NiCl2-catalyzed hydrophosphinylation

Article abstract of DOI:10.1021/jo050096l

A new nickel-based catalytic system has been developed for phosphorus-carbon bond formation. The addition of alkyl phosphinates to alkynes is catalyzed by nickel chloride in the absence of added ligand. The reaction generally proceeds in high yields, even with internal alkynes, which were poor substrates in our previously reported palladium-catalyzed hydrophosphinylation of alkyl phosphinates. The method is useful for the preparation of H-phosphinate esters and their derivatives. The one-pot synthesis of various important organophosphorus compounds is also demonstrated. The reaction can be conducted with microwave heating.

Full text of DOI:10.1021/jo050096l

NiCl2-Catalyzed Hydrophosphinylation
Patrice Ribie`re, Karla Bravo-Altamirano, Monika I. Antczak, Jennifer D. Hawkins, and
Jean-Luc Montchamp*
Department of Chemistry, Box 298860, Texas Christian University, Fort Worth, Texas 76129
j.montchamp@tcu.edu
Received January 17, 2005
A new nickel-based catalytic system has been developed for phosphorus-carbon bond formation.
The addition of alkyl phosphinates to alkynes is catalyzed by nickel chloride in the absence of
added ligand. The reaction generally proceeds in high yields, even with internal alkynes, which
were poor substrates in our previously reported palladium-catalyzed hydrophosphinylation of alkyl
phosphinates. The method is useful for the preparation of H-phosphinate esters and their
derivatives. The one-pot synthesis of various important organophosphorus compounds is also
demonstrated. The reaction can be conducted with microwave heating.
Introduction
does take place in very high yield, if the correct catalyst
is employed.1 More recently, we also described a reusable
catalyst system, which gave good results with com-
mercially available aqueous H3PO2.3 Although our pal-
ladium-catalyzed hydrophosphinylation has a broad scope
and proceeds with low catalyst loadings or can now be
conducted with a reusable catalyst, we became interested
in exploring still cheaper and, more importantly, possibly
more reactive nickel-based catalysts. Herein, we report
the development of a simple and inexpensive nickel
chloride catalyzed alkyne hydrophosphinylation.4
We reported recently a novel palladium-catalyzed
phosphorus-carbon bond-forming reaction via the addi-
tion of hypophosphorous compounds to various unsatur-
ated substrates (eq 1).1 Catalytic P-C bond formation is
With the exception of PH3,5 the compounds usually
employed in transition-metal-catalyzed reactions do not
contain more than one P-H bond,6 and therefore the
possibility for transfer hydrogenation2 is removed or
drastically decreased. Various researchers have described
addition reactions involving compounds containing a
single P-H bond. For example, Beletskaya has reported
the addition of secondary phosphines to styrenes.7 Marks
also developed the hydrophosphination of unsaturated
compounds using lanthanide catalysts.8 Tanaka devel-
oped the catalytic addition reactions of H-phosphonates
and secondary phosphine oxides using rhodium or pal-
ladium catalysts.9 Maybe more relevant to the present
an increasingly active field, but the reactions that use
hypophosphorous acid or its derivatives as starting
materials have been overlooked. Undoubtedly, this is the
result of the well-known transition-metals-catalyzed
transfer hydrogenation2 expected and observed with
these reagents, which suggested that P-C bond forma-
tion would be difficult. However, we showed that addition
(1) Depre`le, S.; Montchamp, J.-L. J. Am. Chem. Soc. 2002, 124, 9386.
(2) For references on the catalytic transfer hydrogenation with
hypophosphorous derivatives, see: (a) Brieger, G.; Nestrick, T. J. Chem.
Rev. 1974, 74, 567. (b) Johnstone, R. A. W.; Wilby, A. H., Entwistle,
A. I. Chem. Rev. 1985, 85, 129. (c) Boyer, S. K.; Bach, J.; McKenna, J.;
Jagdmann, E., Jr. J. Org. Chem. 1985, 50, 3408. (d) Johnstone, R. A.
W.; Wilby, A. H. Tetrahedron 1981, 37, 3667. (e) Sala, R.; Doria, G.;
Passarotti, C. Tetrahedron Lett. 1984, 25, 4565. (f) Khai, B. T.; Arcelli,
A. J. Org. Chem. 1989, 54, 949. (g) Brigas, A. F.; Johnstone, R. A. W.
Tetrahedron 1992, 48, 7735. (h) Marques, C. A.; Selva, M.; Tundo, P.
J. Chem. Soc., Perkin Trans. 1 1993, 529. (i) Khai, B. T.; Arcelli, A.
Chem. Ber. 1993, 126, 2265.
(3) Depre`le, S.; Montchamp, J.-L. Org. Lett. 2004, 6, 3805.
(4) Preliminary results were presented at the 228th National
Meeting of the ACS, Philadelphia, August 22-26, 2004; poster 581.
(5) Metal-catalyzed PH3 addition and related: (a) Costa, E.; Pringle,
P. G.; Smith, M. B.; Worboys, K. J. Chem. Soc., Dalton Trans. 1997,
4277. (b) Costa, E.; Pringle, P. G.; Worboys, K. Chem. Commun. 1998,
49. (c) Wicht, D. K.; Kourkine, I. V.; Kovacik, I.; Glueck, D. S.;
Concolino, T. E.; Yap, G. P. A.; Incarvito, C. D.; Rheingold, A. L.
Organometallics 1999, 18, 5381. (d) Trofimov, B. A.; Arbuzova, S. N.;
Gusarova, N. K. Russ. Chem. Rev. 1999, 68, 215.
10.1021/jo050096l CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/19/2005
4064
J. Org. Chem. 2005, 70, 4064-4072

NiCl2-Catalyzed Hydrophosphinylation
TABLE 1. Comparison of Pd versus Ni as Catalyst in
work, Han and co-workers recently described the nickel-
catalyzed addition of dimethyl phosphite, diphenyl phos-
phine oxide, and ethyl H-phenylphosphinate to alkyne.10
However, the reaction is a Tanaka-like addition, which
does not have to contend with transfer hydrogenation
pathways, and only two alkynes were tested.10 Addition-
ally, all of these P-C bond forming reactions lead to a
specific phosphorus-containing functional group, which
does not have the synthetic flexibility offered by H-
phosphinates.11
a
Hydrophosphinylation with ROP(O)H2
NMR
entry substrate
R
solvent
catalystd
yield, %e
1b
2b
3
1-octene Bu CH3CN, reflux Pd2dba3/xantphos
1-octene Bu PhCH3, reflux Cl2Pd(dppf)
1-octene Bu PhCH3, reflux Cl2Ni(dppf)/MeLi
1-octene Bu PhCH3, reflux Cl2Ni(dppf)
1-octene Bu CH3CN, reflux Cl2Ni(dppf)
1-octene Et PhCH3, reflux Cl2Ni(dppp)
100
100
33
4
38
5
14
6
20
7
1-octene Et PhCH3, rt
1-octene Et PhCH3, rt
1-octene Et PhCH3, rt
Cl2Ni(dppp)
Cl2Ni(PPh3)2
NiCl2
69
8
65
9c
25
Results and Discussion
10c 4-octyne Et CH3CN, reflux Pd2dba3/xantphos
11c 4-octyne Et CH3CN, reflux NiCl2
40
100
During the development of our palladium hydrophos-
phinylation, we tested various ligand and catalyst com-
binations.1 Although Cl2NiL2/MeLi did produce some
addition product in the reaction of BuOP(O)H2 with
1-octene,1 the yields were considerably lower than several
of our Pd-based catalysts (Table 1, entries 1 and 2 versus
entries 3 and 6). Further studies showed that the yields
a Best conditions. b See ref 1. c This work. d Catalyst loadings
vary from 1 to 4 mol %. e NMR yields are determined by integra-
tion of all the resonances in the 31P NMR spectra.
of alkene hydrophosphinylation could be significantly
improved (Table 1, entries 7 and 8) up to 60-70%, by
adjusting temperature and solvent, but these results
were still not sufficiently good to compete with our
palladium-catalyzed reaction.1,3 Despite much experi-
mentation, the yields could not be improved significantly
beyond the 70% mark.
