid/ aq. CH3CN, 60 oC, ii) Catalyst free

Scheme 43 The one pot three component reactions of heterocyclic ketones 100, amine and triethyl phosphite in ethanol or toluene/acetonitrile at 60 °C afforded α-aminophosphonates 51 in low to good yields (Scheme 44).88

O

X n

i) RNH2, solvent, AcOH ii) P(OEt)3,60 oC, 1-2 days

O

OEt OEt P

RNH

X

30-92 % n

100

51

X = NMe, O, S RNH = PhCH(CH3)NH2, PhCH2NH2, PhCH(CH2OH)NH2 Solvent = EtOH, Toluene, Acetonitrile

Scheme 44

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2-, 3-, And 4-formylpyridines 101 reacted with different alkyl and aromatic amines and trialkyl phosphite or dialkyl phosphite under different reaction conditions to give the corresponding α-(pyridyl)-α-aminophosphonates 102 in good to excellent yields (Scheme 45) (Table 4).10,52,58,59,61,66-68,71,72,84,89-93

CHO

P(OR`)3 / HP(O)(OR`)2

R`O R`O P

H

+ RNH2 Reaction Conditions

N

O

NHR N

43-99 %

101

102

Scheme 45 Table 4. Reaction conditions of 2-, 3- and 4-formylpyridines 101 and amines with tri- or di-alkyl phosphite to give the corresponding pyridyl α-aminophosphonates 102 Entry No.

Aldehyde 101

Amine H N

1

H N

N

O

S

NH2 N

NH2

R´

Conditions

Ref.

Me, Et

MgClO4/ neat/ RT/ 2-6 min /or 80 °C / 0.5 – 6 h

66

Et

Reflux / 60 °C

92

Et

BF3.SiO2/[bmim][HCl]/ 5-10 min/RT/neat

93

1

R 2 R

2

3

NH2 R

n=0,1,2 R1=R2=R3=H, OMe F N

O

CHO

F

3

O NH2

4

Bu, PhCH2NH2

Et, Ph

toluene

10

5

PhNH2

Et

Nano Fe2O3 /neat/ 50 °C

91

6

PhNH2

Et

Solvent free

84

Et

MeOH/ Et3N / Me3Si

61

Et

tPcAlCl / molecular sieves

72

Me, Et

TMG/ toluene / 50-60 °C, 5- 6 h

67

CHO

7 N

8

HO O P (CH2)n HO n=1, 2

2-, 3-,4-aminopyridine CHO

9

N

O NH2

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Table 4. Continued Entry No.

Aldehyde 101

Amine

R´

Conditions

Ref.

10

(Me3Si)2NH

Et

Al(OTf)3 (10 mol%) / solvent free /80 °C

59

11

(Me3Si)2NH

Et

I2 (10 mol%) / solvent free

58

12

PhNH2

Me

TiCl4 / CH3CN/ RT

89

PhNH2

Me

AlCl3 / CH3CN/ RT

52

2-aminopyridine

Et

Solvent free

71

Me, Et

toluene/TMG/ 60 -70 °C

68

Et

toluene / 110 °C

90

13

CHO

14

N

O

15

O P

O

16

2-, 3-,4formylpyridines

NH2

BuNH2, PhNH2, Ph2CHNH2, PhCH2NH2

Reactions of various arylamines, 3-acetylpyridine and triphenyl phosphite in the presence of lithium perchlorate were carried out to give α-(pyridine-3-yl)-α-aminophosphonates 103 in high yields (Scheme 46).94 O

O

ArNH Me

P(OPh)3 / LiClO4 +

N

ArNH2

DCM, RT,20-30 h

P

OPh OPh

Me N 103

Ar= C6H5, 4-ClC6H4, 4-MeC6H4, 4-HOC6H4, NHC6H5

Scheme 46 The three-component reaction of 4-(pyridin-4-yl)benzaldehyde and triethyl phosphite with various aryl/heteroaryl substituted primary amines led to the formation of diethyl (aryl/heteroaryl aminopyridine-4-yl)phenyl)methyl phosphonates 104 (Scheme 47).95 The interesting α-quinonylmethylenyl α-aminophosphonate 107 was prepared in moderate yield through reaction of 8-formylmethylquinoline 105, 3-[5-[(1S)-1-amino-2-(biphenyl-4-yl) ethyl]-1H-tetrazol-1-yl]propanenitrile (106) and dibenzyl phosphite in the presence of MgSO4 and Me3SiCl (Scheme 48).82

