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Home , Curtius rearrangement, Diphenylphosphoryl azide, Sodium azide

number 134

Contribution

Diphenyl Phosphorazidate (DPPA) − More Than Three Decades Later

Takayuki Shioiri Graduate School of Environmental and Human Sciences, Meijo University

1. Introduction my interests were aroused about reactivity of acyl phosphates which are a mixed anhydride from carboxylic More than thirty years have already elapsed since we and phosphoric acids. I synthesized the acyl phosphate 3 introduced diphenyl phosphorazidate (diphenylphosphoryl from benzoic acid (1) and diethyl phosphorochloridate (2) by a known procedure and the reaction of 3 was , DPPA, (PhO)2P(O)N3) as a reagent for in 1972 (Figure 1).1,2 During these years, DPPA investigated. As one of several trials, the reaction with has been found to be effective for a variety of organic azide was found to give benzoyl azide (4), as shown reactions as a versatile synthetic reagent. It is not too much in Scheme 1. Although this reaction proceeded in two steps to say that DPPA has secured an established position as a from benzoic acid (1), I thought that the acyl phosphate 6 reagent. SciFinder will indicate you about 1,000 references would be temporally formed if the phosphorazidate 5 were about DPPA, and there will be found about 46,000 examples used in place of the phosphorochloridate 2, and the acyl of reactions when you will search for DPPA as “Reaction- phosphate 6 would react in situ with the azide giving Reactant”. DPPA is now estimated to be produced over 50 the acyl azide 7. tons per year in Japan and easily available commercially.

This review will first describe why and how the works 2 OEt - + OR 1 on DPPA started and then an overview will be made on the PhCO2H + Cl P R CO2 BH + N3 P utility of DPPA in organic synthesis mainly developed by 1 O OEt O OR3 3 5 our group including recent achievements by other groups. Et3N 2 2 A comprehensive review is not intended, but characteristic OEt OR - + R1CO P + N BH B : Base features of DPPA on organic synthesis will be focused. PhCO2P 2 3 OEt O OR3 3 O 6 2 NaN3 quant. + OR 1 - 2. Why and how has DPPA been developed? R CON3 + BH O P 3 PhCON3 7 O OR 4 I worked about biosynthetic studies of steroids under the supervision of Professor Sir Derek Barton (1969 Nobel Scheme 1. Formation of acyl : practice and hypothesis. laureate) at Imperial College, London, as a postdoctoral fellow during 1968-1970. I experienced there the Wittig reaction to synthesize some substrates for biosynthetic Known diethyl phosphorazidate (8) was thus prepared experiments.4 The Wittig reaction was not described in any and reacted with benzoic acid (1) in the presence of textbooks at that time, and I deeply interested in a triethylamine. The formation of benzoyl azide (4) was behavior of reagents. In addition, before this detected on a TLC plate, and the reaction with experiment, I had a great interest about serendipitous proceeded to give the corresponding 9 and anilide discovery of polyphosphoric acid (PPA) when I learned it 10. Refluxing the mixture in afforded the ethyl from Professor Shigehiko Sugasawa as an undergraduate 11 through the , shown 5a student, which drew my interests to synthetic reagents and in Scheme 2. Further, it was found that the same phosphorus. These experiences and interests led me to carbamate 11 was directly obtained by refluxing a mixture investigate organic reactions utilizing phosphorus of benzoic acid (1), diethyl phosphorazidate (8), and compounds after return to Japan. When I consulted triethylamine in ethanol. However, the yields of the textbooks at that time from biosynthetic viewpoint, I found products were moderate in each case. The rate 1 2 determining step of the reaction was thought to be the stage that acyl phosphates, R CO2P(O)(OR )2, played an important role in biosynthesis of peptides and proteins. Thus of the attack of the carboxylate anion to the phosphorus

PhO + - PhO - + PhO - + PhO + P N NN P N NN P N NN P N NN PhO PhO PhO PhO O O O O -

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

2 number 134 atom of the phosphorazidate. If so, the reaction would temperature for a long time, it might be slowly and partially proceed more efficiently if the phosphorus atom of the hydrolyzed with moisture in air to produce diphenyl phosphorazidate was attached to more electron-withdraw- phosphate and toxic . In this case, ing functions. These experiments and considerations led it will be recommended to use after washing DPPA with me to develop DPPA which has more electron-withdrawing aqueous sodium carbonate followed by drying.5b phenyl group. In fact, DPPA was revealed to be much more efficient in the amide synthesis and Curtius rearrangement. 4. Peptide synthesis using DPPA

BuNH2 PhCONHBu 50% DPPA is useful for amide and peptide bond formation 9 PhCO2H reactions. One of the remained problems in the present 1 Et3N PhNH2 advanced peptide synthesis will be epimerization which PhCON3 PhCONHPh 71% CH Cl 2 2 4 10 occurs to some extent at the stereogenic center in the (EtO)2P(O)N3 EtOH C-terminal amino acids of peptides through activation with 8 PhNHCO2Et 58% reflux 11 the condensing agents during the coupling of the peptide Et3N fragments. There will be no coupling reagents and EtOH, reflux 62% procedures which induce no epimerization. This situation Scheme 2. Reaction of diethyl phosphorazidate with will be quite similar to the coupling of sugars in which α- benzoic acid. and β-isomers could not be separately formed at will. Dare I say it, this will be an old but new problem. DPPA is a coupling reagent with little epimerization (and racemization),1,5a and inactive to the functional groups in 3. Preparation of DPPA and its physical the following amino acids:1,7,8 serine (Ser), threonine (Thr), properties valine (Val), asparagine (Asn), glutamine (Gln), histidine (His), pyroglutamic acid (pGlu), tryptophan (Trp), DPPA is easily prepared in high yield by the reaction methionine (Met), S-benzylcysteine (Cys(Bzl)), nitroarginine of the corresponding chloride 12 with sodium azide in (Arg(NO2)). Thus the peptide synthesis using DPPA will .1,5 Combination of sodium azide and 18-crown-6 proceed without any side reactions for these amino acids. in the same reaction was reported,6a and the use of a DPPA can be used for both liquid- and solid-phase peptide quaternary ammonium as a phase-transfer catalyst in synthesis,9 and dimethylformamide (DMF) is a favorable a biphasic phase of and an organic solvent was also reaction solvent in both cases. In addition, a base such as reported to be effective,6 as shown in Scheme 3. triethylamine is necessary to generate the carboxylate anion from the carboxyl part. A short while after developing DPPA, we introduced

(PhO)2P(O)Cl (PhO)2P(O)N3 diethyl phosphorocyanidate (DEPC, (EtO)2P(O)CN) as 10 12 DPPA another suitable reagent for the peptide bond formation. 5) DEPC proved to be a versatile synthetic reagent quite A. NaN3, acetone, 20-25 ¡C, 21 h (84-89%) 6a) 3b,10 B. NaN3, 18-crown-6, AcOEt, rt, 20-30 min (74%) similar to DPPA. However, DEPC is slightly more + - 6b) C. NaN3, Bu4N Br , cyclohexane-H2O, 20 ¡C, 1 h (94%) active than DPPA and the rate of epimerization (or racemization) will be lower in peptide synthesis. It will be Scheme 3. Preparation of DPPA. superior to DPPA in the construction of linear peptides. Scheme 4 shows the results of the classical Young DPPA is a colorless or pale yellow liquid which boils at racemization test (through the measurement of specific 134-136 °C/0.2 mmHg, and it will be stable at room rotation),1,5a,10a,10b which is said to be the most stringent temperature under shading. It is non-explosive just like the test of racemization, as well as the results of our develop- other phosphorazidate. When DPPA is stored at room ment epimerization test (through HPLC measurement).11

