The first mitsunobu protocol for efficient synthesis of α-acyloxyphosphonates using 4,4′-azopyridine

Article abstract of DOI:10.1080/10426507.2011.582594

This is the first report on applying the Mitsunobu protocol for the synthesis of various α-acyloxyphosphonates using 4,4′-azopyridine and PPh₃ with diverse aromatic and aliphatic carboxylic acids. Under these conditions, diethyl azodicarboxylat

Full text of DOI:10.1080/10426507.2011.582594

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The First Mitsunobu Protocol
for Efficient Synthesis of α-
Acyloxyphosphonates Using 4,4′-
Azopyridine
Nasser Iranpoor a , Habib Firouzabadi a & Dariush Khalili a
a Department of Chemistry, College of Sciences , Shiraz University ,
Shiraz, Iran
Published online: 31 Oct 2011.
To cite this article: Nasser Iranpoor , Habib Firouzabadi & Dariush Khalili (2011) The First Mitsunobu
Protocol for Efficient Synthesis of α-Acyloxyphosphonates Using 4,4′-Azopyridine, Phosphorus, Sulfur,
and Silicon and the Related Elements, 186:11, 2166-2171, DOI: 10.1080/10426507.2011.582594
To link to this article: http://dx.doi.org/10.1080/10426507.2011.582594
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Phosphorus, Sulfur, and Silicon, 186:2166–2171, 2011
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2011.582594
THE FIRST MITSUNOBU PROTOCOL FOR EFFICIENT
SYNTHESIS OF α-ACYLOXYPHOSPHONATES
USING 4,4ꢀ-AZOPYRIDINE
Nasser Iranpoor, Habib Firouzabadi, and Dariush Khalili
Department of Chemistry, College of Sciences, Shiraz University, Shiraz, Iran
GRAPHICAL ABSTRACT
Abstract This is the first report on applying the Mitsunobu protocol for the synthesis of various
α-acyloxyphosphonates using 4,4ꢁ-azopyridine and PPh3 with diverse aromatic and aliphatic
carboxylic acids. Under these conditions, diethyl azodicarboxylate (DEAD) as the traditional
reagent for Mitsunobu reaction is not efficient. The insoluble pyridine hydrazine byproduct can
be simply isolated and recycled to its azopyridine by an oxidation reaction and reused again.
[Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements for the following free supplemental
resource: Characterization data of compounds 3a–3z2 and NMR spectra.]
Keywords Mitsunobu reaction; esterification; α-hydroxyphosphonates; α-acyloxyphos-
phonates; azopyridine
INTRODUCTION
Organophosphorus compounds have found diverse applications in organic and inor-
ganic chemistry.1 Among these, α-acyloxyphosphonates are considered as pivotal and pre-
cious phosphorus compounds for the synthesis of optically active α-hydroxyphosphonates.
α-hydroxyphosphonates are important compounds and some of them have been shown
to possess enzyme inhibitor activity2 such as inhibitor of renin,3 human immunodefi-
ciency virus (HIV) protease, and polymerase.4 They also show anticancer5 and antiviral6
activities. In addition, α-hydroxyphosphonates are useful precursors for the preparation
of α-functionalized phosphonates, such as amino, keto, and halophosphonates.7–9 Bio-
catalysts such as enzymatic systems have been introduced for the enantioselective hy-
drolysis of racemic α-acyloxyphosphonates.10 Surprisingly, given the extensive use of
α-functionalized phosphonates in biological systems and organic synthesis, there are only
Received 1 March 2011; accepted 16 April 2011.
We gratefully acknowledge the financial support from the Shiraz University research council.
Address correspondence to Nasser Iranpoor, Department of Chemistry, College of Sciences, Shiraz Univer-
sity, Shiraz 71454, Iran. E-mail: iranpoor@susc.ac.ir
2166