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CHO Conventional

P(OEt)3

+ RNH2

EtO

100 - 110 oC, 14-20h 70 -76 %

O

H

P

N

OEt

H

R

Toluene PEG-SO3H N

40 - 50 oC, 2-6h 82 - 91 %

N 104

R= 4-pyridyl, 1-(pyridin-3-yl)methyl, 1,3-thiazol-2-yl, 1,3-benzothiazol-2-yl, 5-nitro-1,3-benzothiazol-2-yl

Scheme 47

N 1) MgSO 4 +

N

H2N

N N

NC

2) (PhCH2O)2POH / Me3SiCl

N

BnO BnO P

25 - 50 %

N 105

106

H

CHO

N

N H

N N

O

N

NC 107

Scheme 48 One-pot three-component reaction of quinoline-3-carboxaldehyde and aniline with diethyl phosphite under microwave irradiation reaction proceeded in the formation of diethyl [α-anilino(3-quinolylmethyl)]phosphonate 108 in a relatively good yield of about 80%. Unexpectedly, the corresponding monoester 109 (3%) and a very interesting phosphorus compound that proved to be bis(hydrophosphonate) phosphate monoester derivative 110 (7%) were isolated as byproducts (Scheme 49).96

P

NH2 CHO +

HP(O)(OEt)2 H

N

EtO

OEt

O

O

OR N H

+

H

P

OEt

H P

O O EtO P OH

O

NH

N H 108, R= Et (80%) 109, R= H (3%)

N 110, 7%

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A mixture of a 2-chloro-3-formylquinoline derivative 111, an amine and dialkyl phosphite and/or trialkyl phosphite was added to the solvent used under the reaction conditions shown to afford the corresponding α-(quinolin-3-yl)-α-aminophosphonates 112 in good to excellent yields (Scheme 50).42,48,85 OR

O P 1

CHO

R

+

R4NH

2

N

R

Cl

3

R

R

P(OR)3 / HP(O)(OR)2 2

OR

1

4

NHR H

2

Reaction conditions i-iii 75 - 99 %

Cl

N

R 3

R

111

112

R = Me, Et

,

R3 = H, Me, Et

R1=

H, Me, MeO, EtO

,

R2

= H, Me, MeO

, R4 = Ph, PhCH2, 3-MeC6H4, 4-MeOC6H4, 4-FC6H4

Reaction conditions : i) KH2PO4/ r.t. ii) Yttria-Zirconia Lewis acid/ aq. CH3CN, 60 oC iii) TMSCl, CH3CN, reflux

Scheme 50 3.4. Six-membered heterocycles with two or more heteroatoms Hybrid compounds of α-aminophosphonate 114 with pyrimidine nucleosides were synthesized in good to excellent yields starting from 5-formyl-2-deoxyuridine (113), aniline and dimethyl phosphite in one pot (Scheme 51).97,98 O

O

PO(OMe)2 Ar

CHO

HN

HN

N H H

O

O N neat, 60 oC

RO O

OR 113

+ ArNH2 + HP(O)(OMe)2

N

RO O

75-96 %

OR 114 R = H, Ac Ar= Ph, p-FC6H4, p-BrC6H4, p-ClC6H4, p-CH3C6H4, p-OCH3C6H4

Scheme 51 The target α-aminophosphonates 116 were synthesized via the Mannich-type reactions of aldehyde 115, aromatic amines, and dialkyl phosphites or triphenyl phosphite in the presence of Mg(ClO4)2 in moderate to good yields. It was found that Mg(ClO4)2 can reduce the reaction time and improve the yields of products greatly (Scheme 52).99

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MeO OMe

MeO

N N

N

N HP(O)(OR) or P(OPh)3 O

+

H

R` CHO 115

O

NH2 Mg(ClO4)2

N

41 - 87 %

OR

H

R = H, Me, Et, n-Bu R`= Me, Et, 4-NO2, 4-MeO, 2-Cl, 4-Cl, 3-Br, 4-Br, 4-CF3

R`

P OR

O 116

Scheme 52 The reaction of 10-ethyl-10H-phenothiazine-3-carbaldehyde 117, anilines, and diethyl phosphite in PEG-400 was complete in 24 hour at room temperature; the corresponding αaminophosphonates 118 was obtained in low yield (30%). However, the yield was dramatically increased by increasing the temperature to 100 °C. Under optimized conditions, the reaction proceeded well at 100 °C and the desired α-aminophosphonate 118 (Ar=Ph) was obtained in 91% yield. PEG-400 was found to be more effective in the synthesis of 118 (Ar=Ph) in terms of reaction time (6 h) and yields (91%) (Scheme 53).100 Ar HN S

