Fast and Chemoselective Addition of Highly Polarized Lithium Phosphides Generated in Deep Eutectic Solvents to Aldehydes and Epoxides

Article abstract of DOI:10.1002/cssc.202001449

Highly polarized lithium phosphides (LiPR₂) were synthesized, for the first time, in deep eutectic solvents as sustainable reaction media, at room temperature and in the absence of protecting atmosphere, through direct deprotonation of both ali

Full text of DOI:10.1002/cssc.202001449

Chemistry–Sustainability–Energy–Materials
Accepted Article
Title: Fast and Chemoselective Addition of in Deep Eutectic Solvent
Generated Highly Polarized Lithium Phosphides (LiPR2) to
Aldehydes and Epoxides at Room Temperature and Under Air
Authors: Joaquin García-Álvarez, Luciana Cicco, Alba Fombona-
Pascual, Joaquin García Álvarez, Gabino A. Carriedo, Filippo
M. Perna, Vito Capriati, Alejandro Presa Soto, and Alba
Sánchez-Condado
This manuscript has been accepted after peer review and appears as an
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: ChemSusChem 10.1002/cssc.202001449
Link to VoR: https://doi.org/10.1002/cssc.202001449
01/2020

10.1002/cssc.202001449
ChemSusChem
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Fast and Chemoselective Addition of in Deep Eutectic Solvent
Generated Highly Polarized Lithium Phosphides (LiPR2) to
Aldehydes and Epoxides at Room Temperature and Under Air
Luciana Cicco,a Alba Fombona-Pascual,b,c Alba Sánchez-Condado,b Gabino A. Carriedo,b Filippo M. Perna,a Vito
Capriati,*,a Alejandro Presa Soto,*,b and Joaquín García-Álvarez*,c
[a]
[b]
[c]
Dr. L. Cicco, Prof. F. M. Perna, Prof. V. Capriati
Dipartimento di Farmacia-Scienze del Farmaco.
Università di Bari “Aldo Moro”, Consorzio C.I.N.M.P.I.S.
Via E. Orabona, 4, I-70125 Bari, Italy
E-mail: vito.capriati@uniba.it
A. Fombona-Pascual, A. Sánchez-Condado, Prof. G. A. Carriedo, Prof. A. Presa Soto
Departamento de Química Orgánica e Inorgánica, (IUQOEM) Facultad de Química
Universidad de Oviedo
Julián Clavería, 8, 33006, Oviedo, Spain
E-mail: presaalejandro@uniovi.es
A. Fombona-Pascual, Prof. J. García-Álvarez
Laboratorio de Compuestos Organometálicos y Catálisis (Unidad Asociada al CSIC). Departamento de Química Orgánica e Inorgánica, (IUQOEM), Centro
de Innovación en Química Avanzada (ORFEO-CINQA), Facultad de Química
Julián Clavería, 8, 33006, Oviedo, Spain
E-mail: garciajoaquin@uniovi.es
Supporting information for this article is given via a link at the end of the document.
Abstract: Highly polarized lithium phosphides (LiPR2) have been
synthesized, for the first time, in Deep Eutectic Solvents (DESs) as
sustainable reaction media, at room temperature and in the absence
of protecting atmosphere, through direct deprotonation of both
aliphatic and aromatic secondary phosphines (HPR2) by n-BuLi. The
subsequent addition of in-situ generated LiPR2 to aldehydes or
epoxides proceeds fast and chemoselectively, thereby allowing the
straightforward access to the corresponding α-hydroxy- or β-hydroxy
phosphine oxides, respectively, under air and at room temperature
(bench conditions), which are traditionally considered as textbook-
prohibited conditions in the field of polar organometallic chemistry of
s-block elements.
