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number 134

Contribution

Diphenyl Phosphorazidate (DPPA) − More Than Three Decades Later

Takayuki Shioiri

Graduate School of Environmental and Human Sciences, Meijo University

1. Introduction

More than thirty years have already elapsed since weintroduced diphenyl phosphorazidate (diphenylphosphorylazide, DPPA, (PhO)2P(O)N3) as a reagent for organicsynthesis in 1972 (Figure 1).1,2 During these years, DPPAhas been found to be effective for a variety of organicreactions as a versatile synthetic reagent. It is not too muchto say that DPPA has secured an established position as areagent. SciFinder will indicate you about 1,000 referencesabout DPPA, and there will be found about 46,000 examplesof reactions when you will search for DPPA as “Reaction-Reactant”. DPPA is now estimated to be produced over 50tons per year in Japan and easily available commercially.

my interests were aroused about reactivity of acylphosphates which are a mixed anhydride from carboxylicand phosphoric acids. I synthesized the acyl phosphate 3from benzoic acid (1) and diethyl phosphorochloridate (2)by a known procedure and the reaction of 3 wasinvestigated. As one of several trials, the reaction withsodium azide was found to give benzoyl azide (4), as shownin Scheme 1. Although this reaction proceeded in two stepsfrom benzoic acid (1), I thought that the acyl phosphate 6would be temporally formed if the phosphorazidate 5 wereused in place of the phosphorochloridate 2, and the acylphosphate 6 would react in situ with the azide ion givingthe acyl azide 7.

PhOP

PhON

O

N N+ - PhO

PPhO

N

O

N N+- PhO

PPhO

N

O

N N+- PhO

PPhO

N

O

N N-

+

Figure 1. Resonance structures of diphenyl phosphorazidate (DPPA).

This review will first describe why and how the workson DPPA started and then an overview will be made on theutility of DPPA in organic synthesis mainly developed byour group including recent achievements by other groups.3

A comprehensive review is not intended, but characteristicfeatures of DPPA on organic synthesis will be focused.

2. Why and how has DPPA been developed?

I worked about biosynthetic studies of steroids underthe supervision of Professor Sir Derek Barton (1969 Nobellaureate) at Imperial College, London, as a postdoctoralfellow during 1968-1970. I experienced there the Wittigreaction to synthesize some substrates for biosyntheticexperiments.4 The Wittig reaction was not described in anytextbooks at that time, and I deeply interested in abehavior of phosphorus reagents. In addition, before thisexperiment, I had a great interest about serendipitousdiscovery of polyphosphoric acid (PPA) when I learned itfrom Professor Shigehiko Sugasawa as an undergraduatestudent, which drew my interests to synthetic reagents andphosphorus. These experiences and interests led me toinvestigate organic reactions util izing phosphoruscompounds after return to Japan. When I consultedtextbooks at that time from biosynthetic viewpoint, I foundthat acyl phosphates, R1CO2P(O)(OR2)2, played animportant role in biosynthesis of peptides and proteins. Thus

Scheme 1. Formation of acyl azides: practice and hypothesis.

Known diethyl phosphorazidate (8) was thus preparedand reacted with benzoic acid (1) in the presence oftriethylamine. The formation of benzoyl azide (4) wasdetected on a TLC plate, and the reaction with aminesproceeded to give the corresponding amide 9 and anilide10. Refluxing the mixture in ethanol afforded the ethylcarbamate 11 through the Curtius rearrangement, shownin Scheme 2.5a Further, it was found that the samecarbamate 11 was directly obtained by refluxing a mixtureof benzoic acid (1), diethyl phosphorazidate (8), andtriethylamine in ethanol. However, the yields of theproducts were moderate in each case. The ratedetermining step of the reaction was thought to be the stageof the attack of the carboxylate anion to the phosphorus

R1CO2 BH + POR2

OR3N3

R1CON3

+-

R1CO2POR2

OR3N3 BH

+-

POR2

OR3BH O+ -

+

+

B : BasePhCO2POEt

OEtO

PhCO2H +

Et3N

PhCON3

NaN3 quant.

POEt

OEtCl

12

3

4

5

6

7

O

O

O

O

3

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atom of the phosphorazidate. If so, the reaction wouldproceed more efficiently if the phosphorus atom of thephosphorazidate was attached to more electron-withdraw-ing functions. These experiments and considerations ledme to develop DPPA which has more electron-withdrawingphenyl group. In fact, DPPA was revealed to be much moreefficient in the amide synthesis and Curtius rearrangement.

temperature for a long time, it might be slowly and partiallyhydrolyzed with moisture in air to produce diphenylphosphate and toxic explosive hydrazoic acid. In this case,it will be recommended to use after washing DPPA withaqueous sodium hydrogen carbonate followed by drying.5b

4. Peptide synthesis using DPPA

DPPA is useful for amide and peptide bond formationreactions. One of the remained problems in the presentadvanced peptide synthesis will be epimerization whichoccurs to some extent at the stereogenic center in theC-terminal amino acids of peptides through activation withthe condensing agents during the coupling of the peptidefragments. There will be no coupling reagents andprocedures which induce no epimerization. This situationwill be quite similar to the coupling of sugars in which α-and β-isomers could not be separately formed at will. DareI say it, this will be an old but new problem. DPPA is acoupl ing reagent wi th l i t t le epimer izat ion (andracemization),1,5a and inactive to the functional groups inthe following amino acids:1,7,8 serine (Ser), threonine (Thr),valine (Val), asparagine (Asn), glutamine (Gln), histidine(His), pyroglutamic acid (pGlu), tryptophan (Trp),methionine (Met), S-benzylcysteine (Cys(Bzl)), nitroarginine(Arg(NO2)). Thus the peptide synthesis using DPPA willproceed without any side reactions for these amino acids.DPPA can be used for both liquid- and solid-phase peptidesynthesis,9 and dimethylformamide (DMF) is a favorablereaction solvent in both cases. In addition, a base such astriethylamine is necessary to generate the carboxylateanion from the carboxyl part.

A short while after developing DPPA, we introduceddiethyl phosphorocyanidate (DEPC, (EtO)2P(O)CN) asanother suitable reagent for the peptide bond formation.10

DEPC proved to be a versatile synthetic reagent quitesimilar to DPPA.3b,10 However, DEPC is slightly moreactive than DPPA and the rate of epimerization (orracemization) will be lower in peptide synthesis. It will besuperior to DPPA in the construction of linear peptides.Scheme 4 shows the results of the classical Youngracemization test (through the measurement of specificrotation),1,5a,10a,10b which is said to be the most stringenttest of racemization, as well as the results of our develop-ment epimerization test (through HPLC measurement).11

PhCO2HEt3N

PhCON3CH2Cl2

BuNH2PhCONHBu

PhCONHPhPhNH2

PhNHCO2Et

Et3N

EtOH, reflux 62%

58%

50%

71%

EtOH

reflux

(EtO)2P(O)N3

1

8

4

9

10

11

Scheme 2. Reaction of diethyl phosphorazidate withbenzoic acid.

3. Preparation of DPPA and its physicalproperties

DPPA is easily prepared in high yield by the reactionof the corresponding chloride 12 with sodium azide inacetone.1,5 Combination of sodium azide and 18-crown-6in the same reaction was reported,6a and the use of aquaternary ammonium salt as a phase-transfer catalyst ina biphasic phase of water and an organic solvent was alsoreported to be effective,6 as shown in Scheme 3.

