Synthesis of functionalized α-amino-phosphine oxides and -phosphonates by addition of amines and aminoesters to 4-phosphinyl- and 4-phosphonyl-1,2-diaza-1,3-butadienes

Tetrahedron 61 (2005) 2815–2830

Synthesis of functionalized a-amino-phosphine oxides and

-phosphonates by addition of amines and aminoesters to

4-phosphinyl- and 4-phosphonyl-1,2-diaza-1,3-butadienes

*

Francisco Palacios, Domitila Aparicio, Yago Lopez and Jesus M. de los Santos

´

´ ´ ´

Departamento de Quımica Organica I, Facultad de Farmacia. Universidad del Paıs Vasco, Apartado 450, 01080 Vitoria, Spain

Received 27 October 2004; revised 14 January 2005; accepted 20 January 2005

Abstract—1,2-Diaza-1,3-butadienes derived from phosphine oxides and phosphonates and with optically active substituents on N-1 and C-3

are obtained by 1,4-elimination from chlorohydrazonoalkyl-phosphine oxides and -phosphonates in the presence of bases. Michael addition

(1,4-addition) of ammonia, aliphatic and aromatic amines and aminoesters to these azo-alkenes gives functionalized a-amino-phosphine

oxides and -phosphonates.

1. Introduction

organophosphorus functionalities in simple synthons could

be very interesting from a synthetic point of view because

they can be useful substrates for the preparation of

biologically active compounds.

Hydrazones constitute an important class of compounds due

to the rich chemistry of the hydrazono group and have

attracted a great deal of attention in recent years because of

their range of applications.¹They form part of the structure

of new azapeptides,²biologically active antibiotic com-

pounds,^3a,bas well as potent anticancer^3cand antimalarial

agents^3dand have been also extensively used as versatile

precursors in acyclic⁴and heterocyclic synthesis.⁵1,2-

Diaza-1,3-butadienes I (Fig. 1) are widely used intermedi-

ates in organic synthesis^6,7because they offer easy access to

a broad range of heterocycles.⁸Many of these heterodienes

containing alkyl^9a(I, R¹ZMe), aryl^9b,c(I, R¹ZAr), tosyl^9c

(I, R¹ZArSO₂), or carbonyl^6a(I, R¹ZCOR, COOR,

CONR₂) derivatives as substituents in the terminal nitrogen

(N-1) and with alkyl^9d(I, R³ZMe), halogen^9e(I, R³ZBr,

Cl), carbonyl^6a,9f(I, R³ZCOR, COOR, CONR₂) or

carbohydrate^7d(I, R³ZD-arabino-(CHOAc)₃CH₂OAc)

derivatives as well as without substituents^9cin the terminal

carbon (C-4) have been described. However, very little

information about the behaviour of 1,2-diaza-1,3-buta-

dienes II (Fig. 1) containing phosphorus substituents have

been reported.¹⁰Furthermore, it is known that phosphorus

substituents regulate important biological functions,¹¹and

that molecular modiﬁcations involving the introduction of

Figure 1.

We have previously described the synthesis of 2-aza-

dienes¹²and the application of phosphorus substituted

enamines,¹³oximes¹⁴and hydrazones¹⁵as starting materials

for the preparation of acyclic and cyclic compounds. In this

context, the usefulness of carbanions derived from hydra-

zones for carbon–carbon bond formation reaction, has been

well documented.^1,16Besides enantioselective a-alkylations

of aldehydes and ketones, the carbanion hydrazone method

can be successfully applied to the introduction of electro-

philic reagents in the Ca–carbon atom (Scheme 1) and we

have used this strategy for the functionalization of

hydrazonoalkyl-phosphine oxides and -phosphonates^15aIV

(Scheme 1). Hydrazones can be considered as protected

carbonyl compounds and can also be used as starting

materials for the preparation of 1,2-diaza-1,3-butadienes.⁶

These heterodienes react very easily with nucleophilic

reagents through a conjugate addition (1,4-addition).⁶We

Keywords: a-Amino-phosphine oxides; a-Amino-phosphonates; 4-Phos-

phinyl-1,2-diaza-1,3-butadienes; 4-Phosphonyl-1,2-diaza-1,3-butadienes;

Hydrazones; Michael addition.

* Corresponding author. Tel.: C34 945 013103; fax: C34 945 013049;

e-mail: qoppagaf@vc.ehu.es

doi:10.1016/j.tet.2005.01.081

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F. Palacios et al. / Tetrahedron 61 (2005) 2815–2830

Scheme 2.

(R¹ZCO₂(K)-Ment, R²ZYZH) and on the carbon (C-3)

atoms VIII-X (R¹ZCO₂R, R²ZMe, YZOBn) in the

Michael addition of amine derivatives to phosphorylated

1,2-diaza-1,3-butadienes IX (RZPh, OEt) is also reported.

2. Results and discussion

2.1. Preparation of 1,2-diaza-1,3-butadienes 5

The required functionalized b-hydrazones X (RZPh, OEt;

R²ZYZH) were prepared by the reaction of allenic

phosphine oxide 1a (RZPh) or phosphonate 1b (RZOEt)

with carbazates 2, in a similar way to that previously

reported for simple hydrazines.^15eAddition of ethoxycar-

bonylhydrazide 2a (R¹ZEt) to allene 1a in reﬂuxing

chloroform (TLC control) led to the formation of b-hydrazono

phosphine oxide 3aa (RZPh, R¹ZEt) (Scheme 3, Table 1,

entry 1). This compound 3aa was characterized by its

spectroscopic data, which indicated that it was isolated as

the anti-hydrazone 3aa. ³¹P NMR spectrum of 3aa showed

one absorption at d_P32.3 ppm. Likewise, the ¹H NMR

spectra of 3aa gave a well resolved doublet for the

methylene proton at d_H3.33 ppm (²J_PHZ14.8 Hz) and a

singlet at 10.63 ppm for the NH group,²²while in ¹³C NMR

a doublet appeared at d_C36.2 ppm (¹J_PCZ63.0 Hz) for the

carbon bonded to the phosphorus atom.

Scheme 1.

envisaged the use of hydrazonoalkyl-phosphine oxides and

-phosphonates (III, XZNNHR, RZYZH) and derivatives

containing a chiral substituent at 3-position (III, XZ

NNHR, RZMe, YZOBn) as starting materials for the

preparation of functionalized hydrazones containing a

nucleophilic substituent V. The sequence involve halogena-

tion with formation of an a-halogenated hydrazone VI,

subsequent formation of aza-alkene VII, and Michael

addition of nucleophiles to the heterodiene.¹⁷Therefore

with this strategy it could be possible to reverse the polarity

of Ca–carbon atom of the phosphonate (or phosphine oxide)

group favouring the introduction of nucleophiles in order to

prepare functionalized hydrazones or their synthetic equiv-

alent carbonyl compounds V (Scheme 1).

The process was extended to allenes derived from

phosphonate, and this allene 1b (RZOEt) reacted also

with hydrazide 2a and gave b-functionalized phosphonate

3ba (RZOEt, R¹ZEt) (Scheme 3, Table 1, entry 2),

This strategy could present special interest for the

introduction of amino substituents (NuHZRNH₂) in the

Ca–carbon atom of hydrazones, because we could obtain

azapeptides²or a-aminophosphonates. It is noteworthy that

a-aminophosphonates^18,19are important substrates in

organic and medicinal chemistry because they can be

considered as surrogates for a-aminoacids,^20aand have been

used as haptens for the generation of catalytic antibodies,^20b,c

as antibacterial agents,^20d,eand as nucleoside,^20for as

phosphapeptide enzyme inhibitors.^20g–kFor this reason,

here we wish to describe a novel strategy for the preparation

of functionalized a-amino-phosphine oxides VIII (RZPh)

and -phosphonates VIII (RZOEt) from hydrazones X (RZ

Ph, OEt) involving nucleophilic addition of racemic and

optically pure amines to 1,2-diaza-1,3-butadienes IX as

shown in Scheme 2. The effect of optically active

substituents²¹on the terminal nitrogen (N-1) VIII-X

Scheme 3.

F. Palacios et al. / Tetrahedron 61 (2005) 2815–2830

Table 1. Hydrazones 3 and 4 and 1,2-diaza-1,3-butadienes 5 obtained

2817

Entry

Compound

R

R¹

Yield (%)

1

2

3

4

5

6

7

8

3aa

3ba

3bb

3bc

4aa

4ba

4bb

4bc

5aa

5ba

5bb

5bc

Ph

Et

92^a

OEt

Ph

OEt

Ph

76^b

Bn

(K)-Ment

Et

Bn

(K)-Ment

Et

95^b

93^b

70^a

47^c

55^c

43^c

9

O98^b,d

O98^d

10

11

12

OEt

Bn

(K)-Ment

^aYield of isolated puriﬁed compounds.

^bConversion calculated by ³¹P NMR on the crude reaction mixture.

^cYield of isolated puriﬁed compounds 4 in a ‘one pot’ reaction from allene 1b.

^dNon-isolated compounds 5.

although in this case hydrazone 3ba was isolated as a

mixture of the syn- and anti-isomers in a ratio of 57:43 (d_P

23.5 and 24.1 ppm). Likewise, the ¹H and ¹³C NMR spectra

gave singlets for the NH at 7.67 (syn-isomer) and 9.21 ppm

(anti-isomer) and well resolved doublets for the methylene

diazabutadiene 5aa in the crude reaction mixture was

conﬁrmed by NMR spectroscopy and showed as a mixture

of the E- and Z-isomers in a ratio of 85:15 (d_P20.5 and

26.4). Likewise, the ¹H NMR spectrum showed a well

resolved doublet at d_H2.18 ppm (⁴J_PHZ1.5 Hz) for the

methyl group corresponding to the Z-isomer, while in the

case of the E-isomer this signal appeared at lower ﬁeld at d_H

proton at d_H2.79 (²J_PHZ23.2 Hz, anti) and 2.88 (²J_PH

22.1 Hz, syn) as well as for the carbon at d_C28.6 (¹J_PC

Z

4

2.29 ppm (doublet, J_PHZ2.3 Hz).^9a,9fA similar behaviour

132.4 Hz, syn) and 35.1 (¹J_PCZ135.0 Hz, anti) of 3ba. The

same strategy was used for the preparation of the hydrazone

with a benzyl carboxylate in the terminal nitrogen 3bb (RZ

OEt, R¹ZBn) by using benzyl carbazate 2b (R¹ZBn)

(Scheme 3, Table 1, entry 3).

was observed for chlorohydrazones 4ba (RZOEt, R¹ZEt)

and 4bb (RZOEt, R¹ZBn) and after addition of triethyl-

amine 4-phosphonyl-1-alcoxycarbonyl-1,2-diaza-1,3-buta-

diene 5ba and 5bb were obtained (Scheme 4, Table 1,

entries 10 and 11) as a mixture of the E- and Z-isomers in a

ratio of 90:10. 1,2-Diaza-1,3-butadienes 5 were used in situ

without isolation in subsequent Michael additions.

The preparation of 1,2-diaza-1,3-butadienes 5 involves base

treatment of hydrazone derivatives bearing a leaving group

in the Ca–carbon atom of the hydrazono carbon-nitrogen

double bond.⁶For this reason, we explored the synthesis of

Ca–chlorohydrazones derived from phosphine oxides and

phosphonates 4 and their use for the preparation of the

diaza-alkenes by treatment with bases. Functionalized

chlorohydrazone (RZPh, R¹ZEt) 4aa was prepared

from b-hydrazone 3aa by treatment with 1.1 equiv of

N-chlorosuccinimide (NCS) in reﬂuxing carbon tetra-

chloride (Scheme 3, Table 1, entry 5). This compound 4aa

was isolated as the anti-substituted hydrazone (d_P

28.0 ppm). In the case of phosphonates 4ba (RZOEt,

R¹ZEt) and 4bb (RZOEt, R¹ZBn), these hydrazones were

directly prepared from allene 1b and crude products 3ba or

3bb, obtained from allene 1b and carbazates 2a or 2b, were

treated without isolation with 1.1 equiv of NCS in CCl₄at

room temperature to give anti-chlorohydrazone derived

from phosphonate 4ba or 4bb in moderate yield (Scheme 3,

Table 1, entries 6 and 7).

Scheme 4.

2.2. Michael addition of ammonia and amines to 1,2-

diaza-1,3-butadienes 5

The presence of electron-poor groups on the terminal

nitrogen atom of the azo-ene system of 1,2-diaza-1,3-

butadienes favoured the Michael addition of nucleophilic

reagents on the terminal carbon atom (1,4-addition). On the

other hand, electron-withdrawing groups enhance the

electrophilic character of this atom.⁶Some conjugate

additions of amines to 1,2-diaza-1,3-butadienes have been

reported.^22,23However, both Michael additions of ammonia

and amines to phosphorus substituted 1,2-diazadienes, and

the effect of an optically active group²¹on the N-1 and C-3

atoms of 1,2-diazadienes towards nucleophilic additions

have not been reported. For these reasons, we explored the

addition of amine derivatives to phosphorus substituted 1,2-

diaza-1,3-butadienes 5. In addition, this strategy could be

useful for the preparation of functionalized a-aminophos-

phorus derivatives.

Heterodienes 5 were synthesized from chlorohydrazones 4

in the presence of bases (Scheme 4). The addition of an

excess (1.5 equiv) of triethylamine to a solution of

functionalized chlorohydrazone 4aa (RZPh, R¹ZEt) in

dichloromethane underwent 1,4-elimination of HCl and led

to the formation of the red coloured 4-phosphinyl-1-

ethoxycarbonyl-1,2-diaza-1,3-butadiene 5aa (RZPh, R¹Z

Et) in almost quantitative yield (Scheme 4, Table 1, entry 9).