Young racemization test Et3N Bz-L-Leu-OH+ H-Gly-OEt HCl Bz-L/D-Leu-Gly-OEt DMF Yield (%) D-isomer (%)

(PhO)2P(O)N3 83 5.5

(EtO)2P(O)CN 86 4

Epimerization test using HPLC

t H-Pro-OBu , Et3N CF3CO2H Z-Phe-Val-OH Z-Phe-L/D-Val-Pro-OBut Z-Phe-L/D-Val-Pro-OH 0 ¡C, 4 h; rt, 20 h HPLC analysis Yield (%) D-isomer (%)

(PhO)2P(O)N3 86.8 2.2

(EtO)2P(O)CN 87.6 1.4 Scheme 4. Racemization and epimerization tests usin DPPA and DEPC.

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However, Veber and Merck chemists revealed that between 0 °C and room temperature for a longer time (1-3 DPPA was suitable for macrolactamization of linear days).12-18 peptides.12 Since then, DPPA is quite often utilized for the Bislactamization shown in Scheme 6 will be synthesis of macrocyclic peptides by macrolactamization.13 considered to proceed first intermolecular and then High dilution conditions will be required for the intramolecular coupling, and no high dilution conditions are macrolactamization to suppress the intermolecular required.19 Benzoyl-glycyl-L-proline (13) affords the reaction, and sodium hydrogen carbonate is often employed corresponding diketopiperazine 14 by reaction with DPPA- instead of organic bases such as triethylamine. Scheme 5 triethylamine in the co-existence of 2-mercapto- or shows some examples, most of which employed DPPA- 2-hydroxypyridine (PySH or PyOH),20 shown in Scheme 6. NaHCO3 in DMF under high dilution conditions (ca. 5 mM)

OMe OH

Me H N N HN MeN H O O N O O NH O O NH HN O O HN O O O O NMe NH N N Me H NHCbz

12b) Cyclic analog of somatostatin (77%) MeO O O-Methyl deoxybouvardin (58%)14)

OBzl O O HN O I O O H N MeN O NH NBzl HO BzlO2C O NH

HO O K13 precursor (60% in 2 steps)15) Geodiamolide A (34% in 3 steps)16)

O O O O N N O NH O H O HN MeN NH O O N O O HN H NH O 17c) 17e) HO N Antillatoxin (29% and 63% in 2 steps) S Ph

Mollamide precursor18) -NH CO- shows a cyclization point. DPPA, i-Pr2NEt, DMF, 52% (2 steps) Yields are overall ones including deprotection.

Scheme 5. Cyclic peptides obtained by macrolactamization with DPPA.

Ts Ts O CO H H N O 2 N N O N (PhO)2P(O)N3 TsN + NTs TsN NTs Et N, DMF N O N 3 N O N CO H 2 H 82% Ts Ts O

O O BzNH (PhO)2P(O)N3 BzN PySH : PyOH : HO C N N 2 PySH or PyOH O NSH NOH Et3N, DMF 64% 13 14 75%

Scheme 6. Lactamization using DPPA.

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Cyclodimerization21) O S N O O H 1) TMSOTf N N S N 2) NaOH O O N H N NH HN 3) (PhO)2P(O)N3 O CO2Me K2HPO4, DMF N N NHBoc H O 27% (3 steps) S N O

Ascidiacyclamide

Cyclotrimerization22b) H N N O (PhO)2P(O)N3, Et3N O O N N CO H H N 2 HN O O 2 DMF O O 25% NH N

An ion binding peptide

O Cycloorigomerization22c) O N O O H N O NN 1) H2, Pd/C O H N N O N CO2Me 2) NaOH, aq. MeOH ZNH + NH HN 3) (PhO) P(O)N O 2 3 NH HN O O DMF N N N H O O N O O O Westiellamide (20%) Tetramer (25%) Scheme 7. Cycloorigomerization using DPPA.

In addition, DPPA proved to be useful for cyclo- Each route would respectively contribute more or less, and dimerizatiom,21 cyclotrimerization,22 and so on, as shown the Young racemization test (cf. Scheme 4) was adopted in Scheme 7. to find out which route would be predominant. Thus, the Nishi and co-workers developed a convenient acyl phosphate 16 and acyl azide 7 were prepared from polymerization method for the preparation of polypeptides benzoyl-L-leucine (Bz-L-Leu-OH), and reacted with glycine from amino acids or monomer peptides which were ethyl ester (H-Gly-OEt) to check the rate of racemization unprotected at both N- and C-terminals.23 The DPPA and chemical yield. The most favorable result was obtained method is simple in the work-up, and useful for the by the addition of triethylamine to a mixture of Bz-L-Leu- synthesis of sequential polypeptides (Scheme 8). OH, H-Gly-OEt, and DPPA followed by the reaction in both The reaction mechanism of the peptide (or amide) racemization rate and chemical yields of the dipeptide, Bz- synthesis using DPPA would be as shown in Scheme 9. L-Leu-Gly-OEt, which proved to be superior to the acyl The carboxylate anion would attack to the phosphorus atom phosphate (16) and azide (7) methods. These experiments in DPPA to give the acyl phosphates 15 and 16. The acyl would suggest the concerted transition state shown in 17 in which 15 is first formed and then the will come to azide would be formed by SNi type rearrangement of 15 or react.1,7a This amide bond formation is the N-acylation of SN2 type reaction of 16 with the azide anion. Reaction of the amine with the acyl phosphates 15 and 16 as well as the amine as a . When the nucleophile is the acyl azide 7 would form the amide or peptide bond. replaced with the thiol or active methylene anion,

(PhO)2P(O)N3, Et3N CO2H CO (ref. 23a) H2N HN n Me2SO

(PhO)2P(O)N3, Et3N H-His-OH Poly-His (ref. 23b) Me2SO (PhO)2P(O)N3, Et3N H-Ser(Bzl)-Arg(Mts)-Arg(Mts)-Arg(Mts)-OH Me2SO (Ser(Bzl)-Arg(Mts)-Arg(Mts)-Arg(Mts))n (ref. 23c)

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

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1 - R CO2 + N3 P(OPh)2 O

O- 1 1 R CO2 P(OPh)2 R CO2P(OPh)2 15 N3 O 16 - - N3 OO 1 O R CON3 R1 P(OPh) 2 7 2 Nu: R N N3 Nu: Nu : H H R2NHR3, R2SH, Y-CH--Z 17 Nu:

R1CONu

Scheme 9. Reaction mode of DPPA.

