Celebrating 20 years of synlett - Special essay: General procedure for the palladium-catalyzed selective hydrophosphorylation of alkynes

Article abstract of DOI:10.1055/s-0029-1217739

A novel catalytic system has been developed to accomplish the hydrophosphorylation of terminal and internal alkynes with high isolated yields (up to 96%) and excellent regio- and stereoselectivity (>99:1). The key factor was to apply a low-ligated palladi

Full text of DOI:10.1055/s-0029-1217739

ACCOUNT
2375
Celebrating 20 Years of SYNLETT – Special Essay:
General Procedure for the Palladium-Catalyzed Selective Hydrophos-
phorylation of Alkynes
T
he Palladium-Cat
a
alyzed Sele
l
ctive
H
e
ydrophosp
n
horylation of
t
A
lkyn
i
es ne P. Ananikov,*a Levon L. Khemchyan,a Irina P. Beletskaya*b
a
Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, Moscow 119991, Russian Federation
Fax +7(499)1355328; E-mail: val@ioc.ac.ru
Chemistry Department, Lomonosov Moscow State University, Vorob’evy gory, Moscow 119899, Russian Federation
Fax +7(495)9393618; E-mail: beletska@org.chem.msu.ru
b
Received 8 May 2009
decreased the selectivity to 90:10. Furthermore, use of the
traditional catalyst [Pd(PPh3)4] gave poor selectivity of
86:14 (67 °C, THF, 18 h).8 Changing from linear to cyclic
H-phosphonates resulted in the formation of completely
Abstract: A novel catalytic system has been developed to accom-
plish the hydrophosphorylation of terminal and internal alkynes
with high isolated yields (up to 96%) and excellent regio- and stereo-
selectivity (>99:1). The key factor was to apply a low-ligated palla-
dium/triphenylphosphane (1:2) catalytic system in the presence of a different species, and compound 3 was observed only as a
minor product.11 It has also been reported that a diphe-
catalytic amount of trifluoroacetic acid. The catalytic system so de-
veloped has been applied successfully to permit the formation of di-
nylphosphinic acid additive may influence the regioselec-
verse alkenylphosphonates utilizing a variety of available H-
tivity of the reaction, but the proposed mechanism is
phosphonates and alkynes.
rather questionable.12
Key words: addition reactions, alkynes, palladium, homogenous
catalysis, phosphorylations
O
R1
cat.
R1
(R2O)2P
H
+
(R2O)2P
Transition-metal-catalyzed element–hydrogen (E–H) ad-
dition to unsaturated compounds is a rapidly developing
area of synthetic chemistry for constructing carbon–
element bonds in an atom-economic manner.1,2 Recent
studies have highlighted catalytic E–H addition to triple
bonds of alkynes as an area of special interest, providing
several opportunities for easy access to heterofunctional-
ized vinylic derivatives. Carbon–phosphorus bond forma-
tion via phosphorus–hydrogen addition to alkynes has
been successfully implemented as a route to alkenylphos-
phonates,3 some of which are biologically active,4,5 while
others act as versatile reagents in synthesis6 or are estab-
lished building blocks in polymer sciences.7
1
2
O
3
Other observed products:
R1
O
R1
P(OR2)2
P(OR2)2
R1
P(OR2)2
6
O
O
4
5
O
R1
R1
(R2O)2P
R1
P(OR2)2
P(OR2)2
O
P(OR2)2
(R2O)2P
O
(R2O)2P
O
8
O
O
7
9
The transition-metal-catalyzed hydrophosphorylation of
alkynes was discovered by Han and Tanaka in 1996.8 Scheme 1 Alkyne hydrophosphorylation reaction leading to Mar-
kovnikov product 3 and possible byproducts
Phosphane complexes of palladium were found to cata-
lyze the addition of H-phosphonates 2 to alkynes 1 lead-
ing to the formation of Markovnikov products 3
(Scheme 1). After Han and Tanaka’s discovery, several
studies appeared3,9,10 giving the impression that a solution
to the problem of the selective hydrophosphorylation of
alkynes had been found. However, a deeper look at the
published material revealed a rather complicated picture.
