A new type of oxidation-reduction condensation by the combined use of phenyl diphenylphosphinite and oxidant

Article abstract of DOI:10.3987/REV-09-SR(S)1

A new type of oxidation-reduction condensation of alcohols with sulfur, nitrogen, and oxygen nucleophiles by the combined use of phenyl diphenylphosphinite (PhOPPh₂) and oxidants such as azides or diethyl azodicarboxylate (DEAD) are described. In these reactions, chiral secondary and tertiary alcohols are converted into the corresponding chiral sulfides, azides, esters and ethers under mild and neutral conditions with almost complete inversion of stereochemical configuration.

Full text of DOI:10.3987/REV-09-SR(S)1

HETEROCYCLES, Vol. 80, No. 1, 2010
63
HETEROCYCLES, Vol. 80, No. 1, 2010, pp. 63 - 82. © The Japan Institute of Heterocyclic Chemistry
Received, 13th February, 2009, Accepted, 11th March, 2009, Published online, 12th March, 2009
DOI: 10.3987/REV-09-SR(S)1
A NEW TYPE OF OXIDATIONREDUCTION CONDENSATION BY THE
COMBINED USE OF PHENYL DIPHENYLPHOSPHINITE AND
OXIDANT
Teruaki Mukaiyama,*1 Kiichi Kuroda,2 and Yuji Maruyama3
1Tokyo Chemical Industry Co., Ltd., 6-15-5 (TCI) Toshima, Kita-ku, Tokyo
114-0003, Japan
2Department of Applied Chemistry, Faculty of Science, Tokyo University of
Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
3Department of Industrial Chemistry, Faculty of Engineering, Tokyo University
of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
E-mail; mukaiyam@abeam.ocn.ne.jp
Dedicated to Professor Dr. Akira Suzuki on the occasion of his 80th birthday.
Abstract – A new type of oxidationreduction condensation of alcohols with
sulfur, nitrogen, and oxygen nucleophiles by the combined use of phenyl
diphenylphosphinite (PhOPPh2) and oxidants such as azides or diethyl
azodicarboxylate (DEAD) are described. In these reactions, chiral secondary and
tertiary alcohols are converted into the corresponding chiral sulfides, azides, esters
and ethers under mild and neutral conditions with almost complete inversion of
stereochemical configuration.
INTRODUCTION
The fundamental concept of oxidationreduction condensation is to perform dehydration condensation
between two molecules by removing H2O as 2[H] and [O] by a combined use of a weak reductant and an
oxidant. The characteristic feature of this reaction is that it proceeds under mild and neutral conditions
without any assistance of acidic or basic promoters. In 1963, the first example of oxidationreduction
condensation was reported from our laboratory that two moles of carboxylic acids were dehydrated to
form the corresponding acid anhydrides in high yields by combined use of diphenyl- or bis
(p-methoxyphenyl)mercury (Ar2Hg) (hydrogen acceptor) and tributylphosphine (nBu3P) (oxygen
acceptor) as shown in Scheme 1.1

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HETEROCYCLES, Vol. 80, No. 1, 2010
O
2
Bu3P
Ph2Hg
R
OH
ꢀ[H2O]
2[H]
[O]
O
O
Bu3P O
Hg
2PhH
R
O
R
Scheme 1
It was reported also that the condensation reaction between BzL-Leuand HGlyOEt proceeded
smoothly in the presence of triphenylphosphine (PPh3) and di(2-pyridyl)disulfide (PySSPy) to afford
dipeptide, BzL-LeuGlyOEt, in high yield (Scheme 2).2 Corey et al. developed an effective method for
a macrocyclic lactone synthesis by treating a hydroxycarboxylic acid with PPh3 and PySSPy,3 which was
also applied to the syntheses of a number of important macrocyclic compounds including, erythronolide
B,4 vermiculine,5 and enterobactin.6
R1
PPh3
O PPh3
XHN C COOH
H
R1 O H R2
[O]
XHN C C N C COX'
2[H]
H
H
R2
H2N C COX'
H
2
N
H
S
N
S S
N
Scheme 2
Phosphoric esters were prepared by treating allyl diethyl phosphite and diethyl azodicarboxylate (DEAD)
in the presence of alcohols (1967).7 Later, Mitsunobu applied this concept to an efficient dehydration
condensation between alcohols and various nucleophiles such as carboxylic acids by using PPh3 and
DEAD in combination (Mitsunobu reaction).8 The scope of this reaction system was expanded to the
alkylation reactions of various acidic components including phenols, imides, hydrogen azide, active
methylene compounds, and thiols (Scheme 3).9 In recent years, Tsunoda et al. also demonstrated
dehydration reactions by using novel phosphorane reagents such as cyanomethylenetributylphosphorane
(CMBP), which was applied to the nucleophiles having the high pKa values.10 After the efforts on these
condensation reactions, however, a challenging problem still remained when bulky secondary or tertiary
alcohols were used as a substrate because the formation of a key reaction intermediate,
alkoxyphosphonium salt, was strongly interfered by steric hindrance of alcohols.11

