Systematic Evaluation of 2-Arylazocarboxylates and 2-Arylazocarboxamides as Mitsunobu Reagents

Article abstract of DOI:10.1021/acs.joc.8b00486

2-Arylazocarboxylate and 2-arylazocarboxamide derivatives can serve as replacements of typical Mitsunobu reagents such as diethyl azodicarboxylate. A systematic investigation of the reactivity and physical properties of those azo compounds has revealed that they have an excellent ability as Mitsunobu reagents. These reagents show similar or superior reactivity as compared to the known azo reagents and are applicable to the broad scope of substrates. pK_a and steric effects of substrates have been investigated, and the limitation of the Mitsunobu reaction can be overcome by choosing suitable reagents from the library of 2-arylazocarboxylate and 2-aryl azocarboxamide derivatives. Convenient recovery of azo reagents is available by one-pot iron-catalyzed aerobic oxidation, for example. SC-DSC analysis of representative 2-arylazocarboxylate and 2-arylazocarboxamide derivatives has shown high thermal stability, indicating that these azo reagents possess lower chemical hazard compared with typical azo reagents.

Full text of DOI:10.1021/acs.joc.8b00486

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Systematic Evaluation of 2-Arylazocarboxylates
and 2-Arylazocarboxamides as Mitsunobu Reagents
Daisuke Hirose, Martin Gazvoda, Janez Košmrlj, and Tsuyoshi Taniguchi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00486 • Publication Date (Web): 23 Mar 2018
Downloaded from http://pubs.acs.org on March 24, 2018
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Systematic Evaluation of 2ꢀArylazocarboxylates and
2ꢀArylazocarboxamides as Mitsunobu Reagents
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†
‡
,‡
Daisuke Hirose, Martin Gazvoda, Janez Košmrlj,* and Tsuyoshi
Taniguchi*
,†,
§
†
§
Graduate School of Natural Science and Technology and School of Pharmaceutical
Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa
University, Kakumaꢀmachi, Kanazawa 920ꢀ1192, Japan
‡
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot
113, SIꢀ1000, Ljubljana, Slovenia
TOC Graphics
Abstract: 2ꢀArylazocarboxylate and 2ꢀarylazocarboxamide derivatives can serve as
replacements of typical Mitsunobu reagents such as diethyl azodicarboxylate (DEAD).
Systematic investigation of reactivity and physical property of those azo compounds has
revealed that they have an excellent ability as Mitsunobu reagents. These reagents show
similar or superior reactivity as compared to the known azo reagents and are applicable
to the broad scope of substrates. Effects of pKa and steric effect of substrates have been
investigated, and the limitation of the Mitsunobu reaction can be overcome by choosing
suitable reagents from the library of 2ꢀarylazocarboxylate and 2ꢀarylazocarboxamide
derivatives. Convenient recovery of azo reagents is available by oneꢀpot ironꢀcatalysed
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aerobic oxidation, for example. SCꢀDSC analysis of representative 2ꢀarylazocarboxylate
and 2ꢀarylazocarboxamide derivatives has shown high thermal stability, indicating that
these azo reagents possess lower chemical hazard compared with typical azo reagents.
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INTRODUCTION
Mitsunobu reaction has been widely used since the first report by Mitsunobu and
1
coꢀworkers in 1967. It is a condensation reaction between alcohol and acidic compound
as a nucleophile, and is induced by a betaine intermediate that is formed from the
2
appropriate azo and phosphine reagents. A starting alcohol is activated through the
formation of an alkoxyphosphonium intermediate and undergoes the Walden inversion
in the reaction with the partnering nucleophile. Consequently, conversion of secondary
alcohols into the corresponding condensation products is accompanied by inversion of
stereochemistry. Owing to the fact that this transformation is viable under mild reaction
conditions, the Mitsunobu reaction often appears in the syntheses of natural products,
medicines, and materials. Nevertheless, truly practical application of the Mitsunobu
reaction is sometimes deterred due to some serious issues connected to the typical azo
3
reagents like diethyl azodicarboxylate (1: DEAD, Figure 1A). First, these compounds
4
are toxic and highꢀenergy materials, potentially possessing an explosive character.
Second, large amounts of hydrazine waste 2 that are produced during the reaction often
make the purification process tedious and contaminate the target products. Third, due to
the moderate basicity of typical betaine intermediates, the yields of the Mitsunobu
products strongly depend on acidity of nucleophiles. Thus, with pronucleophiles having
pKa values of 11−13, the yields are generally decreased whereas less acidic
2
pronucleophiles (pKa>13) are inactive partners in the Mitsunobu reaction.
With a strong focus to avoid the above problems many replacements of DEAD (1) have
5
been developed. Representative examples are shown in Figure 1B. Curran and
coꢀworkers developed azo reagents having fluorous tags (FꢀDEAD), such as compound
6
3
, the hydrazine waste of which can be removed by fluorous extraction techniques.
Lipshutz and coꢀworkers reported that the hydrazine compound produced from
di(pꢀchlorobenzyl)azodicarboxylate (4: DCAD) could be easily removed by filtration
7
and chromatography due to its high polarity and insolubility in dichloromethane.
Di(2ꢀmethoxyethyl)azodicarboxylate (5: DMEAD) is one of the newest azo reagents
developed by Sugimura and coꢀworkers, and the corresponding hydrazine byproduct
8
can be removed by washing with water. Very recently, Soós and coꢀworkers developed
an orthogonal phase tagging approach for chromatographyꢀfree Mitsunobu reaction by
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using water soluble (dimethylamino)methylazocarbonamide carboxylate and lipophilic
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derivatives of triphenylphosphine. Tsunoda and coꢀworkers developed Mitsunobu
10
reagents that are substantially improved in reactivity. As a representative example,
,1’ꢀ(azodicarbonyl)dipiperidine (6, ADDP) performs well in the Mitsunobu reactions
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of moderately acidic substrates (pKa≈11−13). This reagent generates a highly polar
hydrazine byproduct, easily removable by filtration or chromatography, just like in the
case of DCAD (4). They also reported highly reactive phosphorane reagents, including
(cyanomethylene)tributylphosphorane (CMBP), which enable Mitsunobu reaction with
11
less acidic pronucleophiles (pKa>13). However, phosphorane reagents are extremely
sensitive to air and moisture, and many modifications in reagents and methods are
12,13
rather focused on waste removal.
A few examples of reagents and methods aimed at
14,15
improving the reactivity in the Mitsunobu reaction are notable.
We recently developed catalytic Mitsunobu reactions using 2ꢀarylhydrazinecarboxylate
derivatives, which provided the prerequisite azo reagent by in situ aerobic oxidation of
16–20
hydrazine precursors with a catalytic amount of iron phthalocyanine [Fe(Pc)].
2
ꢀArylazocarboxylates have been identified as valuable alternatives to the previously
1
6
developed azo compounds. Noteworthy are the stability and recyclability of
2
ꢀarylazocarboxylates: i) these reagents are stable under ambient conditions at least for
1
6b
a few months and do not decompose even at 200 °C; and ii) after the completion of
the Mitsunobu reaction, they can be quantitatively recovered.
In spite of the development of catalytic Mitsunobu reactions, the stoichiometric
Mitsunobu protocol with traditional azo reagents is still used in synthesis because it is a
reliable method to assure results.
We originally designed 2ꢀarylazocarboxylates to realize the catalytic Mitsunobu
reaction and to solve serious problems of traditional Mitsunobu reaction. However, the
above features strongly suggested that these compounds could reduce the disadvantages
of Mitsunobu reaction even in stoichiometric protocol from both the convenience and
chemical safety aspects. In addition, the aryl group directly linked to the azo moiety
21
enables a fineꢀtuning of its reactivity through a simple choice of substituents. Thus, we
expected that disclosing the properties of our azo reagents will expand choice in
Mitsunobu reaction, either in catalytic or stoichiometric protocol.
