Base-Free Direct Synthesis of Alkynylphosphonates from Alkynes and H-Phosphonates Catalyzed by Cu2O

Article abstract of DOI:10.1021/acs.joc.5b02528

A simple and mild methodology for the direct synthesis of alkynylphosphonates is presented. The reaction of a variety of terminal alkynes with dialkyl phosphites in the presence Cu₂O (14 mol %) led to the formation of the corresponding alkynylp

Full text of DOI:10.1021/acs.joc.5b02528

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Article
Base-free direct synthesis of alkynylphosphonates
2
from alkynes and H-phosphonates catalyzed by CuO
Yanina Moglie, Evangelina Mascaró, Victoria Gutierrez, Francisco Alonso, and Gabriel Radivoy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02528 • Publication Date (Web): 03 Feb 2016
Downloaded from http://pubs.acs.org on February 3, 2016
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Base-free direct synthesis of alkynylphosphonates from alkynes and
H-phosphonates catalyzed by Cu2O.
Yanina Moglie,a,* Evangelina Mascaró,a Victoria Gutierrez,a Francisco Alonso,b and Gabriel Radivoy.a,*
a
Instituto de Química del Sur, INQUISUR (CONICETꢀUNS), Departamento de Química, Universidad Nacional del Sur,
Avenida Alem 1253, 8000 Bahía Blanca, Argentina.
b Instituto de Síntesis Orgánica (ISO) and Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicanꢀ
te, Apdo. 99, 03080, Alicante, Spain.
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ABSTRACT: A simple and mild methodology for the direct synthesis of alkynylphosphonates is presented. The reaction of
a variety of terminal alkynes with dialkyl phosphites in the presence Cu2O (14 mol%) led to the formation of the correspondꢀ
ing alkynylphosphonates in good to excellent yields. Reactions are performed under air, in acetonitrile as solvent, and in the
absence of base or ligand additives. This new methodology is compatible with the presence of a wide variety of functional
groups on the starting alkynes and can be scaledꢀup to a gramꢀscale.
INTRODUCTION
Alkynylphosphonates are one of the most valuable phosphorus derivatives in synthetic organic chemistry. The
increasing interest in these compounds is mainly related to the wide presence of the phosphonic functionality
(acid or ester) in many natural or synthetic bioactive compounds.1 On the other hand, the carbonꢀcarbon triple
bond provides great synthetic versatility to these phosphorus derivatives, allowing a variety of subsequent strucꢀ
tural modifications such as addition or cycloaddition reactions,2 including “click” reactions for the synthesis of
triazolylꢀfunctionalized phosphonates with distinct biological activity.3
Traditional synthesis of alkynylphosphonates, by reacting (RO)2P(O)Cl as phosphorus electrophiles with Li or
Mg acetilydes,4 suffers from several drawbacks such as the use of airꢀ and humidityꢀsensitive chemicals, and lack
of functional group tolerance. Consequently, alternative methods have been developed in recent years, most of
them based on the use of transition metal catalysts. Many of the reported methodologies require the use of funcꢀ
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tionalized starting alkenes or alkynes, including 1,1ꢀdibromoalkenes,5 propiolic acids,6 metal acetylides,7 alkynyl
sulfones,8 trialkylsilyl alkynes,9 and 4ꢀarylꢀ2ꢀmethylꢀ3ꢀbutynꢀ2ꢀols.10 For technical and economic reasons, the
direct synthesis of alkynylphosphonates from commercial or readily available starting alkynes, is the most attracꢀ
tive way for the synthesis of these phosphorous compounds. In this regard, only two general direct synthetic
methods have been published so far. In 2009, Han et al.11 reported an efficient procedure based on copperꢀ
catalyzed oxidative coupling of terminal alkynes and dialkyl phosphites, by using CuI as copper source and
DMSO as solvent, under dry air. It is noteworthy that the use of MeCN, THF, dioxane, CH2Cl2 or toluene as solꢀ
vent, only produced trace amounts of the desired product. The proposed reaction mechanism involves the forꢀ
mation of copper acetylide species, so the use of a base is mandatory for the deprotonation of the starting alkyne.
In 2011, Wang and coworkers,12 reported the direct synthesis of alkynylphosphonates by using a silicaꢀsupported
carbeneꢀCu(II) catalyst. Even though the synthesis of the catalyst is not straightforward, the process is baseꢀfree
but the catalyst could be recovered and reused. Here again, the choice of the reaction solvent was crucial for the
crossꢀcoupling to take place. Thus, the use of solvents different from DMSO (DMF, THF, toluene, CH3OH), gave
no reaction product. Very recently, the group of Han reported a Pd(II)/Ag(I)ꢀmediated method for the dehydroꢀ
genative coupling of terminal alkynes with different P(O)ꢀH compounds,13 but only one example for the synthesis
of an alkynyl phosphonate was reported.
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Owing to our recent interest in phosphorus chemistry,14 we have recently reported our findings on the direct
synthesis of βꢀketophosphonates and vinylphosphonates from alkynes or alkenes catalyzed by copper nanopartiꢀ
cles supported on ZnO.14c In the course of further studies aimed at exploring other synthetically useful applicaꢀ
tions of this methodology, we found that commercial Cu2O was able to catalyze the direct crossꢀcoupling between
phenylacetylene and HP(O)(OEt)2, leading to the corresponding alkynylphosphonate product in good yield, toꢀ
gether with minor amounts of 1,4ꢀdiphenylꢀ1,3ꢀbutadyine coming from the homocoupling of the starting alkyne
(Glaser dimerization). The reaction was performed in the presence of 7 mol% of Cu2O, in MeCN as solvent, unꢀ
der air, and in the absence of any base additive or ligand (Scheme 1).
Scheme 1. Cu2Oꢀcatalyzed crossꢀcoupling of phenylacetylene with diethyl phosphite.