HETEROCYCLES, Vol. 80, No. 1, 2010
65
PPh3
O PPh3
[O]
OH
R2
Nu
R2
H Nu
R1
2[H]
O
R1
O
H
N N
H
EtO
N N
OEt
EtO
OEt
O
O
Scheme 3
It was reported from our laboratory that the oxidationreduction condensation1217 of alkyl
diphenylphosphinites (ROPPh2), that were prepared from the corresponding alcohols and
chlorodiphenylphosphine, with various nucleophiles (NuH) gave the dehydrated condensation products
(RNu) in the presence of benzoquinone derivatives as oxidants. It is noteworthy that chiral tert-alkyl
diphenylphosphinites are converted into the corresponding chiral products with inversion of configuration
when carboxylic acids,13 diethyl cyanophosphonate,14 2-sulfanyl-1,3-benzothiazole,15 or trimethylsilyl
azide17 was used as a nucleophile (Scheme 4). Then, in order to improve the synthetic utility of this
reaction system, it is important to develop a new method for a direct synthesis of products from
tert-alcohols and nucleophiles without preparing alkyl diphenylphosphinites in advance.
O
O
R3 O
R
R
OH
R1
R2

O
R3 NC
(EtO)2P CN
R
Ph2PCl
base
R1
R2
R3 OH
R3 OPPh2

O
O
R1
R2
R1
R2


N
N
HS
tert-alkyl
diphenylphosphinite
tertiary alcohol
R3
S
S
S
R1
R2

TMSN3
R3 N3
R1
R2

Scheme 4
A new combination of phosphorus compound and oxidants, benzoquinone derivatives for direct synthesis
of the condensation products from alcohols and nucleophiles was first examined. By using the above
combination, condensation of an alcohol with a sulfur nucleophile such as 2-sulfanyl-1,3-benzothiazole

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HETEROCYCLES, Vol. 80, No. 1, 2010
(BtzSH) was tried as a model. Then, a new type of oxidationreduction condensation by the combined
use of phenyl diphenylphosphinite (PhOPPh2) and benzoquinone derivatives was found, which in turn
was applied effectively to the thioetherification of various alcohols.18,19 When chiral sec-alcohols were
used, the corresponding sulfides were obtained in good to excellent yields with inversion of configuration.
On the other hand, chiral tert-alcohols bearing -ester groups were converted into the inverted sulfides in
moderate yield via alkoxyphosphonium salt C along with undesired olefins (Scheme 5). In order to
improve the yields of tert-alkyl sulfides, another type of oxidationreduction condensation reaction was
next considered in which organic azides were employed as oxidants in place of the above mentioned
benzoquinone derivatives.
Me
O
O
PhOPPh2
Me
Me SBtz
Me OH
Me
H SBtz
N
Me


Et
CO2Bn
CO2Bn
major side product
Et
CO2Bn
toluene, rt
(>99%ee)
55%, >99%ee
Btz =
S
SN2
Me
OH
Me
Me
OH
Me
Ph Ph
PhO P O
Ph
Me
Ph
P O
Ph Ph
PhO P O
HSBtz
Me O
O
Me OH
PhOH
Et
CO2Me
SBtz
Me
Et
CO2Me
SBtz
A
B
C
Scheme 5
A reaction of organic azides20 with trivalent phosphorus compounds that affords the corresponding
iminophosphoranes (aza-ylides) is known as the Staudinger reaction.21 Although this iminophosphorane
is a versatile synthetic intermediate,22 there are only few papers reported23 on the intermolecular
dehydration condensation reactions between alcohols and acidic compounds. Thus, the use of azide
compounds as oxidants was tried next to confirm if this iminophosphorane works as an intermediate in
the oxidationreduction condensation because iminophosphorane C would be expected to be equivalent
to the betaine A or B (Scheme 6).
In this article, we would like to describe a new type of oxidationreduction condensation by using
PhOPPh2 and the oxidants such as azides or DEAD that leads to novel CS18,19,24, CN25 and CO bond
forming reactions together with their applicabilities.

HETEROCYCLES, Vol. 80, No. 1, 2010
67
R
O
O
R
X3P O
O
A
EtO2C N N CO2Et
X3P
PX3
EtO2C N N CO2Et
B
R N3
X3P N R
X3P N R
Iminophosphorane C
(aza-ylide)
Scheme 6
CARBONSULFUR BOND FORMING REACTION
The carbonsulfur bond forming reaction by way of Mitsunobu reation (PPh3DEAD) is recognized as
versatile preparative methods of various sulfides and thioesters from the corresponding alcohols and
sulfur nucleophiles such as thiols or thioacetic acid.26,27 In this reaction, chiral sulfides and thioesters were
formed from the corresponding chiral sec-alcohols with inversion of configuration. However, it is
generally known that sterically-hindered tert-alcohols are not converted to the corresponding sulfides and
thioesters. Therefore, the oxidationreduction condensation by using a combination of PhOPPh2 and
azide compound, an oxidant, was examined so as to develop a method of converting tert-alcohols to the
corresponding sulfides via SN2 nucleophilic substitution.
In order to find the most suitable oxidant, commercially available various azides were examined in the
first place by taking the condensation reaction of 4-phenylbutan-2-ol (1a) and BtzSH in the presence of
PhOPPh2 (Table 1). A condensation reaction using trimethylsilylmethyl azide afforded the desired
product 2a in moderate yield while alkyl azides such as benzyl azide and ethyl azidoacetate gave 2a in
good yields (Entries 1–3). When the reactions were carried out in toluene instead of 1,2-dichloropropane,
the yields increased up to 81 and 84%, respectively (Entries 2 and 3). On the other hand,
1-azidoadamantane, diphenylphosphoryl azide, or trimethylsilyl azide did not work well (Entries 46).
Next, thioetherification of various tert-alcohols was tried in order to examine the scope of this reaction
under the optimized conditions (Table 2). The reaction of tert-alcohol 1b having an -ester group
afforded the corresponding sulfide also in high yield, while the cases with 1c and 1d that bear -ketone
and -phenyl groups were moderate (Entries 13). With an aliphatic substrate 1e, the yield of the desired
sulfide markedly decreased because of the elimination reactions that accompanied to give undesired
olefins (Entry 4).