Diaza-alkene 5aa proved to be not enough stable for

chromatography, yet not puriﬁed crude mixtures could be

satisfactorily used for the next step. The presence of the

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F. Palacios et al. / Tetrahedron 61 (2005) 2815–2830

Initially, we explored the addition of ammonia to 1,2-

diazadiene 5aa (RZPh) and generated in situ from

chlorohydrazone 4aa. When ammonia was bubbled through

a solution of chlorohydrazone 4aa in chloroform, the

reaction mixture became red, showing the formation of

1,2-diazadiene 5aa. The red colour disappeared very fast

(!10 min) and TLC control showed the end of the reaction

with the formation of only the anti-a-amino phosphine

oxide 6aa (RZPh, R¹ZEt) in good yield (Scheme 5,

Table 2, entry 1). Mass spectrometry of 6aa supported the

molecular ion peak, while in the ³¹P NMR spectrum the

phosphonate group resonated at d_P31.3 ppm. The ¹H NMR

spectrum showed an absorption at d_H4.53 ppm as a doublet

(1,4-addition) of ammonia to conjugated diaza-alkene 5aa

(Scheme 5).

The process was extended to 4-phosphonyl-1-benzyloxy-

carbonyl-1,2-diaza-1,3-butadiene 5bb (RZOEt, R¹ZBn).

However, in this case after the addition of ammonia to

hydrazone 4bb, a-amino phosphonate 6bb (RZOEt, R¹Z

Bn) was not isolated, being very unstable, although its

protection with tosyl chloride in the presence of base, made

possible the isolation of the corresponding anti-a-tosyl-

amino phosphonate 7bb (RZOEt, R¹ZBn) (Scheme 5,

Table 2, entry 2).

2

We also studied the addition of primary amines. The

addition of aryl 8a (R²Zp-MeO-C₆H₄) or propargyl 8b

(R²ZCH₂C^CH) amines to 4-phosphinyl-1,2-diaza-1,3-

butadiene 5aa, generated in situ from chlorohydrazone 4aa

and triethylamine, led to the formation of functionalized

anti-a-amino phosphine oxide 9aaa (RZPh, R¹ZEt, R²Z

p-MeO-C₆H₄) and 9aab (RZPh, R¹ZEt, R²ZCH₂C^CH)

in good yields (Scheme 6, Table 2, entries 3 and 4). The

reaction can be extended to functionalized amines such as

ethyl glycinate 10. Treatment of a-aminoester 10 with 1,2-

diaza-1,3-butadiene 5aa (RZPh) afforded functionalized

anti-a-amino phosphine oxide 11aaa (RZPh, R¹ZEt)

derived from glycine in excellent yield (Scheme 6,

Table 2, entry 7).

with coupling constant J_PHZ10.4 Hz for the methine

proton and ¹³C NMR spectrum showed an absorption at d_C

1

58.6 ppm as a doublet with coupling constant J_PC

Z

74.0 Hz for the carbon atom directly bonded to the

phosphorus atom. The formation of anti-a-amino phosphine

oxide 6aa could be explained by selective Michael addition

In a similar way, the treatment not only of aryl 8a (R²Zp-

MeO-C₆H₄) and alkyl amines 8c (R²ZBn) but also of

functionalized amines such as a-aminoester 10 to 4-

phosphonyl-diaza-1,3-butadienes 5ba and 5bb gave func-

tionalized anti-a-aminophosphonates 9 (RZOEt) and 11

(RZOEt) in excellent yields (Scheme 6, Table 2, entries 5,

6 and 8, 9). The anti-conﬁguration is supported by the

chemical shift of the hydrazone protons (d_HZ7.69–

8.10 ppm) and NOE experiments on 9baa showed that

selective saturation of the NH singlet at 7.77 ppm afforded

positive NOE (7.8%) over the adjacent methyl group. It is

noteworthy that these new functionalized a-aminophos-

phonates 11baa and 11bba derived from a-aminoesters can

be considered as ‘depsi-phosphapeptides’ and could be

interesting substrates in medicinal chemistry.^18a,b

Scheme 5.

Table 2. Michael addition of ammonia and amine derivatives to azo-alkenes 5

Entry

Compound

R

R¹

R²

Yield (%)^a

1

2

3

4

5

6

7

8

6aa

Ph

OEt

Ph

Et

Bn

Et

Bn

Et

—

68

7bb

9aaa

9aab

9baa

9bbc

11aaa

11baa

11bba

18

19

20

21

22

38^b

86

p-MeO-C₆H₄

CH₂C^CH

p-MeO-C₆H₄

Bn

—

Ph

78

92

98

89

99

93

43

82

OEt

Ph

OEt

9

Bn

10

11

12

13

14

(K)-Ment

92

83^c,d

79^e,d

^aYield of isolated puriﬁed compounds.

^bYield of isolated puriﬁed compound 7bb obtained in a two-step procedure (addition of ammonia and protection of primary amine with TsCl).

^cd.e. 10.

^dd.e. was determined by ³¹P NMR on the crude reaction mixture.

^ed.e. 15.

F. Palacios et al. / Tetrahedron 61 (2005) 2815–2830

2819

2.3. Michael addition of amine derivatives to 1,2-diaza-

1,3-butadiene 5bc

Then, we explored the inﬂuence in this process of the

presence of an optically active group ((K)-menthyl-

carboxylate substituent)²¹in the terminal nitrogen atom

(N-1) of 1,2-diazadienes. (K)-Menthyl carbazate 2c was

prepared by addition of (K)-menthyl chloroformiate in

dichloromethane to hydrazine hydrate in the presence of

carbon tetrachloride, potassium carbonate and triethyl-

benzylamonium chloride. Treatment of (K)-menthylcar-

bonylhydrazide 2c with allene derived from phosphonate 1b

in reﬂuxing chloroform (TLC control) afforded anti- and

syn-b-hydrazono phosphonate 3bc (62:38) (Scheme 3,

Table 1, entry 4). Functionalized chlorohydrazone 4bc

was directly prepared from allene 1b and crude product 3bc

was treated without isolation with 1.1 equiv of NCS in

reﬂuxing CCl₄to give anti-chlorohydrazone derived from

phosphonate 4bc in moderate yield (Scheme 3, Table 1,

entry 8). 4-Phosphonyl-1,2-diaza-1,3-butadiene 5bc (E/Z

ratio 83:17) was synthesized from chlorohydrazones 4bc by

addition of triethylamine in almost quantitative yield

(Scheme 4, Table 1, entry 12). Diaza-alkene 5bc is unstable

and crude reaction mixture without puriﬁcation was used.

Scheme 6.

Conjugateadditionsofammoniaand aminederivativesto azo-

alkene 5bc were then explored. Ammonia was bubbled

through a solution of 1,2-diazadiene 5bc in chloroform and

anti-a-amino phosphonate 17 was obtained. As before, this

a-amino phosphonate 17 could not be isolated, although its

protection with tosyl chloride gave the corresponding anti-

a-tosylamino phosphonate 18 as a diastereisomeric ratio of

1:1 (Scheme 7, Table 2, entry 10). The addition of aryl

amine 8 (R²Zp-MeO–C₆H₄) or ethyl glycinate 10 (R²Z

CH₂CO₂Et) to 1,2-diaza-1,3-butadiene 5bc gave functiona-

lized anti-a-amino phosphonates 19 and 20, respectively, in

good yields (Scheme 7, Table 2, entries 11 and 12).

Likewise, optically active amines (R)-benzylmethylamine

12a (R²ZPh, R³ZMe) or ethyl (S)-valinate 12d (R²ZⁱPr,

R³ZCO₂Et) were used and adducts 21 and 22 were

obtained with very low diastereoselectivity (Scheme 7,

Table 2, entries 13 and 14). These results suggest that the

chiral group on the nitrogen atom of the azo-alkene is too

distant from reaction centre (C-4 atom) with negligible

inﬂuence on it.

Then, we studied the diastereoselective addition of optically

active amines 12 to 1,2-diaza-1,3-butadienes 5. Very low

diastereoselectivity (!10% d.e.) was obtained when (R)-

benzylmethylamine 12a (R²ZPh, R³ZMe) was treated at

0 8C with 1-ethoxycarbonyl-4-phosphinyl-1,2-diaza-1,3-

butadiene 5aa (RZPh, R¹ZEt). Functionalized a-amino-

phosphine oxide 13aa (RZPh, R¹ZEt, R²ZPh, R³ZMe)

was obtained as a non-separable diastereoisomeric mixture

and very low diastereoselective excess (!10% d.e.) was

observed²⁴(Scheme 6, Table 3, entry 1).

A similar behaviour was observed when 1,2-diaza-1,3-

butadienes containing a phosphonate group was used and, as

before, a very low diastereoselectivity was obtained when

(R)-benzylmethylamine 12a (R²ZPh, R³ZMe), methyl

(R)-valinate 12b (R²ZCO₂Me, R³ZⁱPr) or (S)-valinate 12c

(R²ZⁱPr, R³ZCO₂Me) as well as ethyl (S)-valinate 12d

(R²ZⁱPr, R³ZCO₂Et) were treated at 0 8C with 1-

ethoxycarbonyl-4-phosphonyl-1,2-diaza-1,3-butadiene 5ba

(RZOEt, R¹ZEt) and benzyloxycarbonyl-4-phosphonyl-

1,2-diaza-1,3-butadienes 5bb (RZOEt, R¹ZBn). Adducts

13ba and 14–16 were obtained as non-separable diastereo-

isomeric mixtures and very low diastereoselective excess²⁴

(Scheme 6, Table 3, entries 2–6). At low temperatures

(K40 8C) the ratio (d.e.) (Table 3, entries 5 and 6) can

be slightly enhanced.

2.4. Michael addition of amine derivatives to 1,2-diaza-

1,3-butadiene 26

Finally, we explored the effect of the presence of an

optically active group²¹at C-3 of 1,2-diazadienes II (Fig. 1)

in the Michael addition of these substrates. The preparation

Table 3. Diastereoselective addition of optically active amines to azo-alkenes 5

Entry

Compound

R

R¹

R²

R³

T (8C)

d.e. (%)^a

Yield (%)^b

1

2

3

4

5

6

13aa

13ba

14

15

16ba

16bb

Ph

Et

Bn

Et

Ph

Me

0

K40

!10

12

20

79

88

91

96

95

91

OEt

CO₂Me

ⁱPr

CO₂Me

CO₂Et

ⁱPr

Bn

ⁱPr

18

^ad.e. was calculated by ³¹P NMR on the crude reaction mixture.

^bYield of isolated puriﬁed compounds.

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F. Palacios et al. / Tetrahedron 61 (2005) 2815–2830

Phosphonate 25 was directly prepared from carbonyl

compound 23, and crude product 24 were treated without

isolation with 1.1 equiv of NCS in carbon tetrachloride at

room temperature to give syn-chlorohydrazone 25 in

moderate yield (Scheme 8, Table 4, entry 3). Addition of

triethylamine to a solution of chlorohydrazone 25 in

dichloromethane gave the red coloured heterodiene 26

(Scheme 8, Table 4, entry 4). Diaza-alkene 26 is unstable to

chromatography and crude reaction mixture without

puriﬁcation was satisfactorily used for the next step. As

before, the presence of the diazabutadiene 26 in the crude

reaction mixture was conﬁrmed by ³¹P NMR spectroscopy

(E/Z ratio 83:17).

Michael addition of primary amines to heterodienes 26 was

explored. The addition of benzyl amine 8c (R²ZBn) or

ethyl 3-aminopropanoate 8d (R²ZCH₂CH₂CO₂Et) to 1,2-

diaza-1,3-butadiene 26 derived from lactate gave func-

tionalized syn-a-aminohydrazone 27a and 27b, respec-

tively, (Scheme 9, Table 4, entries 5 and 6) with moderate

diastereoisomeric excess. The hydrazonic protons appeared

1

in H NMR at higher shifts than 10 ppm, and is consistent

with the syn-conﬁguration, because in the case of a-amino-

hydrazones the hydrazonic protons were found between 7.5

and 8.5 ppm.²²However, a considerable increase of

diastereoselectivity was observed when aryl amines 8a

(R²Zp-MeO–C₆H₄) or 8e (R²Zp-EtO₂C–C₆H₄) was treated

with heterodiene 26 to give syn-a-aminohydrazones 27c

and 27d, respectively, with quite good d.e. (70–84%)

(Scheme 9, Table 4, entries 7 and 8). The high diastereo-

selectivity observed in the case of aryl amines could be

explained by means of a p-stacking interaction between the

phenyl group of aromatic amines and the benzyl group of

the substituent at C-3 in aza-alkene.

Scheme 7.

of phosphorus substituted 1,2-diaza-1,3-butadiene IX

(Scheme 2, R²ZMe, YZOBn) derived from lactate was

performed in several steps. Initially, we synthesized

optically pure b-ketophosphonate 23 by addition of (2S)-

ethyl lactate benzyl ester to lithium salts derived from

diethyl methylphosphonate through a modiﬁed procedure of

the Shapiro method²⁵(Scheme 8, Table 4, entry 1).

Condensation reaction of b-ketophosphonate 23 with benzyl

carbazate 2b in reﬂuxing methanol led to the formation of

unstable syn-b-hydrazone 24 (Scheme 8, Table 4, entry 2).

Finally, we studied the diastereoselective addition of

optically active amino esters 12 to 4-phosphonyl-1,2-

diaza-1,3-butadiene 26 to give syn-a-aminohydrazones

28a (R²ZⁱPr, R³ZCO₂Me) obtained also as a non-

separable diastereoisomeric mixture and moderate dia-

stereoselectivity (40% d.e.) when (S)-valine ester 12c

(R²ZⁱPr, R³ZCO₂Me) was used (Scheme 9, Table 4,

entry 9). Aryl substituents in the amino esters did not seem

to play such an important role as before in the case of

aromatic amines, because when (S)-phenylalanine ester 12e

(R²ZBn, R³ZCO₂Me) was used moderate diastereoselec-

tivity (50% d.e.) in the preparation of a-aminophosphonate

28b (R²ZBn, R³ZCO₂Me) was observed (Scheme 9,

Table 4, entry 10). The diastereoselectivity increases in the

case of methyl (R)-valinate 12c (R²ZCO₂Me, R³ZⁱPr) and

even in this case major diastereoisomer 28c (R²ZCO₂Me,

R³ZⁱPr) was isolated (Scheme 9, Table 4, entry 11).

In conclusion, the synthesis of 1-alcoxycarbonyl-1,2-diaza-

1,3-butadienes containing a phosphine oxide group 5aa or

a phosphonate group 5ba and 5bb at 4-position as well as

4-phosphonyl-1,2-diaza-1,3-butadienes containing optically

active substituents at the terminal nitrogen (N-1) 5bc and at

C-3 (derived from lactate) 26, is described. The process

implies 1,4-elimination of HCl from chlorohydrazones in

the presence of amines. Michael addition of ammonia, alkyl

and aryl amines and aminoesters on phosphorylated 1,2-

diaza-1,3-butadienes 5 and 26 is reported and functionalized

Scheme 8.

