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 we
introduced diphenyl phosphorazidate (diphenylphosphoryl
azide, DPPA, (PhO) 2P(O)N 3) as a reagent for organic
synthesis in 1972 (Figure 1).1,2 During these years, DPPA
has been found to be effective for a variety of organic
reactions as a versatile synthetic reagent. It is not too much
to say that DPPA has secured an established position as a
reagent. SciFinder will indicate you about 1,000 references
about DPPA, and there will be found about 46,000 examples
of reactions when you will search for DPPA as “ReactionReactant”. DPPA is now estimated to be produced over 50
tons per year in Japan and easily available commercially.
This review will first describe why and how the works
on DPPA started and then an overview will be made on the
utility of DPPA in organic synthesis mainly developed by
our group including recent achievements by other groups.3
A comprehensive review is not intended, but characteristic
features of DPPA on organic synthesis will be focused.
my interests were aroused about reactivity of acyl
phosphates which are a mixed anhydride from carboxylic
and phosphoric acids. I synthesized the acyl phosphate 3
from benzoic acid (1) and diethyl phosphorochloridate (2)
by a known procedure and the reaction of 3 was
investigated. As one of several trials, the reaction with
sodium azide was found to give benzoyl azide (4), as shown
in Scheme 1. Although this reaction proceeded in two steps
from benzoic acid (1), I thought that the acyl phosphate 6
would be temporally formed if the phosphorazidate 5 were
used in place of the phosphorochloridate 2, and the acyl
phosphate 6 would react in situ with the azide ion giving
the acyl azide 7.
OR2
-+
R1CO2 BH + N3 P
O OR3
5
OEt
PhCO2H + Cl P
O OEt
1
2
Et3N
OR2
+
R1CO2P
O OR3
6
OEt
PhCO2P
O OEt
3
NaN3 quant.
R1CON3
2. Why and how has DPPA been developed?
I worked about biosynthetic studies of steroids under
the supervision of Professor Sir Derek Barton (1969 Nobel
laureate) at Imperial College, London, as a postdoctoral
fellow during 1968-1970. I experienced there the Wittig
reaction to synthesize some substrates for biosynthetic
experiments.4 The Wittig reaction was not described in any
textbooks at that time, and I deeply interested in a
behavior of phosphorus reagents. In addition, before this
experiment, I had a great interest about serendipitous
discovery of polyphosphoric acid (PPA) when I learned it
from Professor Shigehiko Sugasawa as an undergraduate
student, which drew my interests to synthetic reagents and
phosphorus. These experiences and interests led me to
investigate organic reactions utilizing phosphorus
compounds after return to Japan. When I consulted
textbooks at that time from biosynthetic viewpoint, I found
that acyl phosphates, R 1 CO 2 P(O)(OR 2 ) 2 , played an
important role in biosynthesis of peptides and proteins. Thus
PhO
PhO
+ P N N N
O
PhO
PhO
- +
P N N N
O
PhCON3
7
B : Base
OR2
BH O P
O OR3
+ -
4
Scheme 1. Formation of acyl azides: practice and hypothesis.
Known diethyl phosphorazidate (8) was thus prepared
and reacted with benzoic acid (1) in the presence of
triethylamine. The formation of benzoyl azide (4) was
detected on a TLC plate, and the reaction with amines
proceeded to give the corresponding amide 9 and anilide
10. Refluxing the mixture in ethanol afforded the ethyl
carbamate 11 through the Curtius rearrangement, shown
in Scheme 2. 5a Further, it was found that the same
carbamate 11 was directly obtained by refluxing a mixture
of benzoic acid (1), diethyl phosphorazidate (8), and
triethylamine in ethanol. However, the yields of the
products were moderate in each case. The rate
determining step of the reaction was thought to be the stage
of the attack of the carboxylate anion to the phosphorus
PhO
PhO
+
P N N N
O
PhO
+
P N N N
PhO
O-
Figure 1. Resonance structures of diphenyl phosphorazidate (DPPA).
2
+
-+
N3 BH
number 134
atom of the phosphorazidate. If so, the reaction would
proceed more efficiently if the phosphorus atom of the
phosphorazidate was attached to more electron-withdrawing functions. These experiments and considerations led
me to develop DPPA which has more electron-withdrawing
phenyl group. In fact, DPPA was revealed to be much more
efficient in the amide synthesis and Curtius rearrangement.
temperature for a long time, it might be slowly and partially
hydrolyzed with moisture in air to produce diphenyl
phosphate and toxic explosive hydrazoic acid. In this case,
it will be recommended to use after washing DPPA with
aqueous sodium hydrogen carbonate followed by drying.5b
4. Peptide synthesis using DPPA
BuNH2
PhCO2H
1
(EtO)2P(O)N3
Et3N
CH2Cl2
PhCON3
4
PhNH2
EtOH
8
reflux
PhCONHBu
9
50%
PhCONHPh
10
71%
PhNHCO2Et
58%
11
Et3N
EtOH, reflux
62%
Scheme 2. Reaction of diethyl phosphorazidate with
benzoic acid.
3. Preparation of DPPA and its physical
properties
DPPA is easily prepared in high yield by the reaction
of the corresponding chloride 12 with sodium azide in
acetone.1,5 Combination of sodium azide and 18-crown-6
in the same reaction was reported, 6a and the use of a
quaternary ammonium salt as a phase-transfer catalyst in
a biphasic phase of water and an organic solvent was also
reported to be effective,6 as shown in Scheme 3.
(PhO)2P(O)Cl
(PhO)2P(O)N3
12
DPPA
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)
Scheme 3. Preparation of DPPA.
DPPA is a colorless or pale yellow liquid which boils at
134-136 °C/0.2 mmHg, and it will be stable at room
temperature under shading. It is non-explosive just like the
other phosphorazidate. When DPPA is stored at room
DPPA is useful for amide and peptide bond formation
reactions. One of the remained problems in the present
advanced peptide synthesis will be epimerization which
occurs to some extent at the stereogenic center in the
C-terminal amino acids of peptides through activation with
the condensing agents during the coupling of the peptide
fragments. There will be no coupling reagents and
procedures which induce no epimerization. This situation
will be quite similar to the coupling of sugars in which αand 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
the following amino acids:1,7,8 serine (Ser), threonine (Thr),
valine (Val), asparagine (Asn), glutamine (Gln), histidine
(His), pyroglutamic acid ( p Glu), tryptophan (Trp),
methionine (Met), S-benzylcysteine (Cys(Bzl)), nitroarginine
(Arg(NO2)). Thus the peptide synthesis using DPPA will
proceed without any side reactions for these amino acids.
DPPA can be used for both liquid- and solid-phase peptide
synthesis,9 and dimethylformamide (DMF) is a favorable
reaction solvent in both cases. In addition, a base such as
triethylamine is necessary to generate the carboxylate
anion from the carboxyl part.