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HETEROCYCLES, Vol. 80, No. 1, 2010
Table 1. Screening of azide compounds
PhOPPh2 (1.1 equiv)
azide (1.1 equiv)
OH
Me
SBtz
Me
BtzSH
Ph
1a (1.0 equiv)
Ph
1,2-dichloropropane
reflux, 3 h
2a
(1.0 equiv)
Yield/%a
Yield/%a
Entry
1
Azide
Entry
4
Azide
53
34
N3
TMS
N3
O
2
3
67 (81)b
69 (84)b
5
6
N.D.
7
N3
N3
Ph
(PhO)2P N3
TMSN3
CO2Et
aIsolated yield. bToluene was used instead of 1,2-dichloropropane.
Table 2. Thioetherification of various tert-alcohols
PhOPPh2 (4.0 equiv)
N3CH2CO2Et (4.0 equiv)
ROH
1 (1.0 equiv)
BtzSH
R SBtz
toluene, 40 °C, 24 h
(4.0 equiv)
2
Yield/%a
Entry
1b
ROH
Me OH
1
Product
2
Me SBtz
1b
2b
94
42
Me
CO2Me
Me
CO2Me
Me OH
Me
Me SBtz
Ph
Ph
1c
2c
2
Me
O
O
Me OH
Ph Me
Me OH
Me
Me SBtz
1d
1e
2d
2e
53
17
3
4
Ph
Me
Me SBtz
Me
Ph
Ph
aIsolated yield. bThe reaction was carried out by using BtzSH (2.0 equiv ),
PhOPPh2 (2.0 equiv) and N3CH2CO2Et (2.0 equiv).
Taking the above results into consideration, thioetherification of various chiral alcohols were next tried in
order to examine the stereochemistry of this reaction (Table 3). A reaction of chiral sec-alcohol 1a
proceeded smoothly to afford the corresponding sulfide in excellent yield with complete inversion of
stereochemistry (Entry 1). Chiral benzylic alcohol 1f and propargylic alcohol 1g also gave the desired
products in high yields with high enantiomeric excesses (Entries 2 and 3). The thioetherification of
sterically-hindered (─)-(l)-menthol (1h) gave the inverted product in high yield without accompanying
any other products (Entry 4). Further, more hindered tert-alcohols 1i1l were tried as substrates in order

HETEROCYCLES, Vol. 80, No. 1, 2010
69
to find potential applicability of this reaction to the asymmetric construction of quaternary carbon. Then,
a reaction of chiral tert-alcohol 1i having an -ester group was found to proceed smoothly and afforded
the corresponding sulfide in good yield with complete inversion of stereochemistry (Entry 5). Similarly,
chiral benzylic alcohol 1j gave the desired product in high yield with excellent enantiomeric excess
(Entry 6). Also, thioetherification of chiral propargylic alcohol 1k gave the inverted product in high yield
(Entry 7). On the other hand, the reaction of (R)-terpinen-4-ol (1l) did not take place under the above
conditions and 1l was recovered, which is probably because its bulky isopropyl group interfered the
attack of 1l on the positively charged phosphorus atom (Entry 8).
Table 3. Thioetherfication of various chiral alcohols
PhOPPh2 (1.5 equiv)
N3CH2CO2Et (1.5 equiv)
R1 OH
R1 SBtz
BtzSH
R2
R3
R2
R3
toluene
1 (1.0 equiv)
(1.1 equiv)
2
Yield/%a
(%ee)b
1 (%ee) Temp., Time
Entry
ROH
OH
Me
Product
SBtz
Ph Me
2
99
(>99)
1a (>99)
1f(>99)
1
40 °C, 24 h
rt, 12 h
2a
2f
Ph
OH
SBtz
83
(97)
2c
Ph
Me
Ph
Me
SBtz
OH
89
3c
4
1g (98)
rt, 24 h
2g
2h
(98)
3
3
OH
SBtz
1h
80 °C, 6 h
85
Me OH
Et CO2Bn
Me SBtz
Et CO2Bn
5d
6d
76
1i (>99) 40 °C, 48 h
1j (>99) 40 °C, 48 h
2i
2j
(>99)
Me OH
Ph CO2Me
Me OH
Me SBtz
Ph CO2Me
Me SBtz
CO2Et
90
(99)
7c,d
87
(92)
1k (92)
27 °C, 48 h
2k
CO2Et
Ph
Ph
OH
SBtz
1l
8
40 °C, 48 h
2l
N.R.
c
aIsolated yield. bDetermined by HPLC analysis. The solution of PhOPPh2 and ethyl
azidoacetate was stirred at 80 °C for 20 min, followed by addition of alcohol and
BtzSH at rt. dThe reaction was carried out by using BtzSH (4.0 equiv), PhOPPh2 (4.0
equiv) and ethyl azidoacetate (4.0 equiv) .