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We want to present herein a new simple and mild protocol for the direct synthesis of alkynylphosphonates from
terminal alkynes and dialkyl phosphites catalyzed by copper(I) oxide.
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RESULTS AND DISCUSSION
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We started our study by optimizing the reaction conditions, using phenylacetylene (1a) as model substrate.
Thus, the alkyne (0.5 mmol) was added to a brownishꢀred suspension of HP(O)(OEt)2 (0.7 mmol) and Cu2O (5
mg, 0.035 mmol) in MeCN (2 mL), and stirred at 70 ˚C overnight under air. The reaction mixture turned to a clear
paleꢀgreen solution and, after chromatographic purification, gave the alkynylphosphonate 2a in 77% yield, toꢀ
gether with 15% of 1,4ꢀdiphenylꢀ1,3ꢀbutadyine and minor amounts of (EtO)2P(O)OH and [(EtO)2P(O)]2O. As
shown in Table 1, the choice of the solvent demonstrated to be important for the crossꢀcoupling reaction but not
as crucial as for the methodologies previously reported by Han and Wang.11,12 Thus, the use of polar protic solꢀ
vents such as H2O or CH3OH, gave no conversion to the desired alkynylphosphonate, whereas the use of DMSO
or THF led to the corresponding crossꢀcoupling product (Table 1, entries 2ꢀ5), albeit in significantly lower yield
compared to that obtained by using MeCN as solvent.
Table 1. Screening of reaction conditionsa
Entry
Catalyst
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuCl
CuCl2
CuI
Solvent
MeCN
H2O
Yield (%)b
77 (86)c
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2
ꢀꢀꢀ
3
CH3OH
DMSO
THF
ꢀꢀꢀ
4
53
5
32
55d
6
MeCN
MeCN
MeCN
MeCN
MeCN
7
ꢀꢀꢀ
8
ꢀꢀꢀ
9
ꢀꢀꢀ
10
CuO
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aStandard reaction conditions: phenylacetylene (0.5
mmol) added to a suspension of diethyl phosphite (0.7
mmol) and the copper catalyst (7 mol%, referred to the
starting alkyne) in 2 mL of solvent, stirred overnight at
70˚C, under air atmosphere. bDetermined by GC using
internal standard. cReaction performed using 14 mol% Cu2O. dReaction performed under N2 atmosphere.
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As expected, the reaction carried out under nitrogen atmosphere allowed to minimize the formation of the diyne
byꢀproduct, but the conversion to the desired alkynylphosphonate was lower than that obtained by working under
air (Table 1, entry 6). Different copper sources were then tested as catalysts. As shown in Table 1 (entries 7ꢀ10)
CuCl, CuCl2 and CuI failed in catalyzing the crossꢀcoupling reaction, whereas CuO gave only 38% of conversion
into the alkynylphosphonate product. We then optimized the catalyst loading and found that by doubling the
amount of Cu2O (10 mg, 14 mol%) the reaction yield was increased from 77% to 86% (Table 1, entry 1). A furꢀ
ther increase in the amount of Cu2O did not improve the reaction yield. Then, the influence of the order of addiꢀ
tion of reactants was studied. Thus, when the synthesis of 2a was carried out by adding diethyl phosphite to a
suspension of 1a and Cu2O in MeCN, only 57% conversion into 2a was obtained.
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With the optimized conditions in hand, we then studied the substrate scope of our methodology by reacting a
wide range of alkynes bearing different functional groups. As shown in Table 2, the Cu2Oꢀcatalyzed crossꢀ
coupling reaction proved to be compatible with the presence of a great variety of functional groups in the starting
alkyne. Aromatic substrates gave the corresponding alkynylphosphonate products in good to excellent yields,
irrespective of the electronic properties of the substituents attached to the aromatic ring (Table 2, entries 2ꢀ7).
Aliphatic alkynes, including those substituted with other functional groups (halogen, nitrile, hydroxyl, ketal, imꢀ
ide) also gave the desired alkynylphosphonate products in good yields (Table 2, entries 8ꢀ13, 19). It is worth notꢀ
ing that the reaction of 1,8ꢀnonadiyne with an excess of HP(O)(OEt)2 gave 70% of the corresponding monophosꢀ
phonated product (Table 2, entry 14). Except for alkynes containing carboxylic acids or primary amino groups,
which gave no coupling products, our methodology could be also applied to ynones, propiolates and enynes (Taꢀ
ble 2, entries 15ꢀ18). Interestingly, ethynylestradiol could be converted into its alkynylphosphonate analogue in
good yield (Table 2, entry 20). On the other hand, dibutylꢀ and dimethyl phosphite could also be used as starting
Hꢀphosphonates giving the corresponding alkynylphosphonates in good yield (Table 2, entry 1). Unfortunately,
the methodology could not be extended to the synthesis of other alkynyl phosphorus derivatives such as alꢀ
kynylphosphine oxides and alkynylphosphonites. The reaction of diꢀphenylphosphine oxide with phenylacetylene
under the optimized conditions, led to a low conversion of the starting alkyne (30%) giving minor amounts of the
corresponding alkynylphosphine oxide (8%), together with a mixture of diꢀphenylvinylphosphine oxide products,
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probably coming from the hydrophosphorylation of phenylacetylene. On the other hand, the reaction of diꢀ
butylphosphonite with phenylacetylene gave no conversion of the starting alkyne.
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Taking into account that gramꢀscale synthesis of alkynylphosphonates could surely be of interest in various
fields of application, we decided to study whether our methodology could be scaledꢀup. Thus, the synthesis of
alkynylphosphonate 2a (R’ = Et) was carried out by using a twelveꢀfold amount of the reactants, giving the correꢀ
sponding crossꢀcoupling product in 75% yield (1.07 g) after 24 h of reaction time (Table 2, entry 1, footnote c).