In this study, we systematically evaluated the properties of 2ꢀarylazocarboxylates and
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their derivatives as Mitsunobu reagents. Development of new Mitsunobu protocols
based on modified Mitsunobu reagents possessing good stability, recyclability and
reactivity is reported.
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Figure 1. Azo reagents used in Mitsunobu reaction.
RESULTS AND DISCUSSION
1. Screening of reagents and scope of typical substrates
Our study was initiated by a brief screening of selected azo reagents (1.2 equivalent)
and conditions in a model reaction between (−)ꢀ(S)ꢀethyl lactate (9), 4ꢀnitrobenzoic acid
(
10), and triphenylphosphine (PPh
3
) in toluene (Table 1). Although the reaction with
2ꢀphenylazocarboxylate (7a) did not lead to the completion in as much as 48 h, and
gave (R)ꢀester 11 in only low yield, it proceeded with full inversion of stereochemistry
as indicated by chiral HPLC analysis (entry 1). While azo reagents 7b and 7c having
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electronꢀreleasing 4ꢀmethyl and 4ꢀmethoxy groups failed to provide any product (entries
2
and 3), those with electronꢀwithdrawing 4ꢀchloro (7d), 4ꢀbromo (7e), 3ꢀchloro (7f),
3,4ꢀdichloro (7g), 4ꢀtrifluoromethyl (7h), 4ꢀcyano (7i), and 4ꢀnitro (7j) groups enabled
the formation of ester 11 in good yields (entries 4−10). Especially effective were
compounds 7g and 7h affording excellent results in both the yield and the enantiomeric
ratio of 11 (entries 7 and 8). Interestingly, slight erosion of the enantiomeric ratio in
ester 11 was observed in reactions with strongly electronꢀdeficient azo reagents 7i and
7j (entries 9 and 10).
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Although thus far investigated reagents performed similarly, at this point azo compound
7g was tentatively identified as the reagent of choice over 7h, as based on the price and
availability comparison. Namely, 3,4ꢀdichlorophenyl derivative 7g can be prepared from
considerably less expensive starting materials. Compound 7g was thus used in the
subsequent solvent screening experiments (entries 11–13). The results indicate that
toluene could be replaced by tetrahydrofuran whereas dichloromethane and acetonitrile
decreased the yield and the enantiomeric ratio of ester 11.
a
Table 1. Mitsunobu reaction with various ethyl 2ꢀarylazocarboxylates 7a−j.
b
c
entry
X
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
time (h) yield (%) Er
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2
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4
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7
8
9
H (7a)
48
72
72
8
19
0
>99:1
−
4ꢀOMe (7b)
4ꢀMe (7c)
4ꢀCl (7d)
4ꢀBr (7e)
3ꢀCl (7f)
3,4ꢀdiCl (7g)
0
−
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81
99
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>99:1
>99:1
>99:1
>99:1
>99:1
97:3
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5
5
4ꢀCF (7h)
3
5
4ꢀCN (7i)
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3,4ꢀdiCl (7g)
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3,4ꢀdiCl (7g)
3,4ꢀdiCl (7g)
2 2
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Reaction conditions: 9 (0.5 mmol), 10 (0.6 mmol), 7a−j (0.6 mmol), PPh
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(0.6 mmol)
b
c
in solvent (1 mL) at room temperature.
Determined by chiral HPLC analysis.
Yield of the isolated pure product.
The results of substrate scope screening with azo reagent 7g in the Mitsunobu reaction
are shown in Figure 2. Reactions of 3ꢀphenylpropanꢀ1ꢀol with different oxygen,
nitrogen and sulphur nucleophiles such as benzoic acid, phenol, phthalimide,
22
Nꢀbenzylꢀ4ꢀnitrobenzenesulfonamide,
and 2ꢀmercaptobenzothiazole gave the
corresponding products 12−16 in good yields. Surprisingly, malononitrile as a carbon
pronucleophile afforded no alkylated product 17 but only unidentified products, unlike
2
3
in the reaction with DEAD. However, this seemed to be a special case because other
tested carbon pronucleophiles returned the desired alkylated products (vide infra, Figure
4
). The reactions between chiral secondary alcohols and benzoic acids provided the
corresponding esters 18−21 in good yields and in high inversion ratios. The only
exception was the reaction between (−)ꢀ(S)ꢀethyl lactate (9) and 3ꢀphenylpropionic acid
forming the corresponding ester 22 in moderate inversion ratio (er: 82:18). In this case
the replacement of azo reagent 7g with ethyl 2ꢀ(4ꢀchlorophenyl)azocarboxylate (7d)
improved the yield (97%) and inversion ratio (er: 97:3), though excessive amounts (2
equiv) of the reagents were required to complete the reaction. Incidentally, the reaction
with DEAD (1) gave ester 22 in 83% yield and the same inversion ratio (er: 97:3) as
with 7d. Dihydrocholesterol reacted with 4ꢀnitrobenzoic acid (10) into the ester 23 in
8
8% yield as a single inverted isomer. Finally, phthalimide and pꢀmethoxyphenol were
efficiently converted with (S)ꢀethyl lactate (9) into highly enantiomerically rich
Nꢀsubstituted phthalimide 24 and ether 25. The yields of 24 and 25 were better than
1
2e,24,25
those of the reactions with typical azodicarboxylate reagents such as DEAD (1).
Thus, these experimental results illustrated that
ethyl
2
ꢀ(3,4ꢀdichlorophenyl)azocarboxylate (7g) could work as a good reagent in general
Mitsunobu reaction.
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Figure 2. Examples of Mitsunobu reaction with 7g. Reaction conditions: Alcohol (0.5
mmol), nucleophile (0.6 mmol), 7g (0.6 mmol), PPh
3
(0.6 mmol) in toluene (1 mL) at
a
room temperature (SM refers to starting material). Each 2 equiv of 7d and PPh
3
were
b
used. Each 2 equiv of DEAD and PPh
3
were used. Ns = 2ꢀnitrobenzenesulfonyl
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An eightꢀmembered ring construction through the Mitsunobu intramolecular alkylation
was tested by using the model substrate 26 and the reaction conditions reported by
26
Fukuyama (Table 2). The reaction with DEAD was readily reproduced to give
cyclized product 27 in 60% yield (entry 1). However, under the same reaction
conditions azo reagent 7g gave product 27 in only 30% yield with dimerization of 26 as
the main side reaction (entry 2). An additional experimental work had indicated that the
use of 7i in place of 7g gave the desired cycle 27 in 52% yield indicating that 7i could
serve as a replacement for DEAD in this case (entry 3). The reaction under more diluted
conditions improved the result, but the reaction time had to be prolonged (entry 4).
a
Table 2. Cyclization of aminoalcohol 26 into sulfonamide 27.
b
entry azo reagent
conc.
M)
0.01
7g (3,4ꢀdiCl) 0.01
time
(h)
3
yield (%)
(
c
1
2
3
DEAD
60 (59)
3
30
52
7i (4ꢀCN)
7i (4ꢀCN)
0.01
3
d
4
0.005
23
64 (61)
a
Reaction conditions: 26 (0.5 mmol), azo reagent (1.835 mmol), PPh (1.835 mmol) in
3
b
toluene/THF (3:1) (50 or 100 mL) at room temperature. NMR yield unless otherwise
c
d
noted (internal standard: 1,3,5ꢀtrimethoxybenzene). Yield reported in ref. 25. Yield of
the isolated pure product.