HP(O)(OEt)2

CHO

PEG + Ar N

O

S P

OEt

H

NH2 100 oC 80 - 91 %

117

OEt N

118

Ar = Ph, PhCH2, C6H11, 4-CH3C6H4, 4-(OCH3)C6H4, 4-(CH3)2CHC6H4, 4-Br-3-CH3-C6H3, 4-OH-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-NO2-C6H4

Scheme 53 3.5. Macrocycles α-Aminophosphonic acid derivatives of benzo-15-crown-5-ether 120 can be easily obtained from the 4-formylbenzo-15-crown-5 (119), primary amines, and trimethyl phosphite or diethyl phosphite. The aminophosphonic acid 120 was obtained as a free base by using bromotrimethylsilane as a deprotecting agent of phosphonic esters (Scheme 54).101

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O

1) Ph2CHNH2 / CH2Cl2 2) (MeO)3P/ (EtO)2POH / Me3SiBr / CH2Cl2

O O O

O O O

CHO

O

119

PO3H2

O

3) MeOH 4) aq. 6M. HCl, reflux 3h

O

H NH2.HCl

73 - 86 %

120

Scheme 54

4. Miscellaneous Methods 4.1. From diethyl α-azido-α-(benzoylaminomethyl)phosphonate Also, diethyl (2-benzoylamino-2-(4,5-dicarboxymethyl-1,2,3-triazol-1-yl)-methyl) phosphonate (122) was prepared by a reaction of diethyl-(2-azido-2-benzoylaminomethyl) phosphonate (121) with dimethyl acetylenedicarboxylate in dry benzene at room temperature (Scheme 55).102 O H PhCONH

O O PhCONH

P(OEt)2 N3

O

C6H6

+ MeO

OMe

rt

MeO2C

P(OEt)2 N N N

MeO2C

121

122

Scheme 55 Similarly, some 1-(prop-2-ynyl)-5-aryltetrazoles (123) and 2-(prop-2-ynyl)-5-aryltetrazoles (124) were submitted to undergo cycloaddition reaction with the azido phosphonate 121 in dry benzene under reflux to give the interesting biheterocyclic α-aminophosphonic acid diesters 125, 126 and 127, 128, respectively (Scheme 56).103

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P(OEt)2 N3 121

reflux benzene N

Ar

N

N

N O PhCONH H5 Ar N N

N N

H

N

N

Major 7a, 8a 1,4-Isomer

N

P(OEt)2

Major (2-6)a 1,4-Isomer

H5

20-98 %

53-90 %

N

N

N

Ar

H

N

N

N

N 127

O

N

Minor 7b 1,5-Isomer

O

PhCONH

Minor (2-5)b 1,5-Isomer

P(OEt)2

N

Ar

N

H

N

N N

H4

O

PhCONH

N

P(OEt)2 N

N 124

N

125 PhCONH

Ar

N

123

P(OEt)2

Ar

N

N

N H4

N

H

N

N N

128

126

Ar= 5: alpha-thienyl

Ar= 7: alpha-furyl, 8: alpha-pyrryl

Scheme 56 4.2. Nucleophilic substitution reactions The reactions of different heterocyclic nucleophiles (benzimidazole, imidazole, pyrazole, 3,5dimethylpyrazole and 1,2,4-triazole) with diethyl α-azido-α-aminomethylphosphonate (121) were conducted at room temperature in acetone in the presence of DIPEA (diisopropylethylamine) resulting in the corresponding α-heterocyclic α-aminophosphonates 129 (Scheme 57).104 O PhCONH

P(OEt)2

O Nu-H / DIPEA 70-94%

PhCONH

P(OEt)2

H Nu

N3

129 121 Nu-H= Benzimidazole, Imidazole, Pyrazole, 3,5-Dimethylpyrazole, 1,2,4-Triazole

Scheme 57 Nucleophilic substitution of trichloromethyl moiety in ureidophosphonate 130 with morpholine gave diethyl {1-[3-(2-hydroxyphenyl)ureido]-2-morpholino-2-oxoethyl}phosphonate (131) in 82 % yield (Scheme 58).105