Chemistry[4] and s-block organometallic chemistry, we have
recently reported on the successful generation of C–C bonds
through the direct nucleophilic addition of organolithium (RLi) or
organomagnesium (RMgX) reagents to different unsaturated
organic electrophiles (e.g., ketones,[5] imines or nitriles,[6] and
alkenes[7]), at room temperature and in the absence of protecting
atmosphere, using the so-called Deep Eutectic Solvents (DESs)
as sustainable reaction media.[8] These eutectic mixtures can be
easily obtained by mixing in a fixed molar ratio hydrogen bond
acceptors (HBAs) [e.g., the non-toxic and biorenewable
ammonium
salt
choline
chloride
(ChCl;
2-
hydroxyethyl(trimethyl)ammonium chloride)] with different
hydrogen bond donors (HBDs) [e.g., glycerol (Gly), water,
urea].[9]
Although a wide variety of synthetic methods have been
developed to create C–N,[10] C–O[11] and C–S[12] bonds, the
number of useful protocols available to form new C–P
connections is much more limited. Since the pioneering work of
Hirao et al.,[13] transition-metal catalyzed cross-coupling
reactions[14] involving various phosphorous sources like
dialkyl/diaryl phosphites, H-phosphonates, or secondary
phosphine oxides, have been privileged over oxidative[15] or
radical[16] protocols for the construction of C–P bonds. In this
context, the metal catalyzed addition of phosphorus-
nucleophiles to unsaturated bonds emerged as a flourishing
research area.[17] Very recently, Mulvey et al. have extended this
field to main-group-mediated organic transformations by
developing an efficient and smart methodology to create C-P
bonds by metalation of HPPh2 with mixed-metal lithium
aluminates followed by reaction with a variety of alkynes.[18,19]
However, these synthetic methodologies: i) usually require a
large excess of catalyst/oxidant, ligand, or a P-H source (low
atom and step economies); ii) need to be conducted under
strictly anhydrous conditions; iii) involve expensive metal
catalysts; and iv) are limited by a poor functional group tolerance.
Introduction
Polar organometallic chemistry, and in particular the chemistry
of compounds of s-block elements (typically organolithium and
organomagnesium reagents), constitutes one of the most
commonly used instruments within the synthetic organic
chemist´s toolbox to forge new C–C bonds.[1] In this sense, it is
estimated that 95% of drugs in the pharmaceutical industry are
manufactured making use of organolithium reagents at least in
one of the steps of their synthesis.[2] In order to minimize the
undesired and frequently occurring decomposition of these
highly reactive organometallic compounds, these commodity
reagents are traditionally employed: i) under inert atmosphere; ii)
using rigorously dry aprotic organic solvents; and iii) at low
temperatures (up to -78 °C).[1] However, recently reported
synthetic advances in this field have revealed the possibility to
promote organic transformations with these reagents using
unconventional solvents (e.g., water or bio-based solvents) and
bench reaction conditions (air atmosphere and room
temperature).[3] Building new bridges between Green
1
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10.1002/cssc.202001449
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These shortcomings (among which is also included the
notorious strong coordination of the phosphorus moiety to the
metal catalyst) have precluded the wide application of these
synthetic methodologies. Therefore, the development of
sustainable and effective transition-metal-free protocols for the
selective formation of new C–P bonds is highly desirable
especially because phosphorous-containing organic scaffolds
are key players in medicine, biochemistry, material science,
catalysis, and organic synthesis.[20]
Among the variety of organophosphorus compounds,
particular attention has recently been paid to tertiary phosphine
oxides (P(=O)R3). In addition to their high air and moisture
stability in comparison to phosphines, their weak coordinating
abilities to various metal centres have been extensively
in DES generated lithium phosphides (LiPR2) to either aldehydes
or epoxides (Scheme 1), under air and at room temperature
(bench conditions), using DESs as environmentally responsible
reaction media. This new one-pot methodology: i) allows the
straightforward utilization of in-situ formed highly-reactive lithium
phosphides, thus minimizing both the required time and energy;
ii) simplifies the practical aspects of the whole synthetic
procedure (bench conditions); and, more importantly, iii)
efficiently transfers the nucleophilicity from commercially
available organolithium solutions to a variety of disubstituted
phosphines (R2PH), eventually leading to the incorporation of
the phosphine oxide functional group (R2P=O) into different
organic electrophiles by selective C–P bond formation reactions.