A short while after developing DPPA, we introduced
diethyl phosphorocyanidate (DEPC, (EtO) 2P(O)CN) as
another suitable reagent for the peptide bond formation.10
DEPC proved to be a versatile synthetic reagent quite
similar to DPPA. 3b,10 However, DEPC is slightly more
active than DPPA and the rate of epimerization (or
racemization) will be lower in peptide synthesis. It will be
superior to DPPA in the construction of linear peptides.
Scheme 4 shows the results of the classical Young
racemization test (through the measurement of specific
rotation),1,5a,10a,10b which is said to be the most stringent
test of racemization, as well as the results of our development epimerization test (through HPLC measurement).11
Young racemization test
Bz-L-Leu-OH + H-Gly-OEt HCl
Et3N
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
Z-Phe-Val-OH
H-Pro-OBut, Et3N
Z-Phe-L/D-Val-Pro-OBut
CF3CO2H
0 °C, 4 h; rt, 20 h
Yield (%)
D-isomer (%)
(PhO)2P(O)N3
86.8
2.2
(EtO)2P(O)CN
87.6
1.4
Z-Phe-L/D-Val-Pro-OH
HPLC analysis
Scheme 4. Racemization and epimerization tests usin DPPA and DEPC.
3
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between 0 °C and room temperature for a longer time (1-3
days).12-18
Bislactamization shown in Scheme 6 will be
considered to proceed first intermolecular and then
intramolecular coupling, and no high dilution conditions are
required. 19 Benzoyl-glycyl-L-proline (13) affords the
corresponding diketopiperazine 14 by reaction with DPPAtriethylamine in the co-existence of 2-mercapto- or
2-hydroxypyridine (PySH or PyOH),20 shown in Scheme 6.
However, Veber and Merck chemists revealed that
DPPA was suitable for macrolactamization of linear
peptides.12 Since then, DPPA is quite often utilized for the
synthesis of macrocyclic peptides by macrolactamization.13
High dilution conditions will be required for the
macrolactamization to suppress the intermolecular
reaction, and sodium hydrogen carbonate is often employed
instead of organic bases such as triethylamine. Scheme 5
shows some examples, most of which employed DPPANaHCO3 in DMF under high dilution conditions (ca. 5 mM)
OMe
OH
H
N
MeN
O
O
HN
O
O
Me
N
HN
O
H
N
NH
HN
O
O
NH
N
H
O
O
O
NH
O
O
NMe
N
Me
NHCbz
Cyclic analog of somatostatin (77%)12b)
O
MeO
O-Methyl deoxybouvardin (58%)14)
OBzl
O
O
HN
I
O
H
N
NBzl
NH
BzlO2C
O
O
O
MeN
HO
O
NH
HO
O
Geodiamolide A (34% in 3 steps)16)
K13 precursor (60% in 2 steps)15)
O
O
N
O
O
NH
N
H
O
O
O
HN
NH
MeN
O
N
H
O
NH
HO
Antillatoxin (29%17c) and 63%17e) in 2 steps)
S
O
HN
O
O
N
Ph
-NH
Mollamide precursor18)
DPPA, i-Pr2NEt, DMF, 52% (2 steps)
CO- shows a cyclization point.
Yields are overall ones including deprotection.
Scheme 5. Cyclic peptides obtained by macrolactamization with DPPA.
Ts
N
O
H
N
CO2H
TsN
NTs
+
N
Ts
O
O
BzNH
HO2C
13
N
CO2H
(PhO)2P(O)N3
PySH or PyOH
Et3N, DMF
(PhO)2P(O)N3
Et3N, DMF
N
H
Ts
N
N
PySH :
N
O
PyOH :
N
SH
75%
Scheme 6. Lactamization using DPPA.
4
O
NTs
N
Ts
O
BzN
14
N
TsN
82%
O
O
O
N
OH
64%
number 134
O
Cyclodimerization21)
O
O
N
1) TMSOTf
S
N
H
S
N
H
N
N
O
2) NaOH
N
CO2Me
NHBoc
O
HN
NH
O
3) (PhO)2P(O)N3
K2HPO4, DMF
N
27% (3 steps)
N
H
N
S
O
O
Ascidiacyclamide
H
N
Cyclotrimerization22b)
N
N
H2N
(PhO)2P(O)N3, Et3N
CO2H
DMF
25%
O
O
O
HN
O
O
O
O
N
NH
N
An ion binding peptide
O
Cycloorigomerization22c)
N
ZNH
O
1) H2, Pd/C
CO2Me 2) NaOH, aq. MeOH
O
N
NH
HN
DMF
N
N
O
O
NH
HN
O
N
O
O
N
H
N
+
3) (PhO)2P(O)N3
O
O
O
N
H
N
O
O
N
H
N
O
O
Westiellamide (20%)
Tetramer (25%)
Scheme 7. Cycloorigomerization using DPPA.
In addition, DPPA proved to be useful for cyclodimerizatiom,21 cyclotrimerization,22 and so on, as shown
in Scheme 7.
Nishi and co-workers developed a convenient
polymerization method for the preparation of polypeptides
from amino acids or monomer peptides which were
unprotected at both N- and C-terminals. 23 The DPPA
method is simple in the work-up, and useful for the
synthesis of sequential polypeptides (Scheme 8).
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 atom
in DPPA to give the acyl phosphates 15 and 16. The acyl
azide would be formed by SNi type rearrangement of 15 or
SN2 type reaction of 16 with the azide anion. Reaction of
the amine with the acyl phosphates 15 and 16 as well as
the acyl azide 7 would form the amide or peptide bond.
H 2N
H-His-OH
CO2H
Each route would respectively contribute more or less, and
the Young racemization test (cf. Scheme 4) was adopted
to find out which route would be predominant. Thus, the
acyl phosphate 16 and acyl azide 7 were prepared from
benzoyl-L-leucine (Bz-L-Leu-OH), and reacted with glycine
ethyl ester (H-Gly-OEt) to check the rate of racemization
and chemical yield. The most favorable result was obtained
by the addition of triethylamine to a mixture of Bz-L-LeuOH, H-Gly-OEt, and DPPA followed by the reaction in both
racemization rate and chemical yields of the dipeptide, BzL-Leu-Gly-OEt, which proved to be superior to the acyl
phosphate (16) and azide (7) methods. These experiments
would suggest the concerted transition state shown in 17
in which 15 is first formed and then the amine will come to
react.1,7a This amide bond formation is the N-acylation of
the amine as a nucleophile. When the nucleophile is
replaced with the thiol or active methylene anion,
(PhO)2P(O)N3, Et3N
HN
Me2SO
(PhO)2P(O)N3, Et3N
Poly-His
CO
n
(ref. 23a)
(ref. 23b)
Me2SO
H-Ser(Bzl)-Arg(Mts)-Arg(Mts)-Arg(Mts)-OH
(PhO)2P(O)N3, Et3N
Me2SO
(Ser(Bzl)-Arg(Mts)-Arg(Mts)-Arg(Mts))n
(ref. 23c)
Scheme 8. Polymerization of amino acids and peptides using DPPA.