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HETEROCYCLES, Vol. 80, No. 1, 2010
Next, reactions of various arenethiols with tert-alcohol 1b were examined in order to extend the scope of
this reaction (Table 4). When benzenethiol derivatives were used as sulfur nucleophiles, the order of
increase in the yields is as follows: 4-nitrobenzenethiol (pKa 5.11 in EtOH/H2O, 5.5 in DMSO)28
>
benzenethiol (pKa 7.76 in EtOH/H2O, 10.3 in DMSO)28 > 4-methoxybenzenethiol (pKa 7.99 in EtOH/H2O,
11.2 in DMSO)28 (Entries 13). These results indicate that the yields are influenced by the pKa values of
nucleophiles.12,16,29 It is considered that deprotonation of thiol having low pKa value by iminophosphorane
proceeds effectively to afford the desired product in high yield. Also, the reactivity of
5-nitro-2-sulfanylpyridine was shown to be higher than that of 2-sulfanylpyridine (Entries 4 and 5).
Further, the reactions of various heteroarenethiols were examined (Entries 69). It was found then that
1-methyl-1H-tetrazole-5-thiol could also be used successfully in this reaction (Entry 6), and
2-sulfanyl-1,3-benzothiazole (BtzSH; pKa 7.00 in EtOH/H2O)30 was the most reactive of the heteroarene
thiols (Entry 7). When thiobenzoic acid (pKa 5.3 in DMSO)31 was used, the yield of the desired product
was poor though its acidity was sufficient (Entry 10).32
Table 4. Condensation of tertiary alcohol 1b with various ArSH
PhOPPh2 (2.0 equiv)
N3CH2CO2Et (2.0 equiv)
Me OH
Me CO2Me
Me SAr
Me CO2Me
ArSH
toluene, 40 °C, 24 h
1b (1.0 equiv)
(2.0 equiv)
3
Yield/%a
Yield/%a
83 (68)b
Entry
1
Entry
6
ArSH
Product 3
ArSH
Product 3
N
N
44 (83)b
3f
HS
3a
HS
N
Me
N
N
85 (72)b
19 (78)b
72 (67)b
7
94 (90)b
2b
3g
2
3b
3c
HS
HS
HS
HS
HS
NO2
S
N
3
4
8
9
91 (83)b
89 (82)b
OMe
S
N
NO2
N
N
3d
3e
3h
3i
HS
HS
O
O
5
97 (21)b
10
34 (19)b
HS
NO2
Ph
aIsolated yield. b2,6-Di-tert-butyl-1,4-benzoquione was used instead of ethyl azidoacetate. See ref. 19.
In order to confirm further the utility of the above results, condensation of chiral tert-alcohols 1i and 1j
with BtzSH were examined with other oxidation–reduction systems (Table 5). Then, it was shown that
the reaction using PhOPPh2 and oxidants such as DEAD, DMBQ and N3CH2CO2Et afforded the desired
sulfides with inversion of configuration while the PPh3DEAD system (Mitsunobu conditions) did not.
The yields of products 2i and 2j were found to increase in the order of PhOPPh2N3CH2CO2Et >

HETEROCYCLES, Vol. 80, No. 1, 2010
71
PhOPPh2DMBQ > PhOPPh2DEAD > PPh3DEAD combination systems. Therefore, it is noted that
PhOPPh2 is an essential reductant for thioetherification of tert-alcohols.
Table 5. Yields and enantiomeric excesses (in parentheses)
in thioetherification of tertiary alcohols
reductant (4.0 equiv)
oxidant (4.0 equiv)
R1 OH
R1 SBtz
R2 R3
BtzSH
R2
R3
toluene, 40 °C, 48 h
1 (1.0 equiv)
(4.0 equiv)
2
PPh3
PhOPPh2
DMBQa
Reagent
N3CH2CO2Et
DEAD
DEAD
ROH 1
Me OH
43
55
76
trace
N.D.
1i
1j
(>99)
(>99)
(>99)
Et
CO2Bn
Me OH
53
(>99)
56
(>99)
90
(99)
Ph
CO2Me
aThe reaction was carried out at rt for 24 h.
A plausible reaction mechanism is shown in Scheme 7: the Staudinger reaction of PhOPPh2 with an azide
compound initially affords an iminophosphorane followed by a successively deprotonation of BtzSH
results in the formation of phosphonium salt A. A subsequent nucleophilic attack of an alcohol on the
positively charged phosphorus atom leads to the formation of alkoxyphosphonium salt B which is a key
intermediate, and the following nucleophilic attack of thiolate anion (BtzS－) on the carbon atom adjacent
to an oxygen atom of alkoxy group via SN2 substitution gives the inverted sulfide.
Ph Ph
PhO P N R
Ph Ph
PhO P N R
H SBtz
PhOPPh2 RN3
N2
iminophosphorane
Ph Ph
PhO P N R
Ph
H
R1 SBtz
Ph
R1 O
O
P N R
H
H
R1 OH
Ph2P NR
R2
R3
SBtz PhOH
R2
R3
R2
R3
SBtz
'' Inversion''
A
B
Scheme 7
As the chiral tert-alkyl Btz sulfide 2j was converted to the corresponding chiral thiol in high yield on
treatment with LiAlH4,15 a concise method for the preparation of chiral thiols from the corresponding
alcohols was established (Scheme 8).

