Tributylphosphine catalyzed addition of diphenylphosphine oxide to unsubstituted and substituted electron-deficient alkenes

Article abstract of DOI:10.1016/j.tetlet.2018.03.040

The PBu₃-catalyzed conjugate addition of diphenylphosphine oxide to unsubstituted and substituted electron-deficient alkenes is reported. β-Substituted α,β-unsaturated esters, trans-methyl crotonate and trans-methyl cinnamate, known for their r

Full text of DOI:10.1016/j.tetlet.2018.03.040

Accepted Manuscript
Tributylphosphine Catalyzed Addition of Diphenylphosphine Oxide to Unsub-
stituted and Substituted Electron-Deficient Alkenes
Alexey V. Salin, Anton V. Il'in, Rustem I. Faskhutdinov, Vladimir I. Galkin,
Daut R. Islamov, Olga N. Kataeva
PII:
S0040-4039(18)30354-X
https://doi.org/10.1016/j.tetlet.2018.03.040
TETL 49809
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 January 2018
5 March 2018
15 March 2018
Please cite this article as: Salin, A.V., Il'in, A.V., Faskhutdinov, R.I., Galkin, V.I., Islamov, D.R., Kataeva, O.N.,
Tributylphosphine Catalyzed Addition of Diphenylphosphine Oxide to Unsubstituted and Substituted Electron-
Deficient Alkenes, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.03.040
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Graphical abstract
R1
R2
O
P
R2
Ph
Ph
O
H
PBu3 (5-100 mol%)
MeCN, r.t., 0.5-48 h
Ph
Ph
P
+
EWG
EWG
R1
68-95%
R1 = H, Me, Ph
R2 = H, Me, CH2CO2Me
EWG = CO2Me, CN, CONH2

Tributylphosphine Catalyzed Addition of Diphenylphosphine Oxide to
Unsubstituted and Substituted Electron-Deficient Alkenes
Alexey V. Salin,a,* Anton V. Il'in,a
Rustem I. Faskhutdinov,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
The PBu3-catalyzed conjugate addition of diphenylphosphine oxide to
unsubstituted and substituted electron-deficient alkenes is reported. β-Substituted
α,β-unsaturated esters, trans-methyl crotonate and trans-methyl cinnamate, known
for their reluctance to participate in phosphine-catalyzed transformations, also
react well under the developed conditions. Mild reaction conditions, simple work-
up and the ease of catalyst recovery make the proposed methodology useful for the
preparation of functionalized tertiary phosphine oxides. The utility of this method
was demonstrated by the gram-scale reactions of diphenylphosphine oxide with
electron-deficient alkenes.
Keywords:
Pudovik
reaction,
Phospha-Michael
addition,
Phosphine
organocatalysis, X-Ray analysis
Introduction
Tertiary phosphine oxides represent an important class of organophosphorus
compounds with applications in industrial chemistry and the life sciences. The
reduction of tertiary phosphine oxides provides convenient access to tertiary
phosphines, which are broadly applied in organometallic catalysis and
organocatalysis.1 Due to their hydrolytic, thermal and oxidative stability, tertiary
phosphine oxides are versatile ligands for the extraction of transuranic,2 rare-earth3
and noble metals;4 as well as the stabilization of quantum dots and other metal
nanoparticles.5 Furthermore, tertiary phosphine oxides are well-established flame
retardants for polymers.6 Consequently, the development of novel efficient
methods for the preparation of tertiary phosphine oxides is highly appealing.