(6) For general references on P-H addition to unsaturated com-
pounds, see: (a) Wicht, D. K.; Glueck, D. S. In Catalytic Heterofunc-
tionalization; Togni, A., Gru¨tzmacher, H., Eds.; Wiley-VCH: Weinheim,
2001; Chapter 5 and references therein. (b) Alonso, F.; Beletskaya, I.
P.; Yus, M. Chem. Rev. 2004, 104, 3079. (c) Beletskaya, I. P.;
Kazankova, M. A. Russ. J. Org. Chem. 2002, 38, 1447. (d) Han, L.-B.;
Tanaka, M. Chem. Commun. 1999, 395. For some recent examples:
(e) Allen, A., Jr.; Ma, L.; Lin, W. Tetrahedron Lett. 2002, 43, 3707. (f)
Allen, A., Jr.; Manke, D. R.; Lin, W. Tetrahedron Lett. 2000, 41, 151.
(g) Je´roˆme, F.; Monnier, F.; Lawicka, H.; De´rien, S.; Dixneuf, P. H.
Chem. Commun. 2003, 696. (h) Kovacik, I.; Wicht, D. K.; Grewal, N.
S.; Glueck, D. S.; Incarvito, C. D.; Guzei, I. A.; Rheingold, A. L.
Organometallics 2000, 19, 950. (i) Takaki, K.; Takeda, M.; Koshoji,
G.; Shishido, T.; Takehira, K. Tetrahedron Lett. 2001, 42, 6357. (k)
Gaumont, A.-C.; Simon, A.; Denis, J.-M. Tetrahedron Lett. 1998, 39,
985. (l) Mimeau, D.; Gaumont, A.-C. J. Org. Chem. 2003, 68, 7016.
(m) Milton, M. D.; Onodera, G.; Nishibayashi, Y.; Uemura, S. Org. Lett.
2004, 6, 3993.
(7) (a) Shulyupin, M. O.; Kazankova, M. A.; Beletskata, I. P. Org.
Lett. 2002, 4, 761. (b) Kazankova, M. A.; Efimova, I. V.; Kochetkov, A.
N.; Afanas’ev, V. V.; Beletskaya, I. P.; Dixneuf, P. H. Synlett 2001,
497. (c) Kazankova, M. A.; Efimova, I. V.; Kochetkov, A. N.; Afanas’ev,
V. V.; Beletskaya, I. P. Russ. J. Org. Chem. 2002, 38, 1465. (d)
Goulioukina, N. S.; Dolgina, T. M.; Beletskaya, I. P.; Henry, J.-C.;
Lavergne, D.; Ratovelomanana-Vidal, V.; Geneˆt, J.-P. Tetrahedron:
Asymmetry 2001, 12, 319. (e) Goulioukina, N. S.; Dolgina, T. M.;
Bondarenko, G. N.; Beletskaya, I. P.; Henry, J.-C.; Lavergne, D.;
Ratovelomanana-Vidal, V.; Geneˆt, J.-P. Russ. J. Org. Chem. 2002, 38,
600.
However, we discovered that the situation was very
different in the case of alkynes (Table 1, entry 11 versus
5). With palladium, internal alkynes are poor substrates
with alkyl phosphinates (even if H3PO2 and PhNH3‚OP-
(O)H2 do react in good yield), whereas with nickel both
terminal and internal alkynes are excellent substrates.
A notable feature of our reaction is the fact that inex-
pensive NiCl2 (2-4 mol %) is an excellent catalyst. In
fact, as little as 0.5 mol % NiCl2 still delivered a
quantitative yield of alkenyl-H-phosphinate in 12 h, in
refluxing acetonitrile. Of course, no P-C bond formation
is observed in the absence of the nickel catalyst. Other
readily available nickel sources were tested, and several
gave satisfactory results (Table 2). It is interesting to note
that PdCl2 is a very poor catalyst (entry 12), even if it is
not surprising based on our previous work on the pal-
ladium-catalyzed hydrophosphinylation.1 The fact that
Ni(cod)2 is not necessary is significant since this complex
is highly air-sensitive and requires careful handling.
With the Ni(II) catalysts, it is likely that ROP(O)H2
serves as the reducing agent to form a catalytically active
Ni(0) species that could be complexed by excess alkyl
phosphinate present in the reaction mixture. There was
no significant difference between various nickel halide
precatalysts (Table 2, entries 1-6), but other nickel
sources were not satisfactory (Table 2, entries 8-11).
Interestingly, various usually adverse reaction conditions
were well-tolerated, including moisture and even air
(Table 2, entries 13-15). Nickel chloride hydrate was also
tested (Table 2, entry 2) since 1 equiv of water did not
interfere with the reaction, and as expected the reaction
took place in excellent yield. Although anhydrous NiCl2
was generally selected for our subsequent study, the
hydrate gave similar results in every instance where it
was tested.
(8) (a) Kawaoka, A. M.; Marks, T. J. J. Am. Chem. Soc. 2004, 126,
12764. (b) Kawaoka, A. M.; Douglass, M. R.; Marks, T. J. Organo-
metallics 2003, 22, 4630. (c) Douglass, M. R.; Ogasawara, M.; Hong,
S.; Metz, M. V.; Marks, T. J. Organometallics 2002, 21, 283. (d)
Douglass, M. R.; Marks, T. J. J. Am. Chem. Soc. 2001, 123, 10221. (e)
Douglass, M. R.; Marks, T. J. J. Am. Chem. Soc. 2000, 122, 1824.
(9) (a) Han, L.-B.; Zhao, C.-Q.; Onozawa, S.-y.; Goto, M.; Tanaka,
M. J. Am. Chem. Soc. 2002, 124, 3842. (b) Han, L.-B.; Tanaka, M. J.
Am. Chem. Soc. 1996, 118, 1571. (c) Han, L.-B.; Mirzaei, F.; Zhao, C.-
Q.; Tanaka, M. J. Am. Chem. Soc. 2000, 122, 5407. (d) Zhao, C.-Q.;
Han, L.-B.; Goto, M.; Tanaka, M. Angew. Chem., Int. Ed. 2001, 40,
1929. (e) Zhao, C.-Q.; Han, L.-B.; Tanaka, M. Organometallics 2000,
19, 4196. See also: (f) Reichwein, J. F.; Patel, M. C.; Pagenkopf, B. L.
Org. Lett. 2001, 3, 4303. (g) Stockland, R. A., Jr.; Levine, A. M.; Giovine,
M. T.; Guzei, I. A.; Cannistra, J. C. Organometallics 2004, 23, 647. (h)
Levine, A. M.; Stockland, R. A., Jr.; Clark, R.; Guzei, I. Organometallics
2002, 21, 3278.
(10) Han, L.-B.; Zhang, C.; Yazawa, H.; Shimada, S. J. Am. Chem.
Soc. 2004, 126, 5080.
(11) Reviews: (a) Frank, A. W. Chem. Rev. 1961, 60, 389. (b)
Nifant’ev, E. E. Russ. Chem. Rev. 1978, 47, 835. (c) The Chemistry of
Organophosphorus Compounds; Hartley, F. R., Ed.; Wiley: New York,
1996; Vol. 4. (d) Quin, L. D. A Guide to Organophosphorus Chemistry;
Wiley: New York, 2000. (e) Methoden der Organischen Chemie
(Houben-Weyl); Sasse K., Ed.; Thieme: Stuttgart, 1964; Band XII/1,
pp 294-337. (f) Methoden der Organischen Chemie (Houben-Weyl);
Regitz, M., Ed.; Thieme: Stuttgart, 1982; Vol. E2. (g) Frank, A. W. In
Organic Phosphorus Compounds; Kosolapoff, G. M., Maier, L., Eds.;
Wiley: New York, 1972; Vol. 4, Chapter 10.