A. NaN3, acetone, 20-25 °C, 21 h (84-89%)5)

B. NaN3, 18-crown-6, AcOEt, rt, 20-30 min (74%)6a)

C. NaN3, Bu4N+Br-, cyclohexane-H2O, 20 °C, 1 h (94%)6b)

(PhO)2P(O)Cl (PhO)2P(O)N3

12 DPPA

Scheme 3. Preparation of DPPA.

DPPA is a colorless or pale yellow liquid which boils at134-136 °C/0.2 mmHg, and it will be stable at roomtemperature under shading. It is non-explosive just like theother phosphorazidate. When DPPA is stored at room

Scheme 4. Racemization and epimerization tests usin DPPA and DEPC.

Z-Phe-Val-OH Z-Phe-L/D-Val-Pro-OBut Z-Phe-L/D-Val-Pro-OHH-Pro-OBut, Et3N CF3CO2H

HPLC analysis0 °C, 4 h; rt, 20 h

(EtO)2P(O)CN

Yield (%) D-isomer (%)

(PhO)2P(O)N3 86.8

87.6

2.2

1.4

Bz-L-Leu-OH Bz-L/D-Leu-Gly-OEt

Young racemization test

(EtO)2P(O)CN

Yield (%) D-isomer (%)

(PhO)2P(O)N3 83

86

5.5

4

Epimerization test using HPLC

Et3N

DMF+ H-Gly-OEt HCl

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However, Veber and Merck chemists revealed thatDPPA was suitable for macrolactamization of linearpeptides.12 Since then, DPPA is quite often utilized for thesynthesis of macrocyclic peptides by macrolactamization.13

High di lut ion condit ions wi l l be required for themacrolactamization to suppress the intermolecularreaction, and sodium hydrogen carbonate is often employedinstead of organic bases such as triethylamine. Scheme 5shows some examples, most of which employed DPPA-NaHCO3 in DMF under high dilution conditions (ca. 5 mM)

between 0 °C and room temperature for a longer time (1-3days).12-18

MeN

HN

NH

HN

NH

NH

OO

OH

O

HN

OO

O

NHCbz

Cyclic analog of somatostatin (77%)12b)

HN

MeN

NH

HN

NMe

NMe

OO

OMe

O

OO

O

OMeO

O-Methyl deoxybouvardin (58%)14)

OBzl

N

O

NBzlNH

O

O

BzlO2C

H

HO

K13 precursor (60% in 2 steps)15)

-NH CO- shows a cyclization point.

NH

MeN

HN O

O

O

O

O

I

HO

NH

MeN

NH

O

O

OO

Geodiamolide A (34% in 3 steps)16)

Antillatoxin (29%17c) and 63%17e) in 2 steps)

NO

NH

O

NH

SN

O HN

Ph

HN

O

O

NH

O

O

HO

Mollamide precursor18)

DPPA, i-Pr2NEt, DMF, 52% (2 steps)

O

Yields are overall ones including deprotection.

TsNN

N

O

O

Ts

Ts

CO2H

CO2H

NTsN

N

H

H

NTsN

NTsN

N

N

O

O

Ts

Ts

+(PhO)2P(O)N3

Et3N, DMF

82%

O

O

BzNHN

O

HO2C

BzNN

O

O

(PhO)2P(O)N3

PySH or PyOHEt3N, DMF 75%

N SH

PySH :

N OHPyOH :

64%13 14

Scheme 5. Cyclic peptides obtained by macrolactamization with DPPA.

Bislactamization shown in Scheme 6 wi l l beconsidered to proceed first intermolecular and thenintramolecular coupling, and no high dilution conditions arerequired.19 Benzoyl-glycyl-L-proline (13) affords thecorresponding diketopiperazine 14 by reaction with DPPA-triethylamine in the co-existence of 2-mercapto- or2-hydroxypyridine (PySH or PyOH),20 shown in Scheme 6.

Scheme 6. Lactamization using DPPA.

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In addition, DPPA proved to be useful for cyclo-dimerizatiom,21 cyclotrimerization,22 and so on, as shownin Scheme 7.

Nishi and co-workers developed a convenientpolymerization method for the preparation of polypeptidesfrom amino acids or monomer peptides which wereunprotected at both N- and C-terminals.23 The DPPAmethod is simple in the work-up, and useful for thesynthesis of sequential polypeptides (Scheme 8).

Scheme 7. Cycloorigomerization using DPPA.

NNHN

SO

NH

N HNS

HN

NO

O

O

O

ON

NHN

SO

NHBocCO2Me

O1) TMSOTf

2) NaOH

3) (PhO)2P(O)N3

K2HPO4, DMF

27% (3 steps)

Ascidiacyclamide

Cyclodimerization21)

N

HN

N

HN

NNH

OO

OOO

O

N

OH2N

CO2H (PhO)2P(O)N3, Et3N

Cyclotrimerization22b)

25%

An ion binding peptide

O

NZNH

CO2Me

NH

HNNH

O

O

O

N

OO

N

N

O

NH

HN

NH HN

ON N

O

O

NO

O

N

O

O

O

DMF

Westiellamide (20%)

1) H2, Pd/C2) NaOH, aq. MeOH

3) (PhO)2P(O)N3

DMF

+

Tetramer (25%)

Cycloorigomerization22c)

Scheme 8. Polymerization of amino acids and peptides using DPPA.

The reaction mechanism of the peptide (or amide)synthesis using DPPA would be as shown in Scheme 9.The carboxylate anion would attack to the phosphorus atomin DPPA to give the acyl phosphates 15 and 16. The acylazide would be formed by SNi type rearrangement of 15 orSN2 type reaction of 16 with the azide anion. Reaction ofthe amine with the acyl phosphates 15 and 16 as well asthe acyl azide 7 would form the amide or peptide bond.

H2NCO2H

HNCO

(PhO)2P(O)N3, Et3N

Me2SOn

H-His-OH Poly-His(PhO)2P(O)N3, Et3N

Me2SO

H-Ser(Bzl)-Arg(Mts)-Arg(Mts)-Arg(Mts)-OH

(Ser(Bzl)-Arg(Mts)-Arg(Mts)-Arg(Mts))n

(PhO)2P(O)N3, Et3N

Me2SO

(ref. 23a)

(ref. 23b)

(ref. 23c)

Each route would respectively contribute more or less, andthe Young racemization test (cf. Scheme 4) was adoptedto find out which route would be predominant. Thus, theacyl phosphate 16 and acyl azide 7 were prepared frombenzoyl-L-leucine (Bz-L-Leu-OH), and reacted with glycineethyl ester (H-Gly-OEt) to check the rate of racemizationand chemical yield. The most favorable result was obtainedby the addition of triethylamine to a mixture of Bz-L-Leu-OH, H-Gly-OEt, and DPPA followed by the reaction in bothracemization rate and chemical yields of the dipeptide, Bz-L-Leu-Gly-OEt, which proved to be superior to the acylphosphate (16) and azide (7) methods. These experimentswould suggest the concerted transition state shown in 17in which 15 is first formed and then the amine will come toreact.1,7a This amide bond formation is the N-acylation ofthe amine as a nucleophile. When the nucleophile isreplaced with the thiol or active methylene anion,

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number 134

S-acylation or C-acylation will occur, as described later. Ifthere is no nucleophile, the reaction will stop at the stageof the acyl azide, which thermally undergoes the Curtiusrearrangement to furnish the isocyanate.