One of the most atom-economical and straightforward approaches for the
synthesis of tertiary phosphine oxides is the addition of secondary phosphine
oxides to unsaturated species, known as the Pudovik reaction or phospha-Michael
addition.7 Due to the relatively low reactivity of the P(O)–H bond, the direct
addition to activated carbon-carbon multiple bonds typically occurs only at high
temperature.8 In order to proceed under milder conditions, the reaction can be
catalyzed by organic and inorganic bases such as alkaline alkoxides (e.g. MeONa,
EtONa), KOH, Ca(OH)2, NaH, n-BuLi, Et2Zn;7,9 transition metal salts;10 or radical
initiators such as AIBN.11 Despite the abundance of examples where tertiary
phosphines are used as organocatalysts in Michael-type additions for carbon-
carbon and carbon-heteroatom bond formation,12 there exist only a few reports
regarding the phosphine-catalyzed Pudovik reaction. Recently, Han and co-
workers introduced PMe3 as an efficient and easily removed catalyst for the
addition of dialkyl phosphites, alkyl H-phosphinates and secondary phosphine
oxides to electron-deficient alkenes.13 Our group, as well as Kim and co-workers,
developed an efficient PBu3-catalyzed Pudovik reaction, that can be performed
without a protective inert atmosphere and easy catalyst recovery.14 The scope of
this reaction was examined with several electron-deficient alkenes, and it was
noted that best yields and shortest reaction times were achieved when the
concentration of PBu3 was varied with respect to the nature of unsaturated reagent
(typically, 5-50 mol% of the catalyst were required).14b,c
However, secondary phosphine oxides have not been tested for the PBu3-
catalyzed P(O)–H bond addition reaction, which stimulated us to explore the scope
of this reaction using diphenylphosphine oxide as a substrate.
Results and Discussion
Initially, the model reaction of diphenylphosphine oxide with methyl
methacrylate in the presence of PBu3 was examined under the conditions
developed previously for the reaction using dialkyl phosphites as substrates.14b,c α-
Substituted methyl methacrylate was examined first, since due to the relatively low
reactivity of this alkene in phosphine-catalyzed transformations, the synthetic
outcome depends significantly on small variations of the reaction conditions.
MeCN was used as a solvent, which facilitates the P(O)–H bond addition.14,15 We
were pleased to find that the application of PBu3 (50 mol%) in MeCN at room
temperature afforded the anticipated product 1a in 96% yield after 2 h (Table 1,
entry 1). This result was superior to that obtained previously for the related
reaction of dimethyl- and diethyl phosphites, where the yields were limited to 75%
and 78%, respectively.14b When lower concentrations of the catalyst were used, the
yield of 1a decreased dramatically (Table 1, entries 2, 3). With less nucleophilic

PPh3, the reaction did not proceed (Table 1, entry 4). For this reason, reactions
with other electron-deficient alkenes were performed using the conditions
optimized for PBu3-catalyzed addition of dialkyl phosphites. Various functional
groups (ester, nitrile, amide) were tolerated under these reaction conditions (Table
1, entries 5-8). As a general trend, the catalyst loading was increased as: (i) the
electrophilicity of the alkene decreased (cf. methyl acrylate and acrylonitrile with
acrylamide, Table 1, entries 5, 7, 8); (ii) the electron-donating effect of a
substituent at the α-carbon atom increased (cf. methyl methacrylate with dimethyl
itaconate, Table 1, entries 1, 6). These data correlate well with the rate of addition
of tertiary phosphines to unsaturated species as determined from kinetic
measurements.16
Table 1. Conjugate addition of diphenylphosphine oxide to electron-deficient
alkenes under phosphine catalysis.a
O
R2
R1
R2
Ph
Ph
O
H
Ph
Ph
PR3
P
P
+
MeCN, r.t.
EWG
EWG
R1
1
Entry PR3 (mol%)
R1
R2
EWG Product Time Yield 1
(h)
2
4
(%)b
96
70
<5
0
1
2
3
4
5
PBu3 (50)
PBu3 (30)
PBu3 (10)
PPh3 (50)
PBu3 (5)
H
H
H
H
H
H
H
H
Me
Me
Me
Ph
Me
Me
Me
Me
H
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
1a
1a
1a
1a
1b
1c
1d
1e
1f
4
48
0.5
1
0.5
1
12
24
8
90
95
79
91
77
77
77
68
6
7
PBu3 (30)
PBu3 (5)
CH2CO2Me CO2Me
H
H
H
H
H
H
CN
8
9
10
11
12
PBu3 (20)
PBu3 (50)
PBu3 (50)
PBu3 (100)
PBu3 (100)
CONH2
CO2Me
CO2Me
CO2Me
CO2Me
1f
1f
1g
48
aReagents and conditions: diphenylphosphine oxide (5 mmol), alkene (5 mmol),
PR3 (5-100 mol%), MeCN (15 mL).
bIsolated yield.
The sequence of reagents addition was found to be crucial to the
chemoselective reactions of diphenylphosphine oxide with methyl acrylate and
acrylonitrile under PBu3 catalysis. Tertiary phosphine oxides 1b and 1d were the
sole products, if the alkene was added slowly (dropwise) to the mixture of