The resulting α-hydroxy- and β-hydroxy phosphine oxides
(Scheme 1), in which the hydroxy functional group is responsible
for the hydrophilicity of the molecule, are attractive candidates
for designing phase-transfer catalysts.[27] α-Hydroxy phosphine
oxides are also useful precursors of phosphorylated vinyl ethers,
which are interesting monomers to prepare phosphorus-
containing polymers.[28]
exploited on
a
wide variety of catalyzed organic
transformations.[21] Interestingly, the Lewis base character of the
phosphorus oxide moiety, which is derived from the highly
polarized P=O bond, assists on controlling various
organocatalyzed reactions.[22] For instance, chiral 2,2´-
bis(diphenylphosphino oxide)-1,1´-binaphthyl (BINAPO, Figure
1) is widely used as efficient organocatalyst in asymmetric
transformations,[22]
whereas
(2-
hydroxybenzyl)diphenylphosphine oxide (Figure 1) promotes
nucleophilic substitution reactions of primary and secondary
alcohols (Mitsunobu-type reactions).[23] In addition, the
phosphine oxide moiety has recently been employed as a
perspective functional group in medicinal chemistry.[24] Indeed,
its incorporation into the scaffold of targeted drugs is known to
enhance their medicinal properties. For instance, the presence
of the phosphine oxide functional group in both Brigatinib (Figure
1), an active inhibitor of anaplastic lymphoma kinase (ALK),[25]
and AP23464 (Figure 1), a potent adenosine 5´-triphosphate
(ATP)–based inhibitor of Src and Abl kinases,[26] decreased
lipophilicity, increased aqueous solubility, reduced protein
binding, and enhanced the metabolic stability.
Scheme 1. In-situ generation of lithium phosphides and their one-pot
chemoselective addition to aldehydes and epoxides, under air and at room
temperature, in Deep Eutectic Solvents (DESs) as sustainable reaction media.
Results and Discussion
We firstly examined the operationally simple direct addition of an
equimolecular amount of
a
preformed LiPPh2 (1a) to
benzaldehyde (2a), at room temperature and in the presence of
air (see Experimental Section), using the prototypical eutectic
mixture 1ChCl/2Gly (Scheme 2a). The formation of α-hydroxy
phosphine oxide 3a occurred in high yield (92%) after only 3 s
reaction time as a result of the fast and selective addition of 1a
to 2a followed by concomitant and spontaneous oxidation of the
corresponding putative α-hydroxy phosphine intermediate Ph2P-
C(OH)Ph2. With regard to that, it has been reported that hydroxy
phosphines are species “especially sensitive to air and moisture
and must be handle with extreme care”.[29] Thus, it comes as no
surprise that, following this methodology, α-hydroxy phosphine
oxides are obtained as sole reaction products.
Figure 1. Representative examples of phosphine oxide containing molecules
in synthetic and medicinal chemistry.
In light on this result, we decided to investigate whether
the oxidized lithium phosphide LiP(=O)Ph2 (4) could also
undergo addition to 2a to produce directly the expected
phosphine oxide 3a (Scheme 2b). Under the aforementioned
conditions, however, the reaction lead to unreacted 2a and the
protonated phosphine oxide HP(=O)Ph2 (5), likely generated by
a spontaneous acid/base reaction between 4 and the protic
Bearing this idea in mind and trying to take the
aforementioned aerobic organolithium-Deep Eutectic Solvents
(DESs) partnership[5–8] into a new territory in synthetic organic
chemistry, we decided to focus our attention on the
organolithium-promoted formation of C–P bonds under greener
and bench conditions (presence of air and at room temperature).
Herein, we first describe the chemoselective and fast addition of
2
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10.1002/cssc.202001449
ChemSusChem
FULL PAPER
eutectic mixture 1ChCl/2Gly (i.e., quenching of LiP(=O)PPh2 (4)
by the protic eutectic mixture is faster than the addition reaction
to 2a). In a subsequent experiment, we observed that phosphine
oxide 5 did not react with 2a in the eutectic mixture to produce
3a (Scheme 2c). All these experimental evidences point towards
a fast and selective addition of the putative lithium phosphide 1a
to 2a as the first step of the process, which is then followed by a
spontaneous oxidation of the fleeting α-hydroxy phosphine
Ph2P-C(OH)Ph2.
because of the easier handle of stock solutions of this
commercially available reagent.
Table 1. Direct conversion of secondary phosphines (HPR2) into the
corresponding anionic phosphides (M-PR2) through in-situ deprotonation
with s-block reagents (M-R’) and concomitant chemoselective and fast
addition to benzaldehyde (2a) in different sustainable solvents.[a]
Finally, by directly reacting the secondary phosphine
HPPh2 with 2a, adduct 3a could be isolated, but only in a 55%
yield (Scheme 2d). This observation is consistent with the fact
that LiPPh2 is essential to synthesize α-hydroxy phosphine oxide
3a in high yields. 31P{1H} NMR analysis also disclosed the
presence in the crude of a mixture of 3a (δP = 28 ppm) and 5 (δP
= 22 ppm). Relative integration of both peaks revealed a 3a:5
ratio of 1:1.