Scheme 9. Reaction mode of DPPA.

R1CO2- + P(OPh)2N3

R1CO2 P(OPh)2

N3

O-

R1CO2P(OPh)2

R1CON3

R1CONu

O

N3

P(OPh)2R1

O O-

NR2

HHNu: Nu:

Nu:

N3-

Nu : R2NHR3, R2SH, Y-CH--Z

15 16

17

7

O

O

5. The Curtius rearrangement using DPPA

Hofmann, Curtius, Schmidt, and Lossen rearrange-ments are well-known as a useful method to convertcarboxylic acids or derivatives to amines or derivativeshaving one less carbon unit, whose key step is the transferof a carbon atom to an electron deficient nitrogen atom.24

DPPA is also quite useful for the Curtius rearrangement(cf. Scheme 2). Carboxylic acids react with DPPA in thepresence of bases such as triethylamine to give acyl azides,which thermally undergo the Curtius rearrangementaccompanied with expulsion of nitrogen. The isocyanate

Scheme 10. The Curtius rearrangement using DPPA.

R1CO2H R1 CO

N N N-

+R1 N C O

R2OHR1NHCO2R2

R2NHR3

H2OR1NH2

(PhO)2P(O)N3

Baseheat

-N2R1NHCON

R3

R2

718

19

20

21

R1CO2H

(PhO)2P(O)N3, Base

R2OH, heat

1) (PhO)2P(O)N3, Base

2) R2OH, heat

Method A

Method BR1NHCO2R2

N NHCO2But

NO2

NHCO2But N

S

O

PhCH2CONHH

NHCO2But

Me NHCO2CH2Ph

O O

73% (Method A) 90% (Method A)80% (Method A)

83% (Method B)

19

The carbamate 19 will be obtained by the one-potprocedure (method A) in which a mixture of carboxylicacids, DPPA, and triethylamine is directly refluxed in asolvent, e.g. tert-butanol, inert to DPPA.1,25 In some cases,addition of alcohols followed by thermal treatment is betterafter the formation of acyl azides, shown in Scheme 11.When alcohols are reactive and will easily react with DPPA,the carbamates will be efficiently prepared by the tworeactions-in-one pot (two-in-one) procedure (method B) inwhich the reaction of carboxylates with DPPA and thermaltreatment are conducted in an inert solvent, and thenalcohols are added to isocyanates. Method B is suitablefor the preparation of ureas and amines.

Scheme 11. Two procedures for the Curtius rearrangement with DPPA.

18 thus formed will react with alcohols, amines, water, andother nucleophiles to produce carbamates 19, ureas 20,amines 21, and so on (Scheme 10). The intermediates,acyl azides or isocyanates, could be isolated if they arethermally stable.

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The application of method A using tert-butanol witha lky lmalon ic ac id ha l f es ters 22 affo rded thecorresponding diesters 23, as shown in Scheme 12. Incontrast, method B in which the half esters 22 were firstconverted to the isocyanates followed by heating the wholemixture after addition of alcohols afforded α-amino acidderivatives, the products by the Curtius rearrangement. Inmethod A, the half esters will first afford the acyl azideswhich will be in equilibrium with the ketenes 25 formed byelimination because of the high acidity of α-hydrogen.Alcohols will irreversibly add to the ketenes 25 to give thediesters 23. The malonic acid half ester 26 which wouldnot undergo the ketene formation, because they have noα -hydrogen, smoothly afforded the α -amino acidderivative 27 by method A.26 The above esterificationusing DPPA commonly occurs in the case of RCH(X)CO2H(X=electron-withdrawing functions such as CO2Et, CN,CONH2, etc.)

Scheme 12. Reaction of ethyl hydrogen malonates with DPPA.

R1CO2Et

CO2H

R1CO2Et

CO2But

R1CO2Et

NHCO2R2

(PhO)2P(O)N3, Et3N

ButOH, heat

1) (PhO)2P(O)N3, Et3N

2) R2OH, heat

R1CO2Et

CO

O

O

CO2EtMe

CO2H

O

O

CO2EtMe

NHCO2But

(PhO)2P(O)N3, Et3N

ButOH, reflux

80%

22

23

24

25

26 27

MeO OMe

CO2HMeO2C

MeO OMe

NHCO2CH2PhMeO2C

1) NaOH

2) (PhO)2P(O)N3

3) PhCH2OH

88%

(CH2)n-1

ButO2C CO2H

(CH2)n-1

ButO2C N=C=OEt3N, benzene

reflux

(CH2)n-1

ButO2C NHCO2R

9-Fluorenylmethanol

toluene, reflux

n = 21, 83%n = 18, 82%n = 15, 88%

R = 9-Fluorenylmethyl

R1 R2

EtO2C CO2H PhCH2OHbenzene, reflux

(PhO)2P(O)N3, Et3N R1 R2

EtO2C N=C=O

(PhO)2P(O)N3

+R1 R2

EtO2C NHCO2Bzl

R1 = R2 = n-Propyl

R1 = R2 = Undecyl

R1 = R2 = -(CH2)14-

68%

0

0

trace

82%

68%

28 29

30 31 32

33 34 35

The analogous α-amino acid synthesis from thecyclopentanedicarboxylic acid 28 efficiently afforded thecarbamate 29 by method B, as shown in Scheme 13.27

However, the reaction with the macrocyclic dicarboxylicderivatives 30 stopped at the isocyanates 31 stage inrefluxing benzene even in the presence of benzyl alcoholdue to the possible steric hindrance.28 The isocyanates 31were stable and could be isolated. Conversion of theisocyanates 31 to the carbamates 32 required moreforcing conditions such as refluxing toluene in thepresence of 9-fluorenylmethanol.

The non-cyclic alkyl malonic acid half ester 33 havingshorter alkyl group such as the propyl function affordedthe carbamate 35 while the half ester 33 having longer alkylside chain, e.g. the undecyl function, stops at the stage ofisocyanate 34 (Scheme 13).

Scheme 13. The Curtius rearrangement of cyclic and dialkyl malonic acid half esters with DPPA.

The urea synthesis from sugar carboxylic acids by theCurtius rearrangement with DPPA smoothly proceeds ingood yields when using triethylamine, a common base, e.g.36+37→38.29 However potassium carbonate proved to bea better base in the carbamate synthesis using alcohols asa nucleophile, as shown in Scheme 14. The addition of acatalytic amount of silver carbonate to triethylamine orpotassium carbonate is often effective to conduct thereaction, e.g. 39+40→ 41.

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Scheme 14. The Curtius rearrangement of sugar carboxylic acids using DPPA.

As an unusual example, the proline derivative 42afforded the allophanate 44 as the main product rather thanthe carbamate 43. However, co-existence of tert-butylcarbamate (45) afforded the carbamate 43 as the majorproduct though racemization occurred (Scheme 15).30

OMPMO

OBn

CO2H

BnO OBn

OHO

OBn

OMe

BnO OBn

OMPMO

OBn

HN

BnO OBn

OO

OBn

OMe

BnO OBnO

(PhO)2P(O)N3 (2 eq)K2CO3 (2 eq)

40 (2 eq)

Ag2CO3 (0.1 eq)benzene, reflux

+

41 : 81%

OMPMO

OBn

CO2H

BnO OBnHN

OBn

OBn

OBn

OBnO

MPMO

OBn

HN

BnO OBn

N

O

(PhO)2P(O)N3 (2 eq)Et3N (2 eq)

37 (1.2 eq)

benzene, reflux+

38 : 87%

OBn

OBn

OBn

OBn

MPM : 4-methoxyphenylmethyl

36

39

Scheme 15. The Curtius rearrangement of carbobenzoxy-L-proline with DPPA.