5
number 134
R1CO2- + N3 P(OPh)2
O
OR1CO2 P(OPh)2
N3
15
O
R1
R2
N
H
O
O-
R1CO2P(OPh)2
O 16
R1CON3
P(OPh)2
N3-
7
N3
Nu:
Nu:
H
17
Nu:
Nu :
R2NHR3, R2SH, Y-CH--Z
R1CONu
Scheme 9. Reaction mode of DPPA.
S-acylation or C-acylation will occur, as described later. If
there is no nucleophile, the reaction will stop at the stage
of the acyl azide, which thermally undergoes the Curtius
rearrangement to furnish the isocyanate.
5. The Curtius rearrangement using DPPA
Hofmann, Curtius, Schmidt, and Lossen rearrangements are well-known as a useful method to convert
carboxylic acids or derivatives to amines or derivatives
having one less carbon unit, whose key step is the transfer
of 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 the
presence of bases such as triethylamine to give acyl azides,
which thermally undergo the Curtius rearrangement
accompanied with expulsion of nitrogen. The isocyanate
18 thus formed will react with alcohols, amines, water, and
other 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 are
thermally stable.
The carbamate 19 will be obtained by the one-pot
procedure (method A) in which a mixture of carboxylic
acids, DPPA, and triethylamine is directly refluxed in a
solvent, e.g. tert-butanol, inert to DPPA.1,25 In some cases,
addition of alcohols followed by thermal treatment is better
after 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 two
reactions-in-one pot (two-in-one) procedure (method B) in
which the reaction of carboxylates with DPPA and thermal
treatment are conducted in an inert solvent, and then
alcohols are added to isocyanates. Method B is suitable
for the preparation of ureas and amines.
R2OH
R1CO2H
(PhO)2P(O)N3
Base
+
R1 C N N N
O
7
heat
-N2
R1NHCO2R2
19
R2NHR3
R1 N C O
18
H2O
R2
R1NHCON 3
R
20
R1NH2
21
Scheme 10. The Curtius rearrangement using DPPA.
Method A
(PhO)2P(O)N3, Base
R2OH, heat
R1CO2H
2)
NHCO2But
73% (Method A)
19
R2
OH, heat
NO2
N
R1NHCO2R2
Method B
1) (PhO)2P(O)N3, Base
PhCH2CONH
NHCO2But
90% (Method A)
O
H
S
Me
O
N
NHCO2CH2Ph
O
NHCO2But
83% (Method B)
80% (Method A)
Scheme 11. Two procedures for the Curtius rearrangement with DPPA.
6
number 134
The application of method A using tert-butanol with
alkylmalonic acid half esters 22 afforded the
corresponding diesters 23, as shown in Scheme 12. In
contrast, method B in which the half esters 22 were first
converted to the isocyanates followed by heating the whole
mixture after addition of alcohols afforded α-amino acid
derivatives, the products by the Curtius rearrangement. In
method A, the half esters will first afford the acyl azides
which will be in equilibrium with the ketenes 25 formed by
elimination because of the high acidity of α-hydrogen.
Alcohols will irreversibly add to the ketenes 25 to give the
diesters 23. The malonic acid half ester 26 which would
not undergo the ketene formation, because they have no
α-hydrogen, smoothly afforded the α-amino acid
derivative 27 by method A. 26 The above esterification
using DPPA commonly occurs in the case of RCH(X)CO2H
(X=electron-withdrawing functions such as CO 2Et, CN,
CONH2, etc.)
The analogous α-amino acid synthesis from the
cyclopentanedicarboxylic acid 28 efficiently afforded the
carbamate 29 by method B, as shown in Scheme 13.27
However, the reaction with the macrocyclic dicarboxylic
derivatives 30 stopped at the isocyanates 31 stage in
refluxing benzene even in the presence of benzyl alcohol
due to the possible steric hindrance.28 The isocyanates 31
were stable and could be isolated. Conversion of the
isocyanates 31 to the carbamates 32 required more
forcing conditions such as refluxing toluene in the
presence of 9-fluorenylmethanol.
The non-cyclic alkyl malonic acid half ester 33 having
shorter alkyl group such as the propyl function afforded
the carbamate 35 while the half ester 33 having longer alkyl
side chain, e.g. the undecyl function, stops at the stage of
isocyanate 34 (Scheme 13).
The urea synthesis from sugar carboxylic acids by the
Curtius rearrangement with DPPA smoothly proceeds in
good yields when using triethylamine, a common base, e.g.
36+37→38.29 However potassium carbonate proved to be
a better base in the carbamate synthesis using alcohols as
a nucleophile, as shown in Scheme 14. The addition of a
catalytic amount of silver carbonate to triethylamine or
potassium carbonate is often effective to conduct the
reaction, e.g. 39+40 → 41.
(PhO)2P(O)N3, Et3N
CO2Et
R1
22
CO2H
1) (PhO)2P(O)N3, Et3N
Me
CO2Et
O
CO2H
C
25
CO2Et
R
CO2Et
R1
23
CO2But
1
2) R2OH, heat
O
CO2Et
R1
ButOH, heat
NHCO2R2
O
24
(PhO)2P(O)N3, Et3N
O
Me
CO2Et
ButOH, reflux
80%
O
NHCO2But
26
27
Scheme 12. Reaction of ethyl hydrogen malonates with DPPA.
MeO
OMe
MeO2C
CO2H
28
1) NaOH
2) (PhO)2P(O)N3
MeO
OMe
3) PhCH2OH
MeO2C
88%
(CH2)n-1
NHCO2CH2Ph
29
(CH2)n-1
(CH2)n-1
(PhO)2P(O)N3
ButO2C
CO2H
30
Et3N, benzene
reflux
9-Fluorenylmethanol
ButO2C
toluene, reflux
N=C=O
31
n = 21, 83%
n = 18, 82%
n = 15, 88%
R1 R2
EtO2C
CO2H
33
(PhO)2P(O)N3, Et3N
PhCH2OH
benzene, reflux
R1 = R2 = n-Propyl
R1 = R2 = Undecyl
R1 = R2 = -(CH2)14-
R1 R2
ButO2C
NHCO2R
32
R = 9-Fluorenylmethyl
R1 R2
+
EtO2C
N=C=O
34
trace
82%
68%
EtO2C
NHCO2Bzl
35
68%
0
0
Scheme 13. The Curtius rearrangement of cyclic and dialkyl malonic acid half esters with DPPA.
