Advances and mechanistic insight on the catalytic Mitsunobu reaction using recyclable azo reagents

Article abstract of DOI:10.1039/c6sc00308g

Ethyl 2-arylhydrazinecarboxylates can work as organocatalysts for Mitsunobu reactions because they provide ethyl 2-arylazocarboxylates through aerobic oxidation with a catalytic amount of iron phthalocyanine. First, ethyl 2-(3,4-dichlorophenyl)hydrazinecarboxylate has been identified as a potent catalyst, and the reactivity of the catalytic Mitsunobu reaction was improved through strict optimization of the reaction conditions. Investigation of the catalytic properties of ethyl 2-arylhydrazinecarboxylates and the corresponding azo forms led us to the discovery of a new catalyst, ethyl 2-(4-cyanophenyl)hydrazinecarboxylates, which expanded the scope of substrates. The mechanistic study of the Mitsunobu reaction with these new reagents strongly suggested the formation of betaine intermediates as in typical Mitsunobu reactions. The use of atmospheric oxygen as a sacrificial oxidative agent along with the iron catalyst is convenient and safe from the viewpoint of green chemistry. In addition, thermal analysis of the developed Mitsunobu reagents supports sufficient thermal stability compared with typical azo reagents such as diethyl azodicarboxylate (DEAD). The catalytic system realizes a substantial improvement of the Mitsunobu reaction and will be applicable to practical synthesis.

Full text of DOI:10.1039/c6sc00308g

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DOI: 10.1039/C6SC00308G
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ARTICLE
Advances and mechanistic insight on the catalytic Mitsunobu
reaction using recyclable azo reagents
Daisuke Hirose,a Martin Gazvoda,b Janez Košmrlj*b and Tsuyoshi Taniguchi*c
Received 00th January 20xx,
Accepted 00th January 20xx
Ethyl 2‐arylhydrazinecarboxylates can work as organocatalysts for Mitsunobu reactions because they provide
ethyl 2‐arylazocarboxyaltes by aerobic oxidation with a catalytic amount of iron phthalocyanine. First, ethyl
2‐(3,4‐dichlorophenyl)hydrazinecarboxylate has been identified as a potent catalyst, and reactivity of the
catalytic Mitsunobu reaction was improved by strict optimization of reaction conditions. Investigation of the
catalytic property of ethyl 2‐arylhydrazinecarboxylates and the corresponding azo forms led us to discovery
of a new catalyst, ethyl 2‐(4‐cyanophenyl)hydrazinecarboxylates, which expanded the scope of substrates.
The mechanistic study of the Mitsunobu reaction with these new reagents strongly suggested formation of
betaine intermediates as in typical Mitsunobu reactions. The use of atmospheric oxygen as sacrificial
oxidative agent along with the iron catalyst is convenient and safe from the viewpoint of green chemistry. In
addition, thermal analysis of developed Mitsunobu reagents supports sufficient thermal stability compared
with typical azo reagents such as diethyl azodicarboxylate (DEAD). The catalytic system realizes substantial
improvement of the Mitsunobu reaction and will be applicable to practical synthesis.
DOI: 10.1039/x0xx00000x
www.rsc.org/
amount of waste, i.e., diethyl hydrazinedicarboxylate and
triphenylphosphine oxide, is unavoidable. These byproducts
often contaminate the desired product. In addition, DEAD is
hazardous due to toxicity and potential explosiveness. As a
result, the use of the Mitsunobu reaction tends to be avoided
in practical synthesis on plant scales.4
Several modified methods have been developed to
facilitate removal of waste generated by the Mitsunobu
reaction.5 However, there has been no substantial approach to
reducing problematic waste in the Mitsunobu reaction until
the report on the catalytic Mitsunobu reaction by Toy in 2006.6
Toy succeeded in reducing DEAD in the Mitsunobu reaction to
a catalytic amount (10 mol%) by employing a sacrificial
oxidative reagent, i.e., iodobenzene diacetate. Recently,
Mitsunobu‐type reactions without azo reagents were
reported.7 In 2013, we reported the second example of the
catalytic Mitsunobu reaction with azo reagents recyclable by
aerobic oxidation with iron phthalocyanine (Fig. 1A).8 Ethyl 2‐
Introduction
Many reactions have been utilized as important tools in the
synthetic organic chemistry. “Name reactions”, such as Wittig,
Suzuki‐Miyaura, and Mitsunobu reaction, to name just a few,
have an outstanding utility that influenced broad fields of
academia and industy.1 In view of economic and
environmental concerns, however, many of these synthetic
methods suffer from serious limitations, diminishing their
practical applicability. Therefore, substantial improvements of
known synthetic protocols are currently an important subject
in chemistry.
Indeed, the Mitsunobu reaction is a typical example
including both, wide utility and serious drawbacks.2 The
reaction is one of the oxidation‐reduction condensations
reported by Mitsunobu and co‐workers in 1967.3 Since then, it
has been widely used for substitution of hydroxyl groups or
inversion of the stereochemistry of secondary alcohols.
(3,4‐dichlorophenyl)hydrazinecarboxylate
(
1a)
has been
Typically,
diethyl
azodicarboxylate
(DEAD)
and
tentatively identified as the best catalyst. A catalytic concept
of this reaction is beneficial from a viewpoint of green
chemistry because atmospheric oxygen is economically and
environmentally ideal as a sacrificial oxidant to generate
reactive azo form 2a (Fig. 1B). However, scope of substrates
and product yields were still moderate, and the reaction
required heating conditions to obtain products in acceptable
yields. Thus, the applicability of the method was still inferior to
that of the original Mitsunobu reaction.
triphenylphosphine are employed as an oxidant and a reducing
agent in the Mitsunobu reaction, but production of a large
a. Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma‐machi, Kanazawa 920‐1192, Japan.
b. Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot
113, SI‐1000, Ljubljana, Slovenia. E‐mail: janez.kosmrlj@fkkt.uni‐lj.si
c. School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and
Health Sciences, Kanazawa University, Kakuma‐machi, Kanazawa 920‐1192,
Japan. E‐mail: tsuyoshi@p.kanazawa‐u.ac.jp
†Electronic Supplementary Information (ESI) available: Full experimental details
and copies of analytical data. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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substantial improvement of the reaction and insiVgiehwtsAritinclteoOntlhinee
reaction mechanism.
(A) Catalytic Mitsunobu reactions under previous conditions
DOI: 10.1039/C6SC00308G
CO2Et
H
Cl
N
N
H
(10 mol%)
Cl
Results and discussion
Strict Optimization of Reaction Conditions.