Anilines, in general, have weak nucleophilicity andcoupling with carboxylic acids does not smoothly proceedto give the corresponding anilides using DPPA. In contrast,anilides will be prepared in good yields by use of a two-in-one procedure: (1) conversion of aromatic carboxylicacids to isocyanates by the DPPA method and then (2)addition of the other carboxylic acids.31 Scheme 16 showsthe preparation of the anilide 48 from tert-butoxycarbonyl-L-leucine (Boc-L-Leu-OH, 47) and 4-nitrobenzoic acid (46).

BocNH CO2H

BocNH

HN

ONO2NO2

HO2C

NO2

N

Et3NCl(CH2)2Cl

(PhO)2P(O)N3C

O

reflux

Cl(CH2)2Cl

46

47

48

NCO2CH2Ph

CO2H

NCO2CH2Ph

NHCO2But NCO2CH2Ph

NHCONHCO2But

NCO2CH2Ph

NHCO2But

(PhO)2P(O)N3, Et3N

ButOH, reflux

(PhO)2P(O)N3, Et3N

H2NCO2But (45)benzene, reflux

+

43 : 5% 44 : 35%

rac-43 : 66%

42

Scheme 16. Preparation of amino acid amides of aromatic amines using DPPA.

Similarly to the above, carboxylic acids are firstconverted to isocyanates using DPPA, and then hydrolysisunder aqueous or acidic conditions affords amines, e.g. 49→ 50.32 In the case of the reaction of the α,β-unsaturatedcarboxylic acid 51 with DPPA, the ketone 53 was obtainedfrom the intermediate acyl azide 52 through thermalrearrangement to the isocyanate and then acidichydrolysis to the amine (Scheme 17).33

NCON3

Me NO

MeN HCl

CO2H

Me(PhO)2P(O)N3, DMAP

Na2CO3, CH2Cl2

53 : 78%

1N HCl

reflux

N

Br

CO2MeMeO2C

CO2H 1) (PhO)2P(O)N3, Et3N

2) H2O71%

N

Br

CO2MeMeO2C

NH2

DMAP : 4-(dimethylamino)pyridine

49 50

51 52

Scheme 17. Preparation of amines and ketones by the Curtius rearrangement with DPPA.

Carboxylic acids having hydroxyl or active methylenefunctions in the same molecules, as shown in Scheme 18,afford the cyclic carbamates, 5434a and 55,34b and thelactam 56 through intramolecular cyclization by use of theDPPA method.

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Scheme 18. Intramolecular cyclization of isocyanates.

The Curtius rearrangement utilizing DPPA proceedsunder mild reaction conditions by simple procedure incomparison with the usual Curtius, Hofmann, Schmidt, andLossen rearrangements. The DPPA method will have awider applicability in synthesis, and will be the first choicein the conversion of carboxylic acids to amines andderivatives having one less carbon.

H

HO2C

O

O

NH

H

(PhO)2P(O)N3, Et3N

toluene, reflux

O65%

HN

OO

CO2H

OHPh

MeH

H

Me

Ph

H

H

(PhO)2P(O)N3, Et3N

benzene, refluxquant.

O

HN O

CO2H

OH

1) (PhO)2P(O)N3, Et3N

2) benzene, reflux high dilution

80%

54

55

56

O

OBocN

O O

OH

TBS

NMe O

OMeNO

ONH

MeO

MePMBOAcS

OMe

+

NMe O

OMeNO

ONH

MeO

MePMBOS

OMe

O

OBocN

O OTBS

80% (2 steps)

HSR2

Et3N, DMFPhCONH COSEt

(PhO)2P(O)N3

1) K2CO3, MeOH

2) (PhO)2P(O)N3

Et3N, CH2Cl2

R1CO2H + R1COSR2 PhCH2CH2COSEt

85%83%

57

58

Bz-L-Leu-SEt Bz-L-Leu-Gly-OEtEt3N, Me3CCO2H (59)

pyridine

Boc-Gly-L-Ala-SEtMe3CCO2H (59)

pyridineBoc-Gly-L-Ala-L-Leu-OBut

Young test using thiol ester

Izumiya test using thiol ester

R1CO2H R1CO2P(O)(OR2) R1COSR2 R2

R1CONR3

R2SH R2NHR3

Biosynthesis of peptide antibiotics

H-L-Leu-OBut+

H-Gly-OEt HCl+

Scheme 19. Preparation of thiol esters using DPPA.

We further found that thiol esters react with amines inthe presence of pivalic acid (59), a bifunctional catalyst, inDMF to give amides or peptides.38 As shown in Scheme20, the react ion proved to proceed without anyracemization (or epimerization) in the Young racemizationtest as well as the Izumiya test. Peptide synthesis fromcarboxylic acids via thiol esters will be the same as thebiosynthesis of peptide antibiotics, and regarded as organicchemical realization of in vivo reactions. Pivalic acid is asort of organic catalysts39 equivalent to enzymes.

Scheme 20. Peptide synthesis from thiol esters.

6. Thiol ester synthesis using DPPA and peptidesynthesis from thiol esters

Thiol esters (thioesters) 57 will be easily obtained byS-acylation of thiols with carboxylic acids using DPPA inthe presence of triethylamine in DMF under similarreaction conditions to the amide or peptide bondformation, as shown in Scheme 19.36 Direct conversion ofcarboxylic acids to thiol esters without the intermediacy ofacid chlorides was first explored by our group in 1974.DEPC can be also used for thiol synthesis. One of therepresentative examples in the application of the DPPAmethod to natural product synthesis will be the synthesisof the thiol ester 58 which is an intermediate in the totalsynthesis of apratoxin A, a macrocyclic depsipeptide.37

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7. Oxazole synthesis by C-acylation

DPPA can be applied to direct C-acylation of activemethylene compounds with carboxylic acids just like S-acylat ion. Treatment of carboxyl ic acids 60 andisocyanoacetic esters 61 with DPPA-base affords oxazolederivatives 62 having ester functions at the C4 position byC-acylation followed by cyclization, as shown in Scheme21.40 The oxazole derivatives 62 undergo acidic hydrolysisto give β-keto-α -amino acid derivatives 63, whosecarbonyl group is reduced to furnish β-hydroxy-α-aminoacid derivatives 64. The C-acylation conveniently proceedsby use of a combination of DPPA and potassiumcarbonate sesquihydrate while use of sodium salts ofisocyanoacetic esters is also effective. No or littleracemization at the α-position was observed in the C-acylation with α-amino or α-oxy acids 60. Utilizing thisseries of reactions as a key step, various amino sugarssuch as prumycin,41a L-daunosamine,41b L-vancosamine,41c

and D-ristosamine41d were conveniently synthesized, andthe synthesis of mugineic acid,41e a phytosiderophone, wasaccomplished by this procedure.41f

R1CHCO2H+

XH2C

N=C:

CO2R2

O:C

N

CHCCO2R2CH

X

R1

HO:C

N

CCCO2R2CH

X

R1

NO

CH CO2R2R1

X

O NH2

CHCCO2R2CH

X

R1

HO NH2

CHCHCO2R2CH

X

R1

(PhO)2P(O)N3

K2CO3 1.5H2O

H+ [H]

DMF

OOH

NH2HO

H-D-Ala-CONH

Prumycin

OOH

H2N

HOO

OH

H2N

HOO

OH

H2N

HO

L-Daunosamine L-Vancosamine D-Ristosamine

N NH

OHHO

CO2H CO2HCO2H

Mugineic acid

CbzNH CO2H

OBut MeO2CCH2N=C:(PhO)2P(O)N3

K2CO3 1.5H2ODMF

NO

CO2MeCbzNH

OBut

62%

MeOCH2O CO2EtNO

CO2MeMeOCH2O

1) LiOH, aq. THF2) (PhO)2P(O)N3, DMF

3) MeO2CCH2N=C: NaH, DMF 70%

O O

HO NH2 HCl

HClMeOH

N CO2H

CO2Bzl BzlO2CCH2N=C:(PhO)2P(O)N3

K2CO3 1.5H2O

DMFNO

CO2BzlN

80%

CO2Bzl

6061

62 63 64

8. Azidation of alcohols and phenols

The conversion of alcohols to azides is quite usefulsince azides can be easily converted to amines by areductive process. Generally, the two step process isemployed to convert alcohols to azides: transformation ofalcohols to halides, mesylates, or tosylates followed byreaction with the azide anion. There are not so manyprocedures of one step conversion of alcohols to azides.The Mitsunobu reaction using DPPA (Bose-Mitsunobumethod)42 and the DPPA-DBU (18-diazabicyclo[5.4.0]-7-undecene) method (Merck method)43 shown in Scheme 22will be representative, and both methods proceed withinversion of configuration to azides 65 or 65'. The Bose-Mitsunobu method util izes safe DPPA in place ofdangerous hydrazoic acid and is useful for the preparationof various azides. However, it is not so easy to removehydrazino esters 67 and phosphine oxides 68 formed inthe reaction. On the other hand, the DBU salt of diphenylphosphate 66 formed in the Merck method is easily removedby washing with water hence work-up after the reaction issimple. In addition, the Merck method proceeds to a lesserextent of racemization than the Bose-Mitsunobu methodfor the substrates which easily racemize.43 However,

Scheme 21. Oxazole synthesis using DPPA.

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number 134

only reactive alcohols such as benzyl type alcohols andα-hydroxycarboxylic acid esters smoothly undergo theazidation by the Merck method. In contrast, a combinationof DBU and bis(p-nitrophenyl) phosphorazidate (p-NO2DPPA, (p-NO2C6H4O)2P(O)N3), which was alsodeveloped by our group,7a proved to be much moreeffective for the azidation of a wide range of alcohols.44

Azidation using both DPPA and p-NO2DPPA will proceedthrough the formation of the phosphate esters followed bySN2 type reaction with the azide anion.

Scheme 22. Azidation of alcohols.

Quinolines, pyridines, and quinazolines 69 having theketo group at the C4 position can be converted to thecorresponding azides 70 in moderate yields by heating at100 °C with DPPA-triethylamine in DMF.45 The reaction willproceed by enolization (phenolization), formation ofphosphate esters, addition of the azide anion, followed byelimination of the phosphate group to give the azides 70,as shown in Scheme 23.

+ ++

NN

CO2EtCO2Et

+ +HNHN

CO2EtCO2Et

+ Ph3P=O+ +

2) Merck method

+

(PhO)2P(O)N3 DBU

(PhO)2P(O)N3 Ph3P

(PhO)2P(O)OH DBU

1) Bose-Mitsunobu method

HO H

R1 R2

H N3

R1 R2

H N3

Ar R

HO H

Ar R

Azidation of alcohols

DBU :

(PhO)2P(O)OH

O

OH

O

N3

Bose-Mitsunobu method91 yield (97.5% ee) 1%

O+

81 yield (82% ee) 6-8%

Merck method

N

N

65 66 6768

65'66 DBU

Scheme 23. Azidation of 4-pyridone derivatives.

NH

O

aromaticsystem

N

N3

(PhO)2P(O)N3

Et3N, DMF100 °C N

HO

N3

N

N3

PhMe

Me

61% 74%

N

N3

55%

S

69 70

9. Synthesis of phosphate esters and

phosphoramidates

Interestingly, the application of the above Merck methodusing DPPA-DBU to 2',3'-O-isopropylidenenucleosides 71furnished not the azides but the phosphate esters 72 atthe C5 position, which were converted to the azides 73 byfurther treatment with sodium azide, as shown in Scheme24.46 The reason why the reaction stops at the phosphateesters step is due to the mild reaction conditions at roomtemperature. Heating in this reaction will cause sidereactions.

Scheme 24. Phosphorylation with DPPA.

Treatment of DPPA with water, butanol, ammonia, andamines affords diphenyl phosphate, butyl diphenylphosphate, diphenyl phosphoramidate, and diphenyl N-alkylphosphoramidate, respectively.47

O

O

O O

(PhO)2P(O)N3

DBU

dioxane

NaN3

15-crown-5

HOBase O

O O

OBase(PhO)2P O

O O

N3Base

Nucleoside : adenosine inosine

quant.quant.

75%61%

71 72 73

12

number 134

10. Ring opening of epoxides using DPPA

The epoxides 74 regioselectively produce β-azidophosphates 75 by the reaction with DPPA in the presenceof 4-(N,N-dimethylamino)pyridine (DMAP) and lithiumperchlorate in DMF.48 The reaction will proceed throughthe formation of the pyridinium azides 76 from DPPA andDMAP followed by the ring opening of the epoxide 74ac t iva ted w i th l i th ium perch lo ra te , g iv ing theβ-azidophosphate 75, as shown in Scheme 25. The α,β-epoxyketone 77 affords the α-azido vinylketone 78 whichwill be formed by elimination of diphenyl phosphate fromthe azido phosphate once generated.

78 : 88%

LiClO4, DMF

O

O

ON3

(PhO)2P(O)N3, DMAPPhO N3

OP(O)(OPh)2

86%

N3

OP(O)(OPh)273%

OR1 R3H R2 (PhO)2P(O)N3

DMAP, LiClO4

N3

OP(O)(OPh)2

R1 R3H R2 OR1 R3

H R2

N3

OP(O)(OPh)2

R1 R3H R2

N+ NMe2(PhO)2P(O)

N NMe2

N3-

(PhO)2P(O)N3

DMAP

DMF

Reaction mechanism

74 75

7674

75

77

CH2(CH2)n-2

O

CH(CH2)n-2

N

(CH2)n-2C

N

N-P(O)(OPh)2H

(CH2)n-2

H

NN

NN

P(O)(OPh)2

(CH2)n-2

H

CO2H

NH

BF3•Et2Otoluenereflux

-N2

n

6 7 81216

76.574756068

ethylene glycolreflux, 24 h

yield (%)

40-48%

1) pyrrolidine, BF3·Et2O2) (PhO)2P(O)N3

3) KOH

O

CO2H

KOH

toluene or EtOAcreflux

(PhO)2P(O)N3

79 80

81 82

Scheme 25. Ring opening of epoxides with DPPA.