7
number 134
OBn
CO2H
O
MPMO
+
BnO
HN
OBn
O
CO2H
+
BnO
BnO
OBn
OBn
39
OBn
OBn
OBn
OBn
38 : 87%
(PhO)2P(O)N3 (2 eq)
K2CO3 (2 eq)
MPMO
Ag
2CO3 (0.1 eq)
OBn
BnO
benzene, reflux
OBn
O
N
O
OBn
BnO
OBn
OBn 37 (1.2 eq)
HO
H
N
O
MPMO
benzene, reflux
OBn
36
MPMO
OBn
OBn
(PhO)2P(O)N3 (2 eq)
Et3N (2 eq)
OMe
H
N
O
O
O
O BnO
OBn
OBn
40 (2 eq)
OMe
OBn
OBn
41 : 81%
MPM : 4-methoxyphenylmethyl
Scheme 14. The Curtius rearrangement of sugar carboxylic acids using DPPA.
(PhO)2P(O)N3, Et3N
ButOH, reflux
NHCO2But +
N
CO2CH2Ph
NHCONHCO2But
N
CO2CH2Ph
43 : 5%
CO2H
N
CO2CH2Ph
(PhO)2P(O)N3, Et3N
42
H2NCO2But (45)
benzene, reflux
44 : 35%
NHCO2But
N
CO2CH2Ph
rac-43 : 66%
Scheme 15. The Curtius rearrangement of carbobenzoxy-L-proline with DPPA.
O
HO2C
(PhO)2P(O)N3
NO2
46
C
BocNH
47
N
Et3N
Cl(CH2)2Cl
CO2H
NO2
H
N
BocNH
Cl(CH2)2Cl
reflux
O
NO2
48
Scheme 16. Preparation of amino acid amides of aromatic amines using DPPA.
MeO2C
N
CO2Me
MeO2C
CO2Me
N
CO2H 1) (PhO)2P(O)N3, Et3N
2) H2O
Br
71%
49
Me
NH2
Br
50
Me
N HCl
CO2H
(PhO)2P(O)N3, DMAP
Me
N
CON3
Na2CO3, CH2Cl2
51
DMAP : 4-(dimethylamino)pyridine
52
1N HCl
N
O
reflux
53 : 78%
Scheme 17. Preparation of amines and ketones by the Curtius rearrangement with DPPA.
As an unusual example, the proline derivative 42
afforded the allophanate 44 as the main product rather than
the carbamate 43. However, co-existence of tert -butyl
carbamate (45) afforded the carbamate 43 as the major
product though racemization occurred (Scheme 15).30
Anilines, in general, have weak nucleophilicity and
coupling with carboxylic acids does not smoothly proceed
to give the corresponding anilides using DPPA. In contrast,
anilides will be prepared in good yields by use of a twoin-one procedure: (1) conversion of aromatic carboxylic
acids to isocyanates by the DPPA method and then (2)
addition of the other carboxylic acids.31 Scheme 16 shows
the preparation of the anilide 48 from tert-butoxycarbonylL-leucine (Boc-L-Leu-OH, 47) and 4-nitrobenzoic acid (46).
8
Similarly to the above, carboxylic acids are first
converted to isocyanates using DPPA, and then hydrolysis
under aqueous or acidic conditions affords amines, e.g. 49
→ 50.32 In the case of the reaction of the α,β-unsaturated
carboxylic acid 51 with DPPA, the ketone 53 was obtained
from the intermediate acyl azide 52 through thermal
rearrangement to the isocyanate and then acidic
hydrolysis to the amine (Scheme 17).33
Carboxylic acids having hydroxyl or active methylene
functions in the same molecules, as shown in Scheme 18,
afford the cyclic carbamates, 54 34a and 55, 34b and the
lactam 56 through intramolecular cyclization by use of the
DPPA method.
number 134
Me
Ph
H
H
Me
CO2H (PhO)2P(O)N3, Et3N
Ph
O
H
54
CO2H
H
N
1) (PhO)2P(O)N3, Et3N
OH
HO2C
6. Thiol ester synthesis using DPPA and peptide
synthesis from thiol esters
O
benzene, reflux
quant.
OH
H H
N
2) benzene, reflux
high dilution
O
55
80%
NH
(PhO)2P(O)N3, Et3N
H
Thiol esters (thioesters) 57 will be easily obtained by
S-acylation of thiols with carboxylic acids using DPPA in
the presence of triethylamine in DMF under similar
reaction conditions to the amide or peptide bond
formation, as shown in Scheme 19.36 Direct conversion of
carboxylic acids to thiol esters without the intermediacy of
acid chlorides was first explored by our group in 1974.
DEPC can be also used for thiol synthesis. One of the
representative examples in the application of the DPPA
method to natural product synthesis will be the synthesis
of the thiol ester 58 which is an intermediate in the total
synthesis of apratoxin A, a macrocyclic depsipeptide.37
We further found that thiol esters react with amines in
the presence of pivalic acid (59), a bifunctional catalyst, in
DMF to give amides or peptides.38 As shown in Scheme
20, the reaction proved to proceed without any
racemization (or epimerization) in the Young racemization
test as well as the Izumiya test. Peptide synthesis from
carboxylic acids via thiol esters will be the same as the
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.
O
toluene, reflux
O
65%
O
O
H
56
Scheme 18. Intramolecular cyclization of isocyanates.
The Curtius rearrangement utilizing DPPA proceeds
under mild reaction conditions by simple procedure in
comparison with the usual Curtius, Hofmann, Schmidt, and
Lossen rearrangements. The DPPA method will have a
wider applicability in synthesis, and will be the first choice
in the conversion of carboxylic acids to amines and
derivatives having one less carbon.
R1CO2H + HSR2
(PhO)2P(O)N3
Et3N, DMF
R1COSR2
PhCH2CH2COSEt
57
85%
PhCONH
OMe
Boc
N
COSEt
83%
O
O
O
TBS
O
O
OH + AcS
PMBO
Me
1) K2CO3, MeOH
2) (PhO)2P(O)N3 80% (2 steps)
Et3N, CH2Cl2
Boc
N
Me
N
N
H
O
OMe
N
Me
O
O
OMe
O
O
O
TBS
O
O
S
PMBO
Me
N
H
Me
N
O
O
N
Me
OMe
O
58
Scheme 19. Preparation of thiol esters using DPPA.
Young test using thiol ester
Bz-L-Leu-SEt + H-Gly-OEt HCl
Et3N, Me3CCO2H (59)
Bz-L-Leu-Gly-OEt
pyridine
Izumiya test using thiol ester
Boc-Gly-L-Ala-SEt + H-L-Leu-OBut
Me3CCO2H (59)
Boc-Gly-L-Ala-L-Leu-OBut
pyridine
Biosynthesis of peptide antibiotics
R1CO2H
R1CO2P(O)(OR2)
R2SH
R1COSR2
R2NHR3
R1CON
R2
R3
Scheme 20. Peptide synthesis from thiol esters.