2. The reactions with modestly acidic nucleophiles
We evaluated the performance of ethyl 2ꢀarylazocarboxylates in the Mitsunobu reaction
with modestly acidic nucleophiles. 3ꢀPhenylpropanꢀ1ꢀol (28) and pꢀtoluenesulfonamide
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9 (pKa = 11.7) were selected as model substrates and the results are collected in Table
3
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. With DEAD and PPh as the reagents, Nꢀalkylated compound 30 was formed in low
yield (Table 3, entry 1). Although the starting alcohol 28 was fully consumed, a
competitive Nꢀalkylation of the hydrazine byꢀproduct that was produced by reduction of
DEAD complicated the Mitsunobu reaction. On the other hand, a combination of ADDP
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and triꢀnꢀbutylphosphine (PBu
3
) significantly improved the yield (87%) of product 30
(entry 2). The results of these control experiments are consistent with previous
10a,11a,27
reports.
Turning to 2ꢀarylazocarboxylates, compound 7g enabled the formation
of product 30 in good yield (73%) (entry 3). This implies that the range of nucleophile
pKa values in the reaction with 7g is broader as compared that of DEAD. As noted
above for DEAD, in this case the Nꢀalkylated hydrazine derivative formed from 7g and
was isolated in 22% yield. Whereas chloro and cyano derivatives 7d, 7f and 7i gave
similar results (entries 4−6), unsubstituted ethyl 2ꢀphenylazocarboxylate (7a) proved to
work better in this model reaction, despite the considerably longer reaction times
required (entry 7). Replacing the reaction solvent in this case with dichloromethane
significantly accelerated the rate of the reaction (entry 8) whereas replacement of PPh
with PBu resulted in almost the same outcome as that of ADDP (entry 9). Azo reagents
c and 7b, having electronꢀreleasing 4ꢀmethyl and 4ꢀmethoxy groups, in combination
with PBu also gave product 30 in modest yield with the starting alcohol 28 remained
partially unconsumed (entries 10 and 11). A significant improvement in the performance
of 7b/PBu was noted in dichloromethane as the reaction solvent, affording product 30
3
3
7
3
3
in improved yield (89%, entry 12). A conclusion from this part of the work could be
drawn that ethyl 2ꢀ(3,4ꢀdichlorophenyl)azocarboxylate (7g) is an effective reagent for
the Mitsunobu reaction of modestly acidic nucleophiles, with the electronꢀrich
3
analogues 7a and 7b performing superior in combination with PBu .
a
Table 3. Mitsunobu reaction between alcohol 28 and sulfonamide 29.
b
entry azo reagent
R
time
h)
yield (%)
(
c
1
2
DEAD
ADDP
Ph
Bu
3
29 (32)
c
24
87
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3
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3
3
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5
5
5
5
5
5
5
6
c,d
3
4
5
6
7
8
9
7g (3,4ꢀdiCl) Ph
3
73
62
54
49
78
73
86
56
59
7d (4ꢀCl)
7f (3ꢀCl)
7i (4ꢀCN)
7a (H)
Ph
Ph
Ph
Ph
Ph
Bu
Bu
Bu
Bu
18
16
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
72
18
24
40
72
40
e
7a (H)
c
7a (H)
10
7c (4ꢀMe)
7b (4ꢀOMe)
7b (4ꢀOMe)
1
1
e
c
12
87 (89)
a
Reaction conditions: 28 (0.5 mmol), 29 (0.6 mmol), azo reagent (0.6 mmol), PR
3
(0.6
b
mmol) in toluene (1 mL) at room temperature unless otherwise noted. NMR yield
c
d
unless otherwise noted (internal standard: trioxane).
Isolated yield.
Ethyl
2
ꢀ(3,4ꢀdichlorophenyl)ꢀ1ꢀ(3ꢀphenylpropyl)hydrazineꢀ1ꢀcarboxylate was isolated in 22%
e
yield as a side product. The reaction was performed in CH
2
Cl
2
. Ts = pꢀtoluenesulfonyl.
Next, we considered 2ꢀphenylazocarboxamides as a potential replacement for
ꢀarylazocarboxylate reagents. Based on the fact that in the Mitsunobu reaction the
former reagents would produce betaines with increased basic character this should be
2
10
beneficial in the reactions with moderately acidic pronucleophiles. To prove the
concept, 2ꢀphenylazocarboxamides 7k and 7l were prepared and tested in a model
3
reaction between 28 and 29 as shown in Figure 3. With PBu as the phosphine reagent,
product 30 was obtained in excellent yields already at room temperature. As anticipated,
an elevated reaction temperature decreased the reaction time. We thus confirmed that 7l
afforded good results in the reaction of secondary alcohol 31 to produce the
27
corresponding sulfonamide 32. Regarding the stability, azo reagent 7k slowly
decomposed under ambient conditions whereas the analogue 7l proved to be stable for a
few months.
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9
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
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4
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5
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0
1
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5
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7
8
9
0
1
2
3
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5
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8
9
0
1
2
3
4
5
6
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8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3. The reaction of 2ꢀphenylazocarboxamides 7k and 7l. Reaction conditions:
3
Alcohol (0.5 mmol), 29 (0.6 mmol), 7k,l (0.6 mmol), PBu (0.6 mmol) in toluene (1
mL) at room temperature unless otherwise noted. Yields are determined by NMR
analysis of the crude product (internal standard: 1,3,5ꢀtrimethoxybenzene). The yields in
parentheses refer to the isolated pure product.
We tested the Mitsunobu reaction between representative pronucleophiles having
modest acidity (pKa = ca. 11−14) and primary alcohol 28 using selected azo compounds
10,11,24
(7a,b,l,m) and PBu
3
as the reagents (Figure 4).
Alkylation of
2ꢀ(phenylsulfonyl)acetonitrile (33) into 37 proceeded in excellent yield. The reaction of
less acidic benzimidazole (34; pKa = 12.8) with 2ꢀarylazocaroxylate reagents 7a and 7b
provided low yields of alkylated benzimidazole 38, but could be increased by using
2ꢀphenylazocarboxamide 7l. Further improvement, especially at elevated temperature,
was seen by applying 2ꢀ(4ꢀmethoxyphenyl)azocarboxamide 7m. The above trend
appears to be consistent in the reaction of diethyl malonate (35; pKa = 13.3) and
Nꢀbenzylꢀ2,2,2ꢀtrifluoroacetamide (36; pKa = 13.6) of lesser acidity, further decreasing
the yields of the alkylated product 39 and 40, while the results were comparable to those
10
of the reactions with ADDP and related reagents.
These reactions were not applicable to the catalytic reactions because reagents 7a, 7b, 7l
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9
1
1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
6
and 7m did not work well under the current catalytic conditions. In addition, PBu3
1
7b
cannot be used in the catalytic reactions because it deactivates iron phthalocyanine.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 4. Effect of pKa of pronucleophiles in Mitsunobu reaction of 28. Reaction
conditions: 28 (0.5 mmol), 29,33−36 (0.6 mmol), 7a,b,l,m (0.6 mmol), PBu (0.6
mmol) in toluene (1 mL) at room temperature or 80 ºC unless otherwise noted. Yields
3
are determined by NMR analysis of the crude product (internal standard:
a
1
,3,5ꢀtrimethoxybenzene) unless otherwise noted. Yields of the isolated pure product.