Although the exact mechanistic pathway is difficult to ascertain at this stage, the fact that the crossꢀcoupling reꢀ
action takes place in the absence of any added base, led us to think about a plausible reaction mechanism different
from that proposed by Han et al.,11 i.e. copper acetylide species should not be the main reaction intermediates
under our reaction conditions. Moreover, it is striking to note that Han and coꢀworkers also tested Cu2O as cataꢀ
lyst, and a conversion of only 7% to the crossꢀcoupling product was observed. This could indicate that the forꢀ
mation of a copper acetylide is negligible in the presence of Cu2O and DMSO as solvent, even when K2CO3 is
being used as base.
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Table 2. Cu2Oꢀcatalyzed direct synthesis of alkynylphosphonatesa
Entry
Product
Yield (%)b
R’ = Et: 86c
R’ = Me: 90
R’ = Bu: 83
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Entry
Product
Yield (%)b
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Cl
O
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94
P
OEt
2f
OEt
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aReaction conditions: alkyne (0.5 mmol) added to a suspension of Hꢀ
phosphonate (0.7 mmol) and Cu2O (14 mol%) in MeCN (2 mL), stirred overꢀ
night at 70˚C under air. bIsolated yield after column chromatography.
cScaledꢀup synthesis of 2a (R = Et): phenylacetylene (6 mmol), (EtO)2P(O)H
(8.4 mmol), Cu2O (14 mol%) in MeCN (20 mL), 24 h, 75% yield.
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To confirm our assumptions, we carried out some additional experiments. Initially, the reaction by using copper
phenylacetylide as starting material, both in the presence or absence of Cu2O, gave no conversion into the alꢀ
kynylphosphonate 2a. In another experiment, when 1ꢀoctyne was reacted with diethyl phosphite under the optiꢀ
mized conditions, in the presence of K2CO3 or Et3N as base, a notably lower conversion to the alkynyl phosphoꢀ
nate 2h was obtained (25% and 40%, respectively) compared to that of the reaction performed in the absence of
any added base (92%, Table 2, entry 8). Finally, the synthesis of 2a (R’ = Et) under the optimized conditions, was
not affected by the addition of TEMPO as radical scavenger.
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In the light of our experimental results, and those previously reported by Han and coworkers,11 it could be inꢀ
ferred that the crossꢀcoupling reaction might take place through different pathways depending on both the source
of copper and the solvent used. Moreover, the experimental results observed when using different solvents for the
coupling reaction (Table 1), could be related to the ability of the solvent to act as a ligand for copper, thus possiꢀ
bly favouring an oxidative additionꢀreductive elimination process under our reaction conditions. Even though the
specific oxidation states and structures of the copper intermediates remain unclear, we speculate that a
Cu(I)/Cu(III) redox couple is required since the efficiency of the reaction decreased in the absence of oxygen. 15
Based on these premises, a reaction mechanism has been proposed including: (a) copper activation by the solvent
to form MeCNꢀCu(I) species, (b) reaction of Cu(I) with the dialkyl phosphite leading to copper(I) dialkyl phosꢀ
phite, (c) reaction of the latter with the terminal alkyne in the presence of oxygen to provide a Cu(II) intermediꢀ
ate, (d) oxidation of copper(II) to copper(III) and (e) subsequent reductive elimination16 to produce the alkynyl
phosphonate with the concomitant regeneration of copper(I) (Scheme 2).
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Scheme 2. Proposed reaction pathway.
CONCLUSION
In conclusion, we have described a one pot methodology for the baseꢀfree direct synthesis of alkynylphosphoꢀ
nates from commercial or readily available terminal alkynes, catalyzed by Cu2O under air atmosphere. The new
methodology showed to be compatible with a wide variety of functional groups in the starting alkynes and could
be scaledꢀup to a gramꢀscale. Although the exact mechanistic pathway remained to be studied more in detail,
based on our experimental observations and previous results reported by other authors, we assume that an oxidaꢀ
tive additionꢀreductive elimination process could take place under our reaction conditions. This new methodology
is simple, efficient and allows the direct synthesis of alkynylphosphonates with high atom economy. Further
mechanistic studies, including computational analysis using DFT, are now in progress.
EXPERIMENTAL
1. General
All starting materials were of the best available grade and were used without further purification. Column chroꢀ
matography was performed using silica gel 60 (0.040–0.063 ꢀm, 240–400 mesh). Reactions were monitored by
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thinꢀlayer chromatography on silica gel plates (60Fꢀ254) visualized under UV light and/or using 5% KMnO4 in
water.
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Nuclear magnetic resonance (NMR) spectra were recorded at 300 MHz for H NMR; 75 MHz for C NMR and
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121 MHz for P MNR; using CDCl3 as the solvent and tetramethylsilane (TMS) as internal reference. Chemical
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shifts (δ) are reported in parts per million (ppm) from tetramethylsilane (TMS) using the residual solvent resoꢀ
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nance (CDCl3: 7.26 ppm for H NMR, 77.16 ppm for C NMR). Multiplicities are abbreviated as follows: s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet; brs = broad signal). Coupling constants (J) were reportꢀ
ed in Hz.
Mass spectra (EI) were obtained at 70 eV on a GC/MS instrument equipped with a selective mass detector. Infraꢀ
red (FTꢀIR) spectra were obtained on a spectrophotometer equipped with an ATR component. Melting points are
uncorrected. The purity of volatile compounds and the chromatographic analyses (GC) were determined with a
instrument equipped with a flameꢀionisation detector and a 30 m column (0.25mm, 0.25ꢀm), using nitrogen as
carrier gas. High resolution mass spectra were recorded on a spectrometer equipped with a Orbitrap XL mass
analyzer, (for EI) and a MAT 95 (for ESI).
2. General procedure for the synthesis of alkynylphosphonates 2.
The dialkyl phosphite (0.7 mmol) was added to a brownishꢀred suspension suspension of Cu2O (10 mg, 0.07
mmol) in acetonitrile (2 mL). Then, the corresponding alkyne (0.5 mmol) was added and the reaction mixture was
warmed to 70ºC and stirred overnight under air. The reaction mixture turned a paleꢀgreen clear solution. The solꢀ
vent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica gel,
hexane/AcOEt).
