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Bulky phosphazenium cation catalysis for dehydrative condensation of
phosphoric acid with alcohols{{§
Akira Sakakura,a Mikimoto Katsukawa,a Takaomi Hayashib and Kazuaki Ishihara*a
Received 25th May 2007, Accepted 31st July 2007
First published as an Advance Article on the web 6th August 2007
DOI: 10.1039/b707974e
A metal-free phosphazenium cation-catalyzed direct dehydrative condensation of phosphoric acid with alcohols has been
developed for the environmentally benign synthesis of phosphoric acid monoesters.
Phosphoric acid monoesters are among the most important
substances in materials chemistry, medicinal chemistry, and so
on. Many phosphoric acid monoesters have been synthesized on an
industrial scale and are used as necessities in our daily life.1,2 From
the perspective of green chemistry, the direct catalytic condensation
of equimolar amounts of phosphoric acid and alcohols is attractive
for the synthesis of phosphoric acid monoesters, especially for
industrial-scale synthesis, since the reaction produces only water as
a byproduct.3 Although various methods for the direct catalytic
condensation of carboxylic acids with equimolar amounts of
alcohols have been reported,4,5 there are only a few successful
methods for the direct catalytic condensation between phosphoric
acid and alcohols.6,7 Previously, we reported that a catalytic
amount of nucleophilic bases such as N-butylimidazole promoted
the dehydrative condensation of phosphoric acid and alcohols.7a
However, this condensation is not a true catalytic process, since the
reaction requires one equivalent of tributylamine (n-Bu3N). Very
recently, we reported that perrhenic acid (1 mol%) showed excellent
catalytic acitivity in the condensation between phosphoric acid and
alcohols in the presence of dibutylamine (20 mol%).7b Since
rhenium is a rare metal and the oxorhenium(VII) complexes are very
expensive, the recovery and reuse of the oxorhenium compounds is
strongly needed, especially for industrial-scale synthesis. However,
we haven’t been able to establish it yet. The contamination of
phosphoric acid monoesters with oxorhenium compounds makes
purification of the products very difficult. From the perspective of
green chemistry, a metal-free catalytic method is more desirable for
preparation of phosphoric acid monoesters. We report here a
phosphazenium salt as a metal-free catalyst for the dehydrative
condensation between phosphoric acid and alcohols.
In our previous work, a 1 : 1 (v/v) mixture of DMF and EtNO2
was used as a solvent.7a Since phosphoric acid can not be dissolved
a
Graduate School of Engineering, Nagoya University, Chikusa, Nagoya,
464-8603, Japan. E-mail: [email protected];
Fax: +81 52 789 3222; Tel: +81 52 789 3331
b
Mitsui Chemical Inc., 580-32 Nagaura, Sodegaura, Chiba, 299-0265,
Japan
{ Dedicated to late Professor Yoshihiko Ito.
{ This paper was presented at the Japan/ UK Green Sustainable
Chemistry Symposium at the 87th Chemical Society of Japan Annual
meeting, March 2007.
§ Electronic supplementary information (ESI) available: Experimental
details; 1H and 13C NMR spectra for all products. See DOI: 10.1039/
b707974e
1166 | Green Chem., 2007, 9, 1166–1169
in that solvent, 100 mol% of n-Bu3N is required to dissolve
phosphoric acid and promote the reaction. We considered that
some organic bases might catalyze the condensation in N-methyl2-pyrrolidon (NMP)–o-xylene (1 : 1 v/v) in the absence of any
auxiliary base, since phosphoric acid dissolves well in NMP–
o-xylene (1 : 1 v/v) even without an auxiliary base.7b Therefore, we
examined the catalytic activities of several organic bases in the
condensation of an equimolar mixture of phosphoric acid and
stearyl alcohol in NMP–o-xylene (1 : 1 v/v) (Table 1). When the
reaction was conducted in the presence of n-Bu3N (100 mol%),
stearyl phosphate was obtained in 87% conversion yield (entry 1).