S-acylation or C-acylation will occur, as described later. If 18 thus formed will react with , amines, water, and there is no nucleophile, the reaction will stop at the stage other to produce 19, 20, of the acyl azide, which thermally undergoes the Curtius amines 21, and so on (Scheme 10). The intermediates, rearrangement to furnish the . acyl azides or , could be isolated if they are thermally stable. The carbamate 19 will be obtained by the one-pot 5. The Curtius rearrangement using DPPA procedure (method A) in which a mixture of carboxylic acids, DPPA, and triethylamine is directly refluxed in a 1,25 Hofmann, Curtius, Schmidt, and Lossen rearrange- solvent, e.g. tert-butanol, inert to DPPA. In some cases, ments are well-known as a useful method to convert addition of alcohols followed by thermal treatment is better carboxylic acids or derivatives to amines or derivatives after the formation of acyl azides, shown in Scheme 11. having one less carbon unit, whose key step is the transfer When alcohols are reactive and will easily react with DPPA, of a carbon atom to an electron deficient atom.24 the carbamates will be efficiently prepared by the two DPPA is also quite useful for the Curtius rearrangement reactions-in-one pot (two-in-one) procedure (method B) in (cf. Scheme 2). Carboxylic acids react with DPPA in the which the reaction of carboxylates with DPPA and thermal presence of bases such as triethylamine to give acyl azides, treatment are conducted in an inert solvent, and then which thermally undergo the Curtius rearrangement alcohols are added to isocyanates. Method B is suitable accompanied with expulsion of nitrogen. The isocyanate for the preparation of ureas and amines.

R2OH 1 2 R NHCO2R 19 2 3 (PhO)2P(O)N3 + heat R NHR R2 1 R1 C NNN R1 NCO 1 R CO2H R NHCON 3 Base - -N2 R O 18 20 7 H2O 1 R NH2 21 Scheme 10. The Curtius rearrangement using DPPA.

Method A (PhO)2P(O)N3, Base R2OH, heat 1 R1NHCO R2 R CO2H Method B 2 19 1) (PhO)2P(O)N3, Base 2) R2OH, heat

H NO PhCH CONH 2 2 S Me NHCO2CH2Ph OO t t N N NHCO2Bu NHCO2Bu O t NHCO2Bu 73% (Method A) 90% (Method A) 83% (Method B) 80% (Method A)

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

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The application of method A using tert-butanol with However, the reaction with the macrocyclic dicarboxylic alkylmalonic acid half esters 22 afforded the derivatives 30 stopped at the isocyanates 31 stage in corresponding diesters 23, as shown in Scheme 12. In refluxing even in the presence of benzyl contrast, method B in which the half esters 22 were first due to the possible steric hindrance.28 The isocyanates 31 converted to the isocyanates followed by heating the whole were stable and could be isolated. Conversion of the mixture after addition of alcohols afforded α- isocyanates 31 to the carbamates 32 required more derivatives, the products by the Curtius rearrangement. In forcing conditions such as refluxing toluene in the method A, the half esters will first afford the acyl azides presence of 9-fluorenylmethanol. which will be in equilibrium with the ketenes 25 formed by The non-cyclic alkyl malonic acid half ester 33 having elimination because of the high acidity of α-hydrogen. shorter alkyl group such as the propyl function afforded Alcohols will irreversibly add to the ketenes 25 to give the the carbamate 35 while the half ester 33 having longer alkyl diesters 23. The malonic acid half ester 26 which would side chain, e.g. the undecyl function, stops at the stage of not undergo the ketene formation, because they have no isocyanate 34 (Scheme 13). α-hydrogen, smoothly afforded the α-amino acid The synthesis from sugar carboxylic acids by the 26 derivative 27 by method A. The above esterification Curtius rearrangement with DPPA smoothly proceeds in using DPPA commonly occurs in the case of RCH(X)CO2H good yields when using triethylamine, a common base, e.g. 29 (X=electron-withdrawing functions such as CO2Et, CN, 36+37→38. However potassium carbonate proved to be CONH2, etc.) a better base in the carbamate synthesis using alcohols as The analogous α-amino acid synthesis from the a nucleophile, as shown in Scheme 14. The addition of a cyclopentanedicarboxylic acid 28 efficiently afforded the catalytic amount of carbonate to triethylamine or carbamate 29 by method B, as shown in Scheme 13.27 potassium carbonate is often effective to conduct the reaction, e.g. 39+40 → 41.

(PhO)2P(O)N3, Et3N CO2Et CO2Et R1 23 R1 t t C CO2Et Bu OH, heat CO2Bu 1 O R 25 CO2H 1) (PhO)2P(O)N3, Et3N CO2Et 22 R1 24 2 2 2) R OH, heat NHCO2R

Me Me CO2Et CO2Et O (PhO)2P(O)N3, Et3N O t NHCO But O CO2H Bu OH, reflux O 2 2680% 27

Scheme 12. Reaction of ethyl hydrogen malonates with DPPA.

MeO OMe 1) NaOH MeO OMe

2) (PhO)2P(O)N3

3) PhCH2OH MeO C CO H MeO C NHCO CH Ph 2 2 88% 2 2 2 28 29

(CH2)n-1 (CH2)n-1 (CH2)n-1

(PhO)2P(O)N3 9-Fluorenylmethanol

t Et3N, benzene t toluene, reflux t Bu O2CCO2H reflux Bu O2C N=C=O Bu O2C NHCO2R 30 31 32 n = 21, 83% R = 9-Fluorenylmethyl n = 18, 82% n = 15, 88%

1 2 1 2 1 2 R R (PhO)2P(O)N3, Et3N R R R R + EtO2CCO2H PhCH2OH EtO2C N=C=O EtO2C NHCO2Bzl 33 benzene, reflux 34 35

R1 = R2 = n-Propyl trace 68% R1 = R2 = Undecyl 82% 0 1 2 R = R = -(CH2)14- 68% 0

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

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OBn OBn (PhO)2P(O)N3 (2 eq) H O CO2H Et N (2 eq) O N N OBn MPMO 3 MPMO + HN OBn benzene, reflux O BnO OBn BnO OBn OBn OBn OBn OBn OBn OBn 36 37 (1.2 eq) 38 : 87%

(PhO)2P(O)N3 (2 eq) H O OMe O CO2H O OMe K CO (2 eq) O N O MPMO HO 2 3 MPMO + Ag CO (0.1 eq) O BnO OBn BnO OBn BnO OBn 2 3 BnO OBn benzene, reflux OBn OBn OBn OBn 39 40 (2 eq) 41 : 81% MPM : 4-methoxyphenylmethyl

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

(PhO) P(O)N , Et N 2 3 3 t t N NHCO2Bu + N NHCONHCO2Bu ButOH, reflux CO2CH2Ph CO2CH2Ph

N CO2H 43 : 5% 44 : 35%

CO2CH2Ph (PhO)2P(O)N3, Et3N t 42 N NHCO2Bu H NCO But (45) 2 2 CO2CH2Ph benzene, reflux rac-43 : 66%

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

O BocNH CO2H HO2C C 47 H (PhO)2P(O)N3 N N BocNH Cl(CH2)2Cl NO Et3N 2 NO reflux O Cl(CH2)2Cl 2 NO2 46 48

