Bu4NI-catalyzed synthesis of pyrophosphate esters from H-phosphonates

Article abstract of DOI:10.1080/10426507.2012.690121

A n-Bu₄NI/t-BuOOH catalysis system has been developed to promote oxidative dehydrogenative coupling of H-phosphonates to form pyrophosphate tetraesters. This novel iodide (I) ion-catalyzed reaction provides easy access to pyrophosphate derivatives in the absence of a metal and solvent. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Taylor and Francis Group, LLC.

Full text of DOI:10.1080/10426507.2012.690121

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Bu NI-Catalyzed Synthesis of
4
Pyrophosphate Esters from H-
Phosphonates
a
a
a
Juan Huang , Wen He & Bin Wang
a
College of Pharmacy, State Key Laboratory of Medicinal Chemical
Biology and Tianjin Key Laboratory of Molecular Drug Research,
Nankai University , Tianjin , China
Accepted author version posted online: 11 May 2012.Published
online: 20 Jul 2012.
To cite this article: Juan Huang , Wen He & Bin Wang (2012) Bu NI-Catalyzed Synthesis of
4
Pyrophosphate Esters from H-Phosphonates, Phosphorus, Sulfur, and Silicon and the Related Elements,
187:10, 1125-1131, DOI: 10.1080/10426507.2012.690121
To link to this article: http://dx.doi.org/10.1080/10426507.2012.690121
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Phosphorus, Sulfur, and Silicon, 187:1125–1131, 2012
Copyright ꢀ
Nankai University
C
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.690121
Bu NI-CATALYZED SYNTHESIS OF PYROPHOSPHATE
4
ESTERS FROM H-PHOSPHONATES
Juan Huang, Wen He, and Bin Wang
College of Pharmacy, State Key Laboratory of Medicinal Chemical Biology and
Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin,
China
GRAPHICAL ABSTRACT
Abstract A n-Bu4NI/t-BuOOH catalysis system has been developed to promote oxidative
dehydrogenative coupling of H-phosphonates to form pyrophosphate tetraesters. This novel
−
iodide (I ) ion-catalyzed reaction provides easy access to pyrophosphate derivatives in the
absence of a metal and solvent.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Iodide; H-phosphonate; pyrophosphate; tetra-n-butylammonium iodide; tert-butyl
hydroperoxide
INTRODUCTION
Pyrophosphate linkages are found in many biologically active molecules including
1
adenosine diphosphate (ADP), isopentenyl pyrophosphate (IPP), the substrates and in-
2
,3
hibitors of glycosyltransferases, as well as food additives, such as sodium pyrophosphate
4
(
E450) (Figure 1). The traditional chemical approaches for pyrophosphates synthesis suf-
fer from several problems, such as the need for preactivation of monophosphate partners,
3
,5–8
low yields, tedious procedures, and incompatibility with some functional groups.
9
Recently, Han and coworkers have developed a novel copper-catalyzed prepara-
tion of pyrophosphates with H-phosphonates using amine as ligand. From the sustainable
chemistry point of view, the metal- and ligand-free process is desirable. The catalytic uti-
lization of hypervalent iodine compounds has received considerable attention due to their
Received 1 April 2012; accepted 21 April 2012.
We gratefully acknowledge financial support by the National Natural Science Foundation of China
(
Nos. 21172120 and 20902050).
Address correspondence to Bin Wang, 94 Weijin Road, College of Pharmacy, Nankai University, Tianjin
3
00071, China. E-mail: wangbin@nankai.edu.cn
1
125

