Phosphine-catalyzed addition of P(O)-H compounds to ethyl phenylpropiolate

Article abstract of DOI:10.1016/j.tetlet.2015.09.137

An efficient PBu₃-catalyzed α-addition of the P(O)-H bond to ethyl phenylpropiolate has been developed. This strategy offers a facile method for the preparation of synthetically useful alkenyl phosphonates and phosphinates proceeding under neut

Full text of DOI:10.1016/j.tetlet.2015.09.137

Accepted Manuscript
Phosphine-Catalyzed Addition of P(O)–H Compounds to Ethyl Phenylpropio-
late
Alexey V. Salin, Anton V. Il’in, Fanuza G. Shamsutdinova, Albert R.
Fatkhutdinov, Vladimir I. Galkin, Daut R. Islamov, Olga N. Kataeva
PII:
S0040-4039(15)30178-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.137
TETL 46809
Reference:
Tetrahedron Letters
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8 June 2015
24 September 2015
28 September 2015
Please cite this article as: Salin, A.V., Il’in, A.V., Shamsutdinova, F.G., Fatkhutdinov, A.R., Galkin, V.I., Islamov,
D.R., Kataeva, O.N., Phosphine-Catalyzed Addition of P(O)–H Compounds to Ethyl Phenylpropiolate, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.09.137
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Graphical abstract

Phosphine-Catalyzed Addition of P(O)–H Compounds to Ethyl
Phenylpropiolate
Alexey V. Salin,a,* Anton V. Il'in,a Fanuza G. Shamsutdinova,a
Albert R. Fatkhutdinov,a Vladimir I. Galkin,a Daut R. Islamov,a Olga N. Kataevab
aA.M. Butlerov Institute of Chemistry, Kazan Federal University,
Kremlevskaya str. 18, Kazan, 420008, Russia
bA.E. Arbuzov Institute of Organic and Physical Chemistry,
Russian Academy of Sciences, Arbuzov str. 8, Kazan, 420088, Russia
Tel.: +7432337416; fax: +7432387901; E-mail: salin555@mail.ru
Abstract
An efficient PBu3-catalyzed α-addition of the P(O)–H bond to ethyl
phenylpropiolate has been developed. This strategy offers a facile method for the
preparation of synthetically useful alkenyl phosphonates and phosphinates
proceeding under neutral reaction conditions with high atom economy.
Keywords: α-Addition, Acetylenes, Phosphine organocatalysis, X-Ray analysis
Introduction
During the past decades, tertiary phosphines have been recognized as
versatile nucleophilic catalysts for a wide variety of synthetically useful
transformations of electron-deficient alkenes, allenes, and alkynes.1 In comparison
with nitrogen nucleophiles, tertiary phosphines in many cases show divergent
catalytic behavior which mainly results from their stronger nucleophilic properties
along with weaker basic character, the ability to play the role of a good leaving
group, as well as their unique potential to form ylide-type intermediates. For
example, phosphines are known to alter the regioselectivity of nucleophilic
addition to electron-deficient alkynes from the Michael-type β-addition to a non-
classical α-addition (Scheme 1).
Scheme 1. Reactivity patterns for nucleophilic addition to electron-deficient
alkynes.