OCOR3
R2
Fe(Pc) (10 mol%)
PPh3 (2 equiv)
OH
R3CO2H
R1
R1
R2
We previously found that combination of ethyl 2‐(3,4‐
dichlorophenyl)hydrazinecarboxylate
MS 5Å, air, THF, 65 C
inversion
(
1a
)
and
iron
phthalocyanine [Fe(Pc)] formed an optimum catalytic system
(both 10 mol%), and that addition of activated molecular
sieves was required to induce the reaction (vide infra).8 We
tentatively improved the yields of products by using 3,5‐
dinitrobenzoic acid as a nucleophile when secondary alcohols
were used as substrates.8 We employed a model reaction
(B) The concept of catalytic Mitsunobu reactions
Mitsunobu reaction
CO2Et
CO2Et
H
Cl
Cl
N
N
Cl
Cl
N
N
H
1a
2a
between (S)‐ethyl lactate (
) using this catalytic system to strictly optimize the
conditions. The reaction between and in heating THF (65
C) gave ester product in 50% yield and in 97% inversion
(Table 1, Entry 1).
3, 99:1 er) and 4‐nitrobenzoic acid
(
4
N
3
4
N
N
N
oxidation
Fe
º
5
N
N
[Fe(Pc)/O2]
N
N
In the previous study, the effect of solvents was
investigated at a very preliminary stage using unoptimized
catalysts.11 We could not find a large effect of the solvents at
that time, and thereby, the effects of solvents and
temperature were re‐investigated using the optimum catalytic
Iron phthalocyanine [Fe(Pc)]
(C) Improvement based on new insights
1) Strict optimization
2) Mechanistic studies
3) A new catalyst
Limitation:
Improvement:
• room temperature
• good yield
Table 1 The effect of solvents.a
• heating conditions
• moderate yield
• insufficient scope
• wide scope
1a (10 mol%)
Fig. 1 An outline of the catalytic Mitsunobu reaction.
Fe(Pc) (10 mol%)
CO2H
Me
CO2Et
PPh3 (2.0 equiv)
The effect of substituents on the aromatic ring of the
hydrazine catalysts was drastic. Clearly, electronic properties
of catalysts affected both Mitsunobu reactivity of the azo form
as well as aerobic oxidation of the hydrazine form. At the first
glance, these seem incompatible because electron‐
withdrawing groups would promote the addition reaction of
triphenylphosphine to the azo form but would suppress
oxidation of the hydrazine form to the azo form. In the case of
electron‐donating groups there is the same dilemma, though
the situation is interchanged. We presumed that 3,4‐
dichlorophenyl group had an electronic property that made
the two processes moderately compatible.
Quite recently, we have reported a detail of the aerobic
oxidation process of 2‐arylhydrazinecarboxylates with iron
phthalocyanine, indicating two important observations.9 First,
the oxidation process was promoted in apolar solvents such as
toluene or dichloromethane, and second, electron‐
withdrawing substituents at the aryl group did not suppress
the hydrazine‐to‐azo compound oxidation. Interestingly,
halogen atoms at the para‐position rather promoted the
reaction. Thus, this study provided us important insights to
improve the catalytic Mitsunobu reaction.
solvent (0.5 M)
air, MS 5Å
OH
O2N
3 (1.0 equiv)
4 (1.1 equiv)
O2N
Me
O
CO2Et
CO2Et
H
Cl
N
N
H
O
Cl
1a
5
Entry
1
2
3
4
5
6
7
8
Solvent
THF
Temp. (°C)
Time (h)
24
24
24
24
24
24
24
24
12
29
36
24
48
24
24
Yield (%)
50
46
70
76
40
14
69
74
78
88
75
80
75
70
75
Er
65
65
65
55b
65
65
65
65
110b
rt
97:3
96:4
97:3
98:2
58:42
19:81
99:1
94:6
49:51
99:1
99:1
38:62
12:88
59:41
95:5
1,4‐dioxane
CPME
MTBE
DME
MeCN
n‐hexane
toluene
toluene
toluene
CPME
9
10
11
12
13
14
15
rt
CHCl3
CH2Cl2
PhCl
62b
rt
65
65
PhCF3
Providing the serious limitations indicated in Fig. 1C are
avoided, the catalytic Mitsunobu reaction will gain a large
potential in practical synthesis.10 In this paper, we describe
new advances in our catalytic Mitsunobu reaction including
aReaction conditions: 3 (1.0 mmol), 4 (1.1 mmol), catalyst 1a (0.10 mmol), Fe(Pc)
(0.10 mmol), PPh3 (2.0 mmol), solvent (2 mL), MS 5Å (500 mg) at room
temperature under air atmosphere. MS 5Å was activated by heating by a heat
gun (ca. 450 °C) in vacuo (ca. 0.1 mmHg) for 5 min. bUnder reflux.
2 | J. Name., 2012, 00, 1‐3
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system (Table 1).12 Ether solvents such as 1,4‐dioxane,
cyclopentyl methyl ether (CPME)13 and tert‐butyl methyl ether
(MTBE), except for dimethoxyethane (DME), provided product
Table 2 The effect of desiccants.a
View Article Online
DOI: 10.1039/C6SC00308G
5
in high inversion ratio (Entries 2
gave a contrasting result (Entry 6).14 Reactions in hydrocarbon
solvents such as n‐hexane and toluene at 65 C afforded good
results (Entries 7 and 8). However, chlorinated solvents gave
product in a low inversion ratio, though total product yield
was good (Entries 12 14). This drastic change in the results
−5), whereas acetonitrile
º
5
−
was attributed to the presence of chlorine atoms in the solvent,
and is based on the fact that the reaction in α,α,α‐
trifluorotoluene15 provided similar results to those in toluene
(Entry 15). The enantiomeric ratio was sensitive to
temperature in the reaction in toluene (Entries 8
delight, the reaction in toluene at room temperature provided
the product in excellent yield (88%) and in perfect inversion
ratio. CPME also gave a relatively good result in the reaction at
room temperature. The reactions were basically clean. In the
case of low yields of the product, starting materials remained
unconsumed.
The effect of molecular sieves was drastic, and no reaction
was induced in their absence (Table 2, Entry 1).16 This is likely
due to the high moisture sensitivity of the intermediate
generated from the azo form of catalyst 1a and
triphenylphosphine. Molecular sieves would serve for
removing residual moisture as well as water generated by iron‐
catalyzed aerobic oxidation of the hydrazine catalyst. The use
of at least 500 mg MS 5Å (1.0 mmol scale), activated by
heating with a heat gun (ca. 450 °C) under reduced pressure
−10). To our
Entry
1
2
3
4
5
6
7
8
Desiccant
None
Amount (mg/mmol)
Yield (%)
0
Er
−
−
5
MS 5Å (A)
MS 5Å (A)
MS 5Å (A)
MS 5Å (A)
MS 4Å (A)
MS 3Å (A)
MS 5Å (B)
MS 5Å (C)
MS 5Å (D)
MS 5Å (E)
MS 5Å (F)
Na2SO4
100
300
500
1000
500
500
500
500
500
500
500
500
500
500
32
77
88
95
32
26
13
16
25
67
94
0
99:1
99:1
99:1
99:1
97:3
98:2
96:4
91:9
97:3
98:2
99:1
−
9
10
11
12
13
14
15
CaSO4
MgSO4
0
0
−
−
aReaction conditions: 3 (1.0 mmol), 4 (1.1 mmol), catalyst 1a (0.10 mmol), Fe(Pc)
(0.10 mmol), PPh3 (2.0 mmol), toluene (2 mL), desiccant (0−1000 mg) for 24−48 h
at room temperature under air atmosphere. Methods for activation of molecular
sieves: A: heated by a heat gun (ca. 450 °C) in vacuo (ca. 0.1 mmHg) for 5 min; B:
(ca. 0.1 mmHg), was desirable to obtain the product
yield (Entries 2 5). MS 4Å and MS 3Å were ineffective in the
present reaction (Entries 6 and 7).