11. DPPA as a 1,3-dipole

DPPA works as not only the azide anion equivalentsalready described but also a 1,3-dipole.

We have explored the ring contraction of cyclicenamines 84 using DPPA as a 1,3-dipole.49 Thus, thepyrrolidine enamines 80 obtained from the cyclic ketones79 react with DPPA to give the ring-contracted phosphorylamidines 81 through the 1,3-dipolar cycloaddition followedby ring contraction accompanied with evolution of nitrogen.The phosphoryl amidines 81 are hydrolyzed withpotassium hydroxide to produce the ring-contractedcarboxylic acids 82, as shown in Scheme 26.

Scheme 26. Ring contraction of enamines of cyclic ketones with DPPA.

Analogously, the reaction of DPPA with the pyrrolidineenamines 84 derived from aromatic ketones 83 followedby the alkaline hydrolysis of the resulting phosphorylamidines 85 affords α-alkylarylacetic acids 86 in good yields(Scheme 27).50 Especially, better results are obtained bythe successive treatment without the isolation of anyintermediates. The method will be a general method forthe synthesis of α -alkylarylacetic acids 86 fromalkylarylketones 83. Utilizing this method, nonsteroidalantiinflammatory agents having the α-alkylarylacetic acidskeleton such as rac-naproxen, ibuprofen, ketoprofen, andflurbiprofen can be conveniently synthesized.50c

L’abbé and co-workers first clarified the action of DPPAas a 1,3-dipole,2 and reported that the reaction of DPPAwith carbethoxymethylenetriphenylphosphorane (87)afforded a mixture of ethyl diazoacetate (89) and theiminophosphorane 90. The intermediate would be thetriazoline 88 which undergoes 1,3-dipolar elimination toyield 89 and 90, shown in Scheme 28.

The bicyclic lactams, 2-substituted 2-azabicyclo-[2.2.1]hept-5-en-3-one 91, react with DPPA under highpressure reaction conditions to give two triazolinederivatives 92 and 93 different from each other about theaddition mode.51a Irradiation of a mixture of 92 and 93affords the aziridine derivatives 94. However, heatingunder microwave reaction conditions instead of highpressure directly gives the same aziridines 94, as shownin Scheme 29.51b

13

number 134

Scheme 27. Synthesis of α-arylacetic acids using DPPA.

Scheme 28. Reaction of carbethoxytriphenylphosphorane with DPPA.

Scheme 29. High-pressure and microwave assisted cycloaddition with DPPA.

R1

R2

Ar R1

R2

Ar

NOR2

R1 ArN

NN

NP(O)(OPh)2

ArR1

R2 N P(O)(OPh)2

NCO2H

ArR1

R2

NH

-N2 KOH

MeO

COCH2Me

MeO

CHMe

1) pyrrolidine, BF3•Et2O benzene, reflux2) (PhO)2P(O)N3, THF 85% (2 steps)

rac-Naproxen

3) KOH, ethylene glycol reflux 83%

CHMe

CO2H

CO2H

OCHMe

CO2H

F

CHMe

CO2H

Ibuprofen Ketoprofen Flurbiprofen

(PhO)2P(O)N3

83 84

8586

CH PPh3EtO2C

NN

N P(O)(OPh)2-+

CH

NN

N

PPh3

P(O)(OPh)2

EtO2C

CHN2EtO2C

Ph3P N P(O)(OPh)2

+ +CH2Cl2

rt, 1 day

89 : 84%

90 : 85%

87

88

N

O

R

N

O

R

N

O

BocN

O

BocNNN

NNN(PhO)2P(O)

P(O)(OPh)2

+

N(PhO)2P(O)microwave

(PhO)2P(O)N3

R = Boc980 MPa

92 : 56% 93 : 14%

hν 0 °C, 3 h

toluenert, 7 days

140 °C, 0.5 h

R = Boc : 17%

R = TBS : 61%

45%MeCN

91

94

12. Reaction of DPPA with organometalic reagents

DPPA is useful as a diazo-transter reagent just likeother azides. Reaction of DPPA with the Grignard reagent96 prepared from trimethylsilylmethyl chloride (95) givestrimethylsilyldiazomethane (97), a diazo-transter product,after aqueous work-up, as shown in Scheme 30.52 The othersilyldiazomethanes can be prepared by the sameprocedure.53

MgMe3SiCH2Cl Me3SiCH2MgCl

Me3Si C N Me3SiCHN2H2O

67-70% from DPPA

(PhO)2P(O)N3

H

HN N P(O)(OPh)2

MgCl

95 96

97

Scheme 30. Preparation of trimethylsilyldiazomethane.

Trimethylsilyldiazomethane, now commerciallyavailable, is a stable and safe (“green”) substitute forhazardous and labile diazomethane which should beprepared just before its use. Trimethylsilyldiazomethaneproved to be a useful and versatile synthetic reagents as aC1 unit introducer, a [C-N-N]azole synthon, and analkylidene carbene generator.54

14

number 134

DPPA reacts with aromatic Grignard or lithium reagents98 to give the phosphoryltriazene derivatives 99, whichundergo reduction with a hydride reductant such as lithiumaluminum hydride or sodium bis(2-methoxyethoxy)-aluminum hydride to give aromatic primary amines 100, asshown in Scheme 31.55 Hydrogen chloride in methanolcould be used in place of hydride reductants though withless efficiency.55b This is an amino-transfer reaction in whichDPPA works as a +NH2 synthon. The intermediaryphosphoryltriazenes could be isolated but labile.Consequently, successive reactions will give better results.The method is useful for the preparation of a wide varietyof both aromatic and heteroaromatic primary amines.

Ar-Br

Ar-H

Ar-N=N-N-P(O)(OPh)2

M

Mg

BuLi H- : LiAlH4 or NaAlH2(OCH2CH2OMe)2

Ar-NH2

MeO

NO

MeO

NO

NH21) BuLi, THF, -45 °C, 1.5 h2) (PhO)2P(O)N3, -45 °C, 1 h

67% (3 steps)

H

Et2O or THF

(PhO)2P(O)N3

3) NaAlH2(OCH2CH2OMe)2

-5 °C, 35 min; rt, 1 h

9899

100

H-

[ Ar-M ]

R1

NPh

R2

O

Me

R1

R2

O-Li+

N PhMe

R1

R2

O

N PhMe

P

O-Li+

OPhOPh

N3

:

NR1

R2

Ph

MeN3-

+ R1

R2

N

N3

MePh

N

NPh

Me

R1

R2

Pri2NLi

THF

(PhO)2P(O)N3

- (PhO)2P(O)O-Li+ -N2

R1 = PhCH2, R2 = Et : 82%R1 = R2 = -(CH2)4- : 86%

101 102 103

104 105

106

Scheme 31. Conversion of aromatic organometallics to aromatic amines.

Interestingly, the lithium enolates of N-methylanilidederivatives react with DPPA to give three different typeproducts according to reaction substrates or reaction

Scheme 32. Synthesis of 2H-azirines using DPPA.