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HETEROCYCLES, Vol. 80, No. 1, 2010
Me SBtz
Me SH
LiAlH4
OH

Et2O, reflux

Ph
CO2Me
2j
Ph
95% yield
Scheme 8
Thus, a new type of oxidationreduction condensation by using a combination of PhOPPh2 and azide
compounds was established. Chiral sec- and tert-alkyl sulfides were formed from the corresponding chiral
alcohols with almost complete inversion of configuration under mild and neutral conditions. This is the
first example of the direct and stereospecific synthesis of an inverted chiral tert-alkyl sulfide from a chiral
tert-alcohol via an SN2 displacement.
CARBONNITROGEN BOND FORMING REACTION
Conversion of alcohols to their corresponding azides is one of the most important functional group
transformations in organic synthesis.33 The most fundamental method known for azidation is the
Mitsunobu reaction that uses hydrogen azide,34 diphenyl phosphorazidate (DPPA)35 or zinc
azide/bis-pyridine complex.36 More recently, methods using DPPA/DBU,37 p-NO2DPPA/DBU38 and so
forth39 have been reported. In all these reactions, chiral sec-alkyl azides are formed from chiral
sec-alcohols with complete inversion of configuration via SN2 displacement. On the other hand,
sterically-hindered tert-alcohols are not known to be converted to the corresponding tert-alkyl azides.40
Therefore, it is desired to develop a convenient method for tert-alcohols to be transformed into the
inverted azides. Next the application of the above oxidationreduction condensation to stereospecific
azidation of alcohols was studied by using a combination of PhOPPh2 and an azide compound as
oxidants.
Table 6. Optimization of reaction conditionsa
PhOPPh2 (2.0 equiv)
oxidant (2.0 equiv)
Me OH
Me N3
azide
Ph CO2Me
1j (1.0 equiv)
Ph CO2Me
toluene, rt, 48 h
(2.0 equiv)
4j
Yield/%b
Entry
Azide
Oxidant
1c
2c
N.D.
34
Bu4NN3
DPPA
N3CH2Ph
N3CH2Ph
57
N3CH2Ph
3
4
N3CH2CO2Et
9
TMSN3
12
82
AdN3
5
6
N3CH2TMS
aThe solution of PhOPPh2 and oxidant was stirred at 80 °C for 20 min,
followed by addition of alcohol and Azide at rt. bIsolated yield. cThe
reaction time was 24 h.

HETEROCYCLES, Vol. 80, No. 1, 2010
73
In order to find the most suitable azidation reagent, a reaction using tert-alcohol 1j in the presence of
PhOPPh2 and benzyl azide was first examined (Table 6, Entries 13). The reaction using
tetrabutylammonium azide did not afford the desired azide 4j while DPPA gave 4j in low yield. In the
case with TMSN3, the yield of 4j increased up to moderate yield and therefore TMSN3 was chosen as the
reagent for the present azidation. Next, various azide compounds were examined to find which was the
suitable oxidant (Entries 46). The use of ethyl azidoacetate and 1-azidoadamantane was then shown to
lower the yield while trimethylsilylmethyl azide gave 4j in high yield.
Table 7. Azidation of various chiral alcohols
PhOPPh2 (2.0 equiv)
TMSCH2N3 (2.0 equiv)
R1 OH
R1 N3
TMSN3
R2 R3
1 (1.0 equiv)
R2
R3
toluene, rt, 5 h
(2.0 equiv)
4
Yield/%a
(%ee)
Entry
1 (%ee)
ROH
OH
Me
Product
N3
4
quant
(>99)b
1
2
1a (>99)
1m (>99)
1n (>99)
4a
Ph
Ph
Me
OH
N3
98
(>99)c
4m
4n
Ph
CO2Et
OH
Ph
CO2Et
N3
85
(97)b
Me
Me
3
Me OH
Et CO2Bn
Me N3
Et CO2Bn
84
4d,e
5d,g
6d,g
1i (>99)
1j (>99)
1o (80)
4i
(96)f
Me OH
Ph CO2Me
Me N3
Ph CO2Me
86
(>99)b
4j
Ph
OH
Me
Ph
N3
Me
86
(61)c
4o
EtO2C
EtO2C
aIsolated yield. bThe ratio of enantiomer was determined by HPLC analysis after
reducing the azide (4a, 4n, 4j) to the corresponding amines.cThe ratio of enantiomer
was determined by HPLC analysis. dPhOPPh2(3.0 equiv), trimehylsilylmethyl azide
(3.0 equiv), TMSN3 (3.0 equiv) were used. eThe reaction time was 24 h. fThe ratio
of enantiomer was determined by HPLC analysis after converting the azide to 1,4-
disubstituted 1,2,3-triazole. gThe reaction time was 48 h.
A suitable azidation reagent and an oxidant were then chosen and condensation reaction of various chiral
alcohols with TMSN3 was tried in order to examine the scope of this reaction under the optimized
conditions (Table 7). A reaction of chiral sec-alcohol 1a proceeded smoothly to afford the corresponding