3. Gram-scale synthesis of diethyl (phenylethynyl)phosphonate. Diethyl phosphite (8.4 mmol, 1082 ꢀL) was
added to a suspension of the Cu2O (60 mg, 14 mol%) in MeCN (20 mL). Then, phenylacetylene (6.0 mmol, 660
ꢀL) was added and the reaction mixture was warmed to 70 ºC overnight under air atmosphere. The solvent was
removed in vacuo and the product was purified by flash column chromatography (hexaneꢀEtOAc, 4:6) to give
diethyl (phenylethynyl)phosphonate in 75% yield (1.07 g).
4. Compound characterization data.
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All known compounds were characterized by comparison of their physical and spectroscopic data with those
described in the literature. For new compounds, copies of 1Hꢀ, 13Cꢀ and 31PꢀNMR graphical spectra are also
provided (see Supporting Information).
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Diethyl (phenylethynyl)phosphonate (2a, R = Et)17: Yellow oil. 102.4 mg, 86% yield. H NMR (300 MHz,
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CDCl3) δ 7.61 – 7.53 (m, 2H), 7.49 – 7.33 (m, 3H), 4.31 – 4.17 (m, 4H), 1.41 (t, J = 7.1 Hz, 6H). 13C NMR (75
MHz, CDCl3) δ 132.7 (d, J = 2.5 Hz), 130.8, 128.7, 119.7 (d, J = 5.7 Hz), 99.2 (d, J = 53.0 Hz), 78.5 (d, J = 300.0
Hz), 63.4 (d, J = 5.5 Hz), 16.2 (d, J = 7.0 Hz). 31P NMR (121 MHz, CDCl3) δ ꢀ5.9 ppm.
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Dimethyl (phenylethynyl)phosphonate (2a, R = Me)18: Colorless oil. 87.2 mg, 83% yield. 1H NMR (300 MHz,
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CDCl3) δ 7.55 – 7.48 (m, 2H), 7.44 – 7.28 (m, 3H), 3.79 (d, J = 12.3 Hz, 6H). C NMR (75 MHz, CDCl3) δ
132.8 (d, J = 2.5 Hz), 131.0, 128.7, 119.4 (d, J = 5.7 Hz), 100.2 (d, J = 53.4 Hz), 76.9 (d, J = 303.3 Hz), 53.6 (d, J
= 5.5 Hz). 31P NMR (121 MHz, CDCl3) δ ꢀ2.7 ppm.
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Dibutyl (phenylethynyl)phosphonate (2a, R = Bu)19: Colorless oil. 132.4 mg, 90% yield. H NMR (300 MHz,
CDCl3) δ 7.60 – 7.53 (m, 2H), 7.50 – 7.42 (m, 1H), 7.40 – 7.34 (m, 2H), 4.21 – 4.12 (m, 4H), 1.79 – 1.67 (m,
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4H), 1.53 – 1.39 (m, 4H), 0.95 (d, J = 7.4 Hz, 6H). C NMR (75 MHz, CDCl3) δ 132.8 (d, J = 2.5 Hz), 130.8,
128.7, 119.8 (d, J = 5.6 Hz), 99.2 (d, J = 52.7 Hz), 78.5 (d, J = 299.5 Hz), 67.1 (d, J = 5.9 Hz), 32.4 (d, J = 7.1
Hz), 18.9, 13.7. 31P NMR (121 MHz, CDCl3) δ ꢀ5.56 ppm.
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Diethyl (p-methylphenyl)ethynyl phosphonate (2b)17: Pale yellow oil. 112.2 mg, 89% yield. H NMR (300
MHz, CDCl3) δ 7.44 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 4.26 – 4.16 (m, 4H), 2.36 (s, 3H), 1.39 (t, J =
7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 141.3, 132.5 (d, J = 2.5 Hz), 129.3, 116.4 (d, J = 5.6 Hz), 99.6 (d, J =
53.3 Hz), 77.7 (d, J = 301.1 Hz), 63.2 (d, J = 5.5 Hz), 21.6, 16.1 (d, J = 7.0 Hz). 31P NMR (121 MHz, CDCl3) δ ꢀ
5,7 ppm.
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Diethyl (m-tolylethynyl)phosphonate (2c)20: Yellow oil. 88.2 mg, 70% yield. H NMR (300 MHz, CDCl3) δ
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7.41 – 7.33 (m, 2H), 7.30 – 7.22 (m, 2H), 4.30 – 4.17 (m, 4H), 2.35 (s, 3H), 1.41 (t, J = 7.1 Hz, 6H). C NMR
(75 MHz, CDCl3) δ 138.5, 133.2 (d, J = 2.5 Hz), 131.7, 129.9 (d, J = 2.5 Hz), 128.6, 119.4 (d, J = 5.6 Hz), 99.6
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(d, J = 53.1 Hz), 78.0 (d, J = 300.7 Hz), 63.4 (d, J = 5.5 Hz), 21.2, 16.2 (d, J = 7.0 Hz). P NMR (121 MHz,
CDCl3) δ ꢀ5.9 ppm.
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Diethyl (4-methoxyphenyl)ethynylphosphonate (2d)17: Yellow oil. 118.0 mg, 88% yield. H NMR (300 MHz,
CDCl3) δ 7.45 (d, J = 8.8 Hz, 2H), 6.82 (d, J = 8.9 Hz, 2H), 4.22 – 4.09 (m, 4H), 3.77 (s, 3H), 1.34 (t, J = 7.1
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Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 161.5, 134.4 (d, J = 2.5 Hz), 114.3, 111.3 (d, J = 5.7 Hz), 99.8 (d, J = 53.9
Hz), 77.1 (d, J = 302.3 Hz), 63.1 (d, J = 5.5 Hz), 55.4, 16.1 (d, J = 7.1 Hz). 31P NMR (121 MHz, CDCl3) δ ꢀ5.5
ppm.