The pioneering work in this field by Trost and Dake2 introduced nitrogen
pronucleophiles at the α-position of propiolate esters using PPh3 as a catalyst, and
was later expanded by Tomita and co-workers who utilized this methodology for
oxygen pronucleophiles.3 More recently, Taran and co-workers reported the first α-
addition of phosphorus pronucleophiles; dialkyl phosphites, H-phosphinates, and
secondary phosphine oxides to alkynes activated by a phosphine oxide moiety in
the presence of PBu3, providing a new strategy to construct pharmacologically
active geminal bisphosphonates.4 However, a limited number of electron-deficient
alkynes and nucleophilic reagents have been shown to react with each other to
furnish α-addition products.
Inspired by the elegant work of Taran and co-workers4 we wished to expand
the scope of the phosphine-catalyzed α-addition of dialkyl phosphites and H-
phosphinates using ethyl phenylpropiolate as an electrophilic partner. The resultant
multifunctional alkenes (currently accessible by somewhat tedious synthetic
procedures) would be useful skeletal motifs for further chemical manipulations
aimed at the synthesis of biologically active molecules such as cyclopropane
phosphonic acids,5 thiochomenes,6 pyrrolizine-3-ones.7 The presence of an ester
group makes the anticipated products readily convertible to phosphonate- and
phosphinate-containing carboxylic acids, of which there are many examples
presently used as drugs for the treatment of various diseases.8 Moreover,
phosphorylated carboxylic acids attract considerable interest due to their ability to
serve as ligands for chelating metal cations.9
It is well known that the success of phosphine-catalyzed transformations
largely depends on the efficiency of the initial nucleophilic addition of phosphine
to the electron-deficient alkene, allene, or alkyne to generate a reactive
phosphonium zwitterionic intermediate.1 Ethyl phenylpropiolate, which is
activated by a carbonyl moiety, was expected to react more rapidly with a tertiary
phosphine and therefore undergo subsequent α-addition of a dialkyl phosphite or
H-phosphinate more readily than alkynes bearing a phosphine oxide activating
moiety as previously employed by Taran and co-workers.4 At the same time, the
increased electrophilicity of the alkyne bond also favors nucleophilic addition at
the β-position, and deprotonated dialkyl phosphites are known to react readily with
propiolates and afford mono- and bisphosphorylated esters in a Michael fashion.10
Since tertiary phosphines can also serve as catalysts for Michael addition to
activated alkyne bonds,1b questions regarding the reaction’s regioselectivity remain
controversial, i.e. α-addition versus the β-addition, and the synthetic outcome
might be determined by the thermodynamic and/or kinetic preference of the two
possible pathways.
Results and Discussion
At the outset, diethyl phosphite 1a was reacted with ethyl phenylpropiolate 2
in the presence of PBu3 (20 mol%) using MeCN as a solvent. Diethyl phosphite
was selected as the P(O)–H component for the model reaction, as both the products

of possible α- and β-additions have previously been obtained via alternative
synthetic procedures and characterized with relevant spectroscopic data.6,11
Analysis of the 31P{1H} NMR spectrum of the crude reaction mixture after stirring
for 1 h at room temperature revealed that the addition proceeded with complete
regioselectivity (as indicated by a singlet at 13.5 ppm) and 69% conversion of
diethyl phosphite. However, prolonged reaction times did not substantially
enhance the conversion. The spectroscopic data of the isolated product 3a were
consistent with that reported earlier for (E)-ethyl-2-(diethoxyphosphoryl)-3-
phenylacrylate6,11b clearly implying that addition had occurred at the α-position of
the propiolate ester (Scheme 2).
Scheme 2. Reaction of diethyl phosphite with ethyl phenylpropiolate in the
presence of PBu3.
1
Most notably, analysis of the H NMR spectrum showed a diagnostic
doublet, centered at 7.66 ppm (3JPH=24.1 Hz), from the strongly deshielded ethenyl
proton, indicating its geminal position relative to the phenyl substituent. If addition
had occurred at the β-position, the signal of the ethenyl proton would be expected
to shift upfield by nearly 1 ppm.11c A small amount of the (Z)-isomeric α-addition
product, (Z)-ethyl-2-(diethoxyphosphoryl)-3-phenylacrylate, was also detected in
the crude reaction mixture (4 %) and present in the isolated material.
Next, optimization of the reaction conditions was performed (Table 1).
Increasing the catalyst loading from 20 mol% to 30 mol% gave an increased yield
(entry 2), however further increases showed no improvement (entry 3). No reaction
was observed when PBu3 was replaced with less nucleophilic PPh3 (Table 1, entry
4).
Table 1. Reaction condition optimization for the phosphine-catalyzed α-addition of
diethyl phosphite to ethyl phenylpropiolatea
Entry Catalyst (mol%)
Solvent
MeCN
MeCN
MeCN
MeCN
C6H6
EtOH
i-PrOH
DMF
Conversionb (%)
1
2
3
4
5
6
7
8
9
PBu3 (20)
PBu3 (30)
PBu3 (40)
PPh3 (30)
PBu3 (30)
PBu3 (30)
PBu3 (30)
PBu3 (30)
PBu3 (30)
69
79
79
0
67
75
74
76
31
DMSO