74
HETEROCYCLES, Vol. 80, No. 1, 2010
azide in quantitative yield with complete inversion of stereochemistry (Entry 1). The reaction of
sec-alcohol 1m having an -ester group also afforded the inverted azide in high yield (Entry 2). When
benzylic alcohol such as (S)-1-(2-naphthyl)ethanol (1n) was employed, the desired product was obtained
in high yield with almost complete inversion (Entry 3). Further, tert-alcohols were tried as substrates so
as to investigate potential application of this reaction to the asymmetric construction of quaternary carbon.
Then, the reaction of chiral tert-alcohol 1i having an -ester group was found to proceed smoothly to
afford the corresponding azide in high yield with high enantiomeric excess (Entry 4). Similary, chiral
benzylic alcohol 1j with an -ester group gave the desired product in high yield with complete inversion
of stereochemistry while enantiomeric excess of the desired product was lowered if chiral tert-alcohol 1o
with an -ester group was used (Entries 5 and 6). When azidation of tert-alcohol 1o (80%ee) was
performed at 0 ºC, the desired product was obtained with almost complete inversion (78%ee) though the
yield was lowered to 44% because of the undesired trimethylsilyl ether 5 produced (Scheme 9).
PhOPPh2 (3.0 equiv)
TMSCH2N3 (3.0 equiv)
Ph
OH
Me
Ph
N3
Me
Ph
OTMS
Me
TMSN3
EtO2C
EtO2C
EtO2C
toluene, 0 C, 48 h
1o (80%ee)
(3.0 equiv)
5
41%
4o
44%, 78%ee
Scheme 9
The chiral tert-alkyl azides 4j is reduced into the corresponding chiral tert-alkyl amine in high yield by
hydrogenation, therefore, a concise method for the preparation of chiral amines from the corresponding
alcohols is established (Scheme 10). In hydrogenation process, tert-alkyl azides 4i is converted into the
corresponding ,-disubstituted -amino acid 6 (isovaline) and the optical rotation of 6 was also in good
agreement with the reported value concerning sign and absolute value41 (Scheme 11). Also, the azide 4i is
converted into 1,4-disubstituted 1,2,3-triazole on treatment with phenylacetylene in the presence of
CuSO4·5H2O and sodium ascorbate (Scheme 12).
Me N3
Ph CO2Me
Me NH2
Ph CO2Me
H2, Pd/C
EtOAc, rt
4j
96% yield
Scheme 10
[]D34  10.0 (c 0.93, H2O)
Me N3
Et CO2Bn
4i
Me NH2
H2, Pd/C
MeOH, rt
Lit.,41 for 6:
[]D15  10.8 (c 1.00, H2O)
Et
CO2H
quant.
(R)-isovaline (6)
Scheme 11

HETEROCYCLES, Vol. 80, No. 1, 2010
75
Ph
N
CuSO4•5H2O
Me N3
Et CO2Bn
4i
Me N N
sodium ascorbate
Ph
H2O/tBuOH, rt
Et
CO2Bn
87%, 96%ee
Scheme 12
A plausible reaction mechanism is shown in Scheme 13: a reaction of PhOPPh2 and trimethylsilylmethyl
azide affords initially the corresponding iminophosphorane which in turn results in forming of
phosphonium salt A by subsequent N-silylation with trimethylsilyl azide. The following nucleophilic
attack of an alcohol to the positively charged phosphorus atom leads to alkoxyphosphonium salt B which
－
is a key intermediate. Finally, a nucleophilic attack of the azide anion (N3 ) to the carbon atom adjacent
to an oxygen atom of alkoxy group via SN2 manner gave the inverted azide.
Ph Ph
PhO P N R
Ph Ph
PhO P N R
TMS N3
PhOPPh2 RN3
(R = CH2TMS)
N2
iminophosphorane
Ph Ph
PhO P N R
Ph
R1 N3
Ph
R1 O
O
P N R
TMS
R3
TMS
R1 OH
Ph2P NR
R2
R3
N3
PhOH
TMS
R2
R2
R3
N3
'' Inversion''
A
B
Scheme 13
CARBONOXYGEN BOND FORMING REACTION
Stereoinversion of a chiral sec-alcohol is a versatile method for constructing a new chiral center and is
commonly carried out by condensation of a sec-alcohol with a carboxylic acid under Mitsunobu
conditions followed by hydrolysis of the resulting ester. However, it is also known that Mitsunobu
reaction is not applicable to the sterically-hindered tert-alcohols. Then, the application of the above
oxidationreduction condensation to oxygen nucleophiles was next studied in order to develop a new
method for stereoinversion of a chiral tert-alcohol.
In order to find a most reactive oxygen nucleophile and a suitable oxidant, reactions of tert-alcohol 1i
with various carboxylic acids were first examined in the presence of PhOPPh2 and various oxidants
(Table 8, Entries 17). The esterification of tert-alcohol 1i with benzoic acid did not give good results
under any oxidants such as benzyl azide, DMBQ or DEAD (Entries 13). As a result of the examination