F. Palacios et al. / Tetrahedron 61 (2005) 2815–2830

Table 4. Hydrazone compounds derived from lactate 23–28

2821

Entry

Compound

R²

R³

d.e. (%)^a

Yield (%)^b

1

2

3

4

5

6

7

8

23

24

25

26

27a

27b

27c

27d

28a

28b

28c

—

79^b

O98^c,d

56^e

O98^c,d

75^b

Bn

40

30

70

84

40

50

65

CH₂CH₂CO₂Et

p-MeO-C₆H₄

p-EtO₂C-C₆H₄

ⁱPr

Bn

CO₂Me

64^b

83^b

77^b

9

10

11

CO₂Me

ⁱPr

87^b

81^b

57^b,f

^ad.e. was calculated by ³¹P NMR on the crude reaction mixture.

^bYield of isolated puriﬁed compounds.

^cNon-isolated compound.

^dConversion calculated by ³¹P NMR of the crude reaction mixture.

^eYield of isolated puriﬁed compound 25 from ketone 23.

Yield of isolated major diastereoisomer.

f

1

uncorrected. H (300 MHz), ¹³C (75 MHz) and ³¹P NMR

(120 MHz) spectra were recorded on a Varian Unity Plus

300 MHz spectrometer using tetramethylsilane (TMS)

(0.00 ppm) or chloroform (7.24 ppm) as an internal

reference in CDCl₃solutions for ¹H NMR spectra, or

chloroform (77.0 ppm) as an internal reference in CDCl₃

solutions for ¹³C NMR spectra, and phosphoric acid (85%)

for ³¹P NMR spectra. Chemical shifts (d) are given in ppm;

multiplicities are indicated by s (singlet), bs (broad singlet),

d (doublet), dd (double-doublet), t (triplet), q (quadruplet) or

m (multiplet). Coupling constants (J) are reported in Hertz.

Low-resolution mass spectra (MS) were obtained on a

Hewlett Packard 5971 MSD Series spectrometer at 50–

70 eV by electron impact (EI) or on a Hewlett Packard 1100

MSD Series spectrometer by chemical ionization (CI). Data

are reported in the form m/z (intensity relative to baseZ

100). Infrared spectra (IR) were taken on a Nicolet FTIR

Magna 550 spectrometer, and were obtained as solids in

KBr or as neat oils in NaCl. Peaks are reported in cm^K1

.

Scheme 9.

Elemental analyses were performed in a Perkin Elmer

Model 240 instrument. [a]²_D⁰were taken on a Perkin Elmer

Model 341 polarimeter using a Na/HaI lamp. Methyl

phosphonic acid diethyl ester²⁶and 2-benzyloxy propionic

acid ethyl ester²⁵were synthesized according to literature

procedures.

a-amino-phosphine oxide and -phosphonates are obtained

in very good yields. These hydrazonoalkyl-a-aminophos-

phonate derivatives may be important synthons in organic

synthesis and for the preparation of biologically active

compounds of interest to medicinal chemistry.^2,18–20

3.1.1. Synthesis of (K)-menthyl carbazate (2c). Following

the literature procedure²⁷with some modiﬁcations: to a

stirred solution of benzyltriethylammonium chloride

(0.02 g, 0.1 mmol) and K₂CO₃(2.07 g, 15 mmol) in CCl₄

(10 mL) and CH₂Cl₂(40 mL), was added hydrazine hydrate

80% (2.0 g, 50 mmol) at room temperature. After 15 min at

room temperature a solution of (K)-menthyl chloroformate

(2.14 mL, 10 mmol) in CH₂Cl₂(10 mL), was added

dropwise. Then, the mixture was stirred at room temperature

for 3 h. The crude mixture was washed with H₂O (2!

20 mL) and extracted with CH₂Cl₂(10 mL), and the solvent

was dried over MgSO₄and evaporated under vacuum. The

crude product was puriﬁed by crystallization from hexanes

to give 2c (1.88 g, 88%) as a white solid: mp 97–98 8C.

Anal. Calcd. for C₁₁H₂₂N₂O₂: C, 61.65; H, 10.35; N, 13.07.

Found C, 61.73; H, 10.32; N, 13.05.

3. Experimental

3.1. General

Solvents for extraction and chromatography were of

technical grade. All solvents used in reactions were freshly

distilled. All other reagents were recrystallized or distilled

as necessary. All reactions were performed under an

atmosphere of dry nitrogen. Analytical TLC’s were

performed with silica gel 60 F₂₅₄plates. Spot visualization

was accomplished by UV light or KMnO₄solution. Flash

chromatography was carried out using silica gel 60 (230–

400 mesh). Melting points were determined with a

Electrothermal IA9100 digital apparatus and are

2822

F. Palacios et al. / Tetrahedron 61 (2005) 2815–2830

2

1

3.2. General procedure for the preparation of

functionalized b-hydrazones derived from phosphine

oxides and phosphonates (3)

6.6 Hz, syn), 61.7 (d, J_P₁_CZ6.6 Hz, anti), 36.5 (d, J_PCZ

136.0 Hz, anti), 30.5 (d, J_PCZ135.0 Hz, syn), 25.0, 15.8;

³¹P NMR (CDCl₃) d 24.1 (anti), 23.4 (syn); IR (NaCl) 3230,

2979, 1739, 1513, 1228; MS (CI) m/z 343 (M^CC1, 67).

Anal. Calcd. for C₁₅H₂₃N₂O₅P: C, 52.63; H, 6.77; N, 8.18.

Found C, 52.80; H, 6.75; N, 8.21.

To a stirred solution of phosphorylated allene 1a or 1b

(10 mmol) in dry chloroform (50 mL), was added carbazate

2 (12 mmol) under a nitrogen atmosphere. Then, the mix-

ture was stirred and heated at reﬂux for 16–24 h. The solvent

was evaporated under vacuum, and the crude product was

precipitated with diethyl ether and recrystallized from a

mixture of hexanes/CH₂Cl₂(for b-hydrazones derived from

phosphine oxides 3aa); while b-hydrazones derived from

phosphonates 3ba, 3bb and 3bc were puriﬁed by ﬂash-

chromatography (silica gel).

3.2.4. Syn- and anti-diethyl [2-((K)-menthyloxycarbonyl

hydrazono)propyl] phosphonate (3bc). 93% conversion

calculated by ³¹P NMR on the crude reaction mixture.

Obtained as an oil from allene 1b (1.76 g, 10 mmol) and

(K)-menthyl carbazate 2c (2.57 g, 12 mmol) as described in

the general procedure. The crude product was puriﬁed by

ﬂash-chromatography (silica gel, AcOEt/hexanes 70:30,

R_fZ0.24 and 0.38 AcOEt/hexanes 50:50): ¹H NMR

(CDCl₃) d 9.06 (s, 1H, syn), 7.63 (s, 1H, anti), 4.76–4.67

(m, 1H, syn and anti), 4.22–4.11 (m, 4H, syn and anti), 2.95

(d, J_PHZ21.8 Hz, 2H, anti), 2.85 (d, J_PHZ23.2 Hz, 2H,

syn), 2.14–0.78 (m, 27H, syn and anti); ¹³C NMR (CDCl₃) d

154.2 (syn), 153.4 (anti), 145.2 (syn), 144.7 (anti), 75.3

(anti), 74.6 (syn), 62.5–62.0 (m), 47.1 (anti), 46.7 (syn), 40.9

(anti), 40.7 (syn), 36.3 (d, ¹J_PCZ136.0 Hz, anti), 34.0 (anti),

33.8 (syn), 31.1 (anti), 30.9 (syn), 30.5 (d, ¹J_PCZ135.0 Hz,

syn), 25.9 (anti), 25.6 (syn), 23.2 (anti), 23.0 (syn), 21.7

(anti), 21.6 (syn), 20.5 (anti), 20.3 (syn), 16.1 (syn), 16.0

(anti), 15.8 (syn), 15.9 (anti), 15.8 (syn), 15.7 (anti); ³¹P

NMR (CDCl₃) d 24.2 (anti), 23.4 (syn); IR (NaCl) 3230,

2952, 1725, 1699, 1540, 1235; MS (CI) m/z 391 (M^CC1,

100). Anal. Calcd. for C₁₈H₃₅N₂O₅P: C, 55.37; H, 9.04; N,

7.17. Found C, 55.56; H, 9.01; N, 7.17. [a]²_D²K36.0 (c 0.78,

CH₂Cl₂).

3.2.1. Anti-ethyl N-[2-(diphenylphosphinoyl)-1-methyl-

ethylidene] hydrazinecarboxylate (3aa). (3.16 g, 92%)

obtained as a white solid from allene 1a (2.40 g, 10 mmol)

and ethyl carbazate (1.25 g, 12 mmol) as described in the

2

1

general procedure: mp 168–169 8C; H NMR (CDCl₃) d

3

10.63 (s, 1H), 7.74–7.21 (m, 10H), 4.20 (q, J_HHZ7.0 Hz,

2

2H), 3.33 (d, J_PHZ14.8 Hz, 2H), 1.58 (s, 3H), 1.25

3

(t, J_HHZ7.0 Hz, 3H); ¹³C NMR (CDCl₃) d 155.8, 146.8,

132.8–128.6 (m), 61.5, 36.2 (d, ¹J_PCZ63.0 Hz), 26.0, 14.6;

³¹P NMR (CDCl₃) d 32.3; IR (KBr) 3186, 2989, 2957, 1741,

1521, 1244, 1164, 1043; MS (EI) m/z 344 (M^C, 8). Anal.

Calcd. for C₁₈H₂₁N₂O₃P: C, 62.78; H, 6.15; N, 8.14. Found

C, 62.58; H, 6.17; N, 8.17.

3.2.2. Syn- and anti-diethyl [2-(ethoxycarbonyl hydrazono)

propyl] phosphonate (3ba). 76% conversion calculated

by ³¹P NMR on the crude reaction mixture. Obtained

as an oil from allene 1b (1.76 g, 10 mmol) and ethyl

carbazate 2a (1.25 g, 12 mmol) as described in the general

procedure. The crude product was puriﬁed by ﬂash-

3.3. General procedure for the synthesis of

functionalized chlorohydrazones derived from

phosphine oxides and phosphonates (4)

1

chromatography (silica gel, AcOEt, R_fZ0.23, AcOEt): H

NMR (CDCl₃) d 9.21 (s, 1H, anti), 7.67 (s, 1H, syn), 4.13

Method A. To a stirred solution of phosphorylated b-

hydrazones 3 (10 mmol) in dry carbon tetrachloride

(150 mL), was added dropwise NCS (1.50 g, 11 mmol)

under a nitrogen atmosphere. Then, the mixture was stirred

at room temperature for 16 h. The crude mixture was diluted

with CH₂Cl₂(20 mL), washed with H₂O (2!20 mL) and

the solvent was dried over MgSO₄and evaporated under

vacuum. The crude product was puriﬁed by precipitation

with diethyl ether. Method B. To a stirred solution of

phosphorylated allene 1 (10 mmol) in dry chloroform

(50 mL), was added carbazate 2 (12 mmol) under a nitrogen

atmosphere. Then, the mixture was stirred and heated at

reﬂux for 16–24 h. The solvent was evaporated under

vacuum, and crude products 3 were diluted in dry carbon

tetrachloride (150 mL). NCS (1.50 g, 11 mmol) was added

dropwise under a nitrogen atmosphere and the mixture was

stirred at room temperature for 16 h. The crude mixture was

diluted with CH₂Cl₂(20 mL), washed with H₂O (2!

20 mL) and the solvent was dried over MgSO₄and

evaporated under vacuum. The crude product was puriﬁed

by ﬂash-chromatography (silica gel).

(m, 6H syn and anti), 2.88 (d, ²J_PHZ22.1 Hz, 2H, syn), 2.79

2

4

(d, J_PHZ23.2 Hz, 2H, anti), 2.06 (d, J_PHZ2.9 Hz, 3H,

syn), 1.92 (d, ⁴J_PHZ2.9 Hz, 3H, anti), 1.26 (m, 9H, syn and

anti); ¹³C NMR (CDCl₃) d 157.2 (syn), 153.0 (anti), 144.5

(syn), 143.7 (anti), 61.1–59.4 (m), 35.1 (d, ¹J_PCZ135.0 Hz,

1

anti), 28.6 (d, J_PCZ132.4 Hz, syn), 14.5, 15.1 (syn), 12.8

(anti); ³¹P NMR (CDCl₃) d 24.1 (anti), 23.5 (syn); IR

(NaCl) 3264, 2986, 1726, 1527, 1249; MS (CI) m/z 281

(M^CC1, 100). Anal. Calcd. for C₁₀H₂₁N₂O₅P: C, 42.86; H,

7.55; N, 10.00. Found C, 42.77; H, 7.56; N, 9.96.

3.2.3. Syn- and anti-diethyl [2-(benzyloxycarbonyl

hydrazono)propyl] phosphonate (3bb). 95% conversion

calculated by ³¹P NMR on the crude reaction mixture.

Obtained as an oil from allene 1b (1.76 g, 10 mmol) and

benzyl carbazate (1.99 g, 12 mmol) as described in the

general procedure. The crude product was puriﬁed by ﬂash-

chromatography (silica gel, AcOEt/hexanes 70:30, R_fZ

0.14, AcOEt/hexanes 50:50): ¹H NMR (CDCl₃) d 9.36 and

8.06 (s, 1H, syn and anti), 7.41–7.31(m, 5H, anti and syn),

5.22 (s, 2H, syn and anti), 4.18–4.05 (m, 4H, anti and syn),

2

2.92 (d, 2H, J_PHZ22.1 Hz, anti), 2.83 (d, 2H, J_PH

Z

3.3.1. Ethyl N-[2-chloro-2-(diphenylphosphinoyl)-1-

methylethylidene] hydrazinecarboxylate (4aa). (2.65 g,

70%) obtained as a white solid from hydrazone 3aa (3.44 g,

10 mmol) as described in the general procedure (method A).