5 in good
−
Various “traditional methods” for the activation of not activated; C: heated in an oven (140 °C) for 24 h; D: heated by microwave
(1000 W for 1 min, three times); E: heated by an oil bath (200 °C) in vacuo (ca. 0.1
mmHg) for 24 h; F: heated by a gas burner (>1000 °C) in vacuo (ca. 0.1 mmHg) for
5 min.
molecular sieves are used in many laboratories.
Representative activation methods were tested to assure a
reliable experimental procedure. The use of MS 5Å without
activation gave the product in very poor yield (Entry 8). MS 5Å
1.5 equivalent in the reaction in high concentration (2.0 M or
heated for 24 h at 140 °C in an oven was also ineffective (entry
4.0 M), good yield was maintained in this model reaction
9). Although heating by microwave is sometimes used for
(Entries 5 and 8). However, the use of a lower amount (1.1
activation of molecular sieves, this method did not afford a
equiv) of triphenylphosphine diminished yield of the product
5
good result in the present reaction (Entry 10). When the
reaction was tested with MS 5Å activated by heating at 200 °C
with an oil bath under reduced pressure (ca. 0.1 mmHg), the
product yield was still insufficient (Entry 11). Heating by flame
under reduced pressure would be a strict method for
activation of molecular sieves, and this method provided the
(Entries 6 and 9). High concentration conditions would be
beneficial to practical synthesis because the solvent can be
saved. The good result was reproducible in a scale‐up
experiment (10 mmol), though the reaction time was
somewhat prolonged (entry 7, results in parentheses).
Triphenylphosphine
is
sometimes
replaced
with
product
5 in excellent 94% yield (Entry 12). As a result, and
trialkylphosphines because they often provide good results
due to their high nucleophilicity.17 We tested a representative
reaction with tri‐n‐butylphosphine, but the result was very
poor (entry 8, results in parentheses). TLC analysis of the
from viewpoints of safety and convenience, we consider the
activation with a heat gun as the method of choice.
Incidentally, sulfate salts did not work as a desiccant in the
reaction (Entries 13
A concentration of the reactants is likely to affect the
product yield (Table 3, Entries 1 4 and 7). The reaction was
promoted and gave improved yield of the product in high
−15).
reaction
mixture
implied
decomposition
of
iron
phthalocyanine presumably by strong coordination with tri‐n‐
butylphosphine. When most of triphenylphosphine was
consumed in the reaction, the Mitsunobu catalyst was
detected as the azo form on TLC. The latter was easily
−
5
concentrations (2.0 M or 4.0 M) (Entries 4 and 7). When the
amount of triphenylphosphine was decreased to
recovered in 80
−90% yield by silica gel chromatography due to
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DOI: 10.1039/C6SC00308G
Table 3 Effects of amounts of reagents and concentrations.a
Entry
1
2
3
4
5
6
7
8
1a (mmol%)
Fe(Pc) (mmol%)
PPh3 (equiv)
2.0
Conc. (M)
0.1
Time (h)
52
29
18
14
Yield (%)
Er
98:2
99:1
98:2
98:2
10
10
10
10
10
10
10
10
10
10
10
10
5
10
10
10
10
10
10
10
10
10
5
1
1
10
5
3
80
88
91
97
91
2.0
2.0
2.0
1.5
1.1
2.0
1.5
1.1
1.5
1.5
2.0
1.5
1.5
1.5
0.5
1.0
2.0
2.0
2.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
14
12
99:1
99:1
68
12 (24)b
12 (48)c
12
93 (88)b
92 (10)c
76
99:1 (99:1)b
99:1 (46:54)c
99:1
9
10
11
12
13
14
15
21
18
36
38
24
39
84
81
89
78
76
68
99:1
99:1
99:1
99:1
99:1
99:1
5
3
aReaction conditions: 3 (1.0 mmol), 4 (1.1 mmol), 1a (0.030−0.10 mmol), Fe(Pc) (0.010−0.10 mmol), PPh3 (2.0, 1.5 or 1.1 mmol), toluene (10, 2, 1, 0.5 or 0.25 mL), MS
5Å (500 mg) at room temperature under air atmosphere unless otherwise noted. MS 5Å was activated by heating by a heat gun (ca. 450 °C) in vacuo (ca. 0.1 mmHg) for
5 min. bThe reaction was performed on 10 mmol scale. cPBu3 was used instead of PPh3.
its low polarity. The hydrazine form of the catalyst, if remained DEAD. Therefore, reaction rates were estimated from the
in the reaction mixture, usually did not cause problems in model reaction of azo compounds 2b
−j (50 mM) with
purification of the product. Finally, iron phthalocyanine could excessive amounts (10 equiv) of triphenylphosphine and water
be easily removed by filtration of the reaction mixture through in THF at 25
a pad of Celite® or filter paper. The impact of decreasing the
amount of hydrazine catalyst 1a seemed to be larger than that
of decreasing the amount of iron phthalocyanine (Entries
°C. The reactions were monitored by measuring
10−15). It is noteworthy that good results were maintained
with as low as 1 mol% of iron phthalocyanine (Entries 11 and
12) indicating that its amount can be flexibly changed
depending on substrates or situations of reactions. No reaction
was induced in the absence of the iron catalyst.8,9
Kinetic Property of Ethyl 2‐Arylazocarboxylates.
The catalytic cycle between hydrazines and azo compounds
would affect the efficiency of formation of an
alkoxyphosphonium intermediate to provide the final product.