10
PBu3 (30)
THF
58
aReagents and conditions: diethyl phosphite (1 mmol), ethyl phenylpropiolate (1
mmol), solvent (2 mL), room temperature, 1 h.
bDetermined by 31P NMR spectroscopy and based on both E and Z isomers.
A solvent screen revealed that a variety of solvents could be employed for
this reaction; polar and nonpolar, protic and aprotic solvents were all suitable
(Table 1, entries 5-10), however, none gave better conversion to the desired
product than MeCN (Table 1, entry 2). This observation differed from the solvent
effect observed for α-addition of P(O)–H bonds to alkynes activated by the
phosphine oxide moiety,4 where the use of a proton donor solvent (EtOH) was
essential to achieve high yields of the desired products.12 The less pronounced
solvent effect using ethyl phenylpropiolate as the substrate was likely to result
from the higher electron deficiency of this alkyne leading to increased
concentration (and lifetime) of the intermediate phosphonium zwitterion, which is
responsible for continuation of the catalytic cycle.
Thus, the optimal reaction conditions were determined as PBu3 (30 mol%),
MeCN at room temperature. With the optimal reaction conditions in hand, the
scope of this transformation was explored using a variety of P(O)–H compounds
(Scheme 3, Table 2).
Scheme 3. PBu3-Catalyzed α-addition of the P(O)–H bond to ethyl
phenylpropiolate.
The reaction was found to be quite general with respect to the P(O)–H
component. Surprisingly, even diisopropyl phosphite possessing a P(O)–H bond
about ten times less acidic than diethyl phosphite13 afforded the corresponding α-
addition product 3c in good yield after the same reaction period (Table 2, entry 3).
Similarly, the introduction of long chain alkoxy groups at the phosphorus atom did
not impact the reaction efficiency (Table 2, entries 6, 7). This was noteworthy
since phosphonates containing lipophilic alkoxy groups constitute an important
class of compounds for rare earth metal extraction,14 and their preparation remains
a significant challenge in organophosphorus chemistry. Ethyl phenylphosphinate
bearing a phenyl group attached to the phosphorus atom was also found to be
suitable for this transformation, furnishing alkenyl phosphinate 3h in a
synthetically useful yield of 72% (Table 2, entry 8). All the reactions were slightly
exothermic, as judged by handling of the reaction flask, and to avoid overheating
and the promotion of side reactions, the mixtures were kept in a water bath at room
temperature during the reaction.

Table 2. Substrate scope for the PBu3-catalyzed α-addition of P(O)–H bonds to
ethyl phenylpropiolatea
Entry
R1
R2
Product Yieldb (%) E/Z ratio
1
2
3
4
5
6
7
8
EtO
EtO
73
90
72
83
88
82
84
72
96:4
95:5
98:2
96:4
96:4
96:4
96:4
95:5
3a
3b
3c
3d
3e
3f
MeO
i-PrO
BuO
i-BuO
MeO
i-PrO
BuO
i-BuO
n-C7H15O n-C7H15O
C8H17Oc
EtO
C8H17Oc
Ph
3g
3h
aReagents and conditions: P(O)–H compound (10 mmol), ethyl phenylpropiolate
(10 mmol), PBu3 (30 mol%), MeCN (15 mL), room temperature, 1 h.
bIsolated yield.
cC8H17O = CH3(CH2)3CH(C2H5)CH2O.
The reactions proceeded stereoselectively and primarily afforded the more
thermodynamically stable E-isomeric products, with E/Z ratios of at least 95:5
(Table 2). The E configuration of the synthesized compounds was assigned on the
1
basis of H NMR spectra which showed doublets for the ethenyl protons with
3
coupling constants of JPH 21.1-24.6 Hz, typical for a cis-orientation of the
phosphorus and hydrogen atoms around the alkene bond. The structure and
configuration of the crystalline product 3c were unequivocally confirmed by
single-crystal X-ray analysis (Figure 1).
Figure 1. ORTEP representation of 3c showing 50% probability thermal
ellipsoids; disorder of the ethyl group was omitted for clarity.
It should be noted that α-addition of the P(O)–H bond to ethyl
phenylpropiolate was found to be exclusively compatible with phosphine catalysis,
since the reaction did not proceed in the presence of nitrogen nucleophiles such as