31
P NMR analysis indicated that the crude products included the
phosphoric acid diester (10%) and pyrophosphoric acid esters
(17%) as byproducts and that the purity of stearyl phosphate was
73% aside from phosphoric acid. We then tried to reduce the
catalyst loading, but unfortunately the use of 10 mol% of n-Bu3N
decreased reactivity to give the product in 46% yield and 94%
purity (entry 2). While a catalytic amount of n-Bu3N did promote
the present reaction (entry 2 versus entry 10), the catalytic activity
Table 1 Direct condensation of phosphoric acid with stearyl alcohol
catalyzed by an organic base in NMP–o-xylene (1 : 1 v/v)a
Entry
Organic base (mol%)
X (equiv.)
Conv. (%)b [purity (%)]c
1
2
3
4
5
6
7
8
9
10
n-Bu3N (100)
n-Bu3N (10)
N-butylimidazole (10)
DMAP (10)
DBU (10)
1 (10)
1 (10)
n-Bu4N+OH2 (10)
n-Bu4P+OH2 (10)
No organic base
1
1
1
1
1
1
1.5
1.5
1
1
87
46
54
55
55
79
96
61
40
11
[73]
[94]
[91]
[91]
[91]
[82]
[97]
[94]
[96]
[100]
a
Reactions were carried out with stearyl alcohol (2 mmol) and
H3PO4 (2 or 3 mmol) in the presence of an organic base (0–
100 mol%) in NMP–o-xylene (1 : 1 v/v, 10 mL) at azeotropic reflux
for 10 h. b Determined by 1H NMR analysis. The product contains
the phosphoric acid diester and pyrophosphoric acid esters, as well
as the phosphoric acid monoester. c The ratio of the phosphoric acid
monoester in the product. Determined by 31P NMR analysis on the
basis of the alcohol.
This journal is ß The Royal Society of Chemistry 2007
was low. Interestingly, an organic base could catalyze the
dehydrative condensation under acidic conditions with phosphoric
acid. Other organic bases (10 mol%), such as N-butylimidazole,
4-(N,N-dimethylamino)pyridine (DMAP) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), showed reactivities (54–55%) and
purities (91%) similar to those with n-Bu3N (entries 3–5). Very
interestingly, tetrakis[tris(dimethylamino)phosphoranilidenamino]phosphonium hydroxide (1)8,9 showed good catalytic activity (79%
yield and 82% purity, entry 6). See the ESI§ for the comparison
of solvents at the same reaction temperature. The use of
1.5 equiv of phosphoric acid gave excellent results (96% yield
and 97% purity, entry 7). In contrast, tetrabutylammonium
hydroxide (n-Bu4N+OH2) and tetrabutylphosphonium hydroxide
(n-Bu4P+OH2) gave poor results (entries 8 and 9).
To explore the generality and scope of the phosphazenium
cation-catalyzed condensation, the reactions of phosphoric acid
(1.5 equiv) with various alcohols were examined in the presence of
10 mol% of 1 (Table 2). After the reaction was completed,
phosphoric acid monoesters were purified as follows: 1 was
removed by purification using cation-exchange resin (DOWEX1
50WX2-200, H+ form), and excess phosphoric acid was then
removed by extraction using 1 M aqueous HCl and diethyl ether.
Saturated and unsaturated primary alcohols, such as stearyl
alcohol and oleyl alcohol, could be easily converted to the
corresponding phosphoric acid monoesters in excellent isolated
yields (92 and 87% yields, entries 1 and 3). The geometry of the
CLC double bond in oleyl alcohol was maintained during the
reaction. The present protocol could be easily applied to a largescale process, and the condensation of phosphoric acid (1.5 equiv.)
with oleyl alcohol (100 mmol) gave oleyl phosphate in 93% yield
(entry 2). Diethylene glycol dodecyl ether also showed high
reactivity (95% yield, entry 4). Phosphoric acid monoesters of
Table 2 Synthesis of phosphoric acid monoestersa
Entry
Alcohol
1
2d
3
4
5
6f
n-C18H37–OH
n-C18H37–OH
(Z)-n-C8H17CHLCH(CH2)8–OH
n-C12H25(OCH2CH2)2–OH
b-cholestanol
Isolated yield (%)b
[purity (%)]c
92 [97]
93e [91]
87 [96]
95 [98]
90 [93]
62g [—]
a
Reaction of H3PO4 (3 mmol) with alcohols (2 mmol) was carried
out in the presence of 1 (0.2 mmol) in NMP–o-xylene (1:1 v/v,
10 mL) at azeotropic reflux for 10 h. b The product contains the
phosphoric acid diester and pyrophosphoric acid esters as well as the
phosphoric acid monoester. c The ratio of the phosphoric acid
monoester in the product. Determined by 31P NMR analysis. d The
reaction of phosphoric acid (150 mmol) and alcohol (100 mmol) was
conducted with 1 (10 mmol) for 12 h. e Estimated by 1H NMR
analysis. f The reaction was conducted with 2 equiv of H3PO4.
g
Estimated by RP-HPLC analysis.