RN

PhO

Me

R O-Li+

N PhMe

H

RN

PhO

MeN2

Pri2NLi

THF

(PhO)2P(O)N3

Mechanism 1

R = Ph : 65%R = But : 76%

PO-

PhOPhO

N N N+ R O-Li+

N PhMe

HP

Li+O-

PhOPhO

NN N

H R

O

Ph

Me

PO

PhOPhO

NN N

O-Li+

Ph

Me

RHR

NPh

O

MeN2

(PhO)2PO-Li+

NH+

R O-Li+

N PhMe

H

Mechanism 2

NN

N P(O)(OPh)2-+ N

NN P(O)(OPh)2+

O-

NR

H

PhMe

N2

RNHP(O)(OPh)2

O- N MePh

107 108109

109

110

On the other hand, l ithium enolates 108 fromα-monoalkyl-N-methylacetanilide 107 react with DPPAunder the analogous reaction conditions as above, givingthe α-diazo anilides 109 but not the 2H-azirines 106.56a

conditions. Reaction of DPPA with lithium enolates 102derived from the α ,α-dialkyl-N-methylacetanilides 101affords 2H-azirine derivatives 106.56a The proposedmechanism of the reaction is shown in Scheme 32.The first products by the reaction of DPPA with the enolates102 will be the phosphate 103, from which lithium diphenylphosphate will be eliminated to give the ketenimminiumazides 104. Attack of the azide anion to the ketenimminiumcation will furnish the azide enamines 105, and then finallythe 2H-azirines 106 will be formed by loss of nitrogen andcyclization. The process is a sort of azide-transfer reactionfrom DPPA.

Scheme 33. Diazo-transfer reaction with DPPA.

15

number 134

RN

PhO

Me

R O-Li+

N PhMe

HR

NPh

NH

O

Me

Pri2NLi

THF

1) (PhO)2P(O)N3

2) (Boc)2O THF -78 °C ~ rt

Boc

R = Ph : 80%R = Et : 76%

R O-Li+

N PhMe

HP

Li+O-

PhOPhO

NN N

H R

O

Ph

Me

(PhO)2P(O)N3PO

PhOPhO

NN N-

H R

O

Ph

MeLi+

Boc2OPO

PhOPhO

NN N

H R

O

Ph

MeBoc

POH

PhOPhO

NN N

H R

O

Ph

MeBoc

HOR

NPh

NH

O

MeBoc

107 108111

108 112

111

α-Diazo compounds are also formed from N,N-dimethyl-phenylacetamide, methyl phenylacetate and benzylphenyl ketone though in low yields. The reaction will be adiazo-transfer reaction initiated by attack of the lithiumenolates to the terminal nitrogen of DPPA, or a 1,3-dipolarcycloaddition of the enolates 108 to DPPA by which thetriazolines 110 will be formed, as shown in Scheme 33.

In contrast, the l i th iat ion of α -monoalkyl-N-methylacetanilides 107 and addition of DPPA followed bydi-tert-butyl dicarbonate (Boc2O) furnished α-Boc-aminoderivatives 111 in good yield, as shown in Scheme 34.56b

In this reaction, the lithium enolates 108 will react with DPPAto give the phosphoryltriazene anions 112, to which tert-butoxycarbonylation will occur, and then a fragmentationreaction will give the Boc-amino derivatives 111. DPPA actsas a +NH2 synthon and the amino-transfer reaction occursjust like the reaction of DPPA with the aromatic Grignard orlithium reagents.

Scheme 34. Amination with DPPA.

13. The Staudinger reaction of DPPA

The well-known Staudinger reaction is a formationreaction of iminophosphoranes having a pentavalentphosphorus atom from azides and trivalent phosphoruscompounds. Since the hydrolysis of iminophosphoranesaffords amines, iminophosphoranes are a usefulintermediate for the transformation of azides to amines. Inaddition, they are used for the aza-Wittig reaction withvarious carbonyl compounds. DPPA also reacts withtriphenylphosphine, a representative trivalent phosphoruscompound, to give the iminophosphorane 90, shown inScheme 35.2

Utilizing the Staudinger reaction of DPPA, an efficientconvers ion of a l ly l ic a lcohols to a l ly l ic aminesaccompanied with rearrangement was developed.57 Afterthe reaction of the allylic alcohols 113 with the phospholidine114, the resulting phosphoramidites 115 were successivelytreated with DPPA to give the phospholidines 116, aStaudinger reaction product, in an efficient manner.Treatment of the phospholidines 116 with the palladiumcatalyst PdCl2(MeCN)2 induced the [3,3]-sigmatropicrearrangement to give the phosphoramides 117, which werehydrolyzed with hydrochloric acid to the allylic amines 118.Tosyl azide can be used analogously to DPPA, but the finalhydrolysis products were the tosyl amides.

Scheme 35. Staudinger reaction of DPPA.

R1 R2

OHMeN

PNMe

NMe2

R1

OP

NMeMeN

R1 R2

OP

NMeMeN

R2

N(PhO)2P(O)

R1 R2

OP

NMeMeN

N(PhO)2P(O)R1 R2

NH2

(PhO)2P(O)N3

benzenert

[PdCl2(MeCN)2] (5%) HCl (1M)

THF

(PhO)2P(O) N N N+-

(PhO)2P(O) N N N PPh3-

(PhO)2P(O) N PPh3

N N(PhO)2P(O) N PPh3

+ :PPh3

90

113

114

115 116

117118

CH2Cl2

16

number 134

14. DPPA as a nitrene source

Nitrenes are formed by photolysis of various azides,and DPPA also generates the phosphoryl nitrene 119.58

The nitrene 119 is reactive and undergoes the C-Hinsertion reaction with a variety of hydrocarbons.Cyclohexane (120) used for a solvent reacts with DPPA togive the cyclohexylamine derivative 121, as shown inScheme 36.

Scheme 36. Phosphoryl nitrenes generated from DPPA.

DPPA reacts with styrene derivatives 122 by thecatalytic action of cobalt(II) porphyrin complex (Co(TPP))at 100 °C in chlorobenzene to yield the N-phosphorylatedaziridines 123 in moderate yield.59 As shown in Scheme37, the reaction of DPPA with Co(TPP) affords a cobalt-nitrene intermediate which undergoes the aziridination ofthe styrene derivatives 122. Chlorobenzene is the solventof choice for the aziridination, and the other metals exceptcobalt are not effective at all. Further, it is necessary to use5 equivalents of the styrene derivatives.

(PhO)2P(O)N3

NHP(O)(OPh)2

hν

67%

(PhO)2P(O)N:

119

121

120

Scheme 37. Cobalt-catalyzed aziridination of styrenederivatives with DPPA.

15. Decarbonylation using DPPA

DPPA can be used for the decarbonylation ofaldehydes, which smoothly occurs at room temperature byslow addition of an equivalent amount of DPPA toaldehydes 124 in the presence of a catalytic amount of

R

N N

NN

Ph

Ph

PhPh Co

R

N(PhO)2P(O)N3

Co(TPP) (10 mol%)

PhCl100 °C, overnight

Co(TPP) :

P(O)(OPh)2

(PhO)2P(O)N3

CoIV(TPP)

NP(O)(OPh)2

CoII(TPP)

Ar

Ar

N

P(O)(OPh)2

N2

122 123

122

123

triphenylphosphine rhodium chloride (Rh(PPh3)3Cl) inTHF.60 The decarbonylation will be considered to proceedas shown in Scheme 38: carbon monooxide will migratefrom the aldehydes 124 to the rhodium catalyst and thenDPPA will catch the carbon monooxide from the catalyst togive the isocyanate 125 accompanied with loss ofnitrogen.

Scheme 38. Decarbonylation of aldehydes using DPPA.