While the addition of the simplest H-phosphonate, dime-
thyl phosphonate [(MeO)2P(O)H], to oct-1-yne was pos-
sible with a special cis-[Me2Pd(PPh2Me)2] catalyst
leading to Markovnikov/anti-Markovnikov (a/b) selectiv-
ity of 95:5,8 the involvement of the more sterically hin-
dered diethyl phosphonate reagent in the addition reaction
In addition to desired compounds 3, a broad range of spe-
cies 4–9 have been observed in the reaction as byproducts
and sometimes as major products (Scheme 1). For exam-
ple, species 4 and 5 were formed as byproducts in palladi-
um-catalyzed reactions or as major products in rhodium-
or nickel-catalyzed reactions.8–16 In addition to the cata-
lytic pathway, some contribution to the formation of 4 and
5 originates from nucleophilic or free-radical addition
without the involvement of a transition-metal catalyst.13,14
The formation of alkynylphosphonates 6 as byproducts
was observed under [Pd(PPh3)4]-catalyzed conditions.15
Dehydrogenative addition of two molecules of an H-phos-
phonate leading to products 7 and 8 (sometimes with high
yields) was observed with various palladium catalysts
{e.g., PdCl2, Pd(OAc)2, and [Pd(PPh3)4]}.11,16 The forma-
tion of compounds 9 was suggested to proceed via the pal-
SYNLETT 2009, No. 15, pp 2375–2381
x
x
.x
x
.2
0
0
9
Advanced online publication: 27.08.2009
DOI: 10.1055/s-0029-1217739; Art ID: A54309ST
© Georg Thieme Verlag Stuttgart · New York

2376
V. P. Ananikov et al.
SPECIAL ESSAY
ladium-catalyzed addition of H-phosphonates 2 to vinylic ity of the reaction yield and selectivity to the nature of the
products 3 (in moderate to high yields),15 thus decreasing metal, ligand, H-phosphonate, and alkyne.3,8–11 The sys-
the yield of vinylphosphonates 3. The reaction leading to tem has to be optimized each time the structure of the H-
byproducts 9 was also observed under metal-free condi- phosphonate or alkyne is changed.
tions.11,14,15
For practical reasons, substituents with pronounced struc-
Thus, a number of side reactions, either involving a metal tural variation are required. For instance, the alkyl group
complex or proceeding in a concurrent noncatalytic fash- of the H-phosphonate would be phenyl and benzyl for bi-
ion, introduce significant difficulties in achieving high se- ological activity enhancement, CnH2n+1 with n > 6 for mi-
lectivity towards the formation of products 3. It appears celle precursors and incorporation into a hydrophobic
that the catalytic systems described so far have succeeded environment, and branched and cyclic alkyl residuals for
in selective transformation only for a specific combina- material science applications. Obviously, designing a cat-
tion of starting reagents, while attempts to create a general alytic system for each particular case would be time-
synthetic procedure have suffered from the high sensitiv- consuming and inefficient.
Biographical Sketches
Valentine Ananikov re- Academy of Sciences, and has been supported by
ceived his diploma in 1996 he was made Laboratory grants from the President of
from Donetsk State Univer- Head of the ND Zelinsky In- Russia (2004, 2007). In
sity (Donetsk, Ukraine), his stitute of Organic Chemistry 2008, he was elected as a
Ph.D. degree in 1999, and in 2005. He has been the re- corresponding member of
his Doctor of Chemistry de- cipient of a Russian State the Russian Academy of
gree in 2003 from the ND Prize for Young Scientists Sciences. His scientific in-
Zelinsky Institute of Organ- for Outstanding Achieve- terests are focused on transi-
ic Chemistry of the Russian ments in Science and Tech- tion-metal-catalyzed addi-
Academy of Sciences (Mos- nology (2004), a Science tion reactions to unsaturated
cow, Russian Federation). Support Foundation Award molecules, the development
In 2004, he became Profes- (2005), and a Medal of the of new NMR spectroscopic
sor of the High Chemistry Russian Academy of Sci- methods, and theoretical
College of the Russian ences (2000). His research studies of catalytic reac-
tions.
Levon Khemchyan be- Russian Academy of Sci- on transition-metal-catalyzed
came a Ph.D. student at the ences (Moscow, Russian carbon–phosphorus bond
ND Zelinsky Institute of Federation) in 2007. His re- formation.