diphenylphosphine oxide with PBu3 in MeCN. However, when PBu3 was added to
the equimolar mixture of diphenylphosphine oxide with methyl acrylate (or
31
acrylonitrile) in MeCN, by-product 2 (<10%) could be detected by P NMR
spectroscopy of the crude reaction mixture. Evidently, product 2 could result from
phosphine-catalyzed dimerization of the activated alkene (Rauhut-Currier
reaction)17 followed by the addition of diphenylphosphine oxide to the newly
formed alkene 3 (Scheme 1). These side reactions can be successfully
circumvented by lowering the concentration of the alkene in the reaction mixture.
Notably, PBu3 is less prone to form 1:2 adducts 2 than PMe3.13c
Ph
O
O
P
EWG
P
EWG
PBu3
Ph
Ph
Ph
H
2
EWG
EWG
PBu3
EWG
2
3
EWG = CO2Me, CN
Scheme 1. Dimerization of electron-deficient alkenes in the presence of PBu3 and
subsequent phosphine-catalyzed addition of diphenylphosphine oxide to alkene 3
Noting that diphenylphosphine oxide possessed higher reactivity in the
PBu3-catalyzed addition to electron-deficient alkenes than the simpler dialkyl
phosphites, we directed our efforts to broaden the reaction scope using β-
substituted activated alkenes. All previous attempts to perform such additions in
the presence of tertiary phosphines using dialkyl phosphites and alkyl H-
phosphinates as substrates were unsuccessful even under harsh reaction
conditions.14b The inertness of β-substituted activated alkenes in phosphine-
catalyzed reactions is ubiquitous and generally explained by slow addition of
tertiary phosphines to these substrates due to steric hindrance of the terminal
carbon atom.17 To our delight, the PBu3 (50 mol%) catalyzed addition of
diphenylphosphine oxide to trans-methyl crotonate at room temperature gave the
corresponding product 1f in 77% yield after 12 h (Table 1, entry 9). Prolonged
reaction times had no effect on the yield (Table 1, entry 10). Using PBu3 (100
mol%), the reaction could be accelerated and gave similar results (Table 1, entry
11). trans-Methyl cinnamate bearing a more bulky phenyl group at the β-carbon
atom, also reacted with diphenylphosphine oxide in the presence of PBu3 (100
mol%) to give the desired product 1g in a synthetically useful 68% yield after 72 h
(Table 1, entry 12). The ability of PBu3 to catalyze the addition of secondary
phosphine oxides to β-substituted activated alkenes under mild conditions is quite
remarkable, since these reactions typically require more forcing conditions.

