Ti(O-isoPr)4 Catalyzed hydrophosphonylation of activated alkenes by diphenyl H-phosphonate

Article abstract of DOI:10.1016/j.tetlet.2007.02.055

Diphenyl 2-(alkoxycarbonyl)alkylphosphonates were synthesized via a titanium alkoxide catalyzed Pudovik reaction under mild conditions. Methacrylates or acrylates were selectively hydrophosphonylated by diphenyl H-phosphonate even in the presence of a dia

Full text of DOI:10.1016/j.tetlet.2007.02.055

Tetrahedron Letters 48 (2007) 2749–2753
Ti(O-isoPr)4 Catalyzed hydrophosphonylation of activated
alkenes by diphenyl H-phosphonate
Qiang Yao*
Supresta US LLC, 430 Saw Mill River Road, Ardsley, NY 10502, USA
Received 26 September 2006; revised 8 February 2007; accepted 9 February 2007
Available online 15 February 2007
Abstract—Diphenyl 2-(alkoxycarbonyl)alkylphosphonates were synthesized via a titanium alkoxide catalyzed Pudovik reaction
under mild conditions. Methacrylates or acrylates were selectively hydrophosphonylated by diphenyl H-phosphonate even in the
presence of a dialkyl phosphite.
Ó 2007 Elsevier Ltd. All rights reserved.
Formation of P–C bonds is of considerable importance
in organophosphorus chemistry.1 The hydrophosphonyl-
ation of C@C by H-phosphonates is doubtlessly the
most atom-economic method to form P–C bonds. His-
torically, the free radical addition of H-phosphonates
to alkenes2 has been the method of choice. However,
the electrophilic nature of phosphoryl radicals essen-
tially excludes the use of electron-deficient alkenes;3,4
thus acrylates and methacrylates are not suitable sub-
strates for the free radical hydrophosphonylation. On
the other hand, these electron-deficient alkenes are acti-
vated by the adjacent carboxyl group, and are subject to
the base or Lewis acid catalyzed Pudovik reaction.5,6
Although a number of examples of Pudovik reaction
of dialkyl H-phosphonates have been documented, the
hydrophosphonylation of (meth)acrylate-type activated
alkenes by diaryl H-phosphonates has witnessed few
reports.7
but also because they have largely been ignored, prob-
ably because of the lack of good synthetic methods to
access them. Due to their relatively high molecular
weights and thus low volatility compared with the dialkyl
2-(alkoxycarbonyl)alkylphosphonates, diaryl 2-(alkoxy-
carbonyl)alkylphosphonates caught our attention in our
search of a new type of organophosphorus additives.
Naturally, the Pudovik reaction is our first choice to
synthesize diaryl 2-(alkoxycarbonyl)alkylphosphonates
from diaryl H-phosphonates and carbonyl-activated
alkenes. However, it has been long recognized that di-
aryl and dialkyl H-phosphonates often follow a different
reaction pathway and the reaction conditions which are
suitable for dialkyl H-phosphonates often fail to apply
to diaryl H-phosphonates.12,13 This dissimilarity
presents a synthetic challenge to utilize diaryl H-
phosphonates.
In this Letter, we report an efficient method with high
selectivity to synthesize diphenyl 2-(alkoxycarbonyl)-
alkylphosphonates from diphenyl H-phosphonate, the
most important and readily available diaryl H-phospho-
nate, and a variety of (meth)acrylate-type activated alk-
enes under mild conditions.
In our ongoing program to develop organophosphorus
polymer additives, we aimed to synthesize diaryl phos-
phonates.8 These compounds are attractive not only be-
cause the variation of ester groups on the phosphonates
changes their many physical and chemical properties
such as toxicity,9 volatility, and stereochemistry out-
comes10,11 in Horner–Wadsworth–Emmons reaction,
We began with the traditional easily handled base cata-
lysts such as triethylamine and 1,8-diazabicyclo-
[5.4.0]undec-7-ene (DBU), which have been proven
to be successful in the Pudovik reaction of dialkyl
H-phosphonates, and Lewis acids in an attempt to
synthesize methyl 2-(diphenylphosphono)propionate
from diphenyl H-phosphonate and methyl acrylate.