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

MeO2C N CO2Me MeO2C N CO2Me

1) (PhO) P(O)N , Et N CO2H 2 3 3 NH2 Br 2) H2O Br 71% 49 50 Me Me Me N HCl N N (PhO)2P(O)N3, DMAP 1N HCl O CO2H CON3 Na2CO3, CH2Cl2 reflux

51 DMAP : 4-(dimethylamino) 52 53 : 78%

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

As an unusual example, the proline derivative 42 Similarly to the above, carboxylic acids are first afforded the allophanate 44 as the main product rather than converted to isocyanates using DPPA, and then hydrolysis the carbamate 43. However, co-existence of tert-butyl under aqueous or acidic conditions affords amines, e.g. 49 carbamate (45) afforded the carbamate 43 as the major → 50.32 In the case of the reaction of the α,β-unsaturated product though racemization occurred (Scheme 15).30 carboxylic acid 51 with DPPA, the ketone 53 was obtained Anilines, in general, have weak nucleophilicity and from the intermediate acyl azide 52 through thermal coupling with carboxylic acids does not smoothly proceed rearrangement to the isocyanate and then acidic to give the corresponding anilides using DPPA. In contrast, hydrolysis to the amine (Scheme 17).33 anilides will be prepared in good yields by use of a two- Carboxylic acids having hydroxyl or active methylene in-one procedure: (1) conversion of aromatic carboxylic functions in the same molecules, as shown in Scheme 18, acids to isocyanates by the DPPA method and then (2) afford the cyclic carbamates, 5434a and 55,34b and the addition of the other carboxylic acids.31 Scheme 16 shows lactam 56 through intramolecular cyclization by use of the the preparation of the anilide 48 from tert-butoxycarbonyl- DPPA method. L-leucine (Boc-L-Leu-OH, 47) and 4-nitrobenzoic acid (46).

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H H H Me CO H Me N 6. Thiol ester synthesis using DPPA and peptide 2 (PhO)2P(O)N3, Et3N O synthesis from thiol esters benzene, reflux O Ph OH Ph H quant. H 54 Thiol esters (thioesters) 57 will be easily obtained by CO2H H 1) (PhO)2P(O)N3, Et3N N O S-acylation of thiols with carboxylic acids using DPPA in 2) benzene, reflux the presence of triethylamine in DMF under similar O OH high dilution 80% 55 reaction conditions to the amide or peptide bond formation, as shown in Scheme 19.36 Direct conversion of HO2C NH (PhO)2P(O)N3, Et3N carboxylic acids to thiol esters without the intermediacy of H toluene, reflux acid chlorides was first explored by our group in 1974. O 65% H DEPC can be also used for thiol synthesis. One of the O O 56 representative examples in the application of the DPPA Scheme 18. Intramolecular cyclization of isocyanates. method to synthesis will be the synthesis of the thiol ester 58 which is an intermediate in the of apratoxin A, a macrocyclic depsipeptide.37 We further found that thiol esters react with amines in The Curtius rearrangement utilizing DPPA proceeds the presence of pivalic acid (59), a bifunctional catalyst, in under mild reaction conditions by simple procedure in DMF to give amides or peptides.38 As shown in Scheme comparison with the usual Curtius, Hofmann, Schmidt, and 20, the reaction proved to proceed without any Lossen rearrangements. The DPPA method will have a racemization (or epimerization) in the Young racemization wider applicability in synthesis, and will be the first choice test as well as the Izumiya test. Peptide synthesis from in the conversion of carboxylic acids to amines and carboxylic acids via thiol esters will be the same as the derivatives having one less carbon. biosynthesis of peptide antibiotics, and regarded as organic chemical realization of in vivo reactions. Pivalic acid is a sort of organic catalysts39 equivalent to enzymes.

(PhO)2P(O)N3 1 2 1 2 R CO2H +HSR R COSR PhCH2CH2COSEt Et3N, DMF 57 85% PhCONH COSEt 83% OMe

Boc N O TBS O OO O Me O N OMe OH + AcS N N H PMBO Me O Me O

1) K2CO3, MeOH 2) (PhO)2P(O)N3 80% (2 steps) OMe Et3N, CH2Cl2 Boc N O TBS O OO O Me O N OMe S N N H PMBO Me O Me O 58

Scheme 19. Preparation of thiol esters using DPPA.

Young test using thiol ester Et3N, Me3CCO2H (59) Bz-L-Leu-SEt + H-Gly-OEt HCl Bz-L-Leu-Gly-OEt pyridine

Izumiya test using thiol ester Me3CCO2H (59) Boc-Gly-L-Ala-SEt + H-L-Leu-OBut Boc-Gly-L-Ala-L-Leu-OBut pyridine Biosynthesis of peptide antibiotics R2SH R2NHR3 2 1 1 2 1 2 1 R R CO2H R CO P(O)(OR )RCOSR R CON 2 R3

Scheme 20. Peptide synthesis from thiol esters.

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7. Oxazole synthesis by C-acylation 8. Azidation of alcohols and phenols

DPPA can be applied to direct C-acylation of active The conversion of alcohols to azides is quite useful methylene compounds with carboxylic acids just like S- since azides can be easily converted to amines by a acylation. Treatment of carboxylic acids 60 and reductive process. Generally, the two step process is isocyanoacetic esters 61 with DPPA-base affords oxazole employed to convert alcohols to azides: transformation of derivatives 62 having ester functions at the C4 position by alcohols to halides, mesylates, or tosylates followed by C-acylation followed by cyclization, as shown in Scheme reaction with the azide anion. There are not so many 21.40 The oxazole derivatives 62 undergo acidic hydrolysis procedures of one step conversion of alcohols to azides. to give β-keto-α-amino acid derivatives 63, whose The Mitsunobu reaction using DPPA (Bose-Mitsunobu carbonyl group is reduced to furnish β-hydroxy-α-amino method)42 and the DPPA-DBU (18-diazabicyclo[5.4.0]-7- acid derivatives 64. The C-acylation conveniently proceeds undecene) method (Merck method)43 shown in Scheme 22 by use of a combination of DPPA and potassium will be representative, and both methods proceed with carbonate sesquihydrate while use of sodium salts of inversion of configuration to azides 65 or 65'. The Bose- isocyanoacetic esters is also effective. No or little Mitsunobu method utilizes safe DPPA in place of racemization at the α-position was observed in the C- dangerous hydrazoic acid and is useful for the preparation acylation with α-amino or α-oxy acids 60. Utilizing this of various azides. However, it is not so easy to remove series of reactions as a key step, various amino sugars hydrazino esters 67 and oxides 68 formed in such as prumycin,41a L-daunosamine,41b L-vancosamine,41c the reaction. On the other hand, the DBU salt of diphenyl and D-ristosamine41d were conveniently synthesized, and phosphate 66 formed in the Merck method is easily removed the synthesis of mugineic acid,41e a phytosiderophone, was by washing with water hence work-up after the reaction is accomplished by this procedure.41f simple. In addition, the Merck method proceeds to a lesser extent of racemization than the Bose-Mitsunobu method for the substrates which easily racemize.43 However,