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Diethyl (4-dimethylaminophenyl)ethynylphosphonate (2e)17: maroon oil. 126.5 mg, 90% yield. 1H NMR (300
MHz, CDCl3) δ 7.35 (d, J = 8.9 Hz, 2H), 6.53 (d, J = 8.9 Hz, 2H), 4.20 – 4.07 (m, 4H), 2.94 (s, 6H), 1.32 (t, J =
7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 151.6, 134.2 (d, J = 2.5 Hz), 111.5, 105.3 (d, J = 5.9 Hz), 102.3 (d, J =
54.7 Hz), 76.4 (d, J = 305.1 Hz), 63.0 (d, J = 5.4 Hz), 40.1, 16.3 (d, J = 7.1 Hz). 31P NMR (121 MHz, CDCl3) δ ꢀ
4.5 ppm.
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Diethyl (3-chlorophenyl)ethynylphosphonate (2f): Pale yellow oil. 127.9 mg, 94% yield. IR (neat): 2990, 2933,
2904, 2197, 1564, 1474, 1274, 1021, 976, 902, 796 cmꢀ1. 1H NMR (300 MHz, CDCl3) δ 7.52 (s, 1H), 7.47 – 7.37
(m, 2H), 7.35 – 7.26 (m, 1H), 4.26 – 4.16 (m, 4H), 1.39 (t, J = 7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 134.6,
132.4 (d, J = 2.6 Hz), 131.1, 130.8 (d, J = 2.4 Hz), 130.0, 121.4 (d, J = 5.7 Hz), 97.1 (d, J = 52.5 Hz), 79.7 (d, J =
298.0 Hz), 63.5 (d, J = 5.6 Hz), 16.2 (d, J = 6.9 Hz). 31P NMR (121 MHz, CDCl3) δ ꢀ6,7 ppm. MS: m/z = 272
(M+, 5%), 244 (11), 229 (12), 216 (15), 209 (10), 201 (11), 199 (25), 165 (14), 164 (13), 163 (27), 162 (28), 155
(10), 154 (11), 145 (13), 139 (18), 138 (40), 137 (15), 136 (100), 129 (11), 128 (12), 123 (19), 107 (12), 101 (13),
89 (14), 75 (11). HRMS (EI) calcd for C12H14ClO3P 272.0369, found 272.0374.
Diethyl (3-trifluoromethylphenyl)ethynylphosphonate (2g): Pale yellow oil. 128.5 mg, 84% yield. IR (neat):
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2990, 2937, 2908, 2197, 1319, 1270, 1139, 1029, 874, 775 cmꢀ1. H NMR (300 MHz, CDCl3) δ 7.74 – 7.64 (m,
2H), 7.58 – 7.49 (m, 2H), 4.29 – 4.13 (m, 4H), 1.37 (t, J = 7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 135.2 (d, J
= 2.7 Hz), 132.7 (qd, J = 31.1, 1.7 Hz), 131.8, 130.6, 126.2 (q, J = 5.0 Hz), 123.1 (q, J = 273.6 Hz), 117.9 – 117.7
(m), 94.1 (d, J = 51.8 Hz), 83.8 (d, J = 293.0 Hz), 63.6 (d, J = 5.7 Hz), 16.1 (d, J = 7.1 Hz). 31P NMR (121 MHz,
CDCl3) δ ꢀ7.3 ppm. MS: m/z = 306 (M+, 3%), 286 (14), 279 (11), 278 (18), 277 (11), 250 (26), 248 (17), 239 (10),
238 (34), 237 (10), 233 (12), 214 (10), 213 (33), 211 (35), 210 (13), 209 (17), 197 (25), 196 (16), 186 (16), 185
(51), 177 (39), 174 (11), 171 (11), 170 (100), 169 (45), 159 (10), 158(12), 157 (38), 155(17), 151 (45), 138 (35),
137 (11), 128 (13), 120 (10), 119 (10), 116 (13), 99 (10), 88 (10). HRMS (EI) calcd for C13H14F3O3P 306.0633,
found 306.0638.
Diethyl oct-1-yn-1-ylphosphonate (2h)21: Yellow oil. 113.2 mg, 92% yield. 1H NMR (300 MHz, CDCl3) δ 4.21
– 4.08 (m, 4H), 2.34 (td, J = 7.1, 4.4 Hz, 2H), 1.65 – 1.52 (m, 2H), 1.43 – 1.25 (m, 6H), 1.37 (t, J = 7.1 Hz,
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6H), 0.89 (t, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 103.4 (d, J = 53.2 Hz), 70.5 (d, J = 303.9 Hz), 63.0
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(d, J = 5.5 Hz), 31.2, 28.5, 27.5 (d, J = 2.2 Hz), 22.5, 19.3 (d, J = 4.5 Hz), 16.1 (d, J = 7.1 Hz), 14.0. P NMR
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(121 MHz, CDCl3) δ ꢀ6.1 ppm.
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Diethyl (5-chloropent-1-yn-1-yl)phosphonate (2i): Colorless oil. 115.5 mg, 97% yield. IR (neat): 2986, 2929,
2904, 2206, 1262, 1160, 1029, 972, 800, 771 cmꢀ1. 1H NMR (300 MHz, CDCl3) δ 4.24 – 4.07 (m, 4H), 3.65 (t, J
= 6.2 Hz, 2H), 2.57 (td, J = 6.9, 4.4 Hz, 2H), 2.10 – 2.02 (m, 2H), 1.37 (t, J = 7.1 Hz, 6H).13C NMR (75 MHz,
CDCl3) δ 100.9 (d, J = 53.0 Hz), 71.6 (d, J = 302.4 Hz), 63.2 (d, J = 5.5 Hz), 43.2, 30.2 (d, J = 2.3 Hz), 16.7 (d, J
= 4.6 Hz), 16.1 (d, J = 7.0 Hz). 31P NMR (121 MHz, CDCl3) δ ꢀ6.7 ppm. MS: m/z = 238 (M+, 1%), 185 (10), 183
(33), 176 (33), 175 (23), 165 (10), 161 (10), 149 (12), 148 (100), 147 (46), 133 (10), 129 (16), 120 (14), 93 (21),
91 (10), 83 (10), 81 (11), 66 (11), 65 (45). HRMS (EI) calcd for C9H16ClO3P 238.0526, found 238.0531.