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9
In our previous report, we indirectly estimated the rate of the reaction of ethyl
16b
3
2ꢀarylazocarboxylates with PPh to form betaine. Since the reaction was suggested to
be reversible, unlike the reaction of DEAD, the rate constants were determined by a
pseudo firstꢀorder kinetics using excess water in THF, showing a Hammett plot with a
positive value of ρ. Now, to compare the difference in reactivity between ethyl
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
ꢀarylazocarboxylates and ADDP, we first tested the reaction of ADDP with PPh
3
and
−
3
−1
found out that it was faster (kobs = 34.9 × 10 min , Table 4, Entry 5) than that of ethyl
−3
−1
2ꢀ(4ꢀchlorophenyl)azocarboxylate (7d, kobs = 19.5 × 10 min , Entry 4), but slower
16b
−3
−1
than that of ethyl 2ꢀ(3,4ꢀdichlorophenyl)azocarboxylate (7g, kobs = 85.1 × 10 min ,
not shown in Table 4). Next, we turned our attention to PBu . With this phosphorous
3
reagent, the reaction of either ADDP or 7d was too fast for the rate constants to be
determined (entries 4 and 5). On the other hand, this was not the case for less
electrophilic azo reagents 7a−c where the correlation between the reaction rate and
electrophilicity of the azo reagents was similar to the reaction with PPh
The above results indicated that the reaction with PBu is about 50ꢀtimes faster as
compared to PPh
3
(entries 1−3).
3
3
.
The kinetic results from Table 4 appear to be partially inconsistent with the reactivity
trend from Table 3. In production of compound 30, as compared to reagent 7g (Table 3,
entry 3), neither less electrophilic 7d (entry 4) nor more electrophilic 7i (entry 6)
worked better. On the other hand, poorly electrophilic 7a gave good yield of 30 either
with PPh
3
or PBu
3
(entries 7 and 9), but again, even less electrophilic 7b and 7c
as the phosphine reagent (entries 10 and 11). Those
operated worse even with PBu
3
observations could be rationalized by the fact that in addition to the electrophilicity of
the azo reagent, basicity of the intermediately formed betaine is also important in the
reaction with modestly acidic pronucleophiles. Although the azo reagent electrophilicity
and the betaine basicity are unrelated, these two parameters seem to be perfectly
balanced in 7a for the reaction with modestly acidic pronucleophiles. As seen from
3
Table 4 (entry 6), the reactions of 2ꢀarylazocarboxamide derivative 7l with PBu are
slow, but the Mitsunobu reaction of poorly acidic pronucleophiles (Figure 4) does not
seem to be interfered by the slow reaction rate for the betaine formation. Probably, this
is because the reaction of such pronucleophiles with highly basic betaines rather
promotes the irreversible step in the betaine formation.
Table 4. Kinetic data of the reaction between azo reagents and phophines.
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5
6
PPh or PBu (500 mM)
3
3
COR
H
COR
N N
H2O (500 mM)
N N
H
THF (1.0 mL)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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2
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
X
X
25 °C
7a d,l
or
ADDP
50 mM)
8a d,l
or
ADDP-H2
(
−3
−1
entry azo reagent
kobs (10 min )
PPh
3
PBu
3
a
1
2
3
4
5
X = OMe, R = OEt (7b)
0.5
22.2
116
a
X = Me, R = OEt (7c)
X = H, R = OEt (7a)
X = Cl, R = OEt (7d)
ADDP
2.1
a
6.2
291
a
19.5
34.9
−
>1000
>1000
8.7
6
a
X = H, R = piperidyl (7l)
Values taken from ref. 16b.
3
. The reactions with sterically hindered alcohols
28
The Mitsunobu reaction is generally sensitive to the bulkiness of the substrates. For
instance, the reaction of (−)ꢀmenthol (41) with benzoic acids often provides the
corresponding ester products in low yield. In such a case, the use of highly acidic
4
ꢀnitrobenzoic acid (10) is known to improve the outcome in the reaction with DEAD.
28a,b
While we could easily reproduce the literature
reaction between 41 and 10 with
PPh
3
/DEAD into ester 45 (51% yield, Table 5, entry 1), surprisingly, a combination of
gave no product (entry 2). With 7g and PPh as the reagents, a mixture
ADDP and PBu
3
3
of ester 45 and its diastereomer was obtained in 30% yield and only moderate inversion
ratio (entry 3). While replacement of 7g with 7a failed to induce the transformation
(
entry 4), a 7a/PBu
inversion ratio (entry 5). Now, turning to 4ꢀmethoxybenzoic acid (42), its reaction with
−)ꢀmenthol (41) with 7g/PPh or 7a/PBu combination gave the corresponding ester 46
3
combination afforded the ester 45, although in modest yield and
(
3
3
as a single inverted isomer, but the yields were still low (entries 6 and 7). Although
elevating the reaction temperature to 80 °C improved the product yield, it was
accompanied by erosion of the inversion ratio (entry 8). Next, when
2
ꢀmethylꢀ6ꢀnitrobenzoic acid (43) was used instead, the corresponding ester 47 was
generally produced as a single isomer in improved yield (entries 9–11). Interestingly,
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with acid 43, the use of strongly electrophilic azo reagent 7j and PPh worked well
(
3
entry 11). The reaction of 43 with 7a/PBu gave ester 47 in low yield at room
temperature (entry 12) while increasing the reaction temperature to 80 °C significantly
improved the result, with no retention product being detected (entry 13). An increase in
the amounts of the reagents further improved the outcome (entry 14). In contrast, less
electrophilic azo reagent 7b hardly provided any product (entry 15). Finally, the
esterification of (−)ꢀmenthol (41) with 2ꢀnitrobenzoic acid (44) into 48 gave comparable
results to those of 43 (entries 16−18).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Other representative alcohols 49−51 were subjected along with 2ꢀnitrobenzoic acid (44)
to the reaction conditions from entry 18 in Table 5 (Figure 5). While alcohol 49 could be
readily transformed with into the corresponding inversion products 52, attempts to do so
with highly sterically demanding substrates 50 and 51 failed. With (–)ꢀborneol (50), no
ester product could be detected either conducting the reaction at room temperature or
80 °C. Instead, careful monitoring of the reaction by NMR and mass spectral techniques
revealed a nearly quantitative formation of the corresponding alkoxyphosphonium salt
intermediate 53, suggesting that bulky 2ꢀnitrobenzoic acid (44) is unable to approach
the congested reactive center at 53 and complete the S
N
2 step of the Mitsunobu reaction.
+98.7
4.01 ppm was
The alkoxyphosphonium salt intermediate exhibited characteristic resonance at
δ
31
ppm in the P NMR spectrum. The methyne resonance of the alcohol at
δ
replaced by the resonance at
δ
4.75 ppm. Highꢀresolution electrospray ionization mass
+
spectra of the reaction mixtures indicated m/z 355.3135 (calcd for C22
H44OP :
355.3124) in positive mode (ESI+). Although replacement of acid 44 with sterically less
demanding chloroacetic acid seemed to be a sound solution of the problem, it
29
surprisingly gave similar result (data not shown). Alcohol 51, on the other hand, could
be esterified with 2ꢀnitrobenzoic acid (44) in up to 60% yield (69% conversion) into 54
with exclusive retention of configuration as indicated by NMR analyses of the crude
reaction mixtures. The esterification of 51 with retention of configuration could be
explained by a reaction of acyloxyphosphorane intermediates that could be in
equilibrium with alkoxyphosphonium salts as previously proposed by several research
30
groups.
a
Table 5. Mitsunobu reaction between (−)ꢀmenthol (41) and carboxylic acids.