We conducted kinetic experiments to investigate the
substituent effect of azo compounds 2b−j in the reaction with
triphenylphosphine (Fig. 2). The analysis of a mixture of 2b−j
and triphenylphosphine (10 equiv) in CDCl3 by 1H NMR
spectroscopy revealed the presence of some starting azo
compound after 10 hours. In contrast, in an independent
1
experiment, H NMR analysis showed that DEAD immediately
disappeared under the same reaction conditions, indicating an
irreversible process in this case.18 Obviously, the addition of
triphenylphosphine to ethyl 2‐arylazocarboxylates is reversible,
and the formation of adducts is less favorable as compared to
Fig. 2 The Hammett plot of reactions of ethyl 4‐substituted phenylazocarboxylates with
PPh3 in the presence of water. b: p‐OMe, c: p‐Me, d: H, e: p‐F, f: p‐Cl, g: m‐Cl, h: p‐
CO2Et, i: p‐CF3, j: p‐CN.
4 | J. Name., 2012, 00, 1‐3
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absorbance of azo compounds 2b
constants were calculated from plots of a pseudo‐first‐order
dependence.
ARTICLE
−j at λ= 419−450 nm. Rate
View Article Online
DOI: 10.1039/C6SC00308G
The Hammett plot in these reactions shows a linear fit with
a relatively large positive slope value of ρ = +2.71 (Fig. 2). The
value is close to that of alkaline hydrolysis of benzoate esters
(ρ = +2.51).19 The result reflects a dependence of the
electronic density at the aromatic ring of azo compounds in
the rate of the addition reaction of triphenylphosphine. Ethyl
2‐(3,4‐dichlorophenyl)azocarboxylate (2a) was also applied to
2
the kinetic experiment, and its reaction rate (kobs = 8.5
×
10−
1
min− ) was approximately 13.7 times faster than that of ethyl
3
1
2‐phenylazocarboxylate (2d, kobs = 6.2
addition, it is still 2.3 times faster as compared to that of ethyl
×
10− min− ). In
2
1
2‐(3‐chlorophenyl)azocarboxylate (2g, kobs = 3.75
×
10− min− ).
Fig. 3 An outline of the substituent effect of Mitsunobu catalysts in the catalytic cycle.
This supports high reactivity of 2a in the catalytic Mitsunobu
reaction.
without significantly suppressing the aerobic oxidation process.
For instance, as monitored by NMR spectroscopy, the aerobic
oxidation of ethyl 2‐(4‐cyanophenyl)hydrazinecarboxylate (1j
When benzoic acid or 4‐nitrobenzoic acid (each 10 equiv)
was added to the reaction system with 2d, only a minor impact
to the reaction rate was noted (2d with benzoic acid: kobs = 7.1
)
3
1
3
was completed within 5 hours, which was roughly the same
×
10− min− ; 2d with 4‐nitrobenzoic acid: kobs = 6.8
×
10−
1
reaction time as that of ethyl 2‐phenylhydrazinecarboxylate
min− ). This observation supports that the model reaction
reflects the reactivity of azo compounds toward
triphenylphosphine and indicates that acids do not kinetically
affect the reaction.
(
1d) (ca. 4 hours).9 On the other hand, higher electrophilicity of
2‐(4‐cyanophenyl)azocarboxylate (2j) over 3,4‐dichlorophenyl
derivative 2a is consistent with higher (3.8 times) reaction rate
1
1
of 2j (kobs = 3.2
×
10− min− ) over 2a (Fig. 3). This suggested
The kinetics of catalytic aerobic oxidation of ethyl 2‐
that ethyl 2‐(4‐cyanophenyl)hydrazinecarboxylate (1j) might
work as a good catalyst in the catalytic Mitsunobu reaction.
arylhydrazinecarboxylates
(
1)
with iron phthalocyanine
basically show zero‐order dependence, but the substituent
effect is of irregular tendency probably due to a participation
of radical species in the mechanism.9 The reaction rates of
When ethyl 2‐(4‐cyanophenyl)hydrazinecarboxylate (1j
was used in the reaction between (S)‐ethyl lactate ( ) and 4‐
nitrobenzoic acid ( ) under optimal conditions, product was
obtained in excellent yield, although with slightly decreased
inversion ratio. On the other hand, when phenol ( ) or
phthalimide ( ) was used as the reaction partner of 3‐
phenylpropanol ( ), both reactions using 1j provided better
results (87% and 84% yields) than the reactions with 1a (51%
and 66% yields). Although 2‐(4‐
nitrophenyl)hydrazinecarboxylate should generate
)
3
4
5
aerobic
oxidation
of
ethyl
2‐(4‐
chlorophenyl)hydrazinecarboxylate
(1f)
and ethyl 2‐(4‐
7
bromophenyl)hydrazinecarboxylate to the corresponding azo
compounds are approximately 1.5 times faster than that of
8
6
ethyl 2‐phenylhydrazinecarboxylate
(
1d).9 In the model
reaction in dichloromethane as a solvent, the aerobic
oxidation of ethyl 2‐(3,4‐dichlorophenyl)hydrazinecarboxylate
(
1k)
a
(
1a) with iron phthalocyanine is completed within 2 hours. This
strongly electrophilic azo compound,20 the results with this
catalyst were disappointing. Gradual decomposition of 1k or
its azo form was observed in the reaction with
is clearly faster than the oxidation (4 hours)9 of ethyl 2‐
phenylhydrazinecarboxyalte (1d), though kinetics of the
reaction of 1a do not show clear a zero‐order dependence
(Figure S14 in the Supplementary Information). Thus, the 4‐
chlorine atom on the aromatic ring of 1a promotes oxidation
to the corresponding azo form 2a by stabilization of
intermediary radical species, whereas the 3‐chlorine atom of
azo compound 2a contributes to an increased electrophilicity
by its inductive effect. This is the reason why azo compound 2a
operates as a good catalyst in the catalytic Mitsunobu reaction.
In short, two processes involving Mitsunobu activity and
hydrazine re‐oxidation are compatible by the 3,4‐
dichlorophenyl group (Fig. 3). Catalytic activity of ethyl 2‐(4‐
chlorophenyl)hydrazinecarboxylate (1f) was insufficient under
the optimal conditions compared to that of 1a (Fig. 4).