Diethyl (5-cyanopent-1-yn-1-yl)phosphonate (2j): Pale yellow oil. 91.6 mg, 80% yield. IR (neat): 2978, 2929,
2896, 2242, 2210, 1254, 1041, 967 cmꢀ1. 1H NMR (300 MHz, CDCl3) δ 4.19 – 4.06 (m, 4H), 2.57 – 2.42 (m, 4H),
1.99 – 1.86 (m, 2H), 1.34 (t, J = 7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 118.5, 99.5 (d, J = 52.7 Hz), 72.6 (d,
J = 301.5 Hz), 63.3 (d, J = 5.6 Hz), 23.5 (d, J = 2.4 Hz), 18.3 (d, J = 4.5 Hz), 16.2 (d, J = 7.2 Hz), 16.1 (d, J = 7.0
Hz). 31P NMR (121 MHz, CDCl3) δ ꢀ7.1 ppm. MS: m/z = 229 (M+, 1%), 185 (11), 183 (100), 157 (14), 156 (36),
155 (21), 144 (47), 143 (98), 142 (30), 131 (17), 130 (52), 129 (21), 128 (20), 127 (21), 118 (16), 117 (62), 116
(60), 115 (99), 104 (55), 103 (76), 102 (24), 91 (53), 90 (19), 89 (63), 78 (27), 77 (68), 76 (21), 75 (21), 74 (18),
65 (15), 64 (13), 63 (48), 62 (14), 51 (24), 50 (16). HRMS (EI) calcd for C10H16NO3P 229.0868, found 229.0875.
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Diethyl (3-hydroxyprop-1-yn-1-yl)phosphonate (2k)22: Pale yellow oil. 61.5 mg, 64% yield. H NMR (300
MHz, CDCl3) δ 4.84 (s, 1H), 4.34 (d, J = 3.8 Hz, 2H), 4.20 – 4.10 (m, 4H), 1.35 (t, J = 7.1 Hz, 6H). 13C NMR (75
MHz, CDCl3) δ 100.4 (d, J = 50.6 Hz), 74.1 (d, J = 298.7 Hz), 63.6 (d, J = 5.6 Hz), 50.6 (d, J = 4.4 Hz), 16.1 (d, J
= 7.1 Hz). 31P NMR (121 MHz, CDCl3) δ ꢀ6.8 ppm.
Diethyl (4-hydroxybut-1-yn-1-yl)phosphonate (2l): Yellow oil. 74.2 mg, 72% yield. IR (neat): 3399, 2986,
2933, 2908, 2210, 1245, 1164, 1029, 980 cmꢀ1. 1H NMR (300 MHz, CDCl3) δ 4.85 (s, 1H), 4.22 – 4.07 (m, 4H),
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3.79 (t, J = 6.5 Hz, 2H), 2.61 (td, J = 6.4, 4.6 Hz, 2H), 1.37 (t, J = 7.2 Hz, 6H). C NMR (75 MHz, CDCl3) δ
101.1 (d, J = 53.2 Hz), 71.4 (d, J = 302.8 Hz), 63.3 (d, J = 5.5 Hz), 59.8 (d, J = 2.5 Hz), 23.6 (d, J = 4.5 Hz), 16.1
(d, J = 7.1 Hz).31P NMR (121 MHz, CDCl3) δ ꢀ6.3 ppm. MS: m/z = 206 (M+, 1%), 176 (53), 148 (45), 147 (25),
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133 (23), 121 (13), 120 (100), 115 (12), 102 (21), 81 (10), 65 (13). HRMS (EI) calcd for C8H15O4P 206.0708,
found 206.0711.
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Diethyl 3-(tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-ylphosphonate (2m): Pale yellow oil. 109.1 mg, 79%
yield. IR (neat): 2949, 2210, 1270, 1123, 1033, 976 cmꢀ1. 1H NMR (300 MHz, CDCl3) δ 4.79 (t, J = 2.8 Hz, 1H),
4.36 (d, J = 3.8 Hz, 2H), 4.21 – 4.12 (m, 4H), 3.86 – 3.76 (m, 1H), 3.58 – 3.49 (m, 1H), 1.81 – 1.51 (m, 6H), 1.37
(t, J = 7.0 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 97.4, 96.9 (d, J = 50.3 Hz), 75.8 (d, J = 295.5 Hz), 63.4 (d, J =
5.5 Hz), 62.2, 54.0 (d, J = 4.4 Hz), 30.2, 25.4, 18.9, 16.2 (d, J = 7.0 Hz). 31P NMR (121 MHz, CDCl3) δ ꢀ7.3 ppm.
MS: m/z = 276 (M+, 1%), 275 (12), 221 (81), 203 (18), 193 (52), 192 (20), 191 (28), 177 (15), 165 (100), 163
(18), 162 (12), 149 (11), 148 (48), 147 (43), 146 (25), 137 (21), 136 (16), 135 (26), 134 (13), 121 (13), 120 (43),
119 (29), 107 (10), 103 (37), 102 (18), 85 (18), 84 (15), 83 (14), 82 (10), 81 (14), 65 (18), 56 (10), 55 (44).
HRMS (EI) calcd for C12H21O5P 276.1127, found 276.1130.