SYNTHESIS OF α-ACYLOXY PHOSPHONATES
2167
a few reports on the synthesis of α-acyloxyphosphonates in the literature. In an earlier
report, Shingare and coworkers11 have synthesized new α-acetoxyphosphonate derivatives
of tetrazolo [1,5-a] quinoline using Ac2O/DBU at room temperature and their antimicro-
bial activities were evaluated. In a reaction reported by Hammerschmidt, various α- and
β-acyloxyphosphonates were synthesized by hydrolases with isopropenyl acetate as acyl
donor in organic solvents.12 Reaction of α-hydroxyphosphonates with Ac2O under mi-
crowave irradiation,13 aldehydes and ketones with acyl phosphites,14 direct acetylation of
α-hydroxyphosphonates with ketene catalyzed by BF3·OEt215 or H2SO4,16 and using of en-
zymatic systems17 to preparation of α-acylphosphonates are the other reported procedures.
Although the Mitsunobu reaction using diethyl azodicarboxylate (DEAD) and PPh3 has
been widely used for the acylation of alcohols, this potentially useful method has not been
applied to α-hydroxyphosphonates.18 Recently, we have reported efficient esterification
of alcohols using 4,4ꢁ-azopyridine19 and 5,5ꢁ-dimethyl-3,3ꢁ-azoisoxazole20 as good alterna-
tives for the traditional DEAD in Mitsunobu reaction. With the good results obtained by this
protocol in mind and continuing our pursuit in transformation of α-hydroxyphosphonates
to other derivatives,21 we have decided to exploit the scope of this method for the synthesis
of the α-acyloxyphosphonates.
RESULTS AND DISCUSSION
α-hydroxyphosphonates were synthesized according to the literature22 and subjected
to the Mitsunobu esterification with acids using different heterocyclic azo compounds
(A1–A6) as well as DEAD and PPh3. With the use of a model reaction based on diethyl
α-hydroxy-4-methylbenzylphosphonate (1a) and benzoic acid, some different conditions
have been screened. Among the studied azo reagents A1–A6, 4–4ꢁ-azopyridine (A3) was
found to be the most efficient one for this reaction. Surprisingly, the use of DEAD and
Table 1 Optimization of conditions
Entry
Azo (Solvent, T)
Time (h)
Yield of 2a (%)
1
2
3
4
5
6
7
8
9
A1 (CH3CN, reflux)
A2 (CH3CN, reflux)
A3 (CH3CN, reflux)
A3 (CH3CN, r.t)
A4 (CH3CN, reflux)
A5 (CH3CN, reflux)
A6 (CH3CN, reflux)
DEAD (CH3CN, reflux)
DIAD (CH3CN, reflux)
17
24
12
48
72
72
72
24
24
55
28
82
N.R
N.R
N.R
N.R
40
34

2168
N. IRANPOOR ET AL.
DIAD was not suitable, and under similar reaction conditions, only 40% and 34% of 2a
were obtained, respectively (Table 1, entries 8 and 9). The results of the optimization are
shown in Table 1.
Among the various solvents such as CH2Cl2, CHCl3, THF, 1,4-dioxane, DMF, and
acetone that were evaluated, refluxing CH3CN gave the best results. Finally, the optimized
mole ratio of the reactants was found to be: α-hydroxyphosphonate (2 equiv.): acid (1.3
equiv.): azo (1.8 equiv.): PPh3 (1.8 equiv.). With the optimized reaction conditions in hand,
the scope of the esterification of α-hydroxyphosphonates with different carboxylic acids
was investigated. The results are summarized in Table 2.
a
Table 2 Conversion of α-hydroxyphosphonates 1a–d to corresponding esters 3a–3z2 using A3 and PPh3
Entry
R
Rꢁ
Product
Time (h)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
4-CH3-C6H4-(1a)
4-CH3-C6H4-
4-CH3-C6H4-
4-CH3-C6H4-
4-CH3-C6H4-
4-CH3-C6H4-
4-CH3-C6H4-
C6H5-(1b)
C6H5-
C6H5-
C6H5-
C6H5-
4-NO2-C6H4-(2a)
C6H5-(2b)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
9
12
15
15
12
12
14
10
12
15
15
12
12
15
18
24
24
18
18
24
12
14
15
15
12
12
16
16
88
8223a
76
4-CH3-C6H4-(2c)
2-Cl-C6H4-(2d)
3-Cl-C6H4-(2e)
4-Cl-C6H4-(2f)
CH3CH=CH-(2g)
4-NO2-C6H4-(2a)
C6H5-(2b)
4-CH3-C6H4-(2c)
2-Cl-C6H4-(2d)
3-Cl-C6H4-(2e)
4-Cl-C6H4-(2f)
CH3CH2-(2h)
4-NO2-C6H4-(2a)
4-CH3-C6H4-(2c)
2-Cl-C6H4-(2d)
3-Cl-C6H4-(2e)
4-Cl-C6H4-(2f)
CH3CH=CH-(2g)
4-NO2-C6H4-(2a)
C6H5-(2b)
4-CH3-C6H4-(2c)
2-Cl-C6H4-(2d)
3-Cl-C6H4-(2e)
4-Cl-C6H4-(2f)
CH3CH=CH-(2g)
CH3CH2-(2h)
79
83
85
77
83
8023a
7123b
75
84
8523b
75
74
65
72
75
78
69
76
7723a
73
77
74
79
69
71
C6H5-
C6H5-
2,6-di-Cl-C6H3-(1c)
2,6-di-Cl-C6H3-
2,6-di-Cl-C6H3-
2,6-di-Cl-C6H3-
2,6-di-Cl-C6H3-
2,6-di-Cl-C6H3-
4-Cl-C6H4-(1d)
4-Cl-C6H4-
4-Cl-C6H4-
4-Cl-C6H4-
4-Cl-C6H4-
4-Cl-C6H4-
4-Cl-C6H4-
4-Cl-C6H4-
3t
3u
3v
3w
3x
3y
3z
3z1
3z2
aReaction conditions: 1 (2.0 mmol), acid (1.3 mmol), A3 (1.8 mmol), PPh3 (1.8 mmol) in acetonitrile (4 mL)
at 80◦C. bIsolated yields.