9
number 134
7. Oxazole synthesis by C-acylation
8. Azidation of alcohols and phenols
DPPA can be applied to direct C-acylation of active
methylene compounds with carboxylic acids just like Sacylation. Treatment of carboxylic acids 60 and
isocyanoacetic esters 61 with DPPA-base affords oxazole
derivatives 62 having ester functions at the C4 position by
C-acylation followed by cyclization, as shown in Scheme
21.40 The oxazole derivatives 62 undergo acidic hydrolysis
to give β-keto-α-amino acid derivatives 63, whose
carbonyl group is reduced to furnish β-hydroxy-α-amino
acid derivatives 64. The C-acylation conveniently proceeds
by use of a combination of DPPA and potassium
carbonate sesquihydrate while use of sodium salts of
isocyanoacetic esters is also effective. No or little
racemization at the α-position was observed in the Cacylation with α-amino or α-oxy acids 60. Utilizing this
series of reactions as a key step, various amino sugars
such as prumycin,41a L-daunosamine,41b L-vancosamine,41c
and D-ristosamine41d were conveniently synthesized, and
the synthesis of mugineic acid,41e a phytosiderophone, was
accomplished by this procedure.41f
The conversion of alcohols to azides is quite useful
since azides can be easily converted to amines by a
reductive process. Generally, the two step process is
employed to convert alcohols to azides: transformation of
alcohols to halides, mesylates, or tosylates followed by
reaction with the azide anion. There are not so many
procedures of one step conversion of alcohols to azides.
The Mitsunobu reaction using DPPA (Bose-Mitsunobu
method)42 and the DPPA-DBU (18-diazabicyclo[5.4.0]-7undecene) method (Merck method)43 shown in Scheme 22
will be representative, and both methods proceed with
inversion of configuration to azides 65 or 65'. The BoseMitsunobu method utilizes safe DPPA in place of
dangerous hydrazoic acid and is useful for the preparation
of various azides. However, it is not so easy to remove
hydrazino esters 67 and phosphine oxides 68 formed in
the reaction. On the other hand, the DBU salt of diphenyl
phosphate 66 formed in the Merck method is easily removed
by washing with water hence work-up after the reaction is
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
R1CHCO2H
X
+ H2C
60
X
(PhO)2P(O)N3
N=C:
61
K2CO3 1.5H2O
DMF
CO2R2
H+
X
CO2H
63
62%
O
K2CO3 1.5H2O
DMF
CO2Me
MeOCH2O
O
HO
N
H2N
L-Vancosamine
N
80%
O
HO
NH2 HCl
H2N
D-Ristosamine
CO2H
N
N
Scheme 21. Oxazole synthesis using DPPA.
10
HO
O
OH
CO2H
CO2Bzl
NH2
HO
O
OH
CO2Bzl
OH
O
HCl
MeOH
O
OH
H2N
CO2H
Prumycin
70%
L-Daunosamine
N
O
N
O
BzlO2CCH2N=C:
(PhO)2P(O)N3
CO2R2
CH
CH CH
HO
NH2
64
H-D-Ala-CONH
CO2Me
CO2Et 3) MeO2CCH2N=C:
NaH, DMF
CO2Bzl
X
NH2
CbzNH
K2CO3 1.5H2O
DMF
HO
[H]
OBut
1) LiOH, aq. THF
2) (PhO)2P(O)N3, DMF
MeOCH2O
N
:C
R1
O
MeO2CCH2N=C:
(PhO)2P(O)N3
CO2R2
CH
C C
HO
N
CH
C CH
N
X
:C
CO2R2
62
CbzNH
O
R1
R1
CH
O
OBut
R1
CO2R2
CH
X
C CH
CO2R2
HO
N
H
Mugineic acid
CO2H
OH
number 134
Azidation of alcohols
1) Bose-Mitsunobu method
HO
H
R1
R2
+ (PhO)2P(O)N3 +
N CO2Et
+ Ph3P
N CO2Et
2) Merck method
HO H
+ (PhO)2P(O)N3 + DBU
Ar
R
H
H
N3
1
R2
65
R
+ (PhO)2P(O)OH +
66
N
N3
+ (PhO)2P(O)OH DBU
Ar
R
66 DBU
65'
OH
HN CO2Et
+ Ph3P=O
HN CO2Et
68
67
DBU :
N
N3
+
O
O
O
Bose-Mitsunobu method
81 yield (82% ee)
91 yield (97.5% ee)
Merck method
6-8%
1%
Scheme 22. Azidation of alcohols.
O
N3
N3
N3
Et3N, DMF
100 °C
N
H
aromatic
system
N
N
H
70
69
N3
Me
(PhO)2P(O)N3
S
N
O
Ph
N
Me
61%
55%
74%
Scheme 23. Azidation of 4-pyridone derivatives.
only reactive alcohols such as benzyl type alcohols and
α-hydroxycarboxylic acid esters smoothly undergo the
azidation by the Merck method. In contrast, a combination
of DBU and bis( p -nitrophenyl) phosphorazidate ( p NO 2 DPPA, ( p -NO 2 C 6 H 4 O) 2 P(O)N 3 ), which was also
developed by our group, 7a proved to be much more
effective for the azidation of a wide range of alcohols.44
Azidation using both DPPA and p-NO2DPPA will proceed
through the formation of the phosphate esters followed by
SN2 type reaction with the azide anion.
Quinolines, pyridines, and quinazolines 69 having the
keto group at the C4 position can be converted to the
corresponding azides 70 in moderate yields by heating at
100 °C with DPPA-triethylamine in DMF.45 The reaction will
proceed by enolization (phenolization), formation of
phosphate esters, addition of the azide anion, followed by
elimination of the phosphate group to give the azides 70,
as shown in Scheme 23.
9. Synthesis of phosphate esters and
phosphoramidates
Interestingly, the application of the above Merck method
using DPPA-DBU to 2',3'-O-isopropylidenenucleosides 71
furnished not the azides but the phosphate esters 72 at
the C5 position, which were converted to the azides 73 by
further treatment with sodium azide, as shown in Scheme
24.46 The reason why the reaction stops at the phosphate
esters step is due to the mild reaction conditions at room
temperature. Heating in this reaction will cause side
reactions.
Treatment of DPPA with water, butanol, ammonia, and
amines affords diphenyl phosphate, butyl diphenyl
phosphate, diphenyl phosphoramidate, and diphenyl Nalkylphosphoramidate, respectively.47
O
O
HO
O
O
O
Base (PhO)2P(O)N3 (PhO)2P
O
DBU
dioxane
71
Base
NaN3
O
O
15-crown-5
72
Nucleoside : adenosine
inosine
quant.
quant.