Organic Chemistry of the search project is focused
Irina Beletskaya received she became a full member (1982), the Nesmeyanov
her diploma degree in 1955, (Academician) in 1992. She Prize, (1991), the Demidov
her Ph.D. degree in 1958, is currently Head of the Prize (2003), the State Prize
and her Doctor of Chemistry Laboratory of Organoele- (2004), and the Internation-
degree in 1963 from Mos- ment Compounds in the De- al Arbuzov Prize (2007).
cow State University (Mos- partment of Chemistry at She is the author of more
cow, Russian Federation). Moscow State University. than 600 articles and 4
The subject for the latter Irina Beletskaya is Chief monographs. Her current
was electrophilic substitu- Editor of the Russian Jour- scientific interests are fo-
tion at saturated carbon. She nal of Organic Chemistry. cused on transition-metal
became Full Professor at She was President of the Or- catalysis in organic synthe-
Moscow State University in ganic Chemistry Division of sis, organic derivatives of
1970, and in 1974 she be- IUPAC from 1989 to 1991. lanthanides, and carbanions
came a corresponding mem- She has been a recipient and nucleophilic aromatic
ber of the Academy of of the Lomonosov Prize substitution.
Sciences (USSR), of which (1979), the Mendeleev Prize
Synlett 2009, No. 15, 2375–2381 © Thieme Stuttgart · New York

SPECIAL ESSAY
The Palladium-Catalyzed Selective Hydrophosphorylation of Alkynes
2377
To overcome these limitations, we have carried out a se-
ries of mechanistic studies and have found a general cata-
lytic system for the highly selective formation of
Markovnikov products 3 independent of the nature of H-
phosphonates 2 and alkynes 1a–e containing typical or-
ganic functional groups (Scheme 2). The limits of the per-
formance of our developed catalytic system were tested
with sterically hindered reagents 2a and 2e, by varying the
electronic properties of the substituents, e.g. use of phos-
phonates 2b and 2c, and through the use of activated17
five-membered cyclic H-phosphonate 2d.
Table 1 The Influence of Various Additives on the Yield and Selec-
tivity of Diisopropyl Phosphonate (2a) Addition to Hept-1-yne (1a)a
Entry Additive
Yielde (%)
Product 3a Unreacted 2a Other productsf
1
2
3
4
5
6
7
8
9
None
63
25
26
67
56
59
60
71
85
18
47
0
19
28
74
23
12
19
32
16
8
Et3Nb
H2Oc
g-terpinened
10
32
22
8
b
H2SO4
R2
R1
O
AcOHb
[Pd]/L
R1
R2
(R3O)2P
H
+
(R3O)2P
HO2C–CO2Hb
BzOHb
O
1
2
3
R2 = H;
13
7
R
R
1 = (CH2)4Me (1a),
1 = (CH2)3CN (1b),
(CH2)3Cl (1c),
(CH2)2OH (1d),
TMS (1f),
TFAb
a Reaction conditions: 1a (1 mmol), 2a (1 mmol), Pd2(dba)3 (3 mol%),
Ph3P (12 mol%), THF (0.5 mL), 100 °C, 3 h.
b Using 10 mol% of the additive.
CMe2OAc (1g)
R
1 = R2 = Et (1e)
c Using 50 mL of the additive.
d Using 20 mol% of the additive.
e Determined by 31P{1H} NMR spectroscopy.
f Overall amount of phosphorus-containing byproducts.
O
O
(i-PrO)2P
H
(BnO)2P
H
2a
2b
2c
2d
O
O
rather small change in the product yield indicated a very
minor contribution of side reactions involving free-radical
species (Table 1, entry 4).
O
(PhO)2P
H
P
H
O
O
O
H
2e
Sulfuric acid and acetic acid decreased the yield of prod-
uct 3a (Table 1, entries 5 and 6, respectively). Oxalic acid
also decreased the product yield and increased the amount
of byproducts (entry 7). Benzoic acid was found to im-
prove the addition reaction in terms of better product yield
(71%) and smaller amounts of impurities (entry 8). Re-
markably, excellent performance of the catalytic system
was observed in the presence of trifluoroacetic acid
(TFA), resulting in 85% product yield and only 8% of
byproducts (entry 9).