16. DPPA analogs

One of the disadvantages of DPPA from the viewpointof green chemistry will be the formation of diphenylphosphate as a waste after reactions using DPPA as anazide equivalent. Thus the polymer-supported DPPA 126was prepared, and the Curtius rearrangement using 126was exploited, as shown in Scheme 39.61 Diphenylphosphate bounded to the polymer will be easilyrecovered, and can be recycled by conversion to the azide126.

R CH2 CHO(PhO)2P(O)N3

Rh(PPh3)3Cl (5 mol%)THF, rt, 22~46 h

R Me

H

O

R RMe

RhPPh3Cl

Ph3P CO

PO

N3PhO

PhO

PO

NCOPhOPhO

RhPPh3Cl

Ph3P L

CHOMe

99%

CHO

See Above

See AboveMe

90%

+ N2

124

125

Scheme 39. Polymer-supported DPPA.

OH O P ClO

OC6H5

O P N3

O

OC6H5

C6H5OP(O)Cl2

Phenol resinNaN3

15-crown-5

Polymer-DPPA126

Et3N

ROH

CO2H

O2N

HN

O2N

OR

O

HN

O2N

HN

ORRNH2

126

17

number 134

As described in the one-pot azidation of alcohols, DPPAis slightly less active and the reaction subtrates will berestricted to active alcohols, while p-NO2DPPA preparedeasily by nitration of DPPA is much more reactive and canbe applied to a wide range of alcohols.44 The futuredevelopment of p-NO2DPPA in organic synthesis will beexpected because it is now commercially available and acrystalline solid more easily usable than oily DPPA.

17. Conclusion

Various reactions using DPPA can be classified by thereaction modes as shown in Figure 2.

Figure 2. Role of DPPA in organic synthesis.

Presumably, the Curtius rearrangement reaction withDPPA wil l be used most frequently. The one-potconversion of alcohols to azides by the Bose-Mitsunobumethod will also be used quite often, especially inlaboratories. Anyway, as you will see here, exploitation ofa new synthetic reagent will open the frontier of syntheticorganic chemistry. Again, according to SciFinder, reactionexamples utilizing DPPA are increasing especially from2000, and there are more than 5,000 examples of the usesof DPPA in 2002, 2004, and 2005. I believe that DPPA willbe used more and more in the future, and that new usefulreactions utilizing DPPA will be developed hereafter.

a) As an azide anion equivalentPhO

PPhO

N

O

N N+ -

PhOP

PhON

O

NN+-

b) As a 1,3-dipole

d) As a nitrenePhO

PPhO

N

O

N N+-

PhOP

PhON

O

N N+-

Rc) As an electrophile -

Role of DPPA Reaction Mode Synthesis & Reactions

N-Acylation (Amide & Peptide Synthesis)Curtius RearrangementO-Acylation of Malonates (Ester Synthesis)S-Acylation (Thiol Ester Synthesis)C-Acylation (Oxazole Synthesis)Azidation of Hydroxyl FunctionsO- & N-PhosphorylationAzide Phosphate Synthesis

Ring ContractionSynthesis of α-Alkylarylacetic Acids1,3-Dipolar EliminationAziridine Synthesis

Diazo-transfer Reactions+NH2 SynthonAzide-transfer ReactionsStaudinger Reactions

C-H Insertion ReactionsAziridine SynthesisDecarbonylation of Aldehydes

Acknowledgements - The author would like to expresshis grateful acknowledgement to the late ProfessorShun-ichi Yamada of the University of Tokyo for generoussupport and encouragement. Thanks are due to ProfessorYasumasa Hamada, now at Chiba University, who playeda central role in many studies of DPPA. The author isindebted to the late Mr. Kunihiro Ninomiya who developedmuch of the early stage DPPA work, and many co-workerswith creativity and invention described in the references.

Finally, the author’s works were financially supportedby Grants-in-Aid for Scientific Research from the Ministryof Education, Culture, Sports, Science, and Technology,Japan and Japan Society for the Promotion of Science, towhom the author’s thanks are due.

References and notes

1. Shioiri, T.; Ninomiya, S.; Yamada, S. J. Am. Chem. Soc. 1972,94, 6203-6205.

2. There is one paper on the use of DPPA before ourpublication,1 but the preparation of DPPA is not described:L’abbé, G.; Ykman, P.; Smets, G. Tetrahedron 1969, 25, 5421-5426.

3. Reviews: a) Shioiri, T.; Yamada, S. J. Synth. Org. Chem.Japan 1973, 31, 666-674. b) Shioiri, T. Ann. Rep. Fac. Pharm.Sci. Nagoya City Univ. 1977, 25, 1-28. c) Shioiri, T. PureChemicals “Daiichi”, 1978, 9, 11-15. d) Thomas, A. V. InEncyclopedia of Reagents for Organic Synthesis, PaquetteL. A., Ed., John Wiley & Sons, Chichester, 1995, 2242-2245.

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4. a) Barton, D. H. R.; Shioiri, T.; Widdowson, D. A. J. Chem.Soc. Chem. Commun. 1970, 939-940. b) Barton, D. H. R.;Shioiri, T.; Widdowson, D. A. J. Chem. Soc. (C), 1971, 1968-1974.

5. a) Shioiri, T.; Yamada, S. Chem. Pharm. Bull. 1974, 22, 849-854. b) Shioiri, T.; Yamada, S. Org. Synth. 1984, 62, 187-188, Coll. Vol. 7, 1990, 206-207

6. a) Shi, E.; Pei, C. Synth. Commun. 2005, 35, 669-673. b)Miyashige, R.; Nakazawa, S.; Hara, K.; Mitsui, O. 1999,JP11029588.

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8. Symbols and abbreviations of amino acids, peptides, and theirderivative will follow the rule by IUPAC-IUB Commission onBiochemical Nomenclature, J. Biol. Chem. 1985, 260, 14. Theconfigurations of chiral amino acids show L-configurationunless otherwise described.

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Introduction of the authors

Takayuki ShioiriAdjunct Professor, Graduate School of Environmental and Human Sciences, Meijo University

Education:B. S. and M. S. University of TokyoPh. D. University of TokyoProfessional Experiences:1962-1977 Assistant Professor, University of Tokyo1968-1970 Postdoctoral Fellow, Professor D. H. R. Barton (1969 Nobel Laureate) at the Imperial College1977 Associate Professor, University of Tokyo1977-2001 Professor, Nagoya City University2001 Emeritus Professor, Nagoya City University2002-2007 Professor, Graduate School of Environmental and Human Sciences, Meijo University1990-2007 Regional executive editor of Tetrahedron2000-2002 President of the Japanese Peptide Society2001-present President of the Japanese Society for Process ChemistryHonor:1974 Pharmaceutical Society of Japan Award for Young Scientists1978 Abbott Prize, Pharmaceutical Society of Japan1981 Aichi Pharmaceutical Association Encouragement Award1993 Pharmaceutical Society of Japan Award1999 Japanese Peptide Society AwardExpertise and Speciality:Organic Synthesis

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(Received July, 2007)

TCI Related Compounds

O P

O

O

N3

CH3 Si CHN2

CH3

CH3

Diphenylphosphoryl Azide (DPPA)

250g, 25, 5g [D1672]Trimethylsilyldiazomethane (ca. 10% in Hexane, ca. 0.60 mol/L)

25ml, 10ml [T1146]