1
triphenylphosphine by H NMR analysis, which appears to be
the main reason of poor results.21
The
reaction
rate
of
ethyl
2‐[4‐
2
(ethoxycarbonyl)phenyl]azocarboxylate (2h, kobs = 6.4
×
10−
1
min− ) and ethyl 2‐[4‐(trifluoromethyl)phenyl]azocarboxylate
1
1
(
2i, kobs = 1.2
roughly close to that of 2a. Good yield of ester
obtained in the reaction between (S)‐ethyl lactate (
nitrobenzoic acid ( ) using these hydrazine forms 1h and 1i as
a catalyst, but reaction times were prolonged. When phenol
) or phthalimide ( ) was used as a nucleophile in the reaction
with 3‐phenylpropanol ( ), catalysts 1h and 1i did not provided
×
10− min− ) with triphenylphosphine was
were
) and 4‐
5
3
4
(
7
8
6
better results than catalyst 1j, though catalyst 1i somewhat
improved results compared with catalyst 1a. Thus, catalysts 1h
showed reactivity similar to that of 1a, and a position in
Given
the
above
considerations,
ethyl
2‐
arylhydrazinecarboxylates having strong electron‐withdrawing
groups on the aromatic ring should be more effective catalysts
as these groups should promote the Mitsunobu reaction
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DOI: 10.1039/C6SC00308G
1a,f,h k (10 mol%)
O
Fe(Pc) (10 mol%)
PPh3 (2.0 equiv)
CO2H
Me
CO2Et
Ph
OH
NH
or
or
or
PhOH
5, 9, 10
toluene (4.0 M)
air, MS 5Å, rt
OH
6
O2N
7
4
8
3
O
1f (4-Cl)
1a (3,4-diCl)
1h (4-CO2Et)
1i (4-CF3)
1j (4-CN)
1k (4-NO2)
O2N
Me
CO2Et
36 h
36 h
36 h
24 h
36 h
12 h
O
79% yield
98:2 er
92% yield
99:1 er
94% yield
98:2 er
95% yield
93:7 er
75% yield
92:8 er
93% yield
99:1 er
O
5
9
48 h
36 h
36 h
48 h
48 h
18 h
Ph
OPh
O
26% yield
51% yield
65% yield
73% yield
25% yield
87% yield
Ph
N
48 h
60 h
48 h
48 h
60 h
48 h
63% yield
45% yield
66% yield
61% yield
68% yield
84% yield
O
10
Fig. 4 Catalytic activity of representative hydrazine catalysts. Reaction conditions: Alcohol (1.0 mmol), nucleophile (1.1 mmol), catalyst 1a,f,h−k (0.10 mmol), Fe(Pc) (0.10 mmol),
PPh3 (2.0 mmol), toluene (0.25 mL), MS 5Å (500 mg) at room temperature under air atmosphere unless otherwise noted. MS 5Å was activated by heating by a heat gun (ca. 450 °C)
in vacuo (ca. 0.1 mmHg) for 5 min. The reaction between 6 and 8 to give 10 was performed in 2 mL of toluene (0.5 M).
reactivity of catalyst 1i was likely to lie between 1a and 1j
.
Hydroxyphthalimide also worked as a good nucleophile to give
These trends are consistent with results of the Hammett study. O‐alkylated product 17 in the presence of catalyst 1h. Similarly,
Incidentally, when model experiments of iron‐catalyzed a sulfur nucleophile (2‐mercaptobenzothiazole) underwent the
aerobic oxidation of 1h and 1i were conducted in Mitsunobu reaction with the alcohol to give the corresponding
dichloromethane, the reactions were completed at 4h and 6h, alkylated sulfide 18 in good yield. Reactions of the alcohol with
respectively (see the Supplementary Information). A trend of representative nitrogen nucleophiles were tested using
the oxidation process is similar to that of other hydrazide catalyst 1h and produced alkylated phthalimide 10, and
derivatives.9
sulfonylamides 1922 and 2023 in good yields. Reactions with
The above results imply that there is no perfect catalyst for phthalimides and the nosylamide needed to be performed in
the catalytic Mitsunobu reaction. Instead two catalysts can 0.5 M solution due to the solubility issues. In such the case,
complement each other. In short, ethyl 2‐(3,4‐ heating the reaction mixture at 65 ˚C improved results in a
dichlorophenyl)hydrazinecarboxylate (1a) would be suitable reaction time and product yield. Alcohols sensitive to oxidative
for the reactions of carboxylic acids whereas 2‐(4‐ conditions were tested with several nucleophiles and were
cyanophenyl)hydrazinecarboxylate (1j) could serve for the transformed into the corresponding Mitsunobu products
reactions of other nucleophiles except for carboxylic acids.
21−24 in good yields. It is noteworthy that a trisubstituted
olefin, a thiophene and an indole were intact under the
aerobic oxidation condition. The catalytic Mitsunobu reaction
using catalyst 1j was applicable to intramolecular reactions of
alkyl sulfonamides having a hydroxyl group to give the
corresponding cyclic amines 25 and 2623b in reasonable yields.
Next, various combinations of secondary alcohols and
nucleophiles were tested (Fig. 6). Reactions of (S)‐ethyl lactate
Scope of Substrates Using the Optimized Protocol.
The discovery of new catalyst 1j largely expanded the scope of
the catalytic Mitsunobu reaction. Fig. 5 shows the results of
catalytic Mitsunobu reactions applying catalyst 1a or 1j to
various substrates. Typically, the reactions were performed
under the optimal conditions that provided the best result
(Table 3, Entry 7), but more practical conditions (e.g., Table 3,
Entry 11) were also applicable to several substrates. Reactions
between 3‐phenylpropanol and various carboxylic acids with
(
3
)
with several aromatic carboxylic acids gave the
corresponding esters 34 36 in good yields with almost full
inversion of stereochemistry. The reaction of alcohol with
−
3
3,5‐dinitrobenzoic acid in toluene gave ester 35 in a moderate
level of enantioenrichment (er, 83:17). In the reaction of 3,5‐
catalyst 1a provided the corresponding esters 11
excellent yields. The reaction of the alcohol with phenols gave
the corresponding ethers and 16 in improved yields when
−15 in
dinitrobenzoic acid, previous conditions (in THF at 65 °C)
9
provided 35 in a higher level of enantioenrichment.8 In the
catalyst 1j was employed. An iodine atom was intact under the
present condition in the reaction of4‐iodophenol to give 16. N‐
6 | J. Name., 2012, 00, 1‐3
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Fig. 5 Reactions of primary alcohols with various nucleophiles. Reaction conditions: Alcohol (1.0 mmol), nucleophile (1.1 mmol), catalyst 1a or 1j (0.10 mmol), Fe(Pc) (0.10 mmol),
PPh3 (2.0 mmol), toluene (0.25 mL), MS 5Å (500 mg) at room temperature under air atmosphere unless otherwise noted. MS 5Å was activated by heating by a heat gun (ca. 450 °C)
in vacuo (ca. 0.1 mmHg) for 5 min. a1 mol% (0.010 mmol) of Fe(Pc) and 1.5 equiv (1.5 mmol) of PPh3 were used. b3 mol% (0.030 mmol) of Catalyst 1a, 3 mol% (0.030 mmol) of
Fe(Pc), and 1.5 equiv (1.5 mmol) of PPh3 were used. c2 mL (0.5 M) of toluene was used. d65 °C. e20 mL (0.05 M) of toluene was used.