1
126
J. HUANG ET AL.
Figure 1 Examples of biologically active molecules that contain pyrophosphate linkage.
mild, safe, and environmentally benign characteristics in organic synthesis.10–13 They are
ideal alternatives to expensive transition metal catalysts and toxic heavy-metal-based oxi-
dants in many organic transformations.1
4–20
More recently, a novel tetraalkylammoniumio-
dide/peroxide oxidants catalysis system has been developed for the C–H functionalization
2
1–28
− −
It is proposed that in situ generated hypoiodite ([IO] ) and iodite ([IO2] )
reactions.
display higher catalytic activities than the corresponding aryl λ -iodanes or λ -iodanes and
3
5
2
3,25,27
−
the byproduct iodoarene is completely avoided.
To our knowledge, the iodide (I ) ion
catalyzed P–H bond functionalization reaction is unknown. Herein, we report the first tetra-
n-butylammonium iodide (Bu4NI) catalyzed oxidative dehydrogenative coupling reaction
of P–H bonds. This metal-free, solvent-free, and facile process is a useful complementary
method for the synthesis of pyrophosphates.
RESULTS AND DISCUSSION
Our initial studies focused on the diethyl H-phosphonate 1a as the substrate for the
transformation and various peroxide oxidants were investigated (Table 1, entries 1–5). We
were pleased to find that use of 0.2 equiv of Bu4NI and 2 equiv of tert-butyl hydroperoxide
(TBHP, 70% aqueous solution) could provide tetraethylpyrophosphate 2a in 80% yield
(Table 1, entry 1). When similar peroxide oxidants were employed instead of TBHP, the
reaction took place to afford tetraethylpyrophosphate 2a in low yields (Table 1, entries
–4). Only trace product 2a was obtained by use of H2O2 (Table 1, entry 5). Other potential
2
catalysts related to Bu4NI were also examined (Table 1, entries 6–11). Me4NI, Bu4NBr,
Bu4NCl, KI, and I2 proved ineffective for this reaction (Table 1, entries 6–10). The use of
BnMe3NI instead of Bu4NI gives the product 2a in 15% isolated yield under the conditions
same as entry 1 (Table 1, entry 11). The reaction of 1a in the absence of any catalyst did
not occur at all (Table 1, entry 12). When the solvent of TBHP was switched from water
to decane, the efficiency of the reaction dramatically decreased, affording the product 2a
◦
◦
in only 25% yield (Table 1, entry 13). Reactions conducted at 25 C or 40 C gave lower
◦
yields than those conducted at 60 C (Table 1, entry 14, 15). Further optimization revealed

SYNTHESIS OF PYROPHOSPHATE ESTERS
Table 1 Screening of catalyst and peroxide oxidanta
1127
Entry
Catalyst
Oxidant
Yield (%)
Entry
Catalyst
Oxidant
Yield (%)
1
2
3
4
5
6
7
8
Bu4NI
Bu4NI
Bu4NI
Bu4NI
Bu4NI
Me4NI
Bu4NBr
Bu4NCl
TBHP
TBPB
DTBP
CHP
H2O2
TBHP
TBHP
TBHP
80
48
18
5
Trace
0
9
KI
I2
BnMe3NI
–
Bu4NI
Bu4NI
Bu4NI
Bu4NI
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
0
0
10
11
12
13
14
15
0
25
48
29
80
b
c
d
0
0
15
16
e
a
Unless otherwise noted, the reaction conditions were as follows: 1a (0.2 mmol, 1 equiv), catalyst (0.04 mmol,
◦
0
6
.2 equiv), oxidant (0.4 mmol, 2 equiv), 60 C, 1 h, without a solvent. TBHP = tert-butyl hydroperoxide (entry 1,
–12, 14–16, 70% solution in water), H2O2 (30% solution in water), TBPB = tert-butyl peroxybenzoate, DTBP =
di-tert-butyl peroxide, CHP = cumyl hydroperoxide; isolated yield.
b
TBHP (0.5–0.6 M, in decane).
c
◦
4
2
0 C, 4 h.
d
◦
5 C, 24 h.
e
Bu4NI (0.01 mmol, 0.05 equiv).
that 5 mol% of Bu4NI was required to achieve full conversion of 1a and the highest
yield (80%) is obtained (Table 1, entry 16). Under the optimized conditions described
in entry 16 of Table 1, ethyl, isopropyl, and n-butyl H-phosphonates were compatible
substrates in this transformation (Table 2, entries 1–3). Moreover, these reactions are
facile, good yielding, and easy to work up without requiring chromatography. Although
31
the desired products of other commercially available substrates could be detected by
P
NMR, unfortunately all attempts to separate them from byproducts failed. Silica gel column
chromatography and reduced pressure distillation can completely decompose the desired
products. It should be noted that no competitive P–P bond coupling reaction such as the
formation of hypophosphate was observed in these transformations.
Some control experiments were carried out to investigate the reaction mechanism.
When a radical inhibitor, 2,2,6,6-tetramethylpiperidine-N-oxy l (TEMPO) was used under
the optimized conditions, the reaction of 1a gave pyrophosphate 2a in 60% yield. This
result excluded the possibility of radical process under the present reaction conditions. As
shown in Table 1 entry 10 and Table 3 entry 1, neither catalytic amounts nor stoichiometric
amounts of the iodine (I2) can promote this reaction. We also examined polyvalent iodine
(I, III, and V) oxidants in this transformation in the absence of a catalyst. As shown in Table
3
, the reaction of 1a offered pyrophosphate 2a in moderate NMR yields by the use of IOAc,
−
PhI(OAc)2, or IBX as oxidant. We speculate that the in situ generated hypoiodite ([IO] )
−
29
and iodite ([IO2] ) may be the catalytic species in this transformation. To investigate
the possible intermediates, the reaction was monitored by 31P NMR spectroscopy. After
1
(
5 min, the diethyl phosphate 3 was detected by comparison with the standard sample
31
P NMR, δ 0.19). Obviously, the diethyl H-phosphonate was oxidized to diethyl phos-
30–32
phate by TBHP.
Notably, trace amounts of diethyl phosphoroiodidate 4 were identified