R1 R1 2 2 1 CO R2 (PhO) P(O)N CH CO2R CH CO2R R CHCO2H 2 2 3 X X + H2C C CH C C X N=C: K2CO3 1.5H2O 60 O N HO N 61 DMF :C :C

R1 R1 R1 2 2 CH CO2R + CH CO R [H] 2 X H 2 CH CO2R X C CH X CH CH O N O NH2 HO NH2 62 63 64

OBut O MeO2CCH2N=C: OBut H-D-Ala-CONH OH (PhO) P(O)N CO Me 2 3 CbzNH 2 K CO 1.5H O HO NH2 CbzNH CO2H 2 3 2 O N Prumycin DMF 62%

1) LiOH, aq. THF O O 2) (PhO)2P(O)N3, DMF CO2Me HCl MeOCH2O MeOCH2OCO2Et 3) MeO CCH N=C: MeOH 2 2 O N HO NH HCl NaH, DMF 70% 2

O O O HO OH HO OH HO OH

H2N H2N H2N L-Daunosamine L-Vancosamine D-Ristosamine

CO Bzl CO2Bzl CO H 2 BzlO2CCH2N=C: 2 CO2HCO2H (PhO)2P(O)N3 CO2Bzl NCO2H N NNOH K2CO3 1.5H2O H O N HO DMF 80% Mugineic acid

Scheme 21. Oxazole synthesis using DPPA.

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Azidation of alcohols 1) Bose-Mitsunobu method HO H HN N CO2Et 3 HN CO2Et ++(PhO)2P(O)N3 + Ph3P +(PhO)2P(O)OH + + Ph3P=O R1 R2 N CO2Et 1 R2 HN CO2Et R 68 65 66 67 2) Merck method N HO H HN3 + (PhO) P(O)N + DBU + (PhO)2P(O)OH DBU DBU : 2 3 N Ar R Ar R 66 DBU 65'

OH N3

+ O O O

Bose-Mitsunobu method 81 yield (82% ee) 6-8% Merck method 91 yield (97.5% ee) 1%

Scheme 22. Azidation of alcohols.

O N3 N3 N3 N3 Me (PhO)2P(O)N3 S Et N, DMF N 3 N N O N Ph N H 100 ¡C H 69 70 Me 55% aromatic 61% 74% system Scheme 23. Azidation of 4-pyridone derivatives.

only reactive alcohols such as benzyl type alcohols and 9. Synthesis of phosphate esters and α -hydroxycarboxylic acid esters smoothly undergo the phosphoramidates azidation by the Merck method. In contrast, a combination of DBU and bis(p-nitrophenyl) phosphorazidate (p- Interestingly, the application of the above Merck method NO DPPA, (p-NO C H O) P(O)N ), which was also 2 2 6 4 2 3 using DPPA-DBU to 2',3'-O-isopropylidenenucleosides 71 developed by our group,7a proved to be much more furnished not the azides but the phosphate esters 72 at effective for the azidation of a wide range of alcohols.44 the C5 position, which were converted to the azides 73 by Azidation using both DPPA and p-NO DPPA will proceed 2 further treatment with sodium azide, as shown in Scheme through the formation of the phosphate esters followed by 24.46 The reason why the reaction stops at the phosphate S 2 type reaction with the azide anion. N esters step is due to the mild reaction conditions at room Quinolines, , and quinazolines 69 having the temperature. Heating in this reaction will cause side keto group at the C4 position can be converted to the reactions. corresponding azides 70 in moderate yields by heating at Treatment of DPPA with water, butanol, , and 100 °C with DPPA-triethylamine in DMF.45 The reaction will amines affords diphenyl phosphate, butyl diphenyl proceed by enolization (phenolization), formation of phosphate, diphenyl phosphoramidate, and diphenyl N- phosphate esters, addition of the azide anion, followed by alkylphosphoramidate, respectively.47 elimination of the phosphate group to give the azides 70, as shown in Scheme 23.

O

O Base (PhO)2P(O)N3 (PhO) P O Base O Base HO 2 O N DBU NaN3 3 dioxane 15-crown-5 O O O O O O

71 72 73 Nucleoside : adenosine quant. 75% inosine quant. 61%

Scheme 24. Phosphorylation with DPPA.

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Analogously, the reaction of DPPA with the pyrrolidine 10. Ring opening of epoxides using DPPA enamines 84 derived from aromatic ketones 83 followed by the alkaline hydrolysis of the resulting phosphoryl β amidines 85 affords α-alkylarylacetic acids 86 in good yields The epoxides 74 regioselectively produce -azido 50 phosphates 75 by the reaction with DPPA in the presence (Scheme 27). Especially, better results are obtained by of 4-(N,N-dimethylamino)pyridine (DMAP) and lithium the successive treatment without the isolation of any perchlorate in DMF.48 The reaction will proceed through intermediates. The method will be a general method for α the formation of the pyridinium azides 76 from DPPA and the synthesis of -alkylarylacetic acids 86 from DMAP followed by the ring opening of the epoxide 74 alkylarylketones 83. Utilizing this method, nonsteroidal α activated with lithium perchlorate, giving the antiinflammatory agents having the -alkylarylacetic acid β α β skeleton such as rac-naproxen, ibuprofen, ketoprofen, and -azidophosphate 75, as shown in Scheme 25. The , - 50c epoxyketone 77 affords the α-azido vinylketone 78 which flurbiprofen can be conveniently synthesized. will be formed by elimination of diphenyl phosphate from L’abbé and co-workers first clarified the action of DPPA 2 the azido phosphate once generated. as a 1,3-dipole, and reported that the reaction of DPPA with carbethoxymethylenetriphenylphosphorane (87) afforded a mixture of ethyl diazoacetate (89) and the 11. DPPA as a 1,3-dipole iminophosphorane 90. The intermediate would be the triazoline 88 which undergoes 1,3-dipolar elimination to DPPA works as not only the azide anion equivalents yield 89 and 90, shown in Scheme 28. already described but also a 1,3-dipole. The bicyclic lactams, 2-substituted 2-azabicyclo- We have explored the ring contraction of cyclic [2.2.1]hept-5-en-3-one 91, react with DPPA under high 49 enamines 84 using DPPA as a 1,3-dipole. Thus, the pressure reaction conditions to give two triazoline pyrrolidine enamines 80 obtained from the cyclic ketones derivatives 92 and 93 different from each other about the 79 react with DPPA to give the ring-contracted phosphoryl addition mode.51a Irradiation of a mixture of 92 and 93 amidines 81 through the 1,3-dipolar cycloaddition followed affords the aziridine derivatives 94. However, heating by ring contraction accompanied with evolution of nitrogen. under microwave reaction conditions instead of high The phosphoryl amidines 81 are hydrolyzed with pressure directly gives the same 94, as shown potassium hydroxide to produce the ring-contracted in Scheme 29.51b carboxylic acids 82, as shown in Scheme 26.

Reaction mechanism 2 HR + (PhO)2P(O) N NMe2 1 3 N3 R R - HR2 (PhO)2P(O)N3 HR2 O N3 1 3 1 3 74 76 R R DMAP, LiClO4 R R O N DMF OP(O)(OPh)2 HR3 2 74 75 R1 R3 (PhO) P(O)N N NMe2 2 3 OP(O)(OPh)2 75 DMAP

N3 O O OP(O)(OPh)2 (PhO)2P(O)N3, DMAP N PhO N 3 3 OP(O)(OPh) 2 LiClO , DMF 86% 73% O 4 77 78 : 88%

Scheme 25. Ring opening of epoxides with DPPA.