The crude product was recrystallized from CH₂Cl₂/hexanes:

23.2 Hz, syn), 2.12 (d, 3H, ⁴J_PHZ2.9 Hz, syn), 1.95 (d, 3H,

⁴J_PHZ3.1 Hz, anti), 1.30 (t, 6H, J_HHZ7.0 Hz, anti and

3

syn); ¹³C NMR (CDCl₃) d 154.4 (syn), 153.7 (anti), 145.9

2

(syn), 145.7 (anti), 135.8–127.6 (m), 66.7, 62.5 (d, J_PC

Z

F. Palacios et al. / Tetrahedron 61 (2005) 2815–2830

2823

1

mp 161–162 8C; H NMR (CDCl₃) d 7.74–7.39 (m, 11H),

(20 mL), washed with H₂O (2!20 mL) and the aqueous

phase was extracted twice with CH₂Cl₂(10 mL). The

solvent was dried over MgSO₄and evaporated under

vacuum. Diaza-alkenes 5 proved to be unstable to

chromatography and were then used in the next steps

without further puriﬁcation.

5.30 (s, 1H), 4.20 (q, ³J_HHZ7.1 Hz, 2H), 1.96 (s, 3H), 1.22

3

(t, J_HHZ7.1 Hz, 3H); ¹³C NMR (CDCl₃) d 153.8, 145.7,

134.0–128.0 (m), 62.1, 59.5 (d, ¹J_PCZ68.5 Hz), 14.4, 12.6;

³¹P NMR (CDCl₃) d 28.0; IR (KBr) 3238, 2933, 1700, 1441,

1262, 1189; MS (CI) m/z 379 (M^CC1, 100). Anal. Calcd.

for C₁₈H₂₀ClN₂O₃P: C, 57.07; H, 5.32; N, 7.40. Found C,

56.84; H, 5.34; N, 7.36.

3.4.1. 4-(Diphenylphosphinoyl)-1-ethoxycarbonyl-3-

methyl-1,2-diaza-1,3-butadiene (5aa). O98% conversion

calculated by ³¹P NMR on the crude reaction mixture, from

chlorohydrazone 4aa (1.90 g, 5 mmol) as described in the

general procedure: (R_fZ0.81, AcOEt). ¹H NMR (CDCl₃) d

7.89–7.40 (m, 11H), 4.48 (q, ³J_HHZ7.2 Hz, 2H, E), 4.21 (q,

3.3.2. Diethyl [1-chloro-2-(ethoxycarbonyl hydrazono)-

propyl] phosphonate (4ba). (1.48 g, 47%) obtained as an

oil in a ‘one pot’ reaction from allene 1b (1.76 g, 10 mmol)

as described in the general procedure (method B). The crude

product was puriﬁed by ﬂash-chromatography (silica gel,

AcOEt, R_fZ0.43, AcOEt): ¹H NMR (CDCl₃) d 8.07 (s, 1H),

4

³J_HH₄Z7.2 Hz, 2H, Z), 2.29 (d, J_PHZ2.3 Hz, 3H, E), 2.18

3

(d, J_PHZ1.5 Hz, 3H, Z), 1.43 (t, J_HHZ7.2 Hz, 3H, E),

4.78 (d, J_PHZ13.6 Hz, 1H), 4.32–4.09 (m, 6H), 2.00 (d,

1.26 (t, J_HHZ7.2 Hz, 3H, Z); ¹³C NMR (CDCl₃) d (E-

2

3

2

1

⁴J_PHZ2.1 Hz, 3H), 1.39–1.23 (m, 9H); ¹³C NMR (CDCl₃) d

154.5, 145.0, 65.2–61.3 (m), 55.5 (d, ¹J_PCZ158.6 Hz), 15.8,

13.9, 11.9; ³¹P NMR (CDCl₃) d 15.5; IR (NaCl) 3230, 2979,

1725, 1533, 1208; MS (CI) m/z 315 (M^CC1, 100). Anal.

Calcd. for C₁₀H₂₀ClN₂O₅P: C, 38.17; H, 6.41; N, 8.90.

Found C, 38.05; H, 6.44; N, 8.89.

isomer) 165.1 (d, J_PCZ7.1 Hz), 161.8, 135.2 (d, J_PCZ

3

97.2 Hz), 134.7–127.8 (m), 64.1, 13.5 (d, J_PCZ9.1 Hz),

11.3; ³¹P NMR (CDCl₃) d 26.4 (Z), 20.5 (E); IR (NaCl)

2979, 1732, 1533, 1440, 1228.

3.4.2. 4-(Diethoxyphosphoryl)-1-ethoxycarbonyl-3-

methyl-1,2-diaza-1,3-butadiene (5ba). O98% conversion

calculated by ³¹P NMR on the crude reaction mixture, from

chlorohydrazone 4ba (1.57 g, 5 mmol) as described in the

general procedure: (R_fZ0.63, AcOEt). ¹H NMR (CDCl₃) d

6.84 (d, ²J_PHZ13.0 Hz, 1H, E), 6.70 (d, ²J_PHZ13.0 Hz, 1H,

3.3.3. Diethyl [1-chloro-2-(benzyloxycarbonyl hydrazono)

propyl] phosphonate (4bb). (2.07 g, 55%) obtained as an

oil in a ‘one pot’ reaction from allene 1b (1.76 g, 10 mmol)

as described in the general procedure (method B). The crude

product was puriﬁed by ﬂash-chromatography (silica gel,

AcOEt/hexanes 30:70, R_fZ0.45, AcOEt/hexanes 50:50):

¹H NMR (CDCl₃) d 8.06 (s, 1H). 7.39–7.28 (m, 5H), 5.23 (s,

Z), 4.52–4.10 (m, 6H), 2.04–2.00 (m, 3H), 1.47–1.24 (m,

2

9H); ¹³C NMR (CDCl₃) d (E-isomer) 164.7 (d, J_PC

Z

15.1 Hz), 161.9, 129.8 (d, ¹J_PCZ187.9 Hz), 64.3–61.9 (m),

16.0–11.4 (m); ³¹P NMR (CDCl₃) d 14.2 (E), 13.0 (Z); IR

(NaCl) 3482, 2979, 1752, 1255.

2

2H), 4.77 (d, J_PHZ13.4 Hz, 1H), 4.29–4.09 (m, 4H), 2.00

(s, 3H), 1.36–1.27 (m, 6H); ¹³C NMR (CDCl₃) d 153.5,

145.7, 135.5–128.4 (m), 128.3, 67.6, 64.2 (d, ²J_PCZ6.5 Hz),

2

1

63.7 (d, J_PCZ7.1 Hz), 55.7 (d, J_PCZ158.1 Hz), 16.2,

12.0; ³¹P NMR (CDCl₃) d 15.4; IR (NaCl) 3204, 2992,

1699, 1540, 1261; MS (CI) m/z 377 (M^CC1, 45). Anal.

Calcd. for C₁₅H₂₂ClN₂O₅P: C, 47.82; H, 5.89; N, 7.44.

Found C, 47.98; H, 5.86; N, 7.47.

3.4.3. 4-(Diethoxyphosphoryl)-1-benzyloxycarbonyl-3-

methyl-1,2-diaza-1,3-butadiene (5bb). O98% conversion

calculated by ³¹P NMR on the crude reaction mixture, from

chlorohydrazone 4bb (1.88 g, 5 mmol) as described in the

general procedure: (R_fZ0.78, AcOEt). ¹H NMR (CDCl₃) d

7.46–7.37 (m, 5H), 6.84 (d, ²J_PHZ13.0 Hz, 1H, E), 6.69 (d,

²J_PHZ13.0 Hz, 1H, Z), 5.42 (s, 2H, E), 5.40 (s, 2H, Z), 4.22–

3.3.4. Diethyl [1-chloro-2-((K)-menthyloxycarbonyl

hydrazono)propyl] phosphonate (4bc). (1.83 g, 43%)

obtained as a white solid in a ‘one pot’ reaction from allene

1b (1.76 g, 10 mmol) as described in the general procedure

(method B). The crude product was puriﬁed by ﬂash-

chromatography (silica gel, AcOEt/hexanes 30:70): mp 70–

71 8C; ¹H NMR (CDCl₃) d 7.76 (s, 1H), 4.82–4.70 (m, 2H),

4

4.06 (m, 4H), 2.21 (d, J_PHZ2.90 Hz, 3H, E), 1.98 (s, 3H,

Z), 1.38–1.21 (m, 6H); ¹³C NMR (CDCl₃) d (E-isomer)

2

1

164.4 (d, J_PCZ15.2 Hz) 161.5, 130.2 (d, J_PCZ187.9 Hz)

2

133.6–127.6 (m), 69.3, 61.6 (d, J_PCZ5.5 Hz), 15.7 (d,

³J_PCZ6.0 Hz), 11.1; ³¹P NMR (CDCl₃) d 14.2 (E), 12.8 (Z);

IR (NaCl) 3456, 2979, 1765, 1235.

4

4.32–4.15 (m, 4H), 2.03 (d, J_PHZ2.0 Hz, 3H), 1.94–0.79

(m, 24H); ¹³C NMR (CDCl₃) d 153.0, 144.8, 76.2, 64.4 (d,

3.4.4. 4-(Diethoxyphosphoryl)-1-(K)-menthyloxycarbonyl-

3-methyl-1,2-diaza-1,3-butadiene (5bc). O98% conver-

sion calculated by ³¹P NMR on the crude reaction mixture,

from chlorohydrazone 4bc (2.12 g, 5 mmol) as described in

the general procedure: (R_fZ0.78, AcOEt). ¹H NMR

2

1

²J_PCZ6.6 Hz), 63.8 (d, J_PCZ7.1 Hz), 55.8 (d, J_PC

Z

158.1 Hz), 47.3, 41.1, 34.2, 31.4, 26.2, 23.4, 22.0, 20.7,

16.4, 16.3, 11.8; ³¹P NMR (CDCl₃) d 15.5; IR (KBr) 3217,

2965, 1706, 1533, 1261; MS (CI) m/z 425 (M^CC1, 38).

Anal. Calcd. for C₁₈H₃₄ClN₂O₅P: C, 50.88; H, 8.07; N,

6.59. Found C, 51.04; H, 8.09; N, 6.56. [a(²_D²K32.0 (c 1.00,

CH₂Cl₂).

2

(CDCl₃) d 6.75 (d, J_PHZ13.0 Hz, 1H, E), 6.60 (d, J_PH

Z

13.0 Hz, 1H, Z), 4.87–4.78 (m, 1H), 4.15–4.08 (m, 4H),

2.16–0.74 (m, 27H); ¹³C NMR (CDCl₃) d (E-isomer) 164.7

(d, ²J_PCZ15.5 Hz), 161.7, 129.2 (d, ²J_PHZ187.9 Hz), 78.7,

2

61.7 (d, J_PCZ5.5 Hz), 46.0, 40.1, 33.5, 31.0, 25.7, 22.9,

3.4. Preparation of 1,2-diaza-1,3-butadienes (5)

21.4, 20.1, 15.8, 15.7–11.3 (m); ³¹P NMR (CDCl₃) d 14.5

(E), 13.1 (Z); IR (NaCl) 3482, 2959, 1752, 1248.

To a room temperature solution of chlorohydrazone 4

(5 mmol) in dry CH₂Cl₂(25 mL), was added dropwise

triethylamine (0.85 mL, 6 mmol) under a nitrogen atmos-

phere. The mixture was stirred at this temperature for

45 min. The crude mixture was diluted with CH₂Cl₂

3.4.5. Synthesis of ethyl N-[2-amino-2-(diphenylphos-

phinoyl)-1-methylethylidene] hydrazinecarboxylate

(6aa). To a stirred solution of chlorohydrazone 4aa

2824

F. Palacios et al. / Tetrahedron 61 (2005) 2815–2830

(0.38 g, 1 mmol) in chloroform (10 mL), ammonia was

bubbled for 10 min at room temperature. Then, the solvent

was evaporated under vacuum and the crude product was

puriﬁed by ﬂash-chromatography (silica gel, CH₂Cl₂/

MeOH 95:5) affording compound 6aa (0.24 g, 68%) as a

white solid: 174–176 8C; ¹H NMR (CDCl₃) d 7.96–7.46 (m,

11H), 4.53 (d, ²J_PHZ10.4 Hz, 1H), 4.24–4.17 (m, 2H), 2.19

(bs, 2H), 1.92 (s, 3H), 1.28–1.24 (m, 3H); ¹³C NMR

(CDCl₃) d 150.0, 144.5, 132.8–128.0 (m), 61.2, 58.6 (d,

¹J_PCZ74.0 Hz), 14.4, 14.0; ³¹P NMR (CDCl₃) d 31.3; IR

(KBr) 3350, 2972, 1712, 1427, 1235; MS (CI) m/z 360

(M^CC1, 7). Anal. Calcd. for C₁₈H₂₂N₃O₃P: C, 60.16; H,

6.17; N, 11.69. Found C, 60.48; H, 6.20; N, 11.69.

under vacuum. Diaza-alkenes 5 were diluted with CH₂Cl₂

(10 mL) and a solution of primary amine (1.2 mmol) in

CH₂Cl₂(5 mL) was then added at the same temperature.

The reaction mixture was stirred at room temperature for

20–120 min. The solvent was evaporated under vacuum and

the crude product was puriﬁed by ﬂash-chromatography

(silica gel).

3.5.1. Ethyl N-[2-(diphenylphosphinoyl)-2-(4-methoxy-

phenylamino)-1-methylethylidene] hydrazinecarboxy-

late (9aaa). (0.40 g, 86%) obtained as a white solid from

4aa (0.38 g, 1 mmol) and 4-methoxyaniline (0.15 g,

1.2 mmol) as described in the general procedure (method

A). The crude product was crystallized from ethyl ether: mp

183–184 8C; ¹H NMR (CDCl₃) d 7.73–6.55 (m, 15H), 4.94

(dd, ³J_HHZ9.2, ²J_PHZ12.2 Hz, 1H), 4.76 (m, 1H), 4.06 (q,

³J_HHZ7.0 Hz, 2H), 3.56 (s, 3H), 1.56 (s, 3H), 1.11 (t,

³J_HHZ7.0 Hz, 3H); ¹³C NMR (CDCl₃) d 152.8, 149.1,

140.2–114.8 (m), 61.6, 60.8 (d, ¹J_PCZ74.0 Hz), 55.6, 14.4,

12.4; ³¹P NMR (CDCl₃) d 31.5; IR (NaCl) 3357, 3291,

1746, 1501, 1441, 1235; MS (CI) m/z 466 (M^CC1, 100).