reaction of
enantioenrichment of ester 37 was not good (er, 78:22), but results could be attributed to the catalytic system. The
the reaction at low temperature (0 C) gave an improved result reaction with a catalytic amount of the azo reagent maintains
(er, 90:10). Other nucleophiles such as phenol and phthalimide a low concentration of an intermediary alkoxyphosphonium
were applicable to reactions of chiral secondary alcohol to salt. There would be an equilibrium process between an
provide the corresponding Mitsunobu products 38 and 39 alkoxyphosphonium intermediate and an acyloxyphosphonium
though the product yields were somewhat moderate. intermediate.25 If
subsequent reaction of the
Reactions of other representative secondary alcohols alkoxyphosphonium intermediate with a carboxylic acid to give
27 32with 4‐nitrobenzoic acid ( ) readily provided the an inversion product is slow, a retention product would
corresponding inversion products 40 45 in good yields. There increase via the equilibrium process to give the
3
with 3‐phenylpropionic acid, the nitrobenzoic acid was used as a nucleophile. These contrasting
°
3
,
a
−
4
−
was a slight loss of the optical purity of ester 42, which was acyloxyphosphonium intermediate because the concentration
also observed in the typical Mitsunobu reaction with DEAD.6a of a free carboxylic acid is sufficiently higher than that of the
However, the case of (−)‐menthol (33) was still a limitation in alkoxyphosphonium intermediate in the catalytic system. 2‐
the catalytic Mitsunobu reaction even though a highly acidic Methyl‐6‐nitrobenzoic acid has a sufficient acidity but is
carboxylic acid was employed.24 For instance, the reaction of sterically hindered. Therefore, conversion of the
33 with 4‐nitrobenzoic acid gave inversion product 46 as a alkoxyphosphonium intermediate into the corresponding
minor isomer. Fortunately, we found out that inversion acyloxyphosphonium intermediate would be an unfavourable
product 47 was produced exclusively when the 2‐methyl‐6‐ process due to a steric factor of the carboxylic acid.26
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DOI: 10.1039/C6SC00308G
Fig. 6 Reactions of secondary alcohols with various nucleophiles. Reaction conditions: Alcohol (1.0 mmol), nucleophile (1.1 mmol), catalyst 1a or 1j (0.10 mmol), Fe(Pc) (0.10
mmol), PPh3 (2.0 mmol), toluene (0.25 mL), MS 5Å (500 mg) at room temperature under air atmosphere unless otherwise noted. MS 5Å was activated by heating by a heat gun (ca.
450 °C) in vacuo (ca. 0.1 mmHg) for 5 min. a1 mol% (0.010 mmol) of Fe(Pc) and 1.5 equiv (1.5 mmol) of PPh3 were used. bTHF was used as a solvent. c2 mL (0.5 M) of solvent was
used at 65 °C. d0 °C. eDetermined by 1H NMR analysis of the crude product. f3 mol% (0.030 mmol) of Fe(Pc) and 1.5 equiv (1.5 mmol) of PPh3 were used.
Mechanistic Studies of the Reaction by NMR Spectroscopic
Methodologies.
used in the study, along with some unlabeled analogues (Fig.
7).
The addition of triphenylphosphine (10 equiv) into the
solution of azo compounds in CDCl3 resulted in the appearance
of low‐field resonances in the 31P NMR spectra (2d: +33.9 ppm,
2a: +34.5 ppm, 2j: +35.4 ppm) that are supportive of the
formation of betaine intermediates. In light of electron
densityof a nitrogen atom, these chemical shifts are roughly
consistent with that of di‐15N‐DEAD (+44.2 ppm) and DEAD
(+44.8 ppm).27
Although it is predicted that Michael‐type addition of
triphenylphosphine to ethyl 2‐arylazocarboxylates (an attack
to N2) takes place to form betaines,28 the formation of other
intermediary structures should be considered. Unlike for the
symmetric DEAD,29 the issue of the regiochemistry of the
Does the reaction of ethyl 2‐arylazocarboxylates with
triphenylphosphine form Morrison‐Brunn‐Huisgen betaine
intermediates27 like in the typical Mitsunobu reaction?
Precedent mechanistic studies indicate the formation of
betaine intermediates from azo reagents and phosphines. To
obtain insights into the intermediates in the present reaction,
we monitored the reactions of ethyl 2‐arylazocarboxylates
with triphenylphosphine with multinuclear (1H, 13C, 31P, 15N) 1D
and 2D NMR spectroscopy. To assist an unambiguous structure
elucidation and assignment of NMR parameters, two kinds of
15N‐labeled ethyl 2‐phenylazocarboxylates 2d‐15N and 2d‐15N’,
15N‐labeled potent Mitsunobu reagents 2a‐15N, 2j‐15N and
doubly 15N‐labeled DEAD (di‐15N‐DEAD) were prepared and
8 | J. Name., 2012, 00, 1‐3
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CO2Et
CO2Et
DOI: 10.1039/C6SC00308G
CO2Et
CO2Et
15N
N
15N
N
15N
15N
N
Cl
Cl
N
CO2Et
15N 15N
EtO2C
NC
2d-15
NCO 107 ppma
N
2d-15N'
2a-15
N
2j-15
N
di-15N-DEAD
NCO 150 ppmg
125 ppme
145 ppme
114 ppmc
142 ppmd
NCO
NAr
NCO
NAr
149 ppma,b,f
NAr
O
O
O
Ph3P
N
Ph3P
N
Ph3P
O
Ph3P
Cl
Cl
N
OEt
N
OEt
N
N
OEt
N
N
OEt
EtO2C
NC
DEAD-PPh3
ppmg
48d
+33.9 ppmf
182 ppma
83 ppma,f
48a
48j
+34.5 ppmc,d
182 ppmc
85 ppmd
+35.4 ppme
179 ppme
90 ppme
+44.2
171 ppmg
ppmg
P
P
P
P
N
=C
N
=C
N
=C
N=C
N-P
113
N-P
N-P
N-P
Fig. 7 15N‐labeled ethyl 2‐arylazocarboxylates 2d‐15N, 2d‐15N’, 2a‐15N, 2j‐15N and di‐15N‐DEAD with 15N NMR chemical shifts (up), and 31P and 15N NMR data in CDCl3 of betaine
intermediates produced by the reaction of triphenylphosphine (10 equiv) with azo compounds (bottom). The data were obtained from: a2d‐15N, b2d‐15N’, c2a‐15N, dunlabeled 2a,
e2j‐15N, funlabeled 2d, gdi‐15N‐DEAD.