N (PhO) P(O)N N P(O)(OPh)2 O H N 2 3 N (CH2)n-2 (CH2)n-2 (CH2)n-2 N CH2 BF3¥Et2O CH toluene or EtOAc N toluene reflux H 79 reflux 80 n yield (%)

N 6 76.5 -N 2 C 7 74 KOH CO2H (CH2)n-2 N-P(O)(OPh)2 8 75 (CH2)n-2 H 12 60 ethylene glycol H 16 68 reflux, 24 h 81 82

O 1) pyrrolidine, BF3áEt2O 2) (PhO)2P(O)N3 CO2H 3) KOH 40-48%

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

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N 1 1 1 R R Ar H R Ar (PhO)2P(O)N3 Ar R2 N 2 2 R O R N N N 83 84 N P(O)(OPh)2

-N2 Ar KOH Ar N 1 1 R CO2H R 2 2 R R N P(O)(OPh)2 86 85

1) pyrrolidine, BF3¥Et2O benzene, reflux Me 2) (PhO)2P(O)N3, THF COCH2Me 85% (2 steps) CH CO2H MeO 3) KOH, ethylene glycol MeO reflux rac-Naproxen 83%

O Me F Me Me CH CH CO2H CO2H CH CO2H

Ibuprofen Ketoprofen Flurbiprofen

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

EtO2C CHN2 EtO C CH PPh 89 : 84% 2 3 87 CH2Cl2 EtO2C CH PPh3 + + + - rt, 1 day N N P(O)(OPh)2 N N P(O)(OPh) N 2 Ph3P N P(O)(OPh)2 N 88 90 : 85% Scheme 28. Reaction of carbethoxytriphenylphosphorane with DPPA.

P(O)(OPh)2 R = Boc N Boc N Boc 980 MPa N N N + N N N toluene (PhO)2P(O) rt, 7 days O 92 : 56% 93 : 14% O R ν 0 ¡C, 3 h N (PhO)2P(O)N3 h MeCN 45% O R 91 microwave (PhO)2P(O) N N 140 ¡C, 0.5 h O R = Boc : 17% 94 R = TBS : 61% Scheme 29. High-pressure and microwave assisted cycloaddition with DPPA.

12. Reaction of DPPA with organometalic reagents

DPPA is useful as a diazo-transter reagent just like other azides. Reaction of DPPA with the Grignard reagent

96 prepared from trimethylsilylmethyl chloride (95) gives Mg (PhO)2P(O)N3 trimethylsilyldiazomethane (97), a diazo-transter product, Me3SiCH2Cl Me3SiCH2MgCl after aqueous work-up, as shown in Scheme 30.52 The other 95 96 H silyldiazomethanes can be prepared by the same H2O Me Si C N N N P(O)(OPh) Me3SiCHN2 procedure.53 3 2 H MgCl 97 Trimethylsilyldiazomethane, now commercially 67-70% from DPPA available, is a stable and safe (“green”) substitute for hazardous and labile diazomethane which should be Scheme 30. Preparation of trimethylsilyldiazomethane. prepared just before its use. Trimethylsilyldiazomethane proved to be a useful and versatile synthetic reagents as a C1 unit introducer, a [C-N-N]azole synthon, and an alkylidene carbene generator.54

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Ar-Br Mg - (PhO)2P(O)N3 H [ Ar-M ] Ar-N=N-N-P(O)(OPh)2 Ar-NH2 Et O or THF 98 2 M 100 - BuLi 99 H : LiAlH4 or Ar-H NaAlH2(OCH2CH2OMe)2

MeO MeO 1) BuLi, THF, -45 ¡C, 1.5 h H NH2 2) (PhO)2P(O)N3, -45 ¡C, 1 h

O 3) NaAlH2(OCH2CH2OMe)2 O N -5 ¡C, 35 min; rt, 1 h N

67% (3 steps) Scheme 31. Conversion of aromatic organometallics to aromatic amines.

O-Li+ OPh O i 1 - + 1 O P OPh Pr 2NLi R O Li (PhO)2P(O)N3 R R1 Ph N3 N THF R2 NPh R2 2 :NPh R Me Me 101 102 103 Me Ph 1 - + 1 1 R Ph - (PhO)2P(O)O Li R + Ph R N Me -N2 N N R2 Me 2 R2 Me N - R N3 3 N 104 105 1 2 R = PhCH2, R = Et : 82% 106 1 2 R = R = -(CH2)4- : 86% Scheme 32. Synthesis of 2H-azirines using DPPA.

O O i - + Pr 2NLi ROLi (PhO)2P(O)N3 R Ph R Ph N N THF H NPh N2 Me Me Me 107 108 R = Ph : 65% 109 R = But : 76% Mechanism 1

+ - O- Li O +RO-Li+ HRPh PhO P NNN PhO P N NN Me PhO H NPh PhO Me O O H R Ph O PhO P N R Ph - + N + (PhO)2PO Li PhO NN Me NH O-Li+ N2 Me 109 Mechanism 2 - + Ph ROLi R O- Ph N Me - H NPh H O NMe R + Me N N P(O)(OPh) NH + 2 - N N P(O)(OPh) N N P(O)(OPh)2 2 2 N 110 Scheme 33. Diazo-transfer reaction with DPPA.

DPPA reacts with aromatic Grignard or lithium reagents conditions. Reaction of DPPA with lithium enolates 102 98 to give the phosphoryltriazene derivatives 99, which derived from the α,α-dialkyl-N-methylacetanilides 101 undergo reduction with a hydride reductant such as lithium affords 2H-azirine derivatives 106.56a The proposed aluminum hydride or sodium bis(2-methoxyethoxy)- mechanism of the reaction is shown in Scheme 32. aluminum hydride to give aromatic primary amines 100, as The first products by the reaction of DPPA with the enolates shown in Scheme 31.55 Hydrogen chloride in 102 will be the phosphate 103, from which lithium diphenyl could be used in place of hydride reductants though with phosphate will be eliminated to give the ketenimminium less efficiency.55b This is an amino-transfer reaction in which azides 104. Attack of the azide anion to the ketenimminium + DPPA works as a NH2 synthon. The intermediary cation will furnish the azide enamines 105, and then finally phosphoryltriazenes could be isolated but labile. the 2H-azirines 106 will be formed by loss of nitrogen and Consequently, successive reactions will give better results. cyclization. The process is a sort of azide-transfer reaction The method is useful for the preparation of a wide variety from DPPA. of both aromatic and heteroaromatic primary amines. On the other hand, lithium enolates 108 from Interestingly, the lithium enolates of N-methylanilide α-monoalkyl-N-methylacetanilide 107 react with DPPA derivatives react with DPPA to give three different type under the analogous reaction conditions as above, giving products according to reaction substrates or reaction the α-diazo anilides 109 but not the 2H-azirines 106.56a

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O i - + O Pr 2NLi ROLi 1) (PhO)2P(O)N3 R Ph R Ph N N THF H NPh2) (Boc)2O Me Boc NH Me 107 108 Me THF -78 ¡C ~ rt 111 R = Ph : 80% R = Et : 76%

+ - - + Li O Ph O ROLi (PhO)2P(O)N3 HR HRPh PhO P N PhO P N H NPh NN Me NN- Me PhO PhO + Me O Li O 108 112 O O Ph HO OH HRPh Boc2O HR R Ph PhO P N PhO P N N NN Me NN Me PhO PhO Boc NH Me Boc O Boc O 111

Scheme 34. Amination with DPPA.