A competition experiment was conducted with an
equimolar amount of 1-octene and 4-octyne. The internal
alkyne smoothly undergoes hydrophosphinylation reach-
ing 88% yield, whereas P-C bond formation from the
J. Org. Chem, Vol. 70, No. 10, 2005 4065

Ribie`re et al.
TABLE 2. Comparison of Nickel Catalyst and Influence
of Additives
generally satisfactory, but tetrahydrofuran gave only low
yields.
The scope of our nickel-catalyzed alkyne hydrophos-
phinylation is very broad (Table 3). Internal and terminal
alkynes react in general to form the product in high
yields. With unsymmetrical alkynes, the regioselectivity
is often poor (ranging from 1:1 to 3:1) and the low isolated
yields reflect the difficulty in separating the two regioi-
somers. With terminal alkynes, our previously reported
palladium-catalyzed reaction is more selective for linear
products with Pd2dba3/xantphos and highly selective for
the branched isomer with Cl2Pd(PPh3)2/MeLi (eq 1).1,13
However, some substrates still display useful regioselec-
tivities with the nickel catalysts when significant steric
or electronic biases are present. For example, alkynes
with a terminal tert-butyl or trimethylsilyl group react
regioselectively to afford the â-substituted H-phosphinate
(entries 5, 12, and 13). In the case of 2,4-hexadiyne, high
regioselectivity is also observed (entry 8). Other alkynes
substituted with a phenyl, alkene, or ethoxy group tend
to give a significant amount of the “branched” product
where addition takes place at the substituted carbon.
Intrinsically, terminal alkynes give the linear product as
the major isomer (entry 11), but inductively electron-
withdrawing substituents increase the amount of the
branched isomer (entries 6, 9, 10). In all the cases,
excellent stereospecificity for syn addition (E-isomer) is
observed.
NMR yield, %a
entry
catalyst
NiCl2
NiCl2‚6H2O
NiBr2
NiI2
NiCl2(PPh3)2
NiBr2(PPh3)2
Ni(acac)2
Ni(OAc)2‚H2O
NiCp2
additive
(isolated yield, %)
1
none
100 (75)
99 (84)
97
2
none
3
none
4
none
99
5
none
100 (83)
100
6
none
7
none
94
8
none
47
9
none
15
10
11
12
13
14
15
Ni powder
Ni on SiO2/Al2O3
PdCl2
none
11
b
none
8
none
11
NiCl2
H2O (1 equiv)
EtOH (3 equiv)
100 (80)
100 (81)
100 (86)
NiCl2
c
NiCl2
O2
a NMR yields are determined by integration of all the reso-
nances in the 31P NMR spectra. b 65 wt % Ni. c Open to air with
a drierite trap.
alkene never reaches more than a few percent. However,
the alkene does disappear slowly presumably with for-
mation of isomerized and reduced products. Similar
results were obtained when a competition experiment
was conducted with 4-octene and 4-octyne.
Although regiocontrol is often difficult to achieve in the
present reaction, we have already provided a regio- and
stereospecific alternative to prepare alkenyl H-phosphi-
nates using the palladium-catalyzed cross-coupling of
anilinium hypophosphite14 and alkenyl phosphinates15
(eq 2). Nonetheless, the direct addition to an alkyne is
often more convenient because the starting material is
more generally available than the corresponding alkenyl
halide.
Various alkyl phosphinates (ROP(O)H2, R ) Me, Et,
Bu, i-Pr) react in high yield (Table 3, entries 1a-1c, 2a)
and the method used for their synthesis12 does not appear
to significantly affect the outcome. We have found that
several variations of our silicate-based methodology for
the preparation of alkyl phosphinates12 are equally
successful. In fact, stock solutions of alkyl phosphinates
appear stable at room temperature and under nitrogen
for at least 2 months, and these alkylphosphinate stock
solutions can also be used in the present reaction. The
alkyl phosphinate can also be formed in situ in a single
reaction step (entry 1d), instead of preforming it prior to
the hydrophosphinylation. Interestingly, even the use of
the trifluoroacetate salt of an aminosilicate is also
possible, the hydrophosphinylation still taking place in
high yield (Table 3, entries 2b, 6b, 7b, 11, 12). As we
previously showed in other reactions,12 this method of
alkyl phosphinate preparation allows removal of the
silicate byproducts by extraction and therefore simplifies
the workup. Here, the products can often be obtained in
better than 90% purity by a simple aqueous workup.
Isolated yields are sometimes improved because the crude
reaction mixture is purer (Table 3, entries 2b vs 2a and
7b vs 7a).
Even acetylene gas bubbled through the reaction
mixture at room temperature can cleanly afford the
corresponding H-vinyl phosphinate (entry 4); however,
we were not able to isolate the product in reasonable yield
because of the polarity and ease of hydrolysis of vinyl-
H-phosphinates. Further optimization of this particular
reaction will be conducted because the corresponding
vinyl-H-phosphinates are generally difficult to obtain,
although it would be a useful synthon for the preparation
of a variety of compounds. O-Ethyl vinylphosphinate has
been prepared previously by Maier using a multistep
sequence from ClCH2CH2PCl2.16
Whereas alkyl phosphinates react very well, both H3-
PO2 and PhNH3OP(O)H2 fail to undergo the nickel-
catalyzed reaction to any significant extent (less than
20% yield). Again, this contrasts with the palladium-
catalyzed version of our reaction.1,3 The solvent is also
important: acetonitrile was found to be ideal, toluene was
As shown in Table 3, a variety of alkynes react in
satisfactory yields. With a propargylic chloride (entry 14),
(13) Montchamp, J.-L. J. Organomet. Chem. In press.
(14) Dumond, Y. R.; Montchamp, J.-L. J. Organomet. Chem. 2002,
653, 252.
(15) Bravo-Altamirano, K.; Huang, Z.; Montchamp, J.-L. Tetrahe-
dron In press.
(16) Maier, L.; Rist, G. Phosphorus Sulfur 1983, 17, 21.
(12) Depre`le, S.; Montchamp, J.-L. J. Organomet. Chem. 2002, 643-
644, 154.
4066 J. Org. Chem., Vol. 70, No. 10, 2005

NiCl2-Catalyzed Hydrophosphinylation
TABLE 3. NiCl2-Catalyzed Hydrophosphinylation of Alkynesa
a All yields are isolated. Ratios in parentheses indicate regioselection determined on the crude reaction mixture. All reactions were
conducted in refluxing reagent grade CH3CN. Details can be found in Experimental Section. b One-pot process where esterification and
d
hydrophosphinylation take place simultaneously (see text). c Conducted on a 50 mmol scale. 31P NMR yield: 43%, conducted at room
e
temperature. 31P NMR yield: 31%, conducted at room temperature. f Approximately 85% pure.
an allylic product was obtained as the major product,
apparently through the allene intermediate. Interest-
ingly, in the case of 2-ethynylpyridine, the saturated
product is obtained cleanly (entry 15). At this time, the
mechanistic details of this reaction remain unclear.
The reactivity of two particularly interesting substrates
was tested (Scheme 1). With cyclohexylallene, the reac-
tion proceeds normally to provide the corresponding
allylic-H-phosphinate in 59% NMR yield, but the isolated
yield was low (29%).17 With cinnamyl chloride, cinnamyl-
H-phosphinate is cleanly obtained in 70% yield (100%
(17) Allenes also undergo the palladium-catalyzed hydrophosphin-
ylation: unpublished results.
J. Org. Chem, Vol. 70, No. 10, 2005 4067

Ribie`re et al.
FIGURE 1. Hydrophosphinylation of 4-Octyne with EtOP(O)H2
SCHEME 1. NiCl2-Catalyzed Hydrophosphinylation of Cycloxexylallene and Cinnamyl Chloride
NMR yield, 95:5 allyl/reduced), which suggests a direct
cross-coupling reaction. The latter reaction type was
previously observed and studied in some detail in our
cross-coupling work,15 and we are currently developing
a general allylic cross-coupling reaction with alkyl phos-
phinates.18 Taken together, both results support an allene
intermediate in the reaction of the propargyl chloride
(Table 3, entry 14).