76
HETEROCYCLES, Vol. 80, No. 1, 2010
Table 8. Optimization of reaction conditionsa
PhOPPh2 (2.0 equiv)
oxidant (2.0 equiv)
Me OH
Me Nu
Nu H
Et
CO2Bn
Et
CO2Bn
toluene
1i (1.0 equiv)
(2.0 equiv)
Yield/%a
Entry
Temp., Time
Nucleophile
Oxidant
1
2
3
4
5
6
7
C6H5CO2H
C6H5CO2H
N3CH2Ph
DMBQ
DEAD
DEAD
DEAD
DEAD
DEAD
rt, 24 h
rt, 24 h
rt, 24 h
rt, 1 h
N.D.
trace
5
C6H5CO2H
2-NO2C6H5CO2H
4-NO2C6H5CO2H
2-MeOC6H5CO2H
4-MeOC6H5CO2H
52
rt, 72 h
rt, 24 h
rt, 24 h
24
N.D.
9
8
9
N3CH2Ph
N3CH2CO2Et
DMBQ
trace
trace
49
BtzOH
BtzOH
BtzOH
BtzOH
40 °C, 24 h
40 °C, 24 h
0 °C, 24 h
0 °C, 1 h
10
11
DEAD
60
aIsolated yield.
Table 9. Reactions of various tert-alcohols with oxygen nucleophiles
PhOPPh2 (2.0 equiv)
DEAD (2.0 equiv)
2-NO2-C6H4CO2H
R OR4
ROH
or
BtzOH
toluene, rt, 1 h
1 (1.0 equiv)
7 or 8
(2.0 equiv)
7
8
Yield/%a
R4
Entry
ROH
1
Product
Me OR4
Me OH
2-NO2-C6H4CO
Btz
1
2b
7b
8b
76
70
1b
Me
Ph
CO2Bn
Me
CO2Bn
Me OR4
Me OH
Me
3c
4c
7c
8c
39
50
2-NO2-C6H4CO
Btz
Ph
1c
1d
Me
O
O
Me OR4
Me OH
Ph Me
2-NO2-C6H4CO
Btz
5
6b,d
7d
8d
43
38
Ph
Me
Me OR4
Me
Me OH
Me
2-NO2-C6H4CO
Btz
7
8b
7e
8e
39
43
1e
Ph
Ph
aIsolated yield. bThe reaction was carried out at 0 C. cThe reaction was carried out at 80 C.
dThe reaction time was 24 h.
of the influence of substituents on the aromatic carboxylic acid in the presence of DEAD, the desired
product was found to obtain in 52% yield when 2-nitrobenzoic acid was used as a nucleophile (Entry 4).
Because 2-sulfanyl-1,3-benzothiazole (BtzSH) showed high nucleophilicity as a sulfur nucleophile as