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O P(OEt)2 CCl3

O

O

N H

N

P(OEt)2 O HO

O HO H

N H

N H

82 %

H

N H

N H

O 131

130

Scheme 58 Similarly, the reaction of different amines Nu-H with the α-bromo-α-aminophosphonate derivative 132 resulted in the formation of α-heterocyclic α-aminophosphonates 133 (Scheme 59).106 O

O P(OEt)2

H N

Br

P(OEt)2

H N

Base / Nu-H

H Nu

80-92%

O

O

132

133 N

N

O

N

Nu =

N H

O

Scheme 59 4.3. Cycloadditions of α-alkynylaminophosphonates The cycloaddition of diethyl [(1-[(benzyloxycarbonyl)amino]-1-(trifluoromethyl)prop/but-2-yn1-yl]phosphonate (134) to organic azides proceeded only at 80 °C in the presence of a solvent mixture to afford the corresponding α-CF3-α-(triazol-4-yl)-α-aminophosphonates 135 (Scheme 60).107 N

N N

O

(5 mol%)

CuSO4

n

O

R

n

Sodium carbonate (30 mol %) RN3

+

Ph

O

P(OEt)2 N H CF 3 O 134

RN3= PhN3 , F C(CF ) 3 2 7

H2O- tBuOH

Ph

(1:1)

O

n= 0, 1 AcO N3

,

O

N3

, AcO

O N3

AcO O

P(OEt)2 N H CF 3 O 135

OAc

Scheme 60

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Also, the ethynyl-substituted aminophosphonate 134 demonstrated comparable reactivity towards different nitrile oxides under similar reaction conditions, yielding the corresponding isoxazole-containing α-trifluoromethyl α-aminophosphonates 136 in good yield (Scheme 61).108 Cbz

Ar Cbz

N H

P(O)(OEt)2 CF3

Cl

CuSO4

CF3 P(O)(OEt)2

HN

sodium ascorbate

+

O

N

KHCO3, t-BuOH-H2O

HO

55-80 %

134

N Ar 136

Ar= 4-CH3OC6H4, C6H5, 4-F-C6H4, 4-NO2-C6H4, 4-CF3-C6H4 Cbz = benzyloxycarbonyl

Scheme 61 4.4. Reduction of -hydroxyimino phosphonate Simple reduction of the 1-hydroxyiminophosphonate 137 with NaBH4 in the presence of transition metal compounds such as MoO3 or NiCl2.6H2O at ambient temperature in methanol and at normal pressure gave the corresponding diethyl aminoalkyl(aryl)phosphonates 138 in good yields (Scheme 62).109 HO

NH2

N OEt OEt P

X

O

NaBH4 / MoO3

X P

85-89 %

OEt OEt

H O

R= O, S 138

137

Scheme 62 4.5. Hydrolysis of S-adenosyl-L-homocysteine derivative Reaction of the thiolate anion of 139 with diethyl [3-bromo-1-(diphenylmethyleneamino)propyl] phosphonate (140) was performed to give the fully protected AdoHcy analogue 141 in 63% yield. Deprotection was achieved via hydrolysis with trimethylsilyl iodide (TMSI) to generate the desired α-aminophosphonic acid nucleoside 142 in 75% yield (Scheme 63).110

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ARKIVOC 2015 (vi) 246-287 NH 2

NH 2 N

N

O

N

OEt

OEt Ph Ph

P

OEt

+ Br

N H

O

N

N

N

O Ph

MeOH, KOH 63 %

KS

Ph

P

O

OEt

N

N

S

N H

141

140 139

O

O

O TMSI, H 2O

O

NH 2

75 % N

O O P + H3N

N

O

OH

N

N

S H O

O

142

Scheme 63 4.6. Curtius rearrangement of -acylazidophosphonate Curtius rearrangement of the S,S-dioxide of α-acylazidophosphonate 143 in dichloromethane afforded α-Boc-α-aminophosphonate 144 (Scheme 64).111 O

O

O

P(OMe)2

N3

S

143

P(OMe)2

BocHN 3 steps 1. mCPBA, CH2Cl2, 82 %, 2. Toluene, reflux, 3. t-BuOH, reflux, 53 %

SO2

144

Scheme 64 4.7. Addition of diethyl phosphite to chiral N-benzyl nitrones When N,N-diprotected α-aminonitrones 145 were treated with TBDMSOTf and then diethyl phosphite in THF or CH2Cl2 at -20 °C, the syn α-(hydroxyamino)phosphonates 146 were obtained in good yields after flash chromatography (Scheme 65).112

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NBoc 1) TBDMSOTf / THF or CH2Cl2, -20 oC, 10 min + -