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Diethyl nona-1,8-diyn-1-ylphosphonate (2n): Colorless oil. 87.1 mg, 68% yield. IR (neat): 3301, 2990, 2937,
2855, 2206, 1258, 1045, 967 cmꢀ1. 1H NMR (300 MHz, CDCl3) δ 4.22 – 4.06 (m, 4H), 2.42 – 2.32 (m, 2H), 2.26
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– 2.15 (m, 2H), 1.96 (t, J = 2.6 Hz, 1H), 1.66 – 1.50 (m, 6H), 1.37 (t, J = 7.2 Hz, 6H). C NMR (75 MHz,
CDCl3) δ 103.0 (d, J = 53.3 Hz), 84.1, 70.5 (d, J = 304.1 Hz), 68.6, 63.1 (d, J = 5.5 Hz), 27.9, 27.8, 27.0 (d, J =
2.2 Hz), 19.2 (d, J = 4.5 Hz), 18.2, 16.1 (d, J = 7.1 Hz). 31P NMR (121 MHz, CDCl3) δ ꢀ6.3 ppm. MS: m/z = 256
(M+, 1%), 207 (10), 200 (31), 199 (32), 185 (12), 172 (24), 171 (10), 161 (12), 148 (19), 147 (21), 145 (12), 135
(10), 133 (21), 131 (24), 121 (11), 120 (39), 119 (31), 118 (60), 117 (100), 115 (20), 105 (17), 103 (12), 102 (12),
93 (10), 92 (11), 91 (57), 81 (16), 79 (30), 77 (19), 65 (21), 53 (10). HRMS (EI) calcd for C13H21O3P 256.1228,
found 256.1231.
Diethyl (3-oxobut-1-yn-1-yl)phosphonate (2o): Yellow oil. 96.9 mg, 95% yield. IR (neat): 2990, 2921, 2839,
1687, 1266, 1204, 1021, 980, 857 cmꢀ1. 1H NMR (300 MHz, CDCl3) δ 4.29 – 4.15 (m, 4H), 2.43 (s, 3H), 1.40 (t, J
= 7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 182.5 (d, J = 4.3 Hz), 92.7 (d, J = 43.0 Hz), 77.8 (d, J = 278.1 Hz),
64.2 (d, J = 5.7 Hz), 32.5, 16.2 (d, J = 6.8 Hz).31P NMR (121 MHz, CDCl3) δ ꢀ9.1 ppm. MS: m/z = 204 (M+, 1%),
189 (31), 177 (18), 175 (13), 161 (71), 159 (30), 149 (81), 148 (49), 147 (39), 135 (25), 134 (100), 133 (88), 131
(14), 131 (67), 121 (11), 117 (13), 116 (11), 115 (20), 109 (15), 107 (47), 99 (10), 96 (11), 95 (30), 93 (21), 91
(14), 89 (59), 85 (11), 81 (27), 79 (11), 78 (13), 69 (10), 65 (46), 53 (44). HRMS (EI) calcd for C8H13O4P
204.0551, found 204.0555.
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Methyl 3-(diethoxyphosphoryl)propiolate (2p): Pale yellow oil. 106.7 mg, 97% yield. IR (neat): 2990, 2962,
2132, 1732, 1433, 1282, 1164, 1045, 984, 882 cmꢀ1. 1H NMR (300 MHz, CDCl3) δ 4.29 – 4.13 (m, 4H), 3.83 (s,
3H), 1.38 (t, J = 7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 152.1 (d, J = 5.9 Hz), 86.5 (d, J = 46.6 Hz), 75.5 (d, J
= 279.1 Hz), 64.3 (d, J = 5.7 Hz), 53.6, 16.2 (d, J = 6.8 Hz). 31P NMR (121 MHz, CDCl3) δ ꢀ9.8 ppm. MS: m/z =
220 (M+, 1%), 193 (13), 189 (47), 177 (13), 175 (13), 165 (58), 162 (16), 161 (33), 160 (21), 147 (56), 135 (83),
134 (82), 133 (100), 132 (14), 118 (13), 116 (16), 115 (25), 81 (24), 80 (24), 79 (39), 69 (11), 65 (32), 53 (32).
HRMS (EI) calcd for C8H13O5P 220.0501, found 220.0508.
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(E)-Diethyl (5-methoxy-3-methylpent-3-en-1-yn-1-yl)phosphonate (2q): Yellow oil. 116.9 mg, 95% yield. IR
(neat): 2982, 2933, 2908, 1650, 1474, 1249, 1168, 1029, 976, 861 cmꢀ1. 1H NMR (300 MHz, CDCl3) δ 6.17 (t, J =
6.2 Hz, 1H), 4.17 – 4.03 (m, 4H), 3.97 (d, J = 6.3 Hz, 2H), 3.28 (s, 3H), 1.78 (s, 3H), 1.31 (t, J = 7.1 Hz, 6H). 13C
NMR (75 MHz, CDCl3) δ 140.2 (d, J = 3.4 Hz), 118.4 (d, J = 5.9 Hz), 101.1 (d, J = 52.1 Hz), 76.2 (d, J = 300.3
Hz), 68.6, 63.3 (d, J = 5.5 Hz), 58.6, 16.8 (d, J = 1.8 Hz), 16.2 (d, J = 7.0 Hz). 31P NMR (121 MHz, CDCl3) δ ꢀ5.9
ppm. MS: m/z = 246 (M+, 68%), 231 (55), 218 (16), 217 (28), 203 (38), 190 (12), 189 (29), 175 (100), 171 (20),
161 (22), 160 (11), 159 (20), 157 (96), 147 (14), 143 (12), 141 (21), 129 (17), 109 (28), 95 (34), 91 (10), 81 (14),
79 (35), 78 (17), 77 (39), 67 (19), 66 (10), 65 (30), 53 (10), 51 (15). HRMS (EI) calcd for C11H19O4P 246.1021,
found 246.1024.