The proposed methodology performed well for gram-scale synthesis of
tertiary phosphine oxides 1. Approximately 80-90% of PBu3 could be recovered
from the reaction mixture by extraction with n-pentane followed by vacuum
31
distillation; only minimal oxidation of the catalyst was observed by P NMR for
the reactions carried out in air. In contrast to the reactions of dialkyl phosphites, no
noticeable heat evolution was detected during the PBu3-catalyzed addition of
diphenylphosphine oxide to electron-deficient alkenes. Additionally, no tedious
chromatographic procedures were required to isolate the tertiary phosphine oxides
1 from the reaction mixture; simple recrystallization or vacuum distillation could
be used to afford analytically pure samples. Compounds 1a-e,g were isolated as
white solids with sufficiently high melting points, while compound 1f was a
1
colorless oil at ambient temperature. Their structures were confirmed by H,
31
13C{1H} and P spectroscopies, and HRMS. The structure of 1c was studied by
single crystal X-ray crystallography; the crystals suitable for this analysis were
grown by slow evaporation of a Et2O solution. The ORTEP diagram is shown in
Figure 1. The three P–C bonds of 1c are nearly equal in length (1.811(1) Å); this is
typical for diaryl alkyl tertiary phosphine oxides.
Figure 1. ORTEP representation of 1c showing 50% probability thermal
ellipsoids
The results obtained in the current and previous studies allow some
generalizations to be made. The reactivity of P(O)–H compounds in the PBu3-
catalyzed addition to electron-deficient alkenes follows the trend: Ph(EtO)P(O)H <
(EtO)2P(O)H << Ph2P(O)H. This indicates that replacement of alkoxy groups by
phenyl groups at the phosphorus atom provides a nonlinear effect on the reaction
rate. While the reactivity of dialkyl phosphites correlates well with their pKa
values,14b the acidity cannot be used to predict the reactivity of alkyl H-
phosphinates and secondary phosphine oxides, therefore, additional effects should
be taken into account. For example, alkyl H-phosphinates and structurally related

secondary phosphine oxides have very similar pKa values,18 but exhibit very
different reactivities in the PBu3-catalyzed addition.
On the basis of kinetic studies for the reactions of tertiary phosphines with
electron-deficient alkenes,19 we propose the catalytic cycle shown in Scheme 2, in
which methyl acrylate is used as a representative example. Initial conjugate
addition by the phosphine to the alkene results in formation of phosphonium
enolate 4. Direct observation of this type of zwitterion by routine spectroscopic
methods is very complicated due to the known tendency of these intermediates to
decompose to the corresponding starting materials. For example, the calculated
lifetime for the zwitterion derived from PPh3 and acrylonitrile is only 138 fs.20a
When an electron-donating group is introduced to the α-position, or a bulky
substituent is in the β-position of the activated alkene, the equilibrium
concentration of the phosphonium zwitterion reduces significantly, and increased
concentrations of PBu3 (50-100 mol%, Table 1, entries 9-12) are necessary for
such reactions to proceed at reasonable rate. During its short lifetime, the generated
zwitterion 4 should deprotonate diphenylphosphine oxide to furnish reactive
diphenylphosphinite anion 5. Since protonation of heteroatoms is easier than with
carbon, proton transfer from diphenylphosphine oxide occurs first on the carbonyl
oxygen of 4 to give enol 6, which then transforms to the thermodynamically more
stable keto form 6a. Secondary kinetic isotope effects observed for related
reactions support this mechanistic pathway.20 As expected, the more acidic but less
stable trivalent tautomeric form 7 of diphenylphosphine oxide might be involved in
the deprotonation step by enolate 4. Nucleophilic attack of the phosphorus atom of
the anion 5 on methyl acrylate gives phosphorylated enolate 8. The generated
intermediate 8 deprotonates another molecule of diphenylphosphine oxide to give
product 1b and another anion 5. Then, the attack of 5 on methyl acrylate is
repeated. In the presented mechanism, PBu3 actually acts as an initiator, but not a
typical catalyst. Once diphenylphosphinite anion 5 been generated, the addition
could proceed without the participation of PBu3 until the active species 8 is formed
in the reaction mixture. According to NMR spectroscopy data, phosphonium
species 6a does not accumulate in the reaction mixture in any detectable amount,
since the concentration of the preceding phosphonium enolate 4 is expected to be
very small, and decomposition of 6a to the starting materials in the presence of
enolate 8 also cannot be excluded (Scheme 2).