N O

2) HP(O)(OEt)2

Bzl

P(O)(OEt)2

N

70 - 82 %

HO

145

Bzl 146

NBoc =

O

NBoc

O

NBoc

NBoc

S

NBoc

Scheme 65 4.8. From phosphonyliminium salts The optimized reaction conditions involved refluxing of the phosphonyliminium salt 147 and some nucleophilic aromatic compounds in THF gave the highest yields of novel α113 heteroaryl-α-aminophosphonates 151 (Scheme 66). O P EtO

+ N(CH3)2

Cl

N

THF, reflux, 3h. + Ar

H Ar

43-63 %

OEt

H

PO(OEt)2

150

147 Me N

Me

O

Ar = N Me

Scheme 66 4.9. From oxazolyl phosphonates Heating diethyl 5-(2-acylhydrazino)-2-[(4-methylphenyl)-1,3-oxazol-4-yl]phosphonates 151 in acetic acid led to the formation of the phosphonic acid derivatives 152 through ring opening and recyclization of the oxazole derivative and ester hydrolysis (Scheme 67).114

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P(O)(OEt)2

N H3C

H N

O

Het

N

AcOH

N H

H N

heat

H

H N

O

O

H

H3C

Het O

P(O)(OH)2

O

151

- H2O

H3C H H N

P(O)(OH)2

N

O

O

Het. = 2-furyl, 2-thienyl, 5-phenyl-3-isooxazolyl, 3-coumarinyl, 6-methylchromonyl

N

152

Het

Scheme 67 Finally, reaction of the oxazolyl phosphonates 151 (Het=6-methylchromone) with hydrazine hydrate in ethanol for 2 hours afforded diethyl [5-[5-(2-hydroxyphenyl/2-hydroxy-5methylphenyl)-1Н-pyrazol-3-yl]-1,3,4-oxadiazol-2-yl][(4-methylbenzoyl)amino]methylphosphonates 153 in good yields, which were boiled in acetic acid to afford the corresponding phosphonic acid derivatives 154 (Scheme 68).114 H3C H H P(O)(OEt)2 N

O N H3C

O

P(O)(OEt)2

R

NH2NH2.H2O

O

H N

N

N H

O

O

N

R= H, Me

O

R N

153 151

N H AcOH

HO

47 - 91 % H3C H H P(O)(OH)2 N O N

O

N R 154

N N H HO

Scheme 68

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5. Conclusions During the last few years, the α-aminophosphonic acids have attracted considerable attention in the scientific community and a great variety of methodologies have been reported for the synthesis of these compounds. The importance of having new relevant structures has allowed the development of new strategies and synthetic procedures. The authors of this review have collected the most relevant procedures reported up to the end 2013 on the synthesis of αheterocyclic/heteroaryl α-aminophosphonic acids and their esters that will be a fundamental key in the design of new bioactive agents with improved pharmacological properties. The review is built up according to the used methods and starting with the smallest rings of each method.

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Authors' Biographies

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Tarik El-Sayed Ali was born in Cairo, Egypt, in 1975. He is presently assistant professor of Organic Chemistry, Department of Chemistry, Faculty of Education, Ain Shams University, Cairo, Egypt. He graduated with B.Sc. (Physics and Chemistry) from Ain Shams University in 1997. He received his M.Sc. and Ph.D. degrees in 2001 and 2005, respectively, in Heterocyclic Chemistry from Ain Shams University. Awarded a post doctoral scientific grant for supporting young researchers (2007) from the Ministry of High Education and Scientific Research (Egypt) in organophosphorus laboratory, Institute of Polymers, Bulgarian Academy of Science, Sofia, Bulgaria. His CV was included in Who's Who in the World in 2011, 2012, 2013 and 2015. He won the award for the best research article in the field of Heterocyclic Chemistry at the Egyptian universities and research centers in 2011. He has published more than 40 scientific papers including 10 review articles, all in international journals. His research interests are in synthesis and chemical reactivity of phosphorus compounds containing bioactive heterocyclic systems.

Somaia M. Abdel-Karim was born in 1985 in Cairo, Egypt. In 2006 she graduated from Ain Shams University, Faculty of Education, Department of Chemistry. Also, she received her M.Sc. and Ph.D. degrees in 2011 and 2014, respectively, in Organophosphorus Chemistry. She has published about 10 scientific papers, all in international journals. Her research interests are in synthesis and chemical reactivity of phosphorus compounds containing bioactive heterocyclic systems.

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