This journal is ß The Royal Society of Chemistry 2007
diethylene glycol dodecyl ether are useful as surfactants in
detergents.1c A secondary alcohol, b-cholestanol, was also
converted to the corresponding phosphoric acid monoester10 in
92% yield without decomposition, even though the reaction
conditions were significantly acidic (entry 5). Since the reaction
of 29,39-O-isopropylidene uridine proceeded slightly slower than
that of stearyl alcohol, 2 equivalents of phosphoric acid were used
(entry 6). Reversed-phase HPLC analysis of the crude product
revealed that the yield of the corresponding 59-O-monophosphate
was 62% and significant amounts of byproducts were produced.
One of the byproducts might be generated by cleavage of the
isopropylidene group due to the high reaction temperature.
When the condensation between phosphoric acid (2 equiv.) and
stearyl alcohol was conducted in NMP–n-butyronitrile (n-PrCN)
(1 : 1 v/v), the reaction proceeded more smoothly than that in
NMP–o-xylene (1 : 1 v/v) despite the fact that n-PrCN has a much
lower boiling point (116 uC) than o-xylene (144 uC) (Table 3). See
the ESI§ for the comparison of solvents at the same reaction
temperature. However, stearyl butyrate was produced as a
byproduct in 18% yield along with stearyl phosphate (81% yield)
(entry 1). Stearyl butyrate must be produced by the reaction
between stearyl alcohol and n-PrCN. As discussed below, n-PrCN
might act as a condensation reagent to activate phosphoric acid.11
To reduce the production of stearyl butyrate, we examined the
slow addition of stearyl alcohol. During the 10 h reaction, stearyl
alcohol was added to the reaction mixture in four portions
(method B). 1H NMR analysis of the obtained crude product
revealed that the production of stearyl butyrate was reduced to 5%
and stearyl phosphate was obtained in 94% conversion yield
(entry 2).
Since the reaction in NMP–n-PrCN could be conducted at a
lower temperature than the reaction in NMP–o-xylene, it
should be suitable for the synthesis of phosphoric acid monoesters
of alcohols that are sensitive to heat, such as 29,39O-isopropylidene ribonucleosides. Therefore, we examined the
phosphorylation of 29,39-O-isopropylidene uridine. The reaction
proceeded well without significant decomposition of the alcohol.
After the removal of solvents in vacuo, the resultant crude product
was purified by anion-exchange chromatography (DOWEX1
1X2-200, HCO22 form) to give 29,39-O-isopropylidene uridine
59-O-monophosphate in 83% isolated yield (entry 3).
Phosphorylation of three other ribonucleosides was also carried
out under the same reaction conditions to give the corresponding
59-O-monophosphate in isolated yields of 70–73% (entries 4–6).
No phosphorylation of nucleobases was detected even without any
protection.7a
We now discuss the possible mechanism of the phosphazenium
cation-catalyzed condensation of phosphoric acid with alcohols
(Scheme 1). When 1 (PZN+OH2) is mixed with phosphoric acid,
phosphazenium phosphate 2 should be formed immediately. Since
the bulky phosphazenium cation (PZN+), in which the positive
charge is highly delocalized, makes the phosphate anion free," 2 is
dehydrated to give monometaphosphate 312 as an active species
under heating in NMP–o-xylene (path a).I** Compound 3 reacts
rapidly with alcohols to give phosphoric acid monoesters 4. In
NMP–n-PrCN, 2 would initially react with n-PrCN to produce
active intermediate 5 (path b).** Compound 5 easily decomposes
to give 3 even at a lower reaction temperature. Compound 5 would
also react directly with alcohols, to give 4 or butyric acid esters
Green Chem., 2007, 9, 1166–1169 | 1167
Table 3
Direct condensation of phosphoric acid with alcohols catalyzed by 1 in NMP–n-PrCN (1 : 1 v/v)a
Yield (%)
b
Entry
Alcohol
Method
Conv.c
Isolatedd
1
2
3
n-C18H37–OH
n-C18H37–OH
A
B
B
81 (18)e
94 (5)e
85
ND
ND
83
4
B
82
72
5
B
82
70
6
B
77
73
a
Reaction of H3PO4 (4 mmol) with alcohols (2 mmol) was carried out in the presence of 1 (0.2 mmol) in NMP–n-PrCN (1 : 1 v/v, 10 mL) at
azeotropic reflux for 10 h. b Method A: an alcohol was added to the reaction mixture in one portion; method B: an alcohol was added to the
reaction mixture in four portions during the reaction. c Determined by 1H NMR analysis. d Purity of the product is .98%. e Yields of stearyl
butyrate are shown in parentheses.