Et3N, DABCO, or DBU. These amines were also not sufficiently basic to initiate
Michael-type additions.
Although a detailed mechanism of the reactions studied has not been
rigorously proven, according to the experimental results and literature precedent,
we propose a possible mechanism for this reaction, as outlined in Scheme 4.
Scheme 4. Proposed catalytic cycle.
Attack of a phosphine at the β-carbon atom of ethyl phenylpropiolate
initially generates zwitterionic intermediate 4. This zwitterion deprotonates the
phosphite (phosphonite) tautomeric form 1' of the P(O)–H compound to give
vinylphosphonium salt 5, in which the α-carbon atom becomes electrophilic and
undergoes attack of anion 6 affording phosphorus ylide 7. A [1,2]-prototropic shift
in ylide 7 and subsequent elimination of phosphine gives the resulting product 3.
Further phosphine-catalyzed addition of a second molecule of the P(O)–H
compound to bisactivated alkene 3 was not observed even when a twofold excess
of dialkyl phosphite or alkyl phosphinate was used. This was probably due to steric
hindrance at the β-carbon atom caused by the presence of the phenyl substituent.
Previous attempts to utilize cinnamates in phosphine-catalyzed phosphorylation
were also unsuccessful.15 This mechanism featuring the vinylphosphonium salt and
phosphorus ylide as key intermediates readily explains why α-addition could not
be catalyzed by amine nucleophiles.

The high regioselectivity for 3 in the studied reactions was quite remarkable.
It was speculated, that if the reaction conditions favored thermodynamic control,
nucleophilic attack of anion 6 on the α-carbon atom of vinylphosphonium salt 5
leading to product 3 would be preferred in comparison to attack on the β-carbon
atom of ethyl phenylpropiolate, since ylide 7 would be expected to be more stable
than intermediate 8 in which the carbanion centre is stabilized only by the adjacent
ester group (Scheme 4). Most probably, the formation of α-addition product 3 is
also kinetically preferred, since attempts to detect β-addition product 9 at low
temperature (–20 oC) were unsuccessful, and again, only isomer 3 was observed.
In conclusion, we have reported an efficient α-addition of the P(O)–H bond
to ethyl phenylpropiolate using PBu3 as the catalyst. This reaction provides a one-
step approach to access synthetically useful alkenyl phosphonates and
phosphinates 3 from readily available starting materials without generating waste
or by-products.16 Good chemical tolerance of the phosphine-catalyzed
transformation has also been demonstrated by the application of structurally
different P(O)–H compounds.
Acknowledgments
This research was supported by a grant of Russian Foundation for Basic
Research (project 15-33-20067 a). D.R.I. and O.N.K. are thankful for the Russian
Government Program of the Competitive Growth of Kazan Federal University.
Supplementary data
Experimental procedures for synthesis and full characterization for
13
31
compounds 3a-h, copies of 1H, C{1H}, P{1H} NMR spectra for 3a-h, and table
with X-ray crystallographic data for 3c. CCDC 1405145 (3c) contains the
supplementary crystallographic data for this paper. These data can be obtained free
of
charge
from
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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16. A previous general method for the preparation of alkenyl phosphonates
involved the Arbuzov reaction of trialkyl phosphite with 2-bromoethyl acetate,
followed by the titanium mediated Knoevenagel condensation of the obtained 2-
(dialkoxyphosphoryl)acetate with benzaldehyde; this method gave lower product
yields within longer reaction times.6,11a