We have also studied the influence of the temperature
on the rate of our hydrophosphinylation (Figure 1). The
various runs were followed by both 31P NMR (product
formation) and GC chromatography (alkyne disappear-
ance).19 Remarkable agreement was observed (perfect
agreement would be mirror images around the 50%
mark), which also validated the 31P NMR yield measure-
ments. The validity of the NMR yields was also checked
using authentic samples (see Supporting Information).
Whereas the thermal reaction generally proceeds to
completion within a few hours, we noted that at room
temperature the reaction reached completion in about 20
h, after an induction period (Figure 1). Reasoning that
it could be due to the slow formation of a catalytically
active nickel(0) species (through reduction of the Ni(II)
precursor), we looked for a preactivation procedure. When
nickel chloride was heated for 15 min with the alkyl
phosphinate in the absence of the alkyne and then the
resulting mixture allowed to cool to room temperature
for 15 min before alkyne addition, the reaction proceeded
much more rapidly reaching completion within 6 h. This
room-temperature protocol was also the one employed
with acetylene gas (Table 3, entry 4).
Because the thermal reaction gave excellent results,
we studied the feasibility of a microwave process. Reac-
tions conducted under microwave irradiation are cur-
rently receiving a great deal of attention because of the
very short reaction times involved.20 As expected, excel-
lent hydrophosphinylation yields can be obtained in
minutes in a microwave reactor (Table 4). Conditions did
not affect significantly the regioselectivity of the reaction.
With phenylacetylene, the microwave reaction appears
slightly more regioselective than the thermal reaction
(see Table 3, entry 6). The corresponding products can
be isolated in good yields (Table 4).
Next, we turned our attention to representative syn-
thetic applications of this reaction. Since various func-
tional group transformations of H-phosphinates are well-
established in the literature,21 some one-pot tandem
functionalizations were investigated. A variety of reac-
tions can be conducted on pure H-phosphinate esters,21
so focus was placed exclusively on one-pot reactions
without intermediate purification, to maximize practical-
ity and broad applicability. Since the H-phosphinates are
often difficult to purify thus decreasing the isolated
yield,13 a tandem sequence of reactions could be a clear
(20) Reviews: (a) Hayes, B. L. Aldrichimica Acta 2004, 37, 66. (b)
Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250. (c) Lidstro¨m, P.;
Tierney, J.; Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225. (d)
Loupy, A.; Petit, A.; Texier-Boullet, F.; Jacquault, P.; Mathe´, D.
Synthesis 1998, 1213.
(18) Bravo-Altamirano, K.; Montchamp, J.-L. Unpublished results.
(19) See Supporting Information for experimental details.
4068 J. Org. Chem., Vol. 70, No. 10, 2005

NiCl2-Catalyzed Hydrophosphinylation
TABLE 4. Nickel-Catalyzed Hydrophosphinylation with Microwave Heatinga
a General procedure for the hydrophosphinylation of alkynes by microwave irradiation (using a commercial instrument): To the alkyne
(1.25 mmol) and the catalyst (0.025-0.037 mmol, 2-3 mol % relative to the alkyne) was added a solution of EtOP(O)H2 (2.5 mmol) in
CH3CN (5 mL, 0.5 M) at room temperature. The mixture was prestirred for 30 s before being irradiated under normal adsorption. The
mixture was then concentrated in vacuo. The residue was diluted with EtOAc and washed with 1 M aqueous NaHSO4 and then brine.
Drying on MgSO4 and concentration afforded the crude compound, which was purified by radial chromatography (hexanes, 100% v/v to
EtOAc, 100% v/v). b Branched only.
TABLE 5. Tandem One-Pot Alkyne
advantage. Some examples of tandem reactions are
Hydrophosphinylation-Functionalization
shown in Table 5. As expected, alkenylphosphonate
diesters are readily obtained by oxidative esterification
(Table 5, entries 1 and 7). Unsymmetrical phosphonate
diesters or phosphonate monoesters should also be ac-
cessible using a similar approach. More interestingly,
tandem cross-coupling (Table 5, entry 2), conjugate
second
isolated
addition (Table 5, entries 3 and 6), and alkylation (Table
5, entries 4 and 5) can all be conducted to provide
acceptable yields (generally 50-60%) of unsymmetrically
disubstituted phosphinate esters. The lower yield ob-
tained in entry 6 presumably comes from the sensitivity
entry
R1
R2
Pr
Pr
Pr
Pr
Pr
R3
reactiona yield, %
1
2
3
4
5
6
7
Pr
Pr
Pr
Pr
Pr
OEt
Ph
A
B
C
D
E
F
A
48
58
63
76
62
32
57
CH2CH2CN
allyl
Me
(21) See also ref 11. For some representative examples of specific
functional group transformations for H-phosphinate esters, see: (a)
Karanewsky, D. S.; Badia, M. C. Tetrahedron Lett. 1986, 27, 1751. (b)
Baylis, E. K. Tetrahedron Lett. 1995, 36, 9385. (c) Baylis, E. K.
Tetrahedron Lett. 1995, 36, 9389. (d) Froestl, W.; Mickel, S. J.; Hall,
R. G.; von Sprecher, G.; Diel, P. J.; Strub, D.; Baumann, P. A.; Brugger,
F.; Gentsch, C.; Jaekel, J.; Olpe, H.-R.; Rihs, G.; Vassout, A.; Wald-
meier, P. C.; Bittiger, H. J. Med. Chem. 1995, 38, 3297. (e) Froestl,
W.; Mickel, S. J.; von Sprecher, G.; Diel, P. J.; Hall, R. G.; Maier, L.;
Strub, D.; Melillo, V.; Baumann, P. A.; Bernasconi, R.; Gentsch, C.;
Hauser, K.; Jaekel, J.; Karlsson, G.; Klebs, K.; Maitre, L.; Marescaux,
C.; Pozza, M. F.; Schmutz, M.; Steinmann, M. W.; van Riezen, H.;
Vassout, A.; Mondadori, C.; Olpe, H.-R.; Waldmeier, P. C.; Bittiger,
H. J. Med. Chem. 1995, 38, 3313. (f) Cristau, H.-J.; Coulombeau, A.;
Genevois-Borella, A.; Pirat, J.-L. Tetrahedron Lett. 2001, 42, 4491. (g)
Thottathil, J. K.; Przybyla, C. A.; Moniot, J. L. Tetrahedron Lett. 1984,
25, 4737. (h) Chen, S.; Coward, J. K. J. Org. Chem. 1998, 63, 502. (i)
McCleery, P. P.; Tuck, B. J. Chem. Soc., Perkin Trans. 1 1989, 1319.
(j) Reiff, L. P.; Aaron, H. S. J. Am. Chem. Soc. 1970, 92, 5275. (k)
Mucha, A.; Kafarski, P.; Plenat, F.; Cristau, H.-J. Tetrahedron 1994,
50, 12743. (l) Bartlett, P. A.; Giangiodano, M. A. J. Org. Chem. 1996,
61, 3433. (m) Fatima Fernandez, M.; Vlaar, C. P.; Fan, H.; Liu, Y.-H.;
Fronczek, F. R.; Hammer, R. P. J. Org. Chem. 1995, 60, 7390. (n) Seo,
K.; Yamashita, M.; Oshikawa, T.; Kobayashi, J.-i. Carbohydr. Res.
1996, 281, 307. (o) Emmick, T. L.; Letsinger, R. L. J. Am. Chem. Soc.
1968, 90, 3459. (p) Hall, R. G.; Riebli, P. Synlett 1999, 1633. (q) Xu,
Y.; Wei, H.; Xia, J. Liebigs Ann. Chem. 1988, 1139. (r) Schuman, M.;
Lopez, X.; Karplus, M.; Gouverneur, V. Tetrahedron 2001, 57, 10299.