SYNTHESIS OF α-ACYLOXY PHOSPHONATES
2169
Substrates with either electron-donating or electron-withdrawing groups on the
phenyl group of α-hydroxyphosphonate could be applied in this transformation. For exam-
ple, diethyl α-hydroxy-4-methylbenzylphosphonate 1a was examined as a substrate and it
was found that the reaction of 1a with various acids proceeded smoothly in good yields.
In the cases of carboxylic acids 2a and 2d–f having –NO2 and or –Cl substitutents, the
reactions proceeded more cleanly and smoothly, affording the corresponding products 3a,
3d–f in higher yields (79%–88%) (Table 2, entries 1, 4–6). However, if an electron-donating
group such as –Me was introduced on the benzene ring of the acid, the yield of 3c decreased
to 76% (Table 2, entry 3). Also, unsaturated and saturated aliphatic carboxylic acids such
as crotonic and propionic acids 2g, h were used in this reaction (Table 2, entries 7, 14, 20,
27, and 28). A key benefit associated with the use of 4,4ꢁ-azopyridine in the synthesis of
α-acyloxyphosphonates is not only its ease of preparation but also its capacity to remove
its hydrazine byproduct from the reaction mixture by simple filtration. In addition, the
produced hydrazine byproduct can be simply recycled to its azo compound by oxidation
with iodosobenzene diacetate in DMSO.18
CONCLUSION
This report describes the first application of the Mitsunobu method using 4,4ꢁ-
azopyridine and PPh3 for the efficient synthesis of various α-acyloxyphosphonates. The
method is general and can be applied to wide range of aliphatic and aromatic carboxylic
acids and also varieties of α-hydroxyphosphonates. Advantages of using 4,4ꢁ-azopyridine
as an easily prepared azo reagent are (a) its more efficiency compared to DEAD and DIAD;
(b) simplicity in separation of its hydrazine byproduct; and (c) its easy recyclability for
further use.
EXPERIMENTAL SECTION
Typical procedure for conversion of 4-methylbenzaldehyde to its corresponding
α-hydroxyphosphonate22: To a mixture of 4-methylbenzaldehyde (1.20 g, 10 mmol) and
diethyl phosphite (1.3 mL, 10 mmol), CaO (560 mg, 10 mmol) was added. The reaction
mixture was stirred at room temperature. After 30 min, a bulk white solid was obtained.
EtOAc (10 mL) was then added to the reaction mixture, and the mixture was stirred for
30 min at room temperature. The obtained solution was filtered and the filtrate was
evaporated. Purification of the crude product was achieved by crystallization using
EtOAc/petroleum ether (3/7). The corresponding α-hydroxyphosphonate was obtained in
91% yield (235 mg).
Acylation of α-hydroxy-4-methylbenzylphosphonate using 4,4ꢁ-azopyridine in
modified Mitsunobu protocol as a typical procedure: Triphenylphosphine (0.47 g,
1.8 mmol) was added to a solution of 4,4ꢁ-azopyridine (0.32 g, 1.5 mmol) and 4-nitrobenzoic
acid (0.22 g, 1.3 mmol) in refluxing acetonitrile (5 mL), and the solution was stirred
to dissolve the solids. Then, α-hydroxy-4-methylbenzylphosphonate (0.516 g, 2 mmol)
was added. The resulting solution was stirred at 80◦C (reflux) for 9 h. After the re-
action was filtered off to remove the produced pyridine hydrazine (262 mg, isolated
yield: 81%), the solvent was removed in vacuo. The so-formed α-(4-nitrobenzoate)-4-
methylbenzylphosphonate was isolated by chromatography on a short column of silica gel
(n-hexane:ethyl acetate = 2:1) in 88% yield (716 mg).

2170
N. IRANPOOR ET AL.
The Supplemental Materials contain the complete 1H and 13C NMR data for 3a–3z2,
in addition to elemental analysis information and sample NMR spectra.
Oxidation of 4,4ꢁ-pyridinehydrazine to 4,4ꢁ-azopyridine by iodosobenzene diac-
etate PhI(OAc)2: Iodosobenzene diacetate (0.322 g, 1.0 mmol) was added in one portion
to a stirred solution of 4,4ꢁ-pyridinehydrazine (0.186 g, 1.0 mmol) in 7 mL of DMSO and
the reaction mixture was stirred at room temperature for 6 h. H2O (20 mL) was then added
and the reaction solution was extracted with EtOAc (3 × 20 mL). The organic extracts were
combined together and dried over anhydrous MgSO4. Upon concentrating the solution
under vacuum, 4,4ꢁ-azopyridine A3 was precipitated as orange crystals (127 mg, 69%).
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