triphenylphosphine attack to ethyl 2‐arylazocarboxylates is formed in situ from 2a‐15N and triphenylphosphine in CDCl3,
raised as a consequence of their non‐symmetric nature and was treated in an NMR tube with iodomethane. 15N NMR
potential electrophilicity of azo benzene derivatives toward chemical shifts of the starting compounds and products are
triphenylphosphine.30,31
shown in Scheme 1. The reaction of 2a‐15
N
with
15N NMR spectroscopy was sought as a probe for the in situ triphenylphosphine followed by treatment with iodomethane
investigation of the regiochemistry. The formation of adducts
formed between triphenylphosphine and azo reagents was
1
1
1
1
monitored by H, 13C, 31P, H 1H COSY, H 13C HSQC, H 13C
− − −
142 ppm
O
Ph3P
N
1
1
HMBC, H− −
31P HMBC, H 15N HMBC experiments, as well as
CO2Et
15N
OEt
182 ppm
Cl
Cl
N
15N
Cl
Cl
PPh3
HRMS. The results are summarized in Fig. 7 (and Tables S3 and
S4 in the Supplementary Information). In ethyl 2‐
114 ppm
N
arylazocarboxylates (e.g. 2a
atoms resonate in the regions of 107
,
d
,
j
), the NCO and N‐Ar nitrogen
125 ppm and 142 149
85 ppm
48a-15N
2a-15
–
–
ppm, respectively. Upon the addition of triphenylphosphine, a
MeI
large downfield shift of NCO to around 180 ppm, and a
significant upfield shift of NAr to approximately 83−90 ppm is
109 ppm
Me
observed for the betaine intermediates. The nitrogen atoms
resonating in di‐15N‐DEAD at 150 ppm appear after the
addition of triphenylphosphine at 113 ppm and 171 ppm.
Since, to the best of our knowledge, this is the first 15N
NMR study of the intermediates formed in the Mitsunobu
reaction, no direct comparison with the literature data is
possible. Nevertheless, the downfield 15N resonances, which
are common for all phosphine intermediates from Fig. 7,
suggest carbonimidate structural fragments as they are
consistent with the 15N NMR data of dimethyl
cyclohexylcarbonimidate (50 in Scheme 1, N 181 ppm).32
Although this reminds of a five‐membered oxadiazophosphole
I
O
O
Ph3P
N
Me
O
N
15N
OEt
Cl
Cl
Me
181 ppm (ref. 31)
89 ppm
49
50
O
O
Ph3P
OEt
Cl
N
N
OEt
Cl
Cl
N
N
PPh3
Cl
51
52
ring structure (e.g., O,N‐phosphorane 52 in Scheme 1), the 31
P
Ph3P
O
NMR chemical shift of such an intermediate should possess a
negative value.27c Perhaps, the O,N‐phosphorane is formed as
a transient intermediate,27c but formation of the betaine
intermediate having a carbonimidate anion appears to be
predominant in the reaction mixture.
Cl
Cl
N
N
OEt
53
unlikely structures
Scheme 1 A trapping experiment of a betaine with iodomethane and chemical shifts of
To further support the structure of the intermediate we
15N NMR analysis.
carried out a trapping experiment in which betaine 48a
,
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readily afforded a methylated product holding a phosphine, as
Table 4 Detection of phosphorane intermediate 54 from butan‐1‐ol and betaine 48a by
View Article Online
31P NMR analysis in different solvents.
confirmed by 1H
−
31P HMBC. A correlation between N‐CH3
DOI: 10.1039/C6SC00308G
1
proton resonance with that of C=O carbonyl in the H–13C
HMBC spectrum, along with the absence of N‐CH3 correlations
with aromatic carbons, strongly suggested the formation of
15N‐methylated phosphonium salt 49. An upfield 15N NMR shift
from 182 ppm (in 48a‐15N) to 109 ppm by methylation
additionally supports the structure of 49. By repeating the
trapping experiment with 15N‐unlabeled 2a in a preparative
way, the corresponding phosphonium salt decomposed during
chromatographic purification on silica gel into ethyl 2‐(3,4‐
dichlorophenyl)‐1‐methylhydrazine‐1‐carboxylate (see the
Supplementary Information). Although the intermediates
Entry
Solvent
P (ppm)
54
48a
1
2
3
4
THF‐d8
CDCl3
−56.0
−55.3
−55.2
−55.8
+21.1
+34.5
+33.7
NDa
CD3CN
toluene‐d8
aNot detected.
generated
from
dialkyl
azodicarboxylates
and
triphenylphosphine are generally presented in a form of a
resonance structure with a negatively charged nitrogen atom
and a C=O double bond, our NMR data suggest that the
alternative with the sp2 hybridized nitrogen atom more
accurately represent the true structure of the betaine (Fig. 7).
This is also in agreement with oxygen being more
electronegative than nitrogen.
210−250 °C by differenꢀal scanning calorimetry (DSC),
indicating exponential decomposition of these compounds.33
We investigated thermal properties of ethyl 2‐(3,4‐
dichlorophenyl)azocarboxylate
cyanophenyl)azocarboxylate
(
2a
)
and
ethyl
2‐(4‐
(2j) with thermogravimetry‐
differential thermal analysis (TG‐DTA). Interestingly, it
indicated the absence of exothermic peaks, whereas
endothermic peaks were observed at 191.3 °C (3,4‐
dichlorophenyl derivative 2a, mp: 52.1°C) and 225.7 °C (4‐
cyanophenyl derivative 2j, mp: 55.4 °C) with loss of weight of
samples. These peaks likely show boiling points of azo
compounds that are accompanied by some evaporation. A
possibility of endothermic decomposition is unlikely because
decomposition of azo compounds is generally exothermic. To
eliminate the possibility of the endothermic decomposition,
we representatively tested to heat 2a in a solution‐phase. A
solution of 2a in benzene‐d6 was kept for 10 min at 200 °C in
an autoclave and then analyzed by 1H NMR spectroscopy,
which indicated no decomposition (See the Supplementary
Overall, NMR experimental results support the formation
of P
our reagents and indicate that other structures such as
regioisomer 51 and P O betaine 53 are unlikely. Formation of
−N betaines such as 48 in the Mitsunobu reaction using
−
O,N‐phosphorane 52 could not be ruled out but was not
detected in our NMR analysis.
By treating butan‐1‐ol (10 equiv) with triphenylphosphine
(10 equiv) and azo reagent 2a (1 equiv) in solvents like THF‐d8,
CD3CN, CDCl3, or toluene‐d8,
corresponding to di‐n‐butoxytriphenylphosphorane
appeared in spectra between 56.0 ppm and 55.2 ppm
(Table 4), which is consistent with the data for DEAD ( 55.0
a
31P NMR resonance
(
54)
−
−
−
ppm in THF‐d8).27a On the other hand, unlike for THF‐d8, CD3CN
and CDCl3, the resonance of betaine 48a in toluene‐d8 could
not be detected. This suggests that equilibrium toward betaine
48a from 2a is unfavorable but the reactivity of 48a toward an
alcohol is sufficiently high in toluene. Thus, the fate of the
betaine generated from ethyl 2‐arylazocarboxylates and
triphenylphosphine appears to be very similar to that from the
typical Mitsunobu reaction using DEAD.
Information).