Yield
Entry
Solvent
R
M-R’
M-PR2 (equiv.)
(%)[b]
3a: 95[d]
3a: 72
3a: 65
3a: 91
3a: 85
3a: 90
3a: 28
3a: 52
3a: 26
3a: 65
3a: 93
3b: 72
3c: 76
1
2
1ChCl/2Gly
1ChCl/2Gly
1ChCl/2Gly
1ChCl/2Gly
1ChCl/2Gly
1ChCl/2Urea
1ChCl/2Fru[e]
1ChCl/2Sor[f]
2Pro/5Gly[g]
H2O
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
i-Pr
t-Bu
n-BuLi[c]
n-BuLi[c]
n-BuLi[c]
NaH
Li-PPh2 (1)
Li-PPh2 (2)
Li-PPh2 (3)
Na-PPh2 (1)
K-PPh2 (1)
Li-PPh2 (1)
Li-PPh2 (1)
Li-PPh2 (1)
Li-PPh2 (1)
Li-PPh2 (1)
Li-PPh2 (1)
Li-P(i-Pr)2 (1)
Li-P(t-Bu)2 (1)
3
4
5
KH
6
n-BuLi[c]
n-BuLi[c]
n-BuLi[c]
n-BuLi[c]
n-BuLi[c]
n-BuLi[c]
n-BuLi[c]
n-BuLi[c]
7
8
9
10
11
12
13
Gly
Scheme 2. Addition of different organophosphorus reagents to benzaldehyde
(2a), at room temperature and under air, in the eutectic mixture 1ChCl/2Gly as
the solvent.
1ChCl/2Gly
1ChCl/2Gly
At this point, we explored the feasibility of developing a
straightforward, one-pot protocol in which lithium phosphide
could be directly generated in-situ by deprotonating the
secondary phosphine HPPh2 with n-BuLi in the eutectic mixture
1ChCl/2Gly (see Table 1). The direct addition of n-BuLi to a
solution of the secondary phosphine in the 1ChCl/2Gly, under air
and at room temperature, produced an instantaneous change of
color (from colorless to orange) in the reaction vessel, while the
subsequent addition of 2a resulted in the instantaneous
disappearance of the orange color and the almost quantitative
[a]
General conditions: reactions performed under air, at room temperature,
using 1.62 mmol of H-PR2 and 1.62 mmol of the polar organometallic reagent
[b]
M-R’, in 1.6 mL of the desired solvent.
Yields determined by 1H NMR
spectroscopy using CH2Br2 as the internal standard. [c] Commercial solution of
[d]
n-BuLi (2.5 M in hexanes) was added at room temperature and under air.
Yield of 3a after isolation and purification: 90%.
sorbitol. [g] Pro: L-proline.
[e]
[f]
Fru: D-fructose.
Sor:
The employment of 1ChCl/2Urea as the eutectic mixture
provided 3a in 90% yield (entry 6, Table 1). On the other hand,
by changing the HBD for sugar-based alcohols [e.g., D-fructose
(Fru), sorbitol (Sor)] or the HBA for an amino acid like L-proline
(Pro), the yield of 3a dropped down to 26–52%, the remaining
being only starting material (entries 7–9, Table 1). Considering
the recently described successful and unprecedented addition of
organolithium and Grignard reagents to organic electrophiles
using water as reaction medium,[5b,6b] we have investigated other
protic solvents different from DESs. Thus, when bulk water or
pure Gly were employed, although α-hydroxy phosphine 3a was
successfully prepared, no improvements in terms of yield were
observed (entries 10,11, Table 1). Pleasingly, not only aromatic
(HPPh2) but also aliphatic secondary phosphines like HP(i-Pr)2
or HP(t-Bu)2 proved to be effective in promoting the addition of
the corresponding phosphides to 2a as they furnished the
desired α-hydroxy phosphine oxides 3b,c in 72–76% yields
(entries 12,13, Table 1).
1
formation of 3a (95% yield, H-NMR analysis; entry 1, Table 1).