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2
2
2
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3
3
3
3
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3
3
3
4
4
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4
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4
4
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1
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4
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0
1
2
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4
5
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8
9
0
1
2
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4
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8
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0
1
2
3
4
5
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9
0
1
2
3
4
5
6
7
8
9
0
b
c
entry Acid
azo reagent
DEAD
R
time (h) product, yield
dr
1
2
3
4
5
6
7
8
9
1
1
10
10
10
10
10
42
42
42
43
43
43
43
43
43
43
44
44
44
Ph
Bu
Ph
Ph
Bu
Ph
Bu
Bu
Ph
Ph
Ph
Bu
Bu
Bu
Bu
Ph
Bu
Bu
6
45, 51%
45, 0%
>99:1
ꢀ
ADDP
24
16
40
20
16
42
3
7g (3,4ꢀdiCl)
7a (H)
45, 30%
45, 0%
47:53
ꢀ
7a (H)
45, 22%
46, 19%
46, 13%
46, 60%
47, 43%
47, 63%
36:64
>99:1
>99:1
65:35
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
>99:1
97:3
7g (3,4ꢀdiCl)
7a (H)
e
7a (H)
7g (3,4ꢀdiCl)
7i (4ꢀCN)
7j (4ꢀNO2)
7a (H)
20
6
0
1
d
3
47, 81% (84%)
47, 25%
12
24
3
e
d
d
1
3
7a (H)
47, 84% (83%)
47, 95% (91%)
47, 4%
e,f
e
14
7a (H)
3
1
1
1
5
6
7
8
7b (4ꢀOMe)
7g (3,4ꢀdiCl)
7a (H)
10
20
3
48, 31%
e
48, 73%
>99:1
>99:1
e,f
d
1
7a (H)
3
48, 90% (92%)
a
Reaction conditions: 41 (0.5 mmol), 10,42−44 (0.6 mmol), azo reagent (0.6 mmol),
PR (0.6 mmol) in toluene (1 mL) at room temperature unless otherwise noted. NMR
b
3
c
yield unless otherwise noted (internal standard: dimethyl sulfone). Determined by
d
e
NMR analysis of the crude product. Yields of the isolated pure product. The reaction
f
was performed at 80 °C. Each 1.5 equiv of 7a and PBu were used.
3
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CO Et
2
N N
Ph
7
O
a (1.5 equiv)
PBu (1.5 equiv)
HO
O N
3
R OH
1,49 51
1.0 equiv)
results
4
(
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
toluene (0.5 M)
rt or 80 °C
2
4
4
(1.2 equiv)
Me
Me
O
NO2
0 °C, 3 h, 92% yielda
8
single isomer
O
OH
(
inversion product)
Me
Me
Me
Me
41
48
O N
2
OH
Ph
8
0 °C, 5 h, 94% yielda
single isomer
O
O
Ph
(
inversion product)
49
52
Examples of limitation
Me
Me
Me
Me
Me
Me
H
H
rt, 6 h or 80 °C, 4 h
no ester product
OH
O
PBu3
50
2
-(NO )C H CO
2 6 4
2
53
b
9
4% conv. (RT, 4 h)
Me
Me
O
Me
Me
NO2
O
rt, 24 h, 60% yielda
OH
O
O
O
O
rt, 22 h, 69% conv.b
O
O
80 °C, 4 h, 43% conv.b
O
O
O
single isomer
O
Me
(
retention product)
Me
Me
5
1
54
Me
Figure 5. The reaction between some sterically hindered alcohols and 44 with 7a.
Reaction conditions: 49−51 (0.5 mmol), 44 (0.6 mmol), 7a (0.75 mmol), PBu
mmol) in toluene (1 mL) at room temperature or 80 °C. Yields of the isolated pure
3
(0.75
a
b
product. Estimated by NMR analysis of the crude product.
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2
2
2
2
2
2
2
2
2
3
3
3
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5
5
5
5
5
5
5
6
4
. Recovery of ethyl 2ꢀ(3,4ꢀdichlorophenyl)azocarboxylate
Representative methods for recovery of azo reagent 7g are illustrated in this section.
Intramolecular alkylation of sulfonamide 55 with 7g and PPh quantitatively produced
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
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2
3
4
5
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7
8
9
0
1
2
3
4
5
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7
8
9
0
pyrrolidine 56 (Scheme 1). However, purification of 56 by silica gel chromatography
was troublesome due to the similar polarity of 56 (Rf = 0.3) and hydrazide 8g (Rf = 0.2)
produced from 7g, as well as tailing of 8g in TLC. Subjecting the reaction mixture from
31
Scheme 1 to the conditions of previously reported ironꢀcatalyzed aerobic oxidation,
hydrazide 8g was fully converted to azo compound 7g in 12 hours. Owing to the
significantly lower polarity of azo compounds (Rf = 0.6 for 7g) as compared to the
hydrazides, this enabled an easy separation of 7g and pyrrolidine 56 from the resulting
mixture by chromatography and their isolation in excellent yields and in high purity.
With comparable success, this method was then applied to reaction mixtures composing
of substrates that are sensitive to the oxidative conditions (Figure 6). Products 57−60
having electronꢀrich (hetero)aromatic rings, alkene functionality or sulfur atoms were
intact under the applied aerobic oxidation conditions and were isolated from the reaction
mixtures with concomitant recovery of azo reagent (7g), both in excellent yields. The
conversion of 55 into 56 and recovery of 7g protocol was successfully conducted on a
gram scale, though bubbling air was required to effectively promote the oxidation of 8g
into 7g (Scheme 2).
Scheme 1. Recovery of 7g using oneꢀpot telescoped aerobic oxidation. TLC analysis
was performed by using nꢀhexane/EtOAc (3:1).
CO Et
2
Cl
Cl
N N
H
CO Et
2
Cl
Cl
N N
H
7g (1.2 equiv)
N
+
Ts
PPh (1.2 equiv)
OH
NHTs
5 (0.5 mmol)
3
8g
5
6
Rf = 0.2 (tailing)
toluene (0.5 M)
3 h, rt
Rf = 0.3
5
O=PPh3
Rf = 0.1
+
+
other impurities
Reaction mixture
CO Et
Silica gel
chromatography
Fe(Pc)
(5.0 mol%)
2
Cl
Cl
N N
N
Ts
n-hexane/EtOAc Air (open flask)
7g
56
99% yield
Rf = 0.3
rt,12 h
9
5% recovery
one-pot
Rf = 0.6
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7
8
9
O
Ph
N
Ph
S
O
Ns
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NO2
5
7: 3 h + 12 h, 98%
58: 6 h + 12 h, 91%
(7g: 93%)
(
7g: 98%)
OMe
N
S
MeO
MeO
S
O
N
H
OMe
5
9: 3 h + 12 h, 89%
60: 2 h + 8 h, 85%
(7g: 91%)
(
7g: 89%)
Figure 6. Examples of oneꢀpot Mitsunobu reaction and ironꢀcatalyzed aerobic
oxidation. Reaction conditions: Alcohol (0.5 mmol), pronucleophile (0.6 mmol), 7g (0.6
mmol), PPh
mmol) at room temperature under air (open flask). Percentages of yield and recovery of
g were based on isolation by chromatography.
3
(0.6 mmol) in toluene (1 mL) at room temperature, then Fe(Pc) (0.025
7
Scheme 2. Scaleꢀup reaction.
CO Et
2
Cl
Cl
N N
7
g (1.2 equiv)
PPh (1.2 equiv)
3
toluene (0.5 M)
OH
NHTs
RT, 6 h
7g
N
then
Ts
9
5% recovery
55
Fe(Pc) (5.0 mol%)
Air (bubbling)
rt, 12 h
56
(
1.22 g, 5 mmol)
92% yield
Polymerꢀsupported phosphine reagents serve for an easy removal of generated
32
phosphine oxides in the Mitsunobu reaction. Despite the fact that the generated
phosphine oxides usually caused no trouble in our protocol, a polymer supported
3
triphenylphosphine (PSꢀPPh ) was tested in the Mitsunobu cyclisation of compound 55
using azo reagent 7g (Scheme 3). After the oneꢀpot Mitsunobu reaction and reꢀoxidation
sequence, the generated phosphine oxide could be easily removed by filtration while
product 56 and recovered 7g were obtained in good yields. Similarly, the intermolecular
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
process between alcohol 28 and phenol afforded product 13 and recovered 7g in good
yields.