HETEROCYCLES, Vol. 80, No. 1, 2010
77
shown in Table 3, etherification using 2-hydroxy-1,3-benzothiazole (BtzOH) as an oxygen nucleophile
was further examined (Entries 811). A reaction of tert-alcohol 1i and BtzOH in the presence of azide
compounds as an oxidant scarcely afforded the desired product while the use of DMBQ gave the
corresponding product in 49% yield (Entries 810). On the other hand, the yield of the desired product
increased to 60% in the case of using DEAD (Entry 11). Thus, it is apparent that 2-nitrobenzoic acid and
BtzOH were suitable nucleophiles in this reaction system.
Next, esterification and etherification of various tert-alcohols was tried in order to examine the scope of
this reaction under the optimized conditions (Table 9). The reactions of tert-alcohol 1b having an -ester
group afforded either ester and ether in good yields (Entries 1 and 2) while it was moderate in the cases
with 1c bearing -ketone (Entries 3 and 4). Also, the reactions of benzylic alcohol 1d or aliphatic
substrate 1e afforded the corresponding products in moderate yields along with undesired olefins (Entries
5–8).
Table 10. Reactions of various tert-alcohols with oxygen nucleophiles
PhOPPh2 (2.0 equiv)
DEAD (2.0 equiv)
R1 OH
R1 OR4
2-NO2-C6H4CO2H
or
R2 R3
R2 R3
7 or 8
BtzOH
(2.0 equiv)
toluene, rt, 13 h
1 (1.0 equiv)
1
7
8
Yield/%a
91
R4
Entry
1
ROH
Product
OR4
ee/%b
>99
(%ee)
OH
1a
(>99)
2-NO2-C6H4CO
7a
Ph
Me OH
Et CO2Bn
Me
Ph
Me OR4
Et CO2Bn
Me
2
3c
2-NO2-C6H4CO
Btz
7i
8i
52
60d
96
96
1i
(>99)
Me OR4
Me OH
4
5c
2-NO2-C6H4CO 7j
42
54
85
94
1j
(>99)
Btz
8j
Ph
CO2Me
Ph
CO2Me
Ph
EtO2C
OH
Me
Ph
EtO2C
OR4
Me
2-NO2-C6H4CO 7o
6
7c
32
46
78
79
1o
(80)
8o
Btz
aIsolated yield. bDetermined by HPLC analysis. cThe reaction was carried out at 0 C. dWhen
the reaction was carried out at 100 C for 24 h under Mitsunobu conditions (PPh3/DEAD), the
desired product was scarcely obtained.
Taking the above results into consideration, reactions of various chiral alcohols were next tried in order to
examine the stereochemistry of this reaction (Table 10). The esterification of sec-alcohol 1a proceeded
smoothly to afford the corresponding ester in excellent yield with complete inversion of stereochemistry
(Entry 1). The esterification and etherification of chiral tert-alcohol 1i having an -ester group afforded

78
HETEROCYCLES, Vol. 80, No. 1, 2010
the corresponding products (7i and 8i) in moderate yield with high enantiomeric excess while 8i was
scarcely obtained under Mitsunobu condition (Entries 23). Chiral benzylic alcohol 1j gave the desired
products also in moderate yield but with slightly lowered optical purity (Entries 4 and 5). In the case of
chiral tert-alcohol 1o, the corresponding products were obtained in moderate yield with almost complete
inversion (Entries 6 and 7).
A plausible reaction mechanism is shown in Scheme 14: a reaction of PhOPPh2 and DEAD initially
affords the corresponding betaine followed by successive deprotonation of 2-nitrobenzoic acid or BtzOH
to result in the formation of phosphonium salt A. A subsequent nucleophilic attack of an alcohol on the
positively charged phosphorus atom leads to the formation of alkoxyphosphonium salt B which is a key
intermediate, and the following nucleophilic attack of carboxylate anion or aryloxy anion (BtzO－) on the
carbon atom adjacent to an oxygen atom of alkoxy group via SN2 substitution gives the inverted product.
Ph
Ph
PhO P
CO2Et
CO2Et
H OR4
N
PhOPPh2 DEAD
N
betaine
Ph
Ph
CO2Et
CO2Et
Ph
PhO P
N
R1 OR4
R2 R3
'' Inversion''
PhO
R1 O
O
P Ph
HN
Ph2P OPh
R1 OH
OR4
DEAD-2H
OR4
R2
R3
R2
R3
A
B
Scheme 14
O
Me OH
Me O
NaOMe
NO2

Ph
CO2Me

Ph
CO2Me
MeOH/MeCN, rt
85% yield
7j
Scheme 15
Me OBtz
Me OH
LiAlH4
OH


Ph
CO2Me
8j
Ph
59% yield
THF, reflux
Scheme 16
As the chiral ester 7j or ether 8j treated by NaOMe or LiAlH4 was converted to the corresponding chiral
alcohol in high or moderate yield, respectively, (Scheme 15 and 16), a new method for stereoinverion of
chiral tert-alcohols was established.

HETEROCYCLES, Vol. 80, No. 1, 2010
79
In summary, a new type of oxidation–reduction condensation by the combined use of PhOPPh2 and
oxidants such as azides or DEAD was established. It is noted that this reaction system was applicable to
stereospecific C–S, C–N and C–O bond forming reaction from chiral sec- and tert-alcohols under mild
and neutral conditions.
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Teruaki Mukaiyama was born in 1927. He received his B.Sc. from the Tokyo Institute of
Technology (T.I.T) in 1948, and Ph.D. from the University of Tokyo in 1957. He first became
Assistant Professor at Gakusyuin University in 1953 and then at T.I.T in 1958. He was appointed
Full Professor at TIT in 1963 and moved to the University of Tokyo in 1974. In 1987 he became
Professor of Chemistry at Science University of Tokyo and moved to the Kitasato Institute in
2002. Since 2009 he supervises basic research on new synthetic reactions at TCI; as well as
Emeritus Professor at the University of Tokyo, the T.I.T, and the Science University of Tokyo. He
is a recipient of many major awards and is currently a member of the Japan Academy as well as a
foreign member of the Academy of Sciences in American, France and Poland.
Kiichi Kuroda was born in 1981 and received B.Sc. (2004) and Ph.D. degree (2009) from Tokyo
University of Science. He was a JSPS research fellow during 2006-2009.

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Yuji Maruyama was born in 1984 and received B.Sc. (2007) and M.S degree (2009) from Tokyo
University of Science.