Anal. Calcd. for C₂₅H₂₈N₃O₄P: C, 64.51; H, 6.06; N, 9.03.

Found C, 64.29; H, 6.08; N, 9.00.

3.4.6. Synthesis of diethyl [2-(benzyloxycarbonyl hydra-

zono)-1-(toluene-4-sulfonylamino)propyl] phosphonate

(7bb). To a stirred solution of chlorohydrazone 4bb

(0.38 g, 1 mmol) in chloroform (10 mL), ammonia was

bubbled for 10 min at room temperature. Then, the solvent

was evaporated under vacuum and the crude product was

diluted in CH₂Cl₂(5 mL). TsCl (0.23 g, 1.2 mmol) and

Et₃N (0.21 mL, 1.5 mmol) were then added at room

temperature. The mixture was stirred at this temperature

for 6 h. The crude mixture was diluted with CH₂Cl₂

(10 mL), washed with H₂O (2!5 mL) and the aqueous

phase was extracted twice with CH₂Cl₂(5 mL). The solvent

was dried over MgSO₄and evaporated under vacuum. The

crude product was puriﬁed by ﬂash-chromatography (silica

gel, AcOEt/hexanes 70:30) to obtain (0.19 g, 38%) of 7bb

as a white solid. mp 145–146 8C; ¹H NMR (CDCl₃) d 7.82–

7.27 (m, 10H), 6.28 (bs, 1H), 5.22 (s, 2H), 4.34–4.11 (m,

5H), 2.30 (s, 3H), 1.62 (d, ⁴J_PHZ2.6 Hz, 3H), 1.31–1.26 (m,

6H); ¹³C NMR (CDCl₃) d 153.6, 144.9, 143.6–126.4 (m),

3.5.2. Ethyl N-[2-(diphenylphosphinoyl)-2-propargyl-

amino-1-methylethylidene] hydrazinecarboxylate (9aab).

(0.31 g, 78%) obtained as a white solid from 4aa (0.38 g,

1 mmol) and propargilamine (0.066 g, 1.2 mmol) as

described in the general procedure (method A). The crude

product was crystallized from ethyl ether: mp 134–136 8C;

Z

3

¹H NMR (CDCl₃) d 8.00–7.40 (m, 11H), 4.35 (d, J_PH

13.9 Hz, 1H), 4.23–4.16 (m, 2H), 3.35 (s, 2H), 2.45 (bs, 1H),

2.17 (s, 1H), 1.92 (s, 3H), 1.28–1.22 (m, 3H); ¹³C NMR

(CDCl₃) d 153.5, 148.7, 132.0–128.2 (m), 81.1, 72.1, 63.8

2

67.6, 64.5 (d, J_PCZ7.1 Hz), 63.7 (d, J_PCZ7.1 Hz), 56.4

(d, J_PCZ155.1 Hz), 21.4, 16.2, 14.2; ³¹P NMR (CDCl₃) d

(d, J_PCZ79.6 Hz,), 61.6, 37.1 (d, J_PCZ14.6 Hz), 14.6,

14.5; ³¹P NMR (CDCl₃) d 29.5; IR (NaCl) 3330, 3197,

2979, 1739, 1527, 1447, 1241; MS (CI) m/z 398 (M^CC1,

5). Anal. Calcd. for C₂₁H₂₄N₃O₃P: C, 63.47; H, 6.09; N,

10.57. Found C, 63.62; H, 6.10; N, 10.53.

1

3

16.7; IR (NaCl) 3350, 3297, 3138, 1745, 1454, 1195; MS

(CI) m/z 512 (M^CC1, 100). Anal. Calcd. for

C₂₂H₃₀N₃O₇PS: C, 51.66; H, 5.91; N, 8.21. Found C,

51.70; H, 5.89; N, 8.25.

3.5.3. Diethyl [2-(ethoxycarbonyl hydrazono)-1-(-4-

methoxyphenylamino)propyl] phosphonate (9baa).

(0.37 g, 92%) obtained as an oil from 4ba (0.32 g,

1 mmol) and 4-methoxyphenilaniline (0.15 g, 1.2 mmol)

as described in the general procedure (method A). The crude

product was puriﬁed by ﬂash-chromatography (silica gel,

AcOEt, R_fZ0.44, AcOEt): ¹H NMR (CDCl₃) d 7.77 (s, 1H),

6.77–6.67 (m, 4H), 4.55–4.49 (m, 2H), 4.31–4.13 (m, 6H),

3.73 (s, 3H), 1.86 (d, ⁴J_PHZ2.7 Hz, 3H), 1.34–1.28 (m, 9H);

¹³C NMR (CDCl₃) d 152.6 148.2, 140.3–114.4 (m), 63.4 (d,

3.5. General procedure for the addition of primary

amines to azo-alkenes (5)

Method A. To a stirred solution of chlorohydrazone 4

(1 mmol) in CH₂Cl₂(5 mL) was added Et₃N (0.21 mL,

1.5 mmol) at room temperature and under a nitrogen

atmosphere. The mixture was stirred at room temperature

for 15–45 min and a solution of primary amine (1.2 mmol)

in CH₂Cl₂(5 mL) was then added at the same temperature.

The reaction mixture was stirred at room temperature for

20–120 min. The crude mixture was diluted with CH₂Cl₂

(10 mL), washed with H₂O (2!5 mL) and the aqueous

phase was extracted twice with CH₂Cl₂(5 mL). The organic

layer was dried over MgSO₄and evaporated under vacuum

and the crude product was puriﬁed by ﬂash-chromatography

(silica gel). Method B: to a stirred solution of chloro-

hydrazone 4 (1 mmol) in CH₂Cl₂(5 mL) was added Et₃N

(0.21 mL, 1.5 mmol) at room temperature and under a

nitrogen atmosphere. The mixture was stirred at room

temperature for 30–45 min. The crude mixture was diluted

with CH₂Cl₂(10 mL), washed with H₂O (2!5 mL) and the

aqueous phase was extracted twice with CH₂Cl₂(5 mL).

The organic layer was dried over MgSO₄and evaporated

²J_PCZ7.1 Hz), 62.9 (d, ²J_PCZ7.1 Hz), 61.4, 58.9 (d, ¹J_PC

Z

151.6 Hz), 55.3, 16.0, 14.2, 12.5; ³¹P NMR (CDCl₃) d 20.8;

IR (NaCl) 3323, 2998, 1739, 1513, 1235, 1049; MS (CI) m/z

402 (M^CC1, 100). Anal. Calcd. for C₁₇H₂₈N₃O₆P: C,

50.87; H, 7.03; N, 10.47. Found C, 51.03; H, 7.00; N, 10.43.

3.5.4. Diethyl[2-(benzyloxycarbonyl hydrazono)-1-benzyl-

aminopropyl] phosphonate (9bbc). (0.44 g, 98%) obtained

as an oil in a reaction from 4bb (0.38 g, 1 mmol) and

benzylamine (0.13 g, 1.2 mmol) as described in the general

procedure (method A). The crude product was puriﬁed by

ﬂash-chromatography (silica gel, AcOEt/hexanes 30:70,

R_fZ0.32, AcOEt/hexanes 50:50): ¹H NMR (CDCl₃) d 7.85

F. Palacios et al. / Tetrahedron 61 (2005) 2815–2830

2825

(s, 1H), 7.42–7.22(m, 10H), 5.25 (s, 2H), 4.21–4.08 (m, 4H),

C₁₉H₃₀N₃O₇P: C, 51.46; H, 6.82; N, 9.48. Found C,

51.59; H, 6.80; N, 9.47.

2

3.85 (d, J_PHZ21.7 Hz, 1H), 3.78–3.67 (m, 2H), 2.27 (bs,

4

1H), 1.85 (d, J_PHZ2.6 Hz, 3H), 1.32–1.26 (m, 6H); ¹³C

NMR (CDCl₃) d 153.7, 148.2, 138.8–126.6 (m), 66.6, 62.7

3.5.8. Ethyl N-[2-(diphenylphosphinoyl)-1-methyl-2-(1-

(R)-phenylethylamino)ethylidene] hydrazinecarboxylate

(13aa). (0.37 g, 79%) obtained as an oil from hydrazone 4aa

(0.38 g, 1 mmol) and (R)-methylbenzylamine (0.16 mL,

1.2 mmol) as described in the general procedure (method A)

and addition of primary amine at 0 8C. The crude product

was puriﬁed by ﬂash-chromatography (silica gel, AcOEt,

R_fZ0.60, AcOEt): ¹H NMR (CDCl₃) d 7.95–7.03 (m, 16H),

4.40–4.09 (m, 3H), 3.69–3.51 (m, 1H), 2.48 (bs, 1H), 2.45

2

1

(d, J_PCZ6.6 Hz), 62.2 (d, J_PCZ7.5 Hz), 61.5 (d, J_PC

Z

152.6 Hz), 51.7 (d, J_PCZ17.8 Hz), 15.8, 13.1; ³¹P NMR

(CDCl₃) d 22.2; IR (NaCl) 3211, 2965, 1752, 1527, 1208;

MS (CI) m/z 448 (M^CC1, 100). Anal. Calcd. for

C₂₂H₃₀N₃O₅P: C, 59.05; H, 6.76; N, 9.39. Found C,

58.88; H, 6.73; N, 9.42.

3

3.5.5. Ethyl [1-(diphenylphosphinoyl)-2-(ethoxycarbonyl

hydrazono)propylamino] acetate (11aaa). (0.40 g, 89%)

obtained as a white solid from cholorohydrazone 4aa

(0.38 g, 1 mmol), glycine ethyl ester hydrochloride (0.17 g,

1.2 mmol) and Et₃N (0.42 mL, 3 mmol) as described in the

general procedure (method A). The crude product was

puriﬁed by ﬂash-chromatography (silica gel, AcOEt): mp

147–149 8C; ¹H NMR (CDCl₃) d 7.93–7.30 (m, 11H), 4.43

(bs, 1H), 1.87 (d, ⁴J_PHZ2.1 Hz, 3H, mayor), 1.56 (d, ⁴J_PH

Z

2.1 Hz, 3H, minor), 1.42–1.25 (m, 6H); ¹³C NMR (CDCl₃) d

153.8 (minor), 149.2 (mayor), 144.6 (minor), 143.5 (mayor),

1

132.1–125.6 (m), 63.4 (d, J_PCZ79.6 Hz, minor), 61.7 (d,

3

¹J_PCZ80.1 Hz, mayor), 61.1, 57.3 (d, J_PCZ11.1 Hz,

3

minor), 55.8 (d, J_PCZ13.6 Hz, mayor), 24.3 (mayor),

22.5 (minor), 14.2, 13.6; ³¹P NMR (CDCl₃) d 30.5 (mayor),

29.7 (minor); IR (NaCl) 3217, 2985, 1706, 1447, 1222; MS

(CI) m/z 464 (M^CC1, 72). Anal. Calcd. for C₂₆H₃₀N₃O₃P:

C, 67.37; H, 6.52; N, 9.07. Found C, 67.28; H, 6.51; N, 9.04.

2

(d, J_PHZ11.8 Hz, 1H), 4.22–4.07 (m, 4H), 3.33 (s, 2H),

2.56 (bs, 1H), 1.89 (s, 3H), 1.27–1.18 (m, 6H); ¹³C NMR

(CDCl₃) d 171.5, 153.4, 148.9, 132.0–128.2 (m), 64.7 (d,

3

¹J_PCZ78.6 Hz), 61.7, 60.7, 49.3 (d, J_PCZ13.6 Hz), 14.4,

14.0, 13.5; ³¹P NMR (CDCl₃) d 29.5; IR (KBr) 2979, 1732,

1533, 1440, 1228; MS (CI) m/z 446 (M^CC1, 100). Anal.

Calcd. for C₂₂H₂₈N₃O₅P: C, 59.32; H, 6.34; N, 9.43. Found

C, 59.11; H, 6.37; N, 9.41.

3.5.9. Diethyl [2-(ethoxycarbonyl hydrazono)-1-(R)-

(methylbenzylamino)propyl] phosphonate (13ba). (0.35 g,

88%) obtained as an oil in a reaction from 4ba (0.32 g,

1 mmol) and (R)-methylbenzylamine (0.16 mL, 1.2 mmol)

as described in the general procedure (method A) and

addition of (R)-methylbenzylamine at 0 8C. The crude

product was puriﬁed by ﬂash-chromatography (silica gel,

3.5.6. Ethyl [1-(diethoxyphosphoryl)-2-(ethoxycarbonyl

hydrazono)propylamino] acetate (11baa). (0.38 g, 99%)

obtained as an oil from hydrazone 4ba (0.32 g, 1 mmol),

glycine ethyl ester hydrochloride (0.17 g, 1.2 mmol) and

Et₃N (0.42 mL, 3 mmol) as described in the general

procedure (method A). The crude product was puriﬁed by

ﬂash-chromatography (silica gel, AcOEt, R_fZ0.25,

AcOEt, R_fZ0.50, AcOEt): ¹H NMR (CDCl₃) d 7.79 (s, 1H),

2

7.34–7.20 (m, 5H), 4.28–4.02 (m, 6H), 3.89 (d, J_PH

Z

2

21.7 Hz, 1H, mayor), 3.82–3.65 (m, 1H), 3.55 (d, J_PH

4

23.5 Hz, 1H, minor), 2.32 (bs, 1H), 1.89 (d, J_PHZ2.8 Hz,

4

3H, minor), 1.59 (d, J_PHZ2.6 Hz, 3H, mayor), 1.41–1.23

(m, 12H); ¹³C NMR (CDCl₃) d 154.6 (minor), 149.1

(mayor), 145.2 (minor), 144.4 (mayor), 128.9–125.8 (m),

1

AcOEt): H NMR (CDCl₃) d 8.10 (s, 1H), 4.20–4.05 (m,

2

4

1

8H), 3.87 (d, J_PHZ20.6 Hz, 1H), 3.33 (d, J_PHZ1.8 Hz,

63.4–62.3 (m), 62.5 (d, J_PCZ141.0 Hz, mayor), 60.2 (d,

4

2H), 1.90 (d, J_PHZ1.5 Hz, 3H), 1.34–1.18 (m, 12H); ¹³C

3

¹J_PCZ154.6 Hz, minor), 57.3 (d, J_PCZ13.6 Hz, minor),

2

NMR (CDCl₃) d 171.6, 153.9, 148.4, 63.1 (d, J_PC

56.4 (d, ³J_PCZ17.1 Hz, mayor), 24.9 (mayor), 23.0 (minor),

16.6–13.5 (m); ³¹P NMR (CDCl₃) d 22.7 (minor), 22.2

(mayor); IR (NaCl) 3462, 2965, 1725, 1228, 1016; MS (CI)

m/z 400 (M^CC1, 100). Anal. Calcd. for C₁₈H₃₀N₃O₅P: C,

54.13; H, 7.57; N, 10.52. Found C, 54.24; H, 7.61; N, 10.55.