P
O
Scheme 2 Palladium-catalyzed, regioselective alkyne hydrophos-
phorylation investigated in our studies
In the case of the hydrophosphorylation of hept-1-yne
(1a) using isopropyl derivative 2a under typical palladi-
um-catalyzed conditions, the reaction resulted in low
product yield (63%) and very poor selectivity (~3:1)
(Table 1, entry 1). The 31P{1H} NMR spectrum of the
crude mixture of the reaction contained a number of sig-
nals and indicated the formation of several byproducts.18
With insight from the mechanistic study, we evaluated the
effects of a base, water, radical scavengers, and acids. The
addition of a base deteriorated the catalytic reaction, with
the yield dropping from 63 to 25% (entries 1 and 2, re-
spectively). Approximately half of reagent 2a remained
unreacted, with a noticeable increase in the byproduct for-
mation from 19 to 28%. A quantity of water as small as 50
mL added to the reaction mixture caused the yield to drop
to 26% (entry 3). Moreover, in this case, the remaining
amount of reagent 2a was completely converted into
byproducts without the possibility for recycling. To avoid
the possible influence of water, we utilized dried THF
throughout subsequent studies.
Thus, this investigation highlights the rather complicated
nature of the acid effect in which both the influence on the
yield of the catalytic reaction and on the amount of impu-
rities formed have to be taken into account.
The performance of the catalytic hydrophosphorylation
reaction was studied in various solvents (THF, benzene,
CH2Cl2, MeCN, and DMSO).18 In all cases, the addition
of TFA increased the product yield, while triethylamine
suppressed product formation. Benzene and THF were
found to be the best solvents in which to carry out the hy-
drophosphorylation reaction.
To verify the possible influence of the acid on the final
product yield, we next investigated the catalytic reactions
with different amounts of TFA. Thus, 85% yield of prod-
uct 3a and 11% yield of overall impurities were observed
with 5 mol% of TFA (Table 2, entry 1). Increasing the
amount of TFA to 10 mol% slightly decreased the amount
of impurities (entry 2). The maximum product yield of
We estimated the contribution of the free-radical pathway
by addition of g-terpinene, which is known to behave as a
radical trap in transition-metal-catalyzed reactions.19
A
Synlett 2009, No. 15, 2375–2381 © Thieme Stuttgart · New York

2378
V. P. Ananikov et al.
SPECIAL ESSAY
best performance was observed with triphenylphosphane
which gave complete conversion of the starting materials
and high selectivity of the reaction. A comparison of the
results for acid-free and acid-containing catalytic systems
revealed the superior performance of the latter.18
Table 2 The Influence of the Amount of Acid on the Yield and Se-
lectivity of Diisopropyl Phosphonate (2a) Addition to Hept-1-yne
(1a)a
Entry Amount of TFA
(mol%)
Yieldb (%)
Product 3a Unreacted 2a Other productsc
The next important characteristic of the catalytic system
was the amount of ligand needed to achieve high activity.
An equimolar palladium/ligand (Pd/L) ratio led to only
27% of the product after 8 hours at 50 °C (Table 3, entry
1). The best performance of the catalytic reaction, 94%
product yield, was observed using a ratio (Pd/L) of 1:2
(entry 2). Changing the ratio to 1:4 and 1:8 resulted in 81
and 41% yield of the product, respectively, with some in-
crease in the amount of impurities to 11 and 12% (entries
3 and 4, respectively). Therefore, the ratio (Pd/L) of 1:2
should be considered for the catalytic system of choice.
1
2
3
4
5
5
10
20
30
50
85
85
89
84
75
4
7
11
8
5
6
10
19
6
6
a Reaction conditions: 1a (1 mmol), 2a (1 mmol), Pd2(dba)3 (3 mol%),
Ph3P (12 mol%), THF (0.5 mL), 100 °C, 3 h.
b Determined by 31P{1H} NMR spectroscopy.
c Overall amount of phosphorus-containing byproducts.
Table 3 The Influence of the Palladium/Ligand Ratio on the Yield
and Selectivity of Diisopropyl Phosphonate (2a) Addition to Hept-1-
yne (1a) at 50 °Ca
89% was observed with 20 mol% of TFA (entry 3). Fur-
ther increase in the amount of acid led to a decrease in the
product yield, but retained the trace level of impurities
(entries 4 and 5).