These results are consistent with an in DES formation of the
lithium phosphide 1a. A higher amount of the putative LiPPh2
was detrimental on both the yield of 3a (2 equiv: 72%; 3 equiv:
65%; entries 2,3, Table 1) and the overall chemoselectivity of
the addition process as a variety of by-products also formed
(31P{1H} NMR analysis). We then explored the effect of the s-
block alkaline metal on the outcome of the reaction. By
performing the deprotonation of HPPh2 with solid hydrides (e.g.,
NaH, KH) in the absence of any volatile organic compound
(VOC) under strict stoichiometric conditions, immediately
followed by the addition of 2a, adduct 3a formed in remarkable
85–91% yields (entries 4,5, Table 1).[30] Although similar yields
were attained compared to n-BuLi, we decided to employ the
latter in the further optimization of protocol design, especially
3
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In order to support these results, we studied the lifetime of
To further explore the utility of this new protocol using
eutectic mixtures, we investigated the nucleophilic addition of
the in-situ generated LiPPh2 to epoxides, at room temperature
and under air, for the preparation of β-hydroxy phosphines as a
result of the concomitant opening of the three-membered ring
(Scheme 5). It is worth noting that such addition has always
been reported to take place under strict Schlenk-type reaction
conditions (that is, at low temperature, using anhydrous VOCs
and inert atmospheres).[29] In contrast, under the aforementioned
reaction conditions, lithium phosphide 1a was found to add
instantaneously to symmetric cyclohexene (4a) or cyclooctane
(4b) epoxides to produce the corresponding cyclic β-hydroxy
phosphine oxides 5a,b in good (62%) to excellent (89%) yields,
and after only 3 s reaction time (Schemes 5a,b).
the LiPPh2 reagent in the protic eutectic mixture 1ChCl/2Gly. By
stirring the in-situ generated LiPPh2 for 5 s before adding 2a,
adduct 3a was still isolated in a remarkable yield (86%). Even
after a half a minute interval, the yield of 3a was still good (77%).
Conversely, the formation of 3a was almost totally suppressed
(<5% yield) after 1 min reaction time (Scheme 3).
We then explored the regiochemistry of this ring-opening
reaction in DES towards non-symmetrical epoxides. The
reaction of 1a with propylene oxide (4c) was found to proceed
with complete regioselectivity, thus giving rise only to the adduct
deriving by an exclusive attack at the less-substituted carbon
atom, however, as an almost 1:1 mixture of the oxidized (5c)
and unoxidized (5c’) form [5c (31P NMR at ca. 34 ppm) and 5c'
(31P NMR at ca. -23 ppm)] with an 82% overall yield (Scheme
5c). These adducts could be separated and isolated by column
chromatography on silica-gel (ESI). On the other hand, the
addition of 1a to styrene oxide (4d), provided a regioisomeric
mixtures of adducts 5d (31P NMR at 34.2 ppm) and 6d (31P NMR
at 33.8 ppm) with a 72% overall yield, as the result of an attack
at either the less- or the more-substituted carbon atom of 4d,
respectively. 1H and 31P NMR analysis of the reaction crude
showed a regioisomeric ratio (rr) 5d:6d of 63:37 (Scheme 5d,
ESI). Overall, the above described results mirror the outcome of
ring-opening of mono-substituted epoxides with LiPPh2 already
reported in the literature in hazardous VOCs and under inert
atmospheres. Indeed, i) Pizzano et al. disclosed the
regioselective formation of enantiopure 5c' by reaction of LiPPh2
with (R)- or (S)-propylene oxide in THF, at 0 °C, and under
argon or nitrogen atmosphere,[31] whereas ii) Müller et al.[29] and,
more recently, Vidal-Ferrán et al.[32] reported that a 70:30
mixture of regioisomers formed by reacting 1a with 4d in THF at
-30 °C.
Scheme 3. Lifetime of LiPPh2 in the protic eutectic mixture 1ChCl/2Gly.
With these optimized conditions (equimolecular amounts of
LiPPh2 and aldehyde, ambient temperature, under air), we
sought to capitalize on this process by exploring the scope of the
reaction with a variety of aldehydes (Scheme 4). With 1a, very
good yields (68–94%) of the desired adducts (3d–f) were
obtained after 3 s reaction time with aryl aldehydes bearing an
alkyl substituent (Me, 3f), electron-donating (MeO, 3e) or
electron-withdrawing (Cl, 3d) groups despite potential
competitive side reactions like: i) a Li-Cl halogen-exchange
reaction (3d); or ii) a deprotonation at the benzylic position (3f).