Similarly,
TG‐DTA
of
ethyl
2‐(3,4‐
dichlorophenyl)hydrazinecarboxylate (1a, mp: 114.0 °C) and
ethyl 2‐(4‐cyanophenyl)hydrazinecarboxylate (1j, mp: 138.1 °C)
showed endothermic peaks with loss of weight of samples at
250.3 °C and 267.4 °C, though partial decomposition seems to
occur around this temperature in the case of 1j. Thus, we did
not observe clear exponential decomposition of our azo and
hydrazine compounds under the ambient pressure unlike in
typical Mitsunobu reagents, though we did not test thermal
stability of these compounds at higher temperature in a
pressured vessel.34 Overall, experimental results support that
our Mitsunobu catalysts can be safely stored and used without
special precautions.
Thermal Stability of Developed Mitsunobu Reagents.
When typical azo reagents such as DEAD are used, a sufficient
care is often required from a viewpoint of their thermal
instability. Ethyl 2‐(3,4‐dichlorophenyl)hydrazinecarboxylate
(
1a), ethyl 2‐(4‐cyanophenyl)hydrazinecarboxylate (1j) and
their azo forms 2a and 2j are stable crystalline solids under
ambient conditions, and no decomposition of these
compounds were observed after two months. Incidentally,
when di(2‐methoxyethyl) azodicarboxylate (DMEAD), that is
crystalline solid, was exposed to ambient conditions for two
months, a partial but clear decomposition was observed in 1H
NMR analysis. It is known that DEAD, diisopropyl
Conclusions
Ethyl 2‐arylazocarboxylates can operate in the Mitsunobu
reaction like typical Mitsunobu reagents such as diethyl
azodicarboxylate (DEAD). The former, however, are recyclable
by
aerobic
re‐oxidation
of
resulted
ethyl
2‐
arylhydrazinecarboxylate with cheap and nontoxic iron
phthalocyanine. This outstanding ability enables catalytic
Mitsunobu reactions by using these reagents as
azodicarboxylate
(DIAD)
and
di(2‐methoxyethyl)
azodicarboxylate (DMEAD) show a large exothermic peak at
10 | J. Name., 2012, 00, 1‐3
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5
For reviews on the modification of Mitsunobu reactions: (a)
organocatalysts. Our systematic study reveals that Mitsunobu
activity of azo forms of these catalysts is compatible with an
oxidation process of hydrazine forms. Two effective catalysts
R. Dembinski, Eur. J. Org. Chem., 2004, 2763V–ie2w7A7r2tic;le(Obn)linSe.
DOI: 10.1039/C6SC00308G
Dandapani, and Curran, D. P. Chem. Eur. J., 2004, 10, 3130–
3138. See also refs 2c−e. For a recent example of
modification, see: (c) M. Figlus, N. Wellaway, A. W. J. Cooper,
S. L. Sollis and R. C. Hartley, ACS Comb. Sci., 2011, 13, 280–
285; (d) P. K. Maity, A. Rolfe, T. B. Samarakoon, S. Faisal, R. D.
Kurtz, T. R. Long, A. Schätz, D. L. Flynn, R. N. Grass, W. J.
Stark, O. Reiser and P. R. Hanson, Org. Lett., 2011, 13, 8–10.
(a) T. Y. B. But and P. H. Toy, J. Am. Chem. Soc., 2006, 128,
9636–9637; (b) T. Y. S. But, J. Lu and P. H. Toy, Synlett, 2010,
1115–1117.
For Mitsunobu and related reactions without azo reagents:
(a) C. M. Vanos and T. H. Lambert, Angew. Chem., Int. Ed.,
2011, 50, 12222–12226; (b) E. D. Nacsa and T. H. Lambert,
Org. Lett., 2013, 15, 38–41; (c) X. Tang, C. Chapman, M.
have
been
identified.
Ethyl
2‐(3,4‐
dichlorophenyl)hydrazinecarboxylate
(
1a) is suitable for
catalytic Mitsunobu reactions with carboxylic acids, working
best for inversion of stereochemistry of secondary alcohols.
Ethyl 2‐(4‐cyanophenyl)hydrazinecarboxylate
(1j) provides
6
7
excellent results in reactions with nucleophiles other than
carboxylic acids, serving for transformation of the hydroxyl
group of alcohols to other functional groups. Thus, the
catalytic Mitsunobu reaction has been complemented by two
potent reagents and strict optimization of reaction conditions.
The present catalytic protocol is comparable to the original
Mitsunobu reaction in both, reactivity and scope. It is also
noteworthy that these reagents are stable solids, and their
thermal behavior is different from the typical Mitsunobu
reagents. Our study has illustrated that serious limitations of
the Mitsunobu reaction are avoidable by new reagents and
improved procedures. We expect that the improved method
will promote the use of the Mitsunobu reaction in the practical
synthesis.
Whiting and R. Denton, Chem. Commun., 2014, 50
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,
8
9
D. Hirose, T. Taniguchi and H. Ishibashi, Angew. Chem., Int.
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10 Examples of catalytic Mitsunobu reactions using a catalytic
amount of phosphine reagents: (a) C. J. O’Brien, PCT Int. Appl.
WO2010/118042A2., 2010; (b) J. A. Buonomo and C. C.
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Although Aldrich reported “a fully catalytic system” of the
Mitsunobu reaction by combining with our catalytic system
in this publication, only limited scope of substrates
(combination of two benzyl alcohols and 4‐nitrobenzoic acid)
has been shown. An original concept of phosphine catalysts:
(c) C. J. O’Brien, J. L. Tellez, Z. S. Nixon, L. J. Kang, A. L. Carter,
S. R. Kunkel, K. C. Przeworski and G. A. Chass, Angew. Chem.,
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Acknowledgements
Authors are thankful to Dr. Jun Kamitani (Industrial Research
Institute of Ishikawa) for measuring TG‐DTA and helpful
discussion. D.H. and T.T. are thankful to Profs. Shigeyoshi
Kanoh, Katsuhiro Maeda and Tomoyuki Ikai (Kanazawa
University) for their kind support. This work was supported by
MEXT/JSPS KAKENHI Grant‐in‐Aid for Scientific Research (C)
(Grant No. 25460011) and Grant‐in‐Aid for JSPS Fellows (Grant
No. 14J02441). Financial support from the Ministry of
Education, Science and Sport, Republic of Slovenia, the
Slovenian Research Agency (Grant P1‐0230) is acknowledged.
11 See the Supplementary Information of ref. 8.
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believing
that
aerobic
oxidation
having
of
ethyl
2‐
arylhydrazinecarboxylates
strong
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Chemical Science
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ARTICLE
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our TG‐DTA and DSC experiments of DMEAD, an exothermic
peak was observed at 210–220 °C (see the Supplementary
Information).
34 In our tentative DSC analysis of four compounds in a sealed
pan under ambient pressure, no exothermic peak was
observed below 300 °C similarly to TG‐DTA (see the
Supplementary Information).
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