O
N3
Base
O
O
73
75%
61%
Scheme 24. Phosphorylation with DPPA.
11
number 134
10. Ring opening of epoxides using DPPA
The epoxides 74 regioselectively produce β-azido
phosphates 75 by the reaction with DPPA in the presence
of 4-( N,N -dimethylamino)pyridine (DMAP) and lithium
perchlorate in DMF.48 The reaction will proceed through
the formation of the pyridinium azides 76 from DPPA and
DMAP followed by the ring opening of the epoxide 74
activated with lithium perchlorate, giving the
β-azidophosphate 75, as shown in Scheme 25. The α,βepoxyketone 77 affords the α-azido vinylketone 78 which
will be formed by elimination of diphenyl phosphate from
the azido phosphate once generated.
11. DPPA as a 1,3-dipole
DPPA works as not only the azide anion equivalents
already described but also a 1,3-dipole.
We have explored the ring contraction of cyclic
enamines 84 using DPPA as a 1,3-dipole.49 Thus, the
pyrrolidine enamines 80 obtained from the cyclic ketones
79 react with DPPA to give the ring-contracted phosphoryl
amidines 81 through the 1,3-dipolar cycloaddition followed
by ring contraction accompanied with evolution of nitrogen.
The phosphoryl amidines 81 are hydrolyzed with
potassium hydroxide to produce the ring-contracted
carboxylic acids 82, as shown in Scheme 26.
Analogously, the reaction of DPPA with the pyrrolidine
enamines 84 derived from aromatic ketones 83 followed
by the alkaline hydrolysis of the resulting phosphoryl
amidines 85 affords α-alkylarylacetic acids 86 in good yields
(Scheme 27).50 Especially, better results are obtained by
the successive treatment without the isolation of any
intermediates. The method will be a general method for
the synthesis of α-alkylarylacetic acids 86 from
alkylarylketones 83. Utilizing this method, nonsteroidal
antiinflammatory agents having the α-alkylarylacetic acid
skeleton such as rac-naproxen, ibuprofen, ketoprofen, and
flurbiprofen can be conveniently synthesized.50c
L’abbé and co-workers first clarified the action of DPPA
as a 1,3-dipole,2 and reported that the reaction of DPPA
with carbethoxymethylenetriphenylphosphorane (87)
afforded a mixture of ethyl diazoacetate (89) and the
iminophosphorane 90. The intermediate would be the
triazoline 88 which undergoes 1,3-dipolar elimination to
yield 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 high
pressure reaction conditions to give two triazoline
derivatives 92 and 93 different from each other about the
addition mode. 51a Irradiation of a mixture of 92 and 93
affords the aziridine derivatives 94. However, heating
under microwave reaction conditions instead of high
pressure directly gives the same aziridines 94, as shown
in Scheme 29.51b
Reaction mechanism
H
R1
R2
O
74
R3
(PhO)2P(O)N3
H
R1
DMAP, LiClO4
DMF
N3
75
H
R1
R2
R3
OP(O)(OPh)2
PhO
(PhO)2P(O) N+
N 3-
74
H
R1
N3
75
N3
OP(O)(OPh)2
N3
R2
R3
O
NMe2
76
R2
R3
OP(O)(OPh)2
N
(PhO)2P(O)N3
NMe2
DMAP
O
O
(PhO)2P(O)N3, DMAP
OP(O)(OPh)2
86%
73%
N3
LiClO4, DMF
O
78 : 88%
77
Scheme 25. Ring opening of epoxides with DPPA.
N
H
O
(CH2)n-2
CH2
79
N
(CH2)n-2
BF3•Et2O
toluene
reflux
CH
N
(PhO)2P(O)N3
toluene or EtOAc
reflux
N
(CH2)n-2
H
80
P(O)(OPh)2
N
N
n yield (%)
N
-N2
(CH2)n-2
C
H
N-P(O)(OPh)2
81
6
7
8
12
16
76.5
74
75
60
68
KOH
O 1) pyrrolidine, BF3·Et2O
2) (PhO)2P(O)N3
3) KOH
CO2H
(CH2)n-2
ethylene glycol
reflux, 24 h
H
82
CO2H
40-48%
Scheme 26. Ring contraction of enamines of cyclic ketones with DPPA.
12
number 134
R1
Ar
R2
O
N
H
R1
Ar
R2
N
83
R1
(PhO)2P(O)N3
R2
84
-N2
Ar
R1
R2
Ar
R1
R2
KOH
N
N P(O)(OPh)2
Ar
N
N
N
N P(O)(OPh)2
CO2H
86
85
COCH2Me
1) pyrrolidine, BF3•Et2O
benzene, reflux
2) (PhO)2P(O)N3, THF
85% (2 steps)
Me
CH
CO2H
3) KOH, ethylene glycol MeO
reflux
rac-Naproxen
83%
MeO
O
Me
CH CO2H
Ibuprofen
F
Me
CH
Me
CH CO2H
CO2H
Ketoprofen
Flurbiprofen
Scheme 27. Synthesis of α-arylacetic acids using DPPA.
EtO2C CHN2
EtO2C CH PPh3 87
CH2Cl2
+
+
rt, 1 day
N N P(O)(OPh)2
N
89 : 84%
+
CH PPh3
EtO2C
N P(O)(OPh)2
N
N
Ph3P N P(O)(OPh)2
88
90 : 85%
Scheme 28. Reaction of carbethoxytriphenylphosphorane with DPPA.
R = Boc
980 MPa
R
N
N
N
toluene
rt, 7 days
(PhO)2P(O)
microwave
(PhO)2P(O) N
N
N
+
N
N
N
Boc
N
O
93 : 14% O
0 °C, 3 h
hν
MeCN 45%
92 : 56%
(PhO)2P(O)N3
O
91
P(O)(OPh)2
Boc
R
N
140 °C, 0.5 h
94
O
R = Boc : 17%
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
trimethylsilyldiazomethane (97), a diazo-transter product,
after aqueous work-up, as shown in Scheme 30.52 The other
silyldiazomethanes can be prepared by the same
procedure.53
Trimethylsilyldiazomethane, now commercially
available, is a stable and safe (“green”) substitute for
hazardous and labile diazomethane which should be
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
Me3SiCH2Cl
95
Mg
Me3SiCH2MgCl
(PhO)2P(O)N3
96
H
Me3Si C N N N P(O)(OPh)2
H MgCl
H2O
Me3SiCHN2
97
67-70% from DPPA
Scheme 30. Preparation of trimethylsilyldiazomethane.