Unfortunately, although both the tested base catalysts
Keywords: Diphenyl H-phosphonate; Titanium iso-propoxide; Acryl-
ates; Pudovik reaction.
*
Tel.: +1 914 269 5920; fax: +1 914 674 9438; e-mail:
john.yao@supresta.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.055

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Q. Yao / Tetrahedron Letters 48 (2007) 2749–2753
Table 1. Catalyst screening for the hydrophosphonylation of methyl
longed reaction time (5 h) in order to complete the
reaction. Phenyl acrylate has an intermediate reactiv-
ity. The similar pattern was also observed in the meth-
acrylate series where methyl methacrylate is more
reactive than phenyl methacrylate (Table 2, entries 5
and 6).
acrylate by diphenyl H-phosphonatea
Entry
Catalyst
Yieldb (%)
1
2
3
4
5
Triethylamine
DBU
AlCl3
TiCl4
Ti(O-isoPr)4
8
13
0
0
95c
The presence of substituents at a or b position of the
activated alkenes also substantially reduces the reaction
rate. For instance, methyl acrylate was much more easily
subject to the phosphonylation than methyl methacryl-
ate or ethyl crotonate/cinnamate (Table 2, entries 1, 5,
7, and 8). Obviously, steric hindrance and the changing
of the electron density of C@C caused by the substitu-
ents accounted for these differences.
a Reactions were run at a mol ratio of diphenyl H-phosphonate/methyl
acrylate:catalyst = 1.64/1/0.10 with diphenyl H-phosphonate =
0.100 mol at room temperature for 30 min.
b 31P NMR yield.
c 5% (iso-PrO)(C6H5O)P(@O)CH2CH2C(O)OCH3.
gave the targeted product, the yields were very low
(Table 1, entries 1 and 2), and Lewis acids such as AlCl3
and TiCl4 were totally ineffective (Table 1, entries 3
and 4).
Interestingly, a high selectivity was observed between di-
phenyl H-phosphonate and iso-propyl phenyl/di(iso-
propyl) H-phosphonates produced by the transesteri-
fication of diphenyl H-phosphonate and iso-propanol
(Scheme 2, top right part). Under the reaction condi-
tions used, the products mainly arose from diphenyl
H-phosphonate (P95%). The selectivity among the
phosphonylating agents can be controlled at higher than
98% by adjusting the feed ratio. In fact, when diphenyl
H-phosphonate and diethyl H-phosphonate were mixed
with methyl acrylate and Ti(O-isoPr)4 at a mole ratio of
2/2/1/0.1 (Table 2, entry 10), the only phosphonate
product observed was methyl 2-(diphenylphos-
phono)propionate. Therefore, titanium iso-propoxide
provides an excellent way to selectively hydrophospho-
nylate the (meth)acrylate-type alkenes by diphenyl
H-phosphonate.
Since the attacking species diaryl phosphite exits in two
tautomeric forms, the phosphite (II, Scheme 1) and the
H-phosphonate (I, Scheme 1) with the latter predomi-
14
nating under neutral conditions,
We speculated that
catalysts that aid to shift the reaction to the right may
accelerate the reaction; therefore, we tested titanium
iso-propoxide which is reported to undergo the trans-
esterification with the hydrogen phosphite to form a
metallo-phosphite (III, Scheme 1),15,16 a species which
has a lone pair of electrons and thus is a potential
attacking species. The result was very satisfactory.
Methyl 2-(diphenylphosphono)propionate was obtained
in 95% yield at room temperature (Table 1, entry 5).
Titanium iso-propoxide was subsequently applied to a
variety of (meth)acrylate-type alkenes. Most of the
tested compounds produced the targeted diphenyl
2-(alkoxylcarbonyl)alkylphosphonates at high yields
(Table 2, entries 1–5 and 7). For example, ethyl and
tert-butyl 2-(diphenylphosphono)propionates were
formed quantitatively from diphenyl H-phosphonate
and the corresponding acrylates at the 10 mol % catalyst
loading under the mild reaction conditions.