OMe
OMe
..
+
PBu3
Bu3P
O
O
4
..
Ph
O
H
P
Ph
OH
P
Ph
Ph
Ph
7
OMe
..
OMe
..
P
P
+
Ph
O
OH
+
Ph
Bu3P
OH
Ph
Bu3P
O
6
4
5
7
OMe
Bu3P
O
6a
O
P
OMe
..
Ph
P
+
OMe
Ph
O
Ph
O
Ph
5
8
O
..
P
Ph
OH
Ph
7
O
P
O
P
..
Ph
Ph
Ph
Ph
P
OMe
+
OMe
Ph
O
Ph
5
1b
OH
O
O
P
O
P
OMe
OMe
Ph
Ph
Ph
Ph
OMe
+
OMe
+
Bu3P
O
Bu3P
OH
4
8
6
OH
O
1b
OMe
+
PBu3
O
Scheme 2. Proposed mechanism for the PBu3-catalyzed addition of
diphenylphosphine oxide to methyl acrylate and other electron-deficient alkenes
An alternative mechanism in which PBu3 acts as a base to deprotonate
diphenylphosphine oxide seems to be unlikely due to the low basicity of the
catalyst (pKa (PBu3)=8.4).21
Based on the proposed mechanism, the reactivity of a P(O)–H compound
can be generally assigned to: (i) the acidity of the P(O)–H bond; (ii) the
nucleophilicity of phosphorus anions of type 5; (iii) the ease of tautomerization to
trivalent form 7. For this reason, simple structure-reactivity relationships can be
found only for chemically related P(O)–H compounds from one class (for example,
a series of dialkyl phosphites),14b and attempts to find similar correlations for
P(O)–H compounds from different classes has proved to be unsatisfactory. The

high reactivity of diphenylphosphine oxide in comparison with dialkyl phosphites
and alkyl H-phosphinates can be attributed to the strongest nucleophilicity of the
corresponding diphenylphosphinite anion 5 resulting from the absence of electron-
withdrawing alkoxy groups at the phosphorus atom as well as the facile
tautomerization of diphenylphosphine oxide to reactive trivalent species 7.22
Conclusion
In summary, the PBu3-catalyzed addition of diphenylphosphine oxide to
unsubstituted, as well as α- and β-substituted electron-deficient alkenes has been
developed. This methodology provides efficient access to a range of tertiary
phosphine oxides under neutral conditions with high atom economy. The synthetic
procedure is facile23 and allows catalyst recovery from the reaction mixture.
Current studies are focused on further exploration of the substrate scope and
mechanistic implications of the proposed methodology.
Acknowledgments
We are grateful to Russian Foundation for Basic Research (grant 15-33-
20067 a) for the financial support. A.V.I. thanks Russian Ministry of Education for
fellowship in program № 4.5888.2017/8.9. D.R.I. and O.N.K. are thankful for the
Russian Government Program of the Competitive Growth of Kazan Federal
University.
Supplementary data
Detailed experimental procedures and full characterization for compounds
13
31
1a-g, copies of 1H, C{1H}, P{1H} NMR spectra for 1a-g, and table with X-ray
crystallographic data for 1c. CCDC 1815742 (1c) 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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23. To a stirred mixture of diphenylphosphine oxide (5 mmol, 5 mL of MeCN)
with PBu3 (5-100 mol%, see Table 1), a solution of the electron-deficient alkene (5
mmol, 10 mL of MeCN) was added dropwise over 15 min; the mixture was then
stoppered and stirred at room temperature for 0.5-48 h (see Table 1). After reaction
completion (31P NMR spectroscopy), the solvent was removed under reduced
pressure. In the case of the reaction of trans-methyl crotonate, the residue was
distilled (oil pump) under argon to give PBu3 (low-boiling fraction) and the
corresponding phosphine oxide 1f as a colorless oil (high-boiling fraction). In the
case of products 1a-e,g, the residue was washed with n-pentane to give a white
solid, which was recrystallized from Et2O upon cooling, and then dried. PBu3 can
be recovered from n-pentane by vacuum distillation.

1) Tributylphosphine catalyzes addition of diphenylphosphine oxide to activated alkenes
2) β-Substituted α,β-unsaturated esters reacted well under the conditions developed
3) Gram-scale synthesis of tertiary phosphine oxides was performed