Aldehydes decorated with
a naphtyl or a heteroaromatic
(thiophene) group as well as aliphatic aldehydes like
cyclohexane carbaldehyde also participated smoothly in the
nucleophilic addition triggered by 1a to afford α-hydroxy
substituted phosphine oxides 3g–i in 83–93% yield after 3 s
reaction time (Scheme 4). Importantly, all the above products
could be isolated by simply adding a brine aqueous solution to
the eutectic mixture, which favored their precipitation. Therefore,
they could be purified directly by filtration without using organic
toxic VOCs. Even the addition of the solid aromatic dialdehyde
isophthalaldehyde to a solution of 1a (2 equiv) in 1ChCl/2Gly
straightforwardly furnished the bis(hydroxy phosphine oxide) 3j
in 70% yield (Scheme 4).
Scheme 4. Chemoselective and fast (3 s) addition of in DES prepared LiPPh2
to various aldehydes. General reaction conditions: 1.6 mL of DES per 1.62
mmol of HPR2, 1.62 mmol n-BuLi and 1.62 mmol of the desired aldehyde,
under air and at room temperature. The yields reported are for isolated
Scheme
epoxides at room temperature, under air and in 1ChCl/2Gly. Yields of 5a
and 5b refer to isolated products. Yield of reaction of LiPPh2 1a) with
styrene oxide (4d) refers to the crude reaction mixture containing both
5. Addition of LiPPh2 to symmetric and non-symmetrical
(
products
.
4
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the regioisomers 5d and 6d. Regioisomeric ratio (rr) was calculated by
chromatography to afford the corresponding β-hydroxy phosphine oxide
5a as a white solid in 62% yield.
1H and 31P{1H} NMR analysis of the reaction crude.
Conclusion
Acknowledgements
In summary, this work demonstrates that the biorenewable
eutectic mixture 1ChCl/2Gly can be used as an environmentally
friendly reaction medium to promote a fast (within 3 s reaction
time) and chemoselective addition of in-situ generated highly
polarized lithium phosphides (LiPR2) to both aldehydes and
epoxides, at room temperature and under air, thereby granting
access to α-hydroxy- and β-hydroxy-phosphine oxides,
respectively, in very good yields (68–94%). This new
contribution reinforces the argument that it is possible to merge
main-group polar organometallic chemistry with aerobic
conditions and protic bio-based solvents, thus fulfilling several
important Principles of Green Chemistry.
L.C. and J.G.A thanks the Spanish MINECO (Project CTQ2016-
75986-P and CTQ2016-81797- REDC). A.F. A.S.-C., G.A.C and
A.P.S are indebted to Spanish MINECO (Project CTQ2014-
56345-P, CTQ2017-88357-P, and RYC-2012–09800), and
Gobierno del Principado de Asturias (FICYT, Project FC-15-
GRUPIN14-106) for financial support. A.P.S. is also grateful to
the COST action Smart Inorganic Polymers (SIPs-CM1302—
http://www.sips-cost.org/home/index.html), and Spanish MEC for
the Juan de la Cierva and Ramón y Cajal programs. J. G.-A.
thanks: i) the Fundación BBVA for the award of a “Beca
Leonardo a Investigadores y Creadores Culturales 2017”;[33] and
ii) PhosAgro/ UNESCO/IUPAC for the award of a “Green
Chemistry for Life Grant”. This work was carried out under the
framework of the project “Development of Sustainable Synthetic
Processes in Unconventional Solvents for the Preparation of
Molecules of Pharmaceutical Interest” realized with the
contribution of Fondazione Puglia, which is gratefully
acknowledged by L.C. and V.C.
Experimental Section
All reagents were obtained from commercial suppliers and used without
further purification with the exception of Deep Eutectic Solvents [choline
chloride (ChCl)/glycerol (Gly) (1:2 mol/mol); ChCl/D-fructose (Fru) (1:2
mol/mol); ChCl/D-sorbitol (Sor) (1:1 mol/mol); ChCl/urea (1:2 mol/mol);
ChCl/L-proline (Pro) (5:2 mol/mol)], which were prepared by heating
under stirring at 75 °C for 10–30 min the corresponding individual
components until a clear solution was obtained. NMR spectra were
obtained using a Bruker DPX-300 instrument at 300 MHz (1H), 121.5
MHz (31P), or 75.4 MHz (13C) with SiMe4 or 85% H3PO4 as standard.