Z

2

1

6.8 Hz), 62.9 (d, J_PCZ7.0 Hz), 62.0 (d, J_PCZ152.8 Hz),

61.6, 60.7, 49.0 (d, J_PCZ16.3 Hz), 16.3–13.0 (m); ³¹P

3

NMR (CDCl₃) d 20.9; IR (NaCl) 3237, 2979, 1732, 1546,

1367, 1222, 1029; MS (CI) m/z 382 (M^CC1, 100). Anal.

Calcd. for C₁₄H₂₈N₃O₇P: C, 44.09; H, 7.40; N, 11.02. Found

C, 43.98; H, 7.43; N, 11.03.

3.5.10. Methyl 2-(R)-[2-(benzyloxycarbonyl hydrazono)-

1-(diethoxyphosphoryl)propylamino]-3-methyl butyrate

(14) and methyl 2-(S)-[2-(benzyloxycarbonyl hydra-

zono)-1-(diethoxyphosphoryl)propylamino]-3-methyl

butyrate (15). (0.43 g, 91%) and (0.45 g, 96%) obtained as

an oil from 4bb (0.38 g, 1 mmol) and D-valine methyl ester

hydrochloride (0.20 g, 1.2 mmol) or L-valine methyl ester

hydrochloride (0.20 g, 1.2 mmol), respectively, as described

in the general procedure (method A) by using Et₃N

(0.42 mL, 3 mmol) and addition of amine at 0 8C. The

crude product was puriﬁed by ﬂash-chromatography (silica

gel, AcOEt/hexanes 70:30, R_fZ0.32, AcOEt/hexanes

3.5.7. Ethyl [1-(diethoxyphosphoryl)-2-(benzyloxycarbonyl

hydrazono)propylamino] acetate (11bba). (0.41 g, 93%)

obtained as an oil in a reaction from 4bb (0.38 g, 1 mmol)

and glycine ethyl ester hydrochloride (0.17 g, 1.2 mmol) as

described in the general procedure (method A) by using

Et₃N (0.42 mL, 3 mmol). The crude product was puriﬁed by

ﬂash-chromatography (silica gel, AcOEt, R_fZ0.22, AcOEt/

hexanes 50:50): ¹H NMR (CDCl₃) d 7.86 (s, 1H), 7.41–7.35

2

(m, 5H), 5.23 (s, 2H), 4.23–4.10 (m, 6H), 3.87 (d, J_PH

Z

4

20.7 Hz, 1H), 3.38 (d, J_PHZ2.8 Hz, 2H), 1.93 (d, J_PH

Z

2.6 Hz, 3H), 1.34–1.20 (m, 9H); ¹³C NMR (CDCl₃) d 171.2,

50:50): H NMR (CDCl₃) d 7.79 (s, 1H), 7.69 (s, 1H),

7.24–7.20 (m, 5H), 5.16–5.08 (m, 2H), 4.09–3.93 (m, 4H),

1

153.5, 148.2, 135.6–128.0 (m), 127.8, 66.7, 62.7 (d, ²J_PC

Z

2

1

2

7.1 Hz), 62.5 (d, J_PCZ7.0 Hz), 61.8 (d, J_PCZ144.5 Hz,),

3.74 (d, J_PHZ20.0 Hz, 1H), 3.67 (d, J_PHZ19.1 Hz, 1H),

3.55 (s, 3H), 3.41 (s, 3H), 2.98–2.93 (m, 1H), 2.76–2.71 (m,

3

60.3, 45.6 (d, J_PCZ16.1 Hz), 15.8, 13.6, 12.8; ³¹P NMR

(CDCl₃) d 20.8; IR (NaCl) 3224, 2985, 1725, 1208, 1023,;

4

1H), 2.27 (bs, 1H), 1.78 (d, J_PHZ2.9 Hz, 3H), 1.75 (d,

MS (CI) m/z 444 (M^CC1, 100). Anal. Calcd. for

⁴J_PHZ2.3 Hz, 3H), 1.29–1.18 (m, 6H), 0.91–0.82 (m, 6H);

2826

F. Palacios et al. / Tetrahedron 61 (2005) 2815–2830

¹³C NMR (CDCl₃) d 175.0, 174.2, 154.2, 154.1, 149.4,

148.5, 135.4–127.1 (m), 66.2, 65.5 (d, ³J_PCZ16.1 Hz), 64.1

(5 mL). The organic layer was dried over MgSO₄and

evaporated under vacuum. Diaza-alkene 5bc was diluted

with chloroform (10 mL) under a nitrogen atmosphere and

ammonia was bubbled for 10 min. The solvent was

evaporated under vacuum and the crude product was diluted

with CH₂Cl₂(5 mL). Et₃N (0.21 mL, 1.5 mmol) and tosyl

chloride (0.23 g, 1.2 mmol) was added at room temperature.

Then, the mixture was stirred at room temperature for 6 h

and the crude mixture was diluted with CH₂Cl₂(10 mL),

washed with H₂O (2!5 mL) and the aqueous phase was

extracted twice with CH₂Cl₂(5 mL). The organic layer was

dried over MgSO₄and evaporated under vacuum and the

crude product was puriﬁed by ﬂash-chromatography (silica

gel, AcOEt/hexanes 70:30) affording compound 18 (0.24 g,

3

(d, J_PCZ16.1 Hz), 62.6–60.5 (m), 50.8, 50.6, 31.1, 30.6,

18.7–12.3 (m); ³¹P NMR (CDCl₃) d 21.1, 20.6; IR (NaCl)

3217, 2959, 1739, 1540, 1222; MS (CI) m/z 472 (M^CC1,

100). Anal. Calcd. for C₂₁H₃₄N₃O₇P: C, 53.50; H, 7.27; N,

8.91. Found from L-Valine C, 53.31; H, 7.25; N, 8.94; from

D-Valine C 53.38; H, 7.28; N, 8.92.

3.5.11. Methyl 2-(S)-[1-(diethoxyphosphoryl)-2-(ethoxy-

carbonyl hydrazono)propylamino]-3-methyl butyrate

(16ba). (0.40 g, 95%) obtained as an oil from 4ba (0.32 g,

1 mmol) and L-valine ethyl ester hydrochloride (0.22 g,

1.2 mmol) as described in the general procedure (method A)

by using Et₃N (0.42 mL, 3 mmol) and addition of amine at

K40 8C. The crude product was puriﬁed by ﬂash-chromato-

graphy (silica gel, AcOEt, R_fZ0.50, AcOEt): ¹H NMR

(CDCl₃) d 7.83 (s, 1H, mayor), 7.71 (s, 1H, minor), 4.30–

1

43%) as a white solid: 162–164 8C; H NMR (CDCl₃) d

7.72–7.69 (m, 2H), 7.35 (s, 1H), 7.21–7.20 (m, 2H), 6.32

(bs, 1H), 4.72–4.64 (m, 1H), 4.36–4.10 (m, 5H), 2.39 (s,

3H), 2.19–0.81 (m, 27H); ¹³C NMR (CDCl₃) d 152.8, 144.0,

143.3, 136.6–127.6 (m), 76.1, 75.8, 63.7–62.8 (m), 54.3 (d,

¹J_PCZ155.1 Hz), 47.0, 41.0, 34.0, 31.2, 26.2, 26.1, 23.3,

23.2, 21.9, 21.4, 20.6, 16.2, 16.1–13.4 (m); ³¹P NMR

(CDCl₃) d 16.4, 16.2; IR (KBr) 3297, 3138, 2959, 2919,

1752, 1520, 1215; MS (CI) m/z 560 (M^CC1, 100). Anal.

Calcd. for C₂₅H₄₂N₃O₇PS: C, 53.65; H, 7.56; N, 7.51.

Found C, 53.42; H, 7.59; N, 7.53.

2

4.09 (m, 8H), 3.84 (d, J_PHZ20.1 Hz, 1H, mayor), 3.11–

3.06 (m, 1H), 2.88–2.83 (m, 1H), 2.34 (bs, 1H), 1.95 (d,

4

⁴J_PHZ2.8 Hz, 3H, mayor), 1.91 (d, J_PHZ2.1 Hz, 3H,

minor), 1.41–1.19 (m, 12H) 0.99–0.90 (m, 6H); ¹³C NMR

(CDCl₃) d 174.0 (minor), 173.1 (mayor), 153.6 (minor),

3

148.2 (mayor), 65.6 (d, J_PCZ16.1 Hz, minor), 64.4 (d,

³J_PCZ16.1 Hz, mayor), 63.9–59.1 (m), 31.4 (minor), 30.9

(mayor), 18.9–12.3 (m); ³¹P NMR (CDCl₃) d 21.1 (mayor),

20.7 (minor); IR (NaCl) 3224, 2985, 1725, 1235, 1016; MS

(CI) m/z 424 (M^CC1, 100). Anal. Calcd. for C₁₇H₃₄N₃O₇P:

C, 48.22; H, 8.09, N, 9.92. Found C. 48.37; H. 8.06; N. 9.89.

3.5.14. Diethyl [2-((K)-menthyloxycarbonyl hydra-

zono)-1-(4-methoxyphenylamino)propyl] phosphonate

(19). (0.42 g, 82%) obtained as an oil from 4bc (0.42 g,

1 mmol) and 4-methoxyaniline (0.15 g, 1.2 mmol) as

described in the general procedure (method A) and addition

of amine at K40 8C. The crude product was puriﬁed by

ﬂash-chromatography (silica gel, AcOEt/hexanes 50:50,

R_fZ0.48, AcOEt/hexanes 50:50): ¹H NMR (CDCl₃) d 7.74

(bs, 1H), 6.77–6.66 (m, 4H), 4.76–4.67 (m, 1H), 4.50 (d,

²J_PHZ23.0 Hz, 1H), 4.25–4.12 (m, 4H), 3.73 (s, 3H), 2.08–

3.5.12. Ethyl 2-(S)-[2-(benzyloxycarbonyl hydrazono)-1-

(diethoxyphosphoryl)propylamino]-3-methyl butyrate

(16bb). (0.44 g, 91%) obtained as an oil from 4bb (0.38 g,

1 mmol) and L-valine ethyl ester hydrochloride (0.22 g,

1.2 mmol) as described in the general procedure (method A)

by using Et₃N (0.42 mL, 3 mmol) and addition of amine at

K40 8C. The crude product was puriﬁed by ﬂash-chromato-

graphy (silica gel, AcOEt/ hexanes 70:30, R_fZ0.54, AcOEt/

0.79 (m, 27H),; ¹³C NMR (CDCl₃) d 152.9, 153.4, 148.1,

1

140.5–114.7 (m), 75.8, 63.7–62.2, 59.2 (d, J_PC

Z

1

151.6 Hz), 55.6, 47.3, 41.1, 34.1, 31.3, 26.3, 26.1, 23.5,

23.3, 21.9, 20.8, 20.7, 16.4, 16.3, 16.2, 16.1, 12.4; ³¹P NMR

(CDCl₃) d 20.7, 20.6; IR (NaCl) 3230, 2965, 1712, 1513,

1235, 1036; MS (CI) m/z 512 (M^CC1, 25). Anal. Calcd. for

C₂₅H₄₂N₃O₆P: C, 58.69; H, 8.27; N, 8.21. Found C, 58.73;

H, 8.24; N, 8.20.

hexanes 50:50): H NMR (CDCl₃) d 7.83 (s, 1H, mayor),

7.71 (s, 1H, minor), 7.63–7.27 (m, 5H), 5.27–5.22 (m, 2H),

2

4.26–3.99 (m, 6H), 3.82 (d, J_PHZ19.8 Hz, 1H, mayor),

3.73–3.71 (m, 1H, minor), 3.16–3.10 (m, 1H), 2.85–2.79 (m,

1H), 2.33 (bs, 1H), 1.92 (d, ⁴J_PHZ2.9 Hz, 3H, mayor), 1.89

(d, ⁴J_PHZ2.2 Hz, 3H, minor), 1.35–1.13 (m, 9H), 0.99–0.90

(m, 6H); ¹³C NMR (CDCl₃) d 174.1, 173.2, 154.2, 153.8,

148.4 (minor), 147.9 (mayor), 135.6–127.7 (m), 66.6, 65.7

(d, ³J_PCZ16.1 Hz, minor), 64.4 (d, ³J_PCZ17.0 Hz, mayor),

3.5.15. Ethyl [1-(diethoxyphosphoryl)-2-((K)-menthyl-

oxycarbonyl hydrazono)propylamino] acetate (20).

(0.45 g, 92%) obtained as an oil from hydrazone 4bc

(0.42 g, 1 mmol), glycine ethyl ester hydrochloride (0.17 g,

1.2 mmol) and Et₃N (0.42 mL, 3 mmol) as described in the

general procedure (method A) and addition of primary

amine at 0 8C. The crude product was puriﬁed by ﬂash-

chromatography (silica gel, AcOEt/hexanes 50:50, R_fZ

1

62.8–62.0 (m), 60.9 (d, J_PCZ148.1 Hz), 60.1, 59.9, 31.4

(minor), 30.9 (mayor), 19.0–12.4 (m); ³¹P NMR (CDCl₃) d

21.1 (mayor), 20.6 (minor); IR (NaCl) 3230, 2998, 1739,

1235, 1036; MS (CI) m/z 486 (M^CC1, 100). Anal. Calcd.

for C₂₂H₃₆N₃O₇P: C, 54.42; H, 7.47; N, 8.65. Found C,

54.21; H, 7.46; N, 8.63.