α-Diazo compounds are also formed from N,N-dimethyl- 13. The of DPPA phenylacetamide, methyl phenylacetate and benzyl phenyl ketone though in low yields. The reaction will be a The well-known Staudinger reaction is a formation diazo-transfer reaction initiated by attack of the lithium reaction of iminophosphoranes having a pentavalent enolates to the terminal nitrogen of DPPA, or a 1,3-dipolar phosphorus atom from azides and trivalent phosphorus cycloaddition of the enolates 108 to DPPA by which the compounds. Since the hydrolysis of iminophosphoranes triazolines 110 will be formed, as shown in Scheme 33. affords amines, iminophosphoranes are a useful α In contrast, the lithiation of -monoalkyl-N- intermediate for the transformation of azides to amines. In methylacetanilides 107 and addition of DPPA followed by addition, they are used for the aza-Wittig reaction with α di-tert-butyl dicarbonate (Boc2O) furnished -Boc-amino 56b various carbonyl compounds. DPPA also reacts with derivatives 111 in good yield, as shown in Scheme 34. , a representative trivalent phosphorus In this reaction, the lithium enolates 108 will react with DPPA compound, to give the iminophosphorane 90, shown in to give the phosphoryltriazene anions 112, to which tert- Scheme 35.2 butoxycarbonylation will occur, and then a fragmentation Utilizing the Staudinger reaction of DPPA, an efficient reaction will give the Boc-amino derivatives 111. DPPA acts conversion of allylic alcohols to allylic amines as a +NH synthon and the amino-transfer reaction occurs 2 accompanied with rearrangement was developed.57 After just like the reaction of DPPA with the aromatic Grignard or the reaction of the allylic alcohols 113 with the phospholidine lithium reagents. 114, the resulting phosphoramidites 115 were successively treated with DPPA to give the phospholidines 116, a Staudinger reaction product, in an efficient manner. Treatment of the phospholidines 116 with the palladium catalyst PdCl2(MeCN)2 induced the [3,3]-sigmatropic rearrangement to give the phosphoramides 117, which were hydrolyzed with hydrochloric acid to the allylic amines 118. Tosyl azide can be used analogously to DPPA, but the final hydrolysis products were the tosyl amides.

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

(PhO)2P(O) N PPh3 (PhO)2P(O) N PPh3 NN 90

MeN NMe P OH MeN NMe MeN NMe 114 NMe2 P (PhO)2P(O)N3 P 1 2 O (PhO) P(O) N O R R benzene 2 113 rt R1 R2 R1 R2 115 116

MeN NMe NH2 [PdCl2(MeCN)2] (5%)P HCl (1M) (PhO)2P(O) N O CH Cl THF R1 R2 2 2 1 2 R R 118 117

Scheme 35. Staudinger reaction of DPPA.

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triphenylphosphine rhodium chloride (Rh(PPh3)3Cl) in 60 14. DPPA as a source THF. The decarbonylation will be considered to proceed as shown in Scheme 38: carbon monooxide will migrate are formed by photolysis of various azides, from the aldehydes 124 to the rhodium catalyst and then and DPPA also generates the phosphoryl nitrene 119.58 DPPA will catch the carbon monooxide from the catalyst to The nitrene 119 is reactive and undergoes the C-H give the isocyanate 125 accompanied with loss of insertion reaction with a variety of hydrocarbons. nitrogen. Cyclohexane (120) used for a solvent reacts with DPPA to give the cyclohexylamine derivative 121, as shown in (PhO)2P(O)N3 Scheme 36. RCH2 CHO RMe Rh(PPh ) Cl (5 mol%) 124 3 3 THF, rt, 22~46 h hν (PhO)2P(O)N3 (PhO)2P(O)N: 119 CHO See Above Me 120 99% NHP(O)(OPh)2 67% 121 CHO Me Scheme 36. Phosphoryl nitrenes generated from DPPA. See Above

90% DPPA reacts with styrene derivatives 122 by the O catalytic action of cobalt(II) porphyrin complex (Co(TPP)) R Me R at 100 °C in chlorobenzene to yield the N-phosphorylated H aziridines 123 in moderate yield.59 As shown in Scheme Ph3PCO Ph3PL 37, the reaction of DPPA with Co(TPP) affords a cobalt- Rh Rh Cl PPh Cl PPh nitrene intermediate which undergoes the aziridination of 3 3 the styrene derivatives 122. Chlorobenzene is the solvent O O PhO P PhO P of choice for the aziridination, and the other metals except N3 NCO + N2 PhO PhO cobalt are not effective at all. Further, it is necessary to use 125 5 equivalents of the styrene derivatives. Scheme 38. Decarbonylation of aldehydes using DPPA.

P(O)(OPh)2 (PhO)2P(O)N3 Co(TPP) (10 mol%) N R 16. DPPA analogs PhCl R 122 100 ¡C, overnight 123 One of the disadvantages of DPPA from the viewpoint P(O)(OPh)2 N of green chemistry will be the formation of diphenyl II (PhO)2P(O)N3 Co (TPP) phosphate as a waste after reactions using DPPA as an Ar 123 azide equivalent. Thus the polymer-supported DPPA 126 P(O)(OPh)2 was prepared, and the Curtius rearrangement using 126 N N2 Ar 61 122 was exploited, as shown in Scheme 39. Diphenyl CoIV(TPP) phosphate bounded to the polymer will be easily recovered, and can be recycled by conversion to the azide Co(TPP) : Ph 126.

NN Co Ph Ph O C6H5OP(O)Cl2 N N OH OPCl

OC6H5 Phenol resin O Ph NaN3 OPN3 15-crown-5 Scheme 37. Cobalt-catalyzed aziridination of styrene OC6H5 derivatives with DPPA. 126

H N OR ROH Polymer-DPPA 15. Decarbonylation using DPPA CO2H O 126 O2N Et N H H O N 3 N N DPPA can be used for the decarbonylation of 2 RNH2 R aldehydes, which smoothly occurs at room temperature by O O2N slow addition of an equivalent amount of DPPA to aldehydes 124 in the presence of a catalytic amount of Scheme 39. Polymer-supported DPPA.