The high selectivity observed between diaryl and dialkyl
(or alkyl aryl) H-phosphonates can be attributed to their
different acidities. High acidity facilitates the formation
of Ti–phosphite (III, Scheme 1). Although diethyl H-
phosphonate reacts with titanium alkoxide too15,16 and
forms methyl 2-(diethylphosphono)propionate when
methyl acrylate was present (Table 2, entry 9), it cannot
compete with diphenyl H-phosphonate because of the
latter’s higher acidity. Therefore, the reaction selectively
uses diphenyl H-phosphonate as the hydrophosphonyl-
ating agent.
It is noted that the carboxylic ester groups considerably
affected the reaction course. The bulky ester groups sig-
nificantly retard the reaction. Changing the methyl to
tert-butyl or phenyl group of the acrylates required
much high temperatures and/or long reaction times in
order to achieve a satisfactory conversion (Table 2,
entries 1, 3, and 4). The results in Table 2 show that
methyl acrylates readily reacted with diphenyl H-phos-
phonate at room temperature in the presence of
10 mol % titanium iso-propoxide but tert-butyl acrylate
needed an elevated temperature (65 °C) and a pro-
A possible mechanism of the titanium alkoxide cata-
lyzed Pudovik reaction of diaryl H-phosphonate is
shown in Scheme 2. Transesterification produces a Ti–
phosphite (I, Scheme 2) that attacks C@C to form II
(Scheme 2). While II could extract a proton from H-
phosphonates18 followed by the tautomerization to an
ester intermediate (III, Scheme 2) that is subject to the
further reaction at the metal center (Path a), the negative
effect of the bulky ester groups on the reactivity regard-
less of their electron-donating or electron-withdrawing
nature seems to disfavor this path since Path (a) would
exhibit a normal reactivity order; that is, phenyl
(meth)acrylate > methyl (meth)acrylate due to the phen-
oxy group’s activation on C@C.19 An alternative path
(Path b) involves the direct attack of the Oꢀ nucleo-
phile (II, Scheme 2) on the metal via a seven-membered
ring in the transition stage to generate a phosphonate
Ti(OR)4
O
ArO P
OAr
P
OAr
P
OAr
OH
ArO
OTi(OR)3
H
ArO
ROH
III
II
I
Scheme 1. Formation of the Ti–phosphite.

Q. Yao / Tetrahedron Letters 48 (2007) 2749–2753
2751
a,17
Table 2. The hydrophosphonylation of (meth)acrylates by diphenyl H-phosphonate in the presence of Ti(O-isoPr)4
O
R2
Ti(O-i soPr)
O
P
O
P
OPh
4
OR
R1
PhO
PhO
+
H
PhO
OR
R2
R1
O
R1 = H, Me, Ph
R2 = H, Me
R = Me, Et, tBu, Ph
Entry
1
Mol ratiosb DPP/C@C/[Ti]
Temperature (°C) & Time (h)
Product
Yieldc (%)
1.64/1/0.060
1.64/1/0.10
2.00/1/0.10
25, 0.5
25, 0.5
25, 0.5
84d
95e
O
O
PhO P
OMe
100 (82)
OPh
O
O
2
2.00/1/0.10
25, 0.5
100 (87)
PhO
P
OEt
OPh
O
O
3
4
5
1.64/1/0.10
2.00/1/0.10
25, 0.5
65, 5
20d
PhO P
OPh
OtBu
OPh
OMe
97d (72)
O
O
P
OPh
1.64/1/0.10
25, 0.5
25, 72
30d
92d (61)
PhO
O
O
1.64/1/0.10
1.64/1/0.15
2.77/1/0.26
25, 0.5
25, 0.5
60, 0.5
12
22
100 (88)
PhO P
OPh
O
O
O
O
P
OPh
6
7
8
1.64/1/0.15
25, 0.5
25, 240
0
PhO
PhO
PhO
OPh
OEt
OEt
50d (40)
O
P
OPh
1.64/1/0.10
2.77/1/0.26
25, 0.5
105, 3
50d
85d (70)
Ph
O
P
OPh
1.64/1/0.10
2.77/1/0.26
65, 8
105, 3
60
60d (52)
O
O
9
2.00/1/0.10
25, 168
25, 24
100
0
EtO P
OEt
OMe
OMe
OMe
O
O
O
EtO P
10
DEP/DPP
OEt
/MA/[Ti]f=
2.00/2.00
/1/0.10
O
100
PhO P
OPh
a Reactions were run at diphenyl H-phosphonate = 0.0500–0.100 mol. Results were the average of two runs.