(s) Luke, G.; Shakespeare, W. C. Synth. Commun. 2002, 32, 2951. (t)
Zeiss, H.-J. Tetrahedron 1992, 48, 8263.
CtCMe Me
Me
CH2CH2CO2Bn
t-Bu OEt
a Reactions: (A) EtOH (55 equiv), CCl4 (33 equiv), Et3N (10
equiv), room temperature, 12 h. (B) PhI (3 equiv), Et3N (6 equiv),
2 mol % Cl2Pd(PPh3)2, reflux, 12 h. (C) acrylonitrile (3 equiv), DBU
(3 equiv), room temperature, 6 h. (D) allyl chloride (3 equiv), BSA
(6 equiv), reflux, 3 h. (E) Me2SO4 (2 equiv), BSA (6 equiv), room
temperature, 3 h. (F) benzyl acrylate (3 equiv), DBU (3 equiv),
room temperature, 6 h.
of the enyne product, but the hydrophosphinylation step
is highly regioselective (see Table 3, entry 8).
Other tandem reactions are shown in Scheme 2.
Phosphonothioic acids can easily be obtained by simply
treating the crude hydrophosphinylation mixtures with
elemental sulfur. The product can even be obtained in
good purity using a simple extractive workup with
hexane. The resolution of phosphonothioic acids with
chiral amines has been reported in the literature as a
way to access P-chiral compounds.22 Thus the methodol-
ogy we are developing for the preparation of H-phosphi-
nate esters could ultimately become useful for the
preparation of P-chiral ligands. Scheme 2 also shows an
J. Org. Chem, Vol. 70, No. 10, 2005 4069

Ribie`re et al.
SCHEME 2. Phosphonothioate and Tertiary Phosphine Oxide via Tandem Reactions
interesting and potentially very useful example of three
phosphorus-carbon bond-forming reactions in a single
pot. After hydrophosphinylation, a Grignard reagent
displaces the ester group,21ï-q and the resulting second-
ary phosphine oxide anion can be trapped with an
electrophile. In this case, a solvent switch from acetoni-
trile to THF was required after the first step, to be
compatible with the Grignard reagent, but no intermedi-
ate purification was conducted during the entire se-
quence. Such access to functionalized phosphine oxides
could be particularly useful since the reduction of tertiary
phosphine oxides is very well-precedented and leads to
tertiary phosphines.23
Although we have not yet studied the mechanism of
this novel nickel-catalyzed hydrophosphinylation, it is
likely to proceed similarly to that of the palladium
version.1 One experiment that was conducted was the
hydrophosphinylation of an internal alkyne with EtOP-
(O)D2 (eq 3). Deuterated ethyl phosphinate was prepared
some mechanistic issues remain to be clarified, the
practical aspects of this reaction should prove a useful
tool in the synthesis of alkenyl H-phosphinates and their
derivatives. The fact that inexpensive NiCl2 (or its
hydrate) is employed catalytically makes this novel P-C
bond-forming reaction particularly convenient. We also
demonstrated conditions that employ microwave heating
to produce the alkenyl phosphinates in high yield in a
few minutes. Since the alkenyl-H-phosphinates are now
readily available, their reactivity and use for the prepa-
ration of other compounds can be investigated. Along
these lines, the one-pot elaboration of the hydrophos-
phinylation products was also demonstrated for a variety
of common reactions to provide access to functionalized
organophosphorus compounds. Taken with our previously
reported palladium-catalyzed hydrophosphinylation,1,3
radical-based hydrophosphinylation,24 and palladium
cross-coupling of aryl15,25 and alkenyl halides,14,15 this
methodology further expands the scope of H-phosphinic
acid derivatives that can be obtained. Thus access to a
wide variety of functionalized H-phosphinates should
significantly enhance the synthetic usefulness of these
intermediates, for example, in the preparation of biologi-
cally active compounds or phosphine ligands.
Experimental Section
Experimental Procedures for Table 3. General Pro-
cedure for the Hydrophosphinylation of Alkynes with
a Stock Solution of ROP(O)H2. To the alkyne (2.5 mmol)
and the catalyst (0.05-0.075 mmol, 2-3 mol % relative to the
alkyne) was added a solution of EtOP(O)H2 (5 mmol) in CH3-
CN (10 mL, 0.5 M) at room temperature. The mixture was
stirred at reflux until completion of the reaction (NMR
monitoring on a sample of the crude reaction mixture). The
mixture was then concentrated in vacuo. The residue was
diluted with EtOAc and washed with 1 M aqueous NaHSO4
and then brine. Drying on MgSO4 and concentration afforded
the crude compound, which was purified by radial chroma-
tography (hexanes, 100% v/v to EtOAc, 100% v/v). The product
was generally obtained as a light yellow oil.
in 94% isotopic purity from D3PO2 (itself obtained by
exchanging H3PO2 with D2O) using our alkoxysilane
esterification. As expected, the deuterium is incorporated
via a syn addition in 80-90% isotopic purity.
In conclusion, we have developed a novel nickel-
catalyzed phosphorus-carbon bond-forming reaction.
Although the regioselectivity needs to be improved and
(22) (a) Aaron, H. S.; Braun, J.; Shryne, T. M.; Frack, H. F.; Smith,
G. E.; Uyeda, R. T.; Miller, J. I. J. Am. Chem. Soc. 1960, 82, 596. (b)
Krawiecka, B.; Michalski, J. Bull. Acad. Pol. Sci. Ser. Sci. Chim. 1971,
19, 377.
(23) Reduction of phosphine oxides to phosphines: (a) Kagan, H.
B.; Sasaki, M. The Chemistry of Organophosphorus Compounds;
Hartley, F. R., Ed.; Wiley: New York, 1990; Vol. 1, Chapter 3. (b)
Coumbe, T.; Lawrence, N. J.; Muhammad, F. Tetrahedron Lett. 1994,
35, 625. (c) Imamoto, T.; Takeyama, T.; Kusumoto, T. Chem. Lett. 1985,
1491. (d) Imamoto, T.; Kikuchi, S.-i.; Miura, T.; Wada, Y. Org. Lett.
2001, 3, 87 and references therein.
Representative Procedure with Alternate Workup:
Preparation of Ethyl (1-Propyl-pent-1-enyl) Phosphi-
nate (Table 3, entry 2a). To a solution of EtOP(O)H2 (0.5
M, 10 mL, 5 mmol) in CH3CN (prepared from (EtO)2SiMe2 as
described above) was added 4-octyne (0.37 mL, 2.5 mmol) and
(24) Depre`le, S.; Montchamp, J.-L. J. Org. Chem. 2001, 66, 6745.
(25) Montchamp, J.-L.; Dumond, Y. R. J. Am. Chem. Soc. 2001, 123,
510.
4070 J. Org. Chem., Vol. 70, No. 10, 2005

NiCl2-Catalyzed Hydrophosphinylation
nickel chloride (0.01 g, 0.075 mmol, 3 mol %), at room
temperature. The solution was refluxed under N2 for 7 h. After
cooling to room temperature, 31P NMR analysis showed the
product at 31.8 ppm. The mixture was then diluted with EtOAc
and washed with dilute aqueous HCl (1 ×), the resulting
aqueous phase was extracted with EtOAc (3 ×). The combined
organic fractions were washed with saturated aqueous NaH-
CO3 (1 ×) and brine. Drying and concentration afforded the
crude compound, which was purified by radial chromatography
(2 mm thickness, hexanes/EtOAc 3:1, v/v, EtOAc). The product
was obtained as a colorless oil (0.510 g, 100%). 1H NMR
(CDCl3) δ 6.99 (d, J ) 542 Hz, 1 H), 6.36 (dt, J ) 26 Hz, J )
6 Hz, 1 H), 3.89-4.1 (m, 2 H), 2.0-2.27 (m, 4 H), 1.3-1.52
(m, 4 H), 1.12-1.3 (m, 3 H), 0.72-1.0 (m, 6 H); 13C NMR
(CDCl3) δ 146.9 (d, JPCC ) 14 Hz), 131.6 (d, JPC ) 124 Hz),
10 Hz), 129.4 (JPC ) 175 Hz), 61.5 (JPOC ) 6 Hz), 30.7 (JPCCC
) 19 Hz), 29.6 (JPCC ) 11 Hz), 22.6 (JPCCCC ) 2 Hz), 22.1 (JPCCC
) 2 Hz), 16.5 (JPOCC ) 7 Hz), 14.3, 14.0; 31P NMR (CDCl3, Me4-
Si) δ 23.47; MS (EI+) m/z 248 ([M]+); HRMS (EI+) calcd for
C12H25O3P 248.1541, obsd 248.1534.