Entry Ratio (Pd/L)b
Yieldc (%)
Product 3a Unreacted 2a Other productsd
1
2
3
4
1:1
1:2
1:4
1:8
27
94
81
41
72
4
1
2
The NMR spectroscopic monitoring of the catalytic reac-
tion performed at a lower temperature (50 °C) showed that
TFA not only enhanced the yield of the product, but also
increased the rate of the reaction. A graphical representa-
tion of observed acid affect is shown in Figure 1. For prac-
tical reasons, we have chosen a compromise value of 10
mol% of TFA to be used in the catalytic system.
8
11
12
47
a Reaction conditions: 1a (1 mmol), 2a (1 mmol), Pd2(dba)3 (3 mol%),
given amount of ligand (Ph3P), TFA (10 mol%), THF (0.5 mL), 50
°C, 8 h.
b The reaction did not take place in the absence of the ligand.
c Determined by 31P{1H} NMR spectroscopy.
d Overall amount of phosphorus-containing byproducts.
With an optimized synthetic procedure in hand,20 we in-
vestigated the scope of the hydrophosphorylation reaction
using various alkynes. For product separation, a simple
purification procedure based on flash chromatography
was utilized.21–23 In the cases of alkynes 1a–c, the catalyt-
ic reaction was carried out at 50 °C and resulted in excel-
lent product yields of 91–94% and 85–91% isolated yields
(Table 4, entries 1–3). Monosubstituted alkyne 1d bearing
a terminal hydroxy group on the alkyl substituent was less
reactive and required a higher temperature of 70 °C (entry
4). The reaction with internal alkyne 1e was the slowest
and required an even higher temperature of 120 °C (entry
5). A remarkable feature of the developed catalytic system
is the excellent regio- and stereoselectivity possible with-
in the large temperature range of 50–120 °C. A (3/4) regio-
selectivity of >99:1 was observed for the reactions of
alkynes 1a–d (entries 1–4, respectively), and syn-addition
stereoselectivity of >99:1 was found for the reaction of
substrate 1e (entry 5). Carrying out the reaction at some-
what higher temperatures and for a longer time made it
possible to decrease catalyst loading. For the synthesis of
product 3a, the reaction with 1.5 mol% of the catalyst was
carried out at 70 °C for 24 hours and resulted in 92% yield
Figure 1 The yield of palladium-catalyzed diisopropyl phospho-
nate (2a) addition to hept-1-yne (1a) using various amounts of TFA
(30, 20, 10, and 5 mol% and no acid) at 50 °C
The choice of ligand was crucial to achieving high selec-
tivity in the studied reaction. The following ligands were
evaluated in the catalytic reaction: triphenyl-, tris(4-meth-
oxyphenyl)-, tris(2-methoxyphenyl)-, tris(2,6-dimethoxy-
phenyl)-, tri-2-tolyl-, benzyl(diphenyl)-, methyl-
(diphenyl)-, ethyl(diphenyl)-, cyclohexyl(diphenyl)-,
dimethyl(phenyl)-, tributyl-, dicyclohexyl(phenyl)-, and
tricyclohexylphosphane, bis-phosphino ligands (dppe,
dppb, dppm), and triphenyl and tributyl phosphite.18 The
Synlett 2009, No. 15, 2375–2381 © Thieme Stuttgart · New York

SPECIAL ESSAY
The Palladium-Catalyzed Selective Hydrophosphorylation of Alkynes
2379
of the product (cf. 50 °C, 8 h, and 94% yield using 3 mol%
of the catalyst, entry 1).
Table 4 The Scope of the Palladium-Catalyzed Diisopropyl Phos-
phonate (2a) Addition to Alkynesa
Reagent control of the direction of the phosphorus–hydro-
gen addition reaction was observed using alkyne sub-
strates substituted with bulky trimethylsilyl and 2-
acetoxypropan-2-yl groups (Table 4, entries 6 and 7, re-
spectively). In these cases, anti-Markovnikov products 4a
and 10 with E-configuration at the double bond were
formed with high selectivity and in excellent yields (82–
91%). The formation of an analogue of 4a in 41% yield
was reported previously in the reaction of 2 equivalents of
trimethylsilyl-substituted alkyne 1f and (MeO)2P(O)H.8
In the catalytic system developed in our study, a 91%
yield was observed using only 1.2 equivalents of the
alkyne (entry 6). In the case of derivative 1g, the phospho-
rus–hydrogen addition reaction was followed by acetic
acid elimination, resulting in the formation of a conjugat-
ed 1,3-diene skeleton (entry 7).