Scheme 3. The reaction using a polymerꢀsupported triphenylphosphine.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CO Et
2
Cl
Cl
N N
7
g (1.2 equiv)
PS-PPh3
(
1.2 1.5 mmol/g, 500 mg)
toluene (0.1 M)
rt, 6 h
substrate
0.5 mmol scale)
product
recovered 7g
(
then
Fe(Pc) (5.0 mol%)
Air (open flask)
rt, 24 h
OH
7
g
N
89% recovery
NHTs
Ts
5
6
55
90% yield
Ph
OH
2
8
(1.0 equiv)
+
Ph
Ph
O
7g
1
3
85% recovery
Ph OH
1.2 equiv)
8
8% yield
(
Providing the Rf value of the Mitsunobu ester product is sufficiently high (Rf > 0.3) as
compared to that of hydrazide 8g, its isolation is easily achieved without the necessity
of the above aerobic oxidation step. It can easily be isolated from the silica gel column
by elution with nꢀhexane/ethyl acetate as the mobile phase, whereas elution of the
mixture of all other side products, including 8g, can be achieved with ethyl acetate.
From this mixture of side products, azo reagent 7g should be easily regenerated and
isolated by applying the above mentioned ironꢀcatalyzed aerobic oxidation protocol. To
prove the concept, the mixtures of side products from ten different reactions shown in
Figure 2 (0.6 mmol × 10) were collected, combined, and subjected to ironꢀcatalyzed
aerobic oxidation for 10 h at room temperature. The resulting reaction mixture was
filtered through a short pad of silica gel with toluene as eluent to almost quantitatively
recover pure 7g (Scheme 4). This procedure further illustrates convenient recovery of
the azo reagent.
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Scheme 4. Recovery of 7g from combined waste. TLC analysis was performed by
using nꢀhexane/EtOAc. (3:1).
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Despite the fact that relatively long reaction times are required for the reꢀoxidations of
hydrazides into the corresponding azo derivatives in the above purification procedures
(schemes 1–4, Figure 3), the efficiency in terms of clean reactions, i.e. inertness to the
products under this investigation and excellent recovery yields, and the absence of
additional workups render it an attractive alternative, especially to several consecutive
chromatographic separations.
Alternatively, we tested the recovery of 7g from the reaction between a thiophene
functionalized alcohol 61 and carboxylic acid 10 by using Nꢀbromosuccinimide (NBS)
3
3
as an oxidant in a oneꢀpot telescoped reaction (Scheme 5). After the ester formation
step was completed, treating the resulting reaction mixture with NBS/pyridine afforded
the target compound 57 and recovered 7g in good yields, though small amounts of
brominated side product 62 was obtained. The NBS oxidation in the absence of pyridine
increased the side product 62 formation and decreased the amount of recovered 7g.
Although additional wastes are generated from NBS and pyridine, this recovery
protocol may serve as an alternative to the aerobic oxidation when the latter is
undesirable.
Although we have not tested these procedures in the case of recovery of
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2
2
2
2
2
2
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5
5
6
2
ꢀphenylazocarboxamide 7l, the 2ꢀphenylhydrazinecarboxamide formed in the reaction
with 2ꢀphenylazocarboxamide 7l (e.g., reactions in shown Fig. 4) did not interfere
purification of the desired product by silica gel chromatography due to its high polarity
[
Rf: <0.05 (nꢀhexane/EtOAc, 3:1); 0.3 (nꢀhexane/EtOAc, 1:1)]. Consequently, the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
hydrazine side product was easily recovered in around 80% yield by chromatography.
More simply, a portion (53%) of the hydrazine could be recovered as crystalline solids
by a filtration because it precipitated in toluene after the reaction. The recovered
2ꢀphenylhydrazinecarboxamide was reconverted to 7l in 94% yield by ironꢀcatalyzed
2 2
aerobic oxidation in CH Cl at room temperature (see the Supporting Information).
Scheme 5. Recovery of 7g using Nꢀbromosuccinimide (NBS) as a reoxidizer. Yields
in parentheses refer to the reaction in the absence of pyridine.
It has been reported that nucleophilic aromatic substitutions at the benzene ring proceed
with aromatic amines and alcohols under mild conditions at tertꢀbutyl
34
phenylazocarboxylates. In contrast, no products indicating such kind of reactions
could be detected under Mitsunobu conditions.
5. SCꢀDSC analysis of representative ethyl 2ꢀarylazocarboxylates
Most of the azo reagents are high energy compounds possessing potential explosive
4
,8b
character.
For instance, DEAD violently decomposes below 200 °C, releasing high
energy. Previously, we tested preliminary thermal stability of representative ethyl
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1
6b
2
ꢀarylazocarboxylates. Thermogravimetryꢀdifferential thermal analysis (TGꢀDTA) of
azo compounds showed endothermic behavior with a weight loss at approximately
200 °C, indicating evaporation of the compounds. Importantly, clear exothermic
decomposition was not observed by preliminary differential scanning calorimetry
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
16b
(DSC) analyses. The results implied that ethyl 2ꢀarylazocarboxylates have superior
thermal stability compared with DEAD. Indeed, ethyl 2ꢀarylazocarboxylates were stable
for more than a few months under ambient conditions. However, TGꢀDTA analysis did
not provide exact information on thermal stability of 2ꢀarylazocarboxylates because the
sample evaporated before thermal decomposition. Thermal stability of azo reagents
should be strictly evaluated when stoichiometric amounts of azo reagents are used in
reactions under high temperature or pressure on a large scale. Therefore, we performed
sealed cellꢀdifferential scanning calorimetry (SCꢀDSC) analysis of representative azo
reagents,
ethyl
2ꢀphenylazocarboxylate
(7a)
and
ethyl
2
ꢀ(3,4ꢀdichlorophenyl)azocarboxylate (7g), to reveal an exact decomposition
temperature and energy (Table 6). Onset of exothermic decomposition of azo reagent 7a
was observed at 289.7 °C, and the peak top was 312.0 °C. The calorific value in
decomposition was estimated at 1231.3 J/g, and this large value was consistent with that
of typical azo compounds. On the other hand, analysis of azo reagent 7g showed two
exothermic peaks. Onset of the first exothermic was observed at 249.7 °C, but the peak
was broad showing the relatively low calorific value (791.0 J/g). Onset of the second
exothermic was observed at 360.7 °C, and the peak was a sharp form having a top at
3
68.7 °C and a large calorific value (1272.2 J/g). To shed light into this interesting
double exothermic behavior, we conducted mass spectrometry analysis of 7g in direct
analysis in real time (DART) mode at different temperatures (200−500 °C).
+
Fragmentation peaks based on [M − CO
decrease peaks of [M + H] (m/z: 247, 249, 251) by elevating the temperature. Small
2
Et] (m/z: 173, 175, 177) increased with
+
+
fragmentation peaks based on [M − OEt] (m/z: 201, 203, 205) were also observed.