b DPP = diphenyl H-phosphonate, C@C@alkenes, [Ti] = Ti(O-isoPr)4.
c 31P NMR yields based on the activated alkenes. The isolated yields were in the parenthesis. Purification was not optimized.
d Selectivity P98% from the 31P NMR results.
e Selectivity = 95% from the 31P NMR results.
f DEP = diethyl H-phosphonate, MA = methyl acrylate.
intermediate (IV, Scheme 2). Apparently, any bulky
groups either in the carboxylic ester part or at the a/b
positions of carboxylic esters will introduce ring strain
in the transition stage and reduce the reactivity. Inter-
mediate IV subsequently undergoes a transesterification
at the metal center and consequently forms the product
and regenerates the catalyst.
In conclusion, we developed a method to synthesize di-
phenyl 2-(alkoxylcarbonyl)alkylphosphonates from di-
phenyl H-phosphonate and (meth)acrylates under mild
conditions. The method relies on the titanium alkoxide
catalyzed Pudovik reaction. It is efficient and highly
selective among different types of hydrogenphosphonyl-
ating agents.

2752
Q. Yao / Tetrahedron Letters 48 (2007) 2749–2753
O
Product
P
ArO P
H
OH
OAr
ArO
Ti(OR)4
OAr
ROH
O
RO P
O
DAP
OR'
HO
O
P
H
ArO
P H
ROH
OR
OR
ArOH
ArOH
P
ArO
OTi(OR)3
ArO
OAr
OAr
O
I
(ArO)2POH
OR'
Product
OR'
(RO)3Ti
(RO)3TiO
O
(ArO)2PO-
OH
OR'
O
P+
P
OAr
ArO
ArO
OAr
III
IV
(a)
(ArO)2POH
(b)
(RO)3Ti -O
OR'
O
P+
ArO
OAr
II
DAP=diaryl H-phosphonates
Scheme 2. A possible mechanism of the Ti(OR)4 catalyzed Pudovik reaction of diaryl H-phosphonates.
Hakimelahi, G. H.; Moosavi-Movahedi, A. A.; Tsay, S.
C.; Tsai, F. Y.; Wright, J. D.; Dudev, T.; Hakimelahi, S.;
Lim, C. J. Med. Chem. 2000, 43, 3632–3640.
Acknowledgments
We thank Professor Edward Weil at Polytechnic Uni-
versity for helpful discussions. We also wish to thank
reviewers for their helpful suggestions and bringing
our attention to the Ref. 6.
8. Yao, Q.; Levchik, S. Tetrahedron Lett. 2006, 47, 277–
281.
9. Roy, N. K.; Nidiry, E. S. J.; Vasu, K.; Bedi, S.; Lalljee, B.;
Singh, B. J. Agric. Food Chem. 1996, 44, 3971–3976.
10. Ando, K. Tetrahedron Lett. 1995, 36, 4105–4108.
11. Ando, K. J. Org. Chem. 1999, 64, 8406–8408.
12. Kers, A.; Kers, I.; Stawinski, J.; Sobkowski, M.; Kra-
szewski, A. Tetrahedron 1996, 52, 9931–9944.
Supplementary data
General experimental procedures, 1H, 31P, and 13C
NMR data and spectra of compound 1–8 in Table 2.
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.02.055.
13. Medina, P. D.; Ingrassia, L. S.; Mulliez, M. E. J. Org.
Chem. 2003, 68, 8424–8430.