1
128

SYNTHESIS OF PYROPHOSPHATE ESTERS
Table 3 Iodine-mediated reaction of diethyl H-Phosphonate 1a
1129
Entry
Oxidant
31P NMR yield (%)
1
2
3
4
I2
IOAc
PhI(OAc)2
IBX
0
64
65
56
(31
P NMR, δ −41.1) (Figure 2). Some phosphorylation processes involving in situ gener-
33
ated iodophosphates have been reported. The iodophophate shows a higher reactivity than
that of chloro- and bromophosphate and can be consumed immediately in the presence of
nucleophiles.
Figure 3. The iodide ion (I ) is oxidized into active hypoiodite ([IO] ) and iodite ([IO2] )
species by TBHP. The reaction of diethyl H-phosphonate 1a with the active species of-
fered intermediates diethyl phosphoroiodidate 4 and 5. A portion of diethyl H-phosphonate
3
3–35
Based on these results, a possible mechanism was proposed as shown in
−
−
−
Figure 2 31P NMR spectra of reaction mixture after 15 min.

1
130
J. HUANG ET AL.
Figure 3 A possible pathway for the synthesis of pyrophosphate 2a.
1a was oxidized to diethyl phosphate 3 by TBHP and further transformed into ammo-
nium 6. The final pyrophosphate product 2a was obtained through a nucleophilic attack of
ammonium 6 to diethyl phosphoroiodidate 4 or 5.
CONCLUSIONS
In summary, we have developed a mild reaction for construction of pyrophosphate
esters based on the Bu4NI/TBHP catalyzed dehydrogenative coupling of H-phosphonates.
This metal- and solvent-free reaction constitutes a simple and economical protocol for the
synthesis of pyrophosphate esters. Further studies of the detailed mechanism of this process
are currently underway.
EXPERIMENTAL
1H NMR, 13C NMR, and P NMR spectra were recorded on a Bruker AV 400
31
1
13
31
spectrometer (400 MHz for H NMR, 101 MHz for C NMR, and 162 MHz for P NMR
spectroscopy). CDCl3 was used as the solvent and 85% H3PO4 was used as an external
31
standard for P NMR measurement. Chemical shifts were reported in parts per million
downfield from tetramethylsilane (TMS) as the internal standard and coupling constants in
hertz (Hz). Data were reported as follows: chemical shift, multiplicity (d = doublet, t =
triplet, m = multiplet, q = quartet), coupling constant, and integration.
A General Procedure for Synthesis of Pyrophosphate Esters 2a–c
To 20 mL tube were added Bu4NI (0.1 mmol, 36.9 mg), H-phosphonates (2 mmol),
and TBHP (4 mmol, 500 µL) under air, and then the tube was sealed. The reaction mixture
◦
was stirred at 60 C for 1 h. The resulting mixture was extracted with CHCl3 (8 mL), dried

SYNTHESIS OF PYROPHOSPHATE ESTERS
1131
over MgSO4, and filtered. The organic phase was concentrated under vacuum to give NMR
spectroscopically pure products.9
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