(n-PrCO2R) (path c). It is conceivable that path c is suppressed
when the alcohol is added slowly.
Pyrophosphoric acid monoester 6, which might be generated by
the reaction of 3 with 4, should reversibly decompose to 3 and 4
with promotion by intramolecular hydrogen bonding (eqn (1)).13
In contrast, the decomposition of 6 to monometaphosphoric acid
ester 7 and 2 should be very slow because of the absence of
promotion by intramolecular hydrogen bonding (eqn (2)). It is
conceivable that the present reaction produced 4 selectively
because of the slight generation of 7, the reaction of which with
the alcohol and 4 generates the phosphoric acid diester and
pyrophosphoric acid esters, respectively, as byproducts.
ð1Þ
ð2Þ
Scheme 1 Proposed mechanism for the phosphazenium cation-catalyzed
condensation of phosphoric acid with alcohols.
1168 | Green Chem., 2007, 9, 1166–1169
In conclusion, we have developed a metal-free phosphazenium
cation-catalyzed direct condensation of phosphoric acid with
alcohols for the efficient synthesis of phosphoric acid monoesters.
The present method is more advantageous for the phosphorylation
of 29,39-O-isopropylidene ribonucleosides than the perrhenic acidcatalyzed method, since the yields of the corresponding phosphoric
acid monoesters were low in the perrhenic acid-catalyzed method
because of the significant decomposition of the starting materials.
This journal is ß The Royal Society of Chemistry 2007
Financial support for this project was provided by JSPS
KAKENHI (15205021 and 18750082), the 21st Century COE
Program ‘‘Nature-Guided Materials Processing’’ of MEXT, Toray
Science Foundation, the Mazda Foundation and the Uehara
Memorial Foundation.
6
7
References
" In comparison to alkali and alkali earth metal hydroxides, the
characteristics of 1 are that its cationic part is comprised with only nonmetal atoms, and has a very large molecular size. Those features weaken
the interaction between cationic and anionic moiety.
I The monoanion forms of phosphoric acid monoesters are thought to be
the most reactive for the hydrolysis (ref. 10b).
** We could not observe the generation of the proposed intermediates 3
and 5 by 31P NMR analysis. See ESI for more details.
1 (a) T. F. Tadros, Applied Surfactants: Principles and Applications, Wiley,
Weinheim, 2005; (b) A. D. F. Toy and E. N. Walsh, Phosphorus
Chemistry in Everyday Living, American Chemical Society, Washington,
DC, 2nd edn, 1987; (c) A. Matsunaga, A. Fujiu, S. Tsuyutani, T. Nozaki
and M. Ueda, WO Pat., 17 852, 1996.
2 For reviews of the synthesis of phosphoric acid esters, see: (a)
Y. Hayakawa, in Comprehensive Organic Synthesis, ed. B. M. Trost,
I. Fleming and E. Winterfeldt, Pergamon, Oxford, 1991, vol. 6, ch. 2.8,
pp. 601–630; (b) C. B. Reese, Org. Biomol. Chem., 2005, 3, 3851.
3 P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice,
Oxford University Press, Oxford, 1998.