Entry Alkyne 1
Product
Yieldb (%)
1
94 (91)
(i-PrO)2P
1a
O
3a
NC
2
91 (89)
92 (85)
82 (65)c
NC
(i-PrO)2P
O
1b
3b
Cl
3
The geometry of the double bond in products 4a and 10
was established from 3JH,H coupling constants determined
from a combination of 1H and 1H{31P} NMR spectra; the
geometry of compound 3e was determined based on the
3JP,H coupling constant.18
Cl
(i-PrO)2P
1c
O
3c
HO
4
Recording the reactivity profile for different phosphorus
reagents was a further crucial test of the catalytic system.
In our study, excellent regioselectivity and yields were
achieved using various H-phosphonates 2a–e (see
Scheme 2 for structures). The reaction of hept-1-yne with
H-phosphonates 2a and 2c–e was carried out under mild
conditions at 50 °C (Table 5, entries 1 and 3–5, respec-
tively). For the activated cyclic reagent 2d, a short reac-
tion time of 2 hours was sufficient to reach near
quantitative conversion (entry 4), and 4–8 hours of reac-
tion time was employed for substrates 2a, 2c, and 2e (en-
tries 1, 3, and 5, respectively). To complete the reaction
with less-reactive reagent 2b, a higher temperature of 70
°C was utilized (entry 2). Very good yields of 94–99%
and excellent (3/4) regioselectivity of >99:1 was observed
in the reactions of all the reagents studied. Surprisingly,
even bulky substituents, as in long-chain derivative 2e,
did not affect the yield or selectivity of the reaction (entry
5).
HO
(i-PrO)2P
1d
O
3d
5
78 (65)d
91 (83)c
(i-PrO)2P
O
1e
3e
TMS
TMS
6
(i-PrO)2P
1f
O
4a
AcO
7
82 (65)e
P(Oi-Pr)2
O
1g
10
a Reaction conditions: alkyne (1 mmol), 2a (1 mmol), Pd2(dba)3 (3
mol%), Ph3P (12 mol%), TFA (10 mol%), THF (0.5 mL), 50 °C, 8 h.
b Determined by 31P{1H} NMR spectroscopy; isolated yields are in
parentheses and the overall amount of impurities in all cases was
<10%.
To summarize, in the present article we have reported a
detailed study of palladium-catalyzed alkyne hydrophos-
phorylation and have revealed the major factors needed
for designing a highly selective catalytic system. We
achieved this by addressing the following important is-
sues: (i) the solvent dependence of selectivity and yields,
(ii) the influence of acids on reaction rates and final
yields, (iii) ligand effects, (iv) the optimal metal/ligand
ratio, and (v) reliable reaction conditions.
c From the reaction at 70 °C, using1.2 mmol of the alkyne and a reac-
tion time of 4 h.
d From the reaction at 120 °C, using 1.5 mmol of the alkyne.
e From the reaction at 100 °C.
of the reaction, while base and water additives caused the
deterioration of the desired catalytic activity.
We found that low-ligated metal complexes [(Pd/L) ratio
of 1:2] prepared from a convenient metal source
[Pd2(dba)3] and the readily available triphenylphosphane
ligand represent the catalytic system of choice when used
in the presence of a catalytic amount of TFA. The addition
of acid dramatically enhanced the activity and selectivity
The catalytic system developed is tolerant to typical or-
ganic functional groups present in the alkynes and to the
nature of different substituents in the H-phosphonates.