Ethyl Phenyl-(1-propyl-pent-1-enyl) Phosphinate (Table
4, entry 2). To 4-octyne (0.282 g, 2.56 mmol) and NiCl2 (9.8
mg, 0.076 mmol, 3.0 mol %) was added 10 mL (5 mmol) of
EtOP(O)H2 (0.5M solution in CH3CN) at room temperature.
The solution was stirred at reflux for 3 h. To the reaction
mixture were added iodobenzene (1.5 g, 7.51 mmol), Cl2Pd-
(PPh3)2 (35 mg, 0.05 mmol, 1.9 mol %), and triethylamine (1.52
g, 15.1 mmol) at room temperature. The resulting mixture was
stirred at reflux overnight. The solution was concentrated,
partitioned between 1 M NaHSO4 and ethyl acetate. The
organic layer was washed with brine, dried over MgSO4, and
concentrated to afford the crude compound. Purification over
silica gel (hexanes, 100% v/v to EtOAc, 100% v/v) produced
the expected compound (419 mg, 58%) as an oil. 1H NMR
(CDCl3, Me4Si) δ 7.64 (ddd, J ) 11.7 Hz, J ) 1.5 Hz, J ) 0.6
Hz, 2 H), 7.29-7.45 (m, 3 H), 6.39 (dt, J ) 22.3 Hz, J ) 7.3
Hz, 1 H), 3.91/3.91 (ddq, J ) 22.4 Hz, J ) 10.1 Hz, J ) 7.0
Hz, 1 H/1 H), 1.96-2.10 (m, 4 H), 1.25-1.40 (m, 2 H), 1.22 (t,
J ) 7.2 Hz, 3 H), 1.0-1.2 (m, 2 H), 0.79 (t, J ) 7.3 Hz, 3 H),
0.70 (t, J ) 7.3 Hz, 3 H); 13C NMR (CDCl3, Me4Si) δ 146.4
(JPCC ) 10 Hz), 131.9 (JPC ) 127.5 Hz), 131.5 (JPCCCC ) 3 Hz),
131.3 (JPCC ) 10 Hz), 131.0 (JPC ) 131 Hz), 128.0 (JPCCC ) 12
Hz), 60.2 (JPOC ) 6 Hz), 30.3 (JPCCC ) 17 Hz), 28.9 (JPCC ) 12
Hz), 22.5 (JPCCC ) 2 Hz), 21.6 (JPCCCC ) 1 Hz), 16.1 (JPOCC ) 7
Hz), 13.9, 13.5; 31P NMR (CDCl3, Me4Si) δ 35.89; MS (EI+) m/z
280 ([M]+); HRMS (EI+) calcd for C16H25O2P 280.1592, obsd
280.1588.
61.7 (d, JPOC ) 7 Hz), 30.3 (d, JPCC ) 18 Hz), 28.1 (d, JPCCC
)
12 Hz), 22.4, 21.7, 16.1 (d, JPOCC ) 3 Hz), 13.9, 13.6; 31P NMR
(CDCl3) δ 32.2 (dm, J ) 543 Hz). HRMS (EI) calcd for
C10H21O2P (M+) 204.1279, obsd 204.1275.
Representative Procedure for One-Pot Hydrophos-
phinylation with Anilinum Hypophosphite: Prepara-
tion of Butyl (1-Propyl-pent-1-enyl) Phosphinate (Table
3, entry 1d). To a suspension of PhNH3OP(O)H2 (0.800 g, 5
mmol), (BuO)4Si (1.122 g, 3.5 mmol), and 4-octyne (0.37 mL,
2.5 mmol) in CH3CN (10 mL) was added NiCl2 (0.01 g, 0.075
mmol, 3 mol %). The reaction mixture was then refluxed for
16 h. After cooling to room temperature, 31P NMR analysis
showed the product at 31.2 ppm (100%). The mixture was then
diluted with EtOAc and washed successively with diluted HCl
(1 ×). The resulting aqueous phase was extracted with EtOAc
(3 ×), and the combined organic fractions were washed with
saturated aqueous NaHCO3 (1 ×) and brine. Drying, concen-
tration, and purification by radial chromatography (2 mm
thickness, hexanes/EtOAc 3:1, v/v, EtOAc) afforded the product
as a colorless oil (0.521 g, 90%).
Representative Procedure with Aminosilicate/TFA:
Preparation of Ethyl (trans-2-Trimethylsilyl-vinyl) Phos-
phinate (Table 3, entry 12). To a solution of concentrated
H3PO2 (5 mmol) in HPLC grade CH3CN (10 mL) were added
3-aminopropyl)triethoxysilane (1.107 g, 5 mmol), trimethyl-
silylacetylene (0.35 mL, 2.5 mmol), trifluoroacetic acid (0.39
mL, 5 mmol), and nickel chloride (0.01 g, 0.075 mmol, 3 mol
%), at room temperature. The solution was refluxed under N2
for 2.5 h. After cooling to room temperature, 31P NMR analysis
showed the product at 25.3 ppm (98%). The mixture was then
diluted with EtOAc and washed successively with diluted
aqueous HCl (1 ×). The aqueous phase was then extracted with
EtOAc (3 ×) and the combined organic fractions were washed
with saturated aqueous NaHCO3 (1 ×) and brine. Drying and
concentration afforded the product as a colorless oil (0.350 g,
75%).
Ethyl (2-Cyano-ethyl)-(1-propyl-ent-1-enyl) Phosphi-
nate (Table 4, entry 3). To 4-octyne (0.282 g, 2.56 mmol) and
NiCl2 (9.8 mg, 0.076 mmol, 2.9 mol %) was added 10 mL (5
mmol) of EtOP(O)H2 (0.5 M solution in CH3CN) at room
temperature. The solution was stirred at reflux for 3 h. To the
reaction mixture was added acrylonitrile (0.403 g, 7.6 mmol)
and DBU (1.1 g, 7.36 mmol) at room temperature. The
resulting mixture was stirred at room temperature for 6 h.
The solution was quenched with 1 M NaHSO4 and extracted
with ethyl acetate. The organic layer was washed with brine,
dried over MgSO4, and concentrated to afford the crude
compound. Purification over silica gel (hexanes, 100% v/v to
EtOAc, 100% v/v) produced the expected compound (415 mg,
1
63%) as an oil. H NMR (CDCl3, Me4Si) δ 6.58 (dt, J ) 21.4
Hz, J ) 7.3 Hz), 3.95-4.16 (m, 1 H), 3.82-3.96 (m, 1 H), 2.56-
2.70 (m, 2 H), 1.35-1.60 (m, 4 H), 1.32 (t, J ) 7.3 Hz), 0.98 (t,
J ) 7.0 Hz), 0.95 (t, J ) 7.3 Hz, 3 H); 13C NMR (CDCl3, Me4-
Si) δ 149.8 (JPCC ) 9 Hz), 130.7 (JPC ) 118 Hz), 119.0 (JPCCC
17 Hz), 60.7 (JPOC ) 6 Hz), 31.1 (JPCCC ) 16 Hz), 29.5 (JPCC
12 Hz), 24.5 (JPC ) 97 Hz), 23.2 (JPCCCC ) 2 Hz), 22.1 (JPCCC
)
)
)
Tandem Reactions (Table 4). Diethyl (1-Propyl-pent-
1-enyl) Phosphonate (Table 4, entry1).26 To 4-octyne (0.275
g, 2.50 mmol) and NiCl2 (9.7 mg, 0.076 mmol, 3.0 mol %) was
added 10 mL (5 mmol) of EtOP(O)H2 (0.5 M solution in CH3-
CN) at room temperature. The solution was stirred at reflux
overnight. To the reaction mixture was added CCl4 (8 mL, 12.7
g, 83 mmol), ethanol (8 mL, 6.3 g, 137 mmol), and triethy-
lamine (4 mL, 2.9 g, 29 mmol) at room temperature. The
resulting mixture was stirred at room temperature for 6 h.