1

0.57, AcOEt/hexanes 50:50): H NMR (CDCl₃) d 7.69 (s,

3.5.13. Synthesis of diethyl [2-((-)-menthyloxycarbonyl

hydrazono)-1-(toluene-4-sulfonylamino)propyl] phos-

phonate (18). To a stirred solution of chlorohydrazone

4bc (0.42 g, 1 mmol) in CH₂Cl₂(5 mL) was added Et₃N

(0.21 mL, 1.5 mmol) at room temperature and under

nitrogen atmosphere. Then, the mixture was stirred at

room temperature for 30 min. The crude mixture was

diluted with CH₂Cl₂(10 mL), washed with H₂O (2!5 mL)

and the aqueous phase was extracted twice with CH₂Cl₂

1H), 4.69–4.67 (m, 1H), 4.20–4.11 (m, 6H), 3.87 (d, ²J_PH

Z

20.6 Hz, 1H), 3.37 (s, 2H), 2.14–0.78 (m, 30 H); ¹³C NMR

(CDCl₃) d 170.8, 153.2, 147.1, 74.6, 62.3 (d, ²J_PCZ5.5 Hz),

62.1 (d, ²J_PCZ6.5 Hz), 61.5 (d, ¹J_PCZ152.6 Hz), 59.8, 48.3

3

(d, J_PCZ16.6 Hz), 46.5, 40.5, 33.5, 30.6, 25.4, 22.8, 21.2,

19.9, 15.6, 13.4, 12.3; ³¹P NMR (CDCl₃) d 21.2, 21.1; IR

(NaCl) 3217, 2972, 1739, 1387, 1228, 1016; MS (CI) m/z

492 (M^CC1, 8). Anal. Calcd. for C₂₂H₄₂N₃O₇P: C, 53.75;

H, 8.61; N, 8.55. Found C, 53.59; H, 8.62; N, 8.56.

F. Palacios et al. / Tetrahedron 61 (2005) 2815–2830

2827

3.5.16. Diethyl [2-(2-(K)-menthyloxycarbonyl hydra-

2H), 4.18–4.07 (m, 5H), 3.35–3.18 (m, 2H), 1.36 (d, ³J_HH

Z

zono)-1-(1-(R)-phenylethylamino)propyl] phosphonate

(21). (0.42 g, 83%) obtained as an oil from hydrazone 4bc

(0.42 g, 1 mmol) and (R)-methylbenzylamine (0.16 mL,

1.2 mmol) as described in the general procedure (method A)

and addition of primary amine at K40 8C. The crude

product was puriﬁed by ﬂash-chromatography (silica gel,

AcOEt/hexanes 50:50, R_fZ0.52, AcOEt/hexanes 50:50):

¹H NMR (CDCl₃) d 7.76 (s, 1H, minor), 7.47 (s, 1H, mayor),

7.35–7.20 (m, 5H), 4.74–4.66 (m, 1H), 4.25–3.70 (m, 5H),

6.8 Hz, 3H), 1.34–1.28 (m, 6H); ¹³C NMR (CDCl₃) d 203.6

2

(d, J_PCZ6.6 Hz), 137.4–127.7 (m), 80.2, 71.8, 62.3 (d,

1

²J_PCZ6.5 Hz), 36.5 (d, J_PCZ131.3 Hz), 16.3, 16.1; ³¹P

NMR (CDCl₃) d 20.4; IR (NaCl) 3462, 2992, 1719, 1454,

1387, 1255; MS (CI) m/z 315 (M^CC1, 100). Anal. Calcd.

for C₁₅H₂₃O₅P: C, 57.32; H, 7.38. Found C, 57.19; H, 7.36.

[a]²_D⁰K31.4 (c 1.00, CH₂Cl₂).

3.5.19. Synthesis of syn-diethyl [3-(S)-benzyloxy-2-

(benzyloxycarbonyl hydrazono)butyl] phosphonate

(24). To a stirred solution of ketone 23 (1.57 g, 5 mmol)

in MeOH (5 mL), was added benzyl carbazate 2b (1.00 g,

6 mmol) at room temperature. The mixture was reﬂuxed for

20 h and the solvent was evaporated under vacuum. The

crude mixture was diluted in CH₂Cl₂(5 mL) and dried over

MgSO₄. Finally, the solvent was evaporated under vacuum

to give crude product 24 which was not possible to purify

and was then used in the next step without further

puriﬁcation. O 98% conversion calculated by ³¹P NMR

on the crude reaction mixture. (R_fZ0.56, AcOEt/hexanes

2

3.50 (d, J_PHZ24.9 Hz, 1H, mayor), 2.80 (bs, 1H), 2.14–

0.80 (m, 30H); ¹³C NMR (CDCl₃) d 153.9 (minor), 147.9

(mayor), 144.9 (minor), 144.1 (mayor), 128.3–125.9 (m),

75.7, 63.3–62.2 (m), 61.0 (d, ¹J_PCZ153.1 Hz, minor), 59.8

1

3

(d, J_PCZ154.1 Hz, mayor), 57.2 (d, J_PCZ14.1 Hz,

3

minor), 56.2 (d, J_PCZ17.1 Hz, mayor), 47.1, 41.0, 34.0,

31.2, 26.1 (minor), 26.0 (mayor), 24.6 (minor), 23.4

(mayor), 23.2, 21.8, 20.6 (minor), 20.5 (mayor), 16.2,

16.1–13.1 (m); ³¹P NMR (CDCl₃) d 22.7 (minor), 22.2

(mayor); IR (NaCl) 3217, 2965, 1712, 1235, 1023; MS (CI)

m/z 510 (M^CC1, 100). Anal. Calcd. for C₂₆H₄₄N₃O₅P: C,

61.28; H, 8.70; N, 8.25. Found C, 61.11; H, 8.74; N, 8.23.

1

50:50). H NMR (CDCl₃) d 10.3 (bs, 1H), 7.44–7.25 (m,

10H), 5.30–5.22 (m, 2H), 4.42 (dd, ²J_HHZ21.9 Hz, ⁴J_HH

Z

3

11.8 Hz, 2H), 4.35 (q, J_HHZ6.7 Hz, 1H), 4.13 (q, J_HH

3.5.17. Ethyl 2-(S)-[1-(Diethoxyphosphoryl)-2-((K)-

menthyloxycarbonyl hydrazono)propylamino]-3-methyl

butyrate (22). (0.42 g, 79%) obtained as an oil in a reaction

from 4bc (0.42 g, 1 mmol) and L-valine ethyl ester

hydrochloride (0.22 g, 1.2 mmol) as described in the general

procedure (method A) by using Et₃N (0.42 mL, 3 mmol)

and addition of amine at K40 8C. The crude product was

puriﬁed by ﬂash-chromatography (silica gel, AcOEt/hexanes

50:50, R_fZ0.63, AcOEt/hexanes 50:50): ¹H NMR (CDCl₃)

d 7.71 (s, 1H, mayor), 7.60 (s, 1H, minor), 4.71 (bs, 1H),

3

7.5 Hz, 4H), 1.36 (d, J_HHZ6.7 Hz, 3H), 1.32–1.28 (m,

6H); ¹³C NMR (CDCl₃) d 154.8, 138.0, 136.2–127.7, 78.6,

1

71.0, 67.2, 63.1–63.0 (m), 24.7 (d, J_PCZ138.5 Hz), 18.9,

16.3, 16.2; ³¹P NMR (CDCl₃) d 24.8; IR (NaCl) 2972, 1752,

1241, 1049; MS (CI) m/z 463 (M^CC1, 100).

3.5.20. Synthesis of syn-diethyl [3-(S)-benzyloxy-2-

(benzyloxycarbonyl hydrazono)-1-chlorobutyl] phos-

phonate (25). To a stirred solution b-hydrazone 24

(4.62 g, 10 mmol) in dry carbon tetrachloride (150 mL),

was added dropwise NCS (1.50 g, 11 mmol) under a

nitrogen atmosphere. Then, the mixture was stirred at

room temperature for 16 h. The crude mixture was diluted

with CH₂Cl₂(20 mL), washed with H₂O (2!20 mL) and

the solvent was dried over MgSO₄and evaporated under

vacuum. The crude product was puriﬁed by ﬂash-chromato-

graphy (silica gel, AcOEt/hexanes 30:70, R_fZ0.27, AcOEt/

hexanes 50:50) affording compound 25 (2.78 g, 56%) as an

2

4.24–4.08 (m, 6H), 3.85 (d, J_PHZ20.4 Hz, 1H, mayor),

3.29–3.12 (m, 1H, mayor and minor), 2.89 (bs, 1H), 2.36

(bs, 1H), 2.09–0.81 (m, 36H); ¹³C NMR (CDCl₃) d 175.2

(minor), 174.7 (mayor), 153.2 (minor), 148.2 (mayor), 75.5,

3

74.6, 66.2 (d, J_PCZ16.1 Hz, minor), 64.9 (d, J_PC

Z

16.1 Hz, mayor), 63.3–59.7 (m), 47.1, 41.0, 34.0, 31.2

(minor), 31.1 (mayor), 26.0, 23.3 (minor), 23.2 (mayor),

21.8, 20.5, 19.4–14.0 (m); ³¹P NMR (CDCl₃) d 22.1

(minor), 21.7 (mayor); IR (NaCl) 3211, 2939, 1719, 1367,

1235, 1036; MS (CI) m/z 543 (M^CC1, 100). Anal. Calcd.

for C₂₅H₄₈N₃O₇P: C, 56.27; H, 9.07; N, 7.87. Found C.

56.07; H. 9.10; N. 7.90.

1

oil; H NMR (CDCl₃) d 10.50 (bs, 1H), 10.33 (bs, 1H),

7.54–7.26 (m, 10H), 5.42–5.12 (m, 2H), 4.85–4.02 (m, 8H),

3

1.59 (d, J_HHZ6.9 Hz, 3H), 1.58 (d, J_HHZ6.9 Hz, 3H),

1.46–1.18 (m, 6H); ¹³C NMR (CDCl₃) d 154.8, 153.2,

146.4, 145.7, 138.0–127.3 (m), 74.8, 73.5, 72.0, 71.7, 67.6–

3.5.18. Synthesis of diethyl (3-(S)-benzyloxy-2-oxobutyl)

phosphonate (23). To a K78 8C stirred solution of methyl

phosphonic acid diethyl ester²⁶(1.82 g, 12 mmol) in THF

(70 mL) was added a solution of MeLi (8.1 mL, 13 mmol)

under a nitrogen atmosphere. The mixture was stirred at the

same temperature for 1 h. Then, a solution of 2-benzyloxy

propionic acid ethyl ester²⁵in THF (5 mL) was added at

K78 8C, and stirred for 16 h allowing to standing from

K78 8C to room temperature. The solvent was evaporated

under vacuum and the crude reaction mixture was hydro-

lyzed by adding 10% HCl solution (15 mL) for 1 h. The

crude mixture was extracted with CH₂Cl₂(3!10 mL), the

organic phase was dried over MgSO₄and evaporated under

vacuum. The crude product was puriﬁed by ﬂash-chromato-

graphy (silica gel, AcOEt/hexanes 1:20, R_fZ0.27, AcOEt/

hexanes 50:50) affording compound 23 (2.98 g, 79%) as an

1

63.8 (m), 55.0 (d, J_PCZ160.0 Hz), 54.6 (d, J_PC

Z

159.1 Hz), 18.6–16.2 (m); ³¹P NMR (CDCl₃) d 15.1, 14.6;

IR (NaCl) 3297, 2972, 1752, 1500, 1222; MS (CI) m/z 497

(M^CC1, 100). Anal. Calcd. for C₂₃H₃₀ClN₂O₆P: C, 55.59;

H, 6.09; N, 5.64. Found C, 55.82; H, 6.08; N, 5.68.

3.5.21. Synthesis of 1-benzyloxycarbonyl-3-(1-(S)-benzyl-

oxyethyl)-4-diethoxyphosphoryl-1,2-diaza-1,3-butadiene

(26). To a room temperature solution of chlorohydrazone 25

(2.48 g, 5 mmol) in dry CH₂Cl₂(25 mL), was added

dropwise triethylamine (0.85 mL, 6 mmol) under nitrogen

atmosphere. The mixture was stirred at this temperature for

45 min. The crude mixture was diluted with CH₂Cl₂

(20 mL), washed with H₂O (2!20 mL) and the aqueous

phase was extracted twice with CH₂Cl₂(10 mL). The

solvent was dried over MgSO₄and evaporated under

1

oil; H NMR (CDCl₃) d 7.36–7.28 (m, 5H), 4.63–4.51 (m,

2828

F. Palacios et al. / Tetrahedron 61 (2005) 2815–2830

vacuum. Diaza-alkene 26 proved to be unstable to

chromatography and was then used in the next steps without

further puriﬁcation. O 98% conversion calculated by ³¹P

NMR on the crude reaction mixture. (R_fZ0.62, AcOEt/

16.4, 16.3, 14.1; ³¹P NMR (CDCl₃) d 21.7 (minor), 20.0

(mayor); IR (NaCl) 3310, 2979, 1725, 1500, 1228, 1023;

MS (CI) m/z 578 (M^CC1, 100). Anal. Calcd. for

C₂₈H₄₀N₃O₈P: C, 58.22; H, 6.98; N, 7.27. Found C,

58.39; H, 7.01; N, 7.28.

1

hexanes 50:50). H NMR (CDCl₃) d 7.48–7.24 (m, 10H),

6.95 (d, ²J_PHZ12.1 Hz, 1H, E), 5.72 (d, ²J_PHZ10.6 Hz, 1H,

Z), 5.42 (s, 2H), 5.32 (s, 2H), 4.57–4.38 (m, 3H), 4.17–4.08

(m, 4H), 1.70 (s, 3H, E), 1.68 (s, 3H, Z), 1.41–1.22 (m, 6H);

3.5.24. Synthesis of syn-diethyl [3-(S)-benzyloxy-2-(benzyl-

oxycarbonyl hydrazono)-1-(4-methoxyphenylamino)

butyl] phosphonate (27c). (0.48 g, 83%) obtained as a

pale yellow oil from cholorohydrazone 25 (0.49 g, 1 mmol)

and p-anisidine (0.15 g, 1.2 mmol) as described in the

general procedure for the addition of primary amines to azo-

alkenes 5 (method A), and addition of p-anisidine at 0 8C.