4 J. Otera, Esterification, Wiley, Weinheim, 2003.
5 For our recent contributions to catalytic direct condensations of
carboxylic acids, see: (a) K. Ishihara, S. Ohara and H. Yamamoto,
J. Org. Chem., 1996, 61, 4196; (b) K. Ishihara, S. Ohara and
H. Yamamoto, Science, 2000, 290, 1140; (c) K. Ishihara,
M. Nakayama, S. Ohara and H. Yamamoto, Synlett, 2001, 1117; (d)
K. Ishihara, M. Nakayama, S. Ohara and H. Yamamoto, Tetrahedron,
2002, 58, 8179; (e) M. Nakayama, A. Sato, K. Ishihara and
H. Yamamoto, Adv. Synth. Catal., 2004, 346, 1275; (f) A. Sato,
Y. Nakamura, T. Maki, K. Ishihara and H. Yamamoto, Adv. Synth.
This journal is ß The Royal Society of Chemistry 2007
8
9
10
11
12
13
Catal., 2005, 347, 1337; (g) K. Ishihara, S. Nakagawa and A. Sakakura,
J. Am. Chem. Soc., 2005, 127, 4168; (h) A. Sakakura, S. Nakagawa and
K. Ishihara, Tetrahedron, 2006, 62, 422; (i) Y. Nakamura, T. Maki,
X. Wang, K. Ishihara and H. Yamamoto, Adv. Synth. Catal., 2006, 348,
1505.
M. Honjo, Y. Furukawa and K. Kobayashi, Chem. Pharm. Bull., 1966,
14, 1061.
(a) A. Sakakura, M. Katsukawa and K. Ishihara, Org. Lett., 2005, 7,
1999; (b) A. Sakakura, M. Katsukawa and K. Ishihara, Angew. Chem.,
Int. Ed., 2007, 46, 1423; (c) K. Ishihara, A. Sakakura and M. Hatano,
Synlett, 2007, 686(account).
For preparation of 1, see: T. Nobori, T. Suzuki, S. Kiyono, M. Kuono,
K. Mizutani, Y. Sonobe and U. Takaki, Eur. Pat., 791 600, 1997.
(a) T. Nobori, T. Hayashi, S. Kiyono and U. Takaki, Eur. Pat.,
879 838, 1998; (b) S. Yamasaki et al., WO Pat., 23 500, 2000; (c)
P. Hupfield, A. Surgenor and R. Taylor, Eur. Pat., 1 008 610, 2000; (d)
G. Moloney, P. Hupfield, A. Surgenor and R. Taylor, Eur. Pat.,
1 008 612, 2000; (e) T. Nobori, A. Shibahara, S. Kiyono, T. Hayashi,
K. Funaki, I. Hara, K. Mizutani and U. Takaki, Eur. Pat., 1 044 989,
2000; (f) T. Nobori, S. Fujiyoshi, I. Hara, T. Hayashi, A. Shibahara,
K. Funaki, K. Mizutani and S. Kiyono, WO Pat., 81 274, 2001; (g)
S. Maeda, T. Urakami, T. Kawabata, K. Suzuki and T. Nobori, WO
Pat., 29 322, 2003; (h) N. Yoshimura et al., WO Pat., 3 902, 2006; (i)
K. Suzawa, M. Ueno, A. E. H. Wheatley and Y. Kondo, Chem.
Commun., 2006, 4850.
M. Sprecher, R. Breslow, R. Philosof-Oppenheimer and E. Chavet,
Tetrahedron, 1999, 55, 5465.
For selected recent reports for phosphorylation of alcohols using
CCl3CN, see: (a) A. Onoda, Y. Yamada, T. Okamura, M. Doi,
H. Yamamoto and N. Ueyama, J. Am. Chem. Soc., 2002, 124, 1052; (b)
J. W. Newman, C. Morisseau, T. R. Harris and B. D. Hammock, Proc.
Natl. Acad. Sci. U. S. A., 2003, 100, 1558; (c) K. Sorensen-Stowell and
A. C. Hengge, J. Org. Chem., 2005, 70, 4805; (d) H. V. Thulasiram,
R. M. Phan, S. B. Rivera and C. D. Poulter, J. Org. Chem., 2006, 71,
1739.
(a) F. H. Westheimer, Chem. Rev., 1981, 81, 313; (b) C. A. Bunton,
D. R. Llewellyn, K. G. Oldham and C. A. Vernon, J. Chem. Soc., 1958,
3574.
D. L. Miller and F. H. Westheimer, J. Am. Chem. Soc., 1966, 88,
1507.
Green Chem., 2007, 9, 1166–1169 | 1169