Diethyl (cyclohex-1-en-1-yl)ethynylphosphonate (2r): Pale yellow oil. 112.6 mg, 93% yield. IR (neat): 2984,
2937, 2868, 2173, 1687, 1258, 1160, 1037, 984 cmꢀ1. 1H NMR (300 MHz, CDCl3) δ 6.42 (s, 1H), 4.21 – 4.07 (m,
4H), 2.15 – 2.10 (m, 4H), 1.65 – 1.55 (m, 4H), 1.35 (t, J = 7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 142.0 (d, J
= 3.3 Hz), 118.5 (d, J = 5.9 Hz), 101.6 (d, J = 52.8 Hz), 75.7 (d, J = 302.8 Hz), 63.1 (d, J = 5.4 Hz), 28.0 (d, J =
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1.6 Hz), 26.0, 21.9, 21.1, 16.2 (d, J = 7.1 Hz). P NMR (121 MHz, CDCl3) δ ꢀ5.2 ppm. MS: m/z = 242 (M+,
64%), 241 (27), 214 (28), 213 (45), 207 (30), 199 (16), 197 (22), 187 (12), 186 (76), 185 (72), 171 (11), 170 (20),
169 (42), 159 (10), 158 (11), 150 (16), 149 (22), 145 (15), 135 (17), 134 (25), 133 (40), 132 (35), 131 (34), 122
(13), 121 (13), 120 (16), 119 (15), 117 (44), 107 (21), 106 (98), 105 (91), 104 (70), 103 (69), 102 (12), 93 (14),
92 (15), 91 (100), 89 (12), 81 (12), 79 (36), 78 (48), 77 (66), 65 (31), 63 (11), 55 (13), 51 (13). HRMS (EI) calcd
for C12H19O3P 242.1072, found 242.1075.
Diethyl (3-(1,3-dioxoisoindolin-2-yl)prop-1-yn-1-yl)phosphonate (2s): White solid; mp 76.0 – 78.2 ºC. 141.3
mg, 88% yield. IR (KBr): 2990, 2962, 2921, 2218, 1715, 1609, 1425, 1258, 1119, 1045, 1021, 963, 726, 665
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cmꢀ1. H NMR (300 MHz, CDCl3) δ 7.92 – 7.86 (m, 2H), 7.80 – 7.74 (m, 2H), 4.58 (d, J = 3.9 Hz, 2H), 4.23 –
4.07 (m, 4H), 1.36 (t, J = 7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 166.5, 134.5, 131.8, 123.8, 93.5 (d, J = 50.6
Hz), 73.5 (d, J = 293.5 Hz), 63.5 (d, J = 5.5 Hz), 27.3 (d, J = 4.6 Hz), 16.1 (d, J = 7.0 Hz). 31P NMR (121 MHz,
CDCl3) δ ꢀ7.8 ppm. MS: m/z = 321 (M+, 1%), 293 (11), 292 (10), 276 (13), 265 (10), 248 (19), 214 (17), 213
(100), 212 (26), 186 (11), 185 (31), 184 (66), 161 (12), 160 (40), 157 (13), 156 (11), 148 (10), 146 (34), 133 (15),
130 (71), 129 (11), 119 (11), 105 (16), 104 (42), 102 (17), 77 (13), 76 (32). HRMS (EI) calcd for C15H16NO5P
321.0766, found 321.0772.
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Diethyl [(8R,9S,13S,14S,17S)-3,17-dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-
cyclopenta[a]phenanthren-17-yl]ethynylphosphonate (2t): Pale yellow solid; mp 79.5 – 82.0 ºC. 170.7 mg,
1
79% yield. IR (KBr): 3321, 2986, 2937, 2872, 2197, 1617, 1511, 1450, 1241, 1025, 980, 816 cmꢀ1. H NMR (300
MHz, CDCl3) δ 7.02 (d, J = 8.5 Hz, 1H), 6.67 (dd, J = 8.5, 2.4 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 4.27 – 4.14 (m,
4H), 2.82 – 2.69 (m, 2H), 2.41 – 2.27 (m, 1H), 2.20 – 2.10 (m, 1H), 2.07 – 1.97 (m, 2H), 1.94 – 1.83 (m, 1H),
1.82 – 1.68 (m, 4H), 1.61 – 1.48 (m, 1H), 1.45 – 1.33 (m, 3H), 1.39 (td, J = 7.0, 2.8 Hz, 6H), 0.86 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ 154.5, 137.8, 131.5, 126.5, 115.3, 112.9, 105.3 (d, J = 49.5 Hz), 80.3 (d, J = 3.8 Hz),
75.3 (d, J = 314.0 Hz), 63.7 (dd, J = 5.5, 1.2 Hz), 50.2, 48.0, 43.3, 39.4, 38.7, 31.1, 29.7, 27.4, 26.4, 23.1, 16.3
(dd, J = 6.9, 1.2 Hz), 12.8. 31P NMR (121 MHz, CDCl3) δ ꢀ6.2 ppm. (The signal corresponding to OH were not
observed). MS: m/z = 432 (M+, 1%), 271 (20), 270 (100), 214 (10), 213 (21), 186 (12), 185 (34), 172 (27), 160
(16), 159 (17), 158 (12), 157 (15), 146 (31), 145 (18), 144 (10), 133 (12), 131 (11), 115 (12). HRMS (EI) calcd
for C24H33O5P 432.2066, found 432.2065.
Supporting Information.
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Copies of Hꢀ, Cꢀ and PꢀNMR spectra of all alkynylphosphonate products. This material is available free of
charge via the Internet at http://pubs.acs.org.
Corresponding Author.
Eꢀmail: gradivoy@criba.edu.ar; ymoglie@uns.edu.ar
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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This work was generously supported by the Consejo Nacional de Investigaciones Científicas y Técnicas
(CONICET, PIPꢀ2011ꢀ11220100100268), Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT,
Préstamo BID PICTꢀ2010ꢀ0669) and Universidad Nacional del Sur (UNS, PGI 24/Q044) from Argentina. V.G.
thanks the CONICET for a postdoctoral fellowship.
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