Excellent selectivity and yields were observed over the
large temperature range of 50–120 °C, thus expanding the
Synlett 2009, No. 15, 2375–2381 © Thieme Stuttgart · New York

2380
V. P. Ananikov et al.
SPECIAL ESSAY
Table 5 Palladium-Catalyzed Addition of H-Phosphonates 2a–e to Hept-1-yne (1a)a
Entry
1
H-Phosphonate 2
Product 3
Yieldb (%)
94 (91)
2a
(i-PrO)2P
O
O
O
O
3a
2
3
4
5
2b
2c
2d
2e
99 (92)c
94 (85)d
99 (96)e
99 (87)
(PhO)2P
3f
(BnO)2P
3g
O
P
O
3h
O
O
P
O
3i
a Reaction conditions: 1a (1 mmol), H-phosphonate (1 mmol), Pd2(dba)3 (3 mol%), Ph3P (12 mol%), TFA (10 mol%), THF (0.5 mL), 50 °C, 8 h.
b Determined by 31P{1H} NMR spectroscopy; isolated yields are in parentheses and the overall amount of impurities in all cases was <10%.
c From the reaction at 70 °C.
d After a reaction time of 4 h.
e After a reaction time of 2 h.
Angew. Chem. Int. Ed. 2004, 43, 3368. (d) Suginome, M.;
Ito, Y. J. Organomet. Chem. 2003, 685, 218. (e) Suginome,
M.; Ito, Y. J. Organomet. Chem. 2003, 680, 43. (f) Kondo,
T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205.
scope of the preparative synthesis of alkenylphospho-
nates.
(2) (a) Beletskaya, I. P.; Ananikov, V. P. Eur. J. Org. Chem.
2007, 3431. (b) Beletskaya, I. P.; Ananikov, V. P. Pure
Appl. Chem. 2007, 79, 1041.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
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Eur. J. Org. Chem. 2008, 3601. (b) Tanaka, M. Top. Curr.
Chem. 2004, 232, 25. (c) Baillie, C.; Xiao, J. Curr. Org.
Chem. 2003, 7, 477. (d) Beletskaya, I. P.; Kazankova, M. A.
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Acknowledgment
The research was supported in part by the Russian Foundation for
Basic Research (Project No. 07-03-00851), Program No. 1 of the
Division of Chemistry and Material Sciences of RAS, and Program
No. 20 of RAS.
Soultanas, P. Biochemistry 2003, 42, 3239. (c) Jung, K.-Y.;
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(e) Amori, L.; Costantino, G.; Marinozzi, M.; Pellicciari, R.;
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Synlett 2009, No. 15, 2375–2381 © Thieme Stuttgart · New York

SPECIAL ESSAY
The Palladium-Catalyzed Selective Hydrophosphorylation of Alkynes
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facilitated the preferred formation of double addition
product 7 in the palladium-catalyzed reaction, rather than the
formation of product 3, e.g. see ref. 11.
(18) See Supporting Information for a detailed description.
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(20) Palladium-Catalyzed Hydrophosphorylation; General
Procedure: Under argon, Pd2(dba)3 (31.1 mg, 3.0 × 10-5
mol) and Ph3P (31.5 mg, 1.2 × 10-4 mol) were placed into a
septum-sealed tube equipped with a magnetic stir bar,
followed by the addition of THF (0.5 mL) through the
septum, and the mixture was stirred for 3 min. When the
color of the solution became brown, the H-phosphonate (1.0
× 10-3 mol) and alkyne (1.0 × 10-3 mol) were added to the
mixture through the septum. Then, TFA (11.4 mg, 1.0 ×
10-4 mol) was added, and the tube was capped with a PTFE-
sealed screw cap. The mixture was stirred at 50 °C (see
Tables 4 and 5 for additional details relating to the ratio of
the reagents or conditions). After completion of the reaction,
the color of the solution remained brown or changed to light
brown.
(21) Compound Isolation and Purification: After completion
of the reaction, the products were purified by dry-column
flash chromatography on silica gel, see ref. 23. Hexane–
EtOAc (for 3a-c, 3e-i, 4a, and 10) and hexane–EtOAc–
EtOH (for 3d) gradient elution was applied. After drying in
a vacuum, the pure products were obtained. The products
were isolated as colorless or light-yellow oils, and their
isolated yields given in Tables 4 and 5 were calculated based
on the initial amount of the corresponding H-phosphonate.
(22) Complete characterization of all the isolated products with
1H, 13C, and 31P NMR spectroscopy, mass spectrometry, and
microanalysis is provided in Section 6 of the Supporting
Information.
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