The crude product was puriﬁed by ﬂash-chromatography

(silica gel, AcOEt/hexanes 50:50, R_fZ0.15, AcOEt/hexanes

2

¹³C NMR (CDCl₃) d (E-isomer) 169.5 (d, J_PCZ13.9 Hz),

1

161.3, 137.8–127.6 (m), 109.1 (d, J_PCZ191.2 Hz), 71.3,

3

2

71.2, 70.5 (d, J_PCZ12.8 Hz), 70.2, 70.1, 62.4 (d, J_PC

Z

6.0 Hz), 62.3 (d, ²J_PCZ5.9 Hz), 21.0, 16.4, 16.3; ³¹P NMR

(CDCl₃) d 14.0 (Z), 13.7 (E); IR (NaCl) 2985, 1765, 1454,

1235, 1023.

1

50:50): H NMR (CDCl₃) d 10.40 (bs, 1H), 7.44–6.70 (m,

3.5.22. Synthesis of syn-diethyl [1-benzylamino-3-(S)-

benzyloxy-2-(benzyloxycarbonyl hydrazono)butyl] phos-

phonate (27a). (0.43 g, 75%) obtained as an oil from

cholorohydrazone 25 (0.49 g, 1 mmol) and benzyl amine

(0.13 mL, 1.2 mmol) as described in the general procedure

for the addition of primary amines to azo-alkenes 5 (method

A) and addition of benzyl amine at K40 8C. The crude

product was puriﬁed by ﬂash-chromatography (silica gel,

AcOEt/hexanes 50:50, R_fZ0.20, AcOEt/hexanes 50:50):

¹H NMR (CDCl₃) d 10.62 (bs, 1H), 7.38–7.26 (m, 15H),

5.31–5.22 (m, 2H), 4.62–4.58 (m, 3H), 4.25–4.13 (m, 4H),

14H), 5.28 (d, ²J_HHZ12.2 Hz, 1H), 5.18 (d, ²J_HHZ12.1 Hz,

1H), 4.57–4.20 (m, 8H), 3.75 (s, 3H), 1.92 (bs, 1H), 1.42 (d,

³J_HHZ6.9 Hz, 3H), 1.35–1.26 (m, 6H); ¹³C NMR (CDCl₃) d

153.1, 149.1, 140.4–114.7 (m), 75.0, 71.7, 67.1, 64.0 (d,

2

1

²J_PCZ7.0 Hz), 63.3 (d, J_PCZ7.5 Hz), 57.1 (d, J_PC

Z

154.1 Hz), 55.6, 16.6–16.2 (m); ³¹P NMR (CDCl₃) d 20.5

(minor), 19.8 (mayor); IR (NaCl) 3303, 2979, 1759, 1513,

1228; MS (CI) m/z 584 (M^CC1, 100). Anal. Calcd. for

C₃₀H₃₈N₃O₇P: C, 61.74; H, 6.56; N, 7.20. Found C, 61.92;

H, 6.59; N, 7.18.

2

3.92–3.70 (m, 2H), 3.47 (d, J_PHZ24.0 Hz, 1H), 2.48 (bs,

3

1H), 1.53 (d, J_HHZ6.9 Hz, 3H), 1.38–1.28 (m, 6H);¹³C

NMR (CDCl₃) d 153.4, 148.6, 139.1–127.0 (m), 77.1

(mayor), 75.5 (minor), 72.2 (mayor), 71.7 (minor), 67.2

3.5.25. Synthesis of syn-ethyl 4-[3-(S)-benzyloxy-2-(benzyl-

oxycarbonyl hydrazono)-1-(diethoxyphosphoryl)butyl-

amino] benzoate (27d). (0.48 g, 77%) obtained as a pale

yellow oil from cholorohydrazone 25 (0.49 g, 1 mmol) and

ethyl 4-aminobenzoate (0.20 g, 1.2 mmol) as described in

the general procedure for the addition of primary amines to

azo-alkenes 5 (method A) and addition of ethyl 4-

aminobenzoate at 0 8C. The crude product was puriﬁed by

ﬂash-chromatography (silica gel, AcOEt/hexanes 50:50,

R_fZ0.30, AcOEt/hexanes 50:50): ¹H NMR (CDCl₃) d 10.41

(bs, 1H), 7.92–6.74 (m, 14 H), 5.34–5.21 (m, 2H), 4.58–4.54

2

(minor), 67.1 (mayor), 63.8 (d, J_PCZ7.0 Hz, mayor), 63.3

2

(d, J_PCZ6.8 Hz, minor), 63.0 (d, J_PCZ7.2 Hz, mayor),

2

1

62.8 (d, J_PCZ7.2 Hz, minor), 60.7 (d, J_PCZ150.3 Hz,

1

3

minor), 58.1 (d, J_PCZ156.3 Hz, mayor), 52.5 (d, J_PC

Z

12.7 Hz, minor), 51.1 (d, ³J_PCZ14.8 Hz, mayor), 16.6–16.3

(m); ³¹P NMR (CDCl₃) d 22.0 (minor), 20.5 (mayor); IR

(NaCl) 3310, 2985, 2919, 1752, 1493, 1215; MS (CI) m/z

568 (M^CC1, 100). Anal. Calcd. for C₃₀H₃₈N₃O₆P: C,

63.48; H, 6.75; N, 7.40. Found C, 63.22; H, 6.83; N, 7.44.

(m, 4H), 4.37–4.17 (m, 6H), 2.02 (bs, 1H), 1.48 (d, ³J_HH

Z

6.9 Hz, 3H), 1.40–1.28 (m, 9H); ¹³C NMR (CDCl₃) d 166.5,

153.2, 150.0, 136.5–112.8 (m), 75.0, 71.8, 67.3, 64.1 (d,

3.5.23. Synthesis of syn-ethyl 3-[3-(S)-benzyloxy-2-(benzyl-

oxycarbonyl hydrazono)-1-(diethoxyphosphoryl)butyl-

amino] propionate (27b). (0.37 g, 64%) obtained as a

pale yellow oil from chlorohydrazone 25 (0.49 g, 1 mmol)

and b-alanine ethyl ester hydrochloride (0.19 g, 1.2 mmol)

as described in the general procedure for the addition of

primary amines to azo-alkenes 5 (method A) by using Et₃N

(0.42 mL, 3 mmol) and addition of b-alanine ethyl ester

hydrochloride at 0 8C. The crude product was puriﬁed by

ﬂash-chromatography (silica gel, AcOEt/hexanes 50:50,

R_fZ0.40, AcOEt): ¹H NMR (CDCl₃) d 10.51 (bs, 1H),

7.36–7.28 (m, 10H), 5.28–5.15 (m, 2H), 4.61–4.52 (m, 3H),

²J_PCZ7.0 Hz), 63.4 (d, ²J_PCZ7.6 Hz), 60.3, 55.7 (d, ¹J_PC

Z

154.0 Hz), 16.7–14.3 (m); ³¹P NMR (CDCl₃) d 19.6

(minor), 18.9 (mayor); IR (NaCl) 3270, 1706, 1606, 1487,

1281; MS (CI) m/z 626 (M^CC1, 100). Anal. Calcd. for

C₃₂H₄₀N₃O₈P: C, 61.43; H, 6.44; N, 6.72. Found C, 61.31;

H, 6.42; N, 6.75.

3.5.26. Synthesis of syn-methyl 2-(S)-[3-(S)-benzyloxy-2-

(benzyloxycarbonyl hydrazono)-1-(diethoxyphosphoryl)

butylamino]-3-methyl butyrate (28a). (0.51 g, 87%)

obtained as a pale yellow oil from cholorohydrazone 25

(0.49 g, 1 mmol) and L-valine methyl ester hydrochloride

(0.20 g, 1.2 mmol) as described in the general procedure for

the addition of primary amines to azo-alkenes 5 (method A)

by using Et₃N (0.42 mL, 3 mmol) and addition of L-valine

at 0 8C. The crude product was puriﬁed by ﬂash-chromato-

graphy (silica gel, AcOEt/hexanes 50:50, R_fZ0.41, AcOEt/

3

4.24–4.10 (m, 6H), 3.79 (d, J_PHZ23.4 Hz, 1H, minor),

3

3.56 (d, J_PHZ23.6 Hz, 1H, mayor), 2.96–2.76 (m, 2H),

3

2.50–2.46 (m, 2H), 2.30 (bs, 1H), 1.51 (d, J_HHZ6.8 Hz,

3

3H, minor), 1.47 (d, J_HHZ6.9 Hz, 3H, mayor), 1.37–1.24

(m, 9H),; ¹³C NMR (CDCl₃) d 172.2, 153.3 (minor), 153.2

(mayor), 148.9, 137.0–127.9 (m), 76.4, 75.2, 72.0 (mayor),

2

1

71.7 (minor), 67.0, 63.7 (d, J_PC₂Z6.9 Hz, mayor), 63.2 (d,

hexanes 50:50): H NMR (CDCl₃) d 10.5 (bs, 1H, mayor),

10.3 (bs, 1H, minor), 7.37–7.28 (m, 10H), 5.28–5.14 (m,

²J_PC₂Z6.9 Hz, minor), 62.9 (d, J_PC₁Z7.3 Hz, mayor), 62.7

(d, J_PCZ7.2 Hz, minor), 61.9 (d, J_PCZ149.7 Hz, minor),

2H), 4.62–4.50 (m, 3H), 4.28–4.17 (m, 4H), 3.71 (s, 3H,

mayor), 3.67 (s, 3H, minor), 3.59 (d, J_PHZ20.4 Hz, 1H,

60.4, 60.3, 60.2 (d, ¹J_PCZ154.2 Hz, mayor), 44.3 (d, ³J_PC

Z

2

15.2 Hz, mayor), 44.2 (d, ³J_PCZ13.3 Hz, minor), 35.1, 34.7,

mayor), 3.50 (d, ²J_PHZ20.4 Hz, 1H, minor), 3.12 (d, ³J_HH

Z

F. Palacios et al. / Tetrahedron 61 (2005) 2815–2830

2829

5.1 Hz, 1H, mayor), 2.52 (bs, 1H), 2.10–2.00 (m, 1H), 1.51

51.5, 31.7. 19.3–14.0 (m); ³¹P NMR (CDCl₃) d (mayor

diastereoisomer) 19.7; IR (NaCl) 3317, 2959, 1739, 1500,

1222; MS (CI) m/z 592 (M^CC1, 100). Anal. Calcd. for

C₂₉H₄₂N₃O₈P: C, 58.87; H, 7.16; N, 7.10. Found C, 59.03;

H, 7.18; N, 7.08. [a]²_D⁰K28.7 (c 0.60, CH₂Cl₂).

3

(d, J_HHZ6.8 Hz, 3H, minor), 1.46 (d, J_HHZ6.9 Hz, 3H,

mayor), 1.38–1.27 (m, 6H), 1.00–0.96 (m, 6H); ¹³C NMR

(CDCl₃) d 174.3 (minor), 173.9 (mayor), 154.8 (mayor),

153.3 (minor), 148.1 (mayor), 147.7 (minor), 137.1–128.1

(m), 76.8 (mayor), 75.7 (minor), 72.1 (mayor), 71.6 (minor),

71.4 (minor), 67.1(mayor), 65.8 (d, ³J_PCZ13.7 Hz, mayor),

3

65.7 (d, J_PCZ7.4 Hz, minor), 63.9–63.0 (m), 60.3 (d,

Acknowledgements

1

¹J_PCZ155.7 Hz, minor), 58.4 (d, J_PCZ151.6 Hz, mayor),

51.5, 31.5 (minor), 31.4 (mayor), 19.2–13.7 (m); ³¹P NMR

(CDCl₃) d 21.3 (minor), 19.6 (mayor); IR (NaCl) 3303,

2972, 1752, 1507, 1215; MS (CI) m/z 592 (M^CC1, 100).

Anal. Calcd. for C₂₉H₄₂N₃O₈P: C, 58.87; H, 7.16; N, 7.10.

Found C, 58.71; H, 7.13; N, 7.10.

´

The present work has been supported by the Direccion

General de Investigacion del Ministerio de Ciencia y

´

Tecnologıa (MCYT, Madrid DGI, PPQ2003-00910) and

by the Universidad del Paıs Vasco (UPV-GC/2002). Y. L.

´

thanks the Consejerıa de Educacion, Universidades e

Investigacion del Gobierno Vasco (Vitoria) for a predoc-

´

3.5.27. Synthesis of syn-methyl 2-(S)-[3-(S)-benzyloxy-2-

(benzyloxycarbonyl hydrazono)-1-(diethoxyphosphoryl)

butylamino]-3-phenyl propionate (28b). (0.52 g, 81%)

obtained as an oil from cholorohydrazone 25 (0.49 g,

1 mmol) and L-phenylalanine methyl ester hydrochloride

(0.26 g, 1.2 mmol) as described in the general procedure for

the addition of primary amines to azo-alkenes 5 (method A)

by using Et₃N (0.42 mL, 3 mmol) and addition of L-

phenylalanine methyl ester hydrochloride at K40 8C. The

crude product was puriﬁed by ﬂash-chromatography (silica

gel, AcOEt/hexanes 50:50, R_fZ0.37, AcOEt/hexanes

toral fellowship, and J. M. de los S. thanks the Ministerio de

´ ´

Ciencia y Tecnologıa (Madrid) for Ramon y Cajal Program

ﬁnancial support.

References and notes

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3

(m, 3H), 1.81 (bs, 1H), 1.49 (d, J_HHZ6.8 Hz, 3H, minor),

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2

3.49 (d, J_PHZ19.7 Hz, 1H), 3.26 (bs, 1H), 2.84 (bs, 1H),

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2.06–1.82 (m, 1H), 1.45 (d, J_HHZ6.9 Hz, 3H), 1.38–1.27

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77.0, 72.0, 67.2 (d, J_PCZ8.7 Hz), 67.0, 63.8 (d, J_PC

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Article Doi

Synthesis of functionalized α-amino-phosphine oxides and -phosphonates by addition of amines and aminoesters to 4-phosphinyl- and 4-phosphonyl-1,2-diaza-1,3-butadienes

DOI: 10.1016/j.tet.2005.01.081

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