CDCl3, [D6]-DMSO or [D6]-acetone were used as the deuterated solvents.
Analytical thin layer chromatography (TLC) was carried out on precoated
0.25 mm thick plates of Kieselgel 60 F254; visualization was
accomplished by UV light (254 nm). Microanalyses were carried out with
a Perkin Elmer 2400 microanalyzer.
Keywords: Phosphine oxide • Organolithium • Deep Eutectic
Solvent • organophosphorus • Sustainable Chemistry
[1]
a) J. Clayden, Organolithiums: Selectivity for Synthesis, Pergamon,
Elsevier Science Ltd., Oxford, 2002; b) The Chemistry of
Organomagnesium Compounds, (Eds.: Z. Rappoport and I. Marek),
Patai Series, Wiley, Chichester, 2008; c) H. J. Reich, Chem. Rev., 2013,
113, 7130; d) V. Capriati, F. M. Perna, A. Salomone, Dalton Trans.,
2014, 43, 14204; e) E. Carl, D. Stalke, Lithium Compounds in Organic
Synthesis-From Fundamentals to Applications (Eds.: R. Luisi and V.
Capriati), Wiley-VCH, Weinheim, 2014.
Representative procedure for the synthesis of α-hydroxy phosphine
oxides 3a–j.
[2]
[3]
U. Wietelmann, J. Klett, Z. Anorg. Allg. Chem., 2018, 644, 194.
For recent reviews/concept articles covering this topic see: a) J. García-
Álvarez, Eur. J. Inorg. Chem., 2015, 5147; b) J. García-Álvarez, E.
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E. Hevia, V. Capriati, Chem. Eur. J., 2018, 24, 14854.
Synthesis of [hydroxy(phenyl)methyl]diphenylphosphine oxide (3a):
A commercially available solution of n-BuLi (2.5 M in hexanes, 1.62
mmol) was added by rapidly spreading it out over a mixture of HPPh2
(1.62 mmol) in the eutectic mixture 1ChCl/2Gly, at room temperature,
under air and with vigorous stirring, followed by the addition (after 3 s of
reaction) of benzaldehyde (2a, 1.62 mmol). After additional 3 s, the
reaction was quenched with brine, and this allowed the precipitation of a
white solid from the aqueous mixture. The latter was filtered off by using
a Büchner funnel and washed with brine, giving rise to an almost
quantitative recovery of the corresponding α-hydroxy phosphine oxide 3a
in 90% yield.
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Synthesis of (2-hydroxycyclohexyl)diphenylphosphine oxide 5a: A
commercially available solution of n-BuLi (2.5 M in hexanes, 1.62 mmol)
was added by rapidly spreading it out over a mixture of HPPh2 (1.62
mmol) in the eutectic mixture 1ChCl/2Gly, at room temperature, under air
and with vigorous stirring, followed by the addition (after 3 s of reaction)
of cyclohexene oxide (4a, 1.62 mmol). After additional 3 s, the reaction
was quenched with brine and the reaction mixture was extracted with
EtOAc (3 x 5 mL). The combined organic phases were dried over
anhydrous Na2SO4, and then filtered off and evaporated under reduced
pressure. The resultant crude was purified by silica gel column
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Entry for the Table of Contents
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α-Hydroxy- and β-hydroxy phosphine oxides have been smoothly synthesized by a fast and chemoselective one-pot addition of the
in-situ generated highly polarized lithium phosphides (LiPR2) to both aldehydes and epoxides using eutectic mixtures as
biorenewable reaction media. Despite the well-known air and moisture sensitivity of organolithium compounds, the proposed
synthetic protocol allows carrying out all the reactions (preparation and reactivity of LiPR2) at room temperature, using protic solvents,
and under air atmosphere.
Institute and/or researcher Twitter usernames:
Prof. A. Presa Soto: @APresaSoto_Chem
Prof. V. Capriati: @Capriati_V
Prof. J. García-Álvarez: @JoaquinGA78
7
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