The solution was quenched with 1 M NaHSO4 and extracted
with ethyl acetate. The organic layer was washed with brine,
dried over MgSO4, and concentrated to afford the crude
compound. Purification over silica gel (hexanes, 100% v/v to
EtOAc, 100% v/v) produced the expected compound (299 mg,
48%) as an oil. 1H NMR (CDCl3, Me4Si) δ 6.48 (dt, J ) 24 Hz,
J ) 7 Hz, 1 H), 3.97 (q, J ) 7 Hz, 2 H), 2.05-2.18 (m, 4 H),
1.25-1.40 (m, 4 H), 1.24 (t, J ) 7 Hz, 6 Hz), 0.86 (dt, J ) 3
2 Hz), 16.6 (JPOCC ) 6 Hz), 14.5, 14.1, 10.8 (JPCC ) 2 Hz); 31P
NMR (CDCl3, Me4Si) δ 43.25; MS (EI+) m/z 257 ([M]+); HRMS
(EI+) calcd for C13H24NO2P 257.1545, obsd 257.1547.
Ethyl Allyl-(1-propyl-pent-1-enyl) Phosphinate (Table
4, entry 4). To 4-octyne (0.281 g, 2.55 mmol) and NiCl2 (10.1
mg, 0.078 mmol, 3 mol %) was added 10 mL (5 mmol) of EtOP-
(O)H2 (0.5M solution in CH3CN) at room temperature. The
solution was stirred at reflux for 3 h. To the reaction mixture
was added at room temperature BSA (1.46 g, 7.2 mmol) and,
after 5 min of stirring, allyl chloride (0.582 g, 7.61 mmol). To
the mixture was stirred at reflux for 3 h. The reaction mixture
was then cooled, quenched by saturated NaHCO3, extracted
with EtOAc, and the combined organic phases were washed
with brine. Drying over MgSO4, and concentration afforded
the crude compound. Purification over silica gel (hexanes,
100% v/v to EtOAc, 100% v/v) produced the expected compound
(475 mg, 76%) as an oil. 1H NMR (CDCl3, Me4Si) δ 6.48 (dt, J
) 21.1 Hz, J ) 7.3 Hz, 1 H), 5.7-5.85 (m, 1 H), 5.1-5.22 (m,
2 H), 3.85-4.2 (m, 2 H), 2.5-2.75 (m, 2 H), 2.1-2.25 (m, 4 H),
1.35-1.55 (m, 4 H), 1.30 (t, J ) 7.0 Hz, 3 H), 0.95 (t, J ) 7.3
Hz, J ) 7 Hz, 6 H); 13C NMR (CDCl3, Me4Si) δ 147.6 (JPCC
)
(26) Mimouni, N.; About-Jaudet, E.; Collignon, N.; Savignac, P.
Synth. Commun. 1991, 21, 2341.
J. Org. Chem, Vol. 70, No. 10, 2005 4071

Ribie`re et al.
Hz, 3 H), 0.93 (t, J ) 7.3 Hz, 3 H); 13C NMR (CDCl3, Me4Si) δ
147.7 (d, JPCC ) 9 Hz), 130.7 (d, JPC ) 116 Hz), 127.3 (d, JPCC
) 9 Hz), 119.5 (d, JPCCC ) 13 Hz), 59.8 (d, JPOC ) 6 Hz), 34.0
(d, JPC ) 94 Hz), 30.1 (d, JPCCC ) 13 Hz), 29.1 (d, JPCC ) 12
Hz), 22.4 (d, JPCCCC ) 1 Hz), 21.6 (d, JPCCC ) 1 Hz), 16.8 (d,
JPOCC ) 7 Hz), 13.9, 13.5; 31P NMR (CDCl3, Me4Si) δ 45.18;
MS (EI+) m/z 244 ([M]+); HRMS (EI+) calcd for C13H25O2P
244.1592, obsd 244.1587.
J ) 0.59 Hz, 3 H), 3.9-4.1 (m, 4 H), 1.88 (ddd, J ) 15.8 Hz, J
) 1.47 Hz, J ) 0.59 Hz, 3 H), 1.28 (t, J ) 7 Hz, 6 H), 1.14 (s,
9 H); 13C NMR (CDCl3, Me4Si) δ 155.8 (d, JPCC ) 4 Hz), 123.2
(d, JPOC ) 175 Hz), 61.7 (d, JPOC ) 6 Hz), 34.5 (d, JPCCC ) 21
Hz), 30.2, 16.5 (d, JPOCC ) 6 Hz), 13.5 (d, JPCC ) 10 Hz); 31P
NMR (CDCl3, Me4Si) δ 24.44; MS (EI+) m/z 234 ([M]+); HRMS
(EI+) calcd for C11H23O3P 234.1585, obsd 234.1380.
Tandem Reactions (Scheme 2). (1-Propyl-pent-1-enyl)-
phosphonothioic Acid O-Ethyl Ester. To 4-octyne (0.281
g, 2.55 mmol) and NiCl2 (10.0 mg, 0.077 mmol, 3 mol %) was
added 10 mL (5 mmol) of EtOP(O)H2 (0.5M solution in CH3-
CN) at room temperature. The solution was stirred at reflux
overnight. To the reaction mixture was added sulfur (0.24 g,
7.5 mmol) and triethylamine (0.762 g, 7.53 mmol) at room
temperature. The resulting mixture was stirred at room
temperature overnight. The solution was extracted with hex-
ane, the acetonitrile layer was partitioned between 1 M HCl
and ethyl acetate. The organic layer was dried over MgSO4
and concentrated to afford the crude compound. Purification
over silica gel (hexanes, 100% v/v to hexanes/EtOAc, 90/10%
v/v) produced the expected compound (424 mg, 70%) as a
Ethyl Methyl-(1-propyl-pent-1-enyl) Phosphinate (Table
4, entry 5). To 4-octyne (0.279 g, 2.5 mmol) and NiCl2 (9.9
mg, 0.076 mmol, 3 mol %) was added 10 mL (5 mmol) of EtOP-
(O)H2 (0.5 M solution in CH3CN) at room temperature. The
solution was stirred at reflux overnight. To the reaction
mixture was added at room temperature BSA (1.46 g, 7.2
mmol) and, after 5 min of stirring, dimethyl sulfate (0.633 g,
5.02 mmol). The mixture was stirred at room temperature for
2 h. The reaction mixture was then quenched by saturated
NaHCO3 and extracted with EtOAc, and the combined organic
phases washed with brine. Drying over MgSO4 and concentra-
tion afforded the crude compound. Purification over silica gel
(hexanes, 100% v/v to EtOAc, 100% v/v) produced the expected
compound (343 mg, 62%) as a light yellow oil. 1H NMR (CDCl3,
Me4Si) δ 6.55 (dt, J ) 21.4 Hz, J ) 7.3 Hz, 1 H), 3.8-4.05 (m,
2 H), 2.1-2.25 (m, 4 H), 1.49 (d, J ) 13.8 Hz, 3 H), 1.35-1.55
(m, 4 H), 1.30 (t, J ) 7.0 Hz, 3 H), 0.96 (t, J ) 7.3 Hz, 3 H),
0.94 (t, J ) 7.3 Hz, 3 H); 13C NMR (CDCl3, Me4Si) δ 147.0 (d,
JPCC ) 9 Hz), 132.5 (d, JPC ) 118 Hz), 59.9 (d, JPOC ) 6 Hz),
30.8 (d, JPCCC ) 16 Hz), 29.5 (d, JPCC ) 12 Hz), 23.0 (d, JPCCCC
) 1 Hz), 22.2 (d, JPCCC ) 1 Hz), 14.5, 14.5 (d, JPC ) 99 Hz),
14.1; 31P NMR (CDCl3, Me4Si) δ 45.77; MS (EI+) m/z 218 ([M]+);
HRMS (EI+) calcd for C11H23O2P 218.1436, obsd 218.1438.