13
number 134
Ar-Br
Ar-H
Mg
(PhO)2P(O)N3
[ Ar-M ]
Et2O or THF
98
BuLi
MeO
M
MeO
NH2
3) NaAlH2(OCH2CH2OMe)2
-5 °C, 35 min; rt, 1 h
O
N
Ar-NH2
100
H- : LiAlH4 or
NaAlH2(OCH2CH2OMe)2
99
1) BuLi, THF, -45 °C, 1.5 h
2) (PhO)2P(O)N3, -45 °C, 1 h
H
H-
Ar-N=N-N-P(O)(OPh)2
O
N
67% (3 steps)
Scheme 31. Conversion of aromatic organometallics to aromatic amines.
O
R1
Ph
N
R2 Me
101
Pri2NLi
O-Li+ (PhO)2P(O)N3
R1
THF
R
2
102
1
- (PhO)2P(O)O-Li+ R
+
N3-
R2
Ph
N Me -N2
R1
N
R2
R1
N Ph
Me
Ph
Me
O-Li+
OPh
O P OPh
N3
R2
: N Ph
103 Me
R1
R2
N3
Me
N
105
104
Ph
N
106
R1 = PhCH2, R2 = Et : 82%
R1 = R2 = -(CH2)4- : 86%
Scheme 32. Synthesis of 2H-azirines using DPPA.
O
R
Ph
N
Me
Pri2NLi
R
O-Li+ (PhO)2P(O)N3
THF
H
N Ph
Me
107
108
O
R
Ph
N
Me
N2
R = Ph : 65%
109
R = But : 76%
Mechanism 1
O+
PhO P N N N
PhO
R
O H
PhO P N
N N
PhO
R
O-Li+
H
N Ph
Me
Li+OH
PhO P N
N
N
PhO
R Ph
Me
O
O
Ph
R
Me
N2
O-Li+
Ph
- +
N
+ (PhO)2PO Li
NH
Me
109
Mechanism 2
R
O-Li+
H
N Ph
+ Me
+
N
N P(O)(OPh)2
N
R OH
Ph
N Me
O-
Ph
N Me
N2
NH
P(O)(OPh)2
R
N P(O)(OPh)2
N
N
110
Scheme 33. Diazo-transfer reaction with DPPA.
DPPA reacts with aromatic Grignard or lithium reagents
98 to give the phosphoryltriazene derivatives 99, which
undergo reduction with a hydride reductant such as lithium
aluminum hydride or sodium bis(2-methoxyethoxy)aluminum hydride to give aromatic primary amines 100, as
shown in Scheme 31. 55 Hydrogen chloride in methanol
could be used in place of hydride reductants though with
less efficiency.55b This is an amino-transfer reaction in which
DPPA works as a + NH 2 synthon. The intermediary
phosphoryltriazenes could be isolated but labile.
Consequently, successive reactions will give better results.
The method is useful for the preparation of a wide variety
of both aromatic and heteroaromatic primary amines.
Interestingly, the lithium enolates of N-methylanilide
derivatives react with DPPA to give three different type
products according to reaction substrates or reaction
14
conditions. Reaction of DPPA with lithium enolates 102
derived from the α,α-dialkyl- N-methylacetanilides 101
affords 2 H -azirine derivatives 106. 56a The proposed
mechanism of the reaction is shown in Scheme 32.
The first products by the reaction of DPPA with the enolates
102 will be the phosphate 103, from which lithium diphenyl
phosphate will be eliminated to give the ketenimminium
azides 104. Attack of the azide anion to the ketenimminium
cation will furnish the azide enamines 105, and then finally
the 2H-azirines 106 will be formed by loss of nitrogen and
cyclization. The process is a sort of azide-transfer reaction
from DPPA.
On the other hand, lithium enolates 108 from
α-monoalkyl- N -methylacetanilide 107 react with DPPA
under the analogous reaction conditions as above, giving
the α-diazo anilides 109 but not the 2 H-azirines 106.56a
number 134
O
R
107
Pri2NLi
R
O-Li+ 1) (PhO)2P(O)N3
THF
H
N Ph 2) (Boc)2O
THF
Me
-78 °C ~ rt
108
Li+OH
PhO P N
N
N
PhO
O-Li+ (PhO)2P(O)N3
R
H
Ph
N
Me
N Ph
108 Me
Boc2O
O
R
Ph
N
Boc NH Me
111 R = Ph : 80%
R = Et : 76%
O
H R Ph
PhO P N
Me
Me
N
N
PhO
Li+ O
O
112
O
HO
OH H R Ph
R
Ph
PhO P N
N
N N
Me
PhO
Boc NH Me
Boc O
111
O
H R Ph
PhO P N
N N
Me
PhO
Boc O
R Ph
Scheme 34. Amination with DPPA.
α-Diazo compounds are also formed from N,N-dimethylphenylacetamide, methyl phenylacetate and benzyl
phenyl ketone though in low yields. The reaction will be a
diazo-transfer reaction initiated by attack of the lithium
enolates to the terminal nitrogen of DPPA, or a 1,3-dipolar
cycloaddition of the enolates 108 to DPPA by which the
triazolines 110 will be formed, as shown in Scheme 33.
In contrast, the lithiation of α-monoalkyl- N methylacetanilides 107 and addition of DPPA followed by
di-tert-butyl dicarbonate (Boc2O) furnished α-Boc-amino
derivatives 111 in good yield, as shown in Scheme 34.56b
In this reaction, the lithium enolates 108 will react with DPPA
to give the phosphoryltriazene anions 112, to which tertbutoxycarbonylation will occur, and then a fragmentation
reaction will give the Boc-amino derivatives 111. DPPA acts
as a +NH2 synthon and the amino-transfer reaction occurs
just like the reaction of DPPA with the aromatic Grignard or
lithium reagents.
13. The Staudinger reaction of DPPA
The well-known Staudinger reaction is a formation
reaction of iminophosphoranes having a pentavalent
phosphorus atom from azides and trivalent phosphorus
compounds. Since the hydrolysis of iminophosphoranes
affords amines, iminophosphoranes are a useful
intermediate for the transformation of azides to amines. In
addition, they are used for the aza-Wittig reaction with
various carbonyl compounds. DPPA also reacts with
triphenylphosphine, a representative trivalent phosphorus
compound, to give the iminophosphorane 90, shown in
Scheme 35.2
Utilizing the Staudinger reaction of DPPA, an efficient
conversion of allylic alcohols to allylic amines
accompanied with rearrangement was developed.57 After
the reaction of the allylic alcohols 113 with the phospholidine
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 PdCl 2(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.