Fragmentation peaks based on [Ar] (m/z: 145, 147, 149) were detected at high
+
temperatures (400−500 °C), though the peaks were very unintense. These results
indicated that the first thermal decomposition was decarboxylation and that the second
one was based on a release of a nitrogen molecule. This is consistent with the large
calorific value in the second exothermic decomposition. Mass spectrometry analysis of
azo reagent 7a gave a similar spectrum, but decarboxylation and nitrogen release of 7a
occurred almost concurrently. Thus, thermal decomposition based on the azo groups of
reagents 7a and 7g occurs at a temperature higher than that of typical azo reagents such
as DEAD. On the other hand, the exothermic energy of these reagents was similar to
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
that of typical azo compounds, but potential explosiveness of high energy compounds
largely depends on a decomposition temperature. These results strongly support that
2ꢀarylazocarboxylate derivatives have high thermal stability and can be handled safely
compared with typical azo reagents in Mitsunobu reaction. Decomposition of
2ꢀphenylazocarboxamide 7l occurred at lower temperature as for 7a, but a calorific
value (812.0 J/g) was small.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 6. SCꢀDSC data of 7a,g,l. Heating rate is 10 °C/min.
azo reagent
extrapolated
temp. in
a
heat of decom.
onset temp. (ºC) peak top (ºC) (J/g)
7
7
a
g
289.7
312.0
−1231.3
1st peak
nd peak
249.7
360.7
251.5
293.1
368.7
263.8
−791.0
−1272.2
−812.0
2
7l
CONCLUSIONS
We have systematically evaluated ethyl 2ꢀarylazocarboxylate and 2ꢀarylazocarboxamide
derivatives as Mitsunobu reagents. Promising azo reagents selected in our study are
shown in Figure 7. Ethyl 2ꢀ(3,4ꢀdichlorophenyl)azocarboxylate (7g) can readily serve as
a replacement of DEAD as it is applicable to a broad scope of substrates. Ethyl
2ꢀ(4ꢀcyanophenyl)azocarboxylate (7g) works well in the medium ring construction.
Overall, these serve as catalysts in the catalytic protocol or as replacement of DEAD
(Figure 7A). From the standpoint of pKa limitations in substrates, 7g is likely to be
superior over DEAD because the reaction of modestly acidic
Nꢀmethylꢀpꢀtoluenesulfonamide afforded the product in good yield. However, the
screening of other moderately acidic substrates indicated that ethyl
2ꢀphenylazocarboxylate
(7a),
2ꢀphenylazocarboxamide
7l
and
2
ꢀ(4ꢀmethoxyphenyl)azocarboxamide 7m are more effective in the presence of PBu3
than PPh . Overall, these are replacement of ADDP (Figure 7B).
3
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(A) Use in a catalytic protocol or as a replacement of DEAD
O
O
Cl
Cl
N N
OEt
N N
OEt
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
NC
O
7g
7i
(B) Use as a replacement of ADDP
O
O
N N
OEt
N N
N
N N
N
MeO
7a
7l
7m
Figure 7. Potent azo reagents selected in our study.
Although the performance of these reagents is sensitive to a steric hindrance of the
alcohol substrates, similarly to the known Mitsunobu reagents, our experimental results
indicate that by careful selection of the reaction conditions and partnering acids there is
a room for further improvements.
We have demonstrated that the azo reagents under this investigation can be easily
recycled by utilizing ironꢀcatalyzed aerobic oxidation under mild conditions. This
feature was applicable to easy and scalable recovery of the reagents. The emergence of
recyclable azo reagents in the Mitsunobu reaction shall inspire development of new
3
5
protocols for the parent hydrazine oxidations.
Most of the 2ꢀarylazocarboxylates and 2ꢀarylazocarboxamides were stable for more than
a few months under ambient conditions. SCꢀDSC analyses of representative azo
reagents revealed considerably higher exothermic decomposition points as compared to
the typical Mitsunobu azo reagents such as DEAD. This strongly supports low
explosiveness of the azo compounds under this investigation. Thus, the developed
reagents could be handled safer than DEAD, though we did not evaluate the safety from
a viewpoint of toxicity.
In conclusion, ethyl 2ꢀarylazocarboxylates and 2ꢀarylazocarboxamides are safe in terms
of chemical reactivity hazards, highly reactive, and easily recyclable Mitsunobu
reagents, which will in the future find wide applications in practical syntheses.
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1
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1
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2
2
2
2
2
2
2
2
3
3
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6
EXPERIMENTAL SECTION
General remarks.
Japan: All reactions were performed in ovenꢀdried glassware. All reagents purchased
commercially were used without further purification unless otherwise noted. Iron
phthalocyanine was purchased from Tokyo Chemical Industry Co., Ltd. Dehydrated
0
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9
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0
2 2
THF, toluene and CH Cl were purchased from Kanto Chemical Co., Inc. Other solvents
were dried with activated molecular sieves. Thinꢀlayer chromatography (TLC) analysis
was performed by illumination with a UV lamp (254 nm) or staining with
phosphomolybdic acid (PMA) and heating. Silica gel column chromatography was
carried out on silica gel 60N (Kanto Chemical Co., Inc., spherical, neutral, 40−50 ꢁm).
The chromatographic separation of enantiomers was performed using a JASCO
PUꢀ2080 Plus liquid chromatography equipped with Multi UVꢀVis (JASCO MDꢀ910).
Melting points were recorded on Yanako melting point apparatus and were uncorrected.
1
13
H and C NMR spectra were recorded with JEOL JNM ECS400 (400 MHz and 100
MHz), JEOL JNM ECS500 (500 MHz and 125 MHz) and JEOL JNM ECA600 (600
MHz and 150 MHz) spectrometers at 293−295 K. Proton spectra were referenced to
13
TMS as an internal standard. Carbon chemical shifts were determined relative to the C
signal of CDCl (77.0 ppm). Coupling constants (J) are given in Hz. Multiplicities are
indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) or br
broadened). IR spectra were recorded with a JASCO Fourier Transform IRꢀ460
3
(
spectrometer. Mass spectra were recorded on JEOL JMSꢀT100TD (direct analysis in
real time, DART) or JEOL JMSꢀ700 (fast atom bombardment, FAB), and exact mass
values were calculated as neutral molecules by calibration using an appropriate internal
standard (triphenylphosphine oxide or PEG). Optical rotations were measured on a
JASCO Pꢀ1030 polarimeter. Absorption spectra were measured in a 0.1 mm quartz cell
on a JASCO Vꢀ570 spectrophotometer. Differential scanning calorimetric (DSC)
analysis was performed on Seiko Instruments Inc. EXSTAR 6000 DSC6200R (heating
rate of 10.0 °C/min) under a nitrogen atmosphere.
Slovenia: All reactions were performed in ovenꢀdried glassware under nitrogen
atmosphere. All reagents purchased commercially from SigmaꢀAldrich were used
without further purification unless otherwise noted. Toluene and tetrahydrofuran were
distilled over sodium wire. Dichloromethane was distilled over calcium hydride.
Thinꢀlayer chromatography (TLC) analysis was performed on Fluka Silica gel on TLC
Al foils (silica gel matrix, with fluorescent indicator, 60 Å medium pore diameter).
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Visualization of compounds was done by illumination with a UV lamp (254 nm) or by
using a solution of KMnO
KMnO , 10 g K CO and 1.25 mL 10% NaOH in 200 mL of water) followed by heating.
Silica gel column chromatography was carried out on silica gel 60N. Melting points
4 2 3
/K CO /NaOH in water (prepared by dissolving 1.5 g of
4
2
3
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were recorded on a Kofler micro hot stage and were uncorrected. H, P and C spectra
were recorded with a Bruker Avance III 500 MHz NMR (500 MHz, 202 MHz and 126
MHz) instrument at 300 K or with a Bruker Avance DPX 300 spectrometer (300 MHz,
122 MHz and 76 MHz) at 302 K. Proton spectra were referenced to TMS as an internal
13
standard. Carbon chemical shifts were determined relative to the C signal of CDCl
3
3
1
(77.0 ppm). P NMR spectra were referenced to external 85% phosphoric acid (δ = 0
ppm). Assignments of some proton, carbon and phosphorous resonances were
1
1
1
13
1
13
performed by 2D NMR techniques ( H− H gsꢀCOSY, H− C gsꢀHSQC, H− C
1
31
gsꢀHMBC and H− P gsꢀHMBC). Coupling constants (J) are given in Hz.