Benzyl 3-[Ethoxy-(1-ethylidene-but-2-ynyl)-phosphi-
noyl]propionate (Table 4, entry 6). To 2,4-hexadiyne (0.199
g, 2.55 mmol) and NiCl2 (7.0 mg, 0.054 mmol, 2.1 mol %) was
added 10 mL (5 mmol) of EtOP(O)H2 (0.5M solution in CH3-
CN) at room temperature. The solution was stirred at reflux
overnight. To the reaction mixture was added benzyl acrylate
(1.22 g, 7.5 mmol) and DBU (1.12 g, 7.36 mmol) at room
temperature. The resulting mixture was stirred at room
temperature for 6 h. The solution was quenched with 1M
NaHSO4 and extracted with ethyl acetate. The organic layer
was washed with brine, dried over MgSO4 and concentrated
to afford the crude compound. Purification over silica gel
(hexanes, 100% v/v to EtOAc, 100% v/v) produced the expected
compound (271 mg, 32%) as an oil. 1H NMR (CDCl3, Me4Si) δ
7.3-7.4 (br, 5 H), 6.9-7.1 (m, 1 H), 5.13 (s, 2 H), 4.05-4.2 (m,
1 H), 3.85-4.1 (m, 2 H), 2.55-2.8 (m, 2 H), 2.1-2.3 (m, 2 H),
1.95-2.05 (m, 6 H), 1.30 (t, J ) 7.0 Hz, 3 H); 13C NMR (CDCl3,
Me4Si) δ 172.1 (d, JPCCC ) 19 Hz), 152.1 (d, JPCC ) 8 Hz), 135.7,
1
brown oil. H NMR (CDCl3, Me4Si) δ 6.66 (dt, J ) 27.5 Hz, J
) 7.2 Hz, 1 H), 6.4-6.65 (s br, 1 H), 4.05-4.2 (m, 2 H), 2.25-
2.4 (m, 2 H), 2.1-2.25 (m, 2 H), 1.4-1.6 (m, 4 H), 1.33 (t, J )
7.0 Hz, 3H), 0.95 (dt, J ) 2.3 Hz, J ) 7.3 Hz, 6 H); 13C NMR
(CDCl3, Me4Si) δ 146.6 (d, JPCC ) 14 Hz), 134.1 (d, JPC ) 141
Hz), 62.3 (d, JPOC ) 6 Hz), 30.9 (d, JPCCC ) 20 Hz), 29.5 (d,
JPCC ) 12 Hz), 23.1, 22.2, 16.3 (d, JPOCC ) 8 Hz), 14.5, 14.2;
31P NMR (CDCl3, Me4Si) δ 85.69; MS (EI+) m/z 236 ([M]+);
HRMS (EI+) calcd for C10H21O2PS 236.1000, obsd 236.0992.
Methyl-phenyl-(1-propyl-pent-1-enyl)phosphine Ox-
ide. To 4-octyne (0.279 g, 2.5 mmol) and NiCl2 (9.9 mg, 0.076
mmol, 3 mol %) was added 10 mL (5 mmol) of EtOP(O)H2 (0.5
M solution in CH3CN) at room temperature. The solution was
stirred at reflux overnight. The mixture was then concentrated
in high vacuo. The residue was diluted with 5 mL of dry THF.
To the mixture at 0 °C was added 7.5 mL (7.5 mmol) of
phenylmagnesium bromide (1 M solution in THF). The mixture
was warmed to room temperature and then stirred at reflux
for 1 h 30. After addition at 0 °C of methyl iodide (1.08 g, 7.61
mmol), the mixture was warmed to room temperature and
stirred for 2 h. The reaction mixture was then quenched by
10 mL of 1 M HCl, extracted with EtOAc and the combined
organic phases washed with 1 M sodium thiosulfate and then
brine. Drying over MgSO4 and concentration afforded the crude
compound. Purification over silica gel (hexanes, 100% v/v to
EtOAc, 100% v/v) produced the expected compound (334 mg,
53%) as a light yellow oil. 1H NMR (CDCl3, Me4Si) δ 7.65-7.8
(m, 2 H), 7.4-7.55 (m, 3 H), 6.41 (dt, J ) 21.1 Hz, J ) 7.3 Hz,
1 H), 2.0-2.25 (m, 4 H), 1.8 (d, J ) 12.9 Hz, 3 H), 1.42-1.46
(m, 2 H), 1.20-1.35 (m, 2 H), 0.95 (t, J ) 7.3 Hz, 3 H), 0.82 (t,
128.6, 128.3, 128.2, 117.3 (d, JPC ) 128 Hz), 95.5 (d, JPCCC
)
8 Hz), 73.0 (d, JPCC ) 13 Hz), 66.6, 60.7 (d, JPOC ) 7 Hz), 26.7
(d, JPCC ) 2 Hz), 22.5 (d, JPC ) 106 Hz), 17.3 (d, JPCCC ) 14
Hz), 16.4 (d, JPOCC ) 7 Hz), 4.6 (d, JPCCCC ) 2 Hz); 31P NMR
(CDCl3, Me4Si) δ 41.41; MS (EI+) m/z 334 ([M]+); HRMS (EI+)
calcd for C18H23O4P 334.1334, obsd 334.1340.
J ) 7.3 Hz, 3 H); 13C NMR (CDCl3, Me4Si) δ 144.5 (d, JPCC
)
9 Hz), 134.4 (d, JPC ) 94 Hz), 133.9 (d, JPC ) 98 Hz), 131.4 (d,
JPCCCC ) 3 Hz), 130.4 (d, JPCC ) 10 Hz), 128.5 (d, JPCCC ) 12
Hz), 30.8 (d, JPCCC ) 15 Hz), 29.5 (d, JPCC ) 12 Hz), 23.1, 22.1,
14.9 (d, JPC ) 72 Hz), 14.3, 13.9; 31P NMR (CDCl3, Me4Si) δ
33.74 (m); MS (EI+) m/z 250 ([M]+); HRMS (EI+) calcd for
C15H23OP 250.1487, obsd 250.1488
Diethyl (1,3,3-Trimethyl-but-1-enyl) Phosphonate
(Table 4, entry 7). To 4,4-dimethyl-2-pentyne (0.240 g, 2.50
mmol) and NiCl2 (9.8 mg, 0.076 mmol, 3.0 mol %) was added
10 mL (5 mmol) of EtOP(O)H2 (0.5M solution in CH3CN) at
room temperature. The solution was stirred at reflux for 24h.
To the reaction mixture was added CCl4 (8 mL, 12.7 g, 83
mmol), ethanol (8 mL, 6.3 g, 137 mmol), and triethylamine (4
mL, 2.9 g, 29 mmol) at room temperature. The resulting
mixture was stirred at room temperature for 12 h. The solution
was quenched with 1M NaHSO4 and extracted with ethyl
acetate. The organic layer was washed with brine, dried over
MgSO4 and concentrated to afford the crude compound.
Purification over silica gel (hexanes, 100% v/v to EtOAc, 100%
v/v) produced the expected compound (354 mg, 57%) as an oil.
1H NMR (CDCl3, Me4Si) δ 6.54 (ddd, J ) 27 Hz, J ) 1.47 Hz,
Acknowledgment. We gratefully acknowledge the
National Science Foundation (CHE-0242898) and the
Robert A. Welch Foundation (P-1435) for the financial
support of this research.
Supporting Information Available: Additional experi-
mental procedures, and representative NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO050096L
4072 J. Org. Chem., Vol. 70, No. 10, 2005