- +
N N N + :PPh3
(PhO)2P(O)
(PhO)2P(O)
N
PPh3
(PhO)2P(O) N
N N
MeN
OH
R2
R1
113
114
NMe
P
NMe2
benzene
rt
N N N PPh3
(PhO)2P(O)
PPh3
90
MeN
P
NMe
O
MeN
(PhO)2P(O)N3
(PhO)2P(O) N
R
R
R
MeN
CH2Cl2
(PhO)2P(O) N
P
NMe
117
NH2
HCl (1M)
O
R2
R1
O
116
115
[PdCl2(MeCN)2] (5%)
NMe
R2
1
2
1
P
THF
R2
R1
118
Scheme 35. Staudinger reaction of DPPA.
15
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-H
insertion reaction with a variety of hydrocarbons.
Cyclohexane (120) used for a solvent reacts with DPPA to
give the cyclohexylamine derivative 121, as shown in
Scheme 36.
triphenylphosphine rhodium chloride (Rh(PPh 3 )3 Cl) in
THF.60 The decarbonylation will be considered to proceed
as shown in Scheme 38: carbon monooxide will migrate
from the aldehydes 124 to the rhodium catalyst and then
DPPA will catch the carbon monooxide from the catalyst to
give the isocyanate 125 accompanied with loss of
nitrogen.
(PhO)2P(O)N3
R CH2 CHO
R Me
Rh(PPh3)3Cl (5 mol%)
THF, rt, 22~46 h
124
hν
(PhO)2P(O)N3
(PhO)2P(O)N:
119
CHO
Me
See Above
120
99%
NHP(O)(OPh)2
67%
121
CHO
Scheme 36. Phosphoryl nitrenes generated from DPPA.
Me
See Above
90%
DPPA reacts with styrene derivatives 122 by the
catalytic action of cobalt(II) porphyrin complex (Co(TPP))
at 100 °C in chlorobenzene to yield the N-phosphorylated
aziridines 123 in moderate yield.59 As shown in Scheme
37, the reaction of DPPA with Co(TPP) affords a cobaltnitrene intermediate which undergoes the aziridination of
the styrene derivatives 122. Chlorobenzene is the solvent
of choice for the aziridination, and the other metals except
cobalt are not effective at all. Further, it is necessary to use
5 equivalents of the styrene derivatives.
N
Ar
N
123
P(O)(OPh)2
Ar
CoIV(TPP)
122
Ph
Co(TPP) :
N
O
N
PPh3
O
PhO P N
3
PhO
PhO P NCO + N
2
PhO
125
Scheme 38. Decarbonylation of aldehydes using DPPA.
One of the disadvantages of DPPA from the viewpoint
of green chemistry will be the formation of diphenyl
phosphate as a waste after reactions using DPPA as an
azide equivalent. Thus the polymer-supported DPPA 126
was prepared, and the Curtius rearrangement using 126
was exploited, as shown in Scheme 39. 61 Diphenyl
phosphate bounded to the polymer will be easily
recovered, and can be recycled by conversion to the azide
126.
Ph
N
OH
O
O P N3
OC6H5
126
NaN3
15-crown-5
Scheme 37. Cobalt-catalyzed aziridination of styrene
derivatives with DPPA.
Polymer-DPPA
CO2H
126
15. Decarbonylation using DPPA
DPPA can be used for the decarbonylation of
aldehydes, which smoothly occurs at room temperature by
slow addition of an equivalent amount of DPPA to
aldehydes 124 in the presence of a catalytic amount of
O
O P Cl
OC6H5
C6H5OP(O)Cl2
Phenol resin
Ph
16
L
Rh
N
Co
Ph
Cl
PPh3
123
CoII(TPP)
N2
Ph3P
CO
Rh
16. DPPA analogs
R
P(O)(OPh)2
(PhO)2P(O)N3
Cl
N
R
PhCl
100 °C, overnight
Ph3P
H
P(O)(OPh)2
(PhO)2P(O)N3
Co(TPP) (10 mol%)
122
O
R
R Me
O2N
Et3N
H
N
ROH
OR
O
O2N
H
N
H
N
RNH2
O2N
Scheme 39. Polymer-supported DPPA.
O
R
number 134
Role of DPPA
a) As an azide anion equivalent
PhO
P
PhO
c) As an electrophile
P N
PhO
O
PhO
PhO
d) As a nitrene
PhO
PhO
N-Acylation (Amide & Peptide Synthesis)
Curtius Rearrangement
O-Acylation of Malonates (Ester Synthesis)
S-Acylation (Thiol Ester Synthesis)
C-Acylation (Oxazole Synthesis)
Azidation of Hydroxyl Functions
O- & N-Phosphorylation
Azide Phosphate Synthesis
+ N N N
O
PhO
b) As a 1,3-dipole
Synthesis & Reactions
Reaction Mode
N
+
- +
P N N N
O
P N
Ring Contraction
Synthesis of α-Alkylarylacetic Acids
1,3-Dipolar Elimination
Aziridine Synthesis
N
+
N N
O
R
-
Diazo-transfer Reactions
NH2 Synthon
Azide-transfer Reactions
Staudinger Reactions
+
C-H Insertion Reactions
Aziridine Synthesis
Decarbonylation of Aldehydes
Figure 2. Role of DPPA in organic synthesis.
As described in the one-pot azidation of alcohols, DPPA
is slightly less active and the reaction subtrates will be
restricted to active alcohols, while p-NO2DPPA prepared
easily by nitration of DPPA is much more reactive and can
be applied to a wide range of alcohols. 44 The future
development of p-NO 2DPPA in organic synthesis will be
expected because it is now commercially available and a
crystalline solid more easily usable than oily DPPA.
17. Conclusion
Various reactions using DPPA can be classified by the
reaction modes as shown in Figure 2.
Presumably, the Curtius rearrangement reaction with
DPPA will be used most frequently. The one-pot
conversion of alcohols to azides by the Bose-Mitsunobu
method will also be used quite often, especially in
laboratories. Anyway, as you will see here, exploitation of
a new synthetic reagent will open the frontier of synthetic
organic chemistry. Again, according to SciFinder, reaction
examples utilizing DPPA are increasing especially from
2000, and there are more than 5,000 examples of the uses
of DPPA in 2002, 2004, and 2005. I believe that DPPA will
be used more and more in the future, and that new useful
reactions utilizing DPPA will be developed hereafter.
Acknowledgements - The author would like to express
his grateful acknowledgement to the late Professor
Shun-ichi Yamada of the University of Tokyo for generous
support and encouragement. Thanks are due to Professor
Yasumasa Hamada, now at Chiba University, who played
a central role in many studies of DPPA. The author is
indebted to the late Mr. Kunihiro Ninomiya who developed
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
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
whom the author’s thanks are due.
References and notes
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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
CH3
O
O P O
N3
Diphenylphosphoryl Azide (DPPA)
250g, 25, 5g [D1672]
CH3
Si
CHN2
CH3
Trimethylsilyldiazomethane
(ca. 10% in Hexane, ca. 0.60 mol/L)
25ml, 10ml [T1146]
19