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Role of DPPA Reaction Mode Synthesis & Reactions

N-Acylation (Amide & Peptide Synthesis) Curtius Rearrangement O-Acylation of Malonates (Ester Synthesis) PhO + - S-Acylation (Thiol Ester Synthesis) a) As an azide anion equivalent P N NN C-Acylation (Oxazole Synthesis) PhO O Azidation of Hydroxyl Functions O- & N-Phosphorylation Azide Phosphate Synthesis

Ring Contraction PhO N Synthesis of α-Alkylarylacetic Acids b) As a 1,3-dipole P N N PhO - + 1,3-Dipolar Elimination O Aziridine Synthesis

Diazo-transfer Reactions + PhO - + - NH2 Synthon c) As an electrophile P N NN R PhO Azide-transfer Reactions O Staudinger Reactions

C-H Insertion Reactions PhO - + d) As a nitrene P N NN Aziridine Synthesis PhO O Decarbonylation of Aldehydes

Figure 2. Role of DPPA in organic synthesis.

As described in the one-pot azidation of alcohols, DPPA Acknowledgements - The author would like to express is slightly less active and the reaction subtrates will be his grateful acknowledgement to the late Professor restricted to active alcohols, while p-NO2DPPA prepared Shun-ichi Yamada of the University of Tokyo for generous easily by nitration of DPPA is much more reactive and can support and encouragement. Thanks are due to Professor be applied to a wide range of alcohols.44 The future Yasumasa Hamada, now at Chiba University, who played development of p-NO2DPPA in organic synthesis will be a central role in many studies of DPPA. The author is expected because it is now commercially available and a indebted to the late Mr. Kunihiro Ninomiya who developed crystalline solid more easily usable than oily DPPA. much of the early stage DPPA work, and many co-workers with creativity and invention described in the references. Finally, the author’s works were financially supported 17. Conclusion by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology, Japan and Japan Society for the Promotion of Science, to Various reactions using DPPA can be classified by the whom the author’s thanks are due. reaction modes as shown in Figure 2. Presumably, the Curtius with DPPA will be used most frequently. The one-pot conversion of alcohols to azides by the Bose-Mitsunobu References and notes method will also be used quite often, especially in laboratories. Anyway, as you will see here, exploitation of 1. Shioiri, T.; Ninomiya, S.; Yamada, S. J. Am. Chem. Soc. 1972, a new synthetic reagent will open the frontier of synthetic 94, 6203-6205. organic chemistry. Again, according to SciFinder, reaction 2. There is one paper on the use of DPPA before our examples utilizing DPPA are increasing especially from publication,1 but the preparation of DPPA is not described: 2000, and there are more than 5,000 examples of the uses L’abbé, G.; Ykman, P.; Smets, G. Tetrahedron 1969, 25, 5421- 5426. of DPPA in 2002, 2004, and 2005. I believe that DPPA will 3. Reviews: a) Shioiri, T.; Yamada, S. J. Synth. Org. Chem. be used more and more in the future, and that new useful Japan 1973, 31, 666-674. b) Shioiri, T. Ann. Rep. Fac. Pharm. reactions utilizing DPPA will be developed hereafter. Sci. Nagoya City Univ. 1977, 25, 1-28. c) Shioiri, T. Pure Chemicals “Daiichi”, 1978, 9, 11-15. d) Thomas, A. V. In Encyclopedia of Reagents for Organic Synthesis, Paquette L. 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. 25. Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30, Soc. Chem. Commun. 1970, 939-940. b) Barton, D. H. R.; 2151-2157. Shioiri, T.; Widdowson, D. A. J. Chem. Soc. (C), 1971, 1968- 26. a) Yamada, S.; Ninomiya, K.; Shioiri, T. Tetrahedron Lett. 1973, 1974. 14, 2343-2346. b) Ninomiya, K.; Shioiri, T.; Yamada, S. Chem. 5. a) Shioiri, T.; Yamada, S. Chem. Pharm. Bull. 1974, 22, 849- Pharm. Bull. 1974, 22, 1398-1404. c) Ninomiya, K.; Shioiri, 854. b) Shioiri, T.; Yamada, S. Org. Synth. 1984, 62, 187- T.; Yamada, S. Chem. Pharm. Bull. 1974, 22, 1795-1799. 188, Coll. Vol. 7, 1990, 206-207 27. Tanaka, M.; Demizu, Y.; Doi, M.; Kurihara, M.; Suemune, H. 6. a) Shi, E.; Pei, C. Synth. Commun. 2005, 35, 669-673. b) Angew. Chem. Int. Ed. 2004, 43, 5360-5363. Miyashige, R.; Nakazawa, S.; Hara, K.; Mitsui, O. 1999, 28. Ohwada, T.; Kojima, D.; Kiwada, T.; Futaki, S.; Sugiura, Y.; JP11029588. Yamaguchi, K.; Nishi, Y.; Kobayashi, Y. Chem. Eur. J. 2004, 7. a) Shioiri, T.; Yamada, S. Chem. Pharm. Bull. 1974, 22, 855- 10, 617-626. 858. b) Shioiri, T.; Yamada, S. Chem. Pharm. Bull. 1974, 22, 29. Sawada, D.; Sasayama, S.; Takahashi, H.; Ikegami, S. 859-863. Tetrahedron Lett. 2006, 47, 7219-7223. 8. Symbols and abbreviations of amino acids, peptides, and their 30. Murato, K.; Shioiri, T.; Yamada, S. Chem. Pharm. Bull. 1975, derivative will follow the rule by IUPAC-IUB Commission on 23, 1738-1740. cf. Yamada, S.; Murato, K.; Shioiri, T. Biochemical Nomenclature, J. Biol. Chem. 1985, 260, 14. The Tetrahedron Lett. 1976, 17, 1605-1608 and Murato, K.; Shioiri, configurations of chiral amino acids show L-configuration T.; Yamada, S. Chem. Pharm. Bull. 1977, 25, 1559-1565. unless otherwise described. 31. Shioiri, T.; Murata, M.; Hamada, Y. Chem. Pharm. Bull. 1987, 9. a) Yamada, S.; Ikota, N.; Shioiri, T.; Tachibana, S. J. Am. Chem. 35, 2698-2704. 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(Received July, 2007)

Introduction of the authors

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

Education: B. S. and M. S. University of Tokyo Ph. D. University of Tokyo Professional Experiences: 1962-1977 Assistant Professor, University of Tokyo 1968-1970 Postdoctoral Fellow, Professor D. H. R. Barton (1969 Nobel Laureate) at the Imperial College 1977 Associate Professor, University of Tokyo 1977-2001 Professor, Nagoya City University 2001 Emeritus Professor, Nagoya City University 2002-2007 Professor, Graduate School of Environmental and Human Sciences, Meijo University 1990-2007 Regional executive editor of Tetrahedron 2000-2002 President of the Japanese Peptide Society 2001-present President of the Japanese Society for Process Chemistry Honor: 1974 Pharmaceutical Society of Japan Award for Young Scientists 1978 Abbott Prize, Pharmaceutical Society of Japan 1981 Aichi Pharmaceutical Association Encouragement Award 1993 Pharmaceutical Society of Japan Award 1999 Japanese Peptide Society Award Expertise and Speciality: Organic Synthesis

TCI Related Compounds

O CH3

OPO CH3 Si CHN2

N3 CH3

Diphenylphosphoryl Azide (DPPA) Trimethylsilyldiazomethane 250g, 25, 5g [D1672] (ca. 10% in , ca. 0.60 mol/L) 25ml, 10ml [T1146]

19