14. Kirby, A. J.; Warren, S. G. The Organic Chemistry of
Phosphorus. In Reaction Mechanisms in Organic Chemis-
try; Eaborn, C., Chapman, N. B., Eds.; Elsevier Pub.
Com.: New York, 1967; pp 17–22.
15. Titanium alkoxides have been applied in the hydrophos-
phonylation of aldehydes by dialkyl H-phosphonates
presumably through a metallo-phosphite. Yokomatsu,
T.; Yamagishi, T.; Shibuya, S. Tetrahedron: Asymmetry
1993, 4, 1779–1782.
16. Duxbury, P. J.; Warne, N. D. J.; Mushtaq, R.; Ward, C.;
Thornton-Pett, M.; Jiang, M.; Greatrex, R.; Kee, P. T.
Organometallics 2000, 19, 4445–4457.
References and notes
1. Engel, R.; Cohen, J. I. Synthesis of Carbon-Phosphorus
Bonds, 2nd ed.; CRC Press: Boca Raton, 2004; pp 1–3.
2. Stiles, A. R.; Vaughan, W. E.; Rust, F. F. J. Am. Chem.
Soc. 1958, 80, 714–716.
17. A typical experimental procedure for Ti(O-isoPr)4 cata-
lyzed Pudovik reaction: Diphenyl phosphite (DPP, 95%,
16.300 g, 0.0661 mol) and methyl acrylate (2.860 g,
0.0332 mol) were mixed in a vial. To this mixture was
then added titanium(IV) propoxide (0.940 g, 0.00331 mol)
at room temperature. A strong exotherm was observed.
The reaction was stopped after half hour. The mixture was
then diluted with toluene and washed by aqueous HCl
followed by caustic washes and water washes then dried in
a RotavaporÒ. The product methyl 2-(diphenylphos-
phono)propionate was further recrystallized from the
ether solution. Mp: 41–43 °C; 1H NMR (CDCl3): 7.1–
7.36 (m, 10H), 3.70 (s, 3H), 2.74–2.87 (m, 2H), 2.35–2.51
3. Hypophosphite radicals have been speculated to be
electrophilic. Deprele, S.; Montchamp, J. L. J. Org. Chem.
2001, 66, 6745–6755.
4. Lopin, C.; Gouhier, G.; Gautier, A.; Piettre, S. R. J. Org.
Chem. 2003, 68, 9916–9923.
5. Savignac, P.; Iorga, B. Modern Phosphonate Chemistry;
CRC press: Boca Raton, 2003; pp 432–433.
6. For different activation methods of PH addition to C@C
or C„C bonds please see: Semenzin, D.; Etemad-Mogh-
adam, G.; Albouy, D.; Diallo, O.; Koenig, M. J. Org.
Chem. 1997, 62, 2414–2422.
7. We noticed one example using diphenyl H-phosphonate as
the hydrophosphonylating agent in special acrylates con-
taining a-lactam ring by using NaH as a catalyst.
13
(m, 2H); C NMR: 171.698 (d, J3PC ¼ 19:32 Hz), 149.915

Q. Yao / Tetrahedron Letters 48 (2007) 2749–2753
2753
(d, J2PC ¼ 9:05 Hz), 129.627, 125.077, 120.232 (d,
J3PC ¼ 4:60 Hz), 52.024, 27.115 (d, JP2C ¼ 3:70 Hz),
21.378 (d, J1PC ¼ 145:10 Hz); 31P NMR: 23.53
(J2PH ¼ 17:80 Hz, JP3H ¼ 11:87 Hz).
works for diethyl H-phosphonate suggests the proton
abstraction from EtOH unlikely because EtOH has
weaker acidity than diethyl H-phosphonate.
19. Phenyl acrylate has been shown to be more reactive than
methyl acrylate in the base-catalyzed Michael addition.
For example, Shi, M.; Chen, L. H.; Li, C. Q. J. Am. Chem.
Soc. 2005, 127, 3790–3800.
18. One can draw a mechanism based on the proton abstrac-
tion from alcohols that shares the same intermediate (II)
in Scheme 2. However, the fact that Ti(O-isoPr)4 also