Multiplicities are indicated as follows: s (singlet), d (doublet), t (triplet), m (multiplet)
or br (broadened). IR spectra were recorded with a PerkinꢀElmer Spectrum 100
(equipped with a Specac Golden Gate Diamond ATR as a solid sample support). HRMS
spectra were recorded on a timeꢀofꢀflight (TOF) mass spectrometer equipped with a
double orthogonal electrospray source at atmospheric pressure ionization (ESI) coupled
to an HPLC instrument.
Preparation of azo reagents:
Ethyl 2ꢀarylhydrazinecarboxylates 7a–j were prepared from the corresponding
phenylhydrazine derivatives and ethyl chloroformate according to established
3
1,33
methods.
Azocarboxamides 7l, 7k and 7m were synthesised as below:
33
Following modified literature procedure, to a solution of 7a (713 mg, 4.0 mmol) or 7b
833 mg, 3.5 mmol) in ethanol (2 mL), piperidine (550 ꢁL, 468 mg, 5.5 mmol) or
(
dimethyl amine (1 mL of 33% (5.6 M) solution in ethanol, 5.5 mmol) was added at
room temperature, and the mixture was stirred until TLC indicated complete
consumption of the starting material. The mixture was evaporated to dryness, and the
crude product was recrystallized from the mixture of nꢀhexane and ethyl acetate to
obtain the corresponding pure azocarboxamide in high yield.
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N,NꢀDimethylꢀ2ꢀphenyldiazeneꢀ1ꢀcarboxamide (7k). 5 h. 74% yield (524 mg, 2.96
36
mmol) (after recrystallization). Red solid. Mp 64–65 °C (nꢀhexane/EtOAc); mp (lit)
–
1 1
6
2–63 °C; IR (ATR): 2804, 1693, 1494, 1443, 1255, 1080, 770 cm . H NMR (500
1
3
MHz, CDCl
3
) δ 7.94–7.91 (2H, m), 7.58–7.50 (3H, m), 3.20 (3H, s), 3.15 (3H, s);
C
NMR (126 MHz, CDCl
3
) δ 162.7, 152.0, 133.0, 129.2, 123.5, 36.56, 36.54; HRMS
+
+
(ESI+) calcd for C H N O ([M+H] ) 178.0975, found 178.0974.
9
12 3
(
Phenyldiazenyl)(piperidinꢀ1ꢀyl)methanone (7l). 5 h. 81% yield (704 mg, 3.24 mmol)
37
(after recrystallization). Red solid. Mp 77–78 °C (nꢀhexane/EtOAc); mp (lit.) 78–
–
1 1
7
9 °C; IR (ATR): 2942, 2858, 1695, 1424, 1254, 1188, 1131 cm . H NMR (500 MHz,
CDCl
3
) δ 7.93–7.90 (2H, m), 7.58–7.51 (3H, m), 3.75–3.72 (2H, m), 3.60–3.56 (2H, m),
13
1.76–1.71 (4H, m), 1.65–1.59 (2H, m); C NMR (126 MHz, CDCl
3
) δ 161.5, 152.0,
+
16 3
132.9, 129.2, 123.5, 45.9, 44.5, 26.1, 25.5, 24.3; HRMS (ESI+) calcd for C12H N O
+
(
[M+H] ) 218.1288, found 218.1289.
((4ꢀMethoxyphenyl)diazenyl)(piperidinꢀ1ꢀyl)methanone (7m). 15 h. 88% yield (770
mg, 3.11 mmol) (after recrystallization). Red solid. Mp 90–91 °C (nꢀhexane/EtOAc). IR
–
1 1
(
ATR): 2932, 2851, 1660, 1603, 1502, 1411, 1250, 1015, 854 cm . H NMR (500 MHz,
CDCl ) δ 7.93 (2H, d, J = 9.1 Hz), 6.99 (2H, d, J = 9.1 Hz), 3.90 (3H, s), 3.75–3.70 (2H,
m), 3.66–3.62 (2H, m), 1.74–1.68 (4H, m), 1.64–1.59 (2H, m). C NMR (126 MHz,
3
1
3
CDCl
3
) δ 163.6, 161.6, 146.4, 125.9, 114.2, 55.6, 45.9, 44.5, 26.1, 25.5, 24.3; HRMS
+
+
(ESI+) calcd for C13
H
18
N
3
O
2
([M+H] ) 248.1394, found 248.1393.
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N'ꢀPhenylpiperidineꢀ1ꢀcarbohydrazide (8l).
To a solution of 7l (109 mg, 0.5 mmol) in chloroform (1 mL), tributylphospine (190 ꢁL,
51 mg, 0.75 mmol) was added under nitrogen atmosphere at room temperature and the
1
mixture was stirred for 30 minutes at room temperature. Then, the reaction flask was
opened and was exposed to air for 5 h, followed by addition of 1 mL of water. The
mixture was stirred for additional 15 h at room temperature. Water (10 mL) was added
and the mixture was extracted with dichloromethane (3 x 10 mL). Organic layers were
combined and dried over sodium sulfate, filtered and evaporated to dryness. Silica gel
chromatography (nꢀhexane/ethyl acetate = 1:1) was performed to regenerate
N'ꢀphenylpiperidineꢀ1ꢀcarbohydrazide in 79% yield (86.2 mg, 0.393 mmol). Beige solid.
Rf 0.33 (nꢀhexane/EtOAc = 1:1). Mp 180–182 °C (nꢀhexane/EtOAc). IR (ATR): 3338,
–1
1
3
286, 3037, 2933, 1633, 1592, 1513, 1470, 1436, 1261 cm . H NMR (500 MHz,
CDCl ) δ 7.23–7.18 (2H, m), 6.91–6.84 (3H, m), 6.27 (1H, br s), 6.11 (1H, br s), 3.41–
3
1
3
3
.37 (4H, m), 1.65–1.36 (6H, m). C NMR (126 MHz, CDCl
3
) δ 158.2, 149.4, 129.0,
+
+
1
20.8, 113.8, 44.8, 25.6, 24.3. HRMS (ESI+) calcd for C12H N O ([M+H] ) 220.1444,
18 3
found 220.1445.
31
Aerobic oxidation of 8l: According to a method reported previously, to a stirred
solution of 8l (43.9 mg, 0.2 mmol) in dichloromethane (1.0 mL, 0.2 M), iron
phthalocyanine (5.7 mg, 10 ꢁmol, 5 mol%) was added at room temperature. The
resultant mixture was stirred for 4 h at room temperature under an air atmosphere
(balloon). The reaction mixture was filtered through filter paper, and the solvent was
removed under reduced pressure. The crude material was purified by silica gel
chromatography (eluent: nꢀhexane/EtOAc = 3:1) to give 7l (41.0 mg, 0.189 mmol,
95%).
Experimental details and analytical data for synthesized compounds:
General procedure for stoichiometric Mitsunobu reactions:
To a stirred solution of alcohol (0.5 mmol) and nucleophile (0.6 mmol) in toluene (1.0
mL), azo reagent 7a–m (0.6 mmol) and phosphine (0.6 mmol, PPh
3 3
: 157 mg; PnBu :
1
21 mg) and were added at room temperature under N (balloon). The addition order of
2
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